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and the number of years since cessation. Smoking cessation reduces respiratory symptoms and respiratory infections. Smokers who quit have better pulmonary function than continuing smokers.177 For persons without overt COPD, pulmonary function improves about 5% within a few months of quitting. Cigarette smoking accelerates the age-related decline in lung function; with abstinence, the rate of decline returns to that of never smokers. With sustained abstinence, the risk of developing COPD and the COPD mortality rate are lower than they are in continuing smokers,16 but do not return to the level found in nonsmokers, probably because smoking has resulted in irreversible injury to the airways and parenchyma.1 For example, in the U.S. Veterans Study, the mortality ratio for current smokers was about 12, and was reduced to 10 among ex-smokers 10 years after cessation. After more than 20 years of abstinence, the mortality rate was still twice that of nonsmokers.178 Smokers with destructive lung changes can often stabilize after cessation but do not regain lost lung function.175 Smokers have more respiratory symptoms than do nonsmokers. The frequency of respiratory symptoms in children and adolescents is greater in current smokers than nonsmokers or former smokers.179 The 2004 Surgeon General’s report concluded that smoking was a cause of wheezing in children and adolescents, that there was insufficient evidence to determine whether there was a causal relationship between active smoking and physician-diagnosed asthma in children and adolescents, and that the evidence was suggestive but not sufficient to infer a causal relationship between active smoking and a poorer prognosis for children and adolescents with asthma.1 The 2004 Surgeon General’s report concluded that there is a causal relationship between active smoking and chronic respiratory symptoms (chronic cough, phlegm, wheezing, and dyspnea) among adults.1 These symptoms have a dose-response relationship with the number of cigarettes smoked per day, and they decrease with cessation. Smoking contributes to these symptoms by decreasing tracheal mucous velocity, increasing mucous secretion, causing chronic airway inflammation, increasing epithelial permeability, and damaging parenchymal cells.16 The Surgeon General also concluded that there was inadequate evidence to determine whether there was a causal relationship between active smoking and asthma in adults, that the evidence was suggestive but not sufficient to infer a causal relationship between active smoking and increased nonspecific bronchial hyperresponsiveness, and that active smoking was a cause of poor asthma control.1

Gastrointestinal Disease Cigarette smoking is associated with symptomatic gastroesophageal reflux disease. Compared with nonsmokers, smokers have reduced lower esophageal sphincter pressure and reduced salivary function, which contribute to a longer acid clearance time.180 Up to 100% of duodenal ulcers and 70–90% of gastric ulcers are associated with H. pylori infection.181 The remaining ulcers are linked to the use of nonsteroidal anti-inflammatory drugs.182,183 Smokers of both sexes have a high prevalence of peptic ulcer disease, with a clear dose-response relationship.1,56 The ACS CPS-I found that the relative risk of mortality for peptic ulcer among men was 3.1 for current smokers and 1.5 for former smokers compared with lifetime nonsmokers.12 Duodenal ulcers heal more slowly among smokers than nonsmokers, even with therapy. Both gastric and duodenal ulcers are also more likely to recur among smokers. Smoking cessation is associated with fewer duodenal ulcers, improved short-term healing of gastric ulcers, and reduced recurrence of gastric ulcers.16 Likely mechanisms by which smoking promotes peptic ulcer disease include the potential for tobacco smoke or nicotine to increase maximal gastric acid output and duodenogastric reflux, and to decrease alkaline pancreatic secretion and prostaglandin synthesis.1 Bicarbonate secretion from the pancreas is reduced immediately after smoking, leading to a decrease in duodenal bulb pH.184 The pH level appears to be the most important determinant for the development of gastric metaplasia in the duodenum, which allows colonization by

H. pylori.185 Four studies controlling for H. pylori infection have shown an association between smoking and ulcer.1 The 2004 Surgeon General’s report concluded that smoking causes ulcers in persons who are H. pylori-positive and that the evidence was suggestive but not sufficient to infer a causal relationship between smoking and the risk of peptic ulcer complications.1

Diseases of the Mouth Epidemiological studies from several countries have shown that cigarette smokers have more periodontal disease than do nonsmokers, and the 2004 Surgeon General’s report concluded that smoking causes periodontitis.1,186,187 A recent study concluded that more than 50% of the cases of adult periodontitis in the United States are attributable to cigarette smoking.188 A strong association has been noted between both the duration of smoking and the number of cigarettes smoked per day and the level of periodontal disease.1,188,189 Data from two cohort studies suggest that cigar and pipe smokers also have significantly greater periodontal disease and bone loss than nonsmokers.190,191 Moderate-to-severe periodontal disease occurred in 8% of nonsmokers, 13% of pipe smokers, and 16% of cigar and cigarette smokers.192 Risk decreases with sustained cessation.1 The likely mechanism for smoking-related periodontal disease is reduction in immune response, possibly making the smoker more susceptible to bacterial infection. Smoking also impairs the regeneration and repair of periodontal tissue. The 2004 Surgeon General’s report also concluded that the evidence was not adequate to determine causality between smoking and coronal dental caries, and that the evidence was suggestive but not sufficient to infer a causal relationship between smoking and root-surface caries.1 Chewing tobacco has also been implicated in the development of root-surface caries, and to a lesser extent, coronal caries.193 Leukoplakia or gum recession occurs in 44–79% of smokeless tobacco users133,194 and can occur even among young people.179,195 Gum recession commonly occurs in the area of the mouth adjacent to where the smokeless tobacco is held. Among adult users of smokeless tobacco or snuff, the risk of oral disease has been well documented, and changes in the hard and soft tissues of the mouth, discoloration of teeth, decreased ability to taste and smell, and oral pain have been reported.196–198 One study of smokeless tobacco users in a high school population reported that 49% of these teenaged users (averaging 1.7 years of smokeless tobacco use) had soft tissue lesions, periodontal inflammation, or both, or erosion of dental hard tissues.199

Other Diseases The 2004 Surgeon General’s report reported several other causal relationships between smoking and disease. The report concluded that smoking causes diminished health status that could manifest as increased absenteeism from work and increased use of medical care, adverse surgical outcomes related to wound healing and respiratory complications, low bone density in postmenopausal women (the evidence was suggestive but not sufficient to infer causality in men), and hip fracture.56 It was noted that smoking is one of the major causes of fracture in older persons that can be prevented. The report also concluded that smoking causes nuclear cataracts.1 The 2004 Surgeon General’s report concluded that the following relationships between smoking and disease were suggestive but not sufficient to infer causality: erectile dysfunction, exudative (neovascular) age-related macular degeneration, atrophic age-related macular degeneration, and the opthalmopathy associated with Graves’ disease.1 A recent cohort study reported that smoking is a risk factor for cognitive decline from ages 11 to 64, after adjusting for childhood IQ, level of education, occupational status, and other factors.200 Current smoking is also associated with mental illness. In 2003, among those aged 18 or older who had serious mental illness in the past year, 44% were past month cigarette smokers.201


54

In Utero Effects of Maternal Smoking The effects of maternal smoking on the fetus have been extensively studied. It is well documented that infants born to women who smoke during pregnancy weigh an average of 200–250 g less than those born to nonsmokers.1,16,56 The incidence of low birth weight (less than 2500 g) in infants born to mothers who smoke is twice that of infants born to nonsmokers.16,56 The relationship between maternal smoking and low birth weight is dose dependent and independent of other factors known to influence birth weight, including race, parity, maternal size, socioeconomic status, sex of child, and gestational age.56 Women who stop smoking before becoming pregnant have infants of the same birth weight as never smokers. In addition, pregnant smokers who quit in the first 3–4 months of pregnancy and remain abstinent through the rest of the pregnancy have normal birth weight infants. Pregnant women who stop smoking before the 30th week of gestation have infants with higher birth weight than do continuing smokers.16 Smoking causes both reduced fetal growth and early delivery (often from pregnancy complications).56 However, smoking affects birth weight primarily by retarding fetal growth. The risk of a small-for-gestationage infant is 3.5–4 times higher among women who smoke during pregnancy than among nonsmoking women. Fetal growth restriction could be reduced by an estimated 30% if all women abstained from smoking during pregnancy.1 In 1985, the Centers for Disease Control defined the fetal tobacco syndrome as follows: (a) the mother smoked five cigarettes or more a day throughout the pregnancy; (b) the mother had no evidence of hypertension during pregnancy, specifically no preeclampsia and had documentation of normal blood pressure at least once after the first trimester; (c) the newborn infant had symmetrical growth retardation at term (37 weeks) defined as birth weight less than 2500 g and a ponderal index (weight in grams divided by length) > 2.26; and (d) there was no obvious cause of intrauterine growth retardation, such as congenital malformation or infection.12 Several mechanisms are thought to cause the reduction in fetal growth, including impaired maternal weight gain, increased cyanide exposure (leading to impaired vitamin B12 metabolism), and increased cadmium exposure. The primary mechanism, however, is thought be intrauterine hypoxia, which is caused by increased carboxyhemoglobin production from carbon monoxide (CO) exposure, vasoconstriction of the umbilical arteries, reduced blood flow to the uterus, placenta, and fetus, and direct effectors of nicotine and other toxins in tobacco on the placenta and fetus.1,16 Although fetal growth is diminished among smokers, placenta-to-birth-weight ratios are larger than those of nonsmokers,202 probably because of the larger placental surface necessary to provide adequate fetal oxygenation in smokers. A few studies have shown an association between smokeless tobacco and low birth weight.203,204 The Surgeon General has concluded that maternal smoking causes preterm delivery (RR = 1.5) and shortened gestation. An estimated 7–10% of preterm deliveries could be prevented by eliminating smoking during pregnancy.1 Maternal smoking is also associated with higher fetal, neonatal, and infant mortality, independent of sociodemographic factors for such mortality.16 One large study showed adjusted infant mortality rates of 15.1 per 1000 for white nonsmokers and 23.3 per 1000 for white women who smoked more than one pack per day. Comparable infant mortality rates for black women were 26.0 and 39.9 per 1000, respectively.205 A large retrospective cohort study found that infant mortality was 40% higher if the mother smoked during pregnancy, with a dose-response relationship, and estimated that 5% of infant deaths in the United States were attributable to maternal cigarette smoking. Among American Indians and Alaska Natives, this attributable fraction was 13%. The authors estimated that nearly 1000 infant deaths could be averted if no maternal smoking occurred. 206 Smoking during pregnancy causes placenta previa, abruptio placentae, and premature rupture of membranes.1,16 Up to 10% of placental abruption could be avoided if smoking during pregnancy were eliminated.207 The 2004 Surgeon General’s report concluded that the evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking and ectopic pregnancy and spontaneous abortion. The report also concluded that smoking reduces the risk for

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preeclampsia, but that this decreased risk did not outweigh the many adverse outcomes of maternal smoking.1 The 200156 and 20041 Surgeon General’s reports determined that maternal smoking during and after pregnancy causes sudden infant death syndrome (SIDS). Studies have consistently shown a two- to fourfold increased risk of SIDS among infants whose mothers smoked during pregnancy compared with infants of nonsmoking mothers, even after controlling for other risk factors. Most hypotheses about possible mechanisms center around the effects of maternal smoking on fetal oxygenation and neural development.1,56 One animal study reported that fetal exposure to nicotine led to reduced tolerance of hypoxic episodes and increased mortality.208 Although some studies suggested that smoking during pregnancy might affect physical growth, mental development, and behavior of children, studies are limited by small numbers and the infrequency of events of interest. The 2004 Surgeon General’s report concluded that there is inadequate evidence to determine causality between maternal smoking and congenital malformation, physical growth, and neurocognitive development of children. The report also concluded that the evidence is suggestive but not sufficient to infer a causal relationship between maternal smoking and oral clefts.1 Many studies have shown that smoking results in reduced fertility and fecundity for couples in which one or both partners smoke.1 Animal studies suggest that polycyclic aromatic hydrocarbons have a destructive effect on oocytes and may affect the release of gonadotropins, corpora lutea formation, gamete interaction, and implantation.1 Smoking also increases anovulation and shortens cycles, which may also contribute to reduced fertility and fecundity.209 The 2004 Surgeon General’s report concluded that smoking causes reduced fertility in women, but that evidence was inadequate to determine whether there was a causal relationship between smoking and sperm quality.1

Health Effects on Young People Although many of the adverse health effects from tobacco occur later in life, smoking also has health implications for young people. High school seniors who are regular cigarette smokers are more likely to report shortness of breath when not exercising, cough, productive cough, or wheezing and gasping, even after adjustment for sex, other drug use, and parental education level.210 Cigarette smoking during adolescence also appears to reduce the rate of lung growth and the level of lung function achieved. Young smokers are more likely to be less physically fit than nonsmokers. Smoking by children is also associated with an increased risk for early atheromatous lesions and increased cardiovascular risk factors. Smokeless tobacco use by children is associated with halitosis, periodontal degeneration, and soft tissue lesions.179 Cigarette smoking is also associated with other high risk behaviors among young people, including other drug use, fighting, and high-risk sexual behavior.179 Most young people who smoke regularly are already addicted to nicotine. For example, at least one symptom of nicotine withdrawal was reported by 92% of daily cigarette smokers and 93% of daily smokeless tobacco users aged 12–22 years who had previously tried to quit.211 Among adolescents aged 12–17 years, nearly two-thirds reported at least one indicator of dependence.56 In another study using different measures of nicotine dependence, 91% of daily cigarette users (smoked daily for 2 consecutive weeks or more in the past year), 48% of daily alcohol users, 60% of daily marijuana users, and 79% of daily cocaine users reported one or more indicators of dependence.212 Although it was generally thought that addiction did not occur until after a person started smoking regularly, recent evidence suggests that nicotine addiction may begin to emerge earlier.213

HEALTH RISKS OF SECONDHAND SMOKE Constituents of Secondhand Smoke Secondhand smoke (SHS) is a serious health hazard. In 2006, the Surgeon General concluded that SHS causes premature death and disease


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in children and adults who do not smoke and that there is no riskfree level of exposure to SHS.213a The Society of Actuaries has estimated that SHS costs American society $10 billion annually in health care costs and lost productivity.213b In January of 2006, the California Air Resources Board classified ETS as a Toxic Air Contaminant.213c SHS is a diluted mixture of “mainstream” smoke exhaled by smokers and “sidestream” smoke from the burning end of a cigarette or other tobacco product. It is chemically similar to the smoke inhaled by smokers and contains a complex mix of more than 4000 chemicals, including more than 50 cancer-causing chemicals and other toxic substances such as benzene, cadmium, arsenic, nicotine, carbon monoxide, and nitrogen (Table 54-3).114,213b,214,215 Sidestream smoke is the major component of SHS, providing nearly all of the vaporphase constituents and more than half the particulate matter. Sidestream and mainstream smoke are different in the temperature of combustion of the tobacco, pH, and degree of dilution in air. Five known human carcinogens, nine probable human carcinogens, three animal carcinogens, and several toxic compounds such as ammonia and carbon monoxide are emitted at higher levels in sidestream smoke than in mainstream smoke.114,214,215 Because of their greater mass, cigars generate higher levels of indoor air pollutants than cigarettes. Smoke from one cigar burned in a home can take five hours to dissipate.41 Particulate polycyclic aromatic hydrocarbon (PPAH) levels in restaurants and bars prior to a smoking ban were higher than those at a busy intersection in rush hour or a heavily trafficked city neighborhood.216 Considerable work has been done to develop sensitive and specific markers of exposure to SHS. Vapor-phase nicotine and respirable suspended particulate matter have been identified as markers for the presence and concentration of SHS in the environment, and cotinine (a metabolite of nicotine), and to a lesser degree nicotine, are widely used biomarkers of SHS exposure and uptake in people.114,213a,214,215 Levels of SHS constituents encountered indoors are large enough to be absorbed and result in measurable doses in exposed nonsmokers. However, individual biomarkers of exposure represent only one component of a complex mixture, and measurements of one marker may not wholly reflect exposure to other components of concern.213a Selfreported exposure to SHS underestimates exposure and therefore the risks of such exposure.217 For example, a study of a large nationally representative sample of persons aged 4 years and older indicated that 88% of nontobacco users had detectable levels of serum cotinine, although only 37% of adults and 43% of children were aware they were exposed to SHS.218 The Surgeon General concluded that cotinine is the biomarker of choice for assessing SHS exposure.213a

who have not previously been symptomatic.214 The same conclusions were reached after updated reviews in 1997 and 2004 by the California Environmental Protection Agency (CA EPA).215, 224 The 2006 Surgeon General’s Report also supported these conclusions, determining that SHS causes lower respiratory illnesses in infants and children; middle ear disease (acute and recurrent otitis media and chronic middle ear effusion) in children; cough, phlegm, wheeze, and breathlessness among school-age children; ever having asthma among school-age children; the onset of wheeze illness in early childhood; and lower levels of lung function during childhood. The report concluded that the evidence was suggestive, but not sufficient to infer a causal relationship between SHS exposure and the onset of childhood asthma; and between maternal exposure to SHS during pregnancy and both preterm delivery and a small reduction in birth weight among term infants. Other diseases where the evidence was deemed to be suggestive included prenatal and postnatal exposure to SHS and cancer, leukemia, lymphomas, and brain tumors in children.213a The Surgeon General’s report concluded that the evidence was insufficient to infer a causal relationship between SHS and impaired cognitive development213a; this issues continues to be an active area of research.225 On average, children exposed to SHS have 1.87 more days of restricted activity, 1.06 more days in bed, and 1.45 more days absent from school each year than do nonexposed children. Nationwide, this means 18 million days of restricted activity, 10 million days of bed confinement, and 7 million days of school absence each year attributable to daily SHS exposure.226 A study of 4th grade students reported that exposure to SHS led to 27% more absenteeism due to respiratory illness, and children living in a household with two or more smokers had a 77% increased risk of such absenteeism. Children with asthma were particularly at risk, but those without asthma also had an increased risk of absenteeism if exposed to two or more smokers.227

Secondhand Smoke and Sudden Infant Death Syndrome The California EPA (1997, 2004) and the Surgeon General (2006) have all concluded that there is a causal association between SHS and SIDS, independent of the effect of maternal smoking during pregnancy.213a,215,224 This relationship has been found for SHS exposure from maternal smoking, paternal smoking, and smoking by others in the household. A dose-response relationship was noted with increasing numbers of cigarettes, increasing number of smokers, and increasing duration of exposure to SHS.215,228,229,230

Secondhand Smoke and Adults Secondhand Smoke and Children’s Health Homes are the predominant location for childhood exposure to SHS.213a Exposures are decreasing over time. In 1992/1993, 43% of U.S. households had a smokefree home policy; in 2003, 72% of households had such a policy.219 Similarly, in 2003, 4 million (16%) adolescents aged 12-17 reported being exposed to SHS in the home, a decrease from 26% in 1999. However, among households with a smoker, 40% of adolescents were exposed to SHS daily.220 Urinary cotinine concentrations in infants and young children correlate with the number of smokers in the home 214, 215 and the number of cigarettes smoked by the mother during the prior 24 hours.221 More than 100 epidemiological studies have been published on the health effects of SHS exposure among children. In 1986, the National Academy of Sciences National Research Council (NRC)222 and the Surgeon General223 and concluded that SHS is a major contributor to impaired respiratory health among children, especially young children. In 1993, the U.S. Environmental Protection Agency (EPA) concluded that SHS is causally associated with lower respiratory infections (e.g., bronchitis and pneumonia), increased prevalence of fluid in the middle ear, symptoms of upper respiratory tract irritation, a small but significant reduction in lung function, additional episodes and increased severity of asthma, and new cases of asthma among children

Among adults, exposure to SHS primarily occurs in the workplace and in the home.213a Among healthy adults, the most common complaints after exposure to SHS are irritant effects in the eye conjunctiva and mucous membranes of the nose, throat, and lower respiratory tract.223 The 1997 and 2004 CA EPA reports concluded that SHS causes eye and nasal irritation in adults.215,224 In 2006, the Surgeon General concluded that SHS causes odor annoyance and nasal irritation, but that the evidence was suggestive, but insufficient to infer causality for persons with nasal allergies or a history of respiratory illness to be more susceptible to developing nasal irritation from SHS exposure.213b

Secondhand Smoke and Cancer Lung Cancer In 1986, the U.S. Public Health Service; the NRC; and the Interagency Task Force on Environmental Cancer, Heart, and Lung Disease, each independently concluded that substantial number of lung cancer deaths among nonsmokers could be attributed to involuntary smoking;222,223,231 both the Surgeon General and NRC reports concluded that SHS exposure causes lung cancer in nonsmokers. The EPA reviewed the updated scientific evidence in 1993 and also concluded that exposure to SHS causes lung cancer in nonsmokers. The


54

Tobacco: Health Effects and Control

TABLE 54-3. CHEMICAL CONSTITUENTS OF TOBACCO SMOKE THAT HAVE BEEN CLASSIFIED OR IDENTIFIED AS TO THEIR CARCINOGENICITY, REPRODUCTIVE TOXICITY OR OTHER HEALTH HAZARD

CAL/EPA COMPOUND PROP65c//TACd Organic Compounds Acetaldehyde Acetamide Acrolein Acrylonitrile 4-Aminobiphenyl Aniline o-Anisidine Benz[a]anthracene Benzene Benzo[b]fluoranthene Benzo[j]fluoranthene Benzo[k]fluoranthene Benzo[a]pyrene 1,3-Butadiene Captan Carbon disulfide Carbon monoxide Chrysene DDT Dibenz[a,h]acridine Dibenz[a,j]acridine Dibenz[a,h]anthracene 7H-Dibenzo[c,g]carbazole Dibenzo[a,e]pyrene Dibenzo[a,h]pyrene Dibenzo[a,j]pyrene Dibenzo[a,l]pyrene 1,1-Dimethylhydrazine 1-Naphthylamine 2-Naphthylamine Nicotinee 2-Nitropropane N-Nitrosodi-n-butylamine N-Nitrosodiethanolamine N-Nitrosodiethylamine N-Nitroso-n-methylethylamine N’-Nitrosonornicotine N-Nitrosopiperidine N-Nitrosopyrrolidine Styrene Toluene 2-Toluidine Urethane Vinyl chloride Arsenic Cadmium Chromium V1 Leade Nickel

IARC

U.S. EPA

CLASSIFICATION a

CLASSIFICATIONb

2B 2B 3 2A 1 3 2B 2A 1 2B 2B 2B 2A

B2 C B1 B2 B2 A B2 B2 B2 B2

3

3 2B 2B 2B 2A 2B 2B 2B 2B 2B 2B 3 1 2B 2B 2B 2A 2B 2B 2B 2B 2B 2B 2B 1 1 2A 1 2B 1

B2

B2

B2 B2 B2 B2

A B1 A B2 A

yes/yes yes/yes —//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//— yes//yes yes//— yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes yes//— yes//— yes//— yes//yes yes//— yes//— yes//— yes//— yes//— yes//— —//yes —//yes yes//yes yes//yes yes//— yes//yes yes//yes yes//yes yes//yes yes//yes yes//yes

California Environmetnal Protection Agency. Health Effects of Exposure to Environmental Tobacco Smoke. Final Report, 1997. ARB(1993); IARC (1985, 1986, 1987, 1992); California Code of Regulations (1994); U.S. EPA (1994) a International Agency for Research on Cancer (IARC) Classification: 1, carcinogenic to humans, 2A, probably carcinogenic to humans; 2B, possibly carcinogenic to humans; 3, not classified as to its carcinogenicity to humans. b U.S. EPA Classification: A, human carcinogen; B1, probable human carcinogen (primarily on the basis of epidemiological data); B2, probable human carcinogen (primarily on the basis of animal data); C, possible human carcinogen. c Chemicals listed under Proposition 65 are known to the State to cause cancer or reproductive toxicity (California Health and Safety Code Section 25249.5 et seq.) d Substances identified as Toxic Air Contaminants by the Air Responses Board (ARB), pursuant to the provisions of AB 1807 and AB 2728 (includes all Hazardous Air Pollutants listed in the Federal Clean Air Act Amendments of 1990.) e Reproductive toxicant.

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EPA report classified SHS as a “Group A” (known human) carcinogen, a classification that includes asbestos and benzene,214 and estimated that 3000 lung cancer deaths occur among U.S. nonsmokers each year as a result of exposure to SHS. The CA EPA (1997, 2004) also concluded that exposure to SHS causes lung cancer.215,244 In 2002, IARC examined the evidence from 58 studies. Consistent findings of increased risk, a significant dose-response trend with increasing numbers of cigarettes smoked by the spouse, an increased risk in the highest exposure group, and a statistically significant trend for the number of years married to a smoker were noted. IARC also reported that all previously published meta-analyses showed a significant increased risk (relative risks ranging from 1.1-1.6) for exposure to spousal smoking. IARC did its own meta-analysis, which included more recent studies, and found a relative risk of 1.24.114 The 2006 Surgeon General’s report concluded that smoking causes lung cancer among lifetime nonsmokers and that there is a 20-30% increase in the risk of lung cancer from SHS exposure associated with living with a smoker. The risk is lower than that seen with active smoking due to the lower carcinogenic dose received. The report also concluded that the mechanisms by which SHS causes lung cancer are probably similar to those observed in smokers. For example, exposure to SHS causes a significant increase in urinary metabolites of the tobaccospecific lung carcinogen NNK. The report also specifically looked at workplace exposure and noted that indoor air nicotine and/or respirable suspended particulate concentrations levels were comparable between work and residential environments, and that SHS exposures in homes and workplaces were qualitatively similar in chemical composition and concentration. The report examined 25 studies that provided information on workplace SHS exposure and the risk of lung cancer among lifetime non-smokers. The pooled relative risk from a meta-analysis of the studies was 1.22. Studies showed a trend of increased risk with increased duration of exposure, and a threefold increased risk among persons with the highest level of workplace exposure (based on both years and intensity of exposure). As a result, the Surgeon General concluded that the risk of lung cancer applies to all SHS exposure, regardless of location.213a

in adults and estimated that respiratory symptoms are 30 to 60% higher in nonsmokers exposed to SHS than in non-exposed nonsmokers.214 Similarly, exposure to SHS has been estimated to increase the symptoms and severity of existing bronchitis, sinusitis, and emphysema by 44%232 and respiratory work related disability by 80% (from exposure to SHS at work).233 The 2006 Surgeon General’s report concluded that there are multiple mechanisms by which SHS causes injury to the respiratory tract. The report concluded that the evidence was suggestive, but insufficient to infer a causal relationship between SHS exposure and several respiratory diseases: acute respiratory symptoms including cough, wheeze, chest tightness, and difficult breathing among both persons with asthma and healthy persons; chronic respiratory symptoms; adult-onset asthma; worsening of asthma control; and risk for chronic obstructive pulmonary disease.213a Both the 1986 Surgeon General’s report and the 1986 NRC report reviewed the evidence available on SHS and pulmonary function in adults. The Surgeon General’s report concluded that healthy adults exposed to SHS may have small changes in pulmonary function tests, probably because of the irritants in SHS, but are not likely to have significant reduction in pulmonary function as a result of exposure as an adult.223 The NRC concluded that it was difficult to determine how a single factor such as SHS affects lung function, but reported that SHS may add to the burden of environmental insults that can cause chronic lung disease.222 The 1993 EPA report reviewed additional studies of SHS and adult lung function and respiratory symptoms and concluded that SHS exposure may result in small decreases (2.5%) in lung function among adult nonsmokers.214 The 1997 CA EPA report concluded that the small differences in lung function were a basis for concern.224 The 2004 CA EPA report, which identified additional relevant studies, concluded that newer data supported a small but potentially biologically significant effect of SHS on pulmonary function in adults.215 The 2006 Surgeon General’s report concluded that the evidence is suggestive, but not sufficient to infer a causal relationship between short-term SHS exposure and an acute decline in lung function in persons with asthma; and between chronic SHS exposure and an accelerated decline in lung function.213a

Sinus Cancer

Cardiovascular Disease

Both the 1997 and 2004 California EPA report concluded that SHS causes nasal sinus cancer.215,224 IARC noted that there have been four cohort studies and one case-control study that looked at the relationship between exposure to SHS and upper respiratory track cancers. A positive association was found in most of the studies.114 The Surgeon General concluded that the evidence was suggestive, but not sufficient to infer a causal relationship, primarily because of the modest sample sizes of the studies and the need to establish dose-response relationships and to characterize the risk by source and the timing of exposure.213a

More than 20 studies have examined the association between heart disease and exposure to SHS in nonsmokers.213a,215 Although some negative studies have received significant press attention,234 most studies have reported an increased risk of heart disease among persons exposed to SHS. Many of the studies controlled for other cardiovascular risk factors and several demonstrated a positive doseresponse relationship between exposure and disease. A large study that used data from the ACS CPS-II and controlled for other cardiovascular risk factors found about a 20% higher CHD mortality among never smokers exposed to SHS; however, a consistent dose-response trend was not found.235 A review article concluded that exposure to SHS accelerated atherosclerotic lesions.236 A recent cohort study that measured SHS exposure among nonsmokers by cotinine levels rather than self-report and followed participants for 20 years, found that the relative hazards for CHD were 1.45, 1.49, and 1.57 in the 2nd , 3rd, and 4th quartiles of cotinine levels after adjustment for other risk factors.217 A 1999 meta-analytic review of 18 studies concluded that there was a 25% higher CHD risk among never smokers exposed to SHS than in non-exposed never smokers.237 The elevated risk was seen in men, women, those exposed at home, and those exposed at work and a significant dose-response relationship was found.237 In both 1997 and 2004, the CA EPA concluded that there was a causal association between SHS and heart disease mortality and acute and chronic coronary heart disease morbidity.215,224 In 2006, the Surgeon General concluded that SHS causes coronary heart disease morbidity and mortality among both men and women and estimated that there was a 10-30% increased risk.213a Several observational studies have reported that hospital admissions for acute MI declined after a comprehensive local clean indoor air ordinance came into effect.238,238a,238b Various experimental and clinical studies suggest mechanisms for the cardiovascular effects of SHS. The 1997 and 2004 CA EPA reports

Other Cancers The 2004 California EPA report concluded that SHS causes breast cancer, but there is not scientific consensus on this finding.215 IARC noted that there have been five published cohort studies and 10 case-control studies examining this association. Two of the cohort studies were positive (but not statistically significant); three were negative. Seven of the case-control studies showed non-significant increased risk, but no studies showed a dose-response relationship with level of exposure.114 The Surgeon General concluded that the evidence was suggestive, but not sufficient to infer a causal relationship (due to inconsistent findings by age, the lack of an association in large cohort studies, and the lack of causal evidence between active smoking and breast cancer).213a

Secondhand Smoke and Other Diseases Respiratory Disease The effect of SHS on chronic respiratory symptoms or disease in adult nonsmokers is difficult to measure. The EPA concluded that SHS exposure may result in increased frequency of respiratory symptoms


54 concluded that SHS causes altered vascular properties.213c,214 In 2006, the Surgeon General concluded that SHS has a prothrombotic effect, causes endothelial cell dysfunctions, and causes atherosclerosis in animal models. It was also noted that these acute cardiovascular effects occur with short duration of exposure.213a Others have noted that SHS appears to cause decreased oxygen supply and increased oxygen demand—all effects consistent with the mechanisms found for active smoking. Many of the effects are believed to be caused by nicotine and carbon monoxide in SHS, but other toxins may also be important.236 In 2006, the Surgeon General also concluded that the evidence is suggestive, but not sufficient to infer a causal relationship between exposure to SHS and stroke and between exposure to SHS and atherosclerosis in humans.213a

 TRENDS IN TOBACCO USE

Prevalence of Cigarette Consumption among Adults and Teenagers Annual per capita consumption of cigarettes reached a peak of 4345 in 1963, a year before the first Surgeon General’s report was published, and, except for an increase from 1971 through 1973, steadily declined (Fig. 54-3). Per capita cigarette consumption was 1691 in 2006, the lowest level since 1935.239,240 Overall the numbers of cigarettes sold in the United States declined from 640 billion in 1981 to 372 billion in 2006. 239,240 From 1964 to the late 1980s, smoking prevalence in the United States decreased an average of 0.5% per year (from 42 % in 1965 to 26% in 1990; in the early 1990s, prevalence was flat,241,242 but then prevalence decreased from 25% in 1997 to 21% in 2005 (Fig. 54-4). 243 In preliminary estimates for the first 9 months of 2006, smoking prevalence was unchanged at 21%.244 In the 2005 National Health Interview Survey (NHIS), smoking prevalence was higher for men (24%) than for women (18%) (Table 54-4). Smoking prevalence was highest in the 18–44 age group (24%) and lowest among Americans aged 65 years and older (8%).243 In 2002, for the first time, there were more former smokers than current smokers.245 Smoking prevalence varies threefold by state, ranging from 12% in Utah to 29% in Kentucky in 2005.246 Among both women and men, the trend in smoking prevalence has been downward. In 1965, smoking prevalence was higher for men

Tobacco: Health Effects and Control

(52%) than for women (34%). From 1965 to 1983, the decline in smoking prevalence was greater for men (17 percentage points) than for women (4 percentage points); however, from 1983 to 2005, the decline in smoking prevalence was comparable for women and men (11 percentage points).241,243 In 2005, the percentage of ever smokers who had quit was marginally for men (51%) than for women (50%).247 The higher proportion for men has sometimes been interpreted to mean that women are less likely to quit smoking than men. However, because men are more likely than women to switch to or continue to use other tobacco products when they stop smoking cigarettes, the sex difference disappears when assessing the cessation of all tobacco use.56 In addition, from 1965 to 2005, the percentage of ever smokers who had quit increased by 31 percentage points for women but by only 23 percentage points for men.241,247 The patterns of cessation among ever smokers are consistent with the historical patterns of smoking among women and men: men began quitting in greater numbers in the 1950s, but women began to quit in the 1960s. Thus, the comparable trend in conjunction with the higher absolute value for men, reflects the fact that early quitters were predominantly male.56,248 Other data show that women are as likely as men to quit for a day and to remain abstinent.249,250 In 1978, the first year data were available from the NHIS for whites, blacks, and Hispanics, smoking prevalence was lower among Hispanics (32%) than among whites (34%) or blacks (37%).241 In 2005, smoking prevalence was 13% among Asians, 16% among Hispanics, 22% and 32% among blacks, and whites, and 32% among American Indians and Alaska Natives.243 Smoking prevalence has declined faster for African Americans that for whites so that prevalence among African American men (formerly higher than for white men) is now comparable to that among white men, and the prevalence in African American women (formerly comparable to white women) is now lower than in white women.251 In 2005, the percentage of ever smokers who have quit was 53% for whites, 45% for Hispanics, 44% for Asians, 39% for blacks, and 38% for American Indians. Unlike the sex differences, which are explained by historical patterns in smoking behavior, the lower proportion among blacks reflects differences in quitting behavior: blacks are more likely than whites to try to quit smoking and are less likely to succeed, even after adjustment for demographic differences.249,252,253 This difference remains even after adjustment for other tobacco use.16 Formal educational attainment exhibits a striking association with smoking prevalence and cessation rates. However, this relationship is

5,000 1st Surgeon general’s report

Broadcast ad ban

4,000 Number of cigarettes

End of WW II

Master settlement agreement

Fairness doctrine messages on TV and radio Nonsmokers’ rights movement 1st Smoking-Cancer begins concern

3,000

2,000

Federal cigarette tax doubles

1,000 Great depression 0 1900

1910

1920

1930

1940

967

1950

1960

1970

1980

1990

2000

Figure 54-3. Adult per capita cigarette consumption and major smoking and health events—United States, 1900–2006. (Source: USDA Tobacco & Situation Outlook report, 2004;1986-2000 Surgeon General's Reports.)


968

Behavioral Factors Affecting Health 60

50

Males

Percent

40

30

20

Females

10

19 55 19 57 19 59 19 61 19 63 19 65 19 67 19 69 19 71 19 73 19 75 19 77 19 79 19 81 19 83 19 85 19 87 19 89 19 91 19 93 19 95 19 97 19 99 20 01 20 03

0

Year Figure 54-4. Trends in cigarette smoking among adults (18+) by gender—United States, 1955–2003. Note: Estimates since 1992 include some-day smoking. (Source: 1955 Current Population Survey: 1965-2005, NHIS.)

not linear. The “less than high school graduate” category consists of two groups with distinct smoking patterns: people with 0–8 years and those with 9–11 years of education. Smoking prevalence and cessation rates in the former group are similar to those found among people with 12 years of education, whereas a person in the latter group is

most likely to be a current, ever, or heavy smoker, and the least likely to have quit smoking. After 11 years of education, the likelihood of smoking decreases with each successive year of education. These results persist after adjustment for age, sex, ethnicity, poverty status, employment status, marital status, geographic region, and year of

TABLE 54-4. PREVALENCE OF SMOKING AND PREVALENCE OF QUITTING FOR PERSONS AGED > 18 YEARS, NHIS 2005 Prevalence of Smokinga (%)

RACE/ETHNICITY White, non-Hispanic Black, non-Hispanic Hispanic American Indian/Alaska Native Asian EDUCATION (yr)c <8 9–11d 12 (diploma)e 13–15 >16 AGE GROUP (yrs) 18–24 25–44 45–64 >65 POVERTY STATUS At or above Below Unknown TOTAL

% Ever Smokers Who Have Quitb

MEN

WOMEN

TOTAL

MEN

WOMEN

TOTAL

24.0 26.7 21.1 37.5 20.6

20.0 17.3 11.1 26.8 6.1

21.9 21.5 16.2 32.0 13.3

54.0 37.7 45.2 NA 42.1

52.1 40.8 45.6 NA 47.7

53.1 39.1 45.4 37.7 43.5

21.0 35.3 30.7 26.2 10.1

13.4 27.5 22.3 19.5 8.8

17.1 31.2 26.3 22.5 9.5

60.6 45.5 49.1 51.3 70.8

48.0 41.2 49.1 53.0 68.2

56.3 43.6 49.1 52.1 69.7

28.0 26.8 25.2 8.9

20.7 21.4 18.8 8.3

24.4 24.0 21.9 8.6

19.8 35.7 55.3 85.9

26.4 38.5 55.0 77.4

22.7 37.0 55.1 82.2

23.7 34.3 21.2 23.9

17.6 26.9 16.1 18.1

20.6 29.9 18.4 20.9

51.5 35.4 55.1 51.0

53.4 32.1 49.9 50.4

52.3 33.7 52.8 50.8

CDC, 2006, MMWR; National Interview Survey, 2005. a Persons who reported smoking >100 cigarettes during their lifetime and who reported at the time of interview smoking every day or some days. b Persons who reported smoking >100 cigarettes during their lifetime and who reported at the time of interview that they did not smoke. c Persons aged >25 years d Includes those who attended school for 12 years and did not receive a diploma. e Includes those who received a GED and a high school diploma. NA - Data was not sufficient for reporting, due to small sample sizes.


54 survey.252 In 2005, smoking prevalence was highest among people with 9–11 years of education (31%) and lowest for persons with 16 or more years of education (10%) (Table 54-4).247 Similarly, the percentage of ever-smokers who have quit was lowest among the group with 9–11 years of education (44%) and highest among persons with 16 or more years of education (70%).247 Although the percentage of employees who smoke has decreased, certain subpopulations, including blue-collar and service workers, continue to smoke at higher levels. For the years 1987–1990, roofers (58%) and crane and tower operators (58%) had the highest prevalence of cigarette smoking, and physicians (5%) and clergy (6%) had the lowest prevalence of cigarette smoking.254 The unemployed; the widowed, separated, or divorced; and those below the poverty level are more likely to have ever smoked or to be current smokers and to be heavy smokers (15 or more cigarettes per day). 243,254,255 In 2006, 25% of 8th graders, 36% of 10th graders, and 50% of 12th graders had tried cigarette smoking.256 The prevalence of current smoking (defined as smoking within the past 30 days) among high school seniors decreased from 39% in 1976 to 29% in 1981, and was then relatively stable until 1992, but increased to 36% by 1997 and then decreased to 22% in 2006 (Fig. 54-5). Similarly, prevalence among 10th graders increased from 21% in 1991 to 30% in 1996, then decreased to 14% in 2006. The prevalence of smoking among 8th graders increased from 14% in 1991 to 21% in 1996, then decreased to 9% in 2006. Similar patterns were seen for daily smoking. Among high school seniors, smoking prevalence was higher for girls than for boys until the late 1980s; since 1990, current and daily smoking prevalence has been comparable for girls and boys.256 A larger decline in current smoking prevalence occurred among black high school seniors from 1977 (37%) to 1992 (9%) than among white high school students (38% to 32%).241 Smoking prevalence among black high school students increased from 9% in 1992 to 15% in 1998, but then decreased to 9% in 2004.256 The increase in smoking prevalence from 1992 to 1998 was greater for African American boys than girls, but the subsequent decline was also greater among boys than girls.257,258

The Changing Cigarette Low-Tar Cigarettes Tar is a complex mixture of compounds, including 69 identifiable carcinogens and cocarcinogens.114 Nicotine is the principal constituent responsible for a smoker’s pharmacological response (addiction).3,12 In the early 1950s, when smoking was first associated with lung cancer, a majority of Americans smoked unfiltered (plain) high-tar cigarettes, with a sales-weighted average tar and nicotine content per cigarette of 38 mg and 2.7 mg, respectively, in 1954. By 1998, the sales-weighted average content per cigarette had dropped to 12 mg tar and 0.89 mg nicotine. 1 However, these averages are based on yields from cigarettes as measured by the U.S. Federal Trade Commission (FTC) smoking machine under

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standardized laboratory conditions and do not reflect the actual smoking patterns of persons who smoke filtered cigarettes.101,119 Filtered cigarette use increased from 0.56% in 1955 to 99% in 2003.259 The machine-measured tar and nicotine reductions have come through the use of efficient filters, highly porous cigarette paper, and changing the composition of the tobacco blend. Filters are generally composed of cellulose acetate, although some also have charcoal. Filters reduce the amount of tar inhaled and selectively reduce some of the volatile components of cigarette smoke. Since 1968, filters increasingly have contained perforations (which may or may not be visible) that allow air to dilute the smoke, thus reducing the machine-measured tar and nicotine yield.119,260 Other methods used to reduce the tar and nicotine content yields on the standard smoke assays include the use of porous cigarette paper, which lowers tar, CO, and nitrogen oxides inhaled. Use of reconstituted tobacco (made from tobacco dust, fines, particles from ribs and stems, and additives such as adhesives and cellulose fiber) decreases the tobacco content. Similarly, the use of puffed, expanded, and freeze-dried tobacco decreases the amount of tobacco needed to fill a cigarette. Increasing the length of the cigarette allows more air to enter the paper and for more of the volatile components to diffuse out of the cigarette. Increasing the filter length decreases the amount of tobacco in the cigarette, lengthening filter overwraps reduces the amount of the cigarette smoked under the FTC protocol, decreasing the cigarette circumference reduces the amount of tobacco available for burning, using a more coarsely cut tobacco means the tobacco burns less efficiently, and blending the tobacco with lower nicotineyield strains or different leaf positions can reduce the amount of nicotine available.101,261 However, low tar cigarettes have an elasticity of delivery that allows smokers to get much higher yields of tar and nicotine by altering their pattern of puffing (larger puffs, inhaling more deeply, taking more rapid or more frequent puffs), by blocking the ventilation holes in the filters with their lips or fingers, or by increasing the number of cigarettes smoked per day. These alterations allow smokers to receive much higher deliveries of tar and nicotine from the cigarette, so that most smokers who switch do not substantially alter their exposure to tar and nicotine and therefore do not significantly lower their risk of disease.119 Studies show that low tar cigarettes can deliver the same tar and nicotine as regular cigarettes. Although there appear to be some differences in human nicotine exposure between high- and low-yield cigarettes, these differences are small and do not correspond to the difference in the yields as measured by the FTC smoking machine. Similarly, studies have generally found no relationship between CO levels in the human body and FTC machine yields. In addition, studies suggest that the published tar-to-nicotine ratio based on the FTC machine test does not correspond to actual ratios of tar and nicotine absorbed by smokers. Thus, published tar-to-nicotine ratios cannot be used to estimate the tar exposure of smokers. Studies using biomarkers of exposure to, and doses of, tobacco smoke

45 40 35 30 25 20 15 10 5 0 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 12 th Grade

10 th Grade

8 th Grade

Figure 54-5. Trends in cigarette smoking anytime in the past 30 days* by grade in school— United States, 1975–2006. *Smoking 1 or more cigarettes during the previous 30 days. (Source: Institute for Social Research, University of Michigan, Monitoring the Future Project.)


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Behavioral Factors Affecting Health

components have shown little relationship between biomarkers and tar/nicotine yields as measured by the FTC method.99,119 In general, the FTC method underestimates human exposure to the chemicals in cigarette smoke.101 This machine takes 2-second, 35-mL puffs every 60 seconds until the cigarette is smoked to 3 mm of the filter overwrap, whereas humans, on average, take puffs of greater than 35 mL over 1.8 seconds, every 34 seconds. The FTC method underestimates by a greater degree the amount of smoke drawn from low-yield cigarettes than from high-yield cigarettes.101 In addition, since the FTC machine smokes to within 3 mm of the overwrap, lengthening the overwrap can decrease the apparent yield, even though the remaining tobacco can be smoked.119 Changes in smoking patterns are related to smoker’s self-regulation of their blood nicotine levels and higher yields of nicotine can be obtained by alternating the frequency and depth of inhalation, increasing the number of cigarettes smoked, or mechanically compressing filter tips and blocking air channels with the lips or fingers.12,101,119,260 One study of participants who spontaneously switched to cigarette brands with a lower reported yield compared the smoker’s cotinine levels before and after the switch. Although the FTC-measured nicotine yield was reduced from 1.09 mg to 0.68 mg, the serum cotinine levels were unchanged.262 Another study found that even those smoking ultra-low-yield cigarettes could be exposed to high levels of nicotine and CO.101 Therefore, smokers should be informed that they may not be deriving any health benefit from lowtar products and strongly advised to quit smoking completely. Since their introduction to the U.S. cigarette market in the late 1960s and early 1970s, the so-called low-tar and low-nicotine cigarettes have had rapid increases in market share. The market share of cigarettes yielding 15 mg of tar or less increased from 2% in 1967 to 87% in 1999, and has remained stable at 84% through 2005.259 In addition, since their introduction in the late 1970s, the cigarette brands with 12 mg or less of tar captured 58% of the U.S. market in 2001 and has remained at that level those with less than 7 mg tar, 12%, and less than 4 mg tar, 1%.259 The significant growth of the low-tar cigarette market in the past two decades is attributable to increased public awareness that cigarette smoking, particularly exposure to tar and nicotine, is detrimental to health and to the perception that low-tar cigarettes are safer.119 The progression from unfiltered high-tar, to filtered high-tar, to filtered middle-tar, and to filtered lowtar cigarettes has also been observed in most industrialized countries, although at a slower pace and 5–10 years after the introduction of these changes in the United States.101 Early studies conducted to ascertain the health consequences associated with reduction of cigarette tar and nicotine yields looked promising, with smokers of low-tar or filtered cigarettes appearing to have lower lung cancer risk. Even some later studies have also reported lower risk for lung cancer. However, these studies generally adjusted for the number of cigarettes smoked per day. If increasing the number of cigarettes smoked is a common compensatory mechanism, such adjustment would not be appropriate. In addition, later prospective studies revealed an increase in the risks associated with smoking over the period when tar and nicotine yields were decreasing. For example, lung cancer risk was higher for participants in ACS’s CPS II compared with CPS I, even after adjusting for number of cigarettes smoked per day and duration of smoking.120 Three publications recently reviewed the evidence on cigarette yield and lung cancer risk. The Institute of Medicine (IOM) found the evidence mixed, but concluded that unfiltered cigarettes probably conferred a greater risk than filtered cigarettes.263 National Cancer Institute (NCI) Monograph #13 also reported the evidence on yield and lung cancer risk to be mixed, but noted that lung cancer rates have increased over time and found no convincing evidence that changes in cigarette design have resulted in an important decrease in the disease burden either for smokers as a group or for the whole population. The NCI monograph also noted that adenocarcinoma has replaced squamous cell as the leading cause of lung cancer death in the United States.119 Analyses suggest that the increase in incidence parallels changes in smoking behavior and cigarette design. It has been hypothesized that the smoke from high-tar, unfiltered

cigarettes was too irritating to be inhaled deeply and was deposited in the central bronchi where squamous cell carcinomas occur. Smoke from milder filtered, low-tar cigarettes could be inhaled more deeply, allowing for the development of the more peripheral adenocarcinomas.99,103,104 In addition, low-tar cigarettes have higher levels of tobacco-specific nitrosamines, which have been linked to the development of adenocarcinomas.99,102 The 2002 IARC report concluded that any reduction in lung cancer risk associated with the changing cigarette has been small.114 In addition, the Tobacco Advisory Group of the Royal College of Physicians concluded “there are therefore reasonable grounds for concern that low tar cigarettes offer smokers an apparently healthier option while providing little if any true benefit.”264 With respect to heart disease, studies are mixed. Many of these studies also adjusted for number of cigarettes smoked per day. In addition, CO is thought be a major etiologic agent in CHD, and CO levels do not necessarily correlate with tar or nicotine levels. Differences in cigarette design can influence tar and CO yields in different directions, so studies looking at CHD by tar/nicotine levels may not measure important factors.1,119 The 2004 Surgeon General’s Report concluded that products with lower yields of tar and nicotine have not been found to reduce coronary heart disease risk substantially,1 and the NCI monograph concluded that there is no clear consensus on CHD risks from the use of filtered or low-yield cigarettes.119 Little evidence is available on the relative risks of developing COPD from the smoking of low-tar, low-nicotine cigarettes, but the existing studies generally have not found reduced risk for FEV1 decline or COPD-related mortality from smoking lower yield cigarettes.115,175 The 2004 Surgeon General’s Report concluded that the evidence is suggestive but not sufficient to infer a causal relationship between lower tar cigarettes and lower risk for cough and mucus hypersecretion, that the evidence is inadequate to infer the presence or absence of a causal relationship between lower yield cigarettes and reduction in FEV1 decline rates, and that the evidence is inadequate to infer the presence or absence of a causal relationship between lower tar cigarettes and reductions in COPD mortality. The report concluded that given the strong benefits from smoking cessation on COPD, little public health benefit would be gained by further research on the relationship between cigarette type and COPD.1 The NCI monograph concluded that there was little evidence of a substantial difference in COPD mortality among users of low-tar cigarettes and that there is equivocal evidence for a reduced rate of respiratory symptoms.119 Evidence suggests that the persons most likely to use low-tar cigarettes are those most concerned about smoking and most interested in quitting. Some low tar cigarettes were marketed to smokers who were thinking about quitting with such tags as “All the fuss about smoking got me thinking I’d either quit or smoke True. I smoke True.”119 The data suggest, however, that switchers are not more likely than nonswitchers to become nonsmokers. It has been suggested that the existence of low-tar cigarettes has kept many smokers interested in protecting their health from quitting, and the net effect might have been an increased number of smoking-attributable deaths.101

Potential Reduced Exposure Products (PREPs) Tobacco companies have introduced novel, nontherapeutic nicotinedelivery devices. For example, the Favor Smokeless Cigarette, a nicotine inhaler, was introduced in 1985. The U.S. Food and Drug Administration (FDA) determined that this device delivered a drug, and the inhaler was withdrawn from the market. In 1987, the Pinkerton Tobacco Company introduced Masterpiece Tobacs, a chewing gum containing shreds of tobacco. The FDA determined that chewing gum is a food product and tobacco had not been approved as a food additive and the product was withdrawn from the market. In 1987, the R.J. Reynolds Tobacco Company introduced Premier, a device that heated tobacco rather than burning it. Adverse publicity and consumer complaints about the taste and difficulty lighting the product caused the company to withdraw it before the FDA could determine whether it was a drug delivery device.261 In 1996, the company test marketed Eclipse, which was promoted as a low-smoke cigarette and which, like Premier, heated tobacco.


54 More recently, other tobacco products and devices have been developed and marketed with implied claims for reduced disease risk. For example, Omni cigarettes advertise that they have “Reduced carcinogens. Premium taste.” Advance is marketed as having “a significant reduction in many of the toxins delivered to the smoker.” And Eclipse claims they “may present smokers with less risk of certain smoking-related diseases compared to other cigarettes.”265 The public health community is divided on whether use of PREPs is a viable strategy to reduce tobacco morbidity and mortality. PREPs have the potential to be widely adopted by smokers, much as low-tar cigarettes and filtered cigarettes now dominate the market. A recent JP Morgan survey found that 91% of smokers would be willing to switch brands if a lower risk cigarette became available.266 Recently, the major U.S. tobacco companies have either bought smokeless tobacco companies or developed their own product. These smokeless products are being promoted for “when you can’t smoke,” as a cessation aid, and as a harm reduction strategy.266a However, there are no studies showing smokeless tobacco use increases cessation, and a recent study showed that “switchers” had a higher mortality rate than smokers who quit cigarettes and did not switch to smokeless tobacco.266b In order to conclude that PREPs reduce population risk, several assumptions would need to be met: (a) measurements suggesting reduced exposure to carcinogens and toxins would need to translate into actual reduced exposure (which did not occur with low-tar cigarettes); (b) reduced exposure would need to translate into reduced individual risk; (c) reduced individual risk would need to translate into reduced population risk (e.g., no corresponding increase in initiation or reduction in cessation that negates any reduction in individual risk); and (d) no increase in other diseases or risks (e.g., the increase in adenocarcinoma with low-tar cigarettes). Although promoting the use of purportedly lower risk products seems to make sense at some level, the reality is that none of these assumptions is necessarily true (as was clearly demonstrated by the low-tar experience) and they all need to be tested on a case-by-case basis. Also, the population effects will be determined not only by the characteristics of the products, but also by the way they are marketed and by how consumers respond to that marketing. Several past “harm reduction” strategies have not reduced harm. For example, reducing the amount smoked by 50% may not reduce mortality from tobacco-related disease (probably because of compensation).267,267a Even efforts to eliminate compensation by using nicotine replacement therapies (NRT) so smokers reduce the amount smoked have not reduced their levels of carcinogenic biomarkers as expected.268,269 Similarly, people who switch tobacco products use them differently than those who have always used the other products (e.g., inhalation patterns and number of cigars smoked by former cigarette smokers).1 Finally, the experience with low-tar cigarettes suggests that they may have provided little if any reduction in individual risk and actually increased population harm.119 Cigarettes contain almost 5000 chemical compounds and 60 known carcinogens.114 It is unclear if reducing the levels of a few of these substances will reduce risk. It is also possible that methods used to reduce the level of one toxin or carcinogen could increase the level of others. For example, Eclipse has reduced levels of a few carcinogens, but increased carbon monoxide levels, which increases the risk of CHD.270 Also, there is often not a linear relationship between exposure and disease. For example, the risk of lung cancer is much more strongly related to duration of smoking than to amount smoked per day.271 Also, risk of CHD increases rapidly at very low levels of exposure and then plateaus.272 Any attempt to assess the probable impact of a PREP needs to look at multiple effects and outcomes, since tobacco use affects nearly every organ of the body. Even with modern cigarettes, which have been available for nearly 100 years, new causal risks are still being found.1 Finally, people may use PREPs concurrently with cigarettes, which could expose them to multiple risk factors that may interact in complex and unpredictable ways. Several unintended consequences could actually increase population risk. First, there might be an increase in initiation resulting from the perception that PREPs are safer. Also, some users may later switch

Tobacco: Health Effects and Control

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to cigarettes, potentially resulting in increased disease risk. For example, youth consider low-tar cigarettes to be safer, to have lower tar and nicotine levels than regular cigarettes, believe that these cigarettes take longer to cause addiction, and think that they are easier to quit than regular cigarettes.273 Second, smokers are ambivalent about quitting. The belief that they have taken a positive step to reduce their risk by switching to a PREP allows smokers to rationalize postponing quitting, as was seen with low-tar cigarettes. Thus smokers may not reduce their risk as much as they would have if PREPs had not been on the market. Third, former smokers might relapse. Finally, as was noted earlier, PREPs may introduce unforeseen new disease risks, either from increased exposure to existing toxins, exposure to new toxins, or through the simultaneous use of several products. “Harm reduction” is being pushed as a remedy for smokers who cannot or will not quit. However, this implies that all efforts have been made to help smokers quit and that these efforts have failed. However, effective, low-cost cessation treatments are not yet widely available. This premise also ignores the fact that 70% of smokers want to quit,274 that 42% make a quit attempt of one day or longer each year,243 and that only about 20% use any proven therapies in their quit attempts.275 There is no safe form of tobacco use and there are “clean” forms of nicotine available through NRT. Even long-term use of nicotine would be preferable to the use of a different tobacco product as an alternative to quitting. The Institute of Medicine concluded that an unsuccessful “harm reduction” strategy could lead to long-lasting and broadly distributed adverse consequences, suggesting that these interventions may need to be held to a higher standard of proof and that government should be particularly careful. The fact that it could take decades to be certain about the effects of tobacco PREPs was noted as a reason for particular caution.263 The IOM also recommended that any such strategy should occur only under comprehensive regulation of tobacco products and be implemented within a comprehensive tobacco control program that emphasizes abstinence, prevention, and treatment.263

Cigars and Pipes In the United States, total consumption of cigars decreased yearly from 8108 million in 1970 to 2138 million in 1993, then increased to 5024 million in 2006.240 This increase corresponded with an aggressive marketing campaign, beginning in 1992, that glamorized cigar use.41,114 A 2004 national survey found that 5% of middle school students and 13% of high school students had smoked a cigar in the past 30 day. Prevalence was 2.5 times as high for high school boys as girls.276 Cigar use increases steadily with grade in school, from 12% among 9th graders to 18% among 12th graders.277 Cigar smoking among men decreased from 16% in 1970 to 3% in 1992, then increased to 4% in 2005.241,278 Over the same time period, cigar smoking among women decreased from 0.2% in 1970 to 0.02% in 1992, then increased to 0.3% in 2005. A substantial number of former and never cigarette smokers are cigar smokers. In contrast to cigarettes, the increase in adult cigar use appears to have occurred among those with higher educational and income levels.41 Cigar smoke contains the same toxic and carcinogenic constituents as cigarette smoke,41 but the tar from cigars contains higher concentrations of carcinogenic polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamine levels are higher in cigar smoke. Carbon monoxide and ammonia are also produced in greater quantities by cigars than cigarettes.279 The 1998 NCI Monograph on cigars concluded that they cause oral, esophageal, laryngeal, and lung cancer.41 Some studies suggest that cigar smoking also increases the risk of pancreatic, bladder, and colon cancer.114,123 The NCI report also concluded that regular cigar smokers have risks of oral and esophageal cancers similar to cigarette smokers, but lower risks of lung and laryngeal cancer, COPD, and CHD.41 However, regular cigar smokers who inhale, particularly those who smoke several cigars a day are at increased risk for COPD and CHD.279,280 The magnitude of risk is proportional to the type and intensity of exposure, so reduced inhalation yields lower risk. However, even those who do not


972

Behavioral Factors Affecting Health

inhale are at a higher risk of disease than never-users of tobacco. Mixed smokers (those who use both cigars and cigarettes) and cigarette smokers who switch to cigars are much more likely to inhale and to use cigars regularly, and therefore remain at much higher risk for all major smoking-related diseases.41,43,45 Cigars can deliver nicotine concentrations comparable to or higher than those from cigarettes and smokeless tobacco. Cigar smoke also contains a substantial proportion of its nicotine as freebase nicotine, which is easily absorbed through the oral mucosa. Thus cigar smokers do not need to inhale to ingest substantial quantities of nicotine, although oral absorption produces lower quantities and lower peak blood levels than does inhalation. Because cigars are addictive, their use by young people may potentially lead to switching to other products such as cigarettes.41,279 From 1965 to 2005, the prevalence of pipe smoking among men decreased from 14% to 0.9%.241,247 Pipe smoking has never been common among women (0.2% or less). In 1991, men aged 35–64 years of age (3%) were the primary pipe smokers, with those 18–24 years of age being the least likely to smoke pipes (0.2%). By 2005, use varied from 0.3–0.4% among men aged 25–44 to 1.8% among men aged 45–64.278 Men who smoke pipes are often previous users of another form of tobacco, particularly cigarettes.124 Pipe smoking causes lip cancer1 and is also associated with other diseases, including oropharyngeal, laryngeal, esophageal, and lung cancer and COPD.43–45,61,114,126,281 Some studies have suggested an increased risk of colorectal, pancreatic, and bladder cancer with pipe smoking.114,281 The 1983 Surgeon General’s report concluded that smokers who have used only pipes are not at greater risk for CHD than nonsmokers, but some recent studies suggest an association between pipe smoking and CHD, particularly if the smoke inhalation pattern mimics that for cigarettes.43,44,281 It has been estimated that pipe smoking kills 1100 Americans each year.124

and a cross-sectional study in Sweden found that smokeless tobacco users were more likely to have hypertension.49,283 Some, but not all, studies of the effect of smokeless tobacco on lipids have shown a higher risk of hypercholesterolemia, lower high-density lipoprotein levels, and higher triglyceride levels.48 One study showed an elevated risk of diabetes in smokeless tobacco users.48 A large Swedish cohort study found that smokeless tobacco users were more likely to die of cardiovascular disease than nonusers,49,50 but two case-control studies have not found an increased risk.48 An analysis of both CPS I and CPS II showed increased risk of death from CHD and stroke among smokeless tobacco users.51 Starting in 1986, smokeless tobacco products and advertisements were required by federal law to carry warning labels about the health hazards of their use. Smokeless tobacco is addictive; its use may predispose those who try it to become cigarette smokers.284

Other Tobacco Products Other tobacco products, such as bidis or kreteks (clove cigarettes) are used by 2% of middle school students and 4% of high school students.276 When compared to filter cigarettes, bidis deliver higher amounts of nicotine (1.2 times), tar (2.2 times), and CO (2 times).285 Bidi smoke contains other toxic compounds, including tobacco-specific nitrosamines, phenol, hydrogen cyanide, and benzo[a]pyrene.286,287 Studies have suggested an increase in all-cause mortality among bidi smokers.288 Bidi smokers may have twice the risk of lung cancer as smokers of Western-style cigarettes, and three times the risk of CHD as nonsmokers.289 Some studies also suggest increased risk for oropharyngeal, stomach, esophageal, and laryngeal cancer and adverse reproductive effects.114,290–293  TOBACCO INTERVENTIONS

Smokeless Tobacco Smokeless, “spit,” or oral tobacco (chewing tobacco or snuff) contains tobacco leaves plus sweeteners, flavorings, and scents. Chewing tobacco may be in the form of strands, cakes, or shreds and is either chewed or placed in the mouth. Snuff, which is marketed in a small round can, or tin, is supplied dry or moist and is held (“dipped”) between the gingiva and the lip or cheek. Whereas the smoking of tobacco has declined, the overall prevalence of smokeless tobacco use among U.S. adults has changed little during the last 20 years. The NHIS found that the prevalence of smokeless tobacco use was 5% for men and 2% for women in 1970 and 4.5% for men and less than 1% for women in 2005.241,282 Prevalence tends to be higher in the South and in rural regions, and higher among whites than African Americans.56 Although the overall prevalence of smokeless tobacco use has remained low for the past two decades, the demographics of smokeless tobacco use have changed dramatically. This behavior was formerly found predominantly among older people, particularly older black men and women and older white men. Since the late 1980s, however, smokeless tobacco use, particularly snuff use, has been seen primarily among young white males.241 In 2004, the prevalence of smokeless tobacco use among middle school boys was 4% and among high school boys was 10%. Among high school boys, use was highest among whites (14%), and lower for blacks (3%), Hispanics (8%) and Asians (2%).276,277 Long-term smokeless tobacco use causes periodontal disease and oral leukoplakia, with manifestation occurring even among young people.135,179,195 Among users of smokeless tobacco or snuff, changes in the hard and soft tissues of the mouth, discoloration of teeth, and decreased ability to taste and smell have been reported.197 There is also strong evidence that smokeless tobacco use causes cancer in humans.133 The association for specific cancers is strongest for cancers of the oral cavity,1,133 but increased risks for cancers of the pharynx and stomach have also been reported.139 Smokeless tobacco use causes acute cardiovascular effects, such as increased heart rate and blood pressure levels48 and both a large population-based study

Clinical Treatment for Tobacco Use/Nicotine Dependence The reduced national prevalence of smoking means that many millions of smokers (more than half of ever smokers) have quit smoking.245 In addition, 70% of current smokers want to stop smoking completely,274 and 42% of current daily smokers have stopped smoking for at least 1 day in the previous 12 months because they were trying to quit completely.243 Reasons to quit reported by ex-smokers as contributing to their cessation attempts and continued abstinence include: health problems; strong family pressures, both from spouses and children; peer pressure from friends and coworkers; cost of cigarettes, especially for lower-income individuals; fear of potential adverse effects on personal health or on the health of their children; the likelihood of their children starting to smoke; and concern for cleanliness and social acceptance.12,294 In 2000, the Public Health Service (PHS) published updated clinical guidelines on tobacco dependence treatment that were based on a systematic review of the scientific literature from 1976 to 1998. Meta-analyses of randomized controlled trials that contained at least five months of follow-up served as the basis for the recommendations. The primary findings were that brief advice to quit is effective (30% increase in cessation rates), more intensive counseling is more effective (doubles the quit rate), counseling can be delivered via individual counseling, group programs or telephone counseling, and that FDA-approved medications double quit rates. Patients should also be encouraged to obtain social support for their quit attempt, since this increases cessation rates by 50%.295 Similarly, the U.S. Preventive Services Task Force (USPSTF) strongly recommends that clinicians screen all adults for tobacco use and provide tobacco cessation interventions (brief counseling and pharmacotherapy) to those who use tobacco products. The USPSTF strongly recommends that clinicians screen all pregnant women for tobacco use and provide augmented pregnancy-tailored counseling to those who smoke.296


54 For primary care providers, the recommendations emphasize the importance of (a) systematically asking about tobacco use (so that every patient at every clinic visit has his or her tobacco use documented), (b) strongly advising (in a personalized manner) all tobacco users to quit, (c) assessing the patient’s willingness to quit, (d) assisting the patient in quitting and (e) arranging follow-up (the 5 A’s). The primary care intervention is designed to be brief. Patients not yet willing to quit smoking should receive a motivational intervention to promote later quit attempts. For patients willing to make a quit attempt, the provider should help the patient set a quit date, provide key advice on dealing with problem situations, encourage the use of FDA-approved medications (nicotine patch, gum, lozenge, tablet, inhaler, nasal spray, and the nonnicotine medications bupropion and varenicline) unless contra-indicated, and refer the tobacco user to a telephone quitline or community program. All patients who attempt to quit should have scheduled follow-up in person or by telephone. These recommendations assume that office systems will be developed to assure the assessment of tobacco use and appropriate treatment.295 Evidence of the effectiveness for cessation interventions among youth is lacking.297,298 The PHS guideline gave, a “C” or expert opinion, recommendation that in clinical settings, providers should screen pediatric and adolescent patients and their parents for tobacco use and give a strong message about the importance of abstaining from tobacco use. The guideline also stated that counseling should be considered, but the content modified to be developmentally appropriate, and medications could be considered when there is evidence of nicotine dependence and a desire to quit.295 Similarly, the USPSTF also concluded that there was insufficient evidence to recommend for or against routine screening or interventions to prevent or treat tobacco use and dependence among children and adolescents.296 The Surgeon General concluded that youth smoking cessation programs have low success rates, and it is difficult to attract and keep adolescents in such programs.179 One study determined, however, that in clinical settings where physicians use existing visits to provide cessation counseling, even a very low success rate could still be highly cost effective because of the low cost of such opportunistic interventions and the large potential impact. This conclusion would not extend to youth cessation programs in other settings.299 The PHS guideline gave a “B” recommendation to offering advice and interventions to parents to limit children’s exposure to SHS.295 Administrators, insurers, and purchasers of health care delivery can also promote the treatment for tobacco use/nicotine dependence. Administrators can help ensure that institutional changes to promote cessation interventions are systematically and universally implemented. Insurers should make effective treatments a covered benefit, and purchasers should make tobacco use assessment, counseling, and treatment a contractual obligation. The PHS guidelines recommend that (a) a tobacco use identification system be implemented in every clinic; (b) education, resources, and feedback to promote intervention be provided to clinicians; (c) staff be dedicated to provide effective cessation treatment, and the delivery of this treatment assessed by performance evaluations; (d) hospital policies support the provision of cessation services; (e) effective smoking cessation treatment (both pharmacotherapy and counseling) be included as paid services in health insurance packages; and (f) clinicians be reimbursed for providing effective cessation treatments, and these interventions be among the defined duties of salaried clinicians.295 The PHS guidelines are consistent with other published recommendations.300,301 Tobacco treatment is extremely cost-effective, more so than other commonly covered preventive interventions, such as mammography, treatment for mild-to-moderate hypertension, and treatment for hypercholesterolemia.302–304 An analysis of recommended clinical preventive services that ranked the services based upon disease impact, treatment effectiveness, and cost-effectiveness concluded that treatment of tobacco use among adults ranked first, along with childhood immunizations and aspirin therapy, to prevent cardiovascular events in high risk adults. It also had the lowest delivery rate among the top ranked interventions.304a Some data suggest there are cost savings from

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the treatment of tobacco use, even in the first year, as a result of the rapid decline in risk of acute myocardial infarction and stroke.305 Another study found that the cost of a moderately priced cessation program (brief clinical interventions, free telephone counseling and free NRT) paid for itself within 4 years due to lower hospital costs among successful quitters compared with continuing smokers.306 The managed care plan found that tobacco treatment interventions not only improved quality of care, but also decreased use of medical services: after one year of cessation, ex-smokers’ medical costs dropped progressively and reached levels comparable to those of never-smokers.306 This plan also found that systematic implementation of tobacco treatment interventions accelerated the reduction in smoking prevalence among plan members compared with the general population.307 In addition, provision of preventive services in a health plan is associated with increased patient satisfaction with the plan.308 Telephone quitlines increase cessation rates compared to selfhelp materials.295,309,310 Quitlines have been used within health care systems to provide support for physician advice and brief counseling. When offered a choice of free group programs or free quitline support, more smokers chose quitline support. Group Health Cooperative found that a routine screening system with primary care providers giving cessation advice, medication, and encouragement to get more intensive support; marketing the program; providing quitline services; and covering counseling and medication (with the usual $5 copay) resulted in an annual increase in use of counseling services from 0.5% to 10% of smokers in the plan,307 and a decrease in smoking prevalence from 25% to 15% over 10 years.311 Employers can support employees who want to quit tobacco use by offering (or referral to) a variety of cessation assistance options, including telephone quitlines, self-help programs, formal cessation programs, counseling from a health care provider, and pharmacological aids. Workplace smoking-cessation assistance can be provided on- or off-site, may be run by outside or in-house personnel, and can be an isolated activity or integrated into a comprehensive employee health promotion program. Company incentives to support employee cessation efforts may include full or partial payment of any costs, including pharmacological agents, time released from work for cessation assistance, and lower employee contributions to health benefit costs for nonsmokers.312 Studies have been mixed on the effectiveness of work-site programs. Although one meta-analysis suggested a modest impact, two large trials published subsequently showed either no impact or very small and nonsignificant results.313–315

Performance Measures for the Treatment for Tobacco Use The Institute of Medicine identified cessation help for adult smokers as one of 20 national priority areas for health care quality improvement.316 Treatment of tobacco use is also increasingly a performance measure for accreditation or quality assurance. For example, a majority of plans reported at least some of the measures in the Health Plan Employer Data Information Set (HEDIS).317 A measure of a plan’s smoking cessation activities was first included in December 1996, when HEDIS 3.0 was released. Under this survey measure, managed care plans report the proportion of smokers or recent quitters (within the past year) who had been seen in the plan during the previous year and who had received advice to quit smoking.318 In 2003, the measure was expanded to include the proportions whose health care provider had discussed medications and the proportion whose health care provider had given other assistance in quitting. In 2005, 66–71% (depending on whether Medicare, Medicaid, or commercial plan). Provided advice, 32–39% recommended or discussed medication use, and 34–39% provided other assistance in quitting.319 The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) now requires hospitals to document their provision of smoking cessation treatment for patients admitted for acute MI, heart failure, and community acquired pneumonia.320 In 2005, the Center for Medicare and Medicaid Services (CMS) began a pilot project that provides financial incentives to physicians who deliver targeted interventions.


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Tobacco cessation advice and assistance were among those quality measures.321

Community Interventions to Reduce Tobacco Use Beginning in the 1970s, attention began to focus on community interventions to reduce risk factors. Examples include Finland’s North Karelia Project,322 South Africa’s Coronary Risk Factor Study,323 the Stanford Three Communities Study,324 the Stanford Five Cities Project,325 the Multiple Risk Factor Intervention Trial,326 the Minnesota Heart Health Program,327 and the Pawtucket Heart Health Program.328 Some showed positive results, but in others, unanticipated secular changes in the control group or inappropriate or inadequate interventions led to nonsignificant results. These were followed by the American Stop Smoking Intervention Study for Cancer Prevention (ASSIST) in 1991, a demonstration project in 17 states for community tobacco control activities. ASSIST, funded by the NCI, and conducted in collaboration with the ACS, funded state health departments to form community-based tobacco coalitions that were responsible for developing and implementing comprehensive state plans for tobacco use prevention and control. An evaluation of ASSIST reported that consumption was lower in ASSIST states than in the rest of the country.329 Around the same time, California and Massachusetts had their own statewide initiatives funded by tobacco taxes, providing further data for the evaluation of community-based interventions.

Evidence for Specific Community Interventions As a result of community trials and other controlled studies, enough evidence is available to allow recommendations for effective community interventions. The Guide to Community Preventive Services, an evidence-based guideline, noted that: effective interventions to decrease initiation include raising the price of tobacco products, media campaigns combined with other interventions (such as price increase or community interventions), and community mobilization around minors’ access when combined with other interventions.330 Effective interventions to reduce exposure to secondhand smoke include smoking bans or restrictions. Effective interventions to increase cessation include raising the price of tobacco products, sustained media campaigns (in conjunction with other interventions), telephone quitlines, and reducing the out-of-pocket costs of treatment (i.e., insurance coverage of treatment). Provider reminders alone or in combination with provider training also increased quitting, but provider training alone did not have sufficient evidence of its efficacy to be recommended.309

Preventing Tobacco Use Evidence that knowledge of adverse and long-term health effects did not translate into reduced smoking among youth has led to increased attention on the development of valid theoretical models of smoking initiation and prevention programs. Five stages to smoking initiation among children and adolescents are currently recognized: (a) A preparatory stage in which attitudes and beliefs about the utility of smoking develop. Smoking may be viewed as having positive benefits even though it has yet occurred. (b) The trying stage, which includes the first two or three times an adolescent tries to smoke (usually in a situation involving peers). (c) An experimentation stage with repeated but irregular smoking, in which smoking is usually a response to a particular situation. (d) Regular use; at least weekly smoking across a variety of situations. (e) Nicotine dependence, the physiological need for nicotine.179 Community-based interventions (tobacco price increases, countermarketing campaigns, minors’ access restrictions, and school programs) have been the primary modalities used to prevent initiation.

Increasing Price In 1993, an NCI consensus panel concluded that an increase in cigarette excise taxes may be the single most effective intervention for

reducing tobacco use by youth.331 There is a robust body of evidence on the effectiveness of price increases on youth initiation.179 The Guide to Community Preventive Services identified eight studies that specifically looked at the impact of price on youth and young adults. The Community Guide concluded that a 10% increase in price reduced youth prevalence by 3.7%, decreased initiation by 3.8%, and also decreased the amount smoked by adolescents who continued to smoke.309 One study concluded that youth consumption may be three times more sensitive to price increases than adult consumption.179,331 Another analysis of cigarette excise taxes concluded that an increase in the federal cigarette excise tax would encourage an additional 3.5 million Americans to forgo smoking, including more than 800,000 teenagers and almost two million young adults aged 20–35 years.331,332 Other studies have reported that for every 10% increase in price, total cigarette consumption among youth decreases 7%.309,331–335 Even the tobacco industry has privately acknowledged the effectiveness of price increases on reducing youth smoking: Philip Morris noted that “it is clear the price has a pronounced effect on the smoking prevalence of teenages, and that the goals of reducing teenage cigarette smoking and balancing the budget would both be served by increasing the Federal excise tax on cigarettes.”336 Other tobacco products also respond to price interventions: increases in the price of smokeless tobacco reduce use by adolescent boys, with most of the effect coming from reduced prevalence rather than the amount used by continuing users.333 Studies have also shown that higher cigarette prices increase smokeless tobacco use. Increased cigarette prices also led to more cigar use in New Jersey, and the authors concluded that when excise taxes on other tobacco products do not keep pace with cigarette taxes, substitution occurs.337

Countermarketing Campaigns Media campaigns, when combined with other interventions, are an effective strategy to reduce youth initiation.179 The Community Guide determined that mass media campaigns are effective in reducing youth prevalence. Sustained (at least two years) media countermarketing campaigns reduced self-reported tobacco prevalence by eight percentage points and, for those studies reporting odds ratios, by a median of 74%.309 The 2000 Surgeon General’s Report noted that multicomponent youth-directed programs with a strong media presence have shown long-term success in reducing or postponing youth tobacco use.333 Youth-focused campaigns have been developed and evaluated in several states and nationally. In Massachusetts, adolescents aged 12–13 who had been exposed to the countermarketing campaign as part of a comprehensive program were half as likely to become smokers as those who were not able to recall campaign advertisements.338 In Minnesota, when a youth-focused media campaign was ended, youth awareness of the campaign declined from 85% to 57%, and youth susceptibility to initiate smoking increased from 43% to 53% within 6 months.339 As part of the youth-focused tobacco control program in Florida that was funded by the tobacco industry settlement, the “truth” media campaign was developed. Evaluation results included a 92% brand awareness rate among teens, a 15% increase in agreement with key attitudes about smoking, a 20% decrease in smoking among middle school students and an 8% decrease in smoking among high school students.340 Florida teens exposed to the campaign were also more likely to agree with antitobacco industry attitudes. A longitudinal study reported that Florida teens with strong anti-industry attitudes were four times less likely to start smoking and 13 times less likely to become established smokers than teens with low anti-industry attitudes.341,342 In 2000, the American Legacy Foundation ran a national “truth” campaign. Evaluation results show that exposure to this campaign was associated with an increase in antitobacco attitudes and beliefs.343 Adolescents in tobaccoproducing states were as responsive to the anti-industry ads as adolescents in non-tobacco-producing regions.344 It is estimated that 20% of the decline in youth smoking prevalence in the late 1990s was a result of the “truth” media campaign.345 In contrast, exposure to the


54 Philip Morris’s “Think Don’t Smoke” campaign did not cause an increase in antitobacco attitudes and those exposed to the campaign were more likely to be open to the possibility of smoking.343 Similarly a study of the Phillip Morris parent-targeted campaign “Talk. They’ll Listen” found that each additional viewing of the ad was associated with lower perceived harm of smoking, stronger approval of smoking, stronger intentions to smoke in the future, and greater likelihood of having smoked in past 30 days.345a

School-Based Tobacco Prevention Programs School-based tobacco prevention programs have been shown effective when combined with concurrent, complementary community interventions.179 Current recommendations on quality school-based smoking prevention programs emphasize helping children understand and effectively cope with social influences associated with smoking, highlighting the immediate negative social consequences, and inoculating youth against the effects of pressure to smoke.346,347 Most prevention programs focus on students in grades 6–8, the time of greatest increase in smoking experimentation.348 However, the effects of these programs are not sustained without additional educational interventions, media campaigns, or supportive community programs. Thus, although school-based skills’ training is important for preventing smoking, more sustained and comprehensive interventions may be necessary for long-term success.179

Smoke-Free Policies Another approach to discouraging smoking among youth is the establishment of strong no-smoking policies in schools and on school grounds. Such policies not only directly discourage smoking by youth but increase the likelihood that their teachers, who are role models, will not be seen smoking.

Minors’ Access Restrictions Tobacco products are widely available to minors and commercial outlets are an important source of tobacco for them.333,349 Since 1986, numerous published studies involving purchase attempts by minors confirm that, despite state and local laws banning such sales, they can easily buy tobacco from over-the-counter outlets and vending machines.179,333,349 Active enforcement of tobacco laws increases retailer compliance.179,350 Studies looking at their impact on prevalence, however, are mixed.333,351–353 The Guide to Community Preventive Services reviewed the literature on the effectiveness of minors’ access laws and concluded that they are only effective in conjunction with other community interventions.330 An evaluation in Massachusetts after the defunding of the program showed that communities that had a dramatic reduction in tobacco control funding saw an average increase of 74% in illegal sales to minors, and communities that completely lost their programs had even larger increases.354 It is important to keep in mind that as commercial sales to minors decrease, “social” sources (other adolescents, parents, and older friends) may become more important sources of cigarettes. Thus a comprehensive approach is needed so that smokers of all ages, as well as retailers, do not provide tobacco to minors.333

Eliminating Exposure to Secondhand Smoke Clean Indoor Air Laws Despite substantial progress, 125 million Americans are still exposed to SHS.213a In 2006, the Surgeon General concluded that eliminating smoking in indoor spaces fully protects nonsmokers, but that separating smokers from nonsmokers, cleaning the air, and ventilating buildings cannot eliminate exposure to SHS.213a Homes and workplaces are the primary locations for adult exposure, so interventions include smokefree homes, workplaces, and public places. Although the purpose of smokefree policies is to reduce SHS exposure, these policies also reduce consumption, increase quitting, decrease relapse, and possibly reduce initiation.213a, 309, 330, 333

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The entertainment and hospitality industries have particularly high SHS exposure.213a One study evaluated respirable particle (RSP) air pollution and carcinogenic particulate polycyclic aromatic hydrocarbons (PPAH) in a casino, six bars, and a pool hall. SHS contributed 90–95% of the RSP and 85–95% of the PPAH in these venues. These levels were greater than the levels of these contaminants on major truck highways and polluted city streets. Another study showed that levels of SHS in restaurants are 160–200% higher, and levels in bars are 400-600% higher than in office workplaces.355 Yet, wait staff and bartenders are less likely to have smokefree workplaces.356 Both the Surgeon General’s report and the Guide to Community Preventive Services evaluated the effect of smoking bans and restrictions on exposure to SHS. Both found that smoking bans reduced exposure more than smoking restrictions;213a,309 the Surgeon General also noted that full compliance with smoking bans eliminated exposure. A recent study examined cotinine levels in a nationally representative survey: 12.5% of nonsmoking adults living in counties with extensive smokefree laws were exposed to SHS, compared with 35.1% in counties with limited coverage and 45.9% in counties with no law.356a The health impacts of state-wide smokefree laws have also been studied. Two studies showed dramatic declines in RSP and PPAH after smoking bans were implemented;216,357 other studies have shown improvements in respiratory symptoms, sensory irritation, and lung function in hospitality workers.357a Concerns are often raised about possible adverse economic consequences of smokefree laws on the hospitality industry. A review of the studies on economic effects showed that higher quality studies generally found a positive economic impact of smoking bans. Studies using subjective outcomes (e.g., owner expectations) tended to show a negative impact, while studies using objective outcomes (e.g., revenues, employment, restaurant sale price) usually showed a positive impact. Few of the negative studies were peer reviewed; all were funded by the tobacco industry.358 The Surgeon General concluded that smokefree policies do not have an adverse economic impact on the hospitality industry.213a

Increasing Cessation Increasing the Price of Tobacco Products Price increases are one of the most effective interventions to increase adult cessation, as shown by a substantial body of evidence. The Guide to Community Preventive Services identified 56 studies in the literature. After combining those that used the same data and eliminating weak ones, 17 studies formed the basis of the Guideline conclusion that a 10% price increase decreases consumption by a median of 4.1%. For every 10% increase in price, cessation increased 1.5%.309 Consistent with the larger impact of price on adolescents, one study found that these effects were doubled for persons 20–25 years of age compared with adults aged 26–74.333 Some data suggest that men are more responsive to price than women.333,359 Other data have shown that less educated persons are more responsive to price increases than more educated persons, that blacks are twice as responsive as whites, that Hispanics are even more price sensitive, and that those with family incomes at or below the median were 70% more responsive than those with higher family incomes.333 The 2000 Surgeon General’s Report concluded that the price of tobacco products has an important influence on the demand for tobacco products and that substantial increases in the excise tax on tobacco would have considerable impact on the prevalence of smoking.333 Another study estimated that increasing the federal cigarette tax by $2.00 would reduce total cigarette sales by more than 4 billion packs per year, would decrease adult smoking prevalence rates by 10%, and 4.7 million smokers would quit.360 Even the tobacco industry has privately acknowledged the effect of price on reducing adult cigarette consumption. As Philip Morris noted, “when the tax goes up, industry loses volume and profits as many smokers cut back.”361 “A high cigarette price, more than any other cigarette attribute, has the most dramatic impact on the share of the quitting population . . . price, not tar level, is the main driving


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force for quitting.”362 Smuggling reduces the impact of price increases by making cheaper cigarettes available and it also reduces government revenue from a tax. Large differences in price between states or countries increases the profitability of smuggling. There is also evidence that the cigarette companies themselves have been directly involved with smuggling activities.362a

Countermarketing Evidence for the effectiveness of counteradvertising comes from both national and international data. An econometric analysis of the U.S. Fairness Doctrine (which required one antismoking message for every three to five tobacco advertising messages) concluded that counteradvertising substantially deterred smoking.363 Another study of the Fairness Doctrine concluded that the number of people who successfully quit smoking tripled during the period that the doctrine was in effect.364 An evaluation of a paid media campaign against smoking in Australia found that there was a marked decrease in smoking prevalence attributable to the campaign.365 An evaluation of a Greek media campaign showed that the annual increase in tobacco consumption was reduced to nearly zero as a result of the campaign. When the campaign stopped, consumption again rose at the precampaign rate.366 The Guide to Community Preventive Services found 15 high-quality studies of the effect mass media campaigns on increasing cessation. In all studies, the campaign was concurrent or coordinated with other interventions such as tax increases, community education programs, self-help cessation materials, individual counseling, or other mass media efforts. Various endpoints were measured in the various studies. The campaigns increased cessation by a median of 2.2 percentage points, reduced tobacco consumption by a median 17.5%, and reduced prevalence by a median of 3.4 percentage points.309

Advertising Bans Evidence for the effectiveness of advertising bans is mixed. One study used multiple regression analysis to evaluate the effectiveness of advertising restrictions, price, and income on tobacco consumption in 22 countries from 1960 to 1986. Above threshold levels, both advertising restrictions and higher prices were effective in decreasing tobacco consumption.367 However, an analysis of the 1971 U.S. broadcast media ban did not show an effect.368 This apparent lack of effect may be due in part to these bans being frequently circumvented, such as during the promotions of televised sporting and entertainment events. For example, during a Marlboro Grand Prix telecast, the Marlboro logo was seen or mentioned nearly 6000 times and was visible for 46 minutes of the 94-minute broadcast.369 In addition, after the broadcast ban went into effect in the United States, tobacco advertising merely shifted to other media—newspapers, magazines, outdoor signs, transit, point of sale, and a variety of promotions—at much higher expenditure levels.259 Similarly, other studies have suggested that partial bans are not effective, but that complete bans can decrease consumption.370–372

Quitlines Quitlines have been shown to increase cessation rates. The Guide to Community Preventive Services found 32 high-quality studies of the effectiveness of quitlines. In all studies, telephone support was coordinated with other interventions, such as patient education, providerdelivered counseling, NRT, a cessation clinic, or a televised cessation series. Cessation rates were increased by a median of 2.6 percentage points. Six studies that examined the effect of quitlines plus patient education materials compared with patient education materials alone had a similar magnitude of effect. Five studies examined proactive telephone counseling (quitlines that make follow-up calls). These studies found a median increase in cessation of 41%.309 Quitlines are also offered by states as part of a comprehensive tobacco control program. Some quitline services offer free NRT with the counseling service.373 California was the first state to develop such a quitline. Both randomized clinical trials and real-world evaluation trials of the quitline have shown that it doubled quit rates over self-help materials

alone.374,375 It has been estimated that up to 15% of smokers would use a quitline service, but current quitlines have the capacity to only serve 1–3% of smokers.360

Reducing Out-of-Pocket Costs of Treatment Reducing out-of-pocket costs for cessation treatment increases cessation. The Guide to Community Preventive Services found five high-quality studies assessing the impact of programs that reduced or eliminated costs for nicotine replacement therapy. One study reported that use of treatment increased with reduced payment level. All these studies observed an increase in cessation, with a median increase of 7.8 percentage points. One study reported an increased odds ratio for quitting of 1.63.309

Effectiveness of Comprehensive Tobacco Prevention and Control Programs In the absence of the antismoking campaign, an estimated additional 42 million more Americans would have smoked in 1992. As a result of these campaign-induced decisions not to smoke, an estimated 1.6 million Americans postponed death between 1964 and 1992, gaining 21 years of additional life expectancy on average, and an estimated additional 4.1 million deaths will be avoided or postponed between 1993 and 2015.376 Such analyses must be interpreted cautiously, however, because they rely heavily on assumptions about what would have occurred in the absence of antismoking campaigns. Evaluation of the California tobacco control program has shown that per capita consumption of cigarettes declined significantly in California from January 1989 through December 1993 and the decline was greater than for the United States as a whole.376a From 1989 to 1993, adult smoking prevalence also declined almost twice as rapidly as the rest of the country. One study showed that the increase in youth smoking in the early 1990s was smaller in California than in the rest of the country.333 From 1993 to 1996, in conjunction with program cuts, the rate of decline slowed in California, but still was greater than for the country as a whole.377 From 1988 to 2003, tobacco consumption in California decreased 60%, and California now has the lowest per capita consumption in the United States.378 California has also seen improvements in health outcomes. Lung cancer incidence has declined three times more rapidly in California than in the rest of the country, and has declined among women whereas the rest of the country is still experiencing increasing lung cancer rates among women.379 Six of nine tobacco-related cancers have a lower incidence rate in California than in the rest of the United States (lung/bronchus, esophagus, larynx, bladder, kidney, pancreas).378 Reductions in cardiovascular disease have also been reported. A study of the California program reported that mortality from heart disease declined at a significantly greater rate in California (2.93 deaths per 100,000 population) than in the rest of the country, and estimated that the program was associated with 33,000 fewer deaths from heart disease between 1989 and 1997 than would have been expected without the program.380 Studies have estimated that the California tobacco control program saved $11 million in the first two years and $100 million over seven years by reducing the number of smoking-related low-birthweight babies,381 and another $25 million in the first two years and $390 million over seven years through declines in smoking-related heart attacks and strokes.305 California has reported that for every dollar spent on the program, statewide health care costs are reduced by more then $3.60.382 Massachusetts also experienced a persistent decline in per capita cigarette consumption since the start of its program. From 1992 to 1997, per capita consumption in Massachusetts decreased 31%, compared to an 8% decline in the rest of the country (excluding California). Prevalence declines were also greater (3 percentage points compared to 1 percentage point) than in the rest of the country. And, like California, the increase in youth smoking prevalence in the early 1990s was less in Massachusetts than in the rest of the country. The effect was particularly evident among younger adolescents.333,383


54 Massachusetts reported that its program paid for itself through declines in smoking among pregnant women.384 Arizona also noted greater declines in per capita sales than the rest of the United States after implementation of its program. The state reported that adult prevalence declined at a faster rate than in the rest of the country and that young adult prevalence declined in Arizona at a time when it was increasing nationally.333 The program noted that the decrease in smoking prevalence among low income and low education groups meant a narrowing of disparities in tobacco use.385 In Oregon, trends in per capita consumption were also compared to the rest of the country (excluding California, Massachusetts, and Arizona) preprogram (1993–1996) and postprogram (1997–1998). In 1997–1998, consumption declined 11.3% in Oregon compared to 1% in the rest of the country.333 Oregon also noted an impact from their school program: smoking prevalence decreased faster in schools funded for prevention programs than in nonfunded schools. Even after adjustment for other risk factors, students in funded districts were 20% less likely to smoke than students in nonfunded districts. Changes in prevalence were also greater in school districts with high implementation of the program, whereas smoking prevalence in districts with low implementation stayed nearly the same as in nonfunded districts.386 Florida had focused an effort on youth (“truth” media campaign, youth community activities including youth advocacy groups, school programs, minors’ access enforcement, and youth involvement in the design and implementation of the program). The state documented dramatic declines in current smoking and ever smoking, and large increases in the proportion of “committed never-smokers” among both middle and high school students.387 Evaluations across multiple programs and nationally have also demonstrated the effectiveness of comprehensive tobacco prevention and control programs. An evaluation of the ASSIST demonstration project reported that ASSIST states had a greater reduction in smoking prevalence than non-ASSIST states, and estimated that if all states had implemented ASSIST, there would be 280,000 fewer smokers.329 A national analysis concluded that state tobacco control expenditures reduced cigarette sales over and above any price increases that occurred concurrently (and adjusting for cross-border sales). The study also noted that larger, more established programs may have a larger impact dollar for dollar, and concluded that if states had begun investing at the CDC-recommended minimum funding levels in 1994, the aggregate sales decline would have doubled (i.e., decreased an additional 9%) by 2000.388 A second national analysis reported that increased state tobacco control expenditures reduced youth smoking prevalence and the number of cigarettes smoked per day, and that had states spent the CDC-recommended minimum levels, youth smoking prevalence would have been between 3.3% and 13.5% lower than the observed rate.389 Evidence from well-funded comprehensive state programs (particularly California and Massachusetts) and from controlled studies were analyzed and developed into CDC’s “Best Practices.” In addition, the annual costs to implement comprehensive state tobacco control programs were estimated to range from $7–$20 per capita in smaller states (population less than 3 million), $6–$17 per capita in medium-sized states (population of 3–7 million), and $5–$16 per capita in large states (population greater than 7 million).390

Current Status of Tobacco Control Programs Tobacco Excise Taxes At the end of 2006, the federal cigarette tax was $0.39 per pack.391 By the end of 2006, state excise taxes ranged from $0.07 cents per pack in South Carolina to $2.46 in Rhode Island, with an average state tax of $0.78 per pack (up from $0.381 at the end of 1997). However, federal and state taxes as a percentage of retail price declined from 51.4% in 1965 to 34% in 2006.392 In addition, 44 states and D.C. imposed general sales taxes on cigarettes as of 2006. In 2006, 20 states had a cigarette tax of $1.00 or more and 5 states had a tax of $2.00 or more per pack. New York City increased its local cigarette tax from $0.08 to $1.50 in 2002, and Cook County, Illinois (includes Chicago), increased its cigarette tax from $0.18 to $1.00 in 2004.392

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In 2002, the federal tax on smokeless tobacco was only $0.04 per can of snuff and $0.012 per package of chew tobacco. As of January 2007, 49 states taxed smokeless tobacco.392

Media Campaigns The 1997 Master Settlement Agreement (MSA) imposed restrictions on cigarette marketing in the United States. There could no longer be (a) brand name sponsorship of concerts, team sporting events, or events with a significant youth audience; (b) sponsorship of events in which paid participants were underage; (c) tobacco brand names in stadiums and arenas; (d) cartoon characters in tobacco advertising, packaging, and promotions; (e) payments to promote tobacco products in entertainment settings, such as movies; (f) sale of merchandise with brand name tobacco logos; and (g) transit and outdoor advertising (including billboards).333

Smoke-free Indoor Air Nonsmokers are increasingly able to breathe smoke-free air in indoor environments. Federal agencies have taken action to reduce exposure to SHS. In 1987, the U.S. Department of Health and Human Services instituted a smoke-free buildings policy, and in 1994, the U.S. Department of Defense prohibited smoking in its facilities worldwide. In addition, the Pro-Children Act of 1994 banned smoking in indoor facilities that are regularly or routinely used to provide services to children (e.g., school, library, day care, health care, and early childhood development settings).213a The Occupational Safety and Health Administration proposed standards to restrict exposure to SHS in workplaces, but then withdrew its Indoor Air Quality proposal in 2001, citing the substantial success states and communities, as well as private employers, were having with this issue. In August 1997, the President issued an Executive Order making all federal facilities of the executive branch smoke free, thus banning smoking in all interior space owned, rented, or leased by the executive branch unless there were separately ventilated smoking areas. In November 2004, the Secretary of the Department of Health and Human Services announced a property-wide ban on tobacco use beginning in January 2005, to be implemented as contracts came up for renewal. Policies were also being implemented in the private sector. Effective in 1994, the Joint Commission on the Accreditation of Healthcare Organizations required hospitals to be smoke free. In 1990, smoking was banned on all U.S. domestic flights of less than 6 hours’ duration. Delta Airlines made all its flights smoke free as of January 1, 1995, and other airlines subsequently banned smoking on their trans-Atlantic flights. In 2000, legislation made all flights to and from the United States smoke free. In 1993, Amtrak made most trains smoke free.399 California became a leader in smoke-free environments for its citizens when all workplaces, including restaurants and bars, became smoke free on January 1, 1998. As of January 12, 2007, eight states had comprehensive indoor smoke-free policies that included all workplaces, restaurants, and bars. Five more had state-wide smokefree policies that included workplaces and restaurants, but not bars. As of January, 2007, 2507 localities had passed some form of clean indoor air law, including Lexington, Kentucky. However, as of December 2006, 18 states had legislation that preempted localities from enacting laws to restrict smoking in public places that were more stringent that state laws.355, 402a In addition to reducing the number of and degree of protection afforded by local regulations, preemption prevents the public education that occurs as a result of the debate and community organization around the issue.402 Workplace smoking policies, originally implemented primarily for safety reasons, are now adopted because of health concerns.312 The vast majority of adults recognize the danger of exposure to SHS.213a,403,404 The percentage of Americans who support totally smoke-free indoor workplaces increased from 58% in 1993 to 68% in 1999 405 and 75% in 2002213a Support generally increases after institution of a ban.213a,406 A 1995 survey found that 87% of work sites with 50 or more employees had a smoking policy of some kind.407 A 1994 survey of businesses with up to 25,000 employees found that 54%


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had smoke-free policies and only 7% had no policy on smoking.312 A nationally representative survey of workers conducted in 1992–1993 and again in 1998–1999 found that 46% were covered by a smoke-free workplace policy in 1992–1993 and 70% in 1998–1999. However, significant variation existed by state in 1998–1999, from a high of 80% (Utah, Maryland) to 50% (Nevada).407a Young workers (aged 15 to 19 years), men, blue-collar workers, and service workers were less likely to work in smokefree workplaces, although disparities have narrowed over time.213a,408 In Los Angeles, California, both patron and employee compliance with the smoke-free bar and restaurant laws increased; by 2002, 76% of patrons in freestanding bars and 98% of patrons in bars/restaurants, and 95% of employees in freestanding bars and 96% of employees in bars/restaurants were complying with the law.409 However, in 2000, only 24.5% of states, 45.5% of districts, and 44.6% of schools provided tobacco-free environments in middle, junior, or senior high schools.410 In California, which enacted the first statewide smoke-free workplace law provided sustained media campaigns about the dangers of SHS, the proportion of adults with smoke-free homes increased from 38% in 1992 to 74% in 1999.411 The percentage of households with smoke-free rules increased nationally from 43% in 1992–1993 to 72% in 2003. In 2003, Utah had the highest proportion of homes with such rules (88.8%), and Kentucky had the lowest (53.4%).411a Exposure to SHS has been decreasing in the United States. From 1988–1991, 88% of Americans aged 2 years and older were estimated to be exposed to SHS.218 In the third national report on human exposure to environmental carcinogens, CDC reported that from 1988-1991, the median level (50th percentile) of serum cotinine (a marker for secondhand smoke) among non-smokers was 0.20 ng/mL. From1988–1991 to 1999-2002, the median cotinine level decreased 70% (to 0.059 ng/mL), suggesting a dramatic reduction in exposure. Exposure declined 68% in children, 69% in adolescents, and 75% among adults. Although levels declined in all age, sex, and racial/ethnic categories, exposure was still high among non-Hispanic blacks and in children and adolescents.412 After implementation of the California law creating smoke-free bars, self-reported exposure of bartenders decreased from 28 to 2 hours per week, 59% of those with previous respiratory symptoms reported they no longer had the symptoms, 78% of those with sensory irritation no longer reported those symptoms, and there was an improvement in mean lung function measurements.413

Minors’ Access In 1992, Congress enacted the Synar Amendment. This federal statute and its implementing regulations issued in 1996 require every state to have a law prohibiting tobacco sales to minors under age 18, to enforce the law, to conduct annual statewide inspections of tobacco outlets to assess the rate of illegal tobacco sales to minors, and to develop a strategy and time frame to reduce the statewide illegal sales rate to 20% or less.414,415 Overall, the national retailer violation rate decreased from 41% in 1996 to 12% in 2005.416,417 In 2005, 48 states and DC states met the overall goal of a 20% violation rate.417 Unfortunately, as states have developed minors’ access laws, some have adopted weak laws that include preemptive language preventing stronger local legislation. As of January 1, 2007, 22 states had such preemptive language in their minors’ access legislation.416a,402a In August of 1996, the FDA issued regulations that prohibited the sale of tobacco to persons less than 18 years of age, required retailers to obtain photo identification to verify the age of all persons less than 27 years of age, banned vending machines and self-service displays except in facilities where only adults were allowed, banned sales of single cigarettes and packages with fewer than 20 cigarettes, and banned free samples.418 The FDA rule was challenged in federal court by the tobacco industry, and in 2000, the Supreme Court ruled that Congress had not given the FDA authority to regulate tobacco products.419 Legislation to give FDA such authority has been proposed several times, most recently in early 2007. The MSA of 1998 also contained the following youth access restrictions: restricted free samples except where no underage persons were present, prohibited gifts to youth in exchange for buying tobacco products, prohibited gifts through the mail without proof of

age, and prohibited the sale or distribution of packs smaller than 20 for three years.333 Studies show that internet sales provide easy access by minors to cigarettes because many Internet vendors don’t check ages or have a verification process.420 By the end of 2005, 29 states had passed laws prohibiting delivery of tobacco to individual consumers and/or restricting internet sales in some way.355,420a

Coverage for Tobacco-use Treatment Insurance coverage for tobacco-use treatment has been slowly increasing. In 1996, 18 states had some form of Medicaid coverage for tobacco-use treatment, but none covered all counseling modalities (individual, group, or telephone) and all FDA-approved medications. By 2005, 38 states covered some form of tobacco use treatment for all medicaid recipients, and 1 state offered comprehensive coverage.421 Coverage under managed care also increased from 1997 to 2002. The proportion offering full coverage in 2002 was 5% for OTC NRT gum, 9% for OTC NRT patches, 36% for NRT inhaler and nasal spray, and 41% for Zyban. The proportion offering full coverage for counseling was 16% for group counseling or classes, 19% for individual counseling for pregnant women, 26% for self-help materials, 41% for faceto-face counseling, and 52% for telephone counseling. However, 15% had annual or lifetime limits on coverage for smoking cessation interventions.422 A survey of work sites having at least 10 employees and providing health insurance reported that there was at least some coverage for devices and drugs in 23% of workplaces, for counseling in 22%, but only 5% offered coverage of both drugs/devices and counseling.423 In a survey of state requirements for provision of preventive services, as of June 2001, one state mandated tobacco-use treatment coverage for group health plans only, one for HMOs only, and one for both group plans and HMOs; one required only medication coverage while the others specified cessation counseling coverage.424 An analysis of the extent to which states required insurance coverage for tobacco-use treatment for state employees (5 million workers) at the end of 2002 found that (of 45 reporting) 29 states required coverage for at least one PHS-recommended treatment for at least some employees, but only 17 provided coverage that was fully consistent with the PHS guideline for at least some employees, and only 7 required coverage consistent with the guideline for all state employees.425

Quitlines California was first to have a state quitline (1992). As of August 2006, all states offered quitline services, although historically funding has been erratic, with some states losing and then regaining them. In 2004, the Secretary of DHHS developed a national network of quitlines. This network has a single portal number: 1-800-QUIT NOW. This portal routes callers to their state’s quitline service. As part of the initiative, CDC provided funding to states without these services so that every state had a quitline. CDC also provided funding to states so they could enhance their existing quitline services.425a The Secretary did not provide funding for this initiative, but in 2005, some funding was allocated by Congress for the network. However, for most states, current funding is not high enough to allow widespread promotion and provision of counseling and medication to all tobacco users interested in quitting.

Comprehensive Programs ASSIST, funded from 1991 to 1998 by NCI and conducted in collaboration with ACS, funded 17 states to form community-based tobacco coalitions responsible for developing and implementing comprehensive state plans for tobacco prevention and control. In 1993, CDC began funding, at lower levels, the other 33 states and the District of Columbia through the IMPACT (Initiatives to Mobilize for the Prevention and Control of Tobacco Use) program. In 2000, the ASSIST and IMPACT programs were combined into CDC’s National Tobacco Control Program, with funding averaging $1 million per state. The program had four goal areas (prevent initiation, promote cessation, eliminate exposure to SHS, and eliminate tobacco-related disparities). States are expected to use community and policy interventions and


54 countermarketing campaigns to meet these goals and to evaluate their programs’ success.426 In 1998, the MSA between the states and the major tobacco companies provided $246 billion over 25 years to the states to compensate them for Medicaid costs incurred by tobacco users.427 Although it was expected that states would fund comprehensive tobacco control programs using this settlement, in most cases the funds have been used for other purposes, particularly as states have experienced budget deficits in the first few years of the twenty-first century. Raising the excise tax on tobacco reduces consumption, but the effect is greater if a portion of the tax is used to fund a comprehensive tobacco control program. California was the first state to do so in 1988, when an initiative to increase cigarette taxes by $0.25 per pack dedicated 20% of the increase to tobacco control activities.376a Other states to fund programs using excise taxes included Massachusetts in 1992,383 Arizona in 1995,385 and Oregon in 1997.386 However, all four of these programs have sustained cuts. By 2004, the Massachusetts program had been virtually eliminated (a 92% cut) and the California, Arizona, and Oregon programs severely reduced (45%, 37%, and 69%, respectively).427 Florida’s campaign, funded by its individual settlement with the tobacco industry, was cut 99%, eliminating the effective “truth” marketing campaign.428 Other states dedicated significant cigarette excise tax dollars or MSA funds to tobacco control programs, but from 2002 to 2005, funding for tobacco control programs was cut by 28%. The use of only 8% of excise taxes and the MSA funds dedicated to tobacco control would fund these programs at the CDC-recommended minimum level.390,427 By 2007, only 3 states were funding their tobacco control programs at this level, 28 states and the District of Columbia were funding at less than half the minimum level, and 5 states were not funding these programs at all.428a

Protobacco Influences Advertising and Promotion In 1970, the cigarette industry spent $360 million on advertising and promotion, two-thirds of which was for television and radio advertising. In the United States, broadcast media advertising was banned as of January 1, 1971. In 1975, the cigarette industry spent $490 million on advertising and promotion, two-thirds of that for newspaper, magazine, and outdoor ads. In 1997 (the year of the MSA), the industry spent $5.7 billion in advertising and promotion, with 80% used for promotions, specialty items, and coupons.429 Industry spending on advertising nearly tripled from 1997 to 2001 (to $15.2 billion). Expenditures decreased slightly to 13.1 billion in 2005. The share used for coupons and discounts increased from 27% to 87%. Smokeless tobacco companies spent $251 million on advertising in 2005. Price discounts and free samples accounted for 60% of the advertising budget.429a Tobacco companies maintain that their advertising and promotion are not intended to appeal to teenagers or preteen children. However, on March 20, 1997, the Liggett Group, Inc., as part of the settlement of state lawsuits, acknowledged that the tobacco industry markets to youth under 18 years of age.430 Similarly, documents released in January 1998 showed that in 1975, R.J. Reynolds Tobacco wanted to increase the market share of Camel filter cigarettes among young people 14–24 years of age “who represent tomorrow’s cigarette business.”431 One study found that the MSA had little effect on cigarette advertising in magazines. In 2000, the tobacco industry spent nearly $60 million on advertising in youth-oriented magazines, and advertisements for the three most popular youth brands reached 80% of young people an average of 17 times in 2000.432 A Massachusetts study found that cigarette advertising in magazines with high youth readership increased 33% after the MSA,433 and another study reported that the United States Smokeless Tobacco Company (USST) increased advertising in magazines with high youth readership by 74% from 1998 to 2001 and that nearly half the company’s advertising was in youth-oriented magazines.434 In 2002, a California judge fined R.J. Reynolds Tobacco Company $20 million for advertising in magazines with high youth readership in violation of the state tobacco settlement agreement.435 The promotion of televised sporting and entertainment events heavily expose youth to tobacco

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advertising as well.56,179,436 Moreover, the kinds of activities promoted by tobacco companies (often popular musical and sporting events) and the effort to associate smoking with maturity, glamour, and selfconfidence have a strong appeal to youth. In a 2005 national survey, 81% of youth smokers aged 12–17 preferred Marlboro, Camel, or Newport, the three most heavily advertised brands. Marlboro, the most heavily advertised, was used by 48% of youth, and 40% of smokers over the age of 25.436a Teens have been shown to be three times more sensitive to cigarette advertising than adults.437 One study reported that teens were more likely to be influenced to smoke by tobacco advertising than by peer pressure,438 and another showed that receptivity to advertising was associated with smoking initiation. The biggest impact comes from influencing nonsusceptible youth to become susceptible to smoking.439 After the Joe Camel cartoon character was introduced in 1988, Camel’s share of the adolescent cigarette market increased from 2% in 1978–1980, to 8% in 1989, to more than 13% in 1993.179,440 One study found that the cartoon camel was as familiar to six-year-old children as Mickey Mouse’s silhouette.441 The Joe Camel campaign was one of the tobacco industry’s most heavily criticized advertising campaigns, and there was increased pressure to drop the campaign after the Federal Trade Commission (FTC) filed suit against the company in May of 1997, alleging that the Joe Camel symbol enticed children to smoke. In July of 1997, R.J. Reynolds announced that they were discontinuing Joe Camel in the United States, although they still planned to use the cartoon character for overseas advertising.442 Tobacco company marketing efforts have also targeted women and minorities. The uptake of smoking among women beginning in 1967 was associated with the marketing of cigarette brands specific for women.443 In 1990, after the Secretary of the Department of Health and Human Services, Dr. Louis Sullivan, denounced R.J. Reynolds for “slick and sinister advertising” and for “promoting a culture of cancer,” the company abruptly decided to cancel the launch of Uptown, their new cigarette aimed at blacks.444 Only a month later, the same company was preparing to introduce a new cigarette aimed at young, poorly educated, blue-collar women.445 This cigarette, called Dakota, was also withdrawn after public outcry. Another campaign, called “Find Your Voice” targeted minority women, and brands such as “Rio,” “Dorado,” and “American Spirit” targeted Hispanics and American Indians.355 In 2004, R.J. Reynolds settled a lawsuit with 13 states over Reynolds’ “Kool Mixx” marketing campaign, which the states alleged targeted urban minority youth in violation of the MSA.446 In 2006, R.J. Reynolds settled a lawsuit with 38 states over their candy, fruit, and alcohol flavored cigarettes. The company agreed to a U.S. ban and to restrictions on marketing flavored cigarettes in the future. These examples suggest that new tobacco product introductions aimed at young and minority populations are likely to be aggressively attacked as exploitative. Several studies have looked at the effect of tobacco advertising on smoking, particularly among young people. The 1994 Surgeon General’s Report concluded that “cigarette advertising appears to increase young people’s risk of smoking by affecting their perceptions of the pervasiveness, image, and function of smoking.”179 Similarly, an IOM report concluded that the preponderance of evidence suggests that tobacco marketing encourages young people to smoke.350 The FDA reviewed the evidence when developing the case for regulation of tobacco, and concluded that cigarette advertising is causally related to the prevalence of smoking among young people.418 The U.K. Scientific Committee on Tobacco and Health also concluded that tobacco advertising and promotion influences young people to begin smoking.448 Smoking in the movies has also recently emerged as a tobacco control issue. Several studies have now shown that exposure to smoking in the movies increases youth initiation. For example, one study showed that students in the highest quartile of exposure were 2.72 times more likely to begin smoking compared with students in the lowest quartile of exposure. The effect of exposure was stronger in adolescents with nonsmoking parents. The authors estimated that 52% of smoking initiation could be attributed to exposure to smoking in the movies.449 Another study found that susceptibility to begin smoking increased with higher levels of exposure to smoking in the


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movies.450 In a recent cohort study, one-third of adolescent neversmokers nominated as their favorite film stars those who smoked onscreen. These nominations independently predicted later smoking.451 Although smoking in the United States has declined since the 1950s, and smoking in the movies likewise decreased from 1950 (10.7 incidents per hour) to 1980–1982 (4.9 incidents per hour), it rebounded to 1950 levels in 2002 (10.9 incidents per hour).452 Other studies have shown that smoking is frequent even in G or PG movies.453 Tobacco advertising in magazines can also limit the information provided on the health effects of smoking. For example, many women rely on magazines for information about health. Yet studies have found little coverage of the serious consequences of smoking in these magazines. A recent study examined health and smokingrelated coverage during 2001–2002 in 15 women’s magazines (10 of which were assessed in previous studies), and found that there were only 55 antismoking articles, compared with 726 on nutrition, 424 on ob/gyn issues, 347 on fitness, 340 on diet, and 268 on mental health.454 Only six (out of 4000) articles focused primarily on lung cancer, and two of these did not address the importance of avoiding cigarettes in order to prevent lung cancer. Over the same time period, there were 176 prosmoking mentions (half of which were photographs or illustrations) and three magazines had more prosmoking mentions than antismoking messages. There were 6.4 pages of cigarette advertising for each page of antismoking ads.454 In the United States, the federal Public Health Cigarette Smoking Act of 1969 preempted most state advertising restrictions.455 In addition, as of 1998, 17 states preempted localities from passing their own laws to restrict the marketing of tobacco products.456 As of June 1997, only nine states had laws that restrict the advertising of tobacco products. These laws included restricted advertising on lottery tickets or video games, prohibited advertising within certain distances of schools, and required warning labels on billboards advertising smokeless tobacco products.418,455 In August 1996, the FDA issued a rule that all tobacco advertising must be in black-and-white text only except when it appears in adult publications or in locations inaccessible to young people. Billboards were banned within 1000 feet of schools and playgrounds; events, teams, and entries could be sponsored only in the corporate name, not a brand name; brand name nontobacco items, such as t-shirts, were banned; gifts and items provided in exchange for proof of purchase were banned; and the use of nontobacco names on tobacco items was banned.418 The FDA rule was challenged in federal court and, in 2000, the Supreme Court ruled that the FDA did not have the authority to regulate tobacco.419 In 2004, a bill giving FDA the authority to regulate tobacco failed in conference committee; a similar bill was introduced in early 2007. Some other countries have very broad advertising restrictions.370 For example, Canada passed legislation in 1988 to ban all tobacco advertising in newspapers and magazines published in Canada as well as all point-of-sale tobacco advertising and promotion. In Europe a number of countries have enacted similar restrictions on the use of graphics in tobacco advertising. As of late 2004, at least 12 countries had implemented a total ban on tobacco advertising and marketing.457

Other Interventions Warning Labels Warning labels can have an impact on consumers if they take into account consumers’ previous knowledge of the risks, levels of education, and reading ability. To be effective, labels need to stand out, have a visual impact, be visible, and be content specific (not give just general information).370 There is some evidence that warning labels can have an impact on smoking behavior. In South Africa, tobacco consumption decreased 15% in three years after new warning labels were introduced. Stronger warning labels in Australia appear to have a larger effect on quitting behavior than the old labels, and half of Canadian smokers said that the warning labels had contributed to their desire to quit or to cut back on their consumption.370

individual suits against the tobacco industry.458–462 There have also been successful class action lawsuits against the tobacco industry. One of the earliest successful class action lawsuits involved flight attendants. This lawsuit, brought in 1991, sought damages for diseases in and deaths of flight attendants caused by exposure to SHS in airplanes. The settlement included waivers of all statutes of limitations, thus enabling flight attendants whose exposure happened decades earlier to pursue their claims. It also included the establishment of the Flight Attendant Medical Research Institute as a not-for-profit medical research foundation with funding by the tobacco industry of $300 million.463 Another class action lawsuit that originated in Florida, sought damages against cigarette companies and industry organizations for alleged smoking-related injuries. Initially the class action lawsuit verdict awarded $12.7 million in compensatory damages to three individual plaintiffs, and $145 billion in punitive damages.464 In May of 2003, the Florida appeals court threw out the verdict, concluding that each smoker’s claim was too unique and individualized to be tried collectively in a class action suit. In 2006 this finding was upheld by the Florida Supreme Court, but the court also ruled that the companies are negligent and their products are defective, unreasonably dangerous and addictive. In their individual cases, the plaintiffs must only prove that smoking caused their disease.465 Another class action lawsuit claimed that Philip Morris had defrauded “Lights” smokers by suggesting that light cigarettes were less hazardous than full-flavor cigarettes. In 2003, the Madison County (Illinois) Circuit Court awarded compensatory and punitive damages totaling $10.1 billion. The Illinois Supreme Court overturned this verdict and U.S. Supreme Court let that ruling stand. Lawsuits in other states over “light” cigarettes are still pending.465,466 States have also sued the tobacco companies and some have filed class-action lawsuits over light cigarettes.467 In 1994, Mississippi became the first state to sue the tobacco industry for medical expenses incurred by Medicaid for the treatment of tobacco-related illnesses. In January 1998, the industry had settled with three states (Florida, Mississippi, and Texas) for amounts ranging from $3.4 billion to $15.3 billion. Minnesota also reached a settlement with the tobacco industry. Under the MSA in 1997, the remaining states settled with 11 tobacco companies. Under the MSA, the companies agreed to pay $246 billion over 25 years. Other provisions of the MSA included the significant marketing and minors’ access restrictions mentioned earlier, prohibited the industry from supporting diversion of settlement funds to nonhealth use, restricted the tobacco industry from lobbying against restrictions of advertising on or in school grounds, prohibited new challenges by the industry to state and local tobacco control laws enacted before June 1, 1998. The MSA also required the tobacco industry to contribute $25 million annually for 10 years to support the American Legacy Foundation, to contribute $1.45 billion over five years to support the National Public Education Fund for a national sustained advertising and education program to counter youth tobacco use, and then to contribute $300 million annually to the fund so long as the participating companies hold 99.05% of the market.333 As of early 2007, because of market share losses, there will be no further annual payments to the fund. In 1999, the Department of Justice sued the largest tobacco companies under the Racketeer Influenced Corrupt Organization Act (RICO), charging the tobacco companies with conspiring to conceal the health risks and addictive powers of cigarettes. The government sought the “disgorgement” of $280 billion in “ill gotten gains” that the industry has received by selling cigarettes to people who got addicted before the age of 21 (since the enactment of the act in 1970). The judge found the defendants guilty in late 2006, but said that a district court ruling prevented her from imposing any penalties. As of early 2007, the tobacco industry had announces their intention to appeal the ruling.468,468a  TOBACCO ECONOMICS

Industry Lawsuits Historically, individual lawsuits against the tobacco industry have not been successful. However, more recently there have been successful

In 2003, consumers in the United States spent nearly $87 billion on tobacco products, equal to 1.1% of personal disposable income.240,469


54 One recent study estimated that smoking is associated with lower net worth, even after adjusting for a variety of demographic factors. Heavy smokers had a reduction in net worth of more than $8300 and light smokers had a reduction of $2000, compared to nonsmokers. Each adult year of smoking was associated with a 4% reduction in net worth, and the author concluded that smokers appear to pay for tobacco expenditures out of income that is saved by nonsmokers. The author also concluded that a reduction in smoking would boost wealth, especially among the poor.470 The industry directly accounted for about 260,000 jobs in 1993 (tobacco growing, warehousing, manufacturing, and wholesaling.333 In 2005, U.S. tobacco farmers produced an estimated 647 million pounds of tobacco leaf with a value of 1.1 billion, and in 2005 U.S. cigarette manufacturers produced an estimated 496 billion packs of cigarettes, 16% of which were exported.240 In monetary value, domestic tobacco exports (cigarettes, other manufactured tobacco products, and unmanufactured tobacco) accounted for 0.1% of the total export earnings of the United States in 2004.471,471a Cigarette production in the United States is highly concentrated; four major cigarette manufacturers produce nearly all cigarettes in this country.240 In the twentieth century, the importance of tobacco to the overall U.S. economy declined, although its regional and local importance remains high. A 1996 study that looked at the impact of tobacco at the regional level estimated that eliminating spending on tobacco products would have led to 300,000 fewer jobs in the Southeast, but would have increased jobs in all other regions by about the same number. They further estimated that by 2000, the loss of jobs in the tobacco region would fall to about 220,000 while the net impact nationally would be an increase of 133,000 jobs.472 Similarly, a USDA report found that the large declines in tobacco production in the 1980s had a relatively minor impact on the macroeconomy of the major tobacco-growing regions.473 This was attributed to the relatively small share of tobacco (less than 1% of total income) in these regional economies. Until late 2004, a tobacco price support program that was first introduced during the Depression regulated both the number of tobacco producers and the quantity of tobacco produced through a complex system of quotas. This program led to a higher price of tobacco for farmers. In 2003, the estimated gross income per acre for tobacco was $3851, compared with $232 for corn and $242 for soybeans (U.S. Department of Agriculture, unpublished data, 2003). Although the price support program increased prices only marginally (0.52%), it provided a political constituency of quota owners and tobacco farmers who opposed tobacco control interventions. Studies of the impact of the farm support program suggested that the overall impact of the program on tobacco control was probably negative.333,474 In 2004, Congress passed a law that eliminated the price support system and provided a $10.14 billion payout (over 10 years) to tobacco farmers and quota holders; the cost of the buyout will be paid by the tobacco industry.475

Trade Policies In 2003, 70% of tobacco production occurred in six countries: China, India, the United States, Brazil, Indonesia, and Turkey, with most being used to make cigarettes.476 Cigarette production largely occurs in China, the United States, and the European Union. World trade in cigarettes has been continually expanding, and U.S. companies increased exports from 24.3 billion cigarettes per year in the late 1960s to 240 billion in 1996; exports then declined to 111 billion pieces in 2006.240 In the 1990s, 30% of U.S. cigarettes were exported. This amount probably would have been higher except for trade policies that protected domestic tobacco growers and producers. In addition, the laws that apply to domestic cigarettes, such as warning labels and advertising restrictions, do not apply to exported cigarettes. U.S. policies and programs, particularly the Trade Act of 1974, have helped growers and producers expand into foreign markets. The threat of retaliatory trade sanctions under this act successfully opened some foreign markets to U.S. manufacturers. Under the Doggett Amendment of 1998 and guidelines distributed by the Clinton

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administration, the U.S. government stopped promoting the sale or export of tobacco or tobacco products or seeking the removal of nondiscriminatory restrictions on the marketing of tobacco or tobacco products (discriminatory practices could still be challenged). U.S. diplomats were also encouraged to assist and promote tobacco control efforts in host countries.333 However, adherence has varied over time.  SMOKING AND THE WORKPLACE

Employee smoking is very costly. Smokers increase absenteeism, health insurance and life insurance costs and claims, worker’s compensation payments and occupational health awards, accidents and fires (and related insurance costs), property damage (and related insurance costs), cleaning and maintenance costs, and illness and discomfort among nonsmokers exposed to SHS. Smokers also take more breaks, averaging 18 days per year on breaks477 and are less productive. One study reported that former smokers are 4.5% more productive than current smokers.478 Former smokers also have less absenteeism than current smokers, but more than never-smokers. Among former smokers, absenteeism decreases with years of cessation.478 Male smokers are absent four days more than male nonsmokers each year (female smokers miss two more days).479 Male smokers incur $15,800 and female smokers incur $17,500 (in 2002 dollars) more in lifetime medical expenses than nonsmokers.480 The economic cost of smoking for the United States, including direct medical costs and loss of productivity from smoking-related deaths, is about $167 billion per year.8 The health-care expenditures attributable to smoking were $75 billion in 1998, or 7.1% of direct medical expenditures for the United States.20 It is estimated that a 1% reduction in health care costs for businesses could increase retained profits by 5%.481  INTERNATIONAL PERSPECTIVE ON TOBACCO

Tobacco use is a major preventable cause of death worldwide. The World Health Organization (WHO) estimates that there are about 1.2 billion smokers in the world.482 Most of these smokers are in developing countries (800 million), and are men (1 billion). Smoking prevalence for men ranges from 29% in the Africa region to 61% in the Western Pacific region. Prevalence for women ranges from 5% in the Southeast Asia region to 21% in the Region of the Americas (Fig. 54-6). Smoking prevalence varies by level of economic development: for men the prevalence is 34% in developed countries, 50% in developing countries, and 54% in transitional countries. For women the respective percentages are 21%, 7%, and 14%.482 For men, prevalence was highest in Kenya (67%), Republic of Korea (65%) and the Russian Federation (63%) and lowest in Sweden (17%). For women, prevalence was highest in Argentina (34%), Norway (32%), Kenya (32%), Denmark and Germany (30%) and lowest in the United Arab Emirates (1%), Thailand (2%), Singapore (3%), China (4%), and Egypt (5%).483 It should be noted, however, that South Asia has high bidi (a type of hand-rolled cigarette) prevalence (21% for men and 4% for women). Low-income and middleincome countries, have four-fifths of the world’s population, and 82% of the world’s smokers.370 Current cigarette smoking among youth aged 13–15 years, according to a survey that assessed 224 sites in 118 countries and 1.7 million students was 9.8% in the Africa region, 18.4% in the Americas region, 4.1% in the Eastern Mediterranean region, 16.2% in the European region, 4.5% in the Southeast Asia region, and 11.8% in the Pacific region.484 Current use of any tobacco product by youth aged 13–15 years, according to a survey conducted in 75 sites in 43 countries and the Gaza Strip/West Bank, ranges from 3% (Goa in India) to 63% (Nagaland in India). Current cigarette smoking in this group ranges from less than 1% (Goa in India) to 40% (Coquimbo in Chile), with nearly 25% of students who smoke having smoked their first cigarette before age 10.485 Other findings included a lack of gender differences in tobacco use among youth and a high rate of use of tobacco products other than cigarettes.486 From


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70

% of smokers among adults Stage 1

% of deaths caused by smoking

Stage 2

Stage 3

40

Stage 4

60 % Male smokers

30

50

% Female smokers

40 Figure 54-6. A model of the cigarette epidemic. (Source: Lopez AD, Collinshaw NE, Piha T. A descriptive model of the cigarette epidemic in developing countries. Tobacco Control. 1994;3:242–7. Reproduced with permission from the BMJ Publishing Group.)

20 30 % Male deaths 20 10 % Female deaths

10

0

0 0

10

20

1970–1972 to 1990–1992, per capita cigarette consumption decreased in the Americas (an average annual decrease of 1.5%), remained unchanged in Europe, and increased in Africa (average annual increase of 1.2%), the eastern Mediterranean (1.4%), Southeast Asia (1.8%), and the Western Pacific (3%). China is a good example of the size and scope of the smoking problem because it is the largest producer and consumer of cigarettes in the world. An estimated 300 million Chinese smoke (53% of men and 3% of women),487 the same number as in all the developed countries combined. By 2025, an estimated 2 million Chinese men will die annually from smoking.488 Before the middle of this century, very few developing countries either produced tobacco or had significant consumption of manufactured cigarettes. In the late 1950s, cigarette manufacturers sought to establish new markets in the developing countries. These countries, with more than half of the world’s population, who may be unaware of the health problems associated with tobacco use, represented a huge, potentially untapped resource for tobacco cultivation, cigarette manufacture, and cigarette marketing. In 1995, 6 low income and 18 lower middle income countries where classified as either net (consumes more tobacco than they produce) or full (does not produce any tobacco but consumes it) importers of tobacco. In these countries reduced expenditures on tobacco imports could have impacts on economic development through improving and increasing trade balance and foreign exchange reserves to fund other essential development projects.370,489,487 Currently, tobacco is grown in more than 100 countries, including 80 that are developing. From 1975–1998, production in developed countries decreased by 31%, and production in developing countries increased 128%. Asia increased its share of world tobacco production from 40% to 60%. The four major tobacco producing countries are China, the United States, India, and Brazil. These four countries account for about two-thirds of world production. The top 20 countries account for 90% of the world’s production. However, in only three countries does the employment as a percentage of the total labor force exceed 1% (Malawi at 2.03%, Turkey at 1.29%, and the Philippines at 1.24%). The average across the 28 highest countries is 0.63%.370 Export earnings from tobacco exceed 1% of total export earnings in nine countries. Two countries are particularly dependent on tobacco exports as a major source of earnings: in 1998, 61% and 23% of export earning came from tobacco for Malawi and Zimbabwe respectively.370 Thus, even very stringent tobacco control policies would likely have minimal negative long-term economic impact, with the largest effect in those few countries that earn a significant share of foreign earnings from tobacco such as Malawi and Zimbabwe.370

30

40

50

60

70

80

90

100

Trade liberalization was estimated to have increased global cigarette consumption by 5%.370 Another study calculated that markets opening in Japan, Taiwan, South Korea, and Thailand increased cigarette consumption by 10%. Two factors are thought to account for this: first, opening the markets decreased the price of both domestic and imported cigarettes, and second, cigarette advertising increased. For example, in Japan, cigarette advertising by U.S. companies doubled, and the domestic companies responded with their own increased advertising.370 Many tobacco-producing countries are poor and lack the resources to grow or import sufficient quantities of food for their populations, yet they divert agricultural land that could be used for growing staple crops such as sorghum and maize to tobacco cultivation. They may perceive tobacco production as (a) a relatively simple mechanism for raising substantial revenue from taxation of tobacco products, (b) an easy way to generate the foreign exchange necessary to buy commodities from abroad and to improve their balance of trade, and (c) a significant source of rural employment and wage production.490 The short-run economic advantages of tobacco growth and consumption come at a high cost. Most obvious are the direct, welldocumented health problems associated with tobacco use. Indirect effects of tobacco production include destruction of agricultural lands and forests and improper use of insecticides by rural farmers. According to United Nations sources, the deforestation problem in many developing countries may soon become a “poor man’s energy crisis.”491 This problem is traceable in large part to the wood burned to flue-cure many varieties of tobacco at high temperatures. Tobacco farmers in developing countries, most of whom depend on wood as their sole source of energy, use the trees from approximately 2 hectares for each ton of tobacco cured, equivalent to two trees for every 300 cigarettes, or 15 packs of cigarettes, produced.492 A direct result of deforestation is soil erosion, which in hilly rural areas may lead to silt-filled rivers and dams during the rainy season and denuded croplands during growing seasons. In addition, because tobacco grows well in sandy soils and many developing countries are located in semiarid lands, tobacco is often grown on agricultural fringe land that borders deserts. As trees in nearby forests are cut down to fuel the curing process, desertification is accelerated and tobacco farmers are forced to move into other, less arid regions. Thus, cultivation of tobacco displaces staple food crops, leading to lost food production.491 Further, the lack of adequate education among rural area tobacco farmers on the proper use of modern insecticides often leads to their indiscriminate dispersal in lakes and rivers. The resultant pollution


54 endangers water sources of rural villagers and surrounding wildlife. Failure to use the gloves and protective garments needed to limit exposure to toxic chemicals in insecticides also increases rural tobacco farmers’ long-term risk of occupationally related diseases such as skin, lung, and bladder cancer.492 The major health consequences associated with smoking (e.g., cancer, heart disease, and COPD), which are well established in developed countries, are becoming increasingly prevalent in the developing world. In 1995, an estimated 1.4 million men in developed countries and 1.6 million men in developing countries (more than half from China) died from smoking-related diseases. Tobacco use also caused an estimated 475,000 deaths among women in developed countries, and an estimated 250,000 deaths among women in developing countries (including 20,000 to 30,000 deaths from smokeless tobacco) in 1995. WHO estimates that smoking caused 3.8 million deaths globally in 1995 (7% of all deaths).489 It is estimated that China will see a dramatic increase in lung cancer deaths, from 30,000 per year in 1975 to 900,000 per year by 2025, and total tobacco deaths will increase to one million before 2010, and to two million by 2025. Similarly, it is estimated that 80 million Indian males currently aged 0–34 will be killed by tobacco. Tobacco is expected to cause 500,000 million deaths among smokers alive today, and before 2020, deaths will average 8–10 million per year or 12% of all deaths. Most of these deaths will be in developing countries.370,489 It has also been estimated that tobacco will kill a billion people in the twenty-first century (10 times more than in the twentieth century).370 There are disturbing parallels between the advertising and promotion techniques used to sell cigarette smoking in the United States and other developed countries in the early twentieth century through the 1920s and the current efforts to promote smoking as a pleasurable status symbol in developing countries. There is also a tragic difference. In the 1920s, producers, consumers, and governments did not know about the adverse health effects of tobacco use. Today, the scientific evidence is incontrovertible. In 1986, the World Health Assembly unanimously adopted a resolution for member states to consider a comprehensive national tobacco control strategy containing nine elements: reducing exposure to SHS; reducing initiation by young people; reducing smoking among health personnel; eliminating those socioeconomic, behavioral, and other incentives that maintain and promote tobacco use; placing health warnings on all tobacco products; establishing educational and cessation programs; monitoring tobacco use and tobacco-related diseases, and the effectiveness of interventions; promoting viable economic alternatives to tobacco production; and establishing a national focal point to coordinate all these activities.489 In 1990, the World Health Assembly passed another resolution urging all member states to implement multisectoral comprehensive tobacco control strategies that contain the nine elements previously listed plus legislative action to protect from SHS in indoor workplaces, enclosed public places, and public transport, with special attention to risk groups such as pregnant women and children; progressive financial measures to discourage the use of tobacco; and progressive restrictions and concerted actions to eventually eliminate all direct and indirect advertising, promotion, and sponsorship concerning tobacco.489 In 1992, the World Bank developed a formal five-part tobacco policy. (a) World Bank activities in the health sector discourage the use of tobacco. (b) The World Bank does not lend directly for, invest in, or guarantee investments or loans for tobacco production, processing, or marketing. For those countries where tobacco constitutes more than 10% of exports, the World Bank is more flexible, but works toward helping these countries diversify. (c) The World Bank does not lend indirectly for tobacco production activities, to the extent practical. (d) Unmanufactured and manufactured tobacco, tobaccoprocessing machinery and equipment, and related services are not included among imports financed with World Bank loans. (e) Tobacco and tobacco-related producer or consumer imports may be exempt from borrowers’ agreements with the World Bank that seek to liberalize trade and reduce tariff levels.493

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In 1996, the World Health Assembly passed a third resolution requesting the director-general to initiate the development of an International Framework Convention for tobacco control (FCTC).494 The FCTC became a top priority for WHO in 1998, due to concern for the growing disease burden from tobacco worldwide. In 1999, the World Health Assembly established an intergovernmental negotiating body to draft and negotiate the FCTC. This negotiating body met six times from October 2000 to March 2003. The World Health Assembly adopted the FCTC in 2003 and within the one-year time frame provided, 167 countries (including the United States) signed the treaty. The treaty came into force for ratifying countries in February 2005, after the required 40 countries had ratified it. As of early 2007, the United States had not yet ratified the treaty. The FCTC calls on countries to: 1. Adopt a nonpreemption clause, making FCTC a floor, not a ceiling for action. 2. Develop and implement a comprehensive, multisectoral national tobacco control strategy and establish focal points for tobacco control; cooperate, as appropriate, with other parties in developing appropriate policies; protect public health policies from commercial and other vested interests of the tobacco industry in accordance with national law. 3. Report on rates of taxation and trends in tobacco consumption. 4. Adopt “in areas of existing national jurisdiction as determined by national law” effective measures to protect from SHS exposure in indoor workplaces, public transport, and indoor public places. Promote adoption of these measures at other jurisdictional levels. 5. Adopt effective measures for the testing of tobacco products and for regulation “where approved by competent national authorities.” 6. In accordance with national law, adopt and implement measures to disclose to government authorities “information about the contents and emissions of tobacco products.” 7. Adopt measures to promote access to educational programs on the health risks of tobacco use and SHS, information about the tobacco industry, training on tobacco control, and involvement of public and private organizations in tobacco control programs. 8. Develop and disseminate guidelines and promote cessation of tobacco use; implement cessation programs in a variety of environments, including national health and education programs and health care facilities; collaborate with other parties to facilitate the accessibility and affordability of treatment, including pharmaceutical products. 9. Adopt and implement measures at the appropriate government level to prohibit sales of tobacco to “persons under the age set by domestic law, national law, or eighteen.” 10. Initiate and coordinate research; promote research that addresses the consequences of tobacco consumption and exposure “as well as research for identification of alternative crops.” 11. Establish, as appropriate, programs for surveillance of tobacco consumption and exposure. 12. Establish a national system for epidemiologic surveillance of tobacco consumption. 13. Subject to national law, “promote and faciliate exchange of publicly available information relevant to the convention; endeavor to establish and maintain an updated database of laws and regulations on tobacco control.”495 In the 1990s, about 13 high-income countries and 30 lowincome countries had laws prohibiting the sale of cigarettes to minors, 11 high-income countries and 6 low-income countries banned vending machines, and 14 high-income and 15 low-income countries had minimum age restrictions for purchase of cigarettes.370 However, few countries effectively enforced these laws. Many jurisdictions also had laws that banned or restricted smoking in public places, workplaces, and transit vehicles. For example, 24 high-income and 74 low-income


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countries required smoke-free public places, 9 high-income and 19 low-income countries required smoke-free restaurants, 9 highincome and 11 low-income countries required smoke-free cafes, 18 high-income and 32 low-income countries had workplace smoking restrictions, and 20 high-income and 23 low-income counties required smoke-free health establishments.370 Enforcement was again the issue. Some 75 countries have at least some type of advertising restriction,487 but the number with comprehensive bans is much lower,489 and such restrictions are frequently circumvented unless they are comprehensive. For example, after a 1976 law in France banned tobacco advertising, it was replaced by advertisements for matches and lighters with the tobacco brand names and logos, until a law was passed banning both direct and indirect advertising. By the end of the 1990s, about 137 countries required health warnings to appear on tobacco product packages. However, in most countries, the warnings were small and ineffective. By the mid1990s, a number of countries had adopted more stringent warnings, including more direct statements of risk, multiple messages, and large and rotating messages. Beginning in 2000, some countries started putting graphic pictures on warning labels (Canada, Brazil, Norway, Thailand, and the European Union).496 In 2002, taxes on cigarettes in the United States ranged from 17% of price (lowest state) to 38% of price (highest state) (Table 54-5). Prices also include $0.46 per pack to cover the MSA. If this cost were also considered a tax, the percentage of price in New York would be 47% and in Kentucky 31%. In comparison, in Europe, New Zealand, Australia, and Hong Kong, tax as a percentage of price ranged from 52% (Hong Kong) to 82% (Denmark).497 A number of countries use part of the revenue generated to operate their comprehensive tobacco control programs.489 Many countries have had difficulty implementing comprehensive tobacco control measures. However, Finland, Iceland, Norway, Portugal, and Singapore have comprehensive tobacco control policies developed since the 1970s. Australia, New Zealand, Sweden, Poland, and Thailand have more recently implemented tobacco control programs. One study used multiple regression analysis to evaluate the effectiveness of advertising restrictions, price, and income on tobacco consumption in 22 countries from 1960 to 1986.498 Above threshold levels, both advertising restrictions and higher prices were effective in decreasing tobacco consumption. Moreover, programs that included high prices, comprehensive bans on advertising, and stringent health warnings decreased tobacco consumption most. This analysis estimated that banning tobacco advertising, requiring strong and varied health warnings on packages, and implementing a 36% increase in real price would decrease tobacco consumption by 13.5%. In 2006, New York City mayor Bloomberg announced a $125M initiative to reduce tobacco use in low and middle income countries with a particular focus on China, India, Indonesia, the Russian Federation and Bangladesh (which have half the world's smokers).498a However, powerful economic forces will continue to militate against a strong tobacco control policy in developing countries. Only a concerted effort by international organizations (i.e., the WHO, the International Monetary Fund, the Food and Agriculture Organization, UNICEF, and NGOs) is likely to be effective in helping developing countries assign a high priority to tobacco prevention and control.  CHALLENGES IN TOBACCO USE PREVENTION AND CONTROL

Despite considerable progress, smoking remains the largest cause of preventable death in the United States and most of the industrialized world, and it is rapidly becoming a major cause of death in developing countries as well. Lessons from the considerable progress achieved in tobacco use prevention and control during the past 25 years can help us successfully confront the remaining challenges. The growth of knowledge about the adverse health effects of tobacco has been substantial. Public education campaigns have helped to translate scientific knowledge into improved public awareness

TABLE 54-5. AVERAGE RETAIL CIGARETTE PRICE AND TOTAL TAXES PER PACK (U.S./DOLLARS/PACK OF 20), SELECTED INDUSTRIAL COUNTRIES, JUNE 17, 2002 Country

Price

Tax Incidence

Norway United Kingdom United States (Highest-NY) Canada (Highest-Saskatchewan) Ireland Australia Hong Kong New Zealand Canada (sales-weighted average)c Denmark Sweden Finland Canada (Lowest-Ontario) United States (Lowest-Kentucky) Germany France Belgium Netherlands Austria Luxemberg Italy Greece Spain Portugal

$7.56 $6.33 $5.32 $4.76 $4.46 $4.02 $3.97 $3.88 $3.80 $3.77 $3.64 $3.53 $3.48 $3.27 $2.76 $2.76 $2.63 $2.56 $2.37 $1.94 $1.93 $1.79 $1.66 $1.63

79.2% 79.5% 38.4%a 77.3% 79.0% 68.9% 51.9% 74.5% 71.6% 81.7% 70.5% 79.0% 69.0% 16.9%b 68.9% 75.5% 74.4% 73.0% 73.7% 67.7% 74.7% 72.8% 71.2% 80.7%

Nonsmokers Rights Association Smoking and Health Action Foundation. All figures given in U.S. dollars, for equivalent of 20-cigarette pack in most popular price category. Tax incidence refers to the portion of the total retail price made up of applicable taxes and fees, including excise, sales, VAT Exchange rates as of May 31st, 2002. European Union. “Tax Burden on Tobacco”; U.S., budget/tax documents; Canada, Australia, New Zealand, Hong Kong, Norway, Tobacco Journal international. aNote that U.S. prices include approx. $0.46 per pack to cover the cost of the November 1998 settlement with State Attorneys General. If this amount were considered a tax, tax incidence in New York would be 47%. No municipal taxes are included in this tabulation. bU.S. prices include approx. $0.46 per pack to cover the cost of the November 1998 settlement with State Attorneys General. If this amount were considered a tax, tax incidence in Kentucky would be 31%. cCalculated by provincial proportion of total 2001 cigarette sales. Note that Canadian prices include June 17th, 2002 tax increases.

of some smoking-caused problems, such as lung cancer and cardiovascular disease, but awareness of other smoking-caused cancers, COPD, and reproductive effects is still limited. SHS is increasingly appreciated as a health problem: By 1992, 97% of nonsmokers and 79% of current smokers agreed that exposure to SHS was harmful to healthy adults.499 Smokers are concerned that their addiction is likely to adversely affect their health. In the United States, more than half of all persons who have ever smoked have quit,245 and most continuing smokers have tried.56 Market responses to consumer concerns have included the filter cigarette, substantial reductions in average tar and nicotine content, and new delivery systems. However, because these innovations were perceived as “safer,” it appears that smokers concerned about health issues switched to such products rather than quit tobacco use entirely119 and derived little or none of the purported health benefit due to compensation (e.g., increased number of cigarettes smoked, increased depth of inhalation, smoking more of the cigarette, vent blocking). It is imperative that tobacco users realize there is no safe way to use tobacco and they need to quit. Tobacco companies spend huge sums to advertise and promote cigarettes ($13.1 billion in 2005).259 Although the effect of this


54

Figure 54-7: Influences on the decision to use tobacco. (Source: Tobacco and Situation Outlook Report, 2004;1986–2000 Surgeon General’s Report.)

Antitobacco Health education Economic policy Minors’ access Product regulation Clean indoor air regulation Social advocacy Personal litigation Advertising restrictions Promotional restrictions Widespread social norms Local community norms Behavioral treatment Pharmacologic treatment

activity on overall cigarette consumption is difficult to assess, advertising and promotion likely make smoking more attractive to youth, make continuing smokers less motivated to attempt cessation, and perhaps increase recidivism by providing omnipresent cues that smoking is fun and relaxing and contributes to conviviality (Fig. 54-7). It also appears that advertising was specifically increased to counteract tobacco prevention and control funding of comprehensive tobacco control programs.333 The inverse correlation between the percentage of a magazine’s health articles that discuss smoking and cigarette advertising revenue as a percentage of the magazine’s total advertising revenue suggests that tobacco money also affects editorial decisions.56 Counteradvertising decreases consumption, reduces initiation, and increases cessation, even in the presence of several-fold greater brand-specific, procigarette advertising.309 Some data also suggest that broad bans on tobacco advertising are also effective in reducing tobacco consumption.500 From 1970 to 2002, the percentage of cigarette advertising expenditures allocated to promotions increased from 15% to 87%.259 Promoted cigarette sales have increased since the MSA and are higher in areas with higher cigarette taxes and areas with more comprehensive tobacco control programs.500a Some of these promotional dollars sponsor sports events associated with being healthy, being fit, and being outdoors. The subliminal message is that smoking contributes to health and fitness. Other tobacco company promotional money goes to exhibitions at leading art museums, promoting the association of smoking with culture, sophistication, and artistic achievement. This support may also buy silence, or active opposition to smoking control proposals. In 1994, arts organizations in New York that had been recipients of tobacco philanthropy spoke out against an ordinance to ban smoking in public places.501,502 Continuing the process of changing the social norms of acceptability of tobacco use offers the greatest promise. Nonsmoking is an accepted norm in many socially defined groups in the United States. Rapid growth of community, state, and federal legislation and administrative actions that limit or ban smoking in places of public assembly, coupled with growing and increasingly stringent public and private employer restrictions on workplace smoking, should further limit smoking opportunities and increase the likelihood of quitting. Public health agencies and preventive medicine practitioners can help accelerate social pressure to not smoke by supporting enactment of strict clean indoor air legislation and its enforcement. Economic incentives are one of the most effective strategies to reduce cigarette consumption, prevent initiation, and increase cessation.309,333 Lower-income Americans, overrepresented among current smokers, are especially sensitive to price increases in tobacco products. Health and public health professionals can support initiatives to raise tobacco taxes.

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A young nonsmoker

A current smoker

A former smoker

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Protobacco Psychosocial factors Peer pressure Industry influence Perceived social norms Advertising Promotion Legislation Regulation Economic policy Education

Since 70% of current smokers want to quit smoking,274 and 42% attempt cessation each year,243 both public and private health organizations should be prepared to assist them. Health care professionals should routinely assess tobacco use and advise users to quit. Use of medication and telephone quitlines should be strongly encouraged. Treatment should be fully covered under both public and private insurance. Prevention programs have demonstrated the ability to delay smoking initiation for students in grades 6–10. However, these programs are only effective when they are reinforced by additional educational interventions and supportive community programs. Such programs could include mass media efforts that make smoking appear unattractive, socially unpopular, and sexually unappealing. Communication should also stress that tobacco is an addictive drug. The fact that tobacco use is associated with increased risk of other drug use179 is a potentially powerful message for parents and youth. With the budget deficits of the early twenty-first century, funding for tobacco control programs in states was slashed. If we are to meet the Healthy People 2010 goal of an adult smoking prevalence of 12% and a youth smoking prevalence of 16%, substantially increased funding for comprehensive tobacco control programs that use proven policy, countermarketing, and community interventions will be required. The enactment of an increase in cigarette taxes in California and Massachusetts, with all or part of the revenues used for tobacco control and education, has led to an accelerated decrease in cigarette consumption.333,378 In addition, two national studies have shown that comprehensive tobacco prevention and control programs reduce cigarette consumption overall and smoking prevalence among youth, over and above the effect of any tax increase that funded the program or occurred concurrently. Comprehensive programs are needed that reduce barriers to and involve the widespread use of known effective strategies. Furthermore, new and innovative strategies, particularly that address tobacco use among youth, are also needed. The decrease in cigarette consumption has been termed one of the greatest public health achievements of the twentieth century, but it is only half achieved.503 The challenge of the twenty-first century is to accelerate progress so that the morbity, mortality, and disability caused by tobacco use no longer occurs either in the United States or internationally.

 ACKNOWLEDGEMENTS

A special thanks to the following individuals who contributed to this book chapter: Caran Wilbanks, T. Taylor, Lynn Hughley and Brian Judd.


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 REFERENCES

1. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Office on Smoking and Health; 2004. 2. Jarvis MJ. Why people smoke. BMJ. 2004;328:277–9. 3. U.S. Department of Health and Human Services. The Health Consequences of Smoking: Nicotine Addiction. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, Office on Smoking and Health; 1988. 4. McGinnis JM, Foege WH. Actual causes of death in the United States. JAMA. 1993;270:2207–12. 5. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238–45. 6. Mokdad AH, Marks JS, Stroup DF, et al. Correction: actual causes of death in the United States, 2000 [letter]. JAMA. 2005; 293:293–4. 7. Doll R, Peto R, Boreham J, et al. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ. 2004; 328:1519. 8. Centers for Disease Control and Prevention. Annual smokingattributable mortality, years of potential life lost, and productivity losses—United States, 1997–2001. MMWR. 2005;54:625–8. 9. Centers for Disease Control and Prevention. Projected smokingrelated deaths among youth—United States. MMWR. 1996;45:971–4. 10. Centers for Disease Control and Prevention. Addition of prevalence of cigarette smoking as a nationally notifiable condition. MMWR. 1996;45:537. 11. Centers for Disease Control and Prevention. Smoking-Attributable Mortality, Morbidity, and Economic Costs (SAMMEC): Adult SAMMEC and Maternal and Child Health [database online]. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2004. Available at: http://www.cdc.gov/ tobacco/sammec. Accessed January 15, 2005. 12. U.S. Department of Health and Human Services. Reducing the Health Consequences of Smoking: 25 years of Progress: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Office on Smoking and Health; 1989. 13. Thun MJ, Day-Lally CA, Calle EE, et al. Excess mortality among cigarette smokers: changes in a 20-year interval. Am J Public Health. 1995;85:1223–30. 14. Centers for Disease Control and Prevention. Cigarette smokingattributable morbidity—United States, 2000. MMWR. 2003;52: 842–4. 15. Nusselder WJ, Looman CWN, Marang-van de Mheen PJ, et al. Smoking and the compression of morbidity. J Epidemiol Community Health. 2000;54:566–74. 16. U.S. Department of Health and Human Services. The Health Benefits of Smoking Cessation: A report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, Office on Smoking and Health; 1990. DHHS Publication (CDC) 90–8416. 17. Sachs DPL. Cigarette smoking. Health effects and cessation strategies. Clin Geriatr Med. 1986;2:337–62. 18. Omenn GS, Anderson KW, Kronmal RA, et al. The temporal pattern of reduction of mortality risk after smoking cessation. Am J Prev Med. 1990;6:251–7. 19. Taylor DH, Hasselblad V, Henley SJ, et al. Benefits of smoking cessation for longevity. Am J Public Health. 2002;92:990–6. 20. Centers for Disease Control and Prevention. Annual smokingattributable mortality, years of potential life lost, and economic costs—United States, 1995–1999. MMWR. 2002;52:300–3.

21. Centers for Disease Control and Prevention. State estimates of neonatal health-care costs associated with maternal smoking United States, 1996. MMWR. 2004;53:915–7. 22. Sloan FA, Ostermann J, Picone G, et al. The Price of Smoking. Cambridge, MA: Massachusetts Institute of Technology, 2004. 23. Hall JR. The smoking material fire problem. Quincy, MA: National Fire Protection Association; 2006. 24. Kochanek KD, Murphy SL, Anderson RN, et al. Deaths: Final data for 2003: National Vital Statistics Report 54 No. 13. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics, 2006:1–120. 25. Doll R, Peto R, Wheatley K, et al. Mortality in relation to smoking: 40 years’ observations on male British doctors. BMJ. 1994;309: 901–11. 26. Doll R, Gray R, Hafner B, et al. Mortality in relation to smoking: 22 years’ observations on female British doctors. Br Med J. 1980;280:967–71. 27. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and time course of decreased risks of coronary heart disease in middleaged women. Arch Intern Med. 1994;154:169–75. 28. Freund KM, Belanger AJ, D’Agostino RB, et al. The health risks of smoking. The Framingham study: 34 years of follow-up. Ann Epidemiol. 1993;3:417–24. 29. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16–22. 30. Rosenberg L, Kaufman DW, Helmrich SP, et al. Myocardial infarction and cigarette smoking in women younger than 50 years of age. JAMA. 1985;253:2965–9. 31. Croft P, Hannaford P. Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners’ oral contraception study [letter]. BMJ. 1989;298:165–8. 32. Thun MJ, Myers DG, Day–Lally CA, et al. Age and the exposure response relationships between cigarette smoking and premature death in Cancer Prevention Study II. In: Burns DM, Garfinkel L, Samet JM, eds. Changes in Cigarette-Related Disease Risks and their Implication for Prevention and Control. Rockville, MD: U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute; 1997. Smoking and Tobacco Control Monograph No. 8. 33. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project. J Chronic Dis. 1978;31:201–306. 34. Watkins LO. Epidemiology and burden of cardiovascular disease. Clin Cardiol. 2004;27(6 Suppl 3):III2–6. 35. Lotufo PA, Gaziano JM, Chae CU, et al. Diabetes and all cause and coronary heart disease mortality among U.S. male physicians. Arch Intern Med. 2001;161:242–7. 36. McBride PE. The health consequences of smoking. Med Clin North Am. 1992;76:333–53. 37. Sidney S, Siscovik DS, Petitti DB, et al. Myocardial infarction and use of low-dose oral contraceptives: a pooled analysis of 2 U.S. studies. Circulation. 1998;8:1058–63. 38. Vessey M, Painter R, Yeates D. Mortality in relation to oral contraceptive use and cigarette smoking. Lancet. 2003;362:185–91. 39. Rosenberg L, Palmer JR, Rao RS, et al. Low-dose oral contraceptive use and the risk of myocardial infarction. Arch Intern Med. 2001;161:1065–70. 40. Doring A, Frohlich M, Lowel H, et al. Third generation oral contraceptive use and cardiovascular risk factors. Atherosclerosis. 2004; 172:281–6. 41. National Cancer Institute. Cigars: Health Effects and Trends. Bethesda, MD: U.S. Department of Health and Human Services,


54

42.

43. 44.

45.

46. 47.

48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

National Institutes of Health, 1998. Smoking and Tobacco Control Monograph No. 9. Iribarren C, Tekawa IS, Sidney S, et al. Effect of cigar smoking on the risk of cardiovascular disease, chronic obstructive pulmonary disease, and cancer in men. N Engl J Med. 1999;340:1773–80. Nyboe J, Jensen G, Appleyard M, et al. Smoking and the risk of first acute myocardial infarction. Am Heart J. 1991;122:438–47. Carstensen JM, Pershagen G, Eklund G. Mortality in relation to cigarette and pipe smoking: 16 years’ observation of 25,000 Swedish men. J Epidemiol Community Health. 1987;41:166–72. Shaper AG, Wannamethee SG, Walker M. Pipe and cigar smoking and major cardiovascular events, cancer incidence and all cause mortality in middle-aged British men. Int J Epidemiol. 2003;32: 802–8. Castleden CM, Cole PV. Inhalation of tobacco smoke by pipe and cigar smokers. Lancet. 1973;2(7819):21–2. Wald NJ, Watt HC. Prospective study of effect of switching from cigarettes to pipes or cigars on mortality from three smoking related disease. BMJ. 1997;314:1860–63. Gupta R, Gurm H, Bartholomew JR. Smokeless tobacco and cardiovascular risk. Arch Intern Med. 2004;164:1845–49. Bolinder GM, Ahlborg BO, Lindell JH. Use of smokeless tobacco: blood pressure elevation and other health hazards found in a largescale population survey. J Intern Med. 1992;232:327–34. Bolinder G, Alfredsson L, Englund A, et al. Smokeless tobacco use and increased cardiovascular mortality among Swedish construction workers. Am J Public Health. 1994;84:399–404. Henley SJ, Thun MJ, Connell C, et al. Two large prospective studies of mortality among men who use snuff or chewing tobacco (United States). Cancer Causes Control. 2005;16:347–58. Critchley JA, Unal B. Is smokeless tobacco a risk factor for coronary heart disease? A systematic review of epidemiological studies. Eur J Cardiovasc Prev Rehab. 2004;11:101–12. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation in relation to total mortality rates in women: a prospective cohort study. Ann Intern Med. 1993;119:992–1000. Goldenberg I, Jonas M, Tenenbaum A, et al. Current smoking, smoking cessation, and the risk of sudden cardiac death in patients with coronary artery disease. Arch Intern Med. 2003;163:2301–5. Stokes J, Kannel WB, Wolf PA, et al. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation. 1987;75[6 Pt 2]: V65–73. U.S. Department of Health and Human Services. Women and Smoking: A Report of the Surgeon General. Rockville, MD: U.S. Public Health Service, Office of the Surgeon General; 2001. Tomatis LA, Fierens EE, Verbrugge GP. Evaluation of surgical risk in peripheral vascular disease by coronary arteriography: A series of 100 cases. Surgery. 1972;71:429–35. Zheng ZJ, Sharrett AR, Chambless LE, et al. Associations of anklebrachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. 1997;131:115–25. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381–6. Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study Group. Arteriolscler Thromb Vasc Biol. 1999;19:538–45. U.S. Public Health Service. The Health Consequences of Smoking: Cardiovascular Disease: A Report of the Surgeon General. Washington, DC: Public Health Service, Office on Smoking and Health; 1983. DHHS Publication (PHS) 84-50204.

Tobacco: Health Effects and Control

987

62. Howard G, Wagenknecht LE, Burke GL, et al. Cigarette smoking and the progression of atherosclerosis. JAMA. 1998;279:119–24. 63. Levey LA. Smoking and peripheral vascular disease. Clin Podiatr Med Surg. 1992;9:165–71. 64. Auerbach O, Garfinkel L. Atherosclerosis and aneurysm of aorta in relation to smoking habits and age. Chest. 1980;78:805–9. 65. Lee AJ, Fowkes FG, Carson MN, et al. Smoking, atherosclerosis and risk of abdominal aortic aneurysm. Eur Heart J. 1997;18:671–76. 66. American Heart Association. Heart disease and stroke statistics— 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:69–171. 67. Robbins AS, Manson JE, Lee IM, et al. Cigarette smoking and stroke in a cohort of U.S. male physicians. Ann Intern Med. 1994;120: 458–62. 68. Shaper AG, Phillips AN, Pocock SJ, et al. Risk factors for stroke in middle aged British men. BMJ. 1991;302:1111–5. 69. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. BMJ. 1989;298:789–94. 70. Haheim LL, Holme I, Jermann IH, et al. Smoking habits and risk of fatal stroke: 18 years follow up of the Oslo study. J Epidemiol Community Health. 1996;50:621–4. 71. Wannamethee SG, Shaper AG, Whincup PH, et al. Smoking cessation and the risk of stroke in middle-aged men. JAMA. 1995;274:155–60. 72. Kannel WB. New perspectives on cardiovascular risk factors. Am Heart J. 1987;114(1 pt 2):213–9. 73. Bronner LL, Kanter DS, Manson JE. Primary prevention of stroke. N Engl J Med. 1995;333:1392–1400. 74. Petitti DB, Sidney S, Bernstein A, et al. Stroke in users of low-dose oral contraceptives. N Engl J Med. 1996;335:8–15. 75. Allen DR, Browse NL, Rutt DL, et al. The effect of cigarette smoke, nicotine, and carbon monoxide on the permeability of the arterial wall. J Epidemiol Community Health. 1988;39:286–93. 76. Celermajer DS, Sorensen, KE, Georgakopoulos, et al. Cigarette smoking is associated with dose-related and potentially reversible impariment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88(5 pt 1):2149–55. 77. Fusegawa Y, Goto S, Handa S, et al. Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. Thrombosis Research. 1999;93:271–8. 78. Spagnoli LG, Mauriello A, Palmieri G, et al. Relationships between risk factors and morphological patterns of human carotid atherosclerotic plaques: a multivariate discriminate analysis. Atherosclerosis. 1994;108:39–60. 79. Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombenicity of human atherosclerotic plaques. Circulation. 1997;95:594–9. 80. Burke AP, Farb A, Malcom GT, et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;36:1276–82. 81. Friedman GD, Siegelaub AB, Seltzer CC, et al. Smoking habits and the leukocyte count. Arch Environ Health. 1973;26:137–43. 82. Kuller LH, Tracy RP, Shaten J, et al. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1996;144:537–47. 83. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–9. 84. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001;103:1813–8. 85. Di Napoli M, Papa F, Bocola V. C-reactive protein in ischemic stroke: an independent prognostic factor. Stroke. 2001;32:917–24.


988

Behavioral Factors Affecting Health

86. Craig WY, Palomaki GE, Haddow JE. Cigarette smoking and serum lipid and lipoprotein concentrations: an analysis of published data. BMJ. 1989;298:784–8. 87. Krupski WC. The peripheral vascular consequences of smoking. Ann Vasc Surg. 1991;5:291–304. 88. Fortmann SP, Haskell WL, Williams PT. Changes in plasma high density lipoprotein cholesterol after changes in cigarette use. Am J Epidemiol. 1986;124:706–10. 89. Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholestersol. Modifactions of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320:915–24. 90. Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997;29:1422–31. 91. Cruickshank JM, Neil-Dwyer G, Dorrance DE, et al. Acute effects of smoking on blood pressure and cerebral blood flow. J Hum Hypertens. 1989;3:443–9. 92. Yamashita K, Kobayashi S, Yamaguchi S, et al. Effect of smoking on regional cerebral flow in the normal aged volunteers. Gerontology. 1988;34:199–204. 93. Rogers RL, Meyer JS, Shaw TG, et al. Cigarette smoking decreases cerebral blood flow suggesting increased risk for stroke. JAMA. 1983;250:2796–800. 94. American Cancer Society. Cancer Facts and Figures, 2007. Atlanta, GA: American Cancer Society; 2007:1–52. 95. Vincent RG, Pickren JW, Lane WW, et al. The changing histopathology of lung cancer: a review of 1682 cases. Cancer. 1977;39:1647–55. 96. Churg A. Lung cancer cell type and occupational exposure. In: Samet JM, ed. Epidemiology of Lung Cancer. New York, NY: Marcel Dekker; 1994:413–36. 97. Travis WD, Travis LB, Devesa SS. Lung Cancer. Cancer. 1995;75(1 Suppl):191–202. 98. Wingo PA, Reis LA, Giovino GA, et al. Annual report to the nation on the status of cancer, 1973–1996. With a special section on lung cancer and tobacco smoking. J Natl Cancer Inst. 1999;91:675–90. 99. Hoffmann D, Hoffmann I. The changing cigarette. 1950–1995. J Toxicol Environ Health. 1997;50:307–64. 100. Wynder EL, Muscat JE. The changing epidemiology of smoking and lung cancer histology. Environ Health Perspect. 1995;103(Suppl 8): 143–8. 101. National Cancer Institute. The FTC Cigarette Test Method for Determining Tar, Nicotine, and Carbon Monoxide Yields of U.S. Cigarettes. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health; 1996. Smoking and Tobacco Control Monograph 7. NIH Publication 96-4028. 102. Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194–210. 103. Levi F, Franceschi S, La Vecchia C, et al. Lung carcinoma trends by histologic type in Vaud and Neuchatel, Switzerland, 1974–1994. Cancer. 1997;79:906–14. 104. Thun MJ, Lally CA, Flannery JT, et al. Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst. 1997;89:1580–6. 105. Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1975–2001. Bethesda, MD: National Cancer Institute; 2004. 106. American Cancer Society. Cancer Facts & Figures, 2005. Atlanta, GA: 2005:1–61. 107. U.S. Department of Health, Education, and Welfare. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, DC: Public Health Service; 1964. PHS Publication 1103. 108. Ochsner A. My first recognition of the relationship of smoking and lung cancer. Prev Med. 1973;2:611–4.

109. Wynder EL, Mushinski MH, Spivak JC. Tobacco and alcohol consumption in relation to the development of multiple primary cancers. Cancer. 1977;40:1872–8. 110. Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors. Br Med J. 1956;2:1071–81. 111. Lange P, Groth S, Nyboe J, et al. Decline of the lung function related to the type of tobacco smoked and inhalation. Thorax. 1990;45, 22–6. 112. Doll R, Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong nonsmokers. J Epidemiol Community Health. 1978;32:303–13. 113. Hammond EC. Smoking in relation to the death rates of one million men and women. In: National Cancer Institute. Epidemiological Approaches to the Study of Cancer and Other Chronic Disease. Washington, DC: National Cancer Institute; 1966. National Cancer Institute monograph, 19. 114. International Agency for Research on Cancer. Tobacco Smoke and Involuntary Smoking. Lyon, France: International Agency for Research on Cancer; 2004. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 83. 115. Samet JM. The changing cigarette and disease risk: current status of the evidence. In: The FTC Cigarette Method for Determining Tar, Nicotine and Carbon Monoxide Yields of U.S. Cigarettes: Report of the NCI Expert Committee. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service; 1996. 116. Hammond EC. The long term benefits of reducing tar and nicotine in cigarettes. In: Gori GB, Bock FG, eds. A Safe Cigarette? Banbury Report 3, Proceedings of a Meeting Held at the Banbury Center, Cold Springs Harbor Laboratory, NY, October 14–16, 1979. New York, NY: Cold Spring Harbor Laboratory; 1980:13–8. 117. Tang JL, Morris JK, Wald NJ, et al. Mortality in relation to tar yield of cigarettes: a prospective study of four cohorts. BMJ. 1995;311: 1530–3. 118. Kaufman DW, Palmer JR, Rosenberg L, et al. Tar content of cigarettes in relation to lung cancer. Am J Epidemiol. 1989;129:703–11. 119. National Cancer Institute. Risks Associated with Smoking Cigarettes with Low-Machine Measured Yields of Tar and Nicotine. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health; 2001. Smoking and Tobacco Control Monograph 13. NIH Publication 02-5074. 120. National Cancer Institute; Changes in Cigarette-Related Disease Risk and Their Implications for Prevention and Control. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health; 1997. Smoking and Tobacco Control Monograph 8. NIH Publication 97-4213. 121. Chow WH, Schuman LM, McLaughlin JK, et al. A cohort study of tobacco use, diet, occupation and lung cancer mortality. Cancer Causes Control. 1992;3:247–54. 122. Doll R, Peto R. Mortality in relation to smoking: 20 years’ observations on male British doctors. Br Med J. 1976;2:1525–36. 123. Shapiro JA, Jacobs EJ, Thun MJ. Cigar smoking in men and risk of death from tobacco-related cancers. J Natl Cancer Inst. 2000;92:333–7. 124. Nelson DE, Davis RM, Chrismon JH, et al. Pipe smoking in the United States, 1965–1991: prevalence and attributable mortality. Prev Med. 1996;25:91–9. 125. Boffetta P, Pershagen G, Jockel KH, et al. Cigar and pipe smoking and lung cancer risk: A multicenter study from Europe. J Natl Cancer Inst. 1999;91:697–701. 126. Lange P, Nyboe J, Appleyard M, et al. Relationship of the type of tobacco and inhalation pattern to pulmonary and total mortality. Eur Respir J. 1992;5:1111–7. 127. Armitage P, Doll R. The age distribution of cancer and a multistage theory of carcinogenesis. Brit J Cancer. 1954;8:1–12.


54 128. Denissenko MF, Chen JX, Tang MS, et al. Cysotine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA. 1997;94:3893–8. 129. Denissenko MF, Pao A, Moon-shong T, et al. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996;274:430–2. 130. Kashiwabara K, Oyama T, Sano T, et al. Correlation between methylation status of the p16/CDKN2 gene and the expression of p16 and Rb proteins in primary non-small cell lung cancers. Int J Cancer. 1998;79:215–20. 131. Franceschi S, Barra S, La Vecchia C, et al. Risk factors for cancer of the tongue and the mouth. a case-control study from northern Italy. Cancer. 1992;70:2227–33. 132. McLaughlin JK, Hrubec Z, Blot WJ, et al. Smoking and cancer mortality among U.S. veterans: a 26-year follow-up. Int J Cancer. 1995;60:190–3. 133. International Agency for Research on Cancer. Smokeless Tobacco and Some Related Nitrosamines. Lyon, France: 2005. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 89. 134. Council on Scientific Affairs. Health effects of smokeless tobacco. JAMA. 1986;255:1038–44. 135. U.S. Department of Health and Human Services. The Health Consequences of Using Smokeless Tobacco. A Report of the Surgeon General. Bethesda, MD: Public Health Service; 1986. DHHS Publication 86-2874. 136. International Agency for Research on Cancer. Cancer Monodial. Available at http://www-dep.iarc.fr. Accessed August 11, 2005. 137. Winn DM. Tobacco use and oral diseae. J Dental Educ. 2001;65: 306–12. 138. Schlecht NF, Franco EL, Pintos J, et al. Effect of smoking cessation and tobacco type on the risk of cancers of the upper aerodigestive tract in Brazil. Epidemiol. 1999;10:412–8. 139. Boffetta P, Aagnes B, Weiderpass E, et al. Smokeless tobacco use and risk of cancer of the pancreas and other organs. Int J Cancer. 2005;114:992–5. 140. Califano J, van der Reit P, Westra W, et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Research. 1996;56:2488–92. 141. U.S. Department of Health and Human Services. 9th Report on Carcinogens. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program; 2000. 142. Kuratsune M, Kohchi S, Horie A. Carcinogenesis in the esophagus. I. Penetration of benzo[a]pyrene and other hydrocarbons into the esophageal mucosa. Gann. 1965;56:177–87. 143. Brennan JA, Boyle JO, Koch WM, et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med. 1995;332:712–7. 144. La Vecchia C, Franceschi S, Bosetti, F, et al. Time since stopping smoking and the risk of oral and pharyngeal cancers [letter]. J Natl Cancer Inst. 1999;91:726–8. 145. Gammon MD, Schoenberg JB, Ashan H, et al. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst. 1997;89:1277–84. 146. Lagergren J, Bergstrom R, Lindgren A, et al. The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int J Cancer. 2000;85:340–6. 147. Kabat GC, Ng SKC, Wynder EL. Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia. Cancer Causes Control. 1993;4:123–32. 148. Silverman DT, Morrison AS, Devesa SS. Bladder cancer. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer Epidemiology and Prevention. New York, NY: Oxford University Press; 1996: 1156–79.

Tobacco: Health Effects and Control

989

149. McLaughlin JK, Blot WJ, Devesa SS, et al. Renal cancer. In: Schottenfeld D, Fraumeni JF Jr, eds. Cancer Epidemiology and Prevention. New York, NY: Oxford University Press; 1996:1142–55. 150. Yamasaki E, Ames BN. Concentration of mutagens from urine by absorption with the nonpolar resin XAD–2: cigarette smokers have mutagenic urine. Proc Natl Acad Sci USA. 1977;74:3555–9. 151. Shiao YH, Rice JM, Anderson LM. von Hippel Lindau gene mutations in N-nitrosodimethylamine-induced rat renal epithelial tumors. J Natl Cancer Inst. 1998;90:1720–3. 152. Public Health Service, Office on Smoking and Health. The Health Consequences of Smoking: Cancer. A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services; 1982. DHHS Publication (PHS) 82-50179. 153. Muscat JE, Stellman SD, Hoffmann D, et al. Smoking and pancreatic cancer in men and women. Cancer Epidemiol Biomarkers Prevention. 1997;6:15–9. 154. Alguacil J, Silverman DT. Smokeless and other noncigarette tobacco use and pancreatic cancer: a case-control study based on direct interviews. Cancer Epidemiol Biomarkers Prevention. 2004; 13:55–8. 155. Gajalakshmi CK, Shanta V. Lifestyle and risk of stomach cancer: a hospital-based case control study. Int J Epidemiol. 1996;25:1146–53. 156. Chao A, Thun MJ, Henley J, et al. Cigarette smoking, use of other tobacco products and stomach cancer mortality in U.S. adults: The Cancer Prevention Study II. Int J Cancer. 2002;101:380–9. 157. Stryker WS, Kaplan LA, Stein EA, et al. The relationship of diet, cigarette smoking, and alcohol consumption to plasma betacarotene and alpha-tocopherol levels. Am J Epidemiol. 1988; 127:283–96. 158. Bosch FX, Manos MM, Munoz N, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst. 1995;87:796–802. 159. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9. 160. Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA. 2001;285:2995– 3002. 161. Castle PE, Wacholder S, Lorincz AT, et al. A prospective study of high-grade cervical neoplasia risk among human papillomavirusinfected women. J Natl Cancer Inst. 2002;94:1406–14. 162. McCann MF, Irwin DE, Walton LA, et al. Nicotine and cotinine in the cervical mucus of smokers, passive smokers, and nonsmokers. Cancer Epidemiol Biomarkers Prevention. 1992;1:125–9. 163. Prokopczyk B, Cox JE, Hoffmann D, et al. Identification of tobacco-specific carcinogen in the cervical mucus of smokers and nonsmokers. J Natl Cancer Inst. 1997;89:868–73. 164. Holly EA, Petrakis NL, Friend NF, et al. Mutagenic mucus in the cervix of smokers. J Natl Cancer Inst. 1986;76:983–6. 165. Phillips DH, She MN. DNA adducts in cervical tissue of smokers and non-smokers. Mutation Res. 1994;313:277–84. 166. Siegel M. Smoking and leukemia: evaluation of a causal hypothesis. Am J Epidemiol. 1993;138:1–9. 167. Brownson RC, Novotny TE, Perry MC. Cigarette smoking and adult leukemia. A meta-analysis. Arch Intern Medicine. 1993;153: 469–75. 168. Wallace L. Environmental exposure to benzene: an update. Environ Health Perspectives. 1996;104(Suppl 6):1129–36. 169. Winn DM. Epidemiology of cancer and other systemic effects associated with the use of smokeless tobacco. Adv Dent Res. 1997;11: 313–21. 170. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971–2000. MMWR. 2002;51(SS–6):1–16.


990

Behavioral Factors Affecting Health

171. Troisi RT, Speizer FE, Rosner B, et al. Cigarette smoking and incidence of chronic bronchitis and asthma in women. Chest. 1995;108:1557–61. 172. Dean G, Lee PN, Todd GF, et al. Report on a second retrospective mortality study in North-east England. Part i. Factors related to mortality from lung cancer, bronchitis, heart disease and stroke in Cleveland County, with a particular emphasis on the relative risks associated with smoking filter and plain cigarettes. Research Paper 14. London, England: Tobacco Research Council; 1977. 173. Beck GJ, Doyle CA, Schachter EN. Smoking and lung function. Am Rev Respir Dis. 1981;123:149–55. 174. Walter S, Jeyaseelan L. Impact of cigarette smoking on pulmonary function in non-allergic subjects. Natl Med J India. 1992;5:211–3. 175. U.S. Department of Health and Human Services. The Health Consequences of Smoking: Chronic Obstructive Lung Disease. Washington, DC: Public Health Service, Office on Smoking and Health; 1984. 176. Brown CA, Woodward M, Tunstall-Pedoe H. Prevalence of chronic cough and phlegm among male cigar and pipe smokers. Results of the Scottish Heart Health Study. Thorax. 1993;48: 1163–7. 177. Higgins MW, Enright PL, Kronmal RA, et al. Smoking and lung function in elderly men and women. The Cardiovascular Health Study. JAMA. 1993;269:2741–8. 178. Rogot E, Murray JL. Smoking and causes of death among U.S. veterans: 16 years of observation. Public Health Rep. 1980;95:213–22. 179. U.S. Department of Health and Human Services. Preventing Tobacco Use among Young People: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, Office on Smoking and Health; 1994. 180. Kahrilas PJ. Cigarette smoking and gastroesophageal reflux disease. Dig Dis. 1992;10:61–71. 181. Kuipers EJ, Thijs JC, Festen HP. The prevalence of Helicobacter pylori in peptic ulcer disease. Aliment Pharmacol Ther. 1995;9(Suppl 2):59–69. 182. Borody TJ, George LL, Brandl S, et al. Helicobacter pylorinegative duodenal ulcer. Am J Gastroenterology. 1991;86:1154–7. 183. Borody TJ, Brandl S, Andrews P, et al. Helicobacter pylorinegative gastric ulcer. Am J Gastroenterol. 1992;87:1403–6. 184. Eastwood GL. Is smoking still important in the pathogenesis of peptic ulcer disease? J Clin Gastroenterol. 1997;25(Suppl 1):S1–7. 185. Tytgat GN, Noach LA, Rauws EA. Helicobacter pylori infection and duodenal ulcer disease. Gastroenterol Clin North Am. 1993;22: 127–39. 186. Mandel I. Smoke signals: an alert for oral disease. J Am Dental Assoc. 1994;125:872–8. 187. Akef J, Weine FS, Weissman DP. The role of smoking in the progression of periodontal disease: a literature review. Compend Contin Educ Dent. 1992;13:526–31. 188. Tomar SL, Asma S. Smoking-attributable periodontitis in the United States: findings from NHANES III. J Periodontol. 2000;71: 743–51. 189. Fox CH. New considerations in the prevalence of periodontal disease. Curr Opin Dent. 1992;2:5–11. 190. Albandar JM, Streckfus CF, Adesanya MR, et al. Cigar, pipe, and cigarette smoking as risk factors for periodontal disease and tooth loss. J Periodontol. 2000;71:1874–81. 191. Krall EA, Garvey AJ, Garcia RI. Alveolar bone loss and tooth loss in male cigar and pipe smokers. J Am Dent Assoc. 1999;130:57–64. 192. Johnson GK, Slach NA. Impact of tobacco use on periodontal status. J Dent Educ. 2001;65:313–21. 193. Tomar SL, Winn DM. Chewing tobacco use and dental caries among U.S. men. J Am Dent Assoc. 1999;130:1601–10.

194. National Cancer Institute. Tobacco effects in the mouth: a National Cancer Institute and National Institute of Dental Research Guide for Health Professionals. Bethesda, MD: National Institutes of Health; 1993. NIH Publication 93-3330. 195. National Cancer Institute, Smokeless Tobacco or Health: an International Perspective. Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health; 1992: Smoking and Tobacco Control Monograph 2. NIH Publication 92-3461. 196. Christen AG, Swanson BZ, Glover ED, et al. Smokeless tobacco: the folklore and social history of snuffing, sneezing, dipping, and chewing. J Am Dent Assoc. 1982;105:821–9. 197. NIH Consensus Development Panel. National Institutes of Health consensus statement: health implications of smokeless tobacco use. Biomed Pharmacother. 1988;42:93–8. 198. Riley JL, Tomar SL, Gilbert GH. Smoking and smokeless tobacco: Increased risk for oral pain. J Pain. 2004;5:218–25. 199. Greer RO, Poulson TC. Oral tissue alterations associated with the use of smokeless tobacco by teenagers. Oral Surg Oral Med Oral Pathol. 1983;56:275–84. 200. Whalley LJ, Fox HC, Deary IJ, et al. Childhood IQ, smoking, and cognitive change from age 11 to 64 years. Addict Behav. 2005;30: 77–88. 201. Substance Abuse and Mental Health Services Administration. Results from the 2003 National Survey on Drug Use and Health: National Findings. Rockville, MD: Office of Applied Studies; 2004. NSDUH Series H-25, DHHS Publication SMA 04-3964. Available at www.oas.samhsa.gov/nhsda/2k3tabs/Sect7peTabs1to57.htm. Accessed August, 5, 2005. 202. Wingerd J, Christianson R, Lovitt WV, et al. Placental ratio in white and black women: relation to smoking and anemia. Am J Obstet Gynecol. 1976;124:671–5. 203. Gupta PC, Ray CS. Smokeless tobacco and health in India and South Asia. Respirology. 2003;8:419–31. 204. England LJ, Levine RJ, Mills JL, et al. Adverse pregnancy outcomes in snuff users. Am J Obstet Gynecol. 2003;189:939–43. 205. Kleinman JC, Pierre MB Jr, Madans JH, et al. The effects of maternal smoking on fetal and infant mortality. Am J Epidemiol. 1988;127:274–82. 206. Salihu HM, Aliyu MH, Pierre-Louis BJ, et al. Levels of excess infant deaths attributable to maternal smoking during pregnancy in the United States. Matern Child Health J. 2003;7:219–27. 207. Werler MM. Teratogen update: smoking and reproductive outcomes. Teratology. 1997;55:382–8. 208. Slotkin TA, Lappi SE, McCook EC, et al. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syndrome. Brain Res Bull. 1995;38:69–75. 209. Windham GC, Elkin EP, Swan SH, et al. Cigarette smoking and effects on menstrual function. Obstet Gynecol. 1999;93:59–65. 210. Arday DR, Giovino GA, Schulman J, et al. Cigarette smoking and self-reported health problems among U.S. high school seniors, 1982–1989. Am J Health Promotion. 1995;10:111–6. 211. Centers for Disease Control and Prevention. Reasons for tobacco use and symptoms of nicotine withdrawal among adolescent and young adult tobacco users—United States, 1993. MMWR. 1994;43:45–50. 212. Centers for Disease Control and Prevention. Symptoms of substance dependence associated with use of cigarettes, alcohol, and illicit drugs—United States, 1991–1992. MMWR. 1995;44:830–1, 837–9. 213. DiFranza JD, Rigotti NA, McNeill AD, et al. Initial symptoms of nicotine dependence in adolescents. Tob Control. 2000;9:313–9. 213a. U.S. Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke. A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health


54

213b. 213c.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

and Human Services, Centers for Disease Control and Prevention, Office on Smoking and Health; 2006. Behan DF, Eriksen MP, Lin Y. Economic Effects of Environmental Tobacco Smoke. Schaumburg, IL: Society of Actuaries; 2005. California Air Resources Board, California Environmental Protection Agency. Final regulation order: Identification of environmental tobacco smoke as a toxic air contaminant. Available at http://www.arb.ca.gov/regact/ets2006/etsfro.pdf. Accessed April 4, 2007. U.S. Environmental Protection Agency. Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. The Report of the U.S. Environmental Protection Agency. Bethesda, MD: National Institutes of Health; Office of Research and Development, Office of Air and Radiation; 1993. NIH Publication 98–3605. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency. Proposed identification of environmental tobacco smoke as a toxic air contaminant. 2005. Available at http://www.oehha.ca.gov/air/environmental_tobacco/ 2005 etsfinal.html. Accessed April 4, 2007. Available at http:// repositories.cdlib.org/ context/tc/article/1194/type/pdf/viewcontent/. Accessed April 27. 2007. Repace J. Respirable particles and carcinogens in the air of Delaware hospitality venues before and after a smoking ban. J Occup Environ Med. 2004;46:887–905. Whincup PH, Gilg JA, Emberson JR, et al. Passive smoking and risk of coronary heart disease and stroke: prospective study with cotinine measurement. BMJ. 2004:329:200–5. Pirkle JL, Flegal KM, Bernert JT, et al. Exposure of the U.S. population to environmental tobacco smoke. JAMA. 1996;275:1233–40. Centers for Disease Control and Prevention. State-specific prevalence of cigarette-smoking adults, and children’s and adolescents’ exposure to environmental tobacco smoke—United States, 1996. MMWR. 1997;46:1038-43. American Legacy Foundation. Second Hand Smoke: Youth Exposure and Adult Attitudes. Washington, DC: American Legacy Foundation, 2005. First Look Report 14. Available at http://www. americanlegacy.org/americanlegacy/skins/alf/display.aspx?Action=d isplay_page&mode=User&ModuleID=8cde2e88-3052-448c-893dd0b4b14b31c4&ObjectID=67f143bf-4dac-400e-a0055f3577160f69. Accessed August 5, 2005. Greenberg RA, Haley NJ, Etzel RA, et al. Measuring the exposure of infants to tobacco smoke: nicotine and cotinine in urine and saliva. N Engl J Med. 1984;310:1075-8. National Research Council, Committee on Passive Smoking. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washington, DC: National Academy Press; 1986. U.S. Department of Health and Human Services. The Health Consequences of Involuntary Smoking. A Report of the Surgeon General. Rockville, MD: Centers for Disease Control and Prevention, Office on Smoking and Health; 1986. DHHS Publication (CDC) 87-8398. California Environmental Protection Agency. Health Effect of Exposure to Environmental Tobacco Smoke. Sacramento, CA: Office of Environmental Health Hazard Assessment; 1997. Yolton K, Dietrich K, Auinger P, et al. Exposure to environmental tobacco smoke and cognitive abilites among U.S. children and adolescents. Environ Health Perspect. 2005;113:98–103. Mannino DM, Siegel M, Husten C, et al. Environmental tobacco smoke exposure and health effects in children: results from the 1991 National Health Interview Survey. Tob Control. 1986;5:13–8. Gilliland FD, Berhane K, Islam T, et al. Environmental tobacco smoke and absenteeism related to respiratory illness in school children. Am J Epidemiol. 2003;157:861–9.

Tobacco: Health Effects and Control

991

228. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA. 1995;273:795–8. 229. Schoendorf KC, Kiely JL. Relationship of sudden infant death syndrome to maternal smoking during and after pregnancy. Pediatrics. 1992;90:905–8. 230. Blair PS, Fleming PJ, Bensley D, et al. Smoking and the sudden infant death syndrome: results from 1993–1995 case-control study for confidential inquiry into stillbirths and deaths in infancy. BMJ. 1996;313:195–8. 231. U.S. Environmental Protection Agency. Environmental Cancer and Heart and Lung Disease: Annual Report to Congress (8th). Rockville, MD: Task Force on Environmental Cancer and Heart and Lung Disease; 1985. 232. Mannino DM, Siegel M, Rose D, et al. Environmental tobacco smoke exposure in the home and worksite and health effects in adults: results from the 1991 National Health Interview Survey. Tob Control. 1997;6:296–305. 233. Blanc PD, Ellbjar S, Janson C, et al. Asthma related work disability in Sweden. The impact of workplace exposures. Am J Respir Crit Care Med. 1999;160:2028–33. 234. Enstrom JE, Kabat GC. Environmental tobacco smoke and tobacco related mortality in a prospective study of Californians, 1960–1998. BMJ. 2003;326:1057. 235. Steenland K, Thun M, Lally C, et al. Environmental tobacco smoke and coronary heart disease in the American Cancer Society CPS-II cohort. Circulation. 1996;94:622–8. 236. Glantz SA, Parmeley WW. Passive smoking and heart disease: mechanisms and risk. JAMA. 1995;273:1047–53. 237. He J, Vupputuri S, Allen K, et al. Passive smoking and the risk of coronary heart disease: a meta-analysis of epidemiologic studies. N Engl J Med. 1999;340:920–6. 238. Sargent RP, Shepard RM, Glantz SL. Reduced incidence of admissions for myocardial infarction associated with public smoking ban: before and after study. BMJ. 2004;328:977–80. 238a. Bartecchi, C, Alsever, RN, Nevin-Woods, C, et al. Reduction in the incidence of acute myocardial infarction associated with a citywide smoking ordiance. Circulation. 2006;114:1490–96. 238b. Barone-Adesi, F, Vizzini, L, Merletti, F, et al. short-term effects of Italian smoking regulation on rates of hospital admission for acute myocardial infarction. Eur Heart J. 2006; 20:2468–3472. 239. Capehart T. Tobacco Outlook. Washington, DC: U.S. Department of Agriculture; 2006. Publication TBS–261. 240. Capehart T. Tobacco Situation and Outlook Yearbook. Washington, DC: U.S Department of Agriculture; 2006. Publication TBS2006. 241. Giovino GA, Schooley MW, Zhu BP, et al. Surveillance for selected tobacco-use behaviors—United States, 1900–1994. MMWR. 1994:43(SS–3):1–43. 242. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 1995. MMWR. 1997;46:1217–20. 243. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2005. MMWR. 2006;55:1145–48. 244. Schiller JS, Coriaty Nelson Z, Hao C, et al. Early Release of Selected Estimates Based on Data from the January–September 2006 National Health Interview Survey. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; 2007. Available at http://www.cdc.gov/nchs/data/nhis/earlyrelease/ 200703_08.pdf. Accessed April 15, 2007. 245. Centers for Disease Control and Prevention. Cigarette Smoking Among Adults—United States, 2002. MMWR. 2004;53:427–31. 246. Centers for Disease Control and Prevention. State-specific prevalence of current cigarette smoking among adults—United States, 2005. MMWR. 2006;55:1148–51.


992

Behavioral Factors Affecting Health

247. National Center for Health Statistics, National Health Interview Survey, public use data tapes, 2005. 248. Husten CG, Chrismon JH, Reddi MN. Trends and effects of cigarette smoking among girls and women in the United States, 1965–1993. J Am Med Womens Assoc. 1996;51:11–8. 249. Centers for Disease Control and Prevention. Smoking cessation during previous year among adults—United States, 1990 and 1991. MMWR. 1993;42:504–7. 250. Jarvis MJ. Gender differences in smoking cessation: real or myth. Tob Control. 1994;3:324–8. 251. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2001. MMWR. 2003;52:953–6. 252. Zhu BP, Giovino GA, Mowery PD, et al. The relationship between cigarette smoking and education revisited: implications for categorizing persons’ educational status. Am J Public Health. 1996;86: 1582–9. 253. U.S. Department of Health and Human Services. Tobacco Use among U.S. Racial/Ethnic Minority Groups: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, Office on Smoking and Health; 1998. DHHS Publication (CDC) 87–8398. 254. Nelson DE, Emont SL, Brackbill RM, et al. Cigarette smoking prevalence by occupation in the United States: a comparison between 1978 to 1980 and 1987 to 1990. J Occup Med. 1994;36: 516–25. 255. Novotny TE, Warner KE, Kendrick JS, et al. Smoking by blacks and whites: socioeconomic and demographic differences. Am J Public Health. 1989;78:1187–9. 256. Johnston LD, O'Malley PM, Bachman JG, et al. (December 21, 2006). Decline in daily smoking by younger teens has ended. University of Michigan News and Information Services: Ann Arbor, MI. [On-line]. Available: www.monitoringthefuture.org; accessed 04/15/2007. 257. Centers for Disease Control and Prevention. Cigarette use among high school students—United States, 1991–2003. MMWR. 2004;53: 499–502. 258. University of Michigan, Monitoring the Future Survey, public use data tapes, 1996–2006. 259. Federal Trade Commission. Federal Trade Commission Cigarette Report for 2004 and 2005. Washington, DC: 2007. 260. Centers for Disease Control and Prevention. Filter ventilation levels in selected U.S. cigarettes, 1997. MMWR. 1997;46: 1043–7. 261. Orleans CT, Slade J, eds. Nicotine Addiction: Principles and Management. New York, NY: Oxford University Press; 1993. 262. Lynch CJ, Benowitz NL. Spontaneous cigarette brand switching: consequences for nicotine and carbon monoxide exposure. Am J Public Health. 1978;78:1191–4. 263. Institute of Medicine. Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction. Washington, DC: National Academy Press; 2001. 264. Tobacco Advisory Group of the Royal College of Physicians. Nicotine Addiction in Britain. London, England: Royal College of Physicians of London; 2000. 265. Campaign for Tobacco Free Kids. New tobacco products—lower risk or more of the same? Available at http://www.tobaccofreekids. org/research/factsheets/pdf/0164.pdf. Accessed August 5, 2005. 266. Morgan JP. The path to a safer cigarette. Potentially Reduced Exposure Products (PREPs). Global Equity Research; 2004. 266a. Rodu B, Godshall WT. Tobacco harm reduction: an alternative to cessation strategy for inveterate smokers. Harm Reduction Journal. 2006:3:37–59. 266b. Henley SJ, Connell CJ, Richter P, et al. Tobacco-related disease mortality among men who switched from cigarettes to spit tobacco. Tobacco Control. 2007;16:22–28.

267. Godtfredsen N, Holst C, Prescott E, et al. Smoking reduction, smoking cessation, and mortality: a 16-year follow-up of 19,732 men and women from the Copenhagen Centre for Prospective Population Studies. Am J Epidemiol. 2002;156:994–1001. 267a. Tverdal, A, Bjartveit, K. Health consequences of reduced daily cigarette consumption. Tob Control. 2006;15(6):472–80. 268. Hurt RD, Croghan GA, Wolter TD, et al. Does smoking reduction result in reduction of biomarkers associated with harm? A pilot study using a nicotine inhaler. Nicotine Tob Res. 2000;2:327–36. 269. Hatsukami DK, Henningfield JE, Kotlyar M. Harm reduction approaches to reducing tobacco-related mortality. Annu Rev Public Health. 2004;25:377–95. 270. ECLIPSE Expert Panel. A safer cigarette? A comparative study, a consensus report. Inhal Toxicol. 2000;12[suppl 5]:1–57. 271. Peto R. Influence of dose and duration of smoking on lung cancer rates. In: Zaridze DG, Peto R, eds. Tobacco: A Major International Health Hazard. Lyon, France: International Agency for Research on Cancer; 1986:22–33. 272. Pechacek TF, Babb S. How acute and reversible are the cardiovascular risks of secondhand smoke? BMJ. 2004;328:980–3. 273. Kropp RY, Halpern-Felsher BL. Adolescents’ beliefs about the risks involved in smoking “light” cigarettes. Pediatrics. 2004;114:445–51. 274. Centers for Disease Control and Prevention. Cigarette smoking among adults—United States, 2000. MMWR. 2002;51:642–5. 275. Yankelovich Partners. Smoking Cessation Study. New York, NY: American Lung Association; 1998. 276. Centers for Disease Control and Prevention. Tobacco use, access and exposure to tobacco in media among middle and high school students—United States, 2004. MMWR. 2005;54:297–301. 277. Centers for Disease Control and Prevention. Youth risk behavior surveillance—United States, 2005. Surveillance Summaries. MMWR. 2006;55(SS-5):1–108. 278. Malaracher AM, Thorne SL, Jackson K, et al. Surveillance for selected tobacco use behaviors-United States, 1900–2005. MMWR. (In press) 279. Baker F, Ainsworth SR, Dye JT, et al. Health risks associated with cigar smoking. JAMA. 2000;284:735–40. 280. Jacobs EJ, Thun MJ, Apicella LF. Cigar smoking and death from coronary heart disease in a prospective study. Arch Intern Med. 1999;159:2413–8. 281. Henley SJ, Thun MJ, Chao A, et al. Association between exclusive pipe smoking and mortality from cancer and other disease. J Natl Cancer Inst. 2004;96:853–61. 282. National Center of Health Statistics, National Health Interview Survey, public use data tape, 2005. 283. Bolinder GM, de Faire U. Ambulatory 24-h blood pressure monitoring in health, middle-aged smokeless tobacco users, smokers, and nontobacco users. Am J Hypertension 1998;11:1153–63. 284. Tomar SL. Is use of smokeless tobacco a risk factor for cigarette smoking? The U.S. experience. Nicotine Tob Research. 2003;5: 561–9. 285. Watson CH, Polzin GM, Calafat AM, et al. Determination of tar, nicotine, and carbon monoxide yields in the smoke of bidi cigarettes. Nicotine Tob Research. 2003;5:747–53. 286. Pakhale SS, Jayant K, Bhide SV. Chemical analysis of smoke of Indian cigarettes, bidis and other indigenous forms of smoking— levels of steam-volatile phenol, hydrogen cyanide and benzo(a)pyrene. Indian J Chest Dis Allied Sci. 1990;32:75–81. 287. Nair J, Pakhale SS, Bhide SV. Carcinogenic tobacco specific nitrosamines in Indian tobacco products. Food Chem Toxicol. 1989;27:751–3. 288. Gupta PC, Mehta HC. Cohort study of all-cause mortality among tobacco users in Mumbai, India. Bull WHO. 2000;78:877–83. 289. Rahman M, Fukui T. Bidi smoking and health. Public Health. 2000;114:123–7.


54 290. Gupta PC, Sreevidya S. Smokeless tobacco use, birth weight, and gestational age: population based, prospective cohort study of 1217 women in Mumbai, India. BMJ. 2004;328:1538. 291. Notani NP, Nagaraj Rao D, Sirsat MV, et al. A study of lung cancer in relation to bidi smoking in different religious communities in Bombay. Indian J Cancer. 1977;14:115–21. 292. Sankaranarayanan R, Duffy S, Padmakumary G, et al. Risk factors for cancer of the oesophagus in Kerala, India. Int J Cancer. 1991: 49:485–9. 293. Dikshit RP, Kanhere S. Tobacco habits and risk of lung, oropharyngeal and oral cavity cancer: a population-based casecontrol study in Bhopal, India. Int J Epidemiol. 2000;29: 609–14. 294. Halpern MT, Warner KE. Motivations of smoking cessation: a comparison of successful quitters and failures. J Subst Abuse. 1993;5: 247–56. 295. Fiore MC, Bailey WC, Cohen SJ, et al. Treating Tobacco Use and Dependence: Clinical Practice Guidelines. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service; 2000. 296. U.S. Preventive Services Task Force. Counseling to Prevent Tobacco Use and Tobacco-Caused Disease: Recommendation Statement. Available at http://www.ahrq.gov/clinic/3rduspstf/tobaccoun/tobcounrs.htm. Accessed August 5, 2005. 297. McDonald P, Colwell B, Backinger CL, et al. Better practices for youth tobacco cessation: evidence of review panel. Am J Health Behav. 2003;27(Suppl 2):S144–58. 298. Milton MH, Maule CO, Lee SL, et al. Youth Tobacco Cessation: A Guide for Making Informed Decisions. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2004. 299. Coffield AB, Maciosek MV, McGinnis JM, et al. Priorities among recommended clinical preventive services. Am J Prev Med. 2001; 21:1–9. 300. American Medical Association. How to Help Patients Stop Smoking: Guidelines for Diagnosis and Treatment of Nicotine Dependence. Chicago, IL: American Medical Association; 1994. 301. Raw M, McNeill A, West R. Smoking cessation guidelines and their cost effectiveness. Thorax. 1998;53(Suppl 5):S1–38. 302. Tsevat J. Impact and cost-effectiveness of smoking interventions. Am J Med. 1992;93(suppl 1A):S43–7. 303. Cummings SR, Rubin SM, Oster G. The cost-effectiveness of counseling smokers to quit. JAMA. 1989;261:75–9. 304. Cromwell J, Bartosch WJ, Fiore MC, et al. Cost-effectiveness of the clinical practice recommendations in the AHCPR guideline for smoking cessation. JAMA. 1997;278:1759–66. 304a. Maciosek, MV, Coffield, AB, Edwards, NM, et al. Priorities among effective clinical preventive services. Am J Prev Med. 2006;21:52–61. 305. Lightwood JM, Glantz SA. Short-term economic and health benefits of smoking cessation. Myocardial infarction and stroke. Circulation. 1997;96:1089–96. 306. Wagner EH, Curry SJ, Grothaus L, et al. The impact of smoking and quitting on health care use. Arch Intern Med. 1995;155: 1789–95. 307. McAfee T, Wilson J, Dacey S, et al. Awakening the sleeping giant: mainstreaming efforts to decrease tobacco use in an HMO. HMO Pract. 1995;9:138–43. 308. Schauffler HH, Rodriguez T. Availability and utilization of health promotion programs and satisfaction with health plan. Med Care. 1994;32:1182–96. 309. Hopkins DP, Fielding J. Task Force on Community Preventative Services, eds. The guide to community preventive services: tobacco use prevention and control, reviews, recommendations, and expert commentary. Am J Prev Med. 2001;20[2 (Supplemental)]:1–88.

Tobacco: Health Effects and Control

993

310. Stead LF, Perera R, Lancaster T. Telephone counselling for smoking cessation. Cochrane database of Systematic Reviews. 2006. Available at http://www.cochrane.org/reviews/. Accessed April 21, 2007. 311. McAfee T, Sofian NS, Wilson J, et al. The role of tobacco intervention in population–based health care: a case study. Am J Prev Med. 1998;14(3S):46–52. 312. Centers for Disease Control and Prevention. Making your workplace smokefree: a decision maker’s guide. Atlanta, GA: U.S. Department of Health and Human Services, Office on Smoking and Health; 1996. Available at http://www.cdc.gov/tobacco/ secondhand_smoke/00_pdfs/fullguide.pdf. Accessed April 27, 2007. 313. Fisher KJ, Glasgow RE, Terborg JR. Work site smoking cessation: a meta-analysis of long-term quit rates from controlled studies. J Occup Med. 1990;32:429–39. 314. Glasgow RE, Terborg JR, Hollis JF, et al. Take Heart: results from the initial phase of a work-site wellness program. Am J Public Health. 1995;82:209–16. 315. Sorensen G, Thompson B, Glantz K, et al. Work site based cancer prevention: primary results from the Working Well Trial. Am J Public Health. 1996;86:939–47. 316. Institute of Medicine, Adams K, Corrigan JM. Priority Areas for National Action: Transforming Health Care Quality. Washington, DC: 2003. 317. Sennett C. An introduction to HEDIS—The Health Plan Employer Data and Information Set. J Clin Outcomes Management. 1996;3: 59–61. 318. Committee on Performance. HEDIS 3.0. Washington, DC: National Committee for Quality Assurance; 1996. 319. National Committee for Quality Assurance. State of Health Care Quality 2006. Available at http://web.ncqa.org/Default.aspx? tabid=447. Accessed April 15, 2007. 320. Joint Commission on Accreditation of Healthcare Organizations. Specification Manual for National Implementation of Hospital Core Measures Version 2.0. Available at http://www.jcaho.org/pms/ core+ measures/information+on+final+specifications.htm. Accessed August 5, 2005. 321. U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services. Doctor’s Office Quality Project; 2004. Available at http://www.cms.hhs.gov/quality/doq. Accessed August 5, 2005 322. Puska P, Salonen J, Nissinen A, et al. Change in risk factors for coronary heart disease during 10 years of a community intervention programme (North Karelia project). Br Med J. 1983;287: 1840–4. 323. Roussouw JE, Jooste PL, Chalton DO, et al. Community-based intervention: the coronary risk factor study (CORIS). Int J Epidemiol. 1993;22:428–38. 324. Farquhar JW, Wood PD, Breitrose H, et al. Community education for cardiovascular health. Lancet. 1977;1:1192–5. 325. Farquhar JW, Fortmann AP, Flora JA, et al. Effects of communitywide education on cardiovascular disease risk factors: the Stanford Five-City Project. JAMA. 1990;264:359–65. 326. Multiple Risk Factor Intervention Trial Research Group. Multiple risk factor intervention trial: risk factor changes and mortality results. JAMA. 1982;248:1465–77. 327. Lando HA, Pechacek TF, Pirie PL, et al. Changes in adult cigarette smoking in the Minnesota Heart Health Program. Am J Public Health. 1995;85:201–8. 328. Carleton RA, Lasater TM, Assaf AR, et al. The Pawtucket Heart Health Program: community changes in cardiovascular risk factors and projected disease risk. Am J Public Health. 1995;85: 777–85. 329. Stillman FA, Hartman AM, Graubard BI, et al. Evaluation of the American Stop Smoking Intervention Study (ASSIST): a report of outcomes. J Natl Cancer Inst. 2003;95:1681–91.


994

Behavioral Factors Affecting Health

330. Task Force on Community Preventive Services. Tobacco. In: Zaza S, Briss PA, Harris KW, eds. The Guide to Community Preventive Services: What Works to Promote Health? New York, NY: Oxford University Press; 2005. 331. National Cancer Institute. The Impact of Cigarette Excise Taxes on Smoking Among Children and Adults: Summary Report of a National Cancer Institute Expert Panel. Washington, DC: National Cancer Institute; 1993. 332. Warner KE. Smoking and health implications of a change in the federal cigarette excise tax. JAMA. 1986;225:1028–32. 333. U.S. Department of Health and Human Services. Reducing Tobacco Use: A Report of the Surgeon General. Washington, DC: Centers for Disease Control and Prevention, Office on Smoking and Health; 2000. 334. Tauras JA, O’Malley PM, Johnston LD. Effects of Price and Access Laws on Teenage Smoking Initiation: A National Longitudinal Analysis. 2001. NBER Working Paper No W8331. 335. Ross H, Chaloupka FJ. The effect of cigarette prices on youth smoking. Health Econ. 2003;12:217–30. 336. Johnston M. Teenage Smoking and the Federal Excise Tax on Cigarettes, PM Document No. 2001255224, September 17, 1981. Available at http://www.pmdocs.com/getimg.asp? pgno=0&start= 0&if=avpidx&bool=2001255224&docid=2001255224/5227&doc num=1&summary=0&sel1=. Accessed August 5, 2005. 337. Delnevo CD, Hrywna M, Foulds J, et al. Cigar use before and after a cigarette excise tax increase in New Jersey. Addict Behav. 2004;29:1799–1807. 338. Siegel M, Biener L. The impact of an antismoking media campaign on progression to established smoking: results of a longitudinal youth study. Am J Public Health. 2000;90:380–6. 339. Centers for Disease Control and Prevention. Effect of ending an antitobacco youth campaign on adolescent susceptibility to cigarette smoking—Minnesota, 2002–2003. MMWR 2004;53:301–4. 340. Zucker D, Hopkins RS, Sly DF, et al. Florida’s “truth” campaign: a counter-marketing, anti-tobacco media campaign. J Public Health Manag Pract. 2000;6:1–6. 341. Sly DF, Trapido E, Ray S. Evidence of the dose effects of an antitobacco counteradvertising campaign. Prev Med. 2002;35:511–8. 342. Niederdeppe J, Farrelly MC, Haviland ML. Confirming “truth”: more evidence of a successful tobacco countermarketing campaign in Florida. Am J Public Health. 2004;94:255–7. 343. Farrelly MC, Healton CG, Davis KC, et al. Getting to the truth: evaluating national tobacco countermarketing campaigns. Am J Public Health. 2002;92:901–7. 344. Thrasher JF, Niederdeppe J, Farrelly M, et al. The impact of antitobacco industry prevention messages in tobacco producing regions: evidence from the U.S. truth campaign. Tob Control. 2004;13:283–8. 345. Farrelly M, Davis KC, Haviland ML, et al. Evidence of a doseresponse relationship between “truth” antismoking ads and youth smoking prevalence. Am J Public Health. 2005;95:425–31. 345a. Wakefield M, Terry-McElrath Y, Emery S, et al. Effect of televised, tobacco company-funded smoking prevention advertising on youth smoking-related beliefs, intentions and behavior. Am J Public Health. 2006;96:2154–60. 346. Centers for Disease Cotnrol and Prevention. Guidelines for school health programs to prevent tobacco use and addiction. MMWR. 1994;43(RR–2):1–18. 347. National Institutes of Health. School Programs to Prevent Smoking: The National Cancer Institute Guide to Strategies that Succeed. Bethesda, MD: National Institutes of Health; 1990. NIH Publication 90-500. 348. Flay BR. What we know about the social influences approach to smoking prevention: review and recommendations. In: Bell CS, Battjes R, eds. Prevention Research: Deterring Drug Abuse among

349.

350.

351.

352. 353.

354.

355.

356.

356a.

357.

357a.

358.

359.

360.

361.

362.

362a.

363.

Children and Adolescents. Washington, DC: U.S. Department of Health and Human Services, Alcohol, Drug Abuse and Mental Health Administration, National Institue on Drug Abuse; 1985. NIDA Research Monograph 63. DHHS Publication (ADM) 85–1334. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Fewer Retailers Sell Cigarettes to Youth, 2002. Available at http://prevention.samhsa. gov/tobacco. Accessed August 5, 2005. Lynch BS, Bonnie RJ, eds. Growing Up Tobacco Free: Preventing Nicotine Addiction in Children and Youths. Washington, DC: National Press, 1994. Jason JA, Ji PY, Anes MD, et al. Active enforcement of cigarette control laws in the prevention of cigarette sales to minors. JAMA. 1991;266:3159–61. Di Franza, JR, Carlson RP, Caisse RE. Reducing youth access to tobacco. Tob Control. 1992;1:58. Rigotti NA, DiFranza JR, Chang Y, et al. The effect of enforcing tobacco sales-laws on adolescents’ access to tobacco and smoking behavior. N Engl J Med. 1997;337:1044–51. Tobacco Free Mass. Data reveals 74% increase in illegal cigarette sales to minors. Available at http://www.tobaccofreemass.org/ release31604.php. Accessed August 5, 2005. American Lung Association. State of Tobacco Control: 2004. New York, NY: Available at http://lungaction.org/reports/tobaccocontrol04.html. Accessed August 5, 2005. Shopland D, Anderson CM, Burns DM, et al. Disparities in smokefree workplace policies among food service workers. J Occup Environ Med. 2004;46:347–56. Pickett, MS, Schober, SE, Brody, DJ, et al. Smoke–free laws and secondhand smoke exposure in U.S. non-smoking adult, 1999–2000. Tobacco Control. 2006;15:302–07. Centers for Disease Control and Prevention. Indoor air quality in hospitality venues before and after implementation of a clean indoor air law—Western New York, 2003. MMWR. 2004;53: 1038–41. Farrelly, MC, Nonnemaker, JM, Chou, R, et al. Changes in hospitality workers’ exposure to secondhand smoke following the implementation of New York’s smoke-free law. Tob Control. 2005; 14:236–41. Scollo M, Lal A, Hyland A, et al. Review of the quality of studies on the economic effects of smoke-free policies on the hospitality industry. Tob Control. 2003;12:13–20. Lewit EM, Coate D. Potential for Using Excise Taxes to Reduce Smoking. Cambridge, MA: National Bureau of Economic Research, Inc.; 1981. NBER Working Paper Series 764. Fiore MC, Coyle RT, Curry SJ, et al. Preventing 3 million premature deaths and helping 5 million smokers quit: A national action plan for tobacco cessation. Am J Public Health. 2004;94: 205–10. Merlo E, Senior Vice President of Corporate Affairs, Philip Morris, 1994 draft speech to the Philip Morris USA Trade Council. Available at http://legacy.library.ucsf.edu/tid/oyf35e00. Accessed August 5, 2005. Philip Morris Executive Claude Schwab, “Cigarette attributes and quitting,” PM Doc. 2045447810, March 4, 1993. Available at http://www.pmdocs.com/getimg.asp?pgno=0&start=0&if=avpidx &bool=2045447810&docid=2045447810&docnum=1&summary=0&sel1=. Accessed August 5, 2005. Campaign for Tobacco Free Kids. Tobacco smuggling. 11th world conference on tobacco or health, tobacco fact sheet. Available at http://tobaccofreekids.org/campaign/global/docs/smuggling.pdf. Accessed April 23, 2007. Hamilton JL. The demand for cigarettes: advertising, the health scare, and the cigarette advertising ban. Rev Econ Stat. 1972; 54:401–11.


54 364. Horn D. Who is Quitting and Why. Progress in Smoking Cessation. Proceedings of the International Conference on Smoking Cessation. New York, NY: American Cancer Society; 1978. 365. Pierce JP, Macaskill P, Hill DJ. Long-term effectiveness of mass media anti-smoking campaigns in Australia. Am J Public Health. 1990;80:565–9. 366. Doxiadis SA, Trihopoulos DV, Phylactou HD. Impact of nationwide smoking: why young people do it and ways of preventing it. In: McGrath P, Firestone P, eds. Pediatric and Adolescent Behavioral Medicine. New York, NY: Springer; 1983:132–83. 367. Laugesen M, Meads C. Tobacco advertising restrictions, price, income and tobacco consumption in OECD countries, 1960–1986. Br J Addict. 1991;86:1343–54. 368. Warner KE. Selling health: a media campaign against tobacco. J Public Health Policy. 1986;7:434–9. 369. Blum A. The Marlboro Grand Prix—circumvention of the television ban on tobacco advertising. N Engl J Med. 1991;324:913–7. 370. Jha P, Chaloupka F, eds. Tobacco Control in Developing Countries. New York, NY: Oxford University Press; 2000. 371. Saffer H, Chaloupka F. Tobacco advertising: Economic Theory and International Evidence. Cambridge, MA: National Bureau of Economic Research; 1999. 372. Joossens L. The effectiveness of banning advertsing for tobacco products; 1997. Available at http://www.globalink.org/tobacco/ docs/eu-docs/9710joos.html. Accessed August 5, 2005. 373. North American Quitline Consortium. Mission and Background. Available at http://www.naquitline.org/index.asp?dbid=2&dbsection= about. Accessed April 15, 2007. 374. Zhu S, Stretch V, Balabanis M, et al. Telephone counseling for smoking cessation: effects of single-session and multiple-session interventions. J Counsult Clinical Psychol. 1996;64:202–11. 375. Zhu S, Anderson CM, Johnson CE, et al. Centralised telephone service for tobacco cessation: the California experience. Tob Control. 2000;9(Suppl 2):ii48–55. 376. Office of Disease Prevention and Health Promotion, and Centers for Disease Control and Prevention. For a Healthy Nation: Returns on Investment in Public Health. Washington, DC; 1994. 376a. Hu TW, Bai J, Keeler TE, et al. The impact of California Proposition 99, a major anti-smoking law, on cigarette consumption. J Public Health Policy. 1994;15:26–36. 377. Pierce JP, Gilpin EA, Emery SL, et al. Has the California tobacco control program reduced smoking? JAMA. 1998;280:893–9. 378. California Department of Health Services. California Department of Health Services: Fact sheets. Available at http://www.dhs.ca.gov/ tobacco/html/factsheets.htm. Accessed August 11, 2005. 379. Centers for Disease Control and Prevention. Declines in lung cancer rates—California, 1988–1997. MMWR. 2000;49:1066–70. 380. Fichtenberg CM, Glantz SA. Associations of the California tobacco control program with declines in cigarette consumption and mortality from heart disease. N Engl J Med. 2000;343:1772–7. 381. Lightwood J, Phibbs CS, Glantz SA. Short-term health and economic benefits of smoking cessation: low birth weight. Pediatrics. 1999;104:1312–20. 382. Tobacco Control Section, California Department of Health Services. California Tobacco Control Update, 2000. Available at http://www.dhs.ca.gov/tobacco/documents/pubs/CTCUpdate.pdf. Accessed april 15, 2007. 383. Centers for Disease Control and Prevention. Cigarette smoking before and after an excise tax increase and an antismoking campaign—Massachusetts, 1990–1996. MMWR. 1996;45:966–70. 384. Connolly W, Director, Massachusetts Tobacco Control Program, Joint Hearing of the Pennsylvania House of Representatives Committee on Health and Human Services and the Pennsylvania Senate Committee on Public Health and Welfare, June 22, 1999. Campaign for Tobacco-Free Kids (CFTFK) Fact Sheet, Harm caused

385. 386.

387. 388.

389. 390.

391.

392. 393.

394.

395. 396.

397. 398. 399.

400. 401.

402.

402a.

403.

404. 405.

406.

Tobacco: Health Effects and Control

995

by pregnant women smoking or being exposed to secondhand smoke. Available at http://tobaccofreekids.org/research/factsheets/ pdf/ 0007.pdf. Accessed August 10, 2005. Centers for Disease Control and Prevention. Tobacco use among adults—Arizona, 1996 and 1999. MMWR. 2001;50:402–6. Centers for Disease Control and Prevention. Effectiveness of school-based programs as a component of a statewide tobacco control initiative—Oregon, 1999–2000. MMWR. 2001;50:663–6. Florida Department of Health. Monitoring program outcomes in 2002. Florida Youth Tobacco Survey. 2002;5(1):1–23. Farrelly M, Pechacek T, Chaloupka F. The impact of tobacco control program expenditures on aggregate cigarette sales: 1981–2000. J Health Economics. 2003;22:843–59. Tauras JA, Chaloupka F, Farrelly M, et al. State tobacco control spending and youth smoking. Am J Public Health. 2005;95:338–44. Centers for Disease Control and Prevention. Best Practices for Comprehensive Tobacco Control Programs. Atlanta, GA: U.S. Department of Health and Human Services, Office on Smoking and Health; 1999. Campaign for Tobacco-Free Kids. State cigarette excise tax rates and rankings. Available at http://www.tobaccofreekids.org/research/ factsheets/pdf/0097.pdf. Accessed April 15, 2007. Orzechowski W, Walker RC. The Tax Burden on Tobacco: Historical Compilation—2006. Arlington, VA; 2006. Department of Labor. Indoor air quality. Federal Register. 2001;66:242. Available at http://www.osha.gov/FedReg_osha_pdf/ FED20011217.pdf. Accessed August 5, 2005. Executive Office of the President. Executive Order 13058— Protecting federal employees and the public from exposure to tobacco smoke in the federal workplace. Federal Register. 1997;62: 43449–52. U.S. Department of Health and Human Services. Tobacco-Free HHS; November 10, 2004. Joint Commission on Accreditation of Healthcare Organizations. Smoking standards of the Joint Commission on Accreditation of Healthcare Organizations. Jt Comm Perspect. 1991;Nov/Dec:12–4 Delta Air Lines is the first smokefree U.S. airline worldwide. Wall Street Journal. November 15, 1994:A15. Jones D. Airlines join forces to ban trans—Atlantic smoking. USA Today. January 25, 1995:B1. Americans for Nonsmokers’ Rights. Smokefree transportation chronology. Available at http://www.no-smoke.org/document.php? id=334. Accessed August 5, 2005. Cal Labor Code §6404.5; 1996. Americans for Nonsmokers’ Rights. Overview list—how many smokefree laws? Available at http://www.no-smoke.org/goingsmokefree. php?id=519. Accessed April 15, 2007. Centers for Disease Control and Prevention. Preemptive state smoke-free indoor air laws—United States, 1999–2004. MMWR. 2005;54:250–3. Centers for Disease Control and Prevention. State tobacco activities tracking and evaluation (STATE) System. Available at http://apps. nccd.cdc.gov/statesystem/. Accessed April 15, 2007. McMillen RC, Winickoff JP, Klein JD, et al. U.S. adult attitudes and practices regarding smoking restrictions and child exposure to environmental tobacco smoke: changes in the social climate from 2000 to 2001. Pediatrics. 2003;112:55–60. Blizzard R. Secondhand smoke: harmful or hyperbole. Health & Healthcare. 2004;100–1. U.S. Department of Commerce. National Cancer Institute Sponsored Tobacco Use Supplement to the Current Population Survey, Census Bureau. Public use data tapes, 1993; 1999. Gilpin EA, Pierce JP. Changes in population attitudes about where smoking should not be allowed: California versus the rest of the U.S.A. Tob Control. 2004;13:38–44.


996

Behavioral Factors Affecting Health

407. National Center for Health Statistics. Healthy People 2000 Review, 1997. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 1997. DHHS Publication (PHS) 98–1256. 407a. Shopland DR, Gerlach KK, Burns DM, et al. State-specific trends in smoke-free workplace policy coverage: The current population survey tobacco use supplement, 1993 to 1999. Journal of Occupational Medicine. 2001;43:680–6. 408. Gerlach KK, Shopland DR, Hartman AM, et al. Workplace smoking policies in the United States: results from a national survey of more than 100,000 workers. Tob Control. 1997;6:199–206. 409. Weber MD, Bagwell DAS, Fielding JE, et al. Long term compliance with California’s smokefree workplace law among bars and restaurants in Los Angeles County. Tob Control. 2003;12:269–73. 410. Centers for Disease Control and Prevention. Tobacco Use Prevention from CDC’s School Health Policies and Programs Study (SHPPS)— 2000. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2001. 411. Gilpin EA, Farkas AJ, Emery SL, et al. Clean indoor air: advances in California, 1990–1999. Am J Public Health. 2002; 92:785–91. 411a. Centers for Disease Control and Prevention. State-specific prevalence of smoke-free home rules—United States, 1992–2003. MMWR. 2007. In press. 412. Centers for Disease Control and Prevention. Third National Report on Human Exposure to Environmental Chemicals. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Environmental Health; 2005. 413. Eisner MD, Smith AK, Blanc PD. Bartenders’ respiratory health after establishment of smoke-free bars and taverns. JAMA. 1998;280:1909–1914. 414. Substance Abuse and Mental Health Services Administration. Final regulations to implement section 1926 of the Public Health Service Act, regarding the sale and distribution of tobacco products to individuals under the age of 18. Federal Register. 1996;13: 1492–1500. 415. U.S. Department of Health and Human Services. Synar Regulation Guidance Series: Sampling, Inspection, and Change Strategies. Rockville MD: 1996. 416. U.S. Department of Health and Humans Services, Substance Abuse and Mental Health Services Administration. Retailers Cut Cigarette Sales to Youth. Available at http://www.samhsa.gov/SAMHSA_ news/VolumeXIII_5/article11.htm. Accessed April 19, 2007. 416a. American Lung Association. State of Tobacco Control: 2005. New York, NY: American Lung Association; 2005. Available at http:// lungaction.org/reports/tobacco-control06.html. Accessed April 20, 2007. 417. Substance Abuse and Mental Health Services Administration. Tobacco: State Synar non-compliance rate table FFY 1997-FFY 2005. Available at http://prevention.samhsa.gov/tobacco/01synartable. aspx. Accessed April 15, 2007. 418. Food and Drug Administration. Regulations restricting the sale and distribution of cigarettes and smokeless tobacco products to protect children and adolescents—final rule. Federal Register. 1996;61:41, 314–75. 419. Campaign for Tobacco-Free Kids. FDA Authority over tobacco: Legislation will protect kids and save lives. Available at http://www. tobaccofreekids.org/reports/fda. Accessed April 15, 2007. 420. Ribisi KM, Williams RS, Kim AE. Internet sales of cigarettes to minors. JAMA. 2003;290:1356–9. 420a. American Lung Association. State Legislated Actions on Tobacco Issues 2005. Available at http://slati.lungusa.org/ reports/SLATI_05.pdf. Accessed April 20, 2007.

421. Centers for Disease Control and Prevention. State Medicaid Coverage for Tobacco-Dependence Treatments—United States, 2005. MMWR. 2006;55:1194–7. 422. McPhillips-Tangum C, Bocchino C, Carreon R, et al. Addressing tobacco in managed care: results of the 2002 survey. Prev Chronic Dis. 2004;1:1. 423. Partnership for Prevention. Why Invest in Disease Prevention? It’s a Good Business Decision. And It’s Good for American Business. Washington, DC: Partnership for Prevention; 1998. 424. Partnership for Prevention. Preventive services: Helping states improve mandates; 2002. Available at http://prevent.org/images/stories/ Files/publications/Preventive_Services_State_Mandate_Brief_FINAL. pdf. Accessed April 15, 2007. 425. Burns ME, Bosworth TW, Fiore MC. Insurance coverage of smoking cessation treatment for state employees. Am J Public Health. 2004; 94:1338–40. 425a. United States of Department of Health and Human Services. HHS announces national smoking cessation quitline network. Available at http://www.hhs.gov/news/press/2004pres/20040203.html. Accessed April 15, 2007. 426. Centers for Disease Control and Prevention, Office on Smoking and Health. National Tobacco Control Program (NTCP). Available at http://www.cdc.gov/tobacco/ntcp_exchange/index.htm. Accessed August 5, 2005. 427. Campaign for Tobacco-Free Kids. A Broken Promise to Our Children: The 1998 State Tobacco Settlement Six Years Later. Washington, DC; 2004. 427a. Hu, TW, Bai, J, Keeler, TE, et al. The impact of California Proposition 99, a major anti-smoking law, on cigarette consumption. J Public Health Policy. 1994;15:26-36. 428. Schroeder S. Tobacco control in the wake of the 1998 master settlement agreement. N Eng J Med. 2004;350:293–301. 428a. Campaign for Tobacco-Free Kids. A Broken Promise to Our Children: The 1998 State Tobacco Settlement Eight Years Later. Washington, DC: Campaign for Tobacco Free Kids; 2007. 429. Federal Trade Commission. Report to Congress for 1995: Pursuant to the Federal Cigarette Labeling and Advertising Act. Washington, DC; 1997. 429a. Federal Trade Commission. Federal Trade Commission Smokeless Tobacco Report for the Years 2002–2005. Washington, DC: Federal Trade Commission; 2007. 430. Attorneys General Statement Agreement. In: Glob @ Link Resources on Tobacco Control—North American [online database] (cited 20 March 1997). 431. Meier B. Files of R.J. Reynolds tobacco show effort on youths. New York Times, January 15, 1998. 432. King C, Siegel M. The master settlement agreement with the tobacco industry and cigarette advertising in magazines. N Engl J Med. 2001;345:504–11. 433. Bowker D, Hamilton M. Cigarette Advertising Expenditures Before and After the Master Settlement Agreement: Preliminary Findings. Boston, MA: Massachusetts Department of Health; 2000. Available at http://tobaccofreekids.org/reports/addicting/magazines/connolly. pdf. Accessed August 10, 2005. 434. Massachusetts Department of Health. Smokeless Tobacco Advertising Expenditures Before and After the Smokeless Tobacco Master Settlement Agreement. Boston, MA: Massachusetts Department of Health, Massachusetts Tobacco Control Program; 2002. Available at http://tobaccofreekids.org/pressoffice/release503/smokeless.pdf. Accessed August 5, 2005. 435. Girion L, Levin M. R.J. Reynolds fined for ads aimed at teens: tobacco: judgement of $20 million for magazine pitches is first financial penalty for violation of 1998 national settlement. Los Angeles Times. June 7, 2002.


54 436. Siegel M. Counteracting tobacco motor sports sponsorship as a promotional tool: is the tobacco settlement enough? Am J Public Health. 2001;91:1100–6. 436a. Substance Abuse and Mental Health Services Administration. Cigarette Brand Preferences in 2005. The NSDUH Report. 2007. Available at http://oas.samhsa.gov/2k7/cigBrands/cigBrands.htm. Accessed April 24, 2007. 437. Pollay RW, Siddarth S, Siegel M, et al. The last straw? Cigarette advertising and realized market shares among youths and adults, 1979–1993. J Mark. 1996;60:1–16. 438. Evans N, Farkas A, Gilpin E, et al. Influence of tobacco marketing and exposure to smokers on adolescent susceptibility to smoking. J Natl Cancer Inst. 1995;87:1538–45. 439. Kaufman NJ, Castrucci BC, Mowery PD, et al. Predictors of change on the smoking uptake continuum among adolescents. Arch Pediatr Adolesc Med. 2002;156:581–7. 440. Centers for Disease Control and Prevention. Changes in the cigarette brand preferences of adolescent smokers—United States, 1989–1993. MMWR. 1994;43:577–81. 441. Fischer PM, Schwartz MP, Richards JW, et al. Brand logo recognition by children aged 3 to 6 years. JAMA. 1991;266:3145–8. 442. Ono Y, Ingersoll B. RJR retires Joe Camel, adds sexy smokers. Wall Street Journal. July 11, 1997:B1. 443. Pierce JP, Lee L, Gilpin EA. Smoking inititation by adolescent girls, 1944 through 1988: an association with targeted advertising. JAMA. 1994;271:608–11. 444. Ramirez A. Reynolds, after protests, cancels cigarette aimed at black smokers. New York Times. January 20, 1990. 445. Freedman AM, McCarthy MJ. New smoke from RJR under fire. Wall Street Journal. February 20, 1990. 446. Maryland Attorney General. Landmark settlement of “KoolMixx” tobacco lawsuits. Available at http:// www.oag.state.md.us/Press/ 2004/1006c04.htm. Accessed April 19, 2007. 447. Office of the New York State Attorney General. Attorneys general and R.J. Reynolds reach historic settlement to end the sale of flavored cigarettes. Available at http://www.oag.state.ny.us/press/2006/ oct/oct11a_06.html. Accessed April 15, 2007. 448. Scientific Committee on Tobacco and Health. Report of the Scientific Committee on Tobacco and Health. London, England: Her Majesty’s Stationery Office; 1998. 449. Dalton M, Sargent J, Beach M, et al. Effect of viewing smoking in movies on adolescent smoking initiation: a cohort study. Lancet. 2003;362:281–5. 450. Sargent J, Dalton M, Beach M, et al. Viewing tobacco use in movies. Am J Prev Med. 2002;22:137–45. 451. Distefan J, Pierce JP, Gilpin EA. Do favorite movie stars influence adolescent smoking initiation? Am J Public Health. 2004;94: 1239–44. 452. Glantz SA, Kacirk KA, McCulloch C. Back to the future: smoking in movies in 2002 compared with 1950 levels. Am J Public Health. 2004;94:261–3. 453. Polansky JR, Glantz SA. First-run smoking presentations in U.S. movies 1999–2003. Available at http://repositories.cdlib.org/cgi/ viewcontent.cgi?article=1047&context=ctcre. Accessed August 12, 2005. 454. Weiser R. Smoking and Women’s Magazines, 2001–2002. New York, NY: American Council on Science and Health; 2004. Available at http://www.acsh.org/publications/pubID.1004/pub_detail.asp. Accessed April 15, 2007. 455. The Public Health Cigarette Smoking Act of 1969. Public Health Law, 91–222. 456. Centers for Disease Control and Prevention. Preemptive state tobacco control laws—United States, 1982–1998. MMWR. 1999;47:1112–4. 457. Campaign for Tobacco-Free Kids. The United States: no longer a world leader in tobacco control. Available at

458. 459. 460. 461. 462. 463. 464. 465.

466.

467.

468. 468a.

469.

470. 471.

471a.

472.

473.

474.

475. 476. 477. 478.

479.

Tobacco: Health Effects and Control

997

http://www.tobaccofreekids.org/campaign/global/pdf/Straggler. pdf. Accessed August 5, 2005. Keating G. Retrial in L.A. tobacco case set for September. Reuters. August, 15, 2003. Gray M. New York jury awards widow $350,000 in tobacco lawsuit. Associated Press. December 19, 2003. Missouri family awarded $20 million in tobacco suit. Associated Press. February 03, 2005. First individual award against big tobacco in Arkansas is upheld. Associated Press. January 8, 2005. List of large awards in tobacco lawsuits. Associated Press. May 22, 2003. Flight Attendant Medical Research Institute. History. Available at http://www.famri.org/history/index.php. Accessed August 5, 2005. Haggman M, Cunningham L. Tobacco industry lawyers argue against $145B award. Miami Daily Business Review. May 22, 2003. Daynard RA, Sweda EL, Gottlie M. Despite headlines, FL Supreme Court's decision in Engle case will prove to be an enormous blow to cigarette companies. July 6, 2006. Available at http://tobacco.neu.edu/ litigation/cases/pressreleases/ENGLEVFLSUPCT2006.htm. Accessed April 24, 2007. Associated Press. Supreme Court won’t hear ‘light’ cigarette case. MSNBC News. November 27, 2006. Available at http://www.msnbc. msn.com/id/15924872/. Accessed April 24, 2007. Zuckerbrod N. Light cigarette smokers sue tobacco industry in courts nationwide. Detroit News. March 25, 2002. Available at www.detnews.com/2002/health/0204/01/-449181.htm. Accessed August 5, 2005. Harding A. U.S. government opens racketeering case against tobacco industry. BMJ. 2004;329:701. United States of America vs. Philip Morris. Final judgement and remedial order. Available at http://tobaccofreekids.org/reports/doj/ JudgmentOrder.pdf. Accessed April 15, 2007. Capehart T. The Changing Tobacco User’s Dollar. Washington, DC: U.S. Department of Agriculture; 2004:1–8. Publication TBS 257–01. Zagorsky JL. The wealth effects of smoking. Tob Control. 2004;13:370–4. U.S. Department of Agriculture. U.S. Trade Internet System -FAS online. 2007. Available at http://www.fas.usda.gov/ustrade/. Accessed April 27, 2007. Central Intelligence Agency. The world factbook—United States. 2005. Available at https://www. cia.gov/cia/publications/factbook/ geos/us.html Warner KE, Fulton GA, Nicolas P, et al. Employment implications of declining tobacco product sales for the regional economics of the United States. JAMA. 1996;275:1241–6. U.S. Department of Agriculture. Tobacco Situation and Outlook Report. Washington, DC: Economic Research Service; 1997. Publication TBS-239. Zhang P, Husten C. Impact of the tobacco price support program on tobacco control in the United States. Tob Control. 1998;7:176–82. Womach J. Tobacco Quota Buyout. Washington, DC: Congressional Research Service; 2005. Womach J. Tobacco Price Support: an Overview of the Program. Washington, DC: Congressional Research Library; 2004. Weis WL. Can you afford to hire smokers? Pers Adm. 1981;26: 71–3,75–8. Halpern MT, Shikiar R, Rentz AM, et al. Impact of smoking status on workplace absenteeism and productivity. Tob Control 2001;10:233–8. Warner KE, Smith RJ, Smith DG, et al. Health and economic implications of a work-site smoking-cessation program: a simulation analysis. J Occup Environ Med. 1996;38:981–92.


998

Behavioral Factors Affecting Health

480. Hodgson TA. Cigarette smoking and lifetime medical expenditures. Milbank Q. 1992;70:81–115. 481. Center for Prevention and Health Services. Reducing the burden of smoking on employee health and productivity. Issue Brief. National Business Group on Health; 2005;1:1–8. 482. Guindon GE, Boisclair D. Past, Current and Future Trends in Tobacco Use. HNP Discussion Paper No. 6, Economics of Tobacco Control Paper No. 6. Washington, DC: The World Bank; 2003. Available at http://www1.worldbank.org/tobacco/pdf/ Guindon-Past,%20current-%20whole.pdf. Accessed August 10, 2005. 483. Corrao MA, Guindon GE, Sharma N, et al, eds. Tobacco Control: Country Profiles. Atlanta, GA: American Cancer Society; 2000. 484. Global Tobacco Surveillance System Collaborating Group. Global Tobacco Surveillance System (GTSS): purpose, production, and potential. J School Health. 2005;75:15–24. 485. Global Youth Tobacco Survey Collaborating Group. Tobacco use among youth: a cross country comparsion. Tob Control. 2002;11: 252–70. 486. Global Youth Tobacco Survey Collaborating Group. Differences in worldwide tobacco use by gender: findings from the Global Youth Tobacco Survey. J School Health. 2003;73:207–15. 487. Shafy O, Dolwick S, Guindon GE, eds. Tobacco Control: Country Profiles, 2nd ed. Atlanta, GA: American Cancer Society; 2003. 488. Yu JJ, Mattson ME, Boyd GM, et al. A comparison of smoking patterns in the People’s Republic of China with the United States: an impending health catastrophe in the middle kingdom. JAMA. 1990;264:1575–9. 489. Tobacco or Health Programme. Tobacco or Health: First Global Status Report. Geneva, Switzerland: Wor1d Health Organization; 1996. 490. Muller M. Preventing tomorrow’s epidemic: the control of smoking and tobacco production in developing countries. N Y State J Med. 1983;83:1304–9. 491. Whelan EM. A Smoking Gun: How the Tobacco Industry Gets Away with Murder. Philadelphia, PA: George F. Stickley; 1984:166–76.

492. Madeley J. The environmental impact of tobacco production in developing countries. N Y State J Med. 1983;83:1310–1. 493. Barnum H. The economic burden of the global trade in tobacco. Tob Control. 1994;3:358–61. 494. Forty-ninth World Health Assembly. International Framework Convention for Tobacco Control; May 25, 1996. WHA49.17. 495. World Health Organization. WHO Framework Convention on Tobacco Control. Geneva, Switzerland: 2003. 496. Blanke DD. Tools for Advancing Tobacco Control in the XXIst century: Tobacco Control Legislation: An Introductory Guide. Geneva, Switzerland: World Health Organziation, 2003. 497. Smoking and Health Action Foundation. Average retail cigarette price and total taxes per pack (U.S. dollars/pack of 20), selected industrial countries, June 17, 2002. Available at http://www.nsraadnf.ca/cms/index.cfm?group_id=1200. Accessed April 15, 2007. 498. Laugese M, Meads C. Tobacco advertising restrictions, price, income and tobacco consumption in OECD countries, 1960–1986. Br J Addict. 1991;86:1343–54. 498a. Tobacco Free Kids. Michael Bloomberg Announces grantees $125 million to promote freedom from smoking (Press Release). Available at http://tobaccofreekids.org/pressoffice/BloombergRelease.pdf. Accessed April 15, 2007. 499. The Gallup Organziation. Survey of the Public’s Attitudes toward Smoking. Princeton, NJ: The Gallup Organization; 1992. 500. Chaloupka F, Warner KE. The economics of smoking. In: Culyer AJ, Newhouse JP, eds. Handbook of Health Economics. Amsterdam, Netherlands: Elsevier Science Ltd; 2000. 500a. Loomis BR, Farrelly MC, Mann NH. The association of retail promotions for cigarettes with the Master Settlement Agreement, tobacco control programmes and cigarette excise taxes. Tobacco Control. 2006;15:458–63. 501. Qunidlen A. Quid pro quo. New York Times. October 8, 1994. 502. Hicks JP. In council, bill gains to restrict smoking. New York Times. December 8, 1994:B2. 503. Centers for Disease Control and Prevention. Achievements in public health, 1900–1999: Tobacco Use—United States, 1900–1999. MMWR. 1999;48:986–93.


Alcohol-Related Health Problems

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Brian L. Cook • Jill Liesveld

 INTRODUCTION

The abuse of alcohol is more common than any other form of drug abuse throughout the world. The consequences of alcohol use are pervasive in society. From a public health perspective, alcohol use presents a unique dilemma, referred to as the “prevention paradox.”1 This paradox stems from the observation that health and economic consequences resulting from alcohol use are far greater due to hazardous drinking than drinking patterns that constitute a formal diagnosis of alcohol dependence.2 This paradox is further complicated by findings that suggest that low to moderate levels of alcohol use may play a role in reducing mortality for certain disorders, such as cardiovascular disease.3 To better understand this paradox and the risk of alcohol use, it is helpful to stratify alcohol use and risk along a continuum. This continuum stretches from abstinence to alcohol dependence.  CATEGORIES OF ALCOHOL USE ALONG THE DRINKING CONTINUUM

week be regarded as harmful because of the biological differences between men and women c. that abstinence be promoted as highly desirable during pregnancy d. that persons who intend to drive, operate machinery, or undertake activities in hazardous or potentially hazardous situations should not drink e. that in any given situation it is difficult to say that there is an absolute safe level of consumption and thus in situations of any doubt people should not drink In this report, a unit or standard drink was equivalent to 8–10 g of alcohol compared with Canada and the United States, where one unit or standard drink contains approximately 13.6 g of alcohol. In essence, no level of alcohol consumption will always be safe for all individuals under all conditions. Rather, increasing levels of consumption hold a progressively increasing risk of causing either acute or chronic damage. Moreover, the level at which risk occurs and its significance are influenced by a combination of personal and environmental factors that render the individual more or less vulnerable to damage from alcohol.

Safe (Low-Risk) Drinking Based on the concept of a continuum of risk, some organizations have proposed guidelines for “safe” (low-risk) drinking, some of which include both the characteristics and circumstances of the drinker as well as levels of consumption. American guidelines for safe drinking generally recommend no more than 2 drinks per day for men, and 1 drink per day for nonpregnant females.4 Slightly higher limits are proposed by U.K. authorities.5 One example of safe drinking guidelines, which also include characteristics of the drinker as well as levels of consumption, is contained in the report of the Australian National Health and Medical Research Council (NHMRC).6 “Is there a safe level of daily consumption of alcohol for men and women?” Recommendations regarding responsible drinking behavior, in which it is recommended that responsible drinking be considered as the consumption of the least amount of alcohol that will meet an individual’s personal and social needs and in any case: a. that men should not exceed 4 units or 40 g of absolute alcohol per day on a regular basis, or 28 units per week; that 4–6 units per day or 28–42 units per week be considered as hazardous and that greater than 6 units per day or 42 units per week be regarded as harmful b. that women should not exceed 2 units or 20 g of absolute alcohol per day on a regular basis, or 14 units per week; that 2–4 units per day or 14–28 units per week be considered as hazardous and that greater than 4 units per day or 28 units per

Hazardous Drinking The term “hazardous drinking” has been used to describe levels of alcohol consumption that expose the drinker to a high risk of physical complications.7 Under certain circumstances, relatively low levels of consumption on isolated occasions may result in damage to the individual drinker. There is evidence as well that levels of consumption far below those found in people diagnosed as alcohol dependent are linked with increased risks of adverse health consequences.8,9 A special case involves the survival and normal development of the fetus of the drinking pregnant woman.10 In this instance, some authorities would assert that there is no safe level of consumption, or that it may be impossible to define such a level.11 As information grows on how alcohol is hazardous to health we find ourselves less secure in defining what is safe.12,13 Rather, alcohol use involves a continuum of risk, defined by host and environmental factors as well as by the levels of alcohol consumption.  ALCOHOL ABUSE AND ALCOHOL DEPENDENCY DEFINITIONS

The definitions of alcohol abuse and dependency have evolved over time, and differ somewhat among various organizations (e.g., the World Health Organization (WHO), American Psychiatric Association [APA]). The WHO has recently published its 10th edition of the International Classification of Diseases (ICD-10),14 while The APA recently 999

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published its fourth edition, text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR).15 The definitions differ primarily in the number and definition of symptoms required before a diagnosis of alcohol abuse or dependency are met. The ICD-10 and DSM-IV were compared in a study by Caetano.16 The one-year prevalence rate of alcohol dependence was higher (5.5% vs. 3.9%) when ICD-10 criteria were applied as compared to the DSM-IV criteria. Predictors of meeting ICD-10 versus DSM-IV criteria were slightly different in the study, thus highlighting differences in these two criteria sets which should be considered in epidemiological research. The DSM-IV definition is most widely used in alcohol use disorder research in the United States at this time. The DSM-IV15 defines alcohol abuse as a “maladaptive pattern of alcohol use leading to clinically significant impairment or distress, as manifested by one or more of the following, occurring within a 12-month period: (a) recurrent alcohol use resulting in failure to fulfill major role obligations at work, school, or home; (b) recurrent alcohol use in situations in which it is physically hazardous; (c) recurrent alcohol-related legal problems; (d) continued alcohol use despite having a persistent or recurrent social or interpersonal problem caused or exacerbated by the effects of alcohol.” The DSM-IV15 defines alcohol dependence as a “maladaptive pattern of alcohol use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following occurring at any time in the same 12-month period: (a) tolerance; (b) withdrawal; (c) alcohol use in greater quantity or for a longer period than intended; (d) persistent desire or unsuccessful efforts to cut down or control alcohol use; (e) a great deal of time is spent acquiring, using, or recovering from alcohol’s effects; (f) important social, occupational, or recreational activities are given up or reduced because of alcohol use; (g) alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused by or exacerbated by alcohol use.” In the DSM-IV15 classification, once an individual meets dependency criteria, the diagnosis of alcohol abuse should no longer be used for that individual. Course specifiers should be used to describe the individual after no criteria for dependence have been met for at least one month. The course specifiers include early full remission, early partial remission, sustained full remission, sustained partial remission, on agonist therapy, or in a controlled environment. Several observations are important regarding the DSM-IV classification system. The DSM-IV classification emphasizes the central role that alcohol comes to play in the life of a dependent individual, not simply the physiological changes associated with heavy alcohol use. Thus, an individual can be classified as alcohol dependent without classical signs or symptoms of physical tolerance and resultant withdrawal upon abrupt discontinuation of alcohol. Also, complete abstinence is not required before the remission course specifiers can be used. If none of the seven dependence criteria symptoms are met during a period of a month or longer, a form of remission is reached which is defined as either partial or full. If continued drinking does not result in full return of three or more dependence criteria symptoms, but does cause at least one dependence symptom, the remission is considered partial. If the full dependence criteria are not met for 12 months or more, the remission category is considered sustained. The utility and predictive validity of these categories remain to be established.  EPIDEMIOLOGY OF ALCOHOL ABUSE AND DEPENDENCY

Alcohol is regularly consumed by slightly more than half of the adult United States population. In the 2003 National Survey on Drug Use & Health (formerly called the National Household Survey on Drug Abuse [NHSDA])17 50.1% of all Americans over age 12 reported consuming alcohol. The prevalence of past month alcohol consumption was higher for men (57.3%) than for women (43.2%). 54.4% of nonblacks and 37.9% of blacks admitted to past month use of alcohol. A total of

22 million people in the United States used alcohol in the past month in 2002 compared to 21.6 million in 2003. For those in the over age 18-year group, 62.4% of males and 46.0% of females were current drinkers. While male drinking percentage remained the same as in 2002, for females there was a 2% decrease from the 47.9% identified in 2002. Of interest is that in the age 12–17 age group, 17.1% of males and 18.3% of females were identified as current drinkers, closing the gender gap. In another study by SAMHSA using data from 2002 to 2003, 50.5% of those surveyed had a drink within the past month and 7.6% of those age 12 and over were identified with alcohol abuse or dependence.18,22 Large population-based studies have demonstrated that the lifetime prevalence of alcohol use disorders (abuse and dependence) is even more common. The Epidemiologic Catchment Area study demonstrated that among community-dwelling, nontreatment seeking individuals, that the lifetime prevalence of alcohol dependency was 13.7%.19 Results from the National Comorbidity Survey (NCS) by Kessler et al. demonstrated a lifetime prevalence of alcohol abuse plus dependency of 14.6% in females and 23.5% in males.20 Given these prevalence rates, a conservative estimate of the number of individuals directly affected by alcohol use disorders is at least 20–30 million in the United States at any given time. Additionally, it should be remembered that the number of individuals affected by those with alcohol use disorders through marriage and family, the worksite, and the highways is far greater than the number of individuals with alcohol use disorder. Surveys done in health care settings present a startling example of alcohol-related costs. In a primary care outpatient setting, problem drinking rates of 8–20% are seen, and between 20–40% of patients admitted to general medical hospitals have a history of alcohol use disorders.21 Medical morbidity of this extent obviously translates into significant mortality. United States data from the National Center for Health Statistics indicate 85,000 deaths due to either excessive or risky drinking in the U.S., making alcohol the third leading actual cause of death in 2000.22 This estimate is considered an underestimate, as many deaths which are associated with alcohol use are not coded as such on death certificates. A review of studies across multiple nations examining alcohol-related mortality demonstrated that alcoholics lose on average more than 20 years of potential life.23 In 1998, the estimated economic cost of alcohol abuse exceeded $184 billion in the United States, equivalent to roughly $638 for every man, woman and child living in the United States.24 Economic costs to industry alone in the United States have been estimated at $136 billion for 1990.25 Such costs include absenteeism, sick leave, decreased worker efficiency, and employee replacement costs through workers quitting, being fired, or dying prematurely. These summary statistics can be further broken down into risk indicators, which are more useful for preventive health purposes, such as targeting screening and prevention efforts. Alcohol use disorders are more common in males than females, with the ratio of affected males:females being approximately 2–3:1. While rates of females affected with alcohol use disorders are lower, health-related consequences of alcohol use in females who do not meet diagnostic criteria for alcoholism are more severe than in males. Review of health-related consequences of alcoholism in females later in this chapter will include medical risks associated with alcohol use in nonalcohol dependent drinkers. Age is another factor which can be used to characterize risk. Alcohol use disorders typically are most common in those under 45 years of age. Health-related morbidity is different across the age span, with more unnatural deaths (e.g., accidents, suicides, homicides) observed in younger age groups and more chronic disorders seen in the older age groups. Screening tools and definitions of alcohol use disorders in the elderly are less satisfactory than in middle age, and thus rates of alcohol use disorders in the elderly may be underestimated. A study in the International Journal of Geriatric Psychiatry, focusing on a review of different screening instruments, found that the AUDIT-5 has had promising results over other instruments such as the CAGE and MAST. No studies of alcohol use disorders in


55 elderly people with cognitive impairment were found, indicating a need for research in this area.26 Alcohol use disorders are seen across all socioeconomic groups. Alcohol use disorders cluster weakly in lower socioeconomic groups, but this may simply be secondary to alcohol’s contribution to poor school and job performance. Persons of Asian decent have lower rates of alcohol related disorders, presumably related to decreased levels of alcohol-metabolizing enzymes leading to flush reactions, tachycardia, and headache. Differences between blacks and nonblacks are significant, generally with nonblack rates being lower in both males and females. Drinking is most prevalent in urban America, and geographically in the Northeast. The comorbidity of alcohol use disorders and other psychiatric disorders is very common. The ECA study found that about half of individuals with alcohol use disorders had a concomitant psychiatric disorder.19 In the 2003 NSDUH study, those with a serious mental illness had a 21.3% rate of alcohol dependence and abuse and those without a serious mental illness had a dependence/abuse rate of 7.9%.17 The most commonly observed psychiatric comorbidities include antisocial personality disorder, mood disorders, and anxiety disorders.  GENERAL MECHANISMS OF ALCOHOL-RELATED DYSFUNCTION AND DAMAGE

A general schema of the mechanisms involved in alcohol-related tissue injury is provided in Fig. 55-1. Tissue in this context refers to either a single type of cell or a single organ. Besides having direct toxic effects on target tissue, alcohol also may act indirectly through a variety of mechanisms. Other alcohol-associated behaviors involving tobacco, risky sexual behavior, illicit drugs, and other drugs and chemicals as well as nonalcohol-related disease processes, may contribute as cofactors to the development, course, and outcome of alcohol-induced primary damage. In addition, alcohol may act as a factor influencing the development, course, and outcome of coincidental diseases.

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Much of the tissue damage that occurs in association with alcohol use has been attributed, at least in part, to direct toxic effects; for example, alcoholic hepatitis, cardiomyopathy, and neuronal degeneration. New findings however suggest that excitotoxicity mediated through alterations in glutamate neurotransmission may be responsible for many of the central nervous system (CNS) degenerative processes associated with alcoholism (e.g., WernikeKorsakoff syndrome, cerebellar degeneration, dementia associated with alcoholism).27 The effects on the CNS are of also of great importance in the development of various alcohol-related problems associated with acute intoxication and withdrawal from alcohol, as well as alcohol dependence.27,28 Acute effects are particularly important in circumstances under which drinkers may injure themselves or others.29 Alcohol also may act indirectly through the production of metabolic disturbances, endocrine changes,30 immune system changes,31 aggravation of obstructive sleep apnea,32 and displacement of dietary nutrients or impairment of their absorption or use,33 as well as through the effects of diseases caused by alcohol. Obstructive sleep apnea, a complication of alcohol use that occurs as a result of acute intoxication, is potentially important as a direct cause of morbidity and mortality.32 It may contribute also to the course and outcome of other alcohol- as well as nonalcohol-related diseases. This disturbance and its precipitation and aggravation by alcohol have been recognized only recently.34–36 When an alcohol-related health problem does occur, its course and outcome may be influenced by whether or not the affected individual continues to be exposed to alcohol and alcohol-related hazards. Furthermore, course and outcome may be influenced by whether or not he or she seeks, has access to, receives, and adheres to effective treatment, not only for the complications of alcohol use but also for the drinking behavior itself. A summary of the etiological significance of alcohol and associated variables that contribute to the excess mortality of heavy drinkers is provided in Table 55-1.

Ethanol

Tobacco Potential adverse effects

Direct effects

Illicit drugs

Metabolic

Neuroendocrine

Tissue vulnerable or resistant

Other drugs & chemicals

Non-alcoholic diseases

Consumption

Diseases

Response to infection Indirect effects

Adverse effects on target tissue

Adverse environment

Neglect

Sleep apnea Utilization Absorption Nutrient displacenent

Diet

Figure 55-1. Schematic representation of the general mechanisms involved in the development of alcoholrelated tissue injury.


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TABLE 55-1. ETIOLOGICAL SIGNIFICANCE OF ALCOHOL AND ASSOCIATED VARIABLES IN THE EXCESS MORTALITY OF CHRONIC HEAVY DRINKERS Heavy Tobacco Smoking

Effects of Alcohol

Cause of Death Tuberculosis Carcinoma Mouth Larynx Pharynx Esophagus Liver Lung Alcoholic cardiomyopathy Other cardiovascular disease Pneumonia Peptic ulcers Liver cirrhosis Alcoholic Nonalcoholic Suicide Accidents

Emotional Problems

Poor Food Habits

Other Personal Neglect

Increased Environmental Hazards

X

X

X

X XX XX XX XX X X XX XX XX XX

XX XX XX XX XX XX XX XX X

XX X XX XX

X

X XX X

X

XX

X XX XX X

XX

X

X

X, probably indicated; XX, clearly indicated. Where a space is left blank, either the factor is probably of no significance or its role, if any, is unknown. Source: Modified from Popham RE, Schmidt W, Israelstam S. Heavy alcohol consumption and physical health problems. A review of the epidemiologic evidence. In: Smart RG, Cappell HD, Glaser FB, et al (eds). Research Advances in Alcohol and Drug Problems. New York: Plenum Press, 1984, vol 8, pp 149–182.

Morbidity and Mortality The important health problems related to alcohol use were reviewed by the Institute of Medicine.37 The major health problems associated with alcohol use named in this report included alcohol withdrawal syndrome, psychosis, hepatitis, cirrhosis, pancreatitis, thiamine deficiency, neuropathy, dementia, and cardiomyopathy. Alcohol use also plays a key role in injury and accidents, suicide, and homicide. Also

important is a range of adverse pregnancy outcomes and fetal abnormalities caused by the embryotoxic and teratogenic effects of alcohol. The most common medical problems in alcohol-dependent and heavy drinking men, in terms of decreasing lifetime incidence, are trauma, acute alcoholic liver disease, peptic ulceration, chronic obstructive lung disease, pneumonia, hypertension, gastritis, epileptiform disorders, acute brain syndromes, peripheral neuritis, ischemic heart disease and cirrhosis (Table 55-2).38 This pattern of lifetime

TABLE 55-2. RANKING OF LIFETIME INCIDENCE, RATIO OF OBSERVED TO EXPECTED MORTALITY, AND PERCENTAGE OF EXCESS MORTALITY FOR SELECTED CAUSES IN MALE SAMPLES OF ALCOHOL-DEPENDENT AND OTHER HAZARDOUS DRINKERS Lifetime Incidence (%)a Rank 1 2 3 4 5 6 7 8 9 10 11 12

Disease a

Trauma (81.9) Acute alcoholic liver disease (49.9) Peptic ulcer (22.8) Obstructive lung disease (19.0) Pneumonia (16.8) Hypertension (12.4) Gastritis (11.5) Epileptic disorders (10.9) Acute brain syndromes (7.7) Peripheral neuritis (7.1) Ischemic heart disease (8.1) Cirrhosis (6.4)

Mortality Ratiob Rank 1 2 3 4 5 6 7 8 9 10

Cause of Death b

Cirrhosis (7.6) Suicide (4.4) Upper GI and respiratory cancer (4.1) Accidents (3.5) Tuberculosis (2.8) Peptic ulcer (2.8) Pneumonia (2.3) Cardiovascular disease (1.8) All cancer (1.7) Cerebrovascular disease (1.2)

Excess Mortality (%)c Rank

Cause of Death

1 2 3 4 5 6 7

Cardiovascular disease (21.4)c Suicide (14.7) Accidents (11.1) Cirrhosis (11.0) Malignant neoplasms (11.8) Pneumonia (8.8) Cerebrovascular disease (5)

a Based on lifetime incidence of certain diseases and complications in male patients admitted to a Canadian hospital for the treatment of alcoholism. From Ashley MJ, Olin JS, le Riche WH, et al. The physical disease characteristics of inpatient alcoholics. J Stud Alcohol. 42:1–14, 1981. The percentage, in parentheses, is shown after each disease or complication. b Based on analyses of ratios of observed to expected mortality by cause in male samples of alcohol-dependent and other heavy drinkers. From Popham RE, Schmidt W, Israelstam S. Heavy alcohol consumption and physical health problems. A review of the epidemiologic evidence. In: Smart RG, Cappell HD, Glaser FB, et al (eds). Research Advances in Alcohol and Drug Problems. New York: Plenum Press, 1984, vol 8, pp 149–182. The median mortality ratio, in parentheses, is shown after each cause of death. cBased on analyses of percentages of excess mortality in alcohol-dependent and heavy drinking men attributable to selected causes. From Ashley MJ, Rankin JG. Hazardous alcohol consumption and diseases of the circulatory system. J Stud Alcohol. 41:1040–1070, 1980. The median percentage value for excess mortality, in parentheses, is shown after each cause of death.


55 morbidity contrasts greatly with the ranking in terms of excess mortality, namely, cardiovascular disease, suicide, accidents, cirrhosis, malignant neoplasms, pneumonia, and cerebrovascular disease.39 These differences in patterns of morbidity and mortality are related to the lethality of the conditions, the risk of this population dying from these disorders compared with the community-at-large,40 and the frequency of the conditions in the general adult population. The three most common causes of excess mortality, that is, cardiovascular disease, suicide, and accidents, occur as acute problems, associated with sudden and usually unexpected death, whereas cirrhosis of the liver is the main chronic physical health problem in terms of incapacity and excess morbidity. Alcohol use in females results in exposure to all of the risks reviewed for men. Several consequences of drinking are more common in females, often with less quantity of alcohol use than in males. In females, accidents and suicidal mortality predominate in adolescence and young adulthood as health consequences of drinking. In middle age, breast cancer and osteoporosis become issues of concern. Compared to nondrinkers, women who consume an average of one drink per day, increase their risk of breast cancer by approximately 7% while those who consume an average of 2–5 drinks per day increase their risk by 50%.41 Drinking appears to be more detrimental to women than men with respect to liver disease. Higher cirrhosis rates among female alcoholics as compared to male alcoholics, with females having lower consumption rates has been observed in a variety of studies.42–44 Alcohol is also the most widely used substance associated with domestic violence. Females are most commonly the battered party, and both their use of alcohol and their partner’s use of alcohol appear to increase risk. The risk of HIV/AIDS and alcohol use presents similar concerns in females as well as males. Use of alcohol my influence the risk of acquiring HIV infection both through direct effects on the immune system, as well as increased likelihood of unsafe sexual behavior during periods of intoxication.  ESTIMATING THE PUBLIC HEALTH IMPORTANCE OF ALCOHOL-RELATED PROBLEMS

In alcohol-consuming nations the public health importance of alcoholrelated health problems usually is considered by each country to be significant.45 There are differences, however, from country to country, concerning the impact of alcohol-related health problems on the total burden of ill health.

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The impact of alcohol-related health problems is felt, both directly and indirectly, by many different groups. This includes those with alcohol-related health problems, their families, other individuals or groups who may suffer injury or loss due to the use of alcohol by others, those who provide services for the prevention and treatment of alcohol-related problems, and the community at large. Many of the effects are tangible but immeasurable, such as the pain and suffering experienced by the alcohol-damaged individual and his or her family. However, other manifestations of alcohol-related problems are suitable for empirical study, for example, the incidence and prevalence of alcohol-related heath problems, the costs of health and social services attributable to these problems, the number of people who are disabled or die from alcohol-related problems, and the economic costs of illness, disability, and death. It may be possible to make reasonably good estimates for specific aspects of mortality and morbidity, for example, the burden of alcoholic psychoses in specialized institutions. Unfortunately, such direct consequences are only a small part of the total problem. This is illustrated in a report on alcohol-related deaths in Canada in 1980 (Table 55-3). Of the almost 18,000 such deaths (10.5% of all deaths), the vast majority (88%) were classified as indirectly related, that is, they were due to accidents, cancers, and circulatory and respiratory diseases in which alcohol was a contributing factor.46 This problem is further exemplified by U.S. studies in which only about 3% of recorded deaths were officially attributable to alcohol, 1.9% were attributable to an alcoholrelated condition, and the remaining 1.2% had an alcohol-related condition listed along with the specified cause of death.47 These figures are small when compared with estimates that alcoholdependence is responsible for 1 in 10 deaths the United States,48 and when follow-up studies demonstrate high alcohol-related mortality.49 Despite such shortcomings in available statistics, there is no doubt about the serious toll of morbidity and mortality that alcohol use exacts from alcohol-consuming societies, such as the United States and Canada. These countries rank as moderate consuming nations, and one can assume that the toll is higher in heavier consuming nations. Selected indicators of the public health impact of alcohol use in Canada (Table 55-3)46,50 illustrate this clearly. In the period of these studies, 1979–1980, of Canadians 15 years and over, at least 12% regularly were consuming enough alcohol to be at increased risk of health consequences, 5% of current drinkers were alcohol-dependent and almost 10% experienced at least one alcohol-related problem. More than one in 10 deaths were alcoholrelated. In an earlier study of premature deaths and potential years of

TABLE 55-3. SELECTED INDICATORS OF THE PUBLIC HEALTH IMPACT OF ALCOHOL USE IN CANADA Indicator Population 15 years and over drinking 14+ drinks per week53

Year 1978–1979

Selected Findings Overall 12% Age group 20–24

Alcohol-dependent persons49 Current drinkers 15 years and older with alcohol-associated problem49

Current drinkers 15 years and over with at least one alcohol-associated problem49 Alcohol-related deaths49

a

1980 1978–1979

1978–1979

1980

Males 19.4% Females 4.8% Males 31.0% Females 8.1%

600,000 persons; 1 in 19 (5.3% of) current drinkers Tension or disagreement with family or friends Problems with health Difficulty with driving Injury to self or other Trouble with the law Trouble with school or work Overall 9.7% Males 12.4% Females 6.1%

6.1% 2.3% 1.5% 1.3% 1.3% 1.2%

17,974 (10.5%) of all deaths Directly related deaths: 2,110a Indirectly related deaths: 15,864b

Deaths due to alcohol-related cirrhosis, alcohol dependency syndrome, the nondependent abuse of alcohol, alcoholic psychoses, and accidental poisoning by alcohol. Deaths due to motor vehicle accidents, falls, fires, drownings, homicides, suicides (5,554 in 1980), as well as circulatory and respiratory diseases and certain types of cancer (e.g., oral, esophageal, and laryngeal) totaling 10,310 in 1980. b


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TABLE 55-4. ESTIMATED COSTS OF ALCOHOL-RELATED PROBLEMS IN THE UNITED STATES IN 1983 $Billion  Core Costs Direct

Indirect

Treatment Health support services Subtotal Mortality Reduced productivity Lost employment Subtotal

13.457 1.549 15.006 18.151 65.582 5.323 89.056 104.062

Motor vehicle crashes Crime Social welfare administration Other Subtotal Victims of crime Incarceration Motor vehicle crashes Subtotal

2.697 2.631 0.049 3.673 9.050 0.194 2.979 0.590 3.763 12.813 116.875

Total core costs  Other Related Costs Direct

Indirect

Total other related costs  Total Costs

%

12.8

76.2 89.0

7.8

3.2 11.0 100.0

Source: Adapted from U.S. Department of Health and Human Services. Sixth Special Report to the U.S. Congress on Alcohol and Health from the Secretary of Health and Human Services. DHHS Publication No. (ADM) 871519. Rockville, MD: U.S. Government Printing Office, 1987 and U.S. Bureau of the Census: Statistical Abstract of the United States, 106th ed. Washington, DC: U.S. Bureau of the Census, 1985. Gross national product (GNP) in 1983: $3305.0 billion; costs of alcohol-related problems: 3.54% of GNP. Total costs of health services in 1983: $355.4 billion; cost of direct services for alcohol-related problems: 4.22% of total costs of health services.

life lost in Canada in 1974, it was concluded that no other risk factor was responsible for more premature mortality than either smoking or hazardous drinking.51 The adverse health consequences of drinking remain a major health problem, despite evidence since this period of study and in association with a plateauing and modest fall in alcohol consumption, that there has been a significant decline in various indicators of alcohol-related health problems in Canada.52,53 Furthermore, tobacco and alcohol continue to rate first and second as risk factors responsible for premature mortality. A different approach to quantifying the effects of alcohol-related health problems is to express them in monetary terms. Such an approach is useful because it provides an estimate of the relative distribution of the costs, for example, across organ systems or various health and social services, as well as a measure of total costs. Thus, these figures can be used to compare the costs of alcohol-related problems with other health problems as a basis for focusing the attention of the community or making policy decisions regarding the funding of prevention, treatment, and research. An example of an economic approach to measuring the magnitude of alcohol-related problems is contained in Table 55-4, which provides an estimate of the costs of alcohol-related problems in the United States in 1983.54,55 First, notice that the total cost is large, $116.875 billion. Of this amount, 89.0% was attributable to core costs, including losses in productivity associated with disability and death (76.2%) and costs incurred in the treatment and care of people with alcohol-related health problems (12.8%). Total alcohol-related health costs ranked a close second to heart and vascular disease, as the prime health cause of economic loss and were well ahead of cancer and respiratory disease. In this analysis, other related costs covered nonhealth alcohol-related costs attributable to motor vehicle crashes and fires, highway safety and the fire protection, and the criminal justice and social welfare systems. The costs of alcohol-related problems were equal to 3.54% of the gross national product, and the direct costs for health services were equal to 4.22% of the total costs of health services. Although these figures are

large, very likely they are underestimates of the true economic costs of alcohol-related problems.

Prevention Strategies The public health approach to disease prevention was first classified in 1957 as proposed by the Commission on Chronic Illness.56 Primary, secondary, and tertiary prevention techniques were defined. In this model, primary prevention is geared towards efforts to decrease new cases of a disorder (incident cases), secondary prevention is designed to lower the rate of established cases (prevalent cases), and tertiary prevention seeks to decrease the amount of disability associated with existing disorder or illness. Gordon57,58 later proposed an alternative classification system which incorporated the concept of the risks and benefits in the evaluation of prevention efforts. His categories of prevention strategies consisted of universal measures, selective measures, and indicated measures. Universal prevention measures are measures of low cost, and low risk for which benefits outweigh costs when they are applied to everyone in an eligible population. Selective measures are desirable only for a select population at above average risk of development of a disorder. Indicated preventive measures are applied to individuals who, upon screening examination, demonstrate high risk of development of a disorder. The Institute of Medicine (IOM) noted that both of these classification systems were designed and worked best for traditional medical disorders59, but that their application to mental disorders was not straightforward. An alternative system was proposed by the IOM, which is referred to as the Mental Health Intervention Spectrum for Mental Illness. This system incorporates the whole spectrum of interventions for mental disorders, from prevention, through treatment, to maintenance. Table 55-5 outlines this spectrum. The term prevention is reserved for those interventions that occur before the initial onset of the disorder, and it incorporates many of Gordon’s concepts such as universal, selective, and indicated measures.


55 TABLE 55-5. MENTAL HEALTH INTERVENTION FOR MENTAL DISORDERS62 1. Prevention Universal Selective Indicated 2. Treatment Case identification Standard treatment for known disorders 3. Maintenance Compliance with long-term treatment After-care

Universal Prevention Efforts A significant amount of evidence suggests that early use of alcohol along with under-achievement, school problems, and aggressive behavior predict future problem drinking. While some of this risk may be due to genetic vulnerability to alcohol use disorders (covered under selective prevention efforts below), clearly genetic-environmental interactions are likely. Broader community context factors external to the individual are also strong predictors of alcohol use and problems. Community use patterns, availability of alcohol (including legal drinking age, cost, and enforcement), and peer group behavior affect the use and abuse of alcohol. Universal prevention efforts have been tried in various forms. Community-based programs for the prevention of alcohol abuse and alcohol-related problems were recently reviewed by Aquirre-Molina and Gorman.60 This review summarized studies concerned with changing the behavior of individuals rather than environmental changes such as altering availability. Data analysis for many such studies is ongoing and hence their ultimate impact is unknown. Community-based studies designed to change behavior of individuals are difficult to design, implement, and complete. A more direct universal prevention strategy involves limiting availability, increasing enforcement of laws pertaining to alcohol use, legislating stricter laws, improving community standards, and increasing the cost of alcoholic beverages through taxation. A substantial body of evidence now supports the view that increases in overall or per capita consumption are associated with higher rates of heavy drinking and, consequently, with increased frequencies of alcohol-related health problems.61–65 Studies of relationships between per capita alcohol consumption and alcohol-related morbidity and mortality have focused on cirrhosis, where a strong positive correlation has been established.66 Per capita consumption also has been correlated positively with total mortality in men,67 international variations in deaths from diabetes mellitus,68 deaths from alcohol-related disease,69 alcoholism death rates,70 and hospital admission for alcohol dependence, alcoholic psychosis, liver cirrhosis, pancreatitis,71 Wernicke’s encephalopathy, and Korsakoff’s psychosis.72 Recognition of the relationships among per capita alcohol consumption, rates of heavy use, and the incidence of alcohol-related health problems has focused attention on universal prevention strategies aimed at the drinking population, generally with the principal objective of reducing per capita alcohol consumption. Critical reviews suggest that measures addressing the economic and physical accessibility of alcohol are among the most effective in this regard.73

Economic Accessibility Numerous studies, reviews, and reports have examined the use of price control via taxation in reducing alcohol consumption and alcoholrelated problems. The accumulated evidence indicates that price control could be effective and, in some instances, powerful, both in relation to other measures and in combination with them.7,54,74–77 According to Cook78,79 and Cook and Tauchen,80 doubling the federal

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tax on liquor in the United States would reduce the cirrhosis mortality rate by at least 20%. An effect on automobile fatalities also was postulated.78 Holder and Blose81 used a system dynamics model to study the effect of four prevention strategies; raising the retail price of all alcoholic beverages by 25% once, indexing the price of alcoholic beverages to the consumer price index (CPI) each year, raising the minimum drinking age to 21 years, and reducing high-risk alcohol consumption through state-of-the-art public education on alcohol-related family disruptions and alcohol-related work problems, against a background of business as usual in three counties of the United States. Although both outcome measures were modestly sensitive to one-time changes in price, the largest effect was obtained by instituting a community education effort concurrently with indexing the prices of alcoholic beverages to the CPI. From an analysis of the price of beer and spirits, other economic and sociodemographic factors, and various regulatory control variables, Ornstein82 concluded that price was the most important policy tool available to regulators in the United States. A similar conclusion arose from a study of the effects of various regulatory measures on the consumption of distilled spirits in the United States over a 25-year period.83 Levy and Sheflin,84 using methods intended to overcome the problem of beverage substitution when price control is not directed at all beverages, estimated that the price elasticity for total alcohol consumption, although less than one (implying that demand is inelastic), was large enough for price policies to be effective in reducing alcohol consumption. Others,85–90 however, have been more guarded in their support for price manipulation as a control measure, pointing out the methodological limitations in econometric analyses, the modest or conflicting implications of some findings, and the possible role of countervailing forces. In a study of individual drinkers, Kendell and colleagues91,92 found that overall consumption and associated adverse effects fell 18% and 16%, respectively, among 463 “regular drinkers” in the Lothian region of Scotland when prices were increased via the excise duty. Heavy and dependent drinkers reduced their consumption at least as much as light and moderate drinkers, with fewer adverse effects as a result. Clinical data also show that alcohol-dependent persons reduce their alcohol consumption as a function of beverage costs.93,94 Further, in an experimental study of price reductions during afternoon happy hours, Babor and associates95 found that such reductions significantly increased alcohol consumption by both casual and heavy drinkers. With the reinstatement of standard prices, drinking in both groups returned to previous levels. These findings and others75,79,80,96 seriously challenge the previously held view that a reduction in overall consumption does not affect consumption by the heaviest drinkers. Further, liver cirrhosis mortality rates, which are considered the most accurate indicator of the prevalence of heavy drinking, respond directly and rather quickly to major restrictions on availability, including economic ones, that produce declines in per capita consumption.7,62,80 It is reported that 4% of deaths worldwide are due to alcohol, putting alcohol deaths on a par with the 4.1% deaths caused by smoking and the 4.4% of deaths caused by high blood pressure. Aldridge reported that if prices for alcohol increase by 10%, deaths in cirrhotic males decrease by 7%, showing that price increase is effective in reducing harm.97 Price elasticities of alcoholic beverages vary by type of beverage, across time, and among countries.7 In the United States, as in Canada and the United Kingdom, beer tends to be relatively price inelastic.62,98,99 However, this general inelasticity does not hold in certain age groups. Grossman and colleagues100–103 estimated the effects on young people of increases in alcoholic beverage prices with regard to alcohol use and motor vehicle mortality. They showed that for beer, the alcoholic beverage of preference in the young, the price elasticity was considerably higher than that usually reported, a 10 cent increase in the price of a package of six 12-once cans resulting in an 11% decrease in the number of youths drinking beer and a 15% decrease in the number of youthful heavy beer drinkers (3–5 drinks per day).100 Further, they predicted that a national policy simultaneously taxing the alcohol in beer and distilled spirits at the same rates and offsetting the erosion in the real beer tax since 1951 would reduce the number of youths 16–21 years old who drink beer frequently (4–7 times a week, about 11% of youths) and fairly


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frequently (1–3 times a week, about 28% of all youths) by 32% and 24%, respectively.104,105 Additional analyses showed dramatic effects of excise tax policies on motor vehicle accidents in youths.101–103 In a multivariate analysis, it was estimated that a policy that fixed the federal beer tax in real terms since 1951 would have reduced the number of motor vehicle fatalities in youths ages 18–20 in the period 1975–1981 by 15%, and a policy that taxed the alcohol in beer at the same rate as the alcohol in liquor would have lowered fatalities by 21%. A combination of the two policies would have caused a 54% decline in the number of youths killed. In contrast, the enactment of a uniform drinking age of 21 years in all states would have reduced such fatalities by 8%, with considerable additional costs in enforcement. Since the principal objective of price control in the public health context is universal prevention, differentially higher price sensitivity among young drinkers for beer is an especially important finding. Price control via taxation has been recommended repeatedly as a strategy for stabilizing or reducing per capita consumption and, thereby, preventing alcohol-related health problems.77,106–108 In the United States, recent public opinion polls indicate clear, majority support for excise tax increases on alcohol for public health purposes.77 However, federal excise taxes on distilled spirits, wine, and beer remained constant in nominal terms (current dollar value) between November 1, 1951, and the end of fiscal year 1985.101 In 1985, the federal excise tax on distilled spirits was raised slightly (as a deficit reduction measure), but federal tax rates on beer and wine were not changed. Thus, the real price of alcoholic beverages has actually declined in recent years, such that between 1960 and 1980 the real price of liquor declined 48%, beer 27%, and wine 20%.78 A similar situation has been documented in Ontario, Canada, where a taxation policy that would maintain a reasonably constant relationship between the price of alcohol and the consumer price index has been a key element in a long proposed, but unimplemented prevention strategy.106 Examples of increased taxation and improved health outcomes can be see in two more recent studies. In 2000, Switzerland imported 2 million bottles of “alcopops” but that jumped to 39 million bottles in 2002. In 2004, Swiss officials quadrupled taxes on alcopops and slowed consumption and decreased sales to young people by half in doing so.109 In the United States on January 1, 1991, the federal excise tax on beer increased for the first time since 1951.109 The rates of STDs, violence, and traffic fatalities decreased when the price of beer increased.110

Similarly, sudden, marked relaxation in the availability of alcohol is associated with increases in overall consumption, heavy drinking, and alcohol-related problems. The Finnish experience, which included a very marked increase in overall consumption in connection with liberalizing legislation that led to an extensive and rapid increase in outlets in previously dry areas, has been detailed115 and summarized105 elsewhere. A number of additional factors play a role in physical accessibility to alcohol. These factors include the times of sale permitted, the types, characteristics, and location of outlets, and the distribution system of alcoholic beverages. Different positive and negative consequences may be seen as a result of even subtle changes. For example, while restricting the number of outlets may lead to decreased consumption, a rise in automobile crashes associated with alcohol use can be seen due to driving after acquiring the beverage of choice, as location of purchase is related to where it is consumed.116 The rapidity with which community changes are made also of importance upon the outcome of the change.45,105,111 If multiple outlets for alcohol sale are added in formerly dry areas, the subsequent marked increase in overall consumption has been previously discussed.111,115 These examples all point to the need for careful consideration and monitoring of changes made in the physical availability of alcohol in society.

Legal Accessibility Age limitations represent a legal barrier to alcohol. Most countries have age restrictions on its purchase or consumption or both.45 Although the data are neither unflawed nor entirely consistent, there is much evidence that the lower the drinking age, the higher the consumption of alcohol45,101,117–120 and the higher the incidence of alcoholrelated problems, particularly among teenagers.45,105,112,117,118,121,122 Lowered blood alcohol content (BAC) limits for legal driving have recently been instituted in most states in the United States. The effect of such measures on automobile crashes and automobile fatalities will be an important outcome measure. The tradeoff of increased costs, potential social stigma, and consequent increased rates of alcohol use disorder diagnoses for individuals caught with the lowered alcohol blood levels has not been factored into decisions to lower the legal driving limits, but obviously some price will be paid.

Selective Intervention Efforts Physical Availability The relationship between the physical availability of alcohol and alcohol consumption and related problems is multifaceted and complex. It is difficult to show the effect of small changes and to untangle the effects of changes in physical availability that take place simultaneously with others, either nonspecific changes (e.g., in the general economy) or specific changes (e.g., in the economic and legal accessibility of alcohol). It is not surprising, therefore, that the evidence concerning the effectiveness of limitations on physical accessibility is mixed.7,45,61,104,105,111–114 Taken together, there is considerable evidence that controls on physical availability can reduce alcohol-related problems and that the consumption of both heavy and moderate drinkers can be reduced. Prohibition is successful in reducing consumption and attendant health risks.7,45,61,105 Such a situation prevails in some countries today.105 With the institution of Prohibition in the United States earlier in this century, cirrhosis mortality rates fell dramatically and remained well below their former levels during the earlier years and to a considerable extent even in the later years, indicative of greatly decreased consumption.61 On repeal of Prohibition and the subsequent increase in the availability of alcohol, consumption rose, and cirrhosis mortality rates gradually increased toward previous levels. Similar trends have been observed in the face of other severe limitations on availability, for example, in Paris during the two World Wars7,65 and during some strikes and periods of rationing.45,104,105,111 Under such conditions, the consumption of both heavy and moderate drinkers is reduced.104,105,111,112

Selective intervention efforts are those efforts geared towards individuals at greater than average risk of development of alcohol use disorders. The strongest predictor of who will develop alcohol dependency comes from the genetic literature. Family studies of alcoholics have clearly demonstrated that alcohol dependency is familial.123 First-degree offspring of an alcohol dependent parent are threefold to fourfold more likely to develop alcohol dependence than those without such a parent. Family studies are not useful in separating environmental factors from genetic factors important to the development of alcohol dependency. Studies of twins124,125 and adoptees126,127 have produced evidence for such genetic factors, although at this time no alcohol dependency gene has been found. While a gene for alcohol dependency awaits discovery, the results of the adoptee studies have demonstrated that heterogeneity in alcohol dependency exists, that is, there exists at least two types of alcohol dependence. The two types of alcoholism have been referred to as milieu-limited alcoholism, which requires the presence of environmental factors for alcoholism to develop (Type I alcoholism), and male-limited alcoholism (Type II alcoholism), which does not.128 These forms of alcohol dependency differ in terms of age of onset and associated symptoms. Type II alcoholism has an early age of onset, and often serious legal manifestations such as driving while intoxicated and fighting. Furthermore, there is evidence of various biological markers that potentially may prove valuable for targeting high-risk populations for intervention trials that have been discovered through various family and genetic studies of alcoholism.129


55 If a strong family history of alcohol dependence is discovered, it is important to educate unaffected individuals in the pedigree of their enhanced risk. This educational component should be added to the other interventions to be described later in this chapter.

Indicated Intervention Efforts Indicated intervention efforts are targeted towards high-risk individuals who are identified through screening to have hazardous drinking or early symptoms of alcohol dependence that have gone undetected. Screening methods are also important to uncover undiagnosed individuals with alcohol dependence, but who are able to mask such symptoms from others.

Screening for Alcohol Dependence Assessing patients for alcohol use disorders in a busy primary care setting is difficult. The importance of screening for alcoholism in primary care settings is essential to public health efforts to reduce the burden of alcohol-related problems. To ascertain a full history of alcohol use, and to assess whether an individual meets DSM-IV criteria for alcohol abuse or dependency, is generally considered too time consuming by many clinicians, and some doubt exists among clinicians of the validity of selfreport regarding use of alcohol. In 2000, only 37% of family physicians felt that their intervention could change an alcoholic’s drinking habits despite 88% of physicians asking new outpatients whether they drank alcohol and 13% using formal screening tools.130 Because of these concerns, a variety of screening tools have been proposed. The most commonly used tools are screening questionnaires and laboratory values. The most common screening questionnaires include the Michigan Alcoholism Screening Test (MAST),131 the abbreviated Brief-MAST,132 and the CAGE instrument.133 Several newer instruments include the Alcohol Use Disorders Identification Test (AUDIT)139 and the TWEAK instrument.140 Laboratory screening tests include blood alcohol levels, liver enzymes elevations, erythrocyte mean corpuscular volume, lipid profiles, and carbohydrate-deficient transferrin.

Screening Questionnaires A number of review articles are available which describe the use of alcohol use screening questionnaires. The U.S. Preventive Services Task Force’s Guide to Clinical Preventive Services, 2nd Edition136 provides a detailed review of the sensitivity and specificity for the MAST (84–100% and 87–95% respectively), Brief-MAST (66–78% and 80% respectively), CAGE (74–89% and 79–95% respectively for alcohol abuse and dependence; but only 49–73% sensitivity for heavy alcohol use), and the AUDIT134 (96% and 96% respectively in an inner city clinic; but only 61% and 90% in a rural setting). These sensitivity and specificity figures are for middle-aged adults. Adolescents and the elderly may not be as adequately screened by these instruments. Other limitations of these screening instruments include the MAST being rather lengthy for routine use (25 questions), the CAGE being most sensitive for alcohol abuse or dependency and not heavy drinking, and both the CAGE and MAST fail to distinguish current from lifetime problems due to alcohol. The AUDIT is very sensitive and specific for “harmful and hazardous drinking,” but uses a one-year timeframe for screening and hence is less sensitive for past drinking problems. Allen et al.137 offer guidelines for selection of screening tests in primary care. Based upon their review of the literature, use of the AUDIT, CAGE, or MAST was recommended. Because of time constraints in primary care, the AUDIT or CAGE were first choice recommendations, and the TWEAK was recommended for pregnant women.135 For adolescents, the adolescent drinking index (ADI)138 was suggested as a good option. In the elderly, two studies139,140 point to deficiencies in the CAGE as a screening tool, and suggest the need for more sensitive and specific tools in this population. Adams et al.140 suggests asking about quantity and frequency of alcohol use in addition to the CAGE to

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increase the detection of elderly hazardous drinking. O’Connell, et al. reported that the AUDIT-5 has had promising results as well in the elderly.26 The National Institute on Alcohol Abuse and Alcoholism (NIAAA) in collaboration with the American Medical Association offers the Helping Patients with Alcohol Problems: A Health Practitioner’s Guide free to help primary care physicians with patients who are risky drinkers. A growing body of research has shown that primary care practitioners can promote significant reductions in drinking levels of problem drinkers who are not alcohol dependent.141

Laboratory Screening Tools Alcohol induces a number of laboratory abnormalities. Unfortunately, to date laboratory tests for screening have not been as sensitive nor as specific for alcohol use disorders when compared to the screening questionnaires reviewed above. Liver enzymes, including gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase have all been used as screening tests. The GGT is the most useful of the liver tests. It demonstrates a sensitivity of between 50–90% for ingestion of 40–60 g of alcohol daily (3–4 standard drinks).142 The GGT rises most rapidly in response to heavy alcohol use, and with abstinence it returns to normal most rapidly. Other liver enzyme tests such as the AST, ALT, and alkaline phosphatase are less specific and sensitive than the GGT. Some have suggested use of the AST:ALT ratio of 1.5–2:1 as being an indicator of liver damage being more likely due to alcohol than other causes. While the AST and ALT are not adequately sensitive or specific to be recommended as screening laboratory tests, they have some utility as supportive tests. The GGT may be most useful as a marker for return to heavy drinking after a period of abstinence in which the GGT has returned to normal. If the GGT rises by 20%, a high likelihood for return to drinking can be assumed. Increase in mean corpuscular volume (MCV) is less sensitive to alcohol use than elevation in the GGT, but it is quite specific to heavy alcohol intake (up to 90%).143 Utility of the MCV is much like that of the AST and ALT, that is, helpful as supporting evidence, but not as a screening tool. The blood alcohol concentration (BAC) is useful, and can even support a diagnosis of alcohol dependence as outlined by the National Council on Alcoholism (NCA).144 A BAC of 100 mg/100 mL is considered a legally intoxicated level in most states, and is conclusive evidence for a driving while intoxicated charge. Individuals nontolerant to alcohol will generally appear intoxicated at such levels. A BAC of 150 mg/100 mL without gross evidence of intoxication suggests significant tolerance to alcohol, and fulfills criteria for alcohol dependence according to the NCA. A BAC of 100 mg/100 mL during a routine physical examination is highly suggestive of alcohol use problems according to the NCA. Thus, screening of BAC in patients who may appear intoxicated or smell of alcohol during a clinic visit can be very useful. A breath analysis of BAC is also a useful tool, and can be used to screen for individuals too impaired to drive home from emergency rooms or clinic visits if intoxication is suspected, and serum BAC cannot be readily performed or if patients refuse blood drawing. Carbohydrate-deficient transferrin (CDT), a protein associated with iron transport, appears to effectively distinguish alcoholics consuming large amounts of alcohol from light social drinkers or abstinent individuals. CDT levels (which elevate due to few conditions other than heavy drinking) decrease the probability of false positives and elevate substantially earlier with heavy drinking than GGT levels. While excellent sensitivity and specificity could be demonstrated, disadvantages include lower sensitivity in women and adolescents, and the high cost of the laboratory analysis.145 Presently, none of the laboratory markers reviewed offer advantages in sensitivity or specificity over the screening questionnaires reviewed. However, in a general medical setting, liver enzymes and


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MCV are often ordered as part of the medical work-up for individuals presenting for care. The laboratory studies in combination with screening questionnaires can be useful in discussions with patients regarding the health consequences of their alcohol use.

Treatment Interventions This chapter is devoted primarily to prevention strategies. While this is the focus of the chapter, unless primary care clinicians become aware of their potential impact on reducing hazardous and problem drinking, it is doubtful that prevention strategies will be emphasized. Similarly, physicians are unlikely to inquire about alcohol use if they feel they lack the skills to intervene or if they feel interventions are unsuccessful. In a survey of Australian medical trainees in internal medicine, psychiatry, and general practice, there was a high level of agreement that alcohol use history should be obtained from all patients, and that problem drinking should be managed, but views on treatment were less positive.146 There was considerable uncertainty regarding treatment modalities most readily available to the primary care physician, that is, brief advice and cognitive-behavioral therapies. In this study, the trainees were most certain that alcoholics anonymous (AA) techniques for treatment were well supported in the literature. While AA has been a well-supported and beneficial treatment for alcohol-dependent individuals since its beginnings in 1935, its fellowship is most appropriate for individuals who are alcohol-dependent and less likely to be an acceptable treatment modality for patients who are nondependent, but who are displaying hazardous drinking styles. This distinction is imperative, as the hazardous drinking population far exceeds the dependent population of drinkers, and as previously noted contributes greatly to the societal burdens of alcohol use problems. The hazardous, but nondependent, population of drinkers is also more likely to respond to brief interventions for alcohol problems. Another reason the primary care physician should be familiar with brief intervention techniques involves the lack of many alcohol-dependent individuals to follow through on recommendations to seek more formal treatment on referral. In a study of 1200 emergency room patients diagnosed as alcohol dependent advised to seek treatment, only 5% did so.147 A similar finding was noted in a study of U.S. veterans screened for at-risk drinking. Of those who were identified as having at-risk drinking, only 5% followed advice to return for a single consultation session regarding their drinking.148 These studies point to the need for the primary care physician to be skilled in office-based techniques to help patients modify and reduce or stop their alcohol use.

Effective Intervention Recent evidence strongly suggests that brief interventions in the early stages of heavy drinking are both feasible and effective.148,149 Edwards and colleagues,150 in a controlled clinical trial of intensive inpatientoutpatient treatment versus brief advice for alcoholism, found the latter to be more effective in nondependent alcohol abusers after two years of follow-up,151 whereas physically dependent patients achieved better results with more intensive treatment. In a randomized controlled trial of general practitioner intervention in patients with excessive alcohol consumption, Wallace and associates152 showed that advice on reducing alcohol consumption was effective. If the results of their study were applied to the United Kingdom, intervention by general practitioners in the first year could reduce to moderate levels the alcohol consumption of some 250,000 men and 67,500 women who currently drink to excess. Other studies have shown the effectiveness of brief intervention in socially stable, healthy, problem drinkers who do not have a high degree of alcohol dependence and whose histories of problem drinking are short.153–157 A careful assessment of alcohol dependence in detected heavy drinkers underpins the determination of the appropriateness of brief intervention.158

To examine whether brief intervention has benefits beyond one year, investigators in Norway159 reassessed 247 adults who in 1986 had been drinking at least 2–3 times per week, had elevated GGT levels and had entered a randomized trial of brief intervention. They received either a 10-minute discussion of possible reasons for elevated GGT or 15 minutes of counseling regarding decreasing drinking and monthly visits until GGT levels normalized or no intervention. Nine years after the original trial (70% follow-up) those who had received brief intervention, had significant decreases in GGT levels. The better outcomes among drinkers with high GGT levels than among those with lower levels suggests that the intervention played a role. This study suggests that brief intervention for risky drinking may be more effective than previously thought. The degree of alcohol dependence also is crucial in determining whether the treatment goal should be moderation (i.e., controlled drinking) or abstinence.149,158,160 Moderation appears to be a realistic alternative in problem drinkers who are not heavily alcohol dependent, as is often the case in the early-stage heavy drinkers.149,154,158,161–163 It may be a more acceptable treatment goal, particularly in environments where alcohol use is especially diffuse163 and among young drinkers, who may perceive the costs of abstinence to outweigh the risks from continued drinking.158,164 A five-step early intervention and treatment strategy for use in clinical practice settings has been developed158, along with self-help manuals149 and procedures for teaching moderate drinking and abstinence.164 Evaluations of brief interventions conducted as part of a general health screening project,165 among problem drinkers in a general hospital,166,167 in community referral centers for referred problem drinkers,161,168 and in a family practice setting169 are promising. This approach may be applicable beyond the clinical setting, for example, in the workplace, with considerable potential for public health impact.153,161 A review of 32 controlled studies of brief interventions demonstrate effectiveness of such techniques across 14 nations.148 Skinner170 has discussed the reasons why early detection and effective intervention strategies deserve major emphasis. To summarize: most heavy drinkers do not seek treatment for their alcohol problems, socially stable persons at early stages of problem drinking have a better prognosis, health professionals in primary care settings are in an excellent position to identify problem drinkers, and brief intervention by health professionals can be effective in reducing heavy alcohol use. Skinner cited reasons why early detection and effective intervention are not occurring, namely, widespread pessimism among health professionals about being able to intervene effectively, confusion regarding responsibility for confronting alcohol problems, uncertainly about the target population, lack of appreciation of what are appropriate interventions, and deficiencies in the practical skills and techniques to carry them out. He suggested that training materials and opportunities be readily available and incorporated into core education programs, and that strenuous efforts be made to convince key people in the health professions to give early detection and effective intervention a high priority.

 SUMMARY

Alcohol use problems are not restricted to those with alcohol abuse or dependency. Recognition of hazardous drinking as being linked to many health-related and societal burdens of alcohol is a first step towards a rational public health policy. Primary care providers are asked to screen for and be able to treat many different disorders. Alcohol use problems have, for too long, been viewed as either untreatable, or in all cases needing specialty management. Evidence exists that office screening tools, combined with relatively brief interventions, can be powerful methods to help assist a large population at risk. While the alcohol screening must compete with many disorders for primary care providers’ attention, it is hoped that the data presented in this chapter will raise the priority of alcohol use disorder in the minds of those caregivers.


55  REFERENCES

1. Kreitman N. Alcohol consumption and the prevention paradox. Br J Addict. 1986;81:353–63. 2. Davidson DM. Cardiovascular effects of alcohol. West J Med. 1989;151:430–39. 3. National Institute on Alcohol Abuse and Alcoholism: Moderate drinking. Alcohol Alert No. 16. Bethesda, MD: U.S. Department of Health and Human Services; 1992. 4. Dietary Guidelines Advisory Committee. Report of the Dietary Guidelines Advisory Committee on the Americans, 2005, to the Secretary of Health and Human Services and the Secretary of Agriculture. Washington, DC: U.S. Department of Agriculture; 2005. 5. Secretary of State for Health. The Health of the Nation: A Strategy for Health in England. London: Her Majesty’s Stationery Office; 1992. 6. Pols RG, Hawks DV. Is there a safe level of daily consumption of alcohol for men and women? Recommendations responsible drinking behavior. Technical Report for the National Health and Medical Research Council, Health Care Committee. Canberra: Australian Government Publishing Service; 1987. 7. Bruun K, Edwards G, Lumio M, Makeli K, Pan L, Popham RE, et al. Alcohol Control Policies: Public Health Perspective. Vol 25. The Finnish Foundation for Alcohol Studies. Helsinki: Finnish Foundation for Alcohol Studies; 1975. 8. Kreitman N. Alcohol consumption and the prevention paradox. Br J Addict. 1986;81:353–63. 9. Pequignot G, Tuyns A. Rations d’alcool consommees “declarers” et risques pathologiques. In: INSEAM. Paris; 1975:1–15. 10. Streissguth AP, Clarren SK, Jones KL. Natural history of the fetal alcohol syndrome. Lancet. 1985;2:85–92. 11. Little RE, Streissguth AP. Effects of alcohol on the fetus: impact and prevention. Can Med Assoc J. 1981;125:159–64. 12. Lieber CS: Medical disorders of alcoholism. N Engl J Med. 1995;333(16):1058–65. 13. Popham RE, Schmidt W. The biomedical definition of safe alcohol consumption: a crucial issue for the researcher and the drinker. Br J Addict. 1978;73:233–5. 14. World Health Organization (WHO). The ICD-10 Classification of Mental and Behavioural Disorders. Geneva: World Health Organization, 1992. 15. American Psychiatric Association. DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders. 4th ed., Text Revision. Washington, DC: American Psychiatric Association, 2000. 16. Caetano R, Tarn TW. Prevalence and correlates of DSM-IV and ICD-10 alcohol dependence: 1990 U.S. national alcohol survey. Alcohol Alcohol. 1995;30:177–86. 17. Department of Health and Human Services, National Survey on Drug Use and Health, SAMHSA, Office of Applied Studies, Rockville, MD; 2003. 18. Office of Applied Studies. Results from the 2005 National Survey on Drug Use and Health: National Findings. SAMHSA, U.S. Department of Health and Human Services, 2005. Available at www.oas.samhsa.gov. 19. Helzer J. Psychiatric diagnoses and substance abuse in the general population: the ECA data. NIDA Res Monogr. 1988;81:405–15. 20. Kessler RC. McGonagle KA, Shanyang Z, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the national comorbidity survey. Arch Gen Psychiatry. 1994;51:8–19. 21. Allen JP, Maisto SA, Connors GJ. Self-report screening tests for alcohol problems in primary care. Arch Intern Med. 1995;155(16): 1726–30. 22. Mokdad A, Marks J, Stroup D, Gerberding J. Actual cause of death in the United States. JAMA. 2004;291:1238–45.

Alcohol-Related Health Problems

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23. Poldrugo F, Chick JD, Moore N, Walburg JA. Mortality studies in the long-term evaluation of treatment of alcoholics. Alcohol Alcohol Suppl. 1993;2:151–5. 24. National Institute on Alcohol Abuse and Alcoholism, 2000. 10th Special Report to the U.S. Congress, Chapter 6, NIH Publication 001583, Rockville, MD: Department of Health and Human Services; 2000. 25. Burke TR. The economic impact of alcohol abuse and alcoholism. Public Health Rep. 1988;103:564–8. 26. O’Connell H, Chin A, Hamilton F, Cunningham C, Walsh JB, Coakley D, et al. A systematic review of the utility of self-report alcohol screening instruments in the elderly. Int J Geriatr Psychiatry. 2004;19:1074–86. 27. Tsai G, Gastfriend DR, Coyle JT. The glutamatergic basis of human alcoholism. Am J Psychiatry. 1995;152(3):332–40. 28. Gross MM. Psychobiological contributions to the alcohol dependence syndrome: a selective review of recent research. In: Edwards G, Gross MM, Keller M, et al, eds. Alcohol Related Disabilities. Geneva: World Health Organization; 1977:107–31. 29. Borkenstein RF, Crowther RF, Shumate RP, Ziel WB, Zylman R. The Role of the Drinking Driver in Traffic Accidents. Bloomington, IN: Department of Police Administration, Indiana University; 1964. 30. Lieber CS. Medical disorders of alcoholism. Pathogenesis and treatment. In: Smith LH, Jr, ed. Major Problems in Internal Medicine. Vol 22. Philadelphia: WB Saunders; 1982. 31. Kronfol Z, Nair M, Hill E, Kroll P, Brower K, Greden J. Immune function in alcoholism: a controlled study. Alcohol Clin Exp Res. 1993;17:279–83. 32. Remmers JE. Obstructive sleep apnea. A common disorder exacerbated by alcohol. Am Rev Respir Dis. 1984;130:153–5. 33. Rankin JG. Alcohol—a specific toxin or nutrient displacer. In: Hawkens WW, ed. Drug-Nutrient Interrelationships: Nutrition & Pharmacology—An Interphase of Disciplines, Miles Symposium III. Hamilton, Ontario: McMaster University; 1974:71–87. 34. Issa FQ, Sullivan CE. Alcohol, snoring and sleep apnea. J Neurol Neurosurg Psychiatry. 1983;45:353–9. 35. Bonora M, Shields GI, Knuth SL, Bartlett D Jr, St. John WM. Selective depression by ethanol of upper airway respiratory motor activity in cats. Am Rev Respir Dis. 1984;130:156–61. 36. Krol RC, Knuth SL, Bartlett D Jr. Selective reduction of genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir Dis. 1984;129:247–50. 37. Institute of Medicine. Causes and Consequences of Alcohol Problems: An Agenda for Research. Washington, DC: National Academy Press; 1987. 38. Ashley MJ, Olin JS, le Riche WH, Kornaczewski A, Schmidt W, Corey PN, et al. The physical disease characteristics of inpatient alcoholics. J Stud Alcohol. 1981;42:1–14. 39. Ashley MJ, Rankin JG. Hazardous alcohol consumption and diseases of the circulatory system. J Stud Alcohol. 1980;41:1040–70. 40. Popham RE, Schmidt W, Israelstam S. Heavy alcohol consumption and physical health problems. A review of the epidemiologic evidence. In: Smart RG, Cappell HD, Glaser FB, et al, eds. Research Advances in Alcohol and Drug Problems. Vol 8. New York: Plenum Press; 1984:149–82. 41. American Cancer Society. Detailed Guide: Breast Cancer, 2006. http://documents.cancer.org/104.00/104.00.pdf. 42. Pequignot G, Chabert C, Eydoux H, Courcoul MA. Increased risk of liver cirrhosis with intake of alcohol. Rev Alcohol. 1974;20:191–202. 43. Wilkinson P, Santamaria JN, Rankin JG. Epidemiology of alcoholic cirrhosis. Australas Ann Med. 1969;18:222–6. 44. Loft S, Olesen KL, Dossing M. Increased susceptibility to liver disease in relation to alcohol consumption in women. Scand J Gastroenterol. 1987;22:1251–6.


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45. Moser J. Prevention of Alcohol-Related Problems: An International Review of Preventive Measures, Policies, and Programmes. Published on behalf of the World Health Organization, Toronto: Alcoholism and Drug Addiction Research Foundation; 1980. 46. Health and Welfare Canada. Alcohol in Canada. A National Perspective. 2nd ed. Ottawa: Health and Welfare Canada; 1984 47. Van Natta P, Malin H, Bertolucci D, Kaelber D. The influence of alcohol abuse as a hidden contributor to mortality. Alcohol. 1985;2: 535–9. 48. U.S. Department of Health and Human Services. Fifth Special Report to the U.S. Congress on Alcohol and Health from the Secretary of Health and Human Services. DHHS Publication No. (ADM) 841291. Washington, DC: U.S. Government Printing Office; 1983. 49. Finney JW, Moos RH. The long-term course of treated alcoholism: I. Mortality, relapse, and remission rates and comparisons with community controls. J Stud Alcohol. 1991;52(l):44–54. 50. Ableson J, Paddon P, Strohmenger C. Perspectives on Health. Ottawa, Ontario: Statistics Canada; 1983. 51. Ouellet BL, Romeder JM, Lance JM. Premature mortality attributable to smoking and hazardous drinking in Canada. Am J Epidemiol. 1979;109:451–63. 52. Smart RG. Mann RE. Large decreases in alcohol-related problems following a slight reduction in alcohol consumption in Ontario 1975–83. Br J Addict. 1987;82:285–91. 53. Mann RE, Smart RG, Anglin L. Reductions in liver cirrhosis mortality in Canada: demographic differences and possible explanations. Alcohol Clin Exp Res. 1988;12:1–8. 54. U.S. Department of Health and Human Services. Sixth Special Report to the U.S. Congress on Alcohol and Health from the Secretary of Health and Human Services. DHHS Publication No. (ADM) 871519. Rockville, MD: U.S. Government Printing Office; 1987. 55. U.S. Bureau of the Census. Statistical Abstract of the United States. 106th ed. Washington, DC: 1985. 56. Commission on Chronic Illness. Chronic Illness in the United States. Vol 1. Cambridge, MA: Harvard University Press; 1957. 57. Gordon R. An operational classification of disease prevention. Public Health Rep. 1983;98:107–9. 58. Gordon R. An operational classification of disease prevention. In: Steinberg JA, Silverman MM, eds. Preventing Mental Disorders. Rockville MD: U.S. Department of Health and Human Services; 1987:20–6. 59. Institute of Medicine. Reducing Risks for Mental Disorders. Washington DC: National Academy Press; 1994. 60. Aguirre-Molina M, Gorman DM. Community-based approaches for the prevention of alcohol, tobacco, and other drug use. Annu Rev Public Health. 1996;17:337–58. 61. Popham RE, Schmidt W, de Lint J. The effects of legal restraint on drinking. In: Kissin B, Begleiter H, eds. The Biology of Alcoholism, Vol 4. Social Aspects of Alcoholism. New York: Plenum Press; 1976:579–625. 62. Terris M. Epidemiology of cirrhosis of the liver. Am J Public Health. 1967;57:2076–88. 63. Makela K. Concentration of alcohol consumption. Scand Studies Ciminol. 1971;3:77–88. 64. Schmidt W. Cirrhosis and alcohol consumption: an epidemiologic perspective. In: Edwards G, Grant M, eds. Alcoholism: New Knowledge New Responses. London: Croom Helm; 1977:15–47. 65. Schmidt W, Popham RE. An approach to the control of alcohol consumption. In: Rutledge B, Fulton EK, eds. International Collaboration: Problems and Opportunities. Toronto: Addiction Research Foundation of Ontario; 1977:155–64. 66. Schmidt W. The epidemiology of cirrhosis of the liver: a statistical analysis of mortality data with special reference to Canada. In: Fisher MM, Rankin JG, eds. Alcohol and the Liver. New York: Plenum Press; 1976:1–26.

67. Ledermann S. Alcool, Alcoolisme, Alcoolization: Mortalite, Morbitite. Accidents du Travail Institut National d’Etudes Demographiques, Travaux et Documents, Carrier. No 41. Paris: Presses Universitaires de France; 1964. 68. Keilman PA. Alcohol consumption and diabetes mellitus mortality in different countries. Am J Public Health. 1983;73:1316–7. 69. La Vecchia C, Decarli A, Mezzanotte G, Cislaghi C. Mortality from alcohol-related disease in Italy. J Epidemiol Community Health. 1986;40:257–61. 70. Imaizumi Y. Alcoholism mortality rate in Japan. Alcohol Alcohol. 1986;21:159–62. 71. Poikolainen K. Increasing alcohol consumption correlated with hospital admission rates. Br J Addict. 1983;78:305–9. 72. Truswell AS, Apeagyei F. Incidence of Wernicke’s encephalopathy and Korsakoff s psychosis in Sydney. Paper presented at: Meeting on Alcohol, Nutrition and the Nervous System. Coppleston Postgraduate Medical Institute; March 18, 1981; University of Sydney. 73. Ashley MJ, Rankin JG. A public health approach to the prevention of alcohol-related health problems. Annu Rev Public Health. 1988;9:233–71. 74. Makela K, Room R, Single E, Sulkunen P, Walsh B. Alcohol, Society, and the State I: A Comparative Study of Alcohol Control. Toronto: Addiction Research Foundation; 1981. 75. Popham RE, Schmidt W, de Lint J. The prevention of alcoholism: epidemiological studies of the effects of government control measures. Br J Addict. 1975;70:125–4. 76. Rush B, Steinberg M, Brook R. The relationship among alcohol availability, alcohol consumption and alcohol-related damage in the Province of Ontario and the State of Michigan 1955–1982. Adv Alcohol Subst Abuse. 1986;5:33–4. 77. Wagenaar AC, Farrell S. Alcohol beverage control policies: their role in preventing alcohol-impaired driving. In: Surgeon General’s Workshop on Drunk Driving. Background Papers, Washington, DC, December 14–16. 1988. Rockville, MD: Office of the Surgeon General; 1989. 78. Cook PJ. The effect of liquor taxes on drinking, cirrhosis and auto accidents. In: Moore MH, Gerstein DR, eds. Alcohol and Public Policy: Beyond the Shadow of Prohibition. Washington, DC: National Academy; 1981. 79. Cook PJ. Alcohol taxes as a public health measure. Br J Addict. 1982;77:245–50. 80. Cook PJ, Tauchen G. The effect of liquor taxes on heavy drinking. Bell J Econ. 1982;13:379–90. 81. Holder HD, Blose JO. Reduction of community alcohol problems: computer simulation experiments in three counties. J Stud Alcohol. 1987;48:124–35. 82. Ornstein SI. A survey of findings on the economic and regulatory determinants of the demand for alcoholic beverages. Subst Alcohol Actions Misuse. 1984;5:39–44. 83. Hoadley JF, Fuchs BC, Holder HD. The effect of alcohol beverage restrictions on consumption: a 25-year longitudinal analysis. Am J Drug Alcohol Abuse. 1984;10:375–401. 84. Levy D, Sheflin N. New evidence on controlling alcohol use through price. J Stud Alcohol. 1983;44:929–37. 85. Davies P. The relationship between taxation, price and alcohol consumption in the countries of Europe. In: Grant M, Plant M, Williams A, eds. Economics and Alcohol: Consumption and Controls. London: Croom Helm; 1983. 86. Maynard A. Modeling alcohol consumption and abuse: the powers and pitfalls of economic techniques. In: Grant M, Plant M, Williams A, eds. Economics and Alcohol: Consumption and Controls. London: Croom Helm; 1983. 87. Walsh BM. The economics of alcohol taxation. In: Grant M, Plant M, Williams A, eds. Economics and Alcohol: Consumption and Controls. London and Canberra: Croom Helm; 1983.


55 88. McGuinness T. The demand for beer, spirits and wine in the UK, 1956–1979. In: Grant M, Plant M, Williams A, eds. Economics and Alcohol: Consumption and Control. London: Croom Helm; 1983. 89. Heien D, Pompelli G. Stress, ethnic and distribution factors in a dichotomous response model of alcohol abuse. J Stud Alcohol. 1987;48:450–5. 90. Walsh BM. Do excise taxes save lives? The Irish experience with alcohol taxation. Accid Anal Prev. 1987;19:433–48. 91. Kendell RE, de Roumanie M, Ritson EB. Effect of economic changes on Scottish drinking habits, 1978–1982. Br J Addict. 1983;78:365–79. 92. Kendell RE, de Roumanie M, Ritson EB. Influence of an increase in excise duty on alcohol consumption and its adverse effects. Br Med J. 1983;287:809–11. 93. Bigelow G, Liebson I. Cost factors controlling alcohol drinking. Psychol Record. 1972;22:305–14. 94. Mello NK. Behavioural studies of alcoholism. In: Kissin B, Begleiter H, eds. The Biology of Alcoholism, Vol 3. Physiology and Behaviour. New York: Plenum; 1972. 95. Babor TF, Mendelson JH, Greenberg I, Kuehnle JC. Experimental analysis of the “happy hour.” Effects of purchase price on alcohol consumption. Psychopharmacology. 1978;58:35–44. 96. Moore MH, Gerstein DR. Alcohol and Public Policy: Beyond the Shadow of Prohibition. Washington, DC: National Academy Press; 1981:116. 97. Aldridge S. Alcohol deaths world wide. Lancet. February, 2005. 98. Duffy M. The influence of prices, consumer incomes and advertising upon the demand for alcoholic drink in the United Kingdom. Br J Alcohol Alcohol. 1981;16:200–8. 99. Ornstein SI. Control of alcohol consumption through price increases. J Stud Alcohol. 1980;41:807–18. 100. Grossman M, Coate D, Arluck GM. Price sensitivity of alcoholic beverages in the United States. In: Holder HD, ed. Control Issues in Alcohol Abuse Prevention: Strategies for Communities. Greenwich, CT: JAI Press; 1987. 101. Coate D, Grossman M. Change in alcoholic beverage prices and legal drinking ages: effects on youth alcohol use and motor vehicle mortality. Alcohol Health Res World. 1987;12:22–5, 59. 102. Saffer H, Grossman M. Beer taxes, the legal drinking age, and youth motor vehicle fatalities. J Legal Stud. 1987;16:351–74. 103. Saffer H, Grossman M. Drinking age laws and highway mortality rates: cause and effect. Econ Inquiry. 1987;25:403–18. 104. Room R. Alcohol control and public health. Annu Rev Public Health. 1984;5:293–317. 105. Farrell S. Review of National Policy Measures to Prevent AlcoholRelated Problems. Geneva: World Health Organization; 1985. 106. Schmidt W, Popham RE. Alcohol Problems and Their Prevention. A Public Health Perspective. Toronto: Addiction Research Foundation; 1980. 107. Mosher JF, Beauchamp DE. Justifying alcohol taxes to public officials. J Public Health Policy. 1983;4:422–39. 108. Vernberg WB. American Public Health Association. Alcohol tax reform. Proposed Position Paper, American Public Health Association. Nation’s Health. August, 1986. (Proposed Position Paper.) 109. Huber M. Swiss tax hike causes alcopop sales to fall. Swissinfo. 2005. 110. Chesson H, Harrison P, Kessler WJ. Sex under the influence: the effect of alcohol policy on sexually transmitted disease rates in the United States. J of Law and Econ. 2000;XLII:215–38. 111. Addiction Research Foundation. Alcohol, public education and social policy. Report of the Task Force on Public Education and Social Policy. Toronto: Addiction Research Foundation, 1981. 112. Single E. International perspectives on alcohol as a public health issue. J Public Health Policy. 1984;5:238–56.

Alcohol-Related Health Problems

1011

113. Smith DI. Effectiveness of restrictions on availability as a means of reducing the use and abuse of alcohol. Aust Alcohol Drug Rev. 1983;2:84–90. 114. MacDonald S. Whitehead P. Availability of outlets and consumption of alcoholic beverages. J Drug Issues. 1983;13:477–86. 115. Makela K, Osterberg E, Sulkunen P. Drink in Finland: increasing alcohol availability in a monopoly state. In: Single E, Morgan P, de Lint J, eds. Alcohol, Society and the State. 2. The Social History of Control Policy in Seven Countries. Toronto: Addiction Research Foundation; 1981. 116. Ryan BE, Segars L. Mini-marts and maxi-problems. The relationship between purchase and consumption levels. Alcohol Health Res World. 1987;12:26–9. 117. Smart RG, Goodstadt MS. Effects of reducing the legal alcohol purchasing age on drinking and drinking problems. A review of empirical studies. J Stud Alcohol. 1977;38:1313–23. 118. Vingilis ER, DeGenova K. Youth and the forbidden fruit: Experiences with changes in the legal drinking age in North America. J Criminal Justice. 1984;12:161–72. 119. Williams TP, Lillis RP. Changes in alcohol consumption by 18-year-olds following an increase in New York State’s purchase age to 19. J Stud Alcohol. 1986;47:290–6. 120. Engs RC, Hanson DJ. Age-specific alcohol prohibition and college students drinking problems. Psychol Rep. 1986;59:979–84. 121. Smith DI, Burvill PW. Effect on juvenile crime of lowering the drinking age in three Australian states. Br J Addict. 1986;82: 181–8. 122. Cook PJ, Tauchen G. The effect of minimum drinking age legislation on youthful auto fatalities, 1970–1977. J Legal Stud. 1984;13:169–90. 123. Cotton NS. The familial incidence of alcoholism. J Stud Alcohol. 1979;40:89–116. 124. Hrubec Z, Omenn OS. Evidence of genetic predisposition to alcohol cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcohol Clin Exp Res. 1981;5:207–12. 125. Schuckit MA. Twin studies on substance abuse: an overview. In: Gedda L, Parisi P, Nance W, eds. Twin Research 3: Epidemiological and Clinical Studies. New York: Alan R Liss; 1981:61–70. 126. Goodwin DW. Alcoholism and genetics. Arch Gen Psychiatry. 1985;42:171–4. 127. Bohman M, Sigvardsson S, Cloninger R. Maternal inheritance of alcohol abuse: cross-fostering analysis of adopted women. Arch Gen Psychiatry. 1981;38:965–9. 128. Cloninger CR, Sigvardsson S, Gilligan SB, et al. Genetic heterogeneity and the classification of alcoholism. In: Gordis E, Tabakoff B, and Linnoila M, eds. Alcohol Research from Bench to Bedside. New York: Haworth Press; 1989:3–16. 129. Tabakoff B, Hoffman P, Lee J, Saito T, Willard B, Leon-Jones F. Differences in platelet enzyme activity between alcoholics and nonalcoholics. N Engl J Med. 1988;318:134–9. 130. Friedmann, PD, McCullough D, Chin MH, Saitz R. Screening and intervention for alcohol problems: a national survey of primary care physicians and psychiatrists. J Intern Med. 2000, 15:4–91. 131. Selzer ML. Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am J Psychiatry. 1971;127:89–94. 132. Pokorny AD, Miller BA, Kaplan HB. The brief MAST: a shortened version of the Michigan Alcoholism Screening Test. Am J Psychiatry. 1972;129:342–5. 133. Mayfield D, McLeod G, Hall P. The CAGE questionnaire: validation of a new alcoholism screening instrument. Am J Psychiatry. 1974;131:1121–3. 134. Babor TF, Grant M. From clinical research to secondary prevention: international collaboration in the development of the Alcohol Use Disorders Identification Test (AUDIT). Alcohol Health Res World. 1989;13:371–4.


1012

Behavioral Factors Affecting Health

135. Russell M, Martier SS, Sokol RJ, Mudar P, Bottoms S, Jacobson S, et al. Screening for pregnancy risk-drinking. Alcohol Clin Exp Res. 1994;18:1156–61. 136. U.S. Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Baltimore: Williams & Wilkins; 1996. 137. Allen JP. Maisto SA, Connors GJ. Self-report screening tests for alcohol problems in primary care. Arch Intern Med. 1995;155(16): 1726–30. 138. Harrell AV, Wirtz PW. Screening for adolescent problem drinking: validation of a multidimensional instrument for case identification. Psychol Assess. 1989;1:61–3. 139. Fink A, Hays RD, Moore AA, Beck JC. Alcohol-related problems in older persons. Determinants, consequences, and screening. Arch Intern Med. 1996;156(11):1150–6. 140. Adams WL, Barry KL, Fleming MF. Screening for problem drinking in older primary care patients. JAMA. 1996;276(24):1964–7. 141. National Institute on Alcohol Abuse and Alcoholism. The Physician’s Guide to Helping Patients with Alcohol Problems. NIH Publication No. 95-3769, and the ASAM reference guide. 2003. 142. Magruder-Habib K, Durand AM, Frey KA. Alcohol abuse and alcoholism in primary health care settings. J Fam Pract. 1991;32:406. 143. Skinner HA, Holt S, Schuller R, Roy J, Israel Y. Identification of alcohol abuse using laboratory tests and a history of trauma. Ann Intern Med. 1984;101:847–51. 144. Criteria Committee, National Council on Alcoholism: Criteria for the diagnosis and alcoholism. Am J Psychiatry. 1972;129:127–35. 145. Helander A. Biological markers of alcohol use and abuse in theory and practice. In: Agarwal DP, & Seitz HK, (eds.) Alcohol in Health and Disease. New York: Marcel Dekker, 2001. pp. 177–205. 146. Saunders JB. Management and treatment efficacy of drug and alcohol problems: what do doctors believe? Addiction. 1995;90(10): 1357–66. 147. Chafetz ME, Blane HT, Abram HS, Lacy E, McCourt WF, Clark E, et al. Establishing treatment relations with alcoholics. J Nerv Ment Dis. 1962;134:385–409. 148. Bien TH, Miller WR, Tonigan JS. Brief interventions for alcohol problems: a review. Addiction. 1993;88(3):315–35. 149. Babor TF, Ritson EB. Hodgson RJ. Alcohol-related problems in the primary health care setting: a review of early intervention strategies. BrJ Addict. 1986;81:23–46. 150. Edwards G, Orford J, Egert S, Guthrie S, Hawker A, Hensman C, et al. Alcoholism: a controlled trial of “treatment” and “advice.” J Stud Alcohol. 1977;38:1004–31. 151. Orford J, Oppenheimer E, Edwards G. Abstinence or control: the outcome for excessive drinkers two years after consultation. Behav Res Ther. 1976;14:397–416. 152. Wallace P, Cutler S, Haines A. Randomized controlled trial of general practitioner intervention in patients with excessive alcohol consumption. Br Med J. 1988;297:663–8.

153. Sanchez-Craig M, Leigh G, Spivak K, et al. Superior outcome of females over males after brief treatment for the reduction of heavy drinking. Br J Addict. 1989;84:395–404. 154. Sanchez-Craig M, Annis HM, Bornet AR, MacDonald KR. Random assignment to abstinence and controlled drinking: evaluation of a cognitive-behavioural program for problem drinkers. J Consult Clin Psychol. 1984;52:390–403. 155. Skutle A, Berg G. Training in controlled drinking for early-stage problem drinkers. Br J Addict. 1987;82:493–501. 156. Zweben A, Pearlman S, Li S. A comparison of brief advice and conjoint therapy in the treatment of alcohol abuse: the results of the marital systems study. Br J Addict. 1988;83:899–916. 157. Sannibale C. Differential effect of a set of brief interventions on the functioning of a group of “early-stage” problem drinkers. Aust Drug Alcohol Rev. 1988;7:147–55. 158. Skinner HA, Holt S. Early intervention for alcohol problems. J R Coll Gen Pract. 1983;33:787–91. 159. Nilssen O. Long-term effect of brief intervention in at-risk drinkers: a 9-year follow-up study. Alcohol. 2004;39(6):548–51. 160. Stockwell T. Can severely dependent drinkers learn controlled drinking? Summing up the debate. Br J Addict. 1988;83:149–52. 161. Babor TF, Treffardier M, Weill J, Fegueur L, Ferrant JP. Early detection and secondary prevention of alcoholism in France. J Stud Alcohol. 1983;44:600–16. 162. Alden LE. Behavioural self-management controlled-drinking strategies in a context of secondary prevention. J Consult Clin Psychol. 1988;56:280–6. 163. Taylor JR, Heizer JE, Robins LN. Moderate drinking in ex-alcoholics: recent studies. J Stud Alcohol. 1986;47:115–21. 164. Rush BR, Ogborne AC. Acceptibility of nonabstinence treatment goals among alcoholism treatment programs. J Stud Alcohol. 1986;47:146–50. 164. Sanchez-Craig M. A Therapist’s Manual for Secondary Prevention of Alcohol Problems. Procedures for Teaching Moderate Drinking and Abstinence. Toronto: Addiction Research Foundation; 1984. 165. Kristenson H, Hood B. The impact of alcohol on health in the general population: a review with particular reference to experience in Malmo. Br J Addict. 1984;79:139–45. 166. Chick J, Lloyd G, Crombie E. Counselling problem drinkers in medical wards: a controlled study. Br Med J. 1985;290:965–7. 167. Elvy GA, Wells JE, Baird KA. Attempted referral as intervention for problem drinking in the general hospital. Br J Addict. 1988;83:83–9. 168. Chick J. Secondary prevention of alcoholism and the Centres D’Hygiene Alimentaire. Br J Addict. 1984;79:221–5. 169. Mcintosh M, Sanchez-Craig M. Moderate drinking: an alternative treatment goal for early-stage problem drinking. Can Med Assoc J. 1984;131:873–6. 170. Skinner HA. Early detection of alcohol and drug problems—why? Aust Drug Alcohol Rev. 1987;6:293–301.


Prevention of Drug Use and Drug Use Disorders

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Elizabeth B. Robertson • Wilson M. Compton

Drug use and drug use disorders interfere with the normal, healthy functioning across the lifespan but are fundamentally preventable. In considering the opportunities for preventing drug use and drug disorders, it is important to consider that the initiation of drug use, a necessary precursor to drug disorders, is in most cases a voluntary activity. However, the onset of drug disorders (namely abuse and dependence) is much more dependent on genetic variation in combination with specific environmental factors. The onset of drug use is most common during the late childhood and adolescent years. Proximal and distal biological, psychological, social, and environmental precursors originating as early as the prenatal period play a large role in whether experimentation occurs and use persists. On the other hand, for some individuals, the initiation of drug misuse and illicit use of drugs extends well beyond adolescence into adulthood, even in late adulthood. What follows is a review of basic information about drug use and drug use disorders and a review of prevention opportunities.  PHARMACOLOGY OF DRUGS OF ABUSE

An understanding of the pharmacological properties of drugs is essential to the understanding of the development of drug abuse and dependence and hence the design of prevention interventions. Four processes are important to the development of drug abuse and dependence: (a) exposure, including timing of exposure and genetic susceptibility; (b) physical dependence, an adaptive state that manifests itself as intense physical disturbance when drug use is suspended; (c) psychological dependence (or “addiction”), a condition under which there is a drive toward periodic or continuous administration of the drug to produce pleasure or avoid discomfit; and (d) tolerance, or the need for increasingly higher doses of a drug to recapture the original effects of the drug. Drug abuse may occur as the result of exposure only, as in the case of binge drinking on the first occasion of alcohol use or driving a vehicle under the influence of an illicit drug. Processes of abuse and dependence reflect characteristics of the drug, the individual user and the context of use. Among the goals of psychopharmacology, epidemiology and etiology research is to gain a better understanding of the processes implicated in the development of dependence based on the drug, the user and their interactions with one another. For example, initial use of a psychoactive drug often results in a pleasurable response. This response is reinforcing or rewarding leading to the desire to use the substance again, thereby maintaining the behavior. The more reinforcing the drug is the more likely the individual will seek the drug and abuse it. This characteristic of the drug is called its abuse liability and has been assessed for

numerous drugs through animal self-administration research. In most cases, this research has shown strong correlations between drugs animals will self administer and those that humans will abuse. In other cases, animals will not self administer drugs humans use, but the value of the animal studies is still great in that it allows for the determination of the general pharmacology and abuse liability of many substances that are then classified according to the Controlled Substance Act (CSA). Classification by the CSA provides one route to prevention as it is intended to curb the distribution of classified substance, thus making them less available to the public. Prevention interventions approach the relaying of information concerning classes of drug in several ways. First, some interventions, especially those for general populations of young children, provide very little or no information on drugs of abuse. Instead they concentrate on skill development and other proven prevention strategies. Other interventions concentrate on targeting a specific group of drugs for a specific population. Drugs to target are typically determined through epidemiologic studies of the population of interest. Finally, some interventions target one specific drug that is a serious problem for a specific population again determined through epidemiologic studies. Some examples of these are steroid abuse among athletes and inhalant abuse among Native Americans.1,2

Cannabinoids Cannabinoids are obtained from the flowering top of the hemp plant. More than 60 cannabinoids have been isolated from the hemp plant, and 1-delta-9-tetrahydrocannabinol (delta-9-THC) has been identified as the constituent responsible for most of the characteristic effects of this category of drug. Cannabis affects cognition, memory, mood, motor coordination, perception, sense of time and, under some conditions, produces feelings of relaxation and well-being. Tolerance is clearly seen after high doses and/or sustained use. Differential tolerance occurs with various effects as well as cross-tolerance to some hallucinogens. Disruption of performance and withdrawal symptoms have been noted after discontinued use of delta-9-THC.3 In particular, withdrawal symptoms characterized by irritability, restlessness, nervousness, decreased appetite, and weight loss have been reported. Cannabis affects the cardiovascular system by increasing heart rate and differentially altering standing and supine blood pressure.

Depressants Depressants generally share sedative and hypnotic properties and are used medically to produce drowsiness, sleep, and muscle relaxation and to prevent convulsions. In addition, barbiturates have anesthetic properties. The effects of these drugs are dose dependent, progressing 1013

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from relaxation to sedation through hypnosis to stupor. In the 1950s, depressants were developed with high anxiolytic and low central nervous system (CNS) depressant properties. These are the benzodiazepine agents, which allow relief of anxiety symptoms with less impairment of respiratory, cognitive, attention, and motor functions than the barbiturates. Depressants have complex effects. For instance, the relative degree of safety, tolerance, and dependence vary from the benzodiazepines, assigned to schedule IV, to those barbiturates, assigned to schedule II, which are associated with toxicity and high abuse liability. Tolerance for and dependence on the various drugs of this class generalize within the class and across classes to some opiates and alcohol. This is termed cross-tolerance and cross-dependence. Since, in our society, alcohol often is not recognized as a depressant drug, its use with sedative-hypnotic drugs results in stupor and death more frequently than might be the case were alcohol’s depressant characteristics more fully appreciated.4

Dissociative Anesthetics Dissociative Anesthetics include drugs such as PCP (phencyclidine), ketamine, and dextromethorphan. PCP was initially developed in the 1950s as an intravenous general anesthetic for surgery. However it has never been approved for use with humans, although it is used in veterinary medicine. Its sedative and anesthetic effects are trance-like and patients experience a feeling of being “out of body”. Other effects are distorted perceptions of sight and sound and feelings of detachment or dissociation from the environment and self. These mind altering effects are not hallucinations. PCP and ketamine are therefore more properly known as dissociative anesthetics. The dissociative drugs act by altering distribution of the neurotransmitter glutamate throughout the brain. Glutamate is involved in perception of pain, responses to the environment, and memory. PCP is considered the typical dissociative drug. Ketamine was developed in 1963 and is currently used as an anesthetic in both humans and animals in an injectable liquid form. For illicit use, the drug is typically evaporated to form a powder that is odorless and tasteless, resulting in some cases of its use as a “date rape” drug.5,6,7

Hallucinogens Hallucinogens, unlike many abused drugs, have no accepted medical use. These drugs share an ability to distort perception and induce delusions, hallucinations, illusions, and profound alteration of mood. Mescaline and psilocin-containing plants have been used ceremonially for centuries, and LSD was synthesized 1925. Under certain conditions, drugs from a variety of classes show hallucinogenic properties. Because of similarities between experiences of persons ingesting hallucinogens and those of mentally ill persons and persons reporting profound religious experiences, these drugs also are called psychotomimetics or psychedelics. Their effects reflect activity at receptors of the serotonergic, cholinergic, and possibly other systems. Tolerance occurs with repeated use of all hallucinogens. As is true for other psychoactive substances, differential tolerance to their various effects can be demonstrated. For example, tolerance to the subjective effects of hallucinogens is greater than that seen for the cardiovascular effects. Considerable cross-tolerance exists among drugs in this category. Symptoms of physical dependence after abrupt withdrawal of phencyclidine have been described, but similar reports for LSD do not exist.7,8

Opioids and Morphine Derivatives Opioids and Morphine Derivatives are drugs that cause analgesia, sedation, and euphoria. Opioids stimulate the higher centers of the brains and slow down the activity of the CNS. The term opioid refers to natural drugs produced from the opium poppy such as opium, morphine, and codeine. Some semisynthetic opiates include heroin and methadone. Many opiate preparations are used in medical practice to manage pain, diarrhea and cough, with therapeutic doses being carefully managed to minimize side effects. Opioids can produce euphoria and are highly addictive, thus there are legal restrictions on their sale and use.9,10

Stimulants Stimulants generally are classified as excitatory in recognition of their main effect on the CNS; specifically the increase in levels of dopamine and inhibitory neurotransmitter. These include cocaine, amphetamines, methylphenidate, and related substances. At low doses, stimulants are associated with feelings of increased alertness, euphoria, vigor, motor activity, and appetite suppression. At high doses, they can cause convulsions and changes in thought characterized on a continuum from hyper-vigilance to suspicion to paranoia. Amphetamine and cocaineinduced psychoses are described in chronic abusers. Paranoid ideation generally is reported in persons with histories of chronic stimulant abuse, but transient psychotic symptoms have been reported with initial use of high doses, and instances of psychoses associated with use of medically prescribed doses also have been reported. With repeated use, tolerance to some drug effects occurs, for example, euphoria and appetite suppression, convulsion, whereas there are increases in other effects such as motor activity, stereotypy, and possibly paranoia. Cocaine has various toxic effects especially upon the cardiovascular system and when cocaine and alcohol are taken together; cocaethylene is produced, which is even more lethal than cocaine.11,12

Inhalants Inhalants are a diverse group of chemicals that easily evaporate, such as solvents, aerosols and gases that cause intoxication when their vapors are inhaled. Vapors of liquid solvents can be sniffed directly from a container, may be poured on a rag and held over the mouth, or may be emptied into a bag that is held over the mouth and nose for inhalation. The rebreathing of exhaled air causes an oxygen deficiency, which can intensify the intoxicating effects. Inhaled vapors enter the bloodstream rapidly and are distributed to the organs with large blood circulation (e.g., liver, brain) and are absorbed quickly into the CNS, depressing many bodily functions. Particularly concerning are the hydrocarbon inhalants, such as solvents, gasoline, paint thinner, etc. These agents are CNS depressants and in moderate doses result in intoxication similar to that caused by alcohol (i.e., giddiness, disinhibition, muscle weakness, lack of coordination, slowed reflexes and slurred speech). High doses can cause severe breathing failure and death. Chronic abuse can lead to irreversible liver damage, brain damage and other health problems.13

Other Compounds Other Compounds that do not fall into the above categories but are abused include anabolic steroids and some over-the-counter (OTC) drugs. Anabolic steroids14,15 are synthetic substances related to the male sex hormones (androgens) that promote the skeletal muscle development (anabolic effect) and the development of male sexual characteristics (androgenic effects). Medical uses of anabolic steroids include treating conditions where the body produces abnormally low amounts of testosterone (e.g., delayed puberty) and treating body wasting (e.g., AIDS and related diseases). These drugs are obtained illegally through diversion from pharmacies; illegal imports from other countries and production in clandestine laboratories. The use of these substances is widespread among athletes motivated, in most cases, by the desire to build muscle and improve sports performance. Anabolic steroids are injected, taken orally or are rubbed into the skin in an ointment form. Most abusers take doses of up to 100 times greater than a therapeutic dose. In addition, many abusers take multiple anabolic steroids together and administer them in multiple ways; sometimes mixing them with other drugs such as stimulants and painkillers. Health consequences associated with abuse of anabolic steroids include: reduced sperm production, shrinking of the testicles, impotence, difficulty and painful urination, baldness, and irreversible breast enlargement in males. In females, health consequences include: development of masculine characteristics such as decreased body fat and breast size, deepening of the voice, excessive body hair, and loss of scalp hair. For adolescents of both genders, abuse can result in termination of the adolescent growth spurt permanently stunting growth. Other severe health, social, and psychological consequences occur for


56 abusers of both genders at all ages and include: liver cysts and cancer, clotting, cholesterol changes, heightened aggression, depressed mood, insomnia, loss of appetite, and muscle/joint pain.1,14

Over-the-counter (OTC) drugs Over-the-counter (OTC) drugs include a variety of preparations with which people self treat for minor ailments from the common cold to pain relief or to improve performance in some way, for example, stimulants, sleep enhancers, and weight control products. Many of these products include a combination of drugs that interact with one another to produce the most positive effect. Taken as directed most OTC drugs are safe, however prolonged use or excessive dosages of some of these drugs can be problematic. For example, long-term or excessive use of analgesics increases the likelihood of gastrointestinal irritation (aspirin) or liver damage (acetaminophen). Excessive dosages of a caffeine product can cause anxiety, increase in general metabolism, elevated heart rate and blood pressure and gastrointestinal irritation. Dextromethorphan, a widely available cough suppressant can, when taken in high doses, produce effects similar to the dissociative anesthetic effects of PCP and ketamine.5

 EPIDEMIOLOGY OF DRUG USE

Understanding the nature, extent, and patterns of use and abuse of psychoactive drugs and compounds is a necessary prerequisite to the development of efficacious and effective prevention interventions. Two epidemiological studies, the National Survey on Drug Use and Health (NSDUH)16 and the Monitoring the Future17 survey (MTF), are particularly helpful in tracking drug use over time. Examples from these two data sets are used to demonstrate trends in drug use over time.

Comparison of National Survey on Drug Use and Health (NSDUH) and the Monitoring the Future (MTF) The NSDUH, formerly known as the National Household Survey on Drug Abuse is the primary source of statistical information on the use of illegal drugs by the overall U.S. population and has been conducted by the federal government since 1971. The survey collects data by administering questionnaires to a representative sample of the population 12 years of age and older through face-to-face interviews at their place of residence. Residence is defined as: residents of households, noninstitutional group quarters (e.g., shelters, rooming houses, dormitories), and civilians living on military bases. Homeless persons who do not use shelters, active military personnel, and residents of institutional group quarters, such as jails and hospitals, are excluded. Prior to 1999 the NSDUH’s sensitive data sections were collected using a self-administered answer sheet that the respondent sealed in an envelope, to maximize the sense of privacy, thus facilitating the accuracy of reporting. Nonsensitive sections were administered by the interviewer. Since 1999, the NSDUH interview has been carried out using computer-assisted interviewing (CAI) methodology. The survey uses a combination of computer-assisted personal interviewing (CAPI) conducted by the interviewer and audio computerassisted self-interviewing (ACASI). Sensitive questions previously administered using respondent-completed answer sheets are now administered using ACASI, a procedure designed to be highly private and confidential for sensitive questions thereby increasing the level of honest reporting. The MTF study uses a multistage nationally representative sampling design of secondary schools in the 48 contiguous United States. Data have been collected annually from high school seniors beginning in 1975. From 1991 to the present, data also have been collected yearly from 8th and 10th grade students. The study uses a three stage sampling strategy: (a) geographic region, (b) approximately 420 schools per year, and (c) between 42,000 and 49,000 students per year.

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Weights are assigned to each student to account for school sample sizes and any potential variations in selection throughout the sampling process.17 There are numerous important methodological differences between the NSDUH and the MTF study when it comes to the youth population. Chief among them are differences in setting and method of survey administration. The MTF is conducted in the school setting whereas the NSDUH collects data in homes. Collection in the school setting is thought to provide youth a greater sense of privacy and to promote more accurate reporting; household-based collection is generally thought to yield underreporting of sensitive behaviors such as drug use. Additionally, the NSDUH universe includes school dropouts, who are not represented in the MTF sample. The parental consent procedures are quite different between the two surveys with NSDUH requiring signed parental consent (obtained in person in the household) and MTF using either passive or signed active consent with documents sent from the school to the parents. The second major difference is that MTF uses self-administered paper-pencil questionnaires for data collection while the NSDUH uses interviewer and computer-administered verbal questions. Finally, NSDUH data are collected throughout the year while MTF data are collected primarily in February through May. Figure 56-1 compares data from the NSDUH and MTF on past month use of marijuana by high school seniors.18 Note that the trend lines are very similar in shape over time; however, the MTF data indicate somewhat higher use than the NSDUH. This is thought to be the result of differences in data collection methodology described previously. Figure 56-2 presents comparative data for the same time period for use of cocaine in the past month by 12th grade youth.18 Note that the levels of cocaine use are much lower than those for marijuana and interestingly the trend patterns are quite different. Marijuana use peaked in 1979 and then made a steady decline until the early 1990s whereas cocaine use peaked at about the same time but levels of use remained relatively high until the mid-1980s. Difference in drug use trends are evident for many drugs of abuse and typically relate to factors such as availability and popularity of a particular drug in a particular region or among particular subpopulations.

Etiology Understanding the causal factors that lead to exposure, initiation, progression, and maintenance of drug abuse is fundamental to the development of prevention interventions. Substance use, abuse and dependence result from complex interactions between biological, psychological, and sociologic factors such as the interaction styles of individuals, family members, peers, and other significant others in combination with features of the social context or environment. The life course bio-psycho-social developmental perspective suggests that individual and environmental factors interact to increase or reduce vulnerability to drug use, abuse, dependence, and associated problem behaviors. Vulnerability can occur at many points along the life course but peaks at critical life transitions. Thus, prevention researchers pay particular attention to the significance of timing interventions to coincide with important biological transitions, such as puberty; normative transitions, such as moving from elementary to middle school; social transitions, such as dating; and traumatic transitions, such as the death of a parent. In addition, because vulnerability to drug abuse involves dynamic intrapersonal (e.g., temperament), interpersonal (e.g., family and peer interactions) and environmental (e.g., school environment) influences, prevention intervention research must target interactions between individuals and social systems across the life span. To address this complexity, intervention research needs to test strategies designed to alter specified modifiable mediators to determine which are most related to and effective in reducing drug use initiation and escalation, with what audiences, and under what conditions. An appreciation for the complexity of this work can be gleaned through examining a graphic depiction of spheres of influence on and from the developing human across time (see Fig. 56-3).19


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This meta-theoretical perspective provides a broad view of the complex forces and interactions that inďŹ&#x201A;uence developmental, in general, and problem behaviors in particular. In addition, drug abuse and drug-related HIV prevention programs utilized a number of more discrete theoretical perspectives for predicting differential drug use trajectories and elucidating developmentally grounded mediators, or risk and protective factors, malleable to change. Basing an intervention on theory is essential because it guides the development of the intervention content, length of exposure and for whom the intervention should work. It also provides the basis for the development of hypotheses and information critical to the development of a comprehensive evaluation design. Three commonly used theories in prevention are behavioral theory, social learning theory, and social cognitive theory.

Behavioral Theory 20

Social Learning Theory 21 Social learning theory21 emphasizes learning that occurs within social contexts: the family, school, the neighborhood, and community. The basic premise is that people learn from interacting with and observing other people. People who are most salient to the learner (e.g., the parent in early childhood, peers in adolescence) tend to have the most impact on both social knowledge and behaviors. Social learning that translates to changes in behavior occurs through

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Figure 56-2. Trends in past month cocaine use by 12th graders in monitoring the future and national survey on drug use and health surveys (Source: Data from Glantz MG, et al. Personal Communication; 2005).

Percent of 12th graders using cocaine in month prior to survey

Behavioral theory,20 including information processing, places emphasis on learning skills and knowledge and assumes that behavior is based on cognition rather than external forces. Major foci of this

theoretical perspective are that learning occurs through making cognitive connections between stimuli and responses and that when rewarded, especially in close temporal proximity to the response, the connections are reinforced. Additionally, active participation in the learning process is critical. A number of steps in the learning process are delineated that begin with shaping or making successive approximations to the parts of or the whole behavior with increasing accuracy over time. This stresses the importance of repetition, reinforcement, and raising standards to produce successful learning. Behaviors that are not reinforced are not learned.

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Social welfare services Figure 56-3. Bronfenbrenner’s four ecological settings for developmental change.

modeling and imitation, but not all social learning results in behavior change. When behavior is modeled or imitated it is more likely to become integrated into the individual’s repertoire of behaviors if it is positively reinforced by a significant other or a significant other receives strong reinforcement leading to the experience of strong vicarious reinforcement. In other cases the behavior itself can be reinforcing for example through sensory stimulation that is satisfying.

Social Cognitive Theory 21 Social cognitive theory21 is an offshoot of social learning theory emphasizing the cognitive processes that occur during learning. Attention is a critical cognitive feature of this paradigm in that it is associated with expectation of rewards or negative consequences (e.g., when a parent asks “Do you want to do the dishes?” there is no implied consequence for saying no). Individuals develop cognitive expectation about associated behavioral consequences based on verbal and nonverbal reactions they have experienced. Other cognitive strategies related to the development of behaviors, including skills, self-monitoring, self-talk, and self-reinforcement.

Risk and Protective Factors The bio-psycho-social perspective and theories related to prevention implicitly recognize the role of risk and protective factors in shaping developmental trajectories. The concept that risk is associated with increased vulnerability and protection is associated with decreased vulnerability to disease has been a central and longstanding concept in medicine. This paradigm has been adapted for behaviorally-based diseases with one major caveat; for many medical conditions a single source is associated with causation, whereas with behaviorallybased diseases such as substance abuse it is commonly accepted that there are multiple factors associated with disease causation. The bio-psycho-social perspective recognizes that the course of development is affected by multiple factors at multiple contextual levels over time. However it also places the individual at the center because so much of

what occurs during the developmental process is determined by individual characteristics such as temperament, learning and communication styles, and genetic vulnerability to disease.19 The study of behavioral genetics provides a framework for one line of etiologic investigation of risk and protective factors. These studies use standard research designs to look at relationships among individual genetic and environmental factors that appear to influence behavioral outcomes. For example, twin studies compare identical and fraternal twins for similar behavioral endpoints. Adoption studies compare biological and adoptive parents. Heritability, a statistical description of the portion of variability in the behavior that can be ascribed to genetic factors, can be determined by these approaches and can clarify the contribution of genetic and environmental factors to behavioral outcomes that have been demonstrated to be related to familial factors. Intelligence, personality, temperament, psychopathology, alcoholism, and to a lesser extent drug abuse have been shown to be heritable. However, few complex behaviors are under the control of a single gene; rather it appears the multiple genes in combination with environmental influences are responsible for the expression of familial-related characteristics. Over the past two decades other studies have tried to determine constellations of behavioral and environmental risk factors associated with the origins and pathways to drug abuse. Many of these studies have successfully identified factors that help differentiate those more vulnerable to drug abuse from those less vulnerable. Risk and protective factors can affect children through establishing and/or reinforcing a negative developmental trajectory. A trajectory captures how individual children adapt either positively or negatively to their circumstances and is affected by intrapersonal, interpersonal, and environmental factors encountered at different developmental stages over the life course.22,23,24 There are several basic concepts pertaining to risk and protective factors that help to put into perspective their role in development in general and in the development of substance abuse in particular. First, there are many types of risk and protective factors and they occur at all levels of the human ecosystem, but some may be more potent for some individuals than for others or may be more potent at


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one particular developmental stage than another.25,26 Most risk factors have nonspecific effects and a major question is “Do different risk constellations result in particular patterns of negative behaviors and if so what are the mechanisms that account for this?” Many individuals experience multiple risk factors and this places them at greater risk. This is due in part to the fact that after a certain threshold of risk is attained or exceeded there appears to be an accumulation effect. Figure 56-4 illustrates this principle. Note that those individuals with 4–10 protective factors exhibit relatively few risk factors and very low prevalence of 30-day marijuana use. On the other hand, at the 6–7 risk factors threshold there is an absence of protective factors and a steep incline in the prevalence of marijuana use.27 The same principle holds for protective factors, the greater the number of protective factors relative to risk factors the less likely the individual is to experience negative outcomes. In this example (see Fig. 56-5)27 prevalence of academic success, a variable highly associated with low levels of drug use, is highest when there are many protective factors and few risk factors. Note as the number of risk factors increases academic success declines steeply.

A key concept is that some risk and protective factors can not be changed at all (such as genetic vulnerability and gender) and others are not easily changed (such as socioeconomic status). Because these factors are not malleable, they are not good targets for prevention. Rather factors that can be modified, such as specific behaviors and skills are more appropriate intervention targets.25,26 Perhaps the most important consideration about risk for substance abuse is that not all individuals at heightened risk actually use or abuse drugs. For example, a young person with a strong family history of substance abuse and a chaotic home environment who has strong extra-familial support systems such as a positive peer group, a supportive school environment, a community with low tolerance for use, and low availability of drugs may never initiate use. Figure 56-6 provides a framework for characterizing risk and protective factors in five contexts. These contexts often serve as foci for prevention practices. As the second examples suggest, some risk and protective factors may operate on a continuum. That is, in the family domain, lack of parental supervision, a risk factor, indicates the absence of parental monitoring, a key protective factor.26

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However, in most cases risk and protective factors are independent of each other, as demonstrated in the examples in the peer, school, and community contexts. For example, in the school domain, a school with strong “antidrug policies” may still have high availability of drugs if the policies are weakly enforced. An intervention to strengthen enforcement of school policies could create the intended school environment. Because development takes place in context, it is important to consider the ways in which developmental contexts can influence risk and protective factors and life course trajectory. Children’s earliest interactions occur within the family and factors that affect early development are crucial to development. Families foster optimal development when strong bonds are established between parents and the child, parents are involved in the child’s activities, parents meet the child’s material needs (e.g., food, clothing and shelter) and emotional needs (e.g., support and warmth), and firm, clear and consistent limits for behavior are set and enforced in a nonhostile, matter-of-fact manner. On the other hand, children are more likely to experience negative developmental outcomes when there is a lack of mutual attachment and nurturing by parents or caregivers, parenting is inconsistent or harsh, the home environment is chaotic, or the caregiver abuses substances, suffers from mental illness, engages in criminal behavior, or has other severe behavioral or mental health problems. These latter developmental environments, such as households where parents’ abuse of drugs can impede bonding to the family and threaten feelings of security that children need for healthy development.28 For young children already exhibiting serious risk factors, delaying intervention until late childhood or adolescence makes it more difficult to overcome risks because attitudes and behaviors have become well established and not easily changed.29 One of the most well-delineated risk trajectories for subsequent substance abuse is out-of-control aggressive behavior in very young children.30,31,32 If not addressed through positive parental actions, this behavior can lead to additional risks when the child enters school— including heightened aggressive behavior which leads to peer rejection, punishment by teachers, and academic failure. If not successfully addressed through preventive intervention within the home and school contexts, over time these risks can lead to more distal risk behaviors for drug use, such as truancy, delinquency, and associating with drug-abusing peers. This example illustrates several important aspects of successful prevention that will be reiterated later. First, intervening early increases the likelihood of success.28 Second, life transitions, in this case school transitions, are points of vulnerability and provide opportunities for intervention. Finally, interventions that address the problem in multiple contexts are more successful than those confined to a single context.33 Implicit in this example is the idea that later in development, settings outside the family, such as school, with peers and teachers, and in the community, increasingly affect the quality of children’s development. Difficulties in these contexts influence children’s physical, emotional, cognitive, and social development. During the preadolescent and adolescent years, association with drug-using peers is often the most immediate risk for exposure to drug abuse and other delinquent behavior. But other factors such as drug availability, perception that drug abuse is accepted, and inflated misperceptions about the extent to which same-age peers use drugs can influence adolescents to initiate drug use. Even in the adolescent years when youths spend a great deal of time outside the home, parents and caregivers can

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Figure 56-6. Prevalence of academic success by number of risk and protective factors.

provide protection through age-appropriate parental monitoring of social behavior, including establishing curfews, ensuring adult supervision of activities outside the home, knowing the children’s friends, enforcing household rules, facilitating and valuing success in academics, involvement in extracurricular activities, and fostering strong bonds with prosocial institutions, such as the school, recreation activities, and religious institutions. Moreover, research demonstrates that while peers are a major force in determining immediate behaviors, such as choice of clothing styles, activities to participate in and people with whom to associate, parents remain the most important source of information and decision-making around long-term life choices such as school and career.34

Elements of Effective and Ineffective Programs and Strategies Much research has gone into determining what elements of preventive interventions are effective. There is much more to be learned about intervention strategies that do and do not work and about general principles of effective delivery. Thus, an area of research for which there is particular interest is the translation of basic science findings for the development of innovative interventions. To date the program content strategies that have been demonstrated to work typically involve the development of skills. Some of these have been mentioned previously and it was noted that the program or strategy should reflect the needs of the target population. In this section effective and ineffective programs and strategies will be more fully described and related to the pertinent social contexts with some attention to developmental timing. At the intrapersonal level the most important strategies are those that build skills and competencies. Obviously these become more complex over the course of development. For the very young child learning to conform to rules, to behave in prosocial ways, to identify and appropriately express feelings and to control impulses are some of the important skills to learn. During the school years these skills remain important and more skills are added to the repertoire, including academic competence, social resistance, social emotional learning, and normative education.

Family-Based Interventions35 So how does family-based prevention programming aid in building these skills? For the very young the emphasis is on the parent and targets training parents to have developmentally appropriate expectations for their children, adjusting these as the child matures. One universal program teaches the important strategy of reinforcing appropriate behaviors that the child naturally expresses and to the extent possible, ignoring inappropriate behaviors. The program developers call this strategy “catching them being good.”36 Reinforcing weak but existing skills is extremely important because it gives the child a sense of control over her environment while emphasizing that the child has the ability to behave in socially acceptable ways. Of course some children exhibit problem behaviors from a very young age and more targeted approaches are needed. For example, the high pitched cries of prematurely born infants often illicit negative reactions from caregivers, which in turn results in poorer care of these very vulnerable infants. Thus, teaching parents strategies to cope with these and other early problems such as difficult temperamental characteristics can prevent


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the escalation of problem behaviors, help the parents to accept the reality of the problem, and to be patient in training the child in more appropriate reactions, thus providing the parents with the sense of efficacy they need in parenting a difficult child.36,37,38,39 As mentioned, transitions are points of vulnerability and the transition to school and to each additional school level after that are major periods of risk. New expectations for academic and social performance escalate over the school years and these can be very threatening to some children. Parental support and interest is important during these transitions. This generally means becoming familiar with their child’s friends, their friends’ parents and their teachers, monitoring their school work and social opportunities, and taking an active interest in their developing autonomous life.

School-based Interventions At school a number of programs and strategies have also been demonstrated to make for successful transitions and academic careers. One important strategy is appropriate classroom management. Classroom management trains teachers in building strategies for rewarding positive behaviors and over time has the effect of reducing the bulk of negative classroom behaviors.40,41,42 This results in an environment where learning is the primary goal and the primary source of reward. While this may seem self-evident, many beginning teachers are not equipped to manage the types of classroom problem behaviors that take away from the priority of the school—learning. Thus, training teachers to use consistent, easy to learn routines that are fun for the children can enhance learning and bonding to school—two important protective factors. This type of strategy is called an environmental change strategy because it changes the classroom environment from one centered on reducing negative behaviors to one focused on promoting positive behaviors and learning. Another type of classroom management approach, typically used with students in grades K through 3 is called social emotional learning.30–32,43,44 This approach helps children to identify their feelings, such as frustration, anger, and over-stimulation and then provides them tools to manage these feelings. Because this is a classroombased intervention, all of the children know the approach and understand when a particular child is signaling that he or she are having a difficult time and respects his or her efforts to overcome the problem in a prosocial manner. Developing social emotional awareness at a very young age has long term positive effects on both academic and social performance across the school years and into adulthood. The other type of intervention that can take place with young students is promoting academic competence. While this is not restricted to the early grades it can have the most profound effects at that developmental period in fostering a positive attitude toward learning, a sense of accomplishment, and of course, an understanding of the basics necessary for future learning.45 These are all protective factors leading to a greater likelihood of a positive life trajectory. For example, one very potent risk factor for subsequent substance abuse, delinquency, school drop out, and under employment is the inability to read by the end of the second grade.39,40 By ensuring that children get the additional support they may need to achieve reading by this critical period helps to ensure on-going academic success. Of course academic problems can occur throughout an individual’s school career and providing the necessary academic support is an important responsibility of schools. However, parents often need to be the driving force in seeing that this occurs. The transition to middle school or junior high school is typically the transition most proximal to exposure to and/or experimentation with drugs. For this reason several program components have been developed that target this age group in particular. The first is social resistance skills. Resistance skills training is based on the social learning theory and stresses the importance of social factors in the initiation of drug use. Thus, the intervention paradigm focuses on teaching youth skills to handle peer pressure to experiment with drugs. This often includes either role play or video vignettes where an offer

is made and then strategies for rebuffing the offer are taught. Given the developmental status of this age group and their need to conform and maintain peer friendships, resistance strategies that do not alienate peers are taught. Social resistance programs applied in a regular classroom setting are highly successful. For example, in one randomized controlled trial, youths in the intervention groups were 30–40% less likely to initiate tobacco use compared to those in the nonintervention group.46,47 Interestingly, recent findings indicate that six years after this drug abuse prevention intervention was completed, those who received the intervention during junior high school were significantly less likely to have driving violations and points on their Department of Motor Vehicles records than those who did not receive the intervention. This finding illustrates relatively common phenomen in long-term follow-up studies of interventions—cross-over effects—positive effects on behaviors not addressed in the original intervention.48 Normative education is another strategy that has some positive effects but only when used in conjunction with skills development strategies. The goal of normative education is to correct misperceived positive norms about the actual use and acceptance of drug use. One strategy used is to actually survey students in a school about their perceptions of drug use among their peers, their perceptions of their peers’ acceptance of use, and their own drug use. In most cases students’ perceptions of use and acceptance of use are much higher than actual use and acceptance. These data are then reported back to students placing the “real school drug climate” in perspective and allowing students to feel that they are the norm rather than the outliers. It also reinforces the perception of the school as a safe and nurturing environment.46,49,50

Community-based Interventions At the community level and beyond, prevention strategies typically involve policy and media interventions. Policy interventions include activities such as training shopkeepers on how to request identification from purchasers of tobacco and alcohol products and how to refuse sales to those that do not meet the minimum age requirements. Other policy approaches include enforcing college campus rules about the underage use of illicit drugs and any use of illicit drugs.51,52 Media can be a successful tool in reducing the initiation and progression of drug abuse when it is appropriately used. One risk factor for substance abuse is a personality trait called high sensation seeking. For youth with this trait, a media strategy that works is offering alternative activities. In one media intervention study, young adult marijuana users with the high sensation seeking trait were targeted with media messages that offered alternative activities with high sensation value such as rock climbing. Spots were aired in one community; a second community did not receive the media spots. Identified groups of high sensation seekers were followed over time. The intervention community group had a 27% reduction in marijuana use compared to the control community group after 6 months.53,54,55

Ineffective Intervention Strategies Unfortunately, prevention programs and strategies that have been demonstrated to be effective are not always used. The strategy that has been demonstrated to be the least effective is fear arousal.56,57 One way of introducing this strategy is through testimonials from former substance abusers. These types of testimonials can actually have the unintended negative effect of making the drug-dependent life sound romantic. Other fear-inducing strategies include media spots that inaccurately portray the harmfulness of drugs. Youths tend to discount these and substitute the negative information with information that is unrealistically positive. Other ineffective strategies do not have unintended negative effects; however, they are ineffective in the absence of effective strategies. For example, information is an important component of most interventions; however information alone is not effective in altering behaviors. Similarly effective education where children are


56 involved only in activities to build self-esteem, while not harmful, is not effective in developing positive behaviors. Finally, alternate programming only, for example extracurricular activities, is not effective. Thus, these types of strategies should be looked at as “add-ons”.

Program Delivery The state of the knowledge at this point clearly shows that the skills/competency development interventions are the most potent in terms of effectiveness. In addition, there are some general principles of delivery that are often the determining factors in whether an intervention is successful or not. Delivery refers to the way in which the program or strategy is implemented with the target population. Programs that involve interactive activities providing participants with skills practice and then reinforce those skills over time have been found to be the most successful in facilitating the desired behavior change; on the other hand, didactic strategies in which information is delivered in a lecture format have been found to have little effect.56,57,58 Dosage is also critical. That means that a significant amount of the “active ingredients” of the intervention must be delivered and received for it to have the desired effect. In the same vein, providing “booster sessions” in the months and years postintervention to reinforce the important skills that have been developed help to maintain positive behavior change and skills. This implies that the intervention was delivered with fidelity to the program or strategy as originally designed and validated. At this time, little is known about what defines the “active ingredients” of behavioral interventions, thus deviations in the delivery of a program or strategy can inadvertently leave out the most important features of the intervention. Finally, it is critical that prevention efforts be consistent across contexts. That is, efforts at the individual, family, school, and community levels should reinforce one another. Inconsistency across contexts creates confusion and may result in the discounting of all efforts.59  A FINAL MESSAGE TO HEALTH CARE PROVIDERS

This chapter is intended to give an overview of the current state of drug abuse prevention interventions and the knowledge on which they are based. Absent is the role of the physician and other health care providers in reducing the initiation and progression of drug use. Health care personnel have the unique opportunity to interact one-onone with patients about their health behaviors. However, few take the opportunity to screen patients for substance abuse or risks that may subsequently lead to substance abuse. A small but growing body of research is developing and being tested in medical offices, clinics, and hospitals. One approach being investigated is the use of technologybased tools to screen for potential drug-related problem behaviors. For example, one of the most developed research-based tools at this time is for women who have been raped. The intervention is intended to reduce the trauma caused by the rape itself and the postrape forensic evidence collection procedures. Following these experiences substance abuse may begin or be exacerbated. The intervention is provided through a two-part video presentation that addresses the process of the forensic examination to reduce stress and future emotional problems. It also provides information and skills to reduce postrape substance use and abuse. Early findings suggest reductions in alcohol and marijuana use among women who were active users prior to the rape compared to the nonviewers.60,61 Another example of medically-oriented tools being developed and tested is for drug abuse risk and screening among youth. The goals of developing and testing these tools are to involve the primary care physician or physician’s assistant in identifying patients at risk, providing brief interventions, and potentially providing referrals for more intensive intervention. As with all interventions, life transitions may be critical periods for physicians to screen their patients, for example, during school physicals and/or pregnancy examinations.

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 REFERENCES

1. Goldberg L, Elliot D, Clarke GN, et al. Effects of a multidimensional anabolic steroid prevention intervention: The Adolescents Training and Learning to Avoid Steroids (ATLAS) program. JAMA. 1996;276(19):1555–62. 2. Kurtzman TL, Otsuka KN, Wahl RA. Inhalant abuse in adolescents. J Adolesc Health. 2001;29(3):170–80. 3. Budney AJ, Moore BA, Vandrey R. Health consequences of marijuana use. In: Brick J, ed. Handbook of Medical Consequences of Alcohol and Drug Abuse. New York: Hawthorn Press, Inc. 2004; 171–217. 4. Yu S, Ho IK. Effects of acute barbiturate administration, tolerance and dependence on brain GABA system: Comparison to alcohol and benzodiazepines. Alcohol. 1990;7(3):261–72. 5. Smith KM, Larive LL, Romanelli F. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and gamma-hydroxybutyrate. Am J Health-Syst Pharm. 2002:59(11): 1067–76. 6. Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs. 2000;32(4):419–33. 7. National Institute on Drug Abuse. Hallucinogens and Dissociative Drugs. National Institute on Drug Abuse Research Report Series. Washington, DC: NIH Publication No. 01-4209, 2001. 8. Abraham HD, Aldridge AM, Gogia P. The psychopharmacology of hallucinogens. Neuropsychopharmacology. 1996;14:285–96. 9. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther. 2004;11(5):354–65. 10. Zacny JP, Gutierrez S. Characterizing the subjective, psychomotor, and physiological effects of oral oxycodone in non-drug-abusing volunteers. Psychopharmacology. 2003;170(3):242–54. 11. National Institute on Drug Abuse. Methamphetamine Abuse and Addiction. National Institute on Drug Abuse Research Report Series. Washington, DC: NIH Publication No. 02-4210, 2002. 12. National Institute on Drug Abuse. Cocaine Abuse and Addiction. National Institute on Drug Abuse Research Report Series. Washington, DC: NIH Publication No. 99-4342, 2004. 13. National Institute on Drug Abuse. Inhalant Abuse. National Institute on Drug Abuse Research Report Series. Washington, DC: NIH Publication No. 05-3818, 2005. 14. National Institute on Drug Abuse. Community Drug Alert Bulletin: Anabolic Steroids. Washington, DC: NIH Publication Number 004771, 2000. 15. Bahrke MS, Yesalis CE, Wright JE. Psychological and behavioural effects of endogenous testosterone and anabolic-androgenic steroids: An update. Sports Med. 1996;22(6):367–90. 16. Office of Applied Studies, Substance Abuse and Mental Health Services Administration. Results from the 2003 National Survey on Drug Use and Health: National Findings. Rockville, MD: DHHS Publication No. SMA 04-3964, NSDUH Series H-25, 2004. 17. Johnston LD, O’Malley PM, Bachman JG, et al. Monitoring the Future National Results on Adolescent Drug Use: Overview of Key Findings, 2004. Bethesda, MD: NIH Publication No. 05-5726, 2005. 18. Glantz MD, Brodsky MD, Fletcher BW, et al. Twenty years of adolescent drug use: Comparing national survey findings (submitted). 19. Bronfenbrenner U. Ecological Systems Theory. In: Bronfenbrenner U, ed. Making Human Beings Human: Bioecological Perspectives on Human Development. Thousand Oaks, CA: Sage Publication Ltd. 2005. 20. Bijou S. Behavior Analysis. In: Vasta R, ed. Six Theories of Child Development: Revised Formulations and Current Issues. London: Jessica Kingsley Publishers, Ltd. 1992. 21. Bandura A. Social Learning Theory. Englewood Cliffs, New Jersey: Prentice Hall, 1977.


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22. Hawkins JD, Catalano RF, Miller JY. Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: Implications for substance abuse prevention. Psychol Bull. 1992;112:64–105. 23. Hawkins JD, Catalano RF, Kosterman R, Abbott R, Hill KG. Preventing adolescent health-risk behaviors by strengthening protection during childhood. Arch Pediatr Adolesc Med. 1999;153:226–34. 24. Hawkins JD, Catalano RF, Arthur MW. Promoting Science-Based Prevention in Communities. Addict Behav. 2002;(27):951–76. 25. Durlak JA. Effective prevention and health promotion programming. In: Gullotta TP, Bloom M, eds. The Encyclopedia of Primary Prevention and Health Promotion. New York: Kluwer Academic/ Plenum Publishers, 2003. 26. National Institute on Drug Abuse. Preventing Drug Abuse among Children and Adolescents: A Research-Based Guide. National Institute on Drug Abuse, Washington, DC: NIH Publication No. 04-4212(A);2003. 27. Pollard JA, Hawkins JD, Arthur MW. Risk and protection: Are both necessary to understand diverse behavioral outcomes in adolescence? Soc Work Res. 1999;23(8):145–58. 28. Catalano RF, Haggerty KP, Fleming CB, et al. Children of substance abusing parents: current findings from the Focus on Families project. In: McMahon RJ, Peters RD, eds. The Effects of Parental Dysfunction on Children. New York: Kluwer Academic/Plenum Publishers, 2002;179–204. 29. Ialongo N, Werthamer L, Kellam S, et al. Proximal impact of two first-grade preventive interventions on the early risk behaviors for later substance abuse, depression, and antisocial behavior. Am J Community Psychol. 1999;27:599–641. 30. Bierman KL, Bruschi C, Domitrovich C, et al. Early disruptive behaviors associated with emerging antisocial behavior among girls. In: Putallaz M, Bierman KL, eds. Aggression, Antisocial Behavior and Violence among Girls: A Developmental Perspective. Duke Series in Child Development and Public Policy. New York: Guilford Publications, Inc. 2004;137–61. 31. Farmer AD Jr, Bierman KL. Predictors and consequences of aggressivewithdrawn problem profiles in early grade school. Lawrence Erlbaum. J Clin Child Adolesc Psychol. 2002;31(3):299–311. 32. Miller-Johnson S, Coie JD, Maumary-Germaud A, Bierman K. Peer rejection and early starter models of conduct disorder. J Abnorm Child Psychol. 2002;30(3):217–30. 33. Webster-Stratton C, Reid J, Hammon M. Preventing conduct problems, promoting social competence: a parent and teacher training partnership in Head Start. J Clin Child Psychol. 2001;30:282–302. 34. Hunter FT, Youniss J. Changes in functions of three relations during adolescence. Dev Psychol. 1982;18:806–11. 35. Ashery RS, Robertson EB, Kumpfer KL, eds. Drug Abuse Prevention through Family Interventions. NIDA Research Monograph Number 177. Washington, DC: U.S. Government Printing Office, 1998. 36. Kosterman R, Haggerty KP, Spoth R, et al. Unique influence of mothers and fathers on their children’s antisocial behavior. J Marriage Fam. 2004;66(3):762–78. 37. Madon S, Guyll M, Spoth R. The self-fulfilling prophecy as an intrafamily dynamic. J Fam Psychol. 2004;18(3):459–69. 38. Redmond C, Spoth R, Shin C, et al. Engaging rural parents in familyfocused programs to prevent youth substance abuse. J Prim Prev. 2004;24(3):223–42. 39. Kosterman R, Hawkins JD, Haggerty KP, et al. Preparing for the drug-free years: session-specific effects of a universal parent-training intervention with rural families. J Drug Educ. 2001;31:47–68. 40. Petras H, Schaeffer CM, Ialongo N, et al. When the course of aggressive behavior in childhood does not predict antisocial outcomes in adolescence and young adulthood: an examination of potential explanatory variables. Dev Psychopathol. 2004;16(4):919–41. 41. Schaeffer CM, Petras H, Ialongo N, et al. Modeling growth in boys’ aggressive behavior across elementary school; Links to later criminal involvement, conduct disorder, and antisocial personality disorder. Dev Psychol. 2003;39(6):1020–35.

42. Crijnen AAM, Feehan M, Kellam SG. The course and malleability of reading achievement in elementary school: The application of growth curve modeling in the evaluation of a mastery learning intervention. Learning and Individual Differences. 1998;10(2): 137–57. 43. Elias MJ, Zins JE, Weissberg RP, et al. Promoting Social and Emotional Learning: Guidelines for Educators. Alexandria, VA: Association for Supervision and Curriculum Development; 1997. 44. Greenberg MT, Weissberg RP, O’Brien MU, et al. Enhancing school-based prevention and youth development through coordinated social, emotional, and academic learning. Am Psychol. 2003;58(6–7):466–74. 45. Barrera M, Biglan A, Taylor TK, et al. Early elementary school intervention to reduce conduct problems: a randomized trial with Hispanic and non-Hispanic children. Prev Sci. 2002;3:83–94. 46. Botvin GJ, Griffin KW, Paul E, et al. Preventing tobacco and alcohol use among elementary school students through life skills training. J Res Adolesc. 2004;14(1):73–97. 47. Botvin GJ, Griffin KW. life skills training: Empirical findings and future directions. J Prim Prev. 2004;25(2):211–32. 48. Griffin KW, Botvin GJ, Nichols TR. Long-term follow-up effects of a school-based drug abuse prevention program on adolescent risky driving. Prev Sci. 2004;5:207–12. 49. Dusenbury LA, Hansen WB, Giles SM. Teacher training in norm setting approaches to drug education: A pilot study comparing standard and video-enhanced methods. J Drug Educ. 2003;33(3): 325–36. 50. Donaldson SI, Graham JW, Piccinin AM, et al. Resistance-skills training and onset of alcohol use: evidence for beneficial and potentially harmful effects in public schools and in private Catholic schools. In: Marlatt GA, Vanden Bos GR, eds. Addictive Behaviors: Readings on Etiology, Prevention and Treatment. Washington, DC: American Psychological Association. 1997;215–38. 51. Pentz MA. Institutionalizing community-based prevention through policy change. J Community Psychol. 2000;28(3):257–70. 52. Pentz MA. Comparative effects of community-based drug intervention. In: Baer JS, Marlatt GA, eds. Addictive Behaviors across the Life Span: Prevention Treatment and Policy Issues. Thousand Oaks, CA: Sage Publications, Inc. 1993;69–87. 53. Palmgreen P, Donohew L, Lorch EP, et al. Television campaigns and adolescent marijuana use: tests of sensation seeking targeting. Am J Public Health. 2001;91:292–6. 54. Palmgreen P, Donohew L, Lorch EP, et al. Television campaigns and sensation seeking targeting of adolescent marijuana use: a controlled time series approach. In: Hornik RC, ed. Public Health Communication: Evidence for Behavior Change. Mahway, NJ: Lawrence Erlbaum Associates, Publishers. 2002;35–56. 55. Stephenson MT, Morgan SE, Lorch EP, et al. Predictors of exposure from an antimarijuana media campaign: Outcome research assessing sensations seeking targeting. Health Commun. 2002;14(1):23–43. 56. Tobler NS, Roona MR, Ochshorn P, et al. School-based adolescent drug prevention programs: 1998 meta-analysis. J Prim Prev. 2000;20(4):275–336. 57. Tobler NS. Lessons learned. J Prim Prev. 2000;20(4):261–74. 58. Dusenbury L, Brannigan R, Falco M, et al. A review of research on fidelity of implementations for drug abuse prevention in school settings. Health Educ Res. 2003;18(2)237–56. 59. Ringwalt CL, Ennett S, Johnson R, et al. Factors associated with fidelity to substance use prevention curriculum guides in the nation’s middle schools. Health Educ Behav. 2003;30(3): 375–91. 60. Resnick H, Acierno R, Kilpatrick DG, et al. Description of an early intervention to prevent substance abuse and psychopathology in recent rape victims. Behav Modif. 2005;29:156–88. 61. Acierno R, Resnick HS, Flood A, et al. An acute post-rape intervention to prevent substance use and abuse. Addict Behav. 2003;28: 1701–15.


57

Community Health Promotion and Disease Prevention Stephanie Zaza • Peter A. Briss

 INTRODUCTION

In 1988, the Institute of Medicine (IOM) released The Future of Public Health,1 a seminal report that found the national public health infrastructure to be in disarray. The IOM committee defined the mission of public health as fulfilling society’s interest in assuring conditions in which people can be healthy. It then developed clear statements about the role of government in three core public health functions: assessing health status, developing policy, and assuring that necessary services are provided. Finally, the committee made specific recommendations for responsibility and action at the national, state, and local levels to achieve the core functions. The 1988 IOM publication was ultimately complemented by the 1994 report of the Department of Health and Human Services (DHHS) Public Health Functions Steering Committee, which described 10 essential public health services that corresponded to the IOM core functions (Table 57-12). The core functions and essential services focused on the roles and responsibilities of governmental public health organizations at the national, state, and local level and were important for refocusing public health organizations and for promoting organized approaches to public health. With the publication in 2003 of The Future of the Public’s Health in the 21st Century,3 the IOM expanded its definition of public health to include all of society’s efforts to achieve improved health. Recommendations addressed health policy at every level of American society and expanded efforts to enlist all sectors in improving health outcomes. For example, in this later report, recommendations for responsibility and action in public health are made not only for governmental entities but also for community representatives and organizations (e.g., congregations, civic groups, and schools), the health care delivery system, employers and business, the media, and academia. In 2005, the Task Force on Community Preventive Services (a nonfederal committee supported by the U.S. Centers for Disease Control and Prevention) released the Guide to Community Preventive Services4 to assist communities in realizing the expanded version of public health suggested by the IOM report. The Community Guide, which provides syntheses of the best available scientific information to support health programs and policies, can help make delivery of the 10 essential health services more effective at the local level.5

Note: The findings and conclusions in this chapter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Taken together, these four reports illustrate the need for a holistic public health approach—one that includes several important emerging themes. First, the reports call for a holistic public health approach that comprehensively and fairly marshals the skills and resources of the entire community to promote health and prevent disease. In addition, they underline the principles of widespread community participation and building of partnerships in public health planning and action. Finally, they highlight the importance of taking an organized and thoughtful approach to the planning and implementation of health programs, which should include using the best available evidence to support decisions and action. This chapter will describe the holistic approach proposed in these seminal reports and provide specific examples of how such an approach is being implemented. In addition, the chapter will provide examples of making the link between different kinds of public health decisions and the best types of evidence to support those decisions.  THE HOLISTIC APPROACH

In the holistic approach to public health, communities are the public health agents, and they must concentrate on the needs, preferences, and assets of the entire community. In doing so, they must consider a broad range of health conditions (e.g., chronic diseases such as diabetes and atherosclerosis, viral and bacterial infections, accidental injury), risk factors (such as smoking and inactivity), and protective factors (e.g., education, exercise programs). They must also consider the distribution of life stages within the community, cultural differences, the array of health organizations in the community, and the various assets available in the community to promote health and prevent disease. Organized holistic approaches improve efficiency by allowing programs within the community to leverage each other’s strengths or by allowing programmatic activities to address multiple related outcomes (e.g., reduced levels of smoking, fewer complications of diabetes, improved cardiovascular health). Through broad-based public health activities that involve key stakeholders throughout the community, a richer and more detailed body of information is provided for decision-making. With these relationships and the information they provide, the likelihood that these issues will go unrecognized is reduced, problems can be identified earlier in their natural course, or more proximate solutions might be identified.

Socioecologic Model The socioecologic model is useful for explaining a holistic approach to public health.6 This model describes patterned behavior, such as 1023

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TABLE 57-1. THE CORE FUNCTIONS AND TEN ESSENTIAL SERVICES OF PUBLIC HEALTH Core Functions

Essential Services

Assessment

1. Monitor health status to identify health problems. 2. Diagnose and investigate health problems and health hazards in the community. Policy Development 3. Inform, educate, and empower people about health issues. 4. Mobilize community partnerships to identify and solve health problems. 5. Develop policies and plans that support individual and community health efforts. Assurance 6. Enforce laws and regulations that protect health and ensure safety. 7. Link people to needed personal health services and assure the provision of health care when otherwise unavailable. 8. Assure a competent public health and personal health workforce. 9. Evaluate effectiveness, accessibility, and quality of personal and population-based health services. Serving all 10. Research for new insights and innovative Functions solutions to health problems. Source: Institute of Medicine. The Future of Public Health. Washington, DC; National Academies Press; 1988. Public Health Functions Steering Committee. The Public Health Workforce: An Agenda for the 21st Century. Full Report of the Public Health Functions Project. Washington, DC: U.S. Department of Health and Human Services; 1994.

health risk behaviors (e.g., diet, smoking patterns, drinking), as the outcome of interest; these outcomes are determined by individual, interpersonal, institutional, community, and public policy factors. The model makes explicit the importance of coordinated public health actions at each level to effect change in health behaviors. The focus of the socioecologic model on multiple interacting levels of influence on behavior is consistent with taking broad approaches to public health programming that are not limited to any one agency or sector; indeed, the model allows for and even assumes the need for input and action across the community. A holistic approach that involves all of the stakeholders in an issue is more likely to be accepted by the target population and to identify and avoid unintended consequences. Finally, a holistic approach allows the linking of health promotion activities across different conditions and risk factors to achieve both increased efficiency and greater sustainability.

Infrastructure Realizing the benefits of taking a holistic approach to community health requires a well-organized infrastructure (preferably with predictable and sustainable funding) that can serve as the interface for various community sectors (e.g., schools, work sites, and health care delivery organizations). This infrastructure can serve as the focal point for convening and planning public health activities, securing and distributing funding for these activities, and communicating with staff of other programs and with the public. The infrastructure can consist of both formal and informal networks, paid staff and volunteer experts, leadership teams, and large community coalitions. The infrastructure is only useful, however, insofar as it develops, implements, and supports programs and policies that achieve health goals the community considers important. The inputs to public health activities provided by the infrastructure are important elements in describing those activities and their impacts. Thus, it is also important to document all of the components of the infrastructure as part of the record describing how public health programs were accomplished.

Steps to a HealthierUS A modern example of a federally funded program that follows a holistic approach is Steps to a HealthierUS (www.healthierUS.gov/steps). The program’s purpose is to develop an integrated program of chronic disease prevention and health promotion in each funded community. A range of sectors—public health, education, business, health care delivery, and community and social services—are represented in an infrastructure that is created by Steps to a HealthierUS for each community. The infrastructure provides overall strategic planning and leadership; offers an interface through which sectors can interact; communicates the program to community leaders and residents; and integrates the program with other statewide initiatives, particularly those that are federally funded. Together with sector partners, the program develops, implements, and coordinates programs and activities to accelerate progress toward established Healthy People 20107 objectives for health behavior and health outcomes in six focus areas: diabetes, asthma, obesity, nutrition, physical activity, and tobacco. Clearly, involving multiple sectors and community partners is needed to make progress in the focus areas listed. For example, achieving the public health objectives of improving the quality of care for diabetes, reducing hospitalizations from exacerbations of asthma, or increasing the use of appropriate health care services cannot be achieved without direct improvements to the health care delivery sector. Similarly, complex health risk behaviors, such as smoking, binge drinking, and combining a high-calorie diet with inactivity, will not be addressed in the health care sector alone. There is, therefore, a growing recognition of the importance of school, work-site, and community settings for health promotion activities. For example, activities such as tobacco cessation and nutrition programs as well as organized recreation may require the involvement of the school, business, philanthropic, faith-based, and community-based sectors of the community. Furthermore, these sectors may have less opportunity to meet their objectives if they work independently rather than cooperatively. Ideally, programs should be coordinated across the sectors. For example, some school-based programs have been shown to be more effective if conducted in the context of broader community efforts (such as supporting school smoking bans with community cessation programs for students, faculty, and staff). The Steps to a HealthierUS program adds value by helping to flexibly integrate efforts across the community and across various health challenges.  EVIDENCE-BASED DECISION-MAKING IN A HOLISTIC COMMUNITY APPROACH

While local community needs and preferences are driving forces in public health decision-making, other types of evidence are required for long-term sustainability of outcomes, including scientific evidence. Unfortunately, community control may be seen as antagonistic to the recent trend to use the best available science to inform public health decisions, creating tension between public health scientists and on-the-ground practitioners. The tension may be more apparent than real, however. For many public health problems (e.g., type 2 diabetes, smoking, heart disease), we have a good deal of knowledge about their prevalence and causes as well as effective solutions; this information can be learned across communities and then applied in specific contexts. This is similar to the case in clinical medicine, in which a generalizable science tells us about the causes of problems and the solutions that work for most people, but where individual patients and providers must still make decisions about how to proceed. Recent developments in the fields of “evidence-based medicine” and “evidence-based public health” have not only improved the science but have also helped to improve its credibility while speeding its way to the bedside or the community. In communities as well as at the bedside, however, locally appropriate decisions can be informed but not solely determined by this science.


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Evidence

Four Decisions

In common usage, “evidence” is simply “A thing or things helpful in forming a conclusion or judgment.”8 As in the courtroom, some forms of evidence are more persuasive than others, and different types of evidence apply to different types of decisions or questions. In public health we make hundreds of decisions every day, informed by various types of evidence. A call for improving or increasing evidence-based decisionmaking in public health should, therefore, focus on transparently and reliably matching appropriate types of evidence to the various types of decisions.

In establishing programs for promoting health and preventing chronic disease, four primary decisions must commonly be made: (a) Should something be done? (b) What should be done? (c) How should it be done? (d) Is it working or does it need to be modified? As shown in Table 57-2, in each case there are related questions that should be posed9 for each decision. Approaches to making these decisions can be found in a variety of health promotion and planning models and tools, such as Mobilizing for Action through Planning and Partnership (MAPP) and the PRECEDE-PROCEED model.10–11 This section

TABLE 57-2. A FRAMEWORK FOR USING DIFFERENT TYPES OF EVIDENCE TO MAKE DECISIONS IN PUBLIC HEALTH Decision Should something be done? What is the burden of disease?

What is the urgency?

Is it a priority for the community? What is the perceived need?

What should be done? What is the nature of the problem?

What works? What is acceptable to the community?

What can be afforded? What is feasible? How should it be done? What steps are needed to implement this intervention?

What barriers must be overcome to implement this intervention?

Is it working or does it need to be modified? Is it being implemented well?

What does the community think?

Is it improving health risks or outcomes?

Type of Evidence • Surveillance data (measuring morbidity, mortality, years of potential life lost, incidence, prevalence) • Survey data • Vital statistics data • Medical utilization data • Cost data • Basic medical data (e.g., does the condition or risk factor progress rapidly or have serious complications?) • Trend data • Degree to which the problem is understood (e.g., emerging issues such as avian flu or environmental hazards might merit more attention than can be justified based on current burden) • Perceived interest or importance based on surveys, focus groups, political processes, or other information Information gleaned from analysis of conceptual and empirical information on causes, natural course of the problem, and possible points of intervention • Scientific evidence of effectiveness from individual evaluation studies • Systematic reviews of evaluation studies • Information about community members’ understanding and approval of possible intervention strategies from: • Focus groups • Key interviews • Town hall meetings • Anecdote • Political processes Information based on a comparison of typical costs and cost-effectiveness (gleaned from economic analysis) and local assets • Organizational assessment • Experience, interviews, etc. • Documentation from previous implementation of the specific intervention and other related interventions • “Best process” information • Anecdotal experience from others who have implemented the intervention • Documentation from previous implementation • Anecdotal experience from others who have implemented the intervention • Complex systems modeling • Focus groups

• “Process” measures from checklists, interviews, and other data collection tools • Achievement of behavior or health outcomes from evaluation and program monitoring efforts • Focus groups • Interviews • Less formal data collection • Political processes Achievement of behavior or health outcomes from evaluation and program monitoring efforts

Source: Gard B, Zaza S, Thacker SB. Connecting public health law with science. J Law Med Ethics. 2004;32(4 Suppl):100–3.


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focuses on the types of evidence that are used to make decisions and points out the wide variety of information, from scientific to anecdotal, that is applicable. The first decision, “Should something be done?” is the essence of community-based planning for promoting health and preventing disease. Often, the decision about whether to take action relies on surveillance data, surveys, or other studies that indicate the burden of the disease or risk factor in question, frequently expressed as years of potential life lost or costs incurred. Here, communities must also consider the urgency of the issue: Is there an increasing trend? Is the problem particularly severe or disabling? Finally, communities must also consider whether addressing the problem is a priority. In some cases, the level of understanding about the problem will drive priority (e.g., issues that seem more novel may be given higher priority); the perception of risk and the acceptability of potential solutions may also determine priority. In addressing “What should be done?,” communities must first consider the essential nature of the problem. In the PRECEDE portion of the PRECEDE-PROCEED model, Green and Kreuter point out that, “The determinants of health must be diagnosed before the intervention is designed; if they are not, the intervention will be based on guesswork and will run a greater risk of being misdirected and ineffective.”11 For example, a mass media campaign to improve the population’s coverage for a vaccine is unlikely to increase immunization rates if the real problem is that people do not have access to clinics where the vaccine is offered. In brief, a detailed analysis of the local situation is required to understand how the problem should be addressed. Failing to take advantage of the best available generalizable knowledge in addressing local priorities can also result in ineffective or misdirected efforts. The second part of the “what should be done” decision is an understanding of what works. Scientific evidence is the most reliable and generally most appropriate type of evidence for determining what works; scientific evidence consists of individual studies and reviews that synthesize those studies. Ideally, this evidence will show how much change can be expected in the outcomes of interest based on work from other communities or contexts. Individual studies can be an excellent basis for making recommendations; they are relatively easy to find, can provide specific “recipes” for what to do, and are easy to understand. On the other hand, in many cases there will be numerous studies that seem potentially relevant, making it difficult for practitioners to keep up with them, and their results may conflict. In addition, they typically provide little information on which characteristics of the intervention or context contribute most to effectiveness. Literature reviews are helpful for identifying and summarizing the vast scientific literature, but each approach to performing these reviews has disadvantages as well as advantages. Expert or narrative reviews are carried out by experts who gather information based on their own experience and knowledge. These reviews are useful for giving a conceptual overview of a subject but can be subject to conscious or unconscious bias in how information is collected and assembled and how the conclusions relate to that information. In contrast, systematic reviews are based on a priori rules that lay out the study question, a search strategy, criteria for including or excluding studies, parameters that will be applied to judge the quality of each study, and methods for analyzing data. Meta-analyses, a subset of systematic reviews, allow for the calculation of an overall effect size (i.e., the quantifiable effect of the intervention on desired outcomes) for the group of studies included according to specific statistical methods. The advantages of systematic reviews (e.g., reduced bias and improved transparency) come at a cost, however, as they require greater time and technical expertise to conduct, resulting in fewer of these types of reviews being available. Two examples of systematic reviews used to support recommendations for preventive medicine and public health are the Guide to Clinical Preventive Services12 and the Guide to Community Preventive Services.4 The Guide to Clinical Preventive Services, developed by the U.S. Preventive Services Task Force (USPSTF), provides reviews and recommendations about individual clinical services, such as screening tests, counseling on health behavior, and

chemoprophylaxis (www.ahrq.gov12). The Guide to Community Preventive Services,4 in contrast, provides reviews and recommendations about a variety of public health interventions, such as strategies that use education, policy, system change, or environmental approaches to effect change (www.thecommunityguide.org). Together, the two references provide a broad range of interventions that have been shown through extensive scientific study to be effective. Reviewing scientific studies to know what works is necessary for decision-making, but determining “What should be done?” means that additional questions must be asked: (a) What is acceptable to the community? (b) what can our community afford? and (c) what is feasible given our resources and capacity? These questions are answered through focus groups, interviews with key informants, and economic and systems analyses. To address the third major decision, “How should it be done?” communities may be able to consult practice guidelines that provide additional information about how to implement recommended interventions, such as policies to ban smoking, standing orders for routine delivery of vaccinations, or campaigns to enforce laws on safety belt use. With increasing frequency, developers of guidelines and other public health practitioners are developing tool kits and materials to help move recommended interventions into practice. In addition, communities can review “best processes” to obtain information and advice about the ways of implementing programs that have been most successful across studies, as found, for example in the “Community Toolbox” developed by the University of Kansas (http://ctb.ku.edu). Finally, community leaders and members can draw on personal experience and anecdotes as well as documentation from previous implementations to answer the question of how things should be done. The last of the major decisions, “Is it working or does it need to be modified?” is tied to program management, as evaluation of a program is used to determine a program’s effectiveness and, where possible, to improve performance. Ideally, this evaluation process should involve a broad range of stakeholders. The Centers for Disease Control and Prevention (CDC) has outlined a basic framework for evaluating programs that is used widely in public health and consists of just six steps: (a) engage stakeholders; (b) describe the program; (c) focus the evaluation design; (d) gather credible evidence; (e) justify conclusions; and (f) ensure use and share lessons learned.13 The developers of the CDC framework emphasized that the evidence gathered in step 4 must be perceived by stakeholders as relevant in addition to being believable. Thus, a variety of types of evidence might be needed, ranging from systematically collected data obtained through a well-controlled experiment to the results of document review, focus groups, and interviews with key informants. For all of the decisions that have been discussed here, debates are ongoing about what evidence is most appropriate, how to improve the quality of that evidence, and when a body of evidence is sufficiently credible to support action. It is important to report that the need to improve the quality and transparency of the science that supports public health decisions has been recognized and that efforts to make those improvements are ongoing.  CONCLUSION

To be successful, initiatives to promote health and prevent disease require a holistic approach, a commitment from the entire community, and a reliance on credible information. The approach described here incorporates all of these elements.  REFERENCES

1. Institute of Medicine. The Future of Public Health. Washington, DC; National Academies Press; 1988:19–34. 2. Public Health Functions Steering Committee. The Public Health Workforce: An Agenda for the 21st Century. Full Report of the Public Health Functions Project. Washington, DC: U.S. Department of Health and Human Services; 1994:21.


57 3. Institute of Medicine. The Future of the Public’s Health in the 21st Century. Washington, DC: National Academies Press; 2003:1–18. 4. Task Force on Community Preventive Services. The Guide to Community Preventive Services: What Works to Promote Health? Zaza S, Briss PA, Harris KW, eds. New York: Oxford University Press; 2005:1–506. 5. McGinnis JM. With both eyes open. The Guide to Community Preventive Services. Am J Prev Med. 2005;28(5 Suppl):223–5. 6. McLeroy KR, Bibeau D, Steckler A, et al. An ecological perspective on health promotion programs. Health Educ Q. 1988;15:351–77. 7. U.S. Department of Health and Human Services. Healthy People 2010. 2nd ed. Vols. 1 and 2. Washington, DC: U.S. Department of Health and Human Services, 2000. Vol 1: pp 1–608; Vol 2: pp 1–664. 8. The American Heritage Dictionary of the English Language. 4th ed. Retrieved March 28, 2007, from Dictionary.com website: http:// dictionary.reference.com/browse/evidence.

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9. Gard B, Zaza S, Thacker SB. Connecting public health law with science. J Law Med Ethics. 2004;32(4 Suppl):100–3. 10. National Association of City and County Health Officials. www.naccho.org. Accessed May 16, 2005. 11. Green LW, Kreuter MW. Health Promotion Planning: An Educational and Ecological Approach. 3rd ed. New York: McGraw-Hill; 1999:32–37. 12. Introducing the Third U.S. Preventive Services Task Force. Article originally in Am J Prev Med. 2001;20(3S):3–4. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/ clinic/ajpmsuppl/berg.htm. Accessed February 2, 2006. 13. Centers for Disease Control and Prevention. Framework for program evaluation in public health. Morb Mortal Wkly Rep. 1999;48(RR-11): 1–35.


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Risk Communication—An Overlooked Tool for Improving Public Health

58

David P. Ropeik

One thousand and eighteen more Americans died in motor vehicle crashes October through December 2001 than in those 3 months the year before, according to researchers at the University of Michigan’s Transportation Research Institute. As those researchers observed “. . . the increased fear of flying following September 11 may have resulted in a modal shift from flying to driving for some of the fearful.”1 One thousand and eighteen people dead, more than one-third the number of people killed in the attacks of September 11, in large part because they perceived flying to be more dangerous and driving less so, despite overwhelming evidence to the contrary. In 1971, President Richard Nixon signed the National Cancer Act and declared “War on Cancer.” In 2004 the National Cancer Institute had a budget of $4.7 billion.2 In 2002, cancer killed 557,271 Americans. That same year, heart disease killed 696,9473. Yet the National Heart, Lung, and Blood Institute spent approximately $1.8 billion on cardiovascular diseases, including heart disease, in 2004.4 And there is no National Heart Disease Act, nor a national “War on Heart Disease”, despite the fact that heart disease kills roughly 25% more Americans each year than cancer, roughly 140,000 more deaths in 2002 alone. Chronically elevated stress is known to weaken the immune system, contribute to cardiovascular and gastrointestinal damage, interfere with fertility, impair the formation of new bone cells, impede the creation of long-term memory, and contribute to a greater likelihood and severity of clinical depression.5 What do these three cases have in common? They demonstrate the threats to public health caused by gaps between risk perception, informed by the intuitive reasoning by which humans gauge the hazards they face, and risk realities based on science. The examples above demonstrate the vital role risk communication can play in advancing public health, by helping narrow those gaps.  RISK COMMUNICATION DEFINED

Currently, there are multiple definitions of risk communication; however, most embody the basic idea that by providing people with more information, they will be able to make smarter choices about their health. But that was not always true. The term “risk communication” arose largely as a result of environmental controversies in the 70s, when public concern was high about some relatively lower threats to human and environmental health. Scientists, regulators, and the regulated

community described people as irrational, and their frustration gave rise to efforts to educate the public and defuse those controversies. Early risk communication was viewed as a one-way process in which experts would explain the facts to the ill-informed lay public in ways that would help people behave more rationally, especially about such issues as air and water pollution, nuclear power, industrial chemicals, hazardous waste, and other environmental hazards. Thus, the goal of early risk communication was not always to enlighten people so they might improve their health. Instead, it was frequently a tool to reduce conflict and controversy, and often it was simply an effort by administrators, regulators, or company representatives to diminish opposition to particular product or technology or facilityciting proposal. One researcher defined risk communication as “a code {word} for brainwashing by experts or industry.”6 But risk communication has evolved. This chapter will use the following definition: Risk communication is a combination of actions, words, and other interactions responsive to the concerns and values of the information recipients, intended to help people make more informed decisions about threats to their health and safety.

This definition attempts to embody the ways that risk communication has evolved and matured over the past 15 years or so. Most importantly, the consensus among experts in the field now rejects the one-way “We’ll teach them what they need to know” approach. A National Research Council committee effort to move the field forward produced this definition in 1989. “Risk communication is an interactive process of exchange of information and opinion among individuals, groups, and institutions. It involves multiple messages about the nature of risk and other messages, not strictly about risk, that express concerns, opinions, or reactions to risk messages or to legal and institutional arrangements for risk management.”7 In other words, risk communication should be considered a dynamic two-way interaction. Both sides express their perspectives, and both sides have to listen and respond to information from the other. Perhaps even more fundamental, and intrinsic to the idea of the two-way street, is the growing acceptance among risk communication experts that risk means something inherently different to the lay public than what it means to scientists and regulators. When laypeople are asked to rank hazards in terms of mortality rates, they tend to 1029

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generally agree with the vital statistics. But ask them to rank what is risky and their responses change, with some lesser hazards, such as nuclear power, moving toward the head of the list, and some relatively larger risks, like smoking, moving further down.8 “Risk” is perceived as more than a number by the general public. Other attributes, like trust, dread, control, and uncertainty, also factor into the judgments people make that subsequently influence the nature and magnitude of their fears. As risk communication has evolved, there is increasing (but by no means, universal) acceptance by practitioners that both the science-based view of experts and the intuitive view of risk among the general public are valid, and both must be respected and incorporated if communications about risk is to be effective. This evolution is summed up in Risk Communication and Public Health, edited by Peter Bennett and Kenneth Calman: “. . . there has been a progressive change in the literature on risk: • from an emphasis on ‘public misperceptions’, with a tendency to treat all deviations from expert estimates as products of ignorance or stupidity • via empirical investigation of what actually concerns people and why • to approaches which stress that public reactions to risk often have a rationality of their own, and that ‘expert’ and ‘lay’ perspectives should inform each other as part of a two-way process.”9 People are not being irrational when their fears don’t match the expert view of a potential high-risk situation. While they may not be exclusively relying on evidence from toxicology, epidemiology, statistics, economics, and the other sciences of risk assessment and risk analysis, research from a number of fields has established that the lay public’s perception of risk develops under conditions of “bounded rationality”.10 As it is applied to the perception of risk, bounded rationality essentially describes the process individuals use to make judgments when they have less information, time, or cognitive skills than a fully rational judgment would require. As Reinhard Selten writes “Fully rational man is a mythical hero who knows the solutions to all mathematical problems and can immediately perform all computations, regardless of how difficult they are. Human beings are in reality very different. Their cognitive capabilities are quite limited. For this reason alone, the decision-making behavior of human beings cannot conform to the ideal of full rationality.”11 Gigerenzer and Selten refer to bounded rationality as “the adaptive toolbox,” the set of “fast and frugal rules” or mental processes humans have evolved to apply fact, feelings, instinct, and experience to the choices we face about threats to our survival.12 Neuroscientists have determined that some of the processing of threat information may be determined by aspects of human brain structure. Psychologists have identified a set of affective characteristics that make some risks seem larger and some smaller, the scientific data notwithstanding. Others have described a number of common heuristics and biases, mental shortcuts that turn complicated choices into simple ones, sometimes leading to judgments that seem suboptimal, based solely on “the facts”. These are powerful insights into more effective risk communication. By understanding the biology and psychology of how humans perceive risk, we can understand why and how lay and expert definitions of the very concept of risk vary. Such insights provide critical tools for effective risk communication because they help communicators both understand and respect the validity of the “intuitive reasoning” people use to gauge risk. By understanding and respecting lay perceptions of risk, the risk communicator can choose content, tone, and information delivery processes that increase the likelihood that their audience(s) will be more receptive, and their information will have more utility for the people with whom they are interacting. The Greek Stoic philosopher Epictetus said “People are disturbed, not by things, but by their view of them.” Understanding the roots of what shapes those views allows the true dialogue of modern risk communication to take place.

 THE BIOLOGY OF FEAR

Neuroscientist Joseph LeDoux and others have made remarkable discoveries about how the human brain processes raw sensory data into perceptions of threat and hazard. They have found that what we consciously describe as fear begins in the amygdala. External sensory information travels from end organs along neural pathways that send the information to the amygdala and the cortex. But the amygdala, where fear begins, responds before the cortex has a chance to process the information and add its analysis to the risk perception process. This same time lag (LeDoux estimates it at about 20 milliseconds) applies to nonsensory inputs as well, such as thoughts, memories, etc. In very simplified terms, this means that information is processed in the part of the brain where we fear before it is processed in the part of the brain where we think. That alone has profound implications for risk communication since it appears that the hard wiring of the brain, in managing fear, may favor rapid response (i.e., fight-or-flight) over deliberation of the best course of action. Thus, biology may help to explain why risk means one thing to experts and another to the lay public.13  RISK PERCEPTION PSYCHOLOGY

Some of what we are commonly afraid of seems instinctive; snakes, heights, the dark. Indeed, Charles Darwin recognized this and visited the London Zoo’s poisonous snake exhibit, repeatedly tapping on a glass window to provoke a strike by the snake inside, trying to teach himself not to recoil in fear. His effort in self-delivered risk communication failed. The innate fear, and the adaptive “fear first, think second” construction of the brain’s hazard perception systems could not be overcome. But how do people subconsciously decide what to be afraid of, and how afraid to be, when the threat does not trigger an instinctive reaction? When people hear about a new disease, product, or technology; when individuals try to gauge the risk of something against its benefits; when persons learn new information about a potential hazard and try to fit it into what they already know. How does the human mind filter incoming data and translate it into our perceptions of what is risky and what is not? The answers are to be found in two literatures, both of critical relevance to risk communication. The first is the study of how people generally make judgments of any kind, including judgments about risk, under conditions of uncertainty. This work has identified a number of systematic biases that contribute to what seem to be suboptimal irrational choices. The second is the specific study of the psychology of risk perception, which has identified more than a dozen affective attributes of risk that tend to make us more or less afraid, even when our apprehension doesn’t seem consistent with the scientific data.

General Heuristics The discovery of systematic biases that lead to suboptimal choices was championed by, among others, Daniel Kahneman, a social psychologist who was awarded the 2002 Nobel Prize in Economics for his work. Kahneman, Amos Tversky, and others, identified a number of heuristics—mental shortcuts that simplify decision tasks when time, complete information, or both are unavailable. This field has direct relevance to risk communication, as noted in a seminal paper on risk perception: “When laypeople are asked to evaluate risks, they seldom have statistical evidence on hand. In most cases, they must make inferences based on what they remember hearing or observing about the risk in question.” “These judgmental rules, known as heuristics, are employed to reduce difficult mental tasks to simpler ones.”14 Here are some of the heuristics and biases of greatest relevance to risk perception, and therefore to risk communication. Optimism. Many studies have found that people believe their personal risk is lower than the same risk faced by others in similar circumstances. A greater percentage of people think an adverse event might happen than think it will happen to them.15 These biases are often strongest when the risk involves personal choice, such as lifestyle risks including


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Risk Communication—An Overlooked Tool for Improving Public Health

smoking, obesity, or wearing safety belts. This underestimate of personal risk poses obvious challenges to achieving effective risk communication about some of the major threats to public health. Availability. Individuals assess probability based on how readily similar instances or occurences can be brought to mind of conceptualization. The risk of terrorism in the United States is statistically quite low. But apprehension is high since September 11, 2001, in part because such an event is more “available” to our consciousness. The availability heuristic explains why, when a risk is in the news, (flu vaccine issues, West Nile virus, child abduction, etc.) it evokes more fear than when the same risk is around, at the same level, but not making headlines. Framing. The way a choice is presented can shape the judgment that results. Imagine you are the mayor of a city of one million people and a fatal disease is spreading through your community. It is occurring mostly, but not exclusively, in one neighborhood of 5000 residents. With a fixed amount of money, you can either (a) save 1000 of the 5000 residents in that neighborhood, 20%, or (b) save 2000 people out of the entire city of 1 million, 0.2%. What do you do? A sizable number of people in risk communication classes choose option A, which produces a greater percentage effectiveness, but condemns 1000 people to death. Reframed, the choice would be: You can spend a fixed amount of money and save 1000 people or 2000. Presented that way, the choice is obvious. But the framing of the question in terms of percentages skews the judgment. Anchoring and Adjustment. People estimate probabilities based on an initial value and adjust from that point. In one experiment, separate groups were asked how many nations there are in Africa. Before giving their answer, each group spun a wheel of chance. The group for which the wheel settled on the number 10 estimated 25 nations. The group whose wheel landed on 65 estimated 45 nations. In another experiment, two groups of high school students estimated the sum of two numerical expressions they were shown for just 5 seconds, not long enough for a complete computation. The median estimate for the first group, shown 9x8x7x6x5x4x3x2x1, was 2250. The median estimate for the second group, shown the same sequence but in ascending order—1x2x3x4x5x6x7x8x9—was 512.16 Representativeness. Kahneman and Tversky describe this as “the tendency to regard a sample as a representation . . .” of the whole, based on what we already know.17 They offer this illustration. Consider a person who is “very shy and withdrawn, invariably helpful, but with little interest in people, or in the world of reality. A meek and tidy soul, he has a need for order and structure, and a passion for detail.” Then consider a list of possible professions for this person; farmer, salesman, airline pilot, librarian, or physician. Without complete data by which to make a fully informed choice, the representativeness heuristic gives you a simple mental process by which to judge, and leads to the choice that the person is probably a librarian. Applied to risk communication, this suggests that if you describe “an industrial chemical used to kill pests,” people are likely to associate it with the universe of industrial chemicals and regard it as a risk, without regard to the details about that specific chemical. Kahneman and Tversy also found that people think a short sequence of events generated by a random process, like coin tossing (or, in the case of risk communication, random natural events like floods, earthquakes, etc.) will represent their understanding of the basic characteristics of the whole process, People think that when tossing a coin, H-T-H-T-T-H is more likely than H-H-H-T-T-T because the second sequence isn’t random, which they expect coin tossing to be. They disregard statistical rationality (both coin toss sequences are equally as likely) because of the heuristic of representativeness.

Risk Perception Characteristics Work in a related field, the specific study of the perception of risk, has gone further and identified a number of attributes that make certain risks seem more worrisome than others.

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These “risk perception factors” are essentially the personality traits of potential threats that help us subconsciously decide what to be afraid of and how afraid to be. They offer powerful insight into why “risk” means different things to the lay public than it does to experts. The following list has been reviewed by Paul Slovic, one of the pioneers in the field of risk perception research. It includes examples to demonstrate each factor, and in some cases, suggestions of how awareness of the factor can be used to guide more effective risk communication. Trust. The more individuals trust, the less they fear, and vice versa. When persons trust the people informing them about a risk, their fears go down. When individuals trust the process deciding whether they will be exposed to a hazard, they will be less afraid. When they trust the agency or company or institution creating the risk, they are less afraid. Most critically, when people trust the agencies that are supposed to protect them, they will be less afraid. If people don’t trust the individuals informing them, the process determining their exposure to a risk, the institution(s) creating the risk in the first place, or the people protecting them, they will be more afraid. Trust comes from openness, honesty, competence, accountability, and respecting the validity of the lay public’s intuitive reasoning about risk. Trust is the central reason why two-way risk communication, in language that validates the feelings and values and heuristic instincts of the audience, is likely to be more effective than one-way communication that only offers the facts. Risk versus Benefit. From taking prescription drugs that have side effects to picking up a cell phone to make that important call while driving, people intuitively measure hazards by comparing risks and benefits. The more they perceive a benefit from any given choice, the less fearful they are of the risk that comes with that choice. This factor explains why, of more than 400,000 “first responders” asked to take the smallpox vaccine in 2002 fewer than 50,000 did. They were being asked to take a risk of about one in a million—the known fatal risk of the vaccine—in exchange for no immediate benefit, since there did not appear to be an actual smallpox threat. Imagine if there was just one confirmed case of smallpox in a U.S hospital. The mortality risk of the vaccine would still be one in a million, but the benefit of the immunization would appear tangible. Control. If a person feels as though he or she can control the outcome of a hazard, that person is less likely to be afraid. This can be either physical control as when a person is driving and controlling the vehicle, or a sense of control of a process, as when an individual feels that he or she is able to participate in policy making about a risk through stakeholder involvement through hearings, voting, etc. This is why shared control, from the one-on-one relationship between doctor and patient, up to community empowerment in the citing of potentially hazardous facilities, is an effective form of risk communication. This is also why, whenever possible, risk communication should include information not just about the risk (“The risk of terrorism has gone from Code Yellow to Code Orange”) but also offer information about what audience members can do to reduce their risk (“Have a family emergency plan in place, just in case”). Imposed versus Voluntary. This is the choice of taking a risk, not the physical control over what happens next. People are much less afraid of a risk when it is voluntary than when it is imposed on them. Consider the driver using his cell phone who looks over at the car in the lane next to him and sees that driver on his phone, speeding up and slowing down and not staying in his lane. Driver A, voluntarily engaged in the same behavior, is angry at Driver B for imposing the risk. Natural versus Human-made. If the risk is natural, people are less afraid. If it’s human-made, such as nuclear radiation, people are more afraid. Radiation from the sun evokes less fear in some people than radiation from a nuclear power plant, or from a cell phone tower. Here is an example of how to use this principle in risk communication. Resmethrin, the chemical used to kill mosquito larvae to


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Behavioral Factors Affecting Health

reduce the risk of West Nile virus, is a pesticide, and its use often evokes community concern. When the minimal risks of resmethrin are described, community resistance is largely unchanged. But when told that resmethrin is essentially a manufactured form of chrysanthemum dust, in essence a natural pesticide, concern (among some people) about the spraying goes down.18 Dread. We are more afraid of risks that might kill us in particularly painful, gruesome ways than risks that might kill us less violently. Ask people which risk sounds worse, dying of a heart attack or dying in a shark attack, and they will say shark attack, despite the probabilities. This principle helps to explain why the United States has a “War on Cancer” but not “War on Heart Disease”, a greater killer. Cancer is perceived as a more dreadful way to die, so it evokes more fear, and therefore more pressure on government to protect us, though heart disease kills far more people each year. Catastrophic versus Chronic. People tend to be more afraid of threats that can kill many in one place at one time (e.g., a plane crash) as opposed to events such as heart disease, stroke, chronic respiratory disease, or influenza, which cause hundreds of thousands more deaths, but spread out over time and distance. This helps to explain the substantial risk communication challenge of getting people to modify behaviors that contribute to these major causes of death. It also suggests how risk communication that frames these killers as cataclysmic might have more impact. An example of such messaging would be, “On September 11, 2001, when catastrophic terror attacks killed roughly 3000 people, 2200 Americans died of heart disease. We don’t see those deaths because they are spread out over the whole country, but heart disease is causing tremendous loss of life in America every day.” Uncertainty. The less people understand a risk, the more afraid they are likely to be. Sometimes uncertainty exists because the product or technology or process is new and has not yet been thoroughly studied, such as nanotechnology. Sometimes uncertainty exists because of unpredictability, as with the sniper in Washington D.C. in 2003, or acts of terrorism. Sometimes scientific answers are available but uncertainty remains because the risk is hard for people to fully comprehend, as with nuclear power or industrial chemicals. Sometimes uncertainty exists because the risk is invisible, as with radon. This is why risk communication should reduce uncertainty by making the risk easier for people to understand. This principle makes clear why risk communication should avoid jargon, and why risk numbers should be conveyed in ways people can relate to (“A one in ten risk is like the risk to one player on a soccer team, excluding the goalie”). When uncertainty exists because all the scientific questions haven’t been answered, the fear that results must be acknowledged and respected. Personal Risk. Understandably, a risk that people think can happen to them evokes more concern than a risk that only threatens others. This is why numbers alone are ineffective as risk communications. One in a million is too high if you think you could be the one. As a demonstration of this, consider how the attacks of September 11th made clear the risk of terrorism not just to Americans anywhere but in America, and the subsequent anthrax attack put the potential threat of bioterrorism into every American mailbox. The idea of “The Homeland” took on a whole new meaning. When the first case of mad cow disease in America was found on a Washington farm in 2003, beef sales barely changed nationwide, but they fell sharply in the Northwest, where people thought the risk was more likely to happen to them. Risk communication that offers only numbers to show that a risk is low is less likely to be trusted, and therefore won’t be as effective as communication that acknowledges that the risk is not zero and accepts that some people might still be concerned. Familiar or New. When people first learn of a risk, and don’t know much about it, they are more afraid than after they have lived with

that risk for awhile and adjusted to it. For example, West Nile virus evokes more fear in communities in which it first appears than in those where its been around for awhile. Using this perception factor in their risk communication, local health officials in one section of Arizona had some success in helping local residents deal with the onset of West Nile virus in 2004 by pointing out that although the risk of West Nile virus was new to them, other communities where the same risk had existed for a few years were far less worried.19 Future Generations. Any risk to children evokes more fear than the same risk to adults. When the Washington D.C. sniper wounded a 13-year-old boy, after having murdered five adults, the local police chief said “He’s getting personal NOW!” The EPA requires all schools in the United States to be tested for asbestos, but not all offices, factories, or other adult workplace locations. This powerful fear must be appreciated in communicating about any risk that involves children. Personification. A risk made real by the identification with of a specific victim particulary when depicted with an image, such as news reports showing someone who has been attacked by a shark or a child who has been kidnapped, becomes more frightening than a risk that may be real, but is not described with an individual to personify it. So, risk communication to encourage healthier lifestyle choices that uses numbers (e.g., “60% of Americans are overweight or obese, representing an important risk factor for heart disease”) may not be as effective as communication that uses those numbers and includes names and faces of actual victims of heart disease, to personify the risk. Fairness/Equity. People are more upset by risks when those who suffer the peril get none of the benefits. Individuals are more upset by risks to the poor, the weak, the vulnerable, the handicapped, than they are about the same risk to the wealthy, or the powerful. An example might be that the developers of a potentially hazardous facility guarantee that local residents get preference in hiring for the jobs at the facility, so that those bearing its risks share in some of its benefits. Risk communication, in actions more than in words, should address this issue. There are a few important general rules about the heuristics and biases mentioned earlier, and the risk perception factors listed immediately above. Several of these factors are often relevant for any given risk. (e.g., cell phones and driving, where issues of risk-benefit, control, optimism bias, and familiarity all play a part.) And, while the research suggests that these tendencies are apparently universal and that people tend to fear similar things for similar reasons, any given individual will perceive a risk uniquely depending on his or her age, gender, health, genetics, lifestyle choices, demographics, education, etc. For example, most people fear cancer, but men fear prostate cancer, and women fear breast cancer. As with population-based risk estimates, risk perception has underlying generalities which are overlaid by individual differences. This means that while it is good risk communication practice to consider the emotional concerns of the audience, not everyone in a large audience shares the same concerns. As the National Research Council report suggests, “For issues that affect large numbers of people, it will nearly always be a mistake to assume that the people involved are homogeneous . . .” It is often useful to craft separate risk communication approaches appropriate for each segment.20  RECOMMENDATIONS

As the National Research Council report noted, “. . . there is no single overriding problem and thus no simple way of making risk communication easy.”21 Therefore, this chapter provides general guidance on the fundamentals of risk communication that need to be applied with good judgment and tailored to each particular situation. The following are widely accepted general recommendations: Include risk communication in risk management. Far more is communicated to people by what you do than what you say. “Risk


58

Risk Communication—An Overlooked Tool for Improving Public Health

communication . . . must be understood in the context of decision making involving hazards and risks, that is, risk management.” (NRC)22 Consider the example cited above of the modest response to federal first responder smallpox vaccination policy. Had the risk perception factor of “risk versus benefit” been considered when the policy was being discussed, officials might have developed a different implementation plan with stronger risk communication strategies. Information that affects how people think and feel about a given risk issue is conveyed in nearly all of the management actions an agency or a company or a health official takes on that issue. All risk management should include consideration of the risk perception and risk communication implications of any policy or action under review. Quite specifically, this means that organizations should include risk communication in the responsibilities of senior managers, not just of the public relations or communications staff. As the NRC report finds, “Risk managers cannot afford to treat risk communication as an afterthought,” that comes at the end of the process after risk assessment has been completed and policy implemented. Recognize that the gaps between public perception and the scientific facts about a risk are real, and lead to behaviors that can threaten public health. These gaps are part of the overall risk that must be managed. Whether people are more afraid of a risk than they need to be or not appropriately concerned, this perception gap is a risk, in and of itself, and must be included in dealing with any specific risk issue and in all risk management and public health efforts, generally. Accepting that these gaps are part of the overall risk is perhaps the key step in recognizing that risk communication is integral to risk management. Consider this example. When the first case of mad cow disease was found in the U.S. in December 2003, the federal government quickly moved to recall from the market all muscle meat that was processed in the region where the sick cow was found. This despite studies in the U.K. that did not find muscle meat to be a vector for spreading bovine spongiform encephalopathy (BSE), the animal version of the disease, into variant Creutzfeld Jacob Disease (vCJD), the human form. Yet even though the science suggested the physical risk from the meat might have been negligible, the government recognized that public apprehension was part of the overall risk and ordered the recall. It was an intelligent action of risk management that had powerful risk communication impact on public judgments about the threat of mad cow disease. Public reaction to that first case of mad cow disease was surprisingly mild. (Wendy’s, the number threehamburger chain in the U.S., reported January 2003 sales up 8.3%. compared to the previous year. Smith & Wollensky’s, which operates 17 steakhouses in the U.S. reported annual January sales up 7.2%.23 The principles of risk communication pertain to all public health issues, not just the environmental issues around which the discipline began. The dichotomy between risk communication, which has generally been thought of as trying to get people to calm down, and health communication, which is often thought of as trying to get people to be more concerned and take action to improve their health, is false. Any action or message that conveys information relevant to someone’s health, ergo his or her survival, triggers risk perception biology and psychology, and the principles of risk communication should be applied. Even an individual doctor describing a treatment or medication or a surgical procedure to a patient in order to get “informed consent” is a form of risk communication. The principles described in this chapter are tools that can make that consent more truly “informed”. Trust is fundamentally important for effective risk communication, and it is on the line with everything you do. “. . . messages are often judged first and foremost not by content but by the source: ‘Who is telling me this, and can I trust them?’ If the answer to the second question is ‘no’, any message from that source will often be disregarded, not matter how well-intentioned and well delivered.”(Bennett and Calman)24 Trust is determined in part by who does the communicating. When the anthrax attacks took place in the fall of 2001, the principal government spokespeople were the Attorney General, the Director of the FBI, and the Secretary of Health and Human Services, and not the director of the CDC or the U.S. Surgeon General— doctors likely to be more trusted than politicians. Indeed, a survey by

1033

Robert Blendon et al. of the Harvard School of Public Health, 10/24-28/2001, found that 48% of Americans would trust the director of the CDC as a source of reliable information in the event of a national outbreak of disease caused by bioterrorism. Only 38%, however, would trust the Secretary of Health and Human Services (HHS), and only 33% would trust the director of the FBI.25 Had risk communication been considered as the anthrax issue was beginning to develop, and incorporated into the deliberations of how to manage the overall anthrax risk, the more trusted officials would have done the majority of the public speaking. This might have helped the public keep its concern about the risk of bioterrorism in perspective. But trust is more than just who does the talking. Trust also depends on competence. If people believe that a public health or safety agency is competent, they will trust that agency to protect them and be less afraid than if they doubt the agency’s ability. When the first mad cow case was found, the U.S. Department of Agriculture and the Food and Drug Administration were able to point out the effective regulatory actions they had taken for years to keep the risk low. Thus, the actions taken by those agencies, years before that first case, established trust, thereby affecting the public’s judgment about the risk. Trust is also heavily dependent on honesty. Honesty is conveyed in many different ways. In some instances, it can even mean apologizing and taking responsibility for mistakes. When leaks developed in underground tunnels that are part of a major transportation project in Boston, press attention and public criticism focused on the contractor responsible for the tunnels until the chairman of the company said at a tense public hearing “We apologize for our mistakes”.26 (Note that the apology was made ‘sincere’ by offering to put money behind it.) Attention thereafter focused less on the company’s culpability. Another example of honesty is avoiding the desire to overreassure. Again, the way the USDA handled mad cow disease illustrates one example. In the years prior to that first sick cow being found, top officials never said there was “zero” risk of mad cow disease, either in animals or in humans, just that the risk was very low. Had they followed the initial inclination of senior USDA officials and promised that the risk was zero, that single case would probably have provoked a more worried public reaction because people might rightly have feared that the government wasn’t being honest and couldn’t be trusted. Obviously, honesty includes not keping secrets, and not lying. In early 2005, Boston University received local and state approval to build a biocontainment level 4 (BL4) laboratory to study highly dangerous pathogens. But news reports surfaced that the university had hidden from local and state approval authorities the fact that workers had mistakenly been contaminated with tularemia in a BL2 lab at BU. Under public pressure, the government approval and review processes had to be reopened. Establish mechanisms to empower real community input. Give people control—a say in their fate. Such mechanisms are a concrete way to follow the widely-accepted recommendation that risk communication is more effective when it is an interaction, not a one-way process. It is even more effective to do this proactively, so shared control and real input into decision-making are well-established should a risk crisis arise. This input must be given more than perfunctory attention. Many government public hearing processes allow people to speak, but prevent officials conducting the meeting from answering the public’s questions and concerns. Such an interaction fails to give the audience a sense of control, and more importantly, can destroy trust since it seems disingenuous to claim an interest in public input but then fail to acknowledge it. Making risk communication an intrinsic component of risk management requires fundamental cultural change. Sharing control, admitting mistakes, acknowledging the validity of intuitive reasoning, accepting that a realistic goal for risk communication is to help people make better judgments for themselves, assuming a nondirective approach, even being open and honest . . . are counter-intuitive and perhaps even counter-cultural to institutions and people who are used to control. These principles may seem foolish in a litigious society. They conflict with the myth of the purely rational decisionmaker. As risk communication researcher and practitioner Peter


1034

Behavioral Factors Affecting Health

Sandman has observed “What is difficult in risk communication isn’t figuring out what to do; it’s overcoming the organizational and psychological barriers to doing it.”27 Nonetheless, countless examples demonstrate how adoption of the principles of risk communication are in the best interests of most organizations, as well as the interest of public health.28 These institutional benefits include: reduced controversy and legal costs, increased support for an agency’s agenda or a company’s brand and products, political support for a candidate or legislation, and more effective governmental risk management that can maximize public health protection by focusing resources on the greatest threats. While these benefits may not be readily quantifiable, and only realized over the long-term, they are supported by numerous case studies, and justify the cultural change necessary for the adoption of risk communication principles. Finally, within constraints of time and budget, any specific risk communication should be systematically designed and executed, and should include iterative evaluation and refinement. “We wouldn’t release a new drug without adequate testing. Considering the potential health (and economic) consequences of misunderstanding risks, we should be equally loath to release a new risk communication without knowing its impact.”29 An empirical process by which to do this has been labeled the “Mental Models” approach. As its developers say “. . . in the absence of evidence, no one can predict confidently how to communicate about a risk. Effective and reliable risk communication requires empirical study. Risk messages must be understood by recipients, and their effectiveness must be understood by communicators.”30 The basic components of the Mental Models approach are: 1. Create an expert model, based on review of the scientific literature and in consultation with experts in the field, that describes in detail the nature of the risk; its hazards, where exposures occur, the range of consequences, and the probabilities. 2. Conduct open-ended interviews to find out what your target audience already knows or doesn’t know about the risk. 3. Based on this smaller interview sample, create a questionnaire to administer to a larger sample to see how well the mental model of the smaller group corresponds to what the larger sample knows and doesn’t know about the risk. 4. Draft risk communication messages that address incorrect beliefs and fill in knowledge gaps between what people don’t know and what the expert model indicates they need to know. Pay attention to the tone and affective qualities of the messages. 5. Evaluate and refine the communication using one-on-one interviews, focus groups, closed-form questionnaires, or problem-solving tasks, trying to develop messages that have the most impact on the greatest number of recipients. Repeat the test-and-refine process until evaluation shows the messages are understood as intended.31  CONCLUSION

Whether terrorism or avian influenza nanotechnology or mad cow disease, risks continually arise. Old ones may fade and our attention to them may wane, but new ones will certainly develop, and our awareness of these new threats will be magnified in an age of unprecedented information immediacy and availability. The human imperative of survival will compel people to use their “adaptive toolbox” to make the best judgments they can about how to stay safe from this evolving world of threat, even though those judgments might sometimes create greater peril. Populations need to understand the risks around them as thoroughly as possible to be able to make sound decisions. It is critical that effective risk communication become an intrinsic part of how government, business, the public health sector, and the medical care system design and execute risk management policy, so that, armed with accurate information, we can make wiser and safer choices for ourselves and for our fellow citizens.

 REFERENCES

1. Sivak M, Flanagan M. Consequences for road traffic fatalities of the reduction in flying following September 11, 2001. Transportation Research Part F. July–Sept., 2004; vol. 7, 4–5;301–5. 2. http://cis.nci.nih.gov/fact/1_1.htm 3. http://www.cdc.gov/nchs/fastats/deaths.htm 4. Personal communication, Diane Striar, senior press liaison, NHLBI. 5. Sapolsky R. Why Zebras Don’t Get Ulcers. Owl Books, 2004. 6. Jasanoff S. Differences in national approaches to risk assessment and management. Presented at the Symposium on Managing the Problem of Industrial Hazards. The International Policy Issues, National Academy of Sciences, Feb. 27, 1989. 7. Improving Risk Communication. National Research Council, National Academy Press, 1989;21. 8. Slovic P. Perceptions of Risk. Science. 1987;236,280–5. 9. Bennett P, Calman K. Risk Communication and Public Health, Oxford U. Press, 1999;3. 10. Simon HA. Rational choice and the structure of environments. Psychology Review. 1957;63:129–38. 11. Gigerenzer G, Selten R, eds. Bounded Rationality, the Adaptive Toolbox. MIT Press, 1999;14. 12. ibid, 9. 13. This very simplified synthesis of LeDoux’s work comes from Ledoux J, The Emotional Brain: the Mysterious Underpinnings of Emotional Life. New York: Simon and Schuster, 1998. 14. Slovic P, Fischhoff B, Lichtenstein S. A revised version of their original article appears. In: Kahneman D, Slovic P, Tversky A, eds. Judgment Under Uncertainty: Heuristics and Biases. Cambridge U. Press, 2001;463–89. 15. Weinstein ND. Optimistic biases about personal risks. Science. 1987;246:1232–3. 16. Kahneman D, Slovic P, Tversky A. Judgment and uncertainty...” 1982; 14–15. 17. ibid, 24. 18. Personal observation. Cambridge and Concord, MA, 2002. 19. McNally J. Personal Communication. Mohave Co., AZ: Health Dept., 2004. 20. Improving Risk Communication. National Research Council. Nat. Academy Press, 1989;132. 21. ibid, 3. 22. ibid, 22. 23. Notes obtained from author’s website. 24. Bennett P, Calman K. Risk Communication and Public Health. Oxford U. Press, 1991;4. 25. Blendon B, Benson, J, DesRoches C, et al. Survey Project on American’s Response to Biological Terrorism. http://www.hsph. harvard.edu/press/releases/blendon/report.pdf. 26. Big Dig Firm Apologizes, Considers Fund for Repairs. Boston Globe, Dec. 3, 2004;1. 27. Sandman P. The Nature of Outrage (Part 1). http://www.psandman. com/handouts/sand31.pdf. 28. Powell D, Leiss W. Mad Cows and Mother’s Milk, the Perils of Poor Risk Communication. McGill-Queen’s University Press, 2001. (see also) Bennett and Calman, Part 2, Lessons from Prominent Cases, 81–130. 29. Morgan Granger M, Fischhoff B, Bostrom A, et al. Risk Communication: A Mental Models Approach. Cambridge U. Press, 2002;180. 30. ibid, 182. 31. Morgan, Granger M, Fischhoff B, et al. Risk Communication: A Mental Models Approach. Cambridge U. Press, 2002; Summary of pp 20–1.


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Health Literacy Rima E. Rudd • Jennie E. Anderson • Sarah C. Oppenheimer • Lindsay E. Rosenfeld • Carmen Gomez Mandic

 INTRODUCTION AND OVERVIEW

Health literacy has been used as a metaphor as is science literacy or computer literacy, referring to knowledge about and facility with a particular area or process. However, most references to health literacy in scholarly articles move beyond the metaphor and highlight the importance of literacy skills applied in health contexts. Literacy skills encompass a set of related activities that include reading, writing, engaging in oral exchange, and using basic math. Adults apply these skills to numerous health-related activities at home, at work, in the community, and in social service and health care settings. The Institute of Medicine (IOM) report, Health Literacy: A Prescription to End Confusion, proposed that an individual’s health literacy capacity is mediated by education, and its adequacy is affected by culture, language, and the characteristics of health-related settings.1 Health literacy is firmly established as a field of inquiry in medicine and public health. Improved health literacy was included as a communication objective in Healthy People 2010 and the US Department of Health and Human Services (DHHS) articulated an action plan for reaching this objective in its report Communicating Health: Priorities and Strategies for Progress.2 Studies linking health literacy to health outcomes were examined by the Agency for Healthcare Research and Quality (AHRQ) and its report, Literacy and Health Outcomes,3 concluded that the weight of evidence supported a link between literacy and health outcomes. The IOM was asked to examine the scope and rigor of health literacy research. The IOM issued a report offering recommendations for policy makers, researchers, government agencies, and the private sector for needed action and further research.1 Evidence for increased interest in health and literacy links may be found in the published literature. The approximately one dozen published journal articles of the 1970s grew to three dozen in number in the 1980s and burgeoned in the 1990s after the publication of findings from the first National Adult Literacy Survey (NALS). By the end of the century, the published literature addressing health literacy consisted of approximately 300 studies.4 An additional 300 articles have been published between 2000 and 2004.5 Most of the published studies are focused on the reading level of health materials such as patient package inserts, informed consent materials, and patient education pamphlets and booklets. Over time, assessments of materials have included examinations of the match between the reading level of printed health materials and the reading skills of the intended audiences. More recent studies have expanded beyond print materials and are examining health information delivered through various channels of communication including television, websites, and other computer-based technologies. Overall, findings continue to indicate that the demands of health materials and messages exceed the average skills of the public and of the average high school graduate.4,1

A smaller section of the literature has focused on health outcomes. Supported by the development of rapid assessment tools, researchers in the 1990s and beyond were able to explore links between approximations of reading skills and a variety of health outcomes. Most of these outcome studies differentiate between those with high and low scores on rapid assessment tools such as the Rapid Estimate of Adult Literacy in Medicine (REALM)6 and the short form of the Test of Functional Health Literacy in Adults (TOFHLA),7 both of which correlate well with short tests of reading skills. Researchers, in approximately 50 studies, report differences in a wide range of health-related outcomes based on readings skills. Outcome measures included awareness and knowledge of disease and/or medicines, participation in healthful activities (such as screening or breastfeeding), ability to follow a regimen (for a variety of chronic diseases), hospitalization, and indicators of successful disease management (such as glucose measures for diabetes control).

 HEALTH LITERACY AS AN INTERACTION

Various definitions of health literacy were put forth in the 1990s when the term health literacy started being used in abstracts, key word listings, and conference titles rather than health and literacy. The following definition used in Healthy People 2010 was most frequently cited: “the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.”8

HHS and the IOM adopted this definition. At the same time, reports issued from both noted that the focus on the “capacity of individuals” needed to be balanced by a concurrent understanding of the communication delivery side as well. Consequently, the IOM committee report states that health literacy is an interaction between social demands and individuals’ skills.1 The IOM report notes that culture, language, and processes used in health care settings were unfamiliar to and often erected barriers for adults seeking advice and care.1 The report also cites findings that the demands of public health and medicine are burdensome and may erect unnecessary barriers to access and care.

Health Demands People engage in a wide range of activities when they take healthrelated action at home, at work, and in the community. In all of these health contexts, adults are provided with materials and tools they are expected to use as they access information and resources and as they 1035

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Behavioral Factors Affecting Health

participate in decisions and actions that influence their health and that of their families.9,10,1 Health information is communicated in a variety of ways. Sometimes it is conveyed via continuous text (prose) such as in the explanatory paragraphs on an informed consent sheet, a discussion of air quality in a newspaper editorial, or a description of the etiology of a particular disease in a patient education brochure or pamphlet. Documents, which include graphic displays, tables, and lists, comprise another type of material used to convey health information. These include weather charts, graphs of health-related trends over time, nutrition labels, as well as tables provided on packages of over-the-counter medicines for determining dose. In addition, documents, such as the open-ended forms ubiquitous in health and social service institutions, serve as the vehicle for information gathering for a wide range of activities including those related to health history, insurance, or research. Critical public and personal health information is also communicated in speech, whether over the airways or in conversation between a care provider and a patient. Social demands in health contexts include the following: • Assumptions made about the public’s background knowledge, culture, and skills; • Reading level of health-related materials designed to provide both background information and tools for action; • Specialized processes used in detection and treatment protocols; • Time limitations on interactions between patients and providers; • Expectations related to priorities and behavior; • A pervasive use of professional jargon and scientific terms in print and oral communication. Researchers have developed and applied several tools for assessing the readability of written materials such as the simplified measure of Gobbledygook (SMOG)11 and other readability formulas, the suitability assessment of materials (SAM)12 and other text assessment approaches, and the PMOSE/IKIRSCH tool which assesses lists and tables.13 However, as of 2005, no studies of health literacy have reported on the development and use of tools to assess and quantify the ease or difficulty of open entry forms, visuals, or oral discourse.

Skills Accessing, comprehending, and acting on health information and services requires individuals to have and use a full range of literacy skills. Individuals’ skills include, but go beyond, word recognition and reading comprehension to encompass a broader range of linked literacy skills such as writing, speaking, listening, and basic math. The 1992 national adult literacy survey (NALS) focused attention on adults’ ability to use print materials for everyday tasks.14 Materials used on the NALS were drawn from six contexts of everyday life including home and family, health and safety, community and citizenship, consumer economics, work, and leisure and recreation. Questions were based on the use of these materials and approximated the tasks adults would undertake in everyday life. Tasks included, for example, determining the price of a food item on sale for a 10 % discount, figuring out the correct dose of medicine to give a child, and filling out a bank deposit slip. Materials included a variety of prose materials (such as narratives, expositions, description, argumentation, and instructions) and documents found in everyday life (such as records, charts, tables, graphs, entry forms, and lists). Both the materials and the tasks associated with the materials were calibrated for level of difficulty. NALS scores were based on adults’ ability to accomplish tasks using printed texts and ranged from 0 to 500. The average NALS score for U.S. adults was 273. Analysts examining both national and international assessments of adult literacy

skills in industrialized nations indicated that scores above 275 reflect an ability to meet the demands within industrialized nations.15 The U.S. findings indicate that about half of U.S. adults have difficulty with complex materials and are limited in their ability to integrate information from complex text.14 A 2004 follow-up analysis of adult literacy skills as applied specifically to health materials and tasks indicates that a majority of adults encounter difficulties with materials such as labels on medicines, health benefit packages, product advertisements, and discussions of health policy issues in newspapers.9 The health activities literacy scale (HALS) yielded scores that are essentially the same as those for NALS, after all, the HALS was based on a sub-set of materials and tasks drawn from the NALS and the international assessments known as the international adult literacy survey (IALS). However, the focus on health materials and tasks grounds the discussion in a health context. New analyses yielded insight into the importance of a number of variables including the importance of access to wealth and its influence on literacy. Scores for the HALS varied by critical factors such as educational attainment, age, wealth, race/ethnicity, and nativity. Educational attainment is the strongest predictor of literacy skills. Overall, those with less than a high school degree or general educational development (GED) certificate have more limited literacy skills than do those with a diploma or education beyond high school. Both the NALS and HALS analyses found that persons over the age of 60 were significantly more likely to have limited functional and health literacy skills than were younger working adults. Older adults’ literacy limitations may be attributed to a number of factors including less schooling than younger adults, visual and cognitive impairments, and lost literacy skills due to diminished use.16,17 Those who are without resources (defined as interest from savings accounts or income from dividends) are also more likely to have limited literacy skills. Table 59-1, drawn from the Education Testing Service (ETS) policy report, Literacy and Health in America, illustrates the interplay among population groups by educational attainment, age, and wealth variables. Overall, the average score for those without a high school diploma or a GED is lower than the scores for others. However, the additional impact of resources may be seen in the difference between the average score of elders who have access to resources and those who do not. Underserved populations such as minorities and immigrants are more likely to have limited literacy skills than are native-born whites.14,9 In addition, one analysis of the NALS offered a portrait of inmates and concluded that prisoners have literacy skills well below those of nonincarcerated persons. However, these skill levels match those of the communities from which they came.18,19 Unfortunately, population groups with limited literacy skills may also have more frequent interactions with social service agencies, legal services, and health care institutions. These environments are saturated with print. Thus the mismatch between the demands of the systems and peoples’ general skills becomes all the more troublesome.

Health Activities and Literacy Challenges A broad notion of health literacy serves to move attention from the clinical encounter to the health-related tasks adults grapple with in the multiple contexts of everyday life. Literacy and Health in America offers a schema for examining health materials, tasks, and skills within five commonly used groupings: health promotion, health protection, disease prevention, health care and maintenance, and navigation. Table 59-2, offers a brief description of each of these groups of activities with examples of a range of materials that adults use and the associated tasks they undertake. While the materials and tasks needed within health care settings and for navigating health and social service systems are arduous, so too are many of the materials and tasks needed for mundane health-related activities at home, at work, and in the community.


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Health Literacy

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TABLE 59-1. AVERAGE HALS PROFICIENCY BY WEALTH STATUS AND LEVEL OF EDUCATION

Wealth Status

Less than High School

High School or GED

Beyond High School

1. Working adults with high likelihood of having savings or dividends, low likelihood of poverty

273

291

321

2. Young adults with low likelihood of both poverty and additional assets

218

267

293

3. Retired adults with high likelihood of additional assets

216

257

285

4. Adults with high likelihood of poverty and receiving food stamps, low likelihood of additional assets

217

264

281

5. Retired adults on social security with high likelihood of poverty, low likelihood of additional assets

188

240

261

Proficiency refers to the average score based on the NALS range of a low of 0 to a high of 500. The mean score for U.S. adults is 273. Education and economic scholars note that literacy scores in the range of 275 and above are needed for participation in the economy of the 21st century. Source: This table is adapted from: Rudd RE, Kirsch I, Yamamoto K. Literacy and Health in America. ETS Policy Report #19. Princeton NJ: Educational Testing Services. 2004.

TABLE 59-2. HEALTH ACTIVITIES, MATERIALS, AND TASKS

Health Activities

Focus

Health Promotion

Enhance and maintain health

Health Protection

Safeguard health of individuals and communities

Disease Prevention

Take preventive measures and engage in screening and early detection

Health Care & Maintenance

Seek care and form a partnership with a health professional such as a doctor or dentist or nurse

Navigation

Access needed services, and get coverage and benefits

Materials Adults are Expected to Use

Tasks Adults are Expected to Accomplish

Label on a can of food or recipes Articles in newspapers and magazines Charts and graphs such as the Body Mass Index Health education materials [such as a well baby booklet] A newspaper chart about air quality A water report in the mail A health and safety posting at work A label on a cleaning product Postings for inoculations & screening Letters re: test results Articles in newspapers and magazines Graphs, charts Health education Health history forms Labels on medicine Develop plan for taking medicine as described Health education booklets Directions for using a tool such as a peak flow meter Schedule and keep appointment Application forms Statements of rights and responsibilities Informed consent forms Benefit packages

Purchase food Prepare a dish from a recipe Plan exercise Maintain healthy habits [re: nutrition, sleep, exercise] Take care of one’s health and that of family members Decide among product options Use products safely Vote on community issues Avoid harmful exposures Take preventive action Determine risk Engage in screening or diagnostic tests Follow up Seek professional care when needed Describe symptoms Follow directions Measure symptoms Maintain health with chronic disease [follow regimen, monitor symptoms, adjust regimen as needed, seek care as appropriate] Locate facilities Apply for benefits Fill out forms Offer informed consent

Source: Rudd RE, Kirsch I, Yamamoto K. Literacy and Health in America. ETS Policy Report #19. Princeton, NJ: Educational Testing Services. 2004.


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Behavioral Factors Affecting Health

 IMPLICATIONS

The AHRQ report, Literacy and Health Outcomes, indicates that the new field of health literacy has established links between literacy and health outcomes.3 Approximately 50 such studies are focused on medical settings but have not yet included other health areas such as dentistry, mental health, social work, or pharmacy, for example. Nor have any studies examined outcomes related to activities undertaken at home, at work, or in the community.9 The field of inquiry is broad with a good deal of work yet to be done. Some of this work will contribute to an understanding of health disparities.

Opportunities for Research Health literacy research findings offer important implications for investigators. The very process of research, and the accepted language in and format of documents and questionnaires used for research must be examined through a literacy lens. More rigor must be applied to the development of questionnaires and interview protocols which form the foundation for research. Health researchers have long collected information on income and health as indicators of social status, and the links between income and/or education and health are wellestablished.20 A new focus on education and its component parts will shed light on pathways between education and health outcomes and more clearly establish the role of literacy. Inquiries into socioeconomic and racial/ethnic disparities in health outcomes must include attention to the added barrier of poorly designed materials. For example, parents must grapple with small font and jargon as they attempt to enroll in health insurance programs or to make sense of the handouts and materials they are given for chronic disease management. Furthermore, studies of literacy demands in various contexts such as health care, housing, or employment settings may shed light on how the impact of limited health literacy on health can be modified by access to resources and supports within social environments.21 The differences in health literacy skills by age, race/ethnicity, poverty status, and immigrant status9 may well reflect long-standing discrimination with respect to access to education and other resources for human development especially among older cohorts, racial/ethnic minorities, impoverished communities, and immigrants from underdeveloped countries. Health disparities are also seen between these populations groups and majority population groups in the U.S. The extent to which these differences in health literacy skills are causally related to observed disparities in health outcomes—and thus, the extent to which attention to health literacy in medical and public health interventions can ameliorate such disparities—is a critical area of current and forthcoming health literacy research.

Implications for Practitioners Health literacy is intimately tied to client and practitioner interactions. Studies indicate that many long standing practice recommendations serve to lower literacy demands.22–24 Health educators, for example, have long emphasized the importance of pilot testing materials and programs with members of the intended audiences.24 Public health program developers often engage members of the community as participants in the design and evaluation of programs.25,26 The activated patient model is supported as an important approach for the management of chronic diseases.22 Several approaches hold promise but have not yet been fully evaluated. For example, the American Medical Association suggests that health providers speak with their patients using plain, everyday language.27 Health practitioners are urged to use teach-back approaches, for example, asking patients to describe how they will tell others what they just learned. Effective innovation and progress in this field cannot be made without the ongoing participation and leadership of practitioners and policy makers. The development of all health communications must be appropriately designed with the audience in mind, based on accurate assessments of the public’s knowledge and skills, and be

designed for use. Rigorous formative process and outcome evaluations most be undertaken for health communication efforts whether the focus is on print materials or oral delivery, or interpersonal or mass media channels. Plain language, well designed materials and documents, and educational approaches that go beyond a reliance on the written word will improve health literacy. While the education sector maintains responsibility for building literacy skills, health policy makers and practitioners maintain responsibility for health materials, messages, and procedures. The recommendations for action outlined in the HHS and IOM reports call for the development and testing of programs and materials, and evaluations of new approaches and technologies. This work can be supported through partnerships among and between health professionals, K-12 teachers, adult educators, librarians, and social service agency staff.  REFERENCES

1. Institute of Medicine. Health Literacy: A Prescription to End Confusion. Washington, DC: The National Academies Press. 2004. Available at: http://www.nap.edu/books/0309091179/html/. Chapters, 1, 2, & 4. 2. Rudd R. Objective 11-2. Improvement of health literacy. Communicating Health: Priorities and Strategies for Progress. Washington, DC: U.S. Department of Health and Human Services. 2003:35–60. 3. Berkman ND, DeWalt DA, Pignone MP, et al. Literacy and Health Outcomes. Summary, Evidence Report/Technology Assessment: Number 87. AHRQ Publication Number 04-E007-1, January, 2004. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/litsum.htm 4. Rudd RE, Moeykens BA, Colton TC. Health and literacy: A review of medical and public health literature. In: Comings JP, Garner B, Smith C, eds. The Annual Review of Adult Learning and Literacy. San Francisco: Jossey-Bass Publishers. 2000;158–99. 5. The Harvard School of Public Health: Health Literacy Studies Web Site. Available at: http:www.hsph.harvard.edu/healthliteracy. Accessed February, 2005. 6. Davis TC, Long SW, Jackson RH, et al. Rapid estimate of adult literacy in medicine: A shorthand screening instrument. Family Medicine. 1993;25(6):391–5. 7. Parker RM, Baker DW, Williams MV, et al. The test of functional health literacy in adults: A new instrument for measuring patients’ literacy skills. Journal of General Internal Medicine. 1995;10(10): 537–41. 8. U.S. Department of Health and Human Services. Healthy People 2010: Understanding and Improving Health. 2nd ed. Washington, DC: U.S. Government Printing Office, November, 2000. 9. Rudd RE, Kirsch I, Yamamoto K. Literacy and Health in America. Princeton, NJ: Educational Testing Services. 2004. 10. Rudd RE, Renzulli D, Pereira A, et al. Literacy demands in health care settings: the patient perspective. In: Schwartzberg JG, Van Geest JB, Wang CC, eds. Understanding Health Literacy; Implications for Medicine and Public Health. 2005:69–84. 11. McLaughlin GH. SMOG grading: A new readability formula. Journal of Reading. 1969;12:639–46. 12. Doak L, Doak C, Root J. Teaching Patients with Low Literacy Skills. 2nd ed. Philadelphia, PA: J.B. Lippincott Company. 1996. 13. Mosenthal PB, Kirsch I. A new measure for assessing document complexity: The PMOSE/IKIRSCH Document Readability Formula. Journal of Adolescent and Adult Literacy. 1998;41(8):638–57. 14. Kirsch I, Jungeblut A, Jenkins L, et al. Adult literacy in America: The first look at the results of the National Adult Literacy Survey (NALS). Washington, DC: U.S. Department of Education. 1993. 15. Comings J, Reder S, Sum A. Building a Level Playing Field: The Need to Expand and Improve the National and State Adult Education


59

16.

17.

18.

19.

20.

21. 22. 23.

and Literacy Systems. Cambridge, MA: National Center for the Study of Adult Learning and Literacy (NCSALL); December, 2001. Brown H, Prisuta R, Jacobs B, Campbell A.. Literacy of Older Adults in America: Results from the National Adult Literacy Survey. Washington, DC: National Center for Education Statistics; 1996. Roberts P, Fawcett G. At Risk: A Socio-economic Analysis of Health and Literacy Among Seniors. Ottawa, Ontario: Statistics Canada; 1998. Haigler KO, Harlow C, O’Connor P, et al. Literacy behind Prison Walls: Profiles of the Prison Population from the National Adult Literacy Survey. Washington, DC: National Center for Education Statistics; 1994. Reder S. The State of Illiteracy in America: Estimates at the Local, State, and National Levels. Washington, DC: National Institute for Literacy; 1998. Pamuk E, Makuc D, Heck K., et al. Socioeconomic Status and Health Chartbook. Health, United States. Hyattsville, MD: National Center for Health Statistics; 1998. Lee S, Arozullah A, Cho Y. Health literacy, social support, and health: a research agenda. Social Science and Medicine. 2004;58(7):1309–21. Roter R, Margalit R, Rudd RE. Current perspectives on patient education in the U.S. Patient Education and Counseling. 2001;1472:1–8. Rudd RE, Comings JP. Learner developed materials: an empowering product, Health Education Quarterly. 1994;21(3): 33–44.

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24. National Institutes of Health. Making Health Communication Programs Work. Office of Cancer Communications, National Cancer Institute; 1989. 25. Minkler M, Wallerstein N. Improving health through community organization and community building: a health education perspective. In: Minkler M, ed. Community Organizing and Community Building for Health. 2005;26–50. 26. Centers for Disease Control and Prevention. Principles of Community Engagement. Atlanta, GA: CDC Public Health Practice Program Office; 1997. 27. Weiss B. Health Literacy: A Manual for Clinicians. American Medical Association Foundation and American Medical Association; 2003.

 SUGGESTED READINGS

Kirsch I. The International Adult Literacy Survey (IALS): Understanding What Was Measured. Princeton, NJ: Educational Testing Services; 2001. Shire N. Effects of race, ethnicity, gender, culture, literacy, and social marketing on public health. Journal of Gender Specific Medicine. 2002;5(2):48–54.


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V Noncommunicable and Chronic Disabling Conditions

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Screening for Early and Asymptomatic Conditions

60

Robert B. Wallace

 DEFINITION OF SCREENING

The typical natural history of diseases and conditions dictates that at some point the biological onset of the disease occurs and progresses at varying rates until they become clinically evident. These rates may be as short as instantaneous, as in acute trauma, or could be life-long, as in a genetic risk factor for Alzheimer’s disease. Primary prevention attempts to intercept the conditions that lead to disease onset, while secondary prevention generally relates to the early and asymptomatic detection of disease; that is, disease screening, in the hope that the trajectory toward clinical illness can be stopped or mitigated in a helpful way. When overt clinical illness is present, tertiary prevention refers to rehabilitative and other factors that deter disease progression and help return the patient to a healthier state. Disease screening usually takes two general forms: (a) screening for proven, biological, or behavioral risk factors for diseases that lead to interventions or treatments in themselves, such as abnormal blood cholesterol or blood pressure levels; or (b) screening directly for evidence of the disease itself, followed by provision of effective treatment to cure or to prevent the progression of pathophysiological processes that will cause overt clinical manifestations. This implies that screening may be done in stages, for instance by screening for general disease susceptibility first, such as for certain demographic or anatomic characteristics, or only if informed consent for the screening procedure is obtained. Disease screening may be applied to general populations irrespective of receipt of medical care (i.e., mass screening), or to clinical populations with various characteristics. In general, disease screening is applied to populations with a relatively low risk of the condition of interest. Because of the great increase in types of screening that have been developed, the general definition of disease screening does not fit all situations. For example, the disease may be overt and the screening is to determine the cause, as in the detection of family violence, or the condition may be overt, but not clinically explored at a primary care visit, as in the case of cognitive impairment or depression.

preventive intervention or therapy must exist and should not encumber a more beneficial outcome when applied to the presymptomatic rather than to the symptomatic stage; (d) The screening test should be acceptable to the population and suitable for general, routine application. Many other criteria for an effective screening test could be added, such as maintenance of test accuracy over time and freedom from screening-related adverse effects. Even with concerted application of these screening criteria, major pitfalls may cause an erroneous assessment of a screening program’s value. An example is lead time bias, the interval between presymptomatic disease detection by a screening test and symptom onset.2 If the natural history of a disease is variable or not thoroughly understood during the presymptomatic and symptomatic stages, a screening test may identify a presymptomatic condition earlier and increase the interval to overt morbidity but not change the ultimate outcome. Length bias occurs when there is a correlation between the duration of disease latency and the natural history of the symptomatic phase.2 If the mild form of a disease has a longer latency and is hence more easily found on screening than are more severe forms of disease, the screening test may appear falsely beneficial. In general, the validity of a screening test depends on the evidence base to justify the screening intervention. Many screening tests may be proven only through one or more randomized clinical trials. Excellent examples of creating the evidence base for screening tests can be found in the work of the U.S. Preventive Services Task Force, part of the Agency for Healthcare Research and Quality.3 Selection and interpretation of screening tests require a combination of subjective and objective criteria. Objective criteria include operating characteristics, predictive value, and cost-effectiveness of the tests, which are tempered by subjective evaluations of individual and public acceptability and financing. The operating characteristics of a screening test are its sensitivity and specificity. These are general test characteristics that can apply to any laboratory or diagnostic test data as well as other information collected from the medical history and physical examination. Sensitivity is the proportional detection of individuals with the disease of interest in the tested population, expressed as follows:

 THE ASSESSMENT OF SCREENING TESTS

There are several criteria that aid in selecting and applying an appropriate screening test.1 (a) The disease should be common enough to warrant a search for its risk factors or latent stages because screening for excessively rare diseases may result in unacceptable cost-benefit ratios; (b) The morbidity or mortality (i.e., burden of suffering) of the untreated target condition must be substantial; (c) An effective

Sensitivity (%) =

True positives × 100 True positives + False negatives

True positives are individuals with the disease and whose test result is positive. False negatives are individuals whose test result is negative despite having the disease. Specificity is the proportional detection of individuals without the disease of interest, expressed as follows: 1043

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Noncommunicable and Chronic Disabling Conditions

Specificity (%) =

True negatives × 100 True negatives + False negatives

True negatives are individuals without the disease and whose test result is negative. False positives are those who have a positive test result but do not have the disease. Sensitivity is limited by the proportion of cases missed by the test (false negatives) and specificity is limited by the proportion of noncases found to be positive (false positives). Ideally, a test would have a 100% sensitivity and specificity, but few if any tests have achieved this. Unfortunately, sensitivity and specificity are often inversely related. This relationship has been expressed as the receiver operating characteristic (ROC)4 of a numerically continuous test result. The ROC allows optimal specification of test sensitivity and specificity. The sensitivity, or true-positive ratio, is displayed along the ordinate, and the specificity, or false-positive ratio, is exhibited on the abscissa. As the sensitivity increases, so does the false-positive ratio in most instances. When a ROC has been established for a test, any one of several sensitivity and specificity combinations may be evaluated for suitability in test application and contrasted with potential alternate tests. Further information on the application of ROC curves is available.5 Sensitivity and specificity values from the literature are most applicable to populations and test conditions similar to those under which the values were established. However, it is possible that test properties may differ according to mode of administration (e.g., telephone vs. mail questionnaire) or by any demographic feature of the target population, and thus, further generalization or extrapolation of these values can be misleading. For example, it has been suggested that the increasingly common use of hormone replacement therapy among postmenopausal women may decrease the sensitivity and specificity of mammographic screening.6 Whereas the operating characteristics of a test are of major help in selecting a screening test, the predictive value of a test is a major aid in interpretation of a result. The predictive value of a positive test is the proportion of all individuals with positive tests who have the disease and is expressed as follows: Positive Predictive Value (%) =

True positives × 100 True positives + False positives

The predictive value of a negative test is the proportion of all individuals with negative tests who are nondiseased. This is expressed as follows: Negative Predictive Value (%) =

True negatives × 100 True negatives + False negatives

Predictive values are dependent on both the operating characteristics and the prevalence of the disease in the target population. For any given set of operating characteristics, the positive predictive value is directly related to prevalence, and the negative predictive value is inversely related to prevalence. Therefore, in screening situations where the prevalence is relatively low, the operating characteristics must be very high to avoid low positive predictive values. In most screening situations for serious fatal conditions, such as cancer, the test or test sequence offering the highest sensitivity ordinarily will be preferred. This has the effect of finding as many cases as possible but may correspondingly increase the number of false positives. The effect of sensitivity, specificity, and prevalence on predictive values has been clearly demonstrated.7 Cost-effectiveness is especially important in screening programs because of the number of asymptomatic individuals who must be evaluated for the relatively small number of diseased cases. Formal cost-effectiveness analysis8–10 should be undertaken before program initiation. The program’s value must include an assessment of all costs and a realistic appraisal of effectiveness. Positive predictive values are usually well below 50% for most initial screening situations, so that secondary diagnostic evaluation is nearly always required to eliminate false positives, adding substantially to program cost.

Exhaustive reviews of the efficacy of clinically applicable screening programs have been undertaken by the U.S. Preventive Services Task Force3 and several other disciplinary, specialty and international groups, with recommendations offered in part with consideration of cost-effectiveness. On the other hand, public screening, or mass screening, may have inherent advantages from the standpoint of efficiency. The tests and procedures selected for use are often highly standardized and can be administered more inexpensively than they can in clinical or more specialized settings, and generally they can be applied without the need for direct physician supervision. To enjoy the efficiency of mass screening, such programs must be carefully organized and managed. Recipients of both normal and abnormal test results must be considered. Those with abnormal test results must have a properly organized follow-up evaluation protocol, and those with normal results should be informed of the predictive value of a normal test to avoid false reassurance. Even with the inherent efficiency of mass screening, most such programs must still be focused on populations with sufficient disease or risk factor prevalence to maximize program efficiency. Another application of screening programs is in the clinical context where patients have active clinical problems. Examples include screening on the first evaluative ambulatory clinic visit or at hospital admission. Comprehensive clinical screening with routine physical examinations or laboratory tests, or both, remains controversial, largely because there is very little if any evidence in the scientific literature concerning the efficacy or effectiveness of standard screening tests in the face of existing comorbid illness. For example, is mammography effective in persons with active insulin-dependent diabetes, or cholesterol screening in the face of an active carcinoma? These are questions yet to be adequately addressed in research. In the past, so-called “multiphasic” screening programs had been proposed for persons being admitted to the hospital. It now appears that these procedures have limited utility and high cost primarily because of numerous false-positive tests and irrelevant findings and should be discarded in favor of diagnostic and therapeutic activities directed at the immediate clinical problems.11–13 However, inpatient hospital services have been used as opportunities for categorical screening programs such as undiagnosed human immunodeficiency virus infection,14 alcoholism,15 or nutritional problems among the elderly.16 Multiphasic biochemical screening is still being proposed as a useful inpatient tool.17 Another important issue that has arisen is screening for genetic conditions. This is covered elsewhere in this text.

 REFERENCES

1. Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Rep. 34, 1968. 2. Pelikan S, Moskowitz M. Effects of lead time, length bias, and false negative assurance on screening for breast cancer. Cancer. 1993;71: 1998–2005. 3. U.S. Preventive Services Task Force. Proceedings available at: http://www.ahrq.gov/clinic/uspstfix.htm. Downloaded Sept. 1, 2006. 4. Swets JA. Measuring the accuracy of diagnostic systems. Science. 1988;240:1285–93. 5. Linden A. Measuring diagnostic and predictive accuracy in disease management: an introduction to receiver operating characteristic (ROC) analysis. J Eval Clin Pract. 2006;12(2):132–9. 6. Laya MB, Larson EB, Taplin SH, et al. Effect of estrogen replacement therapy on the sensitivity and specificity of screening mammography. J Natl Cancer Inst. 1996;88:643–9. 7. Galen RS, Gambino SR. Beyond Normality: The Predictive Value and Efficiency of Medical Diagnosis. New York: John Wiley, 1975. 8. Schneider JE, et al. Clinical practice guidelines and organizational adaptation: a framework for analyzing economic effects. Int J Technol Assess Health Care. 2006;22:58–66.


60 9. Johannesson M. The relationship between cost-effectiveness analysis and cost-benefit analysis. Soc Sci Med. 1995;41:483–9. 10. Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost Effectiveness in Health and Medicine. New York: Oxford University Press, 1996. 11. Whitehead TP, Wotton IDP. Biochemical profiles for hospital patients. Lancet. 1974;2:1439. 12. Korvin CC, Pearce RH, Stanley J. Admissions screening: clinical benefits. Ann Intern Med. 1975;83:197. 13. Burbridge TC, Edwards F, Edwards RG, et al. Evaluation of benefits of screening tests done immediately on admission to hospital. Clin Chem. 1976;22:968.

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14. Trepka MJ, Davidson AJ, Douglas JM, Jr. Extent of undiagnosed HIV infection in hospitalized patients: assessment by linkage of seroprevalence and surveillance methods. Am J Prev Med. 1996;12: 195–202. 15. Bothelho RJ, Richmond R. Secondary prevention of excessive alcohol use: assessing the prospects for implementation. Fam Pract. 1996;13:182–93. 16. Cotton E, Zinober B, Jessop J. A nutritional tool for older patients. Professional Nurse. 1966;11:609–12. 17. Ferguson RP, Kohler FR, Chavez J, et al. Discovering asymptomatic abnormalities on a Baltimore internal medicine service. M Med J. 1996;45:543–6.


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61

Cancer Leslie K. Dennis • Charles F. Lynch • Elaine M. Smith

Neoplasms are diseases characterized by abnormal proliferation of cells. If the proliferating cells invade surrounding tissues, the resultant tumor is malignant; if they do not, it is benign. Some benign neoplasms may be fatal, including histologically benign brain tumors that grow and displace normal brain tissue in the confined space of the skull, and hepatocellular adenomas that rupture and cause bleeding into the peritoneal cavity. Some benign tumors such as intestinal polyps are considered premalignant lesions and confer a high risk of progression to malignancy. The term cancer usually implies a malignant tumor (malignancy), but refers also to brain tumors and some other benign neoplasms.  DESCRIPTIVE EPIDEMIOLOGY

Classification Cancers are classified according to their organ or tissue of origin (site or topography code) and histological features (morphology code). A number of classification schemes have been developed, the most recent and widely used of which appears in Chap. 2 of the International Classification of Diseases, 10th revision (ICD-10), which is largely a topography code,1 and the International Classification of Diseases for Oncology, 3rd edition (ICD-O), which contains an expanded version of the topography code in ICD-9 as well as a detailed morphology code.2

Sources of Incidence and Mortality Rates Mortality rates are calculated from death certificate records and population census data. Mortality rates from various countries have been compiled periodically.3 Cancer mortality rates for the United States are published by the United States’ National Cancer Institute (NCI) and Centers for Disease Control and Prevention (CDC).4–6 Population-based cancer registries, which have been established in many countries, provide information on incidence rates. These have been compiled in Cancer in Five Continents, which is jointly published periodically by the International Agency for Research on Cancer (IARC) and the International Association of Cancer Registries (IACR).7 The best source of cancer incidence rates for the United States is the Surveillance, Epidemiology, and End Results (SEER) program of the NCI, which supports a network of 18 population-based cancer registries throughout the country. Results from this program are published annually and more detailed monographs are published periodically.8,9 Both incidence and mortality statistics for the United States are summarized for the lay public and published annually by the American Cancer Society.10 A North American Association of Central Cancer Registries (NAACCR) was established in 1987, and beginning in 1991 the CDC made funds available to individual states for cancer registration. The

cost of collecting high-quality data on a sufficiently large proportion of all cases in a defined population is considerable; however, utilization of these data for research or cancer control purposes justifies cancer registration efforts.

Magnitude of the Cancer Problem In the aggregate, cancer is second only to heart disease as a cause of death in the United States and accounts for about 23% of all deaths.10 Approximately 190 deaths from cancer occur per 100,000 people per year, compared with about 232 per 100,000 from heart disease, 53 per 100,000 from cerebrovascular diseases, 43 per 100,000 for chronic lower respiratory diseases, and 37 per 100,000 from accidents.10 Based on U.S. incidence and mortality rates for 2001–2003, the lifetime probabilities of developing cancer have been estimated to be 45.3% in men and 37.9% in women; the lifetime probabilities of dying of cancer are estimated at 23.4% in men and 19.8% in women.4,10 The National Cancer Institute estimates the direct medical costs of cancer to be $72 billion annually, or about 5% of the total health-care costs in the United States.11

Relative Importance of Specific Neoplasms Age-adjusted incidence and mortality rates, as well as 5-year survival rates, in men and women in the United States are readily available, and Table 61-1 shows such rates for 1998 through 2003.4,10 The most common cancers in men are those of the prostate, lung, and colon and rectum; the cancers causing the most deaths in the United States are lung, colon and rectum, and prostate. In women, breast cancer is by far the most common neoplasm, followed by cancers of the lung, and colon and rectum.10 However, because of the more favorable survival of women with breast than lung cancer, mortality rates of female lung cancer exceed those for female breast cancer in the United States. Another way to judge the importance of a malignancy is by the number of years of life lost due to its occurrence in a population. This measure reflects the incidence of the cancer, the fatality rate in those who develop it, and the age at which the cancer tends to occur. This measure gives more weight to childhood cancers than overall mortality rates, and because of economic implications, it can be of value in setting priorities for research and prevention. In order of estimated years of life lost, the 10 most important cancers in the United States are lung, female breast, colon and rectum, pancreas, leukemia, nonHodgkin’s lymphoma, brain, prostate, ovary, and liver.4 The estimated age-standardized incidence rates of all cancers vary among the various regions of the world, and the cancers of most importance in developing countries are different from those in developed countries such as the United States. In order by numbers of cases, the 10 most common cancers across the globe are those of the 1047

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1048

Noncommunicable and Chronic Disabling Conditions

TABLE 61-1. AVERAGE ANNUAL AGE-ADJUSTED (2000 STANDARD) INCIDENCE AND MORTALITY RATES (1998–2003) AND 5-YEAR RELATIVE SURVIVAL RATES (1998–2002 CASES) BY PRIMARY SITE AND SEX, ALL RACES, SEER 13 AREAS COMBINED Rates (per 100,000) Incidence Site Oral cavity and pharynx Digestive system Colon and rectum Colon Rectum and rectosigmoid Pancreas Stomach Esophagus Respiratory system Lung and bronchus Larynx Bones and joints Soft tissues (including heart) Skin (excluding basal and Squamous cell carcinoma) Melanomas of skin Breast Female genital system Cervix uteri Corpus uteri Ovary Male genital system Prostate gland Testis Urinary system Urinary bladder Kidney and renal pelvis Eye and orbit Brain and nervous system Endocrine system Thyroid Lymphomas Non-Hodgkin’s Hodgkin’s Myeloma Leukemia All sites

5-Year Relative Survival (%)a

Mortality

Male

Female

Male

Female

Male

Female

15.5 110.9 61.4 42.9 18.5 12.6 12.2 7.6 86.6 77.5 6.3 1.0 3.6 25.8

6.3 74.9 45.5 34.2 11.3 9.9 6.1 2.0 51.4 49.1 1.3 0.7 2.4 15.6

4.2 59.9 24.5 20.6 3.9 12.2 6.2 7.7 78.6 75.6 2.5 0.5 1.5 5.3

1.6 36.8 17.1 14.8 2.3 9.2 3.2 1.8 41.7 41.0 0.5 0.3 1.2 2.2

58.1 43.8 66.0 66.0 65.9 5.0b 23.8 16.2 18.2 13.2 65.6 65.9 65.3 88.2

60.6 46.6 63.9 62.8 67.1 5.0b 25.8 17.2b 19.0 17.5 55.0 71.1b 66.0 93.5

22.0 1.2 — — — — 178.9 172.5 5.2 53.8 36.1 16.4 0.9 7.6 4.9 4.1 26.4 23.4 3.0 7.0 16.1 551.8

14.1 132.3 50.3 8.8 23.6 13.8 — — — 17.7 9.0 8.2 0.6 5.3 12.1 11.5 18.4 16.0 2.3 4.5 9.4 411.5

3.9 0.3 — — — — 30.1 29.6 0.3 14.0 7.6 6.1 0.1 5.5 0.8 0.4 10.6 10.0 0.6 4.7 10.1 245.2

1.8 26.2 16.6 2.7 2.0 8.9 — — — 5.2 2.3 2.8 0.1 3.7 0.8 0.5 6.9 6.5 0.4 3.2 5.8 164.7

91.0 88.30b — — — — 99.9c,b 99.9c,b 95.9b 76.7 83.3 65.9 83.7 32.6 90.2b 95.3b 65.2 61.9 82.5 36.6 49.7b 66.6

93.5 89.3 70.5 72.5 84.3 45.8 — — — 71.4b 77.6b 66.5b 83.0 36.2 95.8b 97.4b 69.6 66.2 87.0b 28.8 48.4 65.9

Source: Incidence data from SEER 13 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta, San Jose-Monterey, Los Angeles, Alaska Native Registry, and Rural Georgia). Mortality data are from the NCHS public use data file for the total United States. aRates are based on follow-up of patients through 2003. bThe relative cumulative rate increased from a prior interval and has been adjusted. cThe relative cumulative rate is over 100% and has been adjusted. Citation: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission.

lung, stomach, liver, colon and rectum, breast, esophagus, lymphomas and myeloma, mouth and pharynx, prostate, and leukemia.12

Age Cancers most probably arise from DNA-damaged cells that are capable of mitotic division and differentiation. In adults, most cancers are carcinomas that arise from basal epithelial cells of ectodermal or endodermal origin. In children, most cancers are of mesodermal origin and consist largely of leukemias and lymphomas that arise from hematopoietic and lymphoid stem cells and sarcomas that probably develop from undifferentiated cells of embryonal origin.

Incidence rates for the most common childhood cancers in the United States are shown in Table 61-2.4,10 The mortality rates for even the most frequent cancers in children are many times lower than the rates of comparable tumors for all ages (Table 61-1), which largely reflect rates in adults. Cancer is primarily a disease of older adults. With some notable exceptions (e.g., cancers of the female breast and uterine cervix), there is an exponential increase in incidence rates with age. The median age at which cancer was diagnosed from 2000 to 2003 was 68.0 for males and 67.0 for females, and most cancers develop in the sixth, seventh, and eighth decades of life.4


61 TABLE 61-2. ANNUAL INCIDENCE OF SELECTED CANCERS IN CHILDREN UNDER AGE 15, 1998–2003a Ages 0–14 Site All sites Bone and joint Brain and other nervous Hodgkin’s disease Kidney and renal pelvis Leukemia Acute lymphocytic Non-Hodgkin’s lymphomas Soft tissue

Male

Female

15.5 0.6 3.3 0.7 0.7 5.1 4.1 1.2 1.1

13.9 0.6 3.1 0.4 0.9 4.4 3.5 0.6 0.9

Source: Incidence data from SEER 13 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta, San Jose-Monterey, Los Angeles, Alaska Native Registry, and Rural Georgia). a Rates are per 100,000 and are age-adjusted to the 2000 U.S. standard population (19 age groups—Census P25-1130). Citation: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission.

Sex Most major cancers occur more frequently in men than in women, exceptions being carcinomas of the breast, thyroid, gallbladder, and other biliary.10 Smoking-related cancers, described in detail subsequently, occur more frequently in men, at least in part because of their earlier and greater exposure to tobacco smoke. Some other cancers, such as carcinomas of the bladder and mesotheliomas, are more frequent in men, at least in part because of their greater occupational exposure to various chemical carcinogens and asbestos, respectively. Other cancers that occur more frequently in men include the lymphomas and leukemias, malignant melanomas, sarcomas of the bone, and carcinomas of the nasopharynx, stomach, kidney, pancreas, colon, rectum, parotid gland, and liver. The reasons for the excess of these cancers in males are uncertain. Women could be either constitutionally less susceptible to these neoplasms or less exposed to whatever environmental factors contribute to their development. Recently, a higher number of new cases of colon cancer were reported among women in the United States.10 It is unclear if this is a change in risk factors, screening activity, or age differential between men and women in the United States.

Cancer

1049

migrants from these countries than in lifelong residents of such areas as North America and Western Europe include cancers of the colon and rectum, which may be related to diets rich in animal products; cancers of the prostate, ovary, corpus uteri, and breast, which have to some extent also been related to high consumption of meats and fats, as well as to endocrinological and reproductive factors; Hodgkin’s disease, which has been hypothesized to be due to a common infectious agent, probably the Epstein-Barr virus that, like polio viruses, may cause clinically overt disease with a frequency directly related to age at initial infection; and non-Hodgkin’s lymphomas and neoplasms of the brain and testis, the causes of which are largely unknown. Other cancers occur more frequently in developing countries and in migrants from these countries. For example, compared to white populations of the United States and Western Europe, migrants from Asian countries have higher rates of stomach cancer, possibly related to intake of preserved foods and infection with Helicobacter pylori; liver cancers, which may, in part, be caused by the production of aflatoxins in contaminated foods and by hepatitis B and C viruses; cancers of the nasopharynx, caused in part by the Epstein-Barr virus (EBV); and cancer of the uterine cervix, which is caused by some types of human papillomaviruses. Cancers that are strongly related to smoking occur with a frequency commensurate with the smoking habits in the population. Thus, cancers of the lung, larynx, bladder, kidney, and pancreas have tended to occur more frequently in developed than developing countries, but rates of these neoplasms are increasing in developing countries where more widespread cigarette smoking has accompanied economic changes. The overall incidence and mortality rates and the ratio of mortality to incidence in various racial and ethnic groups in the United States for 1998–2003 are shown in Table 61-3.4 Compared with data from 1988 to 1992, rates in all racial/ethnic groups have increased with the possible exception of American Indian/Alaska natives, which have the lowest cancer rates. Differences among specific Asian or Pacific Islander groups are available elsewhere for the 1988–1992 rates by racial/ethnic group.14 Similar data from the United States 2000 Census are not available yet. Variations in overall cancer incidence reflect the mix of cancers in the different groups. Variations in mortality are due to differences in both incidence and survival. The differences in the ratio of mortality to incidence rates provide a rough indicator of differences in overall survival from cancer. These are a reflection of both the types of cancer that predominate in the different groups and the level of utilization of screening and treatment services by their members. Less advantaged groups have the highest ratios of mortality to incidence, clearly indicating that improvement of services could have an impact on the cancer burden in these populations.

Time Trends Race and Geography Within individual races, incidence and mortality rates of all cancers vary considerably from one geographic region to another; migrants from one country to another, or their descendants, tend to eventually develop most cancers at rates more similar to those in their country of adoption than to those in their country of origin, suggesting an important role for environmental risk factors in most cancers.13 In the United States, the patterns of cancer occurrence in recent immigrants reflect the cancer patterns in their countries of origin and become less distinct as these groups become more acculturated with the passage of time. The frequency of occurrence of many cancers also varies among racial groups residing in the same country. This variation may be due to factors related to their distinct cultural patterns, social behavior, or economic status, but in some instances may be due to genetic differences among the races. Some cancers appear to be related to a “Western” lifestyle. Cancers that tend to occur at lower rates in developing countries and

Figure 61-1, A and B, shows trends in incidence rates for various cancers in the United States from 1975 to 2002 for men and women, respectively.10 Figure 61-2, A and B, shows trends in mortality rates for the most common cancers in the United States from 1930 to 2002, for men and women.10 The striking increase in rates of lung cancer is largely due to cigarette smoking. The reason for the marked decline in rates of stomach cancer is unknown but may be related to changes in dietary habits, with consumption of less preserved and more fresh and frozen foods. The decline in mortality from uterine cancer is probably due to the decrease in incidence resulting from screening. Breast and prostate cancer incidence increased dramatically in the 1980s and early 1990s as a result of mammography and prostate-specific antigen (PSA) screening, respectively. Recently, there have been declines in mortality rates of these two cancers. Dating back to 1990, mortality rates for all cancer sites have been declining in the United States for the first time in recorded history. Incidence rates have not shown a similar declining pattern, supporting


Noncommunicable and Chronic Disabling Conditions TABLE 61-3. AGE-ADJUSTED INCIDENCE AND MORTALITY RATES OF ALL CANCERS COMBINED IN RACIAL AND ETHNIC GROUPS IN THE UNITED STATES, 1998–2003a Men

Women

1998–2003 Race/Ethnic Group

Incidence*

Mortality*

Ratio

American Indian/Alaska Nativeb Asian or Pacific Islander Black White Hispanicc

275.6 377.9 677.5 555.2 417.4

156.4 146.3 334.5 240.5 168.4

0.57 0.39 0.49 0.43 0.40

Incidence*

Mortality*

231.4 297.4 398.5 427.2 309.0

Ratio

112.5 99.1 193.3 163.7 109.1

0.49 0.33 0.49 0.38 0.35

Incidence data from SEER 13 areas (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, Atlanta, San JoseMonterey, Los Angeles, Alaska Native Registry, and Rural Georgia). Mortality data are from the NCHS public use data file for the total U.S. a Rates are per 100,000 and age-adjusted to the 2000 U.S. standard population (19 age groups—Census P25-1103). b Incidence data for American Indians/Alaska Natives include cases from Connecticut, Detroit, Iowa, New Mexico, Seattle, Utah, Atlanta, and the Alaska Native Registry for the time period 1998–2002. Mortality data are from the entire U.S. for the time period 1998–2003. c Hispanic is not mutually exclusive from Whites, Blacks, Asian/Pacific Islanders, and American Indians/Alaska Natives. Incidence data for Hispanics are based on NAACCR Hispanic Identification Algorithm (NHIA) and exclude cases from Hawaii, Seattle, and Alaska Native Registry. Mortality data for Hispanics exclude deaths from Maine, Massachusetts, New Hampshire, and North Dakota. Citation: Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence— SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2003), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November 2005 submission.

260

260

Male

240

Female

240 Prostate

220

220

200

200

180

180

160

160

140

140

120

120 Lung and bronchus

100 80

Colon and rectum

60

Breast

100 80 Colon and rectum

60 Urinary bladder

40

40

Lung and bronchus Uterine corpus

Non-Hodgkin’s lymphoma 20

Ovary

20 Melanoma of the skin

Non-Hodgkin’s lymphoma

Year of diagnosis

2001 2002

1999

1997

1995

1993

1991

1987

1985

1983

1981

1979

1977

1975

2001 2002

1999

1997

1995

1993

1991

1989

1987

1985

1983

1981

1979

1977

0 1975

0

1989

Rate per 100,000 population

1050

Year of diagnosis

Figure 61-1. Annual age-adjusted cancer incidence rates* among males and females for selected cancers, United States, 1930–2002. ∗ Rates are age-adjusted to the 2000 U.S. standard population and adjusted for delays in reporting with the exception of melanoma.


61 100

Cancer

1051

Lung and bronchus

90

Rate per 100,000 population

80 70 60 50

Stomach

Prostate

40

Colon and rectum

30 20 Pancreas 10 Leukemia

Liver

1930 1932 1934 1936 1938 1940 1942 1944 1946 1948 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002

0

A

Year of death 100 90

Rate per 100,000 population

80 70 60 50 Lung and bronchus 40 Breast 30 20

Stomach

10

Ovary

Colon and rectum

Uterus†

Pancreas 1930 1932 1934 1936 1938 1940 1942 1944 1946 1948 1950 1952 1954 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002

0

B

Year of death

Figure 61-2. A. Annual age-adjusted cancer death rates* among males for selected cancer, U.S., 1930–2002. B. Annual age-adjusted cancer death rates* among females for selected cancer, U.S., 1930–2002. Rates are per 100,000 and are age-adjusted to the 2000 U.S. standard population. *Rates are age-adjusted to the 2000 U.S. standard population. Note: Due to changes in ICD coding, numerator information has changed over time. Rates for cancer of the lung and bronchus, colon and rectum, uterus (uterine cervix and uterine corpus), ovary, and liver are affected by these changes.

the concept that increasing screening and improved therapies are contributing more to the declining mortality. A report evaluating the reduction of breast cancer mortality in the United States from 1975 to 2000 concluded that both screening mammography and treatment primarily contributed to the reduction.15 Comparing 1983–1985 with 1995–2001 newly diagnosed cancer patients, 5-year relative survival

rates have increased from 53% to 65% for all races across all cancer sites in the United States.10 Temporal trends in survival from cancer in children are most encouraging. From 1974 to 2001, five-year survival rates in children under age 15 increased for all sites. From 1995 to 2001, five-year survival rates were 86% for acute lymphocytic leukemia, 52% for acute


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Noncommunicable and Chronic Disabling Conditions

myeloid leukemia, 73% for brain and other nervous system, 86% for non-Hodgkin’s lymphoma, 95% for Hodgkin’s disease, 73% for sarcomas of the bone, 92% for Wilms’ tumor, and 79% for all cancer sites combined.4,10 There has been little change in the incidence of these neoplasms in children, thus reductions in mortality have resulted in prolonged survival due primarily to improved therapy.  ETIOLOGY AND PRIMARY PREVENTION

Criteria for Causality Primary cancer prevention is prevention of the initial development of a neoplasm or its precursor. This can be accomplished only if one or more causes of the neoplasm are known, and it is achieved by reducing or preventing exposure to the causative agent or enhancing exposure to the protective agent. A harmful agent is considered causal if reducing or removing a population’s exposure to it results in a decrease in the amount of disease occurring in that population; a protective agent is considered truly beneficial if increasing or expanding a population’s exposure to it results in a decrease in the amount of disease occurring in that population. To determine whether an agent is a cause of a particular disease in humans, information from all relevant studies must be assessed critically. In making such an assessment, evidence for causality is strengthened if the criteria listed in Chap. 2 are met. Additional criteria include evidence that risk is reduced following a reduction in exposure. Attempts to determine whether an agent is carcinogenic in humans must often be made without information on all of these criteria; yet assessment of whatever evidence is available must frequently be made. Investigators must examine existing evidence to identify additional questions that should be addressed by further studies, physicians must assess available evidence to be able to give their patients adequate advice, and public officials must assess the evidence to determine needs for laws and regulations to limit exposure. Each must weigh the evidence for a causal relationship and consider the consequences of falsely implicating a substance as being carcinogenic when it is not and of failing to identify as carcinogenic a substance that is. All must also be willing to alter their opinions as results of additional investigations become available. Errors of judgment can be minimized by a clear understanding of basic epidemiologic principles and by careful examination of available evidence using the above-referenced criteria for assessing causality.

General Etiological Considerations At the level of the cell, cancer is a genetic disease. The development of a cancer appears to involve a multistep accumulation of genetic damage, leading eventually to the development of an abnormal clone of cells with a selective advantage over normal cells, and finally to an incipient tumor that acquires the ability to invade surrounding tissue.16 The molecular epidemiology of cancer involves the use of molecular techniques in epidemiologic studies to provide new insights.17 For each organ site, a tumor is the end result of multiple genetic aberrations that may be caused by multiple agents, and the same endpoint may be reached via different pathways. As a result, multiple risk factors are observed for all cancers, and only a small proportion of individuals who are exposed to most known carcinogens develop cancer. For example, a factor may increase cancer risk if it contributes directly to DNA damage, alters the ability of the cell to recognize or repair damage, inhibits apoptosis, encourages cell proliferation, enhances vascularization of the incipient tumor, or otherwise confers a selective advantage to that clone of cells. Similarly, agents that inhibit tumor development might act by reducing epithelial absorption of carcinogens, inhibiting the enzymatic activation of procarcinogens, enhancing the metabolic destruction of carcinogenic agents, promoting DNA repair, or causing cell differentiation or

apoptosis and thereby reducing the number of stem and intermediate cells susceptible to the effects of carcinogens. Most of the genes in which mutations appear to play a mechanistic role in carcinogenesis are categorized as either oncogenes or tumor suppressor genes, or are involved directly in DNA repair. Most identified oncogenes are mutated forms of genes (proto-oncogenes) that code for proteins involved in signal transduction, the regulation of gene expression, or growth-regulating mechanisms such as growth factors or growth factor receptors; overexpression of these genes results in enhanced cell proliferation. Most known tumor suppressor genes function as negative regulators of cell proliferation. The tumor suppressor gene p53, for example, is mutated in a majority of epithelial tumors. Other contributors to the carcinogenic process probably include genes affecting angiogenesis, metastasis, and other components of the process such as the ability to evade or disable the immune response. The latent period between exposure to some agent and the development of a neoplasm is dependent in part on the mechanism by which the agent operates. For example, mesothelioma follows exposure to asbestos only decades after exposure; the same is true of breast cancers following radiation to the chest, suggesting that these agents act early in the carcinogenic process. On the other hand, endometrial cancers can occur within two years of exposure to exogenous estrogens, suggesting a late-stage effect of these hormones. Reticulum cell sarcomas have developed within just months of exposure to immunosuppressive drugs in persons with renal transplants. A single exposure may act at one or more points in the progression to neoplasia, and its mechanism of action may vary across cancer sites. For example, epidemiologic evidence suggests that tobacco acts early in the carcinogenesis of esophageal and gastric adenocarcinoma, late in pancreatic tumors, and at both early and late stages in lung tumors. It must be emphasized, however, that a risk factor can represent a cause in the public health sense, as defined previously, whether or not its precise mode of action is known. For example, we have only incomplete knowledge of the exact mechanisms by which tobacco smoke increases a smoker’s risk of lung cancer. For the purpose of primary prevention, however, the mechanisms of action are unimportant. Cessation of smoking will significantly reduce the incidence of lung cancer, and that is what we need to know to take preventive action. Some of the known causes of various cancers are described below.

Tobacco Tobacco use is the single largest preventable cause of cancer (and other disease) and premature death in the United States.18 Use of tobacco is responsible for about 21% of all cancer deaths worldwide, which is more than all other known causes of cancer combined.19 Tobacco increases the risk of cancers of the lung, oral and nasal cavities, esophagus, stomach, liver, pancreas, kidney, bladder, cervix, and myeloid leukemia.18–21 Table 61-4 shows the estimated proportion of cases that would be prevented in the absence of tobacco use (the population-attributable risk percent), and the estimated annual number of deaths worldwide and in the United States attributable to tobacco.18,19 Population-attributable risks for tobacco are dependent on the proportion of people in the population who use tobacco, the relative risk of the particular cancer in users of tobacco, and the presence of other causes of the cancers of interest in the population. Estimates of population-attributable risks thus vary among populations, and the values for the United States are different from values for other parts of the world. Overall, these estimates outline the importance of cancer prevention through eliminating smoking in populations. Cigarette smoking is responsible for most cancers of the oral cavity, esophagus, and bladder; and it is a cause of kidney, pancreatic, cervical, and stomach cancers along with acute myeloid leukemia.22,23 In addition to the major cancer sites mentioned above for which the associations with tobacco are well established, a growing body of evidence implicates cigarette smoking as a contributor to the risk of colon and rectal cancers.24 There is little or no evidence of an association with cutaneous melanoma and conflicting evidence for prostate cancer.


61

Cancer

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TABLE 61-4. CANCER DEATHS ATTRIBUTABLE TO SMOKING: WORLDWIDE AND U.S. ESTIMATES∗

Cancer Site Lung and bronchus Oral cavity Esophagus Bladder Pancreas Liver Stomach Leukemia Cervical, uterus All Cancer ∗

Smoking Population Attributable Fraction 70 42 42 28 22 14 13 9 2 21

2001 Deaths Worldwide 856,000 131,000 184,000 48,000 50,000 85,000 111,000 23,000 6,000 1,493,000

Smoking Population Attributable Fraction 86 71 71 41 30 29 25 17 11 29

2006 Deaths in U.S.† 139,716 5,275 9,777 5,355 9,690 4,698 2,858 3,788 407 81,963

Estimated smoking population attributable fraction and worldwide death rates based on Danaei et al., 2005.19 Based on 2006 death rates estimated by the American Cancer Society (Jemal et al., 2006).10

Many of these estimates are based on studies of individuals who smoked cigarettes that were popular decades ago. Risks in comparable smokers of filter and low-tar products may be lower but still appreciable. Furthermore, the number of puffs per cigarette and the number of cigarettes smoked per hour are inversely proportional to the amount of nicotine in the tobacco. Low levels of nicotine therefore result in an increased exposure to carcinogens in tobacco smoke. There is no safe cigarette. Risks of a variety of neoplasms are also increased in users of other forms of tobacco. Compared to nonsmokers, risk in pipe and cigar smokers is approximately doubled for lung cancer, increased fourfold for cancer of the larynx, and doubled or tripled for neoplasms of the esophagus, oral cavity, pharynx, and bladder. Pipe smoking approximately triples one’s risk of lip cancer, and chewing tobacco or using snuff results in a fourfold increase in the risk of oral cancer.25 Secondhand smoke and environmental tobacco smoke also significantly increase the risk of lung cancer.26 Secondhand smoke contains more than 50 carcinogens and there is no risk-free level of exposure. Thus, passive smoking may account for the majority of the lung cancer not due to smoking, residential radon, or industrial exposures. The 2006 Surgeon General’s report found that millions of Americans are still exposed to secondhand smoke in their homes and workplaces despite substantial progress in tobacco control.26 Secondhand smoke also causes premature death and disease in children and adults who do not smoke.26 Separating nonsmokers from smokers, ventilating buildings, and cleaning air cannot eliminate exposure to nonsmokers; only eliminating smoking in indoor spaces will do so.

Alcohol The risk of several human neoplasms is clearly associated with alcohol consumption, especially for cancer of the liver, oral cavity, esophagus, and breast.19,27 Risk of hepatocellular carcinomas is increased in heavy drinkers, but the extent to which this is due to the unusually high prevalence of hepatitis B and C in alcoholics is unknown. These tumors tend to develop in alcoholics with macronodular cirrhosis, probably as a result of the rapid regeneration of liver cells in such individuals. If alcohol is a cause of liver cancer, it is an uncommon complication of its use, because these tumors are rare in countries such as the United States where exposure to alcohol is common. Cancer risk is typically increased only in those tissues that come in direct contact with undigested alcohol. Risk is thus increased for squamous cell carcinomas of the mouth (buccal cavity and pharynx), esophagus, and supraglottic larynx, but not, for example, of the lung or bladder. Esophageal, oral, and laryngeal squamous cell cancers are all also related to smoking, and most studies show the effect of smoking on the risk of these tumors to be greater in drinkers than in nondrinkers. Alcohol thus appears to modify the carcinogenic effect of tobacco smoke. It is not known whether alcohol use increases risk of these neoplasms in the absence of tobacco smoke or other carcinogens.28 The

effect of alcohol on these neoplasms may also be greater in individuals with marginal nutritional status than in better nourished individuals. In the United States, alcohol and tobacco account for about 80% of these cancers. Adenocarcinomas of the lower esophagus, gastroesophageal junction, and gastric cardia have also been consistently associated with alcohol use, but the relationship is not as strong as for the squamous cell carcinomas of the upper aerodigestive tract. Risks of cancer of the distal stomach, pancreas, colon, and rectum have not been consistently related to alcohol use, but observed associations between beer and rectal cancers and between heavy drinking and pancreatic cancer warrant further study. An association between alcohol intake and breast cancer has been observed in multiple investigations, even after controlling for known risk factors for breast cancer; while this relationship is not well understood, a recent consensus group suggests that 4–9% of breast cancers may be caused by alcohol consumption.19 Approximately 5% of all cancer deaths worldwide and 4% of cancer deaths in the United States can be attributed to alcohol use.18,19 Most alcohol-related neoplasms develop as a result of smoking as well as drinking, and cessation of smoking would have nearly the same impact on the occurrence of these neoplasms as cessation of drinking.

Industrial Exposures In 1972, the IARC in Lyon, France, initiated a series of monographs on the evaluation of carcinogenic risks to humans. As of 2006, 88 multidisciplinary committees of experts have reviewed the published literature on approximately 900 suspect chemicals, industrial processes, drugs, radiation exposures, and infectious agents and classified them as to their likely carcinogenicity in animals and humans. Of the over 800 chemical and industrial processes evaluated, the available evidence was considered sufficient to clarify 19 agents and groups of agents, 6 mixtures, and 13 industrial processes with exposure circumstances as carcinogenic to humans (Group 1).29–39 These, and the neoplasms most strongly and consistently associated with them, are shown in Table 61-5. Over 50 other chemicals, mixtures, and exposure circumstances were judged to be probably carcinogenic to humans (Group 2A); over 200 others were considered possibly carcinogenic to humans (Group 2B). The remaining chemicals, mixtures, and exposure, circumstances were considered not classifiable as to their carcinogenicity to humans (Group 3). Estimates of the global burden of occupational cancer are in the 2–4% range.40–42

Environmental Pollution The evidence that the agents shown in Table 61-5 are carcinogenic in humans comes from studies of relatively high exposure in the workplace. Exposures outside the workplace to most of these agents are sufficiently rare or at such low levels as to be of little importance. However, there are a few exceptions to this that included indoor exposure


1054

Noncommunicable and Chronic Disabling Conditions

TABLE 61-5. OCCUPATIONAL CAUSES OF CANCER Specific Exposures

Site or Tumor Type

Ionizing Radiation

 Agents and Groups of Agents 4-Aminobiphenyl Arsenic and arsenic compounds Asbestos Benzene Benzidine Beryllium and beryllium compounds Bis (chloromethyl) ether and chloromethyl methyl ether Cadmium and cadmium compounds Chromium compounds Erionite Ethylene oxide Formaldehyde Mustard gas (sulphur mustard) 2-Naphthylamine Nickel and nickel compounds Silica, crystalline Talc containing asbestiform fibers 2,3,7,8-Tetrachlorodibenzo-para-dioxin Vinyl chloride

Bladder Lung, skin Lung, mesothelioma Leukemia Bladder Lung Lung Lung Lung, sinonasal Mesothelioma Leukemia, lymphoma Nasopharynx Lung, larynx Bladder Sinonasal, lung Lung Lung All-cancer mortality Liver, lung, brain, leukemia, lymphoma

 Mixtures Coal tar pitches Coal tars Mineral oils, untreated and mildly treated Shale oils Soots Wood dust

Skin, lung, bladder Skin Skin Skin Skin, lung Sinonasal

 Industrial Processes with Exposure Circumstances Aluminum production

Manufacture of auramine Boot and shoe manufacture and repair Coal gasification Coke production Furniture and cabinetmaking Hematite mining, underground, with exposure to radon Occupational exposure to strong— inorganic—acid mists containing sulfuric acid Iron and steel founding Isopropyl alcohol manufacture, strong acid process Manufacture of magenta Painters

Rubber industry

as a risk factor for lung cancer. A recent report estimates 5% of lung cancers worldwide are attributable to urban air pollution with this risk rising to 7% in low and middle income countries.19

Lung, bladder, lymphosarcomas and reticulosarcomas Bladder Nose, bladder Lung, bladder, skin Lung, bladder, skin Nose Lung Lung, larynx, nasal sinus Lung Nasal sinus Bladder Lung, larynx, esophagus, stomach, bladder, leukemia, lymphoma Bladder, leukemia, lymphoma

to vinyl chloride and asbestos, arsenic in air and drinking water, and point sources of arsenic, chromium, and nickel from industrial pollutants. Numerous efforts have been made to assess the impact of ambient air pollution on lung cancer risk.19,43,44 Although rates of lung cancer are higher in urban than in rural areas, smoking is also more prevalent in urban areas. Primarily from large cohort studies in Europe and the United States, there are now results supporting air pollution

Ionizing radiation can cause a variety of human neoplasms.45 Most of the evidence for this comes from studies that followed individuals exposed to moderate or high doses from nuclear explosions, medical treatments, and occupational sources. Exposures have been both external and internal. IARC has identified radionuclides (plutonium-239, radium-224, radium-226, radium-228, radon-222, and thorium-232) and their decay products as well as phosphorus-32, radioiodines, α-particle-emitting radionuclides, and β-particle-emitting radionuclides, in addition to x- and gamma (γ)-radiation, and neutrons, as carcinogenic to humans.46,47 All humans are exposed to natural radiation. Primary sources of natural radiation include inhalation (mainly radon gas), ingestion, cosmic rays, and terrestrial gamma rays.48 Approximately half of all ionizing radiation received by individuals in the United States comes from natural background sources. Radium is found in soil where it decays to a radioactive gas, radon-222, which can seep into houses and accumulate under conditions of poor ventilation. Overall, radon gas is the greatest contributor to natural radiation exposure, accounting for about 50% of the total average annual effective dose. Radon222 progeny, primarily plutonium-218 and plutonium-214, are the likely cause of lung cancer in uranium miners, and with recent data it is felt that residential radon-222 progeny contribute appreciably to the population’s lung cancer burden.49,50 It has been estimated that 18,600 lung cancer deaths per year are attributable to residential radon progeny in the United States alone.51 Man-made sources of radiation also exist and include medical uses of radiation, atmospheric nuclear testing, nuclear power production, and occupation activities. In developed countries, medical uses of radiation are the largest source of man-made exposure and, on average, amount to about 50% of the 240 mrem global average level of natural exposure.48 Studies of individuals who have received total body radiation from external sources have shown that some organs are more susceptible to the carcinogenic effects of radiation than others. In the atomic bomb survivors in Japan, there were large increases in rates of carcinomas of the anatomically exposed thyroid and mammary glands and of leukemias arising from the highly susceptible cells of the bone marrow; lesser increases in rates of lymphomas and carcinomas of the stomach, esophagus, and bladder were observed; and risks of cancer at other sites were either not altered or the increases were too small to measure with certainty. Risk of leukemia was also increased in early radiologists who took few precautions to reduce their general exposure to radiation and probably also in individuals exposed in utero to x-rays from pelvimetry. Cancer survivorship has been increasing to where cancer survivors now constitute 3.5% of the U.S. population. This is a high-risk group for second cancers, which now account for 16% of all cancer incidence (excluding nonmelanotic skin cancers).52 These second cancers represent a serious side effect of treatment with radiation and chemotherapy. Most types of cancer can be caused by exposure to ionizing radiation.53 External sources of radiation directed at specific sites have resulted in a variety of neoplasms. Breast cancer was induced in women treated with x-rays for a variety of benign breast conditions and in women who received multiple fluoroscopies of the chest in conjunction with pneumothorax treatment of tuberculosis. Individuals treated with x-rays for ankylosing spondylitis have had increased rates of leukemia and lung cancer and, like the atomic bomb survivors, lesser increases in rates of lymphomas and cancers of the stomach and esophagus. An increased risk of lung cancer has been observed in women who received radiation following mastectomy for breast cancer and radiotherapy for Hodgkin’s disease. A strongly elevated risk for breast cancer has been seen after radiotherapy for Hodgkin’s disease. Children treated with x-rays for tinea capitis and enlarged thymus have developed leukemia and neoplasms of the


61 salivary and thyroid glands. Those treated for an enlarged thymus have also had an increased risk of leukemia, and those with tinea capitis developed more brain tumors than expected. Internal exposures to radiation have likewise resulted in increased risks of cancer at specific sites. Inhalation of radioactive dusts contributed to the increased rates of lung cancer in the atomic bomb survivors, and inhalation of radon and its decay products resulted in elevated rates of lung cancer in miners of uranium, iron, and fluorspar. Radium inadvertently swallowed by radium-dial watch painters and administered for treatment of ankylosing spondylitis was concentrated in osseous tissues and caused high rates of bone cancers. Individuals exposed to iodine-131 (I-131) in fallout from a hydrogen bomb test and in emissions from the nuclear power plant accident at Chernobyl subsequently had increased rates of thyroid cancer. The radiopaque contrast material thorotrast that was used to x-ray the liver has resulted in hepatic cancers, as well as leukemias and lung carcinomas. Women receiving cervical radium implants and other forms of pelvic radiation for a variety of gynecological conditions have had increased rates of cancers of the rectum, vagina, vulva, ovary, and bladder, as well as leukemia. The results of most studies show a linear increase in risk of neoplasms with the amount of radiation received over a wide range of observed doses, with a possible decrease in the slope of the doseresponse curve at very high levels of exposure (perhaps due to cell killing). These observations are based primarily on studies of individuals who received from tens to hundreds of rads. Doses commonly received today are orders of magnitude lower, and it is uncertain whether the dose-response curve should be linearly extrapolated to these low levels to provide an estimate of the associated risk. There may be a threshold level below which radiation does not induce neoplasms, perhaps because mechanisms of DNA repair are adequate. If so, linear extrapolation would yield estimates of risk to low levels of radiation that are too high. Conversely, chronic exposure to low levels of radiation might be more carcinogenic, rad for rad, than acute exposure at a higher dose. If so, linear extrapolations would underestimate the risk of low doses. Since there is little evidence for the latter possibility, most authorities believe that it is reasonable, as well as prudent, to assume a linear, nonthreshold dose-response relationship. Recent experimental studies have documented that a single alpha particle can provide permanent damage to a cell.51 This finding supports the biologic plausibility of the linear, nonthreshold relationship. It is difficult to accurately estimate the number of cancers attributable to radiation from all sources experienced by the general population.54 Nevertheless, available knowledge indicates that reducing medical exposures and residential (indoor) radon will have the most impact toward reducing population exposure and radiogenic cancer risk. Political efforts to reduce the likelihood of environmental contamination from nuclear power plants and nuclear weapons will also obviously reduce the risk of radiation-induced neoplasms.

Nonionizing Radiation Nonionizing radiation, in contrast to ionizing radiation, is electromagnetic radiation that does not have sufficient energy to remove electrons to form an ion (charged particle). Nonionizing radiation includes ultraviolet (UV) radiation, visible light, infrared, and microwave and radio frequencies. Among these the major carcinogen is UV radiation which comes from the sun or artificial sources such as tanning beds or booths. UV Radiation. Sunlight is definitely a cause of nonmelanoma skin cancers (squamous and basal cell carcinomas), as evidenced by the observations that these tumors tend to occur on exposed parts of the body, risk increases with the amount of sun exposure, and incidence rates are greater in light-skinned than in dark-skinned individuals. However, these skin cancers are rarely deadly, and routine data on nonmelanoma skin cancer are not collected by cancer registries in the United States. The American Cancer Society estimates over one million cases of basal cell and squamous cell skin cancer in the United States in 2006.18

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The relationship of cutaneous malignant melanomas to sunlight is more complicated.55,56 Various types of sun exposure have been reported to be associated with melanoma, ranging from severe sunburns, occupational activities, vacation sun exposure, beach activities, other recreational activities, cumulative or chronic sun exposure, and early migration to sunny places. Incidence rates for cutaneous melanoma are highest in individuals with little natural skin pigmentation, often with intermittent sun exposure such as sunburns or sunny vacations.55,56 Investigation of migrants to Australia provided evidence that sun exposure at an early age or long-term exposure may be of particular importance.55 Early UV exposure is of concern with the expanding popularity of tanning beds and booths. Current evidence suggests an increase in melanoma risk among tanning bed users. Modern tanning bed units have UV levels comparable to tropical sunlight and irradiate almost 100% of the skin, which is assumed to be 2–10 times more skin surface area than sunlight exposure.57 Incidence rates may increase as younger populations expose more of their bodies to such units. In the white U.S. population, incidence rates of melanomas of the skin have dramatically increased over the last few decades, due in part to changes in diagnostic criteria and enhanced awareness of the importance of early evaluation of melanotic lesions. Melanoma increases with age (the mean age at diagnosis is about 57). While the relationship between cutaneous melanoma and specific types of sun exposure is complex, the American Cancer Society estimates that nearly all skin cancers are related to UV radiation (even familial cancers that are likely related to genetic and UV radiation).18 Because nonmelanotic skin cancers are common and largely attributable to sun exposure, sunlight accounts for approximately 40% of all neoplasms.10,19 Sunlight accounts for less than 2% of cancer deaths, since these neoplasms are infrequently fatal. Since only cutaneous melanoma is routinely collected and reported by cancer registries, less than 2% of reported cancers appear to be due to UV radiation.10 All individuals, but particularly those with light skin who burn easily, should be encouraged to avoid excessive direct exposure to intense sunlight and to use sunshades and sunscreens. Electric and Magnetic Fields. Recent studies have focused public attention on the possible association between exposure to electric and magnetic fields (EMF), particularly from electric power lines and appliances, and risk of cancer. Based on methodological concerns and the lack of experimental evidence, no clear relationships between EMF and chronic disease have been established.58,59 However, an association is observed most consistently in studies of childhood leukemia in relation to postnatal exposures above 0.4 microT.58,59 Study of EMF is made particularly difficult by our inability to identify and accurately measure the relevant exposure. A number of reviews of the subject have been published.58–61

Sex Hormones and Reproductive Factors Sex Hormones. Sex steroid hormones have been associated with an increased risk of most reproductive cancers, including breast, endometrium, ovary, cervix, prostate, and testis. This section will evaluate endogenous and exogenous hormonal risks as well as other reproductive factors, many of which also are linked indirectly to potential hormonal alterations. In evaluating the effects of exogenous female sex hormones on the risk of neoplasms in women, it is important to categorize these substances according to their estrogenic or progestogenic pharmacological effect. At one end of the spectrum are the pure progestational agents, such as depot-medroxyprogesterone acetate (DMPA), which is used as a long-acting injectable contraceptive in many countries and to treat malignant and benign proliferative disorders of the endometrium. Other progestational contraceptives include the “minipill” which is an oral contraceptive (OC), the injectable contraceptive, norethindrone, and subcutaneous implants, such as Norplant. At the other end of the spectrum are the pure estrogen preparations. Between the two ends of the estrogen-progestin spectrum are the sequential OCs which contained only estrogen in pills taken for 2 weeks of a cycle followed by a weak progestin of short duration


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and which had a net estrogenic effect, and the more commonly used combined OCs with an estrogen and a progestin in each pill, and therefore a net pharmacological effect more progestational than the sequential pills. More recent products differ from these older formulations in dosage and in types of estrogens and progestins contained and are referred to as biphasic and triphasic OCs. These products were developed to reduce side effects of the monophasic OCs that administer the same estrogen/progestin dosage throughout the cycle. Because of the breakthrough bleeding side effect of the biphasic formulations, these are not widely used. Although the findings from studies linking these drugs to reproductive cancers that were conducted through the mid-1990s may not be applicable to the newer contraceptive agents, it would seem prudent to assume that they do until results of additional epidemiologic investigations provide evidence to the contrary. The most common are the conjugated “natural” estrogens (e.g., Premarin), used largely to treat or prevent symptoms and conditions associated with menopause, and the nonsteroidal synthetic estrogen, DES (diethylstilbestrol), to prevent early miscarriage. Those used during peri- and postmenopause to reduce menopausal side effects and osteoporosis include estrogen replacement therapy (ERT) and estrogen/progestin hormone replacement therapy (HRT), the most common of which is Prempro. More recent formulations have been marketed with reduced hormonal formulations yet having similar beneficial effects with fewer adverse side effects. Although some studies, including a clinical trial, of breast cancer in women given DES for threatened abortion show no evidence of an increased risk of cancer,62,63 a larger investigation showed a 40% increase risk with a latency period of 20 years after DES exposure.64 The effect of combined OCs on risk of breast cancer has been evaluated in a number of large cohort and case-control studies as well as in meta-analyses65 and the risk is increased by about 25% in current users and declines to that of never users about 10 years after cessation of use. The relative risk estimate (RR) in women who ever used OCs was estimated to be 1.1. Tumors tended to be more localized in users than in nonusers, suggesting enhanced surveillance in recent and current users as an explanation for the increased risk. Even if the findings represent a causal phenomenon, use of OCs would result in few additional cases of breast cancer because most current and recent users of OCs are young women with a low background rate of this disease. However, among those who last used OCs less than 10 years ago, for greater than 5 years, the risk is increased approximately 13%.65 A combined analysis of two studies of DMPA and breast cancer similarly found an increase in risk in recent and current users of this progestational agent but no increase in risk after 5 years since last use, and an overall RR of 1.1 in women who had ever used this agent.66 Studies of breast cancer in relation to ERTs given at menopause have shown an increased risk in women particularly among those who are current users of ERTs for 5 years or longer (RR = 1.2–1.4).67 A small increase in risk with years of use beyond 5 years has been observed in most studies, with a decline in risks to that of nonusers from 2 to 5 years after cessation of use.68 A collaborative reanalysis of 51 studies69 on this issue found that during or shortly after use, there was a RR of 1.02 for each year of use for those with 1–4 years of use, and 1.03 for those with more than five years of use. The addition of a progestin to the regimen increases the risk by an additional 10% over that of ERT users or a 40% greater risk than among never HRT users. Tamoxifen, which has antiestrogenic properties in the breast, and raloxifene, a selective estrogen receptor modulator, have been shown to reduce the risk of breast cancer in the contralateral estrogen receptor positive breast of a woman who receives these adjuvant therapies for primary breast cancer. In regard to risk of breast cancer associated with endogenous sex steroid hormones, several studies have shown that risk is significantly elevated for women in the top quintile of total estradiol (RR = 1.9), or free estradiol (RR = 2.7) after adjustment for BMI and other risk factors.70–73 The risk of endometrial cancer is increased twofold or more in women who took sequential oral contraceptives and who were not monitored for endometrial hyperplasia.67,74,75 In contrast, risk of cancer remains significantly decreased (RR = 0.5) for 20 years or longer in

users of combination OCs76 compared to never users. The reduction in risk is even lower among those who used the progesterone-only OCs and in users of DMPA77 because of their net progestational effect on the endometrium. Those who received estrogens for menopausal conditions, primarily as ERTs, also are at significantly greater risk of endometrial cancer. Tamoxifen, which is used as an adjuvant therapy for breast cancer, has an estrogenic effect on the uterus and has also been shown to increase the risk of endometrial cancer.78 To reduce the risk of endometrial cancer in users of drugs containing estrogens, a progestin is often included, either continuously with the estrogen or cyclically for a specified number of days each month, and this has been shown to markedly reduce the risk of endometrial cancer to that of never users. Several case-control studies have shown an increased total and bioavailable estrogens and decreased plasma levels of sex hormone binding globulin in postmenopausal women who develop endometrial cancer as compared to healthy controls.79,80 In premenopausal women, one epidemiologic study showed a decrease in total and bioavailable estradiol.81 It has further been suggested that in this group of women it is lower progesterone rather than higher estrogen that increases the risk of premenopausal endometrial cancer. Additional evidence of the effects of endogenous hormones on cancer development comes from the increased risk in polycystic ovarian syndrome, a disease that is characterized by low progesterone levels in women who have normal estrogen levels. In both pre- and postmenopausal women, obesity and chronic hyperinsulinemia are associated with changes in total and bioavailable sex steroid levels, especially estrogen. In sum, there are few if any studies that have used a prospective design to directly examine endogenous hormonal levels well in advance of malignancy. Risk of epithelial ovarian cancer in women who have ever used combined OCs is approximately 50% of that of never users, and the risk decreases with duration of use.82 A further reduction in risk is seen in the progesterone-only OCs. The benefit of either type of OC persists 10–20 years after use has been discontinued. The benefit includes women with a family history of ovarian cancer and those with a mutation in the BRCA1 or BRCA2 gene.83,84 Furthermore, the reduced risk is similar in parous and nulliparous women without known infertility. A single study has shown no effect of DMPA on risk of ovarian cancer, thus the association is unclear to date. Several large case-control studies have shown an increased risk of ovarian cancer among either ERT (RR = 1.6) or HRT (RR = 1.2) as well as a significant duration effect (RR = 1.3–1.8).85 In contrast, the Breast Cancer Detection Demonstration Project cohort follow-up study showed no increased risk with either ever or duration in HRT use of four years or more, whereas risk was elevated in ERT users (RR = 1.8–3.2).86 Studies of endogenous hormones associated with ovarian cancer are limited and rely on indirect evidence such as the protective effects of pregnancies and OC use which suppress pituitary gonadotropin secretion and increased risk among women with polycystic ovarian syndrome, who are known to have elevated circulating lutinizing hormones (LH). However, these findings are contradicted by the lack of an increase in risk among those with an early age at menopause and with twin pregnancies, both of which are associated with an increase in gonadotropin levels; in the lack of an increase in ovarian cancer after menopause which is associated with increasing LH and follicle stimulating hormone; and in the increased risk with ERT use and obesity. Research also has shown a lack of association between circulating androgens and ovarian cancer risk in postmenopausal women, but an increased risk is seen with androstendione and dehydroepiandrosterone in premenopausal women. Despite the link between insulin and insulin-like growth hormones (IGF-I) receptor and activation of intracellular signaling pathways and its effects on metabolism of other hormones, studies to date do not support its involvement with ovarian cancer. Likewise, IGF-I, which has been associated with increased risk of other reproductive cancers, breast and prostate, did not show evidence of an association in the only epidemiologic investigation of risk based on prediagnostic data to date.87 In summary, although evidence is accumulating regarding endogenous hormones associated with ovarian cancer, additional investigations particularly among prospective study designs are required.


61 Studies of cervical cancer and menopausal estrogens have not been conducted. Most studies of OCs and invasive cervical cancer have shown an increased risk with greater than 5 years duration of use in the presence of an oncogenic human papillomavirus (HPV) infection. OCs provide hormonal conditions favorable to the persistence of HPV infection88 or transformation of infected cells. Studies of HRTs and risk of cervical cancer are limited but suggest an increased risk in users (RR = 2.3–2.7) and with increasing duration in use.89,90 Combined OCs have clearly been shown to cause benign hepatic cell adenomas and focal nodular hyperplasia. These are highly vascular tumors that can rupture, bleed into the peritoneal cavity, and cause death. Fortunately, they are a rare complication of OC use, occurring at a rate of less than 3 per 100,000 women-years in women under 30 years of age. Case-control studies conducted in developed countries have shown that primary hepatocellular carcinomas are also rare complications of OC use.91 Some of these studies, plus investigations conducted largely in developing countries, provided evidence that this adverse effect is not mediated by enhancing the influence of other factors such as hepatitis B or C on risk. DES was prescribed between 1938 and 1971 to treat up to 5 million women in the United States for threatened abortion. Approximately 80% of the female offspring exposed to DES in utero have been found to have glandular epithelium resembling that of the endometrium, and presumably of Müllerian origin, in the vagina or cervix. This is referred to as adenosis. A small portion of women with this condition have developed clear cell adenocarcinomas of the vagina or (less frequently) the cervix in their teens or twenties especially if their mother took DES early in pregnancy.92 The risk of clear cell carcinoma is between 1.4/1000 and 1/10,000 among exposed women.93 This represents a high proportion of neoplasms in this age group, including virtually all vaginal cancers. Women exposed in utero to DES with vaginal or cervical adenosis should be followed carefully for the development of clear cell carcinoma. Males exposed in utero to DES are at increased risk of cryptorchidism, which is a significant risk factor for testicular cancer. However, only one study has shown a nonsignificant threefold increased risk of testicular cancer among males with prenatal DES exposure. These neoplasms represent the first documented instances of transplacental carcinogenesis in humans. In some countries, DES has been used as a “morning after” pill to prevent pregnancy or to treat menopausal symptoms. These findings suggest that precautions must be exercised not to give DES to women who may be pregnant. Colorectal cancer risk has been shown to be protected among OC ever or new users (RR = 0.4–0.7) compared to never users94–96 as well as in HRT current or ever users (RR = 0.3–0.5).95 Case-control, cohort studies, and a meta-analysis have failed to confirm earlier reports that risk of malignant melanoma is increased by use of OCs.76 Compared to never users, those who used OCs for greater than 1 year showed no excess risk (RR = 0.82–1.15), nor for duration, age first used, recency, or latency effects.97,98 Isolated reports of associations between OCs and pituitary adenomas, choriocarcinomas, gallbladder carcinomas, and thyroid tumors have also appeared, but these observations have not been convincingly confirmed by epidemiological investigations.76 Both prostate and testicular cancers in males have been associated with endogenous sex hormones with the primary hypothesis that androgens are causally related to prostate cancer etiology. Although there have been a number of studies that have investigated the role of androgens, few have had an adequate sample size, serum taken prior to cancer development and diagnosis, or controlled for confounding, especially age-related, known changes in serum hormone levels that may not reflect current cancer risk. In the one prospective study that addressed these issues, the Physicians’ Health Study showed that risk of prostate cancer was greater with increasing testosterone quartile levels (RR = 1.0–2.4), and decreased with increasing sex hormone binding globulin (RR = 1.0–0.4) and estradiol regardless of comparative quartile level (RR = 0.5).99 Testicular cancer has been hypothesized to be associated with initial hormonal exposure levels in utero and in the belief that excess estrogen or insufficient androgens lead

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to testicular cancer. Maternal exogenous estrogen use during pregnancy has been associated with both cryptochordism, a significant risk factor for testicular cancer, and subsequent development of testicular cancer in offspring. Also, risk is greater in male offspring of women having their first child as compared to multiparous women, consistent with plasma estrogen levels which are noted to be higher in primiparous women.100 Although it has been suggested that maternal exposure to DES leads to increased testicular cancer risk, there is insufficient evidence to support this claim.101 Among the testicular cancer risk factors, it appears that late age at puberty is linked to a significant decrease (~50%) in risk of testicular cancer, supporting a hormonal influence in its etiology.102,103 Reproductive Factors. Among women, nulliparity is associated with an increased risk of cancers of the endometrium, ovary, and breast. Risk of ovarian and endometrial cancers decreases with increasing number of pregnancies, whereas pregnancies beyond the first have a lesser protective effect against breast cancer. Risk of breast cancer increases strongly with age at first full-term birth, in contrast to risk of ovarian cancer which actually decreases with increasing age at first birth.104–107 Late age at last birth has been associated with a significant reduction in risk independent of parity for endometrial cancer.108 Earlier age at menarche and late age at menopause are associated with an increased risk of cancers of the breast and endometrium, but not the ovary. Lactation, which suppresses ovarian function, has been inconsistently associated with increasing the risk of breast cancer. The benefit of lactation occurs due to ovulation suppression which is maximal soon after delivery, and short-term lactation appears to have only a small protective effect against ovarian cancer, whereas prolonged lactation seems to confer little additional benefit. Risk of endometrial cancer may be inversely related to duration of lactation, but the effect also is short term, thus there is little or no protection in the postmenopausal years when most endometrial cancers occur. Induced abortion may enhance risk of breast cancer, but studies to date have yielded inconsistent findings. In regard to infertility independent from nulliparity, most studies report an increased risk of epithelial ovarian cancer.82 Although the mechanism is not understood, several studies have shown endometriosis to increase the risk of ovarian cancer, and the risk is further increased among those with ovarian endometriosis.109,110 Although somewhat less clear, most studies have shown that use of fertility agents is not associated with an increased risk of ovarian cancer.111 Tubal ligation confers a 10–80% reduction in ovarian cancer risk regardless of parity and including prospective studies that reduce a potential detection bias of case-control evaluations.112–114 Mechanisms for the associations with parity and lactation are not fully understood, but likely involve endogenous pituitary and ovarian hormones. The development of epithelial ovarian tumors is believed to be promoted by gonadotropin stimulation and reduced by suppression of gonadotropins during pregnancy and lactation. Nulliparous women are on average less fertile than parous women and have more anovulatory menstrual cycles, hence more constant production of estrogens without cyclic progesterone each month. The relative excess of unopposed estrogens is believed to promote endometrial tumor development. Although several mechanisms for the relationship of breast cancer to age at birth of first child have been proposed, none appears adequate. Studies of the endocrinological events associated with childbearing and other endocrinological studies in women at varying risks of cancers of endocrine target organs continue to be conducted to explain the mechanisms by which factors related to childbearing alter risk.

Infectious Agents Significant knowledge has accumulated over the past several decades about the molecular biology of cell transformation by oncogenic DNA and RNA viruses. The evidence is based on the ability of these viruses to modify gene expression in the host cell leading to a better understanding of how these infectious agents are related to the development of cancers. Among the DNA-related cancers in humans are EBV, hepatitis B and C (HBV and HCV), and HPV.


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Among the DNA viruses, EBV, a herpes virus, has been etiologically associated with Burkitt’s lymphoma (BL), nasopharyngeal carcinomas (NPC), and Hodgkin’s disease.115 The EBV genome established a latent infection in B lymphocytes and is transmitted when these lymphocytes replicate. In healthy individuals, cytotoxic T-cell responses against the latent viral proteins prevent uncontrolled replication of the virus in these B cells. This cancer, which is noted as especially aggressive, has the hallmark chromosomal translocation between 8 and 2, 14, or 22.116 Primary EBV is usually asymptomatic in humans and exists as a latent infection which is seroprevalent in over 90% of the adult population worldwide. Almost all individuals with BL or NPC have antibodies against EBV, compared with lower percentages in unaffected persons, and antibody titers are higher in the diseased cases. A cohort study has clearly shown that EBV infection precedes the development of African BL, where it is referred to as endemic BL. In contrast, isolated cases of non-endemic BL occur throughout the world at a much lower incidence and the association with EBV is much weaker, with only 15–30% of cases outside Africa having evidence of prior EBV infection.117 The EBV genome has been demonstrated in tumor cells from most African BL and virtually all NPCs. However, only a small proportion of individuals infected with EBV develop either of these neoplasms and the worldwide distribution of the two malignancies is different. Thus, it is apparent that other factors are essential in conjunction with EBV for these tumors to develop. Chronic malaria and the subsequent immunosuppression or antigenic stimulation may play a role in African BL although the spread of EBV is through saliva not mosquitoes as originally hypothesized. EBV is associated with the undifferentiated NPC type which is detected primarily in men over age 40 years of age, regardless of geographic location. Although the neoplasm is rare, the incidence is very high in Asian and Alaskan native populations with rates between 25–50/100,000 compared to less than 1/100,000 in Caucasian populations.118 In Singapore, where Chinese, Malays, and Indians live in close proximity and share similar dietary and social habits, the incidence of NPC is 18.5, 3.1, and 0.9 per 100,000 in males, respectively, suggesting that genetic rather than environmental exposures are important to the development of this tumor. Although cofactors for NPC are unknown, they may include human leukocyte antigen (HLA) profiles and environmental risks (e.g., chemical exposures, tobacco smoke, or cooking fumes), and dietary factors such as salted fish. An increased risk of NPC has been identified in Chinese populations for HLA types A2, B14, and B46 whereas a reduced risk is found with HLA A11, B13, and B22.118,119 EBV also contributes to the development of Hodgkin’s disease. The virus causes infectious mononucleosis, and those with a history of infectious mononucleosis have a two- to threefold increase in risk of Hodgkin’s disease but not EBV-negative HL. Compared to nondiseased individuals, cases of Hodgkin’s disease have a higher prevalence of antibodies against EBV and higher antibody titers. However, EBV DNA or gene products can be demonstrated in only half of cases, and only 30–40% of cases have anti-EBV antibodies, suggesting either the existence of causal pathways not including EBV or loss of EBV infection after tumor development. In immunodeficient patients such as those receiving transplants or having AIDS, there also is an increased incidence of EBV-associated Hodgkin’s disease.120 There is strong evidence that hepatitis B and C viruses cause hepatocellular carcinoma (HCC), and an IARC working group has judged that both of these viruses are carcinogenic to humans.121 HCC has been increasing worldwide and is now the fifth most prevalent cancer with mortality reaching 500,000 people yearly.122 Although rare in the United States except among Eskimos, HCC is the most common cancer in parts of Africa and China. This cancer can develop in individuals who are chronic carriers of HBV or HCV. In parts of Africa, Asia, and the Pacific, HBV is endemic with most infections occurring during childhood, and 90% of HCC are infected with HBV. Determinants of the chronic carrier states are not fully understood. Transmission of HBV or HCV is through contact with infected bodily fluids. In high-risk areas, perinatal transmission of HBV from mother to child at or soon after birth, before immune competence is fully developed, results in the child becoming a chronic HBV carrier

and at higher risk of subsequently developing HCC. In areas with lower prevalence of HBV, most infections are acquired horizontally in early adulthood through intravenous drug use or unprotected sex. Less commonly, contaminated surgical instruments and donor organs and medical personnel who are in frequent contact with infected blood products are at highest risk if not vaccinated against HBV. Currently there is no vaccine to protect against HCV. Although blood transfusions were once a significant route of transmission, improved diagnostic tests, greater screening, and vaccination against HBV have dramatically reduced the risk of acquisition of HBV. It is uncertain whether either HBV or HCV directly causes hepatomas or whether they cause chronic hepatitis and liver cirrhosis, which lead to repeated periods of cell death and regeneration, and increase the risk of HCC, perhaps in the presence of other carcinogens such as aflatoxins. Kaposi’s sarcoma is caused by another DNA virus, human herpesviridae (HHV-8). Once very rare, in the early 1980s a more aggressive form of Kaposi’s sarcoma associated with immune deficiency began to be seen in AIDS patients and was one of the first indications of the AIDS epidemic. Although the cancer cannot be cured, by treating the immune deficiency, progression of Kaposi’s sarcoma can be slowed or halted. As the mortality rate of AIDS dropped in the 1990s, so also did that of Kaposi’s sarcoma. Blood tests can detect antibodies against Kaposi’s sarcoma and determine whether the individual is at risk of transmitting HHV-8 infection to a sexual partner or whether a donated organ is infected with Kaposi’s sarcoma. It is now well established that oncogenic HPV types are causative in the development of human cancers. HPV is a necessary but not sufficient cause of cervical cancer and also is associated with a high proportion (60–85%) of vulvar, vaginal, penile, and anal sites. Males, most likely due to the characteristics of their genital tissue, have a much lower prevalence of these genital cancers but are the primary source of sexual transmission to the higher-risk females. Recent evidence indicates that 25% of head and neck tumors also are caused by HPV independent of other significant risk factors at these sites, such as tobacco and alcohol. Among the most prevalent and highly oncogenic types are HPV 16 and 18 with a number of other less prevalent oncogenic types that cause genital cancers (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82). Although the majority of cervical cancers are associated with HPV 16, HPV 18 is most frequently associated with aggressive adenocarcinomas of the cervix in younger aged women. HPV is transmitted primarily through sexual contact and invades the tissues by epithelial microtears. Although well over 50% of adults are thought to have been infected in their genitals with HPV during their lifetime, infections usually are cleared or become latent and undetectable. However, in individuals in whom infection persists for a prolonged period of time, intraepithelial lesions are likely to develop, some of which eventually progress to invasive carcinomas. The factors responsible for progression to anogenital malignancies include hormonal factors (e.g., steroid contraceptives), chemical factors (e.g., cigarette smoking), and immunodeficiency (e.g., human immunodeficiency virus [HIV] infection, immunosuppression for renal transplantation). In contrast, HPV is an independent risk factor for head and neck cancer and does not require the other major risk factors for malignancy to develop. HPV types associated with head and neck cancers have been limited primarily to HPV 16, 18, 31, and 33, and both younger age and male gender are more likely to be infected with the virus in the oral tissues. Recently several HPV vaccines have undergone clinical trials and been approved by the United States Food and Drug Administration. Currently, the HPV vaccine is being targeted only to prepubescent and teenage females prior to their sexual debut, but this focus has raised considerable concern as the source of viral infection to the genitals is primarily from male to female. In addition, this strategy fails to address prevention of HPV-associated head and neck cancers which occur predominantly among males. Among the RNA tumor viruses, the most significant is human immunodeficiency virus (HIV or HTLV-III) which causes acquired immunodeficiency syndrome (AIDS), are at greatly increased risk of Kaposi’s sarcoma and of non-Hodgkin’s lymphomas.123 As of 2006 an estimated 25 million people have died from AIDS alone.124


61 Transmission is through direct contact of a mucous membrane with a bodily fluid containing HIV (e.g., blood, semen, vaginal fluid, breast milk). In addition to destroying CD4+T cells, which are required for functioning of the immune system, and subsequently leading to AIDS, HIV also directly attacks and destroys the kidneys, heart, and brain. Rates of intraepithelial cervical and anal squamous cell carcinomas are also increased in AIDS patients, but increased rates of invasive cancer at these sites have not been observed. Testicular seminomas also occur more frequently in AIDS patients, and there are unconfirmed reports of increased risks of testicular teratocarcinoma, malignant melanoma, leiomyosarcoma, non-small cell lung cancer, multiple myeloma, hepatocellular carcinoma, and Hodgkin’s disease. Another RNA tumor virus, HTLV-I, has been strongly implicated as a cause of adult T-cell leukemias and lymphomas, particularly in some areas of Japan, the South Pacific, the Caribbean, and Africa where the virus is endemic, but this virus is of less significance in the nonendemic United States. The actual population seropositivity level is unclear as most studies have examined selective, high-risk groups. Transmission is believed to occur through cell to cell contact of virusinfected cells during the exchange of bodily fluids (e.g., breast milk, semen, blood transfusions, and contaminated needles of drug users). Four infectious agents other than viruses have been strongly implicated as causes of human cancers. In 1994, an IARC working group125 judged that Shistosoma haematobium was a definite cause of bladder cancer (Group 1), that the liver flukes Opisthorchis viverrini and Clonorchis sinensis were definitely (Group 1) and probably (Group 2) causes of cholangiocarcinomas of the liver, respectively, and that the bacteria H. pylori was a carcinogen for the stomach (Group 1). Schistosomiasis affects more than 200 million people and humans are the host for the blood fluke which infects them through the skin exposed to water containing the infective larvae. The eggs elicit granulomas that cause disease in the urogenital system. O. viverrini infects humans who eat undercooked fresh-water fish and the adult parasite lives within the intrahepatic bile ducts. The highest incidence of cholangiocarcinoma in the world is in Thailand where the parasite is endemic and the vast majority of these cases are caused by this fluke. The relationship of H. pylori to gastric cancer is of potential importance in developed countries. This pathogen has been associated with both intestinal and diffuse histologic types, and most strongly with tumors developing outside the cardia.126 It is estimated that H. pylori infects the gastric mucosa of about half of the world population and 15% of those infected are associated with the development of gastric cancer, the second leading cause of cancer deaths worldwide. In the United States, blacks, Hispanics, and other minorities are more commonly infected with H. pylori and have an incidence and mortality rate 2–3 times that of Caucasians. Over 60% of gastric adenocarcinomas have been attributed to infection with H. pylori. The malignancy can be prevented or produce resolution of premalignant lesions by use of antibiotic therapy.

Nutrition and Physical Activity Reasons for the large international differences in the incidence of most cancers are unknown. Studies of rates in migrants have clearly shown that they are largely due to variation in environmental factors, not in genetic predisposition or susceptibility to carcinogens. Correlational studies have been conducted to identify factors that vary across countries in accordance with variations in the rates of various cancers. These studies have shown a variety of dietary components to be related to a number of different neoplasms. To investigate these associations further, many case-control studies and several large cohort studies have been conducted,127,128 a variety of laboratory investigations have been performed to elucidate possible mechanisms for observed epidemiological findings, and randomized trials of dietary supplements or modifications have been conducted or are under way.129–132 Bias in Dietary Studies. Epidemiological studies of diet and cancer are difficult to perform and evaluate for a variety of reasons. One common problem in all epidemiological approaches is that many individual dietary constituents are highly correlated. For example,

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diets that are poor in animal protein are also likely to be poor in animal fat and high in carbohydrates and fiber. Additionally, food frequency questionnaires (FFQs) vary in the type of nutrients emphasized through kinds of foods listed, methodology for food selection, definitions of food groups, nutrients in databases, instructions given to responders relative to serving size estimations, format for completing the questionnaire (self-administered or clinicianadministered), and methodology for quality control (method of contacting the respondent to resolve items left blank). Under such circumstances, it is difficult to determine which of the interrelated dietary constituents (if any) is responsible for observed variations in risk. Another difficulty is that diet many years prior to the development of a neoplasm may be of the greatest etiological relevance and diets may change over time. Such information is difficult (although not impossible) to obtain in case-control studies. Cohort studies can theoretically overcome this problem, but must include large numbers of subjects and must be continued for decades and hence require large commitments of time and money. Despite these methodological problems, results of recent research strongly suggest that dietary factors contribute to the etiology of a variety of neoplasms. Some of the more likely mechanisms are briefly summarized in the following paragraphs. Overview of Risk. When reviewing preventable lifestyle and environmental factors related to cancer, a recent consensus group examined major dietary issues and physical activity.19 They found evidence that low fruit and vegetable intake are associated with cancer of the colon and rectum, stomach, lung, and esophagus. However, low fruit and vegetable consumption is interrelated to dietary fat intake, obesity, and possibly physical inactivity. Being overweight or obese (high body mass index) have been associated with cancer of the corpus uteri, colon and rectum, breast (postmenopausal), gallbladder, and kidney. Obesity is likely also related to physical inactivity which has been associated with breast, colorectal, and prostate cancers.19 The lack of independence among these factors makes understanding true causal associations difficult. Carcinogenic Mechanisms. Food items may be contaminated by preformed carcinogens. Aflatoxins produced by fungi that can grow in grains and other crops in warm, moist climates have been linked to liver cancers in some parts of the world. In China, mutagens have been detected in fermented pancakes and vegetable gruels, and these have been related to both esophageal cancer in humans and neoplasms of the gullet in chickens; and nasopharyngeal carcinomas have been related to consumption of salted fish and fermented food during infancy. Carcinogens may be formed in the body by bacteria. Nitrites may be ingested in small amounts with preserved meats and fish or formed in larger quantities from dietary nitrates, either spontaneously before being eaten or in the presence of bacteria in the body; and carcinogenic N-nitroso compounds may then be produced from ingested amines and nitrites by bacteria in the stomach of people with chronic gastritis, in the bladder of individuals with urinary tract infection, or in the normal colon and mouth to produce cancers of the stomach, bladder, colon, and esophagus, respectively. Smoked and cured foods, charcoal-broiled meats, and some fruits and vegetables from contaminated areas may contain carcinogenic polycyclic aromatic hydrocarbons. A high-fat diet may increase bile production and produce an environment in the large bowel conducive to the growth of bacteria capable of forming carcinogens, and perhaps steroid hormones, from bile salts. Production of such substances provides one plausible explanation for the observed associations between a high-fat diet and cancers of the colon, breast, and prostate. Obesity. Overnutrition, leading to obesity, has been associated with endometrial and postmenopausal breast cancers. A possible mechanism is tumor promotion by excess endogenous estrogens. In postmenopausal women, estrogens are derived from androgens produced by the adrenal gland. This reaction takes place in adipose tissue and is enhanced in obese women. Also, early menarche is a risk factor for


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breast cancer, late menopause is a risk factor for both breast and endometrial cancers, and both of these factors have been directly or indirectly related to overnutrition. Physical Activity. Although the epidemiologic evidence is not completely consistent, regular exercise appears to reduce the risk of breast cancer, perhaps because of the effects of physical activity on body weight. There is also evidence that exercise exerts an independent effect on the risk of colon cancer, possibly by decreasing stool transit time and therefore the duration of exposure to carcinogens in the gut. Protective Dietary Constituents. Dietary constituents may also protect against cancer. Diets high in fresh fruits and raw vegetables have been associated with decreased risks of carcinomas of virtually all sites within the gastrointestinal and respiratory systems, the uterine cervix, and (less consistently) other tissues. Foods rich in retinol (preformed vitamin A) have also been associated with reduced risks of some epithelial cancers. Levels of many of the potentially protective micronutrients are highly correlated in human diets, making it difficult to determine which micronutrients are most strongly associated with reduced risks, and the specific substances in fruits and vegetables responsible for the apparent protective effects have therefore not been conclusively identified. It is likely that different micronutrients or combinations of micronutrients operate at different sites, and a variety of protective mechanisms have been suggested. For example: the reduced risks of stomach and esophageal carcinomas may be due to inhibition by vitamin C of N-nitroso compound formation; vegetables of the Brassicaceae family have been hypothesized to induce activity of mixed-function oxidases, which may detoxify ingested carcinogens responsible for colon cancer development; and vitamins C, E, and b-carotene quench free radicals that cause oxidative damage to DNA. Dietary fiber may increase the bulk of the bowel contents, dilute intraluminal carcinogens, and enhance transit time through the gut. These mechanisms would reduce contact of the colonic mucosa with carcinogens and explain the inverse association between dietary fiber and the risk of colon cancer. Certain plant foods also contain phytoestrogens. These weak estrogens may reduce the risk of hormonally mediated cancers by binding competitively to estrogen receptors and thereby exerting antiestrogenic effects. Although the evidence that a diet high in fruits and vegetables decreases cancer risk has been used as one rationale for marketing vitamin supplements, there is no evidence that such products are protective against any neoplasm, and some evidence that they may even be harmful. For example, a number of studies have linked high fruit and vegetable intake, as well as high serum b-carotene levels, with a reduced risk of lung cancer, but recent clinical trials of b-carotene supplementation in individuals at high risk of lung cancer found increased lung cancer rates among supplemented patients.133 These findings serve as a reminder that our current understanding of the constituents of fruits and vegetables, and their mechanisms of action, is incomplete. Current knowledge suggests that a prudent diet (rather than the average Western diet) should be lower in meats and animal fats and higher in fresh fruits, vegetables, and fiber. Citrus fruits with high levels of vitamin C, vegetables of the Brassicaceae family, and vegetables rich in b-carotene might be of particular importance. Smoked, charred, or cured meats would be avoided or used in moderation, as would alcoholic beverages. Caloric intake would be optimized to avoid obesity. This diet would do no harm, probably reduce the risk of cancers, and be compatible with diets advocated to reduce risks of cardiovascular and cerebrovascular diseases. There is little evidence that supplementation of a prudent diet with vitamins would have a beneficial effect on cancer risk.

Genetic Factors Initial investigations of the role of genetic factors in cancer etiology limited their focus to determining the prevalence and degree of a specific malignancy in family clusters. Such studies suggested that the

risk of a number of cancers, including breast, ovary, colon, kidney, lung, brain, and prostate, was increased in individuals with a history of the disease in a first-degree relative.134 Segregation analysis suggested that for many of these cancer sites one or more rare autosomal genes was associated with increased cancer susceptibility. Recent work has identified a number of these inherited cancers that result from germline mutations (Table 61-6). However, only a small number of cancers are produced by these single gene mutations and it is likely that most of these have been identified by now. The larger proportion of human cancers is due to multiple gene mutations which are much more difficult to identify. Major genetic causes of cancer involve gene-environmental interactions. Inherited mutations in a cancer susceptibility gene predispose the affected individual to develop cancer, usually at an earlier age than occurs in those with nonfamilial causes. Familial retinoblastoma, the prototype of such a condition, arises because an individual inherits a germline mutation in one allele of the Rb gene, which is then followed by a somatic mutation in the other allele.135 Somatic mutations at both alleles of the gene are required to cause the more rare sporadic cases of retinoblastoma. In the Li-Fraumeni syndrome involving the other major tumor suppressor gene, p53, there is a germline p53 mutation in 50% of these individuals which is associated with a greater incidence of rhabdomyosarcoma, any childhood tumor or sarcoma, brain tumors, breast cancer, leukemia, or adenocortical carcinomas.136 Inherited BRCA1 and BRCA2 mutations affect risk of breast and ovarian cancer.137 The overall portion of breast cancers in the general population or a random selection is significantly lower (~5%) than in studies that usually focus on high-risk familial populations where rates are as high as 80%.138 These genes have received intense public attention because breast cancer is a common disease and because the penetrance of the gene is very high, that is, a large proportion of individuals with the gene mutation will develop cancer. Furthermore, there is significant variability in cancer risk among the BRCA1/2 mutation carriers which will preferentially predispose to ovarian rather than breast cancer or the converse. Other factors can modify the BRCA1/2 breast cancer risk including genes at other loci, such as those involved in hormone or carcinogen metabolism, reproductive history, and exogenous exposures such as OCs and smoking. Nonetheless, the prevalence of these germline mutations among women with breast cancer and in the general population is low and accounts for more than a small percent of all breast or ovarian cancers.

TABLE 61-6. GERMLINE MUTATIONS ASSOCIATED WITH FAMILIAL CANCERS Syndrome

Gene

Cancer

Retinomablastoma

RB

Li-Fraumeni

P53

Familial breast, ovary

BRCA1/ BRCA2 ATM

Retinomablastoma, osteoscarcoma Breast, sarcoma, leukemia, brain Breast, Ovary

Ataxia telangiectasia WAGR Familial adenomatious polyposis/Gardner’s syndrome Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Multiple endocrine neoplasia type 1 Von Hippel-Lindau

WT2/WT1 APC

hMSH2, hMLH1, hPMS1, hPMS2 MEN1 VHL

Breast lymphoma, leukemia, others Wilms’ tumor Colon

Colon

Carcinoids, pancreas, parathyroid, pituitary Renal cell carcinoma, hemangioblastoma


61 Additional genes also have been implicated in breast cancer: CKEK2 and ATM. The CHEK2 gene has a moderate penetrance and is independent of the BRCA1/2 mutations. Those who are carriers of the ATM gene have a rare recessive disorder, ataxia-telangiectasia, which greatly increases the risk of breast cancer.139 Approximately 6% of colorectal cancers can be attributed to known heritable germline mutations. Familial adenomatous polyposis (APC) is an autosomal dominant syndrome presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene. Adenomas typically develop in the mid-teens in these patients, and colorectal cancer is almost certain if this condition is untreated. Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) is an autosomal dominant disorder characterized by early onset of colorectal cancer with microsatellite instability. Mutations in mismatch repair genes lead to a lifetime colon cancer risk of 85% in these individuals, and carcinomas of the endometrium, ovary, and other organs also occur with increased frequency in association with HNPCC.140 Other familial genes that have been identified are WT1 and WT2, associated with Wilms’ tumor, nephroblastoma, in children with approximately 2% of those with Wilms’ tumor having a family history and most germline WT1 mutations are de novo mutations.141 The incidence is approximately three times higher in African Americans and Africans than in Asians with rates in United States and European Caucasians intermediate between Africans and Asians.142 Those with bilateral tumors have a germline mutation of the gene and tumors arise only if a second event occurs with loss of function of the remaining normal allele. MEN1 (multiple endocrine neoplasia type 1) syndrome is a hereditary condition characterized by the presence of duodeno-pancreatic endocrine tumors and is an autosomally dominant inherited disorder with a high penetrance. It is characterized by the occurrence of tumors of the parathyroid glands, endocrine pancreas/duodenum, and anterior pituitary gland.143 Individuals with Von Hippel Lindau are at risk for the development of tumors of renal carcinoma, as well as cancers of the pancreas, adrenal glands, brain, spine, eye, and ear.144 Although only a small proportion of cancers appear to be caused by inherited mutations at single loci, it is increasingly clear that genetic factors play an important role in tumors. While some individuals exposed to known carcinogens develop cancer, others with similar exposure do not. These risk modifier genes consist of a number of types. First there are genes involved in the metabolism of environmental carcinogens that can modulate exposure to potentially mutagenic occurrences. One of these groups includes inherited polymorphisms in genes that code for enzymes affecting the ability of the body to metabolize or detoxify carcinogens or potential carcinogens. These include those that code for the glutathione S-transferases (GST), cytochrome P-450 enzymes (CYP), and N-acetyltransferases (NAT). Some of the presumed high-risk genotypes are highly prevalent and may contribute substantially to the overall cancer risk within populations. Growth regulation effects associated with bioavailable steroid hormones can be modified by several of the CYP inherited genotypes which may affect those with BRCA1/2 mutations. Among Caucasians, 40–50% have the glutathione S-transferase M1 (GSTM1) null genotype, which appears to confer a several-fold increased risk of lung and bladder cancer and other tumors.

 CANCER CONTROL AND PREVENTION

Overview of Known Causes of Cancer Migrant studies have shown that most unknown causes of cancer are environmental. Such factors are likely related to lifestyle which may include such areas as smoking habits, diet, chemical exposures, and infectious agents. Among worldwide deaths, nine modifiable risk factors are estimated to be responsible for just over one-third of cancer deaths.19 The large task of summarizing such data was undertaken by

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TABLE 61-7. PERCENTAGE OF 2001 WORLDWIDE AND 2006 U.S. CANCER DEATHS MOST PROBABLY ATTRIBUTABLE TO VARIOUS CAUSES OF CANCER*

Cause Smoking Alcohol use Low fruit and vegetable intake Human papilloma virus (HPV) Overweight & obesity Physical inactivity Contaminated injections in health-care settings Urban air pollution Indoor smoke from household use of solid fuels Total joint effect

Worldwide Cancer Deaths in 2001

U.S. Cancer Deaths in 2006†

21% 5% 5%

32% 5% 3%

3%

1%

2% 2% 2%

3% 2% 0.1%

1%

1%

0.2% 35%

0% 41%

∗Estimated risk factor population attributable fractions and worldwide death rates based on Danaei et al., 2005.19 † Based on 2006 death rates estimated by the American Cancer Society (Jemal et al., 2006).10

the Comparative Risk Assessment collaborating groups.19 They examined cancer deaths attributable to smoking (along with indoor smoke from fuel use and urban air pollution), alcohol use, low fruit and vegetable intake, human papillomavirus, overweight and obesity, physical inactivity, and contaminated injections in health-care settings. Their worldwide data and their estimates for high-income countries as applied to U.S. data are summarized in Table 61-7.19,145 The potentially modifiable cancer deaths are largely made up of lung cancer (37%), liver cancer (12%), and esophageal cancer (11%) reflecting cancers with higher proportions of deaths related to potentially modifiable risk factors. While many assumptions were made to create these estimates, the estimates highlight areas in which to focus cancer prevention efforts in order to reduce cancer burden. The largest cancer mortality reduction could be seen if smoking was eliminated. These data also highlight how little is known about preventative factors for cancer in general. We know more about prevention for specific cancer sites. Smoking is estimated to cause 21% of cancer worldwide and 29% in high-income countries. Based on site-specific cancer rates due to smoking in high-income countries and estimated 2006 U.S. cancer rates, smoking may cause as much as 32% of cancer in the United States. Overall, these estimates outline the importance of cancer prevention through eliminating smoking in populations. An additional 10% of worldwide deaths are estimated to be due to alcohol and low fruit and vegetable intake (5% each). Other items are related to specific cancer sites, including human papillomavirus and cervical cancer, contaminated injections in health-care settings and liver cancer, and lung cancer with urban air pollution and indoor smoke from household use of solid fuels.19 The American Cancer Society estimates that while a small percentage of all cancer deaths are due to UV exposure, more than one million cases of basal and squamous cell cancers and all 62,190 new cases of melanoma in 2006 are likely due to UV exposure.18 Use of tanning booths and sunbeds adds to this exposure.

Comprehensive Cancer Control Comprehensive cancer control is an integrated and coordinated approach to reducing cancer incidence, morbidity and mortality


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through prevention, early detection, treatment, rehabilitation, and palliation.146 Cancer researchers and practitioners in federal agencies, public health departments, research centers, medical practices, advocacy groups, and other settings are engaged in an ongoing effort to develop and implement a comprehensive approach to cancer prevention and control in the United States.147 This nationwide effort emphasizes the implementation of evidence-based cancer prevention and cancer strategies at the community level. Such an effort is needed to achieve the ambitious national goals to minimize suffering and death from cancer that have been stated by Healthy People 2010 and the American Cancer Society.

Goals for Cancer Reduction In 1999, the American Cancer Society set bold cancer-reduction goals for 2015 for the United States as a challenge.18 The general goals include a 50% reduction in age-adjusted cancer mortality and a 25% reduction in age-adjusted cancer incidence. Their specific objectives include reducing adult tobacco use (to 12%) and youth tobacco use (to 10%), along with increasing consumption of fruits and vegetables (to 75%), physical activity (to 90% of high school students and 60% of adults), school health education, and sun protection (to 75%). The goals also include increasing detection of breast, colorectal, and prostate cancer through screening.18 The American Cancer Society has focused many goals and prevention efforts on youth related to their belief that starting healthy behaviors in youth is linked to health in adults. The 10 leading health indicators for Healthy People 2010 include several related to cancer, including physical activity, obesity, tobacco use, substance abuse, responsible sexual behavior, and access to health care. The goals related to cancer are to reduce the number of new cancer cases as well as the illness, disability, and death caused by cancer. More information can be found on the Healthy People 2010 website at www.healthypeople.gov.

Strategies for Prevention Efforts The following is a summary of actions that can be taken to reduce cancer burden: 1. Develop effective smoking cessation programs and continue to urge all users of tobacco to stop using this substance in any form, and encourage all nonusers not to start (especially the young). 2. Advise use of alcohol in moderation, especially by smokers. 3. Suggest a diet higher in fresh fruits and vegetables (and fiber), and lower in fats and meats than the average American diet. Avoid blackened, charred, or smoked foods. 4. Urge obese individuals to lose weight and others not to become overweight. 5. Encourage regular exercise. 6. Emphasize the risks of sexually transmitted infections. More specifically, caution women that multiple sexual partners (of both themselves and their partners) enhances their risk of cervical and other anogenital cancers. Caution men that receptive sexual practices are associated with anal cancer and AIDS, which can lead to Kaposi’s sarcoma and other malignancies. Suggest use of barrier contraceptives, especially condoms, to reduce risk of infection. 7. Urge individuals to avoid excess exposure to sunlight and all use of tanning beds or booths, especially if they are light skinned and easily sunburned, and recommend protective clothing and sunscreen use. 8. Support efforts to reduce exposures to known carcinogens in the workplace. 9. Support efforts to identify and reduce exposures outside the workplace to known carcinogens such as arsenic, chromium, nickel, vinyl chloride, and asbestos.

10. Mitigate elevated residential radon levels. Use radiation prudently for medical use. 11. When estrogens are prescribed, use the lowest dose necessary to achieve the therapeutic objective and include a progestin in the regimen.

Screening and Secondary Prevention Screening is often considered a secondary prevention through prevention of the progression of a disease to a fatal outcome by means of early detection followed by definitive treatment. Screening is one component of early detection, but requires effective treatment. The American Cancer Society believes that early detection can help save lives and reduce suffering from cancers of the breast, colon, rectum, cervix, prostate, testis (testicles), oral cavity (mouth), and skin by use of physical examinations and available screening tests. Physical examinations may find cancer early by examination of the breast, colon and rectum, prostate, testicles, oral cavity, and skin. Laboratory tests or x-rays include mammography (for breast cancer), the Pap test (for cervical cancer), and the prostate specific antigen (PSA) blood test (for prostate cancer). In many cases a combination approach is most effective. For colorectal cancer, a combination of fecal occult blood testing, flexible sigmoidoscopy, double-contrast barium enema, and colonoscopy are recommended by the American Cancer Society (www.cancer.org) beginning at age 50. Secondary prevention against a cancer can be achieved only if there is a stage of that cancer that is amenable to cure, and if there is a means of detecting the cancer at that stage.

Planning a Screening Program A number of factors must be considered before initiating a screening program:148,149 1. The sensitivity and specificity of the tests or procedures used for screening: The number of diseased people that will be missed (false negatives) increases as the sensitivity of the test decreases, and the number of well people that will erroneously be considered possibly diseased (false positives) increases as the specificity of the test decreases. 2. The target population: Individuals at highest risk for the disease should be identified, and special efforts should be made to screen such persons. 3. The prevalence of the disease in the target population: For any test of given sensitivity and specificity, numbers of false-positive and false-negative tests are functions of the prevalence of the disease in the target population. More falsenegative tests occur if the disease is common, and more falsepositives if the disease is rare. The latter is of particular importance in screening for cancer. 4. The predictive value of a positive test: This is the proportion of individuals with a positive test who actually have the disease. This proportion declines only slightly as test sensitivity decreases, but declines markedly as test specificity declines. In addition, the predictive value of a positive test declines as the prevalence of the disease diminishes. For example, if we have a test of high sensitivity (e.g., 95%) and high specificity (e.g., 98%), and if the prevalence of the cancer in the target population is 1 per 1000, then only 4.6% of the individuals with a positive test will actually be found to have the disease on further evaluation. The rest will have a false-positive test. 5. The consequences of false-positive tests: A false-positive test is a false alarm. The consequences of this for the individual, the medical care system, and the screening program must be considered. How much inconvenience or psychological trauma will the individual erroneously screened have to bear? Are there sufficient facilities and personnel to provide the necessary diagnostic tests to determine who actually has the disease? What are the costs of these services and who will pay them? Is morbidity associated with further testing


61

6.

7.

8.

9.

10.

11.

(such as biopsies of the breast) acceptable? Do physicians want to have referred to them large numbers of healthy people for diagnostic evaluation? Will possible adverse reactions to the screening program by those falsely screened positive or their physicians have a negative impact on the screening program itself? Consequences of a false-negative test: A false-negative test gives the person screened a false sense of security, and the neoplasm may then progress to a noncurable stage and kill the patient. This could have medical-legal implications, particularly if a more sensitive test could have been used. One missed case can result in unfavorable publicity that can have an adverse impact on the screening program. Applicability of the test: Can the test be administered to the people in the target population? Are special equipment or special resources needed (e.g., electrical power, water, a mobile van, transportation for the potential screenees)? Can the test be administered rapidly? Acceptability of the test: Having made the test available to people in the target population, will the people agree to be screened? What kind of publicity should be given? Are there esthetic or cultural barriers? Is the cost to those being screened acceptably low? Adverse consequences of the test: Is there a possibility that the test will do harm? This issue had originally been a great concern in using mammography to screen for breast cancer. The breast is a radiosensitive organ, high doses of ionizing radiation are known to cause breast cancer, and early mammographic techniques resulted in considerable levels of exposure. This controversy had an adverse impact on breast cancer screening programs, with many women fearing mammography. Similar problems should be anticipated with any future radiographic screening techniques. Life expectancy: Is the individual’s life expectancy longer than the time gained by early screening of asymptomatic individuals? This issue is a concern in screening men over age 75 with PSA for prostate cancer. Older men with no symptoms may die of other causes before a nonsymptomatic prostate cancer grows into a fatal cancer. Thus, it may not be ethical to tell an older man who is more likely to die of other causes that he also has a small prostate cancer. The evaluability of the program: Public and private resources are all too often spent on service programs that are never evaluated, and program evaluators are all too often called upon to assist in program evaluation after a project is fully under way or even completed. The time to begin program evaluation is when the program is being planned.

Evaluation of Methods of Screening and Secondary Prevention The aim of secondary prevention is the prevention of fatal outcome. This implies that a method of secondary prevention of a disease should reduce mortality from that disease, and reduction in mortality should be the measure used to evaluate the method. This is not always done. Two other forms of evaluation have commonly been used, both of which can give misleading results. One of these is the comparison of cases detected at screening with cases detected by other means, with respect to their stage at diagnosis. It is not surprising that those detected at screening tend to be at a less advanced stage. This does not indicate whether the early detection altered the course of the disease, however. This method of evaluation is based on the assumptions that early lesions have the same natural history as symptomatic lesions and that treatment of early lesions alters the course of the disease. Neither assumption is necessarily correct. For example, not all carcinomas in situ of the uterine cervix progress to invasive disease, and individuals with early lung cancer detected at screening with chest x-rays do not have a more favorable prognosis than persons with lung cancer diagnosed later after development of symptoms.

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The other misleading method of evaluating secondary prevention is by comparing survival rates, or time to death, in cases detected at screening and cases detected by other means. There are two problems with this method. One is that the time from diagnosis to death may be longer for individuals who have been screened, not because their death is postponed but only because their disease is diagnosed earlier. This is referred to as lead-time bias. The other problem is known as length-bias sampling and results from the fact that neoplasms grow at varying rates: at any point in time (when screening is performed), there will exist more tumors that are progressing slowly than rapidly. Therefore, compared to tumors in symptomatic cases, a higher proportion of tumors detected at screening will be slow growing, so that survival from time of detection will tend to be longer in screened than symptomatic patients, even if early detection does not result in a prolongation of time to death. Because of the problems of lead-time and length-bias sampling, there is no way of knowing from a comparison of survival rates or survival times whether a secondary prevention program results in a prolonging of life. This can be done only by comparing risks of dying (or risks of advanced disease as a surrogate for mortality) in screened and unscreened individuals. Individuals who volunteer to be screened may differ from those who do not with respect to factors related to risk of death, and these factors must be taken into consideration when comparing mortality rates in screened and unscreened persons. This can be done in two ways: It is preferable to conduct a randomized trial of the secondary prevention method to be evaluated. The other method is to control statistically for differences between the screened and unscreened during data analysis. A classic example of a randomized trial of a procedure for secondary prevention is the study of mammography conducted among members of the Health Insurance Plan (HIP) in New York.150 In 1963, approximately 62,000 women between the ages of 40 and 64 were randomly allocated to one of two groups. Approximately half were offered a series of four annual screenings by mammography and breast palpation (the experimental group). The other half served as a control group and received their usual medical care. Not all women in the experimental group agreed to participate. To eliminate a possible bias due to the remainder being volunteers, the mortality rate due to breast cancer in the entire experimental group was compared to the breast cancer mortality rate in the control group. Inclusion of those not screened in the experimental group gave a conservative estimate of the impact of the program on breast cancer mortality, which represented a combined evaluation of the efficacy and the acceptability of the screening procedures. After 5 years of follow-up, in women in their 50s there was over a 50% reduction in mortality from breast cancer; breast cancer mortality was reduced by one-third in women older than 50. Although there was no beneficial effect on breast cancer mortality in women under 50 after 5 years, follow-up for 18 years showed a small reduction in mortality from breast cancer in these women as well. This observation demonstrates the importance of long-term follow-up in studies of secondary prevention. Once a screening technique is widely believed to be useful, regardless of whether or not it has been rigorously tested, a randomized trial becomes ethically questionable and operationally impossible. Other less satisfactory methods of evaluation must then be used. This is exemplified by the Pap smear for early detection of cervical cancer. When this technique was first introduced, it was greeted with such enthusiasm that suggestions for a randomized trial were not taken. The need to evaluate this procedure subsequently became evident, but by then it was too late for a randomized trial. As a result, a large number of less satisfactory epidemiological studies have been conducted to attempt to measure the effectiveness of the Pap smear.151 Correlational studies have shown that mortality rates from cervical cancer in many populations have declined following the introduction of screening programs, that the magnitude of the decline is correlated with the amount of screening, and that the decline within some of the populations was greatest in those racial and age groups that received the most screening. Case-control studies of women with


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invasive cervical cancer have shown that, compared with normal control subjects, fewer of the cases had prior Pap smears; and a cohort study showed, after controlling for socioeconomic differences between women who enrolled in a screening program and women who did not, that there was a decline in cervical cancer mortality rates in the screened women compared to an increase in rates in those not screened. None of these methods to evaluate the Pap smear are as satisfactory as a randomized trial would have been, although in the aggregate they do provide strong evidence that the procedure reduces mortality.

Current Status of Secondary Prevention of Selected Cancers

Colorectal Cancer Fecal occult blood testing (FOBT) and sigmoidoscopy are both used to screen for colorectal cancer. Randomized trials have suggested that use of FOBT leads to a reduction in colon cancer mortality.160,161 Screening guidelines for colorectal cancer recommend annual FOBT or sigmoidoscopy for individuals age 50 and older, but suggest that evidence is insufficient to determine which test is more effective or whether the use of both tests together would produce additional reductions in mortality.162 However, the level of reduction conferred by FOBT is small, and a large proportion of positive tests are false positives, resulting in many unnecessary clinical follow-up evaluations. The cost-benefit ratio of this procedure is therefore low, as is its acceptability, given the aversion that some people have to fecal testing.

Breast Cancer

Prostate Cancer

Mammographic screening in women over age 50 years has clearly been shown in multiple randomized trials to reduce subsequent mortality from breast cancer by 30–40%,152 and annual mammograms beginning at age 50 are generally recommended. Eight randomized trials of mammography in women 40–49 years of age at entry into the trial have yielded inconsistent results, with none showing a statistically significant reduction in breast cancer mortality after 5–18 years of follow-up. Meta-analyses of data from these trials have yielded different results due to varying lengths of follow-up or methodological concerns about exclusion of some studies. However, meta-analyses with longer follow-up periods show a reduction in risk of dying from breast cancer.153 Mammography may be less efficacious in women under age 50 than in older women because breast tissue of women under age 50 is radiographically more dense than that of older women, and early neoplasms are more difficult to visualize on mammographic films. Also, relatively fewer malignancies and more benign lesions occur in younger women, resulting in more falsepositive screenings. Despite the lack of consistent scientific evidence,154 in 1997 NCI recommended mammographic screening for women in their 40s.155 Nevertheless, there is currently no consensus among experts regarding mammographic screening in women under age 50. Physical examination of the breast by a medical practitioner has been shown to result in the detection of some malignancies missed by mammography and may therefore be of value as a screening modality in conjunction with mammographic screening. Tumors detected by physical examination or by women practicing breast selfexamination have been shown in some studies to be less advanced at diagnosis than symptomatic cancers, but the efficacy of these procedures as primary screening modalities in reducing mortality from breast cancer has not been demonstrated. Randomized trials of breast self-examination have shown no benefit.156,157 Indirect evidence suggests clinical examination of the breast is an important means of averting some breast cancer deaths.156

PSA has been widely incorporated into medical practice as a screening test for prostate cancer and has resulted in an apparent increase in prostate cancer incidence rates in the early 1990s with a suggestion of a reduction in prostate cancer mortality.163 Although PSA testing may prevent deaths by identifying tumors at a treatable stage, there is concern that the test may also identify tumors that would have remained clinically irrelevant during the remainder of a patient’s lifetime and thereby may lead men to undergo invasive and potentially unnecessary treatment. The American Cancer Society recommends annual PSA screening in conjunction with digital rectal examination in men ages 50 and over who are expected to live at least 10 more years, but the screening guidelines from the United States Preventive Health Services Task Force recommend against routine screening by PSA.162,164 This disagreement will not be resolved without substantial further research.

Cervical Cancer Cancer of the cervix has also been clearly shown to be amenable to secondary prevention. Results of a critical review of cytologic screening for cervical cancer were published in 1986.158,159 By combining data from 10 screening programs in eight countries, it was shown that two negative cytologic smears were more effective than one in reducing mortality from cervical cancer (presumably because of a reduction in false-negative diagnoses) and that the protective effect did not decline until 3 years after a second negative smear. Based on these findings, it is recommended that screening for cervical cancer every 3 years is sufficient after a woman has had two normal smears. Some women, however, do develop invasive disease soon after an apparently normal smear, and studies are needed to determine what proportion of such events are a result of prior false-negative smears and how many represent a rapidly progressing form of the disease. This recommendation also does not take into consideration the benefits of an annual appointment, thus it is suspected that women also will not receive an annual pelvic or breast examine or referral for an annual mammogram or assessment for osteoporosis. Furthermore, this recommendation does not consider that many women utilize gynecologists as their routine physician.

Other Cancers A variety of other techniques has been developed for the early detection of cancer. Some have not been rigorously evaluated, and some that have do not show great promise. Studies in industrial settings of urinary cytology for bladder cancer have not yielded encouraging results, and although NCI guidelines recommend oral examination by medical practitioners to screen for oral cancer, the effectiveness of the technique is questionable because of the poor compliance of those individuals at highest risk of the disease.165 The vagueness of clinical symptoms of gastric (stomach) cancer is the major reason patients do not get diagnosed until the cancer has progressed. Current diagnostic modalities consist of endoscopy, which is the most sensitive and specific method for obtaining a definitive diagnosis. It has replaced barium contrast radiographs due to its ability to biopsy and its ability to directly visualize the lesions. Endoscopy has a sensitivity of 98% versus 14% for barium in the early diagnosis of most types of gastric cancer.166,167 Administration of antibiotics against H. pylori have also shown a significant reduction in the incidence of gastric cancer.168 Various screening trials are ongoing in Japan where incidence rates are high.169,170 The disease is sufficiently rare in the United States that large-scale screening is not recommended. Alpha-fetoprotein (AFP) blood levels have been used to screen for primary hepatocellular carcinoma (liver cancer) in individuals serologically positive for hepatitis B surface antigen (HBSAg) in areas where hepatitis B is endemic and liver cancer highly prevalent. A study from China showed improved survival in asymptomatic persons with small tumors detected by this method, but studies to determine whether it reduces mortality from liver cancer have not been completed. Several methods of screening for chronic liver disease include ultrasound, CT scans (computer tomography), MRI (magnetic resonance imaging), angiography, laparoscopy, biopsy, and AFP. Ultrasound is highly specific but not sufficiently sensitive to detect hepatocellular carcinoma or to support its use in an effective surveillance program when a cut-off value of 20 ng/mL is used to differentiate hepatocellular carcinoma from HCV-infected individuals (80–94% specificity and 41–65% sensitivity).171 Use of CT and MRI as an early diagnostic tool in patients with underlying liver cirrhosis who are at high risk of hepatocellular carcinoma is still unclear. It


61 appears that both ultrasound and preferentially MRI would provide greater sensitivity as a screening test.172 Angiography is an x-ray that tends to be uncomfortable, while laparoscopy is a surgical incision of a tube. Thus neither is used for population screening. AFP has limited utility in differentiating hepatocellular carcinoma from benign hepatic disorders because of its high false-positive and falsenegative rates. Serum AFP-3 (one of the three glycoforms of AFP) and DCP (des-gamma-carboxyprothrombin) are other widely used tumor markers for hepatocellular carcinoma and appear to be more sensitive than AFP in differentiating hepatocellular carcinoma from nonmalignant hepatology. Despite considerable interest in the development of ovarian cancer screening using transvaginal ultrasonography or the circulating tumor marker CA-125, neither method is clearly associated with reduced mortality from this disease.173 Improved cancer screening must be a part of any long-term strategy to reduce cancer mortality. These efforts must include both the evaluation of new screening methods and research into the most effective ways to implement the techniques that are of demonstrated benefit. The American Cancer Society believes that early detection is warranted for cancers of the breast, colon, rectum, cervix, prostate, testis, oral cavity, and skin. More information on site-specific recommendations can be found at www.cancer.org.

10. 11.

12.

13.

14.

15.

16.

Cancer Survivorship The National Cancer Institute’s SEER program estimates there are 10.5 million invasive cancer survivors in the United States as of 2003.4 This number is increasing primarily as a result of earlier diagnoses and more effective therapies. This has created a new challenge in comprehensive cancer control that has been recognized in three recent national reports.174–176 Concerns of cancer survivors and their families can include long-term physical, psychosocial, and economic effects of treatment as well as rehabilitation and palliation. Care of these survivors and their families can involve the entire spectrum of comprehensive cancer control from prevention to early detection, treatment, rehabilitation, and palliation.177 To effectively address the needs of this growing population will require a coordinated approach among health-care providers, policymakers, researchers, insurers, advocates, communities, and families.  REFERENCES

1. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th revision, ed. Geneva: World Health Organization, 1992. 2. Fritz AG. International Classification of Diseases for Oncology: ICD-O. 3rd ed. Geneva: World Health Organization, 2000. 3. Coleman MP, Esteve J, Damiecki P, et al. Trends in cancer incidence and mortality. IARC Sci Publ. 1993;(121):1–806. 4. Ries L, Harkins D, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2003. Bethesda, MD: National Cancer Institute, 2006. 5. Edwards BK, Brown ML, Wingo PA, et al. Annual report to the nation on the status of cancer, 1975–2002, featuring populationbased trends in cancer treatment. J Natl Cancer Inst. 2005;97(19): 1407–27. 6. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2002 Incidence and Mortality. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Cancer Institute, 2005. 7. Cancer incidence in five continents. Volume VIII. IARC Sci Publ. 2002;(155):1–781. 8. Bleyer A, O’Leary M, Barr R, Ries LAG, eds. Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age: Including Seer Incidence and Survival, 1975–2000. Bethesda, MD: National Cancer Institute, NIH Pub. No. 06-5767;2006. 9. Singh GK. National Cancer Institute (U.S.). Area Socioeconomic Variations in U.S. Cancer Incidence, Mortality, Stage, Treatment,

17. 18. 19.

20. 21.

22.

23.

24.

25.

26.

27. 28. 29.

Cancer

1065

and Survival, 1975–1999. NIH publication ; no. 03-5417. Bethesda, MD: U.S. Dept. of Health and Human Services, National Institutes of Health, National Cancer Institute, 2003. Jemal A, Siegel R, Ward E, et al. Cancer statistics. CA Cancer J Clin. 2006;56(2):106–30. Cancer trends progress report-2005 update. http://progressreport. cancer.gov. National Cancer Institute, National Institute of Health, Department of Health and Human Services, 2005. Shibuya K, Mathers CD, Boschi-Pinto C, et al. Global and regional estimates of cancer mortality and incidence by site: II. Results for the global burden of disease 2000. BMC Cancer. 2002;2:37. Kolonel L, Wilkens L. Migrant studies. In: Schottenfeld D, Fraumeni J, eds. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press, 2006. Miller BA, Kolonel LN. National Cancer Institute (U.S.). Cancer Control Research Program. Racial/Ethnic Patterns of Cancer in the United States, 1988–1992. NIH publication; no. 96-4104. [Washington, D.C.]: U.S. Department of Health and Human Services, National Institute of Health, 1996. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353(17):1784–92. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8. Chen YC, Hunter DJ. Molecular epidemiology of cancer. CA Cancer J Clin. 2005;55(1):45–54; quiz 57. American Cancer Society. Cancer Prevention and Early Detection Facts & Figures 2006. Atlanta: American Cancer Society, 2006. Danaei G, Vander Hoorn S, Lopez AD, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366(9499):1784–93. Vineis P, Alavanja M, Buffler P, et al. Tobacco and cancer: recent epidemiological evidence. J Natl Cancer Inst. 2004;96(2):99–106. Sasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer. 2004;45 Suppl 2:S3–9. U.S. Department of Health and Human Services. Targeting Tobacco Use: The Nation’s Leading Cause of Death. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2003. U.S. Department of Health and Human Services. The Health Consequences of Smoking: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2004. Heineman EF, Zahm SH, McLaughlin JK, et al. Increased risk of colorectal cancer among smokers: results of a 26-year follow-up of U.S. veterans and a review. Int J Cancer. 1995;59(6):728–38. United States Advisory Committee to the Surgeon General, United States. Public Health Service. The Health Consequences of Using Smokeless Tobacco: A Report of the Advisory Committee to the Surgeon General. NIH publication, No. 86-2874. Bethesda, MD.: U.S. Dept. of Health and Human Services, Public Health Service, 1986. U.S. Department of Health and Human Services. The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention, Health Promotion, Office on Smoking and Health, 2006. Thomas DB. Alcohol as a cause of cancer. Environ Health Perspect. 1995;103Suppl 8:153–60. Altieri A, Garavello W, Bosetti C, et al. Alcohol consumption and risk of laryngeal cancer. Oral Oncol. 2005;41(10):956–65. Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl. 1987;7:1–440.


1066

Noncommunicable and Chronic Disabling Conditions

30. Some organic solvents, resin monomers and related compounds, pigments and occupational exposures in paint manufacture and painting. IARC Monogr Eval Carcinog Risks Hum. 1989;47: 1–442. 31. Chromium, nickel and welding. IARC Monogr Eval Carcinog Risks Hum. 1990;49:1–648. 32. Occupational exposures to mists and vapours from strong inorganic acids and other industrial chemicals. Working Group views and expert opinions, Lyon, 15–22 October, 1991. IARC Monogr Eval Carcinog Risks Hum. 1992;54:1–310. 33. IARC working group on the evaluation of carcinogenic risks to humans: occupational exposures of hairdressers and barbers and personal use of hair colourants; some hair dyes, cosmetic colourants, industrial dyestuffs and aromatic amines. Proceedings. Lyon, France, 6–13 October, 1992. IARC Monogr Eval Carcinog Risks Hum. 1993;57:7–398. 34. Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. Working Group views and expert opinions, Lyon, 9–16 February, 1993. IARC Monogr Eval Carcinog Risks Hum. 1993;58:1–415. 35. IARC working group on the evaluation of carcinogenic risks to humans: some industrial chemicals. Lyon, 15–22 February, 1994. IARC Monogr Eval Carcinog Risks Hum. 1994;60:1–560. 36. Wood dust. IARC Monogr Eval Carcinog Risks Hum. 1995;62: 35–215. 37. Formaldehyde. IARC Monogr Eval Carcinog Risks Hum. 1995;62: 217–375. 38. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Polychlorinated Dibenzo-Para-Dioxins and Polychlorinated Dibenzofurans. Lyon, France, 4–11 February, 1997. IARC Monogr Eval Carcinog Risks Hum. 1997;69:1–631. 39. Formaldehyde, 2-Butoxyethanol and 1-tert-Butoxy-2-propanol. IARC Monogr Eval Carcinog Risks Hum. In preparation. 40. Doll R. Epidemiological evidence of the effects of behaviour and the environment on the risk of human cancer. Recent Results Cancer Res. 1998;154:3–21. 41. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66(6):1191–308. 42. Peto J. Cancer epidemiology in the last century and the next decade. Nature. 2001;411(6835):390–5. 43. Vineis P, Forastiere F, Hoek G, et al. Outdoor air pollution and lung cancer: recent epidemiologic evidence. Int J Cancer. 2004;111(5): 647–52. 44. Cohen AJ. Outdoor air pollution and lung cancer. Environ Health Perspect. 2000;108 Suppl 4:743–50. 45. Boice J. Ionizing radiation. In: Schottenfeld D, Fraumeni J, eds. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press, 2006. 46. Ionizing radiation, part 2: Some internally deposited radionuclides. Views and expert opinions of an IARC working group on the evaluation of carcinogenic risks to humans. Lyon, 14–21 June, 2000. IARC Monogr Eval Carcinog Risks Hum. 2001;78(Pt 2):1–559. 47. IARC Working group on the evaluation of carcinogenic risks to humans: ionizing radiation, Part I, X- and gamma- radiation and neutrons. Lyon, France, 26 May–2 June, 1999. IARC Monogr Eval Carcinog Risks Hum. 2000;75 Pt 1:1–448. 48. UNSCEAR 2000. The United Nations Scientific Committee on the Effects of Atomic Radiation. Health Phys. 2000;79(3):314. 49. Krewski D, Lubin JH, Zielinski JM, et al. A combined analysis of North American case-control studies of residential radon and lung cancer. J Toxicol Environ Health A. 2006;69(7):533–97. 50. Darby S, Hill D, Deo H, et al. Residential radon and lung cancer— detailed results of a collaborative analysis of individual data on 7148 persons with lung cancer and 14,208 persons without lung cancer from 13 epidemiologic studies in Europe. Scand J Work Environ Health. 2006;32 Suppl 1:1–83.

51. National Research Council (U.S.). Committee on Health Risks of Exposure to Radon. Health Effects of Exposure to Radon. Washington, D.C.: National Academy Press, 1999. 52. Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorship— genetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst. 2006;98(1):15–25. 53. Van Leeuwen FE, Travis LB. Second Cancers. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer, Principles & Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2001;2939–296. 54. Brenner DJ, Doll R, Goodhead DT, et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A. 2003;100(24):13761–6. 55. Armstrong BK. Epidemiology of malignant melanoma: intermittent or total accumulated exposure to the sun? J Dermatol Surg Oncol. 1988;14(8):835–49. 56. Armstrong BK, Kricker A, English DR. Sun exposure and skin cancer. Australas J Dermatol. 1997;38 Suppl 1:S1–6. 57. Wester U, Boldemann C, Jansson B, et al. Population UV-dose and skin area—do sunbeds rival the sun? Health Phys. 1999;77(4):436–40. 58. Feychting M, Ahlbom A, Kheifets L. EMF and health. Annu Rev Public Health. 2005;26:165–89. 59. Ahlbom IC, Cardis E, Green A, et al. Review of the epidemiologic literature on EMF and Health. Environ Health Perspect. 2001;109 Suppl 6:911–33. 60. Heath CW, Jr. Electromagnetic field exposure and cancer: a review of epidemiologic evidence. CA Cancer J Clin. 1996;46(1): 29–44. 61. Washburn EP, Orza MJ, Berlin JA, et al. Residential proximity to electricity transmission and distribution equipment and risk of childhood leukemia, childhood lymphoma, and childhood nervous system tumors: systematic review, evaluation, and meta-analysis. Cancer Causes Control. 1994;5(4):299–309. 62. Colton T, Greenberg ER, Noller K, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. Further follow-up. JAMA. 1993;269(16):2096–100. 63. Vessey MP, Fairweather DV, Norman-Smith B, et al. A randomized double-blind controlled trial of the value of stilboestrol therapy in pregnancy: long-term follow-up of mothers and their offspring. Br J Obstet Gynaecol. 1983;90(11):1007–17. 64. Greenberg ER, Barnes AB, Resseguie L, et al. Breast cancer in mothers given diethylstilbestrol in pregnancy. N Engl J Med. 1984;311(22):1393–8. 65. Collaborative Group on Hormonal Factors in Breast Cancer, ICRF Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford, UK. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347(9017):1713–27. 66. Skegg DC, Noonan EA, Paul C, et al. Depot medroxyprogesterone acetate and breast cancer. A pooled analysis of the World Health Organization and New Zealand studies. JAMA. 1995;273(10):799–804. 67. Nelson HD. Assessing benefits and harms of hormone replacement therapy: clinical applications. JAMA. 2002;288(7):882–4. 68. Ewertz M. Hormone therapy in the menopause and breast cancer risk—a review. Maturitas. 1996;23(2):241–6. 69. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350(9084):1047–59. 70. Colditz GA. Relationship between estrogen levels, use of hormone replacement therapy, and breast cancer. J Natl Cancer Inst. 1998;90(11):814–23. 71. Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, et al. A prospective study of endogenous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst. 1995;87(3):190–7.


61 72. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95(16):1218–26. 73. Key T, Appleby P, Barnes I, et al. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94(8):606–16. 74. Cook L, Weiss N, Doherty J, et al. Endometrial Cancer. In: Schottenfeld D, Fraumeni J, eds. Cancer Epidemiology and Prevention. 3rd ed. New York: Oxford University Press, 2006. 75. Weiss N. Epidemiology of endometrial cancer. In: Lilienfeld A, ed. Reviews in Epidemiology. Vol. 2. New York: Elsevier, 1983. 76. Prentice RL, Thomas DB. On the epidemiology of oral contraceptives and disease. Adv Cancer Res. 1987;49:285–301. 77. Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer. 1991;49(2):186–90. 78. Curtis RE, Boice JD, Jr, Shriner DA, et al. Second cancers after adjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst. 1996;88(12):832–4. 79. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11(12):1531–43. 80. Zeleniuch-Jacquotte A, Akhmedkhanov A, Kato I, et al. Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. Br J Cancer. 2001;84(7): 975–81. 81. Potischman N, Hoover RN, Brinton LA, et al. Case-control study of endogenous steroid hormones and endometrial cancer. J Natl Cancer Inst. 1996;88(16):1127–35. 82. Riman T, Nilsson S, Persson IR. Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstet Gynecol Scand. 2004;83(9):783–95. 83. Modan B, Hartge P, Hirsh-Yechezkel G, et al. Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation. N Engl J Med. 2001;345(4): 235–40. 84. Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. N Engl J Med. 1998;339(7):424–8. 85. Garg PP, Kerlikowske K, Subak L, et al. Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstet Gynecol. 1998;92(3):472–9. 86. Lacey JV, Jr, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288(3):334–41. 87. Lukanova A, Lundin E, Toniolo P, et al. Circulating levels of insulin-like growth factor-I and risk of ovarian cancer. Int J Cancer. 2002;101(6):549–54. 88. Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum. 1995;64. 89. Smith EM, Ritchie JM, Levy BT, et al. Prevalence and persistence of human papillomavirus in postmenopausal age women. Cancer Detect Prev. 2003;27(6):472–80. 90. Lacey JV, Jr., Brinton LA, Barnes WA, et al. Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix. Gynecol Oncol. 2000;77(1):149–54. 91. Thomas D. Exogenous steroid hormones and hepatocellular carcinoma. In: Tablr E, DiBiceglie A, Purcell R, eds. Etiology, Pathology, and Treatment of Hepatocellular Carcinoma in North America. Advances in Applied Biotechnology Series. Vol. 13. Houston: Gulf Publishing Company, 1990;77–89. 92. Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284(15):878–81. 93. Melnick S, Cole P, Anderson D, et al. Rates and risks of diethylstilbestrolrelated clear-cell adenocarcinoma of the vagina and cervix. An update. N Engl J Med. 1987;316(9):514–6.

Cancer

1067

94. Fernandez E, La Vecchia C, Franceschi S, et al. Oral contraceptive use and risk of colorectal cancer. Epidemiology. 1998;9(3): 295–300. 95. Hannaford P, Elliott A. Use of exogenous hormones by women and colorectal cancer: evidence from the Royal College of General Practitioners’ Oral Contraception Study. Contraception. 2005;71(2): 95–8. 96. Martinez ME, Grodstein F, Giovannucci E, et al. A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 1997;6(1):1–5. 97. Pfahlberg A, Hassan K, Wille L, et al. Systematic review of casecontrol studies: oral contraceptives show no effect on melanoma risk. Public Health Rev. 1997;25(3–4):309–15. 98. Karagas MR, Stukel TA, Dykes J, et al. A pooled analysis of 10 case-control studies of melanoma and oral contraceptive use. Br J Cancer. 2002;86(7):1085–92. 99. Gann PH, Hennekens CH, Ma J, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst. 1996;88(16):1118–26. 100. English PB, Goldberg DE, Wolff C, et al. Parental and birth characteristics in relation to testicular cancer risk among males born between 1960 and 1995 in California (United States). Cancer Causes Control. 2003;14(9):815–25. 101. Strohsnitter WC, Noller KL, Hoover RN, et al. Cancer risk in men exposed in utero to diethylstilbestrol. J Natl Cancer Inst. 2001;93(7):545–51. 102. Coupland CA, Chilvers CE, Davey G, et al. Risk factors for testicular germ cell tumours by histological tumour type. United Kingdom Testicular Cancer Study Group. Br J Cancer. 1999;80(11): 1859–63. 103. Weir HK, Kreiger N, Marrett LD. Age at puberty and risk of testicular germ cell cancer (Ontario, Canada). Cancer Causes Control. 1998;9(3):253–8. 104. Titus-Ernstoff L, Perez K, Cramer DW, et al. Menstrual and reproductive factors in relation to ovarian cancer risk. Br J Cancer. 2001;84(5):714–21. 105. Whiteman DC, Siskind V, Purdie DM, et al. Timing of pregnancy and the risk of epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2003;12(1):42–6. 106. Riman T, Dickman PW, Nilsson S, et al. Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study. Am J Epidemiol. 2002;156(4):363–73. 107. Cooper GS, Schildkraut JM, Whittemore AS, et al. Pregnancy recency and risk of ovarian cancer. Cancer Causes Control. 1999;10(5):397–402. 108. Pike MC, Pearce CL, Wu AH. Prevention of cancers of the breast, endometrium and ovary. Oncogene. 2004;23(38):6379–91. 109. Ogawa S, Kaku T, Amada S, et al. Ovarian endometriosis associated with ovarian carcinoma: a clinicopathological and immunohistochemical study. Gynecol Oncol. 2000;77(2):298–304. 110. Brinton LA, Gridley G, Persson I, et al. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol. 1997;176(3):572–9. 111. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155(3):217–24. 112. Hankinson SE, Hunter DJ, Colditz GA, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer. A prospective study. JAMA. 1993;270(23):2813–8. 113. Kreiger N, Sloan M, Cotterchio M, et al. Surgical procedures associated with risk of ovarian cancer. Int J Epidemiol. 1997;26(4): 710–5. 114. Miracle-McMahill HL, Calle EE, Kosinski AS, et al. Tubal ligation and fatal ovarian cancer in a large prospective cohort study. Am J Epidemiol. 1997;145(4):349–57. 115. Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res. 2004;10(3):803–21.


1068

Noncommunicable and Chronic Disabling Conditions

116. Manolov G, Manolova Y, Klein G, et al. Alternative involvement of two cytogenetically distinguishable breakpoints on chromosome 8 in Burkitt’s lymphoma associated translocations. Cancer Genet Cytogenet. 1986;20(1–2):95–9. 117. Subar M, Neri A, Inghirami G, et al. Frequent c-myc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood. 1988;72(2):667–71. 118. Goldsmith DB, West TM, Morton R. HLA associations with nasopharyngeal carcinoma in Southern Chinese: a meta-analysis. Clin Otolaryngol Allied Sci. 2002;27(1):61–7. 119. Chan SH, Day NE, Kunaratnam N, et al. HLA and nasopharyngeal carcinoma in Chinese—a further study. Int J Cancer. 1983;32(2): 171–6. 120. Dolcetti R, Boiocchi M, Gloghini A, et al. Pathogenetic and histogenetic features of HIV-associated Hodgkin’s disease. Eur J Cancer. 2001;37(10):1276–87. 121. Hepatitis viruses. IARC Monogr Eval Carcinog Risks Hum. 1994;59:1–255. 122. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11(2):97–107. 123. Schulz TF, Boshoff CH, Weiss RA. HIV infection and neoplasia. Lancet. 1996;348(9027):587–91. 124. Joint United Nations Programs on HIV/AIDS. Overview of the global AIDS epidemic. 2006 report on the global AIDS epidemic, 2006. 125. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June, 1994. IARC Monogr Eval Carcinog Risks Hum. 1994;61:1–241. 126. Munoz N. Is Helicobacter pylori a cause of gastric cancer? An appraisal of the seroepidemiological evidence. Cancer Epidemiol Biomarkers Prev. 1994;3(5):445–51. 127. Hunter DJ, Spiegelman D, Adami HO, et al. Cohort studies of fat intake and the risk of breast cancer—a pooled analysis. N Engl J Med. 1996;334(6):356–61. 128. Dennis LK, Snetselaar LG, Smith BJ, et al. Problems with the assessment of dietary fat in prostate cancer studies. Am J Epidemiol. 2004;160(5):436–44. 129. Christen WG, Gaziano JM, Hennekens CH. Design of Physicians’ Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol. 2000;10(2):125–34. 130. Frieling UM, Schaumberg DA, Kupper TS, et al. A randomized, 12-year primary-prevention trial of beta carotene supplementation for nonmelanoma skin cancer in the physician’s health study. Arch Dermatol. 2000;136(2):179–84. 131. Mayne ST, Cartmel B, Baum M, et al. Randomized trial of supplemental beta-carotene to prevent second head and neck cancer. Cancer Res. 2001;61(4):1457–63. 132. Taylor PR, Greenwald P. Nutritional interventions in cancer prevention. J Clin Oncol. 2005;23(2):333–45. 133. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150–5. 134. Mueller H, Weber W. Familial Cancer. Basel: Karger, 1985. 135. Knudson AG, Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68(4):820–3. 136. Varley J. TP53, hChk2, and the Li-Fraumeni syndrome. Methods Mol Biol. 2003;222:117–29. 137. Rebbeck TR. Inherited predisposition and breast cancer: modifiers of BRCA1/2-associated breast cancer risk. Environ Mol Mutagen. 2002;39(2–3):228–34. 138. Thompson D, Easton D. The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia. 2004;9(3):221–36. 139. FitzGerald MG, Bean JM, Hegde SR, et al. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997;15(3):307–10.

140. de la Chapelle A. The incidence of Lynch syndrome. Fam Cancer. 2005;4(3):233–7. 141. Ruteshouser EC, Huff V. Familial Wilms tumor. Am J Med Genet C Semin Med Genet. 2004;129(1):29–34. 142. Green DM. Wilms’ tumour. Eur J Cancer. 1997;33(3):409–18; discussion 19–20. 143. Engelien A, Geerdink R, Lips C. Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening. Eur J Endocrinol. 2003;149:577–82. 144. Linehan WM, Zbar B. Focus on kidney cancer. Cancer Cell. 2004;6(3):223–8. 145. Jemal A, Thomas A, Murray T, et al. Cancer statistics, 2002. CA Cancer J Clin. 2002;52(1):23–47. 146. Abed J, Reilley B, Butler MO, et al. Comprehensive cancer control initiative of the Centers for Disease Control and Prevention: an example of participatory innovation diffusion. J Public Health Manag Pract. 2000;6(2):79–92. 147. Given LS, Black B, Lowry G, et al. Collaborating to conquer cancer: a comprehensive approach to cancer control. Cancer Causes Control. 2005;16 Suppl 1:3–14. 148. Lilienfeld AM. Some limitations and problems of screening for cancer. Cancer. 1974;33(6):1720–4. 149. Cole P, Morrison AS. Basic issues in population screening for cancer. J Natl Cancer Inst. 1980;64(5):1263–72. 150. Shapiro S. Statistical evidence for mass screening for breast cancer and some remaining issues. Cancer Detect Prev. 1976;1:347–63. 151. Shingleton HM, Patrick RL, Johnston WW, et al. The current status of the Papanicolaou smear. CA Cancer J Clin. 1995;45(5):305–20. 152. Hurley SF, Kaldor JM. The benefits and risks of mammographic screening for breast cancer. Epidemiol Rev. 1992;14:101–30. 153. Lisby MD. Screening mammography in women 40 to 49 years of age. Am Fam Physician. 2004;70(9):1750–2. 154. Eddy DM. Breast cancer screening in women younger than 50 years of age: what’s next? Ann Intern Med. 1997;127(11):1035–6. 155. Kopans DB. The breast cancer screening controversy and the National Institutes of Health Consensus Development Conference on Breast Cancer Screening for Women Ages 40–49. Radiology. 1999;210(1):4–9. 156. Gaskie S, Nashelsky J. Clinical inquiries. Are breast self-exams or clinical exams effective for screening breast cancer? J Fam Pract. 2005;54(9):803–4. 157. McCready T, Littlewood D, Jenkinson J. Breast self-examination and breast awareness: a literature review. J Clin Nurs. 2005;14(5): 570–8. 158. Hakama M, Miller AB, Day NE, et al. Screening for Cancer of the Uterine Cervix: from the IARC Working Group on Cervical Cancer Screening and the UICC Project Group on the Evaluation of Screening Programmes for Cancer. IARC scientific publications, no. 76. Lyon, New York: International Agency for Research on Cancer (Distributed in the USA by Oxford University Press), 1986. 159. Screening for squamous cervical cancer: duration of low risk after negative results of cervical cytology and its implication for screening policies. IARC Working Group on evaluation of cervical cancer screening programmes. Br Med J (Clin Res Ed). 1986;293(6548): 659–64. 160. Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 1996;348(9040):1467–71. 161. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet. 1996;348(9040):1472–7. 162. U.S. Preventive Services Task Force. Office of Disease Prevention and Health Promotion. Guide to Clinical Preventive Services: Report of the U.S. Preventive Services Task Force. 2nd ed. [Washington, DC]: U.S. Dept. of Health and Human Services, Office of Public Health and Science, 1996.


61 163. Dennis LK, Resnick MI. Analysis of recent trends in prostate cancer incidence and mortality. Prostate. 2000;42(4):247–52. 164. Harris R, Lohr KN. Screening for prostate cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(11):917–29. 165. Prorok PC, Chamberlain J, Day NE, et al. UICC Workshop on the evaluation of screening programmes for cancer. Int J Cancer. 1984;34(1):1–4. 166. Longo WE, Zucker KA, Zdon MJ, et al. Detection of early gastric cancer in an aggressive endoscopy unit. Am Surg. 1989;55(2): 100–4. 167. Gallo A, Cha C. Updates on esophageal and gastric cancers. World J Gastroenterol. 2006;12(20):3237–42. 168. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291(2):187–94. 169. Ohata H, Oka M, Yanaoka K, et al. Gastric cancer screening of a high-risk population in Japan using serum pepsinogen and barium digital radiography. Cancer Sci. 2005;96(10):713–20. 170. Lee KJ, Inoue M, Otani T, et al. Gastric cancer screening and subsequent risk of gastric cancer: a large-scale population-based cohort study, with a 13-year follow-up in Japan. Int J Cancer. 2006;118(9): 2315–21. 171. Gupta S, Bent S, Kohlwes J. Test characteristics of alpha-fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis

172.

173.

174.

175.

176.

177.

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1069

C. A systematic review and critical analysis. Ann Intern Med. 2003;139(1):46–50. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol. 2006;101(3):513–23. NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995;273(6):491–7. Lance Armstrong Foundation, Centers for Disease Control and Prevention. A National Plan for Cancer Survivorship: Advancing Public Health Strategies. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2004. National Cancer Policy Board (U.S.), Weiner SL, Simone JV. Childhood cancer survivorship: improving care and quality of life. Washington, DC.: National Academies Press, 2003. President’s Cancer Panel. Living Beyond Cancer: Finding a New Balance. Annual Report of the President’s Cancer Panel. National Institutes of Health, National Cancer Institute; 2004. Pollack LA, Greer GE, Rowland JH, et al. Cancer survivorship: a new challenge in comprehensive cancer control. Cancer Causes Control. 2005;16 Suppl 1:51–9.


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62

Heart Disease Russell V. Luepker

 INTRODUCTION

Cardioscular diseases (CVDs) are public health concerns around the world, particularly coronary or ischemic heart disease (CHD), hypertensive heart disease, and rheumatic heart disease. CHD remains the leading cause of adult death in industrial societies, although its incidence differs widely and the mortality ascribed to it is changing dramatically (Figs. 62-1 and 62-2). While deaths from CHD are falling in industrialized nations, they are rising dramatically in others particularly in the developing world.1 The decline of age-adjusted U.S. deaths ascribed to CHD continues for men and women, white and nonwhite (Fig. 62-3). The exact causes of the decline are not established, but much is now known about U.S. trends in out-of-hospital deaths, in-hospital case fatality, and longer-term survival after acute myocardial infarction.2 Parallel to the CHD mortality trends are improvements in medical diagnosis and treatment, in population levels of risk factors, and in lifestyle.3 Nevertheless, the critical explanatory data, including incidence trends from representative populations, are few. This deficiency, along with the difficulty of measuring change in diagnostic custom and in severity of CHD, or of its precursor, atherosclerosis, leaves considerable uncertainty about the causes of the mortality trends. Systematic surveillance is now in place in several areas to improve the future detection, prediction, and explanation of trends in CVD rates.2–5 Deaths ascribed to hypertensive heart disease have diminished over recent decades in many industrialized countries.6 In West Africa, Latin America, and the Orient, however, the high prevalence still found in hospitals and clinics indicates the continued worldwide importance of hypertension. Rheumatic fever and rheumatic valvular heart disease remain public health concerns in many developing countries and are still seen among disadvantaged peoples in affluent nations. On the other hand, syphilitic heart disease, a worldwide scourge until the 1940s, is now rare. Cardiomyopathies, often of unknown or infectious origin, constitute a common cause of heart disease in many regions, particularly Africa and Latin America. Finally, congenital heart disease continues to contribute to the heart disease burden among youth and adults of all countries. The worldwide potential for primary prevention of most CVD is established by several salient facts: (a) the large population differences in CVD incidence and death rates; CVD is rare in many countries and common in others; (b) dynamic national trends in CVD deaths, both upward and downward; (c) rapid changes in CVD risk among migrant populations; (d) the identification of modifiable risk characteristics for CVD among and within populations; and (e) the positive results of preventive trials. The following chapter expands on these cardiovascular diseases, their trends and the magnitude of burden on populations. The population-wide factors associated with risk of these diseases are

described. Because the majority of cardiovascular disease is caused by social, cultural, and economic factors, public health approaches are central to prevention and control strategies.

 CORONARY HEART DISEASE

CHD remains the leading cause of adult deaths in many industrial societies. Much about its causes and prevention has been learned from diverse research methods, including clinicopathological observations, laboratory-experimental studies, population studies, and clinical trials. The evidence of causation from all these disciplines is largely congruent. As a result, several ubiquitous cultural characteristics described below are now established as powerful influences on population risk of CHD. These influences and risk factors appear to be safely modifiable for individuals and for entire populations.7–10 The sum of evidence suggests that there is widespread human susceptibility to atherosclerosis and, consequently, that CHD is maximally exhibited when the environment is unfavorable. These ubiquitous susceptibilities, exposures, and behaviors lead eventually to the mass precursors of CHD found among so many people in highincidence societies. The rationale and the potential for preventive practice, as well as for public policy in prevention, are based on several well-established relationships: between risk factor levels and CHD, between health behaviors and risk factor levels, and between culture and mass health behaviors.

Epidemiology of CHD Summarized here are the salient observations about CHD: • Population comparisons show large differences in CHD incidence and mortality rates (Fig. 62-2) and in the extent of its underlying vascular disease, atherosclerosis. • Population differences in the mean levels and distributions of CHD risk characteristics (particular lipid levels) are strongly correlated with population differences in CHD rates. • Within populations, several risk characteristics (blood cholesterol, blood pressure levels, diabetes and smoking habits) are strongly and continuously related to future individual risk of a CHD event. • Population differences in average levels of CHD risk characteristics are already apparent in youth. Individual values of children tend to “track” into adult years. • CHD risk characteristics and incidence in migrants rapidly approach levels of the adopted culture. • Trends in CHD mortality rates, both upward and downward, occur over relatively short periods of 5–10 years. These trends 1071

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Figure 62-1. Age-adjusted death rates for coronary heart disease by country and sex, Ages 35–74, 2002. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, Maryland, 2004; NIH Publication.)

Figure 62-2. Change in age-adjusted death rates for coronary heart disease in males and females by country, Ages 35–74, 1995–2002. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, Maryland, 2004; NIH Publication.)

Figure 62-3. Death and ageadjusted death rates for coronary heart disease, U.S., 1979–2002. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD, 2004; NIH Publication.)


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Figure 62-4. Average annual percent change in death rates for coronary heart disease by age, race, and sex, U.S., 1999–2002. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD, 2004; NIH Publication.)

tend to be associated with changes in medical care and casefatality rates as well as with trends in incidence and in population distributions of risk characteristics. The recent decrease in age-adjusted CHD mortality rates in the United States is shared by men and women, by whites and nonwhites, and by younger and older age groups (Figs. 62-3, 63-4). The decrease in age-adjusted CHD mortality rates in the United States is associated with an even greater decrease in death rates from stroke. This leads to increases in lifespan. Moreover, in the last decades there has been a lesser decrease in non-CVD deaths and in deaths from all causes (Fig. 62-5). Randomized clinical trials find a direct effect of CHD risk factor lowering on subsequent disease rates. Preventive trials also establish that levels of risk factors, and their associated health behaviors, can be significantly and safely modified. The epidemiological evidence is congruent with clinical animal and laboratory findings about the causes and mechanisms of atherosclerosis, the process that underlies the clinical manifestations of CHD.

Role of Diet Dietary Fats There is considerable evidence that habitual diet in populations, a culturally determined characteristic, has an important influence on the mean levels and distribution of blood lipoproteins and, therefore, on the population risk and potential for prevention of CHD. Several dietary factors influence individual and population levels of lowdensity lipoproteins (LDL) in the blood, a leading pathogenetic factor in atherosclerosis. These include particular fatty acids and dietary cholesterol, the complex carbohydrates of starches, vegetables, fruits and their fibers, alcohol, and caloric excess. Many investigators consider that the cholesterol-raising properties of some habitual diets are essential to the development of mass atherosclerosis, leading in turn to high rates of CHD. Where average total blood cholesterol level in a population is low (less than 200 mg/dL, or 5.2 mmol/L), CHD is uncommon, irrespective of population levels of smoking and hypertension. From this evidence, there is now a consensus about the leading population causes of CHD and general acceptance of policy recommendations that lead toward a gradual, universal change in the

Figure 62-5. Change in ageadjusted death rates since 1950, U.S., 1950–2002. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD, 2004; NIH Publication.)


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habitual diets of populations in which CHD rates are high. Wherever economically feasible, systematic strategies to detect and manage individuals at excess risk are also recommended. Epidemiological studies comparing stable, rural agricultural societies find a strong relationship between habitual diet, average blood cholesterol levels, and incidence of CHD.11–13 For example, diets of populations with a high incidence of CHD are characterized by relatively high saturated fatty acid (greater than 15% of daily calories) and cholesterol intake and low carbohydrate intake (under 50%). Diets in populations with a low CHD incidence are characterized mainly by low saturated fatty acid intake (less than 10% of calories) and high carbohydrate intake but widely varying total fat intake (varying mainly in the proportion of monounsaturated fatty acid calories).12 Most of the difference in mean population levels of serum total (and LDL) cholesterol can be accounted for by measured differences in fatty acid composition of the habitual diet. Moreover, population CHD rates can be predicted, with increasing precision over time, by average population blood cholesterol levels.14 Cross-cultural comparisons of diet versus postmortem findings of atherosclerosis reveal a strong correlation between habitual dietary fat intake of a population and the frequency and extent of advanced atherosclerotic lesions.15 Studies of migrant populations indicate the predominance of sociocultural influences, including diet, in trends of risk and CHD among migrants. For example, Japanese who migrate to California become taller, heavier, more obese, and more sedentary; their diet changes dramatically; they eat more meat and dairy products, saturated fatty acids and cholesterol, and consume less complex carbohydrate and less alcohol than their counterparts in the Nagasaki-Hiroshima area.16 They develop higher risk profiles and disease rates within a generation. With few exceptions, migrant Hawaiian Japanese have risk factor values intermediate between mainland and California Japanese, and the CHD rate in migrants generally parallels their mean values for risk factor levels. The rapid evolving national trends in CHD deaths are another indication of the predominance of culture in the population causes and prevention of CHD, as disease occurrence changes more rapidly than any genetic characteristics. Nevertheless, systematic explanatory studies of trends in CHD mortality are very recent, and current attempts to estimate the relative contribution of cultural versus medical care contributions are quite tentative.2–4,17,18 In a number of countries on an upward slope of CHD mortality, smoking and calorie and fat consumption are increasing and physical activity is decreasing, while cardiological practice is probably becoming less effective.19 In many other industrial countries, including the United States, decreasing CHD mortality rates parallel improved cardiac care and significant reductions in average risk characteristics.2,3,17,20 Standardized measurements of risk and disease trends are not generally available for comparisons among countries, but the public health implications of these simultaneous trends in behaviors, risk, disease rates, and medical care are immense. Another feature of diet, the relative excess of calorie intake over expenditure, influences health through the metabolic maladaptations of hyperlipidemia, hyperinsulinism, and hypertension.21 This is sometimes called the metabolic syndrome.22 This caloric imbalance occurs in sedentary cultures and results in mass obesity. With or without mass obesity, however, high salt intake and low potassium intake in populations appear to encourage the wide exhibition of hypertensive phenotypes. Other cations (e.g., magnesium, calcium) may also be significant dietary influences on population levels of blood pressure, while alcohol intake is clearly involved (see below). Anthropology and paleontology provide insights into the probable effects of rapid cultural change, including modern diets, from the lifestyle to which humans adapted during earlier periods of evolution. Until 500 or so generations ago, all humans were hunter-gatherers. The habitual eating pattern likely involved alternating scarce and abundant calories and a great variety of foods. It surely included lean wild game and usually a predominance of plant over animal calories, a relatively low sodium and high potassium intake, and of course there was universal breast-feeding of infants. Observations of the eating patterns among extant hunter-gatherer tribes confirm the varied nature and the

TABLE 62-1. A MODEL OF INDIVIDUAL DIET–SERUM CHOLESTEROL (TC) RELATIONS WITH INDIVIDUAL EXAMPLES Mean Diet–TC Effect (mg/dL) Genotypic TC Value(mg/dL) 75 150 300

0

+25

+50

+75

+100

75 150 300

100 175 325

125 200 350

150 225 375

175 250 400

Source: Blackburn H. The concept of risk. In: Pearson TA, Criqui MH, Luepker RV, Oberman A, Winston M, eds. Primer in Preventive Cardiology. Dallas: American Heart Association, 1994, pp 25–41; and Keys A, Grande F, Anderson JT. Bias and misrepresentation revisited—“perspective” on saturated fat. Am J Clin Nutr. 1974;27:188–212. It is assumed that an intrinsic lipid regulatory base exists for each individual and is expressed in the first year of life. On this genotype is superimposed the effect of habitual diet, which is either neutral or cholesterol-raising according to properties determined in controlled Minnesota diet experiments, resulting, in this simple additive model, in the adult phenotypes values.

adequacy (or near adequacy) of such an eating pattern for growth and development, as well as for the potential of longevity and the absence of mass phenomena such as atherosclerosis and hypertension.23–25 Although modern humans can scarcely return to such subsistence economies, the anthropological observations suggest that current metabolic maladaptations derived from affluent eating and exercise patterns imposed rapidly on a very different evolutionary legacy result in the mass precursors of cardiovascular diseases found in modern society.24 Despite the generally strong population (ecological) correlations between diet, blood lipid levels, and CHD rates, these correlations are often absent for individuals within high-risk industrial societies.26 This apparent paradox does not negate the causal importance of diet in mass hypercholesterolemia and atherosclerosis. Consider, for example, the simple additive model of Table 62-1, which suggests the powerful influence, in the individual, of inherent lipid regulation. Different individual lipoprotein genotypes may develop widely different adult risk phenotypes and different serum cholesterol levels, while consuming the same U.S.-type diet. Other individuals may have similar blood cholesterol levels while subsisting on very different diets. In contrast, the population model of Table 62-2 makes the assumption that the multiple genes that influence lipid TABLE 62-2. A MODEL OF POPULATION DIET—SERUM CHOLESTEROL (TC) RELATION WITH POPULATION EXAMPLES Mean Diet–TC Effect (mg/dL)

Population mean TC Lower limit (2.5%) Upper limit (97.5%)

Japan 0

Greece +25

Italy +50

United States +75

Finland +100

75

100

125

150

175

150

175

200

225

250

300

325

350

375

400

Source: Keys A, Grande F, Anderson JT. Bias and misrepresentation revisited—“perspective” on saturated fat. Am J Clin Nutr. 1974;27:188–212; and Keys A, ed. Coronary heart disease in seven countries. Circulation. 1970;41–42 (Suppl I). In this oversimplified model, it is assumed that uncommon single gene effects and widespread polygenic determinants of blood cholesterol levels are randomly and usually distributed among large heterogeneous populations, such that a mean population TC value of 150 mg/dL would prevail (SD ± 37.5 mg/dL) in the presence of a habitual average diet having neutral properties in respect to cholesterol. On this mean and population distribution of intrinsic responsiveness is superimposed the average habitual diet effect for a population, which is either neutral or cholesterol-raising according to the country’s measured diet composition and properties.


62 metabolism are randomly and similarly distributed throughout large heterogeneous populations. Under this condition, population means and distributions of blood lipids are seen to be influenced predominantly by the cholesterol-raising or lowering properties of the habitual diet of the population.27,28 The range and degree of this dietary influence are estimated from short-term controlled diet experiments.29–31 Recently, several well-conducted cohort studies have provided evidence of diet-CHD relationships within societies in which CHD risk is high.32–35 With particular care to reduce variability and increase validity of individual dietary intake assessments, all of these studies were able to demonstrate small but significant and often independent prediction of CHD risk based on entry nutrient intake or other dietary characteristics. In our view, this evidence is less persuasive than the powerful synergism of diet, blood lipid levels, and CHD risk so firmly established over 40 years, but it is clearly confirmatory. With this logic, habitual diet has come to be considered the necessary factor in mass hypercholesterolemia and, thus, in the mass atherosclerosis that leads to high rates of CHD. The population data are, however, equally compatible with another idea, that all three of the major risk factors (i.e., elevated population averages of blood cholesterol, blood pressure, and smoking) are essential for a high population burden of CHD. The relationship of habitual diet to population levels of blood lipids and blood pressure, and to CHD rates, is largely congruent with clinical and experimental observations. First, experimental modification of diet has a predictable effect on group blood lipid levels. When calories and weight are held constant in controlled diet experiments and diet composition is varied, the largest dietary contributions to serum total and LDL cholesterol levels are (a) the proportion of calories consumed as saturated fatty and trans fatty acids, (b) dietary cholesterol, both of which raise cholesterol levels, and (c) polyunsaturated fatty acids, which have a cholesterol lowering effect. The role of monounsaturates is debated, with some suggesting a neutral effect while others a cholesterol-lowering effect.29–31,36 Although this is debated, these clinical experiments confirm the broader relation found between long-term habitual diet and population mean levels of blood lipids.11,12 Animal experiments are not treated here but are relevant to the human diet-CHD relationship in that lesions resembling the human plaque are produced by dietary manipulations of blood lipoprotein levels; the fatty components of these animal plaques are reversible with dietary manipulations to lower blood lipoprotein levels.37,38 Plasma cholesterol-lowering preventive trials, which tend to complete the overall evidence for causation, indicate the feasibility and safety of changing risk factors and demonstrate the actual lag times between such change and its effect on CHD rates.22 The synthesis of results of all these trials and their implications for the public health are central because carrying out the “definitive diet-heart trial” is not considered feasible. Therefore, experimental proof of the role of diet in the primary prevention of CHD is not likely to be established. Lipid-lowering trials demonstrate that substantial lowering of blood lipid levels is feasible, that the progress of arterial lesions is arrested, and that CHD morbidity and mortality are reduced, all in proportion to the cholesterol lowering achieved and its duration. These trials, carried out mainly in middle-aged men with moderately elevated blood lipids, have usually involved cholesterol-lowering medication plus diet. However, because they specifically tested the cholesterol-lowering hypothesis and because their effects are congruent with the observational evidence cited here in support of that hypothesis, these experimental findings have been extrapolated by many authorities to the potential for prevention in the broader population, including older and younger age groups, and those with lower lipid and risk levels.22 Many consider, also, that the results of randomized clinical trials, because of their congruence with the other evidence, may be extrapolated to the larger public health, including the potential for CHD prevention by long-term change in eating patterns of the population as a whole, and, finally, to the prevention of elevated risk in the first place.

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Proteins International vital statistics on deaths correlated with national foodconsumption data indicate that, as with fat consumption, strong ecologic correlations exist between animal protein intake and death rates from CHD, but there is little evidence that this association is causal. Anitschkow39 found originally that it was dietary lipid rather than protein that resulted in hyperlipidemia and atherosclerosis in his experimental rabbits. Controlled metabolic ward studies in men under isocaloric conditions, with fat intake held constant while protein intake was varied between 5 and 20% of daily calories, found no change in blood cholesterol level (University of Minnesota, unpublished data). Neither clinical, experimental, nor epidemiological evidence is now sufficient to attribute a specific effect of dietary protein on either blood lipid levels or CHD risk. The overall importance of the consumption of meats from domesticated animals and of fatty milk products is therefore thought to rest mainly in their fatty acid content rather than their protein content, at least with respect to CHD risk.

Carbohydrates There is generally a positive association between population intake of refined sugars and CHD mortality and a negative relationship between complex carbohydrates and CHD mortality. Although these diet components are seriously confounded with other dietary factors that are strongly associated with carbohydrate intake, the effect of certain fibers, including the pectins in fruit, bran fiber, and the guar gum of numerous vegetables and legumes, on blood sugar and on blood lipid regulation has recently attracted greater interest. This is particularly so now that the fatty acid effects are well delineated; yet they fail to explain all of the observed population differences in blood lipid or all the lipid changes seen during experiments involving different nutrient composition. More important, however, is that plausible mechanisms of atherogenesis are not established for sugars. The broader issue of plant foods (fruits, vegetables, pulses, legumes, and seeds), their complex carbohydrates, protein, other nutrients, and fibers is nevertheless of great public health interest because their consumption may affect the risk of cancers as well as of CVD. The summary view is that the different amounts of sugars consumed in “natural diets” around the world do not account for the important differences found in population levels of blood lipids and their associated CHD risk. High carbohydrate intake is confounded with low fat intake (since protein intake is relatively comparable), and both are associated with low rates of CHD.

Alcohol Positive correlations between alcohol consumption and blood pressure levels found for individuals in population studies appear to be dose-related and independent of body weight and smoking habits.40,41 Evidence is also consistent with respect to the positive relationship of alcohol consumption to blood high density lipoprotein (HDL) cholesterol level and of change in alcohol consumption to change in HDL cholesterol level. Substitution of alcohol for carbohydrates in a mixed U.S. diet results in a rise in HDL, mainly the HDL3 subfraction, one that may not be strongly related to CHD risk.42 Experimentally, myocardial metabolism and ventricular function are affected by relatively small doses of alcohol. In addition, neurohormonal links are established between alcohol-stimulated catecholamine excretion and myocardial oxygen requirements. These effects could act as contributory factors to the clinical manifestations of ischemia. The epidemiological evidence from longitudinal studies about the relation of alcohol to CHD risk is, however, conflicting.43–45 Inverse relationships of alcohol intake and CHD are found in some studies, whereas a U-shaped, linear, or no relationship is found in others. Positive relationships, when found, are usually independent of tobacco, obesity, and blood pressure levels.45 Reasons for these inconsistent findings in the alcohol–coronary disease relationship may involve the poor (self-report) measurement


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for alcohol intake as well as misclassification of the cause of death among heavy drinkers who are known to die of sudden, unexplained causes. Moreover, there are many possible confounding factors, including blood pressure levels, cigarette smoking, and diet. Preventive practice with respect to alcohol is, therefore, based on its social and public health consequences rather than on any possible direct effect, favorable or otherwise, on cardiovascular disease risk. A major concern about regular alcohol use is, however, its enhancement of overeating, underactivity, and smoking, along with its intrinsic caloric density. Given these several relationships, public health recommendations for alcohol are not yet indicated in any quantity, as a “protective measure” for heart diseases.

Salt Salting of food, primarily for preservation, began with civilization and trade. Now salting is based mainly on acquired taste and is likely a “new” phenomenon in an evolutionary sense. Moreover, the mammalian kidney probably evolved in salt-poor regions where the predominantly plant and wild game diet was likely very low in sodium and rich in potassium. Thus survival of humans and other mammals in salt-poor environments may have rested on an evolutionarily acquired and exquisite sodium-retaining mechanism of the kidney. The physiological need for salt under ordinary circumstances is approximately only 1–2 g of sodium chloride per day. It is hypothesized that this mechanism is now overwhelmed by the concentrated salt presented to modern humans in preserved meats and pickled foods, in many processed foods, and in the strong culturally acquired taste for salt.24,46 Clinical, experimental, and epidemiological links between salt intake and hypertension are increasingly well forged.46,47 Marked sodium depletion dramatically reduces blood pressure in persons with severe hypertension. Sodium restriction enables high blood pressure to be controlled with lower doses of antihypertensive drugs. In many patients, salt restriction may result in adequate control of mild to moderate hypertension without drugs.48 Weight reduction and salt restriction appear to be independently important in lowering high blood pressure.48 In summary, a culture with high salt consumption appears to encourage maximal exhibition of an inherent human susceptibility to hypertension. Because potassium tends to reduce the blood pressure–raising effects of sodium, the sodium-potassium ratio of habitual diets also may be important in the public health.49 Surveys consistently find strong relationships between average population blood pressure and salt intake.47,50,51 High blood pressure is usually prevalent in high-salting cultures, irrespective of the prevalence of obesity. In contrast, hypertension is usually absent in low-salting cultures, despite frequent obesity. Moreover, rapid acculturation to greater salt intake among South Pacific islanders who migrate to industrialized countries is associated with an increased frequency of hypertension and elevated mean blood pressure.52 Even within high-salting cultures, when special efforts are made to reduce the measurement error for blood pressure and to characterize individual sodium intake with maximum precision, significant individual salt–blood pressure correlations are usually found.52,53 Despite all this evidence, neither preventive practice nor public health policy on reduction of salting is well advanced. This may be due in part to professional skepticism, based perhaps on the relatively weak individual correlations of salt intake and blood pressure. Admittedly, modification of salt intake by traditional dietary counseling has not been very successful. However, when interventions are attempted in a supportive and systematic way, change in salting behavior is readily achievable.54 In the United States, wider education has significantly and widely influenced food processing and marketing of products with lower salt content, and a great deal of voluntary public health action has been taken by food companies. Current U.S. national dietary goals recommend no more than 4.5–6.0 g of salt daily.55 For individuals, this is achievable by not salting foods at the table, by adding no salt in cooking, and by avoidance of salt-rich foods, particularly canned, processed, and pickled foods. Despite the absence of a strong policy, preventive practice and public health approaches to reduced salt consumption are

increasing. Significant public health effects of such population changes might be expected in high-salting societies, in light of recent trends in blood pressure and stroke observed in Japanese populations.56

Blood Lipoproteins Clinical, experimental, and epidemiological evidence of the relationship between certain blood lipoproteins, atherosclerosis, and incidence of CHD is strong, consistent, and congruent. Because much knowledge is available, we present here only a summary of what we regard as the salient facts in this relationship, along with a few key references. The subject was recently reviewed in detail.22 • Associations are consistently strong between mean population levels of total serum cholesterol and measured CHD incidence.11,12 • Associations are variable between mean population levels of fasting serum triglycerides and coronary disease rates. 57–58 • Total serum cholesterol levels at birth have similar means and ranges in many cultures.59 • Average levels and distributions of total serum cholesterol differ widely for populations of school-age children.59 They tend to parallel the differences found in adult population distributions of blood lipid levels, that is, means and distributions are found to be elevated in youth when they are elevated in adult populations.59 • Means and distributions of total serum cholesterol of migrants rapidly approach those of the adopted country, whether higher or lower than the country of origin.16 • Blood lipids measured in cohorts of healthy adults followed over time show consistently positive relationships, usually with a continuously rising individual risk of CHD according to the entry levels of total serum cholesterol (and LDL), at least until late middle age.8,60,61 • Computation of the population risk attributable to blood cholesterol levels indicates that the majority of excess CHD cases occur in the central segment of the population distribution, that is, 220 to 310 mg/dL, whereas only 10 percent derive from values above 310.7,27 • In healthy cohorts, a strong inverse relationship between individual HDL cholesterol level and its ratio to total cholesterol is found with subsequent CHD risk. It is relatively stronger at older ages and within populations that have a relatively high CHD risk overall.36,58,62 • Large-scale experiments indicate the feasibility and apparent safety of blood cholesterol lowering from moderate changes made in dietary composition, with and without weight loss.10,36,63 • Clinical trials of lipid lowering alone in middle-age, high-risk populations indicates a reduction of CHD risk according to the degree and duration of exposure to the lowered cholesterol level.9,10,64–66 Further, clear evidence has emerged that a class of lipid-lowering agents, the “statins” can reduce the risk of further CHD morbidity and mortality when coronary disease is already clinically apparent.67,68 • There has probably been a significant drop, of approximately 10–15%, in the U.S. mean total serum cholesterol level in the last 20 years, which is partly explained by changes in composition of the habitual diet during this period.69,70 Consensus from these facts has resulted in a vigorous population strategy of reduction in blood lipid level in the United States. Major recommendations are now in place for a change in eating patterns among North Americans.36 Moreover, the U.S. National Cholesterol Education Program has apparently increased both public and professional awareness and has improved the medical practice of lowering blood cholesterol.22,71–75


62

Overweight and Obesity Whatever the physiological or cosmetic disadvantages of obesity and overweight, their relationship to CVD risk and mortality remains interesting, difficult to dissect, and basically unsettled. From a clinical perspective, extreme obesity is associated with manifest physical limitations and a propensity for many disabilities and illnesses. Beyond this, however, associations with cardiovascular diseases are not consistent throughout most of the distribution of relative weight or skin-fold measurements.76 Overweight and weight gain tend to raise risk factor levels, and correction of the many metabolic disorders that accompany obesity is prompt and substantial when weight loss is achieved, with or without an increase in physical activity. When weight loss is carried out primarily through increased physical activity, appetite is generally “selfregulated” and body fat is lost, lean body mass is better maintained, insulin activity is lowered, glucose tolerance is improved, LDL and very low density lipoprotein (VLDL) levels are lowered, HDL level is raised, and cardiovascular efficiency is enhanced. As we shall review here, however, the status of obesity and weight gain and loss as risk factors for CVD is complex. Obesity is arbitrarily considered to be present when the fat content of the body is greater than 25% of body mass in men and 30% in women. Overweight is equally arbitrarily chosen as greater than 130% relative weight, according to life insurance build and mortality tables, or on a body mass index (kg/m2) greater than 26. “Ideal weight” criteria are often based on standards associated with the lowest mortality risk in life insurance experience. The prevalence of overweight (and obesity) in U.S. adults is variously estimated from 20 to 50%, depending on the measurement used and the definition chosen, as well as by age, sex, and race classification. A most salient fact about overweight in the United States is that average weight and relative body weight are increasing, according to national health surveys. Obesity based on a body mass index (wt/ht2) of ≥30 kg/m2 in men (20–74 years of age) rose from 10.7% in 1960–1962 to 28.1% in 1999–2002. In women, similar changes have occurred, with the proportion obese in 1960–1962 being 15.7%, rising to 34.0% in the later survey.77 (Table 62-3) The prevalence of extreme overweight is increasing at a greater rate than is average weight.77 This trend affects all gender and major ethnic groups as shown for overweight. The causes of mass obesity in populations are only partly understood. Widespread abundance, availability, and low cost of calorie-dense foods, along with many environmental cues to appetite, encourage overeating in relation to physiologic need. These environmental “facilitators” act on an apparently widespread genetic susceptibility to obesity. This, in turn, may be an evolutionary legacy from hunter-gatherer lifestyles. Moreover, there are other factors that enhance excess calorie intake relative to need. For example, dietary fat is more efficiently stored as adipose tissue than is carbohydrate under conditions of excess calorie intake.36 Refined sugars have less satiety value than the complex carbohydrates of fruits and vegetables. And alcohol is cheap and available in many societies.

TABLE 62-3. AGE-ADJUSTED PREVALENCE OF OBESITY IN AMERCIANS AGES 20–74 BY SEX AND SURVEY Year

Men

Women

1960–62 1971–74 1976–80 1988–94 1999–2002

10.7 12.2 12.8 20.6 28.1

15.7 16.8 17.1 26.0 34.0

NHES 1960–62; NHANES: 1971–74, 1976–80, 1988–94, and 1999–2002. Note: Obesity is defined as BMI of 30.0 or higher. Source: CDC/NCHS. Health, United States, 2004.

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One major cause of mass obesity in Western populations appears to be the increase of relative sedentariness. Americans are, on average, heavier now than they were earlier in this century when, in fact, they consumed significantly more calories per day.36 The stable, rural, laboring populations that consume (and expend) more energy are, in turn, the leaner populations.11 Unfortunately, however, sedentariness in populations is largely confounded with calorie density and other differences in eating patterns. Comparisons among and within populations in the Seven Countries Study illustrate the complexity of the relationship of overweight and obesity to CHD and to death from all causes.11,12 Among populations, CHD incidence is not correlated with any measure of obesity or overweight. The population distributions of skin-fold obesity are, however, strikingly different. They almost fail to overlap, for example, between the highest skin-fold values found among Serbian farmers and the lowest values among sedentary U.S. rail clerks.11 Obesity is, therefore, a mass phenomenon and is apparently strongly determined by (a) the average energy expenditure of the population and (b) the composition (caloric density) of the diet. Within populations the picture is highly variable. In East Finns, with high CHD rates, incident CHD cases are evenly distributed across the entry distribution of skin-fold fatness and overweight. In another population with a high CHD incidence—U.S. railroad workers—the relationship between skin-fold obesity and CHD death is weakly positive, in contrast to an insignificant and opposite relationship for relative body weight. In another population with a high CHD incidence, consisting of rural Dutch men, there is a strongly positive linear relationship between CHD incidence and overweight and obesity throughout the wide range of values found there. Among men from the southern Mediterranean regions of Italy, Greece, and Yugoslavia, there is a U-shaped relationship between overweight or obesity and CHD risk, as well as with deaths from all causes. There the thinnest individuals as well as the heaviest and fattest have the higher disease rates; lowest disease risk is found for those with intermediate weight values.11,12 Multivariate analysis in the Seven Countries Study, used to adjust for the many confounding variables related alike to body mass and to CHD, shows no consistent relationship of 10-year CHD incidence with either relative weight or fatness.12 In most of these populations there is a tendency for CHD incidence to be slightly higher in the upper than in the lower half of the fatness distributions, but this tendency disappears when other variables are simultaneously considered. Similarly, except for men at the extremes of the distribution, within generally high-incidence and overweight U.S. populations, there is little relationship between obesity or overweight and risk of CHD or death in men. Within populations, several other longitudinal studies, including the Framingham Heart Study,78 the Evans County Study,79 and the Manitoba Study,80 suggest that an independent contribution of relative weight to risk in a society with high CHD incidence may be reflected only in very long-term CHD risk. In Framingham, in addition, weight gain since youth is a risk predictor for CHD.78 Finally, in the Evans County Study, initial overweight and weight gain over time are also strongly related to the seven-year incidence of new hypertension.79 The ability to distinguish CVD risk according to the body distribution of obesity, usually measured as the ratio of waist to hip circumference (WHR), is relatively recent.81 WHR is positively related to risk of CHD, premature death, non-insulin–dependent diabetes mellitus, and cancers in women, as well as to established CVD risk factor levels. The finding that several diseases correlate better with fat distribution than with general measures of overweight or obesity has raised major new hypotheses about possible separate metabolic entities and about the pathogenesis, risk, and treatment of obesity.82,83 Results of autopsy studies are inconclusive. The International Atherosclerosis Project concluded that the degree and severity of atherosclerosis were not consistently associated with overweight and obesity.84 Finally, a major gap exists in our knowledge of the effect of weight reduction on disease risk in a relatively overweight society


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at high risk from combined CHD risk factors. This hugely confounded question, as well as the effects of weight cycling, remains to be clarified.85 In summary, obesity and overweight are centrally involved with the many metabolic maladaptations related to diabetes mellitus, hypertension, blood lipids, and probably atherogenesis. It is central to the metabolic syndrome.22 These maladaptations are particularly amenable to correction by weight loss, with or without increased physical activity. The epidemiological evidence indicates, however, that relative body weight and obesity have a different disease-related significance in different populations and cultures. This may be due in part to different composition of the diets by which individuals and populations become obese, as well as to coexisting elevated distributions of other CVD risk characteristics. In most societies with high CHD incidence in which the issue has been systematically studied, the independent relationship between overweight, obesity, and CHD risk is seen mainly at the extremes of relative weight and over the longer term. Inconsistent disease associations and the obvious and dramatic declines in CVD deaths in the United States over the last 40 years, despite the clearly increased average U.S. body mass, indicate the primary importance for population CVD risk of factors other than overweight and obesity.

Physical Inactivity Two primal human activities are the obtaining and consuming of food. Only since the advent of agriculture, and more recently of urbanization and industrialization, has the sustained subsistence activity of humans changed dramatically. In affluent industrial societies with automated occupations, motorized transport, and sedentary leisure, reduced energy expenditure is one of the more profound changes in human behavior. Aside from its likely importance as a fundamental departure from evolutionary adaptations and its apparently determining effect on mass obesity, the evidence specifically linking physical activity to chronic and CVD disease risk is difficult to obtain and interpret. A definitive, long-term controlled experiment on habitual activity with respect to CVD risk is not considered feasible.86 Here is a brief synthesis of the evidence relating habitual activity to CHD risk. The caliber of the coronary arteries at autopsy is larger in very active people, but limitations of design, method, feasibility, and cost have prevented a satisfactory study of the effect of exercise training on changes in coronary angiograms or functional measures of ischemia. Clinical trials of cardiac rehabilitation after myocardial infarction, including the effects of exercise training, are difficult. Nevertheless, Oldridge and colleagues87 carried out a meta-analysis on the “better-designed” studies, noting first that many of the trials demonstrated an effect of exercise on levels of risk factors and exercise tolerance. They used rigorous criteria for inclusion of 10 trials in their statistical summary, which estimated a 24% reduction in deaths from all causes in patients undergoing cardiac rehabilitation and a 25% reduction in CVD mortality. Both estimates were statistically significant and clinically important. The incidence of nonfatal myocardial infarction, however, was 15% higher (not statistically significant) in all the treatment groups combined and 32% higher (P = 0.058) in the groups in which cardiac rehabilitation was begun early (i.e., within eight weeks after infarction). Thus, cardiac rehabilitation with exercise apparently had no overall effect on risk of nonfatal infarction and, when initiated early, may even have increased the incidence of nonfatal infarction. In addition to fatal and morbid outcomes, there is a growing consensus on the benefits of physical activity among patients with clinically significant cardiovascular diseases including myocardial infarction, angina pectoris, peripheral vascular disease, and congestive heart failure. Symptom reduction, improved exercise tolerance and functional capacity, and improvement in psychological wellbeing and quality of life are among the benefits.88 Exercise also improves lipids and blood pressure and helps control obesity.89 The major source of information about the role of physical activity in the primary prevention of CHD is indirect, from observational

studies. These usually involve attempts to identify the confounding effects of lifestyle characteristics other than physical activity.89 A review by Powell and colleagues90 concluded that the majority of observational studies meeting their criteria found a significant and graded relationship between physical inactivity and the risk of first CHD event and that studies with a stronger design were more likely to show an effect. These authors calculated a median risk ratio of 1.9, that is, a 90% excess risk of CHD among physically inactive persons. We analyzed the subset of 16 studies from the review of Powell et al that measured individual levels of physical activity, and we added recent studies from the Multiple Risk Factor Intervention Trial (MRFIT) and U.S. railroad workers.89,91,92 All 18 studies showed that habitual physical activity was inversely related to death from CHD or death from all causes. The more recent studies adjusted for confounding risks and this adjustment usually diminished, but did not abolish, the risk associated with physical inactivity. Several studies found that the relation was largely explained by the level of physical fitness, in that the gradient of risk with the level of physical activity largely disappeared when measures of fitness were controlled. In a cohort study, fitness measured by a maximal exercise treadmill test predicted all-cause mortality for men and women, independently of other risk characteristics.93 The duration, frequency, and intensity of physical activity that may be protective against CHD remain, nevertheless, at issue. Recent studies suggest that an energy expenditure of 150–300 kcal daily, in activity of moderate intensity such as walking and working around the house, is associated with lower risk, as is a moderate amount of vigorous physical activity.89,91,92,94 Anthropologic observations suggest that healthy farmers and herdsmen rarely work at a pace that leads to shortness of breath or exhaustion. Systematic observations in the Seven Countries Study indicate that even a substantial amount of regular, vigorous physical activity does not necessarily protect an individual or a population from CVD risk, particularly if other risk factors such as mass hypercholesterolemia are prevalent. In that study, farmers and loggers in eastern Finland were found to be the most physically active of men, and yet they had the highest rates of CHD; there was little less risk among the more physically active within that population.11,12 The interpretation of these many observations is that habitual, current physical activity very likely protects against coronary death.89 A basic uncertainty that remains is whether the apparent benefit is due to physical activity itself or to its effect on other risk factors. People tend to exercise if they are able to and if they feel good when they exercise. Fitness, a component strongly determined by constitution, may be a major contributor to an apparently protective effect of physical activity. It is possible that fitness determines both who will be active and who will be protected from CHD. At least two other pieces of evidence suggest that constitution is not the major operant. Any protective effect of having once been a college athlete, and thus presumably genetically superior, disappears with time after graduation, whereas current physical activity is associated with lower risk.95 Moreover, it seems that genetic factors are likely to be less important to participation in moderate exercise than to participation in vigorous exercise, but both carry a lower risk of CHD. Finally, safety should be the foremost consideration both in prescribing exercise for individuals and in making recommendations for the public health. Several studies have found an excess risk of primary cardiac arrest during and shortly after strenuous exercise in all subjects, regardless of their level of habitual physical inactivity, despite a much lower overall risk of sudden coronary death in habitually active subjects.96,97 They concluded that the reduced risk of sudden death due to regular physical activity was greater than the excess risk of sudden death during vigorous activity. This view, important for the public health, would be small comfort, however, to the families of those stricken while running. The evidence suggests that brisk walking or other moderately vigorous activity is the more reasonable exercise prescription, at least for sedentary and middle-aged people who have not maintained their fitness from youth.89


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Diabetes and Hyperglycemia

Elevated Blood Pressure: Hypertension

Since the insulin era began, enabling persons with diabetes to survive, a strong relationship between diabetes and atherosclerosis risk has emerged. Most who die with diabetes succumb to advanced atherosclerosis. In addition, there are important mechanistic interrelations between insulin-glucose regulation, lipoprotein and uric acid metabolism, obesity and hypertension, on the one hand, and atherosclerosis on the other. Unfortunately, the prevalence of diabetes in the U.S. population is rising associated with increasing obesity.98 The longterm effects of this trend are unknown. The association of clinical diabetes mellitus with CHD and atherosclerotic manifestations is documented clinically, pathologically, and epidemiologically.99,100 It is thought that hyperinsulinemia, hypoglycemic episodes, or both in treated diabetics, coupled (formerly) with the common prescription of a high-fat, low-carbohydrate lowfiber diet, increases vascular complications. Cross-cultural comparisons suggest that the risk of atherosclerosis and CVD in diabetic patients is indeed related to factors other than the glucose-insulin disorder itself. For example, apparently low rates of atherosclerosis exist in diabetic eastern Jews, Chinese, and Southwest American Indians.99,100 The Pima Indians of Arizona are thought to be an example of the theoretical “thrifty genotype,” that is, a population only recently (in evolutionary terms) exposed to calorie abundance, that frequently (50% of adults) develops an obese, diabetic phenotype but nevertheless manifests little CVD.101 In longitudinal studies among cohorts, clinical diabetes mellitus is associated with excess CHD risk and severity of CHD, and many studies confirm the excess of fatal myocardial infarction in women with diabetes.102 The excess risk among diabetics is not always differentiated by the degree of hyperglycemia or the degree of control. Much of the excess CHD risk in diabetics is, in fact, accounted for by associated risk variables.99,100 More severe atherosclerosis, diabetic cardiomyopathy, and a hypercoagulable state are also thought to contribute to the excess risk of diabetes.100 Finally, in most autopsy studies, coronary artery disease and the frequency and severity of myocardial infarction are greater in diabetics than in control subjects.99,100 Diabetic treatment by the control of blood glucose levels is the mainstay of therapy. However, the role of glucose control in the reduction of cardiovascular and other complications has been controversial. The University Group Diabetes Program (UGDP) reported an increased rate of myocardial infarction with the use of first-generation sulfonyl ureas despite effective blood glucose control.103 These effects are not seen with later agents.104 The Diabetes Control and Complications Trial (DCCT) studied “tight” glucose control in insulin-dependent diabetics. Findings included significant reduction in retinopathy, microalbuminuria, and clinical neuropathy. Elevated LDL cholesterol levels were also reduced with tight control.105 Cardiovascular and peripheral vascular disease was also reduced, but did not reach significance.106 Recently, a meta-analysis of clinical trials of the hypoglycemic drug rosiglitazone found increases in myocardial infarction and cardiovascular death.108 The implications of these observations are still unclear. In healthy persons glucose intolerance alone is weakly and inconsistently associated with CVD risk.100,107 However, high insulin activity was found to be a significant independent predictor of coronary events in cohorts studied in Australia, France, and Finland,100 and it has also been proposed as a cause of excess atherosclerosis in Asian migrants.108 In summary, the relationship between diabetes, atherosclerosis, and coronary disease is well established among persons with clinical diabetes living under the conditions of affluent Western culture. Data from other cultures suggest, however, that other factors, such as physical activity, body weight, blood pressure, blood lipid levels, dietary composition, and smoking habits, greatly affect the risk of CHD among diabetics. This, plus evidence that the metabolic disorders of middle-age persons with diabetes can be significantly improved through exercise and modified by diet and weight loss, provide a sound rationale for preventive practice. More study of these complex issues is needed to develop an effective preventive approach to noninsulin-dependent diabetes mellitus itself.

The epidemiology, control, and prevention of hypertension and its complications are summarized here. It is estimated that hypertension contributes to more than onehalf of adult deaths in the United States. It is a strong and independent risk factor for CHD and stroke, and there are plausible mechanisms for its effects on atherosclerosis and vascular disease. Patients with CHD have higher average blood pressure than control subjects. Experimental atherosclerosis induced in animals is directly related to pressure levels within the arterial system. In cohort studies, elevated blood pressure is positively, continuously, and independently related to CHD risk, according to increasing levels of systolic or diastolic blood pressures. The relationship of elevated blood pressure to risk of cerebrovascular hemorrhage and congestive heart failure is even stronger than the relationship to risk of CHD and thrombotic stroke. The preventive potential for hypertension control is illustrated by drug trials that have demonstrated a significant decrease in rate of stroke and heart failure. The Systolic Hypertension in the Elderly Project (SHEP) demonstrated the importance of systolic blood pressure control in this group.109 Results of other trials suggest that CHD risk is lowered by control of hypertension, but most have had insufficient power to study this question.110 The recent ALLHAT study treated hypertension with diuretics and more recent antihypertensive drugs with CHD as an endpoint. There was no placebo group. They found thiazide-type diuretics to be superior to more modern agents for combined CVD, stroke and heart failure.111 Blood pressure control has greatly improved in the United States in the last 20–25 years, according to surveys showing a substantial decrease in the proportion of hypertensive persons unidentified or not under control.55,112,113 These trends have occurred in parallel with downward trends for both CHD and stroke mortality, although a direct relationship cannot be established. In fact, the mortality rate from stroke was diminishing long before safe and effective antihypertensive therapy was widely used. Moreover, stroke death rates in the United States fell during the 1950s and 1960s, when CHD death rates were rising sharply.2 Estimated changes in death rates for CHD and stroke, based on models of hypertension control, suggest a large potential for the prevention of CVD. Primary prevention of hypertension would likely have even more impressive effects on the public health. Present challenges to preventive practice lie mainly in more effective control of elevated blood pressure in the elderly and in finding the ideal combination of drug and hygienic management for correction of mild or borderline levels of high blood pressure. The larger public health challenge lies in improvement of population wide correlates of hypertension, such as physical inactivity, overweight, and high salt and alcohol intake. Such primary preventive and public health approaches promise to minimize the exhibition of high blood pressure, since human populations are apparently widely susceptible.

Tobacco Smoking The broader relationship of tobacco to disease and health is detailed in Chap. 54. Much of the clinical evidence of a direct relationship between cigarette smoking and coronary disease was, until recently, anecdotal. Experimentally, ischemic pain, angiographic coronary spasm, and electrocardiographic findings are now demonstrated during smoking in patients with compromised coronary circulation.114 For individuals living within societies with a high CHD incidence, smoking is consistently found to be a strong and independent risk factor for myocardial infarction and sudden death.93–95 The risk is continuous from persons who have never smoked, to ex-smokers, to those who smoke even in small amounts and is also related to duration of the habit.115,116 Interactions with other risk factors are also important, as indicated by the weak association of smoking with CHD risk in low-risk societies.11,12 For example, the observed incidence of CHD in populations that do not have a base of relative mass hypercholesterolemia is much lower than the risk predicted with multiple


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regression equations derived from U.S. or northern Europe data.115 The Japanese, for example, with a heavy prevalence of smoking and substantial amounts of hypertension, but without hypercholesterolemia, show much less coronary heart disease than would be predicted.11,12 As is the case with serum cholesterol level, most of the CHD cases attributable to smoking derive from the central part of the distribution, that is, light and moderate smokers; the prevalence of heavy smokers is low. A 17% population-attributable risk fraction for smoking and CHD deaths in the United States was estimated (conservatively) in the Carter Report.117 Smoking is particularly significant in CHD risk among women.118 Smoking cessation is associated with lower CHD rates according to years of cessation.119 While those who have never smoked have the best disease experience, long-term quitters approximate their rates, and even temporary quitters have a better risk experience than persistent smokers.120 Improvement in the prognosis of survivors of myocardial infarction who quit smoking also tend to confirm the harmful cardiovascular effects of cigarettes and supports the potential for CHD prevention by reduction of tobacco use.116,121 Synthesis of this evidence, therefore, suggests that cigarette smoking is neither a primary nor a necessary factor in determining population rates of CHD. It is, rather, a strong and independent risk factor for CHD and vascular disease among individuals living in high-incidence populations where there is a significant background of coronary and peripheral atherosclerosis. Mechanisms presumed to be important in CHD include the physicochemical effects of tobacco, that is, increased heart rate and myocardial contractility and greater myocardial oxygen demand due to raised catecholamine levels, decreased oxygen-carrying capacity of the blood, elevated fibrinogen levels, and platelet-aggregating effects. Other possible mechanisms include elevated fasting blood glucose levels and white blood cell counts and lower HDL levels, all found among smokers.114 A public health policy to foster so-called safer cigarettes, at least with respect to lowering CVD risk, is not supported by the evidence of persistent high exposure to gas-phase toxins in “low-yield” cigarette users.114 Moreover, the promotion and adoption of Western-type cigarettes and smoking patterns in developing countries augurs ill for the future CVD risk in those populations. In contrast, smoking prevalence has decreased substantially in the United States, where large numbers of educated adults in particular have stopped smoking. This is attributed to increased community awareness of the health need to stop smoking, to social pressure and legislation for “clean air” and “smoke-free” environments, and to a greater access to the support and skills needed for quitting. The downward U.S. trend in smoking is not as evident, however, among lower socioeconomic groups and heavy smokers.122 Under “ideal” supportive circumstances, such as that given highrisk participants in the MRFIT, smoking cessation success rates approximate 40% in the first year, with maintenance of this rate for up to four years among volunteer participants. Thus a long-standing medical pessimism about helping patients stop smoking might be replaced by optimism for cessation programs that are systematically applied. Moreover, communitywide educational and legislative efforts are increasingly effective.123,124 The results of all these efforts and the population trends downward in smoking frequency provide a rational basis for more public programs and for a more focused national policy to reduce cigarette smoking and tobacco production. It is equally possible that the currently declining rate of cigarette smoking will level off, unless educational programs and wider social support for nonsmoking behavior reach the lower socioeconomic classes, heavy smokers, women, and youth.

diabetes and insulin levels to atherosclerosis and to thrombosis. The interaction between chronic arterial wall disease and the blood properties leading to coagulation continues to be a major subject for research as it becomes clear that a critical fixed obstructive lesion is not necessary for myocardial infarction. In fact, thrombi forming on so-called “soft plaques” which rupture account for a significant proportion.125 The components of the coagulation system found so far to be of major interest are platelets and fibrin and they aggregate when cell walls are damaged and develop fibrin platelet masses, and platelet aggregation.126,127 Of the several hemostatic variables measured with respect to subsequent CHD risk, fibrinogen has received the most attention. Several investigators conclude that an elevated fibrinogen level is likely to be causally associated with CHD but that its elevation overall may be due primarily to smoking.126 As for primary prevention of CHD events with low-level anticoagulation, such as with small doses of aspirin, this appears now to be established for nonfatal myocardial infarction in men.128

Physical Environment It is increasingly apparent that modern industrialized society developed an environment which is not conducive to good health.129 Communities are built without parks, playgrounds, libraries, nearby stores, sidewalks, or public transit. The result is dependence on personal automobiles and social isolation. These environments may actually promote chronic diseases such as CHD. There is increasing understanding of the effects of these practices and attempts to promote healthier community designs. The weather, particularly the influx of cold fronts and rapid falls in barometric pressure, has been correlated with new hospital admissions for coronary events and sudden death.130 Reasonable preventive practice includes advice to avoid exposure, in particular the combination of isometric work and cold, and to use light face masks to maintain a favorable personal air temperature and humidity. Similarly, atmospheric inversions and air pollution are related to hospitalization and death rates from pulmonary and cardiovascular diseases, particularly in the elderly. These observations are increasingly linked to specific environmental pollution agents including nitrogen, sulfur dioxide, ozone, lead, and particulate matter.131 Most recently fire particles (PM2.5) < 2.5 µm have received attention. The result of combustion, they easily reach the alveoli. Experimental data suggests they may play a role in the etiology and onset of cardiovascular diseases.

Social Support Several prospective population-based studies have established social support or “social connectedness” as a factor associated with reduced risk of death. Two large studies—one from Finland132 and one from Sweden133—examined CVD disease risk. The pattern of results suggests a relationship between social support and mortality, at least in men. Whether this is a causal relationship or is attributable to a confounding variable such as baseline health or to personality characteristics such as hostility is unclear, and this line of investigation might well be continued. Attempts have been made to change psychosocial characteristics experimentally and to measure CHD risk factors and disease changes. Recently, the enhancing recovery in coronary heart disease patients (ENRICH) trial tested cognitive behavioral therapy and antidepression medications post myocardial infarction to increase social support and decrease depression. The trial showed no difference in the endpoint of recurrent myocardial infarction and death.134

Hemostatic Factors For decades, arguments have existed about the relative predominance of the role of classical risk factors versus thrombosis in the pathogenesis of atherosclerosis and CHD. A more unified theory now joins the effects of diet and blood lipids, physical activity and smoking, and

Gender and Estrogens The excess risk of CHD and atherosclerosis in men at earlier ages is documented throughout affluent Western society. The sex differential is much less prominent, however, in nonwhite populations and in


62 areas where the overall incidence is relatively low.135 The particular susceptibility of men is only partly explained by their higher risk factor configurations between the ages of 25 and 60. On the other hand, the relative protection from CHD among premenopausal women is assumed to be related to hormones, although the effect of early oophorectomy, menopause, or estrogen replacement therapy on known risk factor distributions in women fails to completely explain these differences. In countries with a high incidence of CHD, where there is relative mass hyperlipidemia much more of the plasma cholesterol is carried in the HDL fraction in women. Recent experimental evidence concerning mechanisms of LDL and HDL function, related to cell receptors and lipid transport in and out of the arterial wall, confirm this particular biological difference as a likely cause for some of the sex difference in CHD risk. In contrast, women have a proportionately greater risk of angina pectoris than of myocardial infarction or sudden death. While they have less severe atherosclerosis in the coronary arteries, the sex difference is not as apparent in cerebral, aortic, and peripheral vessels. Survival of women after myocardial infarction is poorer in-hospital, although this is balanced by greater outof-hospital death for men. Finally, trends in CHD deaths in the United States indicate that the age-specific decline in mortality is proportionately greater in women than in men.2 Similarly, the rise in CHD death rates among women in eastern Europe, where CVD deaths overall are increasing rapidly, is proportionately greater in women and in young women.136 The excess risk of thromboembolism, stroke, and myocardial infarction in women taking oral contraceptives (OCs), and the interaction of OCs with age and smoking, are well established. Young women taking OCs have systematically higher serum lipid levels, higher blood pressure, and impaired glucose tolerance compared with control subjects.137 Numerous epidemiologic studies evaluated the use of postmenopausal estrogen in the primary prevention of cardiovascular disease.138 Meta-analysis suggested a relative risk of 0.50–0.65 for coronary artery disease in estrogen users.139 These data exemplify the danger of extrapolating observational studies to therapeutic lesions. When randomized studies of hormone replacement therapy were performed the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI) trial, no benefit and potential harm was observed.140,141 In summary, the sex differential for atherosclerosis and cardiovascular disease events and their time trends is not completely explained on the basis of known effects of hormones on the level of risk factors. More study of gender difference is needed.

Genetic Factors Much current work is opening up the understanding of hostenvironmental relationships. The relative contribution of genes to disease risk of populations can be exaggerated, however, by studies of gene effects when limited to homogeneous, high-risk cultures where exposure is great and universal. Most of the lack of understanding, and much of the difficulty in identification of susceptible persons, lies in the unavailability of specific genetic markers for CVD and the incapacity of family studies to discriminate intrinsic components without such markers. Recent findings of the gene loci for apolipoprotein regulation hold great promise of an improved understanding of individual differences in blood lipoproteins and their response to diet. There is, for example, evidence of the genetic inheritance of LDL subclasses HDL, apo-B and apo-E.142 A substantial proportion of the variation in apo-B levels (43%) may be explained by a major locus.143 A major gene controlling LDL subclasses may account for much of the familial aggregation of blood lipids and CHD risk.144 Most intrinsic blood lipoprotein regulation, however, is clearly polygenic and strongly interactive with the environment, especially with composition of the habitual diet. Controlled experiments in metabolically normal people suggest that there is a normal distribution of individual blood lipid responses to a known dietary change.145

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The rare major gene effects that cause extreme manifestations of the hyperlipidemias are increasingly well characterized, but they account for only a small fraction of the mass phenomenon of hypercholesterolemia found in affluent cultures. Thus most atherosclerotic complications and most of the excess CHD events in the general population cannot be attributed to major gene effects. Nevertheless, gene-culture interactions remain important to preventive practice for better detection and individualized therapy of patients who have elevated blood lipid values. A potentially important aspect of genetically determined diet responses now under investigation is the response of individual lipoprotein fractions to specific dietary factors, mainly fatty acids and cholesterol. A wider issue, however, is the relative magnitude of the contribution of intrinsic regulation to the large population differences found for average blood lipid values and their distributions. For the time being, this contribution remains speculative. Genetic control of CVD risk factors other than blood lipids is even less well-known.146 For example, not yet identified are genetic traits that might affect individual sensitivity to salt intake, to the atherogenic effect of cigarette smoking, or to the regulation of blood insulin and glucose levels, arterial wall enzymes, or personality type. There has been growing research on the genetics of hypertension. Markers have been discovered in a disease which is most likely polygenic for the proportion heritable.147 The public health view that a favorable environment assures minimal expression of phenotypic risk provides the rationale for a population approach to prevention. This rationale has not been effectively challenged, but neither has it been universally accepted.

Combined Risk Factors Clinical, laboratory, and epidemiological studies of CVD risk factors have been oriented mainly toward determining individual causal roles for each factor. Cardiovascular diseases are clearly related, however, in both individuals and communities, to multiple factors operating together over time. Multiple-factor risk is firmly established and actually is quantified for both CHD and stroke. Based mainly on Framingham and Pooling Project analysis, a consistent, independent, and at least additive contribution is found for each of the major risk factors: cigarette smoking, arterial blood pressure, and total serum cholesterol level.60 The risk ratio between highest and lowest categories for combined risk within populations is approximately eight- to tenfold, in contrast to the risk ratio for single risk factors, which is approximately two- to fourfold. Prediction regressions derived from follow-up experience in European men, with the use of four major risk factors at baseline, when applied to men in the United States, show the multiple-risk concept to be “universal.” That is, the regressions define a continuum of CHD risk among individual U.S. men in a society that has quite different CHD rates overall.148 The slope of the relationship (regression) between the combined risk factors and disease, however, is much steeper in the United States than in the European population. At any given level of multiple risk, U.S. rates are twice those in Europe. This cultural difference in the “force” of risk factors indicates that a sizable influence on population differences in CHD risk remains unknown, although lifelong exposure to CHD risk is not captured in a single measure. Another indication of the combined force of risk factors comes from studies of low risk groups within industrialized populations. Those with low lipids, normal blood pressure, nonsmokers, nonobese, and without diabetes have very low CHD and stroke rates.149,150,151 Nevertheless, since these few risk factors operate universally and explain a substantial part of individual and population risk differences, public health action on that part of the difference now explained is both promising and indicated. Still another interpretation of the evidence of combined risk of CHD is that the synergism between risk characteristics leads to a major potential for preventive effects in the population by achieving relatively small shifts in the means and distributions of the multiple risk factors. This does not exclude the possibility of a population threshold for risk factors, below which population risk is remote. That


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is indicated by the relative scarcity of mass atherosclerosis and CHD in societies in which average serum total cholesterol levels are less than 200 mg/dL. Nor does it exclude the concept of necessary versus contributory causes. In the absence of the presumed necessary factor (i.e., mass hypercholesterolemia), population risk is negligible. It may be that the departures from perfect prediction, found with the use of multiple regression analysis, are due in part to their failure to include the duration of exposure to, or the directionality of, a particular risk level.  RHEUMATIC HEART DISEASE

Rheumatic fever and rheumatic heart disease remain important public health problems in the world.152 It is a particular problem where poverty, overcrowding, malnutrition, and inadequate medical care are found.153–158 Even in industrialized societies, a relatively high prevalence of rheumatic fever persists in pockets of poverty, and outbreaks have been reported recently in affluent areas.159–164 Despite that rheumatic fever is demonstrably preventable and rheumatic heart disease has declined dramatically in most industrialized nations, this condition remains a major public health problem internationally. For more than 40 years it has been known that group A streptococcus infection underlies initial and recurrent attacks of rheumatic fever (see Chap. 9). The immunologic mechanisms and circumstances by which infection with this organism produces rheumatic fever and rheumatic heart disease and acute and chronic glomerulonephritis are well understood.165 In some surveys, as many as 3% of patients develop rheumatic fever after known streptococcal infections.166 As many as 50% of those who have once had rheumatic fever will, if untreated, experience attacks after a subsequent streptococcal infection. This suggests that host factors significantly determine susceptibility. Age is also an obvious factor, for example, infants do not develop rheumatic fever even though they are susceptible to streptococcal infection and glomerulonephritis. Such differences in susceptibility are clearly developmental, such as the variation with age, but others may have a genetic basis. The tendency of rheumatic fever to cluster in families, however, may be explained by shared environment as well as genes. During the 1960s, the incidence of acute rheumatic fever per 100,000 urban children 2–14 years of age in the United States ranged from 23 to 28 for whites and 27 to 55 for blacks. The incidence was still higher in Puerto Ricans. Currently it is closer to 2 per 100,000 with most cases among the underprivileged. In other parts of the world, the lowest rates of rheumatic fever have been observed in Scandinavia, with 1.3 cases per 100,000. In underdeveloped nations, the rates are much higher. Prevalence among school-age children in South America ranges from 1 to 10%.167 Mortality from rheumatic fever and rheumatic heart disease has fallen significantly in the United States in this century. It was 14.8 per 100,000 in 1950, 7.3 in 1970, and 2.7 in 1986, a decline of 82%. The diagnosis of acute rheumatic fever is made principally from clinical findings with the revised Jones criteria (see Chap. 9).168 These may be insufficiently sensitive, however, to detect mild cases, particularly in Western countries where clinical patterns have changed so that arthritis is often the only presenting manifestation; chorea, subcutaneous nodules, and erythema marginatum are now rarely seen. Diagnosis may be complicated by the lack of a preceding sore throat or an apparent infection.169 Current recommendations for the primary prevention of acute rheumatic fever and rheumatic heart disease and prophylaxis for bacterial endocarditis in those with known rheumatic valve disease are found on the American Heart Association website: www.heart.org.  CONGENITAL HEART DISEASE

Malformations of the cardiovascular system are among the more frequently occurring congenital defects. They result from developmental errors caused by inherent defects in the genetic material of the embryo, environmental factors, or both.170–175

Family studies suggest that the offspring of parents with congenital heart disease have malformation rates ranging from 1.4 to 16.1%.176 Identical twins are both affected 25–30% of the time. While these and other findings of familial aggregation suggest genetic factors, common environment may also play a role.175 Chromosomal aberrations or mutations account for less than 10% of all congenital cardiovascular anomalies. In addition, noncardiac disorders also produce cardiovascular defects; these include Marfan’s syndrome, Friedreich’s ataxia, glycogen storage disease, and Down’s and Turner’s syndromes. Maternal viral infections during pregnancy are estimated to cause up to 10% of all congenital cardiac malformations. Rubella in the first 2 months of pregnancy is associated with congenital malformations in about 80% of live births and is thought to account for 2–4% of all congenital heart disease. Subclinical Coxsackievirus infections may be related to congenital heart disease. Acute hypoxia, residence at high altitudes, high carboxyhemoglobin levels, and uterine vascular changes from cigarette smoking are other potential causes.174 Maternal x-ray exposure results in an increased incidence of Down’s syndrome and possibly other congenital defects.173 Maternal metabolic defects, such as diabetes mellitus and phenylketonuria, are associated with increased incidence of congenital heart defects. Animal investigations, which have not been substantiated in humans, indicate that dietary deficiencies in the mother may result in congenital malformations. Obstetric problems are associated with congenital heart disease, including association of advanced maternal age with Down’s syndrome and a history of vaginal bleeding (threatened abortion) during the first 11 weeks of gestation with prematurity. The teratogenic potential of drugs, such as thalidomide and folic acid antagonists, is well documented. In addition, dextroamphetamines, anticonvulsants, lithium chloride, alcohol, and progesterone/estrogen are highly suspected teratogens acting in the first trimester of pregnancy, as are certain pesticides and herbicides (see Chap. 33).177 Data on the true incidence of congenital heart disease are limited. The chief sources of information are birth certificate and hospital birth data.171,172 Birth certificate data usually underestimate the true rate as the defect may not be discovered until later. It is estimated that there are 32,000 live- births with congenital heart disease in the U.S. and 1.5 million worldwide annually.178,179 A U.S. multicenter collaborative study in 1970 yielded the following incidence rates for congenital heart disease: 8.1 per 1000 total births, 7.6 per 1000 live births, and 16.5 per 1000 twin births.180 Most are correctable by modern medical and surgical methods, including cardiac transplantation; it is estimated that only one child per 1000 cannot be helped by such approaches.181 As a result, infant mortality from congenital cardiovascular disease has fallen steadily (Fig. 62-6). As with other conditions, mortality among black youth has fallen less than for whites. The correction of congenital defects by surgical and other interventions is an important factor in increasing survival. Patients who have been repaired live into adulthood presenting new challenges in their care.178,182 Although the overall incidence of congenital heart disease has apparently remained stable, the distribution of types of defects may be shifting. This includes unexplained increases in ventricular septal defects and patent ductus arteriosus. A decline in the number of infants born with rubella-caused defects may be explained by vaccination programs.180 Primary prevention of congenital heart disease includes the following established measures:171 1. Genetic counseling of potential parents and families with congenital heart disease 2. Rubella immunization programs a. Identification of susceptible women of childbearing age by serologic examination b. Immunization of susceptible women c. Avoidance of pregnancy for 2 months after rubella vaccination 3. Avoidance of exposure to viral diseases during pregnancy


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Figure 62-6. Infant mortality from congenital malformations of the circulatory system by race, U.S., 1970–2001. (Source: National Heart, Lung, and Blood Institute. Morbidity and Mortality Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD, 2004; NIH Publication.)

4. Administration of all usual vaccines to all children to eliminate reservoirs of infection 5. Avoidance of radiation during pregnancy 6. Avoidance of exposure to gas fumes, air pollution, cigarettes, alcohol, pesticides, herbicides, and high altitude during the first trimester of pregnancy 7. Avoidance of drugs of any kind during the first trimester of pregnancy, especially drugs of known or suspected teratogenic potential.  CARDIOMYOPATHIES AND MYOCARDITIS

Cardiomyopathies are a broad group of cardiac diseases that involve the heart muscle. Although less common in industrialized nations, they account for 30% or more of heart disease deaths in some developing countries.183 They are of diverse etiology and are usually classified by the functional results of their effects on the myocardium: dilated or congestive, hypertrophic and restrictive. Some recommendations suggest that the term “cardiomyopathy” be reserved for disease of unknown origin involving heart muscle.183 However, the common use of the term still associates it with specific causal syndromes when these are known. Some cardiomyopathies are diagnosed in their acute phase, where inflammation of the myocardium is common (myocarditis). While myocarditis is particularly difficult to categorize, diagnosis has been facilitated by the widespread use of endomyocardial biopsy.184 These techniques have suggested that an inflammatory reaction is more common than was previously suspected. Identified causes include infectious, metabolic, toxic, allergic, and genetic factors.185 Myocarditis and cardiomyopathy may be mild and undetected but also can be rapidly fatal with progressive heart failure. In industrialized nations, cardiomyopathies appear to be increasing in prevalence, although it is unclear whether there is an actual increase or an increase in professional awareness and improved diagnostic techniques.186 The latter include use of the echocardiogram, Doppler flow studies, and catheter-based endomyocardial biopsy. Surveillance of Olmsted County, Minnesota, found an incidence of idiopathic dilated cardiomyopathy of 6 per 100,000 person years. Overall prevalence was 35.3 per 100,000 population.187 Mortality from cardiomyopathy in the United States varies by age, race and sex (Table 62-4). Mortality is higher in blacks than whites and greater in men than women. Mortality increases with age, suggesting the pattern of a chronic condition. Alcohol abuse is an important cause of cardiomyopathy, accounting for approximately 8% of all cases in the United States.186,188

Alcohol causes myocardial damage by several mechanisms.189,190 These include (a) a direct toxic effect, (b) effects of thiamine deficiencies, and (c) effects of additives such as cobalt in alcoholic beverages. Abstinence from alcohol may halt or even reverse the cardiomyopathy.191 Another major cause of cardiomyopathy in industrialized countries is viral infection, particularly Coxsackie B virus, echovirus, influenza, and polio,192 often beginning as a viral myocarditis. Subclinical viral disease is thought to be more common than was previously suspected, with most patients recovering without sequelae. More severe forms, however, result in dilated cardiomyopathy and death due to congestive heart failure or arrhythmias. Recent research has suggested an autoimmune component and indicated that immunosuppressive therapy may be helpful in modifying the disease.193 However, early clinical trials have shown no benefit for corticosteroids.194 Hypertrophic cardiomyopathy (HCM) is another cause of death.195 Largely undetected until the advent of echocardiographic techniques, it is becoming increasingly clear that this condition can be fatal and be managed with pharmacologic therapy.195 An Italian registry for HCM found a majority of patients were male (62%) and 89% were New York Heart Association class I–II. Most were in their fourth to sixth decade of life. Cardiovascular mortality was 1% per year, mainly due to heart failure.196 The genetic origins of this condition are increasingly apparent.197 In South and Central America, trypanosomiasis (Chagas’ disease) is endemic; an estimated 20 million people are afflicted.198 Extensive chronic myocarditis with heart failure may be observed years after the initial infection with the trypanosome. An acute infectious phase, characterized by fulminant

TABLE 62-4. DEATH RATES FOR CARDIOMYOPATHY BY AGE, RACE, AND SEX, U.S., 2001 Deaths/100,000 Population Ages 35–44 45–54 55–64 65–74 75–84

Black Male White Male 13.09 23.75 43.33 67.19 127.71

3.71 7.22 14.95 35.24 83.03

Black Female

White Female

6.14 11.98 19.72 36.27 69.07

1.28 2.82 6.37 17.22 42.41

In 2001, within sex groups, cardiomyopathy mortality was higher in blacks than in whites at each age; within race groups, it was higher in males than in females.


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and fatal myocarditis, occurs mainly in children. In most cases, however, an average of 20 years passes before Chagas’ cardiomyopathy becomes clinically apparent. An autoimmune process may play some role in the disease.199 Diagnosis is made by means of serologic study or a xenodiagnostic test. Although antiparasitic agents, such as nitroimidazole derivatives, can alter the acute infestation, there is little evidence that they are effective for the cardiomyopathy.183 Schistosomiasis is a major public health problem in the Nile and Yangtze basins where the parasitic infection is endemic, involving 85% of the population in certain areas. Chronic pulmonary embolization leads to pulmonary hypertension and right heart failure, but direct involvement of the myocardium is rare. New antiparasitic agents can limit the infection, but the main preventive strategy is a public health approach to controlling the vectors. There is increasing awareness of cardiomyopathy in Africa where it is suspected to be higher than reported based on autopsy studies.200 Unfortunately, there are few data on etiology and prevalence.  SYPHILITIC HEART DISEASE

Although the prevalence and patterns of syphilis worldwide have been altered significantly in the antibiotic era, it remains an important public health problem in many nations. Recent reports indicate a rise in reported cases of primary and secondary syphilis in the United States, and surveys in developing nations indicate continued high incidence and prevalence rates.201 An increase in reported cases and a general decline in medical alertness to this condition encourage a continuing reservoir for late complications. Life-threatening tertiary syphilis is found in approximately 25–30% of untreated cases.202 Approximately 10% of those are cardiovascular syphilis, manifest predominantly as uncomplicated syphilitic aortitis, aortic aneurysm, aortic valvulitis with regurgitation, and coronary ostial stenosis.203 Although a course of antibiotic therapy is indicated when cardiovascular syphilis is diagnosed, there is little evidence that it alters the course of the cardiovascular disease. Because syphilis remains preventable, detectable, and treatable in the early stages, public health approaches should lead to eradication of the late effects of syphilis, including those in the cardiovascular system.204

 PREVENTIVE STRATEGIES

A population approach to CVD prevention has been formally outlined by the World Health Organization and articulated in the Vancouver Declaration.7,205 It embraces both the systematic practice of screening and education for high risk, where national priorities can afford such practices, and broad public health policy and programs in health promotion for communities. Strategies for preventive practice are now widely available. Community-based strategies, programs, and materials are becoming available. National programs are under way in blood pressure control, diet and blood lipids, and smoking. Finally, healthpromotion resource centers are now established for training in the design and dissemination of preventive programs. The student and the health worker are referred to these sources: the Centers for Disease Control and Prevention, Atlanta, GA (www.cdc.gov/heartdisease/prevention/htm); and the Office of Prevention, Education and Control, National Heart Lung and Blood Institute, Bethesda, MD (www.nhlbi.nih.gov/about/opec/).

 REFERENCES

1. Yusuf S, Reddy S, Ounpuu S, et al. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation. 2001;104:2746–53.

2. Higgens M, Luepker R, eds. Report of a conference on trends and determinants of coronary heart disease mortality: international comparisons. Int J Epidemiol. 1989;18(Suppl 1). 3. McGovern PG, Jacobs DR, Jr, Shahar, et al. Trends in acute coronary heart disease mortality, morbidity, and medical care from 1985 through 1997: the Minnesota Heart Survey. Circulation. 2001;104: 19–24. 4. Tunstall-Pedoe H (ed), Kuulasmaa K, Tolonen H, et al., with 64 other contributors for the WHO MONICA Project. In: TunstallPedoe H, ed. MONICA Monograph and Multimedia Sourcebook. Geneva: World Health Organization, 2003. 5. Evans A, Tolonen H, Hense HW, et al. Trends in coronary risk factors in the WHO MONICA Project. Int J Epidemiol. 2001; 30(Suppl 1):S35–S40. 6. World Health Organization. World Health Statistics 2005. Geneva; 2005. 7. World Health Organization. Prevention of Coronary Heart Disease: Report of a WHO Expert Committee. WHO Technical Report Series, No. 678. Geneva; 1982. 8. Inter-Society Commission for Heart Disease Resources. Optimal resources for primary prevention of atherosclerotic diseases. Circulation. 1984;70:153A–205A. 9. Gotto AM, Jr. Lipid management in patients at moderate risk for coronary heart disease: insights from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Am J Med. 1999;107:36S–39S. 10. The Multiple Risk Factor Intervention Trial Research Group. Mortality after 16 years for participants randomized to the Multiple Risk Factor Intervention Trial. Circulation. 1996;94:946–51. 11. Keys A, ed. Coronary heart disease in seven countries. Circulation. 1970;41–2 (Suppl I). 12. Keys A. Seven Countries: Death and Coronary Heart Disease in Ten Years. Cambridge, MA: Harvard University Press, 1979. 13. Gordon T, Garcia-Palmieri MR, Kagan A, et al. Differences in coronary heart disease mortality in Framingham, Honolulu and Puerto Rico. J Chronic Dis. 1974;27:329–44. 14. Rose G. Incubation period of coronary heart disease. Br Med J. 1982;284:1600–1. 15. McGill HC, Jr, ed. Geographic Pathology of Atherosclerosis. Baltimore: Williams & Wilkins, 1968. 16. Marmot MG, Syme SL, Kagan A, et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: prevalence of coronary and hypertensive heart disease and associated risk factors. Am J Epidemiol. 1975;102:514–25. 17. Blackburn H. Trends and determinants of CHD mortality: changes in risk factors and their effects. Int J Epidemiol. 1989;18 (Suppl 1): S210–S215. 18. Stern MP. The recent decline in ischemic heart disease mortality. Ann Intern Med. 1979;91:630–40. 19. Cooper R. Rising death rates in the Soviet Union: the impact of coronary heart disease. N Engl J Med. 1981;304:1259–65. 20. Luepker RV. Epidemiology of atherosclerotic disease in population groups. In: Pearson TA, Criqui MH, Luepker RV, Oberman A, Winston M, eds. Primer in Preventive Cardiology. Dallas: American Heart Association, 1994;1–10. 21. Elmer PJ. Obesity and cardiovascular disease: practical approaches for weight loss in clinical practice. In: Pearson TA, Criqui MH, Luepker RV, Oberman A, Winston M, eds. Primer in Preventive Cardiology. Dallas: American Heart Association, 1994;189–204. 22. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–39. 23. Truswell AS. Diet and nutrition of hunter-gatherers. In: Elliott K, Whelan J, eds. Health and Disease in Tribal Societies. Ciba Found Symp. 1977;49: 213–22.


62 24. Blackburn H, Prineas RJ. Diet and hypertension: anthropology, epidemiology, and public health implications. Prog Biochem Pharmacol. 1983;19:31–79. 25. Eaton SB, Konner M. Paleolithic nutrition: a consideration of its nature and current implications. N Engl J Med. 1985;312:283–9. 26. Jacobs DR, Anderson J, Blackburn H. Diet and serum cholesterol: do zero correlations negate the relationships? Am J Epidemiol. 1979;10:77–88. 27. Blackburn H. The concept of risk. In: Pearson TA, Criqui MH, Luepker RV, Oberman A, Winston M, eds. Primer in Preventive Cardiology. Dallas: American Heart Association, 1994;25–41. 28. Blackburn H, Jacobs DR. Sources of the diet-heart controversy: confusion over population versus individual correlations. Circulation. 1984;70:775–80. 29. Keys A, Grande F, Anderson JT. Bias and misrepresentation revisited— “perspective” on saturated fat. Am J Clin Nutr. 1974;27:188–212. 30. Hegsted DM, McGandy RB, Myers ML, et al. Quantitative effects of dietary fat on serum cholesterol in man. Am J Clin Nutr. 1965;17:281–95. 31. Ascherio A, Hennekens CH, Buring JE, et al. Trans-fatty acids intake and risk of myocardial infarction. Circulation. 1994; 89:94–101. 32. Shekelle RB, Shryock AM, Paul O, et al. Diet, serum cholesterol, and death from coronary heart disease: the Western Electric Study. N Engl J Med. 1981;304:65–70. 33. Kromhout D, de Lezenne Coulander C. Diet, prevalence and 10-year mortality from coronary heart disease in 871 middle-aged men: the Zutphen study. Am J Epidemiol. 1984;119:733–41. 34. McGee DL, Reed DM, Yano K, et al. Ten-year incidence of coronary heart disease in the Honolulu Heart Program: relationship to nutrient intake. Am J Epidemiol. 1984;119:667–76. 35. Kushi LH, Lew RA, Stare FJ, et al. Diet and 20-year mortality from coronary heart disease: the Ireland-Boston Diet-Heart Study. N Engl J Med. 1985;312:811–8. 36. Mattson FH, Grundy SM. Comparison of effects of dietary saturated, monounsaturated, and polyunsaturated fatty acids on plasma lipids and lipoproteins in man. J Lipid Res. 1985;26:194–202. 37. St. Clair RW. Atherosclerosis regression in animal models: current concepts of cellular and biochemical mechanisms. Prog Cardiovasc Dis. 1983;26:109–32. 38. Clarkson TB, Bond MG, Bullock BC, et al. A study of atherosclerosis regression in Macaca mulatta: V. Changes in abdominal aorta and carotid and coronary arteries from animals with atherosclerosis induced for 38 months and then regressed for 24 or 48 months at plasma cholesterol concentrations of 300 or 200 mg/dL. Exp Mol Pathol. 1984;41:96–118. 39. Anitschkow N. Experimental atherosclerosis in animals. In: Cowdry EV, ed. Arteriosclerosis. New York: Macmillan, 1983;271. 40. Wallace RB, Lynch CF, Pomrehn PR, et al. Alcohol and hypertension: epidemiologic and experimental considerations. Circulation. 1981;64:41–7. 41. Dyer AR, Stamler J, Paul O, et al. Alcohol, cardiovascular risk factors and mortality: the Chicago experience. Circulation. 1981;64: 20–7. 42. Haskell WL, Comargo C, Williams PT, et al. The effect of cessation and resumption of moderate alcohol intake on serum high density lipoprotein subfractions. N Engl J Med. 1984;310:805–10. 43. Ellison RC. Balancing the risks and benefits of moderate drinking. Ann NY Acad Sci. 2002;957:1–6. 44. Djoussé L, Ellison RC, Beiser A, et al. Alcohol consumption and risk of ischemic stroke: The Framingham Study. Stroke. 2002;33: 907–12. 45. Li JM, Mukamal KJ. An update on alcohol and atherosclerosis. Curr Opin Lipidology. 2004;15:673–80. 46. Kare MR, Fregly MJ, Bernard RA, eds. Biological and Behavioral Aspects of Salt Intake. New York: Academic Press, 1980.

Heart Disease

1085

47. Freis ED. Salt, volume and the prevention of hypertension. Circulation. 1976;53:589–95. 48. Writing Group of the PREMIER Collaborative Research Group. Effects of comprehensive lifestyle modification on blood pressure control. JAMA. 2003;289:2083–93. 49. Meneely GR, Battarbee HD. High sodium–low potassium environment and hypertension. Am J Cardiol. 1976;38:768–85. 50. Gleibermann L. Blood pressure and dietary salt in human populations. Ecol Food Nutr. 1973;2:143–56. 51. INTERSALT Cooperative Research Group. INTERSALT: an international study of electrolyte excretion and blood pressure: results for 24 hour urinary sodium and potassium excretion. Br Med J. 1988;297:319–28. 52. Joseph JG, Prior IAM, Salmond CE, et al. Elevation of systolic and diastolic blood pressure associated with migration: the Tokelau Island Migrant Study. J Chronic Dis. 1983;36(7):507–16. 53. Kesteloot H, Vuylsteks M, Costenoble A. Relationship between blood pressure and sodium and potassium intake in a Belgian male population group. In: Kesteloot K, Joossens J, eds. Epidemiology of Arterial Blood Pressure. The Hague: Nijhoff, 1980;345–51. 54. Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47:296–308. 55. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC VII Report. JAMA. 2003;289:2560–72. 56. Shimamoto T, Komachi Y, Inada H, et al. Trends for coronary heart disease and stroke and their risk factors in Japan. Circulation. 1989;79:503–15. 57. Hulley SB, Rosenman RH, Banol RD, et al. Epidemiology as a guide to clinical decisions: the associations between triglycerides and coronary heart disease. N Engl J Med. 1980;302:1383–9. 58. NIH Consensus Development Panel: Triglyceride, high density lipoprotein, and coronary heart disease. JAMA. 1993;269: 505–10. 59. Conference on Blood Lipids in Children: Optimal levels for early prevention of coronary artery disease. Prev Med. 1983;12:725–905. 60. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habits, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chronic Dis. 1978;31:201–306. 61. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:2823–8. 62. Gordon T, Castelli W, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. Am J Med. 1977;62:707–14. 63. National Diet-Heart Study Research Group. The National DietHeart Study: final report. Circulation. 1968;37:1–428. 64. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237–45. 65. Shepherd J, Cobbe SM, Ford I, et al. For the West of Scotland Coronary Prevention Study Group: Prevention of coronary heart disease with provastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–7. 66. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: 1383–9. 67. Kiekshus H, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study. Am J Cardiol. 1995;76:64C–68C.


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68. Pfeffer MA, Sacks FM, Move LA, et al. Cholesterol and recurrent events: a secondary prevention trial for normolipidemic patients. CARE Investigators. Am J Cardiol. 1995;76:98C–106C. 69. Johnson CL, Rifkind BM, Sempos CT, et al. Declining serum total cholesterol levels among U.S. adults. JAMA. 1993;269:3002–8. 70. Arnett DK, Jacobs DR, Luepker RV, et al. Twenty-year trends in serum cholesterol, hypercholesterolemia, and cholesterol medication use: The Minnesota Heart Survey, 1980-1982 to 2000-2002. Circulation. 2005;112:3884–91. 71. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA. 2001;285: 2486–97. 72. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med. 1988;148: 36–69. 73. National Cholesterol Education Program. Second report of the Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). Circulation. 1994;89:1329–1445. 74. National Cholesterol Education Program. Report of the Expert Panel on population strategies for blood cholesterol reduction. Arch Intern Med. 1991;151:1071–84. 75. National Cholesterol Education Program: Report of the Expert Panel on blood cholesterol levels in children and adolescents. Pediatrics. 1992;89:525–84. 76. Barrett-Connor EL. Obesity, atherosclerosis and coronary heart disease. Ann Intern Med. 1985;103:1010–9. 77. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among U.S. adults, 1999–2000. JAMA. 2002;288:1723–7. 78. Hubert HB, Feinlieb M, McNamara PM, et al. Obesity as an independent risk factor for cardiovascular disease: a 26-year followup of participants in the Framingham Heart Study. Circulation. 1983;67: 968–77. 79. Tyroler HA, Heyden S, Hames CG. Weight and hypertension: Evans County studies of blacks and whites. In: Paul O, ed. Epidemiology and Control of Hypertension. New York: Grune & Stratton, 1975. 80. Rabkin SW, Mathewson FAC, Hsu PH. Relation of body weight to the development of ischemic heart disease in a cohort of young North American men after a 26-year observation period: the Manitoba study. Am J Cardiol. 1977;39:452–8. 81. Larsson B, Svardsudd K, Welin L, et al. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13-year follow-up of participants in the study of men born in 1913. Br Med J. 1984;288:1401–4. 82. Donahue RP, Abbott RD, Bloom E, et al. Central obesity and coronary heart disease in men. Lancet. 1987;1:821–4. 83. Bjorntorp P. The associations between obesity, adipose tissue distribution and disease. Acta Med Scand. 1988;723:121–34. 84. Montenegro MR, Solberg LA. Obesity, body weight, body length, and atherosclerosis. Lab Invest. 1968;18:594–603. 85. Lissner L, Bengtsson C, Lapidus L, et al. Body weight variability and mortality in the Goteborg prospective studies of men and women. In: Bjorntorp P, Rossner S, eds. Proceedings of the European Congress of Obesity. London: John Libbey, 1989;55–60. 86. Taylor HL, Buskirk ER, Remington RD. Exercise in controlled trials of the prevention of coronary heart disease. Fed Proc. 1973;32: 1623–7. 87. Oldridge NB, Guyatt GH, Fischer ME, et al. Cardiac rehabilitation after myocardial infarction: combined experience of randomized clinical trials. JAMA. 1988;260:945–50.

88. Blackburn H, Jacobs DR. Physical activity and the risk of coronary heart disease [Editorial]. N Engl J Med. 1988;319:1217–9. 89. NIH Consensus Development Panel on Physical Activity and Cardiovascular Health. Physical activity and cardiovascular health. JAMA. 1996;276:241–6. 90. Powell KE, Thompson PD, Caspersen CJ, et al. Physical activity and the incidence of coronary heart disease. Annu Rev Public Health. 1987;8:253–87. 91. Leon AS, Connett J, Jacobs DR, Jr, et al. Leisure-time physical activity levels and risk of coronary heart disease and death: the Multiple Risk Factor Intervention Trial. JAMA. 1987;258:2388–95. 92. Slattery ML, Jacobs DR, Jr., Nichaman MZ. Leisure time physical activity and coronary heart disease death: the U.S. Railroad Study. Circulation. 1989;79:304–11. 93. Blair SN, Kohl HW, Paffenbarger RS, Jr, et al. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA. 1989;262:2395–2401. 94. Paffenbarger RS, Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol. 1978;108:161–75. 95. Paffenbarger RS, Jr, Hyde RT, Wing AL, et al. A natural history of athleticism and cardiovascular health. JAMA. 1984;252:491–5. 96. Siscovick DS, Weiss NS, Fletcher RH, et al. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med. 1984;311:874–7. 97. Mittleman MA, Maclure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion: protection against triggering of regular exertion. N Engl J Med. 1993;329:1677–83. 98. American Heart Association. Heart Disease and Stroke Statistics— 2005 Update. Dallas, TX: American Heart Association; 2005. 99. West KM. Epidemiology of Diabetes and Its Vascular Lesions. New York: Elsevier,1978;375–402. 100. Pyorala K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987;3:463–524. 101. Knowler WC, Bennett PH, Hammon RF, et al. Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, MN. Am J Epidemiol. 1978;108:497–505. 102. Barrett-Connor E, Wingard DL. Sex differential in ischemic heart disease mortality in diabetics: a prospective population-based study. Am J Epidemiol. 1983;118:489–96. 103. University Group Diabetes Program. A study of the effects of hypoglycemic agents on vascular complications in patients with adult onset diabetes. V. Evaluation of phenoformin therapy. Diabetes. 1975;24:65–184. 104. United Kingdom Prospective Diabetes Study Group. United Kingdom prospective diabetes study (UKPDS) 13: relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. Br Med J. 1995;310:83–8. 105. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86. 106. Nissen SE, Wolski. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71. 107. Stamler R, Stamler J, Lindberg HA, et al. Asymptomatic hyperglycemia and coronary heart disease in middle-aged men in two employed populations in Chicago. J Chronic Dis. 1979;32: 805–15. 108. Hughes LO. Insulin, Indian origin and ischemic heart disease [Editorial]. Int J Cardiol. 1990;26:1–4. 109. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265:3255–64.


62 110. Hypertension Detection and Follow-Up Group. The effect of treatment on mortality in “mild” hypertension. N Engl J Med. 1982;307:976–80. 111. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288:2981–2997. 112. Luepker RV, Arnett DK, Jacobs DR, Jr., et al. Trends in blood pressure, hypertension control, and stroke mortality, 1980 to 2002: the Minnesota Heart Survey. Am J Med. 2006;119:42–49. 113. U.S. Department of Health and Human Services. Morbidity and Mortality: 2004 Chart Book on Cardiovascular, Lung and Blood Diseases. Washington, DC: National Institutes of Health, 2004. 114. McGill HC, Jr. Potential mechanisms for the augmentation of atherosclerosis and atherosclerotic disease by cigarette smoking. Prev Med. 1979;8:390–403. 115. Kannel WB, McGee DL, Castelli WP. Latest perspectives on cigarette smoking and cardiovascular disease: the Framingham Study. J Cardiovasc Rehab. 1984;4:267–77. 116. Wilhelmsen L. Coronary heart disease: epidemiology of smoking and intervention studies of smoking. Am Heart J. 1988;115:242–9. 117. Amler RW, Dull HB, eds. Closing the Gap: The Burden of Unnecessary Illness. New York: Oxford University Press, 1987. 118. Willett WC, Green A, Stampfer MJ, et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med. 1987;317:1303–9. 119. Doll R, Hill AB. Mortality in relation to smoking: ten years’ observations of British doctors. Br Med J. 1964;1:1399–1410. 120. Freidman GD, Petitti DB, Bawol RD, et al. Mortality in cigarette smokers and quitters: effect of base-line differences. N Engl J Med. 1981;304:1407–10. 121. Aberg A, Bergstrand J, Johansson S, et al. Cessation of smoking after myocardial infarction: effects on mortality after ten years. Br Heart J. 1983;49:416–22. 122. Luepker RV, Rosamond WD, Murphy R, et al. Socioeconomic status and coronary heart disease risk factor trends: the Minnesota Heart Survey. Circulation. 1993;88:2172–9. 123. Luepker RV, Murray DM, Jacobs DR, Jr, et al. Community education for cardiovascular disease prevention: risk factor changes in the Minnesota Heart Health Program. Am J Prev Med. 1994;84:1383–93. 124. Public Health Service, Office on Smoking and Health: Report of the Surgeon General. Reducing the Health Consequences of Smoking: Twenty-Five Years of Progress. Rockville, MD: U.S. Department of Health and Human Services, 1989. 125. Farb A, Tang AL, Burke AP, et al. Frequency of active coronary lesions, inactive coronary lesions and myocardial infarction. Circulation. 1995;92:1701–9. 126. Meade TW. Clotting factors and ischemic heart disease. In: Meade TW, ed. The Epidemiological Evidence from Anti-coagulants in Myocardial Infarction: A Reappraisal. New York: John Wiley & Sons, 1984. 127. Libby P, Simon DI. Inflammation and thrombosis: The clot thickens. Circulation. 2001;103:1718–20. 128. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. NEJM. 1997;336:973–9. 129. Jackson RJ. The impact of the built environment on health: an emerging field. Am J Public Health. 2003;93:1382–4. 130. Beard CM, Fuster V, Elveback LR. Daily and seasonal variation in sudden cardiac death, Rochester, Minnesota, 1950–1975. Mayo Clin Proc. 1982;57:704–6. 131. Brook RD, Franklin B, Cascio W, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the expert panel on population and prevention science of the American Heart Association. Circulation. 2004;109:2655–71.

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132. Kaplan GA, Salonen JT, Cohen RD, et al. Social connections and mortality from all causes and from cardiovascular disease: prospective evidence from Eastern Finland. Am J Epidemiol. 1988;128:370–80. 133. Orth-Gomer K, Johnson JV. Social network interaction and mortality: a six year follow-up study of a random sample of the Swedish population. J Chronic Dis. 1987;40:949–57. 134. Writing Committee for the ENRICHD Investigators. Effects of treating depression and low perceived social support on clinical events after myocardial infarction. JAMA. 2003;289:3106–16. 135. McGill HC Jr, Stern MP. Sex and atherosclerosis. In: Paoletti R, Gotto AM, Jr, eds. Atherosclerosis Reviews. New York: Raven Press, 1979; vol 4:157–242. 136. Demirovic J. Recent trends in coronary heart disease mortality among women in Yugoslavia. CVD Epidemiology Newsletter. 1988;44:96–7. 137. Wahl P, Walden C, Knopp R, et al. Effect of estrogen/progestin potency on lipid/lipoprotein metabolism. N Engl J Med. 1983;308: 862–7. 138. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med. 1992;117:1016–37. 139. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63. 140. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605–13. 141. Writing Group for the Women’s Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288:321–33. 142. Austin MA, King MC, Bawol RD, et al. Risk factors for coronary heart disease in adult female twins: genetic heritability and shared environmental influences. Am J Epidemiol. 1987;125:308–18. 143. Hasstedt SJ, Wu L, Williams RR. Major locus inheritance of apolipoprotein B in Utah pedigrees. Genet Epidemiol. 1987;4:67–76. 144. Austin MA, King MC, Vranizan KM, et al. Inheritance of lowdensity lipoprotein subclass patterns: results of complex segregation analysis. Am J Hum Genet. 1988;43:838–46. 145. Jacobs DR, Anderson JT, Hannan P, et al. Variability in individual serum cholesterol response to change in diet. Arteriosclerosis. 1983;3:349–56. 146. Hunt SC, Hasstedt SJ, Kuida H, et al. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. Am J Epidemiol. 1989;129:625–38. 147. Dominiczak AF, Brain N, Charchar F, et al. Genetics of hypertension: Lessons learnt from mendelian and polygenic syndromes. Clin Experiment Hypertens. 2004;26:611–20. 148. Keys A, Aravanis C, Blackburn H, et al. Probability of middle-aged men developing coronary heart disease in five years. Circulation. 1972;45:815–28. 149. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings of the 5 large cohorts of young adults and middle-aged men and women. JAMA. 1999;282:2012–8. 150. Daviglus ML, Stamler J, Pirzada A, et al. Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality. JAMA. 2004;292:1588–92. 151. Daviglus ML, Liu K, Pirzada A, et al. Favorable cardiovascular risk profile in middle age and health-related quality of life in older age. Arch Intern Med. 2003;163:2460–8. 152. Carapetis JR, Steer AC, Mulholland EK, et al. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5:685–94. 153. Strasser T: Rheumatic fever and rheumatic heart disease in the 1970s. Public Health Rev. 1976;5:207–34.


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Noncommunicable and Chronic Disabling Conditions

154. World Health Organization. Intensified Program: Action to Prevent Rheumatic Fever/Rheumatic Heart Disease. WHO Document WHO/CVD/84.3. Geneva: World Health Organization, 1984. 155. Wang ZM, Zou YB, Lei S, et al. Prevalence of chronic rheumatic heart disease in Chinese adults. Int J Cardiol. 2006;107:356–9. 156. Bar-Dayan Y, Elishkevits K, Goldstein L, et al. The prevalence of common cardiovascular diseases among 17-year-old Israeli conscripts. Cardiology. 2005;104:6–9. 157. Hanna JN, Heazlewood RJ. The epidemiology of acute rheumatic fever in Indigenous people in north Queenland. Aust N Z J Public Health. 2005;29:313–7. 158. Ahmed J, Zaman MM, Hassan MMM. Prevalence of rheumatic fever and rheumatic heart disease in rural Bangladesh. Trop Doct. 2005;35:160–1. 159. Veasy LG, Tani LY, Hill HR. Persistence of acute rheumatic fever in the intermountain area of the United States. J Pediatr. 1994;124:9–16. 160. Hoffman JIE. Congenital heart disease. Pediatr Clin North Am. 1990;37:25–43. 161. Zangwill KM, Wald ER, Londino AV. Acute rheumatic fever in western Pennsylvania: a persistent problem into the 1990s. J Pediatr. 1991;118:561–3. 162. Carapetis JR, Currie BJ. Rheumatic fever in a high incidence population: the importance of monoarthritis and low grade fever. Arch Dis Child. 2001;85:223–7. 163. Giannoulia-Karantana A, Anagnostopoulos G, Kostaridou S, et al. Childhood acute rheumatic fever in Greece: experience of the past 18 years. Acta Paediatr. 2001;90:809–12. 164. Kurahara DK, Grandinetti A, Galario J, et al. Ethnic differences for developing rheumatic fever in a low-income group living in Hawaii. Ethn Dis. 2006;16:357–61. 165. Wannamaker LW, Matsen JM, eds. Streptococci and Streptococcal Diseases: Recognition, Understanding, and Management. New York: Academic Press, 1972. 166. Gordis L, Lilienfeld A, Rodriguez R. Studies in the epidemiology and preventability of rheumatic fever. II. Socio-economic factors and the incidence of acute attacks. J Chronic Dis. 1969;21:655–66. 167. Pan American Health Organization. Fourth Meeting of the Working Group on Prevention of Rheumatic Fever. Quito, Ecuador, 1970. 168. Dajani AS, Ayoub EM, Bierman FZ, et al. Guidelines for the diagnosis of rheumatic fever: Jones criteria, updated 1992. JAMA. 1992;268:2069–73. 169. Wannamaker LW. The chain that links the heart to the throat. Circulation. 1973;48:9–18. 170. Elliot RS, Edwards JE. Pathology of congenital heart disease. In: Hurst JW, ed. The Heart. New York: McGraw-Hill, 1978. 171. Congenital Heart Disease Study Group. Primary prevention of congenital heart disease. In: Wright IS, Fredrickson DT, eds. Cardiovascular Diseases, Guidelines for Prevention and Care. Reports of the Inter-Society Commission for Heart Disease Resources. Washington, DC: Government Printing Office, 1972;116. 172. Higgins ITT. The epidemiology of congenital heart disease. J Chronic Dis. 1965;18:699. 173. Nora JJ. Etiologic factors in congenital heart diseases. Pediatr Clin North Am. 1971;18:1059–74. 174. Fredrich J, Alberman ED, Goldsteen H. Possible teratogenic effect of cigarette smoking. Nature. 1971;231:529. 175. Rose V, Gold RJM, Lindsay G, et al. A possible increase in the incidence of congenital heart defects among the offspring of affected parents. J Am Coll Cardiol. 1985;6:376–82. 176. Ferencz C. Offspring of fathers with cardiovascular malformations. Am Heart J. 1986;111:1212–3. 177. Zierler S. Maternal drugs and congenital heart disease. Obstet Gynecol. 1985;65:155–65. 178. Perloff JK, Warnes CA. Challenges posed by adults with repaired congenital heart disease. Circulation. 2001;103:2637–43.

179. Boneva RS, Botto LD, Moore CA, et al. Mortality associated with congenital heart defects in the United States—trends and racial disparities, 1979–1997. Circulation. 2001;103:2376–81. 180. NHLBI Working Group on Heart Disease Epidemiology: Report. NIH Report 79-1667. Washington, DC: Government Printing Office, 1979. 181. Bailey NA, Lay P. New horizons: infant cardiac transplantation. Heart Lung. 1989;18:172–8. 182. Williams RG, Pearson GD, Barst RJ, et al. Report of the National Heart, Lung, and Blood Institute Working Group on research in adult congenital heart disease. J Am Coll Cardiol. 2006;47:701–7. 183. World Health Organization. Cardiomyopathies: Report of a WHO Expert Committee. WHO Technical Report Series, No. 697. Geneva: World Health Organization, 1984. 184. Fowles RE. Progress of research in cardiomyopathy and myocarditis in the USA. International Symposium on Cardiomyopathy and Myocarditis. Heart Vessels Suppl. 1985;1:5–7. 185. Olsen EGJ. What is myocarditis? International Symposium on Cardiomyopathy and Myocarditis. Heart Vessels Suppl. 1985;1:1–3. 186. Shabeter R. Cardiomyopathy: how far have we come in 25 years? How far yet to go? J Am Coll Cardiol. 1983;1:252–63. 187. Gillum RF. Idiopathic cardiomyopathy in the United States, 1970–1982. Am Heart J. 1986;111:752–5. 188. Okada R. Wakafuji S. Myocarditis in autopsy. International Symposium on Cardiomyopathy and Myocarditis. Heart Vessels Suppl. 1985;1:23–9. 189. Rubin E. Alcoholic myopathy in heart and skeletal muscle. N Engl J Med. 1979;301:28–33. 190. Alexander CS. Cobalt-beer cardiomyopathy: a clinical and pathological study of twenty-eight cases. Am J Med. 1972;53:395–417. 191. Regan TJ, Haider B, Ahmed SS, et al. Whisky and the heart. Cardiovasc Med. 1977;2:165. 192. Levine HD. Virus myocarditis: a critique of the literature from clinical, electrocardiographic and pathologic standpoints. Am J Med Sci. 1979;277:132–43. 193. McAllister HA, Jr. Myocarditis: some current perspectives and future directions. Tex Heart Inst J. 1987;14:331–4. 194. Parrillo JE, Cunnion RE, Epstein SE, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med. 1989;321:1061–8. 195. Wigle ED. Hypertrophic cardiomyopathy 1988. AHA-Mod Concepts Cardiovasc Dis. 1988;57:1–6. 196. Cecchi F, Olivotto I, Betocchi S, et al. The Italian registry for hypertrophic cardiomyopathy: A nationwide survey. Am Heart J. 2005;150:947–54. 197. Ahmad F, Seldman JG, Seldman CE. The genetic basis for cardiac remodeling. Ann Rev Genomics & Human Genetics. 2005;6: 185–216. 198. Hagar JM, Rahimtoola SH. Chagas’ heart disease. Curr Probl Cardiol. 1995;20:825–924. 199. World Health Organization. Report of the WHO Consultation on Cardiomyopathies: Approaches to Prevention and Early Detection. WHO Document, WHO/CVD/85.6. Geneva; World Health Organization, 1985. 200. Sliwa K, Damasceno A, Mayosi BM. Epidemiology and etiology of cardiomyopathy in Africa. Circulation. 2005;112:3577–83. 201. Centers for Disease Control. Summary of notifiable diseases— United States. MMWR. 1988;36:54–8. 202. Clark EG, Danbolt N. The Oslo study of the natural course of untreated syphilis: an epidemiologic investigation based on a re-study of the Boeck-Bruusgaard material. Med Clin North Am. 1964;48:613. 203. Musher DM. Syphilis. Infect Dis Clin North Am. 1987;1:83–95. 204. Jackman JD, Jr, Radolf JD. Cardiovascular syphilis. Am J Med. 1989;87:425–433. 205. Farquhar JW. The place of hypertension control in total cardiovascular health: perspectives outlined by the Victoria Declaration. Clin Exp Hypertens. 1995;17:1107–11.


Renal and Urinary Tract Disease

63

Rebecca L. Hegeman

 INTRODUCTION

With over 50 million individuals worldwide having chronic kidney disease (CKD), a well recognized risk factor for cardiovascular disease, CKD is emerging as a worldwide public health problem.1 As countries develop and industrialize, diseases related to infections, crowding, and poor nutrition recede, and chronic disease associated with affluence, aging, overnutrition, medical interventions, drugs, addictions, and other exposures becomes prominent. While diseases of westernized societies are the main focus of this chapter, globalization has contributed to an increasing rate of noncommunicable chronic disease worldwide. In 2003 it was estimated that 60% of deaths worldwide would be due to noncommunicable diseases, with 16 million deaths resulting from cardiovascular disease and 1 million deaths from diabetes.2 Thus, the information in this chapter pertains to an ever widening circle of communities. With ischemic heart disease and cerebrovascular disease now listed as the number one and two causes of death worldwide, it is very probable that renal disease related to vascular disease will become more prevalent. In addition the increase in the prevalence of diabetes virtually assures that chronic kidney disease will continue to be a major cause of morbidity and mortality. Rates of most renal diseases and of end-stage renal disease (ESRD) in westernized societies rise with age, and increased longevity enhances the expression of both. More males than females are affected by many renal diseases, and more males enter ESRD treatment programs. Some groups recently absorbed into industrialized societies, such as U.S. blacks, North American Indians, Hispanics and Mexican Americans, urban South African blacks, Australian aborigines, Pacific Islanders, and New Zealand Maoris, have especially high rates of renal disease, in part from conditions such as hypertension and diabetes that were rare in their forebears. ESRD treatment programs themselves have produced a whole new set of clinical, economic, and sociological perspectives and concerns. Renal and urinary tract diseases are frequently asymptomatic for most of their course, and diagnosis is frequently dependent on laboratory and radiologic studies. Clinical renal disease may be manifested by blood, protein, or white blood cells in the urine, often with hypertension. Heavy protein excretion, decreased levels of serum albumin, hyperlipidemia, and edema characterize the “nephrotic syndrome.” Excretory renal function can be normal or impaired and can remain stable or progress to renal failure. Renal impairment generates, and is exacerbated by, hypertension. ESRD defines a situation of chronic irreversible renal failure in which prolonged survival is not possible without dialysis or renal transplantation. Specific diseases are diagnosed by history and clinical findings, biochemical, serological, imaging, and urodynamic studies, and sometimes by biopsy of the kidneys, bladder, or prostate. Kidney biopsy specimens are examined by light, immunofluorescent, and electron microscopy to aid in diagnosis and prognosis. The serum creatinine

level provides an approximate measure of renal insufficiency, although it varies with muscle mass and diet, underestimates renal insufficiency in the elderly, is relatively insensitive to loss of the first 50% of renal function, and is less sensitive to progressive loss of function in severe renal failure. Glomerular filtration rate (GFR), precisely measured by iothalamate and inulin clearances, can be estimated by creatinine clearance. More recently the MDRD GFR equation has been validated and made readily available. This was developed from data on large numbers of patients screened for a clinical trial in whom iothalamate GFR was measured and takes into account serum creatinine, age, race, and gender.3 Estimating GFR is very important in assessing patients with kidney disease and continues to be a subject of intense interest. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF K/DOQI) guidelines were first officially put forth in February 2002 and have been largely adopted in research and practice communities. In these guidelines chronic kidney disease has been divided into stages 1 through 5 based on an estimation of GFR with treatment recommendations determined by stage. This classification system was recently endorsed by the Kidney Disease: Improving Global Outcomes (KDIGO) group, an independent group dedicated to the improvement of care of kidney disease patients worldwide.4 This classification relies heavily on the level of GFR but is independent of the methods by which GFR is measured thus providing a powerful stimulus to ensure that serum creatinine measurements become uniform across laboratories, more generalizable estimating equations are developed and alternative filtration markers, such as cystatin C, are evaluated more extensively.5 Although specific interventions for many diseases are not yet available, progressive renal damage may be slowed by a few standard maneuvers, thereby avoiding or postponing the development of ESRD. Control of coexisting or secondary hypertension, moderate dietary protein restriction, blockade of the renin/angiotensin/ aldosterone system in patients with proteinuria and in diabetics, and strict control of blood glucose levels are of proven value.6–8 Other strategies recommended include control of hyperlipidemia, control of obesity, reduction of left ventricular hypertrophy, cessation of tobacco use, and improved nutritional status including a low-sodium diet.9

 SPECIFIC RENAL DISEASES

Diabetic Renal Disease Diabetic nephropathy is the leading cause of ESRD in the United States, accounting for approximately 40% of all patients on dialysis.10 While the overall incidence of ESRD due to diabetes has leveled off in recent years, over the last decade the number of new patients with diabetes as their primary cause of ESRD has doubled. With the increasing prevalence of diabetes in the general population it is predicted that 58% 1089

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of all prevalent ESRD patients in 2030 will have diabetes mellitus as their primary diagnosis. Of the estimated 18.2 million diabetic individuals in the United States, 5–10% have insulin-dependent diabetes mellitus (IDDM) and 90–95% have noninsulin-dependent diabetes mellitus (NIDDM). The lifetime risk of developing nephropathy in IDDM is approximately 30–40%, peaking after approximately 18–20 years. The lifetime risk in NIDDM is less well defined but probably is around 33%. Because most patients with diabetes have NIDDM, the majority of patients in dialysis units have NIDDM. The incidence of ESRD caused by diabetic nephropathy is increased in certain racial and ethnic groups including Hispanics, African-Americans, and Native Americans. Most of the increase in these groups seems to be caused by NIDDM. Familial clustering of diabetic nephropathy has also been noted and may be due to genetic inheritance, shared environment or both.11,12 The National Institute of Diabetes, Digestive and Kidney Diseases (NIDDKD) has established a multicenter consortium to identify the gene(s) responsible for diabetic nephropathy.13 It should also be noted that up to 30% of patients with NIDDM and chronic kidney disease do not have diabetic nephropathy, but some other pathology, most commonly vascular disease.14 The pathogenesis of diabetic nephropathy is not yet fully understood. Early on the glomerular and tubular basement membranes thicken, and there is accumulation of extracellular matrix in the glomerular mesangium. Over time the glomerular capillary lumina are obliterated and the glomerular filtration rate eventually declines. Functionally, there may be an initial increase in the glomerular filtration rate, but this is followed by the development of proteinuria and systemic hypertension with an eventual decline in renal function. Hyperglycemia is a necessary factor initiating the above events, and tight glucose control reduces the onset of diabetic kidney disease. Current studies are focusing on the role of advanced glycosylation end-products (AGEs), the polyol pathway, transforming growth factor-β, and endothelins (as well as several others) in the accumulation of the extracellular matrix and other histochemical abnormalities which eventually lead to the decline of renal function in diabetics.15 The most important early clinical marker of diabetic nephropathy is microalbuminuria, or “dipstick-negative” urinary albumin excretion. This corresponds to a urinary albumin excretion rate of 30–300 mg/day or 20–200 mcg/min.16 Unfortunately it is not as early a marker for diabetic nephropathy as might have been hoped in that irreversible kidney damage may have already occurred by the time it is detected. It is also a risk factor for increased overall mortality. Identification of diabetics with microalbuminuria is important because patients with microalbuminuria progress to develop overt diabetic nephropathy (excretion of > 300 mg. protein per 24 hours) and eventually ESRD, and treatment appears to delay this progression.17 Several major clinical trials have provided guidance for therapy in diabetics to prevent diabetic nephropathy and the complications associated with it. Treatment of overt diabetic nephropathy with an angiotensin-converting enzyme (ACE) inhibitor in patients with IDDM and NIDDM has been shown to delay (but not totally halt) the rate of deterioration of renal function. This effect is independent of the effect of ACE inhibition on the treatment of blood pressure.18 This effect has also been shown for angiotensin receptor blockers (ARBs), and there is now evidence that the combination of an ACE inhibitor and an ARB may have additional benefit.19 The Diabetes Control and Complications Trial (DCCT) has demonstrated the beneficial effects of intensive insulin therapy on the development of type I diabetic nephropathy. Since then several other trials have supported this finding, including the United Kingdom Prospective Diabetic Study which demonstrated the benefit of intensive insulin therapy in type II diabetics.20,21 In the DCCT the mean adjusted risk of microalbuminuria (28 mcg/min) was reduced by 34% in the group of patients on intensive insulin therapy with no baseline retinopathy. Unfortunately intensive insulin therapy did not show a significant benefit in preventing the development of overt diabetic nephropathy in patients who already had microalbuminuria. More recently pancreatic transplantation has been shown to stabilize the progression of diabetic kidney disease at several stages.22

Hypertension is more common in diabetics with microalbuminuria, especially in patients with NIDDM, and is both a predictor and a consequence of nephropathy in NIDDM. Hypertension has been shown to increase the rate at which diabetic nephropathy progresses and antihypertensive therapy has been shown to slow its course.23 Although the incidence of diabetic nephropathy among patients who have had IDDM for 25 years or more is falling, the increasing population of elderly patients with NIDDM marks diabetic nephropathy as a continued major cause of morbidity and mortality.24 For this reason annual screening for microalbuminuria is recommended for all diabetics older than 12 years. If microalbuminuria is present and persists, ACE inhibitor or ARB therapy is appropriate in both normotensive and hypertensive patients. Serum potassium and creatinine will need to be monitored, and females of child-bearing age will need to be cautioned about becoming pregnant due to the known adverse effects of ACE inhibition and ARBs on the fetus. Glycemic control should be monitored on a regular basis as well as blood pressure control. In addition, microalbuminuria is frequently associated with elevated levels of cholesterol and triglycerides, so dietary restriction of cholesterol and weight reduction should be emphasized. Cigarette smoking has also been associated with the development and progression of microalbuminuria and should be discouraged.25 While significant advances have been made in the approach to patients with diabetic nephropathy, we await the results of ongoing basic science research studies and clinical trials, which will increase the knowledge and improve the management of diabetic nephropathy, hopefully eliminating or at least significantly reducing the requirement for renal replacement therapy with its attendant comorbidity in this population.

Hypertensive Renal Disease Hypertension can both produce and complicate renal disease, and its contribution to renal insufficiency is probably underestimated. Hypertensive renal disease accounts for 30% of the prevalent ESRD cases in the United States and is particularly common in AfricanAmericans receiving ESRD treatment.26 While most patients with ESRD have hypertension, the majority of patients with hypertension do not go on to develop ESRD. It seems that elevated blood pressure is permissive to renal disease, especially glomerulosclerosis, in only certain individuals. Among hypertensive patients in the Multiple Risk Factor Intervention Trial (MRFIT), the incidence of all-cause ESRD per 100,000 person-years of hypertension was 16.38 for AfricanAmericans compared with 3.00 for white Americans.27,28 Primary hypertensive renal disease can be of two kinds. The more common, sometimes called “nephrosclerosis,” is a form of chronic renal insufficiency associated with long-standing blood pressure elevation. The second, a form of accelerated renal failure associated with malignant hypertension, is now rare where treatment of hypertension is widespread. Additional risk factors for nephropathy in hypertensive persons include the degree of systolic hypertension, the presence of diabetes, male sex, increasing age, and high normal serum creatinine levels. Although widespread treatment of hypertension has reduced other hypertensive morbidities, its effect on hypertensive renal disease is still not clear. Two regional studies in the United States showed that renal damage can progress in some treated hypertensive persons despite adequate blood pressure control,29,30 and the communitybased Hypertension Detection and Follow-up Program (HDFP) confirmed this phenomenon.31 More recently the African-American Study of Kidney Disease and Hypertension (AASK) looked at 1094 African-Americans with long-standing hypertension, proteinuria, and unexplained progressive renal disease. Again there was no significant difference in rate of progression of kidney disease between blood pressure groups, although it should be noted that blood pressure was controlled to at least 140/90 or less in both groups. An ACE inhibitor was shown to be more effective in slowing progression of renal disease.32 The inability to show an effect of lower target blood pressures may be related to the length of follow-up in these studies. Long-term follow-up of the participants in the MDRD study suggest that a lower


63 target blood pressure may slow the progression of nondiabetic kidney disease in patients with moderately to severely decreased kidney function and proteinuria.33 Regardless of study results, most seasoned practitioners feel that blood pressure control is mitigating much hypertensive renal disease, and the HDFP suggests the superiority of aggressive control over a more relaxed treatment approach. The definition of adequate blood pressure control continues to evolve. Fear of the J-curve phenomenon (increased mortality with lower BPs) in the general hypertensive population has been tempered by the results of several studies including the Hypertension Optimal Treatment (HOT) study where lowering of the diastolic BP to the low 80s in hypertensive individuals was associated with lower cardiovascular morbidity and mortality in diabetics.34 In the context of proteinuric renal disease, lowering blood pressure beyond conventional recommendations has been shown to be beneficial in delaying progression of renal disease, but a more recent study did not support this.7,35 It has also become clear that over 50% of hypertensive individuals will require several antihypertensive agents to control blood pressure to the levels obtained in these studies. Retrospective and prospective analyses of large cohorts of hypertensive subjects and comparisons of therapeutic regimens are ongoing and will continue to help clarify some of these issues.

Glomerulonephritis Glomerulonephritis (GN) encompasses several syndromes with a variety of pathological changes in the renal glomerulus. Injury to the glomeruli is manifest by variable degrees of hematuria and/or proteinuria, red blood cell casts, hypertension, edema, oliguria/anuria, and renal insufficiency. This injury is categorized by morphological or clinical features, precipitating events, or associated conditions. Most forms of GN are probably immunologically mediated, and genetic predispositions to some are suggested by family clusters and by associations with certain HLA types. Associations with specific infections are well established, especially in the developing world, but few precursors or etiologic factors are recognized in the common forms of GN that persist in westernized countries. With the accumulation of series of cases from different parts of the world, there is evidence for geographic, climatic and ethnic differences in the incidence and prevalence of various lesions that may lead to further discoveries about the underlying pathogenesis of various GNs. GN is a common cause of renal failure and renal death in the developing world, and it is the third most common cause of treated ESRD in the United States, behind diabetes and hypertension.10 Pathological diagnosis relies on renal biopsy, which does have risks and is done with variable frequency in different parts of the world. Little is known about the distribution or natural history of mild GN or the extent to which subclinical GN might be eroding renal function in the broader community. This could change as more attention is being paid to individuals with GFRs in the 15–60 mL/min range. Chronic Idiopathic GN. The major morphological categories of idiopathic GN are minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), mesangial proliferative GN, membranous GN (MGN), and membranoproliferative GN (MPGN). There are probably interfaces among these categories. Each can afflict subjects of all ages, but the distributions are dependent on age. MCD is the most common lesion in children, whereas adults have a broader distribution of all these forms of GN. Idiopathic GN may be associated with infections such as hepatitis B or C or malignancies. MCD has the best prognosis, with remission usual before adulthood. MGN remains the most common cause of idiopathic nephritic syndrome worldwide. It may remit but remains a common cause of renal failure from GN. The incidence of FSGS has increased significantly in the last two decades and is frequently secondary to or associated with other diseases, including infections. It is now the most common primary glomerulopathy underlying ESRD in the United States.36 MPGN, type I, is frequently associated with hepatitis C but other infections and/or tumors may cause a lesion of MPGN. MCD has typically responded

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to therapy more reliably than other forms of GN although FSGS with nonnephrotic range proteinuria may have a better prognosis. Immunosuppressive therapy continues to be used for treatment of various forms of idiopathic GN, but ACE inhibition and/or angiotensin receptor blockers to reduce proteinuria are now a mainstay of treatment for all proteinuric renal diseases.35,37 Risk factors for progression of idiopathic MGN, and probably other forms of GN, include elevated serum creatinine, hypertension, male gender, age  50, renal biopsy evidence of glomerular sclerosis and/or interstitial fibrosis, and the persistence of heavy proteinuria. Progression is rare if protein excretion remains mild or falls toward normal, whether spontaneously or with treatment. With progressive proteinuria, it is highly probable that patients will progress to ESRD. IgA Nephropathy. IgA nephropathy and thin basement membrane nephropathy continue to be the most common findings underlying a clinical presentation of asymptomatic hematuria and IgA nephropathy is considered to be the most common form of glomerulonephritis in the world.38 It is more common in the western Pacific rim where incidence in older patients is reported to be increasing,39 while in Europe and the United States, lower prevalence rates have been reported. Again local variability in health screening practices and indications for kidney biopsy will influence these statistics. Investigators in Japan found previously unknown IgA mesangial nephropathy in 16% of living kidney donors.40 Males predominate by at least 2:1, and, unlike other glomerular diseases, the prevalence is lower in African-Americans. There have been reports of familial clustering. The pathogenesis of IgA nephropathy remains unknown but it is associated with abnormal deposition of IgA in the glomerular mesangium.39 A number of genetic polymorphisms have been described that may be associated with susceptibility or progression of disease, but it is too early to tell which ones play the largest role. It is thought that multiple viral and bacterial infections can trigger a clinical exacerbation with gross hematuria and sometimes acute renal insufficiency, but again a specific agent has not been clearly identified. The clinical presentation may be quite variable and includes several syndromes. Most patients present with microscopic or macroscopic hematuria. In 30–40% of patients there may be proteinuria usually associated with microscopic hematuria, and in  10% of patients there is acute renal insufficiency, edema and hypertension on presentation. Skin lesions (Henoch-Schonlein purpura) develop more often in children, and these patients may have skin, joint, and intestinal involvement. Glomerular IgA deposition is associated with several disorders including hepatic cirrhosis, gluten enteropathy, HIV infection, Wegener’s granulomatosis, systemic lupus erythematosus, minimal change disease and membranous nephropathy. IgA nephropathy usually has an indolent course with about 25–30% of patients reaching ESRD within 20–25 years.39 Patients who present with hypertension, heavy proteinuria or an elevated creatinine are at higher risk for progression to ESRD. There is currently no definitive cure for IgA Nephropathy, but there is now more emphasis on treatment with immunosuppressive therapy for those with proteinuria ( 0.5–1.0 g/day) and/or rising serum creatinine despite angiotensin inhibition. Randomized clinical trials have demonstrated the benefit of angiotensin converting enzyme inhibitors and/or angiotensin II receptor antagonists.19,41 Efforts should be also be directed at controlling hypertension, goal BP 125/75, and hyperlipidemia if present. A recent multi-centered trial did not demonstrate a benefit of fish oil on progression of disease.42 Allograft survival in patients who receive a kidney transplant is good although recurrence of IgAN after renal transplantation is common and becoming a more important cause of graft failure as control of rejection improves.39 Poststreptococcal Glomerulonephritis. The epidemiology and pathogenesis of poststreptococcal glomerulonephritis (PSGN) are well defined.43 It is characterized by the onset of hematuria, proteinuria, hypertension, and sometimes oliguria and renal insufficiency 7–15 days after a streptococcal upper respiratory infection and 21–40 days after a streptococcal skin infection. Although most common in children, it can


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occur at all ages. Epidemic disease occurs in crowded and unhygienic living conditions and is common in tropical countries and Third World populations, especially in association with anemia, malnutrition, and intestinal parasites. It may occur in seasonal patterns and sometimes in cycles separated by several years. Epidemic disease is now uncommon in most westernized countries, although sporadic cases continue. Asymptomatic disease is more common than clinical disease in most studies. Males predominate among patients with clinical but not subclinical disease. Only certain strains of streptococci have nephritogenic potential: nontypeable group A streptococci may also have that potential. It has been estimated than an average of 15% of infections with nephritogenic strains result in PSGN, with fully 90% of cases being subclinical, but the proportion varies with site of infection, the epidemic (if any), and the strain. Recurrence is uncommon. PSGN is due to glomerular immune complex deposition, although the constituent streptococcal antigens are still being identified. A genetic predisposition is evidenced by attack rates in siblings of index cases of up to 37.8% after throat infections and 4.5% after skin infections. A streptococcal origin of acute GN is suggested if cultures or antigen tests have been positive for streptococci, or serum levels of antistreptolysin O (ASO) antibodies are elevated after throat infections (60–80% of cases), or if antihyaluronidase and antideoxyribonuclease antibodies are elevated after skin infections. A transient depression of serum complement helps differentiate PSGN from some other forms of GN. Renal biopsy is rarely indicated. Prevention of PSGN involves improved nutrition, hygiene, and living conditions. Antibiotic treatment of streptococcal infections does not prevent PSGN, although it can confound the diagnosis by reducing ASO antibody production. Treatment does, however, reduce spread of streptococci to contacts and lessen their risk of getting PSGN. Prophylactic treatment for subjects at risk is recommended during epidemics and for siblings or families of patients with PSGN. When active disease is clinically severe, control of volume status and blood pressure is critical. Urine abnormalities may persist for months after the acute attack. However, with follow-up limited to 10–15 years, studies of broad populations rather than of subjects initially hospitalized show complete recovery for most children, with rapidly progressive acute disease in less than 0.1% and chronic renal failure in less than 1%. More recently an epidemic episode due to group C Streptococcus zooepidemicus was described in Brazil.44 Of the original group of 134 patients, three patients died in the acute phase and five patients required chronic dialysis. Of 69 patients examined after a mean of two years, 42% had hypertension, 34% had microalbuminuria and 30% had reduced renal function.44 Adults have about twice the rate of long-term urine abnormalities as children, and chronic renal failure is more common, although still exceptional. Superimposed hypertension, renal changes with aging, and the hyperperfusion phenomenon might contribute to such a course.

Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disorder and the fourth most common single cause of ESRD in the United States.10 It is characterized by fluid-filled cysts in the kidney, which can compress surrounding tissue leading to renal insufficiency and eventually ESRD. It occurs in every one of 400–2000 live births, and an estimated 500,000 people have the disease in the United States.45 Approximately 86% of patients with ADPKD have an abnormality in a gene on chromosome 16 (PKD1 gene locus), and most of the remaining patients have an abnormal gene on chromosome 4 (PKD2 gene locus)46 The phenotype associated with PKD2 is usually less severe although penetrance can be variable for both. Approximately 10% of patients have a new mutation with no family history of ADPKD. Abnormalities in the regulation of cell growth, epithelial fluid secretion and extracellular matrix metabolism contribute to the clinical problems associated with ADPKD. Renal manifestations of ADPKD include hematuria, urinary tract infections, flank pain, nephrolithiasis,

hypertension, and the most serious, renal failure. Approximately 45% of patients will have end-stage renal disease by 60 years of age. Currently there is no curative treatment for ADPKD. Cyst un-roofing, dietary protein restriction and inhibition of the renin-angiotensin-aldosterone axis have not been shown to clearly delay progression of disease. Control of hypertension to  140/90 is beneficial and should be aggressively pursued although it does not change the rate of progression of disease. Urinary tract infections should be treated immediately. Extrarenal manifestations include hepatic cysts, cardiac valve abnormalities, colonic diverticula, hernias, and intracranial saccular aneurysms. Rupture of the intracranial aneurysms is associated with high morbidity and mortality, and screening is recommended for highrisk patients, such as those with a positive family history of intracerebral bleed, warning symptoms, a previous rupture, or a high-risk occupation where loss of consciousness would place the patient or others at risk. The diagnosis of ADPKD has traditionally been done by ultrasound or CT evaluation of the kidneys. The sensitivity of these tests is not very high when used in patients under 20–25 years of age although ultrasound has been shown to be fairly sensitive and well standardized for patients  30 years. Genetic testing can now establish the genotype in approximately 60% of individuals with ADPKD. If a mutation can be identified within a single family member, then testing can be used to determine if relatives carry that mutation and have ADPKD. Genetic counseling is very important for patients with this disorder.47

Analgesic Nephropathy Analgesic nephropathy (AAN) is a slowly progressive renal disease caused by the long-term ingestion of analgesics, classically a combination of agents including aspirin, phenacetin, acetaminophen, caffeine, and/or codeine. It was estimated to be the cause of ESRD in ~ 1–3% of patients in the United States with a higher prevalence in Australia and Europe. While the prevalence of AAN has decreased secondary to the removal of phenacetin from the market, the disease has not been completely eliminated. The prevalence of AAN has been studied more extensively in Australia and Europe where it has been more prevalent.48,49 The pathogenesis of AAN is not well understood.50 Examination of the kidneys reveals chronic interstitial inflammation and papillary necrosis. In more advanced cases, cortical scarring occurs, most pronounced over the necrotic papillae, and gross examination of the kidneys reveal them to be small and nodular. Involvement of the medulla and papillae is felt to be secondary to increased concentration of the drugs in these areas with the generation of oxygen radicals and reduction of medullary blood flow due to inhibition of prostaglandins. AAN is more common in women. Individuals who have chronic pain for which analgesics may be consumed regularly and those with a history of peptic ulcer disease or gastric complaints are more likely to have a history of analgesic consumption. The patients may not be taking the medications at the time of presentation, but it is estimated that at least 1–2 kg of an offending agent need to have been ingested at some time to cause significant renal disease. The urinalysis may be normal or show pyuria, bacteriuria, and proteinuria, which is usually mild. Reduced ability to concentrate urine and renal tubular acidosis may occur, and there may be evidence for papillary necrosis when the kidneys are imaged as well as the reduced size and nodularity previously noted. In addition to being the sole cause of ESRD in some cases, analgesic use contributes to more minor degrees of renal dysfunction in many other cases, and it is very probable that it contributes to the decline in renal function in patients with other underlying causes of renal insufficiency. The nephrotoxicity of nonsteroidal anti-inflammatory agents (NSAIDs) has been recognized for some time now and is characterized by one of several presentations: acute renal failure secondary to renal vasoconstriction; interstitial nephritis with or without nephrotic syndrome and minimal change disease; hyperkalemia; sodium and water retention; and papillary necrosis. People with underlying volume depletion and/or those with chronic renal insufficiency have a higher risk of developing problems. Most of these conditions


63 are reversible. NSAIDs are nonselective inhibitors of cyclooxygenase. Of the two related isoforms, COX-2 is constitutively expressed and is the predominant form in the kidneys. Selective COX-2 inhibitors, introduced more recently for their favorable GI side-effect profile, have also been shown, not surprisingly, to cause nephrotoxicity.51 AAN is preventable, and renal disease has been shown to decrease with decreased availability of agents such as phenacetin. The United States National Kidney Foundation published a position paper regarding analgesic use. It has been recommended that overthe-counter combination analgesics be eliminated and all prescription combination analgesics have a warning on them regarding the risk of renal damage.52 Aspirin as a single agent does not appear to impair renal function when used in therapeutic doses, especially the small doses recommended for prevention of cardiovascular events. There is an increased risk of larger doses leading to reversible deterioration of renal function in patients with underlying renal disease, and renal function should be monitored. For patients without liver disease, acetaminophen remains the nonnarcotic analgesic of choice, particularly for patients with underlying renal disease. Habitual consumption should be discouraged as a case-control study done in Maryland, Virginia, West Virginia, and Washington, DC suggests that there may be an increased risk of renal insufficiency in patients who have taken large amounts over a lifetime.53 Prolonged regular use of NSAIDs and COX-2 inhibitors have recently been suspected of having adverse cardiac as well as renal effects and prolonged use should be discouraged.54 Renal function should be monitored if regular use is necessary. NSAIDs should be avoided altogether in pregnancy. Use of NSAIDs in combination with other analgesics needs to be prospectively evaluated and should be avoided at this time.

Acute Renal Failure Acute renal failure (ARF) is characterized by a relatively acute deterioration in renal function. Because defining the exact rate and nature of the deterioration is difficult to do, ARF is not well defined and therefore, it is difficult to compare rates and outcomes. Most cases of community-acquired ARF have a single, treatable cause of renal failure that is either prerenal (secondary to vomiting, poor intake, diarrhea, glycosuria, gastrointestinal bleeding and diuretics) or postrenal (secondary to prostate enlargement from hyperplasia or carcinoma).55 It is not very common and the prognosis is usually good. The incidence of hospital-acquired ARF is increasing with one study showing an incidence of 4.9% in the 1970s and another 7.2% in the mid-1990s.56,57 It is more common in patients with underlying chronic kidney disease, 15.7% versus 5.3% in patients with normal renal function.57 Greater than 60% of patients with hospital-acquired ARF have had more than one renal insult. It is frequently caused by decreased renal perfusion usually secondary to volume contraction, poor cardiac output or sepsis. In one study postoperative patients accounted for 18% of all ARF, and contrast media and aminoglycosides combined accounted for another 19%. Prognosis appears to correlate with the severity of renal insufficiency and degree of oliguria/anuria.56 The frequency of ARF in intensive care units ranges from 6 to 23%. Nearly all of these patients have had multiple renal insults, and it is frequently seen in the context of multiorgan failure. Survival is significantly reduced in these patients, especially in the presence of multiorgan failure. ARF caused by blood loss and crush injuries is common during war and natural disasters. ARF secondary to general trauma has declined, as has pregnancy-related ARF. Abortion contributed to much of ARF in the past, and now preeclampsia/eclampsia and uterine hemorrhage cause the majority of pregnancy-related ARF. ARF is being seen more commonly now in patients with AIDS, malignancy, and sepsis. The use of NSAIDs and angiotensin converting enzyme inhibitors may also contribute to the development of ARF in patients with underlying renal hypoperfusion. ARF rates secondary to contrast and antibiotics appears to be stable. Despite increasing awareness of the etiology of ARF and advancing technology, the mortality of ARF has not decreased significantly

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over the last several decades. It appears that ARF is not just a marker for severe comorbid conditions, and even mild episodes are associated with increases in morbidity and mortality. A multicenter observational study of 17,126 ICU patients in Austria showed a mortality of 62.8% in patients requiring renal replacement therapy compared to 38.5% in matched controls without ARF.58 The exact reason for the above is not clear, and may be related to distant biochemical and histologic effects of renal ischemia on cardiac function and other organ systems yet to be elucidated. While short-term survival is not good for patients with ARF in the ICU, the long-term outcomes in patients who survive to hospital discharge are much better. Of the patients who survived to hospital discharge among 979 critically ill patients with ARF requiring renal replacement therapy (RRT), six month survival was 69% and five year survival 50%.59 Preventive options are limited for most causes of ARF and consist of blood pressure support, optimization of cardiac function, treatment of underlying conditions including sepsis and limiting nephrotoxic agents. Volume expansion with normal saline and use of nonionic radiocontrast agents have been shown to reduce the incidence of radiocontrast nephropathy while the role of Nacetylcysteine (NAC) remains less clear. Lack of significant toxicity and low cost have contributed to an increase in its use prior to radiographic procedures which is probably appropriate.60 The Program to Improve Care in Acute Renal Disease (PICARD) is an observational registry of critically ill patients with acute renal failure maintained at five geographically diverse academic medical centers in the United States.61 The PICARD investigators have used their registry to examine the epidemiology of ARF or acute kidney injury (AKI) as it now being called as well as the pathobiology of ARF. Timing and modality of RRT in treatment of ARF remain controversial. There is no clear indication that continuous forms of RRT are superior, but they are frequently used in patients with hemodynamic instability.

Renal Disease and Illicit Drugs Renal disease related to drug abuse is being recognized more frequently as a cause of renal disease and has great social and economic impact. According to the 2001 National Survey on Drug Abuse, an estimated 15.9 million Americans currently use illicit drugs, and a significant positive and independent association between illicit drug use and risk for mild kidney function decline has been demonstrated.62 Several syndromes are recognized. Focal segmental glomerulosclerosis (FSGS) occurs in intravenous heroin addicts, with heavy proteinuria and progression to renal failure in a few months to years. There is no effective treatment. An immunologic mechanism is postulated, mediated through a response to heroin itself, to adulterants, or to infectious agents. FSGS associated with drug abuse occurs in all ethnic groups, but rates are especially high in young black males, leading to the hypothesis that parental drug abuse unmasks a genetic predisposition to FSGS in blacks similar to that seen for hypertension. It has been suggested that heroin nephropathy is on the decline with an increase in HIV nephropathy. Renal deposition of amyloid, associated with chronic inflammation and infection, occurs in skin poppers.63 Proteinuria and sometimes renal failure is diagnosed at an average age of 41 years, 10 years older than FSGS patients. In a New York City autopsy series, 5% of addicts and 26% of addicts with suppurative skin infections had unsuspected renal amyloidosis.64 Other renal diseases related to drug abuse include immunecomplex GN associated with infectious endocarditis or hepatitis B antigenemia, membranoproliferative GN and cryoglobulinemia associated with hepatitis C, necrotizing vasculitis related most strongly to amphetamine abuse, tubular dysfunction and occasionally acute renal failure in solvent sniffers, acute renal failure due to muscle breakdown, and the renal syndromes of human immunodeficiency virus infection. Treatment of addicts with ESRD is often complicated by noncompliance, communicable diseases like hepatitis B, hepatitis C, and AIDS, and, with continued drug abuse, infection and clotting of vascular access and recurrence of disease in kidney transplants. Because


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of the interfaces of drug addiction with crime, some of these subjects are incarcerated. Such problems accentuate dilemmas about responsibility for personal health and allocation of limited resources.

Renal Disease and the Human Immunodeficiency Virus The understanding of renal disease associated with human immunodeficiency virus (HIV) infection continues to evolve. Renal disease may occur at all stages of HIV illness including the asymptomatic stage, but many complications are associated with acute illness. Patients may develop fluid and electrolyte disorders, acid–base disturbances, and/or acute renal failure secondary to volume depletion, infections, drugs and/or abnormal adrenal steroid synthesis and secretion. There is also a histologically unique nephropathy associated with HIV called HIV nephropathy. Patients with this disorder usually have nephrotic range proteinuria accompanied by renal insufficiency which progresses fairly rapidly to ESRD (within three to six months).65 On exam there is frequently no significant peripheral edema or hypertension, and the kidneys are normal to increased in size despite being highly echogenic. This may be contrasted to heroin-associated nephropathy in which hypertension is frequently present, the kidneys are small, and progression to ESRD is a slower process. Although it is not always possible to distinguish HIV-associated disease from other forms of glomerulosclerosis, the following pathological findings are felt to be very suggestive of HIV nephropathy and include focal to global glomerulosclerosis, collapse of the glomerular tuft, severe tubulointerstitial fibrosis with some inflammation, microcyst formation, tubular degeneration, and characteristic tubuloreticular inclusions.65 While HIV nephropathy was initially noted to be more prevalent in young black males who were IV drug users; it is now known that it can occur in most risk groups. It has even been reported in children of HIV-infected mothers, where vertical transmission accounts for infection. Development of HIV nephropathy also appears to be more likely in blacks and males. Patients who are HIV positive and develop acute renal failure due to acute tubular necrosis (ATN) tend to be younger than the non-HIV positive patient with ATN, and frequently the ATN is associated with sepsis. Treatment consists of conservative, supportive care, and hemodialysis may be used until kidney function returns. Much of the ATN associated with HIV disease is preventable if patients receive adequate volume support prior to use of nephrotoxic agents or during episodes of hypovolemia and if attention is paid to medication/ antibiotic dosing.66 There is no proven cure for HIV nephropathy. There has been a decrease in overall morbidity and mortality due to HIV disease with the introduction of highly active antiretroviral therapy (HAART) in the mid 1990s.67 The use of protease inhibitors may be helping to reduce the likelihood of progression of HIV nephropathy to ESRD. Except for a peak in 1998, the number of new ESRD patients with HIV nephropathy has remained stable since 1995; 836 patients were reported in 2002.26 This coincides with the advent of HARRT therapy. Symptom-free HIV-positive subjects with chronic renal failure can do quite well on dialysis, but chronic dialysis of subjects with clinical AIDS is complicated by concomitant illness, cachexia, infectious hazards, and prolonged hospitalizations, and survival is usually short.

Hemolytic Uremic Syndrome (HUS) HUS is one of several clinical syndromes that affect the vasculature of the kidney producing a thrombotic microangiopathy. It is discussed here in relationship to a bacterium, Escherichia coli O157:H7, which has emerged as a major cause of diarrhea, particularly bloody diarrhea, in North America. Several studies68 have now shown that this E. coli is responsible for most cases of HUS in children, which is a major cause of acute renal failure. While it has been isolated in many parts of the world, its prevalence is unknown. Infections are more common in

warmer months, and transmission may occur via undercooked beef, fecally contaminated water, and person-to-person. Infection has also been associated with unpasteurized commercial apple juice.69 Patients typically present with abdominal cramping, diarrhea (nonbloody or bloody), nausea, and vomiting. HUS has been reported to occur in about 6% of patients with infection and is diagnosed anywhere from 2 to 14 days after the onset of the diarrhea. It is more likely to affect young children and the elderly. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Central nervous system manifestations may be present. The renal pathologic lesions include edematous intimal expansion of arteries, fibrinoid necrosis of arterioles, and edematous subendothelial expansion in glomerular capillaries.70 There is no specific therapy which has proven to be effective for HUS secondary to E. coli infection. Treatment involves supportive therapy with red blood cell transfusions, control of hypertension and dialysis if necessary. Apheresis may be helpful in more severe cases with central nervous system involvement. The prognosis for typical childhood HUS is usually good. Neurological involvement, prolonged oliguria, elevated white blood cell count, age under two years, and atypical presentations have been associated with a poorer prognosis. The mortality rate is 3–5%, and about 5% of patients who survive have severe sequelae, including ESRD. To prevent E.coli infection, patients should be counseled about the risk of eating undercooked ground beef. A thorough history should be taken in suspected cases, and cases should be reported early to prevent spread. Hand washing is essential in institutions such as day-care centers and nursing homes, and children with a known infection should be kept at home. Use of antidiarrheals for acute infectious diarrhea is potentially dangerous.  URINARY TRACT DISEASES

Urinary Tract Infections Urinary tract infections (UTIs) are one of the most common types of infection encountered in clinical medicine. They account for more than 7 million physician visits and necessitate or complicate over 1 million hospital admissions annually in the United States.71 The estimated annual cost of UTIs is $1.6 billion for evaluation and treatment.72,73 Uncomplicated UTIs are most frequent in young, healthy, sexually active women with normal urinary tracts, and it is estimated that 40–50% of women will have a UTI in their lifetime. UTIs are also common in preschool girls, in postmenopausal women, and in elderly men and women, especially those who are institutionalized and those with indwelling urinary catheters. UTIs in older men are often associated with urinary retention due to benign prostatic hypertrophy (BPH), urethral strictures, calculi, and debilitating illness and are thus designated as complicated and more difficult to treat. Boys and men with normal urinary tracts are not often affected, but men can acquire bacterial UTIs through heterosexual or homosexual intercourse, and recurrent UTI is the hallmark of chronic prostatitis. Use of immunosuppressive drugs and recent antibiotic use also place individuals at risk for complicated UTIs. Most infections are localized to the bladder and urethra, but some involve the kidneys and renal pelves (pyelonephritis), or the prostate. UTIs rarely lead to renal damage or failure unless they are associated with diabetes, pregnancy, reflux, obstruction, or neurogenic bladder. Diabetic persons with UTIs risk papillary necrosis and sepsis; abortion and other complications can result from UTIs in pregnancy; and morbidity and mortality of UTIs increase greatly in the elderly and in those with complicating conditions, such as spinal cord injury. Most UTIs in young women are new events, are uncomplicated, and caused by E. coli and other bowel organisms that enter the bladder through the short female urethra. Subjects with recurrent UTIs have increased density of bacterial receptors on epithelial cell surfaces in the vagina and bladder. Women with blood groups A and AB who are nonsecretors of blood group substance are at greater risk.


63 Intercourse, diaphragm use, and failure to void after intercourse all increase risk. Women who have closely spaced recurrent infections with the same organisms or who have pyelonephritis should be evaluated for urinary tract abnormality, as should men with persistent infection. Complicated UTIs are frequently caused by non-E. coli pathogens such as Enterococcus and Klebsiella species. In the presence of symptoms, white cells and bacteria in a cleanvoid midstream specimen of urine usually indicate a UTI. The usual bacterial count considered diagnostic on urine culture is 100,000/mL, but many patients have lower counts, including half of those with cystitis and most patients with urethral syndromes. Enterobacteriaceae colony counts as low as 100/mL, have a sensitivity and specificity for UTI of 94% and 85%. Subjects with recurrent UTIs can perform an easy and relatively inexpensive dip slide urine culture technique, and self-treatment under medical guidance can be initiated. Many uncomplicated UTIs are treated based on symptoms and pyuria alone. Screening for bacteriuria in symptom-free persons is not costeffective and may lead to inappropriate treatment, drug reactions, and selection of resistant organisms. Treatment of asymptomatic bacteriuria is not generally recommended, except in pregnant women, diabetics, and children with vesicoureteral reflux. Symptomatic infections are treated by antimicrobials, and infections associated with sexual intercourse can usually be prevented by single-dose prophylactic therapy. Repeated or prolonged antibiotic treatment can select antibiotic-resistant organisms. Some broad-spectrum antimicrobial agents may not pose this threat and are sometimes used for prophylaxis in subjects with chronic infections. UTIs are the leading form of nosocomial infection and are especially common in nursing homes. Spread can be reduced by separation of catheterized patients from others who are debilitated or catheterized, and by washing the hands after patient contact. For subjects who require temporary catheterization, risks of infection can be reduced by aseptic insertion, curtailed duration of catheterization, and meticulous care of the patient and the drainage system. However, infection remains very common in persons with chronic indwelling catheters. The bacterial flora in the urine of catheterized subjects is in flux, colonization is often asymptomatic, and repeated courses of treatment are not advised. Interstitial cystitis is a syndrome of unknown etiology and pathogenesis with symptoms similar to UTIs. It is characterized by nocturia, urgency, and suprapubic pressure and pain with filling of the bladder. It is more common in women and may be the cause of multiple outpatient physician visits. Therapy is frequently not completely effective, and it can occasionally lead to a significant decrease in quality of life.

Urinary Stone Disease Urinary stone disease has been recognized since antiquity and continues to be a major cause of morbidity. The incidence is increasing not only in the United States, but Sweden and Japan, and is felt to be related to increased dietary animal protein intake.74 It is estimated that 10–12% of individuals will have a kidney stone during their lifetime. Risk factors for development of a stone include male sex, Caucasian race, obesity, hypertension, diet high in animal protein and salt but low in calcium and fluid, hot climate or occupation, and family history of kidney stones.75 Drugs such as triamterene and indinavir may precipitate as crystals in the urinary tract. The initial stone usually presents in the third to fifth decade and up to 50% will have a recurrent stone within five years. Geographic variations in incidence may be attributable to temperature and sunlight exposure as well as access to beverages. Urinary stone disease is relatively uncommon in underdeveloped countries where bladder stones predominate. Most kidney stones (75–85%) contain calcium, primarily in the form of calcium oxalate. The remaining stones contain uric acid, struvite, cystine, and/or small amounts of other compounds. The content of the stone may give clues to the underlying physiological problem, especially in the case of stones without calcium. Disorders associated with stone disease include primary hyperparathyroidism, renal tubular

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acidosis, enteric hyperoxaluria, sarcoidosis, cystinuria, and urinary tract infection or obstruction. Risk factors associated with calcium stone formation include low urinary volume, hypercalciuria, hyperoxaluria, hypocitraturia, and hyperuricosuria.76 Most patients present with flank pain radiating into the groin which is abrupt in onset and frequently severe. Gross or microscopic hematuria, dysuria, frequency, nausea, and vomiting can be present. Occasionally, patients will have an ileus. Diagnosis is confirmed by abdominal plain film, ultrasound, IVP, or CT. Most kidney stones pass spontaneously, and the patient can be supported with analgesics. Urological intervention may be required including endoscopic “basket” removal, extracorporeal shock-wave lithotripsy (ESWL), endoscopic lithotripsy with ultrasonic, electrohydraulic, or laser probes, open pyelolithotomy, and percutaneous nephrolithotomy. These procedures have reduced the costs, morbidity, and hospitalization rates compared with open surgery which is rarely used anymore. The primary objective of therapy is to prevent the formation of recurrent stones. Patients are asked to strain their urine for stone collection and composition analysis. Conservative management includes analgesics, adequate fluid intake (≥ 2 L/day), dietary sodium restriction, and moderate calcium intake. Maintaining calcium intake helps prevent absorption of oxalate and outweighs the risk associated with high calcium intake. Oxalate restriction, reduction of animal protein intake, thiazide diuretics, and other agents may also be recommended depending on the patient’s underlying medical condition and the cause of stone formation.

Prostate Cancer Prostate cancer is a disease of aging men and is an important public health problem in the United States as well as throughout the world. It is the most commonly diagnosed cancer in men except for nonmelanoma skin cancer in the United States and is the second leading cause of male cancer deaths.77 It is the sixth most common cancer in the world and the most common cancer in men in Europe, North America, and some parts of Africa. It accounts for 15.3% of all cancers in men in developed countries and 4.3% in developing countries.78 The incidence, prevalence, and mortality rates from prostate cancer increase with age, particularly after 50 years of age. In the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, the incidence of new cases in white U.S. men in 1995 was approximately 200, 600, and 900 per 100,000 in men aged 50–59, 60–69, and 70 or over.79 The incidence of prostate cancer peaked in the early 1990s, in part, but not entirely, related to use of the prostate specific antigen (PSA) as a screening tool. There was a subsequent decline during the mid 1990s perhaps related to the screening effect. The incidence is steadily rising again in almost all countries.78 While the presence of histologic cancer appears to be related to age, both genetic and environmental risk factors appear to increase the development of clinical prostate cancer. Asian men have a lower incidence of and mortality due to clinical prostate cancer while Scandinavian men have a higher incidence. Men tend to take on the risk of their host country, but race is also a factor. AfricanAmerican men have a higher incidence than do black men in Africa or Asia and a higher incidence than white men or Hispanics. AfricanAmerican men are also diagnosed with later-stage disease, and their survival rates are shorter. In general, socioeconomic status is not felt to explain the incidence differences between African-Americans and whites. There is an increased risk of prostate cancer for men with a family history. While both prostate cancer and BPH appear to be androgen dependent, it has been difficult to determine whether or not BPH is a risk factor for prostate cancer because both are common in men as they age. The risk attributable to prostatitis has similar issues. Associations with venereal disease, sexual activity, and smoking have been proposed but not proven. Studies have been conflicting regarding vasectomy, but more recent studies have not found evidence for an association. Additional possible risk factors include elevated testosterone levels, a high intake of dietary fat, and other dietary habits. Several genetic mutations/ deletions and polymorphisms may be associated with an increased risk for prostate cancer but no single prostate cancer gene has been


Noncommunicable and Chronic Disabling Conditions

Bars: Rate per million population

identified. These findings may support increased attention to screening in certain populations such as African-Americans. Patients typically present with symptoms of urinary tract obstruction (urgency, nocturia, frequency, and hesitancy) from an enlarged prostate gland causing bladder-neck obstruction. These symptoms are essentially the same as those seen with BPH. Other less common signs and symptoms include back pain from vertebral metastases and new onset of impotence. A few patients have symptoms related to urinary retention caused by bladder-neck obstruction, bilateral hydronephrosis from periaortic lymph node enlargement, or spinal cord compression from epidural extension. Rarely, patients present with an enlarged supraclavicular node or elevation of liver tests. Prior to the increased use of the PSA for screening, diagnosis was made by assessing symptoms, performing a digital rectal exam of the prostate, and transrectal ultrasonography. Today an increasing number of patients present with elevated PSA levels obtained during screening exams. PSA is a glycoprotein produced almost exclusively by prostate epithelial cells. While PSA is elevated in men with prostate cancer and has been shown to correlate with tumor burden in men with established cancer, it is not specific for prostate cancer and may be elevated in cases of prostatitis and BPH. Concerns have been raised about its use as a screening tool leading to increased detection of insignificant cancers with an increase in expense and side effects. Survival studies have yet to show a reduction in mortality because of screening. Currently there is no consensus on the use of the PSA and digital rectal examination for the detection of prostate cancer, but experts do agree that providing education to patients on the risks and benefits of screening is important and some groups recommend annual screening for males  50 years with a life expectancy of at least 10 years. Many of the small, well differentiated carcinomas remain confined to the prostate and are only detected at autopsy (latent or autopsy cancers). The majority of tumors never become active, but how to predict which will become so has not been determined. It is estimated that the average lifetime risk of developing prostate cancer in an American male is 17% while the risk of dying from prostate cancer is only 3%.77 Management of prostate cancer may include watchful waiting, hormonal therapy, prostatectomy, and radiation therapy depending on the stage of the cancer. Treatment considerations should include age, life expectancy, comorbid conditions, side effects, and costs. Urinary incontinence, impotence, and radiation morbidity comprise the treatment related adverse effects. The Prostate Cancer Prevention Trial looked at the use of finasteride, a 5-alpha reductase inhibitor which prevents conversion of testosterone to dihydrotestosterone, as a chemo preventive agent. While it prevented or delayed the number of cancers and reduced urinary tract symptoms, it also was associated with an increased risk for high-grade prostate cancer.80 Currently there are ongoing trials looking at similar agents as well as chemotherapy for various stages of diagnosed prostate cancer. Multiple clinical trials are currently underway which should help identify the best method of screening, as well as chemo preventive therapies and therapies for the various stages of prostate cancer.

Prostatic Hyperplasia BPH is extremely common in older men. It has been reported that BPH can be found in 88% of autopsies in men ≥ 80 years of age, and that nearly 50% of men ≥ 50 years of age have symptoms compatible with BPH.81 Three men in ten may ultimately require surgery. While it frequently causes morbidity, it is rarely responsible for death. The cause of BPH is not known. Necessary conditions are the presence of androgens and aging. No associations with sociocultural factors, sexual behavior, use of tobacco or alcohol, or other diseases have been consistently demonstrated, and there is no firm evidence that BPH is a precursor of prostate cancer. In BPH subjects, a period of rapid prostate enlargement occurs, usually after the age of 50, followed by stabilization. Clinical symptoms result from variable compression of the bladder outlet, with difficulties in urinating, and the potential for infection, complete obstruction, and bleeding. Age, urinary flow rate and prostate volume are risk factors for acute urinary retention. Serum PSA is a strong predictor of growth and may be a predictor of risk for urinary retention. The natural history of symptoms can vary greatly. Many subjects have mild symptoms for years, with no change, and many do not require surgical intervention. Evaluation consists of rectal examination, blood chemistry studies, urinalysis and culture, measurement of residual urine volume after voiding, cystourethroscopy, urodynamic evaluation, and imaging or contrast studies of the kidneys and ureters.82 Many patients can be observed while monitoring for progression. Alpha-adrenergic blocking agents and 5-alpha reductase inhibitors have been shown to delay progression of the symptoms and when used in combination may have a greater effect. Alpha reductase inhibitors may reduce the size of the prostate and when used alone or in combination with alpha-adrenergic blocking agents in some studies have been shown to reduce the incidence of acute urinary retention.83 For more severe symptoms, prostatectomy is the standard of care. Indications for surgery vary, need better definition, and should be weighed against the comorbidities, complications, outcomes, and costs. Firm indications are acute urinary retention, hydronephrosis, recurrent urinary infections, severe hematuria, severe outflow obstruction, and urgency incontinence. Persistence of symptoms and impotence can result from surgery in a significant minority of subjects. Newer procedures are being developed including the use of prostatic stents, balloon dilatation of the prostate, laser prostatectomy, and microwave hyperthermia.

 END-STAGE RENAL DISEASE (ESRD)

Overall, it is estimated that there are more than 19 million adult Americans affected by chronic kidney disease. ESRD or stage 5, the most advanced stage, affects more than 500,000 people in the United States.26 Although the prevalent ESRD rate has risen each year since 1980, the rate of increase has been falling steadily since the early 1990s. (Fig. 63-1) ESRD can be caused by many renal diseases and by some

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Figure 63-1. End-stage renal disease (ESRD). Adjusted prevalence rates and annual percentage change. (Source: USRDS, 2004.)


63 urinary tract diseases when they are complicated by chronic obstruction or infection. In the United States, diabetic nephropathy is the primary diagnosis in 45% of the prevalent ESRD population, up from 20% of the prevalent population in 1980.26 Hypertension is the primary diagnosis in 30% of the prevalent ESRD population and glomerulonephritis causes  20 % of ESRD compared with 40% in 1980. There appears to be a slowing of the number of patients whose ESRD is caused by more rare diseases such as Wegener’s granulomatosis and lupus, but the number of patients with a primary diagnosis of multiple myeloma/light chain nephropathy continues to increase, perhaps partially related to the aging of the population plus other unknown factors.26 At the end of 2002, approximately 309,000 ESRD patients were being treated in the United States and its territories. Another 122, 375 patients had renal transplants. Both the incidence rate and the prevalence rate of ESRD increase with age until 65–74 years at which point the rates decline. The median age of incident ESRD patients has increased 21% from 54 in 1978 to 65 years in 2002. The greatest increase has occurred among Asian patients, from 44 in 1978 to 65 in 2002, a 47% increase. Patients age 45–64 accounted for 35% of the incident population. Only 13% of the incident population is age 20–44, compared to 27% in 1980. Patients age 75 and older now make up  25% of the population, up from only 8% in 1980. Definite gender and racial differences do exist and they have remained consistent in the United States over the past two decades. While blacks constitute 12–13% of the general population in the United States, they constitute 29–33% of the ESRD population, a rate fourfold higher than that of whites. The ESRD incidence and prevalence rates for Asian/Pacific Islanders and Native Americans are between those of whites and blacks. Prevalent rates of ESRD among males are 1.4 times higher than among females, a rate that has been very consistent over the years.26 The first patient with chronic renal disease was dialyzed in 1960 by Belding Scribner. During the 1960s the development of vascular access, chronic peritoneal dialysis catheters, and improved immunosuppressive therapies allowed patients to choose between some form of hemodialysis, peritoneal dialysis or renal transplantation. With the enactment of the Social Security Amendments of 1972 (effective in July 1973), treatment became available for all patients with ESRD. Currently patients choose one of the above therapeutic modalities based on a combination of medical and social factors. Transplantation is regulated by national and local policies, physician and patient preference, and availability of donor organs. Relatively recent advances in the treatment of ESRD patients include high flux, bicarbonate hemodialysis using biocompatible membranes, automation of peritoneal dialysis, use of vitamin D derivatives for treatment of renal osteodystrophy, and genetically engineered erythropoietin for treatment of anemia reducing the need for blood transfusions. Continued advancements in the development of immunosuppressive agents have improved the one-year first-time cadaveric transplant survival from 70% in 1984 to  90% in 2002. Despite improvements in dialysis technology, mortality remains high. For example, at age 45 the expected remaining lifetime of a white male with ESRD on dialysis is 7.1 years compared with 32.8 years for a white male from the general population. Survival for patients receiving a transplant cannot be directly compared to that for dialysis patients due to selection factors; however, in the example above survival extends to 18.7 years when including all patients with ESRD including those who received a renal transplant. Gross mortality rates of dialysis patients in the United States have been the highest in any surveyed country in the past and continue to be high. An increase in dialysis dose above the currently recommended dose did not improve survival as demonstrated in the HEMO study.84 Age, primary diagnosis, acceptance of patients with multiple comorbid conditions, transplantation rates, dose of dialysis delivered, patient compliance, nutrition, and predialysis therapy all may contribute to this phenomenon. The total Medicare payment per patient year (average for all ESRD patients of all ages) is estimated to be $46,490 for the years 1998–2002. Transplantation costs are less than those for dialysis patients, at $18,394 per patient year. This does not include the cost of organ procurement for transplantation patients. Annual costs for all ESRD patients rise with

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age, primarily due to the decline in transplantation rate for elderly patients. Diabetic patients with ESRD are more costly to treat than nondiabetics.26 Current efforts are being directed at determining if short daily dialysis or prolonged nocturnal dialysis will decrease the mortality rates of ESRD patients. In addition, the Health Care Financing Agency is sponsoring a national study to determine whether more effective and cost efficient ESRD care can be provided using a capitated system. It should be noted that in many low-income countries, such as India, dialysis is currently not available to  95% of the population.1  THE FUTURE

Progress has clearly been made in several areas of renal and urinary tract diseases. In addition to the decrease in the death rate from hypertensive renal disease, renal infections, and renal congenital abnormalities, the incident rate for ESRD caused by diabetes has begun to stabilize, and that for ESRD caused by glomerulonephritis has begun to decline.26 As a specific example, since 1992 the incident rates for white patients with diabetic ESRD have declined 46% in those age 20–29 and 9% in those age 30–39. While rates for blacks remain the highest, the rate of increase appears to be slowing as does the rate of rise for Hispanics. The incident and prevalent rates for Native Americans has slowed but this is due to a change in census methods and will need to be reevaluated.26 While progress has been made, the number of patients age 45–64 reaching ESRD continues to increase in a linear fashion and, with the exception of pediatric patients, waiting times for transplantation continue to increase. Thus, the cost of providing care has not decreased. In 2002, total Medicare costs for the ESRD program were $17 billion. There also continues to be a discrepancy in incidence of ESRD among racial groups, with the rates among black patients having actually increased 27% for those age 20–29 and 62% for those age 30–39. This may reflect the fact that blacks are more likely to have type II diabetes which is becoming more prevalent as obesity becomes a major public health problem. This, along with the increased incidence of hypertension in blacks, makes it more difficult to treat. While development of strategies such as the Kidney Early Evaluation Program (KEEP) to provide early detection and prevent progression of CKD is clearly important, society will need to address how best to support these programs both in terms of manpower and monetary funds. For westernized societies who have already made a large commitment to life support for subjects with irreversible renal failure, supporting the funding for these programs will continue to be a challenge. For all societies, the challenge remains to better understand the factors that contribute to ESRD. The public health perspectives of many of these diseases remain poorly defined and the distributions and natural histories of many remain obscure. While progress has been made in identifying specific prevention and treatment strategies, many diseases continue to lack specific strategies, and the prevalence of ESRD will continue to increase. Epidemiological and health services research in renal and urinary tract diseases continues to expand. In the United States the NIDDKD have collated existing data on rates, morbidities, mortalities, resource utilization, and costs. They are supporting studies on diabetic renal disease, hypertension, progressive glomerular sclerosis, progression of renal failure, urinary tract obstruction, prostatic hyperplasia, prostatic cancer screening, and urinary incontinence. They have also established research initiatives in interstitial cystitis, HIV-associated renal disease, the genetic basis of polycystic kidney disease, and renal disease and hypertension in minorities. The CDC’s National Health and Nutrition Examination Survey (1988–1994 & 1999–2000) collected information that will yield estimates of rates of kidney stones, UTIs, interstitial cystitis, prostate disease, bladder dysfunction, microalbuminuria, and elevated serum creatinine levels and will give us a better understanding of the risk factors for the various stages of chronic kidney disease. To prevent or delay kidney damage, the National Kidney Foundation has established a free screening program (KEEP) for individuals at increased risk for developing kidney


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disease with the goals of raising awareness about kidney disease, providing free testing and encouraging people “at risk” to visit a doctor and follow the recommended treatment plan. Educational information and support is also being provided. The well established United States Renal Data System continues to provide valuable longitudinal data on patients with ESRD. Results of the NIH sponsored Frequent Hemodialysis Nocturnal Trial evaluating the effect of daily and nocturnal dialysis on morbidity and mortality in ESRD patients should be available within the next two to three years.84 The results of these initiatives should invigorate the practice of nephrology, guide judicious apportionment of limited resources, support formulation of rational health policy, and improve the overall outcomes for patients with renal and urinary tract disease.

 REFERENCES

1. Dirks JH, de Zeeum D. Prevention of chronic kidney and vascular disease: Toward global health equity—The Bellagio 2004 Declaration. Kidney Int. 2005;68(S98):S1–S6. 2. Beaglehole R, Yach D. Globalization and the prevention and control of non-communicable disease: the neglected chronic diseases of adults. Lancet. 2003;362:903–8. 3. Levey AS, Bosch JP, Lewis JB, et al. a more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med. 1999;130:461. 4. Levey AS, Eckardt KU, et al. KDIGO. KI. 2005;67:2089–100. 5. Lamb EJ, Tomson CR, Roderick PJ. Estimating kidney function in adults using formulae. Ann Clin Biochem. 2005;42:321–45. 6. Pedrini MT, Levey AS, et al. The effect of dietary protein restriction on the progression of diabetic and nondiabetic renal diseases: A metaanalysis. Ann Intern Med. 1996;124:627–32. 7. Klahr S, Levey AS, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease. N Eng J Med. 1994;330(13):877–84. 8. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47:1703–20. 9. Striker G. Report on a workshop to develop management recommendations for the prevention of progression in chronic renal disease. JASN. 1995;5(7):1537–40. 10. Collins AJ, Kasiske B, et al. Excerpts from the United States Renal Data System 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. AJKD. 2005;45(1), Suppl 1 (January):S61. 11. Borch-Johnsen K, Norgaard K, et al: Is diabetic nephropathy an inherited complication? Kidney Int. 1992;41:719–22. 12. Selby JV, FitzSimmons SC, et al. The natural history and epidemiology of diabetic nephropathy. JAMA. 1990;263(14):1954–60. 13. Genetic Determinants of Diabetic Nephropathy. The Family Investigation of Nephropathy and Diabetes (FIND). JASN. 2003;14: S202–S204. 14. Kramer HJ, Nguyen QD, Curhan G, et al. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289(24):3273–7. 15. Mogyorosi A, and Ziyadeh FN. Update on pathogenesis, markers and management of diabetic nephropathy. Curr Opin Nephrol Hypertens. 1996;5:243–53. 16. Messent JWC, Elliott TG, Hill RD, et al. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twentythree year follow-up study. Kidney Int. 1992;41:836–9. 17. Parving HH, Lehnert H, Brochner-Mortensen J, et al. Irbesartan in patients with type 2 diabetes. N Eng J Med. 2001;345(12):870–8. 18. Lewis EJ, Hunsicker LG, et al. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. N Eng J Med. 1993;329:1456–62.

19. Nakao N, Yoshimura A, Morita H, et al. Combination treatment of angiotensin—II receptor blocker and angiotensin-convertingenzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361(9352):117–24. 20. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J Med. 1993;329(14):977–86. 21. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–13. 22. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Eng J Med. 1998;339(2):69–75. 23. Clark CM, Jr, Lee DA. Prevention and treatment of the complications of diabetes mellitus. N Eng J Med. 1995;332(18):1210–7. 24. Bojestig M, Arnqvist HJ, et al. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Eng J Med. 1994;330:15–8. 25. Bennet PH, Haffner S, et al. Screening and management of microalbuminuria in patients with diabetes mellitus: Recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee on the Council on Diabetes Mellitus of the National Kidney Foundation. Am J Kid Dis. 1995;25(1):107–12. 26. Collins AJ, Kasiske B, et al. Exerpts from the United States Renal Data System 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. AJKD. 2005;45(1):Suppl 1:S61. 27. Klag MJ, Whelton PK, Randall BL, et al. End-stage renal disease in African-American and white men. 16-year MRFIT findings. JAMA. 1997;277:1293–8. 28. Norris KC, Agodoa LY. Unraveling the racial disparities associated with kidney disease. Kidney Int. 2005;68:914–24. 29. Tierney WM, McDonald CJ, Luft FC. Renal disease in hypertensive adults: effect of race and type 2 diabetes mellitus. Am J Kidney Dis. 1989;13:485–93. 30. Rostand SG, Brown G, Kirk KA, et al. Renal insufficiency in treated essential hypertension. N Eng J Med. 1989;320:684–8. 31. Schulman NB, Ford CE, Hall WD, et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function: results from the Hypertension Detection and Follow-up Program. Hypertension. 1989;13(suppl):S180–S193. 32. Agodoa LY, Appel L. African american study of kidney disease and hypertension. JAMA. 2001;285(21):2719–28. 33. Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Annals Internal Med. 2005;142(5):342–51. 34. Hansson L, Zanchetti A, Curruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351(9118):1755–62. 35. Kramer B, Schweda F. Rami in non-diabetic renal failure (REIN study). Lancet. Vol 350, Issue 9079, p. 736. 36. Kitiyakara C, Eggers P, Kopp JB. Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. Am J Kid Dis. 2004;44(5):815–25. 37. Cattran D. Management of membranous nephropathy: When and what for treatment. J Am Soc Nephrol. 2005;16:1188–94. 38. Van Paassen P, van Rie H, Tervaert JW, et al. Signs and symptoms of thin basement membrane nephropathy: A prospective regional study on primary glomerular disease—The Limburg Renal Registry. Kidney Int. 2004;66(3):909–13. 39. Feehally J, Barratt J. IgA Nephropathy. J Am Soc Nephrol. 2005;16:2088–97. 40. Suzuki K, Honda K, Tanabe K, et al. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003;63(6):2286–94.


63 41. Praga M, Gutierrez E, Gonzalez E, et al. Treatment of IgA nephropathy with ACE inhibitors: A randomized and controlled trial. JASN. 2003;14:1578–83. 42. Hogg RJ, Lee J, Nardelli NA, et al. Multicenter, placebo-controlled trial of alternate-day prednisone (QOD-PRED) or daily omega-3 fatty acids (OM-3 FA) in children and young adults with IgA nephropathy (IgAN). Report of the Southwest Pediatric Nephrology Study Group. Abstract SU-PO 979. JASN. 2003;14:751A. 43. Rodriguez-Iturbe B. Acute poststreptococcal glomerulonephritis. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney. 4th ed. Chap. 63. Boston: Little, Brown & Co; 1986. 44. Pinto SW, Sesso R, Vasconceles E, et al. Follow-up of patients with epidemic poststreptococcal glomerulonephritis. Am J Kid Dis. 2001;38(2):249–55. 45. Gabow PA. Autosomal dominant polycystic kidney disease. N Eng J Med. 1993;329(5):322–42. 46. Peters DJ, et al. Chromosome 4 localization of a second gene for autosomal dominant polycystic disease. Nat Genet. 1993;5(4): 359–62. 47. Grantham J. Editorial: “Dangerfield’s disorders”: rise to the forefront. NephSAP. 2005;4:161–5. 48. Sandler DP, Weinberg CR. Analgesic use and chronic renal disease. N Engl J Med. 1989;321:1126–7. 49. Pommer W, Glaeske G, Molzahn M. The analgesic problem in the Federal Republic of Germany: Analgesic consumption, frequency of analgesic nephropathy and regional differences. Clin Nephrol. 1986;26:273–8. 50. Gault MH, Barrett BJ. Analgesic nephropathy. AJKD; Vol 332, no 3. 1998; p. 351–60. 51. Braden GL, O’Shea MH, Mulhern JG, et al. Acute renal failure and hyperkalemia associated with cyclooxygenase-2 inhibitors. Nephrol Dial Transplant. 2004;19:1149. 52. Eknoyan G. Current status of chronic analgesic and nonsteroidal antiinflammatory nephropathy. Curr Opin Nephrol Hypertens. 1994;3: 182–8. 53. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Eng J Med. 1994;331(25):1675–9. 54. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Eng J Med. 2005;352:1092. 55. Kaufman J, Dhakal M, et al. Community-acquired acute renal failure. Am J Kidney Dis. 1991;17:191–8. 56. Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74:243–8. 57. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Disease. 2002;39(5):930–6. 58. Metnitz PG, et al. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med. 2002;30(9):2051–8. 59. Morgera S, Kraft AK, Siebert G, et al. Long-term outcomes in acute renal failure patients treated with continuous renal replacement therapies. Am J Kid Dis. 2002;40(2):275–9. 60. Birtch R, Krzossok S, et al. Acetylcysteine for prevention of contrast nephropathy: meta-analysis. Lancet. 2003;362:598–603. 61. Mehta RL, et al. Program to Improve Care in Acute Renal Disease: spectrum of acute renal failure in the intensive care unit: the PICARD experience. IK. 2004;66:1613–21.

Renal and Urinary Tract Disease

1099

62. Vupputuri S, Batuman V, Muntner P, et al. The risk for mild kidney function decline associated with illicit drug use among hypertensive men. Am J Kid Dis. 2004;43(4):629–35. 63. Neugarten J, Gallo GR, et al. Amyloidosis in subcutaneous heroin abusers (“skin poppers’amyloidosis”). Am J Med. 1986;81:635–40. 64. Menchel S, Cohen D, Gross E, et al. A protein-related renal amyloidosis in drug addicts. Am J Pathol. 1983;112:195–9. 65. Humphreys, MH. Human immunodeficiency virus-associated glomerulosclerosis. Kidney Int. 1995;48:311–20. 66. Rao TKS, Friedman EA. Outcome of severe acute renal failure in patients with acquired immunodeficiency syndrome. Am J Kidney Dis. 1995;25(3):390–8. 67. Mocroft A, et al. Decline in AIDS and death rates in the EuroSIDA study: an observational study. Lancet. 5 July, 2003;362(9377):22–9. 68. Boyce TG, Swerdlow DL, Griffin PM. Escherichia Coli 0157:H7 and the hemolytic-uremic syndrome. NEJM. 1995;333(6):364–8. 69. Morbidity and Mortality Weekly Report: Outbreak of Escherichia coli O157:H7 infections associated with drinking unpasteurized commercial apple juice. JAMA. 1996;276(23):1865. 70. Remuzzi G, and Ruggenenti P. The hemolytic uremic syndrome. Kidney Int. 1995;47:2–19. 71. Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Eng J Med. 1993;329(18):1328–34. 72. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S–13S. 73. Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Disease-A-Month. 2003;49(2):53–70. 74. Stamatelou KK, Francis ME, Jones CA, et al. Time trends in reported prevalence of kidney stones in the United States: 1976–1994. Kidney Int. 2003;63:1817. 75. Curhan GC, Willett WC, Rimm EB, et al. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med. 1993;328:833. 76. Pak CYC. Etiology and treatment of urolithiasis. Am J Kidney Dis. 1991;18(6):624–37. 77. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106. 78. Gronbery H. Prostate cancer epidemiology. Lancet. 2003;361: 859–64. 79. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer Surveillance Series: Interpreting trends in prostate cancer—Part I: Evidence of the screening in recent prostate center incidence, mortality, and survival rates. J Natl Cancer Inst. 1999;91(12):1017–24. 80. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003;349(3):215–24. 81. Napalkov P, Maisonneuve P, Boyle P. Worldwide patterns of prevalence and mortality from benign prostatic hyperplasia. Urology. 1995;46(3 Suppl A):41–6. 82. Boyle P. New insights into the epidemiology and natural history of benign prostatic hyperplasia. Progress in Clinical & Biological Research. 1994;386:3–18. 83. McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Eng J Med. 2003;18:349(25):2387–93. 84. Website: www.clinicaltrials.gov


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64

Diabetes Janice C. Zgibor • Janice S. Dorman • Trevor J. Orchard

 INTRODUCTION

Diabetes is an important chronic disease both in terms of the number of persons affected and the considerable associated morbidity and early mortality. In this review we will focus on the epidemiology and public health implications of diabetes. Diabetes is a chronic disease in which there is a deficiency in the action of the hormone insulin. This may result from a quantitative deficiency of insulin, an abnormal insulin level, resistance to its action, or a combination of deficits. Two major forms of the disease are recognized: type 1 diabetes (formerly referred to as insulin-dependent diabetes) which comprises about 10% of all cases, and type 2 diabetes (formerly referred to as non-insulin-dependent diabetes), which accounts for about 90% of the cases. Type 2 diabetes may occasionally occur as a result of other diseases such as acromegaly and Cushing’s syndrome. Metabolic disorders such as hemochromatosis, can also cause the disease. Diabetes can also be drug induced, for example, by steroids and possibly by the thiazide diuretics and oral contraceptives. Finally, diabetes may occur secondary to disease processes directly affecting the pancreas, such as cancer or chronic pancreatitis, which destroy the insulin-producing beta cells in the pancreatic islets (of Langerhans). However, these are relatively rare causes of diabetes. In addition to these primary and secondary types of diabetes, two further classifications of abnormalities of glucose tolerance are of note. Gestational diabetes occurs during pregnancy but typically remits shortly after delivery. Impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), now termed “prediabetes,” are conditions in which blood glucose is elevated but not high enough to be classified as diabetes. Nonetheless these conditions may carry some increased risk of large vessel (e.g., coronary heart) disease.1 Both gestational diabetes2 and prediabetes3 carry an increased risk for the subsequent development of type 2 diabetes. The types of diabetes and clinical stages are outlined in Fig. 64-1. The other potential precursor to type 2 diabetes is the metabolic syndrome. The metabolic syndrome represents a set of risk factors that predispose individuals to both cardiovascular disease and diabetes. Metabolic syndrome factors include abdominal obesity, atherogenic dyslipidemia (elevated triglyceride levels, smaller LDL particle size, and low HDL cholesterol), raised blood pressure, insulin resistance (with or without glucose intolerance) and prothrombotic and proinflammatory states. The metabolic syndrome is associated with the prediction of both diabetes and cardiovascular disease independent of other factors.4 It is hypothesized that clinical improvement in these factors may prevent or delay the onset of diabetes and cardiovascular disease.  DIAGNOSIS

The diagnosis of type 1 diabetes is fairly straightforward. Type 1 diabetes often, though by no means always, has its onset in childhood. Classically the child will have symptoms of excessive thirst

(polydipsia), excessive urination (polyuria), and weight loss. In a child with high blood sugar, these symptoms almost invariably point to type 1 diabetes. Patients lose virtually all capacity to produce insulin and without treatment they develop severe metabolic disturbances, including ketoacidosis and dehydration, which can lead to death. As death from ketoacidosis is largely preventable, the continuing though small number of deaths from this cause represents a challenge to our preventive health services.5,6 In an international study, wide variations in mortality from acute diabetes complications were noted, with high rates in Japan and low rates in Finland.7 This variation was thought to reflect disease incidence (low in Japan and high in Finland) and resulting availability of skilled health care.7 Type 2 diabetes usually presents in adulthood. In the past, the terms non-insulin-dependent, maturity-onset, and mild diabetes have been used. These terms are somewhat misleading, since type 2 diabetes may present in youth and the complications may be far from mild. Patients with type 2 diabetes, however, produce some insulin, although its secretion is often delayed, and there is usually some resistance to its action in the peripheral tissues. This resistance is often associated with elevated concentrations of insulin, particularly in newly recognized cases. However, concentrations are now recognized to be low in many type 2 diabetes subjects, especially after accounting for obesity and using more specific assays.8 In type 2 diabetes, often the diagnosis is not made on the basis of classic symptoms of diabetes but rather on the presentation of one of the complications. Such complications can be macrovascular (accelerated atherosclerosis with coronary artery, peripheral vascular or cerebrovascular manifestations), microvascular (with disease of the small vessels in the kidneys or the eyes), or neuropathic (which may take the form of a variety of neurological syndromes). In addition, the disease may also be recognized as a result of routine screening for elevated blood glucose or by the presence of glucose in the urine. Some cases, however, may be diagnosed because of classic symptoms. (Table 64-1) Over the years, both the diagnostic criteria and dose of glucose in the standard test for type 2 diabetes (i.e., the oral glucose tolerance test (OGTT)) have varied. Current diagnostic criteria from the American Diabetes Association (ADA) and the World Health Organization (WHO) are presented in Table 64-2. The WHO and ADA criteria differ in that the ADA relies on IFG while the WHO relies on both fasting and post challenge (2 hour) glucose levels. The preference for using a fasting test only, rather than a full OGTT is largely based on the concept that diagnostic testing would be easier and therefore more frequent. The controversy surrounding these tests is based on the fact that these diagnostic tests may identify somewhat different populations.9 Further, data from the Cardiovascular Health Study (CHS) in older Americans suggests that IGT is more predictive of CVD than its fasting corollary IFG.10 The impact of these different criteria on the prevalence of diabetes has been studied by many investigators. 1101

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Noncommunicable and Chronic Disabling Conditions

Stages

Normogloycaemia Normal glucose tolerance

Types

Hyperglycaemia Diabetes mellitus Impaired glucose regulation Not insulin Insulin IGT and/or IFG requiring requiring for control

Insulin requiring for survival

Type 1 • Autoimmune • Idiopathic Type 2∗ • Predominantly insulin resistance • Predominantly insulin secretory defects

Other specific types∗ Gestational diabetes

Because of changes in the criteria for the diagnosis of type 2 diabetes, estimates of the prevalence and temporal trends of type 2 diabetes are difficult, if not impossible, to evaluate. Furthermore, the different criteria for type 2 diabetes used by different research groups and countries make geographical comparisons difficult. As major efforts are made to identify the specific genetic abnormalities in diabetes and to define the disease on the basis of genotypic rather than phenotypic expression, such as hyperglycemia and insulin levels, there may soon be yet another way of classifying diabetes. Furthermore the development of the glycosylated hemoglobin (GHB) test,11 which provides an integrated measure of hyperglycemia over the prior two to three months, represents another dimension that may add to the ability to define diabetes. Currently, clinicians use hemoglobin A1c for this test, although it is not accepted for diagnostic purposes due to methodological variation and other considerations.

Heterogeneity in Primary Diabetes Although the two different primary types of diabetes have been described, the classification of diabetes into these groups is not simple. For example, children classified with type 1 diabetes may actually have Maturity-Onset Diabetes (MODY),12,13 which is characterized by an autosomal dominant pattern of inheritance and a low frequency ketoacidosis. Children in such families, however, are often treated with insulin, although they do not depend on insulin for their survival and actually have type 2 diabetes. Since MODY is uncommon, accounting for <5% of all type 2 diabetes cases, this section will focus on type 1 diabetes and type 2 diabetes. Similarly 5–10% of adults with presumed type 2 diabetes, have evidence of autoantibodies seen in type 1 diabetes, and may have an incomplete form of type 1 diabetes, sometimes called LADA (latent autoimmune diabetes of adulthood).14

Type 1 Diabetes Descriptive Epidemiology. Type 1 diabetes is caused by the autoimmune destruction of the beta cells of the pancreas, and represents approximately 10% of all cases with diabetes. At present, lifelong insulin therapy is the only treatment for the disease. Without exogenous insulin injections, individuals with type 1 diabetes will not survive. Although the prevalence of type 1 diabetes is <1% in most populations, the geographic variation in incidence is

Figure 64-1. Disorders of glycemia: etiological types and clinical stages. ∗In rare instances patients in these categories (e.g., Vacor Toxicity, Type 1 presenting in pregnancy, etc.) may require insulin for survival. (Source: Adapted from the World Health Organization.50)

enormous, ranging from <1/100,000 per year in China to approximately 40/100,000 per year in Finland (Fig. 64-2).15 The only chronic childhood disorder more prevalent than type 1 diabetes is asthma. It has been estimated that approximately 20 million people worldwide, mostly children and young adults, have type 1 diabetes.16 The incidence of type 1 diabetes is increasing worldwide at a rate of about 3% per year.17 This trend appears to be most dramatic in the youngest age groups, and is completely unrelated to the current increase in type 2 diabetes in children. More children with beta cell autoantibodies, a hallmark of type 1 diabetes, are being diagnosed with the type 1 diabetes around the world each year. Although the peak age at onset is at puberty, type 1 diabetes can also develop in adults. Epidemiologic studies have revealed no significant gender differences in incidence among individuals diagnosed before age 15.18 However, after age 25, the male-to-female incidence ratio is approximately 1:5. Significant differences have also been reported depending on socioeconomic status, however results have been conflicting.19 Incidence of type 1 diabetes in Lithuanians aged 0–39 years varies by the urban-rural setting, and the time change differs for men and women during 1991–2000. There is also a notable seasonal variation in the incidence of type 1 diabetes in many countries, with lower rates in the warm summer months, and higher rates during the cold winter.20 Genetic Susceptibility. First degree relatives have a higher risk of developing type 1 diabetes than unrelated individuals from the general population (approximately 6% vs. <1%, respectively).21 These data suggest that genetic factors are involved with the development of the disease. At present, there is evidence that more than 20 regions of the genome may be involved in genetic susceptibility to type 1 diabetes. However, none of the candidates identified have a greater influence on type 1 diabetes risk than that conferred by genes in the HLA (Human Leukocyte Antigens) region of chromosome 6. This region contains several hundred genes known to be involved in immune response. Those most strongly associated with the disease are the HLA class II genes (i.e., HLA-DR, DQ, DP). These molecules are involved in the processing of antigens from inside the cell to its surface in order to stimulate an immune response. However, it has become apparent that neither genetic nor environmental risk factors alone contribute to the development of type 1 diabetes. Rather, it is clear that gene-environmental interactions are involved.


64 TABLE 64-1. PERCENT OF POPULATION WITH PHYSICIAN DIAGNOSED AND UNDIAGNOSED DIABETES AND IMPAIRED GLUCOSE TOLERANCE IN THE U.S. POPULATION AGE ≥ 20 YEARS (NHANES III) FROM 1988 TO 1994167

≥ 20

20–39

40–49

50–59

60–74

≥ 75

Classification

 aDiagnosed Diabetes All Races Both Sexes Male Female White Both Sexes Male Female Black Both Sexes Male Female

5.1 4.9 5.4

1.1 1.1 1.1

3.9 3.3 4.4

8.0 9.6 6.6

12.6 11.8 13.3

13.2 13.8 12.8

5.0 5.0 5.0

1.0 1.2 0.9

3.3 3.0 3.5

7.5 9.9 5.3

11.3 10.9 11.7

12.6 13.2 12.3

6.9 5.9 7.8

1.6 1.6 1.6

6.2 5.5 6.7

13.8 13.0 14.5

20.9 16.8 23.9

17.5 14.7 19.0

Prediabetes†

 bUndiagnosed Diabetes FPG ≥ 126mg/dL All Races Both Sexes Male Female White Both Sexes Male Female Black Both Sexes Male Female

2.7 3.0 2.4

0.6 0.5 0.6

2.5 3.6 1.6

4.6 3.3 5.8

6.2 8.4 4.5

5.7 7.3 4.7

2.5 2.9 2.1

0.4 0.4 0.4

2.1 2.9 1.3

4.0 3.5 4.4

6.0 8.2 4.3

4.9 6.0 4.3

3.4 2.6 4.0

1.4 1.1 1.7

3.9 4.3 3.7

6.1 3.0 8.5

7.7 6.6 8.5

4.9 0.0 7.6

 bImpaired Fasting Glucose (110–125 mg/dL) All Races Both Sexes Male Female White Both Sexes Male Female Black Both Sexes Male Female

6.9 8.7 5.2

2.8 4.5 1.2

7.1 10.1 4.3

8.0 9.2 6.8

14.0 16.2 12.3

14.1 17.9 11.9

6.9 9.0 5.0

2.7 4.8 0.8

6.7 10.2 3.2

7.7 9.1 6.4

13.9 15.6 12.5

13.7 18.4 11.0

6.2 6.7 5.8

2.8 3.3 2.5

7.0 6.7 7.2

10.0 9.3 10.5

12.1 15.4 9.8

15.7 18.7 14.1

aBased on self-report that the persons had been told by a doctor that they had diabetes, plus current or past use of diabetic therapy. bBased on the results of 75-g oral glucose tolerance test conducted in the morning after an overnight 10- to 16-hour fast in persons with no medical history of diabetes.

Figure 64-2. Type 1 diabetes incidence rates worldwide. FIN = Finland, SAR = Sardinia, SWE = Sweden, NOR = Norway, US-WI = US-Wisconsin, US-PA = US-Pennsylvania, ITA = Italy, ISR = Israel, JAP = Japan, CHI = China

1103

TABLE 64-2. CRITERIA FOR THE CLASSIFICATION OF DIABETES

Diabetes*

Age

Diabetes

Gestational diabetes¶

ADA168

WHO

A. Symptoms (polyurea, polydipsia, unexplained weight loss) of diabetes and casual (anytime of day without regard to meals) plasma glucose ≥ 200mg/dL or B. a,§ Fasting plasma glucose ≥ 126 mg/dL or C. 2 hour plasma glucose ≥ 200 mg/dL during an OGTT‡ Impaired fasting glucose Fasting glucose 100mg/ dL to 125 mg/dL

A. Confirmatory symptoms or B. a,§ Fasting plasma glucose ≥ 126 mg/dL and 2 hour plasma mg/dL glucose ≥ 200 during an OGTT‡

Fasting ≥ 95 mg/dL (plasma) 1 h ≥ 180 mg/dL (plasma) 2 h ≥ 155 mg/dL (plasma) 3 h ≥ 140 mg/dL (plasma)

Women meeting the WHO criteria for diabetes or IGT are classified as having gestational diabetes mellitus

Impaired glucose tolerance 2 h plasma glucose§ 140 mg/dL to 199 mg/dL Two or more of the following values after a 100-g oral glucose load after an overnight fast (8–14 h)

∗Diabetes is subclassified as: Gestational: Diabetes or impaired glucose tolerance is first recognized during pregnancy. Usually remits postpartum a criteria need to be present on at least two occasions in the absence of unequivocal hyperglycemia. †Prediabetes = impaired fasting glucose or impaired glucose tolerance. ‡Following 75 g or oral glucose load. §Fast = no caloric intake for ≥ 8 hours. ¶ Risk factor assessment should be done at first prenatal visit.

A. IDDM1. The HLA class II genes, also referred to as insulindependent diabetes mellitus 1(IDDM1), contribute approximately 40–50% of the heritable risk for type 1 diabetes.22 When evaluated as haplotypes, DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 are most strongly associated type 1 diabetes in Caucasian populations. They are in linkage disequilibrium with DRB1*03 and DRB1*04, respectively. Specific DRB1*04 alleles also modify the risk associated with the DQA1*0301-DQB1*0302 haplotype. Other reported high risk haplotypes for type 1 diabetes include DRB1*07-DQA1*0301-DQB1*0201 among AfricanAmericans, DRB1*09-DQA1*0301-DQB1*0303 among Japanese, and DRB1*04-DQA1*0401-DQB1*0302 among Chinese. DRB1*15-DQA1*0602-DQB1*0102 is protective and associated with a reduced risk of type 1 diabetes in most populations. Recent reports suggest that other genes in the central, class I, and extended class I regions may also increase type 1 diabetes risk independent of HLA class II genes.23,24 Individuals with two high risk DRB1-DQA1-DQB1 haplotypes have a significantly higher type 1 diabetes risk than individuals with no high risk haplotype. The type 1 diabetes risk among those with only one susceptibility haplotype is also increased, but the effect is more modest. As shown in Table 64-3, relative risk estimates range from 10 to 45 and 3 to 7, respectively, for these groups, depending on race.21


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Noncommunicable and Chronic Disabling Conditions

TABLE 64-3. SEVERAL TYPE 1 DIABETES SUSCEPTIBILITY GENES Gene HLA-DQB1 INS CTLA4

Locus 6p21.3 11p15. 5 2q31–35

Variant *0201 & *0302 Class I Thr17Ala

Estimated RR† 3–45 1–2 1–2

RR relative risk

In terms of absolute risk, Caucasian individuals with two susceptibility haplotypes have an approximately 6% chance of developing type 1 diabetes through age 35 years. However, this figure is substantially lower in populations where type 1 diabetes is rare (i.e., < 1% among Asians). In addition to IDDM1, two other genes are now known to influence type 1 diabetes risk.25 These include insulin (INS) and cytotoxic T lymphocyte-associated 4 (CTLA-4). B. INS. The INS gene, located on chromosome 11p15.5, has been designated as IDDM2. Positive associations have been observed with a nontranscribed variable number of tandem repeat (VNTR) in the 5’ flanking region.26,27 There are two common variants. The shorter class I variant predisposes to type 1 diabetes (approximate relative increase: 1–2), whereas the longer class III variant appears to be dominantly protective. The biological plausibility of these associations may relate to the expression of insulin mRNA in the thymus. Class III variants appear to generate higher levels of insulin mRNA than class I variants. Such differences could contribute to a better immune tolerance for class III-positive individuals by increasing the likelihood of negative selection for autoreactive T-cell clones. The effect of INS appears to vary by ethnicity, with lesser effects in non-Caucasian populations.28 C. CTLA-4. The CTLA-4 gene is located on chromosome 2q31–35,25 where multiple type 1 diabetes genes may be located. CTLA-4 variants have been associated with type 1 diabetes, as well as other autoimmune disease. CTLA-4 negatively regulates T-cell function. However, impaired activity, which has been associated with the Thr17Ala variant, may increase type 1 diabetes risk. Overall, the relative increase in risk for the CTLA4Ala17 variant has been estimated as approximately 1.5. Environmental Risk Factors. The epidemiological patterns described above suggest that environmental factors contribute to the etiology of the type 1 diabetes. In particular, the recent temporal increase in type 1 diabetes incidence points to a changing global environment rather than variation in the gene pool, which require the passage of multiple generations. Twin studies also provide evidence for the importance of environmental risk factors for type 1 diabetes. Type 1 diabetes concordance rates for monozygous twins are higher than those for dizygous twins (approximately 30% vs. 10%, respectively).22 However, most monozygous twin pairs remain discordant. Thus, type 1 diabetes cannot be completely genetically determined. Environmental risk factors are thought to act as either “initiators” or “accelerators” of beta cell autoimmunity, or “precipitators” of overt symptoms in individuals who already have evidence of beta cell destruction.29 They also may function by mechanisms that are directly harmful to the pancreas, or by indirect methods that produce an abnormal immune response to proteins normally present in cells. The type 1 diabetes environmental risk factors that have received most attention are viruses, infant nutrition, and hygiene. A. Viruses. Enteroviruses, especially Coxsackie virus B (CVB), have been the focus of numerous ecologic and case-control studies.30 CVB infections are frequent during childhood and are known to have systemic effects on the pancreas. Recent

prospective studies are helping to elucidate the role of viruses to the etiology of type 1 diabetes. For example, enteroviral infections occurring as early as in utero appear to increase a child’s subsequent risk of developing the disease.31,32 Other viruses, including mumps,33 cytomegalovirus,34 rotavirus,35 and rubella,36 have also been associated with the disease. B. Nutrition. Another hypothesis that has been the subject of considerable interest relates to early exposure to cow’s milk protein and the subsequent development of type 1 diabetes. The first epidemiologic observation of such a relationship was by Borch-Johnsen et al., who found that type 1 diabetes children were breast-fed for shorter periods of time than their non-diabetic siblings or children from the general population.37 The authors postulated that the lack of immunologic protection from insufficient breast-feeding may increase risk for type 1 diabetes later during childhood. It was also postulated that shorter duration of breastfeeding may indirectly reflect early exposure to dietary proteins that stimulate an abnormal immune response in newborns. Most recently it has been hypothesized that the protective effect of breast-feeding may be due, in part, to its role in gut maturation.38–40 Breast milk contains growth factors, cytokines, and other substances necessary for the maturation of the intestinal mucosa. Breast-feeding also protects against enteric infections during infancy, and promotes proper colonization of the gut. Interestingly, enteroviral infections can also interfere with gut immunoregulation, which may explain the epidemiologic associations between viral infections and type 1 diabetes. C. Hygiene. The role of hygiene in the etiology of type 1 diabetes is also currently being explored.41,42 It has been hypothesized that delayed exposure to microorganisms due to improvements in standard of living hinders the development of the immune system, such that it is more likely to respond inappropriately when introduced to such agents at older (compared to younger) ages. This explanation is consistent with recent reports indicating that factors such as day care attendance,41 sharing a bedroom with a sibling, and contact with pets are protective against type 1 diabetes.42 Further studies are needed to determine if improved hygiene can explain the temporal increase in the incidence of type 1 diabetes worldwide. Treatment and Prevention of Type 1 Diabetes. At the present time, there is no way to prevent type 1 diabetes. Lifelong insulin injections are the only available treatment for the disease. Although a cure for type 1 diabetes is currently unavailable, several large multinational investigations have been designed to evaluate a variety of primary and secondary disease interventions. The tested interventions have included prophylactic nasal insulin (Diabetes Prediction and Prevention Project [DIPP] in Finland),43 oral and injected insulin (Diabetes Prevention Trial-1 [DPT-1] in the U.S.),44 as well as high doses of nicotinamide (European Nicotinamide Diabetes Intervention Trial [ENDIT]),45 and the avoidance of cow’s milk exposure during the first six months of life (trial to reduce in genetically at-risk [TRIGR] in Finland, U.S. and other countries).46 These investigations focus on “prediabetic” individuals identified from families with at least one child with type 1 diabetes. DIPP and TRIGR use HLA-DQB1 screening and recruit only individuals at increased genetic risk. The remaining trials recruit relatives with evidence of beta cell autoimmunity as a pre-clinical marker for disease. To date, none of these interventions have prevented or delayed the onset of type 1 diabetes.44–46 However, with the formation of Type 1 Diabetes TrialNet47 a collaborative network of clinical centers and experts in diabetes and immunology, new intervention strategies are currently being planned. It is ultimately hoped that through genetic testing, individuals at high risk for type 1 diabetes could be identified prior to the onset of the disease—at a time when primary prevention strategies could be safely administered. It is most likely that such predictive genetic testing would be offered to families with an affected individual before it was made available to the general population.


64

Type 2 diabetes Epidemiology. Type 2 diabetes is more difficult to define than type 1 diabetes. The rates among and within countries vary dramatically, partially depending on the specific classification criteria used for type 2 diabetes. Worldwide, it is estimated that in 2000, 171 million people had diabetes. The prevalence is expected to increase to 366 million by 2030 according to estimates from the WHO.48 Type 2 diabetes occurs in all races, but the prevalence tends to be higher among American Indians, Micronesians, Polynesians, African-Americans, and Mexican Americans.49 The prevalence of diabetes is higher in developed countries compared to developing countries, however a considerable increase in prevalence is already being observed in developing nations due to urbanization and westernization.50 For example, in communities where there has been rapid economic development, such as in Korea51 and among the Pima Indians52 there appears to be a marked and rapid increase in the incidence and prevalence of type 2 diabetes.51 In 2005, 14.6 million persons in the United States were estimated to have diagnosed diabetes according to the National Health Interview Survey. This represents an increase from 5.8 million in 1980. It is also estimated that almost one-third as many cases (6.2 million) of type 2 diabetes are undiagnosed. This is made clear by data from the National Health and Examination Survey where the overall prevalence of diagnosed and detected diabetes in the adult U.S. population (> 20 years ) is estimated to be about 7% (~20.8 million), with 1.4 million newly diagnosed cases each year.53 Risk Factors. A pattern of increasing mean weight of the population parallels the increasing prevalence of type 2 diabetes.54 Similarly, within a population there is a strong correlation between degree of obesity and risk of type 2 diabetes.52,55,56 The prevalence of obesity in the United States, defined as a Body Mass Index (BMI) of greater than 30 kg/m2, has increased from 12% in 1991 to 19.8% in 2000,57 for a total of 44.3 million obese adults. The highest prevalence for obesity was reported in Mississippi at 25.9% in 2001. A corresponding increase is reported in diabetes prevalence from 4.9% in 1990 to 7.3% and 7.9% in 2000 and 2001 respectively.57 Interestingly, within a country such as the United States, one generally finds an inverse relationship between obesity and socioeconomic class,58 with higher rates of type 2 diabetes in lower socioeconomic groups.59 However, a risk factor associated with higher socioeconomic status is decreased physical activity. As socioeconomic status increases, the overall level of physical activity generally declines, especially that related to work. Further, lower rates of physical activity are found in ethnic minorities.60 Thus, at the same time that caloric intake is increasing, physical activity is decreasing, most likely leading to an increased prevalence of obesity within the population. Data from the South Pacific suggest that physical activity itself may be an independent risk factor for type 2 diabetes, separate from obesity,61 while a recent prospective study in the U.S. also suggests reduced physical activity predicts type 2 diabetes.62 According to national data from 2003, approximately one-half of U.S. adults age 18–44 achieved recommended levels of physical activity (at least 30 min/day at least 5 days per week).60 Nutrition plays a role in both diabetes risk and prevention, while no clear evidence exists supporting a low fat diet for diabetes risk or prevention, the type and quality of fat may be more important than total fat intake. Substituting unsaturated fat for saturated and trans fat are important, however, for prevention strategies. Also, substituting complex carbohydrates such as whole grains for refined grain foods will help individuals achieve a healthy body weight and thus prevention of diabetes and/or cardiovascular disease.63

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developing type 1 diabetes, they may also play a role in type 2 diabetes.65 Several candidate genes have been found to contribute to type 2 diabetes susceptibility, including mutations in the insulin gene,66 the glucokinase gene,67 and mitochondrial gene.68 However, it is unlikely that any of these alterations explain the genetic susceptibility to type 2 diabetes on a population basis. Thus family and pedigree studies are still needed to determine the contribution of these genetic markers to the development of type 2 diabetes. Diabetes Prevention. The development of type 2 diabetes is a twostage process, with the first stage being resistance to insulin’s action (likely exacerbated by obesity and physical inactivity) and the second stage being failure of the pancreas to increase insulin secretion enough to overcome this resistance. This theory receives support from a number of reports including one from the Pima Indians, which showed differing predictive values of fasting and post challenge insulin values for developing type 2 diabetes consistent with a hyperinsulinemic phase followed by eventual insulinopenia.69 The interaction between obesity and physical inactivity in relation to the prevention of type 2 diabetes has been studied recently through well-conducted randomized controlled trials. These trials applied sound methods for implementing diabetes prevention strategies, and will be briefly reviewed. The focus of these trials was lifestyle modification including weight loss and increased physical activity. The Da Qing study70 followed 577 subjects with IGT from local clinics. Subjects were randomized at the clinic level to diet, exercise, diet and exercise, or a control group and followed for six years. Intervention groups experienced a significantly lower incidence of type 2 diabetes compared to controls (31%, 46%, 42%, and 67.7% respectively). A lower incidence of diabetes was also seen in those with lower BMIs. Similar to the Da Qing trial, the Finnish Diabetes Prevention Study71 examined whether the onset of type 2 diabetes could be prevented through lifestyle modification in subjects with IGT. Five hundred twenty-two subjects were randomized to an intervention group that received individualized counseling aimed at weight reduction, dietary fat reduction, saturated fat reduction, increased dietary fiber, and increased physical activity. The trial demonstrated that lifestyle changes significantly reduced the risk of diabetes in middle-aged, overweight subjects. After a modest (4.7%) weight loss, those in the intervention group experienced a 58% reduction in incidence of diabetes over a mean follow-up of 3.2 years. Moreover, blood pressure, triglycerides, and high-density lipoprotein cholesterol levels also improved significantly. The study to prevent noninsulin-dependent diabetes mellitus (STOP-NIDDM) trial72 randomized 714 (IGT) subjects to acarbose and 715 subjects to a control group. After a mean follow-up of 3.3 years, compared to controls, there was a 25% relative risk reduction in the incidence of diabetes. Finally, in the Diabetes Prevention Program (DPP)73 3234 subjects with IGT were randomized to placebo, metformin (850 mg twice daily) or intensive lifestyle modification. The lifestyle modification consisted of weekly one-on-one counseling for a 16-week curriculum during the first 24 weeks of the study. Subsequent visits were held about once per month. The goal of the lifestyle arm was 7% weight loss and 150 minutes per week of physical activity. Intensive lifestyle modification reduced the incidence of type 2 diabetes in persons at high risk by 58% in comparison to the metformin study group in which incidence was reduced by 31%. The DPP has also shown that these interventions reduce the incidence of new metabolic syndrome by 41% (lifestyle) and 17% (metformin) compared with placebo.74

Screening Genetic Factors. Genetic factors play an extremely important role in the development of type 2 diabetes. In a large study of twins Pyke found that the concordance rates for type 2 diabetes among monozygotic twins was over 90% compared to 50% for type 1 diabetes.64 Twin studies, however, do not provide the complete story. In recent years there have been numerous studies of the relationship of genetic markers to the development of type 2 diabetes as well as of type 1 diabetes. Although HLA genes are related primarily to the risk of

The recent emphasis on diabetes prevention has prompted a growing number of blood glucose screenings. The purpose of screening is to identify asymptomatic individuals who may have diabetes, however, screening is not the same as diagnosis, as diagnostic tests are performed in individuals with signs and symptoms of the disease.75 Further, the effectiveness of diagnosing an asymptomatic individual is still speculative.76 Screening in the community setting outside a health care setting may not be completely effective because of the


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possibility of inadequate follow-up after a positive test, or repeat testing in those who are negative. Therefore this type of screening is currently not recommended.75 Screening by a health care professional or within the health care setting for pre-diabetes and diabetes should be considered in those ≥ 45 years of age, particularly in those with a BMI ≥ 25 kg/m2. In those < 45 years of age, screening should be considered if they have another risk factor for diabetes (e.g., physically inactive, first-degree relative with diabetes, member of a high-risk ethnic population, delivered a baby weighing > 9 pounds or diagnosed with gestational diabetes, are hypertensive (≥ 140/90 mmHg), high-density lipoprotein cholesterol (HDLc) level <35 mg/dL and/or a triglyceride level >250 mg/dL, have polycystic ovarian syndrome (PCOS), previously tested and had IGT or IFG, other clinical conditions associated with insulin resistance, or a history of vascular disease).75 Any screening should be followed by education about results and risk for future disease. A policy ensuring adequate follow-up should also be in place.

 MORBIDITY AND COMPLICATIONS OF DIABETES

Prior to the introduction of insulin in 1922 by Banting and Best, life expectancy of patients with type 1 diabetes was about 1–2 years. After the development and widespread use of insulin, there was a dramatic increase in life expectancy for patients with type 1 diabetes. Suddenly those with type 1 diabetes could lead relatively normal lives. However, 20–30 years later the long-term sequelae of type 1 diabetes began to become evident. Both type 1 diabetes and type 2 diabetes patients are at risk for these long-term complications. Complications come mainly from disorders of the circulation, either macrovascular, including accelerated atherosclerosis resulting in stroke, heart and peripheral vascular disease, or microvascular disorders of the kidney and retina, as well as neuropathy. The complications appear to be similar for both type 1 diabetes and type 2 diabetes, although the prevalence may be somewhat higher in type 1 diabetes mainly due to longer diabetes duration in those with type 1. The relationships with age and duration also vary between the two types of diabetes, partly because of the younger age of onset of type 1 diabetes (which leads to complications at a younger age) and the difficulty of determining the onset of type 2 diabetes (which means complications are often present at the onset of known disease). However, careful analysis controlling for these time-dependent variables suggests that the incidence of the microvascular complications is remarkably similar by true duration.77 The following discussion will mainly focus on type 1 diabetes, since these data are more complete.

Mortality Mortality rates for people with diabetes are two- to threefold higher than those without diabetes, with cardiovascular disease as the leading cause of death.78 In an international study, Diabetes Epidemiology Research International (DERI), mortality in young cohorts of type 1 diabetes cases from four different countries (the United States, Israel, Japan, and Finland) was investigated. The study showed tremendous variation in diabetes-related mortality. In addition to the high mortality from acute complications, the Japanese cohort also had a high mortality from renal disease (276/100,000/y) compared to Finland (16/100,000/y, p <0.05).79 Data from the Children’s Hospital of Pittsburgh diabetes registry as of 1982, demonstrated a sevenfold increased risk of death overall, and a 20-fold increased risk in those over the age of 20 compared to the general population.80 While over half of the deaths were due to renal disease, there was an 11-fold increased risk of death from CVD compared to the general population of the same age. These findings were particularly significant in the 30 age group. The Steno group further demonstrated the strong effect of renal disease with those developing proteinuria, having an eightfold greater risk of coronary heart disease (CHD) than a matched group who did not develop proteinuria.81 These results were supported by Krolewski et al.,82 where in type 1 diabetes subjects seen at

the Joslin Clinic,81 CHD deaths occurred early after the third decade of age, and over the next 25 years. One-half died of or had CHD. The Allegheny County registry has more recently shown an improvement in 20-year survival by diagnosis cohort (1965–69, 1970–74, 1975–79).83 When cause-specific mortality was examined, the County cohort combined with mortality from the Epidemiology of Diabetes Complications Study cohort, a significant decline in renal84 and acute complications85 was noted. There were, however, differential results by race where African-Americans experienced a fivefold excess mortality due to acute complications.85 This decline in mortality may be explained by only a decline in acute complications, but microvascular complications as well. Data from the Steno Clinic in Denmark showed declining trends in microvascular complications by diagnosis cohort at 20 year duration.86 Similar results were also shown in the EDC cohort in those who had reached 20 years of diabetes duration; however there was not a corresponding decline in CHD,87 although the number of events was relatively small. Longer follow-up is necessary to determine any definitive trends in macrovascular disease.

Diabetic Retinopathy Epidemiology. The prevalence of diabetic retinopathy is highly related to diabetes duration for both type 1 and type 2 diabetes.75 After 20 years of type 1 diabetes, virtually 100% of patients show some evidence of damage to the retina called background retinopathy. Similar prevalence rates are seen in type 2 diabetes for patients treated with insulin, although rates are lower (around 55%) for those not on insulin.88 In addition, as many as 70% of patients who have type 1 diabetes89 and 30% of patients who have type 2 diabetes88 on insulin may develop proliferative changes in the eyes that may lead to blindness. In 2002, three million adults age 18 or greater reported some type of visual disturbance. In the 20–74 age group, diabetes is the leading cause of blindness in the United States, and is responsible for approximately 12,000–24,000 new cases of blindness year. The crude prevalence of retinopathy in people over the age of 40 is 40.3% in people with diabetes compared to 3.4% in the general population.90 Prevention. Retinopathy was the primary outcome of a major U.S. study called Diabetes Control and Complications Trial (DCCT).91 This landmark study clearly demonstrated the value of intensive therapy (with normal blood sugars as a goal) for type 1 diabetes subjects in preventing or delaying the microvascular complications. Progression of retinopathy was reduced by 54% in the intensive therapy group compared to conventional therapy over a mean follow-up period of 6.5 years.92 In type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that achieving near normal glycemic control, reduced the risk of two-step progression of diabetic retinopathy by 21%,93 while reducing blood pressures resulted in a 34% risk reduction for deterioration of retinopathy by two or more steps over 7.2 years of follow-up.94 As diabetic retinopathy can be detected before it threatens vision, blindness due to diabetic retinopathy can be prevented in many cases. Detecting and treating diabetic eye disease can reduce vision loss by 50–60%.94 The Diabetic Retinopathy Study has demonstrated that individuals with severe diabetic retinopathy can be treated successfully and their vision preserved with laser photocoagulation therapy.95 It is thus important that patients and physicians be educated about the need for frequent eye examinations and that adequate clinical treatment for diabetic retinopathy be available in the community.

Renal Disease Epidemiology. Diabetic renal disease is a major cause of morbidity and mortality among those with diabetes.5,79,96,97 Diabetes is currently the leading cause of treatment for end stage renal disease (ESRD), accounting for 44% of the 42,813 new ESRD cases during 2001. According to the 2001 data, 142,963 people with diabetes have ESRD and are living on chronic dialysis or with a kidney transplant. Diabetes increases the risk of renal failure 17- to 20-fold. Approximately 40% of people with type 1 diabetes97,98 eventually develop significant


64 clinical proteinuria and renal disease. Studies from Pittsburgh89 suggest that around 70% of type 1 diabetes subjects will eventually have some degree of renal damage (i.e., including those with microalbuminuria—a more modest degree of abnormal urinary albumin excretion that is predictive of more advanced disease). The relative risk of mortality from renal disease for persons with diabetes compared to the general population is highest for those in the 15- to 44-year age group, consistent with a higher prevalence and severity in type 1 diabetes.96 Prevalence rates are somewhat lower in type 2 diabetes overall, partly because the later age of onset means many patients may have died from heart disease before there has been sufficient duration to develop renal disease. Despite recent advances in the diagnosis and treatment of renal failure in diabetes, the problem has not been resolved. Prevention. The presence of microalbuminuria appears to predict the subsequent development of diabetic nephropathy and end stage renal failure.99 Of particular note is the value of ACE inhibitors and angiotensin receptor blockers (ARB) in slowing the progression of renal disease.75 The effect of ACE inhibitors appears to be independent of any blood pressure lowering effect. Hypertension, which may be primary or secondary to the renal disease, accelerates the development of renal failure. Lipid disturbances may also predict the development of microalbuminuria.100 The major predictor, however, of the development of early diabetic renal disease is poor glycemic control.101 The value of an intensive therapy regimen was also clearly demonstrated in the DCCT (54% reduction).91 Interestingly, in type 1 diabetes, insulin resistance is emerging as a powerful predictor of nephropathy102 as well as coronary artery disease (CAD), which may explain their association. Further, much attention is being paid to the genetic susceptibility to nephropathy, as there is clearly a major genetic component.103

Neuropathy Epidemiology. Another major complication of diabetes is neuropathy. Clinically significant neurological disability usually does not occur until at least five years after the diagnosis of diabetes. The major consequences of diabetic neuropathy are pain, weakness, and loss of sensation. Parallel disorders of the autonomic nervous system may lead to problems of sexual function and urinary and gastrointestinal abnormalities. Research has focused on the metabolic causes of the nerve damage and the specific biochemical lesions that lead to neurological changes.104 One recent epidemiological study has demonstrated both a high prevalence of distal symmetrical neuropathy in type 1 diabetes, 70% after 30 years,89 and a strong relationship with cardiovascular risk factors, for example, lipid disturbances, cigarette smoking and especially hypertension.105 A major problem in diabetic neuropathy is how to measure it. Multiple techniques are currently advocated.105–107 However, this further complicates determining the actual prevalence of this complication. Prevention. It has long been recognized that strict control of blood sugar may improve neural function, for example, peripheral nerve conduction.108 The DCCT and UKPDS results also confirm the value of lower blood sugar levels in preventing/delaying clinical neuropathy.91,93 The above findings concerning blood pressure and lipids suggest that studies to evaluate the benefits of controlling these factors may also be worthwhile. Another area that has been investigated recently is the role of a new group of drugs called aldose reductase inhibitors. Although the results have been variable, most trials to date have involved late-stage neuropathy.109 A greater benefit might be seen if these metabolically active drugs were used earlier.

Macrovascular Disease and Atherosclerosis The most convincing epidemiological evidence for increased cardiovascular disease in diabetes comes from large-scale prospective studies, many of which were primarily designed to study cardiovascular disease in the general population. Studies like Framingham110 have demonstrated that the diabetic individual (uniquely defined in Framingham as “glucose intolerant”) has a greatly enhanced risk and that

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cardiovascular disease is the leading cause of death in those with diabetes.111,112 Diabetes leads to a greater than normal risk for all manifestations of atherosclerosis, including coronary, cerebrovascular, and peripheral vascular disease.110,113 The latter is so common in diabetes that half of all lower extremity amputations in the United States occur in persons with diabetes.59 In the general population women have a lower risk of CHD than men, but this advantage is lost in women with diabetes, who have rates approaching those of men.78,114–117 A meta-analysis suggests that a reduction in the gender differential for CHD in diabetes is true for CHD mortality but not for morbidity.118 The survival of diabetic patients, especially women, after a cardiac event also appears to be less than that seen in the general population.119,120 Although when it occurs, atherosclerosis is often more extensive in diabetic121,122 than in nondiabetic subjects, although not all studies show a clear relationship between blood sugar and CVD. For example in the UKPDS, HbA1c was a borderline predictor of myocardial infarction (MI) and intensive therapy had only a borderline (p 0.052) 16% reduction in CHD events.93 Divergent opinions also are apparent in terms of the role of blood sugar in the nondiabetic range. Some studies have shown the group with IGT to have a greater than normal risk of CVD.1,123 Early studies failed to show a relationship between blood glucose levels in the nondiabetic range and CVD,124 however recent meta regression analysis and pooled analyses show a relationship in the normal glucose range.125,126 Recently, investigators from the Epidemiology of Diabetes Interventions and Complications Study (follow-up of the DCCT) reported on the long-term benefit of early intensive glycemic control on the incidence of CVD. Among 1375 patients, the number of incident CVD events in those intensively treated during the DCCT compared to those on conventional therapy (46 compared to 98 events).127 The IGT stage is often characterized by hyperinsulinemia and insulin resistance. In the Paris study, in multivariate analyses, insulin concentration rather than diabetic IGT status was the stronger predictor of CHD.128 A further factor linked with hyperinsulinemia is central adiposity, which was discussed earlier as a risk factor for the development of diabetes.129,130 Central adiposity is also a risk factor for CVD independent of obesity,131 a finding most clearly shown in women. Consequently a male type of fat deposition (if found in women) may be associated with hyperinsulinemia132 and thus may provide a marker for a metabolic derangement predisposing to both diabetes and CVD generally, and the relatively poorer cardiovascular prognosis of diabetic women. This association of central adiposity with insulin resistance and the metabolic syndrome is thought to be the prime basis of the excess CVD in type 2 diabetes and glucose intolerance and also has been proposed as a leading feature of CVD in type 1 diabetes.133,134 As lipoproteins are altered in diabetes, it is tempting to hypothesize that these changes account for the increased CVD risk seen in diabetes. Many studies,110,111,116,129,130 have shown that serum cholesterol levels relate to CVD risk in those with diabetes in a way similar to that seen in the general population. However, total and LDL cholesterol levels are not greatly elevated in many diabetics, so the role of cholesterol in explaining the increased risk in diabetes is limited.135 Data from the Multiple Risk Factor Intervention Study (MRFIT),136 which screened over 360,000 men for CVD risk factors and subsequently followed them for mortality, suggests diabetic men had rates three times higher than nondiabetics all along the cholesterol curve. The MRFIT data is exclusively type 2 diabetes. In type 1 diabetes, as indicated earlier, it appears that the major determinant of CVD risk is proteinuria98 although recent data suggest that hypertension, white blood cell count, HDLc, non-HDLc, diabetes duration and smoking are associated with incident CAD events.134 If cholesterol concentration has a limited role, other lipid measures may be of greater importance to diabetes. Reports suggest that triglyceride level is an independent risk factor for CVD in diabetes.137,138 Furthermore, alterations in HDL concentration and lipoprotein composition occur in diabetes, which may further increase cardiovascular risk.139 Insulin itself, beyond its effect on the lipids, can have direct effects on the arterial wall that promote


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atherogenicity.140–142 Hyperinsulinemia has also been related to blood pressure elevation.143–146 The importance of insulin is also shown by its demonstration as an independent risk factor for CVD in some,147–150 but not all,151–153 prospective studies of men in the general population, however distinguishing insulin effects per se from hyperinsulinemia representing insulin resistance is difficult. Many studies have demonstrated altered hemostatic factors including platelets and fibrinogen which may provide yet another mechanism for the enhanced CVD risk in diabetes.154,155 Thus it is abundantly clear that those with diabetes have severe handicaps to face in terms of cardiovascular risk above and beyond the lipoprotein disturbances.

 SUMMARY AND FUTURE

The DCCT and UKPDS have put beyond question the value of intensive therapy to lower blood sugar levels in terms of the so called triopathy of type 1 and type 2 diabetes complications (retinopathy, nephropathy, and neuropathy).156 As intensive therapy with insulin also increases the risk of severe hypoglycemia91 and is difficult to translate into general practice, it would seem prudent to also focus on other CVD risk factors (e.g., hypertension and hyperlipidemia) to prevent these complications in type 2 diabetes. Studies examining cardiovascular events among people with type 2 diabetes demonstrate that controlling these risk factors can directly impact the occurrence of both new157–161 and repeat events.162–164 Two major trials165,166 are underway testing the value of intensive glycemic therapy in terms of CHD prevention and another trial (BARI2D) addresses the best means of treating patients with diabetes and heart disease. While the evidence for the prevention of diabetes and its complications is clear, translation into the community of diabetes care providers and patients is difficult. The goal of prevention is to improve short and long term outcomes as well as the economic consequences of a disease. Models of chronic illness care that focus on a multilevel approach to primary and secondary prevention are necessary in order to prevent the morbidity and mortality associated with diabetes.

 REFERENCES

1. Fuller JH, Shipley MJ, Rose G, et al. Coronary-heart-disease risk and impaired glucose tolerance: the Whitehall Study. Lancet. 1980;1373–6. 2. O’Sullivan J. Quarter century study of glucose intolerance: incidence of diabetes mellitus by USPHS, NIH, and WHO criteria. In: Eschwege E, ed. Advances in Diabetes Epidemiology. Amsterdam, Elsevier Biomedical Press, 1982:123–31. 3. Jarrett RJ, Keen H, McCartney P. Worsening of diabetes with impaired glucose tolerance: ten-year experience in the Bedford and Whitehall Studies. In: Eschwege E, Ed. Advances in Diabetes Epidemiology. Amsterdam, Elsevier Biomedical Press, 1982:95–102. 4. Lorenzo C, Okoloise M, Williams K, et al. The metabolic syndrome as predictor of type 2 diabetes. The San Antonio Heart Study. Diabetes Care. 2003;26:3153–9. 5. Orchard TJ. From diagnosis and classification to complications and therapy. Diabetes Care. 1994;17:326–38. 6. Holman RC, Herron CA, Sinnock P. Epidemiologic characteristics of mortality from diabetes with acidosis or coma, United States, 1970–78. Am J Pub Health. 1983;73:1169–73. 7. LaPorte RE. Diabetes Epidemiology Research International Mortality Study Group. Major cross-country differences in risk of dying for people with IDDM. Diabetes Care. 1991;14:49–54. 8. Temple RC, Luzio SD, Schneider AE, et al. Insulin deficiency in non-insulin-dependent diabetes. Lancet. 1989;293–5. 9. Unwin N, Shaw J, Zimmet P, et al. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19:708–23.

10. Smith NL, Barzilay JI, Shaffer D, et al. Fasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study. Arch Intern Med. 2002;162:209–19. 11. Duncan BB, Heiss G. Nonenzymatic glycosylation of proteins-a new tool for assessment of cumulative hyperglycemia in epidemiologic studies, past and future. Am J Epidemiol. 1984;120:169–89. 12. Moller AM, Dalgaard LT, Pociot F, et al. Mutations in the hepatocyte nuclear factor-1a gene in Caucasian families originally classified as having type 1 diabetes. Diabetologia. 1998;41:1528–31. 13. Lehto M, Wipemo C, Ivarsson SA, et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia. 1999;42:1131–7. 14. Zimmet PZ, Tuomi T, Mackay IR, et al. Latent autoimmune diabetes in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med. 1994;11:299–303. 15. Karvonen M, Tuomilehto J, Libman I, et al. World Health Organization DIAMOND Project Group: Review of the recent epidemiological data on the world wide incidence of Type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1993;36:883–92. 16. Holt RIG. Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for psychiatrists. Br J Psychiatry. 2004;184:S55–S63. 17. Onkamo P, Vaanenen S, Karvonen M, et al. Worldwide increase in incidence of type 1 diabetes—the analysis of the data on published incidence trends. Diabetologia. 1999;42:1395–1403. 18. Kyvik KO, Hystrom L, Gorus F, et al. the epidemiology of type 1 diabetes mellitus is not the same in young adults as in children. Diabetologia. 2004;47:377–84. 19. Pundziute-Lycka A, Zaliinkevicus R, Urbonaite B, et al. Incidence of type 1 diabetes in Lithuanians aged 0–39 years varies by the urban-rural setting, and the time change differs for men and women during 1991–2000. Diabetes Care. 2003;26:671–6. 20. Dorman JS, LaPorte RE, Songer TJ. Epidemiology of Type 1 Diabetes. In: Sperling MA, ed. Type 1 Diabetes: Etiology and Treatment. Totowa, NJ, Humana Press, 2003:3–22. 21. Dorman JS, Bunker CH. HLA-DQ locus of the human leukocyte antigen complex and type 1 diabetes mellitus: a HuGE review. Epidemiol Rev. 2000;22. 22. Hirschhorn JN. Genetic epidemiology of type 1 diabetes. Pediatr Diabetes. 2003;4:87–100. 23. Nejentsev S, Reijonen H, Adojaan B, et al. The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. Diabetes. 1997;46:1888–92. 24. Lie BA, Todd JA, Pociot F, et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. Am J Hum Genet. 1999;64:793–800. 25. Anjos S, Polychronakos C. Mechanisms of genetic susceptibility to type 1 diabetes: beyond HLA. Mol Genet Metab. 2004;81:187–95. 26. Bennett ST, Wilson AJ, Esposito L. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nat Genet. 1997;17:350–2. 27. Pugliese A, Zeller M, Ferndandez JA. The insulin gene is transcribed in human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM 2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15:293–7. 28. Undlien DE, Hamaguchi K, Kimura A. Type 1 diabetes susceptibility associated with polymorphism in the insulin gene region: a study of Blacks, Caucasians, and Orientals. Diabetologia. 1994;37: 745–9. 29. Rewers M, Norris J, Dabelea D. Epidemiology of Type 1 diabetes mellitus. Adv Exp Med Biol. 2004;552:219–46. 30. Dahlquist G. The aetiology of type 1 diabetes: an epidemiological perspective. Acta Paediatr Suppl. 1998;425:5–10. 31. Dahlquist G, Frisk G, Ivarsson SA, et al. Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM. Diabetologia. 1995;38:1371–3.


64 32. Hyoty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood diabetes in Finland (DiMe) Study Group. Diabetes. 1995;44:652–7. 33. Hyoty H, Hiltunen M, Reuranen A. Decline of mumps antibodies in type 1 (insulin-dependent) diabetic children with a plateau in the risking incidence of type 1 diabetes after introduction of the mumpsmeasles-rubella vaccine in Finland. Diabetologia. 1993;41:40–6. 34. Pak CY, McArthur RG, Eun HM. Association of cytomegalovirus infection with autoimmune type 1 diabetes. Lancet. 1988;2:1–4. 35. Honeyman MC, Coulson BS, Stone NL. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes. 2000;49. 36. McIntosh EDG, Menser M. A fifty-year follow-up of congenital rubella. Lancet. 1992;340:414–5. 37. Borch-Johnsen K, Joner G, Mandrup-Poulsen T, et al. Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis. Lancet. 1984;2:1083–6. 38. Kolb H, Pozzilli P. Cow’s milk and type 1 diabetes: the gut immune system deserves attention. Immunol Today. 1999;20:108–10. 39. Harrison LC, Honeyman MC. Cow’s milk and type 1 diabetes. Diabetes. 1999;48:1501–7. 40. Vaarala O. Gut and the induction of immune tolerance in type 1 diabetes. Diabetes Metab Res Rev. 1999;15:353–61. 41. McKinney PA, Okasha M, Parslow R, et al. Ante-natal risk factors for childhood diabetes mellitus, a case-control study of medical record data in Yorkshire, UK. Diabetologia. 1997;40:933–9. 42. Marshall AL, Chetwynd A, Morris J, et al. Type 1 diabetes mellitus in childhood: a matched case control study in Lancashire and Cumbria, UK. Diabet Med. 2004;21:1035–40. 43. Kupila JS, Keskinen P, Simell T. Intranasally administered insulin intended for prevention of type 1 diabetes—a safety study in healthy adults. Diabetes Metab Res Rev. 2003;19:415–20. 44. Diabetes Prevention Trial-Type 1 Study Group: Effects of insulin in relatives of patients with type 2 diabetes mellitus. N Engl J Med. 2002;346:1685–91. 45. The European Nicotinamide Diabetes InterventionTrial (ENDIT) Group: Intervening before the onset of type 1 diabetes: baseline data from the European Nicotinamide Diabetes Group. Diabetologia. 2003;46:339–46. 46. Paronen J, Knip M, Savilahti E, et al. Effect of cow’s milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Diabetes. 2000;49:1657–65. 47. Type 1 Diabetes Trial Net. Available at: www.diabetestrialnet org. 48. World Health Organization: Diabetes. World Health Organization, 2005. 49. Zimmet P. Epidemiology of diabetes and its macrovascular manifestations in Pacific populations: the medical effects of social progress. Diabetes Care. 1979;2:85–90. 50. World Health Organization. Definition, Diagnosis, and Classification of Diabetes Mellitus and its Complications. Geneva, Department of Noncommunicable Disease Surveillance, 1999;2–7. 51. Min HK, Yoo HJ, Lee HK, et al. Clinico-genetic genesis of diabetes mellitus. In: Minuira A, Baba S, Goyo Y, Kobberling J, eds. Changing Patterns of the Prevalence of Diabetes Mellitus in Korea. Amsterdam, Excerpta Medica, 1982. 52. Bennett PH, Rushforth NB, Miller M, et al. Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res. 1976;32: 333–76. 53. Centers for Disease Control and Prevention: National diabetes fact sheet: general information and national estimates on diabetes in the United States. Atlanta, GA: Department of Health and Human Services; 2005. 54. Medalie JH. Risk factors other than hyperglycemia in diabetic macrovascular disease. Diabetes Care. 1979;2:77–84.

Diabetes

1109

55. Keen H. The incomplete story of obesity and diabetes. In: Howard A, ed. 1st International Congress on Obesity. London, Newman Publishing, 1975. 56. VanItallie TB. Obesity: adverse effects on health and longevity. Am J Clin Nutr. 1979;32:2723–33. 57. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 2003;289:76–9. 58. Rimm IJ, Rimm AA. Association between socioeconomic status and obesity in 59,556 women. Prev Med. 1974;3. 59. Palumbo PJ, Melton JL. Peripheral vascular disease and diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, eds. Diabetes in America. Washington DC, NIH, NIDDK, 1995:401–8. 60. Centers for Disease Control and Prevention: Division of Nutrition and Physical Activity. Department of Health and Human Services, 2005. 61. Taylor RJ, Bennett PH, Legonidec G, et al. The prevalence of diabetes mellitus in a traditional-living Polynesian population: the Wallis Island survey. Diabetes Care. 1983;6:334–40. 62. Manson JE, Nathan DM, Krolewski AS, et al. A prospective study of exercise and incidence of diabetes among U.S. male physicians. JAMA. 1992;268:63–7. 63. Schulze MB, Hu FB. Primary prevention of diabetes: what can be done and how much can be prevented? Annu Rev Public Health. 2005;26:445–67. 64. Barnett AH, Eff C, Leslie RDG, et al. Diabetes in identical twins: a study of 200 pairs. Diabetologia. 1981;20:87–93. 65. Tuomilehto-Wolf E, Tuoilehto J, Cepaitis Z, Lounamaa R, DIME Study Group. New susceptibility haplotype type 1 diabetes. Lancet. 1989;11:299–302. (abstract) 66. Bell GI, Karem JH, Rutter WJ. Polymorphic c DNA region adjacent to the 5’ end of the human insulin gene. Proc Natl Acad Sci USA. 1981;78:5759–63. 67. Vionnet N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356:721–2. 68. Reardon W, Ross R, Sweeney MG, et al. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet. 1992;340:1376–9. 69. Saad MF, Knowler W, Pettitt DJ, et al. The natural history of impaired glucose tolerance in the Pima Indians. N Engl J Med. 1988;319:1500–6. 70. Pan X-R, Li G-W, Hu Y-H, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: The Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537–44. 71. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1390–2. 72. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM Trial Research Group. Lancet. 2002;359:2072–7. 73. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403. 74. Orchard TJ, Temprosa M, Goldberg R, et al. Diabetes Prevention Program Research Group: The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005;142:611–9. 75. American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2005;28:S4–S36. 76. Engelgau MM, Narayan KMV, Herman WH. Screening for Type 2 diabetes. Diabetes Care. 2000;23:1563–80. 77. Knuiman MW, Welborn TA, McCann VJ, et al. Prevalence of diabetic complications in relation to risk factors. Diabetes. 1986;35: 1332–9.


1110

Noncommunicable and Chronic Disabling Conditions

78. Wingard DL, Barrett-Connor E. Heart disease and diabetes. In: National Diabetes Data Group, ed. Diabetes in America. Bethesda, National Institutes of Health;1995, 429–48. 79. Orchard TJ. Diabetes Epidemiology Research International Mortality Study Group. International evaluation of cause-specific mortality and IDDM. Diabetes Care. 1991;294:1651–4. 80. Dorman JS, LaPorte RE, Kuller LH, et al. The Pittsburgh insulindependent diabetes mellitus (IDDM) morbidity and mortality study. Mortality results. Diabetes. 1984;33:271–6. 81. Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, et al. Coronary heart disease in young type 1 (insulin-dependent)diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia. 1987;30:144–8. 82. Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus. Am J Cardiol. 1987;59. 83. Nishmura R, LaPorte RE, Dorman JS, et al. Mortality trends in type 1 diabetes. The Allegheny County (Pennsylvania) Registry 1965–1999. Diabetes Care. 2001;24:823–7. 84. Nishmura R, Bosnyak Z, Orchard TJ. Incidence, treatment and prognosis of end stage renal disease of type 1 diabetes diagnosed between 1965–79 in Allegheny County. Diabetes. 2001;50:A179. 85. Bosnyak Z, Nishimura R, Orchard TJ. Excess mortality in African Americans with type 1 diabetes largely due to acute complications: a population based perspective in the Pittsburgh metropolitan area. Diabetes. 2002;51:A63. 86. Hovind P, Tarnow L, Rossing K, et al. Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care. 2003;26:1258–64. 87. Pambianco G, Zgibor J, Orchard T. Temporal trends in type 1 diabetes: coronary artery disease, proliferative retinopathy, and overt nephropathy. Diabetes. 2003;52:A40. 88. Klein R, Davis MD, Moss S, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: A Comparison of Retinopathy in Younger and Older Onset Diabetic Persons. Plenum Press; 1985. 89. Orchard TJ, Dorman JS, Maser RE, et al. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990;39:1116–24. 90. Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122:552–63. 91. DCCT Research Group. The Diabetes Control