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American Journal of Epidemiology Copyright ª 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Vol. 164, No. 10 DOI: 10.1093/aje/kwj299 Advance Access publication September 12, 2006

Original Contribution In Utero Exposure to Background Concentrations of DDT and Cognitive Functioning among Preschoolers

Nu´ria Ribas-Fito´1, Maties Torrent2, Daniel Carrizo3, Laura Mun˜oz-Ortiz1, Jordi Ju´lvez1, Joan O. Grimalt3, and Jordi Sunyer1 1

Respiratory and Environmental Health Research Unit, Institut Municipal Investigacio´ Me`dica (IMIM), Barcelona, Catalonia, Spain. 2 ` Area de Salut de Menorca, IB-SALUT, Menorca, Spain. 3 Department of Environmental Chemistry, IIQAB-CSIC, Barcelona, Catalonia, Spain. Received for publication December 21, 2005; accepted for publication April 12, 2006.

p,p#-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane) is a persistent organochlorine compound that has been used worldwide as an insecticide. The authors evaluated the association of cord serum levels of DDT and its metabolite, 2,2-bis(p-chlorophenyl)-1,1-dichloroethylene (DDE), with neurodevelopment at age 4 years. Two birth cohorts in Ribera d’Ebre and Menorca (Spain) were recruited between 1997 and 1999 (n ¼ 475). Infants were assessed at age 4 years by using the McCarthy Scales of Children’s Abilities. Organochlorine compounds were measured in cord serum. Children’s diet and parental sociodemographic information was obtained through questionnaire. Results showed that DDT cord serum concentration at birth was inversely associated with verbal, memory, quantitative, and perceptual-performance skills at age 4 years. Children whose DDT concentrations in cord serum were >0.20 ng/ml had mean decreases of 7.86 (standard error, 3.21) points in the verbal scale and 10.86 (standard error, 4.33) points in the memory scale when compared with children whose concentrations were <0.05 ng/ml. These associations were stronger among girls. Prenatal exposure to background, low-level concentrations of DDT was associated with a decrease in preschoolers’ cognitive skills. These results should be considered when evaluating the risk and benefits of spraying DDT during antimalaria and other disease-vector campaigns. child; child development; cognitive science; DDT; dichlorodiphenyl dichloroethylene; mental competency

Abbreviations: DDE, p,p#-DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene; DDT, p,p#-DDT (bis[p-chlorophenyl]-1,1,1trichloroethane); MCSA, McCarthy Scales of Children’s Abilities; SE, standard error.

Organochlorine compounds are persistent and ubiquitous environmental contaminants that were intensively used in the past (1). Today, p,p#-DDT (bis[p-chlorophenyl]-1,1,1trichloroethane (DDT)) is banned from use and production in most Western countries, but it is still sprayed in some developing countries for disease-vector control (2). This compound is metabolized to p,p#-DDE (2,2-bis(p-chlorophenyl)1,1-dichloroethylene (DDE)). These chemicals are resistant to degradation and bioaccumulate in the food chain (3, 4).

Exposure occurs both in utero and, because of their lipophilicity, via breastfeeding (5). Prenatal DDE exposure has been examined in relation to children’s neurodevelopment in two cohorts (6–8). We described an association between prenatal exposure to p,p-#DDE and mental and psychomotor development in children aged 1 year (9) from a rural village of 5,000 inhabitants in the vicinity of an electrochemical factory (Flix, Ribera d’Ebre, Spain), where high concentrations of

Correspondence to Dr. Nu´ria Ribas-Fito´, Respiratory and Environmental Health Research Unit, IMIM, C. Doctor Aiguader 80, 08003 Barcelona, Catalonia, Spain (e-mail: nribas@imim.es).

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956 Ribas-Fito´ et al.

hexachlorobenzene were encountered (10). The factory, built in 1898, has been producing chlorinated solvents for four decades. Production of DDT in the factory ended in 1971 and of polychlorinated biphenyls in 1987. Exposure to DDT in relation to neurodevelopment has been less studied. Animal studies have suggested that exposure to DDT during the brain growth spurt affects the density of muscarinic cholinergic receptors of the cerebral cortex and can cause behavior abnormalities in adult life (11). One recent case study suggested that DDT may be related to hyperactivity (12). Ecologic data from the PISA 2000 studies suggested that DDT was responsible for the observed differences in mental capacities among the countries (13). A study of long-term occupational exposure to DDT found that various neurobehavioral functions and performance deteriorated significantly with increasing years of DDT application (14). In 2005, we reported higher concentrations of DDE in newborns from Menorca, Spain, than those described in the Ribera d’Ebre cohort (15). Menorca is one of the Balearic Islands in the northwest Mediterranean Sea, which has no local pollution sources. Our aim in this study was to follow up the children from the Ribera d’Ebre and Menorca cohorts to assess the association of cord serum levels of DDE and DDT with neurodevelopment at age 4 years.

MATERIALS AND METHODS Study participants

For the Ribera d’Ebre cohort, all singleton children born in the main hospital of the study area between March 1997 and December 1999 were recruited (16). The study area included the village of Flix and all other towns from the same administrative health area. Enrolled were 102 children; for 70 (68.6 percent), complete outcome data for the 4-year visit and organochlorine measurements at birth were available. The Menorca cohort was set up in 1997 within the Asthma Multicenter Infants Cohort study (17); recruited were all women presenting for antenatal care over 12 months starting in mid-1997. Subsequently enrolled were 482 children (94 percent of those eligible), and complete outcome data up to the fourth-year visit were provided for 470 (97.5 percent). Among these children, 405 (86 percent) had organochlorine compounds analyzed in their cord serum (15). This study was approved by the ethics committee of the Institut Municipal d’Investigacio´ Me`dica, and all mothers provided signed informed consent. Study variables

Neuropsychological testing of the children at age 4 years (mean age, 4.4 years in Ribera d’Ebre and 4.3 years in Menorca) included assessment of intellectual abilities, attention, and social competence. Three certified psychologists (one for the Ribera d’Ebre cohort and two for the Menorca cohort) performed the testing, which was supervised by the project’s consulting psychologist (including

intra- and interpsychologist validity at the beginning, midpoint, and end of the study), who rescored the tests. The staff involved in the neuropsychological testing did not know the degree of the child’s exposure to organochlorine compounds or the type and duration of feeding. Cognitive development was measured with the Spanish version of the McCarthy Scales of Children’s Abilities (MCSA) (18) that provides information on cognitive ability and gross- and fine-motor abilities. The MCSA consists of 18 items derived from six different scales (general cognitive, verbal, perceptualperformance, quantitative, memory, and motor). To further improve our understanding of the specific functions associated with exposure to organochlorine compounds, we reorganized the MCSA items into new outcomes according to neuropsychological functions. Each different psychometric trait corresponded to an underlying neurologic function (e.g., executive function and prefrontal areas) (19). The outcomes were reorganized by using confirmatory factor analyses, which showed an acceptable goodness of fit and a Cronbach’s alpha coefficient of 0.69 for internal consistency (unpublished data). The new outcomes were verbal memory (MSCA items 3 and 7II); working memory (MSCA items 5 and 14II); memory span or short-term memory (MSCA items 6, 7I, and 14I); and executive function (MSCA items 2, 5, 6, 14II, 15, 17, and 18). The executive function is involved in coordinating complex behaviors such as attention and working memory (19, 20). A gas chromatograph with electron capture detection (Hewlett Packard 6890N GC-ECD; Hewlett Packard, Avondale, Pennsylvania) was used to quantify p,p#-DDT and p,p#-DDE, as described elsewhere (16). Quantification was performed by using external standards, with the PCB142 injection standard used to correct for volume. Recovery of 1,2,4,5-tetrabromobenzene and PCB209 (75–115 percent) was used to correct results. Limits of detection were 0.02 ng/ml. A value of 0.01 ng/ml was given for the nonquantifiable concentrations. Serum samples were stored at 40C until analysis. All analyses were carried out in the Department of Environmental Chemistry (IIQAB-CSIC) in Barcelona, Spain. Information on socioeconomic background, maternal diseases, obstetric history, parity, child’s gender, fetal exposure to alcohol (ever exposure during pregnancy) and cigarette smoking (at least one cigarette a day during the last trimester), type and duration of breastfeeding, education, and social class was obtained through questionnaires administered in person after delivery and at 48 months. The United Kingdom Registrar General’s 1990 classification was used to group subjects by social class according to maternal and paternal occupation coded using the International Standard Classification of Occupations (ISCO-88) (http://www. warwick.ac.uk/ier/isco/isco88.html). Social class was grouped into six categories: four were created according to maternal occupation (professional, skilled, nonskilled, and unemployed), and unemployed women were categorized into three groups according to their husband’s occupation. Information on birth weight, birth length, and gestational age was obtained through medical records. Duration of breastfeeding was categorized in four groups (<2, 2–15.9, 16– 27.9, and 28 weeks). Am J Epidemiol 2006;164:955–962


DDT and Cognitive Functioning at Age 4 Years

Statistical analysis

Neurodevelopment scores followed a normal distribution, whereas cord serum levels of organochlorine compounds were skewed to the right and were normalized by base 2 logarithmic transformation. Neurodevelopment scores were centered to the mean to facilitate interpretation of the results. DDT concentrations were divided into four categories (0.05, >0.05–0.10, >0.10–0.20, and >0.20 ng/ml). The scores obtained from the MCSA test were examined in relation to level of organochlorine compounds and the study variables by using linear regression models. School trimester, psychologist, age at examination (in days), and the rest of the study variables were treated as potential confounding factors and were selected on the basis of previous studies (21). If adjustment for an additional variable altered the organochlorine compound coefficient by 10 percent or more in the models, the variable was retained in the final model; the same model was used for all neurodevelopment scores. Gender, school trimester, psychologist, age at examination, breastfeeding, maternal social class, and maternal consumption of alcohol and use of tobacco during pregnancy were the variables that met the criteria for confounding. DDT and DDE were analyzed separately and in the same model. We further adjusted the models for polychlorinated biphenyls and hexachlorobenzene, and the DDT/DDE ratio was also studied. Interaction between exposure and duration of breastfeeding, cohort, or gender was assessed by including interaction terms in the regression model. All models were repeated by including data for only those children from the Menorca cohort. All statistical analyses were conducted with Stata 8.0 statistical software (Stata Corporation, College Station, Texas).

RESULTS

The characteristics of the two study populations are described in table 1. Children from the Ribera d’Ebre cohort were more likely to be an only child and to have been breastfed for shorter periods. Compared with mothers of the Menorca cohort, mothers of the Ribera d’Ebre cohort were less educated and were more likely to have a lower social class and to drink and smoke during pregnancy. The crude MCSA scores were higher in the Ribera d’Ebre cohort (table 1). There were no differences between children with organochlorine measurements (mean general cognitive score ¼ 106.9) and those without (mean general cognitive score ¼ 108.0) (p ¼ 0.63). Quantifiable concentrations of DDT were detected in almost 90 percent of the children in both cohorts. All children had quantifiable concentrations of DDE at birth. Concentrations of p,p#-DDT and p,p#-DDE were higher in Menorca, but the difference was not statistically significant (table 2). The DDT/DDE ratio was also higher in Menorca newborns (p ¼ 0.03). Table 3 shows the crude association of DDT, DDE, and the DDT/DDE ratio with neurodevelopment. Both DDT and DDE were negatively associated with all cognitive MCSA areas. Motor skills seemed not to be affected by prenatal Am J Epidemiol 2006;164:955–962

957

TABLE 1. Distribution of child and maternal variables according to cohort recruited in Spain in 1997–1999 (n ¼ 475) Ribera d’Ebre

Sample size at age 4 years Recruitment period Gender (%) Girls Boys Birth length (cm) Birth weight (g) Gestational age (weeks) No. of siblings (%) None One More than one Maternal age (years) Maternal social class (%) Professional Skilled Nonskilled Unemployed, husband professional Unemployed, husband skilled Unemployed, husband nonskilled Maternal education (%) High school Secondary school Primary school Less than primary school Paternal education (%) High school Secondary school Primary school Less than primary school Marital status at child’s age of 4 years With a stable partner Divorced or widowed Intrauterine tobacco exposure, yes Intrauterine alcohol exposure, yes Breastfeeding (%) <2 weeks 2–15.9 weeks 16–27.9 weeks 28 weeks School trimester at examination (%) 3rd year, 2nd and 3rd trimesters 4th year, 1st trimester 4th year, 2nd and 3rd trimesters Age at examination (years) McCarthy scores* General cognitive Perceptual-performance Memory Quantitative Verbal Motor

Menorca

70 405 1997–1999 1997–1998 54.9 45.1 49 3,248 40

48.5 51.5 49 3,186 40

42.9 42.9 14.2 30

28.3 53.2 18.5 29

20.4 15.3 27.6 6.1 7.1 23.5

12.7 51.4 15.3 2.4 14.8 3.4

0.0 51.0 6.1 42.9

13.1 28.5 51.1 7.3

14.3 41.8 35.7 8.2

8.3 24.8 56.5 10.4

97.6 2.4 30.4 41.2

91.0 9.0 21.2 21.5

24.7 36.6 22.6 16.1

20.3 26.2 27.6 25.9

18.6 47.7 33.7 4.4

19.0 31.2 49.8 4.3

115.6 43.8 25.9 20.2 51.5 35.9

106.4 40.3 23.3 18.0 48.1 34.4

* The mean score for the general cognitive scale is 100, with a standard deviation of 15.


958 Ribas-Fito´ et al.

TABLE 2. Distribution (median and centiles 25 and 75) of concentrations of DDT* and DDE* in cord serum (ng/ml) of children by cohort recruited in Spain in 1997–1999y Ribera d’Ebre % Quantified

DDT DDE

Menorca

Centile 25

Median

Centile 75

Maximum

0.01

0.05

0.05

1.87

0.50

0.86

1.70

7.11

0.02

0.04

0.11

1.17

71.43 100

DDT/DDE ratio

% Quantified

91.85 100

Centile 25

Median

Centile 75

0.04

0.08

0.21

Maximum

2.28

0.57

1.03

1.94

19.54

0.04

0.09

0.19

1.24

* DDT, p,p#-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane; DDE, p,p#-DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene. y Spearman correlation between DDT and DDE in cord serum: rho ¼ 0.40, p < 0.0001.

exposure to DDT or DDE. The associations with the cognitive areas were statistically significant for DDT only. The magnitude of the effect was similar among the areas but appeared to be stronger for memory and verbal skills. Further analyses of the underlying neuropsychological functions showed that DDT was negatively associated with the executive function and all memory functions (especially memory span and verbal memory). An analysis of the Menorca cohort alone yielded the same results (i.e., b for the general cognitive score: 2.36 (standard error (SE), 0.79) (p ¼ 0.003)). There was no interaction between cohort and exposure to DDT. An analysis with nonlogarithmically

TABLE 3. Crude association of the McCarthy areas of infant development, the executive function, and memory with concentrations of DDTy and DDEy in cord serum (log-based 2 ng/ml) for the two cohorts recruited in Spain in 1997–1999z Mean

DDT b§

DDE b§

DDT/DDE ratio b§

McCarthy areas{ General cognitive

107.88 2.12** 1.42

1.37

Perceptual-performance

40.86 1.41

1.98

0.31

Memory

23.73 3.53** 2.09

2.43

Quantitative

18.34 2.36*

Verbal

48.63 2.77** 1.21

Motor

34.67

1.17

1.18 0.01

1.75 2.16* 1.21

Executive function Global

44.30 2.82*

1.41

2.63**

Verbal

28.42 3.00*

1.19

2.97

Visuoperceptive

15.86 2.65*

2.03

2.08

8.59 2.79

2.42

1.49

transformed DDT showed a decrease of 9.83 (SE, 2.33; p ¼ 0.006) points in general cognitive score. The DDT/DDE ratio was also associated with the cognitive areas of the MSCA, especially the verbal and memory areas. The fully adjusted associations between DDTand different cognitive areas of neurodevelopment are shown in table 4. The adjusted associations of DDT, DDE, and the DDT/DDE ratio did not differ from the ones observed in the crude analyses. When we adjusted DDT for DDE, the association of DDT with neurodevelopment remained statistically significant, while DDE coefficients decreased noticeably. Further adjustment for hexachlorobenzene and polychlorinated biphenyls did not modify the results. As shown in table 4, the results for the Menorca cohort alone showed no differences compared with those from the joint analyses. The results for the Ribera d’Ebre cohort alone were in the same direction. Table 5 illustrates the association between DDT in categories of exposure and MCSA’s general cognitive, verbal, and memory areas. Prenatal exposure to DDT levels higher than 0.20 ng/ml was associated with a statistically significant reduction in performance of general cognitive, verbal, and memory skills. When we stratified the results by gender, the association was stronger among girls than boys (p for interaction: ‘‘higher category of DDT exposure 3 gender’’ ¼ 0.05 for the verbal area and 0.14 for the memory area). The association between DDT as a continuous variable (log transformed) and the verbal and memory skills was also stronger among girls (verbal: b ¼ 4.17 (SE, 1.53), p ¼ 0.007 for girls; b ¼ 1.52 (SE, 1.39), p ¼ 0.27 for boys; p for interaction ¼ 0.08); (memory: b ¼ 5.69 (SE, 2.07), p ¼ 0.007 for girls; b ¼ 2.54 (SE, 1.85), p ¼ 0.17 for boys; p for interaction ¼ 0.22).

Memory Working memory Memory span Verbal memory

16.39 2.83** 1.40

2.10*

6.11 4.67** 2.41

3.36*

* p < 0.05; **p < 0.01. y DDT, p,p#-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane; DDE, p,p#-DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene. z Each cell is a different crude model. § Change per each doubling of the dose. { The mean score for the general cognitive scale is 100, with a standard deviation of 15.

DISCUSSION

We found that prenatal exposure to low-level, background concentrations of DDT and DDE at birth is associated with a decrease in verbal, memory, quantitative, and perceptualperformance skills among preschoolers. This association was statistically significant for DDT only. A dose-response relation between DDT and the verbal and memory areas was observed for DDT at higher categories of exposure. Children whose DDT concentrations in cord serum were above 0.20 ng/ml had decreases of 7.86 (3.21) points in the verbal scale Am J Epidemiol 2006;164:955–962


DDT and Cognitive Functioning at Age 4 Years

959

TABLE 4. Adjusted associations (b (standard error)) between concentrations of DDTy and DDEy in cord serum (ng/ml) and neurodevelopment at age 4 years, by cohort recruited in Spain in 1997–1999z McCarthy areas§ General cognitive

Memory

Executive function

Verbal

Memory span

Verbal memory

Both cohorts DDT

1.99 (0.75)*

3.79 (1.35)**

2.63 (1.00)**

2.61 (1.04)*

2.82 (1.09)**

6.10 (2.17)**

DDE

1.17 (0.95)

1.93 (0.95)*

0.90 (1.27)

1.24 (1.31)

1.16 (1.39)

2.12 (2.76)

DDT/DDE ratio

1.21 (0.75)

2.67 (1.34)*

0.98 (0.48)*

1.77 (1.03)

2.03 (1.09)

4.64 (2.16)*

DDT adjusted for DDE

1.91 (0.82)*

3.85 (1.47)**

2.75 (1.09)*

2.61 (1.12)*

2.88 (1.19)*

6.39 (2.36)**

Menorca cohort DDT

1.82 (0.82)*

3.80 (1.47)*

2.61 (1.09)*

2.37 (1.13)*

2.69 (1.20)*

5.73 (2.36)*

DDE

0.78 (1.03)

1.19 (1.85)

0.30 (1.36)

0.76 (1.41)

0.58 (1.51)

0.95 (2.97)

DDT/DDE ratio

1.40 (0.85)

3.23 (1.53)*

2.75 (1.12)*

2.00 (1.17)

2.47 (1.24)*

5.46 (2.44)*

DDT adjusted for DDE

1.92 (0.92)*

4.19 (1.64)**

3.22 (1.21)**

2.61 (1.26)*

3.08 (1.34)*

6.69 (2.63)*

* p < 0.05; **p < 0.01. y DDT, p,p#-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane; DDE, p,p#-DDE (2,2-bis(p-chlorophenyl)-1,1-dichloroethylene; MCSA, McCarthy Scales of Children’s Abilities. z Each cell is a different multivariate model. Adjusted for gender, school trimester at examination, psychologist, breastfeeding, maternal social class, and maternal consumption of alcohol and use of tobacco during pregnancy. § The mean score for the general cognitive scale is 100, with a standard deviation of 15.

TABLE 5. Adjusted associations (b (standard error)) between DDTy concentration (ng/ml) and the general cognitive, verbal, and memory McCarthy areasz according to gender for the two cohorts recruited in Spain in 1997–1999§ No.

General cognitive

Verbal

Memory

Reference{

203

104.03

0.051–0.10

86

1.45 (2.72)

1.80 (3.36)

1.64 (4.53)

0.101–0.20

74

2.01 (2.95)

4.02 (3.65)

4.46 (4.92)

112

5.87 (2.60)*

7.86 (3.21)*

10.86 (4.33)*

All infants

>0.20

98.38

88.93

Girls Reference{

101

0.051–0.10

48

104.67 1.37 (3.95)

97.22

88.22

2.26 (4.86)

2.46 (6.61)

0.101–0.20

33

0.44 (4.47)

2.58 (5.51)

4.76 (7.47)

>0.20

55

8.89 (3.89)*

12.79 (4.80)**

17.19 (6.51)**

Boys Reference{

102

0.051–0.10

38

102.64 3.39 (4.09)

101.99 5.66 (5.05)

96.54 2.47 (6.82)

0.101–0.20

41

5.15 (4.06)

6.65 (5.01)

6.30 (6.77)

>0.20

57

3.74 (3.63)

3.41 (4.47)

5.63 (6.04)

* p < 0.05; **p < 0.01. y DDT, p,p#-DDT (bis[p-chlorophenyl]-1,1,1-trichloroethane; MCSA, McCarthy Scales of Children’s Abilities. z The mean score for the general cognitive scale is 100, with a standard deviation of 15. § Each column is a different multivariate model. Adjusted for gender, school trimester at examination, psychologist, breastfeeding, maternal social class, and maternal consumption of alcohol and use of tobacco during pregnancy. { Infants in the lowest quartile of DDT exposure (0.05 ng/ml). Neurodevelopment scores are centered to the mean.

Am J Epidemiol 2006;164:955–962


960 Ribas-Fito´ et al.

and 10.86 (4.33) points in the memory scale when compared with children whose concentrations were below 0.05 ng/ml. These associations were stronger among girls. These results agree with those observed in an ecologic study in which DDT was found to be inversely correlated to the mental capacities of children at school age (13). A recent case report suggested that a mother’s exposure to DDT could be responsible for her son’s neurobehavioral dysfunction (12). A study of 27 workers in Costa Rica who used DDT for malaria control between 1955 and 1986 found that, compared with a group of controls, subjects exposed to DDT performed less well on tests of verbal attention and visuomotor speed and sequencing (14). Evidence on the neurologic impact of DDE is scarce. In North Carolina, prenatal and postnatal exposure to DDE was not associated with mental or motor development at ages 18 and 24 months (6, 7). In the Oswego (New York) study, cord blood levels of DDE failed to predict infant intelligence at 12 months of age (8). However, in the Oswego study, DDE levels were lower than those encountered in our study. In a previous publication with results from the Ribera d’Ebre children, we described an association between DDE and the mental and psychomotor areas at the age of 1 year (9). In the present study, at age 4 years, we also found an association between DDE and cognitive skills, the adjusted association with the memory area being statistically significant. However, this association disappeared when we adjusted for DDT. The association between DDT and neurodevelopment was not presented in any of the previous studies. DDT is one of the most widely studied pesticides in animals, whereas DDE and other DDT metabolites have been studied less. Animal experiments have clearly indicated that neurodevelopmental effects of early life exposure to DDT are among the most sensitive outcomes (22). In 1992, Eriksson et al. (11) reported that neonatal exposure to DDT clearly affected the density of the muscarinic cholinergic receptors of the cerebral cortex in newborn mice, leading to permanent disturbances of the cholinergic system in the brain combined with disruption of learning capacity in adult life. DDT has also been defined as a xenoestrogen that binds to the estrogen receptors ERa (23). The central nervous system is an important target of estrogen action during developmental periods or in adulthood. Estrogen facilitates cholinergic neurotransmission and acetylcholine release (24). It has recently been reported that DDT can also modulate the brain estrogen receptors’ activity with a delayed kinetic action with respect to 17b-estradiol (25). The tasks of learning and memory are related to the ability of estrogen to affect cholinergic neurotransmission (26). In this study, we observed differences regarding the effects of prenatal DDT exposure on neurodevelopment between boys and girls, girls being the most affected. The interaction between DDT and gender was statistically significant for only language skills, but the results for the memory area also seemed to be different according to gender. A recent study found ERa estrogen receptors in several extranuclear sites including dendrites, spines, terminals, and axons in females only, suggesting sex differences in hippocampus functioning (27). Taken together, the differences encountered between males and females could indicate two possible mechanisms of

action of DDT neurotoxicity. One of these mechanisms may apply exclusively to females. One of the cohorts in the present study was recruited from an area in which hexachlorobenzene is the main pollutant because it is located near an electrochemical factory, and the population living in this area has the highest levels of hexachlorobenzene ever reported for nonoccupational exposure (28). The Menorca cohort represents a general population exposed to little industrial activity. Concentrations of DDT and DDE in both cohorts were of the same magnitude, suggesting dietary intake of this pollutant. DDT is an insecticide that was first used to protect military areas and personnel against malaria, typhus, and other vector-borne diseases. Commercial sales began in 1945, and DDT became widely used in agriculture. Although it was banned in Spain in 1978 largely on the basis of ecologic considerations, and although a marked decline in DDT in maternal milk has been described in many countries after its use was restricted (29), we have observed that DDT is still present in cord serum. Prenatal DDE uptake in humans has also been demonstrated to have declined in industrialized countries (30), but the median concentrations in our cohort of children born during the period 1997–1999 (1.01 ng/ml) were higher than those reported in newborns in the Northwest Territories and the Nunavut areas of Arctic Canada (31). A potential limitation of the present study is the nonresponse rate (17 percent). However, in most instances, subjects were not included (n ¼ 77) because of the small quantity of sera in the repository aliquots of cord serum. Quantity of blood was unlikely to be related to DDT levels, and the general cognitive index was similar between those with a blood sample and those without. Geographic differences between Menorca and Ribera d’Ebre were eliminated by analyzing the data by cohort. The results in which the Menorca cohort alone was used showed no differences compared with the two-cohort analyses, and the results from the Ribera d’Ebre cohort alone were in the same direction but were not statistically significant. This lack of significance could be explained by the small size of the cohort. Since Menorca has no local pollution sources, the results encountered here could be representative of other areas where several years have elapsed since DDT use was banned. Residual confounding cannot be discarded because inclusion of social class in the models might not have removed part of the variance in parental intelligence quotient associated with their children’s intelligence quotient (32). Unfortunately, parental intelligence quotient could not be measured in this study. In addition, we did not assess the home environment with a standardized tool such as the HOME Inventory (33) because of cross-cultural differences. The association between DDT and neurodevelopment at age 4 years might not be predictive of long-term effects of DDT. A follow-up is under way, with the aim of evaluating whether the effects of DDT exposure on neurodevelopment encountered in this study persist later in life. Overall, we found that prenatal exposure to current concentrations of DDT is associated with a decrease in cognitive skills among preschoolers, even at low doses. The difference encountered between boys and girls should be studied further in other cohorts and, if confirmed, could Am J Epidemiol 2006;164:955–962


DDT and Cognitive Functioning at Age 4 Years

indicate the underlying mechanisms involved. These results should also be considered when evaluating the risk and benefits of spraying DDT during antimalaria and other disease-vector campaigns. DDT might be useful in controlling malaria, but the evidence of its adverse effects on human health calls for appropriate research on whether it achieves a favorable balance of risk versus benefit (34, 35).

ACKNOWLEDGMENTS

This study was funded by grants from the Spanish Ministry of Health (FIS-97/1102, FIS-PI041436, Instituto de Salud Carlos III (Red RCESP C03/09 and Red INMA G03/176)), ‘‘Fundacio´ La Caixa’’ (97/009-00 and 00/077-00), and the Generalitat de Catalunya-CIRIT (1999SGR 00241). The authors are grateful to Dr. Matthew P. Longnecker of the National Institute of Environmental Health Sciences for his helpful comments on the manuscript. They are also indebted to Carlos Mazo´n, Rosa M. Sabate´, and Maria Victoria Iturriaga for their assistance in contacting the families and administering the questionnaires. Conflict of interest: none declared.

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Am J Epidemiol 2006;164:955–962


Publicación Daniel Carrizo  

Publicación Daniel Carrizo

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