Dedication
ThisbookisdedicatedtomygranddaughtersAdalynnMalaandCamille SimmonsDosi,andtoallofthechildrenintheirgeneration,withthe hopethattheadvancementsinhealthsciencewillreducethescourgeof tobacco-relateddisease.
Contributors
LauraAkers
OregonResearchInstitute,Eugene,OR,UnitedStates
OlalekanA.Ayo-Yusuf
SefakoMakgathoHealthSciencesUniversityMedunsa,Pretoria,SouthAfrica
KevinP.Conway
RTIInternational,ResearchTrianglePark,NC,UnitedStates
KarlO.Fagerstr € om FagerstromConsulting,Vaxholm,Sweden
JudithS.Gordon UniversityofArizona,Tucson,AZ,UnitedStates
DorothyK.Hatsukami UniversityofMinnesota,Minneapolis,MN,UnitedStates
StephenS.Hecht UniversityofMinnesota,Minneapolis,MN,UnitedStates
JackE.Henning field
PinneyAssociates,Bethesda,MDandTheJohnsHopkinsUniversitySchoolofMedicine, Baltimore,MD,UnitedStates
LynnC.Hull
U.S.FoodandDrugAdministration,SilverSpring,MD,UnitedStates
DaliaKhoury
RTIInternational,ResearchTrianglePark,NC,UnitedStates
BartoszKoszowski
BattelleMemorialInstitute,Baltimore,MD,UnitedStates
GretchenMcHenry
RTIInternational,ResearchTrianglePark,NC,UnitedStates
StevenE.Meredith
U.S.FoodandDrugAdministration,SilverSpring,MD,UnitedStates
DevonNoonan DukeUniversity,Durham,NC,UnitedStates
RichardJ.O’Connor
RoswellParkComprehensiveCancerCenter,Buffalo,NY,UnitedStates
MarkJ.Parascandola
NationalCancerInstitute,Bethesda,MD,UnitedStates
StephanieJ.Parker
RTIInternational,ResearchTrianglePark,NC,UnitedStates
WallaceB.Pickworth
BattelleMemorialInstitute,Baltimore,MD,UnitedStates
LarsM.Ramstrom InstituteforTobaccoStudies,T€aby,Sweden
VaughanW.Rees
HarvardT.H.ChanSchoolofPublicHealth,Boston,MA,UnitedStates
HerbertH.Severson OregonResearchInstitute,Eugene,OR,UnitedStates
StephenB.Stanfill
U.S.CentersforDiseaseControlandPrevention,Atlanta,GA,UnitedStates
IrinaStepanov UniversityofMinnesota,Minneapolis,MN,UnitedStates
Foreword
Aplaceforsmokelesstobaccoinpublichealthwith science-guidedtobaccoregulation?
Smokelesstobacco, “ you ’vecomealongway,baby,” toechothephrase fromthe1968VirginiaSlimscigaretteadvertisement.Fromamainlyolder man ’shabitinthe1960sintheUnitedStateswithproductsandspitting behaviorthatseemeddisgustingtononusers,totheemergenceofstarter productsdesignedforyouthintheUnitedStatesinthe1970sthatturned thedemographicsofUSusersupsidedown,1,2 andmorerecentlytosubstantiallycleanedupandmorepopulation-acceptableharmreductionproducts inthe21stcentury.Asevidencedinthisvolume,smokelesstobaccohas comealongwayindeed.
Thereweretwolandmarksinthecleaningupofsmokelesstobacco,and itbeganwithSwedishsnus.In1976the firstpopularportion-packed(spitfree)snusproductwaslaunched,andin1981therewasaswitchtoa modernizedmanufacturingmethod.Theestablishednon-fermentation heattreatmentcharacterofthemethodwasretained,andvariousqualityimprovementsoftheheattreatmentprocesswereintroduced,includinga completelyclosedmanufacturingprocesstominimizecontamination.These effortssubstantiallyreducednitrosaminesandothertoxicantlevels.Swedish snusisregulatedundertheSwedishFoodAct,andSwedishhealthauthoritiesencouragedimprovementofsnusquality.Inaddition,majormanufacturersdevelopedproductstandardstoensurelowlevelsoftoxicants(i.e,the GothiaTekStandard3).SeeadditionaldiscussioninchaptersbyStanfill, Hecht,andStepanovandHatsukamiinthisvolume.4 6
Atthetimeoftheinitialdraftingofthisforeword,threelowtoxicant smokelessproductswereunderconsiderationforpotentialofficialUS FoodandDrugAdministration(FDA)designationasModifiedRisk TobaccoProducts(MRTPs),namely,SwedishMatch’sGeneralSnus, ReynoldsAmerican’sCamelSnus,andUSSmokelessTobaccoCompany’ s CopenhagenSnuffFineCut.7 TheSwedishMatchproductwasthe firsttobaccoproducttohaveitsPremarketTobaccoProductApplication(PMTA) approvedbyFDA,anditwasapprovedwithastatementfromFDAthat wouldhaveseemedunimaginabletomosttobaccocontrolexpertsjusta decadeearlier: “[t]hePMTAdecisionsfortheseproductsreflectevidence
showingthattheseproducts,marketedasdescribedinthemanufacturer’ s application,wouldresultinalowlikelihoodofnewinitiation,delayed cessationorrelapse. [and]thattheseproductswouldlikelyprovideless toxicoptionsifcurrentadultsmokelesstobaccousersusedthem exclusively.”8
Duringthe finalizationofthisforeword,animportanteventinthehistoryoftobaccoproductregulationwasannouncedbyFDAunderthe followingheadlineontheirwebsite: “FDAgrants first-evermodifiedrisk orderstoeightsmokelesstobaccoproducts.FDAconcludescompletely switchingfromcigarettestotheseauthorizedproductslowerscertainhealth risks.” FDA’sMRTPauthorizationwasforeightSwedishMatchsnusproductssoldunderthe “General” brandname.
AharbingerofFDA’sMRTPauthorizationandincreasedtobaccocontrolcommunityacceptanceofsmokelesstobaccoasaharmreduction approachwasareportfromtheRoyalCollegeofPhysiciansofLondon9 thatendorsedtheuseofsmokelesstobaccoinplaceofcigarettesforpeople whocouldnotgiveuptobaccouse;itdiscussedSwedishsnusasanexemplarypotentialharmreductiontobaccoproduct.Thiswasfollowedbya reportfromtheUS-basedStrategicDialogue,chairedbyDorothyHatsukamiandMitchZellerandwhichincludedadiversearrayoftobaccocontrol experts.10 Withoutendorsingsmokelesstobaccoperseasaharmreduction optionforcigarettesmokers,theirreportmadeclearthatcombustibletobaccoproductsaccountedformosttobacco-relatedmorbidityandmortality andthatpublichealthneededtoconsidernoncombustibleoptionsforpeoplewhoareunabletocompletelygiveupnicotine.10 Thelandmark50th anniversarySurgeonGeneral’sReportonTobaccoandHealthtooka generallysimilarposition.11
ResearchpublishedsincetheSwedishMatchPMTAwas filedwithFDA in2014providesfurtherevidencethatsnususebothhampersinitiationof smokingandencouragesandfacilitatescessation.12,13 Whereasitisclear thatoralsmokelesstobaccodoesnotcauselungdiseases,therehavebeen studiessuggestingapossiblelinkbetweensnusandcertaincancers,cardiovasculardiseases,andtype2diabetes.However,themostrecentresearch suggeststhattheserisks,ifreal,aresubstantiallylowerascomparedtocigarettesmoking.14 19 SeeadditionaldiscussioninthechapterbyMcHenry etal.inthisvolume.20
Nonetheless,intheUnitedStatesandmanyothercountries,thereremainsresistancetotheacceptanceofsmokelesstobaccoaspartofacomprehensivepublicstrategytoreducecombustedtobaccosmokeexposure,in
partduetothelegacyofaggressiveyouth-targetedproductdevelopment andmarketingthatemergedinthe1970sand1980s.1,2 SeeadditionaldiscussionofpastandpresentsmokelesstobaccomarketingbyRees,AyoYusuf,andO’Connorinthisvolume.21 Afurthercomplicationinacceptanceofsmokelesstobaccoasaformoftobaccoharmreductionisthatit isadiverseproductcategory,withmanyproductsinIndia,NorthAfrica, andSoutheastAsia,inparticular,thathaveveryhighlevelsoftoxicants andlikelycarryahigherriskofdiseasethanlowertoxicantproducts,asdiscussedbyStanfillinthisvolume.22 SeeadditionaldiscussionbyParascandola andPickworth.7
Amongpublichealthleaderswhodoseesmokelesstobaccoasapotential assetinreducingsmoking-associatedmorbidityandmortality,thereiswidespreadagreementthatsuchtobaccoharmreductioneffortswouldbeideally developedandoverseeninascience-guidedregulatedenvironment.7,10,23 27
Atleastthreeimportantadvanceshaveopenedthedoortobroader acceptanceofsmokelesstobaccoasaformofharmreductionforpeopleunableorunwillingtocompletelygiveuptobacco.First,asillustratedbythis volume,istheadvancementofsciencethatcancontributetotobacco-and health-relatedpolicyandregulation,therebyprovidingaregulatoryframeworkforlabelingandothermessagingthatcouldappropriatelycommunicatethisinformation.Secondistheincreasingrecognitionthatitis combustedproductsingeneralandcigarettesinparticularthatoverwhelmingcontributetotobacco-relatedmorbidityandmortality,andthat oncurrentcourseannualsmoking-causeddeathsrateswillcontinuetoincreasefordecadestocome.23,27 29 Thirdiswhatisoftenreferredtoas theSwedishExperiment,whichshowedthatlarge-scalesubstitutionofnoncombustedformsofnicotine(primarilyintheformofsnusbutalsobyway ofnicotinereplacementmedicines)producedthe firstclearreversalof smoking-associatedmorbidityintheworldatthepopulationlevel,witha levelingoffofsmoking-relateddeathratebyabouttheyear2000andsubsequentsteadydecline.12 17 ThishasresultedinSwedenachievingthe lowesttobacco-relateddeathsintheEuropeanUnion.30,31
TherationaleandapproachinSwedenhavebeendocumentedelsewhere,includinginacommentarybyHenning fi eldandFagerstr € omin 2001.32 Inbrief,theSwedishExperimentbeganinthe1960sfollowing thereportsbythe1962RoyalCollegeofPhysiciansofLondon 33 and theUSSurgeonGeneral 34 thatcigarettesmokingcausedcancerandother diseases.TheconceptadvocatedbySwedishhealthexpertswastoaugment effortstopreventsmokingandsupportcessationwithacceptanceand
eventuallyencouragementoftheuseofsmokelesstobaccoinplaceof cigarettes.
AtthesametimeinSweden,cigarettecompaniesbegantomarketsocalledlight/lowtarcigarettes,astheydidglobally.Swedishwomenquickly adopted “light” cigarettebrands.Itwasdecadesbeforeitbecameevident thatsuchcigarettesdidnotreducemorbidityandmortalityrisks.35 In contrast,menweremorelikelytotransfertheirtobaccousefromcigarettes tosnus,andtheirriskoflungcancerandothersmoking-relateddiseases begantodecline.30,31 TheleadingSwedishtobaccocompany,Swedish Match,begantodevelopprogressivelylowertoxinsmokelesstobaccoproducts,andinthelate1990sdiscontinuedmarketingcigarettesinSweden. Overallnicotineconsumptionandprevalenceofnicotineproductusedid notsubstantiallydecline,butinmenthesourceofnicotinehadshiftedsubstantiallyfromprimarilycigarettestosnus.By2001,Henningfieldand Fagerstr € omdescribeditasapromisingexperimentinprogresswithevidence emergingthatsmoking-associateddiseasewasbeginningtodecline.
WhereastheSwedishExperimentremainsinprogress,bytheearly2000s itbecameincreasinglyacceptedthatsmokelesstobaccowaslessharmfulthan cigarettes,andthatconsiderationshouldbegiventohowpolicyandregulationmightsupporttransitionawayfromcigarettesforpeopleunableto giveuptobaccoandnicotinecompletely,butwithoutunderminingsmokingpreventionandtobaccousecessationefforts.10,11,36 41 IntheUnited States,theregulatorypathwayforsuchapotentialharmreductionuseof oralsmokelesstobaccoandotherproductsisincludedinthe2009Family SmokingPreventionandTobaccoControlActthatestablishedtheCenter forTobaccoProductswithintheFDAandincludedamechanismto approvepotentialMRTPs.26
TheSwedishExperimentremainsongoingwithasteadyoutputofdata, andmain findingsseemclear:namely,evenwithoutreductioninnicotine use,morbidityandmortalitycanbesubstantiallyreducedbysubstitution oflowtoxicantsmokelesstobaccoforcigarettes.Indeed,theexperience fromSwedenmeansthat,amongmales,50yearsofsubstitutionofsnus forcigaretteshasbeenthemajorcontributortoachievingthelowestprevalenceofsmokingandthelowestlevelofmortalityattributabletotobaccoin theWesternWorld.35,36
Bigquestionsremain,however,asdiscussedbyParascandolaandPickworthandinotherchaptersinthisvolume.Theyincludehowtoincreasinglyhelpcigarettesmokerswhoareunabletocompletelygiveup tobaccoornicotinetoreducetheirexposuretotobaccosmokeandits
associatedmorbidityandmortality.Formanypeopleconventionaltreatmentmodalitieswillsuffice.Forothers,asstatedbyGottliebandZeller, “theavailabilityofpotentiallylessharmfultobaccoproductscouldreduce riskwhiledeliveringsatisfyinglevelsofnicotineforadultswhostillneed orwantit.”39 Foranappreciationofhowfarthescienceandpotentialproductshaveadvancedsincethe1990s,seediscussionsoverthepasttwodecades abouthowsuchharmreductionapproachescouldcomplementprevention andtreatmenteffortstoaccelerateprogressinreducingtobacco-associated morbidityandmortalitybyWarner,Slade,Sweanor,andothers 42 44 as wellasinthe2014USSurgeonGeneral’sreport.11 Thesciencetodate, ashighlightedbymuchofthesciencepresentedinthisvolume,suggests harmreductionapproachesincludingappropriatelyregulatedlowtoxicant smokelesstobaccoareanachievablestrategy.
Continuedresearchtoadvanceknowledgeandguideregulationand policyiscriticaltocontinuingprogress.Wearepleasedtowelcomethisvolumeandlookforwardtoanupdate,hopefullywithinafewyears,describing furtheradvancesinnicotineandtobaccoscienceaswellasscience-guided tobaccocontrolefforts,includingtobaccoproductregulation.
JackE.Henningfield,PhD VicePresident,Research,HealthPolicy,andAbuseLiability, PinneyAssociates,Bethesda,Maryland,UnitedStates and
Professor,Adjunct,BehavioralBiology,DepartmentofPsychiatry andBehavioralSciences,TheJohnsHopkinsUniversitySchoolof Medicine,Baltimore,Maryland,UnitedStates
LarsM.Ramstr € om,PhD PrincipalInvestigator,InstituteforTobaccoStudies,Taby,Sweden KarlO.Fagerstr € om,PhD Fagerstr € omConsulting,Vaxholm,Sweden
Disclosures
From2015toOctober2019,Dr.HenningfieldprovidedscientificandregulatoryconsultingservicesthroughPinneyAssociatestoNiconovumUSA, Inc.,R.J.ReynoldsVaporCompany,andRAIServiceCompany,all subsidiariesofReynoldsAmericanInc.(nowownedbyBritishAmerican Tobacco)onsmokingcessationandharmreduction,explicitlyexcluding
consultationoncombustingcigarettes.SinceOctober2019,hehasconsultedonadvancingrelativerisk-basedregulationofnicotineandtobacco productsthroughPinneyAssociatestoJUULLabs,Inc.Alsothrough PinneyAssociates,heconsultstopharmaceuticalcompaniesonthedevelopmentandregulationofnewmedicinesandformulationsforpain,addiction, epilepsy,andothercentralnervoussystemdisorders,andtothedietarysupplementindustryinsupportofcentralnervoussystemactivedietaryingredientsandcannabis-derivedproducts.
Dr.Ramstr € omisleaderoftheInstituteforTobaccoStudies,Sweden,an independentresearchinstitutionworkingininternationalcollaborationwith scientistsdealingwithepidemiologicalresearchontobaccomatters.Hehas receivedconsultingfeesfrompharmacologicalcompaniesthatdevelopand marketproductsforsmokingcessation.
Dr.Fagerstr € omhasreceivedconsultingandspeakingfeesfrommany companiesthatdevelopormarketpharmacologicalandbehavioraltreatmentsforsmokingcessation.Hecurrentlyreceivesconsultingfeesfrom SwedishMatchandhasreceivedfeesinthepastfromPhilipMorrisInternationalandBATtoassisttheireffortstodevelopless-riskytobaccoproducts.
References
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Preface
WhenBrianThomas,theserieseditorofEmergingIssuesinAnalytic Chemistry,askedmetosubmitachapterforthisvolume,Isurprisedhim andevenmyself byagreeingnotonlytoparticipateasanauthorbuttobe theguesteditor.Ithasbeenajourney!My firstandonlypersonaluseofa smokelesstobacco(ST)productwasattheNationalInstituteonDrugAbuse IntramuralResearchProgram.IwasworkinginJackHenningfield’sClinical PharmacologyLaboratoryinaprojecttounderstandtheeffectsofSTproductpHonnicotineabsorptionandothereffects.Mycollaboratorsonthe studywereTomCargulio,apharmacystudentintern,andmylongtime friendandcollaboratorReggieFant.Weweretryingtoperfectadosing schemeformoistsnuffandwereexperimentingwithusingconcentricblood collectiontesttubestocreateaplugsuitableforaunitdoseofabout2grams forourresearchsubjects.Inthespiritofexperimentationandinamomentof bravado,Iplacedaplug “betweencheekandgum,” justasinstructedbyso manypopularmediaads.Withinaminute,Iwasrunningfortherestroom feelingtheheadrush,intensesalivation,awaveoftachycardia,perspiration, and fightingbackemesis.Itwassocholinergic!!Amemorableintroduction toST,aproductthathasbeenapartofthetobaccomarketforcenturies,has adverselyaffectedthehealthofmillionsofpeople,andhasbeenasubjectof myexperimentalandclinicalresearchforthepasttwodecades.
Formanyyears,thediscussionoftobaccousewascenteredoncigarettes, oftentotheneglectofothercombustibleandnoncombustiblemeansof nicotinedelivery.However,tobaccouseprecededthepopularizationof cigarettesmoking,whichbeganwiththedevelopmentofthecigaretterollingmachinein1884.In1907,theUScigaretteproduction(5billionsold) waslessthancigarproduction(7billionsold),butby1928cigaretteproductionreached100billion.Beforeits “discovery” byColumbusintheNew WorldonoraboutOctober15,1492,tobaccowascultivatedandusedby indigenouspeopleinbothcombustibleandnoncombustibleform.There arerecordsoftobaccopowderbeinginsufflatedthroughtubesintothe nose,dippingofsnuff,andsmokingofcigars.Cigarettespeakedinthe UnitedStatesin1964,whenoverhalfoftheadultpopulationsmoked them.TheLutherTerryreportin1964declaredthatcigarettesmoking wasahealthhazardanditsusewasassociatedwithlungcancer.Inthedecadesthatfollowed,intensepublichealthefforts,epidemiologicresearch,
andtherealizationthatsmokingharmstheuserandthoseinhisvicinityled tolaws,policies,andrestrictionsthateventuallydecreasedprevalencetoits currentleveloflessthan20%ofUSadults.
Ascigarettessaleshavedecreased,theuseofothernicotinedelivery methodshasincreased,particularlycigars,cigarillos,andlittlecigarsamong somedemographicgroups.Theintroductionofelectroniccigarettes (e-cigarettes)andthehugeincreaseintheirusehasbeendocumented overthepastdecade.OthertobaccoproductssuchaslozengesandoralnicotinedeliveryproductssuchastheVerveseries(discontinuedinearly2019) havebeenintroduced.Pharmaceuticalproductsthatdelivernicotineinthe formofgum,transdermalpatches,andnasalsprayweredevelopedtofacilitatesmokingcessation.
ThisvolumeprovidesanoverviewofresearchonSTproducts,their placeinthehistoryoftobaccouse,theireffects,andtheirroleinthecurrent environmentofharmreduction.Broadlydefined,anynoncombustible tobaccoproductornicotinedeliverysystemmightbeconsideredsmokeless tobacco.Theusualformsarechewingtobacco,moistsnuff,Swedishstyle snus,anddrysnuff.TheleadingproductintheUnitedStatesismoistsnuff. InSweden,aparticularformofprocessedsnusisordinarilyused,whereasin AfricaandSoutheastAsiatheproductsarefrequentlymadeatthesiteofsale andcontaincompoundssuchasarecanut(inbetelquid),lime,andaleaf wrapping.Productsofvariouscategoriesareusedbymillionsofpeople worldwide.Useisespeciallyevidentamongwomenindeveloping countries.STisknowntocausedental,cardiovascular,andreproductive pathology,andoralandpancreaticcancer.Thepublichealthburdenis considerable,andtheeconomicconsequencesareespeciallyperniciousin developingcountries,whereregulatoryauthoritiesareleastlikelyto respond.
Thechaptersofthisvolumetakevariouspointsofview.Thediversityof productdesignandmarketinghasimplicationsforregulation.Epidemiology domesticallyandworldwideillustratesthemagnitudeoftheproblem.Laboratoryanalysesemphasizetobacco-specificnitrosaminesandahostofother constituentsandshowhowstate-of-the-artknowledgecanbeusedtoset thestandardsforregulation.Laboratoryresultsrevealthemechanismsof exposureandtherapid,robustdeliveryoftheaddictivecompoundnicotine. TreatmentstrategiestohelpthosewishingtoquitSTusearereviewed,asare productmodificationsforharmreduction.Adiscussionofthepolicyand regulationofSTproductsaddressessomeoftheoutstandingandcurrent researchquestions.Forexample,asthisbookwasgoingtoprint,theUS
FoodandDrugAdministrationapprovedaSwedish-stylemoistsnuff (Generalbrandsnus)tobesoldintheUnitedStateswithamodifiedrisk claim.Thisisthe firsttimeatobaccoproducthasbeengivenapprovalto advertiseandbepromotedashavinglowerhealthrisk.Thecomprehensive approachadoptedforthisvolumeprovidesperspectivetostudents,clinicians,researchers,andpolicypersonnelwhoconfrontthechallengesof thisuniquegroupofproducts.
Myentryintothisresearchbeganasasimpleclinicalexperimentto determinewhetherSTproductsofdifferingpHlevelshaddifferentcharacteristicsofnicotineabsorption,cardiovasculareffects,andsubjectiveeffects. Sincethen,the fieldhasbeenexpandedandrefinedbymanyofthecontributorstothisvolume.Wehopethatoureffortsinspirefurthercuriosity, research,discussion,andscience-basedpolicyandregulationonthisfascinatinggroupofproducts.
WallaceB.Pickworth
Baltimore,MD,UnitedStates October24,2019 Preface xxiii
Introduction
WallaceB.Pickworth
BattelleMemorialInstitute,Baltimore,MD,UnitedStates
Thisvolumeprovidesanup-to-datereviewofsmokelesstobaccoproducts intherapidlychangingconsumertobaccomarketplace.Inthepast20years, therehavebeendramaticchangesinthepoliciesandregulationoftobacco. Mostofithasbeendirectedatcigarettes,butthereisacontinuinginterestin otherproducts,includingsmokelesstobacco(ST).TheFramework ConventiononTobacco(FCT),aWorldHealthOrganization(WHO) initiative,andtheFamilySmokingPreventionandTobaccoControlAct (FSPTCA)areamongtheinternationalanddomesticlawsthathavebegun science-basedregulationofthetobaccomarket.IntheUnitedStates,the FSPTCAestablishedanewagency,theCenterforTobaccoProducts (CTP),withintheFoodandDrugAdministration(FDA).TheCTPhas broadandstrongregulatoryauthorityoveralltobaccoproducts.TheirauthorityoverSTwasdefinedintheoriginallegislationin2009andwas extendedtoothertobaccoproducts,includingelectroniccigarettes,in 2014.Astatedgoalofthelegislationistousescience-basedresultstoinform regulationsthatservethepublichealth.Thematerialinthisvolumecontributestothediscussion.
Twootherfactorshavebroughtchangetothetobaccomarketplace.First, therehasbeenanincreasinglyvisibleadaptationofharmreductionapproaches totheregulationoftobaccoproducts.Harmreductionimpliestheacceptance ofsomehealthrisktoreduceoverallrisk.Alltobaccoproductsareassociated withhealthrisks,butthereisconsiderableevidencethattheriskisnotequal. Combustibletobaccoposesthemostrisk,andthecigaretteisthemostpernicious form.Atthelowerendofthecontinuumaretheslow-releasenicotine-onlypharmaceuticaldeliveryproductssuchasthetransdermalpatchandnicotinepolacrilex gum.STproductscarryacknowledgedrisksofaddiction,mouth,head,andneck cancer,andcardiovascularandreproductiveeffects;butrelativetocigarettes,they haveamuchloweroverallriskprofile.Aharmreductionapproachwouldsuggest thatSTproductsshouldbelessregulatedandlesstaxedandhavefewerandless restrictivecontrolregulationsthanmoreharmfulproducts.
SmokelessTobaccoProducts
ISBN:978-0-12-818158-4
https://doi.org/10.1016/B978-0-12-818158-4.00001-7
Thetobaccomarketplacehasbeenrockedbytherecentintroductionof electroniccigarettesorelectronicnicotinedeliverysystems(ENDS)and heat-not-burnproducts.ENDSaffectnicotinedeliverybyheatingsolutions ofnicotineinglycerolorpolyethyleneglycol,whereasheat-not-burnproductsrelyonthelow-temperaturewarmingoftobacco.Theemissionfrom ENDSorheat-not-burnproductsissubstantiallylowerinharmfulcompoundsthantobaccosmokeofconventionalcigarettes.Itwouldseem thattheseproductsmightlowerthehealthrisktotheuseranddiminish exposuretoothersbyreducingsecondhandsmoke.However,electronic cigarettesarerelativelynew,andtheirhealthrisksmaynotbefullyevident. Furthermore,theyhavealreadygonethroughthreeormoregenerationsof products,sothehealthhazardsofeachvariantaresubjecttoindividualstudy. Heat-not-burnproductshavebeenontheinternationalmarketabout5 years,thoughonlyrecentlyapprovedforsaleintheUnitedStates.There areverylittledataonhealthconsequencesoftheirlong-termuse.Incontrast toST,whichisamarketstaple,newproductsthatdeliveronlynicotineor nicotinewithfewerotherchemicalswillcontinuetobeintroduced.Their long-termeffectonthepopulationuseofcigarettesandotherformsoftobaccoisuncertain.ST,givenitsworldwideusethathaspersistedforcenturies,willlikelyremainasignificantpartofthetobaccomarket,exerting personalandpublichealthconsequencesforyearstocome.
Thisvolumeconcentratesonmanyofthemostactivelyresearchedareas inthe fieldoftobaccoscience particularlyastheyapplytoST.Assummarizedbelow,thebeginningchaptersreviewthevariousSTproducts,their epidemiology,andpharmacology.Onechapterdiscussesthediagnosisand treatmentofSTaddiction.Otherchaptersreviewthechemistryinproduct analysisandthebiomarkersofhumanconsumption.Achapterisdevoted solelytoanexplanationofthecarcinogenicmechanismsfromcomponents ofST.The finalchapterdiscussesregulatorypolicy.
VaughanReesandhiscolleagues(Chapter2)coverthevarioustypesof STproductsandtheirdesignandmarketing.STisnotasingularproduct; therearemany.Thisdiversitymustbeappreciatedtounderstandthatitis difficulttodiscussSTasasinglenicotinedeliveryproduct.Eachproduct hasuniquedesignfeatures.Animportantimplicationisthattherearespecific attributesthatcanberegulated,suchas flavor,packaging,pH,nicotinelevel, andtoxicantcontent.Furthermore,tobaccomanufacturers,inanattemptto retainexistingcustomersandgainnewones,haveintroducedinnovative productsandmarketingtechniques.Cigarettemanufacturershavenow enteredtheSTmarketwithsimilarobjectivesandstrategies.Thischapter
addressesthoseinnovationsandhowtheymustbeunderstoodindesigning regulatorypolicytodiscourageinitiationoftobaccouseinanyformor,for personswhowillnotquit,toencourageaswitchtoputativelyless-toxic forms.Typesofproductsandtheregionalanddemographiccharacteristics ofuseinthevariousmarketsaregiven.Innovationsareevaluatedfortheir effectiveness.Thesefactorsarediscussedintermsofhowtheyinformpolicy andregulatorystrategiesforanevolvingtobaccomarket.
GretchenMcHenryandherteamprovideacomprehensivereview (Chapter3)oftheepidemiologyofSTuseintheUnitedStatesandinternationally.Globaluseisestimatedtobenearly300millionpeople,much ofitinlowerincome,developingcountriesandamongwomen.Inthe UnitedStates,about2%ofadultsareusers,buttheyarenotuniformly distributedinthepopulation;incidenceishighestinmen,ruralstates,Native Americans,andyouth.Thatreviewremindsusofthevastnumberof womenwhousetheproductsinAfricaandAsia,wheresmokingamong womenisculturallydisapproved.Unfortunately,useinwomenhasbeen associatedwithpoorbirthoutcomesandotherrecognizedhealthrisks. Epidemiologicdataareimportantindicatorsofusetrends,theeffectiveness ofregulation,andtheinfluenceofnewproductsonthemarket.Someofthe risksarewellknownandacknowledgedbyusers,includingaddiction,dental problems,andoralcancers,butotherestablishedriskssuchascardiovascular andcirculatorydisease,reproductiveeffects,andpancreaticcancerareunderappreciatedorevenunrecognized.Underappreciationmayaccountfor persistentuse.DatasuchasthesecouldinformhealthmessagingthatpromotespreventionofSTinitiationandadvocatescessation.
FindingsfromlaboratorystudiesarepresentedinChapter4.TherelativelyfewsuchstudieshaveinvestigatedtheroleoftheproductpHinnicotineabsorption.Otherstudieshaveinvestigated flavorasadeterminantof useandappeal.Theformatofmoistsnuff,asloosetobaccoorinsmall “teabag” sachets,hasbeeninvestigatedtodeterminewhethersuchdesign changesalterrateofnicotineabsorption.Acentraltenetoftheresearchis thatthespeedofnicotinedeliveryisrelatedtoabuseliability(addictiveness). Thechapterreviewsself-reportquestionnairesthatassessusepatternsand dependencepotential.Datafromsubjectivequestionnairescanbeusedby clinicianstoguideandassesstherapeuticdecisionsandbyresearcherstoassess theeffectsofproductmanipulation.Findingsfromlaboratorystudiesprovideempiricalevidencethatcanbeusedforscience-basedregulation.
HerbertSeversonandhiscolleagues(Chapter5)reviewtheliteratureon thetreatmentofthosewishingtoquitST.Thechaptercoversthemeasures
ofnicotinedependencethatarespecificallydevelopedforSTusers.Drugs, behavioralassistance,andcounselinghavebeenemployed.STusersasa grouparesurprisinglytreatment-resistant,inmanycasesmoredifficultto treatthancigarettesmokers.UniqueinterventionsspecifictoSTusearebeingdevelopedandtested.Ingeneral,researchhasyieldedgoodevidenceand supportforseveralmethods,withsomeoutcomesexceedingthosefor smokingcessation.However,refinementofexistingmethodsanddelivery systemsisneeded,aswellasinnovationinmethods.Futuredirectionsin whichstudiesandtherapeuticapplicationsmightgoareprojected.
IrinaStepanovandDorothyHatsukami(Chapter6)provideacomprehensivereviewofthechemicalcharacterizationofSTproductsandbiomarkersofuseinhumans.Theyreviewtheabsorptionandmetabolismof nicotineandthetoxicantexposuretotobacco-specificnitrosamines (TSNA).Thechapterisanoverviewofsources,levels,andthevariation ofharmfulconstituents.EstablishedbiomarkersthatassessexposuretoST constituentsarediscussed,andtheanalyticalmethodologiesusedforthe measurementofconstituentsandbiomarkersarereviewed.Variationsin thelevelsofkeyharmfulconstituentsacrossproductsandtheimpactofthese variationsonrelatedexposuresareemphasized,andpolicyimplicationsare discussed.Theproductsarecharacterizedbyenormousdiversityoftypesand formulations,fromuncureddrytobaccothatisusedbyitselftocomplexrecipesmadewithvariousadditionalingredientsthatcanmodifyaddictiveness, toxicity,andcarcinogenicity.Addingtothiscomplexityisthediversityof tobaccoplanttypesandprocessing.Dataonexposuretochemicaltoxicants andcarcinogensfromtheuseofSTproductsisscarceandmostlylimitedto theUnitedStates.However,cancerrisksworldwidemirrorthevariationsin thelevelsofkeyknowncarcinogensinproducts.InIndia,manyproducts containhighlevelsofcertaincarcinogens,andincidenceinheadandneck cancersisremarkablyhigh,whileSwedishsnuscontainslowlevelsand theassociatedcancerriskisvirtuallynonexistent.Therefore,chemicalcharacterizationofproductsandrelatedexposureinusersiskeytothedevelopmentofpreventivemeasuresandscience-basedproductregulation.
InChapter7,StevenHechtexploresthecarcinogenicmechanismsofthe TSNAfoundinST.Theyarethemostabundantandpotentcarcinogensin STandareacknowledgedbytheInternationalAssociationonCancer Research(IARC)asClass1carcinogensinhumans.Theyappearespecially responsiblefortumorsofthemouth,esophagus,andpancreas.Interestingly, theyarenotbiologicallyactiveastheyexistintheproduct,butmustbe metabolizedbycytochromeenzymesintheliverandelsewheretoproduce
thetoxicmetabolites.Oneoftheenzymesthatcatalyzethatconversionis CYP4502A6,whichisresponsibleforthemetabolismofnicotinetocotinineand3-OHcotinine.Ironically,theenzymesinvolvedinthemetabolism anddeactivationoftheaddictivecomponentoftobacco,nicotineare responsiblefortheactivationofothercomponentsthatleadtotumors. TherecognitionofthecarcinogenicpotencyoftheTSNAhasledtorecent callstolimittheirconcentrationinSTtolessthan1ng/gdryweight.
Thequestionofhowgrowing,manufacturing,processing,andpackaginginfluencelevelsofTSNAisreviewedbyStephenStanfillinChapter 8.Thischaptercoversthesourcesoftoxicantcompoundsandtheirprecursors.Thereisanextensivediscussionofthemeasurementofheavymetals, TSNA,andadditivesthatcontributetotheoveralltoxicprofile.Tobacco absorptionofsoilnitrate,microbialnitratereduction,andnitrosationare thoughttocontributetotheformationofTSNA,includingpotentcarcinogens.TheencouragingmessagefromthisreviewisthatmanyofthetoxicantsinSTcanbelimitedoreliminatedbyachievableagriculturalor practicalchangestomanufacturingprocess.
Thevolumeconcludeswithadiscussion(Chapter9)onregulatorypolicy.MarcParascandolaandIreviewtheprovisionsoftheFCTandFSPTCA specificforSTregulation.Casestudiesillustratethecounter-advertisingand heathmessagingthatattempttodiminishSTuse.Otherhealthpromotion effortsthathavebeenimplementedareconsidered.Aswithothertobacco products,discussionofSTproductsiscomplex,becausetheyareatonce drugs,legalcommercialgoods,incomesourcesfortheirproducersandthe entitiesthattaxthem,andcauseofsignificantadversehealthoutcomes andpublichealthburden.Sadly,muchofthepersonalandpublichealth consequencesarebornebypeopleinthemostimpoverishedcountries. ThelonghistoryofSTuseandthecurrententhusiasticcommercialmarketingsuggestthattheseharmfulproductsmaybeinthediscussionoftobacco andhealthforyearstocome.Itisourhopethatthecontentsofthisvolume willinformtheon-goingdiscussionofSTandinspirefurtherresearchthat directlyaddressesquestionsofimportancetounderstandingandregulation oftheseproducts.
Smokelesstobaccoproduct designandmarketing:targeting newpopulationsinachanging regulatoryenvironment
VaughanW.Rees1,OlalekanA.Ayo-Yusuf2,RichardJ.O’Connor3 1HarvardT.H.ChanSchoolofPublicHealth,Boston,MA,UnitedStates 2SefakoMakgathoHealthSciencesUniversityMedunsa,Pretoria,SouthAfrica 3RoswellParkComprehensiveCancerCenter,Buffalo,NY,UnitedStates
Introduction
Smokelesstobacco(ST)hasalonghistoryandisthepredominant formoftobaccoinsomeglobalregions,yetithasgarneredasomewhat lowerpriorityforresearchandpolicydevelopmentthancombustedforms. SomeSTproductshavelowerhealthrisksthansmokingbecausetheydonot exposeconsumerstomanyofthehighlytoxicchemicalby-productsof combustion.Still,STusecausesserioushealthproblems,includingincreased riskofcancersoftheheadandneck.1 TheglobalSTmarkethasundergone importantchangesinthepasttwodecades,ascombustedtobaccohas becomemoreheavilyregulatedindevelopedcountriesandconsumers seeklower-riskalternatives.Inresponse,cigarettemanufacturershave enteredtheSTmarketwithnovelSTproductsthatofferputativelower riskandgreaterpersonalconvenience.Thecapacityofthetobaccoindustry toinnovatehasbeenwelldocumented,2,3 yetrelativelylessattentionhas beengiventorecentinnovationsinST.Thischapterwillconsidernewdevelopmentsinproductdesignandmarketingusedbymanufacturerstogain newconsumersandretainexistingones,oftenthroughtargetingsubpopulations.Byfocusingonfactorsusedbymanufacturerstoincreaseappeal ratherthanonhealthriskfactors,thischapterwillconsiderhowtobacco controlregulatoryinitiativesmustaddressindustrystrategies.Thegoalof regulationshouldbenotjusttoprotectthehealthofcurrentconsumers buttopreventpeoplefromeverinitiatinguse.Indevelopedcountries withatraditionofSTuse,suchastheUnitedStatesandScandinavian
SmokelessTobaccoProducts
ISBN:978-0-12-818158-4
https://doi.org/10.1016/B978-0-12-818158-4.00002-9
countries,demandforcombustedtobaccoisdecreasinginfavorofnoncombustedproducts.Thus,adeeperunderstandingofstrategiesusedbySTmanufacturerstodesignandpromotetheirproductscaninformfuturetobacco controlregulationsintendedtoreduceconsumerdemandforST,while identifyingopportunitiestolowerthehealthrisksforadultsmokerswith properlyregulated,reduced-riskSTproducts.
Typesofproducts
STisavailablegloballyinmyriadformsthatareusedorallyornasally. Table2.1 givesinformationoncommonforms,and Fig.2.1 showssomeexamples.Aswithanyproduct,STismanufacturedtomeetthepreferences andexpectationsoftargetconsumergroups.Someformsaretraditional, madewithlimitedtechnologyunderrudimentaryconditions.Othersare technologicallyinnovative,designedtoattractconsumersincompetitive developedmarkets.Traditionalformsoccurmainlyindevelopingcountries intheIndiansubcontinent,partsofAfrica,andtheMiddleEast.InIndia, whichhistoricallyhashadthelargestSTindustrybyvolume,11 useexceeds thatofcombustedtobacco.12 Popularproductsaredrysnuff(e.g.,bajjar,also knownastapkir),a finelygroundtobaccopowderusedorallyornasally,and gutkha,khaini,andnaswar(“ nass ”),whicharemadeofdriedandchopped tobaccoblendedwithotheringredientsincludingcrushedarecanut,slaked lime,ash,and flavorssuchascatechuextract,cardamom,andmenthol.Also popularisapowderedtobaccopastethatisappliedtotheteethandgums, sometimesasadentifrice;commonformsaregudakhu,gul,andmishri (Fig.2.1).Mawa,zarda,kiwam/quiwam,andshamahblend flavorings andbinderssuchasgroundarecanut,lime,oils,andspices;thisformis chewedorplacedbetweenthecheekandgumtodelivernicotineviathe oralmucosa.InNorthAfrica,drysnuffformulationssuchasnaffa(alsocalled tenfehaornufha)areplacedinsidethelip.InsouthernAfrica,apopularform oftraditionalsnuffisamixofpowderedtobaccowithcharredplantand/or ash,whichisalkalineandactsasabuffertofacilitatingnicotineabsorption. IntheSudanregion,toombakisamoistproductmadefromsundriedtobaccothatisfermented,mixedwithsodiumbicarbonate,andcastintosmall ballsfororaluse.OthercountrieshavespecificSTvariants,suchasmarasin Turkey,whichispowderedsundriedtobaccomixedwithoakorgrape leaves,andchimoinVenezuela,ahardenedpastemadefromcrushed,boiled tobaccoleafmixedwithsodiumbicarbonate,sugar,ashes,and flavorings (Fig.2.2).5,13
Table2.1 Majortypesandcharacteristicsofsmokelesstobacco.
Product typeBrandnamesManufacturers
Chewing tobacco RedMan,DaysWork,Apple,Brown, NaturalLeaf,UnionStandard, Tinsley,WNT,LeviGarrett,Taylors Pride,CannonBall,Moore’sRed Leaf,Cumberland,MammothCave, CottonBoll,Kentucky,Warren County,RoughCountry
Moistsnuff (dip)
Copenhagen,Skoal,RedSeal,Husky, Grizzly,Kodiak,Kayak,Redwood, GoldRiver,SilverCreek,Cooper, Silverado,TimbarWolf,Longhorn, RedMan
SnusGeneral,Catch,Ettan,Grovsnus, G€ oteborgsRapé,Kronan(Swedish Match);LuckyStrike,PallMall,du Maurier(BritishAmericanTobacco); Camel(R.J.Reynolds);Marlboro (PhilipMorris);Skoal(U.S.Smokeless TobaccoCompany);Knox,Skruf (ImperialTobacco),Tobaccorette
Dry snuff
Bajjar/ tapkir
LeviGarrettandSons,Dental,Honest, PeachSweet,TubeRose,W.E. Garrett&Sons,SilverDollar
Typicalcottageproductorhomeprepared
SwedishMatchNorth America,AmericanSnuff Company
(mg/g)5 8
ConwoodCompany, NationalTobacco Company,Swisher International,Swedish MatchNorthAmerica,US Tobacco
R.J.Reynolds,PhilipMorris, SwedishMatchNorth America,USTobacco
MeanofUS brands:12.3
Productcharacteristics
(mg/g)5 7 Common flavors/ Flavorants4 10 Preparationand formulations5,6,4,9,7,8,10
Licorice,sugarCuredtobaccotreatedwithleaf extract, flavored,anddried
MeanofUSbrands: 4.0 Mint,wintergreen, fruit,cinnamon
WHOregion1,4
Americas(primarily UnitedStates)
AmericanSnuffCompany, KretekInternational,Inc.
Sweden:12.8 28.2
MeanofUS brands:10.46
MeanofUSbrands: 3.08
Mint,wintergreen, fruit,cinnamon, molasses
Cured,fermented,and flavored tobacco, fineorlongcut; pouchesorloose
Americas,Europe
Pasteurized finelycuttobacco; pouches/sachetsorloose
Americas,Europe (especially Scandinavia)
InUS:4.7 24.84InUS:0.03 3.13Fire-curedandfermentedtobacco withadded flavors;powder Americas,Africa, Europe, South-EastAsia
nanaMenthol, floralRoastedandpowderedtobacco usedasdentifrice Americas,Europe, South-EastAsia (primarilyIndia)
(Continued)
