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ElectronicCigarettesandVaping:ANewChallengeinClinicalMedicineandPublicHealth.ALiteratureReview

ElectronicCigarettesandVaping:ANewChallengeinClinicalMedicineand
PublicHealth.ALiteratureReview
DominicL.Palazzolo1,*
AuthorinformationArticlenotesCopyrightandLicenseinformation

ThisarticlehasbeencitedbyotherarticlesinPMC.

Introduction

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Useofelectroniccigarettes(ecigarettes),referredtoasvaping,isarelativelynewphenomenonthatis
quicklygainingtheinterestofmanylongtimetobaccosmokers.AccordingtoareportbyUBSSecurities
LLC(1),salesfromtheecigarettemarketdoubledfrom$250to$500millionbetween2011and2012,and
areexpectedtoquadrupleby2014.Ecigarettesarebecomingapreferredalternativefornicotinedelivery
amongmanysmokersbecauseoftheirrealisticlook,feel,andtastecomparedtotraditionalcigarettes.
Furthermore,manycigarettesmokershaveturnedtovapingbecauseecigarettevendorshavepreviously
marketedtheirproductasacheaperandsafersmokelessalternativetotraditionalcigarettes,andapossible
smokingcessationtool.TheFoodandDrugAdministration(FDA)rejectedtheseclaims,andinSeptemberof
2010theyinformedthePresidentoftheElectronicCigaretteAssociation(2)thatwarninglettershadbeen
issuedtofivedistributorsofecigarettesforviolationsofgoodmanufacturingpractices,making
unsubstantiateddrugclaims,andusingthedevicesasdeliverymechanismsforactivepharmaceutical
ingredients.Manywebsitesstillclaimthatuseofecigarettesissafebecausetobaccoisnotburnedand
hencethereisnoinhalationofthemanytoxinsfoundincigarettesmoke.Forexample,ElectronicCigarette
ConsumerReviews(3),anecigarettewebsite,isfilledwithanecdotalconsumerclaimsrelatinghowe
cigaretteshelpedthemtoquitsmokingandimprovedtheiroverallhealth.
TheFDAhasreportedthatecigarettecartridgesandsolutionscontainnitrosamines,diethyleneglycol,and
othercontaminantspotentiallyharmfultohumans(4).Fromtheiranalysis,theFDAreasonsthatthesaleofe
cigarettesshouldbeprohibitedorregulatedasdangerousnicotinedeliverysystemsthatcomplywiththe
safetystandardsoftheFederalFoodDrugandCosmeticAct(FDCA)(5).Thispresentsanobviousdilemma
sincetraditionalcigarettes,whichincludenicotine,areproventobeharmfultohumanhealth,butareexempt
fromtheFDCAsafetystandards.AfterSmokingEverywhere,Inc.,filedaninjunctionagainsttheFDAfor
restrictingthesaleoftheirecigarettesintheUnitedStates(6),theUSCourtofAppeals(7)decidedthate
cigarettesmaynotbemarketedasasaferalternativetocigarettes,orasasmokingcessationdevice,but
insteadmustbesoldasasmokelesstobaccoproductsubjecttothesamerulesandregulationsofothertobacco
products.Whatmakesthisrulingsocontroversialisthatecigarettescontainnotobaccootherthanaminiscule
quantityfoundinthetobaccoflavoring.Despitethecourtsdecision,ecigarettevendorshaveembracedthis
ruling,andarehappytoselltheirdevicesasalternativestoconventionalcigarettes,solongastheFDAdoes
notinterferewiththesaleoftheirproducts.Nevertheless,thepotentialharmfuleffectsofvapinghaveledthe
FDAtoissueInternetwarningsregardingtherisksofvaping(8).WhiletheFDAhasseriousconcerns
regardingtheiruse,HealthNewZealandLtd.(HNZ),aprivateenterprisewhichanalyzedthesafetyofthe
RuyanecigarettewithRuyanfinancialsupport,recommendstheuseofecigarettesasanalternativeto
traditionalsmoking(9).HNZbasesitsrecommendationonthelikelihoodthatvapingispotentiallyless
dangerousthantraditionalsmokinginotherwords,theirmessageisharmreduction.CahnandSiegel(10)
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supportHNZsrecommendation,concludingthatelectroniccigarettesshowtremendouspromiseinthefight
againsttobaccorelatedmorbidityandmortality.Inadditiontoreducingtobaccorelatedmorbidityand
mortality,vapingmayalsoreduceharmincurredfromsecondhandsmokeandbenefittheenvironment(11).
Fouldsetal.(12,13)believethatmoreresearchneedstobeconductedtodeterminethesafetyandefficacyof
ecigarettesasasmokingcessationtool.However,theyalsostatethatindividualswhohavesuccessfullyquit
smokinginfavorofvapingshouldcontinuetouseecigarettesasahealthieralternativetoconventional
cigarettes.Althoughthereareclearperceptionsamongecigaretteusersthatecigarettescanbeusedasbotha
smokingcessationtool,andasaferalternativetosmoking,theycanbemarketedasneither.TheFDCA(5)
precludestheiruseasasmokingcessationtool,andtheFamilySmokingPreventionandTobaccoControl
Act(14)precludestheiruseasareducedriskalternativetherefore,ecigarettesmustbesoldasatobacco
product.Ecigarettescouldplayanimportantroleinthefutureofsmokingcessation,buttheiruseiscurrently
cloudedbyatangleoflegalandpoliticalissues.Itisevidentthatmoreresearchonthesafetyandefficacyof
ecigarettesneedstobeconducted,andthatmorestringentqualitycontrolmeasuresshouldbeimplementedin
orderforthelegalandpoliticalramificationssurroundingtheseproductscanbeuntangled.
Themedicalcommunitymustprepareitselftofacethenewchallengeconcerningecigarettesandvapingasa
harmreductiontool.AsaconsequenceofpastlessonslearnedfromBigTobaccocompanies,themedical
communityissuspiciousofecigarettesandhasroutinelyadvisedagainsttheiruse(15).Themedical
communityadvisesonthesideofcaution,indicatingthatverylittlescientificevidenceisavailabletoshow,
onewayortheother,thatecigarettesaresafetouse,orthattheyhelpinthesmokingcessationprocess.In
addition,manyphysiciansfearthatpatientswhovapearemerelysubstitutingoneformofnicotineaddiction
foranother.Whiletherearecertainlypotentialperilsassociatedwithvaping,smoking,theleadingcauseof
preventablediseaseintheUnitedStates,islikelytobemoredangerousthanvaping,especiallywhen
consideringthemyriadofknowntoxinsfoundincigarettesmokeandthediseaseswhichtheypromote.
Assumingthispremiseistrue,whatshouldtheprimarymedicalfocusbeforapatientwhohassuccessfully
transitionedfromconventionalcigarettestoecigarettes?Shoulditbetomaintainsmokingabstinence,or
shoulditbetoquitvaping?Woulditnotbeprudentforapatientwhoisunwillingtoquitsmokingorgiveup
nicotinetovapeinsteadofsmoke?Giventhesecircumstances,howshouldpatientsbeadvised?Thepotential
healthhazardsofnicotineaddictionfromsmokelesstobaccoproductshavepreviouslybeenreviewedina
policystatementbytheAmericanHeartAssociationandincludehemodynamiceffects,endothelial
dysfunction,thrombogenesis,systemicinflammation,andothermetaboliceffects(16).Understandably,the
medicalcommunity(15)isconcernedthatincreasedavailabilityofecigarettescouldincreaseworldwide
nicotinedependence,especiallyamongtheyoungastheyareenticedbythevariousflavoroptionse
cigaretteshavetooffer.Sincevapingdoesnotproducesmokefromburningtobacco,theopponentsofe
cigarettesfearthattraditionalsmokerswillsubstitutevapingforsmokinginsettingswheresmokingisnot
permittedwithoutanyrealintentionofquittingconventionalcigarettes.Furthermore,vapinginpublicplaces,
coupledwithrecentecigarettecommercialsonnationaltelevision,couldpossiblyundermineorweaken
currentantismokingregulations.Healthcareprofessionalswillneedtoconsiderandweighwhatismore
harmfultothepublic,continuedsmokingorincreasednicotineaddiction.Asecigarettesgaingreater
popularityamongsmokers,thesechallengeswillundoubtedlyoccurwithincreasingfrequency.
Inordertofacethisnewchallenge,healthcareprofessionalswillneedtobecomefamiliarwiththeavailable
scientificevidencebasedliteratureconcerningecigarettesandvaping.Currently,thisliteratureissparse,but
growingfast,andprimarilydealswith(1)consumerbasedsurveysregardingpersonalviewsonvaping,(2)
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chemicalanalysisofecigarettecartridges,solutions,andmist,(3)nicotinecontent,delivery,and
pharmacokinetics,and(4)clinicalandphysiologicalstudiesinvestigatingtheacuteeffectsofvaping.Only
afterreviewingthecurrentliteraturecanphysiciansandotherhealthcareprovidersgiveappropriatecounsel
regardingtheroleofecigarettesandvapingasasaferalternativetosmoking,andasasmokingcessationtool
(17).Consequently,theaimofthisarticleistoprovideareviewofthecurrentliteratureconcerninge
cigarettesandvapingsothatthemedicalcommunitycanbetterprepareforthenewchallengethesedevices
bringtoclinicalmedicineandpublichealth.Thesearchforrelevantscientificliteraturewasaccomplished
usingthepubmeddatabaseinwhichthekeywordselectroniccigarette(s)orecigarette(s)wereused.The
searchforarticlesextendedbackto2008andonlyhighlyrelevantevidencebasedprimaryliteraturewas
retrievedforreview.Sixtysixarticlesdealingwithsurveyssolicitingpersonalviewsonvapingstudies
analyzingpotentialtoxinsandcontaminantsinecigarettecartridges,solutions,andmistreportsprofiling
nicotinecontent,delivery,andpharmacokineticsandclinicalandphysiologicalstudiesinvestigatingthe
effectsofacutevapingwereultimatelyused.Ofthesearticles,twowerepublishedbetween2008and2009.
Six,ten,andfifteenarticleswerepublishedin2010,2011,and2012,respectively.Thusfar,33highly
relevantarticleshavebeenpublishedin2013,indicatingaprogressiveincreaseinecigaretterelatedresearch.
ConsumerBasedSurveys

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Surveyshaveshownthatawarenessofecigaretteshasquadrupledbetween2009and2011(18)andthatthey
haveahighadoptionrateamongtraditionalsmokers(19,20).Manycurrentandexsmokersuseecigarettes
asanicotinereplacementtherapy(NRT)tohelpthemreduceorquitsmoking(13,2125)whileothersusee
cigarettesasalessharmfulalternativetosmoking(21,23,26,27).Attheendof6months,Polosaetal.found
thatvapingecigarettesdecreasedconsumptionofconventionalcigarettesby80%after6months(28)and
50%after24months(29).Caponnettoetal.reportedsimilarreductionsincigaretteconsumptionandcigarette
abstinenceafterayearlongtrialofusingecigarettesinbothnormalsmokers(30)andinchronic
schizophrenicsmokers(31).Theauthorsclaimthatwithdrawalsymptomswereminimalandthatthe
perceptionandacceptanceofecigaretteswassatisfactory,evenintheschizophrenicpatients.Theresultsof
Vickermanetal.(32)arelessoptimistic.Theyreportedthatnearlyathirdof2758callerstosixstatetobacco
quitlineshadeverusedecigarettesofwhich61.7%usedtheecigarettesfor<1month.Barbeauetal.(26)
reportedthatusingecigarettes,incomparisontootherFDAapprovedNRTs,suchasnicotinegum,patches,
andinhalers,hadlessannoyingsideeffectsandweremoreeffectiveinpreventingrelapse,primarilybecause
vapingretainedthepsychosocialaspectsofrealsmokingbetterthantheFDAapprovedNRTs.Huaetal.
(33)foundatotalof405differenthealthrelatedeffects(78positive,326negative,and1neutral)reportedby
ecigaretteusersinthreedifferentonlineforums.Usersreportingnegativehealthrelatedeffectsoftenreported
multiplesymptoms,whileusersreportingpositivehealthrelatedeffectsusuallyreportedasinglesymptom.
Additionally,negativehealthrelatedeffectsoccurredmostfrequentlyintherespiratory,neurological,sensory,
anddigestivesystemswhilethepositivehealthrelatedeffectsoccurredsolelyintherespiratorysystem.
Itispossiblethatthedecreaseddailyconsumptionofconventionalcigarettesamongecigaretteusers,asseen
insomestudies(2831),isatleastpartiallyduetoapsychologicalelementinvolvingsmokersmotivationto
quit.SupportforthisideaisseeninarecentHawaiianmultiethnicstudy(34)involving1567traditional
smokersofwhich13%werealsoecigaretteusersattemptingtoquitsmoking.Thissurveyreportedthat
smokerswhousedecigarettesasasmokingcessationtoolweremoreseriousaboutwantingtoquitsmoking
ascomparedtosmokerswhodidnotuseecigarettes.Inaddition,ecigaretteswerealsoviewedasaviable
optiontootherFDAapprovedsmokingcessationtools.Sutfinetal.(35)surveyed4444studentsfromeight
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NorthCarolinacollegesandfoundthat216ofthesestudentshadexperimentedwithecigarettes(evere
cigaretteusers)while4228hadneverusedecigarettes(neverecigaretteusers).Oftheeverecigaretteusers,
12%wereneversmokers,30%wereformerorexperimentalsmokers,33%werecurrentnondailysmokers,
and9%werecurrentdailysmokerscomparedto53,19,14,and4%,fortheneverecigaretteusers,
respectively.Whentheeverecigaretteuserswereaskedaboutecigaretteharmperception,17%indicatede
cigarettesareasharmfulasconventionalcigarettes,45%respondedwithlessharmful,3%thoughtecigarettes
tobemoreharmful,and23%wereunsure.Theneverecigaretteusersrespondedwith16,22,2,and51%,
respectively.Thisdatasuggestthatvapingismorecommon,butnotexclusive,amongtraditionalsmokers.
Anotherstatisticrevealedthatvapingamongyoungcollegestudents(meanage20.72.9years)doesnot
appeartobemotivatedbyanyintentiontoquitsmoking.ThisissomewhatincontrasttoPokhreletal.(34)
whoindicatedmoreseriousintentionstowardsmokingcessationamonganolderpopulationofsmokersusing
ecigarettes(meanage42.31.02years)comparedtosmokersnotusingecigarettes(meanage45.630.35
years).Theyalsoreportedthatindividualswhotookupvapingasameanstoquitsmokingweresignificantly
youngerandhadsmokedforlessyearsthanthosewhonevervaped.
AconcernoftheFDA(8)andthemedicalcommunity(15)isthatavailabilityofecigaretteswillenticeteens
andyoungadultstowardvaping,whichcouldultimatelyleadtosmokingconventionalcigarettes.Currently,
thereislittleornoconcreteevidenceconfirmingthevalidityofthisconcern.Choetal.(36)useddata
collectedfromaKoreanHealthProjecttodetermineawarenessanduseofecigarettes.Theyfoundthat
10.2%of4353studentswereawareofecigarettes,butonly0.5%ofthosestudentshadactuallytriede
cigarettes.Pepperetal.(37)conductedanationalonlinesurveyof228maleadolescents(ages1119)and
determinedthat<1%oftheseindividualsactuallytriedecigarettes.Ontheotherhand,67%ofthe
respondentswereawareofecigaretteswithawarenessbeinghigheramongtheolderboys.Ofthose
individualswhonevertriedecigarettes,18%werewillingtoexperimentwithnopreferencetowardflavored
versusunflavoredecigarettes.Additionally,smokersweremoreamiabletoexperimentwithecigarettesthan
nonsmokers.Incontrast,discussionswith11focusgroupsinvolving66youngadults(ages1826)revealed
thatyoungadultsfavorablyperceiveecigarettesandothernewtobaccoproductsspecificallybecausethey
comeindifferentflavorsandthateliminatingtheseflavorsmayreduceintentionstotrytheseproducts(38).
Anotherstudysurveyed2624USMidwesternyoungadults(ages2028)andindicatedthat69.9%ofthe
respondentswereawareofecigarettes,butthatonly7%actuallytriedvaping(39).Goniewiczetal.(40)
conductedasurveyofstudentsenrolledat176nationallyrepresentativePolishhighschools(ages1519)and
universities(ages2024)andreportedthat23.5%ofhighschoolstudentsand19%ofuniversitystudentshad
evertriedecigarettes.Ofallthestudentswhotriedecigarettes,only3.2%werenonsmokers,which
comparescloselytothe4.9%reportedbySutfinetal.(35).Otherstrongcorrelatesofecigaretteuseamong
adolescentsincludemalegender,andhavingparentswhosmoke(36,40).Whileasmallpercentageofyoung
nonsmokersexperimentwithecigarettes,itismorelikelythatyoungsmokerswillexperimentwithe
cigarettes.Onefactemergesfromthesestudiesasecigarettepopularityincreases,sodoesawarenessofthem
amongyoungindividuals.Howincreasingawarenesswillultimatelyaffectecigaretteusagebyadolescent
andyoungadultsremainstobeseen.
Anumberofstudies(4143)indicatethatallformsofNRTareatleastinitiallysuccessfulinmaintaining
cigaretteabstinence.However,thesuccessfullongtermsmokingcessationratestillremainsrelativelylow.
Employingametaanalysisstudy,Hughesetal.(41)foundthe6monthsmokingquitratesforNRTstobe
between1and11%insevenstudiesascomparedtobetween3and5%insmokerswhotriedtoquitontheir
own(44).Rennardetal.(42)reportedaquitrateof8%amongsmokerswhousedthenicotineinhalerfor15
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months.Incontrast,fewstudieshavetestedecigarettesasasmokingcessationtool(28,29,45).Froman
onlinesurvey,Siegaletal.(45)reportedthat31%(69of216)oftherespondentswerenolongersmoking
cigarettesafter6monthsofusingecigarettes.Ofthoserespondentswhoquitsmoking,57%werestillusing
ecigarettes,9%wereusingothertobaccofreenicotineproducts,and34%werecompletelynicotinefree.
Polosaetal.(28)investigatedtheeffectofecigarettesonsmokingcessationanddiscoveredthat22.5%(9of
40)oftheparticipantshadnothadacigarettein6months.Ofthatcohort,67%werestillusingecigarettes
while33%werenicotinefree.Similarresultswerereportedina24monthstudybyPolosaetal.(29).These
studiesandothers(46,47)suggestthatecigarettescouldplayaroleinsmokingreductionandcessation,and
asaresultcouldreducetheharmincurredbysmokingaseffectivelyasanyFDAapprovedNRT.However,
theroleofecigarettesontotalnicotineabstinenceisstillhighlyquestionable,andithasbeensuggestedthat
oneformofnicotineaddictionissimplyreplacinganother(26).Asummaryofthestudiesinvolving
consumerbasedsurveysregardingpersonalviewsofvapingareshowninTable1.
Table1
Studiesinvolvingconsumerbased
surveysregardingpersonalviews
onvaping.
ChemicalAnalysisofECigaretteCartridges,Solutions,andMist

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Theingredientsfoundinecigarettecartridgesandsolutionsarerelativelyfew,andforthemostpartnontoxic
andnoncarcinogenic,especiallyinthelowquantitiesdelivered.Theyincludenicotine,propyleneglycol,
glycerin,andtobaccoflavoring(4,48).Propyleneglycol,anFDAapprovedsolventusedinfoods,avehicle
forintravenousdiazepam,andasthemajoringredientfoundinecigarettefluids,makesupabout90%ofthe
solution(9).Certaincontaminates,mostofwhicharederivedfromtobaccoflavoring,havebeendetectedin
ecigarettes.Asmallamountofdiethyleneglycol(approximately1%),aknowncarcinogenandaningredient
inantifreeze,wasalsodetectedinoneoutof18cartridgesanalyzedbytheFDA(4).Thesourceofthe
diethyleneglycolcontaminationisnotclearbutcouldreflecttheuseofnonpharmaceuticalgradepropylene
glycol(10).Incomparison,cigarettesmokefromburnedtobaccoproductscontainsthousandsofcompounds,
manyofwhichhavebeenshowntoinduceorpromotecarcinogenesis(49)specificallythetracemetals(i.e.,
cadmium,arsenic,chromium,nickel,andlead),thetobaccospecificNnitrosamines(TSNA),thepolycyclic
aromatichydrocarbons(PAHs),andthevolatileorganiccompounds(VOCs).Whileinvestigationshave
shownsomeofthesehazardouscompoundstobepresentinecigarettecartridges,solutions,andmist,there
areonlyafewreportsdetectinglevelsofthesecontaminateshighenoughtobeofsignificantrisktohumans.
TheHNZstudy(9)foundlevelsofarseniccadmium,chromium,nickel,andleadtobeundetectableine
cigarettecartridgeliquid.Incontrast,Williamsatal.(50)foundlevelsoflead,chromium,andnickeline
cigaretteaerosoltobeequivalentto,andinsomecaseshigherthan,whathasbeenreportedforcigarette
smoke.Theyindicatethattheprimarysourceofthesetracemetalsarethefilamentsinsidetheecigarette
cartomizer(i.e.,theaerosolizingcomponentoftheecigarette),andconcludethatimprovedqualitycontrolof
ecigarettedesignandmanufacturingwouldgreatlyreducethepresenceofthesetracemetals.TheFDA(4)
andHNZ(9)bothreportedthatecigarettescontaintraceamountsofTSNAs,butthelevelsfoundinthee
cigarettesrepresentonlyaverysmallfraction(0.008g/ecigarettecartridgecontaining16mgofnicotine)of
whatistypicallyfoundintraditionalcigarettes(6.3g/fullflavorMarlborocigarette)(51).Toputthisinto
perspective,anecigarettecartridgeisgoodforabout150300puffswhileasingleconventionalcigaretteis
goodforabout1015puffs(52).TheamountoftotalTSNAsfoundinotherFDAapprovednicotine
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productswasroughlyequivalenttothetotalamountofTSNAsfoundinecigarettes(9,10).Otherstudies
(11,5356)confirmthelowlevelsofTSNAspresentinecigarettesolutionsandvapor,aswellasthelowor
undetectablelevelsofparticulatematter,tracemetals,VOCs,andPAHs,especiallywhencomparedtothe
amountspresentincigarettesmoke.
Aspreviouslymentioned(2),theFDAissuedwarningstoseveralecigarettecompaniesforsellinge
cartridgesandrefillsolutionscontainingactivepharmaceuticalingredientssuchasrimonabant(Zimulti)for
thepurposeoflosingweightandreducingsmokingaddiction,andtadalafil(theactiveingredientinCialis)
forthepurposeofincreasingsexualcapacity.FDAanalysesoftheseecartridgesandsolutionsrevealedthe
presenceofaminotadalafilandnottadalafil,andthepresenceofanoxidativeproductofrimonabant,aswell
asrimonabant(57),althoughtheamountofeitherofthesesubstancesthatisabletotransferfromliquidto
vaporphaseislow(58).Table2summarizesthestudiesinvolvingchemicalanalysesofecigarettecartridges,
solutions,andmist.
Table2
Studiesinvolvingchemicalanalysis
ofecigarettecartridges,solutions,
andmist.
NicotineContent,Delivery,andPharmacokinetics

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Ecigarettesaredesignedtodelivernicotineinanaerosolizedmannerthatsimulatesanauthenticsmoking
experiencewithouttherealsmoke.Inthisrespect,ecigarettesaresimilartotheFDAapprovednicotine
inhaler.Bullenetal.(59)determinedtheRuyanecigarettehadanicotinepharmacokineticprofilevery
similartotheNicotrolinhaler,butthestudysparticipantsthoughttheecigarettesweremorepleasanttouse
andproducedlessirritationtothemouthandthroat.Forecigarettes,thenicotineisdeliveredthrough
cartridgesprefilledwithanicotinesolutionorcartridgesthattheuserfillswithanicotinerefillsolution.In
eithercase,thenicotineconcentrationofthesolutionsorcartridgescanbepurchasedinstrengthsranging
from0to24mgormore,accordingtouserpreference.Unfortunately,theamountsofnicotinespecifiedon
thelabelsofvariousbrandsofecartridgesandsolutionshavenotalwaysbeenaccurateorconsistent(60).
TheFDA(4,57,58)confirmedtheabilityofecigarettestodelivernicotine,butstatedthereistoomuch
variabilityintheamountofnicotinedeliveredperpuffofanyecigarettecartridgeforthemtobeconsidered
safe.RepeatedanalysisofamentholhighstrengthNjoyecigarettecartridge(18mgofnicotine)yielded
nicotinedeliveriesof26.8,34.9,and43.2g/100mlpuff.ThemediumstrengthSmokingEverywheree
cigarettecartridge(11mgofnicotine)andthemediumstrengthNjoyecigarettecartridge(12mgof
nicotine)delivered15.7and10.6gnicotine/100mlpuff,respectively,andwerefoundtobesimilartothe
10mgNicotrolinhalershowntodeliver15.2gnicotine/100mlpuff.Ofmajorconcernisthatsomee
cartridgesandsolutionsthatwerelabeledascontaining0mgofnicotinedidinfactcontainsomenicotine
(4,57).TheFDA(4,58)alsodetectedsmallquantitiesofcotinine,ametaboliteofnicotine,andseveral
nicotinerelatedimpuritiestoinclude,anabasine,anatabine,myosmine,andnicotyrineinsome,butnotall,
ecartridgesolutionsandmistsamplesanalyzed.FlourisandOikonomou(61)questiontherigorbywhichthe
FDAconductedtheseanalyses,indicatingthattheseanalysescannotbeusedtodrawconclusionsor
inferencesaboutpotentialeffectsonhealthuntilmorerigorouschemicalanalyses,followedbyextensive
animalandclinicaltrialsinhumans,areconducted.Twootherstudieshavealsofounddiscrepanciesinthe
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labelednicotinecontentcomparedtotheactualnicotinecontentinanumberofecigarettebrands(52,62).
Goniewiczetal.(52)reportedrelativepercentdifferencesbetweenthelabeledandactualnicotine
concentrationpercartridges(orrefillfluids)torangebetween89and28%in30popularbrandsofe
cigarettes.Cameronetal.(62)foundtheactualnicotineconcentrationinecigarettecartridgesandrefillfluids
torangefrom1.8to23.7mg/mllessthanthelabelednicotineconcentration.However,amorerecentstudy
analyzingseveralbrandsofecigaretterefillsolutionsdidfindnicotinecontenttobeaccurateandconsistentto
whatwasprintedonthelabel(63).Inconsistenciesreportedinnicotineconcentrations,andhencedeliveries,
couldbeareasonwhysomeecigaretteusersandnotothersreportadversereactionssuchasmouthandthroat
irritation,vertigo,headache,andnausea(21,26,33).Incidentally,someofthesesameadversereactionshave
alsobeenreportedforvariousFDAapprovedNRTs(64).Inastudyevaluatingdesignfeatures,accuracyand
clarityoflabeling,andqualityofprintedmaterialsandinstructionmanualsforecigarettesitwasconcluded
thatdesignflaws,inadequateproductlabeling,andlackofqualitycontrolinthemanufacturingofecigarettes
areanindicationthatstricteroversightandregulationarerequiredforthesedevices(65).Accurate
production,safepackaging,andproperstorageofecigaretterefillsolutionsarecritical.Typically,a5mlvial
ofecigaretterefillsolutioncouldcontainanicotineconcentrationof20mg/mlor100mg/vial,andtheknown
lethaldoseofnicotinehasbeenestimatedtobeabout10mginchildrenandbetween30and60mginadults
(62).Giventhepotentialhealthhazardsofnicotine(16),inadvertentskincontact,orconsumptionofjustone
ofthesevialsbychildrenorpetscouldhavetragicconsequences.Itisimportantthatextremecautionbeused
whenstoringnicotinesolutions.
Regardlessoftheinaccuraciesandinconsistenciesintheproductionofecigarettecartridgesandsolutions,
puffforpuff,theamountofnicotinefindingitswayintothebloodstreamfromvapinganecigarettehasbeen
showntobelessthanwhatyouwouldexpectfromsmokingaconventionalcigarettewithcomparable
nicotinecontent(59,66,67).Thesestudiesreportlittleornoincreasesinbloodnicotinelevelsofnaive
subjectsafteracutepredefineduseofecigarettescomparedtoconventionalcigarettes.AccordingtoBullenet
al.(59),serumlevelsofnicotineweresimilarafteruseofeithertheNicotrolinhaleroraRuyanecigarette.
Theyfoundserumnicotinelevelstopeakat1.3ng/mlafter19.6minofvapinganecigarette,and2.1ng/ml
after32minofusingtheNicotrolinhaler,comparedto13.4ng/mlafter14.3minofsmokingacigarette.The
Nicotrolinhalerissaidtobeinappropriatelynamedsinceitdoesnotdeliversignificantquantitiesofnicotine
directlytothelungs(68,69).Thisisbecausetheparticlesizeofthedeliverednicotineistoolargeto
effectivelyreachpulmonaryalveoli(70,71).Witheachpuff,theinhalerdeliversnicotinetotheoralcavity
whichissubsequentlyabsorbedbythebuccalmucosaandpharyngealmucosa.Itisnotclearwheremostof
thenicotinefromecigarettesisprimarilyabsorbedthealveoli,theairwaysortheoralcavity.In
vitroevidencesuggeststhatecigaretteaerosolparticlesizeanddistributionintherespiratorysystemissimilar
toconventionalcigarettesmoke(7274).Sahuetal.(72)foundtheparticlesizeofmainstreamcigarette
smoketorangebetween186and198nmanddeliveriestothepulmonaryalveoli,tracheal,andbronchiolar
airways,andoralcavitywerepredictedtobe29.8,15.2,and16.3%,respectively.Zhangetal.(73)
determinedaverageecigaretteaerosolparticlediameterstobeapproximately400nm,andalveolardeliveries
tobebetween7and18%.Zhangetal.(73)alsoindicatethatnicotinedeliveryishighlydependentona
numberoffactors,includingvapingtechnique,particleevolution,andcloudeffects.Itisverylikelythat
aerosolparticlesizeandnicotinedeliveryviaecigarettesmayhavesimilardistributionprofilesthatare
intermediatebetweenconventionalcigarettesandtheNicotrolinhaler.
Incontrasttotheaforementionedinvestigations(59,66,67),threeotherstudy(7577)foundincreasedblood
levelsofnicotineinexperiencedecigaretteuserswithin5minofthefirstpuffofanecigarette.Dawkinset
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al.(76)reportedbloodnicotinelevelstoincreasefrom0.74ng/mlbaselineto6.77ng/ml10minafter10puffs
ofanecigarette,achievingamean13.91ng/mlbytheendofa1hadlibitumvapingperiod.Ithasalsobeen
reportedthatcotinineinthesaliva(78)andserum(79)ofecigaretteusersissignificantlyelevatedtolevels
commonlyfoundincigarettesmokers.VansickelandEissenberg(75)alsoreportedanincreaseinheartrate,
whichisnotsurprisingsincesmokingandnicotinehavelongbeenknowntostimulateheartrateandblood
pressure(80,81).Itisinterestingtonotethatthe2010Vansickeletal.(67)study,andinCzogalaetal.(82),
heartrateandnicotinelevelsweresignificantlyincreasedinsmokers,butnotvapers.However,the2013
VansickelandEissenbergstudy(75)reportedthatbothsmokingandvapinginducedsimilarconcomitant
increasesinheartrateandbloodlevelsofnicotine.AssuggestedbyFarsalinosetal.(83),thisdiscrepancy
couldbeattributedtodifferencesinexperimentaldesign,andpuffingtopographyoftheparticipantsineach
study(i.e.,differentdailydurationsofvaping,experiencewithecigarettedevices,personalpuffing
characteristicstoincludetheamountofvacuumcreatedoneverypuff,andthevapinginduceddepositionof
nicotineintotheoralcavityand/orsizeoftheaerosolizedparticles).Trtchounianetal.(84),determinedthat
smoke/aerosoldensityremainedfairlyconstantwhilepuffingonaconventionalcigarettefromstarttofinish
(approximately10puffs),althoughvariationsdidexistbetweenbrandsofconventionalcigarettes.Theaerosol
densityforecigarettes,whilehigherthanconventionalcigarettesinthreeoutofthefourbrandstested,also
remainedfairlyconstantforthefirst10puffsofanewecigarettecartridge.However,adecrementaldecrease
inaerosoldensitywasobservedaseachcartridgeapproacheditsterminallife.Consequently,thisdecreasein
aerosoldensitywouldrequirethepersonvapingtogeneratemorevacuumtomaintainanaerosoldensity
equivalenttotheinitialpuffsandcouldbeareasoncontributingtolongerpuffdurationforelectronic
cigarettesthanforconventionalcigarettes(85).Similarvariationsintherateofairflowrequiredtoproduce
aerosolbetweenandwithinbrandsofecigaretteswerealsoreportedbyWilliamsandTalbot(86).According
toGoniewiczetal.(52),thesestudiesdemonstratetheimportanceoftheinitialnicotinecontent,theefficiency
ofthevaporizationprocessthatdetermineshowmuchofthenicotinegetsaerosolized,andtheindividuals
puffingtopographyontheefficacyofnicotinedeliveryfromecigarettes.
Manysmokersclaimthatsmokingcigarettesincreasescognitiveawareness,reducesstress,andinducesa
pleasurablefeelingofwellbeing.Consequently,thisiswhatmakessmokingcigarettessoenjoyableand
addictive.Itissuggestedthatsmokinghassomepsychologicalbeneficialeffectsrelatingtojobperformance,
vigilance,andmnemonictasks,andthattheseeffectsareinducedbynicotine,theaddictiveingredientin
tobacco(87).Similareffectshavealsobeennotedinnonsmokersafterasingledoseofnicotine(88),anditis
alsoworthmentioningthatnicotinemayhaveanamelioratingeffectonbothParkinsonsandAlzheimers
patients(89).Dawkinsetal.(90,91)foundadecreaseinthedesiretosmokeandreducedwithdrawal
symptomsassociatedwithtobaccoabstinence(110h)amongsmokersvapingecigaretteswithnicotinein
comparisontoecigaretteswithoutnicotine.Furthermore,thenicotinefromtheecigarettealsoimproved
prospectivememoryandworkingmemoryperformance.Nicotineisacentralnervoussystem(CNS)
stimulant,andassuchitispossiblethatapsychologicalneedtoenhancecognitivefunctioningreinforces
addictioninsmokers(92).Nicotineisalsoknowntostimulateadrenergicanddopaminergicneuronsin
mesolimbicareasofthebraininvolvedwithreinforcingpleasurablerewardbehavior(93).Monoamine
oxidases(MAO)normallyreducenicotineinducedadrenergicanddopaminergicactivitiesbyoxidizingthem
toinactivemetabolites,andtherebylimitingrewardbehavior.Forcigarettesmokers,however,nicotineis
madeevenmoreaddictivebysynergizingwithMAOinhibitorsknowntobepresentincigarettesmoke(94).
SupportingevidencehasbeenshownbyFowleretal.(95,96)inwhichtheactivitiesofbothMAOAand
MAOBwerereducedinvariousbrainregionsofsmokersbutnotofnonsmokers.Lewisetal.(94)indicate
thatthereareatleastsixdifferentMAOinhibitorspresentincigarettesmoke.Incontrast,Laugesenetal.(9)
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wereunabletodetectanyMAOinhibitorsinecigarettecartridgesortheinhaledaerosolmist.Thesestudies
suggestthatnicotinefromecigarettesandotherFDAapprovedNRTsmaybelessaddictivethannicotine
fromburnedtobaccoproducts,andmaybethereasonwhyecigaretteusersreportasuppressionofsmoking
andnicotinecravings(59,66,67,90,91).TheseinvestigationssupporttherationalebehindNRTtreatment
forsmokingcessation,whichisthatnicotinefromNRTs,andpossiblyecigarettes,doesnotoccupythe
nicotinicreceptorstothesameextentasnicotinefromtobaccosmoke(97).Theeffectisreducingwithdrawal
symptomsandcravingsforcigarettes(71,98)whilepossiblystillprovidingsomeenhancedcognitive
awarenessandpleasurablereward(92,93).Asummaryofthestudiesinvolvingnicotinecontent,delivery,
andpharmacokineticsarelistedinTable3.
Table3
Studiesinvolvingnicotinecontent,
delivery,andpharmacokinetics.
ClinicalandPhysiologicalEffectsofAcuteVaping

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Theharmfuleffectsofsmokingonhumanhealthareobviousandwelldocumented.Incontrast,effectsof
vapingonhumanhealthareinconclusiveduetotheextremepaucityofempiricalresearchinvestigatingthe
presenceofvapinginducedhealthhazardsand/orbenefits.Fewstudieshaveactuallyreporteddeleterious
effectsofvaping.Inonereport,McCauleyetal.(99)presentacasestudyconcerninga42yearoldwoman
diagnosedwithexogenouslipoidpneumoniaduetoecigaretteuse.Shepresentedwitha7monthhistoryof
dyspnea,productivecough,andfeverswhichcoincidedwithheruseofecigarettes.Samplesofhersputum,
andbronchoalveolarlavagerevealedlipidladenmacrophages.Glycerin,aningredientaddedtoecigarette
solutionsforthepurposeofproducingvisualsmokewhenvaping,wasthoughttobethecausativeagent.
Computedaxialtomography(CAT)imagesofherlungsrevealedareasofpatchygroundglasssuperimposed
oninterlobularseptalthickening,apatterntypicalofarestrictiveventilatorydefectwithdiffusionimpairment,
andconsistentwiththepatientsdiagnosis.Cessationofecigaretteuseresultedinimprovementofher
symptomsthatwasverifiedbyfollowuplungradiography,however,pulmonaryfunctiontestingstill
indicatedmilddiffusionimpairment.Sincethecasestudydoesnotrevealifthepatientisacurrentorex
smokerandforhowlong,itisunclearwhetherthepersistentdiffusionimpairmentisaresultofaconcurrent
orprevioussmokinghabit,theuseofecigarettes,ortheaftereffectsoflipoidpneumoniaperse.Inanother
report,Vardavasetal.(100)foundthat5minofacutevapingamonghealthysmokershadnoeffectonbasic
pulmonaryparameters[i.e.,forcedexpiratoryvolumein1s(FEV1),forcedvitalcapacity(FVC),peak
expiratoryflow(PEF),ormidexpiratoryflowsat50(MEF50)and75(MEF75)percent].Thisisinagreement
Flourisetal.(79)whoreportedtheFEV1/FVCratioafteracutevapingtobenonsignificantlyreducedby
3.0%(79).Thisstudy,alsoreportedtheFEV1/FVCratioafteracutetobaccosmokingtobesignificantly
reducedby7.2%.Vardavasetal.(100)didfinddecreasedamountsofexhalednitricoxideandincreased
peripheralairwayresistanceandimpedanceinsmokerswhovapedfor5min.Fromtheseresultsthey
concludedthatacutevapinghasimmediateadversephysiologicaleffectssimilartosomeoftheeffects
observedwithsmokingbutthatthelongtermhealtheffectsofvapingarenotknownandpotentially
harmful.Theauthorswentontoqualifytheirconclusionbystatingthatalthoughthedifferencesinexhaled
nitricoxide,airwayresistance,andimpedancewerestatisticallysignificant,thedifferencesareprobablynot
clinicallyimportant.Itispossiblethattheincreasedairwayresistanceandimpedancedemonstratedby
Vardavasetal.(100)ispartiallyduetothenicotineinhaledfromtheecigarettes.Evidenceforthisisseenina
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studyreportingthatnonsmokerswhoinhalednicotine(064mg/ml)showedadosedependentincreasein
boththeamountofcoughingandairwayobstruction,suggestingthatnicotinestimulatesafferentnerve
endingsinthebronchialmucosawhichthentriggersparasympatheticcholinergicpathwaysleadingto
bronchoconstriction(101).
Inrecentyearstherehasbeenanefforttoclinicallyuseexhalednitricoxideasanimportantnoninvasive
adjuncttopulmonaryfunctiontesting(102)inordertomonitorthedegreeofairwayinflammationand
eosinophilia(103,104)commonlyobservedinconditionssuchasasthma.Unfortunately,interpretationof
exhalednitricoxidelevelsintheclinicalsettingiscomplexandconfusingrequiringadjustmentsforgender,
age,height,respiratoryinfection,allergies,andsmoking(105,106).Giventhesedifficulties,itsvalidityis
controversial.Themajorconsensusintheliteratureisthattheamountofexhalednitricoxideisreducedin
longtimesmokers,ascomparedtononsmokers(105109).Inaddition,ithasbeenshownthatsmoking
cessationisassociatedwithanincreaseinexhalednitricoxidebacktowardnonsmokerlevels(110).A
possiblemechanismofactionfortheopposingrelationshipofexhalednitricoxideinsmokersversusnon
smokerscouldbethehighlevelsofcarbonmonoxidepresentincigarettesmokesincethereisstrongevidence
suggestingthatcarbonmonoxideinhibitsnitricoxideproductionbyblockingnitricoxidesynthaseactivity
(111,112).Thismechanismisunlikelytooccurwithlongtermvapingsincecarbonmonoxidelevelsine
cigarettemistarenegligible(9).Inanycase,thereisnoavailableliteratureshowingthelongtermeffectsof
vapingonexhalednitricoxideorcarbonmonoxide,althoughCaponnettoetal.(113)didshowexhaled
carbonmonoxidelevelstodecreasefrom31to4ppm,29to2ppm,and35to5ppminthreeindividualswho
firstsuccessfullytransitionedfromconventionalcigarettestoecigarettesandthenquitecigarettesaltogether.
Thefirsttimecarbonmonoxidewasmeasured,allindividualswereheavysmokers(45pack/year,28
pack/year,and89pack/yearhistories).Thefinaltimethatexhaledcarbonmonoxidewasmeasuredall
individualshadbeensmokeandvapefreefornearly2years.Usinganexperimentalgroupofhealthy
smokers,Vardavasetal.(100)reportedadecreasedfractionofexhalednitricoxide(FENO)afterjust5min
ofvaping(from13.02to10.89ppb)whichtheycorrelatedwithairwayinflammationandoxidativestress.In
theirintroductiontheystatethatsmokershavesignificantlylowerconcentrationsofFENOanoninvasive
markerofbronchialinflammationcomparedwithnonsmokers.Ontheotherhand,intheirdiscussionthey
statethatnitricoxideisanadditionalmarkerthathasbeenimplicatedinthepathophysiologyofairway
diseasesassociatedwithsmoking,isstronglycorrelatedwitheosinophilicinflammationandbronchial
hyperactivity,andhasbecomeanestablishedmarkerforassessingoxidativestress,indicatingtheimmediate
effectecigaretteusagemighthaveonpulmonaryhomeostasis.Fromthesetwostatementsandfromtheir
FENOresults,itisunclearwhethertheymeanthatsmokingandvapingproducelessbronchialinflammation
andoxidativestressormorebronchialinflammationandoxidativestresswhencomparedtonotsmokingor
notvaping.
Althoughbaselevelsofnitricoxidetendtobelowerinsmokerscomparedtononsmokers,Chambersetal.
(114)observedsignificantincreasesinexhalednitricoxidefrom2.6ppbbeforesmokingto4.8ppb1minand
3.2ppb10minaftersmokingacigarette.Budaetal.(115)reportedFENOtobe18,29,and16%higherthan
baseline30,45,and60minaftersmokingacigarette,respectively.ThefindingsofVardavasetal.(100)
concerningFENOlevelsafteracutevapingareindirectoppositiontowhathasbeenobservedimmediately
aftersmokingacigarette(114,115).Theseresultsclearlydemonstratethatacutevapingandacutesmoking
affectpulmonarynitricoxidemetabolism,andtheassociatedairwayinflammatoryresponses,differently.
Fromtheavailableliteratureitisnotclearhowvapingmightaffectpulmonaryinflammatoryprocesses,but,as
previouslyindicated,glycerinhasbeenlinkedtolipoidpneumonia(99),andnicotineisknowntogenerate
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endothelialdysfunctionandsystemicinflammation(16).Propyleneglycolmisthasbeenshowntoproduce
ocularandrespiratoryirritation(116),andincreasetheriskofacquiringasthma(117),althoughRobertsonet
al.(118)reportedthatlongterminhalationofpropyleneglycolvaporbybothmonkeysandratsproducedno
deleteriouspulmonaryeffectsandLaugesenetal.(9)foundnoilleffectsinhumans.Bahletal.(119)
investigatedtheeffectsofanumberofecigaretterefillfluidsonculturedhumanembryonicstemcells
(hESCs),andhumanpulmonaryfibroblasts(hPFs)andfoundthatnicotineinecigaretterefillfluidshadno
effectonhESCorhPFcytotoxicityatanyconcentration.However,theydidreportapositivecorrelation
betweenhESCcytotoxicity,andthenumberandconcentrationofotherchemicalsusedtoflavorecigarette
refillfluids.SimilarresultswerepublishedbyRomagnaetal.(120)whodemonstratedthatanextractofe
cigarettemistwaslesscytotoxictoculturedmurinefibroblaststhananextractoftobaccocigarettesmoke.A
furtherindicationthattherearedifferencesintheinflammatoryresponsesbetweenvapersandsmokersis
illustratedinastudyreportinganabsenceofincreasedinflammatoryindicesinsmokersaskedtovapefor30
mincomparedtosmokerswhowereaskedtosmokefor30min(121).Acutesmokinghaslongbeenknown
toincreasewhitebloodcellcount,whichisasignofacuteinflammatoryload(122).Flourisetal.(121)were
abletoconfirmelevationsofwhitebloodcellcount,lymphocytecount,andgranulocytecountinactive
smokersbutnotinactivevapers.Supportforthisisseeninarecentlypublishedcasereport(123)wherea36
yearoldmalewithaninepackyearhistoryofsmokingexhibitedreversalofchronicidiopathicneutrophilia
symptomsafterhequitsmokingandstartedvaping.Table4summarizesthestudiesinvolvingclinicaland
physiologicaleffectsofacutevaping.
Table4
Studiesinvolvingclinicaland
physiologicaleffectsofacute
vaping.
Conclusion

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Despitethepopularityecigaretteshavegainedworldwide,verylittlerigorousresearchhasbeendone
regardingtheeffectsthesedeviceshaveonhumanhealth.Thisarticlereviewstheexistingevidencebased
literature,dealingwithsurveyssolicitingpersonalviewsonvapingstudiesanalyzingpotentialtoxinsand
contaminantsinecigarettecartridges,solutions,andmistreportsprofilingnicotinecontent,delivery,and
pharmacokineticsandclinicalandphysiologicalstudiesinvestigatingtheeffectsofacutevaping.When
comparedtotheharmfuleffectsofsmoking,thesestudiessuggestthatvapingcouldbeusedasapossible
harmreductiontool.Thereisevidencesupportingecigarettesasanaideforsmokingcessation,atleastas
successfulascurrentlyavailableFDAapprovedNRTs.Lessevidenceexiststosuggestthatecigarettesare
effectiveinrecoveryfromnicotinedependence.Morerigorousresearchisessentialbeforeanysolid
conclusionscanbedrawnaboutthedangers,orusefulnessofecigarettes.Inparticular,morerigorous
researchisrequireddelvingintobothacuteandlongtermcardiopulmonaryeffectsofvaping,especiallythose
experimentscomparingtheeffectsofvapingwiththoseofsmoking.Ecigarettesarefastbecominganew
tobaccoindustry(124)thatcouldreducetheincidenceoftraditionalsmoking.Itisalsopossiblethate
cigarettesmayeitherdecreaseorincreasetheincidenceofnicotineaddiction.Giventheseuncertainties,will
theavailabilityofecigarettesprovideforhealthierU.S.andworldpopulations,asharmreductionistshope,or
willothermoredangerousilleffectsultimatelyemerge?Healthcareprofessionalsmustremaincurrentwith
theliteratureconcerningecigarettesandvaping.Onlythencantheymakeinformeddecisionsaimedat
maximizinghumansafetyandminimizingthepotentialilleffectsecigarettesmayhaveontheirpatientsand
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thepublic.Onlythencanthenewchallengeregardingecigarettesandvapinginclinicalmedicineandpublic
healthbeadequatelyaddressed.
ConflictofInterestStatement

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Theauthordeclaresthattheresearchwasconductedintheabsenceofanycommercialorfinancial
relationshipsthatcouldbeconstruedasapotentialconflictofinterest.
Acknowledgments

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TheauthorwouldliketothankthefacultyandstaffoftheDeBuskCollegeofOsteopathicMedicine,Lincoln
MemorialUniversityforgraciouslyprovidingconstructivecriticism,comments,andeditorialassistanceinthe
preparationofthismanuscript.
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