Snuff Tobacco ebooksclub.org Tobacco or Health Physiological and Social Damages Caused by Tobacco Smoking Second Edition
Box 3.2
Volatilenitrosaminesintobacco:NDMAdimethylamine;NEMAethylmethylamine;NDEA diethylamine;NDPAdipropylamine;NDBAdibutylamine;NPYRpyrrolidine;NPIPpiperidine;
NMORmorpholine Me
Me N
NO Me
Et N
NO Et
Et N
NO Bu
Bu N
N N
N O
NO
NO NO
NO Pr
Pr N
NO NDPA
NPYR NPIP
NMOR NDBA
NDEA NEMA
NDMA Box 3.1
Tobacco-speciicnitrosaminesTSNA.NNNnitrosonornicotine;NATN-nitrosoanatabine; NAB N-nitrosoanabatine; iso-NNAL 4-N-nitrosomethylamino-4-3-pyridyl-1-butanol; NNK
4-N-nitrosomethylamino-4-3-pyridyl-butanone;NNAL4-N-nitrosomethylamino-1-3-pyridyl- 1-butanol
N CH
3
CH
3
CH
3
CH
3
N N
NO NO
NO NO
NO NO
NNN NAT
NAB Anabasine
Anatabine Nornicotine
Nicotine
iso-NNAL NNK
NNAL
N N
N H
N N
OH OH
O N
N N
N N
N
causinganischaemicreactioninthenose.Thisreactionmaybecomelesspronouncedin thesenseoftachyphylaxis.StudiesconductedinIndiansnufftobaccousersindicatethat
mucociliaryclearanceacleansingfunctionisdepressed [28]
.Usingasaccharintest,it hasbeendemonstratedthatfollowingintranasalapplicationofasmallsaccharincrystal,
Box 3.3
Non-volatile nitrosamines in tobacco: NSAR N-nitrosarcosine; NMPA 3-N-nitroso- N-methylamino-propionic acid; NMBA 3-N-nitroso-N-methylamino-butyric acid; NPYRAC
N-nitroso-pyrrolidine-2-aceticacid;NPIPACN-nitroopiperidine-2-aceticacid;NazCAN-nitrosoa- zetadine-2-carboxylic acid; NPRO N-nitrosoproline; NPIC N-nitrosopipecolic acid; NHPRO
N-nitrosohydroxypyroline;NTCAN-nitrosothiazolidine-4-carboxylicacid
N
N N
N N
N
N N
S HO
NO
NO NO
NO NO
NO
NO NO
NSAR
NPYRAC
NAzCA NPRO
NTCA NHPRO
NPIC NPIPAC
Me CH
2
CO
2
H
CH
2
CO
2
H CH
2
CO
2
H
CO
2
H CO
2
H CO
2
H
CO
2
H CO
2
H N
NO
NMPA
Me CH
2 2
CO
2
H N
NO
NMBA
Me CH
2 3
CO
2
H
Nitros-amine Englishmoist
snuffmga Swedishmoist
snuffmga Indianzarda
mga Targetorgancancero-
genity,resultsfrom experimentsintherat
NDMA 0.07
0.16 0.04
Liver,kidneylung NDELA
0.40 0.16
0.04 Liver,nasalcavity
NSAR 0.50
0.10 0.20
Esophagus NMBA
3.5 0.4
0.6 Urinarybladder
NABNAT 45.4
15.3 59.0
Esophagus NNN
37.2 19.5
49.0 Esophagus,nasalcavity
NNK 8.1
4.6 14.7
Liver,lung,nasalcavity
Table 3.8
N-Nitrosocompoundsinoraltobaccosandtheircarcinogenicpotency
TheIndianzardaisapartiallyfermentedtobaccoproducedbyboilingsmallpiecesoftobacco leavesinwaterwithvariousspicesandlimeuntilevaporation.Exposuresbaselonthefollowing
dailyuse:Englishmoistsnuff:4.5gday;Swedishmoistsnuff:14.3gday;Indianzardatobacco: 10gday
[100] mga:annualuptake;testedonlybysubcutaneousinjection
thetimetoreportingasweettasteinthemouthmaybe3timesaslonginusersofIndian snufftobaccocomparedwithcontrolsubjects
[97] .Tissuedamagewasdetectedmacro-
scopicallyandhistologicallyintheaffectedmucosalareasofthenose.Theriskofcancer developmentisincreasedmanytimesifthistypeoftobacco“toombak”isplacedinthe
oralcavityrelativeriskincreased7.3–73.0-fold.ThesnufftobaccosoldinGermanyis lessdangerousthan“toombak”.
ThenitrosocompoundsinIndiantobaccoinclude:
•
N-nitroso-nicotineNNN;136mggsnufftobacco
•
N-nitroso-ana-tabanineNAT;113mgg
•
4-N-methyl-N-nitrosamino-1-3-pyridyl-1-butanoneNNK;110–680mgg
•
N-nitroso-pyrrolidineNPYR
•
N-nitrosodimethylamineNDMA [98]
In animal studies, the puriied components display carcinogenic activity [99, 100]
cf. Table
3.8 ,initiallyproducingareductioninnasalciliarycellsinthemucosaandirrevers-
ibledamagetotheremainingcells.Moreover,changesmetaplasiasoccurinthevarious epithelialcells.Duetothedependence-inducingeffectofnicotine,theconsumeddosesof
snufftobaccoarecontinuouslyincreased,inturndamagingmucociliaryclearancebecause oftheincreasedtobaccodoseandtheprolongedcontactwiththemucosa
[101] .These
reactionsmaydevelopintomalignantchanges.Inrats,too,exposuretothetobacco-speciic nitrosaminesNNKandNDMAhasledtoDNAdamagetocellsofthenasalmucosaand
tolymphocytechanges,withtheoverallresultthattheseanimalstudiesindicategenotoxic effectsoftobaccoconstituentsnotonlyinthenose,butalsointheliver
[102] .
Arecentmeta-analysisaddressedtherelationbetweenEuropeanandAmericansmoke- lesstobaccoandoralcancer
[103] .Followingaliteraturereview,ameta-analysiswascon-
ductedof32epidemiologicalstudiespublishedbetween1920and2005,includingtestsfor homogeneityandpublicationbiasbyWeitkunatetal.Basedon38heterogeneousstudy-
speciicestimatesoftheoddsratioorrelativeriskforsmokelesstobaccouse,therandom- effectsestimatewas1.8795conidenceinterval1.40–2.48.Theauthorsshowedthat
theincreasewasmainlyevidentinstudiesconductedbefore1980.Noincreasewasfound instudiesinScandinavia.Restrictingattentiontothesevenestimatesadjustedforsmoking
andalcoholeliminatedbothheterogeneityandexcessrisk1.02;0.82–1.28.Estimatesalso variedbysexhigherinfemalesandstudydesignhigherincase-controlstudieswith
hospitalcontrols,butmoreclearlyinstudieswhereestimateswereunadjusted,evenfor age.Fromthepatternofestimates,theauthorssuggestedsomepublicationbias.Basedon
limiteddataspeciictonon-smokers,therandom-effectsestimatewas1.940.88–4.28, andbasedonfewexposedcases,theeightindividualestimateswereheterogeneous.Itwas
concludedthatsmokelesstobacco,asusedinAmericaorEurope,carriesatmostaminor increasedriskoforalcancer.However,theauthorsstatedthatelevatedrisksinspeciic
populationsorfromspeciicproductscannotdeinitelybeexcluded [103]
. Overall,inGermany,therearetoofewconsumersofsnufftobaccotodemonstratethe
adverseeffectsofsnufftobaccoonhealthinlargerepidemiologicalstudies.Harmfuleffects on the nasal mucosa have mainly been proven for foreign varieties of snuff tobacco; it
remainsopentoconjecturetowhatextentthelungsarealsoaffectedbytheinhalationof
snufftobacco.Larger-scaleepidemiologicalstudiesshouldhelptoclarifythisquestion,but “without the support of the tobacco industry.” Analysis of saliva obtained from tobacco
chewersshowsthattobacco-speciicnitrosaminesTSNAarerapidlyextractedfromoral tobaccoproducts,evenwhenplacedbetweenthegumandcheekwithoutchewing.InInuit
Indians,largedifferenceshavebeenobservedfortheextractionofTSNAinsnuffTable 3.9
. Following15minsnuffdippingof0.5–1.5gtobacco,22-folddifferencesintheamountof
NNNand37-folddifferencesintheamountsofNABNATinsalivaweredetected.Under extremeconditions,thetotalexposuretoTSNAapproaches440mgday
[94] .Furthermore,
thecarcinogenicriskduetooralintakeofTSNAincreasesasafunctionofgastricpH [100]
. Nitrosationoftobaccoalkaloidsproducesagreaterincreaseintheformationofcarcinogen
NNNthanofNABandNATunderstimulatedgastricconditionspHfrom2.0to3.5; Fig.
3.4
[108] . In addition, slight decomposition of 4-N-nitrosomethylamino-1-3-
pyridyl-1-butanoneduetotransnitrosationhasbeenreported [104]
.
0.5 1.0
1.5 2.0
pH
2.5 3.0
3.5 4.0
4.5 5.0
5 10
15
Amount of tobacco-specific nitrosamine [µgg tobacco]
20
Fig. 3.4
TheeffectofpH onthenitrosationoftobacco
alkaloidsundersimulated gastricconditions.
Nitrosationresultedinthe formationofNABandNAT
stripedcolumnsandNNN opencolumns
[104] Tobaccohabit
NATNAB
a
NNN NNK
Snuff-dippingwomen USA
18712.5–470 15426–420
32.610–96 StudentsUSA
20448–555 9937.4–222
3.4ND-60.6 Inuitsnuffdippers
Canada 1318123–4560
980115–2601 56ND-201
SnuffdippersSweden 18.55–37 36.56–65
2.6ND-9 Betelquid+tobacco
India 4.81.0–10.9
7.51.6–14.7 0.3ND-2.3
Tobaccochewers India
29.813.5–51.7 33.416.5–59.7
ND Masheri,womenIndia ND
28.314.3–43.5 ND
Tobacco+limeIndia 30.4ND-133
11310–430 3.8ND-28.5
Table 3.9
Tobacco-speciicnitrosaminelevelsinthesalivaofhabitualtobaccochewers
NATNAB N-nitrosoanatabineN-nitrosoanabatine; NNN; N-nitrosonornicotine; NNK 4-N- nitrosomethylamino-1-3-pyridyl-1-butanone.Resultsfromusersoftobaccoproductsevenwhen
placedinthemouthbetweenthegumandcheckwithoutchewing [100]
.NDnotdetected
a
RefersprimarilytoNAT,NABmaybepresentinsomecases
Astudypublishedin2007byscientistsoftheSwedishKarolinskaInstituteaddressed thelong-termuseofSwedishmoistsnuffandtheriskofmyocardialinfarctionamongst
men [105]
.Thescientistsaimedatstudyingwhetherlong-termuseofsnuffaffectstherisk ofmyocardialinfarction.Acohortwascreatedwithinformationontobaccouseandother
riskfactors,collectedthroughquestionnairesfromconstructionworkers.Between1978 and1993,allconstructionworkersinSwedenwereofferedrepeatedhealthcheck-upsby
theSwedishConstructionIndustry’sOrganizationforWorkingEnvironmentSafetyand Health.Intotal,118,395non-smokingmenwithoutahistoryofmyocardialinfarctionwere
followedthrough2004bytheresearchers.Informationonmyocardialinfarctionmorbidity andmortalitywasobtainedfromnationalregistersandrelativeriskestimateswerederived
from Cox proportional hazards regression model, with adjustment for age, body mass indexandregionofresidence.Itwasfoundthatalmost30ofthemenhadusedsnuff.In
total,118,395non-smokingmenwithoutahistoryofmyocardialinfarctionwerefollowed through 2004. The multivariable-adjusted relative risks for ever-snuff users were 0.91
95conidenceinterval,0.81–1.02fornon-fatalcasesand1.2895conidenceinter- val,1.06–1.55forfatalcases.Heavyusersor=50gday1hadarelativeriskoffatal
myocardialinfarctionof1.9695conidenceinterval,1.08–3.58.Snuffuseincreased the probability of mortality from cardiovascular disease among non-fatal myocardial
infarctionpatients.Theauthorsconcludedthattheirresultsindicatethatsnuffuseisasso- ciatedwithanincreasedriskoffatalmyocardialinfarction
[105] .