Snuff Tobacco ebooksclub.org Tobacco or Health Physiological and Social Damages Caused by Tobacco Smoking Second Edition

Box 3.2 ฀฀฀Volatile฀nitrosamines฀in฀tobacco:฀NDMA฀dimethylamine;฀NEMA฀ethylmethylamine;฀NDEA฀ diethylamine;฀NDPA฀dipropylamine;฀NDBA฀dibutylamine;฀NPYR฀pyrrolidine;฀NPIP฀piperidine;฀ NMOR฀morpholine 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-speciic฀nitrosamines฀TSNA.฀NNN฀nitrosonornicotine;฀NAT฀N-nitrosoanatabine;฀ NAB฀ N-nitrosoanabatine;฀ iso-NNAL฀ 4-N-nitrosomethylamino-4-3-pyridyl-1-butanol;฀ NNK฀฀ 4-฀N-nitrosomethylamino-4-3-pyridyl-butanone;฀NNAL฀4-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 causing฀an฀ischaemic฀reaction฀in฀the฀nose.฀This฀reaction฀may฀become฀less฀pronounced฀in฀ the฀sense฀of฀tachyphylaxis.฀Studies฀conducted฀in฀Indian฀snuff฀tobacco฀users฀indicate฀that฀ mucociliary฀clearance฀a฀cleansing฀function฀is฀depressed฀ [28] .฀Using฀a฀saccharin฀test,฀it฀ has฀been฀demonstrated฀that฀following฀intranasal฀application฀of฀a฀small฀saccharin฀crystal,฀ 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-acetic฀acid;฀NPIPAC฀N-nitroopiperidine-2-acetic฀acid;฀NazCA฀N-nitrosoa- zetadine-2-carboxylic฀ acid;฀ NPRO฀ N-nitrosoproline;฀ NPIC฀ N-nitrosopipecolic฀ acid;฀ NHPRO฀ N-nitrosohydroxypyroline;฀NTCA฀N-nitrosothiazolidine-4-carboxylic฀acid 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 English฀moist฀ snuff฀mga Swedish฀moist฀ snuff฀mga Indian฀zarda฀ mga Target฀organ฀cancero- genity,฀results฀from฀ experiments฀in฀the฀rat NDMA 0.07 ฀ 0.16 0.04 Liver,฀kidney฀lung NDELA 0.40 ฀ 0.16 0.04 Liver,฀nasal฀cavity NSAR 0.50 ฀ 0.10 0.20 Esophagus NMBA 3.5 ฀ 0.4 0.6 Urinary฀bladder NABNAT 45.4 ฀15.3 59.0 Esophagus NNN 37.2 ฀19.5 49.0 Esophagus,฀nasal฀cavity NNK 8.1 ฀ 4.6 14.7 Liver,฀lung,฀nasal฀cavity Table 3.8 ฀฀฀N-Nitroso฀compounds฀in฀oral฀tobaccos฀and฀their฀carcinogenic฀potency The฀Indian฀zarda฀is฀a฀partially฀fermented฀tobacco฀produced฀by฀boiling฀small฀pieces฀of฀tobacco฀ leaves฀in฀water฀with฀various฀spices฀and฀lime฀until฀evaporation.฀Exposures฀basel฀on฀the฀following฀ daily฀use:฀English฀moist฀snuff:฀4.5฀gday;฀Swedish฀moist฀snuff:฀14.3฀gday;฀Indian฀zarda฀tobacco:฀ 10฀gday฀ [100] mga:฀annual฀uptake;฀tested฀only฀by฀subcutaneous฀injection the฀time฀to฀reporting฀a฀sweet฀taste฀in฀the฀mouth฀may฀be฀3฀times฀as฀long฀in฀users฀of฀Indian฀ snuff฀tobacco฀compared฀with฀control฀subjects฀ [97] .฀Tissue฀damage฀was฀detected฀macro- scopically฀and฀histologically฀in฀the฀affected฀mucosal฀areas฀of฀the฀nose.฀The฀risk฀of฀cancer฀ development฀is฀increased฀many฀times฀if฀this฀type฀of฀tobacco฀“toombak”฀is฀placed฀in฀the฀ oral฀cavity฀relative฀risk฀increased฀7.3–73.0-fold.฀The฀snuff฀tobacco฀sold฀in฀Germany฀is฀ less฀dangerous฀than฀“toombak”. The฀nitroso฀compounds฀in฀Indian฀tobacco฀include: • ฀ N-nitroso-nicotine฀NNN;฀136฀mgg฀snuff฀tobacco • ฀ N-nitroso-ana-tabanine฀NAT;฀113฀mgg • ฀ 4-N-methyl-N-nitrosamino-1-3-pyridyl-1-butanone฀NNK;฀110–680฀mgg • ฀ N-nitroso-pyrrolidine฀NPYR • ฀ N-nitrosodimethylamine฀NDMA฀ [98] In฀ animal฀ studies,฀ the฀ puriied฀ components฀ display฀ carcinogenic฀ activity฀ [99,฀ 100] ฀ cf.฀ Table฀ 3.8 ,฀initially฀producing฀a฀reduction฀in฀nasal฀ciliary฀cells฀in฀the฀mucosa฀and฀irrevers- ible฀damage฀to฀the฀remaining฀cells.฀Moreover,฀changes฀metaplasias฀occur฀in฀the฀various฀ epithelial฀cells.฀Due฀to฀the฀dependence-inducing฀effect฀of฀nicotine,฀the฀consumed฀doses฀of฀ snuff฀tobacco฀are฀continuously฀increased,฀in฀turn฀damaging฀mucociliary฀clearance฀because฀ of฀the฀increased฀tobacco฀dose฀and฀the฀prolonged฀contact฀with฀the฀mucosa฀ [101] .฀These฀ reactions฀may฀develop฀into฀malignant฀changes.฀In฀rats,฀too,฀exposure฀to฀the฀tobacco-฀speciic฀ nitrosamines฀NNK฀and฀NDMA฀has฀led฀to฀DNA฀damage฀to฀cells฀of฀the฀nasal฀mucosa฀and฀ to฀lymphocyte฀changes,฀with฀the฀overall฀result฀that฀these฀animal฀studies฀indicate฀genotoxic฀ effects฀of฀tobacco฀constituents฀not฀only฀in฀the฀nose,฀but฀also฀in฀the฀liver฀ [102] . A฀recent฀meta-analysis฀addressed฀the฀relation฀between฀European฀and฀American฀smoke- less฀tobacco฀and฀oral฀cancer฀ [103] .฀Following฀a฀literature฀review,฀a฀meta-analysis฀was฀con- ducted฀of฀32฀epidemiological฀studies฀published฀between฀1920฀and฀2005,฀including฀tests฀for฀ homogeneity฀and฀publication฀bias฀by฀Weitkunat฀et฀al.฀Based฀on฀38฀heterogeneous฀study- speciic฀estimates฀of฀the฀odds฀ratio฀or฀relative฀risk฀for฀smokeless฀tobacco฀use,฀the฀random- effects฀estimate฀was฀1.87฀95฀conidence฀interval฀1.40–2.48.฀The฀authors฀showed฀that฀ the฀increase฀was฀mainly฀evident฀in฀studies฀conducted฀before฀1980.฀No฀increase฀was฀found฀ in฀studies฀in฀Scandinavia.฀Restricting฀attention฀to฀the฀seven฀estimates฀adjusted฀for฀smoking฀ and฀alcohol฀eliminated฀both฀heterogeneity฀and฀excess฀risk฀1.02;฀0.82–1.28.฀Estimates฀also฀ varied฀by฀sex฀higher฀in฀females฀and฀study฀design฀higher฀in฀case-control฀studies฀with฀ hospital฀controls,฀but฀more฀clearly฀in฀studies฀where฀estimates฀were฀unadjusted,฀even฀for฀ age.฀From฀the฀pattern฀of฀estimates,฀the฀authors฀suggested฀some฀publication฀bias.฀Based฀on฀ limited฀data฀speciic฀to฀non-smokers,฀the฀random-effects฀estimate฀was฀1.94฀0.88–4.28,฀ and฀based฀on฀few฀exposed฀cases,฀the฀eight฀individual฀estimates฀were฀heterogeneous.฀It฀was฀ concluded฀that฀smokeless฀tobacco,฀as฀used฀in฀America฀or฀Europe,฀carries฀at฀most฀a฀minor฀ increased฀risk฀of฀oral฀cancer.฀However,฀the฀authors฀stated฀that฀elevated฀risks฀in฀speciic฀ populations฀or฀from฀speciic฀products฀cannot฀deinitely฀be฀excluded฀ [103] . Overall,฀in฀Germany,฀there฀are฀too฀few฀consumers฀of฀snuff฀tobacco฀to฀demonstrate฀the฀ adverse฀effects฀of฀snuff฀tobacco฀on฀health฀in฀larger฀epidemiological฀studies.฀Harmful฀effects฀ on฀ the฀ nasal฀ mucosa฀ have฀ mainly฀ been฀ proven฀ for฀ foreign฀ varieties฀ of฀ snuff฀ tobacco;฀ it฀ remains฀open฀to฀conjecture฀to฀what฀extent฀the฀lungs฀are฀also฀affected฀by฀the฀inhalation฀of฀ snuff฀tobacco.฀Larger-scale฀epidemiological฀studies฀should฀help฀to฀clarify฀this฀question,฀but฀ “without฀ the฀ support฀ of฀ the฀ tobacco฀ industry.”฀ Analysis฀ of฀ saliva฀ obtained฀ from฀ tobacco฀ chewers฀shows฀that฀tobacco-speciic฀nitrosamines฀TSNA฀are฀rapidly฀extracted฀from฀oral฀ tobacco฀products,฀even฀when฀placed฀between฀the฀gum฀and฀cheek฀without฀chewing.฀In฀Inuit฀ Indians,฀large฀differences฀have฀been฀observed฀for฀the฀extraction฀of฀TSNA฀in฀snuff฀Table฀ 3.9 .฀ Following฀15฀min฀snuff฀dipping฀of฀0.5–1.5฀g฀tobacco,฀22-fold฀differences฀in฀the฀amount฀of฀ NNN฀and฀37-fold฀differences฀in฀the฀amounts฀of฀NABNAT฀in฀saliva฀were฀detected.฀Under฀ extreme฀conditions,฀the฀total฀exposure฀to฀TSNA฀approaches฀440฀mgday฀ [94] .฀Furthermore,฀ the฀carcinogenic฀risk฀due฀to฀oral฀intake฀of฀TSNA฀increases฀as฀a฀function฀of฀gastric฀pH฀ [100] .฀ Nitrosation฀of฀tobacco฀alkaloids฀produces฀a฀greater฀increase฀in฀the฀formation฀of฀carcinogen฀ NNN฀than฀of฀NAB฀and฀NAT฀under฀stimulated฀gastric฀conditions฀pH฀from฀2.0฀to฀3.5;฀ Fig.฀ 3.4 ฀ [108] .฀ In฀ addition,฀ slight฀ decomposition฀ of฀ 4-N-nitrosomethylamino-1-3- pyridyl-1-butanone฀due฀to฀transnitrosation฀has฀been฀reported฀ [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 ฀฀฀The฀effect฀of฀pH฀ on฀the฀nitrosation฀of฀tobacco฀ alkaloids฀under฀simulated฀ gastric฀conditions.฀ Nitrosation฀resulted฀in฀the฀ formation฀of฀NAB฀and฀NAT฀ striped฀columns฀and฀NNN฀ open฀columns฀ [104] Tobacco฀habit NATNAB a NNN NNK Snuff-dipping฀women฀ USA 187฀12.5–470 154฀26–420 32.6฀10–96 Students฀USA 204฀48–555 99฀37.4–222 3.4฀ND-60.6 Inuit฀snuff฀dippers฀ Canada 1318฀123–4560 980฀115–2601 56฀ND-201 Snuff฀dippers฀Sweden 18.5฀5–37 36.5฀6–65 2.6฀ND-9 Betel฀quid฀+฀tobacco฀ India 4.8฀1.0–10.9 7.5฀1.6–14.7 0.3฀ND-2.3 Tobacco฀chewers฀ India 29.8฀13.5–51.7 33.4฀16.5–59.7 ND Masheri,฀women฀India ND 28.3฀14.3–43.5 ND Tobacco฀+฀lime฀India 30.4฀ND-133 113฀10–430 3.8฀ND-28.5 Table 3.9 ฀฀฀Tobacco-speciic฀nitrosamine฀levels฀in฀the฀saliva฀of฀habitual฀tobacco฀chewers NATNAB฀ N-nitrosoanatabineN-nitrosoanabatine;฀ NNN;฀ N-nitrosonornicotine;฀ NNK฀ 4-N- nitrosomethylamino-1-3-pyridyl-1-butanone.฀Results฀from฀users฀of฀tobacco฀products฀even฀when฀ placed฀in฀the฀mouth฀between฀the฀gum฀and฀check฀without฀chewing฀ [100] .฀ND฀not฀detected a Refers฀primarily฀to฀NAT,฀NAB฀may฀be฀present฀in฀some฀cases A฀study฀published฀in฀2007฀by฀scientists฀of฀the฀Swedish฀Karolinska฀Institute฀addressed฀ the฀long-term฀use฀of฀Swedish฀moist฀snuff฀and฀the฀risk฀of฀myocardial฀infarction฀amongst฀ men฀ [105] .฀The฀scientists฀aimed฀at฀studying฀whether฀long-term฀use฀of฀snuff฀affects฀the฀risk฀ of฀myocardial฀infarction.฀A฀cohort฀was฀created฀with฀information฀on฀tobacco฀use฀and฀other฀ risk฀factors,฀collected฀through฀questionnaires฀from฀construction฀workers.฀Between฀1978฀ and฀1993,฀all฀construction฀workers฀in฀Sweden฀were฀offered฀repeated฀health฀check-ups฀by฀ the฀Swedish฀Construction฀Industry’s฀Organization฀for฀Working฀Environment฀Safety฀and฀ Health.฀In฀total,฀118,395฀non-smoking฀men฀without฀a฀history฀of฀myocardial฀infarction฀were฀ followed฀through฀2004฀by฀the฀researchers.฀Information฀on฀myocardial฀infarction฀morbidity฀ and฀mortality฀was฀obtained฀from฀national฀registers฀and฀relative฀risk฀estimates฀were฀derived฀ from฀ Cox฀ proportional฀ hazards฀ regression฀ model,฀ with฀ adjustment฀ for฀ age,฀ body฀ mass฀ index฀and฀region฀of฀residence.฀It฀was฀found฀that฀almost฀30฀of฀the฀men฀had฀used฀snuff.฀In฀ total,฀118,395฀non-smoking฀men฀without฀a฀history฀of฀myocardial฀infarction฀were฀followed฀ through฀ 2004.฀ The฀ multivariable-adjusted฀ relative฀ risks฀ for฀ ever-snuff฀ users฀ were฀ 0.91฀ 95฀conidence฀interval,฀0.81–1.02฀for฀non-fatal฀cases฀and฀1.28฀95฀conidence฀inter- val,฀1.06–1.55฀for฀fatal฀cases.฀Heavy฀users฀or฀=฀50฀g฀day1฀had฀a฀relative฀risk฀of฀fatal฀ myocardial฀infarction฀of฀1.96฀95฀conidence฀interval,฀1.08–3.58.฀Snuff฀use฀increased฀ the฀ probability฀ of฀ mortality฀ from฀ cardiovascular฀ disease฀ among฀ non-fatal฀ myocardial฀ infarction฀patients.฀The฀authors฀concluded฀that฀their฀results฀indicate฀that฀snuff฀use฀is฀asso- ciated฀with฀an฀increased฀risk฀of฀fatal฀myocardial฀infarction฀ [105] .

3.7 Concluding Remarks

• ฀ Between฀1950฀and฀1975,฀important฀changes฀to฀the฀cigarette฀were฀already฀being฀made฀ and฀attempts฀were฀also฀made฀e.g.฀by฀the฀installation฀of฀cigarette฀ilters฀to฀reduce฀the฀ toxic฀and฀carcinogenic฀potential฀of฀the฀cigarette฀that฀had฀been฀demonstrated฀in฀experi- mental฀animal฀work. • ฀ Changes฀in฀the฀cultivation฀and฀production฀of฀cigarette฀tobacco฀led฀to฀an฀increase฀in฀ tobacco-speciic฀ nitrosamines฀ in฀ tobacco฀ smoke,฀ which฀ are฀ also฀ responsible฀ for฀ the฀ increased฀incidence฀of฀adenocarcinomas. • ฀ Efforts฀to฀lower฀the฀nicotine฀content฀of฀cigarettes฀to฀about฀one-third฀were฀ostensibly฀ successful฀ on฀ the฀ basis฀ of฀ measurements฀ of฀ tobacco฀ smoke฀ in฀ FTC฀ machines.฀ As฀ a฀ result฀of฀changes฀in฀smoking฀behaviour฀depth฀and฀frequency฀of฀inhalation,฀2–3-fold฀ yields฀of฀tar,฀nicotine฀and฀CO฀were฀achieved. • ฀ Smokers฀of฀various฀ilter฀and฀light฀cigarettes฀intensify฀their฀smoking฀behaviour฀in฀order฀ to฀obtain฀the฀amounts฀of฀nicotine฀they฀require฀from฀cigarette฀smoke.฀Likewise,฀compared฀ with฀regular฀cigarettes,฀light฀and฀ultralight฀cigarettes฀do฀not฀assist฀smoking฀cessation. • ฀ The฀ use฀ of฀ smokeless฀ tobacco฀ snuff฀ dipping,฀ chewing฀ tobacco฀ facilitates฀ the฀ oral฀ uptake฀of฀TSNA,฀which฀are฀transformed฀in฀the฀stomach฀to฀potent฀carcinogens฀by฀an฀ acidic฀pH.฀The฀same฀scenario฀is฀likely฀when฀smokers฀consume฀cigars฀and฀cigarillos฀ preferentially฀containing฀dark฀tobacco฀types. References ฀ 1.฀Barnes฀DE,฀Hanauer฀P,฀Slade฀J,฀Bero฀LA,฀Glantz฀SA฀1995฀Environmental฀tobacco฀smoke.฀ The฀Brown฀and฀Williamson฀document.฀J฀Am฀Med฀assoc฀274:248–253 ฀ 2.฀Slade฀J,฀Bero฀LA,฀Hanauer฀P,฀Barnes฀DE,฀Glantz฀SA฀1995฀Nicotine฀and฀addiction.฀The฀Brown฀ and฀Williamson฀documents.฀J฀Am฀Med฀assoc฀274:225–233 ฀ 3.฀Todd฀JS,฀Rennie฀D,฀McAfee฀RE,฀Bristow฀LR,฀Painter฀JT,฀Reardon฀TR,฀Johnson฀DH฀Jr,฀Corlin฀ RF,฀Coble฀YD฀Jr,฀Dickey฀NW,฀et฀al฀1995฀The฀Brown฀and฀Willamson฀documents:฀Where฀we฀ go฀from฀here?฀J฀Am฀Med฀assoc฀274:256–258 ฀ 4.฀Bero฀L,฀Barnes฀DE,฀Hanauer฀P,฀Slade฀J,฀Glantz฀SA฀1995฀Lawyer฀control฀of฀the฀tobacco฀indus- try’s฀external฀research฀program.฀The฀Brown฀and฀Williamson฀documents.฀JAMA฀274:241–247 ฀ 5.฀Hanauer฀P,฀Slade฀J,฀Barnes฀DE,฀Bero฀L,฀Glantz฀SA฀1995฀Lawyer฀control฀of฀internal฀scientiic฀ research฀to฀protect฀against฀products฀liability฀lawsuits.฀The฀Brown฀and฀Williamson฀documents.฀ JAMA฀274:234–240 ฀ 6.฀Glantz฀SA,฀Barnes฀DE,฀Bero฀L,฀Hanauer฀P,฀Slade฀J฀1995฀Looking฀through฀a฀keyhole฀at฀the฀ tobacco฀industry.฀The฀Brown฀and฀Williamson฀documents.฀JAMA฀274:219–224 ฀ 7.฀Dukes฀CA฀1975฀Marketing฀plans฀presentation฀to฀RJRI฀board฀of฀directors.฀Trial฀exhibit฀12493.฀ 30-9-1974.฀RJR ฀ 8.฀Hind฀JF฀1975,฀Jan฀23฀Memo฀to฀CA฀Tucker.฀Trial฀exhibit฀12865 ฀ 9.฀Johnson฀RL฀1973,฀Feb฀21฀Memo฀to฀RA฀Pittman,฀B฀฀W.฀Trial฀exhibit฀13820 10.฀Long฀GH฀1980,฀Jun฀22฀MDD฀report฀on฀teenage฀smokers฀14–17.฀Memo฀to฀EA฀Horrigan฀Jr.฀ Trial฀exhibit฀13101 11.฀Colby฀FG฀1973,฀Dec฀04฀Cigarette฀concept฀to฀assure฀RJR฀a฀larger฀segment฀of฀the฀youth฀฀market.฀ Memo฀to฀R฀A฀Blevins฀Jr.฀Trial฀exhibit฀12464 12.฀Dann฀ WL฀ 1980,฀ Mar฀ 21฀ The฀ nicotine฀ receptor฀ program.฀ Memo฀ to฀ RB฀ Seligman,฀ Philip฀ Morris.฀Trial฀exhibit฀26227 13.฀Senkus฀M฀1969฀Invalidation฀of฀some฀reprints฀in฀the฀research฀department.฀Memo฀to฀Max฀ Crohn฀Legal฀department.฀Trial฀exhibit฀26216.฀RJR 14.฀Stanford฀LE฀1993,฀Dec฀02฀Memo฀to฀Phillip฀Morris,฀Document฀collection฀ile฀regarding฀Phillip฀ Morris฀ USA฀ product฀ research฀ performed฀ at฀ INBOFO฀ laboratory฀ in฀ COLOGNE;฀ Germany.฀ Carbon฀ copied฀ to฀ Alfred฀ T.฀ McDonell฀ AP฀ among฀ others.฀ Trial฀ exhibit฀ 26277.฀ Philip฀ Morris 15.฀Doll฀R,฀Hill฀AB฀1950฀Smoking฀and฀carcinoma฀of฀the฀lung,฀a฀preliminary฀report.฀Br฀Med฀J฀2:฀ 739–748 16.฀Wynder฀EL,฀Graham฀EA฀1950฀Landmark฀article,฀May,฀27:฀tobacco฀smoking฀as฀a฀possible฀ etiologic฀factor฀in฀bronchiogenic฀carcinoma.฀A฀study฀of฀six฀hundred฀and฀eighty-four฀proved฀ cases.฀By฀Ernest฀L.฀Wynder฀and฀Evarts฀A.฀Graham.฀J฀Am฀Med฀Assoc฀113:329–336 17.฀Hanners฀D฀1998,฀Feb฀15฀Tobacco’s฀promise฀exemplifed฀early฀PR:฀PR฀irm฀hired฀to฀go฀on฀ offensive฀when฀health฀concerns฀surfaced.฀[1A,฀12A].฀St฀Paul฀Pionieer 18.฀Wynder฀EL,฀Graham฀EA,฀Croninger฀AB฀1953฀Experimental฀production฀carcinoma฀with฀ciga- rette฀tar.฀Cancer฀Res฀13:856–864 19.฀Tobacco฀Industrie฀Research฀Committee฀1954,฀Jan฀04฀A฀frank฀statement฀to฀cigarette฀smokers.฀ Trial฀exhibit฀14115 20.฀Tobacco฀Industrie฀Research฀Committee฀meeting฀1954,฀Jan฀18฀Trial฀exhibit฀14127 21.฀Green฀DR,฀Rodgman฀A฀1996฀The฀Tobacco฀Chemists’฀Research฀Conference.฀A฀half-century฀ of฀advances฀in฀analytical฀methodology฀of฀tobacco฀and฀its฀products.฀Recent฀Adv฀Tob฀Sci฀22:฀ 131–304 22.฀Doull฀J,฀Frawley฀JP,฀George฀W฀1994฀List฀of฀ingredients฀added฀to฀tobacco฀in฀the฀manufacture฀ of฀cigarettes฀by฀six฀major฀American฀cigarette฀companies.฀Tob฀J฀Int฀196:32–39