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

Table 3.2 ฀฀฀Selected฀carcinogens฀in฀tobacco฀smoke฀of฀non-ilter฀cigarettes฀NFC Agent Concentration NFC IARC฀evaluation,฀evidence฀of฀carcinogenity฀in Lab฀animals Humans Group PAH Benzaanthracene 20–70฀ng S 2° Benzoapyrene 20–40฀ng S P 2A Indeno1,2,3-cdpyrene 4–20฀ng S 2B Heterocyclic฀compounds Dibenza,jacridine 3–10฀ng S 2B Furan 18–37฀ng S 2B N-Nitrosoamines N-Nitrosodimethylamine 2–180฀ng S 2A N-Nitrosodiethylamine ND-2.8฀ng S 2A N-Nitrosopyrrolidine 3–110฀ng S 2B 4-Methylnitrosoamino-฀ 1-pyridyl-1-butanone 80–770฀ng S 2B Aromatic฀amines 2-naphthylamine 1–334฀ng S S 1 4-Aminobiphenyl 2–5.6฀ng S S 1 N-heterocyclic฀amines AaC 25–260฀ng S 2B PhlP 11–23฀ng S P 2A Aldehyde Formaldehyde 70–100฀mg S L 2A Acetaldehyde 500–1,400฀mg S I 2B Volatile฀hydrocarbons 1,3-Butadiene 20–75฀mg S I 2B Benzene 20–70฀mg S S 1 Miscellaneous฀organic฀compounds Acrylonitrile 3–15฀mg S L 2A Vinyl฀chloride 11–15฀ng S S 1 DDT 800–1,200฀mg S P 2B DDE 200–370฀mg S 2B Catechol 100–360฀mg S 2B Ethylene฀oxide 7฀mg S S 1 Propylene฀oxide 12–100฀mg S 2B Inorganic฀compounds Hydrazine 24–43฀ng S I 2B Arsenic 40–120฀mg I S 1 Nickel ND-600฀ng S S 1 Chromium฀only฀ hexavalent 4–70฀ng S S 1 Cadmium 7–350฀ng S S 1 Cobalt 0.13–0.2฀ng S I 2B Lead 34–85฀ng S I 2B Polonium-210 0.03–1.0฀pCi S S 1 S฀suficient;฀I฀inadequate;฀P฀probable,฀possible;฀L฀limited;฀ND฀not฀detected;฀PAH฀polynuclear฀aromatic฀ hydrocarbons;฀ AaC฀ 2-Amino-9H-pyrido[2,฀฀3-b]indole;฀ PhlP฀ 2-Amino-1-methyl-6-phenylimidazo฀ [4,฀5-b]pyridine;฀IARC฀Monographs฀on฀the฀Evaluation฀of฀Carcinogenic฀Risks:฀1:฀Human฀carcinogen;฀ 2A:฀probably฀carcinogenic฀in฀humans;฀2B:฀possibly฀carcinogenic฀to฀humans฀ [23] be฀regarded฀as฀more฀toxic฀than฀mainstream฀smoke฀because฀the฀amounts฀of฀various฀sub- stances฀in฀side-stream฀smoke฀benzo[a]pyrene,฀CO,฀benzene,฀formaldehyde,฀hydrazine,฀ cadmium฀etc.฀are฀higher฀by฀several฀multiples.฀In฀contrast,฀however,฀mainstream฀smoke฀ contains฀approximately฀1,000฀times฀more฀particles฀than฀side-stream฀smoke฀5฀×฀10 9 ฀vs.฀฀ 1฀×฀10 5 –1฀×฀10 6 .฀Mean฀particle฀size฀in฀mainstream฀smoke฀is฀0.2฀mm฀0.1–1.0฀mm฀and฀is฀ Agent ConcentrationNFC Toxicity Carbon฀monoxide 10–23฀mg Binds฀to฀haemoglobin,฀inhibits฀ respiration,฀induces฀atherosclerosis Ammonia 10–130฀mg Irritation฀of฀respiratory฀tract Nitrogen฀oxide฀NOx 100–600฀mg Inlammation฀of฀the฀lung Hydrogen฀cyanide 400–500฀mg Highly฀ciliatoxic,฀inhibits฀lung฀ clearance Hydrogen฀sulide 10–90฀mg Irritation฀of฀respiratory฀tract Acrolein 60–140฀mg Ciliatoxic,฀inhibits฀lung฀clearance Methanol 100–250฀mg Toxic฀upon฀inhalation฀and฀ingestion Pyridine 16–40฀mg Irritates฀respiratory฀tract Nicotine 1–3฀mg Induces฀dependence,฀affects฀some฀ endocrine฀functions Phenol 80–160฀mg Tumour฀promoter฀in฀laboratory฀ animals Catechol 200–400฀mg Co-carcinogen฀in฀laboratory฀animals Aniline 360–655฀mg Forms฀methaemoglobin,฀and฀this฀ affects฀respiration Maleic฀hydrazine 1.16฀mg Mutagenic฀agent Table 3.3 ฀฀฀Major฀toxic฀agents฀in฀cigarette฀smoke฀incomplete฀list฀ [23] Condensate zone Distillate zone embers zone about 900°C Ash Main stream 4 mg CO Side stream 40 mg CO Fig. 3.1 ฀฀฀Schematic฀ illustration฀of฀burning฀ cigarette.฀Main฀stream฀and฀ side-stream฀smoke฀differ฀in฀ terms฀of฀the฀temperatures฀ at฀which฀they฀are฀formed฀ and฀the฀composition฀of฀ their฀toxic฀constituents฀cf.฀ CO฀content฀of฀a฀cigarette clearly฀smaller฀than฀that฀in฀side-stream฀smoke฀at฀0.5฀mm฀0.1–1.5฀mm,฀resulting฀in฀a฀higher฀ proportion฀of฀particles฀in฀mainstream฀smoke฀having฀a฀toxic฀effect฀on฀tissues.฀Furthermore,฀ mainstream฀smoke฀contains฀2–3฀×฀10 10 ฀radicals฀per฀ml.฀The฀majority฀of฀naphthalines฀and฀ polynuclear฀hydrocarbons฀are฀formed฀in฀mainstream฀and฀side-stream฀smoke฀as฀a฀result฀of฀ the฀combustion฀process฀Table฀ 3.2 . The฀tar฀content฀of฀cigarettes฀has฀been฀an฀important฀issue฀for฀more฀than฀50฀years.฀The฀ tobacco฀industry฀has฀recognised฀that฀tar฀constituents,฀such฀as฀are฀also฀formed฀by฀the฀burn- ing฀ of฀ tobacco฀ in฀ the฀ mainstream฀ and฀ side-stream฀ smoke฀ of฀ a฀ cigarette,฀ are฀ extremely฀ hazardous฀to฀health.฀Ever฀since฀1950s,฀the฀tobacco฀industry฀has฀striven฀to฀reduce฀the฀tar฀ yield฀of฀cigarettes฀cf.฀Fig.฀ 3.2 .฀Aside฀from฀lowering฀tar฀yields,฀however,฀the฀tobacco฀ industry฀is฀also฀concerned฀with฀nicotine฀release฀during฀the฀smoking฀process,฀particularly฀ since฀lowering฀the฀tar฀yield฀also฀reduces฀the฀nicotine฀content฀Fig.฀ 3.3 .฀As฀a฀result฀of฀ 10 1955 1960 1965 1970 Year 1975 1980 1990 0.3 0.5 0.7 0.9 1.1 1.3 1.5 Nicotine mg 1.7 1.9 2.1 2.3 2.5 2.7 2.9 3.1 12 14 16 18 20 22 24 Tar mg 26 28 Tar Tar Nicotine mg Nicotine Expanded blends Tips ventilation Ventilation and dilution perfected Filter-tips Porous paper Reconstituted tobacco 30 32 34 36 Fig. 3.2 ฀฀฀Tar฀and฀nicotine฀yields฀of฀US฀cigarettes฀over฀the฀past฀35฀years฀and฀measures฀to฀reduce฀the฀ tar฀content.฀Cigarette฀industry฀data฀ [23,฀24] 1959 Tar [mg] Nicotine [mg10g] CO[mg] Bap [ng] 5 10 15 20 25 35 30 [mg] 1967 1971 1977 Year 1981 1988 1991 1997 Bap [ng] 20 30 40 50 60 10 Fig. 3.3 ฀฀฀Changes฀in฀the฀tar,฀ nicotine,฀CO฀and฀ benzo[a]pyrene฀BaP฀yields฀ of฀non-ilter฀US฀cigarettes฀ between฀1959฀and฀1997฀ [23] .฀ The฀nicotine฀yield฀was฀ calculated฀with฀reference฀to฀ 10฀g฀tobacco efforts฀by฀the฀tobacco฀industry฀laboratories,฀tar฀yields฀in฀US฀cigarettes฀have฀been฀lowered฀ from฀38฀mg฀to฀12฀mg฀ [23,฀24] .฀US฀cigarettes฀currently฀have฀a฀nicotine฀yield฀of฀0.95฀mg.฀ Tar฀yields฀have฀been฀similarly฀reduced฀in฀Great฀Britain,฀but฀the฀quantities฀of฀nicotine฀in฀the฀ cigarette฀have฀been฀kept฀at฀a฀higher฀level฀ [25] . Various฀ modiications฀ to฀ the฀ cigarette฀ have฀ been฀ made฀ to฀ achieve฀ these฀ changes฀ as฀ follows: • ฀ Cigarette฀length฀has฀been฀altered • ฀ Modern฀ilters฀have฀been฀incorporated฀into฀cigarettes฀ [26] • ฀ Aromatic฀agents฀terpenoids,฀pyrroles,฀pyrazines฀have฀been฀introduced฀into฀tobacco • ฀ Porous฀citrate-treated฀paper฀has฀been฀used฀increasingly • ฀ New฀tobacco฀mixtures฀employ฀a฀reduced฀tobacco฀volume • ฀ Manufacturing฀technology฀has฀been฀optimised฀e.g.฀glycerol฀and฀propylene฀glycol฀are฀ more฀suitable฀than฀diethylene฀glycol฀and฀sorbitol฀etc.฀for฀moistening฀the฀tobacco฀ [27] Filter฀dimensions฀were฀important฀for฀the฀partial฀removal฀of฀toxic฀substances฀from฀main- stream฀cigarette฀smoke:฀charcoal฀ilters฀reduced฀the฀content฀of฀ciliatoxic฀substances฀cya- nide,฀formaldehyde,฀acrolein,฀acetaldehyde฀by฀up฀to฀66฀ [28–30] ฀and฀were฀superior฀to฀ cellulose฀acetate฀ilters.฀By฀combining฀the฀two,฀even฀better฀results฀were฀achieved฀in฀terms฀ of฀the฀absorption฀of฀toxic฀substances฀e.g.฀volatile฀phenols฀and฀nitrosamines฀from฀main- stream฀smoke฀ [31–33] . The฀porosity฀of฀the฀paper฀reduces฀the฀inhalation฀of฀various฀gases฀hydrogen,฀NO,฀CO,฀ CO 2 ,฀methane,฀ethane,฀ethylene฀by฀outward฀diffusion,฀whereas฀the฀diffusion฀of฀N 2 ฀and฀O 2 ฀ into฀the฀tobacco฀is฀increased฀ [23] .฀The฀reduction฀of฀nitrogen฀oxides฀in฀the฀inhaled฀smoke฀ lowers฀the฀formation฀of฀tobacco-speciic฀N-nitrosamines฀ [34] . One฀previously฀neglected฀aspect฀has฀been฀the฀question฀of฀the฀occurrence฀of฀bacterial฀ endotoxin฀as฀an฀active฀component฀of฀cigarette฀smoke฀ [35] .฀The฀Limulus฀amebocyte฀lysate฀ LAL฀assay฀was฀used฀to฀measure฀the฀lipopolysaccharide฀LPS฀content฀of฀the฀tobacco฀por- tion฀and฀ilter฀tip฀components฀of฀unsmoked฀“light”฀cigarettes,฀as฀well฀as฀in฀mainstream฀and฀ side-stream฀ smoke.฀ In฀ addition,฀ blood฀ LPS฀ activity฀ and฀ plasma฀ cytokine฀ concentrations฀ TNFa,฀IL-6฀were฀measured฀in฀smokers฀and฀non-smokers.฀Bioactive฀LPS฀was฀detected฀in฀ the฀“light”฀cigarettes,฀in฀their฀ilter฀tips,฀and฀in฀both฀mainstream฀and฀side-stream฀smoke;฀no฀ differences฀in฀blood฀LPS฀levels฀were฀detected฀between฀smokers฀and฀non-smokers.฀In฀terms฀ of฀adverse฀effects฀on฀health,฀however,฀it฀is฀estimated฀that฀the฀LPS฀dose฀delivered฀from฀smok- ing฀one฀pack฀of฀cigarettesday฀is฀comparable฀to฀the฀level฀of฀LPS฀exposure฀of฀cotton฀textile฀ workers฀dust฀from฀textile฀manufacture฀and฀that,฀in฀addition,฀LPS฀release฀may฀be฀one฀factor฀ responsible฀for฀the฀development฀of฀chronic฀lung฀diseases฀chronic฀bronchitis฀ [35] .

3.3 Nicotine and Dependence

The฀addictive฀effects฀of฀nicotine฀were฀known฀within฀the฀industry฀as฀early฀as฀1963฀ [2] ,฀ but฀were฀denied฀publicly฀until฀1980฀because฀the฀simultaneous฀admission฀of฀carcinogenic฀ and฀addictive฀effects฀would฀not฀have฀been฀defensible฀ [36] .฀Studies฀in฀rats฀showed฀that฀ only฀ some฀ of฀ the฀ animals฀ became฀ dependent฀ as฀ a฀ result฀ of฀ the฀ tobacco฀ smoke.฀ The฀ dependence-inducing฀ effect฀ was฀ linked฀ to฀ the฀ rate฀ of฀ nicotine฀ delivery฀ to฀ the฀ CNS฀ [37,฀38] .฀The฀delivery฀of฀nicotine฀and฀the฀associated฀“kick”฀were฀enhanced฀by฀the฀addi- tion฀of฀K 2 CO 3 ฀ [39] . Even฀in฀the฀early฀1970s,฀in฀the฀face฀of฀growing฀concern฀over฀the฀harmful฀effects฀of฀ciga- rettes,฀the฀tobacco฀industry฀was฀considering฀a฀strategy฀on฀three฀major฀fronts:฀“Litigation฀–฀ Politics฀–฀Public฀Opinion”฀ [40] .฀The฀decisive฀steps฀were฀to฀create฀doubt฀about฀the฀health฀ charge฀without฀actually฀denying฀it,฀seek฀allies฀in฀Congress฀to฀manipulate฀public฀opinion฀ and฀argue฀in฀the฀media฀that฀cigarette฀smoking฀may฀not฀be฀the฀decisive฀risk฀to฀health,฀and฀ that฀environmental฀factors,฀for฀example,฀might฀be฀responsible฀ [40] .฀This฀resulted฀in฀the฀ development฀of฀“low-tar฀and฀low-nicotine฀cigarettes”฀Fig.฀ 3.2 ,฀purportedly฀to฀provide฀ increasing฀ safety฀ for฀ smokers฀ [41] .฀ The฀ intention฀ was฀ to฀ open฀ up฀ a฀ new฀ market฀ with฀ improved฀and฀“healthier”฀cigarettes฀ [41] .

3.3.1 The Cigarette as a Vehicle for Nicotine Release

Because฀ smokers฀ can฀ regulate฀ the฀ release฀ of฀ nicotine฀ by฀ modifying฀ the฀ frequency฀ and฀ volume฀of฀their฀puffs,฀cigarette฀becomes฀an฀interesting฀model฀for฀the฀release฀of฀an฀active฀ substance.฀Representatives฀of฀tobacco฀companies฀have฀also฀expressed฀themselves฀along฀ these฀lines฀in฀describing฀the฀cigarette฀as฀an฀ideal฀vehicle฀for฀the฀release฀of฀nicotine฀ [42] .฀ Thus,฀the฀tobacco฀industry฀embarked฀upon฀research฀to฀identify฀a฀minimally฀effective฀nico- tine฀dose฀per฀cigarette฀and฀discover฀how฀the฀effect฀of฀nicotine฀might฀be฀improved฀by฀addi- tives,฀pH฀changes,฀etc.฀ [42] .฀Their฀intention฀was฀also฀to฀intensify฀the฀dependence-inducing฀ effect.฀Nicotine฀and฀the฀cigarette฀were฀viewed฀as฀a฀drug฀or฀as฀a฀drug฀formulation฀ [12] .฀The฀ FDA฀itself฀was฀interested฀in฀classifying฀tobacco฀more฀as฀a฀food฀and฀luxury฀commodity,฀ rather฀than฀as฀a฀drug฀ [43] .฀The฀cigarette฀industry฀came฀to฀view฀the฀manufacture฀and฀mar- keting฀of฀its฀goods฀as฀nicotine-release฀products฀ [44,฀45] .฀The฀smoke฀was฀regarded฀as฀the฀ optimal฀vehicle฀for฀nicotine฀and฀the฀cigarette฀as฀the฀optimal฀dispenser฀for฀smoke฀ [46] .

3.3.2 Modifications of Nicotine Release

The฀overriding฀objectives฀of฀the฀tobacco฀industry฀in฀the฀1980s฀were฀to฀increase฀the฀release฀ of฀nicotine฀and฀enhance฀the฀effectiveness฀of฀its฀action฀ [47] .฀At฀that฀time,฀therefore,฀efforts฀ were฀made฀to฀control฀the฀nicotine฀content฀of฀smoke฀ [47] ฀and฀the฀addition฀of฀nicotine฀to฀ cigarette฀tobacco฀was฀even฀considered฀ [48] .฀The฀tobacco฀industry฀invested฀a฀great฀deal฀of฀ research฀into฀optimising฀nicotine฀release฀by฀improving฀the฀availability฀of฀nicotine฀from฀the฀ cigarette฀through฀modiications฀to฀tobacco฀blends,฀cigarette฀size,฀ilters,฀ventilation,฀paper฀ porosity,฀additives฀and฀the฀ratio฀of฀cut฀tobacco฀to฀tobacco฀weight฀per฀cigarette.฀Smoke฀ development฀was฀“improved”฀temporarily฀by฀the฀addition฀of฀freon,฀from฀which฀phosgene฀ is฀formed฀on฀combustion฀ [47] .฀In฀addition,฀attempts฀were฀made฀to฀use฀genetic฀engineering฀ project฀code:฀Y1฀to฀increase฀the฀nicotine฀yield฀of฀tobacco฀plants฀while฀leaving฀tar฀yield฀ unchanged฀ [49] .