Tobacco Documents Online

i ~ Iducation, ~( Health~ ~ fIea:lth, Advisorg p: Wash- Public Public Ilking. A ~ti, Ed'u- 11'ioati'on ~ bg: 1.968 kirttnent ,5hrvioe ~g. 1989 ~rtnient 5ervi~ce~ Iing. A 4, Eflu- [ ) Zi- ~ng: A Edn. ) 72'- j men ioine 1teki :. (2) i l4ue: rimo- >olic 458,. I

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Co~mtemts Page Introductiom-------------------------------------------- 67 ILiing Cancer-------------------------------------------- 68. Egidemiologieal St2idies-__-____________________-____-_ 68' E'x-Smokers----------------------------------------- 71 Lirdnium, Mining and Exposure to RadioactivztV _ _ _ _ _ _ _ _ - _ 72' Air Pollution---------------------------------------- 72 A'sbestos-------------------------------------------- 73 au,topsyand Cytol'ogical SGudies-__--_-_____-__-___-____ 73 nral Cancer -------------------------------------------- 74 Cancer of't.he Esophagus_________________________________ 76 Cancer of t'he Larynx ------------------------------------ 76 Cancer of'the Pancreas___________________________________ 77 C aneer of the Kidney andl Urinary Bladder_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 77 E_.perimentall Carcinogenesis-__________________________-__ 78' R'espzratory Tract Carcinogenesis'_ _-- _ _- _ _ _ _ _ _- _ _ _ _ _ _ _- _ 78' Experiments in Mice_________________________________ 80 Aryl Hydrocarbon Hydroarylase (AHH), _ _ _ _ _ _ _ _- _ _ _- _ _ _ _ 82 Cell an.d Tissue Culture Studies_____-__________________ 84! B~inding of ~Polycy,cli;aH'ydrocarb'onst~~o~~DNA~ dnd~RNA_ __- 86 AT-lVittosdmines in Toba.cco Smoke_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 87 Summary of Recent Cancer Findings_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _. 88 Referenees--------------------------------------------- 88 List of Figures Figure 1.-Standardized lung cancer mortality ratios of' Japanese by number of' cigarettes smoked (1966-70) ------- 69. Figure 2'.-Lung cancer mortality ratios of Ja.panese by age, at initiation of' cigarette smoking (1966-70) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 69 Figure 3.-The survivall of'~ ex-srnokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx,orlarynx------------------------------------ 75. 65

List of Tables Page Table 1.-Age-standardized lung cancer death rates of' British physicians and the population of' England and `?Pales at various time geriods----------------------------------- 70 Table 2.-N-dimethylnitrosamine (DMNA) content of'~ con- densates obtained from several tobaccos grownn in both! . "high"' and "low" ni~~trogen soils------------------------- 87 ' 66

Introduction Tiiis introduction is a brief summary of' the major relationships brt weensmoking, and cancer which have been established in, previous nvl)orts on the healahi consequences of smoking', (;9~L,92,93,,94, 95, 961)~. ('i'(;arette smoking has been clearly identified as the major cause of 14u1- cancer in the TJ.nited S'tates:This conclusion is based on detailed vhi'kllniiological, clinical,autopsy„ and experimental data, which have :uccutnulated over a period of more than 20 years, For both men, and woxmeii,, the~ risk ofdevelopinglung; cancer is directly related to total klxpostu•e to cigarette smoke as measured by the number of cigarettes smoked per day,, the total lifetime number of cigarettes smokedl, the duration of' smoking in, years; the age at initiation of smokingy the depth of inhalation of tobacco smoke; and the "tar" and nscotine levels in the cigarettes smoked. Lung cancer death rates, however,,are lower for Nc•,omen than they are for men, ai finding due, in part;, tloa differencein exposure. `Vomen, smokers use fewer cigarettes a day, choose filtered cigarettes with lower"tar'''' and nicatine~ val!ues,, and also tend to inhale less. E-Iowever; even when women experience comparable levels of' ex- posure to cigarette smoke as men, their mortality rates for lung cancer stiill remain somewhat lower. Those who stop smoking experience a decline in the risk of'develop- ing lung cancer relative to continuing, smokers. The air, pollution! commonly found inan urban setting, appearsto result in elevatedllung cancerdleathi rates; however, thiseffect is relatively small comparedl to the overriding effect of cigarette smoking:. Certain occupational exposures have been found tio be associated with ani increased risk of dying from, lung cancer. Cigarette smoking interacts with many of theseexposures!.toproduce much higher death rates from lung cancer than would result from one e.xposure alone. Inte racting exposure factors may be : experiencedl simul'taneously or at~ different times. The uranium mining and asbestosind'ustries,are exam- ples of occupations in which this interaction occurs. The bronchial epithelium of smokers often shows premalignant changesincludingsquanlous,m!etahlasiay atypical squamous metaplasia,, and carcinoma in situ. Pipe and/or cigar sinokers experience a risk of developing lung cancer that is higher than t'herisk of nonsrn~o~kers;howe,ver, it,remains 495-028 Q'--73 M ,. , d

significantly lbwer than the risk of'cigarette smokers. A more complete discussion of the risks from pipe and cigar smoking, is found in another chapter of this report. Epidemaolbgical, experimental, and autopsy data have demonstrated that cigarette smoking is, a, significant factor in the development of cancer of the larynx, oral cavity, esophagus, and urinary bladder. B-naphthylamine, a carcinogen known to cause cancer of the urinary bladder in humans, has beenidentiified in cigarettesmoke. Thereisalsoe an association between cigarette smoking, and cancer of the pancreas. Experimental studies with animals in which cigarette smoke or one of it's const!ituent' compounds is administered in & variety of assays have confirmed the presence of'complete careinogens„ cocarcinogens such as tumor initiators and tumor promoters, and tumor accelerators in cigarette smoke. Reeent'1y, additional epademiological, autopsy,, and experirnental' studies have added to our understanding of these rel'ationships., Lung, Cancer Epidem,ialogical Sta.t,dies An ongoing prospective epidemiological study condtzcted in Japan provides a unique opportunity to examine the relationship of cigarette smoking ta death~ rates in a population: withgenetic, dietary, and other cultural' differences from previously examined Western popula- tions., Hirayama (37) has now reporte6 5-year foll'otivup data on 265,118 men and women aged40 y ears and older.. This represented 91' to 99 percent of the total' populatiotr in the area of' the 29 health districts where the study was conducted. A totali of' 11,858 deaths occurred dur- ing, the 5-year periodl which incUaded a total of 1,269,382 person-years of observation: Both men and' women wh.o sm.oked cigarettes experi- enced higher death rates from lung cancer than nonsmokers. Among smokers,the lung, cancer mort<alityratio«-as3'.85 ~ fbr men and 2:44 for women as,compared to nonsm~okers~ . (P < 0.001). Dose-response, relation- ships were demonstrated for the number of' eigarettes smoked per dayy andl the age at initiation of smoking (figs. 1 and 2). These mortality ratios,areconside-rablylower than those reported, forthehnited States, Canada,, and Great Bri~taQn, and may reflect ai lowerar-eragenumber of cigarettes smoked a da,y;an olcder.age at imitiation of smoking, or re- duced inhalntion ofe cigarettle smoke among the Japanese. In spite of these differences, thee overall results,of'thisstudy, includingthe dbse- responserelationships, are similar.toAhe resnlt&ofal'l the other major., 68

r'"`w I I l~lete. ~ rated~ it of Ider. h.ary i alsoo reas: ke of. Rave. ~11 as ~ in. I t~tal el,iiioiui,ological investigations. Thus,the rel'iabilityand accuracyof'the iictliods of' population selection and analysis used in previous studies h;r~e<i on population sa,rnples,and the conclnsion that cigarette srnok:- w,L, is the major cause of'lung cancer are again confirmed. Figure 1.-Standardized lung, cancer mort~aiity ratios of'Japanese by number of cigarettes smoked (1966'-1970),. 9'.0 S!.0 7.0' 6.0' 5:0 4.0 3~.0 2'.0 1.0'. 0 1.0 3.6 4.4 7.8' 4.3 Mlorn 1-14 15-24 >24 Ex, smoker cigarettes per day smoker SOURCE: HfFayamaj T. (37). Figure 2.-Lung, cancer mortality ratios of Japanese by age at initiation of cigarette smoking (1966-1970). 5,0 A~ 4.0~ r. 0 2 3',0! 2.0 11.0 ' 0 Non- >25' <24 <19 smoker Age at initiation of smoking SOURCE: Hirayama, T.,(37): 69 0 0 79

TABLE 1I.-Age-stand'ardized lungcan.cerdeath rates of Briti:'sh, physicians and the population of England and Wales at vdrinus time periods Lung cancer standardiied!deiath rate per 1,6C10 men per year in- Dootors. England and Wales Years------.--,-------------------------------------- 1953;-57 185741 196i-65 19M-57 19,58-611 1962-65 Death rate per 1,000~----------------- 1. 10 0. 85 0. 83 1l 49 1. 71 1. 88' Source: Doll, R., Fllee;D3.,C. (tt). Kennedy (~.45); studied primary lung cancer in 29 men and 11 `eomeni diagnosed before the age of 40 land found a strong association betweeni cigarette smoking and'the development of this disease. Boucot, et al. (11) further characterized the 121 cases of lung eancerdetected in the population of tiliePhiladelpllia pul'monaryneoplasm research project. Ti he risk of developing lung cancer in- creased with age, was higher ini nonn-hites than in whites, and increasedd sharply with, increased cigarette consumption. The relationship~ between cigarette smoking and lung cancer was investigated in a retrospective study by: Ferr.ara (25) in La Plata, Argentina. The: smoking,habits of 144' lung cancer patients were con- trasted with those of 386' controls. A dose-response relat'ionship, was found between cigarette usage measured by the number of cigaret.tess smoked per day and the durat'i'on of smoking,and the risk of'develbping lung cancer. A high incidence of' lung, cancer is reported from the island of Jersey in the Channel Isles compared to England and wales.. The island has no heavy industry and only minimal levels of air pollution. Cragg (16) ~ studied 144 patients who developed lung cancer on Jersey during a 4-year study period. Only three nonsmokers were found among the 113'patients for whom histories were available: Fingerland; et al. (26) determsned' the prev.alence of! 1'ung cancer and certain other diseases in an~ autopsy series of 1,338 adults in Czechoslovakia. Some 198 cases of primary lung cancer were identifiedl. In the autopsyy population, 1.4 percent of the nonsmokers, 14'.1 percent of'thosesmoking Tesst11~an200,,O0b'lifetime eigarettes,, and 33.3' percent of those smoking more than 500,000 lifetime cigarettes had lung, cancer. Rickard and Sampson~ (71)~ studied 94 Negro patients with lung, cancer in Washington, D.C.,, and found, that 57 (92 percent) of 63 patient's whose smoking history was available were: regular smokers. Epidemiological studie& conducted in Italy (10)i,, Swe,deni (48), Poland (46), Russia, (42), Cuba (73), 11Tiexico (13), and the Nether- lands (98) demonstrate an association between cigarette smoking and, lung eancer. 70 I # i

omen fween lung mary LC In- ~ased was lAta,, iCon- I was Oes ?ing ~ of T'he. :ion, hsey und icer li in led. ent ;ent tng [ng 63 irs. id Berg, et al. (5) examined the incidence of recurrent primary cancers following initiall prirnary~ cancers~ of~ the~ respiratory and upper di- 'restiti-e systems in New York. During 23,802 man-years of observation in .1,11i5 patients with an initial squamous cell cancer,, 518 second cancers developed at other sites. Patients whose first primary cancer ;nas in the lung had an observedl to~ expected relative risk rat'io~ of' 5'.:7~ ( P< 0.05 ) forr subsequent cancers of' the respiratory or upper GI ~,V:;tem~. Patlient'is, with the~~ first cancer in the~ oral cavity or~ laryna frea(luently developed a second cancer in the lung.. AIiedical records _ ontirnaed long sTnoking, histories among almost all of' these patients Nti IioAeveloped second cancers. C'uncer~~of the~ lung~, oral cavity, larynx, and esophagus were~~ reported !~v Schmidt and De~ Lint, (79)~ to be~comrnon~ causes, ~of~death~ amongg f,WN ' men and women who hadl received treatment~ for~ alcoholism~ in~ Toronto. The authors attributed this finding to the strong, associa- t irn.t that exists between alcohol and tobacco~ u~se~andnot bo~~ the~effect of zi Lcoholl alone. Carcinoma of the trachea is~ a relativeiy~ rare~ condition with, only ahout-1D0 cases~ha:ving~bee~n reported in the literature~.,lii a study~ of~41' l)atients~ w~ith, carcinomai of~ the trachea, I}Iaj'du,: et~al. (.31) found an, ~-,Pparent association between cigarette smoking and the development =4 'epidermoid cancers,of this st'ructure:~ An association between ci:garette~ smok~ing, and the development of~ broncliu:olo-alveolar~ carcinoma in~ 74 patients-~was, described~ by ~ Delarue;~ et al. (18). . Ex-sm;okers Those who stop smoking experience a decline in the ri'sk of dev.elop- ing lung, cancer relative to continuing smokers: Doll and Pike (2N) <<onducted a~~ st~udy~of~ the~ smoking habits and causes~~of death of 40,000~ Briti,sli physicians. Smoking ha.bi~tis, were~ surveyed in~~ 19~511, 1957',~ and . l:)6G., Durii,2;, the~ study ~ perio<l,, more~ than 3,500 physiicians~ becan:ze~ ex-~ .~niokers~., The age-standardized percentage of ex-sni,okers~~ among 1?hy~-~ sicians 65 to 64 years of age rose from 1I8',1 percent in 1951 to 26,5 per- cent in 195 1 and ~?~J~:5 hercent, in~ 1966. Concurrently, t~h,e~percentage~of hhy:sicians~ s~nioking, ci~,rnrettes~~ fell fi-om, 44.1 percent to 22.0 percent, while over ~ the~ same period estimates of' the~~ per capita ci'garet;te~ con- sttmption for the adiilt male population in the~ Linited! Kingdom su~g- (*este<1 ,t slir.ht increase in ciga~ret-te~~ consumption. Over this 15-year~ heriotl, the~ niorttility from hu2g,cancer arnor:7g,physicirans~~dlrophed con- sidera1hly: While~~ lung cancer death rates among,the nnale population in 1!ar,aand and Wales increased to~ some~ extent (tla~ble~ 1)~.: :llthougll cer~- 71

tain limitations apply to the interpretat,ions derived from secular data, analysis~ of the~ study ~ design and the~ magnitude of the results~ ihdi-~ cate that~this study constitutes important evidence~of~some~of'the~bene~-~ fits~~ tliat'~ result fi•onii the cessation of~ cigarette snsoking. Uranium Mining and Fxposure to Padioaetivity Epidemiological evidence supported by autopsy studies has estab- lished that'~airborne~radiationy~ particularly~ in synergi~stie~comb~imation «itlrcigarette smoking,,is the major cause of the excess of respiratoryy cancers among uranium miners. Lundin;, et al. ('53), considered quantitative~ and~~ temporal aspects! of radon.idaughter~exposure and respi'ratory~cancer ini a report'~~fromthe: Epi~d!emiologica1 Study ~ of~ United States~ Uranium Miners. They~ ob-~ served a stati~stiicalZy~ significant excess~~ of~ respilratory~ cancer among «hi~te~u~raniom mii7ers~~at each cu~mulative~~ radiation exposure category dow~n to~~ and' including~ 120-3W WL'M (w~ork~~ing~~ llevel montlLs)~_ The authors~ noted that although cigarette~ smokiirg~ alane~ entailed a risk of the~ dl;~veloprnent, of' eancer~ of~ the respiratory.~ tract in, miners just as it~ does in nonm~iners; cigarette~~ smoking, in combination wi'th; radion~ daughter exposure appeared to result in an even greater risk.~ Several authorsi (30, 44,~63„8/~~, 104) continuelo~ report the presence~~ of' polbni~um-~210 or~one~of the~th:oriurn isotopes in tobacco l~eaf;~ tlobacco~o smoke, or the l ungs of smokers. Air Pollution Data standard'ized, for~cigarette sm:oki~ng~~ind'icate~the existence:of an~ u~~rban factor~in the~develapm~ent of~lung carlc;er; it is~likelythat ai'r~po1- lution,,frequent,ly~ part~ofi the city.~ environment, is~ai component of~ the~ urban factor. Th~e~ National Academy of~ S'ci~ences,published a review (6r')~ of the~ biolbgicall effects of atmospheric polluti~on~ by~ particulate pol!ycyclic~c organic matter.~ Detailed epidemiological,,experimental, physicaI,,and chemical data were revie«-edi., It was concluded that air pollution„ as commonly ~ found in urban settings, was found to~be associated with: in- creased creased lung cancer~ mortality in cities, An examination of the data presented,~however, indicates that eigarette~ srnok~ing is,,i¢l, most~ cases, the~ overridia'ig factor~ in tihe~ development of lurrg, cancer. IPolycyclic hv~d~rocarbons~an~d relatedlcompourrds which~aire~known~to~cause,cancer of the~lhng and other organs in experimental animals were~ found t'~o~ 72 I