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clo- of the ses of di!.- rng from the third s9atitlicl, , of Cal, iepee of ,r.xel pro- :c6- :flo. n cancer studies. s:,a mor: + Pathol mokinE: Orig B I death I low•up JAMA r d+•th C1' r np and Health d mor- ht and er Ins[ /. AMEatfATJUt-RA'A'L OrE'PtoL'MIDLOGY. CopvriCht i' 1w6+'b. T1hrJohns FNopkins Univtrsmy School ofH.peneand Public Htalth All riFh's rrser.edi Vol. 125,1vo: I Pnnted in U.S.A AtISIi FACTORS FOIR' ADENOCARCINOMA OF TIiIELUNG ROSS C. BROWNSOK,' ' JOHN S. R'EIF,: ' THOMAS J. KEEFE.' STANLEh W. FERGC'SON:' AInD JANE A. PRUTZdi' r Brownson, R. C. (Dept: of' Microbiology, and Environmental Health, Colorado State U!, Fort Collins„C0 80'523), J. S. Reif, T. J. Keefe;,S. W: Ferguson, and'J. A. Pritzl. Risk factors for adenocarcinoma of the lung. Am J Epidemiol 1987;125:25- 34. The relation between various risk factors and'adenocarcinmma of the lung was evaluated in a case-control' study. Subjects were selected from the Colorado CentrallCancerRegistry from 1979-1982 in the Denver metropolitan area. A total of 102 (50 males and 152 ' females) adenocarcinoma case interviews and 131 (65 males and 66 females) control interviews were completedl The control group consisted of persons with cancers of the colon and bone marrow. The risk estimates associated with cigarette smoking were significantly, elevated among males (odds ratio (PR) = 4.49) and' females (OR = 3.95) andi were found to increase significantly (,p < 0.01) with increasing levels of cigarette smoking for both males and females. For adenocarcinoma in females, the age- and'smoking- adjustediodds ratios at different levels of'passiire smoke eXposure'followed an increasing overall trend (p = 0.05). After additional adjustment for potential' confounders, prior cigarette use remained the most significant' predictor of risk of adenocarcinoma among imales and females. Analysis restricted to nonsmoking females revealed a risk of adenocarcinomalof 1.68 (9'SD6' confidence interval (CI) = 0.39-2.97) for passive smoke exposure'of'lourpr more hours'per day. Neither sex showed significantly elevated risk for occupational' exposures, although males bordered on significance (OR = 2.23, 95% Cl = 0.97-5.12). The results suggest:the need to develop cell type-specific etiologic hypotheses, air pollution; lung neoplasms; tobaccoIsmoke pollution Recent evidence indicates that lung can• cer may enconopassseveral rnorplOologicallyand clinicallv distinct diseases (1, 2')I In industrialized western nations, incidence rates are highest for squamous cell carci- noma, followed byy adenocarcinoma (3, 4')~ r The relation between squ'arnous' cell and I small cell carcinomas andi cigarette srnok- : _V I t ' Received for publication March 28, 1986. ' Depanment of'Microbiology and Environmental Health. Colorado State Uniiversity„Fort Collins, CO. "Colorado Department of'Health. Denver, CO. "Rearirn reauests to Dr. Ross C: Brownson att cvrrent address: Cancer Epidemiology and Control Program. Division of Environmental Health and Ep- idemiology Services. Missouri'Department of Health. P. 0;,Box I'268, Columbia. MO:652fD5: This study is part of a dissertation Isubmitted to the Academic Faculty of Colorado State University in partial fulfillment of the, requirements for, the degree (,J~'( ("CR ing is well-esnablished, but the relation be- tween adenocarcinoma and cigarette smok- ing is less clear ('3„5, 6). Adenocarcinomal is the most frequently diagnosed form ofiung,cancer in the United States among women and nonsmokers (3, 7). In a series of nearly' 30,000 cases of primary lung cancer, 22 per cent were spec - of Doctor of Philosophy for Ross C. Brownson. This work was supporued in part by l*lationaLInsti'- tutes of Health Biomedical Research Support Grant 2 507 RR=05458-20'and a grant from the American Lung, Association of Colorado. The',authors acknowledge the assistance of the Col- orsdo QentrallCancer Registry. Colorado Department of Health and the staff of the,Department of' Micro- biology and Environmental Healthi Colorado State University_ They also thank D>•s. Richard F. Hammann and Mowafak D. Salman for their helpful comments:

ified as adenocarcinoma among males com- pared i with 37 per cent: among females (8). The role of occupational exposures in the etiology of adenocarcinoma remains inconr clusive'p9, 10). Recently, a disproportionate increase in the incidence of' adenocarci- noma has been noted in the United States ('5). The changing histologic patterns of hing cancer incidence may be due to a change in!diagtaostic practices an&classifi- cation or to increasing exposure to environ- mental carcinogens. The present investigation was designed' to evaluate the role of smoking, p'assiue smoking, occupation, community air pol- lution, and socioeconomic status in the etiology of' adenocarcinoma of the lung; A case-cont'rol! study was conducted to pro- vide additional ldata ~eoncerning the relation, between exposure variables and this infte- quentlyst'udied and poorlhundersteod'y form of lung,cancer:. MATERIALS AND METHODS Cases and controls were identified through the population-based Colorado Central Cancer Registry maintained byt'he Colorado Department of' Health. For the years and counties included, reporting was essentiarly complete. Alll diagnoses were microscopically confirmed an'dI classified according to histologic type. Study pa'rtici- pants were required to have resided in the Denver metropolitan area for at least six months prior to cancer diagnosis in order to reduce migration bias. Case selection A total of' 149 eligible cases of adenocar- cinoma (Lnternational'ClassiJication of 'Dis• eases (IICD) code 1163) were identif ed in the five-county Denver metropolitan area from 1979-1982. Selection was restricted to white males and white females. These ad- enocarcinoma cases were stratified' by age and sex. Of the 14!9'elijgible cases, 31 could not be loeatedJ 15 refused~to be interviewed,, and one did not qualify. A total of'102'case. interviews (50 males and 52' females) were completed. The mean ages for male and [4cl / fiemale cases were 64.9 and 66.3 vears, re- spective'1y. Contro!'selection Controls were chosen from persons in the Colorado 9entral Cancer Registry who had cancer of sites considered to be unrelated to cigarette smoking, Specif calln-,, persons with cancers of' the colon (ICD code 153) and bone marrow (PCD code 169) diagnosed from 1I979-1982 were chosen as controls and group-rnatched to adenocarcinomai cases according to a e and sex. Matching, was done at the group~ eveTso~that the, maximum number of cases and contro'ls Onlti w ites could be used in the analyses. were included in tbe study„ and at least one control was required for each case within each age a'ndlsex stratum. A total ofl 169 eligible controls were iden- tified. Of these, 24 couldlnot be located, 13 refused to be interviewed, and one did not qualify,. A total of'13'1i usable interviews (65 males and 66 females) were completed. Among, controls; 80 were colon cancer pa, tients; and 51 were diagnosed wit'h leuke, mia. The mean: ages for male andl female controls were 65.2' and 68.2' years, respec- tively. Data collpction and analvses Epid'emiologic data were collected by per- sonal interview. The interviewer was un- aware of whether the patient was a!case or a control. A higher percentage of the inter- views in the case group (68ercent) than in the eoritrolll group (3&9 per cent) were completed by a relative or a friend. Among the 7& nonsurviving, cases, 56 interview~: were completed with a spouse, seven inter- views, with~ a child, siawi'th & sibling, and one with a close friend. For the 51 deceased controls, information was obtained from'42 spouses, six children, two siblings, and one close friend. Socioeconomic'status was assessed by ex- amining two: variables, education and in~ come. Educationali level was characterized by the highest grade of formal education completedi Gross income was ascertained for t1 for til Sn cigar. pack- d'ata l able patie: basete was i smok Occ ing to egory: sure carcir tries ~ ated % were i of yea 4 I I Uct sure c subjec. ~1 Z2 h t ~ ma er was a expos( ular c includ mium. gas. P. gers a~ An polluti levels censuK , each c A 10 air parti ci benzer indiicalben2ol pendec each c• was as code c multip pendee'. Int1: tingenr for'agE factors

R15h FACTORE FOR'ADENOCARCIhOn1A OF'TWE UCNG' 27 ,ns in the who had inrelated persons ode 153) iagnosed controls rcinoma iatching :hat the controls y whitess east one ' "hin re'iden- ated, 13'. didi not ews (65 ipleted. icer p'a- leuke- female respec- by per- ,as un- case or ! inter- , t) th'an ) , e Among rviewKs inter g, andl ceased' -om 42 -id one by ex- Id in- erized i cation :ained for the previous year;,or, in case of retirees. for the year prior to retirement.. Smoking history was characterized for cigarettes, cigars. or pipe:ftuls in terms of' pack-years of' exposure: Passive smoking data were analyzedlas a dichotomous vari- able based on the smoking status of' the patient's spouse and as a stratified variable based'on the hours per day that the subject was in the presence of persons who were smoking. Occupational data were analiyzed accord- ingto industrial'category, occupational cat- egory, and a self-assessment of' the' expo- sure of the respondent to known lung carcinogens,in the work'place: Those'indus+ tries and' occupati ons known to be associ- ated with an elevated' risk for lung cancer were coded and' multiplied' by the' number of years:in each category to estimate expo- sure over time (111-13). In addition, eachh subject was shown a list of' 112 ' groups of materials known to be lung carcinogens and was asked whether he or she had been exposed to the substances during a partic- ular occupation. Pulmonary carcinogens included materials such as asbestos, ch'ro- mium, nickel, uranium ore;, and'! mustard gas. Posit~iwe responses were coded as inte- gers and summed. An index of exposure to community air pollution was developed based on estimated levels of total! suspended particulates per census tract' and the years of residence in eaeh census tract, (14). Total suspended particulate air pollution, which contains a benzene soluble fraction; was. used as an, indicator of po'lvcyclic hydrocarbon (e.g., benzo(,a)pyrene)' levels: The total sus- pended particulate data were stratified into 10 air polllution, exposure' subgroups, and each census tract within the Denver area was assigned to a subgroup. The'residence ', code consisted of years at each' residence .i. multiplied by the corresponding',total sus- T .pended~particul'ate exposure subgroup. . t-*-..- In the first set of analyses, stratifiedicon- ,'tir,gency tables were constructed, to adjust ; fior age and smoking for the primary risk factors (15-17). Odds ratios' for each level of exposure were calculated by Miettinen's standardized rate technique which controlss for confbunding factors (18). All' analyses included adjt.ustment for age based on the categories 30-49, 50-59, 60-69;,70-79;,and 80-99 years. An extension,of the Mantel- Haenszel prol was used to statisti- cally evaluate overall trends in the propor- tion of cases according, to level of' exposure' to risk factors (19,,20): Ivlultiple' logistic regression was used to obtain maximum likelihood point and in- terval l estimates of the odds ratiio, as well as to control for the'effects of'various con- founding, risk factors (11-23): The most significant, predictors, based on the Mantel- Haenszel results, were included in the lo- gistic model. The dependent variable in these analyses was lung adenocarcinoma (case (cod'ed as 1) or, control (coded as 0)). Independent variables were entered in in- tervals;, as recommended by Schlesselman (24). In'order to identify the potential'con- founding effect of the induction period of cancer„the exposure'of each case or controli t'o, ambient air pollutants andl industrial carcinogens was analyzed in two ways: 1'), tihe entire residence and work history of' each person was included, and! 2)1 only ex- posures that took place 10 or more years priarr to the time of'diagnosis were considl ered, The analyses were compl'eted'both for all subjects and for primary respondents only;,to assess the validity of the surrogate interview data. A multiple logistic regres- sion model was also constructed for non- smoking,fem'ale cases and controls. FfESUL'fS For bothl males, and females„ the age- standardized odds ratios were found to in. crease significantly (p< 0:01) with iincreas- ing levels of prior cigarette use (table 1'). The age-adjusted odds ratio for prior ciga- rette use among males was 4.49 (95 per cent confidence interval (CI)' = 1i.44-1'3:98): Among females, the risk due to cigarette smoking was 3.95' (9'5' per cent CT = 1I.76- 8.80): For adenocarcinoma in females, the age- and smoking-adjusted odds ratios at I

HR'OwNSON ET AL TABLE I N„-T' RWSrFec2Csy Yo Nznr S f*mlaR3 Adjusrcd uddx roNu. IQRD ond'trrnd'testa /or odcnucorcinomu o/ thr lung occurding to lcueJ o/ cigaretrr u<r and paasive smokr exposure. motropolitnn Denver: CO, l'97N-1987 Factor Prior cigarette use (pack-years) 0' 1-39, 240~ Trend I(ip ralue)' ~.6 `tales No. of No of easer controls Passive smoke exposure (hours/day) . 0-3 16' 28'. 4-7 19 24 ZB Trend (p value) 15 13 Frmales OR' l+l~,of c~.xs.. li:o: of controts OR 1.00 19 47 1.00 4.06 ®3 1-6fi 7-68 2 14.80 (<0.0:1) (<0lol') ~ 1.00, 29' 53 1.00 1.76I 11 8 3.06 t 2;68' 12 5 2.33 (0.46) (0.05) ' Odds ratio for prior cigarette use,adjusted forage:,odds ratio for passive smoke exposure adjusted for age and smkithg; different levelk of passive smoke exposure frollowedl an overall trend, statist!icalliv sig- nificant at the 0:0'5 level. The age- and smokang•adjusted odds ratio ftDr passive . smoke exposure (using 0-3 hours per day as the reference level)'was 11.01 ('95' per cent, Cl = 0:42-2:41) among males. The corre: sponding,risk for females was 2.42 (95per cent CI = 0.94-6.22). 00 dds ratios for pas- sive smoke exposure were also calt ulat'ed on ai ves/no: basis for the regular smoking, histor.- of the patient's spouse. The aden- ocarcinoma risk from smoking, by thee spouse was not significant for males (oddss ratio (OR) = 1.4'0, 95 per cent CI = 0.66- 2.14) or femaies (CR = 1.54„95 per cent CI = 0.72-2.35'). The odds ratios and their 95 per cent confidence intervals for education level, in- come, community air pollution exposure history„ and occupational exposures are presented in table 2: The lowest leve)! of each variable was used as the reference category. Both education and' income showed' inverse trends with adenocarci- noma risk. Among males, annual income approached statistical significance with aw odds ratio of 0.47 (95 per cent CT = 0.19- L.19). No significant risks in the age- and' smoking-adjuste& odds ratios were shown for males or females according to their air pollution exposure history. No difference was noted regardless of whether t!he entire residence history of the patient or onl}•Y the residence history 10 or more years prior too cancer diagnosis, was used in the analysis. 00 f the occupational variables (industnial category, occupationall category, or self'-re- ported exposure to lung carcinogens), onl%- occupa'tional exposures for males bordered on significance (OR = 2.23, 95 per cent CI = 0_97-5.1'2). The multiple logistic regression risk es- timates for income;, occupation, pack-years of cigarette use, and passive smoke expo- sure are shown in table 3. For both sexes combined, annual income showed an in- verse association with adenocarcinomairisk after adjtnstment for other risk factors (OR = 0:85; 95 per cent CI = 0:72'-0M). A positive association between pack-years of cigarette use and cancer risk was found for males, females, andl both sexes combined. 'IThe largest risk for adenocarcinoma asso- ciated with passive smoking was shown for females at the exposure level of 4-7 hours per day, (OR = 1.91, 95 per eentCl = 0.78- 3.03). The first-order interactiom of pack- years of smoking and passive smoking was examined and found tb:be nonsignifcant. Adjustoc educotio Education le (hiFhest, 0-6 9-15 Annual lincor. <$15~000' LS15:000; Residence his 0-99 _a00 Occupation (n 0 t1 ' Odds rari • Missing , - ~ The pro( subgroup. § Occupatii, Afulnpdi• 7tiRi oarordl n: Income Occupation Pack-ears 0 1-39 >_40 Passive smokn (hours/da 0-3 4-7 z6 Odds ratic. M- Logistic i ' !i ing only pt ~ -1swlts were t Jesponden'G was theon! ~ ,3" 0.05 level b; ~ ~respondenL, -of smoking ,printary re, assive sm('( rimary res

iporette use and OR' 1:00. 1"68I 14.80 1 (<0J01'), to their air ~ difference !r the entire or only the -ars priarr to !le analysis. (industrial , or self-re- )gens), only 's bordered per cent CI on risk es- pack-years's noke expo- both sexes vec. -l in- :inoma risk actors (OR 2-0.98). A .k-years of' s found for combined. ioma asso- shown for 4-7 hours CI =0.78- n of pack- ,oking was ;nificant. ~ ~~V_T_ W, W"M RISK FACTORS FOR AUENOCARCItiONfA' OF THE Ll!!NG TAaLE 2 Adjusted odds ratios (OR) and 95¢r cwnJidenne intrruaL+ (C!) /ur odcnutorcinoma o/,tlie tung ot+cordinF to eduaatton; inconte„airpntlution revidencc hisrorn: ond occupotcun. mctropofitan Dnnuer, CO. 19i5-J952 29 N9kleF Females Facc or n OR' 95% CI n OR' 95% CI Education level (highest Rrade) r 0-8 25 1.00 17 1.00 9a1'7 90 0.59 0?3-1154' 101 0.73 0.'23 2:31 Annual income (thousands of dollarslt <$15.000' 25 1.00' 37' 1.00 ZS15;000' 86 0.47 0.19;-1.19 78' 0.71 028-1"85 Residence history (exposure-years)2 0-99 26 1100 31 1:00 zlOU 89 1 "66 0:66-4.1'9 87 1.51 0.56-3.96 Occupation (exposure-years)i 0 76' 1.00. 112 1.00 al 39 2.'29' 0.97-5.12 6' 0J59 0.09-3"51 ' Odds ratio adjusted for age and smoking, tNissing values. ; The producti of years at each residence and the corresponding total suspended particulate exposuree subgroup. § Occupations at high risk for lung,cancer multiplied by the number of'years in each category. TA~aLE. 3. r4fultiple logictic regression odds rotiox (ORJ and,9o'So confidence intert•aL (CI) for odenocorcinomo oJ :he lung areurding to incomc: occupation, cigarette use, and'passiue smoke ezposure; metropotitan !lenuer. C0. )979-1982. Factor All subjects Males Females n OO R' 95% CI n OR 95% Cl n OR 95% CI Income 233 0!85 0:72=0:98 1115 0.85 0.66-1.03' 118 oJ84 0:64-1:.03 Occupation 233 1.00 0!96-1:.04 115 1.00 0:9 7-1.04 116 0.94 0:51-1.3 7, Pack-vears 0 89 1.00: 23' 1.00 66 1.00 1-39 56' 2.62: 1L82-3.40 33 3.74 2.37-5.12 23 1"93 0.88-2.99 L-40 88 5.81 5"01-6'.61 59 5.42 4.1'3-6. 7, 11 29 9.58' 8.31'-10:86 Passive smoking, (hours/dep•) 0-3 126 1.00 44 1.00 82 1.00 4-7 62 1.24 053-1.95 43 0.841 0:00-1"80 1!9 1.91 0.78-3.03 ts 4'5' 1.3;, 0:54-2"20 28 1-17 0.10-2.24 17 1.21 0.00-2.68 ' Oddc ratio adjusted for age, potential confounding factors, and sex when appropriate: Logistic regression was conducted by us- ing only primary respondents. These re- stilts were similar'to those found when all respondents'were included. Active smoking was the only risk factor significant' at the 0.05 levellbasedion the analysis of primary - respondents. The odds ratios for pack-yearss of smoking were consistently srnaller for ; primnary, respondents, whereas those for ;; Passive smoke exposure were larger when riaiary respondents were analyzed. The risk of adenocarcinoma due to pas- sive smoke exposure was examined arnong' female nonsmokers (table 4); in n fe- ale nonsmo'king cases were identif e l36.5 per ce we to size limitations, passive smoking was divided into two cat- egories: 0-3 and'four or more hours per day. An odds ratio of 1.68 (95 per cent CI1 = 0.39-2.97) was computed for the larger ex- posure category after adjustment for age, income, and occupation.

BROWNSON ET AL TABLE 4 ' Nfulciplr 1oRiatuc regression odds rotdos (OR) ond'95% cwnJldrncr intrrnnLs (G'l) /pr odcnocorcinomo of'tVe lung ancurdanF to incamc„rxcupotion: ondpo,csitk' smoke csposurc among,/emale non.mokers, metropoluon Dencrr. CO. 19I79-198?' Factor n OR' 95% CI Income, 66 0.85 0.60-1.11 Occupation 66 0.004. Passive smoking (hours/day) 0-3 56 1L00 a/ 10 1168 0.39-2!9ti ' Odds ratio adjusted for age and potential con- founding factors. D1sctlsslbN Numerous case-control studies of' lung cancer have been conducted over the past 30 yearrs. Few, however„have examined the data according to histologic! type. There appears to be al general consensus that the various histolagic types of lung cancer have a multifactorial etiolrngy which includes cig- arette smoking, and occupational and other enviTonmental factors. Smoking is the major risk factor, fbr most types of' lung cancer. In the Unitedl States, it is estimated that cigarette smoking may, contribute to: at least 80 per cent of lung cancer in males and 4'O perceni in females (25). Several reports have suggested that, smoking may not be the major risk factor, for adenocarcinoma in certain populations (26'-28')i Among white males, the age- standardized relative risk estimates for lung adenocarcinoma according to prior, cigarette use have ranged'ifrom less than one at' low levels of'smoking,to about six at high levels of smoking ('3, 29). Risk esti- mates of adenocarcinoma from smoking for, females are commonly lower and vary widely' among racial groups; for example, the relative risk estimates range from about' one in Chinese women to four in Japanese women, and five in Hawaiian women (26, 30)1 The risk of smoking andl adr'nocarci- noma for white females is usually between one and three, although the risk of lung cancer by histologic type has, been studied less frequently amon'g,females than among males (I110, 30-32): The current study foundlsig'nificant risk estimates for adenocarclnomal associated with smoking of 4.49 for males and 3,9&for females. The 4e•standardized risk esti- mates at different levels of cigarette usee showed significant trends (p < 0.01) for males and females, indicating that a dose- response relation, betweensmoking and ad- enocarcinoma was present. The risk esti- mates based on multiple logistic regression analyses for smoking were generally lower than the odds ratios calculated by the methods of Mantel and hi'aenszel (15) and Ivliettineni(1i7), since logistic regression al- lowed' for adjustment for multiple factors. The risk estimates for smoking and! ade- nocarcinoma found in this study, and thee presence, of' a dose-response relation were consistent with other studies (29, 31. 33). The effect of involu'ntarv inhalation of sidestream smoke (passive, smoking) on lung cancer etiology is & controversiall cur- rent public health issue ('34). Hirayama (35)' reported a significant relative risk for lung cancer of 2.08 among wives of heavy smok-, ers. A study conducted among Greek women found relative risks of 2.4 and' 3.4' for wives of light and heavy smokers, re- specvively (36). A case-control studv in Louisiana identified an increased risk for lung,cancer among nonsmokers married to heavy smokers and fmr: subjects whose motherssmoked (37). Garfinkel et al- (38) found an increased lung cancer risk for women whose husbands smoked 2'0''or more cigarettes per day. A recent study in' Los Angeles foundl a slight increase in risk of adenocarcinorna among, nonsmoking women exposed to passive smoke (39'). Sev- eral other studies have failed to link passive smoke'exposure to amincreased risk of'lung' cancer (40-42). Prior studies that have evaluated passive smoking and lung cancer have differed in the index of passive smoke exposure, cell type, and degree of histologic verificatiian (34). In the present study; indexes of' passive smoke exposure were obtained in two ways: 1,)~bK'ascertor.• of the no basis;,ai' hours per c( to smokin signifucant' smoking'b, dichotomot stratified smoke exp trend' in th females (p and cigaret jpstalent, b: come, occu no sigrtif•ics sive smoke males. The rela smoking f observed in tance of ot noma etiolc per cent n nocarcinon strated a s male nons exposure, ( Wu et al. smoking di no corn'mo stream, smt on other ir don; 3) thc ent!ial in smoke exp and deceas•. of changes thelium of. ~ stream sn: ~ numbers oi a- available ft ~'tations„the 1 ~ ing and liun. , ~ tigation. Al'thougr. 1 .been susper of lung ca ;has been h.. g and me

ian among ficant risk associatedi id 3!95 for risk esti- arette use 0.01) for at a dose- ig and ad- risk estir regression ally lower d by the (15) and ession al~ e factors. and ade- a the ioni were31„33)- latio'n of king) on rsial cur- ama ('35)) for lung ~ smok- ; Greek and 3.4 kers; re- audv in risk for irrie'd to whose aJ. (38)) risk for or r ree in -,)s risk of moking 9). Seve passive of llang t have cancer smoke ;tologic :)ass/ve ) ways: RISK FACTORS FOR ADENOCARC1NOX1A OF THE LL'NG 31 1) by ascertaining the regular smoking his- tory of the spouse of each subject' onia yes/ no basis; and.2)'bv determining the average hours per day that' the subject was exposed to smoking, (at home and at work). No significant risk estimates were shown when smoking by the spouse was considered as a, dichotomous variable: A"hen the data werne stratified according to level of passive smoke exposure, a statistically significant trend in the risk estimates was shown fmrr females (p = 0:05) after adjustment for age and cigarette smoking. However, after ad- justment by logistic regression for age, in- come, oceupation~ and cigarette smoking, no significant' adenocarcinoma risk fbr pas+ sive smoke exposure was found among fe- males. 'P'he relatively large proportion of non- smoking female cases (36-5 per cent)i observed in this study suggested t:he impor- tance of other risk factors in adenocarci- noma etiology. A previous study fbundlll9~i5 per cent nonsmokers among female ade- nocarcinoma cases (39). Our studv demon- strated a slightly elevated risk among fe- male nonsmokers due to passive smokee exposure, consistent' with the fiindings of Wu et al. (39). Deficiencies in passive smoking data in recent studies include: 1) no commonly established index of side- stream smoke exposure; 2) a lack off data on other indoor air pollutants such as ra- don; 3) the existence of a probab'le differ- ential in accuracy of' obtaining passive smoke exposure histories between living an'dideceased subjects; 4) a lack of evidence of, ch'anges in the peripheral bronchial epi- thelium of' nonsmokers exposed to side- stream smoke (40); and 5) insufficient numbers of' nonsmoking lung, cancer cases available f'or analyses. Despite these limi- tations, the relation!betweenpassive smok- ing and lung cancer deserves further inves- tigation: _` Although pollutants in.the air have long _ been suspected to contribute to the etiology -„ of' lung cancer; epidemiologic evaluetion Y:..has been hampered by'diffculties in defin- a i ~g and measuring air pollution and in eval- uating the effects of confounding,variables such as smoking, occup'ation„ and popula, tion mobility (43): A census tract analysis of~ lung cancer data, total suspended partic- ulatt air pollution, and'l median household income was reported, previously for the Denver area (14'). Our p'revious work showed: a significant direct relation be- tween male lung cancer rates and total sus'- pend6d particulate air pollution (p < 0.0'2), However, for both males and females, me- dian household income explained a larger percentage of the variation in lung,cancer rates than did particulate air pollution. The data on residence history of' cases and'controls were analyzed to determine if differences in total suspended particulate air pollution exposure mayhave accounted for a portion of the adenocarcinoma~ inci- dence: There were only slight differences between cases and controls in mean or me- dlan years of residence in metropolitan Denver. Residence history was defined in terms of exposure-years („vears of exposure to high or low total suspended particulates) in order to define an index of exposure for each case and control. Although, in Denver, cases commonly experienced more expo- sure-years, no significant differences be- twe'en cases and controls were detected for males or females. Our data failed to s'how' the presence of a large airpolllution effect. Occupational exposures may be impor- tant risk factors for lung cancer (44-51)'. Prior studies of lung, cancer have demon- strated an increased risk for exposure to substances such as asbestos, arsenic, nickel, radon daughters, diagnostic radiation, and! fossil fuel combustion products (44). incon- sistent findings have been reported regard', ing,the importance of~occupational factors in adenocarcinoma incidence (9;1I0)• Int'his study, occupational risks for adenocarci- noma were examined' in two ways: 1) an a priori listing,ofl industries and' occupations in which workers are at high risk for lung cancer was used to code the work history data from each case or control; and 2) each subject was asked if he or she was ever exposed to a list of'known lung carcinogens I

32 BROWNSON ET AL- in the workplace. The exposures (indus trial, occupational, or pulmonary carcino- gens) were cumulatedi over the lifetirrle off the subject, ande t'he analysis was based on a classification of any or no previous er- posure. Onl}•. high-risk occupational'history showed a borderline significant risk for ad- enocarcinoma among males after adjust. ment for age and smoking history. Thee occupational risk was smaller aftermultiple adjustment for age, income, cigarette smok- ing, and passi ve smoking. The relations between workplaee exposures and adeno- carcinoma risk were unchanged regardless of whether the entire work history of the subjector onlj• the work history, 10 or more years prior to:dlagnosis was usedi A difference im risk for lung cancer by social cl'ass has been observed whether measured primarily by occupation, income, or education (3')'. Part of the socioeconomic differential in lung cancer, risk is due to smoking habits (52). In. th'is study, educa- tion level, and gross income were used as socioeconomic indicators. Income level' showedia stronger association with adeno- carcinoma risk after controlling for age and smoking, than: did education. Since colon cancer is correlatedl with socioeconomic status (I53')', it is possible that the use of colon cancer patients ascontnnobs in this: study magnified the observed inverse rela~ tion between adenocarcinonrla andi income level. No statistically significant inverse association was noted in adenocarcinoma risk with respect to education level„ al- though risk estimates were commonly lower at higher educational levels. The issue of' dietary vitamin A and'.lung cancer risk was not addressed in this study. Evidence is accumuliating that a deficiency in dietary'vitarnin A may result in a higher risk for lung cancer and that a higher intake of vitamin A andl its provitamirls has an apparent protective effect (28, 54L59): Diet may be less important in our study since recent data have suggested that'the inversee relation between vitamin A intake and lung, cancer is strong for squamous eelIa'nd small cell carcinomas but not for adenocarcinome (29, 58). This study used a higher proportion of' surrogate internRiews for cases (i68.61 per cent) than of'surrogate interviews for con, trols ('38'.9percent)! Several investigators have attempted to characterize the validity . of information obtainedlfrom surrogate in- terviews (60-62)i Pickle et al. (60) found that siblings were best able to describe ~ events: that occurred1 early in, life,, whereas spouses and offspring best recounted events during adult life. Other studies have found that bias may be introduced' because off inaccurate work histories given by next of kin, (61) and t'hat' spouses may provide ac- curate demographic information and a crude estimate of smoking, but details of employment' history and diet may be of lower validity (62). To address this prob- lem, we conductedlseparate analyses for all respondents and for primary respondents. The results were highly comparable and indicatedi that some conclusions based on all respondents may have been conservative since adenocarcinoma~ risk estimates for passive smoking were commonly higher among primary respondents. In light of'the changing histopathologic patterns of lung,cancer; the findings of this and other recent studies suggest the need to consider, the various lung, cancer celll types as different diseases. Future research should emphasize accurate histologic typ~ ing and the development of cell type- specific etiologic hypotheses. REFERENCES1. Mulvihill JJ: Host fecton in humanJung tumors: an eiample of' ecogenetics in oncologv. JNCI 1976i57:3-7:. 2: Selawry. OS, Hansen ~ HH. Respiratory tract can- cer. In: Holland JI•', Frei E, eds. Cancer medicine. Philadelphia: Lea & Febiger. 1982:1'709-4C 3. Fraumeni'JF Jr, Blot NW: Lung and pleura. In: Schottenfeld D; Fraumeni JF Jr6 eds, Cancer epi- demioiogy and prevention. Philadelphia: WB'. Saunders; 1982:564-82: 4. Kreyberg,L. Histologioal!lung cancer types:~ amor- phological and biological correlation. Acta Pathol Microbiol Scand Suppl 1962;i52:1-92: 5. Vincent RG, Pickren JR'„Lane W0.Y; et ali The chanp of 1681 6. Shimi¢ :. a). Epl' noma , Cancer Americ u res. I c. , 8. Young in I thee meni J?' tion. P1I 9. Vincent cinoma 70. 10: Sua.'ner and hisl study w Survey. 11. Executi• agemen fication 12. US Dep $tatistic pationa'' CJS CP( 11 Lerchen 14. Browns( relatuom lung,car script). 1& Mantel . analvsis ease. J.N 16:,Can J.. of signif, 17. %4iettine case•refl 197& TAS 18. Miettlne. J E~"pider. 19. Rbihmai w'itihI a p (US DH 20. Mantel freedom : cedure. J. 21. Armitage search. C 1971. 22. Cox DR. thuen, 1K .23. Engelma~ ~ Dizon 'A' ~ lev. CA: I 44'. "~ 24! Schlessel. I t conduct. Press. 19) 25 Ha on m . m ~ in the lJn f 26. HindsM` ~ Differenc J among ii in Hawaii

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