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N0''TI0 E This material may W ProtectEd by copy- E~, lan fTltl~ 17 U!S. Code;, AIMERICAN JOCRNAL OF EP16EhCI0LOGl- Vod. 125. No. 1CopyrtRht ,[ 196- b>,The Johns Hopkins Cnrversrty School of Hygiene and'Publtc Health Pr,nted in U S.A All rightr reun ed! RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG ROSS C. BROWwSOti,'' JOHN S. REIF,' THOMAS J, KEEFE,' STANLEY W. FERGUSON,' AND JANE A. PRlTZL' Brownson, R. C. (Dept of Microbiology and Environmental lieafth, Coiorado State U., Fort Collins, CO 60523); J. S. Reif; T. J. Keefa, S. W. Ferguson, and J. A- Pritzl. Risk factors for adenocarcinoma of the lung. Am J Ep+demktl 1987;125:25- 34. The relation between various risk factors and adenocarcinorna of the lung was evaluated in a case-control study. Subjects were selected from 111e Colorado Central Cancer Registry from 1,979-19a2 in the Denver metropolitan area. A total of 102 (50 maies and 52 females) adenocarcinoma case interviews and 131 (65 males and 66 females) controi' interviews were completed. The control group consisted of persons with cancers of the colon and bone marrow. The riskk estimates associated with cigarette smoking were significantty elevatad among maies (odds ratio (OR) = 4.49) and females (OR = 3.95) and were found to Increase significantly (p < 0:01) with increasing levels of cigarette smoking for both males and females. For adenourcinoma in females, the age- and smoking- adjusted odds ratios at different levels of passive smoke exposure foibwed 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 males and females. Anatysis restricted to nonsmoking females revealed a risk of adenocarcinorna of 1.68 (95% confidence interval (CI) = 0.39-2.97) for passive smoke exposure of four, or more hours per day. Neither sex showed significantly ekvatad risk for occupatyonal exposures, atthough males bordered on significana (OR = 2.23, 95% Cl = 0.97-5.12). The resutts suggest the need to develop cell type-specific etioiogic hypotheses. aic pollution; lung neoplasms; tobacco smoke pollution Recent evidence indicates that lung can- cer may encompass several morphologically and clinically distinct diseases (1, 2). In indusvrialized western nations, incidence rates are highest for squamous cell carci- noma, followed by adenocarcinoma (3, 4). The relation between squamous cell and small cell carcinomas and cigarette amok= ing is well-established, but the relation be- tween adenocarcinoma and cigarette smok- ing is less clear (3, 5, 6)'. Adenocarcinoma is the most frequently diagnosed form of lung 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- Received for publication March 28; 1986. ' Department of Microbiolog, and Environmental Health, Colorado State University;,Fort Collins. CO:, 'Colorado Department of'Health, Denver, CO': ' Reprint requests to Dr. Ross C. Brownson at Current address Cancer Epidemiology and Control Program; Division of EnviFonmental!Health and Ep- idemiolon Setvices, Missouri Department of Health; P. 0. Box 1268; Colitmbia„MO 65205. This study is part of a diasenution submitted to the Academic Faculty of Colorado Stet.e University, in Partial fulfillmenr of the requirementa for the degree of Doctor of Philosophy for Ross C. Bro.vnson: This work was supported in part by National Instir tuus of Health Biomedical~ Research Support Grant. 2 507 RR-Q5458!20 and a grant from the American Lung Association of Colbrado. The authors acknowledge the assistance of the Col- orado Central Cancer Registty„ Colorado Department of Health and the suffl of the Department of Micro- biologN and Environmental Health, Colorado State Universitv. Thev also thank Drs. RichatdF. Hamman, and'Mowafak D. Salman for their helpful comments.. 25

26 HROµ `SON ET AL ified'as adenocarcinoma amongmales com, pared with 37 per cent among females (8). The role of occupational exposures in the etiolbgy of' adenocarcinoma remains incon- clusive (,9„10). Recently;,a disproportionate increase in the incidence of adenocarci- noma has been noted in the United States (5). The changing histologic patterns of lung cancer incidence may be due to a change in diagnostic practices and classifi- cation or to increasing exposure to environ- mental carcinogens: The present investigation was designed to evaluate the role of smoking, passive smoking, occupation, community air pol- lution, and socioeconomic status in the etiology of adenocarcinoma of the lung. A case-control study was conducted to pro- vide additional data concerning the relation between exposure variables and this infre- quently studied and poorly understood form of lung cancer. MATERIALS AND METHODS Cases and controls were identified through the population-based Colorado Central Cancer Registry maintained by the Colorado Department of Health. For the years and counties included, reporting was essentially complete. All diagnoses were microscopically confirmed and' classified according to histologic type. Study partici- 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 seleetion A tota]' of 149 eligible cases of adenocar- cinoma (lnternational'ClassificatioR oj' Dis- eases(ICD) code 163) were identified 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 149 eligible cases, 311 could not be lbcated, 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 female cases were 64.9 and 66.3' years, re- spectively. Control selection Controls were chosen from persons in the Colorado Central Cancer Registry who had cancer of sites considered to be unrelated to cigarette smoking, Specifical'ly, persons with cancers of the colon ('1CD code 153), and bone marrow (ICD code 169) diagnosed! from 1979-1982 were chosen as controls and group-matched to adenocarcinoma cases according to age and sex. Matching was done at the group level so that the maximum number of cases and controls could be used' in the analyses. Only whites were included in the study, and at least one control was required for eaeh case within each age and sex stratum.. A total of 169 eligible controls were iden- tified. Of these, 24 could not be located, 13 refused to be interviewed, and one did not qualify. A total of 131 usable interviews (65 males and 66 females) were completed. Among controls, 80 were colon cancer pa- tients, and 51 were diagnosed with leuke- mia. The mean ages for male and female controls were 65.2' and 68:2 years, respec- tively. Data collection and analyses Epidemiologic 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 (68.6 per cent) than in the control' group (38.9 per cent)~ were completed by a relative or a friend! Among the 70 nonsurviving cases, 56 interviews were completed with a spouse, seven inter- views with a child, six with a 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. Educational level was characterized by the highest grade of formal education completed. Gross income was ascertained

RISh FACTORS FOR ADEtiOCARCINOMA OF THE LXKG 27 for the previous year, or in case of retirees, for the year prior to retirement. Smoking history was characterized for cigarettes, cigars, or pipefuls in terms of pack-years of exposure. Passive smoking data were ana)yzed as a dichotomous vari- able based on the smoking status of the patient's spouse and as a stratified variable basedon the hours per day that the subject was in the presence of persons who were smoking. Occupational data were analyzed accord- ing to industrial category, occupational'cat- egory, and a self-assessment of the expo~ sure of the respondent to known lung carcinogens in the workplace. Those indus- tries and' occupations knowm to be associ- ated with an elevated risk for lung cancer were coded and multiplie& by the number of years in each category to estimate expo- sure over time (11 13'). In addition, each subject was shown a list of 12 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, chro- mium, nickel, uranium ore, and mustard gas. Positive 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 each census tract (14). Total suspended particulate air pollution, which contains a benzene soluble haction; was used as an indicator of polycyclic hydrocarbon (e.g-, benzo[a]pyrene) levels. The total sus- pended particulate data were stratified into 10 air pollution exposure subgroups, and each census tract within the Denver area was assigned to a subgroup. The residence code consisted of years at each residence multiplied by the corresponding total sus- pended particulate exposure subgroup. In the first set of analyses, stratified con- tingency tables were constructed to adjust for age and smoking for the primary risk factors (15-I7). Odds ratios for each level of exposure were calculated by Miettinen's standardized rate technique which controls for confounding factors (18). All analyses included adjustment for age based on the categories 30-49, 50-59, 6049„ 70-79, and 80-99 years. An extension of the Mantel- Haenszel procedure was used to statJst!- callv evaluate overall trends in the propor- tion of cases according to level of exposure to risk factors (19, 20). Multiple logistic regression was used to obtaim maximum likelihood point and in- terval estimates of the odds ratio, as well as to control for the effects of various con- founding risk factors (21-23). 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 (coded as 11) or control (coded as 0)). Independent variables were entered in in- tervals, as recommended by Schlesselman (24). In order to id'entify the potentialcon- founding effect of the induction period of cancer, the exposure of each case or control to ambient air pollutants and industrial carcinogens was analyzed in two ways: 1) the entire residence and work history of each person was included, and 2) only ex- posures that took place 10 or more years prior to the time of diagnosis were consid- ered. The analyses were completed 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 female cases and controls. RESULTS For both males and females, the age- standardized odds ratios were found to in- crease significantly ( p< 0.01) with increas- 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) = 1.44-13.98)- Among females, the risk due to cigarette smoking was 3.95 (95 per cent Cl = 1.76- 8.80). For adenocarcinoma in females, the age- and smoking-adjusted odds ratios at

7 28 BROWNSON ET AL TABLE 1 Adlusted odds ratios (OR) and trend tests for aderwcarctnorna oJ thf lung according to leuel o/'cigarette use and' passtue smoke ezposure, metropolitan DenLer C0.' 19v9-1982' Maln Fem.irs Factor Voof caress tioof controls OR' No, of tafeb. tro: of controll OR Prior,cigarette use Ipeck•yearsl 0 4 19 1.00: 19' 41 1.00 1-39 14' 19 4.06 10' 13 1.68 -40 32 27 7:68' 23' 6 14.80 Trend1 p valiiel (<0:01) I<0,010 Passive smoke exposure I hours/dayl0-3 16 28 L00 29 53, 1.00 4-7 19' 24 1'.76 11 8' 3,06 >8 15 13 2.68 12 5 2:33' Trend' (p value) (0.46) (0.05) ' Odds ratio for prior cigaretu use adjusted for age; odds ratio for passive smoke exposure adjusted for age and'smoking. different levels of passive smoke exposure followed an overall trend, statistically sig- nif cant at the 0.05 level. The age- and smoking-adjusted odds ratio for passive smoke exposure (using 0-3 hours per day' as the reference level) was 1.01 (95 per cent C1 = 0.42-2.41) among males. The corre- sponding risk for females was 2.42 (95 per cent Cl: = 0.94-6.22). Odds ratios for pas- sive smoke exposure were also calcullated on a yes/no basis for the regular smoking history, of the patient's spouse. The aden- ocarcinoma risk from smoking by the spouse was not significant for males (odds ratio: (OR) = 1.40, 95 per cent CI = 0.66- 2.14) or females (OR = 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 im table 2. The lowest level' of each variable was used as the reference cat.egory. Both education and income showed' inverse trends with adenocarci- noma risk. Ameng males, annual, income approached statistical significance with an oddss ratio of 0.47 (95 per cent CI = 0.19- 1.19). No significant risks in the age- and smoking-adjusted odds ratios were shown for males or females according to their air pollution exposure history. No difference was noted regardless of whether the entire residence history of the patient or only the residence history 10 or more years prior to cancer diagnosis was used in the analysis. Of the occupational variables (industrial category, occupational category, or self-re- ported exposure to lung carcinogens); only occupational exposures for males bordered on significance (OR = 2:23, 95 per cent CI = 0.97-5.12). 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 adenocarcinoma risk after adjustment for other risk factors (OR = 0.85, 95 per cent Cl = 0.72-0.98). A positive association~ between pack-years of cigarette use and cancer risk was found for males, females, and both sexes combined. The 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 cent CI = 0.78- 3.03). The first-order interaction~ of pack- years of smoking and passive smoking was examined and found to be nonsignificant.

RISK FACTORS FOR ADENOCARCINOMA OF THE LUNG TABLE 2 ildlusted'odds nataos (OR) and 95% conJtderue intervals (CI) for adenocarcinoma oJ'the Lung according to education, tncome:,atr pollutwn restdpnce /ustor), and occupation, metropo6itan Denver, CO; 1979-1982 29 Malks FemalFs Factor n OR' 95TC1 n OR 95TC1 Education level (highest grade) 0-8 9-17 25 90 1.00 0;59 0.23-1.54 17 101 1.00 0:73 0.23'-2:31 Annual income (thousands of.doli'ars)* <S 15.000 25 1.00 3 7 1.001 tE15:000 86 0:47 0.19-1.19 78 0:71 0:28&1.85 Residence history (e:posure•years); 0-99 26 1.00 31 1.00: L100 89 1.66 0.66-4.19 87 1.51 0;58'-3:96 Occupation (ezposure•years)E' 0 76 1.00 112 1.W L1 39 2:23' 0.97-5:12' 6 0,59! 0.09-3.51 ' Odds ratio adjusted for age and smoking:. 1 Missing values. = The product of years at each residence aod the corresponding total suspended particulate exposure subgroup I Occupations at high risk for lung cancer multiplied by the number of years in each caugory. TABt:E 3 M'ultiple logistic regression odds ratios,(OR) and'95 % confidence intervals (CI) /orodenocarcinoma oJ,the lung according to income, occupation, ctgarette use, and patsiue smoke exposure, metropolitan Denver, CO, 1979-1982' F AlI Iaub7ecla Males FeIDa1K actor n OR` 95% C] n OR 95% CI n OR 95% CI Income 233 0:85 0.72-0.98 115 0.85 0.66-1.03 118 0.84 0.64-1.03 Occupation 233 1.00' 0.96-1.04 116 1.00 0.97-1.04 118 0.94 0.51-1.37 Pack-years 0 89 1.00! 23 1.00 66 1.00 1-39 56 2:62' 1.82-3.41 33 3.74 2.37-5:12' 23' 1.93 0.88-2.99 t40 88 5.81 5.01-6.61 59 5.42 4.13-6.71 29 9.58 8.31-10.86 Paasive smoking (hours/day) 0-3 126 1.00 44 1.00 62 1.00 4-7 62' 1.24 0.53-1.95 43 0.84 0.00-1.80 19 1.91 0.78-3.03 t8 45 1.37 0.54=2.20 28 1.17 0:100. 2.24 17 1.21 0.00-2>68 ' Odds ratio adjusted for age, potential confounding factors, and se:.ehen appropriate. Logistic regression was conducted by us- ing only primary respondents. These re- sults were similar to those found when all respondents were irlcluded Active smoking was the only risk factor significant at the 0':05 level based on the analysis of primary respondents. The odds ratios for pack-years of smoking were consistently smaller for Primary respondents, whereas those for Passive smoke exposure were larger when Primary respondents were analyzed. The risk of adenocarcinoma due to pas- sive smoke exposure was examined among female nonsmokers (table 4). Nineteen fe- male nonsmoking cases were identified (36.5 per cent). Due 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 CI' _ 0.39-2.97) was computed for the larger ex- posure category, after adjustment for age, income, and occupation.

30: BROWNSON ET AL TABLE 4: Multtple logistic regression odds ratios (OR) and 95 c eon/¢dence inrercaLi (CI) /oradenocarcinoma of the lung accordin{r to income. occupatuon. and passWe smoke exposure among /emale nonsmokers, metropolitan Dencer„C0, 1979-1982 Factor n, OR' 95% Cl lncomr 66 0.85 0.60-1.11. Occupation 66 0.004 Passive smoking (hours/day) 0-3 56 1.00 _4 10 1.68 0 39-2:97 * Odds ratio adjusted for age and' potential con, founding fectors.. D]SC4rSS10N Numerous case-control studies of' lung cancer have been conducted'over the past 30 years. Few;, however„have ezamined'the data according to histologic type. There appears to be a general consensus that the various histologic types of lung cancer have a multifactorialletiology which includes cig- arette smoking and occupational' and other environmental factors. Smoking is the major risk factor for most,, types of lung cancer.; In_ the TJniteti=Statesf it is estimated t2iat`eigarette'amokinjV-m* colZt~,ribute~,t~acw~least :8U_per, o~n~"`clif lung c~ncer in males and 40 per cent in females (25). Several reports have suggested that smoking may not be the major risk factor for adenocarcinoma in certain populations (26-28). Among white males, the age- standardized relative risk estimates for lung adenocarcinoma according to prior cigarette use have ranged from~ 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). The risk of smoking and adenocarci- noma for white females is usually between one and three, although the risk of lung cancer by histologic type has been studied less frequently among females than among males (10, 30-32'). The current stud'y found significant risk estimates for adenocarcinoma associated with smoking of 4.49 for males and 3.95 for females. The age-standardized risk esti- mates at different levels of cigarette use showed significant trends ( p< 0.01) for males and females, indicating that a dose:- response relation between smoking 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 Haenszel (15) and Miettinen (17), since logistic regression al- lowed for adjustment for multiple factors. The risk estimates for smoking and ade- nocarcinoma found in this study and the presence of a dose-response relation were consistent with other studies (29, 31, 33). The effect of involuntary inhalation of sidest~ream smoke (passive smoking) on lung cancer etiology is a controversial 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- spectively (36). A case-control study in Louisiana identified an increased~ risk for lung cancer among nonsmokers married to heavy smokers and for subjects whose mothers smoked (37). Garfinkel et al. (38) found an~ increased lung cancer risk for women whose husbands smoked 20 or more cigarettes per day. A recent study in Los Angeles found a slight increase in risk of adenocarcinoma among nonsmoking women exposed to passive smoke (39). Sev- eral other studies have failed to link passive smoke exposure to an increased risk of lung cancer (40-42). Prior studies that have evaluated passive smoking and lung cancer have differed in the index of passive smoke ezposure„cell type, and degree of histologic verification (34). In the present study, indexes of passive smoke exposure were obtained! in two ways: i

R15K FACTORS FOR ADENOCARC1tiOMA OF THE LUNG 1)'by ascertaining the regular smoking his- tory of'the spouse of each subject on a yes/ no basis; and 2) by 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. When the data were stratified according to level of passive smoke ezposure,, a stgtisticalh•y significant trend in the risk estimates was shown for females ( p= 0.05) after adjustment for age and cigarette smoking. However, after ad- justment by logistic regression for age, in- come, occupation, and cigarette smoking, no significant adenocarcinoma risk for pas- sive smoke exposure was found among fe- males. The relatively large proportion of non. smoking female cases /3&.5 per centl observed imthis study suggested the impor- tance of other, risk factors in adenocarci- noma etiology. A previous study found 19.5 per cent nonsmokers among female ade- nocarcinoma cases (39). Our study demon- strated a slightly elevated risk among fe- male nonsmokers due to passive smoke exposure, consistent with the findings of Wu et al. (39). Deficiencies in passive smoking data in recent studies include: 1) no commonly established inde: of side- stream smoke exposure; 2) a lack of data on other indoor air pollutants such as ra- don; 3) the existence of a probable differ- ential in accuracy of obtaining passive smoke exposure histories between living and deceased subjects; 4) a lack of evidence of changes in the peripheral bronchial'epi- thelium of nonsmokers exposed to side- stream smoke (40); and 5) insufficient numbers of nonsmoking lung cancer cases available for analyses. Despite these limi- tations, the relation between passive smok- ing and lung cancer deserves further inves- tigation. Although pollutants in the air have long been suspected to contribute to the etiologyy of lung cancer, epidemiolbgic evaluationn has been hampere&by difficulties in defin- ing and measuring air pollution and in eval- 31 uating the effects of confounding variables such as smoking, occupation, and popula- tion mobility (43). A census tract analysis of lung cancer data„total suspended partic- ulate air pollution, and median household income was reported previously for the Denver area (14)~ Our previous work showed a significant direct relation be- tween male lung cancer rates and total sus- pended particulate air pollution ( p< 0.02). However, for both males and females, me- dian household' income explained a larger percentage of the variation in lung, cancer rates than did: parciculate air, pollution.. The data on residence history of cases and controls were analvxed'to determine if differences in total suspended particulate air pollution exposure may have accounted for a portion of the adenocarcinoma inci- dence. There were only slight differences between cases and controls in mean or me- dian years of residence in metropolitan Denver. Residence history was defined in terms of exposure-years (years 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- tween cases and controls were detected for males or females. Our data failed to show the presence of a large air pollution 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, an& fossil fuel combustion products (44). Incon- sistent f ndings have been reported regard- ing the importance of occupational factors in adenocarcinoma incidence (9, 10). In this study, occupational risks for adenocarci- noma were examined in two ways: 1) an a priori' listing of 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 controlt and 2) each subject was aske& if he or she was ever exposed to a list of known lung carcinogens

32 BROWNSON ET AL. in the workplace. The exposures (indus- trial, occupational, or pulmonary carcino- gens) were cumulated over the lifetime of the subject, and the analysis was based on a classification of any or no previous ex- posure. Only high-risk occupational history showed a borderline significant risk for ad- enocarcinoma among males after adjust- ment for age and~ smoking history. The occupational risk was smaller after multiple adjustment for age, income, cigarette smok- ing, and passive smoking. The relations between workplace exposures and adeno- carcinoma risk were unchanged' regardlesss of whether the entire work history of the subject or only the work history 10 or more years prior to diagnosis was used. A difference in risk for lung cancer by sociat class 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 this study, educa- tion level and gross income were used as socioeconomic indicators. Income leveI' showed a stronger association with adeno- carcinoma risk after controlling for age and smoking than did education. Since colon cancer is correlated with socioeconomic status (53), it is possible that the use of colon cancer patients as controls in this study magnified the observed inverse rela- tion between adenocarcinoma and 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 accumulating that a deficiency in dietary vitamin A may result in a higher risk for lung cancer and that a higher intake of vitamin A and its provitamins has an apparent protective effect (28, 54-59). Diet may be less important in our study since recent data have suggested that the inverse relation between vitamin A intake and lung cancer is strong for squamous cell and small cell carcinomas but not for ad'enocarcinoma (29, 58). This study use& a higher proportion of surrogate interviews for cases (68;6 per cent) than of surrogate interviews f'or con- trols (38'.9 per cent). Several investigators have attempted to characterize the validity of information obtained from surrogate in- terviews (60-62). Pickle et al. (60) found that siblings were best able to describe events that occurred early in life, whereas spouses and offspring best recounted events during adult life. Other studies have found that bias may be introduced because of inaccurate work histories given by next of kin (61) and that 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 conducted separate analyses for all'l respondents and for primary respondents. The results were highly comparable and indicated 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 cell types as different diseases. Future research should emphasize accurate histologic typ- ing and the development of celli type- specific etiologic hypotheses, REFERENCES 1. Mulvihill JJ. Host factors in human lung tumors: sn e:ample of ecogenetics in oncoiogy,. JNC1 1976:57:3-7. 2. Selawry OS. Hanun HH. Respiratorv tract can- cer. In: Holland'JF. Frei E, eds. Cancer medicine. Philadelphia: Lee & Febiger, 1982:1709-44. 3. Fnumeni JF Jr. Blot WJ. Lung and pleura. Im. Schotunfeld'D. Fr.umeni JF Jr.edt. Cancer epi- demiology and~ prevention. Philadelphia: w"8' Saunde rs. 1982:564-82. 4. Kreyberg L. Hiutological lung cancer typer amor- phological and bioloQical'correl.tion. Acu Pathol Microbiol Scand Suppl 1962;152c1-92. 5. Vincent RG. Pickren JW. Lane WW, et al. The

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