Tobacco Documents Online

Environmental Tobacco Smoke and Lung Cancer irf Nonsmoking Women A Multicenter Study Elizabeth T. H. Fontham, DrPH; Pelayo Correa, MD; Peggy Reynolds, PhD; Anna Wu-Williams, PhD; Patricia A. Buffler, PhD; Raymond S. Greenberg, MD, PhD; Vivien W. Chen, PhD; Toni Alterman, PhD; Peggy Boyd, PhD; Donald F. Austin, MD; Jonathan Liff, PhD Objective.-To determine the relative risk (RR) of lung cancer in lifetime never smokers associated with environmental tobacco smoke (ETS) exposure. Design.-Multicenter population-based case-control study. Setting: Five metropolitan areas in the United States: Atlanta, Ga, Houston, Tex, Los Angeles, Calif, New Orleans, La, and the San Francisco Bay Area, Calif. Patients or Other Participants.-Female lifetime never smokers: 653 cases with histologically confirmed lung cancerand 1253 controls selected by random digit dialing and random sampling from the Health Care Financing Administration files ' for women aged 65 years and older. " Main Outcome Measure.-The RR of lung cancer, estimated by adjusted odds ratio (OR) with 95% confidence interval (Cl), associated with ETS exposure. Results.-Tobacco use by spouse(s) was associated with a 30% excess risk of lung cancerr all types of primary lung carcinoma (adjusted OR=1.29; P<.05), pul- monary adenocarcinoma (adjusted OR=1.28; P<.05), and other primary carcino- mas of the lung (adjusted OR=1.37; P=.18). An increasing RR of lung cancer was observed with increasing pack-years of spousal ETS exposure (trend P=.03), such that an 80% excess risk of lung cancer was observed for subjects with 80 or more pack-years of exposure from a spouse (adjusted OR=1.79; 95% C1=0.99 to 3.25). The excess risk of lung cancer among women ever exposed to ETS during adult life in the household was 24%; in the workplace, 39%; and in social settings, 50%. When these sources were considered jointly, an increasing risk of lung cancer with increasing duration of exposure was observed (trend P=.001). At the highest level of exposure, there was a 75% increased risk. No significant association was found between exposure during childhood to household ETS exposure from mother, fa- ther, or other household members; however, women who were exposed during childhood had higher RRs associated with adult-life ETS exposures than women with no childhood exposure. At the highest level of adult smoke-years of exposure, the ORs for women with and without childhood exposures were 3.25 (95% Cl, 2.42 to 7.46) and 1.77 (95% Cl, 0.98 to 3.19), respectively. Conclusion: Exposure to ETS during adult life increases risk of lung cancer in lifetime nonsmokers. (JAMA. 1994;271:1752-1759) From the Department of Pathology (Drs Fontham, Correa, and Chen), Louisiana State University Medical Center, New Orleans; the California Department of Health Services, Emeryville (Drs Reynolds and Austin); the University of Southern California School of Medi- cine, Los Angeles (Dr Wu-Williams); the University of Texas Health Science Center, School of Public Health, Houston (Drs Buffler and Alterman); the Emory Univer- sity School of Public Health, Atlanta, Ga (Drs Green- berg and laff); and the California Public Health Foun- dation, Emeryville (Dr Boyd). Dr Buffler is now with the University of California-Berkeley, School of Public Health. Dr Alterman is now with the National Institute for Occupationat Safety and Health, Cincinnati, Ohio. Dr Austin is now with the Oregon Health Division, Portland. Reprint requests to Louisiana State University Medi- cal Center, Department of Pathology, 1901 Perdido St, New Orleans, LA 70112-1393 (Dr Fontham). IN JANUARY 1993, the US Environ- mental Protection Agency (EPA) issued a report on the respiratory health effects of passive smoking in which it concluded that environmental tobacco smoke (ETS) is a human lung carcinogen, responsible for approximately 30001ung cancer deaths per year in US nonsmokers.' A total of 30 epidemiologic studies conducted world- wide were included in the EPA risk as- sessment, including 11 studies conducted in the United States?--3t Of the US stud- ies, the report of findings-from the first 3 years of this multicenter study2 contrib- uted the greatest individual study weight ~ to the US summary relative risk (RR) estimates for lung cancer:1.19 (95% con- fidence interval [CI], 1.04 to 1.35) associ- ated with "ever exposed" to spousal ETS and 1.38 (95% CI, 1.13 to 1.70) for the highest level of spousal ETS exposure. The weight accorded this study in the EPA report reflected the large number of lifetime nonsmokers with lung cancer (n=420), as well as the study design used 'in this case-control study. This study was designed specifically to evaluate the role of ETS exposure in the etiology of lung cancer in lifetime nonsmokers. Two large US studies have been pub- lished since the preparation of the EPA report.IX Because these studies are simi- lar in size and scope to our first report, their findings would have had a similar impact on the summary US risk esti- mates. Brownson et al-12 observed no in- creased risk in the ever-exposed category for spousal ETS (adjusted odds ratio [OR]=1.0; 95% CI, 0.8 to 1.2); however, the CI includes 1.19, the US summary point estimate. The highest exposure cat- egory (greater than 40 pack years) in the study by Brownson et al yielded an RR estimate of 1.3 (95% CI,1.0 to,1.7), quite similar to the US "high-exposure" sum- niAry estimate of 1.38. In the second study by Stockwell et al,11 the RR estimates are among the highest reported for US studies: 1.6 (95% CI, 0.8 to 3.0) for ever exposed and 2.4 (95% CI, 1.1 to 5.3) for 40 or more smoke-years in adulthood. - This report extends the findings of this multicenter study on completion of 2 additional years of subject accrual. METHODS The methods and procedures followed in this study have been previously de- scribed in detail? The study was a popu- lation-based case-control study oflungcan- cer in women who have never used any tobacco product. Eligible cases included microscopically confirmed primary carci- noma of the lung (Inf,erizational Classi- ficalion ofDiseases, Ninth Revision [ICD- 9], code 162) that were diagnosed between December 1,1986,and November30,1988, 1752 JAMA, June 8, 1994-Vol 271, No. 22 Tobacco Smoke and Lung Cancer-Fontham et al

among female residents of metropolitan Atlanta, Ga (Clayton, Cobb, DeKa1b, Ful- ton, and Gwinnett counties), and Hous- ton, Tex (Galveston and Harris counties), and during 2 additional years, 1989 and 1990, among residents of New Orleans, La (Jefferson, Orleans, and St Bernard parishes), Los Angeles, Calif (Los Ange- les County), and the San Francisco Bay Area, Calif (Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara counties). Additional eligibil- ity criteria included age at diagnosis (20 to 79 years), language (English, Spanish, or Chinese), history of previous cancer (none), and lifetime tobacco use (fewer than 100 cigarettes smoked and no use of any other form of tobacco for more than 6 months). This project was approved by all appropriate institutional review boards. A population-based control group was selected by random digit dialing and supplemented by random sampling from the Health Care Financing Administra- tion files for women 65 years and older. Controls were frequency matched to cases on race and age (younger than 50 years, 50 to 59 years, 60 to 69 years, and 70 to 79 years) in a 2:1 ratio of controls to cases and met the same residence, language, and tobacco use criteriaas cases. The popu- lation control group was selected as the primary comparison group in case-con- trol analyses. A second control group was selected during the first 3 years of the study (December 1, 1985, to November 30,1988) from women aged 20 to 79 years with a diagnosis of primary carcinoma of the colon (ICD-9, code 153) who met the same residence, language, and tobacco use criteria as cases and were frequency matched to the case series by 10-year age group and race. This control group was selected as a means of assessing recall or response bias associated with arecent di- agnosis of cancer or with being ill. In the report based on the first 3 years of case accrual, the results were consistent for case-control comparisons using each con- trol group? This component of the study was not extended into the final 2 years. Lifetime smoking status was deter- mined in a three-tiered approach. Infor- mation was obtained on each potential study subject's personal use of tobacco, fust from the medical record of the can- cer cases, then from the patient's per- sonal physician, and finally from the po- tential study subject or her next of kin for those patients whose medical records and physicians did not indicate a history of smoking. The telephone screening pro- cedure (tier 3) was also used to determine lifetime tobacco use of the population con- trol group. At the interview, the tobacco use screening questions were repeated to confirm each study subject's reported status as a lifetime nonuser of tobacco. Of the 17 447 potential cases ascertained in the five study centers, 800 were found to meet all eligibility criteria. In-person intervieWs were completed for 665 (83%) of 800 incident cases and 1278 (70%) of 1826 population controls. An interview was solicited from the next of kin of cases who were deceased or were too ill to par- ticipate in an interview. Information for 241 lung cancer cases (36%) was obtained from next-of-kin respondents. At interview, a urine sample was col- lected from all consenting study subjects who were able to provide such a sample. Urinary cotinine and creatinine were de- termined and the ratio used as an indi- cator of current smoking status. The re- quest for the sample was not made until the interview. Specimens were stored at -20°C until analysis at the American Health Foundation, Valhalla, NY. Cotinine was quantitated by radioim- munoassay using the method of Haley et al14 with a modification of the antibody of Langone et alV' Cotinine concentrations were adjusted fdr urine flow based on creatinine values by determining the nanograms of cotinine per milligrams of creatinine. Creatinine was determined by spectrophotometry using the Kodak Ek- tachem 400 Clinical Chemistry Analyzer (Kodak, Rochester, NY). Urine samples were analyzed for 356 (53.5%) of 665 cases and 1064 (83.3%) of 1278 controls. The difference in the pro- portions of cases and controls is attrib- utable to deceased cases. A high propor- tion of living study subjects were able and willing to provide a urine sample, and the proportions were similar for cases (81.1%) and controls (83.3%) despite dif- ferences in health status. As in the origi- nal report, subjects in the case and con- trol groups whose cotininelcreatinine con- centration exceeded 100 ng/mg were ex- cluded from the study to eliminate persons likely to be active smokers? Two (0.6%) of 356 cases and 25 (2.3%) of 1064 controls had cotinine/creatinine concentrations of 100 ng/mg or higher. Although no opti- mum concentration has been established as a cut point for distinguishing true non- smokers from smokers in studies that are restricted to women and include subjects with cancer, a concentration of 50 ng/mg or lower has been used as the eligibility criterion in a large study of healthy, free- living subjects,' _and others have been suggested.'," In high-exposure settings, urinary cotinine: in nonsmokers has reached a conceritration of 55 ng/mg of cotinine%reatinine.',40 In this study, nine cases (2.5%) and 29 controls (2.7%) had urinary concentrations of 55 to 99 ng/mg. Analyses of ETS-related risk estimates were also conducted using a cut point of 55 ng/mg of cotinine/creatinine as an ex- clusion criterion to evaluate the possibil- ity that the study findings were biased as a result of inclusion of study subjects with ' borderline concentrations (55 to 99 ng( mg) of cotinine%reatinine. Representative diagnostic specimen slides for each case were requested from the hospital for review by one pathologist specializing. in pulmonary pathology. A total of 562 (85%) of 663 potential cases had diagnostic material available for re- view, and 552 (98%) of the reviewed cases were confirmed as primary bronchogenic carcinoma. After exclusion of the 10 cases that had review diagnoses inconsistent with primar~ bronchogenic carcinoma, the final interviewed case series included 653 lung cancer cases: 497 adenocarcinomas (76.1%); 74Iarge-cell carcinomas (11.3%); 40 squamous cell carcinomas (6.1%); 24 small-cell carcinomas (3.7%); and 18 other primary lung carcinomas (2.8%). The 101 cases with diagnostic slides that were un- available for review were classified ac- cording to the original hospital and tumor registry diagnosis. The distribution by cell type was similar for the reviewed and nonreviewed cases except for a higher proportion of cases in the "other primary lung carcinomas" category among non- reviewed cases. Analyses of ETS-related risk estimates were also conducted ex- cluding cases that did not undergo inde- pendent review to evaluate consistency of the findings. In-person interviews followed an ex- tensive structured questionnaire designed to obtain information on household, oc- cupational, and other exposures to ETS during each study subject's lifetime, as well as other exposures associated with lung cancer. Exposure to ETS was ex- amined by source during childhood (fa- ther, mother, and other household mem- bers who lived in the home for at least 6 months) and during adult life (spouse, other household members, occupational, and social exposures). Childhood included the years from birth through age 18 years. Exposures from parents after that time were classified as other household mem- bers during adult life. Dichotomous ETS exposure (ever or never) was examined by source and type of tobacco. Pack-years of cigarette smoke exposure from spouse were calculated by multiplying the num- ber of packs smoked per day by the num ber of years the spouse smoked cigarettes while living with the study subject. Du- ration of exposure by source was mea- sured in years. Years of exposure in oc- cupational settings represent the sum of years of employment in each job in which persons were reported to have smoked around the study subject. Years of ex- posure from individual sources were ex- amined, and a suinmary measure (smoke- years) of exposure during childhood and adult life was calculated. Smoke-years JAMA, June 8, 1994-Voi 271, No. 22 Tobacco Smoke and Lung Cancer-Fontham et al 1753

i Table 1.-Distribution of Lung Cancer Cases and Controls According to Selected Demographic Characteristics Characteristic Lung Cancer Cases, No. (%) Population Controls, No. (%) Study center Atlanta, Ga 48(7.0) 76(6.1) Houston, Tex 41(6.3) 42(3.4) Los Angeles, Calif 264 (40.4) 512 (40.9) New Orleans, La 34(5.2) 57(4.5) San Francisco Bay Area, Calif 268 (41.0) 568 (45.2) Respondent. Study subject 412 (63.1) 1253 (100.0) Next of kin 241 (36.9) Age, y <50 70 (10.7) 165 (13.1) 50-59 110 (18.9) 154 (12.3) 60-69 213 (32.6) 398 (31.8) 70-79 260 (39.8) 536 (42.8) Racelethnic group White 382 (58.5) 765 (61.1) Black 60 (9.2) 171 (13.7) Hispanic 68 (10.4) 99 (7.9) Asian • 125 (19.1) 184 (14.7) Other 17(2.6) 23 (1.8) Unknown or refused to answer 1(0.2) 11(0.9) Annual income, $ <8000 103 (15.8) 144 (11.5) . 8000-12 999 88 (13.5) 162 (12.9) 13 000-19 999 84 (12.9) 168 (13.4) 20 000-34 999 114 (17.5) 250 (19.9) 35 000-49 999 63(9.7) 136 (10.9) Z'50 000 94 (14.4) 216 (17.2) Unknown or refused to answer 107 (18.4) 177 (14.1) Education <High school 216 (33.1) 266 (21.2) High school 217 (33.2) 393 (31.4) Some college 99 (15.2) 315 (25.1) College 62(9.5) 154 (12.3) Graduate 46(7.0) 116 (9.3) Unknown 13(2.0) 9(0.7) represent the sum of reported years of exposure to ETS from each individual source in childhood (father, mother, and other household members) or in adult life (spouse, other household members, occu- pational, and social). The variable does not represent years per se because these exposures may occur concurrently. All lung cancer cases combined were compared with the controls, as were cases of adenocarcinoma of the lung (76.1% of the total cases) and other histological types combined (squamous cell carcinoma, small-cell carcinoma, large-cell carcinoma, and other types, 23.9% of the total cases). In addition, analyses restricted to self- respondents were compared with those that also included proxy respondents. Unconditional logistic regression analyses were used to estimate the asso- ciations by summary adjusted ORs, 95% CIs, and test statistics 41,42 The ORs were adjusted for design or sampling variables (age, race, and study center), as well as education, family history of lung cancer, employment in potentially high-risk occu- pations for 5 or more years (production jobs in painting, mining, textile, insula- tion, shipyard, cement, roofing, smelting, radiation, petroleum, hairdressing, and printing industries), dietary cholesterol intake, and an index ofdietary antioxidant 1754 JAMA, June 8, 1994-Vol 271, No. 22 Table 2.-Association Between Smoking Status of Spouse and Lung Cancer Risk in Nonsmoking Women* Spouse Ever Smoked Tobacco, by Type ~ Cases, No. Exposed/ No. of Casest Controls, No. Exposed/ No. of Controls Crude OR (95% CI) Adjusted OR • (95% CI) All lung carcinomas Any type of tobacco 433/651 766l1253 1.26 (1.04-1.54)t 1.29 (1.04-1.60)t Cigarettes 386/648 691/1253 1.20 (0.99-1.45) 1.18 (0.96-1.46) Cigars 85/641 138/1253 1.24 (0.93-1.65) 1.25 (0.92-1.71) Pipes 86/640 158/1253 1.08 (0.81-1.43) 1.19 (0.88-1.60) Adenocarcinoma /(ny type of tobacco 334/496 766/1253 1.31 (1.05-1.63)t 1.28 (1.01-1.62)t Cigarettes 298/493 691/1253 1.24 (1.01-1.54)t 1.18 (0.94-1.49) Cigars 58/489 138/1253 1.09 (0.79-1.51) 1.08 (0.76-1.53) Pipes 62/488 158/1253 1.01 (0.74-1.38) 1.04 (0.75-1.46) Other histological types Any type of tobacco 99/155 766/1253 1 1.12 (0.80-1.59) 1.37 (0.92-2.03) Cigarettes 88/155 691/1253 1.07 (0.76-1.50) 1.20 (0.83-1.75) Cigars 27/152 138/1253 1.75 (1.11-2.74) 1.88 (1.14-3.08)t Pipes 24/152 158/1253 1.30 (0.82-2.07) 1.79 (1.08-2.95)t *Adjusted for age; race (white, black, Asian, and Hispanic or other); study area (Los Angeles, Calif, San Francisco Bay Area, Calif, South); education (less than high school, high school graduate, some college or more); fruits, vegetables, and supplemental vitamin index; dietary cholesterol; family history of lung cancer and employment in high-risk occupations. OR Indicates odds ratio; CI, confidence Interval. tThe number of cases and controls with responses to each question. $P<.05. Table 3.-Association Between Risk of Lung Cancer and Pack-Years of Environmental Tobacco Smoke Exposure From Spouse(s) Among Nonsmoking Womenr~" ` ` Pack-Years of Crude OR Adjusted OR Exposure Cases Controls (95% CI) All lung carcinomas (95% CI) 0 267 562 1.00 ... 1.00 ... s15.0 146 300 1.02 (0.80-1.31) 1.08 (0.83-1.39) 15.1-39.9 92 190 1.02 (0.76-1.36) 1.04 (0.76-1.42) 40.0-79.9 80 126 1.34 (0.98-1.83) 1.36 (0.97-1.91) e:80.0 24 27 1.87 (1.06-3.31)t 1.79 (0.993.25) Trend P=.03 Trend P=.03 Adenocarcinoma 0 199 562 1.00 ... 1.00 ... s15.0 109 300 1.03 (0.78-1.35) 1.06 (0.80-1.40) 15.1-39.9 70 190 1.04 (0.76-1.43) 1.02 (0.72-1.42) 40.0-79.9 65 126 1.48 (1.04-2.05)t 1.41 (0.98-2.03) a 80.0 18 27 1.88 (1.02-3.49)t 1.73 (0.91 -3.31) Trend P-.01 Trend P-.05 , Other histological types Ct G7 0 68 562 1.00 1.00 Cl'+ s15.0 37 300 1.02 (0.67-1.56) 1.18 (0.75-1.87) =F.a CO 15.1-39.9 22 190 0.96 (0.58-1.59) 1.12 (0.64-1.96) CJ1 40.0-79.9 15 126 0.98 (0.55-1.78) 1.16 (0.62-2.19) ~_& 10 '80.0 6 27 1.84 (0.73-4.61) 1.97 (0.75-5.19) Trend P-.64 Trend P=.29 *Adjusted forage; race; study area; education; fruits, vegetables, and supplemental vitamin index; dietarychoiesterol; family history of lung cancer and employment in high-risk occupations. OR indicates odds ratio; Cl, confidence interval. tP<.05. consumption based on weekly consump- tion of fruits and vegetables and supple- mental vitamin use at least four times per week. No significant interactions were observed. Previous lung disease and di- etary beta carotene, vitamin C; and vita- min E were siso evaluated, but were not included in the final models because they did not confound the ETS findings and did not contribute further to the association between ETS and lung cancer. RESULTS - ' The distribution of cases and controls by study center, respondent status; age, racial/ethnic group, annual household in- come, and highest level of education com- pleted is shown in Table 1. Approximately 40% of the lung cancer cases and controls were residents of Los Angeles and a simi- lar proportion were from the San Fran- cisco Bay Area, the two largest study centers in which case and population con- trol ascertainment encompassed a 5-year period. The three smaller study centers in the southern United States (Atlanta, Houston, and New Orleans) contributed the remaining study subjects. The case-control series had a relatively large proportion of cases aged 60 to 79 Tobacco Smoke and Lung Cancer-Fontham et al

, years (72%) with a similar proportion of controls in this age group. As noted pre- viously,E the age distribution in this se- ries of female lifetime never smokers with lung cancer is older than all female lung cancer cases in the Surveillance, Epide- miology, and End Results (SEER) Pro- gram, 1973 through 198M The largest proportions of lung cancer cases (58.5°k) and controls (61.1%) were white. A larger proportion of cases were self-identified as Asian American and His- panic and a smaller proportion as African American (blacks) compared with con- trols. Approximately 42% of cases and 38% of controls reported an annual house- hold income of less than $20 000 per year. Compared with controls, lung cancer cases tended to have a lower level of education: 66.3% of cases and 52.6% of controls had no more than a high school education. Table 2 displays the estimated RRs of lung cancer associated with ever living with a spouse who smoked by type of tobacco. A 30% excess risk associated with tobacco use by:spouse(s) was ob- served for all histopathologic types of lung cancer combined (adjusted OR=1.29; P<.05), for adenocarcinoma of the lung (adjusted OR=1.28; P<.05), and for pri- mary lung carcinomas other than adeno- carcinoma (adjusted OR=1.37; P=.18). The only individual types of tobacco as- sociated with significantly elevated risks of lung cancer are cigar- and pipe-smoke exposure for bronchogenic carcinomas other than adenocarcinoma: cigars, ad- justed OR=1.88 and P=.01; pipe, adjusted OR=1.79 and P=.02. The estimated RRs of lung cancer as- sociated with pack-years of exposure to spousal ETS are presented in Table 3. Increasing risk of lung, cancer with in- creasing pack-years of spousal ETS ex- posure is observed for all lung carcino- mas combined and for the two histopatho- logic subgroups. The risk estimates are similar within the histopathologic sub- groups; however, the trend is significant only for all lung cancers combined (P=.03) and pulmonary adenocarcinoma (P<.05). When the analysis was restricted to self- respondents only, similar estimates of risk of lung cancer were observed with a trend of increasing risk of lung cancer at increasing levels of exposure (P=.03). Exposure to ETS during childhood and adult life from multiple sources was evalu- ated. The risks of lung cancer associated with household ETS exposures during childhood as a result of father, mother, or other household member smoking are shown in Table 4. None of the RR esti- mates signifcantlydiffers from unity. The association of cumulative years of house- hold exposure to ETS during childhood with lung cancerriskwas evaluated (Table 5). No increased risk was associated with Table 4.-Association Between Risk of Lung Cancer and Childhood Exposure to Tobacco Smoke Among Nonsmoking Women* ti Ever Smoked Tobacco Cases, No. Exposed/ No. of Cases Controls, No. Exposed! No. of Controls Crude OR (95% CI) Adjusted OR (95% Cl) All lung carcinomas Father 304/603 669/1225 0.85 (0.70-1.03) 0.83 (0.67-1.02) Mother 76/624 161/1240 ' 0.93 (0.69-1.24) 0.86 (0.62-1.18) Other household members 131/617 269/1253 0.99 (0.78-1.25) 1.03 (0.80-1.32) Any household member 377/606 808/1238 0.88 (0.72-1.07) 0.89 (0.72-1.10) Adenocarcinoma Father 238/466 669/1225 0.87 (0.70-1.07) 0.82 (0.66-1.04) Mother 60/480 161/1240 0.96 (0.70-1.32) 0.92 (0.65-1.29) Other household members 98/471 269/1253 0.96 (0.74-1.25) 0.99 (0.75-1.30) Any household member 2901469 808/1238 0.86 (0.69-1.07) 0.85 (0.68-1.08) Other histological types Father 66/137 66911225 ' - 0.77 (0.54-1.10) 0.82 (0.56-1.20) Mother 16/144 161/1240 0.84 (0.49-1.45) 0.61 (0.32-1.16) Other household members 33/146 269/1253 1.07 (0.71-1.61) 1.19 (0.77-1.85) Any household member 87/137 808/1238 0.93 (0.64-1.34) 1.01 (0.68-1.51) *Adjusted for age; race; study area; education; fruits, vegetables, and supplemental vitamin index; dietary cholesterol; family history of lung cancer; and employment in high-risk occupations. OR indicates odds ratio; Cl, confidence interval. Table 5.-Association Between Risk of Lung Cancer and Childhood Smoke-Years of Exposure Among Nonsmoking Women (Self-respondents Only)* Childhood Smoke-Years of Household Exposure Cases Controls Crude OR (95% Cl) Adjusted OR (95% Cl) All lung carcinomas 0 148 444 1.00 ... 1.00 1-17 95 291 0.98 (0.73-1.32) 0.99 (0.73-1.35) 2:18 146 485 0.90 (0.70-1.17) Trend P-.58 0.88 (0.67-1.16) Trend F=.36 Adenocarcinoma 0 120 444 1.00 ... 1.00 ... 1-17 73 291 0.93 (0.67-1.29) 0.92 (0.65-1.29) a:18 123 485 0.94 (0.71-1.25) Trend P=.68 0.89 (0.68-1.19) Trend P6.43 Other histological types 0 28 444 1.00 ... 1.00 ... 1-17 22 291 1.20 (0.67-2.14) 1.32 (0.72-2.41) ~:18 23 485 0.75 (0.43-1.33) 0.85 (0.47-1.54) Trend P=.33 Trend P=.58 *Adjusted for age; race; study area; education; fruits, vegetables, and supplemental vitamin index; dietary cholesterol; family history of lung cancer and employment in high-risk occupations. OR indicates odds ratio; Cl, confidence interval. increasing duration of smoke exposure during childhood. Childhood smoke-years were unknown fora large proportion (20%) of the interviews with proxy respondents and for 5% of the interviews conducted with the study subject. For those inter- views with data available to calculate smoke-years, 54% of proxy respondent interviews vs 38% of direct study subject interviews reported no exposure during childhood. The data presented, therefore, are for analyses restricted to self-respon- dents. No differences were observed by pathology review status; dietary choles- terol intake; level of the fruits, vegetables, and supplemental vitamin use index; age group; or educational attainment. Black study subjects had a twofold elevation in risk in the highest exposure category, and Asians showed twofold reductien in risk at this level; however, these two point estimates did not significantly differ. Re- stricting years of ETS exposure during childhood to those from the motheryielded similar nonsignificant trends. Table 6 presents the estimated RRs associated with adult ETS exposure (ever exposed and years of exposure by indi- vidual sources during adult life). Eleva- tions in risk are associated with increas- ing duration of exposure at home (trend P=.11), on the job (trend P=.001), and in social settings (trend P=.002). The in- creased risk of lung cancer among women ever exposed to ETS during adult life in the household is 24%; in occupational set- tings, 39%; and in social settings, 50%. The pattern of response is similar in the two histologic subgroups; however, the tests of trend are statistically significant only in the largest subgroup, pulmonary adenocarcinoma. ' As shown in Table 7, when all sources of exposure to ETS during adult life are l>0 JAMA, June 8, 1994-Vol 271, No. 22 Tobacco Smoke and Lung Cancer--Fontham et al 1755

Table 6.-Association Between Risk of Lung Cancer and Adult Exposures to Cigarette Smoke Among Nonsmoking Women* Exposure by Source, y Cases, Controls, No. Exposed/ No. ExposedJ ~ No. of Cases No. of Controls All Lung Carcinomas Crude OR Adjusted OR (95% Cl) (95% Cl) Household exposure (spouse and other) Ever exposed 509/653 941/1253 1.17 (0.94-1.47) 1.23 (0.96-1.57) 0 153 321 1.00 1.00 1-15 184 393 0.98 (0.76-1.27) 1.10 (0.83-1.46) 16-30 143 244 1.23 (0.93-1.63) 1.33 (0.98-1.80) >30 173 295 1.23 (0.94-1.61) 1.23 (0.91-1.66) Adenocarcinoma Trend P=.05 Trend P=.11 Ever exposed 389/497 941/1253 1.19 (0.93-1.53) 1.16 (0.89-1.52) 0 115 321 1.00 1.00 1-15 139 393 0.99 (0.74-1.32) 1.04 (0.77-1.42) 16-30 108 244 1.24 (0.91-1.69) 1.26 (0.90-1.76) >30 135 295 1.28 (0.95-1.72) 1.20 (0.87-1.66) Other Histological Types Trend F'=.04 Trend P=.17 Ever exposed 120/156 941/1253 1.11 (0.75-1.64) 1.51 (0.95-2.39) 0 38 321 1.00 1.00 1-15 45 393 0.97 (0.61-1.53) 1.39 (0.83-2.32) 16-30 35 244 1.21 (0.74-1.98) 1.59 (0.92-2.77) >30 38 295 1.09 (0.68-1.75) 1.31 (0.76-2.26) All Lung Carcinomas Trend FL.53 Trend P=.32 Occupational exposure Ever exposed 385/609 756/1247 1.12 (0.91-1.36) 1.39 (1.11-1.74)$ 0 224 491 1.00 1.00 1-15 213 450 1.04 (0.83-1.30) 1.30 (1.01-1.67)t 16-30 118 223 1.16 (0.88-1.53) 1.40 (1.04-1.88)t >30 54 83 1.43 (0.98-2.08) 1.86 (1.24-2.78)$ Adenocarcinoma Trend F-.06 Trend P=.001 Ever exposed 300/465 756/1247 1.18 (0.95-1.47) 1.46 (1.14-1.86)# 0 165 491 1.00 1.00 1-15 167 450 1.10 (0.86-1.42) 1.35 (1.02=1.79)t 16-30 93 223 1.24 (0.92-1.67) 1.49 (1.08-2.05)t >30 40 83 1.43 (0.95-2.18) 1.87 (1.19-2.92)t Other Histological Types Trend P=.05 Trend P=.001 Everexposed 85/144 756/1247 0.94 (0.66-1.33) 1.28 (0.85-1.88) 0 59 491 1.00 1.00 1-15 46 450 0.85 (0.57-1.28) 1.15 (0.73-1.82) 16-30 25 223 0.93 (0.57-1.53) 1.18 (0.68-2.04) >30 14 83 1.40 (0.75-2.63) 2.00 (1.02-3.90)t All Lung Carcinomas Trend P=.62 Trend P=.09 Social exposure¶ Ever exposed 189/615 297/1244 1:42d1.14-1.75)$ 1.50 (1.19-1.89)§ 0 426 947 1.00 1.00 1-15 110 177 1.38 (1.08-1.80)1' 1.45 (1.09-1.92)t 16-30 48 68 1.57 (1.07-2.31)t 1.59 (1.06-2.40)t >30 31 52 1.33 (0.84-2.10) 1.54 (0.93-2.53) Adenocarclnoma Trend P_-.008 Trend P=.002 Ever exposed 147/469 297/1244 1.46 (1.15-1.84)$ 1.53 (1.19-1.97)$ 0 322 947 1.00 ... 1.00 1-15 84 177 1.40 (1.05-1.86)t 1.45 (1.07-1.97)t 16-30 41 68 1.77 (1.18-2.67)# 1.81 (1.18-2.77)$ >30 22 52 1.24 (0.74-208) 1.45 (0.83-2.53) Other Histological Types Trend P=.006 Trend P'-.002 Ever exposed 42/146 297/1244 1.29 (0.88-1.89) 1.36 (0.90-2.06) 0 104 947 1.00 ... 1.00 1-15 26 177 1.34 (0.85-2.12) 142 (0.85-2.35) 16-30 7 68 0.94 (0.42-2.09) 0.89 (0.37-2.15)_ >30 9 52 f.58 (0.76-3.29) 1.90 (0.84-4.31) Trend P=.23 Trend F=.16 sAdjusted for age; race; study area; education; fruits, vegetables, and supplemental vitamin index; dietary choles- terol; family history of lung cancer and employment in high-risk occupations. OR indicates odds ratio; Cl, confidence interval. tP<.05. - ~ $PG.01. . §P<.001. j.Soc:ial exposure is defined as exposure of 2 or more hours per week from sources other than occupational and household. considered jointly, statistically significant increasing risks with increasing duration of exposure are observed for all lung can- cers combined (trend P=.0001), adeno- c,arcinomas (trend P=.001), and for cell types other than adenocarcinoma (trend P=.05). At the highest level of exposure, a 75% increased risk is observed. Similar and statistically significant trends in risk are observed with analyses restricted to self-respondents for all lung cancers com- bined and adenocarcinomas. For other histological types, a significant trend is no longer observed. Similar positive trends were observed regardless of pa- thology review status and within all lev- els of the fruits, vegetables, and supple- mental vitamin use index; dietary cho- lesterol intake; age; and race; although the risk estimates and trends were some- what stronger among white study sub- jects and women younger than 70 years. To determine whether risk associated with adult ETS exposure differs accord- ing to childhood exposure status, the data were stratified by childhood exposure (Table 8). Elevated risks associated with adult ETS exposures were observed in women with (trend P=.01) and without (trend P=.0005) childhood exposures, but the elevations in risk for women exposed during childhood were about twice as high as those without childhood exposures. At the highest level of exposure (48 adult smoke-years or more), an adjusted OR of 3.25 (95% CI, 2.42 to 7.46) was observed among women reporting childhood expo- sure compared with 1.77 (95% CI, 0.98 to 3.19) for those reporting no childhood ex- posure. The estimates based on self-re- sponses only indicate a similar pattern of risk. Although the differences are approxi- mately twofold, the CIs for the ORs at each level of exposure overlap. COMMENT In this report, the RR of lung cancer associated with ETS exposure was as- sessed for all lung cancers, adenocarci- noma of the lung alone, and other histo- pathologic cell types combined. Through- out, the increased risks associated with adult ETS exposures were quite consis- tent for adenocarcinoma and other cell types and, as a result, for all lung cancers combined. Compared with adenocarci- noma cases, the number of other cell types was quite small; therefore, the failure to observe statistically significant trends in this group is more likely a result of lower statistical power than biological differ- ences in response in the two histopatho- logic subgroups. For example, the power to detect an OR of 1.3 associated with ever use of tobacco by a spouse was ap- proximately 73% for all lung cancer cases, 65% for adenocarcinoma, and 31% for other cell types combined. In the 3-year report 1756 JAMA, June 8, 1994-Voi 271, No. 22 Tobacco Smoke and Lung Cancer-Fontham et al

of the study, increased risk of lung cancer from adult ETS exposure was stronger for adenocarcinoma of.the lung than for all cell types combined? That finding is no longer apparent with the additional cases of each cell type. Although the estimates of RR for pulmonary adenocarcinoma are not different from those for other cell types, adenocarcinoma of the lung is by far the predominant cell type diagnosed in women with lung cancer who are life- time nonsmokers, and so the effects of ETS exposure may be particularly rel- evant for this histopathologic cell type. More than 75% of the cases in this study were diagnosed with primary pulmonary adenocarcinoma, twice the proportion of adenocarcinoma of the lung diagnosed in all US women without regard to smoking history: 37% among female lung cancer cases in the SEER program.u In other studies of ETS in female nonsmokers in which histopathology was reported, ad- enocarcinoma comprised 60% or more of all cases in six of nine studiesP,l',ffi~= In the other three studies, the proportion of adenocarcinoma cases ranged from 43% to 54%F,11 Differences in the physical and chemical properties of sidestream smoke compared with mainstream smoke, includ- ing the distribution of the vapor and par- ticulate phases and the concentration of known or suspected carcinogens,"' com- bined with differences in inhalation, nasal vs oral, may yield a higher proportion of peripheral adenocarcinomas.45 Misclassification of disease status was minimized in this study by the eligibility criteria (microscopic diagnosis required) and an independent review of diagnostic material that was completed for 85% of the cases. The small proportion of cases found ineligible by independent review mayresult from the population-based tu- mor registry affiliation of four of the five study centers. The consistency of the find- ings with and without nonreviewed cases supports the contention that the study results were not measurably altered by inclusion of ineligible cases. Misclassification of ever smokers as life- time never smokers is more problematic. The objective of this study was to evalu- ate the risk of lung cancer in women who had never smoked. At present there is no known biomarker of lifetime tobacco use. Cotinine, the major metabolite of nico- tine, is the most widely accepted bio- marker of current (1 to 2 days) tobacco exposure and is useful for distinguishing current active smokers from current non- smokers.'-1' The proportion of reported nonsmokers in the present study with a cotinine/creatinine concentration above 100 nglmg was 1.9%, the same proportion with a concentration above 100 ng/mg observed in a 10-country, multicenter study of self-reported ETS exposure.16 Table 7.-Association Between. Risk of Lung Cancer and Adulthood Smoke-Years of Exposure Among Nonsmoking Women* Adult Smoke-Years ` of Exposure 0 1-11 12-28 29-47 ~a8 0 1-11 Crude OR Adjusted OR Cases Controls (95% Cl) (95% Cl) All Lung Carcinomas (All Respondents) 48 118 `1.00 ... 1.00 ... 74 239 0.76 (0.50-1.16) 0.82 (0.52-1.29) 138 307 1.11 (0.75-1.63) 1.12 (0.73-1.70) 153 304 1.24 (0.841.82) 1.35 (0.89-2.04) 163 265 1.51 (1.03-2.23)t 1.74 (1.14-2.65)t Trend P=.0001 Trend P=.0001 Adenocarcinoma (All Respondents) 38 118 1.00 ... 54 239 0.74 (0.46-1.19) 1.00 ... 0.74 (0.44-1.23) 12-28 110 307 1.17 (0.76-1.81) 1.15 (0.73-1.83) 29-47 112 304 1.21 j0.78-1.86) 1.29 (0.81-2.04) a:48 130 265 1.61 (1.05-2.47)t 1.77 (1.12-2.80)t Trend P=.0002 Trend P=.0001 0 1-11 12-28 29-47 ~a8 0 Other Histological Types (All Respondents) 12 118 1.00 1.00 - 20 239 0.82 (0.39-1.74) 1.17 (0.52-2.62) 28 307 0.90 (0.44-1.82) 1.00 (0.46-2.18) 41 304 1.33 (0.67-2.61) 1.58 (0.76-3.31) 33 ^ 265 1.23 (0.61-2.46) 1.76 (0.83-3.75) Trend P6.12 Trend P=.05 All Lung Carcinomas (Self-respondents Only) 30 118 1.00 ... 1.00 1-11 53 238 12-28 103 306 29-47 110 304 a:48 105 265 0.88 (0.51-1.54) 0.79 (0.44-1.42) 1.32 (0.84-2.10) 1.20 (0.74-1.94) 1.42 (0.90-2.25) 1.44 (0.89-2.31) 1.58 (0.98-2.47) 1.67 (1.03-2.70)t Trend P=.002 Trend P=.0006 Adenocarcinoma (Self-respondents Only) 0 23 118 1.00 ... 1.00 ... 1-11 41 238 12-28 88 306 29-47 82 304 ;-48 91 265 0.88 (0.53-1.44) 0.81 (0.48-1.37) 1.48 (0.89-2.45) 1.31 (0.77-2.22) 1.38 (0.83-2.30) 1.39 (0.82-2.36) 1.76 (1.06-2.92)t 1.85 (1.09-3.15)1' Trend f6.001 Trend f-.0005 Other Histological Types (Self-respondents Only) 0 7 118 1.00 ... 1.00 ... 1-11 12 238 12-28 15 306 29-47 28 304 ~_'48 14 265 0.85 (0.33-2.22) 0.91 (0.34-2.45) 0.83 (0.33-2.08) 0.82 (0.31-2.16) 1.55 (0.66-3.65) 1.64 (0.67-4.03) 0.89 (0.35-2.26) 1.12 (0.42-2.96) Trend P=.49 Trend P=.32 *Adjusted for age; race; study area; education; fruits, vegetables, and supplemental vitamin Index; dietary cholesterol; family history of lung cancer and employment In high-risk occupations. OR indicates odds ratio; Cl, confidence interval. tP<.05. A higher proportion of controls than cases was excluded from the study as a result of elevated concentrations of uri- nary cotinine/creatinine, 2.3% vs 0.6%. Cases were identified at hospitals, and screening of inedic_al records and physi- cians about the patient's current and past use of tobacco preceded the screening by telephone and at the interview for all study subjects. This procedure may have elinW- nated some cluxent smokers from the case series who would have been inclined to self-report as nonsmokers in an interview foxmat. Alternatively, some cases who would misreport smoking status may be less likely, because of health status, to be actively smoking and less likely to be re- vealed than healthy, free-living controls. Other data suggest that lung cancer cases who are ever smokers may be less in- clined to misreport smoking status than others in the general population: the pro- portion of ever smokers misclassified as nonsmokers by discordant reports was 1% among female lung cancer cases from five case-control studies and 5.7% among subjects from general population studies.' Neither cases nor controls were informed before the interview that a urine sample would be requested to eliminate the op- portunity for avoidance of personal to- bacco use or substitution of specimens. JAMA, June 8, 1994-Vol 271, No. 22 Tobacco Smoke and Lung Cancer-Fontham et ai 1757

J Table 8.-Association Between Risk of Lung Cancer and Adulthood Smoke-Years Among Nonsmoking Women With and Without Childhood Exposures* No Childhood Exposure Smoke-Years of Exposure During Adulthood Cases Controls 0 33 71 1-11 33 91 12-28 41 97 29-47 54 97 2t48 54 80 0 23 71 1-11 23 90 12-28 28 97 29-47 36 97 ;--48 31 80 M Childhood Exposure "Crude OR '' Adjusted OR Crude OR Adjusted OR (95% Cl) (95% CI) Cases Controls (95% Cl) (95% CI) AII Lung Carcinomas vs Controls (All Respondents) = 1.00 1.00 8 44 0.78 (0.44-1.39) 0.76 (0.40-1.43) 38 137 0.91 (0.52-1.58) 0.80 (0.43-1.46) 88 202 1.20 (0.71-2.04) 1.16 (0.65-2.06) 85 204 1.45 (0.85-2.49) 1.77 (0.98-3.19) 94 182 Trend P=.04 Trend P=.01 All Lung Carcinomas vs Controls (Self-respondents Only) 1.00 ... 1.00 ... 5 44 0.79 (0.41-1.52) 0.68 (0.34-1.38) 29 0.89 (0.47-1.67) 0.64 (0.32-1.28) 69 1.15 (0.63-2.10) 1.04 (0.54-1.98) 67 1.20 (0.64-2.24) 1.34 (0.69-2.60) 70 Trend P=.26 Trend F-.17 137 201 204 182 1.00 1.00 1.53 (0.86-3.52) 1.63 (0.69-3.86) 2.40 (1.08-5.30) 2.43 (1.07-5.51)t 2.29 (1.04-5.07) 2.64 (1.16-6.01)t 2.84 (1.29-6.28) 3.25 (1.42-7.46)$ Trend J6.0013 Trend P=.0005 1.00 ... 1.00 ... 11 1.88 (0.68-5.10) 1.85 (0.66-5.21) 3.02 (1.15-7.93)t 2.99 (1.11-8.05)t 2.89 (1.10-7.59)t 3.33 (1.23-9.00)t 3.39 (1.29-8.89)t 3.83 (1.41-10.42)$ Trend I6.004 Trend P`z.001 *Adjusted forage; race; education; study area; fruits, vegetables, and supplemental vitamin index; dietary cholesterol; family history of lung cancer and employment in high-risk occupation. OR indicates odds ratio; Cl, confidence interval. tP<.05. $P<.01. Refusal to provide a sample was similar among living cases (19%) and controls (17%); however, because of illness and death, a higher proportion of the total subjects in the case series had no cotinine measurement. Of study subjects for whom no sample was available, 63% reported ever having lived with a spouse who smoked; for study subjects with cotinine determinations, 63% of eligible women and 68% of excluded women reported ever having spousal ETS exposure. Analyses using a lower cut point (55 mg(ng) for exclusion based on urinary cotinine concentrations provided slightly higher estimates of risk associated with ETS exposure, but the differences have little or no effect on study conclusions. . Compared with recent large US stud- ies, the proportion of proxy respondents for lung cancer cases in this study was small: 36.9% compared with 65% in the study reported by Brownson et al" and 67% in the study by Stockwell et al.3' Nevertheless, it is important to evaluate whether the findings differ when proxy respondents are excluded from the analy- ses. The only appreciable difference was noted for childhood exposures. Of those interviews with proxy respondents, 31% were conducted with the study subject's spouse and 48% with an adult offspring of the study subject. These individuals had lived with the study subject and shared life experiences during the study subject's adult life, but not during the study subject's childhood years. The op- portunity for misclassification of expo- sures is greater, therefore, for childhood exposures. The lower reliability for child- hood exposures compared with estimates of exposure from a spouse has been noted previously.16," The consistency of find- ings for adult-life exposures in the total series and among self-respondents only suggests that systematic misclassifica- tion by proxy respondents for adult-life ETS exposures was minimal. The inconsistency in the literature with regard to the association of lung cancer with ETS exposure during child- hood3,','=XPXX may stem from the lim- ited power of many of these studies, as well as difficulties in recall of distant events and/or incomplete knowledge by proxy respondents. The effect of each of these factors is likely to vary among dif- ferent cultures, as well as by the propor- tion of proxy respondents in any given study. Failure to find an independent ef- fect of childhood exposure in case-control studies might result also from the latency period of lung cancer and the age distri- bution of female nonsmokers with lung cancer. Lung cancer arising as a result of childhood ETS exposure would be ex- pected to occur relatively early in life. Even with a latent period of 30 or 40 years, these cases would be younger than 60 years at the time of diagnosis, and such cases comprise a small part of the total case series. No differences were ob- served in this study, however, when risk associated with smoke-years of exposure during childhood was examined for sub- jects in the case and control groups who were younger than 60 years compared with those 60 years of age and older. Al- though no independent effect of child- hood exposure was observed, such expo- sure appears to modify the effect of sub- sequent ETS exposure during adult life. Twofold increases in risk are observed at all levels of adult exposure for subjects who had any childhood household expo- sure compared with those who did not. Individual nutrients andmicronutrients associated with lung cancer were included in preliminary analyses. The final model includes an index that captures the intake of both dietary and supplemental antioxi- dants and a variable for dietary intake of cholesterol adjusted for calories. In this study, high intake of fruits and vegetables and supplemental vitamins is associated with decreased risk of lung cancer, and dietary cholesterol is associated with in- creased risk. Although it has been sug- gested that low intake of carotenoids or fruits and vegetables and high intake of dietary fat are potential confounders of the association between ETS and lung cancer,l this was not observed in our study or in the recent report by Kalandidi et al.lb In addition, similar trends of increased risk of lung cancer associated with increas- ing smoke-years of exposure are appar- ent at all levels of both dietary cholesterol intake and the index of ftuits, vegetables, and supplemental vitamin use. Household radon was measured by 48-hour passive diffusion canisters in a sample of study subjects' homes, and these screening lev- els in all five geographic areas were uni- formly low and not associated with case- control status. These observations indi- cate that the strong association in this study between adult ETS exposure and lung cancer risk cannot be attributed to any likely confounder. A positive dose response between ETS exposure during adult life and lung can- cer risk was found when individual sources of exposure, such as household, occupa- tional, and social settings, were exam- ined separately, and this pattern of risk was clearest when these exposure sources were considered jointly. The point esti- mates are somewhat higher for exposures in occupational and social settings than within households, but these differences are not statistically significant. The higher 1758 JAMA, June 8, 1994-Vol 271, No. 22 Tobacco Smoke and Lung Cancer--Fontham et al

0 estimates in the former settings may re- flect chance, some recall bias, or the po- tential for a larger number of smokers and smoke exposures in these settings. Workplace ETS exposure has received less attention than domestic ETS expo- sure in studies of lung cancer to date; however, monitoring of ETS or its con- stituents in workplace settings has dem- onstrated detectable markers of ETS by personal air monitoring and biomarkers with average concentrations similar to residential levels but with higher maxi- mum values.' In a study of workplace ETS, the correlation between number of smokers encountered during a workshift and personal sampler nicotine concentra- tion (micrograms per cubic meter) was 0.62 (P<.05) and with postshift urinary cotinine was 0.63 (P<.05) ~9 Brunnemann et al50 sampled indoor air in bars, restau- rants, and trains and found carcinogenic tobacco-specific N-nitrosamines at con- centrations up to 23 pg/L of N'-nitroso- ilornicotine and 29 pg/L of 4-(methylnit- rosamino)-1-(3 pyridyl)-1-butanone. These settings serve as workplaces for employ- ees and social settings for patrons. The significant elevated risk of lung cancer in this study associated with exposures out- side the home suggests the importance of these settings, in addition to spousal ETS exposure, in the United States. The findings of this study support the conclusion that long-term exposure to ETS increases risk of lung cancer in women who have never personally used tobacco. This increased risk is more marked for women who have also been exposed to ETS during childhood. This research was supported by grant CA40095 from the National Cancer Institute, Bethesda, Md, with additional support from the Louisiana Cancer and Lung Trust Fund Board and the Louisiana State University Stanley S: Scott Cancer Center, New Orleans. The authors are grateful for the cooperation of all of the participating hospitals in the five study areas and the many physicians who helped make this study possible. The authors also thank Gladys Block, PhD, for her thoughtful comments and sug- gestions, particularly related to dietary exposures; S. Donald Greenberg, MD, for the microscopic re- view of diagnostic material; Christopher Powers, MS, Gail Smith, Mahboob Sobhan, PhD, and Wil- liam Johnson, MS, for programming and analytic support; Laurel Cederquist, MS, Annie Fung, Judy Goldstein, Helen Gregory, and Anne Morse for field supervision; the American Health Foundation for conducting the urinary cotinine analyses; and the dedicated medical record abstractors and inter- viewers in each study center. References 1. Office of Health and Environmental Assessment, Office of Research and Development. Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington, DC: US Envi- ronmental Protection Agency; 1992. 2. Fontham ETH, Correa P, Wu-Williams A, et al. Lung cancer in nonsmoking women: a multicenter case-control study. Cancer Epidemiot Biomarkers Prev. 1991;1:35-43. 3. Akiba JD, Kato H, Blot WJ. Passive smoking and lung cancer among Japanese women. Cancer Res. 1986;46:480411807. . - ~ 4. Brownson RD, ReffJS, Keefe TJ, Ferguson SW, Pritzl JA. Risk factors for adenocarcinoma of the lung. Am J Epidemiol. 1987;125:25-34. 5. Buffler PA, Pickle LW, Mason TJ, Contant C. The causes of lung cancer in Texas. In: Mizell M, Correa P, eds. Lung Cancer: Causes and Preven- tion. New York, NY: Verlag Chemie International Inc; 1984:&3-99. 6. Chan WD, Fung SC. Lung cancer in nonsmokers in Hong Kong. In: Grundmann E, ed. Cancer Cam- paign, VL• Cancer Epidemiology. Stuttgart, Ger- many: Gustav Fischer Verlag; 1982:199-202. 7. Correa P, Fontham E, Pickle L, Lin Y, Haenszel W. Passive smoking and lung cancer. Lancet. 1983; 2:595-597. 8. Gao Y, Blot WJ, Zheng W, et al. Lung cancer among Chinese women. Int J Cancer. 1987;40:604- 609. 9. Garfinkel L, Auerbach 0, Joubert L. Involun- tary smoking and lung cancer: a case-control study. J Natl Cancer Inst. 1985;75:463-469. 10. Geng G, Liang ZH, Zhang GL. On the relation- ship between smoking and female lung cancer. In: Aoki M, Hisamichi S, Tominaga S, eds. Smoking and Health. Amsterdam, the Netherlands: Elsevier Science Publishers; 1988:483-486. 11. Humble CG, Samet JM, Pathak DR. Marriage to a smoker and lung cancer risk. Am J Public Health.1987;77:598-002. ~ 12. Inoue R, Hirayama T. Passive smoking and lung cancer in women. In: Aoki M, Hisamichi S, Tominaga S, eds. Smoking and Health. Amsterdam, the Neth- erlands: Elsevier Science Publishers; 198828.3-285. 13. Janerich DT, Thompson WD, Varela LR, et al. Lung cancer and exposure to tobacco smoke in the household. N Engl J Med. 1990;323:632-636. 14. Kabat GC, Wynder EL. Lung cancer in non- smokers. Cancer. 1984;53:1214-1221. 15. Kalandidi A, Katsouyanni K, Volopoulou N, et al. Passive smoking and diet in the etiology of lung can- cer among nonsmokers. Cancer Causes Contrrol.1990; 1:15-21. 16. Koo LC, Ho JH, Saw D, Ho CY. Measurements of passive smoking and estimates of lung cancer risk amongnonsmoking Chinese females. Int JCan- cer. 1987;39:162-169. 17. Lam TH, Kung ITM, Wong CM, et aL Smoking, passive smoking, and histological types in lung cancer in Hong Kong Chinese women. Br J Cancer. 1987;6: 673-67& 1& LamWK.AClinicalandEpidemiologicalStudy of Carcinoma of the Lung in Hong Kong. Hong Kong: University of Hong Kong; 1985. Thesis. 19. Lee PN, Chamberlain J, Alderson MR. Rela- tionship of passive smoking to risk of lung cancer and other smoking-associated diseases. Br J Can- cer. 1986;54:97-105. 20. Liu Z, He X, Chapman RS. Smoking and other risk factors for lung cancer in Xuanwei, China. Int J Epidemiol. 1991;2026-31. _ 21. Pershagen G, Hrubec Z, Svensson C. Passive smoking and lung cancer in Swedish women. Am J Epidemiol. 1987;125:17-24. 22. Shimizu H, Morishita M, Mizuno K, et al. A case-control study of lung cancer in nonsmoking women. Tohoku J Exp Med. 1988;154:389-397. 23. Sobue T, Suzuki R, Nakayama N, et al. Passive smoking among nonsmoking women and the rela- tionship between indoor air pollution and lung can- cer incidence. Gan No Rinsho. 1990;36:329-333. 24. Svensson C, Pershagen G, Klominek J. Smok- ing and passive smoking in relation to lung cancer in women. Acta Oncol. 1989;28:623-629. 25. Trichopoulos D, Kalandidi A, Sparros L. Lung cancer and passive smoking. Lancet.1983;2:667-668. 26. Wu AH, Henderson BE, Pike MD, Yu MC. Smok- ing and other risk factors for lung cancer in women. J Natl Cancer Inst. 1985;74:747-751: 27. Wu-Williams AH, Samet JH. Environmental tobacco smoke: exposure-response relationships in epidemiologic studies. Risk Anal. 1990;10:39-48. 28. Butler TL. The Relationship of Passive Smok- ing to Various Health Outcomes Among Seventh- Day Adventists in California. Los Angeles: Uni- versity of California-Los Angeles; 198& Thesis. 29. Garfinkel L. Time trends in lung cancer mortality among nonsmokeYs and a note on passive smoking. J Natl Cancer Inst. 1981;6:1061-1066. 30. Hirayama T. Cancer mortality in nonsmoking women with smoking husbands based on a large-scale cohort study in Japan. Prev Med. 1984;13:680-690. 31. Hole DJ, Gillis CR, Chopra C, Hawthorne VM. Passive smoking and cardiorespiratory health in a general population in the west of Scotland. BMJ. 1989;299:423-427. 32. Brownson RC, Alavanja MC, Hock ET, Loy TS. Passive smoking and lung cancer in nonsmok- ing women. Am J Public Heal th.1992;82:1525-1530. 33. Stockwell HG, Goldman AL, Lyman GH, et aL Environmental',tobacco smoke and lung cancer risk in nonsmoking women. J Natl Cancer Inst 1992;84:1417- 1422. 34. Haley NJ, Axelrad CM, Tilton KA. Validation of self-reported smoking behavior- biochemical analysis of cotinine and thiocyanate. Am J Public Heal th. 1983;73:1204-1207. 35. Langone JJ, Gjika HB, Van Vunakis H. Nicotine and its metabolites: radioimmunoassays for nicotine and cotinine. Biochemistry. 1973;12:5025-5030. 36. Riboli E, Preston-Martin S, Saracci R, et al. Exposure of nonsmoking women to environmental tobacco smoke: a ten country collaborative study. Cancer Causes Control. 1990;1•.243-262. 37. Jarvis MJ, Turnstall-Pedoe H, Feyerabend C, Vesey C, Saloojee Y. Comparison of tests used to distinguish smokers from nonsmokers. Am J Pub- lic Health. 1987;77:1435-1438. 38. Haley NJ, Colosimo SG, Axelrad CM, Harris R, Sepkovic DW. Biochemical validation of self-re- ported exposure to environmental tobacco smoke. Environ Research.1989;49:127-135. 39. Hoffmann DW, Haley NJ, Adams JW, Brun- neman KD. Tobacco sidestream smoke: uptake by nonsmokers. Prev Med. 1984;13:608-617. 40. Mattsen ME, Boyd G, Boyd D, et al. Passive smoking on commercial airline flights. JAMA.1989; 261:867-872. 41. Schlesselmann JJ. Case-Control Studies: De- sign, Conduct, Analysis. New York, NY: Oxford University Press; 1982. 42. HIeinbaum DG, Kupper LL, Morgenstern H. Epi.- demiologie Research. Principles and Quantitative Methods. Belmont, CaliE Lifetime Learning Publica- tions;1982. 43. Ries LAG, Hankey BF, Miller BA, Hartman AM, Edwards BK. Cancer Statistics Review 1973- 88. Bethesda, Md: National Cancer Institute;1991: I52-VI23. NIH publication 91-2789. 44. Committee on Passive Smoking, Board on Envi- ronmental Studies and Toxicology, National Research Council. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washing- ton, DC: National Academy Press; 1986. 45. Wynder EL, Goodman MT. Smoking and lung cancer: some unresolved issues. Epidemiol Rev. 1983; 5:177-207. 46. Pron GE, Burch JB, Howe GR, Miller AB. The reliability of passive smoking histories reported in a case-control study of lung cancer. Am J Epide- miol. 1988;127:267-273. 47. Coultas DB, Peake GT, Samet JM. Question- naire assessment of lifetime and recent exposure to environmental tobacco smoke. Am J Epidemiol. 1989;130:338-347. 48. LeMarchand L, Wilkins LR, Hanlrin JH, Haley NJ. Dietary patterns of female nonsmokers with and without exposure to environmental tobacco smoke. Cancer Causes Control. 1991;2:11-16. 49. Coultas DB, Samet JM, McCarthy JF, Spen- gler JD. A personal monitoring study to assess workplace exposure to environmental tobacco smoke. Am J Public Health. 1990;80:988-990. 50. Brunnemann KD, Cox JE, Hoffmann D. Analy- sis of tobacco-specific N'-nitrosamines in indoor air. Carcinogenesis. 1992;13:2415-2418. JAMA, June 8, 1994-Vol 271, No. 22 Tobacco Smoke and Lung Cancer-Fontham et al 1759

t . T, JUN 16 ' 94 09 :26A('I PHILIP MORRIS P.1 @2 PHILIP MORM INCORPORATED FACSIlVQLE 'I'RANSMISSION DATE: TO: FROM: RE: June 14 1994 Distribution Mary Pottorff Fontham Study - Review and,Commettts Pages t.o Follow: rrr.rllrlrrrrltiuauaa~..ras.a.~..~.~wM.a....a=.-===x~ex~=~-="== :m~~=. Distribution: t EEC s D. $usb.oxas Asias D. Harris D. G:rrenberg C. Goddard H. Lybei+opoulos T. T1ndom J. Sullivan EEMA: S. Carison AustrslFns D. Davies U. Crettaz R. Hodgson E. Montgomery 0. Fowler PMI: E. Cho Japan: M. Egawa A. OIwniewslri S. Imai IISAs Jack Lenzi Latin C, Leiber Cappi Albertson Amerfca: A. Gonzalez S&T: R. Cnrehsnan Corporate: T. Bom11i G. Patskan L. Met+lpin H. Reif R. Walk cc: - T. And rade wla enal. ca v. Han „ " , rr S Paxri sh „ ,t w . WRA { Gireuiate} c1r ~ ~ IF THE1tEdREANY PROBLEMS 1i'ffff:rMNSMISSI0N OF THIS FAx, PLBASE CONTACT (2I?) 880-9951(teL) OR (212) Ap7-,S$49 (Jhx) The prr~'~rsnces qfboth nox-Amakon and amakeiv care be acaommadated.