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"Environme ntal Tobacco Smoke and Lung Cancer in Nons moking WomenA Mdlticenter Study Elizabeth T. H; Fontharni,DrPH; Pelayo Correa„MD;,Peggy Rey,nolds,,PhD; Anna Wu-Williams, PhD. Patricia A. Buffler, PhD; Raymond S. Greenberg, MD, PhD; Vivien VN. Chen„PhD; Toni Alterrman„PhD; Peggy Boyd. PhD; Donald F. Austin, MD; Jonathan Liff; PhD Objeictive. To determine the relative risk (RR) of'lung cancer in lifetime never, smokers associated with environmental tobacco smoke (ETS) exposure. Design:-iWlutti(:enter population-based case-control study. Setting.---Fnre rnetropoliteniareas in the United States: Atlante, Ga, Houston, Tex, Los Angeles, Califi New Orfeans; La,,and the San Francisco Bay Area, CaGf. Patients or Other Participants.-Female lifetime never smokers: 653 cases with histologically confirmed Ilung Icanr;er and 1253 controls selected by random digit dialing and random sampling from the Health iCare Financirxg Adminfstration files for women aged 65 years and older. Main Outcome Measure. -The RR of lungicancer, estimated'by adjusted odtls ratio (OR) with 95'I'p confidence interval (CI), associated with i ETS exposure. Results.-Tobacco use by spouse(s) was associated with a 30% excess risk of lung cancer all types of prirnary 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=.118): An increasing iRR 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 otDsenred for subjects with 8D or more pack-years of'exposure from a spouse (adjusted O'R=1.79; 95% C1=0:9'9 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°/p. When thesesourices were considered jointly, an increasing risk of lung cancerwith increasing duration of exposure was observed (trend P=.00h ). At the highest level of'exposfure, there was a 75°'p increased nsk. No sigroificantassociation was found between exposure during childhoodito 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 ino childhood exposure. At the highest level of adult smoke-years of exposure, the ORs for women with and without childhood expDsures were 3.25 (951o Cl, 2.42 to 7.46) and 1L77 (95% Cl, 0.98 to 3:19); respectively. Conclusi'on.-Exposure to ETS during adult life increases risk of lung cancer in lifetime nonsmokers. (J,9MA: 1994271 `.1752-1759) Fromthe. Department of Pathology (OrsFontham, Correa. and Chen), CrouisianaState ,Universrty~Medical Center. New.Orleans: the California.Department of Heallh.Services. Erneryvdte (Drs Reyndds and Austm): the Universioyy of ~Southern California. School of Medi- cine:,Uos:Angeles (Dr Wu-Wiltfams): the Uihiversity,ol Texas Health Science,Center: School of Public Health, Hlmuston (Drs ei,Mler and iAnerman): the EmoryiUniver- sitySChoo6of.Public.Health, Atlanta. 6a(Drs Green- berg and Lift); and the Cafff~ornia Public Health ~Foun- dation; Emeryville (Dr Boyd). Dr 13iiffleris;nowwith the University of Caliiornia-Berkeley, School I of Public Heaflh. Dr Alterman iss now with the National Institute for Occupatlonal Safety, andHleatth, Cincinnati, Ohio.. Dr Austin ~ is noww wi7hthe.. Oregon Health Division, Portland. Reprint reqWeststo Louisiana State University ~Medik caLCenter,.Departmentiof Pathology. 1901 PerdiQo.St, New Orleans. LA 7Q112-1393(Dr Fontham). IN JANUARY 1993, the US Environ- mental Protection Ageney (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 forapproxdmately 3000 tungcancerdeaths per year in US nonsmokers.' A total of 30 epidemiologic studies conductedl world- wide were included in the EPA risk as- sessment;,ineluding 11 studies conducted in the United States t" Of the US stud- ies, the report of fuldings from the first 3 years of,t'his multicenter study2 contrib- uted the greatest individual study weight to the US' sunnnary relative risk (RR) estimates for lung cancer 1.191(95%~eon- fidenoe interval [CI11.04!t,o 1.35) associ- ated with "ever exposed" t:o spousal,ET'S and 1.38 (95% CI,,1.13' to 1170) for the highest level of spousal I ETS exposure. The weight accorded this studly in the EPA report reflected the large numberof lifetime nonsmokers with lung cancer (n=420); as well las t,he stud jr 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."-' 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'2 observed'no in- creased risk in the ever-exposed category for spousal ETS (adjusted odds ratio (ORI=1L0; 95% CI, 0:8 to 12); however, the CI includes 1.19, the US sturunary point estimate. The highest exposure cat- egory (greater than 40 pack -years) in the study by Brow~rtson et al,yielded aniRR estimate of'1.3 (95% CI„1.0 to 1.7), quite similar to the,US "high-exposure" sum- maryestnmate of 1.38. In thesecond study by Stockwell et al,?' the RR' est'imatess are among the highest reported for US studies: 1,6 (95%o CI, 0.8'to 3.0) for ever exposed and 2.4 (95No CT,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 2 The studiy was a popu- lAtion-based case-control study of lungcan, cer in women who have never used i any tobacco productL Eligible cases included microseoplcally'confumed primary carci- noma of the liutg,(Interavationa.I CGassi- fuat{ori: of Disaases „Nintdc Rev'sion [lCD- 9], code 162) that were diagnosedlbetween December 1;1986; and i*lovember30;1985, 1752 JAMA, June 8, 1994 Vol 27 1, No. 22' Tobacco Smoke andiLungiCancer-FonGham et al

among,female residents of inetropolitan •Atlanta, Ga(Clayton, Cobb„DeKalb, 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 prleans, La (Jefferson, Orleans; and St Bernard parishes), Los Angeles, Calif (Los Ange- les County), and the San Franciseo Bay Area, Calif! (Alameda, Cont'n a Costa, 1Vlarin, San Francisco, San Mateo, and Santa Clara counties). Additional eligibil- ity criteria included age at diagposis (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 board,s. A population-based control group was selected by random digi,t' dialing and supplemented by random sampling from the Health Care Financing Adtninistra+ tion ®es for women 65 years and older. Controls werefreqpency matehedito cases on race and age (~younger than 50 years, 50'to 59 yeats, 60 to 69 years, and 70 to 799 years) in a 2:11 ratio of controls to cases d met' the same residence, language, .,.,d tobacco use csriteria aseases. The popu• lation control group was selected as the priaMry 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 Nbvember 30; ,1!988) from women aged 120 to 79 yearss with a diagnosis of primary, carcinoma of the colon(IGD-9„eode 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 wass selected as a means of assessing recall' or response bias associated l with a recen t di- agposis 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- troligroup Z This component of the study was not extended into the final 2 years. Lifetime smoking, status was deter- ied in a three-tiered approach. Infor- mation was obtained on each potential study subject's personalluse of'tobacco, first from the medical record of the ean- cer cases, then from the patient's per- sonal physician~,and finally from the po- tential studysubject 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 populationcon- trol group. At the interview, the tobacco use screening questions were repeated to confirm eachistlidysubject!'s reported status as a lifetime nonuser of tobacco. Of the 17 447 p otential cases ascertained in the five study centers, 800 were found I to meet all eligibility criteria, In-person 1 interviews were completed for 665 (83%). of1800 incident cases and 1278 (70%')' of 1'826 population controls. An interview was solicited from the next of kin of cases . who were deceased lor- were too ill lto par- ticipate in an intervietr. 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 werede- termined and the ratio used' as an indi- cator of current smolQng 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,lVR'. Cotinine was quantitated by radioim- munoassayusing the method of Ha1ey et aP' with a modification of the antibodiy of Langone et aL`Cbtinine concentrations were adjusted for urine flow based on creatinine values by determining the nanograms of cotinine per milligrems of ' creatinine. Creatinine was determined'byd spectrophotometry using the Kodak E k- tachem 400 Clinical Chemistry Analy,zer. (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 (8111%) andlcontrols (832%) despite d'sf-s ferences in health status. As in the origi- nal report, subjects in the case and con- trol groups whose cotininelcreatinine con- centration exceeded 1100'ngJing were ex- cluded from the study to eliminate persons likely to be active smokers Y"Itvo (0.6%) of 356 cases and 25'(2.3%) iof 11064 controls had cotinine/creatinine concentrations of 1'00 ng/mg or higher. Although no opti- mum concentration has been established I 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 beeni used as the eligibility criterion in a large,study oflhealthy, free- living subjecis,36 and I others have been suggested."^'e Imhigh.exposure settings;, urinary cotinine in nonsmokers has reached a concentration of 55 ng/mg of cotinine/creatinine.39j/0 In this st'udy, nine . cases (2.5%) and 29 controls (2.7%) had urinary concentrations ofl55 to 99 ng/mg. Analyses of ETS-related risk estimates were also conductediusing a cut point of 55 ng/mg,of cotinine/creatinine as ani ex- clusion criterion to evaluate the possibil- ity that the study findings were biased as aresult'of inclusionofstudy subjects with borderline concentrations (55 to 99 ng/ mg) of cotinine/creatinine. Representative diagnostic, specimen slides for each case were requested from the hospital for review by one pathologist' specialieing, in pulmonarT pathology. A total of' 562'(8.5%) of (i63' potential cases had diagnostic material available for re- view, and 552'(98f/o) of'the reviewed cases .vere confirmed as primary bronchogenic carcinoma. After exclusion of the 10cases that had review diagnoses inconsistent with primary bronchogenic carcinoma, the final interviewed case series included653 lung cancer cases: 497 adenocarcinomas (76.1%); 74!large-cell Irarcinomas (11.3g6)- 40 squamous cell carcinomas (6.1%); 24i small-cell carcinomas (3.7%); and 118 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 andi nonreviewed cases except for a higher proportion of cases in the "other primary lung carcinomas" category among non- reviewed eases. 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 struetiu-ed questionnaire designed to obtain information on household, oc- cupationall and I 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 fbr at least 6 months) and dhring 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 rnem- bers during adult fife. Dichotomous ETS exposure (ever or never) was exantined by source and type of tobacco i Pack-years of cigarette smoke exposure from spouse were calculated by multipl.ving the num- ber of packs smoked per day by the num- ber ofyears the spouse smoked cigarettes while living .vit'h the study subject. Du- ration of exposure by source was mea- sured in years. Years of exposure ini oc- cupational settings represent the sum of' years of employment in each job in which persons were reported to have , smoked around the study subjeet. Years of ex- posure from individual sources were ex- aminedi,and a summarymeasure (smoke- years) of exposure during childhood and adult life was calculated. Smoke-years JAtvAA, June8; 1994-Vol 127 1, No: 22 Tobacco Smoke and Lung Cancer-Fontham et al 1753

Table 1.-Oistribution of Lung Cancer Cases and CtlntrolS Atrcordng to Selected Denlographic Glaraderistks Chartacteristic. Lung'Cancer Cases; No. (9L), Population Contnois, No. Stwdy'center Atfanta,Ga 461(7,0)i 76:(6.1), Houston;:Tex:. 41 (6.3) i 42(3.4) . Los Argeles, Callf 2641(40;4) 512(40:9) New Orleans. Lia 341(5 -2) 5T(4.5): San Francisco Bay. Area, Calif i 268I(4'1.0) 566I(45:2) Respondent. Study. subject . 412'(63::1 p 1253 i(100.of . Nextof kin 241 (36:9) _. A9e, y. <50' 70(10.7) 165i(13:1) 50-59 1'10 (16.9) 1541(12!3). 60-69 213(32.6). 398i(31.8) 70-79 260 (39.8) 536 (42.8) Ri¢e%etlvtiC yroup White 382(58.5) 765i(6h.1) Black 60(9.2) 171(117) Fieparir 68(10.4) 99 (T.9) Asisn 125(19.1) . 154(14.7) . OUter 17 (2!6) 23(118) UtSlolown or rek+sed 10.answer 1(02) 11 (0:9) Amuallinconle, $ ' <8000 103 (15.8) 144 (11.5) 8000-12 999 88(13.5) : 162 (12.9) 18000-19999 84(129). 168(1II.4). 20 00034 999 114 (17.5) 250 (19.9) 35 000+49 999 63 (9:7) 136 (10.9) z50 000: 94(14.4): 216(,172) . Unknown ior refwsedd aansrrer 107(16:4). 149(14.1). Education <Hqh'h soAoot 216(33.1) . 266(212) . High scAool 217 (332) . 393(31.4) . Some colfege 99 (152) 315 (25.1). CoIlege 62 (9.5) 154 (123). GsaWrate 46(7.0) . 1A6(9:3) UnkJwwn, 13(2.0) 9 (0:7) represent the sum of reported years of ex'postme' to ETS fi om each individual source in childhood I (father, mother„and other household members) or in adult life (spouse, other household members, occu- pational, and I social). The variable does not'represent years per se,because these exposures rnay occur concurrently. All , lung cancer cases combined' were compared with the controls, as were cases of adenocarcinoma of 'the lung (R6.11% of the total cases) and other histological types combinedi(squamous cell carcinoma, small-0ell cananoma„large•aell karreinoma, and other types, 23.93b'oflthe total'cases). In addition, analyses restrieted to self, respondents were compared with those that' also included proxy respondents. Unconditional logistic regression analyses were used to estimate the asso- ciations bysummaryadjust'ed ORs, 95% CIs, and test statistics."•'2 The 0'Rs were adjusted for design or sampling variables (age, race, and study center), as well'.as educationj family history of'lung cancer,, employment in ipotentially high-riskoccu- patvons for 5 or more'y,ears (production' jobs in painting, mining, textile, , insula- tion, shipyard, cement, roofing„smelting,, radiation, petroleum, hairdressing, and I printing industries), dietary cholcsteroll intake, and an index of dietaryantioxidant. Table 2-Assoaation Betv reen Srtaking'Status ol'S(louse and iLungiCarloer Risk in Nonsrtak>rg'Women• cas.s, ContrWs. Spouse Evet Smoked No1 ExpossN' No:,Exposad/' Crude OR Ad(usted IOR Tob.oao„by Type No. of Casest NO. of Controls (95% Cl) (95% CI) Alt.kmg!carcindnas. - Any.typeo(tobacao. 433/651 766/1253 1.26(1.04-1.54)t1.29.(1.04;1.60)1 Cgarettes 386/648. 69171253. 1.20(0!99-1.45): 1.18.(0.96-1.46). Cigars 851643 138/J2531.24(0.'93-1.65): 125.(0.92-1.71). Pipes~ 861640 ~. 158/1253~ 1.08.(0.81-1.43)~. L.19~,.(0.88+1.60)~. Adenocardmoma Any.Pypeoftoba¢oo 3313/496'. 766/12531.31!(1.05-1.63)t 1.28i.(1.01-1.62)t Cigarettes298/493'. 69111253 '. 1.24 (1.0Y-1.54)t 1.18 i(0.9n-1.49) : Cgars~ 58/48913811253 ~~. 1.09~.(0.79-1.51)~. 1.08i(0.76-~1.53)1 Pipes~ 62J488 ~~. 15811253 '. 1.011(0.74-1..38) : 1.04 i(0.75-.1.46) , Other histological !lypes . Any'type of ilobaooo 99/155 76611253' 1.12 (0.80-1.59) : 1.37 (0.92-2.03) Cigarettes 86l155 69111253' 1.07 (0.76-1.50) 1 120 (0.83,1.75) Ciysrss 27L152 . 136/1253'. 1.751(1.11-274) : 1.88 qt.14-3.08)t Pipas 24/152 158/1253' 1.30 i(0:824_07) 1 1.79 i(1.08-2.95)t •Atlpted for px race (tMUN, black. Asl.n, Atnd Wispsnio aolhe,); rtudy lrea (Los Anpeles. CaYf: San Francisco Bay Area Cew. SoaAA); sdtitm9on (kss than high sdlod, high sclaol 9ratiuate. some coNepe'or more): kuits, vepetsbles. ArW suppenterksl Witarnin index; ,ddetary ~droleslerd'J 1afn7y 11is0oty of ikrg eano®r, ard errployment in DIgA-risk ooafPatk>r1s. OR irfdiCetes oddi ratio; Cl, confidence irNerval. t'n1e number of aases arKf oorNfds'wi/A responses to each qt/estion, #p<.05: Table 3.--Assocfation Between Risk of',Lung Cancer and Pack-Years of ErwirorrlleMal Tobacco Smoke Evosurs Fmm Spafse(s) Amorg Norlsnlokfng Women' Psck-Years of Exposure Cases Controlf Crude OR Adlusted OR (95% CI) (95% cl) A9 IhNg carcinanas 0 267' 562' 1.00 ... 1.00 s15:0 146 300 1.02(0:8Q1.31) 1.Oei(0.83-!1.39)', 15.1-39.9 92 190 1.02(0.76-1.36) 1.04i(0.7&1.42)~ 40.0-79.9 80' 126' 1.34(0.98-1.83) 1.36I(0.97-1.91)i z80.0 24 27' 1.87 (1106-3:31)',) 1.79 i(0.99-3.25) i TrendlP=.03i Trend Pt:03 AilerrocarcUlorna 0 199 562 1!00 ... 1.00 ... s15!0 109 300 1103(0:78-1.35) 1.06i(0.80+1.40), 15.1+39.9 70 190 ~ 1104 (0:76-1.43)1.02',(0-72-.1.42) , 40.0-79.9 65 126 1146(1:04-2105)',) 1.41 (0-98-2.03)~ Z80:0 18 27 1i88(1.02-3;49)',)1.73i(0.91-3.31)Trend P=.01 i Trend P=,05 Other histologicaltypes0. 68 562.. 1.00 ... 1.00 . s15;0 37 300 1.02 (0i67-1.56). 1.18'(0.75-1.87) 15.1-39.9' 22 190 0'96(0158-1.59). 1.12'(0.64-1.96) 40.0-79.9' 15 126 0:98(oS5•1.78). 1.16(0.62-2.19) z8o10 6 27 1.84(0a3-4.61). 1.9r(0.75-5.19) Trend P=.64 Trend f_-29. 'A*rsted Iarage: raoe: skfdy area; education: fruits. vegetatites., and,supplenental..vi18m'rn iretiex; dietarycholesterol: farrw'ly liistory of lurg carrw. end'srrpfoyment in nigh,riskocapations: OR indicates oddsratio; Cl. confidence interval. t,P<:06. , consumption based on.weekly consump- tion of fruits andI 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 also evaluated, but were not included in'the final models because they did not confound the ETS,findings and did not eont¢ibute further to ~the association between ETS and lung cancer. RESULTS The'distribution oficases and controls by study center, respondent status, age, racial/ethnie'group, annual h ouseh old I in- come; and highest' level'of education com- pleted is shown in Table 1. Approximately 40% ofithe 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 periodl The three smaller study centers' in the southern United States (2#tlanta,. Housfona and New Orleans) contributed the remaining study subjects. The case-control'.series had'a relatively large proportion of cases aged 60~ to 79 1754 JAMA, June 8;,1994-Vo( 271, No. 22 Totfacco'Smoke and Lung Canoet-Fontham el ai

years (7-296) with a similar proportion of controls in this age group.' As noted pre- viously, z the age distnbution in this se- riesof female lifetime!never smokers with lung cancer is older than all female lung, cancer cases in the Surveillance, Epide- miology, and End Results (SEER)'P'ro- gram;,1973't'hrough 1988." The largest proportions of lung cancer cases (58.5%) and contt•ols (61.1'%) were white. A larger proportion ~of cases were self«identified as Asian American and His- panicandla smaller'proportion as African American (blacks) compared with con- trols. Approximately 42% of cases and 3896of controls reported an annuallhouse- hold income of less'than $20000 per year. Compared with controls, lung eancer cases tended to have'a lawer'level~ofeducation: 66.396 of cases and a6% ofioontrols had no more than a high school education. Table 2 displays'the estimated RRs of lung cancer associated with ever liiving, with a spouse who smoked by type of tobacco. A 309'c excess risk assoeiated' with tobacco use by spouse(s)'was ob- served for all histopathologic types of lung cancer eombinedi(adjusted OR=129; P<.05), for adenocarcinoma of the lung ijusted 0R=12fd; P<.05), and for pri- rrtary lung carcinomas other than adeno- carcinoma (adjusted oR=1.37; P-.1s). The only individual types of tobacco as- sociated with signigcantly e)evated'risks of lung,cancer are'cigar- and pipe-smoke exposure for bronchogenic carcinomas other than adenocarcinoma: cigars, ad'- justediOR =1.88 and P=:01;pipe„adjusted OR='1'.79 and P=.02. The'estamated RRs of lung,eaneer as- sociated wit'h, pack-years of exposure too spausal, 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- log'ic subgroups. The risk estimates aree similar within t'he, histopatholbgic sub- groups; however, the trend is'signi5cant only for all lung cancers combined (P=.03) and pulinonary'adenocarcinoma (P<.05). When the analysis'was restrieted toself- pondent's only, similar' estimates of' nsk of lung cancer were observed with a trend of increasing:risk of lung,cancer at increasing levels off exposure (P =.03): Exposure to ETS'during childhood'and adult life'fi omimultiple sourceswas evalu- ated. The risks of'lungcancer 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 estu- mates!sigpi'ficantly'differs from unity. The association,of cumulative years'of house- hold exposure to E'TS' during childhood withillmg cancer risk was evaluatedi(Table 5). No increased risk was associated with Table 4;-1ssDwtion Between Risk of liung Cancer and Childhood EVosure'to Tobacco snloke Among I Nor>srtwkin9 4W«nen• Cases, CoMrols; No.Exposad/No.EzposerYCrudeOR'Ad)ustedOR Ever Smok'ed'Tob.oco No. of Cases No. of Controls (95% C1) (95%,CI). AN Nng carcitqmasFather 304/603 669/1225. 0.85 (0.70-1103) 0.63i(Q.67-1.02) Mothen 761624 161/1240 0.93 (0:69-1:24). 0.86i(p.62-1.18) Otherhouseiroldmerrbers 131Y617 269/12530.99(0:78-1.25). 1.03i(0.80-1.32) Any'houseliold irnesnber 377/606 808/1238 0.88 (0:72-1.07). 0.89'(0.72-1110) Adenocarcinoma Father 238/466: 669/a 225'. 0.87(0:70-1.07) . 0.82 (0.66-1104) Mottrer 601480: 161YI240. 0:96 (0:70-1.32). 0.92 (0;65-1;29) Othertwuselwld~members 98/471 269Y1253! 0~96(0:741125): 0:99(0:75:-1.30). Any household member 290¢469 80871238' 0186 (0.69-1.07): 0.85 (0168-1.0s) Oftrea lrstological iypes . Fatfher 66f137 66911225 0:7-J(0.544-10)' 0.82 (056-120) Mother 16/144 16111240, 0184 i(0.49,1.45) 0161 (0:32-1.16) . Other household merntiers 33/146 269L1253 1.07'(P-71-1.61) 1119. (0.77-1.85) . Any household memtie. 87/137 808/1238 0.93I(Q.64-1.34) 1.01 (0.68,1.51). '/1Q'Krsted for ays: race; study aea; eGqation; fiuits. vegetables. and supplemerkab vitanre irwlex; dietary dloleslaok famiy lwstory of 1ur1p car-. and employmenlt in high+risk oocupatioes: OR indrcates odds ra8o; CIJ oonRdence irMerwa/. Table 5:--Association Between Risk of Lung,CanOer and'CMkOlood Smoke-Years of'E>posure lbnorg Nonsrraldng Womert (Sel(-respordeMs OMy,)• Childhood ISewke-Yeus of Household Exposure Cases Controls Crude OR (95% Cl) Atl)usted'OR (95% Cl) Ail llung carcinomas 0 148 4441 1100: ... ~ 1100 .,.. • ~ 1:17 95' 291 0198 (0.v31.32)i 0:99 (0,731.35). a18 146 485! 0190!(0.70.1..17)i Trend. P':5'8. 0,88(0.67-1.16). Trend P-.36. Aiqenocarairwma 0 120 444 ~ 1.00 . ... i.0D 1-17~ 73 '. 291 0.a'93I(Q.67-129) 0J92I(0.65;1.29) 218 123'. 485 0.94 (P.71-1.25) Trend P=.66 0189i(0.66,1.19) Trend P_-:43 Other hislologital Yypes 01 28 444 1.00: 1-17 22 291 1.20 (0:67.2:14) 1.32I(P.72-2.41) z18' 23 485 0.75 (0:43-1133) 0.85 (0.47-1 i54) Trend.P=.33'. Trend P=.58 •Adjusted for age; race; sludyy area; education; fruits, vegetables, and . supptementall vitamin index; . dietary cholesterol; family.tGstory'of lung cancer; and employment infiigh+riskoecupations, ORhdicates odds ratio; CI; confidence interval.. increasing durationi of smoke' exposure during childhoo(L Childhood smoke -yeats were unknownifora!large proportion (M) 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 directstudy subject interviews reported 1 no'exposure during, childhood. The data presented, therefore;, are for analyses restricted to self-. respon- dents: NoAifferences were observed by pathology review status; dietary choles- terol intake; level of the fruits, uegetables;, 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 reduction in risk' at this' level; however, these two ptaint estimates'did not significantly differ. Re- stricting,years of ETS exposure during chi)dhood to those from the motheryielded similar nonsignificant trends. Table 6 presents the estimated RRs associated with adult ETS'exposlure'(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 (trendl P=.1T); on the job (trend P=.001), and ini sociali settings (t'rend, P=.0(/r2)j The in- creased risk of lung',cancer among women i ever exposed to ETS during adult life in i the household is 24'%;,in'occupational setr tkngsi 39%; and in social settings, 509o:. The pattern of response is similar in the', two 1 histologic subgroups; , however, the . tests ofl trend are statistically significant only in the largest subgroup„pulmonary adenocarcinoma. As shown in Table 7, when all sources of exposure t'o ETS during adult life are JAMA. June 8; 1994-Vol 271, No. 22' Tmbacco Smoke and Lung Cancer--Fonthamet al 1755

Table 6.-Hssociation Between Risk of lung Cancer and Adult Exposures to Cngarette Snake Amorlg Nonsmokirq N(anen• Exposure by Source, y cases CbntrWs, Wo. Expo:ea( Wc. Exvosea(' ew..ot'caxs nw. of icoMro(s. AIIiLung Carcinornas Cnrda OR Arjusted OR (95%~C1) ~. (95% ~CI) ~, Household exposure (spouse and other) Everiexposed 5091653 941/1253 1.17 (0.94-1.47) 1_23 (0.9Cr 1.57) 0 153 321 1.00 1,00 1-15' 184. 393' 0.98 (0:76-1.27)', 1:10 (0.6311.46) 16-30 143 244 1.23 (0.193-1.63)' 1:33 (0.9&i .80) >30 173 . 295. 1.23 (0.94-1.61)~ 1;23 (0.91-1.66). Adenocarcinoma i Trend P=.05 Trend. P-'.11 . Ever.exposed 389/497' 94111253 1.19 (0793-1.53). U16ro.89-1.52) 0 115 321 1.00 1100 1-15 139. 393'. 0.99 (0:74-1.32)' 1104 (0:77-1.42) , 16-30. 108. 2" .. 1.24 (0:91+1.69)'. 1126(0.90-1.76) 1 . >30 135 295' 128 (01951.72)' Trend lh.0N 1120 (0.87-1.66) : Trend F'=.17 OO>a Mstoloqkal'Types Ever exposed 120V156' 9611120 1.11 (0:75-1.64) 1:51 (01952.39). 0. 38 321.. 1.00 liao 1-15 45 393 0.97 (016T 1.53) 1:39 ro!83•x.32). 16,30 35 2441 121 (0:74-1.96) 1:99 (M92 -2.77) , >30 38 295' 1.09 (0;6&1.75) Trend IP6.53 1.31 (0.76-226). Trend f-.32 Aa ~ueq Carcinomas Ooarpatiorat expowra' Ever emosed I 385/M 758/1247 1.12 (0:91-1;96) 1.39 (1.17.1.74)# . 0 224 491 1.00 1.00 1-1'S 213 450 1.04 (0.83-1.30) 1.30 (1.01 A.67)t 16-30 118 223 1.16 (0.88-1:53) 1.40 (1.04-1.88)t >30 54 . 63 1.43 (0.98-2A08) Trerd,i1-.06 1.86 (124-2:78)t Trerxl IR_.001 Atlerrooardnana Ever exposed I 300/465 756/3247 0. 165. 4911 1-15 167 450. 1('r30 93 223 >30 40 83 1.181(0.95-1147) 1.46 (1.14-1.86)t . 1.00' 1.00 1.10 (0:86-1142) 1.35 (1102-1.79)1F 124 (0.92-1 i67) 1.49 (1108-2!05)t' 1.431(0.95-2.18) 1.87(1i19-2!92),# Trend.P-05. Trend P-001 Everexposed! Other ?Iistological Types 85/144 756M 247 0.94I(0.66-1.33) 1.26 (0.85-1:88) 0 59 491 1.00 t.00 1+/5 46. 450 0185d0.57-128) 1.15(0:731182) 1Cr30 25223 0.93i/0.57-153) 1.18(0.68-7:04) >30 14 83 1.401(0.75-2.63) Trend P=,62 2.00(1.02-3:90)t Trend.P=.09. re¶ Social ex os A11 Lung Carcinomas p u Everexposed. 189/615 297/1244'. 1.42(1.14-1.75)# 1.50N1.19-1189)§ 0 426 947 1.00 . 1.00 . 1-15 110 177. 1.38I (1.061.80)1 1.45 (1. o9-u 92 )t .. 16;30 48 68 1.57(1.07-2.31)1 1.59i(1.0fi-2.40)1 >30 31 52 1,33 (0.84-2.10) 1.54 (Q.93-2.53) Adanocarcinorno Trend f=:006 Trend P=,002 Ever exposed 147/469 297/1244 1:46(1.15-.1.84)# /.53I(1.19-i9'F7Y 0 322 947. 1100. 1.00. 1-15, 84 .177. 1140.(1.05+1.86)t 1.451(1-07-1.97)ti 16-30 41 68 1177,(1.18;2.67)# 1.81 (1-1&2,77)#~ , >30 22 52 1124(0.04-2.08): Trend F-006 1.451(0.83,2,53) Trend P-;002 Other Histological Types. Everexposed 421146 297/1244 1:29.(0.88-1.89) . 1.361(0.90:2.06) 0 104 947 1100 1.00 1-15~ 28, 177 1.34 (M'+2.12) 142 (0.65,2.35) 18-30 7' 68 0.94 (Ox2-2.09) . 0189,(0.37-2.15) >30 91 .52 1.58 (0:76 -329) . Trend P--23 1.90(0.84.4.31) Trend P=.16 •Il4lysted Uor age; race; study* area: .educatibn:. Mifs. vegetables. amd sup,plementai vifarrrrl index: dretary choles- terd: tamdy1history oi lungcancer,;and empbyrneM irY tiigtinisk ocoupations_ ORiirWitates odtlsxatio; Cl, confitlenrse intc,va4 fiP<05. yP<:011 §P<:007. 9Sooial exposure mdefined as exposure ~of 2 or more .1wurss per week from souroes;other than occupational and I hou5elqW. considered jointly,statistically significant increasing,risks with inereasingduration of exposure are observed for all lung can- cers combined (trend P=:0001), adeno- carcinomas (ttend I P=,00;1),~ 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 significanttrends'irr,risk are observed witll analyses r•estticted to self-respondents for all IwDng,caneers com- bined and adenocarcinomas. For other histiological types„a significant trend is no longer observed. Similar positive trends were observed regardless of pa- thology review status and!withinall lev - els of the fruits, vegetables, and supple- mental vitamin use index; dietary cho- lesterol intake; age; and' race; although the risk estimates and itrends were some - what stronger among white study sub- jects and women y ounger than 70 years. To determine whether risk associated with adult ETS ezpo6ure'differs aecord+ ing to childhood exposlune'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) ichild hood ~exposures, but the elevations in risk for women exposed during,chlldhood wereabout twice as'high as'those without childhood exposures. At the highest level of exposure (48 adult smoke-years or more), an adjusted OR'of 325 (95% CI; 2.42 to 7:46) was observed among women reporting childhood expo- sure compared'with4.77 (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 differenees are approxi- mately twofoldj, the CIs for the OR's 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 adultETS exposures were quite consis- tent for adenocarcinoma and other cell types and~ as a result, for all lung cancers combined. Compared with~ adenocarci- nomacases, the nlunberof other cell types was quite small;,t'herefore, the failure to observe'statistically significant trends in this group is more likely alresult of lower statiistioal l power than biof ogical differ- ences in response in the two histopatho- logic subgroups.,For example, t'hepower 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 31'96 for other cell types combined. In the 3-year report 1756' JANIA,,June 8, 1994-Vo1 271, No. 22 Tobacco Smoke and Lung Camcer-Fontliam et al.

of't,he study, increased risk of lung cancer -from adult ETS exposure was stronger for adenocarcinoma of the lung than~for all cell ty,pes'combined ZThatSnding isnm longer apparent with the additional cases of each cell type. Although the estimates of'RR for pulmonary adenoi arcinoma are not different from those for other cell types„adenocarcinoma~of the lung is by far the predominant cell Itype 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 adenooarcinoma, twice the proportion of adenoaaexinoma of the lung diagnosed lin all US womenwithlout regard to smoking history: 37% among female lung, rancerr cases in the SEER programn In other studies of ETS in female nonsmokers in which hlstOpathology was reported; ad- enocxrcinoma comprised 6096 or more of all cases insix of nine'sttrdies.2-'•°4AW' In the other three studies, the proportion of adenocarcinonta cases ranged frrom: 439e to 5496Ya' Differences in the physical and chemical properties'of sidestream smoke -tpared with mainstream smoke, inelud- ~ o the distrbutionof the vapor'and par- ticulate phases and the'eoncentration of known or suspected carcinogens," com- bined with differences in hnhalation, nasal vs oral, may yield a higher proportion of peripheral I adenocarcinomas.'0 Misclassification of disease'status was minimizedlin this study by the eligibility criteria (microscopic diagnosis required)) and an independent review of diagnostic material that was completed for 85% off the cases. The small proportion of cases found ineligible by independent review may result from t'he population+based !tu- mor registry'affiliatuon of four of~ the fiue, study centers. The consistencyof the find- ings with and withoutnonreviewed cases supports the contention ~ that the studyy results were not measurabhy altered by inclusion of ineligible cases. Misclassi5eation of ever smokers asdife- time never smokers'is more problematic. ° objective of'this st!udywas to evalu+ aw the risk of lung cancer in women who had never smoked. At present there isno known biomarker of]ifetime tobacco use. Cotinine, the major metabolite of nico- tine, is the most widely accepted bio- marker of~current (1 to 2 days)'tobaceo exposure and is useful for distinguishing, currentaetive smokers from eurrentnon- smokers.''" The proportion iof reported nonsmokers in the present study with a cotinineFcreatinine concentration above 1100 ng/mg was 12%, the same proportion with a concentration above 100 ng/mg observed' in a 10-country, multicenter study of self-reported ETS' exposure ." ' Table 7:--A5so0iation ®etween Risk of Ltxtg C9rtcer and Adulthood Smoke-Yeats ol Exposure Arnorog Mbnsnioking iWomea•' Adult Smolce-Years Ctude OR'I AdjWsted~iOR of Exposure Csses Conttol! (95% CQ (99% p) 0 All iL'ung CarctAomas (All Respondents) 48 118 1.W ..... 1.00 .... 1-r1 74 12-28 138. 29-47 153 >48 ~, 163~. 239 0.76 (0.50-1.16). 0182(0!52-1.29). 3071.11 (0.75-1.63), 1.12'.(0.7311.70)~ 304 1.24 (0184-1.82). 1.35i(Q.89-2.04) , 265 1151.(O.o3-2:23)t 1.74,(1.14-265)1I TrerK1 P~.0001 I Trend P'-,0001 Adenocarcinoma (All Respondents) 0 36 118 . 1.00. ... . 1.0 0, 1 ~-1 1 54, ~. 239. 0:74.(0.46-1.19) i 0.74 (0.44-1123) 12-28~ 110 ~. 307 1.17(0,76+1.81)~ 1.1s(0.73-1:83) 29:47~ 112~.. 304 1.21 (0.M1.66) 1.29 (0:81-2104) z48 130. 265 . 1.61 (1.05-2,47)t, 1.77 (i1.12 218o)t Trend P=:0002', Trend P=.0001 Other Fiistologleal Types (AII RssporWlnts)', 0 12' 118 1.00 ..., 1.00 ... 1-1'1'. 20 239 0.82 (0.39-1174) 1.17 (0:52+2.62) . 12-28' 28 307 0.90 (0.44-1182) 1.00 (0.y&2.18) 29-47 41 304 1.33 (0:67.2!61) 1.58 (0.76+3.3h ) =48' 33 265 123 (0161 -2:46) Treid ii6.12 1.76 i(0.83a3.75) : Trend P=j05 All Lung Carcirtomas (Seihrespondenh Only) 0 30: 116 i;0o. ... 1_00'. ... 1-1 1 53 236 0188 (0151+1.53) 0.79 i(0.44-1.42) 12-28 103~. 306' 1.32 (0.8M2:10), 120 (0.741:94) 29-47 110 ~. 3041 1.42(0.90:225); 1.44 (0:89-2:31) z48 105'. 265. 1.56.(0.96d2.47)1.67(1103-2_70)t Trend P6:002 Trend P..0006 Adenocarcinoma (Self-respondents'Only) 0. 231 118 1.00 ... 1!00 ... 1-11 41 238 0.88 1(p.53-1 :44) 0.81 (0;48-1.37)', 12-28 88 306 1.48 Qo.69-2:45) 131 . (0:77-222)'. 29-47' 82 304 1.36(0.83-2:30) 1;39.(0182-2.36)', =48 91 265 1.76 (1:062:92)t Trend.P=.001 1.85 (tl .09-3:16)t Trend'P4.0005 Other Mistoiogi¢al Types (SeM-respondents Oniy) ~ 0 7 116 1100 ..,. 1.00 1-ill 12 238 0:85 (0133-2:22). 0.91 (0.34-2.45) 12-28 1s 306 0183.(0133-2.08), 0.821(0.31-2,16) 29-47 28 3041 1.55. (0166-3.65) . 1.64 (0.67-4.03) z48 14 265 . 0189: (0:35,2.26) . 1.12 (0.42-2:96) Trend P'-~:49. . Trend . f?--.32 •Atljusted iou age; race;,study area;:ed6cation, frufts, vegetaiiles; and supplementallvitarmnindex;: d'detary, aholesterol;.tamily.liistory.oi'dung cancer;and employment inhigh-risk:oewpatiors:OFB irdit:ates odds ratio; CI, confidence . interval.. tP<,o5: 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 medical records and physi- cians about the patient's cunrent and past use of tobacco preceded the screening by telephone andatthe interviewfor all study subjects. This procedure may have elinai- nated some current smokers from the case series who would have been inclined to : self-report as',nonsmokers in an interview format. Alternativelyi some cases who would misreport smoking,status may be less likely, because of'healt'h status, to be actively smoking,and less likely to be re- vealed than healthy, free-living controls. Other data suggest! that lungeancer cases who are ever smokers ~ may be less in- clined'to misreport smoking status than othels'inthegeneral populatiore the pro- portion of ever smokers misclkssified as nonsmokers by discordant reports was 1% among;female lung cancer cases'fi*om 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- port'unity for avoidance of personal to- bacco ~ use or substitution of specimens: i JAMT8, June.8;, 1994-1y01271, N0: 22Tobacco.Smoke artldlLung:lr.ancer-Flartthamet al 1757'

• Table 8-,. •ssociation Between Risk of Lung iCanaer,and IAdulthood Smoke-Years Amorg Norlsmoking'Women With and Witllout Childhood Exposures` Snwks-YSars of ( Exposure During No Chiitlhood Exposure Childhood Exposure Adulthood Cases. Controts. Ctude OR Adlusted OR Cfude OR Adjusled OR (y5%~c() . (95% Cl) Cases Contro4s(9sxC7) (99x Cq i All Lung Carcinomas.vs' Controls,(All Respondents). 0: 33 71 1.00 ~. ... : 1.00 ~ ... , 8 ~ 44 1.00 1.00 ~. . . . 1-11. 33 91. 0.78~(0.44-1'.39) 0:76(0;40.1.43): 38 137 1.5J(Oi663'52)L631(0.69-3:86) 12-281 41 97 0.9A (0.52-115'8) 0.80(0:43-148). 88 202 2:40(n.08-5;30)2-43;(1.07-5'.57)t 29-47 ' 54 97 1_20(0.71-2:04)1116(Oi65-2.06). 85 204 2'29(n.04-5;07)' 2..64(1.1fi-6.01)1 z48 54 80 1.45(0.85-2:49)1:77(0!98-3:19): 94 182 2~.84(I 29-6:28): 3.25(t42-7.46)t' Trend P=;04': TrendP=.01 TrendiP=.0ot3 Trend P=;00o5 Afl WungCarcinomasvs Controls (SelfPrespondents.Only)', 0 23 711 1.00 1.00. 5 44 1.00 1.001 1-11 23 90 0.79(0:41-1.52), 0168(0:34b1.38), 29 137 1.8&(0.68-5:10)' 185(Ofi6-521) 12-28' 28 97 0.89 (0!47:1.67), 0164 (0:32-1.28), 69 201' 3.02 (1.15-7.g3)t 2.99 (1' 11$ 05)tl 29-47' 36 97 1.15(0i63-2:10), 1.04(05411.98)67 204 2.89i(1.10-7:59)t 333(1i23-900)t'i Z48' 31! 80 120 (0i64-224) 1.34 (0.ti9+2.60) TrerW P.26 Trend P6.17 70 182 3.39i(1.29.8.89)t Trend P=.004 3.89 (1i41-10i42)t Trend,f4-001 'Adruted for age: race: education; study area; fruits. vegetables, and supplemerrEal iritamin lirWex; dietary,choles<erol;fam0y,history of lug oancer; and enployment in hiyh-riskoocupation. OR iineficales odds ratio; Ct, oonfidence interval. tIP<:05. xPe:01. Refusal to provide a,sample was similar among liiving, cases (199fo), and controls (1M, however, because of illness and death„ a higher proportion of the total subjects in the case series had no cotinine measurement. 0fstudysubjects for whom no sample was available,, 63% reported ever having lived with a spouse who smoked; for'study subjects with cotinine determinations, 6596 of eligible'women and 68% of excluded women reported ever having spousal E'I'S' exposure:. Analyses using' a lower cut point (55 mg/ng) for exclusion based' on urinary cotinine concentk-ations provided islightly higher estimates of risk,associated with ETS exposure; Hut't'he differences have little or'no effect onistudy conclusions. Compared with recent large US!stud- ies, the proportion of'proxyrespondents for lung cancer cases in t'his: 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.1'' Nevertheless, it is unportant to evaluate whether the findings differ when proxy respondents are excluded from the analy- ses. The only appreciable'difference wass noted for childhood exposures. Of t'hose' interviews with proxy respondents, 31% were conducted wit'h:the',study subject's spouse and 48% witb,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 dtlring the study subject's childhood years.lThe op- portunity for misclassification of expo- sures is greater, therefore, for childhood exposures. The lower'reliabilityfor child- hood exposures eompared with estimates of exposure from a spouse has been noted previously:",'4 The consistency, of find- ings for adult life exposures in~t'he total series and l among self respondents' only suggests that systematic ml'.crla-ccifica- tion by proxy resppndents for adult-life ETS' exposures was minimal. The inconsistencyin theliterature'with i regard to the association of'htng cancer with ETS exposure during child- hood?-7azn"xx may stem frornthe lim- ited power of many of these studies, as', well as difficulties in recall of distant, events andl'or incomplete lrnowledge'by' proxy respondents. The effect of each of these factors is likely to vary among dif- ferent 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 eancer: 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 diffr?rences were ob- served lin this'study, however, when risk associated with:smoke-years of'exposure during childhoodlwas examinedifor sub- jeets in the case and contr.oligroups 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 expa sure compared with those who did not.. Individual nutrients and micronuttlient's associated with lung cancer were included in prelintinary analyses. The final model I includes an index that captures'the irttakee of both dietary and:supp1emental antioxi- dants.and a variable for dietary intake off cholesterol adjusted for calories: Ih this's studly, high intake offi+uits 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 i that low intake of 'carotenoids or fivits and vegetables'and!high intake off dietary fat are potential confounders of the association between. ETS and lungg cancer,'sthis was not observed in our study or in the recent report by Kalandidi et al;`$In addition, similar trends of inereased', risk of lung cancer associated with Gncreas- ing smoke-years of exposure are appar- ent at all levels of both dietarycholesterol intake and the index of fivit's, vegetables, and',supplemental vitaminuse: Household radon was measured by 48-hour passive difiusion canisters in a sample of study subjects' homes, and these screening 1ev- els in all five'geographic areas were uni- formly, low and not assoeiated'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 bettiveen ETS exposure during adult life and lung'can- cer risk was found when individual sources of exposure, suchi as household, occupa tional, and social settings, were exam- ined separately„and'this pattern of'risk was clearestwhen 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 st'atistically'significant:'Ilhe higher 1758' JA'MA, June 8; 1994-Vol 271, No. 22 Tobacco Smoke'and Lung Cance{--FonSham et' al

~ostamates ~ the former settings may re- t tlect'chan some recall bias, or the po- tential fo larger number of smokers and smtn exposures in these settings. Workp 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- onstratedldetectable:markels 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 Iduring a lworkshift and personal sampler nicotine concentra- tion 1 (micrograms per cubic meter) was 0162 (P<.05) 1 and I with postshift urinary cotinine was'Oi63 i(P<.0b):° Brunnemann et a150 sampled indoor'air'in bars, restau+ rants, and trains and found carcinogenic tobacco-specific Inr nltlbsamines at con+ centrations up to 23 pg(LL of 11J'-nitroso~ nolmiootalle and 129 pg/i, of 41(met}iylnit, rasaznino)-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. thisstudy'associated with exposures out- the 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 womenwho have never personally used tobacco. This increasedl risk is more marked for'women who have also been exposedlto 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 l Lung Trust Fund Board l and'the Louisiana State University Stanley S. Scatt' 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„partieularly related'to dietary exposures;; S. Donald Greenberg, MD, for the microscopic re- view of diagnostic material; Christopher Powers;. MC: Gail,Smith, Mahboob Sobhan, PhD; and Wil- - Johnson, MS, for programming and analytic s,.rNOrt{,Laurel Cederquist, MS; Annie Fung,Judy. 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