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,<a I i ; i i `., we•n(}tar/lh'( eMr?rr 14 V ) Cancer Eptdemroto;v, tttomarken & Prevention 35

Lung Cancer in Nonsmoking Women : A MulticenterCase-Control Study'

Elizabeth T. H . Fon(ham.- Pelayo Correa, Anna Wu-Williams, Peggy Reynolds . Raymond S . Greenberg,Patricia A. Butfler . Vivien W . Chen, Peggy Bovd,Toni Alterman . Donafd F. Austin, fonathan Liff,and S. Donald Greenberg,)roanmeM Or Paln•`Mntv lOu.vanJ )tate Unrveftrtv MrdKal Center

.aw Urteans tourwna l0t ) 2 IE T H F P C . V W C 1 . Depanment

' i aTrhr arld t r•menun/. AtepKNte lJn .verytlv ot )outhern (.alrtornra-• .Ant...+t . ,•-.aMUit,,. ati% ' CJl .lornraU.•pJrtmrmnr

' .ann jen..q r, rn . . .r t a,aarn.a IP R U F A t U.•'vwn or.)em.w,r crrn t . .rvr . xhrxtl or Public Hratth AtUnta ..xtv w s :: t >.'uxH of Pubbc tiratth . Univrnrr..i . .a. ., .aqn .r .•. . . t .,,er rtrxnrOn i euv 110 TO 1 P A B .

` a t ~ . . .~n.a .• r'.•r•rnl .x.nfLtwn drrketMr (.J', LNn/JMJ7 .tO

'~ 8 r a'%3 UIt`a1•^ .^r 4•r YHrK1N)tv Oa .KX l(drqe tN h1.•.)it tne

•' .lw/on ir .a . . ' . L1 • 1) (•

AbstractThe association between eiposure to environmentaltobacco smoke and lung cancer in female lttetimenonsmokers was evaluated using data collected duringthe t)rst 3 rears of an ongoing case-control study . Thislarxe, multicenter. populalion-based study wasdesigned to minimize some ot the methodologicalproblems which have been of concern in previous,tudtes ot enstronmentaf tobacco smoke and lungcancer. Both a cancer control group and a population- ontroi 2roup were setected in order to evaluate recalloias. A unt)orm h)stopatholoRtcaf review ot diagnosticmaterial was conducted for case confirmation anddetailed ciassutcat)on . Biochemical determination ofcurrent exposure to tobacco and screening of multiplesources ot tntormat)on to determine lifetime nonusewere utilized to minimize misclassification of smokersss nonsmokers .

A 30"% increased risk of lung cancer wasassoctated M)th exposure to environmental tobaccosmoke trom a,pousea and a SOY% increase wasobser.ned for adenocaranoma of the lung. Astattsttcaltv stentticant positive trend in risk wasobser.ed as p .uk-vears ot exposure from a spouseincreased. reaching a relative risk of 1 .7 for pulmonaryadenocarcinoma with exposures of 80 or more pack-.ears. ihe preoumtnant cell tvpe oi the reviewed,eligible lung cancer cases was adenocarcinoma (78%) .Results were verv similar when cases were compared toeach control group and when separate analyses were

t+te+.eo a/aVl' Thy resear<n wa, supponed bv (.rant CA40095 from the NatwrvtC+nter )nuduteJ te) wtwm recueses wr reonnts should be addressed . at Department otPrthNnrtv tiU A.trd'ca) Center. 1901 Perdtdo St . New Urleans. LA

conducted for surrogate and personal respondents.Other adult-life exposures in household, occupational,and social settings were each associated with a 40-60% increased risk of adenocarcinoma of the lung . Noassociation was found between risk of any type of lungcancer and childhood exposures from a father, mother,or other household members .

IntroductionApproximately one decade has passed since the initialreports ot increased risk of lung cancer in nonsmoking..omen married to smokers (t• 2)_ The ensuing studieshave provided a body of data which suggests a small butsigniticant elevation in risk of lung cancer associated withexposure to ETS' (3-22). In reported prospective studiesexposure has been assessed by the spouse"s smokinghistory, primarily that ot husbands . In case-control stud-tes, the primary ETS exposure assessed has also beenthat from a spouse, although exposures from parents,other household exposures . and the workplace havebeen examined in some studies .

in general, these studies have included fewer than300 nonsmoking lung cancer cases whose self-reportedsmoking status has not been validated by biochemicaldetermination or other means. Reviews of available stud-tes of E TS and lunq_ cancer in nonsmokers by the NationalResearch Council 123)• the internattonai Agency for Can-cer Research (24), and others (2i. 26) have concludedthat although misclassification is unlikely to account foralt of the observed increased rlsk, some misclassificationof current or former smokers as nonsmokers is likely(0.5-S 0°/.). Because smokers tend to marry smokers,misreporting may introduce some bias in the estimationoi the magnitude of the observed etfect .

This study was undertaken in 1985 in an effort toaddress a number of unresolved issues related to ETS :

(a) M)sclass/t)cahon oi Smoking Status . Multiplesources of information are utilized to ascertain nonsmok-ing status (medical record• physician. and then the studysubject or surrogate). Study respondents are questioned

~-twice (at contact to set up the interview and at theibegmntng of the interview) . Self-reported current non-smoking status is corroborated by measurement of ur)-nary cotinine .

(b) H)stopatho/ogrcal Specrt)c,tv. Microscopic diag-nostic slides are reviewed by one pulmonary pathologistboth to conttrm eligibility of cases as primary lung carctnomas and to provide a detailed review Isubtvpe, dtffer-

' The abbreviations used are : ETS . envrrnnmenui tobacco smoke : SEERSurvetllance. Eptdemwio}ty, arxf End Reudt. OR. odds rata: t.t, cornarlrnce tntervai

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luns Cancer rn Nonsmo4,n4 Women

••nrratront and classnccatron of the hrstopatholoqical celloe-

iRt'cJti fj, .rti I .%e1 control Qroups, ore `.ith ce3lon3rrc c•r anci one rrr)m trie KR'neral pc)purJtlun• 1re setec ted.r ( JsN•trmtrrtt c,rrnnarikuns Uiltert'ntral recall betweent•rs and c c :run t,ir,c t•r c ontrois should be nirnrrnrledu r butn struuus are itrti,wrlv motivated to recatl earlier

• • txnures,Jt -Nource•rt t js flt;usure tntormatron on childhood

•-tjosures uom a t-,thrr, mother, and other household-•r•mners rnci aciutt r%u«surrs rr<tnt nu•oandtst . other•-orusrnold me•mnrrs, rnU oeeupatronat and socrai set-• nsts is obtained bv questtonnatre• 6 he risk associated. .ith e•posure to E1S trum dttterent sources and duringiterent time pe•nruls can be evaluated .

ret Conrounden and Other Risk factort Because the--agnttude of the main ETS etfect is etpected to be small,r s important to tak :• into account potential contoundtng

s tors and rrtec t mndrt%rnt; tactors in a studv L%rth a- .trurntlv 1•trqe numner of cases anti controls . It istrcrt)3tea tnat utiun cumptetron of this stul3v about bUUssrs and t%.ue that number r,r controis t.rii havestthc rUatrc7

r hrs rrpart rr•nretirnts trndrnqs trnm the ongoing,tsv .rnu rnc ruvc•s tne• targest numoc•r r>r trtrtrme nun-mc)krrs w,tn tung c anc ers reported to date . t hrs report

. .rs tt-rt to be tu.t,tted rtr%en the puuuc hejitn importancert the +ssue unde•r rn . r+trqatton .

methods7>'e studv is a popufatron•based case-controi study of.,nst c anc er in women vs ho ha%e ne%er used anv tobaccooduc t f hrs Ure•hmrnarv report rnc ludes cases dtaR-

•osed during the rrr .t three srarS tUecember 1• 1985•-rouRn t3c•c embe•r 31 . tQ881 of a 5 o rar study. At the

+ .rP tyt r4rastnosrs c,rscs %%rre residents of one of tne°• .uor mr•trnpont,tn •uc•as lnrougnout the t_ nrted ~tates,t luarnq .atlanta •c !,,% :un. t<ubb. Ue•Kalb. Eulton, and, .rnn.•tt c„untrc+~ t4 .,uswn tt:3l.c•ston and F i.trns

.,untresr . lus Anstetrs sWs Angeles Luuntvt . New Ur(e-:^s ttrtterson . Urleans. and St . Bernard partshest. and•nr .~i,tn F ranc rx u t3av Area tAlameda• Contra Costa .••s un. ,,in Er-tnc t%c u . mn mateo. and !)anta Clara coun-. r%r, rrpresrntrnK a population ot approximately 18 .5•-* :Nrun people or ts°'o of the U . S. population .

Case and Control Selection•taprd case ascertainment procedures• which includedrevtew of pathology repons trom study hospitals, were.tdrred to tdentrrv potentially eligible lung cancer cases .;irxrbte cases included Enqltsh-, Spantsh-, or Chinese-`peakrnst temates. aged 20-79• who had a htstopatholog-,catlv contrrmed diagnosis of primary carcinoma of the,nK t rnternauunai llassrtrcatton of Drsease, 9th Revtston,

c ode t bZ) made prior to death, had no history of previoustancer- and who were lifetime nonusers of tobacco .t rteame nonusers ot tobacco are dettned for this studyas persons who had smoked fewer than 100 cigarettesind had not used any other form of tobacco for moretn o rnontns .

i'wo controi groups were selected . The first controlgroup. reterreo to as the population control group, wasselected by random digit dialing and supplemented by• tndom samplrntt from the files of the Health Care Fi-

nanctng Administration for women aged 65 and older .Controls were trerluencv matched to cases on age (<S0,30 59. 60-69, ; 0+ vears) rna 2 :1 controF•case ratio . Theymet the same elrqrbrlttv criteria as cases tor age, rest-dence. language, and tobacco use-

Femafes, aged 20-79 . +.rth a diagnosis of primaryc arctnoma ot the colon t!nternattonai Classification ofQisease. 9th Reviston, code 153) who met the language,previous cancer, lifetime nonsmoking, and residentiale(tgtbdttv criteria of the cases, were identified and fre-quencv matched to lung cancer cases bv 10-year agegroups and race. ihis second control group was selectedbecause there is no established increased risk of coloncancer associated with either active or passive smoking,and it provtded an opportunity to examine the issue ofrecall bias associated with a recent diagnosis of cancer .

A multistep procedure was used to determine life-time smoking status . After identification of a potentiallyeligtlt : : lung cancer case or colon cancer control, thehospital chart was reviewed to obtain demographic dataand available tntormatton on tobacco use . Patients tden-trtred as current or tormer smokers in the medical recordwere considered ineligible . !n study areas where individ-ual phrstcian notrttcatton was requtred/preferred, thetobacco use hrstorv was requested trom the physicianfor potentially eligible cases and colon controls identifiedas nonusers of tobacco or mth unknown smoking statusaccording to the hospital record . Women who wererdentteted as current or tormer smokers by their physi-cians were considered ineligible . All remaining cases andcolon cancer controls belte .ed to be nonsmokers or withunknown smoking status aere contacted by telephoneto elicit information on tobacco use . Women who re-ported ever smoking 100 or more cigarettes or using anyother torm of tobacco tor more than 6 months wereconsidered ineligible . The identical telephone screeningprocedure was used for the population control group . Atthe time of the interview, the tobacco use screeningquestions were repeated to conrtrm each study subject'sreported nonuse of tobacco .

The questionnaire was translated from English intoSpanish and Chinese, and interviewers tiuent in thoselanguages conducted the non-English as well as Englishinterviews. Interviews were completed tor 431 of 514incident cases (84%), 358 of 489 colon cancer controls(73%), and 794 of 1105 population controls (72°'0). Sixty-one (3.8%) of the interviews were conducted in Spanish(n - 14) or Chinese (n - 47) : 22 cases t5%1 ; 23 coloncancer controls (6%); and 16 population controls (1.5%).A next-of-kin interview was solicited for lung cancer casesand colon cancer controls who were too ill or deceased .jkll population controls were self-respondents becauseof the sampling method used to identify these controls .At total of 143 lung cancer case interviews and 35 of 352colon cancer control interviews were conducted withnext-of-kin respondents, representing 34% and 10% ofthe eligible respondents .

An extensive structured questionnaire obtained in-formation concerning household, occupational, andother eroosures to environmental tobacco smoke duringthe study subject's lifetime. Data were also collected onlifetime occupational history, usual adult diet, family andpersonal medical histories, and other exposures of inter-est, which are not included in this report.

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Cancer Epidemrologr, tiiomarhen & Prevention 37

"rv'e I t•^narv cotmineccrt•auMne fnRJmqt bv case{ontrol status rable 2 Patholoev review

(unR l.olonpn0ulahon Reviewed . found to be e1iRibie 359 f85541

tJncer :ancert oncrols Adenocarcmoma 281

(Jses C OntrO1S Large cell carcinoma 43Squamous cel/ carcinoma 20`•Jt W Small cell carcinoma 12~ :mp+esro : {9 :60 t)F14 Others and not otherwise specmed 3F• ti,D/e t< 100 nqJm ;/ :1? :i) b'0

h.e•t.;eD1e t Z t UU nvmgj ; . 14 Not revtewed/,nsufftctent matenal 50 (1156)!ne oertormea~r8 reSppnQents a 66 110 HtstoloRy by hospual pathologist

Adenocarcinoma 30`.+at 01 k.n tespondenls 1 14 3 :

Large cell carcinoma 5

sCSquamous cell carctnoma 7

rSUitf Small cell carcinoma 2EI^R-OIe k<1U0 ntJmtu Others and not otherwise specaied 6.tean t"Ut 69Stt2 111 582(tt 681 968t12 881

•sedun 20 0 54 Review pending 11 f3%)ZJnite 0-714 0•884 0-9501

v+et.RdHe ts 100 nR/msl Total cases 420e .nee t 11 .219 9 4G-5 lfsl 1oi-14 nt4

Reviewed, found ro be ineligible 9

Eliqib,bry Review ProceduresBiochemrcal Determination o1 Current iobacco Use . C:o-t ntne a mator mPtabohle of ntcottne t,) an indicator ot•ecent exposure tt> tubaCCO t27) Urinarv cCltlnrnP wasused to c orroborate selt-reported current nonsmoking.tatus of stud . subletts A urtne s .tmpie Nati cullectedfrom ati consenting study sub)ects at the ttme of lnter-4irw ihe specimens were stored at -20'C until ship-ment to the American fieakh foundatton tor anahsls .

Cuttnlne was cuuantttated by radtotmmunoassav us--ntt the method of Nalev rr a/ (28) with a mod/ncatlonof the anttbodv of lanqone et al . t29) . C.otlntne levels..rre adlusted for urine flow based on (reatlrnne valuestlv determining the cottnrne/creaUrrne ratio Creatininesas determrned by spectrophotometrv using the kodakE t.tacht'm 4EHl Clinical Chemistry Analyzer

>t th•s ttme btochemrcal analysis is complete tor 2 39.,t t 11 c,tses t i i i°o) :b0 ot 358 colon cancer controls-= 6°ot .rnd bti-t of :93 papuiatlon cuntrois /86 .1%)Table t t T«o of 2 39 case samples 10 8%) . 7 of 260 colon

t ancer c nntrol samples t2 b%1, and 14 of 684 populationt ontrol samples t? 0°'et had cotinine/creatinine levels ofttitl nit/ms or ¢rt•atrr Fhere is no established cotinine/c reatmtne trvri wht(h clearlo discriminates smokers tromt•ue nclnsrnokers hea4dv r%posed to ETS. Under rela-to.rt. high tr•eh of exposure to ETS in aircraft rind inE•xposure c hambers . urinary excretion has reached a levelof ii ris,t)mR crcianntne t)0. 31). In this study . womenv.hoSe cotenrnekreattntne level exceeded 100 ng/mg~N e .e eitc iuded from the study to eliminate persons likelyto be ac tr . e smokers. while allowing for the possibility of.erv ht¢h ETS exposures retiected in urinary levels of 56-99 n¢jmg creaanrne . Had the lower value of 55 ng/mgt-e•Pn cPtected as a c utoolnt to avoid possible mtsclasst-ticatron ot acttve smokers as nonsmokers . 4 addlttonaFc ases (t 6%) . 2 c olon cancer controls (0 .8%). and 13popu+aaon controls 0 9%1 would have been excludedfrom the analyses . with negligible effect on the results .

Histopathotoriical Review. Representative diagnostic mt-..'+4vD,t ti-t,r si .ues tor each case were rerjuested from

the hospital . These slides were reviewed by one pathoi-agtst specializing in pulmonary pathology . A total of 368of 429 (86%) potential cases have undergone review . Asshown in Table 2 . 359 (98%) of the reviewed cases were._ontrrmed as primary bronchogemc carcinoma . The hts-

topathologtcai prtmarvi cell type of the eligible cases is asfollows: adenocarctnoma, 78%: large cell carcinoma .12%: squamous cell carcinoma. b%: small cell carcinoma,3°l0 : others . 1% The hlstopathofoglcal cell type distribu-tlons were similar in the ttve study centers .

The overall concordance between the review pa-thology diagnosis and the original hospital pathologydiagnosis was 81% (Table 3) . The concordance variedgreatly by histopathological cell type. Nrnety-seven %(237 of 244) of the cases originally classified as adeno-carcinomas were conflrmed as this htstopathological typeupon review . Simtiariv. 10 of 11 (91%) of small cellcarcinomas were so classified upon review . Concordancerates of 56% and 67% were seen for large cell andsquamous cell carcinomas. respectively . A relatively largeproportion of cases originally classttted as large cell orsquamous cell carcinomas were classified as adenocar-clnomas by the review pathologist : 18 of 46 (39%) and 6of 24 (25%)• respectively . Based on hospital pathologyreports. 34 subjects were categorized as -other-prftttarylung carctnomas- which primarily included diagnoses ofpoorly differentiated carcinoma. bronchogenic carci-noma not otherwise specaled . or malignant cells nototherwise specified . Upon review. 94% of these caseswere classified into more spectnc histopathological celltypes .

The nine cases 12%) found not to have primarybronchogenic carcinoma on review were excluded fromall analyses . Three of these nine cases were determinedto be carctnotd tumors, two were ivmphomas, three werecarcinomas metastatic to the lungs trom other primary

~-sites, and one was a benign neopiasm . The 61 cases thatbave not undergone histopathological review are in-cluded in analyses ot all lung cancers combined (n =420) but are not included in analyses stratified by histo-pathologtcaf type.

Statistical AnalysesExposure to ETS was examined by source . Sources in-clude both adult and childhood exposures as follows :spouse, other household members; occupational ETSexposures; and social or leisure time (nonhousehold,nonoccupational) ETS during adult ltfe ; and father .mother, and other household members who lived in the

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j tung Cancer in Nonsrnoktnra Women

p!e 1[), .tnbution ut lunq cancer ntscnpathnloqlcai ced tvpes bv hospltat dlaqnosts and review dlaqnosls

~ .•~ .nv /1~aYM1S11Ndrnrx Jrcdr.-^Ia

trosprtai dlaqnosls

I rrqe ce• I squamous ced -mail t ed t)her sunqr irc :noma t,trrinoma a ar( inoma ,,Irc :noma 'otai

k•tr(Mx .l/( WIrlmJ :3 : F8 b I 19 .8t,rtte (el/ r Ar . •n .u..a '1 t 0 t0 43

' .u[nWU1 ( t -I , .ut ~nnma • t, Ib 3 2 20

""All ( e/i t Irt ,MN-4 -1 1) 1 !U t 12C2•hN prlmarv /unlt t art /ntML• t J 0 0 2 3

vt :'+ ah =1 tt 34 359

rome b montns or more during childhood . Childhood..,as rlettned as the first 18 Nears or hte . Ekposures jromoarents atter that time wrre classttted as other householdiembers during adult ltte . Dichotomous ETS exposures

. .rre rrrst etamrnPrf ieser or neveri by tNpe ur tobacco :;arettes : pipe : c,,tar : or anv ot these t% pes ,r iobacco .

Jose was estlmated, as appropriate. bv intensity te 4 .-z.moer of ct>;arettes/davt . duration te+t , number r,tears e.poseoi. or a c ombtnatton te 4 . pJCk•%rJrst . Pac k-

. rlrs t)t C tst.lrettP r•pUsure trom the •puuse s .rre ( afCu•, .rted by murttpt-, tnK tne numoer ot pdcl.s •moked periav bv the numoer rlt srars tne wousr smoked c tqJrettes

..ntle hv/nq w/th the study subtect. NJck•l.rdrs ot ezpo-,ure wrre summed for all smoking spouses ot each study•uotect .

One or the obtectlves of this study was to evaluatethe assoctatton ot ETS with spectttc htstopatholoRtcal cellrs pes ot lung cancer, t he skewed distribution ot htsto-;,tthoio¢rcal tNpes precluded any mearnngtuf analysis by-pe•ctttc cell ttspr other than adenocarctnoma and allotner cell types cumbtned. The resutts are presented torPi lung cancers combtned in - 4201 and adenocarctno-^.ts conrtrmed ev nlstopathoiosttcai review in - 181) .

( Jses %.tvp cumpdred to each control group with

lirt1 tA the (tl,thtlutlon or rCfevant covar:ates such ds

. :e. e(fucatton . Income. and race/ethnicity. the assoct-.uton of ETS e=posure with lung cancer risk was tnvestt-;3ted first in contingency tables stratified by design or•emottnq variables la4p. race . studvi centerl and relevanttovartates. ~oummarv adtusted odds ratios and test statts-::cs wPre calculated by the method of Mantel and Haen--cet t i :) . l:ncunasttonal logistic regression analyses werer^en used to estimate the associations by summary ad-,usted odds ratios. confidence itmtts, and test statisticst33. 34) .

ResultsDemographic charactensttcs of cases and controls arepresented in fable 4 . Cases and controls were similar. . .Itn respect to matchrng variables and most demo-;rapntc variables. ihe largest number of cases (n s 160,38%) were residents ot Los Angeles . followed by casesfrom the San Francisco 8ay Area in - 149, 35%) . andthen the three smaller study centers in the southernt-'ntted States: Atlanta in - 4f,, 11qo); Houston in = 39,-'oi: anu New Urteans in - 1b .

The age distribution ot cases and controls is untform,wtth 73 to 74% of each series between (he ages of 60through 79 . The proportion of older women in this group:,f female nonsmokers with lung cancer is higher than

that among all female lung cancer cases in the SEERProgram 1974 1986, in whtch only 48% of the caseswere aged 65 or older 05) .

Cases tended to have a somewhat lower householdincome and less education than the population controls .Approximately 35% or cases and controls spent theirc hddhood in cities with populations of 50 .000 or more,and the majority of cases and controls (70%. 68%, 77%for cases, colon cancer controls. and population controls,respectively) resided in cities during most of their adultlife .

The estimated risks of lung cancer in nonsmokingwomen associated with ever having lived with a spousewho smoked are presented in Table 5. The adjusted ORsand the 95% Cl are very similar for all spouse-relatedexposures regardless of control group . For all histopath-ological types of lung cancer combined, a 30% increasein risk is observed (OR - 1 28 and 1 .29 with colon cancerand population controls) . For each of the three types oftobacco smoked, the ORs ranged from 1 .14 to 1 .26 .When the case series is restricted to the 281 pulmonaryadenocarcinomas conttrmed by htstopathologtcal review,the association is more pronounced. Approximately 50%elevations in risk of adenocarcinomas of the lung (P <0,05) are associated with any use of tobacco by spouse(s),and cigarette smoking accounts for most of the tobaccouse. The estimated relative risk of pulmonary adenocar-cinoma associated with cigarette smoking by spouseswas 1 .36 (1 .02-1 .84) with the population controls ascomparison and 1 .31 (0.94-1 .84) with the colon cancercontrols as comparison. No association between spouses'tobacco use and lung cancers other than adenocarci-noma (squamous cell, small cell, large cell, and other; n= 78) was observed .

Separate analyses were conducted for subjects whopersonally responded and for whom information wasobtained from surrogate respondents . The odds ratios for

t involuntary exposure to ETS were very similar for bothroups of respondents; therefore, the results are not

~resented in the tables separately by type of respondent .One such example is the estimated relative risk of pul-monary adenocarcinomas assoctated with cigarettesmoking by the spouse: OR - 1 .38 and 1.30 for surrogateand self-respondents, respectively, companng cases tocolon cancer controls .

Effects by studvi center were also eYamtned . Theodds ratios by center ranged trom a low ot 1 .17 to a highof 2.64 for risk of pulmonary adenocarctnoma associatedwith spouses' cigarette smoking. Because of the limitedsample sizes, none of the individual study center estt-

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Cancer Epidemiofollv, Biomarken & Prevention 3 9

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17 1881 46 11111 98 f1 2 6 1136 11481 109 r31 n 291 ( 17 31

1 to 7) 1 1011 1 ( u 4 1

23 IS 51 15 14 1) 1n tt 31to 12 41 6 (1 7) t l it 7)sq +v 11 .8 t8W sj 1 ;81it (11 b1 b1 11741 IU8 III9)

293 t6981 240 t6841 601 t7701

: tq St 1 to 3 ► 3 tn 4 f

mates were statistically stgnlflcant, and they did not slg-nlflcantlv duter from one another .

Estimates of relative risk associated with the number+ t c trarettes smoked by a spouse were stRntftcantlv ele-%,ated only in the highest exposure category, 40 or more

clgarettes/dav : 2 .06 (1 .19-3 .54) and 1 .69 (1 .28-2 .61) foradenocarcinoma of the lung comparing cases to coloncancer and population controls . respectively . Odds ratioswere similar, although slightly lower, for all types of lungcancer combined : 1 .70 (1 .02-2 .84) and 1 .36 (0.90-2.06) .

Pack-years were examined as a combined measureof duration and dose of exposure to the husband's ciga-rette smoking. The odds ratios for all cell types of lungcancer combined and for adenocarcinoma of the lungare displayed in Fig. 1 . Separate analyses were conductedwith each control group for comparison . Because thefindings were so similar for each group, the results arepresented for the two control series combined (n -1 t 31) . An increasing risk of lung cancer and adenocarci-noma of the lung associated wlth an increasing level ofexposure to the spouse's cigarette smoking was found .The positive trend in risk by pack-years of exposure isstatistically significant for adenocarcinoma of the lung (P< 0.01) . A weaker dose response is observed when allhistopathological types of lung cancer are combineddtrend . P - 0 07) .

Exposure to ETS from various sources during adultItfe was eNaluated . The results are summarized in Table6. For slmpitclty of presentatton, the data in this tablealso represent the findings using the two control groupscombined because the individual results using each con-trol group were entirely consistent Exposures to cigarettesmoking from spousets) . other household members, onthe tob and in other activities of adult life i'social') areeach associated with an overall 40-60% significant ele-vatlon in the risk of adenocarcinoma of the lung. Asnoted prevtously for spouse-related exposures, the riskestimates ror all lung cancers without regard to cell typetend to be slightly lower than the comparable estimatestor adenocarclnoma of the lung . Significant positivetrends (P < 0 .05) in risk of adenocarcinoma of the lungwere associated with increasing duration (years) of ex-posure to c txarette smoke trom a spouse, other house-hold members . and social occasions . For adult householdexposures from a spouse and others, estimates of riskrose from lowest to highest in the 30 or more years ofexposure category ; however, trends were not smooth forexposures in occupational and social setttngs .

No association was found between risk of any typeof lung cancer and childhood exposure to ctgars, pipes,cigarettes, or all types of tobacco combined . Table 7presents the estimated relative risks of lung cancer andadenocarcinoma of the-lung among nonsmoking womenwhose father, mother, or other household membersmoked during childhood . None differed significantlyfrom unity . Years of exposure and amount smoked were

'also examined . No significant elevations in risk werefbund at any level of smoking by household membersduring chtidhood-

DiscussionOne of the most striking findings of this study is thedistribution of the histopathological cell types of lungcancer in a population-based series of cases wellscreened to determine lifetime nonsmoker status . Sev-enty-eight % of 359 reviewed eligible cases in this reportwere classified as adenocarcinomas . This high proportionof adenocarcinomas and the pauutv of squamous andsmall cell carcinomas was consistent across all study

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~ - -- -°- .. . ia.=.. . . .~ .~ . .,. .+.I r=' -- -

lunt; Cancer in NonsmoL,nR Women

' . ltr i ^•u+ . ~Ji .un tx•twrrn .m.rk,nq status r/t spnusrls/ and lunq t anc or nak• ,dl lunq cancer and Jdenotarclnoma ut the lung

Ad(usted odds radw'

a .usr r. W . . •. .. ..r' t1Jta .I • . '

t J1l•1t . , .ltun a dnc cr

a nntruts

P . .pulJtunna u, .uuts

t.ulon e anc ercuntrols

t)R (95•0 ( I)

Pupu/ation controls(aR (95"• CI)

s .1 .01 nIII i711 n - "nUlan~lapr•d~ .r>.aau .•'i :tl ;'t2 1 28 t0 9)• 1 : S) 1 29 10 99-1 691e •Karetu s Er3 :'J9 441 1 17 10 87- 1 591 1 :0 10 9 3 - 1 55)t • .CJr• hl 54 97 1 14 /0 %6-1 71) 1 26 t0 88 1 801~'•nr F 1 i : 110 1 17 (0 78• 1 771 1 :1 (0 8s-1 72)

a .lrntxart .r•a .ny ^l .att n . iit) rt s :1401anr t.w .N 1.•trJCto _U) !St 442 1 44 11 01-1051' 1 47/t u8•20t)•Cnurrur . 183 :09 441 t-31 (094-t 84) 1 36 (1 02-1 84(•C AAr• 41 5a 97 1 05 (067-1 661 t 15 (0 76-1 74).'p, . st ;2 tt0 1 ib(0.74-182) 1 20t0St-) 79)

' Lj'ustrd tor atir .a-anewjusr . Uee iwhur- MaKkk oq+ert . studv area Los Angeles. San franctsco Bay Area . Southern U S . : Adanta. Mouston, and New.•ansr Jnnusi1 rJ-r. wrame a<St {Otiu. $1 1 WO-S)s 99Q S35.(100*1• and education l<h,Rh schoof degree . high sthoof degree, some colieae or

<tlt15

e•ntt•rs in tnr •tt,tSv ttt na)bat and W~nder t8), a similar•nnt:tttrtn t : s•,) t,t Kre%berq 11 npe tumors was toundti tne'tr St'rtN1 r+1 47 nunsmoktnQ tt•mates v%hose srlt•

'a'txuteci non.mtsktnK status was conurmed by chart re-~.rrw tn thN l-lt'i) )tatCS adRnOtart :tnoma is the mostcommon htstop,ttnoloRtcai celf tvpe ut primary lung can•e t .•r in wt,men uut the proportion o) all female lunge ancer cases Mrtn atf subtvpes ot adenocarctnomas tpap-./carvi aunar. proncntoloalveofarL and soltdl is 34% (SEERPublic Lser tave. )'s'%8-iQ87) .

Our studv. in %%ntt h adenocarc tnoma ts predominant,ntf ts lne crtt trivr ttrariv asSUCtaled v.tth increased risk

0 <15

from adult ETS exposures. is in contrast to several of theearlier studies of involuntary exposure to ETS . Tricho-poulos et aL (2) tn the initial case-control study of lungcancer and passive smoking among nonsmoking womenexcluded cases of adenocarcinoma tnciudtng bronchio-laaiveoiar: however, that study included no histopatho-logical review. They reported an odds ratio from 1 .8 to3.4 associated with the husband's smoking habits . Dala-ger et ai . (16) reported a 3-fold elevated risk associatedwith the spouse`s smoking only for squamous and smallcell carcinomas and no increased risk of other cell types,of which adenocarcinoma and its subtype, bronchiofoaf-

15-39Padc Y.ars

40-78 a8o

t C r Arf,usted odds ratros /w all lung cancer and for adenocarctnoma of the lung associated with pack-years of exposures from spouselsi. CL all lung,nc rr . u rnd ,+ ., r l r : t1 adenoc arctnoma . trend P< 0 01 .

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Cancer Epidemio(ottv, iiomarken & hevent(on a i

Ampcytpn Oetweert risk' of IunR cancer and adult exposures

,rl ciWrette smote amonR non9mokinR women

AII IunR Adenocarcinoma

carctnomas of the IunR'• rarS or e .oosure adwsted adwsted

uY SOurt.t odds rat o• odds ratio',Q;w cn iv5% cn

rrnulenord e=Gosure~pou.e(- ere+ooseo' 121(096-1541 t 18t104-181f41 ears 100 1 0

t ; 1 t9t088-16i1 t 11 10 9 3-1 89)sy-10 1 14 1081-1591 1 a0(096-2031>to I25(091-1 721 1 4t(099-209)

7rendP-014 trendP- 001

(-Ithefr household memtkrSever eloosed* 1 23 to 97-1 561 1 19 (t o5-1 82!'0rear. too 1001 5 120(090-16it 1 16(o98-1891n.• 121t089-169r 1 3i(093-193)

tr cuoat .onar etoosureE,r . e .DOSeU

r,.ndt'-nt1

1 13 t t 0 t•( : V

'•rndY- () 03

I 13 11 06-1 9'r~,.a .. tno tnn

ti 11t08h-1 :' . 1 '8t1Ui-1 t9rth-lo l aill0i•1Uur t s1( .197 .2u .'I>{V I 10tU9s- t 8th : s7/09.) .20_t

4 .xa+ e .ooswe'

(- e.e•ouxb'

T.endP-no2

I 58t1 22 20jr

r, .nd P - (1 10

I h011 19-213i0 t00 100r,s t tato9- .1 nl, t 19(o89•18 .'t'6-10 2011119-t t .r 14oU 47-390r>(0 1 65 to 98-2 801 1 50 (0 78-2 771

treMY- nOIxob irrndP=0002

' .rtrweo rcr ate raae, stuav area annua unumea and education` v .rer .n. .w . . . e .a,+eo+~<llr)s

.., r... .oo,., H e .rx-AeA Ih . .ea..

4r e .uV.ure h urhrMeO a+ fa{X)%ure nf .1 ur nltire h/week trqm

+.+wce% ornr tnan occutSatwrui and houwnuKl members, mcludrnot

•r,ous!><001

~.eotar carcinoma . Comprtsed 46 1% ot the total femalenonsmoking cases . In the Swedish study of Pershagen eejt 1351. 5"°0 ot 77 female nonsmokers were adenocar-ctnomas and 31°k squamous and small cell carcinomas .The only statistically significant ETS-associated increasedrisk was tor squamous and small cell carcinomas . the celltvpes with the highest relative risks associated with activesmoking. At the present time small numbers of squamousrelt and small cell carcinomas in our data set precludean aoequate assessment of risk associated with ETS ex-posures tot these cell types .

The ttndtngs of our study lend some support to themechanism proposed by Wvnder and Goodman (36)whereby inhalation of sidestream smoke might primarily••rre3se rnck of adenocarc(noma of the lung. Thev sug-gested that inhalation ot sidestream smoke through thenasal passages would hinder deposition of respirablesmoke particulates in the periphery of the lung whilegaseous components such as volatile N-nitrosamines,(Jrmatdehrde. acetaldehvde, or nitrogen oxldes . would

be likely to reach the deeper part of the lung . Bothsquamous cell and small cell carcinomas tend to becentrally located, rather than in the periphery of the lung.

Our study found statistically significant elevated risksof adenocarcmoma of the lung among female non-smokers who had had household ETS exposure or ETSexposure in occupational settings or from other sources .Each of these exposures occurred during adulthood .Exposures during the first 18 years of life were consist-ently unrelated to the risk of lung cancer .

Any exposure (ever/never) from a spouse whosmoked was associated with at least a 30% excess risk .Increasing amount per day and years smoked significantlyincreased risk. The pattern of risk was the same whencases were compared to colon cancer cases or popula-tion controls and was specific for adenocarcinoma of thelung. Findings for all lung cancers combined reflect theassociation between E TS and adenocarclnoma of the lungdiluted by the weak association with other cell types .

The internal consistency of findings with the twocontrol groups suggests that recall bias resulting fromhaving a diagnosis of cancer is not a likely explanation ofthe observed etfect . The possibility remains that non-smoking lung cancer cases and nonsmoking colon cancercases are not similarly motivated to remember exposuresto the tobacco smoke of others .

The longest duration of exposure to ETS is associatedwith the greatest elevation in rlsk• 1 .43, for exposure of30 or more years to a husbands's cigarette smoking .Although slgnlt(cant trends were found for other adultexposures, the dose response was not monotonic ; rela-tive risk estimates tended to decline in the longest ex-posure category. One possible explanation is that recallot quantitative measures of exposure is less reliable forexposures outside the home and for household f,rembersother than the spouse. A recent ten-country study wascarried out bv the tnternatlonal Agency tor Research onCancer designed to va}hdate self-reported recent expo-sure of nonsmoking women to ETS from any sourcecompared with the urinary concentration of cottnrne .Duration of daily exposure to ETS from the husband wasthe strongest predictor of urinary cotinine (37) . Studiesby Pron et ai . (38) and Coultas et a/ . (39) suggest thatquant/tattve measures, particularly for exposures outsidethe home, are less reliable than categorical measures .

The lack of any association between childhood ETSexposures and lung cancer in our study, as well as thestrong, consistent association with exposures duringadulthood, contrasts with two recent reports by )anertchet aL (22) and Wu-Williams et af . (40). Differences instudy design may contribute to the discrepant findings .About 25% (n - 45) of the 191 cases in the New Yorkstudy were males, whereas our study was restricted to

t female cases (n = 420) (22) . The authors report that therewere only small differences between men and women inthe amount of exposure to ETS measured by duration .The mean exposure of women to their husbands' to-bacco smoke was 16 .2 ± 16.7 years, while men had amean exposure of 13 .0 t 17.0 years from smoking wives .Furthermore, there was a higher correlation betweenexposure trom spouses lifetime ETS exposure tor womenin the study (r = 0.51) than for men (r = 0.37) . Intensity(dose) of exposure and temporality of exposure frommale and female smoker sources may differ considerably .Relatively small differences in dose, temporality, and

Nr_n0~WtnLn

w

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f.unR Cancer in Nonsmokinit Women

_~ . . - .. .. . .. . . . .~ . . - . - ,,,_,_

' .^!e : '• .cx ..uion artweMn rr,k' .tt IunR ( anc rr .tnd r hddhooo° earowres to tobacco smoke amonf( nunsmokmq women

Adlusted udds ratru'r .•r amrur•d t . dun t .rn( rr

fP' •VU( .tuun Culon c anr er Pnpulatron

sar c u c . .ntro s untrrrlst ontrolS ( onirols

(1R 05% Ct) OR (95% CI)

i ., .nY , .r .e .,r .r .+ds

f trhrr 1'0 091 (067- t 241 082 (064-1 07)tlxfrher :s 40 ')? 0 85 (0 53-1 38) 0 84 (0 56-1 261f)ther nuuarrv .4t mrnmtw•r

t

1', 1 i1 t . 7 0 83 (0 .59- t 18) 0% c0 .71-1 29). trnot arr .rwunaf rrhrr s-"0 096(069-1 ISI 0 89 10 66-1 19)•L .rher 1 irl 4 ' 091 (0 54-1 Si1 0 89 (0 56-1 43)t nhrr n,wsrruud mrmew. t ; ; Ii2 (17 081 (055-i 20) 091 (064-1 29)

• t .fiwrru tnr aqr rac e srudv area annuat ux rrmr .mrf l•Uucatrun- r ti .ldhootl rs de•nnru as r .ra Itt aears ut Irte

'euatton in cnmbtnatton may yield more meaningful dtt-r•rences in t• .nosure than that measured by duration)nr i nt, rn( .uswn tir mal(•s in the \t-w YOrk stu(3v,on pussttilv icawrr tft)ses ot ETS etposure trom smoking

.al .rs tr[r it'wrr .r•ars and during a more recent time; rrto(f . may nasr rec]uced the relattve nsK estimates that,rrr not qt'nc1er •t`t'Cttr( ~\ 4tuCtV in northeast Chtna•

. .nt(h s+•aS cumparaule in titte to our study. aetuailv)und a(feec re.tsed risk of lung c ancer assnc tated .. tth

~ TS rxNosures from spouses and a suKKestme tn(rE•asedri .k associated wrth paternal smoking r4U) . As suggestedf,v the authors, these women had heavy exposures tot5oth indoor and outdoor pollutants. Khlch mav haverybscured any rrtect ot EfS .

The studies wntch have examtned r htldhood expo--ures are more limited than those which have tocused<)n tooacco use uv spouses, and the o%eralf t,ndtngs are,nc onc iusive t 3 . 5 . 1 1-1 s- 22 . 411 . Studtes ot the reliability,,r recalt or E TS exposures suggest that recall of a parent's•mnk,ntt hlstorv is iess reliable than that tor spouses 138.

)t . and this may account in part tor tnconststenctesrt..r•rn tituutes . f .tnertch t•t at_ 1L'1 found a 2 told tn-'ease(J risk assUttated wttn 25 or more smoker-years

, .urtnst childhood and adolescence but no increase fort niidhood exposures of less than 25 smoker-years tOR= 1 09) tn most studies which have reported positive.,ssoctattons . the rtndtnps have been primarily tor mater-nal ETS exposures in smokers rather than in nonsmokers .Correa er a( t il found a stgnrncandy increased risk offunt; cancer tUR - 1 36) among smokers whose mother.moked but no increased risk in nonsmokers and noelevated risk associated with the father's smoking . Wu eta/. (14) reported a nonstgnificantly elevated risk of ade-r•ocarctnoma ot the lung tOR = 1 7) in females, 80% of.4hom nad a htstorv or smcktng. Similarly, in a Swedishstudy ot female lung cancer which included primarilysmokers, a nonstantflcantfy elevated risk was assoctated...rtn maternat IUIZ a 1 8) but not paternal tOR - 0 .8)smoking (a2) . Other studies have failed to ttnd an tn-e reased risk ot lung cancer associated with childhoodexposures (11, 12, 43). None of these studies examinedmaternal smoking as distinct from other childhood ex-oosures. Childhood ETS exposures alone may be insuf-'i-+ent to tn( rease tunK cancer risk in ittetlme nonsmokersbut may increase risk in persons exposed transpiacentaUyor during childhood who later smoke themseives (5) .

The female lifetime nonsmokers with lung cancer innur study are considerably older than the female lung

cancer cases reported in the SEER program, most ofwhom have actively smoked. This may represent a cohortetfect : that ls, older women are less likely to havesmoked. The age disparity might also reflect possibleeittterences in response among active and passive smok-ers . Ihe lower dose ot ETS might require a longer dura-tion ot exposure for pulmonary carcinogenesis .

Although this report represents the findings of thefirst 3 years of a 5-year studv, it is nevertheless the largestcase-control study reported to date on this topic . ThefindtnRs provide additional evidence in favor of a causalrelationship between exposure to ET5 and lung cancerin women who have never used tobacco themselves . Adose response, not likely due to chance, was apparentfor exposure to tobacco smoke during adult life from avariety of exposure sources. The association was specificfor both adenocarcinoma of the lung and for all lungcancers combined compared to colon cancer.

AcknowledgmentsThe authors are qratetui for the cooperatron ot alf of the participatinghospdais in the frve studv areas and the many physicians who hdpedmake this study possibie. The authors also thank Rafael larpa. YoupingLrn . Gad Smith. Mahboob Sobhan. and Utego Zavala tor programmingand analytic support : Laurd Cederqutst. Annie FunR, ludy Goldstein.Heten Gregory. and Anne AAorse for held supervnton : Or. Nancy I . Haleyand Caren Axefrad for directing the urinary coanrne analvses : and thededicated medical record abstractors and rntervrewers in each studycenler .

References

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I9 tam I H t,un4 I•t Non! L M lam . W K . Kleevenc I sv

l SaV. U ttw l- 3rnevratne ) Lam, ) Y, lo- K K, and Lhan WC SmoamR pasNve smWr+t and nrstofotpcal Ivpes in lung cancer in

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:0 Inowe t1 arW Hrrasama I Pasyve smoking and lung cancer in«Qnten in ws AotF 5 H .um+cM and S Tomrnaaa teds 1 . Smoking and

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21 Grnt t,, Y t,anR- Z H Z'`.anR, A Y . and Wu G L_ C1n the

rr4atqnsnro ber..een smortnR and terryle lung cancer in M Aoki, S

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: s tK 0 %rnu t D 8'Jnnemann 8 Dodet . and 0 Hotfman teds .l.t nvnunmentar l a,t rnrKens F.trtnods nl Analvsrs and Exposure Measure-ment vnt 9 Vawse )maktnR IARC SuentttFc Publications no . 81 . Lvon,FrarYe• InterrytRXL/ AeerKY tor ReSearch on Cancer. 198)

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Cancer Epidemiology, liomarken & Prevetttion 43

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