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1 I THE 1:AtMCET, SEt'TF14lH ER 10. ) 983 PASSIVE SMOKIIrG AND LU1NG CANCER. lYELAYO CORREA LIIh'DA Wll-L1AMS PICRLE ELLZABETH FO\THAM YoUPltrG Llt. Wll.LtrJN HAENSZEl. Deparrrnnrt of PathoFop; Louiriaw State flnitirrsiry Medtcal, Centn, Nru Orlearcr, Laviriana; EnvirvemewtalEyidrmurlely brandh, Nationaf,Cancr.IrisritutS NationalTrusrtsrter ofHea111a, Ba/u•sda, Mary/anQ-lllrrou Carurr C•wrrci4 CGuq;c, Illiaoi{ UV SrsesnarY Questions about the smoking habits of parents and spouses were asked in a case- control study involving 1338 lu,ng ancer patients and 1393 comparison subjects in Louisiana, USA. Non-smokers married to heavy smokers had an increased risk of lung cancer, snd so did subjects whose mothers smoked- There was no association berween lung cancer risk and paternal smoking. The assoc'sation.vith maternal smoking was found only in smokers and persisted after controlling for variables indicative ofactive smoking. It is not clear whether the results reflect a biological etTect associated with maternal smoking or the inability to eontroliadcquately for confounding factors related to active smoking. This preliminary finding deserves further investigation. IIatsroduction THE possibility,of passive or involuntary smoking being a causative factor in lung, cancer has been investigated in several countria.` s This report describes a ase-crontrol study of lung cancer in Louisiana in which questions were asked about the smoking habits ofthe spouses and parents of 1338 lung cancer patients and 1393 comparison subjects (controls). Materials and Methods Current primary lung cancer ases were identified from admission and pathology records of a11 participating hospitals in twenty-nine Louisiana parishes (cotsntia); which included all aouthern, one central (Rapides), and two northern parishes (Caddo and'Hossier).' Patients a^ith bronchioalveolar carcinomas (32 cases) are not included in the present report. All rnajor hospitals in the study area participated acept some in the city of New Orleans where, for logistic reasons, interviewing was deliberately limited to two large hospitals serving the medically tutinsured population and two large private hospitals. For each subjea a control was randomly selected from patients attending the ume hospital and matched'by race, sex, and age (within 5 yean). Patients whose main diagnosis was emphysema, chronic bronchitis, chronic obstructive pulmonary disease, or cancer ottbelaryna, oral cavity, oaoph.gus, , or bladder were excluded from the control selection procedures. The admusion diagnoses of the controls were distributed in the following categories: ardiovascular I5•346; gastrointestinal 13%; mt»eulcsk'eletal 10%; gennourinary 7-3%; ophthalmology and otorbinolaryngology 6-69e; othertumours 596; diabet a 566; trauau 3• 7R6; peripheral Vascvlsr 3• 7rFs; ptslmonaty, 2• 7%; txrebrovastuLr 2• 596; and infections 2%. Local professionalinterviewen, trained for this mvqtigation and thoroughlyfanuliar with local euhure, interviewed tubiects(76%of the cases and 89% ofthe controls) or their ttat ofkin, The quations tovered occupation, residency, diet, smoking and drinking habits, health, water supply, and other relited items. Information elieited on the smoking babits of the spouse or parent included type of material1 strwkeda duration of smoking habit, and daily amount. Questions on parental habits referred to the period "during most of your childhood". Histologial'confumatioa was obtained for 97% of the ases. Missing data were acluded' from the tables. Stetdard' unmatched pair methods were used to animate relative risks. All p valua are b.sed on 2-sided X= tats. Results 595 Spouse Smohirtg We identificd non-smokers with lung cancer and compared the smoking histories of their spouses with those ofspousa of tsonsmoking controls. Only 10 out of 1036 male cases were non-smoken: 2 reported occupational exposure to dust (Rreet•sweeper, log-cuner); I was a steam-pipe fitter; 2 lived in the immediate vicinity of industrial plants (grain eltvator and oement, oil refinery); 1 was married to a heavy smoker; and 4, were long-time chewers oftobacco. There were 25 non- smoking, ever,married women, with lung cancer out of 302 female ases; 2 of these chewed tobacco regularly. For l female and 2 male non-smoking patients no information was available on the smoking history of the spouse. 2 female patients' husbands were smokers but the amount and duration was unknown, Tablel distributes the non-smoking, ever-married men and women according to taal llfetime pack'-yan smoked by their spouses at the time of the interview. The relative risk of lung :" cancer is raised when the spouse is a ltavy smoker ~~ f Similar tabulations for smoking subjects did not show an increased risk associated with smoking of spousa, except for light smoking men (less than 20 pack-years), who had a relative risk of 1• 5 when married to heavy smokers (41 1 pack- years or more). Caxtontrol comparisons based on currentt daily number of cigarettes smoked by the spouse yielded almost identical findings, inclitding relative risk estimates, with those presented in table 1. The apparent passive exposure effect was present in women over and under 60 years of age, although small numbers made the subgroup findings not statistiallysignifiant. Analyses limited to cases and controls interviewed in person indiated'that systematic bias in personal versus nest of-kin responses can be ruled out as a potential' explanation for the findtngs. The same eonclusiom was reached when relative risks were race adjusted:,Inclusion of bronchioalveolar carcinomas resulted in slightly lower odtls ntios: males I• 69, females 1-77, both sexes 1 • 75. Parrnrs'Smokirrg Habits Smoking habits oftbe parents strongly influenced smoking habits in offspring (table /l). Heavy smokers were more likely than the other patients to have bad smoking parents. The smoking histories of the parents in our aeries were associated with each other. Thers were 201 spouse pairs of smokers, compared with 136 apeaed' if the status of each parenrwas -T1t!<CY 1-NONSMO!RRt6, [vDt-MARIIFDLLMO GfIQa CAfFS AND :'CO/dr'ROtS AND LOITYtE COWt.t.alTT)Ori of t7GAnETTt<S sY THF1R arotaes A(de Cases Contrds CK,rma.moked by..pouae roWk-ye.est. 1Jane. 1 t-40~. >41 0 Odds ratlo 1•0 2-0 F.wo/n C.res 8 S 9 Gmtrols 72 I8. 23 Odds ndo 1-0 f-Is 3-S?` 2-07 ' BnrA'rrr,. Odds rauo. (.diusied for .es). 1-0 t-48 3•11' •p<0.05,

596 TAR1;E tl-OGARETTE USEOF C'ONTROL fUaIELTf aYaMOtUNG~ CATEGORY OF THE1R TARfh?6 Fatlier m,oter Mat bcr o+oker No Yes No Mdn Non•aaokrrs ut~ 12% ea Fi-mrokcn 25+~ 26% 24% 26% c.ur+ent mwkers 5dA 42% 1i 47% Tout numtier •MI 79 !f!0 Fo-i Noeramohen 77'ti f8'M 29% 567e Fi•mwlm 20% 11~1 ISR 19~ Cyrrem cnotcen 43'p 20% 56% 779e Tout aumber 130 1S4 N 2S0 independently distributed. Classification of the status of one member, particularly the motha, indirectly mnveys information on the autus of the marital partner. When the smoking stmts of each parent is t3assi.fied separately the relative risks of lung cancer for persons (both sexes, smokers and non-smokers) with a positive paternal and maternal history ofsmoking are 1•04 and 1•66, respectively (table tu): Scrutiny of the data shows that the inereased risk associated' with matetnal smoking is significant in smoking males (odds ratio 1•4)but not significant in smoking females (odds ratio I• 2). No significant increases in risk were found in non-smokers but small numben preclude adequate analysis (there was only one notrsmoking lung cancer patient whose mother was a smoker): To rrn'wrr the aonfounding effea of the other parent, we considered each subset of cases and controls for which only one of the parents smoked. The respective relative risks, controlled for spouse-smoking aatus, for positive paternal and maternal histories ofsmoking were U•95 and 1i•47, respectively. Thus„smoking status of the mother increases the relative risk of lung cancery but smoking status of the father doa not, The effea ofmaternall smoking did not aeeem to be dose reLted; otu questionnaire did not cover this point extensively because we doubted whether children eould adequately qtsanritate their parents' smoking history. The relative risk of luag cancer when both parents smoked was 1•66; there is thus no evidence of an additional contribution to risk from p.ternal esposure, over and above that contributed by maternal exposure. Given the enhancing effett of paretual smoking on the smoking habits of the offspriag, the effect of parerttal smoking on relative risk of lung cancer oeuld'reflect a subtle indirect ataociation with aetive smoking by the subject. To control for active smoking, a logistic regression analysis was done, taking into aecount all the aaive smoking .ariables which increase lung cancer risk: age at which nu started smoking, tar content of utwal brand, degree of iahalation, use of Iand•rolled oguettes, years of smoking, mttsimum amount smoked. By this method of analysis the relative risk associated with maternal smoking was: I•36 (pCO•02) for both aeses and 1•'5 (pCD•Ol) for males. No increase in risk TAi121n-LUMOGWCE! Gt9tr APJD CottrRAlS (IOTH JE74M~ COMl7NED/ACCDRDtt1G TO t•ATiQiIAL AND M11TflW/1: aMORSNG iRlSTORY Fnber eaokeT Mabet emoler Yes No Yes No LAmtcimoo* Conrrol Odds neio-alde. Odde mio diuwed for aeti.rwookeq (topaac repesinrw-.ee rcr): sn 615 1• o- s9o 652 a n3 1!2 ~ 126 I-6 t•3 to54 1214 6t 6• yCO-o5. tpto•o/. THELVdCET,SEFTEMBER 10;,1983 was found in this model for female subjects or for gubjeas whose fathers smoked.,The risk was significantly raiscd only in male smokers whose mothers smoked. Di.cYat3or, Spousr-,mokrrtg Effect Our data strengthen the contention that heavy, smoking byy one member of the spouse pair increases the lung ancer, risk of the non-smoking panner. Heavy smoking by wives may increase the risk of the light smoking husband but this finding requires further analysis and confirmation in larger series. Smoking by husbands did not affect the risk of lung cancer in women who ttmoked (relative risk I•03), a finding that suggests that laive smoking ia so powerful that it overshad'ows any possible additional effeafrom ooneomiiant passive exposure. The proportion of lung carcinomas that were adt:nocartinorrua in nan-amokiag women was 54°h,, compared with 22% for smoking women.,The association of adenoareinoma with smoking ii weaker than for other histological types. The risk of squamous and small cell carcinomas among smokers, relative to a unit risk for non- smokers, has been reported to be 15 4, compared with 5 1 for adenocarcinoma.' Table t may therefore reflect dilution of the relation by inclusion of adetwartsnomas. Exclusion of adenoarcinomn produced a tiptifirant linear trend in risk, as found by Trichopolous et a1:7 The possibility that differences in the chemical composition of mainstream (active) and sidestrtam (passive)amoke may produtt different proportions of histological types of eumoun ghould' be considered. The nitrosamine content in sidestream smoke is reported to be approximately 50 times greater than that in mainstream smokas The effect of the smoking habits of the spouse on lungg cancer risk was first reported by Hinyatm in a Japanese cohort study:' A cohort study in the United States rtported a positive but not significant increase in risk for non~smoking women married to smoking husbands. ' A tasetrontrol study of non-smoking women diagnosed as having lung cancer in Greece reported'relative risks of approximately 2 5 for those married to moderate smokers and 3 for those married to heavy smokers, with a significant linear trend.r Our numbers are small but we think that the similarity between our findings and those of Triehopolow et a17 strengthens the suspicion that passive smoking may contribute to lung cancer risk.. Pare,erol SrrloAistr Effect As far as we know, otus is the first case-control study oflung cancer reporting on parentd smoking history. Parents' smoking behaviour influences the smoking habits of their offspring," but we found that the smoking behaviour of the 6t5er does not influence the lung cancer rikk ofhis offspring, whereas the behaviour of the mother does. This difference may reflect the closer and more prolonged contact that infants and young ehildren have with their mothers than with their faShers. The risk of bronchitis and pneumonia is increased in children whose nathers smoke." Thu vffea is dose rrlbted and is greater in the winter, strongly suggesting that passive smoking by the infant is causally related to risk of respiratory infection. The excess of bronchitis occurs afta 6 months of agr:, suggesting that the passive immunity transferred from mother to child prevents bacterial colonisation of bronchial mucosa. The effect ofpauive smoking on bronchitis may be independent ofthe mutagenic efTea of the tobacco smoke,1P and it is probably safe to assume that the child is exposed to

THE LANCET, SEPTEMBER 10,1983' both the irritant and the mutagenic insults arried by tidestream smoke. The observation that the bronchitis attributablc to passive smoking occurs mostly, during the fint rearof life and is independent of birtb weight may reflen the intimacy'ofmotherthild contact in that period oftbe child's life." Bronchitis in infants may'have a long-lasting efTea on the respiratory tract' as suggested by the increase in the prevalence of' cough at' age 20 ~ in subjects who have had a respi'ratory illnas during the first 2 yesrs oflife, independent ofcurrent smoking habits." Whether bronchitis is a causative factor in lung cancer is confounded by the fiet that smoking induces both cancer and bronchitis. Cohon'studies havt concluded tbst "persons wbo smoke cigarettes run a higher risk of chronic bronchitis than tsotl-smokers and those who develop bronchitis run a higher risk of developing lung cancer". 1) How maternal smoking causes lung nnceranat thisetage only be a matter of speculation: By itself; passive smoking during childhood' may not be sufficient stimulus for arcinogenesis. However, laboratory'work has shown that: ttansplacental exposure to carcinogens increases the carcinogenic response to post -natal exposure to the same or to a diiTerenu arcinogen;l`"IS benzo(a)pyrene, a mutagenic arcinogen found in tobacco smoke, when injected into pregnant mice, induces caneer of the lung and other organs of the offspring;16 rumours develop in 33% of the offspring of pregnant hamsterLtreated with high doses ofagarette smoke condensate;17 and small doses of arcu>,ogens can induce tumours in fetal tusve.ls The effects of maternal amoking are only significant m males,, especially the heavy smokers. Perhaps maternal smoking enhances active smoking by the offspring in subtle ways not detected' by conventional techniques. If our methods for controlling for active smoking are not sufficiently refined, the inereue in risk associated with '' maternal smoking would not be an effect of passive smoking but one of enhancement of active smoking bebavioural patterns. This is a real possibility and' we would like to encourage further research on the subje.a. ConcHrsiml The differences between the effects of pauive exposure to spouse and maternal smoking are puuling. Passive exposure to spoux smoking is mostly detected in Don-smokers and light smoking males; maternal passive amoking effects are seen mostly in smokers. Passive smoking from spouses is introduced in adult life and in'smokers is concvrrem with their own active smoking. The magnitude of such an effect mav be low when compared with active concomitant smoking and it may not be detectable when both types ofsmoking are present. Eiaternal smoking, on the ot'her, hand, exerts its influences early in lift and in the absence of active smoking is probably insufficient, to produce carcinogenic effects. Our findings indicstethat maternalismoking results in a slight iaaease in lung cancer, risk but do not indicate whether the effect is due to enhanced active sttloking of the offspring or to eahanced' susceptibility, to lung ancer, induction aftc the ehal.lenge of actil'e smoking later in life. Our findings point to the need for more research on the subiea of passive smoking and nntxr. Since large numbers ofascs may be needed for adequateepidemiological analysi:,, multl-institutional collaboration may, be indiated. lh„ .» wtTson.d y.n coetm N01{P-9J023,DCC4, Nauonal ~Gnccr Xauc.nal Jns:rc.mcs ofHeilth. (South l.ouuum) and byy aranm ffom .•.. t-- Caurlrr of the American C~cerSonety.(Nanh tauu+aau) ~. 597 CorrespondcrlcttAwld be .ddreaed to P ~ C., Departmenl ofPahologi-, . T.ouuuru: Sl.n~eUnnveruey. Medical Cetuer, Nr. Orkuu,Couuura LA 70112, USA. tESEttENCEs 1. Kv.r.ma T. N.,wnWnr .ne ar hea+r.wrn+ Y.R. a hsgiss-.h 1hi.y on«r a orOr ,e )aPa. .J.. Md J 4 M 11 322. 1 U-!5, .daU: 1466 1. Tndoqplaw D, ItAlandrdi A, tiprr. l, 7WcMrYm a. taaE aam rpiimia+.rd neotSng /i1Y l.Cos,v. IM 1. !7: L4 '. 1:. G.rf,nhel L. Trar.Ircnd~ m Ju" onRr a.enahhr asmrl a.n...h.naad.~. mf:un, p.nR.mdurK JNM..f.re.lo/ 1MLas: 10F1-" st . Dern HF, ta.cnurl t', H.rro4.K' f"oa Rpon sths S,v{avu,Geml'l Ad.ra1 Canm.rs an S~ .n{ andHrllh 1hiasiaq ard HbIJiL'SDHEV PuWK 1i.ahh. Sn..e P.blouwn No1101 iahusitson, DC. 11M4, 175: S. iueh' SL Rr1u rLe paa,m,aawhn nan. L.mI M0, u106: f..Mtnnd1rrre.fEd.um.T.re.aeasd+eg Ir•.drae/adlaaa+esnpnvroDHE3; Namllsnm.. af EOucwr,, t'.aWhRan tK.. 1%9, ?59. 1. /sior. R)l..a.nb F71, Rrlk+. MD: Sant.e~ bAn,our u w r-uw ppWnan . a rJu.r,rr oerepr.d appoat Ai. J h1 NYI' 1972'. R: a07-I ) S. lllarYp S, Da.r AM , latm .~r.a. r hwsrW 'a.d .warl r.ohaK 1- N7aW u:, S?4-T3: 41. Rr/mia' r. Rd~a.lydrnrl mVel ra mwA4rrr rrolrtr~arllr cfuW qwa/eafrr.. Ae.PdSurlY7l.n: A71:-)1 10. endgo sA. GYmnen.cn 1: supmun T. C.gormt rtna-4as a o.ry a Rnn K. r.t> Mrr.,w: Ae 1979, N: 71 -s1 11. Cd1rr,laT, HblYnd Vi, C.rhpJl IT 1.lhexslp.n.e.m.L,q nd pvrnrd'llKrn on pr,wma nd lrpsWau m arlr,~Wlood L..arr 1974.. 1031'-H 12. calkr JRT. Dou0s lii. ll.d DD' Re.pr.err Araau un rouq aduti. InOr<nn af wlt, c4Ydlinod I..n rapr.on, rran JPmw roal dr, au /W,.,on obsah-ls.Afdl.Ih7Dl uu113-N 13. aa.rawm J I smJ+q. W anrc `r.er4uu nd hr{ mrn.1. Md} 1 f71, u- 779-75 . /N- VomIw.Kcl. SD C..t.r.rw arr4es ., P.nowal oreme~me+~ tb. Tae+ru L, Mm. t:,.b Trsqtsmal oto,..{veaa I.arensd Agacr fnr s.wcE an C.ncr, .nvn rfr publi- wn- ao )LT-. 1971 . 1)-22 15 . N.palho.. NP SeeK R+rnl cardrr.mn, .n tht PraR1lan of tretrlanem a'. o..ou,eErne•r1aTuan. L wA, L', .6 TneraDl.a.nlmc.e.~.nnuIrnanml A{eecr.tp Rssd arCarca .nutXr p8lormo 1o 4 L/on;. t.re: l-t1 Ih- Ndaron. T1'. TmplauaW an.oaf 4an.1alPfra rryae.. /Jl f+P er/ A4d 1977, M:. 1025-27 17: Nrcob.JG. CJnoea®.tr n: Trsun, and krpcrplim rc 4.ws m..Sman h.errrm fdb-ry r-V4cmrj and h.p,n.l trmmrnr .ab npe+rr aerht osndnunr 1. G+cn Xn 66..0.m1d979, M: N~56 li E.nson Rs Indr.W~rl. rmnpl.eenullvaqaed, s arrneal'rai,q o.~br.n ne.ed aKrr nal n doh IJe 1r+u+. INO, w 11 Y-27. ANAYHM.ACTOID REACTIONS TO NEUROMUSCULAR BLOCKING AGENTS: A COMMONLY UNDIAGNOSED COIIDITION? P. R. YoUNGMAN K. M. TAn.oR ). D: WILSON DeJ7arrt#alrx af Maaiarr awd PAanwcdogy; Urvorrriry of Ai.delo nd - Sdoo! of Madinwe, Aac*bnQ New Z.alap&d S.rnrwary' A group of 28 patients with~erneme, life- threateai.ag sensitivity to susamethonium was identified and 15 were studied in detail by skin-testing. The fennlelmale nriomas B/1. Sutsitivity, may be present without~prcviotu exposure to staattxthonium; in 3 patients reactions occurred during the firsr exposure to aaaesthesia.. Most patients showed one or more eosrsensitivicies to alcuronium, tuboeu7arine, and pllamine. Signs of' circulatory collapse were the sok presenting feature in 5086 of the patients. Histamine release induced by the drug in vitro was demonstrated in some instances. llntrodnction DRUGS of the musde-relasnt group are corttmonlyy implicated in systemic reactions, sometimes lik-threatening, which occur during general anantbesia. Since 1977 patients at our hospital who have bad'severe anaestbetic reactions have been skin-tested to dnermine drug sensitivity. After two deaths attributed to suzimethonium inAuc]tlarnd in 1982, a study ofknown sensitive patients was undertaken, initially to determine whether 'Ethycholine', the only sunmethonium ehloride available in New Zealand, differed' in provoking