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HEALTH EFFECTS OF PASSIVE SMOKING: ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN A commentary on issues relating to lung cancer in the 1990 EPA External Review Draft. Author: Guy CREPAT Date: 25.09.90 I am a professor of biochemistry and physiology, Head of the Applied Biology Department at INSTITUT UNIVERSITAIRE DE TECHNOLOGIE. UNIVERSITY OF BURGUNDY. 21000 DIJON FRANCE. As a specialist in medical dosimetry, I carried out research on Environmental Tobacco Smoke health effects on nonsmokers in Burgundy in 1989. With colleagues in Dijon I conducted a retrospective study on living lung.cancer patients in order to establish a protocol for a prospective epidemiological study incorporating the recommendations made in recent literature, and aiming at investigating the possible association between ETS and primary lung cancer. The epidemiological survey has not been launched as we could not find a sufficient number of lung cancer cases in nonsmokers: 3 cases out of 223 patients. This emphasises the fact that lung cancer in nonsmokers is a very rare disease. I have discussed the EPA draft with my colleagues in Dijon as well as with other experts in France and in particular with Dr Alain Viala, Professor of Toxicology at the Faculte de Pharmacie, Marseille, who has recently published a paper on this subject (appendix 1). I am therefore much interested in publications on ETS and its association with lung primary cancer and I have read your report most attentively. As you are inviting comments, here are a few observations: The report estimates that 3,800 lung cancer deaths per year in (US) nonsmokers are attributable to ETS. This estimate is based on:- - A mean adjusted RR resulting from the case control studies reviewed, i.e., 1.28 for female nonsmokers exposed to spousal smoking.

- The assumption that urinary cotinine concentration levels expressed in ng/ml are proportional to cancer relative risk in exposed nonsmokers. - The notion uf background exposure for nonexposed nonsmokers used as controls in case control studies. - An estimate that 60% of nonsmokers, male and female, married or unmarried are exposed to ETS. This leads to an estimated population attributable risk (PAR) which when applied to the estimated figures for- nonsmoking females (6500) and males (3000) who died from lung cancer in 1988 in the USA produces the figure of 3800 deaths (including ex-smokers). This calculation method raises many questions, including the following:- I. What scientific evidence is there to "assume that cancer risk from passive smoking is linearly related to cotinine concentration" and then use it as a postulate? 1.1 Smokers While a number of studies have investigated the quantitative relationship between the number of primary lung cancer deaths and the amount of tobacco smoked (number of pack-years), similar studies have not shown that it is possible to express a relationship between levels of urinary cotinine and risk of lung cancer, RR = f (Urinary cotinine) because: 1.1.1 Cotinine urinary clearance varies by a factor of two with cigarette brands (NEURATH & PEIN 1987, appendix 2). 1.1.2 For the same nicotine uptake clearance varies by a factor of 3. (BARLOW et al 1987, appendix 3). 1.1.3 Correlation between cotinine production (serum ng/ml) and cigarette consumption is very poor r = 0.44. (ADLKOFER et al, appendix 4).

- 3 - In fact it would be preferable to determine blood and urinary cotinine and their metabolic kinetics for each individual. Even for the nonsmoker, the postulate stated above is not justified. 1.2 Nonsmokers Review of the 21 case control and 3 cohort studies leads the EPA to an overall relative risk estimate of 1.41 for nonsmoking females exposed to spousal smoking. After EPA adjusts for misclassification, their risk ratio is reduced to 1.28. The use of the postulate is based on the fact that 13 (in fact only 9) studies have found evidence of increased lung cancer risk as a function of exposure to ETS. This raises more problems: 1.2.1 A nonsmoker absorbs primarily the vapour phase of ETS, rather than the particulate phase. Appendix C of the EPA draft suggests that the particulates in tobacco smoke are of most interest with respect to carcinogenesis. Since the ETS-exposed non-smoker absorbs mostly vapour-phase components, it is unlikely that lung cancer risk is linear to cotinine concentration. 1.2.2 Cotinine half-life is much shorter in a smoker (15 to 20 hours) than in a nonsmoker (30 to 50 hours) which makes comparisons difficult. HOFFMAN et al (1989) and SARACCI (1989) (page 4-16 in the EPA draft). In any event, cotinine is at most an exposure marker, not a risk marker. It is therefore unjustified to assume that cancer RR is proportional to a nonsmoker's urinary cotinine concentrations. 1.2.3 As the same causes should produce the same effects, then, if EPA were correct, anatomically similar types of cancers should be found in active smokers and ETS exposed nonsmokers (page 1-2 of the EPA draft). This does not seem to be the case as there are more adenocarcinomas in nonsmokers (48%) and more squamous cell carcinomas in smokers (52%). TREDANIEL (1990) & JEANNIN (1990).

- 4 - II. How does the postulate that "cancer risk from passive smoking is linearly related to cotinine concentrations" affect the calculations? This as5umption must lead to an overestimate Df risk. Mean urinary cotinine values expressed in ng/ml f(,r exposed nonsmokers and nonexposed nonsmokers vary widely according to various authors (appendices 5 and 6): Cotinine ng/ml Ratio WALD 1984 ETS ncn-exposed: 2.0 =3 ETS exposed: 6.0 WALD & RITCHIE 1984 non-exposed: 8.5 =3 exposed: 25.2 JARVIS 1984 non-exposed: 1.6 =4.8 exposed: 7.7 Such values may vary according to the technique used (RIA, HPLC, GLC) but there is still a ratio of 3 to 1 between an exposed nonsmoker and a nonexposed nonsmoker. On pages 4-29 to 4-32, the notion of background risk affects the calculations as follows: The basic exposure of a nonexposed nonsmoker is used to calculate RR in case control studies. As RRM 1.28 (1.12-1.45) (page B4 in the EPA draft) is calculated after the background, then if background exposure is 1/3 of that of ETS, the report postulates that the actual risk of a nonsmoker exposed to spousal smoking is RRB=1.48 against zero risk of a zero exposure. As a consequence of the postulate, the nonexposed nonsmoker runs a cancer risk which can be assessed. The report goes on to suggest that, assuming that 60% of women are exposed to background exposure and spousal smoking, the P.A.R. is 0.27 and the number of deaths would be 1750 female and 810 male nonsmokers in the US in 1988. Here are a few observations about this method: 1. By estimating chat 60% of nonsmokers are exposed to background risks and ETS, whereas the NRC suggested 17%, the P.A.R. figure which results appears far too high. 2. The notion of a background whose risk can be calculated: RRB/RRM = 1.48/1.28 = 1.156 leads to a

- 5 - P.A.R. = 0.13 for non-exposed non-smokers. Yet there is no evidence to support this. 3. If we use the same postulate that lung cancer risk is proportional to urinary cotinine concentration, but consider data about active smokers rather than mean risk supplied by epidemiological studies, we are struck by the difference in magnitude. Mean cotinine values in smokers' urine range from 1,000 to 2,000 ng/ml. As values for ETS exposed nonsmokers are about 10 ng/ml in urine there is a ratio (smoker/ETS exposed nonsmoker) of 100 to 200 in concentrations. If, as the postulate allows, we apply this ratio to RR, and we assume a RR for smokers of 8 or 12, we obtain an estimated RR for ETS-exposed nonsmokers of 0.04 to 0.08. In fact, we obtain the same values of 1.02 in females and 1.07 in males (page 4-22 in the EPA draft). The same reasoning applied to the background urinary cotinine concentration, which is 3 times lower, yields a RR which is close to zero in females. 4. In Dijon, a preliminary study on 233 primary lung cancer cases was conducted to investigate recent cases developed by nonsmokers, before launching a case control study. Thorough clinical investigation of patients and their records has led us to retain only three cases: two adenocarcinomas in females which could not be diagnosed as primary cancers and a multifocal bronchiolo-alveolar carcinoma in an 83 year old woman. Our experience suggests that the P.A.R. does not correspond to the RR calculated in the EPA draft. III Observations on cancer heredity SELLERS et al (1990) provide evidence for Mendelian inheritance in the pathogenesis of cancer. In their study, collecting data from 337 families, they established that the presence of the locus could account for 69% and 47% of the cumulative incidence of lung cancer in individuals up to ages 50 and 60 respectively. This multiplies cancer risk by 7 for the former and by 5 for the latter. As a consequence, there are at least two and perhaps three populations with varying degrees of susceptibility to lung cancer risk and the above-mentioned postulate likely is incorrect.

- 6 - CAPORASO et al (1990) contributed similar evidence. Individuals with a genetically determined ability to metabolize debrisoquine extensively are at a greater risk of lung cancer than those who are poor metabolizers {odds ratio = 6.1). IV. Other lung cancer factors (appendix 1) If there were 6,500 female and 3,000 male lung cancers in the USA in 1988 among non-smokers, they should be accounted for by all other potential factors. The EPA report consider ETS as the major factor, but one should not exonerate such well-known factors as genetics and environmental risks such as radon, asbestos, heavy metals, industrial and domestic smoke, various occupational exposures such as nitrosamines, polycyclic aromatic hydrocarbons and cadmium. Diet, which can introduce carcinogenic substances or cancer inhibitors such as beta carotene, should also be taken into account. CONCLUSION The parameters to be taken into account in conducting better epidemiological studies than the vast majority of those relied upon by EPA are well summarised in Professor Viala's paper (appendix 1). GUY CREPAT Professor of Biochemistry and Physiology

- 7 REFERENCES ADLKOFER, F. et a1 (1989) In: Nicotine, Smoking and the Low Tar Programme. Eds Wald & Froggatt, Oxford University Press. pp 116-130 BARLOW, R.D. et al ,1y87) J. Chromatography 419 375-380 CAPORASO et al (199U) J. Nat. Cancer. Inst. 82 1264-1272 HOFFMAN, D. et al (1989) In: Reducing Workplace Exposures to Tobacco Smoke. EPA-HHS Manual (In Press) JARVIS, M.H. et al (1984) J. Epidemiol. Comm. Health. 38 335-339 JEANNIN, J. et al (1990) Panorama du Medecin 31.5.90. No 3188 26-28 NEURATH, G. & PEIN, G. (1987) J. Chromatograpny 415 400-406 SARACCI, R. (1989) Passive Smoking and Cancer Risk: IARC Panel of Experts SELLERS, T.A. et al (1990) J. Nat. Cancer Insc. 82 ~ 1272-1279 TREDANIEL, J. (1990) In: Proceedings of 1990 World Conference on Lung Health, Boston (In Press) VIALA, A. (1990) Pollution Atomospherique April-May 1990 pp 185-186 WALD, N.J. et al (1984) Lancet 1 230-231 WALD, N.J. & RITCHIE, C. (1984) Lancet 1 1607

DOCUMENTS Appendixl RAPPORTS EVENTUELS ENTRE TABAGISME PASSIF ET CANCER DU POUMON : PARAMETRES A PRENDRE EN CONSIDERATION par Alain NIALA (•; Le tabagisme passd rbsulte do I'expositlon d'un indwtdu a la fumee do tabac d'autres per- sonnes, fumee exhalbe par las fumeurs et par Ia courant secondaire produd par ta combustion du tabac entre les boutfies. La fum`s do tabac comprend une phase gazeuse. ou I'on retrouve entre autres du monoxyde do carbons, des oxydes d'azote, des aldehydes... et une phase paniculaire qw est notamment se support do la nicotinet'). do nitrosamines. d'hydrocarbures aromatiques polycycliques. du cadmium... La penetration cnez le non-lumeur so fait essen- tiellement par inhalatan. accessouement par ab- sorption dans la salrve. Dans Ie tabagisme passif. la penetration des consatuants do la phase ga- zeuse serart plus importante qua celle des com- posants do la phase particulaue : Ie processus serait different dans Ie cas du tabagtsma actd. Les enqu6tes eptdemiologiques visant a etudier une relation possible entre I'expostUon des non•lumeurs a la lumea do tabac at Ie cancer du poumon-sont tres drtficll.s a itaborsr at sulettas a do multiples btats ou facteurs d• confusion. C'est la raison pour laqualle leurs resultats peuvent apparaitre contradictotres. Plusieurs equipes do cherch.urs s'opposent .n ce domaine : - pour carsains. Ia raatan entr, tabagisma passd at cancer du poumon est ividente. pani- cuherement an ca qui conc.rna 1'exposrtion d. I'ipouse non-tumeuse par un mart fumeur ; - pour d'autres. d ny a pas do retatwn staas- tiquement sgntficattve entre Is tabagisme passf et le cancer du poumon. En fait. tout depend des cntar.s d'avaluatton qualitatds et quanutatds uulisis dans tes ddf6- rantes recherch.s. 8een que la mithodologia 6pi- dimatogtque do ce type d'enquite att constdi- rablement evolua depws las travaux do 1980- 1981. et plus particulsar.ment a partu do 1985. des imperiectans dem.urent. ( r) O'apros O. FJt TO(1GH. ls mooane s.nrr eyararwnr prsserxe dves rs vasse gaz.ut.. Au vu des risultats obt.nus, II n'sat pas possible d'.xdw. /orm.IlsmMri Is oorKtibtAiOn du tabagisme passd a ia qsMsa do oatairts canosrs du poumon, mais if pourrait utistar una raWion dosaieffet (1'axposition davraR abt7 ilrs su/N- samment intense st lonque) at des factsurs autres qua tabagtquas pourraisnt aussi int.rvena. En elfet, do nombrsux paratailitrss doivant itre pris an aonsdoliration pour Nf.ctuar do tallss etudes dans les medlsuras oonditions possblas. II laudraR notamment : 1) Sa m.ttr, a rabri des biais .n ca qui oat- carne la classification des personnq soumisaa • I'enquete an tumeurs, non-fumaurs, anCians fw meurs. 2) Comparsr les risultats • caux d'un groupe tamoin volritabl.m.nt • non exposi •, avec des effactds suffisamm.nt rapKs~ntatils. 3) Pertecttonner les quastbnnairs av.c v:rificatton des • drss • a plusiaurs nivsaux a renouvN.r.a plus ou moins lonpue olodNant:e Is interrogatotr.s. 4) Dans Is cas d'itudes oonduits sur des couples, bien fatre pripsar ai r`poux tumaur Ia nombrs do cgarNt.s, cigarss ou pipsa, N Is typ" do tabac. qu'd fume dans la joumN N suttout ~ son domicd., et d.purs combion d• t.mps ; assaya( d'en deduire Is temps d'sxposition par jour, par an, et ta durio do catte .xpositton pour Ia oonpnt : s'in(orm.r w.ntu.p.m.nt do la dis- tanca moyann• qui sipar. Is fum.ur do non- (umeur. 5) Tenir compte d• rexpositqn au ubaqismo passA sur Ls Iieux do travail, dans las transpoRs e1 dans tes Iocaux qui r.QptvisrN Is public 6) Tenir oompa d. la pollution stmospholi. riqus axt.naua, d'orqine autonqbila, Irtdustrisp. .1 (om.stsqu.. qui p.ut apportar des faWurs po- tenti.llement cancirogin.s (aldNttrdaa, hydro- carbur.s aromauqu.s poycyaiquq, mhwx. tracss typa cadmium ou autras). 87SS4407"U97 7) T.nir oompte d.s oonditions do v.ntlation des locaux N d. Ia popution intMwura ; ainsi, Iss apparads de chauffage ou do cuisine (bois, cMr- bon, fuel. gaz). do mima qua Iss opirations culi- ...

Appendix 1 acroleine at hydrocarbures aromatiques po(y- cycltques ; s'tnformer egalament sur la prosertca possible dans cas ambiancas do radon ou do ses descendants, do meublas agglomaras ou revi- tements suscepttbles do relarguer du formal- d6hyde (a potenttalitos cancerogenes), voir• d'iso(ants susceptibles do rel3cher des fibres d'amiante, ou d'oiseaux qui pourratent itrra impliques dans Ie p(ocessus de carcinogenese. 8) Donner des precisions sur Ilg• des sujets, sur la possibi(iti d'une exposition ant4- rieure au tabagisma passd (in utero, au oours d• laurs premieres annees do vw et plus lard), sur leurs antecedents patho(ogiquos pulmonaires, sur I'6ventuahta d'une exposition pendant 1'en- lance ou plus tardivement aux faux do bois ou d• charbon, sur leur alimentatton (susceptible par example d'apporter des cancerogenes, tels que certatnes nitrosamines qui peuvent blra imp(i- quees dans la survenue do cancer pulmonaue, ou au contraire du f3-carotene dont Ie r81• saraR preventit), sur la consommatton d• boissons alooolisees, do medicaments, do droguas toxioo- manogenes... sur les facteurs haroditaires. 9) Cons4erer avec une granda attention les risques cancerogenes provenant d'expositions protessionnelles autres qua Ie tabagisme. 10) S'assurer par des examens histobgques approtondis qua las types do cancers pris en compte chez les non-lumours exposes au tabagisme passd correspondent bien a ceux qw se devebppent chez les tumeurs acids. (11) Comparer la presence d'adduits des cancerogenes specdiques du tabac avec I'AON chez les lumeurs, acids at passds, at chez des Iemoins n'ayant jamais fume. 12) Conlroler Ie tabagtsme passif des non- fumeurs par plusieurs types do marqueurs : - des marqueurs envrronnamentaux du taba- gisme : dosage dans les ambiances cbses do Ia nicotine. de I'acatald6hyde, voire du monoxyde do carbone : des conlrblas pourraiant aussi porter sur Ie formaldehyde, lea nRrosaminos, lea hydrocarbures aromauquas polycycliqu.s. I• cadmium... du faR do leurs potantiaGtis canc4- rogOnes : - des marqueurs biologiques du tabagisma, tels qua : dosage do la counine .1 do Ia nicotine dans la saliva. Ie sang at runn., sachant qu. Ia cottrnne a une demt-we plus bngue qua celle do la nicotine, dosage des thtocyanatas siriquos at urinaires. dosage des thioithers dans I'urin., avontueUement dosage du monoxydo do carbons dans raw atvootaue ou do la carboxyhinagbbata dans le sang, sans oub/i.r toutalois quo la mono- xyde do carbona peut avoir d'autres orpinss : - Ia mutagenicua des urin.s pourrart auss, constrtuer un oontr8(a d'.xpositqn. Tous las auteurs dont lea artidas ont 44 axa- mines s'acoordent pour insistar stu Ia niosssiti d'6laboror d'autres etudes pour miaux appr*- hender Ia prob(ems des relations possiblas Mlra tabagisme passd al cancer primitill du poumon. Ces etudes davront prsndrs .n oonsidilliration lous Ies points exposes Gdessut, at Ia (Kta n'ast pas exhaustive. Auparavant. d samb(arat opportun do riafisu des •xperim.ntattons sur ('anfmal, autant que fairs sa peut, d• farron a•ssay.r do d`tarmin.r en fonction d.s canditions op`ratcir.s (distanoe temps d'exposrtion, nombre do cigars+tt.s quott- diennes (ou pipes ou cgar.s), dosaga do Ia nioo- tine dans rair... )(a rea(di at Itintans4i do rimpri- gnation tabagtqua, par des dosaqas do nicotine et do cottnine dans Is sang at I'urina at la ra• cherche d'una mutagan6cati daa urinas. Mi.ux encore, at pour amelarer au maximum la spact ficili, iI conviendraa d'un• part d• cherchsr L 6tab(ir staustiquemant chez I'homme un - tndai d'exposibon - fiab(e, base par sxample sur uns relation entra les concentrations atmOspherqua: de nicotine presantes Cans las ddf6ants (ocaux ambtartces, moyons de transport,.. oiu sillijournE Ie non•fumeur, at rexaeaon urinaua do la somme coamne plus nicotine expnm4o par rapport A IL criaanine, d'autr• part, d'approfond'a Ls axa• mans chrnques, hislopatho/ogiquaa at autras desttn6s a Ia caract6nsauon cartain* d.s diH&• rents types do cancer pnmdd du pourtan. A ce four, Ia (itlOratura scisntdiqu• latssG planar un doute sur Ia possible contnbuuon dt. tabagtsm• passtl, •ntrs autres factours, t la genese do cancers pulmonairas. CGux<t no sur• viendratent, si une tal(* contribution •xtstaR. qu'apr6s uno exposition intsnse pandant una tras longue p.riode, et d est improbabla qu• I'oxpo- sition occasionn.lle p.ovoqus do s6riNux af1Ns nocds chez Ia plupart d.s a+dividus. N`anmotns. d'autras travaux sont nkassairas pow savoir s, Is tabagtsms passr/ constitua saulamant une g3n• ou r.pris.nta un veraafsla ptoblima do sant.. ~ ~ ~!T 4 OD Ce document a iti itabli av.c I'aid• d• F. GRIMAlOI a an r.latan av.c PAssocuuon - Indoor Air Int.rnational •(W) i paAir do quet- quss 150 rNir.nc.s couvrarM la p1brioda 19A0- 1989.

Appendix I Comments on the possible relation between passive smoking and lung cancer by A. YIALA, Professor of Toxicology Facultd de Pharmacie (27 Boulevard Jean Moulin, 13385 Marseille Cedex 5) Environmental tobacco smoke (ETS) results in the involuntary exposure of non-smokers to the tobacco smoke exhaled by smokers and the sidestream produced by the burning of tobacco between puffs. Tobacco smoke includes a gaseous phase which contains notably carbon monoxide, nitrogen oxides, aldehydes,.... and a particulate matter whose main constituents are nicottnparticles, nitrosamines, polycyclic aromatic hydrocarbons, caanium ,... ETS enters the non-snoker mainly by inhalation, but also by absorption into the saliva. In passive smoking the uptake of the gaseous phase constituents exceeds that of the particulate matter components ; the uptake process would be different in active smoking. Epidemiologic studies Intended to investigate a possible connection between the exposure of the non-smokers to the tobacco smoke and lung cancer are very difficult to set up and are open to many different interpretations. Tr~is is why their results may appear contradictory. Several teams of researchers are in conflict in this field : - for some, the connection between passive smoking and lung cancer is obvious, particularly in respect of exposure of a non-smoking wife to her smoking husband ; - - for others, there is no statistically significant relationship between passive smoking and lung cancer. In fact, everything depends on the qualitative and quantitative evaluation criteria used in the various studies. Although the eaidemiolo9ic methodology of this type of study has developed considerably since the work done in 1980-1981, and has done so particularly since 1985, some aspects are still not completely satisfactory. 87654999 (•)According to 0. Eatouch nicotine would be also present in the gaseous phase.