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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.

2 Appendix I The obtained results may not formally exclude the contribution of passive smoking to the genesis of certain types of lung cancer, but a dose-effect relationship could exist (the exposure should then have to be sufficiently intense and prolonged), and other contributing factors would also take place. In point of fact, many parameters have to be taken into consideration in order to carry out such studies under optimum conditions. In particular, it would be necessary to : 1°/ Be on one's guard against bias as regards the classification of the subjects in the study as smokers, non-smokers and ex-smokers. 2°/ Conpare the results to those obtained from a really "unexposed" control group, with sufficiently representative cohorts. 3°/ Improve the questionnaires, verifying statements at several levels and renewing the questioning after variable time lapses. a°/ In cases of studying married couples obtain an accurate statement from the smoking husband of the number of cigarettes, cigars or pipes, and type of tobacco, which he smokes during the day and particularly at home, and for how long ; try to calculate f rom this the period of exposure per day and per year from the other spouse, and the duration of that exposure ; find out, where possible , the mean distance between the non smoker and the smoker. S°/ Take into account ETS exposure at work, in public transport and in premi ses open to the publ i c. 8'7655000 6°/ Take into account outdoor atmospheric pollution of road-traffic, indus- trial and domestic origin, which may introduce carcinogenic factors (aldehyde• polycyclic aromatic hydrocarbons, trace metals such as cadmium and others). 1°/ Take into acount ventilation conditions of the premises and indoor pollution, such as heating or cooking facilities (wood, coa1, fuel, gas) and also the actual cooking operations (frying, for example) which can introduce extraneous substances into the air, such as acrolein and polycyclie aromatic hydrocarbons ; also, inquire into the possible presence in these surroundings of radon or its daughters, bonded furniture or coverings capable of releasing formaldehyde (which has carcinogenic potential), or even asbestos fibres 1;..e " 1M .1nn) nr nirrt S....

Appendix I 8°/ Give details of the age of the subjects, the possibility of prior exposu to ETS (in utero, during their early childhood, and 'ater), their history of lung disorders, the possibility of exposure to wood or coal fires during chi hood or later, their diet (for example, foodstuffs capable of introducing carcinogens such as some nitrosamines which may be involved in the aetiolo9, of lung cancer, or on the other hand (J-carotene which will have a preventive role), consumption of alcoholic drinks. drugs, opiates, cocaine, cannabis ant so on, and hereditary factors. 9°/ Pay particular attention to carcinogenic hazards arising from occupation: exposures other than smoking. 10°/ Ensure by means of extensive histological examinations that the types ot cancer taken into account in non-smokers exposed to ETS do indeed correspond to those developed in active smokers. 11°/ Compare the presence of adducts of specific carcinogens from tobacco smoke with DNA In active and passive smokers ana in never-smokers. 12°/ Monitor tFe passive smoking of non-smokers by using several types of marker : environmental markers of smoking : concentration, in enclosed spaces of nicotine, acetaldehyde and even carbon monoxide i cneks should also cover formaldehyde, nitrosamines, polycyclic aromatic hydrocarbons , cadmium,... because of their carcino- genic potential ; biological markers of smoking, such as : content of cotinine and nicotine in the saliva, blood and urine (considering that cotinine has a longer half-life than nicotine), determination of thiocyanates in serum and urine, of thioethers in urine.of carDon monoxide in alveolar air or carboxy-haemoglobin In blood (but carbon monoxide may have other origins) ; the mutagenicity of the urine could also serve as an indication of exposure.

4 Appendix I . All authors whose articles have been examined agree on the need to set up other studies in order to gain a better understanding of the probl of the possible relation between passive smoking and primary lung cancer. These studies will have to take into consideration all the points set out above, and the list is not exhaustive. First, It would seem appropriate to carry out animal experiments, far as possible, so as to try to determine, as a function of the operating conditions (distance, time of exposure, number of cigarettes per day (or cig or pipes) nicotine concentration in the air,...),the reality and intensity o smoking impregnation, i.e. determining nicotine and cotinine contents in the blood and urine and examining the mutagenicity of the urine. Better, to obta a maximum of specificity, it would be suitable to try to establish statisti- cally in man a reliable "exposure index", based for example on a relattonshi between the air concentration of nicotine in different premises, offices, public or personal transport,and various surroundings where the non-smoker is staying, and the urinary excretion of the sum cotinine + nicotine related to creatinine, and to make extensive clinical and histopathological examination aimed at surely determining the presence of any type of primary lung cancer. The current litterature leavesone uncertain as to whether ETS is a possible contributor, along with others, to the origin of lung cancer. If there is a contribution, it would seem to arise only after intense exposure over a very long period, and It is unlikely the occasional exposure of most people has any serious adverse effect. Nevertheless further studies have to be carry out for establishing if the problem of ETS is more one of annoyance than health. This paper was established with the assistance of F. 6RIMALOI and In relattor with the Association "Indoor Air International" (IAI) from any 150 reference: between 1980 and 1989. m ~ ~ tn Cn