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1. VDI Reports 888 ASSOCIATION O'F G'ERMAN ENGINEERS COMMISSION ON~ AIR POLLUTION OF THE VDI AND DIN CARCINOGENIC SUBSTANCES IN THE ENVIRONMENT Origin Measurement Risk Minimization Mannheim Collarquiurn. 23 to 25 April 1991 V'DI VERLAG (D) N O N N W. ~. ~. W

2 Passive smoking - Evaluation of the epidemiolop-ical findines K,-hI. JockelL Bremen Summary The biolbgically plausible hypothesis that'! environmental tobacco smoke causes lung cancer appears to be supported by the evidence available from epidemiological studies. Both case control studies and cohort studies are in agreement' in indicating a trend towards increased relative risks which, in a meta-analysis based on i a total of 14 studies. reveal a 35 % higherr risk of passive smoking due to the partner who is a smoker. The criticism expressed in these studies will be discussed and' will' be appraised in the overall context. Ih ~addition, the results of a study of the methods and initial results of a case control study, will be reported. I . Introduction Tobacco smoke consists: of very many individual chemicall substances; a, large number of which are toxic or have been shown to be carcinogenic both in animals and in humans /3/. While the human carcinogenicity of active cigarette smoking, is no longer seriously disputed,, the health effect& of so-called "passive smoking", more appropriately referred to as Environmental, Tobaeco Smoke (ETS), are the subject of vigorous scientific controversy. It is undisputed that many of the active carcinogens are present in tihe secondary smoke stream in very much higher concentrations than in, the main smoke stream inhaled by the active smoker. ETS,, the mixture inhaled by the passive smoker, is the sum of the two individual component& secondary-stream smoke and exhaled main-stream smoke of the smoker or smokers present in the room. Whether the individual carcinogeniic substances of this mixture actually effectively reach the "target object", the passive smoker, there is stalll controversy about gas phase and particle phase /7J. Animal experiments considered in isolation have been unable in the past, and presumably will continue to be unable in the future,, to provide convincing results, since these experiments have unusually high pollutant concentrations compared with human, situations. The aim of this article is to describe the possible contribution, to date and in the future,, of epidemiology to the question of the carcinogenicity of' passive smoking,, against the background of the situations presented above. The methodological'.problems encountered and their relevance will be discussed in particular;, possible solutions for overcoming such methodological' problems will be indicated and the initial results of an; ongoing st,udy will be presented. Altihou& active smoke is a potent carcinogen also for areas other than the lung (cf. /3/), we shall restrict ourselves. to the effect of lung, cancer. This is because of the extremely high potency of active smoking in connection with pulmonary carcinoma on the one hand and the number of epidemiological investigations on the subject to date on the other hand'.

3' 2. Availgble epidemiological evidence Ln a review which appeared recently, Saracci andlRiboli /10/ present 1!1 epidemiological case control studies and 3 cohort studies whichi are concerned with the relationship between lung cancer and exposure to passive smoking, Owing to: the small numbers of cases in the individual studies (cf. Table 1)„ the confdonce intervals for the relative risk of passive smoking are greater than one for none of the case control studies presented and I only for one : cohort study, ll corresponding to statisticaDl'y significant proof of ai carcinogenic effect. However, ini a, synopsis of all studiies, a so-called' metaanalysis, Saracci and Riboli obtain an estimate for the relative risk of 1.35 with a 95% confidence iintervall from 1.2 to 1.52. As the smallest common denominator of the study, passive smoking is understood as~ exposure to an actively smoking partner. A relative risk of 1.35 means that a nonsmoker exposed to the smoking spouse has a, 35% higher risk of contracting lwng cancer thain an unexposedd nonsmoker. Although a number of' further epidemiological studies on the statedl problem have also appeared after 1987, they do not alter anything with regard to the evidence accumulatied so far,, owing to the relatively small number of cases, assuming that the fiundamentaU validity of thestudiesis not imdo~ubt. IiC is interesting to notie that the relative risk of 1.27 determined from the case control studies presented' does nou differ to a relevant extent from that of the cohort studies (l!.44)„ which contradicts the frequent, presumption that peoplo suffering from a disease (in this case from lung cancer) tend to attribute their conditioni to an exogenic factor, narnel'y, the partner's smoking. Novertheless,,the crux of epidemiological evidence presented to date:is clear from theabove, formulations. Passive smokingi5 reduced totfiepresence of a smoking parmer.However„ it is known that people can also be exposed to tobacco smoke im places other than, ini their private life. A much more serious problem,, however, is that ai carcinogenic effect' can be convincingly proved,, if at all, only in the so-called "complete nonsrnokers", and onee is evidently dependent on the information provided by the persons qpestioned. This raisess the problem of "distortions", which we shadl consider below.

4 Table 1. Epidemiologbcal studies on the relationship betweeni lungicancer and passive smoking Case control studies Author and year Country Lung cancer Controls Relative 951'confi- cases risk dence Exposurel) Exposure interval Yes/Ao Yes/No Chan b Fung, 1982 Hong Kong w 34/50 66f73 0.75 0.45-1.31 Correa et al., U.S.A. w 14/ 8 61/72 2.03 0.81-5.08 1983 m 2/ 6 26/1154 2.29 .30-17.33 Trichopouios Greece w 38/24' 81/109 2.11 1.17=3,78 et al. , 1983 Buffller et al!., U.S.A. w 33/8 164/32 0.80 0.32-11.99 1984 Kabat & Wynder, U!SIa. w 13/1I11, 15/10 0:79 0.25-2.48 1984 a 5/ 7 5/ 7 1.00, 0:20-5.06. Oarfinkel et al,., U.S.A. w 91/43 254/148 1.23 0.81-1.86, 1985 Akiba et al., Japan w 73/21 188/82 1.48 0.87-2.52 1986 a 3/16 9/1101 2.45 .45-13.45 Lee et al., England w 22/10 45/21 1.03 0.41-2.58 '986 a 8/ 7 14/16 11.30 0:37=4.54 Koo et al., Hong Kong w51/35 66/70 1.54 0.89-2.67 1988 Pershagen Sweden w 33/34 150/1197 1.27 0.75-2.18 et al., 11986 Humblie et al,., U.S.A. a 15/ 5 91/71 2.16 0L84-5.52 1987 Tota,l 440/295 1291/1197 1.27 11.06-1.52 (according to Saracci & RiboU (,1'989 ) )' 1) Exposures defined as living together with a smoking partner N I Q 00

5 Table l (continued). EpideOdolopical studies on relationship between luna cancer and passive smokina ICohort studies I I I (Xuthor and year count.ry Lun g cance r Cont rols Relative 951 co'nfi- ~ ~ cas es risk dence li ~' Exp osurel) Expos ure interval ~I ~ Yes No Yes No I 1 s !Garfinkel, 198'1! U.S.A. w88651'2716449422 1.18 0.90-1.54 ~ k;illis et al.. Scotland w 6 2 1388 5211 1.00 0.20-4.91 1 f 1'98+1' t 4 2 306 515' 3'.25 .6041'7.65 I I.I)ilrayaiiiia Japan w 146 37 63287 21858'. 1.63 1.25-2.11 I' let al., 1984 a 7 57 1003 19222I 2.25 1.04-4.86 I ITotal 251 163 19314'8 91538 1.44 1.20-1.72 I I I bNetaanalvsis for case control 1.35 1.20-1.53 Istudfies and cohort studies I f'. Ilaccordanq to Saracci & Riboli 1(19891) I11 Exposures defined'as'living together with a stokina_ partner I 3_--_-- Possible sources' of distortions Various studies have shoHS+n, that a number of people who regard themselves as complete: nonsmokers have in fact actually smoked at, some point in their Iives. Since empirical findings indicate /6/ that smokers marry, smokers rather than nonsmokers,, it, follows that, among smokers incorrectly classified as complete nonsmokers (with a substantially higher risk of lung cancer than true complete nonsmokers), a higher proportion answer ini t'he affirtidative with regard to exposure twlpassive smoking. The effect of this so- calledl misclassification is shown as'a hypothetical example in Figure 1. Dt' was assumed that 2.5% of alll self-reported complete nonsmokers are ini actuality smokers andi that 66% of all true co'mplete nonsmokers but 82'~'p of all alleged, eorplEte nonsmokers answer in the, affirmativewi'tliregard tbexposuretopassive smoking,. These hyp'othetical dat'a are based on the book by Lee /6/. whose work was supported by the Tobacco Advisory Council, a sub-organization of the British cigarette industry. If a rate of newly contracted disease of 5: 100.000~ is assurned, for complete nonsmokers, regardless of whether these are meople exposed toIpassive smoking or unexposed neople, the alleged relative risk is 1.26, the risk for active smoking beine 20 tiimes higher (rate of newdv contracted" disease 100 : 100,000 for active smokers). This means: that with the assumed orders of magnitude and

without ani actual effect of passive smoking, an apparent increase in risk bv 25% is due tK~. the assumed misclassification and the "aggregation behaviour" of smokers. It should be mointed out here that a basic rate of newlv contracted disease other than 5: 1it)p,000 does not change the artificial fndine mentioned. Thus, inian epidemiological study; a relative risk of 1.26, would' be entirely plausible on the basis of the source of distortions described - if this albne were valid'- without, there being any risk of passive smoking in reality. Thus, Lee /6/, too, concludes that'titie higher risks of passive smoking observed in epidemiolbgical studiess to date are very probably due to such distortions. The fact that Wald et, al. /11/ obtained controversial results with sl'ightly different assumptions is frustrating: a 30% increase ini the risk of passive smoking may be entirely probable: The effect of the various parameters on the apparent increase in risk in the hypothetical example presented above are shown iniTable 2.

TRUE NEVER SMOKERS N - 975.000 9T.5Y. FICTITIOUS COHORT OF NEVER SMOKERS OWN INFORMATION N - 1,000.000 2.3% 34% 82% 18% PASSIVE SMOKING EXPOSURE SURE POSITIVE N-20.500 PASSIVE SMOKING EXPOSURE POSITIVE E N a 643.500 PASSIVE SMOKING EXPOSURE NEGATIVF~ Ne331.50 ~0 100:100,000 PASSI VE SMOKING ~ EXPOSURE NEGATIV N=4 500 LUNG CANCER CASES 20.5 EVER SMOKERS N = 25.000 RELATIVE RISK FOR EXPOSURE TO PASSIVE SMOKING 61100,000 81100.000 1001100,000 LUNG CANCER CASES N=32175 LUNG CANCER NCER CASES N - 16.575 LUNG CANCER CASES N- 45 32.175 • 20.5 ~ 16.575 • 4.3 • 1.26 013,500 • 20,500 331,500 • 4,500 Figure 1. Effect of misclassification of smokers as complete nonsmokers on the evaluation of the passive smoking risk by the husband (hypothetical example) sVstzzqzoz

7 66% Passive smoking 5:100,0100 Lung cancer cases = 32.175 exposure positiveN' N = 641,500 True compl ete nonsmokers. smoking N= 97'5,000 P a s s i v e 5:100,000 Lung cancer cases osuiree 5% ex 97 negative . N = 16.575 p Fictitious cohort of "complete nonsmokers" according to~ o~wn, irnformation. N = 1,000,0001 34% N = 331,500. Passive smoking 100:100,000 Lung cancer cases 2.5% 82% exposure positiveN =,20,5 N = 20,500 NeversmoJced N = 25,000 1010:100,000 Lung cancer cases = 4.5. Passive smoking 18% exposure negativeNi N = 4,600 32,175 2'0.5 16,575 4.5 Relative "risk" for exposure to passive smoking = = 1.20 64!3,500 2'0.500 331,5010 4,5001 Figure 1. Effect of misclassification of smokers as complete nonsmokers on the evaluation of the passive smoking risk by the hnasband (hypothetical exa¢nple)

8 Table 2'. Apparent increase in risk for different! assumptions about' the misclassification rate 7r, relative risk of smokin RR and exposure of smokers to passive smokinga(cornpiete nonsmokers ext3ose6 to passive smoking 68%) i Ma 70% 80% 82%_ I r i7r = 2'.5% 2 +0.4% + 1.5%' +1.7% ii (i I {' 110, +3.3% + P2.1 % + 14.0% I f I ~ 20 +5.8% +22.6%'0 +26.5%' ~ Ix=5% 2' +0.8% +2'.9% + 3.3% I ~ 101 +5.5%, +21'.2'% +24.8% I' I I i 20 +8.8% +36.2% +43.0% I t 1 The remarkable feature here is the fact that, the apparent' increase in risk depends in a relcvant' manner on the assumed relative risk of active smoking. This counteracts the criticism of Lee:and others: thus,, it' does not appear very plausible that smokers misclassified as complete nonsmokers are grouped tbgether with the very heavy smokers, for whom, . relative risks greater than 110 must' be assumed. Instead, what is plausiblc is that they belong to the group consisting of those who smoke rarely or to a small extent and for whom we have tb assume substantially lower risks on the basis of alli epidemiological evidence. Another damper for critics who favour the above-mentioned' example is the fact that, the epidemiolbgical studies since performediin connectionwith the risk of cardiovascuilar diseases also indicate relevant increases in risk (cf. /1/). If the observed relationshiID with, liune cancer were due only to the misclassificatiQn described, the estimated risk of passive smoking would have to be an order of magnitude lower (with the same pathogenetic chain of effects) owing to the very much lower risk of active smoking for cardiovascular diseases (about 2':li compared with 1'0:1 for lunQ,cancer), which is also evident from Table 2.. Over and above this, it must not be forgotten that, apart from the source of distortions just described, there may be a number of other possible sources of distortions, some of which, may have effects in the opposite direction (cf. Table 3)

9 Table 3. Effects of further distortions on a derived relative risk (RR) of passive smoking r- I { Cause Effect on RR" J ~"himn-exposed people" are in ~ ~ reality exposed (occurrence of ~ ETS everywhere) ~ ~' Nondifferential misclassification ~ ~ of exposure l ~ ( Cases underestimate/controls ~ ~ exaggerate the exposure ~ ~ ~ Cases exaggerate/controls ~ ~ underestimate the exposure T ~I I 1 ~ Lung cancer cases not, involving, ~ ~i smoking are not recognized as such y ~ 1' ~" 1?i means that the relative ~ ~ risk is underestimated or ~ ~ overestimated'. ~ Whether and how the sources of distortions described, affect epidemiolbgical findings cannot, be established in theory. In empirical terms; it appears that more knonwledge:can be gained only through an improvement of the epidemiological instrument. For this purpose, it is particularly important to arrive at a validl qwantitati•.ve estimate of the exposure to passive smoking taking into account sources of exposure other than the smoking spouse. 4. Results of ai studx of methods Developing an instrument for a more valid estimate of the exposure was the task of an, international study performed by the lntiernationali Agency for Research on Cancer (TARC), in which the Bremer Institut, fiir Praventiionsforschung und Sozialmedizin (BIPS) participated as one of 1'3 study centres in 10 countries. I~n 1'986„ 10Q1 female nonsmokers in Bremen were