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I What Is the Epidemiologic Evidence for a Passive Smoking- Lung Cancer Association? N. Mantel Summary Two survey articles of reports on the association of passive smoking with lung cancer have recently appeared, and'also a comprehensive report on the subject of enviuonmen- tal tobacco smoke by a committee of the National Research Council of the United' States. The observed excess over a relative risk of unity, cannot be explained by chance. Nor can it be fully accounted for by a particular source of bias, the false claims of being non-smokers by individuals who were active or ex-smokers. That possible source off bias leads, in one summary survey, to reducing a relative risk of 1.35 to 1.30, but from 1.34 to 1.15 in the National Research Council report. The latter report suggests that statistical significance would no longer obtain, perhaps, particularly„because of other possible biases. However, to get an estimate of the correct relative risk due to passive smoking, allowance has to be made for actual exposure to passive smoking of those not exposed' at home. Thus, the 1'.30 is adjusted upwards, by 18 in one survey, to 1.53, butt by only 8% in the National Research Council report to 1.24. The National Research Council report had given an anticipated relative risk of 1.1 based on dosimetric considerations. But it is suggested here that that eouldbe as low as 1.05, too low to be detected in an epidemiologic investigation - in any case it wouldi be based on hypothetical assumptions. In November of 1986 there were two near-simultaneous review articles addressing the subject of passive smoking and lirng cancer.,One was an invited'guest editorial by Blot and Fraumeni in the Journal of the National Cancer Institute, the other a contemporary theme discussion by Wald et al. in the British Medical Journal [1, 2]. There was substantial overlapping in the two articles of the various publications on the subject„and on the basis of which the conclusion of a significant positive association was made. The article by Wald et a]. gave, perhaps, more statistical detail' about the results of the several studies covered. But, to my mind; there was uncriticaliacceptance of the results of all the studies. Blot and'Fraumeni did suggest that there were some flaws in a particular study, that by Hirayama [3], but decided that any inherent biases in, that investigation coul& not have given rise to the observed elevated risk. From their overall evaluation of 10 case-control studies (all 10 gave results for females, five separately for males as well) and three prospective studies (two of these eovere&males separately), which provided 20 separate relative risk (actually odds ratio)) values, Wald et al! came up with a summary relative risk of lung cancer due to passive smoking of 1.35 (95% limits 1.19 to 1.54). They trim this down to 1.30 on the basis that some of'the presumed non-smokers exposed to passive smoking were actually smokers. Then, on the added basis that even those unexposed to passive smoking at home may still have been exposed when awayfrom home, theyraise their estimate of relative risk to 1.53. But note that this last modification presupposes the answer„that passive smoking does H. Kuup (Ed.) Indoor Aii Quality 0 Springer-Verlag, Berlin Heidelberp 1990

342 N. Mantel elevate the risk. For if it did not, there would be no basis for adjusting the 1.30 or 1.35 upwards to 1.53. Blot and Fraumeni come up with a similar summary measure of relative risk for passive smoking of 1.3 (95 %d limits of ll 1-1.5), but elevated to 1.7 (95% limits of 1.4-2.1) for heavy, passive smoking. These authors suggest that heavy passive smoking is equivalent, at least in terms of nicotine received, to smoking between 1/2 and 3 cigarettes daily, and estimate that smoking a few cigarettes daily,would give rise to a relative risk of about 1.5-fold to twofold. While Blot and Fraumeni do not address the question of correct reporting of non- smokiag status, Wald et al. do, having used this as a basis for lowering the relative risk estimate from 1.35 to 1.30. Based on reports and communications from others, Wald et al; estimate that persons reporting themselves as never having smoked (lifelong non- smokers) comprise 2.1 % active smokers plus 4.9 % former smokers, for a total of 7% ever smokers among the self-claimed never smokers. Wald et al. estimate thatthese 7% have a combined relative risk of 2, making the assumption in doing this,thatthe active smokers among the 7% smoked on average only a quarter as much as active smokers generally. The relative risk of 2 for the 7% is computed as a weighted average of 3 for active smokers, 1.5 for former smokers, among the 7%If7%n of reported never-smokers were actuallycx-smokers or active smokers„which were they - the spouses, say, of smokers or the spouses of non-smokers?' ln my own caitique of Hirayarna, I had suggested that this false reporting of non-smoking status would preferentially be among those with smoking spouses [4]. If, for example„the 7% overall misreporting of non*smoking status concentrated among spouses of smokers, it would be somewhat higher among persons with smoking spouses who, nevertheless, claimed to be never smokers. Suppose we take it at 20%, in which case the reported lifelong non-smokers relative risk would be 1.20. It could be substantially higher butSor the assumption by Wald et al. tharthe active smokers among the reported never smokers had sharply reduced levels of smoking. However, Wald et al. were ready to make only a small reduction, in relative risk for this factor, from 1.35 to 1.30. Their speculative inarease„which might have no basis at all„was much greater, from 1.30 to 1.53. The effect of false reporting of smoking status, specifically of non-smoking; could be much sharperthan what Wald et al. have suggested.ln a study ofibiochemical markers of smoke absorption, Jarvis et al. branded as "deceivers" 21 individuals who claimed to be non-smokers [5]. These 21 displayed biochemical patterns very similar, to those of actual smokers, not at all like those of accepted non-smokers. The 100 accepted non-smokers comprised 46 without passive smoking, 54 with. Those 21 would constitute 21/121 or about 17% of the total, and these would be active smokers, not just former smokers, or eightfold greater than the 2.1 % Wald at al'L postulated. Perhaps in the epidemiologic investigations made, false reporting of non-smoking status is at a much dower 1'evel, but it would not take much false reporting to account fully forthe seeming association between passive smoking and lung cancer. Recently, a colleague expressed to me the thought that if passive smoking played no role in lung eancer, why are we not finding many negative associations, nor anyy significantly negative associations? Actually; six of the 20 relative risks reported in Wald et al. are at 1.00:or smaller. And some of those reported as in excess of 1.00 conceal rates of under 1.00. Thus, relative to the rate shown of 1.23 for the study reported by Garfinkel et al., I have brought out in my own critique that that represented a composite ofdata for various classes of~respondents [617j. Where the woman with lung cancer, was herself the respondent (as to her husband's level oflsmoking) the relative risk:was 0:g3. Using the husbands' responses, the relative risk was 0.77. It was only on the basis of responses by t 1 t I

What Is the Epidemiologic Evidence for a Aassive Smoking-Lung Cancer Awociation? 343 the sons and daughters, at a time long past when they would have left home, that a relative risk of 3.57'emerged, sufficiently high to raise the overall'estimate of relative risk to 1.23. As I indicated in my cri'tique, the replies by the children were more accusatory in nature than revealing of'any true reiationship: But even so, it would take 40 large studies to get on average a single seemingly significant'negative association of lung cancer with passive smoking„assuming statistical testing at the 59c, two-tailed, level. But we have only 20 evaluations, with many so small that they could'not possibly yield any apparently significant protective effect, not even in the unrealistic situation that passive smoking was 100% protective. Suppose a study had a null expectation of only2'or 3 passive smokers with lung cancer - then there would be some observed number, 5 or 6 or 7 or 8 or more which would be significantly in excess of expectation. But there would be no number, however small or even zeroa which would be significantly below expectation. Yet justisueh low expectations characterize several of the studies reported'on by Wald'et al. In one study, a relative risk of 2.29 is shown based on only 2 actual cases of lung cancer in passive smokers, expectation 1.20. Another relative risk of 2.45 is based'on 3 observed, 1i.77 expected. Fon one prospective study,,4,observed cases have givcnrise to an estimated relat'ivezisk of 3.25, and in another 7 observed cases gave rise to a relative risk of 2.25, suggestive of an expectation little in excess of 3. On the other hand, the four, reported risks of under 1.00 had expectations variously of' 37.67, 34.08, 6.64 and 13.77. Of concern to Wald ev al. was whether the various relative risks were homogeneous. On this point they cite a chi-square test for heterogeneity of 20.01 on 19 degrees of freedom, p> 0;2: However,,this is not so much evidence ofhomogsneity of relative risks as ieis reflective of the high unreliability of the individual relative risks. For 8 of the 20: relative risks shown, the upper limit on the relative risk exceeds the lower limit by a factor of about 10 or more, that factor, attaining a value of 57 in one instance. Blot and Fraumeni express concern about other long term~consequences of passive smoking, particularly in connection with coronary artery disease. They cite a report by Garland ev al. [8J who initially reported a relative risk due to passive smoking of death from ischemic heart disease of 14.9, but seem unaware that the estimate of 14.9 has been revised downwardto 2.7. Inthe report of the National Research Council [9], which I will be discussing below, there is awareness of the downward revision, but not,.of the fact that the suggestive significance of p< 0;10 is lost and becomes p<A.20. That lung eancer may aggregate in families is also of concern to Blot and Fraumeni,, who cite Ooi et al. on the subject [ 10]. Elsewhere, and yet to appear, I have suggested that apparent familial aggregation, in the instance breast; cancer, may be a reflection of an awareness bias rather than of true familial aggregation [11). If information about relatives is not collbcted more directly,,the apparent aggregation based on reports from the Index case may only reflect heightened knowledge by such cases of similar illnesses about ~ relatives. But the report by Ooi et al. i's another instance, like that of Garlan&etal.,, in which there has been unreliable statistical evaluation. Thus, Ooi el all initially reported that the lung cancer risk increased eighteen-fold per 10-year age increase. By letter in the October, 1986 issueaf the Journal of the National Cancer Institute they have revised that factor downwards, giving separate factors for each I0-year age interval. From age 50 to age 60, the factor is now reported at only 2.9.

34.4 N. Manrel The Report of the Committee on ~ Passive Smoking, Board on Environmental Studies and Toxicology, National Research Council [9J I have chosen to discuss the epidemiologic aspects of this Report separately, since it is essentially the definitive work on current knowledge on environmental tobacco smoke. A member: of the committee was Nicholas Wald, senior author of one of the articles discussed above. The report contains a technical appendix which largely duplicates the appendix in the article by Wald et al. and also repeats, with minor variations, the data of Wald et al. The body of the report itself contains those same data, but recast differently;, and it is the same 1'3'studies, with 20 relative risk values, which underlie the epidemiologic aspeas of'the Committee Report. There are a great variety of issues which the Committee Report goes into, whether physiochemistry; toxicology, assessment of exposures, use of questionnaires, exposure- dose relationships, etc. Butmy concern at this time is the epidemiology. There could be a point to estimating the annual number of lung cancer deaths in the United States due to passive smoking, but that would have to be on the presumption that passive smoking does play a causative role. However, the Committee Report is quite restrained in its findings and leaves open the question of whether anything has been established. If the apparent relative risk is significantly greater than unity; the excess cannot be fully explained away by certain biases considered. However, whether there is statistical significance in view of those biases is not addressed. From dosimetric considerations, the Report suggests that the excess risk of lung cancer due to environmental tobacco smoke should be 1% of the excess risk due to active smoking. This leads to a relative risk of 1.14 for men, perhaps less for women. From the epidemiologic data, the summary relative risk is 1.34, butit is brought out that for United States studies only the relative risk would be only 1.14. If only large studies are considered, the overall relative risk would be 1.32: Next addressed by'the Report is the effect of biases, particularly the bias associated with the false reporting of individuals that they were not (or never have been) smokers. This leads to a lowering of the estimated relative risk of 1.34 (or 1.30 to 1.34) to 1.1 S. But note that on this same basis, Wald et aL were willing to reduce an apparent relative risk of 1.35 only slightly, to 1.30. Yet another adjustment is made. If non•smokers are not exposed'to environmental tobacco smoke at home, they might still be exposed to it away from home. An upward adjustment of 8% on account, of this yiel'ds 1L 15 X 1.08 = 1.24. This contrasts with the upward adjustment of 18% made by Wald et ali, who calculated 1L30 X 11.18 = 1.53. The Committee Report differs markedly from the separate report made by one of its own members. In discussing, Wald et al. I suggested that the upward modification they have presupposed a positive role for passive smoking. This same thing is true for the 8% upward adjustment in the Committee Report: For purposes of evaluating the statistical significance of the findings, the relative risk should be taken as 1.15, though the value of' 1.24 might be appropriate for assessing the toll' in excess lung cancer due to passive smoking assuming that there is causality. With the United States studies indicating an unadjusted relativerisknf only 1i.14,rather than 1.34, both the 1.15 and the 1L24,might be sharply lowered if intended to apply only to the United States. But let me stsy with the relative risk of 1.13 pri:or toihe 8% upward'adjustment. Is that relative risk significantly in excess of 1.00? 1 suspecrnot. And even the question of bias remains open. Both in the Committee Report and in the article by Wald et al., the only

What Is the Epidemiologic Evidence for a Passive Smoking-Lung Cancer Aeaociation7 345 1 I biases factored in were just those that would fit into neat mathematicaGLormulas. More subtle biases or ones that had not beenrthought of did notiget in. I gave an example above of the use by Garfmkel et al. of the responses by sons and daughters of the level of smoking by the fathers. I might even speculate about publishing bias. If an investigator got a weakly, or insignificantly negative resulvfor the role of passive smoking in lung cancer„would he bother submitting it for publication7 And if he did, would itbe accepted for publication? Postulating this kind of bias is not necessary for establishing that the 1'.15 relative risk is likely not significant. But I bring it up in connection with a tendency I see towards accepting uncriticallyor less critically manuscripts which are onthe right side of the fence on the issue of passive smoking. A particular example was the publication of the article by Garland et al. on passive smoking and ischemic heart disease mortality, the claims of which fell apart on scrutiny. Let me bring up now another thought. Some time ago the possibility of subtle or not- so-subtle biases in case-control or other epidemiologic investigations was so much a matter of'concern that it was suggested that unless the relative risk were atleast 2.0, any increase in risk should not be accepted. Perhaps we can do better now and might employ a less restrictive criterion. Butl can see no relaxation to the point of accepting the relative risks now observed for passive smoking in~ lung cancer. What we must accept is that it is unlikely that any epidemiologic investigation has been on can be mounted which would establish a causal role for passive smoking in lung cancer. Those who believe such a role exists should continue to believe as much, and might even hazard estimates as to the resulting toll in deaths and disease„with other allowed to hold contrary beliefs. What would ~be incorrect would be to claim that epidemiologic studies have established the correctness of, the belief. If epidemiologic investigations cannot establish a role for passive smoking; the best we can do is to make suppositions estimates of how great that role may be - and suchh suppositions estimates can be too high if any of the underlying supposals are false. One supposal would be that the dosage response curve is linear through the origin, another that some particular biochemical measure„say level of'eotinine, is a proper measure of the equivalent exposure to cigarettes of passive smoking: And;,I pointout, there coul&be the assumption that the temperature at which tobacco smoke is inhaled is not relevant, though Pwould think that fresh hot smoke would be more active than stale smoke. With this thought in mind, we can pick up some clues from the report of Jarvis et a]'L who, after, excluding "deceivers", report average cotinine levels in plasma, saliva„and urine of' 100 non-smokers to be at 0.55%+ 0.554$ and 0.364 respectively of those levels from 94 smokers. Let us take it at 0.5%. If the average cigarette smoker has a relative risk for lung cancer of 10.0 (enhancement of 900%a, though the enhancement may be 1,400% for very active smokers)i this would put the enhanced risk due to environmental tobacco smoke at 4.5%, for a relative risk of 1.045 (it would be 1.07 using the 1,400% enhancement for very active smokers). That relative risk, 1.045„would encompass both passive smoking at home and away from home, including individuals not exposed to passive smoking at home. What matters, however, relative to the conduct of epidemiologic studies on the subject, is the differential in relative risk between those knowingly exposed to passive smoking and those who believe themselves unexposedi From data available in Jarvis et al., it would appear that those seemingly not exposed to passive smoke (46 in number); nevertheless have a relative risk of about 1'.02: For the 54 non-smokers claimed to be aetuaTly'exposed to passive smoking; the relative risk based on cotinine levels would, in

346 N. Mantel similar manner„be 1!.07. Compared then to seeminglynontxposed to passive smoking, the ealeulatedrelative risk for the known exposed to passive smoking would be 1.05. That smallincreascin relative risk just would not show up on any epidemiologic investigation and would be submerged, in any case, by other very likely biases. The National Research Council report had suggested a relative risk, based on dosimetric considerations„of 1.14, but on the assumption that enhancement in~risk due to an active smoking was 1,400%. An enhancement of 900% would have led them to anticipated relative risk of 1.09. But whether we use 1.05, 1.09, or 1.14; the effect would still be undetectable. As a last point, I raise the issue of passive smoking effects on children.,If parents can be shamed into not exposing their children to passive smoking, this is all well and good, even if' the supporting basis is unsound. I note that the ill effects arise mostly in early childhood, and have two questions. Have the passive smoking effects been isolated from effects due to mother's smoking prior to the child's birth? To what extent has account been taken that cigarette smoking concentrates in families with lower socio-economic status, as evidenced by lower educational level and more unemployment etc. Rona et all also brought in the factor of overcrowding at home in their report that passive smoking resulted in some small reduction in the stature of children { 12]: Buteven Rona et al. failed to take properly into account, as I have suggested, the role of some of these important factors on smoking rates in their evaluation {i13]. What with subtle biases, not so subtle biases„and even extravagant errors, one should not accept too readily claimed demonstrations of ill effects of passive smoking. Passive smoking has been the favorite whipping boynf epidemiologists for too lbng already. The~, public is entitled not to be unnecessarily exposed to environmental'tobacco smote•but any panic is unjustified. ~ References 1. Blbt JB, Fnumeni JFJn(1986) Guest aditorial! Panive smoking and'dung cancer. Journal of tbeNational Cancer Institute 77:993-1i000 2. Wild NJ, Nanchabal K, Thompson SG, Cucklr HS (1986) Contemporary theme. Does breathing other people's tobacco smoke cause lung cancer? Br Med J 293:1,217-22 3. Hirayama T(1981) Non-smoking wives of beavy smokers have a higher risk of lung cancer: A study from Japan. Br Med J 282:183-5 4. Mantel N' (1983) Guest editorial. Epidemiologic investigations: Care in conduct, care in analysis and care in reporting. 3 Cancer Res Clin Oncol 105: 113-6 5. Jarvis M,Tunstall-Pedoe H, FeyerabendC, Vesey C,SalloojorY'(1984) Biochemical markers of smoke absorption and self reported exposure to passive smoking. Journal of Epidemiology and Community Health 38:335-9 6.,Garfinkel L, Auerbach 0, Joubert L (1985) Involuntary smoking and lung cancer: A case- control study. Journal of the National Cancer Institute 75:46'3-9 7. Mantd N(1986)'Letter. Involuntary smoking and lung wncer-some object lessons. Journal of the National Cancer Institute 76:1,261-3 8. Garland C, Barrett+Connor E, Suarez L, Criqui M, Wingard D (1985) Effects of passive smoking on iscbemic beatt disease mortality of non-smokers: A prospective study. Am J, Epidemiol 121:645-50 9. National Research Council (1986)'Committe on passive smoking, board on environmentall studies and toxicology. Environmental tobacco smoke - measuring exposures and assessing health effects. National Academy Press, Washingtonj DC 10. Ooi WL, Elston RC, Chen VW„Bailey-Wilson JE, Rothschild H(1986)lncreased funilial risk for lung eancer, Journal of the National Cancer Institute 76:217-22 04 J

What Is the Epidemiologic Evidence for a Passive Smokiag-Lung Canar Association? 347 11. hSantel N(1989)'Letter: Familial breast cancer and the awareness bias. Am 3 Epidemiol (in pma) 12: Rona RJ, Chian S, Florey C(1985)Exposure to cigarette smoking and c6ildren's growth. IntJ Epidemiol 14:402-9 13: M'antel N (1986) Letter: Does passive smoking stunt the growth of children7 lnt J Epidemioli 15:427-8 I