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I I I I I I l I I I I I I I I i I I l -- TABLE OF CONTENTS -- LUNG CANCER .................................................................................................... .................. 1 CARDIOVASCULAR ISSUES ................................................................................... 11 RESPIRATORY DiSEaSES aND CONDITIONS - ADULTS ............................................... 16 RESPIRATORY DISEASES AND CONDITIONS - CHILDREN .......................................... 24 OTHER CANCER .................................................................................................... .............. 41 OTHER HEATH ISSUES .................................................................................................... ...... 45 ETS EXposuP~ aND MONITOPdNG ................................................................................ 52 INDOOR BAR QUMATY .................................................................................................... ...... 62 SMOKING POLICIES AND RELATED ISSUES ....................................................................... 75 STATISTICS AND RISK ASSESSMENT ................................................................................... 79 INDEX .................................................................................................... ......... 85 Please note: This document is not intended to be an encyclopedic summary of scientific literature relating to ETS. Rather, it contains exclusively those studies included in Reports on Recent ETS and IA Q Developments. This document has been prepared for use by Shook, Hardy & Bacon attorneys and analysts. Please, do not distribute this document to persons outside the firm.

I VOLUME. 1[, ISSUES 1-24 JULY 1992 I I ENVIRONMENTAL TOBACCO SMOKE & INDOOR AIR QUALITY i I i i I I I I I i I I i I I LUNG CANCER [I] Letters to the Editor Regarding "Lung Cancer in Nonsmo "klng Women: A Multicenter Case- Control Study," E.T.H. Fontham, P. Correa, A. Wu-Williams, P. Reynolds, R.S. Greenberg, P~. Buffler, V.W. Chen, P. Boyd, T. Alterman, D.F. Austin, J. Liff and S.D. Greenberg, Cancer Epide- raiolo~y, Biomarkers & Prevention 1." 35-43, 1991 [Issue 23, Item 17] Cancer Eioidemiolog7, Biomarkers &Prevention recently published four letters concerning this ardcle, which is a preliminary report of an ongoing U.S. case-control study that currently includes data on 420 female lung cancer cases. As discussed in issue 12 of this Report, December 10, 1991, the authors reported a statistically significant odds ratio for adenocardnoma assodated with spousal smoking. The series begins with a letter from Nathan Mantel, followed by a reply from the authors of the study, then continues with a letter from Peter N. Lee, also followed by a reply from the authors of the study. The letters appear in Cancer Epidemiolag7, Biomarkers & Prevention 1: 331-334, 1992. Mantel stated that certain cotinine data presented in the study indicated misclassification of smoking status. Mantel also noted that possibly "extravagant" bias could be introduced in the study because next of kin provided information for 34 percent of the cases, but did so for only 10 percent of one control group. Moreover, when next of kin provided information, urinary cotinine levels could not be measured in the study partidpants. Finally, Mantel critidzed Fontham, et al., for focusing on only adenocarcinoma, instead of treating all lung cancer cell types: "[I]fthese investigators have had their choice of which type of lung cancer to emphasize, their statistical significance levels should be modified to take the mul- tiple-testing aspect into amount." In their reply to Mantel, Fontham, et al., stated that their identification and exclusion of women with high urinary cotinine values "can only be considered a strength of the study." They also noted, with regard to the next of kin concern, that "estimates of relative risk did not differ in analyses restricted to self or proxy respondents." Finally, Fontharn, et al., stated that they did not have a choice of which histological ~¢pe to emphasize "because most cases turned out to be adenocardnomas a_fi:er histological review." They pointed out that the number of cases with other cell types of cancer was too small to allow reasonable statistical power in specific analyses. Legs letter commented that some data on cotinine and on lung cancer cell type were incomplete in this interim report. He noted that possible confounding factors (e.g., occupation, diet, medical history and other exposures) had not been taken into account. Lee said that confound- ing could also be due to inclusion of unmarried women in the analysis of spousal exposure, never-employed women in the analysis of occupational exposure, and to an unadjusted index ofsodal exposure. According to Lee, this could lead to "an inevitable confusion of possible effects of ETS with possible effects of marital status, occupation, and sodabiliry." Lee also stated that he calculated a relative risk for nonadenocardnoma lung cancer which was not significantly different statistically from the relative risk for adenocardnoma calculated by the authors. According to Lee, this failed to "justify the spedal attention given to the adenocarcinoma results." Finally, Lee questioned the biological plausibility of an elevated risk of adenocarcinoma associated with ETS exposure, "given that the assodation of active smoking with adenocarcinoma is so weak." Fontham, et al., replied to Lee by stating that "the availability of a large data set with which to address an unresolved issue of great public health importance was compelling justification for publishing a report" that represented only three years of a five-year study. They stated that a number of potential confounders, including age, race, geographic region, respondent type, income and education had been considered, and that other potential risk factors "will be examined in further analyses." Specifically, Fontham, et al., commented on an ongoing analysis of dietary factors, and stated that g-carotene has not appeared to be related to spousal smoking habits in this study. N4rith regard to the inclusion of unmarried women in spousal smoking calculations, Fontham, et al., calculated risk estimates with those subjects excluded that were only slightly louver than the original estimates. Exclusion of never-employed women from workplace calculations resulted in risk estimates ~vhich were elevated somewhat compared to the original calculations. Finally, Fontham, et al., defended their "special attention" to adenocarcinoma because of the large proportion of SHB

ETS AND IAQREFERENCE JULY 1992 adenocarcinoma in the study~They also proposed that "exposure to sidestream smoke might result in a distribu- r.ion of histological types of lung cancer different from that associated with exposure to mainstream smoke." [2] "Passive Smoking and Canine Lung Cancer Risk," J.S. Reif, K. Dunn, G.K. Ogilvie and C.K. Harris, American Journal of Epidemiology 135 (3): 234- 239, 1992 [Vol. I, Issue 19, April 10, 1992] This article, published in a major peer-reviewed epidemiologic journal, reports on a case-control study (51 cases, 83 controls) of lung cancer in pet dogs. The authors reported a weak relation between exposure to a smoker in the home and lung cancer in pet dogs (odds ratio of 1.6, 95% CI 0.7-3.7). The authors propose that epidemiologic studies of pets may "add to our under- standing of environmental tobacco smoke effects in human populations." One of the authors of the study, John S. Reif, was coauthor with Ross C. Brownson of the 1987 study "Risk Factors for Adenocarcinoma of the Lung," which discussed ETS. EXCERPTS~ "A case-control study was conducted to determine whether household exposure to environmental tobacco smoke is assodated with an increased risk for lung cancer in pet dogs. Lung cancer cases and controls with other forms of cancer were obtained from two veterinary teaching hospitals during 1958-1987. Exposures assessed included the number of smokers in the household, the amount smoked, and the proportion of time spent indoors by the pet." "A weak assodation was found between exposure to environmental tobacco smoke and the risk of canine lung cancer .... After adjustment for age, sex, skull shape, time spent indoors, and hospital, the odds ratio rose slightly to 1.6 (95 percent CI 0.7-3.7)." "Evidence of a dose-response relation for passive smoke exposure was largely lacking." "The increase in risk found in this study in dogs corresponds reasonably well with the estimate of an increased risk for lung cancer in humans of 1.35 that was calculated in a meta-analysis of the first 13 studies of lung cancer risk and passive smoking conducted worldwide. The current study suffers from some of the same limita- tions found in the studies done in humans, i.e., small sample sizes, impredse risk estimates, and difficulties in measuring exposure." "The finding that increased canine lung cancer risk is restricted to dogs with short and medium length noses is -2- consistent with the hypothesis that the relatively effident air filtration of the tong-nosed breeds may exert a protec- tive effect for lung cancer." "The rarity of lung cancer in dogs makes a collaborative multicenter case control study the design of choice for further studies of canine lung cancer. Studies of nasal cancer, a more common form of cancer in dogs, are under way to examine the effects of environmental tobacco smoke on the nasal epithelium." [3] "Lung Cancer in Nonsmoking Women: Dietary Antioxidants," E. Fontham, R. Coates, A. Dilley, P. Reynolds, Pall. BuYer, A. Wu-Williams, V. Chen, R. Greenberg, P. Boyd, T. Alterman, D.F. Austin and P. Correa, abstract submitted for American Society of Preventive Oncology meeting, Cancer Epidemiology, Biomarkers & Prevention 1(3): 429, 1992 [Vol. I, Issue 19, April 10, 1992] This abstract presents additional data from the ongoing multicenter case-control study of lung cancer in female nonsmokers which has also reported on ETS (see Issue 12, December 10, 1991, of this report). The abstract reported that lung cancer cases consumed fewer vegetables than did controls. Dietary intake of Vitamin C or alpha- carotene was reportedly associated with a small reduction in lung cancer risk, but no such effect was reported for total Vitamin A, Vitamin E, total carotenes or beta- carotene. In the initial, preliminary report of this study, the authors reported (i) no statistically significant risk associated with spousal smoking or childhood exposure to ETS for all lung cancer types; (ii) an OR of 1.38 for adenocarcinoma assodated with spousal smoking; and (iii) statistically significant ORs for all cancers and for adenocarcinoma associated with workplace exposure to ETS. Seelssue 12 of this Report, December 10, 1991. "Most epidemiologic studies which have found a protective assodation between lung cancer risk and con- sumption of fruits, vegetables and thek micronutrient constituents have been conducted in male smokers. This large, on-going, multicenter case-control study of lung cancer in female lifetime never-smokers provides the opportunity to evaluate these dietary factors in the absence of possible confounding by smoking. A total of 273 primary lung cancer cases and 774 controls selected from the general population, all of whom were lifetime never-smokers and self-respondents, were included in this analysis. Cases consumed fewer vegetables and some fruits. Dietary intake i I ! I i 1 I i I I I i I I

"qO~'UM2., I, ISSUES 1-Z4 JULY 1992 I I i of vitamin C, with or without supplementation, was assodated with a small reduction in risk, while no such effect was noted for total vitamin A, vitamin E or total carotenes. Individual carotenes were also evaluated. No reduction in risk of lung cancer was noted for any of the three highest quardles of consumption olin-carotene, but about a 30% decreased risk was assodated with b_igh consumption of_- carotene. All dieta~ risk estimates were adjusted for age, race, study area, education, exposure to environ_mental tobacco smoke, family history of lung cancer, occupational exposures, cholesterol and total calories." [4] "Lung Cancer in Women in the Niagara Region, Ontario: A Case-Control Study," EJ. Holowaty, H.A. Risch, A.B. Miller and J.D. Burch, Canadian Journal of Public Health 82: 304-309, 1991 [Vol. I, Issue 18, March 20, 1992] In this study, 51 female patients with lung cancer and 45 matched controls were interviewed. Information was collected about acdve and "passive" smoking, occupation and residential history. The authors reported a srzong statistical assodation between active cigarette smoking and lung cancer. No assodadon was reported between lung cancer and air pollution or residential history. With regard to ETS, the authors reported no statistically significant odds ratios for lung cancer. These results are not directly comparable to the studies often cited for ETS and lung cancer because the authors did not restrict their analysis to nonsmoking women. Rather, their analyses included all cases, regardless of smoking history. "We report the findings of a case-control study about the possible etiologic assodation between the above factors (i.e. tobacco smoking, ambient air pollution, passive smoking and occupational exposures) and lung cancer among female residents of Niagara Region." "Cases [51] and controls [45] were interviewed in their own homes by an experienced interviewer, using a standardized questionnaire. Information was collected on lifedme residential and occupational history, lifetime tobacco smoldng history, exposure to passive tobacco smoke, personal and spousal exposure to occupational substances and suspect industries, and various socio- demographic variables." "Cigarette smoking was strongly associated with risk of lung cancer in Niagara women." "Overall, 90% (46/51) of cases and 78% (35/45) of controls reported some past exposure to passive tobacco smoke in their homes. After adjustment for personal lifetime cigarette consumption, there was insufiqdent statistical evidence supporting an association between tobacco smoke in the household and lung cancer (OR = 3.6; p = 0.24). Further, there was no association between lung cancer and having a mother, father or husband who smoked in the same household. Passive smoking in the household was also examined in terms of duration (years) that each subject reported exposure as a child, and as an adult. Neither exposure was significantly associated with risk after adjusting for active smoking. There were no evidence that passive smoking exposure in the workplace was assodated ,with lung cancer." "The previously reported excess of farad lung cancer in Niagara females is most likely attributable to active cigarette smoking. This study failed to demonstrate a strong association between air pollution or residential history and risk of lung cancer." [5] "Lung Cancer in Nonsmoking Women: A Multicenter Case-Control Study," E.T.H. Fontham, P. Correa, A. Wu-Williams, P. Reynolds, R.S. Greenberg, P.A. Buffler, V.W. Chen, P. Boyd, T. Alterman, D.F. Austin, J. Lift and S.D. Greenberg, Cancer Epidemiology, Biomarkers &Prevention 1: 35-43, 1991 [Vol. I, Issue 12, December 10, 1991] Th~s preliminary report of an ongoing U.S. case-control study includes data on 420 female lung cancer cases. The authors report no statistically significant risk assodated with spousal smoking or childhood exposure to ETS for all lung cancer types. They do, however, report a statistically significant ORof 1.38 for adenocardnoma assodated with spousal smoking. They also report statlsti,-~lly significant ORs both for all cancers and for adenocardnoma assodated with workplace exposure to ETS. Several individuals contributing to this article were primary authors of other ETS and lung cancer papers. Pelayo Correa reported on a small case-control study from Louisiana in a 1983 paper; Elizabeth Fontham collaborated on that study. Earlier this year, Anna Wu-Willlams published a paper on a large case-control study conducted in northeam China. Patrida Buff!er reported on a case-control study done in Texas in a 1984 paper and additional results were published by Shaw, et al., in 1991, as reported in Volume I, Issue 4 (July 12, 1991) of this report. "The association be~veen exposure to environmental tobac.m smoke and lung cancer in female 1Ketime nonsmok- ers was evaluated using data collected during the first 3 years of an ongoing case-control study. This large, multicenter, population-based study was designed to minimize some of -3-

ETS AND IAQREFERENCE JULY 1992 I the methodological problems which have been of concern in previous studies of envh'onmental tobacco smoke and lung cancer. Both a cancer control group and a population control group were selected in order to evaluate recall bias. A uniform his~opathological review of diagnostic material was conducted for case confirmation and detailed classification. Biochemical determination of current exposure to tobacco and screening of multiple sources of information to deter- mine lifetime nonuse were utilized to minimize misdassification of smokers as nonsmokers." [Although data on possible confounding factors, e.g., diet, were apparently collected, they were not considered in this paper.] "For all histopathological types of lung cancer combined, a 30% increase in risk is observed (OR = 1.28 and 1.29 with colon cancer and population controls) .... The estimated relative risk of pulmonary adenocarcinoma assodated with cigarette smoking by spouses was 1.36 (1.02-1.84) with the population controls as comparison and 1.31 (0.94-1.84) with the colon cance~ controls as comparison. No associa- tion between spouses' tobacco use and lung cancers other than adenocarcinoma was observed." "Exposures to cigarette smoking from spouse(s), other household members, on the job and in other activities of adult life ('social') are each associated with an overall 40- 60% significant elevation in the risk ofadenocarcinoma of the lung." "No association was found between risk of any type of lung cancer and childhood exposure to cigars, pipes, cigarettes, or all types of tobacco combined .... No significant elevations in risk were found at any level of smoking by household members during childhood." "Although fl'tis report represents the findings of the first 3 years of a 5-year szudy, it is neverthdess the Largest case-control study reported to date on this topic The findings provide additional evidence in favor ofa ~,,~ relationship between exposure to ~ and lung cancer in women who have never used tobacco themselves. A dose response, not likdy due to dmnce, was apparent for exposure to mbac-m smoke during adult life fi'om a variety of exposure sources. The assodafion was specific for both adenocardnoma of the lung and for all lung cancers combined compared to colon cancer." [6] "Passive Smoking and Cancer Risk: The Nature and Uses of Epidemiological Evidence," A. Woodward and A.J. McMichael, European Journal of Cancer 27(l l): 1472-1479, 1991 [Vol. I, Issue 12, December 10, 1991] The authors summarize the epidemiologic studies on spousal smoking and lung and other cancers, describing the purported assodation with lung cancer as "most probably causal." The authors also discuss the Sean Carroll and AFCO cases with regard to establishing "proof" of lung cancer risk in courts of law. Alistalr Woodward recently published another article, this one focusing on ETS in the workplace, which is summarized in Volume I, Issue 11 (November 22, 1991) of this newsletter. Anthony McMichael chaired the working group which prepared the Australian National Health and Medical Research Coundl report on ETS in 1986. He was also a witness for the applicant (AFCO) in AFCO v. Tobacco Institute of Australia. "The cancer risk of passive smoking is not a subject of mere sdentific curiosity. The risk of cancer in non- smokers is often the main reason given for prohibiting or restricting smoking in public places. From an economic point of view, much hinges on such prohibitions or restrictions. An obvious example is the reduction in cigarette consumption that is likely to follow workplace smoking bans: Chapman et al. estimate that if half the white collar worksites in Australia were to ban smoking the Australian tobacco industry would lose sales of $6.5 million annually. Because the stakes are so high, the issue of passive smoking and cancer also casts a spotlight on the scientific and legal assessment of risk, revealing different views on how cause and effect should be judged, and what constitutes 'sdentific proof.'" "The apparent effect of passive smoking on cancer risk has become an irnporrant social and political issue. For this reason alone the strength of the epidemiological evidence warrants dose examination. The research published to date indicates a positive assodations of passive smoking with lung cancer, but there is no consistent evidence ofassodations with cancer at other sites. We have sumrr~lrized the epide- miological evidence, and examined the major critidsms raised against these studies. These critidsms include alleged bias arising from misdassification of exposure to environ- mental tobacco smoke (ETS) or of personal smoking history, and from differential publication of positive findings. In their strongest form, these critiques challenge the ability of epidemiology to establish causation on any issue. We argue that epidemiology is not inherently different from other branches of sdence --in each of which sdentific 'proof' of cause and effect involves judgment based on measurement and logical inference. We also describe the application of epidemiological data to esr.ablishing proof, in courts of law, of the lung cancer risk of passive smoking." "The significance of this case [A/CO] was that it produced the first legal judgment anywhere in the world in relation to I I I I i i I i I i i I I °i i

l i I the tor.al,iry of the scientific evidence pertairfing to the effects - of ETS upon human health." "A review of the [AFCO] judgment indicates that Mr. Justice Morling accepted the primary argument that the interprerabilky of the epiderniological evidence depended in particular upon the pattern of findings acxoss studies, and on its coherence with the substantial evidence from studies of active smoking and cancer and from corroborative animal experimental and other bioassay studies -- and did not depend on the compilation of a scorecard of statistical signhqcance tests in a series of individual studies." [7] "Is Passive Smoking in the Workplace Hazardous to Health?" A. Woodward, Scandinavian Journal of Work and Environmental Health 17." 293-301, 1991 [Vol. I, Issue 11, November 22, 1991] This article concludes that, although little information directly addressing workplace ETS exposure and disease is available, the "evidence" from other sources is suffident to conclude that smoking should be reduced at work. The author reviews epidemiological studies and existing exposure data both for the home (from which he extrapo- lates to the workplace) and the workplace itself. "First, passive smoke contains many potentially toxic substances. These include the obvious tars and respiratory irritants. There is also a range of carcinogens and substances shown to be genotoxic. For example, cigarettes are the major cause of public exposure to benzene. Passive smoking is estimated to be responsible for 5 % of the national exposure to benzene in the United States. (This level is orders of magnitude greater than the hazard that led recently to the recall of Perrier water contaminated with traces of benzene.)" "Second, there is no known safe level of active smoking. Ira lot of smoke causes a big increase in the risk of disease, it makes sense to most people that a little smoke, as inhaled by the passive smoke, v,411 be responsible for a small but definite increase in risk." "A similar point is that there is evidence, from the epidemiologic studies, that this exposure is associated with cancer in humans. Many occupational exposures have been regulated in the past solely on the basis of animal evidence. The questions of whether tiffs association is causal, and what the strength of the association is, are less important, in many minds, than the observation that exposure is associated with cancer in human populations." "Third, the effects of passive smoking upon the nose, throat, and eyes make the exposure obvious. Furthermore, tolerance appears to be related to frequency of exposure. As passive smoking becomes less common, nonsmokers are less willing to put up with the smell and irritation of tobacco smoke." "Finally, there axe economic benefits to regulation, and few costs. The benefits not only include fewer fires and lower cleaning costs, but also lower smoking rates in the work force, and hence, it may be predicted, less absentee- ism. The costs of regulation of smoking at work are more difficult to identify." "The recent scientific evidence on passive smoking is consistent with the conclusions of the major reviews of 1986, which were that breathing other people's tobacco smoke is a cause of serious disease, including lung cancer. There is relatively little information available on whether breathing other people's tobacco smoke at work causes disease. However, it appears reasonable to extrapolate from what is known about health effects of passive smoking in other settings (predominantly the home) to the likely health effects in the workplace. It is difficult to quantify the risks involved." [8] "Smoking and Health: A Review Prepared By the Smoking and Health Subcommittee of the To- bacco Industries Council," a Council Formed By the Minister of Finance of Japan, H. Kasuga, H. Katsuld, O. Miyagl, W. Mori, S. Takayama and T. Yanagita, The International Journal of the Addic- tions 26(4): 423-440, 1991 [Vol. I, Issue 11, November 22, 1991] In this review of smoking and health issues, the authors report that evidence is insufficient to claim that "passive smoking" and disease are assodated. They state that irrita- tion "cannot be ignored," but find exposure information insuffident to establish "relations" with other diseases. "Any definition of health is inevitably broad and contains various elements that may differ from one individual to another. Recent studies on the effects of smoking on physical and mental health have progressed remarkably and have great value in the fields of epidemi- ology, pathology, clinical medicine, and psychiatry. This report concludes that while smoking may have benefidal psychological effects on smokers, it may pose a risk to physical health." "Recent research findings on the health effects of exposure to environmental tobacco smoke, what is known as passive smokin~ have aroused concerns about public health. However, the concentrations of tobacco smoke inhaled passively are slight in comparison with mainstream smoke -5-

ETS AND IAQ.REFEtLENCE JULY 1992 I • that is inhaled directly by smokers. Thus, if any correlation between passive smoking and lung cancer exists, it is thought to be ex'a'emdy slight, but at present there is not enough evidence of suffident probability to support the proposition. Similarly, in the case of general prevalence rates for respira- tory diseases, the evidence is not strong enough to prove that a dear distinction can be made between diseases resulting from passive smoking and those mused by other environ- mental factors." "Epidemiology is simply a tool to duddate suspicious factors in diseases affecting the general public. Thus, just because a corrdation exists, there is no reason to conclude that a risk factor constitutes a direct cause. Fsr~lishing causality requires the support of basic medical and clinical "As for the health effects of passive smoking, a certain unpleasanmess to the senses such as irritation to the eyes, nose, and throat cannot be ignored. However, at present the rdations between passive smoking and diseases such as lung cancer have not been confirmed because accurate evaluation methods of exposure levds have not been established." [9] "An Epidemiological Study of Lung Cancer in Xtmn Wei County, China: Current Progress. Case-control Study on Lung Cancer and Cooking Fuel," X. He, W. Chen, Z. IAu and R.S. Chaprrum, Environmental Health Perspectives 94: 9-13, 1991 [Vol. I, Issue 9, October 17, 1991] The information in this paper is nearly identical to that presented in the Idu, et al., paper, which appeared earlier this year (See Vol. I, Issue 2 (May 17, 1991) of this Report). The authors report that indoor polycyclic aromatic hydrocarbon pollution, produced by the burning of coal in unvented pits, plays an important role in the etiology of lung cancer. No association of lung cancer with ETS exposure was reported. [The Liu, et al., 1991, study, which reports nearly identical information, was surnmarized in Vol. I, Issue 2 (May 17, 1991) of this Report.] "Data gathered to date in Xuan Wei discloses [sic] a stronger assodation of lung cancer with domestic coal use than any other risk factors so far assessed, induding tobacco smoking .... Smoking may be contributing to lung cancer in males in Xuan Wd [more than 40% of whom smoke], but it is difficult to explain the marked differences of lung cancer mortality among Xuan Wei communes and the high lung cancer mortality in femal.es." A case-control study of 110 individuals (only 17% cytologically confirmed) and 426 controls matched on age, sex and village of residence was conducted. "No relation- ship between lung cancer and ever having smoked tobacco is observed .... In contrast, a statistically signifi- cant dose-response trend of lung cancer with smoking index is observed." "No association of lung cancer with passive smoking is observed [OR = 0.74, 99% C.I. 0.32-1.68; females only, 45 cases and 176 controls]." "[A] statistically significant relationship of lung cancer with age at which the woman began to cook food is observed, though none of the individual odds ratios is significant." "In both sexes, lung cancer is significandy assodated with family history of lung cancer and personal history of chronic bronchitis." "Conclusion. PAH (BaP as index) pollution in indoor air induced by smoky coal burning in unventilated, shallow pits plays an important role in lung cancer. Smoking is not a main risk factor of lung cancer in Xuan Wei County, China." [10] "Mainstream and Environmental Tobacco Smoke," G.B. Gori and N. Mantel, Regulatory Toxicology and Pharmacology 14: 88-105, 1991 [Vol. I, Issue 6, August 27, 1991] This review describes the inconsisten'des between the dose to nonsmokers from ETS and the purported increased risk of lung cancer based on epidemiology. Describing "irreparable deficiencies" in the epidemiologic studies, the authors focus on the numerous factors for which lung cancer relative ris "ks have been reported but which were not considered in the ETS epiderniologic Sl~udles. a~,XCERP TS "- "Some epidemiologic studies of nonsmokers presumably exposed to ETS have suggested a marginal increase of risk for some diseases previously assodated with active mainstream smoking (MSS). These reported risks, however, border on statisticaJ and epidemiologic insignifi- cance, and could easily derive from numerous and documented biases and confounders." "[T]he lung cell doses for average ETS-exposed non- smokers are probably between 1/10,000 and 1/100,000 of equivalent cell doses for average mainstream active smokers. In practical terms, this implies an annual retained dose of tobacco smoke components equivalent to far less than the dose for the active smoking of one cigarette somehow evenly disbursed over a 1-year period." I i I I I i ir I ! I I

VOLUME I, ISSUES 1-24 JULY 1992 I "IT]he active smoking of 4-5 dgarettes/day is not likely to be statistically assodated with elevated lung cancer risk. . .. It suggests that since ETS retained doses are several thousand dmes less than MSS doses from this level of cigarette smoking, they appear insuffident to generate elevated risks of lung cancer." "ETS is a very elusive entity, undergoing continuous transformations at extremes of dilution that make efforts to define its chemical, physical, and biologic characteris- tics highly difficult. While the components of MSS/SSS may also be present in ETS, it is also dear that with few exceptions they are undetectable by the most sophisti- cated analytical procedures." "[I] f epidemiologic investigations of MSS and lung cancer had been confined to the effects of exposure to a few dgarettes daily, they would have failed to yield significant risk signals .... At the same time it is apparent that subjects included in ETS epiderniologic studies were probably exposed to equivalent MSS-RSP doses below even a single cigarette peryear. Therefore, marginal RR values associated with ETS exposures should be imputed to biases, confounders, and other weaknesses of the investigations, and any judgment that ETS exposure leads to lung cancer and other diseases would flow from argument, not from credible data." "In fact, the majority of epidemiologic studies of ETS suffer from what appear to be irreparable defidendes." "An even greater prejudice to the credibility of ETS epidemiologic studies derives from their failure to account and control for the possible confounding by many independent risk factors." "Since many of the RRs... are substantially larger than any reported for the association of lung cancer and ETS, even weak contributions by combinations of these confounders would be cumulative and could be more than suffident to explain the marginal lung cancer risks that some epidemiologic studies Of ETS have reported... • [W]hese studies have not controlled for the factors.., in any meaningful or comprehensive way, while other investigations provide evidence that several of those risk factors cluster and selectively segregate in families with smokers." "It should be clear that the seemingly insurmountable difficulties in measuring ETS exposures and doses, unresolved classification bias, and the inability to control for numerous independent confounders explain the inconsistency of weak ETS epiderniologic results and speak against scientifically credible conclusions about a risk that, if real at all, remains imponderable." "Indeed, the only justhqable conclusion is that this issue cannot be resolved sdentifically on the basis ofcurrendy available information. Moreover, exposure and dose considerations alone seem to indicate that ETS is an insignificant entity among the substantial mass of exogenous and endogenous challenges to health that we continually face." [11] "Weaknesses in Recent Risk Assessments of Environmental Tobacco Smoke," P.N. Lee, Environmental Technology 12(3): 193-208, 1991 [Vol. I, Issue 6, August 27, 1991] Several risk assessments based on epidemiologic data have given higher risk estimates than those based on dosimetry. The author considers six potential sources of bias in the epiderniologic studies of ETS and lung cancer and offers additional criticisms of risk estimates for heart disease and for cancer other than the lung. "IT]here has been an increasing tendency to carry out risk assessments to estimate annual numbers of deaths due to ETS. The purpose of this paper is to underline a number of problems in conducting such risk assessments, and to comment critically on three that have recendy been published [Wells, Kawachi, et al.; and Repace and Lowrey]." "IT]here is certainly strong evidence of a marked discrepancy between the epidemiology and dosimetry .... [T]he discrepancy seems very large, by two or even three orders of magnitude." "One implication is that risk assessments based on dosimetric evidence are likely to give substantially lower estimates than those based on the epidemiologic evidence. Another implication is that it gives reason to doubt the epidemiology, and to look for sources of bias." "Epidemiology is imprecise. Various sources of bias can produce spurious relative risks of 2 or even more. Since the relative risks seen for ETS exposure are well within this range, and since they seem inconsistent with the dosimetric evidence, it is important to examine the epidemiological evidence critically. Six potential sources of bias are considered below." The author discusses in some detail, misclassification of diagnosis, misdassification of ETS exposure, publication bias, poor design of some studies, confounding, and misdassification of active smokers as nonsmokers. He then concludes: "The epidemlology has indicated a magnitude of risk in relation to spouse smoking that is implausibly large compared with what is known about the -7-

AND IAQREFERENCE JULY 1992 I • extent of ETS exposure involved. There ire clear weak- nesses and sources of bias in the epidemiology which could invalidate risk assessments based on it." "All three risk assessments criticized in this document take the epidemiology virtually at face value, with no real discussion at all of its weaknesses .... No reasonable scientific criteria are used to decide what constitutes a valid study before it can be included in a risk assessment --studies conducted with complete disregard of basic scientific principles ire included as if they were as valid as carefully designed studies." Regarding heart disease, the author claims to demon- strate "that the risk assessment for heart disease essentially rests on the results from two studies [Helsing, et al., and Hirayama], both of which seem unreliable." He makes the following points, "First, there are a very large number of risk factors for heart disease .... Second, the extent of the assodation seen in some of these studies, which in some cases is close to that reported in relation to active smoking, is implausibly high when viewed against the extent of the assodation seen in relation to active smok- ing. Third, there is a major danger of publication bias." "The overall evidence for cancer other than the lung is clearly remarkably unconvindng in demonstrating any effect of ETS exposure." "[Xvc']hile estimates based on retained particulate matter give tens of deaths and those based on nicotine or respirable suspended particulates give hundreds, the epidemiologically based estimates all give thousands of deaths, x,grl~ich answer, if any, one accepts depends to a large extent on the faith one places on the different types of evidence. Wells, Kawachi et al and Repace and Lowrey accept the epidemiology essentially at face value and pay little or no attention to its poor quality and very obvious weaknesses. They either ignore the dosimetric evidence, do not make it clear that it gives different answers and/or dismiss it as inconsistent with the epiderMology, or invoke mechanisms to explain the discrepancy which ire scientifically unappealing. It seems to this author that the epidemiological evidence is untrustworthy and that, between the two, the dosimetric evidence is preferable." "When one restricts attention to lung cancer, to never smokers and to ETS exposure from the spouse, one is at least operating in an area where the epidemiological evidence indicates an association. When one extends risk assessment to other diseases, to ex-smokers and to ETS exposure in the workplace one is stretching the limits of what is sdence .... There is some evidence on ETS exposure in the workplace, but this shows no assodation at all with lung cancer risk." -8- [12] "'Passive Smoking' and Lung Cancer:. A Criticltl Ana/ysis," G. Fetter and D.J. Ecobichon, Modern Medicine of Canada46(4): 26-29, 1991 [Vol. I, Issue 6, August 27, 1991] The authors reviewed the available information on purported health effects of ETS and determined that it is inconclusive. They note that any conclusions as to whether ETS increases the risk of disease will have to wzit until reliable and appropriate data ire available on rnisdassification error, marital concordance and the establishment of spousal smoking as a valid surrogate index of ETS exposure. EXCERP'P$: "Cireful review of the pertinent information relating to the health effects of ETS reveals that the data remain inconclusive with respect to any causal relationship between ETS exposure and lung cancer. The finding of the NRC and other investigators of a statistically signifi- cant composite OR [odds ratio] that links spousal smoking with a modest (20-50%) in,eased risk of lung cancer in the nonsmoker is provocative." "However, a number of reviewers have questioned some of the assumptions on which that finding was based, as well as the appropriateness of using meta-analysis for this particular data base. Whether the increased OR reflects an effect of ETS or statistical artifact will have to await the availability of reliable and appropriate data on misdassificarion error, risks of lung cancer assodated with active smoking, and marital concordance. It also remains to be established that spousal smoking is a valid surrogate index of ETS exposure." [13] "Environmental Tobacco Smoke and Lung Cancer in Never Smokers," H.G. Stockwell, E.C. Candelora, A.W. Armstrong and Pak. Pinkham, Meeting Abstract, Society for Epidemiologic Research Conference, June 11-14, I991 [-Vol. I, Issue 5, August 9, 1991] This ongoing, population-based, case-control study investigated risk factors for lung cancer among never smoking women in Florida. When the abstract was submitted, 124 cases and 241 controls were included; data were reported at the conference based on 148 cases and 265 controls. (A complete copy of the Abstract is reprinted in Appendix A.) Risk factors for lung cancer among women who never smoked cigarettes were examined in an ongoing, popula- tion based case-control study conducted in Florida. One i I i I i I i I i