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VOLUME I, ISSUES 1-24 JULY 1992 hundred and twenty four primary carcinomas of the lung, and 241 control women who had never smoked were included. Results suggest that childhood and adult exposure to environmental tobacco smoke may increase the risk of lung cancer among women who never smoked cigarettes. Having a husband who smoked dgarettes resulted in a statistically significant increase in risk of lung cancer among women who never smoked, with an odds ratio of 1.8 (95% C.I. 1.1-2.9). A 40% increase in risk was observed among women with less than 25 years exposure to a spouse who smoked, when compared to women who repor'~ed their spouse had never smoked, with the risk increasing to 60% among women exposed 25 years or longer. When exposure to tobacco smoke in childhood was considered, the data were less consistent. Having a parent who had smoked during the respondent's childhood did not increase the risk of lung cancer. However, among those respondents with high levels of exposure to parental smoking, an excess risk, although not statistically signifi- cant, was observed. Never smoking women who accumu- lated 25 or more exposure years experienced a 70% increase in risk (OR=l.7, 95% C.I. 0.9-3.6) of lung cancer compared to women who reported neither parent had smoked dgaretres. [14] "Lung Cancer Risk Associated With Cancer in Relatives," G.L. Shaw, R.T. Falk, L.W. Pickle, T.J. Mason and P.A. Buffler, Journal of Clinical Epidemiology 44(4-5): 429-437, 1991 [Vol. I, Issue 4, July 12, 1991] The authors examined data from a population-based case-control study of lung cancer in the Gulf Coast of Texas, and reported that exposure to ETS showed a minimal excess in lung cancer risk after adjustment for smoking. They reported an adjusted OR of 1.2 in females and 1.1 in males. Data from population-based case-control study of lung cancer in the Gulf Coast of Texas. For derails of the study the reader is referred to a paper by Buffler, et al., which was one of those included in the meta-analysis of ETS and lung cancer in the 1986 NRC report. "Exposure to passive smoke showed a minimal excess in lung cancer risk after adjustment for smoking." [Adjusted OR = 1.2 in females (435 exposed cases) and 1.1 in m~es (363 exposed cases). No 95% CI given, but neither OR was statistically significant.] "Consistent with previous studies, we found a modest increase in lung cancer risk assodated with reported cancer in first-degree relatives. Risks were similar for both men and women. Risk was greatest for those subjects with first-degree relatives with lung cancer, followed by first- degree relatives with other TRCs [tobacco-related cancers]." "Differential cancer risk by histologic type, and between first-degree relatives and spouses is consistent with the hypothesis that genetic characteristics may influence risk by increasing host susceptibility to an environmental carcinogen." "The absence of smoking data on farrfily members limits the interpretation of our results, since this may contribute to a number of tobacco-related cancers among relatives." [15] "Dietary Patterns of Female Nonsmokers With ~nd Without Exposure to Environmental Tobacco Smoke," L. Le Marchand, L.R. Wilkens, J.H. Hankin and N.J. Ha/ey, Cancer Causes and Control2: 11-16, 1991 [Vol. I, Issue 4, July 12, 1991] In this study, 82 female nonsmokers were interviewed to assess the possible relationship between dietary confound- ers of lung cancer risk and ETS exposure. The authors concluded that diera.ry beta-carotene and, possibly, dietary cholesterol a_re potential confounders of the ETS/ lung cancer assodation. Therefore, according to the authors, these dietary factors should be carefully measured in future studies. Study subjects were selected from population controls who took part in two lung cancer case-control studies conducted in Hawaii between 1979 and 1985. Eighty- two female nonsmokers were interviewed in 1986 to assess the possible relationship between dietary confound- ers of lung cancer risk and ETS exposure. ETS exposure was assessed by measurement of urinary cotinine and also by marriage to a smoker. "Intakes of vitamin A... decreased as exposure to ETS [urinary cotinine] increased. A similar inverse relationship was observed for each of the two food sources of vitamin A, namely, retinol and carotenoids, including beta- carotene.', "Cholesterol and fat intake were also negatively associ- ated with lETS/urinary cotinine] exposure level; however, the test for trend was statistically significant for choles- terol intake only (P = 0.05)." "Women married to a smoker had lower intakes of total vitamin A and its components, as well as lower intakes of -9-

ETS AND IAQ PdSFERASNCE JULY 1992 cholesterol and fat, than women married to a 'never smoker'.... [W]omen married to an ex-smoker had a dietary pattern which is intermediate between those of the other two groups of women." "We conclude that dietary beta-carotene and, possibly, dietary cholesterol are potential confounders of the passive-smoking/lung cancer assodation. Although the distorting effects of these dietary factors appear modest, they should be carefully measured in future studies since they may interfere with the confirmation of this impor- tant assodation." [16] "Serum Beta-Carotene in Persons With Cancer and Their Immediate Families," A.H. Smith and K.D. Waller, American Journal of Epidemiology 133(7): 661-671, 1991 [Vol. I, Issue 4, July 12, 1991] This study was conducted in New Zealand to test the hypothesis that serum beta-carotene would be lower in the families of patients with cancer than in the families of control patients. The authors reported that low levels of serum beta-carotene were observed in both the cancer patients and their families for cancers of the lung, stomach, esophagus, small intestine, cervix, and uterus. The strongest findings for an individual cancer site were those for lung cancer. EXCERPTS: No mention of ETS. Study conducted in New Zealand to test the hypothesis that serum beta-carotene would be lower in the families of patients with cancer than in the families of control patients. This was accomplished by incorporating family members into a standard case-control study design. "[L]ow levels of serum beta-carotene were observed in both the cancer patients and their families for cancers of the lung, stomach, esophagus, small intestine, cervix, and uterus. The strongest findings for an individual cancer site were those for lung cancer .... Our findings for lung cancer applied to all cell types other than adenocarcinoma." "We found no evidence that confounding by current smoking status could account for the findings." "[M]ost of the cancer sites that were associated with low levels of serum beta-carotene are sites for which smoking is a strong risk factor (with the exception of cancers of the bladder and kidney)." -10- [17] "Diet and Lung Cancer in California Seventh-Day Adventists," G.E. Fraser, W.L. Beeson and R.L. Phillips, American Journal of Epidemiology 133(7): 683-693, 1991 [Vol. I, Issue 4, July 12, 1991] This study looked at data based on six years of follow-up (1977-1982) in the prospective study of Seventh-Day Adventists in California. The authors reported that the dietary item that showed a substantial assodation was all types of fruit. The authors indicated that the protective association with fruit appears to be more marked for adenocarcinomas. EXCERIVl~: No mention of ETS. Data based on 6 years of foLlow-up (1977-1982) in the prospective study of Seventh-Day Adventists in Califor- ilia. "The dietary item that did show substantial assodation upon stratified analysis was fruit (all types). Here a relatively powerful apparent protective effect was seen that is unlikely to have been due to chance." "The protective assodation with fruit appears to be more marked for adenocarcinomas (Kreyberg group II), but it could not be clearly differentiated from a relatively similar effect in the Kreyberg group I tumors [squamous cell, large cell, and small cell]. This result agrees closely with the observations of Koo among Chinese females in Hong Kong." "Foods included in our data set that have substantial beta-carotene content showed no consistent associations." [18] "Smoking and Other Risk Factors for Lung Cancer in Xuanwei, China," Z. Liu, X. He and R.S. Chapman, International Journal of Epidemiology 20(1): 26-31, 1991 [Vol. I, Issue 2, May 17, 1991] Lung cancer rates in Xuanwei County are among the highest in China. Previous studies (not epidemiologic) have suggested that there may be an assodation between the indoor burning of "smoky" coal, as opposed to "smokeless" coal or wood, and lung cancer incidence. This case-control study included 110 cases (56 males, 54 females) and 426 controls matched for age, sex, occupa- tion (all were farmers), and village of residence (which controlled for type of fuel used). Only one of the female cases reported having ever smoked. Among men, the authors reported a statistically significant dose-response relationship with active smok- ing; however, of all the indices used to examine active smoking, a statistically significant odds ratio was reported ! ! i 11 I ! ! ! ! ! I ! i i i i

I VOLUME I, ISSUES 1-24 JULY 1992 ! i ! ! i ! ! I ! ! I I I I I I ! I for only one category. The authors claimed that their data supported the existence of a dose-response relationship in males between lung cancer and a smoking index (calcu- lated as years of smoking x amount of smoking). ETS exposure was assessed in women as whether there was at least one smoker (usuaLly the husband) living in the same household. For 45 cases and 176 controls, an adjusted OR of 0.77 (95% CI 0.30-1.96) was reported. (This is the only index of ETS exposure used; no information was presented on spousal smoking, workplace exposure or the like.) Statistically significant increases in risk were reported for a number of other factors. In females, these were chronic bronchitis, OR = 7.37 (95% CI 2.40-22.66) and family history of lung cancer, OR = 4.18 (95% CI 1.61-10.85). In males, the reported assodations were with chronic bronchi- tis, OR = 7.32 (95% CI 2.66-20.18); family history of lung cancer, OR = 3.79 (95% CI 1.70-8.42); and personal history of cooking food, OR = 3.36 (95% CI 1.27-8.88). (Note that some of the CIs are quite wide, indicating low statistical power.) Assodations with lung cancer were also suggested for duration of cooking food and for age at starting m cook (over coal-fired stoves) for women. [ 19] "Comparative Epidemiology of Cancer Between the United States and Japan," E.L. Wynder, Y. Fujita, R.E. Harris, T. Hirayama and T. Hiyama, Cancer 67: 746-763, 1991 [Vol. I, Issue 2, May 17, 1991] [No mention of ETS.] "It was postulated [in 1977] that as smo "king becomes more common among both men and women in Japan, tobacco-related cancer rates would also increase. As pre- dicted, rapid accelerations in mortality rates due to cancers of the lung and ompharynx have recendy been observed in the heavy smoking male population of Japan." "We also predicted that changes in Japanese patterns of dietary fat intake, fruit/vegetable consumption, and food preservation would result in modified rates of cancers associated with these factors. Accordingly, recent upward trends in Japanese mortality rates of colon and pancreatic cancer are evident.., whereas the rates of stomach cancer continue to decline.., the mortality rates for malignan- cies of the breast, ovary, corpus uteri, and prostate appear m be steadily rising in Japan, which may also be due to continued 'westernization' of the Japanese diet, although other life-style changes affecting the endocrine system cannot be ruled out as potentiating factors." "Still there are some discrepandes in the international trends and differences in cancer mortality that conflict with what is currendy known about the risk factors of specific malignandes. Lar~geal cancer rates in Japanese males are lower than in the US, and surprisingly are declin- ing, despite thdr reladvdy high levels of dgaretr.e smoking. Cancer of the urinary bladder, also a tobacco-rehted malignancy, does not show increased mortality in recent years among the heaw smoking male population of Japan. Esophageal cancer rates in Japan condnue m exceed those in the US, despite comparable levels of alcohol consumption in the two countries. These results in particular have not been satisfactorily explained and must be examined for valuable dues to the risk factors bearing on cancer etiology." [20] "Passive Smoking and Diet in the Etiology of Lung Cancer Among Non-Smokers," A. Kalandidi, tC Katsouy-anni, N. Vompoulou, G. Bastas, R. Saracci and D. Trichopoulos, Cancer Causes and Control 1: 15-21, 1990 [Vol. I, Issue 1, April 30, 1991] This case control study was undertaken in Athens to explore the role of ETS exposure and diet in the causatior; of lung cancer, by histologic type, in nonsmoking women. It reports that marriage ofa nonsmoking woman to a smoker was assodated with a relative risk for lung cancer of 2.1 (95% CI 1.1-4.1). It also reports that the number of dgarettes smoked daily by the husband and years of expo- sure to the husband's smoking were Positivdy, but not significantly, rdated to lung cancer risk. The authors indicated that there was no evidence of any assodation with exposure to smoking of other household members, and the assodation with exposure to ETS at work was small and not statistically significanr~ The authors report that ETS was assodated with an increase of the risk of all histologic types of cancer, although the devation was more modest for adenocardnoma. Dietary data collecraxt through a semi-quantitative food- frequency questionnaire indicated that high consumption of fruits was inversely rdated to the risk of lung cancer (the rdadve risk between extreme quanrdles was 0.27 (CA 0.10- 0.74)). Neither vegetables nor any other food group had an additional protective effect. The reported associations of lung cancer risk with ETS exposure and reduced fruit intake were independent and did not confound each other. Cam)[ovascut o, Issu [1] Letters to the Editor Regarding "An Estimate of Adult Mortality in the United States from Passive Smoking," A.J. Wells, Environment International 14: 249-265, 1988 [Issue 24, Item 36] Environment Inteenationa/recendy published two letters concerning this article, which was published prior to issue -11-

ETS AND IAQ_REFEKENCE JULY 1992 I 1 of this Report. The authors of the letters were (i) Peter N. Lee and (ii) A. Judson Wells, author of the original article. The letters appear at Environment International 18:315-317 and 321-325, 1992. In his original article, Welts calculated that "passive smoking" was responsible for more than 50,000 deaths armually in the U.S. The majority of the daimed deaths (32,000) were said to be due to cardiovascular disease, with the rest attributed to lung cancer and cancer of other sites. Lee's letter critidzed Wells' dalm that chemical and physical differences between ETS and mainstream smoke are related to purported health effects. Lee also com- mented on the "failure" of the American Cancer Society to publish data (which he believes have been collected) on ETS exposure and heart disease; Lee proposed that such data would be an important addition to the sdentific literature on this issue. Lee also called to Wells' attention epidemiologic literature on workplace or childhood exposure m ETS and lung cancer incidence which reported statistically non-significant relative risks. Finally, Lee proposed that sources of bias, namely confounding by dietary differences (e.g., beta-carotene intake), and misdassification of smokers as nonsmokers, could explain the reported association between spousal smoking and lung cancer. In his response to Lee's letter, Wells claimed that Lee's approach to the misclassification question was erroneous. Wells cited the Glantz and Parmley (1991) and Steenland (1992) papers as support for his conclusions. Wells further claimed that epidemiologic studies of ETS exposure and lung cancer have not demonstrated a confounding effect of diet. He also invoked a "latitude effect" in response to Lee's comments that workplace studies supported no assodation, claiming that "lung cancer signals were dearer from the southern studies than from the northern ones." Wells concluded that his estimate of a "passive smoking death toll in the 50,000 range" is still the best estimate, discounting Lee's claim that biasing factors were operating in the ETS studies. [2] ~Sertmn Lipopmteins in Nonsmokers Chronically Exposed to Tobacco Smoke in the Workplace," J.R. White, M. Criqui, Jak. Kulik, H.F. Froeb and P.J. Sinsheimer, Abstract No. 383, Eighth World Conference on Tobacco or Health: Building a Tobacco-Free World, March 30-April 3, 1992, Buenos Aires, Argentina [Vol. I, Issue 20, April 24, 1992] This abstract reported that male and female workers classified as exposed to ETS had statistically significant decreases in high density lipoprotein (HDL) cholesterol (i.e., "good" cholesterol) and elevated ratios of total cholesterol to HDL. In addition, females reportedly had significant elevations in low density lipoprotein (LDL) cholesterol ("bad" cholesterol). United Press International publicized this abstract in a newswire dated April 2, 1992. At the Eighth World Conference on Tobacco or Health in Buenos Aires, Argentina (March 30-April 3, 1992), a study was reported by James tL White, et al. (University of California-San Diego) which claimed that workplace ETS exposure adversely affected cholesterol profiles. This presentation also obtained publidty through a United Press International news'wire dated April 2, 1992. The conference abstract of the White, et al. study is the fourth publication, all since 1990, to address the general issue of a possible assodation of ETS exposure with changes in cholesterol levels. However, it is the first to report data on cholesterol levels and ETS exposure in an adult popula- tion and to specifically address workplace ETS exposure. White, et al. evaluated cholesterol and cholesterol fraction levels in nonsmoking workers. Carbon monoxide levels were used "as an index of dgaret~e smoke in the work place~" [Both the conference abstract and the UPI rdease refer, probably through publishing error, to measurement of carbon dioxide instead ofearbon monoxide.] Both male and female workers classified as exposed to ETS were reported to have statistically significant decreases in high density lipoprotein (HDL) cholesterol (i.e., the "good" cholesterol) and elevated ratios of total cholesterol to HDL. In addition, females exposed to ETS were reported to have significant elevations in low density lipoprotein (LDL) cholesterol (i.e., the "bad" cholesterol). The authors concluded: "Nonsmoking workers are at increased risk of developing coronary heart disease resulting from exposure to second-hand tobacco smoke." [3] "Passive Smoking and Your Heart," G.L. Huber, R.E. Brockie and V.K. Mahajan, Consumers' Research, Apri/1992, pp. 13-19, 32-33 [Vol. I, Issue 19, April 10, 1992] The authors review the biology of cardiovascular disease and discuss the concept of risk factors. They review the epidemiologic studies on ETS and heart disease, discussing in detail a number of factors (including lack of exposure assessment and failure to account for confounding variables) that could affect the reported results of these studies, and conclude that the studies should be "viewed with healthy sdentific skepfidsm." A copy of this article is attached as I i 1 i I I i I I I I I I -12- I

VOLUME I, ISSUES 1-24 JULY 1992 l ! ! ! ! l i i I II I ! I 1i I ! ! Appendix H. Another article by these authors, "Passive Smoking: How Great a Hazard?", which appeared in the July 1991 issue of the same magazine, was appended to Issue 4 of this Report, July 12, 1991. [4] "Passive Smoking and Carotid Artery Wall Thick- hess: The ARIC Study," G. Howard, M. Szido, G. Evans, G. Tell, J. Eckfeldt and G. Heiss, Cardiovas- cular Disease Epidemiology Abstracts, presented at Annual American Heart Association meeting, March 1992 [Vol. I, Issue 19,April 10, 1992] This abstract reported that increasing exposure to ETS was assodated with increases in carotid artery wall thickness. The authors concluded that exposure to ETS may contribute to atherogenesis, that is, narrowing of the armries that may increase the risk of clogging by cholesterol deposits and dots. In press cover-age of the abstract, researchers were described as cautioning that the study's findings were not yet conclu- sive. See Washington Posg March 20, 1992. Seelssue 13 of this Report, January 3, 1982, for a description of another, similar abstract by this group. "The assodation between passive and active cigarette smoking with carotid artery wall thickness was studied in 12,863 men and women ages 45 to 64 examined by the Atherosclerosis Risk in Communities (ARIC) Study. Of these, 3,509 were current smokers, 4,276 past smokers, 3,316 had never smoked but reported exposure to environmental tobacco smoke (ETS or 'passive smoke'), and 1,762 had never smoked and reported no exposure to ETS. Carotid artery wall thickness was measured by... ultrasound. Increasing exposure to dgarette smoke across the gradient from never smoking to current smoking was consistently associated with increases in carotid artery wall thickness within 5-year age groups." "The ETS group had thicker arterial walls than never smokers; these differences were statistically significant only at younger ages. Also, the ETS participants showed an increase in arterial wall thickness with an increasing number of hours per week of ETS exposure. Thus exposure to ETS may contribute to atherogenesis." [5] "Indoor Passive Smoking: Its Effects on Cardiac Performance," A. Leone, L. Moil, F. B.ertanelli, P. Fabiano and M. Filippelli, International Journal of Cardiology33(2): 247-252, 1991 [Vol. I, Issue 17, March 6, 1992] These researchers reported on cardiac performance during exercise testing in 19 male nonsmokers exposed to ETS in one test and tested once without the exposure. ETS exposure was reportedly associated with a decrease in peak exercise capacity in those subjects who had survived a previous myocardial infarction. In both groups of subjects, ETS exposure was reportedly associated with longer time to recovery of pre-exerdse heart rates. Cardiac performance during exercise testing was measured in 19 male nonsmokers, nine of whom were healthy and 10 of whom were myocardial infarction survivors. The subjects were tested twice, once while exposed to environmental tobacco smoke (leading to carbon monoxide concentrations of 30-35 ppm) and once without this exposure. The authors reported that ETS exposure was assodated with a decrease in peak exercise capacity in the myocardial infarction survivors, but not in the healthy subjects. For both groups of subjects, ETS exposure was associated with longer times to recovery of pre-exercise heart rates. ETS exposure during exerdse testing was also associated with increases in expired air and plasma carbon monoxide concentrations, although there were some irregularities in the data pertaining to these comparisons. The authors concluded, "Cardiac response to the exerdse is signifi- cantly worsened by passive smoke, espedally in those subjects with previous myocardial infarction." [6] "Passive Smoking and the Risk of Heart Disease," tC Steenland, JAMA 267(1): 94-99, 1992 [Vol. I, Issue 14, January 17, 1992] This article reviews epidemiological and experimental literature related to the claim that ETS causes heart disease. The author, Kyle Steenland, is affiliated with the National Institute for Occupational Safety and Health and "developed the epidemiology section" of NIOSH Current Intelligence Bulletin 54," Environmental Tobacco Smoke in the Workplace" (see Bulletin 54, Acknowledgement Section). He estimates that ETS exposure leads to 35,000-40,000 annual deaths in the U.S. and concludes that "heart disease mortality is contributing the bulk of the public health burden imposed by passive smoking." Steenland summarizes the data from nine epidemiologi- cal studies on ETS and heart disease. Although he does not perform a meta-analysis, he comments that the "[e]pidemiological evidence has been increasing that passive smoking at home is related to heart disease among never-smokers." Of the nine studies discussed, "Is]even are positive, while one is positive for women but not for -13-

ETg AND L&QR~FERENCE JULY 1992 I men," he says. Several weaknesses in the epidemiological studies are noted, particularly inadequate information on ETS exposure and the difficulties in controlling for multiple confounding variables. Steenland briefiy reviews several experimental and biochemical reports which he considers relevant to ETS and heart disease, insofar as they might suggest biological mechanisms underlying the claimed statistical relation- ship. He focuses especially on reports that low levels of carbon monoxide exposure lead to irregular heart rhythms in heart disease patients. He also rites recent research reporting that ETS exposure is associated with adverse effects on cholesterol and fibrinogen levels. He mentions, but does not discuss, specific studies dealing with a wider range of possible mechanisms, including platelet aggrega- tion, endothelial damage and the involvement of polycy- clic aromatic hydrocarbons. Much of the article's content is an effort to calculate an estimate of the annual number of U.S. heart disease deaths attributable to ETS. In general terms, this estimation process involves estimating an overall increase in heart disease risk assodated with ETS exposure; making adjustments for potential misdassification and for background exposure; estimating the extent of exposure to ETS; and estimating the fraction of never-smoker (and long-term ex-smoker) heart disease deaths attributable to ETS exposure. These estimates are incorporated into a formula using data on U.S. heart disease death rates and population estimates, from which is derived an esrdmated number ofarmual deaths attributed to ETS exposure. According to Steenland's calculations, "the overall estimate of ETS-at~ibutable heart disease deaths for never-smokers and former smokers is 35,000 to 40,000." He further comments that these increased risks of death "are higher than those ac~.epted in regulating environmental toxins. ~ [7] "The Association Between Carotid Arterial Wail Thickness and Active and Passive Cigarette Smok- ing," G. Howard, M. Szklo, G. Evans, G. Tell, J. Eckfeldt, G. Heiss and the ARIC Investigators, Arteriosclerosis and Thrombosis 11 (5): 1432a, 1991 [Vol. I, Issue 13, January 3, 1992] The authors report that ETS exposure is associated with carotid artery wall thickness, an indication of atherosclerosis. As this is only an abstract, only limited information is available. This abstract, from the Bowman Gray School of Medicine, Winston Salem, NC, reports that ETS exposure is assodated with thickness of the walls of the carotid arteries. The importance of carotid artery thickness is that it is an indica- tion of the severity of atherosderotic involvement. Athero- sclerosis of the carotid a.rveries is believed to underlie certain forms of stroke. These data stem from the Atherosderosis Risk in Commu- nities (ARIC) study. Details about the study are not given in the abstract. However, from other publications, it is known that the ARIC project is a longitudinal study of cardiovascu- lar and pulmonary disease sponsored by the National, Heart, Lung and Blood Institum The sample is drawn from communities in Minnesota, Maryland, North Carolina and Mississippi. The specific data in the abstract are based on a subsample of whites, who were categorized into four groups according to smoking history or ETS exposure: (1) current smokers, (2) exsmokers, (3) ETS-exposed never smokers, and (4) non-ETS-exposed never smokers. These groups were examined in terms of average carotid aa-tea-y thickness. Data were further divided into five-year age brackets, covering the range 45-65 years old. The authors reported that for each age group "there was a consistent gradient of wall thickness across the smoking exposure categories." Statistical tests indicated that carotid artery wails were significantly thicker in the ETS-exposed compared to the nonexposed group, but only for the younger age groups. Carotid artery wails were also signifi- cantiy tbdcker in the smokers compared to the exsmokers, but only for the older age groups. The authors concluded: "This graded relationship underscores the importance of smoking as a risk factor for atherosderosis." [8] "Urinary Cotinine Measurement in Patients With Buerger's Disease -- Effects of Active and Passive Smoking on the Disease Process," M. Matsushita, S. Shionoya and T. Matsumoto, Journal of Vascular Surgery 14(1): 53-58, 1991 [Vol. I, Issue 11, November 22, 1991] Buerger's disease, an inflammatory condition affecting the peripheral blood vessels, has been reported to be statistically assodated ~4th smoking. In this study, the authors reported no difference in the progression (i.e., worsening) of the disease between ETS-exposed and non- ETS-exposed nonsmokers. Buerger's disease is an inflammatory condition leading to arterial occlusion in the peripheral vascular system. It has been reported to be strongly associated statistically with cigarette smoking. Matsushita, et al. studied 40 Buerger's disease patients, all of whom had a smoking history. Using urinary cotinine levels as a marker, these l i I I ! I i I I I i I i i I I I I

VOLUME, l, l, ggUF-,S 1-24 JULY 1992 I - patients were classified either as smokers, as "passive smokers" (i.e., as nonsmokers exposed to ETS) or as nonsmokers not exposed to ETS. When the progression or "aggravation" of the disease was examined retrospectively, it was reported to have worsened in seven of 10 of the smokers, in none of the nine "passive smokers" and in four of the 21 non-ETS- exposed nonsmokers. Among this last group, three of the four admitted to "active" smoking and the fourth reported exposure to ETS in the workplace. Statistical tests revealed that the course of Buerger's disease had significantly worsened in the smokers, relative to the other two groups. However, there was no statisti- cally significant difference between the "passive smoking" and non-ETS-exposed group. Based on these data, the authors concluded that their results confirmed the relationship of"active" smoking with Buerger's disease, but that the "effects of passive smoking on the disease process were still inconclusive." [9] "Passive Smoking and the Risk of Heart Attack or Coronary Death," AJ. Dobson, H.M. Alexander, R.F. Heller and D.M. Lloyd, The Medical Journal of Australia 154: 793-797, 1991 [Vol. I, Issue 10, November 1, 1991] This AustraLian case-control study examined male~ and females who experienced a "farad or non-fatal definite or possible myocardial infarction or a corona-7 death." Odds ratios and 95% confidence intervals reported for heart disease risk assodated with ETS exposure at home were 0.97 (0.50-1.86) for men and 2.46 (1.47-4.13) for women. For ETS exposure at work, the odds ratios and confidence intervals were 0.95 (0.51-1.78) for men and 0.66 (0.17- 2.62) for women. This case-control study investigated the potential relationship between environmental tobacco smoke exposure and heart disease in residents of New South Wales, Australia. The cases were males or females who had experienced a "fatal or non-fatal definite or possible myocardial infarction or a coronary death." Controls were selected from partidpants in an ongoing WHO risk factor prevalence study. Data were collected on certain demo- graphic characteristics, medical history, dgarerte smoking and ETS exposure at home and work. Odds ratios and 95% confidence intervals reported for heart disease risk assodated with ETS exposure at home were 0.97 (0.50-1.86) for men and 2.46 (1.47-4.13) for women. For ETS exposure at work, the odds ratios and confidence intervals were 0.95 (0.51-1.78) for men and 0.66 (0.17- 2.62) for women. The authors concluded that their study "confirms previous findings of elevated risk of heart attack or coronary death associated with passive smoking at home." However, they observed that the "odds ratios for passive smoking at work did not suggest increased risk." Based on other aspects of their study, the authors claimed that the data confirmed increased heart disease risk in "active" smokers as well as increased ETS-related heart disease risk in exsmokers. Also, blood fibrinogen (a clotting factor) was measured in controls and correlated with levels of reported ETS exposure. The authors suggested that increased levels of fibrinogen were a marker of ETS-related heart disease risk. The authors commented on a variety of sources of bias in their study, including potential effects of confounding: "On balance, the effects of bias and confounding could have led to overestimation of risks due to passive and active smoking." [10] "Passive Smoking Alters Lipid Profiles in Adoles- cents," J. Feldman, I.R. Shenker, R.A. Etzel, F.W. Spierto, D.E. Lilienfleld, M. Nussbaum and M.S. Jacobson, Pediatrics88(2): 1-6, 1991 [Vol. I, Issue 6, August 27, 1991] This study, featured in the newspaper USA Today, compared cotinine levels (as an index of exposure) and blood lipid profiles in 391 New York adolescents. The authors reported that ETS exposure was associated with decreased high-density lipoprotein cholesterol (HDL-C) and with an increased ratio of total cholesterol to HDL- C. They propose this as a mechanism for the increased heart disease risk purportedly assodated with ETS exposure. [Note: This study was featured on the front page of the newspaper USA Today, on August 6, 1991, under the headline "Study: Parents' Smoke Hurts Teens."] "The TOTAL-C/HDL-C [total cholesterol/high-density lipoprotein cholesterol] ratio is a powerful predictor of the risk of atherosderotic cardiovascular disease and therefore its relationship to passive as well as active smoking has implications for pediatric atherosderosis prevention." "The present study investigated the relationship of passive smoking to lipid profiles in healthy adolescents. Cotinine, a major metabolite of nicotine, was used as a marker of passive exposure to tobacco smoke." Two hundred seven-four boys and 117 girls (mean age 14.8 years) from suburban New York high schools were -15-

ETS AND IAQREFERENCE JULY 1992 -included in the study. Elever~percent of the children had plasma cotinine concentrations _> 2.5 ng/mL, "the level considered indicative of exposure." Mean plasma cotinine concentrations were significantly higher among those who reported that one or both parents smoked. (Contrary to the U.S.A. Today report, the authors stated that sodoeconomic status and diet were not controlled.) "When other factors were adjusted, passive exposure to tobacco smoke was associated with an increased ratio of TOTAL-C/HDL-C and decreased HDL-C concentration of between 7% and 9%. However, compared with other factorssuch as BMI [body mass index] or triglyceride concentration, the impact of passive smoking on the ratio of TOTAL-C/HDL-C was relatively small." "The assodation of passive exposure to tobacco smoke with reduced HDL-C and elevated ratio of TOTAL-C/HDL-C is biologically plausible, inasmuch as several investigators have found that dgarerte smoking results in a lowering of HDL- "The effect of tobacco on lipid levels provides one plausible mechanism (among others such as platelet aggregation, vasoactivity, and compromised oxygen transport) for the wall-established elevation of coronary heart disease risk among smokers and suggests a mechanism for the possible increased coronary heart disease risk in passive smokers." [11] "Health Scare - the Misuse of Science in Public Health Policy," J.R. Johnstone and C. Ulyatt, Australian Institute for Public Policy, Critical Issues No. 14, 99 pp., 1991 [Vol. I, Issue 4, July 12, 1991] This commenrmy by Johnstone provides a critique of the failure of risk factor intervention trials to achieve the reductions in coronary heart disease incidence that might have been expected from the publidty generated by various health authorities based on the epidemiological data. ExceLlent, readable commentary by Johnstone on ETS and lung cancer and an especially devastating critique of the failure of risk factor intervention trials to achieve the reductions in coronary heart disease inddence that might have been expected from the publidty generated by various health authorities based on the epidemiological data. On ETS: "At face value the published studies do little to inspire confidence in anything stronger than a 'not proven' verdict, if not one of'not guilty.' Would such results lead to the banning of barbecues or the exclusion of the deodorised from public sodery? The notion would, I think, be dismissed as absurd and resting on quite inadequate evidence, even though both meat smoke and deodorants may contain cardnogens. But barbecues and the deodorised are not scapegoats. Not yet." On intervention trials: "Our ill-health and death are our own fault. If we lived properly, that is, if we lived as the wowsers and puritans think we should, then we would live forever, or at least a very long tLm~ That is the tadt morality which underpins much of modem medicine. It is scandal that so many people should die of cardiovascular disease and cancer. (What shau/dpeople die of?.)" [emphasis in original] "Medical and scientific vandals have hijacked the tools and results ofsdence and prostituted them to their own ends. Secure in the knowledge that the great majority of a deceived populace believe them, they have untrammeled freedom to persecute oppressed minorities. It is time for change. Let those with an interest in public health and a sense off-air play examine the facts for themselves and draw their own conclusions." Ulyatt's chapter is entitled: "Making the Nanny State Honest." "Two relatively unquestioned assumptions underpin Nanny's actions. First, it is assumed that the messages that Nanny delivers are soundly based on the best sdentific evidence. Second, it is seldom questioned whether it is proper for Nanny to obtrude into the lives of citizens in the way she does. Most of Dr. Johnstone's account challenges the first assumption." Ulyatt challenges the second particularly the tendency for "Nanny" to "exhort rather than inform." RESPIRATORY DISEASES AND CONDITIONS - ADULTS [1] "Does Environmental Tobacco Smoke (ETS) Cause Adverse Health Effects in Susceptible Individuals? A Critical Review of the Scientific Literature: I. Respiratory Disorders, Atopic Allergy and Related Conditions," P. Witorsch, Environ. raen~l Tect~ola~y 13: 323-340, 1992 [Issue 24, Item 37] This article cited 197 sources in a review of the available epidemiologic data on persons with underlying or pre- existing respiratory disorders (e.g., asthma or COPD), atopic allergy, claimed heightened sensitivity, and multiple chemical sensitivity. For these conditions, the author concluded that the available data were inconclu- sive and/or limited with regard to any claimed association with ETS exposure. EXCERPTS: "This paper and a subsequent paper to follow are

I JULY 1992 I i I I I I I I I I I I I i I I I intended to provide a comprehensive, critical review and analysis of the sdentific literature relative to the issue of whether certain groups of individuals are more susceptible than the general population to possible adverse health effects as a result of short- or long-term exposure to ETS. In the present report, Part I, the available data relative to individuals with underlying/pre-existing respiratory disorders, atopic allergy and rdated conditions will be addressed. In the subsequent paper that will follow in the near future, the literature relevant to individuals with cardiovascular disorders, pregnant women, persons taking various drugs and medications, and the elderly will be reviewed and analyzed." "[T]he epidemiological data with respect to long-term effects of ETS exposure on adult asthmatics are quite limited and inconclusive and do not support a finding of an asmdation between exposure and adverse effects. Similarly, the somewhat larger (although still reladvdy few) number of experimental studies of acute effects of ETS exposure in asthmatic adults have produced contradictory and equally inconclusive results. While it appears that a small subset of individuals with asthma may react adversely to ETS exposure with worsening of respiratoty flow rates and, in some cases, even clinical exacerbations of their disease, the reasons for these reactions remain to be determined. Likdy reasons include poor conr_rol of asth.n'm, with increased airway inflammation resulting in a lowered threshold for bronchial reactivity, not only to tobacco smoke but to a large variety of specific and non-specific stimuli as well, and a psychogenically-mediated reaction. These mechanisms axe not mutually exclusive. In any event, there is no evidence that such exacerbations, whatever thdr reasons, result in any long-term effecr.s or alter the course of the disease." "The data with respect to potential effects of both short- term and long-term exposure to ETS on Chronic Oh- • structive Pulmonary Disease (COPD) and other chronic respiratory disorders, for all practical purposes, are virtually non-existent." "It is... not surprising that it has been suggested that a number of complaints putatively attributable to ETS exposure, such as eye and upper respiratory 'irritation', as well as exacerbations of asthma, may be related to . . . allergic reactions to tobacco smoke in susceptible atopic individuals. Nevertheless, studies consistently have failed to find any correlation between subjective complaints of sensitivity to tobacco smoke and either skin or serologic tests of immunologic reactivity to tobacco-related antigens." "ETS can cause annoyance most likely related to odor perception, and eye and upper respiratory irritation, most likely on a non-specific, non-immunologic irritant basis. Such responses to ETS exposure occur in a dose (concen- tration) related fashion, dependent, in part, on levels of ventilation and relative humidity. Evidence also suggests that attitudinal emotional and psychogenic factors play a role in such reactions, at least in some individuals. It has not been convindngly demonstrated however, that certain individuals are particularly hypersensitive or susceptible to such effects on any physiological basis." "[E]xposure to tobacco smoke, including ETS, has been included among the various exposures alleged to predpitate symptoms or perpetuate chronic illness in individuals said to suffer from MCS [multiple chemical sensitivity]. However, the only support offered for this contention are subjective reports lacking objective verification; no acceptable sdendfic studies provide any foundation for such relationship. In short, the unscientific nature of these 'data', the highly questionable validity of the proposed etiologic bases and pathogenetic mechanisms for this condition, and the likdihood that many, if not most, of these individuals suffer from a psychiatric dimmer or adhere to a medical subculture or bellefsystem, coupled with the considerable doubt that exists regarding even the basic concept of MCS as a legiti- mate, defined disease, disorder, syndrome, or nosologic entity, make it very difficult to conclude that individuals said to have MCS are more susceptible to claimed health risks of exposure to ETS than the general population." [2] "Passive Cigarette Smoke-Challenge Studies: Increase in Bmnchlal HyperactMty," P. Menon, RJ. Rando, R.P. Stankus, J.E. Salvaggio and S.B. Lehrer, Journal of Allergy and Clinical Immunology 89: 560-566, 1992 [Vol. I, Issue 22, May 22, 1992] Self-reported "smoke-sensitive" subjects were exposed to ETS in a test chamber. Five of 31 asthmatic subjects reportedly "reacted" to ETS; none of 39 nonasthmadc subjects "reacted" to ETS. The authors reported that almost one-third of the asthmatic and one-fifth of the nonasthmatic subjects exhibited increased bronchial hyperactivity for periods of as long as eight weeks follow- ing the test exposure. "Degree and duration of bronchial hyperactivity (BHR) after environmental tobacco smoke (ETS) inhalation was assessed in 31 smoke-sensitive subjects with asthma who exhibited lower airway symptoms on ETS exposure (group I) and 39 smoke-sensitive subjects without asthma who manifested only upper airway symptoms on ciga- rette-smoke exposure (group II). Subjects were challenged with ETS for 4 hours in a static-test chamber." I -17-

ETS AND LaiQ REFERENCE JULY 1992 "Reactivity to ETS is uniquLg, occurs after 60 or more minutes of continuous cigarette-smoke exposure, and does not represent classic immediate or late pulmonary reactivity. The present study was designed to assess and characterize any increase in BHR after a single ETS challenge. This was achieved by serial MCs [methacholine challenges] administered before and after passive ciga- rette-smoke exposure." "All subjects were 'smoke sensitive' in that the subjects with asthma reported chest tighmess, shormess of breath, cough, or wheezing, and the subjects without asthma reported only upper respiratory symptoms on exposure to ETS." "The study subjects were exposed to mixed mainstream- sidestrearn smoke. During the 4-hour ETS challenge, airborne partioalate levds of 800 cpm were maintained that resulted in a TSP [total suspended particles] of 1266 +283 I~g/m3 and airborne nicotine level of 226 +49 gg/m3." "Five of the 31 SS [smoke sensitive] subjects with asthma reacted (> 20 percent fall from baseline FEV~ [a measure of pulmonary function]) on ETS challenge. These five subjects demonstrated persistent reactivity to ETS on repeated challenges for at least 3 consecutive years .... None of the 39 SS subjects without asthma demonstrated a sigrfificant decline in pulmonary function during or aleter 4-hour ETS challenge." "Our studies of passive dgarerte-smoke challenge in nonsmokers demonstrate that almost 1/3 of SS subjects with asthma and 1/5 of SS subjects without asthma have a marked increase in BHR 6 hours after ETS exposure. The increase in BHR varied. One subject with asthma had a 16-fold increase in BHR. Two other subjects, one subject with asthma and one without, each had increased BLIP, that persisted for up to 8 weeks after cigarette-smoke exposure .... The fact that all subjects were atopic may limit the applicability of these results to the general population." "It is of particular interest r_hat an increase in BHR was observed in asymptomatic subjects without asthma after ETS exposure. Since 'dose' and duration of passive dgaret~e- smoke exposure may have been important factors in their responses, every effort was made during the challenge to simulate ETS levds similar to levels encountered in real life. The dgarerte-smoke levels used in our bronchoprovocation studies have been reported in public places. However, as is the case with allergen challenges, the subjects may have been exposed to rdativdy higher doses of ETS in a shorter period of ti.me during challenge. Some of the subjects demonstrated increased BHR for prolonged periods of time (8 weeks). This finding could be due to ongoing dgaretxe-smoke -18- exposure at home, work, or elsewhere. Six of 11 subjects with asthma and two of seven without asthma who demon- strated increased BHR reported dgarerte-smoke exposure at home or work." "Clearly, passive dgarette-smoke challenge studies performed in the laboratory are limited by experimental conditions and thus cannot always be equated with ETS exposure in real life situation [sic]. However, we believe that our finding of increased mecholyl-induced BHR after ETS exposure, even in asymptomatic subjects, is relevant to the issue of dgarerte-smoke reactivity. Allergen avoidance has been demonstrated to decrease BHR and improve symptoms in a group of subjects with asthma, and it is possible that a similar beneficial effect could occur by avoidance of ETS." [3] "Multipollutant Exposures and Health Responses to Particulate Matter," M.D. Lebowitz, J.J. Q.uackenboss, M. ~owskl, M.tC O'Rourke and C. Hayes, Archives of Environmental Health 47(1): 71-75, 1992 [Vol. I, Issue 21, May8, 1992] This article reports on an ongoing study in Tucson, Arizona, which is investigating lung function and particulate matter exposures. The authors report that ETS is related to some respiratory symptoms. "A study of indoor-outdoor (total) exposures and their respiratory effecr.s is underway in Tucson, Arizona. The objective of the study is to evaluate responses of bronchial responsive subjects (those with greater than normal bron- chial lability who are likely to respond more to environmen- tal stimuli) and matched healthy subjects to total and combined air pollutant exposures. Ofspedal interest are the combinations of pollutants from several sources, including combustion emissions (gas, wood burrfingo ETS), HCHO [formaldehyde] (from materials), and outdoor sources. The quality assurance and analytical procedures are based on previous studies and are described elsewhere." "Each day individuals recorded in a diary the total time that they spent in five location categories: (1) home; (2) work/school; (3) outside, near roads; (4) outside, away from roads; (5) other indoors. Individuals spent more than 65 percent of their time at home, and the average time spent outdoors was 3 l-dd. Basic environmental inventory ques- tionnaires and weekly household ac~:ivity records were completed for each home so that presence and use o£source and removal factors could be identified." "As found previously, the indoor levels of [particulate matter, PM] were markedly higher in homes where I i i I I I I I i I I I I I i I I I