Tobacco Documents Online

Environmental Tobacco Smoke and Heart Disease

~ Literature Review 2o2351i6s5

THIS ISSUE BINDER IS INTENDED TO PROVIDE A BASIC, COMPREHENSIVE REVIEW OF THE SCIENTIFIC LITERATURE REGARDING A SPECIFIC TOPIC ON ETS AND THE HEALTH OF NONSMOKER.S. PRIMARY STUDIES AND REVIEWS HAVE BEEN HIGHLIGHTED TO IDENTIFY (I) USEFUL OR HELPFUL INFORMATION (YELLOW HIGHLIGHT) AND (2) ADVERSE RESULTS OR OPINIONS (BLUE HIGHLIGHT).

TABLE OF CONTENTS 2423511663

performance, potential effects in heart disease patients or in relation to biochemical and cellular processes, including atherosclerosis. 3

ETS and Heart Disease TABLE OF CONTENTS PAGEhTOS . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 1 Provides a description of the scope and organization of the notebook. Epid'emiolocric Reports and Reviews . . . . . . . . . . . . . . 4 Reports with oricrinal data . . . . . . . . . . . . . . . 4 Summarizes the 12 epidemiological studies with~ data on ETS exposure in relation to heart disease incidence or mortality. Includes an~ epidemiological study on stroke and one on Buerger's disease. For more detailed discussions and criticisms of these reports, see Appendix A. Reviews claiming ETS-associated risk . . . . . . . . . .. 8 Discusses articles which have reviewed the epidemiological literature and concluded that ETS exposure is causally related to heart disease in nonsmokers. The focus is on the meta-analyses and' risk assessments by Wells (1988), Glantz and' Parmley (1991) and Steenland (1992). Copies of these articles are in Appendix B. Reviews emphasizing inconclusiveness of the data. . . . . 14 Sets forth the conclusions from several major literature reviews that have judged that the data are inadequate to support a conclusi~on that ETS is related~ to heart disease in nonsmokers. Copies of these publications are provided in Appendix C. Laboratory and Biochemical Studies . . . . . . . . . . . . .. . 21 Identifies and summarizes laboratory studies of exercise performance, biochemical studies involving such issues as platelet activity, cholesterol levels and leukocyte levels and studies of atherosclerosis. Copies of these articles are in Appendix D.

Epid'emiologic Reports and Reviews Reports with original data There are currently 12 studies presenting epidemiological data on~ a possible statistical association between ETS and heart disease incidence and mortality. The ETS associated risks reported in the 12 epidemiological studies are summarized in the following table. - 4 -

ETS and Heart Disease 8/5/93 Introduction This notebook discusses and provides copies of the public literature bearing on the claim that environmental tobacco smoke (ETS) is related to heart disease. The current notebook is an update, following its initial preparation in 1991. Currently, there is a total of 12 epidemiological studies presenting data on a possible statistical~ association between ETS and heart disease incidence or mortality. These epidemiological reports are the primary basis for claims of an elevated~ heart disease risk in~nonsmokers exposed to ETS. However,, the literature also contains several laboratory and statistical reports dealing with ETS and exercise performance (particularly in angina patients), with biochemical factors suggested as involved in the development of heart disease or with atherosclerosis. These reports are also discussed and~ includ'ed in this notebook. Each of the articles included in this notebook has been highlighted in blue and yellow. The blue highlighting identifies t1: "adverse" comments -- that is, comments supporting a relationship Q of ETS with heart disease, or that otherwise express unfavorable (,c data or opinions regarding tobacco. The yellow, highlighting ~ identifies "helpful" comments -- that is, comments that challenge, t~ ~ or at least that are concessionary concerning, the potential ~

involvement of ETS or tobacco in disease causation. Letters to the editor or other editorial comments are included with several of the articles in this notebook. The initial section of this notebook contains an overview and discussion of the literature. The literature itself is grouped into four appendices.. Appendix A (Tabs 1-14) contains the 12 epidemiological reports with data on~a potential association between ETS and! heart disease (Tabs 1-12). Appendix A also contains two epidemiological reports with: data on~other cardiovascular diseases -- namely stroke (Tab 13) and Buerger's disease (Tab 14). A summary and discussion of major criticisms is provided for each of the 12 ETS/heart disease studies. Appendix B (Tabs 15-20) contains major meta-analyses and reviews concluding that ETS is associated with an elevated heart disease risk. Appendix C (Tabs 21-34) contains opinions that the data -3_C.2 inadequate to conclude that ETS is related to heart disease. Appendix D (Tabs 35-51) contains a mixed group of articles which provide data concerning ETS in relation 2 to exercise

Epidemiolosy ETS/Heart Disease Relative Risks Sex Relative Risk Butler (1990)1 F 1.4 Dobson et al. ~ M .97 (Home)~ (1991) F 2.46* M .95 (Work) F .66 Garland, et al. F 2.7 (1985)3 He, et al. F 1.5* (1989)4 Helsing, et al. M 1.3* (1988) F 1.2* Hirayama (1984)6 F 1.3 H'olie, et al. M+F 2.0* (1989)7 Humble et al. F 1.6 (1990)A Lee, et al. M+F 1.0 (198b)'9 Martin et al. F 3'.4* (1986) i0 Palmer et al. F 1.2 (1988) il Svendsen, et al. M 2.2 N (1987)12 N *Reported to be statistically significant at the 95% level of Li CA confidence. N - 5 -

} 5. Failure to control adequately for biases stemming from potential confounding!variables. 6. Failure to confirm causes of death via autopsy or other histological methods. Reviews claiming ETS-associated risk ("unfavorable" reviews) Despite the scientific weaknesses in the epidemiologic literature on ETS and heart disease, several recent reviews have concluded that ETS is associated with an increased risk of heart disease and that, in~fact, such exposure causes a large number of deaths each year. Each of these reviews attempted to estimate an overall risk based on the combined data from the epidemiologic studies. These estimated risk ratios are provided in the following table. 8

Epidemiological data have also been reported for ETS exposure in~relation to Buerger's disease. Buerger's disease is an inflammatory condition leading to arterial occl~usion in the peripheral vascular system. It has been, reported to be statistically associated with cigarette smoking. Matsushita, et al.14 studied 40 Buerger's disease patients, in relation to smoking history and history of ETS exposure. Based on an examination of the progression or "aggravation" of the disease in these patients, 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." A list of the most common weaknesses in, the epidemiological literature on ETS and cardiovascular disease is provided below. It will be recognized that these are characteristic of epidemiological studies of ETS in, general, not simply those relating to heart and other cardiovascular diseases. 1. Small sample sizes. 2. Lack of statistical significance, or failure to test for statistical significance. 3. Potential misclassification of the smoking status of study participants. 4. Inadequate assessment of ETS exposure. - 7 -

Only five of the 12 epidemiological studies regarding ETS and heart disease report a statistically significant result at the 95% level of confidence. These are: (1) He, et al. (1989), a Chinese language report based on only 34 female heart disease patients; (2) Helsing, et al. (1988), a study based~ on a Maryland census in which~the information~regarding spousal smoking (used to estimate ETS exposure) was from 1963; (3) Hole, et al. (1989), a Scottish study based on only 84 heart disease deaths; (4) Martin, et al. (1988), a report based on only 23 women who reported having a heart attack and which was given at a conference but apparently not otherwise accepted for publication; and (5) Dobson, et al. (1991), an Australian study which reported an association with home exposure for women only and not at all for workplace exposure. In sum, seven of the 12 studies of ETS exposure and heart disease have failed to report a statistically significant association. In the five studies that have claimed a statistically significant relationship, three were from outside the United States. Three were very small-scale. All of these studies suffer from a variety of serious methodological weaknesses. In addition to the 12 ETS/heart disease reports, there is also an epidemiological (case-control) study reporting that spousal smoking was associated with increased stroke risk [relative risk of 1.7 (95% CI: 1.1-2.6)],13 - 6 -

cardiovascular diseases and the work environment. Thus, the major reviews were those by Wells in 1988, by Glantz and Parmley in 1991 and by Steenland in 1992. These three reports are discussed further below. A. Judson Wells, a consultant to the American Lung Association, statistically combined the data from several reports on ETS and heart disease, including both prospective (cohort)i and case-control studies. He then calculated overall relative risks (ETS exposed versus nonexposed) for lung cancer (1.44 for females;. 2.1 for males)!, cancers other than lung (1.16 for females; no risk elevation for males) and heart disease (1.23 for females; 1.31 for males). Using, various assumptions and statistical manipulations, Wells calculated' numbers of ETS-related deaths for each disease category. He claimed that ETS exposure resulted in 46,000 deaths per year in nonsmokers. Of these, 3,000 are claimed to be fromi lung, cancer. For cancers other than the lung, he calculated that ETS exposure results in 11,0001annual deaths. The largest number of deaths from ETS exposure was claimed to be due to heart disease. He claimed that 32,000 nonsmoker heart disease deaths per year stemifrom ETS exposure. A more widely publicized review of ETS and heart disease was undertaken by two authors from the Department of Medicine, University of California, San Francisco. In their 1991 paper, - 10 -

Stanton Glantz and William Parmley conclude that ETS exposure is statistically associated~ with an estimated 30% increase (relative risk of 1.3) in heart disease risk in nonsmokers. They argue, relying on~ Wells, that this translates into 37, 000 heart disease deaths in nonsmokers stemming from ETS exposure. Glantz and Parmley also discuss a number of biochemical and experimental studies which purportedly support the biological plausibility of such a relationship. In evaluating the claims by Wells and by GLantz and Parmley, it should'be emphasized that meta-analysis, the technique from which they derive their risk estimates, is appropriately used only when the underlying studies are highly similar and of high quality. If the underlying studies are based~ on different populations and~ procedures and suffer from serious methodological weaknesses, then~any meta-analysis will consequently be invalidated. These considerations are directly applicable to an evaluation of risk claims regarding ETS and~ heart disease. Wells (1988)~ and: Glantz and Parmley (1991) base their claims on meta-analyses of a small group of, epidemiological studies reporting a relationship between ETS exposure and an increased~ risk of heart disease. In general, these studies deal with spousal smoking and assess heart disease risk in the nonsmoking spouse. Otherwise, these studies used widely disparate methodologies, study populations and endpoints. Several are very weak, preliminary, available only in. - 11 -

similar to that reported by Wells and'by Glantz and Parmley. This estimation process involved: positing an overall increase in relative risk of heart disease associated with ETS exposure; making adjustments for potential misclassification and for background exposure; estimating the extent of exposure to ETS; and estimating the fraction of nonsmoker heart disease deaths attributable to ETS exposure. These estimates were incorporated into a formula using data on U.S. heart disease death rates and population estimates, from which~was derived an estimated number of annual heart disease deaths attributed to ETS exposure. According to Steenland's calculations, "the overall estimate of ETS-attributable heart disease deaths for never-smokers and former smokers is 35000 to 40000." He further commented that these increased risks of death "are higher than those accepted in regulating environmental toxins." In a 1992 position statement from the American, Heart Association,, it was concluded that ETS causes heart disease. (Taylor, et al.)20 Reviews emphasizing inconclusiveness of the data ("favorable" reviews) Reviews such as those by Wells, by Glantz and Parmliey and by Steenland often receive a great deal of publicity. However, it is important to recognize that there have been, a number of other - 13 -

abstract form, or are based on such scanty data that they quite arguably are not sufficiently reliable or valid considered seriously in a meta-analysis. even to be Kyle Steenland, a National•Institute for Occupational Safety and Health employee, also performed a risk assessment of ETS and heart disease. In a 1992 paper, he calculated that 35,000- 40,000 annual U.S. heart disease deaths are attributable to ETS exposure. He concluded that "heart disease mortality is contributing the bulk of the public health burden imposed by passive smoking." There were two important differences between Steenland's estimation process and that used by Wells, and later adopted by Glantz and Parmley. First, Steenland did not do a meta-analysis to obtain~ a pooled estimate of relative risk for heart disease mortality associated'with ETS exposure. Instead~, he simply adopted~ the relative risk reported in a single study of a Maryland~ sample (Helsing, et al., 1988; see endnote ref. 5) and applied~ that to the entire U.S. population. Second~, he focused only on~ heart disease and did not attempt to calculate ETS-related deaths from other diseases. Other than the above, Stteenland'.'s procedure for calculating deaths attributable to ETS exposure was generally - 12 -

are instigated, and some objective measure of degree of exposure can be devised. (p. 215)24 c. D.F. Weetman presented a similar conclusion at an indoor air quality conference in~Bangkok, Thailand in November 1991. It is concluded that too many important potentially confounding, factors have been~ overlooked to decide if there is an association between exposure to ETS and cardiovascular diseases. (p. 275)25' d. Another scientific review of this literature was performed! by two physicians from the University of Munich, Germany and given at an international conference in Hungary in June 1990. The conclusion was similar.. Taking into account the small increase in coronary risk in passive smokers as compared to non-exposed subjects and also the low validity and small number of epidemiological studies available and the fact that their results are at least inconsistent, a relationship between passive smoking and cardiovascular diseases cannot be established on these data. (p. 6)26 e. In a 1991 book discussing a wide range of issues involving ETS, the literature on heart disease was reviewed by Alan Armitage, former director of toxicology of a major European research laboratory and head of pharmacology at the - 16 -

scientists have undertaken more balanced and' critical reviews of the more recent data and have j'udged that it remains inconclusive. Several of the most significant of these recent reviews, and their conclusions, are as follows. a. At a major conference on ETS held~ at McGill University in 1989,, Lawrence Wexler, of the New York Medical College, concluded that recent data did not provide a basis for altering the earlier conclusions by the Surgeon General and National Research Council concerning ETS and cardiovascular disease. Based on the available evidence, it is this author's opinion that it has not been demonstrated that exposure to ETS increases the risk of cardiovascular disease. (p. 139)23 b. A similar evaluation was made by two scientists, D.F. Weetman and J. Munby, from the School of Pharmacology,. Sunderland Polytechnic, Sunderland, United Kingdom. They presented their conclusions fr= a review of the literature on ETS and heart disease at an international conference on i_ndoor air quality held'. in Lisbon, Portugal in April 1990. It is concluded that no increased risk of cardiovascular disease can be associated unequivocally with exposure to ETS, and it seems probable that this will continue to be the case until specifically designed trials - 15 -

Tobacco Research Council Laboratories in the United Kingdom. He judged that the scientific data have not established an increased heart disease risk in nonsmokers exposed to ETS. It is clear that the evidence for a harmful effect of ETS in~enhancing CHD [Icoronary heart disease) risk in non,smokers is not very convincing. . . . (p. 114)27 f. In a subsequent review in 1993, Armitage, writing as a consultant pharmacologist and toxicologist, expressed a similar evaluation of the ETS/heart disease literature. On the current evidence a causal relationship between exposure.to ETS and the development of CHD has not been proved. (p. 27)28 g. Armitage's 1993 review appeared in the Journal of Smoking-Related Diseases. In an~editorial in the same journal issue, A.D.S. Caldwell, the journal's managing editor, emphasized that the issue of confounding variables was of particular importance in the case of heart disease. This is because of the hundreds of factors reportedly associated with the disease. Caldwell observed that the numerous heart disease N risk factors make it extremely difficult to make confident ~ CJ statements about a potential role of ETS. N W - 17 -

examinations of the data concerning ETS and heart disease. Several important reviews have concluded that the data on~ this issue are equivocal and inadequate to support claims of an increased heart disease risk in nonsmokers exposed to ETS. The first major reviews of the epidemiological data on ETS and heart disease appeared in 1986. In that year, a report of the United States Surgeon General21 examined the available data and judg,ed that "no firm conclusion" (p. 10) could be made regarding a possible relationship between ETS and heart disease. Also in 1986, a similar evaluation appeared from a committee of the National Research Council of the National Academy of Sciences.22 This committee stated~ that any potential heart disease risk related to ETS would be "difficult to detect or estimate reliably" from eni.cIe-miological studies, and would be "the same order of magnitude as what might arise from expected residual confounding due to unmeasured covariates..10 (p. 263) Thus, both the 1986 Surgeon General's Report and the National Research Council report jud'ged that the data were insufficient to allow a conclusion that ETS exposure is a cause of li.~a,: L disease. Even~ the 1991 review by Glantz and~ Parmley recognized this as a"reasonable" position, at least in 1986. on the other hand~,, Glantz and Parmley argued that data published since 1986 warrant that this conclusion be modified. However, other - 14 -

Meta-Analyses and Reviews of ETS-Heart Disease Data RR Wells (1988)15 Males 1.31 Females 1.23 Kawachi et al. Home (1989) 1t Males 1.3 Females 1.2 Workplace Males 2'. 3 Females 1.9 Kristensen (1989y17 Both sexes ;z 1.3 Glantz and Parmley Both sexes 1.3 (1991) 18 Steenland (1992)19 Males 1.3 Females 1.2 These estimates were generally d'erived~ fr= the stai.istical technique known as meta-analysis. Although these reviews varied somewhat in formy detail and focus, the estimates were generally similar, about 1.3, reflecting a 30% elevation in risk associated with ETS exposure. AV The Kawachi, et al. (1989) discussion was fairly narrowly ~ focused on New Zealand. The Kristensen (1989) discussion was a i limited part of a larger discussion of factors involved in~~ 9

Thus, the possibility is always open that some subjective factor may influence the results. There are very limited data attempting to demonstrate that ETS adversely affects some process that might be involved in blood clotting. The primary focus has been on the possibility that ETS may increase the tendency of certain blood components, known as platelets, to stick together. This claim has been made based mainly on data in four published reports. Three of these are from~ the same Austrian research group. (Sinzinger and Kefalides,, 198239'; Burghuber, et al., 198640'; Sinzinger and Virgolini, 198941) Of these three, one is merely a letter to the editor (Sinzinger and Kefalides, 1982) and another is a German language article with only an English abstract (Sinzinger and~ Virgolini, 1989). The fourth report, Davis, et al., (1989)42 is from a group of researchers in Kansas City, Missouri. It suffers from serious methodological weaknesses, particularly its failure to establish a proper control condition. [Platelet activity has also been assessed in an laboratory animal study involving exposure of rabbits to ETS, where the primary focus was on atherosclerosis. See Zhu, et al., 1993, endnote reference 50.] al ~ U1 There are three reports on children which assessed ~ cholesterol and other blood components in relation to parental ~ smoking status (Moskowitz, et al., 199043; Pomrehn, et al., 199044; - 23 -

adverse effect on exercise performance. Two other studies, one by Aronow (1978)36 and the other by Khalfen andKlochkov (1987)37 used angina patients. In somewhat similar study designs, both~ reports claimed that when heart disease patients were exposed to ETS, they were not able to exercise as long before experiencing angina. The credibility of the Aronow report has been widely challenged in the literature. The Khalfen and Klochkov report is a Russian language article about which relatively little is known. In the fourth exercise performance study, Leone, et al. compared the cardiac performance during exercise testing in healthy subjects versus myocardial infarction survivors, in relation to ETS exposure. The authors reported that ETS exposure was associated 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. The authors concluded: Cardiac response to the exercise is significantly worsened by passive smoke, especially in those subjects with previous myocardial infarction.38 Regarding any of the exercise performance studies, whether with healthy or heart disease patients, a general criticism is that when dealing with ETS, it is almost impossible to "blind" either the experimenter or the subjects with regard to ETS exposure. - 22 ' -

i. In 1992, Peter Lee published a more detailed~, book- length review of the epidemiological literature on ETS exposure in relation to mortality and several diseases. In his view, various weaknesses and biases in the data preclud'ed~ the ability to draw any conclusion as to the potential association of ETS exposure and heart disease. J Mainly because of the problems caused by the strong, likelihood of severe publication bias, it cannot be concluded from the existing evidence that ETS is associated' with heart disease. The present author understands that the American Cancer Society intends to publish withinthe next year or so findings related to ETS based on its second large prospective study. It is hoped that results from its first prospective study will also be released~. Until there is such evidence, and hopefully also evidence from other studies involving substantial numbers of deaths from heart disease with good control of confounding and~ with evidence on ETS exposure from sources other than the spouse or in the home, it is certainly premature to come to any conclusions. (pp. 145-196) 31 j. In 1992, Domingo Aviado, M.D., a consultant with Atmospheric Health Sciences in Short Hills, N.J., published~ .in extensive review of environmental tobacco smoke in the ~ O context of heart disease in the workplace. He did not consider ~ ~ the data supportive of an association of workplace ETS exposure VI i-I with heart disease, and emphasized the low levels of ETS ~-L 4M constituents to which workers might be exposed. ~ - 19 -

severity of atherosclerotic involvement. Atherosclerosis of the carotid arteries is believed to underlie certain forms of stroke. These data were updated in a presentation~ at a March 1992 cardiovascular disease epidemiology conference, the abstract from which included information on some additional subjects, but otherwise reported similar results. (Howard, et al., 1992)49 In an experimental report based on measurements in~ rabbits, tobacco smoke exposure reportedly led'to increased levels of atherosclerosis. (Zhu, et al. 19:93)50 This is the first study to provide such experimental data. The study is subject to criticisms on the basis of questionable exposure protocols and other methodological weaknesses. There have been limited data in the literature suggesting that certain vitamins might be a factor in the development of heart disease. Based on this theory, a 1992 meeting abstract measured dietary and plasma levels of vitamini C (ascorbic acid) in people exposed to ETS. Compared to a control group, ETS-exposed nonsmokers were reported to have decreased plasma levels and dietary intake of ascorbic acid. The authors concluded~: These results suggest that suboptimal AA [ascorbic acid] nutriture may contribute to increased heart disease risk associated with ETS exposure.51 - 25 -

Feldman, et al., 199145), one of which (Pomrehn, et al., 1990) is only available as an abstract from a meeting presentation. These reports claimed'.that parental smoking was associated with decreases in HDL cholesterol, which some literature has argued~ may be associated with heart disease risk. ' A recent study from India made similar claims about adverse changes in adult cholesterol levels in relation to ETS exposure (Whig, et al.),46' as did a report focusing on ETS exposure in the workplace. (White, et al.)47 These cholesterol studies measured components of blood as the endpoint, but are essentially epidemiological studies in that they, at best, may suggest statistical correlations. As such, they swffer fromi weaknesses characteristic of other epidemiological studies of ETS exposure, especially difficulties in controlling for potential confounding variables and inad'equate assessment of ETS exposure. Furthermore, the potential significance of blood values in relation to later heart disease risk, especially in groups of children, is highly speculative. An abstract, from the Bowman Gray School of Medicine (Wi.nsron Salem, North Carolina), based on a presentation at a November 1991 American, Heart Association meeting, reported~ that ETS exposure was associated~ with thickness of the walls of the carotid arteries. (Howard, et al., 1991)48 The importance of carotid artery thickness is that it may be an indication of the - 24 -

References (Alphabetical) 2023511699

The significance of this report is highly questionable. Very few details are available -- not even the ages of the people studied are given in the abstract. In addition, the relationship, if any, of vitamin levels to subsequent heart disease is not scientifically established. Furthermore, even the authors acknowledge that their data on plasma vitamin C may at least in part be a result of different levels of dietary intake, rather than any direct effect of ETS exposure. Some previous researchinvolving,active cigarette smokers has reported that smokers may have higher numbers of leukocytes (white blood cells) than nonsmokers. It has beemspeculated that these higher leukocyte counts may be one mechanism whereby smoking might increase heart disease risk. Green, et al. (1993)52 addressed the question of whether ETS-exposed~ nonsmokers might also show increased leukocyte counts. Green, et al. examined a group of 250! male factory workers. These men were questioned~ regarding their smoking habits and their reported exposure to ETS in the workplace and at home. Urine samples were also collected for cotinine analysis. Green, et al. reported that, on the average, smokers had higher leukocyte counts compared with nonsmokers. However, based both on reported ETS exposure as well as on cotinine data, exposure to ETS was not associated~ with increased leukocyte counts. The authors concluded - 26 -

that, if ETS exposure is associated with increased heart disease risk,, it is not mediated through an effect on leukocyte count. These findings suggest that any association of passive smoking with coronary heart disease is not through an elevation of leucocyte count. (Abstract, p. 14) WLS/tks 10740757 - 27 -

But assessing the impact of ETS is an exercise made hazardous by confounding variables lurking around every statistical corner. In the case of CHD, for example, some 300 risk factors have at some time or other been identified-- by what means is it possible to unravel these data and point the finger with any degree of confidence at ETS per se as a major causative element?29 h. In 1991, Peter Lee, an independent British statistical consultant, published a critical analysis of the epidemiological literature relating to ETS exposure, cancer and heart disease. In the area of heart disease, he was particularly critical of the risk assessments by Wells (1988) and Kawachi, et al. (1989)1. Both of these risk assessments concluded that ETS is associated~ with a large number of heart disease deaths annually. Lee challenged this conclusion, and~ sided with the 1986 National Academy of Sciences and Surgeon General's reports, both, of which had considered the ETS/heart disease data inadequate. In the risk assessment by Wells, heart disease deaths formed 70% of the total. In that by Kawachi et al, they formed 89%. As noted~ above, in 1986 none of the major authorities considered that ETS had been shown to cause heart disease. Evidently Wells and Kawachi, in assuming that ETS causes heart disease, are jumping to a conclusion that a number of panels of distinguished scientists have not reached. While there are more data now thaniin 1986, it remains abundantly clear that the evidence still does not support this conclusion. (p. 199)3'0 - 18 -

concluded that ETS has not been scientifically shown to cause or exacerbate heart disease. Any potential role of carbon monoxide in ETS was considered to be especially unlikely. The role, if any, of environmental tobacco smoke (ETS) in the causation and/or exacerbation of cardiovascular disease remains to be proven and defined. . . . It is concluded that if ETS plays a role in the etiology of cardiovascular disease, it is most likely not mediated through carbon~ monoxide. (p. 77) 34 Laboratory and Biochemical Studies There are several experimental and biochemical studies that have been cited in the literature as supporting an increase in heart disease risk stemming from ETS exposure. A few of these reports claim~that ETS'exposure adversely effects exercise capacity and that in the case of heart disease patients, this can lead to attacks of angina (heart pain). other reports have attempted to demonstrate that ETS exposure adversely affects some aspect of cardiovascular function, such~as blood clotting (,platelet activity) or cholesterol levels, or that it affects the underlying disease process (atherosclerosis). ~ In the area of exercise performance, there are four N studies. In one of these, a 1985 report by McMurray, et al.,35 G healthy subjects were used and ETS exposure was claimed to have an ~ , ~ ~ - 21 -

It is the opinion of this author that the available studies do not support a judgment that ETS exposure is associated with any form of occupation-related heart disease. Although ETS reportedly contains constituents that have been associated with occupational heart disease, the concentrations are so low that it is unlikely for any substance to attain the corresponding TLV (threshold limit value) in a work environment. (pp. 475-476)32 k. G. Crepat, a scientist at the University of Dijon, France, reviewed the literature relating to ETS exposure and heart disease, in~ a presentation at an international indoor air quality meeting in Athens, in April 1992. He concluded that the relative risks for ETS and heart disease reported.in epidemiologic studies have probably been overestimated and are not explained by the availablie "physiobiochemical" data. This suggests that mean RR [relative risk] of CHD due to ETS exposure calculated from available epidemiologic studies, has probably been overestimated as at the moment it cannot be explained by physiobiochemical changes caused~ by ETS in the body. (p. 440y33 1. Carbon monoxide is one of the constituents of ETS ~_;o{oetimes proposed to play a role in heart disease. John, Mennear, of the School of Pharmacy, Campbell University (North Carolina) reviewed the literature relating to carbon monoxide, ETS and cardiovascular disease. His 1993 review paper - 20 -

Appendix A 2023511706 ... _,".

51. Tribble, D.L. and Fortmann, S.P., "RedUced Plasma Ascorbic Acid Concentrations in Women Regularly Exposed to Environmental Tobacco Smoke (ETS),, Circulation 86(4): 1-675, 1992. 52. Green, M.S., Shaham, J., Green, J., Harari, G. and Bernheim, J., "Association of Passive Smoking! with Increased~ Coronary Heart Disease Risk is Not Explained by Elevation of Leucocyte Count," European Journal of Public Health 3(1)~: 14-17, 1993. 10740757 - 33 -

TAB 46 Whig, J., Singh, C.G., Soni, G.L. and Bansal, A.K., "Serum Lipids & Lipoprotein Profiles of Cigarette Smokers & Passive Smoker," Indian J. Med. Res. B96: 282-287, 1992. TAB 47 White, J.R., Criqui, M., Kulik, J.A., Froeb, H.F. and Sinsheimer, P.J., "Serum Lipoproteins in Nonsmokers Chronically Exposed to Tobacco Smoke in the Workplace," 8th World Conference on Tobacco or Health. Building a Tobacco-Free World. March 30-.April 3, 1992, Buenos Aires, Argentina, Abstract No. 383, 1992. TAB 50 Zhu, B.Q., Sun, Y.P., Sievers, R.E., Isenberg, W.M., Glantz, S.A. and Parmley, W.W., "Passive Smoking Increases Experimental Atherosclerosis in~Cholesterol-Fed Rabbits,1° JACC 21(1): 225-232, 1993. 10749816 6

number of deaths, either overall or for any of the individual causes, on which the relative risks were based. 3. There was no reported statistically significant relationship between ischemic heart disease mortality and marriage to a smoker. The author admits that the study was flawed because of the small number of cases and the probable misclassification of passive smoking exposure, which "limited the ability to achieve conclusive results."

N O NW Gl ~ ~ O ~

10. Martin, M.J., Hunt, S.C. and Williams, R.R., "Increased Incidence of Heart Attacks in Nonsmoking Women Married to Smokers," Presented at the Annual Meeting of the American Public Health Association, Abstract, 1986. 11. Palmer, J.R., Rosenberg, L. and Shapiro, S., "Passive Smoking and Myocardial Infarction in Women," Abstract, CVD Epidemiology Newsletter No. 43, 29, Winter 1988. 12. Svendsen, K.H., Kuller, L.H., Martin, M.J. and Ockene, J.K., "Effects of Passive Smoking in the Multiple Risk Factor Intervention Trial," American Journal of Epidemiology 126(5): 783-795, 1987. 13. Donnan, G.A., McNeil, J1.J., Adena, M.A., Doyle, A.E., O'Malley,. H.M. and Neill, G.C., "Smoking As a Risk Factor for Cerebral Ischaemia,"' Lancet 643-647, Sept. 16, 1989. 14. Matsushita, M., Shionoya, S. and Matsumoto, T., "Urinary Cotinine Measurement in Patients with Buerger's Disease-- Effects of Active and Passive Smoking on the Disease Process,", Ji. Vasc. Surg. 14(1): 53-58, 1991. 15. Wells, A.J., "An Estimate of Adulit Mortality in the United' States from Passive Smoking," Environment International 14(3): 249-265, 1988. 16. Kawachi, I., Pearce, N.E. and Jackson,, R.T., "Deaths from Lung Cancer and Ischaemic Heart Disease Due to Passive Smoking in, New Zealand," New Zealand Medical Journal 102(871): 337- 340, 1989. 17. Kristensen, T.S., "Cardiovascular Diseases and~ the Work Environment. on Chemical A Critical Review of the Epidemiologic Literature Factors," Scand. J. Work Environ. Health 15: 245-264, 1989. 18. Glantz, S.A. and Parmley, W.W., "Passive Smoking and Heart Disease: Epidemiology, Physiology, and~ Biochemistry,"' Circulation 83(1): 1-12, 1991. 19. Steenland, K., "Passive Smoking and the Risk of Heart Disease,"' JAMA 267(1):' 94-99, 1992. ~ ~ 20. Taylor, A.E., Johnson, D.C_ and Kazemi, H. "Environmental ~ Tobacco Smoke and Cardiovascular Disease. A Position Paper From the Council on Cardiopulmonary and Critical Care, American ~n Heart Association," Circulation~86(2): 699-702, 1992. ~ ~ ~ ~ 10740757 ~ - 2 9! -

} Butler, T., "The Relationship of Passive Smoking to Various Health Outcomes Among Seventh-Day Adventists in California," Presented at the Seventh World Conference on Tobacco and Health, Abstract, 1990. This report is an abstract from a 1990 conference presentation. The study involved a group of California Seventh Day Adventists who were followed from 1976 to 1982. Nonsmoking women were classified according to their husband's smoking status. The relative risk for fatal ischemic heart disease for women married to smokers was reported to be 1.4 (not statistically significant). Risk ratios were also reported for lung cancer, all "'smoking related" cancers, cervical cancer and all cancers. Confidence intervals were quite large, indicating no statistical significance for these values. However, for cervical cancer, a relative risk of 4.86 had confidence intervals indicatingg statistical significance. Criticisms This is an abstract only, apparently otherwise unpublished and not subject to peer review. 2. There are insufficient details to evaluate this study. For example, the abstract does not contain information on the number of nonsmoking women married to smokers versus those married to nonsmokers. Neither was data reported concerning the

ETSIHEART DISEASE ALPHABETICAL BIBLIOGRAPHY TAB 27 Armitage, A.K., "Environmental Tobacco Smoke and Coronary Heart Disease." In: Other People"s Tobacco Smoke. A.K. Armitage (ed.). Beverly, E. Yorks, U.K., Galen Press, Chapter 7, 109-116, 1991. TAB 28 Armitage, A.K., "Environmental Tobacco Smoke and Coronary Heart Disease," J. Smokincr-Related' Dis. 4(1): 27-36, 1993. TAB 36 Aronow, W.S., "Effect of Passive Smoking on Angina Pectoris," New England Journal of Medicine 299(1): 21- 24, 1978. TAB 32 Aviado, D.M., "Environmental Tobacco Smoke Exposure and Occupational Heart Disease."' In: Cardiovascular Toxicology. D. Acosta (ed.), Raven Press, Ltd., New York, pp. 455-479, 1992. TAB 40 Burghuber, O.C., Punzengruber, Ch., Sinzinger, H., Haber, P. and Silberbauer, K., "Platelet Sensitivity to Prostacyclin~ in Smokers and Non-smokers," Chest 90(1): 34-38, 1986. TAB 1 Butler, T., "The Relationship of Passive Smoking to Various Health Outcomes Among, Seventh-Day Adventists in California,"' Presented at the Seventh World Conference on Tobacco and Health, Abstract, 1990. TAB 29 Caldwell, A.D.S., "Give a Dog-end a Bad Name," J. Smoking- Related Dis. 4(1): 1-2, 19:92. TAB 22 Committee on Passive Smoking, Board on Environmental Studies and Toxicology, National Research~ Council, National Academy of Sciences, Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washington, D.C., National Academy Press, 1986. TAB 33 Crepat, G., "'Passive Smoking and Coronary Artery Disease. Biological Plausibility and Severity of Effect." In: Quality of the Ind'oor Environment. J.N. Lester, R. Perry and G.L. Reynolds (eds.)~. Selper, Ltd., London, 1992, pp. 42'9'-443. TAB 42 Davis, Ji.W., Shelton, L., Watanabe, I.S. and~ Arnold, J., "Passive Smoking Affects Endothelium and Platelets," Arach. Intern. Med. 149: 386-389, 1989. N O N W N #+ ~ ~

41. Sinzinger, H. and Virgolini, I., "Are Passive Smokers at Greater Risk of Thrombosis?"Wiener Klinische Wochenschrift 20: 694-698, 1989. 42. Davis, J.W., Shelton:, L.,, Watanabe, I.S. and Arnold„ J., "Passive Smoking Affects End'othelium and Platelets," Arach. Intern. Med. 149: 386-389, 1989. 43. Moskowitz, W.B., Mosteller, M., Schiekern, R.M., Bossano, R., Hewitt, J.K., Bodurtha, J.N. and Segrest, J.P., "Lipoprotein and Oxygen Transport Alterations in Passive Smoking Preadolescent Children~: The MCV Twin Study," Circulation 81(2'): 586-592, 1990. 44. Pomrehn, P., Hollarbush, J., Clarke, W. and Lauer, R., "Children's HDL--chol: The Effects of Tobacco; Smoking, Smokeliess and Parental! Smoking," Presented at the 30th Annual Conference on, Cardiovascular Disease Epidemiology, Abstract, Circulation 81(2): 720, 1990. 45. FeldYnan, J., Shenker, R., Etzel, R.A., Spierto, F.W., Lilienfield', D.E., Nussbaum, M. and Jacobson, M.S., "Passive Smoking Alters Lipid Profiles in Adolescents," Pediatrics 88(2): 2'59-264, 1991. 46. Whig, J., Singh, C.G., Soni, G.L. and Bansal, A.K., "Serum Lipids & Lipoprotein Profiles of Cigarette Smokers & Passive Smoker," IndianiJ. Med. Res. B96: 282-287, 1992. 47. White, J.R., Criqui, M., Kulik, J.A., Froeb, H.F. and Sinsheimer, P.J., "Serum Lipoproteins in Nonsmokers Chronically Exposed! to Tobacco Smoke in the Workplace," 8th World~ Conference on Tobacco or Health. Building a Tobacco-Free World. March 30-April 3, 1992, Buenos Aires, Argentina, Abstract No. 383, 1992. 48. Howard, G., Szklo, M., Evans, G., Tell, G., Eckfeldt, J., Heiss, G. and The ARIC Investigators, "The Association Between Carotid Arterial Wall Thickness and~ Active and~ Passive Cigarette Smoking," Arteriosclerosis and Thrombosis 11(5): 1432a, 1991. 49. Howard, G., Szklo, M., Evans, G., Tell, G., Eckfeldt, J. and Heiss, G., "Passive Smoking and~Carotid Artery Wall Thickness: The ARIC Study," Circulation~85(2): 3, 1992. 50. Zhu, B.Q., Sun, Y.P., Sievers, R.E., Isenberg, W.K., Glantz, S.A. and Parmley, W.W., "Passive Smoking Increases Experimental Atherosclerosis in Cholesterol-Fed Rabbits," JACC 21(1): 225-232, 199:3. 10740757 - 32 -

TAB 2 Dobson, A.J.,, Alexander, H.M., Heller, R.F. and Lloyd, D.M.,'"Passive Smoking and the Risk of Heart Attack or Coronary Death," The Medical Journal of Australia 154: 793-797, 1991. TAB 13 Donnan, G.A., McNeil, J.J., Adena, M.A., Doyle, A.E., O'Malley, H.M. and Neill, G.C., "Smoking As a Risk Factor for Cerebral Ischaemia,'"' Lancet 643-647, Sept. 16, 1989. TAB 45 Feldman, J~., Shenker, R., Etzel, R.A., Spierto, F.W., Lilienfield, D.E., Nussbaum, M. and Jacobson, M.S., "Passive Smoking Alters Lipid Profiles in Ad'olescents," Pediatrics 88(2): 259-264, 1991. TAB 3 Garland, C., Barrett-Connor, E., Suarez, L., Criqui, X.H. and Wingard, D.L., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study," American Journal of Epidemiology 121(5): 645-650', 19:85. Garland, C., Barrett-Connor, E., Suarez,, L., Criqui, M.H. and Wingard, D.L., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study," Erratum, American Journal of Epid'emiology 122: 1112, 1985. TAB 18 Glantz, S.A. and Parmley, W.W. ,"'Passive Smoking and Heart Disease: Epidemiology, Physiology, and Biochemistry," Circulation 83(1): 1-12, 1991. TAB 52 Green, Mi.S., Shaham, J., Green, J., Harari, G. and Bernheim, J., "Association of Passive Smoking with Increased Coronary Heart Disease Risk is Not Explained by Elevation of Leucocyte Count," European Journal of Publ~ic Health 3(1): 14-17, 1993. TAB 4 He, Y., et al., "Women's Passive Smoking: and Coronary Heart Disease," Chung Hua Yu Fang I Hsuch Tsa Chih 23(1): 19-22, 1989. TAB 5 Helsing, K.J., Sandler, D.P., Comstock, G.W. and Chee, E'., "Heart Disease Mortality in Nonsmokers Living With Smokers," American Journal of Epidemiology 127(5): 915- 922, 1988. TAB 6 Hirayama, T., "Lung Cancer in Japan: Effects of Nutrition and Passive Smoking." In: Lung Cancer: Causes and Prevention. M. Mizell and P. Correa (eds.). New York, Verlag Chemie International, Chapter 14, 175-195, 1984. 2'

TAB 7 Hole, D.J., Gillis, C.R.,, Chopra, C. and Hawthorne, V.M.,. "Passive Smoking and Cardiorespiratory Health in a General Population in the West of Scotland,"' Britishi Medical Journal 299: 423-427, 1989. TAB 48 Howard, G., Szklo, M., Evans, G., Tell, G., Eckfeldt, J., Heiss, G. and The ARIC Investigators, "'The Association Between Carotid Arterial Wall Thickness and Active and~ Passive Cigarette Smoking," Arteriosclerosis and Thrombosis 11(5): 1432a, 1991. TAB 49 Howard, G., Szklo, Mi., Evans, G., Tell, G., Eckfeldt, J. and Heiss, G.,, "Passive Smoking and Carotid Artery Wall Thickness: The ARIC Study," Circulation 85(2): 3, 1992. TAB'8 Humble, C., Croft, J., Gerber, A., Casper, M., Hames, C.G. and Tyroler, H.A., "Passive Smoking and 20-Year Cardiovascular Disease Mortality among Nonsmoking Wives, Evans County, Georgia,"'American Journal of Public Health 80(5): 599-601, 1990'. TAB 16 Kawachi, I., Pearce, N.E. and Jackson, R.T., "Deaths from Lung Cancer and~ Ischaemic Heart Disease Due to Passive Smoking, in New Zealand,"' New Zealand Medical Journal 102(871): 337-340, 1989. TAB 37 Khalfen, E.Sh. and Klochkov, V.A.,"Effect of 'Passive' Smoking on the Physical Load Tolerance of Coronary Heart Disease Patients," Ter. Arkh. 5: 112-115, 1987. [Uncertified translation] TAB 17 Kristensen, T'.S., "Cardiovascular Diseases and the Work Environment. A Critical Review of the Epidemiologic Literature on Chemical Factors," Scand. J. Work Environ. Health 15: 245-264, 1989. TAB 9 Lee, P.N., Chamberlain, J. and~ Alderson, M.R., "Relationship of Passive Smoking to Risk of Lung Cancer and Other Smoking-Associated Diseases," British Journal of Cancer 54: 97-105, 1986. Lee, P.N., "Weaknesses ini Recent Risk Assessments of Environmental Tobacco Smoke,"' Environmental Technology 12Q3): 193-208, 1991. TAB 31 Lee, P.N., Environmental Tobacco Smoke and~ Mortalitv.. Karger, New York, 1992. TAB 38 Leone, A., Mori, L., Bertanelli, F., Fabiano, P. and Filippelli, M., "'Indoor Passive Smoking: Its Effects on - 3 -

TAB 12 Svendsen, K.H., Kuller, L.H., Martin, M.J. and Ockene,. J.K., "Effects of Passive Smoking in the Multiple Risk Factor Intervention Trial," American Journal of Epidemiolocry 126(5) : 783-795, 1987. TAB 20 Taylor, A.E., Johnson, D.C. and Kazemi, H. "Environmental Tobacco Smoke and Cardiovascular Disease. A Position Paper From the Council on Cardiopulmonary and Critical Care, American Heart Association," Circulation 86(2): 699-702, 1992. TAB 26 Thiery, J. and Cremer, P., "Coronary Heart Disease and~ Involuntary Smoking," Paper presented at: Toxicology Forum (Session on "Environmental Tobacco Smoke: Science and Meta-Science"), Budapest, Hungary, June 19, 19901. TAB 51 Tribble, D. L. and~ Fortmann, S. P. ,"Reduced! Plasma Ascorbic Acid Concentrations in Women Regularly Exposed to Environmental Tobacco Smoke (ETS), Circulation 86(4): 1-675, 1992. TAB 21 U.S. Department of Health and~ Human Services, The Health Consequences of Involuntary Smoking: A Re*port of the Surgeon General. Publication No. DHHS (CDC) 87-8398, Washington, D.C., U.S. Government Printing Office, 1986. TAB 24 Weetman, D.F. and Munby, J., "Environmental Tobacco Smoke (ETS) and Cardiovascular Disease." In: Indoor Air Quality and Ventilation. F. Lunau and G.L. Reynolds (.eds.). London, Selper Ltd., 211-216, 1990. TAB 25 Weetman, D.F., "A Critique of the Method's Used to Assess the Toxic Effects on Man of Combustion Products." In: Indoor Air ouality in Asia. Proceedings of the International Conference held at the Central Plaza Hotel, Bangkok, Thailand on 28-29th~ November, 1991, B.R. Reverente, D.F. Weetman and M. Wongphaniach (eds.). TAB 15 Wells, A.J.,"An Estimate of Adult Mortality in the United States from Passive Smoking," Environment International 14(3): 249-265, 1988. `t'A3 23 Wexler, L.M., "Environmental Tobacco Smoke and Cardiovascular Disease: A Critique of the Epidemiological Literature and Recommendations for Future Research." In: Environmental Tobacco Smoke: Proceedings of the International Symposium at MeGill University 1989. D.J. Ecobichon and J.K. Wu (eds.). Lexington, Mass., Lexington Books, D.C. Heath and Company, Chapter 8, 139-152, 1990.. - 5 -

DOBSON, A.J., ALEXANDER, H.M., HELLER, R.F. AND LLOYD, D.M., "PASSIVE SMOKING AND THE'RISK OF HEART ATTACK OR CORONARY DEATH," THEdMEDICAL JOURNAL OF AUSTRALIA 154: 793-797, 1991 This article provides epidemiolog,ical data concerning a potential relationship between environmental tobacco smoke exposure and heart disease. All subjects were residents of the Hunter region of New South Wales, Australia. It used a case-control d'esign. The cases were all individuals, male or female, within that region who experienced a "fatal or non-fatal definite or possible myocardial infarction or a coronary death~..'° The controls were a sample comprising individuals in this region who were participating in~ an ongoing risk factor prevalence study sponsored by the World Health Organization. Data were collected on certain demographic characteristics, medical history, cigarette smoking and ETS exposure at home and at work. Odds ratios and 95% confidence intervals reported for heart disease risk associated with ETS exposure at home were &.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 ,zWtlo.rs concluded that their study "confirms previous findings of el..vated risk of heart attack or coronary death associated with passive smoking at home." (p. 797) However, they observed that the "odds ratios for passive smoking at work did not suggest increasedrisk_ ° (p. 793)

Cardiac Performance, " International Journali of Cardiology 33(2): 247-252, 1991. TAB 10 Martin, M.J., Hunt, S.C. and Williams, R.R., "Increased Incidence of Heart Attacks in Nonsmoking Women, Married to Smokers," Presented at the Annual Meeting of the American Public Health Association, Abstract, 1986. TAB 14 Matsushita, M., Shionoya, S. and Matsumoto, T.,, "Urinary Cotinine Measurement in Patients with Buerger's Disease- - Effects of Active and Passive Smoking on the Disease Process," J. Vasc. Surg. L4(1): 53-58, 1991. TAB 35 McMurray, R.G., Hicks, L.L. and Thompson, D~.L., "The Effects of Passive Inhalation~ of Cigarette Smoke on Exercise Performance," European Journal of Applied Physiology 54(2): 196-200, 1985. TAB 34 Mennear, J.H., "Carbon Monoxide and Cardiovascular Disease: An Analysis of the Weight of Evidence," Regulatory Toxicolocty and' Pharmacology 17: 77-84, 1993. TAB 43 Moskowitz,, W.B., MosteLler, M., Schiekern, R.M., Bossano, R., Hewitt, J.K., Bodurtha, J.N. and'Segrest, Ji.P., "Lipoprotein and~ Oxygen Transport Alterations in.Passive Smoking Preadolescent Children: The MCV Twin Study," Circulation 81(2): 586-592, 1990. TAB 11 Palmer, J.R., Rosenberg, L. and Shapiro, S., "Passive Smoking~ and Myocardial Infarctioni in Women,t° Abstract, CVD EbidemioloQV Newsletter No. 43, 29, Winter 1988. TAB 44 Pomrehn~, P., Hollarbush, J., Clarke, W. and Lauer, R., "Children's HDL--chol: The Effects of Tobacco; Smoking, Smokeless and Parental Smoking,"' Presented at the 30th Annual Conference on Cardiovascular Disease Epidemiology, Abstract, Circulation 81(2): 720, 1990. TAB 39 Sinzinger, H. and Kefalides, A., "Passive Smoking Severely Decreases Platelet Sensitivity to Antiaggregatory Prostaglandins,'" Letter, The Lancet II, pp. 392-393, August 14, 1982. TAi3 41 Sinzinger, H. and Virgolini, I., "Are Passive Smokers at Greater Risk of Thrombosis?" wiener Klinische Wochenschrift 20: 694-698, 1989. TAB 19 Steenland, K., "Passive Smoking, and the Risk of Heart Disease," JAMA 267(1): 94-99, 1992. - 4 -

3. Questions have been raised in the literature, including by the 1986 National Academy of Sciences report, about the possible misclassification or misuse of the statistical test appl ied to the study. 4. The relative risk from ETS exposure was assessed by grouping nonsmoking, women married to either current or to former cigarette smokers. Grouping current with former cigarette smokers provides a particularly weak estimate of ETS exposure. 5. Interpretation of the data is complicated due to 15 of the 19 deaths occurring in nonsmoking women married to husbands who had stopped at the time of entry into the study. 6. No information on any changes in smoking habits was available for the 10-year follow-up.

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, levels of blood fibrinogen (a clotting factor) were evaluated in relation to reported ETS exposure. Increased levels of fibrinogen were suggested to be a marker of ETS-related heart disease risk. The authors commented on a variety of sources of biases in their study, including potential effects of confounding. Despite their belief that their study supports an~ adverse effect of both~ smoking and ETS exposure, they, conceded that: "On balance, the effects of bias and confounding could have led to overestimation of risks due to passive and active smoking." (p. 796)

30. Lee, P.N., "Weaknesses in Recent Risk Assessments of Environmental Tobacco Smoke," Environmental Technology 12(3): 193-208, 1991. 31. Lee, P.N., Environmental Tobacco Smoke and Mortality. Karger, New Y'ork, 1992. 32. Aviado, D.M., "Environmental Tobacco Smoke Exposure and Occupational Heart Disease." In: Cardiovascular Toxicology. D. Acosta ('ed.), Raven Press, Ltd., New York, pp. 455-479, 1992.. 33. Crepat, G., "'Passive Smoking and Coronary Artery Disease. Biological Plausibility and Severity of Effect." In: Quality of the Ind'oor Environment. J.N. Lester, R. Perry and G.L. Reynolds (eds.)~. Selper, Ltd., London, 1992, pp. 429-443. 34. Mennear, J.H., "Carbon Monoxide and Cardiovascular Disease: An Analysis of the Weight of Evidence," Regulatory Toxicology and Pharmacology 17: 77-84, 1993. 35. McMurray, R.G., Hicks, L.L. and Thompson, D.L., "The Effects of Passive Inhalation of Cigarette Smoke on Exercise Performance," European Journal of Applied Physiology 54(2): 196-200, 1985. 36. Aronow, W.S., "'Effect of Passive Smoking on Angina Pectoris," New England Journal of Medicine 299(1): 21-24, 1978. 37. Khalifen, E.Sh. and Klochkov, V.A., "'Effect of 'Passive' Smoking, on the Physical Load Tolerance of Coronary Heart Disease Patients," Ter. Arkh. 5: 112-115, 1987. [,Uncertified~ translation] 38. Leone, A.,, Mori, L., Bertanelli, F., Fabiano, P'. and~ Filippelli, M., "Indoor Passive Smoking: Its Effects on Cardiac Performance," International Journal of Cardiology 33(2): 247-252, 1991. 39. Sinzinger, H. and Kefalides, A., "Passive Smoking Severely Decreases Platelet Sensitivity to Antiag,gregatory Prostaglandins," Letter, The Lancet II, pp. 392-393, August 14, 1982. 40. Burghuber, O.C., Punzengruber, Ch., Sinzinger, H., Haber, P. and Silberbauer, K., "Platelet Sensitivity to Prostacyclin in Smokers and Non-smokers," Chest 90(1): 34-38, 1986. 10740757 - 31 -

21. U!.S. Department of Health and Human Services, The Health Consequences of Involuntary Smoking: A Report of the Surgeon General. Publication No. DHHS (CDC) 87-8398, Washington~„ D.C., U.S. Government Printing!Office, 198'6. 22. Committee on Passive Smoking, Board~ on Environmental Studies and! Toxicology, National Research Council, National Academy of Sciences, Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. Washington, D.C., National Academy Press, 1986. 23. Wexler, L.M., "Environmental Tobacco Smoke and Cardiovascular Disease: A Critique of the Epidemiological Literature and Recommendations for Future Research." In: Environmental Tobacco Smoke: Proceedings of the International Symposium at McGill University 1989. D.J. Ecobichon and J.M. Wu (eds.). Lexington, Mass., Lexington Books, D.C. Heath and Company, Chapter 8, 139-152, 1990. 24. Weetman, D.F. and Munby, J., "Environmental Tobacco Smoke (ETS) and Cardiovascular Disease." In: Indoor Air Quality and Ventilation. F. Lunau and G.L. Reynolds (eds.). Lond'oni, Selper Ltd~., 211-216, 1990. 25. Weetman, D:.F., "A Critique of the Methods Used to Assess the Toxic Effects on Man of Combustion Products." In: Indoor Air 4uality in Asia. Proceedings of the International Conference held at the Central Pliaza Hotel, Bangkok, Thailand on 28-29th November, 1991, B.R. Reverente, D.F. Weetman and M. Wongphaniach (eds.). 26. Thiery, J. and Cremer, P., "Coronary Heart Disease and Involuntary Smoking," Paper presented at: Toxicology Forum (Session~ on "Environmental Tobacco Smoke: Science and Meta- Science"), Budapest, Hungary, June 19, 1990. 27. Armitage, A.K., "Environmental Tobacco Smoke and Coronary Heart Disease." In: Other People's Tobacco Smoke. A.K. Armitage (ed.). Beverly, E'. Yorks, U.K., Galen Press, Chapter 7, 109-116, 1991. 28. Armitage, A.K., "Environmental Tobacco Smoke and~ Coronary Heart Disease," J. Smoking-Related Dis. 4(1): 27-36, 1993. 29. Caldwell, A.D.S., "Give a Dog-end a Bad Name," J. Smoking- Related Dis. 4(1): 1-2, 1992. 10740757 - 30 -

Endnotes l. Butler, T., "'The Relationship of Passive Smoking to Various Health Outcomes Among Seventh-Day Adventists in California," Presented at the Seventh World Conference on Tobacco and Health, Abstract, 1990. 2. Dobson, A.Ji., Alexander, H.Mi. , Heller, R.F. and Lloyd,, D.M., "Passive Smoking and the Risk of Heart Attack or Coronary Death:," The Medical Journal of Australia 154: 793-797, 1991. 3. Garland, C., Barrett-Connor, E., Suarez, L., Criqui, M.H. and Wingard, D.L., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study,°' American Journal of Epidemiology 121(5): 645-650, 1985. Garland, C., Barrett-Connor, E., Suarez, L., Criqui, M.H. and Wingard~„ D.L., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study," Erratumi, American, Journal of Epidemioloary 122: 1112, 1985. 4. He, Y., et al., "Womeni's Passive Smoking and Coronary Heart Disease," Chung Hua Yu Fang I Hsuch. Tsa Chih 23 (1) : 19-22, 1989. 5. Helsing, K.J., Sand'ler, D.P., Comstock, G.W. and~ Chee, E., "Heart Disease Mortality in Nonsmokers Living WithiSmokers," American Journal of Epidemiology 127(5): 915-922, 1988. 6. Hirayama, T., "Lung Cancer in Japan: Effects of Nutrition and Passive Smoking." In: Lung Cancer: Causes and Prevention. M. Mizell and P. Correa (eds.). New York, Verliag, Chemie International, Chapter 14, 175-195, 1984. 7. Hole, D.J., Gillis, C.R., Chopra, C. and Hawthorne, V.M., "Passive Smoking and Cardiorespiratory Health in a General Population in the West of Scotland,"' Britiish Medical Journal 299: 423-427, 1989',. 8. Humble, C., Croft, J.,, Gerber, A., Casper, M., Hames, C.G. and Tyroler, H.A., "Passive Smoking and 20-Year Cardiovascular Disease Mortality among Nonsmoking Wives, Evans County, Georgia," American Journal of Public Health 80(5): 599-601, 1990. 9. Lee, P.N., Chamberlain, J. and A1d'erson, M.R., "Relationship of Passive Smoking to Risk of Lung Cancer and Other Smoking- Associated Diseases," British Journal of Cancer 54: 97-105, 1986. 10740757 - 28 -

5. This is a case-control study, and suffers from common problems with such studies, such as difficulties in establishing appropriate control groups and controlling for potential confounding variables.

He, Y., et al., "Women's Passive Smoking and Coronary Heart Disease," Chung Hua Yu Fang I Hsuch Tsa Chih 23(1): 19-22, 1989. This was published as a Chinese article with an English language abstract. It reports a case-control study of 34 coronary heart disease cases among women, who were classified according to their own and their husband's smoking behavior. The cases were otherwise matched to controls on the basis of age, race, residence and occupation. The authors report a statistically significant increase in the heart disease odds ratio for nonsmoking womenn married to smokers. A significant dose-response relationship was also claimed. Criticisms 1. The English language abstract provides very few details on which to evaluate the article. 2. There are several editorial and bibliographical errors which are apparent even though only the abstract is available in English. These may raise questions about the overall credibility of the report. 3. The report is based on a small sample size of only 34 heart disease cases. 4. The report comes from a Chinese military hospital, a data source of unknown reliability.

Garland, C., Barrett-Connor, E., Suarez, L,, Criqui, M.H. and' Wingard, D.L., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study," American Journal of Eoidemiolocrv 121Q5): 645-650, 1985. In this study, a community of older adults in suburban San Diego, California, was surveyed between 1971 and 1974 for the prevalence of heart disease risk factors. They were then followed for an average of 10 years to determine vital status and cause of death. The nonsmoking women were classified according to their husbands' smoking. Of the 695 nonsmoking women, 19 deaths from ischemic heart disease were recorded. It was reported that, compared to women married to husbands who had never smoked, women married to current or former smokers had a relative risk of 14.9. This was after statistically adjusting for age, systolic blood pressure, total cholesterol, obesity, and years of marriage. In a subsequent "erratum" the authors stated that the 14.9 value was an error and reported a corrected value of 2.7. (Am. J. Epidemiol.: 122, 1112, 1985.) Criticisms 1. Neither the relative risk of 14.9 claimed in the ni.-l(li.nal article, nor the "corrected" value of 2.. 7, was reported to bta statistically significant. 2. The sample size was very small, consisting of only 19 deaths from heart disease.

ERRATUM The Journ.al has been notified by Dr. Cedric Garland of an error that went undetected by his co-authors and himself in a recent article (Garland et al., "Effects of Passive Smoking on Ischemic Heart Disease Mortality of Nonsmokers: A Prospective Study";, Am J Epidemiol 1985;121:645-50). The authors incorrectly reported a multiple-adjuste& (Cox) relative risk of ischemic heart disease in nonsmoking women married to men who ever-smoked of 14.9, with a:p value of p< 0.10: The relative risk should be 2:7, with the p value remaining at p_< 0.10 as originally reported. The correction does not affect the conclusions, and other values in the tables and elsewhere in the text are correct. N I I • t-t mfl~ Sl G N - _j - L__ P_ . 17.) a I!c 1112 ]z

H

4. No data were available for ETS exposure outside the home.

Table 3. Clinical Diagnosis in Passive Smoke Group Exposure to Passive Smoke Exposure to Passive Smoke Yes No Yes No Anq na Psctorxo Myocard,& -"n arct on Subject Group 17 ~ 8 5 Control Group 20 22 10 16 -OR 4.In 2. 550 X= 5.035 1.018 P c0.05 >0.05 C. n2ood cholesterol and Lipoprotein Level Changes in Passive Smokers By controlling for age, weight, and other risk factors, a decrease in serum HDL-C and apoAl isvel was found in passive smokers, whereas LDL-C, apoB and apo B/Al levels are higher than those not exposed to passive smoke. Tha level of HDL-C, apoAi and apoB/Al levels are significantly different between the subject and control groups (Table 4)

<20 12 22 2.303 1.8B0 >20 13 8 6.661 10.09B** Passive Smoke Exposure Years 0 9 36 1.000 ..... 510~ 4 9 1.877 0.266 $20 6 11 3.071 2.581 >20 13 10 5.489 8.230** Cumulative Passive Smoke index (Years) 0 9 38 1.000 ..... 1-199 4 11 1.535 0.066 200-399 6 11 2.303 1.009 400-599 6 5 5.067 4.054' 600' 9 3 12.667 11.35a~" p<o.05 p<a.01 B. Association with Clinical Diagnosis in the patients group, 21 cases were diagnosed with, angina poctoris and 13 cases with myocardial infarction. The number of passive smokars in both clinical settings is similar (X= - 1.298, p>0.5). Thsss results are illuctratnd in Table 3. The results show that angina poctoris is clearly and significantly correlated with passive smoking. Although myocardial infarction in the passive smoking group show an OR of greater than 1, it did not reach statistical significance, which may be related to the small sample size.

lL v% GZrtI t, -C.( . L YA-v, c`'o.-L iow Passive saokinq in 7emales and Coronary Seart Disease Dy Y. He, L.X.Li, C.C. Fong, Znatitute of Infectious Diseases, and L.S. Li, X.L. Chang, Q.L. Qua, Department of Cardioloqy and Internal M®dicina, Xian Medical College. ADBTRACT Thirty four cases of women with coronary heart disease (CHD) (22 cases diagnosed by coronary arterioqraphy, and 12 cases diagnosed as havinq myocardial infarction) were used in an investigation designed to assess the association between passive smokinq in women and the establishment of CxD. The odds ratio (OR) ot non-smoking women developing CHD as a result of exposure to passive smoke is 3.0-3.5 (p<0.05). A dose response relationship was detected between the number of'passive smoke exposure years and' the increase in OR for CHD. Multiple regression analysis shows that of the many risk factors for CHD, passive smoke exposure is significantly correlated with CHD. Women exposed to passive smoke also showed abnormal levels of serum LDL-C, HDL-C, apoAl and apoB, xey words Coronary heart disease, coronary arteriography, passive smoke Experimental investigations have demonstrated that the chemical constituents generated in the sidestream smoke often contain the same harmful chemicals as in mainstream smoke inhaled by smokers, and that there is considerable adverse otfects contributed by sidestream smoke to non-smokars who are passively exposad.'-= A number of reports have appeared showing a correlation between passive smoke and the damage to lunq l~unctions, increased incidence of lung cancer, and angina pectoris."6 A limited number of investigations have bean focused on the subject of passive smoke in the Paople's Republic of China, and have only concentrated on studyinq the influence of passive smokinq on lung functions.7 ' In this communication we report the relationship between passive smoke exposura and female patients who were hospitalized because of coronary heart disease.

Table 4. 8lood Cholesterol and Serum Lipoprotain Levels in Female Passive Smokers Control Group CHD Group Non-txposed Eacposed Non-axposed Exposed Number 26 20 9 24 Total cholastarol (mmol/L) 4.42t0,6s 4.47±0.68 5.15t0.e6 5.80t0.73* LDL (mmol[L)2.34t0.68 2.5210.68 3.3510.86 3.85±0.71 HDL (mnol/L)1.41t0.18 1.Z9t0.18* 1.2610.21 1.12t0.17* LDL/HDL 1.74±0.51 1.98±0.60 2.75±0.79 3.42t0,.74rt apoAi (q/L) 1.27f0.24 1.1110.23* 0.95t0.18 0.81t0.13* apoB (q/L) 0.7110.17 0.7410.14 1.0320.17 1.1610.20 apoB/apoA1 0.61t0.19 0.67t0.22 1.2110.40 1.36t0.22* *Pc0.05, P values re er to compar-ison-,ba-tvQen non-exposed and exposed cases. 3. xultipis Loqistia ReqrOssion Analysis Srven risk factors believed to contribute to CHD were subjacted to logistic regression analysis. These factors include: history of hypertsnsion (xi}, lamily history of hypertension (x2), lamily history of CHD (x3), history of passive smoke exposure (x4), history of drinking (x5), exercise per.formanee test (x6) and history of hypercholsstersmia (x7). The results are shown Sn Table S. Table 5. Multipls Regression Analysis of CHD Risk Factors Hi Var(ni) 6(Bi) t2'D(si) OR G P ~ History or ~ Passive smoka 0.406 0.069 0.083 4.87 1.5004 16.93 <0~.01 ~ History of I-a Hypertension 0.714 0.052 0.227 3.147 2.0429 8.90 <0.01~A _j

2. Effeats of tassive 4moxing Table 1 shows a comparison between disease and paired control groups. The OR of qetting CHD for nonsmoking women living with a smoking husband is 3.0:0, with a 95% CI of 1.256-7.168, i.e. the risk of women gsttinq C'HD is 3 times higher for those with husbands that smoke compared to those with nonsmokers husbands. Diseased + Group - Table 1. A comparison of Passive Smoking Status in Diseased and Control Groups Control Group + + + - - 4 12 9 3 4 3.00 1.256-7.168 6.117 (c 0.05) A. Dose Response Relationship Table 2 illustrates the association between husbandsr average daily cigarette consunption, passive smoke, exposure years, cumulative passive smoke amount index, and the ORe of getting CHD. There is a noticaabls mose response relationship, i.e. ac the amount of passive smoke exposure increasss, ths risk of getting CHD also becomes greater. Table 2. Dosa Response Relationship between Passive smoke Exposure and CHDs Subject Control OR X2 N O Kusbands daily N cigarette consumption G? Git 0 9 38 1.000 ..... }.i ~ .1~ 45

were collected on smoking in 1963, yet many changes probably occurred~ in smoking behavior during the subsequent 12-year follow- up. This concern was noted by the authors. All smoking data were obta•ined in the 1963 census, so no provision can be made for changes in smoking habits which we know took place as a result of publicity about health effects of smoking. (p. 921). 2. Other changes in the compositions of the households may have occurred during the follow-up period. Although the authors assume that any changes might influence the ETS comparison groups randomly, this is mere speculation. We also have no data on changes in the household composition which may have occurred prior to or after 1963. Thus, we implicitly assume that any such changes occurred randomly in the population. (p. 921) 3. Although an~ attempt was made to adjust statistically for some potential heart disease risk factors (age, sex, etc.), no data were available on many potentially important risk factors for heart disease such as diet, exercise, blood pressure, and cholesterol. We have very little data on other risk factors for arteriosclerotic heart disease in the study population. . . other factors such as diet and exercise might differ in families with and without smokers; we cannot ignore the possibility that such differences could influence our findings. (p. 921)

646 GARI.AND ET AL Greece (26, 27), the United States (28), Germany (29), Hong Kong (30); and Japan. (31-34) indicated an excess risk of lung cancer in involuntary smokers. A prospec- tive study by Garfinkel of' the American Cancer society cohort in the United States (13) found no excess risk of lung cancer from involuntary smoking, although the negative findings may be due, at least partly, to miscla.ssification of exposure to passive smoking (35). A cancer-registry-based study in Lancas- ter County, Pennsylvania, revealed no: cases of lung cancer in nonsmoking Amish persons (who are unexpose& to passive smoking because they live ia a closed soci- ety which forbids cigarette use) in a popu- lation of 12,000 observed for a seven-year period (36). We hypothesize& that an excess in is- chemic heartt disease might be, shown in passive smokers, even when the amount of lung cancer induced would be too low to detect. an excess risk„sirrce mortality attrib- utable to iscbemic heart disease as a result of cigarette smoking is greater than that' due to lung cancer (37). This is because lung cancer, even in heavy smokers, is less common than ischemic heart disease. We further hypothesized that nonsmoking women old enough to have died of coronaryy heart disease would have had spouses who provided the major source of cigarette smoke, because until recently most women had little exposure to cigarettes in the workplace. We report here a prospective study of mortality from ischemic heart disease, as well as lung cancer, bronchopulmonary dis- ease (chronic bronchitis, emphysema, and asthma), an& all-cause mortality, in non- smoking married women from a community of older adults who have been followed for 10 years. SUBJECPs AND METHODS Between 1972 and 1974, the entire adult community of Rancho Bernardo, Califor- nia, a predominantly white, upper-middle- class suburb of San Diego, California, was invited to participate in a survey for the prevalence of heart disease risk factors. Eighty-two per cent of adults in the popu- lation responded to the survey. Respond- ents were representative of the total popu- lation with regard to age and sex (38). All participants had a standardized in- terview including questions about age; cig- arette smoking-, history of past hospitali- zations for heart attack, heart failure, or stroke;,and duration of marriage. Cigarette smoking was assessed as current, former, or never. The number of cigarettes smoked per day was determined only for current smokers, and no data were obtained about duration of smoking. Weight and height were measured in light clothing without shoes, and obesity was d'efined by body mass index (weight/height= x 100). Before the interview, after the participant had been seated for at least five minutes, blood pressure was measured; with a standard mercury sphygmomanometer. Plasma cho- lesterol was measured by an Autoanalyzer in a standardized Lipid Research Clinic Laboratory.. Vital status was determined by an annual mailing for an average of 10 years with an overall ascertainment rate of 99.6 per cent. Death certificates„ obtaine& for all dece- dents, were coded by a certified nosologist according to the Eighth Revision of thE International ClassifCcation of Diseases. Adapted (ICDA) (39). Deaths were catego- rized as iscbemic heart disease (ICDA 410.0-414.9); cancer of the trachea, bron- chus, and lung (ICDA 162-163); chronic bronchitis, emphysema, asthma, chroni( obstructive pulmonary disease (ICDA 491- 493); and all causes. A death certificatE diagnosis of ischemic heart disease was val idated by interviews with next of kin, phy sicians, andJor hospita2l records in 85 pe: cent of a subsample of this cohort. Proce dures used~at the time of the survey and fo: follow-up have been described elsewben (40-42). After ezclusion ofwomen who had a prio 2023511723

Helsing, K.J., Sandler, D.P., Comstock, G.W. and Chee, E., "Heart Disease Mortality in Nonsmokers Living With Smokers,'"' American Journal of Epidemiology 127 (5) : 915-922, 1988. In 1963, a private census was taken in Washington County, Maryland, at which time information was collected on smoking habits and a variety of other variables. Death certificates were monitored for the subsequent 12-year period, ending in 1975. The study itself focused on white nonsmoking men and women aged 25 or over who were avai.T_able during the follow-up period. ETS exposure was based on the presence and extent of smoking by other persons also living in the household~. The endpoint data concerned deaths from "'arteriosclerotic heart disease," which includes coronary heart disease. Based on 1358 deaths from arteriosclerotic heart disease, Helsing, et al. reported statistically significant risk elevations in both sexes associated with household exposure, after adjusting! for age, marital status, years of schooling, and quality of housing. For men,, the relative risk was 1.31, but there was "little evidence of a dose-response relation." (p. 915) Among women, the relative risk was 1..24, and a statistically significant dose-response relationship was also reported. Criticisms 1. Attempts to estimate ETS exposure from data on~ household smoking were particularly inadequate because the data

PASSIVE SMOKING AT7D iSCHEM'iC HEART DISEASE history of heart disease or stroke or who reported that they currently or formerly smoked cigarettes, there were 695 currently married' nonsmoking women who were di- vided into three mutually exclusive groups based~ on their husband's self-reported smoking status at the time of entry into the study- never, former, or current smokers. Length of follow-up was virtually identical in aIl' groups. Differences in age-specific and total mortality rates were tested for significance by Fisher's exact test (43). Mortality rates were then age-adjusted by 10-year intervaTs„by the direct method and with the total study population~as the stan- dard The Mantel-Haensrxl test was used to compare age-adjusted rates (44). Coz's proportiona] hazards model (45) was used to adjust cumulative mortality rates and relative mortality risks for age, systolic blood pressure, plasma cholesterol, obesity indez, an&duration~ of marriage to current spouse. Regression coefficients were esti- mated by the method of maximum likeli- hood using a BMDP program (13MDP-2L) (46). Since we were testing previous find- ings concerning the risk of passive smoking, stat'istical significance was assessed at one- sided p levels of <_0.05 and 50.10. Since probability vallies from the Coz model are base& on asymptotic normality assumptions, the values must be inter- preted with caution when cell frequencies are as small' as those in the present study: The Coz regression was performed as a means of summarizing the results and con- trolling for simultaneous variation in pos- s1ly confounding risk factors. I RESULTS Characteristics of the 695 currently mar- ried women aged 50-79'years who reported thar they never smoked' cigarettes were ,1aAy7v-,ul according to husband''s smoking s-tab.as'at the initial examination (table 1). Women whose husbands never smoked or were former smokers were on the average older than wives of current smokers (p <_ 0.05). Wives of never smokers had been 647 married lbnger than wives of currentsmok- ers (p 5 0.05). Although other differences were not significant, wives of nonsmokers tended to have higher systolic blood pres- sure and were slightly heavier for height. Plasma cholesterol did not vary signifi- cantly accordicug to husband's smoking his- tory. Among nonsmoking women, those mar- ried to former or, current smokers had the highest age-adjusted death rates from is- chemic heart disease (table 2). Nearly one third of the age-adjusted mortality in women married to former smokers was at- tributable to ischemic heart disease. There were no deaths from bronchitis, emphy- sema, asthma, chronic obstructive pulmo- nary disease, or lung cancer in womenmar- ried to never smokers, but there was one death from lung cancer in the wife of a former smoker and one death from~chronic obstructive pulmonary disease in the wife of a current smoker. Age-adjusted all-cause death rates were higher in wives of current smokers of 21+ cigarettes per day compared with those of smokers of 1-20-cigarettes per day (table 3), but this result was not statistically sig- nificant. After adjustment for age, systolic blood pressure, total plasma cbolesterol,, obesity index, and years of marriage, the relative risk for death from ischemic heart disease for women married to current or former smokers at entry compared with women married to never smokers was 14.9 (p _< 0.10). The regression results showed that systolic blood pressure, which was on the average 3.$ mmHg higher in wives of non- smokers, significantly (p < 0.05) increased the risk of fatal ischemic heart disease. Women married to former smokers were not at excess risk of mortality from all causes (table 2). Because of reports in the literature of increased mortality during widowhood (47- 50), we examined whether bereavement might have explained the excess mortality in wives of current smokers. We reanalyzed -

THEME 95. SESSION' 37 COHORT STUDY 1141 li( i A( I f 1N`il 11(' Ifl i'A'a:1I VI 'i^1111t I lY{i I II G`flli'('U11`~ I II Ali 1 I1 nO l rllrtl S' Aii ~1IIIH N111-I)AY AI)1!t Nl 1~ 1''i IN' i']11i II (11iN(A. larrE•r,cr I f3u#' It:r Adventi: t 4iE•:alt',h Dcp:mluwul, N(l Itox 14, (:nrckorn, Now `'>tnrFhr WAIe;;:, 2072 Aust.ralia The relaiti'on,hilr nf p~tssive smnkCny tu ttT r: incidcrrac ul r•anccrrs, fatal irrchemic hcart. disease and a1l nutural causa mcrrii among, Cal'ifinrrrian, SFVenth-dey Advc`ntia:, wnt; invcatigirtGd in 1'7F1Fi. frum lhC 3~ 1" ~ yJbjpctu nC 1he Arlvorrl ir:l Nr:rl ll,i SturiY rcahnrl ( 15t7fi-1c)f3Z) r lwq sr:b-clruu;rs werr. :;cJr-rtcd In c:vulu:rtr Ghe rn:;car'cnc tlur••,:l iurrn. Onc, the spouse pair5 rutrnr!', rrurr.i:a.rc{ crf 11,i mrrrrrc:cl crrulrlTttic .r.rnrrd was rr r}rnup of 6,467, ::rrbjrct::;, rcli tcr ;r;c the AttEiM0f1 c-rrhronl, whn, wcrr, inv»lvr.d in rr r.urarrtrrrr:nt :rir prrlIul rnrr ::tr,rty. fullnw-ulr f'ut :fsf:crt;riruocnt nt cruuct:r jut•jdi:nrr. .rnd n,ur'ii was, trrurr 1976 to 1982. Passive smoking exhu::urc for the "spouse pairn"' was based on the hu.:,band's srnoking stalus in marriaye. For the AHSMOE cohort Environmental Tohacrc, Smnkr (I'15) exposure wa:r based on the number of yeary livecl with and the rnunber of ycars worked with a smoker. f or nUn-mmnk iii fcmilliP.i nf 1•fhQ fijlflllSC palr:i tiVhVI'tr age-adjustedl rete raticr.m arie] (9'a % C.1.1 For each nulrcrnre reprc.r.nt those fcmalc5 married ln a smuker rnmlparvd to those VrmAler, married tto a non-smoker. l rmrl ranrr•.r• ItH : Z'.111' ( n. 39-H . 7`I ), a l l :;mok f rrq rrlated cancers iM = 1.22 (F1.G1-2.A4); enrvi'craal c:rncc~r fiit _ 4.f3A ('1i.33-17.6f,) srnct t+l l rrK•iclr~nt c:rrrt•cr!: {t!i _ 1.21) (f1.')G-1.'j4). I nr !'nrralr:•:; marrir:d Lu c•r,rrrul :rmrrkrrr:r I lrr.rr w:r:r itrrrcarc:r:cd r isk for fJCal 1H0, RR = 1.411 (t1.51-5.84). Nh efFect wu:: ubserved fvr all natrrral' cause mortality. tior the AtISMOG cohort the results were less consis- tent by type of exposore mr.;isure and outcome. The small number nf cane; for some oirtrnmes and' the probable misr.3assification of pas:;ive smoking exposure limili the ability to achievc conclusive results. However, the rssults indicate on adverse effect for F1S r.xposure and are consi'stent with uthcr reported results. C1~~s~~~1 ~~ ~1\ ~--~-ti l 6 1G u C C C C, Vi~ \A p(-tVL--,

920 t K~- 17 I_ HEISiNG ET AL .~ w oo' o0 0o w S N f~~ H42 w w w.. wN ~C www w00 .~.~w 3 ~ f.~ ~ M ! O, ~ ~2 2 429 Bi 'SE w 46 w ~ r ~P1lJ ~~ iCi'S FUR R'~ wwN w M~. C O~p f~ !F !~ ONN.. iVrrrJJJ.n NG~ l~'J, ~10 O .. w e- ee' oo wo' : .t ~ ~ ~. ! .~.. ~..: ~.~~o. .:...... w~w w~~ i't' ~ C C C O(~ < 6p Np~'.rp p~. O n F N'C ~ E O f N g~n ee~~ SH S8 -_. 2402 n°_ tixx 11 ~f g-=l m= la: III a o^ % e11 O!: o!: r

~ Lung Cancer: I Causes and Prevention Proceedings of the lnternotloncJ Lung Cancer Update Conference, held In New OrJean; Louislono, March 3-5, 1983 Edtted by Mer1e Mizell and Pslayo Cocrea ., , i/Lu~w CoMco..- S..vt ~ cl I JQ S b..~G l~"r\_ . Qa S< \1 • 4 ~ N ~ tn 0

socioeconomic differences in the use of charcoal or kerosene stoves and other cooking habits, which may involve exposure which could confound any possible effects of ETS. 4. The population studied was unrepresentative of Japanese society, in that it was based primarily on an agricultural population. 5. Inaccuracies in estimates of ETS exposure may have occurred from potential misclassification of the wives' hr«okina habits.

648 GARLAND SrAL TAacz 1 Chcracteristia of nonsmoking women occ»rdinj to husband i cigarette smoking rtabu at entry, T972-I974 Hu.band. -mokint .um VrJ.'s d•a!![Serfsi70 Never (n - 203) Form.r (A - 395) Ctirre6t 40% - 97) M.an S.tand.rd deviatioa Meaa 2 s4nda:d darinion IYfaan S VAndard d.viat~on AP 64.6' :t 6.7 65.4' ± 6.9 62.1 2 7.4 Years of marriage 36.0' = 12.5 34.7 t 13.6 32.4 t 12.4 Systolic blood preasure 140.1 s 22+2 1387 :t 23.1 136.3 :t 20A Obesity iede: 3.50 s 0.58 3.43 t 0.49 3.41 ± 0.45 Plasma cholesterol 225.7 t 36.1 226.2 s 41.0 22fl.7 t 34.6 ' Signi6cantly greater than for wives of currrnt smokers at p S 0.05. Tast:e 2 Age-apecitic and age-adjusted 10-year morrelily rotea, 1974-1983, in nonsmoking monun occordind to husband's cigarette smoking status at enrry, ,1972-1974 Hi+sLaad'a smoking .ucus Ap poup of i Ne.+er Former Current w (7..rs) No. of deatha Po*luion at nak ~ No. of deaths Populatioa atri.k % No. of' dsstho Population at rn.k % Isebemic besrt d'uea.e 50-59 - - 0 41 0.0 0 62 0:0 0 34 0 0 6049 0 116 0.0 6 192 3.1 1 46 . 2.2 70-79 2 46 4.3 9 121 7.4 1 17 5.9 CrtAe rate 2 203 1.0' 15 395 3.8 2 97 21 Ase-adjussed rate 12t 3.6 2.7 All ntres 50-59 1 41 2.4 3 82 3.7 3 34 8.8 6049 12 116 10.3 21 192 10,9 6 46 13.0 70-79 9 46 19.6 21 121 17,4 3 17 17.6 Crude rate 22 203 10.8 45 395 11.4 12 97 12:4 Ace-adjusted rate 11.0 11.0 13.3 ' Io+er (p S 0.05) ~than combined rate for .vivea of current and former, ssmokers. t Lower (p s 0.10), than combined rate for wives of current and former smokers. the data excluding atl'deaths ( n= 29) which occurred at any time after that of the hus- band and observed no change ihthe relative mortality risks from ischemic heart disease or from all causes (not shown). There was therefore no evidence that bereavement fol- lowing the death of a spouse caused the excess mortality. DISCUSSION In this population of nonsmoking women aged 50-79 years, those married to current or former cigarette smokers had an elbvated' risk of death from iachemic heart disease compared with wives of never smokers. Furtbermore, the only two deaths attrib- utable to lung cancer, bronchitis, emphy- N sema, asthma, or chronic obstructive pul- monary disease in nonsmoking women ~ were in women married to current or former ~ smokers. Although we followed 695 women for 10,*e& years and observed: an adjusted relative risk of 14.9 for ischemic heart disease in non- ~ smoking wives of current or former smok-~ ers, the total number 'of deaths was rela-

Hirayama, T., "Lung Cancer in Japan: Effects of Nutrition and Passive Smoking." In: Lung Cancer: Causes and Prevention. M. Mizell and P. Correa (eds.). New York, Verlag Chemie International, Chapter 14, 175-195, 1984. This was a prospective study of a large group of men anc3 women from aged 40 and over in Japan. The participants were first surveyed in 1965 and then followed from 1966 through 1981. Of a total of 265,118 people in the study, 91,540 were nonsmoking women. These were classified according to the smoking habits of their husbands. Over the course of the follow-up, a total of 494 nonsmoking women died from ischemic heart disease, based on which a statistically significant relative risk of 1.31 was reported for women whose husbands smoked 20 or more cigarettes per day compared to women married to nonsmokers. The Hirayama study also reports statistically significant elevations in the lung cancer rates of nonsmoking women married to smokers. Criticisms 1. Important potential risk factors for heart disease were not controlled, such as systolic blood pressure and plasma cholesterol. 2. No information was collected on ETS exposure outside of the home, such as in the workplace or elsewhere. 3. The study involved a disproportionately large number of individuals of lower socioeconomic status. In Japan, there are

922 IiE1SIhIG ET AL. 12't1112 & Hie.xama T. Pa.aive ®okin` a new target of epidemioiogy. J Fsp Gia Med 1985;10:287-93. 9. Svendaen KH. KW1er 1., Naaton J. ff.fiects of yarive smoking in the Multiyle Risk Factor In, tervention Ttial. American Haart Association 58th Scientific Snaiona,1985: 10: Wor1d' Health Organization. Manual of the mter- national'statistical eL.dSeation of di..a.e, iskju- ries and e.u.en of death. Vol 1. Based on the raeommendationa of the seventh r.vision oonfer- .nce,1955. Geneva. S..itserland, 1957: 11. F.Id.tsin MS. A binary variable multiple se;re.- aion mat6od of analyzing factors affecting peri- natal mortality and other outooma of pr.gaancy. J R Stat Soc 1966;129:61-73. I2 Shab Fl{, Abbey H. Effects of some factors on neonatal and yo.t-neonatal mortality. Milbank Mem Fund Q 1971;49:33-57: 13. US Department of Health, F.dueation and Wel- lare. Smoking and bsalth: a report of the advisory committee to the Surgeon General of the Public Health Servioe. Waahington, DC: US GP0.1964. (DHEW publication no. (PHS)1103).

PASSIVE SMOKING AND ISCHEMIC HEART DISEASE 64 9' TAa1.E 3 Ten-ymr al!-ocuse nlarsa!!ry mtes in nonsmohing, asvmen married to current srnokers, acroording to not supported by comparisons of obesity, plasma cholesterol, and'systoli'c blood pres- sure, all of which were similar or lbwer in number oF cigorrrres per day nnoked by /uu6Cnd No. of °9WR°ft ?i f Popu- Crudr Ayr-.djustrd• per day o. o d h Ltion Asatb deatb nte smak.d .at s at risk rate (%) (%) 1 by bmband 1-20 9 72 12.5 12.6 21+ 3 25 22.0 21L1 ' Adjusted for age by the direct method .vitb the total population at risk as the standard tively small, and the results must be con- sidered provocative rather than definitive. Nevertheless, we conclude that the associ- ation is real for the following reasons. First', it appears from the data (table 3) that a dose-response relationship ~ exists between quantity of cigarettes smoked by the bus- band and the age-adjusted mortality rate of the wife. Second, the association of is- chemic heart disease death with smoking by the spouse seems biologically plausible since carbozybemoglobia concentration doubles in the blood of nonsmokers exposed to smokers in a poorly ventilated room for two hours (51), moderately el'evate& room levels of carbon monoxide can precipitate attacks of angina pectoris in persons with preexisting disease (7), and elevatiom of carbon monoxide and carbozyhemoglobim have been shown to decrease cardiac con- tractility and to:raise left ventricular end- diastolic pressure in persons with cardio- vascular disease (8). Other explanations are possible (e.g., dif- ferent smoking patterns in men with chron- ically i]l wives) but seem unlikely, in that we excluded from the analysis all women witn; a history of cardiovascular disease. Widowhood, more common in the wives of saiokers, could have resulted in increased 6sk of death for these women because of t-he s>•c:alled "broken heart" syndrome (47- 50); however, bereavement was unrelated to the excess mortality in this cohort. Al- ternatively, cigarette smoking by a husband could reflect an otherwise less healthy life- style shared by the wife; this possibility was wives of current smokers compared with other women. We should'also note that the results of this study are confined to passive smoking exposures in the marriage in effect' at the time of entry into the stud'y, and exposures during previous (or subsequent)) marriages would be missed: This would tend'to have a generally conservative effect on the results. To our knowledge, this is the first report of an increase in mortality from ischemic heart disease due to involuntary smoking. We hope that others will ezamine their data to determine whether this effect is present in other populations. If this association is confirmed, a strong public health argument exists for prohibition of smoking in en- closed spaces. Legislation is presently un- der consideration or in effect in manyst8tes and localities to this end (5). RLfIIlBNclS 1. Shepard RJ! Tbe n.ks of passive smoking. New York: Oxford University Press, 1982. 2. Rylander R; ed. Environmental tobacco smoke effects on the smoker report of a workabop. Ge- neva: University of Geneva, 1974. 3. Schmeltx I, Hoffmann D, Wynder EL The influ- enae of tobacco smoke on indoor atmosphenx. L An overview. Prev Med 1975;4.'66-$2. 4. Hoegg UR: Cigarette smoke in closed places_ En- viron Health Perspect 1972;2:117-28. 5. White JR; Froeb HT. Small airways dysfisnction in nonsmokers chronically e:poaed to wbaox smoke.,N Engl J~Med 198(%302:720-3. 6. Kaufimann F. Tessier J-F, Oriol P. Adult passive smoking in the home enviivnment a risk factor for chronic airflow limitation. Am J Epidemiol, 1983;117:269-K. 7. Aronow WS, Kaplan MA, Jacob D: Tobacar a precipitating f.coor in angina pactoria. Ann Intern Med 1968;69:529-36. 8. US Department of Health, Education, and We)- fa,re, Public Health Service. Tbe health conse- quences of smoking. (DHEW publication no. (CDC)76-8704). W.shington„DC: US GPO, 1976. 9. US Department of Health and Human Services, Public Health and Human Services, Public Health Service. Surgeon General. The health conse- quences of smoking: cancer. (DHHS publication no. (PHS)82-50179): Washin;ton, DC: US GPO, 1992. 10. Libow M, Schlsnt RC. Smoking and beart disease. l.n: Yu PN, Good.vin JF, edc. Progress in cardiol- ogy: Vol 11. Philad'elphic Les & Febi,ger, 1982:131-61. 11. Lefcoe NM. Ashley MJ, Pederson L,L, et aL Tbe

t Yatsrials aaa xethods 6ubjects consisted of patients hospitalized betwesn 19flS-1987 and diagnosed as having coronary heart dlsease and myocardial infarction. They were matched employing the ls2 method as follows: those who were admitted because of possible coronary heart disease and were later confirmed by coronary arteriography to be normals; patients with endocrine dysfunctions but free of CHDs; and people randomly selected from the population. Thus three groups were included in the present investigation: Group 1, thoss hospitalized and diagnosed with Cf3IDs or myocardial infarction; Group 2, those hospitalized with endocrine problems but having no symptoms of CaDs, and Group 3, normals from the general population. Each of the subjects in the thres groups was interviewed using a standardized questionnaire. Some of the questions addressed included : subjects and the spouses smoking history, ths age at which smoking began, the average daily cigarette consumption. Active and passive smoking were dafined as follows : 1. Smoking at least one cigarette per day for a period of at least one year. The spouse is dofined as an ax-smoker if he has already stopped smoking at least 5 years at the time of interview. 2. Wife who is a non- smokar but has lived with a smoking husband for at least 5 years is classified as a passive smoker. 3. If husband is a smoker before marriage, the wife exposure begins at time of marriage. Alternatively, the wife can become exposed after marriage if the husband picks up the smoking habit after marriage. Total exposure time is determined by divorce, death of husband, or when the husband quits smoking and becomes an ex-smokQr. 4. Single female is considered to be equivalent to a female without a smoking spouse. To verify the accuracy of the data collected by the structured interview, tape recording was used and randomized re-interview was performed. Subject group consist of 34 casas (22 cases diagnosed with CHD, and 12 cases diagnosed with myocardial infarction). Control group consist of 34 hospitalized subjects (with 13 suspectsd of CHDa but later confirmed to be normals) and 34 randomly selected matched for race, occupation, residence and age (+/- 5 years). Multipla regressional analysis was performed and the data analyzed suing a 8un-68000 electronic calculator.9 Results i. Coaparison betrssa the *vDject and the Comtrol Qroups No significant differences exist between the two groups in regard to age, education, the marriaqe age. The mean ages of the diseased and control groups are 53.714.28 and 52.9315.24, respectively (t-2.282, ps0.05)

II6 Taksre Mrarano Introduction The mortality from lung cancer has been ibceasing rapidly in Japan (Figure 1). The number of deaths among males was 520 in 1947 and 17,555 in 1982, the wr- ttsponding number for females was 248 and 6661. 'Ihere esrists lGttJe sign of a slowing down of the rate of increase, and the number of deaths from lung cancer are cicpected to exceed the number of deaths from tttomach cancer in the near future. In parallel to this trend' the number of cigarettes oold in Japan also has been on a sharp rise (Figure 1). The random sample survey conducted by the Tobacco Monopoly Corporation in 1982 revealed that currently a 70.1 q6 of adult males and 15.4% of adult fetnales smoke in Japan. 'Ple purpose of this chapter is to study the causative factors of lung cancer in Japan with special reference to the effect of passive smoking relative to the effect of aictive smoking. The possible influence of nutrition, Q-carotene-rich green-yellow vegetables in particular, on the risk enhancing effect of active and passive smoking also is studied. Methods The materials of our ongoing large-scale cohort study for 265,118 adults aged 40 years and above in Japan were analyzed in detail to discover factors altering the Sh., W.sa ...c *I"-Y r~.r Sion w.r .a.i. 111.0110 a/.1a a.ar ao.a. «n.~ i IRS . M{.~ l A• t,f/ {/st S.r N0! U,1H M.V N Lia a.li f.f7i .1JU &aY Figure 1. Trends in agarstte oo/uumption and lung cancer duths in Japan (1'950-1981).

PASSIVE SMOKING AND ARTERIOSCLEROTIC HEART D1SEA3E 919 TAs[.e 3 DiKribution of midpoint population o/Toiiiw qBed L7B rcare who neuer rmokad, by scz,,pererntqp espo.ed to smoiee at home, and'demoBraphic charncteristia, Washington County, JKD, 1963-1975 Men woman C6uaer.ristic Na x spo..d in the Lomr Na % ezFa.d in the bome 3,454 29.5 12,345 66S A4e (yrus) in 1963 25-44 1,502 30.0 4,618 72.0 45^54 731 34.3 2,553 72.1 55-64 554 28.2 2,472 82.8 65+ 667 24.4 2,702 5fl:5 Marital isttt~u Married 2.929 27:2 9,033 75.7 Other 525 42.7 3,312 37.5 Gr.des of school completed 0-8' 1,578 27:0 5,589' 62.7 9-11 604' 29.4 2,455 70.0 : 12 862 31.7 3,158' 68.6 13+ 510 34:1 1,143' 60.6 Housing index 0-7 594 33.7 2,238 68.2 6-10 2,860 28.7 10,107 64.9 • Includes partieipanta for whom grades of school completad was not know n. shown, death rates and relative risks were also calculated for heart disease deathss coded as a primary cause or a contributing cause of death. A total of 461, nonsmokingg men and 1,281 nonsmoking women had arteriosclerotic heart disease listed on the death certificate. ©f these, 80 per cent of men land 77 per cent of women were consid- ered to have heart'disease as the underlying cause of death. Results were similar whether or not heart disease was considered by the nosologist to be the underlying cause of death. For example, the adjusted relative risk among exposed nonsmoking women compared with nonexposed women was 1.2 for heart disease listed anywhere on the death certiFcate and 1.1 when heart disease was on the death certificate but not consid- ered to be the underlying cause of death. For males, the corresponding relative risks were 1.3 and 1.4. DiscussioN The findings of this study tend to con- firm those of Hirayama (8), whose relative risk from ischemic heartt disease was 1.3 for nonsmoking women married to smokers; our relative risks, however, are consider- ably lower than those of Garland et al. (7) ~ and Svendsen et al. (9) and higher than those of Lee et al. (4). There are a number of strengths in this study. Information on smoking was col- lected for each person in 1963, and follow- up procedures were the same for everyone. Some potential biases were thus avoided: those involved in asking people (or their family members) ~ about prior smoking hab- its after an illness or death, when recall may be colored by an unconscious search for any possible cause of the illness, and those involved in selecting controls from hospital populations. Furthermore, smok- ing histories were recorded prior to publi- cation in 1964 of the Surgeon General's first report on smoking and health (13) and the subsequent increase in concern about smoking. Obviously, the home is not the only place where nonsmokers may be exposed to to- bacco smoke. Any association of household passive smoke exposure with heart disease mortality may, in this study, appear weaker than the actual association to the extent

CHAPTER 14 Lung Cancer - In Japan: Effects of Nutrition and Passive Smoking TAKES}it H(RAYAMA Epidemiolosy Division, Natiorul Canca Genter, Rmrcf 6atirure. T.ukiji 5-chome, Chuo-ku, Tokyo 104, Japan ABSTRACT Lung cancer u on a sharp increase in both men and women in Japan. Nonsmoking..ires with smoking husbands were found to carry an elevated risk of lung cancer and ischernic heart disease by a large•scale cohort study„ 1966-1981, for 265,11'8 adults in 29 MealSh Center Districts in Japan, the risk steadily going up with the increase in number of cigarenes smoked by the husband. In major cancers other than lung, no such risk eltvacan was observed. A nonsmoking husband with a smoking wife also showed an elevated'risk of lung cancer. The risk-reducing efTect of daily intake of green-yellow vegctabl6 on lung cancer was observed for passive smoking just as for active smoking. T}tose women eating green-yellow vegetables daily showed a significantlr lower risk of lung cancer fnom the passive influence of their husbands' amoking. Such risk reduction was not obxrved'for ischemic heart diaease. The observed results suggest that the inlluence of husband's smoking on nonsmoking wives ia raising the risk of lung csnou is as a cancer promoter rather than a cancer initiator. This pro- moter hypothesis may explain why such continuous but low-dosc exposure of passive stnok- ing, which starts after adult age is reached, signifirsntly devaces lung onesr risk in mon- smoking wives. /Ce~ Words: Japan, mhort study, passive smoking, lung caacer, iscbemie 6eart disere, =reen-yellow vegetables, r4-carotme, promoter, prc+mota-iahibitor . O loaA V.rbp dV+. r...ehs~ rc. ksV Corw Caa ore A.w+ias • V5

ANiJIICAN JOURNAL or ErIDLNioLOGY Vol. 1'27iNo..5Geqyrisat O 1988' by T6e Johns Hopkin. Univer.ay School 'of Hygi.ae and Public Health Prin+ad in U.S.A. Allirighu reservad Original Contributions HEART DISEASE MORTALITY IN NONSMOKERS LIVING WITH SMOKERS r K J. HELSING: ' D. P. SANDLER,'' G. W. COMSTOCK.' rwD E. CHEE' Fieliing, K. J. (The Johns Hopkins Training Center for Public Health Research, Hagerstown, MD 21740), D., P. Sandler, G. W. Comstock, and E. Chee. Heart disease mortality in nortsmokers living with smokers. Am 1 Epldentlol' 1988;127:915-22. A private census of Washington County, Maryland, in 1963 obtained knforrtnation on smoking habits of all adults in the census, and death certificates of ati residents who died in the next 12 years were coded for underlying cause of death and matched to the census. Among the white population aged 25 and over, 4,162 men and 14,673 women had never smoked. Jn this group,, death cates han arteriosclerotic heart disease were significantlyy higher among men (relative Ask (RR) = 1.31, 95% confidence Interval (CI) 1.1-1.6) and women (RR = 1.24, 95% Cl 1.1-1.4) who ived' with smokers in 1963, after adjustment for age, martbl status, years of schooling, and quality of housing. Among women, tfie relative risk increased significantly (p < 0.005) with increasing level of exposure; among men, there was tittle evidence of a dose-response reiation: The relative risks for aiortamokers who lived with smokers were greatest among both men and women who were younger than age 45 in 1963, but the number of deaths in these groups was small, and confidence intervais were broad. These results suggest a em.M but measurable risk for arteriosclerotic heart dissase among nonsmokers who live with smokersL heart diseases; smoking; tobacco smoke pollution The association of cigarette smoking with arteriosclerotic heart' disease deaths is well-known (1), and it is now increasingly suspected that the presence of smoke in the Received'for publication May 26, 1987, and in final form September 3f1; 1987. ' Department of E.bidemioloey„The Johns Hopkins University Sc6oo1 of Hygiene and Public Health, B1d+ timore„MD. ' EbidemioloQy Branch, N'ational Institute of Et- vironmental Health Sciencea, Research Ttiangk Paric, NC: Reprint requesta to Dr. Knud J. Helain` The Jomns Hopkins Training Center for Public Health Researca. Washiagton County Health Department, P.O. Bo: 2067, Hagerstown.,MD 21740: This work was supported in part by' Contract 65?548 from the National iInstitute of Environmental Healtt Sciences and by Research Career Award IiL21760 from the National Heart, Lung, and Blood Institute. Data available at the Johns Hopkins Train- i-q Cender for Public Health Research in Haterstos9n, M0; made tliis study possible. -environment may pose a risk to non- w smokers. Evidence on the possible associa- tion of what' is called passive smoking with arteriosclerotic heart disease is as yet far from conclusive, and both the Surgeon General's recent report (2) and that of the National Research Counciliof the National Academy of Sciences (3) emphasize the need for additional studies. As pointed out by the Surgeon General, because heart dis, ease is so prevalent, even a small increase in risk associated with passive smoking could have a substantial public bealth im- pact. Some epidemiologic studies have been conducted concerning the possible associa- tion of arteriosclerotic heart disease with passive smoking. A recent case-control' study by Lee et al. (4) reported no consis- tent evidence of greater passive smoke e:- 915

THE MEDICAL JOURNAL OF AUSTRALIA Vol 154 June 17. 1991 TABLE 3: Passive smoking at work and risk of heart ariack or coronary death (odds ratios and 95% conlidence intervals [CI]) Nurnbers of suolOcts Cruoe Adlusted' Cases Controts' oods rauo(CI)' ooas rsrro (CI1, Men 1141101-6mo/cers Exaoseo 2" 7° No exaosed 48 t26 0 90 (0'S0:1 605: 0:45 (05t.1 78) El,,smoRers Exaoseo e• 85 0.9+ (0 56. 1.581 0.88 (0 e9 1.59) Na enooseo 55 100 . wpnen Non-sr*roliers Exoosaa 5 73 0 71 (Q ~1~e. 2:27) ~~ 0.66 (0 17.,2:62), No eaposed 12 124 E.•tvnoaers J:utoseo 5 20 115 (0 7 18) 29 221 (0 33.14 95) Na,eoosed 5 29 . . •pau NoT wwac awo oantO.+ea ru/Ir n .ne ...la.1& 4r.wV b~p.o a age No nmvv oft.ar•+or sarotinT. aeri .vwrc n.en ar.r d.v sxcrts we, non+wv anols nslo r a rwn ac.ne as +ro.m o er ude TABLE 4: Snwking behaviour and risk of weari attack or coronary death (odds ratios and 95% confidence intervals ICt)) Numbers of sublecls Crudi Adfuaudt Cases Contras" oads ratio odds ratio (Cn , Men Cunent stnokers 321 259 2.26 2 7142.07 3 53) E>•smoke^s 37a 123 1.60 1.25 (0 98. 1.60) Non-smoKers 197 356 1.00 1.00 Toui 895 1037 YMOrnm Cunem, smokers 127 168 2.95 A 7010 35 6 58). Easmo+as ' 86 t8s 1.52 1.51 (1 06 2.16) Non•smowers 174 6''9 100 1.00 Toul 387 103t ieus ra.nsr vrm - cnrx oons uen, 1r -J5: . a. •.' :.000:' .orne^ .- r'•6L r a• 1 ' P<0.001 •Dwts nOr<•GUlHroK .+awilv0w1e0 hilly n Inr /wF UOO4..tv. mfnpere0 Ine DXt4 ouHaOyMwN O.we fMR+Ylwel . n", nn"V.. Ku,aer. ur x9o la.e vea• wr• aamu nne r,•m.v M rnwrwa y'rreloon o or.r wo+sw•+c n.en aw..e Orw ppleqs wnln rlprTiYfln aDOU:: nM1lOrr'd tyanr O4MieMe +bu0en n AS talYe ratios (4.70 for women and 2.71 for men) pOputation-based with almost complete and ex-smokerS and' people exposed to ascertarnment of all cases of heart attack passive smoking at home having lower, but still elevated, odds ratios compared with nOn-smokers. Fibrinogen concentrations for partici- pants in the risk factor survey (i.e., control subjects only) are shownin Figures 1 and 2. Women had consistently higher mean values than men. Mean fibnnogen eoneen- tratipns were highest among current amokers, intermediite among ex-snsokers and: lowest, for non-smokers. People exposed to passive smoking had higher levels tnan those not exposed (axcept tor passive smoking at: home /oa women). The -jit(erences were not statistical(y signincartt (due to high variability in the measure- munts)! but were consistent with a dose- response relationship with ciganne smoke. Discussion The strength ~ of tfwis study is that d was S/AOKSVG aENAVIOUR .. Mon.n...n Ea enrrels C,.nv. sMe.ue FASSNE SMOrcNG AT~ HOME rlenynYare : 795 Or oOrOnary death in the study populit/or1." A1s0 the COntr01l gr0up was Obtalned by randbm sampling from the same popula- tton. Be(ore consldering the magnrtude of the efteas shown, however. it ts necessary to consider lactors whlchi might have affected their accuracy: A potential source of bias in the case- control compansons was that information on smoking was unobtainable for many Case subjRCts who had di.d. Among tatal Case aub)eCxs 1orwhom thif inlomtation was available. however, the patterns of smoking (Cun•ent ambker~ ex-smoker or r10n-smoker) antl psssive smoking were not different fiom those for non•fatal casc subjecta so it is p(ausible that tatal cases for whom infortrution was unobtainablb also had similar panems of exposure. Further, Mschlin et al. have suggested that smoking habits of people who have died are accurately reported by relatives and other informants." T'hus any bias caused by missing data for cases would probably be small. Another source of bias is that people who respontl to risk factori surveys are kss likety than non-respondents to be smOkers." In our study non-respondents to the main survey (which included visiimg a study antra and having physiul measurements taken) were asked to reply to a brief mailed' puestionnaire, and some people who did not complete the brief Ouestuonnaire were visited at home and interviewed. For men aged 35-69 years. smoking prevalence rates wert: 24% current Smokers. 40% ex- smokers and 354b non•smokers for the main respondent group. compared with FI Yyno9en canrtentratlonig/L) r-~ r--. ..+r Hr Ea~ln.as: r..... ~-r ne.. PASSIVE Sr'sGKNG AT WORK IYonFe/11o11eR ". .f..... ~ fIGUR[1. iD-o¢e- eo-C" /rar.iOm ImOftg rnen n e Orr^. rnw-r saMye rMean Cbn-Vn_ s,... E..nl..ers . .~r nara- 1p -1 a, oeww.peo 50 Yyrryrnn o0or inassnGess p• 25 I•D"^'1 cc"na^a' ^re"a DefeO O. ft1~0aro N1d7 MM' s..rw r- ~~ 01 CO+Iry-Ce W 41{.'IrernW-*C oara I 2023511716

Ai+nucAN ' JoURNxli or EtIDEYtOLOGY VoL 121. No. 5 Copyrieht C 1'965 by'I'Ae Johns Hopkins UnivcriKty School of Hyrene and Public Healtb Prvuad in U.SA: f.ll *iibu :vaerved EFFECTS OF PASSIVE SMOKING ON ISCHEMIC HEART DISEASE MORTALITY OF NONSMOKERS A PROSPECTIVE ST4JDY' CEDRIC GARi.AN.., ELIZABE"I'H BARRETT-CONNOR, LUCINA SUAREZ, MICHAEL H. CRIQUI, ru+a DEBORAH L. WINGARD Garland, C. (D'rv: of Epiderniology„Dept of Community and Family Medicine, U. of Califomia, San Diego, La Jolla, CA 92093);,E. Barrett-Connor, L Swrez, M. H. Criqui, and D. L Wingard. Effects of passive smoking omischemic heart disease mortality of nonsmokers: a prospective study. Am J Ep/demb/ 1985;121:645-50. The mortality attributable to ischemic heart disease as a result of cigarette smoking is greater than that due to lung cancer. Between 1972 and'1974„ in a prospective study of a community of older adults In southern Califomia, llhe authors tested the hypothesis tAat nonsmoking women exposed to their hus- band's cigarette smoke would have an elevated risk of fatal ischemic hear3t disease. Married women aged 50-79 years who had never smoked cigarettes (n = 695),were classified'according to the husband's selt-reported smoking status at entry into the study: never, former, or current smoker. After 10 years, non- smoking wives of current or former cigarette smokers had a higher total (p S 0.05) and age-adjusted (p <_ 0.10) death rate from ischemit heart disease than women whose husbands never smoked. After adjustment for diffFrences in risk factors for heart disease, the relative risk for death frorn ischemic heart disease in nonsmoking women married to current or former cigarette smokers was 14.9 (p < 0.10). These data are compatible with the hypothesis that passive cigarette smoking carries an excess risk of fatal ischemic heart disease._ ischemic heart disease; longitudinal studies;,mortality; smoking, passive Although cigarette smoke contains by- drocarbons, nicotine, carbon monozide,. an&multiple carcinogens (1-4), interferes with pulmonary function (5, 6) and with cardiac function in persons with cardiovas- cular disease (7), and is a well established risk factor for emphysema (8), lung cancer Raceived for publication Au`nrt 23,,1984. '' From the Diviaion of Epidemiolo;y, Department of Community and Family Medicine, University of California, San Diego; La Jolla,,CA 92093. (Reprint requecu to Dr. Cedric GarLnd), This work .vas sapported by the Lipid Researr}t Clinics Piogram, National Institutes of Health Con- tract jlo. NIH-NHLBI-H1t-1-2I60-L; the National Iasti;ute of Artbritis, Diabetes, Digestive, and Kidney DiYeaee Research Career Development A.vard' Nb. 5 K04 : AJ+801063:02 (to Dr. Garland); and the Nauonal Ii?a.rt, Lung, and Blood~ lnatitute ResearcbCareer Development Award No. 5 K04 HL00946-03 (to Dr. Criqtu). (9), and cardiovascular disease (10) in smokers, the health effects of passive smok- ing are a subject of much controversy (1, 11-15): Nonsmokers in enclosed places with . smokers are regularly exposed to smoke (15-17), the concentration of noxious agents in the air exceeds that in inhaled smoke (1), and a significant amount of nic- otine is absorbed by exposed nonsmokers (18, 19). Recent studies suggest poorer pul- monary function in nonsmokers exposed to cigarette smoke at work (5), nonsmoking spouses exposed to smoking mates (6), and children exposed to smoking mothers (20- 2'2), and an elevated frequency of respira- tory tract symptoms in exposed child'ren (21, 23-25). Epidemiologic studies in 645

I 916 KELSnNc gr AL posure among 118 hospitalized nonsmoking cases than among nonsmoking controls hospitalized for reasons considered unre- lated to smoking. Gillis et al. (5) reported results of up to 10 years of follow-up for 8,128 Scottish adults aged 45-64 years who participated in a multiphasic health screen- ing exam and for whom smoking history of a spouse or partner was known. At the initial examination, nonsmoking women who lived with smokers had slightly more cardiovascular symptoms such as angina or abnormal electrocardiogram than non- smokers who were not ezposed, No such excess was reported for men. At follow-up, death rates from myocardial infarction for nonsmoking men and women married to smokers were midway between rates for nonezposed~ and' those for active smokers. The number of observed deaths was small, and differences were not statistically aig- nificant. Garland et al. (6, 7): reported a dose-response relation in women aged 50- 79 years between the amount their hus- bands smoked and death rates from isch- emic heart disease„ but the number of deaths was small, and~ the differences were less than statistically significant, despite a relative risk of 2.7. Hirayama (8) ~ reported in his 15-year prospective study, that there was a significantly higher risk of ischemic heartt disease among Japanese women whose husbands smoked as compared with those whose husbands did not smoke, as well as a significant dose-response relationn with amount' smoked. Svendsen et al. (9), in the Multiple Risk Factor Intervention Trial prospective study, found that non- smoking men whose wives smoked had roughly twice the risk of coronary heart disease morbidity and mortality compared with those whose wives did not smoke. Of particular interest is their finding of no difference between the two groups in blood pressure or cholesterol levels. Data from a private census conducted in 1963 and other records available in Wash- ington County, Maryland, were used to evaluate the heart disease risk associated with household smoke exposure among nonsmoking adults. The results of this 12- year follow-up study are reported here. MATERiALS AND METHODS In July 1963; a private census obtained data on an estimated 98' per cent of the households in Washington County, Mary. land. Information included sex, age, race, marital status, years of schooling, and housing characteristics for all 91,909 iuidi- vidtsals enumerated. Information on ciga- rette, cigar, and pipe smoking habits as well as frequency of church attendance was re- corded for each household member aged 161/i or older as of July 15, 1963: A follow- up of a 5 per cent sample of the households in the 1963 census was conducted in 1971 in order to assess the probability of still living in Washington County after, eight years. Since age, marital'status,, years of schooling, and frequency of church atten- dance were the only characteristics that showed aignificant' association with re- maining in the county, a probability of re- maining in the county was calculated for each adult in the census aged 25 and over based on those factors and was entered on the census tape. These probabilities allow the population remaining in the county to be estimated at any point in the eight-year period. Since only about 2 per cent of the noninstitutionalized 1963 population was black, the present study is confined to whites. A1l death certificates of Washington County residents who died between July 1963 and July 1975 have been coded as to primary, contributing, and underlying causes of death without knowledge of cen- sus data, and the information was entered on the census tape for decedents who were in the 1963 census. The Seventh Revision of the Irsternational CltrasWication of Dis- eases (1CD) (10) was used for coding causes of death; for this study, we used only deaths with underlying causes of death classified as arteriosclerotic heart' disease including coronary disease (ICD 420) and other myo- cardial degeneration (ICD 422); We algo analyzed deaths for which arteriosclerotic V

DSSCIIassaN To avoid and minimize bias introduced in studies using hospitalized subjacts, the present investi'gations compared the subjects groups to two control groups, one group consisting of patients hospitalized for reasons other than CHDs, and a second group randomly selected rrom the general population. Thaze two control groups are compared to the CHD-diseasad group. Investigations on the effacts of passive smoking in females are more difficult to perform than comparable studies aimed at the effects of active smoking, because the effects of passive smoking may be dependent on such factors as humidity, ventilation and other indoor environmental considerations. Studies to date have not been ab2e to produce a widely accepted standardized protocol for this type of inv.stigation. One of the methods which have been used to assess passive smoke exposure in females relies upon the smoking status of spousesfl`~~hich have been used in sevaral previous published reports. The method appears to provide a eartain degree of simplicity, f.asibility, and relative obj'eetivity., lamale passive smokars have an OR of 3-3.5 in getting CHD, with 95% CI greater than 1. The exposur. dose is associated with angina pectoris, in agreement with results of other investigators. The associations remain after adjusting for potential confounders, suggesting that there is a direct correlation between passive smoking and CHD in females. Additionally, our invaFtigationa also showed alterations in blood cholesterol and lipoprotein levels, indicating that an alteration in the metabolism of cholesterol and/or lipoprotein could contribute to CHD in female passive smokers. According to Scott et al.1, 85= of indoor smoke is due to sidestream smoke, which is known to contain a higher concentration of many toxic chemicals than mainstream smoke, and presumably exhibit a more pronounced adverse health effect. Previous studies have shown that an increase in blood COHb levels capabl,e of producing an obviously untoward effect in people with heart and lung diseases.' Arrownow studied 10 subjecta with angina pectoris, and reported a doubling of blood COHb 2 hours after exposure to indoor tobacco smoke in a poorly ventilated environment. These subjects also showed a 334 reduction in time of exarcise before reachi'ng a perceived exertion. The mechanism, however, remains to be investigated. In peoplets Republic of China, 33.884 of population aqQ>15 years are smokers and 614 of yaales regular smokers. The indirect public health eoneequencas of smoxinq has not received enough attention. Despite the limited number of eas.o used in the present N investigation which obviously have sevare restrictions, it suggests ~ that passive smoking is related to CKD in females. Thus, smoking N in public should be restricted ~ 'CA . ~ ~ ~ ~ ap

V8 Toksshl'Ffroyamo t+o be 18.396 lower in amokes who do not inhale compared to regular deep in- •"tts, and 48.9% lower in smokers of filtenip cigarettes compared to smokers of tttonfJtertip cigarettes, according to our cohort study. The risk of lung cancer in daily smokers also was noted to approach graduaAy that of nonsmokers with the ...Lpse of years after smoking cessation, risk difference diminishing by 41.6% in 5 years after stopping the habit. This strongly suggests the major part of the influence d.moking during adulthood is the prvnsoter action of subs:artca included in - mainstream smoke. s Effecfi of Nutrition on Active Smokers Daily intake of gmn-yellow vegetables, rich in A-canotcne, was found aignifi- cartt]y to lower the risk of lung cancer (7, 8), particularly when the totaJ amount of cigarettes ever:moked was less than 3W;000 (6) (Figure 3). No other dietary habit showed such risk reduction, Risk reduction after smoking cessation appeired to be more pronounced in case of daily consumers of green-yellow vegetables. Taking similar evidence in laboratory studies into consideration, a promoter-inhibitor in- teraction model' was conceptualized. . -„ ~ ... a s • w. . ..~+w. 1LL .. .JLIL.- - r. r. n L» I 11/1 .. •J. ... i.m •.w • -Sao r.IM I<s 211M .iti ~ 1~~. Iw+aa1 .n sIwot .. ~w .~~. ~ au. ..• s. nlf. s,J i. s tr r r / v..71.}. ~• P.F 1•.7 ¢-t l v. /l ~J OJ 11.5DJ .~ \ Y Figure 3. &andatdiaed mortaiiry rate for lung caneer by total number of cgurttes ever N cnoked' and by frequeney of green-yellow vegetabk intake;, males. (Pro•pactive study, ~ W 1966-1978.) I }"a ~ ~ 44 I

LETTERS TO THE EDITOR THE FIRST AUTHOR REPLIES The error to which Mantel refers (1) was corrected previously (2). The results of the study (3) remain the ,1aIDe overall: nonsmoking.romen married'to men who smoked had higher total (p s 0.05), age-adjusted (p 5 0.10): and multiple-adjusted (p < 0.10) rates of fatal iachemirheart disease than those married to men who did not. The findings have been replicated in women by Hirayama (4) and Gillia et al. (5)! and in MRFIT men by Svendaen at aL (6). Rzroutnctt 1. Mantel N. Re: "EHect+ of passive smoking on iscbsmie 6.art disease mortality of nonsmokers: a prospective swdy' (lstrar.) Am J Epidemiol 19d7;1PS.641. 2. Erratum. Am J Epidemiol 1985;1221112.; 3. Garland C. Barrett•Connor E Suarer L at al. Eff.eta of passive amoking on ischemic heart disease mortality of Cedric Garland Department of Community and Family Medicint Uniuersity oj CotiJorrtio. San Diego Le Jo11a, CA 92093 nonsmokers: a prospective study: Am J Epiiiemiol 19E5:121:645-50: t. Hiraysma T. Table 6: Mortality from iscbemir beart di.e..a in women by age group and'smokme habit of husband In: Pauive amokin` and lung cancer. Paper presenud.t the World Congress on Smoking and Hsaltd. W innipe{. Jdy 7983. 5. GilLL CK Hole DJ, Ha.rtborne VM, a al. Tbe effect of anvironmental tobacco smoke in two urban communities in the .ast of Scotland Eur J Resp Dis 19BA;65(Supp1 t33):121-6: 6. Svendsen KH, Kuller LH. Neaton JD. EQ.eu of psesive smoking in the Multiple Risk Factor Intervention Trial (MRFCIT)j (Abstract.) Circulation 1e85:72:I1]-53. :'EXCESS MORTALITY FROM STOMACH CANCER, LUNG CANCER, A SIS AND/OR MESOTHELIOMA IN CROCIDOLITE MINING DISTRI Permit us to SOUTH AFRICA' your attention to the following lahed in the Americon. Journal aspects of an article pui o/ Epidemiobgy on mo districts in South Africa (1 In the abstract it is atu ity in crocidolite mining ;~Tbese frndings...... are likely to be due to espos crocidolite during mining and mental contamination " In the case o South African or to environ- white females and'colbred females, most personnel w environmental exposures only, which is n from the authors' remarks on page 38. subject to evident Wliile the authors stnea that until 1977 as and/or mesothelioma were combined under IC U* 467; not a single case of asbeatosia u known to hav, been contracted by environmental exposure to asbes- tos. The investigations were based entirely on death certificates. The accuracy of death certificates has been questioned all over the world. In South Africa there is a speciallproblem in that in the rural areas of the Nort:hern Cape-and elsewhere in this vast co try-the bulk of death certificates of coloreds have been eompleted by medical personnel but by me of the South African police. During the ear, under review this may also have applied white farmers and their families. This pr Mr. Hart's statement tha females and colored fem subject to environme strengthens our dedi impact may have than occupational In the case of white most personnel were exposures only" (1) that "a major part of the through environmental rather, ure" (2, p. 38) j Our deduction 0 0 ently still continun according to in ''ea to the legal advisers of the South African M Cal Aasociation. In the South Ahican Meaoth 'oma Regiater, then was in October 1983 a total o,228 cases since 1956 of which 510 cases had no nown connection with aabestos. Some of these m be spontaneous casn (2). By March 1985, the to had increased to 1,459 and the number of "unkn " and/or spontaneous cues to 639, i;e., more th 50 per cent of the increase (J. C. A. Davies, tional Centre for Occupational Health, person communication)j RLrCRCNtaa 1. BotEydL. Irwit LM. StrebellPM. Excess mortality from swrpLch cancer, lung cancer, and asbestosis and/or mss- ot}iElioma in crocidolite mining di.tricu in South Afnca: H. P. Hart South Afriean Asbestos Producen Advisory Committee oz/Bua 10505 s-Y-z , ) 54. 7. NOTICE Tfiis materal' mey be pffltected by c0oyriBnt 1~w Ttle 17 U!S. CWjq.I riesburg 2000 Sot)k~ A/rica was based on the increased risk fo scosis and/or mesothelioma deaths that occurred ` r only for males but: also for females, who, according records, had not been employed on mines until 1950 d then at lower rates than males in most districta" (, .38). Mr, Hart does not cite a reference for his a ment J Epidemiol 1986:123130-40. iona) Centre for Occupational Health, annual i raport

hxtp C,oncer In Joporti Nutntfbrr ono Posshre Srr+oldnp V9 Passive Srnoking and Lung Cancer • In the present cohort study (1966-1981), 427 deaths from lung cancer in women were recorded during 16 years of followup (1966-1981). Of thex ++gmen, 269 wert married, and 200 of these also were nonsmokers. These casrs occurred among ` 9i„540 nonsmoking married women whose husbands' smoking habits wert studied. The risk of lung cancer was csrcfully measured, taking into mnsid'eruion possible confounding variables. There was a statistically significant increased risk in relation to the extent of the husband's smoking (Figure 4), which oonGrmed the .validity of previous reports (9, 10). The association was significant when observed -by age of husbands (Table 1, Figures I and' 5) and also by age of wives (Table 2). 7'he further detailed analysis on materials cross-tabulated' by age and occupation of the husband' also confirmed the association (Table 3): The husband's drinking habits were noted to have no effect in raising, the risk of lung cancer in nonsmoking wives (Table 4). Similar significant risk elevation of lung cancer with the inaesse in the eutenrof husband's smoking also was observe& with ischemic heart disease when observed by husband's age and occupation (Tables 5 and 6). The significant risk elevation of .tancer of the nasal sinus also was observed in nonsmoking wives with husband's smoking. The risk elevation of emphysema and chronic bronchitis with spouse's smoking also was ttoted with borderline significance. However there was no tendency of risk elevation at all in major cancers other than lung (total of cancers of stomach, cervix, and breast), the standardized mortality nte in nonsmoking wives being almost exactly the same regardless of the husband's smoking habit (Table 7, Figure 6). 2.0 1.5 1.0 Twt rE/GNTEDMIMT EfT11MTti Of (LS utt YTJo I" EI., 1•16 /S-1t 7D• . DAY mna.u"s sW1l.a wstr • t,us wcE.: M roruuT 100 : 915b0 s Figure 4. Age-standardized Tnortality rate ratio for lung cancer in nonsmoking ..ives by smoking habits of their husbands.,(Prospcctive study, 1966-1981, Japan.)

LETTERS TO THE EDITOR SOCIAL FACTORS INFLUENCING DISEASE INCIDENCE Ber (11 sutes.,'. .g pathways linking socioen- vironmen condiuonI and social .upport to physical health ouuo need to be more thotlghtfully e:- plored " Thie sta ent i~ parucularly applicable to Native Americans on rvauons where attitudn of the population toward th ealth care systems on the reservation have a profoun the ' pad on the ability of physicians and other he we providers to deliver a quality of inediul eare eo en.urate with their degree of espertise. Mott specificallg, as a pediatricien who nt two years on a resetvation. I was imptes.ed by the " known~ high incidence of acute and recurrent o media among the Native American children (2) 0 ®a the too often associated hearing deficita wit ubae- quent learning disabilities (3). Too often n ~ waa a lack of' parental compliance with prsesc ' medical regimens and routine follbw-up care mmendations for acute and recurrent otitis I believe a cause and effect relation esista betw the degree of paren- tal noneompilance with presatEibed medicaliregimens/ routine follow-up care creased incidence of turn, is known to disabilities secon heari.ng defici be achieved, media, it,i feel th mmendationa and an in- nt otitis media which, in related to subsequent laarning to significant,,terurrent, chronic If better parental compliance could e deleterious sequelae of recurrent otitu hoped, could be significantly eeduced'I1 the attitudes of any population toward  give •'health care system piay a significant role in det~rmining the ability of highly competent health care providers within a health care system to achieve  noteworthy frequency of paren piiance. Positive attitudes of given health care syatem increased patient and' turn, would~help dec of treatable patho ln tronclusio factors im likdih 541 d patient com- pulation toward a d probably result in ntal compliance which, in the frequency and seveeity es. he more one understands how social on disese incidence, the greater the that health care providers will be able to have~{more positive impact on a given population thus, generate a higher degree of patient/parental mpilance resulting in reduced' morbidity and' mor- tality. Rsrots>rcas 1'. IDan LF. Social net.wrk.. support, and health: takttt~ tFie t step dor.~ard' Am J Epidemiol 1986:123:559-62. :... Blue~to ~ CD:.. Reeent~ ad'vances inn the patbogensia, di- atnos~. an anaRement of otitis m.dLL Padutr Clia Ivon.h Am 1 :727~55. 3~ Paradise JL. Ou ' during early life: bow harardous to development'' P trw 198t:68iafiS-73. Albert F. icola Dwision oJ P rac Endocrirtology Statt/ord Uhitxrs Medical Center StattJord, CA 9+t,405 Editor's note: In aecordonee uriah Journal yolicy. Berk- nlan nVt aa*d'{)/ she WYhef to Rtpond to Dr, DiNieolo'i r, but.she chose not~~.to do so.~ RE: `EFFECTS OF PASSIVE SMOKING ON ISCHEJ1iIC HEART DISEASE MORTALITY' OF NONSMOKERS: A PROSPECTIVE STUDY' Garland et al. (1) reported initially that as a restllt of a near 10-year prospective study, with data analyzed by highly sophisticated statistical methods allowing adjustment for various factors, it was found that wives of current or former smokers hZ an increased relative risk for death from iscbemic beart disease of 14.9, highly suggestive if not nominally significant (p s 0.10). A subsequenterntum (2) states that the relative risk of 14.9 was erroneous and should have been 2.7,, p remaining at s0:10. Conclusions in the report were stated not to be affected, other valuss in the tables and elsewhere to be correct. However it was the 14:9'relative riak which was at the beart of the initial report. No other relative riska were cited in the neport. The 14.9 relative risk was repeated several times in the report and motivated the suggestion tbat legialation might be needed A nomig- nificant relative risk of only 2:7 hardly conveys the authority, for such action. Furtbermon:, I note that the authors give some justification for using one-sided p levela on the basis that they were testing previous findings. Yet in their final'.paragraph they state that to their knowledge, their report was the first to relate inereased' mortality from ischemic heart disease to involuntary smoking. In that case, p should be 50.20, not significant at all, and even less supportive of the naed'for action. Rncamcr, 1. Gsriand C. Banest-Connor E. Suarez L, at aL Eff.cn of pasnve smoking on ~ ucEemic bsut . dia.aae mortaltty of non.moken: a pro.p.eu.e study... Am JEpidemiol 1'985:121:645-50. 2. Erratum..Am J Epidemiol 1965:122:1112 Nathan Mantel i Nlathematiu, Stotistiu and' Computer Science The Americon UniuersiEy 8ethesdA MD 2081y N 0 T I C E This material may be protected by copyright law (Title 17 UiS. Cod4 t1Q ~M,°1. 1z~ 8 s4i' r °1 B 'z

1a0 Tokeaf+I 1&oyomo Table 1. Mortality rate for lung eancer in woroen by are group and by anoking habit of htuband (patient berself a nonsmoker): prospective study. 1966-1981. Japan' Husband s Nonsmoker W i *°°P No. Pop. 40-49 4 6.2" ' 50-59 lU 7 791 I 60-69 18 . 7.120 70-79 5 755 Total 37 21,895 'i1w .e:flited p~i sonau of rmr fuw and Ies•1.00 l.+ed 90% ooaMdMM ivnii. Flamel-H.reodt' - ..r-.a8p .lue Husband's smoki.a; habit Numbes ef cigare+ta a day Ea~ oker 1-14/d 1519/d 20+Ed Total j No. rop. No hP. No. Iop. No. Top. No. ' Pop. . 1 3 11 2 1'7 1,255 1,922 2,687 348 6,212 0 8.621 20 9.668 28 7.243 2 612 SE 26.144 6 5.158 8 4,052 9 2,513 1 105 24 11,828 16 10,764 24 9,820 23 4,651', 1 226 64 25,461, 3S 32,027 1 65 33,253 09 24,214 11 2,046 2001 91,540 2.18 2.01 2.38 2.71 1.36 1.42 1S! 1.91 O.tS 1.01 0.06 1.34 ( 1 Mamd euamron 2.02 f X''2.915 i 1.45 wW-uJ~ 1.0i p wJue 0.0017! 1.0855 11290 3.0295 ~ 0.1309 0.0337 0.0012 Table 2. Mortality rate for lung canirr in nonsmoking wives by smoking habit of hus- bands and by age group of wife: prospmive study,; 1966-1981', Japan- Husbsid's snoking habit + ~ Number O( dpietue a day ~ Nommoker Iaimokei ~ } 1-1f/d >'A*/d Total wi<e'. a .ge gee.p No. rop. No. Pop. No. pop. No. top. ~ 40-49 4 7.918 21 17,492 21 12,61',5 46 38,025 30-59 14 7,635 46 15,6/0 31 8,814 4 91 32,089 60-69 16 6,170 31 10,381 10 3,793 37 20.344 70-79 3 172 1 671 2 239 6 1,082 Total 37 21I,895 99 44.1114 64 25,461 200 91.540 '7br .eieh'ied poim .ai+aMe of r.ls L01 2.SS trio and'we- 1.00 1.43 1.74 •.wd:90% I_19 cmGdess Yss Itand enee.ew X' 2.424 MaMd-Marn.,i X' ~ 1.062 2.3731 .r.W aue-ui! p valuc 0.03U0.0008 p..hr 0.0076!

i ~E 1~i i+~l Iti~t ~ k`J ~ xh 5~l1~ ii~r ZR + + + - It + /' 12 9 1" - 3 4 2 OR 3.00 OR 95:: C! 1.256-7.16a x'(J') 6.117 (<0.0s) ER Mt XfT-R.-A:pU4 .e.Hi.,;K J~`JOR I Z f~7~all I IYII m #& >i~ A (A 2), uA FA ~4b IR 'l.$$&P a fb 3+ a16, AR -u9 t. fL& tt j&,4,-. ME 2 A 6( *11-4 OR x. t# B943 (3t/8) 0 9 ie 1.000 ••• <20 12 22 2.303 1.teD >20 13 a 6.e61 1o.09a•1 ~70)°PtAJF IR (if ), 0 9 38 1.000: <10 4 9 1.877 0.266 <20 a 11 3.0712.SeU >20 13 10 5.489 I.230" . 0 9 38 L 000 ••• 1-199 4 11 1.535 0.066 200-399 6 11 :.303 11.009 400-599 6 5 5,067 1'•05/" 600' 9 3 12.667 11.35E'1 'P<O.OS "PG0.01 2. #910011,R WM »d- ~f5~'l•7rLtQ 9 MJ 21 g^l, Z,&T T-1 13 Pl'. KdiR ~t~fiR~~~fa~d`J5~- tkg *-Ik(x'=1.298, I'> 0•5). 01$+1 5Xa$ f~7E}h !t V R ~K 3. f'.~• -1T: d.•WI'14 K4pAm;Nz TIM r,, •i.,bE M ~i aR trL a ~-T 1,L* it -VlI N it 3. Wip17IM. i•rlii'~ C,DII!!3'i' a T a 11 *11 17 4 S 5, 3~°R 20 22 10 16 Oh 4.675 2.,55 0 x 5,035 1.01 1 P <0.05 >0.D a &4MMttf'XHDL-C,&apoAIi 7Jc -T,-Fa, TILDL-C, apoBRapoB/AI**V 7k3Fit, A HDL- C,apo AIIJp apoB/AI0`•j7jc*j{j%:&ljj ~, ~3K 4. _, $5E Logistic ®I)34-ZJ3~* It M 9 k 5>`IF A f~tat PLI ®f ;E;a •0K A A IXA7C Logistic i713MMI , r~~••Z, ~t 7 ^It R.12 Jf iE !-r7M itStrJ1. h.'ttX±LEE#M Si. ?-51t E T- ~3"c ~ =27CEI1.`AVAp- =3o a-~1'r~i ~Az s4,, tk ~~ =s, f~v"w,,*qlR sb, MM ?.~It $afA -t t! A '.nL'~K 5. #13fy~;;~ A IK r1c ~Q I.p 9 #~ n R PS~~C, A A 1 0 a AlkI fsI jri 4E a A !~ JA FA z f f fA 1± ~nP-- is it `D'. fil i~itI7 ~it~'~'IK Br9, 9 'n R I ~~M- w , 519 3+1.JL Ot °r~t it tz kz-, it-t#rti a i0i a I g5q z tt I 4b a z '9 4 4 $, KJLR MT;ttl, tMATz1. MNIFAd'•] t:ai1.t. it #IzZb 71 A#12 h7!* ffl 9hI )~ i=+ z Atii..zi it. Af7. t tt 9 tit R ffitl F-Z. ;XVj 0 R X 3.0~- 3.5, 95°~ pTfkPR*-T 15 OR M;IIT I z Ct. PJfA a #t A:; kt 4hUA a 4 Z• tz w lipf ~~- , it 't4®4h~i-LW-#% o #Rq, 4E ry 1+JI7t:- ftkkqV9A-HJWR'-F, ftk-*tt.!!?rlE, i±bq

918 AE1.snaG Sr AL TAat.e 2 Pnt+entqge d onvi+nl eenaLr poyulation who nponed they hod weuer imohed, by demqgrOic eharoeterisda; whitu aged t25 Yews, Worhington County. MDi 1963 -!to women cbmectensuc S never % OrTt No. ® olud No ®oked Tota1 22,973. 18.1 25,369 58.6 Age (3,eu+) 26-44 10,928 16:5 11,652 46:7 45-54 5,104 16:1 6,378 53.3 55-61 3,631 17.2 4,001 70.1 65+ 3,310 27.6 4,338 86.6 Muitil sutut Married 19,699 17:4, 18,704 55.4 Other 3,274 22.4 6,665 67:6 Grades of whool completed (-.-8• 9,977 19.1 9,929 68:5 9-11 4,527 13:1 5,497 52.4 12 5,256 19.1 002 54.4 13+ 3,213 20.4 3,141 47:6 Hmuin` mde: 0-7 4,591 15.9: 4,512 59.9: &_10 18.382 78.7 20;857 58.4 * 1ucl{Ides parLiclpants for wboID grades of scbool'cAmpleLld :w'16 not known. smoked, are listed, in table 3, which shows the calculated midpoint populations in 1969!and the percentage of each group e=- pose& to tobacco smoked by others in the household. For both men and women, the percentage ezposed'to environmental smoke in the home tends to drop with in- creasing age and with higher quality of housing. There is,however„a sex difference in the association of education with per- centage exposed, nonsmoking men showing slightly increased exposure with more years of schooling and nonsmoking women show- ing a slight trend in the opposite direction. In addition, married men are less likely and married women more likely to be exposed to the smoke of others in the home. Table 4 shows the adjusted rates of death from arteriosclerotic heart disease (ICD 420 and 422) in the 12-year period 1963- 1975 among men and women who never smoked, according to their level of passive smoke exposure at home. The overall rates are adjusted for age, quality of housing, marital status, and years of schooling. For .men, the relative risk for those with some household exposure compared with tbe none:posed is statistically significant (rel- ative risk (RR) = 1.31, 95 per cent confi- dence interval, (CI) 1.1-1.6); but the trend with increasing exposure is negligible. For women, both the difference between the expose& and nonexposed (RR = 1.24, 95 _ per cent Cl: 1.1-1.4) and the trend of in- . creasing mortality with increasing levels of ezposure in the home (Cochran chi-square = 9.2, p< U':005) are atatistically signifi- oant. The balance of table 4 presents the adjusted arteriosclerotic heart disease mor- tality rates for each age group by level of. smoke exposure at home. The age group 25-44 years shows the highest relative rieks for both men and womenj but because of the very small numbers, the 95 per cent confidence limits are quite broad. Never- theless, it is worthy of note that seven of the eight age-sex groups show increased siak of arteriosclerotic heart disease deaths with passive smoke exposure in the home, and five of the eight indicate a trend with increasing level of exposure. Results have been sbown only for heart disease deaths that were classified as un- derlying cause of death. Although not r

. ~~ 1- t ~ i ~!~>l~~,+1~l~#>~~1~'141I~'fl3*Tli4 (r±r). TC LDL HDL LDL,'HDL (mmoi.'L) (torool,I) (mmol/L) apoA1. (Z'L) apo8(j/L) apoD/tpoAJ ' 9'f !1 1@ - 26 4.1+-_o.6a 2.31t_n.6a 1.41_0.16 1.1e!:o.5a 1.27to,24 O.71t0.17 0.11lto.19 + 20 C.li_7.61 2.s2to.se T.29c0.16• 1.96t'0.60 1.11to.23• 0.74t0.1-4 037,±Ot22 tat~Ct~ - 9 5,15=?.66 3.35=0.i6 1.26_0.21 2.t5±o.79 0.95to.16 1.03t0.17 1.21rt0.10 + 24 l 5.6oce.13• 3.:5_0.T1 1.12_0.17` 3.42±0.74' 0s61to.13• 1.16t0.20 1.36t0.22' 3~ 3 s~i•;~t',P'F~'~;~ffJs9t1¢ Lo~isticle79~~f~~ AA2f Bi ror(J9i) s;(ai) STD(Bi) OR 09 !+ It 411A A I J. 0.406 0.069 0.013 1.611 1.500 4 16.93 <0:01 &EiLiliifall:ts, 0.714 0.05z 0.227 3.147 2.042 9 9.90 <O:oi 't; X~'x kt f• IiF N r' SJ ~6 9c7~f~eOt.~'.7~~T~i, ^J Ce.7~.tta7L-.`.~9a 1L1l7ldi Scot.tTA o,. VJ. BJYaJ7Y1 X7CE 7F C7 iIJ1/6 2 X , iff anJt>fia 9 ~t I & M 9 9~;K it tb:g a~': ~~1~~EFt~r~ COHb 7k'F 89 M 3+?w. Z9•)~'sG`a7t t M 3 : 11. Aromow Rt 10 $~~t~~~ R-11i A aA,IStE ARTO ~`•J121; '$'. 2'iJ.Bf F~ R COHb 3i-7% I Mt, * j)f4 r iA'K.L~9'•7Bt A ,E 1,'3: #LM ;1~ 4 t2 Bt3. a a ®', 1 33.88"or Mt;kik 6100"). t~+Jtl~ a 'B'*R'M ~iR'c. LfTi'j%r: ~It rA a r3i -4. ±;a I. Women's Passive Smokin{ and Coronary Heart Disease He Foo, ef ol.. Departrnent of Fpide- miology FonrtA ltilitar. .11e4iral Coliego of PLA. Xi'an Thirty-four, women CHD cases (7_ casrs d,aEnosed by coronary arverlojraphy and 12 myocardial i°farctuon) and 66 oh non-CHD coatrols (34 hospiul based and 34 populatuon based), matched on age (within five years). race. residence. occupation (and casc is to control as 1:2), were interviered re=ardinlt the smoking habits of themselves and their hnsbands The odds ratio (i. a. : OR) of .o°-smokin6 women CHD associated with I+aviag a smoking husband are !.[0+3.52, OR /SfGC/ do not include 1. Signifieaat dose-response relationship. betsveen OR of snome°'s CHD nd their husband's eiaarerte consumption. deratioa of passive smok'ih6 and eumulative quantity ot passive smoking were found ia the study. The logistic regression model anal'ysis rithh othen CHD risk' factors aho.ed that the relktionsbip with CHD and passive smok'ih6 still eaiated'. 11, was found that the metabolism of HDL-ebolksterol and apolipoproteins with passive smokers was abnormsl. 1. Scott TW. es al'. ($Ef;{i#). ~7)~lA7{9r18A : IM. Z~S6d41T'~K ' 198411 3(2):30.. 2. Stanton A.(k7 Ri#).i52flk®J~(dI~)~(!$l6~Ac ,Ts07a16'aft(f'i1.. ®4h~C#-Itg~c#Slll11966, 3:226. 3. Kaufi.mann F, et al. Adult passive smokinj in rhe home e°.iroome°tr-a risk factor for ehroni. airflosrw lim:ut.ioa.Am 1 Epidemiol 1963, 1117, 269. 4. Trschpoulba D. et all Lung cancer and passive smoking 1'nn J Cancer 1961, 29 1. 5. Aronor WS Effect of pass„•e smoking on a°ginl pecroris. N En61' 1' Med 1976: :99:21. 6. Garland C. ct at'Effects of passive smoking on ischem,c heart disease mortaliiv of nonsmolera Am 1 Ep,dem,ol 19951 121,645,

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PASSIVE SMOKING AND ARTERR'>9CL8ROTtC HEART DISEASE 917 heart disease was listed on the death certif- icate but not coded as the underlying cause of death to confirm that simiiar associa- tions were observed. The category, other myocardial degeneration was included be-' cause many physicians in this community refer to deaths due to coronary artery dis- ease as arteriosclerotic cardiovascular dis- ease, which is classified under ICD 422. For the current study, all adults were assigned smoking contribution scores (ta- ble 1) ranging from 0~ to 12 based on their reported smoking histories-never smoked, present or ex-smoker of cigarettes, cigars, or pipe, and amount smoked. In general, current smokers were assigned scores that were twice those of ex-smokers of like amount. The only exception to this was for persons who only smoked a pipe and/or cigars; census data did not distinguish be- tween current or past pipe or cigar smokers. When~pipe and/or cigar smokers also cur- rently smoked cigarettes, however,, they were assume& to be current pipe and/or cigar smokers. The contribution to house- hold exposure of only pipe and/or cigar smoke was treated as less than that of current smokers of fewer than 10 cigarettes. Although the household exposure from a pipe or cigar may equal or exceed that from a cigarette, it was arbitrarily assumed that't cigar or pipe smokers who never smoked cigarettes would;, in general, smoke fewer pipes or cigars per day than~light cigarette smokers: Only 9 per cent of spouses of nonsmoking females smoked only pipes and/or cigars. Thus, the impact of this ar- bitrary ranking of pipe and cigar smokers and current light smokers is not likely to be large. A household exposure score was calculated as the sum of the contributions of all persons living in that household, and each person's passive smoke exposure score is the household score minus his or her awn contribution to it. A housing index (ranging from 0 to 10) based on running water, number of bath- rooms, type of heating system, cooking fuel, and availability of telephone is a rough indicator of quality of housing. In the ab- sence of solid data on household income,, the housing index acts as a surrogate mea- sure, particularly to identify the very low- income households. Among the 22,9?3 white men and 25,369 white women aged 25 and over in the 1963 census, 4,162 men and 14,873 women re- ported that they had never smoked. The calculated 1969 midpoint nem ining popu- lation of these nonsmokera, based on the 1971 follow-up, was 3,454 men and 12,345 women; these constitute the population of interest for this study. Death rates were calculated as deaths in 12 years per 1,000 midpoint population, adjusted for age, housing quality, marital ststus, andyears of schooling by the binary variable multiple regression procedure de- scribed by Feldstein (11) and adapted for epidemiologic use by Shah and Abbey (12). TAas.t 1 RESULTS CaFculation of eochperaon's concr;baaon to smoi<e Table 2 shows the characteristics of the exposure in the horne Washington Cbtmty'white population aged Ea• Current 25 and older oriei.nallv listed in the 1963 -- ~"-'- emok.r ®oker census and the percea tagR in each category Never smoked 0 0 reporting that they had never smoked. As Cisus and/or pipe onW 1 1 was characteristic of that' period, relatively CtIXTettee . <10/day 1 2 10-20/day 9 s 2i+/d,y 6 lo If c4ars and/or pipe in addition ~to ciearettes. add 1 2 ' Ceeuus data did not d'utin`uisb between e:- and eumnt pipe or cigar smoken. few men but more than half the women had never smoked. Among men, there was a slight tendency for the better educated to have a higher percentage of nonsmokers, a trend opposite to that among women. Characteristics of the population of in- terest for this study, those who never

!i I ~ f,3 1 Lu,a "~v t~S9 # 1d~E9~#~it~1989~3;.3 €~ 1 aDf 44 Suc1,TSz °~;h z?`~ :::::.:::: ..... . JK®VEKt* r-, a #e~~ ;F;-ti #-Y;,, it® E e)~-. ~ a ~ S! J'f3atjrt;!•L~n*(slhlsi~YsGlij~22694 i•9Llf4.1 12${:;:.i;r7#AA#BSzz~oi 3.0-•3.5(P <0.05); jt=:?it:l OR(aT~'l~>1LR7~Fiic+s~iz9'e~e~ 3iLl.o;istie®+}JSl~3YeA~tt~irZ LDL-C. HDL-C, apoAl$ apoB 7/c*#lt. 9EtiIl ;Ui:•#R ff14k1rlY's* vtiMl ~~lg:r qk Is i3E t fC,lt}'3 4F *!V3 F~i, 5;r XA'J-~~G # V -13 17I #-Vt(1980 D91r}!A * = a1IN17)t!R'W HZ•1Li9"•'J1.• X Lw- s~ p 'A;z I trl>t fsit , 9m ± !! +'€ iti3i'l(X43 S P~i~tnll, fHLR• ~~&3f>~~kt~~~ . ~~J~Br~?BI'x. f1Bf'It t014i~7a. f~±RIZ5JF1;t±Vt n*:C: =~ Y;-TT,;R+9 LA.Scl ' '1T:')t 1:J':1°ft t'r;rz ] 5 3•'•,`)•7A'I7ijJ'A '7[l',~- 3 aT A 4;t~*4 9t inT,ih I A AIkIttm 0~ o fv a A ffi4F. -X-)N A Jg4* v # rfBl<5~R x At'fr.9f3`5tc KLt 04.1 , #~2tx 4 9ld. MtfiAfi. 1rH&M1RMi i9raixitiGipm. $RM' A$dfr39 31 1~5. $A'. M tt t #0 R. 4 K;M'X:t 5 3W 1:2 JE f-f:, aTcM 1:2 JE7M i{'W''l. 3?Zfi,-4 7C Logistic M)3 {q J:7[5~i#4 Sun-G8000 MSf ~ X 9%R~E4ZP. 7rftES. jR 53.701± 4.28 -W, 3q!Rij 52'.93= 5.24 ~V (t=1.282.P>0.05), -. $k=;hl%m A 1X 1i:2ILjbf ~L rz a:K, X ORf i t 3.00. 1. ~N1L L rx ~~X : 3t-A 4 8IT-, l~1 '~. R~JS~~1a?D1el.~ ~-f~~~7 .l* R011CE This maxerial, maY ht. Mwk~bd bY coPY~i8 law Zit1e I7I).S. CodeL

Table t. Lung cancer monality rate in nonsmoking wives by smoking habit of the husband: comparison be- tween daily and non daily intake of green-yellow vegetables . I Husbend'r Et+nwkrr wnokinR h.bit. Nonrmoker on 1-F9 d.y 2 20/day Wife'r eating babiu Greea-yellow .e6etabkr D.ily Noadaily Daily Nondaily Deiiy Nonddly Lung Lung Lung Lung Lu.g Lung Hu.b.ed'e Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. Pop. Ca. Occupatlo. Age Agriculture 40-49 1,956 1 344 0 5,0S0 5 !91 1 7,037 7 S99 2 50-59 2.805 4 692 0 5,196 11 1,616 3 2,386 9 926 0 r 60-69 ],739 7 725 6 5.106 22 1,739 II 1,588 6 S64 4 70-79 256 3 63 0 287 1 159 0 45 0 44 0 Uthen 40-49 2,492 3 1,103 0 7,286 1 1,803 1 3,377 3 1,731 2 50-59 ],181 S 1,113 1 6.732 12 2.098 3 4,6]7 S 1,673 10 60-69 2,266 4 770 1 4,086 9 1,510 6 1.906 10 399 3 70-79 216 2 216 0 371 1 248 3 8I 1 56 0 Total 16,463 29 S,4]0 6 74,11• 69 10,066 30 19.253 4! 6.206 21 Gr..d tot.l Populatio.t 91340 L.ait ca.eers 200 E3reea-yeliow vegel.bks Manmel<.tenrion xl P-value (two sailed) Daily 2.072 003827 Nondtily 2.487 0.01288 Total 3.090 0.00200 I 16 I s44TTsf:zoz

Table 7s. Mortality rates for major cancen other than lung in women by age group and' by smoking habit of husband (patient herself a nonsmoker): prospective study, 1966- 1981,Japan• . ' Hn.baad"s smoking labit (cigvvita a day) 1 Husband s or croup RX-Insolsw - ~ Neas~oka 1-19 ~' Taa1' ~ No. Pop. No. Pop. Ne. Pop. No. Pop. ~ 40-49 44 6.229 117 15.034 71 10,764 232 32,027 50-59 97 7,791 191 15.642 119 9,t20 407 33,253 60-69 160 7,120 274 12,443 106 4,651 540 24,21'.4 70-79 14 755 20 1,065 • 226 42 2,046 • Total 315 21.895 602 44,164 304 25,461 1,221 91,540 . 1.11:. 1_OS 1.00 1.00 1.00 0.f0 0.93 Kaeed a,ma- Z' 0.115 ~ -0.0015 0.009 .aruB 0.4994 0.41621 p.d~ 0.4542 s Table 7 b. Mortality rates for major eancets other than lung in women by a3e, otcupa- , tion, and'smoking habit of the husband (patient herself a nonstrtoker)' Husbaade age Noaamoker ls•.esoker ar 1-191dty :20/da7 (7-) Oaupatinab No. Pop. No. Pop. No. Pop. 40-49 Total 45 6,229 120 15,034 74 10,764 1 2 324 1 653 3 566 2 90 l 231 2 293 3 9 906 /7 2,247 12 1,667 4 3 476 1 993 8 1,044, 5 17 2.502 S4 5,941 35 3,636 6 46 165 108 7 1 177 6 486 426 t 10 1,112 21 3,431 13 2.241 9 1 162 4 345 1 243 10 2 432 3 542 340 10 50-39 Total 9! 7„791 195 15,642 122 9,t20 1 13 345 2 393 3 446 2 2 175 1 2S3 1 319 3 14 '17 16 1,764 10 1,324 4 1 653 18 1,133 9 1,092 5 49 3.497 $1 6,812 36 3,514 6 35 ~9 5o 7 2 120 4 273 2 234 ! 12 1.375 49 3,478 31 2,155 9 164 7 379 4 251 10 3 610 17 869 6 43S 60-69 Total 161 7,120 227 12,443 306 4,651 1 S 227 S 327 2 179 2 5 91 3 143 3 124 3 7 305 11 594 S 327 4 5 508 28 822 12 S00 5 102 4.084 1511 6,345 58 2,152

Ltnp CcnceF In .lapart Nuhffbl ond P+o~re Smoldrp 177 risk of lung cancer in both men and women. For statistical analysis, programs in- duded in the book £pidrmiololic Andyrir with a Hopmnmable CaltLJator (U.S. Depart- ment ment of Health, Education and Welfare, 1979) mainly were used. R@Su'i11S Active Srrooking and Lung Carcer Rlsk Cigarette smoking was identified by far the most important ntne of lung cancer in Japan, both by caae-oontrod studies conducted by the author and other researdi- ers and by a 1'arge-trcale cohort study (1-6) being conducted by the author for 265,118 adults (122;261 men and 142,857 women) aged 40 and above (9S% of census population) in 29 Health Center Districts in Japan. These subjects were surveyed' in October-December 1965 and followed up from January 1966 until' December 19811. A deartut dose-responae relationship was observed between the number of cigarettes ever smoked and the age-standardized mortality rate of lung cancer. The mortality rate of l'ung cancer also was found to be higher the earlier smoking was begun when age and total number of cigarettes ever smoked were standardized (Figure 2). The lung cancer-standardized mortality rate was obaerved 120 100 80 i 60 } t 1 40 ~ 20 C <8) ' t (b) 114.0 117.2 t 1011.7 .., t 1 t E.~ 1 [1.{ 1 t 7S.S t 1 1 tI 17:1 t f t 7t.~. 40.9 2S- 30- zs- i[.2' f~i~ E%1 .10D.t100 M0D0- r00.o00- -i1 :. [t 74. . 0 1410.000- nD.Oi1- NG[ AT fTAaT ~ NI/OE[ OfCiGARETTEI OF fNOC1NG[VE[ LW[ED Figure 2. Lung Cancer. (a) Attained age- and amount of smoking-standardized mortality rate by age at start of smoking. (b) Attained age- and age at start of uooking-standand'ued mortoliry, rate by total amount of dgarena ever smoked. (Ptospective seudy, 1966-1978 Japan.) i i

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2. This study is merely an update of the Gillis, et al. (1984) report. Thus, if a tally were being made of the studies dealing: with ETS and heart disease, it would be inappropriate to include both studies, since in a sense this would be like listing the same data twice. 3. The authors also report data comparing smokers married to nonsmokers versus smokers married to other smokers. Although not statistically significant, the relative heart disease risk reported for smokers living with a smoker was less than the risk reported for a smoker living with a nonsmoker. 4. The heart disease relative risk reported for ETS exposure was 2.01. This is to be compared to 2.27 that the authors report as the relative risk for smokers compared to nonsmokers. Even the authors question whether this is "biologically plausible." (p. 426)

Ltnp ConCet In Jt;porc NuMMOn ond Possiva 4rntoldnp 187 . (a) m.0 n.o 14.0 DE U (b) t.O 7.9 u.o 6.0 10.0 s.e ..o' i.o O.o 3.a n..a..neas n.r.aa. .•~.41n lorrln ~al. ..n. ~.0 2.0 t.o ~ I 1.0 --{ !}- - 1.0 T .. i . i . . . . .. .. .. . n f ~ I w. r.~ /.. i r. ~/O.It WIT ~ i/r. r/ w - s. •.... I.rr- 00 rT. 14 lT 71 .h t1•.4 t~•1 ~••e• MMr.<MiMI WII' V'~ ~, M IN 11~ V w.n /Iu vM Y A M wr rr~ w v w r• z~ n.N .r W . . . .. .n` Mln MM nrr~. ..la rYr ral 1a INN~. rNl w.a~. Ir I7r . tiet ~ / M NII~ aNN Mf IA1 /N. ~t CMOIrKI 1/ 1 .1 I~~N i ~~~ ~ , . I,N / .M ./ . C~Iptl~. • •.• r . 1~1/wa 1! LN Lt7 7.n I~V~ w t.N a .., . . . s , ~ ~ •~rl.y.....,.a .~... r.~..... Figu:4 7. (a) Active and passive smoking and lung cancer tnortalir+y: telative risks (RR) with 90% confidence intervals; ma)es.(Ptvspective study, 196tr 1981, Japan.) (~),Active and pauive smolung and'lung cancer mortality: relative risks (RR) with 90% confidence iater• va1s;',femalts. (Prospective study, 1966-1981. Japan.) the order of a few percent. 3he effect on lung cancer risk of passive smoking as bome in relation to active smoking for men was alcul'ated as 0.4% in our seriea. Effect of Nutrifion on Passive Smokers ' A signifit:antly lower risk of lung cancer was observed' when nonsmoking wives with smoking husbands consumed green-yellow vegetables daily (Tables 8 and 9. Figures 10 and 11) suggesting that the promoter-inhibitor interaction model also applied to passive smoking just as in active smoking (Figure 9). Such risk reduction caused by daily intake of green-yellow vegetables was not observed for ischemic heart disease (Table 10, Figure 1'2): s

Hole, D.J., Gillis, C.R., Chopra, C. and Hawthorne, V.M., "Passive Smoking and Cardiorespiratory Health in a General Population in the West of Scotland," British Medical Journal 299: 423-427, 1989. The report is a follow-up of the 1984 Gillis, et al. paper dealing with a prospective study of the residents of two urban areas in the west of Scotland. The subjects were healthy middle-aged men and women, first surveyed between 1972 and 1976, and then followed-up for an average of 11.5 years. Based on 84 deaths, a relative risk of ischemic heart disease mortality of 2.01 was reported. This was based on combined data from both men and women, and was reported as statistically significant. Data were also reported concerning a variety of cardiovascular and respiratory symptoms, as well as all cause and lung cancer mortality. For each of these, the relative risks were reported to be consistently above 1.0, although other than for ischemic heart disease, none were reported as statistically significant. In computing relative risks, age, sex, social class, blood pressure, cholesterol and body mass were taken into account. Criticisms 1. Although the authors report an attempt to control &I for several potential confounding variables, a number of factors C N were not controlled, such as outdoor air pollution, the presence ~' of molds or dampness in the home, the use and type of heating fuels, ~ ~ diet, heredity, and many other factors. ~ W

188 ?droaw'Nwyiarro r so sOl1i waT . 0.. / ~ 0 wuu't ...{~ ..... t""' r01t. ~...~.... Ikla. r~~l a,..0 B11TM. 71. fl. Nl. 7 /N {tl N~t. OYULFtIOn. ONf1'. OWS'. N.N UO{ /017f Nlu Ow7n fMf.M t eOaIOLKy h..•t:N .M ..01 .:Y 0.7. L1f /tR(F.L . •.t. I:f{ f.>S !-{1 l.A f.1 ...1 l~.l! /.N ..M YY~•dlylt Fignre 1. Actiive and psoive mwking and h{ng cancer mortality: relative riaks (RR).rith 905'a corTxencT intcrvals. (Prospective study, 1966-1981. Japul.) 1: - "i. (a) .. r.ra0. Ir/. OI0N.tit A.N. Ift 47.5% hE N•06 u. 10 . » M f0 10 30 1 !0 10 a. v,..q. 4,10 „.a ~~- rrl« Ift 53.6% ~ . . • w ,~. .u L L L • s. .. N ~o (b) a• .0 w•0 n { . . » y. snr. a.. s.wr Figure 9. (a) Pertrntage of nonarwken erposed to sidesucam cnoke at home. Japan, 1983. (b) Perorntage of aonuaokers esposed to ridesclearo vaoke at the workplace„Japan, 1983.

482 D a.s n M.I IP IUrGWflat. IDrik/TT 4TL PIr 100,000 IS 10 Tok.lr,r Fislyomo 0.0 . 0.s Sc l 0 /.i 2.3 l r.) a.s A ~0'. !L M~t Y{0 ~0 ~SO {i'. ~0. f0 K W~~ SC f0 If1IHAIW'{ tfi( ,, , ,~ , • MfOM MMM~MM.M~ MMM Mf{.N. ' ~ ~, LU/p Ila{/p r0./,p ytOaE 111R041[C'ifNOttrG W10I TI AGE sT.wyatORt9 •.) 13 1' ) )J.{1{.!1).a rO0.Tl0.1TT 01rt Figurt S, Age-specific mortality rate for lung cancer per 100,000 in nonsmoking wives by c)wking habits of their husbands. (Prvspective study. 1966-1981„Japan.). Table 4. Mortality rate for lung cancer in women byvge group and by alcohol drinking babits of husband: (patient herself a nonsmoker): prospective study, 1966-19$1, Japan Husband's av iroup 40-49 50-59 60r69 70-79 Total Husband's drinking habits Nondrinker Ocus. Rast Daily Oh.curc Totu1 No. Pop. No. Pop. No. rop. No. rop. No. Top. 12 12 23 1 46 6,141' 7,437 6,741 686 21,009 10 15.877 29 14,666 35 9,234• 5 666 79 40,443 13 24 27 4 66 9,935 10,786 7,696 509 20,916 0 0 4 1 3 74 364 633 105 ' 3,176 35 32.027 65 31,253 29 24,214. 11 2.046 200 91,540 1.61 1.l9 1.00 1.05 1.11 o.6c 0.77 N - mae•d men.ion. C Y' 0.676 ~ -0.1019 0 4564 ..ruJ N 0.4594 0: 3Q400 p ..Iur0:26566 W ~R ~~A T' 1 i I

190 Greo-yeDow .e`etables Table 9. Effect of daily intake of grren-yellow vegetables on lung canar esu+rPJiis in nonsmoking wives with smoking htubands• Husband's Ea-+mokrr ®okiog labit .r 1-19/day 2 !D/day Wile's eati6g Yabit YWr ` NoYYiYr LsYr N.oedLly. Laag Lt+.g Lung Lung Husbaed's top. Ca. rop. G. top. G. lop, Ca. Occupatioa Age /tgriculturc 40-49 5,050~ 5 !91 1 3,037, 7 559 2 • 50-59 5,196 11 1.616 5 2,588 9 926 0 60-69 5.106 22 1,739 11 1,588 6 564 4 70-79 287 1 159 0 45 0 44 0 Ot6en 40-49 7,288 9 1,905 1 5,377 5 1,751~ 2 50-59 6,732 12 2,098 3 4,633 5 1.673 10 60-69 4,088 9 1,510 6 1,906 10 593 3 70-79 371 1 248 3 !1 1 56 0 Toul 34,118 69 10,066 30 19,255 43 6,206 21 IMamd•Hrnod,/.. -1,9/6.P(LOL&ilM0:017).Odd.ratio:.KavLily:tsrOee-7ctlo..efetabk.r.ie:..l.000- dsjry gRT^-7elim. •egen6b.dw.ke, 0.707(w.nduduedere erin); f0% ean6dener i®./. ,0:53l-0:4i3. m i..MN'. truq wI r {n...rHOw 0"OW1.6 falaeepr'Fi:hartn Y. tru. t..t..... 1.1. rn/ N N ~r. s+lt/ WM1.(.Iw./M O1 ~ MIN rns 11.811, ..nsrt elftn t.M7 •.i1lN Figure 10. Lung rsrtcer, mortality ratio in nonsrraking wives by smoking habiis of their hushands. Comparison between daily and nondaily, untake of green-yellow vegeta5les. i f I

2. No data were available for remarriage, and this may have influenced the exposure status of the wives. This possibility was acknowledged by the authors. We lack data to examine whether exposure status changed during follow-up due to remarriage. (p. 600) 3. Especially because this is a quite recent article, i; ~. is notable that the authors stated in their introductory comments that research up to that time had failed to demonstrate a clear relationship of ETS exposure with heart disease. . . the risk for all CVD mortality associated with~passive smoking among non-smokers has not been previously investigated. Recent studies of risks for coronary heart disease, stroke, or all cause mortality associated with passive smoking generally have reported weak and/or statistically nonsignificant results. (p. 599) 4. Data were presented separately for blacks, high social status whites and low social status whites. For none of these individual groups was a statistically significant relationship reported~ between spousal smoking habits and cardiovascular disease mortality. Even when all of the groups were considered together, any possible relationship between ETS exposure and total CVD tauti:ality did not reach statistical significance. 5. When only those causes of death which the authors considered to be "smoking-related" were considered, then there was

796 SMOKING BEMav1OUR Man-wraers Fr-smo..n Lrriwa sono..rs PASSIVE SMOKING AT NOME Mrw~.rr..rs «~...~s a..... 6~wn.... ....r... s...... pAS$NE SMOKING AT VIrOFiK Meo-111'eMrrs. 1~w~a s...r Bwrw.n ~.......e rr.« THE MEDICAL JOURNAL OF AUSTRALIA Vbl 154 June 17. 199t Frbnnogen txncentrat/on J?1L ) 3s .! ~ a.~ 9- ..-.. t"- 28%. 42% and 30% for those who replied to the brief questionnaire and 299b. 42% and 29% for those interviewed at home. The correspondrng rates for women were 14%. 19% and : 67% tor the main group, 21 %. 13% and 66% for respondents to the brief, questionnaire and 31%, 16% and 53% for those interviewed' at home. These results illustrate how non-res- ponse among control subjects can lead to underestimation ot prevalence ofamoking. 11 is reasonable to expect that it data had been obtained from everyone selected for the sample then the smoking rates and possrbly prevalence of passive smoking among controls would have been higher and estimates of risk might have been somewhat lower. As the control group was selected from the electoral rotl. bias associated with this sampling trame should be considered. Although registration on the roll is compul- soryfor people born in Australia, about one in three of those aged 18-19 years are not enrolled and about one in 20 of thoseaged 2D-W years: beyond that age only about 1 in 50 eligible people are not enrolled." People born overseas are not necessarily required to enrol so they may be sys- tematrcally under-represented by the roll.° The distribution of countries of birth in the risk factor survey was similar to that lot the whole study population recorded at the 1986 Census: 66% of participants were Australian-born compared with 89% of the study population: 7% compared with 4% were bom in the United Kingdom or Ireland: 4% compared with 2% were born in Nbnhern Europe. 1% were born in FIGURF : . sm•cp;r- ,"-; N`Msrom arno-v • COnrrMrnll',f0mpM .4fI- :Or•- onlaaral fG•-; V* ae.Iroro +."eo 60 re.n .wr or... au -x~ or 25 (.Q•+',/ ;pnnCr-Ce nrwws osec n- stt-:rro NrCrs Monr aqn:f.p or=.8r,.. axr n- eq r;iqs•r-+et a:r l Southern Europe in both the survey and the 1986 Census and 1% were born in other countries. Differences in the methods of' data collection and truthfulness in reporting smoking habits might also have led tp bias. Control subjects completed selt•adminis- tered questionnaires whereas information for case subjects was obtained by a nurse- administered questionnaire or by mailed questionnaires completed by relatives of deceased case subjects. The most likely effect of these differences would be for t:ase subjects t0 under-report their smoking and this would reduce the magnitude of' estimates of risk.M It is also possible that case subjetts might exaggerate the extent of their exposure to passive smoking. looking for "explanations" ot'thely disease. The effects of confounding factors need to be considered. For examp/e, in this study' previous myocardial infarction or history of ischaemic heart disease was found to be a significant confounder for smoking and the risk of ~myocardial infarc- tion or coronary death: This is consistent with the observation that people with, known heart disease are urged to give up smoking and often do so. Thus differences in magnitude of estimates of risk reponed from various studies will be affected by differences in prevalence of heart disease and in the extent to which this is taken into consideration In the analysis. Another potential Confounder is soclo- economic status. Prevalence of cigarette smoking and hence the likelihood of exposure to passive smoking at home and possibly at'work are higher among people of wwer soc,oeconomre status and so is the prevalence of heart disease InAustralla.^" For example. in this study the distributions 01 socroeconomlc status as measured by education were significantly different among cases and conVOls., atter adlust• ment forr difference tn age whemn control subjects were those who partiCtpated fully in the survey or completed the brlet questionnatre (for men. x1. 44.1. dt .4. P< 0.0001: for women. zt . 60.7: dfi. 4. P<0.0001), Adjustments for thls confounder were not included in the analy- ses because of the very'smau numbers in most cross-classified categones. The effect of this factor would be to increase rtsks attributable to active and passive smoking by including effects of~other souoecartorrtre , variables. Lack of statistical power is a limttatron of this study. For many t:ompartsons the numbers of subjects were small - most notably for exposure to environmental tObaCCO smoke at work. because few of the cases, especially among women, wortted outside the home. Also: many factors increase the variation of fibrinogen measurements." Although conslstent differences were appar'ent. the results were not stalistically significant and'4ddmg other covartates such as Cholesterol levels did not reduce the variability: Far more subjects would have been needed to give unequivoCal i results. On balance, the effects of bias and confounding could have led to overestrma- tion of risks due to passive and active smoking. Nevenhelesse the magnnude of increased risks which we found 1or passive smoking at home and tor current smokers and ex-smokers are similar to those reported by others."'- In most studies ot, passive smoking and risk of hean disease. the exposure has been at home, from a smoking spouse. Dose levels from exposure at work have been reponed to be higher because of the larger number of smokers and greater density of smoke." Thus risk associated with exposure at wortc might be expected to be higher than with exposure at home.. Our results do not support this as the oods ratios for exposure at work are less than one (except for women, ex-smokers); atthough the tonfi- dence intervals are wide due tp the small numbers of subjects. Alternative explana- tions should therefore be consldered. such as: the possibility that dose levels of components ofenvironmental: tobact:osmoke which cause heart disease are higher for those exposed a1 home than at work: or inaccurate reporting in this study 2023511'71'7

l'tnp Corlosr in Jbport Ntfinton ond Plzs" S'nddnp 193 •a...~'. irtfq u~ll. in...talw Mqa.a.. allt •~.... p. W.e. L..s..a.r 1 ~ N Mt/~ io .. r.. a+iy Ma.l•C.4..t4.. thl ~.«lr. (tiw•fN I~~} r.7~~ •.eZICs ..~5~ •.ati: Figure 12. Ischemic heart dixase morta]ity tatio in nonutwking wives by smoking habits of their husbands. Comparison between daily and nondaily intake of green-yellow vegetabler . Discusston The age-adjusted mortality rates for lung cancer have been sharply mcrezstttg both for men and' for women in Japan. As only a fraction of Japanese women with lung cancer smoke cigarettes, the reasons for the trend of their mortality from lung cancer have been unclear. The present study appears to explain at least a part of this long-standing riddle. This observation also questions the validity of the conventional method of assess- ing the relative risk of developing lung cancer in smokers by comparing them with nonsmokers. This study shows that nonsmokers are not a homogeneous group and should be subdivided according to the extent of previous exposure to indirect or passive smoking. Although the relative risk of indirect smoking was smaller than tltat of direct smoking, the absolute excess deaths from lung cancer resulting f:om passive smoking must be important because of the large size of the exposed group. Therefore, these results of our current study must be of public health importance, trtrengthenibg already existing evidence (r a health harard from passive smoking ~11-13) (Table 1i). As shown in Figure 9, 47.5% and 32.6% of 158 nonsmoking adult women surveye+d'recently are noted to be exposed to sidestrearn smoke at home and at the workplace, tespextively. One survey conducted in Aichi prefecture in Japan showed that nonsmoking wives are exposed to their husband's smoking 6.7 times a day on the average. Because sidestream smoke contains varieties of cancer promoters ar higher eott- centration than does mainstream smoke, it must be reasonable to eonsider the a

still no statistically significant relationship reported, either when considering any of the subgroups or all subjects together. 6. Any possible relationship between ETS exposure and CVD mortality is high questionable, because it appeared to take opposite directions, depending on the social status of the subjects. In particular, in high social status whites exposed to ETS, the reported relative risk for CVD was elevated. On the other hand, in low social status whites, this relative risk was reportedly lower. It bear noting, however, that no statistical significant was reported concerning,these observations.

Humble, C., Croft, J., Gerber, A., Casper, M., Hames, C.G. and Tyroler, H.A., "Passive Smoking and 20-Year Cardiovascular Disease Mortality amonqNonsmoking Wives, Evans County, Georgia," American Journal of Public Health 80(5): 599-601, 1990. This report stems from a prospective 20-year follow-up of a group of rural women, both blacks and whites, in Evans County, Georgia. The 1990~Humble, et al. report specifically followed-up 328 white and~ 185 black women who had never smoked~ and whose husbands also either never smoked or were current smokers. Determination of the smoking status of both the wives and their spouses was assessed at baseline in 1960. The primary endpoint was the broad~ category of cardiovascular disease ('CVD) mortality. During the 20-year follow-up, 147 deaths occurred, 76 of which were attributed to CVD. After controlling for age, cholesterol, blood pressure and body mass, a relative CVD risk of 1.59 was reported for nonsmoking women married to smokers compared to women married! to nonsmokers. A relative risk of 1.39 was reported~ for all cause mortality. Neither value was statistically significant. Criticisms 1. The women's smoking status was determined in 1960. A,i_ 1-hough some data on smoking status were available from 1967, important changes in smoking could nevertheless have occurred during NO ~ ~ the 20-year follow-up. Some indication of this is from the authors' ~ ~ acknowledgement that 25% of the husbands who reported smoking in 1960 had changed their smoking status by 1967. ~. ~

13unp Canoar in Japort Nufrlftn ond PossMs Smddnp 183 Table 5. Mortality rate for ischemic heart diseaxs in women by age group and by smok- ing ing habiis of husband: prospective uudy, 1966-.1981, Japan Husband'a aatoting halir Number ut cigarenas a day Nonsmoker fs•+moter 1•1!/d 19*/! Toul Huspand's or g*'oup No. Pop. No. pop. No. rop, , Ns Pop. r 40-49 13 6,229 40 15,034 33 10,764 66 32,027 1 50-59 26 7 791 56 15 642 49 9,620 131 33,253 60-69 65 , 7 120 125 , 443. 12 47 4 651 237 24,214 l 70-79 14 , 755 19 , 1,065 7 , 226 40 2,046 , Tou! 1'16 21',895 240 44,164 . 176 25.461 494 91',540 'M •..1t.. •..fIH ..Nie l..)•f7 wtt •s.lul0.. fY[P{. • Itl 1.0 The .eigllled:poanl ewnnale of rue 1.33 - , 1.63 e.eieand lew- t.00 1.10 6..ed A07i 0.91 ~ 1.06 cnnfidenrz luaos Id.eld-Haensin1 x' aee-taiG p ralue Kt st..o..ol us urt uTla 2.0 GllCt. ff1[.. TMY lYi Iv • an. ba.rr. t..a/. •ti-./ IYtWO'f .al YOala IIYiT Mpl.. f .IrIUr r rar ~ eUMh"slM I Figure 6. Standardized mortality rate ratio for selected causn of death in 91,540 nonsmok' ing women by smoking habita of their husbands. (Prospective audy, 1'966-1961, Japan.) L=•-  1 1* • I.N 1.N I.N /:. lft 11.15 !Il'amd olenaua. =r 2.073 0.6504 2.0723 Mosr-ull 0.1976 0.0191 p due 0.01909 1f[I[.1 C e..aT eftlat 1:)1 tMt CfICt 1• • 1M1 ai.+efa. WOIIC M{'I~.Ieli IN /. • Ipl 1.Y j t:M r t.-11O{( „ft a[ml.%aa n+4'ae,.w lf~h 1- 1./i a1N l./t' I..u "l •rf rft Ir. .N. r1t! M R a a M{ Yti Nl.r t.\tl t/.}t YI./' t.Ml YIY 1f~Y //r{I YIY)1.11 AUI -Ylb tIM lIYI i ONE 11Q .. .11LIt i0. iRli •

PASSIVE SMOKING AND ARTERIOSCLEROZ7C HEART DISEASE 921 that some of those presumed to have zero or moderate exposure at home were actually subjectedto moderate or heavy passive smoke at work or elgewhere outside the home. In this population and during the years of the study, among women aged 25 and over, about 50 per cent were nonwork- ing housewives who would be less likely to be exposed to tobacco smoke outside thee home than men, the vast majority of whom were employed This may in part explain the greater consistency over age groups among women than among men in the in- crease in relative risk with indicated level ofezposure. A11 smoking data were obtained in the 1963 census, so no provision can be made for changes in smoking habits which we know took place as a result of publicity about health effects of smoking. Data from a 1975 private census replicating the 1963 census show that the percentage of current cigarette smokers in~ the 40- to 49-year age range, for example, dropped from 78 per cent to 44 per cent among men and from 50 per cent to 36 per cent among women. On the whole, then, our household passive smoke exposure scores based on 1963 cen- sua data will tend to be higher than the actual exposures in later years and to that eztent may exaggerate the amount of ex- posure required to match with a given risk of deathfrom arteriosclerotic heart disease. We also have no data on changes in the household composition which may have oc- curre& prior to or after 1963. Thus, we implicitly assume that any such changes occurred randomly in the population. We have very little data on other risk factors for arteriosclerotic heart disease in the study population. We have tried to ad- just for some: smoking, by restricting the study to nonsmokers; age and sex, by as- sessing the risk separately for eight age-sex groups;'and housing quality, marital status, and years of schooling, by binary variable multiple adjustment. A fumal' check by mul~ tiple logistic and Poisson regression adjust- ment gave virtually identical! results. Two other studies encourage us to disregard hy- pertension and cholesterol' as possible con- founding factors. The Garland et al. (6, 7) study showed no significant differences in systolic blood pressure, obesity index, and plasma cholesterol between women married to present or e=-smokers and those married to men who never smoked. Sim'iLarly, the Svendsen et al. (9) study showed no signif- icant difference in blood pressure and serum cholesterol between men whose wives smoked and those whose wives were nonsmokers. However, other factors such as diet and exercise might differ in families with and without smokers; we cannot ig- nore the possibility that such differences could influence our findings. :In summary, this 12-year study of a non- smoking population of white men and women aged 25 and over suggests that non- smokers who live with smokers are at a higher risk of death from arteriosclerotic heart disease than those who live with non- amokers. It seems reasonable to suppose that tobacco smoke is a factor in the in- creased risk. RETERSNCEB 1. US Department', of Health and Human Servioes. The health consequences of smolcint-cardiovas- cular disease: a report: of the Surgeon General! Washington, DC: US GPO, 1983. (DHHS publi- cation no. (PHS)84-50204). 2. US Department of Health and Human Services. T6e health consequences of involuntary smokin~ a report of the Surgeon General. Washington+DC: US GPO,1986. (DHHS publication no. (CDC)87- 8398): 3. National Research Council. Environmental to• baeco smoke-measuring ezposuees and aseessinj health effects. Wi..hincton, DC: National Acad- emy Press, 1986. 4. Lee PN,,Chamberlain J, Alderson MR. Relation. ship of passive smoking to riik of htna cancer and other smoking-aasociated di.eese. Br J Cannr 1986;64:97-105. 6. Gillis CR, Hole DJ, Hewthorne VM, et aL Effect of environmental tobacco smoke in two urban oommunities in the west of Scotlaad. Eur J R.spir Die 1981;65(Sappl 133):121-6. 6. Garland C, Barrett-Connor E, Svaraz T4 et eL Effects of passive smoking on ischemic beert dir ease mortality of non.mokera: a prospective study. Am J Epidemiol 1985;121:64,5-50. 7. Garland C. F.rr.tum Am J Epidemiol 1985;

J Table 10. Iarhernk hean dieea.e mortality rate In nomnrokin0 wive>I by emokin6 habit of the husband: eom- periann between Orten-yellow ve6elables intake daily and nondaily I I 1 Hu.b.nd's enwklng habit L.-e_eker Nonenakee .e 1-19/da2 :20lday Wite's edl.s babie Onen-Yellnw .eVuWes M.mde-mension x' P vdue (Iwo teiled) Deily 2.307 0.02103 Nondallr 0.02t1 0.41222 Total 2.406 0.01613 Creea-yellow .eteublee Daily Nondelly DdIF Nosddl2 D.ily Nendell2 Heeband'. Lchemk letheslc hps. Heert D. Pop. Heart D. /echesie Tsp. Heed D. leehea.k Isp. Heart D. Lcheslc lechtsk Tb'. Heart D. rep. He.rl D, Oeedpolw Age At;rkuhure 40-49 1,956 6 344 2 3,050 /S 091 7 7,037 14 399 t 30-39 2,603 11 692 4 5,196 23 1,616 2 2.5" 21 926 5 60-69 7,339 30 723 6 3,106 35 , 1,7]9 24 1,366 21 !61 6 70-79 23e 2 63 3 287 10 139 1 45 2 44 0 ahen 40-49 2.422 1 1.303 2 7,20e 10 1.603 s 3.377 12 1,7s1 s 30-39 3,181 6 1,113 3 6,732 le 2,06 11 4.633 17 1,677 6 60-69 2,266 21 770 e 4,066 » 1.510 1] 1,906 11 597 9 70-79 216 7 216 2 371 6 448 2 61 3 56 2 Total 16.463 6S 3,1)0 90 71.11e f73 10,066 63 19,233 101 6.206 35 C.rrd 1.td ieprlati.e: 91360 teche.k beat dlaaeet 494

156 ?*esti Hiroramo Tabie 7 b. (omt.) H..baedr Lz -.moker sr Nos.moker w 1-19/day t 201dsy (}tan) Occupationb No. Pop. No. Pop. No. Pop. 6 9 1 31 ' D4 7 1 ' 43 3 82 2 ~ 55 tl 10 !03 40 1,784 37 i. 736 t 9 2 121 3 208 92 10 24 925 25 1.607 7 472 70 + ToRal 14 755 21 1.065 ! 226 1 32 30 3 2 1 21 14 4 • 3 1 1s 36 R 4 48 1 73 2 20 5 7 323 13 446 4 29 6 1 1 0 7 1 - S 1 tl 1 •7 2 119 1 36 9 11 19 2 10 4 213 3 322 1 61 •Sundard.ed Ruk Amc. 1.000 0.969 1.034 l/aiud.ma~.on.¢: -0.129. enruil p vdoc: 0.4i66B. 60ceypr en: 1:'rokmon.1 .nd neAnicat, .~arlers: 2. aeanrgnm and elrriib.: 7. deric.t and rdaued .oAen..4. rlm rer4,en: S. tammrn. lu,nbrrmen. and fiJicrmen. 6. .orken in minint .nd Quv.yin6 arevpu,om: 7: ,.wYen '.n, van+pon..ndmmn.unicaon oreupuiasv. f. e.tiuvra, peoduction ymcesw aohen...nd I1En.en. 9.,we.'.iee .ohen: 10t fm d..ufi.b~k aed.m reponed Comparison of the Effects of Ac#ive Smokir>0 and Passive Smoking When the risk of lung cancer in nonsmokers with nonsmoking apout+es was taken as a unit, a definite dose-reponse relationship was observed, the highest risk being -iin heavy active smokers, lollowed by mild active smokers, then heavy passive smokers, and then mild passive aaohers (Figure 7). The risk gradient was similar both in men and in women (Figure 8). A signifa`altdy ekvued risk of lung cancer also was noted for nonsmoking husbands with smoking wives. Because the size of population exposed to passive smoking is quite large in the -tase of women, the effect of passive smoking because of the husband's smoking was estimated as 65 9b of that of active smoking. Our recent survey showed that 47.5 S and 32.696 of,]apanese adult women were being exposed to passive smoking at bome and at the workplace, respectively (Figure 9), 'Fherefore it must be a sound estimate that the total effect of passive smoking is approximately equivalent to that of active smoking in women: However, as a majority of adult men are stiR smokers„the total eJkst of passive smoking relative to active smoking must be on I

Lee, P.N., Chamberlain, Ji. and Alderson, M.R., "Relationship of Passive Smoking to Risk of Lung Cancer and Other Smoking- Associated Diseases," British Journal of Cancer 54: 97-105, 1986. Lee, et al. performed a hospital-based case-control study in England that was initially designed to examine disease risk in relation to cigarette smoking. However, as the study progressed, it was also decided to collect information on ETS exposure, the primary estimate of which was based on spousal smoking habits. However, questions were also asked about other possible ETS exposure sources (at home, at work, during daily travel, and during leisure time) from which a combined index was estimated. The cases were hospital patients who had diagnoses o either lung cancer, chronic bronchitis, ischemic heart disease or stroke. The controls were hospital patients without these diseases and were matched to cases on the basis of sex, age, and several other variables. Lee, et al. reported that ETS exposure was not statistically related to ischemic heart disease, nor to any of the three other diseases considered in the study (lung cancer, chronic bronchitis, and stroke). It was concluded that any potential risk of ETS "is at most small, and may not exist at all." The authors discuss several limitations with previous studies of ETS.

Criticisms 1. For neither males nor females, no statistically significant relationship of ETS exposure with heart disease was reported. 2. The authors characterized their data as not indicating an~increased disease risk associated with ETS. 3. The authors note several major flaws in conclusions from previous studies of ETS and disease risk. These flaws relate to low levels of ETS to which nonsmokers are exposed, unreliable exposure data, misclassification of smoking status, and specific scientific criticisms of individual studies. 4. The sample size was very small. 5. This was a case-control study and suffers from common problems with such studies, including difficulties in establishing appropriate groups and controlling for potential confounding variables.

4 THE MEDICAL JOURNAL OF AUSTRALIA Vbl 154 June 17.,1991 ORIGINAL ARTICLES --~--- Passive smoking and the risk of heart attack or coronary death Ansu7tc 1 I3nhcnna Hi)an• M Alcsandrr. Richard F Hr11cr and Dcborah M Lln.:d Objecttvts: To estimate the prevalertce ot eumpand with those not exposed but wen pass.e sanoking in an Australian populstion, not as hiyh as eaneentrations 11t aetiw the magnitude of reak of myocvdial iMuetion strwkers, or coronary death associated witt+ passivt Conclusions: Passive smoking inerras.s smoking and the ettent,to which tibnnogenthe riskof coronary heandisease tnd oorxentrations might be affected by passive H+creased fibrinogen concentration provides amoking. a marker of Its eftOct. Design: A populetion.based ease-eontrol •(Med J Aust 1921. 154: 7i3-797) Study of myocardiau infarction or Coronary death and passive smokinq, and' meuure- onant of fibnnoqer. in s random sample from the same population. S.ftinQ and'paRrcipants: Residerns of the Lower Hunter Region of New South W.Ies aged 35-69 years in 19a8-19a9. Cue subjects were slli those who suffered rnyocardial intarctton or coronary death. Control subjects were participants in a risk factor prevalence survey. Outcome measures: Myocardial Intaretion or coronary death, defined by critena of the WNO MONICA Project, and tibnnogen Con- eentration (measured in controls on6y): Results: Prevalence ot passive smoking att home was 20% for mals case subjects. 13% for maie control subjPcts. 29% for female case subjects and 19% for temale control subjects. The t:orresponding prevalence rates for passive smoking atwork were 40%, NN, 41% and 37%. Odds ratios of myocardial Infarction or coronary death for active @nokertl compared with non-smokers were 4.70 (9SK Confidence interval (Cl1, 3.35-6-8a) Yt women and 2.71 (95% Cl, 2.07-3.53) In fnen. For women the odds ratlos of myocardial iIntarction or coronary death tor I iS well established' that cigarette smokin9 increases the risk of ischaemic heart disease.'•r There is also evidence tnat passive smoking is associated with increased ri:k.••' One of the mechanisms by which smoking acts is by increasing tibnnoqen concentrations whiCh in turn promote tnromtwqenesrs.""' This effect may aiso occur with passive smokinp," To investigate the relktionsnipbetween passive smoktng and iscnaemrc hean disease we conducted a populauon-based' case-control study and a study ot tibrino• gen in, a ranoom sample trorn the same population. Wlk wished to estimate the prevalence oU passive smoking in an Australian community: 10 estimate the magnitude of risk of' heart attack or coronary death associated with, passive smokin9 and to investigate the extent to which tibnnoflen concernrations might be aNected by passive smokinq. th6Neipoeed to passive smoking att home Methods were 2.46 (95w G1. 1.47-a.13) among non- arrwkers and 1.48 (95% Ci, 0.67-3.30) anwng The settmp tor this swdy is provwed by tne ei-amoktrs. For men the odds ratioa for World Meanh Organaatton (WHO) MONICAA passive srnoktng at home were 0.67 (!S% Ct, Pro)•Ci which is monitoring trenos and dettr- 0.50-1.66)for nornsmoken and 1.78 (6S% Cl,: mrnants o1 cardiovascular disease in weCdefuted 1.13-2.76),fores•smokers. The odos raties populations over 10 years. One of these popu- for passi've smoking at work did not suggest latibns is m the Hunter Regron of New South Mtonased nsk. Fibrinogen concentrations Wales. Australia. covering the local gOMrrMrMnt ware generally higher among people exposed areas of Newcastle. Lake Mscou.ne. Gssnock., to passive smoking at horne of work Marttan0 and Pon Stepnens. C.+ers to. Ctrniur Ewdsrmotogy and arosuustre.. pavra Waoaraon Ctrmui, Scwnces auttdrng. hoyai HNwcaafu. nosprur. Nt..c.stle. rtsw2300. ..wra J oee,a, Msc *+c P.a...a a sear.Ka wary M w..ro... s+..WVrC. .•w.e+ w.qw a,{wYe. r rMWr Me eS MZ rRAC' 0roMS1M M. GO-ftwr. WeeryptOTM M LbrO. U MYSbAN O-KM w CO-w.+. MNC~1f Ca.~ warw• . Jpae.o~ ••a..w r aeu...,e u-.w•.., a w...c..~r wsw Taos rt.ww:. Mn 0 M w..w.r cor,. v Crrcr Eae.ewa*, re Mwwrez t>w.wr.er a u.rcasur rrSW tsw Cases The Case subhcts tor this study were ali res- dlnu of the study area aged 35-69 years who durrn0 the study, period had a tatal or nCn-tata1 delinue or possible myocardAl uuarcuon or a eaonary,0tam (wnn msufficrent mformauon tor more specrtrc cttas,frcauonl: Diagnosis was made under the crtteru ot the WHO MONICA Propct.'• The prncipre uMp was to register 0oubttul,uses and suba.Quentty to e:c/ude trom artatyses tnose wnrh 04 not meet, the diagnostic crnerra. Various ouanry Control measures were use0 to Gneck tDmp/elenesf Of Cast aactnarnment. Thest included compir. aoro with ttx hospital morotdey Oats system sro offrerat eeatn records obtsmea trom the Australian Sureau ot'Statuttrs.'• The study perqd was from July 1.,1g88. to October 31. 1989 For people who hao more than one avent dunng this period onlv data for the first wem, were mauded rn the anaiyser presfinednere.d in a0drttort to the Oragn@sUC nforrnatqn. data were colyaQaO On pemoqrtaohC charanerrst,cs. medical history. cigarette srtfokrngan0 exposure to pasirve tirnokrng at, home and alwork: Currenl,smokers were rqtl asaed aDOut tnerr exposurt to passrve srttokrng. SurvMng case sublens were mten..e...o by tne stuoy nurses whde they were st,lu in nosDnai (m this population almost all ttte people wrth a suspected ~hean attacR who atHMVe long enough are somttted to hospital). Most csse sublects +.rho dted some days ahee sOmrss,on to hospital i had been srmilany intervrewed by the atudy nurses. For case subtects who ato before hospriatrsatron,, m the emerqency room. orshonly anlr a0mrfirOn 10 nN warOs. MtOrmatron was ODtarn.d frbm me{IrCat records. rl avaWaZlt. or by questionnanes marled to reutrves. mtor- meuon aDout smoking behaviour was not obtainable tor 34% pf tatal cases and 4% CN~nOn+ tatal Cases:' dala on pasarve smokrngwert missing tot about 16% of an cases. Controls 793 N vl ~ Pamnpants in the eommurntybased nsk taetor .~ prevalence study aonoucted as pan ot the WHO l~~ MONICA PrDlect were control suDlects lor th e ease-control Study an0 were also the suDlects tor the swdy o1 frbr,noqen The risk tactor stuoy ~ was conauered rn June-December 1068 ane June-Novemtxr 1989 A stranbed random

794 ssmpN of tne study t>opulatron was se/ected from the Cornmonweatth.Electoral (ioU with the tantpmg rranton being qreater tor tne older aqe strata. People cnosen foT the sample were invaed to anena sruor centres to complete s sen+ administered quKtqnnsrrt and to have physical t7Nasurements maoe and blood ssmplestaken. E',atensrve systems ot remrnders and folYow• up were used to encouraqe participation. The response rate torr full participation in the studyy for tne aqe group 35-89 years was 63%. Some people w/'W were unabk1o anend a etu0y Cerqre toF the physical maaiuremems anC blood sampMs dkt..noMVet, ronlplete a Dnet OWa• tionnaite which . C,overed demographic CharaC• ]ehfbci..smoking bertsvwurand ,msdiCallLltory.. Others were interviewed at home to obtain this 1nf'Onltatton. b1Cltrsi0nn of data tPomm all tHeet people. gives a response rate of l0% /br tns ape group. For comparisons of smoku+p behaviour among cases and ~ Controls. data tor, all the COrttrof ailb)tCts wPlo participated tul/y m the risk taClor auney or who ony.completed the brief questl0n•naire: or who pantCtpated in horne Invemews were tasetl to teouce non-response bias. tntor- mation on passive smoking. tlowever„was only ootarned from those who panrcrpated tuly in3he survey. As for cue:sub)ects. current.smokers in the Control.group were nouaske0 about their exposure to passrve smokrnp:, Fibrinogen 81ood samples ootained frorn oeot„e wno panrci- psred fully in the risk factor survey were assayed lo determine tibnnoqen C9nCtntrattoeta. Trus was not done for case suofens because this was. of CDurse, impossible tortatal Cases and for tqn• fatal cases n+e Coneentratwn of fibrrnoqen ut the blood could be aMeCteC by the myqcardial ntar9- UOn and treatment for some tlme atter the event:.. Bkboo samples were anttcoaQulated mrmeeiately stter Coblectron with disodiumm eCetate in CommeraatYy, supplied tubes.,Plasma tibnnoflen was assayed by radiormmunodiNuston using eommeneally prepared plates (Behrrnp. Germany) end Norpartigen Ptasma Standard (Bennng. Germany),as the stanoard! StatlsUul analyais Age. sex and a prior history of Ihean disease are lmponant conf0unoers 01 the relationship t>erween risk of heart anaek or eoronarydeatn and ttrnokm9, ep tne estimates 1rom tne Case•- Fpntroli Study were ao)vsteC for these factors. . Y71e stattstrcal program GLIM' was used to '~SItulate ad)ustetl Odds ratiCs and approsilrlate 6onfoenCe intervals by 1oQefttC reQreeaqn." Terms forage (five-year age groups from 35-39 10 6"9 years),and history (prevrous myocarotaw infarcuon or history Of Other uenaemrc heant disease versus no history) and interaction between these two factore ..ert included in the mooel'as weU as terms for the smoking vanablts. Any reuuonsntp t»Iween passive smokrnq THE MEDICAL JOURNAL OF AUSTRALIA, Vol 154 June 17. 1991 ano tht nsli.or heart disease may be aneCted by the person s own smoking history ano ao results tor non-srrlokers and ea-amokerswere cakurated separately The proqram Ea•trrto was used to caKulere esya bonhderlee urtervals atnd tests for trtnd for crude o0ds ratqs " Fibrinogen concerrtrattons are approstmaleNy loq-nomUlly distribute0and tney increase with age and body mass noex (kqrm'). ThMelore the IDQarithmrc.transtoRRatlOn lraa Ufed and m.an values for snloktrl9 groups ware Compared atterr adlvstment for the covarrates o1 age ano booyy mass inoex. The procedure GLM 01 tne SAS program wes usa " For presrntation 01 the results. esunated mean eoncentratrons (prL) art given forpersons sped 50 years witn a body mass r+des o1 25. Rasutts Prevalence rates tor passive smoking at home were higher among cases than Controls and among women compared with men. Prevalence rates for passive smoking at work were around 40% for alf groups (Table 1): Many of the participants in the Study. particularly the case subjects, were retired or. especially among women, did not work putslQe the tto*Te. so the ntJrntxrs available for analysts of passtve smoking at work were smallentnanthose for pissrve smoking at home Fon women the odds ratios for heart attack or coronarydeath for those exposed to passive smoking at home Comp2reo with those not exposed were 2 46 for non• smokers (95% Confidence interval (CIJ. 1.47-4.13)iand 1.48 tor ex-smokers (954e Ct, 0W-3•30) after adjwstment for age and hrstory of heart disease. For men the corresponding ad/usted odds ratios were 0:97 (95% Ci. 0.50-1.86) for non-smokers and 1.78 (95% Cl. 1.13-2.79) for ex- smokers (Table 2). The odds ratios toe passive smoking ar work were not high and the confidence intervals were wide (Table 3). To eompare the magnitude otinsk assoc: ated with passive smoking with risk alioci- aled with active smoking, adjusted odds ratios 1or t:urrent smokers and ex-smokers compared with non-smokers are shown in Tabte 4. There were consistent and statist~ Cally slgnificant dose-relateC gradients with Current, smokers having the highest odds TABLE 1: Prevalence of passive smoking at home and at work among cases and controls who did not themselves smoke At home At work Age lyearsr Cases Con:rols' Cases Contrors' Man 35-a9 30% 10ao •?CI" s.oo, 50-59 27% 1840 43an aear, 60-69 1500, 1300 290r 3040 35-69 2040 12610 400., uar, Women 35-4 ~ 36?0 22r+v 50p•o 394r 50-59 47% 25ab 50C6n 454 60-6? 23ac+ 121IL0 2240 18or 35-E9 2D0ro •9t'o a4a 37ao 'Da:a "7Tcan:rvc «nc oencAaler: 1,rir. , iT,r ra. yccx s::,o, TABLE 2: Passive smoking at home and risk of heart attack or coronary death •(odds ntios and 95% confidence intervals ICIj)! Nr,rnbers of subfects Crude Adlusted? ' Gases Corrrrols• oods rauo (Ct) oaos ratio (Ctl bten Nornamokers E=aoseo 22 34 Not e:oot+ed 167 259 1,04 /0 56 14 1) 0 97 to.So 1 .96) rs K E e s<-smo Eiraosed 8o 49 1.80 (i 20.2 74) 1 78 (1 13. 2.79) N6R ext70ied 256 2E3 Women Non.;7rwkars Er»sed A3 9o 1 61 (i 04 2 47), 2 46 (+ A7 s 13) No= eeaoseo 1 t7 433 E.•vno,ers Eiooseo 23 30: 1 63 10 82 3191 i 1 48 (0 67 3 30 No:'e=DOsed~ 5' 121 -.:a:a "¢'r• eonlrods wno aan~~?a1e_ t•n' ' •ne 'RM7s:eC rO, aqe anC n4oprtv rnvOCaroJ ~aIO V+ a OnY' 5.r%.Wnr rMa•- n YaseCn. UJDWCS .ar• wff'runo• aoo.t nsrort, ofnea,• oAea;e we nuuoen. " ma ude 2Q23~1.1715

11

10

Criticisms 1. This study is available only in the fo= of an~ unpublished abstract, which provides very few details on which to base an evaluation. 2. The source of medical information about these nonsmoking women was highly questionable. It was based only on self-reported health history. There were no reviews of medical records or other evaluation of these self-reports that might have been useful in assessing their accuracy or reliability.. ~ 3. The sample size was very small, consisting of only 23 self-reported heart attacks. 4. The credibility of the entire study is called into question when~one considers that the relative risk that Martin, et al. report to be associated with exposure to ETS is several times greater than~ what the Surgeon General claims is the overall heart disease risk in smokers. 5. No data were available on possible ETS exposure outside of the home, such as the workplace.

194 TokssN Firoyvno '"Tt.ble 11. Passive orroicing is harriedoua to health 1. Eti.terus of tmic +ub.tancat (induding caranctoa) in .idcstrea+n twokc rmJy at ligher amtaen- _vation than in enainetream .noke. 2. Esiwexe of a l.rte atenber of nonvnoilen.rbo have to inliak ridetream .mokr 6aquentlr and in- tenst.d)' ior long yeara at homc and7or at the veorkplace. ~. Existence of tadea[rram .mole oompoerm R blood aud' orine of nommokers apored to pa.ive .ookin:. (eg. oimeine. CZ}Hb in tiiood and Mutagens in rrine.). 4. Eristence of Wncniond abrwrmalities in nonsaoken esposcd 6uviy 1o p..:.T .moivq (eg. eespiratary or tirnJatory function). rS. Lung tiwe damate and destneccion ia chmnic p..i.e .noi<ers r dw..n by ekvsud bydrmy- pedinr esuetioe in urine. -i. Higher incidence of .ekned dueases in nonemoken exposed AeaQy to pua'r.r .enkint (R• pneumonia, bronchitis, astlutu, ialarmic 6ean d'ursae. 4io6 and na.al uiws ort=): w `7. E:perimental eviderce. main effect of passive smoking on lung cancer risk results from the prolonged ex- posure to such promoters in sidestream smoke. The risk-inhibitory efTect of a daily intake of green-yellow vegetables that are rich in 0-carotene must be considered as an additional evidence for such a promoter action hypothesis of passive smoking. The hypothesis also explains why exposure to passive smoking that starts after reaching adult age can significantly influence the risk of lung cancer. The histology of 21 cases of lung cancer in nonsmoking wives of smoking husbands was not essentially different from t!'iat in smoking women (adenocar- cinoma 57.1 %, squamous cell carcinoma 19'.0%„and small-cell carcinoma 4.8%). A ease-eontrol study conducted within our cohort study revealed a significantt dose-response relationship between adenocarcinoma of the lung and the number of cigarettes smoked daily, relative risk being 1.39 and~5.75 for smokers of 1-14 and 15 or more cigarettes daily, the chi square for the trend being 6.848 with a one-tail p value of 0.004. 'Iherefoae the predominance of adenocarcinoma of the lung in nonsmoking women with smoking husbands should not be considered unfavorable evidence for promoter action hypothesis of passive smoking. In passive smoking, ,sidestriam smoke usually is inhaled through the nose, whereas in active smoking mainstream smoke always is inhaled through the mouth. 'Fhis difference ¢oufd be a season for the elevated risk of nasal sinus cancer in passive smokers. The snechanism of the action of passive smoking on the risk of ischemic heart disease, however, tmust be explained in different waps (eg, a combined action of carbon monoxide and nicotine). In stuamary, to reduce the effect of active and passive smoking and to encourage the effect of nutrition, in particular $-carotene intake, would be the most produc- tive course for lung cancer prevention. For selected persons exposed to other known carcinogens, eg, those related to occupation or radiation, such environmen- tal exposure also must be minimized in addition to the preventive measures focused on, lifestyle variables given above. References 1. Hiraya`na T. ProspectisY studies on cancer epidemiolo6o based on eensut population in Japan. In7 Bucalo.si P, Veronesi U and Caacindli N, eds, Proceedings of the Xlth inmernaiional uncer e 2023511780 ,

650 GARLAND LR' AL baalth risks of paaaive amokin` the growirtg caae for control measures in enclosed environmenta. Che,t 1983;8490-5. 12 Weiss ST,Ta=er IB„Scbenker M, et aL The health eflecu of involuntary smoking. Am Rev Raapir Dis 1983;128933--42 13. Garfinkel L Time trends in lung cancer mortality among nonsmokers and a note on passive smok- ing. JNCI 1981;66:1061-6: 14. Hammond EC, Selikotf IJ. Paasive smoking and lung caacer with comments on two new papers. Envie~on Res 1981;24:444 52 15. Friedman GD, Petitti DB, Bawrol RD. Prevalence and correlates of passive smokint. Am J Public Health 1983;73:401-5. 16, Repace JL, Lowrey AN. Indoor air pollution, to- bacco smoke, and public healts. Science 1980--208:464-72 17. Repace JL, I.oerreyAH. Tobacco smoke, ventila- tion, and indoor air quality. ASHRAE Trans 1982:88:894-914. 18. Foliart D, Beno.vitx NI4 Becker CE. Paaaive ab- sorption of nicotine in airline flight attendants. N En`1 J Med 1983;308:1105. 19. Mataukwa S, Taminato T. Kitano N, et aL Etfects of environmental tobacco smoke on urinary cotin- iae excretion in nonamoken: evidence for passive smoking. N Entl J' Med 19&4;311:828-32. 20. Tager IB, Weiss ST, Munot A. et aL Longitudinal study of the effects of maternal smoking on pul- monary function- in efrildten. N Engl J Med 1983;309:699-703: 21. Were JH, Dockery DW, Spiro A III, et al. Passive amoki.tu, gas cooking, and respiratory health of childeen living in aiu cities. Am Rev Respir Dis 1984;129:36fr74.. 22 Tashkin DP, Clark VA, Simmons M, at aL The UCLA population studies of chronic obatructive pulmonary disease. VII. Relationship between pa- rental smoking and children's lung function. Am Rev Respir Dis 1984:129:891-7: 23. Love GJ, Cohen AA, Finklea JF; et all Prospective surveys of acute respiratory disease in volunteer families: 1970-1971 New York studies. In: Health coneequenae of sulfur oxides: a report from CHESS. 1970-71, EPA-650/1-74-004: Research Trian=le Park. NC: US EnviuvnmentiliProtaetion Agency, 1974. 24. Finklea JF. French JG, Lowrimore GR, et aL Prospective surveys of acute respiratory disease in volunteer familiea: Chicago nurxry school study, 1969-1970. In: Health consequences of sul- fur oxides: a report from CHESS, 1970-71, EPA 65011-74-004. Research Triangle Park, NC: US Environmental Protection Agenry. 1974. 25. Schenker MB; Samet JM, Speizer FE. Risk tac- tors for childhood respiratory disease: the effect of host factors and~ home environmental ezpo- sures. Am Rev Rtspir Dis 1983;128:1038-43. 26. Trichopoulos D, Kslandidi A, Sparros L, at al. Lunt cancer and passive smoking. Int J Cancer 1981;27:1-4. 27: Tricbopouloa D, Kalandidi 1, Sparros L, et al. Lunt cancer and passive smoking. conclusion of Greek study. Lancet 1983;2:677-6. 28. Correa P, Fontham E„ Pickle LW, at al: Passive smoking and lung cancer.Lancet 1983;2:595-7. 29. Knoth A. Bohn H, Schmidt F. Paasivrauchen als Luntenkrebsursache bei Nichtnucberinnen. Mad Klla Pras 1983;7834-9. 30. Cheung CW. Zahlen am Hong Kong. MMW 1982;124(0o. 4):16 31. Hirayama T. Non-smoking wives of heavy smok- en have a higher risk from lung cincer. a study from Japan. Br Med J 1981;282:183-5. eancxr. 32 Hinyama T. Passive smoking and lung (Letter): Br Med J 1981;2821393-4. 33. Hirsyama T. Non-smoking wives of heavy smok- ers have a higher risk of lung cancer. (Latter). Br Med J 1981:283d116-17. 34. Hirayama T. Non-smoking wives of beavy smok- ers have a higher risk of lung cancer. (Letter). Br Med J 1981=:1465-6. 35. Repace JL Consistency of research data on pas- sive smoking and lung cancer. Lancet 198411:506. 36. Miller GH: Lung nncer a comparison of inci- dence between the Amish and non-Amish in Lan- caster County. J Indiana State Med Assoc 1983;76:121-3. 37. US Department of Health, Education, and WeJ- tare. Surgeon GenernL Smoking and bealth a reportof the sur`ean general. Part 1. The health consequences of smoking. WaahinPton, DC: US GPO, 1979:1-12 38. Criqui MH, Barrett-Connor F. Austin M. Differ-. ences between respondents and non-respondents ~ in a population-based cardiovascular disease study. Am J Epidemiol 1978;108:367-72 39. US Department of Health, Education, and Wel- fare, Public Health Service. Eighth revision of the international clasaification of, diseisea, adapted for use in the United States. Waahintton, DC: US GPO, 1968. 40. Bamtt-Connor F. Criqui MH. Klauber MR at aL Diabetes and hypertension in a community of older adulta. Am J Epidemiol!1981;113:276-U. 41. Criqui MH, Barrett-Connor E, Holdbrook MJ, at a1 Clustering of cardiovasculhr diseax risk fac- ton. Prev Med 1980,9 525-33. 42. Austin MA. Berrcyesa S, Elliott J7.; at aL Methods for determining long-term survival' in a popuL- tion-based study. Am J Epidemiol 1979;110:747, 52 43, Fisher RA. Statistical methods for research work- eet 5th ed. Edinbursh: Oliver and Boyd, 1934. 44. Mkntel~N, Haenszs( W. Statistical aspects of the analysis of data from retrospectivr studies of dis- ease. JNCI 1959;22719-48. 45: Co: DR. Re=resaion models and life tables. J R Stat Soc Ser B 1972;34:187,220. 46.: Dixon WJ! BMDP stati>ucal aoftWare 1981L Berkeley: University of California Press, 1981. 47. Parkes CM. Effects of bereavement on physical and mentalihealtb-a study of the medical records of widows. Br Med J 1964;2:274-9. 4& Rses WP, Lutkins SG. Mortality of bereavementN Br Med J 1967,4:13-16. ^ 49: Maddison D, Viola A. The health of vidows in thb+/ year, ffollowing bereavement. J Peycboaom ReN 1968;12:297-306: 50. Parkes CM: Benjamin B, Fitzcerald RG. Broke heart a statistical study, of increased mortalit4ill among widowers. Br Med J 1969;1:744-3. 51. Harkc H-P. The problem of `passive smoking. Munch Med Wocbenschr 1970;112:2328-34.

Palmer, J.R., Rosenberg, L. and Shapiro, S., "Passive Smoking and Myocardial Infarction in Women," Abstract, CVD Epidemiology Newsletter No. 43, 29, Winter 1988. This is a hospital-based case-control study which examined 366 female myocardial infarction (MI) cases in relation to spousal smoking status. A relative MI risk of 1.2 was reported for nonsmoking women married to smokers. Also, elevated MI risks were reported~in smokina women, depending on the smoking status of their husband. In women who smoked less than 25 cigarettes per day, the reported relative MI risk was 2.9 if the husbands did not smoke, compared to 3.9 if the husbands did smoke. For heavy smoking women, these estimates were 6.3 and 8.3, respectively. The authors stated~ that these trends were "not accounted for by the known risk factors for MI." It was further stated that these results support an~ elevation of MI risk in relation to spousal smoking, and that these results "are unlikely to be explained by selection or information bias." Criticisms This is an abstract only, apparently not subject to peer review, appearing only in a set of abstracts submitted for presentation at a cardiovascular disease epidemiology meeting sponsored by the AmericanHeart Association. 2. Since this is an abstract only, few details are available on which to evaluate the study.

3. Although several figures for relative risks were reported, there was no information indicating that these figures were evaluated for statistical significance.

Martin, M.J., Hunt, S.C. and Williams, R.R., "Increased Incidence of Heart Attacks in Nonsmoking Women Married to Smokers," Presented at the Annual Meeting of the American Public Health Association, Abstract, 1986. This study is available only in abstract form, based on a presentation at a 1986 meeting of the American Public Health Association. The study was based on the self-reported health history and smoking status of a group of parents of Utah high school students. Women~between the ages of 30 and 59 who had never smoked, were classified according to whether their husbands were smokers, never smokers or exsmokers. Of the 7,115 nonsmoking women, 23 reported having had a heart attack. The authors reported that, compared to women whose husbands had never smoked, women married to smokers had a relative risk of 4.4. After statistically controlling for family history of coronary heart disease, hypertension, diabetes, weight, alcohol intake and amount of exercise, this relative risk was 3.4. Both values were reported as statistically significant. The authors also suggested that the risk may have increased with length of exposure, and that women married to former smokers also had an elevated risk, although not as great as for women married to current smokers. The authors concluded~: These results suggest that women married to smokers have an increased risk of heart attacks as a result of exposure to environmental tobacco smoke.

12

4ulp Ccncer in Japart Nutrtnon ard Pasrsiw Sinohlnp 195 con`resa. Cancer Epidemiolo8y, Fnvironmental Facton. V'ol. 3. Amsterdam: Faseerpta Medica, 1975:26-35. • 2. Hirayama T. Epidemiolosy of lun8 cancrr Ila.ed on population .tudies. In: Finkel A J aad' Dud W C, edi. Clinical implications of air poUution rt:w.ut:h. Chicago: The Amer>vn Medical Association, 1976:69-18. 3. Htrayama T.,Smokin5 and cancer. A prospecei.e study on cancer epidemiotoBY hased on census population in Japan:,tn: Sieinfeld J, GriRtths W. Ball K, and Taylor RM, eda, Praeedinp of the 3rd++orid conference on smoking and health 1975. U.S. Department of Health. Education and Welfare Publ (\iH')77-1413 WashinRton, DC: 1977:65-72. A. Hirayama T. Prospective studies on cancer epidemiolofy baaed'on eensus population in Japan. In: Nieburp HE, ed, Third international symposium on detection and prevention of rarrer, Pt 1, Vd 1. New York: Matcel DtkYer, 1977:1139-48. 5. Hirayama T. Smoking and cancer in Japaa, A prospective studyy on cancer epidemiology based on census population in Japan. Results of 13 yean follow up. In: Tomina8a S, Aoki'K, ed., The U'ICC Smoking Control i Workshop, 1981. Naaoya: Univcrsity of Nagoya Press, 1982:2-8. 6. H'irayuna T. Epidemiolo6ical aspects oflung cancer in the Orient. !n; Ishiltawa S, Hayata Y. Suemasu K, eds, Lung cancer 1982. Amsterdam: E:cerpta Medics, 1982:1-13. 7. Hirayama T. Diet and cancer. Nutr Cancer 1979;1(3);67-81. 8. Hirayama T., Does daily intake of green-yellow vegetables reduce the risk of catrcer in man? An example of the appiication of epidemilo6ical methods to the identification of individuals at low riak. I'n: Bartsch H, Armstrong B. Davis W, eds. Proceeding of symposium on bosr facton in human carcinogenesis. International Agency for Research on Cancer Scientific Pub139: Lyons: World! HealthOrganiration, 1982:531-40. 9. Hirayama T. Non-smoking wives of heavy smokers have a higher risk of lung canca: a study from Japan.,Br Med'J l',981;282:183-5. 10. Trichopoulos D. Kalandidi A, Sparros L. MacNtahon B. Lung cancer and passive amokin~. Int J Cancer 1981:27(l):1-4. 11. Brunnemann KD, Adams JD, Ho DPS, et di The influence of tobacco smoke on indoor ar mospheras. 11. Volatile and tobacco speciflc nitrvsamines in main- and sidestream srrwk's and' their contribution to indoor pollution. In: Proceedings of the 4th joint conference on the srnsin8 of environmental pollutants. New Orleans, 1977. Washin8ton, DC: American Chemical Society. 1978:B76-80. 12. Brunnemann KD, HofTmann D. Chernical stadies on tobacco smoke UX. Analysis of.oiatt7e niteosamines in tobacco smoke and polluted indoor environments. In: Walter EA, Griciutc L. Gaste6naro M, eds, Environmental aspects of.N-nitroso mmpounds: International Asenc7•, fx Research on Cancer Scientific Publ 19. Lyons: World'Health Organization, 1978:343-56: 13. White RJ, Froeb FH. Small.airways dysfunnion in nonsmokers chronically exposed to tobacco smoke. N En6i J Med 198Q',302:720-3. `

Idt P.N t_r-.f ri al Tabk /1I Cnncnrdannc hn.reen st+nuse's manuracturtd eigarette smoking hahits as repnrted a dtrenly and rndirectiy Sex of patrrnrlcasr consrol saatms A4 a/t Frrnalr Casrs Ca.urois Cnsrs ConrroLs Tord Stwusc a smr+ker somcumc in marri.ge acxnrding tn Subjen and spouse 2 6 5 13 26 Only suh)ect I 0 0 3 4 Only spouse 1 1 3 0 5 Neither 3 11 1 9 24 `/, subrct/spouse agreement 71'/,. 94% 6T:; 88;; >!S% Spouse a smoker during ycar or hospital interview accordrng los Sub1ect and spouse 1 6 2 1 13' Only sub1cct. 0 0 0 1 1'. Only spnusc 1 0 0 0 1 Neither 5 12 7 20 4.4 '/,'suhyw/spousc agreement 96. ; g6'; 100„ 100;; 96i 97•,; spouses (3•/.) in respect of smoking during the year of hospital intcrvicw. Thcre was no eonsistcnt pattern in the direction of dtxrepancy: Table IV' summardscs the results of analyses earried out rclitting 7 indices of passivc smoke exposure recordcd in the hospital intcrviews to risk of lung canccr among lifcir+ng non-smokcrs. Here the controls used for eomprrison arc all never smoking paticnts with discases classified as definitcly or probably not associated with smoking who completed the passive smoking questionnaire. Overall the results showed no evid'cncc of an effect or passive smoking on lung cancer incidcnec among lifelong non-smokcrs. In male patients, relative risks were increased for some of the indiaxs but numbers of cases were small and none of the differences approached statisticat significanee. in femalcs, where numbers of cases were larger, such trends as existed tcndcd to be negative and indccd were marginally significantly negative (P<0.05) for passive smoking d'uring trrvel and during Icisurc. For the combined sexes no difTcrcnccs'or trends were statistically significant at thc 95'/% confidence kvcl; such trends as existed lending to be slightly negative. The relative risk in rclation to the spouse smoking during the whole of the marriagc was estimated to be 0.80' for the sexes combined, with 95•/% confidence limits of 0.43 to 1.50. Standardisation for working in a dusty job; the variabk apart from smoking found to have the strongest asvociation with lung cancer risk in the analyses dcscribcd' in Alderson rt a/. (1985), did not affect the conclusion that passive smoking was not associated with risk of lung cancer among never smokers in our study.. Chronic bronchiris, ischarmic lrrorl disrasr and strokr Analyses similar 1o that shown in Table IV'for lungg cancer were also carried out for chronic bronchitis, ischaernic heart disease and stroke Illustrative results for two of the indices ara presented in Table V. No significant relationship of any index of passive smoking to risk of the 3 discases was seen. For the sexes eombinod, the relative risk in rclation to the spouse smoking during the whole of the marriage was 0.83 for chronic bronchitis (95% confidence limits 0.31-2.20). 1.03 3 for ischacmic heart disease (limits 0.65-1.62) and 0.90 for stroke (limits 0.53-1.52). For stroke there was, in both sexes, an approximate 2-fold increase in risk for patients with a combined passive smoke index that was high (scorr of 5 to 12) compared with those where it was low (score of 0 or 1). Howevcr„ numbers of cases with a high scorc were low (14 tnales and 7 femaks) and even for the sexes oombine.d, the relative risk estimate of 2.18 was not uatistiially signifinnt (limits 0.86-5.t8): In interprcting this fsnding, it should be noted that active smoking was not, found to be ekarly related to stroke in the main study (Alderson rr a1., 1985),, rendering a two-fold inerusc in rclation to passive smoking a priori unlikely.

PASSIVE SMOKING ANt) SMOKiNG-RfLJhTF.n DIS[ASES 1 T.Wr IV RelatMnshrp hn.esn various indi¢% of yssive smoke erctKxurt and nsk of lung eaneer among lifclbna non- smokors Isundardisc.l for agr and, for sf+ousc smoking. .'hcsFicr thc marnagr .a% ongoing or endatl Passnr srw,ir Nfolr parrnes r:fnsvrr mdre//nr! Casri Ci+wrrnls R s Frnn/r parwwts Sr:rs rrawAurd Ccs, Cnetrnts R Cavs Crwttrolt R At home Not at all 9 1101 1 21 192 II 30: 293 .1 Little 2' 21 1.22 6 65 0.92 >< 96 09K Avcragc/a lot 1 I I 1.11 5 61 0.81 6 72 0.86 At .ork Not,at all 3 40 1 12 113 1 IS 153 1 s . Lrnlc 6 29 3.24 3 26 ' 1.19 9 55 1.R2 Avcragc.'a lot 1' 29 046 0 19 0.0 1 4R 0.19 , Dunng travel Not,at all E 101 ' I 28 239 1 36 339 1 : Littlc 3 16 2.06 2 51 0.33 5 67 064 Avctage/a lot 0 13 0.00, 0 13 000 0 26 000 Trend (negative) P<0.05 During kisurs Norat all 3 45 / IS 116 11 l8 161 1 Little 4 49 1.12 14 107 1.05 18 155 1.06 Averagc'a lot 5 39 3.1'8 2 95 018 7 134 0.59 Trend (ncgatrve) , P < 0.05 Combined index' Score 0~ 1 1 27 1 10 - 75 1 11 102 1 Score 2J' 7 55 4.34 5 61 0.63 12 116 1.08 ' Score 5-12 2 15 310: 0 21 0.00 2 36 0.50 Spouse smoked man algs. in last 12 months. No 10 105 1 20 193 1. 30; 298 1 Yes 2 29 0.96 11 122 0.76 13 151 0 79 Spouse smoked man. aEs in whok ofirnarrugc No 7 93 1 13 89 1 - 20 182 1 Yes 5 40 2.47 19 229 0.55 24 269 0.80 'Basod on sum of 0 - not at all. 1'=litllc. 2=averaEe, 3- a lot for at,homct at rork, during travol, dunnE li:isurc. r . Discrssion Over the past 4 years there has been considerable research intrrest in the relationship between passive smoking and, risk of lung cancer in nonsmokers. V1'hilc some studies ha.r claimed a positive effect (Hirayama- 1981. Trichopoulos rr al.. 1981. Correa ri al.. 198?r Garfinkcli rr al:- 1995. Giflis et ol:. 1984, 'Knoth er ol., t98?). others (Buffler rt aL, 1984:. Chan, 1982; Garfinkel, 1981; Kabat and' Wyndcr, 1984; Koo rt at. 1984), have found no signifi,::..;; .,._.., ...~i;. °:!=a.r risks of lung cancer for non-smoking women mamed to smokers comparrd to non-smoking women married to non- smokers range from somewhat over 2 in the Trichopoulos and Correa studies to around 0.75 in the BufTlcr and Chan studies. The wcightcd' relative risk from~ thcsc studies has been estimated by us as approiimataly 1.3. Whilc thcrc is, therefore, a lendcncy for a small positive assneiarion between passive smoking and lung unccr, tmcnt reviews of thcsc dutu (l.cc. 19X4. Lchnert rr al:,, 1984) hhave concluded that overall Iherc is no rel'iablc seicntific evidence or a cJusal' relationship between passive smoking and, lung, r.nccr.. In these rcvxws a numbcr of general points have becn made. First. dosimctric studies have show•n that, in eigarettc-cquiv•.lcnt tcrma, passive smoking only results in a relatively small exposure to the non- smoker. Hugod rt al. (1I978), for example, showed that even under quite extreme conditions the time taken for a non-smoker to inhale the equivaknt of

Svendsen, K.H., Kuller, L.H., Martin, M.J. and Ockene, Ji.K., "Eff ects of Passive Smoking in the Multiple Risk Factor Intervention Trial," American Journal of Epidemioloery 126(5): 783-795, 1987. This study was based on data from men who participated in the Multiple Risk Factor Intervention Trial (MRFIT). MRFIT was not designed as a study of ETS, but rather to determine whether reducing levels of cholesterol, blood pressure, and cigarette smoking in middle-aged men would produce corresponding reductions in coronary heart disease mortality. On the basis of a "risk score" which incorporated these factors, all of the MRFIT participants were considered to be at high risk of heart disease. However, this was an overall score and did not require that all participants have high levels of all of these "risk factors." Of the total of 12,866 MRFIT subjects, the Svensden, et al. report focused on tkic 1,400 who had never smoked. At entry into the study, informatioi~u was collected on the wives' smoking habits, which was used~ as the basis for estimating ETS exposure. The men were followed for an average of seven years, during which time 13 coronary heart disease deaths occurred. Comparing nonsmoking men whose wives smoked to those whose wives did not, the relative risk for coronary heart disease death was reported to be 2.11. After statistically adjusting for several other variables, this ratio was 2.23. These ratios were not statistically significant.

7. Although this study attempted to statistically control for several variables, there are a wide variety of behavioral, social, and other factors related to heart disease which are potentially uncontrolled confounding factors but that were not considered in this study.

. CVD EPIDEMIOLOGY NEWSLETTER . t I Number 43 Winter 1988 Milton Z. Nichaman, M.D.., Sc.D. Editor f=in-Day International Teaching Seminar on Cardiovascular Ulsease Epi'de+eiotogy and Prevention Report 1 FourteentK Ten-Day Seminar on the Epidemiology and Prevention of Cardiovascular Diseases Announcement 3 2nd International Conference on Preventive Cardiology and the Annual Meeting of the AHA Council on Epidemiology Announcement 4 1988 Council for High Blood Pressure Research Fall Scientific Sessions 5 Announcement Cardiovascular Behavioral Medicine, Epide+ai'ology, and Biostatistics Research Training Session Announcement 6 Program 7 Submitted Abstracts 9 2Btti Annual Conference on Cardiovascular Disease Epidemiology Submitted Abstracts 13 Index of Correspondents 51 AMA Council on Epidemiology Membership Application 61

Criticisms 1. This study did not report a statistically significant effect of ETS exposure with heart disease risk. 2. The sample size was very small, being based only on 13 deaths from heart disease. 3. The exposure data may be particularly questionable, because the wives' smoking status was based on interviews with the husbands, not on direct questioning of the wives. 4. The sample size was biased, in that all of the MRFIT participants were considered to be at high risk (upper 10-D!.) , L heart disease, according to a risk score based on levels of cholesterol, blood pressure, and smoking. Hence, the possible relevance of the study to people in general is unknown. 5. It is possible that the husband's smoking status was misclassified at entry into the study. 6. There may be an alcohol-related bias in this study. The subjects who were classified~ as being ETS-exposed drank more jU alcohol per week than those who were classified as not being j~ W exposed to ETS. ~

PUBLIDr HEALTH BRIEFS TABLE 1-NNan and Stsndard Error of Baseline Charsetnistics by Passive Snwklnp Ststus of Monsmoklnp Wlvea„Aqes 1tH74 Yesn, Evans County, Georgia, 1960-81 WMte Women Mgti Social Status' Low Social Status' Btadc Women Exposed lh+.xposed Ex(wead llnexposed EAposad lh»xaaed N (78) (83) (101). (66) (117) (68) Age 51.9 s 1.0 54.920.9 $2.1 s 0.0 53.9_0.9 50.3 0.7 7 55.5s 1.0 Systolic Pressure 145.5 s 3.1 150.6 = 2.9 151.6 s 2.9 157:6s4.3 170.6 3.4 4 126:5s5.0 Diastolic Pressure 88.4 s 1.6 90.6 s 1.4 922 - 1.3 93.1'21.7 1031 1.9 9 103.922.5 Serum Cholbsterol l 231.9 x 4.9 237:5 s 4.5 227:0 s 4.4 235.7s7,3 216.5c3.9 216:2t4.6 Body Mass Index 26.3 t 04 26.4 s 0.6 27.0 s 0.5 28.6s0.9 29.2 0.6 6 30:0s0.9 B.w on tn. nww, aa MeGw.Whe. smree la at WWr ae)eeta 1 smoking behavior. Among both Black and White women there were no statistically significanti(p <0.05) differences by passive smoking status for systolic or diastolic blood pres- sure, serum cholesterol or body ~ mass (Table 1). However, passively exposed Black women and high social status White women were younger on average than nonexposed wives by 5:2 years (95% Cl = 3.0, 7.6) and 3.0 years (95% Cl = 0.3, 5:5), respectively. For all Whites combined, nonexposed women were also more likely to be above the mediam SES (socioeconomic status) level than passively exposed women (55.7 percent vs 43.6 percent). Comparison of self-reported~ smoking status in 1960 and T967 showed 98 percent of wives again reported themselves as never having smoked' in 1967. Similarly, 98 percent of never smoking husbands maintained their reported status in 1967 while 25 percent of husbands who smoked in 1960 described' themselves as non.smokers in 19%7. Age-adjusted RRs for all :CVD, smoking-related CVD,and all cause mortality among passively exposed wives were ele- vated in Blacks and high social'status Whites and for all subjects oont5ined (Table 2). The opposite relationship of mortality with passive smoking status was found for low social status White women: Adjustment for other established CVD risk factors (lood pressure, cholesterol, and BMI):generally caused mod- est elevations of the risk estimates (Table 3) but as with the age-adjusted estimates„the confidence intervals for all subject groups included unity. A trend in, risk over level of husband's smoking as reported~ in 1960 was only seen among high social status Whites; RRs for both total and smoking-related CVD mortality among wives whose husbands smoked <10; 10-20, TABLE 2-Aye-adlustad Relattva Risks and 95%Confldenoe Intarwls for Total ICVD, Smokinp•rebted' CYD, and All-Cause Mortality tor ,yrivee Exposed to Paasive Smoke in Evans County, C.eorryla, 1960-80 Whites Y,a._s d Cestti An Sutiiects Blsdcs MSS, t.SS•• CYD Total RR 1.34 1.69 1.66 0.60 95% Cf 0:84, 221' 0.83; 3.46 0.64„4.32 0.27, 1.34. smokie+g• re6ated RR 1.29 1.57 1.67 0.61' 95% CI 0.79, 2.10 0.73: 3.37 0.64„4.36 0.25. 1.47 All cause RR 1.31 1.34 1.60 0.72 95% CI: 0:95. 1.82' 0.79: 2.28 0.94,3.47 0.41, 1.27 ••1CDe mea 41 W56 Mo xOCW qftle •uo. .oon wa,. TABLE 3•-Retative Risks• and 95%' Confidence Intervals for Total CYD; BmoklnQ-.Nited' CVD, and All Cause Mortality for wlvea Exposed to Passive Smoke In Evans County, Ceorpia,1960-W Whites CausW of Death A9 Subqsas Bladcs HSS" LSS- CVD Total RR 1.59 1.78 1.97 0.79 95% Cl 0.99, 2.57 0:86, 3.71 0:72, 5.34 0 32. 1.96 Smoking- related RR 1.54 1.68 1.97 0.82 95% Cl 0.93, 2.55 0.76, 3.71 012, 5.34: 0:31, 2.15 AII cause RR 1.39 1,33 1.97 0.87 95% Cl 0.99, 1.9. 0.78, 2.28 1.00, 3.90 0:48, 1.59 •MiiLOs raLm atllutt W 1or op. Oufto/M[ MooO PWKf We. tafal MrUmdloNabtd, body mats n0ea (BMi ~- kyrtNte2): W BMI=•1CDeaoM~ 410.45s • Mpn aooW sutua to. eoasl waA and >20 cigarettes per day as compared to wives of nonsmokers were 1.02, 2.11, and 2.55, respectively (p for trend <0.06): A marginally significant (p <0.09)i trend in risk for all CVD and smoking-related CVD overctude levels of duration of.exposure was also apparent only among high social status White women. Discussion These data suggest an, elevation of risk for death from CVD and all causes among non-smoking married women whose husbands described themselves as current smokers at the beginning of a 20-year follow-up period. Our findings for Blacks are the first report associating CVD with passive smoking in this racial group. Our observations that social status may modify the effect of passive smoke exposure may be due to chance, but a similar pattern of results for coronary heart disease (CHD) has been reported in other studies of passive smoking, Nonsignificant(p >0.05) two-fold RRs for CHD among passive smokers were reported' from studies of middle-class and'upper-middle-class womenb and men' while CHD risk was significantly but more modestly increased (RR = 1.2) among a much larger sample of predominantly blue collar Washington County, Maryl9ndwomen.eNo increased risk for CHD was reported among public hospital' patients whose husbands smoked in four Bntish hospital!regions.s It is unlikely that these results can be explained by a change in smoking habits since the minimum age of these women in 1960 was 40. We lack data to examine whether exposure status changed'during follow-up due to remarriage. The absence of elevated risk among exposeddbw socialistatus A,1PH May 199Q Vol. 80i,hlo. 5

1t1 P.1V. ILF£ rr al whcn possiblt„ hospttal I waJd and time of interview. Subscqucntly, whcn final discharge diagnosa bccamc available, they were used to reallocate cases and eontrols as neccsury. Patients without a final diagnosis kept their provisional diagnosis. Where changes in casc{ontrol status occurrrd, patients were regrouped into new ease-eontrol pairs as appropriatc. With the assistance of Str Richard Doll and Mr Rtuhard Pcto; non-indcx diagnoses wcre classified as follows: class IA 'dcGnitcly not smok'ing,associated' class 1B 'probably not smoking associated' class 2A 'probably smoking,associated' class 2B 'd'efinitely smoking associated' Controls with no final diagnosis were considered class 18 Overall, there were 12,693 interviews carricd out which resultcd in +,950 pairs with class I controls and 7?t* pairs with class 2 controls. Thcrc were 3.832' intcrvicws of married eases and' controls whcre the passive smoking questionnaire was completed In order to avoid substantial loss of data, duc to one mcmbcr of a pair not being marricd or not eomplcting the passive smoking questionnairc, it was decided to ignore matching when analysing the passive smoking data and' to eompare each indcx group with the combined controls. Numbers by sex and casc-control status art given in Table I'. Tabte I Numhers cf nsMed hospital in-patients completing passive smoking questionnaircs Mdr Frrwalr Tord Lung umzr 347 245 792 Chronic bronchitis 182 94 266 Ischacmic hcart disease 286' 221 507 Stroke 161 137 298 t: ontrols l'lass I'A and 1 B' 239 713 U32 Class 2A and 2B' 269 149 417 Total 2-283 13A 9 3,132 'Othcr di.ean were elassifted by degree of smoking aisociat,on - class IA: dcfinitcly not, class IB. probably not„clras 2A probabty, class 2B. dcfinitclX. _ ln the passrvc smoang part of the qucstionruirc, paticnts were asked when the marriage started, if and when it had ended; the number of manufactured cigarettes per day smoked by, the spouse both during the last 12 months of marriage and also al the period of maximum smoking during the marriagc;,and whether the spouse ever regularly smoked hand-rolled QgarTttes, cigars or a pipe during the marriagc. For ser.ond or subsequentt marriages, questions related to the first marriage to give thc longest latcnt intcrvali bctwccn exposure and dts,casc onscn The paticnts wcrr also askc& to quantify, according to a fourrpoint scak (a lot,. avcragc, a little, not at all), the extent to which they were rrgularly exposed to tobacco smoke from other pcoplc prior to coming into hospital in 4 situations: at homc; at work; dunng daily travel; during leisure time. In thc main questionnaire, detailcd' questions wcrc askcd' on smoking habits and on a whole range of possibk confounding variabks. Follow-srp study ojsporeses oJnon-smoking hospital in-porienrs From the hospital study there were 56 lung cancer cases who rcporncd bcing lift:long non-smokers, who were married at the timc of intcrvinm and who were not known to have been married previously. In a follow-up to the main study, an, attempt was made to interview the spouses of thcsc 56 cases and also tihc spouses of t,wo life-long non-smoking controls for each casc, individually matchcd for sex, marital status and 100.ycar agc group and! as far as possible, hospital. Where multiple potential controls in the same hospital were availablc, those interviewed nearest in timc to the case were sclccted Where suitable controls in the same hospital wcre not available, those in the nearesu hospital wcrc choscn. Bccausc namcs and addresscs of the patients were not rccordcd in the hospital study, it was neerssary, to go back to the hospital both to obtain this information and also to get pcrmission to interview their spouses. Following some rxfusals both by the hospital and by, the spouscs„ sucecssful interviews wcrc obtained from spouscs of 34 cases (10 wives an&2d' husbands) and 80 controls (26 wivcs and 54 husbands) whose condition was dcfinitcly or probably not related to smoking.... Interviewing was carricd out betwcen July 1982 and! August 1983; The spouses were asked about their consumption oG manufacturcd eigarettcs, cigars and pipcs (a), nowadays. (b) during the year of admission of the psticnt or (c)i maximum during the whole of the marriaFc: The spouses were not asked about thc smoking habits of the index patient. The sl+ouscs wcrc also askcd qucsuons on agc, occuputron, social class and a range of other potential confounding faetors. Srarisriral 'ntrrhods The statistical methods art based on classical procedures for analysis of grouped data dcrived from ease{ontrol studies (Breslow & Day. 1980). In general, the material has bccn examined as a 2 x A" x S tabfc, with A' representing the kvels of the t t

~.,..~ ..... ~-~ ..r.w~r,..om. ,....aw...~-~........,.,,.. . -., .,rn~... .,... s.,,,,. .... PASSIVE SMOKING AND SM'OKING-RI:LATEf) DISFaiSfS !9 t risk' factor of interest and S the numbcrr of strata used to t'akc account of potential confoundcrs. Results presented are for the combined strata and show the relative risk (Mantcl'.-Hacnsu) estimate) together with the significancc of its dificrrncc from a base level (risk 1.0), andtor the dosc-rclatcd trend. In analyscs "of the data eollectcd in hospital, comparisons arc made bct..rcn oces with, a particular index disease and all thc controls with, discases definitely or probably not related to smoking Six simple indices of passive smokc exposure were eonsidered in these lattcr analyscs, (i)-(tv) exposure at home. at work, during travcl, during leisure. (v)', spouse smoking manufamured cigarettes in the l5st 12 months- and' (vi) spousc smoking manufactured eigarcttcs in thc wholc of the marriage. Bases for (it) are reduced as not all patients worked': In addition, a combined index of passive smoke exposure was nkulatcd' by the unweighted sum of the four individual' exposure indices (i}-(iv), counting 'not au all' as 0, 'little' as 1, 'average' as 2 and 'a lot' as 3. Resvlts. LLung concrr The follow-up study concerned 56 lung eanecr, eascs and 112 matched eontrols who reported never having smoked in their hospiul'intcrvicw. Of thcsc. there were 47 eascs (1S madc and 32 fcmalc) and 96 controls (30 male and 66 fcmalc) for whom some information on smoking habits of their spouscs was availabit. Of these 643 patients, information on spouse smoking was available both from the sf+ouse and from the patient for 59 (011'/.), from the spouse only for 55 (:;R9.) and from the paticnt onl), fur 29' (20'/.). Table II shows the estimated agc-adjusted relative risk of lung cancer in rclatinn; to sriousc smoking during the whole of the marriage„ hy scx, source of data, and period of smoking. None of the 9 relative risks shown in the table arc stnuztically significant. Whcn data fion both sexes and both sources arc considered, the cstimatcd relattvo risks in relation to spouse smoking arc closc to I( I1. 11). For individual sexes or sources, whcrc numbcrs of cases and controls are smaller, relative risks vary more from unity„ but no eonsistcnt~ pattern is evident. Similar conclusions were reached; when analyses were based omsmoking during the year of hospital interview. Here, the overalll relative risk was again close to I(0.93 with limits 0.4,1-2.09). Table lI1 summarises concordance between spovsr s manufactured eiFarette smoking habits as reported directly and indirectly for the 59' patients with, data from both sources. Discrepancies were seen for 9 spouses (IS'/.) in respect' of smoking at some time during marriage and in the crst of 2 T.Wr 11 Relationship between spousr's manufactured cigarette smokinF dunng the whok ofi the marriage and risk of lung cancer among lifelong non-smokers Isiandardised for age) Spr>ru did' a ot' s"r Spnu.sr s+no4rd Ses of Rtlutrtr ri.%L ppcrirnr Casn Conrrnfs• Cavs Conrrois' (93'. IJwws) Basrd on intrrr.rws oJthr slwm.v in fnlln.-up srrd)• (lYl prsretrt)', Malc S 13 S 13 1.0110.23J41) Fcmal6 5 16 19 38 1.6010"-5.78) Combined 10 29 24 51 IJ3(0.50-34h1 Based oe intrrnrws of the indr: /sotinu'in bspital (M prirers) Male 7 IS S 7 1.S3(0:37-6:31), Female 9 17 b 20 0 75t0 R4-2 40) ', Combined 16 32 13 27 1.001041-2Wll based on h.>rh' sovrcr.% nf rronnotinn,(IlJ patirrtts)• Male 7 16 a 14 1.30(0.3l1:1.391 Female 110 21 22 45 1.00(0.37-2.7)) Combined 17 37 - 30 59 1.11',10.51-2.39) '(!nt} controls rncluded in follor.-up study eonsidered: aIn ibis analysis the spouse was countc& u a smoker if nrponed to bc so either diraaly, by the spouse during l01/ow-up intervicw, or, indir>zt1y, by the patient in hospital. Notc thar the 59 patients for whom information on spouse smoking was availabic from both sources are included in a1113 ana1yw& ~

. ever smoked. If the cohabitees were ex-smokers the index cases were classified as passive smokers if'the% had' never smoked' or as double smokers if they'had ever smoked. Thus the controls represent a group whose passive exposure was as low as possible within the constraints of the study design, ResuRs for the two active smoking groups have been included to give some indication of dose-responsc and provide a perspective for any differences found between the control and passive smoking groups.. A eohabiteetc•as defined as a respondent sharing the same household environment and e2:amined' at~ the same time in the surves as the index case. Some households contained'cohabitees ofthrsame sex. Some of the subjects who were examined were above or below the age range eligible for inclusion in the study. These subjects were not analysed as index cases but information on their smoking behaviour as cohabitees was used as the measure of passive exposure for eligible index cases. Mortalit}• data .ras obtained from the National Health Service et:ntnl register and the General Register TMls ]-Cansycsinoe af rroaeps Ispa.rd so awa+rnta.aii No(!wIdmml:m(%)of.osen (mdo: ou> (mdc. o.n; 7ou1 (:mt:ols (nnther uudca ax nm,rob+tluee r.er mwk'ed: L•n.rvvcnolungI onlp,rnhabum.aer,rnkcd' 428 (10-g~) 213. (61; 419M 1) 1295(32-1) 917 is36 SurElcamwkmg.: onliL udi>.nw ner.moked 1420(35,9:; 331 (62` 175.1 13oubktmakmg(borAmdez:n.eandcvlubneceMeranoked1869iA7-2.) 1922,47-6) 3'91 7ou!. 3960 (100, 4037 (100) 7997 TAa]S 11-Sona1 zltiss of.or JX rarrpt tzposed so eifaaru a.o4e. Fyrca a pnrxs6efu erc pe.n.Wcs Fsposu'e group sooalcLss canuols. Pumc vnwkmt Sm81r WnokSng Dwbk wror+oa I I3 (SJ;. 13. (k3) 61 (4,3,~ 78. (4L2+ II 65(199!'. 3`(1.5-2) 225(15•8~ . 235T12•61 llleon-manual 63:14-7). 23' (9-S, 197(13-9:, 204 (IO•9, ' + Itlmamoal /V 157(367;. /10(18..7). 96(395) 39(24;3) 538(37•9) 315(222) 771 (41i 438R3'4). V 17(1•0) II (4-5) 68 (1g) 122(6•S) ~ Inv,ff~iiinformulon~. 3~ (0L7): 4(lb; 16 (1•1) 21 . (1-1), Toul 428 n00-V 243 (99^9;, 1420(100): 1669(I0o) Office for Scotland. Incidence of cancer was obtained tlxrougli the cancer registry system and used to verify t31at the classification on the death i certificata was the same as that received by the registry. Dau presented are crtlmpltte to the end of December 1985, en average follow up of 1'1'5 years. Prevalencesforrespil•atory and cardiorascularsynrtp• toms were standardised for age and sex using the age and sex distribution of the whole cohort as standard.. Sirrularly; mortality was standardised'for age and sex using life tables to estimate survival at 11 years of, follow ,up." Mean forced expiratory volumes in one second'for the four exposure groups were adjusled for age, height, and sex by determining the best, fit set of parallel regression models for forced expu•atory volume in one second as a li.near function~of age and height for men and women separately in each group. The mean adjusted forced expiratory volume in one sccond4or each group was then calculated for the average age and height of', men and'women separately, and a weighted average (carresponding to the proportion of men and women) was computed. Probability values were obtained from the analvsis of variance.. Estimates of relative risk and 95% con6den(x inter- vals for passive smokers compared with controls were adjusted for age, sex, sociall class, diastolic blood pressure, serum cholesterol concentration and body mass index (weight (kg)/(height (tn)}x1U0)iusing the logistic regression model" for ardiorespiratore symp• totas and Cox's proportional hazards model for morlality." Levels of significance were derived from the partial likelihood function." The biomedical data processing programs (BMDP) package was used to compute estimates of risk and levels ofprobability.° A supplementary' questionnaire in~ two of the 12 centres in which tbe etirveti• was carried out, asked subjects the extent to which they were exposed to cigarette smoke from any other person in the house- holds iirespectiveof whether these people 9cere eligible for or attended the surve.•,, and also in their work environment.. Results 7~'hc number ofinen and women in the four exposure groups is shown in table 1. Passive smokers comprisod TAaLt il1-Sww44np 6abn of coAabvetr rn parnvc swrokinp and deublr uwokmrrwps. Fr(rvcs asr yntnuCtrs (wrenbrn ) lnda nu N6dciErsrner Mrn, t omen Sooked pa d.l.. (y mhabnr: Pmve >mokly pcup Double wookaua group Pnu.e anY.ma group 13oubk makut group 1•14 ~, 31•3 (76)', - 3)" (561)'. 15-1!(196). 11.4 . (IIl9) s15~ ~ 46-~1012)I 32•7(98S). 41•t(541): 56~2{I0t0) 15-24 42-0(102)'~ 4Si(a58)'. • 30-a(399). 37,1(J13) i25~ 4-I (10)~, 6-a(127). U-0(142). 19~1,(367) 6mWokn 22! (SS)', 17•3(323). 13L](S38). 324 (6239 Taat.E ]v-Atc ad sa 6ttndardurd rates eJYSrybatdyad rediocvrtvJar rvr~p/orru n1msd to rryansr to cymrar neoAi: A'wlba: of l V r.ca mid rympowu ae jeeen nr pmaaAerrs Em-u,r group Cmvu14 luv.e®okaog f.aBk-W~ Duubk.no6m8 (n-917) (n-1b38) (n-1751): (6-3791) W ' ~ ~ 1Y/ 1 aeq>.r.ron' ~pam+` tbleaied spunun. ' 2-3(72) 3•3. (44) 10~-5(189)~~ 103. (396)~. Iggh Perusrrnu tpurum. 7-t.(72) 9-9(122) 29-0(5+1)i 28.70079;~. 1753CDoCa 101(95i 122097) 13-4(229i~. )6`6 (61a)~. Hlymeereom 53(49) 6-9I (81) 17t(327)~ 18.3'~ (6f1)~. CGrd/ov..cvb 1rmpama* . tkn8uo+ 44(43) 7~7 065i, 9~1 (331)~. ALqr.boarvubev .faud'ouekrtrarndiap.m , 1-0 (a) 11 (13) 1-4 (D1Y P5~. (49)~. M® (orced eipr.wry ews . me acmd (I); Ua.dw'<ad 2-32 2~21 2-12~ 2-09~ Ndrysud, 2-31 2-23~ . 2-12~ 2-07~ 424 BMJ vol.untf 299 12 AUCUrr 1989

t er J: C.wrrr (19le). SL 97_ 103 Relationship of passive smoking to risk of lung cancer and other smoking-associated diseases P.N. Lee,' J. Charrlberlain~ & M.R. Aldcrsorlt /nstiturc of Cancer Rrsearch. Clijlon Road. BBeUnont: Surrey. UK: $uraaar7 In the latter t+an of a large hospital osc<ontrol study of the nasuonship of tyf}c of ugarette smoked'to rssk of vanous uaok,ng-assoaattx7 dtsases. patlents answersd questions on the smoltnb hutwts uf thc r first spouse and on the estenn of passtve smoke exposure at home. at work. dunns travel jnJ dbnn; leisure. In an extens,on of this study, an attempt was made to obtain smoking habit data diraetly from the spouses of all lift*lont non-smoling lung ono:ri cases and of two lifelong non-smoking matchcd controls fnr each case. The attempt was made regardlas of whether the pauents had answered passrve smoking qucstrons in hospital or not. Amongst lifelong non-smokers. passive smoking was not assoeiated' with any s+gntfieant increase in nsk' of lung ancer, chronic bronchitis. ischacmic hcart disease or stroke in any analysis. C.irnttatrons of past studies on passrve smoking arc discusst:d and the need for funhen recarch underlined.. From all the avaiiable evidencx. it appears that any efieet of passive smoke on nsk of any of the trulor disa.es that have been associated with aatve smoking is at most srnall, and may not esist at all. Sfudu of hospital in-patienrs In 1977 a large hospital case-control was initiated to study the relationship of the type of eigarettc smoked to risk of lung cncer, chronic bronchitis. ischaemic heart diseasc and stroke. This study was nrried out in 10 hospital regions in England; interviewing ended in January 1982. The original questionnaire did not include questions on passive smoking as it was not considered an important issue in 1977. However, in 1979 it was decided to extend the questionnaire to covcr passive smoking for marrie4 patients for the last four regions to begin interviewing. Subsequently, in 1981. ,'following publication of thc pape-s by Hirayama (1981) and by Tnchopoulos rr aL (1981) claiming, that non- smoking wives of smokers had a si¢niftcantly greater risk of lung cancer than, non-smoking wives of non-smokers, it was decided to incretse the number of interviews of marned lung cancer cases and controls. The eztcnded questionnaire was then administered to thcse patients imaltihospitals where interviewing was still continuing. Follow•up srr+dr of spouses of nnn-smnhinp hospital irs-paN[nts In 1982- after interviewing of hospiutl in-patients had bcrn completed- it was decided to carry out a follow-up study. In this study. an auempt was CorTapondenwz: P.N. Lec. •Ptaent addrac 25 Cedar Road Suuon, Surrey, SM2 SDG: t,Praent addi•as: ofl-ics of Poputauon Cetrsuses and Sur.eys. St. Cathcnnc's House. 10 Kingsway, l.ondon. WC2B WP. made to interview the spouses of all of thc married hospital ip-pauents with 11tng cancer who reported never having smoked, as well as of two marned non-smoking controls for ueh of thcsc index lung canecr cases. The follow-up study was intended partly to compare information on spouses' smoking habits obtained Grst-hand: with that obtained second-hand during the in-patient intcrviews. and panly to obtCtin some ditta on spouses' smokin;; habits for those patients who had not answcrt:d passive smoking questions in hospital. This papcr concentrates solely on the issue of passive smoking in lifelong non-smokcrs. Results rzlating to type of cigarette smoked arc described elsewhere (Aldcrson rr a1:. 1985), whilc a dctailcd' rcport, avaitablc on trquat from f NL, eonsiders the over-all fandings from this clscrontrol study. MrKtiods and response Study of liacpita!'in-paticnts For each of the 4 index diagnoses (lung cnc::r' chronic bronehitis, isehaemic heart disease ar,L: strole), the intention was to interview 200 eascs and~ 2W matched controls in cach of the eight sex/age cells (i.e. malc or femalc, and aged 35-4-a: 45-C4; 55-64 or 65-74):. This gave a target of 12-800 patienu. though for some etcgories (e.g: young femak chronic bronchittcs) this would be unattainable. Paticnts were sclected' from medical (induding chest medicinc): thoracic surgery, and radiothcrapy wards. Controls were patients without one of the four index diagnoses, individually matched to cases on sex. age, hospital region ar.d, 0 The Marrnillan Pras Ud'-. I9M6

1!02 P.N LfF rr,at Tahle V Rclatrnnchsp hctrccn, two indrezs or r,+accivc smnke eit+osurc and nsk or chronic brnnchius, ischaemic hcan dtseasc and stroke among lifelong non-smoken (standardised for age and, lor spouse smoksng- whether, the marruge was ongoing or endedl Pa.ccar tww.ie - Ma1F parrrnrs Frnwlr panrnu Srsrs co.ehrnrd [ipncyrr uv/ri/lrtr! Casrs Canrr.dsR Casss Contrnls R Casrs Conrrols R Clrr..nrr hrnnr/trrrs. Com bi ned' mdcx •' Score 0-I 1 27 1' 7 75 1 8 102 1 Score 2J' 2 55 0.83 4 61 1.05, 6 116 1.00 Scorc 5-12 I 1'S 1.90 1 21 1.03 2 36 1.30 Spouse smoked man np- in, whok of marnage No 8 93 I 4 89 II 12 182 I Ycs 1 40 0.34 13 229 IL22 14 269 0.83' ffchorrnlr hrarf dlY4Y Combined mdcs• Scorc 0-a' 13 27' 1 23 75 1 38 102 1 Score 2-4 12 55 043 9 61 0.1.4 21 116 0.52' Score 5-12 3 15 043' 4 21 081 7 36 0.61 Spouse smoked nsan eigs in whnk ofimarriage No 26 93 I 22 89 1 48 182 1' Yes 15 40 1.24 55 229 0.93 70 269 I'_03 Strolr Combined indcs• Score 0-1 5 27 I 19 75 1'. 24 102 1 Score 2-4 10 55 1?4 10 61 0 86 20 116 0.97 Score 5-12 4 15 1.77 7 21 2.44 11 36 218 Spouse smoked man eiFs: in whok of marriage No W 93' 1 19 89 I 37 182 1 Yes 6 40 0.84 49 229 0.92 55 269 0.90 •tiased on sum of 0- not'at all. I - little, 2=avera8c, 3- a lot for at homc, at work, during travcli,during kisure. one eigarctte would be 11 hours as regards particulatc matter and 50 hours as regards nicotine. Similarly. Jarvis rt al:(1985) have shown that the increase in salivary cotininc in relation to passive smoke exposure is less than 1'.e of that in relation to active smoke exposure. Extrapolating linearly from the lafold, relative risk of lung cancer in relation to active smoking would therefore predict a relative risk in relation to passive smoking less than 1.I, while a quadratic extrapolation, as suggested by Doll and Pcto (1978), would predict a lower risk still. The conflict bctwren the dose and the claimed response is parnicuiarly clear for the results of Hirayama (1981) who found a similar effect on lung cancer for passive smoking as for active srnoking of 5 cigarettes a day. Second, all the studies suffer from weak exposure data, most studies only obtaining information on the spousc's smoking habits and, none obtaining objectivc data by mcasurement of ambient levels of smoke constituents in the air of the home or workplace and/or of concentrations of constituents in body fluids. Third. no studies adequately take into aceounv the possibility that misclassifscation of active smokers as non-smokers may have consistently biascd relative risk estimates upward. Active smokers have a high relative risk of lung cancer and spouses' smoking habits are positively, correlated. Because of this, it can be shown that if a relatively small proportion of smokers deny smoking, this results in an apparent elevation in risk of lung cancer in 'non-smokers' married to smokers compared to 'non-smokers' married to non.smokers, even when no rrtar effect of passive smoking exists. A demonstration that this source of bias is of rul~imporvnoe can be found in the study of Garfinkel st a/: (1985). Based on unvalidated smoking data taken from hospital notes, a relative risk of lung cancer in relation to husband's smoking at home of 1.66 was okuiated, with relative risks of at least 1'_3 seen in rclauon to each

Passive smoking and cardiorespiratory health in a general population in the west of Scotland r DaKid J Hole, Charles R Giliis, Carol Chopra, Victor M Hawthorne Abstract Objecrive-To assess the risk of cardiorespiratory symptoms and mortality in non-smokers who wene passively exposed to env'uotunental smoke. Desige-Prospective study of cohort from general population first screened between 1972 and'1976 and followed up for an average of 11 •5 years, with linkage of data from participants in the same household. SettirtQ-Renfrew and Paisley, adjacent burghs in urban west Scotland. Sybjeetr-15399 Men and women (80'/% of all those aged 45-64 resident in Renfrew or Paisley) eomprised the original cohort; 7997 attended for multiphasic screening with a cohabitee. Passive smoking and control groups were defined on the basis of a lifelong non-smoking index case and whether the cohabitee had ever smoked or never smoked. Main orrtcmrte nteasure-Car+diorespiratory signs and symptoms and mortality. Results-Each of the eardiorespiratory symptoms examined produced relative risks >1-0 (though none were signi6cant) for passive smokers compared with eontrols. Adjusted foreed exptratory volume in ooe second was sigaificastly lower in passive smokers than controls. All cause mortality was higher in ' passive smokers than controls (rate ratio 1~27 (95% confidence interval 0•95 to 1•70)); as were all causes .of death related to smoking (rate ratio 1•30 (0'•91 to 1-85)) aad'mottality from lung cancer (rate ratio 2•41 (0•45 to 12-83)) and ischaemic heart disease (rate iatio 2•01 (1-21 to 3•35)). When passive smokers were divided into high and low exposure groups on the basis of the amount smoked by their cohabitees those highly exposed had higher rates of symptoms and deatb, Goncitrsion-Exposurs to environmental tobacco smoke cannot be regarded as a safe involttntary. •-1'tabit. West of Scotland Cancer Inuoduetion Surveillance Unit, Ruchill Though evidence hu accumulated about the risk to Hospitall Glasgow health of involuntary, or passive, exposure to environ- 4',20 9NB David J Hole, ktsc,. at4dsnnas Chi r1ts R t?itlis, Mn, atirxtar 1.*epammew of tpidemioloxy, School of Public fi2altti'„Univeaitr of Michigaa, .Ynn Arbor, Michigan, United States Cara4 Chopra, remarch uwier+i Victor M Hawthorne, stn, proJessor Correspondence and requests for reprintsto: Mr Hole. , . mental tobacco smoke, further information is requirrd' from cohort studies m confirm these observations. Deleteriotu effects on the respiratory system of infants and children have been observed" as have chronic effects on lung function in adults,' " but these findings have been criticised on methodological grounds.'' An overview of 10 case-control and three cohort studies estimated a relative risk of 1!•35' for lung cancer in people passively exposed compared with non-exposed controls.' Three studies have reported increased (though not significant) risks of ischaemic heart disease in non-smokers with partners who smoke.' I* Problems in interpreting these findings include lack of an objective measure of dose or exposure, failure to adjust for confounding variables, inappropriate methods of statistical analysis, and failure to measure other poten- tiaUy important variables." This report is based on the Renfrew-Paisley survey,, e,Mdl m+a++:.2a.7 which was carried out in an area with a high incidence BMJ VOLUME 299 12 AL•GUST 1989 of lung cancer; it overt.vmes manyof these criticisms. The survey prospectively studied a general population aged 45-64 years, and the collected data allowed participants from the same household to be identified. The measure of exposure to environmental tobacco was obtained directly from cohabiiees and did not rely on self reporting. Data on prevalences of symptoms of respiratory and'ardiovaxvlar disease, forced eYpitatory volume in one second, mortality, and incidence of cancer are all availabie for this population. The findings reported here update an earlier rrport; it adds 567 further deaths to the previous findings" and extends the range of baseline measurements to include forced expiratory volume in one second. Confoundingg variables such as social class, blood'pressure,,choles- terol concentntion„body mass index, and socia[class have been allowed for in calculating relative risks for passive smokers. Subjects and methods This general population cohort comprises all l men and women aged 45-64 years resident i in the towns of Renfrew and Paisley in the west of Scotland between 1972 a»d 1976." Eligibility wu established by a door to door census of all households in the two towns. Everyone who met the age and residency criteria was ir111ted to attend one of 12 temporary centres for a multiphasiccardiorespiratory screening examination." Between 1972 and 1976, 15 399 residents (an 80% response) completed a standardised self administered questionnaire that included questions on smoking behaviour and was checked by experienced inter- viewers when subjects attended for scmning. Respira- tory symptoms were assessed with the Medical i Research Council's bronchi tis q uestionnaire. By identi- fying participants from the same household it was possible tostudy var}•ing,exposures to tobacco smoke in a subsample of 3960 men and 4037 women and to calculate relative risks for a range of cardiorespiratory variables including mortality. Fourgroups, in which the iadex case was aged 45-6i. at the time of the survey, were defined based on the index case and on the cohabitees ever or never having smoked. (l ) Control: the index case had never smoked and lived at the same address as another subject who had' never smoked. No one else in the household who attended for screening was a smoker or ex-smoker. (2) Passive smoking: the index case had never smoked and lived atittte same address as a subject wt: had. (3) Single smoking: the index case was a smoker or ex-smoker and lived at the same address as a subject who had never smoked. No one else in the household' who attended for screening was a smoker or ex- smoker. (4) Double smoking: the index case was a smoker or ex -stnoker who lived at the same address as a subject who was also a smoker orex-smoker. If the index cases were ex-smokers they were classified as single smokers or double smokers depend- ing on whether the cohabitecs had never smoked or 423

Abstracts Sub.itted for the 28th COrtference on P.ardiovasailar Disease Epi6e.*i'ology Sartta Fe, New Mexico March U-19, 1981 Abstracts of a1l papers sub.i'tted to the Prograa Cosittee of the Council on Epidemioloqy for the 28th Annual Conference on Cardiovascular Disease Epidemioloqy are reprinted below in the order they were received, except for those deleted at the request of the author. For additi~onal inforsation about any of the abstracts see the index of author correspondents i.,ediately following the last abstract. lLCKEISi 2'g DKI17CcQ O/ IIYTDQ'0S10p 1 C /O7 ffi iAC C010LARY l7lIYVIlSOn ".IAl. (C,TlR) C. a.lund; RP Mdf.hen, Pi Whaley, OI Casiar, S+l+er»t.ia, m. Uel.arsity of Oerth 4eolim t thapel gll1, K. ien (!IS!) is afLen aaseci,aL.d with high latarol l.sla. we sts+di.d 2395 norsoi.nsin (systolic pr.asvrs (tit) }r0 and diastolic yr+ssur. (Dlr)s.o soft) in tae vrt to ..t.:.lna il lw.ring -G d.cr.ass the ri.at af gYT ( tah 1&0 er DHt»G r 3P sadiutim). fas.litr aaatinatiees laclai.d a treae.i11 test ard assaaaot of riaa faetarr and r. rap.at.d arewlly. IIr incid.nu ef 9" alter S years of fe11w-vo w 11.A (lSd/1297) is the P Tac.so traup coWarM ta 9. 2't (111 / 12N ) is tAe cholestn^sai:+. lsvuy. Tbls ditfsranca wrs sigili- eae+t, r0.007, t.sti+g rita a lagistia rigressien .od.l iaeludie4 stadard R7 riat faetors as eo- wariataa. Purtbrr anal'rsr r..aalM that d.cre•se in U)C-C was tEr factor eqla.i" t!r tsvtarnt •ff.ct. ar r.latiw rist ef MT1 (RR-RTP) .s sig- nificantly Oro.o1) rseciatad with tha t+.auctiee in tA-C emtrolliig fer eo.ariataa. A &0 q/tl and a a0 e;ld1 d.cr.asa im lVL-C corr.spondad te a qt-KYT ef 0.71 ard 0.52 s.ap+etiwly. Ye eaneluM 'triat ebel.stTrsi+r *n`-r' lew." of La.-C ia aas,ocsst.d wita a d.er.a.. In tlr risk of NYT, raisirs tAa possibility of lDf.-{ psir4 a.odifiabl• t E 1-9-FF1dt DECLINE OF COROHARY HEAZT DISEASE AND STRO'EE IN TidE HONCLUI:U HEART PROG'1CA?S Dvsyne Reed and Charles MacLean. Honolulu H:art Pro=raa, Nonolu3u, HI Since 1966, th..Honolulu Heart Prograa has sionitored the lncid'ence and mortality rates for coronary heart disease (C8D), and stroke asonj a cohort of 6006 sen of Japanese ancestry living in Rawaii. During 19 years of follow-up there w re )02 cases of total definite CfID of vhich 458 were fataL. and 643 cases of stroke of which 193 were fatal. There was a 182 decrease In age-adjusted CHD sortality rata and a 203 decrease in the incidence of definite CHD. The decrease In srortality rates was less than that for US white sales, and was not statistically significant. During the sasr time period, there was a 64: decrease In stroke eiortality races and a 651 decrease in the incidence of total stroke. The decrease In srortality rates was greater than that for US vhite males and was statistically signiYieant. The eiortality rates of these vascular diseases appear to reflect the changes in total incidence for this cohort. 13

AMERICAN Journal of Epidemiology Fwnw +h Al¢RIG1N )O(JLWAL OF Hy!GgNB O 1987 by The Jomns Hopkina Univenity Schooi of Hygiene and Public H.a/tb' roR VOL. 126 NOVEMBER 1987 NO. 5 Original Contributions Y ! EFFECTS OF PASSIVE SMOKING IN THE MULTIPLE RISK FACTOR !, INTERVENTION TRIAL KENNETH H'. SVENDSEN,' LEWIS H. KULLER,' MICHAEI: J. MARTN' Avn JilIDITH K. OCKENE' Svendsen, K. H. (Coordinating Centers for Biometric Research, U. of Minnesota, Minneapolia, MN 55414), L H. Kuller, M. J. Martin, and J: K. Ockens. Effects of passive smoking in the Multiple Risk Factor Intervention Trial. Am J Epfdernlol 1987;126s763-95.. The Multiple Risk Factor Intervention Trial (MRF1T), conducted in 1973-1982, provided a unique opportunity to study the effect of passive smoking on men whose wives smoke. MRFiT participants who nsported at entry tfW they had never smoked tobacco products were classified according to the smoking status of their wiwes. Men with wives who smoked had similar mean levels of serurn thiocyanate (54.3 vs. 53.9 µmol/liter, p = 0.83) but higher mean levels of expired urbonmonoxide (7.7 vs. 7.1 ppm, p = 0:001). Lower levels of pulmonary function (by maximum forced expiratory volume in one second) were also observed in these men 1 (3,493.1 vs., 3,591.9 ml, p = 0.04). The relative risks, for men whose wives smoked compared with men whose wives did not smoke, for the endpoirtls coronary heart disepse death; fatal'or nonfatal coronary heart disease event, and deathfrorn any cause were 2.11 (p = 0.19, 95% ' confidence Interval (CI) 0.69- 6.46); 1.48 (p = 0.13, 9594 Cl 0.89-2.47), and 1.96 (p = 0.08, 95% Cf 0.93-4.11), respectively.lMhen smokers who quit prior to entry were included in the analyses, the relative risks, for men whose wives smoked compared with men whose wives did not smoke, for the above endopoints were 1:45 (p = 0.25, 95% C10.77-2.73), 1.19 (p = 0.29, 95% CI 0:85-1.65), and 1.72 (p = 0.01, 95% CI 1.12-264), respectively. These relative risk estimates did not change approckbfy after adjusting for ofher baseline risk factors. The results suggest that passive expo- sure to cigarette smoke may have a deleterious Impact on the health of non- smokers and that nonsmokers may be at an incrsased risk of death 1Maqh passive exposun to cigar.tte smoke. eoronary disease; ',tiobacco smoke poQuUon x: Passive smoking is defined as exposure ing from another person's tobacco smoke. of an individual to the air poilution result- The products of tobacco smoke are divided Received for publication September 3; 198fi; and'in one eecond; MRFIT, Multiple FWk Factor Interven- final form January 21, 1987: tion Trial: Abbreviationa: FEV;, forced eryiratory volume in ' Coordinsting Centers for Biometric Research, 783

I I I EFFECTS OF PASSIVE SMOKING dex was the smoking behavior of their wives.. MATERIALS AND ME'I'HDDS' The Multiple Risk Factor Intervention Trial was a primary prevention trial de- signed to test the effect of a multifactor intervention program on mortality from coronary heart disease. The design of the MRFIT has been de- scribed (7). Briefly; men aged 35-57 years were recruited in 18' US cities. They were screened to select those in the upper 10-15 per cent of' a risk score distribution deriveti from Framingham data, based on serum cholesterol concentration, cigarette smok- ing, and diastolic blood pressure. Those free of overt' coronary heart disease by history and resting electrocardiogram who con- sented to participate were randomized to either the special intervention or usual care groups. After randomization~ special inter- vention men participated in an intensive intervention program aimed at lowering blood cholesterol' by nutritional means, eliminating cigarette smoking through ed- ucation and behavior modification tech- niques, and reducing the diastolic blood pressure of those who were hypertensive primarily by using a stepped-care drug reg- imen. Usual care participants were referred to their customary source of medical care with information on their risk factor status but with no~adviee as to intervention. Both special intervention an& usual care partic- ipants were seen annually over six to eight years for risk factor measurement and a medical ezamination. A detailed smoking history was obtained' from all participants during screening and'at each annual'visit. This paper focuses on the effects of pas- sive smoking on participants who reported that they did not smoke cigarettes, pipes, cigars, or cigarillos prior to randomizationn into the trial. Most analyses are restricted to men who had never smoked cigarettes. Endpoint results are shown for never smok- ers and~ all nonsmokers at entry; non- smokers included never smokers and ez- smokers who quit prior to entry into~ the 785 study. Data on the smoking habits of the participants' wives were collected at base- line for participants who smoked and those who di& not smoke. The smoking status of the wife is used as an index of passive smoking exposure for the men who di& not smoke. Only a limited' amount of informa- tion was collected about exposure to to- bacco smoke on the job. Participants were asked the smoking status of their cowork- ers. The results of all'~ analyses presented are for the special intervention and usual care groups combined. Separate analyses for each study group yielded similar results. Measurernents of smoking exposure Serum thiocyanate was measure&duringg screening and at each annual visit. In the planning stages of the MRFIT, it was rec- ognized that special intervention partici- pants who were repeatedly urged to stop or reduce smoking cigarettes might be more likely to misreport their cigarette smoking status than usual care participants. Serum thiocyanate is elevated in smokers because of the cyanide present in tobacco smoke which is metabolized to thiocyanate. The half-life of serum thiocyanate is approzi- mately 14 days, reflecting long-term expo- sure to cigarette smoke. At the th'srd~ and' sixth annual examina- tions, expired air carbon monoxide was measured, using an ecolyzer (series 2000, Energetics Science, Inc., Elmsford, NY), which permitted~ a visual meter reading on a 0-104 parts per million (ppm) scale. The levels of expired air carbon monoxide are directly related to carbozyhemoglobia in the bloodi The half-life of elevated carboxy- hemoglobin levels after exposure to envi- ronmental carbon monoxide is only two to four hours; thus, its measurement reflects only very recent exposures. Other factors, especially any incomplete combustion of carbon-containing substances, can increase environmental carbon monoxide levels and blood carbozyhemogiobin levels. Pulmonary function testing was con- ducted at screening and at each annual ezamination using a 10-L Stead Wells

PUBLIC HEALTH BRIEFS R'hite women may reflect a failure of our passive exposure index to measure exposure within the lower social stratum. Power to test for small differences in effect of passive smoking by'race or social standing was lacking as were data to evaluate the role of other variables such as alcohol use or physical activity: Taken together With the results of previous studies"-a•w and laboratory results suggesting that passive smoke exposure causes decreases in energy production in the mitochondria of heart muscle2O and increased' piatelet aggrc- gability in nonsmokers,=t' our results support the health taazzrds of exposure to passive smoke.m ACKNOWLEDGM'ENTS This work was supponed by NIH grants S-T32-HL07055-13 and 2- R01-ML03341 (Mcrit Award). The authors thank )udson Wellsior his helpful eomments. The results described here were originally presented at the annual tneeting of the Cardiovascular Behavioral Medicine,:Epidemiology and Bio- atatisucs Training Session in San Fmncisco~,Califomia, on March 29, 191119. REFERENCES 1. Fraser GE: Preventive Cardiology. New York: Oxfortl University Press. 1'986;,3. _ 2. US Depanmenuof Health and Human Services: The Health Consequences, of Sttsoking for Women: A Report of, the Surgeon General. Washington, , DC: Govt Printing Office. 1990. 3. H irayama T: Passive smoking-A new target of epidemiology. Tokai J E><p Clin Med 1985: 10:287-293. 4. Gillis CR. Hole DJ. Hawthorne VM. Boyle P: The etkct of environmental tobacco smoke in two urban communities in the west of Scotland. EurJ Respir Dis 1994: 65 (suppl 133):121-126: S. Lee PN. Chamberlain J, Alderson MR: Relationship of passive smoking to risk of,lung cancer and other smoking associated'disuses. Bt 1 Cancer 1986; 34:97=105. 6. Garland C. Batren-Contsor E, Suarcz L,,Criqui;MH. Wingard DL: Effects af pusive smoking on ischemic heart disease mortality of'rtonsmokers: a prospective study. Am 1 Epidcmiol11965; 121:645-650. 7. Svendsen KH. Kulkr LH„Manin MI. tkkenc JK: Effects of passive smoking in the Multiple Risk Factor Interventton TnaC Am J Eptdemiol 1987: 126:783-795. E. Helting K1, Sandler DP. Comstock GW; Chet E: Aean disease mortality in nonsmokers living with smokers. Am I Epidemiol11988, 127:915-922. 9. Vandenbroucke JP, Verliersen JHH. DeBruin A, Mauritz B1. Van Der Heide-Wessel C. Van Der Heide RM: Active and passive smoking in married couples: Results of 25 year folbw-up, Br Med 1 1984; 288:Ig01- 1602. 10. Sandkr DP. Comstock GW, Helsing KJ. Short DL: Deathsfirom all causes in nonsmokers who lived with smokers. Am J Publie Health 1999; '19:163-167. 11. Cornoni, JC, Wdler LE, Cassel JC. et at: The incidence study--study design and methods. Arch Intem Med 1971; 128:896-900'. 12. Johnson JL. Heineman EF. Heiss G. Hames CG. Tyroler HA: Cardio- vascular disease risk factors and'monahty among Black women and White women aged 40 b4 years in Evans Count y; Georgia. Am J Epidemtol 1986: 123:209-20, 13. Tyroler HA. Knowles MG„Wing SM. rt of: Ischemic heart disease risk factors and twenty-year monality in middk-agc Evans County Black men. Am Hean J 19&: 108;73fi-746. 14. National Research Council:,Environmental Tobacco Smoke-Musuring Exposurts and Assessing Health Effects., Washington, DC: National Academy Press, 1986: 234-240:. 15. McGuire C, White GD. The measurement of social status. Research paper in human development No. 3(revised). Department ofi Educational ftychoiogy:,University of,Texas. Austin. 1955. 16. Cox DR:,Regression modeli and life tables. 1 R Stat Soc, senes B 1972; 3r:198-220: , 17. Harrell FE: PHGLM procedure. Depanment of Clinical Biostatistics. Duke University„Durham. NC. I8: SAS Institute Inc: SAS, Reluse 5.18. Cary, NC: SAS Instnute Inc. 1988. 19. Rothman K: Modem Epidemiology. Boston: Little, Brown and Co. 1986: 346-349. 20. Gvozd)akova A, Bada V. Sany L. er aA Smoke cardiomyopathy: distur- bance of oxidative processes in myocardiai mitochondna. Cardiovas Res 1984: 18:229-232: 21. Burghuber OC, Punzengruber CH,,Sinzinger H,,u ali Platelet sensitivity to prostacyci+n in smokers and non-smokers. Chest 1986r90:34-38. 22: We11s Ali An estimate of aduPo mortality in the United States from passive smoking: Environ Int 1988: 1<:249=265. Community Impact of a Localized Smoking Cessation Contest HARRY A., LANDO, PHD, BARBARA LOKEN, PHD, BETH HOWARD-PITNEY, PHD, AND TERRY PECHACEK, PHD lU ~ CO) ~ ~ ~ IJPH May 1990, Vol. B0; No. 5 601 AbitrtaeY: The present study assessed the effectiveness of a local+ iud eommunity contest timed to coincide with a statewide smoking cessation eontest; Follow-up interviews were conducted with 218 local contest participants and 198 participants from the statewidc contest. Ovetall cessation impact (participation i nte x abstinence) was 0.39 percent for the local contest and 0:09 percent for the statewide contest. t,ocalized community contests offcred'in conjunction with statewide or natiorul'carrtpaigns may represent cost-effective methods of reaching laege numbers of'smokers. (Am! Publie Health 1990;80:60)-W3.) Introduction Contests to promote smoking cessation appear to rep- resent cost-effective means of producing quit attempts in From the Division of Epidemiology, School of Public Health. University of Minnesota for the Minnesota Hean Health Program Researeh Group. Address reprint requests to Harry,A. Lando, PhD. Division of Epidemiology: School of Public Health. University of Minnesota„ 1-2 10 Moos Tower. 515 Delaware St.. Minneapolis, MN 55455. This paper, submitted to the Journal fNay 30, 1989. was revised and accepted for publication September Ii 1989. C 1990 Atnerican Journal of Public Health 0090.0036I90S1,50 community settings.- Quit smoking contests have beem offered on,a number of occasions as part of the smokingg intervention in the Minnesota Heart Health Program (MHHP), a 10-year research and demonstration project intended to reduce the prevalence off heart disease.4•` Several smoking cessation contests have been timed too coincide with the Great American Smokeout conducted annually by the American, Cancer Society (referred to as"D-Day" in Minnesota). The present study examined contest participation and outcome for samples of Twin Cities area residents in the 1984 Minnesota D-Day contest. Participants fromone of the intervention communities (Bloomington)' were compared with ia random sample of those from othcr .. Minneapolis suburbs (not within the immediate Bloomington, area). It, was hypothesized that the overalll impact of a contest, measured by participation and abstinence outcome, offered in conjunction with specific localized community recruitment and prizes would be greater than, that of the statewide contest alone. Method Subjects were recruited for a statewide D-Day contest during the Fall of 1984:. Recruitment began August 25, 1984

104 P.N LEf rr a1 Tabk Vl Rclativc nddk of havinF pacvve smoke eiposurc at home awordinE to paucnt s orn manufaoturcd s:prcttc smnk'mg hahMts /9landrrdiscd~ for aEc base - IF comhmed cl.s liand 2'cumroki RrJburn odds 19.R', rnwfiJrnrr bmtul', O.'n.vnw.lurt} hoh f.% . Af a/n Frwralr Never F. I t.2SIO R& 1.111 I 1-2610 A(- 1.1t51 Current •.0012.67- 5.9x 1 2 510 .7a'-3.62I . Chr-squared for trend (2dr) . 57:81 23.34 Y <00011 <0.001 only a further 88' ischacmic hcart' discasc dcaths, Hirayama (1984) rreported a slight: positive trend in risk, but, this was not statisticallj siEnificant. Garland rr a/: (1985), in a small prospective study. rcportcd a 15-foldi highcr risk or ischacmtc heart disease in non-smukrng Califurnian women whosc husbands werc current or formcr smokers compared with those whose husbands were never smok'ars. bunthis enormous and implausihic relative risk was only, significant at the 90`o confidcncc kvcl and had vcry wide confidence limits, being based on only 2 deaths in women whose husbands were current smokers. Sandlcr rr al. (1985): in a casc-eontrol study carried out in North Carohna, reported a strong rclationship~ between risk of cancer or all sites and passive smoking,. This studyy has been criticised by Lee (1985)~.vho notes that it is basicsily ii•nplausib)c that passive smoking should increase risk of cancers not associated with active smoking. Lcc also criticiscd the method of analysis, showing that no association with cancer risk would bc found if a more standard method of analysis was used. Vandcrbrouckc er al: (1984); based on a 25 year follow-up of 1.070 Amsterdam married couplcs, recently reportcd that passive smoking was associated with somc decrease in total'. mortality: There is evidenac indicating that young children whose parents smoke have an excess incidence off respiratory symptoms and some reduction in pulmonary function. Reviewing this evidence. Lee (1984) noted that the interpretation of the association is fraught with difficultics and that other possible explanations, including social e)ass related factors, parental negelct, nutrition, cross- infection and s+....:i::p ,....:.g p:rgnaney, had not been takcn into aeraunt adcquately„ so that a causal effect of passive smoking could not be infcrred. The relevance of these findings to chronic bronchitis or other diseases in adults is iny any case not clear. Our analyscs showed no significant effect of passive smoking on lifclong non-smokers as regards risk of chronic bronchitis, ischaemic heart disease or strokc. ln, all: the analyses relating thc various indices of passive smoke exposure to thcse discases, no significant diRcrenees were seen and slight decreases in nsk were as common as slight increases. Whill more data would be desirable for these discases, lung cancer continues to be the major smoking associated disease for which passive smoking comes under suspicion.. Since all the difTicultles of carrying out good research have eltarly stillinot yet been overcome, furthcr research is certainly needcd. Our findings appear consistent withthc general view, based on all the available evidence, thati any efTect' of passive smoking on risk of lung cancer or other smoking-associated diseases is at most quite small! if it exists at all. The marked increases in risk noted in some studies are more likcly to be a result of bias in the study design than of a true effect of passive smoking. Any views aprrssed' in t'his paper are those or the authors and not of any other person or company. This study was funded by thc Tobacco Research Council (now Tob.ao Advisory Council), to whom we aro most Enteful I> Abcrson was the hober of' the Cancer Rese.rch Campaiftn endowed Chair ofi Eridcmiology at the Institute of Cancer Research dunng the period of the study, dcsiFn and ficld work. Mr. I. Marks from Rrscareh Surveys of Gror Bruain provided adriec in the planninr phase and was rcponsibic for, the iniervic-wers' vital conunbution to the study. We ttunk the many clinicians at the 46 particifuunF hospitals who permitted us to eontact thcir patients and all the patients and spouses who answered the quations. Dr R. Wan6. who hdd a British Council award for the period 1 960-119 8 3; as well,as a number orothcr colleagues provided useful advice at various stages or the study. Mrs BJt Forcy provided invaluable assistance in rarrying out the statutial analysc.

I 786 svErDsEh Er A.L water-filled spirometer (Warren E. Collins, Inc., Braintree, MA) i The forced expiratory volume in one second (FEV1) is defined as the voltime of gas exhaled over an interval of one second, with ezpiration as rapid and as complete as possible. The selection of tracings for analysis was based on carefuli quality control standards defined prior to the current' analyses. The maz.imum of three to five measurements meeting quality standards (maximum FEVI), adjusted for age and height, is used to quantify pulmo- nary function in this paper. The quslity control procedures and measurement tech- niques are described in detail elsewhere (8). Endpoints Classification of cause of death was. per- formed by a committee of three cardiolo- gists who were unaware of treatment as- signment (special intervent'ion f usual care) or passive smoking status. They used hos- pitalrecords, physicians' reports, nert-of- kin interviews, death certificates, and au- topsy reports, when available. Coronary heart disease deaths were subclassified as 1) documented myocardial infarction; 2)) sudden death within 60 minutes, or be- tween one and 24 hours of symptom onset, without documented myocardial infarction; 3)' congestive heart failure due to coronary heart disease; or 4) death associated with surgery for coronary heart disease. Resultss are aiso presented for the endpoint fatal' or nonfatal coronary heart disease event. Thiss endpoint includes coronary heart disease death, serial change from baseline on a resting electrocardiogram, and/or docu- mented evidence of myocardial infarction from a review of hospital records by a panel of physicians (9). Statistical methods Differences in baseline characteristics and changes in risk factor levels from base- line to the sixth annual examination for men who did not smoke who had wives who smoked'versus men who did not smoke who had wives who were also nonsmokers were tested for statistical significance using the Student's t test (two-sided) or the 2 x 2 chi-square tesL. For comparison of mea- sures of smoking exposure between the two groups, mean levels of thiocyanate and the maximum FEV, were calculated for base- line and the average of baseline and all foll'ow-up visits. The latter results in im~ proved precision but smaller sample size. The maximum FEV, means were adjusted for age and height by analysis of covariance. Mean levels of expired air carbon monozide were calculated for year 3 and the average of years 3 and 6. Differences in the means between the two groups for thiocyanate and expired air carbon monoxide were assessed by the Student's t test. Differences in the adjusted means for maximum FEV, were assessed by analysis of covariance. Tests for a dose effect of smoking exposure were performed using regression models with number of cigarettes smoked per day re- ported by wife as an independent variable. Relative risk estimates, for men whose wives smoked compared with men whose wives did not smoke, for the endpoints death from any cause, coronary heart d+.s- ease death, and fatal or nonfatal coronr: i, heart disease event were calculated using the Cox proportionali hszards model (10)) with Breslow's approximation (11)~ Results are shown both unadjusted and adjusted for age,, baseline blood pressure, cholesterol, weight, education (as a measure of socio- economic status), and drinks per week. RESULTS Sample size There were 1,4001 of 12,866 randomized' participants who reported that they ha& never smoked cigarettes, pipes, cigars, or cigarillos at entry into the MRFIT. Of these never smokers, 1,245 were married; 286 to women who smoked and 959 to women who ~ did not smoke (table 1). Q Comparabiiity of neuer smokers by smoking N status of~ui(e ~ Baseline characteristics of these 1,245 }.i men by smoking status of wife are sum- ~.i FV

EFFECTS OF PkS51'VE SMOKING 787 marized in table 2: The two groups of men are similar with respict to age, blood pres- sure, and cholesterol. The average weight for men with wives who smoked was 4.2 pounds greater than that of men whose wives did not smoke (p <0.01)'. Men whose wives smoked consumed an average of 2.1 more alcoholic drinks per week (p < 0:01) and had' 0.5 years less formal' education TAecs 1 than men with wives who did not smoke (p Frequency d;.,rrtbuuion of smoking status at encry- < 0.05). Income was similar between the Multiple Risk Factor Intervention Trial, 1973-/982 groups. Table 3 shows risk factor changes Smokers' 9,244 71.8 Ea-smokers 2,222 17:3 Never smokers 1,400 10.9 Not married 155 1.2 Wife a nonsmoker 959 7.5 Wife a smoker 286 2.2 Total 12:866 100.0 • Includes smokers of cigarettes, pipes, cigars, or cignrillos. and the percentage of men prescribed anti- hypertensive medications at the sixth an- nual examination by smoking status of wife. There were no statistically significant differences between the two groups. Comparisons of smoking exposure Mean serum thiocyanate levels at base- line and the average of baseline and all annual' follow-up visits are shown in table TAat.l: 2' Mean values of selected variables at entry /or 1.245 men urho reported never smoking ci8arrertes„pipes, cigars, or cignrillos, by smoking status of mi(e at entry: Multiple Risk Factor Intervention Trial,' 1973-1982 Smking status of wife 95% Smoker (n - 286) Nonsmoker (n - 959) Differsooe' ooebdence intsrval Age (years) 1 47:4 47.5 -0.2 -1.0-0.6 Diastolic blood preeaue (mmHg) 103.3 103,1 0.2 -0.4-0.9 Systolic blood pressure (mmHg) 152.3 ' 150~8 1.5 -0.4-3.4 Serum cholesterol (mg/dl)' 266.0 264.4 1.6 -2.3-0.5 High density lipoprotein cholesterol (mg/dl) 43.4 42.7 0.7 -0.7-2.0 Low density lipoprouin cholesterol (iag/dl) 166.5 167.1 -0.6 -5.0-3.9 Weight (lbs)' 194.6 190.4 4.2 0.6-7:8 Drinks/week (n) 9.7 7:6 2.11 0.8-3.3 Education (years) 13.8 14.2' -0.5 -0.9-0.0 Income (1,0005) 22.1 22:3 -0.1 -1.4-1.2 ' Difference may not agree because of rounding. TAata 3 Mean change in selected uariables (sixth annual minus baseline uanunation) for men who reported never smoking cigaretter, pipes, cignrs, or cigariLds, by smoking stahu of wife at entry: Multiple Risk Factor Intertxntion Tri4 1973-1982 Smoking status of wife 96% Smoker (n -266) Nonsmoker (n - 889) Difference oonfideaa intervalI Diastolic blood pressure (mmHg)', -10.1 -9.9 -0 3 -1.7-1.1 Systolic blood pressure (mmHg) -12.6 -13.6 1.1 -1.1-0.2 Plasma cbolesterol (mg/dl). -11.4 -11.0 -0!4 -4.7-3.9 High density lipoprotein cholesterol!(mg/dl) -1.4 -0.7 -0!7 -1.9-0.5 Low density lipoprotein cholesterol (mg/dl) -10.8 -10.4' -0!4 -4.4-3.7 Weight (lba) -2.2 -2.5 0!3 -1.4-2.0 Drinks/week (n) -2.7 -2.1 -0:6 -1.7-0.4 On antihypertensive medication (96) 66.5 62.5 4.0 -2.7-10.6

EFFF.G 715 OF PASSIVE SMOICING 791 I smoke on the job. The participants were asked the smoking status of most of their coworkers. Of 1,237 never smokers, 906 (73.2 per cent) reported that most cowork- ers were smokers, and 331 (26.8 per cent) reported that most coworkers were non- smokers. The relative risk for the endpoint death from any cause, for men whose co- workers smoked compared with men whose coworkers did not smoke, adjusted' for age and wife's smoking status is 1.2 (p = 0.63, 95 per cent CI 0.5-1.8). For the endpoint coronary heart disease death, the relative risk is 2.6 (p = 0.23; CI 0.5-12.7), and' for fatal or nonfatal coronary heart disease event, the relative risk is 1A (p = U6; CI 0.8-2.5). Because of the small number of deaths, the joint impact of a spouse who smoked an&coworkers who smoked was estimated only for the endpoint fatal or nonfatal cor- onary heart disease event. The risks for the categories wife and coworkers who smoked, wife who smoked and coworkers who did not smoke, and coworkers who smoked and wife who did not smoke relative to the category wife and coworkers who did not smoke are 1.7 (p = 0.14, 95 per cent CI 0.8- 3.6), 1.2 (p = 0.75, 95 per cent CI 0.4-3.7):, and 1.0 (p = 0.99, 95 per cent CI 0.5-1.9):, respectively; DlscusstoPt To our knowledge, this is the first longi- tudinal study of' the relation between pas- sive smoking and total and coronary heart disease mortality that has included mea- sures of other major risk factors, objective monitoring of smoking behavior in a well defined population at risk, and a careful unbiase& ascertainment and evaluation of causes of death. Our findings, which sup- port the hypothesis that passive smoking is associated with an increase in morbidity and mortality among nonsmokers, are dis- cussed below. Thiocyanate levels did not vary by envi- ronmental tobacco exposure. This finding is similar to that reported by Friedman et al. (4). In other studies, conducted~ in smok- ing chambers, a direct dose-response rela- tion between exposure to tobacco and the cotinine levels in saliva, urine, and blood was found (12).. Jarvis et al. (13) also found a positive correlation between urinary co- tinine levels and'self-reported ezposures to sidestream cigarette smoke. Similar find- ings using urinary cotinine were noted by Mat'sukura et al. (14) i and Wald et ali (15). In these studies, the differences in bio- chemical levels by environmental exposure were small compared with the differences between smokers and nonsmokers. For ex- ample, Wald et al. reported that the median urinary cotinine levels were 1,645 ng/m]!in cigarette smokers, 6 ng/m11 in nonsmokers exposed to environmental tobacco smoke,, and approximately 2 ng/ml in nonsmokers not so exposed. The increase in ezpired' air carbon mon- ozide resulting from passive smoking is rel- atively small even if statistically significant and in and of itself is of relatively little biologic significance. The increase probably reflects exposure to environmental tobacco smoke (16). The half-life of expired air carbon monoxide is somewhat short, around four hours. The men may have been exposed to their wife's tobacco smoke at home prior to going to the clinic for their annual examination or while traveling by car to the clinic. The differences in ezpired' air carbon monoxide or blood carboxyhe- moglobin levels may have been substan- tially greater immediately after exposure to environmental tobacco smoke. The differ- ences presented here also may be conser- vative because of the fact' that the smoking status of the participant's wife was avail- able only at baseline. By the time carbon monoxide was measured, some wives who were smokers may have quit, while others who were nonsmokers may have restarted. This type of misclassification would tend to decrease any observed difference in car- bon monozide. The health effects of exposure to low doses of carbon monoxide are not known~ at present. Earlier studies have reported' that individuals with cardiovascular disease

,. ~.,.... - .. . ~ _ PASSIVE SMOKING AND SMOKING-RELATED DISEASES 101 , kvel of husband's cigarette smoking and in relation to hushand's agar and pipe smoking When additional sources or! information on smoking habits were used, the overall' relative risk was reduced to a marginally, significant 1.31 with an elevated ri'sk onlN rcafl) , discerniblc in relation w heavy cigarette smoking by the husband. Even here,, it is notable that the eltvatuon in risk was not evident when smoking data were obtained' from the subject or her spouse directly, but was only evident whcn the data were obtained from the daughter or son or another informantL i.r. from those people who~ were lesc hkeh.. to have known the fulll smoking history. The lowcr rtlativc risk may stilf: have arisen wholly or partly asa bias resulting from misclassification of smoking habits. Fourth, many of the studies arc open to specific eriticisms. For examplc, the conclusion ofl Gillis rr al. (I'984), that male lung cancer deathsin, non- smokers rose from 4 per 10,000' in those not exposed to passive smoke to 13 per 1'0,000; in, those who were exposed was based on a total of only 6(!) deaths and was not statistically significant. Also the claim by Knoth v al, (1983) of a relationship between passive smoking and lung cancer in non- smoking women was based stmply on the observation thau the proportion of female non- smoking lung cancer patients living together with a smoker exoeeded the proportion of male smokers as rcported in the previous microcensus, ignoring inter aha the faa that in mam• families women live with more than just their husbands. lmthc present study no significant relationshifp of passive smoking to lung cancer i,ncidencc in lifelong non-smokers was seen, either in the analyses based on the information collected in hospital or in subsequent inquiry of the spouses or both: It must be pointe6 out; howevcr, tha; the number of lung cancer patients who had never smoked was rather small so that, though our findings arc consistent with passive smoking having no effea on lungg cancer risk at all, they do not exclude the possibility of a small increase in risk, though the upper 95% confidence limit or, 1_50 for the estimatc of 0.80 (Table IV), in~ relation to the spouse smoking during t'hc whole of the marriage is not consistent with,some or the larger increases elaimed~ by Hirayama (1981. 1984) Tnchol+oulos tr al:(1981i, 1983) an&Corrca er al: (1983). Though the number of lung cancer patients who had never smoked is small, varying around 30=50 depending omc thc analysis. this number is not very diffcrent~ from that reported in a number of other studies, e.g thr find,nea of Cortea rr al. (1983) were based on only 30, while those of Trichopoulos tt al. (1981). even when~ updated'~ (Lrichopoulos tt aL. 1981) wwere tu~cd on only 77, The difTiculty of obtaining an adequate sampk size is underiined when one considers that in our study the 44 never smoking lung, cancer patients who eompkted passive smoking, questionnaires in hospital were extracted from a total of 792 lung cancer patients., It would need a very largc research efTort to iixrrasc precision substantially, and even thcn~ one wouid have to take care that the magnitude or any biases did not excz•ed the magnitude of the efLcct one was looking for. Thc two major prospective studies which have so far rtportcd findings on passive smoking (Hirayama„ 1981i; Garfinkcl! 1981) were not actually designcd to investigate this issue and, as a result, could only use spousc's smoking as an, index of exposure. Our study, on the other hand, though not able to monitor exposure objectively, as would' have been preferable, was able to look ao passive smoking in a wider context, by asking about the extent of exposure at homc, at work, during travel and at kisurs. Although the answers to these questions were subjcctivc, and could have exhibited some bias, their inclusion perhaps allows greater confidence in the eonclusions.. It was interesting that, of the 59 patients for whom sf+ouse-s cigarette smoking habits were obtained from, both the spousc and the patients, there were 9' patients for whom, there was disagrccmcnt as to whether the spouse had been a smoker at some time during thc marriage. It seems reasonable to suppose that some of these were in fact smokers an& may have been erroneously classified as non-smokers had only one sourec of information been used. It was also noteworthy that there was quite a strong correlation in our study between active and passive smoking As illustrated in Table Vi., current smokers were considerably more likely to be exposed to passive smoke exposure at home (from sources other than their own cigarettes) than were never or es-smokers. As noted above, this conreUion, coupled with some misclassification of smokers as non-smokcrs, may spuriously inflate the estimatc ofl risk related: to passive smoking. It is impornant to carry out further, studies to obt.in more accurate information, on reliability of sstatements about,t smoking habits because of this possibility of bias.. Little other evidence is availLbic concerning the relationship betwcen passive smoking and risk or the other smoking-assonrtcd diseases in (adult) non-smokcrs and much of this is open to criticism. In his original paf+cr, Hirayama (1981) prescnte& relative risks or death for various diseases for non- smoking women according to the husband's smoking habits. Based on a total of 6& dcaths, a slight positive trend for emphyscma and asthma was not signifieant, whilc, based on a total of f06 dcaths. no indication, of a tren& at all was seen for ischacrnic heart discase.. Ima later paper, based on

T.atE v--.Area.d sa adJ,m.d .ea.bo-ye* ro0a7 ys3.o. by carpry rf ewa.rs aP qOanm ,woie. Fqccr in yosietrtierrs arr ucnuJ os.bes of dcrAr r....r Pad.c amkam Smdf~ mmkw Dwbh~ mookw s Allcouo Rlr 1(99) ~1 fl-4(tf4) t60e~.(42o) 1554(73q Lunjaem 1-6 R)! 5-0 (9) 21-2 (54) 7114 (") 4mrma t,en.~r 37:3 (D0; ~~, 47n (54) 61-0.(171)6U7(260) 1Woneeofdelial.udemookwS 60.i(?1)', ?2-S(tON) 1!W(367) 129-9(b92) TJtaLE vl-A/r .dpc>ud jreLYls.K of /tSavC7oryy and OoRllOYt0/(0 lJ1.p- 0d Sje -d@Jtaidmortnl+y,paJ0000 prr ysm for uowem m camw' mid p¢mar >..otua pwrpi. Fwva n pmenrhem mr .raben aJ.cauJ cmo P.mK umokm csI (2.409) Ln.ecIpmm (.-75s)~ Hghergaa,c (s-5t1). Amp-Rory vympm>=: lu&ctedipa= Pa +.+nci 2-1(t0)~ 2-1(10)~. 31(1T) Paainmt .pnt® ir(l1), S-a(45)~. a<(46) Dlspom U •7(60)1 1t~2(a4)~. 162(p) 17yp- 4'1(19) , 1.3(29) ~. S-7 (30) CAedmw.wl.rrya~mmc: . Anpr 3s (r+) ~ 4-1(32) ~. sa(st) Ataprabnms.tiry(4md'mdleovoedn~ 0+ (2)~ 1-1 (i)~. 0-5 (s) Aamus r..m* S8~3(32) M-6(70)~. 1nd (Sq LunFcanecr l-I~~ (1t~ 2i. Rl. 57 (3~ 1xL.wic6artd- 6•6 (3) N~3fl4i. 20•0 ( I6) AO au`a of dea>h eelamd m~uI 3`4-9 (t7) 352(39) ~. 47•3(30) 6• 1% (24313960) of inen and 32• 1%(1295/4037) of women. Of the cohabitees, 91-6% (7325),were of the opposite sez The composition of the groups by social class is shown in table 11. The extent of passive exposure experienced byy passive smokers in relation to subjects in the double anoking 8roup is shown intable Ilt: ln all, 46• 1% (112) men and 41-8% (541) women in the passive smoking group lived in households where the cohabitee was smoking 15 or more cigarettes a day. This compared with 52 - 7% (985) men and 56-2%: (] 080) women in the double smoking group: Fs-smokets were more commnn in households in which the indez case had never smoked. The plevalence of signs and' symptoms for the four exposure groups is shown in table IV. Foa each of'the four respintorymeasures (infected sputum, persistent sputum, dyspnoea; and livpersecretion) the rates in the control I group were lower thaa those in the passive smoking group and considerably lower than in the single and double smoking groups. The rates for angina and major abnormalities falnd on elecmo- tardiography were smmaar in the comaol: and passive smoking groups and lower than in the aMive smoking groups. Mean forced ezpiratory volumes in tloe .second' adjusted for sa, age, and height were cgaificaatlyI higher (p<0-01), in controls than in those pasvvelyy exposed to cigarette smoke and were significaady higher than among .ctive smokers. Mortality adjlutedfor ageand>a in the four groups is presented in table V. Total morulirv was higher among passive smokers than mmrmis. This was reflected m the category of all tauses of death related to smoking and was highest for ischaemic heart disease. Lung tsncer mtatalrry was higher amoog passive smokers than conunls, but the number of deaths involved was imall. The suppktnentary questionnaire on espostlrL to cigarette smoke at home and work allowed a check to, be made of the smoking habits of other household members who were not part of the survey : A regular smoker living in the same household was reported by 5% (2/44) of controls compared with 69% (27l39), of passive smokers.,Of women, 21% (13/62) of controls lived ~ in households with a regular smoker n1lmp.red with 63% (125/197) of passive smokers. Women repotted'that most of their passive espoaae was at home rather than at work,.vhich suggested that they were the appropriate group in whicb to tr.,,,ine whether there .vas a dose-mpoasr re.latiom. A high I exposure passive smoking group was therefore defined' as women whose cohabitec was smoking 15 or more cigarettes daily, and the remaining female passive smokers were defined as a low exposure group:,Table VI presents the age standardised rates for respiratory and cardiovascular symptoms and mortality for the control and the loa-and high exposure passive smoking groups. For each of the four respiratory symptoms the highly exposed' passive smokers had rates that were higher than those in passive smokers whose exposure was low and those in the controls. There were no consistent differences between the low passive exposure group and the controls. A similar pattern was found for artgina buM not for maj(a abnntmaluies detected by electrocardiography. The adjusted forced expiratory volume at one second was significantly lower in pssivo smokers with high exposure comuared with those with low exposure (mran 1.-831 c 1-891; p<0•05): Nosigni5canr diffettace was found between passive smokers with low exposure aad controls (1 •891 v I-881). Age adjusted mortalitywas increased for the passive smoke:s with high expostue compared with low and with controls for all cause mortality, al1 cause mortaliiy, related to smoking, ischaemic heart disease, and lung,cancer. Table VIl shows the adjusted relative risks for passive and active smokers compared witb controls. For each variable tbe relative risk associated with passive tmoking was >I •Q The mnfideace interval included 1•0 except for ischaemic bearx disease, for svhieh~the estimate of risk was signi6cantly diSenmt, fro® unity (p=0-008): Table VM shows the relative risks fas double mokers compared with single smokeis afteradditional adjustment for quantity smoked. Dyspnoen was signi- TAai[ Iv-RrJaa<er risks aaacimed>xv4 peaior a.e1a3.djsaI se, .rz, .wd.oeid elm a.d for cmdiomadoamia6la, baaoi+r iJaodDrwx, ~e~o. c6o(me.mf co.unaanoa, md 6o~.aa ade nd.m.crek (pmiveaokvscomyred 95KGm5doa.uL cvaec4) oiv.al 1 Rd.ove ru! wodcvs oomt+orad yv.>e .,mmo.d.) 2V Rnpvavnrvsypspooa: . In(srodqutuv, 1 14 0.7610 2-36 0-1 4-53 Ptruurn,qr¢um. Dym- 1.19 1.0 41 1-67 tr92 m ,i.a5 0-3 Qi 4-49 1.0 H.pencie®. 1 -21 0.9110 hJ2 0-3 T77 [ardwva.oYr qalms:: Ang- t•IJ F7l~e 1~,70 O6 1.0 ' Mawr atamrmaYO tuud.m dicvoa.io~m. 1,.77. 040 b 3-33 1-31 MonaYn : AIJ CumRs trn 0-95 tc 170 d••W - 2-07 AL tauae d Aeaub ,dneEto aakry 1-)0 liliw 1'35 0 15 : 2-33 t.dum,r 6en dser 2.01 1-2110 1-D5 0-001. r27 \[ Lutq mca 241 045 m 12•03. 0-3 I0b4 425 Bdu1J voLamE 299 12 AUGUSr 1989

qtse(~L"¢d ) Annuccl. M¢&nR , Awj;c.~ ~u b! ~ ~k~ Assa-.iaT~Dv% , Cocdzr 4, Aygt;) , Michael J. s~i (,'. Hunt PhiLs aQ yDli7niYSrsiiy-C Qcr-& _Y ~ ms.ND fUn i Q. •//V YF•11MM!0DMI.7[ 3411 df714tID) QU jNC3tEASED I]VCTIredCE oF HEART ATTACKS IN N(S?1W= WOMEN MARRIED TO SMC}KERS. 'lo ibvestigatc the nicidencc of beari attaclrs in never-smoking women cxpbtM tb ewiron7nental tobacco imokci ih~; iuthM Palrud data collected frcnn 18,344 .,nts (9,172 rpouse pairs) of Utah high school utudcnts. Eich parmzt bad ban a;kcd to M port on 1'ils os hes own health history, inetu'di»g tlfc oceunznee and ige of oneet of a laeart artack, etrckc, coronuy hypPsz turgery, , hypertension, diabetes, and cancer. AU never-smoking women (N- 7,115) who were bcta+een the ages of 30 and 39'tmd for wbcm t"ncrc was inforrnatioavn the husband's s,mobng:tatus were includz6 in 6e current study. There were 941 women married to currcnt smokers, 09 women martif,d tb f8l4iei m©Ym, lAd 5214 women matricd to nevcrr-smokert, A total of 23 beart attacks were reportud by these women. Compucd to wosncn married to never- s,roa.Crs, th:c womr:n marricd to curTSnt smokers wc7e 4.4 (pc.01) timts as hkely to hatre had ri heart attack, When a proportional haz.uds raode.l was uud to control for other known rick factors {family h3ttory of CHD, hygeztcnaiott, ~'iiabc;tcs, wcight, alcohol fntake, md unount of excrase) the rclarive risY: rv;Ls stil13.4 (p <.01). 'Ihcre seemed to be an increased risk ariZh in inCCCa'lod hcngih et Gxpwsm; wo= married to former unoiccnz had less of ta incre;esed risk (RRs 1.9) than xomea married to current anojcea (RR-4.4). 'Y'6ese retultt suggestthat.vomcn mairied to tmokett have an iyicrt:aasd risk of heart attukt as a sr.sult of exposure to ravuonmaital mbatCOO cmolcc.

I t 792 SVENDSEN Er AL. (17, 18) have an adverse response to rela- tively low doses of environmental carbon monoxide. There has been controversy con- cerning these findings (19, 20), however, and the studies are currently being repeated in different laboratories. It is possible that transient elevations of carbon monoxide due to environmental tobacco smoke in high-risk individuals may be associated with an increased risk of heart attacks and perhaps cardiovascular deaths. The major- ity of sudden and unezpect,ed deaths in the community occur at home (21). The acute precipitant of many of these heart attacks is unknown but could relate to certain in- door air pollutants. Occupational studies (20) ~ of exposure to carbon monoxide and risk of heart attack have been equivoca] in their results, as have community studies of the relation between ambient carbon mon- oxide and coronary heart disease mortality (22). . There have been a few studies of pulmo- nary function and' exposure to passive smoking among adults (23-28). Three stud- ies in the United States (23), France (24),, and Holland (25) have demonstrated de- creased pulmonary function among pas- sively exposed individuals, with usuallyy about a 1OO- ml difference in FEVI, betweenn the passively exposed compared with the nonexposed nonsmokers. A study in Ha- gerstown, Marylan& (26), noted that 5 per cent of nonsmoking men not passively ex- posed and 7.1 per cent of those passively exposed had FEV, less than 80 per cent predicted (relative risk of 1.4). The relative risk was not statistically significantly dif- ferent from one. Forty families were iden- tified in a study of three communities in the United States in which the mother was a smoker and the father a nonsmoker (27). There was a statistically significant de- crease in the mean residual FEVI for the fathers married to women who smoked compared with those married to women who did not smoke. The effect was, how- ever, substantially reduced when tha ez- smoking men were excluded. A recent re- port from the Federal Republic of Germany (28) also failed to demonstrate any effect of passive environmental tobacco smoke on pulmonary, function among a rel atively young occupationai; cohort. There was also no apparent effect from direct cigarette smoking on~either the forced vital capacity or FEVy. Lebowitz et al. (29), in several studies in Arizona, have been unable to demonstrate any effect of environmental tobacco smoke on pulmonary function among adults who do not smoke. The approximate 100-m1 differences in the FEV', at baseline as noted' in table 6 are consistent with those of several of the other larger studies previously discussed (23-25). It is unlikely that the relatively small dif- ferences in pulmonary function in our study can contribute substantially to chronic ob- structive pulmonary disease or disability. It is possible, however, that there is a subset ofind'ividuals in whom a hypersensitivity to environmentali tobacco smoke causes further progression of pulmonary disease and disability: The excess total' and coronary heart dis- ease mortality and morbidity amoni, MRFIT men who were exposed to environ• mental tobacco smoke is further evidence of a potential! serious health risk for a large segment of the nonsmoking population. Inn the MRFIT study, 23 per cent, of the men who did not smoke were exposed at home to the environment;al tobacco smoke of their wives (table 1). As noted, a study by Friedman et al. (4) has suggested that up to two thirds of nonsmokers are exposed to environmental tobacco smoke. At present, the number of cancer deaths in this study is too small to allow any evaluation of the relation between environmental tobacco smoke and specific cancer and other causes of death. Other studies have evaluated the relation between environmental tobacco smoke and ~' lung or other cancers. 1*learly al1 the cancer ~' studies have been case-control studies (30- N' 36). The cases have usually beea lung or W other cancers and the controle either hos- ~ pital patients, community residents, or ~ friends of the cases. Practically all the stud- ~ ~ ~ r

F I lb I 10 HealthBrief s Passive Smoking, and 20-Year Cardiovascular Disease Mortality among Nonsmoking Wives, Evans County, Georgia, CHARLES HUMBLE, MS, JANET CROFT, MPH, ANN GERBER, MSPH, MICHELE CASPER, MSPH, CURTIS G. HAMES, MD, AND HERMAN A. TYROLER,, MD Abstract: The association of passive smokingand cardiovascular disease (CVD) mortality was assessed in a cohon of 513 rural, matried Black and White women who were disease-free and self- described as never-smokers at baseline in 1960. Over a 20-year period, 76 of 147 total deaths were attrSbuted to CVD. Relative risk estimates adjusted' for age, eholesterot, blood pressure, and body mass from proportional ihazards models were 1.59 for CVD (95% C1 - 0.99. 2-57) and 1.39 (Cl - 0.99, t.94 ) for all cause motulity atrwng women with husbands who smoked cigarettes. (Am J Public Health 1990; 80:599-601_) Introduction. Cardiovascular diseases account for about one-half of all1 deaths in the United States annually,t Althoughiactive smok- ing is well-established as a CVD risk factor,2 the risk for all'. CVD mortality associated with passive smoking among non- smokers has not been previously investigated. Recent studies of risks for coronary heart disease,?-a stroke!-$ or all cause mortality'•9•10 associated with passive smoking generally have reported weak andlor statistically, nonsignificant results. The 20-year mortality experience of nonsmoking women in Evans County, Georgia was used to assess the association of passive smokingwith CVD and all cause mortality: This is the first report that includes data on both Blacks and Whites and' on the consistency of self-reporte& smoking behaviors over time. Methods In 1960-61, 92 percent ofialliresidents ages 40-74 years and a 50 percent sample of individuals ages 15-39'years in Evans County, Georgia participated in a cardiovascular disease study that included risk factor measurements, com- plete physical examinations, and a demographic and medical history interview." Detailed descriptions of the Evans County study design and the 20-year mortality follow-up of the cohort have been reported elsewhere. 11,13 Ati baseline, 554 (82 percent) White and 389 (83 percent) Black women, Address questions or reprim reqyests to H.A. Tyroler, Department of Epidemiology. Rosenau Hall CB r7A00, UniversityofNbrthCarolina. Chapel Hill. NC 27599. Mr, Humble, Ms. Croft, Ms. Gerber and Ms. Casper are cardiovascular disease trainees in that Department. Dr. Hames is principal invesugator with the Evans County, Heart Study. Hames's Clinic, Claston, GA. This paper, submitted to the Journal June t2: 14g9, was revised and accepted for publication October 30, 1989, C 1990 American Journal of Public Health 009t}003690SILXI among a total of the 1,127 women ages 40-74, reponed that they had' never smoked. The present study was restricted to the 328 White women and 185 Black older women,who ha& never smoked' and were married to male examinees who reported they either had never smoked or were current smokers at baseline. Women married to ex-smokers' were excluded from the analyses as the probability for misclassi- fication of these subjects' own smoking habits and those of their husbands was judged to be higher than for spouses of never smokers.t' A second survey of studyy subjects in, 1967 provides data on the stability of reported~ smoking status. Vital status was determined as of May 1. 1980. Under- lying cause of death was abstracted'from d'eath certificates with codes 390456 (ICD 8th Revision) defining' CVD! A]II CVD mortality was chosenias an endpoint given the limita- tions of death certificate data and the small number, of deaths attributed to eachispecific CVD entity.t` Three subjects who did not have follow-up information were excluded. Analyses for White women were stratified by sociall status because of its inverse relationship v.-ith smoking status and CVD mortality in this cohort.t' White women were divided' into high social status and low social status groups based on the median of the McGuire-White index of' sociall status for, alll Evans County Whites. This index, based oni occupation, level of education, and source of income of the head of household, was developed for use imrural settings." Since only 5 percentlof the Black women in the Evans County' population had a social status score above the median for Whites, Blacks were not stratified by social status. Exposure to passive smoking was defined by husband's smoking status (current, never) at the time of'the baseline interview. Mean baseline characteristics by passive smoke expo- sure were compared using t-tests. Cox proportional hazards modelst" were used to estimate the association; of passive smoking with time to all CVD, smoking-related CVD:and all cause mortality in this population while adjusting for age alone and forage, systolic blood prescure. serum cholesterol, body mass index (BMI), an4 a quadratic term for BMI. Relative risks (RR) and 95% confidence intervals (Cl)iwere calculated using the SAS proportional hazards (PHGLM), modeling procedures,~'-t"' and'the statistical significance of trends was tested using a method proposed by Rothman.'v Constancy of the relative risks over time was verified before the proportional hazards were mi Results Among nonsmoking married womeni there were 179'(55 percent) of 328 White women and 117 (63 percent) ofi 185 Black women whose husbands reported current cigarette 599 AJPH May 1990„Vb1J 80, No, 5

\ 13

\ Deputment of Medicine and P.ot?ia 8eference Uniti RoJal S3allamhire Hospitatl, Shzf5eld81ll 2JF A Kapur, arAtostl, wdical midenr G W ild, asc, serlior rcirnlm A Milford- W ard , FRCPATtt; direclor ojprotenR.eJerence umir D R Tnger, rRc?,,naderiw wediaine Correspondence to: Dr Tnger.. B.Ma[J J9W;IMa27-31 for the effects of passive smoking on smokers. Therr fore the main emphasis of this paper is an estimation of the risks of passive smoking in lifelong non-smokers; data are presented for the active smoking groups to provhfe an estimate of dose-response. Our results are based on a general'populat3oD cohort study carried out in an ar!o with a high level of disena related to smoking. A consistent increase in tisk was observed in pRssive smokers for each of the f 0 variables measurcd coverittg respiratory symptoms, , foroed' e=- piratOry'volume in ooe eecond, cardiovascular symp tom5, and subsequent mortalJty, including lung cancer and tschaemtc beart dssease. A dose-response relation was seen, and the risks were b;okJgically plausible in relation to the sia of the risks found for the active smokers. These three factors taken together increase our concern that exposure to other people's tobacco .imoke cannot be tegarded as a safe mvt3luIItaly pACtICG• I Cdk7 JRT. tidYtlVV'. GmYiRT..LEiea dP~ matiq ad p.,an.l /Akrn,oe ppeumar rd lYmrWm r rr1, dJdsoad. L.ra 1974y:1031a.. 2tomc 574 Ta{a la, Spna FE, arec 6. Feris~ !.Ys:-e r.loa. o rsspunmr, dluen, e,prene trtag. aedk+d d pJ.aary 1~ a a . poqdi- sunpk m clWdn:a. Aw Rer Rnpv !h+ 197t:11:M952, 3 wlnc JR. Fab HF. SnaY .,+'.ri dv¢~ a nm-..oMam cYmoly. apoxd ro,eE.cso -ok<..k Eq/ Y Md 1 WUJOI:72P3. 4 K.u(f~ , F', Tmer lF, 4adt<. Aduli.paaa< aa.aYen mt6r bnKl annemmea[: a nat. haer fr elumr a,n6o. Iwuuan. A. JEPrr~d 1993.117:269-80. S LebmaMD. dJlv~dpra.c:okuRmpdmon.rytvncvm:asvey. P.er.Md196/13:645-55. {9 .Id: N3, l:anch.W K. TUep.m SG. CycLJrHS. Du. Ms[Woe etecpeopk-r wE.cto mwta a.rt Wy osce? B. MdJ.19Y61f3:12I7.22. 7. Garluid C. ll.n.a<'aom E. S..e: L. a .1. Effecn d p.w+e ®atmr mm sc6Kmx- hraa . dnwr asrohr} . d aoe-saken: a prnP~ KdY. A.J.Ep4-ef 19t5:121:N5-S0. 1 H..rsT.ra- aaad.e:aw.nnd+.6adcp. T.Y11EyCJ. M1 J9lS;lo:n7-93. 9 S.nd_ RH.K.YaLH,MrmM1.oAtY1R.Efhcvnfp..nematq r tk .duph ,.k 6cu .oesa.e wl. A. JlPdw.d Hr7.lDf 71i-91. IoUS Jkpartem, d. HdtErdHrh se.,as. Raq.op.J/as.J nedwer.ai ta~n. qrw.YI r rr4n RIPsn OJs „1.T. Mry 1913 ' Bath+d.. MaryWd:HmJ Immwm d Fka1W, 1N3: 11 GiOeml. Hdd Dl, - VM;,as,M:P. h ~ d e...~WpErm_Ye . a.u v1r mee,r,m r dr - d Smtlrd..Ea. J: Rwp. Da 19FIyi5. (fAppi 133):JI1l. 12 H..rAvar vM, GJW Cll.. Mslae ix. Ma..rw{ lisnh a Sell.d. /u J,EpdaW11»s:1a69•74. 13 t1..r.a.cvM.Gaea.DA.ar..+DG. Wmdp~..asomrar.. 8e Mcf J. N7a;1:f063. 14'. Rap1uEL..MmK N4epr~evcaaeroe. tro. r®pk.abrv..ara J.rrl a{ W Aw.+r~ Sr~d Aa~.si. HSt33:957.i 1. iS Ca DR. TJ,e...y.~ .JLvy /r. La6m: MeW.m. It70.. 1{ Ca DR. Repsm ma6ei .d Yie .bin.: J-f .J W Ryd Sa~o1 S'.rrry re11m3f: H17.220. 17 Cs DR. Prod 4kd,rnal. ar.W Imf2:7lN.7x. uDRrn. tol, an+a )da. E"dms L.. d a~w.ebr.t/r La~lt 1A~~ 5ramr.lY.Jl_ e 19tS; Lr A.p1n- uv.avry d Citlorlr Pes, 19tS:. 19 . Maoukun S, Taoe.e T. IGn- N, a d. Enarn d o.uaaomdaoM.no m,N<. ao vmvr _ s.nam r. sa-Ulnltas. N'EYI1Md t1N:r11a2432.. 20 Hdimus D: ane.m.r KD. Adw ID,.J. ladev PoOnues.bf alrso . ®oke: radd aird,e a.lle epuka b..ee-. In: Ih0uod a, tl.: f.i.. ~. w~a tro~r ..rk.l..P-rlr, .d'f-W q'/rbp'- Vd 2. SwriYde:S.eds6 Gund tr tk,iN.y Rssreh. NN:113.1,. (Peaceed,op d 1h. 04 re..om.l mak,ma ~.Oaer rr W+1+7 rd • dunuc,.upplDl9.) 21 Vald N,,RnAm C.. VJitlm da.de as Y.r mow doa,mnot~s .aned b wa~es. La NM;t:10i7: . 22 GJW CR. Hok D). HssLora VM. Cprme .mtat a.d a.k A.,e a.~ ~e ao aie d.enh*h mcdeea- 13. t4pa, d a~e+enl popW.- mhen . vud,e tbr im d Sm,iud. J Elr.+d C.~.~n Hrw 19Y;<2:w. 23Lee PN. Alnrid6ouoe. r.6cr r Pm,re. s>~ rot../,.~ra 19f6w:867: 24 nu~A PRJ. tf Wa . mmaL~q a tlYUmd -d ov'.k. A. JErYr 19%323:lY•9. 25. , '.Id Nl, lrelr® J I 31.itrf A. Rari. C, Haddo. lE. Ragsc G. lJrwr m~m,rr a erka d bstEp. nc- pmptr'. e6aaearoYc Lo 19Na130•1. (AaaMd II M..11N) ~ Carbohydrate deficient transferrin: a marker for alcohol abuse A Kaptu, G Wild, A Milford-Ward, D R Triger Abstract Objective-To assess the value of serum earbohydrate deficient transferria as detected byy isoelectric focusing on agarose as an indicator of alcohollabuse. Design-Coded analysis of serum samples taken from patients with carefully defined alcohol intake both with and without liver disease. Comparison of carbohydrate de6cient transferrin with standard laboratory tests for alcohol abuse. Setriig-A teaching hospital unit with an iatetest in general medicine and liver disease. Patientr-22 "Self confessed" alcoholics admitting to a daily alcohol intake of at kast 80 g for a minimum of three weeks; 15 of the 22' self confessed alcoholics admitted'to hospital for alcohol withdrawal; 68 patients with alcoholic liver disease confumed by biopsy attending outpatient clinics and claiming to be drinking Ikss than SO g alcohol daiiy; 47 patients with eon-alcobolic liver disorders confirmed by biopsy; and 38 patients with disorders other than of the liver and no evidence of excessive alcohol consumption. Intenxntibn-Seriat studies performed on the 1S patients undergoing alcohol withdrawal in hospital. Main outcome m.earure-Determinatioa of relative value of techniques for detecting alcohol abuse. Resulu-Carbobydrate deficient transferrin was detected in 19 of tbe 22(86°/.) self confessed alcohol abusers, none of the 47 patients with non-alcoholic BMJ vot.u/.te. 299 12 AuGt,ST 1989 liver disease, and one of the 38 (3%) controls. Withdrawal of alcohol led to the disappearance of carbohydrate deficient transferrin at a variable rate, though in some subjects it remained detectable for up to 15 days. Carbohydrate deficient transferrin was considerably superior to the currently available conventional markers for alcohol abuse. Conclusion-As the technique is fairly simple, sensitive, and inexpensive we suggest that it may be valuable in detecting akohof abuse. Introdtsctioa The medical and social consequences of alcohol abuse are major problems throughout the world. Although many: people rndily acknowledge the eztcnt of their alcohol consumption, others attempt to conceal it, and we lack reliable objective means of identifying surreptitious alcohol consumption. Currently available laboratory markers have considerable limitations, being insensitive, non-specific, or dependent on liver damage. The mean corpuscular volume rises in patients with thyroid disease, folic acid deficiency, and liver disease,' whereas serum yrglutamyltransferase activity is affected' by drugs that induce microsomal enzymes as well as rising in all forms of obstructive liver damage.' Serum aspartate aminotrsnsferase activity is more commonly raised in alcoholics than alanine aminottansferasc activity is, and whereas  ratio of aspartate to alaaine aminotransferase activity of greater than 2:1 is strongly suggestive of alcoholic liver disea~e this is of little value in subjccts in whom the 427

EFFECTS OF PASSiVE SMOKING 793 I ies show a higher prevalence of exposure to passive smoking amo:rg the cases compared with the controls. The estimated odds ra- tios have generally ranged from 1.5 to 2.5. The largest prospective studies have been reported from Japan (37, 38) and the United States (39). In both studies, the populations at risk were predominantly women, and the exposure sources were spouses who smoked. The study in Japan by Hirayama (37, 38) demonstrated a con- sistent increased risk of lung cancer and other cancers among the nonsmoking wives of men who smoked A smaller study amongg nonsmoking men as index subjects also demonstrated an increased risk of lung can- cer among men married to women who smoked cigarettes (40). Our findings on~totalian& coronary heart disease mortality and morbidity are similar to those of two other studies. A study by Garland et al. (41) specifically related en- vironmental tobacco smoke to coronary heart disease. This study followed for an average of 10 years 695 married women, initially examined in 1972-1974, in a re- tirement community in California The women were classified by the self-reported smoking status of their husbands at entry into the study. After 10 years, nonsmoking wives of'current or former cigarette smok- ers had a higher ischemie heart disease death rate than nonsmoking wives of' non- smokers. There were, however, only two ischemic heart disease deaths among the wives of the men who never smoked, 15 among the wives of former smokers, and two among the wives of current cigarette smokers. There were no differences in age- adjusted aTl-cause mortality rates among the wives of never, former, or current cig- arette smokers. In the longitudinaL study in Japan by Hirayama (40), the wives of men who smoked'cigarettes also had higher coronary heart disease mortality rates. Several reasons for the higher overall mortality among the passive smokers have been considered. First, it is possible that some passive nonsmokers were actively smoking cigarettes. The careful'chemical measuremente at baseline and follow-up would almost certalnly' rule out this hy- pothesis in the MRFIT study. Practically all cigarette smokers in the MRFIT study had thiocyanate levels over 100 µmol/liter. Among the passive smokers, 7.5 per cent had thiocyanate levels over 100 Kmol/liter,, compared with 7.3 per cent among the non- passive smokers. If some men were smok- ing, they were equally divided among the two groups. A second hypothesis is that key risk factors may be different among passive and nonpassive smokers. The risk factors in the MRFIT trial, socialLbehavioral, physiologic, and biochemical, were gener- ally similar between the passive and' non- passive smokers. These have been further reviewed in detail by Martin et al. (42). Adjustment for these other risk factors did not decrease the relative risks associated with passive smoking. Third, certain other behavioral and so- cial factors may be different among passive and nonpassive smokers. There is an in- verse relation between education and'other measures of social class and total coronary heart disease mortality (43). Similarly, there is an inverse relation between ciga- rette smoking and social class (44). Thus, it is more likely that passive smokers will be in the lower socioeconomic group. Ad- justment for education or other measures of social class in the MRFIT trial did not reduce the increased relative risk. It is pos- sible, although unlikely, that these adjust- ments did not completely deal with the potential, differences in social and behav- ioral characteristics between the passive smokers and nonexposed men. More de- tailed analyses have failed to demonstrate other significant differences between these two groups. Fourth, the passive smokers at baseline may have been less likely during the trial to change important risk factors that were related& to subsequent mortality and mor- bidity. Analyses of risk factor changes in table 2 do not support this hypothesis. Finally„ follow-up was complete for all MRFIT men, and endpoints were assessed

PASSIVE SMOKfNG AND SMOKING-RF.LATFf2 DISFv\Sf,S 105 s . ( Refen.ca ALDF:RSON; M R.-,LEI_ P N A K'ANG. R(1'9R5) Risks of lung anocr, chronic bronchttis: tschaemic hcarf discasc and sirokc in rel6tton to typc of ca6arettc smoked. J., f4+drm Can+n, H1th .,39, 296 FiRESLOW, N.C i DAY. ItL (1990) Srarirnra! Mrrhodi w CanArr Rrsrarrh 1'ol 1- The Analrsu of Cav-rnnrral Sn.drrs. I'nttrnational AEcncy for Resnrch on Canczr;, Lyon BUFFLER, P A- PICKLE. L W.. MASON. T1. & CONTANT. C. (1984), Thc ouses ofi lung onotr in Tesas In [.ac Canrrr Cm.vs and Prr.rnta.n, Mtrtll. M. & Cotrra„ P. YcrlaE Chcmic Intcrnationa Inc CHAN WC (1982). Zahlen aus Hongkong Alrarh. Med. H och.. /24, I6, CORRih- P.. PICKLE. L W., FONTHAM, E.. LIN. Y: & HALNSZEL, W(1983). P.ssvve smoking and lung an¢r. Lanrrt„ki, 595. DOLL R A PCTO. R(1978) Cigarette smoking and bronchial arnnoma dose and time netationshipss among regular smokers and lifelong non-smokers. J. EPrdrm Cmron. H/rh'. 3Z 303. GARFINKEL. L (1981) Time trends in lung cancer monaltty among non-smokers and a note on passi.c smoking J. Narl'Cancrr. /RSr.. i6, 1061. GARFINKEL L, AUERBACH. O[ 1OUBERT, L(1985) Involuntary smoking and' lung an¢r: A aseeontrol study. J. Nar! Cancer /n.u.. 75, 463. GARLAND. C.. BARRLTf{'ONNOR, E.. SUAREZ. L.-. CRIQUI: M H. & WINGARD. D.L (1985). Efkcis of passive smoking on ischemic hean disease monaliiy of non-smokcrs: A prospxtivc study. Amrr. J. Epidrnr., 121. 615: GILLIS.,C.R „HOLE, DJ.- HAK'THORNC. V.M & lOYLE. P. (1994) TThe effect of environmenul tobacco smoke in Iwo urbam communities in the west of Scotland. E+vop: J. Rrsp Dat.,,s5„(Suln+l 133)- 121. HIRAYAMA- L(1981) Non-smokmp wives of heavy smokers have a higher risk of lung on¢r:, a study from lapan, Br. Mrd J.. 282, 1,93 HIRAYAMA, T, (1986), Lung cancer in Japan. effects of nutrition and passive smoking In Lynx Canccr, Cauva and Prr.rnrun M,1sll, M& Corrca-, P. (ads) VcrLg CAcmtc International 1nc HUGOD. C.. HAM'K1NS. Lit & AST~RttP, *(,19711) Ea)+usurc ofi passive smnktn In Inh.ccn, smoke oonstrtuents lnt. Arch. Orny!. iEr+riron 17Irh, 42, 21. 1ARVIS, M.1.. RUSSCI.L. M A H.. F[iYCRARf.ND: C& 4 others (1985)~ Passive aalwsurc to tobaczo smoke saliva catininc mncrntrations in a nerrc.entatrvc population sampk of non-smoking schoolchildrcn. Br Alyd J'.. 291'.927. KABAT. GC A WYNDER. E.L. (191H). Lunl; tJryorr in non,smokcrs fbnrrr. 53. 1214. KNOTH, A, BOIiN, H t SCHMIDT„ F. (1983) Passive smoking as uusc oflung cancer in fcmak non, tQnokcrs. Nrd Alrn , 711. 54 KOO. L.C., HO: 1H:C. A SAW. D(191(4). Is p,scivc smoking an added risk factnr for lung cancer in Chrncsr womcn? J. Exp. Clm. Cancer Rrc, 3, 277. LEE, P N' (191it) Passive Smnking 6n SmolCuee and lJ+r Larx Cumming. G& Bonsignore. G. (eds) Pknum Publishing Corporaunn~ LEE. P.N (1985'), Lifeumc p.ssivc smoking and! ornorr risk. Lt+nrrt, k, 1'4.t LEHNfeRT, G.. GARFINK'EL., L.- HIRAYAMA. T. • 4 others. (19R4). Round tabk discussion. Prrv. Afrd.., 13, 730. SANDLER. D P.- WILCOX. A 1 t[VCRSON; R.B (19115) CumuL.tix eReas of lifetime smoking on cancer risk (onrrr. L 312. TR.ICHOPOULOS. D.. K.ALANDI1711 A.,. SPARROS. L A - M.cMAHON; B(1981). Lung cancer ard' passive amoking Anr. J. Cancer. 27. 1. TRICHOPOULOS. D.. KALANDIDI, A & SPARRI'1S: L (1983). Lung cancer and' passive smoking Conclusion of'Crreek study. Lantrtt ii, 677:. VANDERBROUCKL 3 P.. VERHCCSEN„1.H H.. DC BRUIN, A.. MAURIT2. BJ. VAN DCR HCIDLW[SSCL. C A VAN OER HEIDC- R.M (1994) : AActive and passrve smoking in marticd cnuplcs results of! 25 year follow up. Br. A1rd. l.. 21tR, 10111.

DONNAN, G.A., MCNEIL, J.J., ADENA, M.A., DOYLE', A.E., O'MALLEY, H.M. AND NEILL, G.C., "SMOKING AS A RISK FACTOR FOR CEREBRAL ISCHAEMIA," THE LANCET, PP. 643-647, SEPTEMBER 16, 1989. This case-control study mainly focused on active smoking as a potential risk factor for stroke. However, in what the authors described.as "'preliminary findings" (p. 647), data were also given om both spousal and parental smoking and stroke risk. Spousal smoking, but not parental smoking, was reported~ to be associated with stroke risk. Exposure to smoking by a spouse was an independent risk factor for the whole group of cerebral ischaemia patients (relative risk 1.7 [1.2, 2.6), but this was not so for smoking by either parent (relative risk 1.2 [0.8, 1.8]) . ... The persistent nature of the risk even after cessation of smoking and the possible risk associated with passive exposure strengthens public health arguments against smoking. (pp. 643-644)

798 SVENDSEN ET Ai.. 4 by smoking status of wife. The mean thiocyanate levels are similar for the two groups, both at' baseline and averaged over aIli visits.. El pired air carbon monoxide was mea- sured at the third and sixth annual exami- nations. The average expired air carbon monoxide at the third annual examination for men whose wives smoked was 7.7 ppm compared with 7.1 ppm for men whose wives did not smoke (table 5). The differ- ence, 0.6, is statistically significant (1p = 0.001), as is the test for linear trend (p = 0.03). Similar results were obtained when the averages of the third and sizth annual' carbon monoxide measurements were com- bined. Men with wives who smoked had signif- icantly lower levels of puImonary function at baseline as measured by the maximum FEV, (table 6). The mean maximum FEVy is 3,493.1 ml for men whose wives smoked versus 3,591.9 for men whose wives did not smoke, a difference of about 100 ml. Similar results were obtained when averaging over all visits, although the difference between the two groups was not statistically signif- icant (p = 0.16). Endpoint results for never smokers Table 7 gives the event rates by smoking status of wife and table 8 shows the relative risk estimates (for men who did not smoke whose wives smoked compared' with those whose wives did not smoke) for the end- points death from any cause, coronary heart disease death, and fatal or nonfatal coronary heart disease event. TAB[s 4 Mean leveLs of rhiocyanate (Kmol/liter) ar baseline and average over all'virits for men who reported never snurking cigarerre.s, pipea, cigan, or eigarillos, by .xrwking statw of wife at entry. Mukiple Risk Factor fnteruention 7}iaf, 1973-1982 Ba.eline Ayerage over all visits Smok'in` .utus of wife - - n Mean n A;rr Nonsmoker 878 Smoker 264 1-19 cigerettee/day 125 220 cigarettes/day 139 53.9 704 51.G 54.3 212 52.3 54.0 102 51.6 54.6 110 52.9 Smoker/nonsmoker difference 0.4 (-3.7; 4.6)' 0.7 (-2.7, 4.0)', p value for linear trend 0.99 0.55 • 95% canfidence limits. TAat.c 5 men who Meon e~ire d air mrbon monazidt (pprn) at the thind anrwa! visir and averuge over all visiLr for reported'never smoking cigarettes, pipes, ci8ar:, or cigariUvs.,by smoking status of wife at entry` Multipk Risk Factor Intervention T}ia 1973-1982 Smkin~ ta:r o(wife T6ied annual .vit n Mun Nonsmoker 828 71 Smoker 244 7:7 1-19 cigarettes/day 112 7:7 220 ciQaretru/day 132 7:8 Smoker/nonsmoker difference 0.6 (0:2. 1.0)' p value for linear trend 0.03 ' 95:'u confidence limits. Avrrate wer al] ivi.itm n Mean 760 6.7 228 7:1 ~ 106 7.1 122 7:2 ~ 0.5 (0.2, 0:7)) <0.01 ~ W ~ T

EFFECTS OF PASSIVE SMOKING 789 3 8 ~ I I TAeix 6 Mean mazimum FE V, ,(m1) adjusted /or age and height at bcseline and average ouer a!l uiuiti for men who reported never smoking cigaretiei, p+pes, cigars, or cigarillos, by smoking status o( wi/e at entry: Multiple Risk Factor 1'ntervention Tria4 1973-1982 Smoking wtw of wife Baseline Average over alI visi4 n Mean n M.an Nonsmoker 514 3,591.9 257 3,491.3 Smoker 162 3,493.1 81 3,403.3 1-19 cigarettes/day 66 3,412.1 • 31 3,263.3 t20 cigarettes/day 96 3,548 8 50 3,489.0 Smoker/nonsmoter difference -98.9 (-192:4„-5.4)' -87.8 (-210.7; 35.2) p value for linean trend 0.52' 0.99' ' 95% confidence limits. TABLE 7 Number of deaths /rom, any rasse and from coronary heart disease and'jatal or nonfatal coronary heart disease events for men who reported'neuer smoking cigarettes, pipes, cigars, or cigarillos, by'smoking status of wi(t at entry:,Multip/e Risk Factor Intervention Tr~ 1973-1982 Smoking eutw No. Death from Coronary 'heart. of wife of men any uuse dia..ue death Fatal or nonfital coronary beart dise..e event Nonsmoker 959 19 (2.83)' 8'(1.19) 48'(7,28) Smoker 286 11 (5.55) 5(2.52) 21 (10.81) 1-19 cigarettes/day 133 3(3.21) 1(1.07) 8(8.70) z20 cigarettre/dny 153 8(7.65) 4 (3.82) 13(12.71) p value for linear trendY 0:08 0:04 0.20 ' Rates per 1,000 person-years. t From Cox proportional hazards regression using number of cigarettee smoked per day by.vife as a covariste. TAaLE 8 Relative risk estimates, , u i/e mho smoked compared with wife who did not smoke, and their 95 per crru eonjidence uuervaLs for men who reported never smoking cigarettes, pcpes„cigara, or cigari!los: Multiple Risk Factor Intervention Trial. 1973-1982 Endpomt Relatuve risk p value 95% rnnfidence interval Death from any cause Unadjusted 1.96 0.08 0.93-4.11 Adjustcd' 1.94 0.08 0.91-4.09 Coronary heart disease death Unadjusted 2.11 0.19 . 0.69-~&46 Adjusted 2.23 0.17 0.72-6.92 Fatal or nonfatal coronary heart disease eventi Unadjusted 1.48 0.13 0.89-2.47 Adjusted 1.61 0.07 0.9fr-2.71 ' Adjusted~ by Cox prnportionali haaards regression for age, baseline blood pressure, cholesterol, weigbt, diinks per week, and education. As of February 28, 1982„after an average married to nonsmokers (2.8 per 1,000 per- of seven years of follow-up, 11 of 286 men son-years). There is some suggestion of a married'to smokers had died (5.6 per 1,000 dose effect for the endpoint death from any person-years)! compared with 19 of 959 men cause, with 3:2 deaths per 1,000 person-

disease, but that the "effects of passive smoking on the disease process were still inconclusive." WLS/tks 10744177 '

EFFECTS OF PASSIVE SMOKING 795 ic e s r 1 x 22. Kuller LH, Radford E, Swift D, eL al. Carbon monoxide and heart attacks. Arch Environ Health 1975;30:477-52. 23. White JR; Ftoeb HF. Small-airways dysfunction in nonsmokers chronically exposed to tobacco smoke. N Engl J M'ed 1980;302:724-3. 24. Kauffmann F, Tessier J-F, Oriol P. Adult passive smoking in the home environment a risk factor for chronic airflow limitation: Am J Epidemiol 1983;117:269-80. 25. Brunekreef B, Fischer P, Remijn B, et al. Indoor air pollution and its effect on pulmonary function of adult nonamoking women., IIl. Passive smoking and pulmonary function. Int J Epidemiol 1985;14:227-0. 26. Comstock GW, Meyer MB, Kelsing KJ, et aL Respiratory effects of household exposures to to- bacco smoke and gas cooking. Am Rev Respir Dia 1981;124i 143--8: 27, Schilliag RSF, Letai AD, Hui SL, et al. Lung function, respiratory disease, and smoking in fam- iliea. Am J Epidemiol 1977;106:274-83:. 28. Kentner M, Triebig G, Weltle D; The influence of passive smoking on pulmonary function-a study of 1,351 office workers. Prev Med'1964;13:65Cr69. 29. Lebowitz MD; Influence of passive smoking on pulmonary function: a survey. Prev Med 1984;13:645-55. 30. Trichopoulos D, Katandidi A, Sparros L Lung cancer and passive smoking conclusion of Greek study. Lancet 1983;2:677-8. 31. Sandler DP, Everson RB, Wilcox AJ. Passive smoking in adulthood and cancer risk. Am J Epi- demiol 1985;121.37-48: 32. Garfinkel L,,Auerbacb 0, Joubert L Involuntary smoking and lung cancer. a caae<ontrol study. JNCI 1985;75:463-9. 33. Wu AH. Henderson BE;,Pike MC, et al. Smoking and other risk factors for lung cancer in women. JNCI 1985;74:747-51. 34. Cban WC, Fung SC. Lung cancer in nonsmokers in Hong Kong. Im Grundmaan E, ed Cancer campaign: cancer epidemiology. Vol!6. Stuttgart: Gustav Fischer Verlag, 1982:199-202. 35. Knoth A, Bohn H, Schmidt F. Passive smoking as a causal factor ofbronchial carcinoma in female nonsmokers. (English translation). Msd Kliaik 1963;78:66-9. 36. Koo LC, Ho JH-C, Fraumeni J,,et aL Me.sore- ments of passive smoking and estimates of risk for lung cancer among nonsmoking Chine~e fe- malss. (Abstract). Fourth World Conference on Lung Cancer, Toronto, Canada. August 25-.'i0, 1985. 37. Hisayama T. Nonsmoking wives oGheavy smokers have a higher risk of lung cancer. a study from Japan. Br Med J 1981;282:183-5. 38. Hirayama T. Cancer mortality in nonsmoking women with smoking huabands based on a large- scale cohort study in Japan. Prsv Med' 1984;13:680-90. 39. GarfinJcel'L. Time trends in lung cancer mortality among nonsmokers and a note on passive smok- ing. JNCI 1981;66:1061-6. 40. Hirayama T. Passive smoking and lung cancer, nasal sinus cancer, brain tumor and iacbemic heart disease. (Abstract). Proceedings of the Fifth World Conference on Smoking and Health, Win- nipeg. Canada„Jlily 1983: 41', Garland C, Barrett-Connor E; Suarez L, et al. Effects of passive smoking on uchemic heart dis- ease mortality of nonsmokere: a prospective study. Am J Epidemiol 1985;121:6i5-50. 42. Martin MJ, Svendsen KH, Kuller LH. Nonsmok- ing men married~ to smokers are similar to non- smoking men msrried'to nonsmokers. (Abstract). Society of Behavioral Medicine, 7th Annual Sci- entific Sessions, San Francism March 5-8, 1986. 43. Kraus JF, Borhani N0, Franti CE. Socioeconomic status, ethnicity, and risk of coronary heart dia- ease. Am J Epidemiol 198o-111:407-14. 44. Kuller L. Meilahn E, Ockene J. Smoking and coronary heart disease. In: Connor WE, Bristow JD, eds. Coronary heart disease-prevention, complications, and treatment. Philadelphia: JB Lippincott Company, 1985: 45. Spengler JD, Sexton K. Indoor air pollution: a public health perspective. Science 1983;221:9-17.

MATSUSHITA, M., SHIONOYA, S. AND MATSUMOTO, T'., "URINARY COTININE MEASUREMENT IN PATIENTS WITH BUERGER'S DISEASE -- EFFECTS OF ACTIVE AND PASSIVE SMOKING ON THE DISEASE PROCESS," J VASC SURG 14(1)1: 53-58, 1991. 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 patients were classified either as smokers, as "passive smokers" (i.e., as nonsmokers exposed to ETS) nonsmokers not exposed to ETS. or as 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 statistically 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

I 784 SVENDSEN ET AL into two components. Those directly ex- haled by the smoker are called mainstream smoke, while those from the lit end of the cigarette, cigar, or pipe which are dis- charged into the environment are referred to as sidestream smoke. The composition of sidestream smoke (1) differs substan- tially from that of mainstream smoke, de- pending upon the different temperatures at which the substances burn and' the avail- able oxygen supply. Particulates, for ex- ample, are about 10 times greater in main- stream~ smoke than in sidestream smoke. After inhalation, sidestream smoke prob- ably reaches the more distant alveolar spaces in the lung (2). Sidestream smoke also contains much more free nicotine in the gas phase, generates more carbon mon- oxide (1)„ and contains mu& higher con- centrations of the reduced products of ni- trogen including several highly carcino- genic substances (3). Most environmental tobacco smoke is from sidestream smoke, and only a very small amount is from ex- haled mainstream smoke. Environmental exposures to tobacco smoke depend on the number of smokers im the area and the amount they smoke, the size of the area, and the ventilation rate. It is now an accepted fact that cigarette smokers have an increased risk of many diseases. In recent years, there has been~ a growing concern that nonsmokers exposed to environmental tobacco smoke may also be at increased risk of certain diseases, especially cancer, chronic obstructive pul- monary disease, and, possibly, heart' dis- ease. Friedman et al. (4) reported that 63.3 per cent of adults were ezposed' to passive Di.vion of Biometry ;, School of Public Health. Uni- venity of Minnesota. Minneapolis, MN. ' Graduate School! of Public Health, University of Pittsburgh, Pitt.burgh. PA. ' Clinical Epidemiology Program, San FYanciaco General Hospital, San Francieco, CA. ' Department of Preventive and Behavioml Medi- eine, University of Massachusetts Medical' Center, worceeter. MA. Reprint requests to Kenneth H; Svendben, Coor- dinating Centers for Biometnc Researeh, Suite 508, 2829 University Avenue S.E., Minneapolis, MN'55414. smoking for at leastone hour per week. A higher percentage was exposed away from home, usually at work. Repace and Lowrey (5) have estimated that the exposure to environmental tobacco smoke of the non- smoking adult population was about 1.43 mg of tar per day. A cigarette smoker, on the other hand, can be expected to inhale about' 420 mg of tar per day (14 mg of tar per cigarette for an average of 30 cigarettes per day). Thus, the dose from passive smok- ing is much less than the dose from ciga- rette smoking. Studies on passive smoking reported to date have depended on self-report.e&histo~ ries of environmental tobacco smoke ex- posure. A workshop on the respiratory ef- fects of enviro~ ental tobacco smoke in 1983 sponsored'by the Division of'~ Lung Diseases at the National Heart, Lung, and Blood Institute (6)! noted that'~ lack of objec- tive measures of dose or exposure, con- founding variables, methods of statistical analysis,, and quantificat'ion~ of other vari~ ables were major concerns in the evaluation of current and future studies. Participants in the Multiple Risk Fact~)r Intervention Trial (MRFIT) (7)! offered an unusual opportunity to study the effect of environmentali tobacco smoke on, men„ es- peciallyy inithe home. Objective measures of cigarette smoking behavior, as wellias other critical risk factors for cardiovascular and other diseases, were carefully monitored in a large population followed for an average of seven years. Fortuitously, at entry into the study, prior to randomization, a de- tailed smoking history was obtained for each of the participants subsequently ran- domized. This history included not only their own smoking history but also that of their wives, family members, and cowork- ers. This trial, to our knowledge, is the first longitudinal study that was able to objec- tively define the participants' smoking sta- tns and possible exposure to environmental tobacco smoke. The study design was also unique because the index subjects were men who did not smoke and who were at high risk of heart disease, and the exposure in- ~

,/cH„~'. Ne...rlehitr ~j..,....L.... `+. PASSIVE S2i0KING AND MYOCARDIAL INFARCTION IN WO?SEN.Ju1Se R. Palmer, 83 Lpnn Rosenberg, Samuel Shapiro. Slone Epidemiology Utiit, Brookline, MA In a hospital-based case-control study of past oral contraceptive use an&myocar- dial infarction (MI) in womemaged 20 to 64, information is being obtained on the 'smokSng habits of subjects' husbands in order to evaluate the effect of passive exposure to sidescream cigarette smoke on, risk of MI. We conducted an interim analysis of data from 336 married cases and 799 married, controls. With a refer- ence category of nonsmoking women marrie to nonsmoking men, the relative risk es- timate for nonsmoking women whose hus- band's smoked was 1.2; for women who smoked less than 25 cigarettes per day the estimates were 2.9 (nonsmoking hus- bands) and 3.9 (husbands smoked); and fo women who were heavy smokers, the esti- mates were 6.3 and 8.3,respeccively. The observed crend'was not accounted for by. Ithe known risk factors for lfl. These re- sults, which lend support to the hypo- thesls that exposure to spouses' smoking increases the risk of MI, are unlikely t be explained by selection or information bias. ~ T 2-~ r m _ ORAL CONTRACEPTIVE USE AND~PfYOCAR- DIAL INFARCTION. Lynn Rosenberg, Julie R, Palmer, Samuel Shapiro, Slo Epidemiology Unit. Brookline, MA A case-control study is being condv1Eted primarily to assess vhether the lo g-term use of oral~ contraceptives(OCs),a t:er discontinuation, increases the r sk of m}iocardlal infarction(MI).In an/interim analysis of data from 675 wome under ag. 65 vith~ first MIs and 1274 coroY women of similar ages,the estimate relative risks of MI for women who h d used OCs 'for 1-4,5-9, and~10+ years ere 1,2(95x confidence interval 0.8-1 ),1.2(0.8-1.9) ,and 1.3(0.7-2.4),respect ely. These re- sults do:not confirm~a evious finding of a doubling in risk ng vomen who ha used the older OCs for at least 5 years; possibly the newer lo,er-dose OCs have less adverse effeets on serum lipids and other cardiovascula ri'sk factors than the older pills. F current OC users,th relative risk esti te vas 2.6(1.0-7.1); although this poi c estimace is compati- b1e with the 4-f! l~d' increase inm risk associated vithAhe older pills, it is also compatible/vith a smaller increase, or with no inc/ease at a11. INTERCORRELATIONS OF LIPOPROTEINS ANDT LOW DENSITY LIPOPROTEIN (LDL) SUBCLASS 86 PATTERNS IN'RELATION'TO RISK AF MTOCARDIAL INFARCTION. Melissa A Austin, Charles H Hennekens, JamL Breslov„ Julie E Buring, Walter C Willett, Karen M/Vranizan, Ronald M Krauss. Univ. of Caldf'., Berkeley, CA In 230'subjects fro e Boston Area Health Study, a case-c ntroll study of styo- eardial infarction O survivors, ve have shovn that a predosi ance of small, densc LDL particles (LDL ubclass pattern B by gradient gel elec ophoresi's) is associ- ated with increa d1risk of MI with an odds ratio (OR) f 3.0 (95X CI 1.7-5.3), independent of ge, sex, relative veight, LDL-cholester and intermediate density lipoprotei'n a(ss (IDL). Adjustment for high densit~1ipoprotein cholesterol l(HDL-C) and triglyceride (TG) reduced the OR to 2.2 95X CI 1.2-4.1) and 1.6 (95Z CI 0.8-3.2) respectively. Because of colli'- nearity n these models, intercorrelations of lip roteins and pattern s were inves- tigat . BDL-C, IDL and TG were aLl found to W independently related to LDL sub- clasi pattern B, after adjustment for age, sex/ relative weight, and case-control' stttus. Biological echanisss aay sisiulta- n}rously influence ulti'ple lipoprouin vriabLes, including LDL subclass pat- erns, and result in increased risk of KI.1 EXERTIONAL CHEST PAIN AND RISK OF FATAL AND NON-FATAL CORONARY HEART DISEASE IN THREE OLDER POPULATIONS ,y. Andrea Z. LaCrob;. Jack M. Guralnik;, Charles H. HennNcens, Robert B. 1Mallrce. Adrian M. Osttad. J. Davfd Curb. NatkxaallrtstRtute on Aptnp, Bethesda, MD % Amonp older people, the proQnOsfk: slpntflcance of ' setf-tsportnd'chest pain for future myocardial Intarctk7n (MI) and' coronary heart' dllease (CHD) death Is unknown. Cohorts aged 65 and older In three i communltfes (East Boston. MA; fVew Hrven, CT: rural I lowa)' wlchout hWory of heart aisack (3067 men, 5291 women) w.re fofl'awedfor 3 years for CHDdeath and'annuatly (seN or proxy) ~ raported~hosptialtzatkm for MI. At baselane, Chest paln on,ixertkxswas found In fi-7% of rnen~(79J1195;,531936;,54(936) and 6-10% of women (197/2046: 131/1435, )'15/1a11) In each communfty, respecttvely: Fatalar)d non-fatal CHD.vents occurred k+ a total of 213 men and 250 wornen. In East Boston, , and Iowa, exertlonal chest pain was slpnl}Icantly associated wlth 14sk of fataf and non.faal I CHD .verrts combined In t~oth men and women: AQe-sd)usted Msk ratbs hx ranged from 2.0 (95% confidence lntervar (Gt)~t J.S)~ In East Bostoni to 5.1 (p5% C! I 2.8-9.E) In..4ovra, with men's rtsk ratlos Intermediate In 'these cotiorts. In New Haven, the association was posltfve1n both sexy butwe.kerand'non•s/pnlhcant! These 'flndlnps suggest that axertlbnal chest paln reported by order p.ople wlttmR txevlous heart sttack can be an Itnportant Indlcator of future CHD everns. 29

I 790 SVENDSEN ET AL years in the category wife smokes 1-19 cigarettes per day and 7.7 deaths per 1,000 person-years in the category wife smokes 20 or more cigarettes per day, although the test for a linear trend was not significant (p- 0.08). The numbers are small for the endpoint coronary heart disease deat'h, but they fol- low the same pat+ternas those for the end- point death from any cause. The coronary heart disease death rate is 2.5 per 1,000 person-years for those whose wives smoked compared' with 1.2 for those whose wives did not smoke. The test for a linear trend was significant (p = 0.04). Among men~ with wives who smoked; there were 10.8' fatal or nonfatal coronary heart disease eventendpoints per1,000 per- son-years versus 7.3 per 1,000 person-years for those whose wives did not smoke. The event rate is higher for those whose wives smoked 20 or more cigarettes per day com- pared with those whose wives smoked 1-19 cigarettes per day, although the test for linear trend for the endpoint fatal or non- fatal coronary heart disease was not, signif~ icant. The relative risk estimates, for men whose wives smoked compared with men whose wives did not smoke, for the end- points death from any cause, coronary heart disease death, and fatal or nonfatal coronary heart disease event are 1.96 (1p = 0.08, 95 per cent confidence interval! (CI) 0.93-4.11), 2.11 (p = 0.19, 95 per cent Cl 0.69-6.46), and 1.48 (p 6 0~:13,95 per cent CI 0.89-2.47), respectively. These relative risks did not change appreciably after ad- justing for other baseline risk factors. Endpoint results for all nonsmokers Table 9 presents unadjusted and adjusted relative risk estimates, for men whose wives smoked compared with men whose wives did not smoke, for the endpoints death from any cause, coronary heart disease death, and fatal or nonfatal coronary heart disease event for all nonsmokers at entry; non- smokers included' never smokers and e:- smokers who quit prior to entry into the study. For the endpoint death from any cause, the relative risk estimate is 1.72, which differs significantly from 1.0 (p = 0.01, 95 per cent Cl 1.12-2.64). For the endpoints coronary heart disease death and fatal or nonfatal coronary heart disease event, the relative risk estimates are 1.45 (p = 0:25; 95 per cent Cl 0.77-2.73) and 1.19 (p = 0.29, 95 per cent CII 0.85-1.65), respectively. As with the analysis restricted to never smokers, adjusting for baseline risk factors did not change the relative risk estimates. Endpoint results by smoking exposure on the job Only a limited amount of information was collected'about exposure tb tobaceo '1'ASLE 9 Relatiue risk ertimates, mi/i who amokedeompared with urite who did not smolre, and their 95 per cent mnjidenctt interuda for nonsmokera': Mukiple Risk Factor Intertrention 7}ial, 1973-1982 Endpoint Relative risk p value 95% aonSdence intsrva! Death from any use Unadjueted 1.72 0.01 1.12-2.64 Adjusudfi 1.79 <0.01 1.17-2.76 Coronary heart dise,se death Unadjusted 1.45 0.25 0:77-2.73 Adjusted~ 1.59 0.15 0.84-3.02 FataJ or nonfatal coronary heartdiieaae event Unadjusted 1.19 0.29 0.85-1.65 Adjusted 1.32 0.10 0.95-1.84 ' Includes both never smokers and e:•smokers who quit prior to entry into the trial, t Adjusted by Co: proportional hazards regression for age, baseline blood pressure, drinks per week, educationjand past smoking history. cholesterol, weight, r

2023511863

i 794 SVEI3IDSEAI ET Ai.L without knowledge of passive smoking sta- tus. It is very unlikely that differential as- certainment of morbidity or mortality could account for the differences in mortality be- tween passive and nonpassive smokers that were notedl It is aNways possible that other unknown factors can explain the increased relative risk of morbidity and mortality among the passive smokers. The men were obviously not randomized to wives who smoked and to those who did not smoke. A man who did not'smoke married to a woman who smoked may have had other llnmeasured health behaviors that increased morbidity and mortality. The consistency of the re- sults of the current studies with many of the other case-control and longitudinal studies plus the biologic plausibility of the hypothesis based'on biochemical measure- ments of exposure to environmental! to- bacco smoke and'knowledge of the patbolL ogy and physiologic changes suggest that passive smoking may result in an increased morbidity and mortality among non- smokers. Environmental tobacco smoke is a major indoor pollutant to which a substantial seg- ment of the population is exposed (45)'. O6viously„ the most successful method of reducing environmental tobacco smoke would be the further reduction of active cigarette smoking in the population. On the basis of these data, a continued red'uction in active cigarette smoking willl have a ben- eficial effect on both the cigarette smoker and on the nonsmoking population. RI.IERtr7QS L Hoffmann D;,Brunnemaan KD, Adams JD, et al. Indoor pollution by tobacoo smoke: model atudies on the uptake by nonsmokers. In: Indoor air, radon, passive smoking.,partieuletes and bousing epidemiology. Proceedings of the 3r& Interna- tional Conference on Indoor Air Quality and Cli- mate. Stockholm. 1984;2(Suppl D17)~313-18. 2 Stober W. Lung dynamies and uptake of smoke oonstitaents by nonsmoken-a survey. Prev Med 1984;11589-W1. 3. Brunnemann KD, Hoffman D. Analysis of volatile nitroaamines in tobacco smoke and polluted in- door environments. IARC Sei PubIi1978;19:343= 56: •: Fsiedman GD, Petitti'DB; Bawol RD. Prevalence and aorrelates of puaive smoking. Am J' Public Health 1983;73:401-5. 5. Repace JL Lavrey AH'. A quantitative estimate of nonsmokers' lung cancer risk from passive smoking. Environ !nt 1985;11:3-22. 6. Division of Lung D'rse.aea, National Heart„Lung, and Blood Institute. Report of Workahopan Rbs- piratory, Effects of Involuntary Smoke Exposure: epidemiologic studies, Bethesda, MD, May 1-3, 1983. 7: Sherwin R. Kaelber CT,,Kezdi P, et al. The Mu]- tiple Risk Factor Intervention Trial i(MRFIT); !1.. The development of the protoeol. Prev Med 1981;10:402-25. & MRFIT Research Group. Multiple Risk Factor Intervention Trial: quality control of technical procedures and data acqy3isition. Controlled Clin Trials 1986;7:179S-192S. 9. MRFIT Research Group: Coronary beart disease death, non-fatal acute myocardial infarction and other clinical outcomes in the Multiple Risk Fac- tor Intervention TriaL Am' J Cardiol 1986:$8:1- 13: 10. Cox DR Regression models and life tables. (with diacuaaion):J~R'Star Soc B 1972;34:187-220:, I1. Brealow NE. Covariance analysis of censored sur- vival data. Biometrics I974;30:89-99. 12:, Hoffmann D, Haley IQJ; Adams JD, et al. Tobacco aidestream smoke: upt.lie by nonsmokers. Prev Med 1984;13:608-18. 13: Jarvis M, Tunstall-Pedoe H„Feyerabend C, et al. Biochemical markers of smoke absorption and self-reported exposure to passive smoking.. J'Epi- demioi Community Health 1984;38:335-9. 14. Matsukura S, Tominato T, Kitono N, et al. Effects of environmental tobacco smoke on urinary cotin - iae excretion in nonsmokers. N Engll J Med 1984;311:828-32. 15. Wald NJ; Boreham J, Bailey A, et al. Urinaryy cotinine as marker of breathing other people's tobacco smoke. Lancet 1984;1:230-1. 16. Avudb DM. Carbon monoxide as an index of environmental tobacco smoke exposure. Eur J RespirDis 1984:65(Suppl 133):47-60. 17. Aronow WS, Iabell MW. Carbon monoxide effect on e:ercise-induud angina pectoris: Ann Intern Med 1973;79:392-5.. 1& Anderson E14', Andeltrun RJ; Strauch JM, et al. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris::a study in ten patients with iacbemic heart disease. Ann Intern Med 1973;79:46-50. 19. US Environmental! Protection Agency, Office of Health and Environmental Asses.ment Revised evaluation of health effects associated with carbon monoxide exposure: an addendum to the 1979 EPA air quality criteria. Document for Carbon Monoxide, Final Report. EPA-600/8-83-033F, August 1984. 20. Scbievelbein H. Richter F. The influence of pas- sive smoking on the cardiovascular system. Prev Med 1984;13:626-44. 21. Kuller LH, Perper JA, Cooper MC: Sudden and unexpected death due to arteriosclerotic beart dis- e.ae. In: Oliver MF, ad Modern trends in cardiol- ogy-3. London: Butterworth, 1975. f

, THE MED)CAL JOURNAL OF AUSTRALIA Vol 154 June 17. 1991 of exposure at work (though fibrinogen qeferences Ievels are consistent with reported exposure);' or effects of confounding vanables not considered in this study. The increased tibnnogen concentrations • Lbw•n S:aw. Dn.w-+tc r od rrartr, :Mr; Mrr,ui among current smokers and ex-smokers : are as eapec'ted.'• "°' Increased hbnnogen ~ associated-with ptssive smoking has not to our, knowleoge been reported before. This f7nding, although not statisticatly sipnificant (possibly because o! the inade- quate statistical Ipower of the study): fi1Q- pests that passive smoking increases the tisk of heart attack or coronary dsath by aa /east some of the same mechanisms as active smoking. For fibnnogen. the effea is bel:wed to be oue to'thrombogenesis rather than promot'ion of atheroselerosis.r' In summary; this study provides esti mates of' the prevalence of passive smoking in Australia in 1988-1989 and confirms previous findings of elevated risk of heart attack or coronary death associa- ted with pauive smoking at home. It'also suggesis that passive smoking is assoc-' iated with increased'' concentrations of fibrinogen and' so thati an least part of its effect is thrornbogenic. Acknowledgements Tne 7AOWICL PrtaCe.., N.+.Ca+.:~ . a.nevre.t t7,,.R• twnra.r w..r Fa..nlm v a ~. a.«: , nr.'orw.. ~.a7M,n aim M/erat~M M:x,.w-: r C~,t.r" Mrlb1A:,.. lnC7o• furrt% rt,n aa}e•S• .:: rr!•! tr.r>!u 1„. 4wa.:.a 110m Y'' NM41RC lrr. :,r- e-C C.^ .1:: 3 4 © SlrY: o: 'a!..m. Tn.r..Fl~ r o• wno,.••c :.i«tq.as:..c:r omM:r.~ a rr.uwo,.nr S.wo.,,r ('M..M7F ra~Jt....•. tVw,NwrK: ~ry llKni.r:rt+.a,. ,W5 t3tvA S.aM17t"O''hh•>y.ilrK5'rWSt~t[ ry.M:+: 6a+oo. aanw+ tsss Tne P.w++O ProM!r t'~e'MUG~ a•o.G RlMa!d+M,n a aoal o•e.rve v.•rr' eate~:NV 77ha.no mu' rets:+r..v.: aml Ew aa> lo •r.r.:et to •ncar:ce a"t.O paorwY OK+tta t.w •e:v/W a.,e Om.,~ Prowc J'CJronc t?e 1978 !• 20: 306 SvMtOlM KN Ktier LMO tiar,-•t.U OReh! JK Ea.es a a7~s.~e.ro.np ^.u wn~ac Aa. cac+a r.a.e+tpn TrW M, JEVceenw'1t16' 176.. 7u 7" 7+n.np R7. Sanoe DP. Ca,mock Gw. Cn.. E Mftan ara•iic maurrv nnprfyna.ersiner,p w~r+ 7e7w.en Am J Eper+rwr TaB' '2' 9115 222 a G+ts CF r.nK DJ hur.evnr trf,l, 9oae P Trw 797 1'.~.+rtl-r~ar.! n..v nV':.rnrhr.htyl,.• n..ww.•.. ,ybT. 25r. Ci.YC-'j- ' o.r•.l,. wV.P...,.wf.+rrn:A.o•.~.rt.+rarna.±r,aotn.D'.nr.W. +rourt+o,e.nsn,:+w.nr,... •9V.•t:., , : i' 1Y•yOM(~Mly~c qon•:+Prnr:7y rn,TS~•WMnra 7re wo•u+ r.naer, V,we~ Jaro • M JNS:.a P.oc•C' tA4... :ur.+y uanrt7e an0 ,tMHma+:,,1. +1 uro u.afGw• mvare a rr.an .ne••rnnu; s.raaa,o. J':.+• : o~oenr l Y86 0i to5 "_ u' ~..'. .U..~.A~s.rrwr wu AWRean k e: ;. ~s•........•yv.r[Mref ..: nNro•el.v nKfot n MONCCA e.e.. rar+ /ir.- Eoer+n a So.r st,o.our 7Q9C 3e 3Si7••0: The GLIM srliMrh 10101,08 3"..' 190 IptJle• 7?Oprarn) Oaaa Nr,rnercy'A1ooWwna Grwp 771s6 ,t 7a En-uro .ra•a+ 5 Ioomoura aroqrar.,l Aar.a Geo.Py Ce.rers tor De.waae Corwa Geneva won0 M.Mrn Orpa+ts2aron tf190 :t! SLS .NS•a• 6 Ioo '^o<OW doorarnJi Carr 7kpnn Caronry SA15 rm.we 7nc. 1is5 Mapwn SF Ky.r.nan JC..Naaant JN _ va+cn. a nwr.aw,,a.•wv.rF Be.eO a, rRrpunecr•.e lno.nG. IrYanMlQnI .Sfaf tNeQ 1949 . a 1797•700Q Go,, MM Ba.reo;Cana E. a.vn kt D+ee.erces QneC. R FhWOTMMIIy It71:111ct• RAO.a f11-p tRCo.n ;0 oar.+vwra r+ ew .ee a Scauro Ft.1 Aeao. _~s toe•=' 13yu+oa7 121•T26 _ 7GX""O c sarrWl'C°r'° E SJ.+rc L _"r E"NUM 7: tr t7aeu.r ,.no..wj, a. .alr+,r nean Os.afrw mawen a nonveo..ra a vara.ar+. quor Am J fDosrncr'7p115, 121 6a5•6i0' a t+c.e DJ Gre CA C••otxa C'+wrvr.rr vr.r PRa•.Pr inta.mp wt7 rmcMaes9morrnearm - a QeitnYvo(itYla, neW .m OdSCdW10 8&MlOJ 19e9, 2!i 423427 . 9 UtiKC: Su.e. Pido.r r•tarrnm Sr•rtn Tr>r nean- A tXrWe01lTll=F.a..ws.NMM 7K,O~n11i a raoor: t7•' r+o Svpron Gnr.w wa*rt<non DC L1S Goti..n :J rhF•'; Prntnp.OltCr. 1tNlb 10 6,am•,el: wB D Apoatrno AB Belwnoe^ •V Fv.ay,m tJta'.wrmc>Pnr•rtr N•+., •a.. re tartwv+K x C+aro rwaarr, •nt.l,R: Mf.n a• rrinnrpvsh Swfh a++ rWer J 1967 113 ' 100151010 1, wOYWnfws L. SY.wtliaK, h Ap•iiln Bn1,o:.P„ A ry r Fo.opCn :e. a•v. L1C.l`• tV artr,r aY: ~wn_~ma +~trr~e+ N lnc-.•a4,n19lL 37 Sfl, i505 12 taea.r:• tw Vk>trtrw•.. S ara'tw: M n w.uuorro %!A.C h.E7t1, :Wtt i:.c.wnC r.M•'. trls.t.r•' 1/epow'. rPoUt a1nr NrrWw.ri P..& «ra.• Su.h.. lwr.ynTtinG : S13 537 13 7wme1 wB waie PA . C71'oM, K'P D Aon'Y+v, R(i t7N+aYn relrlOnOeh!2 anf, h?.-relOaK1eh11 I+ a Ooo..a,o, as.a oreo.anctiae• ossair ftuor Am J'Eooc-.a 1975 106 367 3T2 Iyyrara.'. E4no.a: Ca•.nrc.on Arrt<ytl'Nepai ,fi6P-1969 Canoe•r'. AGPS +a69 Art.. Faaa he.aw,ee Stuor 6esrvpeT.n, ! Con,-ner Raa Fac,aP.evarerre Stuo,• st.rr.,rr 3198m, Cano.•rn kaiKrsy'.yan Fov+aaie,n a A.em+w" arty Msrrav.n tnewwe a r..aan ttr90' L.oePtr u*ournmtauo,~a'sro.+,p naorm aroW tmaw.r vmo.n,p a.r.v.a a Y+e e.r7e.,ce r+e.. rac Snrwe.-ve.nn 196g Doo.a- U G'nnw~m 7i1++ Lw.r SR O Cm.wrD QCLCfar[rw+.OWwnti+ot!•..w b,wnt eWrr nWAyC rntrp.+r.lwlnwlllo~a.,yprara AnrJfYO!"tr 79e5 1= 26J 2AC !F oocerA SJ S+w7r. AG Car DG e: a St7wr tasa .+.h•.% krr .. rc+annrrart net.r .. &.n. r r,e., L.•Kr,. HiF.' : 1'P'2nt :-~ L.W U brneIt wCS L u.e iSDO' Tl,v,luar POU0e ri Pte.rn wt.nwa.,larn tsratarv n., uknra art St:a,•,u, ww, w.wtn S.nr J'.s, ENefM.n''! i19C -13 9:3 YlY rrieCwrNrrOor' 7S.rt7D0. aCt:epNdYay 72. 7e9T1' Australian patterns of tobacco smoking in 19'89 (for editorial eotnment. see peye 798) David'J Hill. Viaorio M Whitr and lVigrl J' Gray Obj.cN7.e: To estimate the national preva- {or7cs of smoking. Desqn: A toW of 4920 adults aped te years end over (23aa men, 2456 women) wrre surveyed throughout Australia in 1919 eby s tsrpe market research company. SettJnp: Interviews were t:onducled in the participants• homes. Resulls: Overatl, 30.2% of tnen sed 27.0% of won7.n wen currenl sewkers:,2s.tIK' of men and 1e.06011 of women wOrs past anwkers. Tha mean daily consumption of tacuuy-rnsde cigar*nes a7nonq nsalY smo/iers was 22 a7nf among female smokers 1a.i. Taking Into accourn the published tar content of the brand sa7oked. M was estimated that the average daily exposure to tobacco tar for tnen was 204 mg and for women 157 nrp. Anri'-Conc.. t_ounck ef viltona. I rlatnee.ne snr..t. Camon..v1C 3014. D.,•rt,.!'Mi tY. 7hD DnRItM CMnM 4r Mr4.dNYMf1.rp, w r.MCF v¢.o-. rr wr,w.. a+~rrawa M..ra, Ons« C.rn,@ tr a.n..rar M..wa w tiwr wq.,. ~ Grq•. ats ss. iwACr. s7uCw t1+.na. .+.-G.wcw G.arr .r ~wrr .w.w. D. 0 j t.e Occupational and educatbnal status were invars./y related to tM prevalence eff smoking. Th. most popular packet atzo was 25 (pr.llrred py 48% Of s+nokers) ai+d thoss in tower occupational and educatlonall categories were R70te. Uketyto purchase ~ ciqarettes in large packet stns. C Concluaront: Cornparison with an eartisr Aa, asnas of studies commenced in 1974 showad r. that the national prevalence ot smoki Wnp ~amonp adults has continusdio tall, panicu- kr/Z IYny among men. ~ (Mad d Aust 1991: 164: 7l7-a.01)I-all, ~ ftj !"~ ~

LE7TERS TO THE EDITOR' 227 givenl. In this analysis, the 13 coronary heart disease deaths imthe never smokers are again included and the proportions to which they contribute are tested for statistical significance three more times. The ap- propriate analysis would have examined only the 2,222 ex-smokers in the same terms, as suggested for table 7. The reader who is interested in outcomes other than coronary heart disease death is forced to use guesswork to subtract this effect from the other data in the tables. For example, even though we are not told the numbers of men imtable 9, the much lower p vahie for "death from any cause" than in table 7 suggests that this difference is due to the contribution of the ex-smokers. Had'these been analyzed sepa- rately, the difference in risk of "death from any cause"' between the exposed and nonexposed ex-smokers would probably have beem even more marked. This would have suggested'that the men who stopped smok- ing were especially susceptible to second-hand tobacco smoke. A presentation of the data that did' not lump and overlap the subsets of interest would have made such speculation unnecessan. The study by Svendsen et al. is presented as an exploration without hyTothesis. This "blurred" anah- sis could have been avoided if,this,repon had set out to investigate an explicit hypothesis that specified the target groupand the expected endpoint. Paradoxicalh, focussing in on a specific research question and follow- ing the method'appropriate to address that question often allows the researchers to isolate and investigate secondary or unexpected results more accurately. RErERENCE 1. Svendnen K.H. Kuller LH, Manin Ma;.etal: Ettects of passive smoking intheMuluple.Risk,Factor Intenrnttmn Trial. Am J EpidemioV 19fiT.:126.'&3-95.. Peter Morgan 118:Mill'Street Lanork, Ontario Conada KOG 1X0 J ` / A ~ VRE: 'EFFECTS OF PASSIVE SMOKING IN THE MULTIRLE RISK FACTOR C1` l..- '- INTERVENTIQN' TRIAL" 7 c. . lkg'i ~.Z2 Svendsen et al. (l') analyze data from the Multiple Risk Factor Intervention Trial (MRFITI'study and report the relative risks of various endpoint events for men who never smoked in relation to spousal smoking. They assert that their data provide "further evidence of a potential'serious health risk for a large segmentt of the nonsmoking population" (1„p. 792). This con- clusion does not appear to be supported by the data presented. For morbidity and mortality, the relative risks are noostatistically significant; except for the "all deaths" category for the group combining 'never smoked" and "ex-smoker" males. Since the relative risk for "coro- nary heart disease deaths" was not significantly ele- vated for that group, the increased relative risk for `all deaths" requires some explenation before the sta- tistics can be assumed to indicate a meaningful in- crease in health risk related to spousal smoking. While the statistics alone raise serious doubt about the conclusion of increased health risk for nonsmokers exposed to environmental tobacco smoke based on spousal smoking, questions also need to be raised about the quality of the evidence on w-hich the assess- ments are based, notably the nonhomogeneity between the groups based on spousal smoking classification. The lack of homogeneity was implicit when adjust- ments were made for differences in some coronary hearo disease risk factors„e.g., age, weight, blood pres- sure, and alcohol consumption;,but there is no indi- cation that the adjustment inclUded'consideration of the additive effect of multiple risk factors, as has been demonstrated in numerous other studies, notably the Framingham Heart Study. There is no indication that other coronary heart disease risk factors, e.g., familyy history and exercise„were considered or adjusted for. Differences in forced'expiratory volume in one second (FEV,) among the groups were also cited. The numer, ous confounding coronary heart disease risk factors should not be disregarded& nor can statistical adjust• ments be made to eliminate their possible roles. Thus. while the MRFIT'study was well designed to assess the effect of various interventions according to se- lected risk factors, it does not appear to have been designed to assess the environmental tobacco smoke exposure as a coronary heart disease risk factor. Svendsen et al: observe that men whose wives smoked had "significant1Y lower levels of pulmonan function at baseline"' (1, p. 786). The authors fail; however, to note and to interpret the data in table 6. which shows FEV,,levels for men whose wives smoked 20+, cigarettes/day were markedly htFh'cr than those of men whose wives smoked 1-19 cigarettes/day, both at baseline and averaged over all visits. R'ithisuch a notable reversal of the dose•response relation; which must be demonstrated! if causal inferenees are to be supported, there seems to be little basis for suggesting the possibility of' any relhtiom bet..een pulmonary function and spousal smoking from this studi: The weakness ofithe evidence thus raise~ imponant questions about the conclitsion that `paai.e smokinF is associated with an increase in morbiditv and mor- tality, among nonsmokers" (1, p. 791)i There ic. cer- tainly no convincing demonstration that spousal smoking constitutes a"potential serious health riak" for anyy segment of the nonsmoking popularion. REFERF.r:CE' 1. CtYndsen KH. Kuller l:H,,\txnin Slll. ev sl EflrrtF of pe~ivexmokinR in thr 1\tuhiple Hi,A FarvIr, lmet+ent.un Triali Am J F.pidemiol 19++ i:1 L'h. S r:'i- p5: Alan 11'. }Catzenstein ltiSotZCrtsatctn r1s.-uCrOtPs. 57 Ruckuuod I)rinr Larchmctn/, .^''V 1033t;

TaeLt vtn -Rtlanos riiks se doub'lrawo4asaowparedmuli riej)t awoken, adpaled Jor atc, trx, awamtr a~toked; atd suial clax aud Jot emdioasuswbr oanabin, d+aualu blaod precmr, ir.um cio7eurrol tonceearanan,:and body naass tedrx 95% c,mrtaetiv Aebo.e nnk . etm•al I p v.lm Re~pvnmc n-mpartr .. 1h(csed tpuaum: 0'% 0.79'to. l • 16. 0-165. Pcrsmc+mn spunun 1.06 ~ 0•92~to1~21 0,45~ nKao- 1 ts I.ostol•.v 002 HrPerseesr•uom l •02 0-i7.to~l40~ 0^75. cmdo.•.wuLff .n=atom:: Anoo+ ata,mabmotmaLues foum oo ekarocirdwp3m : t't7 1.11 0•qstoa•44 0-68 10 1-79 oas o-65 asor,at,t ; Au ~ Au =,es ol docam raaed m =wt,ag t-0a o-w o•s7tot•la 0•s.to1•l6 e•s 0.9 lre~r eon msa+e 099 072toI- 11 0-3 t,noa aocQ 1,13 0A.to1i3. 0-~5 ficantly, more common among dbuble smokers (p= 0•02), and' though none of the other variables was si.gnifianti six had risks > 1•0. Discussion Whether inhaling other people's tobacco smoke is a risk faaorior lung cancerand other diseases related to smoking is now under serious scientific consideration. Studies of the concentrations of cotinine in the urine and saliva of passive smokers suggest that the dose received may be equivalent to smoking up to three cigarettes a day." Though sidestream smoke containss different proportions of chemical constituents than does mainstream smoke and the same dose received passively might not translate directly to the same risk as in active smokers, the risks expected for passive smokerswill probably be of a similar magnitude to those found in active smokers of up to three cigarettes daih•;, consequently, onh• very Lvge studies w•ill have sufficient power to detect such risks. A meta-analysis is currently the only way to establish precise esti,mates of risk, and it is essential that all studies are included. This paper updates a previous publiation" with mortality now extended to an average follow up time of 11 •5 years and the control and passive smoking groups redefined to exclude those who smoked onl.• pipes or cigars and those who smoked cigarettes irregularly. The original: questionnaire in its coded form did'not distinguish pipe and cigar smokers an& those whoo smoked~ fewer than five cigarettes a day from non- smokers. Written information on ~ tlie questionnaires allowed this to be clarified, and these additional data were added to the computer files. The sample size in this study does not provide sufficient statistical power to detecr risks of the magnitude expected. Thus the lack of significance should not be the sole criterion of whether a genuine effect may be present. Sel eral findings should be borae in mind when interpreting thesc results. Firstly, for each o[ the 10 measures czamined, from respintory syrnptoms to causes of mortality, the relative risk was consistently luger than unity. This tzmained so after adjusting for intervening risk factors such as age, sez,, social class, blood pressure, cholesterol contxntration,, and body mass index. Secondly, the one measure for which sufficient statistial power was available -that is, , ioreed expiratory volume in one seoond~-6ave a significant~ resultL Thirdly; when a group of passive smokers with high exposure was defined there was an . iacrease in the dose-response relation for nine of the 10' •-variables. Fourthly, in - comparison with the relative risks found for the two active smoking groups, eaeh increased risk was biologically ~ plausible, with the possible exception of that fonischaemic heart~disease. The findings for respiratory symproms are similar too those of other studies: a decreased ~ forced expiratory, vvolume in one second in passive smokers has been found ptxviousl%,' and the risks for.lpng cancer are consistent with those in the ovetvicu by Wald rt at," Few data relate passive smoking to cardiovascular disease, but a relative risk as high as 2-2 for motulityy from ischaemic heart disease in passive smokers has been quoted.' Our risk of 2-0 seems large in com- parison with that found for active smokers, and the possibility that~ehance has inflated this risk eannot be excluded, but as the lower 95% confidence limit~ for tbe relitive risk is greater than one it would appear that ichance aiooe is notrtesponsible for the acess. When investigating,risks close to unity it is impor- tant to,oonsider the effect of potential biases. Biases may operate ar the time data are collected. Between 1972 and 1976, however, passive smoking was not an issue. Subjects reported their own smoking habits and no self reporting of passive exposure was undertaken. Iv was not tmtil 1983 that subjects within the same household were linked, and this was carried out without any reference to the measures of outcome examined subsequently. There is no direct measure available to prove that the passive smokers received a higher environmeatal dose of tobacco smoke than the controls, but in the supplementary questionnaire that covered the smoking habits of household members irrespective of whether they attended the original survey only 5°ro of controls said that there was a curtent smoker in the household, compared with 63% of passive smokers. Greater etposureto tobacco smoke at work supponed the idea that passive smokers were more likely than controls to be in contact with environmental tobacco smoke outside the home. This was measured by Wald and Ritchie; ' who showed that non-smoking husbands of smoking wives had higher urinary cotinine concentra- tions than non-smoking husbands of non-smoking wives. Our definition of categories of exposure is comparable with that of other studies and would to identify groups with different mean levels of passive exposure. The high level of heavy smoking in. our cohort" might also indicate that this difference is grnter than that found in otherstudics. The problem of smokers deliberately . classifving themselves as non-smokers" is a far less serious bias in cohort studies than in case-control studies, because at the inten•iea• stage there is no indication which subjects will subsequently dic. The likelihood of: misclassification ntes-that is, higher imthe passive smoking than in the control group-i's debatable as this implies tli.at; someone in the doublt smoking group is more likely to pretend to be a non-smoker than someone in the single smoking group: When the cohabitec is a smoker the reverse may be more likely to be true. It has been suggested that non-smokers who marryy smokers may be different from ~ non-smokers who marry non-sntokers.' A higher proportion of passive smokers were in social classes III manual, IV, and'1 V, but no differences were found for other possible risk factors such as occupation, raised blood prrssure,) sholesterol concentration, or body mass index. In any ~ casc the fmal ~analysis, which atimated' the relative h+ risks, adjusted for each of these factors. C The effect of passive smoking on those who alheady &I smoke is far harder, to isolate. The dose received by active smokers from smoking ranges widel~•,"'' and ~*~ adding a small extra component due to passive ex- ~I t posure may oot ~ lead to much of a difference in ~ mean ~A doses for double smokers compared with single ~ j smokers. Hence, the inereased risk for double smokers= relative to single smokers may be substantiallc, less _ ~ than that fonpassive smokers relatit•e to controls. Thus GO the statistial' power of a single stud% is an important 1z consideration and! in ~ tlie absence of other published data on this aspect it is difficult to interprxt our results 426 ' BMJ vOLUM£ 299 12 AUCUST 1999

lhiinary Gaitwint 1wcaArrs+wewt An1 Brn7er} luttrr 57 0 c ., ~ 3000 2000 1000 aj/br tnitieiu 5a0 0 0 0 e 100, ~ 200, 50 20 10 5 3 2 1 t . ~ . 0 0 Ersaokers CGrrat s.okers (N'-31)' (It-t) r_. 4. Urinary cotinine ltvels. PaDentswere ditiided into t+ro groups according to tkteir statementr about ttieir smoking, habits. R'egardlets of their claims, they Rrrc classi5ed as smokers if they had urinary eotinine levels above b0Ing(mg creatininc. those who.rerc in remission, Hown•er; even among those who experienced aggravation, the urinan• Ls4+H:nc li:vels varied w•ideiy. It scems impossiblt to ct which patient will become worse. judging Irum~the number of cigarettes that were smoked. Recent studies have indicated that im•oluntan• vposurc to smoking may be as harmful as active smoking.'s Sinzinger and Kefalides'° reported that passivc smoking reduced platelet sensiti%•irn• to anti, aggregaton, prostaglandins (Es, 12, Di), and the reduction in sensitivity was much more sntrc in Ma*Smokers than in smokers. Passi.•e smoking might ete;t a poor influence on the cardiovascular system fur nonsmokers. In this study, the influence of involuntary exposure to smoking on Buergcr's dis- ease was studied'~ by measuremenr of urinary eotuune ltvels, but no significant relationship betv~rat utvol- untary exposure to smoking and recurrence of the diseue w•as found. However, there was one patient who had aggravation of the disease, who testified to liav=' abandoned smoking habits, and this person had tl.c _rinary cotininc lcvel of a nonsmoker. Because he had been involuntarily exposed to noticeable smok- ing at the time of worsening of the disease and is not ai/.E c S0 rtstiiiu 30 ~ 20 ~ 8 = j~ ~ 10 ~ __" T T a c 5 L 111 I 0 r r Z 3 U i N.t aposed Espesed (1-13) (1-17) Fig. g. Urinary codninr kvels of nonsmokers wittiout involuntar)•, exposure to smoking and nonsmokers with involuntary exposure to smoking, Thcra was a significant difference between the two groups (p < 0.01). 't/eE er t~tisise 3000 . 2000 : 1000 500 . Smo kers ~ 200 0 .~E 0 100 ~ . w ~ 50 20 s Pass ive serokers 0 10 ---- ~--- . 5 2 ~. 0 ~ Noas ootie smok mokers •iteoyt eablr-oassire' ing 1 . .~ Nbl auraYned Aurartted' (r-i9) (r-ll) Fig. 6. Urinuy cotininc kveis and ~ the course of Buergct's disease. There were significant differences in aggtavation between the smokers' group and the other two groups, but no significant differences were found betx•een passive smokers and nonsmokers .vithout noticeable passive smok- ing. Three (arreriskJ) of the four nonsmokers uith aggra- c•ated conditions stated that thet• had been srnoking,at the time of worsening of the discasc. t

Adult mortaltta (romipassi~e smoking =53 T'able3. Femalt relative nsks for cancer other than lung from passive smoktng. Highest, All Mantel Exposure Exposures Trend T l Locale ota Cases RR 2-tail p RR 95 % C.L. I-tail'p Cohort Studies: Hiracama (1984aY Japan 2505 1.16 0.01 1.11 1.0 -1.2 0!05 Gillis el al. (1984) Scotland 43 1.2 0~6 -2:5 Reynolds er'al: (1987) Callfornia 70, 1.7 1.1 -2.7 Combined'Cohort 2618 1.13 1 03-1.?4 Case Control Studies: Miller (1984)= Pennsylvania 84' 1.25 0.7 -:? Sandier et ad: (1985) Nonh Carofina 231 2.0 1.3 - 2.9' Combined Case Control 315 1.7 1', -2 45 Combined Cohort and 2933' 1.16 11.06-1..7 CC I 'Obtained'by subtractin@ data for lung cancer from data for all sites. 'Pro.-ided bv Dr. Revnolds. •A¢e adjusted Mantel+Haenszel values for nonemployed wives. for ages up to abouv5Q. At higher ages there is no trend with an average relative risk of 1!.17 holding out to age 84. For male heart disease and passive smoking there are now four studies (see Table 4). The two new ones are Lee er al. ('1986) and'Helsing et a!: (1988). The resulti of Svendsen er al. (1987) is shown for information, but is not, used in calculating the combined relative risk because it pertains to a high risk group. The combined' relative risk based on 443 cases is 1.31 with 95% con- fidence limits of 1.1 to 1.6 and a combined chi square of, 9.The results are remarkably uniform. As in the female data the relative risk is highi at the younger ages, about 2.9, but declines to a nontrend average ofi 1.28 which extends from age 55 out to the older ages.. Svendsen et al: (1987)! show than there was very little difference between never smoking men married to nonsmokers andIhose married to smokers in the major coronary risk factors such as baseline blood pressure.. total: cholesterol, and LDL cholesterolL Thiswork was reported in more detail in, Martin et al: (1986b). Smalli differences were found in weighr (195 vs. 190 if wivess were smokers) and drinks per week (10 vs. 8 if wives were smokers). On the other hand. Garland etal. (11985) Table 4. Relative risks for heart disease from passive smoking Highest Exposure All Exposures Mantel Trend Localt Total Cases RR 2-tail p RR 95 ri C:L. 1-tail p Females Cohort Studies< Hira}•ama (1984b) Japan 494 1 3 0.038 1.16 0.9- 1.4 0.0: Gdlis er d. (198Y), Scotland 21 - 3:6 U.9-13.8 Garland eraL (1985), California 19 3:5 0.9-13.6 Helsmg eral: (1988) , Maryland 988 1.27 1.24 1'.1- 1.4 0.005. Combined Cohort 1522 1.23 G.1- I.4 1I Case Contro1 Studies: Lee er al: (1986) United Kingdom 77 0:9' 0 7- 1!.3 Martimeral: (1986a) Utah 23 2.6 1.2- 5.7 Combined Case Control 100 1.29 0.8- 2.U Combined'{ohort and CrC 1622 1.23 1.1- 1.4 1 Males Cohort Studies: Gilliseral.(1984)i Scotland 32 1.30 0.7- 2.6 Lee er al.' (1986) United Kingdom 41 L24 0:5- 2.6 Helsing et a!.' (1988) Maryland 370 1_31 1 1- 1.6 Combined Cohort 443 1.31' 1_1- 1.6 Svendseneral: (1987)' United'States 13 2.2 0:7- 6.9 'Based on Cochran chi-square of 9.2. 'MRFIT cohort of high risk individuals. included for information only.

,1 250 Methods Studies to be considered in the analyses were ob- tained originally from the literature searches of the U.S. Office on Smoking and Health (OSH', 1979-85). More recently. studies have come to light primarily through~ personai! contact with workers in the passive smoking field. Criteria for admitting data to the analysis are: 1. Studies on the association of passive smoking with adult mortality or morbidity from lung cancer. other cancer or ischemic heart disease were included. All cause data were not used because essentially no male data are available. The female data, if calculated, yield overall results that are in the same range as the results derived from the three main diseases (see Appendix B)i Emphysema: is not included because the nonsmoker death rate is so low that less than I% of deaths from~ passive smoking would be pre- dicted from this source (see Appendix B). 2. Retrospective studies should have controls. 3. Observations should be base& on spouse exposure or on general exposure of more than 10! years du- rationL The diseases under study are known to have long induction ~ periods, and it is assumed that most married people old enough to die of passive smoking would have been exposed 20 years or more. 4. Enough data should be available from the study to~ allow calculation of a weighting factor~ for combining the relative risks. Two risk models were used' and a third was consid- ered. The primary model used combined relative risks from the various studies that pertaine&to a given sex and'disease and assumed that the combined relative risk was constant with age, although variation with age of the underlying neversmoker deathi rate and'the fraction of the population exposed were included. In the sec- ondarv risk model the combined relative risk was also allowed to vary with age. These models were suggested in part by the considerations in James Robins' Appen- dix D in the National Academy report (NRC. 1986). The third risk model was based on the rate difference between the death rates for exposed and nonexposed populations. A detailed analysis of this model for heart disease in women was carried out (see Appendix C). Itl was concluded that the relative risk models were much superior to the rate difference model when combining data across different cultures as is the case here where some of the studies are from the orient. Wherever a study showed both a crude relative risk or odds ratio and an adjusted ratio, the adjusted ratio was used. To obtain a combined relative risk a method similar to that ofl Blot and Fraumeni (1986) was used. Case control studies were aggregated using Program 2 of Rothman and Boice (1982). Cohort studies were ag- gregated using Program 7. A combined relative risk for A J V.ells the two aggregates was obtained using: "',o In R« - w«, In R« Rr6 = ezp wCo t wrC where R~,. Rro, and R«, are the relative risks for the combined totall the cohort studies, an6the case control studies, respectively, and wro and wK are the weights for the cohort an& case control studies. respectively. which are the inverse of the respective variances. Vari- ance is taken as the square of the standard' deviation which is equal to InA/x, so the weight. w=(X/ln R)=. The source of, these equations is Rothman ( 1986) Con- fidence intervals were calculated fromia combine& X = w"=1n R, For some studies it was necessary to calculate a chil from the confidence limits in order to calculate a weight since no other data were available. These data were then combined with the rest using Eq,. (1). Aees of' death from 35 and up were used and should include essentially all adult deaths from passive smokinQ. In some studies morbidity relative risks were reported whereas our interest is in mortalitv. The morbidity rek ative risks were accepted as surrogates for: mortalitv relative risks because, for cancer. the survivalirates for, exposed and nonexposed cases appeared to be similar, while, for heart disease, incidence relative risks, if anv• thing, are lower than mortality relative risks (Svendsen et al.. 1987). The 1985 smoking status for U.S. residents in 5 vear age increments was obtained from the National Center for Health Statistics. Nonsmokers were equated to never smokers plus exsmokers. The fractions of never smokers living with ever smokers (24~'r for males an& 60% for~ females), all of whom were considered to be exposed~ were obtained from controls of the U.S. base& studies for all three diseases. These fractions were as- sumed to hold4lso for nonsmokers (never plus ex). The fractions of all nonsmokers exposed as nonsmokers liv- ing with nonsmokers, but still exposed at home or at work (37% for males and 16% for females). were ob- tainedfrom Friedman et al: (1983). These fractions were assumed to hold for nonsmokers living with never smok- ers. By adding the two fractions the total nonsmoker exposure of 61% for males and 76% for females was obtained. These overall exposure fractions are known to be higher at younger ages and lower at older ages. The data of Friedinan et al: (1983) were used to develop smoothe& values of fraction exposed 10 years earlier (midpoint of a 20 year exposure) for each sex and 5 year age interval normalized to 611% for males and 76c'c for females. By multiplying each population element by each fraction exposed element, the exposed popu- lation by sex and 5 year age interval could be deten- mined. Death rates for never smokers for lung cancer by sex and 5~year intervals were drawnifrom Garfinkel (1981)

LE7TERS TO: THE EDITOR' 227' I given). ln this, analysis„the 13 coronary heart disease deaths in the never smokers are again included and the proportions to which they contribute are tested for statistical significance three more times. The ap, propriate analysis would have examined only the 2.222 ex-smokers in the same terms, as suggested for table 7. The reader who is interested in outcomes other than coronary hean disease death is forced: to use guesswork to subtract this effect from the other data in the tables. For example, even though we are not told the numbers of inen in table 9, the much lower p value for "death from any cause" than in table 7 suggests that this difference is due to the contribution of the ersmokers. Had these been analyzed sepa- rately, the difference in risk of "death from any cause" between the exposed and' nonexposed ex-smokers would probably have been even more markedl This would have suggested that the men who stopped smok> ing were especially susceptible to second-hand'tobacco smoke. A presentation of the data that did not lump INTERVENTION TRIAL' /1-cl C+ ) and overlap the subsets of Interest would have made such speculatiortunnecessary: The studv by Svendsen et all is presented as an exploration without hypothesis. This "blurred" anak > sis could have been avoided if this report had set out to investigate an explicit hypothesis that specified the target group and the expected endpoint. ParadoxicallY, focussing in on a specific research question and follbw• ing the method' appropriate to address that question often allows the researchers to isolateand investigate secondary or unexpected results more accurately. REr.ERENCE 1. Svendsen KH. Ku11erLH, Martin d1.1: eu.l. Effectc ofpasst.•e smkinR in.the Atuh,pk.Risk.Fanor 1merventwn Trtal. Am J Epidemiol ]96-.;126:583-95. Peter Morgan 11&Mif1 Srreet L.onark, Ontario Canodo~XUG7J;U ,/RE: 'EFFECTS OF PASSIVE SMOKING IN THE MULTIPLE RISK FACTOR Aw ~!e'lu Sven?ken et all (l):anal>ze data from the Multiple Risk FactK Intervention Trial (MRFITI stud, • and report the relative risks of various endpoint events for men who never oked in relation to spousal smoking.. They assert that eir data provide "further evidence of a potential serio health risk for a large segment of the nonsmoking po lation" (1, p. 792). This con- clusion does not appear vo be supported by the dat.a presented.. For morbidity and mors•ali! , the relative risks are not statistically signifieant, exc t for the "all deaths" category for the group combining ever smoked" and "ex-amoker" males. Since the relatt risk for "coro- nary heart disease deaths" was not st ificantly ele- vated for that group, the increased rela 've risk for "all deaths" requires some explanation befo the sta- tistics can be assumed to indicate a meanin ul in- crease in health risk related to spousal smoking. While the statistics alone raise serious doubtabo should not be disregarded, nor can statistical adjust- ments be mad'e to eliminate their possible roles. Thus, while the MRFIT study was well designed to assess the effect of various interventions according to se- lected risk factors, it does not appear to have been designed to assess the environmental tobacco smoke exposure as a coronarv heart disease risk factor. Svendsem en al. observe that men whose wives smoked' had 'significanti? lower levels of pulmonarc function at baseline" (1, p. 78fi). The authors fail„ however, to note and to interpret the data in table 6, which shows FE\•, levels for men whose wt\ es smoked 20+ cigarettes/,dae were markedl. hiFher than those of men whose wives smoked 1-19cigarettes(daY, both at baseline and4veraged over all visits. With such a notable reversaP of the dose-response relbtion, which must be demonstrated if causal inferences are to be supported• there seemF to be little basis,for suggesunp the possibility of ant• relation betM•een pulmonan function and spousal smoking from this studl. the conclusion of increased heal'th,riskfor nonsmokers exposed to environmental tobacco smoke based' on spousal smoking, questions also need to be raised about the quality of the evidence on which the assess- ments are based, notably the nonhomogeneity between the groups based'on spousal'smoking classification. The lack of homogeneity was implicit when adjust- ments were made for differences in some coronary heart disease riskiactors, e.g-, age, weight. blood pres- sure, and alcohol consumption, but there is no indi• cation that the adjustment includ'ed'consideration of the additive effect of multiple risk factors, as has been, demonstrated imnumerous other studies, notably, the Framingham Heart Study: There is no indication that other coronary heart disease risk factors, e.g., family history and exercise, were considered or adjusted for, Differences in forced expiratory volume in one second (FE\',)',among the groups were also cited. The numer- ous confuunding coronary heart disease risk facwrs The weakness of the evidence thus raisec imponant q stionsabout the conclusion that "pa~site smoking is a ciatrd with an increase in morbidit\ and mor tality ong nonsmokers- (1, p. 791). There iF cer- tainiv , n convincing demonstration that spousal smoking co titutes a "potential serious health risk- for any segme of the nonsmoking populanon RErY.RENtE 1. Ga•end•rn KH. Kultrr t,.H, \lrmn \t.l, et al Efiens nf pasnv smuk'tnc in the T~htnlh H~<1 Faci r amenrntmn Triall Am .l Apidem,nl I9n. L6 7ti+'-Ni. an \V katzenstein, lin cn..tPin Aa.uc~ares 51 R ku uod Lritr Larz•h ni. NY ]053F

k- . 7 C i') -Jio:.. 1-,gl 228 IiE7TERS TO THE EDITOR / THE AUTHORS REPL}' Dr. Morgan (1)states that our investigation was not initiated' with an explicit hypothesis. Quite the contrary:,This research investigation (2) within the Multiple Risk Factor Intenrntion Trial!(MRFIT) was carefully planned and undertaken because of the grow- ing body, of' evidence that environmental tobacco smoke is a health hazard to nonsmokers. Reports that document exposure of nonsmokers to environmental tobacco smoke, such as elevated carboxyhemoglobin or cotinine in exposed persons, as well as reports of a possible relation between environmental tobecco~ smoke and diseases such as lung: cancer, pulmonary' disease, and' coronary heart disease prompted this investigation. An advantage of large acale clinicall trials is that data are often collected which can be used to investigate other research questions. Our re- search h}pothesis was formulated to utilizedata that we re collected in t'he !vI RF lIT for anot her purpose. The NfRFIT group had collected data on smoking habits of wives for all of'the 12.866 participants prior to this studv of the relation between environmental tobacco smoke and disease. These data were collected not because of an interest in em•ironmental' tobacco smoke; but rather because we believed'the wife's smok- ing behavior might impact the participant's ability to change risk factors, in particular, the ability to quin smoking for participants,who were smokers. , The endpoints presented in our paper-coronary heart disease (CHD) death. fatal or nonfatal CHD event, and death from any cause-were the endpoints used' for the primary MRFIT trial. Dr. Morgan is correct in observing that the CHD deaths are counted when considering the endpoints fatal or nonfatal ICHD event and death from any'cause. The intent was not to repeatedly test the difference betweem the same proportions: butto investigate ifthe smoking behavior of the participant's,wife was related to these major MRFIT endpoints defined at the beginning of the study: The focus of our paper (2) was on MRFIT men who ha&neversmoked tobacco products. We repeated the table of relative risk estimates for all nonsmokers (which included never smokers and ex-smokers who quit prior to entn• into the MRFIT) to provide data for comparisons with, other studies which may not have such detailed lifetime smoking histories. The lower p value for the endpoint "death from any cause"' in table 9 primarily reflects increased sample size and not strength of association. The hypothesis that the relative risk for this endpoint would be higher if the ex-smokers were considered alone is false. The relative risk is 1.60 (p - 0.08, 95 per cent confidence interval - 0.95-2.69). compared with 1.96 for never smokers (table 8) and 1.72 for allinonsmokers (table 9). Dr. Kat¢enstein (3) suggests lack of homogeneity between the men who had neveramoked tobaecoprodo ucts whose wives smoked versus those whose wives did not smoke. As noted in our paper (2) one of the strengths of the MRFIT data set was the large amount of information available regarding the biologic, social, and behavioral characteristics of the participanu at entry to the trial. Baseline characteristics of men whose wives smoked and men whose wives did not smoke were similar, as we noted in table 2 of ourpsper P, Z..I- i, I and as observed by Martin et' al. (4): The significant differences were men whose wives smoked weighed 4.2 lbs (1.9 kg) more, consumed 2.1' more drinks per week, and had 0.5 years less formal education, than men whose wives did not smoke. Weight was notassociated with coronary heart disease death or total mortality in the MRFIT study (5). Adjustment for baseline differences in weight, alcohol consumption, and ed'u- cation (used'as a measure of'socioeconomic statua)i as well as age, blood pressure, and cholesterol did nott change the relative risk estimates appreciably. Clearly, however, not every' variable that might possibly differ between the husbands of women who smoke and those who do not smoke were measured. There are almost certainly social and behavioral dif- ferences between a man who is a lifetime nonsmoker married to a woman who smokes, and a man married to a woman who also does not smoke. It is possible that a man who does not smoke married to a wife who smokes makes behavioral changes because of the habit of'his,wife which increases his risks of death, inde- pendent of'the known toxic chemicals in the environ- ment from his wife's cigarette smoke.'I1he ideal study, randomizing nonsmoking men to smoking or non- smoking wives, cannot be done. We agree with Dr. Katzenstein that the lack of a dose-response relation makes the pulmonary function data weaker. The difference in FEV,, between men whose wives smoke 1-19 cigarettes per day and those whose wives smoke 20 or more cigarettes per day' is not significant so the dose-response relation is lacking, not reversed; In view of our carbon monoxide and mortality findings, along,with otherstudies referenced in our paper, we see no reason to alter our cortclusions. REf ERENCES 1. MorQan P. Re,'Effectsof passive smoking in the Multiple R sk Factor I ntervrnt ion Trial '(Letter.) Am J:Epidemiol , 1989;129:226-- 2: Svendsen KH, Kuller LH. Martin MJ. et all F-f&cts of passivesmokinR in theMultiple.Risk.Factor Intervention Trial. Am J iEpidemtol l9(3 7,:126:783-95: 3:. Katzenstein AW. Re: `Effects.ofpassivesmoking in,the Multiple Risk Factor: Intervention Tnal.' (Letter.) Am J~ Epldbmol'.19ii9:'129i227:. 4. Martin MJ. Svendsen KH, Kuller LH. Nonsmoking men married to smokers.are similarito nonsmokingmen,mar- ried to nonsmokers. (Atistract.l Sooiet) y ofBehavtoral Medicine. Sth Annual Scientific Sessions. San Francisco, CA. March 5-H, 1986. 5. Multiple Risk Factor Intervention Trial Research Group.. Relationship.be.tween baselinr riskk factors and coronary heart dtsease and total morultty.in the Muhiple Risk. Factor InterventionTriall PrtvMed 19F,6:I5:354-73. Kenneth H. Svendsen Coordinating Centers for Biometric Research '~. School of Public Health Uniuersity of Minnesota Minneapoiu, MN 55414 lv' ~ Lewis H. Kuller Graduate School'oJ Public Health 1rl~l 1" Universiiy of Pittsburgh ~ Pittsburgh;,PA' 15261 TM"~ W V•

i Adult mortality trom passi%c smoking an& smoothed using a semi-log plot against age. For cancers other than lung for females a semi-log plot of 1984 age specific death rates for ages 35+ was devel- oped for malignant neoplasms less malignant respira- tory neoplasms from the data of the National Center for Health Statistics (1986) Then. a parallel plot was developed using as reference points the neversmoker data of Hammond~ (1966) for ages 45-64 and 65-79 to yield neversmoker rates for a¢es 35 + for each 5 year age interval'. For heart disease never smoker death rates by sex and 5 year age intervals for 1963 were developed from the appendix tables in Hammond (1966). These were reduced to 1984 equivalent rates (with the reduc- tiom factors corrected for the effects of smoking) by a technique similar to that used by the U.S. Office of Technology Assessment (OTA. 1985). Semi-log graphs were used to estimate never smoker death rates by 5 year age intervals for the entire age range (see Appen- dix A. Table A3). The excess death rate for never smokers for passive smoking (Dp,) for each sex. disease and 5 year age range was calculated from the never smoker death rates (D.) using the formula: D: . = Dti,(R - 1)l(F,,(R - 1)+ 1): (2)1 where FD is the fraction of the population that is ezpose& and R is the combined relative risk. This excess death~ rate was assumed to apply to all nonsmokers. Deaths were then calculated bymultiplying the passive smoking excess death~ rate by the exposed population for each sex and 5 year age interval, and summed. For those calculations where the relative risk was assumed to have varied with age. the excess death rates for passive smok- ing were recalculated from the age specific relative risks for each 5 year age interval. Additional calculations were carried out to show the effects of bias including those from misclassification of smokers as nonsmokers and exposed nonsmokers as unexposed. using a method similar to that of Wald~er al. (1986) L Results Relarrve risks The results for passive smoking relative risk for fe- males for lung cancer are shown in Table 1. The three cohort studies are listed first an6show a combined rel- ative risk for all exposures including exposures to exsmokers of 1.34. At the time the analysis was made there were fourteen acceptabie case control studies with a combined relative risk of 1.50. The overall combined relative risk, based on 1,174 cases, is 1.44 with 95% confidence limits of 1.3-I.7. The male lung cancer ob- served relative risks are shown in Table 2. There are now nine studies with 144 total cases. The overall com- bined relative risk is 2.1 with~95% confidence limits of =51 1.3-3.2. Data excluded from Tables I an&2 along with~ the reasons were the following: Chan er al. (1979). cur- rent exposure onfy; Knoth et al. (1983). no controls; Kabat and Wynder (1984)' nonspouse data. current ex- posure only; Buffler er al: (1984)~ 0-32 year data. not a: minimumi of 10'vears exposure. A paper ba Dalager et al. (1986) d'escribes a pooling of' data from Correa er al. (1983), Buffler er al: (1984) and a stud~ of males in New Jersey. They observed an adjusted odds ratio for spouse exposure of 1.47, but since Correa er al: (11983). and Buffler, er a!. (1984). were already included iniTa- bles 1 and 2 and' since the New Jersev data were not available separately, it was decided to omit the Dalager er al. (1986) study from this analysis. AI'so. available were abstracts of two recent papers. Gene er al. (1987) from China with a relative risk of 2.2 and Inoue and Hirayama (1987) from Japan with a relative risk of =.3.. both for females. Also NV K. Lam (1985)~ in a thesis from the University of Hong Kong that is quoted in Lam et al. (1987) found a relative risk of 2.0 for ad- enocarcinoma among females. These inputs arrived too late to be included in the analysis. The data ofHlravama (1984a) on femalp lung cancer are sufficiently detailed to indicate a declining relative risk with age from 1.87 at approximately age 501to 1.433 at approximately age 75. These data were used'to de- velop a second death caltulation assuming a declining relative risk. but still! normalized to 1.44. However, Hirayama's data show no such decline in passive smok- ing relative risk with age for, males. Instead, the trend appears to rise with age. so no secondary calculation was made. There are now five studies relating passive smoking to total cancer or cancer, other than lune in females. The individual and combined relative risks for females are shown in Tablt 3. The total combined relative risk is 1.16. The total cases. 2.933, are two and one-half times the total cases for female lung cancer (Table 1) although 2.505 are concentrated in the large Hirayama (1984a) study. This is a large data base. The total com- bined chi square is 11 compared to 27 for female lung cancer. The two largest of the female studies. Hirayama (1984a) and Sandier et a!. (1985): cover different age of death ranges. Hirayama covers 50 to 80 t while Sandler er al: cover <30 to 59. The two studies taken together would indicate a rather sharp decline in rela- tive risk with age fromiabout 3.5 at age 40 to about 1.04' at age 80: The high relative risks at the younger ages may be due to premenopausal breast cancer (see San- dler er al., 1986). Two calculations of Ui.S. female deaths from passive smoking and other cancers were made, one using the 1.16 relative risk from Table 3 at all ages and one using the declining rela;ive risks. Gillis et al, (1984). Sandler era1. (1985). and Rey- nolds (private communication) also report on other can

accumulated 153 deaths from lung cancer and many thousands of deaths from ischaeauc hean fLsease in oon-smokers,. The effect of passive smoking on lung cancer has been looked mto."It is a pttv that its effect on tschaemsc heart disease has -+ot. , PETER N LEE ` :vSist2 5 D A I l.ee P•.'. Pasnve smdung aod ;eud,oresy+uawntira1tL un.Sa:- land:.. Br.Ned J1989299:712.. (16september.' 2Ho& Dl.Gdln CR. ChopraC• Ha.nMrnc V M_ Pasavel smoksry arrd ordwrnpuuorytnlt6: m a genera/ pupulaunotn tne .eau. of Srouand. B:•.HedJ 1969'.-'99:123~:,.~,y;dttgu~i. 3Hole Dl. Gdiu CR l CLopa:C. Hawdioro< t'AS. Psuvr. smaktogand cardurespnrory hdrL m Scodard. Br.MdJ19g9-•29PI I0V 1. 4 Stamcl. N. Haenvel R'. Suusud aapecn ol tte am1.+•su of dau irom tevospreuve srudtn a.Lseaar..7 •V.W Cawrer.l- ..1959; . :71946. 5!se PN. Passive. serokmgandIunB, caocer: faci or 6cnon? 1n: B+era. Cl1 Coumou Y. Gonen. M, eds. P,r.ew l.rre ef uda. . pyafuv. Amasudim:.EUrv,er, 19g9i 119-26. 6Gaaninkef L. Tlme trends m 1.4 - . moruhry amoog rwn-smoken ard. a nore on psave snnakrng- J A'al 6anen lw, 198'd:66:1061b:' AurHORS' REPLt',-Our calculations are neither incorrect nor misleading. .41r Lee is attempting to show how large a bias can be introduced into esumates of rdative risk for passive smokers due to active smokers misclassifying themselves as non- smokers. In doing so he has produced'biases that are excessive because we can show his assumptions are false. His main tnistake has been to assume tliat the "true" reliuve risk for lung cancer is the same for male and femaie smokers (his uble I): Also, although thrextent of smoking denial focour study is nouknown„we can put an upper boundary on it. Our original study estimated the relative risk of 1ung cancer among active smokers as 8 49 for men and 3-33 for women.' Table I shows, under Mr Lee's assumptions, thatl 'bbsen•ed" rel9tive risks fnr active smokers would be lirger forwomen than ~ n. This is incompatible not only with what we .ce observed but also with all other reports we know of. Thus his assumption that the same "true" relative risk holdk for both men and women TABLE tr"Obserxd"redarme riik's foractive andd passiue smokers for var)zng denial'rases of rmoking• RrJati.c nsks for Relauve risksfor Ratr ofactive.smoking.f panwe smokung . denial (Y.), . NSm G'omen \fcatL'omeo 1 10.34 16~20~ 1153 1.15 2 6..90. 13•3? It71 1~25~ 3~. 5`Ii 11-53. 1!S"~ L34 4' 4~10~ 9.99~~ 1'95~ 1-42~ 6~ 2YSfr~. 7. g9~~ 2~~06 134 1 : 2-20. 6~48~~ 2:*11 10 1~76~ 5~45~~ 2`15 I~70~ is untenable. Also, if we accept Mr Lee's aheorrb- cal range of possibiliues for the rates of denial of cigarette smoking then the outcomes become even more unlikely. For each rate of denul ofl4?/e and over suggested'by Mr Lec the relative risk for malt acvve smokers is progressively well below that observed' in our study (table I). Above a denial rate of 8% the "observed" relative risk for male passive smokers exceeds that for active smokers. Our data are, however, compacible with dettial, rates of up to 2% and a "true" relative risk of 4 for female smokers. Mr Lee questums the extent to which tnisclasl sificauon can explain all the reported relative risks for active and passive smoking seen in our study:. Table II shows the relative risks for active smokers foundi in our study for each endpoint and the "true" relative risks with which these are com, patible, assuming a rate of denial of smoking: of 2%. For example, the relative risks for all causes of death assoeiated'with active smoking are 1-85 for, men and 1F87 for women. These figures are compatible with a°true" relative risk of 2, given 9 denial nte of 2%. The figure of 5 that Mr Lee quotes in his letter may be appropriate for some of the endpoints used but certauJy not forall. The final' two columns of' table 11 show the passive smoking relativrrisks foundIin our study for each of the endpoints compared with those that could have occurred through the type of bias Mr Lee attributes to our, study. In particular, the differences are quite noticeable for the four cate- gories of mortality. Thus tnisda.9si6cauon can bias estimates of.relirive risk for passive smokers that use assumptions compatible with our estimates for active smokers. Thesizc of thesrbiasa does not, however, explain our passive smoking results. What is striking about our results is their consistency across a wide range of endpoints in addition: to~ lung cancer and especially for ischaettric heart disease. This is supported by our findings of' a dose-response relation for each of these. Even though bir Lee reaffirms his view that misclassibcaton of'aetive smoking state can explain the average risk of lung cancer with passive smok-mg, we welcome his implication that the effect of passive smoking on ischaemic hean disease is worth further investigation. DAVID f HOLE CHARLFSR GrLL]S wrss of S. m Wd Ca.ea Sw.dtama Lnrt, RudsiO HYnpul, G6sgo.G209N8 Depanmrar a Epd-ulogy,.. l.'m.resm ot.lt,eh,gan. MlrLryu. limted'6uus VICTOR M'HAWTHORh-E I Hok Dl, Gd16 CR. Chopn C, Ha+ehome V M. Paavvr smek,og andcaro,orespu-nory holdt or a grural populauao rn the .eu of Scouaod.. Br.Hed J4989L9i: [23-T. (12 Augusu ) l `.4ssuming '•uve" rclauve nsksof 1-0 for passrve smokusg and 20 for acu.c smokvsg. ." Tliis correspondentt is now closed. - ED, BJK,7. TABLE tt -ReLati;•e: risks ft>und in study tompared ~u•ith"'tr7ue"'re/dave riskr.Jor aative smakens assd "observed" relanae risks forpassrve smaken• . Endpotnt Study findtng. Itiocted:phtcgrn Persvcm phieg:n 4!03.. 4'33 Clyspnora Hvpeesecresron Angnu .ltalor abnonnal Ck:cirocardMsgram 1165 2•95 2,13' 1157 ' 31t CaWSes of dcatb 1185 . `nuc Eon duns< I 136 mg cancu .sIS aasea of dut4 rrutrd w smotung 8I 49 I190 Acticcamokcs Pissive smokers Men. Women Bothsous~. "Trui " "True^ ••Observed": relauvc Study rNaove Study rdiu.c nsk fiM1ag risk findtng nsk 6.0 3925-0 1-34 1114 60 3r935•0 1~19: 1114 1.9 1~3714 : 1~091103~ 5r0 4~15 5.0 121 IIi3' 2-7 I-4-t 1-51~11 1105. 1-8 0_92 1.1; 127. 11022~0 1-97. 2.01~27 1l0e'. 3-0 2-99. 3-0: 2'01 1-0720.0 3-33 4-0. 2 41 I•263-0 2~453•0 1-30' I'07 ' Assumm8 2% of smokers: dcnvsmokSng_ TiheresWrse for botif sczn- cnmbsned: haecw been adtusredd for. se:= ususg.vesgbtsN,Np(N ,/N_ ). -here N;,and :N, ase otiserved numbetss of exposed and unespore.d zuliieets. I/ Congenital malforrnations. StR,-In her editorial on congenital'malformauons Professor Eva Alberman cotrtmentson the excess rate of deaths from malformations, particularly neural tube defects, in infants of mothers born in Pakistan.' Ih~the studies referred:taonlv pennatal deaths were considered. Many neural rube defects in this country are now detected by prenatal screening programmes, and women may, opt for termmauon of the pregnancy when found to have an affected fetus,' so thesc studies may not reflect the true incidence of neural tube defects. Asian women iend to book later for their antenatal care,' and this may acrounrfor the high crontribuuon of neural tube defects to perihatal mortality: second trimester screening would be available to a relatively smaller proportion of Asian women. Furthermore, they may find termination of pregnancy unaccept- able on religious grounds.' We have investigated the overall incidence of neural rube defects by ascertaining all those affected fetuses detected by..' prenatal screening with ulvasonography, as well as all,those found in the perirutal perood': We have alto tried to determine factors that may be impor- tant in explaining any racial differences in the incidencc. We reviewed the materniry ultrasonognpby department records, neonatal land labour tepsters, an&necropsy,reports from January 1980 until the end' of' December 1987 in one district general hospital to ascertain all fetuses, stillbirths, and neonates with a neural tube defect. The maternal notes were then irt.spected'to determine the date of booking for antenatal care, if'and w•hen an ultra- sound scan was performed, and whether a termina- tion of pregnancy was offered. In the Pakistani population there were 111 neural rube defects in a total of 3777 births (2-91 per 1000); there were 32 neural rube defects in 28 834 births to white womI per I000) (nble). Incide+tuof /rearal'aubr defecuu in,fetr.ses and babies:of' wkueand Pakistani tuomen, 1980-7 R'tsice Palustant women vmen Detectcd bv.rvucine ultra.ouad son 17 5Pregrumcyactmmal 17. 4 Ptegnaocy.conunurd . I Not deereted bv rnutine san IS6' Scaa notavailiblr 12. 3 Nor derened by sean 2 1 Booked tooaaee forscaa I I Did not atrcnd for scan I Toul neural nnbc defecn 3211' Toul binhs: 29 834 377 7. lnndcncr= per.1000 binhs 111 291 Routine examination with ultrasound was intro- duced onlyin 19841and hence was not available to many of the women included in this study. The incidence of neural tube defects in the Pakistani population wasaignificuttly higher than that in the white population (p=0j-013; Fisher's exact two tailed test; relative risk 2•62, 95% confidence interval 1-19 to 5•34): One woman in each group booked tooo late for routine prenatal Iscxreening,:and one Pakistani woman failed to attend'for the scan. Thesenumbetsaresmall, but it is of note that the mean gestation arwhich these women booked was 18-2 weeks in the Pakistani group as compared with ~ 14-3 weeks in the white group. Six of the Ill Asian babies with neural' tutie defects were born to women witha consanguineous marriage. We have shown thatt there is arll increased incidence of neural tube defects in the Pakistani population, with late booking and reluctance to terminate an, affected pregnancvy contributusg minimallv to the increased incidence found in pennatal deaths. Changes in customs are difficult to encourage but may well occur spontaneously as BMJ VOLUME 300 13jANUARY 1990 121

t ,4,>, 242 lLETi'ERS TO THE EDITOR RE: 'EFFECTS OF PASSIVE SMOKING IN THE MULTIPLE RISK' FACTOR N O T I C E INTERVENTION TRIAL' This material' may b2 Based on the Multiple Risk Factor Intervention Trial data. Svendsen et al. ( i)'have reported a relative risk of' 1.72 for death from any cause among male passive smokers Imalt nonsmokers married to a smok- ing wife vs. male nonsmoker marned to a nonsmoking wife): This riak compares with a relative risk for male active smoking (mak smokers vs. male nonsmokers) of 1.66, which we caleulated: from the Multiple Risk Factor Intervention Trial data (2). To the other explanations that may be offered for this surprising comparison, we wish to add an alter- native possibility that may not occur to those who are not predisposed to give cigarettes the benefit of the doubt. The effect measured by Svendsen er al. may be caused by stress rather tban by passive exposure to cigarette smoke.. There is considerable evidence that psychologic stress is capable of increasing the risk of developing diseases that are major causes of death. Both Type A behavior and'hi`h levels of hostility have been shown in prospective studies of human populations to predict increased risk of coronary heart disease (3) and death due to all causes (4„5). There is additional evidence from animal studies that behavioral stress and its physiologic concomitants promote the developmentof both cancer 16, 7) and coronary atherosclerosis (8). As we have previously argued (9)i there are sub- stantial grounds for believing that nonsmoking spouses of smokers are subjected to stresses arising therefrom. While the health authorities., given their convictions, have no honorable alternative, it is never- theless stressful to the nonsmoking apouse to be told constantly that the smoking spouse is "killing herself (or himself)" by smoking cigarettes. Repeated at- tempu to persuade the spouse to give up smoking would be a source of contention and their failure an additional soueee of stress. Also, there is reason to believe that smokers are len supportive as spouses than nonamokera, thus ere- ating a stress-relatsd risk for their mates. Current female smokers are nearly three times as likely to be divorced as women who have never smoked cigarettes / rate calculated from data in reference 10). In addition, it has been demonstrated from the Frnmingham Heart Study data ('11) that occupations, ambition, and:symp- toms of anger among wives were more strongly related' to their husbands' coronary health outcomes than the husbands' conventional "risk factors":, More generally, the inferences dra.rrt by Svendlen et al. may be an example of the error potential in attributing a mortality difference between two groups of people to what is presumed by the inveatig.ton to be the only relevant average difference between them. If there is menr in the foregoing. it may also be ttue that the scientific community has been incorrect in, attributing to smoking the mortality rate differ- ences so often reported for active cigarette smokers compared' with nonsmokers. A hitherto undiscussed difference is that the constant ad'atonitions that their smoking u`self:-destructive" must also be stressful to the smoker, while cessation of smoking may have a placebo effect.. RE/EaEMCEs1., Svendsen KH. Kuller LH. Martin M.1;,et al. Effects of pusiveamokina in the Multiple Risk Factor Inurvenuon Trial. Am J Eptderniol 1987:126:783-95.. 2. Multiple Risk Factor Interrention Trial. JAMA 1962.248:1485-77. 3. Rosenman RH. Brand RJ, Jenkins CD. er all Coronary iieart disease in the Western Collaborative Group Study: final follo-up ecperience of. 8 1/2yean. JAMA 1975:233S72-7L 4. Barefoot JC, Daitlstmm WG, Williams RB. Hostility. CHDtncidence and tottl morultty: a 25-year follow-up studyof255physietana. Psyehosom Med 1963:45:59-63 5. Shekelle RB. Gale M. Ostfeld AM, et sl. Hostility, riak of coronary disease. and mortality. Psychosam Med 1983:45:109-14. 6., Rtley % ' Psychoneuroendocnne tn0uencer on immuno- competence snd;nedpla.u. Science 1981-212:1100-9. 7. VwntatneT MA. Volptcelli JR. Seligman ME Tumor, re- pcnon in nu after inestap.bleor escapable shock. Sci- ence 1982116:437-9. 8.. Manuck SB. Kaplan JR. Matthews KA. Behavionl an- tecedenu of coronary heart diseoe and,atherouclerosis. Atherosclerosis 1986;6:2-14. 9. Gann RC. Lincoln JE. Marriage to a attwk'er and cancer nsk. (Letter.i AmJ Public Health. 1988:7B99. 10. Adultuse of iobaceo-1975. Atlanta, GA:. Center for Dis- ease Conttol. 1975: 11. Haynn SC. Eaker ED, Feinkib M. Spouse behavior and coronary hesrt disease in men: prtrpective results from the Framtnaham Hean Study., 1.. Concordance of risk factors and the relacionship,ofpsycholopcalsutus to caronary.tnrndence. AmJ Epidrmioll1983;118:1-22:. Rebecca C. Gantt Jetson E. Lincoln Philip Morris Managerrtent Corp. 120 Pdrk Atxnu[ New York NY 10017 Editor't Notr. In ortordancnu-ithJournal.pol.ey. Dr. Strnd.en et o1: urre Ruvn the opportututvto respond too th'urletrer. 6ut chost not:todo.o.: RE: 'ENVIRONMENTAL AND BEHAVIORAL DETERMINANTS OF FASTING PLASMA GLUCOSE IN WOMEN: A MATCHED CO-TWIN ANALYSIS' Over, 45 years ago, Gesell' (1) described the metliod' of co-twin control, an experimental method that was applied to the study of child'development. Since mon- orygotic co-twins share environment as children and are genetically identical, differences between treated and untreated co-twins were interpreted to result from treatment'Chis method wu recently extended to con- tinuous outcomes in observational studies (2, 3). The method compares associations in an unmatched sam- ple to associations within twin pairs (matched) to identify associations that are independent of familial variables shared by co-twins. The matched analysis consists of a multivariate linear, reegreaaion forced through a ttro ~ intercept with dependent and inde- protected by ccp.;;:~ -t law (Title 17 U-S: Code).

Adult mortaun, from passive smoking 25s. Tablt 6 Annual U. S. female lung cancer deaths from passive smoking, Relative Risk Relative Constant at 1 4-0 Risk Neversmoker No k E d D l A f h R nsmo er xpose ec ining ge o Death Deat ate per 100.000 Population 1000's Fraction Exposed Population 1000's Excess Death Rate Deaths RR Deaths 35-39 1.6 6150 0,94 5781 0.50 29 1.70 39 4U-44 2.4 462? 0;92 425? 0.75 32 11.69 43 45-49 3.6 3836 0:89 3423 1.14' 39 11.68 5_ SO-54 5.3 3856 0;87 3355 1.69 57 1.62 72 55-59 7.8 4161 0!84 3495 2.51 88' 1.56 104 60-64 M0 4192 0.77 3228 3.62' 117 1.J9 126 6_5--69 16.6 4160 0.70~ 2912 5.55 162 1.43 159 70-74 23.5 3447 0.59 2030 8.21 167 1.36 142 75-79 34 3004 0.49 147'_ 12.3 181 1.'_9 1_7 80-84 46 1886 0.29 547 18.0 98 1.IR 43 B5- 52 1'003 0.10 100 21.9 2-1 1.09 4 Totals 13.0 40291 0 76 30595 3.0 992 911 ing deaths might be 46.000. half'wa.• between the 39.000 calculated directly from the relative risks and the 53,000 calculated using the modified relative risks. By disease the total would consist of 3.000 lung cancer. 1'1.000 other cancer. and 32.000 heart disease. For each million of total population the deaths by disease would be 13 for lung cancer, 46 for other cancers, and 134! fon heart disease. These numbers may be useful for populations similar to that of the United States imterms of~ propor- tions of' never smokers. exsmokers, and~ smokers. and in terms of the proportion of'the population tha is less than 35 relative to that over 35. For other populations the permillion numbersare best not used, but the meth- odology can be used. That cancer other than lung and heart disease are legitimate contributors to deaths from passive smoking is supported in Hi'rayama. (1984a.b)) in, his large prospective study. He found significantly elevated risks for all three diseases, and his result, for lun¢ cancer is now believed to be valid, (USSG 1986; NRC, 1986). It'is difficult to:believe that his lung cancer result is valid while the other two are not,., Discussion The cancer sites for passive smoking appear to differ somewhat from those for, direct smoking. Using infor- mationion specific cancer sites from Dri. Hiravama (pri- vate communieation) it appears than cancers common to both types of smoking are lung. liver, cervix, nasal sinus, and leukemia. Some of these cancers are only weakly associated with, direct smoking.. Cancers asso- ciated to some de¢ree with, direct smokine. but absent in passive smoking are buccal cavity. pharynx. larvnx, esophagus, stomach (Hirayama, 1984a),. urinary blad« der (Kabat ec al:, 1986). kidney and pancreas. Cancers related to passive smoking, but absent in direct smoking are brain (Hirayama. 1984a), endocrine glands (Sandler era1., 1985). lvmphoma and breast (:Sandler et al., 1985. 1986( Hirayama. private communication) The first three are significant at the 95% level. The combined breast relative risk of 1.4 ', is significann at on1N 881~%r. Higher relative risks for these four sites might be found for direct smoking if epidemiologists used~ nonpassivel~ Table 7, Summary: IJ.S. annua/'deaths from passive smoking I I Females: 1. Constant combined relative risk. 2. Relative risk declining with,age. 3. (l,) corrected for misclassificauon. Males: 1. Constant combined relative nsk. 2. Relative risk declining with age. 3. (1,) corrected for misclassificatton. Totals for both sexes: 1. Constant combined relative nsk. 2. Relative risk declining with age. 3. (1) corrected for misclassification. Best cvrrent estimate. both sexes (rounded). Lung Other Heart Cancer Cancer Disease Total 992 8599 9769 19359 911 11165 7602 1967R 1232 12-180 14995 28507 1606 0 17335 18931 1606 0 18164 19770 2499 0 2..467' 24966 2598 8509 27103 3R?(Nt 2517 11165 25764, 39-t.SR 3731 12280 37462 53473 30W 71000 32000 46000

226 Per iod Age LETTERS TO ~ THE EDITOR _\!f JI' \ .It~ 5l~ 2y! ~' 21, 21, \ 21, 2p N Coh FIGrRE 1; Rates for the non-linear age model. h#l- culated'in the same way as inTigure 3 ofOsmond artd Gardner (21. models onlv "work" as a result of aggregation and making assumptions of constancy of effect within an intenal!, At present„ we see two avenues for investigators who wish to trvto estimate the separate linear effec ofage. period, and cohort: 1)~use a two•wactable d impose a linear constraint, ignoring the overla ing of.eohorts: and'21 use the individualI records ap roaeh. whichidoes not have the problem of overla ,ing co• horts. This approach will reqwire a cor tion for potential bias brought about by the a mmetry in forcing the continuous data into a t~ •way table. Brown and Conelly (personal comm ication, 1988) have informed us of some very int esting work they are doing in this area. Finally, in our published ex , mple on the use of individuallrecords in, the anal 'is of lung cancer and laryngeal cancer incidence i cotland (31, the cohort effect is approximately qu ratic and the time effect small but non-linear. Su effects cannot be induced by assuming a monoto 'c increasing age effect alone. REFERENCES. 1. Tango T. Re: "Statistical modelling ofllung cancer andleryngeal cancer incidence in Scotland, 1960- 1979." Am J Epidemiol 1988;128:67 -8. 2. Osmond C. Gardner MJ. Age, per ^ and cohort models: non-overlapping eohorta on'c resolve the identification problem. Am J E' tdemiol 1989:129: 31-5. 3. Boyle P, Rohertson C. Sg4istical modelling of lung cancer and laryngelA cancer incidence in Scotland, 1960-1979. A)fi J Epidemiol' 1987;125: 731-44. 4. Osmond C; Gardnej/MJ. Age. period and cohort models applied toy4ncer mortality rates. Stat Med 1982:1:245-59. 5. Clayton D, Sc fflers E. Models for temporal var- ihtion in c cer rates: age-periodi ege•cohort models. S Med 1987;6:449-67. 6. Fienber E. Mason WM. Identification and es- timati of age-period-cohort ine the analysis of discr e and archival data. In: Schuessler KF, ed. ological'methodologv. San Francisco:,Jossey- ss, 1978:, i,/becarli.A; La Vecchia C. Age, period and cohort smodels: review of knowledge and implementation ~c GLIM~ Revista di Statistica Applicata 1987; 2W9+-410! 8. Holfprd TR. The estimation of age, period and eohot~ effects for vital rates.. Biometrics 1983; 39;3 S 1 `4. ~ Petet,Boyle Unit d/.,Anafytical Epidemiology InternttYional'Agency for Research on Cancer 15a'rour~Alberd- Thomas F-69372 [,~~omCedez 08 France Chris Rbbert~qn department o~fathematics. Unitersit-v o/ Strathclvde LiLingstone Tou•e 26 ~R~ichmond'Stre Glasgou Gl 1 XH United Kingdom AtM, 1 -A- I Ll ) Jo-_.. ~4I'`) VRE: "EFFECTS OF PASSIVE SMOKING IN THE MULTIPLE RISK FACTOR ~ Zi 6 -7 INTERVENTION TRIAL" Some of the health effects of'passive smoking may be smallj and are best investigated in large cohort studies of persons exposed over a long period; It is unfortunate that the analysis by Svendsen et al! (1):of the unique data gathered in the course ofthe Multiple Risk Factor Intervention Triall (MRFIT) study is flawed, and may introduce confusion about the role of passive smoking as a risk factor in cardiovascular disease. and does not allow the investigators to fully explore the potential, of passive smoking as a risk factor in other conditions. The Svendsen paper repeatedly tests the statistical significance of the difference between the same pro- portionlsl. For example, table 7, shows that of the 16a00 never smokers„13 men died from coronary, heart disease and 30 from any cause, and that there were 69 fatal or nonfatal coronary heart disease avents. Each group is examined for significant difference in propor- tions according to the wife's smoking status as if it were independent of the two other groups; in fact, the coronary hearu disease death group is a subset of the two other groups, and its contribution to the calcula- tiomof relative risk is,thus taken into account three times in this table. The correct analvsis would have compared 'death from other,causes- and~ "'nonfatal'. coronary hearu disease events" with "death fivm ~cor- onary heart disease". The misuse of statistics is compounded in table 9„ when the 2.222 ex-smokers are added to the 1,400 never smokers /this is my, assumption: no n's are

~ .4Manc 14 ..ienbc ] t~fi.. 1991 Orinitrr aioatine Urinarr coiiaiae sN/.l ctaitioiee al/nt posti.iae r<a.t1 . 3a00 Mi, 3000, 2000 2Q00, / 1000 1000 4I ~ 500 5a0 ~ - 1 200 100 200 160 . 50 • 50 20 , 20 10 i 5 10 5 3 3 2 2 ~ 1 ~ 1 NOllsmol'ers' Smoters NonsmoLers Sslolsers Fig. 1. Urinary tsicotine levc3s (kfl) and cotininc kvels ~ (rsqht) of nonsmokers and smokcrs, in haalthy, control 5:,hjec•tis. T2sere wetr sigtuficant diffcrrnces betwcen the r.: o groups (p < 0.01): Gorinine kncis disaitninate tx- twecn smokers and s+onsmokers more distinctly than } nicotine kwLs do. seven patients were considered active smokers, whereas the other 30 patients .vere regarded' as ezsmokers. The 30 ezsmokcrs were then di-%ided into rwo groups, on the grounds of self-reported invol- ay exposure to smoking: Urinancotirune levels ;_: c 10.2 ± 4.2 ng/mg creatinina in those who wer•c imolluttarily exposed to smoking and 6.1 = 3.5 ng/mg creatinine in those .vho were not a.posed (p < 0.01) (Fig, 5). On the basis of these resuha, we decided that for this study, those with urinary eotinine levels between 10 and 50 nglmg aeatanine would be identified as nonsmokers «tith noticeable passiv' smoking (passive smokers) and those with :°'1s below 10 ng/ing creatinine would be identified i+ i.onsmokcrs without perceptible passive smoking ( Fig. 5). The 40 patients were classified into three groups: (T) those with urinary cotinine levels above 50 ng/mg erztininc (active smokers), (2) those with cotinine lcvels between 10 and 50 ng/mg creatinine (passive smokers), and (3) those with cotinine levels below 10 ngJmg ereaunine (nonsmokers without noticeable Pascive smoking). Eventually, 10 patients west dos- >itied as active smokers, 9 as passive smokers, and 21 as nonsmokers. Z?le disease worsened in 7(70%) of Lhiwsry aonnine .uanrnwenr sn1 Bre.er} Iiruu 5 S a=/ot cre3tinice 3000E 0 . ~ 2000 ~ 0 C .. ~ 0 0 !I . . 0 -! T0-11 20-29 30~- Cq~rettt//ity (N=3) (N~6) (N=9) (N~S) Fig. 2. Urinary, corinine levels in smokers. Smokers wen dassitied' into four groups on the basis of self-reported cigarctre consumption. Urinary corirutx kvels roughly conxlated to daily cgarettc consumption. the 10 smokers; in none (0%) of the 9 passiwc smokers; and' in 4 (19%) of the 21 nonsmokers. Trherc were significant differences in the rlre of the aggnvation of the disease between the smokers and the passive smokers (p < 0.01) and brn-een the smokers and the nonsmokers (p < UAI ); However, no signi5cant diffcrences in the rate of aggravation .vere found between the passive smokers and the nonsmokers (Fig. 6). Of the four c.xsmokers who expericnced worxning of the disuse, three admitted that they had'still been active smokers at that time. The other one stated that he had been involuntirily exposed to noticeable smoking in the .vorkplace all day at the time of rraurence. This patient had sympathetectomx and bypass operation of the Ic.frkg for the initial matmenc: Four years later, fe:morocru- ra1 bypass grafting, in the right kg was necessary beause of right popIiteal artery ocdusion that was a resuh of a skip lesion. Thereafter, howe.=, he has kept away from tobacco smoke in the workplace and he has been doing well for 2 years (Fig. 6). ,•lmong the 10 current smokers, the mean cotininc kvrl' for the seven patients who had aggravation of the disnu was sigtu5cantly higher than the level for the thm patients who did not expetience rdapses (1208 ± 734 ng/mg creatnnine vs 147 = 79 ng/mgg ctatininc, p < O.DS).

It in ,kers :din Ithe why I our ' cies ;5]v. ,, ures • his -ved sub- tin8 udy sive the not do for the uve s of rge: sive = of 1Jy, :crs ses. Sories of mortality quoted are well in excas of that produced by the form of biu suggested. Also, as oontr+ol subjects expertena some level of ta.iron- mental tobacco smoke" otu esumates of risk could be caatervativo. Mr Lee misunderstands our use of urinary cotinine concentrations in passive smokers. We were using published data to establish whether our~ study had sufhcient statistical power to detect the size of risk that might be expected among passive smokers. If Mr Lee is correct and urinary rotinine concentntions are equivalent i to a lower, dose than assumed then our decision not to rely solely on statistical sigaificancc as evidence of a genuine effect was definitely coetxt, Ours was a cohort study of a general population and was not subjecti to the biases associated with a case-control design: , In addition, subjects reported their own smoking histories, and' environmental exposure was based I on record linkage of cobabitees, thereby avoiding, the need to rely on self reporting of passive exposure. Our observations on lung cancer may be based on only nine deaths but arr consistent with the aeatlit of a metaynatyas' combining 13 sep.nte soldies, which concluded that breathing other peoplc's tobaeoo ®oke auses lung cancer. The smporunce of our study lles in the estimates of t•isk for ischaemic heart disease (based on 84 deaths), all causes of death related to smoking (175 deaths), mortaliry from all causes (263 deaths), respiratory, symptoms (292 ases), and cardiovascular .symptoms (117 oses): The consistent increae in riaks for such a wide variety of health otttoomes trom an unbiased prospective cohort study together with a dose-reesponse relauon in passive smokers atrongly, ssuggests that there is now a cse to be answered agttinst pssive smoking that estends beyond the causation of liing cancer. DAViDfHOLE QiARLFS R GILLIS Wen of ScoUMd C.ecv. Sm.eill.e¢ Unir, RWChiB Hospral, G Waw G2a 9NB' CA1tOL CHOPRA VICTOR M HAw7HORNE ~ed ith nd idy tth be 96. ed' ias. Isk Rg' Deprtuu:au d Epdemwloay; UL-ry dMra4pm, Mrch,aan, Umred Sous I I.x PN. Pasove mokint. .od ordiansyuuory lellh, m. Sttoelurod.. Br Med.J 1919;299:742: (16 SepemEer, ). 2Hols DJ.• GiBrsCR, mopn C, Hhtlaw vM~ Pauac®akma. and ordqrespra,ory Aala6 u.aeonl popul+owo m tAe of smtl.m. Be Mrd Ja 9t9;299:Q3-7. (12 Autuw:) . 3w.1d NJ, N4u:haWK, TDomp- SCG,.Cuckk.HS. Don bruNima aNer people'r.oCrco moMe ouu luna oocv?Br. M1dJ 1996;793:1217-22:. Referrals from general practice to hospitaD outpatient departments SIR,-One aspect highlighted in the report by Drs John Emmanuel and Nigel !Walker' is treatment of skin disorders in general practice. Proposals in the white paper are likely to encourage more minor surgery to be undertaken by general practitioners. This may be more cost effective (although our own experience indicates that this tmy not necessarily be so), but skin surgery should be undertaken in general'pnctiee only if the diagnosis is certain- otherwise referrals may be innvsed rather than decreased as intended. We report two problems that resulted from inappropriate skin surgery in general practice. A 49 year old woman had a pigmented lesion removed by curettage and cautery from her lower leg by her general practitioner. Histology, showed ttnlignant melanoma, but~ it was iafpossible to ascertain the depth of the tunwur on the basis of, the inadequately thin cunettage specimen. The patient then had a wide excision and graft, but!it is possible that she would not have required an extensive operation because narrow excision margins can sometimes be adequate for very thin i melanomas. In another patient, a 46 year old woman, a slightl}, raised nodule on the leg was treated by curettage and'autery by her general'practiuoner. Histology showed invasive squamous cell ar- cinoma and the patient was referred for further advice. Because it was diffieult to know the ade- quacy of the initial i treatment the patient was committed to prolonged follow up to exclude recurrence of'tlie lesion. Dep.rtmrni of tleemnoioay, Bnuvqo, Hocp, W ':.. Lnar,n IA1,2JF Dep~i of P.ceolotl, lanarrtt Mnor }io:prud, Luas,a lAl 3RJ i PHILIP HARRISON ROBERT BLEB°ITT 1 t.mm.nuel'~. J, waher N. Refanlf from amer.l P..ctier m tmsfxud oucp.um. dep.otmepn:. stntet\-lor ®peo.®ent.. BrMrd,j 19t9;299:722y(. (16September.) Provision of services SIR,-It seems to be the custom that when a specialist advisory committee pronounces on how sen•ices should be provided this is accepted; but there arc occasions when someone needs to stand up and say "You are wrong." The North West Thames eu, nose, and throat regional advisorv subcommittee says that inpatiem ear, nose„and throat services should be provided only in subregional specialisrcentres and nat,in the smaller district gcnernl'hospitalt. I have been the anaesthetist for three to four nr, nose, and throat lists per week fonover 20'years and knoww that most of these operations are everyday bread and butter surgery, and that over half are on children. Indeed the commonest pudiatric open. uons are ear, nose, and throat-tonsils, glue ean„ etc. These services have ahvavs been available at the local hospital and to say they should all go to subregional eentres is tantamount to saying all hernias and ingrowing toenails should go to specialised units. Not only does this deprive patients of what I would call a core service but it has , profound knock on, effects on most other services in the district general hospital through the possible loss of recognition of anaesthetic jobs. Before someone brings out the old chestnut of "Make rotations"'I will!answer "Just you try to," We are facing this situation in North'i West Hertfordshire District„where the loss of inpauentt ear, nose, and'throat services will disadvantage our patients and could cause havoc with the hospital servtces9s a wliole• Iiam afiaid'that this may be only the beginning of specialist groups building their own little empires without regard to the patients and hospitals from whom they withdraw their services. Sr AItuns OtpHonp-l, 5r At6.ns AL3 9XX MARGARET E PICKERING-PICK Psychiatric illness among the homeless StR,-Dr Max Marshall describes a high pro- poruon of residents of Oxford hostels for the homeless as being ••long term psychiatric patients" and implies that. they are deinstitutionalised long stay patients.' Our findings, however, suggest that hostel l residents with psychiatnc disabilities may have had numerous yet relatively brief hospitall admissions and'inciude those sometimes referred to as "revolving door" patients. We are currently evaluating a psychiatric liiison service to residents of a direct access hostel for homeless women in central London. Of 33 women seen to date„26 are known to have had at least one previous psychtatric admission, but only four have spent periods of more than one year continuously as inpauents: We believe the current emphasis on deinstituuonalised'dong stay patients is mispiaced: it is the needs of those with ~ chronic, severe psychiatric disabilities in the communin• and' the revolving door patients that are not bemgg addressed. Deferring the closure of psychiatric hospitals~ will have little impact on this large group of people. The Department of Hbalth has stated that the forthcroming white paper on cotnmunin are will contain plans to prevent the unplanned discharge of long staypanents into the communin. Thesc safeguards will be of no value to mosl severeh• disabled psyehiatnc patients in the commurlirv: Dr Marshall's findings and our own data both sliow,high levels of unmet need and are in keeping with most surveys of people witli psychiatnc disorders in the commtlniry. These findings clearly indicate inadequate provision of cars, but they should not be used as evidence of the inef7ectiveness of deinstituuonalisation pro- grammes or properly planned'and funded cont- mututy services. The few controlled studies: of selected patients discharged within arefullyv planned community programmes' sliou that long term psychiatric patients (whether or not they have had long stay psychiatric admissions) can be maintained outside hospital without the deterioration in symptoms, poor psychosocial functioning, and readiltissions that are al1 too commonly found in the surveys. Perhaps more importantly, the controlled studies in whicti patients : wishes and satisfaction have been recorded clearli,• show that they prefer to be trnted'in the community. KRLETI¢J.tC R PUGH Depnmrn, dPryduwl , , Mrddksa Ho.pW, Laodoo W I N~~ tAA' I. Marsli.B M, . Golknd;.nd netkcud: - Odordbuqeb for Uu• 6ourku 511mt up~p ab dnfbkd pycEutnr poema? B. Mkd J.19r9;299! 7D6A: (16Sep®bcr. ), 2welYec BGA,.C'6[ke MP9, Coker E„Mahome.d S. C-a au CUnstmu 19a6. Lakrr 14E7 u:553-~:. 3Bnun P: Kocb.nsky" G, Shapvu R, nof. O-: demsuru- uauirarwo of I ps.chmrK p.urn,s... mcual. m•r- doutco®r audin: Aw ) Pryrfmrry19a I:138:736-" . Safety of Picolax in inflammatory bowel disease StR,-In view of the suggestion of Dr A J G McDonagh and colleagues that further evaluation of Picolax is merited' we would like to report our own experience with this preparation in a large cohort of' ehildien undergoing fibreoptic colonoscopy at St Bartholomew's Hospital. Between 1982 and'1988 we performed 534 colono- scopies on 412 children attending this hospital and, with few exceptions, Picolax was used routinely to prepare the colon before endoscopy. This in- cluded the 287 procedures performed on children with chronic inflammatory bowel disease (163 with Crohn's disease, 101 with ulcerstlve colitis, 23 with indeterminate colitis) that was either known to preKxist or suspected and confirmed'at the time of endoscopy: We found the preparation to be successful forcleansing the bowel and free of major complications. Based on our experience we have developed the following regimen for preparing the colon before endoscopy, in children. The child is given only 8uids for 24 hours before the procedure and is given two doses of Picolax, one about 15 hours before endoscopy and the other three hours before. The dose is age dependent: children oven6 years :9 BMJ voLUME 299 28 OCTOBER 1989 1101

(3) En r.onmrnrlmrrnmronu!. Vol Wpp _49-_65. 191tit; Prunted'm the U.'SA. All nghts reserved. AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING A. JUdson Wells 102 Kdoonan~Glen: Wilmington Delaware 19807. USA (Rrcrrvrd 9 December 1987; Aectpred 7 hPo• 1988) (IltXr+al_'11 IiR Si.fMl , ,tNl Copurtght c 190 Pergamon Press plc r+OTIeE This matanial tnaY be prstacted by capyn0't ttw (ritle 1711.5. Code3. The purpose of this paper is to estimate the number of adult deaths per year in the United States from passive smoking. The epidemiological hteratureon passive smoking and adult mortality and'nncer and heart morbidtt% , is reviewed. Combined relative risks for lung cancer. cancers other than, lung. and heart disease are calculated for each sex and disease categon. These data along with estimates of nonsmoker dcath rates and populations exposed allow calculation of annual deaths in each wtegory. Reduced relative nsk and reduced exposure at older ages are taken into aceount as well as aa correction for possible mtsclassihcauon of smokers as nonsmokers and exposed'nonsmokers as nonexposed A6 together 46.000 deaths per year are calculated consisting of fung cancer ('30(M1) other cancer ('11.000)) and'hean disease (32A00). Reasons why such high estimates for other cancer and heart disease may be possible are explored. It is rnncluded'that exposure to environmental tobacco smoke can have adverse long term health effects that are more senous than previously thought.. Introduction Several attempts have been made to estimate U.S. adult mortality from passive smoking. For example, Repace and Lowrey (1985)'estimated the lung cancer deaths to be about 5000~ per year. Fong (1982) estimated total mortality at 10.000 to 50,000. Russell ernl. (1986) es- timated total U.S. mortality at more than 4000. The present estimate is based on epidemiological evidence currently available on lung cancer, cancers other than lung. and heart disease. The Surgeon General of the United States (USSG.. 1986) and the UIS. National Academy of Sciences (NRC. 1986) have issued reports stating that passive smoking can cause lung cancer. In the National Acad- emy report the relative risks from the various lung can- cer studies were combined into an overall relative risk using a proced'ure somewhat similar to that which is used in this work. The Academy report then projects that about 20% of the 12,000 U.S. lung cancer deaths per year among never smokers is due to passive smok- ing. This is reasonably close to the 3000 per year pro- jected here for never smokers plus exsmokers. The methods used in the National Academy report are fur- ther detailed ini Wald etal: (1986). Blot and Fraumeni (1986) have also presented an overview of studies of lung cancer and passive smoking. They use a method of combining the relative risks from variousstudies es- sentially identical to that use& here. Thus, the proce- dure of, combining relative risks from various passive smoking studies to obtain overall relative risks and tighter confidence intervals is now welli established by authorities in the field. Also, the method used here to calculate annual deaths from the relative risks appears to be validated by the National Academy results for lung cancer. However, both the Surgeon General's task force and that of the Nationaf Academy felt that the data, as of 1986, on cancers other than lung and on heart disease were still too meager to allow calculation ofireliable overall risks. Since 1985 considerably new epidemiological infor- mation has become available, particularly on heart dis- ease. This new information is reviewed and combined with the old data to calculate updated relative risks. overall confidence limits, and estimated annual U.S. deaths from passive smoking and the three main dis- eases, namely, lung cancer, cancers other than lung.. an&ischemic heartidisease. The total particulate matter dose retained by passive smokers is too low to account for the health effects of passive smoking, if one startss with the health effects exhibited'by direct smokers and ratios down from the dose retained by them. Reasons why such a discrepancy might occur are explored. 249

Adult mortalirkfnm passn•e smoking can be obtained as shown in Table D3. The nasal deposition from passive smoking could account for the observed nasal sinus cancer. Also. if the observation of Balin er aL (1986) is correct that there is a direct passage for toxics from the nose to~ the brain, it could also account for the observed brainn cancer. Ih the deep alveolar region the ratio of direet to pas- :h` sive deposition is much closer to the inhaled'ratio ~than to the "total retained" ratio. It is from the deep alveolar region thac the smoke particles are solubilized and clearedGnto the blbo& and lymph systems possibly to cause cancers of the liver, breast and endocrine glands, leukemia. h•mphoma and ar- terial plaques.

accumulated 153 deaths from lung cancer and many thousands uf deaths from tschaemtc heart Htsaase us non.smokers. The effect of passive smoking on lune cancer has beeniooked Into.' It is a ptty that its effect on ischaemtc heart dssease has no[. , RETER'N LEE mm~, ~rrey.5;~i1 S DA I! Lee PY. Pzsu- nmoi,utt and.ard,orespte+sor, nealtN.tn S:ot• Idnd: Br.11rd J, 19r9:.99.74;. ! 16 S<oremoer.? 2Holc Dl. GJlis CR. Chopn C. Huwnor.nev.M . Pasn,ve smoksng and cuwornptnwnoealsn tn s: ecnerat pupusu,oo ustAe wt of Seottand. Be.N<d J1969:.99:~ 23-7: t 1: Aweuss•, 3 HoteDI.GJL.CR.UopnC.HavqeorneV\t. Pasuvesmolung; and ordipeesprtaionv.hnlshl m, Scmlusd..Br N<d J:19A9~'99• n0dl. +.tlanml \, Haensrcl fr'. Suusuul saprcu o( tne analvua o( aau Irom rerro.pecuvr stwLn oi!dtseasr. j..\a/ Cwre /nu 1959; 5tse PN. Pasuve amokme.and lunt cancer• fan or 6cuun? 7n:. Biev. Cl: Counou Y,, Go-res 51. Ns. P<nnv! .ne ef.e,im.. av p.a~u+y: Amsserafon: Else•1er. 1989 . I 19• ]s: 6Garnnkel L.. Time uends us lung can<er mortaL, among.non~ smoren andsnwe oo W- smoiwg: J:Nmi Ca+<rrhus 19a1:66:I061+E:- ALR}i6RS' REPLl',-Ot1r calculations are neither incorrect nor tnisleading. Ati- Lee is attempting to show how large a bias can be introduced into estimatesaf relative risk for passive smokers due to actsve smokers misclassifN•ing themseives as non- smokers. In doing so he has produced biases that are excess4`re.because we:ranSDow his assumptions are false. His main austake has been to assume that the "true" «lauve risk for lung cancer is the same for male and' female smokers (his table I). Also, alihough the extent ofsmoking denial for our stud'y is not known, we can put an upper boundary on it. Our origittal study esumated the relative risk of lung cancer among acnve smokers as 5 49 for men and 3-33 for wromen.' Table I shows, under Atr Lee's assumptions, that "abscr>tied" relative risks for active smokers would be larger for women Ihan men. This is incompatible noronly with what we sare observed 5ur also with all other reports we know of. Thus his assumption that the same -true" relative risk holdk for both men and women TASLEt-"Ob~s.rrt:ed" re7ativerisies for aetive and, paniae tvsokrrs fo.va>nzng denial'rau.s afsmowtn;~.' Reianve:. nsks ior R<Fauve. nsks for R- of uuvc smoKSng , passtre smokmg demal Mo 0.'amea]ten Qnmen~ 1 10~.3d 16•.20 1.53. 1~15 ?~ 6.90i 13,4= 1~74 1~.:5~ 3 5,1a I1- 5 3 !~57. 1~3a i 1~.101 9~~99~ 1.9s~~ 1~..2' 6 2.35~ '"9~ 2 ~06~ 1151. 8~~. 2'20, 6-48 ?-:1 1163~~. 10 1-76~ 5-15 ?`l9. 1170 '.{ssumtng."uve" rctauve.rtsks.of 10 for passive smoking and20:foracuvesmoung. is untenable. Also, if we accept Mr Lee's tbeoren- al range of'posstbdiites for the rates of denial of cigarette smoking then the outcomes become even more unlikely. For each rate of demal of 4% and' over suggested by Mr Lee thcrelative ruk for male active smokers is prngresatvely well belbw thar observed in our study (table 1). Above a denial rate of 8% the "observed!" relative risk for male pusive smokers exceeds that for active smokers. Our data arc, however, compatible with detl]al ntes dup to 2% and a"ttve" telative risk of 4 fbr female smokers. Mr Lee quesnons the extent to which misclas- sificauon can explain all the reported relauve risks for active and passive smoking seen in our study. Table II showsahe relat9ve risks for active smokers found in our srudy for each endpoint and the "true" relative risks with whicb these are com- pauble, assuming a rate of denial of smoking of 2%. Fore:ample, the relative risks fbr all causes of death associated with acnve smoking are 1-85 for men and 1•87 for women, These figures are compatible with a "true" relative risk ofQ, given a denial rate of 2%. The figure of 5 that Mr Lee quotes u5 his letter may'be appropriate for some of the endpoints used but certainly not fbr all. The final two colitmns of table II show the passive smoking relative risks found in our study for each of the endpoints compared with those that could havetxcurred'through the type of bias Mr Lee attributes to our study. In particular„ the differenees are quite noticeable for the four carte- gories oCmorulity. Thus mtsclassinaauoo can oias estimatesof relauve risk for passive smokers tbat use assumptions compatible with our estimates for acuve smokers. The size of these biases does not, howcvct, explain our passive smoking restilts., What is striking about our results is their consistency across a wide range of endpoints us addition m lung cartcer and especialJy for ischaemic heart disease. This is supported by our findings of' a dose-response relation for each of these. Even though Ntr Lee reaffirrrls his view that mssclassificaton of acuve smoking state can expYktn the average risk ofl lung cancer with passtvee smakLng, we welcome his implieation that the effect of passive smoking on ischaemic heart disease is worth further iavestigation. DAVID I HOLE C33MLES R GILLIS ~ansof 5. wund Ciincer Sur.eillance Gmu, Ruc6s11 h.,.p, W; , GlasgoW :.:0oNB Deynmam a ~:Epbem,oloty~. Um.ersirv~ of SsmG,pn~, slic~eae, UnnN. S~utn VICT.DRM H.aKTHOR7.-E I Hok Dl: Gillss CR. Chopn C. Ha,sberne V,11: Pasnve smokaog . and eueLonspu'a,onhea/P,h ta a een<ral ipopt+l+uon m tM.~'e+e . of Smouad. Br.ued j.I9r9::99:.I3-7. (1: .iugust., `: Thiscorrespondenceisnowclosed;-En,BbfT. TABLE tt-Rkfative ruks found in s:.rdV rtmspared =1th:"rnee" refative nskrfeir acnvr smokers and "oburved"'relantt nSRs;tor f.ai3l-Jes>RIO!!r3' .{cu+c smmkers Poss,ve smokm .11cn u:omen, Both scxes "Tvuc'.' 'True..' .-Observed.. relaure Studyre/iuve Stud}•. rdauve nsk ussdang; nsk 6c,lsngr nsk 'Assumt:.g 7°e ei smwl.crs damstr.uiur.c. Tlhc r-lts ior, bounsases combsnN. nacc been udtussed ior,se<using: WnttASs \.\'.: \.. N;,, unef[ .\ ~:an.t \: are oC-d numC<tS 0~I expVXd and une'SptHe,! Suotern. BFiJ t+OLti.\tE 300 13 )rjNL'.aRY 1990 6~0~ 3~3:' 5-0: 1~34 1 ~14 6~0~ 3s93~, 5-0: 1-19. 1 -14 1 ~0 1-37~ 1 ~a 1~09 1~03 5 0 4.15~ 5.0: 1~31 1 13. - 1-JJ. 1-5: 1 ~ I1 1-05 ' 1 ~8 0~92 ~ 1 ~11 11-02~ :.-0. 1-3^, ~ 7~0 I 1 ~04 3-0 2-S9' 3-0: 2~Dt 1~07~ ?a~0~. 3;33~1 a-0: ?~i9 1~26~ 3 0 `451 3~0: 1~30 1~07. StR,-In her editorial o Professor Eva rilberma rate of deaths from m neural tube defects, in I Paktsnn.' In tne studies deaths were considerea. in this countrx are no screesing programmes, a termrnanon of the pregt5an an affccted'fetus,' so thesr the true incidence of neu women tend to book later fo and this may account for tb neural tube defects to peri tnmester screctting would be smaller proportion of rtsian they may, find tertninauon o able on religious grounds.' the overall incidence of n ascertaining all those affec prenatal screening with u all those found in the pert also tried to determine fact tan[ in explaining: any ra incidence. We reviewed the mat departmentrecords,:neona and necropsyreportsfro end of December 1987 hospital' to ascertain all neonates with,a neural!tu ' dtfe notes were then inspected to detc booking for antcnatal car , if an sound scan was performc ;,and!w uun of pregnancy was off, red. In the Pakistatu'popul an ther tube defects in a tntal! f 3777 b 1000); there were 32 neu I tube d births to white women 1 11 per eongen ' omm orma ts crr . inv a rs e al ,11 Janu on etuse 'erts in rerur 1980-7 Total tu:ural tube defeen Total titnnsIncsdener per. I000 bsrshs Dapcted bv rouwe uh scan Pregtanc. terrtunatcd Pregnancv.mnunt:ed: \otaetecxed bv rouunexan I Scan not arsdablr. L' Not detecsed bv son Booked Yoo lue for sna I Did nos ancnd forscao il malformauons nts on the excess ons, parncularn' f a5others born in to onlc pennatal ural¢uba defects ted by prenatal bmen: ma}• opt (or hen found to have es may not reflect ube defects. Asian heir antenatal care,' igh contribuuon of al mortalirv: second aila bie to a rdatively, men. Furthermore, regnancy,unaceept- e have investigated tube defects by fetuses detected tiy o¢nohy, as well as period. We have at may be impor- ifferenees in the ultrasonogtaphv labour repstens„ 1980 until the district general stillbirths, and The maternal' ne the date af' whenlan ultra- ther a termina- were 11 neural sf291 per ects in 28 834 10a0) (rtable): Routine examination duced'only in 1984 and manyy of the women in tnc dence of neunl' tu populauon was ngninca tlv hiehcrthan that i ~htte population (p=0 013, Fisher's exact taiied test:, reuuve ns 2 i:. 95¢6 conttd interval I`191o 5•3;):~ e woman in each.er taoked'too late ior rouu c prc,=al screemng, one Pakistani woman fa d to attend for the scAn These numbers are smal but n ts o( natc chat t mean gestation at wntca Jiesc women booked w 1+2weeksin.the Paki ani group as compar wtth:14- 3'w'eeks+n the ..-~tte group Six of the 1!1 Astan abus wsth neural tu defects were barnto wom n with aconsangutneous marnage. \C'e have shown tha[ ere is a real mereased. Inctdence ofneunf tube etects:nehe P.ilztstampopulatton, with late booktngand reluecance too terminate an, affected q.rernancs" cantrtbutsn:mtnimalh•: to the tncrcasedInc:den<e inundi . In pertnatal deaths: Changesiin customs 3re ltincui.l to encourace but mac wellloccur, ser7ntaneousic as~~ th ultnsound' was intro- encrwas not a«d bie ta uded in tfus stud The defects in the Pak stani ithe two nce iupp nd 121 Endpoms Studv 6md,mg, !h ~tised pnl<snn 4 03 Phlvcna pntcgrn +23 D spssoea 1 65 Hvpenccrcuon 2 95 .lncsna ' 13 tt ,uraSnonnalsnane/ectroeardaogtnm. 1 57 ~ll causn oI dQ n 1 55 lxhaer.uc nean d~saase 1 36 ~4nC:aI1Ce' j 19 .{ll causea ui dda.'s r<u teu to smuwez 90

252 Table 1. Female relative risks for, lung cancer from, passive smoking: A. l i We I I s Hichest All Msntel! Exposure Exposures Trend~ T l Locale ota Cases RR 2-tail p RR 95 c7c C.L. I-tail p Cohort Studiesr Hlrayama (1984a) Japan 200 1.9 0.002 1.6 1.1-2.2 0.002 Garfinkel (1981) , l.'nited~States 153 1.2 0.8-11.6 - Gillls er a1. (1984) Scotland 8 - - 1.1 0;.-5.6 Combined Cohort 361 1.34 1.1-1.7 Case Control Studies: Trichopoulos et a!: (1983) Greece 77 2.6 0.19 2.1 1.2-3.6 0.ot15, Cortea enal. (1983) Louisiana 22' 3.5 0.02 2.1 0.8-5.2 Buffler er a!. (1984)'. Texas 27' - - 0.9 0.4-2.3 Kabat and Wynder (1984) United States 24 0.8 0.3-2.5 Sandier er a6 (1985) Nbrth Carolina 2 - - inf - Garfinkel et a1. (1995) United States 11& 2.0 0.05 1.3 0.8-1.9 UA25 Wu eral. (1985'). California 28" - - 1.2 0.5-3'.3 Lee et at: (1986) lJntted Kinedom 32 - - 1.0 0.4-17, Akiba et a!: (1986) Japan 94 ::l - 1.5 0.9-_:6 T06 Koo et al. (1987) Hbng Kong 86 1.2 - 1.6 0.9-3:1 Pershagen et al. (1987) Sweden 67. 3,2 - 1.2 0.7-2.1 012 Humble er a!: (1987). 1New Mexico 20 1.2 - 2.3 09-6:6 Btownson~eraP (1987) Colorado 19 - - 1.7 0 4-3A. Lam et al.' (1987) Hong Kong 199 - - 1.65 1.2-'_-4 Combined Case Control 813 1.50 1.3-1.8 Combined Cohort and C/C 117.3 1.44 11'6-1.66 ' Private communication. "From Blot and Fraumeni (1986). cer in males. The relative risks were 0.6, 1.5 and near unity., respectively. The number of cases.in each study is very small~withino statistical significance. Therefore, it was decided to use a neutral relative risk of 1.0 for males for cancer other than lung until more data become available. There are now six studies of passive smoking and heart disease in females. The individual and combined relative risks are shown in Table 4. Studies new, since 1985 are Lee etal: (,1986), Martin era1:,(,1986a).and the important, large Helsing et al. (1988)paper from Mary- land. The overallicombinedrelative risk based~on 1.622 cases is 1.23 with 95% confidence limits of 1.11 to 1.36 and a combined chi square of 16. Helsin&er al. (1988) and Martin et al: (1986a) provide data for younger women and indicate high relative risks (average 2.45) Table 2. Male relative risks for.lung cancer from passive smoking. Highest Alli Mantel Exposure Exposures Trend Locale Total Eases RR 2-tail p RR 95 % C.L. 1-tad p Cohort. Studies Hirayama (1984a) Japan 64 2:3 0.16 2.25 1.11- 4.9 0.021 Gillis et al.. (1984) Scotland 6 - - 3.3 0.7 -16.5 Combined Cohort 70 2.5 1.2 - 5.0 Case Control ~ Studies: , Correa n ar. (;1983)'! Louisiana 8 - - 2.0 0.4I -10 - ~ Buffler er al: (1984) , TTexas 8' - - 1!.6 0:3' - 811 - O Kabat and Wynder (1984) United States 12 - - 1.0 0:3 - 3:2' - N Lee er ar. (1986), United Kingdom, 15 - - 11.3 0:4 - 4.6 - Akiba et al. (1986) Japan 19 - - 1.8 ~ 0i5 - 5.6 - Humble et al. (1987)' New Mexico 8' - - 4.2 1.0 -16,8' - ~ Brownson er al. (1987)± Colorado 4 2.7 0.2 -31 Combined Case ControV 74 1.8 1.0 - 3.3 Combined Cohort and'C1C 144 2.1, 1.3 - 3.2 ~ 'Private Communication. ~

A. J Wells found that never smoking women married to smokers had slightly lower weight. slightly lower bioodpressure, and slightly higher cholesterol, all nonsignificantlv dif- fi:rent, versus never smoking women married to never smokers. All of these authors conclude that the in- creased passive smoking risks they observed cannot be ascribed to differences in the major coronary risk fac- tors between passively exposed and nonexposed never smokers. It is impressive that the relative risks for heart disease from passive smoking rise in an orderly manner from the lowest risk group. Japanesewomen at 11.16. through American worrlen at 1.27, and American men at 1.31, to highi risk American men at 2.2. A correction for misclassification was attempted for all, three disease categories. Following Wald et aG. (1986), and presuming that the passive smoking studies were done somewhat more carefully than the general questionnaire studies thevcite, it was assumed'that 5% of ever smokers were misclassified, as never smokers. Along with Wald et al' (1986) we assumed that the nonexposed nonsmokers were actually exposed to 1/3 the extent of the exposed nonsmokers except that for Greece. Japan, and Hong Kong, where less than 30% of women had ever smoked, the correction for nonex- posed female nonsmokers was omitted. It is believed that older. nonsmoking women in Greece and Japan. and~probably in Hong Kong also, because of their social habits, were exposed to relatively little tobacco smoke beyond that of their husband's. Since most of the mis- classified smokers were found to be light smokers or longstanding exsmokers, reduced relative risks for the misclassified ever smokers were calculated„as noted in Appendix A. The modified passive smoking relative risks are shown in Table 5. The false relative risks due to smoker misclassification are somewhat lower than calculated earlier by Wells (1986) because of the as- sumption of light smokers and long, term exsmokers among those misclassified, following Wald et al. (1986)'„ and the use of a more accurate formula. lnigeneral. the misclassification of smokers has a large negative effect on male relative risk which is more or less offset by the positive effect of exposure of the "nonexposed! " For females the smoker misclassification effect is small to negligible, burbecause the relative risks are smaller and no correction was made to '"eastern" data (lapan, Greece, and Hong Kong)L the positive effects of ex- posure of "nonexposed" are also smaller. Calculation of Deaths The details for the calculation of female lung cancer deaths from the relative risks. both constant and de- clining. are shown in Table 6 as an example. Similar calculations were made for the other disease and sex categories and are shown in Appendix A. The results of all of the calculations are summarized in~ Table 7. These results are restated per million total population in Table 8. Where the relative risk appears to decline with age and where neversmoker death rates at the younger ages are low, as in female heart~ disease and lung cancer, there is a reduction in mortality calculated' by'using the age specific relative risks. Otherwise, the higher exposed population at the younger ages out. weighs the higher death rate at older ages and total mortality is increased. In terms of total deaths the ef- fects of using age specific relative risks tend to cancel out. The totaL deaths, before adjustment, for misclas- sification. for both males and females are about 19.500 for a totalI for both sexes of about 39.000. The effects of misclassification on total deaths are substantial, raising the total to 53,000. Most of this increase is in heart disease where the numbers are large and the effects of smoker misclassification, although not necessarily small, are still heavily outweighed by the partial exposure of the "nonexposed." To be conservative a best estimate for passive smok- Table 5. Passive smoking relative risks modifiedFor misclassification. Lung Cancer Other Cancer Heart Disease Females 1. Combined relative risk. 1.44 l.lta 1.23 2. False rttative risk due to projected 5% smoker misclassification. E011 1.002 1.01 3. Combined relative nsk corrected for smoken eusclassification, (1) + (2): 1.43 1.16 1.22 4. (3) corteaed'for exposure of"'non- exposed" at 113 that of exposed. I.dg' 1121 1.32 Mata 1. Combined relative risk. 2.1 1.0' 111 2'. False relative nsk due to projected 5% smoker misclassificanon. 1.3 - 1.19 3: Combined relative risk correctedfor smoker misclassification. (1) * (2), 1i.6 - 1.17 4. (3) corrected for exposure of "non- exposed" at 1/3 that of exposed. 24 - 1.29 •Assumed value for lack of better data.

Tt-M LANCET, SEr'T'EMBER 16, 1989 TABLE 1-AGE DtSTAtBl7101-0F 423CASES AND CON'TROLS Age~ ., , I Cues~. 1 Convols ~ <40. 17 40-Yi 11 14 45--}9' 15 T% 5(~-54 22 21 55-59 35 37 60-6a 70 66 65-69 75 87 70-74 98 8- 75-79 61 51 asa, 19 25 Cereb'ra1 infarr] siie or mecharriem uncerrain;-Ttus group had acute onset of a focal neurolo®cal deficit in which the site of infarcvon or the mechanism of its genesis was unelear but causes other than vascular causes were excluded by CT scan. H~•pertennim was defined as a histon of h}~ettension documented' by ' a meditsl practitioner or currnit use of antih}pertensive drugs recorded at interview. High cholestrral was defined as a plasma coneentration of 5 5 nunol I or greater. Results The 422 consecutive patients and their matched controls were of mean age 65 years (range 25-85 in patients, 20-8 i in controls; table 1). There were 256 men and 166 women in each group: The relative risk (rnsde) of cerebral isctiaemia for all faciors which migllt have a confounding effect on srno7<ing as a nsk facZor ae shown in table 11. These factors were controlled for by means of multiple logistic regression atlalysis.' Smoking, hypenension, and a history of' myocardial infarcvon were signifieanrand independent risk factors, whereas alcohol consumption seemed to have a modest but significant protective effeet. Since adjusttnent for all risk factors made little additional difference to the overall relative risks, adjustment for hypertension and age only was made for the rest ofthe analysis. Hence, rhe relative risk of cerebral ischaemia was 3 7(95°/a confidence interval'. [CI] 23, 519) for current smokers and 2•0 (1i3, 3-1) for ex-smokers„ both compared with those who had never smoked (adjusted for age and hyperteasion only). Both risks were significann (XI = 30•0 and 1'1 •0; respectis'ely, each for 1 degree oflfreedom [df]l p<0'001 and p<0•01). In1 women the risk for current, compared with never smoking was 3 2 (1 6, 6 6)l whereas in men:the risk was slightly higher (3 8 [2 1, 7-0]; ',this difference was non significant (X' = 0 1 for I df, A: S): Similarly, there was no difference between the sexes for ex-smoking risk (relative risk for men 1B [1 1; 3 1] and women 3-0 [ 1 3, 7' 1]; X==1 •O for I df, 2` S). The stroke risk was greatest in the group aged 55-64 years and the risk of stroke was significantly higher for current smokers under the age of 65 yearsthan for those of 65 years or older (relative risk 6-813 1,15 0] vs 2-4 [12;,43]; X' =4-8 for I df, p<0 05). However, when the two groups in which smoking was not a risk factor (cardiac embolic and cerebral infarct with site or mechanism uncertain) were excluded from the analysis the difference was no longer apparent (X' = 3 3 for I df, h S). The mean ages of the cardiac embolic group (69 years) and'zhe cerebral infarcZ, site or mechanism unknown group (68 years) were greater than that of the other groups (64'years). There was a positive dose-response effect in that the risk of stroke among current smokers rose with the amount smoked. Two current smokers of the same age and hypertension status and whose dail j' consumption differed by one pack (20 cigarettes per day):were estimated to have a 645 TABLE II-aiL'DE AND ADJUSTED RISKS OF C'EREBRAL ISOiAE.M1A FOR ALL FACTORS' ExA+dIXFD BY A4LITIPLE LOGISTIC REGRESSION 1 1:a ~ %~ I Esnnuicdnik Cases~. Conaols Crudr!Adlusied'95°%o~Cl r: i Curresrsrnoker 135 32". 78 '18'"...,.~ 3" 3'6'2 2, 59., Ex-Imoker 145'~34„ 13 '32° ~,~ 1~9. 20.,13,329 Never smokcd ~ 14- ~ 34 % 207 49° . 1.0~ 10 Hypenension J 281',67.0 145 -91°0: 4 _ 47(32,68' H'gh cholesurol I 45 14„ 3, 11.1°.~ ~ 1-6 1 3(01i,25) . Mvoardiol mfarcnon~. &i '20 50 1129..; ~ 1-9. 1.6(10,25; Aloohol mnsumpnonY'52. 168 °b a 274~ ( 7S"%. ,~ 0~6. 06(04,1 ~.0;. Otaloonnaoepnvesr I 31I~19%., i 39~(23%~~.) ~1 1-0 09.(0.4; 26). •Of subiees whose nsk faetor surus was known. fl'es or~nor iln¢ludess past as well as pnsent use- §Adius=ed for all othcrnsk'r facton~~. risk differing bv 2-1 (1 -1, 3 8; X' for linear trend = 6 7 for, 1 df, p < 0-01 C. The distribution of' patients within each categon of cerebral ischaemia with reference to smoking status is shown in table nt. For attzenrsmokers, the greatest effect on stroke risk was for thromboembolic and lacunar stroke combined: the relative risk in this group w2s 5, 7'(2 8, 12 0; y' = 25 0 for I df, p<0-001): Patients with laeunar, stroke albne had the higliest relative risk associated with current smoking of all subgroups (infinite [3 0, infirtin']); this risk was signifieantl% higher than that for all otherigroups combined (X' = 7-7 for 2 df, p<0-05)„but only 10 matched'pairs were available for, analysis (the analysis method ignores pairs in which smoking status of case and contro) arc the same) and this result should therefore be interpreted with mution. There was no risk associated with either curTent smoking or ex-smoking in the patients with cerebral infarcvon presumed to be due to cardiac emboli and patients in whom the site or, mechanism of infarction was uncertain (table 1Il), However, aslTent, smoking was a significant risk factor for TIAs (52 [2 1, 1i3-0]i, X' =13`0 for 1 df„p < 0 001). TABLE Ill-A1'1.4$ERS'OF PATIENTS AL'D .tiL1TCH5D CO\TROLSIN " EACH CLI\ICAll SL73GROLP OF CEREBRAL ISQdA'E.NIA R'In-I RESPECT TO S.MOKI\G STATUS AND RELiTIVE RISi:S No ~(%). ' Rcliovr nsk ~ I of~.cerebrsl Currrnt ~ t:n•cr isducua• Subgroup smokers ~ E~-smokers smok'ed'~ i, (95 io~ Cl y. T1i1 rn-120, ~ Cases 35:.19%~) ~ 53~eI4',:~,, 32~~27"i- 5~-'(27{13-0)~. Controls 21 r18%;~ 42r33%~i, 57~f7:a; Th.w+o6Kmbotic (n- 1631. Ctsa 59 r36%, 54 ~335;,, 50.31%, 5,0(2'3, 1) -0; Coneois 36~ 122> ) ' 49 ~y0°:7~ 78~~r87.,. ' (d~ ln-S6/' Cases. 25' ~4'tq;, 1&1235:a, IB'~32%) . Infi3~0, Inf.~. Connols 7r13B.; 1900°.6.;, 30~.~S1.'~.:. Ca.d~ anboticn (-46) Cases 7~r15D.r 14r30S:~ , 25,151"~;, 0'~4(011,1~8;'. Consrols 8~ i175:, 15 l335..;. 23 Suu-dsmeiwr ~. vur+smn iw-37.;. Gaus. 9.r2R°o, 11 r30t.~,~ 1p,46%:~, . 019.(0^_,3~~5)~. Canaols. 6~~16°b., 12132'::-~ 19~~51,9e~.,. Toacl i Cases 135 ~32°..~, 145 r34;e~. 1 142 ~34~°,6.,. Conaola. 78 ~ 18'b, 13' ~3:"b,~1 207 ,W6~. 'Current cv nevcr smoked_ 1nf - u,fwsy . I%

66 MRmtAbYta, SnonoYS, axd IHLMdwOto Iq/rst crt7tinint ---Micetiae -Cotiuine 12 2/ 36 48 60 12(hours) After Wive smokiap -- Micetiae -- Catikiu : 10 u c a 0 A . . ,.---~-, ° Betore ~ 12 2/ 36 48 60 72 (hours) Atter passive smokirGY jwTsW d VA.SCZJLAR SURGERY Fig. 3. Utinus nicotine (b.okm tiru) and coQninc (wl:d Jinr) ezavaon over time. After active smoking (abovr). and after high involuntary exposure to smoke (bclcm), in a healthy nonsmokcr. Cotiainc levels decreased more slo..-tv than ~ nicotine kvel4 did.. DISCUSSION Carboayhernoglobimor nicotine concentrations have been used as indicators of smoking.° In vascular surgery, carboayhcmoglobin has been used to determine smoking habits of paoents who had arterial recon.structnvc opcrations,` ° and Vi'iscman et al,° reporte& that the median concentration of earbox)fiemoglobin was significantly higher in those patients whose grafts had failcd than in those whose grafts were patent. Ho..'ever, blood carboxyhcmo• globin concentrations have not proved to be markers specific to smoking, and nicotine measurements have been regarded as providing more accurate assess- ments.1D Recenth•, cotinine has been considered a more sensitivc marker of smoking because it has a much longer plasma half-life than nicotine does (about 30 hours vs about 30 minutcs);,''" In this study, ururary cotininc levels dearly discriminated between smokers and nonsmokers. Bv measurement of cotinine leve1s,10 patients were identified as active smokers, although seven of them daimed to have quit smoking. Of these 10 active stnokcrs, seven experi- encc6aggravation, and there was a significant differ- ence in the rate of aggravation between active smokers and exsmokers. It was confirmed that active smoking was very closely related to recurrences of Buerger's disease. Three former smokers, ho.veva, experienced worsening of the disease even though their urinary cotinine level remained within a non- smoker's or a passive smoker's range. Since the urinary cotinine elevation aftcr smoking hstcd; for only 60 hours, our assessments of smoking were limited to a very short period. Past smoking habits cannot be estimated by ill-tirne& measurement of eotinine, a short-term markcr, when paocnts have abstained from smoking. Serial examination of uri, nary cotininc levels should be performed to solve ttus problem, Bontue the number of cigarcttes smoked roughly correlatcd witti the urinary cotii•iinc kvd,1u'" thiss levd may reflcct the intensity of smoking. Howeva, there was considerable variation in cotnnine exeartion, 4 -F, among subjects who smoked approxirnately the sune . number of cigarettes. These variations were assumed to be caused by differences in nicotine eontent per ~ eigarettc and in the manner of smoking (inhiling or' ~ pufbng, frcqucncy,Jcn.gttr of cigarettes smoked). "" '' In this study, among the patients who continued to .r~. smoke, those who experienced aggravation of the disease had signi5cant]y higher cot3nine levels t3tan 20235118FQ :~:47L

asdrenergic casual1v department. where further, d'ela.•sS would take piace.and possibly furthor errorsbs inext+erneneed lunror staff. Ltnfortunateh', the message of the British Hean Foundation report ts dtcpi% amhi.•alMt. doubtless re8ecting a "dissensu>'^ in the group. The overall result.. howcrcr. will bc to d iscounge genenl pnctitioners ftom pwnpating fullt' and expioning the maior benefits that tbromfwl+^tic treatment can confer. Rather tlun: "contracttng oua.'^' as the report suggests, I hope that gcnenl I pracuuoners will insist on local schemes to bolster their confidence in the full eul}•, nunage^ment of mvoeardial infarc- tton. , Fsnr<EX: atiTi, of the above aufomated methods. and the rather glib dismissal oCnecessarn' technician time shows a lack of undersunding for the problems off latwratories that will be asked to perform thesc investigations on a dav to da, basts„gtven the current volume of requests for markers of aicohol abuse. , Chenual puhologv ' departments that seek to sell this "fatr8s• stmpic, sensitive, and inexpensive" technique to their managerss and clinicians as an alternauve to cheaper current tests (albeit with known limtutwns) mav thus be hoist with their own pctard. L N' SANDLF G H HALL CMmwl Pa,k,dq. D<p.nmm,. Trauoed C af Hsinul... A4a~rAeun .U31 JSL 1 HafIGH n:rlu+suef•,nln.ascaf.er,+no.ardmlm(am.v,-L+.:n I9C;:n:au-t-, _ 2 Bnwslf Ho.n Founda,wn Cnrk npG[wp. Rok ei tli< 0ene<a1 , pra<u<,an<n ,n manaamt r•• •qh mn,c dut,mu.,wn. unrw~,~.oi,MOmep+,.. vo,m<n,. B'. ~LJJf9W,299.'S*-o. .2eAWua, Child sexual abuse SiR,-I am pleased that tnveseiganons for sexually uansmned discases including screentng tests for gonorshoea and HIV infenfon should'be done on sexuall'+ abused~children.' Ot-er rw-o veaZ five children (two g.rls. Shree bovs; aeed =-7!': ycars presented at this teachtne hospiul: not with a hfstory,of sexual abuse but with urethral or vaginal d:scharge proved to:bc due to Neuse+ia gonannoca. One 5 year old girl subse- quently admitted to sexual abuse br a 10 pnr old boy at:schoo4. The boy refused to be investigated by us. Tlie other,girl. aRed 79sycars, dcnied scxual. abuse and had an inuct hsaeen.,Three bo.^s were subsequenth• found to have contncted the disease through a parenvor older member of thefamily. Reports on sexual abuse in children in the developing countries arrnrc,=, but our experience show-s that doctors and. in particular,, paedia- trieians in these countries need to be aware of sexual abuse and d:atithe campaign against HIV infection and other sexually transmitted diseases for at risk subiects should include children who have deenn sextullv abused I: Deponn.m, ef PanLuno.. Bo: lal. uyPmn. Um.m,nn6 Pon ,Harcoun. , Pon Harmun. , Nit<rn FELICIA EKE 1 SaMerE: F. Aomrns R.. QuW t<saul~ abu.<-11. B, N.I J, 19r9LZ9ii%:-t_. S Autun.. 2('1tunEanim BO.. Srsuallrc van.nunnf : dnotr. an N,rrru. A' rer.-.- d [1t< t.exnu inraumn. ir<n A Mr.+. )avn,.J i.! Md>tw 1969.aa:-9.' Marker for alcohol abuse SIR,-Thc prospecuo[a morx re2iable marker for alcoholism as described by Mr A Kapur and callcaguess ismost wc7come.'Unforrunateh•, howes-cr~ their Last paragraph states that"thc cost of the test compares favourably with.that of other stand4rd~ lsbontoryy invesugauons." The gt,•en method does not specify the reagents closely enough for the cosuof consuaubles to be worked out; but let:allengc Mr, I:apurand eolle2gues.to produce artstrJtfor221p per specimen (the eurrcnt'eost of.~ eonsurvbles for a y-glutamvltransfense est.mauon tnthisdepartment):.t( full blood;count (utcludingmean eorpuscular volumc;, performed bv our hacrvtolog%- department rcprescntseven bettcr s-alime at I lp for consumables. The isolation and ideatnncauon of earbohvdnte derietenl tnns- ferrtn sS patemlimore abour intensive than cither I. 1:apun A. 4dJ'4 SS.IfoN-Q'nJ .1 . TntnDR OrMni dra,r d<n.«nu ,nwslrmn r. mart<. foe d.,MM ahw.. Br tft:.l 19a4_79a±,.it. IFAUtu.,, ~ Passive smoking and cardiorespiratory health in Scotiand S1R.-Mr David J Hole and colleagues.' when discussing results from theu prospective stud•', sutr that studies of eotirur•,e in passive smokers suggest thrtthc dose recnred maybe "equivalent to smoking up, to three eigarettes a diy," To supporn this mislhding statement they cite a solinrv study in Japan r in which unnan' cotimnc eoneentntions in non-smokers averaged g'. of those in smokers. This contrasts shatTly with evidence from CGestern , populations," which indicates thar avenge eoai.nine concentrations in non-smokers exposed to environmental tobacco smoke arc about 0-;°% of those in smokers.' Blott and: Fnumteni speculated that Japanese peoplc might have especullc hcar.^, exposure to en.iron- mental'tobacco smoke.' Other studies in Japant (and absttacts presented by S Umemun an& colleagues aad E Higashi and colleagues, inter- natiorul confercncc on indoor air quality, Tokyo, 196i ) have, however, sustained earlier suspicions- that the metliodology ' used in the original stud}= wasfaulty. Rrhen estimating passive exposure rtlarlve to ~ that from active smoking nicotine based indices are of dubious value, panlv, because nicotine in~envtronmantal tobacco smoke, unlike that in mainstream smokc, is largcJv in the vapour phase and need not be absorbed by the lunrrs,• Based' on measutments of retained pareicul4te tnalter, exposurc to environmental tobacco smoke averngesat aboun0 0590 of tAe exposure of a person wtio~ smokes 20 cigarettes each dity'-that is, 0•01 ngarettes a dar. That such tnututc doses should'elicit.observable health effects is surprising, and: epidemiologial, studies that repon associations with exposure to rn.ironmental tobacco smoke have been eriticall.• examined fou possible bias. One tmponant bias arises because some smokers den)• present orput smoking. Mr Holt andlcotleagues rrder to one of mvy papers.' but'. aruonunateiy havetotallr mii- understood how such bias arises. They statc that diffbrrnual ntesn of misclassi5cauon implc that someone ia their'double smoking group"'has to be-'more likeiyto pretend to be a non-smoker than, someone in, the single smnktnggroup." Th,s tsuntruc because rl os•erlooksthe fan thatsmukcrs tend to cohabit with smokers,. The taoie shows hov: differential mulasst.^-.:a- tion can arlsc, assuming 2% om the fndc.:sun,nts bad denied~ smoktng, The higher proporttun of smokcn (I $:6°e'p in the obsen-ed passive smoking group eompared~ w^rth the observed control group (6-g <) would ousc substantial bias for an end poim~stronglp related to active smoktng...Thusif. nskwere increased 20 times in smok'ers. and no1 bv exposure ro: environmental tobacco smokc., the relative risks: observed would be 6+90 for active smoking and; 1-7a for passive smokfnc. noc?0 and 1 rapectively, Marv studles have shown i higher ntess of denial of smoking than: assumed in the tablc,"so this source of bsas is r.id'end, important. It can explain the many, positive assocsauonsreponed in the Scottish stud.-,' most of1whtch wsn not statistically srgnlDcant. The results for lung ancer, from the Scottish studt• were based on onlj• nine deaths among xlf reported non-smokers.. This contnsts with over 2000 deaths in:other published studta. Clnrlj;, the new data contribute little to the overall iptcture. Evidence on enrtronmental tobacco smoke and heann disease hasprcctousl.'been re••tessed and considered tnconclusn•e."' Although the Scottish study reported more deaths from hcart dfsease than from lung cancer. it should not r-..a erulll affect 1lits .•iew. PN tn Suusu_-, and cwnw,cnr. Suuon.Surrr. SAL`SDA, PETERN 1EE 1: HokD11 G,1ti, CR. Chnvra. C. Ha+.hmrnr Cat., Pa- unuunt and cud,onspm- :wliM,n.a tn.<ui ttyull,an Irv tnr - ofScmtanJ. B. .tt.: ~: 19a0:9Darl.'. I: Ama u., 2ma,su<un S. Tutwuao T. 1:.unn N. r. a:. EBraa d rmven. mrnul amex<o armi:< on un,un- <amux n:rnwn mnon-. vrwl'er+: .4 E n<b J.11 , 19.+.3] c:5:432 3 IIS' DnPanm<m~ of Hn1eh anJ Human Stmcn..Th+ M.ln1. r.+..ai Rak,,i1t.,.llanlae,.l+ PuN. Hralin.S-<. 0f6c< m Smowra and Hka7tA.. 1916:10S-i. +' l-n' P\. A. H,rnv,n<.eartlaru,wn for,Br vxr<>,aed.nak of qwr. oncrr u. nan.<euukrn numrd to <molrn. In: PrmR. 3:i<k P¢"_ rd+. J,.an.. .d ..A,..n .a. 4- . t.ondoo. Sdvr*. 1911: t+ast. 5 Bta tt'J. Fnumrm:l. Paw.<v,winrand l.nr nsrr: )wrvl' ./ iai- ~'a.nu/ Qew ~ Jwu.n,ua 97n..^. o'+!9A Murnmu+tu.~riUn.<mmS.Ob1aT.Tom~uH.Eu,manmor' prnonal <zt`m,ur<.,m,eea:rc +motr .,,e: a -i, dr.ewwrd : nmo,u,e y<rwoal moemw. E r.w.w Rn 19H J5'.21 a-Z ~. 7Adltmn. F_ Scnnn G. Hdkr ~. D..Pasv.. v,watmt..\'E.rl7' .Mrs1915312:.719.._0_ t Ronw,l. AprerduaD~E•rws...ewrr!.nA+r.ar..Mr..Nanrwr rayvn+:.wd .,vtnu.4rnna..rrrtn.: aasWnn,an.: \uwnal. Ao.1M+, Prct<. 19Lm:.9.:i3:.. 9lse PN. A1~.-WuAnewr. u a fr,or m rv+•~•<:cnokant nsl. Leun 196E:u't,"10 Spnnrcr-\'<rl.a. 1911 . 11 Sa,~ n~l, Rn<.rcn Caun:T E...^-e+..•o, r.w.M.cw..+.r<ar~n^•.o+ ,.r a.va. rhrm. Q'aNinpnn. Nluona/ Aodnnn P+ess<,19{e:_S: ~f _ Donating drugs to the Third World SIR,-Asdirector of lntermrc, the organisation appros•ed by the BMA Board of Science and Education for promoting the salvacingof suitable medical aamples for use in the Th1rd u'orld^ 1 am happv : to: ansa•er the cnucumsecpressed~ by Dr Frances Grffhths.' DIIJrrrnnel wurlsnirireraon rauarcf'by 1!.:ef fndtz rubJ<cu demnnttmnA,ng: rreardlae.oJ ionoi^9w'i ~mwkine: Aebiu Ea>aure6rewF' Smokrntsu,r ofindraauo,ec, SmotmRw,r ofkolue„ee ^'Iruc:" d,a,nbuuen Pn -rc EffMfoi Ot-.d .hntna.x d<nu4 d,unDU,imrrrnot<d: Cnmroli Non»n.nwer Nonamoio 399 -,9 +25. tr! Pssu.rrmounhmn-er:nour Smntrr 205 ' ~3d. L,, It.o Sinrleanmien.$nmu[!:mn.t:nmkc:r lu9 DouDic:amrcrn SmotaSmota 199, -ib t5 = `.b dt¢nre D, Ho,c r. _... 1 Dua irom nbk I oi H - n.a Zlmnnr M•,-- n: ••., 742 B>t1J vOLzvF M !t' :E:.T_>u;t'R , (98'

54 Matswcbisa, SbionerS and Maax,noro smoking from the stindpoint of the half lifc of cotininc in the human body. For this purpose, urinary nicotine and cotinine levels of a healthy nonsmoker (one of the authors) were measured after hc had smoked one eigaratc and after he had been placed in a passive smoking environment. For our passive smoking experiment, the subject was placed in an airtight room (19.1 m=) and espose& to sidc-strcam tobacco smoke fmm a total of 40 cigarettes for 3 hours. Urine samples from 40 patients with Bucrgds disea.se were cvllocted~ (one for each case) when the patients came to our cTtnic. Each paDent's statement about aurcnt smoking status and inz~olunnn• expo- sune to smoking was trquested, at cach visit. Our clinical criteria for the diagnosis of Buerger's disease are: (1 ), hisrory of smoking; (2) onset before the age of 50 years; (3)~ infrapoplitcal arterial occhuivc disczsc;, (4) either uppcrdimb involvement or phlc- bitns migrans; and (5) absence of athcroscJtrroac risk facaora other than smoking:'Ihe clinical diagnosis of Buerger's disease was made when all five require- mcnts were mct.'•' Infrzpoplitcal obstruction was confirmed by arteriognphyin eachcase, and arterio- graphic findings such as tapering or abrupt occlusion, corkscrew or rootGkc appcarance of collarcnls, and corrugated appearance served as supporting evi- d:ncc. All of the patients had a history of smoking aforc the onset of the disease. Ar onset, the age of these 40 patients ranged from 26 to 49 vears (maan, 37 years). There uere 38 men and 2womcn. All 40 patients had been treated in our insotution for more than~ I rcar, andr their case histories were reviewed retrospectively. The initial treatments of these pa- ticnu were bypass grafting and synpatheteRomy, in 2; bypass grafting in 4, syrnpathercctom}' in 24, and medical'trcatment only in 110. The follow-up period ranged from 1 to 22 years, s~itfi a mean of 8.3 y,cars, In case of recurrence of pain at rest, ischemic ulceration, or graft failure (except early failure, less ttlan 30 days), which wcre eonfirmcd by follow-up surveillance, the patient %,ras considered clinicalli• to have "aggnvation~of the diseasc." Utinary nicotine and cotinine k,xls were derer- mined by high-pcrforrnancc liquid chromatography (HPLC) according to Mizobuchi's mcrhod` wi ti some modifications. Wc changed the extraction procedures in order to assess ven• low levels of these alkaloids. Urine samples were stored at -20° C until! analysis. Ten milliliters of urine was centrifugcd: Afrer the addition of 4 gm sodium chloride, 0.1 ml 2586 anunonium hydroxide, and 2 ml chloroform, the urine samples were shaken for 10 minutes and centrifuged at 12,000 rpm for 10 minutes. The chloroform layer was colJccted and then shaken with 5 ml1 of 0.1 N hydrochioric acid for 10 minutes and eentrifugcd at 12,000 rpm for 10 minutes. The resulting aqueous layer was shaken with 2 gm sodium, hydrochloride, 0.2 ml ammonium hydroehloridc, and 1 ml chloroform, and then centrifugcd'at 12;000 rpm. Fifty microliters of this chloroform~ layer was used for the HPLC. 1t,verage total recoveries were 98% for nicotine and 85% for eotinine. The detec- tion limits of nicotine and cotinine were 2 ng/ml and3 ng/ml, respectively. Urinary rucoanc and cotlninc values were normalized by ercatininc excretion and expressed as nanograms per milligram of ereatinine. Statistical sigrai5canct was assessod by Studeat's t test or ehi-square analysis, and the results were considered significant ar p< 0.05. RESULTS For the healthy control subjects, urinary nicotine levels were 576 ± 474 ng/mg acatininc (mcan value t standard dcviation) in the smokers, an& 5.2 = 3:8 ng/mg creatanine in the nonsmokers who did not havc perceptible involuntary exposure to -~ tobacco smoke (p < 0.01). Urinary cotinine levels for these two groups were also signi5cantly different (859 ± 814 ng/tng creatiiune in the smokers vs 5,6 :t 2.3 ng/mg cscatininc in the non- smokers, p< 0.01).. Urinary cotinine levels dis- criminated berv'eenthc smokers and the nonsmokers more distinct)y than nicotine levels. Therefore those with urinary, cotinine levels above 50 ng/rng ereati- nine may be rrgardcd, as smokers (Fig. 1): In smokers, urinary excretion of cotinine roughy cor- related to sclf-reponc&cigarettc consumption (Fig. 2). Fig. 3 shows urinary nicotine and cotnninc levels in a healthy nonsmoker after he had smoked one cigarette and after he had been exposed to side-stream smoke. Urinary cotinine elevation after active smok- ing lasted for 60 hours. The urinary cotinine level after passive smoking was lower compared with the level after active smoking, but it showed the same rise and fall as thc level after active smoking. The disappearance of nicotinc from the urine was faster than that of cotinine. Because of this, only the urinary cotanine level was used for studies on the paacnts.. Fig. 4 shows the urinary cotininc levels in patients with Buergcr's disease. All, three patients who eon, fesscd themselves to be current smokers had cotinine levels that were higher than 50 ng/mg ereatininc. Of the 37 patients who assertcdthat they were nor active smokers, seven (19%) had cotinine levels above 50 ng/mg crcatininc. According to our definition, these 2Q2:35Z1858

C 3)' . Eniir.u... wvu l0urrn.nnnnIi. \,,I 11..~ ii INh.~ Pnrt+cJ :r the I_» AII nchi, r:~rniJ EDITORIAL 1, S. IMI - /MI ("oInvrnlhi t Ivn. Pcri. mom Prr.+ PI; N'OTICE This ,-.atenal, tnay be prota .,A sy caFyrigttt ta•+ `Ti„e 1' li.S, code). Cardiovascular Risks of Environmental Tobacco Smoke The adverse effects of Environmental Tobacco Smoke (ETS) or passive smoking are being increasingly rec- oenized' bc the scientific community. The detection of a considerable number of carcinogens at significant con- centrations in tobacco smoke lej to studies on risk as- sessment of ETS. There are numerous studies on the carcinogenic impact of ETS, among them several pub- lishedi in Ens•r;•onmenr Inre>•narional. The reason for starting with carcinocenic risk was the availtibilitN of the needed methodology for carcinogenic risk assess- ment. These methods. initially developed for ionizing radiation. were applied to chemical carcinogens and physical agents, and'later on to mixtures. Despite their~ shortcomines. methods for cancer assessment have found acceptance~ by international organizations and by na- tional regulatorv agencies and' are routinelv applied in the regulaton- process.. ••In contrast to cancer assessment. the assessment of risk associated with the exposure to agents causing car- diovascular diseases is in its infancy. There are no con- vincing dose-response mod'els for these diseases and available animal models do not readily lend themsel res to a quantification of cardiovascular risks. Available data: indicates that two to three times as many people die from, heart diseases as compared to those who die from cancer. If one takes into account the age of the affected individuals, this ratio is increased to about five to sevem In other words, the population in the indus- trialized nations lbses five to~ sevem times the number of years of' lite to heart disease as compared to cancer. This issue of the Journal contains a paper on the potential risks associated with exposure to ETS. The paper by Wellk is an attempt to quantify this risk based on available statistical data. Because this paper is prob- ably the first of its kind, the editors were particularl~ concerned over the validity of the orieinal'l data. their applicationito risk assessment. and the statistical treat- ment of the subject. The editors received recommendations from three reviewers. Two reviewers recommended publication subject to revisions recommended bv them. A third reviewer recommended rejFction of the paper on the basis that the paper was too speculative. This latter reviewer did not provide any specific recommendation on how to improve the quality of the paper: Despite the "rrtixed" review, we chose to publish the paper. Given the current~ status of cardiovascular risk as- sessment. there is no doubt that the estimates provid'ed' by Wells will be less than accurate. However, there is no reasomto doubt that ETS mav be associated~ with a, considerable cardiovascular risk. ~ The role of the scientific communitti• is to provide the societal decision makers with the best available sci- entific information. The availability of the paper on the health risks of ETS will provide these decision makers and the general public with the needed information. It is not unreasonable to expect that this new infortnation will become the basis for additional'restnctions of smok- in ft in public places. A. Alan Moghissii

256 T!able 8. Summarv: Deaths per million population in U.S. from passive smoking. (based on 239.000.000 U.S. poputt+tion in 1985) . Lune Cancer Other Cancer Hean Disease Total FFemales: 1. Constant combined'relative ruk. J'.15 35.98 40.87 81.00 2. Relative nsk declinin¢ with~atae. 3;81 46,71 31.81 8?.33 3. (1J corrected for, mtsclassdicatton. 5,15 51.38 62.74 1119,27' Males: l. Constant combined relative risk. 6,72 0 7_:=3 79::5 2. Relative nsk declining with age. 6,i2 0 76.00 8'_:7_ 3. (l) corrected for misdassiGcauon. 1046 0 94.00 104.46 Totals for both.sexes: 1. Constant combined relative risk. 10.87 35.98 113:a0 I60':25 2. Reltrtive nsk declining with age. 10.53 .i6.71i 107.81 165 05 3. (1),corrected for misctassificanon. 15.61 51'.38 156:7.3 223.73 Best current esttmate, both sexes (rounded). 13 46 134 193 exposed never smokers as the referrent category rather than all' never smokers as is usually done. Another dif- ference betweenipassive smoking and direct smokinrt is that the ratio of lun¢ cancer deaths to deaths from other cancer for females or from heart disease for both sexes. is much lower in passive smoking than in direct smok- ing. These differences irt, mortality effects are probablyy real and' reflect differences in chemistry' and physics between direct, smoking and passive smoking. Environ- mental tobacco smoke is generated~ in the burning tip of the cigarette at a lower temperature than, direct smoke and therefore contains higher proportions of, complicated organic compounds that; tend to be carcin- ogenic (Brunnemann cr al:, 1978). More imponantly, (see Appendix D)' the mainstream smoke, although~ generated at a particle size of about, 0.7 µm, is very concentrated and appears to agglomerate into larger particles. Deposition rates are hieh, about, 80%. De- position occurs primarily in the mouth or in the larger airways of the lung where the particles are cleared rel- ativeiiy quickly into the mouth. This material is then swallowed.Some of it may be eliminated and produce no health effects at all or it may cause the digestive type cancers observed. Only a portion of mainstream smoke appears to remain as small particles that can penetrate deeply' into the alveolar region. Environ- mental tobacco smoke, on the other hand', is very d'ilute, with~a mass median diameter of about 0.41µm. Particles in this size range have very low deposition rates, on the order of~ 10%, but: what does deposit does so deep im the aNveolar region of the lung where clearance times are longer.. Black and Pritchard (1984) estimate that ci¢arette tar has a 117 hour half-time rate of clearance from the alveolar region, much longer than clearance times frome the ciliated parts of the lung. but much shorter than for inert particles. This means that smoke particles are very likely dissolving in the fluids in the alveolar region, and are being cleared into the blood and lymph systems for circulation throughout the body: In summary, there are two types of smoking: (a)) large particle smoking. or its equivalent, which is the major component of direct smoking. which resuits in massive deposition in the mouth, and larger airways of the lung, rapid clearance, cancers of the mouth. central lung and digestive system. and possibl v heart disease. and (b) small particle smoking. which is a minor com- ponent of direct smoking, but the entirety of passive smoking. and which results in low doses deep in the lung. slow clearance, some lung cancer, but primarily other cancers and' adverse heart effects. These differences in chemistry and physics also ex- plain, at leastin part-the rather high monality observed for passive smoking relative to the deposited dose of particulate. Smoke retention by a passive smoker is only about 1/400 that retained by a direct smoker m a 16 hour day (0.64 mg for the passive smoker per C;SSG (1986, p: 196) and 2-t0 mg for the direct smoker assum- ing twenty 15 mg tar cigarettes and 80cic retention). In comparison, the ratio of lung cancer death rates is about 1/35. For cancers other tham lung in females the ratio is about 1/7, for heani disease in females about 1. 141 and for heart disease in males about 1/3. Preliminarv calculations which are showtn in Appendix D indicate that the smoke retained deep in the alveolar region may have a dose ratio higher than 1/-100, perhaps as high as 1/60: It may be that' carcinogenic matenali that bollu- bilizes and clears from the alveoli into the blood may cause not only some of the cancers other than lung that are observed in passive smoking, but also some of the heart disease from passive as well as direct smoking. The hypothesis of Benditt and: Benditt (1973) that ar- terial'. plaques are caused by, DNA-modifying agents is receiving increasing support. See, for example. the re- cent work of Penn er al: (1986)~ on cell transforming capability of human atherosclerotic plaque DNA and the earlier work of Albert u al. (1977) an& Penn eral: (1981) on the formation of arterial plaques in cockerels with dimethylbenz(',n)anthracene and benzo(a)pvrene. Another possible factor that, might help explain the disparate mortality effects versus dose isthe le%ell of disease susceptability in passive smokers versus direcn

Adult mortality from passive smoking Table D1. Regionaliparticle deposition from mouth breathing of side stream smoke Fraction of inhaled Aero- Relative particle mass deposued` dvrta i V l M m c diameter Cube of Relative o ume (Weight) ass Distribution mouth trachro• µm diameter eonantration' per 0.liam , 'ii throat, bronchial alveolar 263 F1ass deposited as r~ of totall mass inhaled' 0.20 .008'. 1.5 0.006 0.3 0 0 0.13 0.0a 0.25 .016 6.5 0.051 2.4' 0 0 0.1?' 0:29 0.30 .0.7 10I0, 0.135 6A 0 0 0.115 0:74 0.35 .043 13:0 0:280 13.2 0 0 0.108 1 43 0 40 .064 13.01 0;i 16 19.6 0' 0 0.10 1.96 0.45 .091 6.5 0;296 14.0 0! 0 0.105 1.41 0.50 .125 3.5 032S 15.5 01 0 0.11 1.71 0.60 .216 1.25 0.270 12.7 0 0 0.115 1 .4b. 0.70 .343 0.5' 0.17~_ 8.1'. 0 0 0.12 0.97 0.80 .51L 0.25 0.128 6.0 0 0 0.13 0_78 0:90 .729 0.05 0.036 1.7 0 0 0.14 0.24 1.00 1.0 0 0 0 0 0 0.15 0(K) :.1!18 99.9 11.08 •From Hiller rr a!. (19821. Fig. 1., 'From ~Hevder (1984).,Table 1. 250 cm'fsecond mean flo%% ' rate. 4 second breathing cvcle. This domination of the rate difference model by the Jap• anese study is evident from some rouch death calculations. Use of the combined rate difference (5;a x 10") with the exposed female population from Table A4: (30.6 million)) yields total deaths of L6fi2 compared with 9.768 calculate& from the constant rate ratio modell VJhen the rate differences are plotted against age of death~and weighted accordinglv it is found that the "westertr " rate differences increase sharply with age whereas the Japanese rate difference stays constant at about 4 x 10'. Constructing a weighted average of these ••western-' and ' eastern" death rates for each of the 5 vear age ranges and multiplying h}• the corresponding exposed pop- ulations yields a total of about 2.100 deaths compared with 7.602 in the second relative risk modell Use of the Japanese data alone vield's about 1.200 deaths. Use of oniv the "west- ern" data (Gillis er al.. 1994: ',Garland ei . al.. 1988: Helsing ett al: ) at a constant, rate difference yields 7,950~deaths while use of "western~' data with the rate difference van•ine with age yield5 about 30.000 deaths. Thus. the death caltulations using rate differences are quite vofatile, Also. it is evidentt that with the rate differences it is not feasible to carrn- over the "eastern° experience. in ischemic hearr disease at least, for use in a"western" setting.. Accordmglt. it' was concluded that the absolute risk model' is not as suited to combining risks for passive smoking asthe relative risk models. Table D3: Regional ~ particle deposition from nose breathing of sidestream smoke. Aero- i Fraction of inhaled particle mass deposited" Mass deposited as K of total mass dynam c Mass diameter distribution mouth ttachco- inhaled µm % . nose throat bronchiai alveolar nose alveolar 0:20 0:3 0 0 0 0.19 0.00 0.06 0125 2.4 0.005 0 0 0.172 0.01 0.41 030 6.4 0.01 0 0 0.155 0.06 0.99 0.35 13.2 0.015 0 0 0.13R 0.20 1.82 040 19.6 0.02 0 0 0.12 0.39 2.35 0.45 14.0 0.03' 0 0 0.11-2 0.42 1.70 ~ 0.50 15.5 0.04 0 0 0.125 0.62 1.94 0.60 12.7 0.05 0 0 0.1_R 0;6,t 163 0.70 8.11 0.06 0 0 0.13 0.49 1 05 0 80 6 0 077 0 0 0 0:13; 0!46 (1!Rn', L . 0.90 . 1.7 . 0.093 0 0 0:137 0!16 0;23 #" 1.00 0.0 0.11 0 0 0:1a 0.(10 0,(uiI ~ 3.45 1'_.99 °From Table D1!. ~ "From Hevden(1984). Table 2. 250 cm',second'mean.OoM rate. .4 secondbreathtng cycle..

Adult mortality from passive smoking Table A5: Annual l' S. male heart deaths from passive smoking Neversmoker D R Exposed P Relative Risk Constant at 1.31 Relative Risk f A eath ate 000 100 opulation (Tabl A1) E Declining ge o Death per . (Table A3) e , T000's xcess D.R. Deaths RR Deaths 35-39 20 3815 4.9 187 5.2 780 40-44 36 2980 8.9 265 3.0 879 45-49 68 2440 16.9 41!1 1'.9'- 929 50-54 128 2660 32.11 723' 1.42 951 55-59 237 2155 59.8 1289 1.28 1_'01'. 60-64 412 2051 105 2157 1.28 2009 65-69 730 1695 189 3195 1.28 297. 70-74: 1]50 1099 304 3341 1.28 3103 75-79 1850 633 500 3162 1.28 2933 80-84 2950 249 819 2039' 1.28 1887 85. 4700, 31 1377 565 520 Totals 521 19420 89'3 17335 181t.s (1966) were taken as 2.3 for, males and 2.0 for females.. The excess risks were reduced by 2/3 to vield relative risks for misclassified ever smokers of approximately 1.4 for males and 1.3 for females. These were used worldwide with V4'ells' un- published formulae to calculate the false heart disease relative risks shown on lines : of Table 5. Appendix B Relatrt.e risks for all'causes of death, and for emphrsema and chronic obstructive lung disease Data relating all causes of death with passive smoking for: females have been reported for four prospective studies to• talltng 9537 cases as shown in Table B 1. The combined relative risk is 1.165 with 95% confidence limits of 1.11 to 1.22. The onlv male data available are 75 cases from Gillis et aL (1984)) with a relative risk offl 1.0 so no male analysis was made. The calculation of the total number of female deaths from all causes for passive smoking is shown in Table B2. The total., 3a.1641. is considerably larger than the total for cancer plus hean of 19.359 shown in Table 7. Some of the difference is due to uncenainties in the ealculations, but other causes of 261 death that might contribute to the all cause total. based on data in a pnvate communication from Dr. Htravama. are cerebrovascular disease, other hean disease. diabetes. and ulixr. Hirayama (private communication. also reported preli- minarilv at 5th World Conference on SmokinQ and Health. Winnipeg. 1983)provides data relating deaths from emph.- sema with passive smoking in womem Hisrelativr risk. based on 106 cases is 1.3 with 95rir confidence limits of 0:85 to'_.05. Kalandidi'et a!_ (1987) report incidence data for chronic ob• structive lung disease based on 103 cases with an adjusted relative risk of about 1.4. Lee er aC (',19861 report incidence data for chronic bronchitis from spouse exposure Based~on 17 cases the adjusted relative risk is 1.22. A,wetehted a%eraee of these three relative risks would be about 1.3i. The only neversmoker death rate we have is from Hammond (1966) for emphysema at 2 x 10-`. Assuming 76 r exposure. the excess death rate for passive smoking using Eq. (2) would be 0:55 x 10'5 and the total deaths for an.exposed population of 30.61million would~ be about' 170. Even, if this number iss doubled to take into account deaths from formsof chronic far obstructive lung disease other than emphysema. it u stillT below the total for cancer and ischemic heart dtsease. Table BL. Female relative risks for all causes of death from passive smoking. l All Exposures Mantel Trend Locale Tota Cases RR 95% C.L. 1•tail p Cohort Studies: Hiravama (1987) Japan 9106 1.17• 1.12=1.23' 0:(ItKK)1i Gillis a at.' (198t), Scotland 102 1.45 0.91-2.30 Garland et a!. (1985) California 79 1.06 0.65-1.73' Vandenbroucke et at. (1983)" Holland 250 0.79 0.57-1.09' Combined Chon: 9537 1.165 'Dr. Hiravama (private communication):provided the data necessary to calculate these items., 'Data from 25 vear follow up: Relative risk w•asA!89 (0.50-1.62)ifor 1,5 vear follow up. This stud% is weak in,that exsmokmg women,were tncluded among the "nonsmokers." and nonsmoking women,exposed to exsmoker husbands were included in the "nonexposed " The weakness of the study, is emphasized in that the smoking women had a lower overall death rate (33.a'~/rYthan thc nonexposed nonsmokers (38, l1: )_

176 Letien to :De .dita+ Table 1. Statietieal sianificence of risk valaes for lung eaecer in ralatiaa to spomal smoking. lnMesticatcr Not Statistically SiGniflcint Ststistically tiQ:_:.ilc__3 nt Male Feaale Y.al e Eeaale , •Chan and Funq (1982) 0.75 •8uffler et al. (1984) 0.50 0.78 DalaqEr et al. (1986) (1.00 *Kabat and Yyndrr (1984) 1.00 0.79 Gao et al. (1987) 0.9 • =Gillis et al. (1984) 1.00 •Lee et all. (1986) 1.00 Gao et aL. (1987) 1.1 • Shifiizu et al. (1988) 1.1 •Gartinkell (1981) 1.17e •Pershaqen et al. (1987) 1.20 Yu at al. (1985): 1.20 •Lee at al., (1986) 1.30 •Garfinkel, et al. (1985) 1.31e •Akiba at al. (1986) 1.80 1.50 •Koo at all. (1984) 1.64 Drovnscn et al., (1987) 1.68 Sunble et al. (1987) >1.80 1.80 •Correa et al. (1983) 2.00 2.07e •Hirayiea (19811) 2.=5 1.63 Las at al. (1987) 1.65 •Tri:hopoulos et al. (1981) 2.11 •Gilllis et al. (1984) 3.25 • Risk valuu from Table 12.4, Naa;onal Academy of Scieaoes Report (1996) a E:posuss in aduli life. b Exposure is childhood. c Sutistically ai8nificant aseda is aoe or more data sobasta witlie the study. There remains, however, the fundamental question of the quality of the individual underlying studies whose data are under consideration. Many of the epidemiological studies assessing the risk of lung cancer from spousal smoking have been criticized for a variety of methodological flaws and weaknesses, especially with regard to the potential for misclassi- fication (Oberla 1987; Batter et al. 1986; Lebowitz 1986; OTA 1986)6 Misclassification of subjects is a source of error where patienu claiming to be never smokers are in fact current or exsmokers. Wells conceded the likeli- hood of 5% misclassi6cation. But misclassification of smoker status has been found at levels from 10% to 40% (Schwartz et ai. 1988; Weiss 1988). NAS noted the likelihood of misclassification and lowered iu estimate of the elevated risk to 25% from 349,, but it failed to indicate whether the lower value was statistical]y significant. (NAS found the combined risk from American studies a 14% increase, which was not statistically significant.) Misclassification of disease can also be a source of error. There was a marked potenciaP for misclassi- fied disease in the studies having statistitally signif- icant risk ratios in the NAS and Surgeom General's reports. In Hirayama'e study of Japanese women, his 1984 report suggests that only 21 of the 200 lung cancer cases (10:3%) were histologically confirmed, while tlfe Surgeon Gsneral's report states that'none' were verified. Akiba et al. (1986) studying survivors of the Hiroshima and Nagasalti atom bombings, noted 43% of the lung cancer cases had not been histolog- ically confirmed. Weiss (1988) notes that 'thirteen percent of the cases (in Garfinkel's study), proved on review not to involve lung cancer'. 202 33 511884

260 A 1 %Le11s Table A3. Development of 1984 neversmoker, heart death rates versus age. Death rates from Hammond (1966) Age at enrolltd age Range per100.000, Females:. 1984 1984 wNeversmoker Decline. Fraction Neversmoker Hammond's heart in heart of,deciine Death Rate N.S. D.R. death rate DR's 11 due to as x of1963 corrected by age of 1963-83 smoking (smoothed) for decline death 35-39 71 49 3.5 _' 0! 48 0 . 40-44 14.1 55 7.7 4.4 45-39' 20:.3 ' 60! 12.2 10.2 37 0 50-54 35:5 63 28.7 23 55-59 104 64 66 51 01 60-64 243 64 156 113 65-69 475 64 304 240 37 0 70-731 %f 64 615 480 75-79 1648 65 1072 870 35 0 80183 2774 70 1942 ' 1550 85+ - 21 0 79 - 2770 .Ncles 35-39 T 76 0 20 48 50. 40-44 79:5 77 61 36 45-49 85.5 78 67 68 42 50 50-54 220 77 169 128 55-59 397 75 298 237 37:5 ?5 60 -6s' 741 75 556 412 65-69 1089 76 827 730 32' 25 70-74 1936 76 1472 1150 75-79 2639 77 2021 1850' 25' 10 80-84 a'373'. 81 3343 2950 85+ - 1.4 10. 86 - 3700 (Hi'rayama. 1984a): The 5% of ever smokers who were as- sumed miscliissified as never smokers were assumedito consist of 239e light current smokers and 77% long term exsmokers. The excess risks for currenr, self.reported smokers were re- duced by 2/3 to yield~ relative risks for misclassified current smokers an& by 11/12' for relative risks of misclassified exsmokers essentially as was done by Wald er al: (1986). This resulted in misclassified ever smoker relative risks of 2.4. and' 1.85 for males and4emales in the U.S. and U.K. and 1.5 and 1.25 for Japan. Worldwide misclassified smoker relative risks were then calculated to be 1.8 for males and 1.6 for femalesbased on the proportion of "western" and "eastern" cases. The false relative risks shown on lines 2 in Table 5 were then calculated using the formulae in Welis' unpublished work. For female cancer other than lung. the smoker relative risk of 1.05 was taken from Hammond (11966) and used as is since the effect is too small to make any difference. For ischemic hearr disease the ever smoker relative risks from Hammond' Table A4. Annual'U. S. female heart deaths from passive smoking. Relative Risk Relative Neversmoker Exposed Constant at 1'.23 Risk Death Rate Population Declining Age of per 100:000 (Table 6) Excess Death (Table A3) 1000's D.R. Deaths RR Deaths 35-39 2.0 5781 0.38 22 4.0 91 i0ii.t 4.4 4252 0.84 36 2.0 97' ~ 45-49' 50-51 10.0 23 3423 3355 1.91 4.4 65 148 1.32 1.17 85 114 ~ 55-59' 51 3495 9.8 3" 1.17 :65' ~ 60-64 1,13 3238' _2.1 713 1.17 548 . .~ 65-69 70-7.1 240 480 2912 2030 17.7, 97? 1385 1973 1.17 1.17 1062 1505 IiA 75-79 870 1472 180 2647 1.17 2010 80- 8a 1550 517. 33+t 1828 11.17 1374 ' ~ 85+ 2700 100 607 607 1.17 J51 ~ Totals 291 30595 31.9' 9768' 7602

264 A J MctIA Table D3. Smoke Particle deposition patterns in direct and passive smoking Direct Smokintt Passive Smoking Direm, Passisc Entry site Particulate inhaled per day. me. Mouth :a0 tiose 2.8 86 Particle Size inhaled. µm 0 7 0.4 Particle size exhaled.,µm 07 04 Retained in nose, 5r 0 3.5 Retained in mouth. i7', 25 0 Retained in tracheerbronchial reaion. % 35 0 Retained in near alveolar reeion_ % 19 0 Retained in deep alveolarregion. 4c 9 13 Totallretained. °k 90 16.5 Particulate retained. total. mg. 192, 046 177 Particulate retained. alveolar. mg. 48 0.36 133 Particulate retained. deep alveolar. mg. 2-1 0.36 61 Appendix D Dose considerarions As noted in the text. there is a wide difference between the observed'disease ratio between passive and active smokers and the ratio of cigarette smoke particulate retained by, each. Also, the cancer sites appear to differ. On the assumption that part of these differences may be due to differences in deposition sites between passive smoking and active smoking, calculations were carried out to try to pinpoint these differ- ences. The calt:ulations for passive smoking are reasonably straightforward. Stober (1984) has summarized all the uncer- tainties in this type of calculation. Nevertheless, the best ap- proa& appears to be to use the data of Hiller et al. (1982) for the particle size range of side stream smoke, centering around 0:4 µm, and the mathematical lung modellof Heyder (1983), for inert particles. Integration of these two data sets yields a distribution of deposited weights by particle size for mouth breathing (see Table D1) which. when summed: vields exactlv the total': deposition observed by Hiller et al:. (1982) indicating that the Heyder modeliholds for passive smoking. The same inhaled particle size distribution camthenbe applied to Hevder's nose breathing case (see Table D2) which yields nasal deposition of 3.5c%e and deposition in the alveolar region of the lUng of 13:04c. The model predicts zero deposition for both the mouth,throat and the tracheo-bronchial regions. From the depositiomcurves of Gerrity er aG (1979) (Fig. 2) for iron oxide extrapolated to a particle size of 0.25 µm.(which is eq uivalent to an aerodynamic diameter of 0.4 µm ) it appears that all of the lung deposition from passive smoking probably occurs deep in the alveolar region at generation 19 or beyond. Black and Pritchard (1984) have determined the half-time for alveolar retention for direct cigarette smoke to be 17 hours indicating that the smoke particles dissolve and clear into the blood or lymph system. There is every reason to believe that the passive smoke particles clear the same way. With direct smoking there has so far been no model de- veloped'that explains the observed phenomena, namely that the inhaled particle size is about 0.7' µm, that 70% to 809c of the inhaled smoke is retained, that 15 to 359'e is retained in the mouth, and that the exhaled~panicle size is also about 0.7 µm; The Heyder modeli at 0l7 µm, would predict total retentiomof only 12%. To achieve 75% retention, the Heyder model would require an effective particle size of 6.5 µm, Main streamismoke is knowmto agglomerate. but if it agglomerated to 6.5 µm, the exhaled' smoke. according to the He.der modeli, would be about 6 µm, much too, large compared to that observed. Mitchell (1962) observed that direct smoke particles grow in the mouth to about 1.15~µmi and that the smoke exhaled from the lung after a S second retention period had a mass median diameter size of 0.65 µm. Let us assume that the 0.65 µm part of'the smoke follows Hevder's model an&thar209c of the total smoke inhaled was exhaled', all from the 0;65 µm fraction. The inhaled part of the smoke corre- sponding with the 0.65 µm part exhaled would have the same particle size and would deposit about 12%. deep in the al- veolar region.. This is 1'217c of 22.7ro of the total smoke in- haled'~ or 2.7% of the total inhaled smoke. The balance of the inhaled smoke (77%) would have a larger average particle size„about 1.3 µm. Black and Pritchard (198-1)lfound. based on clearance data, thatthe rates of alveolar c+eposition to alveolar plus tracheo-bronchial deposition, in, direct smoking is 0.36. Also, as noted, some amount, say 25% of the total inlet smoke should deposit in the mouth and throat. all of which would have to come from thislarger size fraction.,Sum- marizing these numbers, of the 100 -'0 -'5 = 55cc of total smoke particulate that reaches the lun¢ and is non ex- haled, 0~64 x 55, = 35% deposits in the tracheo•bronchial region and 0.3& x 55 = 20% deposits in the alveolar region, We have already accounted for 3% of the alveolar deposition from the 0:65 µm particles. The remaining 17% would come from the largerparticles.,Based on the alveolar/tracheo-bron- chial split and using the curves of Gerrity er al: (1979) it would be expected that about 2/3 of the alveolar deposit or l1,rr, would deposit in the "near° alveolar region, generations 16- 18, and 6% in the "deep" alveolar region., generations 19- 21, for a total "deep" alveolar deposition of 9%. These cal- culations are summarized in Table D3. Just what the mechanisms are for so much direct smoke deposition remains unclear. Certainly impaction and sedi- mentatiom(thc Heyder model) do not account for it. Stober (196-t)isuggests that electricallcharges in the newly generated smoke particles (see Melandri er al:, 1983) mav aceounv for some of it. Another possible mechanism is the cloud settling phenomenon as described by Fuchs(196J). Whatever the mechanism, a reasonably clear idea of the regionalI deposition patterns from direct and passive smoking

262 ge Range Nevetsmoker Death Rates (rom Hammond (19661 at enrolled age per T00.000 35-39 136 .t0-4t 178 45-49 254 50-54 352 55-59 561 60-64 867, 65-69 1492 70+-74 2585 75-79 4790 80-8s 8J08 85+ - A. J Wells Table B_. Annual US. female deaths from all causes from passive smoking. Decrement due to heart death rate 1963-84 per 100.000 Corrected Neversrnoker death rate at enrolled age per 100.000 3.6 132.4 6.4 17;1'.6 8.2 245,8 16.8 335:.' 38 523 87 780 171 13211 346 2239 576 4214 832 7576 -- - Totals Deaths per million total population Lee er al: (1986) report data on chronic bronchitis life long nonsmoking in males exposed,to a smoking spouse. Based on nine cases the ad)usted relative risk was 0.34. However. for general' exposure (a' cases) a positive relative risk was ob- served. No analysis of these data was attempted. heversmoker: death rate t d P l9 io F Relative Risk Constant at.1.165 correc e to age of death per 100.000 opu t n exposed 1000's raction of population exposed Excess D R. Deaths 120 5781 0,94 17.1 991 155 J'-s, 0.92 21.2 9a-t 212 3323 0;89' 30.5' Ioi-t 300 3355 0.87 43.3 la5'_ 445 3495 0.81 6-t15 _254 675 3228 077 98':8 31901 1070 2912 0.70 1583, .1609 1830 2030 0.59 275.2 5596 3250 1472' 0:49' 496.1 7303 6000 547 0:29' 9-t-t.8 5168 10!000' 100 0.10 1623 1623 30595 1]1 7 31]6-t 143 Appendix C Rate difference mode!'for assessing female ischemic hearr deaths from passive smoking A rate difference or absolute risk model was investigated for female ischemic heart disease in order to compare it to the relative risk models in ability to translate experience from one type of culture to another. Female ischemic heart disease was chosen because considerable data exist and because heart disease is the largest contributor to total deaths. Also. the relative risk model seems already to be welCestablished for lung cancer (Wald ct al:. 1986; Blot and Fraumeni. 1986) so a comparison~in another disease category appeared to be ap- propriate. Data from the four: cohort studies (see Table 4) were com- bined using the direct pooling equations described on page 183 in Rothman (1986). The two case/control studies were omitted. Although their combined rate difference was essen- tially the same as that for the cohort studies, no good way could be found ao combine it with that from the cohort studies. Death rates for exposed and not exposed populations were obtained by dividing the observed deaths in each category by person years which were equated to the mid-point populations multiplied'bythe years offoll'owup. The rate difference was then obtained by subtracting the nonexposed death rate from the exposed death rate. Vanances and weights were calculated by Rothman's formulae., The combined rate difference was obtained by summing the weighted rate differences and di- viding by the sum of the weights. Confidence limits (95%): were equated',to the rate difference =1.96 (variance)°=. The results of these calculations are summarizcd'in Table Cl. The cohort data were also combined using Program 7 of Rothman and Boice (1982) ,', with results essentiallv,idemical to those shown in Table C1 for direct pooling. The relative heterogeneity of the relative nsks ('RR) vs.,the rate differences (RD) can be approximated; by considering the range of RR- 1 versus the range of RD: The range of RR-1 is from 0;16 to 2.6 for a factor of. 163. The range of~ the rate differences is 3.7 to 262 'or a factor of 71. The ratio for the two large studies, Helsingeral: (1988) land Hiravama (1984b), for RR-I': is 0:2d" 0.16 = 1.5 and for RD is 20.7/3.7 = 5.6. The 95"c confidence limits for the rate ratio combination is tighter than for the rate difference combination_ ,#lso, the Hiravama study dom- inates the rate difference aggregation muchlmore than inithe rate ratio aggregation. providing 64% of the combined weight (last column of Table Cl) in the rate difference case vs. only 17 0 of the combined weight in the rate ratio case. Table C1. Rate difference c alculations for fe male i schemic heart disease. T Relative Risk from Table 3. Rate difference x 10'' Wn¢hts fo RD ~ RD x ~ h otal Cases RR 95% C.L. RD 95Pr C.L. r x 10-" weig t x 10- yN~' Cohort Studies: Hirayama (d98sb) 394 1.16 0.9- 1.4 3.7 -2.1- 9.6 11110 41 a Gillis er al. (19fi3) : 21 3.6 0.9-13'.8 169.1 30.7-307.6 2 31 Garlan&er al. (1985) 19 3.5 0;9-13,6 262.2 36.0-188.4 0 & 2.0 Hetsin¢ n a!: (19681 988 1.25' 1.1- 1.4 :0:7 -0.2- 41.6 88 IR.2 Combined Cohort 1522' 1.23 1.1- l.l 5 1 -0:2- 11.1 1201 65 0 ~

Adult mortalitv from passive smoking 259 Table A]. Annual U.S. male lung cancer deaths from passive smoking Rtlative Rtsk , Constant at '_.1 Age of Death Neversmoker Death'i Rate per 100.000 ~ Nonsmoker Population 1000's Fraction Exposed Exposed Populatton 1000's Excess Death Rate Deaths 35-39 1.8 ~ 5156 0.71 3815 1.09 42 40~-44, 2.9 ' 4136 0.72 2980 1.78 53' 45-49 4.5 3477 0.70 2440 2.80 68 iI 50-54, 7.01 3431i 0.66 2260 4.46 101 55-59 11 3423 0.63' 2155 7.15 154 60-63 16, 3489 0.59 2054 10.7 219 65-69 23 3150 0.54 1695 15.9 269 70r74 33 2443 0.45 1099 24.3 _'67' 75-79' 49 1712 0.3' 633, 38.3 24_°' 80i84 72 921, . 0.27 249' 61.1 15'' 85 - 95 516 0.08 41 96.0 39 Totals 15.9 31844 0.61 19420 8.26 1606 Appendix A Derails of death calculations Tables Al and A2 show the details of the death calculations for male lung cancer and female cancer other, than lung and are similar in all respects to Table 6 in the text except thart no d'eelining relative risk calculation is shown for male lung cancer since the evidence that was available (Hiravama. 1984a) indicated no suchAecline. In Table A3 the details are given for the development ofi the never smoker relative nsks for heart disease that were use&in the death ~ calculations. As noted in the text. the 1963' neversmoker heaR' death rates by 5-year intervals were ob- tained~bv dividing the never smoker coronary heart deaths in HammondTs (1966) appendix. Table 14, by the person years in his appendix tables 2a and2b. Reduction factors to account for the change in heart death rates between 1963 (end ofHammond7s study) and 1984 were then developed by 10:year age intervals from the age specific heart death rates in table 24 ofiHealth U.S. 1986(NCHS.1986): These reduction factors were modified for the fractions thought to be due to smoking which were taken from~a staff report of the Office of Tech- nology Assessment (OTA. 1985) to yield a combine&never smoker reduction factor. interpolated back to 5-vear age in- tervals. for application to the Hammond never smoker death rates. These modified rates. which are forenrollment age and therefore about 2 vearsyounger than age of death. were then, plotted~ agairut age of death on semi.loe graphipaper. Treli lines were then drawn through the female and the male points to yield the values in the last column of Table A3. Tables A4 and A5 are simply the details of the heart death calculations as in Tables 6. Ali. and'A2'for cancer. The deaths shown in Table 7 resulting from the corrections for misclassification were calculated from the relative risks in lines 4 of Table 5 taken as constant over the age ranee. The modification of the observed relative risks for smoker mis- classification as shown in Table 5 are based on misclassified smoker relative risks calculated as follows. Based on as vet unpublished work of Wells on misclassification it was assumed that self-reported current smoker relative risks for male and female lung cancer in the U.S. and U.K. were 11 and 7. and 4'.6 and 2.7 for male and female current smokers in Japan Table A2. Annual U.S. female deaths from cancer other than lung from passive smoking. Exposed Relative Risk Constant ati 1.16 Relative Risk f Neversmoker D R Population T bl 6 E Declining Age o Death eath ate per 100.000 a e ) ( 1000's. xcess Death Rate Deaths RR Deaths 35-39 28 5781 3.9 22.5 4.5 13211 \V 40-44 48 . 425'- 6.7 285 29 14'11 © 45-49 80 3423 11!.2 383 2 0 1--t9 ~ 50-54 125 3355 17.6 589 1.56' 1579 55-59 190 3495 26.8 937 1.30 1591 60-64 265 32-18 37.7 1219 1.18 1352 V1 65-69 355' 2912 5711 1487 1.12 11" ~ 70-74: 470 2030 68.7 1395 1.08 729 75-79 600 1472 89 0 1310 1.05 4'?1 ~ 80-a4 750 547 114.7 627 1.034 138 ~ 8-S* 900 100 14117 142 1.0:21 20 ~ Totals 256 30595 28.1 8599 11165 '

EA.uowwrwr kurwar.owal, YaL 16. pp: t7S-193; 1990 Prumad m tbe l'S.A. AL r&hu e..erv.d A.W. l2),~{ ~75-179.1`~`liL LETTERS TO THE EDITOR AN ESTIMATE OF ADULT MORTALiTY IN THE UNITED STATES FROM PASSIVE SMOKING; A RESPONSE Dear Edi'tor- The health implicatintts of environmental tobacco smoke (ETS) remain controversial. Neither the pub- lished reporu nor statements from public health of- ficials and agencies have resolved the question of ETS health effects, nor are they likely to in the near future.. A. Judson Wells' paper, 'Estitnate of Adult Mor- tality in the United States from Passive Smoking" (1988) is yet another effort to draw scientific verity from a reassessment of published' epidemiological data. But this new look does not change the quality or meaning of the existing evidence, which remains equivocal. Neither does it substantively support the author's statement that exposure to ETS 'can have adverse long term health effects that are more serious than previously thought'. The conclusions of nonsmokers' increased risk of lung cancer from ETS exposure found in the reports of the National Academy of Sciences (NRC 1986) and of the Surgeon General (USSG 1986) were based on epidemiological studies-tbatproduced a wide range of findings. The relative risk (RR) values summa- rized in Table 12.4 of the NAS report ranged from 0.50 to 3.25, with 17 out of 20 risk estimates (for subgroups by sex) lacking statistical significance. In seven additional reports since the NAS docu- ment was published, relative risk values ranged from 'c1.00' to 1.65, with only the latter being ststisu- caIly signifitant. The RR values from aTl 29 sub- groups in the 20 studies included in the NAS repon plus those published later are summarized in Table 1 herein. All of the epidemiological studies that comprise the data base for estimating nonsmokers"rislt of lung cancer in relation to ETS are actually estimates of association based on spousal smoking. Im not a single study was either exposure to ETS or retained dosage determined. A few studies have attempted' to estimate OItD-4 1aY90sJ00 •DO Coqynght 01990 Pcrsamm Prsar pIc pQTiCL rMq fhAtstial tr.ay 66 ~Ww ~ c°eyrrgnt yprr (1o~ U U.S CoCel, the degree of exposure to spousal smoking in terms of hours per day or total years of exposure, but none of the studies measured ETS exposure in objective and quantitative terms or even estimated ETS expo- sure with any degree of reliability. Proximity to a smoker sittiag across the dining table does notpermit an estimate of the nonsmoker's exposure to ETS, which will vary according to room volume, ventila- tion rates, the physical and chemical changes in ETS as it ages., and other factois that influence the con- centrations and duration of ETS exposure. A spouse's smoking in another room or in another building can have even less or no significance at a1J, in assessing the possible role of passive smoking on a subject's health. It should be reeognized, also, that association can never, establish causality. At best, association can only suggest the possibility of causality. Feinsteifl (1988), discussing public alarms based on epidemio- logieal studies, recently pointed ouc<hat'a causal suspicion is supported if aM impressive statistical'. association appears in the 2 by 2 tabulition for sub- groups of people reported as being exposed or non- exposed, diseased or nondiseased'. There are many ways to look at data and try to draw meaning from the aggTegation of values. After deciding that the 13 studies which survi~ved critical assessment did not, individually or collectively, tup- porta definitive conclusion on the risk of lung cancer in relation to spousal smoking, the NAS Committee performed a meta analysis on the aggregated' dau, leading to an estimated risk increase of about 34% for nonsmokers married to smokers. This estimate has been questioned on a variety of grounds by a number of investigators (Letzel et al. 1988). It can be argued that even if a first order relation- ship does notexistbetween diseue and passive smok- ing in the epidemioCogical studies, the data used by Wells are the best evidence available. And it can be argued tbat even the array of values shown in Table 1 is not impressive in the sense that Feinstein specifies, there are other ways of testing the data, as has been done by Wells. 173

Lattsn to tbe editor Misclassifrcation of exposure can be a source of uncertainty in studies that attempt to find exposure- response relationships. There is little basis for con- sidering estimates of spouses'smoking to be reliable. Pron et al. (1988) concluded that "test-retest esti- mates of reliability [over a six-month time span] would suggest that misclassification of such expo- sures may be extensive". Vogt (1977) found"twenty- two percent of persons gave differenranswers on the two questionnaires (on the number of cigarettes smoked per day] given about an hour apart". Among the variety of flaws and weaknesses found in the various epidemiological' studies on ETS and lung cancer, it is worth noting the age bias found by Ahlborn an&Uberla (1988) in Hirayama's study and their conclusion that "the risk increase ... disappears completely when one removes selection bias by age'. Oberla (1987), highlighting the weaknesses of the epidemiological studies comprising the NAS data base, bad earlier concluded, `False plus false does not: equal trite.` In addition, most of the epidemiological studies have fai9ed'to take into account significant confound- ing factors in assessing lnng cancer risk in relation to ETS. Many risk factors for lung cancer have been identified, including exposure to heavy metals, or- ganic chemicals, combustion by-products, natural and man-made radiation, diet, and nutritional status, per- sonal health history, emotional, and psychological factors. Holst et al. (1988)' recently reported signifi- cantly inereased' risk in relation to keeping pet birds and to reduced vitamin C intake. Gao et al. (1987) found no significant increased risk for Chinese women in relation to passive smoking or type of employment but did rind significantly increased risk in relation to previous lung disease, cooking practices„and shorter menstrual cycles, reflecting hormonal factors. Some of these factors may act independently, but many may interact. Any attempt to assess the role of one factor must take into account all other relevant factors. None of the epidemiological studies on spousal smoking took into account confounding factors other than attempting to matcb cases with controls by age,, residence, and general socio-economic status. Of the 20 epidemiological: studies, those by Huayama and by Lam et al. (1987) have the two largest number of lung cancer cases, with the increased risk in both being statistically significant_ Both studies are of Oriental populations, which suggests that many fac- tors like cooking practices and fuels for cooking and heating should have been controlled. All of the studies included in Wells' Table 4, on which he based his estimate of heart disease deaths related to passive smoking, similarly fail to consider the confounding effect ofthe many cardiovascular disease risk factors that have already been estab- lished for thatdisease. Some observers have commented that increased~ risk of lung cancer from ETS exposure seems implau- sible because the ETS components are so dilute in ambient air comparet to the concentrations of these substances in mainstream smoke. In addition, it has been found that nonsmokers retain far less of inhaled ETS than active smokers retain of mainstream smoke. Wells noted that'smoke retention by a passive smoker is only about U/4Xthat retained by a direct smoker in a 16 hour day'. This ia more than one order of magni- tude;reater than Rickert's calculation (1988 ) thatnon- smokers exposed to ETS retain about 1/8000 the amount of particulate matter retained by the active smoker. Lee (1988) cited estimates of the same range: 1/5000 for males, 1/10 000 for females. All of these estimates are probably on the high side, since none of the studies appears to have considered the chemi- cal and physical changes that occur as ETS ages and the losses of ETS through evaporation, fallout, and deposition over time. Other observers have commented on the implausi- bility that lung cancer in nonsmokers might be caused by ETS. Aviado (1988) noted thatn.one of 17 constit- uents of ETS 'designated as suspect carcinogens ... [has] been adequately shown to cause pulmonary cancer via inhalation in animals'. Crawford (1988) noted that 'no atypical cellular changes have been found in the lungs of nonsmokers'. Lee (1987) con- eluded 'that exposure to smoke conatituents of non- smokers is too low to explain the moderate increase in risk of lung cancer seen in epidemiological studies in self-reported never smokers masricd~ to smokers.. This increase in risk is much more plausibly ex- plained by misclassification of smokers as nonsmok- ers thanm by a direct effect of passive smoking'. Wells has attempted to make his calculation of annual deaths from exposure to ETS appear more reasonable by comparing it to the larger estimate of Repace and Lowrey, but their estimate has been se- verely criticized because the controls were Seventh Day Adventists (SDA) whose life style is so radically different from that of the non-SDAs married to smok- ers that the comparison is considered inappropriate (OTA 1985; Balter et al. 1986; Oberla 1987). Taking these and other factors into account. Gostomzyk (1986) concluded, following the Interna- tional Experimental Toxicology Symposium on Pas- sive Smoking in Essen,,FRG, that 'even toxicology has not been able to ascertain with any greater degree

Adult mortality from passive smoking smokers. The median age for passive smoking death from: lung cancer for males is 66 and the deaths con- stitute 0.006rc per year of the exposed populationt The first 0i0069c of male smokers have died of lung cancer~ bv age 46 at which age the lung cancer death rate is doubling evera four years. At~ age 66 the smoker lung cancer death rate is doubling about every 13 years. In other words. in passive smoking deaths we are dealing with only the very most susceptible people, whereas in direct smoking most of the victims are much, nearer average susceptibility. Similar considerations apply to the other diseases here discussed. A qNestion often, raised, is that direcn smokers are also passive smokers. so why do theynot get the passive smoking related cancers. We have already pointedioutt that the use of nonexposed never smokers as the re- ferrent, category for smoker relative risk would increase the apparent risk for smokers. Another possible expla- nation is the probability of competing risks. Most of the highly susceptible direct smokers would have died in their forties or fifties from smoking related disease and would not be available to die of.passive smoking relatedl disease initheir sixties or, seventies. The passive smoking mortality calculated in this study. namely.46:000. mav be lbw: Repace and1owrey (1985) calculate lung cancer deaths from pa$sive smok- ing at, 4.665: or about 50% higher than our estimate.. primarily because of'postulated intense exposure atthe workplace: a factor not taken into account in this study since the relative risks are based largely on home ex- posure. If Repace and Lowrey are eorrect, the higher exposure would lead to corresponding increases in deaths from heart'disease and other cancer. Also, only ischemic heart disease is consid'ered' here. As the all cause data in Appendix B indicate, other cardiovascular diseases and diabetes may be sensitive toanvironmental tobacco smoke and may increase the total deaths. The new epidemiological studies on passive smoking support the earlier ones and indicate that not only lung cancer. but other cancer and heart disease are serious problems. In fact, lung cancer appears to be only the tip of the iceberg. To be on the safe side public health policy should be to protect nonsmokers from environ- mental tobacco smoke. Arknowledgrmenrs - The author is grateful Ito Dr. T. Hiravama for his data on mdi.idual cancerisites and for the detailf of his "all cause" daaa. to R W. Wilson of the U.S. National Center for Health Statistics for, data on the smoking status of U.S. residents bv 5 year age inter- % afs. to L. Garfinkellfor the person years in his 1981 study- to J. M. Samet fon data on male lung cancer in the New Mexico studc: to R. C. Brownson for male lung cancer data in the Colorado study,:,to P. Buffler for hen33- year.data, to StrJohn Crofton for,abstracu of Lam er at. (1987) and Geng rr a!. (1967). to P. Reynolds for the numFerof cases in their studN on femalecancere the number of lung cancer cases. and their qttalitative results on mates. to D. P.' Sandler fornonsmoker data on breast cancer. and toS. C. Hunt for enough data from Manin er al: (1986a) to calculate an a11-exposure relative risk, confidence limits and a weighting factor. The author also wishes to thank James Robins. N. A.Dalager. Ji M Samet. VV.JL Blot. L. C. Koo. A. H Wu. G. Pershagen. D. P. Sandler. D. Trichopoulbs and J. L. Repace for helpful correspondence and'~discussion. 257 References Akiba. S.. Kato. H.. and Blot. 1A' J(19k6) Passi%e smoking and lung wncer, among Japanese women Cancer Res 46. SMU4-i807. Alben. R. D.. Vanderlaan. M.. Burns. F.. andititshazumt. !s1, 11977) Cancer Res 37. 223'-2.^35. Balin. B. J. Broadwell. R. D.. Salcman. M.. EI-Kalhng. M (1996) Avenues for entry of, penpheralh administered protein to the central nervous system in mouse. rat. and squirrel monke). J.' Camp Neurol 251. 26U-38p Bcnditt. E. P. and$endttt. 1. M(1973) Evidence for a monoelonal' ongin,of human atherosclerotic plaques. Proc N'trrl'Arad Sci 70. 1753-175ti. Black: A. and Pntchard. J. N. (1984) A companson:of the regional deposition and short termiclearance of tar particulate material from cigarette smoke. wtthithae of 2:5 ,µm polyst.rene mtcro- spheres. Aerosol Sci 15. 22;'-227. BIbP. W. J. and Fraumeni. J. F. (1986) Passive smoking and lung cancer. J Nar Cancer lnsr 77: 993-100(/: Brownson. R. C.. Reif. JL S.. Keefe. T. J.. Ferguson. S K:. and Pntzl! J.,A. (19871 Risk factors for adenocarnnoma of the lung. Am J Epidemio! 175.,25-34. Brututcmann. K. D.. Adams. J. D.. Ho: D. P S,. and Hoffmanm. D (1978) Theinfiuencesoftobaccosmokeon indoor atmospheres 11. Volatile and tobacco specific nttrosamtnes m mam and sede• stream smoke and their contribution to mdoor polluuon. in Pro- eecdings.4th Joint Conference on Sensrn¢ o( Ent)ronmenral Pofluranu. New Orleans. Louisiana, 1977. American Chemical Societ}. Washington. D.C.. 876-880. B'uffier. P. A.. Pickle. L. W.. Mason, T. J.. and Contant. C. (,198..t) The causes of lung cancer in Texas. in Lung cancer: Causes and preveruion., M. Mizell and P. Correa. eds.. pp. 83-99. Verlag Chemic International. New York. Chan. W. C.. Colbourne. M. J.. Fune. S. C.. and~Ho. H. C. (1979) Bronchial cancer in Hong Kong 1976-1977. B. J Cancer 39. 182- 192. Chan. W. C. and Fung. S. C. (1982) Lunc cancer in non- smokers in Hong Kong. in Cancer campargn. Vol 6. CancerEp- ulemrolbgr_ E. Grund'mann. cd'.. pp. 199-20'. Gustav Fischer Vertag. Stungart. New York. Correa. P.. Pickle. L. W.. Fonahan. E..,Lin. Y.. and Haenszel. 1ti': (1983( Passive smoking and lung cancer. Lancet ii. 595-597. Dalager. N'. A.. Pickle. L, W:. Mason. T. J.. Correa. P.. Fontham. E.. Sternhagen. A.. er a!. (1986) The relation of passi.e smoking to lung cancer. Cancer Res 46. SR(18-4R11 . Fong. P. (196?) The hazard of'cigarette smoke to nonsmokers. J. Bioi: Phts L0.,65-73:, Freidman. G. D.. Pentti. D. B.. andBawol. R'. D. (1983) Prevalenee and correlates of~passive smoking. Am J Public Health 73. 301- 4p5. Fuchs. N. A. (1964) The Mechanics o/Aerosols. pp. 46-49. Mac- millan. New York. Garfinkel! L. (1981) Time trends in lung cancer mortality among nonsmokers and a note on passi.c smoking. J A'or Cancrrlnsr66. 1061-1066. Garfinkel. L.. Auerbach. o;. and~Jouben. L. (1985). fn>.olirntan smoking and tung cancer: A case control stud5. J,1.'ar Cancer Inst 75, 463-itS9:. Garland. C.. Ban•ett•Connor. E.. Suarez. L.. Criqui. M. H.. and Wingard. D. L. (1985) Effects oL passive smoking on ischemc hean disease tnonality of nonsmokers. Am J Eprdsmeol 121. (.45- 650. Geng.,G. Y.. Liang. Z. H.. Zhang. A. 1'.. and Wu. G. L. (1987. 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IEO 1966-79 and 1980-82 data are totally inconsis- tent and statistical, tests confirm the highly sig- nificant (p<0.001) interaction between relative risk and period of follow-up. A possible expla- nation might be that the 1981 dara, but not the 1984 data, were standardised' additionally for occupation,, but if this was important, why did Hirayama not standardise for occupation in 1984? The Maryland prospective study (Helsing et al. 1988); which reported a 24% increase in heart dis- ease risk in women, based on 988 deaths, andd a 3196 increase in men, based on 370 deaths, in relation to living with a smoker, has a number of features that should be considered when interpreting the data. No attempt was made to follow-up people moving out- side Washington County, thus presumably missing large numbers of deaths. No dose-response relation- ship was reported~ Adjustment for age, marital status, years of school and quality of housing had an enor- mous effect on relative risk, changing estimates from 11. 117 to 1.31 in men and from 0.66 to 1.24 in women. No direct adjustment was made for household' size, despite the fact that the larger the household, the more likely it is to contain a smoker. Furthermore, no direct adjustment was made for the possible correla- tion of household size with various coronary risk factors. Also, data were unavailable on a whole range of factors, such as diet and exercise, which might differ in families with and without smokers. In short, several potential confounders were apparently not controlled for. Wells does not consider the problem of publ'ication bias: This may be particularly acute for heart disease. After all, it is a vastly more common disease than lung cancer in nonsmokers, but the numbers of deaths in Wells' tables are only slightly greater. The possi- bility can surely not be excluded that other researeh- ers, perhaps with much larger and better data bases, have looked at the relationship and found nothing. The data for cancer other than the lung are even less convincing than for heart disease. In view of the much greater passive smoke exposure of smokers than nonsmokers, observations that nonsmokers ex- posed to passive smoking have increases in cancers at sites not increased' in smokers seem to me to suggest that something is wrong with the epidemi- ological studies. And, indeed, the paper showing the strongest association ('Sandler et al. 1985) is open to a number of serious criticisms (Lee 1985). Wells, however, remains content to include all epidemio- logical studies in his meta-analyses, regardless of quality, and attempts to explain obviously spurious relationships by an unsupported, and implausible hy- Leneri to the edieor pothesis, involving an especially, susceptible group of individuals who all die early if they smoke but die later by passive smoking if they do not. Mortality patterns for lung cancer in terms of age, dose, and duration of smoking are in fact weU described by models involving no component for variation in sus- ceptibi4ity at all. Wells' estimate of 3000 lung cancer deaths per year based on the epidemiological data contrasts with that of 12 by Arundel et al. (1987) based on exuapo- lation using relative amounts of particulate matter retained in the lung by nonsmokers and smokers. As I argue at length elsewhere (Lee 1987;,1988a; 1988b; 1989a; 1989b), it is far more plausible to conclude that the associatiom observed between lung cancer an& exposure to ETS arises predominantly because of bias than it arises because of a carcinogenic effect of such low doses of ETS. Misclassification of smokers as nonsmokers is likely to be a major source of bias in most studies and is one for which Wells' correction is totally inadequate. He does not allow at all for the possibility of misclas- sified current typical regular smokers, whereas a re- cent summary of data from~ large studies shows an average rate of about 4% (Lee 1989a), Nor do his calculations take into account recent data (USSG 1989) showing much higher relative risks in active smokers than in older studies. Preliminary calcula- tions based on these data suggest that the total num- ber of lung cancers occurring in self-reported never smokers in the U.S. may have been substantially overestimated. Rather than 12,000 the figure may be nearer 8000. If reasonable corrections are made for misclassification, the figure of lung cancer deaths among actual never smokers may be less than 6000. Wells considers his overall estimate of 46 000 deaths conservative. I disagree, When better data are avail- able, it may prove to be about 46 000 too high. Peter N. Lee P. N. Lee Statistics and Computing Ltd. Surrey. United Kingdom REFERENCES Arandei, A.; Starting, T.; weinkam, J. Never smoker 1nng canoer rieks from eiposors to particnlate tobacco rmoi{e. Baviron. Int 11:4Q9-426; 1997. Garland, C.; Banau-Connor, B.; Saarea, L Cnqai, M. H.; Winaard, D. L. Hftecu of paaeive emoldng on iiehemic hean diYeaes monality in nonrmoken lirina with emoken. Am. J. BpidemioL 121:643-63Q; 1995. 2023511.SS9

64-.1'~ risk 1 2'[p-8, lr8]p. These findings suggest that smoking is a more potent risk factor, for the most~ common fotan of ischaemirst7oke than has previously been appreciated. The persistent nature of the risk even after cessation of smoking and the possible risk associated with passive exposure strengthens public health arguments against smoking: Introduction TriE clinical ipimzre of stroke can be produced'by several pathophpsiological mechanisms,, the most importartt of which are atherothrombotic brain infarc[ion,,intracerebral haenorrhage, and subarachnoid haernorrhage. Before the development of rntnputerised tomography (CT), the diagnosis of tutdiSereatnated "srroke" was often tontaminated~ bv other causes of acute, focal neurological deficits, such as cerebral neopl9sm, subdural haematoma, and cerebral abscess. Furthermore, the discrimination between pathophysiological subrypes was difficult. CT sca*+n+*+g; now established as a routine diagnostic procedure in musz deveioped countries, provides an accurate and non-invasive means of subgrouping stroke n•pes. Risk factors for stroke have been identified in c•arious epiderniological studies. Most were carried out before CT becarrte available and attributed'hypertension and ageing ass the primary antecedctts.t-1 Cigarette smoking, which~ is associated'With atheroma generation elsewhere in the body,, has been less consistatth• implicated as a major risk factor for stroke, although the latest studies have shown a more convincing association.y' Our aim, was to examine the risk relation between cigarette smoking and subnpes of cerebral ischaemia whose pathogenesis is related to atherosclerotic change in major cranial and ea-[recranial! blood vessels. The hypothesis examined was that, without the possible diluting efiect of crrebral haemorrhage and other non-th.romboembolic causes of stroke„ the stroke risk associated: w•ith cigarene smoking would be greater than that reponed'previousl}• and that there may be subgroups t<ith ver}' high risk. We also took the oppornutin' to examine the effects of' stopping, smoking on any obsen•ed' risk for cerebral ischacmia„ together w-ith any independent risk which may be attributablt to smoking among other famil}', members. Patients and Methods 1:urse-intervieus ide:nti5ed cases of acute cerebral lisciiaettia in four major hospitals serving the nonh-eactem region of Melbourne betu•ern 1985 and 1986: These hospitals manage mostsuch cases in this area, the exception being the very old, who maybe managed at home, in smaller private hospitalsy or in nursing homes. , Patients wcre enrolled in the study if the clinicrl'evcnt was thei.r first episode of cerebral ischaemia. Patients who died were included in the study by interview of elosest relatives. The duration of cerebral ischaania was defined to rartge from 24 h or, less (tnnsient isehaemic anaek [T1A]) to a permanent defioi (cerebral irtfarcrion): There was no age restricoon for study entry. CT scans were carried out on 98% of ases Kithin 10 days of hospital admission:,'Phose who did not receive CT scans were elderly, in a moribund state on admission, had cerebral isehaemia diagnosed on clinical grounds by the srunering runue of the progressive deficit, and died shortl}• afterwards. Patirnts in whom cerebral haemorrhagc v.as shown on CT were excluded from the study: Patients were asked to take pan in a study of previous diet and lifestyle factors. A sauctnred questionnaire was used to record i.nfot•mation about personal characteristics, habits such as agarene smoking, alcohol consumption, past dietary and ncerasc pracvices, and medical history (including that of treated hypenension). A TtHE L4NCET;,SERTEXtBER 16,,1989. detailed' list of current and past drugs was used to validate information about medical histon. The section of the questionnaire about smoking sought information on current mnsumpuon, prnious consumption in decades, npe of cigarcnc, dgar„or, pipe smoked, anddegree of inhalation. The time since stopping smok:ng was recorded in periods,of'' years and then 5 years from the 19sr ogarene to increase the rctiabiliin of rerrll. For the effects of passive smoking among other family members, patients were asked whether mother, father, or spouse smoked as many as I cigaren e per day for z long as 1.xar and, if sa4 what was the highest number smoked regularl}•, for as long as I'. ynr. The laner was recorded as agaretta per dav in amounts of 10:. Controls were matched indnidualli•y b.•y age (:t 5 ycars) and scx and were identified by knocking on doors in the same sveet (according to a strict protocol) until a household with a matching inditidual frec of prnious cerebrovascular disease was found. When an identified control was absent from the household„the intenie.a•er returned on at least two fizrther occasions to anempu contact. About 10% of identified eontrold refused to paniapate or could not be contacted and in these cases the next suitable ncighbourhood control was choset: Each case and matehing control were inteniewed'by the same nurse-interntiewer. Otth 1°Sb of cases refused interview. In approairnateh 20°.0 of cases eomtnunication was restriczed and the closest available relative was intrnieu•ed;, the closest available relative ofl the matdied control w•as, inteniew•ed' to avoid information btas. Most patients were inten-iewed while in hosptal, but about 5% were imerviewed at home because of rapid discharge from hospital. The relative risk of cerebral ischacnua was estimated for subjem in various categories of smoking histor}., with the group who had never smoked as the reference eategon. Ittitiall};, unadjusted relative risks were nlcvlated with paired data and'then potcttiall}- confounding variables were oontrolled for by means of a eondioonal logisnc trgression model.' Estimates of'the relativ.e risk associated with smoking were then made for the tarious categories of'cerebral iscliaemia with con-ecvon for hfpertension and the small'residual effect of age. Dcfinizirnu Snurkm; carcgnrics.-Vre d'eftned an ever smoker as a person who smoked at least I cigarene, dgar„or, pipe pcr da) for at Itast 3 months at some period during his or her life. a current smoker as a person smoking at least I cigarene, cigar, , or pipe per da\ for the preceding 3 months. and'an ex-smoker as a person who met the mieria for an ever smoker, but had not smoked for the preceding 3 months. The ategor~ never smoked'included people who µ ere not current smokers and'who did'not mee; the m-iteroa for er-smoker or ever smoker. Ce+ebral ischacnna was defined as acute onset of a fi Eal neurological deficit in which CT snn excluded causes other than cQebral isehaania; the duration of ischaemia could be 24 h or less (TIA), or longer than 24 h (cerebral infarcuon). Lacvnar nwdra.nr was acute onset of one of the five recognised lacunar syndromes' (pure motor hemiplegia, ataxio hemiparesis, dysarthna clumsy hand s}ztdrome„sensorimotor suokc, and puroe sensory'stioke) in whieh CT had excluded und'crlying ouobral hae7norrhage: ln many cases the site of infarction was idennfied on CT scan, but this w•as not an absolute req µiiement for classification as a lacunar s.mdi•ome. , Tlrronllwmbnliu mfarction was defined as acute onset of focal neurological defiat with documentation of the site of utfarcvon on CT scan in either cerebral hemispheres or hind brain, in which the mechanism of infarction was attributed to large vessel exmaanial onintncrrtval vascular disease. Ca>diac embnlic cerebral infarczirn, was the acute oncet~of a focal neurologica) deficit in which the site of infarnion, had been docvmented' on CT scan in the pre~ence of atnal fibrillation, myocardial i infarction within the preeedi.ng 3 weeks, or, eirdiomyopatliy. In some cases cerebral angiognph}° or non- invasive studies of the octr2rnttial arculation were done to help exclude carotid occlusive disnse as a causal meehanism„but this %t15 not an.absolule requlremenL

ta 258 Helstng. K.1'.. Sandler. D! P.. Comstoek, G: W.. and Chee. E. (1988) Heart disease mortality in nonsmokers iiving with smokers, Am J Epidrmto! 127. 915-9:,2. Heydcr. J. (;1984); Studies of particle deposition and clearance in humans. in Probinns oJlnhalarorn Toirnn Studies P.' Grosdanoff', er al:, eds.. pp. 155-180:,MMV-Medizm-Verlag. Munich. Hiller. F. C.. MeCusker, K. T.. M'azumder.14. M. K.. W'ilson.l. D.. and Bone. Rl C 1198'_1 Deposition of stdestream dagarette smoke in the human respiratory tract. Am Rcv Resp Dis 1ZS. 406-408. Hirayama. T. (198aa)'Cancer mortality in nonsmoking women with smoktn¢ husbands based on a large-scale cohort study in Japan. Prev Sti<cd 13. 68(1-690 : Hiravama. T. (1984b) Lung cancer in Japan: Effects of nutrition and passive smoking.,in Lung cancer: Causes and prn•enrion: M. Miz- cil. P. Correa. eds.. pp. 175-195'. Vtrlag Chemie Intemational, New York. Hirayama. T. 11987) Passive smoking and cancer: An epidemiological review: in Ganm. Monograph on Cancer Research' 33. Japan Sei: entific Societies Press. Tokyo. pp. 127-135. Humble. C. G.. Samet. J. M.. and Pathak. D. R. (1987) Marria¢e to a smoker, and lung cancer risk. Am! Pub Heallh' 77, 598-602. Inoue,:R. and Hirayama. T. (1987. November) Passive smoking and' lune cancer in women: Paper presented'at the 6th World Con- ferenee on,Smokmg and Health„Tokyo. Kabat. G. C. and Wvnder. E. L. (1984) Lung cancer in nonsmokers. Cancer 53: 1214-1221. Kabat.,G. C.. Diech. G. S,_ and~Wynder. E. L. (1986) Bladder cancer in nonsmokers. Cancer 57. 36?-367. Kalandtdi. A.. Tnchopoulbs, D.. Hatzakis. A.. Tzannes. S.- and Saracci. R. (1987) Passive smoking and chronic obstructive lung disease.. L'ancer u. 1325-1326., Knoth. A.. Bohn. H.. and Schmidt, F. (1983) Passivrauchcn ala Lun, genkrebs-Utsache bei Nichtrauchennnen..Wedianrschc Klinik 79. 66-69: Koo. L.,C:. Ho. J. H. C.. Saw. D.. and Ho. C. (1987) Measurements of,passive smoking and estimates of litntt cancer, risk among non- smoking Chinese fbmales. InrJ'Cancer39. 162-169: Lam. T. H.. Kung, 1. T. M.. Wong: C. M.. Lam: W. K.. Kleevens, 1'. W, L., Saw. D:. rr al: (1987) Smoking, passive smoking and histoio¢ical types in lung cancer in Hong Kong Chinese women. Br J Cancer 56: 673-678: Lam. W: K. ('1985) A clinicaf and epidemiolbttical study of carcinoma of lungcancer in Hong Kong. M:D. thesis. University of Hong Kong. Hon¢ Kong., Lee.:P. V.. Chamberlain. J.. and Alderson.M. R. O9861;Relationship of passive smoking to risk of lung cancer and other smoking- associated diseases. Br J Cancer 54. 97-105. Martin. M. J.. Hunt. S. C.. and Williams. R., R. (19g6a, October). Increased incidence of heart'attacks in nonsmoking women mar- ned to smokers. Paper presented at annual meeting of Amencan, Public Health Association. kfartin. Nf. J..,Svendsen. K. H., and Kuller. L. H. (1986b. March) Nonsmoking men marned to smokers are similar to nonsmoking men married to nonsmokers.,Paper presented at the 7th Annual Meetin¢: Society for Behavioral Medicine. !vtelandn.,C:. Tarroni. G:. Prodi. V.. DcZaiacomo. T.. Formignani. M.. and Lombardii C. C. (1983) Deposition of charged particles in the human airways. J Aerosol Sci 14. 657-669. Nfiller. G.H. (198a)iCancer. passive smoking and non-employed and employed wives. WesrJMtd 140. 632-635. Mitchell: R., 1. (1962) Controlled' measurement of smoke particle retentioniin the respiratory tract. Am Rev Respir Der86, 526- 533. .>,. Jl Wells NationallCenter for Health Statistics f1986)', Health United States 1986: U.S. Dept. of Health and! Human Services. Public Health Service. Hyattsville. MD. 106-109, National Research Council (1986) Environmental tobacco smoke. measuring exposures and assessing health effects. National Acad, emy Press. Washington. D.C. Office of Technology Assessment (1985) Smoking related deaths and financial costs. Office ofTeehnologc Assessment.L'.S. Congress., Washington: D.C. Office on Smokm¢ and Health (d979-851 Bib- liographv on smoking and health. U.S: Public Healttii Service. Rockville. MD. and Smoking and Health Bulletins after 1985. Penn. A.. Batastiiti', G.. Solomon. J.. Burns. F.. and Albert. R. E. (1981) Cancer Res 41. 588-592. Penn. A.. Garte. S. J.. Warren. L.. Nesta. D.. and Mindich. B. (1986) Transforming gene in,human atherosclerotic plaque DNA. Proc N'ar Acad Sci $3. 7951-7955. Ptrshagen. G.. Hrubec. Z.. and Svensson, C. (,1987)',Passii+e smoking and lung cancer in Swedish women. Am J Epidemiol,125., 17-2a.. Repace, 1. L. and Lowrey. A. H. (1985) A qµantrtative estimate of nonsmokers' lung cancer risk from passive smoking. Environ lhr 11. 3-2-1: Reynolds. P.. Kaplan. G. A.. and Cohen. R. D (1987. June):Passive smoking and cancer, ineidence: prospective evidence from the Ala• meda County study. Paper presented at the Society for Epde• miologtc Research. Amherst. Massachusetts.. Rothman: K. J_ and Boice. J. D: (1982) Eprdenuologac Analvsu with a,Progr'ammablt Calcularor, pp. 5-17. Epidemrology Resources, Chesnut Hill. Massachusetts. Rothman. K. J. (1986) Modern Epidemrology: pp. 139-1)37, 184-190. Little. Brown. Boston. Russell. M. A. H.. Jarvis. yl. J.. and West. R. J. (1986)4;se of urinary nicotine concentrations to estimate exposure and mortality from passive smoking in non-smokers. Br J Addicnon 81. 317- 323. Sandler. D. P.. Everson. R. B.- and Wilcox. A. J. (d985) Passive smoking in adulthood and cancer risk. Am J Epiderniol'121. 37- 48. Sandler. D. P.. Everson. R. B'.. and Wilcox. A. J. (;1986);Ci¢arette smoking and breast cancer. Am J Epideamiol 123. 370-371. Stober. W. O984);Lung dtmamicaand uptake of smoke constituents by nonsmokers-a survey. Prev Med 13. 589-601. Svendsen, K. H.. Kuller. L. H.. and Neaton. J. D. (1987) Effects of passive smoking in the multiple risk factor intervention tnal: Am J Epidemiol 11r6. 783-795. Trichopoulos. D.. Kalandidi. A.. and Sparros, L. ('1983) Lung cancer and passive smoking:,Conchttion of the Greek study. Lancer ii. 67'7-678. U:S. Surgeon General (1986) The health consequences of in- voluntary smoking, a report of the Surgeon General. DHHS (CDC): 87-8398. U:S. Public Health Service. Rockville. Mary• land. Vandenbroucke„ J. P.. Verheesen. J. H~ H., deBruin: A.. Mau- ritz. B. J.. Vanider Heide•Wessel. C., and Van dcr Heide. R. %f. (1984) Active and passive smoking in married couples: Results of 25 year follow up. Br .Ned l 288.,1801-1802. Waldi N. J!. Nanchanal. K.. Thompson: S:, G.. and Cuckle. H. S. (Q986) Does breathing other people's tobacco smoke cause lung cancer' Br Med J 293. 1217-1222. Wtlls, A. L(1986) Misclassification as a factor, in passive smoking risk. Lancer u. 638;. Wu.,A. H.. Henderson. B. E..:Pike. M. C.. and Yu. M C. 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THE LA.NCET, SEt`rEJ+iBER' 16, 1989 patients in ~v.•hom stroke was due to atriallfibrillation in our studyl6o'years, compared with'64 }+ears for the remainder), and the fact tlian smoking is not a risk factor for this rhythm disturbance." A signi5cant risk differential with age for smoking and stroke has not beea shown in previous studies, although, in a meta-anah•sis of all known' published studies on smoking and stroke, a signifirantl}• reduced risk with increasing agc w'as showrt." In view ofotu findings, and''the fact that pathophpsiologica] subgroups of stroke were not' classified in most of'the published studies, this effcet in the meta-analysis may well be due to the unrecognised presence of elderly, paoents: with' atrial fibntllazion~ as a saoke mechanism. In other, words, there may nonbe an age effect in patients with cerebral infarction due to exvacraniali or intracTanialluascular disease. The persistence of' the risk of cerebral ischaemia for at least.l0 years after stopping smoking was surprising; since in the two cohort studies that addressed this question,66 the risk was found to return to that of never smokers within 2-5 years. However, in both those studies the number of patients who actually stopped smoking was much smaller and no' distincoon was made between cerebral haemorrhage and infarction in this parnof the ana]ysis Since the knowTt effeets of smoking on plktelet adhesiveness. fibrinogen levels, and blood viscosin• are reversible within a short period„it seems likely that atherogenesis causes tlte petsistence of risk as well ac the maj,rr par, of nsk as'sociated with current smoking. Trie presence of' a smoking spouse appeared to be an independ'ent risk factor for cerebral ischaemia when all patients (smokers and non-smokers) were included in the analvsis. A positive dose-response effect was observed~ for this tisk with the number of cigarenes smoked by the spouse and the risk was more evident when cerebral ischaemia'due onlv to exnaeTanial or intracranial vascular disease was anal}•sed. However, for non-smokers alone, there was a similar but non-signifrcant increase in tisk perhaps because of the restriction to fewer matched pairs in the analysis. Considering these two anal}tioal methods together, it appears likely that passive smoking has a small effect. Since passive smoisrtg is novw such an important social!issue, and has been shown to be a risk factor for non-smokers for other diseases19 our, preliminary findings on this subject cerrairtly warrant further studS'. ThisseudJ.vissupponed by agant:.6om the TobaccoResorch Foundaoon of AusQalia. Corrapondrnrr should be addressed~ to G. A. D., Deparvriclt of t+ieurolog.%-, Austin Hospi~talJ Hadelberg, Vinoria )084; Ausmlia.: REFEREI:CES. 1, WtusnamJP, Fissvbbons JP, Kialvd LT4 S.yrr GP Natssral'IslsxaryW of koote inRorhenserMumesosa, 19M5.Ouou0 1954. Snoke 1971;2: 11-2-1 . 2: Kacsne1 R'B; D-ber TR,. Soorlie P, Q'ol( PA. Cmipasmrs of blood bressure arsd nsaaf astserosbromtiooc ,rsfanaa;: tlsc Fr.rnvs{riam -dy. Sna4e 19 -,6, 7: 327-31 3.: Boruo R, Scraay R, S~A, Jadsm R, Besydwk R. Cprenr smoCr4and nsk of psvrsaner.e saote m snm and'+.vsssa, B.. M.d) 1986; 2f3. 64'. l. Abbon RD, Ym Y, Reed DM, Kanutiito Y: Rak ofaookem mak aprene.nsdse:. N,Eart J ,Md 198tr:315: 717-20. 5. Colditx GA, tlaw R, Sompfe MJ, et d..Gpreetr.amksK and :ruk ofavute in m.ddrr-,a.e ..on>m: N sWr)<M.d 19ea; 31c 937-a1 6. S`o1f PA, D'lyw9no RB, KarundWB, Banso R, Belaastier AJ. Gprenesrrokcst as a nsfc fanot.for.evke. The Frmnrspnm, Seudy, JAMA:1988, 259: 1025-'-'9. 7. G-enck PB, Rod. MB, 1-W-brrt P. H;Q De, CasuPn J. ¢ xly .16oboi aasesanpuon, eprenr smokusland the rnk of udsonic mole~ sauloof a numnovl sssdy .r tlwa suti.n e,edsd im,ress oe Quo{0. 11Ltsoss : A•aso/cd.1989, 39: 339-d3 . 8Heeslb.•.fi•E,Da.,\'E Staosuolme[ISOUta sna>Q,on reaearU;,.al1'.Theanalyusof mrmnvvlsnd,eLycxi~ Insenvoanal Ataseyfor.R-arch on Can¢r, 1980. 24F79: 9. Fn6er Cl-i.lacvsar. snota od ,rJarns~ a mve... h•.voLty.1982; 32: B i 1 -76. Referrnats tontwaed cf Juot of isess tohonn 647 PERCLTA,ti'EOUS CORONARY EXCIMER LASER ANGIOPLASTY: LNTTLAL CLL'`'ICAL RESULTS K. R. KARsaa K. K. HAASE M. MAUSER 0. ICJCR4TH' VZ'. VOELICERS. DUDA, L. SEIPEL Medua! Chmc, Department of Cardia/M, Eberiiard-Kvrls.Umzarrsiry, Tficfngen, Fedcrad Republic of Gmna>r.) Sumsnary A novel 1 3 mrn diameter laser catheter, consisting of 20ieoncentric 100 µtn quartz fibres around''a central lumen for a 0 35 mm flexible guide wire, was used to ablate atherosclerotic tissue in thirty patients with coronary artery disease. The laser catheter was coupled to an excimer laser delivering eaergy al a wavelength of 308 nm and a pulsew-idtli of 60' ns. The primarv , success rate was 90P7o (27 of 30 lesions): The mean (SD; percentage stenosis fell from 85 (15)% to 41 (19;°.0' afier.laser ablation, In ten'paDents the lumen diameter after laser, angioplastv'w•as considered sufficlenty but subsequent balloon angioplast}• was earried' out for the other t.venrc patients. Failure to pass the lesion was caused by vessel kinking in two patients and a total occlusion in one patient. No complications directly attz•ibutable to laser ablation, such as vessel wall perforation; occurred; one disseevon occurred but had no clinical sequel9e. There was one earli• reocclusion and death in'a patient with triple vessel'disease and unstable angina, probably as a result of plaque rupture after balloon angiopl9sty. These results are encouraging and' justif<<'funher clinical investigations. Introduction PERCLTA.`.'EOtS transluminal coronarti• angioplastv has been widely accepted as treatment for coronary anen- disease." Resrenosis, however,, greatlv limits the clinical effime}• of balloon angioplasty:''' The use of laser energy transmitted through' flexible fibreoptic fibres may be a possible adjuna or alternative to:eonventional angioplasn•; because it removes atherosclerotic tissue or thrombus bs- vaporisation tather than by stretching and'fracturing of the stenosis as in balloon angioplasry.6" In-vivo studies have shown not only greater efficacy of laser-heated probes but G. & Don?:A>; A.~,'D o7HFJts REFERF1:cES-conrint.ed 11),.Nehu P, Meho J. Elfecn of snsokvs`.m ptaoeka and on pluns. Nsombo>:ane-pronacvdsn baLnae m man. Pruuqflmas5wr L+sJa.nenv Med I981. f. 1il -50 . 11. Dsnrefass L. Eknnnn of'b4nud'wsman) , sgiti-epnon of trsdaUs; haenuinmi val,re and fsbrusqen kvels m cyareese snnim . Mrd J A,u+. 19^. S, ,61:-:0 , 12. Raws RL, MryeJS•,Sto..TG„Mond. KF, Hardenbera JP, Zud;RR. Cip+enr msoksn` d- mebral.blood tlk- wairaevyune.med hsY for aaukc.. JAAf.t 1983: 25D. 2796,800 13.McGJIHC Posessoslsnediausrn for, theaupnmooon of'aNerosdneass.avsdadseaoscknaocdunse E.' espsenr snsnkulQ An.m .M.d1979, a: W-~403 11. KanndWB, MeGs DL, Cissdfi WP' Lanesc.penpeev.e on oprenevssolorrt vsd ordsovscWardueasr sfrc Frasnsny}sarn 5nsd5, 7 Ca^d.u- RihoMl 1984. a. 26:--, 15.. HugtnanC'G. Musn JI, Ganod A Jnsemunem ctaudsaoon, pmalena.and nsY 4nura. Br M.dy 1976,1 1379-A:1 16.:Kavuset WB,.Abbem RD, S..Ke DD. Mt!tiansva PM'. Epdmuokpe femsrn of mronuacW, Gbrill.nar., tre Frvsws/tumStudl A'N tlr(J Mrd.198=. 30n: 301&22 1' Gvsdofpfio: C, Caponneno. C, t><J Senr M, Sanm,lon D, CUrt C Rnr fanon, u:YcvnarfpndforMSw a su mnnol snud). Ar4: A'rmd Stmd 1988, 77: =-26. 18 SbsrnonR,Ber.enG M~-whsisofrt4oorsbesreoinearenrsnroWavsdsaok'r B+ Md J 1989, 278: 7N9-W ', 19Fwldirii; JE, Pfsaw.K1 , HdN eltecv of n.oiununssrsulisr,a.'.• EKt7 Mrd 19N6, 319-.145'--59'

l.ettert to tl>e editor - N 0 T 1 C E 149 This material may be pfvtetted by copyright law (Tilr, 1' 111.S Crd-' Pron, G: &.; Burch. J. D.; Ho.e„G.R.; Miller, A.B.'1Le reliability of passive smoking histories reported in a ease-eontrol!study of lung cancer. Amer. I. Epidemioi. 1i27:267-273;,1988. Repace, J. L; Lo.my, A. H. A qaantiiative estimate of nonsmokers' lung cancer risk from passiva smoking. Eaviroa. lat. 11: 3-22; 1985. Rickert, W. S. Some eonaidenttions when estimating exposure to environmental tobacco smoke (BTS) with particular reference to the home eavironmeat. Can. J. Public Health 71eS33-S39c 1988. Schwartz, S. L;, Balter, N. J. ETS-lunB cancer e" 'oloBY: supportability of mirdksei6cant and risk u ons. In: Perry, R.; Kirk, P.W., eds. Indoor aad [ air quality. Loadon: Selper Ltd.;1988: pp. 159-1 . Shimisu, H. et al. A u ntrol study of lung eancer in oonsmok- ia8 .romea T J. Bxp. Med. 154:389+397; 1'988. Tricb ; Kalt<ndidi, A.; Sparros, L; MacMabon, B. 1.ane cer and pasdve smoking. 1at. J. Cancer 27:1-4; 1981. Oberla. K Lung cancer from passive smoking: hypothcn onm- viaeia8 evidmceT lat. Arch. Occup. Envimn. tb 59:421- 437;1987: USSG (U!S. Surgeon Genenl) Tbe [h oonuqueaeer of invol- untary smokin8: a repon e Sureeoo General. DHHS (CDC) 87-8398. Wash' , D.C.: U.S. Public Health Servtce;,1986. VoBt, T. M~8 behavioral factors as prrdicton of rieks. ln: rcb on smoking behavior. NIDA Monograph 17, Nauonal Iastitute of Drug Abuse, U:S. Public Healtb Service; 1977: pp. 98-110. Weisa, S. T. What art: tbe health effects of passive smoking? J. Resp. Dis. 9:46-62; 1988. Wells, A. J! An estimue of adult mortality in the United Statei from passive smokiaB.,Bn.iinn. lnt. 14a249•263; 1988. Wn, A. Hl;, Henderson, B. E.; Pike, M.C;, Ya; M.C. Smoking and otber ritk factors for l®8 eaneer in .omen. J! NkL Cancer Inet. 74:747-751;,1985. 1` e e, (P, N'. F_ , z.~-, AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING; A RESPONSE Dear Editor:. Wells (1988) estimates that exposure to environ- mental tobacco smoke (ETS) causes 46 000 deaths per year in the U.S.; 3000 from lung cancer, 11 000 from other cancers, and 32 000 from heart disease. Theseasumates are scientifically unjustified. Far too much faith is placed on results from often fragile epidemiological studies, with major sources of bias ignored or totally underestimated.. In contrast, far too little faith is placed on evidence that nonsmokers have very much lower exposure to tobacco smoke ~I6 ~-L~ ry 1-7 19qo constituents than do smokers, and that smokers are much more exposed to ETS than nonsmokers. The evidence that exposure to ETS increases the risk of developing heart disease is extremely uncon- vincing. Of the studies cited by Wells, some are based on unacceptably small numbers of cases, e.g., Gar- land et a1. (1985) where only two deaths occurred in women married to never-smoking• husbands, while the only two studies with substantial numbers of deaths are both open to question. When referencing the Japanese prospective study, Wells uses Hirayama's 1984 report of a statistically significant positive trend in wife's age-adjusted risk according to husband's smoking, but does not com- menron the fact that, in 1981, Hirayama reported no association whatsoever. As shown in Table 1, the Table L Female relative risks for heart disease from passive smoking in Japaaese study. Husband's smokinR habit Total Ex or Fo1Lov-uD oeriod cases Non-smoker <19/dav, 20+/day 1966-79 406 I 0.97 1.03 1980-82t' 88 1 2.85 5.07 11966-82 494 ~ 1 1.10 1.30 © ~ t Estimated from 1966-79'data (Hirayama 1981) and from 1966-82 data (Hirayama 1984). The 1984 paper provided retati've numbers of deaths as 118, 240, aad 136.

16

8. 6' ~ a ~ tz 3 7, 3_2 3 11 21' r Np. R,SK, - - - - - - - - - r - - - aj Cunrent <2 2'5 5-10 >10 Years since stopping EtTect of sioppiag. smok'mg on relativc risk ofaerebra] ischacmiL Relaavc nskk for,e+cli iniMal unth 95':0CI. R'hen the period since stopping smoking was divided into five interti•als up to 10 years after stopping, a trend towards reduction in relative risk was seen (see acc•ompamingg figure;. However, this trend was not significant (x? = 0 5 for 1 df, \S; and'an appreciable risk A•as,still apparent after 10 vears. The effect of passive smoking as a risk factor for cerebral ischaemia was assessed for each parent and for spouse. After control for the subjects' oWn smoking, hypertension, andhhe residual eftea for age, smoking by the spouse increased the risk of stroke 1 7-fold{]12, 2•6;,r2=7•8:for 1 df, p<0•01),. whereas smoking by a parent increased the risk 1 2-fold (0-8, 1 8; x== 1!2 for 1 df,NS), The effect of a smoking spouse was sligtitly higher after exclusion of the two groups im wn,;di mmmt smoking was not a risk factor (cardiac embolic and sne or meclianisn unknov.v;. The relative risk for the remainder was 1-9 (112, 3 0;: However, because we thought the observed effect of smoking by the spouse could be explained by current smokers with a smoking spouse tending to smoke more than those without, a further control for daily , cigarette consumption of current smokets, was introduced; this control did not change the estimates of' relative risk for either parent or spouse. There appeared to be a positive dose-response effect in that the risk was increased by, 1.3 per pack smoked by ttie spouse per day (x' for trcnd=4-8 for 1 df, p<005). However, for never smokers only among the cases and matched controls, the relative risk associated with a smoking spouse was slightly lower (1-6 [0 6, 3-9j; X'=1 1 for I df, T:S); perhaps because only 88'matched pairs ramained4or analysis, and smoking ln•, either parcrtt was nora risk factor (relative risk 1' •0, (0,5; Z' 1']). Discussion The large number of cases and the high diagnostic precision by use of CT scanning in 98% of our cases has allowed us to extend the findings of previous studies in several important ways. First, in this "pure" sample of patients uith ctrebrali ischaemia, not contaminated with other forms of "suoke", the relative risk associated with smoking was somewhat higher than thav in other oohorrt" and case-control" studies. Itt four of those studies`b the use of CT scan was infrequent or not stated'and the possibilityy thatnon-strokes as well as cerebral laemorrhages may have contaminated the sample is therefoFe higher. In the only J tl T1;iE L.ANGET, SErTE.ti1EER 16„1989. case-control study in which the clinical and CT entry criteria were similar to our: own, outpatient medical clinic rather than comm unirv -based controls wereused.' h5edicall outpatienvcontiol groups are likel.to be contaminated wtith i smoking-related diseases, which may party account for the lower relative risk foundin that study. Second, in the two most common forms ofl stroke due to exaacranial or intracranial vasculiir disease (laautar and thromboembolic infarction), the relative risk associated with smoking was even higher, at five to six times that of those who had never smoked, and was of the same order of magniivde as treated hypertension as a risk factor. Third, the large number of cases in our study has enabled us to examine the nature of the relation between smoking and cerebral ischaernia in more detail than has been~ possible previously, particularly the effects of age and stopping smoking. There are various mechanisms by which smoking may increase the risk of cerebral ischaenva. Smoking is Imouet to increase platelet adhesiveness" and fibrinogen levels and therefore blood',nscosita•."'Cerebral blood flow is reduced in chronic ssrtokers," perhaps because of the higher~ blood viscosity, but also vascular: resistance may be greater because of the atherogenie properoesof smoking." Our finding of an overall three to four times greater risk of cerebral ischaemia for smokers compared with non-smokers is siinilar to that reported for myocardial infarcoon," and higher than the two to three times greater risk previously reported for "stroke"." The five to six fold increase in risk for lacunar and t}iromboembolic infgrction is closer to thar reported for peripheral vascular discase, in which one study reported an eight to nine fold increase in risk." In both mvocardia] infarction and peripheral vascular disease, the pathogenesis relates predorninandy to atheromatouss changes, so the similarly sized risks with pure forms of cerebral ischaetnia would be expectedi Examination of other subgroups in our study showed that smoking is alt;o a potent risk factor for T1As. This finding, confirms the general belief tliat cerebral ischaemia of brief or prolonged duration has,a common underlying mechanism and hence similar risk factors. The reason for the lack of risk associated with~ smoking in the cardiac embolic group is uncertain, but a large proportion of this group:had strokess secondary to atrial fibrillation, a cardiac disorder which is nonassociated with smoking as a risk factor.'d Ih the site and mechanism uncertain group the risk associated Kith smoking was also negligible. This finding emphasises, the importance of' a precise classification of stroke subtypes, since the group would otherwise contaminate the more dearly defined lacunar and tlvombocnbolic groups. Althou$It numbers were small'{56 patients)', the finding of a highly significant risk associated with smoki.ng in the lacunar group compared with 211 other groups combined'suggests that further study of the effects of smoking on small cerebral ~ vessel disease may be useful. In the only , other study to eatamine smoking as a risk factor for lacunar infarction," the relative risk was 2.3, but that study used hospital-based control9 and current smokers were not analysed separately: Given the positive dose-response effect of smoking on risk of cerebral isehaemia and the likelihood that attierogenesis may be at least pardy the reason for this, it was someWhat surprising to find that patients younger than 65 years were at greater risk than those over 65 years. However, when the two groups in whom smoking was not a risk factor (cardiac embolic and site or mechanism uncertain groups) were excluded from the analysis, this differential in risk with age was lost, This finding is mosvlikelv due to the greater age of'

58 Maaacsfiirg,Sbioroys, sa1.tlsnre.anv ezposcd to tobacco smokc now, the worsening of his disca_u may be associated with the pssr imrolunnry exposure to smoking. The incorrect tinung of uruiaty cotinine measurcmcnt mat<cxplain Mh;• no significant rdationstup x•as f'ound bcmmcn passive smoking,and the worsening of thc disease in this study. A cooperative epidemioiogic and eiinialistudy that is based on the long-tcrm and umdy c,zluatton of cff'eas on hcalth of involuntary exposure to smoking may pro.idc the evidence to support the hypothesis that passive smoking can influcncc the occurrence of Buerger's disease and the worsening of the disease process. -In conc)usion, coaninc is a sensitive but short- cerm marker of smoking. Smofdng tobacco was very closely related to tfie course of Bucrget's disease, but no signi5cant corrclarion bctween pa.ssivc smoking and the disease process has been found' yet REFERENCFS 1. Shinono}a S. What is BUcrgees disast? Worid~ J Surg 1983;7:rs44-51_ 2. Mcl:usick \'& Harris tY'S, Ottesen OE, Gfladman R?vl; Shclln• 16?ci; Bloodwclli RD. Buetgers disease: a distinct clinical usd parNologic cncn•: JAMA 1962;181:93-100. 3. Shionoya S. Buerga's diseuc (tluombouigiics ob6tesans). Inl Ruthcrford RB, ed: Vssculzr Issgay: 3rd ad. rhitadelphia: , l1B Saunders. 1989:207-1 7. 4. Shionos•i S, Baa 1, Nakata Y. ct al. Vascular reaonamxtion in BUer¢er's disctsc. Br )iSurg 19r'6;63tS41~6. S. Mizobuchi 1\S- F;iuda Y, Tamasc K. Sssafi M, Ueda Y. Simulnneous dererminaaon of nieoanc and eotininc in tiuman unnc bs fsigh-pcrfocmancc liquid chromatography. )wrtss! d VASGZJ1JlR SUAGY3CY' Annual Rcport of the Nan Prdeaural Irssanm of Public Hcahti 1985;20:60-6. 6. Maav!'nsra S, Taminato T, Kinrw N, a al Effoca of envircxuncncal tobacco smokc on urinary ooonine cartion in nonmsoktrs: evidcrscs for pusivc smoking. N Engl J Med 1984;314-:828-32. 7. Hocscausn M. Ssmpic high-perforttunce liquid c3fromato- graphic medsod for rapid dctasninauon of nicoenc and ooanine in urine. J Osrornacogr 1985;344:391-6. 8. Gnsnhalgh RM, Laing sr, Colc FV, T:ybr GW. Smoking arsd sttrsiaJ rcooasansaion. Br I Surg 1981;64:605-7: 9. Wisertun S, ICrnckungcoo C, Dain R, a aL Iatiuerscc of smoking usd plisma faaon on the parvscy of fe:noropoplianl' vtin grafts. Br Med 1 1959;299:643-6: 10. Rusadl MAH, Fevaabead C: Blood and usin:ry nieodne in non4mokrrs. hncer 1975;,1:179-8L. 11. Langonc f1, Gijika HB, Van Vunakis H. Niaoonc atd its rnerabolias: tsdioimmursoisays for nicaone aud: mtirsi>'sc- Biocherniisay 1973;12:5025-30. 12. Zeidenberg r, Jaffc TH, Kuvler M, l.evitt MD, Laingone T1, Van Vunaltis H. NfcoDne: conNnc le+vJs in blood during czssaoon of smoking. Gompr Psychiac•1• 1977;18:93-101. 13. Masukun S,,Sakamoro N; Scino Y, Tamada T, Mamryami H, Muruuka H., Cooninc ezaroon and diily ag:rertr smoking in habituated smokers. C1in Pharmaml'Tlxr 197'9; 25:555-61. 14. Wikos RG, Hugtsa ); Roland J. Vcri6aoon of smoking history in patients aftar infuction using urinary nicotinc and mtinirx meanurmena. Br Med ), 1979;27:1026-8. 15. Ficlding JE, rhrnow K1; Mcdical progras-hnJdh cffeca of invohurury Imoking. N Engi 1 Med 1988;319:1452-60. 16. Shirssingcr H, l:cfilides A. Passive smoking seuercly doQeases plan:kt scnsio.irr to antiaggrcgarory prnataglusdins. Lanca 1982;2:392-1 Submirted;Sept. 26. 1990; ,acccprcd )an. 30, 1991. t cn ~ I/~~~ ~.J R

t Lenen to the editor 179 Pron, C. E.; Burch. J. D.; Hos, C.R.; Miller. A.B. Tbe reliability of patetve emoking hiiwriee reported in s eaee-eontrol etody of lung cancer. Amer. J. Epidemiol. 127:267-273; 1999. Repace, J. L; Lowrey, A. H. A qoaautsove eseimateof sonamokm" lung cancer ritk from pusivs amokins. Ea.zras. IsL 11: 3-22; 1915. Ricken, W. S. Some eoneidentione .hen eatimatin{ espoeure to eovironmentalitobacco emoke (ETS) rith panicular refercnee to the home environment. Can. 1. Public Hsalth 71:S33-S39; 1939. Schwaru, S. L; Balur, N. J. ETS-lssg eaaar epidemiology: aupportability of miaclarei8cant and riak aewmptiooa.ln! PerrY,. R.;' Kirk, P.W., edi. Indoor and smbiest air quality. Loedos: Se1peT Ltd.;19t1: pp. 159-1". Shimisa, H. et aL A case-eontrol etody of lteg caeesr ie eommok- ia6 women. Tobotu J. Etp. Mad. 13d:319-397; 19911. Teichopoolot, D.; Kalaadidi, A.; Sperms. L; MacMahon, 8. Lm{ cancer and passive emokina. lttt. J. Cancer 27:1-d; 1991. AN' ESTIMATE OF ADULT MORTALITY IN THE fVITED STATES FROM PASSIVE SMOKING; ~ A REAPONSE Dear Editor: Wells (1988) estima that exposure to envi'ron- menul tobacco smote (E causes 46 000 deaths per year in the U.S.; 3000 fro uag cancer, 11 000 from other cancers, and 32 000 fr heart disease. These estimates are scientifically unju 'fied'. Far too much faith is placed on results hom o fragile epidemiologica) studies, with major sources bias ignored or totally underestimated. In contrast, f 00 little faith is placed on evidence that nonsmoke have very much lower exposure to tobacco smoke Table 1. Fsmale eslati.e risks for 406 88 494 ive smokiag in Japaneee stodx. Non-smoker 1 0. 1 2.95 1 1.10 .30 t Estimate4!{fom 1966-79 dau (Hirayams 1991) and from 1966-i2 dau (Hirayama 19a4); 7its 19 papet pro ded releove sembeta of deatba as 1J1„240; and 136. Oaerla. K. Lant cancer fram pusi.e emot'iad: lypotdeaii or ooe- rincing evideacet Jnt. Arcd. Oceop. Eoviree. Htaith 39:A21- 477; 1917: USSG (U.S. Surgeon General) Tbe health conseqnences of invol- unury smokins: a report of the Surgeon General. DHHS' (CDC) 11743911. Waahialton, D:C.: U.S. Public Haalth Serviee;A9i6. Yo{tl T. M. Smoking behavioral factore u predicton of ritkt. Ia: Research oo smoking behavior. NIDA Monograph 17, Natuonal IaniWta of Drug Abuse. U.S. Public Health Service; 1977:,pp. 9i-110: Weiss, S. T. Wbu are the health sffsas of pasei.e emokint7 1. Rasp. Die. 9:46-62; 1991. 9Vsila, A. 1. As snimas of adnlt eortality is t6e Uaitsd States fres peesive smotinS. 8s.iran. Isn 14:249-26J; 1988. We, A. H.; Headenon, B. E.; Pike. M.C; Ys, lS.C. Smoking and ether risk factors for l®g cancer is Woaeea.l. NIL Cancer lnat_ 74:747-731; 1911. constituents tham do smokers, and that smokers ~ much more exposed to ETS than nonsmokers,,% The evidence that exposure to ETS incr;.ases the risk of developing beart disease is ez-1 pmely uncon- vinting. Of, the studies cited by Wells: some are based on unacceptably small numbe land et al. (1985) where on t women married to nev •smo the only two studi with su deaths are both n to questi When refe cing the Japaa Wells use irayama's 1984 r signifi n t posi'tire trend in w acc smoki ing to husband's m of cases, e.g., Gar- wo deaths occutsed' ia~ king husbands, while bstantial numbers of on. ` ese prospective study, eporr of a statistically ife's age-adjusted risk ng, but does not com- nt on the fact that, in 1981, Hirayama reported no association whatsoever. As shown in Table 1, the disease freim p

Letters to the editor ronmental exposures within a study group. Because of the nature of this type of study, all it can conclude is that the exposure and health effect do occur to- gether with a measurable frequency. They do not prove a cause and effect relationship. Koo et al. (1988) performed a detailed investiga- tion of potential confounding factors in the llfestyle of nonsmoking women married to either a nonsmok- ing spouse or a smoking spouse. Overall, women married to ever smokers had a less healthy li'festyle,, ate less vitamin A vegetables, ate more cured foods, ate more spicy foods, and drank more alcohol than women married to nonsmokers. Their analyses show that caution should be exercised when interpreting data on ETS without considering other factors. Feinstein (1988) described some of the problems or failings that have come to characterize many epi- demiological studies. Several examples are given where commonly used substances were accused of being a menace to daily life after epidemiologists reported a relatively weak association between use of the sub- stance and adverse health effects. Some of these accusations have subsequently been refute& or with- drawn. Feinstein states that "[d]espite peer-review approval, the current methods need substantial im- provement to produce trustworthy scientific evidence". Other Cancers: With the exception of the Reyn- olds et al. study (which is unpublished and, therefore, inappropriately included' in the analysis), all of the studies cited in Wells' Table 3 were included in the NAS and Surgeon General's reports. The NAS con- cludes that there is no consistent evidence, based on these studies, of any increased risk of ETS exposure for "cancers other than lung cancer". The Surgeon General's report similarly suggests that further in- vestigation will be needed before any conclusion can be made. Cardiovascular Disease: Wells suggests that a con- siderable body of new epidemiological data on ETS and cardiovascular disease has become available, which significantly impacts the analysis of data for this disease endpoi~nt. This assertion is emphasized in the Inside EPA report. In fact, with the exception of Helsing et al. (1988), all of these data were avail- able to the NAS and Surgeon General's review pan- els. The study of Martin et al. was available at the time but was unpublished, and for good reason, it thus was not cited in these reviews. The study re- mains unpublished, and the data should not be in- cluded in the present analysis. Both the Surgeon General's and the NAS reports find the data on ETS and cardiovascular disease, available at the time of their reviews, to be inconclu- te5 sive. The inconclusiveness of the studies reflects not only small sample sizes but also a number of signif- icant deficiencies in their design, as detailed in both the NAS and Surgeom General's reports. The ques- tionable mathematical combination of the findings of these studies, as done by Wells, overcomes the prob- lem of small sample size but in no way addresses the methodologic issues that have been raised'. The prospective study of Helsing et al. (1988) reports a statistically significant increased risk of death from cardiovascular disease in nonsmokers ex- posed to tobacco smoke im the home compared to those not so exposed. The authors of the study con- clude that "[iJt seems reasonable to suppose that tobacco smoke is a risk factor in the increased risk". That rather weak conclusion reflects, in part, some aspects of the Helsing study that are inconsistent with such a conclusion. For example, the relative risk (RR), of death from heart, disease associate& withh household exposure to ETS is reported as highest in the youngest age group studied (25-44 years old), even though the individuals in the older age groups presumably were exposed to ETS for much longer periods. Given the same estimate of household expo- sure, individuals in the older age groups would be expected to have had a higher risk of cardiovascular death than those in the younger group. Both the Surgeon General's and NAS reports are cautious in their discussions of the quantitative risk associated with ETS exposure. Appendix D of the NAS report, which Wells cites in support of his risk models, emphasizes the underlying assumptions on which the calculations for lung cancer are based. The results are summarized in a section entitled, "Sum- mary of Main Results Under the Assumption That the Summary Rate Ratio of 1.3 is Causal". The Surgeon General's report states (p. 96): "The quantification of the risk associated with involuntary smoking for the U.S. population is dependent on a number of factors for which only a limited amount of data are currently available". These factors include a better understanding of the magnitude of ETS exposure, its distribution among different segments of the U.S. population, and changes in the patterns of ETS expo- sure that have occurred over the last century. There is no better understanding of these factors now than there was in 1986. Wells bases his exposure estimates on data published by Friedman et al. (1983) - data that apparently were considered to be insufficient byy the authors of the Surgeon General's report. As Wells depended to a large extent on the Helsing (1988) report, it is important to review carefully the methodology used in that report. A general census

N 0 T 1 ~ E l/ l Laun to the editor 1!h15 maiEr.a1 'nty ht OT,aected by cc;Y,nrn qw (f~t1e 17 U.S. ~cai! Helsin6, K. ].; Saadler D. P.; Comstoek„ C. W.; Chee, 5. Hean Lee, P. N. Ao elternative ezplaUS, ia6lor the incnatcd risk of 11m6 ditease mortality in nonemoken livin$ with emokerc. Am. J'. cancer in non-amokerr ed to cmoken.:ln: Perry, R.; Kirk, Epidemioll 127:915-922; 1982. P. W:,, edt. Ind and' ambient air quality. London: Selper. Hinyama, T. Non-emoking wives of heavy tmoken have a higher 19tttb:t a. risk oflun6 cancer. a study ftom Japan. Br. Med: J. 2E2:113- Lee p Passive smoking Fact or fiction7 Paper presented at 195: 1991. ~onfereaa on Prssent and Future of ladoor Air Quality. Brw- Hirayama, T. Lung cancerin Japan: aHecu of nutrition and pate •~ ec1a, February 14-16, 1939; 19/9a. rmokin6. In: Miseil.,M.,Correa, P., eds. Lung cane auses Lec, P. N. Problemt in interpreting epidemiolosical dan. Paper and prevention: Ner York: Verlri Chemie ernatioaaln presented at Conference on Aueeemcaaof Inbalacion Hasards. 1984:175-1'9!. Hanover, February 19-24. 1989; 1919b. Lec, P. N. Lifctime passive emokia nd cancer risk. Laneat Sandler, D. P. et al. Passive emokia= in adulthood and eancer risk. 1:1444: 1915. Am. J. Epidcmiol. 121:Y1-N; 1985. Lee„P. N. Passive emokin d lung cancer. Asaoaation a tsault USSO (U.S. Surgeon Geoeral) Reducing the health eonaequenca of bias? Hi:man T- oti. 6:517-524; 19a7. of smoking. 25 yean of prvgrcu.: A report of the Surgeon Lee„P. N. Mis tficatioa of amokin8 habiu and paeeive emok- General. Rockvillc, MD: U.S.,Public Hkaltb Service; 1949. ina. A ew of the evidence. In: International' Archives of Welle, A. J. An estimate of adult mortality in the United States Oc ational and' H'ealth Snpplemaat. Heidelberg: Springer- from passive smoking. Envirtm. lat. 1:4:249•263; 1991. V'erlaa; 19Eta. ,~.v-a~~we; ~tck "10 ISCHEMIC HEART DISEASE; RESPONSE TO LEE Dear Editor: The 1981 report was based on a 14 year follow-up (n-400) and the 1984 report was based on a 16 year follow-up (nm,494) of nonsmoking wives. The rela- tive risks of ischemic heart, disease when husbands were nonsmokers, exsmokers, or daily smokers of 1 00' i 0 garettes were . , or more c Dr. P. Lee questioned the reuons for a discrepancy 1'-19 cigarettes and 2 of my reports in 1981 and in 1984 on husbands' 1.06, and 1.18 (trend p: 0.061 not;ignificant)'in the smoking and ischemic heart disease risk in nonsmok- 14: year follow-up; and 1.00, 1.10, and, 1.31 (trend ing wives. p : 0.019 significant) in the 1984 report. Table 1. Ischemic heartdiuus mortality in women by age 6roup;,by occupauon, and by husbands' smoking habit (patient benelf a nonsmoker). Husband's sn+oking habit ------------------------------------- " ' Hus-0and s oceupation Husband s age group Nonsmoker Agricultural, 40-49 8 2,502 worker S0-59 15 3,497 60-69 36 4,084 70- S 323 Tota1' 64 10.406 Other 40-49 5 3.727 50-59 11 4,294 60-69 29 3.036 70- 9 432 Tota1 54 11.489 The .1iQnted'point eat4i.ate of rate ratio and test-based 90% confddenca Ttadts E,csa+oker 1~19/day 20•/day Total! 25 5,941 17 3.636 50 12.079 27 6.812 27 3,514 69 13,923 79 6.645 27 2,152 142 13,081 11 446 2 89 18 a58 142 20.044 73 9,391 279 39,841 1S 9.093 1S 7,1Z8 35 19„948 29 b,a3'0 23 6.306 63 19„430 46 5,596 20 2.499 95 11.133 a 619 5 137 22 1.188 98 24.140 63 16,070 215 51,699 1.33 /1.6a 1. 00 1'-11 ~ 1. 36,~ 0.92 1.09 0.882 2.331 rtintel-Kaens=el cni 0.19889 0.00988 One-tatl p value /lantel entensiCn chi 2.539 One tail p valut 0.00916

186 was taken in Washington County, MD, in 1963 that included, among other factors, smoking histories of families and number of rooms in the house. Twelve years later, Helsing and colleagues reviewed death certificates to determine cause of' death over the 12 years. They noted those deaths that were coded as arteriosclerotic heart disease and other myocardial degeneration. They then calculated a relative risk of death due to arteriosclerotic heart disease of non- smokers married to smokers versus nonsmokers mar- ried to nonsmokers. The relative risks were 1.31 for men and 1.24 for women after adjusting for age, marital status, years of schooling, and quality of housing. It is very important to note that the authors re- ported that there was a small difference in RR if heart disease was listed as the underlying cause of the death or just li'stedion the certificate as one of several reasons for death. The actual cause of death as listed on death certificates could in itself be a confounding factor in this study. In addition, overall' relative risks were adjusted for age, marital status„etc. There is no description of how the quality of housing is calcu- lated or adjusted for, nor is there any attempt to look at other possibly related health factors in the sub- populations to determine if these factors could have influenced arteriosclerotic heart disease. In addition, no attempt was made to measure smoking status mis- classification. Wells concludes his report by suggesting that ex- posure to ETS actually may cause more than 46 000 additional deaths per year. He quotes Repace and Lowrey (1985) and their estimate of 4665 additional lung cancer deaths as support for that suggestion. The Repace and Lowrey estimate scares a lot of people who have not taken the opportunity to review their underlying assumptions. What is overlooked in the emotionalism is what the Repace and Lowrey report really says. Repace and Lowrey start with the assumption that direct smoking and ETS both cause cancer. They do nothing to prove this. They then use a long series of estimates of exposure concentrations and exposure durations to compare ETS exposure to direct smok- ing. Finally, they calculate the death rate from lung cancer using these assumptions and estimates. What they generate is a calculated guess., not a prediction based on facts. Most of the research done since the Repace and Lowrey study has not supported its findings. One of the better studies has calculated that a person ex- posed to ETS actually retains 0.02 percent (or 1/5000) Letters to the editor of the particulates of a direct smoker (Arundel et al. 1988): Repace and Lowrey calculate a nonsmoker to be exposed to an average of 1.43 mg/day of particulates from ETS. Arundel et al. calculated the amount to be 0.07 mg/day for male nonsmokers and 0.03 mg/day for female nonsmokers. These two estimates of ETS exposure differ by a factor of between 20 and 45. Thus, estimates based on exposure assumptions and models are simply estimates. One needs only to change a few of the basic premises to arrive at a completely different set of conclusions. Wells' reliance on as- sumptions derived from the exposure assumptions of Repace and Lowrey leave his own conclusions highly questionable. It is apparent from this brief overview that Wells' computations rely on risk ratios derived froml epide- miological studies that do not establish a causal link between ETS exposure and the risk of disease. What part, if any, of the association between marriage to a smoker and lung cancer or cardiovascular disease is due to ETS is a matter of debate. Resolution of that debate depends on further research to address the exposure and misclassification issues. Pending reso- lution of these questions, Wells is obligated to state and fully discuss the assumptions that underlie his calculations. Larry C. Holcomb, Ph.D. Holcomb Environmental' Services Olivet, MI 49076 REFERENCES Arundel, A.;, Sterling, T.; Weinkam, J. Exposure and riskbased estimates of never smoking lung cancer deaths in the U.S. in 1980 from exposure to ETS. In: Indoor and ambient air quality. London: Selper Ltd.,1988; 242-251. Blot, W. J.; Fraumeni„J. F. Passive smoking and lung cancer. J. Nat. Cancer Ina. 77:993-1000; 1986. Feinstein, A. R. Scientific standards in epidemiolo8ic studies of the menace of daily life. Science 242;1257-1263; 1988. Friedman, G. D.; Petitti,, D. B.; Bawol, R. D. Prevalence nd correlates of passive smoking. Amer. J. Pnbl. Health 73:401- 405; 19Y3. Helsing, K. L; Sandler, D. P.; Comatock, G. W.; Chee. fi. Heart disease mortality in nonsmokers living with smokers. Amer. J. Epid. 125:915-922; 1988. Koo„ L. C.; Ho. J. H.; Rylander„ R. Lite-history correlates of environmental tobacco smoke: a study on nonsmoking HonB KonB Chincse wives with smoking versus nonsmoking hus- hands. Soc. Sci. Med: 7:251-260; 1988. NRC (National Research Council). Environmental tobacco smoke, measuring exposures and assessing health effects.. Washington, D.C.: National Academy P'reas; 1986.

Lettera to the editor example, of 100 nonsmokers studied by Jarvis ('1987), the 46% who reported "no" exposure had measured urinary cotinine levels which were neari!y a third of the levels of those 27% of nonsmokers who reported "some" or "a lot" of passive smoking exposure. This suggests that there is major misclassification of non- smoking controls as "unexposed". The result of this kind of misclassification of nonsmokers is to cause epidemiological studies to lack statistical signifi- cance or to find no effect. Nevertheless, despite such misclassification of controls, fully two-thirds of the studies shown by Katzenstein in his Table 1 showed a positive result. Are confounding factors such as higher exposure to carcinogenic organic chemicals from non-ETS sources in the spouses of smokers, as Katzenstein assera, really responsible for the consistent reports linking lung cancer to passive smoking from 15 different researchers in six different countries? To the con- trary: Wallace (1989). in making measurements of personal exposure to benzene, a known human carcinogen and a prominent constituent of tobacco smoke, found that benzene exposures were 50% higher in the nonsmoking children and spouses of smokers than for nonsmokers in nonsmoking households. Finally, what of the magnitude of Wells' (1988) estimates which Lee asserts are 46 000 too high? Let us take lung cancer, which Wells has estimated at 3000 U.S. lung cancer deaths (LCDs) per year. Lee selectively contrasts the estimate of 12 LCDs/yr from passive smoking by Arundel ecal. (1987), buromits the mention of eight other risk assessments with which Wells' assessment agrees, all eight of which taken together average 5000 ± 2400 LCDs/yr. (Repace and Lowrey 1990). It is Arundel et al. who are out of step with the rest, not Wells. This lends credence to Wells' risk assessment methodology. As far as heart disease mortal'ity is concerned, this is primarily a disease of those aged 2 35 years. In 1985 there were roughly 105 million Americans in this age bracket, roughly 72 million nonsmokers, and 33 million smokers. Among the 33 million smok- ers, there were 120 000 active smoking-attribut- able bean disease deaths (HDDs) in 1985, or 3.6 x 10'3 HDD/smoker. By comparison, Wells' estimates 32 000 passive smoking-attributable nonsmokers' HDDs per year in a population of 72 miuion, or 4.4 x 10-4HDD/non- smoker.Thus, the ratio of ETS-induced heart disease deaths per nonsmoker to smoking-induced heart dis- ease deaths per smoker is only 1296, which does not seem excessive considering that tobacco smoke is known to be one of three major risk factors for HDD, and synergistic (USSG 1989) with the other two fac- 163 tors (hypertension and elevated serum cholesterol) which are also commom in nonsmokers. A final note on Katzenstein's attack on the risks of passive smoking-induced lung cancer death (LCD) estimated by Repace and Lowrey (11'985, 1986, 1987). The radical difference in lifestyle between never- smoking Seventh Day Adventist (SDA) controls and never-smoking non-SDAs is the avoidance of passive smoking in the SDA lifestyle, which we believe con- vincingly accounts for their lower lung cancer rate. As Katzenstein selectively notes, we were criticised by OTA (1985) and by tobacco industry consultants for attributing the entire LCD rate difference to pas- sive smoking, but what our critics have conveniently ignored' is that, since 60% of the SDA control group were potentially exposed to passive smok- ing, this was in fact a conservative estinlate. More- over, Katzenstein selectively omits mention of the analysis of our work by Weiss (198b), who found our figures to be "the best current estimates of lung can- cer deaths from passive smoking". In sum, contrary to the assertions of Lee and Katzenstein, we find Wells' predictions of 46 000 deaths per year from passive smoking to be credible,, and to indicate, as Wells concluded, that exposure to ETS can have adverse long-term health effects that are more serious than previously thought. James L. Repace Office of Air & Radiation U.S. Environmental Protection Agency• Washington, DC 20460 and Alfred H. Lowrey Laboratory for the Structure of Matter Naval Research Laboratory• Washington, DC 20375 •The comments of the authors represent their opin- ions, and do not necessarily represent the policies of their respective federal agencies. REFERENCES Armdal, A.; Steriiaa, T;, Wsinkam, J. Atsanmoker 1®a eancer riekefrom e:poenrs to putieulatts tobacco amoka. fia.ieoo. lat. 13:409-426; 19a7. Jar+vir, M. J. Upuka of snviroemeaul tobacco smoka. 1a:,0'Nei11. LK., Bratwcmaa4 K.D., Dodet,, B., and Hoffmatm. D., sds. Environmeotaz earciaojeot, metbodt of aaaiyru and ezposu» measurcment. IAAC Scientific Pubticatioae No. 91. Vol. 9. Pucive Smoking. Lyon: Iotarnational A{cocyior Reeeareb oa . Caacer, 1'9i7,

f 184 Lee. P. N. An estimate of adult mortality in the U.S. from passive smoking; a response. Environ. Int: 16:179-181; 1990. Katzenstein; A. W. An estimate of adult mortality in the U.S. from passive smokiag; a response. Environ. Int. 16:173-177; 199 Repaee, J. L.; Lowrey, A. H. Risk assessment me giea in passive smoking. J. Risk Anal. lin p VYa USSG (U. S. Surgeon General cing the health consequences of smoking. 25 of progress, a report of the Surgeon tAa 1co t,.,)6, L • e. E MV. I' Y M. AN ESTIMATE OF ADULT MORTALITY IN THE UNITED STATES FROM PASSIVE SMOKING; A RESPONSE Dear Editor: • MOTICE TWs material may, b` Proteeted by coPyr;ght la* Mre 17 U S, Cod-iJ Letters to the editor General. Washington. D.C.: . ept. of Health dt Human Services; 1989 Wall .. ajor sources of benzene exposure. Environ. Health Perspecu 82:165-169; 1989: Weiu, S: T. Passive smoking and lung cancer: what ii the risk? American Rev. of Resp. Dis. 133:463-465; 1986. Wells, A. Jl An estimate of adult mortality in the United States. Environ. Int. 14:249-265; 1988. 5,,,4.. [ G C'z) ~. ~~ ~-,37 1°l `t u' with ETS exposure. These calculations do not in any way establish that ETS does, in fact, cause death in exposed individuals. Rather, such calculations: rely on an independent conclusion, based on a review of the available data, that ETS causes lung cancer, other cancers, and cardiovascular diseases. If such~ a con- clusion cannot be supported, then the estimate of ETS-associated mortality rests on the assumption that ETS causes these diseases, and it is incumbent upon the author to state this underlying assumption when reporting the results of his calculations. The issue of causation is never addresse& by Wells. The studies cited in Weils"Tables 1-4 are discussed below with particular attention to whether they es- tablish a causal relationship between ETS and dis- ease in non- or never-smokers. The vast majority of the studies were included in reviews published by the National Academy of Sciences (NAS 1986) and the Surgeon General (USSG 1986). Therefore, these re- ports are used as a starting point for addressing the question of causality. Lung Cancer: Almost all of the epidemiological studies listed in Wells' Tables 1 and 2 were consid- ered in the NAS an& Surgeon General's reports, as well as other reviews appearing at about the same time (Blot and Fraumeni 1986; ilberia 1987). The Surgeon General's Report was alone in concluding that ETS causes lung cancer in nonsmokers; the other reviews generally concluded that although a statisti- cal' association appeared to exist between marriage to a smoker and the risk of lung cancer, the lack of adequate exposure information, and the potential in- fluence of differential misclassification of smoking status precluded a conclusion of causality. The lung cancer studies published since these reviews have the same limitations as the previous studies. Little has been published since 1986 that adequately addresses the issues of exposure and misclassification. All of the studies attempting to link cancer to ETS have been epidemiological. An epidemiology study attempts to relate the frequency of a certain health effect or disease with the frequency of specific envi- An article in Inside EPA (January 13, 1989) is headlined: "EPA weighs Impact of Study Linking Passive Smoke Exposure to Heart Deaths..." It leads with the statement: "EPA is giving serious attention to a recently published study that pinpoints passive smoking ... as a significant cause of heart disease and cancer-related deaths". The article states: "Pas- sive smoking causes 46 000 deaths a year, according to a study by A. Judson Wells published last month in Environment Internationa!". An EPA source is quoted: "The 46 000 mortality was surprising be- cause such a large component was from heart disease ..." This statement is similar to one made by EPA's James Repace on national television when the report was first released. What is surprising is that anyone from the EPA can consider this recent review surprising. Dr. Wells has not completed an epidemiol'ogicat study, new or oth- erwise, and has in no way contributed to pinpointing passive smoking as a significant cause of heart dis- ease, lung cancer, or other cancer deaths. What he did was publish the results of a series of calculations based on the results of existing epidemiological stud- ies and a number of assumptions (Wells 1988). Dr. Wells presented a similar analysis at the 1986 Air Pollution Control Association meeting,, which was published in the meeting proceedings (Wells 1986). There should have been no sudden surprise at EPA; an EPA official chaired the 1986 session in which this paper was presented. Dr. Wells encourages the view that he had done something new by failing to even acknowledge his previous presentation. Wells used the data of previously published (and in some cases, unpublished) studies as a basis for calculating annual mortality statistically associated'

Letten to the editor Sinzinger. H.: Kofalides„A. Passive smokin8 severely decreases platelet sensitivity to antia8tre8atory prosta8landins. Lancet (ii):392: 1982. SvendYen„ K. H.: Kuller, L H; Ntaton, J. D: Effects of passive smoking in the multiple risk factor intervenuon trial. Am. J. Epidemiol. 126:783-795; 1987. Svensson, D. Lung caneer, euoloBY in women. Stockholm, Swe- den: Karolinsks Institute; 1988. Dissertation. USSG (U.S: SurBeon General). The health consequences of invol- untary, smoicin8, a report of'the Surgeon General. Rockviile„ MD: U.S. Public Health Service; 1986. Vandenbroueke„J. P.,Passive smoking and lung cancer: a publiea- tion bias1 Br. Med. J. 296:391; 1988. Varela, L. R. Assessment of the association between passive srnok- in8 and lung cancer. New Haven, CT: Yale Univ; 1987. Disser- tauon. Wald, N. J.;,Nanchanel, K.: Thompaon; S. G:,Cuckle, H. S. Does breathing other people's tobacco smoke cause lung eancer7 Br. Med. J. 293:1217-1222; 1986. Wells, A. J. Misclassifseauon as a factor in passive smoking risk. Lancet (ii):638; 1986a. 193 Wells, A. J. Passive smoking mortality: a review and preliminary risk asseasment. ln: Proc. 19th Ann. Meeting. Air Pollut. Con, trol Assoc. Pituburgh, PA: Air Pollutinn Control Association;. 1986b: 86-80.6, 1-16. - Wella, A. J. Hearing before the Subcommittee on Natural Re- sources, Agriculture Research and Environment. Committee on Science and TechnoloBY;, U.S. House of Representauves. Sep• tember 17, 1986.,Washin8ton, D.C.: U:S. Government Printing Office; 1986: 39-7+/; 89-100. WelIa, A. I. An estimate of adult mortality in the United States from passive smoking. Environ. lnt. 14:249-265; 1988a. Wells. A. J. Passive smokin8 and lung cancer: a publicauon bias7 Br. Med. J. 2%: 1128; 1988b. Wells, A. J. Passive smoking and: adult morulity: In: Aoki, M.; Hisamichi; S.; Tomina8a, S., eds. Smoking and health 1987: Amsterdam: Escerpta Medica; 1988c: 287-289. Wu, A. H.; Henderson, B. E.; Pike, M C.: Yu, M. C. Smoking and other risk factors for lung cancer in women. J. Nat. Cancer Inet: 74':747-751:1985. /

r : Urinary cotinine measurement in patients with Buerger's disease - Effects of active and passive smoking on the disease process Misahiro Matsushita, MD, Shigchiko Shionoya, MD, and Takatnshi Mataumoto, MD, NaB%a, Japan Although :Buergcr's disease is knowa to be closely related to smoking, no objectivc analysis of the smoke-associated problems has ban pcrformed+ In this study, cotiniac, the major metabolite of nicotine, was used as a sensitive marker to measure levels of active smoking and the exposure of nonsmokers to tobacco smoke because it has a relatively long half-life and because cotinine kvels can br determined by noninvasive means in urine. According to urinary,eatininc levels, 40 patients with Buerger's diseast were classified as (1) smokrrs:: those with urinary eotinine levels abotc 50 ng/mg etritinure; (2) passive smokers: those with Icvds btt.vecn 10 and 50 nglmg ereatinine; and (3)1 nonsmokers who did not experience noticeable passive smoking: those with levels bcJow 10 ng/mg creatinine. Tberc were 10 smohsrs, 9 passivc smokers, and 21 nonsmokers. Thc course of the discase, after the initial trcatment rt oer hospital, was studied retrospectively. Seven of the 10 smokcrs,, none of the 9 pass•ia smokers, and 4 of the 21 nonsmokers ezpcrien.;ed aggr•~avation of the diseue. Of the four nonsmokers who exprrienced aggravation; t3irre had still been smoknr and one had been exposed to tobacco smoke in the workplace at the time ofrelapse.'Ibere was a significant differcncc in the aggravation rate betwcen the smokers' group and the other two groups. Among the smokers, the seven patients whose conditions worsened showed signi5cant3y higher cotininc levels than the three remaining patients who were: in the stage of remission: The conclusions were: (1)~a very dose relation between active smoking and the course of Buerger's disease was established, and (T) effects of passive smoking on the disease process were still incondusive. (J Vxsc Stn.e 1991;14:53-8.) Buerger's disease is chanctcrizcd by peripheral u~t::al occlusion of the extremities most frequently :.^ ynung, adult male smokers.'= In general, all patients with Buergcr's disease have a history of smoking, and smoking is also known to be closeh• related to exacerbations of the diseasc.' •' The outlook in rcgard'to the effects on the limbs of a patient -Aitli Buerger's disease is favorablc if he stops smoking, but the disease gets progressively worse if he continues to smokc.'•' tiowevcr, we have occuionallr found that the d4assc recurrcd in patients who stated tfiat thn• had abstained from smoking. Many of them may have been lying about thcir smoking habits: some wIerc l=rvm the First Depara»ent of Surgery, N'an, Unnsrsin• Sdwd ofModicnc (Drs. Mnsushin and'Shionorna) and tfie Depart- menv of Surgery, Nagoya Second Red Cross Hospital (Dr. riatstrrnoto). Rr?.rinr requesa: Muatsiro Matsushita, MD; The First Depart- Tit of Surgery, Nagoya University SchooF of Modianc, Tiu-urnai-cho, snuwa-ku, Nagoya, Japan. u/i/yg4p88 deemed to have denied themselves the pleasure of smoking but had been exposed to tobacco smoke in the home and workplacc. Because there is no objective test to evaluate smoking, previous studies have had to depend on paticnd testimony of smoking habits. An objective method oferaluationof the degree of active and passive smoking is necessary to elucidate the relationship bcn+xcn smoking and Buerger's discuc. By measuring urinary conccntrauon of cotininc, the major menbolite of ni¢otinc, we found a correlhtion between smoking and the natural course of Bucrger's disease in trtrospectire study. PATIENTS AND METHODS Urine samples were colleaed for: measurement of nicotine and cotinine levels from 50 volunteers (23 smokers and 27 nonsmokers) without noticeable passive smoking and whose statements of smoking histories were regarded as reliablc. The tune pattcrnn of nicotine and cotiniite excretion was studied to judge whcncer alkaloid is suinblc as the marker for _ . ~...,.,,K fwt"'=_. - 53 i , I

17

Letters to tde editor M" T t lhis ^'3'= " protecteC 07 C-tw (f,de 17 U..) Helsih8, K. J.; Sandler, D. P.; Comstock, G. W.; Chee, E. Heart disease mortality ia nonsmokers living with smokers., Am. J. Epidcmiol. 127:915-922; 1988. Hirayama, T. Non-smokin8 wives of heavy smokers have a hi8her, risk of lung caneer. a study from Japan. Br. Med. J. 282:183- 185; 1981,. Hirayama, T. Lung cancer in Japan c effects of nutrition and passive smokin8. In: Wtizelll M: Corres„ P., eda. Lung cancer: causes and prevention. New York: VerlaB Chemie International. 1984':175-195. Lee, P. N. Lifetime passive smoking and eaneer risk. Lancet 1:1444; 1985, Lee, P. N. Passive smoking and lun8 cancer. Association a result of' biasl Human Tozicol! 6:317-524; 1987. Lee, P. N. Misclltuification of smoking habits and passive smok- ing. A review of the evidence., Inc International Archives of Occupationali and Health Supplemeaa Heidelberg: Springer- Verlag; 1968a. 1S EMIC HEART DISEASE; RES ONSETO LEE Dr. P. Lee questiolitEd of my reports in 19 the reasons for a discrepancy and in 1984 on husbands' M disease risk in nonsmok- smoring and ischemic he ing wives. Table 1. Iscbernic heart disease mortality Lee, P. N. An,alternacive explanauon fortheincreased risk of 14ng cancer in non-smokers marned to smokern. In: Perry, R.; Kirk, P. W., ed1. Indoor and ambient air quality. London: Selper,, 1988b:149-151. Lee, P. N. Passive smoking Fact or fietion7 Paper presented at Conference on Present and Future of Indoor AirQuality.,Brus- sels, February 14-16, 1989; 1989a. Lee„ P. N; Problems in interpreting epidemiological data. Paper presented at Conference on Assessment of Inhalation Hazardt.. Hmover„February 19-24„ 1989; 1989b. Sandi'er, D. P. et al. Passive smoking in adulthood and cancer nak., Am. J. Epidemioll 121:37-43; 1985. USSG (U.S. Surgeon General) Reducing the healtb consequences of smoking. 25 yean of pro8ress. A report of the Surgeon General. Rockville, MD: U.S. Public Health Service; 1989. Welli, A. J. An estimate of adult mortality in the United States from passive smoking. Ei+viron. Iat. 11:249-265; 1988. The 1981 report was based on a 14 year follow-up (p=400) and the 1984 report was based' on a 16 year follow-up (n•494) of nonsmoking wives. The rela- tive risks of ischemic heart, disease when husbands were nonsmokers, exsmokers, or daily smokers of 1-19 cigarettes and'20 or more cigarettes were 1.00, 1.06, and' 1.18 (trend p : 0.061 not significant),in~the 141 year foilow-up; and 1.00, 1.10, and 1.31 (trend p: 0;019'significant) in the 1984 report. women by age group, by occupation„and by huebandi' smoking habit (patient herself a nonemoker): Musband's accupation Nusband's age group Nonsmoker Exsmoker 1-19/day 20•/day Total Agricultural 40-49 8 2.502 Z\ 5.941 17 3.636 50~ 12.079 worker 50-59 1S 3.497 Z7 812 2l 3,514 69 13,823 60-69 36 4„084 79 6, 27 2,152 142 13,081 70- 5 323 11 446 2 89 1B 858 TotaT 64 10,406 142 20.044 9,391 279 39,841 Other 40-49 5 3,,727 15 9,093 1S 128 35 19,948 50-59 11 4„294 29 8,830 23 6, 6 63 19,430 60-69 29 3.036 46 5,598 20 2,499 95 11,133 N 10- 9 432 B 619 5 137 2 1,188' 4= Total 54 11,489 98 24,140 63 16,070 21 51,699 .N C..) ' The weighted point eatieu te of rate ratio 1.00 1. 11 1.33 ~ 1.36 .11.68 Mant: el eNtension. and'test-based 90S 0.92 \ 1.09 I-A 2 conftdence 1'imits cn i ~,539 A I- One tail p value Mantel-MA.enS2e1 Chi One-tail p value U:882 2.331 0.00916 0.18889 0.00988

I1i There are other factors that make the prediction of passive smoking health effects by rationing down from the particulate dose of direct smoking chancy. One factor is the possible protective effects in direct smoking. Smoking is known to depress estrogen lev- els which can protect against breast cancer. Such a protective effect is unlikely from passive smoking. Remmer (1987) postulates that direct smoking acti- vates protective enzymes. Lassila et a1. (1988), in their interesting work with monozygotic twins, have shown that direct smoking results in higher levels of prostacyclin, a reactive vasodilator„which, they note, could compensate for the vasoconstrictive effects of cigarette smoking. The dose from passive smoking is probably too low to promote this protective effect. Sinzinger et al. (1982), later confirmed by Burghuber et; al. (1986) and Davis et al. ('1989), found that platelet sensitivity,, a known risk factor for heart attacks, is depressed about 30% in passive smokers, almost to the level found in active smokers. There is no way that the relative retained' particulate dose could'account for this phenomenon. Direct smoking and passive smoking are both com- plex phenomena, with both disease promoting and disease protective components that differ between direct and passive smoking, and where the balance betwsen them differs among individuals. Lee deni- grates my suggestion that individual susceptibility could explain, in part, the higher than expected ad- verse health effects of passive smoking. The science of identifying highly susceptible people is progress- ing. See for example the work that Caparosa et aI. (1989) are doing at the National Cancer Institute on "fast metabolizers" of potential carcinogenic materi- als. Jones (1986) has shown a substantial difference in sensitivity of different individuals to nicotine and its effect on pulse rate. Khoury et al. (1989) have developed equations for estimating the proportion of persons who are susceptible to a risk factor. They estimate that 13% of smokers are susceptible to lung cancer, w hereas only 0.9% of smokers are susceptible to esophageai' cancer. My calculations, using their for- mulae, indicate that only about 0.4% of nonsmokers are susceptible to death by lung cancer from passi've smoking. Lee says that I am 'content to include a11 epidemi- ological studies' in my meta-analysea, regardless of quality. Actually, I discarded four lung cancer studies because they did not meet stated criteria. The admis- sion criteria are admittedly broad because I did not wish to be accused of biased selection. Originally, I had intended to use only statistically significant data, but the meta-analysis technique allowed the inclu- Lcturs to tds cdicor sion of smaller studies when properly weighted. A eertain amount of scatter is to be expected and is observed in the relatiwe.risks from these smaller, low power studies. Lee (1990) argues that the association between lung cancer and exposure to ETS arises predomi- nattly because of bias caused by mixlassifying smok- ers as nonsmokers. In his analysis he seems to have gone out of his way to stretch the data to fit his hypothesis. For example, he states that current typi- cal regular smokers are misclassified to the extent of about 496. In his workup (Lee 1986, 1987), he has confused smokers who say they art current non-users of tobacco with smokers who say they are never smokers. Yet the epidemiology of passive smoking deals almost exclusively with people who say that they are never smokers. Lee also averages male and female data in order to get' higher misclassification factors. Normally in misclassification calculauons,, one uses sensitivity, which is defined as stated posi- tives divided by stated positiv=s plus false negauves, or in other words, the perQant.correctly cla.ssified' as exposed, or in this case, the percent of ever smokers that are correctly classified as ever smokers. By bas- ing his calculations on the number misclassified rel- ative to never smokers instead of relative to ever smokers as he should have, he claims to be able to average male misclassifieds (who are mostly exsmokers) as 18% of self-reported never smokers with female misclassifieds as 6% of never smokers to yield a 10% misclassification factor. The misclas- sified males as 18% of never smokers are equivalent to only 6% of ever smokars (18% x 25175) which is essentially the sarne as the female result (6% x S0/S0). Of course the safe thing to do when estimating the bias in female passive smoking relative risks is to use only female d'ata. In a paper in preparation for which I am a co-author, we found, when averaging data from five cotinine studies., including Lee's„that only 1% of female ever smokers said they were never smokers when they were actually current regular smokers, not 4% as Lee contends. Lee uses 10 as the observed relative risk for the regular current smokers that are misclassified as never smokers. The proper procedure is to use smoker relative risks that are consistent with the time frame and locale of the epidemiological studies for which a bias calculation is being made. Fortunately many of the passive smok- ing epidemiological studies on lung cancer have con- current estimates of the relative risk of current or ever smokers„and values for the other studies can be estimated from available data. ln fact, many of these values are shown on page 72 of Lee's book (1988). A

Lettert to tbe editor prised in 1986 at the large number of heart deaths and is probably still surprised„as are many othera, but that is the way the numbers come out. Holcomb states that I did not address the issue of causation. Perhaps this should have been done more explicitly in the paper. It was pointed out on the first page of the paper that the Surgeon General's report (U'SSG 1986) and the National Academy report (NRC 1986) both stated that pas- sive smoking can cause lung cancer. I thought that was adequate coverage for that issue. (Incidentally Holcomb states that "the Surgeon General's report was alone in concluding that ETS causes lung can- cer in nonsmokers,' but on page 10 of the National Academy report it is stated, 'Considering the evi- dence as a whole, exposure to ETS increases the incidence of lung cancer in nonsmokers.') Then I went on to show that the heart dau, including the new data, had most of the same characteri'stics as the lung cancer data in terms of number of cases, statistical significance, dose response, and biolog- ical plausibility. Hence one could infer causation. Holcomb references a paper by Koo et a1. (1988) that al'legedly, shows that nonsmoking women mar- ried' to ever smokers had a less healthy life style than nonsmoking women married to nonsmokers. Careful analysis of their voluminous data indicates eight life style factors where the test p and the p for tren& were both reasonably small. Five indi- cated a healthier life style for the women married to the never smokers and three for those married to the smokers. About all this paper shows is that nonsmoking women in Hong Kong who lived in rural areas are more likely to be married to non- smokers and to have a more rural life style. Humble et al. (1990), in their soon-to-be-published paper on passive smoking among never smoking women in Georgia, found that higher social status white women had a higher relative risk of heart disease from ETS than lower social status white women. quite the reverse from what Koo et al. concluded. Humble et al. also adjuated' for age, diastolic blood pressure, total serum cholestero1, and body mass. The tobacco people have used misclasaificitioa as their principal smoke screen to discredit lung can- cer risk from passive smoking. They know that misclassification can't possibly explain the 6eart effects of passive smoking so they have embraced 'life atyle'. This also is proving to be ephemeral. Holcomb complains that I included unpublished studies in the analysia, but Katzenstein complains that publication bias is likely to omit pertinent data. I chose to include all the data 1 knew aboat, favorable or unfavorable. Omission of the unpub- lishedstudies would not change the conclusions. H'olcomb states that I based my exposure estimates on data published by Freidman et al. (1983). Actu- ally, the exposure of never smokers living with ever smokers was obtained from the exposure of controls reported in the various U.S. passive smoking studies.. This represents the major factor in female exposure. Only the exposure of nonsmokers living with non- smokers was estimated using Friedman et al. There is no question that my conclusions on heart disease and cancers other than lung go further than the cautious statements in the Surgeon General', and National Academy of Science reports. So far, how- ever, the new data support my position. Whether causation has been "proved" or not, public health officials need to know the mortality stakes involved. They can then make their own judgments as to the likelihood of causality. Holcomb has not read the paper of Repace and Lowrey (1985) carefulJy. Their estimate of 4665 lung cancer deaths from passive smoking is based on a comparison of lung cancer mortality rates of Seventh Day Adventists who never smoked with those of non-Seventh Day Adventists who never smoked, not on exposure estimates as Holcomb claims. My esti- mates in no way rely on the exposure estimates of Repace and Lowrey. There are some nine studies in the literature that estimate lung cancer deaths from passive smoking. Except for Arundel et al. (1987) estimate, they range from 600 to 5600. The Arundel estimate is based on extrapolation from smokers to nonsmokers of retained particulate dose, an idea dief- credited earlier in this letter. As Kat:enstein uya, death from passive smoking is a serious issue, serious to the health of the tobacco industry, and serious to the public health. We ean expect vigorous (but misleading) attacks from the tobacco side, as these three letters show, but it is still best to lean toward safety when the health of the public is at stake. REFERENCES A. Judson Wells 41 Wiadermere Way Kennett Square, PA 1934BN W ~ Araadsl. A.; stertioa.,T.; Wunkam. J. Nsver>moker Itm= caoes" ritke from eipoeore to parucnlats tob.cco emots. fiaviron. la, 13:409-426; 19a7. ~ *~h

council of the Royal Collbge of General Proc- uuoners and the General Medical Services Committee (Wales). In overall terms our deputation fearedthat the general principles of tbereferral isystem wereeom- prornised, access to specialist psychiatric services was ill defined, and the declaredrole of the meotal health team in primary tsre could Ithd only to 5' fragmentaxion and confusion, Furthermore, the contractualiobligations of the general practitioner were totally bypastedl The deputationreceived a sympathetic hearing, and it was withgreat d'tsappouttment that we read the final paper, Menral Hral1A' Sersiaa, a Suarely for Wakr, issued in June 1989: Littk has changed from that set out in the consultation document, and we are conviitcedthat if the recommendations of this paper are implemented the task of treating psychiatric disorder in Wales is likely to be muddled and expensive. Cr,ekna. u. PowysNPS1AP R C HUMPHREYS Ud.e<.iryora,les cdle~.fMeaictoe, c.tdarGF44XN I Shepherd M Pssnury ose uf pntents r.ith meotddisosdh m tke camasuswty: BrMdJ 1919;299:666-9. (9Sepsmber.) Rape and subsequent seroconversion to HIV SIR,-Thepaper by Dr S Murphy and colleagues highlights the potential risks and worries for women who have been sexually assaulted during the current phase of the HIV epidemic.' If we assume that such assailants are hettsosexual men the overall risk of transmission is likely to be small in view of the present low carriage rate for the virus amottgthis group in Britain,! In addition, vaginal intercoursse is possibly a less likely mode of trans- mission than anal intercourse.! The situation for male victims of sexual assault may, however, be different. Male "rape" as a legal term does notexist in the United Kingdom, as rape specifies forcible vaginal peaetration: Furthermore, taale sexualassattlt is not recogni szi as s distinct entity within the 1976 :? z+ It Offeny: _~ ('.lmendment) Act.' Thismay well itavrwnsequences for thenumber of cases reported and for public awareness of such events.' Docu- mented cases of sexual assault of men by women have been reported,' but it is generally thought that men are more commonly assaulted by other men. In the United States it has been estimated that only J 0+20°/d of all sexual assaults are ever reported.' In addition, there is some evidence to suggest that male victims are more reluctant to come forward thantheir female counterparts, possibly related to the fear of being labelled as bomosexual' or to society's concept that a'"real man" cannot be npeA.' Pat t ! y Ls a.:onscq ttence of its legal non-ezistettce there a, i ao reliable figures of the frequentvand natura of male sexual assault in Britain. The only orgaw irinn providing care for victims of male sexull ?vanlbiu Btitainanpresentis'"Survivors; a servic>, no by ^luntc?rs to which various govern- ment vnd +:iiaritblr agencies refer their clients. The service piovides a telephone belb line (currently ans-wering just over 100 inquiries a month)t ,gether with counselling and support. No studies tu date have assessed'the risk of sexually acquirni'infection in trtale victims ofassault; but of 5 12 v ic? I ms known to Survivors in 1988, 24 of 73 who sought medical advice were diagnosed as naving a sexually transmitted' disease presumed' be consequent on their assault, Data on HIV seroconversion are not available, but 148 of the 512 victims reported skin or mucosal bleeding, and 278: expressed concern about the possibiliry of'ttans- mission of HIV. In 92 of the cases the assailann deliberately threatened the victim with the possi; billrv ofcontracting HIV infection as a consequence of the assault L It has been suggested that between 50%" and 82%' of assailants of male victims are either homosexual or bisexual. The assailants are there- fore in relatively higher risk groups for HIV infection than heterosexual assailants of women. Futhermore„anal penetration, bloody non-genital! violence, and multiple assailants are more likely when the victim is male.' Rape treatment centres have been set up pri- marily for female victims andamy lack the skills to deal with men, We believe that an increased level of awareness of male sexual assault is needed among the general'public and especially by health care professionals to encourage victims to come forward. Only when this happens can the scale of the problem be fully grasped and appropriate treatment provided. RICHARDHILLMANt>rtViD TAYLOR-ROBINSON Dsnssun o(Sccualfy Tnnsmleted Duosn, Glinia4 Rewrch Cmuc, H,.eo., sunw,, to.doo WCI NIGF1 O'AMRA I MunptlyS, Kncbm V,Hartu JRC", Fonur SM. Rape md wbseQucni savconvensou roH1V: BrMd J1969199:718:. 06 Septesn6er.) 2 PHLSCamsnunsobk Dssese SurreiWoce Cenue. Hussuosmmuoode6cxocTy.vus (HIV -1) anobodj. seporss: United, Fnedom;.ak's a445-89139. Gwm+o.nrui4Oruov R pmo 1989;40:3. 3 P~diisn NS. Hcseswaual tnnsnuuton oftcquircd unsouno de6LK0[y', f)RIQtCIOe: Nie(IYtlollil, PCRPCCUVC{ltlld ;ytqpV peoroctaos. ReclnlmDsr. 1987;9;947 40. 4 M~'G„RutaM Thceffectsof sesuulsaWt on tness.: a uurqof 22vsnuns. PMrhof Med 19a9;19:205-9. 5M-y G, Kivts M. Male vsctum of aQUa1 awWt. Me! S. Lea 1987;27:122-4.. 6ScbifrAF. Fsamuuuoo wd tsnssomt of'tbt mJk upe vwtnn. Sattth'MedJ 198013:1498.502. 7Gent FR. SesuaOy rslosed tnuma. E-rr Md Cla NwU Aw 196a:6:439b6.. 8 Rasdman ~A, Divuto P, Jacksaa R. Voorbees D, Ctinstv J. Mak We vscums: nouinautuawoali'sed auWS. Arw J PsyrAusry 1980;137:221-3. 9G1Ler JB, Hamssxnchla8 MR, Mcfasmack WM. Epidemw lop of'reamllytrwsmmeddnuusm tape v+cums. Rm!•fatDu 1939;1t:246-54. IOGrnsA AN,Burses.s AW:MLh sape:oneadesa andv,ctiou. Aw j Prydsany 1980i137:806-10. Passive smoking and cardiorespiratory lhealth, in Scotland StR,-Mr Peter N Lee' implies that our obser- vation of increased risk for four respiratory symptoms and two cardiovascular symptoms, mortality from lung cancer, mortality from ischaemic beart disease, all causes of death related to smoking, and mortality from all causes in passive smokers compared witli controls' can be explained by bias-that of smokers declaring themselves to be lifelong non-smokers. He cites (presumably) lung cancer, for which ifs as he supposes, no increased risk is usociate& with exposure to environmental tobacco smoke and the "true" risk is increased 20 times in active smokers, 2%' of smokers denying smoking would'result in observed relitive risks of 1 74 for passive smokers and 6•90 ifor active smokers. This is illustrated in his table, using the distribution of subjects in the smoking groups defined in our study. But why does he use only men and ignore women when our analysis and results were based on both sexes and' women comprised 84 2% of our passive smokers?, If' he had included women 5-0% of passive smokers and 3•996 of'controls would have smoked'(table I)-quitediffetent from the figures of 15-6% and''6•8% respectively presented in his tablt. Our figures in turn produce an observed relative risk of 1'•12 for passive smoking (sub- stantially less than the ]f74'be quotes by selecting only men) and considerably less than our study finding of 2-41 for lung cancer among passive smokers. Ckeariy; miscl,s.ifinrion owing to the 2% rate of denial of smadcing he suggests does not aplain our finding. in addsnOnl higher rates of dlnial of smoking do aot produce sufficient bias to crpl-in our tisk for „Ittng aocer. Table II presents the effect on the basis of a'"true" relative risk of 20 for active smoking and I for passive smoking and ofrates of denial varying from J% to 1,0%. Two facts emerge: firstly, the bias in the relative risk for passive smokers does not increase linearly as the rate of denial increases, it flattens considerably; secondiy; the observed relative risk for active smokers diminis}ies lapidlV as the rate of denial increases. TABLE tt-Relattrae risks forpatsine and art'roe tmoking fortwrying rates of nnokirtg Raseof denwd (%) Pasv.•e smoken Acuve smokers 1 1•07 13-95 2 1.12 10-67. 3 1.15 B•61 4 1•IB 7•17 5 1•19 6- 14 6 1-20 5•35 7 1.21 473 a 142 443 9 1 •23 3-82 10 123 3•47. This is important, as by comparing the observed relitive risk for active smokers from the table with the relative risk found in the study'an upper bound can be defined for the rate of denial. The study relative risk for active smokers compared with lifelong non-smokers is 5,85. This would be incompatible with rrtes of'denial greater than 5%. Therefore, the li,rgest relative risk to be expected among passive smokers due to this form of has when the "true" risk is ttnity is 1 F20. A relative risk of 2•41 was foundin our study: Again, the same approach applied to iachaemic heart disease assttming a"•rrtte" relative risk of 3 for acaive smokers and 1 for passive smokers and a raee of denial of smoking of 5% produces an obaerved reiative risk of 1•05 for passive smokers and 2•42 for active smokers. Thus if the relative risk for active smokers is considerably kess than 20, as in all i the conditions we considered other than lung C3nCer, the effecrofmicnlo«ifinnuan is to produce onlysmall biases in the relative risk for passive staokers. Our risks for each of the respiratory sympooms, urdiovascttlar, symptnms, and orr TASCS l-Differrniial mircl6ssification canud by 2'Aof rndexrabjectr denvmg xwtoking rejmdleu of cnAabuee'r swrokiwg Aab'its c V 3 0 r. ~ F ~ c Eeposusc Obxrved "Truc" Flfaets of PareeosW wbo F a,ot+p• di.tribt,t,oot dhsribuum Camvola 917 UI Puuve smokers 1538 1461 Suselesmokcn t751 1787 Doubk smoken 3791 3868 defLal have imClkld t363-4 I. a 77 5-0 i -36 - 77 1100 BMJ VOLUME 299' 28'.oc-rosER 1989 1 }ata r

l.attera to tSe editor Rcpace, J. L; Lowrsl, A. H. A quantitative estiinate of nommokers" lung cancer risk frm pauive smokin8. Ewiroa. Int. l!1:3-Z2: 1985. USSG (U. S. Sargtoo General). The health conseQuences oPiavol• unury smokin{. Rockville, MD: U. S. Department of Health , and Human Serviees; 1986, Llberia, K Luaj uncer, from passive amokin{: hypotbeiia or con- vincinz evideacc7 lnt. Arch. Ocatp. Enviroo. Health 59:421- 437; 1987, Mt )?,I : Ii- (* RSa t8f ta l :n3 y t•t pfvlsae~ by ccR'+':f'" .On liunz. 17 ' UIS Ci:.AO;I We1lIr,,A. 1. Passive smoking monality: a revtew and prcltmtoary assesument: 79tb Annual Mee:tng. Air Pollut: Control Assoc., Minneapolis, MN; 1986. Ptttsburgk; PA: Air Pbilut. Control Auociation; 19W Welll', A. J. An estuttate of adult monality in the United States from passive amoking. Environ. 1.ot. 14:249-265; 1988„ La e11~, A, (~k ~ (2) ~..1.7 7-1q3 1 ', '1e, , . } AN! ESTIMATE OF ADULT MORTALITY IN'THE UNIT'ED STATES FROM PASSIVE SMOKING; A RESPONSE TO CRITICISM Dear Editor: Lee (1990); Kauenstein (1990), and Holcomb (1990) . have commented negatively on my paper (Wells 19881) in Environment lnlernarional, in which it was sug- gested that the U.S. death toll from passive smoking may be 46 000 per year. Space does not allow' me to deal with all of the points raised, but the more impor- tant ones are eovered'below: Lee, as tobacco consultants usually do, attacks the underlying studies that I used, particularly the heart studies. I eannot speak for these authors. Dr. Hirayama has written a reply of his own. Dr. Sandler (private communication)~has told me that they (Helsing etai. 1988) did look at family size and found no effect. The Johns Hopkins School of Public Health (Helsing et all 1988) and the University of California, San Diego (Gartand et al. 1985) are respected schools of epide- miology, whose researchers presumably know how to adjust for confounding variables. They, attempted, within the limits of the data available, to account for known heart risk factors as noted in my paper. What io- striking about the heart data in my Table 4('Welis i988a) is the consistency of the various results. It is interesting that Lee et al. (1986) made no attempt to adjust for any of the known heart risk factors except age. Publication bias in smoking studies is an' issue oftgc raised' by tobacco industry eonsultants, but so far no one has found'a live passive smoking case that is negative. I have dealt with that issue vis-i-vis passive smoking and male lung cancer in my com- ment (We11s 1988b) on Vandeabroucke (1988). There, it was pointed out that the only available unpublished data were on the high side of the most probable relative risk, not low or negative. In that letter, I asked investigators to send me any data on passive smoking that had not been published or that they had not been able to get published: So far I have received none. As Lee says, the possibility of a large, unpublished data set that found nothing cannot be excluded; it is just extremely unli~kely: For cancers other than lung that are passive smok- ing related, all except nasal sinus cancer and lung cancer are non-contact sites, as is heartdisease. For these sites to be activated', the disease-producing entities musr, in most cases, be metabolized and'then circulate in the blood and lymphatic systems. Earlier work (Eatough etal. 1986) has shown that9096 of the nicotine in environmental tobacco smoke (ETS) is in the vapor phase. Now Pritchard' et al. (1988), have shown that 70% of the tar in ETS is also in the vapor phase. The nicotine and the tar in direct smoking is ini the particulate phase. lt is true, as Lee.says, that smokers are also passive smokers, but for the non- contact sites there is growing evidence that'smokers have a higher risk if they ase exposed to ETS other than their own than if they ase not so exposed. For example, Palmer et aC (1988) found a relative risk for heart disease of 1.34 for spouse exposure of light smoking women and 1.32 for heavy smoking women,. and Sandler et al. (:1985) found overall cancer risks increasing from unity to 2.4 as active smokers were exposed to an increasing' number of household mem. bers whosmoked. This means that smokers may also be at considerable risk from passive smoking of their own smoke. In other words, for the non-contact sites, the vapor phase tar and nicoune may be the primary culprits, with the paniculate phase having less effect. The particulate phase, at least' most of' it, is relatively quickly cleared. It probably contributes heavily to the contact sites (central lung, mouth, esophagus„and stomach) but then may be eliminated in the feces. Alll this means that Lee's,model for passive imoking, which is based on direct smoking and particulate phase deposition and retention, is likely to predict telative risks for passive smoking that are far, too low for the non-contact sites and probably for peripheral' lung cancer as well.

unllkeiv to be of value and often causes un- necessan anxlen•: Nutrition is better assessed using skmfbld calipers (whleh are also cheaperand more portable than weighing scales: to measure dsrect)v the thickness of subcutaneous fat.' Accurate height measurement (supme length inn infants under 2}•ears) is a sensitive guide to child health.' Growth velocita (caltulated from repated' masurcments of Ihetght at in tervals) iepresents the currenr dpnamics ofl growth much better than ~ a single measurement,: w•hicti reflects previous grow•tli, Regular, accurate measurement of children can idenuf.• those who would benefit from i medical, sociall or educational intervention.' Many height measurements in hospital and the communm are inaccurate and arusacading because of careless techniques and inadequate apparatus. Suitabli•accurate, cheap, and pottable apparatus is now widely availabVe for use in primary care, and' measuring techniques eliminating postural drops and' positional errors arc radil?,• larnt by mou- vated staff. Supine length in children under 2 years lan generally be measured accurately with the help of an assistant. Collected accurate growth (height) ~ data in children have important benefits beeond'ehose to the individual~-as an index of the health of a population or a subgroup (for example, ethnic group or social class). British data are not available and would be valuable. btanv who care for children lack the skill to measure them accurately, plot measurements on a growth chart, and interpretthe data obtainedi As the repon states; such understanding is essential for growth' monitoring. More must be done to make those who look after children aware of! the need to measure height accurately and regularhthroughoutchildhood and'to train them to do so, CHRISTOPHER J.H'3;ELKAR Detunmem of childLfe and Healtti. U m.-ervryof Edm bu rgh. EGmtiurah EH91 u•St' I I PdhatL. CYild heahb, . sunvrdlaoce. B0 AfN.J,19a9i299;135112. fbDecembeul 2Hall D A1B: ed: Hma6 for a1JcAildren. tIr nym ol'~?~ *+atsnr pam-an ekld 4e4hsrxdb+re. Odasd: Oafdrd' UnnernnPress, 1989'. 3Tanna J tit, Q'hstehouse RH. Rnned ssardsnds fdr.tnceps andd subscarwiirsundards.m Briush chitdren. AnA.DuC&I! 1975:5a.14.-1. t Tsnon J,\L. Fou+a mo wan.: 2odd ed; 7Carc: Casrknwd Publra- uo ny19E9. S1R--Health Far A71 Children, discussed bv Dr Leon Polnav''and'Dr D Is4 B Hall,' is the result iof a working patTV, set up by groups represenung' paediatriciansand general pncutsoners, neithenof, wwhom is' disinterested. The British Paediatric Assw:iauon suggested'some years ago that senior clinical medical officers in the child'health'service should 6ereplaced by "communiq• paediatricians"' who would work partltimc as paediatricians in the hospirtal and'w•ould take part in the on call duty roster. Similarly, much of the interest in taking over child health surveillance by general praeti- uoners has been tied to the proposal that extra payments w•ould' be made for such a service.. Practinonerswt.o have a real interest in thiswork provide such a sen^ice already forpatients on their lists. Bodies that actually represent the medicall officers who w•ork in the chiltl'healih:sen•iee were not invited to join t3tc working parrv. Child health surveillance requires a different outlook from clinical medicine, and it is not asy for clinicians whose whole training has Fieen directed to the diagnosisand treatment of disease tostop.thinking in such ter7rtsand abandonrheir prescription pads. Clinicians are not the most appropriate group to adsvsee onn aeliild healthi service that thm' do not fuliv understand. Developmental assessmem and ehild healtli surveillance w•ere pioneered bp the former child! health group of the Societv..'of MediaJ Officers of' HealttiL which started running full trme training courses of six weeks' duration for doctors some 30 vears ago. !n the ari} 1970s when the Facult v of Communirx- Medicine was formed eommunitv health doctors were not ehgible for: membership. Fortunatdk-, a number of medical schools started to run tratning courses in child deeeiopment':to fill the need that resulted. There w•as• hown•er, no orgamsauom or body monitoring the standard' or contenl of those courses.: which caried'widelv. Following the formation of' the Faeulrc of Communitv' Medicine restdual members of the Soeietv oG Communit}• Medicine sought toapro- mote the interests of communin.• health as well as eotnmunin- medicine. ln 1988 the society (which has since changed its name to the Soeiery of Public . Health) w•as mstrumental imestablishmg a new Facultv of Gommunin• Health to produce sylla- buses• set standards, and4ppoint examiners. ]n future, membership of the Faculty of Communin• Health should be evidence of eligibility for pasts as senior clinical medical affscer or as consuttann in aommunin• child health-more appropriate to the needs of the clients and' of the child health and education services than "community paedia- tricians." We hope that this faculn• will'providt training for general practitioners in child health sun•eil- iance and that appropriate diplornas will be established. S- of PuhYK Heahh. Loodor, WI I:aDE P A GARDHER J'SROBERTSON I Po1oa.:U..Gildhealih su-ildance.Bi.MrdJ.1989'~299•13512. ;2 December., 2 HaffiDMB. Cdild heallh surveillancr. B. AtedJ 19g9:W9:1353-3.. f2 Descmher.) Lee, F N.: assive smoking and cardiorespiratory health in Scotland SrR,-In an earlier letter' I claimed that misclas- sitiation of active smoking statc can explain the fact that F4rDavid J Hole and his collagues' found weak positive associations between passive smok- ing and a number of indiators of cardiorespintor}• health in the Scottish prospective stud}'. In their reply Mr Hole and colleagues prescnted'calcula- tions to justify their view: that the effect of misclassification is to produce "only small biases in the relative risk for passive smokcrs„" with the reported relative risk "wcll in excess"' of that produced by' this form of bias.' Uhfortunatel}', these calculations are grossly in error and therefore highly misicading. The error lies in basing aloulations on results for men and women combined withounadjustment for sex. Table I of the original paper° shows a clear TABLE1-"Obsrrvrd" rrlariar risks for passrvr smoking for varwng dental rares of fmoking+ Relau.c nsks for passivc smoking . Ratrof denul. ~~.~bsned (M1.~ Aien Women Ad,ustedt Umdlusted$ 2~ 1~74 1~-25~ 140 1~12 A 1'95'. 1~~42~. 11 58 1~18 6~ 2-06: 1`54 1!70 1~20 8 2~ 11: -63 L~iB 142~~. )0: 2~I5'. 1~~70 1 h9/~ 1.23~. •' Assummg "truc "'relau- nsks of I h0 for passtve smok.g.nd 20-0 fw acuvr smoktng. TAdtustadfdrseaustng warhis Ni\•1;\,+N;'., ~-hac N, and S,+rc the oDxrced numtrn of exprssed. and unexpned sabreen. Thus.o.a conxnauve appraaumauon io the. vue ad,usted frgure, Swhtch unnot bc caiculaN pre<txll lsom the dau prorud2d, b, Hodr rr ndi jAsprrnMHolerra':' association between the smoking habits of the index case and the cohabtttt, with the coneordance. (cross product ) ratio being:2-32 for men and'2 19 forwomen. Amappropnate esumate:of.the.eoncor- dance ratio for the sexes combtned with sex adiustment bv the Mantel Haensaei prtxedure"ss 2_'5. !f: inappropnatelc, the concordance ratio is alculated from the pooled data, a much lower figure of 1-29 tis obtained, and this masks mosl of the true association, This is importanl' because it an readii.v , be shown that the concordance ratio pror•ides the upper limit to the extenl of the observed relauve riskSrom passtve smoking due to misclassifiauon of smoking habtt (assuming a true relative risk of I`0). Table I shows that when correctlv calculated the obsened relative risk can far exceed the value of 1-20 stated b• MF Hole and hrs,collagues to be "the largest risk to be among passive smokers due to this form of bias."' The question arises as to the extent that' this source oflbias can explain all the reponed relaure risks for acttve.and passive smoking seen tn~.the Scottish stud}•. Table II'gives some insight into this question, showing "obsen•edT"and "true" rel5tive risks assuming a 4% denial of smoking; a figure consistent with data from mam• studies of the issue.' Comparing the "Observed" relativerisks of active and passive smoking with those glven in, TABLE rt-"Obser.,ed" relarsrxntk's forpcsnxandaranxnnokmg fortwy.mg "true" relatr.x.ntks fm sen~r rmaking' "Tirur" sliuve- nsks •'Obxrvedl' relnuvo niL, Pis- snaken Acuvc. smoken Passivc. srnokrn A:usr anokers 1 30~~ 1~70 9~~17. I 20~. 1~58 7-g8'. I 10'~ 1~39 5:,62~ I 5 143 3"63 I. 3 1~'13 2`S0~ I 2. I~OT~ t~gl • Assummg~'4 ab smok'rrs drmsmolung. Resulis arc for srxrs . romburcdadtwssed for ses as in ubk I. table V1I of the original papcr shows that there iss no problem whatsoever ia reconciling the data with the bias hypothesis for moscof the cardiorespira- tory endpoints.,Forcxample,,rclative risks of 3'77 (active) and' 121 (passive) for HpJxrscereuon are both verp close to the values given in table II for a "true:" acuve risk of5 (I -23 and 3-63/ respectiveh•). Only two endpoints deserve special comment. The first isdeath from lung cancer, for which risks of110•64 (active) and 2-41 (passive) were observed. The confidence mten'al for the risk with passive smoking was enormously wide (045 1o 12-83), and the point estimate of risk was higher tFian that in any of over20 other, largcr,studies on the issue.' I have claimed elsewhere that' miu7assi5cation of activc smoking state can explain the azeragee relative risk for, passive smoking of about 1-3-1 5 seen in epidemiological studies.' I retain this taew but have never stated that it explatned'1he figure in ehe Scottish studr, of'2-41, to which chance hasy clearlv contnbuted'substanuallp,. The other endpoint is ischaemic heart disease, fon which risks of 227 (active ) and 2-01 (passivel were observed. Although the risk w•ith~ passtvee smoking issignihcant (959beonhdence interval 121 to 3•35) and the lower confidence limit is slightly above the biasaxpectedy I do not:hnd this convincing evidence of a true effect of passtre smoking. ThisispartlN because the signifiancelevel is not high, bearing,in.mindthe number of endpoints stud)ed;, and part)v because d,e point estimate ofrerclativertskf for passive smoking tss difficult to reconcile with that for active smoking. 6earingin mind that smokers havee much'~hi¢her aetivrandpassive exposure to the consutuents.oi'. smoke, in thce ftsrm of both marnsueamand'stdestream smoke, than do passavel},cxposed non, smokers. More evid:ence is cleariv needed here., The American Cancer Srxrervmilhon person studc BA1J VOLUME 300 13 JA~;VARY 1990 120 ~

Leaers to the editor Repace, J. L; Lowrey. A. H. A quanuutive estimate of nonsmokers' lung cancer r'uk from passive smoking. Environ. Int. 11:3-22; 1985. USSG'(U. S. Surgeon General). The health consequences of invol- untary smoking. Rockville, MD: U. S. Department of Health and Human Services; 1986. Oberla, K. Lung cancer from passive smoking: hypothesis or con- vincing evidence? Int. Arch. Qccup~ Environ. Health 59:421- 437; 1987. AN STIMATE OF ADULT MORTALITY IN' THE UNIT STATES FROM PASSIVE SMOKING;. A RESP NSE TO CRITICISM Lee (1990), Katze tein (1990), and Holcomb (1990) have commented nega ely on my paper (Wells 1988a) in Environment lnterna " nal, im which it was sug- gested that the U.S. death 11 from passive smoking may be 46 000 per year. Spa e does not allow me to deal with alU of the points raise but the more impor- tant ones are covered below. Lee, as tobacco consultants usua do, attacks the underlying studies that 11 used, partic arly the heart studies. I cannot speak for these authors. . Hirayama has written a reply of his own. Dr. Sandl (private communication) has told me that they (Helsi et al. 1988) did look at family size and found no effec The Johns Hopkins School of Public Health (Helsin et al. 1988) and the University of California, San Dieg (Garland et al. 1985) are respected schools of epide- miology, whose researchers presumably know how to adjust for confounding variables. They attempted, within the limits of the data available, to account for known heart risk factors as noted in my paper. What is striking about the heart data in my Table 4 (Wells 1988a) is the consistency of the various results. It is interesting that Lee et al. (1986) made no attempt to adjust for any of the known heart risk factors except age. Publication bias in smoking studies is an issue often raised by tobacco industry consultants, but so far no one has found a live passive smoking case that is negative. I have dealt with that issue vis-8-vis passive smoking and male lung cancer in my com- ment (Wells 1988b) on Vandenbroucke (1988)., There, it was pointed out that the only available unpublished data were on the high side of the most probable relative risk, not low or negative. In that letter, I asked investigators to send me any data on passive smoking that had not been published or that they had 187 Wells, A. J. Passive rmok'ing mortality: a review and preliminary assessment. 79th Annual Meeting. Air Pollut. Control Assoc., Minneapolis, MN; 19$6. Pittsburyh, PA: Air Pollut. Control Association; 1986. Wellit„ A. J. An estimate of adult mortality in the United States from passive smoking. Eaviron, Int. 14:249-265; 1988. not been able to get published. So far I have received none. As Lee says, the possibility of a large, unpublished data set that found nothing cannot be excluded; it is just extremely unlikely. For cancers other than lung that are passive smok- ing related, all except nasal sinus cancer and lung cancer are non-contact sites, as is heart disease. For these sites to be activated, the disease-producing entities must, in most cases, be metabolized and then circulate in the blood and lymphatic systems: Earlier work (Eatough etal. 198b) has shown that 90% of the nicotine in environmental tobacco smoke (ETS) is in the vapor phase. Now Pritchard et al. (1988) have shown that 70% of the tar in ETS is also in the vapor phase. The nicotine and the tar in direct smoking is in the particulate phase. It is true, as Lee says, that smokers are also passive smokers, but for the non- contact sites there is growing evidence that smokers have a higher risk if they are exposed to ETS other than their own than if they are not so exposed. For example, Palmer et al. (1988)~ found a relative risk for heart disease of 1.34 for spouse ezposureof light oking women and 1.32 for heavy smoking women, an ' Sandier et al. (1985) found overall cancer risks incr sing from unity to 2.4 as active smokers were expose to an increasing number of household mem- bers who oked. This means that smokers may also be at consi rable risk from passive smoking of their own smoke. I ther words, for the non-contact sites, the vapor phase and nicotine may be the primaryy culprits, with the p icutate phase having less effect. The particulate phas at least most of it, is relatively quickly cleared. It pro ably contributes heavily to the contact sites (central I g, mouth, esophagus, and stomach) but then may beel' inated in the feces. All' this means that Lee's model or passive smoking, which is based on direct smo " g and particulate phase deposition and retention, i Iikely to predict relative risks for passive smoking th are far too low for the non-contact sites and probably r peripheral lung cancer as well.

Letten to the editor log weighted average of the current smoker relative risk for the studies shown in Table I of my paper (Wells I988a) is 4.56 (it was assumed that current smoker relative risk was 3096 higher than ever smoker relative risk if those were the only data avail- able)! which is less than half the value of 10 used by Lee. L='s book (1988) has whole sections devoted so misclassification factors for people who say they are recent ezsmokers. These data appear to be intro-• dueed simply to confuse the reader since they have no bearing on passive smoking epidemiology which .deals essentially entirely in self-reported never smok- ers. lf proper factors are used for the extent of smoker misclassification and smoker relative risk, the bias thatonetalculates agrees with the values previously estimated by Wells (1986a. 1988a) and Wald et al. (1986), and not with those of Lee.. Lee suggests that my estimate of passive smoking deaths may be high. My heart relative risk of 1.23 is supported' by two new studies and an update on a third. Palmer et a1. (1988) report a female heart rel- ative risk for passive smoking of 1.2, and Humble et -a1..(11990) report 1.6. Hole et al. (1989), in an update on the study of Gillis et al. (1984), report a female heart relative risk of 2.1 for low exposure passive smokers and 4.1 for high ezposure. Sandier et al. (1989) found no increase in risk for total cancer in women, buaMiller (1989) in hib new study found that non-smoking, non-employed wives of nonsmokers accounted for only• 3% of cancer deaths but a much higher percentage of tvtal deaths. These two new results will offset each other. Sandler et a1. (1989) also show a statistically significant female all cause relative risk of 1.15 for passive smoking, essentially identical1to the 1.165 value I had derived in Appendix B (Wells 1988a)~ from earlier data. This tends to validate my estimate of 34 000 female al'1 cause deaths from passive smoking. Sandler et al. (1989) also report a statistically significant all cause relative risk for men of 1.17 (the first snch data available), that would result in 29 000 deaths per year for a total for both sexes of 63 000, higher than, but not too far distant from the 46 000 deaths that I estimated from the three-disease approach: In our Western, non-traditional societies, it is very difficult to carry out these low-risk epidemiological studies because of the difficulty of finding a truly nonezposed reference category. Cummings etal (1990) point out that 9.190 of the nonsmokers they inter- viewed had measurable cotinine in their urine while only 76% reported the} had been exposed to tobacco smoke in the previous four days. Eighty-four percent of those not living with a smoker had measurable 119 cotinine. If these people are getting nicotine, known to be in the vapor phase of ETS, they must albo be getting tar, now known also to be in the ETS vapor phase (Pritchard 1988). Miller (1989) has probably done the best job of ferreting out a nonexposed ref- erence group with the result that he is finding very high relative risks for total cancer from passive smok- ing. As Goldstein (1986) has said, 'Chemicals shown to be carcinogenic are considered by regulators as 'guilty untillproven innocent' of having no threshold. This conservative approach essentially puts the bur- den on the producer or user of providing the scien- tific evidence jusufying a threshold iniregulating a carcinogen.` The purpose of my paper was to pro- vide regulators with an estimate of the most probable death toll from passive smoking given the ezisting epidemiological evidence,,and also data from which to calculate an upper bound estimate, as they usually wish to do. Nothing in Lee's comments, with his botched bias analysis and his flimsy dose model, does anything to 'justify a threshold' for this known human carcinogen. Katzenstein (1990) also appears to be very selec- tive in the data that he reports in Table I of his letter and he does not appear to have done his homework in finding all the reports on passive smoking andlung cancer that have issued since the 1986 reports of the National Academy of Sciences (NRC 1986)~ and' the Surgeon General (USSG 1986). Commenting first on the reports that he lisu. Chan and Fung (1982) is simply a restatement of the more dusiled data in Chan et al. (1979). 1 had rejected Chan et al. (1979) and Dalager et al. (1986) for reasons stated in my paper. Dalager's crude relative risk of 1.00 that Katsenstein reports is for both sexes. The only female all exposure relative risk in that paper is 1.96 for spouse exposure, not statistically signifi- cant. However among older women, 63 plus years of age, with high intensity ezposure, the odds ratio was 5.14 with 95% confidence limits of 1.4 to 18.95. A dose response trend was also observed. Kabat et al. (;1984) found a statistically significant odds ratio of 3.3 for male exposure at work and also found a sta- tistically signifcant Manttl test for linear trend in the frequency of exposure (four levels) for maJes (p < 0.005). Garfinkel et al. (1985) had a statistically significant odds ratio of 2.0 at the highest exposure. The results that Katzenstein quotes from Gao et al. (1987) are for never smoking women who ever lived with a smoker. For spouse exposure they report a rising reladve risk from 1.0 for less tban twenty years exposure to a suti'stically significant 1.7 for forty

1/2 Possible reasons would be (1) a longer follow-up period;and more cases in the 1984 report than in the 1981 report, or (2) husbands' age and occupation were standardized for data in 1991, while data reported in 1984 was standardized by age only. However, the latter is definitely not the reason responsible for the discrepancy, as age-occupation standardized data in 1984 showed almost similar re- sults, corresponding relative risks (r.rs) being 1.00, 1.11, and 1.36 (trend p: 0.009), respectively (Table I). The resulu were also similar when stand'ardized by wives' age, corresponding r.ts being 1.00, 1.09, and 1.34 (irend' p : 0.019). Therefore, it should be con- cluded that the more cigarettes the husbands smoke, the higher the ischemic heart disease risk in non- smoking wives. In 1980-198L, r.rs of ischemic heart disease in nonsmoking wives were 1.00,, 1.29, and 1.87 (trend p : 0.041) when husbands were nonsmokers, exsmokers/10-19 daily, and 20+ daily respectively. One may further consider as the possible reasons for REBUTTAL TO LEE/KATZENSTEIN COMMENTARY ON PASSIVE SMOKING RISK Lee (1989) an anstein (1989), in their com- mentary on Wells"(198 per, take issue not only with Wells"estimates of the m itude of the mortal- ity effect of passive smoking on nsmokers, but question whether mortality occurs at a Their argu- ments are based upon the alleged fragiit of the epidemiological' studies of passive smoking an is- ease; the potential for misclassification of subjec disease, or exposure; possible eonfounding f ors; and the lower doses of smoke to which no moken are exposed relative to smokers. Let us examine these issues one one. A?e DOn- smokers exposed to such low do of environmental tobacco smoke (ETS) that W s' estimates of 46 000 nonsmokers' deaths per from passive smoking are about '46 000 too gh', as Lee assertsl Perhaps the most salient p' t to be considered: active smok- ing is a cause o ore than one out of every six deaths in the U.S.y4/~very year (USSO 1989). Intentional exposure'{o tobacco smoke has been judged to cause coron~ry heart disease, atherosclerotic peripheral vas- L` 1-enrn to dte editor this discrepancy the influence of the changing qual- ity of side-stream smoke coming out of the ignited end of cigarettes in recent years due to the intensive chemical manipulation of the products (e.g., inclu- sion of tobacco additives) in order to lower tar and nicotine, to improve the flavor, etc. Also, the recent increase in fat consumption in Japan may interact on the risk of ischemic heart disease when exposed to passive smoking. Takeshi Hirayama Institute of Preventive Medicine Tokyojapan REFERENCES Hiraynma, T. Btoe-smokinj wives of heavy ®oken heve a hi3ber riek of lnag eaoesr, a study from Japan. Br. M,ed. J. 2R2:1f3- 1aJ; 1981. Ftirayama, T. Lung cancer ie Jefpan. Effecu of autriuoo and paa- .ive.motin{. In: itiull„M.; Correa, P., ads. New Yort: Veriaa Chemie Iauraatioeal 1sc.; 19a4:17S-J91. cular disease, lung and larytsgsal cancer, oral cancer, esophageal cancer, chronic obstructive pulmonary disease, chronic bronchitis, intrauterine growth re- tardation, and low birthweight babies. In addition, probable causality has also be successful pregnancies, in and peptic ulcer diseas bladder, pancreas, been reported fo Hardly an o undi as d esublished for un- ased infant mortality. 'as well as cancers of the kidney, and associations have cer of the stomach (USSG 1989). n system of the human body remains upon exposure to tobacco smoke. To argue, e and Katzenstein, that the diseases of smok- are not even plausible in nonsmokers does not give us confidence in their deductive abilities. To be sure, it is possible that thresholds for effect may exist or one or more of the diseases of smoking, but ne wha er Lee nor Katzenstein present any evidence ver that such low dose thresholds exist, let alone th al1 nonsmokers have exposures and sus- ceptibilitiei hieh place them within an adequate margin of safef Are the epideai l'ow, such thresholds. ogical studies of passive smok- ing and lung cancer ly all to be explained by n.as nonsmokers as Lee misclassification of smok has proposed? Nonsmokers who report no passive smokirg nevertheless possess levels of nicotine and cotinine in body fluids which are significant frac- tions of those who report a lot of exposure. For 2V I:r 3ti11 V92

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Gillis, C.R.; Hole, D.I.; Hawthorne, V.M. The effects of envi- ronmental'tobacco smoke ia two urban communities in the west of Stotland., Eur. J. Resp. Dia. 65 (supplement No, 133);121-126; 1984. Goldstein, B. D. Critical review of toxic air polluanu-revisited. I. Air Pollut. Control Assoc. 3b:367-370; 1986. HHelsing, K. J:; Sandier, D. P.; Comstock„G. W.; Chee, E. Heart disease mortality in nonsmokers living with smokers. Am. J. Epidemioll 127:915-922; 1988. Holcomb, L. C. An estimate of adult mortality in the United States from passive smoking; a response. Environ. Int.. 16:184-186; 1990. Hole, D. J.; Gillis, C. R.; Chopra, C.; Hawthorna, V. M. Passive amoking and'cardiorespiratory health in a general Populataon in the wesrof Seotland. Br. Med. 1. 299:423-427; 1989. - Humble, C. G.; Samet, J. M.; Pathak, D. R. Marriage to a smoker and lung cancer risk. Am. J', Public Health 77:598-602 1987. Humble, C.; Croft, L; Gerber; A.; Casper, M.; Hames, C.G:; Tyroler, H'.A.. Passive smoking and twenty year eardio- vucular disease mortality among nonsmoking wives in Evans County. Georgia. Am. 1. Public Health [in pressj;1990. Inoue, R.; Hirayama, T. Passive smoking and lung cancer in women. In: Aoki, M.; Hisamiehi, S.; Tominaga, S., eds. Smoking and1ealth 1987. Amsterdam:$:cerpo Medica; 1988: 2g3-385. Jones, R. A. Individual differences in nicotine sensitivity. Addictive B'ehavior 11:435-438; 1986. Kabat„ G. C.;, Wynder, E. L. Lung cancer in nonsmokers. Cancer 53:121i4-1221: 1984., Katzenstein, A. W. An estimate of adult mortality in the United States from passive smoking: a response. Envtron.. Int. 16:175-179; 1990: Khoury, M. 1.; Flanders„W'D:; Greenland, S.: Adams, M.J: On the measurement of susteptibility in epidemiologic studies. Am.,l. Epidemiol. 1:29:1 g3-1'90; 1989. Koo„L. C.; Ho; I. H-C.; Ryl.adei„R. Life-history correlates of environmental tobacco smoke: a study on nonsmoking Hbng Kong Chinese wives with smoking versus nonsmoking hus- bands. Soc. Sci. Med. 26:751-760;, 1988. Lam, T. H. et al. Smoking, passive smoking and hutologicall types in lung cancer in Hong Kong Chinese women. Br. 1. Cancer 56:673-678; 1987.. Lam„W: K. A clinical and epidemiological study of carcinoma oflung eancer in Hong-Kocg. Hong Kong: Hong Kong Univ.; 1985. Dissertation. Lassila, R:; Seyberthl H.W:; Haapanen, A.; Schweer, H.; Koakenvuo, M.; Laustioli. K.E. Vasoactive and atberogenic effects of cigarette smoking: a study of monozygotic twins discordanrfor smoking. Br. Med. 1. 297:955-957; 1998. lLee, P. N:; Chamberlain,, ].; Alderson, M. R. Relationship of passive smoking to risk of lung cancer and other smoking-as- sociated diseases. Br. 1. Cancer 54:97-105;, 1986. Lee, P. N. Does breathing other people's tobacco smoke cause lung cancer7 Br. Med. 1. 293:1503-1504; 1986. Lee„P.N.,Pasive smoking and lbng cancer association: a resuh of bias? Human Tozicol. 6:517-524; 1987. Lee„ P. N.: Miselassification of' smoking babiti and passive smoking. A review of the evidenee.,International Archives of Occupational and Environmental Health. Berlin: Springer- Verlag; 1988.. Lee, P. N: An estimate of adult mortality in the United States from passive smoking; a response. Environ. Int. 16:179-181; 19901 Miller, G: H~ The impact of passive smoking: cancer deaths among nonsmoking women. Cancer Detecuon and Prev: 14:78; 1989. NRC (National Research Council) Environmental tobacco smoke, measuring exposures and assessing health effects. Washi,ng- ton, DX:: National Academy Press;, 1986. Palmer, J. R.;, Rosenberg. L.; Shapiro, S. Passive smoking and myocardial infarction in women. CVD Epidemiol. Newsdetter, 43(winter):29; 1988. Pritchard, 1. N.; B1ack, A.; McAughey, J. J. The physical behav- ior of sidestream tobacco smoke under ambient conditions. In: Indoor and ambient air quality., London: Selper,, 1988: 49-55., Remmer, H. Passively inhaled tobacco smoke:  challenge to toxicology and preventive medicine. Arch. Toiicot. 61:89- 104; 1987: Repace. 1. L.; Lowrey, A. H. A quantitative estimate of non- smoker's lung cancer risk from passive smoking. Environ. Int. 11:3-22; 1985. Stndier„D. P.; Wilcoz, A. I.; Everson, R. B. Cumulative effects of lifetime passive smoking on cancer risk.: Lancet (i):312- 315;1985. Sandler, D. P.; Comstock„ G. W.; Helsing, K. J'.; Shorc, D. L- Deaths from all causes in noa-smoken who lived with smok- ers. Am. 1. Public Health 79:163-167; 1989. Shimizu, H. et al. A cue control study of lung cancer in non- smoking women, Toboku J. Exper. Med. 1,54:389-397; 1988.

184 Lee, P. N: An estimate of adult mortality in the U.S. from pustve smoking„a response.,Envaroo. lnt. 16:179-181; 1990:, Katzenstetn, A. W. An esrimate of adult monaliiy,in the li.S: from passiNe smoking; a response. Environ. Int. 161173'-177;, 1990. Rcpace„Ji. L.; Lowrey„A. H. Rssk aasessmenrmetAodolopes in passiNe smokinj. J. Risk Anal. (in press] 1990. LSSG (U. S. Surgeon General)!Rcducinj the health eonsequences of smoking. 25 years of' proyress„ a report of the Surgeon AN ESTIMATE OF ADULT MORTALITY IN THE UNITMSTATES FROM PASSIVE SMOKING; A RESPONSE Dear Editor: An article in Inside EPA (January 13, 1989) is headlined: 'EPA weighs_Impact of Study Linking Passive Smoke Exposure to Heart Deaths..." lt leads with the statement: "EPA is giving serious attention to~a recently published study that pinpoints passive smoking ... as a significant cause,of heart disease and cancer-related deaths'. The articl; states: "Pas- sive smoking causes 46 000 deaths a year, according to~a study by A. Judson Wells published lot month in Environmenr lnternarional'. An EPA source is quoted: 'The 46 000 mortality was surprisi,ng,be- cause such a large eomponenvwas from heartdisease Lei:ert :o cmc :-ucr General. Washington. D.C.: U S. Dept. of Health & Human Servicer, 1989. W'allace, L. A Major sources of benzene eaposure. Environ Health Perspect. 82: 165 • 169; 1989. Wetca, S., T Passive smokin8 and lung eancer: .har ts the rssk? American Rev: of Resp. Dts. 133463-465, 1986 Wells, A. J. An estima:e ot adult monality in the Lot,tcd States. Environ. Int. 14':2+9-I65; 1988. with ETS exposure. These calculations do not in any way establish that ETS does, in fact, cause death in expose& individuals. Rather, such calculations rely on an independent conclusion, based on a review of the available data, that ETS causes lung cancer, other cancers, and cardiovascular diseases. If such a con. clusion cannot be supported, then the estimate of ETS-associated mortality rests on the aswmption that ETS causes these diseases, and it is incumbent upon the author to state this underlying assumption when reporting the results of his calculations. The issue ofeausation is neveraddressed by Wells. The studies cited in Wells' Tables 1-4 are discussed below with -particular attention to whether they es- tablish a,causal relationshi'p between ETS and dis- ease in yi~on- or never-smokers. The vast majority of the stud'ies were included in reviews publishedty the Natipnal Academy of' Sciences (NAS 1986) and' the Su1•geon Generall(USSG 1986). Therefore, these re- addressin the i iat f d g ng po or as a start ." Thi's statement is similar to one made by EPA's , pprts are use James Repact on national television when the report '~ '~uestion of causality. was first released. Lung Cancer: A1mosP all of the epidemiological' What is surprising is'that' anyone from the EPA can~ st9dies listed in Wells' Tables I and 2'were consid- consider this recent review surprising. Dr. Wells has ered in the NAS and Surgeon, General's reports, as not completed an epidemiological study, new or ~`'h- well',~s other reviews appearing at about the same erwise, and has in no way contributed to pinpoig #ing time (c'lot and Fraumeni 1986; Uberla 1987), The l passive smoking as a significant cause of hea dis- ease, lung cancer, or other cancer deaths. Wh he did udang Surgeon\General s Report was alone in conc that ETS c^~uses lung cancer in nonsmokers; the other was publish the results of a series of calfftlations reviews genErally concluded that although a statisti- based on the results of existing epidemiolo$ tcal stud- cal associat'taqn appeared to exist between marriage ies and a number of assumptions (Wells!1988). Dr. to a smokec aT.Q the risk of lung cancer, the lack of Wells presented a similar analysis at tp'e 1986 Air adequate expos Pollution Control Association meettng, which was fluence of differ e information, and'the potential in- tial misclassification of smoking onclusion of causality. The lung published in the meeting proceedings. (Wells 1986). status precluded a There should have been no sudden sitrprise at EPA; cancer studies publi an EPA official chaired the 1986 session in which this same limitations as i ed since these reviews have the e previous studies. Little has paper was presented. Dr. Wells eneourages the view been published since l that he had done something new by failing to even the issues of exposure a 86 that adequately addresses d misclassification. ting to link cancer to ETS acknowledge his previous presentation. All of the studies atterri Wells used the data of previously published (and have been epidemiologicaf, : An epidemiology study in some cases, unpublished) studies as a basis for attempts to relate the frequeqcy' of a certain health calculating annual mortality statistically associated effect or disease with the frequency of specific envi-

ace, T. 192 Possible reasons would be (1) a longer follow-up period and moie,cases in the 1984 report than in the 1981 report, or Z2„l husbands' age and occupation were standardized"For data in 1981, while data reporte& in 1984 was andardized by age only. However, the latter is 'nitely not the reason responsible for the discrepan as age-occupat re- standardized data in 1984 showX sulu„ corresponding relative ri.00; 1.11, and 1.36 (trend p: 0.009), 1). esults were also similar by The r wives' age, corresponding r.rs nd 1.34 (trend p: 0:019). The ore, it should be cn~ cluded that the more cig ttes the husbands smoke, the higher the ische`nac heart disease risk in non- smoking wives. In 1980-198, r.rs of ischemic heart disease in nonsmokin~~ivives were 1.00, 1.29, and 1.87 (trend p: 0.0. 'f) when husbands were nonsmokers, ezs ers/10-19 daily, and 20+ daily respectively. O may further consider as the possible reasons for L. u.,,S ow,.ey, A,1k. Sv-- .3,,,t REBUTTAL TO LEE/KATZENSTEIN COMMENTARY ON PASSIVE SMOKING RISK Dear Editor. Let (1989) and Katzenstein (1989), in their com- mentary on Wells"(1988) paper, take issue not only with Wells' estimates of the magnitude of the mortal- ity effect of passive smoking on nonsmokers, but question whether mortality occurs at all. Their argu- ments are based upon the alleged fragility of the epidemiological studies of passive smoking and dis- ease; the potential for misclassification of subjects, disease, or exposure; possible confounding factors; and the lower doses of smoke to which nonsmokers are exposed relative to smokers. Let us examine these issues one by one. Are non- smokers exposed to such low doses of environmental tobacco smoke (ETS) that Wells' estimates of 46 000 nonsmokers' deaths per year from passive smoking are about '46 000 too high', as Lee asserts? Perhaps the most salient point to be considered: active smok- ing is a cause of more than one out of every six deaths in the U.S.A. every year (USSO 1989). Intentional exposure to tobacco smoke has been judged to cause coronary hean disease, atherosclerotic peripheral vas- Nn~T1Ci: This materr,al may 5e protected by c3a-FVt tj,d (fit1e 17 U.S. Code',• Leticrn to thc editor this discrepan the influence of the changing qual- ity of side eam smoke coming out of the ignited end' of ' arettes in recent years due to the intensive che cal, manipulation of the products (e,g., inclu- n of tobacco additives) in order to lower tar and nicotine, to improve the flavor, etc. Al'so, the recent increase in fat consumption in Japan may interact on the risk of ischemic heart disease when exposed to passive smoking. Tateshi Hirayama Institute of Preventive Medicine Tokyo,Japan ERENCES Hinyama, I. Noe-smonin{ wives of heavr ®okers have a digser riek of lon{ cancer, a etedy from Japaa. Br. Mcd. J. 212:113- 119; 1911. "Hinyama, T. Lnnj t•eacer in Japaa. Effects of natriuon and pu- sive smoting. In: Miis11, M.; Ccrre.a.,P.. eds. New Yort: Vertas Cbeenie tnurseuooaJ'Ioc-,.k9 94:17S-199. LL (.Z_) , (t, 119`10 cular disease. lung and laryWal cancer, oral cancer, esophageal cancer, chronic obstructive pulmonary disease, chronic bronchitis, intrauterine growth re- tardation, and low birthweighr babies. In addition, probable causality has also been established for un- successful pregnancies, increased infant mortality. and peptic ulcer disease, as well as cancers of the bladder, pancreas, and kidney, and associations have been reported for cancer of the stomach (USSG 1989). Hardly an organ system of the human body remains undiseased upon exposure to tobacco smoke. To argue, as do Lee and Kauenstein, that the diseases of smok- ing are not even plausible in nonsmokers does not give us confidence in their deductive abilities. To be sure, it is possible that thresholds for effect may exist for one or more of the diseases of smoking, but neither Lee nor Katzenstein present any evidence whatsoever that such low dose thresholds exist. let alone that all nonsmokers have exposures and sus- ceptibilities which place them within an adequate margin of safety below such thresholds. Are the epidemiological studies of passive smok- ing and lung cancer really all to be explained by misclassification of smokers as nonsmokers as Lee has proposed? Nonsmokers who report no passive smoking nevertheless possess levels of nicotine and cotinine in body fluids which are significant frac- tions of those who report a lot of exposure. For 202_03511S93

190 plus years exposure. Shimizu et al. (1988), besides reporting the 1.1 nonsignificantrisk for nonsmoking wives exposed to a husband's smoke also reporta 4.0 significant risk for exposure to a mother's smoking and 3.2 for exposure to the husband"s father's smok- ing. The latter is not unusual since wives in Japan, after they leave their mother's home, often live with the husband's family and the husband's father is often retired. Wu et al. (1985), Brownson etal. (1987), Hum- ble et al. (1987), and Lam et al. (1987) ',were covered in my paper (Wells 1988a). The male relative risk in Humble et al. (private communication) is a statisti.- cally significant 4.2. New reports that Katzenstein evidently is notaware ofare (1) the Hong Kong thesis of W. K. Lam (1985) with 60 female cases and a statistically significant relative risk of 2.01 and a risk for peripheral tumors of 2.64 (p < 0.05); (2) Geng et al. (1988)with 54 casesand,a statistically significant odds ratio of 2.16 for all levels of exposure, an&2.76 with 95% confidence limits of 1.85 to 4.10 for exposure to 20 plus cigarettes per day. They also report a relative risk from ETS for smoking wives of 1.88; (3)4noue an&Hirayama (1988) wi'th 22 cases report a nonsignificant odds ratio of 2.25 for all exposure levels, but for exposure to 2'0 plus ciga- rettes a day the odds ratio is a statistically significant 3.35 (they also report a statistically significant pos- itive trend)t (4) Svensson ('1968), in a thesis from Sweden, with 34 female nonsmoking lung cancer cases, found a relative risk of 1.2 for exposure at home or at work and: a relative risk of 2.1 for expo- sure at home and at work. He also found' a relative risk of 1.4 for exposure as a child or as an adult and 1.9 for exposure both as a child and as an adult. None of Svensson's relative risks is statistically signifi- cant; and (S) Varela (1987) also in a thesis, this one from Yale University, reports on 21:8 female cases and 221 male cases which incl'uded' botb never smok- ers and long-term ezsmokers. He found no increase in risk for spouse exposure or workplace exposure but found a statistically significant relative risk of 1.87 multiple exposures at home. Katzenstein'a attack on the underlying studies is a typical tobacco industry approach. As we know, all epidemiological studies are flawed to one extent or another. However the National Academy and the Sur- geon General, looking at the totalitX of the studies then available, concluded that passive smoking can cause lung cancer, and inclusion of the studies new since 1986 would' not change that conclusion. Katzenstein is wrong when he says that the heart studies failed to consider cardiovascular risk factors. Garland et al. (1985) and Helsing et al. (1988) ad- L.cuen to the edstor justed for several of them. The Svendsen study (1987), considered ten of the most frequently studied heart risk factors, comparing 286 nonsmoking men married~ to smokers and 959 married to nonsmokers. The dif- ferences were small, and adjusting for them did not decrease the observed risk. Katzenstein quotes an American Cancer Society 1988 release saying that currently, available evidence is not sufficient to con- clude that passive or involuntary smoking causes lung cancer in nonsmokers. He must have found this in the rare book store since neither the Delaware office nor the national office of the American Cancer Society could find this reference. On the contrary the ACS 'Cancer Facts and Figures for 1989' states that involuntary smoking in;.reased the risk of lung can- cer, and their 'The Smoke Around You' pamphlet issued in 1987quotes the 35% increase in lung cancer risk for passive smoking that is found in the National Academy report (NRC 1986). In Katzenstein's 'final comment' where he quotes the NAS and USSG reports on passive smoking aad~ heart di'sease, he fails to note that the best heart evidence is in papers issued since those reports came out. It is interesting that the newest reports (Palmer 1989; Hole 1989; Humble 1990) all support a posi- tive relative risk. Holcomb (1990) states that I had encouraged the view that the results in Wells (1988a) were new. Actually that paper has a long history. The original version was presented at a seminar at the Harvard School of Public Health in Deeember, 1984. An up- date was presented to the National Research Council in January, 1986. The version Holcomb refers to was presented at the June, 1986, meeting of the Air Pol- luuon Control Association, and in September, 1986, before the Natural Resources, Agriculture Research and Environment Subcommittee of the Committee on Science and Technology of the U.S. House of Repre- sentatives. It is published in the proceedings of those meetings (Wells 1986b, 2987). After extensive revi- sion, a shortened version was presented at the 6th World Conference on Smoking and Health in Tokyo in November of 1987. A summary is published in the proceedings of that meeting (Wells 1988c). The fir:t draft of the current version (Wells 1988a) contained a summary of this history, but the editors of Enviroe- ment lnttrnatioaal' decided that since none of the earlier versions had been~adequately peer reviewed, reference to them could be omitted. It should be noted that the current paper profited by the many comments received over the years from many experts in the field who either commented gratuitously or whose advice was solicited. James Repace was sur-

hea~A% eNposed µor~kers. Ho ' ~e%er, further anal}sts sho%k~ that, both the share ot pocm%r studies and the postti%e trend %ktth increastng,tud> quauts are %Irtuallye the ame when the dittereni t~re: oi studies are ana- I%zed separatel' %. %%hiie the relationship be:ween IoN-Ie%el lead ex- posure and'blood pressure. h~pertension has been dealt %%tth in detail in the earlier, mentioned revlews trom 198' and 1988 t2"-321, studies of lead'workers utth. constderably higher le%els or exposure haLe not. As these studies are of parncutar interest for occupational medicine, I ha\e included st% dealing wtth mortality in m% review. Dtngwall-Fordyce& Lane (64. 661 found increasing cerebrovascular mortalit' v . wtth increasing lead' ex- posure. The standardized mortalitc ratio (Sx 1R') values were 94. 98; an& 160 for emplo.ed lead workers as exe posure increased and 76, 1i76. and 258 for retired1ead workers. respeetisely. A latertollow-up study showed the same trend, but - as expected - converging SNiR' values (65). Cooper, and his co-workers (57-59) found' moder- atelv elevated or, normallSMR ~alues tot cerebrovas- cular mortality in two lead-exposed cohorts (SMR 132 and 93) but elevated values for "other hypertensive dis- eases" (SIv1R 475 and 320) and "hypertensive heart dis- eases" (SMR 203 and 128). Mctitichaell& Johnson (86) compared the mortali- ty of', workers with previous lead' poisoning wit'h the mortalitL of other lead workers and Austratian men in generall Using proportionate mortality ratios, they found twice as many deaths due to cerebral hemor- rhage and'24 Wo more deaths due to other cerebrovas- cular diseases among the formerly, lead~poisoned work- ers than among the other: lead'workers. In a compari- son with.4ustralian men, the differences were even greater. . Da~tes (62) also studied men with previously regis- tered lead poisoning and found an SMR of 410 for cerebrovascular diseases. Selevan et al (93. 94) found fewer cerebrovascultr deaths than expected (SMR 84), but even in tha "nega- tivc"'studv the SMR values for cerebrovascular deaths increased with increasing exposure (<5 years: SMR 17; 5-19 years:,SMR 75: 220 years: SMR 146). Finally: Gerhard'sson et al (40) found an SMR of 130 for cerebrovascular diseases among lead workers. Internal'comparisons showed a positive correlation be- tween both the mean blood-lead level and the peak blood-lead level and cerebrovascular mortality. These six, mortality studies of lead-exposed wort- ers all have a medium level of'epidemiologic quality: However, when the problems associated with histori- cal prospective mortality studies are taken into con- sideration4 the investigations show a rather consistent pattern with increased'cerebrovascular or hypertensive mortality in the highly exposed groups. In addition, most of the studies showed an increased mortality as a result of chronic renal disease. Even though studtes with high methodological qual- Ity! (-YxXx"'or "xxsxx") are few, the followtng con- clusions seem reasonable on the basis of the existing epidemiologic literature: liD there is a causal relation- ship between lead exposure and blood'pressure even at low exposure levels corresponding to blood-lead levels below 30 µg dl h2'. 28. 3E 70; "3. 74, 106t. and, even if the relattonship is weak, this relationship may ha.e considerable public health implications due to the widespread lead exposure throughout the industriall ized world (32. 72):'(ii) there is an increased'incidence of .erebrovasculhr diseases among workers who have been occupationally exposed toJeado but the c(anfi- cation~oG the dose-response relationship is not possi- bie on the basis of the existing studies: (iiif no studies have been found in which the incidence of ischemic heart disease (dHD) increased as a result of lead'ex- posure. Cadmium The relationship between cadmium and CVD has been treated with considerable variabilityy in general reviews on environmental exposures and CVD. A few authors dealt with the topic rather extensively (6, 10; 11. 13), but none gave more than 10 references. Others men- tioned the possible relationship between cadmium and CVD but treated the topic very superficially (1, 2, 5), while the remaining authors did' not mention cadmi, urn at all (3, 4, 7-9, 12): In those articles in which the topic is discussed, it is concluded that the ques, tion is not sufficiently clarified and that further re- search is nece3sary.. In the special reviews on the associations between trace metals or cadmium and CVD, the possible rela- tionship between cadmium and blood pressure is treat- ed exhaustively by all the authors. In the older, reviews from the 1960s and the first half of the 1970s, there is generally a betief in the hypothesis of a cadmium- blood pressure relationship (16-19, 108-110). Among these reviews, Schroeder's experiments on rats in the early 1960s play an important role. From 1976 on, skeptical articles and reviews (20. 23. 111-116) alternate with, more positive ones (U17-119): Con- sid'erable agreement exists regarding the relationship between cadmium exposure and increased blood pres- sure showmin animallexperimenu with rats, dogs, and rabbits, but there is no consensus on the interpreta- tion of research on humans. After more than a quar- ter of a century of research comprising hundreds of experiments and inveztigations. Spieker et al (116) con- cluded in one of the most recent reviews: "The data available up to now [about the connection between hu- man hypertension and'cadmium polliltionJ can only be considered as a fursnstep to clarify this problem [p 35)~'. This is, indeed„a modest profit from~such great efforts. In the present review, 33 investigations of cadmium and CVD (mainly blood pressure/hypertension) have been evaluated. In 11 of the studies, cadmium in blood! 247.

urine, hair, or kidneys has been compared for live hvpcrtensi.c and~normotensn:e persons. In nine studies persons Nho died from hypertenslve hearn disease or related causes hase been compared with persons who died~ of other causes. ln these studies. the cadmium conieni uas ¢enerally measured from the kldneys or Iner. Fne studies are cross-sectional investigations oi represcntati~c population groups fonwhich the blood pressure ha5 been related to cadmiumdn blood or urine. Four studies ha.e related cadmium pollution in cari+ ous nty areas to morbidiry and mortality, and the last four are occupationallmedical studies. Table 2 contains a surney' ofthe results and qualit% of these studies. The table indicates the following: (i) the studies examined have, in general, a loµ epidemiologic qualny, and none of the studies have been rated "zxxx'" or "xxxxx"; (ii)113 of the studies (39 0'o) show(a tendencytowards) a positive relationship (• or (+ IJlbetween cadmium exposure and CVD: and (iii) there is a negative rela- tionship betv.rcn study quality and "positivir)." Of the studies with a rating of -x," 46 4rro were positive; of the studies with a rating ofi"zx," 44 ro were posi- ti.e: and of the studies with a rating of "xzx," 27 °b~ were positive. Both the low share of positive studies and the nega- uve trend in the table speak against the cad'mium-CVD hypothesis. The conclusion therefore is that the null hypothesis is best supported by the investigations ex- amined. The methodological level of the research, on cad- mium and CVD (especially blood pressure/hyperten- sion) is so low that an identificatiomof the most com- mon errors and flaws is important to facilitate their avoidance in future research. One of the worst prob- lems concerns the measuremenuof cadmium exposure. Many studies estimated the exposure by measuring cad- mium in blood (77„ 80, 124, 137, 138, 140, 141, 148-151, 153): The blood cadmium level is, however, not a very reliable measure of the cadmium body bur- den. As early as 1976, Morgan (155) wrote: "Blood and urine'may be convenient fluids to measure, but neither is well correlated with kidney or liver content, which together, comprise about, one half of the body burdem(p 1361 j." In contrast, the blood contaiits only Tapbe 2. Resuns of 33 eDfaemfotopic studies orcartlfovascu- tar oiseases ICVD) ano8a0mfum exposure according to t1U metnod0i0p.cat Ouaiity ot'tfie stutlres. The taDte fs luseO on references 55. 77, 80, 95-p7, 1U7;,1'20-15r. DaQtN of .aufOnsn,a M.fflOpp/oq,cal eya/ny. _ ,:ii[ _-._[ N. % N % N N. N % f-i 0 -3 2,30 4, ao t tt., 1t1 0 3 23.1 ]33.3 S U.5 u17.3 f.f 2 t6• - o 3 273 5 152 4 70.e a ua_ 0 8 ]a29. 4 30 e - o - 0 4 1211 Totai1 13 1100 a too. 111 100 33 1(70 •$H taD14 1 1101 an e=Otana110n Of.tM er/10dll 6: L°`o ot the body burden. Morgan recommended mea- suring cadmium in hair. kidneys, or llser. This ~leµ is stron¢Ih supported b% other experts. including Lauwerys (11:) and Perry & Kopp (1 19). Several studies have emplo" yed cadmium imurine as a measure of past exposvre. but, this measure must be regarded as ban¢ estnipoorer than cadmium in blood (77. 95, 107. 138. 144. 153). Se.en of, the 13 positive studies in table 2 ha%c emploved cadmium in blood or urine as the measure of exposure. Two of the remaining six positive studies employed the cadmium content in air in a number of American cities as a measure of exposure. The results were then correlated to CVD mortality, and a posati.e relation, ship was found (131, 13'2)1 This method is problemat- ical for many'reasons. For example. r,he influence ofi cadmium in air on body burden is very slight. The stg- nificant factors are food, smoking, water, and occupa• tional exposure. Another, major methodological problem concerns the study design employed. Many of the in.estiaatlons employed a "quasi case-referent" d'estgn tn wh,ch sick persons (wtth hypertension or IHD) were compared to healthy referents (77, 123, 124, 128, I30; 133, 140--142, 14s-154). These studies are called "quasi case-referent"' because in reality they are cross- secuonal studies in which "disease" (hypenension, for example)iis measured simultaneously with "exposvre"' (forexample, cadmium in blood). Thisd'esign is prob- lematical for seseral reasons. First, because blood pres- sure and the blood'cadmium levefare measured simul- taneously, it is not possible to exclude the possibility that thcdirection of causation is reversed, ie, that per- sons with hypertension have aniincreased content of cadmium, in their blood due to metabolic changes. This possibility has, in fact, been mentioned by several'l authors, and one study directly concluded that hyper- tension increases the blood'cadmiumilevel (14'I). Sec- ond, in most studies the selection of both cases and referents has been described very superficially or not at all. Since selection is of paramount importance in ease-referent studies, this is an important potential flaw. Third, in many studies, the researchers had matched for smoking habits, and this is an error as tobacco smoking is not a risk factor for Fiytxrtension. 1'.n reality, it is overmatching because an imponant source of cadmium in the bodyis being blocked! Con- versely, relative weight and eduution/social status have not been matched, and such matching should be done since both~ are risk factors for hypertension. Fourth, comparing normotensive and hypertensive per- sons leads to dichotomy. Instead, one should rather have operated with the whole spectrum of values on the blbod'pressure scale. This problem is especially im- portant because many authors have hypothesized that the relationship between cadmium exposure and blood pressure has a reversed lJ'shapewith the largest effect at medium-high cadmium exposure levels. L"

Tabt. I Results ot 63 eDiOem o1opic stu0res of caroiovasou Ln oiseases ((rVO•1 anc leaC e.oosUre ac,,oro'nQ 1o :ne r*+emoaolcqi.ai ouality Of tne stuot.s The tzoie rs nasec oft •e,e•eaces 26 33-i(I7 Me'^o00iOQrCai . Guawy.' . .. .., .... .-...,, % ~. . N .. N . N . W - - • 53 - 0 - o+ 16 0 0 o- 0 0 0 e.. . 6 316 6 25o - 0 20 3+ 7 -s2r6I rQS 76D- o. 9,a7. 3 +6+ 9 a7. is 667 2 ,00 30 a7 6 + 7 1,, , 5 3 - 0 - 0 . 3 .a Totai r6 +QC rQ +W 24 100 21tqe> >00 •-=e.anor•s?ioo.r..Nl, uaO.aoosYn wo CVO,WOOO o.s.. 11.10 ,.ss1,Qneor,n¢ol1s,si.nr..n.Qarwr.mn.onsn.o Q.nor.rr1.o- sn.p 1~.iP,Q-1Or•nCOn~~l1MfDOS+IiWAIa/iOnfMO.• ~DOfrlw.74a- r,Onsn~3 ana I uncRtU,^ •MaPOnsn,o .. Cnf crr.r4 'o, mernooo-oQ.ca+ Qualiryan .[abn.o N.Inn r.a No swo-.s ,u .,.,. ro• ounliy ti(ied. they have been regarded as separate studies. On the other hand, the same research pro)ect is often pub- lished in several articles. eg. in prospective studies, in -hich successive results are published as the cohort grows olden. In such~cases. all articles have been evalir- ated as a whole with regard to study outcome and methodological quality. R.sults Lead' Many epid'emiologic studies have been published on, lead and CVD. tionetheless. the topic is treated very superficially in the general reviews on the relationship between environmental exposures and CVD. In several more recent reviews, lead is not mentioned at all (3. 4• 7; 8). while the topic is treated very briefly with a maximum of three references in others (1, 2, 5, 9, 12). Only in the early review, by Warshaw from 1960 (13), in Kurppa et al's review of 1994 (6), and in the reports of Rosenman (10, 11) is a reasonably thorough dis- cussion of the possible lead-CVD relationship included! These authors give six to twelve empirical references. The general conclusion drawn by the authors who men- tion the topic is that further research is necessary. In the more specific literature on lead, trace met- als, or trace elements, similar divergencies are found. There are examples of~ CVD not being mentioned in reviews on lead and health (15) and of lead not being mentioned in reviews on: trace metals and CVD (16-18). However, the most common conclusion in these reviews is again that further research is neces- sary (19-24). Some reviews do4 however, conclude thar lead has been shown to increase the risk of CVD. eg, Teleky's review from 1937 (25) and StOfen's review from 1974, which primarily deals with German and East European studies (26). In 1987 and 1988; two reviews were published which marked a new departure in this field of research: One is the comprehensive review by Sharp et al (27) on epidemiologic, clinical, and toxicologic studies con- cerning low•lntl lead exposure and blood pressure. The other is a special issue of Enerronmenra/ Healrh Perspecnves 11968, ~olume'81. which contains papers and discussions from an internauonal symposium on the relationships between lead and blood pressure. This issue contains se.eralire%tews of both experimental and obser,fational invesriganons (2g-32). The conclusion from these comprehensoe reports is that it must be considered probable. though not yrt defirritively pro~ed', that'low-le.el fead'ezposure increases blood pressure and consequently the risk of CVD. In the present re.'teN, 63 empincal studies ha%e been evaluated (table 1). The empirical research in the field can be said to fall into three periods. ie. 1920-1962. 1963- 19801 and 1980-the present. In,the first period several studies were published on the topic, especiallti% on the relationship bet%een occupauonalllead exposure and blood pressure. The methodolbgy,of most.of these studies is, naturally, rather primithe, but there are er• cepttons - for example, Vigdortchik's remarkable study from 1935 (51). I have included six of the irres- tiganons from this earJyy period in my re.te" The sec- ond period, 1963'-1980, was heralded by Dingwall- Fordyce & Lane's histoncal prospective monahty study from 1963 (64• 66). During thts period, at leasn one ini,estigation was published on the topic evem year, but, as suggested earlier• these studies did not arouse any particular attention. From I9801on• the situation has changed dramatically. Many more studies have been published (38 of the 63 investigations in table I are from the 1980s)t and also intereseis sharply rising tn, the possible relationship between lead~ and blood' pressure at veryioµ-level lead exposures, correspond- ing to those levels that the general population is ex- posed to from leaded gasoline, food, water, etc. Table Ireveals five features. First, many empirical investigations have been conducted, Second', virtual, ly all the studies have a low or medium score forr epidemiologic quality: Third, 30 investigations (48 Ifs) show a clear positive relationship between lead ex- posure and CVD (or blood'pressure); while nine (14 ro) show a positive tendency. Fourth, a very clear rela- tionship exists betwezn study quality and study out- come. The percentage of positive studies increases as one moves from "x" to "xxxx" as follows: 17, 47, 67. and 100 01.. Fifth~ there is only one study which shows a negative relationship between lead exposure and'CVD (33). The large number of positive studies and the posi- tive correlation, between study quality and studyout- come supports the hypothesis of a causal relationship between lead exposure and CVD. A more-d'etailed examination of the 63 studies in- dicates that they are very different with regard to study destgn• study end points, and'intensiry of exposure. !vtany of'the studies are, eg, ttoss-sectional'investiga- ttons of the relationship between rather low levels of lead in blood and blood' pressure. while others are historical prospective studies of mortality among 246

FolioNmc rhu :nnque of inethodplop. and turn, tng back to the cmpirncal studies, I found onk three posiu%e stud+es whtch measured the:admtum contenr of the kidnets nlZ8. 1'u:. ls"), These three itudtei are oi~tht "aua, :3i2 re'trent" r~pe justidescribed and ha%r ,) man% me:!i,doioet:at trror, that the\ onk„ored "\' or "\\" for methodological qualrt~,. Thus !ht~ :_r bt :on,;der_c'.o ^r or onk .en lutl'e ,t_e- ntftc3n;e Onl% :hr-e:^~tsui:3nun, ha+e been faund whtch are not "quast a-e-reteren;' and~k%ht:h.do not mcaiure cadmium in blood. urtne., or air. te. the historical proxpe:n\e mor;3ltt~ stud+ of '000 Norkers b% fiazan!_>!s e: ai the historical prospecn~e mortalu% itud% of 525 workers b\ andersson etia! t I3a. Ii351: and'the +anous prolects concerning the Shipham inhabitants These three studies scored "\.>"' for menhodolbgtcal quality, and one of them - the Shipham stud.% - ihowed4 Keak positive rela- toonshtp betNeen cadmium and CVD. while the !wo occupational studies showed a Meak negatt+e relatoon~ ship. Thus the conclusion seems clear, te- the eptdemio- logtc research.aan in no µay be considered to support the hypothes:ts of a causal relationship between cad- mium exposure and~hypertenston or CVD in general. At this point it seems reasonable to conclude that such a relationship does not exist. Over the past 25 years. although the number of studtes tn thts field'ihas grown annuali' v. the bod% of knowled¢e has not. Despite the last three studies menuoned. there tssuB a great need for eptdemiologtcall\ sound studies on this toptc.. Finallt,, tobacco smokers are moderatak exposed to cadmium and should therefore hate increased blbod' pressure. But the cardiok ascular eptdemtology shows %ery, aearl~ that tobacco smoking is notia risk factor for hypertension. This lack of relattonshtp, which has been epidemiologically ,en thoroughly investtgated, is a further argumentaeatnst the cadmum-blbod pres- sure h+pothesis. Cobalt Inahe mid'•1960s, an epidemic of cardiomyopathies was registered in Belgium. Canada, and the United States among hea\} beer d'rinkers. The cause of the epidem- ic was relatively quickly established. Several beerr manufacturers had begun to add cobalt sulfate to the beer imorder to stabilize the foami(156-1,61). Nearly half the patients examined in the various studies died from their cardiomyopathy. In is paradoxic that the consumption of 6-8 mg of cobalt sulfate per day could have this dramatic effecu as cobalt has been used in medicine in much higher doses without adverse ef- fects. There seems to be agreemennthat the genesis of this unexpected adverse effect was a combination of cobalf exposure, long-standing high alcohol consump- tion, and poor nutritional condition. In the general reviews on CVD and environmental exposures. the cobalt-related cardiomyopathies among beer drinkers has been mentioned bv several authors (_'. 6. 9-I1 I, whdc the rematntng rertews do not:men, uon ;obalt as a risk factor for CVD at all. In addt~ uon. two case reports have been mentioned in a few ofi the re% tews:. te. those 6y Barborik & Dusek (i1d2) and F:ennedy et al (163)i These case rrports descrtbe two cobalt-erposed men /slland 48 yearsofiage) who both died from :ardtomyopath% . The authors sug- gesaed'thatcardrom%opathy caused'b%- cobalt exposure miaht often be neglf cted and misdiagnosed. In addttton. three eptd'emtologii; invesugattons of cobah-c\posed workers wcre found'. In 11980 and 1983, Alexandersson & Atterhog ('164, 165) published a study of workers in the hard~metal tndustry who Nere oc- cupataonallk exposed'ito cobalt lexposure level 0:01- 0.06 mg, m'I. The 146 exposed workers wrre compared to an unexposed reference group with regard to elec- trocardiography, pulse rate. and'blood pressure. For, the cobalttxposed workers, Alexandersson & Atterhog /I164) found' a higher prevalence of hypertension, a higher average blood pressure, and more abnormal electrocardiographic changes. The electrocardiographic changes proved to a large extent to be reversible (165).In an abstract from 1985, Horowitz et al (',166) , described cardiac manifestations of cobalt exposure in a group of 35 self-referred hard metal workers. Elec- trocardiographic abnormalities were found in 16 o7i the 35 workers. The third study is a Danish investigation of female porcelatn workers exposed to cobalt blue dye in their work Id!671. The median cobalt concentration in the air was 0.80 mg> m'. When the exposed women were compared' with an unexposed reference group, no differences were found with regard to electrocardio• graphic changes or blood pressure, but a higher aver- age pulse rate was found in the exposed group. The authors had no explanation for this finding.. Despite these empirical studies from the 11980s. a need still remains for more and better investigations of the relationship between occupational!exposure to cobalt and heart diseases. In light of the widespread use of cobalt in industry and medicine (1160), it is sur- prising that most of the literature deals with a brief epidemic of cardiomyopathy among beer drinkers. Arsertrc In the general reviews on cardiovascular diseases and envtronmental exposures, arsenic and arsenic com- pounds arementtoned in seven (1, 2. 6, 9-111. 13) but nor in six (3--5„7, 8, 12). The seven, reviews which deal wtth tlie topic include two to nine references to empirtcall studies. In Landrigan's special' review on health effects from arsenic exposure (168), the cardio- vascular effects were treated very briefly. Three epidemiologic studies of arsenic exposure and CVD ha•e been,found. Pinto et al (169) investigated mortalhy among 527 retired workers from a copper smelterv during the period 1949-1973, while Lee- Feldstetn (170, 17IV studied a cohort of more than 249

males. The highest value (SMR 129) was recorded for those exposed for at least fiwe years. Polvcvchc aromarrc compounds. In a ease-referent stud% (383) of 6000 men employed by a primary alu- minum smeiter}, there were 306 new cases of IHD dur. ing the period 197t- i983. The persons concerned were compared with 5'9 matched referents. Among the bl'ue-tolliir workers. a relanve risk for IHD of 2J was found. The risk aas particularly elevated among workers emplo)ed' in the reduction divisions. These workers had a relative risk of 1.7 for IHD when com- pared with the remaining blue-collar workers. Unfor.- tunately, the referents were matched for duration of employment- and this type of matching prevented the researchers from uncovering a possible relationship with the duration of the exposure. Both a Danish (284) and a Swedish (285) mortality study of chimney sweeps found an excess frequency of' IHD. The Danish, studyy cohort consisted' of 713 chimney sweeps, and the SMR for, IHD was 222when employed men were used as the reference. The Swed- ish, study cohort consisted of more than 5000 chim- ney sweeps, and the SMR' for IHD was found to be 135 when all Swedish men were used as the reference group. In both instances, the excess was significant at the 5 Ma level. In a historical prospective study of gas workers, Gustavsson & Reuterwall (286) found excess mortali- ty due to IHD (SMR 125) and stroke (SMR 152): In this study;,occupationally active persons in Stockholhn were used as the reference group. Due to the small numbers, these results were not statuticallysignifiunt. Common for aluminum reduction workers„chim- ney sweeps, and gas workers is that they are exposed to combustion products. According to several authors (6, 284, 286), it can be hypothesized that polycyclic aromatic hydrocarbons or other polycyclic aromatic compounds are not only carcinogenic, but also increase the risk'for IHD: This assumption is in accordance with the monoclonal'hypothesis of atherosclerosis proposed by Bendirt & Benditt (287);, according to which atherosclerotic lesions might be derived from the proliferation of a single cell and could be considered to be benign tumors. The excess frequency of both IHD and lung cancer among, Danish cooks and bakers (288) in the national Danish, mortality study further supports this theory, as it must be assumed that many working in these trades are exposed to polycyclic aro• matic hydrocarbons. Concluding r.marhs During my collection of the material for this review of the literature, 1 found no additional'studies that could be judged as sufficiently relevant for inclusion. Since, of course, the judgment of which studies are to be regarded as relevant is inevitably sub)ective, the reader may wish to supplement this review with other comprehensive ones dealing with CVD and chemtcal exposure (1, 2, 5, 6, 9, 10). In a recently published' article (283) concerning chemical exposures at work and the risk for IHD. the authors wrote: "Several personal risk factors are known to contribute to the development of IHD, but the effects of adverse working conditions have re- mained almost unexplored [p 659)," (283). This is a very widespread conception, but both the present review of the literature concerning chemical occupational fac- tors and CVD and the previous article concerning non- chemical factors (14) have shown that the conception is not completely correct. Hundreds of studies, in fact, have been carried out in this fieid, and, in several areas, knowledge today is considerable. The present review has, inisome areas. confirmed other reviews of the literature, while in others the con- clustons reached'are contrary to the currenrvieM_ For carbon disulfide and nitroglycenn;',ethylene glycol dini- trate. the general opinion is confirmed. Ih these areas, studies have been conducted which have convineed vir- tually everybody about the causal relauonship between these substances and'CM It should be emphasized', that what has convinced'the scientific community is not the number of'studies - as a matter of fact, there are very few - but the high methodological quality of' the studies. For lead and passive smoking, this review concludes more positively than others. The research concerning lead and CVD is very old, but not until recently has in been "discovered" in earnesn. This phenomenon is, to a large extent, due to the remarkable results con- cerning low-kvelllead exposure and blood pressure from the National Health and Nutrition Examination Survey 11, which were published in highly esteemed journals (70, 72). The research eoncerning passive smoking is new, and there are still relatively few studies, but they have a high quality and the results are consistent. In other areas, the conclusions are more negative than usual; especially for cadmium and carbon monox- ide. The research concerning cadmium and CVD is genenlly of poor quality, but the few good ~ studies, together with the fact that tobacco smoking is not a risk factor for hypertension, makes it reasonable to conclude tbat cadmium is not a CVD risk factor. For carbon monoxide, the situation is more complicated, since there might be acute, short-term, and long-term effects. it is concluded'that there are acute effects and possibly short-term„revenibie effects, but that carbon monoxide does not increase the risk foratherosciero- sts in occupationally exposed individuals. In table 5, an attempt has been made to classify the possible cardiovascular risk factors which have been reviewed in this and the previous article. The basis for this classification is the view tharempirical relation- shtps are not "proved" once and for all. Hypotheses 256

f 8000 men during the period 1938-19". Aselson et al't1"_I conducted a case-reierentstud~ in uhr4ti the evposed~pcnsons uere also copper smelter% workers.. !n alllthree itudres. the exposure Kas arsenic traoxtde. Ih :he t%%e historical prospecune studies. sllghtl% ele- %ated S\IR %alucs %%ere found ior CVD Pinto et all tound a•• alue oC !!C)9 for IHD and 113 for stroke. W hrle Lee-Feld', tern iound'S11R %alues of about 130 for IHD and abuut 1_0 ior ctroke. In bothistudies. a compari- son %%as made \% ith,rhe mortaitn experience of the rest oiithe population in the area. In the stud\ b\ Axelson ci all vhtch is the best of the three ("tx!cx" for methodological qualits t. an increasing relatt.r risk for heart disease Nnh increasing arsenic exposure was found (risk ratio 0 7, 3.0. and 5.6 for three exposure groups), The study by Pinto et al'scored "xx" for, methodologtcallquality, while the Leo-Fcldstetn study scored "rxt." Thus in these three irr.esttaations. clearer e% idence for a relationship between arsenic ex- posure and C\ D w as found as the quality of the studies increased.. Furrthermore. arsenic Has pan of the mixed exposure in Wingren &ALelsonfs case-referent studies on mor- tahtv tn,the 5.%edishiglassworks industry (52. 53). In these in+esugauonsa slight increase in CVD mortali- ty was found. In addition toahese studies of exposed workers, there ha%e been reports of a relationship betstieen hieh les- els of arsenic in drinking water and the de~elopment of both heart disease in children of northern Chile and' peripheral %ascular disease in adults from Taiwan ('1). A special "arsentc beer scandal" took place in Man- chester in 1900„when beer was accidentallv contami- nated µith arsenic. More than 6000 persons became ill and 70 died, almost all from CVD (2. 156). The relationship between another arsenic com- pound. arsine, and heart disease has been described by Pinto et al (173). This studydealuwith 13 poisoned men, of whom four died fio^ acute myocardial in- farction (AMI), while electrocardiographic changes were observed in the remainder. As far as is known, no epidemiologic studies have been conducted'on the relauonship between arsine exposure and CVD. E%en ifthe total epidemiologic research concerning the relationship between exposure to arsenic com- pounds and CVD is limited. a causal'relationship is still Iikely: Further research is needed to clarify the rela- tionship between the level'and duration of the exposure and'the risk for CVD. Carbon monoxide The relationship between carbon monoxide (CO) and CVD is dealt with iniall the generalireviews on CVD and environmental exposures(1-7, 9-13) except one (8). In a few of these reviews (1, 6. 10), the topic has been thoroughly, treated, and many references have been discussed. Naturally; no disagreement exists on the potentially very ser.ious consequences of acute high exposure to carbon monoxide, especially among per- 250 sons t~rth emstrneatherosclerosis, But there is:onsrders able uncertatnt~ and ;ontltcung %rc%ks about the poc- sible ,rgnrfJcan4e or carbon monoxide exposure in the d'e% elopmenv o( atherosc lerosis.,A iew rc~ie%% s :om cluded. ~%ithout an% iurtherdocumentatuonr thar,ar- bon monoxide increases the risk oi IHD 1'. 121' Others presented~ a more .aunous point of ~ reW .k% hich can be illustrated bp k% a% oi the rollowrne aireequotatrons "ICOt ma. prectprwte Askll or senous arrh%tFimtas m percons %kith pre-evistrog :oronar~ atherosclerosis p I!' ," t>1. " tie queinon ot .%hether CO is athcro¢en,c remains unan%+kered e%€n at the bas+cscren.e le~ell,p I'219!" (3). and "there is surprisan¢ly little e%tdence for a chronic atheroscderonc effect of CO [p'_19J" tl 1) . Ih addtuon to these general re.ieHs. there are man% special rcvicr%s on the negau.ehealth effects ofcarbon monoxide exposure t 171!-1891. The~ contain detailed descriptions oi thepn.stological mechanisms K hr.h,re- sutt irom the rormauon of carbo\%hemoelobrn rn blood and'ipresent the results of many ammalle\per,- ments. I!NiIl not drscuss these topics in the present re- % itµ: rather n should'srmph be stres;ed that the de- crease rn the o\.%gen..arrnmg capactt\ of the blood is grcaterthan ,uagested b\ the pcreentage of carbo.%- hemo¢lobrn because of the reduced release toithe tis- sue oi theo\ygen carried by the remaining hemoglobm. The spectfic resieNs on,carbon monoxide and health do not agrer on the role of carbon monoxtd'e rn the etiology of CVD. The most "posru.e" revre%%s are probabl\ the ones b' v .AronoK (171, 175), Goldsmith & AronoN t l'-1. and' .3tkins & Baker I 1'61. %% hrie others are skeptical (179, 182. 168): In the remaining re.iews no clear position is taken, .4mon¢ the most skeptical re.tcM^s, wiir & Fabiano's critical reevalua- tion from 1982 (d!8B), should be emphasized. The authors carry out an explicit and thorough discussion of the evidence for a causal relation between carbon monoxide and CVD They specify the "'. .. three ques- tions that best define the current areas of controversv: (i) Does chronicrrposure to CO influence the d'evelop- ment of atherosclerosis" (ii) By what mechanism does acute exposure to CO reduce maximallexercise ability in, healttiy persons and in persons with pre-eeisting CVD? (iii) Does acute CO exposure predispose in- dividuals to cardiac arrhythmias7 [p 520[." In the evaluatton of the empirical evidence for a causal rela- uonship betweenicarbon monoxide and CVD, it is im- portant to keep these three questions separate, and I have attempted to do so in the following discussion. For the present review„22 empirical'studies have been selected. Of them, most deal with persons who hass been exposed to carbon monoxide occupation- ally, such as firemen, policemen, toll booth operators, garage personnel, motor, vehicle examiners, bridge and tunnel officers, foundry workers. and blast furnace workers (190-210). (Reference 205 has been classi- fie&as two studies.) Four of the empirical studies are not epid'emiologic in,the strict sense, but ratherexperimencal (190-193).

In these rour ~:udie~. %%ti ch are %ern similar. 10 men wuh aneina pectorn< %%ere e\pocad to dttfercnrconcen. tra::am o+ arbon monr.,de.,and the duration of es- rro•e be;ore :hr on<e: oi paini%ta, registered All four ,n+r,t„tatton• :ound ;tia: the nme be(ore the onset of rain aa, •t.n3(i;an !.hor:rr a;ter r\po,urc to car- bun monomdr r~ :a %%icn :hc ;arbo\%hemo¢lobtn It%el kta• onl% _ anou: I ', hi,thrr in :hr evpo,ed', rtuauon than in :hr ;uniroll ,tuation 1193). Thece re.ulr- ;ould ho\e been espected because the angtna pattentc alread> had IHD. ~e%errheless, these e\pentments ~aress ho%k dangerous an increased car- bos\hemoglbbtn ie\cl :anibc ton thts group of patients., as the pre%alenea of IHD is high inithe population. and as exposure to carbon monoxide is common - predomcnantly through smoking and esposure to the e\haust fumes flrom cars - this is a frequentll occur- ring risk situation. Tt%o studies .ompartng the daily incidence oideath from t'HD Ntthithc letel of carbon monoxide in the air :anibe sai&to elucidate the same complex oflprob- lems (195. :09). (n,one. the e\pected relationship %%as found betttren carbon monoxide le.els and fatality from IHD. t%hile the same relationship could not be sho~kn in the other. Both studies had a low methodo- logical quality. %k. hile the aforementioned studies pro%tde et idence of the tntauence of acute exposure to carbon monox- ide onipersons %kitti tscfiemic heart disease. the rematn- intt_ studies hake tried to elucidate the role of carbon monoxide for the deselopment of atherosclerosis.,Ta, ble 3 contains a sura% of these 16 studies. Table 3 ik lustrates the follotktne two points: (il most empirical studies on this topic hat e a Ibw methodological quali- ty ("<" or "rr"), and tiit there is no relationship be- Meen study quality and study outcome, since half of the poor studies ("r" or "rr"),and'halGof the better studies ("trx"'or "tzxs") hate a positive study out- comc [ - or ( - I I The bes) support for the hypothesis ofa relation be- tt\een chronic carbon monoxide exposure and the de- .elopment of', atherosclerosis comes from three posi- tite studies rktth °'rxst" or "ttxx" for quality (201. :0B. :09). A closer examination shows, however, that not eten these studies support the hypothesis veryy clearly. The cross-sectional'study by Hernberg et al (_01)lon angina pectons, electrocardiographic findings. and blood pressure among foundry workers found a relationship between carbon monoxide exposure and' angina pectorts bunnot betueen carbon monoxideand' _._ctrocardiographic findings indicating IHD. Funher- more, slightly higher blood pressure was found among the persons exposed to carbon monoxide., but this finding could ha.e possibly resulted from exposure to heat radiation. Altogether only the relationship be- tween carbon monoxide and the prevalence of angina pectoris wastonvincing, and this relationship does not necessarily support the hypothesis of a lasting effect of carbon monoxide. The older of the tw o studies b- ~ Stern et al (2081 found an S%,1R of 105 for C'k D amon¢ motor %ehicte examiners Clbser anai.ses .ho%%ed than the excess d'eaths occurred among cwminers uarhizero to ntne >ears of exposure ISMR for CX D1l_31 There µas noo increasc in mortaiita among the e.amtners N1th (onger exposure. The more recennof the tn+e,ttaartons b% Stern et al (:09). %.hich con,:erned brtdQe anJ'.tunnellcirfi:ers in \c%% York Cit\ . is probabi% the best epidemtologtc stud%. of carbon monosid'e and Cl, D e%eri published. The studq sho%%ed'srgnrficantl.% h gher IHD mortaltty among the hea~uh,erposed tunnellofficers than among the brtd¢e officers. Nho had4 lokk le%el of exposure. Hoaeser. there was no relationship to the duration of the erposurc. and the excess mortality among the tun- nel officers disappeared in the aourse of a few years after the cessation ofl exposure. This pattern closely resembles than seen in studies of tobacco smokers. in which the increased risk for IHD disappears relative- ly quickly aften the cessauoniof exposure. This pat- tern d'oes not fit the htpothests of a lasting atherosclerotic ef fect ofI carbon monortd'e exposure. In light of the many studies on tobacco smoking and CVD, it is surprising that it is still not kno%%n Kh}~ smoking increases the risk for CVD. A cross-secttonal' stud± by Wa(d et al (210) 'is often quote&to show that carbon monoxide increases the risk foratherosc(ero- sts, but a later, - and methodolo¢ically better- case- referent study by Kaufman et al (203) shows that the carbon monoxide content of cigarette smoke is un- related to thc risk of IHD among smokers. All things considered, there is thus %-0ry little - 1f, anyatitng - in the emptrii:al,studtes referred to which supports the carbon monotide-atherosclerosis hypoth- ests. !n the literature, tho animal experiments by the Astrup-Kjeldsen group have played a large role, as these experiments apparently showtd increased' atherosclerosis in rabbits exposed to carbon monot- ide. However, the group published'a reevaluation in 1978. In these new investigations (211), they were not able to confirm the original findings, probably due to the fact sharthe original studies wene carried outwith small sample sizes and were not blinded. Several Tapte 3 Qesults of t6 eo aem otoqic stuolas of carGaovascu- tar O~seases.~CUDi and carpon mono=ioe taDosure accor0inp to tne.rnetnoOOiopicJt Ouapty otthe stuONS. Tirye titHe is.DiLed or. reterences 194 196-210 peqree ot' Mernoaaiop-cai ouat ty retat'~~sn'~~a ss a=: ssss Total t- t 2 0 2 t t . -t t t 2 3 t t 6 2 2 Tota; 5 5 4 2 t6 ' See +ao4e troran eaptanaUOn of tM syRNbObs. 2S1i

Scand J Work Environ Healrh' 19g9:IS:245-264 Cardiovascular diseases and the work environment A critical review of the epidemiologic literature on chemical factors by Tage S Kristensen, MSc' 7fJ~ '•-. /'- c~r J, I t:Rl5TEN5EN'T5. Cardio.asculardrseases and'the work enstronment: a critical review ofthe epidemio- logic literature on chemical factors. ScandJ K'ork £nvrron Heolfh~19B9:1':24S-26a. This is the second of twc articles reviewrnQ the epidemioloQic research on card+ovascular diseases (CVD) and the work environment. It deals wtth chemtcal'factors. te. lead.,cad'mtum. cobalt, arsenic. arbon monoxtde, pas- crve smoking. organic solvents, carbon disulGde. nitroglycerin. nitroglycol. and others. The epidemiolog- ic literature relating to each is assessed on the basis of a number of mnhodolb;ical criterta. and the need for future research, the methodology of literature resiews. and~preventove implications and perspectives are discussed, It ii concluded that the causal relationship between two ofirhe chemieals. carbon disulfide and nitroglycerin nnroQVycol, and CVD a very well documented'. Forlead'and passive smoktnga causal relation to CVD is llkeh. I tore research is needed concerning eobaltL arsentc. antimony, and other chemi- cal'compounds. Etposure to carbon monoxide mcreases the acute risk of CVD but has probablv no Iastan` atherosclerotic effect. Cadmium and organic solvents are probably not causally related to CVD. Kw rerms arr.imony.,arsenic. berylhum, cadmium. carbon disulfide, carbon monoxtde. chemtcals, cobalt. combusnon products, dtnrtrotoluenes hypertenston, ischemtc heart dtsease. kad, nstroglycenn, nnroglycol', occupauon. organic solwems. orQanophosphatesn pusive smoking. This is the second of two articles on the work environ- ment and cardiovascular, diseases (CVD). It reviews the epidemiologic literature om occupational chemical' fac- tors and CVD. The results of the review are compared with those of earlier reviews in this field' O-13). As in the previous article (14). 1 have dealt with*c- cupationall factors, but not with, individual habits or characteristics. Thus, for example, f discuss passive but not active smoking, lead and cadmium but not soft water. To facilitate the best, possible clarification of the occupational factors considered! I have also in. cluded investigations which are not strictly occupa- tionalibecause most of the exposures are also found outside 2he work environment. The objectives of this article are the same as those ofl the previous one, ie. (i) to record and integrate the epidemiologic literature on CVD and the work environ- ment; (ii) to evaluate the research with the objective of elucidating possible causalities between omspationali factors and CVD; (iii) if possible, to point out areas where enough is known to start employing the research results for,the purpose of prevention, and (iv) to point out defects and deficiencies in existing research with the objective of strengthening and improving future research efforts. Institute of Social Medicine, University of Copenhaaen:. Copenhagen, Denmark. Reprint requeau to: Mr TS Ki•istensen. University of Copen- hagen, Panum Institute. 6Ie=d:msvej 3, DK-2200 Copenha- =en N, Denmark. Mst.rial• and mathods The criteria for collecting and evaiuating the epidemi- ologic literature have been described in detail in the previous anicle (,14): The objectivehu been to include all epidemiologic studies on the exposures in English,. German or the Scandinavian languages (or which have summaries in one of these litttguages). That objective has not been fully realized„although this review is more comprehensive than earlier reviews on the same topic. To give the readers an opportunity to supplement the review of the individual exposures, some special reviews from recent years have also been included.. They contsin extensive lists which also cover the nonepidemiologic literature. The most important objective of the review has been to identify causal risk factors for CVD. With this in mind, lhave evaluated the following five central methodological points for each study: (i) the time dimeruion. (ii) confounding, (iii) selection; (iv) mea- surement of exposure and disease, and (v) adequate design and statisticalanalysis. On the basis of this t3it- ical evaluation, each study ha-s been given a score be- tween "x" and "xxxxx"' for methodological quality: (For more details of this scoring system, see refer- ence 14.) It should be emphasized that, when I refer to "study" in the following discussion, I do not nem- sarily rnean an "article" or "paper." An artick may contain two or more studies, eg, when the same hy- pothesis has been tested on two different popuiauons,, such as men and women or inhabitants of two differ- ent cities. If the analyses are published in such a way that the results for each individual group t:an beiden- 24S

27 SEP'i'EMBER 1989 NEW ZEALAND MEDICAL JOURNAL /v'2, ( SW '1 6)' r~ Passive smoking in Mew Zealand Mr Lee's letter )11 pretends to a scientific basis it does not have. Hirayama's first publication 12) i focused~ on cancer of the lung among nonsmoking J apanese wives and set off a flurry of criticism of the methodology-including the analysis. The analyses have been redone showing significance enhanced'by improved analysis. ,nly someone committed to nonsense would report a p-value for !he difference between the two results.. Mr Lee's criticism of the study by Helsing et al 1s)'makes no sense on the face of~ it. Controlling for 'a whole range:of possibly relevant confounding factors' has as much likelihood of heightening the significance as of lowering it'. The researchers found that adjusting the relative risks has in fact enhanced the significance of their findings. Mr Lee has a greater tolerance for assessing a study as •published' than most'scientists do,,as demonstrated by his tenth reference. Perhaps he gives more weight to studies of 9 subjects which unsurprisingly fail to yield significant results than most epidemiologists would. He may not, however, show so little tolerance for the epidemiological methods he exploits. Spousal smoking has, again and again„been shown to be associated with lung cancer risk 14.5s). The biomedical underpinning-proven studies in animals and dose-related responses ih hn*nAna_relating the constituents of both sidestream and mainstream tobacco smoke to production of cancers of: the lung is undisputed (7.81- Propinquity of the non•smoker to the smoker over time rather than the concentration of single toxic substances in the ambient air determines the degree of exposure. Given the large numbers of exposed nonsmokers even a very low degree of risk has substantial impact. Misclassification bias, a favourite theme of Mr Lee, is a two- edged criticism. As long as misreporting of exposure is as likely for cases as for controls misclassification depresses the relative risk. The risk will be overestimated only when cases whose husbands smoke denyy their own, actual smoking more readily than cases whose husbands do not smoke or when cases exaggeratee their husbands' smoking more than controls do. Where actual exposure has been measured and compared with reported exposure the agreement has been high and the misreported exposure has not been in only one direction. The validity of extrapolating exposure in the home to exposure at work raises other questions about indoor air. If the home setting is one where a nonsmoker can choose another room to be in than~ the one the smoker is in, then exposures at home would be lower than ~worksite exposures. In the workplace freedom to move away from the smoke source is generally denied. By extrapolating Kawachi et al )9) have probably underestimated the risk and the number of deaths attributable to passive smoking. Common sense does more than pseudo-science can to produce credibility. The weight of the evidence is against Mr Lee and others whom the tobacco interests sponsor )tol. J Reinken, FFMS Consultants, W ellington. 1. Lee PN. Deaths from lung cancer and iecheemic lieart'disease due to passive.amoking in Ne.° Zealand. NZMed J 1989'; 102: 448.. 2. Hiuayams T. Nonsmoking wivea of heavys smokers have a highernsh of,lung n.nae- a study fromJapan..Br Med J 1981; .282a 183-5'.. 3: HhJaing KJ. Sandler DP: Comstocjf GK'. Ch'eeE. Heartt disrise.fn, nonsmokers living .itM smokers. Am J Epidemiol 1988; 127: 915-22. 4. Abelin T. Curreno t.rends in the epidemiology of smoking:.p..sive smoic'utg and lung uncer. Sch,veie Rundach Med Prs: 1989; 76:: 87-92. 5.. Svendsen.KH. Kuller LH. Martin MJ. OcYene JK. Effects of passivesmohing:in the multiple risk factor intervention trial. AmJ EpidemioL 1987:.126: 783-95'. 6.. Svendsen.KH. Kuller LH.. Re: 'Effects of passive smoiung in rth'e multiple ruJc factor intervmtion trial'. AmJ Ep,idemiol19895 129. 226-7. 7:. US Departmmt of Health and Human Servioee:'rAe health oonsequeaaes of invohSntary •mdcing" a report of.the Surgeon-Cieneral. US DH1iS.~ Washmgwn..1:986. 8.Saraca R:.Paasivesmolcing and lungcancen. In: Zaridse DG: Peeo R. ads. Tobaoco:, a major international health hazard..lnternationd Agency, for Research on Cancer Scientific Publications No 74:.lARC..Lyon; 1986.. 9. K.vachi 1. Peartc NE. JarYsm.RT. I1vtls from lungcanm~ and iscti'emic heart diseasr due to passive smoking in Nev.Zealand'NZMed J 1989, 102. 337-40. 10. Martin P. Pa.sive smoking. NZ Med J 1987:,100: 69&7. Cancer registration working group We regret that Dr Hitchcock (NZ Med J 1989;,102: 419) regards. our letter on cancer registration )1] as incorrect. We can only repeat what'actually occurred. Dr Hitchcock mentions a submission from the Board of Healt'h., 515 After two letters from the group seeking details the board finally stated: 'In reply to your letter of 22 October 1987 we believe there is nothing to be gained from pursuing,the matters you raise in your letter. Our reference in our original letter referred to apparent breaches in the past and the need to provide effective controls.' That is as much information on, 'instances of breaches of confidentiality''as was ever received from the Board of Health despite the repeated requests from the group for information on actual instances. The board did not refer to any submission from private pathologists. We repeat `no individual, no doctor and no group provided the working group with information on breaches of~confidentiality'' Ill. The essential point' is that, despite all our efforts„ we could not find any substantiated evidence of an actual breach of confidentiality by the New Zealand Cancer Registry. It should not be necessary, but it may be helpful, to emphasise that had the group been given information on~ any instance apparently involving a material breach of confidentiality we would have regarded this as a serious matter and sought to ensure a thorough, , independent and' sensitive investigation. We would like to take this opportunity to thank the many organisations and ~ individuals who submitted comments on our report to the ReviewCommittee on Health Statistics. We appreciate the constructive criticisms and the general support for our proposals. K R Cooke,, Department of Preventive and Social Medicine, University of Otago Medical School; Dunedin; A J Gray, Cancer Society of New Zealand; W ellington; A F Burry, Department of Pathology; Christchurch Hospital, Christchurch; R Stewart, Department of Surgery, Wellington School of Medicine, Wellington. 1i Cooke KR. Gray AJ„Burry. AF. Sce.vart RJ.. NZ MedJ 1989; 102::197. Dietetic advice I was interested to ~ read the paper Children's diets:, what do parents ad&and avoid? by Dr R P'K Ford and colleague (NZ Med J 1989;, 102: 44'3h, with the analysis of advice on various food substances. It is quite staggering to find that none of the 103' children interviewed for this article had been given dietetic advice. Over and over again we are concerned to find that general practitioners give detailed advice when ~they are not trained to d'o so. The whole question of diet and nutrition is underestimatedand'undervalued in the undergraduate and postgraduate curriculum, Fortunately we have an efficient training programme for dietitians in New Zealand and, in my opinion, it is unethical and unprofessional ito attempt to give patients detailed advice on diet when we have well trained and qualified colleagues available to undertake this task. I was provoked to write such a letter because all too frequently we have people referred to hospital with complications of'diabetes who have never had the opportunity to have'a consultation withh a dietitian, who could certainly have influenced their eating patterns. D W Beaven, Department of Medicine,. Christchurch Medical School; Christchurch, Informed consent I recently received a copy of the New Zealand Medical Association's revamped~ informed consent/request for treatment form.. It is impossible for a patient to know that helshe has received an adequate explanation of risks etc when the patient is in no position to assess this. If any aspect of the operation is withheld or overlooked : the patient has no way of knowing.

NOTICE This matzrial' may be THE pr3tected by Copyright law ;>'.itle 17 U:S. Codel. NEW ZEALAND MEDICAL JOURNAL 12 July 1989 Vol'ume 102 lu o 871, Deaths from lung cancer and ischaernic heart disease due to passive smoking in New Zealand I Kawachi MB, ChB. MRC Training Fellow in Epidemiology; N E Pearce PhD, Lecturar in Epidemiology. Department of Community Hea/th. W.Ninqton School of Medicine. Wellington; R T Jackson MCCNZ. Research Fellow in Epidemiolopy. Department of Community H.atth, University of Auckland School of Medicine, Auckland Abstract Pausive smoking is increasingly recogni.ead'u a public haalth hazard. Among New Zealanders who have never smoked. the ptevaleacs of exposure to spousal smoking has been eatimated' to be 12.7% for men and 16.1 % for women- The prevalence of exposure to passive smoking in tbe workplYce has been estimated to be 33.6% and 23.4% for never smoking men and women respectively. Tba pooled risk estimatas from epidemiological studies of the health effects of passive smoking were used to estimate the numbers of deaths from lung cancer and isrtia.r+;r heart dieeax attsibutable to paaova smoking in New Zealand in 1985. The pooled relktive risk estimates for lung cancer mortality were 1.3 (95% confidetue interval (CII: 1.1-1.51 in both men and women expoeed' to passive smoldng at home, and 2.2 (CI 1.4-3.0)'ia both men and women exposed to passive smoking at work. Using these relative risk estimates, it was calculated that 30 lung cancer deaths (rangt: 11-41) were attributable to invohintLry'smoicn~ in New Zealand in 1985. From pooled relative risk eetimates of ixhaamic heart disease death of 1.3 (CI 1'.1-1.61 and' 1'.2(CI 1.1-1.4) for e:po.un to spousal smoking in men and women respectively, it was estimated that a further 91 isch.emic heart disease deatha (range:, 39-177) were due to passive smoking at home. Tba number of iscbaemic heart disease deaths due to passive smoking in the workplace was even higher, at 152 (rangr. 62-2241. aas' R+ing relative risks of 2.3 (Cl 1.4-3.41 and 1.9 (CI I.4-2.5) for men and' women respectively. The total number of deaths due to passive smoking from lung cancer and t.ri.YT'v beart disease was therefore estimated to be 273 pr year (rangti 112-442). !R 1La Ji ta! ta 2046 Introduction Racent reviews bave conduded that ezpostur to passive smaltiitg is harmful to health It~l. Tha effects of pasaave smcAing on health have been reparted'to include acute effecta& sucb u•*a^er++ariM of aathma and aagi.oa, as we11 as chronic eftects such as the incraased'risk of upper and lower airways infection in children and tba inczeaxd risk of fnns uncer in adults Nl: Tbe asaooatioc of lung c.ncer with pasive smoking appear to satiafy epidemiolopcal tritarie of causality le.s1 To dat. 13 studiee have be® completed in siz countries. 10 of which have reported a positive associatioo betwem lung cancr and pasaive smoking /sl Three studies have failed to show an aaaodation r7•sl, but in each study the precision of the effect eatimates was such that an increased risk could not be rubd wt Publication bis, is, bias which occurs when papers with ^o^iificant results are eitber not submitted or aozepted for publication. has been put forward' as an explanation for the association between passive smoking and lung canccr Iiol: However. this claim has been criticised and discredited iiil. More recenUy, evidence has begun to accumulate which implicates passive smoking in the development of ischaemic heart disease I1t•14G Passive smoking is therefore a potentially important public health problem in New Zealand. aad'it is desirable to assess the magnitude of the problem. Taking the relative risk estimates reported in epidemiologlcal studies and applying them ta estimates of the proportion of the New Zealand population exposed to passive smoking, we have made a preliminary eetimate of the impact of pasaive smoking on the health of nonsmokers.. We here report estimates of the numbers of deaths from lung cancer and ischaemic beart disease attributable to prolonged exposure to passive smokmg in New Zealand in 1985: The evidence of excess deaths from other causes-ieu cancers of sites other than the lLwgs. and chronic respiratory disease- due to passive smoking is more tenuous 12G Death from these causes has therefore not been considered hers. StatJsUt:al methods The proportioo of deaths lrom a particnilar di.easa attributablato a speaSa exposure is Jmown aa the pcqulatioa attnbutabie ruk IaLo rcferred to as tbe a.twlbpc frsctoni: If p is the proportion of tbe genai papuLtioo exposed to the raak factor lin this cara involuntary smolnno and RR u tbe relauve nsY tbea of dying of the disease in ezpowd'ventu cone>3xi..d iodividuals, t;be population attributable risk is given by list PAR - p(RR,- 1) pRR-1D+1' 'Ilus measure has bean used in many pr.vious studis.. including two studis wbicb estimated tbe propcrsno of deatds io New Zealand atznbutabie to active smoking jiaj7t u..il as in a Can.diaa awd'y wbuh setlmatsd the proportion of lung caarer deatha attributable to pa=ve smoicns n In tbe current sWdy, the relative riak ercimat.s from ov.rssaa studies wers appliod to New 7.alYnd' data on paacvs smolan~ ezpo.ura and the drivad populatim attributabis risks wa. tbae applied to Iuat cs^ew and iach.emic b.at diiresae deatfts ia 1965 among p.rseaa who had never smoked fisF The populauon attributable nska and deaths attributable to puave smokung ww+ m'ud .eparauty for men and:woeyn. and forarporun at home and'u worit EstJmation of exposura to passive smokirty Farimat/oa of ezpoeurs to passive smotfng at home:. Estimatea of the prevalence of exposure of never smokers to passive smoking at home were obtained from the Auckland heart study (work in progresal: The study found that 12.7% of' never smoking men and 16.1 % of never smoking women aged 35-64 yeirs in Aucklaad in 1987-88 were exposed to paasive smoking in tbeir homea. Thex figures an not limited to ezposttn to spousal smoking, but include exposure to all

I ducuon Norkers. Am J Ind \led 1988:I7:659=66 :B-1' Hansen E5. \tonahn from tancerand tschemrc heart Jucase tn Danish :htmne+ SNeeps: a,fj+e-' %ear foliow • up tm J Eptdemtol 1,983':I1":160-1. :8F Gusta+sson P. Gu.u+sson k.,Hogstedt C. Eeces,s mor- ta1u+ amone S++edishiahtmnet s..eeps. Br1 Ind \led 19S":u '38-s9. :R6. Gusta%eaon P. Reurerwall C. Dodsorsakeroch can.er- yuklighct bl2nd'gas+erksarbetarc Nortaluyand in- cer inaden.e among gasNorkersi. Sto:khoim: irbetar- sksdd+erAet, 1988:1-3a. lArbete och halsa __.i :8" Bendiu EP.,BendurJ`I. E+iden¢rfor,a monoclonall or g n oi human arheros;lerottc plaques Pro: \aei' A,: a d~Sc r US A 197 r.'0 :1 ' S?-6 . :B8. Andersen O. Dedehghed oy erhser. 19'0-80 [llorral- it% and'occupauon 1970-80).Copenhagen: Danmarks Stansuk. 1985 lStaususke undersoselier nri i1.s 289_ .\larmot M. Theoretl T. Social class and'cardtosascu- lar disease: the contribution ofiMork. Ine J Health Ser.. 1988`.18:659-'4. 290 PoMell KE. Thompson PD. CasperseniCJ. Kendrttk 15. Physical acu+tn and the inadence of coronan heart disease. Ann Re+ Public Health 196";3i"?-3" ?91l Tran Z\'. Keitman A. Differential effeas oi escr;,-e on serum lipid and UrpoprotesnJe+els seen wn h;han ee, in bodt Metght a meta-anaiysts. JiMA l98°._~+ 919-.4. 292. Greenland 5. Quantnarne methods in the re++r++ or epid'emtolbgto bterature. Eptdemtol Re+ 198':9'1-?0 293. Thatker 5B. \ieta-anal+srs a quamttan+e approa,h to research integration. Ja\1A 1988..!9'16dr-9 :9.t. Hlatu, D. Rl.hardson& 'vo,e. generalistress reipon.e. and :ardio+as.ular disease pro.ea.es: re,sew and re- ascessmeno oi hppotheazed relattonshtps. Cambridge. \1A: Massachusetts Institute of Technolbg~. 1990 .95. Uerstedi T. Anuwsson 4. iliredsson L. Theorell T Shsfnwork and cardto+as;ular disease. S.and Ji\\ork Emtron Health 1981;10:109-1s. 2%. Thompson S1. Epidemio4og~ reasibilit% ;tud>: eifect, or noose on the:ardiowscu/ar s%,stem. Columbia. SC Lnnerstt> of South Caroltna. 1981 Recened for publicatton: ..' \1a> 1989 264

na" or "Alonda` morninc dcath." The noniatal cases zre attaa6• o hi,h ~r•emhie angzna pe~:ori,. but ~khich are nrt pr,.?, .tl.td hk :~rra.e ur pcti;hi. arousal. The O:,ur I'•1 d,3tie- e.pewre to nnroalveenn sth~;enr _,i:..ji Jtnitrace tr,.!';onscqutnt{y the Jrwrnataon -n ;ra:r ~~:;h rc al -rmPtom..' has been u•r.7. THi• es;*rr-+on,a,a• ~ar:ru• onijittons- ;uch .t..anginu. ,uronar~ •pa•m.,m~o:ardial sntar;tion, ar- rh~thmia, ancJ uJden death. Ini tho.e instances in autop,+ %va, performed. normal coronarN ar- terit• t%tre tound Simar :a,e reports ra%e been published in other ,:ountne. t.61-266t. and tlorton', :omprehensive re- ti tt%+ trom 19-- t.6"1 ;ontatns an excellent review of' the literature .:onrerning %,rrhdra%%al hazards related to occupataonal habituation to aliphatic nttrates (7-t reterencest:.Ir,appears from %(orton's re+ic%% that. dur- tng the period 195:-19'=. articles %%ere published about %londa> mormmne attacks rn,German>. ltalv. Ja- pan. France. S,ktd'en. Czechosto%al.ia. the So%iet Lnion.and theLnned Sta^.es. It appears turrhermorc that the first fimen,can des:rnption %% as not Carmichael & Lteben"s article from 1963 (_6a9, as formerlti be- lietied.,but an article fiomi 19a'3'by Foulaer (2681'. Foul- ger's article on "e\posure to toxic chemtcals- did not mention. ho%ce%er,. that it concerned nttroglycertn: ethylenc gl\ col, dinirrate. [See. in additton. the cor- respondence between Fouieer and Mt7rton (269)land%torton's article omthe ethtcal problems oficonceal- rne medical kno%% ledge %%tthtn ocrupattonal medicine (:"0)i. Half a.ear after %iorton's re~ieK. Hogstedt & Asrlson,t.'1 t introduced a nerr era in this research by publishing the first truly epidemologic study. it was a case-referent study .~hicti~ «as later supplemented kk ith a prospecti%e study (.'2) and with hygienic mea- surements (2"3). µhich together with two additionali articles formed part of Hogstedt's thesis (27.t), In these %torks of highepidemiologic quality„it is documented :n a:on% immng' Nay that, exposure to nitroglycerin/ cth.lene g(.cot dinitrate not only causes symptoms, dis- eases. and deaths due to nitrate wuhdrawal, but also raises the risik for CVD many ycars after the cessation of erposure. Hotastedr's results ha\,r beemconfirmed during the 1980s by two other investigations (275. 276)t both of .khich are historical' prospective studies. In these studies. more CVD deaths were found than expected among the erposed' workers despite preemplbyment screening and%or medical m,.nworing of the employees. Thus it is now clt;ar that nitroglycerin and, especial- (y; ethylene glycol dinitrate increase the risk for,CVD in, the following two ways: partly via the specific "tilonday morning attacks" due to nitrate withdraw- al and partly sia an increased'risk for CVD which per- sists long after the cessation of exposure. This double effect, is described in a few of the reviews, such as Fine's (,I ) and Kurppa et al's (6), while reviews on the topic were still'being published during the i980s which only or almost ecclhsi%ely describe nitrate Ktthdtawali and'-4fonday morntng attacks" (2. 3. 5. 2'")'. Other chemical sUb'srances and compounds This section brie(l~ re~icNS canous studiesconcerntng C% D and other chemical substances - areas in which onh• a fcµ studies ha%e been cond'ucted or in uhic.h se%eral' "competmg" exposures occur in the same itud+. Om(rroroliwne_ (n 1986. Levine ct al (2'8)publtshed a historical prospeeti.e study of,Workers in, two fac- tories in,which the emplotiecs had been exposed to dinurotoluenc (27$). As in so many other instances. it was a susptcion.of carc.tnogenicitv w htch mottrated the studj, but' no tncreased', incidence of cancer was found amone these .corkers. Hoµe.er, an increased, incid'ence of IHD IS51R 1511 appeared when the data firomiboth factories uere combined. with a relatton- ship between the duration and'the intenstty of the er- posure and the incidence of IHD Accordtng to the authors, only s er} few of' the workers had' been er- posed to nitroglycerin or ethylene glircol diniuate. Organoph'osphares. Two cross-sectional studies - one Danish (279) and one Indian (2801 - have shown an increased pre~alence of "ischemic" electroeardio- graphic changes among workers exposed to or ganophosphates. The Indian study included 155 ex- posed persons and 60 referents, while the Danish in- vestigation included 446 workers. of whom 114 were classified as heavily exposed'. fn the Danish study, the higher prevalence of electrocardiographic changes among the heavily exposed'individuals remained after control for age and smoking. Anrimon-v rrist,lfide. fn the work by Brieger et al from 19541(281/, a factory was mentioned in which 125 men were exposed to antimony trisulfide for eight months to twoyears. During this period, eight of the workers died suddenly. Two,of the deaths were due to chronic heart disease. Four of the deceased were under 45 years of age. Because of this finding, the workers were ex- amined. and elbctrocardiographic changes were found in 37 of the 75 examined. A review of the literature on animal experiments with antimony trnsulfide seemed to show that the substance is cardiotoxic. At, the fac- tory studied, the use of antimony trisulfide was stopped, and no further sudden deaths were observed. In 12 of 56 reexamined workers, the observed elec- trocardiographic changes persisted. No other studies on antimony trisu(fide were found in the literature. Beryllium. Im a historical prospective study by. Wagoner et al (282), mortality was investigated in a cohort of 3055 workers who had been exposed to be- ryllium. Despite an assumed healthy worker effect, an SMR of 113 (P'<0.05) was found for heart disease in comparison with the mortality of American white 255

reviews. unfortunarelk. appear not to have been aµare of this ree~aiuataon. Re¢ardtng the first of N1 etr & Fabiano's three ques- tlons, quoted on page _'0, the iolloKtng conciusions canibe dra%%n (11 there is no relationship between stud> qualtnt and support for tAe h)pothests; (ii):%ery fe%k studies are or filehimethod'olo¢tcal quality. and these s;ud,c, g1ka altnoit no support for the hypothesis; and~ t iii l the research group behtnd the animal experiments most ~ii[en auoted in support, of the hypothesis has %%Ithdrawn its results in ~tew of established flaws In stud% destgn. Thereiore. one can only concur with the conclusion of Werr & Fabiano "that there is no e% ie den.e to support the suggestion that exposure to low to moderate le% els of CO increases the rate of the de- %esopment of atherosclerotic disease inman. We be- llese that suffictent evidence is available to support the conclustonitha[n in fact. CO is not of pathogenic con- sequence in atherosclerotic disease [p 523)7 (188). Concerning the second of the three questions menr tioned. " mr & Fablano's conclusion also seems well- founded: "Acute exposure to low levels of CO does result in reverstble. nonprogresst+e, exercise perfor- mance decrements in healthy and diseased tndisidu- als ('p t_3]r' 088). In the present re.iew, I have not examined studies on carbon monoxide exposure and cardiac rhythm, Therefore. I refer the reader again to Weir & Fabiano, who concluded: "ln summary- exposure to CO an acutely toxic levels results in, alterations of cardiac rhvthm, pnobably as a resulii of the induced'hypoxta. There is no constnctng evidence available to suggest that exposure to low to moderate levels of CO affects cardiac rhnthm [Ip 5231f' (188). Even if these conclusions on carbon monoxide and CVD seem welkfounded. there is still a need for fur- ther - and better - research in this field. !n the cpidemiologic area, there is specifically a need for the following: (i) prospective studies in which both the ex- posure and the development of the disease can be fol- lowed (none of the existing studies have been prospec- tive), aod (filstudies in which carbon monoxide is not ani integrated part of a mixed exposure. whlch 1; nce case t%lth cigarette smoke. exhaust, fumes. etc Passive smokrng Passatc smoklne has not been mentioned irra any o( the general',rettews on CVD,and-en.tronmental c\- posures. paralp due [o the fact that almosa all research on passive smoking and chronic diseases - tnci'udtn¢ lung cancer and CVD - has been conducted durln_e the 1980s Most oti the literature on passt%e smokrna and CVD has, on the other hand'. been rc%te%%cd in three thor- oueh reviews on the health effects o[i passl+e smok- mg.at, the Surgeon General"s report (212), the report from the National Research Councill (2311 - both from 1986 - and Fielding & Phenow's revlett from 1988 (214): These reviews alllconclude that furtherre- search on CVD and passive smoking is needed. The most important information concerning the studies which have been published currentlti on IHD and passive smoking is shown in table 4. These studies ha.e all been published'durung the pertod 198z-1988 and are all based on a comparison of the incidence of 1,HD in nonsmokers marned to smokers and nonsmok- ers married to nonsmokers, Five of the studies (C15-220) are prospective cohort studies. Khlle the Irist, one (2.1) is a case-referent studN. As shown in table s, the <' aes yielded'inine esti- mates of relative risk. These esl,::;a[es varied from 0.93 to 3.25 with an accumulation oi values in the area of 1.24 to 1.31. The median relative risk for all the studtes was about 1.3. and it is also approxtmateliv 1-3 when only the better studies ("xxx" or "xxxt" for qualityl are considered'separatelti. Only few ofithese relatise risk valhes are significantl~ different from 1.0 when they are regarded indisiduall.. Howc~er. Lamt inithis paper, more interested in the total pattern that appears when the studies are viewed as a whole. A relative risk of 1.3 for passive smoking seems high in relation to the relative risk of about 2.0 oftenimen, tioned for active smoking. Whencomparing the two Teble 4. Aer,ewotthceproemio/oplc stuotes on rscnem,c.nean olsease ttMDl ano passwe smokinp Stuoy Stuoy Oesrpn PoDu/at+on Mirayama t215:.2161 16-ywar fO1low,uD Gfllis et al1(217) 6- 1011•yearfo/1ow.uD GananO et, afl(116) 10-year lollpw•upSwenosen et at (2191 10-year tollow-up Me1s.n0 et at f220) '. 12•year' follOw•uD lee et, al (221) Case-referent stuayofGatrents 91 450 women~ 627 men 1 917 women 695,women 1 245 man A 162 men 14 $73 women At male IMD pathents ano 133 referents 77 temate IMD Dat+ents anC 316reterents Stuoy oualrty AR for IMD- rr 1L24 rr 1.29 3 25 urr 2 7 arsr 1 61 sar 1 31 1.24 aiz. 1 24 093 •Tne Cnteria for metlippolopical Oualily, are erDla,ne0 in the te=t ~ Relalrre rtak for.IMD among nonsmokers marrre0to smokerSCOTDareO tOnOnsmokerT matneo fOnonsmokers 252

are :onformed or invalidated through the collecti.e and cumulaweMork which researchers carra out, and s%s- temanc :rmcal re~le+ts oi the literature constttute an exer more Important~ pan of this process. Se%eral oi the factors mentioned under "~erc defi- ntte" and "quite deitnna" in table i' are Ntdespread in tndustrtalized countries This is true for physical inaati% it at ttorl.. noise. shttt ttork. µork stratn: lead. and~pass+,e;mokins- Even if the relato;e risk forCVD .onnected tttth e:;.:: of these factors is modest (from apprortmatel' y 1.1 to :.0)i the total'etiologic fraction tattrtbutablertski will be considerable. and therefore the potential pre+entl*e benefit' is great. Nott the classic question "ls enough known to use this kno%.ledee for pre%entive acti.itues' artses. This is naturalln not a scientific questionbut is stilllone with a hlch,researchers are often confronted and are e.r- pected to be able to answer. One ans%ker could be that enour:hiis known about the factors which have been mentioned under "ser% definlte" and "quite definne" in table S to initiate pretienuon, There could howeser be a risk, of making a mistake since one or more of the ei¢ht rtsk factors mentioned, at some point in the future, might prose not to be a risk factor (or CVD. With respect to this possibility, the fol)owing rwo points are worth making: (i/ if one chooses not to act until one has "100 °'s certain evidence," one is likel% to make mistakes whichihave serious consequences for the health and mortaliE,y of many people, and (ii) the factors wfiich~ha%e been mentioned in table S are alli risk factors for diseases other than CVD. If one or more should pro~e not to be a risk factor for CVD, there Nould'stiil be a positi.e effect from reducing or remo.tn¢ these factors. !n should be emphasized that table 5 only includes factors which,.ha%c been mentioned in the literature as possible risk factors for CVD. The absence of'evidence about a causal relationship should, of course, never be confused with evidence about an absent causal'rela- uonship. it should4urther be mentioned that the ta- ble deals with levels of exposure which occur "nor- mall% " au workplaces in Europe and North America. Marmot & Theorell (289) recentiy claimed that psy- chosocial strain at work is probably part of the expla- nation for the negative correlation between social class and CVD incidence which is seenn in industrialized countries. fnitheir review; they emphasize Karasek's job strain modetl The deliberations by Marmot & Theorell are an important: supplement and corrective to the prevailing explanations which virtually always have their starting point in individual risk factors. It should be stressed, however, that not only job strain, but also several of the other factors mentioned in ta- ble S, are more widespread in the lower social classes. Therefore changes in the work environment might con- tribute to the efforts to reduce the social,inequities in morbidity and'mortality which eonstitute an impor- tanr target in the program "Health for All by the Year :000" of the Vworld Health Organization and in the health policy of many tndi.tdual countrtes. Finally_ some remarks on~the form and content of' literature ret teKs Mtthtrnmedlcal researchi It is true for most re.iews that the eraterus for collecting the litera- ture and for esaluating the tnditi tdual studies are net~ ther explicit nor systematic. The most common mode is that the authors of the re; re>{ mention some posl- ti.e and nerratr.r studies, obser%e the evident lack of consensus. and conclude that further research is neces, san. This kind of resteN does not li;e up to elemen- tary sctentificc demands and'does not contribute to the development and claruficatton,of research. One ot the consequences of the steeply rising num- ber of scientific investigations all over the wortdis that researchers and other persons become ever more de- pendent on,reliable re.iews of the existing literature. Therefore re% iews musr, try to live up to the demands forvalidity, reliability, precision, and repooducibility which are in force for ,:^,: individual empirical studies. To the extent tharretu" 5 do live up tothese scienrif• ic demands, they will be able to ser.e two very noble purposes: (il the clarification of future research needs (one must northink only of stressing the ever present' "need'for moreresearch." but of a sharperclarifica- tton of hypotheses. method4nd design problems, mea- surement problems, etc> and (ii) to indicate those areas in which the evidence is so-certain" that preventive activities ought not be postponed further. In this con- nection, it should be pointed out that sottx uncmtatnty must alk•a,vs be accepted, as is the case in other hu- maniand social contexts. As is noted,in this and'the previous article (14), sev- eral reviews have been published in recent years in which.anempts have been made to live up to the men. tioned demands (S„27, 188, 29(}-296). One must hope that development in the direction of more systematic reviews will continue in the years to come. T.W. S. Ctass-t/eation of poss bta nak tactors for carolovas- cuWar 01s.as. tCVpt in tne roru env.lronmant. Cwsal rnal,on to Lvo NOnCMrn1CL Nr{ltactOr Ch.+n-sar v.rp e.hnmr aws,cN w+runtr Caroon msuwaoe nnm~ It .on plyc&nnrwnroplrco/ Ourlt ON,n,N won stqr/, tr,Qalaa& OMN,N oa~anps ano lo. 1narMr+nO bwnca. M,h sort was-bl. no,w Cowrt. ars.nK. can0u1110n .0.00uc,5 Sorn..nal, tiaa" . ,rrn,atwn Orqsnoonosonetta 0,. oosrel. oo.frlr.ou.ncrTaon0rotolu.n, a,t11+wRY. MI,C /yly /o.bIn'14.vA,. COOOrt /rpyNnCT "WM ,nono.qM ~OOaD,r no M.crora.H. CWO' Cao,Mwn: Mpan.C ., mas,onsnio aw..nts' ~ Inanws n,e ns. torCuD tnroupn.mc+as.o wooO waswn a Mpln.laral a.DOluta Inay 0e 44Y sso.uany n.n coMan.a .nn otn• ., „s.:tactons .aooslt,. ,na. Caus. cano%aC aHTylnrn,a anp fY04M o..fh 237

s THE Lq.r:CET, SEI'TEr1BER 16, 1989 antibodies in SCLC patients withounLES has to be further investigated in a larger population to better define their possible pathogenetic role. None of the myasthenic patients tested'had anti-VOCC antibodies,,whereas 11 LES patientt had also antinicotinic receptor antibodies, which suggests the possibility of a combined myastherlic syndrome,' atileasr at the immunochemical ln'el! Use of this new immunoassav to screen a larger number of mya: thenia gravis patients will allow the detection'of cases in~which LES occurs together with rrtyasthetlia gravis. Antigenic modulation is a common mechanism by which anti-receptor antibodies down-regulate the number of receptors expressed at the cell I surface, and this effect is importanr for explaining the biological and clinical activity of the autoantibodies.10 LES antibodies clearly recognise antigenie detemzinants on the VOCC which are "epaernal"' to the site where wCTx binds, since, for the purpose of the immunoassac, this site was alteadv occupied by the toxin. Furthermore, LES autoaraibodies were not able to directly ' inhibit 1351-fuCtx binding to Ih'1R32 membranes. However,. LES antibodies were able to down-regulate the expression of VOCCs' in: This effect was highly specific with respeLZ~ to other~ membrane molecules such as the el-Bgtx receptor. However, we cannot exclude the possibilirv that different patients syrlthesise different antibodies with different specifieities and mechanismsof action, as in the case of anttbodles against nicotinic receptors in myasthenia gravis. We thamkDr V. A.. Latnon for aldowirsgg usto.perform the blind acperunent;..for the pemussionto use these resulu, and4arhelp with the manuumpr;,Dr L. Rosenthal for helping to improve the paper; Prof G. FtsrrugzEli for his criod'suggestions; DrT: Baggi for help with anfuucoaitvc receptor antibods usays; and JNr P: Tinetli for technicJ callabornion... This woric' was panh•funded br.the C~R Special Proiea '".tieurobrolog`'" All torresp,otsdence shouldbed addressed to ~ E. S., C~R. Crnter of Cytoptiamu.rologs, Vu Y'am-iteJ1:32;:'01?9.Nilan, ]rari,. REFEREKCES I. O'Xr&JM, Mum~ N.v.F, I:-Dnx .. r Tbr. Lmsbm-Earon m.asthcue z,nd- . A ~ ~ of 50 osea. BrmnI986,111: 2.:Lamber. EM, RoekrED, Eao- LM;, Hodgsun: CH, . M.astlierne syrsdromr oensanally aooaud rith Drvrseluil neoplium . neurophysiolopc smdras. In: H L Vrtn, ed. .Nmrhmu pans. SpmnafiddCC Thomas, 196.,1. 362-110. 3: Cull-Cs:dy 5G, SLled R. Tnuunan A, Udiirel OD On therelease of mrsmrina an nenru:.myasrlsasn pv.v and ml}stherur synddome aHenedbum.n asdplaces.. J Pm-! .1980; 299: 621-38. . 4. M-dusi. MBi R'alsli,Rl:, Rutirno FA,.BnnrsMan RT, H~e Wi. Avronomu dsfuncvm andEaren,Lambcrt sYrsdrome. J Aurm Nrr..- Sysn 1985, 12: 315-20'. 9~Lmnon VA', Lamberr Eli, Qluraadium S;,Fu-bvrks V. Aumirsununiay:m the tLmberr,Earon myurtrc:uesyndrvme: M-4 h'm,r 1982; S: 821-25. 6: t.ars` B, tie.s®n-Ds.v 1, tt'ny D8, Vmceni A, Muuray; N. Aurovrmsune.euoIop - for-thasic'Earmn,Lamberr,qesd'- . L- 198'1; ii:224-26. 7. Kun tY Pass"ive asnsfer of rhe.L.mEen-Faron m}aatheuc s3ndlomc: neurwnuscu}v. v.nsrsvsswn m msec mlecred wdapuume. Mwc4lvm. 1985; 8. 162-i2. 8.J~ B. \rwsotn-Dnu ); Pnnr C,.~'by Da'.. Mdtiodus m rnotor nme.uerrnusd~.n dacoophyuobp¢sl krudy of.huerm myuttiauc syndrome.oansferred w nq,ac. ],PMym!,1983; 1a4: 335-45: 9. Knn IY- PaasrveJy.v ansfecred. l~ben-Eason syndrome mms¢ remvsrst pun5ed. I{G. Mur Jr' .Vrnr.1986; f: 52}30. 10. 1-Dert EH, I.auson VA. Seleard.leCr eapidlysMUm t-bvr-Faeon myndbauc eyndrome m mrte: c-piensmt ihdepasdenoc and;EMG,abnonmahea. Mmc4 Krrvr 198&, Ia: 11.33-45. 11. Fukunap H, FilRel AV, tAV B, New.orn-Daws J, Vuscesl A.,Pasuvettansfer.of Lmbm-Earoo mysnhetie .vndrnme with IyG fromman ro mouse deplern rhe. praynapuc manbnnc.arnvc nu!se. lbor Irar! vtcnd Sn USJ1:1983;1tr. 7636-80. IP. Fukirok. T„Etsgel AG, Lanj B, N~Dsss:J, Pnos C, Q'nyDW. tLmbm-. Eaaon myasNasc syndrnmc. 1.. Firy'.. morphologrnl effecss ofi IgG on the prenynapoc manbnnc .cvve mnes Ain Narro! 198- , 22: 193-99. 13. Fukurup H, EneeliAG, Osrrn CN, Lmben M...Pauananddiwryuuanon of pra}supIDC n~rs6rane .cove m die Lambm-Earon myschervc syndroma- Masc4 A'nu 1982; S: 686-97. 14. Rooeru A, Pexn S, lun[ B, Vareer,c A, Ne.r~orn-Deviv )'. Parweoplasac mlueheruu. synCtame la('imluErx •'G"' Cu m a hurwr,small lorcss,oma lunc h'ansr..1985'. 317: 73 7-39 Refhmcrs rontirwrd otfoor.oJ nezr colsnm: SMOKD~G AS A R1SF4 FACTOR FOR CEREBRAL ISCHAEMiA, GEoFFREY A. Doh'NANs-I JoH:: J. M,GNEILS MJCHAEL A. ADENA' AL'Sr1': E. Do11.E' HF1a773ER IW1. O'MALLEY' GEpRGINA C. hiEILLs'' Deparrmerau of hreurologl,''aw' Medianc,? A'usasn Flospifal, (imz+rroiiti~ of Melooirrne Department of Socia1 and Preventive Medieine, Monruh' Crrmursiry, Melbourne,' and'lnlseaf Ascstralta Pry Ltd; Cmtb'erra,` Australia Summary To assess whether a rigorous clinical classification, based on aomputeriscd tomogsaphy, of patients with cerebral ischaemia would identify' subgroups at higher or lower risk with, respeca to cigarette smoking habits„a ease-control study was carried out on 422 cases of first-episode cerebral ischaemia matched for age and sex with 422 community-based neighbourhood controls. Patients with ischaemic stroke due to extracranial or intracranial vascular disease were at higher risk from smoking than has previously been reponed' for stroke (relative risk 5 7, 95 °io confidence inter\'al 2 8, 12 0) whereas those with stroke due to cardiac enboh hadino excess risk associated with smoking (relative risk 0 4 [0 1, 1 8];. After cessation of smoking. the relative risk declined gradually over l O vears, at the end of which time a significant risk was still evident, This fihding,may imply that the risk incurred by smoking is d'ue mainly to ather'oma formatDon„ rather than transient haematological effects. Exposure to smoking by a spouse was an independent risk factor for the whole group of cerebrral isehaemia patients (telative tisk 1 7 [1 1, 2,61),,but this wasnot sofor smoking by'eitherparent' (relative E. SHER A.\D OTHERS'.REFERENCES-r.ont7mccd 15. De. Aupwma H7, Ismben EH, Grxsnunn GE, Ouwen B\l. Le.non \A' AntaBausm of salusgr-pred aloum diarsnrl> v~ arrull dl a~nnorrsi of pammu.nh oo rnhouu Ly flen-Earon m.asdimnc. slndrome o.auroenubnGn. wmnorown.andadc,osmc C.vur Ru 19b6:4&: i711a 16.Kun IY, Nehc E. 1CG 6:vm p.IDmrs.wtb I-bm-Firoe nrdrvrm., blocks .vltla{edcpmdencoalaumrLrvxh Sanc..198b',239:a[,s-0E. I7:CruxLJlOlireecBS4 C~Imumdururdcsaaerxsua-amep- G\'tAd'efvnesa ne- h*i a.sou) vrc. J,Hu1C6i.e 1986, 2YI162Y133 I B.: Feldmaa DH I Ob.m B.N, Yoslirkarni D. Omep C- ta+t.; •^. .roun . a pepcdr thae bl.ds osFoum dsarmeh. FEBS'Len lofi', 214:'95-30P 19: R,wtt 1, Gahrm. R, G- 37t. Aamu.7cnaox. A', .Nclhman JM. Cru: LI, Oh. mBS4. Neurvr.al alchum. char:nd Ivilab:rors J e.a CA_- :1967, 26:': I 1-+-% 20; Bstirarun J, Sd=dA, tuziumskr ~M Properoei of struccure v.d mrescvon of rlie te.m, ror for omer -mnorom:,. a po.lyprpode.cn•ron Ca=" dunneu Brof,.h,.a Rr, i C- 198',15P1051-62~ 21. Ye.eer RE, Yoshikana D, Rrvw.J, C+ur.L); Mslurudr GP Tevsurunrr rcl/asc from , praynapec- vmsuWh ofdeeasc orpn srJubimor.: b, Ihee olourn ehannell v,ta9onssr.. omeQc Camus roan J.l:mosn 1987, 7:.39ia46' 22. rboln -. DJ! Lupp A, Hemm,t G. I+JUbsoon of amvaJ ineu,vwwwner.relesu b% omep-otui, e pepode rnod.ulatorr of the T:-e)yc wlorr-smuns<- oltium , durmaLl A'a. yn-Sc/w.rde6r7s A.rA'. P6erwsorol 1987; 336:.46'-70. 23-McOakey.ECr, Fm AP; Feldesus DH, n.1 as-L-.orsaomn , duenand pennrmr. blat.da of speciBc nres ef olourn rhwse4 m neurons bw non musde P+crr .\'-!' . Arad So C"SA.198", 54; 4327-311 ?A.. CeuzL JoM.us DS. Obva B.N' Cbannersaoon of tbe.amp- uree. E~sdc,oc fer oa.ue-ryec5c Aerero8asory'-doum dunncl ryye 6-A-r3 . 198 7:7[:.820-24 25:. Sher E, Pmdsdla A, Llarsasti F Omep~w bmduu vrd effrcn onn olnumdvmrl fumeaan m human neun>blardrs. and rar phroCUOnne~- ¢Ui Imes FEBSLrrr 1988, 235: 17H$'. 26'Gato C,: Mamessua R. Clbnotu F N- mnt-. lot .nmbodv.. desecmn m rnyasNerua p-.ns l.'ixoiq, I CL. 198-1, 34: 37i-' 27. Oonarnu F, Cabrsru ~ D, Goro C, Sher E Pfs.mvmlopd' dunnma~ of dsohneryrc.re.tpron mu human nrueobianom- re4'.bnr J.\.v.nsM.~.f9h6., a: 291-07 28Clensena F, Sli- E Motwdl.mduced5 mrersabamom of a¢nICholme rucvu-~c r epror hmcoo mecharusm. md s<kev- - Ero J,C.!!' R.n! 9oE5, 37, 29 . M,lia Rl-.Nuloplt alnum rlsannrls aM neurmul fvn<vmn S-la6:. ] 35: 4s 5:30 CJernmuF, :Shn. E. AnoMh -mduceddown eetulouon of ine:noramr rca-epr,.n u.i humar:drra.es In Koerir: TM, a al., ad,~tolnvh• mechamsm,of doenumrauonm-vlpul,nohnileh Berlm Sprm,er\'rrlat, 19E7 30'1-1-

0 shows estimates of the power of each of the studies to detect a 20% increase in risk of heart disease (i.e.,, a relative risk of 1.2) with the available samples. The 'power was computed as described in Muhm and Ol'shan,-'41 using a two-sided test for the relative risk with a type I risk of 5% (i.e., requiring the 95% confidence interval for the relative risk to exclude 1.0 before concluding a statistically significant elevation in risk in an individual study). Most of the studies have low power. This low power of the individual studies argues against drawing an overall negative conclusion concerning the link between ETS expo- surc and risk of death from heart disease, based on the individual studies taken one at a time. Last, and of note, all these studies are based on the smoking habits of: the nonsmoker's spouse and, therefore, the exposure to ETS at home. Household exposures to ETS at home are generally much smaller than exposures at work, where the density of smokers is generally higher.31-« As a result, these studies generally underestimate the risk and~atten• dant public health burden due to ETS-induced heart disease. Kawachi:et al" adjusted Wells'S relative risks to account for workplace exposures to ETS and found that the relative risks increase to 2.3 (95% CI, 1.4-3.4) for men and 1.9 (95% Cl, 1.4-2.5) for women. Thus, any potential confounding of the re- sults because of exposure to ETS outside the home will! tend to produce underestimates rather than overestimates of the effect of ETS. Likewise„ esti+ mates of public health impact base& om risks comr puted from household exposuress will be lower than the true public health impact. In addition, Wellss and Kawachi ct al" indicate that the number of heart disease deaths due to passive smoking i's an order of magnitude greater than the number~ of lung cancer deaths due to passive smoking. Even though the relative risks for heart disease and lung cancer caused by ETS are similar (about Is3 for both diseas- es); the attributable deaths for heart disease is greater because heart disease is much more common than, lung cancer. Of 53,000 annual deaths in the United States attributed to passive smoking,s 37,000 arc attributed to heart disease compared with 3,700 for lung cancer (Figure 2). These epidemiological studies demonstrate a con- nection between ETS exposure and death from heart disease. We now turn our attention to possible physiological and biochemical mechanisms that ex- plain these observations. Short-term Effects of ETS Exposure Long-term exposure to ETS exerts carcinogenic effcets by increasing the cumulative risk that a carci- nogcnic molecule from f'TS will damage a cell and then initiate or promott the carcinogenic process. The situation with heart disease is different. In heart disease, important long-term changes (i.e., the devel= opment of atherosclerotic lesions) and shon-term changes occur. The latter include an increased myo- Deaths from Passive Smoking Total Deaths: 53,000 t+...t tDi..as. $7000 o+n« c.rlo.. 12000 w.V c.no« 2700 FtGUAE 2. Pic charr of US dearhs from environmenml tobacco smoke. The majority ojannual deaths arr atrribused !o hcan direase. Modified from Wtlis.'" cardial oxygen demand that may outstrip the oxygen supply and produce ischemia and an increased plate- let aggregation that may lead to coronary thrombosis and acute myocardial, infarction: When the coronary circulation eannot, provide enough oxygen to the myocardium to meet the de- mand, the result is ischemia„which can, be a silent or an anginal episode. Earlier onset of angina or hypo- tension during exercise is a reflection of more severe heart disease. Oxygen supply can be reduced by atherosclerotic narrowing or, vasoconstriction of the coronary aneries or by reducing the oxygen-carrying capacity of the blood because the carbon monoxide in the ETS forms carboxyhemoglobin, which, in turn, reduces the blood's oxygen-carrying capacity. Khal- fen and Klochkov*A confirmed earlier work by Flronowu demonstrating that exposure to ETS sig- nificantly reduced both the exercise ability in patients with coronary artery disease and the rate-pressure product (heart rate multiplied by systolic blood pres- sure). In both studies, patients were exposed to realistic levels of ETS by sitting in, a waiting room while someone was smoking. These effects were present in smokers and nonsmokers" and regardless of whether the room was ventilated! 3'-35 Exposure to ETS also increased resting heart rate and systolic and diastolic blood pressure and resulted in a lower, heart rate at the onset of angina." Blood carboxyhemoglo- bin was increased by about 1% after exposure to ETS:ys Thus, short-term exposure to ETS leads to an imbalance between myocardial oxygem supply and demand during exercise in patients with coronary artery, ddisease. While this discussion has concen- trated on the carbon monoxide in ETS as the active agent, some other component of the ETS may be causing,or contributing to this effec[. The effects of ETS on cardiac performance art, in fact, severe enough to affect exercise performance in

2 Circulation Vd 83, No 1. January 1991 TAatt 1. Epidemiobgkal Studies ot Farir...eotal' Tob.cco Smokc and'Genoaary Heart Disea.e Dntb Author Males Gillis et al" (1984) lse eV at' (1986) Svendsen e1 all" (I 9g7)# Helsing et all, (1988) Poofedi Females Hirayamau (1984) Gi1Vis et al" (1984)' Garland et alts ();9g5) Lee et at (1986) ~ Htlsingtt all I (1988) He (1989)" Humble et aP! (1990): ButlerN (1990) Pooled Both sexes combined Hole a al" (1989) d Pooled9 Deaths 95% ' Type lroeation or cases (n) Relative Confidence Dose' Powcrt risk interval response?, (5r). Controlling for P Scotland 32 13 0.7-2.6 - 5 Age C United tGngdom 41 1.2' 05-26 - 4 Age, marital status P United States 13 2:1 0.7-6.5 Yes 3 Age, blood pressure, P arrlsnd 70 3 .1-1.6 o 0, serum cholesterol, .veight„education4 alcohol Age, marital status, 1.3 1J-1.6 trousing, education P Japan 494 1.2 0.9-1.1 Yes 40 Age, diet P Sootland 21 3.6 0.9-13.8 - 2 Age P Califorttia 119 27 0.9-13.6 - 2 Age, btood pressure, C nited Kingdom 7 .9 5-1.6 - 6 plasma choluterol, weight, years of marriage Age, marital status P Maryland 988 1.2 1.1-1.4 Yes 2 .,ge, housing, marital' C China 34 15 13-1.g Yes 3 status, education Age. race, residence, P eorgia 6 !6 .0L26 es 8 occupation, hypertension, f'amily history of hypertension or CHD, alcohol, exertise, hyperlipidemia Age, serum cholesterol, P California 64 1.4 0.5-3.8 - 4 blood pressure, weight Age 1,.3 1.2-1.4 P Seotdand 84 2.0 1.2=3.41 - ]0 Age, aex, social class, I L3 1.2-1.4 blood pressure, eholestero4, weight P. Prospective cohort; C, Case control; CHD, coronary heart disease. 'Notmry in this column indicates no comment on the presence or absence of dose-esponse relation. tPower to detect relative risk of 1.2 with 95% confidence. tHigh-risk population; members of Multiple Risk Factor Intervention Trial. ;Poo6ed relative risk computed as R=exp (I w, In, RJfw,), where w,-(Xlln R;)r. I This repon is a laterfollow-up of the population reported in Gillis et al." UtII studies combined without regard for sez, with Gillis et a!' excluded because Hole et allr report later follow-up on the same people. in cigarette smoke can injure the arterial endothe- hum and' iniaiate the atherosclerotic process. All the compounds from cigarette smoke that have been implicate& as damaging to the cardiovascular system of active smokers have been identified in bTS.t•' Epidemioiogical Studies on ETS and Heart Disease Since 1984, the epidemiological evidence linking exposure to ETS with heart disease has rapidly accumulated. The results of the 10 published stud- ies"-t7 that use dcathas an end point are summarized in Table I and Figure 1; four studies present data on men, eight on women, and one on both sexes com- bined. Despite minor differences in methodology'or end points (some used' death from ischemic heart disease of any origin, and some were limited to death from myocardial infarction), the results of these studies are remarkably consistent! All the studies on menyielded relative risks of death from heart disease exceeding 1.0 when a nonsmoking man was married to a woman who smoked, with an overall risk of 1.3. All but one of the studies on women" 'yielde&relativc risks exceeding 1, with an overall'relative risk of 13. Five studiestu•t7-19-w have also suggested an increase in the risk of nonfatal coronary symptoms, incfudingg angina and myocardial infarction, Consistency of an observation across different studies increases the eonfidence that a particular association is causal. Several investigative teams also observed' a dose- response relation between increasing amounts of

;rease in preTature %rntncular, bbeats. These results %%ere unc\peaed :n a group or %.oune. healthn adults Kramer e; al i_79t ewmtned 141 industrial workers t%ho had been crposed to I.I • 1-trichloroethane and 151 man:hed re:erent, There "as no difference wtth re• gard to ela:;rocardloeraph% . blood pressure, or serum ,hol'e tersil'. Most cit~ the persons e\amtned were %%omen. and most %%ere belot+ 35 sears of age. Blair et al I.10Leramtned the distribution ofcauses of aeath amon¢ ? 30 deceased dr} cleanine Norkers e\- posed to tetrachloroeth% lene. For C\ D. a proportion- ate mortalttn ratio ol"9 was found'. stgntficantly less than the "etpected" %alue of 100. The proportionate mortalft\ ratio has %~ell kno%% n limitations, an& this negati%e stud'y only sa.orcd'"xx" for study qualit~r. In the histortcal prospective stud) by Wilcosky & Tyroler (211 !. the mortalin of 1284 workers etposed~ to se%eralld'tffcrentisohents Kas analkzed. An excess frequenc%at deaths from IHD was found among workers who had been exposed to carbon disulfide. ethanoll and phenol. Finally. Eskenazt eral (.4:) studicd the pre%alence of ad~erse pregnancy complications among 90 Nomen exposed to oraantc sol>,ents an& 180 unexposed matched referents. The> found a significantly higher proportton of women with preeclampsia (a disorder of pregnancy characterized by hypertension. edema, and protetnuria) and hypenensiomamong the exposed women. These epidemiologic studies are %ery different with regard to exposures, study design, and study end points. Therefore it is not' possible to draw any con- clusions on the basis of thesc investigations. No studies of occupationallmortality have found increased CVD mortalit% among painters or other groups exposed to organic solvents. It is, therefore, not very likely that organic solvent exposure at moderate levels increases the risk for, CVD. Carbon disulfide Carbon disulfide has been mentioned and recognized as a risk factor for IHD in virtually all reviews of CVD and environmental exposures published during the last 20 years. As will become apparent, this unique scien- tific consensus is primarily due to the Finnish study of viscose rayon workers, which was conducted by Hernberg. Nurminen, Tolonenl and their co-workers. The first researchers to call attention to the relation- ship between carbon disulfide and IHD were Tiller et al, who in 1968 published their study of mortality among viscose rayon workers exposed to carbon dts- ulfid'c (243). It actually consisted of two studies. one of the proportion ofllHD deaths among workers from three factories, and the other a historical prospectove mortality study of a cohort from one of the factories. Both.studies showed a positive reiatlonship between carbon disulfide exposure and 1HD mortality. The results from the study on Finnish viscose rayon workers have been published in many articles during a t5-vear period (.-W-:53), Furthamore. the ,tuJ', has been used4s a pedagogtcallexample tnione of rhe fe•k te\tbooks on the eptdemtolo_e> of occupa~ionali meJicine The studs s%as a I5-~ear follb%% •up ai two cohorts uith 343 men in each. The stud~ ;ohorn was exposed~to carbon disulfide in aviscose ractor%. but otherwise resembled the reference cohort. %ktit;h worked at another factorn in, the iame tov,n. Atter, about~ fi%e.ears or folloN-up. a relan.e risk of'.6 for coronar% deaths "as determined fur the e\posed group This findine resulted in se%era+ Jtfferent inter%ennons to reduce both the carbon disulfide le%efand the e\- posure of the indt~tdual workers in the ~tscose tactor\. Eight %rars afterthis inter.ernton the relattse rt*k ..as approttmately one (.;8).. This exemplary epidemiologtc studk %%as scored "rxtrx'' forquaiit}. It is a prospective stud\ o%tr If years Ktthigood confounder control, reasonable knot%l- edae of pastand presenterposuret mam rele% ant stud% end points. a good. cleard and understandabie analk - sis, and intervention (reduced~ erposurel that was fol~ lowed b> the espected reducnon in the disease studicd'. The study demonstrates that it is posstble to con% tnee the scientific communit' % of a causallrelattonshtp via a"small"' studN of 2 x 3.43, persons tf one has well selected study groups, a good analti sas, and~ a lot of patience. The relationship between carbon disulfide and IHD has been confirmed' during the 1980s in 4mertcan studies (255. 256). of which the latest (2561 is the largest ever und'craaken.:the cohort studied comprising more than 10 000 workers. Since the causal relationship betweemcarbon disul- fhde and IHD is. withigood reason, generally accepted. there is no reason to go into more detail. R'efenences to additional studies on this subject cambe found in the very exhaustive reviews which ha-.e been published (257-261). Nirroglycerrn and ethylene glyco/ dinrtrare (nrtroglycol) The relationship between heart disease and' aliphatic nitrates is mentioned in virtually all reviews on CVD and environmental exposures, and it is one of the few relationships which all authors regard: as definitis•ely demonstrated. Nitroglyceain.has been used both in the medical'industry and for the production of dynamite since the middle of the laso century. Ethylene glycol dinitrate has been used'together with nitroglycerin for dynamite production since the 1930s„as ethylene glycoll dtnitrate improves the quality of the product and is cheaper. However, ethylene glycol dinitrate is farr more toxic and more volatilt than nitroglycerin. The first studies of the relationship between nitro- glycerin/ethylene glycol dinitrate and heart disease were published in Germany and Italy in the 1950s ((262. 263), They were case descriptions of the phenomenon which has later beemcalled "Monday morning angi+ 254

I 7 6 . Q 5 4 2 1 0 m rn J FwmN f I m a 7----~- ~ R © ww smoking by the spouse and the risk of heart disease in the . nonsmoking spouse, "-'s•" which in most cases was statistically significant. The presence of such dose-responsc effects across multiple studies,, eon- ducted in different locations with different criteria, supports the hypothesis that ETS causes heart dis- ease in nonsmokers. While all but one of the studies in Table I and Figure 1 yielded' relative risks greater than 1.0, the fact remains that~ three of the studies in men and five of the studies in women had 95% confidence inter- vals for the relative risk of passive smoking for heart disease that included 1.0, meaning that the risk was not statistically significantly elevated ~ above 1.0 (with p<0.05). Of note, the 95% confidence intervals do not lie symmetrically about 1.0 but are skewed toward higher risks. By examining the eonfidence intervals, the conclusion is reached that exposure to ETS elevates the risk of heart disease (Figure 1). Also, the results of these studies may, be combined in a formal analysis to derive a global estimate of the relative risk and associated 95% confidence Interval. By combining the studies, the sample size and, there- fore, the power to detect an effect increases. Wellss used then-availablc studics"•9•13-t3•" to compute a pooled relative risk of 13 (95% confidence interval, 1.1-1.6) for men and 1.2 (95% confidence interval, 1.2-1.4) for women. Our analysis on all the studies in Table I yields a combined relative risk of 13 (95% confidence intervall 1.2-1.4). When interpreting the results of such epidemiolog- ical studies, it is always important to consider biolog- ical plausibility and potential confounding variables that can explain the results. Aside from noting that the hydrocarbons in mainstream smoke already, im- plicated in heart disease are also in ETS, we will defer the discussion of biological plausibility until we discuss the effects of ETS on platelets and the atherogenic agents in ETS. For now, we will concen- trate on potentiat confounding variables, which are particularly important in a disease like heart disease i Glana and Parmley, Passire Smoking and Heart Disease 3 . . , Both r..a FIGURE 1. Graph of relative rssk in epi- demioJogical studies of the risk of death from coronary hean disease or myocardial infarction among' nocsmokers living with smokers compared with nonsmokers living with nonsmokers. Lines indicate 95%a can- fidenee intervalr. Note that two studies have upper bounds to the 95% confidence ituerval ofJthe scale of the graph. because it is known to be caused by multiple risk factors. All the studies controlled' for the most important confounding variable, age, and several'u•1.1-1y17 eon• trolled for known risk factors for coronary aneryy disease, ut patticular levels of serum or plasma cholesterol, blood pressure, and body mass. Most of the studies also included one or more measures of socioeconomic status, such as housing or education. Ind'eed; studies that estimated the relative risk both with and without taking these confounding variables into account found an increase in risk associated'with ETS after taking the confounding variables into atxount.1u.u Lee21-u suggested that the elevated risk of hean. (and other) disease with passive smoking may be due to misclassification of nonsmokers who are really smokers. In ad'dition, Waldz• noted that some people who say they live with nonsmokers have detectable levels of the nicotine metabolite cotinine in their blood, indicating that they are actually exposed to ETS, either at work or at home. The former type of misclassification tends to lead to overestimating the risks associated with ETS an& the latter leads to underestimating the risk. Careful analysis of the question of misclassification, which applies generally to studies of ETS, has demonstrated that the ob- served risk cannot be explained by this problem s-36-2x The possibility always exists that some other'eon- founding variable relates to cultural factors, such as the nature of housing or employment or the nature of time spent outside the home. Also, it is possible that there are other confounders, such as a correlation of spouses' poor health behaviors (e.g., diet), which are not controlled for in analysis. The fact that results art from all over the world in widely varying cultural settings-including several regions in the United States, the United Kingdom, lapan+, and China- argues against this concern. One can assess fortnally the confidence in reaching a negative conclusion by computing the power of the study to detect an effect of specified size.2" Table l

96 Staessen~l. Bruaut P. Claevs-Thorau F, eral. The rela- 121. tionshtp berseen blood pressure and emsronmentalles- posure to lead and admtum in Bblgtum Enaron I.: Health Perspeci 1988;"8'.1."-9. 9" loors' AH'. Shuman MS: Johnson, t1'D! .Addttt.e ;tausn.ai effects of'cadmtum and lead'on heart-related' 1_3 atsca.e in,a `orth Caro1 na autopsy sertes. .arch En- ,aren,Health 198_.3":96-102. 9n loorc Asl. Shuman A1S. W"oodward GP. Gallagher P\ Artsnal lead lesels and cardiac death: a h.pothe- 1_1 sts En+tron Health Perspect 19?3:4 '9% 49. Ketss ST. Munoz A. Stein A. Sparro- ' D. Spetzer FE. The relationship of blood lead to blood pressure in a Ion@ttudtnal study ofiworkmg men. Am J Epiderniol 1,5. 1986:1L'3:800-g. 100. uussST, Munoz A. Stein A. Sparrow D. Spetzer, FE. 126. The relationship of blood lead'to systolic blood pres- sure tn, a longstudinall study of'poficemen, Envtron 127. Health Perspect 1988:'8:53-6. 101. Lane RE. The care of the lead worker. 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I Clinical Progress Series Passive Smoking and Heart Disease Epidemiology, Physiology, and Biochemistry Stanton A. Glantz, PhD„and William W. Parmley, MD he first disease linked definitively to active smoking was lung cancer. lt~ is, therefore, not surprising that the firsn disease identified as causcd by passive smoking was also lung cancer.t Before the advent of mass-marketed cigarettes, lung cancer was a rare disease. Because smoking is the primary cause of lung cancer, identification of this link-for both active2 and passive smoking'-was relatively straightforward. This situation contrasts with heart disease, which has many risk factors„and unsurprisingly, the scientific community was longer in concluding that active smoking caused heart disease! Once the link between smoking and heart disease was established, smoking was found to kill more people by causing or aggravating heart disease than lung cancer. In fact, smoking is the most important, preventable cause of coronary disease. Exposure to environmental tobacco smoke (ETS) has now been linkedito heart disease in nonsmokers.'M, Much of the evidence for this link has appeared since 1986, when the US Surgeon Generalt and the National Academy of Sciencesl reviewed the evi- dence on the health effects of ETS. Based on the information available then, both report6 concluded that the evidence linking ETS and heart disease was equivocall and that more research was necessary, before any definitive statements coul& be made. These conclusions were reasonable in 1986. How- ever, in the 4 years since publication of these reports, considerable information on both the epidemiologyand biological mechanisms by which, ETS causes heart disease has accumulated: Most of the results presented here were published after the 1986 Sur- geon General and National Academy of Sciences reports. There are now 10 epidemiological studies on the relation between exposure to environmental tobacco From the Divisitm of Ca-diobgy Depanment of Medicine, CardilWVascular Rcaearch Institutc. University of California, San Francisco. This manuscript is based'on a bachground'paper prepared for the US Environmcntal Protenion,Agenry. It was also presented at the Seventh Worltl Conferencc on Tobaceo and Health, Perth, Auctralia; April 1-5. 171011, and the Wurld Conference on Lung ttcaltft, &xton• May, 20-24. l990'~ Funded in part with it gift from Pyramid Film and Video. Address for conespondencc: Stanton A. Glantz. PhD. Professor of Medicine. Division of Cardiology; Box 0124 M1186; Universiry uf California: San Franciscn, CA 94 1 43-01 24. smoke in the home and the risk of heart disease death in the nonsmoking spouse of a smoker and five epidemiological studies that examine nonfatal car- diac events. All but one of these studies yielded relative risks or odds ratios greater than 1.0: There are several lines of biological evidence that make this association piausiblc. There is evidence that expo- sure to ETS reduces exercise tolerance of healthy individuals and people with existing coronary artcry disease. Such reduced exercise capability is one of the landmarks of acute compromises to the coronary, circulation. There is good evidence, from both hu. man and animali studies, that exposure to tobacco smoke, including passive smoking, increases aggrega- tion of blood platelets. Such increases in platelet aggregation are an important step in the genesis of atherosclerosis. In addition, increasing platelet ag- gregation contributes to risk of coronary thrombosis, a cause of acute myocardial, infarction. Last,,carcino- genic agents in ETS, including benzo(a)pyrene, have been shown to injure the endothelial cells that, line arteries. Such injpries are the first step in the devel, opment of atherosclerosis. Thus, exposure to ETS can contribute to short- and, long-term insults to the coronary circulation and the heart. It is not surpris- ing, therefore, that epidemiological studies have identified an increase in the risk of coronary artery disease in nonsmokers living with smokcrs. Effects of Primary Smoking Before reviewing the evidence linking ETS with eoronary , artery disease, summarizing the evidence that links active smoking with coronary artery disease is worthwhile. This evidence was summarized in the 1983 Surgeon General's R'eport,4 which was devoted entirely, to eardiovascular disease; it concluded that cigarette smoking is one of the three major indepen- dent heart disease risk factors. It also concluded that the magnitude of the risk associated with cigarette smoking is similar to that associated with the other two major heart disease risk factors, hypertension and hypercholesterolemia; however, because ciga• rette smoking is present in,a larger percentage of the US population than either hypertension or hypercho- lesterolemia, cigarette smoking ranks as the largest preventable cause of heart disease in the United States. Since 1983, an increasing body of evidence has shown that the polycyclic aromatic hydrocarbons !

Glanu and Pamdcy Passive Smoking and Heart Diseasc 7 SI LO PGtz 0.5 O+ MC1r'~'t•slll ' } 1la t406 ethRf AFTER SI I PC* 0 BEFORE AFTER FIGURE 3: Plots of effect of active (lcft) and passivr (right) smoking on platelet aggregarlon in smokers and ntMsmokers. The sensitiviry inrlet; S1 PGl,, isdcfnrd as the inmse of the eonctntrction oJPnutaglandin It necessary to inhibit ADP-induced platekt ss aggtegarion by S(l%. Lower vaGres of SI 'PG1 y indicate grcateu platelet agg+egation. Adapted from Figures 3 and 4 of Bwgliuber tt al5 ers to ETS in an 18 m' room in whi& 30 cigarettes had been smoked just before exposing the nonsmok- ers. They measured the sensitivity of platelets to the disaggregating substance prostaglandin 12 that is re- leased by endothelium and inhibits platelet aggrega- tion. Figure 3 shows the results of this experiment. ln smokers, neither smoking nor passive smoking af- fected the sensitivity of the platelets to the disaggre- gating effect of prostaglandin 12. The sensitivity, of platelets in-smokers was also significantly lower than that of nonsmokers. In contrast, platelets were more sensitive to prostaglandin 12 in nonsmokers, with both smoking an& passive smoking producing a similar reduction in platelet sensitivity to prostaglandin 1.. These results suggest that the platelets of smokers are already desensitized to the antiaggregatory sub- stance prostaglandin 12 so that no further decrease in aggregation is seen. The significant decrease in plate- let sensitivity to prostaglandin after short-term expo- sure to ETS suggests that after ETS exposure plate- lets are more likely to aggregate with adverse consequences. Earlier work by Saba and Mason% also indicated that nicotine increased a variety of ineasures of platelet aggregation in nonsmokers and smokers. Although the in vitro effects of nicotine on platelets from smokers was greater than that in nonsmokers, the effect generally did not vary with dose (between 2x lU"9 and 2x 1Q-' M), suggesting that the effects of nicotine on platelets occur at low doses and that the system saturates quickly. This observation may ex- plain why passive and active smoking have such similar effects on platelets.s1-s2-t Tlne probable link between nicotine and adverse physiological, effects is nicotine-indutxd release of catecholatnines. Catecholarrtines are then responsi- blc for increased platelet aggregation. This reasoning suggests that 0-adrenergic receptor blockers may provide some protection in smokers. This premise is borne out by a trial comparing the effects of the A-blocker metoprolol to a thiazide diuretic in the control of moderate hypertension.s'' For the same reduction in blood pressure, the metoprolol-treated group had a significantly lower mortality rate than did the thiazide-treated group. Practically all of this reduction in mortality;,however„was seen in smokers and not nonsmokers. This study provides evidence that blocking the effects of catecholamines (released by nicotine) was the cause of the reduced mortality in smokers who were receiving metoprolol. In sum, passive smoking increases platelet aggre- gation, with a magnitude similar to that observed~ in active smoking. Moreover, the response of nonsmok- ers to both active and passive smoking appears to be different from smokers, with nonsmokers being more sensitive to lower exposures to cigarette smoke thann are smokers. This observation indicates that the pharrnacology, of ETS in nonsmokers may be dif- ferent than in smokers, with nonsmokers being more sensitive to low doses of ETS. In particular, it inval= idates attempts to estimate "cigarette equivalent" doses of ETS in nonsmokers or extrapolating from ri'sks of smoking in smokers to effects of ETS on nonsmokers.t" The resulting increase in platelet ag- gregation can contribute to acute thrombus forma- tion and rnyocardial, infarction. Imaddition to the role of platelets in acute throm- bus formation„ platelets are also important in the development of atherosclerosis,'" Once there is dam- age to the arterial endothelium, either through me- chanical or chemical factors„platelets interact with or adhere to subendotheliall connective tissue and ini- tiate a sequence that leads to atherosclerotic plaque. When platelets interact with or adhere to suben- docardial connective tissue, they are stimulated to release their granule contents. Endothelial cells nor- mally prevent platelet adherence because of the nonthrombogenic character of their surface and their eapacity to form antithrombotic substances such as prostacyclin, Once the endothelial cells have been damaged, the platelets can stick to them. Once the platelets arc bound to the endothelium, they release mitogcns such as platelet-derived growth factor, which encourage migration and proiiferation, of smooth, muscle cells in the region of the endothelial injury:"' If platelet aggregation is increased because of exposure to ETS, the chances of platelets building up at an endothelial injury will be increased. Thus, in addition to contributing to short-term effects through increasing the likelihood of thrombus formation, the . "'

%alues. one should keep tn mind the follot%mg three fa,ts~ ttlithe relgnse risk foractr.e smokers is usuall, "i,ulated %tith nonsmokcr; a, the reference group:tm;: nun<mokers are almost.al;says passise smokers. and~ noi raaily unespo;ed. too low a relattse risk is %te:d:J ;ora:uvr ;moktna: uu ce+eral :tudtes tndicate thacthe mar¢tnal effe.a per ;iY3rette on the risk for IHD t, hizht;t a~ a lo" Ib%rl.of consumption and is thus not linear and', tuur main;tream and side- ;trtam ,moke contain almost the same components- but, not in the same proportions. One does not knoM %.h.~ o¢arctte smot.in¢ increases the rtsk for IH'D: therafore- n ts dirfi,:ultto extrapolate dtrectl+ from ac- tne to passi%e smoking. In e+aluatmg toda> "hether there is an increased risk ior IHD among passi;e smokers. the biegest problem is not the statisucal, uncertaini or other methodoloe- tcal difficulties. In fact, the studies in table 4 are of rather high quality compared M1th the other research referred to in this article. The greatest problem must be assumed to be a possible publication btas. as it can. mtth some justificanon, be claimed that negative studies Nere of no interest until a number of positi%r studies were recently published. Therefore. more methodolbaically good studies of' IHD and passive smokine need toibe carried out and to bo published' reYardless of the result. In addition to the aforementioned studies of IHD, and passi;e smokine„there are sesrral in.estigations addresstng the time lag before the onset of pain in an- gina pectoris patients exposed to passive smoking or, carbon monoxide. These in%tstiaations have been re- terrtd to in the section on carbon monoxide since the increased ltvel of, carboxyhemoglobitt is very proba- bly the factor which provokes the earlier onset of an- gina. Finally. an abstract Kas published in 1987 by tiloskowttz et all(2_'3'1. It claims that passive smoking increases the risk of 1HD among pubertal boys. E%en if more studies on passive smoking and IHD are itill needed. it is now reasonable to conclude that the studiespubGshed hast a high methodological qual+ itc. that the results are relatii.ely consistent (relative risk for 1HD about 1.3), and that a small„but increased risk for lHD is biologically plausible. Orgpn rC SOl rerrrS A feu of the general reviews treat organic sollents thoroughlr..• (1, 2. 6. 10)t Others treat the topic more superfictaili (3, 7, 9. 11, 13), and some do not men- tion it at alli(3. 5, 8. 12) In those reviews in which the topic is dealt with, most of the emphasis is placed' on the halogenated hydrocarbons (perchloroethylene, Irichlbroethanet trichloroethylene, fluoroearbons, methclene chloride, and'other solvents containing chlo- rine, fluorine,bromine or iodine) Most of the studies mentioned have co%ered acute heavy exposures result- ing in arrhythmia or sudden death. Cardiovascular effects ofexposure to organic sol- vents have also been treated in several special reviews Retnhardt et al (_2S)',,oncluded that the sudden deaths tn,eonnection Nrth acute hea%\ exposure to.ohents uere due to %entnculhr ftbrtilanonidue to sensitization of the heart to eptnephrtnc. The re>iew bt Retnhardt etal also included a surve\ in Khtch the sol%ents were eAaluatcd according to cardiac sensiti- zation properties. The most acwe group contained', benzene, heptane. chloroform and trtchluroerh' vlene. Steffe>'s reN iew t2.61 of the cardto%ascular effects of rnhaling anesthetics is ~ern thorough. ltsting'_01 refer- :nces. I'n addition. the res ieµ by Zakhan & A.tado (.Z'Jion the cardto+ascular toctcolog~ of halogenated hsdrocarbons is both tnoroueh and' comprehenstFe (218 references and a sen useful appendix wtth chem- ical formulas and properttes)'. The empirical basis for the aforementioned re% iews consists primarily of animal experiments, which I have not discussed'in this revieM, several case reporas, and' a feN epidemtologic studies. There are tMo types of case reports. Thoy deal with exposure to very high,leveis ofisol~ents either in con- nection with glue sniffing or iniconnection with oc- cupational exposure. Gluc sniffing has prtmarily been practiced by teenagers (2241 228'-232), and many sud'. den deaths ha~e been reported~in both the United'States and the United~ Kingdom, although, a clear under- reporting is like)y since no anatomical changes can be observed in deceased~ persons.. In some of the cases described, the strongly affected young "sniffer" stood up, started running, and then dropped dead (228). The occupational case reports deal! with, workers who, in most instances, have beenexposed to very high levels of solvents (231, 233-237). Most, of the case reports concern the sudden death, of' healthy men 20-50 years of age after exposure to chlorinated sol- vents, but also after exposure to benzene (234) and' methyl-celiulose paint (233). These case reports have manv features in common- and several of the authors suggest that underreporung probably takes place with respect to this type of exposure also. In addition to the case reports mentioned, five epidemiologic studies have been found (238-242). They were published during the period 1975-1988, and there is no indication of increasing research ac- tivity in this area despite the increased interest in or- ganic solvents. The methodological quality score for these studies is medium ("xx" to "xxxx"). Speizer et al (238) studied the residents in a hospi- tal pathologydepanmentwho were exposed to fluoro- carbon aerosols during the processing of cryostat sec- tions and used radiology department employees as Ihe reference group. They found a much higher prevalence of palpitation among the pathology residents and also a dose-response relationship between exposure to fluorocarbon 22 and the prevalence of palpitation. Moreover, resting electrocardiograms and' 24-h elec- trocardiographic monitoring indicated premature atnal contractions, paroxysmalatrial fibrillation„and an in- 253

I greater were the changes in these variables. Pomerehn et all,' observed similar effects of ETS on high density hpoprotcin in children whose parents smoked and in children who smoked or chewed tobacco themselves. High levels of total cholesterol and low levels of high densiry'lipoprotein are impor- tant for the development of plaque. Data on total cholesterol and high density lipoprotein from non- smokers marricd to smokers are inconclusive.M14 To further elucidate the possible mechanisms by which PAHs induce atherosclerotic changes, Majesky et al"s administered a single injection of benzo(a)py- rene to White Carneau and Show Racer pigeons„then looked for metabolites of the benzo(a)pyrene in aortic and hepatic tissues 48 hours later. White Carneau pigeons typically develop severe atherosclerosis by 3 years of age, whereas Show Racer pigeons are rela- tively resistant to aortic atherosclerosis. Aortic prep- arations of the White Carneau strain exhibited a much greater inducibility of the microsomal monooxygenase system than did those of the Show Racer strain, particularly in young pigeons. Aortic tissues from White Carneaulpigeons aged'6-12 months exhibited a threefold to 12-fold inducibility, whereas aortic tissues from the same strain at 2-5 years of age exhibited only minor (maximum; 3.3-fold) and, for the most part, statistically insignificant increases. No age differences in inducibility couid be detected in the Show Racer strain. Interestingly, the differences in inducibility manifest in aortic tissues were grcater in aortic tissues than in hepatic tissues from the same birds. Thus, the PAHs seem to accelerate any preexisting tendency to develop atherosclerosis. Regardless of' the ultimate mechanism by which PAHs exhibit atherogenic effects, it seems logical to suppose that the reactive intermediary metabolites of these chemicals are the proximate atherogenic or coatherogenic agents because the parent compounds are relatively inert both chemically and biologically. Thus bioactivation and inactivation (an& regulatoryy control of these processes) may be presumed to play extremely important roles in their atherogenic prop- erties. Bioactivated chemicals vary in their stability and reactivity according to four generali categories: 1) those that are extremely unstable and persist only at the immediate site (enzyme) of bioactivation, 2) those that persist only within cells inwhich bioac- tivation occurs, 3) those that persist primarily only, within tissues in which bioactivation occurs, and 4) those capable of being transferred in the circulation from one organ to another. For the first three of these four categories, biotransformation in the aorta per se (target tissue activation) would be of prime interest and importance. Thus, it appears that PAHs could be playing either a mutagenic or mitogenic role in beginning the atherosclerotic process in suscepti- ble cells or individuals, depending on how the PAHs in ETS are metabolized in the aorta. The finding that enzymes that metabolize DMBA and benzo(a)pyrene are in the artery wall led Penn ev all,' to search for specific molecular events in plaque GJanu and Pannky, P'assive Smoking and Heart Disease 9 cells that would lead' to DNA changes similar to those previously found in tumors. Identification of such processes would be supportive of the monoclo- nal hypothesis of atherogenesis. They obtained hu- man DNA samples from coronary artery plaques ass well as DNA from~ normal sections of the coronary arteries at surgery to remove the plaque. These DNA samples were tested with:the NIH 3T3 cell transsec- tion assay. Foci'arose in cells transfected'with each of the DNA samples obtained from the human coronary plaque, with an efficiency (number of foci/µg of DNA) ranging from 0.016 to 0.060 (mean, 0.036). The transfection efficiencies for DNA from normal coronary artery, liver, spleen, lung, kidney, and tra- chca were alli less than 0.008. The transformed cells were also idjected into the scalps of nude mice, where they developed tumors. These results provide directt evidence for similarities on the molecular level in the development of plaques and! tumors. Human coro- nary artery plaque DNA contains sequences capable of transforming NIH 3T3 cells, and these trans- forme& cells can cause tumors after injection into nude mice. Control experiments verified that the transforming cells did' indeed contain humam DNA and that the tumorigcnic (or transforming) activity was not due to the ras oncogene family: Although these results clearly demonstrate that human plaque DNA has transforming ability, the temporall expres- sion of this activity in vivo is not known. The plaques were taken from adult patients in late stages of vascular disease. Thus, we eannot' determine from these samples whether the manifestation of transfor- mation is a relatively late event, in plaque develop, ment or an early but stable event. Oncogene activa- tion and expression is an important early event in transformation and tumor genesis. These results identify specific molecular events that may underlie the proliferation of smooth muscle cells that is a hallmark of atherosclerotic plaque development and demonstratcs that plaque cells exhibit molecular alterations that had previously only been thought to be present in cancer-cell transformation and turnori- genesis. These results provide direct support for the monoclonal 1 hypothesis. Randerath et ald" also demonstrated that onnstit- uents of cigarette "tar," including benzo(a)pyrene, are preferentially attracted to the heart and damage DNA there. They studied molecular mechanisms of smoking-related carcinogenesis by examining the in- duction and distribution of covalent DNA damage in internal organs of the mouse after topical application of eigarette smoke condensate daily, for 1„3, or 6 days then killed 24 hours later. DNA samples were ob- tained from skin, lung, heart, kidney; liver, and spleem Adducts containing benzo(a)pyrene.derived moieties were identified, together with others. At all three times, the number of adducts in heart and lung. DNA was about frve times higher than that in liver and slightly higher tham that in skin. Covalent DNA damage was estimated to be 6.2, 5.7, 3.9,, and 1:.9' times higher, respectively, in lung; heart„ skin, and I

. . 6 Ciesi+latioa Yo183, No 1, JonuarI 1991 TaatE 2. EQect of Pasatie and Aeti.c StaoiUnB ea Ptatelet ASVeptioo and EadotbetLl Crll' Damage Platelet aggregate ratio EndotheUalicell onunt' Before After Change t3efore After Change n Passive smoking (nonsmoker) ~ 0.87 0.78' -0.09 2:8 3.7 0.9 10 Tobacco (nonsmoker) 0 8I 0.65 -0.15 23 4.8 2.5 . 20 Nbntobaooo cigarette (t;xutQnoker) 0.81 0:7b -0.03 2-5 3.0 0.5 Inhale cigarette (smokor) 0.81 0.68 -0.13 4.0 5.4 1.4 24 Not inhale cigarette (nonsnroker)' 0.82 0.73 -0.09 33 4.7 1.4 22 Smoke (smoker) 0.85 0.70 -0.15 4.4 6.4 2.01 17 Snufl.(smokcr)' 0.82 0.76 -0.06 3.9 4.7 0.8 Alt studies are paired and reflect significant differences (p<0.005). Platelet aggregate ratio is the ratio of platelet oount of piateletrrich plasma; prepared immediately after venipuneture with a aolution oontaining edctic acid and formaldehyde, to that of platelet-rich plasma prepared in the same manner4 except for the absence of formaldehyde. A decrease in the platelet aggregate ratio reflects an increased formation of plateleraggregrtes: Endothelial cell oount is mean number of anuetur eell carcasses in 0.9-µL ehamtxrs. Modified from Davis et at4rA11.51.3= especially in the arterial system. In addition, increas- ing evidence has shown that platelet deposition and thrombus formation can contribute to the growth and progression of atherosclerotic plaques,4s•'d An arte- rial thrombus appears to develop in three phases; platelet adhesion, platelet aggregation, and activat- ing of clotting mechanisms. Passive smoking in- creases platelet aggregation and, thus, increases the likelihood of thrombus formation and myocardial infarction. Table 2 summarizes the results of several studies by Davisat al*1-w on the effects of cigarette smoke on platelet aggregation and damage to the arterial en- dothelium. Davis et al;t, also measured platelet ag- gregate ratios and endothelial cell' counts in non- smokers before and' after exposure to 20 minutes of ETS while sitting in a hospital atrium. The platelet aggregate ratio in these studies is the ratio of the platelet count of platelet-rich plasma prepared from blood mixed immediately with EDTA and formalde- hyde to the same mixture without formaldehyde. This method assumes that platelet aggregates circulating in blood are fixed in the EDTA-fotzrtaldehyde solu- tion and'that they break apart in the EDTA solution. Thus, a decrease in the platelet aggregate ratio reflects an increased formation of platelet aggre- gates. Mean values before and after passive smokingg were 0.87 and 0:78 (p=0:002) for platelet aggregate ratios and 2.8 and 3.7 (p=0:002) for counts of anuclear endothelial cell carcasses in venotu blood. These changes are intermediate between the effects observed after nonsmokers smoked two tobacco cig- arettes an& the effects observed after smoking two nontobacco cigarettes'7 and similar to the values observed in nonsmokers who smoked two cigarettes while trying not to inhale'"' These effects were not correlated with the level of nicotine in the blood of the experimental subjects in any of these or otherw-w relatedIstudies on how drugs modify platelet aggre- gation and endothelialicell counts. In particular, the effects observed in nonsmokers who smoked without inhaling were similar to the effects on smokers who smoked two cigarettes even though the plasma nico- tine levels in the nonsmokers were five times lower than those observed in the smokers.SO Other work in the same laboratory comparing smoking with snuff use revealed similar changes in platelet function in response to these two forms of tobacco use.52 7-his result, combined with the finding that smoking non- tobacco cigarettes" failed to produce changes in platelet function as large as observed with tobacco cigarettes, suggests that nicotine is an important active agent. Because nontobacco cigarettes also affected platelet aggregation somewhat, however, carbon monoxide or other combustion products may also influence the platelets. Sinzinger and Kefalidess3 measured platelet sensi- tivity to antiaggregatory prostaglandins (E„ Iz, and D2) before, during, and after 15 minutes of exposure to ETS in healthy nonsmokers an&smokers. Passive smoking reduced platelet sensitivity to the antiaggre- gatory prostaglandins lz and E, significantly (p<0.01) by a factor of about 2 by the end of 15 minutes of exposure to ETS among nonsmokers. This effect persisted at 201minutes after the end of exposure and ceased by, 40, minutes. Platelet response to pros- taglandin D2 ehanged modestly in a similar pattern but was not, significant. Among smokers, the control level of platelet aggregation was higher (p<0;01), and the prostaglandins had no significant effects on platelet aggregation over time during or after expo- sure to E'TS. Sinzingcr and Virgolinix also showed that repeated exposure to ETS for I hr/day for 10 days produced lasting changes in platelet function in nonsmokers similar to those observed in smokers. Thus, nonsmokers' platelets seem much more sensi- trve to a single exposure to ETS than do smokers' platelets, and change in platelet sensitivity to disag- gregating prostaglandins in nonsmokers exposed to ETS' for short periods is similar to that observed in smokers. Further evidence from the same laboratory that passive smoking increases platelet aggregation comes from work by Burghuber et al?s' who studied smokers and nonsmokers who smoked two cigarettes and also exposed a different group of smokers and' nonsmok-

Y ' 8 Circulation Vol 83, No 1', January 1991 effects of ETS on platelets also increase the chances , that cndothclial injury will lead to arterial plaque. ETS also plays a role in causing damage to the endothclium and initiating the atherosclerotic pro- cesa: As discussed above, Davis et als' found that short-term exposure to ETS, like active smoking"-3°' and use of chewing tobaoco,52 leads to a significant increase (p<0.002) in the appearance of anutdear endothelial cell carcasses in the blood of people exposed to ETS (or tobacco product) constituents. The appearance of these cell carcasses indicates dam. age to the endothelium, which ~ is the initiating step in the atherosclerotic process. As noted above, the ap- pearance of endotticlial cells after passive smoking is almost as great as after primary smoking (Table 2). Exposure to ETS has been shown to produce injuries similar to those observed with exposure to primary smoke and also affects platelets in a way that increases the chances that theywill bind'to the injured area and promote growth of smooth muscle cells!° Role of the Polycyd'ic Aromatic Hydrocarbons in ETS Many atherosclt'rotic plaques in humans are either monoclonal or possess a predominantly monoclonal component;a" which~indicates that the smooth muscle cells of each plaque have a predominant cell type. Several animal studies have also shown that injections of polyryclic aromatic hydrocarbons (PAHs), in par- ticular 7,12-dimethylbenz(a,h)anthracene (I7MBA)) and benzo(a)pyrene!1-65 accelerate the development of atherosclerosis. Benzo(a)pyrene is an important element in E"I'S' The effects of PAHS or other carcinogenic or mutagenic elements in E'T'S°6 relate directly to the response to injury theory of atherogen- esis discussed above!" Changes in the undertyirt& smooth muscle stimulated by these agents can thcn initiate the "injury^'that leads to platelet aggregation and plaque formation: Thus, long-term exposure to £TS can affect plaque formation through mechanisnts similar to those by which long-term exposures produce cancer in other organs. Albert et al61 gave chickens weekly intramuscular injections of DMBA and benzo(a)pyrene for up to 22 weeks, then killed the chickens at various times beginning after 13 weeks and measured the plaque volume in the chickens' aortas. Thcy found thatboth DMBA and benzo(a)pyrene significantly increased the volume of plaque compared with control chickens who had just received injections of the solvent used to carry these agents. This study provided the first evidence that known carcinogenic chemicals can be atherogenic as welli Penm et alO extended this result in a similar expcriiment by showing that the effects of DMBA on the extent of plaque buildup iri chiFkens was dose dependent. The median cross-sectional area of plaques on individual aortic segments and the plaque volume index (an approximate measure of the total volume of plaque per aorta) increased in a nearly linear fashion with DMBA dose. In contrast to the marked' increase in plaque area in the DMBA- treated animals, the percentage of aonic sections with plaques in carcinogen-treated animals was only slightly higher than in controls. Plaques with a small cross-sectional area were present in all animals. Lesions of widely differing cross-sectional areas ap- peared to be similar histologically under the light microscope. Together, these data suggest strongly that a major effect of long-term DMBA exposure is to~increase the size of spontaneous aortic lesions. Rather than induc- ing a eaneerlike change in an individual cell that begins the process that ultimately leads to plaque formation, Penn et al63 suggested that long-tertn DMBA exposure causes preferential division of indi- vidual, cells or patches of cells within the preexisting spontaneous lesions. From this perspective, DMBA and other exogenous compounds would be acting as a mitogen, similar to that released by activated platelets, to stimulate division of' aortic smooth muscle.. Revis et a102 found similar results in White Carneau pigeons injected with, DMBA and ben- zo(a)pyrene weekly for 6 months, beginning when the pigeons were 3 months old. Compared with the work described above, they found that benzo(a)pyrene had a greater effect on atherogenesis than did DMBA,, and they also failed to observe a dose-response relation between the dose given and the amount of aortic plaque. These differences from the work just described may be related to species differences, differences in the carrier used to inject the PAHs (dimethyl sulfoxide in the previous studies compared with corn oil in this one); or differences in the age of the pigeons or dosing schedule. They also found' an increase in aortic plaques in pigeons treated with the PAH 3-methylcholanthrene but not the carcinogen 2,4,6-trichlorophenol or the PAN benzo(e)pyrene, which is not considered a carcinogen. This result suggests that carcinogenic PAHs„rather than carcin- ogens or PAHs in general„ are implicated in the atherosclerotic process. Revis et al62 also studied the distribution of these compounds after they had been radiolabeled. Forty, eight hours after the injection of PANs, radioactivity in the liver, aorta, and lung accounted for 75% of'the injected dose, whereas in animals injected with 2,4,6- trichlorophenol, radioactivity in the liver and kidney accounted for 80% of the dose. In addition; 80% of the radioactivity observed in the plasma immediately after injection of radiolabeled PAHs was associated with the low density and high densiry, lipoprotein cholesterol fractions compared with only 24% of the 2,3,6-trichlorophenol, suggesting that plasma lipo- proteins are an important vehicle for transporting PAl-Is to their sites of activation in the arteries. There is also evidence that ETS directly affects plasma lipoproteins. Moskowitz et al'* showed that adolescent children whose parents smoked had e1e- vated levels of cholesterol and depressed levels of high density lipoproteins, even after correcting for age, weight„height, and sex. These effects were dose dependent; the greater the exposure to ETS, the

171 of probability thsn did' epidemiology that there exisu a link between damage to bealtb and pusive smok• inQ'. Perhaps it is the rveitbrof these facts, interpreta- tions, and opinions that caused no less ao antbority tRan the American Cancer Society to assert last year that 'tAe currently available evidence is not :atG- cient to conclude that passive of involantary smokin8 causes lung cancer in noosmokers..' (ACS 1988). A final comment: both the title and the contsnt of the editoriall tlsat accompanied the Wellrt paper sn=- =ests tlsat the paper provides stronjer evidence of risk of cardiovascalar disease (EVD) for nonsmokers married to smokers than the paper in fact offers. In 1986, both the NAS and USSO reports noted the lack of convincing evidence of siWicant CVD risk from ETS exposure. More recentir, Fielding and Pbenor (1988) commented on papers reporting an associa- tion between ETS exposure and CV?) risk, conelod'- iaj tbst 'na fil3a-concitaioa 'bst a saasil re1 3tion exists is yet M arnnaed'. Wells' calcuLuiona with respect to CVD a3+e based on data from tpidemiolotical studies that ba.e the same weaknesses as the 1'on= cancer studies. There is, thns, no buis for =reater confidence in his essti- mate of bezrt disease deaths la relation to ETS tdan his estimate of lung cancer destiss. It is commendable thu tbose who ue not aatisfled contiaoe to seek more meaninj from the data. Bnt in an issue as serious as this, it is important to note when the data fail to meet the sundards for scientific in- ference. Alan W. Latresstei. L.tse>atein Associates Luclmost, tiY 10538 REFERENCES AAlbc*s, wL; Cb.ds, L Pusfw aelfms asd lai ea•er. r.aaalyw of Hlrq...'s dri Is: Arry, L; [tit. L M., or. Iadooi ad amhi.u alr pdiry. 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Laat eue.r in seermot.n ia Noq Xo.g. la: Gradmaaa, L, sd: Cascer .piLaiolo17, .oi. 6. N.. Yorl: Goru. Fiubar Verlaa; 1912::pp. 199-302. Corrsa. P.; Fickle. L W: Footlu, I.; Lh Y.; Hua».l. W. raaiive rmotias ud 1sa f caswr. T.soet i1 2:l9l-J97; 1993. Cra.ford. W.A. Hsa!h eff.cu of pani.e rmotiss in rl. .ee!- placa. Ia: terry, It.; [irt, RN., eds. Isdoor sad aahuat air qnalisy, l.osdn: Salper 11d.,,19q:p. 203-210. Dal.g.r, N. A. a al. Tbe r.latios of pua3we smokisp t. 1.y eaacsr. Caseer lu. ":11i0i-si11: 19K. Fsisrtaia. A. L Sdotirc ruadar0a is epihsaieiolic rr.&a el tbM mmaoe of d.ily life. Seisos 2<2:12J7-12q. Fisldis&. J. L; Fbao.. L I. Haaltl.Ceeu of ie..Luoe3 amoi- isa. N. Eaa. 1. Med. 71l:14lZ-11f0:19tL 0ae, Y-T. st aT Laag ease.- a.eq C>ti.w weas. Lt J. Caseer I0:b0c-609; 1997. :darfiotel, L Time vsda ia lua cscer monaliry u.ong sv- cmoter. uid . sw oi p.aairs satins. 7. Nat: C..oer Isn. 661061-1064c 1981. OarfiakaL L; Aserbech. 0A loaberi L Ir*olaur7 emataa ad 1asg caaoer.. cw-oaatrd rsfy. I. Nat. Caacar Iart 73:K3- sbl. 1915. OMia, C. L; 8ois. D. J.t' Bk•d•orss, P. BeytA F. Tbe asa d se.ire,seatai tob.cao rmats a r.o erbu coe,sasb..m tf. .an d Sarlal Bist 1. R..p Dla. (3.pp. 133) L7:121-124 1964. Oonaas7t. 0. J. Tudnascb.a - Baisbt Ob.r m iatav.atir. salu 37mpoabem (23-25 Ottoiet 19" Baaa) hblk Basltf 49: 212-213; 1957. Heln, P. A.; Lnabo.t, D.: Bnsd. L For dsbaia: pa birds aa ss i.depod.n rlak faener for lag sasar. Bnt H.d. 1. 297:1319-1321; liZti. HsbL. C(7.: Sa.ay J:11[.: Fatlak.,D. L 14rriap too emeter sad lmad oeaer rial Asa I: taWib H.altJt T739if02; 1017. NLrlra.a, T. Na.-aotls3 .fsr af bra.T vatan b..s a lis isr risk of 1ag ca.esr: s sc.17 fra. Japsm. Brit. HrL J. 2i1:1i3- 1es: loil. [sbet, 0. C: O'ysin. L L La.d ursr is soaa.eltartl Casea: 33:1214-1221; 119" tee. LC.: 6e, J.LC.; 3a., D. Is paufs setiaa as ad.t rWt f.osar fs laa me.r 's Cti.aan wo.a7 J.1sp. Cii.. Caee.t Rw. 3:277;, 1964. Lu.. T. tL r.L r d J.atis. pu d.. naatis{ d Wsoiepeal ryp.a in lasa escer in Haal Loay Ckia.ao .orra Briz J. Casoar 3i:t7!<7ie 19[7. Lbo.irt, DC D. TL peuadal u.edatia. .f laas saswr .irlt puaia sotisg Bs.ina Iat 123-l; 191i. L.e, P. N. Claberiais. 1.: ATder.o., 1L 1L BslssfouYiF ef paaals ootiy ts riai ef l:ag assosr d rlar s,oWa-s+- wdacN di..aaes. BriL 1. Cawr 3i:97>106; 191i La, L N. Faaatma s-atia~ as/ tis g eoe+n auaoosds: a waalr .f Wa7 8sas TsJooL d:l17•S31;,19lr. Lw, P. N. An ahrsadn snrla.uias fer de iasr.awd rlak d lai caaa.r in w-aotarw msrri.d Yametsn. Ia: hrr}r. L.; [1it. F. M, e4 Indoor an[ ss bi smt sir q.aiisy. L..fea: 3.tpv Ld.; 19i9: p. 1dp-1!L h NlC (Nado.al Rasaani Cets.efl) Bo.trameaasas ubew aaots: maasvi.a esFosare o.d uwrhl b.alsk aseaa. ~ Mubisrua, D.C.: Natfoaal Aoi..7 hs.a; 19K. h. OTA (Offow of 7kiaotaty Assaamat), hsai.e saetiag ii tbe W .ortplaoe: .alaa.d l,rnu. w'.akialtoe, D.C.: Ofiia d T.eis- ~~ solon Aisarrss. U.S. Ceaais.cl 19K i1 ~ F.rsiagas, 0.t' &.tls, ZSwa+sesa, C. Tuan aoby ad lmy eaas.r a S..~al~ .a~a Arc I. BpilsioL 123:17 .24: 19i7. ~„a 0

n

:: JULt' 1989 %E>t' ZEALA.NQ vtEDif.41 JOt'RNtL Estimation of lus= tascer deaths attribuubie to paasive smoking in the workplace: Assuming a relatave rtsk of2:2: the population attributable risk for lung cancer deaths due to passive smoking in the workplace is 28.7% lrange: 11.&40.M (or men. and 21.9% (rattgec 8.6•31.9°61 for women,lTable 31. The number of lung cancer deaths in never smokers attributable to pasatve smokutg ut thi workplace is therefort: estimated to have been 20 (range: 8•28) for men. and 6(range: 2•71 for women. giving a total of 26 (range: 10-351 (Table 31. The tocal annual number of lung cancer deaths attributable to pusive smoking is thus estisaated to have been 30 (range: 1'1•41). of which 97% iY attributable to exposure in the workplace. Tabl.l.- Estitnated nutnbet of deeths from lung cancew attributable too passive {mokinp in.the work p/ica in New Zealand. iM..bv se. %'o of lung cancer deatles in never smokers Prevalence of esposure to passive smoking to exver smokan who work Relauve risk ot lung cancer for ezposuts to paaslve smoking at work iCl) PAR. work exposure Irana.f No lung cancer deaths in never smoken attribucable te passive smoktns at work ' traagel PAR- population aCtrlbfitable risk Men Women 139 Deaths from iachaemic bean diaeaae attributablk to passive smoking is tbe workplaee: Since the risk of tschaern,c heart diseax from active smoking dimirwhes rapidly after cessation of smoking. it was assumed that the risk of lschaemu heart disease death from exposure to paasive smoking in the workplace would similarly decline after withdrawal from the workforce. Fiuthertaore, the estimates of workplace exposure used in this study (Tables 3 and 51 were based on data for Aucklanders aged 35-64 years. Thus. conservative estimates of ischaemic heart disease deaths due to exposure to pas„ve smoking in the workplace were denved, from the number, of ischaertuc heart disease deaths which occurred among those of workutg age, ie: those aged under 65 years. L6 this age group there were 1276 deaths in men and 366 in women in 1985 11en (Table SI. Tabu 6-Esomat.d nun+ba of derW Iront iect+e.rnic +wrt 6400" attributab/e to paaaive amokinf in.tM workplaca in New Zealand in t= 69 26 `teo Women 33.6% 23.4'>i Total number of ischrmic heart disease deaths in Ppp4 +Ksid 2 2 2 2 <6S years 1276 366 . 11.4•7.01 . 11.4•3.01 'b of people who had never smoked 32.3% 42.0% 26 746 21 9% Number of iacrsem.ic lieartdis.w . 111.8•4a.2*.l . e8:b34:9~1 deaths to never smokers ated <65 years 412 164 Prevalenu of espoeure to passive 20 6 smoking iq never smoken who work 33.6% 23 4% *261 i2-71 Relateve rtsk of uchaemsc Fieart diseaae from exposure to paaatve Deaths trom iaebaemic beart diieaae attributable to pasaive amokiag at bome: Data on the proportion of iachaemic heart disease deaths occurring in never smokers in New Zealand were not available. We astunaced this proportion by applying the relative risks of ischaemic beart disease death - obtained from the cohort study by Doll aad Peto (ps.2el-for each category of smoking (never smoked. ezsmoker, smoking between 1-14. 15-24. and over 25 cigarettes per dayl to the proporuoss of New Zealanders aged over 25 years in each cateaory: based on the 1981 cearus data lrli!, The proportions of aever smokers among iacbaemic beart deaths were then calculated as the percentage of all iscbaetnic beart disease deaths that would be expected to oavr. based oo there relative risks. It was thua estimated that 32.3% aad 42.0% of ischaemic heart disease deaths otns in male and female never smoken, respectively. T6ese Ctgures are in close agreement .nth unpublished data from a coronary beart disease register in Auckland (Jackson R: work in progress). The population attributab{e risks for ischy^w b.artn dissase deaths in persons ezpoeed to spousal smoke were est.imat.d to be 3:71% (range: 1.3•7.1961in men. and 3.1% (1.6-6.1961 in women (Table 41, The number of ischa.mic baan: disease deaths attributable to passive smoking ia the hom* ia estimated to have been 51(rangs•. 18-971',i=1 mea aad 40/ransa: 21•801 in women. a total of 91 deaths (ranie: 3P1771: Tabh 4. -Estlmated number ef M.trta from iaehaeenlt h.ert dlseree emibutabN to paeeive eapoaas to spoua.l anokino In Now 2aWnd. 101011. by esa M.o tvomae Total' no -Yf deetlis from IHD 4'!34 310! % of pera}'s who had o.vNr -moilad 32.3% 42.0% No of W41e wbo bad never smakad 13ia E306 Ptevsle]ra of ilpOfUrtr to spoYaal fmoke a1SOn[ mafrled neMf amokaLL'a 12.7% 14.1% Ralative riak of IHD for a:po.ure to'pouslJamoka 1.? 1.2 /CII i1.1•1.61 11.T•1.41 PAR. spouaal smoit. 3.7% 3.1% /ranse/ (1.b7:1T.1 Il.b 6:I7~1 No of I7dD sl.aths ia oever smokrs attributable to apousal naokias 51 40 lrsaaa 116•971 121•601 PAR - populatwn attnbuuble nak: IHD~- iscbaamic lrart dis.ese smoking in tha workplace 2.3 1.9 ICI) . 01.4.3;41I 11 .4•2:5v PAR. worltplan exposure 30.4% 1' 4% iranae) (11.8-44.6%1 16.6-26.0".I tio of tachaaauc Mart di...ase deaths in never smokets attributable to smoking in the workplace 125 27 lransel 149•1841 r13-401 PAR - populatidn attribut+able risk The population attributable risks for deaths from ischaemic heart disease due to passive smokiag in the workpliace. assuming relative riska of 2.3 for maa and 1.9 for women. were 30.4% (rangr: 11.8-44.6961 in men and 17.4% (raage: 8.6-26.0'S/ in, women. These yielded estimates of 125 (raage: 49-1841 iscbaemic heart diseaae deaths in men. and 27 (range: 13-40) deaths in womm a total of 132 deatlls (rangr 62•224! fTabik 51: Discussion The estimated'total of 30 lung cancer deaths attributable to passive smoking represents 2.5% of all lung cancer deaths in 1985: and 31.6% of lung cancer deaths in those who had never smoked. These resulta are similkr to previous estimates for USA lei and' Canada Isl Repace and Lvwr.y estimated that paasive smoking was responsible for 5% of the totallannua]' lung cancer deatha, and 30% of the lung cantw d.aths in never smokers in the USA la} Wigle and Collishaw estimated that in Canada passive smoking .ca,s r*eponsible for 2.3% of the total annual lung c,nca- daathst and'S1qs of lung caaar daatlis in never smokers Ia{.! It is eetimated that 243 deaths fsom isckW*Y h.art dis.ase occurred in 1985 due to passive smohing.'ibis ewpe..ecta 3.3% of all ixhaemic heart diaeaae daatha. and 9.1% of iacba..m;c heart disease deatha in never smokes•s. The total number of daaths in Nlrw Zalaland in 1983 h,= h.tn; riacor, e.nrd iVclao•^i^ heart di,ease due to passive smoking was estimated to have been 273 (range: 112-44,2K of which 6b.2'1[, was attributable to exposure in th. workplace (Tabli 61. As we have stressed throughout, there are a number of uncertaunt;.a in these calntlarions, and the toul of 273 d'eath,s per year from lung cancer aod iacbaamic beart disease due to passive smoking should be regarded as only a preliminary estimate. Nevertheltys it doee indicate the Likely magnitude of the mortality due to passive smoking in New Zealand. The findiaga of this study will need to be revised as more acrurats data particularly os the relative risks of diseaaes due to workplace ezpo.ure to pasaive smoking, become available.

338 NEW ZEALJ.ND SfED1CAL JOURNAL II lULY 190% other sourcas of passive smoking withia the household On the other Sand theee figuree are likelN to undetesumau the effects of iong term exposure to spousal smoking. stace we have not waen account of never, smoiters who have been previously exposed to passive smoking: but are currently widowed': separated. divorced. or tivtng wtch ezsmoker3, E.timatoos of exposure to paaaive smoking in the warkplJ.ac The prevalence of exposure to passive smokmg in the woricplac+ was also obtatned from the Auckland bears study. Itl this study. 33.6% and 23.4% of never smoking matt and .vomen. aged 35-64 years ia Auckland in 1987•88. wen exposed to passvve smoking at worr A recant random teiephone survey of the Wellington reglon reported that the proportion of nonsmokers exposed to pan.uve smoking in the .•oritplan may be even higher. reaching up co 80°b,i19t However a ssgaificant proportion af the respondents reported: that most of their exposure occurred dutang tea and lunch breaks. Therefore we adopted the more conservative prevalence esttmaus. Estimation of r.Iatllre risks associated'with e:posurs to passive smoking FAcimatioa ot the relative risk of lung cancer doe to p..ai.. .moking at bome: The relative risk of dyusg of lung canars in never smokers exposed to spousaPsmoking was obtaaned' from the pooled resulta of 10 case control studies and two prospective studies 1201. The relative risk of lung cancer mortality in women who harl never smoked and who were marrud'to ever smokersm weignted by the Mantd'Ha.ns,t.l pmocedura was 1.3 (95% confidence intarvaLl 1.1-1.51 Iml There have been few studies .:' lung cancer among men who have never smoked We have i+sumed. as others have done RIL that the relative rask of luag cancer ih never smoking men asrrled to ever smoking women is the same as for nsv.r smoking women marned to ever smoking men ITable 1). Tebie 1.-EarUmats of rn/atiw -x ofdrthe from 14ne canCM.snd i.c6semic heart df.aese due to a.sive .motina. I>a% confldenca intervaJl Dis.as. RelLtove rs from exposure a home R.lative risk from e==poswe at wot Sfee w'omm Mea Woman Luns cancer 1.3 1.3 2.2 2.2 I1.1•LS1 ;1.1•1.51 (1.4-3.01 I1I4-3.01 Iscbrmu heart di+ease 1.3 1.2 2.3 1.9 hl.l•1_Q1 L1•1i.el (1sW.4/ (1.4_TSI' Eatimatiun of tbe relative riai ol lo.as eascQ due to p.saive smokzng in the workplace: Tb& elevated lung cancer risk from passive smoking has beea well eeublish.d but few studiee have specifically examined ruks from woricpiica ezpoeur+s. Thus iasuad of uaing direct escimat.ea, the relative rutk for lung cancer death from ezpoetue to passive smoking in the workplace was estimat..d via an ezpoettre reaponse relationship derived by Repan and Lowrey If.21y They estimated that the degree of exposure to passive smokin.g at home_ at work. and at both sa ces correspooded'to respective daily inhalation of 0.45. 1.82 and 2.27 mg of the particulate pdu. of ambient tobacco smoke (e~ Aornrding to this model~ espcxure to palave smoidag at woric should rvult in a hiatier r>sic for lung cancer than erposure at homa Haaed an tke relacive risk rumate of 1.3 for bome espo.urs (Table 11, the relative risk of lung cancer in per.oos arpoeed to paasve smoking in the workpllsee was estimated to be 1+ 40:3 z 1.8?J0.48). yielding a r.tative risk ..amatr a[ 2.2 (raoge: L4-3.011Tabl. 1). Thia estimate is ennaist:mt with the relative risk of 3.3 196% a.+a8da-o iat..wa1• 1:0-10.51 ftr twer amnitaes exposed to passove amokcng at work reqertad by Kabas aad Wyndar issL in one of the few studl.e that has di-t;*: ;-b-^ e=pwur+ at worti 4om arpo.ar* at bu- Ho+.vair. ws have .doptrd tbe mc:e conacvacve aetimaru of 22 (Table 11. Eitima dra of the e.i.tfve ri.k d Lcka®ie bret di....e d.etf doe to prsed" safto(IC/sg as bcmc ?be snnmat.s for the tdattrf r¢sk ot iscb+.micheat dSa.w d.ath m nev.r smnitss ezz+a..d mp"ytvsalokFSg w•r. oix~a.d Sr~ W.da• pnoid anabais of 5ve cohort studies and'two casm control studies lut The poo/.d' rolauve rtsk for man exposed to spou»L amona. +etght.d by the 'Wantal-H'senszal proc.dure. was 1-3 /CI: 1.1•1.61: and the eoereapoading eetiT-•- fa women was l.2 ICI: 1.1,1.41 12st Fitisnatioe of the relicve rcuh of iaeh.amirbeart dls.a.edrth due to passive smokin= in the woraplaci: Then u at prwnt scaat data Otl the relauve rtsk Of irh-TK heut disaaae drath due to passive smoking in the workplaee. The study by 5vendsen et aI (13L based on daa from the MRFIT tnaL reported that the ralattve risk of coronary heart disease death in men exposed to coworkers smake compared with mea whose coworiters did not smoke. was 2.6 Iln However. the risk estimau wau lmpredae CI: 0:5•12.7: p-O:231. and m addition. the MRFIT trsal'iavolved mea who were at high rvk of coronary heart disease at entry. Neverthdaes, a higher vdue for the relettve riak of iae aemie beaet disease death from ezposure to passive smoking in tbe workplace aompared to the home ia c++nso-taat with tne greats prevalence and intensity of exposure obtaused ia tbe former setting Is4 Using th. same assumptions as in our caltuLauon of the r.lative rult of lung cancer frcm paasive smokoing tn thl workplace, we eetimated that the relative risk of ixhaettue 4r:eart disease death from paanve smoking in the workplan was 2.3 Irange: 1.4-3:41 for maa and 1.9 (rang.c 1.4-2.3) for woman. respectively (Table 11j Estimation of deaths du• to passive smoking Tbere aea a cottsid.rable number of uncertaintaes in the estimation of deaths due to pveive smoking in New Zealand. These redau to unrR•„*ties in the number of deaths in never smokers, the prevalence of ezposure to passive smoking, and the relative risks due to passive smoking. The main uncertainty stems from the relative rtsk esumates. Aceordingiy, to provide a range of plausible valuen for the population attzibutable rvics- the 95% confidenci interval for the relative risk estimatas (Table 1) have been usedL and the other e.stimates have beea rsgtirded u fized Rangp have alao been provided for the estimates of the numliar of deaths in never smokere ITablse 2•5) in order to give an indication of their prsdsioa but thetie rsngea have not bem ua.d~ia furtbt caicuiationa. Estimatiba of lung taatesr deaths attributable to passi.e smoldag at homc In 1985 there were 1197 lung cancer deaths in New Zealkad (lal-86fi in mm aa&331 in womm. It was estimated from the cancer regutry dtta that 8% Of these deaths oeeurred in never smolCess (z.l. Therefore 69 male lung cancer deaths. and 28 famale lling cancer deatha occurred in never smokeas (TabL 2). Tabi.2-Esdrnetad numbeeof deetls hoen h+np onear erttib%rtaW.. ta o..we.rywun to spoad vnoke in..M~ 2riand in tSMS..bV sa M.a Wom.a Total m of lung cancer deachs B66 331 % of'p.opl. who h.d tw~ smoitd 8% 8% No at lung canc.r d.aths in rltor wbo Ead never smobad 69 28 PrWvajdace of ae~w sawkwo arpo..d to syw..l +mdrms 127; 16.110 Ralaave nak of htnt c-aor fer a~o~~n rn spnoaal amos 1.3 1.3 . IC11 tl.l•1.s1 (1.1•1.51 PAR apouasf smdoa 3.7% e.Et (rsaae/ f 1.Sd:0 x I I t.67. S S I No ol Am= oaoer d.erJu a o.vw smok.n atatbutahie te R~W --k+at 3. 1 /nasw/ 11!dl 162f PA&-pepalaioa amsDasabi+ tzak Tb. poWlaac:i .m'sbutibie naka were calealated to be 3.7% (tiasc 1_3•l.0%1 for mea aad 4.6% (raaQc 1.B-7.5'y) for wam.n (Table 21. 'I3s numbrs ot ]ung ra M- deacha in 1983 atal.'batibie to paea.e amoitms at home were therefore ..amaud tn ha~n been 3(rangc 1~) for men and 1 IrusgC 0-M Eor wosns. Qv=S at cc ~ of 4 Itanget 1.4 1.

I young healthy subjects with no evidence of heart • discase, McMurray et al'" exposed young healthy women to pure air and air contaminated with ETS while they exercised on a treadmill. The results were similar to those observed in patients wi'th~ coronary artery disease. Resting heart rate was increased' during cxposure to ETS, which increased blood car- boxyhemoglobin by, about 1%. Exposure to ETS significantly reduced maximum oxygen uptake (by 0.25 11min) and time to exhaustion (by 2.1 minutes). Exposure to ETS also increased the perceived level of exertion during exercise, maximum heart rate, and' carbon dioxide output. It also significantly increased' levels of lactate in venous blood (from a mean of 5.5 mM during the control period to 6.8 mM after exposure to ETS). This greater lactate at a lower oxygen consumption during the passive smoking tri- als indicates a greater reliance on ancrobic metabo- lism: The combined effects of the reduced oxygen- carrying capacity, and increased lactate resulted in a reduction in maximal aerobic power and the duration of exercise. Thus, even in healthy subjects, exposure to ETS adversely affects exercise performance. Lamb-17 suggested'that at maximal exertion levels,,up to 90% of the oxygen-carrying capacity of the blood may be needed. Probably because of carbon monox- ide, ETS reduces this capacity;,so the muscle cannot maintain, its high rate of aerobic metabolism unless cardiac output is further increased; people with heart disease and reduced ventricular reserve have diffi- culty meeting this demand. Imsum, exposure to ETS increases the demands on the heart during exercise and reduces the capacity of the heart to respond. This imbalance increases the ischemic stress of exer- cise in patients with existing coronary artery disease and' can quickly precipitate symptoms. Moskowitz et al'"' found' evidence that adolescent children of parents who smoked may suffer from chronic tissue hypoxia such as that observed in anemia, chronic pulmonary disease, cyanotic heart disease, or high altitude. These children had signifi- cantly elevated levels of 2;3-diphosphoglycerate (DPG), even after correcting for age, weight, height, and sex. DPG acts as a physiological modulator of'; hemoglobin oxygen affinity. It binds to specific amino acid sites and increases the Pso (lowets the oxygen affinity), thus making more oxygen available to pe- ripheral tissues. This observation suggests that the body is attempting to compensate for hypoxia by increasing the DPG level in blood to meet tissue oxygen requirements. The changes were dose depen- dent; the greater the exposure to ETS (measured both in terms of parental smoking and serum thiocy- anate levels in the children), the greater the increase in D~PG.. There is also evidence that short-term exposure to ETS directly, affects respiration of the myocardium at a cellular Icvel: Gvozdjakova er al'y exposed rabbits im a 50 I child's incubator to the smoke of three burning cigarettes smoked during a 30-minute pe- riod, an6they measured several variables related to 11- Gana and Parmlty Passive Smoking and 1Neart Disease 5 the metabolism of cardiac mitochondria. They had three groups of rabbits: one group was exposed to a single dose of ETS, one group was exposed to 30 minutes of ETS twice daily for~ 2 weeks, and one group was exposed to 30 minutes of ETS twice daily for 8 weeks. They measured mitochondrial respira- tiomas the consumption of oxygen after adding ADP to a vcsscl containing mitochondrial' fragments. Us- ing pyruvate as a substrate,,mitochondrial respiration was reduced significantly compared with control (pure air) for all doses of ETS, by, even a single exposure, to about half the controlvalue. The oxida- tive phosphorylation rate was also reduced signifi- cantly at all exposures by about one third. There were no significant changes in the coefficient of oxidative phosphorylation with ETS exposure. Gvozdjakava et al"' concluded that pyruvate as a substrate was a sensitive indicator of the toxic action,of the ETS on the oxidative process. Later, to further isolate where in the process of mitochondrial respiration the ETS acted, Gvozdja- kova et a1w and Gvozdjak et al41 reported data om succinate, NADR ; and cytochrome oxidase activity in the mitochondria in the four groups of rabbits. Exposure to ETS affects the activity of NADH oxi- dasc, succinate oxidase, and cytochrome oxidase of myocardial mitochond'ria. The activiry, of the first twoo oxidases exhibited no changes compared with the control group;,neither after a single exposure to ETS or after exposures to 2 weeks. tytochromc oxidase activity decreased both after a single exposure to ETS and over time, with greater decreases as the duration of exposure to ETS was extended. The observation that cytochrome oxidase and not NADH or succinate oxidase activity was affected by ETS suggests that the deleterious effects of; ETS on myo- cardial mitochondrial respiration occur at the termi- nal segment of the mitochondrial respiration process. Prolonged exposure to carbom monoxide has been shown to induce ultrastructural changes in myocar- dium42-" and may account for the adverse effects of ETS exposure on mitochondrial function. Thus, short-term exposure to ETS not only in- creases the demand and compromises the supply of oxygen to the heart, but also reduces the myocardi- um's ability to use the oxygen to create ATP to provide energy to support the heart's pumping activity. Effects on Ptateliets The action of ETS to increase platelet ag,gregationn is another way in which ETS can increase the risk of a coronary event. Platelets arc important for the normal process of hemostasis, to prevent blood loss after an injury. When blood platelets aggregate inap- propriately and form a thrombus in the coronary circulation, they can precipitate a myocardial infarc- tion. Hemostasis depends on complex interactions among the dynamics of~ blood flow; components of the vessel wall; platelets, and plasma protcins. De- finitive evidence has confirmed that platelets play a major role in thrombus formation and emholization; f

h © ?:7 2y ~

NEW ZEALAND MEDICAL JOURNAL What is of greater concern is the way in which your ndents have sought to obecttre the message of our paper. This is that patients in our study were unhappy about cliar hich had' inflated at 24~+ per annum. No amount of analysis o total fee: of GST or of general practitioner incomes wiL change ese facts. Nor will they be altered' by claims that patients have right to determine what they deem to be a fair and reasonable c t for medical care. Further. some o our correspondents imply that the purpose of our paper wu to c cise general practice and to bring general practitionen into disre ' te. This is not so. as will be seen from our provious article (ul on ' topic: The purpoae of the present article was not to denigrete e efforts of general'~practitioners but rather to bring to attention curnent public perception of the cost of their services. We woul hope that this evidence will contribute positively to policy atte ts to devise a fee structure which ensures that family doctors ve a fair return for their efforts while at the same time protecting tients from the current inflation in patient charges which has large been caused by the way in which the relationships between the tal fee and GMS are set. G2 I ~S 7r > 23 AUGUST 1989' proportion of smokers as nonsmokers. As argued at iength elsewhere 16-12~ this biaa can produce an artefactual association of a similar magnitude to the association ciaime&by Kawachi et aliftl to be due to passive smoking. Wells 121 correction for this bias was totally inadequate, failing to allow for the possibility of miscltssified current typical regular smokers, whereas a recrnt summary of data from large studies shows an average rate of about 4% lul. Although there is virtually no epidemiological data on risk in relation to workplace exposure to passive smoking. Kawachi et al (Il present estimates based on unjustified extrapolations from the spouse smoking estimates. which are themselves hopelessly biased. The authors present numbers of deaths with ranges, so giving the uninformed reader  spurious idea of accuracy. When one considers no major authority has yet concluded passive smoking causes IHD: it is difficult to see what usefulI meaning one can attach to the cited lower limits of 39 IHD deaths for spousali smoking and 62 for workplace exposure. Peter N' Lee (Mr);. PN' Lee Statistics and Computing Ltd., Cedar Road. Sutton, Surrey' SM2 5DA. UK. D M Fergusson. L J Horwood, F T Shannon., Christc Developme Christchurch h Child Study, pital. e", , F Dy _ i' Christch h. 1. Fargusan DM. B..uttw AL SAamoo FT. Maveal wud.esaoente pnmrry. Y.Nth tan NZM.d:J 1e61-9.-291'.a. Oeaths from lung canc.r and ischaemic heart disaase due to passive smoking in N.w Z.aland Kawachi, Pearce and Jackson )l,i estimate that passive smoking causes 273 deaths per year in New Zealand. 30 from lung cancer and 243 from ischaemic heart disease (IHDI. Some 65% of'these deaths are attributed to workplace ezposure, the rest to spousal smo{dng: Tbae estimates are sdentifically'unjustified. Too much weight is given to fragile epidemiological data, major sources of bias being totally underestimated. Too little weight is given to evidence that nonsmokers have very low exposure to tobacco smoke coIIStltuents.. The evidence that passive smoking increases risk of IHD is very unconvincing. The authors t1I'cite a meta•analysis by Wells 1z1ifor their estimate of risk in relation to spouse smoking. This is based on 7 studies, maay of which involve unacceptably small numbers of cases, eg, as low as two deaths in women married to never smoking husbands 136 The two studies with adequate numbers are both open to question. One of these ie the Japanese prospective study h•al Walls cited results from 17 years follow' up (6) which claimed' a ai,gnificant trend in IHD in relation to spouse smoking, but failed to m.ntioa that this finding significantly Ip <0.001) 'conflicted with an ear}ier report, based on 14 years follow up which claimed no association whatso.ver! The other is the Maryland prospective study pl Iwhich reported 34% and 24% increases in IHD in men and woman in relation to spouse smoking. This study has many featurea that we notawortby. It made no attempt to follow up paopl* moviog outside Washington County, thus missing large numben of deaths. It found no doee response relationahip. It failed to collect data on a whole raagp of possibly relevant confoundiisg factors. Tboae it did adjust for (Ylge, marital statua, ye.n of school, qualityy of housing) had' an enormous effect on rdative risk. changins estimates from 1.17 to 131 in - and fiam 0•66 to 1.24 m wnmed emphasising the fragility of the results. The evidence relating passive smoking to lunt eancer is mon extensive than for IHD. being based on 27 published studiea, not 13 as Kawachi et aI sutt!' WhiL there is an asaooatioo of spouse smoking to lung cancer risk that cannot plausibly be a:plai6ed by ixtblicatian bias. it cannot be reliably inferted this results from a causal effect of pusive smoking. In the first place, exposure of nonsmokars to smoke constituents is very low. Thus typical nonsmokers retain only about 0.01-0.029G of the amount of smoking related particuiates retained by a smoker (Tl. Furthermora, there are various sources of persistent bias in the epidemiology, a major one caused by misc1~--ificstioo of a 1. Kaw.e)u.1. Peoro NE. J.aiam RT Douhs bam hieg ueor and umwnc A..rtatrn dn" tcp..ev. amobea mliw 7r1.e4 tiZM.tl J 1969 102337-.0 2W.ti. AJ An.rum.u of aAutt.mortaAkty.te tb Uaet.dStatw fiompaaav..motu„6 Eevvaom.nv Idt.rnauod.l 11il6. 1.. 24945 3. G.Aaad C. B.r..uCmnm E. Su.~ L.t.1 Eftactu of pe.n- soaot- hrn dlr. mart.lny m om®oY~a Lvts. atL .moY.n. Am JEqd.md 1966. ,121.. y4}50 4 Hln.yama T Veo-.mdom~ -w of,hrry..aa4,s h.r..hu~r n.kof liusa cmt- a ttutlyhom Jipan Br M.dJ 1961.2a2..1156S. Hu.yama T l.un6 csner m Jap.n.ff.ee. of nutruon .ad p..u...mot'.- . Ic MiWI i M. Ca.n.. P: .d.. Luee c.eer ala aedm p.wretm K.. Yort V.r4y Cl.ar la•am•••_•, 1964 .: 17S% 6. Hdan. KJ. S.ndl. DP: Gem.meY C W. Ch. E. Howes mar mmn.a4ty to L+we ac6 ueatrs. Am J Epm.omi 19M. 1Zf:.l1SYJ. 7~ Arupdd A. St.Ata6 T. W.ekam J Y~ makam, IaY( cm~ naku flem .ayo.ttn to prrtuulitw tobaQO ®a4a. EortemmrIwmre.ue..l.1tQ7, 13. Mi26B. Lsa PN, P..arv. ®oktn6.ed 4w6 ~ Aam.cm a rwrlt of bu.'.Hua.a Tos.ea/' 1967. 6~ 51724 9. La PN. MisJS6raum of~y.haMt. mdPrv. aabo.. A.i.vrA of td. .vdaon. tntre.t+mal AucEUw of OantFamd'rd H.NthSuyp+.mst: H.GaOrr Sprmrrv+rla.., 1tie6: 10; lr PH An altarnaav- mcp----pmfor the uevaaG raY of ptn6 o.eet m na4mauYrs marrrE to amoi'as. !c Prry R. Itnt P'W. d. In6av aed .mtirt.r yu.4ty tsOm S.lar. 1 YlB. 1 YP56. 11. Laa Ph'. Pa...w ~a6. F.et or6cum' Prpe }r.ammmud .tCaLf.m oa Pe~et and Funue of ls6es Au Qw{ttr A.ad mBrvairLm Feen.ry It16. 1909 . 12 ~ 1- PN . Probi.m. mmtrpr.ueg pd.mroiopeal d&ta P.P.r Pe..mmaud at Ca1~ oaArrmant of IeAa~•~y- H..ed. 6.Id mH~ v Fetiru.ry1YY1: IM9. iled vasectomy A t ACC appeal case was published 'm the Otago Daily Timn and I it vary disturbing Isee Medicoiegal p 4531: This couple was a ca6apeosatioc aft,er the alleged fa0urs of a va..ctomy part t O•m-^' Hoepital in 1979. A.her this operation it took nine ths befon the sperm count was sero. Nearly five years later appellant•s wife fall pregnant. Tseee happanings can be eaaily lained in that tb. vasectomy was performed correctJy but the count took a long time to reach zero because the patiemt as alow to ej aculat. all the aperm from his body. Ttis u qufte seen. 'Ib pregnancy resulted from recanaalisation of tbe v dafeens and can occur once in about every 500 vasectomies.. Y 'te the above asplanaoaaa, anme other surgeon has stated it is standard medical practice to recommend a rapeat v after three or at the most four positive sperm tests after a v y. Judge Middletan has accepted this surYeoa..vid.ooe as and this psaad.d th. judge to allow the c-1aiia If the facta case an as I reed thtm in the Otago Daily T'uaee tben,then a clear miscartiage of justice. Compensation has bean wrmgfy awarded a docttr wrongly accused of negligenee. This case may set a f Qrec.deat. Tbe Accident Compansation Corpontion abould not allowed to accept this appeal dewion and' this case should a higher court .ar. -rr