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86-80.6 between passive smoking and fatal disease. The lung cancer data are particularly persuasive, and there are preiiminary data that indicate an association with total cancer, ischemic heart disease and emphysema and chronic bronchitis. Third, the cancer patterns in direct smoking and passive smoking appear to be different. Cancer Sites Table IV shows a comparison of cancer sites for direct smoking (from reference 28), and passive smoking (from Table IIF;). It is ev i dent that the entry s i tes are di fferent, there i s a qualitative difference in the location of the lung cancer sites 29,30 , and the sites elsewhere in the body (except for cervix) are different. Possible reasons for these differences are discussed later. One conclusion that can be drawn, however, Is that passive smokers are not a mixture of true non-smokers and a small percentage of misclassified direct smokers. Such a mixture would exhibit the same pattern of excess disease rates as direct smokers except that the Increases in relative risks would be smaller. Table IV. Cancer site aatterns in direct and oassive smokina Direct Smoking • Passive Smoking Buccal Cavity - - Nasal Sinus Pharynx - Larynx - Lung - largely Lung - largely bronchial peripheral Esophagus - Stomach - Urinary Bladder - Kidney - Pancreas - - Breast - Brain - Endocrine glands Cervix Cervix Particle Size Effects Probably the most important difference between mainstream and sidestream smoke Is the difference in effective particle size and its effect on where the smoke particles are deposited. A careful study of the smoke and aerosol deposition literature discloses a number of differences which are summarized in Table V. Direct smokers retain about 82% 31 of the inhaled particulate of wh i ch about 37% i s reta i ned i n the bucca 1 cav i ty and 45% i n the lower respiratory tract. Although particle size measurements made as mainstream smoke is generated indicate a mass median 9

86-80.6 aerodynamic diameter of about 0.5}anz, the particles, in the moist, high concentration conditions of direct smoking, apparently Table V. Deposition patterns in direct and passive smoking. Entry Site Particulate inhaled per day, mg. Effect i ve part i c l e s i ze i nha l ed, ~um. Percent retained in mouth Percent retained In nose Percent retained in bronchus Percent retained In near alveolar region Direct P_assive Mouth 240 a Nose 0.5 to 3.5 b 5 , 0.4 37 '` 0 0 8 20 0 21 0 Percent retained in or near alveoli -A IL Percent retained, total 82 19 Percent exhaled IS 81 Particle size exhaled, pm 0.7 0.4 aBased on 15 mg. per ci arette and 20 cigarettes per day. bBased on 100-700 ,ug/m ~32 and 10 1 iters/min. inhaled for S hrs. agglomerate to a much larger effective particle size. To exhibit deposition behavior such as that cited above the effective particle size would have to be in the 5,um range33. This Increase could be brought about either by direct agglomeration34, by electrical charges generated on the particles 35, by a dense layering effect36, or by some combination of these. Particles of this effective size would deposit heavily in the larger bronchial a i rways 37 , part i cu l ar l y at the b i furcat i ons, and i n the l arger airways of the alveolar region. The exhaled smoke has a particle s i ze of about 0. 7,um 31. On l y about one-f i fth of th i s s i ze wou i d be deposited, being 25% of the 18% exhaled or about 4% of the total Inhaled, and this would come down deep in the alveolar region, in or near the alveoli themselves 33,37. In contrast sidestream smoke is very dilute. It has a mass med i an aerodynami c diameter of about 0.4}im3g and does not agglomerate. This is a very difficult size to trap in the respiratory tract because It is too large to deposit by diffusion and too small to deposit by impaction. Some of the larger particles in the sidestream smoke (about 8% of the amount inhaled) would be deposited in the nose 33. The other 11% that will deposit 38 apparently goes all the way through the bronchial and larger alveolar airways and deposits in or near the alveol i 33,37. The particulate from direct smoking is either deposited in the mouth directly, or in the bronchial region or near alveolar region where it will be cleared into the mouth. It is then swallowed and is either eliminated or absorbed Into the blood stream via the gut. This is believed to result in the cancers shown in Table IV except possibly for cervix. The particulate l0

86-80 . 6 from passive smoking deposits either in the nose, resulting In nasal sinus cancer, or deep in the alveoli from whence it is very difficult to clear into the mouth. It is speculated that most of this particulate is solubilized or metabolized'directiy into the blood or lymph system. It then circulates In these systems and results in the cancers observed. In passive smoking the digestive related cancers are absent. Chemistry and Other Effects Another difference between mainstream and sidestream smoke is the chemistry. Side stream smoke Is formed at a lower temperature than mainstream smoke, and, therefore, a larger fraction of the more complex molecules is preserved. The amounts of tumorigenic agents in sidestream and mainstream smoke have been measured 39. The sidestream/mainstream ratios for such amounts vary from 0.7 for catechol to 39 for 2-naphthylamine. The mean value is 12. Therefore, It would be expected that sidestream smoke particulate, per milligram deposited, would have higher carcinogenic potential than mainstream particulate. Another difference between direct smoking and passive smoking is the difference in disease susceptibility between the direct and passive sfiokers. Deaths attributed to direct smoking constitute about 18% of total deaths. Thus a direct smoker dying of a smoking related disease, while perhaps more sensitive than the average of the total population, would not be substantially more sensitive. Passive smokers dying of passive smoking disease, on the other hand, constitute only a very small percentage of total deaths, in the range of 0.025 to 2.5%. This is a much smaller proportion than in the case of direct smoking; only the very most sensitive individuals would be dying from such an effect, and the expected dose to achieve such a response would be less than that for a direct smoker. One approach to predicting the health effects of passive smoking has been to factor down the health effects of direct smoking by the ratio of inhaled or deposited smoke dose. As can be seen from the data in Table V the dose ratio is quite high, being about 70 to 500 for Inhaled dose and about 300 to 2100 for deposited dose. However, taking into account the differences in particle size effects, chemistry and individual susceptibility, it Is seen that such a simplistic dose/response approach is unlikely to yield results that are accurate even within an order of magnitude. Risk Assessment Just how dangerous might passive smoking be? Table VI provides a summary of the combined relative risks for each sex and disease. Probably the most reliable number In the table is the 1.44 relative risik for female lung cancer, based, as it Is, on eight 11

86-80.6 stud i es i nc l ud i ng those by some of the most promi nent investigators in the field. The least reliable numbers are those for male other cancer, where an arbitrary relative risk of 1.0, denoting no association, was adopted, and for male ischemic heart disease. Clearly more work Is needed in these areas. The relative risk for emphysema and chronic bronchitis also has poor statistical significance, but the underlying death rates for non- smokers from these diseases is so low that only a very few deaths would be involved. , . ~ Table Vi. Combined Risk Ratios from Eeidemlological Studies Disease Cases g /R 2-taii p 951 conf. int. , Female: Lung cancer 463 1.44 <0.001 1.2 - 1.7 Other cancer 2091 1.56 <0.001 1.3 - 1.9 ischemic heart dis. 276 1.27 0.04 1.0 - 1.6 Emphysema & chr. br. 102 1.4 0.18 0.9 - 2.1 li8.L1L= Lung cancer 13 2.5 0.009 1.3 - 4.7 Other cancer 7 1.0 - - Ischemic heart dls. 14 1.3 0.46 0.7 - 2.6 To calculate numbers of deaths per year from the relative risks In Table VI it Is necessary to know the total non-smoking population, the percent exposed to sidestream smoke and the death rates for non-smokers by disease category. The non-smoker population was estimated from the national health statistics. The percent of non-smokers exposed to spouse's smoke was estimated from the controls in the U.S. studies In Tables I and 11. Other exposure was estimated using data developed by Friedman, et a1.40 Non-smoker death rates for each sex and disease were obtained from Hammond ¢t. By combining these inputs it was possible to calculate excess death rates due to passive smoking, again by sex and disease. Applying these death rates to the non-smoking population passively exposed, the desired number of deaths per year in the U.S. was obtained. Details of this calculation are In a manuscript that has been submitted for publication elsewhere. By this procedure deaths from passive smoking for lung cancer for ma l es p l us fema l es came to 1800 per year, we 1 l centered i n the range of 500 to 5000 obtained in a previous study . For other cancer and heart disease the relative risks are in the same range as lung cancer (Table VI), but the underlying non-smoker death rates are much higher. Therefore, the estimated deaths are much higher. The total deaths came to 47,000 per year of which 22,000 were from cancer (Including the 1800 lung cancer deaths) and 25,000 were from heart disease. This assumes no excess deaths from male cancer other than lung but does include deaths from male ischemic heart disease at a relative risk of 1.3. This 12

86-80.6 value, as noted eariler, Is supported by Svendsen, et a123, and •is very close to the female relative risk of 1.27. Even If these male deaths are excluded, the total passive smoking deaths would still calculate out to 32,000 per year. CONCLUSIONS The epidemiological literature on mortality from passive smoking is growing. An association between passive smoking and lung cancer Is becoming increasingly evident, and th_ere are beginnings, at least, of evidence that other cancers and heart disease are also Involved. If these trends continue, lung cancer will become only the tip of the Iceberg with deaths from these latter diseases amounting to ten to twenty times those from lung cancer. Tobacco smoke is known to be carcinogenic and to produce heart disease. Millions of non-smokers, estimated in this study at 32 mlliion, are exposed. What we have, in other words, are the slowly emerging shapes and dimensions of a major public health problem. Furthermore it is an indoor problem. That means that it is a home-oriented and workplace problem because that is where the average passive smoker spends most of his or her time. There may not be much that can be done about the home setting, but officials and managers who are responsible for worksites need to become aware of this increasingiy acknowledged threat to the safety of Indoor air and the workers who are exposed to it. Also this is not a traditional workplace air pollutant that emanates from some facet of the work Itself and on the factory floor. Rather it occurs in offices, smoke break rooms, washrooms and other places that have always been considered safe; and the po l l utant ar i ses not from the work i tsel f but from the other workers. The first action required is to protect the non-smokers from the smokers. The next thing to consider is a smoke-free workplace. ACKNOWLEOGEMENTS The author wishes to acknowledge maJor assistance from Graham A. Co l d'i t z, M. D., who d i d the stat i st i ca l meta-ana l ys i s, and very helpful suggestions from William J. Blot, Ph.D., Kenneth P. Cantor, Ph.D., Norman H. Edelman, M.D., Edwin B. Fisher, Ph.D., F. Charles Hiller, M.D., James L. Repace, Ph.D., Jonathan M. Samet, M.D., Dale P. Sandier, Ph.D., and Frank E. Speizer, M.D. This work was supported In part by the American Lung Association. The opinions expressed are those of the author. No official endorsement by the American Lung Association should be inferred. 13

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