Tobacco Documents Online

-9= Gillis et a1.72 reporte~preliminary results of a study of passive smoking and lung cancer in 91 male controls without domestic passive smoking and in 901subjects expose at home, and in 40 female controls and 58 subjects. No effects of lung cancer were noted'in the females, but elevated rates of myocardial infarction were reported (risk ratio 3.0). In the males, elevated rates of both lung cancer (risk ratio 3.25) and myocardial infarction (risk ratio 1.45) were reported. When smokers were included, (156 smokers plus 156 smokers withipassive smoke exposure) a clear dose-res relationship was shown,. The statistical significance i's not given. RISKS IN SMOKERS WHO 00 NOT INHALE Wynder and Goodman61'and Jarvis and Russell!62 assert that pipe and ci'gar smoking i~nvol~ve heavy passive smoke exposure. Epidemiologic evidence suggests that pipe and cigar smokers tend~not to directly inhale the smoke, and pathologic findings show lung abnormalities in such smokers which are intermediate between those of nonsmokers and cigarette smokers.1,15 Simflarly, the lung,cancer risk. for pipe and cigar smokers is less than for cigarette smokers, but greater than that for nonsmokers, and• dose-response relationships are observed.1,15 Most importantly, lung cancer risks in very, light pipe and ci'gar smokers (less than five cigars or pipesful per day) are nea / the same as those of "nonsmokers;"1,15 yet, cigar and~pape tobacco tars appear to have a carcinogenic potential comparable to that of cigarette tars.1,1'5 This suggests that pipe and'cigar smokers may experience tobacco smoke exposure similar to that experienced by nonsmokers who are subjected' to very heavy passive smoking, a supposition supported by modeling the exposure of a non-inhaling cigar smoker (see Appendix A). Thus, pipe and ciigar smoking are also lifestyl'es with both increased exposure to ambient tobacco smoke and increased risk of lung cancer.

. -10- U M LI'FESTYLES WITH DECREASED LUNG CANCER RISK. It might be expected that subgroups of the population which proscribe smoking among their membership woul&have a lower probability of passiive smoking, and therefore shoulid'also have a lower incidence of smoking-related disease than the general nonsmoking population. One such subgroup is the Church of Jesus Christ of the Latter Day Saints, popularly known as the Mormon Church, which advises against the use of tobacco. Enstrom40 found that active Mormons who were nonsmokers had standardi'lzed mortality rates for lung cancer which were 21%, compared to 19: for a sample of the U.S. general!population "who had never smoked cigarettes." Interestingly, however, this result occurred despite the fact that 31% of the active Mormon cohort were former smokers. This confounding factor was not present for certain subgroups in the following study. Phillips et. al!.41,42 have studied~mortality (1960'-1976) in Seventh Day Adventists (SDAs), a conservative religious group who also follow rigorous proscriptions against the use of tobacco. As with with the Mormons, SDAs have rates of mortality from lung cancer and'other smoking related cancers that are fractions, respectively 21: and 661., of the rates for a demographically comparable group inithe general U'.S. population among whom smoking is epidemic.41 A sizable subgroup (35".) of SDAs report prior cigarette use, especially among men.42' SDAs appear to be less likely than the general, population to be involuntarily exposed to tobacco smoke, as children or as adults, at home or in the workplace, because neither SDA homes nor SDA businessE are likely to be places wnere smoking is permitted, and because the great majority of SDA family and'socfal contacts are among other SDAs who do not smoke (,See Appendix C)~.

Phillips et. a1!.41,42 compared mortalilty in two demographiically similar groups of Southern Californians: SDAs (from 1960 to 1976) and non-SDAs (from 1960 to 1971). In particular, for two select subgroups of each group, 25,264 SDAs and 50,21'6 non-SDAs who were self-reported nonsmokers whoinever smoked, age- adjusted mortality rates were compared for smoking-related and nonsmoking-re- lated diseases.42 Table 2 compares age-adjusted'lung cancer mortality ratios for two SDA cohorts relative to nonsmokers in the general population who never smoked. The first cohort consists of all SOA, and includes those who never smoked, ex-smokers, and smokers. The first row of Table 2 gives the mortality ratios relative to the never-smoked non-SDAs in the general population. The second row compares the second SDA cohort (those who never smoked),to the non-SDA who never smoked. The val~ues given are averaged over both sexes. From Table 2 the results show that the non-SDA group of nonsmokers who never smoke& (but who were more likely to suffer involuntary exposure to tobacco smoke)ihad an average lung cancer mortallity rate of 2.4 times that of the never-smoked-SDAs (the group less likely to have suffered such exposure by virtue of their liifestyle). This ratio is consistent with the mortality ratio of 1.8 reported by Hirayama34, the value of 2.4 foun6by Trichopoulos et al.33, and'the value of 2.0 foun6 by Correa, et a159. Furthermore, the difference in the annual age-adjusted lung cancer mortality rates between non-SDA and SDA men is 6.3 per 100,000 persons, and between non-SDA women and SDA women is 8.6 per 100',000!(Tablie 3). These differences are consi'lstent with the value of 6.8 per 100,000 which Hirayama34 found for the average risk of lung cancer in passive smoking Japanese women.* Phillips, et a1.42, who did not have the benefit of comparison of their study with that of the passive wI !

r-. -12- smoking studies, nevertheless cortcnented that the difference in SDA/non-SDA lung cancer risk strongly suggests that factors other than direct cigarette smoking may be etiologically related to lung cancer, and observed that SDAs are likely to have much less passive smoke exposure than non-SDAs.42' _ DOES AMBIENT TOBACGO SMOKE POSE A CARCINOGENIC HAZARO? The Internati'onal' Agency For Research on Cancer (IARC) criteria for causaliity to be inferred between exposure and human cancer state that confidence in causality increases when o Independent studies agree o Associations are strong o Dose-respcnse relationships exist o Reduction in exposure is followed by red'uction iin cancer incidence.7 We now wish to interpret the evidence we have discussed. We first summarize some arguments against an effect of passive smoking: two epildemiological studies, one large one in the U.S., and a small one in Hbng Kong, find little or no effect. The absence of a threshold for carciinogenesi's has not been proven,. Sidestream smoke has not been demonstrated'to cause cancer in humans. And, as Wynder and' Goodmanbl have observed: lung cancer in smokers is predominantly associated with Kreyberg16 type I, carcinomas, whereas Kreyberg type II predominates in nonsmokers, especially females; moreover, these twoltypes of cancers tend to occur in different parts of the lung; the histologic changes observed in the de- velopment of lung cancer in smokers are rarely seen in nonsmokers;,if measurements of blood levels of nicotine, cotinine, and car5oxyhe:noglobin are truly representativ of uptake of particles and volatiles, it remains doubtful whether ambient tobacco smoke could lead to a pathologic response in otherwise healthy lung,tiissues; pipe * The crude LCD rate in SDA women is also consistent with Hirayema's controls to Y within 80,. ~ Gb O O ~ C11 ~--r CJ

r-• and cigar smokers who claim to be noninhalers may be underreporting inhalation dept On the other hand', mainstream tobacco smoke is a potent human carcilnogen, which is associated~with a wide variety of lung cancer histopathology.16 Evidence of a threshold for cancer is doubtful. Bioassays indicate that sidestream tobacco smoke is an experimental carcinogen. Tobacco smoke is a common indoor contaminant in microenvironments where most persons spend the majority of their time. Of eight epidemiologiic studies of passive smoking,and'lung cancer, five, im, the U.S., Japan, Greece, Germany, and Scotland, suggest that nonsmokers are at elevated risk of lung cancer from exposure to spouses' smoking. Each of the first three studies fin&a doubl'ing of risk, on the average, and displays a dose-response relationshi'p. Moreover, the cross-cultural nature of the studies suggests that the same confoundil factors are not likely to be present.* Lung,cancer risks and histopathology in pipe and cigar smokers (who~appear to have mostly sidestream smoke exposure) are far closer to "nonsmokers" than they are to smokers who inhale routinely (i.e. cigarette smokers). Lung cancer risks in nonsmckers who never smoked are half as high among a religious group which proscriibes smoking than in a comparable subgroup in the general population,. Because society is ni'sk-aversive, public health agencies assess and controlI carcinogenic risks despite incomplete evidence. For example, under section 112 of the U.S. Clean Air Act, enacted to control emissions of carcinogenic and other especially harmful airborne contaminants, the basic criterion is not whether absoi,. confidence in causality between exposure and human disease has beemestablishedi, but simply whether the pollutant "may be reasonably anticipated to result in an i'ncrease in mortality or an increase i'n serious irreversible, or i'.ncapacitating reversible il'lness."13 Pn d'etermining! "reasonablie anticipation" in practice, this criterioniamounts to a determination of the probablility that the pollutant * For a discussion of confounding factors, see Appendix D. 4

-14- Is a human carcinogen, the extent of human exposure, and the use of quantitative risk assessment.12 Even though numbers generated in such risk assessments are often held~to be preliminary and subject to change, nevertheless, such numbers are consi'dered as evidence of the order of magnitude of the effects, and are used in policy-making and risk management.5,6'+12 On the basis of the LARC criteria, we believe the evidence is sufficient for "reasonable anticipation" of an increase im lung cancer mortality from~passive smoking, meeting the test for a hazardous air pollutant risk assessment. We now estimate the significance of the public health risk. ESTIMATION OF TOTAL LCD RISK AND AN EXPOSURE-RESPONSE RELATIONSHIP We now estimate a phenomenological exposure-response relationship based on consi!stency65 of evidence provided by studies of lung cancer i'n nonsmokers and from our exposure assessment. In both the Japanese34 and SOA41,42 studies, which we take respectively as consistent with arguments for increased risk with increased exposure, and decreased~risk with decreased'exposure, the magnitude of the risk increase was about 8'LCDs per year per 100,000 at risk. The population at risk1'5 is nonsmokers over the age of 35. (Iin,1979, there were about 62,424,000 men andiwomeniin this category.38 Applying the risk factor of 8 LCOs/l!00,000 to this popullation, we estimate that the contribution of passive smoking to lung canser in nonsmokers is 5000 LCDs per yeart (Thi';s is about 5: of 1980 LCD rate). We have estimated that nonsmokers in the U.S. population of working age_ '~+ i ~ , 4.t,t~~. J 0..4 : are exposed on the average to about 1.5 mg of tobacco tar per d'ay,~ncluding, the estimated 15: of the population who receive no exposure at home or work. t By comparison, in 1982, an estimated~17000 U.S. nonsmokers died of lung cancer.1

-15- « We shall assume that this is the exposure of physiological relevance, even to~retired persons, whose exposures appear to be less than the employed,3 since there is a long latency for the induction of lung cancer. Using the statistical risk of 8 LCDs per 100,000, we estimate a phenomenological exposure-response relation appropriate for the general U.S. population at risk, of about 5 LCDs per 100,000 person-years at risk per 1 mg/day nominal, exposure. We have previously estimate6the range in nominal exposure as 0 to 14 mg/day.2 Three cross cultural studies of lung cancer and passive smoking showed'an exposure- response relationship. Assuming!a linear exposure-response function4,5,6,63 (this assumption has been shown to be valid under almost any model of carcinogenisis with respect to low-dose k~netics)63, and zero excess risk from tobacco smoke for zero exposure, we calculate a maximum risk of about 70 LCDs per 100,000 person-years for the most-exposed'lifestyle. We have previously modeled this lifestyle as typified by that of a nonsmoking musician who performs regularly in a smoky nightclub and who resides in a small apartment with a chaiinsmoker; many other scenarios may be drawn.2 We now wish toldetermine the reasonableness of this phenomenologic exposure- response rel!ationshilp by comparing the estimated risk for the most-exposed lifestyle with those of pipe and cigar smokers; by comparing its predictions with those from an exposure-response relationship extrapolated from smokers who do inhale, and finalily by estimatTng a crude range from two ULS. studies of passive smoking anc lung cancer.

-16- ISTIMATED LOSS OF LIFE EXPECTANCY. One way of testing the reasonableness of our phenomenological exposure-response relationship is by using it to predict the loss of life expectancy for the most- C exposed 1!ifestyle, and comparing it to the loss of life expectancy in various types of smokers, particularly those who do not inhale. ~ Rei'f50 argues that there exists a genetically-determined di!stribution in, natura1susceptibility to lung cancer in people; the effect of exposure to tobacco smoke is to shift this distribution toward death at earlier ages. In other words, exposure to tobacco smoke produces a loss of life expectancy. One method of presenting risk data involves calcul'ation of the loss of life expectancy, ilniunits of days of life lost per individual, averaged over the entire population at risk. When the average 1!ife-loss is multiplied by the number of individuals at risk, the impact of the hazard on society in person-years of life lost can be assessed. More importantly, we can dasplay the age-specific probabilities of death from the hazard, as well as the average number of years of life lost by the average victim. Appendix C gives the method of calculation. Averaged over all of the population at risk, (i.e., including those who die of other causes), the average loss of life expectancy from passive smoking is calculated to be 16 days, which is equivalent to an ultimata loss of 2.T mill1ion person-years of life for the totad' at-risk U. S. populiation in 1979 over 35 years of age (62.7 million persons). The estimated worst-case loss of life expectancy is 149 days, again averaged over al!l of the popul'ation at risk. The estimated numoer of lung cancer deaths per year age standardized to the 1979 population at risk - Clvw to .... p-e...:.b w-.K rf.-Jrl', Z is about 4700 nonsmokers. The estimated mean life expectancy lost by a passive-s~,c• lung cancer victim is 17 + 9 years. In order to test the reasonableness of our estimates, we compare the estimatec loss of life expectancy from our worst-case estilmate to the loss of li~fe expectanc;• found in pipt and cigar smokers. As we have argue~l earlier, pipe and cigar smokers ~ ~ ~ ~ ~. ~

-17- . canibe viewed as very heavy passive smokers. Thus our model!ed worst-case life- style might be reasonably expected to have exposure comparable to, but probably less than, suchismokers, with commensurate risks. Table 4, adapted'from Cohen and Lee49 gives this comparison. The estimated most-exposed lifestyle has about 2/3 the loss of li'fe expectancy of the average pipe smoker, and about 1/2 the loss of the average cigar smoker. ESTIMATE OF AGGREGATE RISK BASED ON RISKS IN SMOKERS We now derive an alternative estimated exposure-response relationship frcm evidence provided by studies of lung cancer in cigarette smokers (see Appendix 8'). Using the Surgeon General's estimate that 850. of all lung cancers are due to smoki- we estimate a current annual LCD rate to smokers at risk of about 316 per 100,00U. Assuming a one-hit mod'e1 for extrapolation of the risk (which in this range is functionally equivalent to the assumption that that a mi'llIgram of tobacco tar inhaled by a nonsmoker produces a response equivalent to that i'nia smoker) we produce an estimate of about 0.87 LCDs/100,000,person-years, and a corresponding annual aggregate risk estimate of aoout 555 LCDs per year, an order of magnitude lower than our phenomenological, estimate. We now speculate an why these two different methods produce such disparate estimates of risk. One possibility is that nonsmokers may have a reduced tol- erance to the effects of tobacco smoke. Another possibiIi'ty is a"large dose" effect62, whereby incremental amounts of tobacco tar at the large doses experienca- by smokers do not produce proportilonal incremental damage to lung tissue already heaviily damaged by active smoking, causing a single-hit model to underestimate ttie risk when extrapolated48 over two orders of magnitude to low doses. A third possi- bility is generated by modeling the dose, as opposed to the exposure, of nonsmcker_ to tobacco smoke. We have translated the nonsmokers' exposure into dose by means - a simple single-ccmpartment model for•lung deposition and clearance.22 This mocel

. -18'- su95ests that tar may accumulate on the surface of nonsmokers' lungs to an equilibri_ dose an order of magnitude higher than the nominal exposure, to a level of about 16 mg per day, due to the long,pulmonary residence times for respirable aerosols. - If this 16 mg dose, rather than the 1.5 mg1exposure, is the operative factor, then the typical passive smoker would have a risk, accordi,ngito thds model, of about 9' per 100,000, in agreement with the phenomenological estimate. In our earlier work2 we discussed anecdotal evidence that aryl'hyd'rocarbon hydroxylase levels and pigmented alveolar macrophages were increased in two passive smokers, consistent with the existence of such an effect. It has also been found that serum thiocyznate~ benzpynene69 and urinary hydroxyproli'net levels tn some passive smokers have been found to be be comparable to the elevated levels typically found'in smokers. These observations lend support to the notion that the dose in equilibrium may in- deed be larger than the dailly exposure. Moreover, the simple model we have proposed ignores the effect of cancer la~~tency. The long latency period for lung cancer indicates that childhood passive smoking may be an important factor affecting risk iniadulit life: Dolliand Peto4 have suggested that the effect of passive smoking may be surprisingly large because lifelong exposure may produce a lung-cancer effect four times as great as that which is limited to adult life (recall the observation of Correa et a159 childhood passive smoking appeared to elevate the LQO1risk of future smokers). As Bonham and'Ylilson55 have shown frcm a national' study o,` 40,000;children,in 197'0, 62°. came from homes with one or more smokers. If the exposure-response relationship based upon LCDs in cigarette smokers is multiplied by the estimated~exposure for very heavy cigar smokers (Appendix A), we would~expect a mortality rate of (45 mg/day x .5 x 10-5 LCDs/yr/mg/day) about 23/100,000ILCDs/yr for cigar smokers. In fact, Enstrom and Godley53 in a study of mortality rates (11966-1968) in, 1'D'million men and 24 million women nonsmc+ce^ who had never smoked cigarettes --inclludina„ however, oilce and ciaar smckers -- feur.z: tKasuga, op. cit.