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calculations, we couldn't confirm these fiqures, At the very least, all these assumptions should be made explicit. 7. The Fontham et al. study was designed specifically to minimize potential smoker-status misclassification bias. Kisclassification rates are reported in their paper and strongly suggest that in their study design, there is no upward bias due to smoker status misclassification. In fact they suggest, if anythinq, a small downward bias in their study. Thus, Table 5 ignores the available data in order to hypothesize a "what if" scenario. 8. With respect to the "second question" raised at the bottom of CRS-33, i.e., "whether there is reason to believe that the (saoker] misclassification rate would be higher for those most intensively exposed", such speculation is counterintuitive. 3mokinq women whose spouses snoke a lot are more likely to smoke a lot themselves and less likely to be misclassified as never-ssokers. It is generally former smokers and occasional current smokers that are misclassified (about 20), not heavier current smokers (about lt) (See EPA Report, Appendix B) . _ 9. Also, see again the comments above on smoker-status misclassification rates necessary to account for the observed increasas in Japan and Greece (General Comments #3). BTS and Lung Cancer Deaths 1. On CRS-35, "backqround" ETS exposure needs to be defined so that it is clear that this refers to all sources of exposure (e.g., work, social settings, etc.) other than the spouse. 2. On CRS-36, in discussinq the approach used by EPA to estimate the population risk, it should be noted that EPA used two approaches, one based on the pooled estimate for the II.S. studies and the other based on the results of the Fontham et al. (1991) study. 3. On CRS-37, CSS claims that "in essence, background ETS, accordinq.to the =PA and NRC calculations at least, appears to be considerably aoree potent than spousal BTS". The difference in.amount of risk from spousal versus background ETS reflects differences in amount of exposure, not potency. Claiming one source of ITS is more- "potent" than another suQQests that there are differences in risk from the same amounts of ETS generated from different sourcea. Furthermore, som. of EPA's calculations (based on the Fonthas et al. study; See EPA report, page 6-23) found the same risk or greater risk from spousal exposure as from background STS. Similarly, the NRC calculations estimate more risk from spousal than from I I I I I I I I I I I I I I I I r~ - 10 ~ ~ . ~ ~ ~ I

I I I . I I I 5. I I 6. I I I I . I I I 8. I I I background sources of ETS, contrary to what the CRS draft suggests. Also on CRS-37, the CRS draft claims that "EPA assumes that atter a certain point, the risk of ETS becomes greater to these individuals than the risk due to having smoked". This statement is incorrect. The ETS risk to tormer smokers is not necessarily greater than the risk from having smoked, but it is greater than if they were not involuntarily exposed and it becomes relatively more significant compared to the "voluntary" risk they assumed from previously smoking. On CRS-38, CRS claims that "the (LCMRJ method just described is exactly equivalent to assuming that the values of relative risk... are the sase...". This statement is false. ' As groups, both former smokers and male never-smokers have greater background risks of lung cancer than female never- smokers; therefore, it.they have the same ETS exposures and risks (LClQts) as femala never-smokers, they would have lower, not the same, relative risks. On CRS-38, it is illogical to claim that SP71 assumed that all of the never and long ago former smokers who have been expos?~si to spousal smoking have been subjected, on a.eraqe, to ths same combined level of spousal and background sTS, and all never and long ago former smokers not exposed to spousal ETS, received, on averaQe, the same amount of background ETS (emphasis added)". If the point is that never and former smokers were assumed to be exposed to th. same average Lveli, then the issue of dose-response in the remainder of the paragraph does not follow. It appears, rather, that CRS is trying to suggest that EPA assumed everyone was exposed to the same level rather than an average level (See also comment #1 in the Dose-Response Relationships section). Also on CRS-38, CRS states "that the risk only becomes maasurable after a long term, intense exposure to ETS (emphasis added)". "lieasurable" is a critical concept given the imprecise nature of the epidemioloqic studies and the absence of a truly "unexposed" group (See comment #3 in the Dose-Response Relationships section). CRS then ignores these issues and assumes that there is no risk at exposure levels below those for which the risk becomes measurable. CRS tbenAclaims that fthe number of non smokers ... who are' exposed to levels of ETS... extensive enough to be at a significant risk of developing lung cancer is likely to be considerably smaller than that entire non smoking population (as was assumed by EPA and NRC)" (CRS-38). cRS does not define "significant risk". If EPA had done a dose-based quantitative risk assessment, people exposed to lower than average ETS levels would, in general, have lower than average 11

I risks; however, this would be offset by people with above average exposures having above average risks. 9. The suggestion that "the 13!" with the highest ETS exposure is at "at least 20 times" greater risk based on coaparinq unadjusted RRs of 1.42 and 1.02 from two different exposure levels (CRS-39) again ascribes too much precision to the specific rasulta of a single epidasioloqic study. The comparison also suffers from the use of the unadjusted RRs rather than the adjusted RRs. 10. Furthermore, the 13% of the Pontham et al. controls exposed to 40 or more pack-years of spousal smoking may not represent the entire adult U.S. nevarsmoking population. The controls were selected to match the cases on aqe and race; they ware not selected as a random population sample. 11. The Riboli at al. 10-country results may not reflect exposures in the o.S. . 12. On CRS-40, paragraph 1, it is unclear why CRS switches from discussing the "13:" exposed to 40 or more pack-years (CitS-39)- to the "4%" exposed to 80 or more. It does not follow that "it is probable that only 2 percent of the background only group was subjected to $TS' exposure amounting to the equivalent of 40 pack-years"; half of 13% would be 6.5% by these calculations. 13. On CRS-40, paragraph 3, CR4 repeats its mistaken assertion that the LC'!at method "is equivalent to assuminq that the relative risks from ETS for [aale never saokers and long ago former smokersj is exactly the same as for female never smokers". See comment #5 above. 14. The "threshold" methodology proposed on CRS-41 for estimating lunq cancer deaths from ETS is seriously flawed. As described above, the apidemioloqic studies are not sufficiently pracise and suffar from exposurs misclassification; therefore, there is no sound foundation for assuminq that a threshold (or abruptly sublin.ar exposura-rasponsa curve) exists for exposure levels of practical concern (See comment #3 in the Dose-Response Ralationships'section). 15. In addition, thsre is no sensible scientific basis for assuming a"thrashold"-for a carcinogenic agent that has both initiating and promoting capabilities and has demonstrated its carcinogenic potential at typical environmental exposure levals. The concept of ascribing a practical threshold to low levels of exposure say have some merit when extrapolating from, say, high occupational to low environmental levels of exposure, which typically range over a factor of 100 to 1,000 times. It is much sor* problematical when the factor from 12 I I I I I I I I I I I I I I I I I

a I ~ ' . , 16. ~ ~ i  ' , / . ' - -! . r , 17. !   lower to higher is 2 to 3 times, and there is a damonstrated downward bias operating in addition. While the Draft does try to make that argument, we feel that it lacks logic. Considerinq how quick the Draft is to adopt uncertainties regarding unspecified confounders (especially for heart disease and ETS) as a rationale for rejecting observed associations, it is hard to understand how the threshold concept becomes so uncritically embraced. Furthermore, even if a"threshold" were assumed to exist, the methodology used by CRS leaves no marqin for human variability or saasuremant error. For exaaple, applying the EPA method for deriving reference doses (i.s., an estimate of the daily exposure to the human population, including sensitive subgroups, that is likely to be without an appreciable risk of deleterious effects during a lifetime; see attached reference by Barnes and Dourson) for noncarcinoqenic agents, which are presumed to have exposure thresholds for inducing noncarcinoqanic effects, to the exposurs-response results based on pack-years of spousal exposure from the lonthas et al. study miqht proceed as follows: The 15.1-39.9 pack-year exposure group (OR-1.02) siqht be considered a"no observable adverse effect leval•, or NOARL, while the 40.0-79.9 (OR-1.34) would be considered a"lowest observable adv~ rs4 effect level", or i.ZA8L. These levels are sensitive to the specific cut-points u..d and to the statistical power of the study to detect an effect in the exposure groups.- For example, a significant increase aay have be.a observable in the lower exposure groups if the sample size had been greater or in a 30-50 pack-year group if different cut-points had been used. In the absence of a NOAZL, the LOAEL is used with an uncertainty factor of 10, because of the uncertainty as to where the threshold may lie. In this study, the NOaEL of 15.1-39.9 would be usQd. Then an uncertainty factor of 10 would be applied for interindividual variability within the human population, to allo;r a margin of safety to protect more sensitive subpopulations. Finally, a sodifyinq factor of 2-10 siqht be applied to take into account the fact that lung cancer is a serious, generally fatal, health effect, as oppos.d to moderate changes in body weiqht, for exaaple. So, even if a threshold were assumed (which is not appropriate in the cass of ETSI), a sore responsible analysis would not assume that a"safe" axposure level exists abovs that which results in the dose received by the 15-40 pack-year group divided by 20-1001 - If the purpose of the CRS quantitative risk calculations is to distinguish between spousal and nonspousal exposures, the lung cancer deaths in nonsmokers exposed to spousal smoking should be broken down into thoss LCD's attributable to the spousal saokinq and those attributable to other sources of ETS (CRS-42 to CRS-43). As it is now, the Table (CRS-42) could be N CZ1 13 ~ t•.~ ~ ~ ~ I

misinterpreted as suggesting that all the LCD,,s in the spousally-exposed group are from spousal smoking. Occupat.ional S'TS Lunq Cancer JUsk 1. On C8S-43, CRS claims, with respect to quantitative risk assessment, that "EPA sade no attempt to assess the lung cancer risk from occupational (i.e., workplace) exposure to ETS, arguing that there are too few workplace ETS studies to conduct a aeta-analysis, and that it is difficult to obtain reliable assessments of workplace ETS exposure". In fact, EPA did not quantitatively assess the lung cancer risk from occupational exposure to ETS because it was beyond the scope of EPA's risk assessment. EPA does believe that the workplace lung cancer results are generally unreliable and should not be used in a aata-analysis. If EPA had done a workplace risk assessaant, the Agency most likely would have used the Fonthaa st al. occupational results, because the Fonthaa .t al. study is th. highest quality.study and it is a large multi-regional U.S. study. EPA did use the Fonthaa et al. (1991) results for one of its population risk calculations. 2. On CRS-44, last paragraph, it is not legitimate to claim that "only one of these was well-conducted, according to EPA". Spl1 categorized the biqhst quality (for th. purposes of obtaining information on BTS) studies in "Tier 1"i however, EPA's categorization does not assert that studies in lower tiers ware not "w.ll-conductul". 3. On CRS-45, with respect to the Srownson et ai. occupational results, it is worth noting that lung cancer risks were increased in the two highest exposure quartiles. 4. On CRS-45, CRS cites the results of the Lavois and Layard workplace aeta-analysis. There are, however, serious probleas with this analysis. Please sea the attached paper, "Passive smoking and lung cancer: the U.S. EPVs weight-ot-evidenca analysis, with emphasis on the epidemiology studies•. 5. On CRS-47, the Riboli et al. results aay, not be applicable to the U.S. 6. The statements on CRS-47 starting with "Stropq evidence ----" and anding with "These data suggest that the+workplace is not the dominant place of exposure and that workplace and residential exposures aay not be comparable" ar. all, at best, insupportable by the Draft's analysis of the Jenkins study, as detailed above. We suggest that a such better exposure analysis is needed, not only of the Jenkins et al study; but of the many other exposure studies. See also the coaaents above on exposure. 14 I I I I I I I I I I I I I I I I I

a I I I I I I I I I I I I I I I I I 7. The conclusion that "I!, on averaqe, workplace ETS exposure is lower than residential exposure, then it is likely that aost, if not all, workers would not be exposed to sufficient levels of bTS to be at increased risk tor lung cancer" is not warranted in any event. Even if high exposure levels were required to develop lung cancer, and even if avarage workplace levels were lower than average residential levels, there are a substantial nusber of workers, especially in the hospitality industries and in other workplaces with no smoking restrictions, that are exposed to very high levels of ETS. 8. The linal sentence, claiainq "The evidence ... casts doubt on OSHA's risk assessment and suggests that it say have siqnilicantly overestisated the occupational 8T3 lung cancer risk", is just not supported by the Dralt"s analysis. Apportdiz A 1. This presentation oi the EPA's conclusions about the respiratory health effects of passive smoking should include the Agency's conclusion that BTS is a known huaan carcinoqen, because this classification conveys the co:.clusion of a causrl, association and the strength of the evidence supporting this conclusion. Appendix B 1. Appendix B is Aisleadinq. It should state aore explicitly and immediately that this extrapolation illustrated lroa active to passive smoking pertains to the cigarette equivalent approach, and it should clarify that this was not the sethodology employ.d by the =PJ1. 2. The illustration ostits the possibility of a supralinsar dose- response relationship, which, incidentally, is likely to be the appropriate extrapolation lroa high to low doses of tobacco ssoks for cardiovascular risk (See coaunts on Appendix C below). Appendix C 1. The stateaant (pq. cR8-51) that "Whereas the EPA estisate of passive smoking lung cancer deaths used a value of Z-1.75, Wells ahose a higher value of Z-2.6, based on Fonthas"s study ..." is inaccurate. The EPA derived its estiaate using two different approaches, one of which eaployed Z values of 2.0 and 3.6 obtained troa the Fonthas study (See the EPA report pages 6-21 to 6-26). 2. The coaparison of an active smoking h.art disease risk of 1.7 with'a passive saokinq heart disease risk of 1.22 is flawed by 15 I

oversimplification. For one thinq,'studias of active smoking use navar-s=okars (including those exposed to ETS) as the baseline camparison group, while studies of STS use "unaxposad" navar-smokars as the comparison group; therefore, these relative risks are not directly comparable. In addition, because heart disease risk drops dramatically upon smoking cessation, a more raasonable comparison would be to compare the risks for current active smokers to those for current passive ssokers. Furthermore, the summary age- adjusted relative risk of 1.7 for heart dis.asa from ever smoking obscures the much larger aqe-specific relative risks from smoking observed in younger aqa groups (Saa, a.q., The B.alth Consequenc.s of 8moklnq:. Card.iovaicular Dissse, U.S. DIDiS, 1983, pqs. 103 and 113-115, and the recent study of Parish at al., 1995, Bi6T 311:471-7, which reports risk ratios for nonfatal myocardial infarction for current saokers vs. nonsmokers of 6.3 for 30-39 year-olds, 4.7 for 40-49, 3.1 for 50-59, 2.5 for 60-69, and 1.9 for 70-79.). Also, more recent studies of active saol4inq are reporting higher RRs for heart disease than earlier studias, apparently as a result of decreasing baseline risks for heart disease dua to recent lifestyle changes such as better diets and exercise. If these issues wara taken into account, the diffarence in RRs betwaeS active and passive smoking wouid be larger. 3. Furthermore, the CRS analysis does not satisfactorily present the possibility that a supralinear dose-response relationship exists between active and passive saokers with respect to CVD risk, i.e., that some of the effects of tobacco smoke on the cardiovascular system saturate at higher doses. The CRS draft does not discuss the mechanistic evidance supporting this hypothesis. For example, platelet activation appears to saturate at low doses of tobacco smoke, and nonsmokers appear to be more sensitive than smokers to tobacco smoke-induced andothelial damaqa (S.a Glants and Paralay, 1995, JA1i71 273:1047-1053). See also the recent studies of willett at al. (1987, N8J1t 317:1303-1309) and Palmer at al. (1989, NEJK 320:1569-1573), which both report statistically significant relative risks of about 2.4 in the groups that smoked only 1-4 ciq/day. 4. The CRS draft should discuss more fully the mechanistic •videnca that ZTS causes cardiovascular ef~ects.(See Glants and Parsley, 1995). For sxampla,'thars is strong avidence• that ETS promotes the development of atherosclerosis, a major cause of heart disease. Animali models have shovn that subchronic exposures to low levels of ETS promote the development of atherosclerosis, and there is human evidence that ETS exposure increases the carotid artary vall thickness, suggesting that 8'TS also contributes to the development of atherosclerosis in humans.- The role of ETS in atheroqanesis r.~ I I I I I I I I I I I I I I I I I _'

I I I I I r r 5. ., , i 6. ' ,  , ~ ~ ~ ~ ,  ~ , I is likely mediated, at least in part, by polycyclic aromatic hydrocarbons (PkBs). A recent biomarkar study suggests that passive smokers receive up to 40% of the PA8 dose of active smokers (Crawford at al., 1994, JNCI 86:1398-1402). The sachanistic evidence that ETS can create an isbalance.b.twean oxyqin supply and desand, as revealed by decreased exercise tolerance, and can activate platelets similarly warrants sore discussion. Other machanistic evidence is oiitted from the CRS draft altogether (See Glants and Parsley, 1995). For axample, anisal studies have deaonstrated that STS decreases the ability of the styocardius to process oxygen to produce ATP for energy and that ETS exacerbates ischeaia/reparfusion injury. The CRS draft suggests that "one cannot rule out the possibility that the heart disease risk values in ths api studies may be largely due to confoundinq", but presents no evidence that confoundinq is affecting the apidemioloqy results. The draft claiss that nonsmokinq spouses of smokars are likely to share soma of the unhealthy lifestyle characteristics -qenarally associated with their ssoking spouaas, but again presents no evidence that this explains any of the epide'ioloqy results. Zn the discussion of contoundinq in the lung cancer section (paqes CRS-27 to CRB-31), it is noted that Le Marchand (1991) reported decreasing cholesterol and total fat consuaption with incraasinq ETS exposure, while Alavanja at al. (1993) found no correlation between saturated fat intake and exposure to ETS. Fonthaa et al. (1994) reported an increased risk of lung cancer associated with dietary cholestarol, but their lung cancer results from sTS exposure were not affected by dietary cholesterol, similarly suqqestinq no correlation between dietary cholesterol intake and exposure to STS.' Both cholesterol and fat consuicption are risk factors for CVD. The CRS draft also cites. Friedman at al. (1963) as raportinq a correlation between 8TS exposure and alcohol consumption. Moderate alcohol consusption is generally considered to be protective aqainst CVD. These results, presented by the CRS, suqqest that these "potential confoundinq factors" ari either not associated with ETS exposure or say actually be exerting a downward blas on the relative risk estimates for CVD. The CRS draft notes that only 4 of 12 epidasioloqy studies controlled for at least 6 potential confounders and that the largest study failed to control for any of thes (although it did, in fact, attempt to control for SES by adjusting for education and quality of housing). Six is not a maqic nusbar, and not all of the potential confounders are equally important. Roughly half of the itudies controlled for at least the major CVD risk factors of hypertension, cholesterol, ~~ ~ 17 ~` Co Pr ~

I l and obesity. In addition, Wells (1994) observed that the relative risk estiaates of studies that adjusted for the aost factors were generally higher, indicating that the net effect of any confounding in these studies say be to bias the risk estisates downward. While potential confounding can never be ruled out, a thorough review of the epideaiology studies suggests that it is highly unlikely that the observed increases in CVD risk from ETS exposure are due to confounding. The aajority of studies controlled for at least the major CVD risk factors, and there is a strong consistency of results across different studies from different countries with different lifestyles and diets. Furthermore, a number of studies reported positive dose- response relationships, which are difficult to explain in terms of confounding. 7. Even if the Draft's review were an accurate representation of the available data .and even if its superficial and hypothetical concerns about the reported risks were more convincing, the Draft's conclusion that "the ETS heart disease wholl risk should probably be viewed with soae skepticisa" isl inadequate in view of the potential magnitude of the healt~ risk. k sore appropriate conclusion would be "Because of the known causal association between activ. smoking and CVD, observed even at the lowest doses, the increased risks of CVD from STS exposure consistently observed in epidemiology studies, and the mechanistic data demonstrating cardiovascular effects from low exposures to tobacco smoke,- and because of the potential for substantial morbidity and aortality, the ETS heart disease risk should be viewed with eztreae concernl" I I I I I I I I I I I I I I I