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1 I I EPA COI4IEN'PS ON CRS DRA.FT "ENVIRONMENTAL TOBACCO SMOKE CANCER RISR" (June 5, 1995) Gaaraau co1oasarrs AND LUNG 1. The Draft has no stated purposa-and seems not to be dealing with any current or proposed legislation. Without a stated purpose, review comments become difficult. If the purpose is to provide a de novo CRS analysis of ETS and lung cancer hazard or risk, the analysis lacks rigor. If the purpose is to provide Congress with a better CRS review of the lung cancer section of the EPA Report (on the Respiratory Health $ffacts of Passive Smoking) than was done in the previous CRS report, then this should be stated. If the purpose is to provide Congress with an analysis of the OSF1A proposed Indoor Air Quality Rule on E'TS, then the Draft should have stated *this (and CRS should have provided comments to the OSAA docket). If ths purpose is to provide an uncritical analysis of tobacco industry vs. Govarn=ent/scientific and public health community positions, then this should be stated and arguments should be identified by source. Currently, -xquments presented by industry and their consultants are not properly identified. Without a stated purpose, we will assume that the purpose of this Draft is to do an independent analysis of ETS and lung cancer risk, giving arguments from both sides equal a priorl credence and relyinq on the author's analytical abilities to arrive at an unbiased judgement. 2. The Draft's literature rsview is inadequate, especially with respect to ETS exposure. For the exposura assesssant, too much weight is given to the unpublished Jenkins at ai. U.S. data and the 13 country Riboli et al. results, which include non-U.S. populations, while other published U.S. results are not reviewed. Faulty use of both these studies in the Draft's risk assessment leads to erroneous conclusions, especially about the relativs home vs. workplace 8TS sxposurss, and subsequent risk estimates. 3. The Draft's analysis of lung cancer risk, mostly limited to three recent studies, loses perspective by failinq to show the consistency of results in thirty other studies from different countries. Since bias is mostly a function of study design, and potential confounding factors for lung cancer are often cultural or dietary, failure to acknowledge these consistent increases from many studies in eight different countries could lead to the Draft's overstating the asount of uncertainty. For example, the amount of smoker sisclassification bias necessary to explain the observed increased lunq cancer risks in Japan and Greece is over 50%, far higher than has aver been hypothesized. 6 ra 1 I I I I I I I I I I I I I I I

I I I I I I I I I I I I I I I 4. The Draft takes the potential upward bias of smoker-status sisclassification as truth and as if it is the only operational bias, and then seeks to determine the amount of smoker status misclassification necessary to observe the increased lung cancer risk in one study. The Draft's method is improper for several reasons, detailed within our specific comments, and leads to the incorrect conclusion that "only a small number of case group members would need to be misclassified as never smokers to account for all the measured risk" (CRS-2). The Draft's approach in this area leads one to be suspicious of its intent (see also next point). 5. There is almost no consideration of the substantial downward bias on the lung cancer relative risk (RR) estimates from two types of exposure misclassification. The first type occurs, because people with nonsmokinq spouses are still exposed to other sources of BTS and there is no clean "unexposed" group. The second type occurs because some people whose spouses smoke may not actually be exposed to auch of the smoke; e.g., some spouses who smoke a lox say not smoke such at home. Analyses of lung cancer risk from workplace ETS exposure are generally prone to even greater exposure misclassification than the spousal smoking analyses. Failure to consider these well established downward biases for 8TS could lead to erroneous conclusions, especially ons of a possible threshold. 6. The quantitative risk assessment methodology used to estimate the lung cancer risk is seriously flawed. First, there is no sound rationale for the Draft assuming an effective threshold at exposure levels of practical concern. The reliance on portions of two studies as total support for an effective threshold, iqnorinq the exposure-rasponse results from other studies, several of which report increased risks from lower exposures (see EPA Report Table 5-11), suqqests, at worst, selective biased use of data. At best, the Draft ascribes too much sensitivity and precision to the low exposure region of the two epidemiology studies, especially qiven the exposure misclassification problems in all t$ess studies. Furthermore, the methodology used allows no margin for variability in the human populatioa or measurement error. In addition, the results presented rely on a faulty exposure assessment (see specific comments below). 7. Appendi= C - While the EPA has no official position on the risk of cardiovascular disease (CVD) from ETS, the CRS analysis presented in Appendix C is cospletely inad:quate. In addition, it is unclear why heart disease is beinq included in a report entitled "Environmental tobacco smoke and lung cancer risk". If the Draft is intended to be more comprehensive than a review of only lunq cancer, it should acknowledge that there are also other health effects attributable to ETS, including noncancer respiratory disorders, especially in children. w v 2 CO N . . ~ I

8PECI?IC COIO[EI1Tf OvQrviow 1. The EPA does not agree with the suggestion that its approach to assessing the lung cancer risk in its 1992 Passive Smoking Repoit "may be misleading" or the claim that "it appears that any risk which aay be present is concentrated in a relatively small portion of that (the adult nonsmoking] population" (C1tS- 1). The EPA's approach was reviewed in public session by independent scientific experts in the field, who concurred in the EP71's methodology (See attached SAB Report). The EPA had already sent these SAB comments to the CRS, along with the EPA's review of the previous CRS report. A responsible CR.S approach would be to acknowledge the degree of concurrence the EPA report has received, rather than to simply pejoratively state that "it may be misleading". 2. Furthermore, there is no support for the Draft's claim that the rasainder (not exposed to ETS at home) of the nonsmoking population would be "at a minisua, 20 times less likely to be at risk" (CRS-1). This conclusion, based on looking at parts of two lung cancer studies and one exposure study instead of the whole body of evidence suggests a conclusion in search ait data. This selection of data is exactly what, on the very next page, the Draft accuses OSHA of doing, "OSHA based its risk assessment on one such estimate, which indicated an increased risk, and disregarded the remaining estimates which found no overall association between workplace exposure and lung cancer." In short, the methodology used by the Draft to generate its lung cancer death estimates is seriously flawed (CRS-i). (See our specific comaents on the dose-response section). 3. The overview of "sources of uncertainty" (CRS-2) omits exposure misclassification, a major sourc. of downward bias. The EPA agrees with the conclusion that potential confounders cannot explain the observed increases in RR. However, the Agency does not support the conclusion that smoker misclassification bias could be responsible. The EPA Report actually corrects each of thirty individual studies for potential smoker-status misclassification bias bsL= doing specific analyses. (See other coments on dose-response section). 4. Regarding the overview of "occupational risk• (CRS-2), the Draft's conclusion that "residential and other non-workplace exposure tends to exceed workplace exposure by a factor of 4 to 6" is based on faulty comparisons in the Jenkins at al study and is incorrect. A proper analysis of that study will reveal that workplace ETS levels where there are no smoking restrictions'are higher on average, as well as for 80th and 3 I I I I I ~ I I I I I I I I I I I

I I I I I ~ 95th percantilss, than are smoker-occupied hoae ETS levels. Even if workplace ETS exposures were on averag. slightly lowar than smoker-occupied residential exposures, this does not preclude sany exposed workers from being at increased lung cancer risk. 5. Regarding the overview of "biological and chemical issuss" (CRS-2), difficult, although measurements of ETS concentration are the EPA concluded that nicotine is generally a good marker for ETS exposure (1992 BEPA report, Chapter 3). 6. The concluding statement (CRS-3) that "thara raaains considerable uncertainty about the biological processes linking ETS to possible onset of lung cancer" is specious; the same claim could be made of active smoking or asbestos, yet - there is no doubt that they cause lung cancer. , Introduction , 1. The HPA, objects to tha.Draft's claim (CRS-5) that "whil• (th.  EPA report] has received support from the public health community, it has been criticized on scientific grounds". In fact, the EPA report has received support from the public ~ health community and from the larger scientific coaiunitv based on its scientific marit. The Draft should acknowlsdqs that the EPA's conclusions are very similar to those of the ' 1986 report of ths National Research Council of the National , Academy of Scianc.s, a non-qovarnmental body of the Nations most prestigious scientists, certainly part of the scientific community. Similar conclusions in both the 1986 Surgeon ~ Gane.ral ls and the 1991 NIOSH Reports have been authored by scientific axp.rts and received extensive review before release. Also, the National Cancer Institute has republished the EPA Report in slightly abridged form in a monograph series ~ under its own logo. By sharp contrast, criticisms of the EPA Report have qenarally bs.n orchestrated by thee tobacco industry and have not withstood scientific scrutiny. The I Draft's oquatinq industry supported criticism of• these critically, reviewed assessments with the assessments themselves suggests a bias in ths Draft"s development. ~ , 2. '  ~  I Furthermore, the assessments are all based on a substantial body_of literature, a fact which the Draft ssams to disregard. Th.+pr sviQu~, CRS report, cited on CRS-5 as alsq being critical of 3;':'F~~s analysis, was seriously flawed, aod any citation of it should be accompanied by a refarenoe to EPA's rebuttal (See attached letter to Dan Mulhollan). Isn't that why.th, current Draft is being prepared? Furthermore, the statement in the footnote that, "It was necessary (for the CRS) to review the evidence of a passive smoking health risk because this is a potential component of the cost calculation" is open to interpretation. As an economic analysis, the previous CRS ~ 4 "~ aa ~ ro ~ ~ CO

report by Gravalla and Zimmerman went beyond its expertise and its scop. in reviewing the "evidsnca of a passive smoking health risk". Since the potential "external" or "spillover" costs of health effects of ETS are so small compared to the direct costs of health effects from active smoking, it was "necessary" only to put a cost value on these "axternals", not to discuss the uncertainties as the authors saw thes. In fact, the authors of the previous CRS Report on Cigarette Taxes discuss fairly extensively the "evidence on passive smoking [hsalth] effects", but they never discuss the evidence on the health effects from activa!smokinq, which contribute far more to the health costs. The question of "why?" is, we feel, connected to the question of "what is the purpose of this draft?" 3. The statament that "confounding and smoker misclassification (ars) the two principle sources of uncertainty in the epi studias" (CRS-6) again iqnoraa the major downward bias resulting from exposure misclassification in these studies. 4. On CRS-7, footnote 10, OSHA is part of the Dept. of Labor, not Energy. The same mistake occurs in footnote 48. Spideaiologic Studies ' 1. On CRS-8, paragraph 3, the Draft reads as if the EPA adjusted the risk estimates from the individual epidemiology studies for background ETS exposure. This needs to be clarified. The EPA did adjust the individual risk estimates for potential smoker misclassification bias in its hazard idsntification analysis; however, it did not adjust the individual risk estimates for "background" bTS wrporurs. uter conducting its hazard identification analysis, the EPA did adjust the pooled overall O. S. RR estimate and the overall Pontham at al.(1991) RR estimate for EPA's two quantjtativs risk analyses. 2. In the section on bias and confounding (CRS-11), it should be noted that bias and confounding can work in both directions, and that nondifferential biases exert a downward bias on the relative risk estimate. 3. The statement (CRS-12) that "EPA adjusted the risk•astimates to account-.,for bias and confoundinq ..." is incorrect. EPA did axaminr•potantial bias and confounding and concluded that they could not account for the consistent dosa-rslated increases in lunq cancar risk observed across numerous studias from different countries. However, the only adjustment that EPA mada to the individual relative risk estimates was for the potential upward bias from smoker misclassification. There is no consistent evidence that any other upward bias is operative in thasa apidemioloqic studies, and even the evidence for an 5 I I I I I I I I I I I I I I I I r3o ' ~ oo _cz I

I I I I I I I I I I I I i I I I I upward bias from smoker misclassification is not conclusive (Saa discussion of smoker misclassification below). 4. In discussing the consistently increased risks in the highest exposure groups (CRS-12 to CRS-13), it is misleading to single out the U.S. studies and contend that only two of these six were statistically significant without considering the issue of the low statistical power in most of thesa epidemioloqic studies, especially when the study population is broken down into smaller exposure subgroups. 5. In the section on meta-analysis (CRS-13 to CR3-ls), it should be clarified that the meta-analysis of pooling overall relative risk estimates by country was only one of several analyses performed by EPA and that EPA's conclusions do not rely on the meta-analysis. 6. •In the paragraph (CRS-13) discussing the EPA Report's weighting of the relative risk estimates, the Draft's wording is very deceptive. it"implies that EPA did something devious by giving the larger studies more weight. In fact, EPA weighted the studias by the inverse of the variance, which is stan$ard statistical methodology. The same deceptive wordinq was used in the previous CR8 report and was addressed in RPA's rebuttal (Sea attached letter to Dan Kulhollan, section D.3.). 7. In discussing the pooled relative risk estimate of 1.19 in the EPA Report from the U.S. data (CRS-13), it should be emphasized that this is ths pooled estimate for the effects of spousal smoking, unadjusted for other sources of ETS exposure. 8. The discussion of $PA's use of a one-tailed significance test is very misleading and slanderous (CRS-13 to CRS-14). A one- tailed test is a standard statistical procedure when there is prior evidence that if there is an affect, it is likely to be in a specific direction. EPA did not "(argue] that there is no biological reason to expect passive smoking to reduce the risk of lunq cancar• (CRS-14) but, rather, demonstrated that based on prior knowledge of the carcinogenicity of active smokinq and the similarities between mainstream saoke and ETS, any lung cancer affact of BTS would be expected to be causativa versus protactive. In addition, with respect to the "crucial point• (CRS-14),, where EPA is accused of changinq tests between drafts, the CRS draft is totally erroneous; EPA used a one-tailad test in both drafts as well as in the final report. Bnvironmentsl Tobacco 3'soke 1. There are more than 40 known or suspected human carcinogens in STS not just 14 as mentioned on CRS-17. 6 I

I 2. The CR3 draft correctly concludes.(CR,4-lg) that "cigarette- equivalent exposure estimates vary siqnificantly depending on which STS component is chosen" and "are probably of liait.d use in determining risk". Then, three pages later (CRS-22), the draft contradicts itself and inappropriately suggests that "typical ETS exposure is equivalent to saokinq approximately one-tenth of a cigarette every day", based on relative nicotine levels. 3. The near total reliance on the unpublished Jenkins et al. study to deteraine ETS exposure represents, at best, a highly selective and questionable use of available data. This extensive dependence on a tobacco industry-supported study, with tobacco industry co-investigators, hardly gives assurance to EPA and, we suspect, to a great many research scientists, as well as the public health community, that the CRS, with all its literature retrieval resources, is interested in an unbiased analysis. 4. Furthermore the Draftls analysis of the Jenkins .t al. data is incorrect. Table 3(tR.S-21) is used to show the "average nicotine concentration and actual nicotine exposure", based on the recent RJ Reynolds - Oak Ridge (RJR-OR) unpublished 1i city U.S. study. The implication is that "rssidential anil other non-workplace exposure •tends to exceed workplace exposure by a factor of 4 to 6" (CRS-2) and (CRS-47), so "that many workers would not be exposed to sufficient ETS to be at increased risk for lung caAcer" (CRS-2). However, this interpretation is incorrect. The correct conclusion to be derived from results in the RJR-Oak Ridge study is that where there are no ssaking restrict3ons, 8TS coac.ntrations at boass and t n the workplaco are siAilar. In soae workplaces, 8TS levels and average daily exposures are considerably higher than at hose. This is saen in the enclosed Table which compares the RJR-OR nicotine concentrations in "hoss" and "work" settings. The Table also presents estimates of total daily exposures based on two breathing rat. scenarios: 1) 1.2 al/hr. .( us.d by CRS ), and 2) 10 s3/ 8 hr. at work and 10 as/ 16 hr. at hoa. (sore physiologically realistic). Caaparison of the two tables highlights several flaws in CRS' Tablo 3. First, the "non-work" n-548 should not be used as it includes the n-41s hose and is ;rrdundant and misleading. Second, the home (n-t1s smoker occupied- hoses) should be compared with the work n-168 (no smoking restrictions). This allows direct comparisons in unrestricted saokinq environments. Third, the exposure comparisons should be made using the breathinq-rate scenario of 10 m~ for both hose and workplace (this is what both EPA and OSHk use). Also, weekend non-work conditions should probably be taken into account. I I I I I I I I I I I I i I I ~ 7 IM ~ ~ ~. I

ar .. w. w.. .r r i.. .r r+.. r.. .M s+r r a.. en Table: B'1'S Nicotine C.awaUrations wrd Exposure Pstimata for Smoher-oocupiod Homes versus Wodcplaoes Based on Jenkuu et al Data and Various Breadtin,8ltate Aswmptioas' BNYIRONM6NT NICOTINE AIR CONCENTRATION (uWm') EXFOSURE (ui/d.y) at 1.2 m'/hr .t 10 m'/day 6ome ar waic Home 16 rr MwA at 15 hr x 1.2 m'/hrr st 19 m'/16 hr (N •• 4 15) (UN*W-OMpW boew mly) me" . 0.68 12.1 6.8 mm 2.16 38.8 21.6 BQq~ ~k 2.79 48.7 27.9 ~ 7.10 127 71.0 Wat ~brTwA at t ar x 1.2 m'/hr at 10 ®'/8 br (N w 520 Toad No Smokiq Ratriction 1'Lu Sa~oki~ 1~ ~ No S~ ~~ $~ ~ no*aod A~• t?~I~/) " p~~+ R,~pMiriotio~l DodVMod Dedjn~led No Smoking ~~ Atrn Oldy No Snoidq6 SaWmilim Ann Only Me S Ratricxlons N s 168 ,no" 0.09 0.9 a,P 5.6 0.9 5.8 : Muuu 0.79 2.77 7.5 26.6 7.9 27.7 IiDt6 por+caWZo • 0.48 3.59 ' 4.6 34.5 4.8 35.9 9Sth porawdle 3.90 14.0 37.4 134.4 39.0 140.0 $Re( - SAB CRS: 'ttibb 3: Rqmura .Ad Aitbaps ~x~oeatrukr~ of NbodAO (U.S. )6{.:'!y Study) of Iodividu.lx Reoordft Tobacao Pioduct ' ' IUb1a 6, 7, tW t. l=WMy 1V4?J94, Ob~lb~ in Airlwa Vam (QIB. CRS-21). RM bM UMMS . OSHA wlb4 • 12.4% Tcol Noatibor ot WakoM SaopMd 1336 z6COBUtoz

i In addition, note that only 12.4% (168/1356) of tha total numbar of workplaces samplad by Jenkins at al. had no smoking restrictions. our recollection is that national surveys suggest that at least 358 of all U.S. workplaces have no smoking restrictions. In any event, workplace HTS exposures are far aore variable than are homa axposur.s. This ia because of the high variability in workplacs sizes, ventilation rates and smoker densities. This is sosawhat apparent in the coaparisons presented in the enclosed Table. Note that while the aadian cotinina concentrations are higher for hom: vs. work (0.68 vs. 0.58), the corresponding maans (2.16 vs. 2.77), 80th percentiles (2.79 vs. 3.58) and 95th percentiles (7.10 vs. 14.0) are all lower. Thus, even a blanket statasent of comparability of home vs. workplace exposures is too precise. Again, the CRS has depended mainly on the RJR-OR study for its exposure aatiaatas, and has mada the wrong comparisons. Thara are many mora (and published) studies availabla.. The CRS sathodoloqy and primary dependence on this unpublished study for a conclusion of low workplace axposura should be corrected. 5. with respect to the discussion of biomarkars (CRS-22), a compound need not be directly related to a specific health risk to be a markar of 8TS exposure. DosQ-Rospons• Relationships 1. The EPA Report did not "(assuma] that the entire population of never saokars was subject to the saas risk" (CRS-24). Rather, the Report used av.rage, risks, as aatimatad by the apidamiology studies, to calculate population astisatas, and different average risks wara used for people with and without ETS exposure fros spousal smokinq. An alternative could have been to usa sos. sort of linaar dosa-basad approach, although there is substantial uncertainty regarding what doses are associated with what exposures. However, to infer a threshold froa these apidasioloqy studias, as the Draft has done, is not justifiable, especially given the exposure misclassification problams inherent in these studies. 2. On CRS-26, the increased risks observed in the lower exposure groups of the Stockwall at al. study should not be dismiss.d as "not statisticallx siqnificant at the 95% confidanca laval.• These small exposure subgroups have low statistical power and 8'TS is a known human carcinoqanf therefore, the observed increased risks in these lower exposure groups are likely to be biologically significant, avan if not statistically significant. 0 Ct 4h 8 ~ ~ ~ w ~ I I I I I I I I I I I I I I I I I

I I ~ 3. Also on CRS-26, it is totally inaccurate to determine that "the risk values at the lower exposure lavals are all sufficiently close to unity to conclude that there is a high ~ probability that only the highest exposures to ETS aay present any risk of developing lung cancer". These studies of spousal smoking are subject to substantial exposure misclassification becauss many people are exposed to ETS from a variety of . sources, not just spouses, and there is no truly "unexposed" ! comparison group. The effects of axposure.aisclassification would be especially pronounced in a low spousal exposure _ group, because thase women with low spousal exposures and I variable other exposures would be compared with women without spousal exposure but also with variable other exposures. The high background "noise" from the variable other exposures in ~ both groups is highly likely to mask any sffact of the low spousal oxposure! 4. The CRS draft ascribes far too auch precision to the relative ~ risks reported for individual subgroups. These are relative risk eitisatea, based on a crude exposure surrogate, not a true indicator of total dose; and observed in a small , subsp.apla of the population. Overall, the study results show consistent dosa-related increases in lung cancer risk from ETS exposure. However, the specific estimates should not ba treated as exact, and the C,RS should not dwell so auch on an I apparent anomaly in a specific dose-response relationship (e.g., discussion of Fonthaa et al. results based on total years of exposure, CRS-26 to CRS-27). / 5. Regarding smoker aisElassification bias (CRS-31 to CRS-35}, an a inherent but unspoken assumption is that former or current , ! ~ ' , _  w 6. , / ! sackers are equally likely to be aisclassified as nevar- saokers whether or not their spouses saoka. Then, it is explicitly assumed that aisclassified sackers are more likely to be married to other smokers because smokers tend to marry other smokers. Howevar, there is no evidence that the first assumption is accurate. In fact, it seems plausible that smokers married to other sackers may be less likely to misrepresent th.aselves as nevar-smokars in self-reports than sackers married to nonsmokers, who aay faal aore sslf- conscious and stigmatized about their smoking habit. If this is the case, then smoker misclassification may not actually result in any measurable upward bias in thase apideaiologic studias,~ and may even produce a downward bias. The CRS analysis of the smoker aisclassification rate required to eliminate trend in the Fonthaa et al. study (CRS-32 to CRS- 35) relies on an unstated assumption that there is no saoker misclassification of cases in the baseline comparison group (i.e., 0 pack-years exposure), vhich may not be warranted. It apparently also assumes that there is no misclassification in the control groups, although since.thara are,no accompanying 0 9 ~' ~ ~ .~ ~ ~ .~ I