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COMMEN'rS OF R. J. REYNOLDS TOBACCO COMPANY ON HEALTH EFFECTS OF PASSIVE SMOKING - ASSESSMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHJLDREN (EPA/60015q~:)IOO54 - :~temal ]~eview Draft:) October I, 1990

TABLE OF CONTENT~; EXECUTIVE SUMMARY ...................................... 4 The Meta-Analvsis Is Fundamentally Flawed And Provides No Ra~_s For Derivin~ ETS ~-,ung Cancer Mortali~v Proiection.~ ................... ae B. C. D. E. F. 12 ~ .................................... 13 Oualitv of Studifi~ ................................. 21 Inclusion of Non-U. S. Studie~ ......................... 30 Misclassification of Smoking Statu.~ ....................... 30 Adiustment for Back~,round Exposu~ ..................... 31 Nicotine sources other than ETS ................ 33 ETS and urinary cotinin_e .................... 33 Urinary cotinine and lun~ cancer ............... 35 Urinary cotinine levels from background exposure, ..... 35 Cultural differences in background exposure ........ 39 0) (iv) (v) (vi) G. The Wilcoxon Analvsi.~ 40 H. ~ ..................................... 42 II. ETS Has Not Been Proven Scientifically To Be A Human Lung Carcinogen .. 43 Statistical Significmlce ............................... 43 Confoundin~ 45 Bias ..... . ..................................... 45 Dose-Re _sponse ................................... 50 Consistency/Breadth of Evider~ ........................ 55 Biologic Plausibility ................................ 57 Weight-of-Evidence ................................ 62 (i) (ii) (iii) Hazard ldentificatigr} ....................... 63 Dose-Res_~nseYExposure Assessment .......... ; .. 66 Risk Characterization ...................... 67 Ao B. C. D. E. F. G. H. EPA's Analysis Of Parental Smokin~ And Childhood Resp_ ir~tory_ Health Superficial. Disguises Policy Preferences As Science And Will Misl~d~ The- Public ............... . .............................. 69

A. The Agency's Analysis is Su~rflci.] ...................... Respiratory Symptoms ...................... Acute Lower Re~iratory Tract llln,~ ............ Pulmonary_ Function ....................... B. The Agency's Review Will Misled_ The Public: ............... M~nstream smoHn~ ~d COPD ................ ETS ~d ~ult ~irato~ h~l~ ................ BIBLIOGRAPHY .......................................... RJR APPEND.IX A: A STATISTICAL REVIEW OF THE EPA REPORT POR APPENDIX B: COMMENTS ON EPA'S HEALTH ASSESSMENT APPENDIX C (DOSIMETRY OF ENVIRONMENTAL TOBACCO SMOKE) RJR APPENDIX C: COMMENTS ON EPA'S HEALTH ASSESSMENT APPENDIX D (ALTERNATE APPROACHF~) '70 72 72 14 75 75 76 77 82 ii

BEFORE THE UNITED STATES ENVIRONMENTAL PROTECTION AGENCY HEALTH EFFECTS OF PASSIVE SMOKING: ASSF__~SMENT OF LUNG CANCER IN ADULTS AND RESPIRATORY DISORDERS IN CHILDREN FR DOC. 90-20013 The Environmental Protection Agency ('EPA" or "the Agency.') released on June 25, 1990, a draft document rifled, Health Effects of Passive Smoking: Assessment of Lun~ Cancer in Adults and Re~_ iratory Disorders in Children, EPA 1600/6-90/006A (IVlay 1990) (External Review Draft) (the "Health Assessment'). Release of the Health Assessment was noticed in the ~.~aJ_Kf, g~ and comment on its technical accuracy and policy implications was solicited. 55 Fed. B_fg, 25874. R.J. Reynolds Tobacco Company ('RJR") submits these comments in response. The Health Assessment concludes that environmental tobacco smoke ('ETS") is causally related to lung cancer in adults and should be designated a Group A carcinogen (known human). The Agency bases this conclusion on what it describes as a weight-of- evidence evaluation of six factors: biological plausibility; broad-based evidence; consistency of response; upward trend in dose-response; detectable association at environmental exposure levels; and effects remaining after adjustment for potential bias. (The Health Assessment at 1-3 to 1-4). A meta-analysis of selected epidemiologic studies of spousal smoking and lung cancer that computes a summary overall relative risk is a crucial element of the Agency's analysis. That summary risk estimate is integrated with assumptions regarding ETS exposure

and the overall incidence of lung cancer in nonsmokers to project the number of annual U. S. lung cancer deaths attributable to ETS exposure. The Agency concludes that the number of deaths attributable annually to ETS exposure lies between 1800 and 6100. The Health Assessment purports to adhere to The Risk Assessment Guidelines of 1986, EPAJ60018- 871045, August 198/(the "Risk Assessment Guidelines') in deriving these projections? The conclusions reached in the Health Assessment are not supported by the scientific data or by the EPA's analysis. The Agency's Health Assessment is inconsistent with its own guidelines for assessing health risks. Weaknesses of the assessment, including uncertainties, assumptions and limitations of the data are ignored. The Agency advances arbitrarily from a statistical exercise to the conclusion that ETS is a group A carcinogen. In general, the Health Assessment is a risk management proposal disguised as a risk assessment and is an abuse of the Agency's discretion. EPA has no statutory authority to regulate indoor air quality. Title IV of Superfund (The Radon Gas and Indoor Air Quality Research Act of 1986) charges EPA with researching indoor air quality issues but expressly withholds regulatory authority. EPA has exceeded its statutory authority and not acted in accordance with law. The Health Assessment constitutes de facto rulemaking. It is not designed to disseminate in a neutral fashion information regarding indoor air quality. Instead, it is clearly d~rected at formulating a basis for regulating smoking in indoor spaces. The Health Assessment is an abuse of the Agency's discretion. PJR's comments address EPA's as~ons, analyses, and cool.ions contained in the Health Asse~ment. No ~_~¢p~nnce by PJR of the EPA's approach in developing the Health Assessment should be inferred.

The Health Assessment also analyzes studies of parental smoking and non-malignant respiratory disease in children. It concludes that there is no proof that the observed associations between parental smoking and various respiratory disorders in children reflect a causal nexus. F_,PA is correct in this regard - there is no scientific proof that the observed associations are causal. However, the Health Assessment is misleading, policy preferences are interwoven with scientific analysis and the data are overinterpreted. This section of the Health Assessment is therefore also arbitrary and capricious. The Agency has the statutory authority to inform the public, not to mislead the public, and doing so is an abuse of its discretion. Our comments are presented in three sections.2 Section I examines EPA's meta- analysis of spousal smoking and lung cancer studies. Section II disproves EPA's identification of ETS as a lung cancer baTnrd. In Section HI, the Agency's analysis of ETS and childhood respiratory disease is reviewed. Thes~ commmts track the format of the Health Asse~meat. "rh¢ body is reslricted to commenti~ ca ]~PA's interpretafi~m of epidemiologic studies of ErS and health. Commeats on Appendices C and D to the Health Assessmeat are appended to these comments, lqo specific comments have been provided for Appendices A and B. ILIR does not, however, concede the accuracy of those appendices. 3

EXECUTIVE S~ARy The Agency has selectively meta-analyzed 22 epidemiologic studies of spousal smoking and lung cancer to calculate a summary relative risk for ETS and lung cancer. In doing so, the Agency has failed to justify the use of meta-analytic techniques and violated three conditions required to achieve a result of any reliability (Glass, e~ a/., 1981; Hunter & Schmidt, 1990). It is apparent that the studies were not evaluated critically before inclusion in the Agency's calculations. One is left to conclude that studies were combined on two bases: lack of exclusion by the National Research Council in its 1986 review of ETS and availability of published data that would fit the chosen statistical technique; no other criteria for inclusion have been identified. The chosen technique is only one of several available and other available techniques,/.e., a weighted general linear model (P.JR Appendix A), are capable of analyzing all published studies. R JR does not agree that meta-analysis is the proper method for analyzing data of the type evaluated by the Agency. The National Research Council has questioned the applicability of any meta-analysis techniques to studies of environmental epidemiology. (NRC 1985, at 218, 219). No meta-analytic technique can replace a reasoned narrative analysis of the study set. At best, if done properly, meta-analysis may provide a means to integrate and summarize overall quantitative trends demonstrated by comparable studies. Combined studies must be comparable in terms of design, conduct and analysis, and must be investigations of the same dependent and independent variables (Glass, eta/:, 1981; Hunter, et aL, 1982; Hedges and Olkir~, 1985; Wolf, 1986; Hunter and Schmidt, 1990). "Comparable" means more than selecting some of the population studies which have 4

evaluated some estimate of exposure to ETS in relation to the incidence of lung cancer in nonsmokers. "Comparable" does not mean that the analyst can, as the Agency has done, simply exclude studies which do not provide similar conclusions, e.g., the Agency has arbitrarily excluded several studies which find no association between spousal smoking and lung cancer in nonsmokers. EPA's justification for combining the case-control studies - testing for statistical homogeneity - is an irrelevant exercise in comparability. Those studies have relatively small sample sizes, and therefore lack statistical power. Not surprisingly, the 95 % confidence intervals overlap. The point estimates, however, vary widely. The combined studies are noncomparable in several respects: 1. The studies were conducted in disparate cultures, ranging from Chinese women to American men and women to Greek women, all of which have differences in lifestyle, other environmental exposures, and perhaps genetic susceptibility. The foreign studies of nonsmoking women drive the summary risk to significance in the technique selected by the Agency. In contrast, if all available data are analyzed, a nonsignificant summary risk estimate for U. S. studies alone of 1.08 (95% CI ffi 0.68, 1.73) is produced, without considering other indicia of appropriateness for inclusion and without adjustment for bias. OUR Appendix A). 2. Combination of case control and cohort studies is inappropriate. The studies have different durations of observation and were conducted at different time periods. 3. Varying histological lung cancer types were evaluated. Some studies (e.g., Brownson, 1987) looked only at adenocarcinoma cases; others (e.g., Trichopoulos, 1981), on . the other hand, specifically excluded all cases of adenocarcinoma.

4. The sources of controls differ greatly, from other cancer patients to atomic bomb survivors to licensed drivers. OUR Table I). Factors used in matching controls vary widely. (PJR Table 11). 5. Though generally a person was considered "exposed" if married to a smoker, the basis for determining whether the sPOuSe was a smoker varied widely. (RJR Table l]I). 6. Inconsistent adjustments were made for confounding factors other than age and marital status, and virtually none of the studies controlled for precisely the same confounding factors. (R JR Table IV). Study selection has exaggerated EPA's summary risk estimate. As a result of EPA's failure to apply rational criteria for the inclusion of studies in the meta~analysis, poor studies have been included and other studies finding relatively low estimates of risk have been -excluded. A notable example of questionable inclusion is the Hirayama study, about which - despite the Agency's contention otherwise -- serious unanswered questions have been raised that cast doubt on the validity of that study's conclusions. An example of studies excluded from the Agency's meta-analysis is the Varela study. This is the largest case control study conducted to date; it examined a U. S. population; and it was excluded by EPA because the statistical method for analysis chosen by EPA could not accommodate its data. The Varela study reported a nonsignificant relative risk of 0.93 (95% CI = 0.55, 1.57). EPA has arbitrarily dismissed the issue of publication bias despite evidence both that researchers are less likely to submit negative results for publication and that journals are less likely to .accept such results for publication. (Chalmers, eta/:, 1990). Failure to verify the existence of non-published studies is a violation of the Agency's duty to ensure that all or a 6

representative sample of all studies of the hypothesis were included in its meta-analysis. Adjustment of the summary relative risk upward for "background exposure" is inappropriate for several reasons. The adjustment assumes that a causal association is demol~su-ated; it is not. The adjustment further assumes that urinary cotinine is a quantitative marker of ETS exposure and that it is related to lung cancer risk; it is neither. Dietary nicotine (present in solanaceous vegetables and other foods) must be controlled for. (Castro and Monji, 1986; Idle, 1990). Moreover, atmospberi¢ nicotine does not appear in constant ratio to other ETS constituents (Nelson 1989, 1990a, 1990b), and its retention by nonsmokers is dissimilar to other ETS constituents. (See Hiller, et a~, 1982; Ingebrethsen, 1989). Urinary cotinine concentrations in nonsmokers are useless for quantifying ETS exposure. In nonsmokers, urinary cotinine is present, if at all, at levels very close to or below current limits of detection (Biber, et a~, 1987), and substances such as caffeine interfere with cotinine determinations (Thuan, et a~, 1989). At best, urinary cotinine is a qualitative marker of atmospheric nicotine exposure. The Agency subjected its overall data to a statistical test of significance using a Wilcoxon analysis. In doing so, the Agency did not apply the same tests for bias (e.g., mis- classification) that it did for its meta-analysis. More important, it applied a one-tall test for significance, when a two-tail test is generally accepted in the scientific literature. This ignores the possibility of values less than one, biases the results, and overstates the observed relative risk. (Denton, 1990). The meta-analysis is fundamentally flawed. Even if it were statistically sound, statistical tests alone cannot establish a causal inference. It is unclear upon what bases EPA