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RJR APPENDIX C COMMENTS OF THE R. J. REYNOLDS TOBACCO COMPANY ON APPENDIX D TO THE HEALTH ASSESSMENT - ALTERNATIVE APPROACHES FOR ESTIMATING THE YEARLY NUMBER OF LUNG CANCER DEATHS IN NONSMOKERS DUE TO ETS BASED ON DOSE RESPONSE MODELING September 19" RJ• Reynolds Tub.ooo Company Comments - RJR Appendix C

CnMMENTS ON EPA APPENDIX D Appendix D of the Health Assessment discusses potential methods for the derivation of a dose-response model for ETS exposure and age-specific lung cancer death rates. Appendix D presupposes that a causal connection has been established between lung cancer and ETS exposure. No such causal connection has been established, the appendix should be deleted from the Risk Assessment. However, since the EPA solicits comments, we have reviewed this appendix and provide comments on several shortcomings. The Agency identifies three elements that are required to generate dose-response modeling approaches to directly estimate the "number of lung cancer deaths in nonsmokers attributable to ETS" :(1) the distribution of the time-weighted exposure of ETS in a nonsmoking population, (2) the age distribution of the nonsmoking population, and (3) a mathematical dose-response model describing the relationship between the age-specific lung cancer rate and the independent variable age, sex, race and ETS exposure. The Health Assessment at D-1. The Agency suggests that it has already collected sufficient information with regard to elements one and two to perform the modeling. Nowhere is that information presented. The assertion that the time- weighted exposure of ETS in the nonsmoking population is known with certainty is baseless. Even less is known about time-weighted EI'S exposure to specific age groups. Measurement of ETS is a complex undertaking for which no consensus methodology exists. Appendix D is devoted to suggesting alternative approaches for fulfilling the third element described above - developing mathematical dose-response models. The three proposed general approaches for deriving ETS dose-response models are: C1 ~ ~

1. Establish a dose-equivalent relationship between ETS and a positive control such as inhaled benzo[a]pyrene (B[a]P) which has an animal-based inhalation cancer dose-response model associated with it. Heavy use would be made of animal carcinogen test results in this approach. This approach will be subsequently referred to as the Relative Potency Approach ("RPA"). 2. Establish an equivalency relationship between the number of cigarettes smoked per day and ETS exposure levels in mg/m3 inhaled air. This relationship would then be used to estimate risk based on direct state-of-the-art cigarette smoking dose-response model obtained from multiple sources of epidemiological data. This will be referred to as the Cigarette-equivalent Approach ("CEA"). 3. Use ETS epidemiological studies where a dose-dependent increase in the risk of nonsmoking women is associated with ETS. This will be referred to as the Direct Approach ("DA"). The Health Assessment at D-2. The CEA presumes: that smoking causes lung cancer, that the epidemiologic data are quantitatively accurate and not confounded, and that ETS exposure is a quantitative variant of smoking. None of these assumption is accurate. Decades of research have failed to prove that smoking causes cancer and, as demonstrated by RJR's comments in Section II. G., ETS exposure cannot be quantitatively related to cigarette smoking. As the Agency concedes, there are no data available to derive an ETS dose-response model using the DA. In fact, the absence of those data is a fundamental flaw in the Agency's Health Assessment. RJR's further comments are restricted to the RPA. THE RELATIVE POTENCY APPROACH The Agency attempts to describe relative carcinogenic potency of ETS compared to B[a]P by using the data collected by Grimmer et aL, 1988, in a rat implant study. The Agency then suggests a number of alternatives upon which a standard inhalation dose-response model could C2

be based: (1) hamster inhalation B[a]P dose-response, (2) rat inhalation diesel exhaust dose- response, and (3) human inhalation coke-oven response. Bfa1P The Agency relies on the work by Grimmer et al, 1988, to derive the relative carcinogenic potency of ETS to B[a]P. This reliance is misplaced. That study employed an animal model using beeswax pellets that were surgically implanted by thoracotomy into rat lungs. The method is an extreme, highly artificial approach that does not in any way simulate the qualitative or quantitative aspects of smoking or ETS exposure, and human target doses cannot be predicted from this model. The beeswax pellet itself provides a strong foreign-body tissue response in rat lungs, and this would be expected to contribute to tumor development. The pellets are not passive delivery devices. In earlier work (Hirano et aL, 1974), two control animals with beeswax pellets alone developed squamous metaplasia, which indicates the degree of irritation produced. Therefore, data obtained using the beeswax technique are totally inappropriate for quantitative risk assessment. The EPA ignores other work on beeswax implantation (Grimmer et aL, 1987a) that should be included as part of Table D-1. This work has shown that the contribution of B[a]P to total carcinogenicity of flue gas condensate is less than 2%. Data are also available on diesel exhaust condensate (Grimmer et al. , 1987b). The lung implant technique used by Grimmer does not allow accurate estimates to be made of the actual dose. In addition, as the EPA points out, the exposure levels will most likely exponentially decrease with time. Multiple exposures cannot be used. Overall, the technique is very non-representative of any human exposure. The Office for Science and Technology C3

Policy (1985), in its review of carcinogenesis, points out that the data derived from such highly experimental systems are not relevant to human exposure. The OSTP uses as examples pellet implants in urinary bladders and subcutaneous injections in experimental animals, which are analogous to the lung implant studies. The Agency suggests at D-6 that ETS condensate was implanted in the rats' lungs. In fact, sidestream smoke condensate was used. EPA's Appendix D presents many details of the work that are not in fact present in the original Grimmer article, eg., duration of study, method of introducing the implant, and the histological typing of the neoplasms. The Agency should describe the source of this unpublished information. In addition, the EPA specifically neglects to mention one of the data sets from the original Grimmer paper, Le., lack of a strong dose- relationship. Tables D-2 and D-3 import historical lung tumor control data from a different laboratory (Goodman, 1980). The combined data set is used in the establishment of a model. This combination of data from different laboratories in different countries in different years using different pathologists is scientifically unacceptable. The conclusion reached by the EPA, that the implant technique can be used to estimate the relative potencies of other complex PAH mixtures including, by implication, ETS, is invalid. Hamster Inhalation Bjg]P Dose-ReWnse Only a single group of workers (Thyssen et aL, 1981) have shown inhaled B[a]P to cause cancer. Several other groups have failed to replicate the observations (Pepelko, 1984). Anatomically, the cancers reported by Thyssen et aL to occur as a result of B[a]P inhalation were C4

not lung cancers. They were neoplasms of the nasal cavity, larynx/pharynx, trachea, esophagus, and forestomach and so are irrelevant to any discussion of lung cancer. No evidence is given on the histologic typing of the neoplasms in the Thyssen B[a]P inhalation experiment; they could have been non-malignant. The EPA statement that careful histopathological examinations were made on each animal is not supported by the description or the published report. The data in Table D-5 (the number of hamsters with one or more malignant laryngeal or pharyngeal tumors) cannot be obtained from the Thyssen paper to which the table refers. Other results presented in the table including lifetime exposure, average survival time, animals examined, are different than those published in Thyssen's paper. Moreover, the Thyssen paper is deficient in many technical areas and should be viewed as a technical note providing uncorroborated data - not as a reference method for use in extensive modelling. The modelling technique used and quoted by the EPA has not been published and comments ran therefore not be made. The value of models based on inhaled B[a]P is thus questionable. The conclusion reached by the EPA on the use of Relative Potency Approach (RPA), namely that such an approach can be used to generate comparative data on ETS, is not valid for the reasons given above. Diesel Exhaust Study EPA's Appendix D reviews only cursorily the diesel exhaust inhalation study of Mauderly (1987). This limited review, only 21 lines of text, is despite the fact that the diesel exhaust study was designed to be a pulmonary carcinogenicity study, and uses a material which in some respects is more similar to ETS than the other described approaches (the EPA document uses the C5

ambiguous phrase "the PAH-matrix is reasonably similar to the type one might expect with human exposures"). In exposures of up to 30 months (7 h/d, 5 d/w) at RSP concentrations at least 100-fold higher than typical ETS concentrations, i.e., 35 mcg/m3, the diesel study showed no increase in malignant lung tumors. Only in the high exposure groups (200 times typical EI'S RSP concentrations) were malignant tumors found. The diesel exhaust data show that the rat can respond positively in an inhalation carcinogenicity study, the test material producing a few malignant tumors. However, such results are not found at lower concentrations, lower but still much higher than typical ETS concentrations. At doses of diesel exhaust, 100-fold greater than ETS exposure, no differences were noted from sham exposed animals. The minimal attention to a key paper, and a lack of an examination of the dose response and a comparison with likely ETS exposures, is a misrepresentation of the relevant facts by the Agency. Conclusion The models presented rest on unfounded assumptions and scientific data which, even if they can withstand peer scrutiny, are irrelevant to human EI'S exposure. Appendix D does nothing to inform the public about potential health-related effects of EI'S. Instead it is an arbitrary exercise which is an abuse of the Agency's discretion because its existence is an attachment to the Health Assessment implies that it contains useful information on that subject. It should be withdrawn. C6

REFERENCES Grimmer, G., Brune, H., Deutsch-Wenzel, R., Dettbarn, G., and Misfeld, "Contribution of polycyclic aromatic hydrocarbons and polar polycyclic aromatic compounds to the carcinogenic impact of flue gas condensate from coal-fired residential furnaces evaluated by implantation into the rat lung," Wo, 78:935-941, 1987a. Grimmer, G., Brune, H., Deutsch-Wenzel, R., Dettbarn, G., Jacob, J., Naujack, K.-W., Mohr, U., and Ernst, H., 'Contribution of polycycGc aromatic hydrocarbons and nitro-derivatives to the carcinogenic impact of diesel engine exhaust condensate evaluated by implantation into the lungs of rats," Cancer Letters, 37:173-180 1987b. Grimmer, G., Brune, H., Dettbarn, G., Naujack, K.-W., Mohr, U., and Wenzel-Hartung, R., "Contribution of polycyclic aromatic hydrocarbons to the carcinogenicity of sidestream smoke of cigarettes evaluated by implantation into the lungs of rats," Cancer Letters, 43:173-177, 1988. Goodman, D. G., Ward, J. M., Squire, R. A., Paxton, M. B., Reichardt, W. D., Chu, K. C., and Linhart, M. S., "Neoplastic and nonneoplastic lesions in aging Osborne-Mendel rats,' Toxicology & Applied Pharmacology, 55:433-447, 1980. Hirano, T., Stanton, M., and Layard, M., "Measurement of epidermoid carcinoma development in the lungs of rats by 3-methylcholanthrene-containing beeswax pellets," RtCI, 53:1209-1215, 1974. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. Tobacco Smoking. Volume 38, Lyon, 1986. Kuhn, 1985, "Lung and Mediastinum," In Anderson's Pathology, ed. J.M. Kiassane, C.V. Mosbey & Co., St Louis. Mauderly, J. L., Jones, R. K., Griffith, W. C., Henderson, R. F., and McClellan, R. 0., "Diesel exhaust is a pulmonary carcinogen in rats exposed chronically by inhalation," Fundamental & Applied Toxicology, 9:208-221, 1987. Office of Science & Technology Policy. Chemical carcinogenesis: a review of the science and its associated principles. Federal Register, March 14, 1985. Pepelko, W. E., "Experimental respiratory carcinogenesis in small laboratory animals,' , 33:144-188, 1984. Thyssen, J., Althoff, J., Kimmerle, G., and Mohr, U., "Inhalation studies with Benzo[a]pyrene in Syrian Golden Hamsters," JNCI, 66:575-577, 1981. pp ~ ~ Gn ~ r+

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