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RTR APPENDIX B COMMENTS OF THE R. J: REYNOLDS TOBACCO COMPANY ON APPENDIX C TO THE HEALTH ASSESSMENT - DOSIMETRY OF ENVIRONMENTAL TOBACCO SMOKE seprember 1990 R. J. Reynolds Tob.coo Comp.ny Comments - RJR Appendix B

COMMENTS ON EPA'S APPENDIX C Appendix C of the Health Assessment is concerned with the estimation of organ dose due to exposure to chemicals present in tobacco smoke. A mathematical model is proposod which the EPA claims is applicable to both active smoking and ETS exposure. The dosimetry models discussed in Appendix C are simplistic, improperly applied and contain many errors. At the very least, Appendix C should be rewritten to include a discussion of the consequences of simplifying assumptions, errors should be corrected, and a more realistic sample calculation should be supplied. According to the executive summary of the EPA Report to Congress on Indoor Air Quality [1], the EPA Health Assessment document was written to support EPA efforts to "provide the public with an understanding of the hazards of ETS as well as reliable methods for risk mitigation." Considerable controversy surrounds the potential health effects of ETS exposure. Due to the influence of public opinion, ETS issues have become as much or more political in nature than they are scientific. The responsibility of the EPA is to present an unbiased scientific perspective on the issues surrounding ETS exposure without being swayed by politics or public opinion. The EPA's Health Assessment should provide a complete review, giving equal consideration to the strengths and weaknesses of data which support both sides of the issue. Unfortunately, the discussion of exposure assessment presented in Appendix C of the Health Assessment suffers from improper assumptions and does not comprise an objective B1

literature review. Both faulty assumptions and improper calculations characterize the biologically active dose calculations presented in Appendix C. Worse yet, equations derived for the purpose of estimating biologically active dose were ignored or misused. Lung intake is proposed as the best available estimate of exposure - despite the severe deficit of information about ETS component concentrations. Furthermore, exposure estimates are assumed rather than measured. (Frequently, measurements do not exist because concentrations fall below analytical detection limits.) Exposure estimates used in the calculations are biased high and disagree with published data. In addition, correlation of sidestream component concentrations with ET'S concentrations were not performed using representative real-world concentrations. The calculations of exposure are biased and serve only to add "shock value" to this EPA draft document. Calculated concentrations poorly represent the real-world ETS exposures reported in the literature. Comments on C.1 On pages C-i and C-2 of the document the EPA discusses potential etiological agents found in mainstream smoke. While interesting, this information is irrelevant to a discussion of ETS risk. Mainstream concentrations of these substances are many orders of magnitude greater than those experienced by exposed nonsmokers. No substantiating animal bioassays have been performed at characteristic ETS concentrations for the compounds listed on page C-2 to determine whether they are causative agents for cancer of the lung. In the absence of realistic (ETS-level) bioassays, one cannot conclude that the compounds listed are etiological agents in ETS. Furthermore, in many environments ETS is not a major source of many compounds listed on page C-2 [2-10]. B2

Comments on C.2 The dosimetry models discussed in Section C.2 suffer three deficiencies. First, the models are simplistic. Physical, biochemical and biological phenomena are treated in an empirical fashion with little attention given to underlying physico-chemical complexity. Empirical models are not de facto objectionable, but their application to real systems must be accompanied by a full explanation of model limitations and careful evaluation of error propagation. Accurate input parameters are of paramount importance in empirical models. Second, the model development section contains mis-statements and unjustified approximations. Some equations contain typographical errors making them difficult to calculate or analyze fully. Finally, calculations performed to illustrate the model's utility are impaired not only by drastic simplifications, but also by highly questionable parameter estimates. Each of these shortcomings is addressed in more detail below. Deficiencies in the Empirical Model: The process by which the human lung (and subsequently, other organs) is exposed to a biologically active dose of environmental aerosol involves a coupling of complex physical and chemical mechanisms. [See, for example, contributions in reference 11.] These include the fluid dynamics of aerosol flow from the environment into the lung passageways; component migration through the circulatory system; microscopic aerosol dynamics of particle/vapor evolution; mass transport by diffusion, convection, sedimentation, inereial impaction, etc.; thermodynamics of chemical reaction and heat transfer; biophysics of tissue/cellular transport; and biochemistry of chemical-receptor binding. This excludes the preliminary but equally B3

important factors which control aerosol dynamics in the environment, eg., ventilation, source- sink location, filtration, etc. The discussion of exposure-dosimetry modeling in Appendix C document gives little or no attention to any of these influences. Rather than approach the exposure-dose phenomenon from a"first principles" perspective, the EPA Risk Assessment has chosen an empirical description. Empirical models are often necessary substitutes for systems whose complexity precludes a more comprehensive treatment. Human exposure-dosimetry phenomena fall within this category. However, when an empirical approach is selected, a cautionary rule applies: The more empirical the model, the more limited is the apylication. For example, reducing a dynamically evolving ETS particle size distribution to a single average-diameter, uniformly dispersed, constant-concentration aerosol severely limits the environments for which the model is appropriate [page C-17]. If cancellation of effects or time-averaging serves to increase confidence in the approximation, then justification should be provided. Simplification for the sake of mathematical tractability alone is never acceptable. At best, the EPA provides scant support for the simplifications invoked. The model is simplified to an even greater extent when sample calculations are presented. Empirical models usually require input of experimentally measured parameters, eg., initial concentrations, transfer coefficients, partition coefficients, etc., in addition to more fundamental physical and chemical constants, eg., diffusion coefficients, molecular weights, vapor pressures, etc. For this reason, the accuracy of input data and propagation of error from input assumptions are very important. The EPA does not provide propagation-of-error analysis, however simple, for any equations. This is especially troubling since many of the models' input parameters are of questionable accuracy or even validity. B4

Mis-statements, Approximations and Errors: The development of the mathematical exposure-dosimetry model in pages C-4 through C- 17 of the document contains mis-statements, unsubstantiated approximations and simple errors. Several are enumerated below. (1) Concentration is assumed, beginning in equation (1), to be a function of time only. Later it is assumed to be constant. For particulate matter, this is a gross approximation both within the lung and in the external environment. [See, for example, reference 12.] Properly, concentration is a function of both time and position; i.e., C(r,t). This approximation should be clearly stated in the text. (2) The upper integration bound on the inner integral in equation (14) should be "t" rather than "T. " (3) Following equation (15) in the text, the EPA states, "When K is unknown (as is true for ETS), it is ignored and the dose is replaced by the integral of the organ burden, IB." This is a misleading statement. In fact, the EPA has assumed a specific value of "K"; i.e., "1.' A critical factor cannot be "ignored" or arbitrarily equated to a convenient value because the true value is unknown. (4) In the discussion of "biologically active dose" on page C-11, the EPA states, "In general, kA will be the fraction of the inhaled chemical biotransformed into the active form." More correctly this should read, "In the simplest approximation, kA willbe.... " (5) On page C-11 the EPA states, "For most chemicals (particularly those in ETS), kA is unknown and BB or DB must be approximated by B or D as described B5

earlier." This statement is misleading for two reasons. i) It contradicts the EPA's previous statement on page C-4: "Sinee the incidence of effect per unit concentration can be quite different for [gas-phase and particle-bound nicotine], total exposure intensity may act as a poor measure of risk.' ii) The EPA has argued that "DB = k,,D". This conclusion that DB must be approximated by D when kA is unknown, implies the choice of a specific value for the unknown; Le., kA = 1. By the EPA's own interpretation of kA, this is equivalent to the assumption that all the inhaled chemical is transformed into a biologically active form. (6) Equation (16) likely represents an oversimplification of the actual processes taking place in the lung. As stated in the discussion on page C-10, retention may be approximated either by a single exponential function or by a sum of exponential functions. A simple, realistic scenario suggests that a sum of exponential functions is more appropriate. Suppose the biologically active constituent is actually a metabolite of the inspired substance. In that case, the retention function is a combination of formation rate of the compound, transfer rate of the parent compound from the organ to the blood, and elimination rate of the biologically active compound. This scenario is probably characteristic of many compounds in ET'S alleged to have detrimental health effects. For example, polycyclic aromatic hydrocarbons (PAH) and nitrosamines exhibit no inherent biological B6

activity [13-16]. Rather, it is their metabolites that are associated with biological effect. Depending upon the complexity of metabolite kinetics, the assumption of a single, exponential retention function could introduce significant error. The use of simple exponential functions also assumes, without substantiation, that metabolism rate and transport across cell membranes are governed by first-order mechanisms. (7) Equation (17) should read "B(T) _ ..." rather than 'D(T) _ ...'. (8) Nicotine and cotinine are mentioned extensively throughout Appendix C, although neither has been associated with any adverse health effects at concentrations present in ETS. Furthermore, the discussion adds nothing to the understanding of the biological activity of ETS. Many studies suggest that nicotine is of little value in predicting exposure to other ETS constituents [17-22]. The excessive attention paid to nicotine gives the reader the impression that nicotine is a typical ETS component; an impression which is not substantiated in the literature. In fact, the EPA states on page C-15, "If the dose to the blood is calculated for nicotine, therefore, the dose to other organs or tissues may be obtained by multiplying the ratios in Table C-1. It is unlikely, however, that the same ratios will apply to other chemicals in ETS." A more complete discussion of nicotine and cotinine as biomarkers is presented in Section I.F. of the main RJR comments. (9) In Figure C-2 on page C-13, the deposition fraction labels fT8,m and f,p,m are missing from the appropriate "arrows." B7

The summary on pages C-15 to C-17 is also misleading. The EPA claims that measurement of exposure to "given chemical[s] in ETS can take several forms." This is a peculiar statement as most of the 4700 compounds alleged by the EPA to be in ETS [23] have never been measured in ETS. In addition, most of the "43 known or suspected carcinogens identified in tobacco smoke" [The Health Assessment at 2-1] have not been detected in real-world ETS. Even if detected, the question of origin remains unanswered. What fraction of the substance originated in ETS, and what fraction came from another source? Some examples of alternate sources for alleged carcinogens in indoor air are given in references 2-5,8,9. The calculation of exposure-dose outlined in the summary is simplistic. For those compounds which can be measured, exposure intensity, cumulative exposure and lung intake can be estimated under certain conditions. For example, external ETS aerosol dynamics must be simple enough to permit measurement of environmental concentrations, and volumetric breathing rate must be reasonably constant over the exposure period. But for most compounds, total lung uptake "U", or regional uptakes, cannot be calculated because the fraction of material deposited in the lung, "f", is unknown. Neither total lung burden "B", nor regional burdens, can be calculated because the retention function "R" is unknown. Although the EPA points out that "R" may be estimated for particles, no references for its use with other ETS components are given. Subsequent calculation of integral organ burden "IB" is similarly flawed. Items 7 through 12 in the summary deal with dose to the lung, dose to other organs, and biologically active dose. The gross assumptions and myriad usilrnowns which characterize these "measures" make useful calculations impossible. In light of the absence of critical information, the EPA concludes on page C-17, that "intake" is by default "the best available measure of B8

exposure." But the extent of their own derivations suggests that intake is a relatively poor measure of exposure or risk. In addition, alternate routes of intake may provide dose contributions for compounds present in ETS. For example PAHs and nitrosamines may originate in foods rather than air [6,24-26]. All sources of exposure must be carefully considered when relative risk assessments are made. Finally, the EPA states, "The measure of exposure to a chemical depends upon the level of available information." This statement and those following read like an apology for failing to attempt a more rigorous mathematical description of exposure and dose. It is not the "measure of exposure" that depends upon the "level of available information," but the accuracy of the approximation. What the EPA refers to as an "upstream" measure is nothing more than a less accurate approximation of an equation which is already empirical.. Comments on C.3 Section C.3 purports to estimate intakes based upon assumed exposure conditions. But several erroneous assumptions tend to invalidate the results. Errors include miscalculation of exposure conditions, use of inapplicable ratios, and biased exposure data which have not been corrected for non-ETS, i.e, background, sources of compounds. Several specific problems are identified below. The unnumbered equation on page C-18 is approximate, even within the context of the given empirical description, and depends upon all the prior approximations which went into the derivation of the equations in Section C-2. It is mathematically exact only when the burden function, B(t), is constant; an unlikely prospect. If R(t) is of exponential form, as the EPA B9