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CRITIQUE OF THE REPORT ENTITLED Environmental Tobacco Smoke:. A Compendium of Technical Information U.S. Environmental Protection Agency Chapters 5-8 Prepared by: Mark J. Reasor, Ph.D. , L 7 Ii I received the B.S. (1967) and M.A. (1969) degrees in Biochemistry from Purdue and Duke Universities, respectively. I received the Ph.D. degree in Biochemical _Toxi-cology from <the.-Johns =Hopkins--Univers~.ty in 1975. In 1975-76, I performed postdoctoral work in pharmacology- at the National Institute of Environmental Health Sciences, North Carolina. I then became an Assistant Proi:essor of Pharmacology and Toxicology at West Virginia University in 1976, and achieved tenure at that institui:ion in 1984. I am certified in general toxicology by the American Board of Toxicology. Since 1969, I have published 66 research articles in the fields of pharmacology and toxicology. I am an Editorial Board member of Toxicology and Applied Pharmacology, an .official journal of the Society of Toxicology, and am an Associate Editor of Journal of Toxicology and Environmental Health. I have published one book chapter and one review article on environmental tobacco smoke: (1) Biological markers in assessing exposure to environmental tobacco smoke. In: Environmental Tobacco-Smoke: Proceedings_.of the

- 2 - International Symposium at..McGi11 UniversiLy (D. Ecobichon-.and J.M. Wu, eds.), Lexington Books, Lexington, MA, pp. 69-77, 1990; (2) The composition and dynamics-of environmental tobacco smoke. J. Environ. Health 50: 20-24, 1987. A copy of my curriculum vitae is attached. I have been asked to review Chapters Five through Eight of an EPA draft compendium of technical literature on environmental tobacco smoke. OVERVIEW •As•presented, the four chapters addressing aspects of exposure to ETS do not effectively present the issues associated with this topic. This is due, in part, to the omission of cer,tain information and redundancy among the chapters. One way to remedy this situation would be to reorganize this section with the addition of another chapter. A suggested framework for this reorganization is presented in this introductory overview. The remaining sections of this critique will provide specific comments on individual chapters. The first chapter in the series on exposure should be concerned with the chemical compositiorr of ETS. This chapter would provide a basis for discussing the issues related to exposure. Without an appreciation of the problems inherent in analyzing the composition and properties of ETS, a discussion of the assessment of exposure cannot be fully evaluated. Aspects of composition are sczttered throughout - ob. T ~ N ~ rA ~A

- 3 - r i J LI the four chapters-; thus. the -reader never- iecei-ves :a comprehensive analysis of the subject. Azeas that should be- discussed include the-results and limitations-of controlled laboratory studies examining sidestream smoke as a surrogate for ETS, a critique of the use of mainstream to sidestream smoke ratios in the comparison of exposure to ETS with active smoking, and field studies on the composition of ETS. The role of aging in determining the chemical composition and particle sizes of ETS should also be carefully considered. A chapter examining the significance of ETS in indoor air pollution-should be the second chapter in the series. This chapter should include a more general discussion of indoor air pollution, in which the overall contribution of ETS is put in a proper perspective.. Chapter 6, "Exposure to Air Pollutants," does not succeed in this respect; the chapter's singular focus on ETS gives the reader the impression that it is the only significant: source of indoor air pollution. The chapter on "Measuring Exposure to Environmental Tobacco Smoke" would follow, expanded to provide an in-depth discussion of the problems inherent in specifically measuring exposure to ETS. Considerations of poteni:ial airborne markers and their limitations, proper experimenta:L design, and appropriate equipment to measure the various ETS constituents should be included. At present, Chapter !i does only a fair job on part of this topic.

- 4 - f- I Next, the Compendium-,might- include--a-chapter- on - mathematical modeling, which may present a usefuI approach to exposure estimation under appropriate.cirtumstances:- However,-. the contribution of this approach to a better understanding of ETS exposure can only be assessed if the limitations of modeling are clearly discussed. At present, Chapter 7 fails to address these limitations, particularly the heavy reliance on existing data and the necessity of making certain assumptions of questionable validity. As presented, Chapter 7 should be retitled to more correctly reflect the nature of the material_presented. -For example, a title of "Assessment of Exposure to ETS: Use of Mathematical Mode!ls" is more - descriptive of the author's presentation. The final chapter of this section would discuss the use of biological markers for assessing exposure to ETS. The present Chapter 8 provides a good general overview of the subject, but the evaluation of the literature could be more comprehensive. Overall, I found the chapters superficial in places, somewhat redundant (particularly regardin(.1 the composition of ETS and the use of biological markers),*contradictory on certain topics (use of carbon monoxide as a marker for ETS: Chaps. 5 & 6; use of cigarette equivalents: Chaps. 6 & 8), and not very effective in achieving the goal stated in the title of the document. The individual chapters were of widely varying quality, and except for Chapter 5 and parts of Chapter 8, did a poo-r job- of present-ing,a balanced==ana1_ys-is.-of- the--

- 5 - issues. At the least, each :chapter- shoul9.=contain-.a. section..- dealing with future needs to give the rea9er an idea of where deficiencies exist and how-they can-be ad3ressed.-.With these general comments in.mind, the following.discussion-will focus on the problems associated with each chapter. Suggestions for improvements will be made where appropriate. The page on which an item of attention is located will be noted in brackets, e.g., [p.54]. Additional relevant references will be cited at the end of the discussion of each chapter. C<~S

- 6 - Chapter 5 Measuring Exposure to Environmental Tobacco Smoke Br.ian P. Leaderer In general, Dr. Leaderer presents a reasonably balanced analysis of this topic. In particular, he is careful to list the limitations associated with the use of certain substances as markers for ETS. The author should discuss and reference recent studies from the laboratcry of Dr. Delbert Eatough (Eatough et al., 1989, 1990; Tang et al., 1988) that - have-, examined:tobacco-specific chemicals Euch as solanesol, 3-ethenylpyridine, and particulate phase ricotine, for_use as markers. These are significant studies ir this field, and should be thoroughly reviewed in any chapter on exposure. Eatough et al. utilized 'the annular denuder system for measuring vapor phase nicotine; therefore, in light of the discussion on this technique [p.62], the <<uthor should be familiar.with this research. Ultraviolet particulate matter (UV-PM) may have value in monitoring the particulate phase of ETS (Carson and Erikson, 1988). The use of tobacco-specific nitrosamines as markers For ETS would be of particular value because of their potential health effects, However, they have not been detected in room air (Klus et al,, 1985). - Personal monitoring can provide an integrated measure of an•individual's exposure since all of the material collected by a sampler is retained for analysis. In contrast to what the author states [p.54], biomarkers- are not

- 7 - necessarily effective in providing= an--integrated-measure of - exposure. Since biomarkers decay with time from tissue and fluids, a person heavily exposed to an airborne contaminant- may show no detectable level of the biomarker if sampling occurs long after exposure is terminated. In this circumstance, an integrated measure of exposure would be impossible to obtain. In general, statements made by the author could be better referenced. For example, in Table 1, it would be valuable to provide citations of studies ahere these --techniques formeasur-ing-RSP have been used. This would enable the interested reader to evaluate the statement that all of the methods have been used with success in chamber and field studies [p. 60-61]. By referencing articles, it would be possible to obtain more detailed technical information on the technique. A general problem throughout the chapter in evaluating statements was that no references were included in the copy I received. REFERENCES Carson JR and Erikson CA: results from survey of environmental tobacco smoke in offices in Ottawa, Ontario. Environ. Tech. Lett. 9: 501-508, 1988. Eatough DJ, Benner CH, Bayona JM, Richards G, Lamb JD, Lee ML, Lewis EA, and Hansen LD: Chemical composition of. environmental tobacco smoke. I. Gas--phase acids and - bases. Environ. Sci. Technol. 23:, 679-687, 1989. Eatough D.J.,•Hansen LD, and Lewis EA: The chemical characterization of environmental tobacco smoke in Environmental Tobacco Smoke, Proceed'.ngs of the International Symposium at McGill Un:.versity of 1989, Ecobichon DJ and--Wu-JM, edi-tors-, Lex'..ngton--Books, DC-- Health and Co., Lexington, Mass., pp,. 3-50, 1990

- 8 - Klus H, Begutter H, Nowak A, Pinterits= G, -Ult-sch-, •and •Wihli~dal- H: Indoor air pollution due to tobacco smoke under real conditions. Preliminary results. Tokai J. Exp. Med. 10: 331-340, 1985. Tang H, Richards G., Gunther K, Crawford J, Lee ML, Lewis EA, and Eatough DJ: Determination of ga:>-phase nicotine and 3-ethenylpyridine and particulate phase nicotine in environmental tobacco smoke with a collection bed capillary gas chromatography system. J. High Resol. Chromat. Chromat. Commun. 11: 775-782, 1988. ~..

- 9 - I i Chapter..6 Exposure to Air Pollutants John McCarthy,_ Elizabeth Miesner,.arid -John Spengler.- This chapter does not present a balanced picture of the subject. The title of the chapter is misleading; the authors do not discuss exposure to air pollutants, rather they limit their presentation to ETS. The reader does not obtain an impression of the relationship of ETS to the overall problem of indoor air pollutants. In fact:, as Dr. Spengler has discussed in a previous publication (;tpengler and Sexton, 1983),.indoor.air pollution,can arise from a multitude of sources. The authors should be encouraged to discuss this relationship in an effort to provide a more balanced pre- sentation of the topic. The authors do not discuss the ].imitations or qualifications associated with the statements they make on a number of issues. For example, their discussion of the composition of ETS [p. 76] is much too siriplistic and misleading. The studies and values cited in Table 3 relate to freshly generated sidestream smoke and noi: to ETS. It is also important to point out that these values were generated under .standardized laboratory conditions and may have little relationship to ETS as it exists in the arabient environment. The-reasons for this include: 1) ETS is composed of both sidestream smo,ke and exhaled mainstream smoke, the latter of which has not been characterized. The re:lative contribution of each of these types.of-smoke to ETS-has not-been.measured - c.r

under laboratory or ambient_conditions; and 2) the process of= aging markedly affects the composition-of ETS, making simple sidestream smoke. values -difficult, if not impossible-,--to interpret. The aging of ETS should be discussed in detail, since an appreciation of this process is essential in -evaluating da,ta on ETS. For example, Pritchard et al., (1988) reported that a significant fraction of the particulate matter in ETS evaporates under ambient conditions. Benner et al., (1989), reported that particles in ETS -coagulate as they age. Tang et al., (1988),•=demonstrated that constituents of ETS decay at different rates in a ventilated indoor laboratory. Also, ultraviolet light caused marked changes in the phase distribution of nicotine in ETS. Vu Duc and Huynh (1987) observed that the half-lives of particles from sidestream smoke vary as a function of size. It should follow that an additional problem is the use and interpretation of ratios of sidestream smoke to mainstream smoke to compare levels of chemicals in each type of smoke. Considering the problems of using sidestream smoke as a surrogate for ETS, such values are virtually meaningless. Furthermore, the amounts of each type of smoke generated are dependent on the smoking patterns of individuals; the deeper the inhalation (leading to increased deposition) and the more frequent the puff ( leading to increased production.of mainstream smoke), the less ETS will be generated from a cigarette. I

i ; i _: For the_ sake o£-balance-,--the-_aul;.hor-s..-should--discuss._ the published studies indicating that ETS does not appear to make a major contr-ibution-to indoor~air pollution.: In studies in the United States and Canada, Sterling et al., (1987-) and Sterling and Mueller, (1988) concluded that ETS does not make a significant contribution to either indoor air quality or health and comfort symptoms associ-ated with the "sick building syndrome." Since 1978, NIOSH has conducted numerous investigations of buildings with health and comfort complaints. Nearly half of the complaints were associated with-,;i-nadequate,ventilation (Mehlius et al., 1984). Only 2% of the complaints involved ETS. _ Another problem area is the sec:ion in which the authors present data on levels of RSP in homes [p.68-69]. What conclusions are to be drawn from the results of these studies? In the article by Spengler et aL., (1981), the actual amount of smoking was not reported, thus the reader has no way of assessing the limitations of the conclusions regarding levels of RSP per smoker. It would be appropriate for the authors to discuss problems in interpreting such data, and to indicate how particular levels relate to health effects. Certain conclusions in the Summary section are not supported by information presented in the text or in the literature. For example, the statement that "Environmental ~ tobacco smoke is the primary contaminant causing elevated RSP C?~ ~ levels in enclosed spaces.°- is too-absolute-:- A more-accu-rate- .F _tV ~ U1 W

~1d statement would_be "In enclosed spac.es--in which smoking occurs,. ETS may be a major cause of elevated RSP levels." Certainly, there are many enclosed spaces in which ETS makes- no contribution to RSP because smoking is not occurring. Even where smoking does occur, not all studies have been properly controlled to permit such an absolute statement. For example, in the study by Weber and Fisher (1980) cited by the authors, baseline values of particles were determined at a time when the rooms were unoccupied. These values ;aere subtracted from values obtained when the rooms were occupied and smoking was occurring. -To control for particles generated by occupancy, the proper condition to establish the baseline is wherL the only variable is the occurrence of smoking. Occupancy and other human activity should be the same during the baseline and experimental conditions. In summary statement #2, the authors are in conflict with the conclusions of Dr. Leaderer in Chapter 5[p.56]. Evidence has•not been provided which allows this statement to be made. In fact, it is well established that carbon monoxide levels do not change very much due to ETS (Carson and Erikson, 1988; Hugod, 1985; Proctor, 1988; Sterling and Mueller, 1988). None of the other chemicals mentioned in the statement have been•studied thoroughly enough to support this conclusion. If the authors have references in support of these statements, they should be provided. Generally, the authors should te more comprehensive in citings references for statemen.ts- they make- throughout- the; -

LJ chapter. Further.,. there -are several point:s.-.on_ whi-ch_ .the - authors have presented inappropriate information, not . thoroughly referenced- statements, or have.-cited --studies -thart are not contemporary and omitted those that are contemporary. For example, inclusion of the work by Wallace et al. (1987), [p.71], is inappropriate, since that study's conclusion that cigarettes are a major source of benzene is relevant only to active smoking and not e:cposure to ETS. Another example is the citation to Dzubay and Stevens, 1975, as support for the statement that at leasi: 75$ of the sulfur, zinc,-bromide-and lead are •found •in the s:.ze range of <2.5 um. [p.66]. Based on one reference from that long.ago, it_ is not valid to make such a definitive statement. It is not clear that the data collected in 1981 and presented in Figure 3 are an accurate ref:lection of present exposure conditions [p.68]. Since this document deals with. technical information, it would be an app::opriate place to discuss the proper experimental design fo:- studies measuring the contribution of ETS to RSP or any other constituent of indoor air. For example, as mentioned ea:lier, the proper controls in such studies should be measurements in the same environment with the same number of peopl,2 and the same level of activity, but with no smoking occurring. It is appropriate to critique the studies of Weber and Fiscler, (1980) [p.69], Quant et al.,'(1982) [p.69], and others on the basis of design flaws, and to question the conclusions that can be drawn if proper experimental design is not utilize3-.-

,J A number. of articles more recent -than those- cited--in - Tables 5 and 6 have been reported where particulates and nicotine have been measured under--realist_i::-conditions: For- example: Sterling et al., 1987; Mattson et al, 1989; Henderson et al., 1989; Sterling and Mueller, 1988. These articles should be cited and reviewed. Comments on future directions that should be taken in this area would be appropriate. REFERENCES L .Benner CL,.--Bayona JM, Caka FM, Tang H, Lewis L, Crawford J, Lamb JD, Lee ML, Lewis EA, Hansen LD, and Eatough DJ: Chemical composition of environmental tobacco smoke. 2. Particulate-phase compounds. Environ. Sci. Technol. 23, 688-698, 1989. - Carson JR and Erikson CA: Results from survey of environ- mental tobacco smoke in offices in Ottawa, Ontario. Environ. Tech. Lett. 9: 501-508, 1988. Eatough DJ, Hansen LD, and Lewis EA: The chemical characterization of environmental tobacco smoke in Environmental Tobacco Smoke, Proceedings of the International Symposium at McGill University 1989, Ecobichon DJ and Wu JM, editors, Lexington Books, DC Heath and Co., Lexington, Mass. pp. 3-50, 1990. Henderson FW, Reid HF, Morris R, Wang O-L, Hu Pc, Helms RW, Forehand L, Mumford J, Lewtas J, Haley NJ, and Hammond SK: Home air nicotine levels and urinary cotinine excretion in preschool children. Am. Rev. Resp. Dis. 140: 197-201, 1989. Hugod C: Exposure to smoke constituents by passive smoking. Tokai. J. Exp. Med. 10: 401-405, 1985. Mattson ME, Boyd G, Byar D, Brown C, Callahan JF, Corle D, Cullen JW, Greenblatt J, Haley NJ, Hammond SK, Lewtas J, and Reves.W: Passive smoking on commercial airline flights. JAMA 261: 867-872, 1989. Mehlius J, Walingford R, Keenlyside R, et. al.: Indoor air quality; the NIOSH experience.- Meeting-of -the-=American-= - Congress of Government Hygienists, 1984.

Muramatsu M, Umemura S,.Fukui_J-, Arai T, and-Kira S: Estimation of personal exposure to ambient nicotine in daily environment. Int. Arch. Occup. Environ. Health 59: 545-550, 1987. Pritchard JN, Black A, and McAughey JJ: The physical behavior of sidestream tobacco smoke under ambient conditions. Environ. Tech. Lett. 9: 545-552, 1988. Spengler JD and Sexton K: Indoor air pollution: A public health perspective. Science 221: 9-17, 1983. Sterling TD, Collet CW and Sterling EM: Environmental tobacco smoke and indoor air quality in modern office work environments, J. Occup. Med. 57-62, 1987. Sterling TD and Mueller B: Concentrations of nicotine, RSP, CO and CO in nonsmoking areas of offices ventilated by air recirgulated from smoking designated areas. Am. Ind. Eya. Assoc. J. 49: 423-426, 1988. Vu Duc TV and Huynh CK: Deposition rates of sidestream smoke particles in an experimental chamber. Toxicol. Lett. 35: 59, 1987.

Chapter 7 Exposure Assessment in Passive! Smoking James L. Repace---- {1 In this Chapter, the author relies extensively on modeling to assess exposure to ETS. While modeling may be useful under appropriate circumstances, the author's approach to it here oversimplifies a complex exposure problem. For the presentation to be balanced, it should be pointed out that there are limitations to modeling, such as the heavy reliance on published data and the need to make nurierous assumptions that might not be valid. The lack of qua:.ifications gives the reader a misleading impression of the nature of such an approach. In many instances, the author has relied on reviews of the literature, such as the reports by the Surgeon General, the National Research Council and IARC. ~'he primary literature sources, rather than these rev::ews, should be cited. The statement is made that ETS :Ls the dominant contributor to indoor levels of RSP [p.801. What is the evidence to support that statement? A mo:-e correct statement would be "that in certain indoor environments, ETS may be the dominant contributor to RSP levels." A strong case can be made that RSP is not the best measure of air contamination due to ETS []?.80], principally due to its lack of specificity for ETS. Nicotine may be a better marker because of its tobacco-specificity and ease of measurement (Eatough et al., 1990). However, because of its U

r Lii rapid decay during ag.ing,_ severe limitationsn exist. in the.use_= of nicotine as a surrogate for ETS (Eatoucih et al., 1990). It is-not clear that the author is correct in assuming that it is almost impossible for nonsmokers to avoid some exposure to ETS, [p.80). This is too strong of a generalization. While there may be some data to support this statement, it is clear that many nonsmokers can avoid exposure to ETS, particularly with all of the present smoking restric- tions. For a balanced presentation, the ZLuthor should cite and discuss other work that indicates that, ETS may not contribute significantly to indoor RSP (Sterling et al., 1987). In places, the author relies on data that were obtained as long as 20 years ago. For exzimple, the author cites a 1970 reference to support an assertion about the number of homes containing children and smokers [p.86]. There is no reason to-believe that these figures are accurate, particularly•with the decline in cigarette! smoking. The author should cite more contemporary research in this area or qualify his statements. The same comments apply to the data in Table 10. A number of publications have ai:tempted to quantitatively compare exposure to ETS wit:h that of active smoking through the use of "cigarette equ:.valents." While alluding to the limitations of using such a value, the author should comment more thoroughly on the ovel-a11 validity of this concept in order-to have a balanced presentation-of the -

r subject [p.89].. Cons.ideri-ng-the-chemical complexity and.. dynamics of ETS, the concept of cigarette equivalents has little util.ity. This is particularly true when-.values are based upon a single component of ETS such as nicotine or cotinine levels in biological fluids. The presentation contains a numter of misleading statements, assumptions, and omissions. For example, in contrast to what the author claims [p.89], there is evidence that nicotine is cleared from the body at different rates in smokers and nonsmokers (Kyerematen et al., 1982). Further, in addressing:the use of-nicotine as a marker for ETS exposure [p.89], the author states that "it has been calculated- that a nonsmoker would inhale volatile nitrosamires equivalent to 10 nonfilter cigarettes or 35 filter cigaretts." The term "calculated" implies that there is no question of the validity of the data from which the calculations were made. The term "estimated" would be more accurate here since the data being relied on are only estimates to begin with. It is also inappropriate for the author to use the term "typical nonsmoker" in making generalizations about: body burden nicotine [p. 91-92]. A more accurate typology would be "nonsmokers who work with smokers." Another example is the author's use of the term "ETS carcinogens" [p.92]. This statement assumes that ETS is carcinogenic, but this has not been proven. Finally, the citation for Kuller et al., (1986) [p.90] should be provided.

It would- als-o- be useful. to incLx,de:-a sect.i.on.-on- future needs in this area. REFERENCES Eatough DJ, Hansen LD, and Lewis EA: The chemical characterization of environmental tobacco smoke in Environmental Tobacco Smoke, Proceedings of the International Symposium at McGill University 1989, Ecobichon DJ and Wu JM, editors, Lexington Books, DC Heath and Co., Lexington, Mass. pp. 3-50, 1990. Kyetematen GA, Damiano MD, Dvorchik BHT, and Vessell ES: Smoking-induced changes in nicotine disposition: Application of a new HPLC assay for nicotine and its metabolites. Clin. Pharmacol. Ther. 32: 769-780, 1982. Sterling TD, Collet CW and Sterling EM: F,nvironmental tobacco smoke -and -indoor air quality in modern office work environments, J. Occup. Med. 57--62, 1987. - t

E rl Chapter 8 Absorption of Smoke Constituents by Nonsmokers Dietrich Hoffmann, Klaus- D. Brunnemann; and:=Nancy J. Haley The authors have presented a reasonably balanced discussion of the use of biological marke::s in the assessment of exposure to ETS. Several points should be expanded upon or clarified in order to more completely evaluate the authors' statements. These will be addressed in the following para- graphs. The authors have not provided a citation in support of their statement that exhaled mainstream smoke makes few contribution to ETS [p. 95]. In fact, there are little quantitative data on which to base any co-iclusions on this question. For example, the more frequent the puffs and the more shallow the inhalation (the less deposition), the larger the contribution of exhaled mainstream smoke to ETS. Additionally, the type of tobacco being s:noked will influence the contributions of each. The authors snould acknowledge the fact that little information exists in this area. The authors should more fully discuss the problems associated with interlaboratory comparisons of nicotine and cotinine in human serum and urine as presented in the ref-erence by Biber et al. [p.98]. These investigators found that absolute_,values for these parameters show large CZ) CD interlaboratory variations which are particularly high in the -.1 samples from subjects exposed to ETS. In addition, in another C~ study (Letzel et al., 1987), it was reported that estimating N

low level ETS exposure_by._measur-ing urinary_:_cotinine..is highly-._ susceptible to-uncontrolled-variations and errors. In light of these problems; standardization of procedures and Ii methodology would permit more meaningful correlations to be established among various studies. If the authors are making the point that there is a relationship between urinary nicotine/cotinine levels in infants and respiratory infections, they r:eed to discuss the link more clearly [p.100). They also neecd to discuss the limitations of such studies. For example, both prenatal .exposure-from,women-who=smoke dur-ing pregnancy and exposure to tobacco-derived chemicals during breast feeding are substantial confounding factors. Unless exposure through these routes can be ruled out, interpretat.ion of studies involving infants may be difficult. The authors do not make a clear case for the significance of genotoxicity in physiological fluids [p.104], particularly•at the low levels of activity that have been reported. There is no evidence that bacterial mutagens in the urine at such low levels are a reflection of any health consequences, particularly cancer. What evidence is there that the refinements presented in refs. 86 & 88 will enable more sensitive measurements of urine to be made [p.104]? Further, it is an unwarranted as,sumption that upon refinements of the methodology, the assay for urinary mutagenicity will reflect the uptake of genotoxic ETS constituents by nonsmokers.-= As

- 22 - the urine of involuntary smokers can already be.assayed for genotoxic agents, the last sentence of this paragraph does not represent what the authors-intend: - The authors should discuss the strengths and weak- nesses associated with the use of macromolecular adducts in assessing exposure to ETS [p. 104j. A potential advantage of such a marker in blood or tissue is the atility to monitor exposure on a more chronic basis than witt other markers (e.g., hemoglobin his a lifespan of 120 days). However, cessation of smoking in humans (Bryant et al., 1987) or termination of:e_xposure of-animals to carcinogens (Belinsky et al. 1986), results in a more rapid loss of adducts than would be expected, making their value in monitoiing long-term exposure questionable. A problem with studies using BaFl or 4-aminobiphenyl adducts is that neither is tobacco-specific. Since alleged increases in adduct formation are quite small in persons exposed to ETS (Maclure et al. 1989; Perera et al., 1987), it is not possible to state, with certainty, that the adduct arose from ETS. A similar lack of specificity exists in the use of hemoglobin adducts of alkenes as an assessment of exposure to ETS (Persson et al., 1988). A more useful approach would be to have a DNA or protein adduct originating from a tobacco--specific chemical. NNK, a nitrosation product of nicotine, has been shown to form DNA and protein adducts when injected into animals (Hecht and Trushin,--19.88). Measurement- of. the methy:iguanine.= and -_

- 23 - f 7-methylguanine_moieties occu.r.ring- in-.tissues- or. -cells-may--be useful in assessing exposure to NNK and ETS. Nicotine is bioactivated to a species that binds macromolecules (Shigenaga et al., 1988). Little information exists as to the feasibility of using nicotine-derived adducts to monitor exposure to ETS. Finally, it is not appropriate to cite unpublished and non-peer reviewed data to support a pcint [p.99, Haley]. REFERENCES -Belinsky SA, White CM, Boucheron J, Richardson FC, Swenberg J and Anderson MA: Accumulation and persistence of DNA adducts in respiratory tissue of rats following multiple administrations of the tobacco-specific carcinogen 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone. Cancer 46: 1280-1284, 1986. Bryant, M. et al.: Hemoglobin Adducts of 4-Aminoloiphenyl in Smokers and Nonsmokers. Cancer Research 47: 602-608, 1987. Hecht SS and Trushin N: DNA and hemoglobin alkylation by 4-(methylnitresamino)1-(3-pyridyl)-1-butanone and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol'in F344 rats. Carcinogenesis9: 1665-1668, 1988. Letzel H, Fischer-Brandies A, Johnson LC, Uberla K, and Biber A: Measuring problems in estimating the exposure to passive smoking using the excretion of cotinine. Toxicol. Lett. 35: 35-44, 1987. Maclure, M., et al.: Elevated Blood Levels of Carcinogens in Passive Smokers. A.J.P.H. 79: 1381-]384, 1989. Perera FP, Santella RM, Brenner D, Poirier MC, Munshi AA, Fischman NH, and Van Ryzin J: DNA aciducts, protein adducts and sister chromatid exchange! in cigarette smokers and nonsmokers J. Nat. Cancer 79: 449-456, 1987. Persson KA, Berg S, Tornqvist M, Scalia-Tomba G-P, and Ehrenberg L: Note on ethene and othE!r low molecular weight hydrocarbons in environmental tobacco smoked. Acta Chem. Scand. 42: 690-698, 1988.

- 24 - Shigenaga MK,..Trevor.-AJ, and Castagnoli N,. Jr.:. Metabolism-dependent covalent bindinq of (S)[5-H] nicotine to liver and lung microsoma:. macromolecules. Drug Metab., Dispos. 16: 397-402, 19F38.