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Comments on: ENVIRONMENTAL TOBACCO SMOKE: A GUIDE TO WORKPLACE SMOKING POLICIES [DrattJ EPA 400/6-90/004 Response Addressing: Chapter 1: What Is ETS? Chapter 2: Measuring ETS in the Air and Body Section: Assessing ETS Exposure Section: Biomarker Studies Prepared by: Joseph D. deBethizy, Ph.D. Senior R&D Toxicologist Manager. Pharmacology R.J. Reynolds Tobacco Company October 1990

SUMMARY: Many statements in the first two chapters of the EPA draft document "Environmental Tobacco Smoke: A Guide to Workplace Smoking Policies", (the "Guide" or the "Policgr Guide") are misleading and not scientifically rigorous. CO1VIIIUNTARY: The commentary below follows the organization of the draft Policy Guide. Questionable statements in Chapters 1 and 2 of the Guide are quoted, then critiqued. Recommendations are offered. Chapter 1: WHAT IS ETS? "The dose absorbed is small, but after absorption, the chemicals circulate widely in the body, tending to remain in the body longer than mainstream smoke in active smokers." [The Guide, p. 7). The language used in this sentence depicts an alarmist's position. This statement simplistically concludes that the components in Environmental Tobacco Smoke (ETS) remain in the body longer than those from mainstream smoke absorbed by active smokers, and insinuates there is something insidious about ETS. In fact, only a few compounds have been reported to be eliminated more slowly by nonsmokers than smokers [1]. The Guide's reference 14 [The Guide, p. 7] has not been peer•reviewed and should not be used as a basis for this far reaching conclusion. Most xenobiotics are eliminated at the same rate from smokers and nonsmokers [2].

Chapter 1: Chemical Make-Up "Sidestream smoke contains more toxic and carcinogenic chemicals then mainstream smoke, although the concentrations are much higher in active vs. passive smokers." [The Guide, p. 8). This statement is misleading because it relies on unproven assertions regarding mainstream smoke constituents and because it does not address ETS composition. An ETS policy guide should address ETS! RECOMMENDATION: It would be correct (and more appropriate) to state: "ETS differs qualitatively and quantitatively from mainstream and sidestream smoke. The single most significant contrast is the difference in constituent concentrations. ETS constituents are extremely dilute in room air. The concentrations of individual ETS constituents are hundreds or thousands of times lower for ETS than for mainstream or sidestream smoke [s] " Other Contaminants "In addition to chemicals that are Intrinsic to tobacco....contain pesticides and herbicides." [The Guide, p. 8] Alleged exposure to commercial/synthetic pesticides through inhalation of ETS must be 2

challenged since exposure to pesticides from other sources, e.g., dietary exposure, is more likely and much more significant (5]. RECOMMENDATION: The authors should indicate that synthetic/commercial pesticides have never been found in ETS and that they are routinely found in the diet. Furthermore, the body has developed biological defenses against normal levels of such pesticides [5J. Chapter 1: Toxins and Irritants: "In addition to ... mainstream smoke.u" [The Guide, p. 9) Although ETS contains carbon monoxide, it is insignificant in comparison to other sources of carbon monoxide found in indoor environments. The human body produces carbon monoxide during normal metabolism. Blood carboxyhemoglobin concentrations resulting from normal metabolism are comparable to those found in the blood of nonsmokers exposed to ETS [6,7]. The concentrations of CO to which nonsmokers are exposed in ETS do not result in a biologically significant change in the oxygen-carrying capacity of the blood. RECOMMENDATION: The discussion of carbon monoxide in this section is inaccurate and should be rewritten to place CO that comes from ETS in proper perspective in relation to other sources. 3

Chapter 2: Measuring ETS in the Air and Body: Assessing ETS Exposure (3 statements): Statement 1: "Biological markers are indicators of exposure in a person's body fluids." [The Guide, p. 12] This statement is simplistic and ambiguously expressed. RECOMMENDATION: The statement should read: "Biological markers are chemicals present in a person's body fluids which may indicate exposure to an ETS constituent " Statement 2: "Mathematical models calculate the degree of exposure that Is likely in a given airspace." [The Guide, p. 12) This statement is not correct. Mathematical models only estimate exposure parameters. Furthermore, no valid model exists for calculating the degree of exposure in a given airspace. RECOMMENDATION: This statement should be rewritten: Mathematical models give an estimate of exposure for a given airspace. 4

Statement 3: "Since 1981, approximately 50 studies have been done of ETS concentrations in buildings. Using these methods, researchers have found that ETS diffuses rapidly through buildings, persists for long periods after smoking ends, and represents one of the major sources of indoor particle pollution." [The Guide, p. 12] ETS is often the most visible form of indoor air contamination, but is very often not the major source of indoor particle pollution. RECOMMENDATION: This statement should be rewritten in the following way: "The clearance of ETS from indoor air environments is a function of the efficiency of the air handling capacity of the building [8]. In buildings with proper ventilation, ETS is quickly and efficiently removed." Assessing Exposure: Biomarker studies This entire section suffers from both a biased treatment as well as an oversimplification of the use of cotinine as a biomarker for ETS exposure. Since the alleged relationship between E'I'S exposure and adverse health effects is controversial, exposure to ETS should be estimated as accurately as scientific methods permit. A major criticism of health-related studies of ETS has been the lack of valid methods to quantify ETS exposure [9]. The use of questionnaires to assess exposure has serious deficiencies, thus scientists recommend that 5

objective, quantitative measures of ETS exposure (biomarkers) should be used. The function of a biological marker is to provide a benchmark to assess whether exposure to a specific chemical or mixture of chemicals has occurred, and whether that exposure will lead to a biological effect. Cotinine has been used as a biomarker of exposure only; its concentration in the body has no relationship to biological injury or disease. At best, biomarkers of exposure can provide an estimate of the amount of material to which a person was exposed. However, if the material to which a person is exposed is a complex mixture such as ETS, then measurement of a single constituent may be irrelevant to estimating exposure to the complex mixture or to other constituents contained in the mixture. Quantitation of an isolated chemical species is useful only if that species is proven to parallel the behavior of other ETS constituents in the air or body. RECOMMENDATION: Paragraph I of this section should read: "Some of the constituents found in tobacco smoke can be found in the body fluids of people who have been exposed to smoke, indicating that they may have been exposed to ETS. Scientists use these chemicals as biomarkers, which provide a benchmark or surrogate for assessing exposure to ETS. They are not direct measures of the actual exposure of an individual to ETS." 6

Biomarker studies "Since it (cotinine) is totally unique to tobacco, it is a reliable indicator of ETS exposure." [The Guide, p. 13] As pointed out previously, cotinine can only reliably indicate exposure to nicotine, not ETS! In addition, the statement that the presence of nicotine and/or its metabolite cotinine (or any other metabolite of cotinine for that matter) in biological fluids is "totally unique to tobacco" is on t true. Sheen [10] and Castro and Monji [11] demonstrated that nicotine is present in solanaceous vegetables such as potato, egg plant, tomato, and green pepper which are commonly consumed by nonsmokers. Sheen also detected nicotine in several tea samples. The statement on p. 13 that "Cotinine has also been measured in the urine of people who were unaware they had been exposed" is entirely consistent with uptake of nicotine from the diet. These people were unaware that they were exposed to ETS because it is likely that they were not exposed to ETS, but rather generated the metabolite cotinine from nicotine in their diet. T'his explanation would easily explain why "in several British studies, nearly all nonsmokers had measurable cotinine levels, regardless of reported exposure." If nonsmokers can be exposed to nicotine in the diet, then the conclusion that "positive cotinine concentrations in three out of four nonsmokers, including persons reporting no exposure to tobacco smoke in the measuring period, demonstrate the ubiquity of ETS exposure in nonsmokers" is a fallacious conclusion. 7

In addition to the fact that the nicotine (and consequently its metabolite, cotinine) found in body fluids is not uniquely attributable to tobacco smoke, there is the complication that urinary cotinine measurement is subject to sizable error. The study by Cummings et aL [13], cited by the EPA (ref 37 in EPA policy guide) to conclude that ETS exposure is ubiquitous, suffers from serious methodological problems. Cummings et aL [13] used the Machacek and Jiang [14] HPLC method to screen urine of 663 never- and ex-smokers for nicotine and cotinine. However, the mean urinary cotinine concentrations were unusually high (9.5 ng/ml) for people who claimed no exposure to ETS. One explanation for these high concentrations of cotinine may be interference of caffeine with the cotinine determination in this HPLC method. Thuan et aL [15] found that caffeine, which eluted between cotinine and the phenylimidazole internal standard, interfered with the cotinine determinations. A better estimate of nonsmoker exposure to environmental nicotine is found in a study by Matsunga et aL [3] where nicotine and cotinine were determined by gas chromatography. In this report the mean urinary cotinine concentration was 0.4 ± 0.2 ng/ml in nonsmokers and 3.5 ± 2.1 ng/ml in nonsmokers with confirmed exposure to ETS. 8

REFERENCES 1) Jusko, W.J. (1978). Role of tobacco smoking in pharmacokinetics. J. Pharmacokin. Biopharm. 6: 7-39. 2) Eldon, MA, Luecker, P.W., MacGee, J., and Ritschel, WA (1987). The effect of acute withdrawal from cigarette smoking on indocyanine green and antipyrene clearance. J. Clin. Pharmacol. 27: 226-232. 3) Matsunga, S.K., Plezia, P.M., Karol, M.D., Katz, M.D., Camilli, A.E., and Benowitz, N.L (1989). Effects of passive smoking on theophylline clearance. Clin. Pharmacol. Ther. 46: 399-407. 4) U. S. Surgeon General. (1986). pp. 141-2, 146, 186, 229. 5) Ames, B.N. (1989). Mutagenesis and Carcinogenesis: Endogenous and Exogenous Factors. Environ. Mol. Mutagenesis 14, (Suppl.) 16: 66-77. 6) Jarvis, M.J. and Russell, MAH. (1984). Measurement and estimation of smoke dosage to nonsmokers from environmental tobacco smoke. Eur. J. Respirat. Dis. (Suppl.) 133: 68-75. 9