2
The Physicochemical Nature of Sidestream Smoke and Environmental Tobacco Smoke

INTRODUCTION

Mainstream smoke (MS) is the aerosol drawn into the mouth of a smoker from a cigarette, cigar, or pipe. Sidestream smoke (SS) is the aerosol emitted in the surrounding air from a smoldering tobacco product between puff-drawing. SS is a major source of environmental tobacco smoke (ETS), i.e., air pollution caused by the burning of tobacco products. Other contributors to ETS are the exhaled portion of MS and the smoke that escapes from the burning part of a tobacco product during puff-drawing. In addition, some volatile components (e.g., carbon monoxide) diffuse through cigarette paper and contribute to ETS.

Tobacco smoke aerosols are diluted with air by the time they are inhaled as ETS air pollutants. Furthermore, the physical characteristics and chemical composition of ETS change as the pollutants “age”: nicotine is volatilized; particle sizes decrease; nitrogen oxide gradually oxidizes to nitrogen dioxide; various components of the ambient air (e.g., radon daughters) can be adsorbed on the particles; and other physicochemical changes can occur.

In the scientific literature, the terms “passive smoke,” “passive smoking,” and “involuntary smoking” are used often. These terms do not adequately describe ETS and its inhalation, but they are used interchangeably with “ETS” in this report.

Most of the reported data on MS, SS, and ETS pertain to cigarette smoking. Few comparative data on smoke pollutants from other tobacco products are available.



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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects 2 The Physicochemical Nature of Sidestream Smoke and Environmental Tobacco Smoke INTRODUCTION Mainstream smoke (MS) is the aerosol drawn into the mouth of a smoker from a cigarette, cigar, or pipe. Sidestream smoke (SS) is the aerosol emitted in the surrounding air from a smoldering tobacco product between puff-drawing. SS is a major source of environmental tobacco smoke (ETS), i.e., air pollution caused by the burning of tobacco products. Other contributors to ETS are the exhaled portion of MS and the smoke that escapes from the burning part of a tobacco product during puff-drawing. In addition, some volatile components (e.g., carbon monoxide) diffuse through cigarette paper and contribute to ETS. Tobacco smoke aerosols are diluted with air by the time they are inhaled as ETS air pollutants. Furthermore, the physical characteristics and chemical composition of ETS change as the pollutants “age”: nicotine is volatilized; particle sizes decrease; nitrogen oxide gradually oxidizes to nitrogen dioxide; various components of the ambient air (e.g., radon daughters) can be adsorbed on the particles; and other physicochemical changes can occur. In the scientific literature, the terms “passive smoke,” “passive smoking,” and “involuntary smoking” are used often. These terms do not adequately describe ETS and its inhalation, but they are used interchangeably with “ETS” in this report. Most of the reported data on MS, SS, and ETS pertain to cigarette smoking. Few comparative data on smoke pollutants from other tobacco products are available.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects In the laboratory, cigarettes, cigars, and pipes are smoked by machines under standardized conditions (Wynder and Hoffmann, 1967) to obtain reproducible data for the determination of various individual constituents of undiluted MS and SS. Such data provide a scientific basis for comparing tobacco products and brands. The standardized machine-smoking conditions were developed 3 decades ago to simulate human smoking behavior (Wartman et al., 1959). However, these can differ substantially from those of today’s cigarette smokers, especially in the case of filter-tipped products that are designed to deliver low yields of tar and nicotine (Herning et al., 1981). For cigarettes and cigarette-like cigars weighing up to 1.5 g, the most widely used machine-smoking conditions in the test laboratory are as follows: one 35-ml puff lasting 2 seconds taken once a minute. The butt length for nonfilter cigarettes is 23 mm. For filter-tipped cigarettes, the total length is increased 3 mm for filter tip plus overwrap (Pillsbury et al., 1969; Brunnemann et al., 1976). For cigars, the conditions are as follows: a 30-ml puff taken once every 40 seconds and a butt length of 33 mm (International Committee for Cigar Smoke Study, 1974). For pipe smoking the test calls for a bowl filled with 1 g of tobacco and for a 50-ml puff lasting 2 seconds to be taken every 12 seconds (Miller, 1964). Several devices have been used for generating SS from cigarettes and cigars (Dube and Greene, 1982). Among them, the Neurath and Ehmke chamber or modification thereof have been used for chemical analytic work on SS (Neurath and Ehmke, 1964; Brunnemann and Hoffmann, 1974). When SS is generated, a stream of air is sent through a chamber at 25 ml/second. At this rate, the tar and nicotine yields in the MS of cigarettes and cigars smoked in the chamber are similar to those obtained by smoking cigarettes or cigars in the open air. However, the velocity of the airstream through the chamber has considerable influence on the yields of individual compounds in SS (Rühl et al., 1980; Klus and Kuhn, 1982). In order to collect the particulate matter of MS and SS, the aerosols are directed through a glass-fiber filter that traps more than 99% of all the particles with diameters of 0.1 µm or more (Wartman et al., 1959). The portion of the smoke that passes through the filter is designated as the vapor phase. This arbitrary separation into particulate phase and vapor phase does not necessarily reflect the physicochemical conditions prevailing in MS and

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects SS. However, it does reflect specific trapping systems and analytic methods that have been developed for the standardized determination of individual components or groups of components in MS or SS (Brunnemann and Hoffmann, 1982; Dube and Greene, 1982). Standardized machine-smoking conditions do not exactly duplicate the smoking patterns of an individual, which depend on many factors. For example, low nicotine delivery in cigarette smoke generally induces a smoker to puff more frequently (up to 5 puffs/minute), to draw larger volumes (up to 55 ml/puff), and to inhale more deeply. Puffing more frequently increases the amount of tobacco consumed during generation of MS and thus diminishes the amount of tobacco burned between puffs. This, in turn, affects the release of combustion products in SS, so an increase in puff frequency diminishes the production of SS and ETS. Also, smoking behavior appears to depend strongly on the blood concentration of nicotine that the smoker desires to reach (Krasnegor, 1979; Grabowski and Bell, 1983). The smoker, because of proximity to the source, usually inhales more of the SS and ETS originating from the burning of the tobacco product than a nonsmoker; however, we do not know the exact amount and we do not know the degree to which inhaled SS and ETS aerosols are retained in the smoker’s respiratory tract. Model studies with MS have shown that more than 90% of some hydrophilic volatile components (e.g., acetaldehyde) is retained after inhalation by the smoker (Dalham et al., 1968a). Therefore, one may assume that a large proportion of the hydrophilic agents in the vapor phase of SS and ETS is also retained when smoke-polluted ambient air is inhaled. In the case of hydrophobic components of the vapor phase of MS (e.g., carbon monoxide), the retained fraction depends on the depth of inhalation, but it hardly ever exceeds 50% (Dalham et al., 1968b). An active smoker generally retains 90% or more of MS particles (Dalham et al., 1968b; Hiller, 1984), whereas a nonsmoker exposed to ETS appears to retain a smaller percentage of ETS particles. It has been calculated that, depending on the degree of SS pollution, a nonsmoker exposed to ETS can retain 0.014 to 1.6 mg of particles per day from ETS (Hiller, 1984).

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects SIDESTREAM SMOKE The SS generated between puffs originates from a strongly reducing atmosphere. Therefore, undiluted SS contains more combustion products that result from oxygen deficiency and thermal cracking of molecules than does MS. In addition, SS formation involves generation of higher amounts of compounds from nitrosation reactions. Consequently, SS differs substantially from MS. Table 2–1 compares MS and SS from nonfilter cigarettes. During the consumption of one whole cigarette under standard smoking conditions, the formation of cigarette MS generated during 10 puffs (each 2 seconds) of a blended nonfilter cigarette requires 20 s and consumes 347 mg of tobacco. The formation of SS from the same cigarette smoldering requires 550 seconds and consumes 411 mg of tobacco. However, as shown with experimental cigarettes, the amounts of tobacco consumed during and between puffs depend greatly on the type of tobacco (Johnson et al., 1973a). In addition, MS and SS are generated at different temperatures. For example, under laminar atmospheric conditions, the SS of a smoldering cigarette enters the surrounding atmosphere about 3 mm in front of the paper burn line, at about 350°C (Baker, 1984). The pH of the MS of a blended American cigarette ranges from 6.0 to 6.5, whereas the pH of SS is 6.7 to 7.5. Above a pH of 6.0, the proportion of unprotonated nicotine in undiluted smoke increases; therefore, SS contains more free nicotine in the gas phase than MS. The pH of SS of cigars is 7.5 to 8.7; pH values for pipe smoke have not been reported (Brunnemann and Hoffmann, 1974). Under conditions prevailing in MS, SS, and ETS, unprotonated nicotine is primarily present in the vapor phase; its absorption through the mucous membranes is faster; thus, its pharmacologic effect is different from that of unprotonated nicotine in the particulate matter (Armitage and Turner, 1970). About 300–400 of the more than 3,800 compounds identified in tobacco smoke have been measured in MS and SS. Table 2–2 lists the amounts of selected substances reported to occur in the MS and in SS from the burning of a whole nonfilter cigarette and the range of the ratio of their amounts in SS/MS. A ratio greater than unity means that more of a substance is released in SS than in MS. The separation of the compounds in Table 2–2 into vapor phase and particulate phase constituents reflects the conditions

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects TABLE 2–1 Some Physiocochemical Characteristics of Fresh, Undiluted Mainstream and Sidestream Smoke from a Nonfilter Cigarettea Characteristics MS SS Reference Duration of smoke production, s 20 550 Neurath and Horstmann, 1973 Tobacco burned, mg 347 411 Neurath and Horstmann, 1973 Peak temperature during formation, °C 900 600 Wynder and Hoffmann, 1967 pH 6.0–6.2 6.4–6.6 Brunnemann and Hoffmann, 1974 Number of particles per cigarette 10.5×1012 3.5×1012 Scassellatti-Sforzoline and Savino, 1968 Particle size, µm 0.1–1.0 0.01–0.8 Carter and Hasegawa, 1975; Hiller et al., 1982 Particle mean diameter, µm 0.4 0.32 Carter and Hasegawa, 1975; Hiller et al., 1982 Gas concentration, vol.%   Carbon monoxide 3–5 2–3 Keith and Derrick, 1960 Carbon dioxide 8–11 4–6 Wynder and Hoffmann, 1967 Oxygen 12–16 1.5–2 Baker, 1984 Hydrogen 3–15 0.8–1.0 Hoffmann et al., 1984a,b aData were obtained under standard laboratory smoking conditions of one puff per minute, lasting 2 s, and having volume of 35 ml. Mainstream smoke collected directly from end of cigarette. Sidestream smoke was measured 4 mm from burning cone (gas temperature, 350°C). prevailing in MS and does not apply to the distribution of these compounds in the vapor phase and particulate phase of SS. The ratio of the amount of tobacco burned during SS generation to that burned during MS generation is 1.2:1 to 1.5:1 (see Table 2–1 for data on nonfilter cigarettes). Therefore, if one assumed that the combustion process is the same during the generation of the two kinds of smoke, the ratios of their various constituents would also be between 1.2:1 and 1.5:1. That is not the case, as indicated by the higher SS/MS values in Table 2–2. For instance, in the first part of Table 2–2, which lists volatile compounds, the ratios for carbon monoxide range from 2.5 to 4.7, for carbon dioxide from 8 to 11, for acrolein from 8 to 15, and for benzene about 10.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects TABLE 2–2 Distribution of Constituents in Fresh, Undiluted Mainstream Smoke and Diluted Sidestream Smoke from Nonfilter Cigarettesa Constituent Amount in MS Range in SS/MS Vapor phaseb   Carbon monoxide 10–23 mg 2.5–4.7 Carbon dioxide 20–40 mg 8–11 Carbonyl sulfide 18–42 µg 0.03–0.13 Benzenec 12–48 µg 5–10 Toluene 100–200 µg 5.6–8.3 Formaldehyde 70–100 µg Acrolein 60–100 µg 8–15 Acetone 100–250 µg 2–5 Pyridine 16–40 µg 6.5–20 3-Methylpyridine 12–36 µg 3–13 3-Vinylpyridine 11–30 µg 20–40 Hydrogen cyanide 400–500 µg 0.1–0.25 Hydrazined 32 ng 3 Ammonia 50–130 µg 40–170 Methylamine 11.5–28.7 µg 4.2–6.4 Dimethylamine 7.8–10 µg 3.7–5.1 Nitrogen oxides 100–600 µg 4–10 N-Nitrosodimethylaminee 10–40 ng 20–100 N-Nitrosodiethylaminee ND-25 ng <40 N-Nitrosopyrrolidinee 6–30 ng 6–30 Formic acid 210–490 µg 1.4–1.6 Acetic acid 330–810 µg 1.9–3.6 Methyl chloride 150–600 µg 1.7–3.3 Particulate phaseb     Particulate matterc 15–40 mg 1.3–1.9 Nicotine 1–2.5 mg 2.6–3.3 Anatabine 2–20 µg <0.1–0.5 Phenol 60–140 µg 1.6–3.0 Catechol 100–360 µg 0.6–0.9 Hydroquinone 110–300 µg 0.7–0.9 Aniline 360 ng 30 2-Toluidine 160 ng 19 2-Naphthylaminec 1.7 ng 30 4-Aminobiphenylc 4.6 ng 31 Benz[a]anthracenee 20–70 ng 2–4 Benzo[a]pyrened 20–40 ng 2.5–3.5 Cholesterol 22 µg 0.9 γ-Butyrolactonee 10–22 µg 3.6–5.0 Quinoline 0.5–2 µg 8–11 Harmanf 1.7–3.1 µg 0.7–1.7 N′-Nitrosonornicotinee 200–3,000 ng 0.5–3 NNKg 100–1,000 ng 1–4 N-Nitrosodiethanolaminee 20–70 ng 1.2

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Constituent Amount in MS Range of SS/MS Cadmium 100 ng 7.2 Nickeld 20–80 ng 13–30 Zinc 60 ng 6.7 Polonium-210c 0.04–0.1 pCi 1.0–4.0 Benzoic acid 14–28 µg 0.67–0.95 Lactic acid 63–174 µg 0.5–0.7 Glycolic acid 37–126 µg 0.6–0.95 Succinic acid 1 10–140 µg 0.43–0.62 aData from Elliot and Rowe (1975); Schmeltz et al. (1979); Hoffmann et al. (1983); Klus and Kuhn (1982); Sakuma et al. (1983, 1984a,b); Hiller et al. (1982). Diluted SS is collected with airflow of 25 ml/s, which is passed over the burning cone. bSeparation into vapor and paniculate phases reflects conditions prevailing in MS and does not necessarily imply same separation in SS. cHuman carcinogen (U.S. Department of Health and Human Services, 1983). dSuspected human carcinogen (U.S. Department of Health and Human Services, 1983). eAnimal carcinogen (Vainio et al., 1985). fl-methyl-9H-pyrido[3,4-b]-indole. gNNK=4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. The high SS/MS values of carbon monoxide and carbon dioxide show that more of each of these constituents is generated in the oxygen-deficient cone during smoldering than during puff-drawing. After passing briefly through the hot cone, most of the carbon monoxide is oxidized to carbon dioxide, probably because of the high temperature gradient and sudden exposure to air. The high SS/MS values of volatile pyridines are thought to be due to the fact that these compounds are formed from the alkaloids during smoldering (Schmeltz et al., 1979). Hydrogen cyanide is formed primarily from protein at temperatures above 700°C (Johnson and Karg, 1971). Thus, smoldering of tobacco at 600°C does not favor the pyrosynthesis of hydrogen cyanide to the extent that it occurs during MS generation. With regard to the carcinogenic potential of SS, it is important to consider the SS/MS ratio of NOx—4 to 10. More than 95% of the NOx inhaled by the smoker is in the form of nitric oxide, and only a small portion is oxidized to the powerful nitrosating agent, nitrogen dioxide. Only a small fraction of nitric oxide is expected to be retained in the respiratory system by being bound to hemoglobin. NOx released into the environment in SS

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects is partially oxidized to nitrogen dioxide (Vilicins and Lephardt, 1975). Thus, environments polluted with SS are expected to contain increased concentrations of the hydrophilic nitrosating agent, nitrogen dioxide. Perhaps the most remarkable data in this portion of Table 2–2 are the very high SS/MS values of ammonia, nitrogen oxide, and the volatile N-nitrosamines. Studies with [15N]nitrate have shown that, during burning of tobacco, nitrate is reduced to ammonia, which is released to a greater extent in SS than in MS during puff-drawing (Just et al., 1972). An extreme example is the case of a cigarette made exclusively from burley tobacco, a variety generally rich in nitrate (2.0–5.0% in U.S. survey); ammonia is released in SS at 8,500 µg/cigarette (SS/MS 170, according to Johnson et al., 1973b). (In the case of a blended cigarette, the greater generation of ammonia in SS causes an increased pH, which can be above 7, whereas the pH of MS is about 6.) The ranges of high SS/MS ratios of the highly carcinogenic volatile N-nitrosamines (such as N-nitrosodimethylamine—20 to 100) have been well established (Brunnemann et al., 1977, 1980; Rühl et al., 1980). The second part of Table 2–2 lists some constituents of particulate matter, their amounts reported to occur in MS during the burning of one cigarette, and ranges of the relative amounts in SS/MS. The increases in SS of tobacco-specific N-nitrosamines, such as 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosodiethanolamine, and N′-nitrosonornicotine, are up to fourfold. Presently we do not know whether the tobacco-specific N-nitrosamines are present in the particulate phase or in the vapor phase of ETS (Hoffmann and Hecht, 1985). Constituents of the vapor phase would be less likely to settle with the smoke particles, but would remain in the ambient air for longer spans of time. Research is needed to evaluate this distribution, which is important with respect to the carcinogenic potential of SS. The meaning of the abundant release of amines in SS (SS/MS, to 30-fold)—as indicated by the data in aniline, 2-toluidine, and the alkaloids—should also be examined. Some amines are readily nitrosated to N-nitrosamines, but analytic data on secondary reactions of amines in polluted environments are lacking.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects TABLE 2–3 Relative Concentrations (SS/MS) of Selected Components in Fresh, Undiluted Smoke of Four 85-mm Commercial American Cigarettesa Constituentc Constituent Concentrations in Smokeb Cigarette A, NF Cigarette B, F Cigarette C, F Cigarette D, PF SS SS/MS SS SS/MS SS SS/MS SS SS/MS Tar, mg/g 22.6 1.1 24.4 1.6 20.0 2.9 14.1 15.6 Nicotine, mg/g 4.6 2.2 4.0 2.7 3.4 4.2 3.0 20.0 CO, mg/g 28.3 2.1 36.6 2.7 33.2 3.5 26.8 14.9 NH3, mg/g 524 7.0 893 46 213.1 6.3 236 5.8 Catechol, µg/g 58.2 1.4 89.8 1.3 69.5 2.6 117 12.9 BaP, ng/g 67 2.6 45.7 2.6 51.7 4.2 448 20.4 NDMA, ng/g 735 23.6 597 139 611 50.4 685 167 NPYR, ng/g 177 2.7 139 13.6 233 7.1 234 17.7 NNN, ng/g 857 0.85 307 0.63 185 0.68 338 5.1 aData from Adams et al. (1985). Tar values for MS: cigarette A, 20.1 mg; cigarette B, 15.6 mg; cigarette C, 6.8 mg; cigarette D, 0.9 mg. bNF=nonfilter cigarette; F=filter cigarette; PF=cigarette with perforated filter tip; BaP=benzo[a]pyrene. cNDMA=N-nitrosodimethylamine; NPYR=N-nitrosopyrrolidine; NNN=N′-nitrosonornicotine. To comprehend the data in Table 2–2 fully, some aspects should be emphasized. First, the data are based on analyses of nonfilter cigarettes that were smoked under standard laboratory conditions. Second, those conditions, established according to smoking patterns observed 3 decades ago, have been shown not to reflect today’s smoking behavior. The difference is especially evident in the case of filter cigarettes designed for low smoke yields. Most consumers inhale the smoke of such cigarettes more intensely than the smoke of nonfilter cigarettes (Hill and Marquardt, 1980; Herning et al., 1981). This difference affects the yield of SS. Conventional cigarette filter tips primarily influence the yield of MS, but have little impact on SS yield. However, highly active filter tips, especially those with perforations, also affect the yield of SS (Adams et al., 1985). It is apparent in Table 2–3 that for all cigarettes studied the SS/MS values are greater than 1 for many toxic and carcinogenic constituents.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects TABLE 2–4 Measured Concentrations of Carbon Monoxide in ETSa Location Tobacco Burned Ventilation Carbon Monoxide Concentrations, ppm References   Nonsmoke Controls Mean Range Mean Range Rooms — — — 4.3–9 2.2±0.98 0.4–4.5 Coburn et al., 1965 Train 1–18 smokers Natural — 0–40 — — Harmsen and Effenberger, 1957 Submarines (66 m3) 157 cigarettes/day 94–103 cigarettes/day Yes Yes <40 <40 — — — — — — Cano et al., 1970 18 military aircraft — Yes <2–5 — — — U.S. Department of Transportation, 1971 8 commercial aircraft — Yes <2 — — — U.S. Department of Transportation, 1971 Rooms — — — 5–25 — — Porthein, 1971 14 public places — — <10 — — — Perry, 1973 Ferry boat — — 18.4±8.7 — 3.0±2.4 — Godin et al., 1972 Theater foyer — — 3.4±0.8 — 1.4±0.8 — Godin et al., 1972 Intercity bus 23 cigarettes 3 cigarettes 15 changes/h 15 changes/h 32 18 — — — — — — Seiff, 1973 2 conference rooms — 8 changes/h — 8 (peak) 1–2 — Slavin and Hertz, 1975 Office — — 236 m3/h Natural — — <2.5–4.6 < 2.9–9.0 — — — — Harke, 1974 — Automobile 2 smokers (4 cigarettes) Natural Mechanical — — 42 (peak) 32 (peak) — — 13.5 (peak) 15.0 (peak) Harke and Peters, 1974 9 night clubs — Varied 13.4 6.5–41.9 — — Sebben et al., 1977 14 restaurants — — 9.9±5.5 — 9.2 (outdoor) 3.0–35 Sebben et al., 1977 45 restaurants — — 8.2±2.2 7.1±1.7 — — Sebben et al., 1977

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects 33 stores — — 10.0±4.2 11.5±6.5 11.5±6.5 — Sebben et al., 1977 3 hospital lobbies — — — 4.8 — — Sebben et al., 1977 6 coffee houses Varied — 2–23 — — — Badre et al., 1978 Room 18 smokers — 50 — — — Badre et al., 1978 Hospital lobby 12–30 smokers — 5 — — — Badre et al., 1978 2 train compartments 2–3 smokers — — 4–5 — — Badre et al., 1978 Automobile 3 smokers 2 smokers Natural, open Natural, closed 14 20 — — — — — — Badre et al., 1978 10 offices — — 2.5±10 1.5–1.0 2.5±1.0 1.5±4.5 Chappell and Parker, 1977 15 restaurants — — 4.0±2.5 1.0–9.5 2.5±1.5 1.0–5.0 Chappell and Parker, 1977 14 night clubs and taverns — — 13.0±7.0 3.0–29.0 3.0±2.0 1.0–5.0 Chappell and Parker, 1977 Tavern — — Artificial None 8.5 — — 35 (peak) — — — — Chappell and Parker, 1977 Office — Natural, open 1.0 10.0 (peak) — — Chappell and Parker, 1977 Restaurant — Mechanical 5.1 2.1–9.9 4.8 (outdoors) — Fischer et al., 1978 Restaurant — Natural 2.6 1.4–3.4 1.5 (outdoors) — Fischer et al., 1978 Bar — Natural, open 4.8 2.4–9.6 1.7 (outdoors) — Weber et al., 1976 Cafeteria — 11 changes/h 1.2 0.7–1.7 0.4 (outdoors) — Weber et al., 1976 44 offices — — 1.1 6.5 (max) — — Weber, 1984 25 offices — — 2.78±1.42 — 2.59±2.33 — Szadkowski et al., 1976 Tavern — 6 changes/h 11.5 10–12 2 (outdoors) — Cuddeback et al., 1976 Tavern — 1–2 changes/h 12.0 3–22 — — Cuddeback et al., 1976 aTime-weighted average (TWA) of carbon monoxide, 50 ppm (55 mg/m3). TWA=average concentration to which worker may be exposed continuously for 8 h without damage to health (National Institute for Occupational Safety and Health, 1971).

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects 3 In Vivo and In Vitro Assays to Assess the Health Effects of Environmental Tobacco Smoke INTRODUCTION Suitable methods for assessing the potential for adverse health effects resulting from exposure to environmental tobacco smoke (ETS) are limited by the complexity of the composition of the mixture. In vivo and in vitro assays are commonly used to establish carcinogenicity and in some cases to extrapolate risks to humans. For complex mixtures such as ETS, these assays may be done on the mixture itself or on individual chemical constituents. Many properties of ETS change as the smoke “ages” after its initial generation. Aging probably affects the bioavailability, as well as physicochemical characteristics, of the smoke. As inhalation is the primary route by which humans are exposed to tobacco smoke, it is obviously the preferred method of administration in animal models for evaluating the toxicological properties of both cigarette smoke and ETS. While extensive inhalation studies have been performed on the toxicological properties of mainstream cigarette smoke (MS), far fewer studies have been performed on sidestream smoke (SS) and ETS. The selection of appropriate animal models requires familiarity with exposure systems, as well as with basic anatomical differences between the model and human respiratory tracts. Methods other than inhalation, such as in vitro assays, have been developed for the evaluation of MS. A few of these methods have been applied to the assessment of the relative toxicological properties of SS versus MS. These methods are frequently criticized because of differences in the way the smoke constituents

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects are presented to the test system as compared with that which occurs in the human situation. Despite these limitations, the use of cigarette smoke condensate (CSC) from MS has provided insight into the relative carcinogenic potential of various constituents in the MS of cigarettes. Similar studies using suitable condensates from SS and aged ETS could provide additional data on the effects of ETS. IN VIVO ASSAYS ON ENVIRONMENTAL TOBACCO SMOKE Exposure Methods in Laboratory Research Several methods are available to evaluate the potential health effects of inhaled pollutants. Some common ones are whole-body exposure, head-only exposure, nose- or mouth-only exposure, lung-only exposure, or partial-lung exposure. Since the primary objective of an inhalation experiment is to determine the effects of the test substances or mixture on the respiratory system, it is preferable to eliminate or limit exposure through the skin or through ingestion (such as through contact with materials deposited on the fur or contaminated food and water). Three methods have been used to determine the amount of material deposited in the respiratory tract (Phalen, 1984): direct measurement, calculations using airborne concentrations and uptake models, and calibration of the exposure apparatus using tracer substances. Direct measurement requires analysis of major components and their metabolites in tissues as well as in urine and feces or measurement of the amounts of material in the inspired and expired air. Aside from calculating dose based upon particle aerodynamic size and physiological data on lung function of experimental animals, tracers can provide reasonable estimates of exposure. Inhalation exposure chambers are used for those studies in which whole-body exposure is desired. The ability to expose a large number of animals at one time and the absence of a need to restrain or anesthetize the animals are among the advantages in using this approach. There are, however, several major disadvantages. The animals are exposed through skin absorption and mouth ingestion and, in prolonged instances, by food and possibly water contamination. Animals tend to avoid exposure in such

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects chambers by huddling together or covering their noses with their own fur. Losses of particulate aerosols to the interior walls of the chambers are also frequently a problem. Head-only exposure systems eliminate many of these problems. The disadvantages of these systems are that the animal must be restrained and is stressed or anesthetized, and there is difficulty in forming an adequate seal. Nose- or mouth-only exposure systems further limit exposure to the oral cavity and the respiratory tract. Masks or the use of catheters in the nose are generally used with larger animals. Lung and partial-lung-only exposure systems such as endotracheal tubes are employed to bypass the upper respiratory tract and to directly expose the lung. Most of these methods require that the animal be anesthetized, which may alter normal respiration. Other disadvantages include disruption of normal airflow by the presence of tubes in the airways and the loss of normal humidification and thermal regulation of the inspired air caused by bypassing the upper respiratory tract. Intratracheal instillation is an alternative to inhalation for evaluating the effects of individual compounds on the respiratory system. While there are several advantages in employing this bioassay technique, it is also known that the distribution of test material to respiratory tissue may differ from that which would be obtained by actual inhalation exposures. Instillation of an aqueous suspension of radiolabeled particles resulted in a less uniform deposition than inhalation (Brain et al., 1976). Animal Models in Inhalation Studies The selection of an appropriate animal model for inhalation studies with potentially toxic agents is compounded by the fact that one of the major functions of the mammalian sensory apparatus is to limit the exposure to toxic agents either by altering breathing or by producing avoidance behavior (Alarie, 1973; Wood, 1978). Also, the selection of animal species and strains for inhalation exposure studies requires thorough evaluation. The use of several (at least three) animal species, several dose levels, and animals that metabolize the suspect toxin in a similar manner to humans is recommended for those studies that attempt to evaluate human hazards (Stuart, 1976). The appropriate animal model should have (1) a similarity to the human respiratory tract with

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects respect to anatomy, physiology, and susceptibility; (2) a life span appropriate for the proposed study; (3) a sensitivity to certain classes of toxic agents; (4) anatomical or physiological properties that could lead to increased precision in empirical measurements; (5) an existing data base; (6) a documented history of appropriate procedures; and (7) an adaptability for generating data that might be used for mathematically modeling the animal system and its responses to airborne particulates. Results of Inhalation Studies Inhalation studies on the carcinogenicity of MS have been performed on a variety of laboratory animals. The early studies with rodents have been previously reviewed (Wynder and Hoffmann, 1967; Mohr and Resnik, 1978). More recent studies verify these findings for several animal species exposed to whole smoke or MS. A few studies have exposed mice to the vapor phase of fresh MS, and one (see below) exposed mice to the vapor phase of flue-cured MS. Because commonly utilized filter systems do not remove many of the vapor-phase constituents, studies contrasting the effects of exposure to whole smoke with the effects of exposure to the gas phase should throw some light on the possible health effects of ETS. Male and female C57Bl mice (100 in each group) were exposed nose only for 12 minutes daily to the gas phase of smoke of cigarettes prepared from flue-cured tobaccos (Harris et al., 1974). The treated mice had lung tumors and emphysema, independent of the tumors, which were not found in control mice. A total of 219 C57Bl and 186 BLH mice were exposed to the gas phase of cigarette MS. The particulate matter was removed by passing the smoke through a Cambridge filter. The animals were exposed to the gas phase of 12 cigarettes for 90 minutes daily over 27 months. The percentages of mice with lung adenomas were 5.5% and 32% in the smoke-exposed C57Bl and BLH mice, as compared with 3.4% and 22% for their respective controls (Otto and Elmenhorst, 1967). Therefore, it appears that there are carcinogenic constituents in the vapor phase of the smoke. Using Snell’s mice, similar studies evaluated the toxicological properties of whole MS and the gas phase of MS. In these studies, the animals were housed in individual chambers during the exposure (Leuchtenberger and Leuchtenberger, 1970). There was

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects a significant difference (p<0.1) in the incidence of pulmonary tumors between the animals exposed to whole smoke and control animals. The difference was greater (p=0.005) for animals exposed to only the gas phase of cigarette smoke as compared with the same controls, so that the rate of tumors among the gas-phase-exposed animals was greater than among the whole-smoke exposed animals. In Vivo Bioassays Other Than Inhalation Alternative methods have been used to assess the relative chronic toxicity of cigarette MS in an attempt to reduce the cost and technical difficulties associated with inhalation experiments. The most common approach has been to use the CSC in bioassay procedures. In preparing the condensate, many of the volatile and semivolatile components are lost. In addition, it is not known how the aging of the CSC may affect chemical composition and biological activity. To date, only one study has examined the carcinogenic potential of the condensate of SS of cigarettes (Wynder and Hoffmann, 1967; International Agency for Research on Cancer, 1986). Cigarette “tar” from the SS of nonfilter cigarettes, which had settled on the funnel covering a multiple-unit smoking machine, was suspended in acetone and applied to mouse skin for 15 months. Fourteen of 30 Swiss-ICR mice developed benign skin tumors, and 3 had carcinomas. In a parallel assay of MS from the same source, a 50% CSC:acetone suspension applied to deliver a comparable dose of CSC to 100 Swiss-ICR female mice led to benign skin tumors in 24 mice and malignant skin tumors in 6. This indicates that the smoke condensate of SS has greater tumorigenicity per equivalent dose on mouse skin than MS “tar” (p<0.05; Wynder and Hoffmann, 1967). IN VITRO ASSAYS ON ENVIRONMENTAL TOBACCO SMOKE Several short-term bioassays have been performed to evaluate the genotoxicity of cigarette MS. These studies have been the subject of two recent reviews (DeMarini, 1981; Obe et al., 1984). While most of them have evaluated the effects of CSC, some have attempted to evaluate either the gas phase or the whole smoke.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects The most commonly employed assay for mutagenic activity employs various strains of Salmonella typhimurium. Whole smoke as well as CSC from four types of tobacco were found to be mutagenic in S. typhimurium TA1538 (Basrur et al., 1977). Recent studies have shown that SS is also mutagenic in a system where the smoke was tested directly on the bacterial plates (Ong et al., 1984). They support extensive assays performed on CSC that indicate that tobacco smoke has significant mutagenic potential and show that the particulate matter of SS is likely to be a significant contributor to the mutagenic activity of indoor air particulate matter (Bos et al., 1983; Lofröth et al., 1983). Thus, similar mutagenic activity for the CSC of SS would be expected. In another study (Lewtas et al., in press), condensate from air polluted with ETS for 10 hours was used in an assay employing S. typhimurium. The average indoor air mutagenicity per cubic meter was significantly correlated with the number of cigarettes smoked. Another in vitro assay measures the number of sister-chromatid exchanges (SCEs) in human lymphocytes. Valadand-Barrieu and Izard (1979) used a solution of the gas phase from cigarette MS. They showed that this solution induced a significant dose-related increase in SCEs. SUMMARY AND RECOMMENDATIONS Sufficient data are not available to assess the relative genotoxicity and toxicity of whole ETS. A few isolated reports have dealt with the genotoxicity of SS and ETS, and the relative toxicity of MS and SS. In order to evaluate ETS, it is suggested that in vitro genotoxicity assays in at least two systems should be done with ETS per se as well as with its particulate matter. These assays under controlled and, subsequently, under field conditions should not be limited to freshly generated ETS, but should also attempt to determine effects of various degrees of air dilution and aging. In a comprehensive analytical approach, data should be generated to determine systematically the concentrations of toxic and tumorigenic agents in various milieus with ETS. At the same time, it may be useful to examine the uptake of tobacco-specific agents as well as the mutagenicity of the urine of nonsmokers exposed to ETS. All of these measures should be considered in the context of detailed exposure histories.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects What Is Known The lungs of various species have different physiological properties, making each of them the experimental species of choice only for certain situations, depending on the objective of the research study. ETS and SS have been shown to be mutagenic in a system where the smoke was tested directly on bacterial plates. The extensive studies of MS can serve as a guideline for the evaluation of ETS. Many of the constituents in the smokes are similar. Despite the limitations of extrapolating from various bioassays to man, the use of CSC from MS has provided insight as to the contribution of various components to the carcinogenic potential of MS from cigarettes. In the only study reported to date using SS condensate, SS condensate was shown to be more carcinogenic than MS condensate. What Scientific Information Is Missing Only a few laboratory methods have been applied toward the assessment of the relative toxicological and genotoxic properties of SS generated from cigarettes and, more importantly, of ETS. Research is needed to clarify the appropriate methods for estimating genotoxicity and to isolate and identify the active agents in body fluids of ETS-exposed nonsmokers. Comparative inhalation studies with MS, SS, and ETS are still needed. Such assays, while not duplicating human exposure patterns, would provide more definitive information about the relative carcinogenic potential of SS in comparison to the MS of the same cigarettes. The aging of the atmosphere in which ETS occurs can have a profound effect on its chemical composition, physical characteristics, and overall biological effects. Therefore, studies of aged ETS are needed. Where exposure histories can be specified clearly, validation and quantitative determination of genotoxic markers for substances in ETS that also occur in the environment would be of value for measuring dose of ETS. In examining the effects of MS, many research workers have used condensates of the smoke painted on the shaved skin of mice.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Similar work with skin painting has not been done with ETS and would be of value for assessing the differential toxicity of ETS and MS. In vitro assays are needed for estimation of the tumor promotion and cocarcinogenic effect of ETS. In vitro tests are quicker than in vivo tests, and enough material can not be collected to do in vivo tests. REFERENCES Alarie, Y. Sensory irritation by airborne chemicals. CRC Crit. Rev. Toxicol. 2:299–363, 1973. Basrur, P.K., S.McClure, and B.Zilkey. A comparison of short term bioassay results with carcinogenicity of experimental cigarettes, pp. 2041–2048. In H.E.Nieburgs, Ed. Prevention and Detection of Cancer, Vol. 1. New York: Marcel Dekker, 1977. Bos, R.P., J.L.G.Theuws, and P.Th.Henderson. Excretion of mutagens in human urine after passive smoking. Cancer Lett. 19:85–90, 1983. Brain, J.D., D.E.Kundson, S.P.Sorokin, and M.A.Davis. Pulmonary distribution of particles given by intratracheal instillation or by aerosol inhalation. Environ. Res. 11:13–33, 1976. DeMarini, D.M. Mutagenicity of fractions of cigarette smoke condensate in Neurospora crassa and Salmonella typhimurium. Mutat. Res. 88:363–374, 1981. Harris, R.J., G.Negroni, S.Ludgate, C.R.Pick, F.C.Chesterman, and B.J.Maidment. The incidence of lung tumours in c5761 mice exposed to cigarette smoke: Air mixtures for prolonged periods. Int. J. Cancer 14:130–136, 1974. International Agency for Research on Cancer (IARC) Monographs: Evaluation of Carcinogenic Risk of Chemicals to Humans, Vol. 38, pp. 163–314. Tobacco Smoking. Lyons: IARC, 1986. 421 pp. Leuchtenberger, C., and R.Leuchtenberger. Effects of chronic inhalation of whole fresh cigarette smoke and of its gas phase on pulmonary tumorigenesis in Snell’s mice, pp. 329–346. In P.Nettesheim, M.G. Hanna, Jr., and J.W.Deatherage, Jr., Eds. Morphology of Experimental Respiratory Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory, Conference, Gatlinburg, Tenn., May 13–16, 1970. Washington, D.C.: U.S. Atomic Energy Commission, 1970. Lewtas, J., S.Goto, K.Williams, J.C.Chuang, B.A.Petersen, and N.K. Wilson. The mutagenecity of indoor air particles in a residential pilot field study. Atmos. Environ., in press. Lofröth, G., L.Nilsson, and I.Alfheim. Passive smoking and urban air pollution: Salmonella/microsome mutagenicity assay of simultaneously collected indoor and outdoor particulate matter, pp. 515–525. In M.D. Waters, S.S.Sandhu, J.Lewtas, L.Claxton, N.Chernoff, and S.Nesnow, Eds. Short-Term Bioassays in the Analysis of Complex Environmental Mixtures. III. New York: Plenum, 1983.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Mohr, U., and G.Resnick. Tobacco carcinogenesis, pp. 263–367. In C.C. Harris, Ed. Pathogenesis and Therapy of Lung Cancer. New York: Marcel Dekker, 1978. Obe, G., W.-D.Heller, and H.-J.Vogt. Mutagenic activity of cigarette smoke, pp. 223–246. In G.Obe, Ed. Mutations in Man. Berlin: Springer-Verlag, 1984. Ong, T., J.Stewart, and W.Z.Whong. A simple in situ mutagenicity test system for detection of mutagenic air pollutants. Mutat. Res. 139:177–181, 1984. Otto, H., and H.Elmenhorst. Experimentelle Untersuchungen zur Tumorinduktion mit der Gasphase des Zigarettenrauchs. Z. Krebsforsch. 70:45–47, 1967. Phalen, R.F. Inhalation Studies: Foundations and Techniques. Boca Raton, Florida: CRC Press, 1984. Stuart, B.O. Selection of animal models for evaluation of inhalation hazards in man, pp. 268–288. In E.F.Aharonsen, S.Ben-David, and M.A. Klingberg, Eds. Air Pollution and the Lung. New York: John Wiley & Sons, 1976. Valadaud-Barrieu, D., and C.Izard. Action de la phase gazeuse de fumée de cigarette sur le taux d’echanges des chromatides-soeurs du lymphocyte humain in vitro. C.R. Acad. Sci. (Paris) 288:899–901, 1979. Wood, R.W. Stimulus properties of inhaled substances. Environ. Health Perspect. 26:69–76, 1978. Wynder, E.L., and D.Hoffmann. Tobacco and Tobacco Smoke: Studies in Experimental Carcinogenesis. New York: Academic Press, 1967. 730 pp.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects II ASSESSING EXPOSURES TO ENVIRONMENTAL TOBACCO SMOKE

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