4
Introduction

Exposure to a variety of air contaminants has been shown to produce adverse health and discomfort responses in humans. In another report from the National Academy of Sciences (NRC, 1985), the methodological issues of studying exposures to air pollutants and subsequent health effects are discussed in detail. This part of the report considers issues relevant to assessing exposure to ETS. Ideally, evidence for health effects in humans should be demonstrated in epidemiologic studies that are consistent with a plausible hypothesis across a range of exposures or doses. However, many epidemiologic studies have substantial uncertainties associated with exposure variables. A framework for assessing exposures to environmental tobacco smoke (ETS) is discussed below. A variety of approaches to current and historic exposures to ETS, such as personal monitoring, locational monitoring, questionnaires, and biologic monitoring, are presented.

Concentrations of air contaminants exhibit pronounced spatial and temporal variations, regardless of the microenvironments in which they are found (outdoors, residential, industrial, etc.). Ideally, identifying the air contaminant or class of contaminants implicated in producing adverse health or comfort effects is essential in designing an air-monitoring program. In practice, however, it is often necessary to monitor a class of contaminants (for instance, total mass of respirable particles) or a proxy contaminant (for instance, nicotine), when the specific air contaminant producing the adverse impact can not be identified or easily measured. The air contaminants associated with ETS are comprised of a



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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects 4 Introduction Exposure to a variety of air contaminants has been shown to produce adverse health and discomfort responses in humans. In another report from the National Academy of Sciences (NRC, 1985), the methodological issues of studying exposures to air pollutants and subsequent health effects are discussed in detail. This part of the report considers issues relevant to assessing exposure to ETS. Ideally, evidence for health effects in humans should be demonstrated in epidemiologic studies that are consistent with a plausible hypothesis across a range of exposures or doses. However, many epidemiologic studies have substantial uncertainties associated with exposure variables. A framework for assessing exposures to environmental tobacco smoke (ETS) is discussed below. A variety of approaches to current and historic exposures to ETS, such as personal monitoring, locational monitoring, questionnaires, and biologic monitoring, are presented. Concentrations of air contaminants exhibit pronounced spatial and temporal variations, regardless of the microenvironments in which they are found (outdoors, residential, industrial, etc.). Ideally, identifying the air contaminant or class of contaminants implicated in producing adverse health or comfort effects is essential in designing an air-monitoring program. In practice, however, it is often necessary to monitor a class of contaminants (for instance, total mass of respirable particles) or a proxy contaminant (for instance, nicotine), when the specific air contaminant producing the adverse impact can not be identified or easily measured. The air contaminants associated with ETS are comprised of a

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects broad range of many vapor- and particle-phase inorganic and organic chemicals noted in Chapter 2, some of which can undergo pronounced physicochemical changes. Assessing impact on human health and comfort requires the identification of proxy air contaminants for ETS that will permit a determination of exposure in a background of contaminants from other sources (see Chapter 5). In epidemiologic studies of air contaminants, it is important to specify exposure to specific particulates or gases on a time scale corresponding to the health or comfort effect sought. The impact of exposure to an air contaminant should, ideally, be evaluated in terms of the biologic dose of the contaminant or its metabolites received by the target tissue. In most cases, this is not practical. The uptake, distribution, metabolism, and site and mode of action of the contaminant in humans is neither well understood nor easily measured. Moreover, dose cannot be directly assessed. Factors affecting the uptake of air contaminants include physical characteristics of the contaminant, as well as physiological characteristics and activity levels of the exposed person (see Chapter 7). In the absence of an ability to measure or specify the dose of a contaminant received, exposures to air contaminant(s) are assessed by either using biological markers, measured in the subject population, or by measuring the air-contaminant concentrations in the physical environment (Figure 4–1). Exposures to airborne contaminants can be assessed by three basic approaches (Figure 4–1): personal air-contaminant monitoring, modeling, based on air sampling, time-activity patterns, and questionnaires, and biological markers. Personal monitoring employs samplers (worn by subjects) that record the integrated concentration individuals are exposed to in the course of their normal activity for time periods of several hours to several days (see Chapter 5). The modeling approach employs the use of stationary monitors to measure the air-contaminant concentrations in a number of microenvironments. These measured concentrations are combined with time activity patterns (time budgets) to determine the average exposure of an individual as the sum of the concentrations in each environment weighed by the time spent in that environment.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects FIGURE 4–1 Flow diagram of components for assessing human exposures to air contaminants from environmental tobacco smoke. Questionnaires are employed in two capacities: (1) to provide information on the physical properties of each environment, including source use parameters, in order to model the concentration of air contaminants in the microenvironment, thus permitting a prediction of air-contaminant concentrations in spaces not monitored; and (2) to provide a simple categorization of exposure levels, such as exposed versus unexposed or none versus low versus high. Questionnaires have been used to categorize subjects’ exposure to ETS in all studies of risk of chronic lung disease reported to date. Chapter 6 discusses the use of questionnaires to categorize ETS exposures. Chapter 7 reviews assumptions required to estimate exposure-dose relationships for ETS and gives an approximation to the dose received under a specific situation.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Chapter 8 examines the use of biological markers, such as urinary cotinine, as indices of exposure to ETS. There are several factors (Figure 4–1) that determine the composition and level of ETS air contaminants in the indoor environments. Determining the range of values for each of these factors will lead to an understanding of their impact on ETS exposures. Efforts to modify or eliminate exposures to ETS must focus on the factors that control the concentrations in the physical environment, since these factors result in the exposure that relates to the adverse health or comfort effect. REFERENCE National Research Council, Committee on the Epidemiology of Air Pollutants. Epidemiology and Air Pollution. Washington, D.C.: National Academy Press, 1985. 224 pp.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects 5 Assessing Exposures to Environmental Tobacco Smoke in the External Environment Environmental tobacco smoke (ETS) is composed of more than 3,800 compounds. The emitted compounds are found in vapor or particulate phases, or in some cases both. Volatile material may evaporate from particles within seconds to minutes after emission (e.g., nicotine, see Chapter 2). ETS has not yet been adequately characterized such that its chemical and physical nature can be clearly defined. The concentration of any individual or group of ETS constituents in an enclosed space is a function of: (a) the generation rate of the contaminant(s) from the tobacco, (b) the source consumption rate, (c) the ventilation or infiltration rate, (d) the concentration of the contaminant(s) of interest in the ventilation or infiltration air, (e) the degree to which the air is mixed, (f) the removal of the contaminant(s) by surfaces or chemical transformations, and (g) the effectiveness of any air-cleaning devices that may be in use. Exposure to ETS takes place in many settings—such as public, industrial, nonindustrial occupational, and residential buildings—and is a function of the time an individual spends in a microenvironment and the concentration of the ETS constituents in that environment. ETS exposures can be determined either by extrapolation from fixed-location monitoring survey instruments that are portable or by direct personal monitoring, using lightweight pumps and filters worn by subjects. This chapter will consider the methodology and data available for assessing human exposures to ETS in the physical (external) environment, including the suitability of proposed tracers or proxy air contaminants that would be representative of ETS, available data on ETS exposure from personal monitoring and monitoring of

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects indoor environments, and the application of modeling to assessing ETS exposures. TRACERS FOR ENVIRONMENTAL TOBACCO SMOKE It is difficult to assess the ETS contribution to exposures because it usually exists in a complex mix of air contaminants from other sources. It is not practical, or possible, to monitor the full range of air contaminants associated with ETS, even under laboratory conditions. Chamber and field studies of ETS have monitored proxy contaminants as indicators of ETS. Most studies to date have been less than ideal because the component that was measured did not meet all the following criteria for an ETS tracer. A marker or tracer for quantifying ETS concentrations should be: unique or nearly unique to the tobacco smoke so that other sources are minor in comparison, a constituent of the tobacco smoke present in sufficient quantity such that concentrations of it can be easily detected in air, even at low smoking rates, similar in emission rates for a variety of tobacco products, and in a fairly consistent ratio to the individual contaminant of interest or category of contaminants of interest (e.g., suspended particulates) under a range of environmental conditions encountered and for a variety of tobacco products. While a variety of measures have been used as proxies or tracers of ETS, no single measure has met all the criteria outlined above, nor has any measure been universally accepted or recognized as representing ETS exposure. Carbon monoxide (CO) has been measured extensively both in chamber studies (Bridge and Corn, 1972; Hoegg, 1972; Penkala and De Oliveira, 1975; Weber et al., 1976, 1979a,b; Weber and Fisher 1980; Weber, 1984; Muramatsu et al., 1983; Leaderer et al., 1984; Winneke et al., 1984; Clausen, et al., 1985) and in occupied public and nonindustrial occupational indoor spaces (see Table 2–4) to represent ETS levels. Under steady-state conditions in chamber studies, where outdoor CO levels are known and the tobacco brands and smoking protocols constant, CO can be a reasonably reproducible indicator of ETS exposure. The variability

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects of CO production from tobacco combustion is not well known and may vary considerably as a function of a number of variables (puff volume, puff duration, temperature, etc.). The ratio of CO, a nonreactive contaminant, to the more reactive gas-phase contaminants in ETS and to reactive suspended particulate mass is not well established, particularly in the dynamic phase of smoking, that is, the non-steady-state phase. Chamber and field studies have indicated that, under realistic smoking conditions that would be encountered in residences or offices, the typical smoking and ventilation rates would produce CO levels well within the levels observed in the outdoor air or in the indoor air generated from the indoor sources, such as kerosene heater, gas stove, etc. Consequently, it is difficult to factor out the contribution of CO from ETS in any specific, uncontrolled situation. In areas where heavy smoking is experienced, and where other sources of CO do not exist, CO may provide a rough measure of ETS exposure because the CO produced by the tobacco combustion will dominate. Both chamber and field studies (Table 5–1) have demonstrated that tobacco combustion has a major impact on the mass of suspended particulate matter in occupied spaces in the size range <2.5 µm, defined in this report as respirable suspended particulates (RSP). Suspended particulate mass is a major component of environmentally emitted tobacco smoke. Even under conditions of low smoking rates, easily measurable increases in RSP have been recorded above background levels (Table 5–1). The term RSP, however, encompasses a broad range of particulates of varying chemical composition and size emanating from a number of sources (outdoors, cooking indoors, etc). Smoking is not the only source of particulate matter suspended in the indoor air. The apportionment of the measured RSP to tobacco combustion in an occupied space will not be accurate unless the RSP emission rates for a variety of brands of tobacco are similar under a variety of conditions and source use information is obtained. The variability of RSP emissions into the environment for a variety of brands of tobacco needs to be investigated, as does the relationship between the vapor and particulate phases of tobacco-combustion emissions under a variety of environmental conditions, such as different humidities, and under a variety of smoking conditions, such as subject smokers versus smoking machines.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects TABLE 5–1 Particulate Levels Measured in Indoor Environments, Including Smoking and Nonsmoking Occupancy Study Type of Premise Occupancy Volume, m3 Ventilation Type/Rate Monitoring Type/Time Concentrations Mean (range), µg/m3 Comments Brunekreef and Boleij, 1982 4 residences NS — N/— G/2 mo 55 (20–90) TSP, repeat measures 0.2 mg 7 residences S=1 — N/— G/2 mo 125 (60–250) TSP sensitivity 14 residences S=2 — N/— G/2 mo 152 (60–340) TSP sensitivity 1 residence S=3 — N/— G/2 mo 335 (—) TSP sensitivity Outdoors — — — G/2 mo —(41–73)   Cuddeback et al., 1976 2 taverns S=5–40 NS=5–260 T=10–300 — N,M/1–6 ach G/9 h 446 (233–986) TSP ventilation estimated Elliot and Rowe, 1975 3 arenas NS — — G/24 h 55 (42–92) TSP 3 arenas S T=2,000–14,277 — M/— G/0.3 h 350 (148–620) TSP First, 1984 1 school NS — M/— P/— 20 (—) TSP   8 public buildings S — N,M/— P/— 260 (40–660) TSP Hawthorne et al., 1984 11 residences NS 150–674 M/0.18–0.96 QCMI/5–15 min (over 6 h) 9–40 (—) RSP, winter/summer—no sources 8 residences NS 150–674 M/0.26–1.98 QCMI/5–15 min (over 6 h) 12–46 RSP, winter/summer—sourcese 2 residences S 150–674 M/0.27–1.47 QCMI/5–15 min (over 6 h) 96–106 RSP, winter/summer—sourcese+cig. Leaderer et al., personal communication 3 public buildings NS 163–1,326 M/0.37–5.6d G/4–21 h 17.8 (9.1–32.2) TSP, repeat measures, all var. 7 public buildings 1.7–4.57b T=2–6 168–600 M/0.77–7.53d G/2–24 h 205.1 (58–452) Measured (160.0 peak)

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Moschandreas et al., 1981 Outdoors — — — G/24 h 17.0 (—) RSP, TSP also measured 2 offices — — — G/24 h 16.8–20.2 (53 peak) RSP, TSP also measured 5 residences NS T=2–6 — N/0.5–1.3 ach G/24 h 19.4–4.01 (118.9 peak) RSP, TSP also measured 5 residences S — N/0.5–1.3 ach G/24 h 36.9–99.9 RSP, TSP also measured Nitschke et al., 1985 Outdoors — — — G/168 h 11.3±6.0 (1–28) RSP 19 residences NS 315–1,021 N/— G/168 h 26.0±22.6 (6–88) RSP, repeat measures, source mixe 11 residences S 290–800 N/— G/168 h 59.2±38.8 (10–144) RSP, repeat measures, source mixe Parker et al., 1984 1 residence NS T=3 — N/0.2–1.9 ach 0/24 h <10 (—) TSP 2 residences S=1–2 T=3–4 — N/0.2–0.7 ach 0/24 h 10–46 (—) TSP Repace and Lowrey, 1980, 1982 Outdoors — — — P/2 min 42.9 (22–63) RSP, average of 2-min samples 27 Public buildings 0.13–3.54f — M/— P/2 min 278 (86–1,140) RSP, average of 2-min samples Sexton et al., 1984 Outdoors 19 homes — — — G/24 h 17.0±1.6 (6–23) RSP, repeat samples 24 residences NSc — N/— G/24 h 25.0±1.0 (13–63) Used fireplaces Spengler et al., 1981 Outdoors — — — G/24 h 21.1±11.9 (—) RSP, repeat measures 35 residences NS — N/— G/24 h 24.1±11.6 (—) RSP, repeat measures 15 residences S=1 — N/— G/24 h 36.5±14.5 (—) RSP, repeat measures 5 residences S=2 — N/— G/24 h 70.4±42.9 (—) RSP, repeat measures Spengler et al., 1985 Outdoors — — N/— G/24 h 18±2.1 (—) RSP, repeat measures 73 residences NS — — G/24 h 28±1.1 (—) RSP, repeat measures 28 residences S — — G/24 h 74±6.6 (—) RSP, repeat measures Sterling and Sterling, 1983 1 office S restr. — — G (?)/— 25.5 (15–36) TSP 22 offices S — — G (?)/— 31.7 (—) TSP

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Study Type of Premise Occupancy Volume, m3 Ventilation Type/Rate Monitoring Type/Time Concentrations Mean (range), µg/m3 Comments U.S. Department of Transportation, 1971 8 domestic planes S T=27–110 — M/— G/1–1/4, 2–1/2 h Not given (—) TSP 20 military planes S T=165–219 — M/— G/6–7 h <10–120 (—) TSP Weber and Fischer, 1980 44 offices S — N,M/— P/2 min (30 ea) 133±130 (962 peak) RSP, minus background level aActive smokers per 100 m3. bGrams of tobacco consumed. cSome smoking was reported during 9 of the 280 samples. dMeasured during 24-h periods by the perfluorocarbon tracer technique. eSome residences had combinations of sources (kerosene heaters, wood stoves, etc.) and no cigarettes. fActive smokers density per 100 m3. ABBREVIATIONS: ach=Air changes per hour G=Gravimetric M=Mechanical ventilation N=Natural ventilation NS=No smokers O=Optical monitor P=Piezoelectric balance QCMI=Quality Crystal Microbalance Cosade Impactor RSP=Respirable suspended particles S=Smokers T=Total occupants TSP=Total suspended particles restr.=building with smoking restrictions

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Nicotine exhibits many of the properties necessary to serve as a potential marker for ETS. It is unique to tobacco smoke, is a major constituent of the smoke, and occurs in environmental concentrations that are easily measurable. It has been used as a marker for ETS in several studies (Table 2–5). The major problems with using nicotine are: (a) the ratio of nicotine [recently found to be in vapor phase in ETS (Eudy et al, 1985)] to other ETS constituents (RSP, in particular) for a variety of brands of tobacco is not known, (b) the reactivity rate (removal rate) of nicotine relative to other ETS constituents is not known, (c) particulate-or vapor-phase nicotine once deposited on surfaces may be re-emitted, and (d) until recently sampling methods for nicotine have not been efficient in collecting total nicotine (both vapor and particulate phase). Two new air-sampling methods for nicotine (Muramatsu et al., 1984; Hammond et al., in press) hold promise for obtaining total nicotine concentrations with the sensitivity and accuracy required for environmental air monitoring. A number of aromatic hydrocarbons (benzene, toluene, benzo[a]pyrene, pyrene, etc.) have been measured in field studies (Galuskinova, 1964; Just et al., 1972; Perry, 1973; Elliot and Rowe, 1975; Badre et al., 1978) investigating the impact of smoking on indoor air quality. Many of these air contaminants have other important sources, indoors and outdoors, that make measured levels difficult to interpret. Therefore, the aromatic hydrocarbons generally are poor indicators of ETS alone. Controlled chamber studies that elevate the variability of emission of the compounds from a variety of brands of tobacco have not been carried out, and the ratios of these compounds to categories of ETS contaminants (for instance, RSP) have not been established. Tobacco-specific nitrosamines and nitrogen oxides (Tables 2–6 and 2–9), acrolein and acetone (Tables 2–7 and 2–8), and polonium-210 have been measured as indicators of ETS. The low environmental concentrations, existence of other sources, reactivity of the tracer contaminants, and lack of data on the ratios of these contaminants to ETS contaminants for a variety of brands of tobacco limit their usefulness as indicators of ETS in indoor spaces. Research efforts need to be directed toward identifying a tracer or proxy air contaminant for ETS that meets the four criteria outlined above. At present, RSP is widely used as a general measure of ETS exposure indoors, particularly if the measurements are limited to locations where the levels of RSP from other sources

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects will also furnish reliable data on such adducts in the blood of passive smokers. FUTURE NEEDS At present, the best method for quantifying human exposure to ETS is the assay of nicotine and cotinine in urine and possibly saliva. Nicotine and cotinine can also be determined in serum samples, but these samples require invasive techniques. In smoke-polluted environments, nicotine is present in the vapor phase as a free base, thus its uptake by the passive smoker may not be representative of the uptake of acidic and neutral smoke components from the vapor phase nor of any component in the particulate phase. Thus, future studies should be concerned with developing techniques to measure the uptake by the nonsmoker of various other types of tobacco-specific ETS components. This may include assays for the vapor-phase 3-vinylpyridine or flavor components that are indigenous to tobacco. Particulate-phase agents to be traced could include solanesol, tobacco-specific nitrosamines, and polyphenols such as chlorogenic acid or rutin. These components are likely to be found only in trace amounts in ETS, and, thus, only minute quantities would be found in the circulating blood of passive smokers, making the development of assays difficult. The development of new trace methods for quantifying the levels of some tobacco-specific materials in nonsmokers may require the identification of adducts formed between the ETS components and the proteins in blood. This approach would require the development of highly sensitive methods such as immunoassays (e.g., RIA, ELISA) or postlabelling with radioisotopes or other markers. The epidemiological studies on the effects of exposure to ETS by nonsmokers have to consider a number of non-ETS-related factors. This fact underlines the urgent need for the development of highly sensitive dosimetric methods for ETS-specific carcinogens that can be applied in field studies. SUMMARY AND RECOMMENDATIONS Passive smokers are exposed to trace amounts of toxic agents including tumor initiators, tumor promoters, carcinogens, and organ-specific carcinogens when inhaling ETS. The determination of thiocyanate, nicotine, and cotinine in body fluids such as saliva,

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects serum, and urine, as well as quantitication of CO in alveolar air and COHb in blood, has been useful for the assessment of the habits of individuals and groups of smokers of cigarettes, cigars, and pipes. Currently, for measuring the exposure to ETS by nonsmokers, nicotine and cotinine appear useful. In acute exposure studies, COHb can be a useful marker. Nicotine and cotinine, however, may not be directly related to the carcinogenic potential of the smoke. Indicators that are related to the carcinogenic risk are needed. To assess the risks involved in the exposure to carcinogenic agents from ETS, sensitive dosimetry methods for tobacco-specific compounds are urgently needed. During the last decade, immunoassays and postlabelling methods have been developed for tracing toxic and carcinogenic agents in circulating blood. These methodologies should be used for the development of dosimetry studies in nonsmokers exposed to ETS. Protein and DNA adducts may provide exposure measures that could be effectively used in epidemiologic studies. What Is Known Determinations of thiocyanate, nicotine, and cotinine in saliva, serum, and urine, as well as quantification of CO in alveolar air and carboxyhemoglobin in blood, have been shown to be useful parameters for the assessment of the habits of individuals and groups of active smokers of cigarettes, cigars, and pipes. However, in general, only nicotine and its metabolite cotinine have proven useful for measuring the exposure to ETS of nonsmokers. Assessment of average daily exposure on the basis of cotinine levels in saliva and urine is independent of the restrictions posed by variations of the half-life of nicotine in smokers and nonsmokers. The determination in urine of the amount of cotinine per milligram of creatinine should provide a more stable measure of recent environmental exposure to nicotine from ETS than cotinine without reference to creatinine, particularly when limited volumes of urine are available. It is likely that the exposure of nonsmokers to ETS increases the mutagenic activity of their urine over the activity observed in urine of the same nonsmokers when not exposed to ETS.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects What Scientific Information Is Missing The question of urinary hydroxyproline excretion in nonsmokers exposed to ETS is not settled. A study on the urinary excretion of aromatic amines in nonsmokers exposed to ETS is needed in order to correlate the total amounts of individual amines and their metabolites in the urine of nonsmokers exposed to ETS. Where exposure histories can be specified clearly, validation of the use of adduct assays to determine and quantify uptake of tobacco smoke carcinogens is needed. Information is needed on certain tobacco-specific constituents and their fate in the ETS-exposed nonsmoker, including solanesol, tobacco-specific nitrosamines, and polyphenols such as chlorogenic acid or rutin. Knowledge of the levels of nitrosothioproline following exposure to ETS as well as nitrosoproline is needed. Knowledge of the effects of diet is needed when interpreting results of the Ames bacterial assay for mutagenicity of the urine of ETS-exposed nonsmokers. Identification of the mutagenic agents in the urine of ETS-exposed nonsmokers needs to be made. Future studies should be concerned with methodologies that enable us to assay the uptake by the nonsmoker of various other types of ETS components that are tobacco-specific. New trace methods will have to be developed for dosimetry studies of carcinogens involving adducts (DNA and protein) and the development of highly sensitive methods such as immunoassays or postlabelling for other products. The epidemiological studies on the effects of ETS exposure in nonsmokers should consider a number of non-ETS-related factors. This fact underlines the urgent need for the development of highly sensitive dosimetric methods for ETS-specific carcinogens that can be applied in field studies. REFERENCES Adlkofer, F., G.Scherer, and W.D.Heller. Hydroxyproline excretion in urine of smokers and passive smokers. Prev. Med. 13:670–679, 1984. Adlkofer, F., G.Scherer, and U.von Hees. Passive smoking. N. Engl. J. Med. 312:719–720, 1985.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects Aldrige, W.N. A new method for the estimation of micro quantities of cyanide and thiocyanate. Analyst 69:262–265, 1944. Beckett, A.H., J.W.Gorrod, and P.Jenner. The analysis of nicotine—1′-N-oxide in urine, in the presence of nicotine and cotinine, and its application to the study of in vivo nicotine metabolism in man. J. Pharm. Pharmacol. 23:55S–61S, 1971. Benowitz, N.L., F.Kuyt, and P.Jacob III. Circadian blood nicotine concentrations during cigarette smoking. Clin. Pharmacol. Ther. 32:758–764, 1982. 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. Bowler, R.G. The determination of thiocyanate in blood serum. Biochem. J. 38:385–388, 1944. Brunnemann, K.D., J.C.Scott, N.J.Haley, and D.Hoffmann. Endogenous formation of N-nitrosoproline upon cigarette smoke inhalation. IARC Sci. Publ. 57:819–828, 1984. Butts, W.C., M.Kuehneman, and G.M.Widdowson. Automated method for determining serum thiocyanate to distinguish smokers from nonsmokers. Clin. Chem. 20:1344–1348, 1974. Cano, J.-P., J.Catalin, R.Badre, C.Dumas, A.Viala, and R.Guillerme. Determination de la nicotine par chromatographie en phase gazeuse. II. Applications. Ann. Pharm. Fr. 28:633–640, 1970. Coburn, R.F., W.J.Williams, and R.E.Forster. Effects of erythrocyte destruction on carbon monoxide production in man. J. Clin. Invest. 43: 1098–1103, 1964. Coultas, D.B., J.M.Samet, C.A.Howard, G.T.Peake, and B.J.Skipper. Salivary cotinine levels and passive tobacco smoke exposure in the home. Am. Rev. Respir. Dis. 133:A157, 1986. El-Bayoumy, K., J.M.Donahue, S.S.Hecht, and D.Hoffmann. Identification and quantitative determination of aniline and toluidines in human urine. Cancer Res., in press. Everson, R.B., E.Randerath, R.M.Santella, R.C.Cefalo, T.A.Avitts, and K.Randerath. Detection of smoking-related covalent DNA adducts in human placenta. Science 231:54–57, 1986. Faulkner, W.R., and J.W.King. Renal function, pp. 981, 997–999. In N.W. Tietz, S.Berger, and W.T.Caraway, Eds. Fundamentals of Clinical Chemistry. Philadelphia: Saunders, 1976. Feyerabend, C., T.Higgenbottam, and M.A.H.Russell. Nicotine concentrations in urine and saliva of smokers and nonsmokers. Br. Med. J. 284:1002–1004, 1982. Feyerabend, C., and M.A.H.Russell. Assay of nicotine in biological materials: Sources of contamination and their elimination. J. Pharm. Pharmacol. 32:178–181, 1980. Foiles, P.G., N.Trushin, and A.Castonguay. Measurement of 06-methyldeoxyguanosine in DNA methylated by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone using a biotin-avidin enzyme-linked immunosorbent assay. Carcinogenesis 6:989–993, 1985. Foliart, D., N.L.Benowitz, and C.E.Becker. Passive absorption of nicotine in airline flight attendants. N. Engl. J. Med. 308:1105, 1983.

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Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects III HEALTH EFFECTS POSSIBLY ASSOCIATED WITH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE BY NONSMOKERS

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