Risk Analysis, Vol. 10, No. 1, 1990
Workshop on Indoor Air Quality
Risk Assessment Methodologies for Passive SmokingInduced Lung Cancer’ James L. Repace2 and Alfred H. Lowref Received March 3, 1989; revised September 21, 1989
Risk assessment methodologies have been successfully applied to control societal risk from outdoor air pollutants. They are now being applied to indoor air pollutants such as environmental tobacco smoke (ETS) and radon. Nonsmokers’ exposures to ETS have been assessed based on dosimetry of nicotine, its metabolite, continine, and on exposure to the particulate phase of ETS. Lung cancer responses have been based on both the epidemiology of active and of passive smoking. Nine risk assessments of nonsmokers’ lung cancer risk from exposure to ETS have been performed. Some have estimated risks for lifelong nonsmokers only; others have included ex-smokers; still others have estimated total deaths from all causes. To facilitate interstudy comparison, in some cases lung cancers had to be interpolated from a total, or the authors’ original estimate had to be adjusted to include ex-smokers. Further, all estimates were adjusted to 1988. Excluding one study whose estimate differs from the mean of the others by two orders of magnitude, the remaining risk assessments are in remarkable agreement. The mean estimate is approximately 5000 2 2400 nonsmokers’ lung cancer deaths (LCDSs) per year. This is a 25% greater risk to nonsmokers than is indoor radon, and is about 57 times greater than the combined estimated cancer risk from all the hazardous outdoor air pollutants currently regulated by the Environmental Protection Agency: airborne radionuclides, asbestos, arsenic, benzene, coke oven emissions, and vinyl chloride. KEY WORDS: Environmental tobacco smoke; risk assessment; nonsmokers’ lung cancer; passive smoking.
1. INTRODUCTION
contaminant, so-called environmental tobacco smoke (ETS), and to compare the risks of breathing ETS to those from other indoor and outdoor air pollutants. The breathing of ETS by nonsmokers is variously known as passive or involuntary smoking. The smoke inhaled directly by smokers from smoking instruments is called mainstream smoke. ETS is created by the combination of exhaled mainstream smoke, and the direct emissions into room air from the burning of cigarette, pipe, and cigar tobacco, called sidestream smoke. The crudest attempts at risk assessment of passive smoking have employed the “cigarette-equivalent” concept. To inhale one cigarette equivalent by passive smoking, a nonsmoker would inhale the same mass quantity of ETS as of mainstream smoke inhaled by a smoker smoking one cigarette.“) The cigarette equiva-
Risk assessment has long been used by federal regulatory agencies and others to understand and rank the relative risks of nuclear power, outdoor air pollutants, and contaminants in food and drinking water, for the purposes of controlling risk to society. Recently, risk assessment has begun to be applied to indoor air pollutants such as radon and tobacco smoke. The purpose of this work is to review the various methodologies used in risk assessment of tobacco smoke as an indoor air The statements made in this paper are the opinions of the authors and do not necessarily represent the official policies of the U.S. EPA or the Naval Research Laboratory. * U.S. Environmental Protection Agency, Washington, D.C. 20460. Naval Research Laboratory, Washington, D.C. 20375.
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0272-4332/90/0300-0027506.W/l 0 19M Society for Risk Analysis
Repace and Lowrey
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lent has been used as a unit of exposure, as well as a unit of risk. However, when used as a measure of exposure it is imprecise, and when used as a measure of risk it is a complex and potentially meaningless process.(') For example, the statement that "nonsmokers' exposures are orders of magnitude lower than the exposures represented by smoking a single cigarette"(43) might conceal a significant risk from ETS compared to a de minimis risk, or a significant exposure to harmful pollutants.(') More sophisticated attempts at risk assessment of passive smoking have ranged from extrapolation from the risks in smokers to the risks in nonsmokers by scaling the levels of nicotine or its metabolite, continine, in the body fluids of smokers to that in nonsmokers, to directly using the epidemiology of passive smoking to derive an exposure-response relationship. These will be reviewed in the context of the four classic components of risk assessment: Hazard Assessment, Exposure Assessment, Exposure- or Dose-Response, and Risk Characterization.
halation of the smoke from tobacco products, it is not surprising that in the absence of any known threshold for effect, exposure to diluted exhaled and sidestream smoke should also be capable of causing human morbidity and mortality. Combustion of tobacco products indoors contaminates indoor air with nearly 5000 chemicals,("g) 43 of which are carcinogenic with "sufficient evidence" by IARC criteria.('O) The source strength of tobacco products is such that smoking indoors causes large elevations of indoor pollutants above ba~kground.("-'~)On the basis of controlled experiments and field studies, nonsmokers are known to absorb significant amounts of tobacco combustion product^;(^^-^^) amounting to, in the most-exposed individuals, to levels 5-7% of those in smokers, and in the average case, about 1%of the levels in active smokers. On'the basis of 13 epidemiologic studies('v2)available in 1985, ETS was judged as a cause of lung cancer in nonsmokers by the U.S. Surgeon General and the National Research Council.
3. EXPOSURE ASSESSMENT 2. HAZARD ASSESSMENT
In 1986, more than 50,000,000 U.S. smokers aged 2 17 yr smoked about 584 billion cigarettes They consumed an additional 3.2 billion cigars, as well as an estimated 24.4 million pounds of tobacco for pipes and hand-rolled cigarettes.(2)The average U.S. cigarette smoker smokes 32 cigarettes per day at a rate of 2 cigarettes per Measurements of the mass of tobacco from 7 popular brands of filtered and unfiltered cigarettes showed that the average is about 314 gram per cigarette,(46)indicating that the total tonnage of tobacco consumed in the U.S. is 471,480 metric tons (tonnes) [438,000 tonnnes of tobacco from cigarettes plus 11,078 tonnes from pipes, plus (at about 7 gkigar) 22,000 tonnes from cigars]. The average person spends about 90% of the time indoors,(24)suggesting an estimated 424,330 metric tons are emitted into U.S. indoor microenvironments each year from tobacco smoking at 1986 consumption rates. The toxicity of tobacco smoke is such that a 35-yr old male smoker incurs a 33% lifetime risk of dying from his smoking, and if he dies from his smoking, he will lose on average 13 years of life.c3) Currently, the excess mortality from intentional inhalation of tobacco smoke is estimated at 390,000 deaths per year,(21)a total unapproached by any other environmental agent. Given the large magnitude of mortality caused by exposure to tobacco smoke by high-level exposure from direct in-
Exposure to ETS can be quantified either by atmospheric or biological markers. Of the latter, expired carbon monoxide, carboxyhemoglobin, plasma thiocyanate, plasma, urinary, or salivary nicotine, and cotinine have been used to evaluate exposure to ETS. However, successful attempts to quantify the degree of exposure have been limited largely to measurements of nicotine and cotinine. Urinary nicotine is a sensitive indicator of recent ETS exposure, while continine appears to be the short-term marker of choice for epidemiologic studies. Nicotine and cotinine are the best markers currently available. Levels in body fluids may be elevated 10 or more times in the most heavily exposed groups of nonsmokers compared with the least-exposed groups. Few nonsmokers have been found to have body fluids free of ~ o t i n i n e Mean .~ levels of urinary nicotine and cotinine in body fluids both increase with an increasing self-reported ETS exposure, and with an increasing number of cigarettes smoked per day by active smokers.(') The average concentration of cotinine in the blood of habitual smokers is about 300 ng/ml, and has been calculated to represent the consumption of about 36 mg of nicotine per day.cg) Based on the assumption that formation of cotinine from nicotine and clearance from the body does not differ substantially from smokers to nonsmokers, present data suggest that average urban nonsmokers (in the U.K.) take in 0.2 mg of nicotine per day") (0.2 mg represents 0.6% of the smokers' dose).
29
Risk Assessment Methodologies in Passive Smoking
However, since nonsmokers clear cotinine at about 1/3 to 1/2 of the rate of the effective dose may be proportionately higher. A recent study of urinary cotinine levels in 663 U.S. never- and ex-smokers who attended a cancer screening clinic in Buffalo, New York in 1986 showed that 91% of the subjects had detectable concentrations, averaging about 10 ng/ml. The most frequently mentioned sources of exposure were at work (28%) and at home (27%) (K.M. Cummings, personal communication). In summary, based upon the limited studies (none of which are a probability sample of U.S. nonsmokers) of cotinine in body fluids of nonsmokers,(’) nonsmokers appear to have on the order of 1% of the nicotine uptake of smokers. However, these estimates must be interpreted with caution; relative absorption of nicotine in smokers and nonsmokers may substantially underestimate exposure to other components of ETS.(’) Alternatively, human exposure to ETS has been estimated using approaches similar to those used for other airborne pollutants. Measures of exposure to individual atmospheric smoke constituents can be used as estimates of whole smoke exposure. The accuracy of this approach is limited by changes in the composition of ETS with time and conditions of exposure. One widely reported marker of ETS is respirable suspended particulate matter (RSP). Although tobacco smoke is not the sole source of RSP, the prevalence and number of smokers correlates well with RSP levels in homes and other enclosed areas. The Harvard study of indoor air pollution in six cities,” demonstrated that exposures to ETS at home and at work are significant contributors to personal exposures. In general, measurements in a large number of locations using measures of smoke generation, such as the number of people smoking or the number of cigarettes being smoked, have shown a definite relationship of smoke generation to particulate levels. In US. homes, there are few other sources of RSP and, therefore, the relationships of RSP measurements to ETS are quite accurate.(l) Repace and L o ~ r e y ( ~measured l) RSP concentration using a piezobalance in several public and private locations, in both the presence and absence of smoking. They then developed an empirical model utilizing the mass balance equation. Using both measured and estimated parameters as input to the model, they validated the model for predicting an individual’s exposure to RSP from ETS.(’) They estimated that the average exposure of the nonsmoking adult population to tars from ETS was 1.43 mg/day, varying from 0 to 14 mg/day.(%)Kuller et al.Q5)in reviewing the latter estimate, observed that
the ratio of average exposure in passive smoking to that in active smoking, was about 0.3%. This translates into 3% of the smoker’s exposure for the most-exposed passive smokers, reasonably consistent with estimates based on doses from nicotine and cotinine, above. Based upon field studies in smoking buildings, RSP from ETS appears to account for 80-90% of the RSP levels in these spaces.(42) In summary, using either the best biological marker (cotinine) or the best atmospheric marker (RSP) produces a consistent assessment of average ETS exposure (i.e., on the order of 0 5 1 . 0 % of that in smokers). The most-exposed individuals appear to have levels about 10 times higher.(24)Based upon limited data, the typical nonsmoker appears to carry a daily body burden of about 0.2 milligrams (mg) of nicotine. The cotinine-based estimates have the advantage that they reflect actual dose of an ETS constituent. They have the disadvantage that they do not reflect a wide distribution of target populations, are based mostly on UK ETS exposures, and may substantially underestimate exposures to other constituents of ETS. The RSP-based estimates have the advantage that they are model-based, can be used to estimate exposures in a variety of microenvironments, represent the great bulk of ETS carcinogens, and can be compared with atmospheric measurements of RSP. They have the disadvantage that they do not represent whole smoke exposure, and do not reflect absorbed dose. The greatest source of uncertainty is that neither cotinine nor RSP measurements are based on a national probability sample, and on an absolute scale, represent a limited amount of data. Nevertheless, the NRC (1986), the SG (1986), and IARC (1987) have found this an adequate basis for exposure assessment purpose^.('*^^^) 4. EXPOSURE-RESPONSE
In 1986, there were 13 epidemiologic studies, spanning six cultures, which formed the basis for the judgments of the NRC and the Surgeon General about lung cancer from passive smoking. Although exposures take place outside the home, nearly all of these studies assessed exposure solely on the basis of reported spousal smoking habits as the surrogate exposure variable. This might be expected to dilute the power of these studies to show an effect. Nevertheless, when these 10 casecontrol and three prospective studies of passive smoking are broken down by gender into 21 substudies, 15 of the 21 epidemiologic studies(’.’) implicate ETS as a cause of lung cancer in nonsmokers. The Surgeon General,(’) the National Research Council,(’) and the World Health
30
Organization(lo)concluded that these studies prove causality between ETS exposure and lung cancer. (Since 1986, five additional studies examining the relation between ETS and lung cancer in nonsmokers have been published; three of five noted a significant correlation.) Based mostly on these studies, a number of workers have moved to quantify this risk. There are now nine risk assessments of lung cancer deaths (LCDs) from ETS; they may be conveniently divided into three groups: (1) extrapolations of risks in smokers; (2) attributable risk estimates; and (3) phenomenological estimates. Where numerical estimates of lung cancer are not given separately, estimates are inferred based upon information given in each paper. 4.1. Extrapolation Based on Risks in Smokers
F ~ n g (estimated ~~) the hazard of ETS exposure to nonsmokers (both never- and ex-smokers) by comparing the ratio of the average estimated inhaled exposure to nonsmokers’ lungs with that of mainstream smoke to smokers-ETS comprises two thirds of the total smoke produced from a cigarette. Fong assumed the carcinogenic response to ETS in nonsmokers is the same as that for active smoking in smokers, and that it extrapolates linearly, with alternative consideration of possible sublinear effects at low doses. Fong estimated that ETS has from about 2% to about 8% of the effect on nonsmokers that it does on smokers, and estimated that this causes from 10,000-50,000 nonsmokers deaths per year from all causes, in a population of 220,000,000 nonsmokers, and causes an average loss of life expectancy from 48 days to 225 days averaged over this population. Although Fong did not give a separate estimate of LCDs, by using the figures that 25% of smokers who die from smoking succumb to lung cancer,(21)and assuming nonsmokers’ deaths from ETS to be in the same ratio, these figures roughly place Fong’s estimate of LCDs from ETS in 1980 at 2500-12,500 per 220,000,000 at risk. Since there were only about 62 million nonsmokers at risk for lung cancer in 1980,(24)this would place the LCD estimate interpolated from Fong’s calculation at 600-3500 LCDs per year from ETS exposure. Adjusted to 1988 by the ratio of total LCDs in 1988 (139,000) to that in 1980 (101,300) American Cancer Society, personal communication, Fong’s interpolated estimates become 960-4800. Fong used physical and statistical analysis based on low- and high-density exposures to ETS, where he assumed that the average daily exposure of a working adult consisted of l l h of low-density exposure and 1 hr of
Repace and Lowrey
high-density exposure. Fong considered every workplace with more than three workers to have at least one smoker. He calculated a daily low-density exposure of a nonsmoker at 0.93 cigarette equivalents, and highdensity exposure to result in 0.64 cigarette-equivalents per day, for a total of 1.56 cigarette equivalents per day (ceqd) at the upper extreme, or 1/13th of that of a smoker, for an estimated 1980 death rate from passive smoking of 50,OO deaths per year. Alternatively, based on Hirayama’s Japanese prospective study of passive smoking and lung cancer, Fong estimated a nonsmoker’s ETS exposure 1/60 of that of an active smoker from smoking, corresponding to an excess death rate of 10,000 deaths per year from passive smoking. ) a dose-response relation Russell et a f . ( 2 2derived based upon the ratio of the (1985) mortality rate in the U.K. from active smoking to the average urinary nicotine concentration in a sample of smokers. They multiplied this (linear extrapolation) by the average urinary nicotine concentration in a sample of nonsmokers to yield an estimate of the nonsmokers’ (presumably including both never- and ex-smokers) mortality rate from passive smoking. Russell et a f . found that the average concentration of nicotine in the urine of 188 nonsmokers was 10.8 ng/ml, 0.7% of the average of 1471 ng/ml in a sample of 229 cigarette smokers. The highest values of urinary nicotine reported were 92.6 ng/ml, reported after two h exposure in a “poorly ventilated public house,” or 6.3% of the average levels found in smokers, which was said to be about half the steady-state value that nonsmokers could reach if they spent most of the day in such conditions (the plasma half-life of nicotine in smokers is about 2 hr).(22)Thus, the range between the estimated mean nonsmoker ETS dose of nicotine (1%)and the extreme dose (10%) is about a factor of 10. Then, predicated upon an assumption that smokers and nonsmokers excrete nicotine at the same rate (an incorrect(’5) but conservative assumption), and that these results are representative of the whole U.K. population (these “biased upwards in social class” nonsmokers were expected to have “slightly less” exposure than the general population), Russell et af. estimated 4000 total U.S. ETS-related deaths peryear from all causes. Russell has stated that his estimates were intended to be “conservative” and that the true risk could “well be double” his estimate (M.A.H. Russell, personal communication). Based upon the foregoing, the number of lung cancer deaths from passive smoking implied by Russell’s figure may be estimated as follows: again assuming 25% of the U.S. deaths from smoking are due to lung cancer,(21)and that smokers inhale 36 mg of nicotine per day,(g)a unit LCD risk from ETS can be estimated [using
Risk Assessment Methodologies in Passive Smoking
nicotine as a surrogate for the carcinogenic agents in ETS-nicotine has been found to bear a 1:lO ratio to RSP in ETS (B. Leaderer, personal communication)]. Predicated upon Russell et al.3 analysis, it is estimated at 5000 LCDsbr per mg of nicotine inhaled per day, based upon linear extrapolation from the risks in smokers. Russell et aZ.'s interpolated estimate of U.S. lung cancer deaths is calculated to be 1000 LCDs/yr (5000 LCDs/yr per mg nicotine/day x 0.2 mg nicotine/day). Adjusting the 1985 figure to 1988 by the ratio of total LCDs in 1988 to those in 1985 (139,000/125,600), yields an estimated 1107 LCDslyr. Robins23 also estimated 1985 U.S. LCD rates in never-smokers from ETS using urinary cotinine dosimetry, extrapolating by applying the nonlinear multistage model of cancer risk to the data on the lung cancer experience of active smokers. Robins estimated a range of exposure for nonsmokers to ETS from 0.1 to 2.8 cigarette equivalents per day (cpd), where those with smoking spouses have a range of from 0.4-2.8 cpd, and those with nonsmoking spouses have a range of from 0.1-0.9 cpd, based on extrapolations from urinary cotinine in smokers. In this manner, Robins estimated about 2500-5200 U.S. deaths in lifelong nonsmokers per year from passive smoking; 1770-3320 in females, and 7201940 in males. The range in estimates was developed over 30 exposure histories and 5 choices of extrapolation coefficients in the model. Robins estimates the average lifetime risk to never-smokers to range from 4-9.9 per thousand, and for ex-smokers (1 pack per day, ages 1845) to range from 5-20 per thousand. Adjusting Robins 1985 estimate to 1988, as above, yields an estimated 2768-5535 LCDslyr, or an average of 4152 LCDs/yr. Adjusting further to include ex-smokers (in 1985, according to Statistical Abstracts of the U.S., 43.7% of the population were never-smokers, and 24.4% were exsmokers), Robins' estimates, adjusted to 1988, range from 4314-8625, and average 6470 LCDs/yr. Repace and Lowrey(") estimated a lower-bound exposure-response relationship for passive smoking and lung cancer based on active smoking lung cancer risks in smokers and their lung exposure to RSP from mainstream smoke. It was in magnitude about 6 x LCDs/yr per mg tadday per smoker of lung cancer age (235 yr). Using the one-hit model for cancer induction (equivalent to a linear assumption in this dose-range) for extrapolation of the risks to the modeled exposure of the typical nonsmoker (1.4 mg/day), multiplied by the nonsmoking population at risk (62 million persons, aged 1 35 yr) Repace and Lowrey estimated 555 nonsmokers' 1980 lung cancer deaths per year using this technique. Adjusted to 1988, this yields 760 LCDs/yr. However,
31
this exposure-response relationship was found to be inconsistent with the epidemiology of passive smoking, and was abandoned in favor of a phenomenologic model, described below.(".25) Arundel, et u L . ( ~ O ) used a linear extrapolation based upon the risks in smokers to estimate the risks of passive smoking and lung cancer in nonsmokers (never-smokers only). The exposure part of the exposure-response relation was based upon a weighted exposure of nonsmokers to particulate matter from ETS, taken over homes, workplaces, and restaurants and bars separately for men and women, and equaled 0.62 mg/day for men, and 0.28 mg/day for women. Averaged over men and women, this is about 0.45 mg/day, or about 1/3 of that estimated for the typical nonsmoker by Repace and Lowrey bel0w.0~)Retained exposures were calculated by assuming an 80% retention in smokers' lungs and an 11% retention in nonsmokers. The response was estimated to be 284 LCDs per 100,000 male current smokers, and 121 LCDs per 100,000 in female smokers all of age 35 or greater. [The exposure-response relationship is calculated here approximately (averaging over men and women smokers for purposes of comparison) as 203 LCDs per 100,000 LCDs per PY PY per 280 mg/day, or about 7 x per mg/day.] Arundel et al. estimate that the average domestic exposure retained is 0.09 mg/day (men and women averaged here) for a predicted excess risk of domestic passive smoking of 0.06 LCDs per 100,000 PY. If the baseline risk is taken as 8.7 LCDs per 100,000 PY,(24) the relative risk from domestic passive smoking according to Arundel et al. is calculated as 1.006. This is inconsistent with epidemiologic observations of the risk of domestic smoking and lung cancer which have been estimated by the NRC to be about 1.3. This approach of Arundel et al. has also been criticized by Repace and Lowrey(") as inconsistent with the dose-response curve for active smoking, which appears to be nonlinear. The risk of lung cancer from passive smoking is calculated by Arundel et al. by multiplying the smokers' risk times the retention ratio to calculate an average passive smoking risk of 0.064 LCDs per 100,000 PY for men, and 0.015 LCDs per 100,000 PY for women. An average of about 4 x lo-' LCDsPY is calculated, about an order of magnitude lower than the one-hit model estimate of Repace and Lowrey, above. By multiplying by the never-smoking population at risk (ex-smokers are excluded), and taking other uncertainties into account, Arundel et aZ. estimate between 12 and 62 LCDs per year. Adjusting this estimate for 1980-1988 yields an estimated 16-85 LCDs per year, for an average of 50 LCDs/yr. Further adjusting to include exsmokers, the
32 range varies from 19-97, and the estimated average becomes 58 LCDs/yr. 4.2. Attributable Risk Estimates
Wigle ef ~ l . ( ~compiled l) information on the proportion of people who had never smoked among victims of lung cancer in Canada. They estimated that exposure of the Canadian population to ETS respirable suspended particulate matter (RSP) was similar to that estimated for ~ )mg/ the U.S. population by Repace and L o ~ r e y , ‘ ~1.4 day. Wigle et al. observed that Canadian ETS exposure values appear to be similar to those in the U.S. Wigle et al. calculated the population proportion attributable to the risk of lung cancer using the Cole-McMahon formula, estimates of the prevalence of exposure to smoking by spouses, and the weighted-average relative risk of lung cancer for exposed nonsmokers in 12 epidemiological studies. They then applied this relative risk to the age- and sex-specific rates of death from lung cancer used by Repace and L o ~ r e y (to~ derive ~) the excess risk of lung cancer from passive smoking in Canada. They estimated that Canada, with about 10% of the population of the U.S. has 330 lung cancer deaths per year attributable to domestic and workplace smoking, with about 16% of those deaths estimated to come from domestic exposure to ETS, and 83% from workplace (a ratio of about 5:1, comparable to the estimates of Tancrede et al. and Repace and Lowrey, below.) Extrapolating Wigle et d ’ s Canadian estimate to the U.S. population places the estimate at 3300 LCDs/yr, and adjusting to 1988 places the U.S. estimate extrapolated from Wigle’s estimate at 3652 LCDsbr. Further adjusting to include ex-smokers yields 5691 LCDs/yr. Wells(32)reviewed the literature on adult mortality from passive smoking. Combined relative risks for lung cancer, other cancer, heart disease, and emphysema for males and females were calculated via a meta-analysis technique which calculated weighted-average risk ratios from epidemiologic studies of passive smoking. A correction for misclassification of smokers as nonsmokers was applied. Nonsmokers’ baseline death rates in the absence of passive smoking were estimated from the American Cancer Society study of mortality in 1,000,000 U.S. men and women by Hammond (NCI monograph 19), and Garfi11ke1.c~~) Wells’s preliminary risk assessment of U.S. passive smoking deaths from the four diseases was made by applying the relative risks from the passive smoking literature to estimates of the exposed population and nonsmoker death rates. Wells estimated
Repace and Lowrey
that as a result of passive smoking, in 1985 there were 3000 passive smoking lung cancer deaths per year in nonsmokers (never-smokers plus ex-smokers) aged 2 35 yrs., 11,000 from other cancers, and 32,000 deaths from heart disease, for a total of 46,000 nonsmoker deaths per year. Adjusting Wells 1985 LCD estimate to 1988 yields 3320 LCDs/yr. Wald et performed a statistical analysis of 10 case-control and three prospective studies of lung cancer in nonsmokers from ETS exposure. They calculated a weighted relative risk of 1.35 (95% CL 1.19-1.54) for nonsmokers living with smokers relative to nonsmokers living with nonsmokers. They estimated that adjustment for the effect of misclassification of smokers as nonsmokers reduced this risk to 1.30, but a further adjustment for finite urinary cotinine levels in nonsmokers living with nonsmokers (i.e., the effect of exposure outside the home) raised the total estimated risk to 1.53. That is, 57% of the risk was estimated to come from domestic smoking, and 43% of the risk from other exposures e.g., the workplace based on two U.K. studies of urinary cotinine. Wald et al. estimate that about a third of the cases of lung cancer in nonsmokers who live with smokers, and about a quarter of the cases among nonsmokers (never-smokers) in general, may be attributed to ETS exposure. Since there were about 20,850 LCDs in U.S. nonsmokers in 1988, this would place Wald et al.’s estimate adjusted to 1988, at about 5213 LCDs per year in both male and female lifelong nonsmokers, and adjusting to include ex-smokers yields 8124 LCDs/yr. ) reviewing the 13 epidemologic Kuller et u I . , ( ~ ~ in studies, considered issues of misclassification of exposure, of pathology, and of controls. Without formally defining an exposure-response relationship (husbands’ smoking is the surrogate exposure variable, and lung cancer in the nonsmoking wife is the response), they concluded that data indicate that “the greater number of lung cancers in nonsmoking (never smokers only) women is probably related to environmental tobacco smoke.” Kuller et al. estimate that there are 6000 to 8000 lung cancer cases each year from all causes in lifelong nonsmoking women; this would place Kuller e f al.’s 1985 estimate roughly at 3500 LCDs per year in never-smokers. Adjusting to 1988 yields 3873 LCDs/yr. If the estimate is extended to include effects in ex-smokers, this would increase to about 6035 LCDs per year. They also concluded that effects of ETS on the cardiovascular system, especially among high-risk individuals, may be of greater concern than cancer and would require further study.
Risk Assessment Methodologies in Passive Smoking 4.3. Phenomenological Risk Estimates
Repace and Lo~reqX*~) assessed nonsmokers’ (neversmokers plus ex-smokers) risk of lung cancer due to RSP exposure from ETS using a phenomenological model. An exposure-response relationship was derived, with the response estimated from the age-standardized differences in lung cancer mortality rates between two demographically comparable cohorts of lifelong nonsmokers, one of which (SDAs) had a lifestyle with a high percentage of restrictions on smoking at home and at work relative to the other cohort (NonSDAs). This method avoids problems of misclassification in nonsmokers’ selfreports, since two groups of lifelong nonsmokers are compared. Also, the SDA study is independent of the 13 epidemiological studies considered by the Surgeon General and the NRC. The estimated average nonsmoker’s exposure of 1.43 mg/day was calculated by modeling the population’s exposure to RSP from ETS in the two most-frequented microenvironments(88% of people’s time), at home and at work. Repace and L o ~ r e y (estimated ~~) for 1980 that 4700 LCDs occurred annually due to ETS exposure in the home and the workplace among 62.4 million nonsmokers (never-smokers plus ex-smokers) age 2 35 years. The initial calculation did not differentiate between male and female nonsmokers, and age-standardized the calculation to the entire U.S. population, which included smokers. However, in a later calculation, the results were adjusted for sex and standardized to the nonsmoking population.(25)This new calculation estimated about 1440 male nonsmoker and 3450 female nonsmoker deaths, for a revised total of about 4900 LCDs per year. Adjusting this 1980 population estimate to 1988 yields 6724 ? 336 LCDs/yr. To estimate uncertainty, Repace and Lowrey,(2”-26) using an exposure-response relation derived from combining the risks from the SDA study with the average estimated RSP inhalation for nonsmokers, calculated the expected risk ratio and risk rate for the 1981 American Cancer Society cohort studied by Garfinkel,cZ7)the odds ratio in a 1985 case-control study by Garfinkel,c2*)and the risk ratio for domestic passive smoking derived from the 13 world epidemiological studies analyzed by the NRC.(2) The calculations in every case agreed with observational results to within 5%. This suggested the uncertainty(29)in this risk estimate is ? 5%, or ? 300 LCDs. The predicted risk of domestic passive smoking using the phenomenologic model is 26%, for a relative risk ratio of 1.26, which compares with Wald’s estimated risk of 1.30, and the NRC‘s of 1.32, adjusted for
33 misclassification. Repace and L o ~ r e y (utilized ~ ~ ) an exposure-response relationship of 5 lung cancer deaths per 100,000 person-years at risk, per mg of exposure to tobacco tar per day. They estimated a lifetime risk of about 2/100to the most-exposed passive smokers. Based on estimates of probability-weighted exposure given by that the probabilRepace and L o ~ r e y , (and ~ ~ assuming ) ity of exposure for a nonsmoker (men and women averaged together) who is exposed to ETS both at work and at home is the same for both microenvironments, they estimated average home and workplace exposures at 0.55 mg/day (for 70 yr) and 0.89 mg/day (for 40 yr), respectively, with the longer exposure at home accounting for childhood exposures. Under these assumptions, the estimated home and workplace risks are each about 2/1000 and 50% of the average population risk from passive smoking is estimated to be workplace-related, which compares with an estimate of 43% derived from Wald et al. Tancrede et u Z . ( ~ O ) analyzing Repace and Lowrey’s calculations, used a 4:l ratio between workplace and domestic exposures, and estimated an average excess lifetime cancer risk for domestic passive smoking of 2/ 1000, and for the workplace, 8/1000. Nine published risk assessments, performed by US., Canadian, and U.K. researchers, have examined the question of the risk to nonsmokers from exposure to ETS. These assessments employed three different methodologies: dosimetry based upon nocotine or cotinine in body fluids; modeled exposure of the population to tobacco tar (i.e., ETS-derived RSP), and attributable risk based upon the presence or absence of a substantial (i.e., household) ETS exposure history. Several of the methods applied extrapolation models, and several used epidmemiologic results only. Some tried both approaches. The results of the nine risk assessments are given in Table I, and for the purposes of interstudy comparison of these diverse risk assessment methodologies, are adjusted to 1988, and include ex-smokers, where the authors did not include them (in two cases, the number of LCDs had to be interpolated from the authors estimate of total mortality from passive smoking). These risk assessments have utilized three different methodologies: dosimetry based upon nicotine and its metabolite, cotinine; exposure, based upon RSP from ETS; and epidemiology, based on an assessment of nonsmokers’ lung cancer rates in the presence and absence of an ETS exposure histov. The range of estimates runs from 58 LCDs per year to 8124 LCDs per year. The mean and standard deviation of all estimates is 4500 f 2800, and if Arundel et al.’s estimate (which is more than 2 SD from the
34
Repace and Lowrey Table I. Summary of Risk Assessments of Lung Cancer in U.S. Nonsmokers from ETS Exposure (Adjusted 1988 LCD Figures) ~
Study Fong (1982)" Repace and Lowrey (1985-1987) Russell et al. (1986)" Robins (1986) Wells (1988) Wald ef al. (1986) Kuller et al. (1986)" Wigle er al. (1987) Arundel el al. (1987) Mean, all nine studies: Mean, eight studies, excluding Arundel et al.
Range of estimates (LCDs per year)
-
96P 480W 685d - 685P 43148 - 8625h
(female LCDs only) (83% workplace)" 19 - 97
Mean or best estimate (LCDs per year) 2900 6700 2 340 1107' 6470 332@ 812@ > 6035' 5691' * 58'" 4500 2 2800 5000 2 2400
Based on linear extrapolation from nicotine in smokers. Based on urinary cotinine and ETS epidcmiology. * Based on linear multistage from smokers and urinary cotinine. Lower bound based on smokers' RSP exposure extrapolation (adjusted to include ex-smokers). Best estimate based on epidemiology (adjusted to include ex-smokers). Based on extrapolation of Canadian results to U.S. nonsmokers. I Based on ETS epidemiology and nonsmokers' LCD rates (adjusted to include ex-smokers). * Based on sublinearity assumption at low doses. Based on linearity assumption at low doses. j Based on urine cotinine in U.K. nonsmokers, ETS epidemiology (adjusted to include ex-smokers). Based on numerical interpretation of qualitative judgment. Based on linear extrapolation from retained RSP in smokers. a Estimate ours, interpolated from author's overall risk estimate. f
8
'
mean of the others) is excluded, 5000 & 2400 LCDs per year. In the latter case, given the disparity in the various methodologies used by the different risk assessors, there is a remarkable agreement (for risk assessments) with a SD about the mean of about ? 50%. The three studies which explicitly estimated the workplace contribution to the risk suggest that the workplace contributes at least half of the risk. By comparison, a study(39) of chronic obstructive pulmonary disease in SeventyDay Adventists in California showed a 7% increased risk from passive smoking at home (p < 0.01) and an 11% increased risk from passive smoking in the workplace (p < 0.001); thus for individuals exposed both at home and at work in this study, 61% of the risk appears to come from the workplace. Based upon presently available information from nicotine and cotinine dosimetry as a surrogate for total ETS exposure in nonsmokers, coupled with the epidemiologic studies of passive smoking and lung cancer, it is estimated that, for nonsmokers, there is an estimated 1% lifetime increase of lung cancer risk from ETS exposure per 1 nanogram of cotinine excreted per milliliter (ml) of urine. Similarly, the estimated risk of lung cancer from ETS exposure at home appears to amount to a
125% average lifetime increase in lung cancer risk per milligram (mg) of nicotine inhaled per day. The average levels of exposure, 0.2 mg of nicotine inhaled and 25 ng/ml of urine excreted, each corresponds, based upon epidemiologic studies of passive smoking, to an average of about 34% (risk ratio 1.34) increase in lifetime risk of lung cancer for nonsmokers. In contrast, each method (RSP and nicotinekotinine), if based upon a linear extrapolation of the risks in smokers down to the nonsmokers' dose levels (the so-called cigarette-equivalent method), yields about a 10% increase in lifetime risk per average exposure. Interestingly, however, if this latter figure is adjusted by multiplying by the ratio of the excretion half-life of urinary cotinine in nonsmokers to that in smokers, the estimated excess risk increases to about 27% (RR 1.27), consistent with the estimates based upon epidemiology. However, these half-lives are based on a small sample of smokers and nonsmokers, and further research is needed. Based upon ETS-generated RSP exposure, the phenomenological model of nonsmokers' risk of lung cancer suggests that the average risk of lung cancer from ETS exposure at home is 26% (RR 1.26), in good agreement with the biomarker estimates and with epidemiology.
35
Risk Assessment Methodologies in Passive Smoking The estimated exposure-response relation based upon ETS-generated RSP (tobacco tar) is 5 lung cancer deaths per year per 100,000 person at risk (aged 35 years or more) per milligram of tar inhaled per day, where tar is used as a surrogate for all of ETS. This exposure-response relationship has been shown to predict the observed summary odds ratio found in the 13 epidemiologic studies to within 5%, and to predict the observed risk ratio and risk rate in the large American Cancer Society cohort study of passive smoking and lung cancer also to within 5%. By contrast, extrapolation of the RSP-estimated risks from smokers' exposures to that in nonsmokers yields an estimated exposure-response relation only about 10% as high, based upon extrapolation by the one-hit or linearized multistage models. This implies a lack of linearity in the exposure-response curve at the high doses of active smoking which has been reported.(2S) 5. CHARACTERIZATION OF RISK 5.1. Risk in Perspective
The mean of all the studies, excluding Arundel et al, which differs from the others by more than two standard deviations, is 5000 +. 2400 LCDs/yr. Considering the disparity in approaches, there is a remarkable consistency in estimated nonsmokers' lung cancer mortality from ETS. Based upon two assessments of the average population risk, it is concluded that the estimated lifetime risk of ETS exposure in the U.S. appears to be about 2 x with an estimated risk of 2 x to the most-exposed nonsmokers. The risk from ETS in workplace microenvironments in general appears to be on the same order as that from the home. The fatal risks of sustained exposure to tobacco smoke at the high doses to which smokers are exposed are well established; although the chronic exposures of nonsmokers are lower, they are often significantly higher than the exposures from other indoor contaminants to which nonsmokers are typically subject from other sources. ETS contains numerous toxic and carcinogenic substances, some of which may be synergistic with other powerful lung carcinogens to which most nonsmokers are exposed (e.g., radon and asbestos). In 1990, the American Cancer Society projects 142,000 lung cancer deaths(45);of these, about 15%,or an estimated 21,000 lung cancer deaths (LCDs) occurred among US. nonsmokers (lifelong nonsmokers plus exsmokers). Although the risk estimates given above are
necessarily based on a relatively few studies which do not represent national probability samples, it appears that based upon an analysis of the risk assessment literature, ETS exposure may cause an estimated 5000 LCDs per year, or about one fourth of the lung cancer deaths of nonsmokers. By contrast, it is estimated that about 4000 LCDs per year, or about one fifth of the lung cancer deaths in nonsmokers, appear to be due to indoor radon exposure (Appendix A). Nonoccupational asbestos-related mortality has been estimated to cause less than 15 cancer deaths per year. Also, the risks of ETS exposure appear large when compared with outdoor air pollutants under regulation by EPA as hazardous air pollutants, whose total estimated cancer mortality before control is < 87 deaths per year. These risk estimates are illustrated in Table 11. Thus, it appears that the relative risks of ETS exposure to nonsmokers are 25% greater than from radon gas, and about one hundred times as great as the total from all carcinogenic outdoor air pollutants currently regulated by EPA under the Clean Air Act. Risk assessment has been useful when applied to the regulation of outdoor air pollutants; similarly, as it is applied to indoor pollutants, it can be expected to promote reductions in the much larger cancer risks attendant to the indoor environment. APPENDIX A Estimated Population Radon Risks
The NRC(37)has estimated a dose-response relationship for radon of a magnitude of 350 lung cancer
Table 11. Comparison of Estimated Cancer Deaths (CDs) from Various Airborne Carcinogens in the U.S."
Indoor pollutants Environmental tobacco smoke (homes and workplaces) 5000 CDs/yr Radon gas in homes (nonsmokers only) 4000 CDsiyr Outdoor pollutants Asbestos Vinyl chloride Airborne radionuclides Coke-oven emissions Benzene Arsenic
15 CDsiyr
Workshop on Indoor Air Quality
Risk Assessment Methodologies for Passive SmokingInduced Lung Cancer’ James L. Repace2 and Alfred H. Lowref Received March 3, 1989; revised September 21, 1989
Risk assessment methodologies have been successfully applied to control societal risk from outdoor air pollutants. They are now being applied to indoor air pollutants such as environmental tobacco smoke (ETS) and radon. Nonsmokers’ exposures to ETS have been assessed based on dosimetry of nicotine, its metabolite, continine, and on exposure to the particulate phase of ETS. Lung cancer responses have been based on both the epidemiology of active and of passive smoking. Nine risk assessments of nonsmokers’ lung cancer risk from exposure to ETS have been performed. Some have estimated risks for lifelong nonsmokers only; others have included ex-smokers; still others have estimated total deaths from all causes. To facilitate interstudy comparison, in some cases lung cancers had to be interpolated from a total, or the authors’ original estimate had to be adjusted to include ex-smokers. Further, all estimates were adjusted to 1988. Excluding one study whose estimate differs from the mean of the others by two orders of magnitude, the remaining risk assessments are in remarkable agreement. The mean estimate is approximately 5000 2 2400 nonsmokers’ lung cancer deaths (LCDSs) per year. This is a 25% greater risk to nonsmokers than is indoor radon, and is about 57 times greater than the combined estimated cancer risk from all the hazardous outdoor air pollutants currently regulated by the Environmental Protection Agency: airborne radionuclides, asbestos, arsenic, benzene, coke oven emissions, and vinyl chloride. KEY WORDS: Environmental tobacco smoke; risk assessment; nonsmokers’ lung cancer; passive smoking.
1. INTRODUCTION
contaminant, so-called environmental tobacco smoke (ETS), and to compare the risks of breathing ETS to those from other indoor and outdoor air pollutants. The breathing of ETS by nonsmokers is variously known as passive or involuntary smoking. The smoke inhaled directly by smokers from smoking instruments is called mainstream smoke. ETS is created by the combination of exhaled mainstream smoke, and the direct emissions into room air from the burning of cigarette, pipe, and cigar tobacco, called sidestream smoke. The crudest attempts at risk assessment of passive smoking have employed the “cigarette-equivalent” concept. To inhale one cigarette equivalent by passive smoking, a nonsmoker would inhale the same mass quantity of ETS as of mainstream smoke inhaled by a smoker smoking one cigarette.“) The cigarette equiva-
Risk assessment has long been used by federal regulatory agencies and others to understand and rank the relative risks of nuclear power, outdoor air pollutants, and contaminants in food and drinking water, for the purposes of controlling risk to society. Recently, risk assessment has begun to be applied to indoor air pollutants such as radon and tobacco smoke. The purpose of this work is to review the various methodologies used in risk assessment of tobacco smoke as an indoor air The statements made in this paper are the opinions of the authors and do not necessarily represent the official policies of the U.S. EPA or the Naval Research Laboratory. * U.S. Environmental Protection Agency, Washington, D.C. 20460. Naval Research Laboratory, Washington, D.C. 20375.
27
0272-4332/90/0300-0027506.W/l 0 19M Society for Risk Analysis
Repace and Lowrey
28
lent has been used as a unit of exposure, as well as a unit of risk. However, when used as a measure of exposure it is imprecise, and when used as a measure of risk it is a complex and potentially meaningless process.(') For example, the statement that "nonsmokers' exposures are orders of magnitude lower than the exposures represented by smoking a single cigarette"(43) might conceal a significant risk from ETS compared to a de minimis risk, or a significant exposure to harmful pollutants.(') More sophisticated attempts at risk assessment of passive smoking have ranged from extrapolation from the risks in smokers to the risks in nonsmokers by scaling the levels of nicotine or its metabolite, continine, in the body fluids of smokers to that in nonsmokers, to directly using the epidemiology of passive smoking to derive an exposure-response relationship. These will be reviewed in the context of the four classic components of risk assessment: Hazard Assessment, Exposure Assessment, Exposure- or Dose-Response, and Risk Characterization.
halation of the smoke from tobacco products, it is not surprising that in the absence of any known threshold for effect, exposure to diluted exhaled and sidestream smoke should also be capable of causing human morbidity and mortality. Combustion of tobacco products indoors contaminates indoor air with nearly 5000 chemicals,("g) 43 of which are carcinogenic with "sufficient evidence" by IARC criteria.('O) The source strength of tobacco products is such that smoking indoors causes large elevations of indoor pollutants above ba~kground.("-'~)On the basis of controlled experiments and field studies, nonsmokers are known to absorb significant amounts of tobacco combustion product^;(^^-^^) amounting to, in the most-exposed individuals, to levels 5-7% of those in smokers, and in the average case, about 1%of the levels in active smokers. On'the basis of 13 epidemiologic studies('v2)available in 1985, ETS was judged as a cause of lung cancer in nonsmokers by the U.S. Surgeon General and the National Research Council.
3. EXPOSURE ASSESSMENT 2. HAZARD ASSESSMENT
In 1986, more than 50,000,000 U.S. smokers aged 2 17 yr smoked about 584 billion cigarettes They consumed an additional 3.2 billion cigars, as well as an estimated 24.4 million pounds of tobacco for pipes and hand-rolled cigarettes.(2)The average U.S. cigarette smoker smokes 32 cigarettes per day at a rate of 2 cigarettes per Measurements of the mass of tobacco from 7 popular brands of filtered and unfiltered cigarettes showed that the average is about 314 gram per cigarette,(46)indicating that the total tonnage of tobacco consumed in the U.S. is 471,480 metric tons (tonnes) [438,000 tonnnes of tobacco from cigarettes plus 11,078 tonnes from pipes, plus (at about 7 gkigar) 22,000 tonnes from cigars]. The average person spends about 90% of the time indoors,(24)suggesting an estimated 424,330 metric tons are emitted into U.S. indoor microenvironments each year from tobacco smoking at 1986 consumption rates. The toxicity of tobacco smoke is such that a 35-yr old male smoker incurs a 33% lifetime risk of dying from his smoking, and if he dies from his smoking, he will lose on average 13 years of life.c3) Currently, the excess mortality from intentional inhalation of tobacco smoke is estimated at 390,000 deaths per year,(21)a total unapproached by any other environmental agent. Given the large magnitude of mortality caused by exposure to tobacco smoke by high-level exposure from direct in-
Exposure to ETS can be quantified either by atmospheric or biological markers. Of the latter, expired carbon monoxide, carboxyhemoglobin, plasma thiocyanate, plasma, urinary, or salivary nicotine, and cotinine have been used to evaluate exposure to ETS. However, successful attempts to quantify the degree of exposure have been limited largely to measurements of nicotine and cotinine. Urinary nicotine is a sensitive indicator of recent ETS exposure, while continine appears to be the short-term marker of choice for epidemiologic studies. Nicotine and cotinine are the best markers currently available. Levels in body fluids may be elevated 10 or more times in the most heavily exposed groups of nonsmokers compared with the least-exposed groups. Few nonsmokers have been found to have body fluids free of ~ o t i n i n e Mean .~ levels of urinary nicotine and cotinine in body fluids both increase with an increasing self-reported ETS exposure, and with an increasing number of cigarettes smoked per day by active smokers.(') The average concentration of cotinine in the blood of habitual smokers is about 300 ng/ml, and has been calculated to represent the consumption of about 36 mg of nicotine per day.cg) Based on the assumption that formation of cotinine from nicotine and clearance from the body does not differ substantially from smokers to nonsmokers, present data suggest that average urban nonsmokers (in the U.K.) take in 0.2 mg of nicotine per day") (0.2 mg represents 0.6% of the smokers' dose).
29
Risk Assessment Methodologies in Passive Smoking
However, since nonsmokers clear cotinine at about 1/3 to 1/2 of the rate of the effective dose may be proportionately higher. A recent study of urinary cotinine levels in 663 U.S. never- and ex-smokers who attended a cancer screening clinic in Buffalo, New York in 1986 showed that 91% of the subjects had detectable concentrations, averaging about 10 ng/ml. The most frequently mentioned sources of exposure were at work (28%) and at home (27%) (K.M. Cummings, personal communication). In summary, based upon the limited studies (none of which are a probability sample of U.S. nonsmokers) of cotinine in body fluids of nonsmokers,(’) nonsmokers appear to have on the order of 1% of the nicotine uptake of smokers. However, these estimates must be interpreted with caution; relative absorption of nicotine in smokers and nonsmokers may substantially underestimate exposure to other components of ETS.(’) Alternatively, human exposure to ETS has been estimated using approaches similar to those used for other airborne pollutants. Measures of exposure to individual atmospheric smoke constituents can be used as estimates of whole smoke exposure. The accuracy of this approach is limited by changes in the composition of ETS with time and conditions of exposure. One widely reported marker of ETS is respirable suspended particulate matter (RSP). Although tobacco smoke is not the sole source of RSP, the prevalence and number of smokers correlates well with RSP levels in homes and other enclosed areas. The Harvard study of indoor air pollution in six cities,” demonstrated that exposures to ETS at home and at work are significant contributors to personal exposures. In general, measurements in a large number of locations using measures of smoke generation, such as the number of people smoking or the number of cigarettes being smoked, have shown a definite relationship of smoke generation to particulate levels. In US. homes, there are few other sources of RSP and, therefore, the relationships of RSP measurements to ETS are quite accurate.(l) Repace and L o ~ r e y ( ~measured l) RSP concentration using a piezobalance in several public and private locations, in both the presence and absence of smoking. They then developed an empirical model utilizing the mass balance equation. Using both measured and estimated parameters as input to the model, they validated the model for predicting an individual’s exposure to RSP from ETS.(’) They estimated that the average exposure of the nonsmoking adult population to tars from ETS was 1.43 mg/day, varying from 0 to 14 mg/day.(%)Kuller et al.Q5)in reviewing the latter estimate, observed that
the ratio of average exposure in passive smoking to that in active smoking, was about 0.3%. This translates into 3% of the smoker’s exposure for the most-exposed passive smokers, reasonably consistent with estimates based on doses from nicotine and cotinine, above. Based upon field studies in smoking buildings, RSP from ETS appears to account for 80-90% of the RSP levels in these spaces.(42) In summary, using either the best biological marker (cotinine) or the best atmospheric marker (RSP) produces a consistent assessment of average ETS exposure (i.e., on the order of 0 5 1 . 0 % of that in smokers). The most-exposed individuals appear to have levels about 10 times higher.(24)Based upon limited data, the typical nonsmoker appears to carry a daily body burden of about 0.2 milligrams (mg) of nicotine. The cotinine-based estimates have the advantage that they reflect actual dose of an ETS constituent. They have the disadvantage that they do not reflect a wide distribution of target populations, are based mostly on UK ETS exposures, and may substantially underestimate exposures to other constituents of ETS. The RSP-based estimates have the advantage that they are model-based, can be used to estimate exposures in a variety of microenvironments, represent the great bulk of ETS carcinogens, and can be compared with atmospheric measurements of RSP. They have the disadvantage that they do not represent whole smoke exposure, and do not reflect absorbed dose. The greatest source of uncertainty is that neither cotinine nor RSP measurements are based on a national probability sample, and on an absolute scale, represent a limited amount of data. Nevertheless, the NRC (1986), the SG (1986), and IARC (1987) have found this an adequate basis for exposure assessment purpose^.('*^^^) 4. EXPOSURE-RESPONSE
In 1986, there were 13 epidemiologic studies, spanning six cultures, which formed the basis for the judgments of the NRC and the Surgeon General about lung cancer from passive smoking. Although exposures take place outside the home, nearly all of these studies assessed exposure solely on the basis of reported spousal smoking habits as the surrogate exposure variable. This might be expected to dilute the power of these studies to show an effect. Nevertheless, when these 10 casecontrol and three prospective studies of passive smoking are broken down by gender into 21 substudies, 15 of the 21 epidemiologic studies(’.’) implicate ETS as a cause of lung cancer in nonsmokers. The Surgeon General,(’) the National Research Council,(’) and the World Health
30
Organization(lo)concluded that these studies prove causality between ETS exposure and lung cancer. (Since 1986, five additional studies examining the relation between ETS and lung cancer in nonsmokers have been published; three of five noted a significant correlation.) Based mostly on these studies, a number of workers have moved to quantify this risk. There are now nine risk assessments of lung cancer deaths (LCDs) from ETS; they may be conveniently divided into three groups: (1) extrapolations of risks in smokers; (2) attributable risk estimates; and (3) phenomenological estimates. Where numerical estimates of lung cancer are not given separately, estimates are inferred based upon information given in each paper. 4.1. Extrapolation Based on Risks in Smokers
F ~ n g (estimated ~~) the hazard of ETS exposure to nonsmokers (both never- and ex-smokers) by comparing the ratio of the average estimated inhaled exposure to nonsmokers’ lungs with that of mainstream smoke to smokers-ETS comprises two thirds of the total smoke produced from a cigarette. Fong assumed the carcinogenic response to ETS in nonsmokers is the same as that for active smoking in smokers, and that it extrapolates linearly, with alternative consideration of possible sublinear effects at low doses. Fong estimated that ETS has from about 2% to about 8% of the effect on nonsmokers that it does on smokers, and estimated that this causes from 10,000-50,000 nonsmokers deaths per year from all causes, in a population of 220,000,000 nonsmokers, and causes an average loss of life expectancy from 48 days to 225 days averaged over this population. Although Fong did not give a separate estimate of LCDs, by using the figures that 25% of smokers who die from smoking succumb to lung cancer,(21)and assuming nonsmokers’ deaths from ETS to be in the same ratio, these figures roughly place Fong’s estimate of LCDs from ETS in 1980 at 2500-12,500 per 220,000,000 at risk. Since there were only about 62 million nonsmokers at risk for lung cancer in 1980,(24)this would place the LCD estimate interpolated from Fong’s calculation at 600-3500 LCDs per year from ETS exposure. Adjusted to 1988 by the ratio of total LCDs in 1988 (139,000) to that in 1980 (101,300) American Cancer Society, personal communication, Fong’s interpolated estimates become 960-4800. Fong used physical and statistical analysis based on low- and high-density exposures to ETS, where he assumed that the average daily exposure of a working adult consisted of l l h of low-density exposure and 1 hr of
Repace and Lowrey
high-density exposure. Fong considered every workplace with more than three workers to have at least one smoker. He calculated a daily low-density exposure of a nonsmoker at 0.93 cigarette equivalents, and highdensity exposure to result in 0.64 cigarette-equivalents per day, for a total of 1.56 cigarette equivalents per day (ceqd) at the upper extreme, or 1/13th of that of a smoker, for an estimated 1980 death rate from passive smoking of 50,OO deaths per year. Alternatively, based on Hirayama’s Japanese prospective study of passive smoking and lung cancer, Fong estimated a nonsmoker’s ETS exposure 1/60 of that of an active smoker from smoking, corresponding to an excess death rate of 10,000 deaths per year from passive smoking. ) a dose-response relation Russell et a f . ( 2 2derived based upon the ratio of the (1985) mortality rate in the U.K. from active smoking to the average urinary nicotine concentration in a sample of smokers. They multiplied this (linear extrapolation) by the average urinary nicotine concentration in a sample of nonsmokers to yield an estimate of the nonsmokers’ (presumably including both never- and ex-smokers) mortality rate from passive smoking. Russell et a f . found that the average concentration of nicotine in the urine of 188 nonsmokers was 10.8 ng/ml, 0.7% of the average of 1471 ng/ml in a sample of 229 cigarette smokers. The highest values of urinary nicotine reported were 92.6 ng/ml, reported after two h exposure in a “poorly ventilated public house,” or 6.3% of the average levels found in smokers, which was said to be about half the steady-state value that nonsmokers could reach if they spent most of the day in such conditions (the plasma half-life of nicotine in smokers is about 2 hr).(22)Thus, the range between the estimated mean nonsmoker ETS dose of nicotine (1%)and the extreme dose (10%) is about a factor of 10. Then, predicated upon an assumption that smokers and nonsmokers excrete nicotine at the same rate (an incorrect(’5) but conservative assumption), and that these results are representative of the whole U.K. population (these “biased upwards in social class” nonsmokers were expected to have “slightly less” exposure than the general population), Russell et af. estimated 4000 total U.S. ETS-related deaths peryear from all causes. Russell has stated that his estimates were intended to be “conservative” and that the true risk could “well be double” his estimate (M.A.H. Russell, personal communication). Based upon the foregoing, the number of lung cancer deaths from passive smoking implied by Russell’s figure may be estimated as follows: again assuming 25% of the U.S. deaths from smoking are due to lung cancer,(21)and that smokers inhale 36 mg of nicotine per day,(g)a unit LCD risk from ETS can be estimated [using
Risk Assessment Methodologies in Passive Smoking
nicotine as a surrogate for the carcinogenic agents in ETS-nicotine has been found to bear a 1:lO ratio to RSP in ETS (B. Leaderer, personal communication)]. Predicated upon Russell et al.3 analysis, it is estimated at 5000 LCDsbr per mg of nicotine inhaled per day, based upon linear extrapolation from the risks in smokers. Russell et aZ.'s interpolated estimate of U.S. lung cancer deaths is calculated to be 1000 LCDs/yr (5000 LCDs/yr per mg nicotine/day x 0.2 mg nicotine/day). Adjusting the 1985 figure to 1988 by the ratio of total LCDs in 1988 to those in 1985 (139,000/125,600), yields an estimated 1107 LCDslyr. Robins23 also estimated 1985 U.S. LCD rates in never-smokers from ETS using urinary cotinine dosimetry, extrapolating by applying the nonlinear multistage model of cancer risk to the data on the lung cancer experience of active smokers. Robins estimated a range of exposure for nonsmokers to ETS from 0.1 to 2.8 cigarette equivalents per day (cpd), where those with smoking spouses have a range of from 0.4-2.8 cpd, and those with nonsmoking spouses have a range of from 0.1-0.9 cpd, based on extrapolations from urinary cotinine in smokers. In this manner, Robins estimated about 2500-5200 U.S. deaths in lifelong nonsmokers per year from passive smoking; 1770-3320 in females, and 7201940 in males. The range in estimates was developed over 30 exposure histories and 5 choices of extrapolation coefficients in the model. Robins estimates the average lifetime risk to never-smokers to range from 4-9.9 per thousand, and for ex-smokers (1 pack per day, ages 1845) to range from 5-20 per thousand. Adjusting Robins 1985 estimate to 1988, as above, yields an estimated 2768-5535 LCDslyr, or an average of 4152 LCDs/yr. Adjusting further to include ex-smokers (in 1985, according to Statistical Abstracts of the U.S., 43.7% of the population were never-smokers, and 24.4% were exsmokers), Robins' estimates, adjusted to 1988, range from 4314-8625, and average 6470 LCDs/yr. Repace and Lowrey(") estimated a lower-bound exposure-response relationship for passive smoking and lung cancer based on active smoking lung cancer risks in smokers and their lung exposure to RSP from mainstream smoke. It was in magnitude about 6 x LCDs/yr per mg tadday per smoker of lung cancer age (235 yr). Using the one-hit model for cancer induction (equivalent to a linear assumption in this dose-range) for extrapolation of the risks to the modeled exposure of the typical nonsmoker (1.4 mg/day), multiplied by the nonsmoking population at risk (62 million persons, aged 1 35 yr) Repace and Lowrey estimated 555 nonsmokers' 1980 lung cancer deaths per year using this technique. Adjusted to 1988, this yields 760 LCDs/yr. However,
31
this exposure-response relationship was found to be inconsistent with the epidemiology of passive smoking, and was abandoned in favor of a phenomenologic model, described below.(".25) Arundel, et u L . ( ~ O ) used a linear extrapolation based upon the risks in smokers to estimate the risks of passive smoking and lung cancer in nonsmokers (never-smokers only). The exposure part of the exposure-response relation was based upon a weighted exposure of nonsmokers to particulate matter from ETS, taken over homes, workplaces, and restaurants and bars separately for men and women, and equaled 0.62 mg/day for men, and 0.28 mg/day for women. Averaged over men and women, this is about 0.45 mg/day, or about 1/3 of that estimated for the typical nonsmoker by Repace and Lowrey bel0w.0~)Retained exposures were calculated by assuming an 80% retention in smokers' lungs and an 11% retention in nonsmokers. The response was estimated to be 284 LCDs per 100,000 male current smokers, and 121 LCDs per 100,000 in female smokers all of age 35 or greater. [The exposure-response relationship is calculated here approximately (averaging over men and women smokers for purposes of comparison) as 203 LCDs per 100,000 LCDs per PY PY per 280 mg/day, or about 7 x per mg/day.] Arundel et al. estimate that the average domestic exposure retained is 0.09 mg/day (men and women averaged here) for a predicted excess risk of domestic passive smoking of 0.06 LCDs per 100,000 PY. If the baseline risk is taken as 8.7 LCDs per 100,000 PY,(24) the relative risk from domestic passive smoking according to Arundel et al. is calculated as 1.006. This is inconsistent with epidemiologic observations of the risk of domestic smoking and lung cancer which have been estimated by the NRC to be about 1.3. This approach of Arundel et al. has also been criticized by Repace and Lowrey(") as inconsistent with the dose-response curve for active smoking, which appears to be nonlinear. The risk of lung cancer from passive smoking is calculated by Arundel et al. by multiplying the smokers' risk times the retention ratio to calculate an average passive smoking risk of 0.064 LCDs per 100,000 PY for men, and 0.015 LCDs per 100,000 PY for women. An average of about 4 x lo-' LCDsPY is calculated, about an order of magnitude lower than the one-hit model estimate of Repace and Lowrey, above. By multiplying by the never-smoking population at risk (ex-smokers are excluded), and taking other uncertainties into account, Arundel et aZ. estimate between 12 and 62 LCDs per year. Adjusting this estimate for 1980-1988 yields an estimated 16-85 LCDs per year, for an average of 50 LCDs/yr. Further adjusting to include exsmokers, the
32 range varies from 19-97, and the estimated average becomes 58 LCDs/yr. 4.2. Attributable Risk Estimates
Wigle ef ~ l . ( ~compiled l) information on the proportion of people who had never smoked among victims of lung cancer in Canada. They estimated that exposure of the Canadian population to ETS respirable suspended particulate matter (RSP) was similar to that estimated for ~ )mg/ the U.S. population by Repace and L o ~ r e y , ‘ ~1.4 day. Wigle et al. observed that Canadian ETS exposure values appear to be similar to those in the U.S. Wigle et al. calculated the population proportion attributable to the risk of lung cancer using the Cole-McMahon formula, estimates of the prevalence of exposure to smoking by spouses, and the weighted-average relative risk of lung cancer for exposed nonsmokers in 12 epidemiological studies. They then applied this relative risk to the age- and sex-specific rates of death from lung cancer used by Repace and L o ~ r e y (to~ derive ~) the excess risk of lung cancer from passive smoking in Canada. They estimated that Canada, with about 10% of the population of the U.S. has 330 lung cancer deaths per year attributable to domestic and workplace smoking, with about 16% of those deaths estimated to come from domestic exposure to ETS, and 83% from workplace (a ratio of about 5:1, comparable to the estimates of Tancrede et al. and Repace and Lowrey, below.) Extrapolating Wigle et d ’ s Canadian estimate to the U.S. population places the estimate at 3300 LCDs/yr, and adjusting to 1988 places the U.S. estimate extrapolated from Wigle’s estimate at 3652 LCDsbr. Further adjusting to include ex-smokers yields 5691 LCDs/yr. Wells(32)reviewed the literature on adult mortality from passive smoking. Combined relative risks for lung cancer, other cancer, heart disease, and emphysema for males and females were calculated via a meta-analysis technique which calculated weighted-average risk ratios from epidemiologic studies of passive smoking. A correction for misclassification of smokers as nonsmokers was applied. Nonsmokers’ baseline death rates in the absence of passive smoking were estimated from the American Cancer Society study of mortality in 1,000,000 U.S. men and women by Hammond (NCI monograph 19), and Garfi11ke1.c~~) Wells’s preliminary risk assessment of U.S. passive smoking deaths from the four diseases was made by applying the relative risks from the passive smoking literature to estimates of the exposed population and nonsmoker death rates. Wells estimated
Repace and Lowrey
that as a result of passive smoking, in 1985 there were 3000 passive smoking lung cancer deaths per year in nonsmokers (never-smokers plus ex-smokers) aged 2 35 yrs., 11,000 from other cancers, and 32,000 deaths from heart disease, for a total of 46,000 nonsmoker deaths per year. Adjusting Wells 1985 LCD estimate to 1988 yields 3320 LCDs/yr. Wald et performed a statistical analysis of 10 case-control and three prospective studies of lung cancer in nonsmokers from ETS exposure. They calculated a weighted relative risk of 1.35 (95% CL 1.19-1.54) for nonsmokers living with smokers relative to nonsmokers living with nonsmokers. They estimated that adjustment for the effect of misclassification of smokers as nonsmokers reduced this risk to 1.30, but a further adjustment for finite urinary cotinine levels in nonsmokers living with nonsmokers (i.e., the effect of exposure outside the home) raised the total estimated risk to 1.53. That is, 57% of the risk was estimated to come from domestic smoking, and 43% of the risk from other exposures e.g., the workplace based on two U.K. studies of urinary cotinine. Wald et al. estimate that about a third of the cases of lung cancer in nonsmokers who live with smokers, and about a quarter of the cases among nonsmokers (never-smokers) in general, may be attributed to ETS exposure. Since there were about 20,850 LCDs in U.S. nonsmokers in 1988, this would place Wald et al.’s estimate adjusted to 1988, at about 5213 LCDs per year in both male and female lifelong nonsmokers, and adjusting to include ex-smokers yields 8124 LCDs/yr. ) reviewing the 13 epidemologic Kuller et u I . , ( ~ ~ in studies, considered issues of misclassification of exposure, of pathology, and of controls. Without formally defining an exposure-response relationship (husbands’ smoking is the surrogate exposure variable, and lung cancer in the nonsmoking wife is the response), they concluded that data indicate that “the greater number of lung cancers in nonsmoking (never smokers only) women is probably related to environmental tobacco smoke.” Kuller et al. estimate that there are 6000 to 8000 lung cancer cases each year from all causes in lifelong nonsmoking women; this would place Kuller e f al.’s 1985 estimate roughly at 3500 LCDs per year in never-smokers. Adjusting to 1988 yields 3873 LCDs/yr. If the estimate is extended to include effects in ex-smokers, this would increase to about 6035 LCDs per year. They also concluded that effects of ETS on the cardiovascular system, especially among high-risk individuals, may be of greater concern than cancer and would require further study.
Risk Assessment Methodologies in Passive Smoking 4.3. Phenomenological Risk Estimates
Repace and Lo~reqX*~) assessed nonsmokers’ (neversmokers plus ex-smokers) risk of lung cancer due to RSP exposure from ETS using a phenomenological model. An exposure-response relationship was derived, with the response estimated from the age-standardized differences in lung cancer mortality rates between two demographically comparable cohorts of lifelong nonsmokers, one of which (SDAs) had a lifestyle with a high percentage of restrictions on smoking at home and at work relative to the other cohort (NonSDAs). This method avoids problems of misclassification in nonsmokers’ selfreports, since two groups of lifelong nonsmokers are compared. Also, the SDA study is independent of the 13 epidemiological studies considered by the Surgeon General and the NRC. The estimated average nonsmoker’s exposure of 1.43 mg/day was calculated by modeling the population’s exposure to RSP from ETS in the two most-frequented microenvironments(88% of people’s time), at home and at work. Repace and L o ~ r e y (estimated ~~) for 1980 that 4700 LCDs occurred annually due to ETS exposure in the home and the workplace among 62.4 million nonsmokers (never-smokers plus ex-smokers) age 2 35 years. The initial calculation did not differentiate between male and female nonsmokers, and age-standardized the calculation to the entire U.S. population, which included smokers. However, in a later calculation, the results were adjusted for sex and standardized to the nonsmoking population.(25)This new calculation estimated about 1440 male nonsmoker and 3450 female nonsmoker deaths, for a revised total of about 4900 LCDs per year. Adjusting this 1980 population estimate to 1988 yields 6724 ? 336 LCDs/yr. To estimate uncertainty, Repace and Lowrey,(2”-26) using an exposure-response relation derived from combining the risks from the SDA study with the average estimated RSP inhalation for nonsmokers, calculated the expected risk ratio and risk rate for the 1981 American Cancer Society cohort studied by Garfinkel,cZ7)the odds ratio in a 1985 case-control study by Garfinkel,c2*)and the risk ratio for domestic passive smoking derived from the 13 world epidemiological studies analyzed by the NRC.(2) The calculations in every case agreed with observational results to within 5%. This suggested the uncertainty(29)in this risk estimate is ? 5%, or ? 300 LCDs. The predicted risk of domestic passive smoking using the phenomenologic model is 26%, for a relative risk ratio of 1.26, which compares with Wald’s estimated risk of 1.30, and the NRC‘s of 1.32, adjusted for
33 misclassification. Repace and L o ~ r e y (utilized ~ ~ ) an exposure-response relationship of 5 lung cancer deaths per 100,000 person-years at risk, per mg of exposure to tobacco tar per day. They estimated a lifetime risk of about 2/100to the most-exposed passive smokers. Based on estimates of probability-weighted exposure given by that the probabilRepace and L o ~ r e y , (and ~ ~ assuming ) ity of exposure for a nonsmoker (men and women averaged together) who is exposed to ETS both at work and at home is the same for both microenvironments, they estimated average home and workplace exposures at 0.55 mg/day (for 70 yr) and 0.89 mg/day (for 40 yr), respectively, with the longer exposure at home accounting for childhood exposures. Under these assumptions, the estimated home and workplace risks are each about 2/1000 and 50% of the average population risk from passive smoking is estimated to be workplace-related, which compares with an estimate of 43% derived from Wald et al. Tancrede et u Z . ( ~ O ) analyzing Repace and Lowrey’s calculations, used a 4:l ratio between workplace and domestic exposures, and estimated an average excess lifetime cancer risk for domestic passive smoking of 2/ 1000, and for the workplace, 8/1000. Nine published risk assessments, performed by US., Canadian, and U.K. researchers, have examined the question of the risk to nonsmokers from exposure to ETS. These assessments employed three different methodologies: dosimetry based upon nocotine or cotinine in body fluids; modeled exposure of the population to tobacco tar (i.e., ETS-derived RSP), and attributable risk based upon the presence or absence of a substantial (i.e., household) ETS exposure history. Several of the methods applied extrapolation models, and several used epidmemiologic results only. Some tried both approaches. The results of the nine risk assessments are given in Table I, and for the purposes of interstudy comparison of these diverse risk assessment methodologies, are adjusted to 1988, and include ex-smokers, where the authors did not include them (in two cases, the number of LCDs had to be interpolated from the authors estimate of total mortality from passive smoking). These risk assessments have utilized three different methodologies: dosimetry based upon nicotine and its metabolite, cotinine; exposure, based upon RSP from ETS; and epidemiology, based on an assessment of nonsmokers’ lung cancer rates in the presence and absence of an ETS exposure histov. The range of estimates runs from 58 LCDs per year to 8124 LCDs per year. The mean and standard deviation of all estimates is 4500 f 2800, and if Arundel et al.’s estimate (which is more than 2 SD from the
34
Repace and Lowrey Table I. Summary of Risk Assessments of Lung Cancer in U.S. Nonsmokers from ETS Exposure (Adjusted 1988 LCD Figures) ~
Study Fong (1982)" Repace and Lowrey (1985-1987) Russell et al. (1986)" Robins (1986) Wells (1988) Wald ef al. (1986) Kuller et al. (1986)" Wigle er al. (1987) Arundel el al. (1987) Mean, all nine studies: Mean, eight studies, excluding Arundel et al.
Range of estimates (LCDs per year)
-
96P 480W 685d - 685P 43148 - 8625h
(female LCDs only) (83% workplace)" 19 - 97
Mean or best estimate (LCDs per year) 2900 6700 2 340 1107' 6470 332@ 812@ > 6035' 5691' * 58'" 4500 2 2800 5000 2 2400
Based on linear extrapolation from nicotine in smokers. Based on urinary cotinine and ETS epidcmiology. * Based on linear multistage from smokers and urinary cotinine. Lower bound based on smokers' RSP exposure extrapolation (adjusted to include ex-smokers). Best estimate based on epidemiology (adjusted to include ex-smokers). Based on extrapolation of Canadian results to U.S. nonsmokers. I Based on ETS epidemiology and nonsmokers' LCD rates (adjusted to include ex-smokers). * Based on sublinearity assumption at low doses. Based on linearity assumption at low doses. j Based on urine cotinine in U.K. nonsmokers, ETS epidemiology (adjusted to include ex-smokers). Based on numerical interpretation of qualitative judgment. Based on linear extrapolation from retained RSP in smokers. a Estimate ours, interpolated from author's overall risk estimate. f
8
'
mean of the others) is excluded, 5000 & 2400 LCDs per year. In the latter case, given the disparity in the various methodologies used by the different risk assessors, there is a remarkable agreement (for risk assessments) with a SD about the mean of about ? 50%. The three studies which explicitly estimated the workplace contribution to the risk suggest that the workplace contributes at least half of the risk. By comparison, a study(39) of chronic obstructive pulmonary disease in SeventyDay Adventists in California showed a 7% increased risk from passive smoking at home (p < 0.01) and an 11% increased risk from passive smoking in the workplace (p < 0.001); thus for individuals exposed both at home and at work in this study, 61% of the risk appears to come from the workplace. Based upon presently available information from nicotine and cotinine dosimetry as a surrogate for total ETS exposure in nonsmokers, coupled with the epidemiologic studies of passive smoking and lung cancer, it is estimated that, for nonsmokers, there is an estimated 1% lifetime increase of lung cancer risk from ETS exposure per 1 nanogram of cotinine excreted per milliliter (ml) of urine. Similarly, the estimated risk of lung cancer from ETS exposure at home appears to amount to a
125% average lifetime increase in lung cancer risk per milligram (mg) of nicotine inhaled per day. The average levels of exposure, 0.2 mg of nicotine inhaled and 25 ng/ml of urine excreted, each corresponds, based upon epidemiologic studies of passive smoking, to an average of about 34% (risk ratio 1.34) increase in lifetime risk of lung cancer for nonsmokers. In contrast, each method (RSP and nicotinekotinine), if based upon a linear extrapolation of the risks in smokers down to the nonsmokers' dose levels (the so-called cigarette-equivalent method), yields about a 10% increase in lifetime risk per average exposure. Interestingly, however, if this latter figure is adjusted by multiplying by the ratio of the excretion half-life of urinary cotinine in nonsmokers to that in smokers, the estimated excess risk increases to about 27% (RR 1.27), consistent with the estimates based upon epidemiology. However, these half-lives are based on a small sample of smokers and nonsmokers, and further research is needed. Based upon ETS-generated RSP exposure, the phenomenological model of nonsmokers' risk of lung cancer suggests that the average risk of lung cancer from ETS exposure at home is 26% (RR 1.26), in good agreement with the biomarker estimates and with epidemiology.
35
Risk Assessment Methodologies in Passive Smoking The estimated exposure-response relation based upon ETS-generated RSP (tobacco tar) is 5 lung cancer deaths per year per 100,000 person at risk (aged 35 years or more) per milligram of tar inhaled per day, where tar is used as a surrogate for all of ETS. This exposure-response relationship has been shown to predict the observed summary odds ratio found in the 13 epidemiologic studies to within 5%, and to predict the observed risk ratio and risk rate in the large American Cancer Society cohort study of passive smoking and lung cancer also to within 5%. By contrast, extrapolation of the RSP-estimated risks from smokers' exposures to that in nonsmokers yields an estimated exposure-response relation only about 10% as high, based upon extrapolation by the one-hit or linearized multistage models. This implies a lack of linearity in the exposure-response curve at the high doses of active smoking which has been reported.(2S) 5. CHARACTERIZATION OF RISK 5.1. Risk in Perspective
The mean of all the studies, excluding Arundel et al, which differs from the others by more than two standard deviations, is 5000 +. 2400 LCDs/yr. Considering the disparity in approaches, there is a remarkable consistency in estimated nonsmokers' lung cancer mortality from ETS. Based upon two assessments of the average population risk, it is concluded that the estimated lifetime risk of ETS exposure in the U.S. appears to be about 2 x with an estimated risk of 2 x to the most-exposed nonsmokers. The risk from ETS in workplace microenvironments in general appears to be on the same order as that from the home. The fatal risks of sustained exposure to tobacco smoke at the high doses to which smokers are exposed are well established; although the chronic exposures of nonsmokers are lower, they are often significantly higher than the exposures from other indoor contaminants to which nonsmokers are typically subject from other sources. ETS contains numerous toxic and carcinogenic substances, some of which may be synergistic with other powerful lung carcinogens to which most nonsmokers are exposed (e.g., radon and asbestos). In 1990, the American Cancer Society projects 142,000 lung cancer deaths(45);of these, about 15%,or an estimated 21,000 lung cancer deaths (LCDs) occurred among US. nonsmokers (lifelong nonsmokers plus exsmokers). Although the risk estimates given above are
necessarily based on a relatively few studies which do not represent national probability samples, it appears that based upon an analysis of the risk assessment literature, ETS exposure may cause an estimated 5000 LCDs per year, or about one fourth of the lung cancer deaths of nonsmokers. By contrast, it is estimated that about 4000 LCDs per year, or about one fifth of the lung cancer deaths in nonsmokers, appear to be due to indoor radon exposure (Appendix A). Nonoccupational asbestos-related mortality has been estimated to cause less than 15 cancer deaths per year. Also, the risks of ETS exposure appear large when compared with outdoor air pollutants under regulation by EPA as hazardous air pollutants, whose total estimated cancer mortality before control is < 87 deaths per year. These risk estimates are illustrated in Table 11. Thus, it appears that the relative risks of ETS exposure to nonsmokers are 25% greater than from radon gas, and about one hundred times as great as the total from all carcinogenic outdoor air pollutants currently regulated by EPA under the Clean Air Act. Risk assessment has been useful when applied to the regulation of outdoor air pollutants; similarly, as it is applied to indoor pollutants, it can be expected to promote reductions in the much larger cancer risks attendant to the indoor environment. APPENDIX A Estimated Population Radon Risks
The NRC(37)has estimated a dose-response relationship for radon of a magnitude of 350 lung cancer
Table 11. Comparison of Estimated Cancer Deaths (CDs) from Various Airborne Carcinogens in the U.S."
Indoor pollutants Environmental tobacco smoke (homes and workplaces) 5000 CDs/yr Radon gas in homes (nonsmokers only) 4000 CDsiyr Outdoor pollutants Asbestos Vinyl chloride Airborne radionuclides Coke-oven emissions Benzene Arsenic
15 CDsiyr
