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suggest that a continuum of exposures to tobacco products starting in fetal life may contribute to the decrements in lung function found in older children. Exposure to tobacco smoke products inhaled by the mother during pregnancy may contribute significantly to these changes, but there is strong evidence indicating that postnatal exposure to ETS is an important part of the causal pathway. With respect to lung function effects in adults exposed to E7S, the 1986 NRC and Surgeon General reports found the data at that time inconclusive, due to high interindividual variability and the existence of a large number of other risk factors, but compatible with subtle deficits in lung function. Recent studies confirm the association of passive smoking with small reductions in lung function. Furthermore, new evidence also has emerged suggesting a subtle association between exposure to ETS and increased respiratory symptoms in adults. Some evidence suggests that the incidence of acute upper respiratory tract illnesses and acute middle ear infections may be more common in children exposed to ETS. However, several studies failed to find any effect. In addition, the possible role of confounding factors, the lack of studies showing clear dose-response relationships, and the absence of a plausible biological mechanism preclude more definitive conclusions. In reviewing the available evidence indicating an association (or lack thereof) between E'IS exposure and the different noncancer respiratory disorders analyzed in this report, the possible role of several potential confounding factors was considered. These include other indoor air pollutants; socioeconomic status; effect of parental symptoms; and characteristics of the exposed child, such as low birthweight or active smoking. No single or combined confounding factors can explain the observed respiratory effects of passive smoking in children. For diseases for which ETS has been either causally associated (LRIs) or indicated as a risk factor (asthma cases in previously asymptamatic children), estimates of population-attribuable risk can be calculated. A population risk assessment (Chapter 8) provides a probable range of estimates that 8,000 to 26,000 cases of childhood asthma per year are attributable to ETS exposure from mothers who smoke 10 or more cigarettes per day. The confidence in this range of estimates is medium and is dependent on the suggestive evidence of the database. While the data show an effect only for children of these heavily smoking mothers, additional cases due to lesser ETS exposure also are a possibility. .If the effect of this lesser exposure is considered, the range of estimates of new cases presented above increases to 13,000 to 60,000. Furthermore, this report estimates that the additional public health impact of ETS on asthmatic children includes more than 200,000 children whose symptoms are significantly aggravated and as many as 1,000,000 children who are affected to some degree. 1-15

two-thirds of ail children in this age group, may be exposed to cigarette smoke in the home (American Academy of Pediatrics, 1986; Overpeck and Moss, 1991). With regard to the noncancer respiratory effects of passive smoking, this report focuses on epidemiologic evidence appearing since the two major reports of 1986 (NRC and U.S. DHHS) that bears on the potential association of parental smoking with detrimental respiratory effects in their children. These effects include symptoms of respiratory irritation (cough, sputum production, or wheeze); acute diseases of the tower respiratory tract (pneumonia, bronchitis, and bronchiolitis); acute middle ear infections and indications of chronic middle ear infections (predominantly middle ear effusion); reduced lung function (from forced expiratory volume and flow-rate measurements); incidence and prevalence of asthma and exacerbation of symptoms in uthmatics; and acute upper respiratory tract infections (colds and sore throats). The more than 50 recently published studies reviewed here essentially corroborate the previous conclusions of the 1986 reports of the NRC and Surgeon General regarding respiratory symptoms, respiratory illnesses, and pulmonary function, and they strengthen support for those conclusions by the additional weight of evidence (Chapter 7). For example, new data on middle ear effusion strengthen previous evidence to warrant the stronger conclusion in this report of a causal association with parental smoking. Furthermore, recent studies establish associations between parental smoking and increased incidence of childhood asthma. Additional research also supports the hypotheses that in utero exposure to mother's smoke and postnatal exposure to ETS alter lung function and structure, increase bronchial responsiveness, and enhance the process of allergic sensitization, changes that are known to predispose children to early respiratory illness. Early respiratory illness can lead to long-term pulmonary effects (reduced lung function and increased risk of chronic obstructive lung disease). This report also summarizes the evidence for an association between parental smoking and SIDS, which was not addressed in the 1986 reports of the NRC or Surgeon General. SIDS is the most commoncattse of death in infants ages I month to I year. The cause (or causes) of SIDS is unknown; however, it is widely believed that some form of respiratory pathogenesis is generally involved. The current evidence strongly suggests that infants whose mothers smoke are at an increased risk of dying of SIDS, independent of other known risk factors for SIDS, including low birthweight and low gestational age, which are specifically associated with active smoking during pregnancy. However, available studies do not allow this report to conclude whether that increased risk is related to in utero versus postnatal exposure to tobacco smoke products, or to both. The 1986 reports of the NRC and Surgeon General conclude that both the prevalence of ' respiratory symptoms of irritation and the incidence of lower respiratory tract infections are higher in children of smoking parents. In the 18 studies of respiratory symptoms subsequent to 1-13

exposure to their smoking husbands' ETS is large enough to be observed, even for all levels of their spousal exposure combined. Carcinogenic responses are usually detectable only in high-exposure circumstances, such as occupational settings, or in experimental animals receiving very high doses. In addition, effects are harder to observe when there is substantial background exposure in the comparison groups, as is the case here. • Effects remain after adjustment for potential upward bias. Current and ex-smokers may be misreported as never-smokers, thus inflating the apparent cancer risk for ETS exposure. The evidence remains statistically significant and conclusive, however, after adjustments for smoker misclassification. For the United States, the summary estimate of relative risk from nine case-control plus two cohort studies is 1.19 (90% confidence interval (C.L) - 1.04, 1.35; p.< 0.05) after adjustment for smoker misclassification. For Greece, 2.00 (1.42, 2.g3), Hong Kong, 1.61 (1.25, 2.06), and Japan, 1.44 (1.13, 1.g5), the estimated relative risks are higher than those of the United States and more highly significant after adjusting for the potential bias. • Strong associations for highest exposure groups. Examining the groups with the highest exposure levels increases the ability to detect an effect, if it exists. Nine of the sixteen studies worldwide for which there are sufficient exposure-level data are statistically significant for the highest exposure group, despite most having low statistical power. The overall pooled estimate of 1.81 for the highest exposure groups is highly statistically significant (90% C.I. - 1.60, 2.05; p< 10-6). For the United States, the overall pooled estimate of 1.38 (seven studies, corrected for smoker misclassification bias) is also highly statistically significant (90% C.I. - 1.13, 1.70; p - 0.005). • Confounding cannot explain the association. The broad-based evidence for an association found by independent investigators across several countries, as well as the positive exposure-response trends observed in most of the studies that analyzed for them, make any single confounder highly unlikely as an explanation for the results. In addition, this report examined potential confounding factors (history of lung disease, home heat sources, diet, occupation) and concluded that none of these factors could accouotfor the observed association between lung cancer and ETS. GD ~ ~ tn 1-10 N N W

1.2. BACKGROUND Tobacco smoking has long been recognized (e.g., U.S. Department of Health, Education, and Welfare (U.S. DHEW], 1964) as a major cause of mortality and morbidity, responsible for an estimated 434,000 deaths per year in the United States (Centers for Disease Control [CDC], 1991 a). Tobacco use is known to cause cancer at various sites, in particular the lung (U.S. Department of Health and Human Services (U.S. DHHS], 1982; International Agency for Research on Cancer [IARC), 1986). Smoking can also cause respiratory diseases (U.S. DHHS, 1984, 1989) and is a major risk factor for heart disease (U.S. DHHS, 1983). In recent years, there has been concern that nonsmokers may also be at risk for some of these health effects as a result of their exposure ('passive smoking') to the tobacco smoke that occurs in various environments occupied by smokers. Although this ETS is dilute compared with the mainstream smoke (MS) inhaled by active smokers, it is chemically similar, containing many of the same carcinogenic and toxic agents. In 1986, the National Research Council (NRC) and the Surgeon General of the U.S. Public Health Service independently assessed the health effects of exposure to ETS (NRC, 1986; U.S. DHHS, 1986). Both of the 1986 reports conclude that ETS can cause lung cancer in adult nonsmokers and that children of parents who smoke have increased frequency of respiratory symptoms and acute lower respiratory tract infections, as well as evidence of reduced lung function. More recent epidemiologic studies of the potential associations between E7S and lung cancer in nonsmoking adults and between ETS and noncancer respiratory effects more than double the size of the database available for analysis from that of the 1986 reports. This EPA report critically reviews the current database on the respiratory health effects of passive smoking; these data are utilized to develop a hazard identification for ETS and to make quantitative estimates of the public health impacts of ETS for lung cancer and various other respiratory diseases. The weight-of-evidence analysis for the lung cancer hazard identification is developed in accordance with U.S. EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a) and established principles for evaluating epidemiologic studies. The analysis considers animal bioassays and genotoxicity studies, as well as biological measurements of human uptake of tobacco smoke components and epidemiologic data on active and passive smoking. The availability of abundant and consistent human data, especially human data at actual environmental levels of exposure to the specific agent (mixture) of concern, allows a hazard identification to be made with a high degree of certainty. The conclusive evidence of the dose-related lung carcinogenicity of ~ ~ ~ tJi 1-2 N F+ tn Ul

exposure group; 9 of these are significant at the p< 0.05 level, despite most having low power, another result highly unlikely to occur by chance (p < 10'7). Similarly, the proportion (10/14; p< 10'9) showing a statistically significant exposure-response trend is highly supportive of a causal association. Combined results by country showed statistically significant associations for Greece (2 studies), Hong Kong (4 studies), Japan (5 studies), and the United States (I I studies), and in that order of strength of relative risk. Pooled results of the four Western European studies (three countries) actually showed a slightly stronger association than that of the United States, but it was not statistically significant, probably due to the smaller sample size. The combined results of the Chinese studies do not show an association between ETS and lung cancer, however, two of the four Chinese studies were designed mainly to determine the lung cancer effects of high levels of other indoor air pollutants indigenous to those areas, which would obscure a smaller ETS effect. These two Chinese studies do, however, provide very strong evidence on the lung carcinogenicity of these other indoor air pollutants, which contain many of the same components as ETS. When results are combined only for the other two Chinese studies, they demonstrate a statistically significant association for ETS and lung cancer. The heterogeneity of observed relative risk estimates among countries could result from several factors. For example, the observed differences may reflect true differences in lung cancer rates for never-smokers, in ETS exposure levels from nonspousal sources, or in related lifestyle characteristics in different countries. For the time period in which ETS exposure was of interest for these studies, spousal smoking is considered to be a better surrogate for ETS exposure in more 'traditional' societies, such as Japan and Greece, than in the United States. In the United States, other sources of ETS exposure (e.g., work and public places) are generally higher, which obscures the effects of spousal smoking and may explain the lower relative risks observed in the United States. Nevertheless, despite observed differences between countries, all showed evidence of increased risk. Based on these analyses and following the U.S. EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a), EPA concludes that environmental tobacco smoke is a Group A (known human) carcinogen. This conclusion is based on a total weight of evidence, principally. • Biological plausibility. ETS is taken up by the lungs, and components are distributed throughout the body. The presence of the same carcinogens in ETS and MS, along with the established causal relationship between lung cancer and active smoking with the dose-response relationships exhibited down to low doses, establishes the plausibility that ETS is also a lung carcinogen. 1-8

MS in active smokers (Chapter 4), coupled with information on the chemical similarities of MS and ETS and evidence of E7S uptake in nonsmokers (Chapter 3), is sufficient by itself to establish ETS as a known human lung carcinogen, or'Group A' carcinogen under U.S. EPA's carcinogen classification system. In addition, this document concludes that the overall results of 30 epidemiologic studies on lung cancer and passive smoking (Chapter 5), using spousal smoking as a surrogate of ETS exposure for female never-smokers, similarly justify a Group A classification. The weight-of-evidence analyses for the noncancer respiratory effects are based primarily on a review of epidemiologic studies (Chapter 7). Most of the endpoints examined are respiratory disorders in children, where parental smoking is used as a surrogate of El5 exposure. For the noncancer respiratory effects in nonsmoking adults, most studies used spousal smoking as an exposure surrogate. A causal association was concluded to exist for a number of respiratory disorders where there was sufficient consistent evidence for a biologically plausible association with ETS that could not be explained by bias, confounding, or chance. The fact that the database consists of human evidence from actual environmental exposure levels gives a high degree of confidence in this conclusion. Where there was suggestive but inconclusive evidence of causality, as was the case for asthma induction in children, E7S was concluded to be a risk factor for that endpoint. Where data were inconsistent or inadequate for evaluation of an association, as for acute upper respiratory tract infections and acute middle ear infections in children, no conclusions were drawn. This report also has attempted to provide estimates of the extent of the public health impact, where appropriate, in terms of numbers of ETS-attributable cases in nonsmoking subpopulations. Unlike for qualitative hazard identification assessments, where information from many sources adds to the confidence in a weight-of-evidence conclusion, for quantitative risk assessments, the usefulness of studies usually depends on how closely the study population resembles nonsmoking segments of the general population. For lung cancer estimates among U.S. nonsmokers, the substantial epidemiology database of ETS and lung cancer among U.S. female never-smokers was considered to provide the most appropriate information. From these U.S. epidemiology studies, a pooled relative risk estimate was calculated and used in the derivation of the population risk estimates. The large number of studies available, the generally consistent results, and the condition of actual environmental levels of exposure increase the confidence in these estimates. Even under these circumstances, however, uncertainties remain, such as in the use of questionnaires and current biomarker measurements to estimate past exposure, assumptions of exposure-response linearity, and extrapolation to male never-smokers and to ex-smokers. Still. given the strength of the evidence for the lung carcinogenicity of tobacco smoke and the extensive human database from actual environmental exposure levels, fewer assumptions are necessary than 1-3 m ~ ~ tn N 4+ C!1 C7

considered to have the lowest confidence, and the assumptions used are thought to make this estimate low as well. Workplace E7S levels are generally comparable with home ETS levels, and studies using body cotinine measures as biomarkers demonstrate that nonspousal exposures to ETS are often greater than exposure from spousal smoking. 'I'hus, this report presents an alternative breakdown of the estimated 3,000 E7S-attributable lung cancer deaths between spousal and nonspousal exposures. By extension of the results from spousal smoking studies, coupled with biological measurements of exposure, more lung cancer deaths are estimated to be attributable to ETS from combined nonspousal exposures--2,200 of both sexes--than from spousal exposure--g00 of both sexes. This spouse-venus-other-sources partitioning depends on current exposure estimates that may or may not be applicable to the exposure period of interest. Thus, this breakdown contains this element of uncertainty in addition to those discussed above with respect to the previous breakdown. An alternative analysis, based on the large Fontham et al. (1991) study, which is the only study that provides biomarker estimates of both relative risk and ETS exposure, yields population risk point estimates of 2,700 and 3,600. These population risk estimates are highly consistent with the estimate of 3,1N10 based on the combined U.S. studies. While there is statistical variance around all of the parameters used in the quantitative assessment, the two largest areas of uncertainty are probably associated with the relative risk estimate for spousal ETS exposure and the parameter estimate for the background ETS exposure adjustment. A sensitivity analysis that independently varies these two estimates yields population risk estimates as low as 400 and as high as 7,000. These extremep, however, are considered unlikely; the more probable range is narrower, and the generally conservative assumptions employed suggest that the actual population risk number may be greater than 3,000. Overall, considering the multitude, consistency, and quality of all these studies, the weight-of-evidence conclusion that ETS is a known human lung carcinogen, and the limited amount of extrapolation necessary, the confidence in the estimate of approximately 3,000 lung cancer deaths is medium to high. , 1.3.2. E75 aa1 No.caacer Respiratory Disorders Exposure to ETS from parental smoking has been previously linked with increased respiratory disorders in children, particularly in infants. Several studies have confirmed the exposure and uptake of E7S in children by assaying saliva, serum, or urine for cotinine. These cotinine concentrations were highly correlated with smoking (especially by the mother) in the child's presence. Nine to twelve million American children under 5 years of age, or one-half to 1-12

the 2 reports, increased symptoms (cough, phlegm production, and wheezing) were observed in a range of ages from birth to midteens, particularly in infants and preschool children. In addition to the studies on symptoms of respiratory irritation, 10 new studies have addressed the topic of parental smoking and acute lower respiratory tract illness in children, and 9 have reported statistically significant associations. The cumulative evidence is conclusive that parental smoking, especially the mother's, causes an increased incidence of respiratory illnesses from birth up to the first IS months to 3 years of life, particularly for bronchitis, bronchiolitis, and pneumonia. Overall, the evidence confirms and strengthens the previous conclusions of the NRC and Surgeon General. Recent studies also solidify the evidence for the conclusion of a causal association between parental smoking and increased middle ear effusion in young children. Middle ear effusion is the most common reason for hospitalization of young children for an operation. At the time of the Surgeon General's report on passive smoking (U.S. DHHS, 1986), data were sufficient to conclude only that maternal smoking may influence the severity of asthma in children. The recent studies reviewed here strengthen and confirm these exacerbation effects. The new evidence is also conclusive that ETS exposure increases the number of episodes of asthma in children who already have the disease. In addition, the evidence is suggestive that ETS exposure increases the number of new cases of asthma in children who have not previously exhibited symptoms, although the results are statistically significant only with children whose mothers smoke 10 or more cigarettes per day. While the evidence for new cases of asthma itself is not conclusive of a causal association, the consistently strong association of ETS both with increased frequency and severity of the asthmatic symptoms and with the established ETS effects on the immune system and airway hyperresponsiveness lead to the conclusion that ETS is a risk factor for induction of asthma in previously asymptomatic children. Regarding the effecta of passive smoking on lung function in children, the 1986 NRC and Surgeon General reports both conclude that children of parents who smoke have small decreases in tests of pulmonary output function of both the larger and smaller air passages when compared with the children of nonsmokers. As noted in the NRC report, if ETS exposure is the cause of the observed decrease in lung function, the effect could be due to the direct action of agents in ETS or an indirect consequence of increased occurrence of acute respiratory illness related to ETS. Results from eight studies on ETS and lung function in children that have appeared since those reporti add some additional confirmatory evidence suggesting a causal rather than an indirect relationship. For the population as a whole, the reductions are small relative to the interindividual variability of each lung function parameter. However, groups of particularly susceptible or heavily exposed children have shown larger decrements. The studies reviewed 1-14