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EPA/600/6-90/006F December 1992 RESPIRATORY HEALTH EFFECTS OF PASSIVE SMOKING: LUNG CANCER AND OTHER DISORDERS Major funding for this report has been provided by the Indoor Air Division, Office of Atmospheric and Indoor Air Programs Office of Health and Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Washington, D.C.

Unhed Statea ONke ol P,aaearcn and pBlce al Alr and EPNB00ia-yU/006F EnvlronmenteiProtection Deveiopmam Rad?atlon Decemberi992 qQency Waehinpton. DC 20480 WuhMpton. DC 2oGB0 i~EPA Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders

This report estimates that ETS exposure contributes 150,000 to 300,000 cases annually of lower respiratory tract illness in infants and children younger than 18 months of age and that 7,500 to 15,000 of these will require hospitalization. The strong evidence linking ET'S exposure to increased incidence of bronchitis, bronchiolitis, and pneumonia in young children gives these estimates a high degree of confidence. There is also evidence suggesting a smaller E7S effect on children between the ages of IS months and 3 years, but no additional estimates have been computed for this age group. Whether or not these illnesses result in death has not been addressed here. In the United States, more than 5,000 infants die of SIDS annually. It is the major cause of death in infants between the ages of I month and I year, and the linkage with maternal smoking is well established. The Surgeon General and the World Health Organization estimate that more than 700 U.S. infant deaths per year from SIDS are attributable to maternal smoking (CDC, 1991a, 1992b). However, this report concludes that at present there is not enough direct evidence supporting the contribution of ETS exposure to declare it a risk factor or to estimate its population impact on SIDS. 1-t6

1. SUMMARY ANI) CONCLUSIONS 1.1. MAJOR CONCLUSIONS Based on the weight of the available scientific evidence, the U.S. Environmental Protection Agency (EPA) has concluded that the widespread exposure to environmental tobacco smoke (ETS) in the United States presents a serious and substantial public health impact. jpadul ~: • EfS is a human lung carcinogen, responsible for approximately 3,0001ung cancer deaths annually in U.S. nonsmokers. In children: - • ETS exposure is causally associated with an increased risk of lower respiratory tract infections (LRIs) such as bronchitis and pneumonia. This report estimates that 150,000 to 300,000 cases annually in infants and young children up to 18 months of age are attributable to ETS. • ETS exposure is causally associated with increased prevalence of fluid in the middle ear, symptoms of upper respiratory tract irritation, and a small but significant reduction in lung function. • ETS exposure is causally associated with additional episodes and increased severity of symptoms in children with asthma. This report estimates that 200,000 to 1,000,000 asthmatic children have their condition worsened by exposure to FiTS. • ETS exposure is a risk factor for new cases of asthma in children who have not previously displayed symptoms. 1-1

in this estimate, and the true number may be higher or lower, the assumptions used in this analysis would tend to underestimate the actual population risk. The overall confidence in this estimate is medium to high. B. Noncancer Respiratory Diseases and Disorders 1. Exposure of children to ETS from parental smoking is causally associated with: a. increased prevalence of respiratory symptoms of irritation (cough, sputum, and wheeze), b. increased prevalence of middle ear effusion (a sign of middle ear disease), and c. a small but statistically significant reduction in lung function as tested by objective measures of lung capacity. 2. ETS exposure of young children and particularly infants from parental (and especially mother's) smoking is causally associated with an increased risk of LRIs (pneumonia, bronchitis, and bronchiolitis). This report estimates that exposure to ETS contributes 150,000 to 300.000 LRIs annually in infants and children less than 18 months of age, resulting in 7,500 to 15,000 hospitalizations. The confidence in the estimates of LRIs is high. Increased risks for LRIs continue, but are lower in magnitude, for children until about age 3; however, no estimates are derived for children over 18 months. 3. a. Exposure to ETS is causally associated with additional episodes and increased severity of asthma in children who already have the disease. This report estimates that ETS exposure exacerbates symptoms in approximately 20% of this country's 2 million to 5 million asthmatic children and is a major aggravating factor in approximately 10%. b. In addition, the epidemiologic evidence is suggestive but not conclusive that ETS exposure increases the number of new cases of asthma in children who have not previously exhibited symptoms. Based on this evidence and the known ETS effects on both the immune system and lungs (e.g., atopy and airway hyperresponsiveness), this report concludes that ETS is a risk factor for the induction of asthma in previously asymptomatic children. Data suggest that relatively high levels of exposure are required to induce new cases of asthma in children. This report calculates that previously asymptomatic children exposed to E7S from mothers who smoke at least 10 cigarettes per day will exhibit an estimated 8,000 to 26,000 new cases of 1-5

report addresses that question by reviewing and analyzing the evidence from 30 epidemiologic studies of effects from normally occurring environmental levels of ETS (Chapter 5). Because there is widespread exposure and it is difficult to construct a truly unexposed subgroup of the general population, these studies attempt to compare individuals with higher ETS exposure to those with lower exposures. Typically, female never-smokers who are married to a smoker are compared with female never-smokers who are married to a nonsmoker. Some studies also consider E'IS exposure of other subjects (i.e., male never-smokers and long-term former smokers of either sex) and from other sources (e.g., workplace and home exposure during childhood), but these studies are fewer and represent fewer cases, and they are generally excluded from the analysis presented here. Use of the female never-smoker studies provides the largest, most homogeneous database for analysis to determine whether an ETS effect on lung cancer is present. This report assumes that the results for female never-smokers are generalizable to all nonsmokers. Given that ETS exposures are at actual environmental levels and that the comparison groups are both exposed to appreciable background (i.e., nonspousal) ETS, any excess risk for lung cancer from exposure to spousal smoke would be expected to be small. Furthermore, the risk of lung cancer is relatively low in nonsmokers, and most studies have a small sample size, resulting in a very low statistical power (probability of detecting a real effect if it exists). Besides small sample size and low incremental exposures, other problems inherent in several of the studies may also limit their ability to detect a possible effect. Therefore, this report examines the data in several different ways. After downward adjustment of the relative risks for smoker misclassification bias, the studies are individually assessed for strength of association, both for the overall data and for the highest exposure group when exposure-level data are available, and for exposure-response trend. Then the study results are pooled by country using statistical techniques for combining data, including both positive and nonpositive results, to increase the ability to determine whether or not there is an association between ETS and lung cancer. Finally, in addition to the previous statistical analyses that weight the studies only by size, regardless of design and conduct, the studies are qualitatively evaluated for potential confounding, bias, and likely utility to provide information about any lung carcinogenicity of ETS. Based on these qualitative considerations, the studies are categorized into one of four tiers and then statisticall y analyzed successively by tier. Results from all of the analyses described above strongly support a causal association between lung cancer ETS exposure. The overall proportion (9/30) of individual studies found to show an association between lung cancer and spousal ETS exposure at all levels combined is unlikely to occur by chance (p < 10). When the analysis focuses on higher levels of spousal exposure, every one of the 17 studies with exposure-level data shows increased risk in the highest 1-7

is usual in EPA quantitative risk assessments, and confidence in these estimates is rated medium to high. Population estimates of ETS health impacts are also made for certain noncancer respiratory endpoints in children, specifically lower respiratory tract infections (i.e., pneumonia, bronchitis, and bronchiolitis) and episodes and severity of attacks of asthma. Estimates of ETS-attributable cases of LRI in infants and young children are thought to have a high degree of confidence because of the consistent study findings and the appropriateness of parental smoking as a surrogate measure of exposure in very young children. E;timates of the number of asthmatic children whose conditioe is aggravated by exposure to ETS are less certain than those for LRIs because of different measures of outcome in various studies and because of increased extraparental exposure to ETS in older children. Estimates of the number of new cases of asthma in previously asymptomatic children also have less confidence because at this time the weight of evidence for asthma induction, while suggestive of a causal association, is not conclusive. Most of the ETS population impact estimates are presented in terms of ranges, which are thought to reflect reasonable assumptions about the estimates of parameters and variables required for the extrapolation models. The validity of the ranges is also dependent on the appropriateness of the extrapolation models themselves. While this report focuses only on the respiratory health effects of pnssive smoking, there also may be other health effects of concern. Recent analyses of more than a dozen epidemiology and toxicology studies (e.g., Steenland, 1992; National Institute for Occupational Safety and Health [NIOSH], 1991) suggest that ETS exposure may be a risk factor for cardiovascular disease. In addition, a few studies in the literature link ETS exposure to cancers of other sites; at this time, that database appears inadequate for any conclusion. This report does not develop an analysis of either the nonrespiratory cancer or the heart disease data and takes no position on whether ETS is a risk factor for these diseases. If it is, the total public health impact from ETS will be greater than that discussed here. 1.3. PRIMARY FINDINGS A. Lung Cancer in Nonsmoking Adults 1. Passive smoking is causally associated with lung cancer in adults, and ETS, by the total weight of evidence, belongs in the category of compounds classified by EPA as Group A (known human) carcinogens. 2. Approximately 3,000 lung cancer deaths per year among nonsmokers (never- • smokers and former smokers) of both sexes are estimated to be attributable to ETS in the_ United States. While there are statistical and modeling uncertainties 1-4

asthma annually. The confidence in this range is medium and is dependent on the conclusion that ETS is a risk factor for asthma induction. 4. Passive smoking has subtle but significant effects on the respiratory health of nonsmoking adults, including coughing, phlegm production, chest discomfort, and reduced lung function. This report also has reviewed data on the relationship of maternal smoking and sudden infant death syndrome (SIDS), which is thought to involve some unknown respiratory pathogenesis. The report concludes that while there is strong evidence that infants whose mothers smoke are at an increased risk of dying from SIDS, available studies do not allow us to differentiate whether and to what extent this increase is related to in utero venus postnatal exposure to tobacco smoke products. Consequently, this report is unable to assert whether or not ETS exposure by itself is a risk factor for SIDS independent of smoking during pregnancy. Regarding an association of parental smoking with either upper respiratory tract infections (colds and sore throats) or acute middle ear infections in children, this report finds the evidence inconclusive. 1.3.1. ETS aad Lung Cancer 1.3.1.1. Barard Ideaq/icadoa The Surgeon General (U.S. DHHS, 1989) estimated that smoking was responsible for more than one of every six deaths in the United States and that it accounted for about 90% of the lung cancer deaths in males and about 80% in females in 1985. Smoken, however, are not the only ones exposed to tobacco smoke. The sidestream smoke (SS) emitted from a smoldering cigarette between puffs (the main component of ETS) has been documented to contain virtually all of the same carcinogenic compounds (known and suspected human and animal carcinogens) that have been identified in the mainstream smoke (MS) inhaled by smokers (Chapter 3). Exposure concentrations of these carcinogens to passive smokers are variable but much lower than for active smokers. An excess cancer risk from passive smoking, however, is biologically plausible. Based on the firmly established causal association of lung cancer with ictive smoking with a dose-response relationship down to low doses (Chapter 4), passive smoking is considered likely to affect the lung similarly. The widespread presence of ETS in both home and workplace and its absorption by nonsmokers in the general population have been well documented by air sampling and by body measurement of biomarken such as nicotine and cotinine (Chapter 3). This raises the question of whether any direct evidence exists for the relationship between ETS exposure and lung cancer in the general population and what its implications may be for public health. This 1-6

• Supporting evidence from animal bioassays and genotoxicity experiments. The carcinogenicity of tobacco smoke has been demonstrated in lifetime inhalation studies in the hamster, intrapulmonary implantations in the rat, and skin painting in the mouse. There are no lifetime animal inhalation studies of ETS; however, the carcinogenicity of SS condensates has been shown in intrapulmonary implantations and skin painting experiments. Positive results of genotoxicity testing for both MS and ETS provide corroborative evidence for their carcinogenic potential. • Consistency of response. All 4 of the cohort studies and 20 of the 26 case-control studies observed a higher risk of lung cancer among the female never-smokers classified as ever exposed to any level of spousal ETS. Furthermore, every one of the 17 studies with response categorized by exposure level demonstrated increased risk for the highest exposure group. When assessment was restricted to the 19 studies judged to be of higher utility based on study design, execution, and analysis (Appendix A), 17 observed higher risks, and 6 of these increases were statistically significant, despite most having low statistical power. Evaluation of the total study evidence from several perspectives leads to the conclusion that the observed assoeiation between ETS exposure and increased lung cancer occurrence is not attributable to chance. • Broad-based evidence. These 30 studies provide data from g different countries, employ a wide variety of study designs and protocols, and are conducted by many different research teams. Results from all countries, with the possible exception of two areas of China where high levels of other indoor air lung carcinogens were present, show small to modest increases in lung cancer associated with spousal ETS exposure. No alternative explanatory variables for the observed association between ETS and lung cancer have been indicated that would be broadly applicable across studies. • Upward trend in exposure-response. Both the largest of the cohort studies--the Japanese study of Hirayama with 200 lung cancer cases--and the largest of the case-control studies--the U.S. study by Foatham and associates (1991) with 420 lung cancer eases and two sets of controls--demonstrate a strong exposure-related statistical association between passive smoking and lung cancer. This upward trend is well supported by the preponderance of epidemiology studies. Of the 14 studies that provide sufficient data for a trend test by exposure level, 10 were statistically significant despite most having low statistical power. • Detectable association at environmental exposure levels. Within the population of married women who are lifelong nonsmokers, the excess lung cancer risk from 1-9

1.3.1.2. EsalnsaJio r of PopvlNioa Risk The individual risk of lung cancer from exposure to ETS does not have to.be very large to translate into a significant health hanrd to the U.S. population because of the large number of smokers and the widespread presence. of ETS. Current smokers comprise approximately 26% of the U.S. adult population and consume more than one-half trillion cigarettes annually (1.5 packs per day, on average), causing nearly universal exposure to at least some ETS. As a biomarker of tobacco smoke uptake, cotinine, a metabolite of the tobacco-specific compound nicotine, is detectable in the blood, saliva, and urine of persons recently exposed to tobacco smoke. Cotinine has typically been detected in 50% to 75% of reported nonsmokers tested (50% equates to 63 million U.S. nonsmokers age 18 or older). The best estimate of approximately 3,0001ung cancer deaths per year in US. nonsmokers age 35 and over attributable to ETS (Chapter 6) is based on data pooled from all 11 U.S. epidemiologic studies of never-smoking women married to smoking spouses. Use of US. studies should increase the confidence in these estimates. Some mathematical modeling is required to adjust for expected bias from misclassification of smoking status and to account for ETS exposure from sources other than spousal smoking. The overall relative risk estimate of 1.19 for the United States, already adjusted for smoker misclassification bias, becomes 1.59 after adjusting for background ETS sources (1.34 for nonspousal exposures only). Assumptions are also needed to relate responses in female never-smokers to those in male never-smokers and ex-smokers of both sexes, and to estimate the proportion of the nonsmoking population exposed to various levels of ETS. Overall, however, the assumptions necessary for estimating risk add far less uncertainty than other EPA quantitative assessments. This is because the extrapolation for ETS is based on a large database of human studies, all at levels actually expected to be encountered by much of the U.S. population. The components of the 3,000 lung cancer deaths figure include approximately 1,500 female never-smokers, 500 male never-smokers, and 1,000 former smokers of both sexes. More females are estimated to be affected because there are more female than male nonsmokers. These component estimates have varying degrees of confidence; the estimate of 1,500 deaths for female never-smokers has the highest confidence because of the extensive database. The estimate of 500 for male never-smokers is less certain because it is based on the female never-smoker response and is thought to be low because males are generally subject to higher background ETS exposures than females. Adjustment for this higher background exposure would lead to higher risk estimates. The estimate of 1,000 lung cancer deaths for former smokers of both sexes is 1-11