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95-1115 SPR S.c:2 9,4 1 I 1 I I I I I I I 0 CRS Report for CongressH Environmental Tobacco Smoke and Lung Cancer Risk C. Stephen Redhead Analyst in Life Sciences and Richard E. Rowberg Senior Specialist in Science and Technology Science Policy Research Division November 14, 1995 Congressional Research Service • The Library of Congress 2 ...,.. rrrrr CRS IIAIl19101RR ... I

The Con~t~essiono.i Researcn Service Nrorl:.; exc!u:ive?y for the Congress, conducting _E:arch, analyzing,egislaric-n, and providing information at the request of committee< -NIenlber; an,-l eir z tazfs. _ '?`he Si•:rvi<•e r.:axes ~uch re: r3rch available, ~i:thout partisan bias, in many forms inci ..I- inv ;t.r.idies, reh ,rts, c„cnhaations, digests, and backsround briefings. Upon request, CR: as~,i, ts committees in analyzing legislative proposals and issues, and in assessin_ t he nossit:le E-_ftctc~:& these prnposals and their alternatives. The Service's senior specia?`.-a ar.d subject analt-: ts are also available for personal consultations in their respective f;,-lcls of expertise. ! I I I I I I I I I 1 I I I

I TABLE OF CONTENTS I I ~ I I I 11 I I I I OVERVIEW ................................................ 1 GENERAL ISSUES ....................................... 1 SOURCES OF UNCERTAINTY ............................. 2 OCCUPATIONAL RISK ................................... 3 INTRODUCTION ............................................ 5 ENVIRONMENTAL TOBACCO SMOKE .......................... 9 MAINSTREAM AND SIDESTREAM SMOKE ................... 9 ETS COMPOSITION AND MEASUREMENT ................. 11 ETS INDOOR AIR CONCENTRATIONS AND EXPOSURE ...... 12 Stationary Air Samplers ............................... 13 Personal Monitors ................................... 14 Biomarkers ......................................... 16 ETS CANCER RISK ..................................... 16 ETS AND LUNG CANCER - EPIDEMIOLOGY .................... 19 INTRODUCTION ....................................... 19 BACKGROUND ......................................... 19 OVERALL EFFECTS AND PREVIOUS STUDIES .............. 22 RESULTS ............................................. 27 ANALYSIS ............................................. 30 Risk and Exposure Measurement ........................ 30 Confounding ........................................ 31 Misclassification Bias ................................. 36 Smoker Misclassification ........................... 36 Exposure Misclassification ......................... 38 R,ecallBias ..................................... 38 Discussion ...................................... 40 Smoker Misclassification - Discussion ............. 40 Exposure Misclassification - Discussion ............ 42 Recall Bias -- Discussion ....................... 43 Final Comments ................................. 45 ETS AND LUNG CANCER DEATH RISK ........................ 47 INTRODUCTION ....................................... 47 METHODS ............................................ 47 Population Attributable Risk ........................... 47 Background ETS .................................... 48 RESULTS ............................................. 49 Exposure Patterns ................................... 49 Background Exposure ................................ 50 Lung Cancer Deaths .................................. 50 DISCUSSION .......................................... 53 RISK COMPARISON ..................................... 55 I

OCCUPATIONAL ETS LUNG CANCER RISK .................... 59 I ESTIMATES OF OCCUPATIONAL ETS LUNG CANCER RISK ... OCCUPATIONAL ETS EXPOSURE ......................... APPENDIX A - PASSIVE SMOKING HEART DISEASE RISK AND RESPIRATORY DISEASE RISK IN CHILDREN ............... HEART DISEASE AND ETS .............................. 60 62 65 65 I I ETS AND RESPIRATORY DISEASE RISK IN CHILDREN 69 ....... APPENDIX B -- RESIDENTIAL EPIDEMIOLOGICAL STUDIES OF PASSIVE SMOKING AND LUNG CANCER ................... 73 I I I I I I I I ca I r4 Lq ah I

I I I I I t I I I 1 I OVERVIEW GENERAI. ISSUES In response to requests from Congress, this report presents an analysis of the potential health effects of environmental tobacco smoke (ETS). The report concentrates on possible lung cancer risk because of the availability of published literature and resource constraints within CRS. A brief overview of ETS and the risk of heart disease and childhood respiratory illness is also presented. A substantial body of evidence built up over the last 40 years indicates that smoking is a major cause of illness and premature death. In recent years, several reports have also concluded that exposure to environmental tobacco smoke (ETS) can cause lung cancer in people who have never smoked. In 1992, the Environmental Protection Agency (EPA) classified ETS as a known human carcinogen and estimated that ETS exposure is responsible for about 3000 lung cancer deaths each year among adult nonsmokers. EPA's findings have received much support from the scientific community, but have been criticized by other scientists, statisticians and the tobacco industry. Environmental tobacco smoke is a highly diluted combination of mainstream smoke exhaled by smokers and sidestream smoke released directly from the burning tips of cigarettes. Researchers have concluded that ETS contains most, if not all, of the carcinogenic and toxic compounds that are present in mainstream smoke. Studies that measured cotinine - a nicotine derivative - levels in blood and urine indicate that there is widespread exposure to ETS, and measurable uptake of ETS by nonsmokers. According to the EPA, the chemical similarities between mainstream smoke and ETS, and the evidence of exposure to, and uptake of, ETS among nonsmokers is sufficient to conclude that ETS is a lung-cancer hazard. The EPA based its estimate of the magnitude of the ETS lung cancer risk among nonsmokers on an analysis of over 30 epidemiologic studies of lung cancer among adult non-smoking women. These studies relied on spousal smoking as a surrogate for ETS exposure and classified the women as exposed or unexposed on the basis of whether their husbands smoked. The lung cancer risk among the exposed women was compared to that of the unexposed women. Since the EPA report was issued, the largest and most recent case-control epidemiologic study included in the EPA findings has been completed, and three other large, case-control studies have been published. Two of these studies 1 show no increased average risk, one2 shows a statistically significant increased 1 Kabat, G.1., et.al., American Journal of Epidemiology, Vo1.142, No.2, 1995, p.141-148; Brownson,R.C., et.al., American Journal of Public Health, Vol.82, No.11, 1992, p.1525-1530. 2 Fontham, E.T.H., et.al.,Journal of the American Medical Associ.ation, Vo1.271,No.22, 1994, p.1752-1759. I

CRS-2 average risk while the fourth3 shows an increased average risk which is not statistically significant at the 95 percent level. An extensive review of the literature on ETS and lung cancer risk indicates that any lung cancer risk appears to increase as integrated (time and quantity) exposure to ETS increases. Three of the four recent studies (Fontham, et.al., Brownson, et.al., and Stockwell, et.al.) report statistically significant excess risk values at the highest exposure levels (measured in pack-years [packs per day times years exposed] in two cases and in smoker years in another), and about one-third of the studies reviewed by EPA for dose response behavior show a statistically significant (at the 95 percent level) upward trend. While there is evidence of an upward dose reponse trend, the results are not definitive. And. even at- the greatest integrated exposure levels, the measured risks are still subject to uncertainty. Calculations based on data from the Fontham, et.al., study and assuming an average exposure for the entire population at risk (a no-threshold model) result in a range of 470 to 5500 annual lung cancer deaths in the U.S. from ETS with a mean value of 2780. This compares to a mean value of 3300 calculated by EPA under the same assumption. Data from the Brownson, et.al, study, on the other hand, produce no annual lung cancer deaths from ETS also under the no-threshold assumption. If a threshold model is used to si•aulate the upper limit of a possible upward dose response behavior, the mean number of lung cancer deaths is 440 calculated from the Fontham, et.al, data and 530 for the Brownson, et.al., data. Over 70 percent of these deaths calculated in the no- threshold example and all those calculated in the threshold model occur to individuals who are exposed to both spousal and background ETS. The remaining deaths in the no-threshold model would result from exposure only to background ETS. The threshold model results are consequences of the model chosen. It is possible that there may be some exposed to sufficient background ETS to be over the threshold without spousal ETS. An effect like this, however, may be very difficult to detect without very large samples. Using the results obtained from the Fontham, et.al., data in the no- threshold example, a person exposed to spousal and background ETS has about a 2/10 of one percent chance of dying of lung cancer from the ETS over her lifetime. For a person exposed only to background ETS, the number drops to about 7/100 of one percent. SOURCES OF UNCERTAINTY The major sources of uncertainty for interpreting the epi results are confounders -- factors other than ETS which could explain the measured risk values, and misclassification. The latter includes identifying current smokers or g StockweIl, H.G.,et.al.,Journal of the National Cancer Institute, Vo1.84,No.18, 1992, p.1417- 1422. I I I I I I I I I I I

I I t I I I I I I I I I I I CRS-3 recently quit smokers as never smokers (smoker misclassification), identifying a person as exposed to ETS because her spouse smoked when in reality she was not subject to any exposure (exposure misclassification), and under or over estimating the amount of ETS exposure (recall bias). Evidence from a number of studies examining possible confounders appears inconclusive about whether they may be responsible for the risk values measured in the ETS studies. The statistical uncertainties exhibited in the epi studies of most of these possible confounders suggests that none can be considered a clear cause or inhibitor of lung cancer. Furthermore, there is mixed evidence about the correlation of these confounders with increasing integrated exposure to ETS. The number of studies on confounders is not large, however, and it is possible that other confounders exist which have not been identified. Additional research appears to be important. There are several types of misclassification errors that could occur in these epi studies. Some of them, such as exposure misclassification, would result in measured relative risk values below the actual values, while others, including smoker misclassification and recall bias would result in the measured risk values being overstated. For the Fontham, et.al., and Brownson, et.al., data, smoker misclassification rates of less than 10 percent would account for all of the m-:asured risk at the highest exposure levels in those studies. An even smaller rate -- less than 3 percent -- would cause those risk values to be no longer statistically significant at the 95 percent level. While accounting for exposure misclassification will raise the measured risk values, simulated calculations using the Fontham, et.al., data indicate that misclassification rates greater than 20 percent would be necessary to increase risk values by as much as 5 percent. Recall bias simulations on the same data indicate that overestimating exposure by 10 to 20 percent would result in a reduction of measured risk by about 20 percent at the higher exposure levels. Information on misclassification rates is skimpy at best. For the exposure and recall categories, it is virtually non-existent. Nevertheless, these simulated calculations indicate that misclassification can be a potent uncertainty in these ETS epi studies, and could account for the measured risk values. Further research on this issue appears called for. OCCUPATIONAL RISK The Occupational Safety and Health Administration (OSHA) assessed the lung cancer risk from workplace exposure to ETS as part of its proposed indoor air quality rule. The agency may choose to make substantial revisions to the ETS risk assessment before releasing a final regulation. Independent scientists and tobacco industry researchers and consultants have submitted new data and analyses to the agency for possible inclusion in a revised risk assessment. Although there are no specific occupational epi studies, several residential studies also collected data on workplace ETS exposure and reported estimates of occupational lung cancer risk. OSHA based its risk assessment on a I

CRS-4 workplace risk estimate by Fontham et al., which indicated an increased risk, and chose not to use the remaining estimates which found no overall association between workplace exposure and lung cancer. Moreover, it assumed that workplace exposure is comparable to residential exposure, though studies that measured cotinine levels in nonsmokers suggest that residential and other non- workplace exposure may be more important that workplace exposure. If, on average, workplace ETS exposure is lower than residential exposure, then it is likely that relatively few workers would be exposed to sufficient ETS to be at increased risk for lung cancer. More extensive workplace exposure data are required before this issue can be resolved. I I I I I I I I I I 'I I I ~ I I

a I ~ I I I i I I I I I ~ I I I CRS-5 INTRODUCTION The health effects of cigarette smoking have been the subject of intensive scientific investigation since the 1950s. Smoking is linked to leading causes of chronic illness and premature death, including lung cancer and other malignancies, heart disease and stroke, and chronic obstructive pulmonary disease (e.g., bronchitis and emphysema). The Public Health Service estimates that smoking accounts for 87 percent of all lung cancer deaths, 82 percent of all deaths from chronic obstructive pulmonary disease, and 21 percent of all coronary heart disease deaths. More recently, there has been concern that nonsmokers may be at risk when exposed to environmental tobacco smoke (ETS) that occurs in indoor environments occupied by smokers. Researchers often refer to the involuntary inhalation of ETS by nonsmokers as passive smoking. In 1986, the National Research Council (NRC) and the Surgeon General of the U.S. Public Health Service both released reports on the health effects of passive smoking.4 Both reports concluded that ETS can cause lung cancer in adult nonsmokers. That same year, a report by the International Agency for Research on Cancer (IARC) concluded that passive smoking gives rise to some risk of cancer, based on considerations related to biological plausibility.' A recent review of the health effects of passive smoking in the workplace conducted by the National Institute for Occupational Safety and Health determined that "the collective weight of evidence" indicates that ETS poses an increased risk of lung cancer and possibly heart disease in occupationally exposed workers.s An extensive analysis of the health effects of ETS was released by the Environmental Protection Agency (EPA) in January 1993.7 In its report, EPA classified ETS as a Group A (known) human carcinogen under 4 National Research Council. Environmental Tobacco Smoke: Measuring Exposures and Assessing Health Effects. National Academy Press, Washington, DC, 1986; U.S. Dept. of Health and Human Services. The Health Consequences of Involuntary Smoking. A Report o f the Surgeon General. U.S. DHHS, Public Health Service, Office of the Assistant Secretary of Health, Washington, DC, 1986. DHHS Pub. No. (PHS) 87-8398. 6 International Agency for Research on Cancer. IARC Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Man, Volume 38: Tobacco Smoke. 1986. World Health Organization, Lyon, France. The IARC report found the available epidemiological evidence to be equivocal, but stated that "knowledge bf the nature of mainstream and sidestream smoke, or the materials absorbed during passive smoking, and of the quantitative relationships between dose and effect that are commonly observed from exposure to carcinogens ... leads to the conclusion that passive smoking gives rise to some risk of lung cancer." s National Institute for Occupational Safety and Health. Environmental Tobacco Smoke in the Workplace: Lung Cancer and Other Health EJf `'ects. Current Intelligence Bulletin 54. U.S. Dept. of Health and Human Services, NIOSH, 1991. 7 National Institutes of Health, Respiratory Health E/~'ects of Passive Smoking: Lung Cancer and Other Disorders; THe Report o f the Environmental Protection Agency, Monograph 4, NIH Publication No. 93-3605, August 1993, Washington, DC. (Here after referred to as the EPA Report.) I

CRS-6 its carcinogen assessment guidelines and concluded that widespread exposure to environmental tobacco smoke presents a substantial public health risk. The EPA report's conclusions are summarized in the text box. EPA estimated that passive smoking is responsible for about 3000 lung cancer deaths per year in the adult, non-smoking (never smokers and long-ago former smokers) population, and poses a serious threat to the respiratory health of young children. Environmental Protection Agency - 1993 Respiratory Health Effects of Passive Smoking In adults: • ETS exposure is responsible for approximately 3000 lung cancer deaths each year; • ETS exposure has subtle, but significant respiratory health effects among nonsmokers, including chest discomfort and reduced lung function. In children: • E`lz exposure results in 150,000 to 300,000 cases of bronchitis and pneumonia annually among young children up to 18 months of age; • ETS exposure in children irritates the upper respiratory tract and reduces lung function; • ETS exposure increases the prevalence of fluid in the middle ear and contributes to middle ear infection; • ETS exposure increases the frequency of episodes and severity of. symptoms in asthmatic children. Between 200,000 and 1,000,000 asthmatic children are, affected by ETS. The EPA report received widespread support from the public health community and from the larger scientific community. But it has been criticized by tobacco industry researchers and scientific consultants. A few independent statisticians and epidemiologists have also raised objections to EPA's statistical analysis of the ETS epidemiologic studies.° The Congressional Research Service 8 The reader is referred to two congressional hearing at which researchers who support and criticize the EPA study testified: (i) U.S. Congress, House Committee on Energy and Commerce, Subcommittee on Health and the Environment, Environmental Tobacco Smoke, 103d Congress, I I I I I I I I I I I I I I I