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ATTRIBUTABLE RISK OF LUNG CANCER IN NONSMOKING WOMEN: ESTIMATES FROM A CAS'E-CONTROL STUDY Alavanja, Michael C.R. Divsion of Cancer Etiology; National Cancer Institute Rockville, Maryland, tJSA Abstract Backqroundt In 1992, approximately 13,000 lung cancers occurred in nonsmoking U.S, women but the cause of these cancers is not well understood. Methods: A population-based, case-coiitroistUdy"of incident lung cancer among non-smoking women in;Missouri was conducted between 1986 and 1992. The study included;618 lung cancer" cases and 1402 population-based, matched controls. Information on lung cancer risk factors was obtained by personal interview, or next-of-kin (Einterviews (36% and 64% respectively). Year-long (rado measurements were sought in every dwelling occupied for the previous 5-30 years. Population attributable risk was computed for this population among lifetime nonsmokers, ainong l'ong-term ex- smokers, and by histologic cell type. Results: The mean agp of women with lung cancer was 71 years old and nearly 50% of the lung cancers were histologically confirmed adenocarcinomas. The cause of 40% of all lung cancers among lifetime nonsmokers and 50% of lung cancers among all subjects in the study was identified. bietary intake of saturated fat and nonmalignant lung disease were the two leading causes of disease

among lifetime nonsmokers, followed by environmental tobacco smoke, occupational exposures to known carcinogens and possibly to domestic radon exposure. A similar pattern of risk was identified among former smokers, but in this group the lingering effect of a history of smoking was also very important along with the combined effect of previous active smoking in the study subject and a history of lung cancer among first degree relatives. Conclusion: ~Lung cancer is a highly preventable disease with 80% or more of the cases in women being due to active cigarette smoking.] rNearly forty percent of the cases among lifetime nonsmokers can also be prevented if identified diet, occupational and general environmental factors were controlled. Genetic or familial factors seem to be most important to former smokers (and possibly to current active smokers) with little excess risk being seen.among lifetime nonsmokers. The risk of lung cancer associated witYr, domestic radon is dependent on the level of exposure. In Missouri, which resembles radon exposure in the United States as a whole, no more than 5% of the cases of lung cancer in lifetime nonsmokers resulted from this exposure. The etiologic link between some'of these factors (i.e., saturated fat and domestic radon) has not been examined in many other studies so a cautious interpretation of the population attributable risks presented for these exposures seems warranted. - 2 -

Although smoking is by far the major cause of lung cancer, it is not the only cause. Lung cancer in nonsmokers may account for more U. S. deaths than any other cancer except colon and breast cancer in women and colon and prostate cancer in men (1). During the period from June 1, 1986 to April 1, 1991 nineteen percent of all female lung cancer cases in Missouri occurred among nonsmokers (2). Despite its large public health impact, the etiology of lung cancer among nonsmokers is poorly defined. We had the opportunity to evaluate the magnitude of the relative risk of a number of new and previous identified risk factors for lung cancer in a large, population-based, case-control study of women who were either lifetime nonsmokers or former smokers who had ceased smoking for at least 15 years. The results of these etiologic studies have been previously published (2-7). Since the effect of a risk factor on community health is related to both relative risk and the percentage of the population exposed to the factor, it is important to define the population attributable risk of cancer associated with each of the identified risk factors. Although attributable risk varies depending on the frequency of the risk factors in the population being studied, we believe the results of this large study of lung cancer among nonsmoking women ~ in Missouri is reflective of a large portion of the nonsmoking female population in the United States generally and perhaps in other western nations. - 3 -

METHOD$ Eliaibilitv White nonsmoking women 30-84 years of age who were residents of Missouri at the time of this study were eligible for inclusion. Both lifetime nonsmokers and long term former smokers were examined. Lifetime nonsmokers consisted of those women who had not smoked more than 100 cigarettes or used any other tobacco products for more than 6 months in their lifetime. Former smokers were defined as women who ceased using all tobacco products 15 or more years prior to interview; the median period of smoking cessation in our study was 26 years. Cases Cases were nonsmoking white women between 30-84 years of age with primary cancer of the lung who were reported to the Missouri Cancer Registry between June 1, 1986 and June 1, 1991. Of the 3475 women with lung cancer reported to the Registry, 650 were identified as being eligible for this study on the basis of their smoking status and demographic variables. A total of 618 (95%) agreed to enroll in the study. Participation rates in subsequent phases of the study varied (2-7). - 4 -

In addition to the registry-reported diagnosis of lung cancer, tissue slides were reviewed for histologic verification for 468 (76%) of the cases by a panel of respiratory pathologist (8). Controls A population based sample of white, nonsmoking women control subjects were selected from two sources. For women aged 30-64 years, names and addresses were randomly generated from driver's license files provided by the Missouri Department of Revenue. For women between 65-84 years, names and addresses were randomly generated from lists of Missouri women provided by the Health Care Financing Administration, which include an estimated 95% of the women in this age group (9). A total of 1527 nonsmoking control women responded to the initial screening interview; 1402 (92%) agreed to enroll in the study. Ouestionnaire Administration and Design A telephone-administered screening questionnaire was used to deter;nine and/or verify the eligibility of cases and controls on age, gender, race, and smoking status. - 5 -

Information on residential history, passive smoking exposure, family health history, occupational history, diet, previous lung disease or prior active smoking history was obtained from a structured questionnaire administered by a trained telephone interviewer. Next-of-kin interviews were conducted for 64 percent (n=396) of the cases and none of the controls due to disabling illness or death. Radon Measurements Current residential radon concentrations were measured by placing two alpha track detectors in each dwelling occupied for at least one year by the study subject during the preceding 30 years in the state of Missouri. One detector was placed in the bedroom and the other in the kitchen for 12 months. Extensive quality control procedures were implemented to assure reliable radon measurements (7). Time-weighted average (TWA) concentrations for this period were calculated. For subjects with a single measured home, the TWA exposure was equal to the mean radon concentration of all measured in this home. For women with more than one home during this period, the TWA exposure estimated was the mean radon concentration of all measured homes weighted by the years of residence spent in each home. Residential occupancy was obtained from questionnaire information to account for time spent outside - 6 -

the home (i.e., worktime, recreation time) during each period of radon measurement. Attributable Risk Computation The percentage of the attributable risk for the population (10) was computed as follows: Percentage of attributable risk (PAR) _ P(OR-1)/[I+(P)(OR-1)) X 100, where P is the prevalence of exposure in the control population and OR is the odds ratio for exposure to the independent variables under study. Since both the odds ratio and the prevalence of exposure effect population attributable risk (PAR), both the odds ratio and prevalence of exposure are presented. For smoking history, nonmalignant lung disease, occupation (use of asbestos, pesticides or working in the dry cleaning industry), and a family history of lung cancer PAR was computed based on the comparison of ever vs. never exposed. - 7 -

For variables such as passive smoking, saturated fat intake and domestic radon, where exposure is ubiquitous, judgements had to be made to define exposure cut points along the exposure continuum that might be achieved in Missouri. For passive smoking the exposed group were women with >40 pack years of smoking from a spouse, while the unexposed group was for women with <40 pack years of exposure. For saturated fat intake which showed a significant dose-response effect (5) and no indicated threshold level, we compared the upper half of the exposure continuum with the lower half, assuming that a dietary modification of this extent might be possible. Finally, for domestic radon exposure, we estimated PAR by defining the exposed group as those subjects with a time- weighted-average (25 years) domestic radon exposure of 4pCi/l or greater (the current EPA action level). Each of these exposures cut points were associated with a significant excess relative risk of lung cancer in our earlier study (3,5,7). For two variables, a history of non-malignant lung disease and residential history (for radon exposure), odds ratios based on in-person interviews were greater than those based on estimates including next-of-kin interviews. Odds ratios based on in-person interviews were used because they were considered more accurate sources of information of exposure. Logistic regression methods were used to estimate adjusted odds ratios. Only those variables that were associated with a - 8 -

significant univariate increase or decrease in lung cancer risk were used in the logistic regression model (2-7). These variables included saturated fat intake (grams/day), history of active smoking (ever/never) , previous nonmalignant lung disease (ever/never), passive smoking (total pack-years of exposure from spouse), occupational exposure to carcinogens (ever vs. never), family history of lung cancer (ever vs. never), and domestic radon (TWA > 4pCi/1 vs TWA < 4pCi/1). Saturated fat intake was further adjusted to account for the caloric content of the daily diet (5). Analysis of risk by cell type was limited by the small number of nonadenocarcinoma cases of any specific histologic type, so all analyses were limited to a comparison of adenocarcinoma risk vs. nonadenocarcinoma risk of lung cancer. RESULTS Most women in our series developed lung cancer after the age of 70 years, were married, and had completed high school (table 1). There were few differences between the 618 cases and 1,402 controls in any of the demographic characteristics evaluated. However, the propo'rtion of former smokers (women who had quit smoking more than 15 years previously : median period of cessation=26 years), was about twice as high as among lung cancer cases (30 percent) as among controls (17 per cent). - 9 -

Pathologic material from 468 cases was available for review. Adenocarcinoma was the most frequent lung cancer cell type (62 percent), followed by squamous cell carcinoma (6 percent), bronchoalveolar adenocarcinoma (4 percent), small cell carcinoma (3 percent), and all other cell types combined (25 percent) (table 2). Women in the upper half of the saturated fat consumption continuum were at a fifty percent excess risk of lung cancer compared to women in the lower half. This relatively small excess relative risk translates into a population attributable risk of approximately 20% since the exposed population in this case, constitutes 50% of the total population. We estimate that reducing the saturated fat intake below the 50th percentile (i.e., in this study 18.8 grams/day) would be the single most effective factor identified to reduce lung cancer incidence in a nonsmoking female population in Missouri (Table 3). Further reducing the saturated fat consumption to below the 20th percentile would reduce the risk of lung cancer even more (5). Both life-long nonsmokers and long term ex-smokers achieved a similar degree of benefit from a reduction in saturated fat intake. Fruit and/or vegetable consumption, which has been clearly demonstrated to have a beneficial effect of reduced lung cancer incidence in smoking populations and some nonsmoking populations (11), did not have a measurable impact on lung cancer risk in this study. The - 10 -