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A case-control study of passive smoking and bladder cancer risk in Los Angeles
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A case-control study of passive smoking and bladder cancer risk in Los Angeles
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A CASE-CONTROL STUDY OF PASSIVE SMOKING AND BLADDER CANCER RISK IN LOS ANGELES by Xuejuan Jiang A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment o f the Requirements for the Degree MASTER OF SCIENCE (APPLIED BIOSTATISTICS AND EPIDEMIOLOGY) December 2004 Copyright 2004 Xuejuan Jiang Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 1424222 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. UMI UMI Microform 1424222 Copyright 2005 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGMENTS I would like to thank all my committee members for their advices. Also appreciation goes to: Canlan Sun, Esteban J. Castelao, Manuela Gago-Dominguez, and Donna Murdock. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. iii TABLE OF CONTENTS ACKNOWLEDGMENTS................................................................................................ii LIST OF TABLES............................................................................................................iv LIST OF FIGURES...........................................................................................................v ABSTRACT........................................................................................................................v CHAPTER 1 INTRODUCTION......................................................................................1 1. Bladder Cancer....................................................................................................... 1 2. 4-aminobiphenyl hemoglobin (4-ABP-Hb) adducts......................................... 2 3. Passive Smoking....................................................................................................4 CHAPTER 2 METHODS & MATERIALS...................................................................7 1. Study Design...........................................................................................................7 2. Study Population and Recruitment.......................................................................7 3. Data Collection:..................................................................................................... 8 4. Statistical Analysis............................................................................................... 14 CHAPTER 3 CHARACTERISTICS OF THE STUDY POPULATION................. 15 1. Selection of study subj ects.................................................................................. 15 2. Demographic Characteristics..............................................................................16 CHAPTER 4 PASSIVE SMOKING & 4-ABP-HB ADDUCTS............................... 18 1. Introduction........................................................................................................... 18 2. Subj ects and M ethods.......................................................................................... 19 3. Results....................................................................................................................21 4. Discussion............................................................................................................. 23 CHAPTER 5 PASSIVE SMOKING & BLADDER CANCER R ISK ..................... 26 1. Introduction...........................................................................................................26 2. Subjects and M ethods..........................................................................................27 3. Results....................................................................................................................28 4. Discussion............................................................................................................. 33 REFERENCE....................................................................................................................35 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. iv LIST OF TABLES Table 3-1 Study Population of LA Bladder Cancer Case-Control Study................. 15 Table 3-2 Demographic Characteristics of Lifelong Nonsmokers............................ 17 Table 4-1 4-ABP-Hb Adducts (pg/g hemoglobin) by Passive Smoking...................21 Table 4-2 ORs of having 4-ABP-Hb Adduct Level above median associated with Passive Sm oking............................................................................................22 Table 4-3 Level of 4-ABP Hemoglobin Adducts (pg/g hemoglobin) in Relation to Passive Smoking by Gender......................................................................... 23 Table 5-1 Risk o f Bladder Cancer in Relation to Passive Sm oking..........................30 Table 5-2 Risk of Bladder Cancer in relation to Passive Smoking in Male and Female Lifelong Nonsmokers...................................................................... 31 Table 5-3 Risk of Bladder Cancer in relation to Passive smoking............................32 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. V LIST OF FIGURES Figure 1-1 Chemical structure of 4-ABP........................................................................ 2 Figure 4-1 Metabolism of 4-A B P.................................................................................. 18 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT The role of passive smoking in the etiology of bladder cancer is largely unknown. A case-control study of bladder cancer was conducted in Los Angeles County from 1987-1999. The associations between passive smoking and 4- aminobiphenyl hemoglobin adducts (4-ABP-Hb adducts), and between passive smoking and bladder cancer risk were examined in lifelong nonsmokers. Lifelong nonsmokers who had been exposed to passive smoking showed increased level of 4-ABP-Hb adducts compared with nonsmokers without any passive smoking exposure. The increase in 4-ABP-Hb adducts was most apparent in subjects who were exposed to passive smoking from their spouse or domestic partners. Passive smokers had statistically non-significant increased risk of bladder cancer, especially among females. Our results suggest that passive smoking may be a risk factor for bladder cancer in nonsmokers. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 CHAPTER 1 INTRODUCTION A case-control study of bladder cancer was conducted in Los Angeles County among non-Asian population between 1987 and 1999. The general objective of this study was to better understand the mechanism by which cigarette smoking induces bladder cancer, and to identify other risk/protective factors for bladder cancer. Based on data from lifelong nonsmokers of this study, the following issues have been addressed in this thesis: A. The association between passive smoking exposure and level of 4-ABP-Hb adducts among control subjects; B. The association between passive smoking and risk of bladder cancer among nonsmokers. 1. Bladder Cancer Bladder cancer is the 4th most common cancer among males and the 10th most common among females in the United States. A total of 57,400 people were estimated to be diagnosed of bladder cancer and 12,500 were estimated to die from bladder cancer in 2003 (Jemal et al., 2003). Men are 2.5 to 5.0 times more likely to develop bladder cancer than women (Yu & Ross, 2002), and have higher 5-year relative survival rates for all stages (overall: 84% vs. 75%), when compared to women (Gloeckler-Ries et al., 2003). Non-Hispanic white men have the highest incidence rate, twice the rate of Hispanic white men or black men (Yu & Ross, 2002). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2 Cigarette smoking and industrial exposure to carcinogenic arylamines, such as 2-naphthylamine, 4-aminobiphenyl, and benzidine, are the two most well- established risk factors for bladder cancer in the United States. Other risk/protective factors also have been reported, which include hair dyes, dietary carotenoids, and analgesics (Yu & Ross, 2002). 2. 4-aminobiphenyl hemoglobin (4-ABP-Hb) adducts Figure 1-1 Chemical structure of 4-ABP 4-ABP is a recognized human bladder carcinogen, capable of forming DNA adducts and inducing mutations in DNA. Exposure to 4-ABP is mainly from cigarette smoking and from rubber, coal, textile dye and printing processing industries (IARC, 1986a). Historically, workers in the rubber, coal, textile dye and printing processing industries were exposed to high level of 4-ABP. Such occupational exposures have been under federal regulation since 1944, at least in the developed countries, including the United States. Cigarette smoking is now the most prominent point source of 4-ABP in humans. Recently 4-ABP was found in samples of permanent hair dyes (Turesky et al., 2003), which have been implicated as risk factors for bladder cancer in United States women (Gago-Dominguez et al., Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3 2001). Exposure to 4-ABP can induce bladder cancer in animals such as dogs and rats (Block et al., 1978; Hirao et al., 1981). The carcinogenicity of 4-ABP also has been supported by many epidemiologic studies, most of which are studies of workers in the dye industry (Levy B.S., 1988; Ross et al., 1988). After 30 years of follow-up of a cohort of workers at a benzidine manufacturing facility in Connecticut, male workers showed a significant increase in bladder cancer incidence with a standardized incidence ratio (SIR) of 343 as compared to Connecticut population (Meigs et al., 1986). Similar results were found in a cohort of benzidine-exposed workers in China, of which the exposed group had a 25-fold increase in incidence as compared to unexposed group, ranging from 4.8 fold for low exposure to 158 fold for high exposure (Bi et al., 1992). In humans, 4-ABP-Hb adduct levels correlate well with total DNA adduct levels in exfoliated urothelial cells (Talaska et al., 1991), and therefore, 4-ABP-Hb adducts are effective biomarkers of 4-ABP exposure to the bladder. Smokers have higher levels of 4-ABP-Hb adduct than non-smokers (Phillips, 2002), and the level of 4-ABP-Hb adducts increases with increasing number of cigarettes smoked (Yu et al., 1994). In tobacco smoke, 4-ABP is 30 times more concentrated in side- stream smoke (146 ng/cigarette) than in main-stream smoke (4.6 ng/cigarette) (Hammond et al., 1993). Among nonsmokers, 4-ABP-Hb adduct level also increases with the increasing level of exposure to environmental tobacco smoke (ETS) (Hammond et al., 1993; Maclure et al., 1989; Phillips, 2002). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4 3. Passive Smoking Although cigarette smoking is the main risk factor for bladder cancer, it explains only about 50% of incident bladder cancer cases in the US and other Western countries (IARC, 1986b). There still is a substantial proportion of bladder cancer cases that are not associated with any known risk factors. Animal studies have shown that passive smoking can induce DNA adducts in bladder cells (Izzotti et al., 1999; Takenawa et al., 1994). In humans, exposure to ETS increases 4-ABP- Hb adduct level (Hammond et al., 1993; Maclure et al., 1989; Phillips, 2002) and urinary mutagenicity in nonsmokers (Bos et al., 1983). This suggests that passive smoking is a potential risk factor bladder cancer in nonsmokers. Risk of bladder cancer from passive smoking has been evaluated in three case- control studies (Burch et al., 1989; Kabat et al., 1986; Sandler et al., 1985), and one cohort study (Zeegers et al., 2002). Results are inconsistent. The first study was conducted by Sandler et al. (1985) among smokers and nonsmokers, using spousal smoking as the measure of ETS exposure. Based on 6 cases of bladder cancer with a history of ETS exposure, the authors failed to find an association between passive smoking and bladder cancer risk (odds ratio (OR): 1.1, 95% confidence interval (Cl): 0.2-7.6). This study had severe limitations because of the extremely small sample size and inclusion of active smokers. Kabat et al. (1986) conducted a study among lifelong nonsmokers (152 cases and 492 controls). In that study, 58% of the participants reported spousal smoking status, and only 21% reported information of exposure to ETS at home and at work. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5 Their findings are inconsistent by source of ETS and gender. Male cases relative to controls reported more exposure at home (30.4% vs. 22.7%), less exposure at work or in transportation settings (47.8% vs. 59.1%) and were less likely to have a wife who smoked (30.6% vs. 36.5%). Female cases relative to controls reported less exposure at home (35.3% vs. 46.4%), more exposure at work or in transportation setting (35.3% vs. 17.9%), and were more likely to have a husband who smoked (68.6% vs. 64.8%). None of the above differences were statistically significant. Besides the problem of a high prevalence of missing data, this study only assessed current passive smoking exposure, rather than lifelong ETS exposure. In addition, controls were selected from hospital patients and may not have had an ETS profile representative of the underlying base population. The third case-control study was conducted in Canada by Burch et al between 1979 and 1982. It included 142 histologically confirmed never-smoking cases and 217 never-smoking controls. Exposure to passive smoke from anyone at home or at work was measured. No association was found between ETS and bladder cancer risk. ORs (95% CIs) for bladder cancer associated with ETS exposure at home were 0.94 (0.5-2.0) in males and 0.75 (0.3-1.7) in females. The corresponding ORs for ETS exposure on the job were 0.97 (0.5-1.9) in males and 0.93 (0.5-1.8) in females. Zeegers et al (2002) reported the results of a cohort study from the Netherlands. Among never-smokers (55 cases), ORs (95% Cl) were 1.2 (0.56-2.4) for parent’s smoking, 1.4 (0.7-2.6) for work-related ETS, 0.74 (95% Cl: 0.3-1.9) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 6 for current domestic partner’s smoking, and 0.64 for (95% Cl: 0.29-1.4) more than 3 hours’ of total ETS exposure per day. In order to appropriately evaluate the effect of ETS, a study must be able to define a reference group consisting of subjects who had never been exposed to any ETS over lifetime. One common problem in all four studies described above is that a reference group containing ETS-exposed subjects would lead to an underestimation of the OR associated with ETS exposure. In addition, except for the study from Canada (Burch et al., 1989), statistical power in those studies was low for testing an association between ETS and bladder cancer. Assuming the relative risk associated with ETS is 1.5 and prevalence rate of ETS is 70% (based on observations in these 4 studies), 500 cases are required in order to obtain 80% power at significance level of 0.05 (2-sided) in a cases-control study with one control per case; 258 cases with 6.6 years of follow-up are required in a cohort study with 120,000 45-64 years-old subjects in United States (Garcia-Closas & Lubin, 1999). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7 CHAPTER 2 METHODS & MATERIALS 1. Study Design The present study was based on a subset population of the Los Angeles Bladder Cancer Study, a population-based case-control study of bladder cancer in non- Asian residents of the Los Angeles County (Castelao et al., 2001). In these analyses, we only included lifelong nonsmokers who were interviewed after January 1992. Cases and controls were not paired. 2. Study Population and Recruitment - the Los Angeles Bladder Cancer Study The Los Angeles County Cancer Surveillance Program (CSP) is a population- based cancer registry of Los Angeles County (Bernstein & Ross, 1991), and the largest of the Surveillance, Epidemiology and End Results (SEER) cancer registries. This registry covers more than 9 million people of the Los Angeles County and has been collecting nearly complete cancer incidence data since 1972 (Liu et al., 1998). Non-Asians aged 25-64 years, with histologically confirmed diagnosis of bladder cancer between January 1st, 1987 and April 30th, 1996, and identified by CSP were eligible cases for this study. Controls were individually matched to the index cases by gender, date of birth (± 5 years), race (non-Hispanic white, Hispanic White, or African American) and neighborhood of residence at the time of cancer diagnosis of the index cases (Castelao et al., 2001). One control was selected per case: controls were identified by a standard procedure defining a sequence of houses on specified neighborhood Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8 blocks. Gender, age and race of all residents of each selected housing unit were identified; ‘not-at-home units’ were systematically revisited to complete the census. The first resident along this route meeting all criteria for a control was asked to participate in this study. If this first eligible individual refused to participate in the study, the next eligible resident in the route was asked and so on, until an eligible control subject who agreed to be interviewed was found. If no eligible subject was found after visiting 150 housing units, race was not considered as a matching factor anymore. If no matched control based on this relaxed criteria was found within a maximum of 300 housing units, the case was dropped from the study. All study subjects signed informed consent forms, which were approved by the University of Southern California, Keck School of Medicine Human Subjects Committee. 3. Data Collection: I. Main Questionnaire A structured questionnaire was used to request general information and exposure information up to 2 years prior to the diagnosis of cancer of the cases, and 2 years prior to the diagnosis of cancer of the index case for matched controls. The questionnaire includes the following sections: (a). Background Information: participants were asked to provide information on age, date of birth, race, religion, education, height, weight, marital status, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9 and place of birth. For women who were ever married, the husband’s level of education and occupation was asked. (b). History of Tobacco Use: Use of cigarette, cigar, pipe, chewing tobacco, snuff was asked. If lifetime use of cigarettes was less than 100, or lifetime use of each of the other tobacco products was less than once a week for 6 months, then participants were classified as nonusers of that particular tobacco product. If participants were users, they were asked about the age at starting regular use, age at stopping regular use, number of years of use, and the average amount used for each tobacco product. For cigarette smoking, usual type of cigarettes (filtered, non-filtered, or both equally) and pattern of inhalation (deeply, moderately, lightly) also were asked. (c). Beverage Consumption: participants were asked about their history of drinking coffee, tea, alcoholic beverages, and water, separately. For subjects who reported consuming alcoholic beverages once or more times a week for 6 months or longer (definition of drinkers), we further asked for age at starting to drink regularly, number of years of drinking, and number of drinks per day or per week for beer, wine and hard liquor separately. (d). Medical History: Personal history of hypertension, diabetes, angina, heart attack, stroke, analgesic nephropathy, renal papillary necrosis, kidney or renal stones, bladder stone, polycystic kidney disease, hereditary kidney disease, injury to kidney, urinary tract infection or other diseases, and cancer. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 10 (e). Medication History: use of nonprescription and prescription pain medicines, antihypertensive prescription medicines, diuretics, nonprescription and prescription diet pills, amphetamines, and birth control and other hormone pills/injections. (f). Dietary History: In order to assess dietary vitamins A and C, carotenoids and nitrosamines or their precursors, we asked the intake frequency of forty food groups including vegetables, fruit juices and fruits, meats, main dishes, dairy products, and fats. We also asked intake frequency, duration of use and brand name of the multiple vitamin supplements. (g). Occupational History: for each job lasting 1 year or more, we asked about job title and usual activities on the job, type of industry, location of employment, starting and ending years, and number of hours worked per week. Starting from January 1992, the main questionnaire was expanded to include assessments of the following: (h). Details on cigarette smoking pattern, including starting age and total years of filtered and non-filtered cigarette smoking separately, and low-tar cigarettes, brand name of usual cigarettes smoked; (i). History of drinking hot chocolate, and soda: age at starting to drink regularly, duration and frequency of drinking. For soda, asked about whether it’s regular or diet, with or without caffeine; Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 11 (j). Family history of urinary tract and other cancers; (k).Use of phenobarbital and hormone patch; and (1). Use of hair dyes. II. Supplemental Questionnaire Starting from January 1992, nonsmokers at the time of interview or blood draw were asked to complete a supplemental questionnaire soliciting lifetime history of ETS exposure. Questions cover: (a). Smoking history of parents: whether father or mother smoked any cigarette, cigar, or pipe, and corresponding duration, while participants were under age 18 and living at home. (b). Smoking history of other household members during childhood: similar questions as in (a) above for any other person who lived in the same house with the participant for at least one year, while participant was under age 18. (c). Marital history and smoking history of spouse/partner: If participant was ever married or currently living with a spouse/dometic partner, we first asked whether the spouse/partner used any tobacco products. If yes, then type of tobacco, number of years, and amount of tobacco used while the study subject were living with them were asked for each smoking partner. These questions were repeated to each of spouse/domestic partners who ever used any tobacco. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 12 (d). Smoking history of other household members in adulthood: Similar questions as in (c) above were asked for any other person who had shared living quarters with the subject in his/her adult life. (e). Co-workers’ smoking history: number of smoking coworkers, number of hours of their smoking on the job per day, and indoor/outdoor working environment. (f). Other adult smoking contacts: the number of hours per week of contact with smokers and the number of years of exposure were asked by decade of participant’s age from 20’s to 60’s. III. Interview All interviews were conducted at the home of participants by trained interviewer throughout the study. Most cases and their matched controls were interviewed by the same interviewer. Among case patients, median time interval between bladder cancer diagnosis and interview was 13 months. 75% of cases were interviewed within 24 months of diagnosis. IV. Collection of Blood and Urine Samples: Beginning from January 1992, all cases and their matched controls were asked to donate blood and urine samples at the end of the in-person interview. Separate informed consent forms were signed for biospecimen donations. Two 10-ml blood samples, one heparinized and the other non-heparinized blood, were collected from Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13 each subject. Each subject also was given 2 packets of instant coffee (about 70 mg of caffeine) to be drunk between 3 to 6 pm. The overnight urine including the first morning void following the coffee drinking was collected in a one liter plastic bottle. Tobacco use in the two months preceeding the time of blood draw was recorded. History of drinking tea and caffeinated soda, intake of chocolate products, and use of pain medicine during the day before urine donation, and history of drinking coffee, tea, chocolate, soda, and alcohol in the 2 weeks prior to urine donation also were determined. V. Processing o f Blood and Urine Samples Plasma, buffy coat, and red blood cells were isolated from heparinized whole blood, and serum was isolated from the unheparinized whole blood. All blood components were stored at -80°C prior to analysis. Red blood cells were sent on dry ice to the Massachusetts Institute of Technology (MIT) for quantitative analysis of 4-ABP and 3-ABP hemoglobin adducts as described previously (Skipper, 2002). Samples were identifiable only by code numbers so that investigators at MIT were blinded to the case/control status of the test samples. Matched cases and controls were tested in a single batch. For cases without matched controls or controls without matched cases, the number of cases was always similar to the number of controls in a given batch (Skipper et al., 2003). Urine samples were processed on the same day of collection. They were acidified before storage at -20°C (400mg of ascorbic acid per 20 ml of urine). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 14 4. Statistical Analysis In the Los Angeles Bladder Cancer Study, the following risk or protective factors for bladder cancer unrelated to active smoking were identified: level of education (Castelao et al., 2000), lifelong use of non-steroidal anti-inflammatory drugs (NSAIDs) (Castelao et al., 2000), employment in high-risk industry (Gago- Dominguez et al., 2001), intake of carotenoids and vitamin C (Castelao et al., 2004), and use of permanent hair dyes (Gago-Dominguez et al., 2001). These risk or protective factors were potential confounders for the association between passive smoking and bladder cancer. In our multivariate analysis, we included the following covariates in the models: NSAID use (never use, < 1441 pills, >1441 pills over lifelong), carotenoid intake (quintiles), ever use of permanent hair dyes (yes versus no), history of high-risk jobs (yes versus no) and all the matching variables (age, gender, and race). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 15 CHAPTER 3 CHARACTERISTICS OF THE STUDY POPULATION Between January 1, 1987 and April 30, 1996, the Los Angeles County Cancer Surveillance Program identified 2,395 non-Asians patients with bladder cancer aged 25-64 years. Two hundred and ten (9%) died before we could contact them or they were too ill to be interviewed. Permissions to contact 103 (4%) patients were refused by their physicians. Four hundred and four patients (17%) refused to participate in the study. Therefore, we interviewed 1678 (70%) patients with bladder cancer and 1592 individually matched controls (Table 3-1). Among them, 1089 were first eligible controls, 330 second eligible controls, and 111 third eligible controls. Table 3-1 Study Population of LA Bladder Cancer Case-Control Study Cases Controls Total 1678 1592 Interviewed before January 1992 635 616 Interviewed after January 1992 1043 976 Tobacco smokers 869 646 Lifelong nonsmokers 174 330 With passive smoking data 154 313 1. Selection of study subjects Among the enrolled cases and controls, 1043 cases and 976 controls were interviewed after January 1992. 174 cases and 330 controls are never smokers of cigarette, cigar, or pipe. Passive smoking information was obtained from 154 (89% of 174) cases and 313 (95% of 330) controls, and all were interviewed with the Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 16 expanded questionnaire. 4-ABP-Hb adducts were measured on 253 of the controls, representing majority of them (77%). In order to maximize the number of cases and controls included in the analysis, matching pairs of cases and controls were broken. All our analyses of the association between passive smoking and bladder cancer risk were based on these 154 cases and 313 controls. These subjects represented most of the eligible nonsmokers and cases and controls were selected in a comparable way. Results from the analysis should be applicable to the nonsmoking population covered by this case-control study. 2. Demographic Characteristics Gender, race and education distributions are similar between cases and controls. About 70% of cases and similar proportion of controls were men; 50% of cases and 47% of controls were college graduates; and 84% of cases and 90% of controls are non-Hispanic White (Table 3-2). Average ages were 53 years for cases at diagnosis of bladder cancer and 54 years for controls at the time of bladder cancer diagnosis of the index case. Overall, cases and controls had similar distribution of year of birth. However, the interview of controls was shifted toward later years. Up to 1996, 80% of cases were interviewed, while only 63% controls were interviewed then. The reason for the lag time was that controls matched to the index cases, by definition, could only be identified after the cases’ interview. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 17 Table 3-2 Demographic Characteristics of Lifelong Nonsmokers______ Cases Controls Number % Number % Total 154 100 313 100 Gender Male 110 71 214 68 Female 44 29 99 32 Race Non-Hispanic White 130 84 281 90 Others 24 16 32 10 Education High School 35 23 76 24 1-3 yrs’ College 42 27 89 28 College graduate 77 50 148 47 Year o f Birth 1922-30 22 14 58 19 1931-35 44 29 84 27 1936-40 27 18 57 18 1941-45 19 12 45 14 1946-50 17 11 32 10 1951-71 25 16 37 12 Year of Interview 1993 2 1 4 1 1994 56 36 59 19 1995 34 22 76 24 1996 31 20 58 19 1997 22 14 61 20 1998-99 9 6 55 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18 CHAPTER 4 PASSIVE SMOKING & 4-ABP-HB ADDUCTS 1. Introduction 4-ABP, together with 2-naphthylamine and benzidine, are classified as human bladder carcinogens (Yu & Ross, 1998). Cigarette smoking is now the major source of these aromatic amines, following their tight regulations in occupational settings. Aromatic amines are thought by many to be the principle etiologic factor by which cigarette smoking induces bladder cancer (Yu & Ross, 2002). 4-ABP N-OH-4-ABP Figure 4-1 Metabolism of 4-ABP 4-ABP is activated and becomes N-hydroxylamines by N-oxidation in human (Bryant et al., 1987). N-hydroxylamines conjugate with glucuronide to be transported to the bladder. Hydrolysis of these compounds in the acidic bladder lumen can produce highly electrophilic nitrenium ions, which is capable of binding to urothelial DNA (Kadlubar et al., 1977; Poupko et al., 1979). Mutations from misrepair of DNA damage caused by these adducts are critical to the bladder carcinogenesis. N-hydroxylamines can also form adducts with hemoglobin, which Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 19 can persist stably in blood as long as the hemoglobin is in the blood (Skipper & Tannenbaum, 1990; Skipper et al., 2003). It is shown that Hb-adduct levels correlate with DNA adduct levels in exfoliated urothelial cells (Talaska et al., 1991). Even among nonsmokers, there is still substantial level of 4-ABP-Hb adduct in blood. The level can be precisely and sensitively measured by current laboratory method (Skipper, 2002). Quantitative measurement of 4-ABP-Hb adduct in blood can assess 4-ABP exposure during the past 60 days (Skipper & Tannenbaum, 1990). There are sources of 4-ABP other than active cigarette smoking. As described before, exposure to ETS is another source of 4-ABP (Hammond et al., 1993; Maclure et al., 1989; Phillips, 2002). Exposure to incomplete combustion product of kerosene heater emissions (Tokiwa et al., 1985) and diesel engine exhaust (Paputa-Peck et al., 1983) can produce 4-ABP hemoglobin adducts in humans (Suzuki et al., 1989). Some azo dyes (Manning et al., 1985), commercial hair dyes (Turesky et al., 2003), and fumes from heated cooking oils (Chiang et al., 1999) are other potential sources of 4-ABP exposure in humans. 3-ABP, isomeric with 4-ABP, is also a human bladder carcinogen with different toxicological properties(Yu & Ross, 1998). Analysis has found that 3-ABP hemoglobin adduct level was negligibly low among lifelong nonsmokers (Skipper et al., 2003). Thus, 3-ABP adduct level was not evaluated in this study. 2. Subjects and Methods Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 20 We only used control subjects who were lifelong non-tobacco users for the analysis o f 4-ABP adduct level by the passive smoking exposure during adulthood in this analysis. As a biomarker of recent exposure, 4-ABP hemoglobin adduct level can only represent the exposure in the last 2 months (Skipper & Tannenbaum, 1990). However, in the Los Angeles Bladder Cancer study, passive smoke exposure was assessed in cases only up to 2 years before cancer diagnosis. For controls subjects, such exposures were assessed up to two years before the cancer diagnosis of the index cases. Therefore there is a gap of average 3.6 years between the time of 4- ABP-Hb adduct assessment and latest known status on passive smoking among cases. The corresponding figure among control subjects was 4.5 years. For any subject, we took their last known ETS status as their ETS status at blood draw. For occupational passive smoking, only indoor ETS was considered. Exposure to ETS at social gathering events was not considered since it’s considerably diluted. The reference group consisted of those who had never been exposed to any passive smoke. The distribution of hemoglobin adduct levels of 4-ABP were largely skewed, therefore, values of adduct levels were logarithmically transformed for analysis. Analysis of covariance method by using PROC GLM from SAS 9.0 was used to compare the hemoglobin adduct levels between different ETS exposure levels among all non-smoking control subjects. Age was categorized into 6 groups, <45, 45-49, 50-54, 55-59, 60-64, and >65 years. All other covariates are defined as in Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 21 Chapter 3. The laboratory measurement of 4-ABP adduct level was performed over 7 years (Skipper, 2002), during which there was seven-fold improvement in sensitivity and a gradual increase in the 4-ABP-Hb adduct level possibly due to degradation of the internal standard. Because of this, it is important to include laboratory batch as a covariate to minimize the systematic measurement error. Logistic regression was used to test the association between passive smoking and risk of having high levels of 4-ABP-Hb adducts (greater than median value). Geometric (as opposed to arithmetic) mean values of 4-ABP-Hb adduct level are presented. All p values quoted are 2-sided. 3. Results Table 4-1 4-ABP-Hb Adducts (pg/g hemoglobin) by Passive Smoking Passive smoking N 4-ABP-Hb*(95% Cl) Difference P Never 28 19.2 (14.9-24.7) 0.0 / Current exposure 193 22.7 (19.8-26.0) 3.4 0.19 Spousal or partner’s 70 24.1 (20.4-28.6) 5.0 0.09 Other domestic 83 22.3 (18.6-26.6) 3.1 0.27 Occupational 147 22.4 (19.3-26.0) 3.2 0.23 *: Adjusted for age, race, gender, and level of education 4-ABP-Hb adduct levels were obtained for 81% (253/313) of lifelong nonsmoking controls with passive smoking data. Six of these controls smoked in the 2 months before blood draw. They were excluded for this analysis. The level of 4-ABP-Hb adducts varied from 6.0 to 399.0 pg/g hemoglobin. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 22 Among controls, subjects exposed to passive smoke tended to have higher (3.4 pg/g hemoglobin) 4-ABP adduct level than lifelong non-passive smokers (Table 4- 1). This difference was maximized among subjects exposed to partner or spousal smoking (5.0 pg/g hemoglobin, p =0.09). There was no substantial change in the difference of 4-ABP-Hb adduct levels when additional covariates were adjusted for. Table 4-2 ORs of having 4-ABP-Hb Adduct Level above median associated with ____________________________Passive Smoking___________________________ Passive smoking 4-ABP-Hb adducts OR1 95% Cl P <median2 >median Never 18 10 1.00 / / Current exposure 95 98 2.03 0.86-4.76 0.10 Spousal or partner’s 29 41 2.65 1.03-6.78 0.04 Other domestic 45 38 1.72 0.69-4.31 0.25 Occupational 74 73 1.93 0.81-4.61 0.14 1: Adjusted for age, race, gender, and level o f education 2: Median level (19.70 pg/g hemoglobin) of 4-ABP adducts of all never-smoking controls with 4-ABP-Hb adduct measurement. As shown in table 4-2, controls currently exposed to passive smoke were 2.03 times more likely to have elevated level of 4-ABP-Hb adducts (greater than median), compared to controls who had never been exposed to passive smoke. The effect was stronger if passive smoking due to spousal or partner’s smoking (2.65, 95% Cl: 1.03-6.78). Males were found to have higher background level of 4-ABP-Hb adducts than females (20.6 vs. 16.3 pg/g hemoglobin). However females exposed to passive smoke had higher 4-ABP-Hb adduct level than exposed males (23.8 vs. 22.4), suggesting that passive smoking may have stronger impact of 4-ABP exposure on women than on men (table 4-3). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 23 Table 4-3 Level of 4-ABP Hemoglobin Adducts (pg/g hemoglobin) in Relation to _______________________ Passive Smoking by Gender_______________________ Passive Smoking Males Females N 4-ABP*(95% Cl) N 4-ABP*(95% Cl) Never 19 20.6(15.4-27.5) 9 16.3 (9.7-27.4) Current exposure 132 22.4 (19.0-26.5) 61 23.8 (18.4-30.7) *: Adjusted for age, race, and level o f education 4. Discussion Our study is the largest study that ever measured the effect of passive smoking on level of 4-ABP-Hb adducts among nonsmokers. Passive smokers were found to have higher levels of 4-ABP adduct (22.7 vs. 19.2 pg/g), suggesting that passive smoking is a possible source of carcinogenic 4-ABP in human. Considering the non-differential misclassfication caused by using adulthood exposure experience instead of the real current exposure status, the real amount of increase in 4-ABP-Hb adduct level should be greater. Bartsch et al (Bartsch et al., 1990) found a difference of 4.0 pg 4-ABP-Hb adducts per gram of hemoglobin among nonsmokers with slow acetylators (homozygous for the slow acetylator gene), and overall difference of 18.4 among all nonsmoking volunteers. In Hammond’s study of women in Massachusetts (Hammond et al., 1993), passive smokers’ 4-ABP-Hb adduct level was 3.2-10.2 pg/g hemoglobin higher than non passive smokers’. In the study population of the Los Angeles bladder cancer case- control, 53% of nonsmokers are slow acetylators. So we believe that our results are similar to the findings from those studies. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 24 Compared to other sources of passive smoking, partners’ or spousal smoking was less common but more effective in increasing the 4-ABP-Hb adduct level. It is possible that partners or spouses had more frequent and closer contact with each other, which resulted in higher exposure to the passive smoke. Females had more increase in 4-ABP-Hb adduct level if ever exposed to passive smoking (table 4-3). It is possible that females are more susceptible to passive smoking, or spouse/partners of female subjects smoked more intensively. Logarithmical transformation of 4-ABP-Hb adduct level and adjustment to laboratory batch were employed to minimize the variation from the measurement of 4-ABP-Hb adducts. Since laboratory personnel were blind to the status of passive smoking of participants, we believe there was no differential measurement error and our results were unlikely to be biased away from null. Recall bias should not be an issue here, since participants were not aware of their levels of 4-ABP adducts. However, it is possible that passive smoking is just a surrogate of another exposure, which is also capable of producing 4-ABP adduct in blood. Alternatively the group of people who reported never being exposed to any passive smoke was different from exposed people in other aspects, which we are not aware of or we could not fully adjust for in the analysis. In this study population, lifelong nonsmoking cases were found to have higher level of 4-ABP than lifelong nonsmoking controls (26.1 vs. 21.4 pg/g, p=0.002, (Skipper et al., 2003). This indicates other sources of 4-ABP exist for this population than active smoking, and cases have higher level of exposure to these Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 25 sources. However the difference in 4-ABP adducts between cases and controls, which still exists after adjustment for passive smoking exposure, can not be fully explained by passive smoking. Other sources of 4-ABP besides passive smoking must be present in the living environment of the study subjects (Chiang et al., 1999; Manning et al., 1985; Paputa-Peck et al., 1983; Tokiwa et al., 1985; Turesky et al., 2003). The increase in 4-ABP-Hb adduct level by passive smoking indicates passive smoking is a possible risk factor for bladder cancer, and 4-ABP is the carcinogenic component in it. However, the magnitude is relatively small, when compared with the magnitude increased by active smoking. In the Los Angeles Bladder Cancer study, actively smoking no more than 1 pack of cigarette per day can increases 4-ABP-Hb adduct level by 23 pg/g Hb for males, 45 pg/g for females, which is associated with relative risks of 1.3 for males, and 1.9 for females (Castelao et al., 2001). Based on these observations, we expect the association between passive smoking and bladder cancer risk to be modest, and relatively stronger among females than males. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 26 CHAPTER 5 PASSIVE SMOKING & BLADDER CANCER RISK 1. Introduction • Cigarette smoke & bladder cancer The role of cigarette smoking in the carcinogenesis of bladder has been firmly supported by many epidemiologic studies (Yu & Ross, 2002; Zeegers et al., 2000). A meta-analysis showed that compared to nonsmokers, current and ex- cigarette smokers have 3.33 and 1.98 times higher risk of urinary tract cancer (Zeegers et al., 2000). The risk increases with the number of cigarettes smoked and the duration of smoking, and decreases with years of cessation (Zeegers et al., 2000). Cigarette smoking accounts for 48% and 50% of bladder cancer incidences among males and females in the Los Angeles Bladder Cancer Case-Control study. Cigar and pipe smoking are weakly associated with bladder cancer, while other smokeless tobacco is not linked at all (Yu & Ross, 2002). Some studies have suggested that women may be more susceptible to smoking- related lung cancer (Haugen, 2002). The Los Angeles Bladder Cancer Study found that female smokers have higher bladder cancer risk than male smokers given comparable dose and duration of smoking (Castelao et al., 2001). The mechanism behind these findings is still unknown. • Passive smoking & bladder cancer Passive smoke, also called second-hand smoke, environmental tobacco smoke (ETS), or involuntary smoke, is the combination of diluted side-stream smoke and Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 27 mainstream smoke. The Environmental Protection Agency (EPA) identified environmental tobacco smoking as a group A carcinogen (being associated with the greatest probability of human carcinogenicity, (U.S. EPA, 1992). The National Cancer Institute also concluded that passive smoke is a human carcinogen (National Cancer Institute, 1999). It has been positively linked to lung cancer, cardiovascular disease, adverse reproductive outcomes, asthma, etc. Since active smoking is a strong risk factor for bladder cancer, it is possible that passive smoking could play a role in the development of bladder cancer, especially at high dose. Considering the relatively moderate association between ETS and lung cancer (Fielding & Phenow, 1988), we predict a comparably moderate association between passive smoking and bladder cancer. 2. Subjects and Methods All study participants included in this analysis are lifelong nonsmokers of cigarettes, cigar, and pipe, defined as never having smoked more than 100 cigarettes, and never having smoked cigar or pipe more than once a week for 6 months or longer. Most (70%) of the reported durations of passive smoking in social setting were less than one hour per day. Considering the dilution of passive smoking in outdoors and short duration of passive smoking in social setting, outdoor passive smoking and socially passive smoking were both ignored. Unconditional logistic regression method was used to examine the association between passive smoking and bladder cancer risk (Breslow & Day, 1980). PROC Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 28 LOGISTIC from SAS 9.0 was used to conduct the regression analysis. The associations were measured by odds ratios (ORs) as measure of relative risk, corresponding confidence intervals (CIs) and 2-sided P-values from likelihood ratio tests. Since we broke the matched case-control pair, all regression runs were adjusted for the matching factors: age, race, and gender. Additional adjustment was made for other potential confounders including level of education, use of NSAIDs, use of permanent hair dyes, high-risk occupation, and intake of dietary carotenoids. Age was categorized into 6 groups, <45, 45-49, 50-54, 55-59, 60-64, and >65 years. All other covariates were categorized as shown in tables in chapter 3. Mediums for passive smoking were calculated according to the distribution of the exposed control group separately for passive smoking from spouse/partners and from coworkers. Linear trends were tested by regression analysis with an ordinal exposure variable. 3. Results In order to compare our results with published data (Burch et al., 1989; Kabat et al., 1986; Sandler et al., 1985), we assessed each source of passive smoke under the assumption that all other sources of passive smoke were unrelated to the risk (table 5-1), even though it was not a reasonable assumption. Exposure from parent, partner/spouse, any household members or coworkers was not associated with an increased risk of bladder cancer. Further adjustment for other potential risk factors and other ETS did not materially change the results. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29 Females seemed to be more susceptible to passive smoke than males (Table 5- 2). While the odds ratios among males were consistently below 1.0, the odds ratios for females were all higher than 1.0, almost most were not statistically significant. The differences in risk between males and females remained even after adjustment for other risk factors. The gender difference was especially apparent for risk from mother’s smoking (heterogeneity test, p=0.04). Considering different ETS may overlap with each other and share common carcinogenic pathway, analysis based on a relatively “clean” reference group was also conducted (Table 5-3). Subjects in the reference group were never exposed to passive smoke from any source. No significant association between passive smoking and bladder cancer risk was found, even though all the odds ratios for bladder cancer associated with passive smoking were between 1.0 and 1.5. There were some evidences of a dose-response relationship with duration of passive smoking from spouse/partners, and duration of passive smoking from workplace (Table 5-3). No other dose-response relationship by the amount or the duration of passive smoking exposure was found. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 5-1 Risk of Bladder Cancer in Relation to Passive Smoking Passive Smoking Cases/Controls OR'(95% Cl) OR2 (95% Cl) During Childhood (before age 18) Father smoked No 71/140 1.00 1.00 Yes 82/172 0.93 (0.6-1.4) 0.96 (0.6-1.4) Mother smoked No 118/238 1.00 1.00 Yes 36/75 0.94 (0.6-1.5) 0.92 (0.6-1.5) Any parent smoked No 62/127 1.00 1.00 Yes 91/185 1.00 (0.7-1.5) 1.00 (0.7-1.5) Any household member smoked No 58/116 1.00 1.00 Yes 95/197 0.95 (0.6-1.4) 0.94 (0.6-1.4) During Adulthood Spouse/partner smoked No 120/230 1.00 1.00 Yes 34/83 0.81 (0.5-1.3) 0.83 (0.5-1.4) Any household member smoked No 85/158 1.00 1.00 Yes 69/155 0.84 (0.6-1.3) 0.90 (0.6-1.4) Any coworker smoked No 55/117 1.00 1.00 Yes 89/183 1.07 (0.7-1.6) 1.10(0.7-1.7) 1: Adjusted for age, race, gender, and education level. 2: Additionally adjusted for use of NSAIDs, use o f permanent hair dyes, high-risk occupation, and intake of dietary carotenoids. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 5-2 Risk of Bladder Cancer in relation to Passive Smoking in Male and Female Lifelong Nonsmokers Passive Smoking Ca/Co1 Males OR2 (95% Cl) Ca/Co1 Females OR2 (95% Cl) p for test of interaction During Childhood (before age 18) Father smoked No 53/96 1.00 18/44 1.00 Yes 57/118 0.87 (0.5-1.4) 25/54 1.11 (0.5-2.4) 0.98 Mother smoked No 92/161 1.00 26/77 1.00 Yes 18/53 0.58(0.3-1.1) 18/22 2.35 (1.0-5.4) 0.04 Any parent smoked No 50/89 1.00 12/38 1.00 Yes 60/125 0.85 (0.5-1.4) 31/60 1.60 (0.7-3.6) 0.18 Any household member smoked No 47/80 1.00 11/36 1.00 Yes 63/134 0.80 (0.5-1.3) 32/63 1.63 (0.7-3.7) 0.03 During Adulthood Spouse/partner smoked No 99/178 1.00 21/52 1.00 Yes 11/36 0.55 (0.3-1.1) 23/47 1.29 (0.6-2.8) 0.15 Any household member smoked No 72/123 1.00 13/35 1.00 Yes 38/91 0.72 (0.4-1.2) 31/64 1.34 (0.6-3.0) 0.53 Any coworker smoked No 39/71 1.00 16/46 1.00 Yes 63/133 0.90 (0.5-1.5) 26/50 1.83 (0.8-4.0) 0.14 1: Ca/Co: Number o f cases / controls 2: Adjusted for age, race, and education level. Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission. Table 5-3 Risk of Bladder Cancer in relation to Passive smoking Passive Smoking All subjects' Males2 Females2 Ca/Co3 OR(95% Cl) Ca/Co3 OR(95% Cl) Ca/Co3 OR(95% Cl) Never Ever 15/41 136/269 1.00 1.39(0.7-2.6) 12/28 95/184 1.00 1.20 (0.6-2.5) 3/13 41/85 1.00 2.51 (0.7-9.6) Domestic 114/227 1.38(0.7-2.6) 75/151 1.15 (0.6-2.4) 39/76 2.60 (0.7-9.9) D om estic, Childhood Father smoked Mother smoked Any parent smoked 95/197 82/172 36/75 91/185 1.32 (0.7-2.5) 1.30(0.7-2.5) 1.27 (0.6-2.6) 1.34 (0.7-2.6) 63/134 57/118 18/53 60/125 1.09 (0.5-2.3) 1.12(0.5-2.4) 0.77 (0.3-1.8) 1.11 (0.5-2.4) 32/63 25/54 18/22 31/60 2.54 (0.7-9.8) 2.33 (0.6-9.2) 3.90 (0.9-16.4) 2.58 (0.7-10.0) Domestic, Adulthood Spouse/partner smoked <11 years >11 years p for trend 69/155 34/83 14/39 19/39 1.22 (0.6-2.4) 1.14(0.5-2.4) 0.93 (0.4-2.2) 1.33 (0.6-3.2) 0.53 38/91 11/36 0.97 (0.4-1.1) 0.72 (0.3-1.9) 31/64 23/47 2.48 (0.6-9.6) 2.57 (0.6-10.3) Any coworker smoked <12 years >12 years p for trend 89/183 39/83 42/85 1.35 (0.7-2.6) 1.27 (0.6-2.6) 1.37(0.7-2.8) 0.41 63/133 1.10(0.5-2.3) 26/50 2.94(0.7-11.7) Adulthood: domestic/ occupational 114/241 1.29 (0.7-2.4) 74/161 1.06 (0.5-2.2) 40/80 2.61 (0.7-10.0) 1. Adjusted for age, gender, race, and education level. 2. Adjusted for age, race, and education level 3. Ca/Co: Number of cases / controls 33 4. Discussion To our knowledge, this is the largest population-based study ever conducted among never smokers to assess the relation between passive smoking and bladder cancer risk. Despite a lack of statistical significance due to the modest study sample size, our study nonetheless shows a remarkable internal consistency in its findings and collectively, the data provide convincing evidence that passive smoking exposure plays a role in bladder cancer among never smokers. Passive smoking has been positively linked to lung cancer (Reynolds & Fontham, 1995). The effect has been precisely estimated in a pooled analysis conducted by International Agency for Research on Cancer (Brennan et al., 2004). The OR for ever exposure to secondhand smoking was 1.22 (95% Cl: 0.99-1.51), and 1.32 (95% Cl: 1.10-=1.79) for long-term (39+ years) exposure. No difference by sources of passive smoking was found. These results were just like what we found in this study, convincingly suggesting passive smoking is a risk factor bladder cancer in nonsmokers. The higher susceptibility in women than men toward passive smoke, as noted in this study, is consistent with our earlier observation that active smoking shows a stronger adverse effect on urothelial cells in women than men (Castelao et al., 2001). We also have demonstrated that female smokers had higher 3, 4-ABP-Hb adducts than men smoking comparable amounts. Males have a much higher risk background from other factors than females. So alternatively, it is possible that a constant additive risk of bladder cancer risk associated with passive smoking may Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 34 create a larger relative risk in women than in men. Passive smoking is not widely known as a risk factor for bladder cancer. So recall bias differentiated by sex is unlikely to explain the risk difference between males and females. The differences in results from table 5-1 and 5-3 clearly indicated that independent assessment of passive smoking from different sources can mask a truly existing association between passive smoking and bladder cancer risk. This may explain why some of the earlier studies couldn’t find a positive association and more often they found protective effect of passive smoking. Misclassification of the exposure is inevitable, since the subject’s exposure status was decided retrospectively by recalling other people’s smoking habits, and some of the events were decades old. However, differential miclassification is unlikely since passive smoking has never been known to be a risk factor for bladder cancer. Non-differential misclassification of the exposure status tends to bias the results towards null. 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Jiang, Xuejuan
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A case-control study of passive smoking and bladder cancer risk in Los Angeles
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Master of Science
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Applied Biostatistics and Epidemiology
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Jiang, Xuejuan
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