1 Division of Occupational and Environmental Medicine, University of California, San Francisco, CA.
2 School of Public Health, University of California, Berkeley, CA.
Received for publication November 13, 2002; accepted for publication June 23, 2003.
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ABSTRACT |
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arsenic; bladder neoplasms; smoking; water supply
Abbreviations: Abbreviations: CI, confidence interval; HCFA, Health Care Financing Administration.
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INTRODUCTION |
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Several populations in the United States have been exposed to arsenic-contaminated drinking water at levels near 100 µg/liter (13). However, since there is little information on the cancer risks at these levels, risk estimates for these exposures have involved extrapolations from the results of studies from highly exposed populations in Taiwan (5, 1416). Such extrapolations have suggested that the cancer risk from drinking water containing arsenic at 50 µg/liter may be as high as one in 100 (5, 16, 17). Many different models have been used in these extrapolations, and differences in the models have led to large disparities in estimated risks (14). These disparities have fueled controversy and uncertainty in the low dose risk estimation process, highlighting the importance of actual studies at low exposures. According to the 1999 National Research Council Subcommittee on Arsenic in Drinking Water, "Additional epidemiologic evaluations are needed to characterize the dose-response relationship for arsenic-associated cancer and noncancer endpoints, especially at low doses. Such studies are of critical importance for improving the scientific validity of risk assessment" (5, p. 3). The purpose of the present study was to investigate bladder cancer risk using a case-control study design in a population exposed to low to moderate arsenic levels in drinking water.
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MATERIALS AND METHODS |
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Cases were subjects aged 2085 years, with primary bladder cancer first diagnosed between 1994 and 2000, who lived in the study area at the time of diagnosis. Lists of subjects meeting these criteria were provided by the Nevada Cancer Registry and the Cancer Registry of Central California. Completeness of case ascertainment for the Nevada Cancer Registry has been estimated at 94.5 percent for the years 1995 and 1996 (19). Completeness for the Cancer Registry of Central California has been estimated at 95 percent (20). In Nevada, rapid case ascertainment, involving hospitals and physicians, was used to ascertain cases for the last 3 years of the study period. All pathology laboratories and associated hospitals in the study area and in Reno, Nevada, the nearby referral area, participated in rapid case ascertainment.
Controls were frequency matched to cases by 5-year age group and gender. Controls with a history of bladder cancer were excluded. Random digit dialing was used to gather controls under the age of 65 years (21). Controls over 65 years of age were randomly selected using Health Care Financing Administration (HCFA) rolls or random digit dialing.
Participants were interviewed over the telephone using a standardized questionnaire. For participants who were deceased, attempts were made to interview the nearest relative. Interviewers were blinded to the case-control status of the subject. Participants were asked to provide the address or location of all residences they had lived at for 6 months or longer over their lifetime. For each residence, participants were asked about sources of their drinking water (private well, community supply, bottled water, or other) and water filter use. Participants were asked their typical intake of drinking water and beverages, such as coffee and soups, made with tap water 1 year prior to the interview or prior to any recent illness, 20 years ago, and 40 years ago. Participants were also asked to provide the amount of tap water and fluid consumption separately for home, work, and away from home or work.
Participants were asked to describe all jobs they had held for 6 months or longer. Jobs were classified as low risk and possible risk, based on the degree of evidence linking specific jobs to elevated bladder cancer risks (2227). Smoking questions covered age when smoking began, age of cessation, total years smoked, and typical number of packs smoked per week.
To determine arsenic exposure for each subject, we linked each residence within the study area to a water arsenic measurement for that residence. By doing so, an arsenic concentration could be assigned to each year of a subjects life within the study area. Arsenic exposures for residences outside the study area were assigned a value of zero. The average daily arsenic intake (µg/day) for a given year was then calculated by multiplying the arsenic concentration (µg/liter) for that year by the daily water intake (liters/day) estimated from responses to questions on water consumption. Estimates of daily water consumption for each year were ascribed from intake data for the nearest time period available. For example, information on drinking water intake from 20 years ago was used to estimate water intake for years 1030 prior to diagnosis or ascertainment. The use of bottled water and water treated with a filter known to remove arsenic was assigned an arsenic level of zero.
Arsenic measurements for all community-supplied drinking water within the study area were provided by the Nevada State Health Division and the California Department of Health Services. We obtained over 7,000 arsenic measurements for community and domestic wells within our study area. For all large community water sources, records dated back 15 years or more. Records were available for both Hanford and Fallon documenting arsenic levels near 100 µg/liter since the 1940s. Over the last 10 years, the arsenic levels in Hanford have dropped to below 50 µg/liter because of the development of new wells. In Fallon, levels remain near 100 µg/liter, although a treatment plant is currently being built. Most of the remaining public water supplies in the study area contain less than 10 µg of arsenic per liter, although a few small cities have public water supplies with arsenic levels between 10 and 50 µg/liter. Most private wells in the study area contain arsenic below 10 µg/liter, although levels in private wells near Fallon and Hanford vary dramatically, from 0 to over 1,000 µg/liter.
When historical records were unavailable, more recent measurements were used. In an analysis using nationwide data, arsenic levels in a particular well have been shown to be relatively stable over time (13). In a separate analysis performed as part of our investigation, a Pearson correlation coefficient of 0.84 (95 percent confidence interval (CI): 0.74, 0.90) was obtained when we compared recent and past arsenic measurements taken at least 10 years apart from 69 wells in the study area.
Some arsenic measurements for private wells were obtained from the Nevada State Health Division. When records were not available, the residence was visited, and a water sample was collected. If a well could not be located, proxy estimates were used. These were calculated as the mean arsenic level on file at the Nevada State Health Division for all wells of similar depth within the same township/range/section as the unlocated well. Estimates were made only if at least five other wells existed within the same section, and the range between the highest and lowest arsenic level was less than 20 µg/liter. Researchers were blind to the case-control status when calculating proxy estimates. For residences where arsenic measurements could not be located or estimated, arsenic levels were assigned a value of zero.
Odds ratios were calculated using unconditional multiple logistic regression. Several indices of arsenic exposure were assessed. These were as follows: 1) the highest average daily arsenic intake for any one year, 2) the highest daily average arsenic intake averaged over any contiguous 5 years, 3) the highest daily average arsenic intake averaged over any contiguous 20 years, and 4) total lifetime cumulative exposure, calculated by multiplying the daily average arsenic intake for each year of a subjects life by 365 to produce yearly intakes and then summing yearly intakes to produce total lifetime exposures. Stratification of the first three indices was based on a priori hypotheses regarding the current and past US drinking water standards. Stratification levels were set so that subjects exposed below the new US standard of 10 µg/liter would generally end up in the lowest exposure category, while subjects exposed above the current standard of 50 µg/liter would end up in the highest exposure category, assuming an average drinking water intake of 2 liters per day. Cumulative exposures were divided into tertiles. Other stratification levels were also assessed. Each exposure index was assessed with exposure lags of 5 years, 20 years, and 40 years from diagnosis. A time window analysis was performed in which the average arsenic intake in 10-year windows was the measure of exposure (28). Tests for linear trends were performed by the Cochran-Armitage test using category means.
Potential confounding variables entered into the logistic regression models included sex, age, smoking (categorized as never smokers, former smokers, current smokers averaging less than one pack per day, current smokers averaging one pack per day or more), highest education, occupation associated with elevated rates of bladder cancer, and income. In addition, adjustment for smoking was performed using pack-years or average cigarettes smoked per day in seven categories: never smokers, tertiles in former smokers, and tertiles in current smokers.
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RESULTS |
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Information on age, gender, and last known residence was available on nonparticipants. We compared the percentages of participants and nonparticipants whose last known residences were in areas with public water supplies containing more than 40 µg of arsenic per liter. Nonparticipants included those whom we were unable to locate and those who declined participation. For controls, 20 percent and 21 percent of participants and nonparticipants, respectively, lived in exposed areas. For cases, 20 percent of participants and 26 percent of nonparticipants lived in exposed areas.
A total of 181 cases and 328 controls were enrolled in the study (table 1). Cases and controls were of similar age, race, and gender distribution. Cases were more likely to be in the lower income bracket, less educated, and current smokers. Next-of-kin interviews were used for 35 cases (19 percent) and 20 controls (6 percent).
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Analyses using different stratification cutoff points produced similar results. For example, adjusted odds ratios for exposures greater than 100 µg/day lagged 40 years were 1.85 (95 percent CI: 0.88, 3.92) for all participants and 4.54 (95 percent CI: 1.53, 13.45) for smokers.
Table 5 presents the results of the time-window analysis. In the overall analysis, no clear elevations in relative risk were seen. However, in the analysis confined to smokers, elevated odds ratios were seen for exposures 5160 years prior to diagnosis (odds ratio = 4.99, 95 percent CI: 1.31, 18.9) and for 6170 years prior to diagnosis (odds ratio = 10.1, 95 percent CI: 1.17, 87.1).
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DISCUSSION |
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Numerous studies have reported increased risks of bladder cancer with arsenic ingestion, although most have involved exposures higher than those reported here (69, 11, 12, 2931). The results of studies in populations with lower exposures have been mixed. A cohort mortality study in Utah, where exposures ranged from 14 to 166 µg/liter, showed reduced risks of bladder cancer mortality in people with cumulative exposures greater than 5,000 ppb-years (standardized mortality ratio = 0.44 in males and 0.22 in females) (32). These findings were based on three male and two female bladder cancer deaths, and they did not include data on water intake or smoking (33). A cohort mortality study in Taiwan found evidence of increased bladder cancer risks from consuming arsenic-containing water at levels greater than 640 µg/liter, but no increases were seen at lower levels (34). This study also did not include individual data on arsenic intake or level of smoking. In a more recent cohort study in Taiwan, relative risks of 8.2 (95 percent CI: 0.7, 99.1) and 15.1 (95 percent CI: 1.7, 139.9) for bladder cancer were reported for those exposed to arsenic levels of 50100 µg/liter and greater than 100 µg/liter, respectively (35). This study had two cases in the 50- to 100-µg/liter category, and the range of exposures in the highest exposure category (1003,590 µg/liter) was substantially greater than the range in our study.
In this study, arsenic-associated cancer risks were analyzed for several different subgroups. When evaluating multiple outcomes such as this, one needs to consider the issue of multiple comparisons and the likelihood that positive associations may be due to chance. The positive outcomes identified in this study are consistent with findings from other studies. There is a growing amount of evidence supporting the hypothesis that arsenic and cigarette smoke act synergistically in causing cancer. In two studies involving very low arsenic exposures, elevated risks of bladder cancer associated with arsenic intake were identified only in smokers. In a case-control study in Utah, Bates et al. (28) found an odds ratio of 3.31 (95 percent CI: 1.1, 10.3) in smokers and of 0.53 (95 percent CI: 0.1, 1.9) in nonsmokers for those with cumulative arsenic exposures greater than 53 mg. In a case-control study in Finland, Kurttio et al. (36) reported odds ratios of 10.3 (95 percent CI: 1.16, 92.6) in smokers and of 0.87 (95 percent CI: 0.25, 3.02) in nonsmokers for arsenic exposures greater than 0.5 µg/liter. Two studies have also identified synergistic relations between smoking and ingested arsenic in lung cancer (6, 37). For example, in a lung cancer case-control study in Chile, odds ratios of 8.0 in never smokers and of 32.0 in smokers were reported for arsenic exposures above 200 µg/liter (37). A synergistic relation has also been identified with smoking in several studies of inhaled arsenic and lung cancer (38).
The results presented here suggest that the latency of arsenic-caused cancer may be greater than 40 years. Other chemical carcinogens appear to have latency or induction periods of at least several decades, although the data on ingested arsenic are mixed (39). In a time-window analysis of arsenic-exposed populations in Utah, Bates et al. (28) reported increased risk in smokers in the 30- to 40-year period, but they did not find increased risks in other periods, including the 40- to 50-year period. The Finish cohort study of bladder cancer found relative risks of 2.44 (95 percent CI: 1.11, 5.37) for arsenic exposures 39 years prior to diagnosis and of 1.51 (95 percent CI: 0.67, 3.38) for exposures 10 years and earlier (36). Both of these studies were based on exposures substantially lower than those reported in this study. In a cohort study of bladder cancer and Fowlers solution (potassium arsenite), three of the five cancer deaths in the study occurred within the first 10 years of exposure, and two occurred more than 20 years after the first exposure (11). Case series of arsenic ingestion and skin cancer report a wide range of latencies, although most of these are 20 years or more (4044).
One aspect of this study warranting comment is that it did not incorporate arsenic exposures from outside the study area. However, the likelihood that participants received substantial exposures in other areas appears small. In the US Geological Surveys data set of potable groundwater supplies, arsenic levels above 50 µg/liter were found in only 79 of the 5,306 (1.5 percent) domestic well samples and 18 of the 1,982 (0.9 percent) public water samples (45). In a report by the US Environmental Protection Agency that includes both ground- and surface water, it was estimated that only 0.36 percent of the nations community water systems contain arsenic levels greater than 50 µg/liter (46). The US Geological Survey has estimated that the median arsenic concentration in all potable groundwater resources in the United States is approximately 1.0 µg/liter (13). Ascribing this number for exposures outside the study area had no impact on our results.
The major advantage of this study is that the assessment of arsenic exposure is based on not only drinking water arsenic concentrations but also the volume of water consumption, the use of bottled water, and the use of water filters that remove arsenic. The importance of this is highlighted by the data presented in table 2, showing that the maximum concentration to which participants were exposed was similar among cases and controls. In addition, adjusted odds ratios calculated without the use of water consumption data resulted in odds ratios that were lower than the elevated odds ratios presented in tables 35. For example, the adjusted odds ratios for highest 1-year exposures greater than 40 µg/liter compared with 5 µg/liter or less, lagged 40 years, were 1.13 (95 percent CI: 0.52, 2.50) for all participants and 2.45 (95 percent CI: 0.83, 7.23) for smokers. Studies with less detailed data may be more likely to incorrectly classify arsenic intake and therefore could be more likely to miss true causal associations.
Errors in assessing arsenic intake may have arisen from errors in measuring drinking water intake or from errors in assigning arsenic concentrations to drinking water sources. We were able to link drinking water sources to data on arsenic concentrations for almost 90 percent of the total time the participants lived in the study area. This percentage was similar for both cases and controls. Most other aspects of exposure assessment were also similar for both cases and controls, including the volume of tap water consumed, the percentage of proxy well measurements used, the median arsenic value assigned using proxy measurements, and the percentage of participants lives spent outside the study area. These data suggest that most errors in assessing exposure were nondifferential and therefore not likely to have been responsible for the positive associations identified in this paper.
Cases and controls differed in several characteristics. The higher percentage of controls in the upper income brackets is likely related to the increased participation rates among those in higher socioeconomic brackets (4750). Other studies have shown little or no association between socioeconomic status and bladder cancer, suggesting that this variable is not likely to act as a substantial confounder (51). The crude odds ratios for the upper income categories increased only slightly when adjusted for smoking, age, gender, and arsenic exposure.
A greater percentage of next-of-kin interviews was performed for cases compared with controls. This may have led to a greater rate of misclassification among cases. Correcting for this misclassification would result in odds ratios that are higher than those reported here (52). For example, if 5 percent of the exposed cases were actually unexposed, and 5 percent of the unexposed cases were actually exposed, the crude odds ratio for smokers with highest 1-year exposures greater than 80 µg/day lagged 40 years would increase from 3.52 to 4.99.
Cases and controls also differed in the percentage of nonparticipants with last known residences in arsenic-exposed areas. The percentage of nonparticipants from exposed areas was 5 percent higher among cases than controls. In analyses based on recent exposures, this difference would probably mean that more exposed cases were missed, biasing the odds ratio toward the null. The impact on analyses of exposures from the distant past is unknown.
In conclusion, the results of this study suggest that smokers who drink water containing arsenic at concentrations near 200 µg/day may be at increased risk of bladder cancer compared with smokers at lower arsenic exposures. This study also adds to evidence suggesting a long latency between arsenic exposure and bladder cancer diagnosis, although further confirmatory work is needed.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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