1 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, NH.
2 Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH.
3 Research Reactor Center, University of Missouri, Columbia, MO.
4 Department of Medicine, Dartmouth Medical School, Lebanon, NH.
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ABSTRACT |
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arsenic; case-control studies; metals, heavy; neoplasms, basal cell; neoplasms, squamous cell; skin neoplasms; water
Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; SCC, squamous cell carcinoma; SE, standard error
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INTRODUCTION |
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Prior epidemiologic studies in the United States have found no relation between skin cancer and drinking water arsenic concentrations (69
); however, these studies involved ecologic analyses using geographic areas with widely varying arsenic levels or included too few subjects to detect small elevations in risk. Studies based on skin cancer mortality (10
) were possibly inconclusive because nonmelanoma skin cancer is rarely fatal. Arsenic concentrations in toenails, which presumably reflect body burden from all sources of exposure, correlate with arsenic concentrations found in drinking water in areas with high arsenic levels (11
, 12
). In areas with low water levels of arsenic, however, other sources of exposure (i.e., food or occupation) may be more important (12
); thus, in such areas, substantial misclassification could result from an exposure measure based on water concentrations alone. As part of a US population-based case-control study of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin, an assessment was made of the risks of these malignancies in relation to arsenic concentrations measured in individual toenail clipping samples.
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MATERIALS AND METHODS |
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We chose a control group from among New Hampshire residents aged 2574 years, frequency matched on age (2534, 3544, 4554, 5564, 6569, 7074 years) and sex to the combined distribution of the SCC and BCC cases. To select controls for cases aged less than 65 years, we used population lists obtained annually from the New Hampshire Department of Transportation. The file contains the names and addresses of those holding a valid driver's license for the state of New Hampshire. We selected controls for cases aged 65 years and older from data files provided annually by the Health Care Financing Administration's Medicare Program. The method of control selection in our study has been successfully used in other case-control studies conducted in the region (15).
We attempted to obtain an equal number of controls to BCC cases (or a 2/1 ratio to SCC cases). For interviewing purposes, controls were randomly assigned a comparable reference date to the cases' diagnosis dates. Of the 1,051 controls selected, 21 percent (n = 224) did not have an identifiable telephone number, and 1 percent (n = 7) were non-English speaking. Of the 820 potential participants, 2 percent (n = 12) were reported as deceased by a member of the household; in 2 percent (n = 12) of the households, no one answered after 40 attempts distributed over days, evenings, and weekends; 228 (28 percent) declined; and 28 (3 percent) were mentally incompetent or too ill to take part. A total of 540 controls were interviewed, of which 524 (97.0 percent) had a toenail sample analyzable for arsenic.
Personal interview
Beginning in January 1994, we sent an introductory letter to potential cases and controls explaining the general purpose of the study and that an interviewer would soon telephone. Those who agreed to take part underwent a detailed in-person interview, usually at their home. Questions covered sociodemographic information (including level of education), use of tobacco, and medical history (including previous radiotherapy) prior to the reference date. Participants were queried about their skin sensitivity to the sun after first exposure in the summer and after prolonged exposure (i.e., tendency to sunburn).
Questions relating to household water supply included type of water source used in their current residence (e.g., private well vs. public water), years of use of their current water system, and use of water filters. For private, domestic systems, we asked whether the water source was a dug/surficial well, spring, or deep/artesian well. We further asked the average number of glasses of water they consumed each day from the household water system. In 1995, we began collecting a tap water sample from participants' homes to permit comparison of arsenic concentrations in water with those in toenails (12). The case-control status and main objectives of the study were not disclosed to the interviewers. To ensure consistent quality of the study interviewer, interviews were tape recorded with the consent of the participants and routinely monitored by the interviewer supervisor (<1 percent of participants refused to be taped). To assess comparability of cases and controls, we asked subjects if they currently held a driver's license or a Medicare enrollment card.
Arsenic determinations
In addition to the study interview, we requested a toenail clipping sample for analysis of arsenic. Subjects were mailed the instructions and materials to save a toenail clipping specimen prior to the interview; a self-addressed envelope was left for those who needed to send their sample in after the interview. Samples were analyzed for arsenic using instrumental neutron activation analysis at the University of Missouri's research reactor center (Columbia, Missouri) (16). Prior to analysis, nail samples were carefully washed to remove external contamination. Each batch of analyses included quality control samples composed of matrix-matched samples with known content and analytical blanks along with study samples and standards. The between-assay coefficient of variability for matrix-matched samples is about 8 percent. All samples were labeled with an identification number that did not reveal the case-control status of the study participants.
Statistical analysis
We classified cases (i.e., BCC, SCC) based on their first primary skin cancer diagnosed during our survey. Controls selected for interview who had skin cancer before the study period (or who subsequently developed skin cancer) remained as controls in the primary analysis. Likewise, a case of SCC was analyzed as such, even if he or she later developed BCC or had a BCC before our survey period. Nonmelanoma skin cancer is highly curable. Therefore, it is usually possible to distinguish new primaries from recurrences. Classification of subjects according to this plan should result in relative risk estimates that are accurate estimates of incidence density ratios (17).
To assess the relation between toenail arsenic and the risk of BCC and SCC, we first conducted a logistic regression analysis using categories of toenail arsenic, classifying subjects by percentiles of the control distribution. To evaluate the form of the dose-response function, we plotted the smoothed observed proportions of cases as a function of log toenail arsenic values (18). Since the distribution of toenail arsenic values was right skewed, a natural log transformation was used to provide more normally distributed data. We used logistic regression to model the continuous arsenic values using both linear and quadratic models (19
). Separate logistic regression models were run for each histologic type of skin cancer, BCC and SCC. All models controlled for age and sex. We conducted the analyses controlling for the original age categories applied for control selection and compared the results using age as a continuous variable. Because results were essentially the same, we used continuous age in the final models. We further evaluated the potentially confounding effects of educational attainment (high school or less, college, or graduate school), smoking status (never, former, or current), skin reaction to first exposure to the sun in the summer (blister, peel, mildly burn, or tan) or after prolonged exposure (very tan, moderately tan, mildly tan, or freckle/no tan), and history of radiotherapy (no or yes).
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RESULTS |
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DISCUSSION |
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Despite concerns regarding the potential carcinogenic effects of low levels of arsenic exposure, relatively few studies have examined this issue in the United States. Earlier US studies of water arsenic and skin cancer were, for the most part, ecologic studies using broad geographic areas with varying arsenic concentrations. Thus, there was likely significant misclassification of individuals who drank arsenic-containing water. Additionally, one of the US studies (10) used mortality rates, a poor measure of nonmelanoma skin cancer occurrence. Studies conducted in regions with unusually elevated well water concentrations of arsenic in Alaska (n = 59 households) (8
) and California (n = 76 households) (9
) were not designed to look at long-term effects such as cancer and had too few subjects to detect an excess skin cancer risk.
The skin cancer prevalence study reported by Tseng et al. (3) involved over 40,000 households from the southwest coast of Taiwan (primarily Chai-yi and Tainan counties). A striking dose-response relation was observed between water arsenic concentrations and skin cancer prevalence; rates were 26, 101, and 214 per 1,000 for villages with median water concentrations of 170 µg/liter, 470 µg/liter, and 800 µg/liter, respectively. In a small case-control study that followed, the prevalence odds ratios of skin cancer increased with duration of residence in endemic regions, duration of drinking well water, and water arsenic concentrations (20
). The occurrence of cutaneous conditions (inferred to be skin cancers) was associated with drinking water arsenic in a comparison of two towns in Mexico, one with a mean drinking water concentration of 411 µg/liter ("the highly exposed town") and a similar town with respect to "environmental and socioeconomic condition" with a mean concentration of 5 µg/liter ("the unexposed town") (21
). Similarly, drinking water arsenic contamination was linked to skin cancer mortality in a region of northern Argentina (22
) with concentrations up to 960 µg/liter (23
).
While these studies point to an etiologic link between drinking water arsenic and skin cancer, they do not provide data regarding the risk at lower levels of exposure. Consequently, the shape of the dose-response at these lower levels has not been determined. Several risk assessment models are based on linear extrapolations of the Taiwanese and Mexican data. These models suggest an excess cancer risk at concentrations below the current US maximal contaminant level of 50 µg/liter (4). In a later reanalysis of the Taiwanese skin cancer survey, a quadratic model appeared to fit the data slightly better than did the linear model, although no definitive conclusions were drawn about the shape of the dose-response curve (4
). In our study, the quadratic model also appeared to fit the data. However, because of the small number of subjects at the highest and lowest levels of exposure, we had limited power to determine the exact form of the dose-response model.
An important aspect of our study is that we used toenail concentrations of arsenic as an individual biomarker of past exposure. In our population, we found that toenail concentrations were correlated with well water concentrations, particularly among those with water concentrations of arsenic of 1 µg/liter or more (r 0.65) (12
, 24
). However, among those with lower water concentrations, the correlation was not so good, raising the possibility of misclassification among persons with low levels of arsenic in drinking water. One of the difficulties in relying on water measurements alone is that the reproducibility of water arsenic is not well characterized, and concentrations could vary seasonally or over longer periods. Moreover, estimation of exposure based on water concentrations would require careful consideration of the amount consumed and the arsenic concentrations of water sources outside the home. We chose a biologic tissue to measure exposure since, in theory, it reflects all sources of exposure. Nonetheless, it is conceivable that exposure misclassification could have attenuated our risk estimates.
The precise latency period for arsenic's effects on skin cancer remains uncertain. Therefore, our results based on toenail concentrations may not cover the relevant exposure period. Patients treated with potassium arsenite (Fowler's solution) for psoriasis and other ailments developed skin cancers from 3 to 40 years after treatment (25). In the case-control study of bladder cancer conducted by Bates et al. (26
), an elevated odds ratio of bladder cancer was observed among smokers beginning 1019 years since exposure, with the highest risk after 3039 years. Toenails reflect exposure in the past several months and perhaps even longer time periods. Based on data from the Nurses' Health Study (27
), toenail arsenic levels were correlated over a 6-year period (r = 0.54). Our study population was relatively stable and remediation efforts had not occurred; over 50 percent used the same water system for over 15 years. We did not find that the relative risk estimates varied significantly by how long subjects used their water system (data not shown).
Part of the current controversy regarding the maximum contaminant level for arsenic in the United States is whether the Taiwanese data apply to the US population. Not only are the levels of exposure far lower in the United States, but the underlying risk of skin cancer in the United States is vastly greater than it is in Taiwan. BCC and SCC, together, are the most common malignancies in the United States, and the incidence rates of these malignancies appear to be rapidly increasing (14). On the other hand, the validity of our findings could be questioned since we did not obtain full cooperation from all eligible subjects. The overall age and sex distributions of nonparticipants were not appreciably different from those of participants; the mean age was 61 years and the proportion of men was about 40 percent in both groups (data not shown). About 20 percent of the participants and nonparticipants lived in the three major urban regions of the state (data not shown). However, we cannot exclude the possibility that arsenic concentrations differed between participants and nonparticipants. Another possible source of bias is that controls with a driver's license or Medicare enrollment may not represent the population at large. On the basis of a comparison of Medicare beneficiaries with US Census data, we expect over 90 percent coverage of residents aged 65 years and older (28
). While we do not have comparable statistics for New Hampshire drivers' license records, in a study done in Iowa, drivers' license records covered over 90 percent of the population (29
). In cases interviewed for our skin cancer study, 98.5 percent of those aged 2564 years had a valid driver's license at the time of interview, and 98 percent of those aged 6574 were enrolled in Medicare.
In the United States and in most other countries, nonmelanoma skin cancers are excluded from central cancer registries. For this reason, epidemiologic data regarding these malignancies are relatively sparse. To identify cases, we established a statewide surveillance system of dermatologists, dermatopathologists, and pathologists in New Hampshire and bordering areas. We restricted our case group to histopathologically confirmed cases. Based on a large chemoprevention trial, the pathologists' diagnostic practices are likely consistent (30). The diagnosis of nonmelanoma skin cancer in studies from Taiwan and Mexico was often based on clinical criteria that may not be reliable (31
). Yeh et al. (32
) performed a histopathologic review of 303 skin cancers that occurred among residents of the endemic arsenic regions. The majority were described as intraepidermal carcinomas,19 percent as epidermal carcinomas, and 15 percent as basal cell carcinomas. All had multiple lesions. Among patients treated with Fowler's solution, squamous cell lesions were commonly associated with keratoses and basal cell carcinomas frequently occurred as multiple superficial lesions (25
). In our study, we specifically excluded in situ (intraepidermal) lesions because the ascertainment of cases could be dependent on screening behavior. We were unable to analyze the risk of multiple BCCs as a subgroup because of the scant number of these cases. Thus, it is possible that both major types of nonmelanoma skin cancer relate to arsenic ingestion, but that further data are needed.
Drinking water exposure to arsenic is a global concern. Arsenic-contaminated drinking water has been detected in several regions of the world including Silesia (33), Argentina (22
), Mexico (21
), Chile (34
), and most recently India (35
) and Bangladesh (36
), as well as the southwest coast of Taiwan and other parts of Asia. In the United States, it is estimated that about 350,000 residents drink water with arsenic concentrations above the current maximal contaminant level and that over 2 million consume water with arsenic concentrations above 2 µg/liter (37
). Public water systems are required to have levels below the maximal contaminant level. However, private wells (serving fewer than 15 households or 25 individuals) are common in rural areas. These sources are not regulated under the US Safe Drinking Water Act. In New Hampshire, we estimate that private wells serve roughly 3540 percent of the households and that over 10 percent of these wells have arsenic concentrations above the present maximal contaminant level (13
). In summary, our findings highlight both the feasibility and need for further investigation of the potential carcinogenic drinking water levels of arsenic exposure found in the United States.
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ACKNOWLEDGMENTS |
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The authors are indebted to L. Mott, C. Robinson, V. Stannard, E. Campbell, J. Harjes, V. Spate, and the staffs of dermatology practices and pathology laboratories throughout New England who assisted in this study.
The New Hampshire Skin Cancer Study Group comprises the following practitioners: Drs. Duane R. Anderson, Robert W. Averill, Anthony J. Aversa, Bruce A. Bairstow, Richard D. Baughman, Lawrence G. Blasik, Carolyn Carroll, William E. Clendenning, Daniel W. Collison, George L. Crespo, Stephen M. Del Guidice, Robert L. Dimond, Wilmot S. Draper, Jeremy P. Finkle, William E. Frank, John L. Fromer, Norman C. Goldberg, David Goldminz, Robert Gordon, David S. Greenstein, Thomas P. Habif, Charles Hammer, Steve A. Joselow, Michael D. Lichter, Maritza O. Liranzo, Michael A. Mittleman, Jose Peraza, Robert B. Posnick, Warren M. Pringle, Mark Quitadamo, Pauline B. Reohr, N. Chester Reynolds, Peter Sands, Mitchell E. Schwartz, Steven K. Spencer, James C. Starke, Susan Sullivan, N. Hakan Thyresson, Andrew P. Truhan, Mauray J. Tye, K. William Waterson, and Kathryn Zug, as well as Tom Hokanson.
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NOTES |
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REFERENCES |
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