Design of an Epidemiologic Study of Drinking 

Water Arsenic Exposure and Skin and Bladder 

Cancer Risk in a U.S. Population 

Margaret R. Karagas,1 Tor D. Tosteson,1 Joel Blum,2 

J. Steven Morris,3 John A. Baron, 1 and Bjoern Klaue2 

1Department of Community and Family Medicine, Dartmouth Medical 

School, Dartmouth College, Hanover, New Hampshire; 2Department 

of Earth Sciences, Dartmouth College, Hanover, New Hampshire; 

3Research Reactor Center, University of Missouri, Columbia, Missouri 

Ingestion of arsenic-contaminated drinking water is associated with an increased risk of several 

cancers, including skin and bladder malignancies; but it is not yet clear whether such adverse 

effects are present at levels to which the U.S. population is exposed. In New Hampshire, 

detectable levels of arsenic have been reported in drinking water supplies throughout the state. 

Therefore, we have begun a population-based epidemiologic case-control study in which 

residents of New Hampshire diagnosed with primary squamous cell (n = 900) and basal cell 

(n = 1200) skin cancers are being selected from a special statewide skin cancer incidence survey; 

patients diagnosed with primary bladder cancers (n = 450) are being identified through the New 

Hampshire State Cancer Registry. Exposure histories of these patients will be compared to a 

control group of individuals randomly selected from population lists (n= 1200). Along with a 

detailed personal interview, arsenic and other trace elements are being measured in toenail 

clipping samples using instrumental neutron activation analysis. Household water samples are 

being tested on selected participants using a hydride generation technique with high-resolution 

inductively coupled plasma mass spectrometry. In the first 793 households tested, arsenic 

concentrations ranged from undetectable (0.01 ~g/1) to 180 ~g/1. Over 10% of the private wells 

contained levels above 10 ~g/1 and 2.5% were above 50 ~g/1. Based on our projected sample size, 

we expect at least 80% power to detect a 2-fold risk of basal cell or squamous cell skin cancer or 

bladder cancer among individuals with the highest 5% toenail concentrations of arsenic. - Environ 

Health Perspect 1 06(Suppl 4):1 047-1050 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-4/ 

1047-1 050karagas/abstract.html 

Key words: epidemiologic studies, case-control studies, non melanoma skin cancer, 

squamous cell skin cancer, basal cell skin cancer, bladder cancer, arsenic, heavy metals, 

exposure assessment 

Introduction 

\Arsenic is one of the eight metals and 22 

agents listed by the Office of Solid Waste 

and Emergency of the U.S. Environmental 

Protection Agency (U.S. EPA) as a concern 

at Superfund sites and is naturally present in 

a variety of ores and minerals. Humans are 

exposed to arsenic primarily through food, 

and in some regions, through drinking 

water. Arsenic also has been used for various 

industrial purposes such as pesticides, wood 

This paper is based on a presentation at the Symposium on the Superfund Basic Research Program: A Decade 

of Improving Health through Multi-Disciplinary Research held 23-26 February 1997 in Chapel Hill, North 

Carolina. Manuscript received at EHP 11 December 1997; accepted 22 April1998. 

We are indebted to the inspirational leadership and scientific insights provided by the late K. Wetterhahn. We 

gratefully acknowledge the collaboration of E.R. Greenberg, S.K. Spencer. T. Stukel, J. Heaney, and A. Schned, 

and the ongoing advice of J. Hamilton. We also appreciate the important contributions of study staff, research 

coordinator, V. Stannard, the statistical analysts J. Weiss and L. Matt, and the many physicians who comprise 

the New Hampshire Skin Cancer Study Group and have made the study possible. Funding for the study was provided by the National Institutes of Health grants NIEHS ES-07373, NCI CA57494, and NCI CA611 08. 

Address correspondence to M.R. Karagas, Dartmouth Medical School, Section of Biostatistics and 

Epidemiology, 7927 Rubin 462M-3, One Medical Center Drive, Lebanon. NH 03756-001. Telephone: (603) 650-

8044. Fax: (603) 650-6485. E-mail: margaret.karagas@dartmouth.edu 

Abbreviations used: BCC, basal cell carcinoma; INAA, instrumental neutron activation analysis; HR-ICP-MS, 

high-resolution inductively coupled mass spectrometer; SCC, squamous cell carcinoma; U.S. EPA, U.S. 

Environmental Protection Agency. 

preservatives, feed additives, and semiconductor applications (e.g., gallium arsenide). 

Patients were treated with arsenic-containing drugs such as potassium arsenite (e.g., 

Fowler solution) for benign skin conditions 

in the 19th and early 20th century, but 

arsenic is now rarely used medicinally (I). 

In high concentrations (e.g., > 2000 

!lglkglday), arsenic is toxic to humans, and 

among the reported long-term health effects 

associated with nonfatal doses are vascular 

diseases, diabetes, and cancers-specifically 

cancers of the skin (basal cell and squamous 

cell), lung, bladder, kidney, and liver. These 

observations have been made among individuals exposed to arsenic occupationally or 

through drinking water contamination or 

pharmacologic uses (2). In humans, organic 

arsenic compounds (e.g., arsenobetaine, 

found in seafood) are not as toxic as inorganic arsenic. The carcinogenic effects of 

organic arsenic are uncertain, although there 

was no apparent increase in skin cancers 

among patients treated with organic arsenics 

for syphillis (3). 

Estimates of the dose-response relationship between drinking water arsenic exposure and cancer have been made from 

studies conducted in a region of Taiwan 

that had artesian well water highly contaminated with arsenic. In a well-known household prevalence survey of skin cancer ( 4) 

published about 30 years ago, villages with 

median water arsenic concentrations of 170, 

470, and 800 11g/l had skin cancer prevalence rates of 26, 101, and 214 per 1000 

persons, respectively ( 4). More recently, 

Brown and colleagues (5) performed a 

reanalysis of these data using a mu!tistaged 

model. A model that included both a linear 

and quadratic term in dose improved the fit 

only slightly; thus there was no definitive 

conclusion regarding the actual shape of the 

dose-response curve. Among the limitations 

of the Taiwanese study are that data are provided for the median concentration for all 

wells in a village, and in some villages concentrations varied considerably, i.e., from 

nearly 0 to over 1200 11g/l. Of some reassurance is that data from a study conducted in 

Mexico (with similar limitations) (5) also 

appeared to fit the model derived from 

Taiwan data. Smith and colleagues (6) 

modeled standardized mortality ratios of 

bladder, liver, lung, and kidney malignancies computed for the endemic region of 

Taiwan using rates for the country at large 

as the standard. A linear dose-response 

relationship was suggested by their analysis. 

Environmental Health Perspectives • Vol I 06. Supplement 4 • August 1998 1047 
The risk models derived from the 

Taiwanese data indicate that concentrations 

below 50 pg/1 (the current maximum contaminant level for drinking water in the 

United States) may be carcinogenic. 

Consequently, there is considerable debate 

about what levels of arsenic are safe. Part of 

the difficulty is that we have limited data 

for the United States at levels found in the 

United States. The assessment of cancer 

risk at concentrations below 170 pg/1 

required extrapolation (i.e., where actual 

data do not exist) and estimates have differed to some extent based on model 

assumptions (e.g., the point of intercept, 

consideration of arsenic exposure through 

food) and model choice (e.g., multistaged 

model or linear regression). Nonetheless, a 

small case-control study conducted in Utah 

found some evidence of an increased risk of 

bladder cancer in relation to drinking water 

arsenic, and in this population water concentrations of arsenic were primarily in the 

10 to 50 pg/1 range (7). Previous ecologic 

studies conducted in the United States have 

not found an association between water levels of arsenic and skin cancer occurrence 

(8,9). These results are difficult to interpret 

because each of the geographic areas studied 

had a broad range of water arsenic concentrations. Additionally, one of the U.S. 

studies (9) used mortality rates, which is a 

poor measure of occurrence for skin cancer. 

Therefore, to help clarify the risk of 

cancer in relation to arsenic exposure in a 

geographically defined U.S. population, we 

began an epidemiologic case-a>ntrol study 

of nonmelanoma skin cancers in 1993 and 

added bladder cancer to our investigation in 

1995. Among our major objectives are to 

evaluate whether arsenic exposure is related 

to an increased risk of skin or bladder cancer 

in the New Hampshire population, to study 

methods of quantifying an individual's 

arsenic exposure, and to examine the sources 

and mechanisms of arsenic's presence in the 

drinking water supply. 

Study Design 

New Hampshire Study 

New Hampshire is a rural state with a population of about 1.1 million (1990 U.S. 

Census) (10). Private water supplies serving fewer than 25 individuals or 15 households are not regulated as part of the U.S. 

EPA Safe Drinking Water Act (1 I) but an 

estimated one-third of the New Hampshire 

population uses private water. Arsenic is 

present in drinking water throughout the 

state, with levels as high as 600 pg/1 

KARAGAS ET AL. 

detected though volunteer testing by the 

State of New Hampshire Water Supply 

and Pollution Control Commission; 5% of 

private wells are estimated to contain 

arsenic concentrations above 50 pg/1. 

A population-based study of nonmelanoma skin cancer incidence is feasible 

in New Hampshire because of the unique 

availability of a statewide skin cancer registry. Nonmelanoma skin cancers are 

excluded from virtually all central cancer 

registries; therefore, epidemiologic studies 

of these malignancies are sparse in the 

United States and elsewhere. Yet nonmelanoma skin cancers are considered the 

most common cancers in humans (12). As 

part of our study, newly diagnosed basal 

cell carcinomas (BCC) and squamous cell 

carcinomas (SCC) of the skin are being 

identified through a network of over 90% 

of practicing dermatologists and all pathology laboratories in New Hampshire and 

bordering areas. Routine visits are made to 

each physician's office and each pathology 

laboratoty. Records are reviewed for basic 

demographic information, prior history of 

skin cancer, and histologic type and 

anatomic location of newly diagnosed 

BCCs and SCCs of the skin. Although in 

situ SCC (including Bowen's disease) is also 

associated with arsenic exposure (13), we 

were concerned that earlier staged lesions 

may be more susceptible to selection factors, i.e., people with known arsenic exposure may be more likely to seek medical 

attention or the physicians themselves more 

likely to biopsy and diagnose a lesion. 

Therefore, our case-control study includes 

only invasive SCC along with BCC. 

We are randomly selecting a populationcontrol group of a comparable age and sex 

distribution as the cancer cases from drivers' 

license records (for those less than 65 years 

of age) and from Medicare enrollment files 

(for those 65 years of age and older). Among 

the advantages of population-based control 

groups (vs clinic or hospitalized patients 

with other diagnoses) are that they are less 

prone to biases and also permit inference 

about exposure prevalence in the population 

at large (14). 

We were particularly interested in 

bladder cancer in New Hampshire because 

maps of cancer mortality for state economic 

areas in the United States showed that bladder cancer mortality rates were in the highest 10% throughout the New England 

states, including New Hampshire (15). A 

case-control study conducted in Vermont 

and New Hampshire approximately 20 

years ago found that occupational exposure 

in the textile and leather industries could 

explain only part of this excess (15). For 

our study, bladder cancers are ascertained 

from the New Hampshire State Cancer 

Registry, which operates a rapid reporting 

system. By state law, practitioners are 

required to provide an initial report of 

cancer within 15 days after diagnosis, and a 

definite report can follow within 120 days. 

To be eligible for our study, both skin and 

bladder cancer cases and controls must be 

residents of New Hampshire and 25 to 

74 years of age. Because our study includes 

an individual biologic measure of arsenic 

exposure, we have not sought surrogate 

responses (e.g., from a spouse, close relative, 

or friend) for deceased individuals. 

Personal Interview 

Those who agree to take part in the study 

undergo an extensive in-person interview 

covering residence, occupation, medical 

history, lifestyle factors (e.g., use of 

tobacco), and family history of cancer. 

This enables us to control for potentially 

confounding factors and to evaluate 

whether other individual characteristics 

(e.g., smoking) modify the association 

between arsenic and skin or bladder cancer. 

Also, we examine whether other factors 

(e.g., occupational histoty) are contributors 

to arsenic exposure. 

Participants are asked to document each 

place they have lived and to indicate the 

type of water supply (private vs public) for 

each residence. Interview questions relating 

to their household water supply include the 

type of water supply that serves their household (e.g., public water, shared well, private 

well, or spring); the duration of use; type of 

supply (for private water supplies; e.g., artesian, shallow, or spring); how many glasses 

of water per day are consumed in foods or 

beverages from this drinking water supply; 

and use of water filters (e.g., what type and 

for how long). 

Arsenic Determinations 

The latency period for arsenic and cancer 

occurrence is not yet known, but is likely 

several years if not decades. For this reason, 

we sought a long-term individual measure 

of exposure. Arsenic is rapidly cleared from 

the blood and excreted in urine. Therefore, 

arsenic concentration in these fluids will 

reflect relatively recent exposure (e.g., in the 

past several hours or a few days). Specific 

forms of arsenic can be analyzed in urine 

(e.g., inorganic and various methylated 

forms), and the fraction of these forms in 

urine may reflect individual differences in 

1048 Environmental Health Perspectives • Vol I 06, Supplement 4 • August I 998 
the ability to metabolize arsenic (1 6). 

Arsenic accumulates in hair and nail tissue 

by binding to sulfhydryl groups of keratin, 

and for this reason, these tissues have been 

used to trace arsenic poisoning. Toenail 

clippings are routinely used in epidemiologic studies because they are relatively easy 

to collect and are less susceptible to external 

contamination than hair. Toenails provide 

a larger sample than fingernails and take 

longer to grow. In a sample of nurses tested 

twice for arsenic and other trace elements 6 

years apart, arsenic was among the most 

highly correlated of the elements they analyzed (a correlation of greater than 0.5) 

(1 7). Measurement of arsenic directly in 

water samples is another alternative. 

However, at the time our study began, we 

were uncertain whether water concentrations varied appreciability over time, i.e., 

seasonally or from year to year. Moreover, 

water is only one potential source of exposure. In our small pilot study, the overall 

correlation between water and toenail concentrations of arsenic was 0.67 (18); however, half of the samples were drawn from 

regions of New Hampshire known to have 

relatively high water levels of arsenic. A significant correlation between water concentrations and both hair and toenail levels of 

arsenic was also recently reported by Chiou 

and colleagues (19). In this study, genetic 

polymorphism in the GSTMJ or GSTTJ 

loci, which had an effect on the metabolic 

forms of arsenic in urine, did not affect nail 

or hair concentrations. 

For our case-control study, toenail 

clipping samples are being analyzed for 

arsenic and other trace elements by instrumental neutron activation analysis (INM) 

at the University of Missouri Research 

Reactor (Columbia, MO) using a standard 

comparison approach as described previously (20). This method reduces and possibly eliminates external contamination. 

Matrix-matched quality control samples, 

having known arsenic content, and analytical blanks are analyzed with the samples 

and standards. The detection limit for 

arsenic measured by INAA is approximately 1 p.g/1. An additional advantage to 

INM is that samples can be analyzed for 

arsenic along with other trace elements 

hypothesized in experimental studies to 

interact with arsenic carcinogenesis (21) 

(e.g., selenium, zinc). 

Water samples are being tested using a 

hydride-generation technique with a highresolution inductively coupled plasma mass 

spectrometer (HR-ICP-MS) (22). Using 

this approach, a quantitative estimate of 

STUDY OF ARSENIC AND CANCER RISK 

arsenic is obtained for 99% of the water 

samples. The instrument is a Finnigan 

MAT Element (Bremen, Germany) HRICP-MS. Although lower detection limits 

are possible, the quantification limit for 

samples was set to 0.01 p.g/1 (0.001 p.g/1 for 

blanks) to avoid excessive washout times. 

Levels below 1 p.g/1 are not suspected of 

posing a health risk; therefore, from a practical perspective it may not be necessary to 

measure arsenic at such trace levels. 

However, we also are interested in the correlation between toenail and water concentrations and arsenic is detectable in all nail 

samples. Likewise, we are examining the 

geographic distribution of arsenic in water 

throughout the state. 

Accurate quantification of arsenic 

necessitates strict precautions against contamination. All sample preparations and 

analyses are carried out in a trace-metal 

clean HEPA-filtered-air environment. 

Commercially washed (mineral-free) highdensity polyethylene bottles meet U.S. EPA 

standards for water collection (I-Chem, 

Newcastle, DE); however, we are unaware 

of any published data on the performance 

of these bottles for arsenic determination. 

Therefore, we prepared acid-washed polyethylene bottles in our class 100 clean room 

and initially used these on all households 

with private wells and on a random sample 

of those with public water. Commercial 

bottles were used for the rest of the households because we expected a smaller fraction of public water would have detectable 

arsenic. Powderless latex gloves are worn 

during the collection and bottles are kept in 

a washed sealed plastic bag. Samples of cold 

water are taken after running the tap for at 

least 1 min to avoid metal precipitation in 

the pipes. Samples are immediately placed 

back into the sealed bag. Duplicate samples 

are drawn on 10% of the households (every 

lOth interview) throughout the study, and 

field blanks are performed quarterly by each 

interviewer. To compare the performance 

of the two bottle-washing methods, we 

tested water from a sample of households 

using both types. All bottles are labeled 

with identification numbers that do not 

reveal the case-control status of the study 

participants or whether the sample was a 

replicate from the same household. In 

addition to these quality control samples, 

analytical blanks and potential instrumental drifts are carefully monitored, and 

instrument standardization and reproducibility is performed with certified 

standard reference materials. 

Water Arsenic Results 

In the 793 households tested to date 

(Table 1), 41% reported using a private 

well or spring (serving 15 or fewer households or less than 25 individuals). Arsenic 

concentrations range from undetectable 

( < 0.01 p.g/1) to 180 p.g/1. Over 25% of the 

private wells contained more than 2 p.g/1 

of arsenic, over 1 0% were above 1 0 p.g/1, 

and 2.5% were over 50 p.g/1. In a preliminary analysis of the population 

controls, we found that participants residing in the three major cities of New 

Hampshire (Concord, Manchester, or 

Nashua) had lower water arsenic on average (data not shown). However, participants from these areas comprise only 

about 20% of our sample. 

A preliminary analysis was performed 

on the replicate samples tested thus far. 

Simple random effects models were used 

to calculate intraclass correlations for the 

log transformed arsenic measurements 

(23). The intraclass correlation coefficient 

for replicate samples was 0.98 and did not 

appear to differ by bottle type (i.e., laboratory cleaned or commercially cleaned containers). Given this high correlation, we 

concluded that the bottle types yield 

highly comparable and reliable results in 

our laboratory. 

Table 1. Preliminary data on water arsenic concentrations among New Hampshire study participants. 

Type of water supply 

Water arsenic, ~g/1 Private, %8 Public, %b Total, %c 

< 0.01 0.9 0.4 0.6 

0.01--0.10 27.8 30.7 29.5 

0.11--0.50 23.5 52.2 40.5 

0.5F1.00 12.3 8.5 10.1 

1.01-2.00 7.7 3.4 5.2 

2.01-10.00 15.4 3.6 8.4 

10.01-50.00 9.9 1.1 4.7 

> 50.00 2.5 0.0 1.0 

Total, all samples 100.0 100.0 100.0 

•Households tested= 324; range < 0.01-180.09; median 0.42. bHouseholds tested= 469; range < 0.01-49.53; 

median 0.17. cHouseholds tested= 793; range <0.01-180.09; median 0.20. 

Environmental Health Perspectives • Vol I 06. Supplement 4 • August 1998 1049 
KARAGAS ET AL. 

Sample Size and Study Power 

Based on existing risk assessment models, 

we expect that the relative risks of cancer 

associated with low levels of arsenic exposure may be relatively small (i.e., on the 

order of 1.5-2.0). We expect to interview 

about 1200 BCC cases, 900 SCC cases, 450 

bladder cancer cases, and 1200 controls. 

With this sample size, we anticipate 80o/o 

power to detect an odds ratio of 1.6, 1.7, 

and 1.9, respectively, for BCC, SCC, and 

bladder cancer among individuals with the 

highest 5o/o of toenail arsenic concentrations 

with a significance level (alpha) of 0.05. At 

an alpha of 0.1 0, the minimum detectable 

odds ratios are 1.5, 1.6, and 1.8 for BCC, 

SCC, and bladder cancer. The minimum 

detectable odds ratios for the highest 2o/o of 

arsenic concentrations are about 2.0 for 

BCC and SCC and 2.5 for bladder cancer, 

with an alpha of 0.05, and 1.9 and 2.3, 

respectively, with an alpha of0.10. We will 

increase our study power by analyzing 

continuous variables (i.e., arsenic concentrations) on a continuous scale. For example, 

the minimum detectable odds ratio for bladder cancer and the highest 2o/o of exposure is 

1.75 based on a linear or quadratic model, 

with 80o/o power and an alpha of0.05. 

are also using a biologic measure of arsenic 

exposure (toenail clippings) that, based on 

our pilot work, is highly correlated with 

water concentrations. We plan to further 

evaluate the relation between water and toenail levels in our larger study and to assess 

the contribution of other sources of arsenic 

exposure such as tobacco smoking and 

occupation on toenail levels. Our analysis 

of household water samples will also help 

clarify the sources and mechanisms of 

arsenic presence in the drinking water supply. As part of the study, we are establishing 

a specimen bank of blood and tumor samples that can be used in future studies to 

evaluate potential susceptibility genes or 

rumor markers of arsenic exposure. Based 

on the projected sample size, we expect that 

our study will help fill important gaps in 

our knowledge regarding the relation 

between arsenic exposure and skin and 

bladder cancer risk in the United States. 

Summary 

We are conducting an epidemiologic study 

to investigate the effects of drinking water 

exposure to arsenic on risk of nonmelanoma skin and bladder cancer in a 

U.S. population. To accomplish this, we 

have specifically established a system of 

identifying nonmelanoma occurrences in 

the general population and utilize the New 

Hampshire State Cancer Registry for bladder cancer. Using HR-ICP-MS and a 

hydride-generation procedure, we are able 

to reliably detect arsenic at concentrations 

present in over 99o/o of samples tested. We 

REFERENCES AND NOTES 

1. Azcue JM, Nriagu JO. Arsenic: historical perspectives. In: 

Arsenic in the Environment. Vol 26 (Nriagu J, ed). New 

York:John Wiley & Sons, 1994;1-15. 

2. IARC. Arsenic and Arsenic Compounds (group 1). In: 

Monographs on the Evaluation of Carcinogenic Risk of 

ChemiCals to Humans. Supplement 7: Overall Evaluations of 

Carcinogenicity: An Updating of IARC Monographs Volumes 

1 to 42. Lyon:lnternational Agency for Research on Cancer, 

1987;100-106. 

3. Franseen CC, Taylor GW. Arsenical keratoses and carcinomas. 

Am J Cancer 22:287-307 (1934). 

4. Tseng WP, Chur HM, How SW. Prevalence of skin cancer in 

an endemic area of chronic arsenicism in Taiwan. J Nat! 

Cancer lnst 40:453-463 (1968). 

5. Brown K, Boyle K, Chen C, Gibb H. A dose-response analysis 

of skin cancer from inorganic arsenic in drinking water. Risk 

Anal9:519-528 (1989). 

6. Smith AH, Hopenhayn-Rich C, Bates MN, Goeden HM, 

Hertz-Picciotto I, Duggan HM, Wood R, Kosnett MJ, Smith 

MT. Cancer risks from arsenic in drinking water. Environ 

Health Perspect 97:259-267 (1992). 

7. Bates MN, Smith AH, Cantor KP. Case-control srudy of bladder cancer and arsenic in drinking water. Am J Epidemiol 

141:523-530 (1995). 

8. Morton W, Starr G, Pohl D. Skin cancer and water arsenic in 

Lane County, Oregon. Cancer 37:2523-2532 (1976). 

9. Berg J, Burbank F. Correlations between carcinogenic trace 

metals in water supplies and cancer mortality. Ann NY Acad 

Sci 199:249-261 (1972). 

10. U.S. Department of Commerce, Economics and Statistics 

Administration, Bureau of the Census. 1990 Census of the 

Population and Housing. Washington:U.S. Government 

Printing Office, 1992. 

11. U.S. Congress, Senate Committee on Environmental and 

Public Works. Safe Drinking Water Act of 1974. PL104-182. 

Environ Reporter 71:5601-5654 (1995). 

12. Armstrong BK, Kricker A. Skin cancer. Dermatol Clin 

13:583-594 (1995). 

13. Yeh S, How SW, Lin CS. Arsenical cancer of skin. Histologic 

study with special reference to Bowen's disease. Cancer 

21:312-339 (1968). 

14. Rothman KJ, Greenland S. Modern Epidemiology. 

Philadelphia:Lippincott-Raven, 1998. 

15. Morris Brown L, Hoar Zahm S, Hoover RN, FraumeniJF. High 

bladder cancer mortality in rural New EnJdand (United States): 

an etiologic srudy. Cancer Causes Conrrol6:361-368 (1995). 

Hsueh Y, Chiou H, Huang Y, Lue L, ChenG, Chen C. 

Serum beta-carotene level, arsenic methylation capability, 

and incidence of skin cancer. Cancer Epidemiol Biomarkers 

Prev 6:589-596 (1997). 

16. 

17. Garland M, Morris JS, Rosner BA, Stampfer MJ, Spate VL, 

Baskett CJ, Willett WC, Hunter DJ. Toenail trace element levels as biomarkers: reproducibility over a 6-year period. Cancer 

Epidemiol Biomarkers Prev 2:493-497 (1993). [Published 

erratum appears in Cancer Epidemiol Biomarkers Prev 

3(6):523 (1994)]. 

18. Karagas MR, Morris JS, Weiss JE, Spate V, Baskett C, 

GreenbergER. Toenail samples as an indicator of drinking 

water arsenic exposure. Cancer Epidemiol Biomarkers Prev 

5:849-852 (1996). 

19. Chiou H, Hsueh Y, Hsieh L, Hsu L, Hsu Y, Hsieh F, Wei M, 

Chen H, Yan H, Leu L, et al. Arsenic methylation capacity, 

body retention, and null genotypes of glutathione S.transferase 

M 1 and T1 among current arsenic-exposed residents in 

Taiwan. Mutat Res 386:197-207 (1997). 

20. 

21. 

22. 

23. 

Cheng TP, Morris JS, Koirtyohann SR, Spate VL, Baskett CJ. 

Study of the correlation of trace elements in carpenter's toenails. J Radioanal Nucl Chern 195:31-42 (1995). 

Agency for Toxic Substances and Disease Registry. 

Toxicological Profile for Arsenic. Atlanta, GA:U.S. Department 

of Health and Human Services, 1993. 

Montassar A, Golightly DW. !CPs in Analytical Atomic 

Spectrometry. Weinheim:VCH Verlagsgesellschaft mbH, 1992. 

Corbeil RR, Searle SR. Restricted maximum likelihood 

(REML) estimation of variance components in the mixed 

model. Technometrics 18:31-38 (1976). 

1050 Environmental Health Perspectives • Vol I 06, Supplement 4 • August 1 998