# Design ofan Epidemiologic Study of Drinking WaterArsenic 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

1

### Department of Community and Family Medicine, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire; 2

### Department of Earth Sciences, Dartmouth College, Hanover, New Hampshire;
3

### Research 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 bladdercanceramong individuals with the highest 5% toenail concentrations ofarsenic.

- Environ Health Perspect1 06(Suppl 4):1047-1050 (1998). http://ehpnet1.niehs.nih.gov/docs/1998/Suppl-4/ 1047-1050karagas/abstract.html
Key words: epidemiologic studies, case-control studies, nonmelanoma skin cancer, squamous cell skin cancer, basal cell skin cancer, bladder cancer, arsenic, heavy metals, exposure assessment



## Introduction
\Arsenic is one ofthe eight metals and 22 agents listed by the Office ofSolid Waste and Emergency ofthe U.S. Environmental Protection Agency (U.S. EPA) as a concern at Superfund sites and is naturallypresent in a variety ofores 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 atthe 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 EHP11 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 ofJ. 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 forthe studywas provided bythe National Institutesof Health grants NIEHS ES-07373, NCI CA57494, and NCI CA61108.

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 nowrarely 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 ofthe 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 amongpatients treatedwith organic arsenics for syphillis (3). Estimates ofthe dose-response relationship between drinking water arsenic exposure and cancer have been made from studies conducted in a region ofTaiwan thathad artesian well water highly contaminated with arsenic. In a well-known household prevalence survey ofskin 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 of26, 101, and 214 per 1000 persons, respectively (4). More recently, Brown and colleagues (5) performed a reanalysis ofthese 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 ofthe dose-response curve. Among the limitations oftheTaiwanese studyare thatdata are provided for the median concentration for all wells in a village, and in some villages concentrations varied considerably, i.e., from nearly0 to over 1200 11g/l. Ofsome 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 suggestedbytheir analysis.

Environmental Health Perspectives • Vol I06. Supplement 4 • August 1998 1047

### The risk models derived from the Taiwanese dataindicate thatconcentrations below 50 pg/1 (the current maximum contaminant level for drinking water in the United States) may be carcinogenic. Consequently, there is considerable debate aboutwhatlevels ofarsenic 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 ofcancer 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 ofintercept, consideration ofarsenic exposure through food) and model choice (e.g., multistaged model or linear regression). Nonetheless, a small case-controlstudyconductedinUtah found someevidence ofan increased risk of bladdercancer in relation to drinkingwater arsenic, and in this population water concentrations ofarsenic were primarily in the 

### 10 to 

### 50 pg/1 range (7). 

### Previous ecologic studies conductedintheUnitedStates have
notfound an association betweenwaterlevels ofarsenic and skin cancer occurrence (8,9). 

### These results are difficult to interpret becauseeach ofthegeographic areas studied had a broad range ofwater arsenic concentrations. Additionally, one ofthe U.S. studies (9) 

### used mortality rates, which is a poormeasureofoccurrencefor skincancer. 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 ofnonmelanoma skin cancers in 

### 1993 and addedbladdercancer to ourinvestigation in 

### 1995. Among our major objectives are to evaluate whether arsenic exposure is related to anincreasedriskofskin orbladdercancer intheNewHampshirepopulation, to study methods ofquantifying an individual's arsenic exposure, andtoexaminethesources and mechanisms ofarsenic's presence in the drinkingwatersupply. 

## Study Design
New

### HampshireStudy

NewHampshireis a rural statewith a population ofabout 

### 1.1 million 

### (1990 U.S. Census) (10). 

### Private water supplies serving fewer than 

### 25 individuals or 

### 15 households are not regulated as part ofthe U.S. EPA Safe DrinkingWaterAct (1I) 

### but an estimatedone-thirdoftheNewHampshire population uses private water. Arsenic is present in drinking water throughout the state, with levels as high as 600 pg/1 KARAGAS ETAL.



### detected though volunteer testing by the State ofNew Hampshire Water Supply and Pollution Control Commission; 

### 5% of private wells are estimated to contain arsenicconcentrations above 50pg/1. A population-based study of nonmelanoma skin cancer incidence is feasible in New Hampshire because ofthe unique availability ofa statewide skin cancer registry. Nonmelanoma skin cancers are excluded from virtually all central cancer registries; therefore, epidemiologic studies ofthese malignancies are sparse in the United States and elsewhere. Yet nonmelanoma skin cancers are considered the
most common cancers in humans (12). As 

### part ofour study, newly diagnosed basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) ofthe skin are being identified through a network ofover 

### 90% ofpracticing 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 ofnewly diagnosed BCCs and SCCs ofthe 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 orthephysicians themselves more likely to biopsy and diagnose a lesion. Therefore, our case-control study includes onlyinvasive SCCalongwithBCC. Weare randomlyselecting a populationcontrol group ofa comparable age and sex distribution as thecancer cases from drivers' license records (for those less than 

### 65 years ofage) and from Medicare enrollment files (forthose

### 65 years ofage andolder).Among the advantages ofpopulation-based control groups (vs clinic or hospitalized patients with other diagnoses) are that they are less prone to biases and also permit inference aboutexposureprevalence in thepopulation atlarge (14). 

### We were particularly interested in bladder cancer in New Hampshire because maps ofcancer mortalityfor state economic

areas intheUnitedStates showedthatbladder 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 ofthis 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

cancerwithin 

### 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 ofNew Hampshire and 

### 25 to 74 years ofage. 

### Because our study includes

an individual biologic measure ofarsenic exposure, we have not sought surrogate responses (e.g., from a spouse, closerelative,

orfriend) for deceasedindividuals. 

### 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 ofcancer. This enables us to control for potentially confounding factors and to evaluate whether other individual characteristics (e.g., smoking) modify the association between arsenic andskin orbladdercancer. Also, we examine whether other factors (e.g., occupationalhistoty) are contributors
to arsenicexposure. Participants are asked to documenteach place they have lived and to indicate the type ofwater supply (private vs 

### public) for each residence. Interview questions relating
to theirhouseholdwater supplyinclude the type ofwater supplythatserves theirhousehold (e.g., publicwater, sharedwell, private well, orspring); theduration ofuse; type of supply (forprivatewater supplies; e.g., artesian, shallow, or spring); how many glasses ofwater per day are consumed in foods or beverages from this drinking water supply; and use ofwater filters (e.g., what type and for howlong).


### ArsenicDeterminations
The latency period for arsenic and cancer
occurrence is not yet known, but is likely several years ifnotdecades. Forthis reason,
we sought a long-term individual measure ofexposure. Arsenic is rapidly cleared from the blood and excreted in urine. Therefore, arsenic concentration in these fluids will reflect relativelyrecentexposure (e.g., in the past several hours or a few days). Specific forms ofarsenic can be analyzed in urine (e.g., inorganic and various methylated forms), and the fraction ofthese forms in urine may reflect individual differences in

1048 Environmental Health Perspectives • Vol I06, Supplement4 • August I998the ability to metabolize arsenic (16). Arsenic accumulates in hair and nail tissue by binding to sulfhydryl groups ofkeratin, 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 collectand are less susceptible to external contamination than hair. Toenails provide

a larger sample than fingernails and take longer to grow. Ina sample ofnurses tested twice for arsenic and other trace elements 6 years apart, arsenic was among the most highly correlated ofthe elements they analyzed (a correlation ofgreater than 0.5) (17). Measurement ofarsenic 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 ofexposure. In our small pilot study, the overall correlation between water and toenail concentrations ofarsenic was 0.67 (18); however, halfofthe samples were drawn from regions ofNew Hampshire known to have relatively high water levels ofarsenic. 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 ofarsenic in urine, did not affect nail

orhairconcentrations. 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 ofMissouri Research Reactor (Columbia, MO) using a standard comparison approach as described previously (20). This methodreduces andpossibly 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 INMis 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 inductivelycoupled plasma mass spectrometer (HR-ICP-MS) (22). Using this approach, a quantitative estimate of STUDY OFARSENIC AND CANCER RISK

arsenic is obtained for 99% ofthe 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 ahealth risk; therefore, from apractical 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 ofarsenic in water throughout the state. Accurate quantification ofarsenic 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 ofany published data on the performance ofthese bottles for arsenic determination. Therefore, we prepared acid-washed polyethylene bottles inour class 100 clean room and initially used these on all households with private wells and on a random sample ofthose with public water. Commercial bottles were used for the rest ofthe households because we expected a smaller fraction ofpublic water would have detectable arsenic. Powderless latex gloves are worn during the collection andbottles are kept in

awashed sealed plastic bag. Samples ofcold 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% ofthe households (every lOth interview) throughout the study, and field blanks are performed quarterlyby each interviewer. To compare the performance ofthe two bottle-washing methods, we tested water from a sample ofhouseholds using both types. All bottles are labeled with identification numbers that do not reveal the case-control status ofthe 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 standardreference materials.


### WaterArsenic

### 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% ofthe private wells contained more than 2 p.g/1 ofarsenic, 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% ofour 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

ourlaboratory.

Table 1. Preliminarydata on waterarsenic concentrations among New Hampshire study participants. Type ofwatersupply Waterarsenic,**~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. cHouseholdstested=793; range <0.01-180.09; median 0.20.

Environmental Health Perspectives • Vol I06. Supplement 4 • August 1998 1049KARAGAS ETAL.



### SampleSizeand

## StudyPower
Based on existing risk assessment models,

we expect that the relative risks ofcancer associated with low levels ofarsenic exposure may be relatively small (i.e., on the order of 1.5-2.0). We expect to interview about 1200 BCCcases, 900 SCCcases, 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 oftoenail arsenic concentrations with a significance level (alpha) of 0.05. At

an alpha of0.10, 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 of0.05, and 1.9 and 2.3, respectively, with an alpha of0.10. Wewill increase our study power by analyzing continuous variables (i.e., arsenic concentrations) on a continuous scale. For example, the minimum detectable odds ratio forbladdercancerand thehighest 2o/o ofexposure is 1.75 based on a linear orquadratic model, with 80o/o powerandan alphaof0.05. are also using a biologic measure ofarsenic exposure (toenail clippings) that, based on

our pilot work, is highly correlated with
water concentrations. We plan to further evaluate the relation between water andtoenail levels in our larger study and to assess the contribution ofother sources ofarsenic exposure such as tobacco smoking and occupation on toenail levels. Our analysis ofhousehold water samples will also help clarify the sources and mechanisms of arsenic presence in the drinking water supply.

### As partofthe study, we are establishing

a specimen bank ofblood and tumor samples that can be used in future studies to evaluate potential susceptibility genes or

rumor markers ofarsenic 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 bladdercancerriskintheUnitedStates. 

### Summary

We are conducting an epidemiologic study
to investigate the effects ofdrinking 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 ofsamples tested. We

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