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Arsenic in Drinking Water: 2001 Update (2001)

Chapter: 2 Human Health Effects

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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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Suggested Citation:"2 Human Health Effects." National Research Council. 2001. Arsenic in Drinking Water: 2001 Update. Washington, DC: The National Academies Press. doi: 10.17226/10194.
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2 Human Health EffecTs This chapter discusses the health effects of arsenic observed in human studies. It begins with a summary of the 1999 NRC report Arsenic in Drinking Water. Following that, the noncancer and cancer studies published since the 1999 report are discussed. SUMMARY OF IIUMAN HEALTH EFFECTS DISCUSSED IN TEIE 1999 REPORT The previous Subcommittee on Arsenic in Drinking Water reviewed the health effects seen in humans following exposure to inorganic arsenic in drinking water. The subcommittee concluded that the observed health effects were dependent on the dose and duration of exposure. Overt nonspecific gastrointestinal effects, such as diarrhea and cramping; hematological effects, including anemia and leukopenia; end peripheral neuropathym~ght occur after weeks or months of exposure to high doses of arsenic (0.04 mg/kg/day). These acute or subacute effects are typically reversible. Specific dermal effects are characteristic of chronic arsenic exposure. Diffuse or spotted hyperpigmentation has been seen after 6 months to 3 years by chronic inges- tion of high doses of arsenic (0.04 mg/kg/day, or 40 ~g/kg/day) or 5 to 15 years of ingestion of low doses (on the order of 0.01 mg/kg/day or higher). Palmer-plantar hyperkeratosis is usually evident within years of the initial 24

HUMAN HEA LTH EFFECTS 25 appearance of~arsenical hyperpigmentation. Perturbed porphyrin metabolism and irreversible noncirrhotic portal hypertension have been seen following chronic exposure to 0.01 to 0.02 mg/kg/day or higher. Chronic exposure to doses sufficient to cause cutaneous effects has been associated with peripheral vascular disease in studies in Taiwan, Chile, northern Mexico, Japan, and Germany. A risk of mortality from hypertension and cardiovascular disease has also been associated with chronic exposure to arsenic. An association has been reported between chronic ingestion of arsenic in drinking water and an increased risk of diabetes mellitus. Some evidence also suggested that the ingestion of arsenic can have effects on the immune and respiratory systems. Teratogenic effects were seen following parenteral arsenic exposure in a number of mammalian species, but little evidence suggests that those effects follow oral or inhalation exposure. There were inadequate data to draw con- clusions on the effects of arsenic on fertility and pregnancy outcomes. Cancer had been seen following exposure to inorganic arsenic in drinking water. Ingestion of inorganic arsenic was an established cause of skin cancer at the time of the previous report (NRC 1999~. On the basis of data from several epidemiological studies, particularly those examining exposed popula- tions in Taiwan, Argentina, and Chile, the Subcommittee on Arsenic in Drink- ing Water concluded that the "evidence is now sufficient to include bladder and lung cancer among the cancers that can be caused by ingestion of inor- ganic arsenic" (NE2C 1999~. The subcommittee further concluded that al- though some evidence indicated an increased risk of cancers other than skin, lung, and bladder, the database was not as strong, and confirmatory studies would be needed to establish arsenic as an underlying cause in other cancers. RECENT STUDIES OF NONCANCER EFFECTS IN HUMANS In this section, recent studies ofthe reproductive, neurological, cardiovas- cular, respiratory, hepatic, hematological, diabetic, and dermal effects of arsenic are presented. No relevant studies were identified for other noncancer end points. Cardiovascular Effects Earlier epidemiological studies have indicated that the cardiovascular system might tee sensitive to chronic ingestion ofarsenic. Effects seen follow-

26 ARSENIC IN DRINKING WA TER: 2001 UPDA TE ing chronic exposure to arsenic in drinking water include hypertension and increased cardiovascular-disease mortality (NRC 1999~. Rahman et al. (1999) conducted a cross-sectional evaluation of blood pressure in ~ ,595 adults (above 30 years of age) who resided their entire lives in one of four villages in a rural area of Bangladesh. Many villages in Bangla- desh have high arsenic exposures resulting from the use of groundwater for drinking water; wells were drilled because of microbial contamination of surface waters. Well-water arsenic concentrations were determined by refer- ence to a database compiled from recent surveys, and most contained arsenic concentrations in excess of 0.05 my/. Examiners were not completely blinded to a subject's general exposure status but had no knowledge of precise levels of exposure. No subjects were taking antihypertensive medication, and the diet, lifestyle, and socioeconomic status of all subjects were similar. Prevalence ratios for hypertension were assessed after adjustment for age, sex, and body-mass index. The Mantel-Haenszel-adjusted prevalence ratios for hypertension increased with increasing arsenic in drinking water. The ratios were I.2 (95°/O confidence interval (CI)= 0.6-2.3; 50 cases, 573 controls), 2.2 (95% CI = 1.14.3; 93 cases, 483 controls), and 2.5 (95% CI = 1.2~.9; 55 cases, 227 controls) for exposure category ~ (arsenic at <0.5 mg/~), ~ (0.5-1.0 Bogy), and m >to mg/~), respectively. The chi-square test for trend was highly significant (p << 0.001~. Cumulative arsenic consumption (arsenic concentration of the well water multiplied by the years of consumption) was also analyzed. The adjusteiprevalence ratios for hypertension were 0.8 (95% CI= 0.3-1.7; 13 cases, 225 controls); I.5 (95% CT= 0.7-2.9; 83 cases, 610 controls), 2.2 (95% CI= 1.1~.4; 40 cases, 239 controls), and 3.0 (95% CI= 1.5-5.~; 62 cases, 209 controls) for cumulative exposures of less than 1.0 mg/~-years, 1.0-5.0 mg/~-years, greater than 5.0-10.0 m^-years, and greater than 10.0 mg/~-years, respectively. The chi-square test for trend was highly significant (p << 0.0011. In a linear regression mode! that took into account age, sex, and body-mass index, mean blood pressure increased with both exposure measures. This study is consistent with early reports in Taiwan associating average and cumulative arsenic exposure in Winking water with a risk of hypertension. L,ewis et al. (1999a) conducted a retrospective cohort mortality study of residents of Millard County, Utah, an area where some drinking-water wells contained concentrations of arsenic up to several hundred micrograms per liter. This study is critiqued in detail in the Cancer Effects section of this chapter. Relative to statewide rates, the cohort had an increased risk of death from "hypertensive heart disease" in mates (standardized mortality ratio (SMR) = 2.20, 95% CI = 1.36-3.36) and in females (SMR= 1.73, 95% CI=

HUMANHEALTHEFFECT5 27 ~ . ~ ~ -2.5 8~. Although statistical power was limited, there was no evidence of a positive dose-response relationship. it is uncertain whether this finding reflects a chronic hypertensive effect of arsenic, because other causes of mor- tality more commonly associated with hypertension, particularly ischemic heart disease and cerebrovascular disease, were significantly decreased in the cohort. "Hypertensive heart disease" is infrequently encountered as a coded cause of death, and because the increased SMRs were based on small numbers (21 deaths in mates and 24 deaths in females), only a slight degree of misclassification bias might have influenced the results. Deaths in the broad category of "nephritis and nephrosis" were increased in males (SMR = 1.72, 95% CI = 1.13-2.50), and the possibility exists that the grouping might have subsumed some cases of nonspecific nephrosclerosis associated with hyper- tension. Hertz-Picciotto et al. (2000) conducted a reanalysis of circulatory disease mortality among a cohort of smelter workers to assess whether the healthy worker survivor effect (HWSE) might have obscured a potential contributory role of cumulative airborne arsenic exposure. Although the route of exposure might have been predominantly by inhalation, the study addresses an impact on a nonpulmonary systemic end point that might also have relevance to ar- senic ingestion. Using the least-exposed cohort members as internal controls, analytical approaches that applied a time-lagging method for exposure assess- ment and adjusted for employment status as a time-dependent variable in each year of follow-up revealed a stronger association between arsenic exposure and cardiovascular disease mortality. A G-null approach that used time- period-dependent exposure rates rather than cumulative exposure to control for the HWSE found no relationship between arsenic and cardiovascular disease mortality; however, because of data-set limitations, the power of that analysis was low. The authors concluded that the HWSE might have contrib- uted to the apparent lack of arsenic-associated cardiovascular disease mortal- ity in prior occupational cohort studies, in contrast to positive effects observed in several drinking-water studies. Dermal Effects Chronic arsenic exposure causes a characteristic pattern of noncancer dennal effects that begins with spotted hyperpigmentation and might later include palmer and planter hyperkeratosis. Many studies about those skin lesions in humans have been published ARC 1999~. Several recent studies have investigated adverse health effects associated with ingestion of arsenic

25 ARSENICIN DRINKING WATER. 2001 UPDATE present in groundwater in the Gangetic plane of West Bengal, India, and neighboring Bangladesh, where over the past decade more than 30 million people might have been consuming water with arsenic concentrations in ex- cess of 50 ,ug/L (Chow~bury et al. 2000~. Mazumder et al. (l 998) conducted a cross-sectional survey of the preva- lence of truncal hyperpigmentation and palmar-plantar keratosis in a region of West Bengal, India, with groundwater arsenic concentrations ranging from nondetectable to 3,400 ,ug/~. Medical examinations, current volume of water consumption, and welI-water arsenic measurements were obtained on 7,683 children and adults (4,093 females and 3,590 mates) recruited from rural villages in a region known to have high groundwater arsenic concentrations and in a referent population from a region thought to have Tower exposures (total population at risk was 150,457~. Heterogeneity of exposure existed within each region, and examiners were blinded to the exact exposures of the subjects. For greater than 80% ofthe participants, well-water arsenic concen- tration was less than 500 Go/. Age-adjusted prevalence of hyperpigmenta- tion was 0.3/100 in females in the lowest exposure level (<50 ,ug/~) and in- creased to 1 ~ .5/100 in the highest exposure level (2 800 Go/. Corresponding prevalences for males were 0.4/100 and 22.7/100. For keratosis, the preva- lence for females ranged from zero in the lowest exposure level (<50 ~g/~) to 8.5/100 in the highest exposure level (2800 Go/, and for mates, it ranged from 0.2/100 to 10.7/100. Of note, 29 subjects with hyperpigmentation and ~ 2 subj ects with keratosis were consuming water from domestic wells contain- ing arsenic concentrations less than 100 ,ug/~. However, as noted by the investigators, because of the cross-sectional nature of the investigation, the possibility existed that these individuals might have consumed water contain- ing higher concentrations of arsenic at their worksites or at past residences. A separate analysis (Mazumder et al. 1998) of 4,443 subjects examined the prevalence of hyperpigmentation and keratosis according to tertiles of arsenic dose calculated on a body-weight basis. The prevalence (not age adjusted) of hyperpigmentation was 0.0/100 for females and 0.4/100 for mates in the lowest fertile (0 to 3.2,ug/kg/day); 3.0/100 for females and 6.5/100 for males in the middle fertile (3.2 to 14.9 ,ug/kg/day); and 5.9/100 for females and 16.6/100 for males in the highest fertile (14.9 to 73.9 ,ug/kg/day). One- tailed chi-square tests of trend were significant (p < 0.001) for mates and females. The corresponding prevaTences for keratosis in females were 0.7/ 100,2.3/100, and 3.5/100 (test for trend p = 0.028) and for keratosis in mates were 0.~/100, 4.2/100, and 12.7/100 (test for trend p < 0.001~.

HUMAN HEA LTH EFFECTS 29 Tondel et al. (1999) conducted a cross-sectional survey for characteristic arsenic-related skin lesions in 1,481 subjects (903 males, and 578 females) at least 30 years of age who resided in four rural villages of Bangladesh. The villages were selected because they exhibited a range of arsenic concentration in the drinking water (nondetectable to 2,040,ug/~. Although specific infor- mation was collected on the water source of each individual, the daily volume of water consumed was not ascertained, and examiners were apparently not blinded to subjects' exposure levels. The crude prevalence of any arsenic- associated skin lesion (pigmentary changes or keratosis) was 29/100. Data were analyzed in five exposure categories. The age-adjusted prevalence of any arsenic-related skin lesion increased in relation to the arsenic concentra- tion ofthe drinking water. In mates in the lowest exposure category (drinking- water arsenic, < ~ 50 ~g/~), the age-adjusted prevalence of any arsenic-associ- ated skin lesion was 18.6/100 and increased to 37.0/100 in the highest expo- sure category (>l,000 ~g/L) (chi-square dose for trend,p < 0.001~. The corre- sponding rates for females were 17.9/100 in the lowest exposure category and 24.9 in the highest exposure category (test for trend, p < 0.02~. At similar levels of arsenic in drinking water, males had a higher prevalence of skin lesions than females. A dose-index, calculated as the arsenic concentration of a subject's drinking water divided by his or her body weight, was used to examine the trend in age-adjusted prevalence of skin lesions across three categories (<5 ~g/L/kg, >S -10 ~g/L/kg, and >10,ug/L/ kg). The correspond- ing age-adjusteUprevalences for mates were 19.6/100,30.2/100, and 34.~/100 (test for trend, p < 0.001~; for females, the respective rates were 19.7/100, 22.~/100, and 30.~/100 (test for trend,p < 0.001~. Ahsan et al. (2000) conducted a cross-sectional survey of"melanosis" (hyperpigmentation) and keratosis in three contiguous rural villages in Bangla- desh within a region suspected of having elevated arsenic in groundwater. In the study, 87 males and 80 females were drawn from a total population of 300 residents; the investigators indicated that there might have been a greater number of affected individuals volunteering than unaffected individuals, resulting in an overestimate of actual prevalence rates. Exposure variables included the concentration of total arsenic in a spot urine sample, the arsenic concentration of drinking water contained in storage pitchers found in each subject's residence, and a cumulative exposure index calculated by multiplying the arsenic concentration in the pitcher water by the estimated amount of water consumed per year and by the estimated number of years that the current tube-well had been used for drinking. Nine of the 167 participants had melanosis, 2 had keratosis, and 25 had both melanosis and keratosis. A sur-

30 ARSENIC IN DRINKING WA TER: 2001 UPDA TE prising finding in this study was the relatively high prevalence of skin lesions in subjects whose current drinking-water samples contained very low concen- trations of arsenic; 13.9% of all subjects with skin lesions were currently drinking water with an arsenic concentration of<lO Egg. In the analyses that evaluated skin lesions as a function of cumulative arsenic index in milligrams, 7 of 38 subjects (~.4%) in the lowest quartile (~!16.4 ma) had skin lesions. In the highest quartile (1,279.9-22,147.! mg), 14 of 39 subjects (35.9%) had skin lesions. Compared with subjects in the lowest quartile of total urinary arsenic excretion, subjects in the highest quartile had an odds ratio of 3.6 for the presence of any skin lesion (95% CT = I.2, 12.~; urinary arsenic at 471- I,840 Go/. However, the correlation between creatinine-adjusted total urinary arsenic and arsenic concentration in drinking water was only 0.5. Tucker et al. (2001) examined the relationship between skin lesions and arsenic ingestion in a cross-sectional study of 3,228 children and adults ex- posed to arsenic in drinking water in Inner Mongolia. Design aspects of this study are critiqued in the Cancer Effects section (see below). In an analytical approach that assessed exposure by using the "peak arsenic concentration" of the well water that was used during the subject's lifetime, there was a dose- dependent increase in the age-adjusted prevalence of both keratoses and "dyspigmentation" (truncal hyperpigmentation). Thirty-seven of the ~ 72 subjects with keratoses and 25 ofthe 121 subjects with dyspigmentation were assigned peak arsenic concentration exposures of less than 100 Egg. Reproductive and Developmental Effects Arsenic exposures have been associated with a number of adverse health outcomes. Relatively little attention, however, has been directed toward assessing the potential impact of arsenic on human reproductive health effects, despite studies in both humans and experimental animals demonstrating that arsenic and its methylated metabolites easily pass the placenta (Concha et al. 19981. Evidence from human studies suggests the potential for adverse effects on several reproductive end points. A small number of epidemiological stud- ies investigating the relationship between arsenic exposure in humans and adverse reproductive effects have been published since the 1999 report, but they suffer from some limitations and are not necessarily applicable in popula- tions exposed to arsenic in drinking water. A hospital case-control study found an increase of stillbirths in relation to the proximity of maternal residence to an arsenical pesticide production plans in Texas (]hrig et al. 1998~. The study was small, however, and the findings

HUMAN0EALTHEFFEC~ 3] seem to be restricted to specific subgroups. In addition, exposures to other agents from the chemical plants were not assessed. An increase in infant mortality (divided into three subcategories: still- births, neonatal, and postneonatal) was observed in a county in northern Chile during a time when there was a substantial increase in the arsenic concentra- tion of the public drinking-water supply (from 90 to 800 ,ug/L) (Hopenhayn- Rich et al. 20001. A subsequent decrease in arsenic was accompanied by a return to the normal Chilean trend in infant mortality over time. A retrospective survey in Bangladesh (Ahmad et al. 2001) compared several outcomes in women exposed to high (mean 240 ~g/~) and Tow (below 20 ~g/~) arsenic concentrations in drinking water and found increases in spontaneous abortions, stillbirths, and preterm births. This study was based on recall of previous pregnancies, however, and ascertainment of the out- comes was not clearly defined. In summary, although several studies have addressed the potential repro- ductive effects of arsenic exposures in humans, the evidence is not conclusive. Many of the studies lacked information on lifestyle or personal factors that affect birth weight, congenital malformation, and other outcomes and infonna- tion on other potential exposures. Several studies are ecological in nature and therefore subject to additional potential biases. Neurological Effects Previous studies of arsenic's neurological effects have generally focused on central-nervous-system effects seen following acute, high-dose intoxication and on the peripheral neuropathy that occurs following subacute or chronic exposure (NRC ~ 9991. Two recent studies discussed below have focused on subtle cognitive effects in children following chronic exposure to arsenic. Siripitayakunkit et al. (1999) investigated the association between envi- ronmental arsenic exposure and the intelligence of children in the Ronpiboon distnct of Thailand, where shallow artesian wells are contaminated with ar- senic at concentrations as high as several milligrams per liter. Head-hair arsenic concentration and performance on the Weschier Intelligence Scale Test for Children (WISTC) in 529 schoolchildren (6 to 9 years of age) were analyzed in a cross-sectional evaluation. Median head-hair arsenic concentra- tion was 2.42 ,ug/g (hoary 0.48 to 26.94 ~g/g). Only 8.3°/O of the subjects had head-hair arsenic concentrations of 1 )lg/g or less. Head-hair arsenic concen- tration was inversely associated with full-scare intelligence quotient (IQ) in an analysis adjusted for age, father's occupation, maternal intelligence, and

32 ARSENIC IN DRINKING WA TER: 2001 UPDA TE family income. There were no data on exposure to lead, a major potential confounder, or on nutritional factors, such as iron. Although subjects lived in areas that apparently had different environmental arsenic concentrations, it was not stated whether the examiners were blinded to the location of resi- dence. In addition, no data were presented regarding the concentration of arsenic in the children's drinking water, the concentration in the subjects' urine, or the presence of arsenic-related skin lesions in any subject. These factors limit the interpretation of the association between A and head-hair arsenic concentration. A recent cross-sectional study in San Luis Potosi, Mexico (Calderon et al. 2001) examined the impact of arsenic and lead on the neuropsychological performance of schoolchildren aged 6 to 9 years. Subjects included 41 chil- dren living within I.5 kilometers (km) of a smelter complex (Morales zone) with increased arsenic and lead concentrations and 39 children living 7 km upwind from the smelter (Martinez zone). The geometric mean total arsenic concentration in urine was higher in the Morales children (62.91 gag of creatinine; from27.54 to IB6.21) than in the Martinez children (40.28 ,ug/g of creatinine; from ~ 8.20 to 70.79) ED < 0.05~. Blood lead concentrations were similar in the two groups. Maternal and paternal educational attainment, socioeconomic status, and iron status were lower in the Martinez group. Neuropsychological performance was assessed using the Weschier Intelli- gence Scale for Children, Revised Version, for Mexico (WTSC-RM). In a comparison unadjusted for indices of metal exposure or other covariates, the Morales children scored significantly higher than the Martinez children on the full-scale A test and other neuropsychological subscores. However, investi- gators reported an inverse correlation between log- transformed total urinary arsenic concentration (micrograms per gram of creatinine) and verbal A after adjustment by age, sex, socioeconomic status, maternal and paternal educa- tion, nutritional factors (transferrin saturation and height by age index), and blood lead. The relationship between Tog-transformed total urinary arsenic concentration and performance A was not significant. Speciation of arsenic in the urine (inorganic arsenic, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA)) was not performed, and the impact of past expo- sure to high levels of arsenic and lead emissions near the smelter was not assessed.

HUMAN HEA [TH EFFECTS 33 Respiratory Effects Noncancer respiratory effects have been reported in populations exposed to arsenic in drinking water (NRC 1999), but the database on this topic has been sparse. Mazumderet al. (2000) recently reported an association between arsenic ingestion in drinking water and the prevalence of respiratory effects in a large cross-sectional survey of subjects residing in one of the arsenic- affected districts of West Bengal, India. Dermal effects have also been stud- ied in this population (Mazumder et al. 1998~. The analysis ofthe respiratory effects excluded ~ ~ 9 of the 7,683 individuals because of current or past his- tory of smoking. Prevalence odds ratio (POR) estimates for abnormal chest sounds on physical examination were increased for subjects who had arsenic skin lesions and who consumed water with arsenic at greater than 500 1lg/L, compared with subjects who had no skin lesions and who consumed water with arsenic at less than 50 Go/. For females, the age-adjusted POR for cough was 7.8 (95% CT = 3.~-19.5) and for chest sounds, 9.6 (95% CT = 4.0- 22.9~. For mates, the age-adjusted FOR for cough was 5.0 (95% CT = 2.6-9.9) and for chest sounds, 6.9 (95% CT = 3.~-15.0~. Examiners were not blinded to the presence of arsenic-related skin lesions. However, the large size of the study, the high odds ratios observed, and the positive trend with current ar- senic exposure were such that the study provides support for reports of arsenic-associated pulmonary effects previously noted in Chile in the 1 960s and ~ 970s (see NRC ~ 999~. Milton et al. (2001) reported an association between chronic arsenic in- gestion and "chronic bronchitis" in a small cross-sectional study in Bangla- desh of 94 individuals with arsenic-associated son lesions. These individuals were attending "health awareness" meetings in three villages. The mean concentration of arsenic in drinking water was 614 ~g/L, and the range was ~ 3 6 to ~ ,000 ,ug/~. The study included ~ 24 nonexposed individuals recruited from three villages "known to be not contaminated with arsenic." All partici- pants never smoked, and all denied a history of asthma or tuberculosis. Chronic bronchitis was defined as a history of cough productive of sputum on most days for at least 3 consecutive months for more than 2 successive years combined with the presence of chest rhonchi andior crepitations on physical examination. Chronic bronchitis was present in 14 of 40 exposed males, ~ ~ of 50 nonexposed males, 15 of 54 exposed females, and 2 of 74 nonexposed

34 ARSENIC IN DRINKING WA TER: 2001 UPDA TE females. The crude prevalence ratios for chronic bronchitis were ~ .6 (95% CT = 0.~-3. ~) and 10.3 (95% C! = 2.4~3. ~) for males and females, respectively. After Mantel-Haenszel adjustment for sex, the prevalence ratio was 3.0 (95% C! = I.6-5.3~. Although this study could have considerable recruitment bias and observer bias, it contributes limited evidence to the studies that suggest an adverse respiratory effect of chronic high-dose arsenic ingestion. In an ecological study of mortality in an area of southwestern Taiwan where blackfoot disease is endemic (Tsai et al. ~ 999; see Diabetes section for description), the SMR for "bronchitis" increased significantly relative to a nearby reference population (SMR = ~ .53; 95% CT = ~ .30-1.80), and to all of Taiwan (SMR = 1.95; 95% CT = 1.65-2.291. The SMR for emphysema was not significantly different from either reference population. The authors noted that it is unlikely that differences in the rate of smoking account for the in- creased bronchitis mortality. Hepatotox~c Effects Hernandez-Zavala et al. (1998) studied liver function in individuals from three towns in the Region Lagunera of Mexico. The mean arsenic concentra- tion in drinking water in each village was 14.0 ~ 3.l vigil, ~16.0 ~ 37 Vigil, and 239.0 it 88 ~g/L, and the corresponding mean total arsenic concentration in urine for each group (n = 17 per village) was 88.0 ~ 27, 398.0 ~ 258, and 2,058.0 ~ 833 ,ug/~. The duration of exposure was not stated, but it was known that the middle-exposure town reduced the arsenic concentration (from 400 ~g/L) in its water supply 3 years prior to the study. No subjects had recently consumed alcohol or had a history of chronic alcoholism. The mean concentrations of serum alkaline phosphatase and total bilirubin were signifi- cantly increased in individuals from the highest exposure town compared with the lowest- exposure town. Total urinary arsenic concentration was also correlated with those end points. Although data were not shown, the authors stated that those correlations were not significantly changed by adjusting for age, pesticide exposure, or history of alcohol or tobacco use or by examining separate correlations with urinary inorganic arsenic, MMA, or DMA. Serum transaminases (ALT, AST, and GGT) and albumin were normal and did not differ significantly between the groups. Twenty-six percent of the subjects from the middle- and high-exposure towns were reported to have at least one skin lesion associated with arsenic exposure. The potential impact of skin lesions as a covariate in the analysis was not reported. The impact of potential

HUMAN HEALTH EFFECTS 35 outliers on the results was not discussed. Although the correlations between urinary arsenic and both alkaline phosphatase and bilirubin concentrations observed in this study are interesting and might suggest an element of cholestasis, the biochemical findings noted are not specific for this hepatic end point. In the recent study by Santra et al. (1999), bilirubin or alkaline phosphatase increases were not a characteristic finding in 93 patients with firm hepatomegaly attnbuted to chronic arsenicosis in West Bengal, India. In that study, liver biopsy results Dom 69 patients with a clinical diagnosis of chronic arsenic poisoning revealed portal fibrosis in 63 (9 ~ .3%) cases, cirrho- sis in 2 cases (2.9%), and normal histology in 4 (5.~%) cases. The degree of fibrosis was considered mild (grade 1) in 34 (53.9%) of the cases. Clinical evidence of portal hypertension (e.g., esophageal varices) was uncommon. Hematological Effects Hemandez-Zavala et al. ~ ~ 999) also examined urinary porphyrin excretion and erythrocyte heme synthesis pathway enzymes in the same population described previously in the section Hepatotoxic Effects (Hernandez-Zavala et al. ~ 998~. A dose- dependent increase in the ratio of urinary coproporphynn ITI to coproporphyrn T and in the ratio of total coproporphynn to total uroporphyrin was observed among the groups ~ ~ 7 individuals per group; mean urinary arsenic excretion, 88.0 ~ 27, 398 ~ 258, and 2,058 ~ 833 ,ug/~. Those ratios are in contrast to earlier findings by those authors in a population with exposures that were somewhat higher and of longer duration (Garcia Vargas et al. ~ 994~. In that study, chronic high-dose arsenic ingestion was associated with inversions of the ratio of coproporphyrin to uroporphyrin (i.e., ratio <it and of coproporphyrin m to coproporphyrin T. It is not clear whether differ- ences in the intensity and temporal pattern of arsenic dose contributed to the disparate findings in those studies. Diabetes The main focus of research looking at the effects of arsenic on the endo- crine system is the association between arsenic exposure and diabetes mel- litus. The NRC ~ ~ 999) report reviewed studies in Taiwan and Bangladesh that associated chronic ingestion of arsenic in Winking water with an increased risk of diabetes mellitus.

36 ARSENIC IN DRINKING WA TER: 2001 UPDA TE More recently, as part of an ecological study examining multiple causes of mortality in a section of the area of southwestern Taiwan where blackfoot- disease is endemic, Tsai et al. (1999) examined mortality from diabetes mel- litus in four townships where artesian well water containing arsenic (median concentration of 0.78 mg/L (780 ~g/L); from 0.25 to 1.14 mg/L) had been consumed from the early 1900s until the mid- to late- 1970s. Observed mortal- ity between ~ 97 ~ and ~ 994 was compared with age and sex-specific expected mortality based on data from (~) a local reference group derived Mom two nearby counties, and (2) all of Taiwan. The locaireference group was consid- ered to be similar to the study group with respect to lifestyle factors; however, the drinking-water arsenic concentration of the local reference area was not stated. The extended time of follow-up resulted in a relatively large number of deaths being available for analysis. Within the high arsenic area, there were ~ I, ~ 93 recorded deaths during ~ ,508,623 person-years of observation for males and 8,874 recorded deaths during ~ ,404,759 person-years of observation for females. Diabetes mellitus (WorId Health Organization's International Classification of Disease (ICD)(CDC 2001) ~ and 9, code 250) was listed as the underlying cause of death for ~ 88 mates and 343 females. For males, the SMRs were ~L.35 (95% CI= I.16-~.55) and 1.14 (95% CI= 0.98-~.31), using the local and the national reference group, respectively. For females, the corresponding SMRs were 1.55 (95% CI= 1.39-~.72) and 1.23 (95% CT= I . ! I-~ .37~. Because only mortality attributed primarily to diabetes mellitus was examined, studies such as this one might underestimate an association between arsenic exposure and the population risk of the disease. Tseng et al. (2000) recently reported the results of a prospective cohort study examining the incidence of diabetes mellitus in three villiages from the arsenic endemic area of southwestern Taiwan. The study population consisted ofthree villages where artesian well water (median arsenic concentration from 0.70 to 0.93 mew) was used for drinking and cooking until the mid-to-late 1970s. The study enrolled 632 subjects over 30 years of age who were deter- mined not to have diabetes mellitus at the time the cohort was assembled (January and February, 1989~. Details of the cohort are described by Lai et al. (1994~. In 1991 and 1993, 446 of the cohort agreed to participate in a follow-up examination that included a fasting blood glucose and an oral glu- cose tolerance test. Diabetes mellitus was defined in accordance with the World Health Organization criteria. The incidence of diabetes mellitus in the study population was calculated as the total number of incident cases divided by the sum of follow-up person-time in all subjects. Data on each subject

HUMANHEALTHEFFECTS 37 included age, sex, body-mass index, and an index of lifetime cumulative ar- senic exposure (CAE). CAE (in units of milligrams per liter-years) was calcu- lated as the product of the median arsenic concentration of the well water in every village that a subject inhabited at some point in his or her life multiplied by the length of time they consumed well water in that village. Individuals were excluded if complete arsenic exposure data were not available. Inci- dences for diabetes mellitus in the study population were compared with those reported for a demographically similar control population that was studied contemporaneously (Wang et al. 1997~. Tseng et al. (2000) reported that during a follow-up period that included 1,499.5 person-years, 41 of 446 sub- jects developed diabetes mellitus (all noninsuTin-dependent diabetes mellitus or type ~ diabetes mellitus). The incidence for new cases was particularly increased in subjects 55 years of age or older (50.8 per 1,000 person-years). The age-specific incidence density ratios were 3.6 (95% CT = 3.5-3.6), 2.3 (95% CT= 1.~.9), 4.3 (95% CI= 2.4-7.7), and 5.5 (95% CT= 2.2-13.5) for individuals 3544, 45-54, 55-64, and 65-74 years of age, respectively. The relative risk for developing diabetes mellitus among those with more than 17 mg/~-years CAE compared with those with less than ~ 7 mg/~-years CAE was 2.l (95% CT = 1.14.2), adjusted for age, sex, and body-mass index in a multivariate Cox proportional hazards model. When considered as a continu- ous variable, the CAE was associated with an adjusted relative risk of devel- oping diabetes mellitus of ~ .03 for every ~ mg/L-years of exposure ~ < 0.051. RECENT STUDIES OF CANCER EFFECTS IN HUMANS Since the previous evaluation of arsenic by NRC (1999), several studies have been completed that contribute to our understanding of dose-response relationships for arsenic in drinking water and cancer risk. In this section, detailed summaries and evaluations are presented of two of the recently com- pleted studies that have adequate data to contribute to quantitative assessment of risk—one for urinary-tract cancers in Taiwan (Chiou et al. 200 I) and the other for lung cancer in Chile (Ferreccio et al. 20001. Other studies from Taiwan, Finland, and the United States with less infor- mation regarding risk of cancer of internal organs are also summarized (Tsai et al. 1998; Kurttio et al. 1999; Lewis et al. ~ 999a). For the most part, the limitations of those studies preclude direct application of their data to a quan- titative risk assessment of arsenic in drinking water. However, one of the

38 ARSENIC IN DRINKING WA TER: 2001 UPDA TE studies provides insight into issues surrounding the EPA risk assessment (Tsai et al. 1998~. Two studies of skin cancer are also discussed (Karagas et al. 2001; Tucker et al. 2001~. Skin cancers, however, are not as great a concern as internal cancers, such as bladder and Jung cancer, because internal cancers are life-threatening, whereas most skin cancers are not. Skin cancer studies by Ma et al. (1999), Buchet and Lison (1998), Hinwood et al. (1999), Tsai et al. (1998), Ahmad et al. (1999), and Kurokawa et al. (2001) were noted by the subcommittee but are not discussed. Table 2-l summarizes the major human studies in which cancer end points have been investigated. The table includes studies that were described in the ~ 999 NRC report as well as studies from the current evaluation. Several qualitative criteria were used in evaluating the available epidem~o- Togical studies of cancer. It is important that studies adhere to basic epidemio- logical principles designed to avoid major sources of bias. In the case of ecological and cohort studies, these principles include accuracy of diagnoses (or cause of death), selection of an appropriate comparison population, and a clear definition of exposed and unexposed populations. In cohort studies, a high rate of successful follow-up is desirable. For case-control studies, evalu- ation criteria include careful attention to accurate diagnoses of cases, an ade- quate response rate among both cases and controls, and appropriate selection of the control group. In all studies, statistical power is a key consideration. Findings from small studies, even those with excellent methodology, are of limited utility. The approach to exposure assessment and the use of estimated exposures in data analysis are key elements in epidemiological studies of all environmen- tal exposures and were a central focus of the subcommittee's review of the literature of arsenic in drinking water and risk of cancer. Therefore, this section begins with a discussion of general issues in exposure assessment in epidem~ological studies, followed by a discussion of specific studies. General Issues with Exposure Measurement In reviewing relevant data developed on measuring arsenic exposure since the 1999 NRC report Arsenic and Drirlking Water, it is worthwhile to begin by considering concepts of exposure and dose, because numerous definitions and methods of estimating exposure have been developed. Exposure and dose are related but separate concepts. Exposure to chemicals occurs when there is a chemical source, transportation of the chemical from the source to the

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HUMAN HEA ETH EFFECTS 4 7 subject, and contact between the chemical and the subject (i.e., ingestion of water or food, dermal contact, or inhalation). Dose refers to the amount of chemical transferred to the exposed subject. Dose should be described in terms of its relationship to the exposed subject, whether as the available, administered, absorbed, or active or biologically effective dose. Measurement ofthe dose (as opposed to simply the fact of exposure) does not just provide the opportunity for a more detailed and informative descrip- tion ofthe relationship between exposure and a disease; it is also important in inferring the absence or presence of a cause-and-effect relationship. One limitation of most epidemiological studies of arsenic is that dose is estimated from measuring the concentration of arsenic in drinking water and assuming an exposure based on drinking-water rates. Details of the exposure assess- ment conducted in each study are discussed belong. The variability and uncer- tainty associated with the exposure assessment and their impact on a human- health risk assessment for arsenic are discussed in Chapters 4 and 5. Chiou et al. 2001 Study Chiou et al. (2001) conducted a prospective cohort study of 8,102 persons in the Lanyang basin of northeastern Taiwan, a region where arsenic-contami- nated shallow wells were used for drinking water from the late- 1 940s through the mid-199Os. All cohort members had used shallow private wells for their primary drinking-water supply. Subjects were interviewed at home between October 1991 and September 1994. There were 4,586 homes represented in the study and 3,901 well-water samples taken and analyzed for arsenic with the use of hydride generation with flame atomic absorption spectrometry. Samples were not taken from 1,136 homes because their wells no longer existed. No biomarkers of arsenic exposure were used. The interview in- cluded information on history of well-water consumption, residential history, sociodemographic characteristics, cigarette smoking, personal and family medical history, occupation, and other potential risk factors. Subjects were followed for cancer incidence from the time of enrollment (1991 to 1994) through December 3 I, 1996, with the use of multiple resources. Detailed analyses oftotal urinary cancer (includes kidney, bladder, end urethra! cancer) and specifically of the most common cell type of urinary cancer, transitional cell carcinoma (TCC), are presented. Nine subjects were diagnosed with bladder cancer, eight with kidney cancer, and one with both. Among those 18 subjects with urinary-tract cancer, 17 had pathological confirmation, and 11 were diagnosed with TCC. The most useful analyses were internal compari-

48 ARSENIC IN DRINKING WA TER: 2001 UPDA TE sons. Age- and sex-adjusted rates of urinary-tract cancer and TCC were first calculated within each exposure stratum. Incidences of urinary-tract cancer for subjects who crank well water with arsenic concentrations of 10.0 or less, 10. ~-50.0, 50. ~-100.0, and greater than 100.0 ~g/L were 37.6 (three subjects), 44.8 (three subjects), 66.4 (two subjects), and 134.1 (seven subjects) per 100,000, respectively. The corresponding incidences for TCC were ~ 2.5 (one subject), 14.9 (one subject), 66.4 (two subjects), and 114.9 (six subjects) per 100,000, respectively. When evaluated by duration of exposure to well water (<20.0, 20.1-39.9, and 40.0 years), rates for urinary cancer were 61.1 (one subject), 46.7 (four subjects), and 77.3 (10 subjects) per 100,000 persons, and rates for TCC were 0, 46.7 (four subjects), and 46.4 (six subjects) per 100,000, respectively. Cox's proportional hazards regression analysis (ad- justed for sex, age, and cigarette smoking) was conducted to estimate relative risks and 95°/O confidence intervals by concentration and duration of arsenic exposure. The multivariate relative risks for urinary cancer by concentration of arsenic in drinking water, using as a nonexposed referent group subjects with exposures at 10 ~g/L or less, were 1.6 (95% CT = 0.3-~.0) for arsenic concen- trations at 10.~-50.0 ALL, 2.3 (95% CI= 0.4-14.4) at 50.1-100.0 PAL, and 4.9 (CT = 1.2-15.3) at greater than 100.0 ,ug/~. Corresponding relative risks for TCC were ~ .9 (0. ~ -32.2), 8. ~ (0.7-98.2), and ~ 5. ~ ( 1 .7- ~ 3 8.5~. In a time- window analysis, the increase in arsenic-induced TCC was more prominent for subjects who had drunk well water for more than 40 years, implying the possibility of a Tong latency between arsenic exposure and the occurrence of TCC author the importance of cumulative dose. A strength of this study is that multiple follow-up resources were used to detect newly diagnosed (incident) cancer cases, ensuring that most newly diagnosed cancers were correctly identified. Other strengths are that residen- tial and water-use histories were obtained from most cohort members and that individual information on other risk factors, such as cigarette smoking, was available. The authors used appropriate analytical techniques to estimate relative risks and 95°/O confidence intervals. The approach to exposure estima- tion has both strengths and weaknesses. The study was conducted in an area of Taiwan with a residentially stable population. Under the assumption that arsenic concentrations from household wells had been relatively constant over time, past individual exposures could be estimated by measuring arsenic in the current household well water of most cohort members. It should be noted that few data directly address the issue of arsenic-concentration consistency over time, and the question of historical consistency of arsenic concentrations in

HUMAN HEALTH EFFECTS 49 various types of groundwater deserves exploration. Consistency is of particu- lar concern with shallow groundwaters, which might be subject to greater fluctuation than water from deeper wells. There were 4,074 study subjects (50.3%) who had drunk well water for more than 40 years, and over 70% of subjects greater than 50 years of age had drunk well water for more than 30 years. The average duration of drinking well water was 40;7 years. For 2,1 19 subjects (26.2%), more than one well had been used in their houses, and their past arsenic exposure data were derived from their current well data (Cantor 2001~. Those 2,1 19 subjects had used their current well for approximately 60% of their life spans (standard deviation = 21 years), and most had used their current well for at least ~ O years (Chen and Chiou 200 ~ ). Although expo- sure assessment was individualized, for all subjects only a single well-water measurement obtained at one point in time was used to characterize long-term arsenic exposure. Foremost among the limitations of this study is the short duration of follow-up, which limited the number of person-years of observation; hence, only a few cases of incident urinary-tract cancer were recorded: a total of 18 cases (15 with exposure information), of which ~ ~ were TCC (10 with expo- sure information). In calculating relative risks, the small number of cases resulted in very wide CIs. For example, the adjusted relative risk of TCC in the highest exposure category (>100.0 p~g/~) was 15.1, with a 95% CT of ~.7- 138.5. Thus, the study by Chiou et al. (2001) is limited by its relatively small numbers, and risk estimates based on these data might be too imprecise for use in a quantitative risk assessment. However, the data can serve as supplemen- tary information, along with data from other selected studies. Since the cohort continues to be studied by the investigators, it is likely to yield more stable risk estimates in the future as more person-years of follow-up are accrued. Ferreccio et al. 2000 Study In a region of northern Chile with a history of increased concentrations of arsenic in drinking water, Ferreccio et al. (2000) conducted a case-control study of incident Jung cancer. Eligible cases included all lung cancer cases diagnosed in the eight public hospitals in regions I, II, and m from November 1994 through July 1996. There were 217 eligible subjects identified, and 15 1 (70°/O) participated. Nonparticipation was largely due to inability to locate the subject. Controls were selected from the hospitals where the lung cancer cases were diagnosed. Two control series were selected: cancers other than

50 ARSENIC IN DRINKING WA TER: 2001 UPDA TE lung cancer and noncancer controls. Another set of similarly identified con- trols was selected for a parallel study of incident bladder cancer. Cases and controls were interviewed regarding residential history, socioeconomic status, occupational history (to ascertain employment in copper smelting), and smok- ~ng. An unusual characteristic of this study is the method used for control selection. Because control selection is a central element of the study design and might influence interpretation, it is worthwhile to describe the selection procedure. If it is assumed that most cases of lung cancer that occurred in the population were included in the study, an appropriate control group would be healthy persons selected randomly from the population at large, matched on age and sex. Instead, the authors selected hospitalized non-lung-cancer pa- tients as controls. These patients could be more readily identified and inter- viewed. This technique has frequently been used in cancer epidemiology and can be an acceptable approach. In an effort to avoid overmatching by geo- graphic area, and thus relative concentrations of arsenic in drinking water, the authors sought to select controls from the study hospitals in a manner that would reflect the distribution of arsenic exposure in the overall population from which the cases arose. To do that, the probability of selecting a control from each ofthe Bight hospitals was based on the relative frequency of adm~s- sion to that institution in 1991. Controls were also matched on sex and age within 4 years of the index case. Two hospital-based controls were selected for each case using this method: a patient diagnosed with a cancer that has not been related to arsenic exposure and a noncancer patient. Historical exposure to arsenic in drinking water for each respondent was estimated by linking residential history inflation with a database of infor- mation on arsenic concentrations in public-water supplies collected for the years 1950 through 1994. Arsenic concentrations in the years prior to 1950 were based on concentrations in the 19SOs. Average arsenic concentration in the place of residence was assigned to each subject on a year-by-year basis for the period of 1930-1994. Population coverage of public-water systems in the main cities in regions ~ and ~ was over 90% and was between 80% and 90°/0 in the major cities of region m. The coverage in smaller cities varied between 64% and 91%. The authors conducted a series of validation checks for the controls. Control- group distribution among hospitals was compared with the target distribution based on admissions in 1991. Major discrepancies were found, the main differences being from the main hospitals of Arica and Antofagasta,

HUMANHEALTHEFFECTS 5] the two largest cities in the study area. There was a deficit in the proportion of observed-to-expected controls from the Arica hospital (0.6) and an excess from the Antofagasta hospital (~.2~. In another comparison, the authors used the distribution of arsenic concentration in the period of 1958-1970 based on population figures from the ~992 census. Population numbers in 1992 were used to estimate an expected water-arsenic distribution for 419 randomly selected controls. This distribution was then compared with the actual distri- bution of the selected controls, and the ratio of the selected numbers of con- trols to that expected was calculated. The baseline exposure stratum (049 ,ug/~) showed a selected-to-expected ratio of 0.~. However, the high-exposure category of 400 ,ug/L and above (selected-to-expected = ~ .4) was overrepre- sented, owing to overselection of controls in Antofagasta, which had unusu- ally high concentrations of arsenic in its drinking water during 1958-1970. Selected-to-expected ratios for intermediate groups were I.3 for 50-99 ,ug/L and O.S for 100-399 ,ug/L. The expected impact of the overselection in the highest-exposure category is to diminish estimates of risk, and underselection in the Tower stratum is to enhance risk estimates. As the authors noted, this assessment is indirect, because in the data analysis the actual historical resi- dential location of cases and controls rather than their location at the time of the study was used to determine arsenic exposure levels. However, the direc- tion of bias is probably as indicated. Odds ratios were used to estimate relative risk of exposure to various concentrations of arsenic in drinking water relative to a referent concentration of 0- ~ O Go/. Odds ratios were calculated using unconditional logistic regres- sion, adjusted for age, socioeconomic status, smoking, and working in a cop- per smelter. In separate analyses, arsenic in Winking water was expressed as average yearly concentration during the peak years of exposure 1958-1970 or as average yearly concentration in the period of 1930-1994. In Antofagasta, there was a peak in exposure during 1958-1970, when arsenic concentrations averaged 860 ,ug/~. When 1958-1970 average arsenic concentrations were used as the estimate of exposure, the odds ratios were 5.7 (95% CT = ~ .9-16.9) for the 400-699 ~g/L exposure stratum and 7.! (95% CT = 3.~-12.~) for 700- 999 ~g/L, relative to 0-10 ,ug/L. Results from the analysis based on average exposures during 1930-1994 and using all controls (419) showed an increase in the odds ratio with arsenic concentration, reaching an odds ratio of 8.9 (95% CT = 4.0-19.6) for the highest exposure group (average exposure 200- 400 Go/. Results from calculations using cancer controls (n = 167), noncan- cer controls (n = 252), or controls frequency-matched to lung cancer cases (n

52 ARSENICIN DRINKING WATER: 2001 UPDATE = 237) were of similar magnitude. Risk estimates based on long-term average exposure were higher per unit exposure than those that used the peak period of exposure (the mid-point of which is about 30 years before diagnosis of study cases). It is not clear at this time whether it is appropriate to give more weight to the risks based on 40+ years of exposure or to risks based on the 12- year peak exposure period about 30 years prior to diagnosis. When the study population was stratified by smoking status, there was suggestive evidence of a synergistic interaction between smoking and exposure to arsenic in drinking water. Relative to nonsmokers with average arsenic exposures of 49,u~ or less (1930-1994), nonsmokers with average exposures of 200 ,ug/L or more had an odds ratio of 8.0 (95% CT= 1.7-52.3), whereas smokers with average exposures of 200 ~g/L or more had an odds ratio of 32.0 (95% CT = 7.22- 198.0~. Strengths of this study include an acceptable response rate, unbiased ascertainment of exposure, individual estimates of exposure, exposure cover- age of most of the life span for most study subjects, incorporation of individ- ual data on other potentially confounding risk factors for lung cancer, appro- priate analyses of study data, and an adequate study size. This is the only study available for risk assessment that has individual estimates of exposure on all subjects for more than 40 years, well beyond the minimum latency for lung cancer. The major limitation of the study, as discussed, is related to methods used for control selection. The data from this study can be used in a quantitative assessment of risk of arsenic in drinking water, along with data from other selected studies. Lewis et al. 1999 Study Lewis et al. (1999a) conducted a retrospective cohort mortality study of 4,058 residents of Millard County, Utah, a region where drinking water is derived from wells and where arsenic concentrations in well water range from undetectable to up to a few hundred micrograms per liter. In a letter to the editor (Lewis et al. ~ 999b), the purpose of the study is described as follows: "We were interested in determining whether studies of health effects related to arsenic in Winking water could be conducted in U.S. populations exposed to relatively low concentrations of arsenic." The study cohort included two groups: 2,073 persons from an earlier study (Southwick et al.1982) and 1,985 additional individuals identif ed from special census records and other records

HUMANHEALTHEFFECTS 53 maintained by the Church of Latter Day Saints (Mormons). The earliest entry in the cohort was in ~ 900, and the most recent was in ~ 945 . Cohort members had lived in the towns of Delta (1,191 persons; 29.4%), Hinckley (1,192 per- sons; 29.4%), or smaller towns, such as Deseret, Abraham, or Oasis (1,675 persons; 41.2%~. Vital status follow-up was through November27, 1996. At the closing date, 38.2% (1,55 1) were alive, 54.3°/O had died (2,203), and 7.4°/O (300) were lost to follow-up. All death certificates were coded according to rubrics of the ICD-9, and SMRs were calculated by cause of death, separately for mates and females in each of three exposure groups, as described below, and for all exposure groups combined. The SMR is the cause-specific ratio of observed-to-expected numbers of deaths, where the expected number is calculated for the age and sex distribution of the study population by using age- and sex-specific rates of a comparison population. In calculating SMRs, the comparison was sex-specific rates for the state of Utah. That metric was calculated by multiplying the concentration of arsenic in the drinking water in parts per billion (micrograms per liter) by the number of years of exposure to yield an exposure with units of parts per billion-years, arranged into three groups: <l,000, 1,0004,999, and 5,000 ppb-yr. This metric represents an estimate of cumulative arsenic exposure for years of residence in study towns. Information on water intake was not available. For several causes of death, statistically significant increases in SMRs occurred in a generally uneven pattern based on exposure level. Among men, the causes of death included hypertensive heart disease, nephritis, nephrosis, and prostate cancer. Among women, they were hypertensive heart disease and all other heart disease (pul- monary heart disease, pericarditis, and other diseases of the pericardium). This study has several strengths. Vital status was determined for all but a small number of cohort members (7.4%), selection into the cohort was unbi- ased with respect to outcome, and numbers of cohort members and deaths within the cohort were adequate to evaluate risk for major causes of death. Several of the limitations concern the estimation of exposure and the consequences for study interpretation. Lewis et al. (1999a) present results of ~ 5 ~ arsenic analyses of drinking water in public and private water supplies for the study towns from a survey of drinking-water wells conducted by the Utah State Health Laboratory since 1976. These data "were used in assessing the potential exposure of cohort members to arsenic in drinking water" (Lewis et al. 1 999a). Lewis et al. (1 999a) present the number of samples taken in each town and the average, median, minimum, and maximum amounts of measured arsenic. The number of wells that contribute to the municipal water supply of

54 ARSENIC IN DRINKING WA TER: 2001 UPDA TE each town is not presented, nor is it stated whether multiple measurements in each town represent repeat samples taken from one well, multiple samples from different wells, or a combination of both. For each year a cohort mem- ber lived in one of the study communities, he or she was assigned the median concentration of measured arsenic for the wells of that community. Presum- ably, exposure that occurred during periods when a person did not live in one of the study communities was not included in the estimate of exposure used in the analysis, creating the possibility that cumulative lifetime arsenic expo- sure might have been incompletely ascertained for some of the cohort. The range of arsenic concentrations reported in Lewis et al. (1999a) for each town was quite broad. For example, arsenic concentrations measured since 1976 in Hinckley ranged from SO to 285 ,ug/~; inDeTta, 3.5 to 125 Ago; and in Deseret, 30 to 620 ,ug/~. However, the median concentration was assigned to individual cohort members during their years of residence. Use of a median level to estimate exposure when the concentrations vary so widely necessarily resulted in misclassification of exposure for many subjects. A similar approach to estimating exposure was taken in the ecological studies from southwestern Taiwan of Chen et al. (1985) and Wu et al. (1989) that were used in the EPA risk assessment. The estimates of exposure from the Taiwanese studies might be more representative of actual exposures than the estimates from Utah. In Utah, arsenic samples came from different types of water supplies, both public and private. The exposure metric used for the analysis (parts per billion-years) was the product of water arsenic concentration (in parts per billion) and duration of exposure (in years). One consequence of using this exposure metric, which inextricably combines intensity and temporal aspects of exposure, is that comparisons of results with findings of many other studies that used measure- ment of average arsenic over extended periods are not possible. Another consequence of using this metric is that persons with very different exposure histories are grouped in the same exposure stratum during data analysis. For example, a value of I ,000 ppb-yr could result from exposure to 20 ~g/L for 50 years or 200 ,ug/I, for 5 years. Such strikingly different exposure scenarios could have very different health consequences. Other studies (e.g., Chiou et al. 2001) suggest that average arsenic concentration over a Tong period is more strongly associated with risk than is the duration of exposure to increased concentrations, suggesting the need to consider concentration and duration of exposure independently. The duration of exposure for cohort members is not explicitly presented and might have been relatively brief for some.

HUMAN HEALTH EFFECTS 55 In addition to limitations regarding exposure ascertainment, the subcom- mittee noted a few epidemiological issues. As the authors recognized in the discussion, "SMRs cannot be directly compared in an analysis that uses indi- rect adjustment," especially where the distributions of age among groups are not comparable. There was a significant difference in the age distribution of the three exposure groups, indicating that comparison of SMRs across expo- sure groups is not appropriate. The difference in age distribution is not sur- prising among exposure groups in which the exposure metric itself is age- dependent. Older people would be likely to have higher cumulative exposure. "Based on this, any conclusions on whether arsenic is an etiologic factor in consideration of increased or decreased SMRs among the groups is uncertain" (Lewis et al. 1999a). Comparison rates used in the analysis of risk were for the state of Utah, and this comparison likely resulted in underestimates of risk for some causes of death and overestimates for others. The study cohort was composed of Mormons, with strict religious prohibitions against smoking and consumption of beverages containing alcohol or caffeine. In addition, the study population was largely rural. As the study authors noted, smoking rates for the state of Utah are low, around 12-13%. However, even this relatively low smoking prevalence is expected to result in rates of several cancers (lung, bladder, kidney, and pancreas) and cardiovascular diseases that are increased relative to a nonsmoking population, such as the study cohort. That factor and the rural setting of the cohort were possible contributors to the deficits observed in SMRs for urinary and pulmonary cancers. A reanalysis of the study data for bladder and lung cancers, without a comparison population, was conducted by the EPA Office of Water (EPA 2000) using Cox proportional hazards regression. The Lewis et al. (1999a) study identified a total of 34 respiratory cancers, of which 30 were lung can- cers, and a total of five bladder cancers. The risk detected in the EPA reanaly- sis was not statistically distinguishable either from zero or from the levels predicted by mode] ~ of Morales et al. (2000) and used by EPA in its arsenic risk analysis (EPA 2000~. In addition to limitations in exposure assessment, it is apparent that the power of the Utah study is too low to allow a precise enough estimate for use in quantitative risk assessment. It is possible that further exploration of the exposure assessment used for this study would be fruitful. If so, then additional follow-up end reanalysis using an internalrefer- ent is to be encouraged. In summary, although this study in its current state has several strengths, several limitations preclude its use for quantitative risk assessment.

56 ARSENICIN DRINKING WATER: 2001 UPDATE Tsai et al. 1999 Study Sex-specific mortality due to several cancer and noncancer causes in the area of southwestern Taiwan where blackfoot-disease is endemic was evalu- ated by Tsai et al. (1999) for the years 1971 through 1994. Formerly, this area had high concentrations of arsenic in drinking water. Standard mortality ratios were calculated twice using two referent groups: the first referent was the mortality experience of the whole of Taiwan and the second referent was the mortality experience ofthe two counties of southwestern Taiwan where black- foot disease is endemic. This study has special significance because it speaks to the issue of possible factors, such as differences in diet, cultural back- ground, smoking, occupational exposures, access to medical care, or other differences (other than arsenic exposures) between the population of south- western Taiwan and the remaining population of the country that might have influenced cancer mortality. In particular, it has been argued that differences in general nutritional status or selenium intake between the relatively poor farming and fishing communities of southwestern Taiwan (the locate of high arsenic exposures from water and the studies used for the EPA risk assess- ment) and the remainder of the country were great enough to result in in- creases of risk that might erroneously be attributed to drinking-water arsenic exposures. Those concerns apparently led EPA, in conducting its risk assess- ment, to reject the notion that the mortality experience ofthe whole Taiwanese population was appropriate as a low-exposure referent. Although there re- mains some possibility that population differences in nutrition, socioeconomic status, or other factors between southwestern Taiwan and the remainder ofthe country have some influence on their respective cancer rates, results from the sex- and cancer-specific calculations of Tsai et al. (1999) provide evidence that such differences are relatively unimportant. As examples, the subcommit- tee used the SMRs from Tsai et al. (1999) for three cancer sites of inter- est Jung, bladder, and kidney cancers among males and females that were calculated using regional and national cancer rates, respectively, as the refer- ent. Among males in the area where blackfoot-disease is endemic, there were 699 deaths due to lung cancer. Using regional rates as the referent, the lung cancer SMR for mates was 3.10 (95% CT = 2.~-3.34), and using national rates, the SMR was 2.64 (95% CI = 2.45-2.84~. There were 312 mate deaths due to bladder cancer. Using regional rates as the referent, the SMR for blad- der cancer was 8.92 (95% CI = 7.96-9.96), and using national rates, the SMR was 10.50 (95% CT = 9.37-11.73~. There were 94 male deaths due to kidney i

HUMAN HEALTH EFFECTS 5 7 cancer, the corresponding SMRs being 6.76 (95% CI = 5.46-8.27) using re- gional rates, and 6.80 (95% CI = 5.49-8.32) using national rates. Among females, there were 471 deaths due to lung cancer. The SMR for women was 4. ~ 3 (95% CT = 3.77-4.52) using regional rates as the referent, and the SMR was 3.50 (95% CT = 3.19-3.84) using national rates. There were 295 female deaths due to bladder cancer. The SMR for bladder cancer was 14.07 (95% CT = 12.5l-l5.78) using regional rates, and the SMR was ~7.65 (95% cr = 5.70-19.79) using rational rates. There were 128 kidney cancer deaths among women. SMRs for kidney cancer mortality were 8.89 (95% CT = 7.42-10.57) using regional rates and 10.49 (95% CT= 8.75-12.47) using nationalrates. As noted by Tsai et al. (1999), the regional referent population was very similar to the area where blackfoot-disease is endemic in lifestyle factors, and thus the similarity of SMRs analyzed with either the regional control population or the national population indicates that significant confounding was unlikely. Finally, it is interesting to note that the study by Tsai et al. (1999) deter- mined that the area of southwestern Taiwan where arsenic is endemic experi- enced significant increases in mortality from many other cancers besides those commonly linked to arsenic. It is possible that the relatively high arsenic exposure of the study population and the large size of the study in terms of person-years of observation might have enabled these statistically significant increases to emerge. Kurttio et al. 1999 Study Water samples from drilled wells in some regions of Finland have been reported to have high concentrations of inorganic arsenic. To test whether drinking water from such sources was associated with risk of bladder or kid- ney cancer, Kurttio et al. (1999) conducted a population-based case-cohort study in Finland of 61 bladder cancer and 49 kidney cancer cases. Cases, diagnosed in the period of 1981-1995, were selected from among Finnish residents of places not served by municipal water supplies who had used drinking water from their own drilled wells between 1967 and 1980 and for whom a water sample was analyzed for arsenic concentrations. A reference group of 275 persons, matched by age and sex to the combined case series, was selected from the same population. Contrary to expectation, arsenic concentrations in the cancer group and the control group were relatively low. Among the 61 bladder cancer cases, 42 drank water from wells with arsenic

58 ARSENIC IN DRINKING WA TER: 2001 UPDA TE below 0.5 Ago. The 95th percentile of the distribution of arsenic in well water among bladder cancer cases was 3.0 ~g/L, and among the referent co- hort, 4.5 ,ug/~. In one analysis, the study population was stratified by period of exposure—one group with exposure in the third to ninth calendar year before cancer diagnosis (shorter latency) and another group with exposure in the tenth calendar year and earlier before diagnosis (Ionger latency). Among persons in the shorter latency group, a relative risk of 2.44 (95% CI = ~ . ~ 1- 5.37, 19 cases) was observed for an average arsenic exposure of 0.5 ,ug/L or more, relative to persons with average arsenic exposure of less than 0.1 Ago. Relative risks for the comparable exposure groups among persons with longer latency were not significantly above one. Increased risk with arsenic exposure was confined to persons who smoked during the ~ 970s. Among the shorter latency group, smokers with average arsenic concentrations of 0.5 ~g/L or above had a relative risk of ~ 0.3 (95% CT = ~ . ~ 6-92.6~; the relative risk among nonsmokers in this arsenic exposure group was 0.87 (95% CT = 0.25-3.02~. Both calculations were relative to people (smokers or nonsmokers, respec- tively) with arsenic concentrations of less than 0. ~ Ago. The finding of increased bladder cancer risk in this study is striking, as the risk is far above that expected at relatively low concentrations of arsenic exposure. Given the small number of bladder cancer cases in the study (61) and the likelihood that much more arsenic would come from food than water in this low-exposure population, that finding might be the result of a chance observation or an unmeasured bias. Karagas et al. 2001 Study Using levels of arsenic in toenails as a biomarker of internal exposure, Karagas et al. (2001) conducted a case-control study of 587 basal-cell carci- noma cases (BCC) and 284 squamous-cell carcinoma cases (SCC) in New Hampshire, where private wells are used by about 40% of the population as the primary source of drinking water. Although the arsenic concentration in a majority of New Hampshire wells is below ~ .0 ,ug/L, the concentration in many underground water sources is higher, with concentrations above 5 0 ,ug/L in some instances. Earlier, Karagas et al. (2000) had demonstrated a correla- tion (r) between arsenic in toenails and arsenic in water in persons exposed to arsenic at ~ .0 )lg/L or more of water (r = 0.65, p ~ 0.001). In the case-controT study, controls were randomly selected from the general population of New

HUMAN HEALTH EFFECTS 59 Hampshire, matching on age and sex to the overall distribution ofthe two case series. Cases and controls were interviewed at home starting in January ~ 994. The questionnaire included questions on type of water supply and the number of years of use. Toenail clippings were collected at the time of the interview and analyzed using instrumental neutron activation analysis for arsenic con- centration. Standard logistic regression methods were used to calculate odds ratios for BCC and SCC relative to toenail arsenic concentration, as stratified into six strata according to percentile of the overall distribution among con- trols. The odds ratios for SCC and BCC were close to unity in all but the highest category. Among subjects with toenail arsenic concentrations above the 97th percentile, the adjusted odds ratios were 2.07 (95% CT = 0.92-4.66) for SCC and 1.44 (95% CT = 0.74-2.~) for BCC, compared with those with concentrations at or below the median. The concentration of drinking-water arsenic that corresponds to the 97th percentile lower cutoff level for the highest stratum of toenail arsenic in this study (0.345 ~g/g), where increased odds ratios were observed, is approxi- mately 30-50 ~g/L (estimated by reference to the earlier publication of Karagas et al.2000), showing a correlation between water and toenail arsenic concentrations in controls in that study. The highest level of toenail arsenic among controls was 0.81 Gig, and given the overall log-normal distribution of toenail arsenic in this population, the median level of toenail arsenic in this stratum was likely to be about 0.450 Gig, corresponding to approximately 100-l 50 ~g/L of drinking water. There are several uncertainties regarding the exposure assessment in this study. Arsenic bound to the toenail matrix can result from external exposure as well as intake of inorganic arsenic in food and water. These and other factors result in significant variability in toenail arsenic levels among individ- uals with similar exposure to arsenic in drinking water. Little is known about the toxicokinetics of arsenic uptake into toenails. In the setting of this study, that lack of knowledge leads to uncertainty about the concentration of arsenic in drinking-water exposures corresponding to toenail arsenic concentrations at which increased risk was observed. Arsenic in toenail clippings typically integrates exposures over a few week period about a year prior to sample collection. The latency for skin cancer is not well defined, but appears to be more than a decade. Thus, the time period of exposures reflected in toenail arsenic does not correspond to the critical exposure period for skin cancer. Over 50% of the study population had used the same water supply for over ~ 5 years. Relative-risk estimates did not vary significantly according to length

60 ARSENIC IN DRINKING WA TER: 2001 UPDA TE of use by subjects, further complicating interpretation of study results. An additional limitation of this study is the relatively Tow control participation rate, 50%, which might have resulted in a biased sample from the general population. Tucker et al. 2001 Study Tucker et al. (2001) analyzed data describing prevalent skin cancer and other skin disorders (hyperkeratoses and dyspigmentation) from a cross-sec- tional study in a region of Inner Mongolia with increased concentrations of arsenic in drinking water. A total of 3,179 persons in three villages were examined in 1992, and well-water-use histories for these individuals were gathered. Water samples were collected from 184 of the 187 local wells in these villages and analyzed for arsenic content. The median age of partici- pants was 29 years, and the average well-use history was 25 years. In the study population, 79.6% were less than 50 years of age. Arsenic in drinking wafer ranged from belong detection (10 ,ug/~) to 2,000 Go/. Skin cancer was observed in eight subjects. In addition, 172 subjects had keratosis, 121 had dyspigmentation, and 94 subjects were diagnosed with both types of lesions. Among the skin cancer cases, all eight had both keratosis and dyspigmenta- tion. Two exposure metrics were used in the data analysis: peak arsenic con- centration (PAC), defined as the highest well-water arsenic concentration reported by an individual, and cumulative arsenic dosage (CAD), estimated by multiplying the arsenic concentration by the duration of well use for each well reported to have been used by each subject and then adding the products together to get cumulative exposure. Thirty-f~ve percent of the study popula- tion had a PAC exposure of less than 50 ,ug/L, and 86% had a PAC exposure of less than 150 ,ug/~. Several statistical models (frequency weighted, simple linear regression, hockey stick, and maximum likely estimate) were used to analyze data for each of the effects noted. Two measures of exposure were used with each model. Dose-response relationships were found for skin cancer and the other health end points, using both metrics of exposure to arsenic in drinking water. Several of the statistical models used in the analysis of these data used an a priori assumption of a threshold exposure concentration of arsenic in drinking water below which skin cancer (and other dermatological effects) would not occur. The data appear to be adequately described by such statistical models; however, they are also well-described by a nonthreshold linear model. That

HUMAN HEALTH EFFECTS 61 is not surprising in view of the small number (eight) of skin-cancer cases observed. The authors do not discuss whether differences in results among the various models used to describe the data were statistically significant. There are limitations in the two exposure metrics (CAD and PAC) that were used in this study. Limitations in using CAD as a measure of exposure are described above in the discussion of the Lewis et al. (1999a) study. The other exposure metric, PAC, was used without reference to the time of peak exposures. That lack of information is problematic, because many of the study subjects might have used more than one well during relevant exposure periods, and the peak exposures might have occurred many years before this cross-sectional study and for as little as 1 year. LATENCY PERIOD For cancers, there is generally a period of time, which may be as long as several decades, between a critical molecular interaction of a carcinogen within a single cell and the first appearance of a malignant cell. The length of this period will vary based on the nature of the cancer and whether the molecular interaction occurs early or late in the chain of events leading to the cancer. That period between the critical exposure to the carcinogenic agent and the occurrence of the cancer is referred to as the latency period. Latency is usually estimated by determining the period between the time of first expo- sure to the carcinogen and the clinical detection of the cancer, and studies have been conducted that provide information on the latency period of arsenic- induced skin cancer and internal cancers. Because skin cancers are visible, the time of their appearance can often be dated with some accuracy, which makes the estimation of the latency pe- riod easier for these cancers. A number of early studies that examined latency for arsenic-induced skin cancer were on patients who had ingested arsenical medications; therefore, those studies have accurate information on the time of exposure (see Table 2-2~. Neubauer (1947) summarized the published data for 143 cases of skin cancer (epitheliomas: basal- and squamous-cell carcinomas) attributed to ingestion of medicine containing arsenic. Latency periods between starting the arsenical medication and detection of cancer ranged from 3 to 40 years, with a mean of 18.1 years. Sommers and McManus (1953) presented data on 22 patients who had an average latency period of 24 years (range of 13-50 years) between first administration of arsenical medication or occupational

62 ARSENIC IN DRINKING WA TER: 2001 UPDA TE TABLE 2-2 Estimates of Latency In Studies of Skin Cancer Associated with Arsenic Ingestion No. of Estimated Latency Study Study Type Subjects Place (years) Neubauer 1947 Case-senes 143 Vanous Mean, 18;range,3-40 Sommers and Case-senes 22 U.S. Mean, 24; range, 13- McManus 1953 50 Fierz 1965 Case-senes 21 Germany Mean: 14 Wong et al. 1998 Case-senes Singapore BD: mean, 39; range, 29-50 SCC: mean, 41; range, 32-47 Smith et al. 1998 Ecological 27 deaths Chile Range, about 20-35 Boonchai et al. Case-senes 34 Australia Mean, 20; range, 6-39 2000 Abbreviations: BD, Bowen's disease; SCC, squamous-cell carcinoma. exposure to arsenic-containing pesticide sprays and appearance of skin can- cers. Fierz (1965) estimated a mean latency of 14 years for 21 patients with skin cancers. That estimate, however, is probably subj ect to bias, because the cases were self-selected from a much larger cohort of patients ~~ ,450) who had received arsenical medication. In addition, the follow-up time was only a maximum of 26 years, which probably resulted in an underestimate of the mean latency. More recently, Wong et al. (1998) studied 17 patients in Singapore with skin lesions who had taken Chinese medicines containing arsenic and esti- mated a mean latency period for Bowen's disease of 39 years (range of 29-50 years), and a mean for squamous-cell carcinoma of 41 years (range of 32-47 years in seven patients) (Won" et al. 19984. Thirty-four self-referred Austra- lian patients who had basal-cell carcinoma and had taken an arsenical asthma medication produced a mean latency estimate of 20 years (range of 6-3 9 years) (Boonchai et al. 2000~. Most of those studies, however, are case series and are limited by their small sample size, the possibility of underestimating la- tency because of lack of follow-up until the deaths of the entire case-series patients, and possible confounding from other causes of skin cancer. Smith

HUMANHEALTHEFFECT5 63 et al. ( 1998) studied cancer rates in a region of Chile, which between 195 8 and ~ 970 had a water supply with a high concentration of arsenic (above 800 ,ug/ L). The SMRs for skin cancer for the period of 1989-1993 were 7.7 and 3.2 for mates and females, respectively. Because those SMRs are for only one time period, they are difficult to interpret, but they would be consistent with a latency of around 20-35 years. However, because the SMRs were already high in the 1989-1993 time window, it is likely that mortality was already elevated before the observation period. In addition, many years usually elapse between the clinical diagnosis of skin cancer and mortality from skin cancer, implying a shorter latency for occurrence of those cancers. ~ the case of internal cancers, the data are from epidemiological studies; however, few of those studies address latency (see Table 2-3~. Chen et al. (1986) conducted a case-control study of cancers in a high- arsenic area of Taiwan. They calculated age- and sex-adjusted odds ratios for cancers in individuals who consumed artesian well water contaminated with arsenic for more than 40 years. The odds ratios at earlier time periods were Tower than those for later time periods. Consistent with those results, in a TABLE 2-3 Estimates of Latency in Studies of Internal Cancers Associated with Arsenic Ingestion . ~ . Study Study type Cancer Type Place Estimated Latency (years) Chen et al. Case-control Bladder, lung, Taiwan >40 1986 liver Cuzick et Cohort Bladder England Mean, 7; range, 6-8 (n=3)a al. 1982, >20 (n=2)a 1992 Tsuda et al. Cohort Lung (n=9) Japan Mean, 27; range, 11-35a 1995 Bladder (n=3) Mean, 32; range, 2S-37a Bates et al. Case-control Bladder Utah, Maximum; 30-39 1995 U.S.A. (smokers only, based on time-window analyses) Smith et al. Ecological 1998 Chiou et al. Cohort 2001 . . a Death as the latency end point. Lung, bladder, Chile kidney Bladder Taiwan >40 Range; about 20-35a

64 ARSENIC IN DRINKING WA TER: 2001 UPDA TE recent cohort study in the same area, Chiou et al. (2001) found a higher blad- der cancer risk for individuals consuming well water for 40 or more years 224- 3324 mg). The latency period was between 6 and ~ years for three of the deaths, and more than 20 years for the other two deaths. Those data suggest the possibility that arsenic might have both early- and late-stage effects on the carcinogenic process, although the number of cases was small and information was lacking on the smoking histories of the individuals. In Japan, Tsuda et al. (1995) followed a cohort of 131 people who had been exposed to well water containing high concentrations of inorganic ar- senic between 1955 and 1959 and followed until 1992. In the highest expo- sure group (>I .0 Bogy), the SMR for bladder cancer was 31.2 (95% cr = s.6- 92) and for lung cancer ~ 5.7 (95% CT = 7.4-3 I). For eight lung cancer cases, the mean latency was 27 years (range of ~ 1-35 years); for three bladder cancer cases, the mean latency was 32 years (range of 25-37 years). Because death is the end point used to calculate the latency period, the latency would tend to be overestimated in this study. Using a time-window analysis of bladder cancer case-control data and arsenic exposure from the state of Utah, Bates et al. (1995) found that in smokers the highest odds ratios occurred 30-39 years after exposure. A simi- lar result was not seen for nonsmokers. However, some doubt is cast on this result because of the relatively Tow arsenic exposures involved. As described above for skin cancer, Smith et al. (1998) studied cancer rates during 1989-1993 in a region of Chile. The SMRs for mate bladder and Jung cancers were 6.0 (95% CT = 4.~-7.4) and 3.8 (95°/O CT = 3.5-4.1), respec- tively; the corresponding SMRs for females were 8.2 (95% CT = 6.3-10.5) and 3. ~ (95% Cl = 2.7-3.71. As with skin cancer, those data would be consistent with a latency period of around 20-35 years. As noted above, because the SMRs were already elevated in the 1989-1993 period of observation, it is likely that the increase in mortality started several years earlier. Chiou et al. (2001) studied a cohort of Taiwanese people who were exposed to arsenic and developed bladder cancer. The latency period for this cancer was estimated to be more than 40 years. Although the data are sparse, they are generally consistent in suggesting that both skin and internal cancers associated with arsenic ingestion have, on average, substantial latency periods, frequently in excess of 20 years from the beginning of exposure. The existing data are insufficiently detailed for a more precise specification of the distribution of latencies. There has been little investigation of the influence of exposure level, duration of exposure, or age at exposure on the latency period for arsenic-induced cancers. Data for

HUMAN HEALTH EFFECTS 65 other carcinogens, however, suggest that dose might not always affect latency period, even though it affects cancer incidence (Armenian 1987~. ESSENTIALITY The question of the essentiality of arsenic was reviewed in the ~ 999 NRC report. At that time, it was concluded that arsenic had not been investigated for essentiality in humans. There have been no new studies since that report identifying a potential need for arsenic in human nutrition. A recent review of dietary reference intakes noted that "[bjecause of the lack of human data to identify a biological role of arsenic in humans, neither an estimated average requirement (EAR), Recommended Dietary Allowances, nor Adequate Intake levels were established" (TOM 2001~. The TOM report made several recom- mendations, including that "the role of arsenic in methyl metabolism and genetic expression requires further study. Necessary for future studies with humans is the identification of a reliable indicator of arsenic status" (IOM 2001~. SUMMARY AND CONCLUSIONS · For many chemicals, health effects must be determined on the basis of animal studies or occupational exposures. In contrast, a large number of general- population epidemiological studies have investigated the noncancer and cancer effects of chronic exposure to arsenic in drinking water. · Since the 1999 NRC report on arsenic in drinking water, additional evidence has emerged linking arsenic consumption in drinking water with two noncancer health conditions that are a major source of morbidity and mortal- ity: hypertension and diabetes mellitus. The recent prevalence study by Rahman et al. (1999) in Bangladesh found a dose-dependent increase in the risk of hypertension that was largely concordant with a prior prevalence study conducted by Chen et al. (1995) in the area of southwestern Taiwan where arsenic is endemic. A prospective cohort study of noninsuTin-dependent dia- betes mellitus (Tseng et al. 2000) in the arsenic endemic area of southwestern Taiwan found a positive association with cumulative arsenic exposure that was generally consistent with the prevalence study by Rahman et al. (1998) in Bangladesh. Although additional studies are needed to assess the dose- response relationship for these end points, it is notable that the arsenic expo-

66 ARSENIC INDRINK[NG WA TER: 2001 UPDA TE sure associated with these substantial noncancer risks in Taiwan and Bangla- desh were within 1 to 2 orders of magnitude of concentrations that are of current regulatory concern (e.g., 20 ,ug/L or below). Few studies ofthe effects of arsenic on reproduction and development had been published at the time of the 1999 NRC report. Since that time, a small number of studies have investigated the relationship between arsenic exposure in humans and adverse reproductive effects, including studies of populations in Chile and Bangladesh exposed to increased concentrations of arsenic in drinking water. There is some evidence from those studies that arsenic increases infant mortality, spontaneous abortions, stillbirths, and preterm births. However, the evidence is not conclusive, because the studies suffer from such limitations as a lack of information on lifestyle and other exposures that could affect reproductive outcomes. Nonetheless, the number of studies investigating whether arsenic might have adverse effects on repro- duction and development is increasing, and there is suggestive evidence of effects on several outcomes. Findings from a large prevalence study in West Bengal, a small preva- lence study in Bangladesh, and an ecological mortality study in the area of southwestern Taiwan where arsenic is endemic add to previous suggestions that arsenic ingestion might be associated with noncancer respiratory effects. The pathology that characterizes these effects has not been defined. · Recent studies from West Bengal, Bangladesh, and Ever Mongolia have examined dose-response relationships between ingestion of arsenic in drinking water and skin lesions. Those studies have reported the presence of arsenic- related skin lesions in some study subjects consuming drinking water with arsenic concentrations of less than 100 ,ug/~; however, the findings might be subject to uncertainties and bias with respect to classification of the expo- sure and the end point. · Two recent small investigations of neuro-cognitive function in young schoolchildren suggest that arsenic exposure might be associated with an adverse effect, but uncertainties regarding the extent ofthe subjects' exposure to arsenic and to other potential confounders, such as lead, limit study inter- pretation. · Since completion of the previous evaluation of arsenic by the NRC ~999), several human-population-based studies have been completed. These studies confirm and extend the observations that were available to the 1999 NRC committee and further contribute to our understanding of dose-response relationships for cancers and arsenic in drinking water.

HUMAN HEALTH EFFECTS 67 Two studies published since the 1999 NRC report (Ferreccio et al.2000; Chiou et al.200 ~ ~ have certain strengths that go beyond the ecological studies of cancer mortality in southwestern Taiwan that served as the primary basis for the previous EPA risk assessment. These two studies evaluated risk fac- tors among newly diagnosed cases (not deaths) of urinary cancer (Chiou et al. 200 ~ ~ or lung cancer (Ferreccio et al.2000~. They incorporated individualized information on long-term arsenic exposure and health outcome. They also gathered and analyzed information on other risk factors, such as smoking habits, from individuals. That information was not available in the previous ecological mortality studies. Although they have limitations related to study size (Chiou et al.2001) or control-selection methods (Ferreccio et al. 2000), these studies represent valuable contributions to the epidemiological database that addresses cancer risk from arsenic in Winking water. As with the data from southwestern Taiwan, the difference between the exposure concentra- tions in these studies and the concentrations of current regulatory concern is relatively small. Therefore, the range of concentrations for which the dose- response curve must be extrapolated is very small. · The findings of mortality in the arsenic endemic area of southwestern Taiwan in the large ecological study of Tsai et al. (1999) indicate that use of the regional and national rates as referents for mortality studies in this region is appropriate and that important confounding is unlikely when these external rates are incorporated in a quantitative risk assessment. · Kurttio et al. (1999) demonstrated increased bladder cancer risks in smokers at very low concentrations of arsenic in drinking water. Because the study was small, the very high risks generated by Kurttio et al. (! 999) are not as concordant as the risks that emerge from the studies in southwestern Tai- wan, northeastern Taiwan, Chile, and Argentina. The possibility exists that the study was distinguished by some unmeasured bias or that the findings occurred by chance. · Several limitations of the study by Lewis et al. (1999a), including issues surrounding the exposure metric and differences between the study population and the control population, preclude its use for hazard evaluation and risk assessment. · The studies by Karagas et al. (2001) and Tucker et al. (2001) con- firmed the association between exposure to arsenic in drinking water and skin cancer. The former study is complicated by the use of an exposure measure (arsenic in toenails) with poorly understood toxicokinetics and significant opportunity for misclassification due to external contamination. The latter .,

68 ARSENICIN DRINKING WATER: 2001 UPDATE study reported few cases and used exposure metrics that were difficult to interpret, limiting its utility for modeling dose-response relationship. Finally, the subcommittee notes that internal cancers are more appropriate as an end point for risk assessment than nonmelanomic skin cancer, because internal cancers are more likely to be life-threatening. · Overall, the data from southwestern Taiwan (Chen et al 1985, 1992; Wu et al. 1989) remain as the preferred data for use in quantitative risk assess- ment. The data from Chiou et al. (2001) and Ferreccio et al. (2000) can be modeled to augment analyses of the southwestern Taiwanese data. From a public-health perspective, the database of epidemiological studies linking arsenic in drinking water with increased risk of skin, bladder, and lung cancer provides a sound and adequate basis for quantitative assessment of cancerrisk. RECOMMENDATIONS Epidemiological studies are highly recommended to investigate the dose-response relationship between arsenic ingestion and the noncancer end points of circulatory system disease (particularly hypertension, cardiovascular disease, and cerebrovascular disease) and diabetes mellitus. Because these end points are common causes of morbidity and mortality, even small poten- tial increases in relative risk at Tow arsenic doses could be of considerable public-health importance. Laboratory and clinical studies should investigate the modes of action of arsenic for these end points. · Epidemiological studies are recommended to further investigate the relationship between arsenic ingestion and adverse reproductive outcomes. · Studies are needed to define the pathological features of a potential link between arsenic ingestion and respiratory function. A possible impact of arsenic exposure on neuro-cognitive development in children requires further investigation. As noted in the 1999 NRC report, the effect of arsenic on im- mune function also merits further study. · There is a need for additional epidemiological research in other popu- lations from other geographic areas. In future epidemiological studies that investigate both cancer and noncancer outcomes of ingestion of arsenic in drinking water, detailed information on exposure should be collected. This information should include water-ingestion rates and intake of food containing arsenic, as well as long-term histories of water sources and arsenic concentra- tions associated with those sources. As was noted in the 1999 NRC report,

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Having safe drinking water is important to all Americans. The Environmental Protection Agency's decision in the summer of 2001 to delay implementing a new, more stringent standard for the maximum allowable level for arsenic in drinking water generated a great deal of criticism and controversy. Ultimately at issue were newer data on arsenic beyond those that had been examined in a 1999 National Research Council report. EPA asked the National Research Council for an evaluation of the new data available.

The committee's analyses and conclusions are presented in Arsenic in Drinking Water: 2001 Update. New epidemiological studies are critically evaluated, as are new experimental data that provide information on how and at what level arsenic in drinking water can lead to cancer. The report's findings are consistent with those of the 1999 report that found high risks of cancer at the previous federal standard of 50 parts per billion. In fact, the new report concludes that men and women who consume water containing 3 parts per billion of arsenic daily have about a 1 in 1,000 increased risk of developing bladder or lung cancer during their lifetime.

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