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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

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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-

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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=

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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

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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~.

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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 (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-

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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 OCR for page 24
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

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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.

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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

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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

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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

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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-

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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.

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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 .,

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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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HUMANHEALTHEFFECTS 69 data related to latency and the relationship between magnitude of dose and time course of exposure should be obtained. Future studies should consider interactions with host factors that might influence susceptibility to the adverse effects of arsenic exposure, in- cluding age at exposure, dietary status, smoking, and genetic polymorphisms that could affect arsenic metabolism. Epidemiological studies should be designed to be of sufficient size to determine risk in subpopulations that might be susceptible to the adverse effects of arsenic and to quantify the extent of interaction with host factors. Data from additional follow-up of exposed populations, including populations in Utah, Chile, Bangladesh and West Bengal, should be consid- ered, as appropriate, in future risk assessments. Explonng different dose metrics in further analyses of the data Mom Utah is also warranted. REFERENCES Ahmad, S., W.L. Anderson, and K.T. Kitchin. 1999. Dimethylarsinic acid effects on DNA damage and oxidative stress related biochemical parameters in B6C3F1 mice. Cancer Lett. 139~2~: 129- 135. Ahmad, S., M.H. Sayed, S. Barua, M.H. Khan, M.H. Faruquee, A. Jalil, S.A. Hadi, and H.K. Talukder. 2001. Arsenic in drinking water and pregnancy outcomes. Environ. Health Perspect. 109~6~:629-631. Ahsan, H., M. Perrin, A. Rahman, F. Parvez, M. Stute, Y. Zheng, A.H. Milton, P. Brandt-Rauf, A. van Geen, and J. Graziano. 2000. Associations between drink- ing water and urinary arsenic levels and skin lesions in Bangladesh. J. Occup. Environ. Med. 42~12~:1195-1201. Armenian, H.K.. 1987. Incubation periods of cancer: old and new. J. Chronic Dis. 40 (suppl. 2~:9S-1SS. Bates, M.N., A.H. Smith, and K.P. Cantor. 1995. Case-control study of bladder cancer and arsenic in ~ng water. Am. J. Epidemiol. 141~6~:523-530. Boonchai, W., A. Green, J. Ng, A. Dicker, and G. Chenevix-Trench. 2000. Basal cell carcinoma in chronic arsenicism occurring in Queensland, Australia, after inges- tion of an asthma medication. J. Am. Acad. Dermatol. 43~4~:664-669. Buchet, J.P., and D. Lison.1998. Mortality by cancer in groups ofthe Belgian popu- lation with a moderately increased intake of arsenic. Int. Arch. Occup. Environ. Health 71~2~:125-130. Calderon, J., M.E. Nava~ro, M.E. Jimenez-Capdeville, M.A. Santos-Diaz, A. Golden, I. Rodriguez-Leyva, V. BorJa-Aburto, and F. Diaz-Barriga. 2001. Exposure to arsenic and lead and neuropsychological development in Mexican children. - Environ. Res. 85~2~:69-76.

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