Exposure to arsenic has long been known to have neurologic consequences in adults, but to date there are no well-controlled studies in children. We report results of a cross-sectional investigation of intellectual function in 201 children 10 years of age whose parents participate in our ongoing prospective cohort study examining health effects of As exposure in 12,000 residents of Araihazar, Bangladesh. Water As and manganese concentrations of tube wells at each child’s home were obtained by surveying all wells in the study region. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children’s intellectual function on tests drawn from the Wechsler Intelligence Scale for Children, version III, was assessed by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead and hemoglobin concentrations. Exposure to As from drinking water was associated with reduced intellectual function after adjustment for sociodemographic covariates and water Mn. Water As was associated with reduced intellectual function, in a dose–response manner, such that children with water As levels > 50 μg/L achieved significantly lower Performance and Full-Scale scores than did children with water As levels < 5.5 μg/L. The association was generally stronger for well-water As than for urinary As.

Exposure to manganese via inhalation has long been known to elicit neurotoxicity in adults, but little is known about possible consequences of exposure via drinking water. In this study, we report results of a cross-sectional investigation of intellectual function in 142 10-year-old children in Araihazar, Bangladesh, who had been consuming tube-well water with an average concentration of 793 μg Mn/L and 3 μg arsenic/L. Children and mothers came to our field clinic, where children received a medical examination in which weight, height, and head circumference were measured. Children’s intellectual function was assessed on tests drawn from the Wechsler Intelligence Scale for Children, version III, by summing weighted items across domains to create Verbal, Performance, and Full-Scale raw scores. Children provided urine specimens for measuring urinary As and creatinine and were asked to provide blood samples for measuring blood lead, As, Mn, and hemoglobin concentrations. After adjustment for sociodemographic covariates, water Mn was associated with reduced Full-Scale, Performance, and Verbal raw scores, in a dose–response fashion; the low level of As in water had no effect. In the United States, roughly 6% of domestic household wells have Mn concentrations that exceed 300 μg Mn/L, the current U.S. Environmental Protection Agency lifetime health advisory level. We conclude that in both Bangladesh and the United States, some children are at risk for Mn-induced neurotoxicity.

Summary Background Millions of people worldwide are chronically exposed to arsenic through drinking water, including 35–77 million people in Bangladesh. The association between arsenic exposure and mortality rate has not been prospectively investigated by use of individual-level data. We therefore prospectively assessed whether chronic and recent changes in arsenic exposure are associated with all-cause and chronic-disease mortalities in a Bangladeshi population. Methods In the prospective cohort Health Effects of Arsenic Longitudinal Study (HEALS), trained physicians unaware of arsenic exposure interviewed in person and clinically assessed 11 746 population-based participants (aged 18–75 years) from Araihazar, Bangladesh. Participants were recruited from October, 2000, to May, 2002, and followed-up biennially. Data for mortality rates were available throughout February, 2009. We used Cox proportional hazards model to estimate hazard ratios (HRs) of mortality, with adjustment for potential confounders, at different doses of arsenic exposure. Findings 407 deaths were ascertained between October, 2000, and February, 2009. Multivariate adjusted HRs for all-cause mortality in a comparison of arsenic at concentrations of 10·1–50·0 μg/L, 50·1–150·0 μg/L, and 150·1–864·0 μg/L with at least 10·0 μg/L in well water were 1·34 (95% CI 0·99–1·82), 1·09 (0·81–1·47), and 1·68 (1·26–2·23), respectively. Results were similar with daily arsenic dose and total arsenic concentration in urine. Recent change in exposure, measurement of total arsenic concentrations in urine repeated biennially, did not have much effect on the mortality rate. Interpretation Chronic arsenic exposure through drinking water was associated with an increase in the mortality rate. Follow-up data from this cohort will be used to assess the long-term effects of arsenic exposure and how they might be affected by changes in exposure. However, solutions and resources are urgently needed to mitigate the resulting health effects of arsenic exposure. Funding US National Institutes of Health.

Health Effects of Arsenic Longitudinal Study (HEALS), a multidisciplinary and large prospective cohort study in Araihazar, Bangladesh, was established to evaluate the effects of full-dose range arsenic (As) exposure on various health outcomes, including premalignant and malignant skin tumors, total mortality, pregnancy outcomes, and children's cognitive development. In this paper, we provide descriptions of the study methods including study design, study population, data collection, response rates, and exposure and outcome assessments. We also present characteristics of the study participants including the distribution of exposure and the prevalence of skin lesion at baseline recruitment. A total of 11,746 married men and women between 18 and 75 years of age participated in the study at baseline (a response rate of 98%) and completed a full questionnaire interview that included a food frequency questionnaire, with a response rate of 98%. Among the 98% of the participants who completed the clinical evaluation, over 90% provided blood samples and spot urine samples. Higher educational status, male gender, and presence of premalignant skin lesions were associated with an increased likelihood of providing blood and urine samples. Older participants were less likely to donate a blood sample. About one-third of the participants consumed water from a well with As concentration in each of three groups: >100 microg/l, 25-100 microg/l, and <25 microg/l. Average urinary As concentrations were 140 and 136 microg/l for males and females, respectively. HEALS has several unique features, including a prospective study design, comprehensive assessments of both past and future changes in As exposure at the individual level, a large repository of biological samples, and a full dose range of As exposures in the study population. HEALS is a valuable resource for examining novel research questions on the health effects of As exposure.

Objective To evaluate the association between arsenic exposure and mortality from cardiovascular disease and to assess whether cigarette smoking influences the association.Design Prospective cohort study with arsenic exposure measured in drinking water from wells and urine.Setting General population in Araihazar, Bangladesh.Participants 11 746 men and women who provided urine samples in 2000 and were followed up for an average of 6.6 years.Main outcome measure Death from cardiovascular disease.Results 198 people died from diseases of circulatory system, accounting for 43% of total mortality in the population. The mortality rate for cardiovascular disease was 214.3 per 100 000 person years in people drinking water containing <12.0 µg/L arsenic, compared with 271.1 per 100 000 person years in people drinking water with ≥12.0 µg/L arsenic. There was a dose-response relation between exposure to arsenic in well water assessed at baseline and mortality from ischaemic heart disease and other heart disease; the hazard ratios in increasing quarters of arsenic concentration in well water (0.1-12.0, 12.1-62.0, 62.1-148.0, and 148.1-864.0 µg/L) were 1.00 (reference), 1.22 (0.65 to 2.32), 1.35 (0.71 to 2.57), and 1.92 (1.07 to 3.43) (P=0.0019 for trend), respectively, after adjustment for potential confounders including age, sex, smoking status, educational attainment, body mass index (BMI), and changes in urinary arsenic concentration since baseline. Similar associations were observed when baseline total urinary arsenic was used as the exposure variable and for mortality from ischaemic heart disease specifically. The data indicate a significant synergistic interaction between arsenic exposure and cigarette smoking in mortality from ischaemic heart disease and other heart disease. In particular, the hazard ratio for the joint effect of a moderate level of arsenic exposure (middle third of well arsenic concentration 25.3-114.0 µg/L, mean 63.5 µg/L) and cigarette smoking on mortality from heart disease was greater than the sum of the hazard ratios associated with their individual effect (relative excess risk for interaction 1.56, 0.05 to 3.14; P=0.010). Conclusions Exposure to arsenic in drinking water is adversely associated with mortality from heart disease, especially among smokers.

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Millions of persons around the world are exposed to low doses of arsenic through drinking water. However, estimates of health effects associated with low-dose arsenic exposure have been extrapolated from high-dose studies. In Bangladesh, many persons have been exposed to a wide range of doses of arsenic from drinking water over a significant period of time. The authors evaluated dose-response relations between arsenic exposure from drinking water and premalignant skin lesions by using baseline data on 11,746 participants recruited in 2000-2002 for the Health Effects of Arsenic Longitudinal Study in Araihazar, Bangladesh. Several measures of arsenic exposure were estimated for each participant based on well-water arsenic concentration and usage pattern of the wells and on urinary arsenic concentration. In different regression models, consistent dose-response effects were observed for all arsenic exposure measures. Compared with drinking water containing <8.1 microg/liter of arsenic, drinking water containing 8.1-40.0, 40.1-91.0, 91.1-175.0, and 175.1-864.0 microg/liter of arsenic was associated with adjusted prevalence odds ratios of skin lesions of 1.91 (95% confidence interval (CI): 1.26, 2.89), 3.03 (95% CI: 2.05, 4.50), 3.71 (95% CI: 2.53, 5.44), and 5.39 (95% CI: 3.69, 7.86), respectively. The effect seemed to be influenced by gender, age, and body mass index. These findings provide information that should be considered in future research and policy decisions.

Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = −0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = −0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = −0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = −0.45 for males, p < 0.0001; −0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.