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.

The contamination of groundwater by arsenic in Bangladesh is a major public health concern affecting 35-75 million people. Although it is evident that high levels (>300 microg/L) of arsenic exposure from drinking water are related to adverse health outcomes, health effects of arsenic exposure at low-to-moderate levels (10-300 microg/L) are not well understood. We established the Health Effects of Arsenic Longitudinal Study (HEALS) with more than 20,000 men and women in Araihazar, Bangladesh, to prospectively investigate the health effects of arsenic predominantly at low-to-moderate levels (0.1 to 864 microg/L, mean 99 microg/L) of arsenic exposure. Findings to date suggest adverse effects of low-to-moderate levels of arsenic exposure on the risk of pre-malignant skin lesions, high blood pressure, neurological dysfunctions, and all-cause and chronic disease mortality. In addition, the data also indicate that the risk of skin lesion due to arsenic exposure is modifiable by nutritional factors, such as folate and selenium status, lifestyle factors, including cigarette smoking and body mass index, and genetic polymorphisms in genes related to arsenic metabolism. The analyses of biomarkers for respiratory and cardiovascular functions support that there may be adverse effects of arsenic on these outcomes and call for confirmation in large studies. A unique strength of the HEALS is the availability of outcome data collected prospectively and data on detailed individual-level arsenic exposure estimated using water, blood and repeated urine samples. Future prospective analyses of clinical endpoints and related host susceptibility will enhance our knowledge on the health effects of low-to-moderate levels of arsenic exposure, elucidate disease mechanisms, and give directions for prevention.

We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase ω1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase ω1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1270–8)

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P2,000 individuals, we show for the first time that variants that influence arsenic metabolism can also influence risk for arsenical skin lesions (the classical sign of arsenic toxicity) through interaction with arsenic exposure. Using array-based genome-wide gene expression data, we show that several of our lead genetic variants are associated with expression of AS3MT and neighboring gene C10orf32, providing a potential mechanism by which 10q24.32 variants influence arsenic metabolism and toxicity. Knowledge of variation in this region and associated biological processes could be used to develop intervention and pharmacological strategies aimed at preventing large numbers of arsenic-related deaths in arsenic-exposed populations.

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