BACKGROUND:Chronic arsenic exposure is a public health concern in many parts of the world, with elevated concentrations in groundwater posing a threat to millions of people. Arsenic is associated with various cancers and an array of chronic diseases; however, the relationship with adverse pregnancy outcomes and child mortality is less established.OBJECTIVES:We evaluated associations between individual-level prenatal arsenic exposure with adverse pregnancy outcomes and child mortality in a pregnancy study among 498 women nested in a larger population-based cohort in rural Bangladesh.METHODS:Creatinine-adjusted urinary total arsenic concentration, a comprehensive measure of exposure from water, food, and air sources, reflective of the prenatal period was available for participants. Self-reported pregnancy outcomes (livebirth, stillbirth, spontaneous/elective abortion) were ascertained. Generalized estimating equations, accounting for multiple pregnancies of participants, were used to estimate odds ratios and 95% confidence intervals in relation to adverse pregnancy outcomes. Vital status of livebirths was subsequently ascertained through November 2015. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals in relation to child mortality.RESULTS:We observed a significant association between prenatal arsenic exposure and the risk of stillbirth (greater than median; adjusted OR = 2.50; 95% CI = 1.04, 6.01). We also observed elevated risk of child mortality (greater than median; adjusted HR = 1.92; 95% CI = 0.78, 4.68) in relation to prenatal arsenic exposure.CONCLUSIONS:Prospective studies should continue to evaluate prenatal and early life health effects of arsenic exposure and arsenic remediation strategies for women of child-bearing age.

1511 Background: Selenium and vitamin E supplementation previously have shown some evidence of a beneficial effect in the secondary prevention of non-melanoma skin cancer (NMSC). More than 100 million people worldwide are at increased risk of NMSC and other cancers due to arsenic exposure from drinking water and diet – a risk that persists for several decades even after the exposure has terminated. Here, we report on the design, methods and main results of the Bangladesh Vitamin E and Selenium Trial (BEST) – a population-based chemoprevention study conducted among 7,000 adults with visible arsenic toxicity. Methods: BEST is a 2 × 2 full factorial, double-blind, randomized placebo controlled trial of 7,000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of NMSC incidence. Results: Excellent compliance was maintained through the course of the trial, based on data from pill counts, self-reported compliance, and bioadherence. Among participants on treatment through the end of the 6-year intervention period, > 85% were adherent to at least 80% of study supplements. More than 500 new NMSC cases were ascertained using a three-tiered biopsy protocol. No significant beneficial effects were observed on NMSC incidence during the study period for selenium or vitamin E. Among more than 500 observed deaths (including 182 cancer-related deaths), there were also no significant treatment effects on total mortality, cancer-related mortality or arsenical cancer-related mortality. Conclusions: This large population-based trial does not support any beneficial effect of vitamin E or selenium supplementation for the primary prevention of NMSC or mortality in an arsenic-exposed population. With the rapidly increasing burden of preventable cancers in low- and middle-income countries, efficient and feasible chemoprevention study designs and approaches, such as employed in Bangladesh, may prove impactful in conceiving large scale cancer chemoprevention trials in low-resource settings. Clinical trial information: NCT00392561.

BACKGROUND:Arsenic exposure through drinking water is a serious global health issue. Observational studies suggest that individuals who metabolize arsenic efficiently are at lower risk for toxicities such as arsenical skin lesions. Using two single nucleotide polymorphisms(SNPs) in the 10q24.32 region (near AS3MT) that show independent associations with metabolism efficiency, Mendelian randomization can be used to assess whether the association between metabolism efficiency and skin lesions is likely to be causal.METHODS:Using data on 2060 arsenic-exposed Bangladeshi individuals, we estimated associations for two 10q24.32 SNPs with relative concentrations of three urinary arsenic species (representing metabolism efficiency): inorganic arsenic (iAs), monomethylarsonic acid(MMA) and dimethylarsinic acid (DMA). SNP-based predictions of iAs%, MMA% and DMA% were tested for association with skin lesion status among 2483 cases and 2857 controls.RESULTS:Causal odds ratios for skin lesions were 0.90 (95% confidence interval[CI]: 0.87, 0.95), 1.19 (CI: 1.10, 1.28) and 1.23 (CI: 1.12, 1.36)for a one standard deviation increase in DMA%, MMA% and iAs%,respectively. We demonstrated genotype-arsenic interaction, with metabolism-related variants showing stronger associations with skin lesion risk among individuals with high arsenic exposure (synergy index: 1.37; CI: 1.11, 1.62).CONCLUSIONS:We provide strong evidence for a causal relationship between arsenic metabolism efficiency and skin lesion risk. Mendelian randomization can be used to assess the causal role of arsenic exposure and metabolism in a wide array of health conditions.exposure and metabolism in a wide array of health conditions.Developing interventions that increase arsenic metabolism efficiency are likely to reduce the impact of arsenic exposure on health.

Background Epidemiologic research suggests that increased cancer risk due to chronic arsenic exposure persists for several decades even after the exposure has terminated. Observational studies suggest that antioxidants exert a protective effect on arsenical skin lesions and cancers among those chronically exposed to arsenic through drinking water. This study reports on the design, methods and baseline analyses from the Bangladesh Vitamin E and Selenium Trial (BEST), a population-based chemoprevention study conducted among adults in Bangladesh with visible arsenic toxicity. Materials and methods Bangladesh Vitamin E and Selenium Trial is a 2x2 full factorial, double-blind, randomized controlled trial of 7000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100mg daily) and L-selenomethionine (200g daily) for the prevention of nonmelanoma skin cancer. Results In cross-sectional analyses, we observed significant associations of skin lesion severity with male gender (female prevalence odds ratio (POR)=0 center dot 87; 95% CI=0 center dot 790 center dot 96), older age (aged 3645years, POR=1 center dot 27; 95% CI=1 center dot 131 center dot 42; aged 4655years, POR=1 center dot 44; 95% CI=1 center dot 271 center dot 64 and aged 5665years, POR=1 center dot 50; 95% CI=1 center dot 261 center dot 78 compared with aged 2535years), hypertension (POR=1 center dot 29; 95% CI=1 center dot 081 center dot 55), diabetes (POR=2 center dot 13; 95% CI=1 center dot 323 center dot 46), asthma (POR=1 center dot 55; 95% CI=1 center dot 032 center dot 32) and peptic ulcer disease (POR=1 center dot 20; 95% CI=1 center dot 071 center dot 35). Conclusions We report novel associations between arsenical skin lesions with several common chronic diseases. With the rapidly increasing burden of preventable cancers in developing countries, efficient and feasible chemoprevention study designs and approaches, such as employed in BEST, may prove both timely and potentially beneficial in conceiving cancer chemoprevention trials in Bangladesh and beyond.