Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid–supplementation trial in Bangladesh

Mary V Gamble, Xinhua Liu, Habibul Ahsan, J Richard Pilsner, Vesna Ilievski, Vesna Slavkovich, Faruque Parvez, Yu Chen, Diane Levy, Pam Factor-Litvak and Joseph H Graziano

Background: Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic-contaminated drinking water. To various degrees, ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes. Consequently, folate nutritional status may influence arsenic methylation and toxicity.

Objective: The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation.

Design: Two hundred adults in a rural region of Bangladesh, previously found to have low plasma concentrations of folate (≤9 nmol/L) were enrolled in a randomized, double-blind, placebo-controlled folic acid–supplementation trial. Plasma concentrations of folate and homocysteine and urinary concentrations of arsenic metabolites were analyzed at baseline and after 12 wk of supplementation with folic acid at a dose of 400 µg/d or placebo.

Results: The increase in the proportion of total urinary arsenic excreted as DMA in the folic acid group (72% before and 79% after supplementation) was significantly (P < 0.0001) greater than that in the placebo group, as was the reduction in the proportions of total urinary arsenic excreted as MMA (13% and 10%, respectively; P < 0.0001) and as InAs (15% and 11%, respectively; P < 0.001).

Conclusions: These data indicate that folic acid supplementation to participants with low plasma folate enhances arsenic methylation. Because persons whose urine contains low proportions of DMA and high proportions of MMA and InAs have been reported to be at greater risk of skin and bladder cancers and peripheral vascular disease, these results suggest that folic acid supplementation may reduce the risk of arsenic-related health outcomes.