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• W4382932217 abstract "Vol. 131, No. 7 Science SelectionOpen AccessFACT Finding: Folic Acid Supplementation May Lower Risk from Arsenic in Drinking Wateris accompanied byThe Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population Wendee Nicole Wendee Nicole Search for more papers by this author Published:3 July 2023CID: 074001https://doi.org/10.1289/EHP13153AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit AbstractChronic exposure to arsenic affects human skin, brain, heart, and lungs, and the endocrine and other systems.1 Arsenic is endemic to the groundwater of countries throughout the world, including many in Southeast Asia where access to other sources of clean water is limited.2 In Bangladesh alone, tens of millions of people are estimated to drink and cook with water containing more than 10 micrograms per liter10μg/L arsenic,2,3 the World Health Organization guideline.4 Research on folic acid and creatine, its amino acid derivative, has suggested that dietary supplementation with one or both may reduce arsenic’s toxicity, potentially decreasing human disease risk.5 A study recently published in Environmental Health Perspectives6 took this research to the next level, monitoring blood levels after supplementation with the compounds.Arsenic occurs naturally in groundwater across the world. In Bangladesh, tens of millions of people are estimated to drink and cook with water containing arsenic levels above the World Health Organization guideline.2,3 Folic acid supplementation shows promise for reducing toxicity of ingested arsenic, according to the new study. Image: © Mufti Munir/AFP via Getty Images.As the body metabolizes inorganic As (InAs), it is methylated first to monomethyl-arsenical (MMAs) species—the most cyto- and genotoxic species7—and then to dimethyl-arsenical (DMAs) species. Because the latter are more readily excreted, full methylation to DMAs generally reduces arsenic toxicity.8 A key nutrient in the pathway that generates methyl groups for these reactions is folate.9The new study reports on the Folic Acid and Creatine Trial (FACT), which included 622 male and female participants 20–65 years of age who drank well water containing more than 50 micrograms per liter50μg/L arsenic. The participants were randomly recruited from the Health Effects of Arsenic Longitudinal Study (HEALS),10 a prospective cohort from Araihazar, Bangladesh. In previous work with FACT participants, researchers found that supplementation with folic acid, creatine, or both increased methylation of arsenic. They reported decreased proportions of urinary InAs and MMAs, and increased proportions of urinary DMAs, compared to placebo. Furthermore, folic acid supplementation lowered participants’ total blood arsenic concentrations by an average of 12%.5In the new study, all participants were given arsenic removal filters for their drinking and cooking water and were randomly assigned to one of five treatment groups. For the first 12 weeks, individuals received either 400 micrograms400 μg folic acid, 800 micrograms800 μg folic acid, 3 grams3g creatine, a combination of 3 grams3g creatine and 400 micrograms400 μg folic acid, or placebo. During the second 12 weeks, half the participants in the two folic acid groups were switched to placebo to see if the effects reversed, and all participants in the other three groups received placebo.Compared with those in the placebo group, participants taking folic acid showed greater increases in blood DMAs concentrations, and those receiving any supplement had greater decreases in blood MMAs concentrations after 12 weeks. Blood DMAs levels declined among participants who were switched to placebo during the second 12-week period, compared with those who continued folic acid, indicating that benefits of folic acid may reverse soon after its cessation.“Our findings provide evidence nutritional interventions may decrease toxicity and increase excretion of arsenic,” says senior author Mary Gamble, a professor of environmental health sciences at Columbia University. “This has important public health implications, particularly in countries without food fortification programs where arsenic exposure and folate deficiency are both common.”Gamble notes the lack of strong associations between creatine supplementation and increased methylation of arsenic, which supports a finding from earlier work.5 “Although some positive shifts in arsenic methylation following creatine supplementation were observed, the treatment effects were far less than those of folic acid supplementation,” she states.Robert Wright, Ethel H. Wise chair of environmental medicine and public health at the Mount Sinai Icahn School of Medicine, who was not involved in the research, highlights the rarity of randomized controlled trials in public health, given that they require so many participants to show that an intervention prevented an illness. Although higher levels of DMAs are not a health outcome, he says, “the authors found a clever way to make such a study more feasible by showing that folic acid supplementation reduced the levels of MMAs through promoting InAs methylation. Since MMAs is more toxic than DMAs, it follows that risk is reduced.”The next step, Wright continues, might be implementation research looking at how to supplement or fortify foods. This would require researchers to partner with local experts to design a feasible, culturally appropriate approach.Rebecca Fry, Carol Remmer Angle Distinguished Professor at the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill, was impressed by the study. “Gamble and team have performed an exciting, solution-oriented study showing that folic acid lowers the levels of the toxic arsenic metabolites in blood,” she notes. “These metabolites are strong indicators of population susceptibility to arsenic-induced disease.” Fry was not involved in the study.Although further research both in other populations and to evaluate changes in long-term health risks is needed, the study adds to the evidence that folic acid supplementation can mitigate effects of arsenic contamination if done in a sustained manner, such as by fortifying foods. Gamble emphasizes that, despite the promise offered by these results, “arsenic-remediation programs aimed at reducing exposure to arsenic-contaminated drinking water should always remain the top priority.”Wendee Nicole is an award-winning science writer based in San Diego. Her work has appeared in Nature, Scientific American, and other publications.References1. Naujokas MF, Anderson B, Ahsan H, Aposhian HV, Graziano JH, Thompson C, et al.2013. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem. Environ Health Perspect 121(3):295–302, PMID: 23458756, 10.1289/ehp.1205875. Link, Google Scholar2. Podgorski J, Berg M. 2020. Global threat of arsenic in groundwater. Science 368(6493):845–850, PMID: 32439786, 10.1126/science.aba1510. Crossref, Medline, Google Scholar3. Uppal JS, Zheng Q, Le XC. 2019. Arsenic in drinking water—recent examples and updates from Southeast Asia. Curr Opin Environ Sci Health 7:126–135, 10.1016/j.coesh.2019.01.004. Crossref, Google Scholar4. World Health Organization. 2022. Guidelines for Drinking-Water Quality: Fourth Edition Incorporating the First and Second Addenda. https://www.who.int/publications-detail-redirect/9789240045064 [accessed 27 June 2023]. Google Scholar5. Peters BA, Hall MN, Liu X, Parvez F, Sanchez TR, van Geen A, et al.2015. Folic acid and creatine as therapeutic approaches to lower blood arsenic: a randomized controlled trial. Environ Health Perspect 123(12):1294–1301, PMID: 25978852, 10.1289/ehp.1409396. Link, Google Scholar6. Abuawad AK, Bozack AK, Navas-Acien A, Goldsmith J, Liu X, Hall MN, et al.2023. The Folic Acid and Creatine Trial: treatment effects of supplementation on arsenic methylation indices and metabolite concentrations in blood in a Bangladeshi population. Environ Health Perspect 131(3):037015, PMID: 36976258, 10.1289/EHP11270. Link, Google Scholar7. Moe B, Peng H, Lu X, Chen B, Chen LWL, Gabos S, et al.2016. Comparative cytotoxicity of fourteen trivalent and pentavalent arsenic species determined using real-time cell sensing. J Environ Sci (China) 49:113–124, PMID: 28007166, 10.1016/j.jes.2016.10.004. Crossref, Medline, Google Scholar8. Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V, Factor-Litvak P, et al.2007. Folic acid supplementation lowers blood arsenic. Am J Clin Nutr 86(4):1202–1209, PMID: 17921403, 10.1093/ajcn/86.4.1202. Crossref, Medline, Google Scholar9. Gamble MV, Liu X, Ahsan H, Pilsner R, Ilievski V, Slavkovich V, et al.2005. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect 113(12):1683–1688, PMID: 16330347, 10.1289/ehp.8084. Link, Google Scholar10. Ahsan H, Chen Y, Parvez F, Argos M, Hussain AI, Momotaj H, et al.2006. Health Effects of Arsenic Longitudinal Study (HEALS): description of a multidisciplinary epidemiologic investigation. J Expo Sci Environ Epidemiol 16(2):191–205, PMID: 16160703, 10.1038/sj.jea.7500449. Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsRelated articlesThe Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population28 March 2023Environmental Health Perspectives Vol. 131, No. 7 July 2023Metrics About Article Metrics Publication History Manuscript received12 April 2023Manuscript accepted30 May 2023Originally published3 July 2023 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days." @default.
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