Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic
Condition: High Blood Arsenic Due to Chronic Arsenic Exposure
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine whether folic acid, alone or together with creatine
      supplementation, can lower blood arsenic concentrations and improve the ability to detoxify
      arsenic.
    

Detailed description: 
      Approximately 140 million people in over 70 countries are chronically exposed to arsenic
      (As)-contaminated drinking water at concentrations far exceeding the World Health
      Organization standard of 10 µg/L. As is a carcinogen known to cause cancers of the skin,
      bladder, and lung, as well as ischemic heart disease and neurologic impairments. Methylation
      of ingested inorganic arsenic (InAs) to methylarsonic-(MMA) and dimethylarsinic acids (DMA)
      relies on folate-dependent one carbon metabolism, utilizing S-adenosylmethionine (SAM) as the
      methyl donor, and facilitates urinary As elimination. The results from our Nutritional
      Influences on Arsenic Toxicity (NIAT) study indicate that folate deficiency and
      hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate arsenic and
      are risk factors for arsenic-induced skin lesions. Furthermore, folic acid (FA)
      supplementation does indeed facilitate As elimination and significantly lowers blood As
      concentrations in individuals who are folate deficient. We have also determined that blood As
      is a good biomarker of As exposure and is directly associated with the risk for As-induced
      skin lesions. Collectively, the implication of these findings is that FA has enormous
      therapeutic potential for ameliorating the long-term health consequences of arsenic exposure
      for the many populations at risk. However, several fundamental questions remain and will be
      addressed in this study. This trial is designed to determine 1) whether FA supplementation
      lowers blood As concentrations in the general Bangladeshi population, 2) at what time point a
      nadir in blood As is achieved, and 3) whether creatine supplementation, alone or in addition
      to 400 µg/d FA, will spare methyl groups, resulting in lower blood As, lower homocysteine
      (Hcys) concentrations, and increased methylation of As. The creatine arms are based on
      multiple studies that show that urinary creatinine concentrations are a very strong predictor
      of As methylation. The final step in creatine biosynthesis is the methylation of
      guanidinoacetate to creatine; this process consumes 50-75% of all SAM-derived methyl groups
      and is also responsible for 50-75% of all Hcys biosynthesis. Thus, this trial will test the
      hypothesis that creatine supplementation, which shuts down endogenous creatine biosynthesis,
      will spare methyl groups, lower Hcys, and increase As methylation.
    

Intervention name(s): Placebo; folic acid; folic acid; creatine; creatine + folic acid
Intervention type(s): Other; Dietary Supplement; Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): daily, 24 weeks; 400 ug/d for 12 or 24 weeks; 800 µg/d for 12 or 24 weeks; 3 mg/d for 12 weeks; 3 mg creatine/d + 400 µg folic acid/d for 12 weeks
Intervention MeSH terms: Folic Acid; Vitamin B Complex
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: arsenic; folate; folic acid; creatine; arsenicosis; nutrition