What was studied in this review?
Arsenic is a common environmental toxin that affects over 140 million people worldwide. Long-term arsenic exposure, through the consumption of arsenic-contaminated drinking water and food, increases the risk of neurotoxicity (damage to the brain or nervous system), skin lesions, birth defects, cancer, and impaired brain development in children. Folic acid may decrease arsenic toxicity by helping to remove arsenic from the body, thus lowering the amount of arsenic in the blood. This review assessed the effect of giving people folic acid through oral supplements, fortified foods, or both, on arsenic-associated health outcomes and arsenic toxicity in adults and children.
What is the aim of the review?
The aim of this review was to determine whether giving folic acid to arsenic-exposed children and adults reduced arsenic toxicity.
Key messages
Folic acid supplementation may reduce blood arsenic concentration, and make it easier to get rid of arsenic through the urine, in arsenic-exposed adults compared to placebo (i.e. dummy pill). This suggests that taking folic acid supplements may reduce arsenic toxicity in arsenic-exposed adults.
What are the main results of the review?
The review authors found two randomised controlled trials (RCT), with 822 adults, conducted in Bangladesh, which assessed the effect of taking folic acid supplements on the concentration of arsenic and homocysteine (a marker of inflammation and folate deficiency) in plasma, blood, and urine. Both RCTs were funded by government programs. One of the RCTs also assessed the effects of folic acid supplements plus another nutrient supplement called creatine. Neither of the studies reported data on cancer, all-cause mortality, neurocognitive function, or congenital anomalies.
The results from these studies suggest that taking folic acid supplements, alone or in combination with other nutrients, might reduce blood arsenic and plasma homocysteine concentrations, and potentially improve urinary arsenic methylation profiles (a measure of arsenic toxicity) in adults who had been exposed to arsenic-contaminated drinking water, compared to placebo.
We judged both RCTs at low risk of bias. We judged the certainty of evidence as moderate for all outcomes included in the comparison of Folic acid supplements alone versus placebo, and low for all outcomes included in the comparison of Folic acid supplements plus other nutrient supplements versus nutrient supplements alone. We downgraded the certainty of the evidence due to the small number of studies. This means that the results may change with further research.
The review highlights the need for more research evaluating the effects of folic acid on arsenic-related health outcomes and arsenic toxicity in adults and children.
How up-to-date is this review?
The review authors searched for studies that had been published up to September 2020.
There is moderate-certainty evidence that FA supplements may benefit blood arsenic concentration, urinary arsenic methylation profiles, and plasma homocysteine concentration versus placebo. There is low-certainty evidence that FA supplements plus other nutrients may benefit blood arsenic and plasma homocysteine concentrations versus nutrients alone. No studies reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies. Given the limited number of RCTs, more studies conducted in diverse settings are needed to assess the effects of FA on arsenic-related health outcomes and arsenic toxicity in arsenic-exposed adults and children.
Arsenic is a common environmental toxin. Exposure to arsenic (particularly its inorganic form) through contaminated food and drinking water is an important public health burden worldwide, and is associated with increased risk of neurotoxicity, congenital anomalies, cancer, and adverse neurodevelopment in children. Arsenic is excreted following methylation reactions, which are mediated by folate. Provision of folate through folic acid supplements could facilitate arsenic methylation and excretion, thereby reducing arsenic toxicity.
To assess the effects of provision of folic acid (through fortified foods or supplements), alone or in combination with other nutrients, in lessening the burden of arsenic-related health outcomes and reducing arsenic toxicity in arsenic-exposed populations.
In September 2020, we searched CENTRAL, MEDLINE, Embase, 10 other international databases, nine regional databases, and two trials registers.
Randomised controlled trials (RCTs) and quasi-RCTs comparing the provision of folic acid (at any dose or duration), alone or in combination with other nutrients or nutrient supplements, with no intervention, placebo, unfortified food, or the same nutrient or supplements without folic acid, in arsenic-exposed populations of all ages and genders.
We used standard methodological procedures expected by Cochrane.
We included two RCTs with 822 adults exposed to arsenic-contaminated drinking water in Bangladesh. The RCTs compared 400 µg/d (FA400) or 800 µg/d (FA800) folic acid supplements, given for 12 or 24 weeks, with placebo. One RCT, a multi-armed trial, compared FA400 plus creatine (3 g/d) to creatine alone.
We judged both RCTs at low risk of bias in all domains. Due to differences in co-intervention, arsenic exposure, and participants' nutritional status, we could not conduct meta-analyses, and therefore, provide a narrative description of the data.
Neither RCT reported on cancer, all-cause mortality, neurocognitive function, or congenital anomalies.
Folic acid supplements alone versus placebo
Blood arsenic. In arsenic-exposed individuals, FA likely reduces blood arsenic concentrations compared to placebo (2 studies, 536 participants; moderate-certainty evidence).
For folate-deficient and folate-replete participants who received arsenic-removal water filters as a co-intervention, FA800 reduced blood arsenic levels more than placebo (percentage change (%change) in geometric mean (GM) FA800 −17.8%, 95% confidence intervals (CI) −25.0 to −9.8; placebo GM −9.5%, 95% CI −16.5 to −1.8; 1 study, 406 participants).
In one study with 130 participants with low baseline plasma folate, FA400 reduced total blood arsenic (%change FA400 mean (M) −13.62%, standard error (SE) ± 2.87; placebo M −2.49%, SE ± 3.25), and monomethylarsonic acid (MMA) concentrations (%change FA400 M −22.24%, SE ± 2.86; placebo M −1.24%, SE ± 3.59) more than placebo. Inorganic arsenic (InAs) concentrations reduced in both groups (%change FA400 M −18.54%, SE ± 3.60; placebo M −10.61%, SE ± 3.38). There was little to no change in dimethylarsinic acid (DMA) in either group.
Urinary arsenic. In arsenic-exposed individuals, FA likely reduces the proportion of total urinary arsenic excreted as InAs (%InAs) and MMA (%MMA) and increases the proportion excreted as DMA (%DMA) to a greater extent than placebo (2 studies, 546 participants; moderate-certainty evidence), suggesting that FA enhances arsenic methylation.
In a mixed folate-deficient and folate-replete population (1 study, 352 participants) receiving arsenic-removal water filters as a co-intervention, groups receiving FA had a greater decrease in %InAs (within-person change FA400 M −0.09%, 95% CI −0.17 to −0.01; FA800 M −0.14%, 95% CI −0.21 to −0.06; placebo M 0.05%, 95% CI 0.00 to 0.10), a greater decrease in %MMA (within-person change FA400 M −1.80%, 95% CI −2.53 to −1.07; FA800 M −2.60%, 95% CI −3.35 to −1.85; placebo M 0.15%, 95% CI −0.37 to 0.68), and a greater increase in %DMA (within-person change FA400 M 3.25%, 95% CI 1.81 to 4.68; FA800 M 4.57%, 95% CI 3.20 to 5.95; placebo M −1.17%, 95% CI −2.18 to −0.17), compared to placebo.
In 194 participants with low baseline plasma folate, FA reduced %InAs (%change FA400 M −0.31%, SE ± 0.04; placebo M −0.13%, SE ± 0.04) and %MMA (%change FA400 M −2.6%, SE ± 0.37; placebo M −0.71%, SE ± 0.43), and increased %DMA (%change FA400 M 5.9%, SE ± 0.82; placebo M 2.14%, SE ± 0.71), more than placebo.
Plasma homocysteine: In arsenic-exposed individuals, FA400 likely reduces homocysteine concentrations to a greater extent than placebo (2 studies, 448 participants; moderate-certainty evidence), in the mixed folate-deficient and folate-replete population receiving arsenic-removal water filters as a co-intervention (%change in GM FA400 −23.4%, 95% CI −27.1 to −19.5; placebo −1.3%, 95% CI −5.3 to 3.1; 1 study, 254 participants), and participants with low baseline plasma folate (within-person change FA400 M −3.06 µmol/L, SE ± 3.51; placebo M −0.05 µmol/L, SE ± 4.31; 1 study, 194 participants).
FA supplements plus other nutrient supplements versus nutrient supplements alone
In arsenic-exposed individuals who received arsenic-removal water filters as a co-intervention, FA400 plus creatine may reduce blood arsenic concentrations more than creatine alone (%change in GM FA400 + creatine −14%, 95% CI −22.2 to −5.0; creatine −7.0%, 95% CI −14.8 to 1.5; 1 study, 204 participants; low-certainty evidence); may not change urinary arsenic methylation indices (FA400 + creatine: %InAs M 13.2%, SE ± 7.0; %MMA M 10.8, SE ± 4.1; %DMA M 76, SE ± 7.8; creatine: %InAs M 14.8, SE ± 5.5; %MMA M 12.8, SE ± 4.0; %DMA M 72.4, SE ±7.6; 1 study, 190 participants; low-certainty evidence); and may reduce homocysteine concentrations to a greater extent (%change in GM FA400 + creatinine −21%, 95% CI −25.2 to −16.4; creatine −4.3%, 95% CI −9.0 to 0.7; 1 study, 204 participants; low-certainty evidence) than creatine alone.