Metal Detox Formula

SCIENTIFIC RESEARCH ON THE FOLLOWING INGREDIENTS:

L-Cysteine

Interaction of zinc, methionine or their combination with lead at gastrointestinal or post-absorptive level in rats

Abstract

The ability of zinc, methionine or their combination given by gavage to prevent or treat experimental oral lead intoxication in rats was investigated. Simultaneous oral supplementation with zinc plus methionine was found to be most effective in reducing lead induced inhibition of delta-aminolevulinic acid dehydratase (ALAD) activity in blood, elevation of urinary delta-aminolevulinic acid (ALA) excretion and in enhancing the hepatic glutathione (GSH) contents. The combination was also most effective in reducing the accumulation of lead in blood, liver and kidney compared to zinc or methionine alone. Prevention was more effective than treatment after lead exposure which may be caused by a decrease in the absorption of lead in the gastrointestinal tract in the presence of zinc and/or methionine.

Source: Flora SJ, Kumar D, Das Gupta S. “Interaction of zinc, methionine or their combination with lead at gastrointestinal or post-absorptive level in rats.” Pharmacol Toxicol. (1991);68(1):3-7. 

The Use of N-Acetylcysteine as a Chelator for Metal Toxicity

Abstract

In this chapter, the effects of N-acetylcysteine (NAC) as a chelator of heavy metals are examined. In a systematic review to identify studies, NAC was shown to chelate toxic metals in 33 animal studies. Metals that were removed in these studies included mercury, lead, cadmium, aluminum, arsenic, and gold. Fifteen human studies were identified. These studies reported no significant adverse effects and no effects on essential metals. Metals removed in these human studies included mercury, lead, gold, and arsenic. However, because of the preliminary nature of these studies, the overall rating was C due to limited evidence, although one double-blind placebo-controlled study using NAC in human lead exposure was promising. The use of NAC as a chelator of heavy metals appears to be a promising area of medical research and further clinical studies to verify these preliminary findings are warranted.

Source: Rossignol, D.A. (2019). The Use of N-Acetylcysteine as a Chelator for Metal Toxicity. In: Frye, R., Berk, M. (eds) The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine. Adis, Singapore. 

Ascorbic Acid

The effect of ascorbic acid supplementation on the blood lead levels of smokers

Abstract

Background: The study subjects were 75 adult men (20 to 30 years of age), who smoked one pack of cigarettes per day (minimum) and had no clinical signs of ascorbic acid deficiency or lead toxicity. None had a history of industrial exposure to lead, and the blood-lead levels were anticipated to be below 1.45 micromol/L, the minimum blood level associated with toxicity symptoms.

Methods: The men were randomly assigned to three study groups of 25, and each group was provided a four-week supply of one level of daily ascorbic acid supplements (placebo, 200 mg or 1000 mg of ascorbic acid). We measured baseline and weekly serum and urine ascorbic-acid levels as well as blood and urine lead levels. The weekly group means and variations of the measured data were statistically compared by means of ANOVA and Pearson's correlation.

Results: The serum ascorbic-acid levels of the groups receiving ascorbic acid increased significantly after one week (p< or =.001). There was no effect of placebo or 200 mg ascorbic-acid supplementation on the blood or urine lead levels. However, there was a 81% decrease in blood-lead levels in the 1000 mg ascorbic acid group after one week of supplementation (p< or =.001).

Conclusions: Daily supplementation with 1000 mg of ascorbic acid results in a significant decrease of blood-lead levels associated with the general population. Ascorbic acid supplementation may provide an economical and convenient method of reducing blood-lead levels, possibly by reducing the intestinal absorption of lead.

Source: Dawson EB, Evans DR, Harris WA, Teter MC, McGanity WJ. The effect of ascorbic acid supplementation on the blood lead levels of smokers. J Am Coll Nutr. 1999 Apr;18(2):166-70. 

Reduction of Blood Lead Levels in Battery Workers by Zinc and Vitamin C

Abstract

A group of 39 storage battery workers was evaluated in terms of pertinent biochemical parameters with regard to duration and degree of occupational exposure to lead. Twenty-two of the group had recognized toxic blood lead levels of greater than 60 mcg/100 ml, but fully 31 exceeded the Center for Disease Control's upper limit of normal for erythrocyte protoporphyrin. Other abnormal values found were decreased hemoglobin, increased serum and whole blood copper, increased serum uric acid, decreased serum inorganic phosphate and increased blood spermine, a new lead-related parameter not reported on previously. The severity of lead poisoning among these workers as revealed by blood lead and several other parameters was not related to the duration of exposure (number of years employed), but only to the degree of exposure (job location within the plant). The battery workers were placed on a regimen of vitamin C and zinc. Twenty-two Brain Bio Center, 1225 State Road, Princeton, New Jersey 08540. of the group were followed while on this regimen for a period of 24 weeks. The mean blood lead level for the group dropped from an initial level of 67.6 ± 14.9 mcg/100 ml to 46.0 ± 14.9 mcg/100 ml after 24 weeks. There was also a significant increase in the mean hemoglobin level and a significant decrease in the mean serum and whole blood copper levels with treatment. These changes were striking in view of the fact that they were achieved while the workers were on the job and constantly exposed to high levels of lead. 

Source: Rhoda Papaioannou, M.S., Arthur Sohler, Ph.D., and Carl C. Pfeiffer, Ph.D., M.D. “Reduction of Blood Lead Levels in Battery Workers by Zinc and Vitamin C”

Renal toxicity of heavy metals (cadmium and mercury) and their amelioration with ascorbic acid in rabbits

Abstract

Cadmium and mercury are among the most toxic and dangerous environmental pollutants that may cause fatal implications. Vitamin C is an important chain-breaking antioxidant and enzyme co-factor against heavy metals. The objective of the present study was to evaluate the toxicological effects of cadmium chloride, mercuric chloride, and their co-administration on biochemical parameters of blood serum and metal bioaccumulation in kidneys and also to elucidate the protective effect of vitamin C in rabbits against these metals. In the current research, cadmium chloride (1.5 mg/kg), mercuric chloride(1.2 mg/kg), and vitamin C (150 mg/kg of body weight) were orally administered to eight treatment groups of the rabbits (1, control; 2, vitamin; 3, CdCl2; 4, HgCl2; 5, vitamin + CdCl2; 6, vitamin + HgCl2; 7, CdCl2 + HgCl2, and 8, vitamin + CdCl2 + HgCl2). After the biometric measurements of all experimental rabbits, biochemical parameters viz. creatinine, cystatin C, uric acid, and alkaline phosphatase (ALP) and metal bioaccumulation were determined using commercially available kits and atomic absorption spectrophotometer, respectively. The levels of creatinine (28.3 ± 1.1 μmol/l), cystatin C (1932.5 ± 38.5 ηg/ml), uric acid (4.8 ± 0.1 mg/day), and ALP (51.6 ± 1.1 IU/l) were significantly (P < 0.05) increased due to administration of mercuric chloride but in the presence of vitamin C, the effects of mercuric chloride on creatinine (21.9 ± 1.4 μmol/l), cystatin C (1676.2 ± 42.2 ηg/ml), uric acid (3.9 ± 0.1 mg/day), and ALP (43.3 ± 0.8 IU/l) were less as compared to metal-exposed specimens. Similar results were found in rabbits treated with cadmium chloride and vitamin C and also with co-administration of both metals and vitamin C. Because of the bio-accumulative nature of cadmium chloride and mercuric chloride, these metals were accumulated in kidneys of rabbits, which might lead to deleterious effects. The results of the present study provide an insight into the toxicity of the cadmium chloride, mercuric chloride, and/or their combination on biochemical parameters as well as kidneys of the rabbits and the ameliorating potential of vitamin C against these metals is also evaluated.

Source: Ali S, Hussain S, Khan R, Mumtaz S, Ashraf N, Andleeb S, Shakir HA, Tahir HM, Khan MKA, Ulhaq M. “Renal toxicity of heavy metals (cadmium and mercury) and their amelioration with ascorbic acid in rabbits.” Environ Sci Pollut Res Int. (2019);26(4):3909-3920. 

Interactions of vitamin C with lead and mercury

Abstract

Ascorbic acid has been found to interact with several elements in such a manner as to render them less available for animals. This property of the vitamin has a negative effect on the animals fed a copper-deficient diet, but a positive effect on those fed toxic levels of copper, selenium, vanadium, and cobalt. The effect of ascorbic acid in alleviating cadmium toxicity has been attributed to the effect of the vitamin on iron metabolism, since ferrous iron will also alleviate cadmium toxicity in the Japanese quail. The results of studies reported here indicate that iron will alleviate lead toxicity but ascorbic acid is ineffective. Ascorbic acid will alleviate mercury toxicity, but iron exacerbates this condition. For these two elements, the effects of iron and ascorbic acid are independent of each other.

Source: Hill CH. “Interactions of vitamin C with lead and mercury.” Ann N Y Acad Sci. (1980);355:262-6. 

Alpha-Lipoic Acid

Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats

Abstract

Alpha-lipoic acid (LA) has been reported to be highly effective in improving the thiol capacity of the cells and in reducing lead induced oxidative stress. These results suggested its possible role as a therapeutic intervention of lead poisoning in combination with a chelator. We investigated the effects of LA, either alone or when administered in combination with succimer (meso 2,3-dimercaptosuccinic acid; DMSA or one of its analogue monoisoamyl DMSA), in influencing the lead induced alterations in haem synthesis pathway, hepatic, renal and brain oxidative stress and lead concentration from blood and soft tissues. The results suggest a significant lead induced inhibition of delta-aminolevulinic acid dehydratase (ALAD), reduction in glutathione (GSH) and an increased zinc protoporphyrin (ZPP) level in blood, indicating altered heme synthesis pathway. Both the thiol chelators were able to increase blood ALAD activity and GSH level towards normal. The most prominent effect on blood ALAD activity was however observed when monoisoamyl DMSA (MiADMSA) was co-administered with LA. Lead exposure produced significant depletion of hepatic GSH, while, oxidized glutahione (GSSG), thiobarbituric acid reactive substances (TBARS) and catalase activity increased significantly, suggesting hepatic oxidative stress. All the treatments were able to increase hepatic GSH and reduce GSSG levels, while, TBARS level reduced significantly in animals administered LA and MiADMSA, individually or in combination. Lead induced increase in renal GSSG, TBARS levels and catalase activity, were effectively reduced by LA, while, the two chelators when administered alone were effective only in reducing GSSG and catalase activity. The most prominent beneficial effects, however, were observed in animals treated concomitantly with LA and one of the chelators (DMSA or MiADMSA). Brain GSH and GSSG levels decreased moderately while superoxide dismutase (SOD) activity remained statistically unaltered on lead exposure. Brain catalase activity, on the other hand, increased significantly. Administration of LA was effective in reducing these alterations in the brain, however, the best effects were achieved in animals co-administered LA and one of the thiol chelators. The results point to a significant beneficial role of LA in the recovery of altered biochemical variables both during monotherapy and when given in combination with succimer. It however, showed no chelating properties in decreasing lead burden from blood, liver and kidneys except for a significantly more pronounced decrease in brain lead concentration in animals administered LA plus thiol chelators, compared to the effects of chelating agents alone. This is an interesting and notable observation, which requires further exploration. The results thus provide evidence of an encouraging role of LA when given in combination with a thiol chelator in the therapeutic intervention of lead poisoning, particularly in reducing the oxidative stress and brain lead concentration.

Source: Pande M, Flora SJ. “Lead induced oxidative damage and its response to combined administration of alpha-lipoic acid and succimers in rats.” Toxicology. (2002);177(2-3):187-96. 

Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection

Abstract

Objectives: To determine whether supplementation with alpha-lipoic acid (ALA), a glutathione-replenishing disulfide, modulates whole blood total glutathione (GSH + GSSG) levels and improves lymphocyte function in human immunodeficiency virus (HIV)-infected subjects with history of unresponsiveness to highly active antiretroviral treatment (HAART).

Design and setting: Randomized, double-blinded, placebo-controlled trial conducted at two study sites: an eye clinic at a county hospital in San Jose and a research clinic in San Francisco, California.

Subjects: A total of 33 HIV-infected men and women with viral load >10,000 copies/cm(3), despite HAART, aged 44-47 years, approximately 36% nonwhite, were enrolled.

Intervention: Patients were randomly assigned to receive either ALA (300 mg three times a day) or matching placebo for 6 months.

Main outcome measures: The change over 6 months in blood total glutathione status, lymphocyte proliferation response to T-cell mitogens, CD4 cell count, and viral load in patients receiving ALA compared to placebo.

Results: The mean blood total glutathione level in ALA-supplemented subjects was significantly elevated after 6 months (1.34+/-0.79 vs. 0.81+/-0.18 mmol/L) compared to insignificant change (0.76+/-0.34 vs. 0.76+/-0.22 mmol/L) in the placebo group (ALA vs. placebo: p=0.04). The lymphocyte proliferation response was significantly enhanced or stabilized after 6 months of ALA supplementation compared to progressive decline in the placebo group (ALA vs. placebo: p<0.001 with phytohemagglutinin; p=0.02 with anti-CD3 monoclonal antibody). A positive correlation was seen between blood total glutathione level and lymphocyte response to anti-CD3 stimulation (R(2)=0.889). There was no significant change in either HIV RNA level or CD4 count over 6 months in the ALA-supplemented compared to the control group.

Conclusion: Supplementation with alpha-lipoic acid may positively impact patients with HIV and acquired immune deficiency syndrome by restoring blood total glutathione level and improving functional reactivity of lymphocytes to T-cell mitogens.

Source: Jariwalla RJ, Lalezari J, Cenko D, Mansour SE, Kumar A, Gangapurkar B, Nakamura D. “Restoration of blood total glutathione status and lymphocyte function following alpha-lipoic acid supplementation in patients with HIV infection.” J Altern Complement Med. (2008);14(2):139-46. 

Antioxidant role of alpha-lipoic acid in lead toxicity

Abstract

The assumption of oxidative stress as a mechanism in lead toxicity suggests that antioxidants might play a role in the treatment of lead poisoning. The present study was designed to investigate the efficacy of lipoic acid (LA) in rebalancing the increased prooxidant/antioxidant ratio in lead-exposed Chinese hamster ovary (CHO) cells and Fischer 344 rats. Furthermore, LA's ability to decrease lead levels in the blood and tissues of lead-treated rats was examined. LA administration resulted in a significant improvement in the thiol capacity of cells via increasing glutathione levels and reducing malondialdehyde levels in the lead-exposed cells and animals, indicating a strong antioxidant shift on lead-induced oxidative stress. Furthermore, administration of LA after lead treatment significantly decreased catalase and red blood cell glucose-6-phosphate dehydrogenase activity. In vitro administration of LA to cultures of CHO cells significantly increased cell survival, that was inhibited by lead treatment in a concentration-dependent manner. Administration of LA was not effective in decreasing blood or tissue lead levels compared to a well-known chelator, succimer, that was able to reduce them to control levels. Hence, LA seems to be a good candidate for therapeutic intervention of lead poisoning, in combination with a chelator, rather than as a sole agent.

Source: Gurer H, Ozgunes H, Oztezcan S, Ercal N. “Antioxidant role of alpha-lipoic acid in lead toxicity.” Free Radic Biol Med. (1999);27(1-2):75-81. 

Dietary Strategies for the Treatment of Cadmium and Lead Toxicity

Abstract

Cadmium (Cd) and lead (Pb) are toxic heavy metals that cause adverse health effects in humans and animals. Chelation therapy, the conventional treatment for heavy metal toxicity, is reported to have a number of safety and efficacy issues. Recent studies have shown that dietary supplements play important roles in protecting against Cd and Pb toxicity. This paper reviews the evidence for protective effects of essential metals, vitamins, edible plants, phytochemicals, probiotics and other dietary supplements against Cd and Pb toxicity and describes the proposed possible mechanisms. Based on these findings, dietary strategies are recommended for people at risk of Cd and Pb exposure. The application of these strategies is advantageous for both the prevention and alleviation of Cd and Pb toxicity, as such supplements can be added easily and affordably to the daily diet and are expected to have very few side effects compared to the chelation therapy.

Source: Zhai Q, Narbad A, Chen W. “Dietary strategies for the treatment of cadmium and lead toxicity.” Nutrients. (2015);7(1):552-71. 

Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial Dysfunction in Adolescents with Type 1 Diabetes: A Pilot Trial

Abstract

After evaluating the prevalence of early endothelial dysfunction, as measured by means of reactive hyperemia in adolescents with type 1 diabetes, we started a 6-month, double-blind, randomized trial to test the efficacy of an antioxidant diet (± alpha-lipoic acid supplementation) to improve endothelial dysfunction. Seventy-one children and adolescents, ages 17 ± 3.9 yrs, with type 1 diabetes since 9.5 ± 5.3 yrs, using intensified insulin therapy, were randomized into 3 arms: (a) antioxidant diet 10.000 ORAC + alpha-lipoic acid; (b) antioxidant diet 10.000 ORAC + placebo; (c) controls. BMI, blood pressure, fasting lipid profile, HbA1c, insulin requirement, dietary habits, and body composition were determined in each patient. An antioxidant diet significantly improved endothelial dysfunction when supplemented with alpha-lipoic acid, unlike diet with placebo or controls. A significant reduction in bolus insulin was also observed. We speculate that alpha-lipoic acid might have an antioxidant effect in pediatric diabetes patients by reducing insulin.

Source: Scaramuzza A, Giani E, Redaelli F, Ungheri S, Macedoni M, Giudici V, Bosetti A, Ferrari M, Zuccotti GV. “Alpha-Lipoic Acid and Antioxidant Diet Help to Improve Endothelial Dysfunction in Adolescents with Type 1 Diabetes: A Pilot Trial.” J Diabetes Res. (2015);2015:474561. 

The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials

Abstract

Objective: This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effect of alpha-lipoic acid (ALA) supplementation on glycemic control and lipid profiles among patients with metabolic diseases.

Methods: We searched the following databases till October 2017: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. The relevant data were extracted and assessed for quality of the studies according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I-squared tests (I2). Twenty-four studies were included in the meta-analyses.

Results: The findings of this meta-analysis showed that ALA supplementation among patients with metabolic diseases significantly decreased fasting glucose (SMD -0.54; 95% CI, -0.89, -0.19; P = 0.003), insulin (SMD -1.01; 95% CI, -1.70, -0.31; P = 0.006), homeostasis model assessment of insulin resistance (SMD -0.76; 95% CI, -1.15, -0.36; P < 0.001) and hemoglobin A1c (SMD -1.22; 95% CI, -2.01, -0.44; P = 0.002), triglycerides (SMD -0.58; 95% CI, -1.00, -0.16; P = 0.006), total- (SMD -0.64; 95% CI, -1.01, -0.27; P = 0.001), low density lipoprotein-cholesterol (SMD -0.44; 95% CI, -0.76, -0.11; P = 0.008). We found no detrimental effect of ALA supplementation on high density lipoprotein-cholesterol (HDL-cholesterol) levels (SMD 0.57; 95% CI, -0.14, 1.29; P = 0.11).

Conclusions: Overall, the current meta-analysis demonstrated that ALA administration may lead to an improvement in glucose homeostasis parameters and lipid profiles except HDL-cholesterol levels.

Source: Akbari M, Ostadmohammadi V, Lankarani KB, Tabrizi R, Kolahdooz F, Khatibi SR, Asemi Z. “The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta-analysis of randomized controlled trials.” Metabolism. (2018);87:56-69. 

Folic Acid

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

Abstract

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.

Source: Gamble MV, Liu X, Ahsan H, Pilsner JR, Ilievski V, Slavkovich V, Parvez F, Chen Y, Levy D, Factor-Litvak P, Graziano JH. “Folate and arsenic metabolism: a double-blind, placebo-controlled folic acid-supplementation trial in Bangladesh.” Am J Clin Nutr. (2006);84(5):1093-101. 

Folic acid supplementation lowers blood arsenic

Abstract

Background: Chronic arsenic exposure currently affects >100 million persons worldwide. Methylation of ingested inorganic arsenic (InAs) to monomethylarsonic (MMAs) and dimethylarsinic (DMAs) acids relies on folate-dependent one-carbon metabolism and facilitates urinary arsenic elimination.

Objective: We hypothesized that folic acid supplementation to arsenic-exposed Bangladeshi adults would increase arsenic methylation and thereby lower total blood arsenic.

Design: In this randomized, double-blind, placebo-controlled trial, we evaluated blood concentrations of total arsenic, InAs, MMAs, and DMAs in 130 participants with low plasma folate (<9 nmol/L) before and after 12 wk of supplementation with folic acid (400 μg/d) or placebo.

Results: MMAs in blood was reduced by a mean ± SE of 22.24 ± 2.86% in the folic acid supplementation group and by 1.24 ± 3.59% in the placebe group (P < 0.0001). There was no change in DMAs in blood; DMAs is rapidly excreted in urine as evidenced by an increase in urinary DMAs (P = 0.0099). Total blood arsenic was reduced by 13.62% in the folic acid supplementation group and by 2.49% in the placebo group (P = 0.0199).

Conclusions: Folic acid supplementation to participants with low plasma concentrations of folate lowered blood arsenic concentrations, primarily by decreasing blood MMAs and increasing urinary DMAs. Therapeutic strategies to facilitate arsenic methylation, particularly in populations with folate deficiency or hyperhomocysteinemia or both, may lower blood arsenic concentrations and thereby contribute to the prevention of arsenic-induced illnesses.

Source: Gamble MV, Liu X, Slavkovich V, Pilsner JR, Ilievski V, Factor-Litvak P, Levy D, Alam S, Islam M, Parvez F, Ahsan H, Graziano JH. “Folic acid supplementation lowers blood arsenic.” Am J Clin Nutr. (2007);86(4):1202-9. 

Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults

Abstract

Background: 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.

Objectives: 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.

Search methods: In September 2020, we searched CENTRAL, MEDLINE, Embase, 10 other international databases, nine regional databases, and two trials registers.

Selection criteria: 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.

Data collection and analysis: We used standard methodological procedures expected by Cochrane.

Main results: 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.

Authors' conclusions: 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.

Source: Bae S, Kamynina E, Guetterman HM, Farinola AF, Caudill MA, Berry RJ, Cassano PA, Stover PJ. “Provision of folic acid for reducing arsenic toxicity in arsenic-exposed children and adults.” Cochrane Database Syst Rev. (2021);10(10):CD012649. 

 

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9. https://pubmed.ncbi.nlm.nih.gov/10443922/#:~:text=LA%20administration%20resulted%20in%20a,on%20lead%2Dinduced%20oxidative%20stress
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303853/
11. https://pubmed.ncbi.nlm.nih.gov/26171398/
12. https://pubmed.ncbi.nlm.nih.gov/29990473/
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2046214/
14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2042963/
15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481525/