Metabolism Of Inorganic Arsenic Research Articles

Metabolism of Inorganic Arsenic in Children with Chronic High Arsenic Exposure in Northern Argentina

This study concerns the metabolism of inorganic arsenic (As) in children in three villages in northern Argentina: San Antonio de los Cobres and Taco Pozo, each with about 200 microg As/l in the drinking water, and Rosario de Lerma, with 0.65 microg As/l. Findings show that the concentrations of As in the blood and urine of the children in the two As-rich villages were on average 9 and 380 microg/l, respectively, the highest ever recorded for children. The concentrations were about 10 and 30 times higher for blood and urine, respectively, than in Rosario de Lerma. Total As in urine was only slightly higher than the sum of metabolites of inorganic As (U-Asmet), i.e., inorganic As, methylarsonic acid (MMA), and dimethylarsinic acid (DMA); this shows that inorganic As was the main form of As ingested. In contrast to previous studies on urinary metabolites of inorganic As in various population groups, the children and women in the present study excreted very little MMA. Thus, there seems to be a polymorphism for the enzymes (methyltransferases) involved in the methylation of As. Interestingly, the children had a significantly higher percentage of inorganic As in urine than the women, about 50% versus 32%. Also, the percentage of inorganic As in the children is considerably higher than in previous studies on children (about 13% in the two studies available) and adults (about 15-25%) in other population groups. This may indicate that children are more sensitive to As-induced toxicity than adults, as the methylated metabolites bind less to tissue constituents than inorganic As. In the children, the percentage inorganic arsenic in urine decreased, and the percentage of DMA increased with increasing U-Asmet, indicating an induction of As methylation with increasing exposure.

Arsenic: exposure and health effects

The value of research on health effects of ingested inorganic arsenic. Human oral exposure to inorganic arsenic. Nationwide and California arsenic occurrence studies. Dietary intake and hazards of arsenic. Determination of total arsenic and arsenic compounds in drinking water. Sources and pathways of arsenic in Southwest England: health implications. Exposure assessment for arsenic concentrations from electric power stations. Ischemic heart disease induced by ingested inorganic arsenic. Urinary excretion of arsenic species in a human population chronically exposed to arsenic via drinking water: a pilot study. Long-term follow-up of patients treated with medicinal arsenic. Epidemiological study designs to address potential high bladder cancer risks from arsenic in drinking water. Arsenic in drinking water and urinary cancers. Arsenic in drinking water and cancers: a brief descriptive review of Taiwan studies. Review of health assessments for US/Canada populations exposed to arsenic in drinking water. Assessment of the dose response for internal cancers and arsenic in drinking water in the blackfoot disease endemic region of Taiwan. Species differences in the metabolism of arsenic. Inorganic arsenic metabolism in humans. Genotoxicity of arsenic and its methylated metabolites. Arsenic essentiality studies and factors affecting its importance. A physiologically based pharmacokinetic model for ingested arsenic. Overview of a physiologically based pharmacokinetic model for the four major arsenic species in mammals. Water utility regulatory and research projects on arsenic. The use of site-specific studies to assess arsenic health risk at superfund site. The process for setting drinking water regulations under the Safe Drinking Water Act. Arsenic in the Canadian general environment: evaluation of risks to health. Impacts of a stringent arsenic drinking water regulation on the western USA. Arsenic in drinking water: health effects and regulatory issues in California. Regulating arsenic in Nevada drinking water supplies: past problems, future challenges. The water utility perspective on arsenic regulation. Derivation of the inorganic arsenic reference dose. Arsenic and human health: some persisting scientific issues.

A unique metabolism of inorganic arsenic in native Andean women

A unique metabolism of inorganic arsenic in native Andean women

A unique metabolism of inorganic arsenic in native Andean women

The metabolism of inorganic arsenic (As) in native women in four Andean villages in north-western Argentina with elevated levels of As in the drinking water (2.5, 14, 31, and 200 μg/l, respectively) has been investigated. Collected foods contained 9–427 μg As/kg wet weight, with the highest concentrations in soup. Total As concentrations in blood were markedly elevated (median 7.6 μg/l) only in the village with the highest concentration in the drinking water. Group median concentrations of metabolites of inorganic As (inorganic As, methylarsonic acid (MMA) and dimethylarsinic acid (DMA) in the urine varied between 14 and 256 μg/l. Urinary concentrations of total As were only slightly higher (18–258 μg/l), indicating that inorganic As was the main form of As ingested. In contrast to all other populations studied so far, arsenic was excreted in the urine mainly as inorganic As and DMA. There was very little MMA in the urine (overall median 2.2%, range 0.0–11%), which should be compared to 10–20% of the urinary arsenic in all other populations studied. This may indicate the existence of genetic polymorphism in the control of the methyltransferase activity involved in the methylation of As. Furthermore, the percentage of DMA in the urine was significantly higher in the village with 200 μg As/l in the water, indicating an induction of the formation of DMA. Such an effect has not been observed in other studies on human subjects with elevated exposure to arsenic.

Liver and intestinal propoxyphene metabolisms: An example of discreprancy in drug pre-systemic biotransformation in the rat: [formula omitted] Dept. of Gastroenterology, Experimental Surgery and Pharmacotherapy Laboratories, Catholic University of Louvain, Brussels

Previous studies have shown that several factors may influence the methylation of inorganic arsenic by rat liver in vitro (Buchet and Lauwerys, 1985). The present study attempts to assess the relevance of these observations in vivo. Like man, rat inactivates inorganic arsenic by methylation to monomethylarsoni (MMA) and dimethylarsinic (DMA) acids which are excreted in urine along with unchanged inorganic arsenic (Asi). The administration of S-adenosylmethionine alone or in association with reduced (GSH) or oxidized glutathione or acetylcysteine and the increase of hepatic GSH level by butylated hydroxytoluene pretreatment do not stimulate the urinary excretion of the methylated arsenic metabolites following a challenge dose of inorganic arsenic. Conversely a reduction of the hepatic GSH level by phorone pretreatment greatly modifies the metabolism of inorganic arsenic in vivo. A reduction exceeding 90% of the control value leads to a decreased urinary excretion of MMA and DMA and an increased urinary excretion of inorganic arsenic. This is also associated with an increased accumulation of inorganic arsenic in the liver. This suggests that a drastic reduction of GSH level in liver not only impairs the methylation of inorganic arsenic but also impairs its biliary excretion. When GSH depletion is less severe, the total amount of arsenic excreted in urine after a challenge dose of NaAsO2 is not significantly different from that found in unpretreated animals but the proportion of the three metabolic forms is different: MMA is reduced whereas Asi and DMA tend to increase. These changes resemble those found in patients with liver insufficiency (J. P. Buchet, A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys (1984). The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55, 151–154). Long-term pretreatment of rats with CCl4 slightly reduces the amount of MMA and DMA excreted in urine following a challenge dose of inorganic arsenic. This effect may result from a reduction of GSH transferase activity by CCl4. This study demonstrates the important role of liver GSH in the metabolism of inorganic arsenic in vivo

In vitro percutaneous absorption of dimethylarsinic acid in mice.

The objective of this study was to investigate the in vitro dermal absorption of [14C]dimethylarsinic acid. This organic arsenical is used as a herbicide and is a product of the mammalian metabolism of inorganic arsenic. Discs of preclipped dorsal skin were cut from adult female B6C3F1 mice and mounted in flow-through diffusion cells. HEPES-buffered Hanks balanced salt solution was used as receptor fluid. Doses of dimethylarsinic acid included 10, 100, and 500 micrograms and were applied onto the skin (0.64 cm2). Experiments (24 h) were conducted using solid compound and aqueous solution (20, 100, and 250 microliters) and soil (23 mg/cm2) as vehicles. The epidermal surface was washed at 24 h to remove compound that did not penetrate. The wash contained the greatest percentage of the dose in all experiments. Absorption of the compound into the skin and receptor fluid was observed and ranged from < 1 to 40% of the dose in experiments with the three exposure scenarios. The rank order of the various exposure conditions of dimethylarsinic acid absorption (10 micrograms) into the skin and receptor fluid was 20 microliters water > 100 microliters water > solid > 250 microliters water > soil. No dose or pH effects on absorption of dimethylarsinic acid was observed. There was also no pH effect on the partitioning of dimethylarsinic acid between 1-octanol and buffer. Short-term (1 h) exposure of dimethylarsinic acid in water followed by wash of the skin resulted in < 1% of the dose being absorbed. Thus, vehicles and duration of exposure have important roles on the in vitro dermal absorption of dimethylarsinic acid in mouse skin.

Identification of methylated metabolites of inorganic arsenic by thin-layer chromatography.

TLC on cellulose plates was used to identify methylated products of inorganic arsenic metabolism (monomethylarsonate and dimethylarsinate) in biological samples. Two solvent systems were tested: methanol-ammonium hydroxide (8:2) and isopropanol-acetic acid-water (10:1:2.5). The latter solvent system produced the most satisfactory separation of radiolabelled methylated arsenic compounds in aqueous solution, in rat liver cytosol incubated with carrier-free or 1 microM [73As]arsenite and in urine of mice given carrier-free [73As]arsenate or 5 mg of [73As]arsenate/kg per os. Oxidation of samples by hydrogen peroxide improved the separation and quantitation of monomethylarsonate in both biological matrices.

Multiple risk factors associated with arsenic-induced skin cancer: effects of chronic liver disease and malnutritional status

In order to evaluate the prevalence and multiple risk factors of arsenic-induced skin cancer among residents in Taiwanese villages in which chronic arseniasis is hyperendemic, a total of 1571 subjects aged 30 or more years were recruited between September 1988 and March 1989. All of them were interviewed personally by a public health nurse using a structured questionnaire, and 1081 interviewed study subjects, including 468 men and 613 women, participated in physical examination, giving a participation rate of 68.8%. The overall prevalence of skin cancer was as high as 6.1%, showing an increase with age in both men and women. There was a significant dose-response relation between skin cancer prevalence and chronic arsenic exposure as indexed by duration of residence in the endemic area, duration of consumption of high-arsenic artesian well water, average arsenic exposure in parts per million (p.p.m.) and cumulative arsenic exposure in p.p.m.-years. Chronic carriers of hepatitis B surface antigen with liver dysfunction had an increased prevalence of skin cancer. Undernourishment, indexed by a high consumption of dried sweet potato as a staple food, was also significantly associated with an increased prevalence of arsenic-induced skin cancer. All these risk factors remained statistically significant in the multiple logistic regression analysis. Consistent with animal experiments, the findings imply that liver function and nutritional status may affect the metabolism of inorganic arsenic and the development of subsequent skin cancers.

Interpretation of inorganic arsenic metabolism in humans in the light of observations made in vitro and in vivo in the rat

AbstractThe toxicity of inorganic trivalent arsenic for living organisms is reduced by in vivo methylation of the element. In man, this biotransformation leads to the synthesis of monomethylarsonic (MMA) and dimethylarsinic (DMA) acids, which are efficiently eliminated in urine along with the unchanged form (Asi). In order to document the methylation process in humans, the kinetics of Asi, MMA and DMA elimination were studied in volunteers given a single dose of one of these three arsenicals or repeated doses of Asi. The arsenic methylation efficiency was also assessed in subjects acutely intoxicated with arsenic trioxide (As2O3) and in patients with liver diseases. Several observations in humans can be explained by the properties of the enzymic systems involved in the methylation process which we have characterized in vitro and in vivo in rats as follows: (1) production of Asi metabolites is catalyzed by an enzymic system whose activity is highest in liver cytosol; (2) different enzymic activities, using the same methyl group donor (S‐adenosylmethionine), lead to the production of mono‐ and di‐methylated derivatives which are excreted in urine as MMA and DMA; (3) dimethylating activity is highly sensitive to inhibition by excess of inorganic arsenic; (4) reduced glutathione concentration in liver moderates the arsenic methylation process through several mechanisms, e.g. stimulation of the first methylation reaction leading to MMA, facilitation of Asi uptake by hepatocytes, stimulation of the biliary excretion of the element, reduction of pentavalent forms before methylation, and protection of a reducing environment in the cells necessary to maintain the activity of the enzymic systems.

Metabolism and disposition of inorganic arsenic in laboratory animals and humans

The carcinogenicity of inorganic arsenic in humans, particularly in the lung and skin, has been reasonably well established through epidemiological investigations. However, there is no substantial experimental evidence for carcinogenicity in animals to support the human studies. Studies of metabolism and disposition of inorganic arsenic in various animal species are particularly relevant to determining the factors that might account for the lack of an animal model. Numerous studies of this type have been reported, but there do not appear to be clear qualitative or quantitative differences in the overall fate and disposition of inorganic arsenic in most animalsversus humans, although little is known at the cellular and subcellular level.Sulphur chemistry, especially thiol status, is emerging as an important regulating factor in the overall fate and distribution of inorganic arsenic in the body, playing a role in the initial reduction of arsenate to arsenite and subsequent methylation, and possibly in determining tissue affinity and distribution properties. The metabolism of inorganic arsenic can be viewed as a redox cycle in which thiol compounds such as glutathione (GSH) possibly function as reducing agents and methyl donors as oxidising agents. One explanation for the possible sensitivity of certain malnourished human populations to the carcinogenic effects of inorganic arsenic may be related to the reduced availability of nonprotein sulphhydryl compounds such as GSH needed to drive the redox cycle and facilitate arsenic detoxification. Future carcinogenicity studies of inorganic arsenic in animals could be designed to address directly this aspect of the problem.

Study of factors influencing the in vivo methylation of inorganic arsenic in rats

Previous studies have shown that several factors may influence the methylation of inorganic arsenic by rat liver in vitro (Buchet and Lauwerys, 1985). The present study attempts to assess the relevance of these observations in vivo. Like man, rat inactivates inorganic arsenic by methylation to monomethylarsoni (MMA) and dimethylarsinic (DMA) acids which are excreted in urine along with unchanged inorganic arsenic (Asi). The administration of S-adenosylmethionine alone or in association with reduced (GSH) or oxidized glutathione or acetylcysteine and the increase of hepatic GSH level by butylated hydroxytoluene pretreatment do not stimulate the urinary excretion of the methylated arsenic metabolites following a challenge dose of inorganic arsenic. Conversely a reduction of the hepatic GSH level by phorone pretreatment greatly modifies the metabolism of inorganic arsenic in vivo. A reduction exceeding 90% of the control value leads to a decreased urinary excretion of MMA and DMA and an increased urinary excretion of inorganic arsenic. This is also associated with an increased accumulation of inorganic arsenic in the liver. This suggests that a drastic reduction of GSH level in liver not only impairs the methylation of inorganic arsenic but also impairs its biliary excretion. When GSH depletion is less severe, the total amount of arsenic excreted in urine after a challenge dose of NaAsO 2 is not significantly different from that found in unpretreated animals but the proportion of the three metabolic forms is different: MMA is reduced whereas Asi and DMA tend to increase. These changes resemble those found in patients with liver insufficiency ( J. P. Buchet, A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys (1984). The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55, 151–154). Long-term pretreatment of rats with CCl 4 slightly reduces the amount of MMA and DMA excreted in urine following a challenge dose of inorganic arsenic. This effect may result from a reduction of GSH transferase activity by CCl 4. This study demonstrates the important role of liver GSH in the metabolism of inorganic arsenic in vivo

In vitro metabolism of inorganic arsenic by the gastro-intestinal microflora of the rat.

The contents of the rat small intestine or caecum reduced sodium [74As] arsenate to arsenite over a period of 2-3 days. In the presence of caecal, but not small intestine, contents, small amounts of methyl arsonic acid and dimethylarsinic acid were formed. Stomach contents reduced arsenic very slowly. The metabolism of arsenate was inhibited by autoclaving the gut contents or by adding antibiotics, thus indicating that bacteria were involved. In prereduced media containing thioglycollate or cysteine in the absence of intestinal bacteria, sodium arsenate was reduced to arsenite. The rate of reduction of arsenate by the gut flora was increased by the presence of hydrogen sulphide or bile acids.

Human retention studies with 74As

An experiment is described in which the human metabolism of inorganic arsenic was investigated. Six volunteers took oral doses of 74As, and were measured in a whole body counter, for periods up to 103 days, with up to 39 separate measurements. Complete collections of their excreta were made for up to 7 days, and the 74As content was measured. The results indicate that the data are best represented by a three-component exponential function, the values of the coefficients for the pooled data being 65.9% with half-life of 2.09 days, 30.4% with a half-life of 9.5 days, and 3.7% with a half-life of 38.4 days.

Whole-body retention, excretion and metabolism of [ 74As] arsenic acid in the hamster

In order to assess the whole-body retention, excretion and metabolism of inorganic arsenic, male and female hamsters were given either a single oral or i.v. dose of 74As(≅33′ μCi/hamster; 0.01 μg arsenic/hamster) as arsenic acid. 74As radioactivity was measured in the whole body, urine and feces for up to 35 days. 24-h samples of urine were analyzed for arsenic metabolites. For the i.v. dosed hamsters, the half-period of elimination for the first component (65% of the dose) was 0.40 days; the second component (35% of the dose) had a half-period of 4.5 days. For the orally dosed hamsters, the half-period of elimination for the first component (98% of the dose) was 0.29 days; the second component (2% of the dose) had a half-period of 3.8 days. Differences in the percent of dose excreted between oral and i.v. dosed hamsters appear to be due to the increased fecal excretion of arsenic (70%) in the orally dosed hamsters as compared to the i.v. dosed hamsters (6%). No statistically significant differences between the i.v. and oral treatments were found in the half- periods of elimination for either of the 2 components. Analysis of the urine for metabolites revealed arsenic was present as dimethylarsinic acid and inorganic arsenic.

Metabolism of inorganic arsenic ( 74As) in humans following oral ingestion

Oral doses of carrier-free 74As (⋍6 μCi/man; ⋍0.01 μg arsenic/man) as arsenic acid were administered to six adult males. Fifty-eight percent of the 74As dose was excreted in the urine in the first 5 days after dosing. The proportion of chemical species of arsenic in the urine was as follows: 51% dimethylarsinic acid, 21% monomethylarsenic compound, and 27% inorganic arsenic.