Arsenic methylation humans

The 10 min median lethal concentrations (LCsqs) reported in the literature for rats and rabbits are 120-210 and 200-300 ppm, respectively. The lethal effect of arsine is dependent on exposure concentration and duration. The rat LC50 at 0.5, 1 and 4-h exposures is 240, 178, and 45 ppm, respectively. Female rats have slightly greater mortality than males. The effects in animals include dyspnea, hematuria, dark material around the head or anogenital area, and pallor of ears and eyes. During necropsy the animals showed red, yellow, or orange fluid in the bladder, stomach, or intestine, and discoloration of the kidneys, lungs, and liver. Most of the available data come from experiments in rats however, some authors state that the rat is not a suitable model for arsine toxicity because of differences in arsenic methylation and excretion compared to humans. 

The excreted arsenic was in the same chemical form as it was in the fish. Less than 0.35% was excreted in the feces. There are no data on tissue distribution of arsenic in humans after ingestion of arsenic present in fish and other seafood. Also, there have been no reports of ill effects among ethnic populations consuming large quantities of fish that result in organoarsenic intakes of about 0.05 mg/kg of body weight per day (WHO, 1989). Inorganic tri- and pentavalent arsenicals are metabolized in man, dog, and cows to less toxic methylated forms, such as monomethy-larsenic and dimethylarsenic acids (Peoples, 1983). 

Le XC, Ma M, Cullen WR, Aposhian HV, Lu X and Zheng B (2000b) Determination of monome-thylarsonous acid, a key arsenic methylation intermediate, in human urine. Environ Health Perspect 108 1015-1018. 

The relative concentrations of the arsenic methylation metabolites in human urine have been used as a surrogate to compare methylation capacity between individuals and between populations (90). For example, a much lower portion (2.2%) of urinary MMA(V) was found in native Andean women (86), compared with 10-20% urinary MMA(V) in other populations. In another study of northern Argentina population, children were found to have a significantly higher percentage of inorganic arsenic (50%) in their urine samples than the adult women (32%) (91). 

Until recently (93-96), little was known about the arsenic methylation intermediates, MMA(lll) and DMA(lll), in the human system, a result of the lack of techniques for the determination of these arsenic species. Recent developments of more sensitive and improved arsenic speciation techniques contribute to the discovery of these intermediary metabolites in human urine (93-96). Figure 3 shows typical chromatograms obtained from the analyses of arsenic compounds in deionized water and in urine samples. Coinjection of the urine sample with authentic MMA(lll) standard (Fig. 3c) demonstrates the coelution of the suspected MMA(lll) in the sample with that of the standard MMA(III), confirming the identity of MMA(lll) in the urine sample. Similarly, coinjection of the urine sample with standard DMA(III) (Fig. 3d) and As(V) (Fig. 3e) confirms the presence of DMA(lll) in the sample (96). Two other research groups have recently also found MMA(lll) and DMA(llI) in human urine samples (123,124). 

Metabolism of arsenic in the body depends on the chemical species of arsenic absorbed. Inorganic As(III) and As(V) are metabolized in humans through a stepwise biomethylation pathway to form methylated arsenicals. Most of the arsenic compounds and their metabolites are readily excreted into the urine. Speciation of arsenic in human urine is the most suitable biomarker to assess recent exposure to arsenic. 

The next eight chapters will be devoted to the ecotoxicology of groups of compounds that have caused concern on account of their real or perceived environmental effects and have been studied both in the laboratory and in the field. These are predominantly compounds produced by humans. However, a few of them, for example, methyl mercury, methyl arsenic, and polycyclic aromatic hydrocarbons (PAHs), are also naturally occurring. In this latter case, there can be difficulty in distinguishing between human and natural sources of harmful chemicals. 

Lafferty BJ, Loeppert RH (2005) Methyl arsenic adsorption and desorption be-hatior on iron oxides. Environ Sci Technol 39 2120—2127 Le XC (2002) Arsenic speciation in the environment and humans. In Frankenberger WT Jr (ed) Environmental chemistry of arsenic. Marcel Dekker, Inc. New York, pp 95-116... 

Arsenic causes both skin and lung cancer. Skin cancer was observed over 100 years ago in patients treated with arsenical compounds, and lung cancer was seen in smelter workers who chronically inhaled arsenic dust. Although arsenic is an established human carcinogen, it has been difficult to confirm and study in animal models. Arsenic readily crosses the placenta, but there appears to be increased methylation of arsenic to its organic form, which reduces its toxicity to the fetus. 

The marine facultative anaerobe bacterium Serratia marinoruhm and the yeast Rhodotoruhi rubra both methylate arsenate ion to methylarsonate, but only the latter produces cacodylic acid (258). Human volunteers who ingested 500 fig doses of As as sodium arsenite, sodium methylarsonate, and sodium cacodylate excreted these compounds in their urine (259). Of these three, approximately 75% of the sodium arsenite is methylated, while 13% of methylarsonate is methylated. Rat liver subcellular fractions methylated sodium arsenate in vitro, providing the first direct evidence for possible mammalian methylation independent of symbiotic bacteria (260). Shariatpanahi el al. have reported kinetics studies on arsenic biotransformation by five species of bacteria (261). They found that the As(V)-As(IIl) reduction followed a pattern of two parallel first-order reactions, while the methylation reactions all followed first-order kinetics. Of the five species tested, only the Pseudomonas produced all four metabolites (arsenite, methylarsonate, cacodylate, trimethylarsine) (261). 

Cohen, S.M., Arnold, L.L., Eldan, M. et al. (2006) Methylated arsenicals the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Critical Reviews in Toxicology, 36(2), 99-133. 

Mass, M.J. and Wang, L. (1997) Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells a model for a mechanism of carcinogenesis. Mutation Research-Reviews in Mutation Research, 386(3), 263-77. 

Styblo, M., Del Razo, L.M., Vega, L. et al. (2000) Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Archives of Toxicology, 74(6), 289-99. 

Yamauchi, H. and Fowler, B.A. (1994) Toxicity and metabolism of inorganic and methylated arsenicals, in Arsenic in the Environment Part II Human Health and Ecosystem Effects (ed. J.O. Nriagu), John Wiley Sons, Inc., New York, pp. 35-43. 

Zakharyan, R.A., Ayala-Fierro, F., Cullen, W.R. et al. (1999) Enzymatic methylation of arsenic compounds. VII. Monomethylarsonous acid (MMA(III)) is the substrate for MMA methyltransferase of rabbit liver and human hepatocytes. Toxicology and Applied Pharmacology, 158(1), 9-15. 

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