Arsenic in Drinking Water (1999) / Chapter Skim
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5 Disposition of Inorganic Arsenic
5 Disposition of Inorganic Arsenic
Pages 150-176
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or arsenate As(V) was absorbed from the gastrointestinal tract of humans and experimental animals (Pomroy et al.
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Variations in arsenic methylation in humans are reviewed in more detail in Chapter 7. Arsenate Reduction and Arsenite Methylation In humans and in most experimental animals, inorganic arsenic is methylated to monomethylarsonic acid (MMA)
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. Essentially the same sequence of alternating reduction and methylation reactions was postulated for various mammals exposed to inorganic arsenic (Challenger 1945)
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reported that the methylating capacity of red blood cells, brain, lung, intestine, and kidneys of rats was insignificant compared with that of the liver. In vitro studies using arsenite methyltransferases from mouse tissues showed that the highest amount of methylating activity is in the testes, followed by kidney, liver, and lung (Healy et al.
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Many experimental animals excrete less MMA and more DMA in the urine than do humans. Mice and dogs methylate inorganic arsenic efficiently,
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Arsenite methyltransferase activity, tested by incubation of liver preparations with arsenite in vitro, has been detected in the liver of the rabbit, rat, mouse, hamster, pigeon, and rhesus monkey but not in the liver of the marmoset monkey, tamarin monkey, squirrel monkey, chimpanzee, and guinea pig
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In decreasing order, the species with liver arsenite methyltransferase activity are the pigeon, rhesus monkey, mouse, hamster, rabbit, marmoset monkey, squirrel monkey, and tamarin monkey. In addition, when guinea pigs were injected intraperitoneally with radioactive arsenate, five of six guinea pigs did not have methylated arsenic species in their urine (Healy et al.
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A further discussion of the dose-dependence of arsenic methylation in humans exposed via drinking water is presented in Chapter 8. Results from in vitro studies suggested that the delay in urinary excretion of DMA might occur because of the high tissue concentrations of arsenite inhibit the methyltransferase catalyzing the second methylation step (Buchet and Lauwerys 1985)
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From page 158... ...
In vitro studies on arsenic methylation in rat-liver cytosol showed that chelating agents, such as DMSA and DMPS (0.05-0.5 mM) , almost completely inhibit the methylation of inorganic arsenic to DMA (Buchet and Lauwerys 1985, 1988)
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. Arsenic concentrations were found to be significantly higher in the serum and erythrocytes of chronic hemodialysis patients compared with controls (De Kimpe et al.
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. Experimental animal studies found that the binding of arsenic is mainly to highmolecular-weight proteins in various tissues; however, arsenic is continuously released from most intracellular binding sites over time following exposure (Marafante et al.
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used neutron-activation analysis to assess the arsenic content of benign and malignant skin lesions of 14 patients exposed at least 4 years earlier to several years of inorganic arsenical medication. Arsenic content of the biopsied skin ranged from 0.8 to 8.9 ppm, and on average exceeded the arsenic content of normal skin and malignant skin lesions from six subjects with no history of
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In a study of pregnant women living in a village in northwestern Argentina where drinking water contains arsenic at about 200 µg/L, arsenic concentrations were about as high in cord blood (on average 9 µg/L) as in maternal blood, indicating that arsenic readily reaches the human fetus (Concha et al.
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. The arsenic concentrations found in human breast milk were slightly higher than the lowest concentrations reported in previous studies (Byrne et al.
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Kinetic Model A physiologically based pharmacokinetic (PB-PK) model for exposure to inorganic arsenic (orally, intravenously, and intratracheally)
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The extended model was validated against empirical data on the urinary excretion of the different metabolites of inorganic arsenic following repeated oral intake of arsenite, intake of inorganic arsenic via drinking water, and occupational exposure to arsenic trioxide. Predicted variation in urinary excretion of arsenic metabolites in relationship to form of arsenic absorbed, route of absorption, and time of urine sampling needs to be validated further.
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Experimental animal studies show that both inorganic arsenic and the methylated metabolites pass the placenta. In humans exposed to arsenic via drinking water, arsenic concentration in cord blood was similar to that in
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The excretion of arsenic in human milk is low, and in areas with high arsenic concentrations in the water, an infant is less exposed to arsenic via breast feeding than via formula prepared from the water. Recommendations Because of interspecies differences in the amounts of various arsenic species excreted in the urine and the amounts of methyltransferases in tissues, extrapolation of animal data to humans is generally not possible.
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1981 a. Comparison of the urinary excretion of arsenic metabolites after a single dose of sodium arsenite, monomethylarsonate or dimethylarsinate in man.
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Part 2. Arsenic concentration in drinking water, hair, nails, urine, skin-scale and liver tissue (biopsy)
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1987. Distribution, metabolism and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration.
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1994. Dose-dependent disposition of sodium arsenite in mice following acute oral exposure.
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1997. Some results of a physiologically based pharmacokinetic modeling approach to estimating arsenic body burdens.
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1997. Factors influencing in vitro methylation of arsenicals in rat liver cytosol.
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1997. Effect of hepatic methyl donor status on urinary excretion and DNA damage in B6C3F1 mice treated with sodium arsenite.
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Enzymatic methylation of arsenic compounds: III. The marmoset and tamarin, but not the rhesus, monkeys are deficient in methyltransferases that methylate inorganic arsenic.
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Page 176 Chemical speciation of arsenic in serum of uraemic patients. Analyst 123:13-17.
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