Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic.
Inorganic arsenic (In-As) is an established human carcinogen. Methylation to monomethylarsonate (MMA) and dimethylarsinate (DMA) is believed to be the detoxification mechanism for In-As. Urinary measurement of In-As, MMA, and DMA is considered a good biological marker of internal dose to In-As, since it excludes other ingested forms of arsenic which are much less toxic, and because urinary excretion is the main form of elimination of In-As. A methylation threshold hypothesis for In-As has been proposed, stating that after exposure to In-As reaches a certain level or threshold, methylation capacity begins to decline, thus increasing the toxic effects of In-As. We investigated the validity of this hypothesis by analyzing the data from studies which measured urinary In-As, MMA, and DMA in different populations, ranging from background to high occupational and environmental exposure groups. We also present data from our study of a highly exposed population in California. Our analysis focused on the proportion of urinary In-As remaining in the unmethylated form [In-As/(In-As + MMA + DMA)]. The results indicate that epidemiological and experimental human data do not support the methylation threshold hypothesis. On average, 20-25% In-As remains unmethylated regardless of the exposure level. The wide range of interindividual variability in methylation capacity found in some studies warrants further investigation.
Hopenhayn-Rich
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Department of Biomedical and Environmental Health Sciences, University of California, Berkeley 94720.
Smith
A H
AH
Goeden
H M
HM
D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D001152:Arsenicals / Q000378:metabolism / Q000652:urine; D002101:Cacodylic Acid / Q000378:metabolism / Q000652:urine; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008745:Methylation; D010865:Pilot Projects; D012044:Regression Analysis
D001152:Arsenicals; D002101:Cacodylic Acid; C020300:monomethylarsonic acid; D001151:Arsenic