Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic

Environ Res. 1993 Feb;60(2):161-77. doi: 10.1006/enrs.1993.1024.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arsenic / pharmacokinetics*
  • Arsenic / toxicity
  • Arsenic / urine
  • Arsenicals / metabolism
  • Arsenicals / urine
  • Cacodylic Acid / metabolism
  • Cacodylic Acid / urine
  • Humans
  • Inactivation, Metabolic
  • Male
  • Methylation
  • Pilot Projects
  • Regression Analysis


  • Arsenicals
  • Cacodylic Acid
  • monomethylarsonic acid
  • Arsenic