Biotransformation of allyl chloride in the rat. Influence of inducers on the urinary metabolic profile.

Allyl chloride (AC) is used as intermediate in the synthesis of epichlorohydrin (ECH). We investigated the biotransformation of AC in rats to select potential urinary biomarkers of exposure. For this purpose, we developed analytical methods to measure different selected urinary metabolites of AC. The earlier described urinary metabolites of AC [allyl mercapturic acid (ALMA) and 3-hydroxypropyl mercapturic acid (HPMA)], as well as two urinary metabolites of ECH [alpha-chlorohydrin (alpha-CH) and 3-chloro-2-hydroxypropyl mercapturic acid (CHPMA)], were determined in this study. After intraperitoneal administration of AC, in doses ranging from 66 to 590 mumol/kg, control rats excreted 30 +/- 6.5% of the AC dose as ALMA. HPMA was a minor urinary metabolite of AC (< 3% of the AC dose), and, for this metabolite, no clear dose-excretion relationship was found. Two other minor urinary metabolites were also found as well, namely CHPMA and alpha-CH, suggesting the formation of ECH. CHPMA excretion was linear from 66 to 330 mumol/kg AC and amounted to 0.21 +/- 0.08% of the AC dose. alpha-CH excretion was linear in the dose range used and was excreted for 0.13 +/- 0.02% of the AC dose. In addition, we investigated the influence of three different enzyme inducers on the urinary metabolite profile of AC, namely pyrazole, beta-naphthoflavone, and phenobarbital. Pyrazole only increased the urinary excretion of alpha-CH. beta-Naphthoflavone induction only enhanced the ALMA excretion significantly. Phenobarbital inducted both the excretion of CHPMA and alpha-CH. From these studies, we conclude that urinary excretion of ALMA, CHPMA, and alpha-CH can be used as biomarkers in humans potentially exposed to AC. However, ALMA seems to be the more appropriate biomarker, because enzyme induction may play a confounding role if CHPMA or alpha-CH is used.