Feasibility of Biomonitoring of Exposure to Permethrin Through Analysis of Long-Lived (Metabolite) Adducts to Proteins
Abstract
Biomonitoring of exposure to the insecticide permethrin is usually performed by analysis of its urinary metabolite 3-phenoxybenzoic acid (3-PBA). However, urinary metabolites have the disadvantage that they are rapidly excreted. We are engaged in the development of a methodology to assess the cumulative internal dose of exposure to permethrin, which is based on the assumption that (reactive) glucuronide conjugates of the major permethrin metabolites 3-PBA and cis/trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (cis/trans-Cl2CA) will form persistent adducts to proteins, in analogy with the glucuronide conjugates of structurally related drugs. The 3-PBA and Cl2CA glucuronide metabolites of permethrin have been successfully chemically and enzymatically synthesized. The reactivity of these metabolites with various amino acids, peptides and albumin has been studied; various distinct adducts could be identified by LC tandem mass spectrometry. Subsequently, a method was developed for analysis of albumin adducts of the glucuronides in plasma, which is based on pronase digestion of albumin followed by LC-tandem MS analysis of the lysine adducts. For 3-PBA glucuronide, it was attempted to quantify adduct formation by using [14C] labelled 3-PBA glucuronides, obtained by combined chemical and enzymatic synthesis. From a 2-D gel electrophoresis experiment with [14C]labelled 3-PBA glucuronide and human plasma, it could be concluded that the major binding site was human serum albumin. In case of liver homogenates only low-molecular radioactive material could be detected, indicating that hydrolysis or binding to low-molecular material predominated. In a preliminary animal experiment the acyl adduct of 3-PBA to lysine could be detected, even 22 days after the exposure. In plasma samples of humans who had worn permethrin-treated suits, however, none of the adducts could be detected.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2009
- Accession Number
- ADA501183
Entities
People
- Daan Noort