Toluene and methylethylketone: effect of combined exposure on their metabolism in rat

Abstract

1. Multiple exposures are ubiquitous in industrial environments. In this article, we highlight the risks faced by workers and complete the data available on the metabolic impact of a common mixture: toluene (TOL) and methylethylketone (MEK).

2. Rats were exposed by inhalation under controlled conditions either to each solvent individually, or to mixtures of the two. How the interaction between the two solvents affected their fate in the blood and brain, their main relevant urinary metabolites (o-cresol, benzylmercapturic acid for TOL and 2,3-butanediols for MEK) and their hepatic metabolism were investigated.

3. Although the cytochrome P450 concentration was unchanged, and the activities of CYP1A2 and CYP2E1 isoforms were not additively or synergistically induced by co-exposure, TOL metabolism was inhibited by the presence of MEK (and vice versa). Depending on the relative proportions of each compound in the mixture, this sometimes resulted in a large increase in blood and brain concentrations. Apart from extreme cases (unbalanced mixtures), the amount of o-cresol and benzylmercapturic acid (and to a lesser extent 2,3-butanediols) excreted were proportional to the blood solvent concentrations.

4. In a co-exposure context, ortho-cresol and benzylmercapturic acid can be used as urinary biomarkers in biomonitoring for employees to relatively accurately assess TOL exposure.

Keywords:

• Benzylmercapturic acid
• metabolic interaction
• methylethylketone
• mixed exposure
• ortho-cresol
• occupational recommendations
• toluene

Acknowledgements

The authors gratefully acknowledge Benoît Rieger, Thomas Venet and Stéphane Viton for their technical assistance, Aurélie Rémy for her statistical support and Marie-Josèphe Décret, Lionel Dussoul and Sylvie Michaux from the laboratory’s animal facility for their help in rat handling and husbandry.

Declaration of interest

No potential conflict of interest was reported by the authors.

This work was entirely supported by the French Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS, France).

Supplementary material available online