Sex Differences in Urinary Levels of Several Biological Indicators of Exposure: A Simulation Study Using a Compartmental-Based Toxicokinetic Model

Abstract

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study to quantify the effect of human variability on a wide range of biological exposure indicators.

The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents—methyl ethyl ketone, 1-methoxy-2-propanol, and 1,1,1,-trichloroethane—and to take into account sex differences. In a previous human volunteer study we assessed the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study.

Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could be even more pronounced.

A general and simple toxicokinetic model, adapted for three well-known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variability, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Keywords:

• toxicokinetic modeling
• human biomonitoring
• sex differences
• organic solvents

ACKNOWLEDGMENTS

We thank first and above all the late Dr Pierre-Olivier Droz for his support and supervision of the project. We also express our thanks to the group of Professor Gunnar Johanson from the Karolinska Institute (Stockholm, Sweden), particularly Ms Anna-Karin Mörk, for their support. We also thank Professor Thierry Buclin from the Division of Clinical Pharmacology and Toxicology, University Hospital, Lausanne, Switzerland, for the insightful discussions.

This work was supported by the National Research Fund (FNR) in Luxembourg, the French Agency of Environmental and Occupational Health Safety (ANSES), and the Swiss Federal Office of Public Health (FOPH).