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.

Association between occupational solvent exposure and cognitive performance in the French CONSTANCES study

“…Moreover, even if this sample was large, showing associations in women remains difficult because of their limited exposure. The potential sex differences could be explained in part not only by differences in prevalence of exposure but also by differences in the metabolism of solvents that could influence the toxicokinetics of the solvents 40…”

Relação entre desempenho neurocognitivo e composição corporal de homens e mulheres expostos a solventes orgânicos

“…Já a hipótese secundária foi investigar a relação entre os resultados de homens e mulheres expostos nos testes neurocognitivos com os índices de composição corpórea. Esperava-se que os efeitos da exposição crônica aos solventes prejudicassem o desempenho neurocognitivo e que os efeitos fossem mais acentuados nos homens do que nas mulheres, por causa das diferenças na composição corporal (Gochfeld, 2007;Mergler, 2012;Tomicic & Vernez, 2014;Vahter et al, 2007;Weiss, 2012). Isto é, como os solventes orgânicos são compostos lipofí licos e as mulheres, geralmente, apresentam concentração de gordura maior, era esperado que o tecido adiposo funcionasse como o fator de proteção nas mulheres (Klaassen & Watkins, 2012).…”

Relationship between Neurocognitive Performance and Body Composition of Men and Women Exposed to Organic Solvents

“…The secondary hypothesis was to investigate the relationship between the results of exposed men and women in the neurocognitive tests with body composition indices. It was expected that the effects of chronic exposure to solvents would impair neurocognitive performance and that the effects would be more pronounced in men than in women due to the differences in body composition (Gochfeld, 2007;Mergler, 2012;Tomicic & Vernez, 2014;Vahter et al, 2007;Weiss, 2012). In other words, since organic solvents are lipophilic compounds and women generally have higher fat concentration, it was expected that adipose tissue would function as a protective factor in women (Klaassen & Watkins, 2012).…”