Toxicological Sciences 59, 209-218 (2001)
Copyright © 2001 by the Society of Toxicology
BIOTRANSFORMATION AND TOXICOKINETICS |
Physiologically Based Pharmacokinetic Modeling of Inhalation Exposure of Humans to Dichloromethane during Moderate to Heavy Exercise
* Toxicology and Risk Assessment, National Institute for Working Life, S-112 79 Stockholm, Sweden;
Institut National de l'Environnement Industriel et des Risques, Verneuil en Halatte, France; and
Department of Medical Sciences, Occupational and Environmental Medicine, Uppsala University Hospital, Sweden
Dichloromethane (methylene chloride, DCM) is metabolized via two pathways in humans: mixed-function oxidases (MFO) and glutathione-S-transferase (GST). Most likely, the carcinogenicity for DCM is related to metabolic activation of DCM via the GST pathway. However, as the two pathways are competing, the metabolic capacity for the MFO pathway in vivo is also of interest in risk assessment for DCM. Past estimates of MFO metabolism are based on the in vitro activity of tissue samples. The aim of the present study was to develop a population model for DCM in order to gain more knowledge on the variability of DCM inhalation toxicokinetics in humans, with main emphasis on the MFO metabolic pathway. This was done by merging published in vitro data on DCM metabolism and partitioning with inhalation toxicokinetic data (Åstrand et al., 1975, Scand. J. Work.Environ. Health 1, 78–94) from five human volunteers, using the MCMC technique within a population PBPK model. Our results indicate that the metabolic capacity for the MFO pathway in humans is slightly larger than previously estimated from four human liver samples. Furthermore, the interindividual variability of the MFO pathway in vivo is smaller among our five subjects than indicated by the in vitro samples. We also derive a Bayesian estimate of the population distribution of the MFO metabolism (median maximum metabolic rate 28, 95% confidence interval 12–66 µmol/min) that is a compromise between the information from the in vitro data and the toxicokinetic information present in the experimental data.
Key Words: dichloromethane; inhalation; pharmacokinetics; physiologically based modeling; Markov chain Monte Carlo simulations; population kinetics.
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