Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise

Dichloromethane (methylene chloride, DCM) is metabolized via two pathways i n humans: mixed-function oxidases (MFO) and glutathione-S-transferase (GST) . Most likely, the carcinogenicity for DCM is related to metabolic activati on 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 r isk assessment for DCM. Past estimates of MFO metabolism are based on the i n vitro activity of tissue samples. The aim of the present study was to dev elop a population model for DCM in order to gain more knowledge on the vari ability of DCM inhalation toxicokinetics in humans, with main emphasis on t he MFO metabolic pathway. This was done by merging published in vitro data on DCM metabolism and partitioning with inhalation toxicokinetic data (Astr and ef at, 1975, Scand. J. Work.Environ. Health 1, 78-94) from five human v olunteers, using the MCMC technique within a population PBPK model. Our res ults indicate that the metabolic capacity for the MFO pathway in humans is slightly larger than previously estimated from four human liver samples. Fu rthermore, the interindividual variability of the MFO pathway in vivo is sm aller among our five subjects than indicated by the in vitro samples. We al so derive a Bayesian estimate of the population distribution of the MFO met abolism (median maximum metabolic rate 28, 95% confidence interval 12-66 mu mol/min) that is a compromise between the information from the in vitro da ta and the toxicokinetic information present in the experimental data.