Physiologically based Modeling of the inhalation kinetics of styrene in humans using a Bayesian population approach

Animal studies have implicated styrene as toxic to the central nervous system and its major metabolite styrene-7,8-oxide as a carcinogen. Therefore, a reliable estimate of the metabolic capacity for styrene in humans is of interest. However, the available models describing styrene kinetics in humans lack rigorous statistical validation and also ignore the population variability in metabolism. The population variability may be estimated by the use of population models. Furthermore, the statistical validation of pharmacokinetic models may be improved by use of Bayesian methods. These two approaches may be combined and recently have been gaining interest in the toxicology literature. A population-based physiologically based pharmacokinetic (PBPK) model for styrene was developed. The model was calibrated to extensive human toxicokinetic data from three previous studies in which 24 volunteers were exposed to 50-386 ppm of styrene at rest and various levels of exercise. Model fitting was performed in a Bayesian framework using Markov chain Monte Carlo simulation. The uncertainty around the partition coefficients and metabolic parameters for styrene was reduced. The metabolic capacity for styrene in humans was estimated to be 0.92 mumol/l kg(-1), with a lognormal standard deviation of 1.66. The estimated V-max is 40% higher than previously estimated, whereas the population standard deviation is estimated for the first time. (C) 2002 Elsevier Science (USA).