The application of global sensitivity analysis in the development of a physiologically based pharmacokinetic model for m-xylene and ethanol co-exposure in humans

Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This analysis informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM) data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost.