An integrated QSAR–PBPK modelling approach for predicting the inhalation toxicokinetics of mixtures of volatile organic chemicals in the rat

Abstract

The objective of this study was to predict the inhalation toxicokinetics of chemicals in mixtures using an integrated QSAR–PBPK modelling approach. The approach involved: (1) the determination of partition coefficients as well as V _max and K_m based solely on chemical structure for 53 volatile organic compounds, according to the group contribution approach; and (2) using the QSAR-driven coefficients as input in interaction-based PBPK models in the rat to predict the pharmacokinetics of chemicals in mixtures of up to 10 components (benzene, toluene, m-xylene, o-xylene, p-xylene, ethylbenzene, dichloromethane, trichloroethylene, tetrachloroethylene, and styrene). QSAR-estimated values of V _max varied compared with experimental results by a factor of three for 43 out of 53 studied volatile organic compounds (VOCs). K _m values were within a factor of three compared with experimental values for 43 out of 53 VOCs. Cross-validation performed as a ratio of predicted residual sum of squares and sum of squares of the response value indicates a value of 0.108 for V _max and 0.208 for K _m. The integration of QSARs for partition coefficients, V _max and K _m, as well as setting the K _m equal to K _i (metabolic inhibition constant) within the mixture PBPK model allowed to generate simulations of the inhalation pharmacokinetics of benzene, toluene, m-xylene, o-xylene, p-xylene, ethylbenzene, dichloromethane, trichloroethylene, tetrachloroethylene and styrene in various mixtures. Overall, the present study indicates the potential usefulness of the QSAR–PBPK modelling approach to provide first-cut evaluations of the kinetics of chemicals in mixtures of increasing complexity, on the basis of chemical structure.

Keywords:

• mixtures
• PBPK model
• pharmacokinetics
• QSAR–PBPK model
• toxicokinetics

Acknowledgements

Grants from NSERC-Canada (Operating grants) and ANSES (EST-2007-85) are acknowledged.