A Quantitative Structure-toxicokinetic Relationship Model for Highly Metabolised Chemicals

Abstract

The aim of the present study was to develop a quantitative structure-toxicokinetic relationship (QSTkR) model for highly metabolised chemicals (HMCs). The proposed QSTkR model is essentially a physiologically based toxicokinetic (PBTK) model, in which the blood:air and tissue:blood partition coefficients (PCs) are predicted from the molecular structure of chemicals, and the liver blood flow rate (Q1) is used to describe hepatic clearance. Molecular structure-based prediction of the blood:air and tissue:blood PCs was performed from the n-octanol:water and water:air PCs of chemicals obtained with the conventional fragment constant methods. The validity of incorporating Q1 instead of metabolic rate constants, as the hepatic clearance factor, in PBTK models for HMCs (extraction ratio > 0.7) was verified by comparing the simulations of venous blood concentration (Cv) profiles obtained with both the QSTkR and PBTK model approaches for 1,1-dichloroethylehe, trichloroethylene and furan in the rat. Following the validation of this alternative approach for describing hepatic clearance of HMCs, a QSTkR model for dichloromethane was constructed. This model used molecular structure information as the sole input, and provided simulations of Cv for human exposure to low concentrations of dichloromethane. The QSTkR model simulations were similar to those obtained with the previously validated, conventional human PBTK model with experimentally determined PCs and metabolic rate constants (Vmax, Km and Kf) for dichloromethane. The present methodology is the first validated example of a mechanistically based prediction of the inhalation toxicokinetics of HMCs made solely from information on molecular structure.