A Quantitative Structure-toxicokinetic Relationship Model for Highly Metabolised Chemicals
Patrick Poulin, Kannan Krishnan · Alternatives to Laboratory Animals · 1998
The aim of the present study was to develop a quantitative structure-toxicokinetic relationship (QST k R) model for highly metabolised chemicals (HMCs). The proposed QST k R 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 (Q 1 ) 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 Q 1 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 (C v ) profiles obtained with both the QST k R 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 QST k R model for dichloromethane was constructed. This model used molecular structure information as the sole input, and provided simulations of C v for human exposure to low concentrations of dichloromethane. The QST k R model simulations were similar to those obtained with the previously validated, conventional human PBTK model with experimentally determined PCs and metabolic rate constants (V max , K m and K f ) 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.