Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and humans

Toxicology and Applied Pharmacology
R TardifK Krishnan

Abstract

The objective of the present study was to develop a physiologically based pharmacokinetic (PBPK) model for a ternary mixture of alkyl benzenes [toluene (TOL), m-xylene (XYL), and ethylbenzene (EBZ)] in rats and humans. The approach involved the development of the mixture PBPK model in the rat and extrapolation to humans by substituting rat physiological parameters and blood:air partition coefficients in the model with those of humans, scaling maximal velocity for metabolism on the basis of body weight0.75 and keeping all other model parameters species-invariant. The development of the PBPK model for the ternary mixture in the rat was accomplished by initially validating or refining the existing PBPK models for TOL, XYL, and EBZ and linking the individual chemical models via the hepatic metabolism term. Accordingly, the Michaelis-Menten equation for each solvent was modified to test four possible mechanisms of metabolic interaction (i.e., no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). The metabolic inhibition constant (Ki) for each binary pair of alkyl benzenes was estimated by fitting the binary chemical PBPK model simulations to previously published data on blood concentration...Continue Reading

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