PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF A MIXTURE OF TOLUENE AND XYLENE IN HUMANS

A physiologically-based pharmacokinetic (PBPK) model for a mixture of toluene (TOL) and xylene (XYL), developed and validated in the rat, wa s used to predict the uptake and disposition kinetics of TOL/XYL mixtu re in humans. This was accomplished by substituting the rat physiologi cal parameters and the blood:air partition coefficient with those of h umans, scaling the maximal velocity for hepatic metabolism on the basi s of body weight0.75, and keeping all other model parameters species-i nvariant. The human TOL/XYL mixture PBPK model, developed based on the quantitative biochemical mechanism of interaction elucidated in the r at (i.e., competitive metabolic inhibition), simulated adequately the kinetics of TOL and XYL during combined exposures in humans. The simul ations with this PBPK model indicate that an eight hour co-exposure to concentrations that remain within the current threshold limit values of TOL (50 ppm) and XYL (100 ppm) would not result in significant phar macokinetic interferences, thus implying that data on biological monit oring of worker exposure to these solvents would be unaffected during co-exposures.