Toxicokinetic modeling of the combined exposure to toluene and n-hexane in rats and humans

We studied the toxicokinetic fate of toluene (TOL) and n-hexane (HEX) in rats exposed to mixtures of these solvents by inhalation during 4 hours. We developed and validated a physiologically based toxicokinetic (PBTK) model for this binary mixture in the rat, which after proper scaling, was used to predict the impact of combined exposure to TOL and HEX in humans, Simultaneous exposure to TOL (125-300 ppm) did not affect the kinetics of HEX (100 or 800 ppm) in blood in rats. Coexposure to HEX, however, increased the concentration of TOL in blood. Coexposure strongly reduced the urinary excretion of 2,5-hexanedione (HD) (up to 75% reduction for TOL 300 ppm + HEX 100 ppm) whereas the urinary excretion of HA and o-CR were reduced to a lesser extent (up to 28% reduction for TOL 200 ppm + HEX 100 ppm). Simulations of exposure to various TOL-HEX mixtures with the human PBTK model suggested that at concentration corresponding to their respective exposure limit values (TOL: 50 ppm; HEX: 50 ppm) coexposure during 7 hours would result in only slight effects on their respective kinetics. This study showed 1) that exposure indicators such as the blood concentration of unchanged TOL and HEX or the amount of their respective urinary metabolite(s) are not equally sensitive to the occurrence of a metabolic interaction and, 2) that such difference of sensitivity can be predicted a priori using a PBTK modeling approach.