Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential.

ABSTRACT

Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100-250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150-250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.