Hepatotoxicological potential of P-toluic acid in humanised-liver mice investigated using simplified physiologically based pharmacokinetic models

p-Toluic acid, a metabolite of organic solvent xylene, has a high reported no-observed-effect level (NOEL, 1000 mg/kg) in rats, possibly because of direct glycine conjugation to methylhippuric acid. In this study, plasma levels of p-toluic acid and its glycine conjugate in mice and humanised-liver mice were evaluated after oral administrations. Although rapid conversion of p-toluic acid to its glycine conjugate was evident from mouse plasma concentrations, the biotransformation of p-toluic acid was slower in humanised-liver mice. The input parameters for physiologically based pharmacokinetic (PBPK) models were determined using fitting procedures to create PBPK-generated plasma concentration curves. The PBPK-modelled hepatic concentrations of p-toluic acid in humanised-liver mice were higher than those observed in plasma. PBPK-modelled hepatic and plasma concentrations of p-toluic acid also indicated slow elimination in humans. These results suggest that rapid conjugations of p-toluic acid reportedly observed in rats could result in overestimation of NOELs for conjugatable chemicals when extrapolated to humanised-liver mice or humans.

Automated summary

The study revealed slower biotransformation of p-Toluic acid in humanized-liver mice compared to regular mice, leading to higher hepatic concentrations of p-Toluic acid. The PBPK modeling also showed slow elimination of p-Toluic acid in humans, highlighting a potential overestimation of NOELs in humanized-liver mice or humans when extrapolated from rapid conjugation observed in rats.