Physiologically-based pharmacokinetic analysis of benzoic acid in rats, guinea pigs and humans: Implications for dietary exposures and interspecies uncertainty

- Multi-species PBPK models have been developed and validated by experimental data.
- Repeated, dietarily-relevant oral doses were assessed to predict internal exposures.
- Humans see less benzoic acid compared to rats due to faster metabolism/excretion.
- These comparisons present very little pharmacokinetic interspecies variation.

Benzoic acid (BA) is a common preservative used in food and beverage products. In this study, we systematically reviewed the available pharmacokinetic data for BA within a variety of animal models to design multiple species-specific physiologically-based pharmacokinetic (PBPK) models. We focused specifically on rat, guinea pig, and human metabolic and dosimetric variations. Rate constants for the hepatic metabolism of BA to hippuric acid (HA) were predicted using elimination curves in conjunction with available liver perfusion data and appropriately optimized compartmental models. Following optimization simulations, the PBPK models were quantitatively validated by previously observed time-course datasets of BA and HA plasma concentrations after administration of different amounts of benzoate salts and/or BA, demonstrating the predictive strength and robustness of our computational approach. After validation of the computational models, we assessed resulting internal exposures that corresponded to repeated dosing schemes within each species (1, 5, 10, 50, 100 mg/kg(bw)/day). Simulated continuous daily exposure to BA at a dose of 5 mg/kg(bw)/day allowed for steady-state plasma concentrations of 0.1288 mg/L and 0.0426 mg/L in rats and humans, respectively. The individual steady-state values reached after different dosing schemes give rise to a human:rat steady-state-based margin of exposure (MOE) ratio range of 0.33-0.44 and a human:rat AUC-based MOE ratio range of 0.33-0.37 for pharmacokinetic extrapolation with respect to the dietary exposure schemes assessed. These data provide implications for reducing the pharmacokinetic component of the interspecies uncertainty factor associated with the current acceptable daily intake for assessing dietary exposures to benzoates.