Liver and Plasma Concentrations of Food Chemicals after Virtual Oral Doses Extrapolated Using in Silico Estimated Input Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats

Abstract

The estimation of health risks of chemical substances was historically investigated using animal studies; however, current research focuses on reducing the number of animal experiments. The toxicity of chemicals in fish screening systems is reportedly correlated with their hydrophobicity. The inverse relationship between absorption rates (intestinal cell permeability) and virtual hepatic/plasma pharmacokinetics of diverse chemicals has been previously evaluated by modeling oral administration in rats. In the current study, internal exposures, i.e., virtual maximum plasma concentrations (C_max) and areas under the concentration–time curves (AUC), of 56 food chemicals with reported hepatic lowest-observed-effect levels (LOELs) of ≤1000 mg/kg/d in rats were pharmacokinetically modeled using in silico estimated input pharmacokinetic parameters. After a virtual single oral dose of 1.0 mg/kg of 56 food chemicals, the output C_max and AUC values in rat plasma generated by modeling using the corresponding in silico estimated input parameters were not significantly correlated with the reported hepatic LOEL values. However, significant inverse relationships between hepatic/plasma concentrations of selected lipophilic food chemicals (i.e., octanol–water partition coefficient log P > 1) using forward dosimetry and reported LOEL values (≤300 mg/kg/d) were observed (n = 14, r=−0.52–0.66, p ≤ 0.05). This simple modeling approach, which uses no experimental pharmacokinetic data, has the potential to play a significant role in reducing the use of animals to estimate toxicokinetics or internal exposures of lipophilic food components after oral doses. Therefore, these methods are valuable for estimating hepatic toxicity by using forward dosimetry in animal toxicity experiments.