Physiologically based toxicokinetic-toxicodynamic (PBTK-TD) modeling of oral exposure to bongkrekic acid in rats.

Bongkrekic acid (BA), a secondary metabolite produced by Burkholderia gladioli pathovar cocovenenans (BGC) in food, represents a major etiological agent of severe foodborne intoxication. The physiologically based toxicokinetic-toxicodynamic (PBTK-TD) model serves as a valuable tool for dose prediction, enabling the estimation of toxicant exposure in biological systems. This study established a multi-compartment PBTK-TD model based on a time-course dataset obtained following single oral administration of BA in rats. Through optimization of kinetic parameters, the PBTK component effectively characterized the toxicokinetic profiles of BA in blood, liver, and other tissues, integrating newly generated experimental data with existing literature. Regression analysis demonstrated coefficients of determination (R2) exceeding 0.93 between model-fitted and observed values. The TD component, by incorporating toxicity-related kinetic parameters in target organs, successfully predicted BA-mediated toxic outcomes. Model validation confirmed that all relative prediction errors fell within the acceptable range (80-125%) as per OECD modeling guidelines. Sensitivity analysis identified parameters with the highest overall sensitivity indices, primarily the liver-to-blood partition coefficient (Pliver) and the metabolic rate constant (kmet). The multi-compartment model provides refined toxicokinetic data and optimized parameters for BA, establishing a robust framework for acute total exposure assessment.