Beyond traditional toxicology: The transformative power of PBTK modeling

Physiologically Based Toxicokinetic (PBTK) modeling has emerged as a crucial tool in toxicokinetics, enabling the quantitative assessment of chemical absorption, distribution, metabolism, and excretion (ADME) across various biological systems. Unlike traditional toxicokinetic approaches, PBTK models integrate physiological and biochemical parameters to allow for precise interspecies and dose extrapolations. This capability enhances their applicability in regulatory risk assessment for pharmaceuticals, industrial chemicals, food additives, cosmetics, and pesticides. High Throughput Toxicokinetics (HTTK) and in vitro-to-in vivo extrapolations (IVIVE) further improve the predictive power of PBTK models by utilizing large-scale experimental datasets and computational approaches. Additionally, these models facilitate route-to-route extrapolations, predicting systemic exposure across different administration routes such as oral, inhalation, and dermal pathways. PBTK modeling also enables the estimation of specific target tissue concentrations, cross-species extrapolations, and extrapolations to special populations, thereby improving human biological modeling. Furthermore, the integration of PBTK models in ecological risk assessment supports the evaluation of environmental chemical exposure effects on diverse species. As regulatory agencies increasingly adopt PBTK models for toxicity evaluations, their role in advancing data-driven risk assessment and reducing reliance on animal testing continues to grow. This review explores the application of PBTK modeling in toxicokinetics and its alignment with regulatory guidelines for risk assessment and interspecies extrapolation.