White Paper: PHYSIOLOGICALLY BASED KINETIC MODELING IN NEW APPROACH METHODOLOGIES

New Approach Methodologies (NAMs) are innovative approaches designed to replace, reduce, or refine traditional animal testing paradigms. Within NAMs, in vitro toxicology assays offer significant promise due to their human relevance, ethical benefits, and cost-effectiveness. These assays can generate vast amounts of toxicological data, presenting a wealth of information that can potentially be used to make informed decisions in chemical risk assessment, without using animals. However, extrapolating in vitro findings to predict in vivo outcomes without the use of clinical experiments remains a challenge. Physiologically Based Kinetic (PBK) modeling, also known as physiologically based toxicokinetic or pharmacokinetic (PBTK/PBPK) modeling, addresses this challenge by simulating the kinetic processes of a chemical in the body based on physiological principles and chemical properties. By doing so, PBK models offer several critical applications within NAM-based chemical risk assessment frameworks, particularly aiming at bridging the gap between experimental in vitro data and real-world scenarios. Some of the more prominent applications of PBK models within NAMs are depicted in table 1, with various other applications and possibilities available. PBK models and toxicokinetics are therefore essential components of NAM-based chemical assessments, as they can cover crucial parts that would otherwise be informed by animal studies. This is further highlighted by the fact that the importance of toxicokinetic data for the current system of chemical safety assessment is increasingly recognized and increasingly implemented in legislative frameworks and guidance documents[1],[2]. This white paper introduces the principles of toxicokinetics within the context of NAMs, discusses the fundamentals of PBK modeling and demonstrates its possible applications, particularly focusing on NAM-based chemical risk assessment. [1] Esther F. A. Brandon, Rivm, and Jos Bessems, "Integration of Toxicokinetics and Toxicodynamics Testing Essential for Risk Assessment." [2] Health Canada "Science Approach Document - Bioactivity Exposure Ratio: Application in Priority Setting and Risk Assessment."