Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment

• DOI: 10.1007/s00204-022-03356-5
• Publication Date: 2022-09-05T08:04:10Z
• Authors: Abdulkarim Najjar; Ans Punt; John Wambaugh; Alicia Paini; Corie Ellison; Styliani Fragki; Enrica Bianchi; Fagen Zhang; Joost Westerhout; Dennis Mueller; Hequn Li; Quan Shi; Timothy W. Gant; Phil Botham; Rémi Bars; Aldert Piersma; Ben van Ravenzwaay; Nynke I. Kramer
• Keywords: Meeting Reports; Regulatory acceptance; Kinetics; 0303 health sciences; 03 medical and health sciences; NAMs; PBK models; Animals; IVIVE; Models, Biological; Risk Assessment; Risk assessment

With an increasing need to incorporate new approach methodologies (NAMs) in chemical risk assessment and the concomitant phase out animal testing, interpretation of vitro assay readouts for quantitative hazard characterisation becomes more important. Physiologically based kinetic (PBK) models, which simulate fate chemicals tissues body, play essential role extrapolating effect concentrations vivo bioequivalent exposures. As PBK-based testing approaches evolve, it will become standardise PBK modelling towards a consensus that can be used vitro-to-in extrapolation (QIVIVE) studies regulatory on assays. Based results ECETOC expert workshop, steps are recommended improve adoption: (1) define context implementation, taking into consideration model complexity building fit-for-purpose (2) harmonise physiological input parameters their distribution criteria quality chemical-specific parameters, especially absence data, (3) apply Good Modelling Practices (GMP) achieve transparency design stepwise development assessors, (4) evaluate predictions using alternatives PK data including read-across approaches, (5) use case facilitate discussions between modellers regulators assessment. Proof-of-concepts generic published scientific literature at rate. Working previously proposed is, therefore, needed gain confidence use.