Extrapolation of in vitro effect concentrations to in vivo bioavailable concentrations using PBK modelling in humans...

Bottom-up in vitro ADME parameterized PBK models play a vital role in Next Generation Risk Assessment (NGRA), which evaluates the toxicological hazards of compounds through New Approach Methods (NAMs). The ZeroPM project, funded by the EU under Horizon 2020, develops strategies to prioritize persistent (P) and mobile (M) compounds for regulatory measures based on exposure levels and toxicological properties. This study developed a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for two classes of PM compounds - 9 triazines and 16 triazoles. The virtual in vitro distribution model (VIVD) derived free medium benchmark concentration values (EC20 and IR1.5 (mol/L)) from a previously published NAMs testing battery. The VIVD model accounted for partitioning and ionization of PM compounds, while a bottom-up PBK model using in vitro ADME data accurately predicted rat plasma concentrations for tebuconazole and cyromazine. The same assumptions were translated to a human oral-route PBK model. Most triazines/triazoles had in vitro ADME data, where the data gaps were filled using read-across approach. The human PBK model employed forward dosimetry to estimate plasma concentrations from preclinical lowest observed adverse effect levels (LOAELs) or hypothetical exposure data, using surface- and groundwater concentrations as worst-case scenarios. Comparison to QIVIVE data indicates that NAMs-derived values are protective and can serve as basis for human risk assessment or risk-based prioritization.