A generic PBTK model implemented in the MCRA platform: Predictive performance and uses in risk assessment of chemicals

Cléo Tebby (1) , Hilko van Der Voet (2) , Georges de Sousa (3) , Emiel Rorije (4) , Vikas Kumar (5) , Waldo de Boer (2) , Johannes Kruiselbrink (2) , Frédéric Bois (1) , Moosa Faniband (6) , Angelo Moretto (7) , Céline Brochot (1)

1 INERIS - Institut National de l'Environnement Industriel et des Risques
2 WUR - Wageningen University and Research [Wageningen]
3 ToxAlim - ToxAlim
4 RIVM - National Institute for Public Health and the Environment [Bilthoven]
5 Universitat Rovira i Virgili
6 Skane University Hospital [Lund]
7 UNIMI - Università degli Studi di Milano = University of Milan

Physiologically-based toxicokinetic (PBTK) models are important tools for in vitro to in vivo or inter-species extrapolations in health risk assessment of foodborne and non-foodborne chemicals. Here we present a generic PBTK model implemented in the EuroMix toolbox, MCRA 9 and predict internal kinetics of nine chemicals (three endocrine disrupters, three liver steatosis inducers, and three developmental toxicants), in data-rich and data-poor conditions, when increasingly complex levels of parametrization are applied. At the first stage, only QSAR models were used to determine substance-specific parameters, then some parameter values were refined by estimates from substance-specific or high-throughput in vitro experiments. At the last stage, elimination or absorption parameters were calibrated based on available in vivo kinetic data. The results illustrate that parametrization plays a capital role in the output of the PBTK model, as it can change how chemicals are prioritized based on internal concentration factors. In data-poor situations, estimates can be far from observed values. In many cases of chronic exposure, the PBTK model can be summarized by an external to internal dose factor, and interspecies concentration factors can be used to perform interspecies extrapolation. We finally discuss the implementation and use of the model in the MCRA risk assessment platform.

Mots clés: Mixtures; Physiologically-based ToxicoKinetic (PBTK) model; Probabilistic model; Risk assessment.

Domaines: Sciences du Vivant [q-bio]; Toxicologie; Santé

Cléo Tebby, Hilko van Der Voet, Georges de Sousa, Emiel Rorije, Vikas Kumar, et al.. A generic PBTK model implemented in the MCRA platform: Predictive performance and uses in risk assessment of chemicals. Food and Chemical Toxicology, 2020, 142, ⟨10.1016/j.fct.2020.111440⟩. ⟨hal-02735573⟩