Considering developmental neurotoxicityin vitrodata for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study

Author:

Maass Christian1ORCID,Schaller Stephan1,Dallmann André2ORCID,Bothe Kathrin3,Müller Dennis3

Affiliation:

1. esqLABS GmbH , Hambierich 34 , Saterland 26683, Germany

2. Pharmacometrics/Modeling and Simulation, Research and Development, Pharmaceuticals, Bayer AG , Leverkusen 51373, Germany

3. Regulatory Toxicology, Research and Development, Bayer AG, CropScience , 40789 Monheim am Rhein, Germany

Abstract

AbstractDevelopmental neurotoxicity (DNT) is a potential hazard of chemicals. Recently, an in vitro testing battery (DNT IVB) was established to complement existing rodent in vivo approaches. Deltamethrin (DLT), a pyrethroid with a well-characterized neurotoxic mode of action, has been selected as a reference chemical to evaluate the performance of the DNT IVB. The present study provides context for evaluating the relevance of these DNT IVB results for the human health risk assessment of DLT by estimating potential human fetal brain concentrations after maternal exposure to DLT. We developed a physiologically based kinetic (PBK) model for rats which was then translated to humans considering realistic in vivo exposure conditions (acceptable daily intake [ADI] for DLT). To address existing uncertainties, we designed case studies considering the most relevant drivers of DLT uptake and distribution. Calculated human fetal brain concentrations were then compared with the lowest benchmark concentration achieved in the DNT IVB. The developed rat PBK model was validated on in vivo rat toxicokinetic data of DLT over a broad range of doses. The uncertainty based case study evaluation confirmed that repeated exposure to DLT at an ADI level would likely result in human fetal brain concentrations far below the in vitro benchmark. The presented results indicate that DLT concentrations in the human fetal brain are highly unlikely to reach concentrations associated with in vitro findings under realistic exposure conditions. Therefore, the new in vitro DNT results are considered to have no impact on the current risk assessment approach.

Funder

Bayer AG

Publisher

Oxford University Press (OUP)

Subject

Toxicology

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