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Considering developmental neurotoxicity (DNT) in Vitro data for human health risk assessment using physiologically-based kinetic (PBK) modeling: deltamethrin case study #431
Maass C, Schaller S, Dallmann A, Bothe K, Müller D. Considering developmental neurotoxicity (DNT) in Vitro data for human health risk assessment using physiologically-based kinetic (PBK) modeling: deltamethrin case study. Toxicol Sci. 2023 Jan 13:kfad007. doi: 10.1093/toxsci/kfad007. Epub ahead of print. PMID: 36637193.
https://pubmed.ncbi.nlm.nih.gov/36637193/
Abstract
Developmental 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.
Maass C, Schaller S, Dallmann A, Bothe K, Müller D. Considering developmental neurotoxicity (DNT) in Vitro data for human health risk assessment using physiologically-based kinetic (PBK) modeling: deltamethrin case study. Toxicol Sci. 2023 Jan 13:kfad007. doi: 10.1093/toxsci/kfad007. Epub ahead of print. PMID: 36637193. https://pubmed.ncbi.nlm.nih.gov/36637193/
Abstract Developmental 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.
Keywords: deltamethrin; developmental neurotoxicity (DNT); fetal brain exposure; modelling and simulation; new-approach methodologies (NAM); physiologically-based kinetics (PBK).
© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology.