Prediction of dose-dependent in vivo acetylcholinesterase inhibition by profenofos in rats and humans using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry.

Content Provider	Europe PMC
Author	Omwenga, Isaac Zhao, Shensheng Kanja, Laetitia Mol, Hans Rietjens, Ivonne M. C. M. Louisse, Jochem
Abstract	Organophosphate pesticides (OPs) are known to inhibit acetylcholine esterase (AChE), a critical effect used to establish health-based guidance values. This study developed a combined in vitro–in silico approach to predict AChE inhibition by the OP profenofos in rats and humans. A physiologically based kinetic (PBK) model was developed for both species. Parameter values for profenofos conversion to 4-bromo-2-chlorophenol (BCP) were derived from in vitro incubations with liver microsomes, liver cytosol, and plasma from rats (catalytic efficiencies of 1.1, 2.8, and 0.19 ml/min/mg protein, respectively) and humans (catalytic efficiencies of 0.17, 0.79, and 0.063 ml/min/mg protein, respectively), whereas other chemical-related parameter values were derived using in silico calculations. The rat PBK model was evaluated against literature data on urinary excretion of conjugated BCP. Concentration-dependent inhibition of rat and human AChE was determined in vitro and these data were translated with the PBK models to predicted dose-dependent AChE inhibition in rats and humans in vivo. Comparing predicted dose-dependent AChE inhibition in rats to literature data on profenofos-induced AChE inhibition revealed an accurate prediction of in vivo effect levels. Comparison of rat predictions (BMDL10 of predicted dose–response data of 0.45 mg/kg bw) and human predictions (BMDL10 of predicted dose–response data of 0.01 mg/kg bw) suggests that humans are more sensitive than rats, being mainly due to differences in kinetics. Altogether, the results demonstrate that in vivo AChE inhibition upon acute exposure to profenofos was closely predicted in rats, indicating the potential of this novel approach method in chemical hazard assessment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00204-021-03004-4.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC8032624&blobtype=pdf
ISSN	03405761
Journal	Archives of Toxicology [Arch Toxicol]
Volume Number	95
DOI	10.1007/s00204-021-03004-4
PubMed Central reference number	PMC8032624
Issue Number	4
PubMed reference number	33651127
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2021-03-02
Publisher Place	Berlin/Heidelberg
Access Restriction	Open
Rights License	Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2021
Subject Keyword	Organophosphate pesticides (OPs) Physiologically based kinetic (PBK) modeling Reverse dosimetry Acetylcholinesterase (AChE) inhibition Novel approach method (NAM)
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology