Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

Autor: Ivonne M.C.M. Rietjens, Shensheng Zhao, Bert Spenkelink, Sebastiaan Wesseling
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Diazinon
Quantitative in vitro to in vivo extrapolation (QIVIVE)
Aché
Health
Toxicology and Mutagenesis
Metabolite
010501 environmental sciences
Pharmacology
GPI-Linked Proteins
Toxicology
Models
Biological
01 natural sciences
03 medical and health sciences
chemistry.chemical_compound
Organophosphorus Compounds
In vivo
Acetylcholinesterase (AChE) inhibition
Physiologically based kinetic (PBK) modelling
Animals
Humans
Toxicokinetics
Toxicologie
0105 earth and related environmental sciences
VLAG
Oxon
WIMEK
Reverse dosimetry
Diazinon (DZN)
General Medicine
Acetylcholinesterase
In vitro
language.human_language
Rats
Kinetics
030104 developmental biology
Liver
chemistry
Microsomes
Liver
language
Cholinesterase Inhibitors
Toxic equivalency factor (TEF)
Toxicokinetics and Metabolism
Zdroj: Archives of Toxicology, 95(5), 1573-1593
Archives of Toxicology 95 (2021) 5
Archives of Toxicology
ISSN: 0340-5761
DOI: 10.1007/s00204-021-03015-1
Popis: The present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03015-1.
Databáze: OpenAIRE
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