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

Autor: Isaac Omwenga, Hans G.J. Mol, Jochem Louisse, L W Kanja, Ivonne M.C.M. Rietjens, Shensheng Zhao
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Novel Foods & Agrochains
Health
Toxicology and Mutagenesis
Profenofos
010501 environmental sciences
Pharmacology
Novel Foods & Agroketens
Toxicology
01 natural sciences
Rats
Sprague-Dawley
BU Contaminants & Toxins
chemistry.chemical_compound
Physiologically based kinetic (PBK) modeling
BU Toxicology
Novel Foods & Agrochains
Chemistry
Reverse dosimetry
BU Toxicology
General Medicine
Acetylcholinesterase
BU Toxicologie
Novel Foods & Agroketens
Microsomes
Liver
language
Female
BU Toxicologie
Aché
In silico
BU Contaminanten & Toxines
Kinetics
Team Toxicology
Models
Biological
03 medical and health sciences
Species Specificity
In vivo
Acetylcholinesterase (AChE) inhibition
Animals
Humans
Computer Simulation
Pesticides
Toxicologie
VLAG
Organophosphate pesticides (OPs)
0105 earth and related environmental sciences
WIMEK
Dose-Response Relationship
Drug
Organothiophosphates
Novel approach method (NAM)
Team Pesticides 2
language.human_language
In vitro
Rats
030104 developmental biology
Cholinesterase Inhibitors
Toxicokinetics and Metabolism
Zdroj: Archives of Toxicology
Archives of Toxicology, 95(4), 1287-1301
Archives of Toxicology 95 (2021) 4
ISSN: 1432-0738
0340-5761
Popis: 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 Information The online version contains supplementary material available at 10.1007/s00204-021-03004-4.
Databáze: OpenAIRE
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