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 |
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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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