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

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.

Application of the Adverse Outcome Pathway Concept to In Vitro Nephrotoxicity Assessment: Kidney Injury due to Receptor-Mediated Endocytosis and Lysosomal Overload as a Case Study

“…Model simulations of plasma and tissue concentrations in rats and humans were within 2 to 5-fold of available measured concentrations. The model was subsequently used to predict dose-dependent rat and human in vivo kidney injury using PBK modeling-facilitated reverse dosimetry of the in vitro concentration-effect relationship for polymyxin B in the CellTiter-Glo® assay with RPTEC/TERT1 (downstream KE) collected in this study, thus providing a proof-of-principle that acute kidney injury in humans can be predicted for both rats and humans without the need for in vivo studies ( Omwenga et al, 2021 ; Punt et al, 2021 ). Predictions on dose-dependent kidney injury inhibition in humans were evaluated by comparison with available clinical data ( Falagas and Kasiakou, 2006 ).…”

Acetylcholinesterase Inhibition in Rats and Humans Following Acute Fenitrothion Exposure Predicted by Physiologically Based Kinetic Modeling-Facilitated Quantitative In Vitro to In Vivo Extrapolation

“…The mechanism of acute neurotoxicity following organophosphate pesticide exposures is the inhibition of neuronal AChE; however, relevant in vivo data for it are usually unavailable especially for humans. In the absence of this information, the inhibition of erythrocyte AChE is considered to be an acceptable surrogate endpoint in scientific studies − and by regulatory bodies because erythrocyte AChE is more sensitive than the neuronal AChE, suggesting that a conservative POD could be derived with this endpoint.…”

“…New approach methodologies are currently explored in accordance with the principles of Next Generation Risk Assessment for chemical exposures to reduce the reliance on animal approaches. , As an example, physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) has been widely employed for the prediction of the in vivo toxicity of chemicals with various endpoints, , including AChE inhibition following acute exposure to organophosphate pesticides in both rats and humans. − PBK models mathematically describe the body tissues as interconnected compartments linked by the blood, and can simulate time profiles of chemical concentrations in tissues under certain dose levels. ,, Using the PBK modeling-based QIVIVE approach, in vitro concentration-based toxic effects can be converted to corresponding in vivo dose-dependent responses, supporting the derivation of PODs for risk assessment without generating new animal data. − …”

Forest Ecological Diversity Change Prediction Discrete Dynamic Model

“…Emily et al [9,10] evaluate the service value of 38 kinds of forest ecological diversity in China. Omwenga et al [11] evaluate the service value of forest ecological diversity according to the evaluation criterion. Periyasamy and Arirangan [12] put forward that forest resources should be used sustainably-the theory of forest sustainable utilization, the core of which is oriented to the use value of forest resources, and the single production of wood resources and the maximum output of wood resources products are private, with the aim of pursuing maximum economic benefits, but the maximum annual forest harvest should be less than the annual growth.…”

“…. , T. In order to minimize the target J in formula (11), it is necessary to minimize the target J in three ways, and the necessary conditions for minimizing L are known according to advanced mathematical knowledge, that is, to make L derivative all its independent variables zero:…”