Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict In Vivo Red Blood Cell Acetylcholinesterase Inhibition Following Exposure to Chlorpyrifos in the Caucasian and Chinese Population

Abstract

Organophosphates have a long history of use as insecticides over the world. The aim of the present study was to investigate the interethnic differences in kinetics, biomarker formation, and in vivo red blood cell acetylcholinesterase inhibition of chlorpyrifos (CPF) in the Chinese and the Caucasian population. To this purpose, physiologically based kinetic models for CPF in both the Chinese and Caucasian population were developed, and used to study time- and dose-dependent interethnic variation in urinary biomarkers and to convert concentration-response curves for red blood cell acetylcholinesterase inhibition to in vivo dose-response curves in these 2 populations by reverse dosimetry. The results obtained revealed a marked interethnic difference in toxicokinetics of CPF, with lower urinary biomarker levels at similar dose levels and slower CPF bioactivation and faster chlorpyrifos-oxon detoxification in the Chinese compared with the Caucasian population, resulting in 5- to 6-fold higher CPF sensitivity of the Caucasian than the Chinese population. These differences might be related to variation in the frequency of single-nucleotide polymorphisms for the major biotransformation enzymes involved. To conclude, the interethnic variation in kinetics of CPF may affect both its biomarker-based exposure assessment and its toxicity and risk assessment and physiologically based kinetic modeling facilitates the characterization and quantification of these interethnic variations.

Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics

“…We have demonstrated for the OPs that the parent compounds are far less potent in inhibiting AChE than their oxon metabolites, indicating that variability and susceptibility is at least partially dependent on the rate of formation of these metabolites. Indeed, interindividual variability in the formation of CPO after exposure to CPF is extensive (Eyer et al 2009 ) and is ethnicity-dependent (Zhao et al 2019 ). Also for PON1-mediated detoxification, pathway-specific UFs and the corresponding interindividual and interphenotypic variability have been assessed previously and have proven to be higher than the default UF of ~ 3.16 for some genotypes (Darney et al 2020 ).…”

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

“…To overcome this issue, alternative testing strategies can be considered, including physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry (Louisse et al 2017 ) that enables quantitative in vitro to in vivo extrapolation (QIVIVE), as a potential novel approach in risk assessment. The PBK modelling-based alternative approach has been successfully used to predict chlorpyrifos-related AChE inhibition (Timchalk et al 2002 ; Zhao et al 2019 ) and also a variety of other chemical-induced adverse effects including for example cardiotoxicity induced by methadone, liver toxicity induced by pyrrolizidine alkaloids and developmental toxicity of retinoids, glycolethers and phenols (Boonpawa et al 2017 ; Louisse et al 2010 ; Ning et al 2019 ; Shi et al 2020 ; Strikwold et al 2013 , 2017 ). In case of DZN, previously a physiologically based pharmacokinetic and pharmacodynamic model was developed for both human and rat (Poet et al 2004 ).…”

Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

“…Over the last decade, several proof-of-principle studies indicated that combining in vitro toxicity assays with physiologically based kinetic (PBK) modeling, which describes the absorption, distribution, metabolism and excretion (ADME) of a compound in a defined species, can adequately predict in vivo dose–response curves (Louisse et al 2017 ; Rietjens et al 2011 ). For example, quantitative in vitro to in vivo extrapolation (QIVIVE) using PBK modeling-based reverse dosimetry was shown to adequately predict the in vivo toxicity for different endpoints, including developmental toxicity (Li et al 2017 ; Louisse et al 2010 ; Strikwold et al 2013 , 2017 ), liver toxicity (Ning et al 2017 ), nephrotoxicity (Abdullah et al 2016 ) and neurotoxicity (Zhao et al 2019 ). To further explore the potential applicability of this in vitro–in silico approach, the aim of the present study was to investigate whether the PBK modeling-based reverse dosimetry can be extended to predict in vivo cardiotoxicity in human, thereby providing a novel testing strategy for cardiac safety testing.…”