Abstract
The present study compares two approaches to evaluate the effects of inter-individual differences in the biotransformation of chlorpyrifos (CPF) on the sensitivity towards in vivo red blood cell (RBC) acetylcholinesterase (AChE) inhibition and to calculate a chemical-specific adjustment factor (CSAF) to account for inter-individual differences in kinetics (HKAF). These approaches included use of a Supersome™ cytochromes P450 (CYP)-based and a human liver microsome (HLM)-based physiologically based kinetic (PBK) model, both combined with Monte Carlo simulations. The results revealed that bioactivation of CPF exhibits biphasic kinetics caused by distinct differences in the Km of CYPs involved, which was elucidated by Supersome™ CYP rather than by HLM. Use of Supersome™ CYP-derived kinetic data was influenced by the accuracy of the intersystem extrapolation factors (ISEFs) required to scale CYP isoform activity of Supersome™ to HLMs. The predicted dose–response curves for average, 99th percentile and 1st percentile sensitive individuals were found to be similar in the two approaches when biphasic kinetics was included in the HLM-based approach, resulting in similar benchmark dose lower confidence limits for 10% inhibition (BMDL10) and HKAF values. The variation in metabolism-related kinetic parameters resulted in HKAF values at the 99th percentile that were slightly higher than the default uncertainty factor of 3.16. While HKAF values up to 6.9 were obtained when including also the variability in other influential PBK model parameters. It is concluded that the Supersome™ CYP-based approach appeared most adequate for identifying inter-individual variation in biotransformation of CPF and its resulting RBC AChE inhibition.
Highlights
Chlorpyrifos (CPF) is the organophosphate most studied in the past decades due to its intensive use as an insecticide in nearly 100 countries (The Dow Chemical Company)
CPF, TCPy, acetylthiocholine iodide (ATC), 5,5’-dithiobis (2-nitrobenzoic acid) (DTNB), bovine serum albumin (BSA), tetraisopropyl pyrophosphoramide, reduced nicotinamide adenine dinucleotide phosphate (NADPH), sodium phosphate dibasic dihydrate (Na2HPO4·2H2O), sodium phosphate monobasic dihydrate (NaH2PO4·2H2O), phenacetin, acetaminophen, bupropion, ( ±)-hydroxybupropion solution, 4-hydroxymephenytoin, testosterone, 6β-hydroxytestosterone solution, and trizma®base were purchased from Sigma-Aldrich (Zwijndrecht, The Netherlands). (S)-Mephenytoin was purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA)
The present study compared the performance of two different approaches on characterization of the inter-individual variation in metabolism of CPF and its resulting red blood cell (RBC) AChE inhibition using physiologically based kinetic (PBK) modeling-based reverse dosimetry linked with Monte Carlo simulations
Summary
Chlorpyrifos (CPF) is the organophosphate most studied in the past decades due to its intensive use as an insecticide in nearly 100 countries (The Dow Chemical Company). Inhibition of acetylcholinesterase (AChE) following irreversible binding of the potent metabolite of CPF chlorpyrifos-oxon (CPO), has been characterized as the main cause of acute CPF exposure-related (neuro)toxicity (Satoh and Gupta 2011). On 10 January 2020, The European Commission formally adopted regulations that revoke the renewal of approval for CPF (European Commision 2020), because: (i) the potential genotoxicity of CPF remained unclear, leading the European Food Safety Authority (EFSA) to conclude that no toxicological reference dose could be derived, hampering the risk assessment for consumers, operators, workers, bystanders and residents; (ii) developmental neurotoxicity has been observed in epidemiological studies; and iii) CPF is classified as reproduction category 1B (regarding developmental toxicity) (EFSA 2019). Given that measuring the AChE inhibition in the nervous system is not straightforward, measurement of red blood cell (RBC) AChE inhibition has been widely used as a surrogate endpoint to derive points of departure (PODs) in human risk assessment for organophosphate pesticides (OPs) including CPF (EFSA 2014; USEPA 2014). In the present study, RBC AChE inhibition was used as critical adverse effect for the assessment
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