Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome cytochromes P450 (CYP)-specific kinetic data as model input

Shensheng Zhao*, Sebastiaan Wesseling, Ivonne M.C.M. Rietjens, Marije Strikwold

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1387-1409
JournalArchives of Toxicology
Volume96
Issue number5
Early online date16 Mar 2022
DOIs
Publication statusPublished - May 2022

Keywords

  • Chlorpyrifos (CPF)
  • Inter-individual differences
  • Monte Carlo (MC) simulation
  • Physiologically based kinetic (PBK) modeling
  • Red blood cell (RBC) acetylcholinesterase (AChE) inhibition

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