ArticleToxicological sciences : an official journal of the Society of Toxicology2020
Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 48 citations in OpenAlex.
- Dose Recommendation of Remimazolam Tosilate for General Anesthesia in Children and Adolescents: Synergistic Combination of PopPK and PBPK Approaches.Pharmaceutics · 2026Article
- Physiologically-Based Pharmacokinetic Modeling of the PARP Inhibitor Niraparib.CPT: pharmacometrics & systems pharmacology · 2026Article
- In vitro and computational approaches to predict developmental toxicity: Integrating PBPK models with cell-based assays.Toxicology and applied pharmacology · 2025Article
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- Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood.Neurotoxicology · 2024Article
- Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood.bioRxiv : the preprint server for biology · 2024Article
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- Effects of prenatal pesticide exposure on the fetal brain and placenta transcriptomes in a rodent model.Toxicology · 2023Article
- Developmental pyrethroid exposure causes a neurodevelopmental disorder phenotype in mice.PNAS nexus · 2023Article
- Considering developmental neurotoxicity in vitro data for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Machine learning and artificial intelligence in physiologically based pharmacokinetic modeling.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Current status and future directions for a neurotoxicity hazard assessment framework that integratesComputational toxicology (Amsterdam, Netherlands) · 2022Article
- IVIVE: Facilitating the Use ofToxics · 2022Review
- Estimating household exposure to pyrethroids and the relative contribution of inhalation pathway in a sample of Japanese children.Environmental science and pollution research international · 2021Article
- Evaluation of Placental Transfer and Tissue Distribution ofFrontiers in pediatrics · 2021Article
- Physiologically Based Pharmacokinetic Modeling in Risk Assessment: Case Study With Pyrethroids.Toxicological sciences : an official journal of the Society of Toxicology · 2020Article
- The Protective Effect of N-acetylcysteine against Deltamethrin-Induced Hepatotoxicity in Mice.Avicenna journal of medical biotechnologyArticle
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Authors and funding
12 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.
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