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Author Spotlight: Developing a Simple and Robust Hepatic Model for Pharmacological and Toxicological Applications
Published on: October 20, 2023
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Development and intercomparison of single and multicompartment physiologically-based toxicokinetic models:
James M Armitage1, Lauren Hughes2, Alessandro Sangion3
1AES Armitage Environmental Sciences, Inc., Ottawa, Ontario K1L 8C3, Canada; Department of Physical and Environmental Sciences, University of Toronto Scarborough, Toronto, Ontario M1C 1A4, Canada.
Environment International
|April 23, 2021
Summary
This study developed generic physiologically-based toxicokinetic (PBTK) models, comparing one-compartment (1Co-) and multi-compartment (MCo-) approaches. Results show 1Co-PBTK models are reliable for many scenarios, but MCo-PBTK may be needed for complex exposures.
Area of Science:
- Toxicology and Environmental Health
- Computational Biology and Modeling
- Pharmacokinetics and Drug Metabolism
Background:
- Physiologically-based toxicokinetic (PBTK) models are crucial for chemical risk assessment.
- Generic PBTK models (G-PBTK) offer a standardized approach but require validation.
- Understanding discrepancies between one-compartment (1Co-) and multi-compartment (MCo-) PBTK models is essential for accurate exposure assessment.
Purpose of the Study:
- To develop and intercompare generic PBTK models (G-PBTK) with 1Co- and MCo- implementations.
- To evaluate model performance using independent toxicokinetic data for diverse organic chemicals.
- To identify conditions where 1Co- and MCo-PBTK models yield significant differences in predicted concentrations and half-lives.
Main Methods:
- Development of internally consistent 1Co- and MCo-PBTK models parameterized with common physiological data and in vitro biotransformation rates.
- Model evaluation using independent concentration-time data and elimination half-lives for various organic chemicals.
- Application of G-PBTK models to hypothetical neutral, acidic, and basic ionizable organic compounds to explore model behavior.
Main Results:
- The G-PBTK models demonstrated acceptable performance, despite uncertainties in biotransformation data and lack of calibration.
- 1Co- and MCo-PBTK calculations were broadly consistent except when biotransformation was rapid (half-life < 5 days).
- Discrepancies were greatest for neutral organics and least for acidic ionizable compounds under rapid biotransformation conditions, linked to volume of distribution differences.
Conclusions:
- 1Co-PBTK models are suitable for chronic exposures, screening, and prioritization, offering reliable predictions in many contexts.
- MCo-PBTK models may be necessary for intermittent, short-term, or highly variable exposure scenarios.
- Harmonizing parameterization and process descriptions across tiered PBTK modeling approaches is recommended for chemical assessment activities.
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