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Assessing the dose-dependency of allometric scaling performance using physiologically based pharmacokinetic modeling
C R Kirman1, L M Sweeney, M E Meek
1The Sapphire Group, Inc., 2000 Auburn Drive, Suite 200 Beachwood, OH 45431, USA. crk@thesapphiregroup.com
Regulatory Toxicology and Pharmacology : RTP
|November 19, 2003
Summary
Allometric scaling of chemical dose in animals for human risk assessment is often untested. This study compared allometric scaling to physiologically based pharmacokinetic (PBPK) models for 12 chemicals, supporting established scaling factors but noting dose-dependency.
Area of Science:
- Toxicology and Pharmacology
- Pharmacokinetics and Drug Metabolism
- Risk Assessment and Environmental Health
Background:
- Allometric scaling of dose based on body weight is a common method for interspecies extrapolation in risk assessment.
- However, its performance across different exposure routes, intensities, and mechanisms of action remains largely untested.
- Physiologically based pharmacokinetic (PBPK) models offer a more mechanistic approach to predicting internal doses across species.
Purpose of the Study:
- To evaluate the performance of allometric scaling for interspecies dose extrapolation compared to PBPK models.
- To compare animal-human internal dose ratios for 12 well-studied volatile and lipophilic chemicals.
- To provide recommendations for applying allometric scaling based on chemical properties and exposure scenarios.
Main Methods:
- Developed animal-human internal dose ratio comparisons for 12 chemicals.
- Utilized PBPK models to predict chemical kinetics in mice, rats, and humans.
- Compared PBPK model predictions against allometric scaling predictions for interspecies extrapolation.
Main Results:
- The study generally supports the use of established allometric scaling factors for risk assessment.
- Specific scaling factors are recommended based on the mode of action (parent compound vs. reactive metabolite) and route of exposure (inhalation vs. oral).
- A dose-dependency was observed, suggesting that scaling factors may need adjustment for high versus low exposure levels due to saturable metabolism.
Conclusions:
- Allometric scaling, when applied judiciously with appropriate scaling factors, remains a valuable tool for interspecies dose extrapolation.
- PBPK models provide a more mechanistic alternative and can help refine allometric scaling recommendations.
- Understanding chemical-specific kinetics and potential saturation of metabolic pathways is crucial for accurate risk assessment.
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