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Interspecies extrapolation of pharmacokinetics
C C Travis1, R K White, R C Ward
1Health and Safety Research Division, Computing and Telecommunications Division Oak Ridge National Laboratory, TN 37831-6109.
Journal of Theoretical Biology
|February 9, 1990
Summary
This study demonstrates that toxic response depends on physiological time. For metabolically deactivated toxins, the scaling law is mg kg-1 per physiological time unit (pt-1), approximating mg kg-0.75 day-1 at low doses.
Area of Science:
- Pharmacokinetics and toxicological scaling
- Physiologically based pharmacokinetic (PBPK) modeling
Background:
- Toxicological response is often linked to the concentration of a toxic substance over time.
- Interspecies scaling of toxicological data is crucial for risk assessment.
Purpose of the Study:
- To demonstrate the appropriate interspecies scaling law for toxic compounds.
- To link toxic response to the time profile of toxicant concentration in target tissues within a physiological time framework.
Main Methods:
- Utilizing physiologically based pharmacokinetic (PBPK) models.
- Analyzing the time profile of toxic moiety concentration in target tissues.
Main Results:
- For metabolically deactivated toxic compounds, the appropriate interspecies scaling law is mg kg-1 per unit of physiological time (mg kg-1 pt-1).
- At low dose rates, this metric approximates mg kg-0.75 day-1.
- For spontaneously deactivated reactive metabolites, an approximate interspecies scaling law is mg kg-1 day-1.
Conclusions:
- Physiological time is a critical factor in interspecies toxicological scaling.
- Different deactivation mechanisms necessitate distinct scaling laws for accurate risk assessment across species.