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Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model
C H Pierce1, R L Dills, M S Morgan
1Department of Environmental Health, University of Washington, Seattle 98195, USA.
Toxicology and Applied Pharmacology
|July 1, 1996
Summary
This study developed a person-specific physiologically based toxicokinetic (PBTK) model, revealing significant interindividual variability in toxicant exposure and metabolism. Subject-specific parameters improved model accuracy for 2H8-toluene toxicokinetics.
Area of Science:
- Toxicology
- Pharmacokinetics
- Computational Biology
Background:
- Physiologically based toxicokinetic (PBTK) models traditionally use generalized parameters for human exposure estimation.
- Existing models often rely on animal-to-human scaling and population averages, limiting precision for individual risk assessment.
Purpose of the Study:
- To develop and validate a PBTK model for person-specific dosimetry.
- To investigate interindividual variability in 2H8-toluene toxicokinetics using subject-specific parameters.
Main Methods:
- Constructed a PBTK model incorporating individual measurements (age, weight, body composition, ventilation, partition coefficients) from 26 male subjects.
- Exposed subjects to 2H8-toluene and toluene, collecting serial blood samples for 120 hours post-exposure.
- Integrated fitted lung metabolism as a novel feature to explain observed systemic clearance patterns.
Main Results:
- Subject-specific PBTK modeling explained 91% of data variability, significantly outperforming models using literature values (53%).
- Identified correlations between physiological parameters (body weight, adipose fraction, blood/air partition coefficient) and toxicokinetic variables (half-life, volume of distribution).
- Demonstrated that interindividual differences in lung metabolism and adipose tissue fraction significantly impact 2H8-toluene distribution and clearance.
Conclusions:
- Person-specific PBTK modeling provides a more accurate assessment of toxicant exposure and toxicokinetics than traditional population-based approaches.
- Individual physiological characteristics and metabolic variations are critical determinants of toxicant disposition in the human body.
- The developed PBTK model highlights the importance of accounting for interindividual differences in lung metabolism and body composition for precise risk assessment.