QSARs for PBPK modelling of environmental contaminants

Area of Science:

• Toxicology and Pharmacology
• Computational Chemistry
• Risk Assessment

Background:

• Physiologically-based pharmacokinetic (PBPK) models are valuable tools for chemical risk assessment, particularly for data-rich compounds.
• A significant challenge in PBPK modeling is obtaining accurate chemical-specific parameters, especially under time and resource constraints.
• Quantitative structure-activity relationships (QSARs) and related approaches offer potential solutions for parameter estimation.

Purpose of the Study:

• To explore the utility of QSARs and related methods for predicting chemical-specific input parameters for PBPK models.
• To assess the current limitations and future potential of QSAR-PBPK models in health risk assessment.

Main Methods:

• Utilized molecular fragment frequency and exposure conditions to develop QSAR-PBPK models for simulating tissue and blood concentrations of inhaled volatile organic chemicals.
• Discussed the conceptual application to non-volatile and high molecular weight organic compounds.
• Identified challenges in predicting parameters like tissue diffusion coefficients, binding association constants, and oral absorption rates.

Main Results:

• Existing QSAR-PBPK models can simulate concentrations for certain inhaled volatile organic chemicals based on molecular fragments and exposure.
• The predictive domain of current QSARs for PBPK modeling is restricted by data availability for diverse chemicals and mechanisms.
• Predicting kinetic parameters for non-volatile and high molecular weight compounds presents greater challenges.

Conclusions:

• QSARs show promise for estimating PBPK model parameters, particularly in data-poor situations.
• Further research into the mechanistic basis of toxicokinetic processes is needed to improve QSAR-based a priori predictions.
• Enhanced QSAR-PBPK models can expedite internal dose-based health risk assessments.