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Development of human biotransformation QSARs and application for PBT assessment refinement
Ester Papa1, Alessandro Sangion1, Jon A Arnot2
1QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Theoretical and Applied Sciences, University of Insubria, Varese Italy.
Summary
This study developed quantitative structure-activity relationship (QSAR) models to predict chemical metabolism half-lives in humans. These models help assess the environmental risk of pharmaceuticals and personal care products (PPCPs).
Area of Science:
- Environmental Chemistry
- Toxicology
- Computational Chemistry
Background:
- Toxicokinetics, encompassing Absorption, Distribution, Metabolism (Biotransformation), and Elimination (ADME), dictates chemical toxicity.
- Biotransformation can either detoxify or bioactivate compounds, influencing chemical half-life and bioaccumulation potential.
- Accurate prediction of biotransformation is crucial for assessing chemical risks.
Purpose of the Study:
- Develop Quantitative Structure-Activity Relationship (QSAR) models to predict in vivo human biotransformation (metabolism) half-lives.
- Validate these QSAR models to meet regulatory standards for fitting, validation, and applicability domain.
- Utilize QSAR models to refine the screening of Persistence, Bioaccumulation, and Toxicity (PBT) behavior for Pharmaceuticals and Personal Care Products (PPCPs).
Main Methods:
- Development of QSAR models using empirical data for over 1000 chemicals, primarily pharmaceuticals.
- Rigorous model fitting, validation, and applicability domain assessment.
- Integration of human biotransformation QSARs with fish biotransformation models for comprehensive PBT screening of PPCPs.
Main Results:
- Successfully developed QSAR models predicting human biotransformation half-lives with high reliability.
- Refined PBT screening for over 1300 PPCPs, identifying compounds with potentially lower environmental concern due to rapid metabolism.
- Distinguished between structurally predicted PBTs and those readily biotransformed, enabling more accurate risk assessment.
Conclusions:
- QSAR models for biotransformation half-lives provide a valuable tool for chemical risk assessment.
- Rapid metabolism significantly reduces the environmental concern of chemicals, even if structurally predicted as PBTs.
- This approach enhances the safety evaluation of pharmaceuticals and personal care products, prioritizing compounds with lower bioaccumulation potential.