Potential systemic availability classification of chemicals for safety assessment

Area of Science:

• Toxicology
• Computational Chemistry
• Pharmacokinetics

Background:

• Current chemical safety assessments face limitations due to the growing number of substances and reliance on animal testing.
• The European Partnership for Alternative Approaches to Animal Testing (EPAA) proposed a new framework using new approach methodologies for systemic toxicity classification.
• A key component of this framework is classifying substances by Potential Systemic Availability (PSA) concern, but a clear method was lacking.

Purpose of the Study:

• To define health-protective classes for Potential Systemic Availability (PSA) concern.
• To develop and present a quantitative method for evaluating PSA concern.
• To address the conceptual and practical ambiguity in PSA classification.

Main Methods:

• Utilized high-throughput physiologically based kinetic (PBK) modeling.
• Applied the method to 150 compounds from the EPAA NAM Designathon.
• Manually annotated compounds to validate predicted PSA classifications against expert judgment.

Main Results:

• Successfully classified the PSA concerns for 139 out of 150 compounds.
• Demonstrated the utility of PBK modeling for prioritizing or deprioritizing chemicals based on toxicokinetic properties.
• Found that most compounds require further assessment beyond PSA alone, necessitating a medium PSA concern classification for broader systemic toxicity evaluation.

Conclusions:

• The developed method provides a quantitative approach to PSA concern classification within the EPAA framework.
• Toxicokinetic properties are crucial for prioritizing chemical safety assessments.
• Integration of bioactivity data is essential for the complete evaluation of this method and the overall EPAA framework.