Integrating Cascade Mechanistic Insights into Structure-Activity Relationships for Quantitative Mode-of-Action...

Area of Science:

• Environmental Chemistry
• Toxicology
• Computational Chemistry

Background:

• Organophosphate flame retardants (OPFRs) are increasingly used and detected globally.
• Their structural diversity complicates traditional toxicological risk assessments.
• OPFRs are linked to potential health concerns, necessitating advanced evaluation methods.

Purpose of the Study:

• To develop a predictive framework for assessing OPFR toxicity.
• To integrate structural properties with mechanistic pathways for risk evaluation.
• To enable rapid risk quantification for existing and novel OPFRs.

Main Methods:

• A quantitative mode-of-action (qMOA) framework was developed using 59 diverse OPFRs.
• Structural attributes, including benzene ring count and substituent type, were identified as key toxicity determinants.
• The structure-activity relationship was validated through experimental assessment of mitochondrial dysfunction.

Main Results:

• The qMOA model identified benzene ring count (55.34%) and substituent type (39.14%) as primary toxicity drivers.
• Experimentally validated links to mitochondrial dysfunction were established.
• MOA-specific threshold doses were calculated, showing higher risks for multibenzene-ring OPFRs.

Conclusions:

• The qMOA framework provides a reliable method for inferring toxicity of diverse OPFRs.
• This approach facilitates rapid risk quantification by comparing predicted thresholds with human exposure data.
• The study advances mechanism-informed strategies for evaluating emerging chemical risks.