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Mode of action frameworks: a critical analysis
Kathryn Z Guyton1, Stanley Barone, Rebecca C Brown
1National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC, USA. guyton.kate@epa.gov
Summary
Evaluating mode of action (MOA) frameworks reveals challenges in human health risk assessment. Current frameworks need improvement to fully integrate scientific judgment and consider additive effects for comprehensive chemical safety evaluations.
Area of Science:
- Toxicology
- Risk Assessment
- Environmental Health
Background:
- Mode of action (MOA) information is crucial for human health risk assessment, informing species extrapolation and human variability.
- Existing frameworks from organizations like IPCS, ILSI, and US EPA analyze MOA data for environmental carcinogens and toxins.
Purpose of the Study:
- Critically evaluate current MOA frameworks used in human health risk assessment.
- Identify gaps and opportunities for advancing the application of MOA information.
Main Methods:
- Critical review and analysis of established MOA frameworks.
- Evaluation of how biological data and scientific judgment are incorporated.
Main Results:
- Notable challenges persist in articulating the role of scientific judgment in MOA determination and human relevance.
- Current frameworks may exclude informative data through binary decisions and lack consideration of additive effects with endogenous processes or other diseases.
- Integrated analysis of multiple MOAs, dose ranges, and life stages is absent, limiting understanding of complex toxicological profiles.
Conclusions:
- Further development is needed to enhance MOA frameworks for human health risk assessment.
- Frameworks should better incorporate scientific judgment, consider additive effects, and analyze integrated impacts of multiple MOAs and life stages for a more holistic toxicological profile.
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