Pathway Based Toxicology and Fit-for-Purpose Assays

Area of Science:

• Toxicology
• Cell Biology
• Regulatory Science

Background:

• The field of toxicity testing for non-pharmaceutical chemicals is shifting towards in vitro assays.
• Initiatives in North America and the EU aim to reduce animal testing.
• Obstacles include developing cellular assays, dose-response models, and in vitro-in vivo extrapolation (IVIVE) tools.

Purpose of the Study:

• To explore the development of fit-for-purpose toxicity assays.
• To demonstrate mode-of-action (MOA)-based approaches using pathway-targeted case studies.
• To address the need for reliable in vitro alternatives to animal testing.

Main Methods:

• Development of targeted cellular assays.
• Creation of pathway-based dose-response models.
• Application of MOA-based approaches grounded in human biology.

Main Results:

• Demonstrated principles of fit-for-purpose assay development.
• Case studies included p53-mdm2-mediated DNA repair, estrogen receptor-mediated cell proliferation, and PPARα receptor-mediated liver responses.
• Highlighted the need to validate assays against MOA data rather than animal study endpoints.

Conclusions:

• Transitioning to in vitro toxicity testing requires developing new assays and models.
• A cultural shift is needed to embrace MOA-based assays in human cells.
• Future efforts must focus on human biology-based extrapolation and safety assessment.