Mechanistic validation.

Area of Science:

• Toxicology
• Regulatory Science
• Systems Biology

Background:

• Current validation of toxicological tests primarily focuses on reproducibility and predictive capacity.
• Novel toxicological approaches, especially those based on mechanisms (e.g., systems toxicology), require assessment of their scientific basis.
• Implementing 21st-century toxicology initiatives like ToxCast/Tox21 and the Human Toxome Project necessitates robust validation of new methods.

Purpose of the Study:

• To explore the underemphasized assessment of a test's scientific basis in toxicological validation.
• To highlight the importance of mechanism and causality in validating new toxicological tests.
• To propose approaches for mechanistic validation in complex biological systems.

Main Methods:

• Review of current practices in toxicological test validation.
• Discussion of challenges in assessing predictive capacity for mechanism-based approaches.
• Exploration of pragmatic adaptations of the Bradford Hill criteria and bioinformatic tools for mechanistic validation.
• Proposal to focus on the target of toxicity, its vulnerability, and perturbation pathway for mechanism identification.

Main Results:

• The scientific or mechanistic basis of toxicological tests is often neglected in validation processes.
• Assessing the predictive capacity of novel, mechanism-based tests presents significant challenges.
• Mechanistic validation requires establishing causality within complex biological systems.
• Emerging tools and criteria (e.g., adapted Bradford Hill criteria, bioinformatics) can aid mechanistic validation.

Conclusions:

• Mechanistic validation is crucial for the reliable implementation of novel toxicological testing strategies.
• Focusing on the target of toxicity, vulnerability, and perturbation can anchor mechanism identification and verification.
• Integrating mechanistic understanding will enhance the scientific rigor and regulatory acceptance of new toxicology approaches.