Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental...

Area of Science:

• Toxicology
• Regulatory Science
• In Vitro Assays

Background:

• The DNT5 meeting addressed challenges in regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB).
• Discussions focused on future research directions and opportunities for DNT-IVB application.

Purpose of the Study:

• To outline key issues and research directions for the regulatory implementation of the DNT-IVB.
• To explore strategies for data interpretation, integration, and validation of NAMs for DNT assessment.

Main Methods:

• Brainstorming session among DNT5 meeting participants.
• Discussion of five key topics related to DNT-IVB implementation and validation.

Main Results:

• Exploration of contextualizing DNT hazard with maternal and non-DNT toxicity data using cytotoxicity from NAMs.
• Identification of opportunities for near-future DNT-IVB application as prioritization or add-on data.
• Discussion on establishing data interpretation procedures for multi-dimensional endpoints and potential use of machine learning.
• Consideration of linking molecular initiating events (MIEs) to the DNT-IVB and optimizing cost-benefit.
• Outline of pathways for scientific validation of DNT NAMs and the DNT-IVB, considering mechanistic information versus traditional animal data.

Conclusions:

• Regulatory implementation of the DNT-IVB requires addressing data integration, interpretation, and validation challenges.
• New Approach Methodologies (NAMs) and machine learning show promise for DNT assessment.
• Further research is needed to establish robust frameworks for DNT-IVB use in regulatory decision-making.