From Causal Networks to Adverse Outcome Pathways: A Developmental Neurotoxicity Case Study

Area of Science:

• Toxicology
• Chemical Risk Assessment
• Pathway Analysis

Background:

• The Adverse Outcome Pathways (AOP) framework is crucial for chemical risk assessment.
• Current AOP development is slow and labor-intensive, hindering its widespread application.

Purpose of the Study:

• To present a faster, semi-automatic approach for generating new AOPs.
• To demonstrate the utility of curated causal toxicological networks for AOP development.

Main Methods:

• Utilized a zebrafish developmental neurotoxicity network containing causally linked molecular events.
• Employed automatic network separation into candidate AOPs.
• Filtered AOPs based on evidence and length, followed by manual refinement and weight-of-evidence evaluation.

Main Results:

• Successfully developed two novel AOPs: AOP 399 (Fyna inhibition to mortality via decreased eye size) and AOP 410 (GSK3beta inactivation to mortality via inner ear defects).
• Demonstrated a semi-automatic method for efficient AOP generation.

Conclusions:

• The presented semi-automatic approach accelerates AOP development.
• Leveraging large toxicological network resources enables fast and straightforward AOP creation for risk assessment.