Adverse Outcome Pathways as Tools to Assess Drug-Induced Toxicity

Area of Science:

• Toxicology
• Risk Assessment
• Pharmacology

Background:

• Adverse outcome pathways (AOPs) offer mechanistic representations of toxicological effects across biological levels.
• AOPs consist of a molecular initiating event, key events, and an adverse outcome, following OECD guidelines.
• Existing AOP frameworks address major drug-induced liver injuries like steatosis, fibrosis, and cholestasis.

Purpose of the Study:

• To outline the development and application of AOP frameworks in toxicology.
• To highlight the utility of AOPs for drug-induced injury assessment.
• To present postulated AOPs for liver injury types.

Main Methods:

• Mechanistic modeling of toxicological effects.
• Adherence to OECD guidelines for AOP development.
• Framework proposal for drug-induced liver injury.

Main Results:

• AOPs provide a structured understanding of toxicity mechanisms.
• Postulated AOPs exist for drug-induced liver injury (steatosis, fibrosis, cholestasis).
• These AOPs support quantitative structure-activity relationships and in vitro testing.

Conclusions:

• AOPs are valuable tools for toxicology and human risk assessment.
• Newly proposed AOPs enhance the safety evaluation of drugs.
• AOPs facilitate the development of novel toxicity screening and prioritization strategies.