An Adverse Outcome Pathway (AOP) for forestomach tumors induced by non-genotoxic initiating events

Area of Science:

• Toxicology
• Chemical Risk Assessment

Background:

• Rodent forestomach tumors are difficult to extrapolate to humans due to differing anatomy and variable modes of action (MOAs).
• Developing reliable methods for hazard identification and risk assessment is crucial for regulatory science.

Purpose of the Study:

• To develop an Adverse Outcome Pathway (AOP) for forestomach tumors induced by non-genotoxic chemicals.
• To utilize the established MOA of ethyl acrylate (EA) to construct this AOP.
• To assess the biological plausibility and empirical support for the proposed AOP.

Main Methods:

• Constructed an AOP detailing the sequence of events from initiating event to adverse outcome.
• Reviewed existing data for ethyl acrylate (EA) and butylated hydroxyanisole (BHA) to support the AOP.
• Applied evolved Bradford Hill criteria for evaluating biological plausibility and evidence strength.

Main Results:

• The AOP links non-genotoxic initiating events, specifically epithelial cytotoxicity, to forestomach tumors.
• Key events include sustained cell proliferation and hyperplasia, driven by regenerative repair.
• Evidence from both EA and BHA supports the proposed AOP, despite potential variability in pre-MIEs and initiating events.

Conclusions:

• The developed AOP provides a framework for understanding forestomach tumorigenesis from non-genotoxic chemicals.
• High confidence in the AOP supports its use in regulatory hazard identification and risk assessment.
• This pathway is applicable to chemicals acting via cytotoxicity and regenerative proliferation.