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

Publication date: Available online 21 April 2018 Source:Regulatory Toxicology and Pharmacology Author(s): Deborah M. Proctor, Mina Suh, Grace Chappell, Susan J. Borghoff, Chad M. Thompson, Karin Wiench, Lavorgie Finch, Robert Ellis-Hutchings The utility of rodent forestomach tumor data for hazard and risk assessment has been examined for decades because humans do not have a forestomach, and these tumors occur by varying modes of action (MOAs). We have used the MOA for ethyl acrylate (EA) to develop an Adverse Outcome Pathway (AOP) for forestomach tumors caused by non-genotoxic initiating events. These tumors occur secondary to site of contact induced epithelial cytotoxicity and regenerative repair-driven proliferation. For EA, the critical initiating event (IE) is epithelial cytotoxicity, and supporting key events (KEs) at the cellular and tissue level are increased cell proliferation (KE1) resulting in sustained hyperplasia (KE2), with the adverse outcome of forestomach papillomas and carcinomas. For EA, a pre-molecular initiating event (pre-MIE) of sustained glutathione depletion is probable. Supporting data from butylated hydroxyanisole (BHA) are also reviewed. Although there may be some variability in the pre-MIEs and IEs for BHA and EA, they share the same KEs, and evidence for BHA confers support for the AOP. Evolved Bradford Hill considerations of biological plausibility, essentiality, and empirical support were evaluated per OECD guidance. Although an MIE is...
Source: Regulatory Toxicology and Pharmacology - Category: Toxicology Source Type: research