You are here:
Adverse Outcome Pathway (AOP) for a Mutagenic Mode of Action for Cancer: AFB1 and Hepatocellular Carcinoma (HCC)
Citation:
Pottenger, L., M. Moore, T. Simon, R. Becker, K. Wise, AND R. Schoeny. Adverse Outcome Pathway (AOP) for a Mutagenic Mode of Action for Cancer: AFB1 and Hepatocellular Carcinoma (HCC). Society of Toxicology, San Diego, CA, March 22 - 26, 2015.
Impact/Purpose:
This is a poster presentation for the Society of Toxicology meeting 2015. It describes development of an adverse outcome pathway (AOP) for uploading on the OECD wiki. EPA has been supporting efforts of OECD in defining information requirements for AOP as well as the structure of the wiki.
Description:
AOPs provide a framework to describe a sequence of measureable key events (KEs), beginning with a molecular initiating event (MIE), followed by a series of identified KEs linked to one another by KE Relationships (KERs), all anchored by a specific adverse outcome (AO). Each KE/KER is supported by data and evaluated against criteria to assess biological plausibility, weight/strength of evidence, specificity, and confidence. AOPs offer an approach to using toxicological data and predictive modeling to actualize use of mode-of-action (MOA) for such purposes as read-across, integrated approaches to testing & assessment, and risk assessment. Different applications will depend partly on the scientific confidence underpinning each KE/KER and the overall AOP. An OECD program encourages development of AOPs, with a wiki that allows for public review & comment to foster collaborations and broaden understanding & application of AOPs. Developing an AOP for a mutagenic MOA for cancer as a case study in the OECD program lays a path towards determination of such an MOA and its use in chemical assessment programs. Aflatoxin B1 (AFB1), with ubiquitous exposure and a rich database, was selected for this case study. AFB1 has been determined to induce HCC via a DNA-reactive MOA in many species, including humans. The sequential KEs identified for AFB1 are as follows: pre-MIE: Hepatic metabolic activation; MIE: Formation of a pro-mutagenic DNA adduct (N7-AFB1-guanine or AFB1-FAPy); KE#1: Inadequate or mis-repair of the pro-mutagenic DNA adducts; KE#2: Induced mutation in critical gene(s); KE#3: Cellular proliferation and clonal expansion of mutant cells (pre-neoplastic lesions); AO: HCC. These KEs and the various KERs—both direct and indirect—are mapped out with supporting data for each. Assessment of quantitative aspects of the dose-response relationships for the KEs and KERs will support its use in quantitative risk assessment.