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Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes
Lake, A., S. Hester, J. Liu, J. Rowland, AND C. Wood. Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes. Presented at Society of Toxicology, Phoenix, AZ, March 21 - 25, 2014.
Mode of action (MOA) provides a central framework for assessing human relevance of adverse health outcomes observed in nonclinical safety studies. The goal of this study was to characterize MOA profiles for known rodent liver tumorigens identified from a database of pesticides assessed by the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs. Among 464 compounds with mouse and rat carcinogenicity study data, liver tumor effects were observed for 23% of compounds (108/464; 95/464 for mouse and 32/464 for rat). Of these, 74% (80/108) were classified by the EPA as possible (43%) or probable/likely (31%) human carcinogens. Twenty-one compounds had a MOA proposed by the registrant for liver tumor outcomes used in quantitative risk assessment. Of these, 16 MOAs were accepted by the EPA Cancer Assessment Review Committee. Molecular initiating events for these MOAs included constitutive androstane receptor (CAR) activation (10/16), peroxisome proliferator-activated receptor (PPAR)α activation (4/16), and sustained hepatic cytotoxicity (2/16), followed by increased liver cell proliferation as measured by BrdU, Ki67, or PCNA labeling index (LI). A significant increase in proliferation was observed at ≤7 days for 13/14 compounds with accepted mitogenic (CAR- and PPARα-mediated) but not cytotoxic (0/2) MOAs, while short-term effects on proliferation LI were not provided (4/5) or inconclusive (1/5) for all rejected MOAs. No compounds included decreased liver cell apoptosis as a key event. These findings highlight the central role of quantitative proliferation data in MOA evaluation and support current efforts to prioritize potential hepatotoxicants based on early key biological effects. This abstract does not reflect the policies of the EPA. 2160 out of 2300 Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the views of policies of the U.S. Environmental Protection Agency. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
This abstract will be presented at the Society of Toxicology Meeting, March 21-27, 2014, Phoenix, AZ
URLs/Downloads:MOA ABSTRACT LAKE SOT 2014 ABST.DOC
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
SYSTEMS BIOLOGY BRANCH