Action Analysis in the EPA Risk Assessment Framework

MODE OF ACTION ANALYSIS IN THE U.S. EPA RISK ASSESSMENT FRAMEWORK  

The framework for analyzing MOA begins with a summary description of the postulated MOA. The judgment of whether a postulated MOA is supported by available data takes into account all of the data in a weight of evidence (WOE) approach. MOA analysis must determine the links between the postulated key events and tumor induction including (i) strength, consistency, and specificity of association, (ii) dose-response relationships between the key events and tumor induction, 

Summary of the Mode of Action and Human Relevance of Liver Tumors Induced by PPARa Activation 

Substantial scientific research on the role of PPARa in rodent hepatocarcinogenesis forms the basis for the cascade of key events that describes the MOA. Although the precise mechanism for the formation of liver tumors by a PPARa activator has not 

There are several plausible explanations for the species-specific effects of PPARa activators (1) Full-length PPARa protein is expressed at levels at least 10-fold greater in rodent liver than in human liver. (2) Humans but not rodents express an inactive form of PPARa in the liver which inhibits the active PPARa. 

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