Framework for Assessing Human Relevance of Animal MOA

The majority of the tumor data available for conducting cancer risk assessments for exposure to enviromnental chemicals come from 2-year cancer bioassays using rats and mice. Thus, a MOA based on key events is inevitably developed for laboratory animals and not humans. There are, of course, a few exceptions for which human tumor data are available (NTP 2005). These human data are generally used together with rodent tumor data as part of dose-response characterization. Thus, the need in all cases is to demonstrate that the animal MOA is plausible in humans. This can be accomplished by use of a human relevance framework (described below in this section and in Table 13.1 and in Eigure 13.1). 

It is of note that this considerable reliance on laboratory animal data for risk assessment purposes for enviromnental chemicals is in sharp contrast to the situation with ionizing radiation. The cancer risk estimates for ionizing radiation (X rays and y rays) are based to a very great extent on human tumor data obtained from the Life Stage Study (LSS) of the atomic bomb survivors in Hiroshima and Nagasaki, Japan 

Postulated MOA. Brief description of the sequence of measured effects, starting with chemical administration, to cancer formation at a given site. 

Key events. Clear description of each of the key events (measurable parameters) that are thought to underlie the MOA. 

Dose-response relationships. Dose-response relationships identified for each key event, and comparisons presented of dose-response relationships among key events and with cancer. 

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