Meeting Agenda

CE 2 Application of the Human Relevance Framework to the Analysis of Rodent Tumor Data

Sunday, June 18, 2006, 1:00 PM–5:00 PM

Chair: Jerry F. Hardisty, DVM, Fellow IATP, Experimental Pathology Laboratories, Inc.,
Research Triangle Park, NC

Douglas C. Wolf, DVM, PhD, Fellow IATP, U.S. Environmental Protection Agency
Durham, NC

Summary: In order to develop a scientifically defensible assessment of the risk for the development of cancer after long-term exposure to xenobiotics, regulatory agencies have adopted a uniform approach which includes the characterization of a carcinogenic mode of action and its biological plausibility in exposed humans. The Human Relevance Framework (HRF) and Mode-of-Action (MoA) analysis is used to assess the relevance of an increased frequency of neoplastic lesions in rodents identified in carcinogenicity studies. This approach provides a framework for assessing possible cancer risks from exposures to pollutants or other agents in the environment. The goal is to make greater use of the scientific understanding of the process of carcinogenesis. The process includes analysis of all available information, identifying the key events in the cancer processes from exposure to adverse health consequence, mode(s) of action, a description of the biological plausibility for the MoA to occur in humans, considering differential susceptibility to subpopulations, and finally characterizing the risk to humans based on the weight of scientific evidence. The MoA is considered biologically plausible in humans unless there is mechanistic evidence to refute this conclusion. Default approaches to risk assessment are only used when there are insufficient data to support a mode of action analysis and human relevancy approach. This basic continuing education course will provide an overview of how the human relevance framework and mode-of-action analysis is applied in the interpretation of study results derived from carcinogenicity bioassays and its application in the submission of study data to regulatory agencies. The course will start with an overview of the cancer risk assessment guidance and then present specific examples for the urinary tract, liver and thyroid.

Time, Title, and Speaker Description

1:00 PM–1:05 PM Introduction, Jerry F. Hardisty, DVM, Fellow IATP

1:05 PM –1:55 PM Guidance on Mode of Action Analysis and Human Relevancy: An Agency Perspective, Douglas C. Wolf, DVM, PhD, Fellow IATP

The Environmental Protection Agency has finalized a guidance document for how to incorporate data into the characterization of a scientifically defensible mode of action for use in cancer risk assessment. How mode of action analysis is developed and biological plausibility for humans is assessed will be presented.

1:55 PM–2:45 PM The Human Relevance of Urothelial Tumors in Rodents, Samuel M Cohen, MD, PhD, Fellow IATP, University of Nebraska Medical Center Omaha, NE

Several precursor events have been identified in the tumorigenicity of renal and urothelial tumors in rodents which can be evaluated with respect to the relevance to humans. These include DNA reactivity, toxicity in the regeneration, mitogenesis, or alterations in normal physiological agent processes of the species.

2:45 PM–3:15 PM Break

3:15 PM–4:05 PM Application of Mode of Action and the Human Relevance Framework for Hepatocellular Neoplasms, Richard T. Miller, D.V.M., Ph.D., GlaxoSmithKline, Research Triangle Park, NC

This presentation will address the DNA-reactive and epigenetic modes of action for rodent hepatocarcinogens. The application of these modes of action in human risk assessment will be discussed in the context of the Human Relevance Framework and from a risk benefit approach.

4:05 PM–4:55 PM Application of Mode of Action and the Human Relevance Framework for Thyroid Follicular Cell Neoplasms, Charles C Capen, DVM, PhD, Fellow IATP, The Ohio State University, Columbus, OH

This presentation will discuss the modes of action by which xenobiotic chemicals result in hormonal imbalances and increase the incidence of thyroid follicular cell neoplasms in rodents. The mode of action by which different chemicals disrupt thyroid hormone economy will be examined in the framework of human relevance analysis.