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INCORPORATION OF MOLECULAR ENDPOINTS INTO QUANTITATIVE RISK ASSESSMENT
Citation:
PRESTON, J. INCORPORATION OF MOLECULAR ENDPOINTS INTO QUANTITATIVE RISK ASSESSMENT. Presented at International Conference on Environmental Mutagens, San Francisco, CA, September 05 - 09, 2005.
Description:
The U.S. Environmental Protection Agency has recently released its Guidelines for Carcinogen Risk Assessment. These new guidelines benefit from the significant progress that has been made in understanding the cancer process and also from the more than 20 years experience that EPA has had in applying risk assessment principles and practices. These guidelines encourage the use of mechanistic data for obtaining a better estimation of tumor responses at low levels of exposure. The aim is to reduce uncertainties in risk assessment and at the same time reduce the reliance on default safety factors. A mode of action (MOA) is defined as a sequence of key events and processes that lead to a tumor. An ongoing effort by the International Life Sciences Institute describes a series of key events that define a MOA by which a particular chemical induces a tumor from a normal cell in an animal model. The Human Relevance Framework is used to establish if an animal MOA is plausible in humans and using kinetic and dynamic factors whether or not key events in the animal MOA are plausible in humans. Thus, these various components of a human cancer risk assessment rely upon considerations of mechanisms of carcinogenesis. Since great strides have been made in our understanding of mechanisms of carcinogenesis at the molecular level, how can we use this information in quantitative cancer risk assessment? The types of data required for this purpose are those that help identify key events in tumor formation following exposure to environmental chemicals. Informative biomarkers of tumor responses could be developed for describing the shape of a dose-response curve at low doses and for predicting tumor frequency at these low doses. A number of recently developed molecular approaches could aid in the identification of informative biomarkers. These methods include quantitative gene expression array techniques, quantitative proteomic assays and the assessment of DNA alterations at the single gene level and at the genome level of detection. It is most likely that a combination of approaches at these different levels of cellular organization (i.e. DNA, RNA and protein) will be the most productive for biomarker development.