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USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES
Citation:
Preston, R J. USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES. Presented at Society of Toxicology, Baltimore, MD, 03/21-25/04.
Description:
Use of Mechanistic Data to Help Define Dose-Response Curves
The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default linear one when appropriate data are lacking, or a linear or nonlinear one when specific informative data are available. The challenge is to define the nature and extent of these specific informative data. Ideally, to use nontumor data for predicting tumor outcomes, the most informative endpoint is one that most accurately predicts the tumor outcome, namely an outcome that is part of the tumor response itself or is proximate to this response and along the tumor pathway. The current rapid development of whole genome response methods, such as RNA or protein array approaches, promises to aid substantially in the selection of informative biomarkers of response. Until progress has been made, it remains a common practice for genotoxic carcinogens to use overall genetic alterations (e.g. mutations and chromosome aberrations) as a tumor surrogate marker. The problem with this selection is that rarely are the appropriate data collected for defining shape of dose-response curve. In addition, since cancer is a multistep, multimechanism process, it is necessary to develop dose-response curves based on interactive processes for predicting tumor outcomes. For example, dose-response curves for mutations need to consider the impact of cell proliferation on the mutation frequency. Other genotypic and phenotypic factors can equally influence the shape of a dose-response curve for mutations. The shape of a dose-response is definable for different scenarios when the mechanistic data to be used are developed on the basis of the need for which they are to be used, thereby helping to avoid their inappropriate use. (This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.)