US Environmental Protection Agency's revised guidelines for carcinogen risk assessment: evaluating a postulated mode of carcinogenic action in guiding dose-response extrapolation

There are new opportunities to using data from molecular and cellular studi es in order to bring together a fuller biological understanding of how chem icals induce neoplasia. In 1996, the Environmental Protection Agency (EPA) published a proposal to replace its 1986 Guidelines for Carcinogen Risk Ass essment to take advantage of these new scientific advances in cancer biolog y. The analytical framework within the new guidelines focuses on an underst anding of the mode of carcinogenic action. Mode of action data come into pl ay in a couple of ways in these new guidelines. For example, such informati on can inform the dose-response relationship below the experimental observa ble range of tumours. Thus, mode of action data can be useful in establishi ng more appropriate guidance levels for environmental contaminants. It is t he understanding of the biological processes that lead to tumour developmen t along with the response data derived from experimental studies that can h elp discern the shape of the dose-response at low doses (linear vs. nonline ar). Because it is experimentally difficult to establish "true thresholds" from others with a nonlinear dose-response relationship, the proposed guide lines take a practical approach to depart from low-dose linear extrapolatio n procedures when there is sufficient experimental support for a mode of ac tion consistent with nonlinear biological processes (e.g., tumours resultin g from the disruption of normal physiological processes). (C) 2000 Elsevier Science B.V. All rights reserved.