Hazard assessment of chemical carcinogens: the impact of hormesis

The recent report of reductions in the number and area of preneoplastic hep atic lesions in response to low doses of the tumor promoter phenobarbital p rovides important new support for the existence of hermetic responses to ca rcinogens. The presence of hermetic responses to carcinogenic agents and th e corollary that beneficial doses of these compounds can be determined have several implications for the bioassay and hazard assessment of carcinogens as well as for public policy regulating exposure to these agents. To be ad equately sensitive to detect and quantify hermetic or other non-linear dose -response functions, current study designs must be modified to include lowe r doses and sufficiently large numbers of animals. Short- or medium-term an imal studies are a cost-effective means of addressing these needs and have been used recently to describe a classical hermetic response to the non-gen otoxic carcinogen phenobarbital. These basic changes should be supported by a continuing emphasis on mechanistic research and the development of biolo gically based quantitative models of toxicant action. Linking these models with physiologically based pharmacokinetic model descriptions of target dos e holds the greatest promise for improving the description of the dose-resp onse curve at low doses. These approaches are generally encouraged by the U SEPA in the form of The 1996 Proposed Carcinogen Risk Assessment Guidelines . However, there remain substantial questions regarding integration of the concept of hormesis into hazard testing and public policy that require care ful consideration. Herein, we explore the issues that surround testing for hermetic responses and the implications for public policy. Copyright (C) 20 00 John Wiley & Sons, Ltd.