Principles underlying dose selection for, and extrapolation from, the carcinogen bioassay: dose influences mechanism

The purpose of the bioassay is not to simply find chemicals that can be labeled as carcinogens. On the contrary, the overall goal is to provide a reasonable assessment of the possible hazard that a chemical might pose to people under realistic conditions of exposure. This paper focuses upon the doses commonly used in the bioassay within the context that dose influences mechanism and, over a wide range of doses, mechanism changes with changing dose. Thus, a carcinogenic effect observed at a high dose is not necessarily expected to occur at lower doses. A variety of examples are provided to illustrate the points that (a) any high dose, no matter how high, that permits test animals to live long enough to develop tumors is not an appropriate criterion for defining an acceptable high dose to employ in a carcinogen bioassay; and (b) emphasis should be placed upon research that may discern probable thresholds for the carcinogenic effect of chemicals, especially nongenotoxic chemicals.