Risk assessment methodology: maximum tolerated dose and two-stage carcinogenesis models.

The Committee on Risk Assessment Methodology of the Board on Environmental Studies and Toxicology of the National Academy of Sciences has considered issues related to the use of the maximum tolerated dose (MTD) in carcinogenesis bioassays and of 2-stage models of carcinogenesis. In each case, the goal has been to consider whether sufficient information is available to lead to a change in current methodology used by regulatory agencies in assessing risk. The majority of the committee favored retention of the MTD but recommended that lower doses also be used for cancer bioassays and, if the results are positive, performance of additional mechanistic studies aimed at improved extrapolation to environmentally relevant concentrations. The minority recommended that additional preliminary studies be done in order to obtain information about the highest dose relevant to extrapolation to humans for use in the cancer bioassay. Two-stage carcinogenesis models were found to be an excellent approach to increase understanding but required an extensive toxicological data base beyond that available for most chemicals. These deliberations have highlighted the value of increased understanding of the basic mechanisms of action of potential cancer-causing chemicals in order to advance the methodology of risk assessment.