Risk Assessment Methodology: Maximum Tolerated Dose and Two-Stage Carcinogenesis Models

Abstract

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.

Keywords

Cancer risk carcinogenesis assay cancer bioassay National Research Council

References

1. Ames BN and Gold LS (1990). Too many rodent carcinogens: Mitogenesis increases mutagenesis. Science 249: 970–971.

2. Cohen SM and Ellwein LB (1990). Proliferative and genotoxic cellular effects in 2-acetylaminofluorene bladder and liver carcinogenesis: Biological modeling of the ED01 study. Toxicol. Appl. Pharmacol. 104: 79–93.

3. Cohen SM and Ellwein LB (1991). Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6493–6505.

4. Gold LS , Sawyer R , Magaw GM , Backman M , DeVeciana , Levinson R , Holoper NK , Havender WR , Bernstein L , Peto R , Pike MC , and Ames BN (1984). A carcinogenic potency database of the standardized results of animal bioassays. Environ. Health Perspect. 58: 9–21.

5. Gold LS , Slone TH , and Bernstein L (1989). Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environ. Health Perspect. 79: 259–272.

6. McConnell EE (1989). The maximum tolerated dose: The debate. J. Am. Coll. Toxicol. 8: 1115–1120.

7. Moolgavkar SH (1988). Biologically motivated two-stage model for cancer risk assessment. Toxicol. Lett. 43: 139–150.

8. Moolgavkar SH and Luebeck G (1990). Two-event model for carcinogenesis: Biological, mathematical, and statistical considerations. Risk Anal. 10: 323–341.

9. National Research Council (1983). Risk Assessment in the Federal Government: Managing the Process. National Academy Press, Washington, D.C.

10.

10. National Research Council (1993). Issues in Risk Assessment. National Academy Press, Washington, D.C.

11.

11. Vogelstein B , Fearon ER , Hamilton SR , Kern SE , Preisinger AC , Leppert M , Nakamura Y , White R , Smits AM , and Bos JL (1988). Genetic alterations during colorectal-tumor development. New Engl. J. Med. 319: 525–532.