Two Mutation Model for Carcinogenesis: Relative Roles of Somatic Mutations and Cell Proliferation in Determining Risk
Two experimental data sets are analyzed within the framework of a two-event model for carcinogenesis. In the first, the number and size distribution of altered hepatic foci, which are thought to be premaligant lesions, are analyzed as functions of dose of an administered agent (N-Nitrosomorpholine, NNM). Definitions of initiation and promotion potencies are proposed. Results of the analysis indicate that NNM is a strong initiator and a weak promoter. In the second, the time to appearance and the probability of malignant lung tumors in rats exposed to radon are analyzed as functions of total exposure and rate of exposure. The results indicate that fractionation of exposure increases the lifetime probability of tumor, and that the efficiency of fractionation can be explained by the relative effects of radon daughters on the mutation rates and the kinetics of growth of initiated cells.
KeywordsTotal Exposure Exposure Rate Intermediate Cell Radon Exposure Lifetime Probability
Unable to display preview. Download preview PDF.
- 1.Campbell HA, Zu, YD, Hanigan MH, Pitot HC: Application of quantitative stereology to the evaluation of phenotypically heterogeneous enzyme-altered foci in the rat liver. JNCI 76:751–767, 1986.Google Scholar
- 3.Emmelot P, Scherer E: The first relevant cell stage in rat liver carcinogenesis: A quantitative approach. Biochimica et Biophysica Acta 605:247–304, 1980.Google Scholar
- 5.Goldfarb S, Pugh TD: Enzyme histochemical phenotypes in primary hepatocellular carcionmas. Cancer Research 41:2092–2095, 1981.Google Scholar
- 9.Moolgavkar SH, Knudson AG Jr: Mutation and cancer: A model for human carcinogenesis. JNCI 66:1037–1052, 1981.Google Scholar
- 11.Moolgavkar SH, Cross FT, Luebeck EG, Dagle RE : A two-mutation model for radon-induced lung tumors in rats. Radiation Research, in press.Google Scholar
- 12.Moolgavkar SH, Luebeck EG, de Gunst M, Port RE, Schwarz M: À method for the quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments I: Single agent regimen. Submitted.Google Scholar
- 13.Nychka D, Pugh TD, King JH, Koen H, Wahba G, Chover J, Golfarb S: Optimal use of sampled tissue sections for estimating the number of hepatocellular foci. Cancer Research 44:178–183, 1984.Google Scholar
- 17.Wickseil DS: The Corpuscle problem, Part I. Biometrika 17:87–97, 1925.Google Scholar