BIOLOGICAL BASES FOR CANCER DOSE-RESPONSE EXTRAPOLATION PROCEDURES

The Moolgavkar-Knudson theory of carcinogenesis of 1981 incorporates the viable portions of earlier multistage theories and provides the basis for both the linearized multistage and biologically based dose-response extrapolation methodologies. This theory begins with the premise that cancer occurs because irreversible genetic changes (mutations) are required for transformation of normal cells to cancer cells; incidence data are consistent with only two critical changes being required, but a small contribution from three or higher mutation pathways cannot be ruled out. Events or agents that increase the rate of cell division also increase the probability that one of these critical mutations will occur by reducing the time available for repair of DNA lesions before mitosis. The DNA lesions can occur from background causes or from treatment with mutagenic agents. Thus, the equations describing incidence as a function of exposure to carcinogenic agents include two separate terms, one accounting for mutagenic ...