A Model for Dose Rate and Duration of Exposure Effects in Radiation Carcinogenesis

Abstract

Multistage models have been used to describe various features of the incidence of cancer including the shape of the age-incidence curve; the influence of age at, duration of, and time since exposure; and the synergistic effect of exposure to multiple carcinogens. However, the models require from five to seven distinct transformations that must occur in a particular sequence. The lack of experimental support for so many events suggests a simpler model involving only two mutational events with a proliferative advantage for intermediate-stage cells. Neither model easily explains the paradoxical phenomenon that protraction of low linear energy transfer (LET) radiation leads to lower risks per unit of total exposure, whereas the reverse occurs for high-LET radiation. In this paper, a three-stage model is considered that consists of two mutations at homologous sites, either or both of which might be induced by radiation, followed by activation of the transformed oncogene, which is not induced by radiation. Single-stranded lesions are potentially repairable, whereas double-stranded lesions may increase the proliferation rate. For low-LET radiation, these two mutations are more likely to occur as the result of independent transversals of a cell by separate quanta of radiation, whereas for high-LET radiation, they are more likely to occur simultaneously as the result of a single particle. The predictions of the model are illustrated for various patterns of exposure and choices of model parameters. Various tests of the proposed model are discussed.

Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk

“…A critical assumption in our analysis of the power-age relationship is that the underlying process is describable by the multistage model of Armitage and Doll, with a constant number of driver mutation stages k . This implies that the incidence at age t a power of age is approximately CN 0 t k −1 [ 4 , 8 , 11 ]. While this is the case for most cancers considered here, with a range of the exponent k between 5 and 7 [ 3 ], it is certainly not the case for certain pediatric tumors, in particular acute lymphocytic leukemia, which is not one of the tumors considered by Tomasetti and Vogelstein [ 2 ].…”

Methods for investigating age differences in the effects of prolonged exposures

“…The belief that cancer development is a multistage process is supported by the evidence of long latency periods between exposures and subsequent cancer, the effects of age on cancer incidence, and evidence that different exposures may act as initiators or promoters of cancer [Pearce, 1988]. Theoretical models of such multistage processes suggest that the effect of an exposure depends on the age at which exposure occurs [Thomas, 1990]. Under a multistage model of cancer, in order for cancer to occur a cell must pass through several sequential changes [Brown and Chu, 1987].…”