An Examination of Radiation Hormesis Mechanisms Using a Multistage Carcinogenesis Model

Abstract

A multistage cancer model that describes the putative rate-limiting steps in carcinogenesis is developed and used to investigate the potential impact on cumulative lung cancer incidence of the hormesis mechanisms suggested by Feinendegen and Pollycove. In the model, radiation and endogenous processes damage the DNA of target cells in the lung. Some fraction of the misrepaired or unrepaired DNA damage induces genomic instability and, ultimately, leads to the accumulation of malignant cells. The model explicitly accounts for cell birth and death processes, the clonal expansion of initiated cells, malignant conversion, and a lag period for tumor formation. Radioprotective mechanisms are incorporated into the model by postulating dose and dose-rate-dependent radical scavenging. The accuracy of DNA damage repair also depends on dose and dose rate. As currently formulated, the model is most applicable to low-linear-energy-transfer (LET) radiation delivered at low dose rates. Sensitivity studies are conducted to identify critical model inputs and to help define the shapes of the cumulative lung cancer incidence curves that may arise when dose and dose-rate-dependent cellular defense mechanisms are incorporated into a multistage cancer model. For lung cancer, both linear no-threshold (LNT-), and non-LNT-shaped responses can be obtained. If experiments demonstrate that the effects of DNA damage repair and radical scavenging are enhanced at least three-fold under low-dose conditions, our studies would support the existence of U-shaped responses. The overall fidelity of the DNA damage repair process may have a large impact on the cumulative incidence of lung cancer. The reported studies also highlight the need to know whether or not (or to what extent) multiply damaged DNA sites are formed by endogenous processes. Model inputs that give rise to U-shaped responses are consistent with an effective cumulative lung cancer incidence threshold that may be as high as 300 mGy (4 mGy per year for 75 years) for low-LET radiation.