Stochastic models of the bystander effect and of transmissible genomic instability: implications for mechanisms and low dose risks

Bystander effects following exposure to α -particles have been observed in C3H 10T cells and in other experimental systems, and imply that linearly extrapolating low dose risks from high-dose data might materially underestimate risk. In many experimental systems there is evidence of saturation of dose response that would be expected from the bystander effect. The ratio of lung cancer risk among persons exposed to low and high doses of radon daughters is 2.4 -- 4.0, with an upper 95% confidence limit of about 14. Assuming the bystander effect observed in the C3H 10T data applies to human lung cells in vivo, the epidemiological data imply that the number of neighbouring cells that can contribute to the bystander effect is between 0 and 1, with an upper 95% confidence limit of about 7. As a consequence, the bystander effect observed in the C3H 10T system probably does not play a large part in the process of radon-induced lung carcinogenesis in humans. Other experimental data relating to the bystander effect after α -particle exposure are surveyed; some of these data are more compatible with the epidemiological data. Three models of genomic instability recently developed by Little and Wright (Math. Biosci. 2003;183:111-34), with two, three and five stages, are compared with the four-stage model proposed by Luebeck and Moolgavkar (PNAS 2002;99:15095-100) and the two-stage model of Nowak et al. (PNAS 2002;99:16226-31). All models are fitted to SEER colon cancer data. Although the five-stage model of Little and Wright (2003) provides the best fit, it is not much superior to that of the model of Nowak et al. (2002) or the two- and three-stage models of Little and Wright (2003). The fit of the model of Luebeck and Moolgavkar (2002) is somewhat worse than these three, particularly for females under the age of 40. Comparison of the predictions of the two-stage models of Little and Wright (2003) and Nowak (2002) with patterns of excess risk in the Japanese atomic bomb survivor colon cancer incidence data indicate that radiation might act on cell proliferation rates in the model, and at least for the model of Little and Wright also on one of the parameters governing progression to genomic destabilization.