Based on consideration of the available in vivo data it is concluded that, at present, only a weak scientific case can be made for a discernible impact of induced genomic instability on radiation cancer risk. This conclusion is strengthened when account is also taken of the uncertainties noted in Chapter 2 regarding the biological basis and generality of the expression of induced genomic instability in cultured mammalian cells.
The preceding discussion of potential mechanisms for radiation-induced cancer has indicated an important role for radiation-induced DNA DSBs, damage response pathways, and gene or chromosomal mutations in the initial events leading to cancer development. On this basis it would be predicted that the form of the dose-response for radiation-induced cancer and the effects of fractionation or reduced dose rate on this dose-response would be compatible with such underlying mechanisms unless factors involved in the expression of initiated cells are limiting in neoplastic development. Such a mechanistic model provides specific predictions with respect to dose-response and time-dose relationships for initial events and provides a framework for prediction of dose-response and time-dose effects for radiation-induced cancer (Ullrich and others 1987). Animal studies can be used to test these predictions. This framework is based on the αD+βD2 dose-response model for chromosome aberration induction described in Chapter 2. For single acute exposures the dose-response would be predicted to follow this model such that at low doses the relationship between cancer incidence and dose would be linear, while at higher doses this relationship would follow a function more closely related to the square of the dose. It is unlikely from a statistical standpoint alone that such a function could be proven to hold to the exclusion of all other dose-response models for any set of experimental data.
Because of this, time-dose studies using both fractionated and low-dose-rate exposure regimens are important components in testing mechanistic predictions. On the basis of this model, it would be predicted that the dose-response following low-dose-rate exposures would be linear, with the same slope as the linear portion of the acute dose response model. In other words, at low doses the risk of radiation-induced cancer is independent of the time over which exposure occurs and is a cumulative function of dose. Fractionated exposures can further test these time-dose relationships and also provide information on the kinetics of processes involved. Such kinetic information, while limited, can provide insight into the nature of cellular versus tissue effects as major components in cancer risks in the specific experimental model under study.
Any critical analysis of quantitative data on radiation-induced cancer requires informed selection of data sets. First, the adequacy of a study with respect to statistical power and use of appropriate analytical methodology must be considered. Second, biological factors involved in the pathogenesis of specific neoplasms must be considered with respect to the applicability of the experimental model to carcinogenesis in general and to cancer risk in humans in particular. Given these caveats, there are relatively few studies on animal carcinogenesis where the data are sufficient to address the issue of dose-response relationships or the issue of dose-rate effects and/or fractionation effects. Those studies in which such analyses are possible are limited mainly to rodent studies, principally mice. Biological factors in neoplastic development must also be noted.
As discussed later in this chapter genetic background has a major role in determining neoplastic development at the level of sensitivity to both initiating events and events involved in expression. Therefore even in mouse studies in which there is sufficient statistical power to address questions of low-dose effects and time-dose relationships, the data are limited to mouse strains that are highly susceptible to specific forms of neoplasias. While variations in susceptibility must be considered potential confounding factors in applying animal data to human risks, careful analyses of human and animal data suggest that animal data do in fact have predictive value—for example, they can guide judgments on the choice of cancer risk models (Carnes and others 1998; Storer and others 1988). On the other hand, there are specific murine neoplasms whose pathogenesis appears to be unique to the mouse. In these specific instances it is unlikely that data derived using these systems would be applicable to human risks. These neoplasms are identified in sections below.
The induction of leukemia and lymphoma has been examined in a number of murine systems, but the most extensive quantitative data on both dose-effects and time-dose relationships are for myeloid leukemia and thymic lymphoma. The most comprehensive data for myeloid leukemia with respect to dose-response relationships, and fractionation and dose-rate effects are in CBA male mice and RFM male mice (Upton and others 1970; Mole and Major 1983; Mole and others 1983). Interestingly, susceptibility in female mice of the same strains is markedly lower. The CBA mouse has also been used as an important model to dissect underlying radiation-induced molecular events described earlier (Bouffler and others 1991; Clark and others 1996; Silver and others 1999). For both strains, studies have been conducted over the dose range 250–3000 mGy (Upton and others 1970; Mole and Major 1983; Mole and others 1983). Analyses of