data sets from both strains have yielded similar conclusions. Briefly, a number of dose-response models were seen to describe the data sets adequately. Data on incidence as a function of dose for both strains could be described by quadratic, linear-quadratic, and simple linear dose-responses with insufficient statistical power to exclude any of these three models on the basis of acute exposure data alone. Fractionation of the dose or low-dose-rate exposures resulted in a linear dose-response consistent with expectations of radiobiological theory in which the dose-response is linear quadratic for acute exposures and linear for low-dose-rate exposures, with the linear slope of the linear quadratic predicting the low-dose-rate and fractionation responses. These results are compatible with the apparent role of alterations in chromosome 2 in initial events for murine myeloid leukemogenesis and consistent with mechanistic predictions of dose and time-dose relationships described previously.

This is not the case for studies on thymic lymphoma. In contrast to myelogenous leukemia, for which male mice are the most sensitive, female RFM mice are significantly more sensitive to the induction of thymic lymphoma following radiation exposures (Ullrich and Storer 1979a). For radiation-induced thymic lymphoma in female RFM mice, the data suggest a more complex relationship between radiation exposure and neoplastic development. Following single acute exposures over the 100–3000 mGy dose range, no simple dose-response model was found to describe the data (Ullrich and Storer 1979a). Low-dose-rate exposures, although significantly less effective with respect to induction of thymic lymphoma than single acute exposures, still resulted in a complex dose-response with a clear suggestion of a large threshold (Ullrich and Storer 1979c). These results should not be unexpected since the development of thymic lymphoma in mice following irradiation is an extremely complex process. The target cells for induction of thymic lymphoma are thought to be in the bone marrow rather than the thymus, and the pathogenesis of the disease appears to be largely mediated through indirect mechanisms with cell killing playing a major role (Kaplan 1964, 1967; Haran-ghera 1976). For example, the expression of thymic lymphoma can be substantially reduced or eliminated by protection of bone marrow stem cells from radiation-induced cell killing. The complex nature of the pathogenesis of this disease and the lack of a comparable counterpart in humans argues against thymic lymphoma as an appropriate model for understanding dose-response and time-dose relationships in humans.

Solid Tumors

Data from experimental studies examining dose-response and time-dose relationships are also available for a limited number of solid cancers in female RFM and BALB/c mice, including pituitary, Harderian gland, lung, and breast cancers (Ullrich and Storer 1979b, 1979c; Ullrich 1983). In a large study examining dose and dose-rate effects in female RFM mice, increased incidences of pituitary and Harderian gland tumors were reported. In spite of the large numbers of animals used, analyses of the data with respect to dose-response models could not distinguish between linear and linear-quadratic models (Ullrich and Storer 1979b).

However, when the data for low-dose-rate exposures were considered as well, they were most compatible with a linear-quadratic model (Ullrich and Storer 1979c). Importantly, with respect to low-dose effects, these data support a linear response at low doses that is independent of exposure time. Such a response is consistent with predictions of the mechanistic model outlined earlier in this chapter. Although the number of animals used was smaller, a study examining radiation-induced lung and mammary adenocarcinomas in female Balb/c mice reached similar conclusions with respect to dose-response functions and low-dose risks (Ullrich and Storer 1979c; Ullrich 1983). This model was tested further in a series of experiments comparing the effectiveness of single acute exposures, acute fractionated exposures, and low-dose-rate exposures on the induction of lung and mammary tumors in the Balb/c mouse (Ullrich and others 1987). Importantly, in this study the hypothesis of time independence of effects at low doses was critically tested and found to hold. Specifically, similar effects were observed whether the same total dose was delivered as acute low-dose fractions or as low-dose-rate exposures.

While the data for solid tumors described above are compatible with mechanistic models detailed earlier in this chapter, there are data sets that do not support a linear-quadratic dose-response model. Extensive data for mammary cancer induction in the Sprague-Dawley rat appear more consistent with a linear model over a wide range of doses and with linear, time-independent effects at low doses, low-dose fractions, and low dose rates (Shellabarger and others 1980). Although questions have been raised about the applicability of this model system to radiation-induced breast cancer in humans, much of the data from this rat model, from the mouse model in Balb/c mice, and from epidemiologic studies in exposed human populations appear to be consistent with respect to low-dose risk functions (Preston and others 2002b).

In contrast to the data for leukemia and for pituitary, Harderian gland, lung, and mammary cancer described above, data from studies examining radiation-induced ovarian cancer in mice and bone and skin cancer in various animal species are more compatible with threshold dose-response models. In each instance it appears that an important role for cell killing in the process of neoplastic development and progression may explain these observations.

Analysis of the dose-response for radiation-induced ovarian tumors following single acute or low-dose-rate exposures in RFM female mice indicated a marked sensitivity to induction at relatively low radiation doses, but equally importantly the analysis of the data strongly supported a threshold dose-response model (Ullrich and Storer 1979b, 1979c).



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