In fact, this is one of the few instances for which a linear relationship could be rejected statistically. Studies in other mouse strains, while having less statistical power, also suggest a high sensitivity to induction of ovarian tumors at relatively low doses but with an apparent threshold (Lorenz and others 1947; Ullrich and Storer 1979c). This relatively unusual dose-response combining a threshold with high sensitivity to induction is unique to the mouse. Ovarian cancer in the mouse appears to involve an indirect mechanism for induction involving oocyte cell killing and subsequent alterations in the pituitary ovarian hormonal interactions (Kaplan 1950; Foulds 1975; Bonser and Jull 1977). The hormonal alterations are the proximate cause of tumor formation, with the role of radiation being relatively indirect as a result of its cell-killing effects. Because mouse oocytes are uniquely sensitive to the killing effects of radiation (the LD50 [lethal dose—50%] is ~50 mGy), ovarian tumors occur at very high frequencies following relatively low doses of ionizing radiation (Ullrich and Storer 1979c). A threshold appears to exist because a certain level of oocyte killing is required to cause the hormonal alterations that result in ovarian tumor formation. The principal effect of lowering the dose rate is to increase the threshold. In the RFM mouse, estimates of thresholds were reported as 110 mGy for acute exposures and 700 mGy for low-dose-rate exposures (Ullrich and Storer 1979b, 1979c). In contrast to the mouse, oocytes in humans are relatively resistant, with an LD50 of several grays. This difference in sensitivity is apparently because mouse and human oocytes are at different stages of differentiation in the ovary (Brewen and others 1976). The unique sensitivity of the mouse ovary to radiation makes it unlikely that results using this model system would have general applicability to risks in humans.

Radiation-induced skin cancer has been studied in both mice and rats, although the majority of such studies have focused on the rat model because the rat is significantly more sensitive to skin tumor induction than the mouse (Burns and others 1973, 1975, 1989a, 1989b). In both rats and mice, relatively high total doses are required to induce skin cancer, and there is a clear threshold below which no tumors are seen. Multiple repeated radiation exposures are generally required for tumors to develop in mouse skin, while a single high dose (>10 Gy) is capable of inducing tumors in rat skin. It was for skin tumorigenesis that many of the concepts of multistage carcinogenesis were developed, including concepts related to initiation, promotion, and progression, and it is within this framework that the data for radiation-induced skin tumors are best considered (Jaffe and Bowden 1986; Burns and others 1989b). It appears from a variety of studies that single doses of ionizing radiation are capable of initiating cells with neoplastic potential, but that these cells require subsequent promotion in order to develop into tumors (Hoshino and Tanooka 1975; Yokoro and others 1977; Jaffe and Bowden 1986). Without this promotion these latent initiated cells will not express their neoplastic potential.

Several lines of evidence support this view. Hoshino and Tanooka have demonstrated that small doses of beta irradiation are capable of inducing initiating alterations in mouse skin that required subsequent promotion with 4-nitroquinoline N-oxide (4NQO) for tumors to develop. Jaffe and Bowden (1986) have demonstrated the initiating potential of single doses of electrons when followed by multiple exposures to the tumor-promoting agent TPA (12-O-tetradecanoylphorbol-13-acetate). Fry and his coworkers (1986) have shown that X-ray-initiated cells can be promoted to develop skin tumors by exposure to ultraviolet light. This group has demonstrated further that the apparent threshold dose-response for skin tumorigenesis can be converted to a linear UVR dose-response when promotion is used to maximize the expression of latent initiated cells.

Based on such observations it is logical to speculate that the multiple high-dose fractions of radiation that are generally required to induce skin tumors in mouse skin are acting not only to initiate cells but also to induce tissue damage via cell killing, which in turn acts as a promoting stimulus to facilitate the progression of these initiated cells into skin tumors. Likewise in the rat, the high doses required to produce tumors are likely to produce both transformation of cells and sufficient cell killing to promote the transformed cells. This phenomenon does not appear to be unique to these animal systems. Most evidence suggests that relatively high doses of radiation are necessary to induce skin tumors in humans and that these effects can be enhanced by exposure to UV light from the Sun (Shore 2001). It is also important to note studies by Jaffe and Bowden demonstrating that multiple low doses of radiation to the skin that did not produce tissue damage were not effective in promoting skin tumors initiated by chemical agents (Jaffe and Bowden 1986). These data support the view that the predominant role for low-dose radiation is tumorigenic initiation.

Studies of bone cancer also suggest a threshold response and a requirement for prolonged exposure for tumor development from exposure to low-LET radiation (NCRP 1990). Unfortunately most of the available data have focused on observations of effects rather than dissecting potential underlying mechanisms. Attempts have been made to model bone tumorigenesis however, and these models have again focused on an important role for a mechanism involved in the expression of initiated cells in controlling tumor development (Marshall and Groer 1977). Although speculative, it is likely that mechanisms similar to those proposed for skin tumorigenesis involving the cell-killing effects of radiation are likely involved in producing a threshold response for bone tumors.

Fractionation Kinetics

Studies using fractionation regimens have been useful in addressing issues of time-dose relationships in radiation carcinogenesis. In a few instances, investigators have also used



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