that these multiple steps can have on the shape of the dose-response relationship at low doses.

RADIATION AND ONCOGENES

The identification of oncogenes and findings on their role in human cancer have made it possible to understand why agents as diverse as retroviruses, ionizing radiation, and chemicals can result in tumors that are indistinguishable from one another (Bishop 1983; Bishop and Varmus 1984). A retrovirus can insert a gene into a cell, and radiation and chemicals can produce a mutation in a gene that is already in the cell; all can activate oncogenes.

A central feature of oncogenes is that they act in a dominant fashion. The presence of a single copy of an activated oncogene in a cell is sufficient to produce a transformed phenotype, even in the presence of a normal copy of the gene (Lee and others 1987). Cells that are already immortal, such as NIH 3T3 mouse cells, can be transformed to a malignant state by transfection with a ras oncogene. Primary rat embryo fibroblasts, which are short-term cultured cells, are not transformed by the ras gene alone or by the myc gene alone, but can be transformed by transfection of the cells with both myc and ras (Land and others 1983). That is interpreted to mean that the myc gene confers immortality, whereas the ras gene produces the change reflected in morphology (Land and others 1983). Generally, at least 2 activated oncogenes in cooperation are needed to convert a primary cell to a tumorigenic line (Hunter 1991). Oncogene products that act in the nucleus cooperate most efficiently with products that act in the cytoplasm, as exemplified by the combination of ras and myc.

Over 100 oncogenes have been identified in human cancer; most belonging to the ras family. However, activated oncogenes are associated with 10–15% of human cancers and tend to be found more commonly in the leukemias and lymphomas and less commonly in solid tumors. Oncogenes have been shown to be activated by a range of genetic changes, for example by point mutations, as in ras (Bos 1990); deletions, as in Nmo-1 (Petersen and others 1989); reciprocal translocations, as in myc (Dalla-Favera and others 1983); and gene amplification, as in myc (Brodeur and others 1984).

Ionizing radiation, including alpha radiation, is not particularly efficient at producing point mutations, but it does produce large interstitial deletions and reciprocal translocations with high efficiency (for example Evans 1991; Metting and others 1992; Searle and others 1976). Consequently, in assessment of the predominant initial radiation damage — the first of the many steps by which alpha particles can induce cancer — deletions or translocations seem to be the most likely candidates for the first changes.

Numerous experimental and epidemiologic studies have demonstrated that radiation can cause cancer (Martland 1931; Court-Brown and Doll 1958; Beebe and others 1962). That it does so via direct or indirect alterations to DNA is clear



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