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Health Effects of Exposure to Low Levels of Ionizing Radiations: Time for Reassessment?
Gibbs and others 1987; Kronenberg and Little 1989; Lutze and others 1990; Whaley and Little 1990; Aghamohammadi and others 1992; Lutze and others 1992, 1994; Jostes and others 1994; Bao and others 1995; Jin and others 1995; Kronenberg and others 1995; Chaudhry and others 1996). There is some indication that after high-LET radiation, more-complex mutational rearrangements are involved, in addition to the short repeat sequences (Meuth 1990; Simpson and others 1993; Thacker 1996).
The findings of short direct-repeat DNA sequences at sites of large-deletion rejoining, as well as the more complex rearrangements, suggest that a form of illegitimate recombination initiated by a break in DNA is involved in the mutational process. That idea is supported by the results of experiments that reconstructed the process of illegitimate recombination in cell-free conditions by using a DNA substrate with a site-specific DSB and showed that misrejoining is associated with short direct—repeat sequences on either side of the break (North and others 1990; Ganesh and others 1993; Thacker 1994). Research with heterozygotes, in addition to indicating tolerance of large deletions, has also indicated the possibility of mitotic recombination or nondisjunction with a suggestion that recombination is more common than deletion in spontaneous mutants (Fujimori and others 1992; Li and others 1992). There is also an interesting result of a comparison of two cell lines derived from the same original cell but differing in p53 status, DSB rejoining, and recombination ability. The cell line resistant to radiation-reduced killing had a higher radiation-induced mutant frequency, which suggests that it has a higher rate of recombination and can then survive with a concomitant higher rate of mutation (Amundson and others 1993; Xia and others 1994). Delayed apoptosis might well be the reason for this cell's resistance to cell killing (Xia and others 1995; Zhen and others 1995).
In addition to the large deletions induced by radiation, a study of the HPRT and APRT genes has revealed that all types of small mutations occur in response to radiation—such as base-pair substitutions, frameshifts, and small deletions—and that they occur at sites distributed throughout the target genes (Grosovsky and others 1988; Miles and Meuth 1989; Nelson and others 1994). In contrast, spontaneous point mutations tend to occur preferentially at particular sites in the genes. Radiation leads to more transversion and frameshift mutations than are found spontaneously, but large intergenic mutants occur spontaneously at a substantial frequency.
The determination of quantitative dose-effect relationships is more difficult in the ease of mutation than in the ease of chromosomal aberrations but the measurements that have been made indicate a curvilinear relationship for sparsely ionizing radiation, in general, and a linear relationship at low doses (Cox and others 1977). Recent molecular-biology techniques are providing more insight into the mechanisms that lead to mutations after radiation. Although DNA DSBs and complex damage are clearly implicated with recombinational repair processes, the precise mechanisms remain to be elucidated.