Effects on DNA, Genes, and Chromosomes

An exposure to low-LET radiation that is lethal to 50 percent of dividing cells—i.e., approximately 1.5 Sv (150 rem)—produces substantial DNA damage, hundreds of strand breaks per cell. Nevertheless, roughly 50 percent of the cells survive, indicating that much of the damage is reparable (Cole et oL, 1980). The effectiveness of repair processes is thus an important factor in determining the fate and effects of lesions in DNA. 

In keeping with the production of damage to DNA, the fiequency of specific locus mutations in mouse spermatogonia increases as a linear-quadratic function of the dose of low-LET radiation in mammalian diploid cells (NCRP, 1980). The increase per unit dose of low-LET radiation is lower by a factor of about three at low doses and low dose rates than at high doses and high dose rates, corresponding to approximately 6 mutations per 10 per locus per 1 Sv (1()0 rem) (NAS/NRC, 1980 UNSCEAR, 1982). With fast neutrons, the frequency of mutations in such cells increases more steeply, as a linear function of the dose, and is relatively independent of the dose rate. As a result, the RBE of neutrons for mutations in mammalian cells increases to about 

For either class of clastogens, chromosomal aberrations, as indicated earlier, appear to be involved mechanistically in the etiology of experimentally induced tumors in animals and of iatrogenic tumors in humans (Radman et oL, 1982 Rowley, 1982, 1984 Yunis, 1983 Sandberg, 1983). 

Chemical clastogenesis and mutagenesis both involve a complex series of processes, including pharmacokinetic mechanisms (uptake, transport, diffusion, excretion), metabolic activation and inactivation, production of DNA lesions and their incomplete repair or misrepair, and steps leading to the subsequent expression of mutations in surviving cells or individuals (Thble 7.1). Each of the steps in these processes might conceivably involve first order kinetics at low doses (e.g., diffusion, MichaeUs-Menten enzyme kinetics) and hence be linear. In principle, therefore, the overall process edso might be linear and without threshold. 

Absorbed ptemutagen activation deactivation transport Pharmacologic dose mg/kg 

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In vivo, neither covalent binding to DNA nor DNA strand breakage was induced in several studies on rat liver, and unscheduled DNA s mthesis was not induced in the liver of either rats or mice. Gene mutations were not induced in the liver of dosed mice in a single study and there was no evidence for induction of chromosomal aberrations in mice or rats. Aberrations were induced, however, in the embryos of dosed pregnant Syrian hamsters. Dominant lethal effects were reported to be induced in male mice, but re-evaluation of these data did not confirm this conclusion. 

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