Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates

Abstract

The mutagenic effect of low linear energy transfer ionizing radiation is reduced for a given dose as the dose rate (DR) is reduced to a low level, a phenomenon known as the direct DR effect. Our reanalysis of published data shows that for both somatic and germ-line mutations there is an opposite, inverse DR effect, with reduction from low to very low DR, the overall dependence of induced mutations being parabolically related to DR, with a minimum in the range of 0.1 to 1.0 cGy/min (rule 1). This general pattern can be attributed to an optimal induction of error-free DNA repair in a DR region of minimal mutability (MMDR region). The diminished activation of repair at very low DRs may reflect a low ratio of induced ("signal") to spontaneous background DNA damage ("noise"). Because two common DNA lesions, 8-oxoguanine and thymine glycol, were already known to activate repair in irradiated mammalian cells, we estimated how their rates of production are altered upon radiation exposure in the MMDR region. For these and other abundant lesions (abasic sites and single-strand breaks), the DNA damage rate increment in the MMDR region is in the range of 10% to 100% (rule 2). These estimates suggest a genetically programmed optimatization of response to radiation in the MMDR region.

Figure 1

DREs of low LET radiation upon HPRT mutations (×10⁸). + and 1, mouse L5178Y cells, per cGy (refs. and –, and reviewed in refs. , , and 5). Points E1 and E2 are Evans and coworkers' data (13). □ and 2, Chinese hamster V-79, subline 85 cells, per 4 cGy (6). × and ▵, Human TK6 lymphoblastoid cells, per cGy. ×, refs. and . Points K1, K2, and K3 are König's and Kiefer's data (18). Points G1–G5 are from Grosovsky and Little (14). Points ▵ G2–G5 resulted from irradiation at multiple acute doses (see text). Curves 1 and 2 are of the parabolic form, y = ax² + bx + c.

Figure 2

DREs on specific locus mutations induced by low LET ionizing radiation in mouse spermatogonia. Data in Table 1: ○, ref. ; □, ref. . The curve fitted to the data are y = 1.55x² + 4.5x + 8.53.

Figure 3

Arrhenius plots. The rate of spontaneous production of AP sites and single-strand breaks in DNA exposed to different temperatures in vitro or in vivo. 1, (○), Spontaneous loss of purines from native Bacillus subtilis DNA heated in buffer at pH 5. The low pH experimental values (34) have been recalculated here for conditions of incubation in the same buffer at pH 7.4 based on the published dependence of DNA depurination on pH (34), to permit comparison of rates of spontaneous production of different DNA lesions at physiological pH. 2, (▵), Spontaneous loss of adenine from native calf thymus DNA in 0.005 M phosphate buffer (pH 6.8) (data from refs. and 40). 3, (◊), Spontaneous hydrolysis of the phosphate-diester bond in single-stranded bacterial DNA in 0.0025 M phosphate buffer, pH 6.8 (data from ref. 41). Points a and b, rates of induction by mild hyperthermia of alkali-labile sites, including AP sites, in DNA of human diploid fibroblasts of strains 18J, L3, and D3. The values of the rate constants for strains 18J and L3 were about the same (data from refs. and 26), and, therefore, these values are shown as one point, b. The plotted data were reviewed in ref. .