presented that the inverse dose-rate effect can be observed when cells do not arrest in G2 and, instead, correlates with low-dose hyper-radiation sensitivity (HRS; Mitchell and others 2002). This conclusion may be consistent with recent results from the same research group (Marples and others 2003), which reported that HRS for acute radiation doses was attributed to cells in radiosensitive G2 failing to arrest before mitosis. For high-LET radiation, the inverse dose-rate effect has been attributed to the traversal of cells through a radiosensitive G2 phase (Brenner and others 1996; Elkind 1996; Tauchi and others 1999). Such an inverse dose-rate effect has been reported for cell lethality and mutations induced by low-LET radiation and for transformation induced by high-LET radiation.

Vilenchik and Knudson (2000) hypothesized that the increase in mutability observed below a dose rate of 1 mGy/min for mouse spermatogonia and 10 mGy/min for cells in vitro is not caused by variations in radiosensitivity during the cell cycle but rather by a diminished activation of error-free repair at very low dose rates inasmuch as the rate of induced DNA damage (signal) is lower than the background rate of spontaneous DNA damage (noise). This interpretation of the data remains controversial, particularly since there is evidence that argues against the inducibility of DNA repair genes. However, Collis and colleagues (2004) reported recently that DNA damage introduced at a very low dose rate of 0.33 or 1.5 mGy/min produced less activation of the radiation damage sensor ATM (ataxia-telangiectasia-mutated), as detected by H2AX foci, than activation at a high dose rate of 750 mGy/min. Furthermore, this reduction of ATM activation was observed after irradiation in Go/G1, S, and G2/M, and correlated with enhanced cell killing. For a discussion of the expression of particular genes involved in DNA repair and controlling checkpoints in the cell cycle, see “DSB Signal Transduction and Inducible Repair” in Chapter 1, along with Figure 1-10.

Although some small transient effects on cell cycle progression have been reported for doses of 20–100 mGy (Puck and others 1997; Amundson and others 1999b), no inverse dose-rate effect would be expected at these dose levels (Brenner and others 1996), and if it did exist, it would be difficult to demonstrate. However, at approximately 100 mGy, an inverse dose-rate effect of fission-spectrum neutrons has been observed between 4 and 100 mGy/min for neoplastic transformation of C3H 10T1/2 cells (Hill and others 1982, 1984) and between 10 versus 250 mGy/min and 0.0083 versus 0.083 mGy/min for induction of lung adenocarcinomas and mammary adenocarcinomas in mice (Ullrich 1984). Apparently, these inverse dose-rate effects could not be explained by perturbations in the cell cycle, and for mammary tumors, the effect was associated with an increased probability of progression of carcinogen-altered cells rather than an increased number of initiated cells (Ullrich 1986). Furthermore, an inverse dose-rate effect was not observed for the induction of ovarian tumors, for which the response to dose at low dose rates was much lower than that at high dose rates (Ullrich 1984). How these data on high-LET fission neutrons can be extrapolated to low-LET radiation is unknown, especially because the RBE for these carcinogenic effects has been estimated to be as high as 10 or more. This means that the equivalent doses and equivalent dose rates mentioned above, when expressed in millisieverts, would be at least 10 times greater than the values expressed in milligrays.

Furthermore, when the same tumors were induced in mice by low-LET radiation at doses of 0.1–6.0 Gy, no inverse dose-rate effect was observed between 0.04 and 0.6 mGy/min; these low dose rates always had a dose-response relationship significantly below that observed for acute high-dose-rate irradiation (Ullrich and others 1976, 1987; Ullrich and Storer 1979a, 1979b, 1979c; Ullrich 1983). Similar observations were reported for neoplastic transformation of C3H 10T1/2 cells by low-LET radiation, for which the dose-response relationship for a low dose rate of 1 mGy/min was much below that observed for an acute high dose rate of 1.0 Gy/min (Han and others 1980). The lack of a low-LET inverse dose-rate effect for tumor induction and neoplastic transformation in vitro contrasts with the inverse dose-rate effect seen for cell killing and induction of mutations that is sometimes attributed to perturbations in cell cycle progression. However, results obtained with mammalian cell lines, in particular those for neoplastic transformation, should be interpreted with great caution if they are to be used in estimating radiation risk to humans.


Organisms, such as bacteria, that live in a highly changeable environment have multiple mechanisms for adapting to environmental stress. The bacterium Escherichia coli has two distinct, inducible, redox-regulated transcriptional switches involving the soxRS and oxyR transcription factors, which respond to exposure to superoxide and hydrogen peroxide, respectively (Demple 1991; Choi and others 2001). After exposure to ionizing radiation, these factors re-program the cellular transcription pattern with increased expression of proteins that inactivate reactive oxygen species and some DNA repair enzymes that process oxidative DNA damage. As a consequence, E. coli cells exhibit a distinct adaptive response to oxidative stress: exposure to a low dose of active oxygen makes the cells more resistant to later exposures for some finite period. In that situation, there is a clear threshold value for deleterious effects of ionizing radiation. However, the soxRS and oxyR gene regulons have not been conserved during evolution, and human cells, which exist in a much more stable cellular environment than bacteria, do not appear to have counterparts. Thus, humans do not have an adaptive response to oxidative damage similar to the well-characterized systems in bacteria.

The National Academies of Sciences, Engineering, and Medicine
500 Fifth St. N.W. | Washington, D.C. 20001

Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement