tions in mouse splenic T lymphocytes, the DDREF was ~1.5 at 1 Gy and ~4 at 5 Gy. Also, in Figure 10-2, dose-response curves for the incidence of solid cancers in Japanese A-bomb studies were constructed over the dose range of 0–1.5 Sv, assuming α/β = 1.45 Sv and α/β = 3.33 Sv, and DDREF values were calculated by dividing the slope of curve B by the slope of curve D. These slope ratios give DDREF values of 1.8 for α/β = 1.45 Sv and 1.3 for α/β = 3.33 Sv.

Several factors may affect the theoretical dose-response relationships described above, namely: variations in radiosensitivity during the cell cycle; induction of an adaptive response to an initial exposure, which can reduce the effect of later exposures; a bystander effect that causes an irradiated cell to have an effect on a nearby unirradiated cell; the induction of persistent genomic instability; and hyper-radiation sensitivity in the low-dose region. Except for the cell cycle, these factors have been identified and studied since the BEIR V report (NRC 1990). These factors, together with data on the induction of gene/chromosomal mutations in somatic cells are discussed in subsequent sections of this chapter.

INDUCTION OF CHROMOSOME ABERRATIONS

Early studies on the mechanisms of chromosome aberration induction summarized by Savage (1996) lead to the following conclusions: Primary radiation-induced break-type lesions can (1) reconstitute without morphological change to chromosomes; (2) rejoin illegitimately with another break close in time and space to produce an intra- or interchromosomal aberration visible at the subsequent mitosis; or (3) remain “open,” leading to a simple break at mitosis. These early conclusions, based primarily on work with plant cells, are supported by subsequent studies with mammalian cells. The quantitative cytogenetic systems developed over the years, particularly in G0 human lymphocytes, have been utilized in studies on the effects of dose, dose rate, and radiation quality. From a mechanistic viewpoint there is compelling evidence that the induction and interaction of DNA double-strand breaks (DNA DSBs or, more correctly, double-stranded lesions) is the principal mechanism for the production of chromosome aberrations. The fundamental arguments supporting this widely accepted conclusion have been discussed in depth (Bender and others 1974; Scott 1980; Cornforth and Bedford 1993; Natarajan and Obe 1996). Of particular note are the data showing excess aberrations following the introduction of DNA DSB-inducing restriction endonucleases into cells (Bryant 1984; Obe and others 1985; Morgan and Winegar 1990). The increased chromosomal radiosensitivity in cells genetically deficient in processes associated with DNA DSB repair, reviewed by ICRP (1998), also supports this conclusion.

The biophysical modeling of the dose-response and LET dependence for chromosome aberration induction has been a major focus in radiobiological research for many years. In the following paragraphs, a brief outline is provided of the current state of knowledge of the mechanisms that are believed to play a role in the induction of chromosomal aberrations (see Bedford and Dewey 2002 for a detailed discussion). Aberrations formed following irradiation of cells in the G0/G1 phase of the cell cycle are dicentric exchanges, centric rings, and monocentric exchanges (translocations). The vast majority of studies show that the dose-response for low-LET radiation is curvilinear and fits well to the equation αD + βD2. At high doses, saturation effects occur, and the dose-response tends to turn down; for human lymphocytes, saturation occurs at doses greater than 4–5 Gy. The linear coefficient α, representing the initial slope of the dose-response, increases with the LET of the radiation, reaches a maximum at ~70 keV μm−1, and then falls. The quadratic coefficient β is approximately constant up to around 20 keV μm−1 but reduces at higher LET (>100 keV μm−1). A reduction in low-LET dose rate reduces aberration yields in a dose-dependent manner; the value of α is unaffected, but the value of β decreases (Edwards and others 1989).

A current explanation of the above dose-response characteristics is that DNA DSBs are the principal causal events for aberration induction and that these are induced with linear kinetics at around 30 DNA DSBs Gy−1. Correct repair and misrepair processes operate in competition for these DNA DSBs, with the majority of breaks restituting correctly and a small fraction taking part in misrepair-mediated chromosomal exchanges (Hlatky and others 1991). The fraction of misrepair events is suggested to be dose dependent, with the close proximity of DNA DSBs promoting exchanges and thereby imposing curvature on the low-LET dose response. The two-track component of DNA lesion production and interaction increases as a quadratic function of dose and produces biophysical curvature on the dose-response. However, the concept of proximity-promoted interaction of lesions gives more weight to lesions arising along the path of single tracks. Such proximity effects have been reviewed (Sachs and others 1997). Modeling procedures of this type, while providing a coherent explanation of low-LET dose-response, are insufficient to account fully for high-LET effects (Moiseenko and others 1997). An additional factor considered in some modeling of dose- and LET-dependent responses is the possibility that some exchanges might involve interaction of a DNA DSB with an undamaged DNA site (i.e., recombinational-like DNA misrepair). It seems likely that a variety of repair and misrepair options are available to the cell and that their relative importance is LET dependent; this feature may relate to the complexity of a significant fraction of initial DNA DSBs (see Chapter 1).

Dose and LET dependence also apply to the morphological complexity of the induced chromosomal aberrations themselves. The development of fluorescence in situ hybridization (FISH) methods of chromosome painting has allowed aberration complexity to be studied in detail. In brief, aberration complexity reflects the number of DNA DSBs in-



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement