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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
volved in a given chromosomal exchange event; not surprisingly, aberration complexity becomes most apparent at high doses of low-LET radiation and at all doses of high-LET radiation (Finnon and others 1995, 1999; Griffin and others 1995; Anderson and others 2000). The precise mechanism of formation of these complexes remains uncertain, but multiple pairwise exchanges involving the same chromosomes play some part (Edwards and Savage 1999). However, cyclic exchanges involving three and four breaks are not uncommon, implying that the interaction of multiple DNA DSBs can occur. Recent studies using multicolor mFISH analyses further emphasize the complexity of many radiation-induced chromosomal exchanges produced after high acute doses of radiation (Loucas and Cornforth 2001). These mFISH analyses also show that even after exposure at very low dose rates, the formation of complex chromosomal exchanges is not completely eliminated (Loucas and others 2004).
Combining FISH painting and premature chromosome condensation techniques (Darroudi and others 1998) has also facilitated studies on the rate of formation of aberrations. In these studies (Darroudi and others 1998; Greinert and others 2000) a substantial portion of exchanges have been shown to form rapidly, although some require several hours. There is some evidence that those aberrations forming rapidly tend to be incomplete exchanges, which suggests a time dependence for pairwise exchange (Alper and others 1988) of DNA DSBs. The general picture that emerges from these biophysical studies is that the misrepair events of radiation-induced DNA DSBs that lead to chromosome aberrations are probably associated with the dominant postirradiation function of the nonhomologous end joining (NHEJ) repair processes described in Chapter 1.
Overall, biophysical approaches to the modeling of dose-response for chromosomal aberrations, although not without some uncertainties on mechanisms, imply that the single-track component of radiation action will dominate responses at low doses and low dose rates (i.e., the dose-response for all forms of aberrations will be linear at low doses and low dose rates). Considerable effort has been expended to test this proposition, and in a very large multicenter study using assays of dicentric aberrations in human lymphocytes, the linearity of the response was evident down to at least 20 mGy of low-LET radiation (Lloyd and others 1992), which is illustrated in Figure 2-5. Below that dose, the statistical power of the data was not sufficient to exclude the theoretical possibility of a dose threshold for radiation effects.
Another important feature of the chromosomal response to radiation is the postirradiation period during which initial DNA damage is fixed and then expressed in the form of aberrations such as dicentric chromosomes. On the basis of direct observation and theory, the conventional cytogenetic view is that all such chromosomal damage sustained within a given cell cycle will be fixed and then expressed at the first postirradiation mitosis. Accordingly, Carrano and Heddle (1973) predicted that the dicentric aberration frequency will fall by a factor of around 2 per cell division on the basis that at each mitotic anaphase, a given dicentric has an equal chance of falling free or producing a lethal anaphase bridge. This prediction has been tested as part of a recent study (Pala and others 2001) that showed dicentric yields falling by up to a factor of 4 between the first and second postirradiation cell division. It seems therefore that the vast majority of initial unrepaired and misrepaired lesions are expressed as chromosomal damage at the first division. Cells carrying unbalanced chromosomal exchanges (dicentrics) or substantial chromosomal losses are not expected to contribute to the viable postirradiation population. By contrast, cells carrying small deletions or balanced exchanges such as reciprocal translocations are likely to remain viable, and some may have the potential to contribute to tumor development.
Later in the chapter this conventional view is contrasted with data implying that in some circumstances, a certain fraction of irradiated cells can express chromosomal damage over many cell cycles (i.e., persistent genomic instability). The proposition that this induced instability phenotype can contribute to tumorigenesis is explored in Chapter 3.
INDUCTION OF GENE MUTATIONS IN SOMATIC CELLS
Ionizing radiation is known to induce a broad range of potentially mutagenic lesions in DNA ranging from damaged DNA bases to frank DNA breaks and chemically complex lesion clusters (see Chapter 1). Not unexpectedly, molecular analyses of radiation-induced somatic mutations at a number of loci provide evidence of induction of point mutations in single genes and of small and large deletions that may encompass a number of physically linked genes (Sankaranarayanan 1991; Thacker 1992). An important factor in the induction and recovery of deletion-type, multilocus mutations is the degree to which multiple gene loss may be tolerated by the cell. There is good evidence that such tolerance is highly dependent on the genetic context of the mutation (i.e., its position in respect to essential genes and, for autosomal loci, the genetic status of the second gene copy on the homologous chromosome). These issues are discussed in depth elsewhere (Thacker 1992); here it is sufficient to note that genetic context can result in up to a twentyfold change in induced mutation frequencies in autosomal genes (Bradley and others 1988; Amundson and Liber 1991). There is strong molecular evidence that in most circumstances, a DNA deletion mechanism dominates mutagenic response after ionizing radiation (Sankaranarayanan 1991; Thacker 1992), and it is for this reason that the genetic context of the mutation is of great importance. In illustration of this, radiation mutagenesis in cells hemizygous (one gene copy deleted) for autosomal APRT (adenine phosphoribosyltransferase) is constrained by the proximity of an essential sequence; induced mutation frequencies are relatively low,