During the last decade, evidence has accumulated that under certain experimental conditions, the progeny of cells surviving radiation appear to express new chromosomal aberrations and gene mutations over many postirradiation cell generations. This feature is termed radiation-induced persistent genomic instability. Some inconsistencies were identified in the data that describe the diverse manifestation of induced genomic instability, and clear evidence of its general involvement in radiation-induced cancer is lacking. Although developing data on the various phenomena classified as genomic instability may eventually provide useful insights into the mechanisms of carcinogenesis, it is not possible to predict whether induced genomic instability will influence low-dose, low-LET response relationships.
Research Need 3. Evaluation of the relevance of adaptation, low-dose hypersensitivity, bystander effects, and genomic instability for radiation carcinogenesis
Mechanistic data are needed to establish the relevance of these processes to low-dose radiation exposure (i.e., <100 mGy). Relevant end points should include not only chromosomal aberrations and mutations but also genomic instability and induction of cancer. In vitro and in vivo data are needed for delivery of low doses over several weeks or months at very low dose rates or with fractionated exposures. The cumulative effect of multiple low doses of less than 10 mGy delivered over extended periods has to be explored further. The development of in vitro transformation assays utilizing nontransformed human diploid cells is judged to be of special importance.
The possibility that low doses of radiation may have beneficial effects (a phenomenon often referred to as “hormesis”) has been the subject of considerable debate. Evidence for hormetic effects was reviewed, with emphasis on material published since the 1990 BEIR V study on the health effects of exposure to low levels of ionizing radiation. Although examples of apparent stimulatory or protective effects can be found in cellular and animal biology, the preponderance of available experimental information does not support the contention that low levels of ionizing radiation have a beneficial effect. The mechanism of any such possible effect remains obscure. At this time, the assumption that any stimulatory hormetic effects from low doses of ionizing radiation will have a significant health benefit to humans that exceeds potential detrimental effects from radiation exposure at the same dose is unwarranted.
Research Need 4. Identification of molecular mechanisms for postulated hormetic effects at low doses
Definitive experiments that identify molecular mechanisms are necessary to establish whether hormetic effects exist for radiation-induced carcinogenesis.
A critical conclusion on mechanisms of radiation tumorigenesis is that the data reviewed greatly strengthen the view that there are intimate links between the dose-dependent induction of DNA damage in cells, the appearance of gene or chromosomal mutations through DNA damage misrepair, and the development of cancer. Although less well established, the data available point toward a single-cell (monoclonal) origin for induced tumors and suggest that low-dose radiation acts predominantly as a tumor-initiating agent. These data also provide some evidence on candidate, radiation-associated mutations in tumors. These mutations are predominantly loss-of-function DNA deletions, some of which are represented as segmental loss of chromosomal material (i.e., multigene deletions).
This form of tumorigenic mechanism is broadly consistent with the more firmly established in vitro processes of DNA damage response and mutagenesis considered in Chapters 1 and 2. Thus, if as judged in Chapters 1 and 2, error-prone repair of chemically complex DNA double-strand damage is the predominant mechanism for radiation-induced gene or chromosomal mutation, there can be no expectation of a low-dose threshold for the mutagenic component of radiation cancer risk.
One mechanistic caveat explored was that novel forms of cellular damage response, collectively termed induced genomic instability, might contribute significantly to radiation cancer risk. The cellular data reviewed in Chapter 2 identified uncertainties and some inconsistencies in the expression of this multifaceted phenomenon. However, telomere-associated mechanisms did provide a coherent explanation for some in vitro manifestations of induced genomic instability. The data considered did not reveal consistent evidence for the involvement of induced genomic instability in radiation tumorigenesis, although telomere-associated processes may account for some tumorigenic phenotypes. A further conclusion was that there is little evidence of specific tumorigenic signatures of radiation causation, but rather that radiation-induced tumors develop in a tumor-specific multistage manner that parallels that of tumors arising spontaneously.
Quantitative animal data on dose-response relationships provide a complex picture for low-LET radiation, with some tumor types showing linear or linear-quadratic relationships while other studies are suggestive of a low-dose threshold, particularly for thymic lymphoma and ovarian cancer. Since, however, the induction or development of these two cancer types is believed to proceed via atypical mechanisms involving cell killing, it was judged that the threshold-like responses observed should not be generalized.