be feasible in the medium term. The likely involvement of multiple and relatively organ-specific sets of polymorphisms and gene-gene or gene-environment interactions makes the provision of meaningful judgments on risk most uncertain. For these reasons it may be more realistic at this stage of knowledge to focus attention on general patterns of gene-radiation interactions and their implications for population risk, rather than risk for specific individuals.
In this chapter, the committee has reviewed cellular-molecular and animal studies relevant to the complex multistage process of radiation tumorigenesis. Attention has also been given to evidence from various studies on the inherited factors that influence radiation cancer risks. The principal objective of this work was to provide judgments on radiation cancer risk of prime importance to radiological protection, particularly where these judgments serve to couple information about the action of radiation on cells (Chapters 1 and 2) with the epidemiologic measures of risk considered in subsequent chapters.
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 indicate 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 injury involved in the carcinogenic process, 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 in this chapter 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. However, further cytogenetic and molecular genetic studies are needed to reduce current uncertainties about the specific role of radiation in multistage radiation tumorigenesis; such investigations would include studies with radiation-associated tumors of humans and experimental animals.
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. However, since 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.
Radiation-induced life shortening in mice is largely a reflection of cancer mortality, and the data reviewed generally support the concept of a linear dose-response at low doses and low dose rates. Other dose-response data for animal tumorigenesis, together with cellular data, contributed to the judgments developed in Chapters 10 and 12 on the choice of a DDREF for use in the interpretation of epidemiologic information on cancer risk.
Adaptive responses for radiation tumorigenesis have been investigated in quantitative animal studies, and recent information is suggestive of adaptive processes that increase tumor latency but not lifetime risk. However, these data are difficult to interpret, and the implications for radiological protection remain most uncertain.
The review of cellular, animal, and epidemiologic or clinical studies on the role of genetic factors in radiation tumorigenesis shows that there have been major advances in understanding, albeit with some important knowledge gaps. An important conclusion is that many of the known, strongly expressing, cancer-prone human genetic disorders are likely to show an elevated risk of radiation-induced cancer, probably with a high degree of organ specificity. Cellular and animal studies suggest that the molecular mechanisms underlying these genetically determined radiation effects largely mirror those that apply to spontaneous tumorigenesis