responses will reduce low-dose cancer risk substantially, perhaps to zero, or even be beneficial to health (see Calabrese and Baldwin 2003 and references therein).
Cellular data and mechanistic considerations on adaptive responses are reviewed in Chapter 2. From this review it is concluded that adaptive responses are not expressed robustly in cells and that a mechanistic basis for the phenomena, particularly in the form of well-characterized DNA damage response, has yet to be established. This situation may be contrasted with the detailed knowledge that has accrued on many other aspects of DNA damage recognition or repair and cellular response (see Chapters 1 and 2). Accordingly, cellular and mechanistic data on adaptive responses are as yet insufficient to develop specific judgments on the fundamental aspects of low-dose cancer risk.
Recent animal studies on adaptive responses to radiation and cancer risk are considered in Chapter 3. These studies provide some evidence that under certain conditions, a low priming dose of radiation can modestly influence the rate of development of certain tumors. However this response is not accompanied by a reduction of overall lifetime cancer risk. Uncertainties remain about the specific conditions of irradiation under which this form of adaptive response is expressed, and its mechanistic basis is a matter of speculation. Accordingly, these animal data, although of considerable scientific interest, are not sufficiently well developed to influence the modeling and interpretation of epidemiologic data.
Induced genomic instability is a term used to describe a set of cellular phenomena whereby radiation exposure alters the state of a cell in a way that generally leads to a persistent elevation of mutation rate over many cell generations. The cellular data reviewed in Chapter 2 highlight the inconsistent mode of expression of this phenomenon and the current lack of information on the cellular mechanisms that might be involved. It is notable that many of these data sets relate to cells established in culture for many years. Despite these problems of interpretation, there has been speculation that radiation-induced genomic instability might make a significant contribution to cancer induction in vivo and thereby confound the interpretation of epidemiologic data. Chapter 3 considers the in vivo expression of radiation-induced genomic instability, possible mechanistic links with cancer induction in animal models, and the expression of such instability in radiation-associated human tumors. Although some uncertainty remains, these in vivo data strongly question the proposition that radiation-induced, genome-wide instability plays a major role in radiation tumorigenesis. One possible exception to this is the instability of altered telomeric sequences at chromosome termini that may trigger ongoing cycles of chromosomal associations and rearrangement (Chapters 2 and 3). However, given the great uncertainty about the contribution of induced and persistent genomic instability to postirradiation tumor development, there is at present no meaningful way in which the phenomenon can be included in the general interpretation of epidemiologic data and, thereby, the derivation of new estimates of low-LET cancer risk.
Chapter 2 details the almost exclusively cellular data for high-LET radiation, indicating that cellular damage response signals may be passed from an irradiated cell to a nonirradiated neighbor. There are few consistent data sets for low-dose, low-LET radiation. The stress-related mechanisms that have been suggested to underlie postirradiation signal transfer via cellular gap junctions or cell culture medium are not well understood. In addition, the in vivo expression of bystander effects and their impact on tumor development have yet to be adequately addressed. For these reasons, the committee judges that current knowledge of these phenomena is insufficient for the purpose of interpreting epidemiologic data and developing judgments on cancer risks at low doses of low-LET radiation.
The data reviewed in Chapters 1 and 3 provide coherent evidence from cellular, animal, and clinical or epidemiologic studies that inheritance of certain germline gene mutations can predispose to radiation-induced cancer. The qualitative linkage between such epidemiologic or clinical and experimental data are particularly strong for rare, strongly expressing human mutations. However, with current knowledge, experimental data cannot quantitatively inform about the magnitude of the increased radiation risk in such genetic disorders. Accordingly, only broad judgments are possible—principally that strongly expressing human mutations of relevance to radiation cancer risk are too rare to an appreciably distort population-based estimates of low-dose risk as derived from epidemiologic data (Chapter 3).
The implication for population risk of weakly expressing but potentially common variant genes is a most difficult issue. Genetic studies with mice (Chapter 3) provide evidence of the potential complexity of germline gene-gene interactions in radiation tumorigenesis. However, human molecular epidemiologic studies in this area are at a very early stage of development, and no specific judgments are possible on the extent to which common genetic variation influences epidemiologic measures of radiation risk. The general judgment made in Chapter 3 is that the potential impact of such variant genes on radiation cancer risk in the population will depend on a complex interplay between their frequency in the population, their tissue specificity, and the strengths of the gene-gene and gene-radiation interactions that may apply.