support an additive interaction of smoking and radiation. Since differences in smoking habits undoubtedly contribute to the differences in baseline risks in Japan and the United States, this finding supports the use of absolute risk transport. Furthermore, lung cancer analyses of A-bomb survivor data based on EAR models may provide a more reliable evaluation of the dependence of radiation risk on factors such as gender and age at exposure than do ERR models, as discussed above. As indicated in Chapter 12, relative risk transport estimates are based on ERR models, whereas absolute risk transport estimates are based on EAR models. Thus, for lung cancer, the weighting scheme used for most other solid cancers is reversed, and a weight of 0.7 is used for the estimate obtained with absolute risk transport and a weight of 0.3 for the estimate obtained with relative risk transport.
For sites other than breast, thyroid, and lung, it is likely that the correct transport model varies by site. However, the committee judged that current knowledge was insufficient to provide separate approaches for other specific sites.
Follow-up of cancer incidence and mortality in Japanese A-bomb survivors (the LSS study) continues to provide the most informative epidemiologic data on the shape of the dose-response for solid tumors and leukemia (Chapter 6), although studies of large-scale populations with low-dose chronic exposures are increasingly informative about the effects of low doses.
Atomic bomb survivor data for solid tumors combined provide statistical evidence of a radiation-associated excess at doses down to around 100 mSv; these combined data are well described by a linear no-threshold dose-response, although some low-dose nonlinearity is not excluded (Pierce and Preston 2000; Preston and others 2003). Indeed, dose-response relationships for individual tumor types in the LSS can differ, and for nonmelanoma skin cancer the dose response is highly curvilinear with an excess seen only at doses higher than around 500 mSv. The LSS dose-response for leukemia is also clearly curvilinear, with a statistically significant excess being evident at doses around 200 mSv.
The above human data well illustrate the problems of limited statistical power that surround epidemiologically based conclusions on the shape of the low dose-response for radiation cancer risk and how it might vary between tumor types. Similar difficulties surround judgments based on data obtained using experimental animals; many studies are broadly consistent with a linear no-threshold dose response, but there are a number of examples of highly curvilinear, threshold-like relationships (Chapter 3).
It is abundantly clear that direct epidemiologic and animal approaches to low-dose cancer risk are intrinsically limited in their capacity to define possible curvilinearity or dose thresholds for risk in the range 0–100 mSv. For this reason the present report has placed much emphasis on the mechanistic data that can underpin such judgments.
First, there is evidence that most cancers are monoclonal in origin (i.e., they develop from progeny of a single abnormal cell; UNSCEAR 1993). Whatever molecular mechanism is envisaged for radiation, at very low doses (e.g., 0–5 mGy low LET), increases in dose simply increase the probability that a given single cell in the tissue will be intersected by an electron track which will have a nonzero probability of inducing a biological effect. Therefore, at these very low doses, a linearity of response is almost certain (Chapter 3).
Second, given the intimate relationship established between DNA damage response, gene or chromosomal mutations, and cancer development, the form of the dose-response for mutation induction in single cells should be broadly informative for cancer initiation. Data from a large-scale study noted in Chapter 2 suggest a linear relationship between low-LET dose and chromosomal mutation down to around 20 mGy.
A central question addressed in this report is the nature of critical DNA lesions after low-LET radiation and the extent to which they may be repaired by the cell without errors. This is a crucial judgment in radiation tumorigenesis since, at the level of cancer-associated gene or chromosomal mutation, the presence of a true dose threshold demands totally error-free DNA damage response and repair.
The detailed information available on the importance of a chemically complex DNA double-strand break (DSB) induced by a single ionization cluster for postirradiation biological effects (Chapter 1), together with the predominance of error-prone nonhomologous end joining (NHEJ) repair in postirradiation cellular response, argues strongly against a DNA repair-mediated low-dose threshold for cancer initiation (Chapters 1–3). The same data provide a strong counter to pro-threshold arguments based on the relative abundance of spontaneously arising and radiation-induced DNA damage. Those arguments fail to take account of the quality of the repair achievable for simple and complex forms of DNA damage.
In principle, complex DNA DSBs may be repaired with full fidelity by homologous recombination (HR) pathways. Since HR operates almost exclusively between sister chromatids in cells that have newly replicated their DNA (Chapters 1 and 2), the cell has a limited cell cycle window for such error-free repair. At any one time, only a small fraction of stem-like target cells in tissues are expected to reside within this postreplication window—many will be in a nonreplicative, quiescent state (e.g., Potten and Hendry 1997; Kountouras and others 2001; Young 2004). On this basis HR-mediated error-free repair is unlikely to be the