dominant feature of in vivo cellular response and tumor induction.
Finally, evidence is emerging that the DNA deletions that are characteristic molecular footprints of NHEJ-mediated misrepair and gene loss in cultured cells are also seen as early events in radiation-induced tumors in rodents; there is also preliminary evidence pointing toward the involvement of NHEJ misrepair in the genesis of early arising RET gene rearrangements in post-Chernobyl childhood thyroid cancer (Chapter 3).
When considered together, these in vitro and in vivo data are seen to provide a scientifically coherent linkage between error-prone postirradiation repair of chemically complex DNA DSBs in target cells in vivo and tumor induction.
Mechanistic uncertainties remain, but the weight of available evidence would argue against the presence of a low dose threshold for tumor induction based on error-free repair of initial DNA damage. In summary, the committee judges that the balance of scientific evidence at low doses tends to weigh in favor of a simple proportionate relationship between radiation dose and cancer risk.
Since much of the informative epidemiologic data on low-LET radiation cancer risk derives from the study of acute exposures, it is necessary to make somewhat indirect judgments about the magnitude of the expected reduction in risk associated with low doses and dose protraction. This reduction in risk is conventionally described by the dose and dose-rate effectiveness factor (DDREF). As illustrated and discussed in Chapter 2 (see Figure 2-1), the reduction in risk for low doses (DEF) and the reduction in risk for dose protraction (i.e., low dose rates; DREF) are assumed to be equal; therefore, the term DDREF is used for estimating effects for either low doses or low dose rates.
Information from cellular and molecular studies strongly suggests that dose and dose-rate effects of low-LET radiation are determined largely by the activity of DNA damage response process in cells. For the induction of gene and chromosomal mutations in cultured somatic cells, values for DDREF generally fall in the range of 2–4 (Lloyd and others 1992; Thacker 1992; UNSCEAR 1993, 2000b; Cornforth and others 2002), although higher and lower values have been recorded in some mutation systems. Together, these data are consistent with the view that the temporal abundance of radiation-induced DNA damage is a major factor in the efficiency or fidelity of DNA repair and hence the frequency of induced mutation (Chapter 2).
In vivo effects of dose protraction or fractionation are likely to be more complex, but available data on animal tumorigenesis show that the reduction of tumor yield with dose fractionation is determined by processes that operate on a time scale of up to 24 h. This time scale is more consistent with the activity of cellular DNA repair than with that of postirradiation whole-tissue remodeling, thus drawing together dose-rate effects at the cellular and whole-animal levels (Chapter 3).
Animal tumorigenesis data and related information from life-shortening studies (Chapter 3) may be used to provide judgments on DDREF that vary up to a value of 10 or more (UNSCEAR 1994). However, when those tumor types that, atypically, depend strongly on cell killing are excluded and analysis is restricted to doses up to a few grays, the DDREF values obtained are in the range of 2–3 (Chapter 3). These values are similar to those of gene mutation and, thereby, broadly consistent with the recurring theme of a close association between DNA damage response, mutation induction, and cancer.
The biological picture overall is that cellular and animal data relating to protracted radiation exposures provide a convincing argument for the inclusion of DDREF in judgments about cancer risk at low doses and low dose rates. The animal data showing reduction in carcinogenic effectiveness, including life shortening, following protracted exposure constitute the strongest element in this argument; the coherence of the mechanistic data adds additional weight.
An alternative approach is to estimate DDREF on the basis of the degree of curvature of the dose-response for excess cancer after acute irradiation. Conventional radiobiological theory holds that the initial linear (α) term of a linear-quadratic (αD + βD2) dose-response (where D is the dose) will represent the low-dose and low-dose-rate response. Accordingly, the α and β terms of the acute dose-response may be used to provide an estimate of DDREF. Note that the BEIR V committee did not apply a DREF (sic) in its analysis of solid tumor data and used a linear-quadratic model for leukemia (NRC 1990). Also, the UNSCEAR (2000) committee commented that the LSS data suggested a “value of about 1.5” for the DDREF. In its report, the International Commission on Radiological Protection (ICRP 1990) stated that “the Commission has decided to recommend that for radiation protection purposes the value of 2 be used for the DDREF, recognizing that the choice is somewhat arbitrary and may be conservative.”
The committee has taken a computational approach to the estimation of DDREF that is based on a Bayesian analysis of combined dose-response data. The data sets considered were (1) solid cancer incidence in the LSS cohort of Japanese atomic bomb survivors; (2) cancer and life shortening in animals; and (3) chromosome aberrations in human somatic cells.
The BEIR VII cancer risk estimates are based on risk models derived primarily from analyses of data on the LSS cohort of Japanese atomic bomb survivors. Historically, and