The role of dose-rate on risk from internally-deposited radionuclides and the potential need to separate dose-rate effectiveness factor (DREF) from the dose and dose-rate effectiveness factor (DDREF).

In 1980, National Council on Radiation Protection and Measurements suggested the term dose-rate effectiveness factor (DREF) to describe the reduction of effectiveness of protracted radiation in producing biological damage and risk. A nonlinear decrease in damage was also noted following low total doses. The International Commission on Radiological Protection therefore combined the influence of low dose and low dose-rate and assigned a single value of 2.0 for a dose and dose-rate effectiveness factor (DDREF) to be applied for estimating risk for both low total dose and low dose-rate exposures. This paper re-evaluates one extensive data set on inhaled radionuclides in dogs which suggests that there may be a need to separate these factors (DREF and DDREF) for larger protracted doses from internally-deposited radioactive materials. Extensive recent research on the mechanisms of action of both low dose and low dose-rate radiation exposure at the molecular, cellular, and animal level of biological organization suggest that the influence of protraction of radiation may be large and variable, due to adaptive and protective responses, following very low doses and dose-rate exposures. Important observations in this paper in dogs exposed by inhalation to beta-gamma emitting radionuclides include (1) discontinuities in the data sets as a function of both dose and dose-rate suggesting shifts in mechanisms of action following high doses from protracted exposure away from those postulated for cancer from low total doses; (2) no increase in non-neoplastic disease, cancer frequency, or life-shortening following low dose-rate exposures to high total lung doses (up to 25 Gy); (3) all dogs that received doses below 25 Gy were combined and a decrease in the frequency of lung cancer in these exposed animals relative to the controls was noted, while very large doses from all radionuclides studied resulted in very marked increases in lung cancer; (4) a significant increase in hemangiosarcoma in the heart and tracheobronchial lymph nodes was observed after very high doses; (5) in this paper the DREF for lung cancer in dogs relative to single acute radiation exposure was as high as 35; and (6) the amount of life-shortening increased per unit dose as a function of the half-life with (90)Y being eight times as effective per unit of dose as (90)Sr. Such information suggests that there may be a need to assign different values for DDREF and DREF, especially in situations where there are large nonuniform total doses delivered by internally-deposited radionuclides. This is extremely important since the risk from radiation exposure from internally-deposited radionuclides in the lungs following nuclear fallout, accidents and terrorist activities may be much less than currently projected.

Calmodulin mediates DNA repair pathways involving H2AX in response to low-dose radiation exposure of RAW 264.7 macrophages.

Understanding the molecular mechanisms that modulate macrophage radioresistance is necessary for the development of effective radiation therapies, as tumor-associated macrophages promote both angiogenesis and matrix remodeling that, in turn, enhance tumor metastasis. In this respect, we have identified a dose-dependent increase in the abundance (i.e., expression level) of the calcium regulatory protein calmodulin (CaM) in RAW 264.7 macrophages upon irradiation. At low doses of irradiation there are minimal changes in the abundance of other cellular proteins detected using mass spectrometry, indicating that increases in CaM levels are part of a specific radiation-dependent cellular response. CaM overexpression results in increased macrophage survival following radiation exposure, acting to diminish the sensitivity to low-dose radiation exposures. Following macrophage irradiation, increases in CaM abundance also result in an increase in the number of phosphorylated histone H2AX foci, associated with DNA repair, with no change in the extent of double-stranded DNA damage. In comparison, when nuclear factor kappaB (NFkappaB)-dependent pathways are inhibited, through the expression of a dominant-negative IkappaB construct, there is no significant increase in phosphorylated histone H2AX foci upon irradiation. These results indicate that the molecular basis for the up-regulation of histone H2AX-mediated DNA repair pathways is not the result of nonspecific NFkappaB-dependent pathways or a specific threshold of DNA damage. Rather, increases in CaM abundance act to minimize the low-dose hypersensitivity to radiation by enhancing macrophage radioresistance through processes that include the up-regulation of DNA repair pathways involving histone H2AX phosphorylation.