seven different doses from 0.25 to 5.0 Gy reported a linear dose-response with a slope of 8 × 10−8 transformants per viable cell per milligray (Mill and others 1998). A study conducted with a human Hela hybrid cell system (Redpath and others 2001) reported a frequency of 4 × 10−8 transformants per viable cell per milligray beyond a threshold of ~0.3 Gy; however, the results were greatly dependent on the time the cells were trypsinized and plated after irradiation for the transformation analysis. Note that these results for transformation are quite variable and that the frequencies are ten- to a thousandfold lower than the frequencies for radiation-induced genomic instability. However, as discussed earlier under adaptive response, studies of malignant transformation in immortalized (already-transformed) cell lines may have little relevance to malignant transformation of normal nonimmortalized cells, especially in vivo where complex interactive processes can occur.
In summary, results of experiments that quantified chromosomal aberrations, malignant transformations, or mutations induced by relatively low total doses or low doses per fraction suggest that the dose-response relationship over a range of 20–200 mGy is generally linear and not affected significantly by either an adaptive or a bystander effect (Table 2-1). No data are available in this dose range for radiation-induced genomic instability. The question of the shape of the dose-response relationship up to about 20 mGy remains, although several of the dose-response relationships described above appear to be consistent with extrapolation linearly down to about 5 mGy. As has been pointed out (Cornforth and Bedford 1983), a macroscopic X-ray dose of about 5 mGy would, on the average, result in one to two electron tracks crossing the nucleus of each cell. Since the tracks are produced randomly, the proportion of nuclei traversed by zero, one, or two electron tracks would be about 0.37, 0.37, and 0.18, respectively. For lower doses, a larger and larger proportion of cell nuclei would receive no dose (track) at all. The nuclei that would receive a track would all receive (on the average) the same dose because the proportion receiving two or more tracks would diminish rapidly. Therefore, unless interactions among neighboring or surrounding cells influence the response, if 5 mGy produces an effect and if the effect is linear above 5 mGy, the dose-response curve must also be linear from 0 to 5 mGy. In addition to the existence of biological information at these very low dose levels, the committee concluded that the biophysical characteristics of the interaction of low-LET radiation with DNA, coupled with the characteristics of DNA repair, argue for a continuation of the linear response at lower doses. However, if a single electron track traversing a cell’s nucleus could induce an adaptive or bystander effect, the dose-response relationship below 5 mGy might deviate from linearity depending on whether cellular effects are decreased or increased. In the committee’s judgment, there is no evidence for either an adaptive response or a bystander effect for doses below 5 mGy.
Furthermore, the calculated value of 5 mGy for an average of one electron track per nucleus depends on the size and shape of the nucleus, as well as on the energy of the radiation (Rossi and Zaider 1996; Edwards and Cox 2000). For example, the calculated doses for an average of one electron track per nucleus are as follows: about 5 mGy for 60 keV and a 6-μm diameter sphere, about 4 mGy for 60 keV and a 7-μm sphere, about 3 mGy for 300 keV and a 6-μm sphere, and about 2 mGy for 300 keV and a 7-μm sphere. For the very low doses for which important signal transduction events may result from ionizations in either the nucleus or the cytoplasm, the volume of the whole cell might be most appropriate for these types of calculations. Possibly, the shape of the dose-response relationship up to 5 mGy might be determined with in vitro and in vivo experiments in which multiple doses of about 1–5 mGy are delivered over a long period. However, the question must be addressed rigorously by defining the molecular processes responsible for the end points in question at these very low doses.
This chapter discusses the biological effects of the ranges of radiation dose that are most relevant for the committee’s deliberations on the shapes of dose-response relationships. Considering the levels of background radiation, the maximal permissible levels of exposure of radiation workers now in effect, and the fact that much of the epidemiology of low-dose exposures includes people who in the past have received up to 500 mGy, the committee has focused on evaluating radiation effects in the low dose range of <100 mGy, with emphasis on the lowest doses when relevant data are available. Effects that may occur as the radiation is delivered chronically over several months to a lifetime are thought to be most relevant.
Considerable emphasis has been placed on the dose-response and mechanisms for inducing chromosomal aberrations and gene mutations because, as discussed in Chapter 3, there is evidence that the induction of cancer is associated with these cellular responses. The general pictures that emerge from biophysical studies is that the misrepair of radiation-induced DNA DSBs that lead to chromosome aberrations are probably associated with the dominant postirradiation function of nonhomologous end joining repair processes described elsewhere is this report. Overall, biophysical approaches to the modeling of dose-response for chromosome aberrations, although not without some uncertainties on mechanisms, imply that the single-track α-component of radiation action will dominate at low doses and LDRs (i.e., the dose-response for all forms of aberrations will be linear at low doses and LDRs). Also, as observed, the response at LDRs and low doses, or after fractionated doses, should be lower by a DDREF; then the response to a single acute high-dose-rate exposure for which the two-hit β-component becomes important. In certain