cases, an inverse dose-rate effect for cell lethality and mutations has been reported for which the effect at very low dose rates is as high or higher than for single, acute, high-dose-rate exposures. The ability to demonstrate this phenomenon, however, is variable, and no mechanisms have been clearly identified to explain such effects.

Several factors may affect the theoretical dose-response relationships described above: variations in radiosensitivity during the cell cycle; induction of an adaptive response to an initial exposure, which can reduce the effect of later exposures; a bystander effect that causes an irradiated cell to have an effect on a nearby unirradiated cell; the induction of persistent genomic instability; and HRS in the low-dose region. Except for the cell cycle, these factors have been identified and studied since the BEIR V report (NRC 1990). These factors together with quantitative data on the induction of gene or chromosomal mutations in somatic cells are discussed.

Radiation genomic instability has been demonstrated by the manifestation of chromosomal damage in a certain fraction of irradiated cells over many cell cycles after they were irradiated. Data are critically needed for the definition of molecular targets and processes responsible for genomic instability in order to define and understand the dose-response relationship, and especially why the induction frequency saturates with only about 10–30% of the surviving cells manifesting genomic instability. A possibility that has not been investigated is that only a certain fraction of the cells, such as those in a certain part of the cell cycle, are susceptible to radiation-induced genomic instability. Because chromosomal instability has been associated with breakage-fusion-bridge cycles, the role of telomeres may be particularly relevant. Chromosome instability can also be initiated by DSBs that result in the loss of a telomere that protects the chromosome end and prevents chromosome fusion. Furthermore, from limited data, the similarity in the frequencies of genomic instability induced in X-irradiated cells and the frequencies of chromosomal aberrations induced directly by irradiation may suggest that the induction of chromosomal aberrations is a primary event that plays a major role in radiation-induced genomic instability. There is also some evidence that reactive oxygen species may play a role. However, until the molecular mechanisms responsible for genomic instability and its relationship to carcinogenesis are understood, extrapolation of the limited dose-response data for genomic instability to radiation-induced cancers in the low-dose range <100 mGy is not warranted.

An apparent adaptive response has been well documented for cell lethality, chromosomal aberrations, mutations, and in vitro transformation. The phenomena are illustrated by a reduction in response to a challenge dose of about 1 Gy delivered a few hours after a low priming dose of about 10–20 mGy. There is much variability in the ability to demonstrate the adaptive response, however. Data are needed, particularly at the molecular level, on adaptation induced when both priming and challenging doses are in the low-dose range <100 mGy; relevant end points should include not only chromosomal aberrations and mutations but also genomic instability and, if possible, tumor induction. Studies of the adaptive response for 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 vitro and in vivo data are needed on the delivery of priming and challenge doses over several weeks or months at very low dose rates or with fractionated exposures. Specifically, an adaptive response resulting from the cumulative effect of multiple low doses of less than 10 mGy should be determined. Such data have not yet been obtained, particularly those explaining the molecular and cellular mechanisms of the adaptive response. Thus, it is concluded that any useful extrapolations for dose-response relationships in humans cannot be made from the adaptive responses observed in human lymphocytes or other mammalian cellular systems. Therefore, at present, the assumption that any stimulatory effects of low doses of ionizing radiation substantially reduce long-term deleterious radiation effects in humans is unwarranted.

A bystander effect in which an irradiated cell induces a biological response in a neighboring unirradiated cell has been observed with high-LET radiation for inducing cell lethality, chromosome aberrations, sister-chromatid exchanges, mutations, genomic instability, signal transduction pathways, and in vitro transformation. There is some evidence that long-lived reactive oxygen species or the diffusion of cytokines plays a role in the bystander effect. For low-LET radiation, the bystander effect has been limited to cell lethality and lethal mutations associated with reduced cloning efficiency. Recent results suggest that a bystander effect for cell lethality from soft X-ray irradiation might be observed down to 50 mGy but not below. Until molecular mechanisms of the bystander effect are elucidated, especially as related to an intact organism, and until reproducible bystander effects are observed for low-LET radiation in the dose range of 1–5 mGy, where an average of about one electron track traverses the nucleus, a bystander effect of low-dose, low-LET radiation that might result in modification of the dose-response should not be assumed.

HRS is a phenomenon for which doses less than about 200 mGy produce a dose-response for cell lethality that is steeper than that predicted from the classic D + D2 model. There are data suggesting HRS for cell lethality and signal transduction at up to 200 mGy and some data suggesting HRS for mutagenesis or genomic instability at up to 50 mGy. Furthermore, from limited data from only one laboratory, an observed inverse dose-rate effect for cell lethality was attributed to HRS seen for low acute doses, and cell cycle analysis suggested that HRS may be related to cells not arresting in radiosensitive G2. Since a high proportion of the target stem-like cells in humans would be noncycling, the last two observations, if generally true, would suggest that neither HRS

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