Research Need 2. Determination of DNA repair fidelity, especially as regards double- and multiple-strand breaks at low doses, and determination of whether repair capacity is independent of dose

Repair capacity at low levels of damage must be investigated, especially in light of conflicting evidence for stimulation of repair at low doses. In such studies the accuracy of DNA sequences rejoined by these pathways has to be determined, and the mechanisms of error-prone repair of radiation lesions must be elucidated. Identification of critical genetic alterations that can be characteristic of radiation exposure would be important.

Consideration of Phenomena That Might Affect Risk Estimates for Carcinogenesis at Very Low Doses

A number of biological phenomena that could conceivably affect risk estimates at very low radiation doses have been reported. These phenomena include the existence of radiation-sensitive human subpopulations, hormetic or adaptive effects, bystander effects, low-dose hyperradiosensitivity, and genomic instability.

Radiation-Sensitive Subpopulations

Epidemiologic, clinical, and experimental data provide clear evidence that genetic factors can influence radiation cancer risk. Strongly expressing human mutations of this type are rare and are not expected to influence significantly the development of estimates of population-based, low-dose risks. They are, however, potentially important in the context of high-dose medical exposures. Evidence for the complex interaction of weakly expressing genetic factors in cancer risk is growing, but current understanding is insufficient for a detailed consideration of the potential impact on population risk.

Adaptive Response

Adaptive responses have been well documented in bacteria, where exposures to radiation or chemicals induce subsequent resistance to these agents by inducing expression of DNA damage repair genes. This induced expression of repair genes does not occur to a significant extent in human cells, although changes in signal transduction do take place. A type of apparent adaptive response, however, has been documented for the induction of chromosomal aberrations in human lymphocytes stimulated to divide.

In most studies, a priming or adaptive dose of about 10 mGy significantly reduces the frequency of chromosomal aberrations and mutations induced a few hours later by 1000–3000 mGy. Similar effects are sometimes seen with other end points. However, priming doses less than 5 mGy or greater than ~200 mGy generally give very little, if any, adaptation, and adaptation has not been reported for challenge doses of less than about 1000 mGy. To have relevance for risk assessment, the adaptive response has to be demonstrated for both priming and challenging doses of 1–50 mGy.

Furthermore, the induction and magnitude of the adaptive response in human lymphocytes are highly variable, with much heterogeneity demonstrated among different individuals. The adaptive response could not be induced when noncycling lymphocytes were given the priming dose. Although inhibitor and electrophoretic studies suggest that alterations in messenger RNA transcription and protein synthesis are involved in the adaptive response in lymphocytes, no specific signal transduction or repair pathways have been identified. At this time, the assumption that any stimulating effects from low doses of ionizing radiation will have a significant effect in reducing long-term deleterious effects of radiation on humans is unwarranted.

Bystander Effects

The bystander effect that results from irradiated cells’ reacting with nearby nonirradiated cells could influence dose-response relationships. Such an effect might come into play at low-LET doses below 1–5 mGy, where some cells of the body would not be irradiated. Current limitations of low-LET bystander studies include the lack of demonstrated bystander effects below 50 mGy and uncertainties about whether the effect occurs in vivo. Another complication is that both beneficial and detrimental effects have been postulated for bystander effects by different investigators. Until molecular mechanisms are elucidated, especially as they relate to an intact organism, and until reproducible bystander effects are observed for low-dose low-LET radiation in the dose range of 1–5 mGy, where an average of less than 1 electron tracks traverse the nucleus, the assumption should be made that bystander effects will not influence the shape of the low-dose, low-LET dose-response relationship.

Hyperradiosensitivity for Low Doses

In some cell lines, hyperradiosensitivity (HRS) has been reported for cell lethality induced by low-LET radiation at doses less than 100–200 mGy. In this dose range, survival decreases to 85–90%, which is significantly lower that projected from data obtained above 1–2 Gy. It is not known whether HRS for cell lethality would cause an increase in deleterious effects in surviving cells or would actually decrease deleterious effects by increased killing of damaged cells. Until molecular mechanisms responsible for HRS that may or may not play a role in carcinogenesis are understood, the extrapolation of data for HRS for cell lethality to the dose-response for carcinogenesis in the 0–100 mGy range is not warranted.

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