RSH > Documents > ANS National Meetings/Sessions > June 1999 > R. E. J. Mitchel

3. Low Dose Effects: Testing the Assumptions

                "Current radiation risk estimates and all radiation-protection standards and practices are based on the so-called linear nothreshold (LNT) hypothesis. The LNT model assumes that risk is linearly proportional to dose, without a threshold, and thus includes a number of assumptions about the dose-effect relationship: (a) every dose, no matter how low, carries with it some risk; (b) risk per unit dose is constant; (c) risk is additive; (d) risk can only increase with dose; and (e) biological variables are insignificant compared to dose. The radiation protection community has historically accepted the LNT model as the basis for a conservative approach to radiation protection practice. There are, however, no actual data to support these assumptions at doses that are relevant to occupational and public exposures. Our work is to investigate the biological responses of cells and animals to low doses and low dose rates of low linear energy transfer radiation and to compare the results to the predictions of the LNT hypothesis.

                "The biological risk of most concern from exposure to ionizing radiation is the risk of cancer. Since cancer ultimately arises from a series of genetic changes in a single cell, it is therefore necessary to understand the effects of radiation on single cells. If we consider the potential biological outcomes of a radiation exposure to a cell, there are three general possibilities. When DNA damage is created as a result of one or more tracks of radiation through a cell, the cell will attempt to repair that damage. If the cellular repair is successful and the DNA is restored to its original state, i.e., an error-free repair, then the cell is also restored to normal. In this case, there is no resulting consequence to the cell and hence no resulting risk. A second possibility is that the cell recognizes that it cannot properly repair the DNA damage and as a consequence activates its genetically encoded programmed cell death process, called apoptosis. Again, in this case, no risk of carcinogenesis results since dead cells do not produce cancer. The third possible outcome of the DNA damage is repair that avoids cell death but is error-prone and creates a mutation. While the vast majority of mutations do not create the potential for cancer, there are some that do, and it is these mutations that represent the risk. Of the three possible outcomes, therefore, only one creates a risk of carcinogenesis.

                "It is useful to remember that the LNT model predicts that risk is influenced only by dose and hence predicts that the relative proportions of the biological possibilities must be constant. If they were not constant, then risk would vary with their relative proportions, i.e., not only as a function of dose. Our experiments show, however, that this is precisely the situation that occurs when cells are exposed to low doses. They respond by altering the relative probabilities of the three possible outcomes.

                "The lowest dose a cell can receive is one charged particle track. Our experiments show that human and rodent cells, exposed to an average of about one track per cell ~1 mGy of 60Cogamma radiation! or to many tracks per cell, respond by increasing, and then selectively applying, their ability to repair broken chromosomes resulting from a second exposure. The net result for the cell was that increasing the dose by preexposing the cells reduced the risk of genetic damage. An average of one track per cell was just as effective at protecting the cells as many tracks per cell. On the other hand, cells unable to adequately repair their genome were sensitized to die by apoptosis, eliminating the possibility that they could transform into cancer cells. These adaptive responses of cells protected them against the risk of being transformed into cancer cells by a subsequent radiation exposure, and it also provided a three- to fourfold protection against their own inherent, spontaneous risk of transforming into cancer cells in the absence of further exposure. Very recent, preliminary results indicate a 'bystander effect' for this protection. It appears that induction of the protective effect does not require a cell to actually receive a track but that the cell will also respond to intercellular communication signals from other cells that have experienced an energy depositing event.

                "In vivo experiments in mice support the concept that low doses reduce rather than increase risk. Preexposure of the skin of mice to beta radiation reduced by about fivefold the frequency of skin tumors in mice whose skin was subsequently exposed to a chemical carcinogen, indicating a protective effect on early tumor initiation events in cells. Another in vivo mouse experiment has shown that a low, whole body dose of gamma radiation substantially extended the latent period for myeloid leukemia induced in the mice by a subsequent large radiation dose, indicating a protective effect of low doses against the late, secondary processes of carcinogenesis.

                "These experiments indicate that at low dose, none of the assumptions of the LNT hypothesis were supported by the data, either in cells or in animals. If these results from human and rodent cells, and from other animals, are applicable to humans, the data further indicate that the use of the LNT hypothesis for radiation protection purposes is not conservative but may actually increase the overall risk of cancer."