Radioadaptive Response: Responses to the Five Questions

Takaji Ikusshima. Ph.D.

Kyoto University of Education

Biology Division

1 Fukakusa-Fujinomori-cho

Fushimi-ku, Kyoto 612-8522, Japan

Tel: 81-75-644-8266

Fax: 81-75-645-1734

E-mail:ikushima@wsml.kyokyo-u.ac.jp



RADIOADAPTIVE RESPONSE

When exposed to a variety of environmental stresses, almost all living organisms from bacteria to humans react promptly so that they may survive the crisis.

An adaptive response was first reported by Samson and Cairns (1977) in Esherichia coli as an inducible pathway of DNA repair acting on alkylation damage, in which bacterial cells exposed to a sublethal level of an alkylating agent became less susceptible to the subsequent toxic dose of the same and other similar agents. 1 This adaptive response to alkylating agents are attributed to the induction of DNA glycosylase and DNA alkyltransferase that remove DNA adducts. 2

The first experiments to show the adaptive response to ionizing radiation were carried out on the induction of chromosomal aberrations in cultures of human lymphocytes. 3 A pre-exposure to low doses of ionizing radiation resulted in a significant reduction in the yield of chromosomal aberrations induced by subsequent high doses. Numerous experimental data have supported the existence of radioadaptive responses in various eukaryotic cell systems. 4,5 The radioadaptive response is characterized phenomenologically by a reduction of certain deleterious genetic effects such as chromosomal damage, gene mutations and cell killing induced by a challenge high dose in adapted cells pre-exposed to low dose of ionizing radiation. The term "radioadaptive response'' is consciously used in contrast to the "chemoadaptive response", because the mechanisms are considerably different each other.

The molecular mechanism underlying the radioadaptive response is not yet elucidated well. An unknown inducible molecular process triggered by low doses might lead to more enhanced repair of DNA damage or cell protection against the deleterious effects induced by subsequent high doses. The involvement of inducible DNA repair has been suggested by the results that the radioadaptive response can be abolished by 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase. 6 More direct evidences for a faster and enhanced DNA repair rate in adapted cells has been presented from experiments performed using a single cell gel electrophoresis. 7 The whole molecular process from the initial triggering to activation of genes for DNA repair is a black box still now.

RESPONSES TO THE QUESTIONS

1. How does the dose that induces the adaptive response (AR) relate to human and environmental (ecological) exposures ?

The experimental results in cultured mammalian cells have indicated that a narrow window of low doses can induce the radioadaptive response. The optimal dose ranges from 0.1 to 10 cGy. 8 The radioadaptive response is, however, dependent both on the total dose of the adapting and the dose rate at which the dose is given. 9 It has been shown that at chronic, low-dose-rate (0.0024 Gy/min) exposures of human fibroblasts, adaptation, in terms of cell survival to second acute exposure, could be seen after a total adapting dose of 2-5 Gy. 10

There are many areas with a high level of background radiation in the world, and epidemiological evidences have been obtained that the natural radiation in these areas is not harmful to residents, and that the cancer mortality rate is significantly lower in the high-background areas than in the control areas. 11 This is one of typical examples of radiation hormesis but if we want to claim that environmental exposures act as an adapting dose, we should study about the radio-resistance of residents in these areas after receiving a high dose.

2. What are the potential up and down sides of having ones AR induced ?

There are many reports on beneficial effects of low-dose irradiation on human health. A typical example is that the whole body irradiation of low doses has been successfully applied to treat malignant lymphoma, though, rigidly saying, this might not be a case in radiadaptive response but in radiation hormesis. As a potential up side, the radioadaptive response may be helpful in the life saving program for those who may receive high doses of ionizing radiation like astronauts and nuclear power plant workers.

In the biological dosimetry, results may not be accurate for those people who had a history of low-dose irradiation. Also, during radiation therapy, a patient is usually exposed to low level radiation for film imaging prior to high dose treatment. The exposure history of the patient prior to therapy may be a potentially important factor for the efficacy of the treatment of certain cancer, because several human tumor cells exhibited greater adaptive survival responses than normal cells. 12

3. Can the induction of AR be manipulated for medical and other benefits ?

The radioadaptive response is dependent both on the total adapting dose and the dose rate. An adapting dose of 50 cGy is only effective when given at 1 cGy/min or lower but not at 10 cGy/min or higher. On the other hand, an adapting dose of 1 cGy induces the adaptive response when given at 20 cGy/min but not at 0.5 cGy/min in cultured human lymphocytes. 9 The most effective adapting treatment may be selected for the induction of adaptive response according to our present knowledge of characteristics of the radioadaptive response.

The human population, however, is heterogenous in the ability to express the adaptive response and their physiological conditions also influence the expression. 13 Lack of adaptive response is observed in the lymphocytes of some donors and in several individuals, the adapting and chalenging doses interacts synergistically. The adaptive response, therefore, may not be manupulated easily even for the responder.

4. How does the AR related to the concept of hormesis ?

Despite there is a great difference between radiation hormesis and adaptive response, they have many things in common: both phenomena can be induced by low dose irradiation. In the radioadaptive response the optimal dose range for the induction is observed just as hormetic zone in radiation hormesis. 14

The most important difference of these two processes is that adaptive response will occur only when the adapted organisms are irradiated by a relatively large dose, but radiation hormesis does not need large doses for its appearance. For example, increase of life span in irradiated organisms with a low level irradiation compared with non-irradiated control group is a hormetic process, but when these irradiated organisms can tolerate higher doses of ionizing radiation than control group, it would be called an adaptive response.

In terms of the mechanism, radiation hormesis and adaptive response may share some common processes. Further investigation is warranted to answer this question more accurately.

5. Should a knowledge of the AR affect current risk assessment methods for carcinogens ?

Many epidemiological studies have indicated that low dose irradiation may lead to decrease in cancer mortality. Recently it has been shown that a single exposure of quiescent C3H 10T1/2 cells to doses as low as 0.1 cGy reduced the risk of neoplastic transformations to a rate three to fourfold below that of the original spontaneous level, as well as the radioadaptive response for neoplastic transformation. 15 Low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation. These results suggest that a single low-dose at background or occupational exposure levels may rather reduce than increase cancer risk.

The radiation protection policy is based on LNT theory, but this assumption is not compatible with observed radiation hormesis and adaptive response by low-level irradiation. Obviously LNT theory and current radiation protection regulations exaggerate the risk of low doses of ionizing radiation and cause radiophobia.

REFERENCES

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2. Evensen G, Seeberg E. Adaptation to alkylation resistance involves the induction of DNA glycosylase. Nature 1982: 296: 773-775.

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