May 20, 2002 Central Research Institute of Electric Power Industry

 

The Central Research Institute of Electric Power Industry (CRIEPI) has confirmed that low-level radiation possesses the action of suppressing cancer development. This finding is based on the results of the research conducted by Dr. Kazuo Sakai, Senior Research Scientist at Low-Dose Radiation Research Center (LDRC) of the Institute.

At the Center, research has been conducted with the aim to correctly evaluate the effect of radiation on living things -- radiation that has been traditionally regarded to be harmful even at trace amounts. As a part of this research, the effect of low-level radiation on the process of carcinogenesis was studied. The results of a two-year plus mouse experiment showed that skin cancer development induced by a carcinogenic drug was suppressed by low-level radiation.

The discovery that low-level radiation suppresses the development of skin cancer is a landmark finding, the first such report in the world.

The results of the present study show that living organisms acquire resistance when irradiated by minute doses. Such results provide valuable information for the correct evaluation of the effect (risk) of minute doses of radiation on human beings. The results of the present study show that living organisms acquire resistance when irradiated by minute doses. Such results provide valuable information for the correct evaluation of the effect (risk) of minute doses of radiation on human beings and may well have the potential for future medical application.



 The part of this result was presented at the 44 th Annual Meeting of Japan Radiation Research Society in the last October and at the International Symposium on Radiation and Health in the last November in Seoul.

Background   Radiation has been regarded to be harmful in whatever minute dose. The same has also been said for carcinogenesis, that radiation has a carcinogenic risk proportional to whatever minute level it may be. However, this is a hypothesis (the linear non-threshold hypothesis) based upon a highly conservative viewpoint, made by extrapolating the findings obtained with high-dose radiation to the low-dose region, about which there is very poor information.

 

  From the later half of the 1980s, investigations began to look at the effects of low-dose radiation on living matters at individual, tissue, cell and molecular levels. The results of these studies have elucidated that living organisms show marvelous responses to minute doses of radiation. These responses include:

  [1] induction of substances that protect cells against reactive oxygen species (anti-oxidants) (CRIEPI, Yamaoka et al., 1991); [2] augmentation of functions to repair damages to genes (DNA repair) (United States, Le et al., 1998); [3] activation of the mechanisms to remove transformed cells in the body (apoptosis, self-destruction mechanisms of cells) (Canada, Mitchel et al., 1994); and [4] augmentation of immune functions (China, Liu et al., 1987).

  Through recent advances in research, the mechanisms of carcinogenesis have gradually unfolded. An outline is shown in Figure 2.

 

  (1) Various carcinogenic substances present in the environment cause damage to genes (DNA), either directly or mediated by a highly reactive molecular species called the reactive oxygen species. (2) Cells with DNA damage transform into cancer cells at a certain rate. (3) Cancer cells deviate from the normal proliferation control mechanisms and proliferate in an orderless manner, subsequently developing into cancer as a disease.  

If antioxidants are induced by low-dose radiation during this process of carcinogenesis, the reactive oxygen species responsible for DNA damage will be removed, consequently augmenting the DNA repair capability, and the two factors interact to reduce DNA damage. In addition, activation of the apoptotic mechanism removes transformed cells (candidates for cancer cells) that possess irreparable DNA damage. What is more, the activated immune system acts against those cells that have developed into cancer cells (Figure 2).

To examine whether such suppression of carcinogenesis actually occurs, we started verification experiments using mice at a low dose rate chronic irradiation facility.

  [Outline of facility]
The facility allows keeping of experimental animals (mainly mice) under chronic exposure to gamma-ray irradiation. A gamma-ray source (cesium 137) was installed in a clean room measuring 9 m in breath, 12 m in depth and 5 m in height. The blue device seen at the front is the radiation source. There is an opening on the reverse side. By remote manipulation, the radiation source stored inside the unit can be moved to the opening, which irradiate gamma-rays in a direction toward the back of the photograph.

  The white shelves that can be seen at the back of the irradiation source house cages with a capacity of 5 to 6 mice per cage. Up to 18 cages can be placed on each shelf.

By changing the distance between the radiation source and animal shelves, irradiation by various dose rates (from 0.7 mGy* to 70 mGy* per day) can be achieved. In this clean room, over 700 mice can be irradiated at the same time. In order to examine the irradiated mice over a long period (one year or longer depending on experiment), the animals have to be kept in a strict infection controlled environment. For this purpose, persons who enter the experimental area of the chronic irradiation facility have to change into sterilized wear and pass through an air shower. In addition, a cap, mask and gloves are worn during manipulations.

Visitors to the facility have asked, "Are the animals handled here so dangerous?" In fact, the reverse is true; these measures are to prevent the introduction of outside bacteria into this area.


What experiments were conducted? What results were obtained?   A total of 140 mice (six week old females from a representative strain widely used in research) were used. The mice were divided into 4 groups of 35 mice each and were placed at distances of 3, 5 and 10 m from the gamma ray source (cesium 137) in the low-dose rate chronic irradiation facility. Irradiation was conducted for 35 days. Then, a carcinogenic agent (methylcholanthrene 0.5 mg) was injected into the groin region of each mouse. Irradiation was continued at the same dose rate and the mice were observed. A group of mice treated in the same manner but placed behind a 60 cm thick concrete wall was used as the non-irradiated control (Figure 4).

  Figure 5 shows the results of cancer development up to 216 days after injection of the carcinogenic agent.

 

  (1) In the group irradiated at a distance of 10 m from the radiation source, there was no difference in tumor (cancer) development rate compared to the non-irradiated control group. (2) In the group placed at a distance of 5 m, a significant decrease in tumor (cancer) development rate was observed. (3) In the group placed at a distance of 3 m, a decrease in tumor (cancer) development rate was observed, although the difference was not significant.  
These findings show a suppressive effect of cancer formation under a certain irradiation condition. There seems to be an optimal dose rate for the cancer suppression effect and dose rates below or above this level are less effective.


Future development   Upon obtaining these results, the LDRC at CRIEPI continued research to explore the functions that are inactivated in vivo in mice irradiated with low dose rates. Although we examined skin cancer induced by a carcinogenic agent in the present study, we are currently investigating whether the same suppressive effect can be observed in other cancers.

Since the antioxidants activated by low-dose irradiation remove the reactive oxygen species in the body, it is possible that they may also suppress diseases caused by the reactive oxygen species (such as diabetes) or alleviate the symptoms. From this viewpoint, we are also moving ahead with research into medical applications.


Approach to research of the low-dose radiation effect at CREIPI   Since 1988, CREIPI has been engaged in research on the effects of low-dose irradiation on living organisms, in collaboration with other research institutions in Japan and overseas. Also, in view of the increasing importance of the association between radiation and human beings in the 21st Century, such as in the utilization of radiation in medicine and industry as well as peaceful application of atomic energy, the LDRC was established in October 2000, with the aims of further promoting research and transmitting research results over a wide area.

 

(1) Information for the correct understanding of low-dose radiation on living organisms (2) Information useful in formulating more rational irradiation protection criteria (3) Information useful in research on the possibility of medical application of low-dose irradiation
The LDRC conducts independent research and at the same time strengthens collaboration with external research institutes. Acting as the base for the research network, the LDRC serves to collect and transmit information related to the correct understanding of the effects of low-dose radiation on living organisms and the applications of such radiation.

 

For reference:
    Are there other biological action phenomena of low-dose radiation?

  [Adaptive response to radiation]
Adaptive response to radiation refers to the phenomenon that prior exposure to low-dose radiation confers resistance to the lethal effects of subsequent high-dose irradiation. This phenomenon has been demonstrated in experiments using cells and mice. One example is shown here.

Mice are irradiated with 7 Gy [Gy (gray) is a unit of radiation dose. One Gy is the radiation dose to generate the energy of 1 J per kg substance] of X-rays. Most mice will die from this magnitude of irradiation and the survival rate after 30 days is approximately 10% (Figure below). However, if the mice are pre-irradiated with 0.5 Gy two weeks before the irradiation with 7 Gy, the survival after 30 days is maintained at a high level of nearly 80%. Such resistance is not acquired if 7 Gy irradiation is given immediately after the 0.5 Gy irradiation. In other words, some changes occur in the mice during the two weeks after the 0.5 Gy irradiation and these changes probably confer resistance to subsequent irradiation with 7 Gy.

This adaptive response to radiation is one example of the superb response of living organisms to low level irradiation.

 

  [What is apoptosis?]
Apoptosis refers to the process by which "extra" cells in the body rapidly die and are removed. This phenomenon can be observed when the tadpoles lose their tails. This mechanism plays a role in removing cancer cells formed inside the body.

 

 

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