We have studied that pre-exposure to the change of environment such as radiation, UV and heat at low doses induces resistance and tolerance to the environment through p53-centered signal transduction pathways in many kinds of organisms. In radiation, pre-irradiation at low dose or low dose-rate induced radio-resistance in the cultured cells and whole body in mice. The radiation-responsive molecule p53 acts important roles in radiation effects through apoptosis, DNA repair, cell cycle control, aging, malformation and carcinogenesis. On the other hand, the p53 gene status of cancer cells decided the radiation sensitivity, heat sensitivity and anti-tumor-drug sensitivity. Therefore, the investigation of the p53 gene status may be a useful for the decision of cancer therapy methods from predictive assay of tailored made therapy. We also found the accumulation of p53 molecules after exposure to space and cold environments. From these findings, we have to progress the molecular function of p53 from the interaction among proteins by using proteomics techniques.

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We have been accumulating the knowledge on radiation effects at various levels: genes, cells, animal experiments or humans. In this presentation, I woul d like to summarize the latest knowledge of radiation effects on humans, and consider about issues that the public at domestic and international level e xpects for study on radiation effects. From my own experiences as Professor o f Medicine at Nagasaki University, as Chairman of Radiation Effects Research Foundation, and as various positions appointed from regulating as well as p romoting sides of the use of radiation, I believe that "radiation effects ar e health effects" and the experts in research of radiation effects are accountable to the public for scientific study results of radiation effects. From the information in the 20th century, the explosion of atomic bombs, Bra vo test in Marshall Islands, the accident of Chernobyl nuclear power plant a re picked up and the dose effects of radiation on humans are summarized. Issu es expected by the public may include compensation of atomic bomb survivors, radiation protection of the public as well as patients, and emergency prepa redness to radiation accidents. The former issues relate to effects of low d ose radiation and what is termed LNT, and I would like to emphasize that in the areas of scientific uncertainty or limitation, many factors have to be t aken into account in the policy and regulatory decision-making process to as sure public health and well-being. The international framework for the latte r issue can be summarized by the explanation of WHO-REMPAN (Radiation Emerge ncy Medical Preparedness Assistant Network) and IAR (International Associati on of Radiopathology).

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Ionizing radiation causes DNA double strand breaks, which lead to change in the chromatin structure. Recently, it has been shown that altered chromatin structure induced by ionizing radiation induces autophosphorylation of ATM protein, by which dimeric or oligometric forms of ATM proteins are dissociated into monomeric form. Using antibodies against phosphorylated ATM at serine 1981, we examined how chromatin structure is changed after irradiation. Immediately after X-irradiation, we detected tiny foci of phosphorylated ATM, and the diameter was approximately 0.1 micrometer. The size of the foci was growing thereafter, and it reached approximately 1 micrometer 1 hour after irradiation. Growing the foci size was detected specifically in cells at G1 and G2 phase, and cells in S phase contained both tiny foci and growing foci. These results indicate that alteration in the chromatin structure is induced by DNA double strand breaks, but it is also suggested that chromatin remodeling is induced during DNA repair of double strand breaks.

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Eukaryotic DNA is packaged in nuclei into nucleosome, which is the basic unit of chromatin, wrapping around histone octamers. Like other nuclear activities involving replication and transcription, the regulation of DNA repair upon damage by irradiation are also regulated at the chromatin level. We have analyzed the kinetics of core histones in living cells using photobleaching techniques. This technique is now applied to analyze dynamics of histone variants during DNA damage and repair. To understand the molecular mechanism of histone exchange found in living cells, we developed an in vitro system that mimics in vivo events using permeablized cells so that the required components can be manipulated. HeLa cells were permeabilized with a non-ioninc detergent, and incubated in extracts prepared from cells expressing histones tagged with the green fluorescent protein (GFP). As is in living cells, H3-GFP and H4-GFP in extracts preferentially targeted to replicated chromatin in permeabilzed cells, and H2A-GFP and H2B-GFP to euchromatin regardless of DNA replication. Although purified H2A-H2B complex containing H2A-GFP failed to assemble into permeabilzed cell chromatin, its assembly was supported by the addition of cell extracts. Using this system, we expect that the factors essential for histone assembly and exchange can be identified and the physiological role of histone modification can be revealed. We hope this permeabilized cell system will be useful for understanding the regulation of DNA damage repair, as is photobleaching in living cells.

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Recent advance in biological imaging has revealed that cell nucleus carries a dynamic higher order architecture showing the close association with nuclear functions, transcription, replication and DNA repair. However, little is known about the dynamic organization of higher order nuclear architectures including chromatin and non-chromatin nuclear domains after induction of DNA damage. To examine the dynamic organization of higher order nuclear architecture for DNA repair, we applied local irradiation of cell nuclei using a focused UV-laser (laser-UV-microirradiation). First, we analyzed the dynamics of DNA repair proteins in fixed human fibroblast cells by immunofluorescence staining after laser-UV-microirradiation. g-H2AX foci were detected within 3 min., and accumulations of MRE11 were observed 5 - 10 min. after irradiation, respectively. RAD51 showed accumulations from 5-10 min. after irradiation, and the number of cells carrying RAD51 accumulations increased until 20 - 30 min. after irradiation. PML showed colocalization with RAD51 accumulation 12 hours after laser-UV-microirradiation. These results suggest that DNA repair associated nuclear domains are formed at sites of DNA damage by the time dependent manner. Fluorescence Recovery after Photobleaching (FRAP) technique has make it possible to examine the dynamics of specific proteins in living cells. Now we are studying the dynamics of chromatin after laser-UVA-microirradiation using FRAP analysis of GFP tagged-histones in living cells. Dynamic organization of higher order nuclear architecture for DNA repair will be discussed.

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Eukaryotic genome is the tightly packed into the chromatin,a hierarchically organized complex of DNA and histone and nonhistone proteins. This packing represents a common obstacle for most of the DNA functions. The role of these chromatin modifications in the cellular response to DNA damage remains largely unexplored. Recently,we revealed that the TIP60 histone acetylase complex involved in DNA repair and apoptosis. However,it remains unknown how the TIP60 complex involves in DNA repair. To better understand the mechanism of the TIP60 complex in DNA repair, the TIP60 complex purifies from chromatin soluble fraction after DNA damage. As a result, TIP60 complex is associated with gamma- H2AX after DNA damage. Histone H2AX is histone H2A variant and double strand breaks(DSBs)induce phosphorylation of histone H2AX. We investigated the relationship between the phosphorylation of H2AX and the HAT activity of the TIP60 complex. As a result,in mutated TIP60 expressing HeLa cells,the amount of the phosphorylation of histone H2AX was reduced compared with the parental Hela cells after DNA damage. Thus,the phosphorylation of H2AX required for the HAT activity of the TIP60 complex. In this talk,I would like to discuss the role of the TIP60 HAT complex in DNA repair focusing on histone H2AX.

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Irradiation with heavy ion particles is one of promising procedure for cancer therapy. Heavy ion particles efficiently kill cancer cells with the high LET and the typical Bragg peak, two major characters. However, we have less knowledge about the character of DNA damage induced by heavy ion particles. Therefore, we estimated the number of DNA damage including strand breaks and oxidative base lesions, and compared the localization on pDEL19 and lambda DNA irradiated by gamma-rays, carbon and iron ions, whose LET were 0.2, 13, and 200 keV/um, respectively. Our result showed that total damage per dose were decreased with increase in LET. Even clustered damage per dose also were decrease, LET-dependently. Thus, the increase of LET did not lead increase of number of clustered damage, that is thought to be major driving force of radio-induced cell killing. It suggests that another factor such as quantity of clustered damage is important.

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Recent molecular biological studies have contributed to elucidation about the radiation-induced signal transduction pathways for apoptosis, anti-apoptosis and cellular proliferation. In radiation cancer therapy, it is useful to sensitize radiation sensitivity of cancer cells by activation of signaling factors involved in radiation-induced apoptosis or suppression of them in anti-apoptosis/cellular proliferation. In a series of examinations using human cancer cell lines and tumor-trasplanted mice, we have shown p53-dependent radiation-induced apoptosis based on the detection of apoptotic bodies, DNA ladders or immunohistochemically positive cells for apoptosis-related proteins. Since mutations of p53 genes are observed in more than 50% of human cancer cells, attempts to overcome the functional impairment of mutant p53 are underway. We have reported that molecular chaperones such as glycerol and p53 C-terminal peptides can restore the wild-type p53 function to mutant p53. On the other hand, radiation activates signal transduction pathways not only for apoptosis but also for cellular survival. Several signaling factors, such as Akt, survivin, heat shock proteins and DNA repair proteins, play important roles in radiation-induced cellular survival signaling pathways. Such pathways are disadvantageous to radiation cancer therapy. Therefore, the targeted inhibition of such signaling factors might be useful for the development of molecule-targeted radiation cancer therapy. We here present that chemical inhibitors and small interference RNAs targeted for those signaling factors are good candidates for radiation sensitizers in radiation cancer therapy.

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[Purpose] To identify a set of genes related to thermoradiosensitivity of cervical carcinoma and to establish a predictive method. [Materials and Methods] A total of 19 patients with cervical cancer (1 Stage IIIA, 11 Stage IIIB, 5 Stage IVA, and 2 Stage IVB) who underwent definitive thermoradiotherapy between May 1995 and August 2001 were included in this study. We compared the expression profiles of 8 thermoradiosensitive and 11 thermoradioresistant tumors obtained by punch biopsy before treatment using a cDNA microarray consisting of 23,040 human genes. [Results] We selected 35 genes on the basis of a clustering analysis, and confirmed the validity of these genes with a cross validation test. Some of these genes were already known to be associated with apoptosis (BIK, TEGT), hypoxia-inducible gene (HIF1A), and tumor cell invasion and metastasis (PLAU, CD44). We developed a "Predictive Score" system that could clearly separate the thermoradiosensitive group from the thermoradioresistant one. [Conclusion] These results from the treatment program between May 1995 and August 2001 showed that by using gene-expression profiles we can predict outcome of thermoradiotherapy for advanced cervical carcinoma. A "Predictive Score" system was developed that could clearly separate the thermoradiosensitive group from the thermoradioresistant group. These results may eventually lead to the achievement of "personalized therapy" for this disease.

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In analyzing the response of quiescent (Q) cells in solid tumors, we have developed a combined method with a micronucleus (MN) assay and the identification of proliferating (P) cells by 5-bromo-2'-deoxyuridine (BrdU) and an anti-BrdU monoclonal antibody. Using this method, the responses of Q tumor cells as well as total tumor (P+Q) cells within murine solid tumors to various DNA-damaging treatments, including radiation therapy, were evaluated. Based on this evaluation, combining with tirapazamine, a well-known bioreductive agent, and/or heat treatment at mild temperatures was thought to be a promising modality for cancer therapy in terms of conventional anticancer treatment-resistant Q cell control. Recently, Our method for detecting the Q-cell response using P cell labeling with BrdU and the MN frequency assay was also shown to be applicable to an apoptosis detection assay. Meanwhile, our method for detecting the intratumor Q-cell response was also applicable toward high linear energy transfer radiation, including reactor neutrons. We are now investigating the impact of p53 status of the tumor cells constituting solid tumors on intratumor Q cell response to various anticancer treatments. In addition, using our method, a new neutron capture compound that has the potential to be distributed in neutron capture therapy-resistant intratumor Q cell populations is now under development.

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Ionizing radiation causes DNA double strand breaks, which are the major cause of detrimental effects of radiation. Induction of DNA double strand breaks has been shown to activate DNA damage checkpoint, and ataxia-telangiectasia mutated (ATM) protein plays a central role in the initiation of this pathway. Recently, it has been reported that ionizing radiation-induced chromatin structure induces autophosphorylation of ATM protein at serine 1981, which results in an activation of ATM as a protein kinase. Although autophosphorylation is shown to convert dimeric or oligomeric forms of ATM to monomeric form, it is not clear how change in the chromatin structure induces autophosphorylation of ATM protein. We have examined phosphorylation of ATM protein at serine 1981 in X-irradiated normal human diploid cells using antibodies recognizing phosphorylated ATM protein at serine 1981. Immunofluorescence study demonstrated that ATM was phosphorylated and formed tiny foci immediately after irradiation, but we also found diffuse pattern of ATM phosphorylation over the nucleus. It is suggested that ATM is phosphorylated not only at the sites of DNA double strand breaks but also phosphorylation is induced in DNA double strand breaks independent manner. The possible mechanism will be discussed.

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We introduce our research on one-electron oxidation of DNA leading to the oxidative damage. 1)Photosensitized one-electron oxidation of DNA2)Hole generation and migration in DNA3)Two-color two-laser oxidative damaging DNA.

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We have investigated DNA damage produced by energy transfer from radiations mainly using monochromatic soft X-rays obtained from synchrotron radiation (SPring-8, BL23SU). The soft X-rays less than 1 keV are available for (1) probes to investigate relationship between energy transferred to molecule and subsequent molecular change, and (2) low-energy secondary electron sources. The DNA damage, direct effect, cannot be neglected when taking condensed chromatin structure in a nucleus into account. Owing to a series of our experimental analyses by electron paramagnetic resonance spectroscopy, high-performance liquid chromatography and quadrupole mass spectrometry, it is found that (i) thymine decomposition products produced by the soft X-irradiation are almost similar to those by ⁶⁰Co gamma-irradiation while quantitative difference is shown, (ii) sugar moiety in DNA is decomposed easier than nucleobases by the soft X-irradiation. In this presentation, we will introduce our up-to-date results for the DNA damage and discuss its characteristic as compared with well-known oxidative damage caused by superoxides such as hydroxyl radical.

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During biological function of proteins in cells, the structural of the proteins change dramatically. In order to understand the principle and the molecular mechanism of the protein reactions, it is essential to elucidate the reaction dynamics in time-domain. Although static protein structures obtained from such as the X-ray crystallographic data are very important, they cannot provide us idea on the reaction dynamics and it is difficult to tell whether or not the protein structures in the crystalline forms are really important in physiological conditions (e.g. in solution phase at room temperature). At the same time, the protein structure is very soft and its structural fluctuation is also very important for the efficient and selective reactions. However, traditional spectroscopies do not possess a capability for these studies. Recently we have developed novel methods to study the conformation, energy, and intermolecular interaction dynamics from a view point of time-resolved thermodynamical properties and transport properties. Here I will briefly summarize the principle and the methods for the measurements, and then discuss biological protein reactions by taking examples of sensory Rhodopsin, which is a photo-sensor of a bacteria, and other protein reactions.

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Ionizing radiation generates isolated and clustered damage in DNA. Among them, bistranded clustered damage that contains multiple oxidized bases and strand breaks on opposite strands within a few helical turns is suggested to be responsible for major deleterious biological consequences. In the present study, we quantified bistranded clustered DNA damage induced by low- and high-LET radiations. pDEL19 DNA and lambda DNA were irradiated in Tris buffer by Fe ions (LET = 200 keV/um), C ions (13 keV/um) ions, and gamma-rays (0.2 keV/um). The yield (site/bp/Gy) of bistranded clustered damage (double-strand breaks and clustered purine and pyrimidine lesions) was decreased with the increase in the LET of radiations. This result is in contrast to the high biological effectiveness (RBE) of Fe and C ions relative to that of gamma-rays, suggesting crucial roles of complex damage clusters that could not be revealed in the present analysis and the error prone repair of these clusters in cells. We also assessed the repair efficiency of clustered base damage by human DNA glycosylases using defined oligonucleotide substrates. Detailed results will also be presented in the meeting.

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To investigate the role of 53BP1 in repair of DNA double-strand breaks in vertebrate cells, we established a 53BP1 knockout cell line by using hyper-recombinogenic chicken B cell line DT40. When asynchronous cells were irradiated, no significant difference was observed in X-ray sensitivity between wild type and 53BP1-null cell lines. When cells were synchronized, 53BP1-null cells showed elevated X-ray sensitivity in G1 phase, whereas Ligase IV-null cells showed elevated X-ray sensitivity in G1- early S phase, suggesting that the repair system defect in 53BP1-null cells dominantly functions in the G1 phase of the cell cycle, and differ from NHEJ pathway. Furthermore, X-ray sensitivity analysis with or without wortmannin in G1-arrested cells revealed that 53BP1-dependent repair pathway was resistant, whereas NHEJ pathway was sensitive to wortmannin. These data suggest that there is the third repair pathway for DNA double-strand breaks, which is 53BP1-dependent, wortmannin resistant and functions dominantly in G1 phase of the cell cycle.

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DNA-PK (DNA-dependent protein kinase) is considered one of, at least, the most important enzymes in the repair and signal transduction of DNA double-strand breaks (DSBs). Although DNA-PK is known to phosphorylate a number of proteins with supposed function in DNA repair, cell cycle checkpoint and apoptosis in vitro, the true substrate(s) in vivo and the significance of phosphorylation are presently unclear. We demonstrated XRCC4 protein, which is implicated in the DNA double-strand break repair and V(D)J recombination with DNA ligase IV, as the first example of in vivo substrates of DNA-PK. Now we identified three phosphorylation site(s) in vitro, two of which were phosphorylated also in vivo after X-irradiaiton. Furthermore, the analysis of mutant lacking these phosphorylation sites strongly suggested an important role of the phosphorylation in the repair of radiation-induced DSBs and cell proliferation probably via the recruitment of XRCC4 to the site of DSBs.

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Defect of homologous recombination (HR), which is a major repair pathway for DNA double strand breaks (DSBs), can result in genomic instability and cancer predisposition. Previously, we have demonstrated that NBS1, responsible for cancer predisposition disorder Nijmegen breakage syndrome, is an important factor of HR. However, the mechanism by which NBS1 functions in HR is unknown. To gain insight into the mechanistic roles of NBS1 in HR, we generated the series of NBS1 mutant cDNAs and examined their HR activities using DR-GFP/SCneo system. These systems utilize the rare-cutting I-SceI endonuclease for the introduction of DSB. The HR activity of NBS1 is completely abolished by deletion of MRE11-binding domain, and severely decreased by mutations in FHA or BRCT domains. In contrast, the mutations in the phosphorylation sites of ATM kinase did not affect the HR activity. We also examined AT cells and found that AT cells have normal HR activities. These results suggest that recruitment MRE11/RAD50 to DSB site by NBS1 is crucial for HR, and that NBS1 can function in HR independent of ATM. We are currently investigating the connections between NBS1 and BRCA1/2 in HR using dominant-negative methods. The results of this current study will also be presented.

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The Mus81-Eme1 complex was proposed to be an essential component of a Holliday junction resolvase. A subsequent study showed, however, that the complex preferentially cleaves 3-flap structures and replication forks rather than intact Holliday junctions, suggesting that Mus81-Eme1 may play a role in replication fork processing and repair. A more recent study has shown that Rad51C or Rad51C-associated proteins are involved in the resolution of intact Holliday junctions in mammals. Despite accumulating evidence for the role of Mus81 in the processing of recombination intermediates, biological functions of the protein in mammals remain to be demonstrated. To help define the roles of Mus81 and Rad51C in human cells, we deleted the genes in the human colon cancer cell line. Here we show that these genes are essential for mitotic homologous recombination. Furthermore, defective recombination repair resulted in checkpoint activation. This finding provides direct evidence for the roles of Mus81 and Rad51 paralogs in the maintenance of chromosome stability through coupling the recombination machinery with the unprocessed intermediates-dependent checkpoint pathway.

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Following DNA damage induced by ionizing radiation, cellular mechanisms, including cell-cycle checkpoint and DNA repair, play crucial roles in maintaining genomic stability. It has been shown that upon DNA damage the nuclear checkpoint kinases Chk1 and Chk2 are phosphorylated and activated by ATM kinase, and mediate cell-cycle checkpoint arrest. However, the mechanisms underlying recovery from DNA damage-induced cell-cycle checkpoint arrest remain largely unknown. Recently, we found that the nuclear Wip1 phosphatase, induced by p53 following DNA damage, associates with Chk1 and Chk2, and dephosphorylates (inactivates) phosphorylated-Chk1 and -Chk2 kinases, thereby mediating recovery from cell-cycle checkpoint arrest. Furthermore, we have shown that Wip1 dephosphorylates phosphorylated (activated) ATM kinase, thereby inhibiting its kinase activity. In my talk, I will overview our current model of on/ off regulation of cell-cycle checkpoint mechanism, and discuss about a possible coupling of cell-cycle checkpoint regulation with DNA repair. Since ATM, Chk2 kinases and Wip1 phosphatase have been considered as anti-oncogenic and oncogenic proteins, respectively, I will also refer to possible relationships between abnormal expression and/or function of these proteins and malignant tumors.

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Results are given on the joint effect of radiation exposure and cigarette smoking on lung cancer risks among A-bomb survivors, based on 592 cases through 1994. Information on smoking was derived from mail surveys and clinical interviews of 45,113 persons in the Life Span Study (LSS) cohort of RERF. Radiation and smoking effects on lung cancer are found to be significantly sub-multiplicative and quite consistent with additivity. The smoking relative risk, previously very low in studies of this cohort, is now similar to that found in Western populations. This increase is likely to be related to the scarcity of cigarettes during and after the war. The smoking relative risk depends little on sex. After adjusting for smoking, the radiation-related risks relative to background rates for nonsmokers are similar to those for other solid cancers: a sex-averaged ERR/Sv of about 0.9 with a female:male sex ratio of about 1.6. Adjusting for smoking removes a spuriously large female:male ratio in radiation relative risk due to confounding between sex and smoking level. The adjustment also removes an artifactual age-at-exposure effect in the radiation relative risk, opposite in direction to other cancers, which is due to birth cohort variation in lung cancer rates.

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Humans are continuously exposed to radiation and chemicals. Consequently, combined effect on carcinogenesis, i.e., modification of radiation-induced carcinogenesis by post-treatments with chemicals is utmost important in animal experiments.
First, we found mice exposed to urethane at early gestational stage (8th day) was sensitive to post-treatment with urethane via mother milk (Cancer Res 1973). More intensive effects were observed in the mice exposed to X-rays (0.36 Gy) at early gestational stage, though in utero radiation exposure itself rarely induced tumors (Environ Mutagen 1984). This suggests that radiation-induced persistent hypersensitivity in the fetus to post-natal urethane treatment for tumor induction remains over the several ten cell-division.
In the mouse fetuses exposed to urethane and X-rays at middle gestational stages, atroply of male and female gonads was observed (Br J Cancer 1976), anticipating the recent finding by endocrine disruptors. In addition, radiation and chemical exposure of male and female germ cells resulted in the higher incidence of tumors and congenital malformations in the offspring (Cancer Res 1975, Nature 1982). Furthermore, F₁ offspring of mice exposed to radiation were more sensitive to postnatal urethane or TPA treatments, developing a cluster of tumor nodules in the lung (and also skin tumors and leukemia). Transgenerationally transmitted tumor susceptibility is manifested by postnatal environmental agents, leading the recent studies on genomic instability (Mutat Res 1983, 2003, Nature 1990).

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Based on investigations in humans, intestinal metaplasia have been considered as precancerous lesions or a predisposing condition for differentiated gastric carcinoma development. An inverse relationship between quantity of intestinal metaplasia and gastric tumor development and its presence does not exert a positive influence on induction of gastric neoplasia by N-methyl-N'-nitro N-nitrosoguanidine (MNNG) or N-methylnitorsoure (MNU) in rats. Male-5week-old CD, Wistar and F344 rats were X-irradiated with a total of 20 Gy in two equal fractions with a 3day interval. Beginning 16 weeks after the first dose, DMH was injected at a dose of 20mg/kg body weight weekly for 10 times in CD and Wistar rats. Azoxymethane (AOM) was injected at a dose of 15mg/kg body weight weekly for 3 weeks and 2 amino 1 methyl 6 phenylimidazol [4,5-b]pyridine (PhIP) was given every 2 days, 3 times per week, for a total 10 doses of 75 mg/kg body weight by intragastric intubation in F344 rats. Twelve months after the initial carcinogen treatment, tumors in pylorus of the glandular stomach were observed in the X-rays pulas DMH, AOM or PhIP group in X-ray irradiated rats. No such lesions were found in the DMH, AOM, PhIP or X-ray alone or nontreated groups. Large intestinal tumors appeared in the glandular stomach by X-ray plus colon carcinogen.

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We are living in the environment with numerous natural and man-made chemicals that are cancer-initiating and promoting potentials. For this reason, radiation carcinogenesis in human is considered as a result of interaction with these factors. But, the quantitative assessment and mechanistic understanding of combined effects of radiation and chemical carcinogens are still insufficient. Murine thymic lymphoma (TL), which are reproducibly induced by radiation and chemicals, has been utilized as a good model for elucidating cellular and molecular mechanism of human lymphocytic leukemia. The aim of this study are (i) to determine the mode of TL induction by combined treatment of X-rays and N-ethyl-N-nitrosourea (ENU), and (ii) to compare the molecular alterations among the TLs induced after X-rays, ENU or combined treatment. The dose-response curve of TLs after single treatment of X-rays and ENU was sigmoidal and linear, both with threshold dose, respectively. For combined treatment, synergistic effect was obvious for high dose radiation, while the effect was marginal for low or threshold dose radiation. It was interesting that there still existed threshold for X-rays in the combination with ENU. The molecular changes in the TLs induced by combined treatment were similar to those by ENU. It is suggested, therefore, that radiation acts as promoter or conditioner for ENU-induced lymphomagenesis.

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It has been considered that the energy of extremely low frequency magnetic fields (ELFMF) is too weak to damage DNA directly. Although environmental ELFMF exposure alone may have no or very little effect, some positive effects were observed with combined exposures to high-density electromagnetic fields and other factors, especially ionizing radiation.
The ELFMF enhanced the formation of spontaneous and X-ray-induced chromosomal aberrations in mouse m5S cells. Mutations induced by X-rays in human melanoma MeWo cells were enhanced by the high-density ELFMF exposure at 400 mT. Combined effects of X-rays and ELFMF at 5 mT were also observed in plasmids which were transfected to E-coli. In human glioma MO54 cells, it appears that exposure to the high-density ELFMF at more than 50 mT may potentiate X-ray-induced DNA strand breaks. Ten tesla static magnetic fields (SMF) exposure for 18 h also may cause an increase in the micronucleus formation induced by 4-Gy X-rays.
It is possible that ELFMF have combined effects with X-ray. We have been exposed to environmental magnetic fields daily and, especially, these combined exposures will be increasing in medical fields. The mechanism of the combined effects of magnetic fields and radiation is not yet clear, we will present the recent research data.

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We examined the correlation between lifestyle and mortality on the basis of health survey interview which 3831 Nagasaki A-bomb survivors underwent in 1997. Items asked at interview were: activities of daily living (ADL), living with family, recollection of atomic bombing, worry about health, relatives' death, visit by friends, socializing with neighbor, club member and mental health. Mental health conditions were assessed by 30-item version of General Health Questionnaire. Among 3700 who completely responded, 477 died from 1 August 1997 to 30 April 2004. The mortality adjusted for sex and age was 2.32-fold higher (p=0.0001) in subjects who could not do any item of ADL without help than in those who could do at least one item of ADL without help. The mortality adjusted for sex and age was 1.68-fold higher (p=0.005) in subjects who did not socialize with neighbor than in those who did. The mortality adjusted for sex and age was 1.03-fold higher (p=0.001) in subjects with high GHQ-30 score than in those without it. The mortality adjusted for sex and age was 1.37-fold higher (p=0.003) in subjects who joined some club than in those who did not join any club.

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The Radiation Effects Research Foundation (RERF) has implemented a new dosimetry system DS02 to replace the DS86. The primary change is an increase of about 10 % in gamma dose estimates for both cities. An anticipated increase of the neutron component in Hiroshima, for low-dose survivors, did not materialize. Risk estimates based on DS02 and DS86 doses were compared for solid cancer and leukemia mortality in the RERF Life Span Study (LSS) cohort for the period 1950 through 2000. Among about 86,000 survivors there were about 10,000 solid cancer and about 300 leukemia deaths. The estimates of solid cancer risk/Sv and the nonlinear dose response for leukemia are both decreased by about 10 % by the dosimetry revision. Estimated age-time patterns and sex difference are virtually unchanged by the dosimetry revision. The apparent shape of the dose response is virtually unchanged by the dosimetry revision, but for solid cancers the additional 3 years of follow-up from the LSS Report 13 has some effect. There is for the first time statistically significant upward curvature on the dose range 0-2 Sv. However, the low-dose slope of a linear-quadratic fit to that dose range should probably not be relied on for risk estimation, since that is substantially smaller than the linear slopes on ranges 0-1 Sv, 0-0.5 Sv, and 0-0.25 Sv.

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The mechanism of radiation-induced leukemia has been supposed to be direct effects that may be quite different from that of solid cancers, because of a shorter latent period and higher relative risk in leukemia than in solid cancers. Nakamura (2003) proposed the hypothesis that radiation exposure does not initiate a normal cell but accelerates the clonal expansion of the chromosomal translocation that arises predominantly in utero. We focus on the age pattern of ALL and AML in the A-bomb survivors. If radiation exposure acts only as a initiating event, a rapid increase in leukemia in several years after exposure is not available by the two-stage stochastic model that involves clonal expansion of the chromosomal translocation such as TEL/AML1 which probably leads to ALL., Since the frequency of excess ALL in adults at exposure is lower than in children at the same dose, the dose would contribute to a smaller influence on cell kinetics in adults than in children.

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Dental enamel is the only tissue in the human body that retains indefinitely the history of radiation exposure of Nagasaki Atomic bomb. The effect of ionizing radiation on dental enamel is to produce free electrons that can be trapped in defects in the crystal lattice. The lifetime of these traps is very long and both electron spin resonance (ESR) and thermoluminescence have previously been used to examine trapped electrons in dental enamel. We have suggested that dental enamel is a useful radiation dosimeter and could be used in reassessment of atomic bomb radiation dosimetry in Nagasaki and Hiroshima. However, dental enamel has not become widely used for determining radiation exposure of atomic bomb survivors, because any medical or dental diagnostic X rays of the teeth will confuse the measurement of their radiation exposure for atomic bomb. We turned our attention to the problem of separating the contribution due to diagnostic X rays. This technique can be readily achieved by the measurement of two divided 17 pieces of extracted human tooth out of dentists in Nagasaki City, Japan. The teeth were then divided into front (buccal side) and back halves (lingual side) before crushing into coarse chips for measurement on an ESR spectrometer. ESR signals with any medical or dental diagnostic X rays were observed for 12 teeth enamel of atomic bomb survivors. We have found that the diagnostic x rays dose can be determined separately from radiation exposure of Nagasaki atomic bomb survivors.

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Research of radiation protection for the public as nuclear terrorism measures becomes a today's task. Historical example is important as this kind of study. We focus effect of indoor evacuation here. For one part of 74 Hiroshima-survivors confirmed in zero grand 500 m radius of range, a personal dose has been evaluated by the measurement of chromosome aberration rate. We define the ratio between this personal dose and outdoors dose without any shielding for the initial nuclear radiation as effective dose evasion rate. The value was estimated to be between 0.003 and 0.03 for the ground-zero-survivors.

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Compared to popular subjects on teratogenesis due to radiation, such as microcephaly/central nervous system malformation, little has been reported on the congenital cardiovascular anomalies following maternal exposures. To collect data on prevention and treatment of congenital teratogenesis, examination of the effects of exposure to various types of radiation and teratogenesis is necessary. We focus on embryonic lethality, external malformations, and visceral malformations of cardiovascular origin caused by maternal exposure to varying dosage of radiations, such as 60Co gamma ray and neutron irradiation. We observed a high frequency of teratogenesis, especially cardiovascular and craniofacial anomalies, in the irradiated groups differing by the day of maternal exposure. These results indicate the high radiation sensitivity of rat fetuses to neurocristopathy syndromes, especially double outlet right ventricle, riding aorta, Tetralogy of Fallot, transposition of the great arteries, aortic arch anomalies, and lung/trachea anomalies. In humans, these conditions are termed Alagille Syndrome and DiGeorge-Velocardiofacial Syndromes, and this animal model is expected to contribute in the human investigation of such teratogenesis as well. Although progress has been made in identifying the mechanism of birth defects on the molecular level, many pieces to the puzzle still remain missing. In future studies of teratogenesis due to radiation, any approach will require not only the observation of human fetal specimen, but also the use of solid animal experiment models.

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Since the Chernobyl accident, joint research on dietary intake of trace elements has been carried out with Ukrainian researchers from the viewpoint of radioecology, hygiene and nutrition science. Concerning high rates of thyroid abnormalities, dietary intake of iodine in this region was investigated and it was found to be remarkably lower than the recommended dietary allowance. Stable iodine, which is known as one of the essential elements, can be index of behavior of radionuclides in the environment. In this presentation, results of analysis of iodine and bromine in milk in Ukraine are reported.
Milk samples were freeze-dried followed by pyrohydrolysis for collecting iodine and bromine in the samples into alkaline solution. Concentrations of the elements were measured by ICP-MS. Detection limits of iodine and bromine were 0.2 and 1 ng/ml, respectively.
Arithmetic mean and standard deviation of iodine concentration in Ukrainian milk were 63 ±53μg/kg-dry. On the other hand, iodine concentration in Japanese milk was 134 ±36μg/kg-dry. Although iodine concentration in Ukrainian milk was largely scattering, its arithmetic mean was about one third of Japanese. Analysis of more number of samples is now proceeding.

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To examine the effects of the Chernobyl accident on non-cancer thyroid diseases in children, we screened children living in Rechitskii, Loevskii, Gomelskii and Hoynikskii districts and Gomel city in the Gomel region of Belarus. We conducted the health screening at all schools, except Gomel city where we sampled seven schools with an enrolment over 1,000. The thyroid gland examination consisted of an ultrasound examination as well as measurement of TSH, FT4 and TPOAb. A total of 21,601 children were examined from February 1998 to December 2000.
Thyroid nodule was diagnosed in 148 children: 22 (11 boys and 11 girls) in 9,472 children (4,826 boys and 4,646 girls) born from 1 January 1987 to 31 December 1989 (Group I), 12 (6 boys and 6 girls) in 2,409 children (1,258 boys and 1,151 girls) born from 27 April 1986 to 31 December 1986 (Group II) and 114 (37 boys and 77 girls) in 9,720 children (4,810 boys and 4,910 girls) born from 1 January 1983 to 26 April 1986 (Group III), respectively. Girls aged 11-13 years at examination showed a significant difference among the Groups I, II and III in the prevalence of thyroid nodule while boys did not. They also showed a significant group difference in the prevalence of adenomatous goiter and thyroid cyst.

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A single cell irradiation system has been developed at JAERI-Takasaki to study radiobiological processes in single-ion-hit mammalian cells and bystander cells, in ways that cannot be achieved using conventional broad field exposures. Individual mammalian cultured cells are irradiated in the atmosphere on the cell dish, the bottom of which is made of ion-track-detector CR-39, with a single or precise numbers of 13.0 MeV/u ²⁰Ne and 11.5 MeV/u ⁴⁰Ar ions. Targeting and irradiation of the cells are performed automatically at the on-line microscope of the microbeam apparatus according to the positional data of the target cells obtained at the off-line microscope before irradiation. However, previously used automatic stages had a potential inaccuracy of stage movement, which affected greatly on the overall targeting and revisiting accuracy. Thus we replaced the automatic stages and measured the improvement of the mechanical accuracy of cell targeting system; object finding and retargeting accuracy using pseudo-cell sample, and accuracy of ion traversal on targeted cells. The samples irradiated with 5 count of ⁴⁰Ar ions using old stages included more than 25% of fail-to-hit cells. On the contrary, the distribution of ion-hits with the new stages indicated that 70% of cells were irradiated with 3-5 ions and less than 5% of cells were failed to hit.

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Plant cells are known to be more radiation-tolerant than mammalian cells. To explore the mechanisms of the radiation tolerance, it is necessary to irradiate plant cells with heavy ions that have a high biological effectiveness. However, the random distribution of tracks had interfered to utilize it. Ion microbeam that can target individual cells exactly is a good way to settle this issue. In this study, we developed a system for irradiating heavy ion microbeam on tobacco protoplasts as a model of single plant cells.
Tobacco protoplasts were embedded in the agarose medium and inoculated into the custom-made sample holder, in which CR-39 is incorporated to detect ion traversals. The colony formation rate of unirradiated protoplasts in this holder was 22.7±6.7%. The cells were irradiated by collimated carbon ions with 20 μm in diameter. The ions that penetrated the sample were detected and counted by the scintillatior-photomultiplier assembly and pulse counter. After the irradiation, the ion tracks on CR-39 was visualized by alkaline treatment and the number of ion hits on the individual cells was scored. Hit rate of the carbon ions on the cells was about 60%. The colony formation rate of tobacco protoplasts was not reduced by the irradiation of 1 to 10 carbon ions.

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Considering the biological effect of low-dose radiation of heavy charged-particle, the bystander effect will play an important role on the response of irradiated cells. However, analyzing bystander effect requires a method to distinguish irradiated cells and bystander cells. Using microbeam irradiation is a good way to solve this issue. Thus we irradiated CHO-K1 cells with heavy ion microbeam at JAERI-Takasaki, and analyzed its response on the point of view of phosphorylation of histone H2AX.
We used a sample holder whose bottom was made by a thin film of a plastic ion-track-detector, CR-39 (100 μm thick). The CHO-K1 cells were kept in exponential growth phase, and 2500-3000 cells were inoculated within the area of 5 mm x 5 mm at the center of a sample holder. Among the inoculated cells, 25 cells were selected and their positions were stored in the object database. Thereafter the cells were irradiated by 5 count of ⁴⁰Ar¹³⁺ ion microbeam (11.5 MeV/u, LET=1610 keV/μm). The irradiated cells were post-incubated for 30 minutes to 6 hours, then fixed and stained immunohistochemically with antibody specific with γH2AX. The frequency of γH2AX positive cells were increased with the postincubation more than 30 minutes in the range of 3-5%. This result suggested that the heavy ion irradiation induced bystander effect on the phosphorylation of histone H2AX in CHO-K1 cells.

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We have developed an X-ray microbeam irradiation system using synchrotron radiation, by which we can recognize cells individually and irradiate one by one with desired dose of monochromatic X-rays. Human fibroblast cells (NB1-RGB) were individually irradiated with X-ray microbeam, and fixed and stained by γ-H2AX antibody. The slit system installed just below the sample stage enables to change the size of the beam easily and the minimum size is 5 micrometer square. We irradiated the cells with two different microbeam in sizes, 5 and 10 micrometer square.
All the irradiated cells could be found at the revisited position, and could be distinguished from surrounding unirradiated cells by their high yield of fluorescence of γ-H2AX. Most fluorescent foci were observed in localized area in cell nuclei, the sizes of which were almost the same as the beam size. Difference in size of the stained area can be easily recognized between cells irradiated with 5-micrometer beam and those irradiated with 10-micrometer beam. Dose dependence of γ-H2AX induction was also clearly observed.

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The detailed mechanism of the bystander response to the radiation of the cells could be studied only with the microbeam irradiation system. Using our synchrotron X-ray microbeam irradiation system, we can irradiate an arbitrarily-defined region as target with desired number of X-ray photons. Using a criterion to distinguish live or dead presented last year, we have measured the survival fractions of cells irradiated with microbeam X-rays.
V79 cells were seeded on the dish in a very low concentration in order to prevent the overlapping of colonies. Targeted cell nuclei were irradiated with 10 µm square X-ray beam (5.35 keV, about 30 R/sec). When targets were irradiated with 200 R, 400 R, 600 R, 800 R and 1000 R, the survival fractions were 62.9%, 51.9%, 22.5%, 15.2% and 13.8%, respectively.
The energy of X-rays is absorbed only by targeted area. In order to compare our results with those in broadbeam experiments, we propose here nuclear-averaged dose, assuming that the cell has a thin double-cylindrical structure; inner cylinder is cell nucleus. Dose-survival curve thus obtained in the microbeam experiments is, almost the same as, or slightly higher than obtained in broadbeam experiments. Considering the difference in the irradiated area, these results may support the idea that damages in cell nucleus are critical to determine the cell death.

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In in vitro irradiation experiments using a broad, non-targeting beam, charged particles pass through the sample randomly, some pass through the cell and others not. In this case, absorbed dose in Gy unit is determined as the quotient of the energy absorbed in the sample to the sample mass, neglecting the information on the site of energy deposition events. Composition of the sample, cells and medium, is averaged all over the dish. In the microbeam experiments, however, the track of charged particles are localized, for example, in the cell nucleus. How can we determine the dose and compare the results obtained in microbeam experiments with those in broad beam experiments? In order to calculate the absorbed dose, we need to define the sample or the target that absorbed the radiation energy. One of the candidates of the target might be the cell itself, since the cell is an independent entity in living organisms. The reports which indicate that the signals for bystander effects are secreted or leaked out from the cell after processing the signal produced by the track seem to support the above idea. When we use an X-ray microbeam, next question will be raised. If the same number of X-ray photons is delivered with microbeam of different sizes, can we think both cases are the same or not? Some discussions and considerations on these points will be presented.

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This study investigated the role of DNA double strand breaks and DNA base damage in radiation-induced bystander responses in Chinese hamster ovary (CHO) cell lines. Two CHO repair deficient clones, xrs5 (DNA double strand break repair deficient) and EM9 (DNA base excision repair deficient) were used in addition to the wild type (CHO). When a single nucleus in the population was targeted with 1Gy, elevated numbers of micronuclei were induced in the neighbouring unirradiated cells in the EM9 and xrs5 cell lines, whereas induction was not observed in CHO. Under these conditions, the surviving fraction in the neighbouring cells was significantly lower in xrs5 than in the other cell lines, showing a higher cell killing effect in xrs5. These results suggest that DNA double strand breaks rather than base damage are caused by factors secreted in the medium from irradiated cells.

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In this experiment cells were irradiated continuously with low-dose-rate (LDR) radiation (0.3 mGy/min) in a confluent state up to 2 weeks. Cellular survival after LDR was much increased compared with the same dose of high-dose-rate (HDR) radiation (2 Gy/min). In accordance with the survival result, induction of micronuclei was also much reduced after LDR irradiation. Induction of mutation of the HPRT gene was also much lower after LDR than HDR. When activation of the ATM and p53 proteins were analyzed, significant amount of phosphorylation of ATM and p53-Ser15 was observed after HDR but little phosphorylation was observed after LDR We then analyzed focus formation of phosphorylated histone H2AX protein after irradiation. After HDR, dose dependent increase in number of foci was observed but after LDR almost no increase was observed, even at the highest dose. These results suggest that in normal cells DNA damage induced by LDR, which is very scattered in time and space, was effectively repaired and effect of LDR on normal human cells is also much smaller than that of HDR.

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As for low-LET radiation, we previously reported that challenge irradiation after pre-irradiation at a low dose or a low dose-rate resulted in lower levels of p53 accumulation and apoptosis incidence than those observed after the challenge irradiation alone in human cultured cells and mice spleen. In this study, to clarify the LET dependency in radioadaptive response, wild-type p53 cells (H1299/wtp53) were irradiated with X-rays (7.5 Gy) 0-18 h after pre-irradiation with X-rays or 70 KeV/µm Carbon-beams at low doses (0-0.50 Gy). On the other hand, p53 deficient cells (H1299/neo) were irradiated with 70 KeV/µm Carbon-beams (4 Gy) 0-18 h after pre-irradiation with X-rays or 70 KeV/µm Carbon-beams at low doses (0-0.50 Gy). The cells were fixed 48 h after the challenge irradiation. Apoptosis incidence was measured by Hoechst33342 staining. We found the suppression of apoptosis induced with X-rays 3-9 h after pre-irradiation with X-rays (0.01-0.05 Gy) to H1299/wtp53 cells but not Carbon-beams. In contrary, we did not find the suppression of apoptosis induced with Carbon-beams after pre-irradiation with X-rays or Carbon-beams in H1299/neo cells. >From these findings, we assume that high-LET radiation induces irreparable DNA damage, because we did not observe the radioadaptive response in the cells exposed to high-LET radiation.

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A derivative of murine immortal NIH/PG13Luc cells stably transfected with p53-dependent luciferase reporter plasmid was used for detection of transcriptional activity of p53 in response to radiation. We have identified several p53-dependent genes by microaray analysis expressed specifically in the cells after high dose rate or low dose rate irradiation. In the present analysis, we identified up-regulated genes specific to low dose rate irradiation (1, 10, 50, 100 mGy/h), but not to high dose rate irradiations (500 mGy/min), and then we performed quantification analysis of gene expression by using real time PCR method. The genes detected by microarray analysis, procollagen type I alpha 2, procollagen type V alpha 1, procollagen type V alpha 2, fibulin 5, tenascin C which are related to extracellular matrix. The expression levels of these genes showed the same tendency as those in real time PCR methods. And these genes expressed in a different manner from those in p53 responsive genes (cyclin G1, MDM2, p21). These data suggested that the low dose rate irradiations (1, 10, 50, 100 mGy/h) could be induced both cellular responses regulated by p53 dependent-transcription factors and other transcriptional factors. (This work was supported by Aomori Prefecture, Japan.)

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We have been studying cellular responses in normal human fibroblasts exposed to low-density high LET radiations. This year we focused on the induction of genomic instability in mutation induction detected with a 6-thioguanie resistant clone targeted on hprt locus. Cells were pretreated with either low-density carbon ions (~1mGy/7h) or low-dose ¹³⁷Cs gamma rays (~0.9mGy/7h) before following irradiation with X-ray challenging doses. There observed no difference in mutation frequency at 1.5Gy of X-ray challenging dose between un-pretreated and gamma-ray pre-treated cells. On the other hand, it was around 7 times higher in carbon-ion pretreated cells than in un-pretreated cells. The results suggest that the pretreatment of low-density carbon ions induce genomic instability in mutation induction.

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Although linear non-threshold model is a basic theory for the regulation of radioprotection, the model does not consider irradiation time or dose rate. We have established Modified Exponential (MOE) model describing dose-rate effect of ionizing radiation, by measuring growth inhibition and micronucleus formation of human osteosarcoma, U2OS. Here, we applied MOE model to various kinds of cells other than U2OS cells to show generality of MOE model.
Cells were irradiated by culturing in the room bearing 50,000 Ci cobalt 60 as an irradiation source, further cultured for 48 h outside of the room, and pulsed with tritium thymidine for 4 h to evaluate growth inhibition. We observed that dose rate effect similar to U2OS in M059K, a human glioma, Jurkat and HL-60, human leukemias, or WI-38, a normal human fibroblast, and it followed to MOE model. In contrast, the dose rate effect was greatly impaired in the cell lines deficient of p53, DNA-PK or ATM. These results suggest that MOE model can be generally applied to vast variety of cell lines, ant that dose rate effect as described by MOE model is at least in part dependent on genes related to DNA repair.

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Recently, issues concerning medical exposure to ionizing radiation have drawn much attention. One of the triggers was the article that appeared in The Lancet (363:345-351, 2004) which claimed that among 15 countries examined, Japan stood highest in doses from X-ray examination. Newspapers in Japan ran headlines proclaiming that 3.2% of cancer in Japan comes from diagnostic X-ray examinations, setting off fear among the general public about radiation and radiation diagnosis. In addition to arguments on the derivation of the 3.2% figure, these instances raised an important issue concerning how to best understand the risks from low level radiation. On the other hand, over-exposure of patients and operators has become a major issue in newly developed technology wherein emphasis tends to be placed on the merits of radiation than on its damaging effects. Ionizing radiation has been described as a double-bladed sword. To use it properly and efficiently, we should neither underestimate nor overestimate its effects.
The aim of this workshop is to review the current situation of medical exposure and to exchange information on how and what kind of information should be disseminated, and to discuss the possible role of the Japan Radiation Research Society in this kind of activity.

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An article appeared in LANCET of its January 2004 edition about risks from diagnostic radiology has clearly caught the attention of not only radiological practitioners, but also medical clinicians in all fields and patients in the public through the news media. The results indicated that 3.2% of the cumulative risk of cancer could be attributable to diagnostic X-rays in Japan which was highest in the world. It has been criticized that the study does not address the benefits of diagnostic imaging, nor does it attempt to balance the benefits of accurate diagnosis against the imputed number of cancers. In spite of the uncertainty involved in the study, it is apparent that reduction of unnecessary X-ray examinations is required. Since CT examination is a single X-ray examination which has shown a largest collective dose, the justification and optimization of CT seem most important. The following problems are discussed in order to achieve the justification and optimization for patient exposure. 1). The reason why the cumulative risk of cancer attributable to diagnostic X-rays is so high in Japan. 2). How can the justification of CT examination be assured? 3). How can the optimization of CT examination be achieved? 4). Toward the effective reduction of medical exposure. 5). Assessment and information of risk-benefit balance in medical exposure.

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Medical use of radiation is firmly established as an essential tool for diagnosis and therapy. On the other hand, it has accounted for the biggest rate in radiation exposure of the human beings by the source of artificial radiation. It is approved that the overwhelming benefit accruing to patients from general medical use of radiation compared with a risk. However, it is also a fact that it occasionally has the difference in one 10 the dose of this by the irradiation part, conditions, and the model of equipment even if the same purpose irradiation. In many cases, individual dose of patient by X ray examination is performed below with a few mGy. However CT bring about a high dose more in individual dose and collective doses. And, the skin dose of the individual by IVR to which diagnosis and medical treatment are performed simultaneously exceeds several Gy. Even if it is medical exposure, unnecessary exposure should avoid and judgment of justification and optimization is desired for every case. Moreover, rapid introduction of a reference dose is required to examination that almost fixed method.

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The paper on the risk of cancer from diagnostic X-rays appeared in the Lancet (363: 345-351,2004) by Prof. Darby and his colleague in Oxford University described the highest attributable risk estimate of cancer in Japan, 3.2% among the UK and 14 other countries. The present paper will make a comment on the risk estimate and its understanding on low dose risk. The risk estimate from medical exposure may contribute to judgment whether a diagnostic radiology can be justified. However, the role of the risk estimate in the paper of the Lancet is quite different since it describes the attributable risk from all the medical exposure in each country. The risk should be characterized by other aspects which can not be expressed by a single value of probability, because the risk characterization in previous radiological protection has contributed to a preventive approach but has failed to communicate with the public. The epidemiological data in the atomic bomb survivors in Hiroshima and Nagasaki show the fundamental facts that we can not detect excess cancer deaths under about 10-50 mSv if high dose rate is received. It should be stressed that these risk estimates are calculated risk not authentic one just like car accidents that are evaluated by statistics, and also that the radiation risk from a low dose can not be detected even if exposed patients would be followed up.

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Space radiation biology will be regarded as important, because human beings will expand more into space in this century. In particular, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events (SPE) containing various kinds of radiations during long-term stays in space. A characteristic of space radiations are low dose, chronic exposure at low dose-rate, high-energy particles, influence of microgravity etc. Many unsolved problems are left how space radiations affect RBE by a dose-rate effect, a reverse dose-rate effect, bystander effect, adaptive response and hormesis. Therefore, it is important to judge correctly the biological effect of space radiations for human health. In addition, research for space radiation might give us useful information concerning birth and evolution of lives on the earth. Here, I will review a view of the future prospects about space radiation biology. I desire to educate the space researcher of the next generation for importance of research for space radiations.

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