The Radiation and Environmental Health (RAD) Unit of WHO/HQ evaluates health risks to environmental and occupational radiation exposure. The programs promote radiation researches, provide advice on emergency medical and public health responses to radiation accidents, and advice national authorities on how to minimize any risk to human health. This paper discusses the scope and structure of the WHO/HQ RAD Unit and identifies areas for the establishment of future joint projects within the framework of the 21st Century Center of Excellence (COE) programs of Nagasaki University, "International Consortium for Medical Care of Hibakusha and Radiation Life Science".

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For many years, Nagasaki University, particularly the Atomic Bomb Disease Institute, has been engaged in research regarding the late health effects of radiation exposure in Nagasaki atomic bomb survivors. Since 1991, we have participated in several Chernobyl projects including the Chernobyl Sasakawa Medical Cooperation Project which demonstrated a marked increase in the incidence of childhood thyroid cancer around Chernobyl, especially in the Gomel region, Belarus. Furthermore, we have performed both fieldwork and research to clarify the late effects of radiation exposure around Semipalatinsk Nuclear Testing Site and participated in bilateral official medical assistance projects between Japan and Kazakhstan to strengthen the medical infrastructure in this area. Through these humanitarian and scientific projects, we have been collaborating closely with our counterparts in the former USSR for the past 15 years. Here, we present a brief review of our past activities and future directions of international cooperative radiation research from Nagasaki to Chernobyl and Semipalatinsk.

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In radiation accidents, biological methods are used for dosimetry if the radiation dose could not be measured by physical means. The knowledge of individual dose is a prerequisite for planning medical treatment and for health risk evaluations. In this paper we represent the summary of biodosimetrical methods used in our laboratory in the patients treated with radioiodine for thyroid cancer. The dose-response relationship was measured by the flow cytometry-based micronucleus assay in transferrin receptor positive reticulocytes (MN-Tf-Ret assay) and by the T-cell receptor (TCR) assay in CD4 lymphocytes. Compared to our previous works, the database for TCR assay was significantly improved, and two groups of thyroid cancer patients (from Belarus and Germany) were studied. In the MN-Tf-Ret test, mutant frequency increased proportionally with the radiation dose, whereas in the TCR-test the dose relationship could be described by an exponential equation which takes into account the limited lifespan of TCR mutants. Finally, these assays are compared with other biodosimetrical assays used in patients treated with radioiodine.

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Massive discharge of liquid radioactive wastes into the Techa River in 1949-1956 by the industrial complex Mayak for production of plutonium for weapon resulted in protracted internal and external radiation exposure of the population living along the river. The Techa River Offspring Cohort comprises individuals born after December 31, 1949, whose one or both parents were exposed in the Techa riverside villages. The study group includes 7,897 individuals. About 40% of the Techa River Offspring Cohort members born in 1950-1956 could be exposed in utero and after birth. The mean dose estimates based on the Techa River Dosimetry System 2000 were: 0.07 Gy for parental gonads, 0.01 Gy for fetus and 0.02 Gy for postnatal exposure of bone marrow. Over 46 years of follow-up from 1950-1995, 916 subjects died and the cause of death was known in 93% of them. Out of 916 subjects dead, 456 (53%) died under 1 year of age, mainly due to respiratory tract diseases (38% of all infant deaths), infections (27%) and perinatal disorders (13%). It has been shown that the baseline infant mortality rate depends on gender, ethnicity and birth year. Radiation risk analysis was based on a simple parametric linear excess relative risk model with adjustment for gender, ethnicity and birth year. There was no evidence of increasing infant mortality risk with parental gonadal dose. The infant mortality rate significantly depended on fetal dose and dose to bone marrow received during the first year of life with a 3% increase in risk per 1 cGy of intrauterine and postnatal doses.

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Analyses of the dynamics of frequency of hematological diseases were conducted in the area of former Semipalatinsk nuclear test site and in different zones of radiation risk during the period of 1994-2003. Hematological diseases were diagnosed in 1,667 persons who were directly exposed to radiation, including their second and third generations. General morbidity of hematological diseases in this period gradually increased from 19.8 to 23.8 per 100,000 population. To observe dynamics of structure of hematological morbidity for the 10-year period we compared the proportion of each disease in 1994, 1999, 2003, i.e., at the beginning, the middle and the end of the observation period. In the analyses, the specific weight of chronic lymphoid leukemia for this period was reduced, the specific weight of acute leukemia increased in 1999 and then decreased in 2003, while chronic myeloid leukemia had no positive dynamics. The increasing tendency of specific weight of autoimmune diseases and pernicious anaemias was marked. There was still a high frequency of blood diseases in the zones of extreme and maximal radiation risk. The changes in structure of hematological diseases in a zone of the former Semipalatinsk nuclear test site are probably related to a hereditable predisposition of radiation induced immune imbalances.

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Under the framework of the International Consortium for Medical Care of Hibakusha and Radiation Life Science (Nagasaki University 21st Century COE Program) and bearing in mind the unique history and responsibility of Nagasaki University, several projects on radiation emergency preparedness are in progress. The critical accident in Tokaimura, Japan in 1999 made us realize that nuclear emergencies happen anywhere radionuclides exist. In fact, nuclear accidents possibly take place in factories, research facilities, hospital and wherever radioactive materials are in transit. Therefore, it is necessary to establish an effective preparedness network system for potential radiation emergency that may occur in Nagasaki and nearby prefectures and to cooperate with other Japanese and worldwide networks.

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Recent advances in stem cell research present us promising possibilities for regenerative medicine. However, investigation on human stem cells is behind from those of murine mostly due to the lack of appropriate analyzing systems. Our NOD/SCID/γ_c^null (NOG) mice model realized complete reconstitution of lympho-hematopoietic system as well as liver regeneration by human hematopoietic stem cell transplantation. This model will provide a versatile tool to investigate not only human hematopoietic system but also other human stem cell systems along with stem cell plasticity.

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The introduction of telemedical technologies in educational process makes preparation of medical specialists more expanded, visual and substantial. For the organization and the use of information technologies they are necessary high-speed connection channels, the computer and digital medical equipment, the trained personnel. Development of technologies is especially needed for communication with remote areas where are suffered most by Chernobyl accident.

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It is well established that tumor suppressor p53 protein is stabilized and activated as a sequence-specific transcriptional factor in response to genotoxic stresses, including ionizing radiation (IR). Previous studies demonstrated that p53 is phosphorylated at N-terminal serines and a threonine after IR. Here, we examined the role of the phosphorylation, especially at Ser15, Thr18, and Ser20, in IR-induced p53 stabilization and activation, using alanine-substituted p53 at phosphorylation site (s). In the present study, we examined p53 stabilization and activation in two different cell lines : stabilization in HT1080-derived clone in which endogenous wild-type p53 was confirmed to be normally stabilized after IR; activation in p53-null H1299-derived clone in which ectopically-expressed p53 levels did not change before and after IR, because the increase in p53 levels affects transactivation by p53. In Western blot analysis and immunofluorescence staining, alanine-substituted p53 at Ser15, Thr18, and/or Ser20 was stabilized in the nucleus comparably with wild-type p53 2 h after 4 Gy of X-rays. However, Ser15-alanine-substituted p53 did not induce the expression of p21 protein, one of the p53-targeted gene products, after IR. These results indicate that phosphorylation at Ser15, Thr18, and Ser20 is not required for IR-induced p53 stabilization, however, Ser15-phosphorylation plays a role in IR-induced p21 induction by p53.

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Radiation therapy is a common treatment for many types of tumors. Therefore, it is vital to understand the cellular responses to radiotherapy in malignant cells, as well as the surrounding normal tissues in order to optimize antitumor efficacy. Clusterin (CLU) is a secreted glycoprotein that has been implicated in many normal biological processes as well as many pathological diseases, including cancer. Our laboratory identified the secreted form of clusterin (sCLU) as a protein/transcript that could be induced by doses of ionizing radiation (IR) as low as 0.02 Gy, suggesting a role for sCLU in the cellular response to IR. While the exact functions of CLU are complex, it has been suggested that sCLU, the fully processed and glycosylated form of the CLU protein, plays a role in cytoprotection after cellular stress. sCLU appears to provide cytoprotection against cellular injury and inflammatory responses potentially by acting as a molecular chaperone, clearing cellular debris or binding to inflammatory and growth suppressive cytokines, such as TGF-ß1. A better understanding of this protein and its various roles in cellular responses to stress will allow us to generate better treatments and therapies for many different pathological processes. The functions of sCLU and its role(s) in disease processes will be discussed.

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For many years, research on oxidative stress focused primarily on determining how reactive oxygen species (ROS) damage cells by indiscriminate reactions with its macromolecular machinery, particularly lipids, proteins and DNA. However, many chronic diseases affiliated with oxidative stress are not always a consequence of tissue necrosis, DNA, or protein damage but rather to altered gene expression. Gene expression is highly regulated by the coordination of extra-, intra- and inter-cellular communication systems that typically maintain tissue homeostasis by sustaining a balance between proliferation, differentiation and apoptosis. Therefore, much research has shifted to the understanding of how ROS reversibly controls gene expression at noncytotoxic doses through cell signaling mechanisms. Cell proliferation typically involves a transient inhibition of gap junctional intercellular communication (GJIC) and the activation of mitogen activated protein kinase pathways (MAPK). We demonstrate that epidermal growth factor (EGF) inhibited GJIC in normal rat liver epithelial cells in addition to activating extracellular signal regulatory kinase, a MAPK. Inhibition of NADPH oxidase, which reduces oxygen to H₂O₂ with the very selective inhibitor diphenyleneiodonium, prevented EGF from inhibiting GJIC, suggesting that the generation of H₂O₂ is an essential component of the intracellular pathway controlling GJIC. We previously demonstrated that reduced-glutathione (GSH) was also a necessary cofactor of H₂O₂-induced inhibition of GJIC. These results demonstrate that ROS and GSH play essential roles in controlling EGF-dependent control of GJIC. Therefore, the overly simplistic approach of either preventing the generation of ROS or accelerate the removal by antioxidants could deleteriously alter normal signaling functions.

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Evidence is accumulating that irradiated cells produce some signals which interact with non-exposed cells in the same population. Here, we analysed the mechanism of such a bystander effect from targeted cells to non-targeted cells. Firstly, in order to investigate the bystander effect in CHO cell lines we irradiated a single cell within a population and scored the formation of micronuclei. When a single nucleus in the population, of double strand break repair deficient xrs5 cells, was targeted with 1Gy of Al-K soft X-rays, elevated numbers of micronuclei were induced in the neighbouring unirradiated cells. The induction of micronuclei was also observed when conditioned medium was transferred from irradiated to non-irradiated xrs5 cells. These results suggest that DNA double strand breaks are caused by factors secreted in the medium from irradiated cells. To clarify the involvements of radical species in the bystander response, cells were treated with 0.5%DMSO 1 hour before irradiation and then bystander effects were estimated in xrs5 cells. The results showed clearly that DMSO treatment during X-irradiation suppress the induction of micronuclei in bystander xrs5 cells, when conditioned medium was transferred from irradiated xrs5 cells. Therefore, it is suggested that radical species induced by ionizing radiation are important for producing bystander signals.

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The controversial use of a linear, no threshold extrapolation model for low dose risk assessment is based on the accepted dogma that the deleterious effects of ionizing radiation such as mutagenesis and carcinogenesis are attributable mainly to direct damage to DNA. However, this extropolation was challenged by the recent reports on the bystander phenomenon. The bystander effect contributes to this debate by implying that the biological effects of low doses, where not all cells are traversed by a charged particle, are amplified by the transfer of factors to un-irradiated neighbors. This interested phenomenon implies that a linear extrapolation of risks from high to low doses may underestimate rather than over estimate low dose risks. Together with some radiation-induced phenomena such as adaptive response and genomic instability, the radiobiological response at low doses is likely to be a complex interplay among many factors.

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For many years, the central dogma in radiobiology has been that energy deposited in the cell nucleus is responsible for the biological effects associated with radiation exposure. However, non-targeted and delayed effects of radiation have shifted this belief. The studies of radiation-induced genomic instability, the bystander and abscopal effects, clastogenic factors, and the Death Inducing Effect have dominated the interest of the radiobiology field of late. The passing of signals from irradiated to non-irradiated cells can be accomplished through cell-to-cell gap junction communication or secretion of molecules, which in turn can elicit a response through activation of signal transduction pathways. Proposed mediators of this phenotype include proteins involved with inflammation. Given their size and connection with oxidative stress, cytokines are an attractive candidate as mediators of the induction of the non-targeted effects of radiation. Here we review the evidence for a possible connection between these delayed non-targeted effects of radiation and the cytokine cascades associated with inflammation.

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Radiation etiology is well known in thyroid carcinogenesis. Ret rearrangement is the commonest oncogenic alterations in Chernobyl-related papillary thyroid cancer (PTC). To evaluate whether there is a radiation signature, we analyzed Ret rearrangement in radiation-associated thyroid cancers with fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR). The FISH analysis demonstrated segmental jumping translocation (SJT) of Ret gene in radiation-associated thyroid cancers but not in sporadic well differentiated PTC. Furthermore, Ret SJT was commonly observed in anaplastic thyroid cancer (ATC) including both radiation-associated and sporadic cancers. In PTC, Ret SJT was restricted to radiation-associated or high-grade cases. Because Ret SJT was not observed in sporadic, well differentiated and low-grade cases of PTC, Ret SJT might be a molecular marker for radiation-induced and/or aggressive cases of PTC. SJTs are unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to multiple recipient chromosome, and mainly reported in treatment-related leukemias, while very rare in solid cancers. We found SJT in radiation-induced and high-grade thyroid cancers, suggesting chromosomal instability. This is the first report showing SJT in thyroid cancer, and probably the third report showing SJT in solid cancer in vivo.

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Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells characterized by ineffective and inadequate hematopoiesis. MDS in a subset of patients arise after previous chemotherapy or radiation exposure for other malignancies. As MDS is a heterogeneous disorder, specific gene abnormalities playing a role in the myelodysplastic process have been difficult to identify. In this study, we analyzed the somatic mutations in the AML1/RUNX1 gene, which is a critical regulator of definitive hematopoiesis and the most frequent targets for translocation of acute myeloid leukemia (AML), in patients with MDS. We detected AML1 point mutations in 26 of 110 (23.6%) patients with refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEBt) and AML following MDS (defined these categories as MDS/AML). Among 22 patients with radiation-related (including 14 atomic bomb survivors) and/or therapy-related MDS/AML, 11 (50%) patients had the AML1 mutations mostly in N-terminal region. In contrast, 15 of 88 (17%) patients with sporadic MDS/AML showed the AML1 mutations equally in both N-terminal and C-terminal region. The MDS/AML patients with AML1 mutations had a significantly worse prognosis than those without AML1 mutations. Most of AML1 mutants lost trans-activation potential, regardless of their DNA binding potential. These data suggested that AML1 point mutation is one of the major driving forces of MDS/AML, and these mutations may represent a distinct clinicopathologic-genetic entity.

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Myelodysplastic syndromes (MDS) are a heterogenous hematological group characterized by an ineffective hematopoiesis resulting in a variety of cytopenias, morphological abnormalities of blood cells, chromosomal aberrations, and an increases risk of transformation into acute myeloid leukemia. Despite of its nature of close relation to leukemia, MDS has been not well investigated in atomic bomb (A-bomb) survivors. We conducted a retrospective cohort study with over 80,000 A-bomb survivors in Nagasaki to assess the incidence of MDS and its relation with A-bomb exposure status. In a preliminary analysis, we confirmed 162 MDS cases during 1980 to 2004. The median age at diagnosis was 71 years old. The incidence rate was higher in men than women, and an inverse relationship was observed between incidence of MDS and the distance from the hypocenter. We suggest that A-bomb radiation may affect the occurrence of MDS in A-bomb survivors even more than 50 years passed after the explosion. Further detail analyses are necessary to confirm these results.

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