FY2013 Report of Activities 1. Research projects on A-bomb survivors health (1) Radiation research based on the LSS, in utero, and AHS cohorts Radiation and Cancer Risks Cancer risks have continued to be the most prominent adverse health effects associated with radiation exposure among A-bomb survivors for more than 60 years after the bombings. A variety of studies related to radiation and cancer risks are in various stages of progress, and several highlights are mentioned below: Updated cancer incidence: Extensive work is underway on a comprehensive analysis to update for an additional nine years the radiation risk for cancer incidence, in collaboration with the US National Cancer Institute. The new analyses will have increased emphasis on radiation risks from childhood and adolescent exposures since that subpopulation is now coming into the ages at which cancers are expressed with much greater frequency. The increasingly robust cancer dataset and the public health interest due to the Fukushima accident also provide a strong rationale for focusing on cancer risks from low-dose exposures. Variations in cancer susceptibility due to lifestyle and other factors motivate analyses to look at the degree to which those factors modify radiation risks. Low-dose workshop: A workshop on The evaluation of the effects of low-dose radiation exposure in the atomic bomb survivors was held in December 2013, to discuss issues in low-dose research and approaches for investigating low-dose radiation risks in the RERF cohorts. The talks and discussions by RERF scientists and experts from the US, Europe and Japan covered many aspects of low-dose studies. Some specific topics were: estimation of low-dose risk uncertainties, dose uncertainties and confounding by other sources of radiation exposure, generalizing risk estimates to other populations, the application of radiation biological studies to epidemiologic risk estimation, the impact of other risk factors in low-dose studies, effect-modification of radiation risks, incorporation of genetic and molecular susceptibility information, and considerations in the interpretation of low-dose studies. Publication of a report on the workshop is planned. In-utero cohort study: This is the only extant study of disease experience in adulthood following prenatal radiation exposure, a topic of importance since in utero exposures have occurred in many settings and the prenatal period may be a time of high radiation sensitivity. An analysis of cancer and noncancer mortality risks for 1950-2008 has been completed and a paper is undergoing internal review before submitting for publication. Solid cancer risk was elevated in relation to radiation dose, with a suggestively higher risk among females. An increased risk in relation to low-birth weight 1
with in-utero exposure to high-dose radiation was observed for total non-cancer disease mortality, but the interpretation of this association is unclear. Breast cancer: The possibility is being explored that breast cancer effects are mediated through radiation-associated alterations in endogenous sex hormone levels. Analyses have been conducted and a paper has been drafted. Breast Cancer Subtypes: A breast cancer pathology study also is underway to determine whether radiation risk varies by histological subtypes or molecular ER/PR/Her2 subtypes. The molecular subtypes are currently of particular interest, since the limited data available from other studies suggest that the ER/PR negative subtype may be more highly associated with radiation exposure, particularly exposure at younger ages. Thyroid cancer: A publication on thyroid cancer showed a continuing high radiation risk among those exposed as children, but little risk following adult exposure (Furukawa et al, Int J Cancer 2013;132:1222 6). The excess risk was evident at doses above about 100-200 mgy and has persisted for over 50 years. (Figure 1) A new statistical method is being applied to better evaluate the uncertainties in risk at low doses. A detailed analysis in relation to radiation and lifestyle factors is being conducted in collaboration with the US National Cancer Institute. Figure 1. Excess relative risk for thyroid cancer by thyroid dose Fitted dose response functions for thyroid cancer incidence in the LSS cohort. The solid line is the fitted linear ERR dose response, and the dashed curve is the fitted ERR based on a linear-exponential dose response model. The line and points are all gender-averaged estimates at age 60 after exposure at age 10. 2
Colon cancer: This study asked the question of whether obesity, which is a risk factor for colon cancer, modifies the risk of radiation-related colon cancer. No radiation effect modification was found (Figure 2) (Semmens et al. Cancer Caus Cont 2013;24:27-37). Figure 2. Radiation risk of colon cancer (excess relative risk at 1 Gy) by the body mass index (BMI) of obesity 2 Excess Relative Risk (ERR) per Gy of timevarying body mass index (BMI) ERR/Gy 1.5 1 0.5 0-0.5 Q1 Q2 Q3 Q4 Quartile of BMI (Semmens EO, et al. Cancer Causes Control 2013;24:27-37) The risk of colon cancer incidence significantly increased independently due to both radiation exposure and increased BMI, but the degree of radiation risk was not significantly modified by BMI. Time-varying, longitudinal BMI estimates were obtained from responses to repeated questionnaires (mail surveys) and adjusted for age. BMI quartile cut-points differed by gender. The ERR/Gy was adjusted for city, sex, not-in-city, and sex-specific attained age and age at exposure. The vertical bars indicate 95% confidence intervals. Radiation, immune genotype and gastric cancer: For the diffuse-type of gastric cancer the association with radiation depends on the major IL-10 genetic haplotype, with no radiation-cancer association for those with the homozygous minor gene haplotype (Hayashi et al, Radiat Res, 2013; 180: 60-9). Radiation, inflammation and cancer risk: Higher serum levels of IL-6 were associated with increased hepatocellular carcinoma (HCC) risk, independently of hepatitis virus, lifestyle, and radiation. The interaction of obesity with IL-6 levels in relation to HCC risk was significant, but that of radiation with IL-6 levels was not observed. (Ohishi et al, Int J Cancer, 2014; 134(1): 154-63). A manuscript on the mediating role of chronic inflammation in promoting radiation-related cancer risk also has been submitted to an international journal. 3
Site-specific LSS cancer studies with histological review: Several pathology studies are currently ongoing in collaboration with the US National Cancer Institute. A paper on skin cancer has been submitted with findings that basal cell and squamous cell skin cancer incidence were dose-dependent, but with an apparent dose threshold of about 0.6 Gy (Figure 3). Risk was most apparent for those exposed at young ages (Figure 4). No association with radiation was seen for malignant melanoma. Figure 3. Basal cell skin cancer incidence by radiation dose Figure 4. Basal cell skin cancer excess relative risk at 1 Gy by age at exposure 35 Excess relative risk at 1Gy 30 25 20 15 10 5 0 0 10 20 30 40 50 Age at exposure (years) (Sugiyama H, et al. Radiat Res in press) Dose-response curves for various excess relative models. The models included sex, period at diagnosis, and log age 70 as the background parameters, and age at the time of bombing as Excess relative risk at 1 Gy by age at exposure based on a linear model with a threshold at 0.63 Gy. an effect modifier. Uterine cancer: Previous analyses of uterine cancer were not able to distinguish reliably between uterine corpus (endometrial) and cervix cancer, two sites that reflect divergent etiologies, because many uterus cancer notifications several decades in the past did not distinguish between the two. Since a preliminary analysis of more recent data suggested that corpus but not cervical cancer might be related to radiation exposure, a histopathological evaluation is being conducted for corpus cancer to more accurately determine the magnitude of radiation risk. Radiation and Circulatory Disease Risks Because of recent findings in the LSS regarding the association of radiation with circulatory diseases, 4
the RERF Cardiovascular Disease Working Group has spurred the development of several studies to learn more about the potential biological mechanisms by which low-to-moderate doses of radiation may confer risk for cardiovascular and cerebrovascular diseases. CVD Workshop report: A CVD Workshop report was published (Takahashi et al, J Radiol Prot 2013; 33(4):869-80). It explored aspects of our current knowledge and issues about radiogenic CVD effects and suggested additional directions for research. The directions included, for example, further analyses of heart disease subtypes; examination of radiation-risk modification by other CVD risk factors; and indications that microvascular damage, altered metabolism, hypertension and damage of other organs (e.g., kidney) may impact CVD risk after low-dose total-body irradiation, Chronic kidney disease (CKD): Radiation effects upon organs other than the heart, such as CKD, may be independently implicated in CVD risk. Chronic kidney disease, assessed by egfr (estimated glomerular filtration rate) measurements in the Adult Health Study (AHS), was associated with CVD risk factors (hypertension, diabetes, hyperlipidemia, and metabolic syndrome), and with radiation dose (Sera et al, Radiat Res, 2013; 179(1): 46-52). Roles of biological and physiological risk factors in radiation-cvd risk: A number of measures relevant to CVD risk from radiation are being studied in the AHS to assess the roles of various biological pathways and pre-clinical indicators of cardiovascular disease. Examples include: markers of chronic inflammation, insulin resistance or adipocytokines, such as TNF-α, IL-6, MCP-1, leptin, resistin, adiponectin and IGF-1; physiological measurements reflecting atherosis (fatty deposits) or arterial stiffness; dilation of retinal veins and arterioles (indices of microvascular damage); visceral fat accumulation and fatty liver disease. Echocardiography: In the AHS we are planning echocardiographic measurements of A-bomb survivors to evaluate preclinical heart dysfunction that may be associated with valvular disease, ischemic heart disease and heart failure. Are LSS radiation-cvd mortality results confounded by the healthy survivor effect?: We have collaborated with researchers from Helmholtz Zentrum München in an analysis that found no evidence that a healthy survivor effect had distorted the radiation dose-response curve for CVD effects (Schöllnberger et al, Radiat Prot Dosim 2014, DOI:10.1093/ rpd/nc0000). Radiation, smoking and microvascular changes: The diameters of retinal veins and arteries can be markers for radiation damage to microvessels of the circulatory system. A study has indicated that the impact of smoking on retinal venular dilation is reversible following long-term smoking cessation. (Yanagi, et al, Invest Ophthalmol Vis Sci, 2014; 55(1): 405-11) The associations of retinal venular and artery caliber with radiation are being analyzed. 5
Experimental circulatory disease: To help confirm the A-bomb studies suggesting that circulatory diseases may be caused by radiation at moderate doses, we are seeking to validate the epidemiologic and clinical findings with an experimental study using strains of rats that are susceptible to hypertension and stroke. The study is examining doses down to 0.25 Gy, with endpoints of: early stroke symptoms and mortality, a pathologic analysis of relevant organs/tissues, blood pressures, and biochemical measurements related to CVD risk. Radiation and Health Outcomes Other than Cancer or Circulatory Disease The A-bomb radiation exposure has been related to a variety of additional health outcomes. Several studies have been published this year. Respiratory diseases: Prior LSS epidemiologic analyses had suggested an association between A-bomb radiation exposure and noncancer respiratory disease mortality. This study aimed to obtain insights regarding the degree to which the association reflects a diagnostic/epidemiologic artifact versus a genuine radiation effect. The study found that a substantial fraction of the association of noncancer respiratory disease mortality with radiation could be accounted for by prior or concurrent cancer or cardiovascular disease which probably reflects misdiagnosis (Pham et al, Radiat Res, 2013; 180:539-45). (see Figure 5) There was no evidence of confounding by lifestyle variables. Figure 5. Radiation risk of mortality diagnosed as noncancer respiratory disease, 1950-2005 Excess Relative risk (ERR) 3 2 1 0-1 Hazard ratio (HR) adjusted for potential confounding factors (smoking, alcohol consumption, body mass index, education, diabetes, and occupation) All noncancer respiratory diseases ERR of all noncancer respiratory diseases by study period 1950-64 1950-1964 with 95%CI Plot estimate with 95% CI Linear-Quadratic -Linear-Quadratic 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Excess relative risk Not adjusted for cancer or CVD 3 2 1 0-1 3 1965-79 1965-1979 1980-2005 Plot 95%CI Plot with 95%CI Plot estimate with 95% CI Plot estimate with 95% CI Linear-Quadratic 2 Linear-Quadratic -Linear-Quadratic -Linear-Quadratic 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Weighted absorbed lung dose (Gy) Adjusted for cancer 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Weighted lung dose (Gy) Adjusted for cancer and CVD 1.19 (1.09, 1.29) 1.12 (1.02, 1.24) 1.12 (1.00, 1.25) (Pham TM, et al. Radiat Res 2013;180:539-45) 1 0-1 6
Radiation, BMI and muscle mass index: Body mass index (BMI) and lean body mass (assessed by DXA) tended to decrease with increased radiation dose. (Tatsukawa et al, Int J Obes, 2013; 37: 1123-8). Radiation and glaucoma: A screening study investigated whether radiation was associated with glaucoma prevalence. It found that radiation may be related to the prevalence of normal tension glaucoma (see Figure 6), but not glaucoma with elevated eye pressure. However, methodologic uncertainties limit the conclusions that can be drawn (Kiuchi et al, Radiat Res, 2013; 180:422-30). Figure 6. Radiation dose and prevalence of normal-tension glaucoma in A-bomb survivors Activities to provide for future high-quality studies of cancer and other health endpoints Hiroshima and Nagasaki tumor/tissue registries: Case collection by notifications and death certificates is nearly complete through 2012 in both Hiroshima and Nagasaki prefectures. Case abstraction from medical records has been completed through 2011 in both areas, and abstraction of the more recent cases is underway. Ongoing F1 clinical examinations: The longitudinal clinical assessment of F 1 offspring of A-bomb survivors was begun in November 2010 on a four-year cycle. The repeat participation rate among those who were initially examined in 2002-06 is about 82%. It is expected that this second round of examinations will be completed during FY2014. Medical radiation exposures: Reported medical diagnostic and therapeutic radiation exposures from the recent mail survey are being analyzed to determine if that source of radiation exposure confounds the A-bomb dose response association or affects the risk estimates. Preliminary analyses suggest there is little confounding, but further analysis is needed. 7
Tissue specimen access: A database that indexes RERF specimens of formalin-fixed paraffin-embedded tissues is being developed for future specimen utilization as part of our Biospecimen Repository. A system to preserve surgically resected materials from the A-bomb survivors in Hiroshima and Nagasaki areas is being worked out with community and university hospitals. Research data documentation: It is now required to submit documented analytic datasets to the Information Technology Department before study publication, so that RERF can be assured of having a record of the data on which its reports are based. Improved assays for old tissue samples: Because the A-bomb studies have been ongoing for over 60 years, many of the stored tissue samples are old and sometimes partially degraded. A technique was developed that increases sensitivity in conducting PCR amplification, one of the fundamental, most widely used methods in molecular biology, that will be particularly useful with our old tissue samples (Taga et al. Int J Clin Exp Pathol, 6:76-9, 2013). (Figure 7) Figure 7. Preheating DNA in borate buffer facilitates PCR-based molecular analyses in old cancer tissue specimens preserved by the usual methods (formalin-fixed paraffin-embedded) Biosample Center: Planning and preparations have been conducted for the Biosample Center to become fully operational in FY2014. This will initially involve the integration of blood and urine biospecimens in a centralized facility, with accompanying database management to facilitate inventories and access. (2) Activities for promotion of the health and welfare of study participants Much effort is devoted to provide advice and support activities for the Adult Health Study participants. A description of those activities is given in Section 1.(2) of the FY2014 Plans of Activities. 8
(3) Research on biological mechanisms related to health effects from radiation among A-bomb survivors Understanding the biological mechanisms underlying radiation effects on health can help sharpen assessments of, for example, low-dose risks and can provide clues regarding disease prevention and treatment. Several studies of biological mechanisms of radiation health effects have already been summarized above in the sections on various types of disease. Additional research is described below. Radiation and other genetic cancer mechanisms: The radiation dose response of GPA mutation frequency was found to vary by p53bp1 polymorphisms (Yoshida et al, Mutat Res-Gen Tox Env, 2013, 755:49-54), suggesting that somatic mutability following radiation exposure may be partly dependent on individual variations in DNA double-strand break repair capability. Radiation and epigenetic cancer mechanisms: We are conducting pilot studies to evaluate epigenetic alterations (i.e., modification of genetic functions by means other than through changing the DNA) based on the hypothesis that radiation might cause epigenetic changes in DNA transcription or DNA methylation that lead to increased risks of selected diseases. Cytogenetic studies following fetal irradiation: Although lymphocytes from maternal irradiation of atomic-bomb survivors and mice show dose-related chromosome translocations, those from their fetally exposed offspring do not. However, we have now found that both rat mammary-tissue cells (Nakano et al, Radiat Res, 2014; 181:172-6) (Figure 8) and mouse thyroid epithelial cells (unpublished data) do show translocations after fetal exposure. The results are similar to our findings about the tissue-dependent induction of malignancies among the in utero-exposed. 9
Figure 8. Difference between chromosome aberration (translocation) frequencies in lymphocytes (spleen cells) versus mammary cells after fetal irradiation 8 Mammary cells Spleen cells 6w 9w 45w 9w 45w Translocation frequency (%) 6 4 2 0 Nakano et al. Radiation Research, 181:172-6, 2014 Maternal and fetal translocation frequencies in mammary cell cultures or spleen cells in rats gamma irradiated with 2 Gy. Fetus irradiation (closed circle); mother, 12 weeks old (square); virgin, 12 weeks old (diamond shape); and nonirradiated control rats (triangle). The time intervals in weeks between irradiation and FISH translocation analyses are shown at the top of the figure. Each point was derived from scoring 800 cells. Radiation and Cancer Mechanisms: Ongoing cancer studies aim to clarify mechanistic relationships between radiation exposure and cancer development among A-bomb survivors. Early molecular events in the development of cancers in the Life Span Study (LSS) cohort are being conducted, particularly studies of gene rearrangements in thyroid cancer, mutator phenotypes in colorectal cancer, and lung cancer mutations in radiation-exposed survivors. Past RERF immunology studies determined that both immune cell counts and immune function were compromised by radiation. Some current studies: Radiation and immune responsiveness to vaccination: Certain blood biomarkers (e.g., GM-CSF and IL-4) associated with influenza vaccine antigens have been found to differ across radiation and age groups. Analyses have not yet been completed on the association of radiation dose with influenza vaccination antibody titers. Radiation and chronic oxidative stress: Intracellular reactive oxygen species levels, especially O 2. - 10
levels, in lymphocyte and granulocyte fractions increased with age and radiation dose. In addition, O 2. - levels in T cells, especially in CD8+ T cells, increased with age and radiation dose. Mechanisms of radiation immune effects: Radiation effects on stem cells, dendritic cells and the thymus gland that may attenuate immune function are being studied (Kyoizumi et al, J Immunol, 190:6164-72, 2013). Assays are nearly completed for the stem cells and dendritic cells, and the thymus study was recently begun. Obesity, inflammation and immune cells: A reduction in newly produced T cells was significantly associated with increased body mass index and inflammation, suggesting that obesity with enhanced inflammation may be involved in the aging of the human T-cell immune system (Yoshida et al, PLoS ONE, 9:e91985, 2014). (Figure 9) Figure 9. Associations of the production of new T cells with radiation and indicators of obesity, inflammation and metabolic diseases Associations of CD4 TRECs with radiation dose, age, and obesity/inflammation indicators Indicator Effect P-value Radiation dose - 0.73 Age 0.001 BMI 0.016 HbA1c 0.010 CRP 0.032 Diabetes 0.001 Fatty liver 0.014 (Yoshida et al, PLoS ONE, 9:e91985, 2014) TRECs: T-cell receptor excision circles, an endpoint of T-cell production Atomic-bomb survivors were examined for production of new (more bioactive) T cells, with the hypothesis that reduced T-cell production may contribute to an adverse metabolic/inflammatory status, which may be enhanced by radiation exposure. T-cell aging status was evaluated in terms of the ability to produce naive T cells, i.e., T-cell receptor excision circles (TRECs) in CD4 T cells. Although there was no significant association between radiation dose and TRECs, TREC numbers were inversely associated with variousobesity/inflammatory indicators, suggesting that those factors may be involved in the effectiveness of the human T-cell immune system. 11
2. Research projects on the health of A-bomb survivors children (F1) (1) F1 mortality study and F1 clinical study F 1 cohort study: A 14-year update of cancer and noncancer mortality risks in the epidemiologic cohort of 77,000 F 1 offspring of A-bomb survivors was submitted for RERF review. No significant increase in cancer or noncancer disease mortality was seen in relation to individual paternal or maternal gonadal doses, but the offspring are still relatively young and are only beginning to experience the diseases of mid- and late-life, so continued follow-up for several more decades is needed. F 1 noncancer genetic effects: Since many diseases besides cancer have a strong genetic component, we have been conducting a clinical study of about 12,000 children (F 1 ) of A-bomb survivors to study whether radiation impacts the frequency of various common noncancer diseases. A paper showed no significant positive association between parental radiation exposure and the prevalence of multifactorial diseases/conditions in their offspring, including diabetes, hypercholesterolemia, hypertension, stroke, angina pectoris, and myocardial infarction (Tatsukawa et al., J Radiol Prot, 33:281-93, 2013). However, the F 1 cohort will need to be followed up for several more decades because much of the incidence of these diseases occurs at older ages. (2) Activities for promotion of health and welfare of F1 study participants Much effort is devoted to advice and support activities of the F1 clinical cohort. They are outlined in the FY2014 Plans of Activities description for AHS study participants, Section 1.(2). (3) Research on biological mechanisms related to the health of A-bomb survivors children Trans-generational genetic effects are being studied using modern technologies with biosamples from the offspring of A-bomb survivors or of experimental animals. Mutational model system: With an innovative genetically-modified mouse model we created, it is possible to see radiation-induced germ-cell (potentially heritable) mutations through expression of a mutant green fluorescent protein (GFP). We are working to develop a GFP system that can specifically target tumor-related genes. This may provide new insights about the genetic effects of radiation at low doses. Experimental estimation of the radiation-induced mutation rate: A study was published using restriction landmark genome scanning that could detect DNA deletions at about 1,200 genomic loci per mouse (Asakawa et al, Radiat Res, 2013; 179:293-303). (Figure 10) Mouse offspring after a 4 Gy paternal dose showed marginally more deletions than the unirradiated-father group. Another 12
study employed 2.1 million probes per genome using CGH (comparative genomic hybridization) technology to study de novo genomic deletions and duplications in the offspring that result from paternal radiation exposure. The study did not find any evidence of heritable radiation effects upon the frequency of genomic deletions or duplications, but possible signatures of radiation effects at the breakpoint sequences of several mutations were identified in the exposed group. Figure 10. Examples of mutations found by RLGS in mouse genomes in a study of the genetic effects of radiation Restriction Landmark Genome Scanning (RLGS) patterns from normal and mutant DNA in mice. Panel A: An example of the loss of one copy of DNA at a two copy spot (spot intensity was reduced by half). Panels B and C: Examples of the loss of a spot (indicated by white squares) that occurred at single copy spots. Panel D: An example of loss of a spot that accompanied a new spot (indicated by mu ) near the normal position (indicated by a white arrow), an indication of a mutation at a repeat sequence. The numbers indicated below each panel represent the spot IDs. Genetic study of A-bomb survivors using high-density microarray CGH analysis: A study of de novo mutations in the F1 children of A-bomb survivors is underway, using a high density array of probes (1.4 million probes per individual) to detect genomic DNA deletions or duplications associated with parental radiation exposure. CGH analyses this year assessed 132 children and their parents along with molecular validation of candidate mutations. 13
Detectability of mutations by DNA sequencing: Two pilot studies are underway to develop expertise in using DNA sequencing to estimate radiation-induced mutation frequencies. The DNA from a cell line, with and without irradiation, was sequenced and analyzed to evaluate the detectability of indel (small) mutations, which may be significant for characterizing radiation mutation risk. The radiation-induced mutation rate in several F 1 mice is also being evaluated by whole genome sequencing; the bioinformatics data are being evaluated. 3. Research to elucidate individual radiation doses and the effects from A-bombs (1) Investigation of conditions required for dose estimates including survivor location, shielding effects and organ dosimetry A-bomb physical dosimetry: The work on creating accurate maps and correcting location (using Geographic Information System technology) and structural shielding data of LSS study subjects has been completed. A greatly improved model of elevation and terrain shielding and its application to LSS subjects is nearly completed. (Figure 11) Preliminary analyses suggest these changes will make relatively little difference overall in the risk estimates, but will reduce uncertainties and increase our confidence in the dose calculations. Figure 11. Both terrain profile and survivor elevation affect whether a survivor was partially shielded from the bomb radiation Height of Bomb Survivor elevation Ground Distance (Cullings, et al. Unpublished) This figure illustrates why the grazing angle to the terrain horizon for a survivor needs to be corrected for the elevation at the survivor s location in calculating terrain shielding. If the survivor and terrain are elevated, with the angle held constant, the angle related to the bomb changes, given that the height of the bomb explosion is held constant. 14
Biodosimetry by electron spin resonance (ESR) of tooth enamel: Molars from Nagasaki survivors showed good correlations among ESR dose estimates, DS02 eye doses and the cytogenetic dose estimates on the same survivors. A summary report is nearly finished. Relative biological effectiveness (RBE) of neutrons: The impact of neutron doses from the bombs has continued to be of interest for risk assessment. We recently submitted a manuscript in collaboration with two outside experts. It identified an error in the way various outside investigators have calculated the RBE of the neutron component upon risks in the A-bomb study. The paper also evaluates how much various assumptions about RBE values for neutrons would influence the slope and shape of the dose-response associations. (Figure 12) Figure 12. Ratios of neutron dose to -ray dose (D n /D ), plotted by -ray dose for Hiroshima (left) and Nagasaki (right). The three white curves in each plot indicate the median and the 10%-ile and 90%-ile of the distribution of A-bomb survivors at each -ray dose. The plots show that neutron doses are a small fraction of gamma-ray doses for all survivors, and at low doses, where variable RBEs tend to become large, the relative size of the neutron dose is very small, so the effect of the variable RBE is minor. Dosimetry for Unknown dose individuals: Two recent international workshops were held (February 2013 and February 2014) on the potential to derive doses for members of the LSS who had previously been assigned as unknown dose, since a number of them were in proximal (<2 km from the hypocenter) locations, but in heavily shielded buildings or air-raid shelters. 15
Examination of a series of building plans and their occupants showed that each building would require separate detailed dosimetric modeling. Given the relatively small number and imprecise locations of occupants in most such buildings, it was thought that any such modeling effort should be on a pilot basis only at this time. Visits were made to several bomb shelters that had recently been located to better determine what issues might be involved in estimating doses for the occupants. Fallout exposures: The RERF data are sparse and not highly specific regarding exposures to radioactive fallout (in black rain ). Nevertheless, because of intense local interest in the fallout issue, especially after the Fukushima accident, a number of analyses to determine if black rain accounts for observed health effects have been undertaken and will be reported. In comparing the mortality and cancer-incidence risks between the groups reporting black rain exposure or no exposure, no clear association with reported fallout exposure was seen. A paper summarizing the results is currently under review. Dose uncertainties: In the area of statistical modeling of dose uncertainties and the use of biodosimetric data to reduce uncertainties, we have extensive collaborations with three different external groups of statistical investigators. One paper is in press (Tekwe et al, Stat Med, 2014) and another has been submitted. (2) Research on statistical methodology needed for risk analyses of atomic-bomb radiation Low-Dose risk uncertainties: The Statistics Department is developing a new method to examine risk uncertainties in dose-response data, particularly at low doses. The method provides more flexibility and less reliance on prior assumptions than the conventional methods. Intermediate risk factors: Work is underway to develop methods for the analysis of intermediate risk factors with stratified (counter-matched) nested case-control and case-subcohort sampling designs. Those methods are needed for several RERF studies but they have not been developed in the statistical literature, and they may have wide applicability. Imputation of missing data: The Statistics Department is examining multiple imputation and other approaches to model missing data (missing for a fraction of the LSS cohort) in estimating the joint effects of radiation and smoking on lung cancer risk. 4. Project to release research results and to collaborate with other scientific organizations Efforts have been made to develop a number of research collaborations and other joint projects with both domestic and international organizations and researchers working in the field of radiation effects. 16
Collaborative research projects i) Research project on radiation-related immunity and aging under contract with the U.S. National Institute of Allergy and Infectious Diseases (NIAID) To define the effects of ionizing radiation on immunological function and aging and gain insights about underlying mechanisms, RERF is now in the fifth year of a collaborative study with four Japanese and five U.S. institutions under a research contract with NIAID. This study will provide a variety of information on fundamental biologic processes and evidence on the impact of radiation on immune-related health effects. ii) Other ongoing collaborative research projects Collaboration with the U.S. National Cancer Institute Several site-specific cancer incidence studies based on histopathological review are now active (female breast, skin, lung, lymphoid tissue, uterus, soft tissue/bone). The collaboration has led to numerous publications over the years, and research activities and mutual feedback will continue. Collaborative research programs in the areas of radiation epidemiology and statistics to increase opportunities for the foundation to recruit researchers in epidemiology and biostatistics to work at RERF. Studies are ongoing with Kurume University investigators. iii) Facilitation of collaborative studies. We currently have collaborations with 22 research institutions in North America, 12 research institutions in Europe and 4 research institutions in Asia. We also have collaborations with investigators at 44 research institutions in Japan. All the research departments at RERF are engaged in such studies. We anticipate that more collaborative studies will be developed during FY2014 and beyond as opportunities, ideas or needs develop. 5. Training programs for domestic and overseas specialists 1) A Training course for biologists: Let us learn more about epidemiology was held to deepen biologists understanding of RERF s epidemiological studies. During the course, lectures such as Radiation biology for non-biologists were also given for the promotion of exchanges among researchers working for radiation-related organizations (August 26-27, 2013; 21 participants in total). 2) RERF accepted overseas research trainees, either on their own initiative or in support of the activities of such organizations as the Hiroshima International Council for Health Care of the Radiation-exposed (HICARE), the Nagasaki Association for Hibakushas Medical Care 17
(NASHIM), and the Japan International Cooperation Agency (JICA) (8 trainees in total). During the long-term training (1 month), trainees received lectures on research methods and the results of past studies and took part in experiments and analyses to deepen their understanding of the health effects of radiation. 3) As a contribution to the collaborative activities between the International Atomic Energy Agency (IAEA) and HICARE, RERF accepted a total of 14 trainees on biodosimetry (June 10-14, 2013). RERF provided lecturers and offered a venue for the training sessions on knowledge and techniques concerning the response to radiation disasters, as well as giving the participants a facility tour (October 28-November 1, 2013; 31 participants in total). 4) RERF accepted visits by students from schools and universities in Japan for tours including research lectures (27 students in total). 5) RERF prepared and provided part of the training materials for IAEA radiation protection specialists and other personnel. 6. Public information programs 1) RERF Open Houses RERF held its 19 th Open House on August 5-6 in Hiroshima and its 17 th Open House on August 8-9 in Nagasaki. With continued high public interest in radiation due to the Fukushima Dai-ichi nuclear power plant crisis, the events this year had the theme, Studying and Understanding Radiation. In addition to the regular exhibits of our latest research results, it featured a special exhibit about how to consider low-dose radiation exposure. The feature exhibit presented RERF s public relations activities, including its public lecture series, facility tours, acceptance of visitors and trainees from overseas and dispatch of lecturers. At the specialist s Q&A corner next to the special exhibit area, many visitors asked questions regarding radiation. The Open House public lectures, which have become part of the regular program in Hiroshima, were delivered on August 5 by Mr. Yuji Yoneyama (radiation protection supervisor) titled, What is radiation? and on August 6 by Dr. Yoichiro Kusunoki (Chief, Department of Radiobiology/Molecular Epidemiology), titled, Why does radiation induce cancer? These two lectures were attended by large enthusiastic audiences, who asked many questions even after the lectures ended. The Open House events attracted 584 and 576 visitors in Hiroshima and Nagasaki, respectively. 2) Public lectures RERF held public lectures for citizens, including A-bomb survivors in Nagasaki and Hiroshima, for outreach and better public understanding of its research activities. The third public lecture, held on Saturday, June 29 in Nagasaki, consisted of two talks. First, Dr. Kusunoki spoke on Physical changes induced by radiation exposure: Cancer development and immune alterations. He explained the mechanisms of radiation-induced disease development and the significance of 18
elucidation of such mechanisms. This provides information to enable the accurate estimation of disease risks and effective prevention and treatment of such diseases. Next, Dr. Ayumi Hida (Assistant Chief, Department of Clinical Studies in Nagasaki) gave a lecture titled, Findings from the long-term health-examination program for A-bomb survivors, introducing in plain language the findings obtained from the Adult Health Study conducted over many years. She also expressed her gratitude to the A-bomb survivors for their cooperation in the study and asked for their continued participation and support. More than 120 people gathered in the Nagasaki Atomic Bomb Museum to hear the talks. On Saturday, November 30, RERF held its fourth public lecture for citizens in Hiroshima. Titled Considering Uses for RERF s Stored Samples, the event elicited feedback from the public about RERF s Biosample Center and its possible uses, including collaborative research, for the center s biosamples. The new facility, established in April 2013, is expected to start full-scale operations in FY2014. The event, which consisted of presentations by two lecturers, a panel discussion among guest panelists and a Q&A session with the audience, was attended by more than 160 people. 3) Permanent exhibits The Hiroshima laboratory has a permanent exhibit showing the history of ABCC-RERF, the organization s international collaborative activities, and basic information on radiation. The RERF overview poster, which explains its research in a straightforward manner at the permanent exhibit corner, was translated into six languages. Departmental posters are also on permanent display for visitors. The Nagasaki laboratory has a permanent exhibition room. 4) Updating public relations materials The brochure, Introduction to the Radiation Effects Research Foundation (Japanese and English), was revised. Revision of the Japanese version of the Basic Guide to Radiation and Health Sciences was completed, with revision of the English version completed in March 2014. RERF Update (summer and winter editions) was published in Japanese and English. The RERF Annual Report (FY2012) was also issued in Japanese and English. The brochure A Brief Description (Japanese and English) is expected to be comprehensively revised by the end of the first half of FY2014. 5) Enhanced RERF website The RERF public website was updated, with a view to enhancing the provision of information on research results. It now promptly posts RERF news accompanied by related photos in the What s New section. It also posts the titles of recent scientific papers, with their abstracts in English (full text if possible) and Japanese, and summaries of approved research protocols (RPs). When papers were published in major scientific journals, easy-to-follow short summaries were posted in the What s New section on the external website. 19
The total number of RERF website hits between April 1, 2013 and March 31, 2014 was about 36.35 million (compared to about 34.21 million in the corresponding period of the previous year), with the daily average being about 100,000 (compared to about 93,000 in the previous year). The total number of website visitors for the same period was about 819,000 (compared to about 758,000 in the previous year), with the daily average about 2,224 (compared to about 2,079 in the previous year). 6) Other public relations activities As part of public relations activities via the mass media, RERF held press conferences at the time of important functions and newsworthy events, as well as publishing topical papers. Specifically, it held an explanatory meeting for media representatives on July 4, 2013, on a paper titled, The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001. It also held preliminary explanatory meetings on July 8 in Nagasaki and July 10 in Hiroshima on the results of the review of basic information used in individual dose estimates and the recalculation of radiation risks, which was information scheduled to be officially released on July 12. RERF also responded to inquiries and requests for interviews from many domestic and overseas mass media organizations, which have increased dramatically after the Fukushima Dai-ichi nuclear power plant crisis. In Hiroshima, a forum for media representatives, which has become a regular event, was held on April 17, with Dr. Yoshiaki Kodama (Chief, Department of Genetics) and Dr. Waka Ohishi (Acting Chief, Department of Clinical Studies) giving talks on the genetic effects of A-bomb radiation and on the clinical study of the F 1 offspring of A-bomb survivors, respectively. A total of 22 media representatives attended the forum, actively engaging in the Q&A session. Another forum was also held in Nagasaki on April 19, where Dr. Y. Kodama and Dr. Hida delivered lectures on the genetic effects of A-bomb radiation and on the clinical study of the F 1 offspring of A-bomb survivors, respectively. The 11 media representatives who attended the forum asked many questions. Five RERF scientists gave a total of five lectures this year in community halls and other sites in Osaka and Hiroshima, accepting as many invitations for lectures as possible originating from outside RERF. In addition to the Open House events, visitors are welcome to tour RERF s facilities at upon request. Last fiscal year, as of March 31, 2014, 1,557 individuals from Japan, including students on school excursions, and 119 individuals from overseas toured the RERF facilities. 20
(Attachment) FY2013 RERF International Collaborative Activities I. Participation in international collaborative activities by RERF directors and staff II. Acceptance of visitors from overseas for briefing and training members WHO-related activity UNSCEAR-related activity ICRP-related activity IAEA-related activity IAEA-HICARE collaborative activities-related activity International Agency for Research on Cancer-related activity Semipalatinsk -related activity A-bomb survivors residing overseas-related activity Others 2 people 4 people 1 person 1 person 4 people 1 person 2 people 1 person 3 people (Hiroshima) Visitors related to HICARE Visitors related to JICA Visitors related to RERF (International Exchange Research Program) Visitors related to JAEA Visitors related to MEXT (Nagasaki) Visitors related to NASHIM 13 people 8 people 2 people 48 people 10 people 6 people Total: 19 people Total: 87 people (Hiroshima: 81 people) (Nagasaki : 6 people) In italics: Funding Organization Ⅰ. Participation in international collaborative activities by RERF directors and staff members (excluding participation in international scientific meetings) 1. World Health Organization (WHO)-related activity (2 people) RERF (MHLW International Exchange Research Program) (1) Hiroaki Katayama, Chief, ITD, participated in Meeting at IAEA and WHO/REMPAN. (Vienna, Austria, Geneva, Switzerland, March 19-24, 2014) (2) Kazunori Kodama, Chief Scientist, visited WHO headquarters to exchange opinions regarding REM (Radiation Emergency Medicine). (Vienna, Austria, March 24, 2014) 2. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR)-related collaborative activity (4 people) 1) United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) Roy E. Shore, Vice Chairman and Chief of Research made a presentation on cancer risk following childhood radiation exposure at the UNSCEAR meeting. (Vienna, Austria, May 27-30, 2013) 2) RERF (1) Kazunori Kodama, Chief Scientist, attended the 60th session of UNSCEAR and the meeting on UNSCEAR Fukushima assessment. (Vienna, Austria, May 24-June 2, 2013) (2) Kotaro Ozasa, Department Chief of Epidemiology, attended the 60th session of UNSCEAR. 21
(Vienna, Austria, May 27-31, 2013) 3) Nuclear Safety Commission Kazunori Kodama, Chief Scientist, attended the UNSCEAR domestic committee meeting. (Tokyo, Japan, March 28, 2014) 3. ICRP (International Commission on Radiological Protection)-related activity (1 person) Roy E. Shore, Vice Chairman and Chief of Research made a presentation on epidemiologic studies of low-dose or low dose-rate radiation exposures at the ICRP task group on DDREF (dose and dose-rate effect modification) assessment. (Munich, Germany, December 10-11, 2013) 4. International Atomic Energy Agency (IAEA)-related activity (1 person) RERF (MHLW International Exchange Research Program) Kazunori Kodama, Chief Scientist, visited IAEA headquarters to discuss collaboration between RERF and IAEA. (Geneva, Switzerland, March 19-21, 2014) 5. International Atomic Energy Agency (IAEA) and Hiroshima International Council for the Radiation-exposed (HICARE) collaborative activities-related activity (4 people) (1) Yoshiaki Kodama, Chief of Genetics participated and gave a lecture on HICARE, IAEA collaboration project "Training Meeting on Biodosimetry in the 21st Century." (Oriental Hotel Hiroshima, June 10-14, 2013) (2) Kazunori Kodama, Chief Scientist, attended the international workshop hosted by HCARE and gave a lecture. (Hiroshima, Japan, October 28-November 1, 2013) (3) Yoshiaki Kodama, Chief of Genetics and Asao Noda, Assistant Chief of Genetics participated and gave a lecture on HICARE, IAEA collaboration project "International Workshop on Medical Response to Radiation Accidents and Disasters." (Sunroute Hotel Hiroshima, October 29, 2013) 6. International Agency for Research on Cancer-related activity (1 person) Hiroaki Katayama, Chief, ITD, participated in Meeting on SEMI-NUC (International Agency for Research on Cancer) in Lyon and visited to the London school of Hygiene. (Lyon, France, London, UK, May 6-11, 2013) 7. Semipalatinsk (Kazakhstan) related activity (2 people) JSPS/MEXT Grant-in-Aid for Scientific Research (1) Hiroaki Katayama, Chief, ITD, discussed with Dr. Grosche at the Federal Office for Radiation Protection. (Munich, Germany, July 8-10, 2013) (2) Hiroaki Katayama, Chief, ITD, visited the Kazakhstan Scientific Research Institute of Radiation Medicine and Ecology, discussed with Kazakhstan members. (Semipalatinsk, Kazakhstan, September 16-19, 2013) 8. A-bomb survivors residing overseas-related activity (1 person) Nagasaki Prefectural Government 22
Daisuke Haruta, Research Scientist, Clinical Studies, Nagasaki, participated in 20th A-bomb survivors medical checkup in Korea. (November 10-13, 2013) 9. Others (3 people) (1) Roy E. Shore, Vice Chairman and Chief of Research participated in a meeting with investigators from numerous American and European institutions pertaining to the modification of radiation effects on breast cancer risk by genetic and environmental factors, focused on the WECARE study of breast cancers after radiotherapy. (New York, USA, May 21-22, 2013) (2) Midori Soda, Adjunct Specialist, Epidemiology, Nagasaki, visited Philippine General Hospital in Manila and had scientific meetings with the representatives from the Philippine Cancer Society at the request of the Graduate School of International Health Development, Nagasaki University. Dr. Soda also visited the St. Lukes Hospital to see Hospital-based cancer registries. (Manila, Philippines, December 11-15, 2013) (3) Roy E. Shore, Vice Chairman and Chief of Research made a presentation on RERF findings regarding radiation exposure and thyroid disease risks at the International Workshop on Radiation and Thyroid Cancer. (Tokyo, Japan, February 21-23, 2014) II. Acceptance of visitors from overseas for briefing and training (Total: 87 people) [Hiroshima: 81 people] 1. Visitors related to Hiroshima International Council for Health Care of the Radiation Exposed (HICARE) (13 people) 1) South Korea (8 people) (1) July 11, 2013: 2 trainees from South Korea (2) November 28, 2013: 6 trainees from South Korea for the A-bomb survivors residing in South Korea. 2) Others (5 people) (1) January 13-Feburary 15, 2014: 1 trainee from Latvia (2) February 21, 2014: 4 trainees from Brazil, the United States and Algeria 2. Visitors related to International Cooperation Agency (JICA) (8 people) Japan Anti-Tuberculosis Association (8 people) November 6, 2013: 8 trainees from Afghanistan, Bangladesh, Cambodia, Kenya, Myanmar and Philippines for the Group Training Course in Tuberculosis Laboratory Management for Achievement of MDGs Targets, FY 2013 3. RERF (MHLW International Exchange Research Program)(2 people) (1) January 14 - February 14, 2014: 1 trainee, Riga Stradins University, Latvia (2) February 13-28, 2014: 1 trainee, National Cancer Center, South Korea 23