Cytogenetic validation of DS02R1-estimated dose for atomic bomb survivors in Hiroshima and Nagasaki with FISH.

INTRODUCTION: For Hiroshima and Nagasaki survivors, it has not been possible to calculate individual doses from the cytogenetic data and compare them with the physically estimated doses. This is because the cytogenetic studies used solid Giemsa staining which only provides the percent of cells bearing at least one stable-type aberration (most of the unstable-type aberrations had already disappeared), and a gamma-ray dose plus a 10-times neutron dose was used to integrate the data for both cities. OBJECTIVES: To compare the FISH-derived gamma-ray dose with the DS02R1-derived gamma-ray dose after correcting for a contribution of the neutron dose. It was also an attempt to determine if the frequency of stable-type aberrations had remained unchanged after the exposure. METHODS: Stable exchange-type aberration data was obtained using the 2-color FISH method from 1,868 atomic bomb survivors in Hiroshima and Nagasaki. The collected frequency was first extended to a genome-equivalent frequency. Then, by using known induction rates of exchange-type aberrations in vitro caused by neutrons and gamma-rays, respectively, and the mean relationship between the neutron and gamma-ray doses in the DS02R1 estimates for the survivors, the gamma-ray effect was estimated from the total yield of translocations. RESULTS: It was found that over 95% of individual cytogenetic gamma-ray doses fell within the expected range of plus/minus about 1 Gy from the DS02R1 dose and the mean slope for the linear regression was 0.98, which reassures us of the validity of the DS02R1 study. CONCLUSIONS: The present results demonstrate the validity of the individual DS02R1 doses, and that the frequency of stable-type aberrations in blood lymphocytes did not decay over the years, and thus is useful for retrospective dose evaluations of exposures which took place in the distant past.

The Use of Joint Models in Analysis of Aggregate Endpoints in RERF Cohort Studies.

In radiation risk estimation based on the Radiation Effects Research Foundation (RERF) cohort studies, one common analysis is Poisson regression on radiation dose and background and effect modifying variables of an aggregate endpoint such as all solid cancer incidence or all non-cancer mortality. As currently performed, these analyses require selection of a surrogate radiation organ dose, (e.g., colon dose), which could conceptually be problematic since the aggregate endpoint comprises events arising from a variety of organs. We use maximum likelihood theory to compare inference from the usual aggregate endpoint analysis to analyses based on joint analysis. These two approaches are also compared in a re-analysis of RERF Life Span Study all cancer mortality. We show that, except for a trivial difference, these two analytic approaches yield identical inference with respect to radiation dose response and background and effect modification when based on a single surrogate organ radiation dose. When repeating the analysis with organ-specific doses, an interesting issue of bias in intercept parameters arises when dose estimates are undefined for one sex when sex-specific outcomes are included in the aggregate endpoint, but a simple correction will avoid this issue. Lastly, while the joint analysis formulation allows use of organ-specific doses, the interpretation of such an analysis for inference regarding an aggregate endpoint can be problematic. To the extent that analysis of radiation risk for an aggregate endpoint is of interest, the joint-analysis formulation with a single surrogate dose is an appropriate analytic approach, whereas joint analysis with organ-specific doses may only be interpretable if endpoints are considered separately for estimating dose response. However, for neither approach is inference about dose response well defined.

Comparison of external dose estimates using different retrospective dosimetry methods in the settlements located near Semipalatinsk Nuclear Test Site, Republic of Kazakhstan.

For correct assessment of health risks after low-dose irradiation, calculation of radiation exposure estimates is crucial. To verify the calculated absorbed doses, instrumental methods of retrospective dosimetry are used. We compared calculated and instrumental-based estimates of external absorbed doses in the residents of Dolon, Mostik and Cheremushki villages, Kazakhstan, affected by the first nuclear weapon test performed at the Semipalatinsk Nuclear Test Site (SNTS) on August 29, 1949. The 'instrumental' doses were retrospectively estimated using the Luminescence Retrospective Dosimetry (LRD) and Electron Spin Resonance (ESR) methods. Correlation between the calculated individual cumulative external absorbed whole-body doses based on typical input data and ESR-based individual doses in the same people was strong (r = 0.782). It was even stronger between the calculated doses based on individual questionnaires' input data and the ESR-based doses (r = 0.940). Application of the LRD method is useful for validation of the calculated settlement-average cumulated external absorbed dose to air. Reconstruction of external exposure can be supplemented with the data from later measurements of soil contamination with long-lived radionuclides, such as, 137Cs. Our results show the reliability of the calculational method used for the retrospective assessment of individual external doses.

Neurocognitive Function in Aged Survivors Exposed to Atomic Bomb Radiation In Utero: The Radiation Effects Research Foundation Adult Health Study.

Although some adverse effects on neurocognitive function have been reported in children and adolescents irradiated prenatally during the atomic bombings and the Chernobyl nuclear accident, little information is available for effects on the elderly. Here we evaluate the effects of prenatal exposure to atomic bomb radiation on subjective neurocognitive function in aged survivors. To evaluate neurocognitive impairment, we mailed the Neurocognitive Questionnaire (NCQ), a self-administered scale, to prenatally exposed survivors, including clinic visitors and non-visitors at the time of the 2011 and 2013 Adult Health Study (AHS) examinations. We received replies from 444 individuals (mean age, 66.9 ± 0.6 years). After adjusting for sex, city, and educational background, we found no significant effects of radiation, clinic visit, or interaction between radiation and clinic visit on the scores of the 4 NCQ factors of metacognition, emotional regulation, motivation/organization, and processing speed. Even in analyses considering gestational age at the time of the bombings, none of the 4 NCQ factor scores was related to maternal uterine dose. There remains the limitation that this study consisted of healthy survivors, but we found no significant radiation effect on late-life cognition in people prenatally exposed to atomic bomb radiation.

Early-life atomic-bomb irradiation accelerates immunological aging and elevates immune-related intracellular reactive oxygen species.

Reactive oxygen species (ROS) play an important role in immune responses; however, their excessive production and accumulation increases the risk of inflammation-related diseases. Although irradiation is known to accelerate immunological aging, the underlying mechanism is still unclear. To determine the possible involvement of ROS in this mechanism, we examined 10,023 samples obtained from 3752 atomic-bomb survivors in Hiroshima and Nagasaki, who participated in repeated biennial examinations from 2008 to 2016, for the effects of aging and radiation exposure on intracellular ROS (H2 O2 and O2 •- ) levels, percentages of T-cell subsets, and the effects of radiation exposure on the relationship between cell percentages and intracellular ROS levels in T-cell subsets. The cell percentages and intracellular ROS levels in T-cell subsets were measured using flow cytometry, with both fluorescently labeled antibodies and the fluorescent reagents, carboxy-DCFDA and hydroethidine. The percentages of naïve CD4+ and CD8+ T cells decreased with increasing age and radiation dose, while the intracellular O2 •- levels in central and effector memory CD8+ T cells increased. Additionally, when divided into three groups based on the percentages of naïve CD4+ T cells, intracellular O2 •- levels of central and effector memory CD8+ T cells were significantly elevated with the lowest radiation dose group in the naïve CD4+ T cells. Thus, the radiation exposure-induced decrease in the naïve CD4+ T cell pool size may reflect decreased immune function, resulting in increased intracellular ROS levels in central and effector memory CD8+ T cells, and increased intracellular oxidative stress.

Fetal atomic bomb survivor dosimetry using the J45 series of pregnant female phantoms with realistic survivor exposure scenarios: comparisons to dose estimates in the DS02 system.

A significant source of information on radiation-induced biological effects following in-utero irradiation stems from studies of atomic bomb survivors who were pregnant at the time of exposure in Hiroshima, and to a lesser extent, from survivors in Nagasaki. Dose estimates to the developing fetus for these survivors have been assigned in prior dosimetry systems of the Radiation Effects Research Foundation as the dose to the uterine wall within the non-pregnant adult stylized phantom, originally designed for the dosimetry system DS86 and then carried forward in DS02. In a prior study, a new J45 (Japanese 1945) series of high-resolution phantoms of the adult pregnant female at 8 weeks, 15 weeks, 25 weeks, and 38-weeks post-conception was presented. Fetal and maternal organ doses were estimated by computationally exposing the pregnant female phantom series to DS02 free-in-air cumulative photon and neutron fluences at three distances from the hypocenter at both Hiroshima and Nagasaki under idealized frontal (AP) and isotropic (ISO) particle incidence. In this present study, this work was extended using realistic angular fluences (480 directions) from the DS02 system for seven radiation source terms, nine different radiation dose components, and five shielding conditions. In addition, to explore the effects of fetal position within the womb, four new phantoms were created and the same irradiation scenarios were performed. General findings are that the current DS02 fetal dose surrogate overestimates values of fetal organ dose seen in the J45 phantoms towards the cranial end of the fetus, especially in the later stages of pregnancy. For example, for in-open exposures at 1000 m in Hiroshima, the ratio of J45 fetal brain dose to DS02 uterine wall dose is 0.90, 0.82, and 0.70 at 15 weeks, 25 weeks, and 38-weeks, respectively, for total gamma exposures, and are 0.64, 0.44, and 0.37 at these same gestational ages for total neutron exposures. For organs in the abdominal and pelvic regions of the fetus, dose gradients across gestational age flatten and later reverse, so that DS02 fetal dosimetry begins to underestimate values of fetal organ dose as seen in the J45 phantoms. For example, for the same exposure scenario, the ratios of J45 fetal kidney dose to DS02 uterine wall dose are about 1.09 from 15 to 38 weeks for total gamma dose, and are 1.30, 1.56, and 1.75 at 15 weeks, 25 weeks, and 38 weeks, respectively, for the total neutron dose. Results using the new fetal positioning phantoms show this trend reversing for a head-up, breach fetal position. This work supports previous findings that the J45 pregnant female phantom series offers significant opportunities for gestational age-dependent assessment of fetal organ dose without the need to invoke the uterine wall as a fetal organ surrogate.

Comparison of Proportional Mortality Between Korean Atomic Bomb Survivors and the General Population During 1992-2019.

BACKGROUND: Atomic bombs dropped on Hiroshima and Nagasaki in Japan in August 1945 were estimated to have killed approximately 70,000 Koreans. In Japan, studies on the health status and mortality of atomic bomb survivors compared with the non-exposed population have been conducted. However, there have been no studies related to the mortality of Korean atomic bomb survivors. Therefore, we aimed to study the cause of death of atomic bomb survivors compared to that of the general population. METHODS: Of 2,299 atomic bomb survivors registered with the Korean Red Cross, 2,176 were included in the study. In the general population, the number of deaths by age group was calculated from 1992 to 2019, and 6,377,781 individuals were assessed. Causes of death were categorized according to the Korean Standard Classification of Diseases. To compare the proportional mortality between the two groups, the P value for the ratio test was confirmed, and the Cochran-Armitage trend test and χ² test were performed to determine the cause of death according to the distance from the hypocenter. RESULTS: Diseases of the circulatory system were the most common cause of death (25.4%), followed by neoplasms (25.1%) and diseases of the respiratory system (10.6%) in atomic bomb survivors who died between 1992 and 2019. The proportional mortality associated with respiratory diseases, nervous system diseases, and other diseases among atomic bomb survivors was higher than that of the general population. Of the dead people between 1992 and 2019, the age at death of survivors who were exposed at a close distance was younger than those who were exposed at a greater distance. CONCLUSION: Overall, proportional mortality of respiratory diseases and nervous system diseases was high in atomic bomb survivors, compared with the general population. Further studies on the health status of Korean atomic bomb survivors are needed.

Mathematical models of the solid cancer induced by atomic bomb and the spontaneous cancer in the daily life-Proposal of a new medical treatment for cancers.

BACKGROUND: A mathematical model of the radiation-induced cancer was devised to explain the change of incidence rates pursued by Radiation Effect Research Foundation for 25 years. AIM: The aim of this work is construction of mechanisms of radiation-induced cancer and cancers observed in the daily life. METHODS AND RESULTS: First, we found a way to separate spontaneous cancers from radiation-induced cancers observed among atomic-bomb victims in Hiroshima and Nagasaki districts by using a constructed algorithm. The isolated incidence rates of radiation-induced cancers were reproduced by a two-stage model mechanical collision of impinging radiation with cells and succeeding mutation of the damaged cell to cancer. This model satisfactorily reproduced observed solid cancer incidence rates. We further attempted to construct a mathematical model for the age-dependence of spontaneous cancers appearing in the daily life and concluded that the cancer should be generated at cell division. CONCLUSION: With these findings, we reached to a conclusion that cancers may be suppressed by eliminating damaged cells with mild-dose radiation.

Cohort Study Protocol: A Cohort of Korean Atomic Bomb Survivors and Their Offspring.

In 1945, atomic bombs were dropped on Hiroshima and Nagasaki. Approximately 70 000 Koreans are estimated to have been exposed to radiation from atomic bombs at that time. After Korea's Liberation Day, approximately 23 000 of these people returned to Korea. To investigate the long-term health and hereditary effects of atomic bomb exposure on the offspring, cohort studies have been conducted on atomic bomb survivors in Japan. This study is an ongoing cohort study to determine the health status of Korean atomic bomb survivors and investigate whether any health effects were inherited by their offspring. Atomic bomb survivors are defined by the Special Act On the Support for Korean Atomic Bomb Victims, and their offspring are identified by participating atomic bomb survivors. As of 2024, we plan to recruit 1500 atomic bomb survivors and their offspring, including 200 trios with more than 300 people. Questionnaires regarding socio-demographic factors, health behaviors, past medical history, laboratory tests, and pedigree information comprise the data collected to minimize survival bias. For the 200 trios, whole-genome analysis is planned to identify de novo mutations in atomic bomb survivors and to compare the prevalence of de novo mutations with trios in the general population. Active follow-up based on telephone surveys and passive follow-up with linkage to the Korean Red Cross, National Health Insurance Service, death registry, and Korea Central Cancer Registry data are ongoing. By combining pedigree information with the findings of trio-based whole-genome analysis, the results will elucidate the hereditary health effects of atomic bomb exposure.

Comparison and multi-model inference of excess risks models for radiation-related solid cancer.

In assessments of detrimental health risks from exposures to ionising radiation, many forms of risk to dose-response models are available in the literature. The usual practice is to base risk assessment on one specific model and ignore model uncertainty. The analysis illustrated here considers model uncertainty for the outcome all solid cancer incidence, when modelled as a function of colon organ dose, using the most recent publicly available data from the Life Span Study on atomic bomb survivors of Japan. Seven recent publications reporting all solid cancer risk models currently deemed plausible by the scientific community have been included in a model averaging procedure so that the main conclusions do not depend on just one type of model. The models have been estimated with different baselines and presented for males and females at various attained ages and ages at exposure, to obtain specially computed model-averaged Excess Relative Risks (ERR) and Excess Absolute Risks (EAR). Monte Carlo simulated estimation of uncertainty on excess risks was accounted for by applying realisations including correlations in the risk model parameters. Three models were found to weight the model-averaged risks most strongly depending on the baseline and information criteria used for the weighting. Fitting all excess risk models with the same baseline, one model dominates for both information criteria considered in this study. Based on the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses.