Atomic Bomb Survivors In Hiroshima Research Articles

Modeling the low-LET dose-response of BCR–ABL formation: predicting stem cell numbers from A-bomb data

Formation of the BCR–ABL chromosomal translocation t(9;22)( q34; q11) is essential to the genesis of chronic myeloid leukemia (CML). An interest in the dose-response of radiation induced CML therefore leads naturally to an interest in the dose-response of BCR–ABL formation. To predict the BCR–ABL dose-response to low-linear energy transfer (LET) ionizing radiation, three models valid over three different dose ranges are examined: the first for doses greater than 80 Gy, the second for doses less than 5 Gy and the third for doses greater than 2 Gy. The first of the models, due to Holley and Chatterjee, ignores the accidental binary eurejoining of DNA double-strand break (DSB) free ends (`eurejoining' refers to the accidental restitution of DSB free ends with their own proper mates). As a result, the model is valid only in the limit of high doses. The second model is derived directly from cytogenetic data. This model has the attractive feature that it implicitly accounts for single-track effects at low doses. The third model, based on the Sax–Markov binary eurejoining/misrejoining (SMBE) algorithm, does not account for single-track effects and is therefore limited to moderate doses greater than approximately 2 Gy. Comparing the second model to lifetime excess CML risks expected after 1 Gy, estimates of the number of hematopoietic stem cells capable of causing CML were obtained for male and female atomic bomb survivors in Hiroshima and Nagasaki. The stem cell number estimates lie in the range of 5×10 7–3×10 8 cells.

Effects of Radiation on Incidence of Primary Liver Cancer among Atomic Bomb Survivors

We describe the radiation risk for primary liver cancers between 1958 and 1987 in a cohort of atomic bomb survivors in Hiroshima and Nagasaki, Japan. The analysis is based on a comprehensive pathology review of known or suspected liver neoplasms that generated 518 incident, first primary cases, mostly hepatocellular carcinoma. Excess relative risk from atomic bomb radiation was linear: 0.81 per sievert weighted liver dose (95% CI [0.32, 1.43]; P < 0.001). Males and females had similar relative risk so that, given a threefold higher background incidence in males, the radiation-related excess incidence was substantially higher in males. Excess risk peaked for those with age at exposure in the early 20s; there was essentially no excess risk in those exposed before age 10 or after age 45. Whether this was due to a difference in sensitivity or possible confounding by other factors could not be addressed retrospectively in the full cohort. A paucity of cholangiocarcinoma and hemangiosarcoma cases suggested that they are not significantly associated with whole-body radiation exposure, as they are with the internal alpha-particle-emitting radiological contrast medium Thorotrast. Because most of the radiation-related excess cases occurred among males, it is important to ascertain what factors put men at greater risk of radiation-related liver cancer.

High incidence of meningioma among Hiroshima atomic bomb survivors.

Since the atomic bomb explosions in Hiroshima and Nagasaki, high incidences of leukemia, thyroid cancer and other tumors have been reported as atomic bomb-induced tumors. We investigated the incidence of meningioma among Hiroshima atomic bomb survivors. Sixty-eight patients surgically treated for meningioma who had been within 2.0 km of the hypocenter of the explosion were identified. Six hundred and seven non-exposed patients with meningioma were also studied. Treatment dates were from 1975 to 1992. The incidences of meningioma among 68 subjects within 2.0 km and 607 non-exposed patients were 8.7 and 3.0 cases per 10(5) persons per year, respectively. The incidences of meningioma among the survivors of Hiroshima in 5-year intervals since 1975 were 5.3, 7.4, 10.1, and 14.9, respectively. The incidences of meningioma classified by distances from the hypocenter of 1.5-2.0 km, 1.0-1.5 km and less than 1.0 km were 6.3, 7.6 and 20.0, respectively. The incidences of meningioma classified by doses to the brain of 0-0.099 Sv, 0.1-0.99 Sv and more than 1.0 Sv were 7.7, 9.2 and 18.2, respectively. The incidence of meningioma among Hiroshima atomic bomb survivors has increased since 1975. There was a significant correlation between the incidence and the dose of radiation to the brain. The present findings strongly suggest that meningioma is one of the tumors induced by atomic bombing in Hiroshima.

Rapid communication: S values are not a signature for a significant contribution of neutrons to the radiation dose received by atomic-bomb survivors

Purpose: It has been proposed previously that the ratio of complete to incomplete translocations as seen by fluorescence in situ hybridization (FISH), the S value, can be a cytogenetic fingerprint of exposure to radiation of di erent qualities. Results from a previous study suggested that the S value is 10 for sparsely ionizing radiations such as X- and gamma -rays, and 2 for densely ionizing radiations. Based on FISH data of atomic-bomb (A-bomb) survivors, which showed an S value of 3.25, a significant neutron component to A-bomb radiation was suggested. To examine the possibility, the present in vitro study was conducted using X-rays. Materials and methods: Human blood lymphocytes were exposed to X-rays and first metaphases were examined with FISH using DNA probes for chromosomes 1, 2 and 4. Results: The S value was 3.16 for X-rays, which di ers from 10 as reported previously, and not larger than the 3.25 obtained from the blood lymphocytes of A-bomb survivors. Conclusions: S values seem to vary among laboratories even after exposure of cells to sparsely ionizing radiations. Data from this study show that S values are not a signature for a significant contribution of neutrons to the radiation dose received by A-bomb survivors in Hiroshima.

A close correlation between electron spin resonance (ESR) dosimetry from tooth enamel and cytogenetic dosimetry from lymphocytes of Hiroshima atomic-bomb survivors

Purpose: To estimate gamma -ray doses received by Hiroshima atomic bomb survivors using electron spin resonance (ESR) of tooth enamel and to compare the results with cytogenetic data. Materials and methods: Tooth enamel ESR was performed for 100 teeth donated from 69 Hiroshima survivors, and conventional cytogenetic examinations were conducted for 61 of the tooth donors. To evaluate possible contamination from dental X-ray exposure, which primarily affects the tooth's buccal surface, each tooth was divided into buccal and lingual parts for subsequent independent enamel isolation and ESR measurement. Results: Almost 20 teeth showed considerably larger buccal doses than lingual doses, but most of these discrepant teeth were incisors and canines. The results are probably attributable to solar light exposure. In contrast, the buccal and lingual doses found in molars were similar. Conventional translocation data of lymphocytes and ESR-estimated doses of 40 donors of molars showed the dose-response for translocations to be almost the same as that expected from in vitro gamma -ray irradiation experiments. Conclusions: Both tooth enamel ESR and lymphocyte cytogenetics are useful measures for individual biodosimetry of acute radiation exposure, even half a century after the exposure occurred.

Neutron versus gamma-ray risk estimates. Inferences from the cancer incidence and mortality data in Hiroshima.

While it is recognized that neutrons contributed to the excess cancer incidence and mortality among the atomic bomb survivors in Hiroshima, there is no possibility to deduce the magnitude of this contribution from the data. This remains true even if the neutron doses in the dosimetry system DS86 are corrected upwards in line with recent neutron activation measurements. In spite of this fact, important information can be obtained in the form of an inverse relation of the risk coefficients for gamma-rays and neutrons. Such an interrelation must apply because the observed excess incidence or mortality is made up of a gamma-ray and a neutron component; increased attribution to neutrons decreases the attribution to photons. Computations with the uncorrected and the corrected DS86 are performed for the mortality and the incidence of solid tumors combined. They refer to doses up to 2 Gy and employ the constant relative risk model and a linear-quadratic dose dependence with variable ratio-the neutron relative biological effectiveness (RBE) at low doses-of the linear component for neutrons and gamma-rays. In line with past analyses, no quadratic component is obtained with the uncorrected DS86. but it is seen, even in these calculations, that the assumption of increased neutron RBEs does not translate into proportional increases of the risk coefficients of neutrons, because it leads to substantially reduced risk estimates for gamma-rays. Calculations with the corrected dosimetry bring out this reciprocity even more clearly. High values of the neutron RBE reduce-in line with recent suggestions by Rossi and Zaider-the risk estimates for gamma-rays substantially. Even a purely quadratic dose relation for gamma-rays is consistent with the data; it requires no major increase of the nominal risk coefficients for neutrons over the currently assumed values. The cancer data from Hiroshima can still provide 'prudent' risk estimates for photons, but with the corrected DS86, they do not prove that there is a linear component in the dose dependence for photons.

Monitoring exposure to atomic bomb radiation by somatic mutation.

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in females and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure.

Prevalence Rate of Thyroid Diseases among Autopsy Cases of the Atomic Bomb Survivors in Hiroshima, 1951-1985

To examine the radiogenic risk of latent thyroid cancer, thyroid adenoma, colloid/adenomatous goiter and chronic thyroiditis, the data for 3821 subjects collected in the course of autopsies of atomic bomb survivors in Hiroshima from 1951 to 1985 by the Radiation Effects Research Foundation (RERF) were analyzed using a logistic model. About 80% of the autopsies were performed at RERF and the remainder at local hospitals. The frequencies of the above diseases were not associated with whether the underlying cause of death was cancer. However, note that our results may be influenced by potentially biasing factors associated with autopsy selection. The relative frequency of latent thyroid cancer (greatest dimension < or = 1.5 cm but detectable on a routine microscopic slide of the thyroid gland) increased as the radiation dose increased and was about 1.4-fold greater at 1 Gy than in the 0-Gy dose group. The relative occurrence of thyroid adenoma also increased as radiation dose increased, and was about 1.5-fold greater at 1 Gy than in the 0-Gy dose group. Sex, age at the time of the bombing or period of observation did not significantly modify the radiogenic risks for thyroid adenoma or latent thyroid cancer. No statistically significant association was found between radiation exposure and the rates of colloid/adenomatous goiter and chronic thyroiditis. The possible late effect of atomic bomb radiation on the frequency of benign thyroid diseases is discussed on the basis of these data.

Trends in the prevalence of diabetes mellitus among Hiroshima atomic bomb survivors

Mass screening for diabetes mellitus has been conducted on 64000 ~113000 atomic bomb survivors resident in Hiroshima City since 1961. The trends in the number of diabetes mellitus patients from 1971 to 1992 based on the results of this mass screening and on death certificates are described. The prevalence of diabetes mellitus has shown an increase with age, but it peaked in the 8th decade and declined after the 9th decade. From 1971 to 1992 a 2.7-fold increase in the prevalence of diabetes mellitus was observed in males and a 3.2-fold increase in females. By age, in males the increase was high in those of less than 49 years of age, and in females the increase was predominant in those of 80 years of age and over. In males the prevalence of diabetes mellitus estimates by death certificates was in good agreement with that observed by mass screening, but in females the prevalence observed by death certificates gave a higher value. During a period of two decades, a 2.1-fold increase was observed in males and a 2,0-fold increase in females.

Aneuploidy in somatic cells of in utero exposed A-bomb survivors in Hiroshima.

Cytogenetic data on cultured lymphocytes of the in utero exposed A-bomb survivors in the RERF Adult Health Study cohort have been analyzed using the G-banding technique to determine the frequency of aneuploid cells. The data consist of blood samples collected between 1985 and 1987 from 264 Hiroshima individuals for whom DS86 maternal uterine dose estimates are available: 124 proximally exposed (74 males and 50 females) with an estimated dose of 0.005 Sv or more, and 140 distally exposed (76 males and 64 females) with a dose estimate of 0 Sv, assuming the neutron relative biological effectiveness (RBE) of 10. A main feature of aneuploidy was that aneuploid frequency in autosomes depended generally on chromosome length; aneuploidies were significantly more frequent in shorter chromosomes than in longer chromosomes. The frequency of aneuploidies also depended on type, with chromosome loss approximately five times more frequent than chromosome gain. However, chromosome 21, as well as the sex chromosomes, were notable in that aneuploidy was much more frequent for these chromosomes than would be predicted from a simple relationship with length. X chromosome aneuploidies were significantly more frequent in females than in males. There was no dependence of aneuploid frequencies on dose when measured 40 years after the exposure.

G-banding analysis of radiation-induced chromosome damage in lymphocytes of Hiroshima A-bomb survivors.

The present report describes the G-band analysis of somatic chromosomes in lymphocytes from 63 A-bomb survivors in Hiroshima to determine the type and frequency of radiation-induced chromosome aberrations. (1) The cells with stable-type chromosome aberrations (Cs cells) predominated among the aberrant cells, and showed a dose-dependent increase. All stable chromosome aberrations were classified into nine categories: reciprocal translocations, translocations of complex type, insertions, complex exchanges, peri- and paracentric inversions, terminal and interstitial deletions, and unidentified rearrangements. The frequencies of aberrations were found to increase with increasing dose for all aberration categories. Reciprocal translocations predominate in all dose ranges and among the chromosome aberrations classified. (2) The linear model was fitted to test the dose-response relationship for Cs cell frequencies. Employing a constant neutron RBEs of 10, an estimated linear slope of 15.2%/Sv was obtained for DS86 bone marrow dose with an intercept of 2.9% at dose 0. (3) Statistical analysis of data on 3,370 break sites showed good correlations between relative DNA content and the distribution of chromosome breaks involved in translocations, although the involvement of chromosome 1 is significantly higher.

The Children of the Atomic Bomb Survivors: A Genetic Study

Do persons exposed to radiation suffer genetic effects that threaten their yet-to-be-born children? Researchers are concluding that the genetic risks of radiation are less than previously thought. This finding is explored in this volume about the children of atomic bomb survivors in Hiroshima and Nagasaki--the population that can provide the greatest insight into this critical issue. Assembled here for the first time are papers representing more than 40 years of research. These documents reveal key results related to radiation's effects on pregnancy termination, sex ratio, congenital defects, and early mortality of children. Edited by two of the principal architects of the studies, J. V. Neel and W. J. Schull, the volume also offers an important comparison with studies of the genetic effects of radiation on mice. The wealth of technical details will be immediately useful to geneticists and other specialists. Policymakers will be interested in the overall conclusions and discussion of future studies.

Hyperparathyroidism among Atomic Bomb Survivors in Hiroshima

To determine the effect of exposure to atomic bomb radiation on the occurrence of hyperparathyroidism, the prevalence was determined among a population of 3,948 atomic bomb survivors and their controls in Hiroshima. The diagnosis of hyperparathyroidism was based upon histopathological findings or the presence of consistent hypercalcemia and elevated levels of serum parathyroid hormone. Primary hyperparathyroidism was diagnosed in 19 persons (3 males, 16 females). Females had approximately a threefold higher overall prevalence of hyperparathyroidism than males (P less than 0.05). The prevalence rates of hyperparathyroidism increased with radiation dose (chi2(1) = 12, P less than 0.001) after adjusting for sex and age at the time of the bombing. The estimated relative risk was 4.1 at 1 Gy (95% confidence limits 1.7 to 14). There was some evidence that the effect of radiation was greater for individuals who were younger at the time of the bombing. In conclusion, exposure to atomic bomb radiation affected the occurrence of hyperparathyroidism, suggesting that doses of radiation lower than those used in radiotherapy may also induce this disorder.

Long-term Follow-up Study of Stroke in a Fixed Japanese Population - A Review of the Hiroshima/Nagasaki Study -

A cohort study is one of the most important methods of investigating epidemiologically the etiological significance of possible risk factors on the occurrence of stroke. The Adult Health Study of the Radiation Effects Research Foundation, which began in 1958 under the aegis of the Atomic Bomb Casualty Commission, is one of a series of epidemiologic studies of the late effects of exposure to ionizing radiation on the atomic bomb survivors in Hiroshima and Nagasaki. This cohort study provides a wealth of information on changes in the incidence over time in cardiovascular diseases, including ischemic heart disease and stroke. When the study began, the population at risk of a stroke was about 16, 500 individuals who were free of cerebrovascular disease at the time of their first medical examination. During 26 years of follow-up, 865 cases of definite or probable strokes have been ascertained. When the cases were classified into strokes arising from cerebral hemorrhage, on the one hand, and cerebral infarction, on the other, age-adjusted incidence rates revealed a declining trend for both types, but especially for cerebral hemorrhage. The results of a multivariate analysis of risk factors showed that hypertension was the most significant predictor of stroke. It appears, however, that stroke occurrence in Japan varies with life style changes in accordance with the results from a comparative study of Japanese men living in Japan and in Hawaii.

Longitudinal study of the association between ABO phenotype and total serum cholesterol level in a Japanese cohort.

The relationship between ABO blood phenotype and total serum cholesterol (TC) level was examined in a Japanese population to determine whether an elevated TC level is associated with phenotype A, as has been demonstrated in many West European populations. Such studies in nonwhite populations are scarce, and findings generally failed to demonstrate the relationship. Inconsistent results from cross-sectional studies of various racial groups with widely varying ages raised an age effect as a possible explanatory factor. It was also suggested that the ABO-TC association may not be apparent in populations with low fat intake or low mean cholesterol level. These hypotheses are addressed by examining long-term TC data collected serially from the unexposed controls of the atomic bomb survivors in Hiroshima and Nagasaki who were participants of the Adult Health Study program at the Atomic Bomb Casualty Commission-Radiation Effects Research Foundation between 1958 and 1986. The statistical method of growth curve analysis, through the mixed effect model of Laird and Ware [1982], was used to model age-dependent changes in cholesterol levels within individuals. The effects of the ABO polymorphism in modifying the resultant growth curve are examined. We demonstrate that TC levels are elevated on average by about 4 mg/dl in phenotype A compared to non-A in the Japanese (P < 0.00001), and that this relationship is maintained from early to late adulthood, independent of sex, body mass index, cohort status, or city of residence. Thus, phenotype A individuals may be more predisposed to cardiovascular disease through one of its major risk factors. This is the first study of the ABO-cholesterol association in the Japanese, and the first based on a cohort with longitudinally collected TC data.

Factors that determine the in vivo dose-response relationship for stable chromosome aberrations in A-bomb survivors.

An overview is given of the dose-response relationship for stable chromosome aberrations (i.e., translocations and inversions) in the peripheral blood lymphocytes of A-bomb survivors in Hiroshima. Special emphasis is placed on (i) the overdispersion of survivor cases with either unexpectedly high or low aberration frequencies relative to the estimated DS86 kerma values assigned to individual survivors, termed "cytogenetic outliers", and (ii) the correlation of chromosome aberration frequencies with other biological endpoints, such as acute radiation symptoms (severe epilation). A new molecular biological technique, known as fluorescence in situ hybridization (FISH) with composite, whole-chromosome probes to paint differentially the target chromosomes, has facilitated rapid, efficient, and extensive scoring of translocation-type chromosome aberrations in which the target chromosomes are involved. Using this methodology, the observed findings on translocation frequencies in A-bomb survivors have shown that the frequency of stable chromosome aberrations, which have persisted for years without change in frequency in irradiated persons, is indeed useful as an indicator for biological dosimetry.

Rapid translocation frequency analysis in humans decades after exposure to ionizing radiation.

This paper presents an analysis of the utility of fluorescence in situ hybridization (FISH) with whole-chromosome probes for measurement of the genomic frequency of translocations found in the peripheral blood of individuals exposed to ionizing radiation. First, we derive the equation: Fp = 2.05fp(1-fp)FG, relating the translocation frequency, Fp, measured using FISH to the genomic translocation frequency, FG, where fp is the fraction of the genome covered by the composite probe. We demonstrate the validity of this equation by showing that: (a) translocation detection efficiency predicted by the equation is consistent with experimental data as fp is changed; (b) translocation frequency dose-response curves measured in vitro using FISH agree well with dicentric frequency dose-response curves measured in vitro using conventional cytogenetic procedures; and (c) the genomic translocation frequencies estimated from FISH measurements for 20 Hiroshima A-bomb survivors and four workers exposed to ionizing radiation during the Y-12 criticality accident are approximately the same as the translocation frequencies measured using G-banding. We also show that translocation frequency dose response curves estimated using FISH are similar for Hiroshima A-bomb survivors and for first division lymphocytes irradiated in vitro. We conclude with a discussion of the potential utility of translocation frequency analysis for assessment of the level of acute radiation exposure independent of the time between analysis and exposure.

An Estimate of the Magnitude of Random Errors in the DS86 Dosimetry from Data on Chromosome Aberrations and Severe Epilation

An analysis of the proportion of cells with chromosome aberrations in cultured blood lymphocytes from A-bomb survivors in Hiroshima and Nagasaki reveals that the dose-response relationship using DS86 assigned dose is significantly steeper in the subsample of individuals who reported severe epilation after the bombings than in those who did not report severe epilation. This effect is due either to random errors in the DS86 dose assignments or to individual differences in sensitivity to radiation, or to both. In this paper, working within a class of dosimetry error models, we estimate the magnitude of random dosimetry errors which would be required to account for all of the difference in the observed dose response between people who did and did not report severe epilation under the assumption that random dosimetry error is the only cause of the effect. We conclude that random dosimetry errors in the range 45 to 50% of true dose are necessary to explain completely the difference in dose response between the two epilation groups. We discuss evidence that the contribution of individual differences in radiation sensitivity to the observed epilation effect is likely to be small, so that random dosimetry errors may be the major cause of this effect.

Parathyroid Tumors in Atomic Bomb Survivors in Hiroshima: Epidemiological Study from Registered Cases at Hiroshima Prefecture Tumor Tissue Registry, 1974‐1987

An examination of registered cases of parathyroid tumor in Hiroshima Prefecture between 1974 and 1987 revealed 23 cases. An epidemiological study showed that the incidence of parathyroid tumors in Hiroshima Prefecture was significantly higher in the total exposed, especially among the proximally exposed (within 2,000 m from the hypocenter), than in the control nonexposed group (P< 0.001). A similar trend was seen for parathyroid tumor associated with primary hyperparathyroidism.

Parathyroid Tumors in Atomic Bomb Survivors in Hiroshima: A Review

Parathyroid tumors in A-bomb survivors in Hiroshima have been studied. Thirteen cases of parathyroid tumor were confirmed from 4, 136 autopsy cases between 1961 to 1977, and an elevated incidence of tumor with increase of dose (T65D) was demonstrated (P<0.01). A high proportion of 42.9%, 6 out of 14 parathyroid tumors extirpated at Hiroshima University Hospital between 1956 and 1988, were atomic bomb survivors exposed within 4.1 km from the hypocenter. From an epidemiological study using 23 parathyroid tumor cases detected in Hiroshima Prefecture between. 1974 and 1987, an elevated incidence of parathyroid tumors with increase of dose (proximally exposed, other exposed and control nonexposed) was demonstrated (P<0.001).