Precise Spectroscopy of the 3n and 3p Systems via the

To search for low-energy resonant structures in isospin T=3/2 three-body systems, we have performed the experiments ^{3}H(t,^{3}He)3n and ^{3}He(^{3}He,t)3p at intermediate energies. For the 3n experiment, we have newly developed a thick Ti-^{3}H target that has the largest tritium thickness among targets of this type ever made. The 3n experiment for the first time covered the momentum-transfer region as low as 15 MeV/c, which provides ideal conditions for producing fragile systems. However, in the excitation-energy spectra we obtained, we did not observe any distinct peak structures. This is in sharp contrast to tetraneutron spectra. The distributions of the 3n and 3p spectra are found to be similar, except for the displacement in energy due to Coulomb repulsion. Comparisons with theoretical calculations suggest that three-body correlations exist in the 3n and 3p systems, although not enough to produce a resonant peak.

Genetic effects of the atomic bombs: a reappraisal.

Data are presented on four indicators of genetic effects from studies of children born to survivors of the atomic bombings of Hiroshima and Nagasaki. The indicators are frequency of untoward pregnancy outcomes (stillbirth, major congenital defect, death during the first postnatal weak); occurrence of death in live-born children, through an average of life expectancy of 17 years; frequency of children with sex chromosome aneuploidy; and frequency of children with mutation resulting in an eletrophoretic variant. In no instance is there a statistically significant effect of parental exposure; but for all indicators the observed effect is in the direction suggested by the hypothesis that genetic damage resulted from the exposure. On the basis of assumptions concerning the contribution that spontaneous mutation in the preceding generation makes to the indicators in question, it is possible to estimate the genetic doubling dose for radiation for the first three indicators (the data base is still too small for the fourth). The average of these estimates is 156 rems. This is some four times higher than the results from experimental studies on the mouse with comparable radiation sources, which have been the principal guide to the presumed human sensitivities. The relevance of these data in setting permissible limits for human exposures is discussed briefly.

Growth and differentiation of circulating hemopoietic stem cells with atomic bomb irradiation-induced chromosome abnormalities.

The effects of atomic bomb irradiation on hemopoietic stem cells were studied cytogenetically using single colonies derived from hemopoietic progenitor cells. The subjects studied were 21 healthy atomic bomb survivors (10 males and 11 females) in the high dose exposure group (100+ rad) with a known high incidence (10% or more) of radiation-induced chromosome abnormalities in their peripheral blood lymphocytes (stimulated with phytohemagglutinin), and 11 nonexposed healthy controls (5 males and 6 females). Colony formation by circulating granulocyte-macrophage (GM-CFC) and erythroid (BFU-E) progenitor cells was made by the methylcellulose method using peripheral blood mononuclear cells. Chromosome specimens were prepared from single colonies by our micromethod. The total number of colonies analyzed in the exposed group was 131 for GM-CFC and 75 for BFU-E. Chromosome abnormalities were observed in 15 (11.5%) and 9 (12.0%) colonies, respectively. In the control group, the total number of colonies analyzed was 61 for GM-CFC and 41 for BFU-E. None of these colonies showed chromosome abnormalities. The difference in incidence of chromosome abnormalities was highly significant by an exact test; p = 0.003 for GM-CFC and 0.017 for BFU-E. The karyotypes of chromosome abnormalities obtained from the colonies in the exposed group were mostly translocations, but deletion and marker chromosomes were also observed. In two individuals, such karyotypic abnormalities as observed in the peripheral lymphocytes were also seen in the myeloid progenitor cells. This finding suggests that atomic bomb irradiation produced a chromosome aberration on multipotent hemopoietic stem cells common to myeloid and lymphoid lineages. These stem cells, although carrying chromosome defects, are likely to have survived for more than 30 years, continuously producing progenitor cells capable of normal-looking growth and differentiation.

Immunoglobulin E (IgE) multiple myeloma: a case report and review of the literature.

A case of immunoglobulin E (IgE) myeloma with clinical features of "classic" myeloma is presented. Skeletal roentgenograms showed osteoporosis and compression fractures of the vertebrae but no osteosclerosis. Protein analyses revealed an M component of the IgE kappa type with a concentration of 3.1 g/dl. Although morphologic examination revealed that the plasma cells were not so differentiated, well-developed Golgi apparatus and abundant rough-surfaced endoplasmic reticulum were observed. An indirect immunofluorescence technique showed characteristic apple green fluorescence. The E myeloma protein of our patient had no antibody activity. Treatment with melphalan or cyclophosphamide resulted in a decrease in the serum IgE level and in the level of Bence Jones protein in the urine. The clinical and laboratory features of IgE myeloma were summarized and compared with those of other classes of myeloma.

Effects of environmental factors on perinatal outcome: neurological development in cases of intrauterine growth retardation and school performance of children perinatally exposed to ionizing radiation.

We performed two studies to investigate environmental factors in relation to neurological development in infants. The first, a field study, examined the elementary school performance of 929 children who were born from mothers exposed to the atomic bombing of Hiroshima, Japan, August 6, 1945. The most severe mental retardation was observed in the group exposed between 8 and 15 weeks following fertilization, and the second most severely damaged group was exposed between 16 and 25 weeks. The second, a clinical investigation, examined infants in the perinatal center who survived intrauterine growth retardation (IUGR). Those who survived with abnormal neurological development had a mean growth arrest corresponding to a uterine height of 27 weeks of gestation. This was at an earlier stage than those who survived with normal neurological development and had a mean growth arrest corresponding to 29-30 weeks of gestation. A smaller head circumference at birth was closely correlated with abnormal neurological sequelae. These results indicate that the brain development of the fetuses may have been affected by neurotoxic events similar to ionizing radiation. We emphasize the importance of avoiding neurotoxic stress to pregnant women when the fetus is in the critical period of neuronal development, before 27 weeks of gestational age.

The analysis of chromosomally aberrant cells based on beta-binomial distribution.

Analysis carried out here generalized on earlier studies of chromosomal aberrations in the populations of Hiroshima and Nagasaki, by allowing extrabinomial variation in aberrant cell counts corresponding to within-subject correlations in cell aberrations. Strong within-subject correlations were detected with corresponding standard errors for the average number of aberrant cells that were often substantially larger than was previously assumed. The extrabinomial variation is accommodated in the analysis in the present report, as described in the section on dose-response models, by using a beta-binomial (beta-B) variance structure. It is emphasized that we have generally satisfactory agreement between the observed and the beta-B fitted frequencies by city-dose category. The chromosomal aberration data considered here are not extensive enough to allow a precise discrimination between competing dose-response models.

Radiation-related posterior lenticular opacities in Hiroshima and Nagasaki atomic bomb survivors based on the DS86 dosimetry system.

This paper investigates the quantitative relationship of ionizing radiation to the occurrence of posterior lenticular opacities among the survivors of the atomic bombings of Hiroshima and Nagasaki suggested by the DS86 dosimetry system. DS86 doses are available for 1983 (93.4%) of the 2124 atomic bomb survivors analyzed in 1982. The DS86 kerma neutron component for Hiroshima survivors is much smaller than its comparable T65DR component, but still 4.2-fold higher (0.38 Gy at 6 Gy) than that in Nagasaki (0.09 Gy at 6 Gy). Thus, if the eye is especially sensitive to neutrons, there may yet be some useful information on their effects, particularly in Hiroshima. The dose-response relationship has been evaluated as a function of the separately estimated gamma-ray and neutron doses. Among several different dose-response models without and with two thresholds, we have selected as the best model the one with the smallest x2 or the largest log likelihood value associated with the goodness of fit. The best fit is a linear gamma-linear neutron relationship which assumes different thresholds for the two types of radiation. Both gamma and neutron regression coefficients for the best fitting model are positive and highly significant for the estimated DS86 eye organ dose.

Cataract in atomic bomb survivors based on a threshold model and the occurrence of severe epilation.

This report re-examines the relationship of radiation dose to the occurrence of cataracts among 1742 atomic bomb survivors seen in the years 1963-1964 for whom the degree of epilation and Dosimetry System 1986 (DS86) doses are known. Of these individuals, 67 had cataracts. A relative risk model with two thresholds, one for the epilation group and the other for the no-epilation group, has been fitted to the data using a binomial odds regression approach and a constant relative biological effectiveness (RBE) for neutrons of 10. Among these models, a linear-linear (L-L) dose-response relationship with two thresholds presents the best fit. Under the L-L threshold model based on DS86 eye organ dose estimates for the epilation and no-epilation groups, the slope estimate for the epilation group was 1.6-2.0 times greater than that for the no-epilation group, but no statistical difference between the two slope estimates was noted. The estimated threshold for the epilation group was 0.86 Sv and 1.54 Sv for the no-epilation group, but again the difference between the two threshold estimates is not statistically significant. When an L-L relative risk model with two thresholds was fitted to the data assuming the dose estimates to be in error by 35%, or when the data were restricted to the 1105 individuals exposed in Japanese houses at distances of less than 2500 m, where the DS86 doses are thought to be most reliable, the results were almost the same as those for the individuals for whom unadjusted DS86 eye organ dose estimates were used.

Congenital malformations, stillbirths, and early mortality among the children of atomic bomb survivors: a reanalysis.

Of all the data sets pertinent to the estimation of the genetic risks to humans following exposure to ionizing radiation, potentially the most informative is that composed of the cohort of children born to atomic bomb survivors. We present here an analysis of the relationship between parental exposure history and untoward pregnancy outcomes within this cohort, using to the fullest extent possible the recently revised estimates of the doses received by their parents, the so-called DS86 doses. Available for study are 70,073 terminations, but DS86 doses have not been or presently cannot be computed on the parents of 14,770. The frequency of untoward pregnancy outcomes, defined as a pregnancy terminating in a child with a major congenital malformation, and/or stillborn, and/or dying in the first 14 days of life, increases with combined (summed) parental dose, albeit not significantly so. Under a standard linear model, when the sample of observations is restricted to those children whose parents have been assigned the newly established DS86 doses (n = 55,303), ignoring concomitant sources of variation and assuming a neutron RBE of 20, the estimated increase per sievert in the predicted frequency of untoward outcomes is 0.00354 (+/- 0.00343). After adjustment for concomitant sources of variation, the estimated increase per sievert in the proportion of such births is 0.00422 (+/- 0.00342) if the neutron RBE is assumed to be 20. A "one-hit" model with appropriate adjustments for extraneous sources of variation results in an almost identical value, namely, 0.00412 (+/- 0.00364). When the sample is extended to include parents lacking the full array of dose parameters necessary to calculate the DS86 dose, but sufficient for an empirical conversion of the previously employed T65DR dose system to its DS86 equivalent, we find under the linear model that the estimated increase per sievert in untoward pregnancy outcomes is some 31% higher than that published previously, 0.00264 (+/- 0.00277), assuming an RBE of 20, after adjustment for extraneous sources of variation. (Since a dose could not be calculated in 367 of the 70,073 outcomes, the n = 69,706). The corresponding value with the one-hit model is 0.00262 (+/- 0.00294).

Evidence of radiation-induced reduction of height and body weight from repeated measurements of adults exposed in childhood to the atomic bombs.

Reduction of growth from exposure to atomic bomb radiation has been examined using individuals under 10 years old at the time of the bombing (ATB) and a growth curve analysis based on measurements of height and weight made in the course of the 4th-7th cycles of the Adult Health Study examinations (1964-1972). As expected, the largest difference in growth to emerge is between males and females. However, a highly significant reduction of growth associated with dose (DS86) was observed among those survivors for whom four repeated measurements of height and weight were available. Longitudinal analysis of a more extended data set (n = 821), using expected values based on simple linear regression models fitted to the three available sets of measurements of height and weight on the 254 individuals with a missing measurement, also indicates a significant radiation-related growth reduction. The possible contribution of such factors as poor nutrition and disruption of normal family life in the years immediately after the war is difficult to evaluate, but the effects of socioeconomic factors on the analysis of these data are discussed.

A longitudinal study of growth and development of stature among prenatally exposed atomic bomb survivors.

Growth retardation due to exposure to the atomic bomb has been evaluated using repeated measurements of stature from 10 to 18 years of age. A highly significant growth retardation due to the DS86 uterine dose was observed in all trimesters combined and in the first and second trimesters of pregnancy. In the first trimester, all parameter estimates based on a linear (L) or linear-quadratic (L-Q) dose-response relationship were negative in relation to the DS86 uterine dose. The positive dose estimate in the second trimester is small and close to the control level. Statistically significant difference was determined by a multivariate test statistic examining whether or not a set of two- or three-parameter estimates including a constant term related to an L or L-Q dose-response relationship was different from zero. A radiation-related growth retardation was demonstrable as a longitudinal result of the repeated measurements of stature. The dose effect in the third trimester was not significant under either the L or the L-Q model. The relationship between birth weights and repeated measurements of stature in adolescence is discussed based on the results obtained by a growth curve analysis.

Radiation-related ophthalmological changes and aging among Hiroshima and Nagasaki A-bomb survivors: a reanalysis.

The relationship of ionizing radiation to the age-related ophthalmological findings of the 1978-1980 ophthalmological examination of A-bomb survivors of Hiroshima and Nagasaki has been reanalyzed using DS86 eye organ dose estimates. The main purpose of this reevaluation was to determine whether age and radiation exposure, as measured using the recently revised dosimetry information (DS86), have an additive, synergistic, or antagonistic effect. The data in this study are limited to axial opacities and posterior subcapsular changes, for which a definite radiation-induced effect has been observed in Hiroshima and Nagasaki A-bomb survivors. The best model fitting for axial opacities gives a significant positive effect for both linear dose and linear age-related regression coefficients and a significant negative effect for an interaction between radiation dose and age. Such a negative interaction implies an antagonistic effect in that the relative risks in relation to radiation exposure doses become smaller with an increase in age. On the other hand, the best-fitting relationship for posterior subcapsular changes suggested a linear-quadratic dose and linear age-related effect. The estimate of the quadratic dose coefficient shows a highly negative correlation with age, but the negative quadratic dose term is extremely small and is of little biological significance.

Relationship between cataracts and epilation in atomic bomb survivors.

Among 1713 atomic bomb survivors who underwent ophthalmological examinations from 1963-1964, the risk of cataract formation per unit dose of radiation was significantly greater for those who reported hair loss of 67% or more after exposure (the epilation group) than for those who reported less or no hair loss (the no-epilation group) (P < 0.01). Such an epilation effect has also been associated with leukemia mortality and the frequency of chromosome aberrations. Although this might be interpreted as indicating differential sensitivity to radiation between the epilation group and the no-epilation group, it could also be explained by imprecision in dose estimates. We have calculated that a 48% random error in DS86 dose estimates could be in accordance with the dose-response relationship for the prevalence of cataracts in the epilation group or the no-epilation group. Possible mechanisms for variation in radiosensitivity are discussed.

Ophthalmologic changes related to radiation exposure and age in adult health study sample, Hiroshima and Nagasaki.

A 2-year ophthalmologic study of age and radiation-related ophthalmologic lesions among the atomic bomb survivors in Hiroshima and Nagasaki was conducted in 1978-80. The study sample in both cities was composed of all persons exposed to 100+ rad, their controls, and all other persons with a previous record of axial opacities or posterior subcapsular changes. Most of the losses were due to persons who refused to participate or for whom it was not possible to arrange for an ophthalmologic examination at the time of the regularly scheduled medical examination. It should be emphasized, however, that the loss of persons in both the control and the 100+ rad groups did not change systematically with increasing age by city. Increased lenticular opacities, other lens changes, and loss of visual acuity and accommodation occurred with increasing age in both exposed and control subjects as manifestations of the normal aging process. A highly significant excess risk for all age categories in the 300+ rad group in comparison to those in the control group was observed for both axial opacities and posterior subcapsular changes in Hiroshima, but not in Nagasaki. A stronger radiosensitive aging effect for persons who were under 15 years old at the time of the bombing (ATB) was observed for both axial opacities and posterior subcapsular changes in Hiroshima.

Radiation-related brain damage and growth retardation among the prenatally exposed atomic bomb survivors.

Many studies of prenatally exposed survivors of the atomic bombings of Hiroshima and Nagasaki have shown that exposure to ionizing radiation during gestation has harmful effects on the developing human brain. Data on the occurrence of severe mental retardation as well as variation in intelligence quotient (IQ) and school performance show significant effects on those survivors exposed 8-15 and 16-25 weeks after ovulation. Studies of seizures, especially those without a known precipitating cause, also exhibit a radiation effect in survivors exposed 8-15 weeks after ovulation. The biologic events that subtend these abnormalities are still unclear. However, magnetic resonance imaging of the brains of some mentally retarded survivors has revealed a large region of abnormally situated gray matter, suggesting an abnormality in neuronal migration. Radiation can induce small head size as well as mental retardation, and a review of the relationship between small head size and anthropometric measurements, such as height, weight, sitting height and chest circumference, shows that individuals with small head size have smaller anthropometric measurements than normocephalics. This suggests that radiation-related small head size is related to a generalized growth retardation. Finally, the issue of a threshold in the occurrence of one or more of these effects, both heuristically and from a regulatory perspective, remains uncertain. Simple inspection of the data often suggests that a threshold may exist, but little statistical support for this impression can be advanced, except in the instance of mental retardation.

Radiation-related small head sizes among prenatally exposed A-bomb survivors.

Of 1566 individuals prenatally exposed to the atomic bombings of Hiroshima and Nagasaki, 1473 had the circumference of their head measured at least once between ages 9 and 19. Among these 1473 individuals, 62 had small heads--the circumference of the heads was two standard deviations or more below the observed specific-age-at measurement mean. Of 26 cases with severe mental retardation, 15 (58%) had small heads. Most (86%) of the individuals with small heads were exposed in the first trimester (about < 12 weeks postovulation) or second trimester (about 12-24 weeks postovulation)--55% in the former period and 31% in the latter. Various dose-response relationships, with and without a threshold, have been fitted to the data grouped by the trimester or postovulatory age (weeks after ovulation) at which exposure occurred. A significant effect of radiation on the frequency of individuals with atypically small heads is observed only in the first and second trimesters and for the intervals postovulation of 0-7 weeks and 8-15 weeks. Although the risk of a small head at 0-7 weeks postovulation increases significantly with increasing dose, no increase in risk for severe mental retardation is noted in this period. No excess risk of a small head was seen in the third trimester (about > or = 25 weeks postovulation) or among individuals exposed at 16 weeks or more postovulation. The mean IQ values of mentally retarded cases with and without small heads were 63.8 and 68.9, respectively. No significant difference exists between these two IQ means, but both were significantly smaller than 96.4, the IQ value for individuals with small heads without severe mental retardation and 107.8, the value for the overall sample.

Threshold for radiation-related severe mental retardation in prenatally exposed A-bomb survivors: a re-analysis.

Significant effects on the developing human brain of exposure to ionizing radiation are seen among individuals exposed in the 8th-25th week after ovulation. These effects, particularly in the highly vulnerable period of 8-15 weeks after ovulation, manifest themselves most dramatically as an increased frequency of severe mental retardation. However, the distribution of cases of severe mental retardation suggests a threshold in the low-dose region. The 95% lower bound of the threshold in those survivors exposed 8-15 weeks after ovulation was zero for the individual data based on the simple linear model, and 0.15 Gy based on the exponential linear model used in our previous report (1987), but the 95% lower bound of the threshold based on all of the data including 21 additional cases with known doses appears to be 0.05 Gy using the maximum likelihood estimates derived from an exponential-linear model. The latter model was selected because it provides the best fit from the standpoint of the stableness and reasonableness of the estimates among the five models applied to the data. When two probably non-radiation-related cases of Down's syndrome are excluded from the 19 mentally retarded cases exposed 8-15 weeks post ovulation, the 95% lower bound of the threshold is in the range of 0.15-0.25 Gy based on the exponential-linear model used in 1987, but is in the range of 0.06-0.31 Gy when the more reasonable and better model applied here is used. For exposure in the 16-25-week period based on the same model, the 95% lower bound of the threshold changed from 0.25 to 0.28 Gy, both with and without inclusion of the two probable non-radiation-related mentally retarded cases; one of these cases was probably familial in origin since there was a retarded sibling, and the other due to infection, since the individual had Japanese B encephalitis at age 4 years.

Changes in the pattern of growth in stature related to prenatal exposure to ionizing radiation.

PURPOSE: To examine the pattern and spurt in growth and development of prenatally exposed atomic-bomb survivors and to determine whether a statistically significant radiation-related growth retardation exists. MATERIALS AND METHODS: The stature of 1566 individuals exposed prenatally to the atomic bombings has been employed to study the effect of such exposure on growth. Among these survivors, 30 were severely mentally retarded, and 66 individuals on whom no physical measurements between ages 9 and 19 exist were excluded from this study. Thus this analysis rests on the measurements obtained on 1470 survivors 9 to 19 years of age at the time of examination. RESULTS: When the > or =0.50 Sv group was compared to the other two prenatally exposed groups, a significant retardation of growth was observed only among those survivors exposed in the first trimester of gestation. The onset of the growth spurt among males in the three exposure groups was at approximately the same age, 11.34 years, but this was not true in females. The maximum velocity in growth for males was at 14.38 years of age, but for females no clear peak velocity was demonstrable. CONCLUSION: A radiation-related growth retardation was demonstrable in this longitudinal study of the stature of individuals prenatally exposed. It is further demonstrated that among these survivors the growth velocity was faster in the high-dose group than in the low-dose group for both males and females.

Further observations on abnormal brain development caused by prenatal A-bomb exposure to ionizing radiation.

The pervasiveness of abnormal brain development caused by prenatal exposure to ionizing radiation is still largely unknown. The relationship between A-bomb radiation dose and two measures of neuromuscular performance, one of grip strength and the other of the fine motor coordination required in repetitive action, is described. A multivariate analysis of covariance was used to evaluate the effect of several covariates, such as prenatal radiation exposure and some physical measurements or IQ adding city and sex as categorical factors. When mentally retarded cases were included, a statistically significant effect of radiation exposure on the grip strength and repetitive-action test scores was seen in the 8-15-week postovulation period, and a statistically suggestive effect at 16-25 weeks postovulation. No effect of radiation exposure on the two test scores was noted for prenatal exposure in either of the aforementioned periods when mentally retarded cases were excluded, but a statistically significant diminution of IQ was noted for exposures > or = 16 weeks postovulation. We discuss, from the biological perspective, the projected standard scores for exposures > or = 16 weeks postovulation, and the possibility of lower IQ, small head and mild mental retardation related to radiation exposures < or = 15 weeks postovulation with mentally retarded cases excluded.

Increased somatic cell mutant frequency in atomic bomb survivors.

Frequencies of mutant T-cells in peripheral blood, which are deficient in hypoxanthine guanine phosphoribosyltransferase (HPRT) activity, were determined for atomic bomb survivors by direct clonal assay using a previously reported method (Hakoda et al., 1987). Results from 30 exposed survivors (more than 1 rad exposed) and 17 age- and sex-matched controls (less than 1 rad exposed) were analyzed. The mean mutant frequency (Mf) in the exposed (5.2 X 10(-6); range 0.8-14.4 X 10(-6)) was significantly higher than in controls (3.4 X 10(-6); range 1.3-9.3 X 10(-6)), which was not attributable to a difference in non-mutant cell-cloning efficiencies between the 2 groups, which were virtually identical. An initial analysis of the data did not reveal a significant correlation between individual Mfs and individual radiation dose estimates when the latter were defined by the original, tentative estimates (T65D), even though there was a significant positive correlation of Mfs with individual frequency of lymphocytes bearing chromosome aberrations. However, reanalysis using the newer revised individual dose estimates (DS86) for 27 exposed survivors and 17 controls did reveal a significant but shallow positive correlation between T-cell Mf values and individual exposure doses. These results indicate that HPRT mutation in vivo in human T-cells could be detected in these survivors 40 years after the presumed mutational event.