Acute radiation-induced symptoms reported in survivors after the atomic bombings in Hiroshima and Nagasaki have been suspected to be associated with rain that fell after the explosions, but this association has not been evaluated in an epidemiological study that considers the effects of the direct dose from the atomic bombs and other factors. The aim of this study was to evaluate this association using information from a fixed cohort, comprised of 93,741 members of the Life Span Study who were in the city at the time of the bombing. Information on acute symptoms and exposure to rain was collected in surveys conducted by interviewers, primarily in the 1950s. The proportion of survivors developing severe epilation was around 60% at levels of direct radiation doses of 3 Gy or higher and less than 0.2% at levels <0.005 Gy regardless of reported rain exposure status. The low prevalence of acute symptoms at low direct doses indicates that the reported fallout rain was not homogeneously radioactive at a level sufficient to cause a substantial probability of acute symptoms. We observed that the proportion of reported acute symptoms was slightly higher among those who reported rain exposure in some subgroups, however, suggestions that rain was the cause of these reported symptoms are not supported by analyses specific to the known areas of radioactive fallout. Misclassification of exposure and outcome, including symptoms due to other causes and recall bias, appears to be a more plausible explanation. However, the insufficient and retrospective nature of the available data limited our ability to quantify the attribution to those possible causes.

Fujiwara, S., Suyama, A., Cologne, J. B., Akahoshi, M., Yamada, Y., Suzuki, G., Koyama, K., Takahashi, N., Kasagi, F., Grant, E. J., Lagarde, F., Hsu, W. L., Furukawa, K., Ohishi, W., Tatsukawa, Y. , Neriishi, K., Takahashi, I., Ashizawa, K., Hida, A., Imaizumi, M., Nagano, J., Cullings, H. M., Katayama, H., Ross, N. P., Kodama, K. and Shore, R. E. Prevalence of Adult-Onset Multifactorial Disease among Offspring of Atomic Bomb Survivors. Radiat. Res. 170, 451–457 (2008). The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81–1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86–1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure.

Heidenreich, W. F., Cullings, H. M., Funamoto, S. and Paretzke, H. G. Promoting Action of Radiation in the Atomic Bomb Survivor Carcinogenesis Data? Radiat. Res. 168, 750– 756 (2007). The age–time patterns of risk in the atomic bomb survivor data on incidence of solid cancers suggest an action of low-LET radiation not only on the initiating event but also on promotion in a biologically motivated model that allows for both actions. The favored model indicates a decrease of radiation risks with age at exposure due to the initiating effect and with time since exposure due to the promoting effect. These result in a relative risk that depends mostly on attained age for ages at exposure above 20 years. According to the model, a dose of 100 mGy is inducing about the same number of initiating events that occur spontaneously in 1 year. Assuming that several mutations are needed to obtain intermediate cells with growth advantage does not improve the quality of fit. The estimated promoting effect could be explained if the number of intermediate cells increases by 80% at 1 Gy, e.g. due to stimulated cell repopulation.

Noda, A., Kodama, Y., Cullings, H. M. and Nakamura, N. Radiation-Induced Genomic Instability in Tandem Repeat Sequences is not Predictive of Unique Sequence Instability. Radiat. Res. 167, 526–534 (2007). Tandem repeat sequences, classified as minisatellite sequences or partially duplicated genes, are inherently unstable. Radiation exposure can increase the instability of such repeat sequences, but the biological consequences of this elevated instability are not well characterized. To learn more about the characteristics of the instability at different sequences in the genome, we created mutant HT1080 cells bearing 8.4 kb of partially duplicated allele at the HPRT locus by gene targeting. The cells were then tested to determine whether repeat-sequence instability (assessed by elevated reversion rate caused by loss of one duplicated segment) accompanied increased forward mutation rates at the restored wild-type HPRT allele. After a 4-Gy X irradiation, 32 clones were selected (out of 500 clones, 6%) that showed elevated reversion rates even after many cell generations. These clones also showed general increases in the forward mutation rate, whereas the paired individual mutation rates did not correlate with each other. Furthermore, levels of intracellular reactive oxygen species (ROS) and nuclear γ-H2AX foci, which are hallmarks for DNA damage responses, were also generally elevated, although the levels did not correlate with the individual reversion rates. It was concluded that repeat sequence instability is not predictive of unique sequence instability, probably because the instability is generated by multiple mechanisms after radiation exposure.

Nakamura, N., Cullings, H. M., Kodama, Y., Wada, T., Miyazawa, C., Lee, K. and Awa, A. A. A Method to Differentiate between the Levels of ESR Signals Induced by Sunlight and by Ionizing Radiation in Teeth from Atomic Bomb Survivors. Radiat. Res. 165, 359–364 (2006). Electron spin resonance (ESR, or electron paramagnetic resonance, EPR) analysis of tooth enamel is an effective method for the retrospective estimation of individual radiation doses. One problem with this technique is that the observed ESR signal may include a contribution from ultraviolet (UV) light exposure from sunlight, especially in front teeth. Thus there has been a need to find ways to estimate the UV-light effect in the total signal so that the net ESR dose from ionizing radiation can be determined. To examine this issue, we measured 96 teeth of various types, but with buccal and lingual parts measured separately, from a control group of atomic bomb survivors (estimated dose <5 mGy). We found that, except for molars, the mean ESR-estimated dose for the buccal halves was, on average, nearly twice that from the lingual side, which indicates that the UV-light-induced lingual dose equals the difference between the two halves. Using these corrections for UV-light exposure to front teeth that had been exposed to both ionizing radiation and UV light, it was found that the estimated radiation doses closely approximated the previously estimated ESR dose to molars from the same donors or the estimated dose arrived at with cytogenetic methods. We concluded that, when using ESR to estimate radiation dose, measuring molars is the first choice, but if only front teeth are available, separate measurements to the buccal and lingual parts can provide an estimation of the mean UV-light contribution to the ESR-determined dose.