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.

Fetal and Maternal Atomic Bomb Survivor Dosimetry Using the J45 Pregnant Female Phantom Series: Considerations of the Kneeling and Lying Posture with Comparisons to the DS02 System.

ABSTRACT: Organ dosimetry data of the atomic bomb survivors and the resulting cancer risk models derived from these data are currently assessed within the DS02 dosimetry system developed through the Joint US-Japan Dosimetry Working Group. In DS02, the anatomical survivor models are limited to three hermaphroditic stylized phantoms-an adult (55 kg), a child (19.8 kg), and an infant (9.7 kg)-that were originally designed for the preceding DS86 dosimetry system. As such, organ doses needed for assessment of in-utero cancer risks to the fetus have continued to rely upon the use of the uterine wall in the adult non-pregnant stylized phantom as the dose surrogate for all fetal organs regardless of gestational age. To address these limitations, the Radiation Effects Research Foundation (RERF) Working Group on Organ Dose (WGOD) has established the J45 (Japan 1945) series of high-resolution voxel phantoms, which were derived from the UF/NCI series of hybrid phantoms and scaled to match mid-1940s Japanese body morphometries. The series includes male and female phantoms-newborn to adult-and four pregnant female phantoms at gestational ages of 8, 15, 25, and 38 wk post-conception. In previous studies, we have reported organ dose differences between those reported by the DS02 system and those computed by the WGOD using 3D Monte Carlo radiation transport simulations of atomic bomb gamma-ray and neutron fields for the J45 phantoms series in their traditional "standing" posture, with some variations in their facing direction relative to the bomb hypocenter. In this present study, we present the J45 pregnant female phantoms in both a "kneeling" and "lying" posture and assess the dosimetric impact of these more anatomically realistic survivor models in comparison to current organ doses given by the DS02 system. For the kneeling phantoms facing the bomb hypocenter, organ doses from bomb source photon spectra were shown to be overestimated by the DS02 system by up to a factor of 1.45 for certain fetal organs and up to a factor of 1.17 for maternal organs. For lying phantoms with their feet in the direction of the hypocenter, fetal organ doses from bomb source photon spectra were underestimated by the DS02 system by factors as low as 0.77, while maternal organ doses were overestimated by up to a factor of 1.38. Organs doses from neutron contributions to the radiation fields exhibited an increasing overestimation by the DS02 stylized phantoms as gestational age increased. These discrepancies are most evident in fetal organs that are more posterior within the mother's womb, such as the fetal brain. Further analysis revealed that comparison of these postures to the original standing posture indicate significant dose differences for both maternal and fetal organ doses depending on the type of irradiation. Results from this study highlight the degree to which the existing DS02 system can differ from organ dosimetry based upon 3D radiation transport simulations using more anatomically realistic models of those survivors exposed during pregnancy.

Japanese pediatric and adult atomic bomb survivor dosimetry: potential improvements using the J45 phantom series and modern Monte Carlo transport.

The radiation exposure estimates for the atomic bomb survivors at Hiroshima and Nagasaki have evolved over the past several decades, reflecting a constant strive by the Radiation Effects Research Foundation (RERF) to provide thorough dosimetry to their cohort. Recently, a working group has introduced a new series of anatomical models, called the J45 phantom series, which improves upon those currently used at RERF through greater age resolution, sex distinction, anatomical realism, and organ dose availability. To evaluate the potential dosimetry improvements that would arise from their use in an RERF Dosimetry System, organ doses in the J45 series are evaluated here using environmental fluence data for 20 generalized survivor scenarios pulled directly from the current dosimetry system. The energy- and angle-dependent gamma and neutron fluences were converted to a source term for use in MCNP6, a modern Monte Carlo radiation transport code. Overall, the updated phantom series would be expected to provide dose improvements to several important organs, including the active marrow, colon, and stomach wall (up to 20, 20, and 15% impact on total dose, respectively). The impacts were especially significant for neutron dose estimates (up to a two-fold difference) and within organs which were unavailable in the previous phantom series. These impacts were consistent across the 20 scenarios and are potentially even greater when biological effectiveness of the neutron dose component is considered. The entirety of the dosimetry results for all organs are available as supplementary data, providing confident justification for potential future DS workflows utilizing the J45 phantom series.

Congenital Malformations and Perinatal Deaths Among the Children of Atomic Bomb Survivors: A Reappraisal.

From 1948 to 1954, the Atomic Bomb Casualty Commission conducted a study of pregnancy outcomes among births to atomic bomb survivors (Hiroshima and Nagasaki, Japan) who had received radiation doses ranging from 0 Gy to near-lethal levels. Past reports (1956, 1981, and 1990) on the cohort did not identify significant associations of radiation exposure with untoward pregnancy outcomes, such as major congenital malformations, stillbirths, or neonatal deaths, individually or in aggregate. We reexamined the risk of major congenital malformations and perinatal deaths in the children of atomic bomb survivors (n = 71,603) using fully reconstructed data to minimize the potential for bias, using refined estimates of the gonadal dose from Dosimetry System 2002 and refined analytical methods for characterizing dose-response relationships. The analyses showed that parental exposure to radiation was associated with increased risk of major congenital malformations and perinatal death, but the estimates were imprecise for direct radiation effects, and most were not statistically significant. Nonetheless, the uniformly positive estimates for untoward pregnancy outcomes among children of both maternal and paternal survivors are useful for risk assessment purposes, although extending them to populations other than the atomic bomb survivors comes with uncertainty as to generalizability.

Dosimetric Impact of a New Computational Voxel Phantom Series for the Japanese Atomic Bomb Survivors: Methodological Improvements and Organ Dose Response Functions.

Owing to recent advances in computational dosimetry tools, an update is warranted for the dosimetry system for atomic bomb survivors that was established by the Joint U.S.Japan Working Group on the Reassessment of Atomic Bomb Dosimetry in 2002 (DS02). The DS02 system, and its predecessor, DS86, at the Radiation Effects Research Foundation (RERF), are based on adjoint Monte Carlo particle transport simulations coupled with stylized computational human phantoms. In our previous studies, we developed the J45 series of computational voxel phantoms representative of 1945 Japanese adults, children and pregnant females. The dosimetric impact of replacing the DS02/DS86 stylized phantoms by the J45 phantom series was also discussed through computation of organ doses for several idealized exposure scenarios. In the current study, we investigated the possible impact of introducing not only the J45 phantom series but also various methodological upgrades to the DS02 dosimetry system. For this purpose, we calculated organ doses in adults for 12 representative exposure scenarios having realistic particle energy and angular fluence, using different combinations of phantoms and dose calculation methods. Those doses were compared with survivor organ doses given by the DS02 system. It was found that the anatomical improvement in the J45 phantom series is the most important factor leading to potential changes in survivor organ doses. However, methodological upgrades, such as replacement of the adjoint Monte Carlo simulation with kerma approximation by the forward Monte Carlo simulation with secondary electron transport, can also improve the accuracy of organ doses by up to several percent.In addition, this study established a series of response functions, which allows for the rapid conversion of the unidirectional quasi-monoenergetic photon and neutron fluences from the existing DS02 system to organ doses within the J45 adult phantoms. The overall impact of introducing the response functions in the dosimetry system is not so significant, less than 10% in most cases, except for organs in which the calculation method or definition was changed, e.g., colon and bone marrow. This system of response functions can be implemented within a revision to the DS02 dosimetry system and used for future updates to organ doses within the Life Span Study of the atomic bomb survivors.

Dosimetric Impact of a New Computational Voxel Phantom Series for the Japanese Atomic Bomb Survivors: Pregnant Females.

An important cohort of the atomic bomb survivors are women who were pregnant when exposed to the photon and neutron fields at both Hiroshima and Nagasaki, as well as their children who were exposed in utero. Estimates of organ dose to the developing fetus allow for the development of dose-dependent and gestational age-dependent models of deterministic (e.g., organ malformation) and stochastic (e.g., leukemia) risk of in utero exposure. To date, both the 1986 and 2002 dosimetry systems at the Radiation Effects Research Foundation have utilized the uterine wall in the non-pregnant adult female as a dose surrogate for individual fetal organs and tissues. Here we present a new J45 (Japanese 1945) series of high-resolution phantoms of the adult pregnant female at 8-, 15-, 25- and 38-weeks post-conception. These models, which were derived from the University of Florida (UF) series of ICRP Publication 89 compliant reference phantoms, have been rescaled to approximate the pregnant mother using 1945 Japanese morphometry data. Fetal and maternal organ doses were estimated by computationally exposing the pregnant female phantom series to DS02 free-in-air photon and neutron fluences at three distances from the hypocenter at both Hiroshima and Nagasaki under frontal (AP) and isotropic (ISO) particle incidence. As for the fetal organ doses, our results indicate that the uterine wall of the non-pregnant female generally underestimates fetal organ dose within the pregnant female. The magnitude of these differences varies with both radiation type and irradiation geometry, with the smallest differences (5-7%) seen for ISO photon fields and the largest differences (20-30%) seen for AP neutron fields. Significant discrepancies were seen in fetal brain dose and its uterine wall surrogate, particularly for photon AP fields (ratio of uterine wall to brain dose varied from 0.9 to 1.3) and neutron AP fields (dose ratios from 0.75 to 2.0). As for the maternal organ doses, the use of organ doses in a non-pregnant female was shown, in general, to overestimate the corresponding organ doses in the pregnant female, with greater deviations seen at later stages of pregnancy (12-16% for AP photons and 44-53% for AP neutrons). The one exception was the uterine wall dose in pregnancy which was seen to be underestimated by that in the non-pregnant female phantom, particularly for ISO and AP neutron fields. These results demonstrate that the J45 pregnant female phantom series offers the opportunity for significant improvements in both fetal and maternal organ dose assessment within this unique cohort of the atomic bomb survivors.

Dosimetric Impact of a New Computational Voxel Phantom Series for the Japanese Atomic Bomb Survivors: Children and Adults.

One of the largest sources of data on radiation exposure in humans is the study of the atomic bomb survivors at Hiroshima and Nagasaki, Japan performed by the Radiation Effects Research Foundation (RERF). As part of their retrospective dosimetry efforts for the atomic bomb survivors, RERF published two core systems: Dosimetry System 1986 (DS86) and Dosimetry System 2002 (DS02). Due to computing limitations at the time, only three stylized phantoms (an infant, child and adult) were used in DS86 and DS02 to represent the entire Japanese population. In this study, we sought to evaluate the dosimetric differences that should be expected from using an updated and age-expanded phantom series with the survivor cohort. To this end, we developed a new series of hybrid phantoms, based on the Japanese population of 1945, which has greater anatomical realism and improved age resolution over those used by RERF. These phantoms were converted to voxel format and compared to their older counterparts through the calculation of organ dose coefficients using DS02 free-in-air particle fluences at three distances from the bomb hypocenter. From the photon portion of the spectra, organ dose differences of up to nearly 25% are expected between the old and new series, while organ dose differences of up to nearly 70% are expected from the neutron portion. We also compared organ dose coefficients among themselves to determine the accuracy in the use of one organ dose as the epidemiological surrogate to another. Certain organ-surrogate pairs were shown to be inappropriate, such as the use of colon dose for breast risk analyses. Overall, our new series of phantoms provides significant improvements to survivor organ dosimetry, especially to those survivors who were previously misrepresented in body size by their stylized phantom and to those who experienced a highly-directional irradiation field.

Population Density in Hiroshima and Nagasaki Before the Bombings in 1945: Its Measurement and Impact on Radiation Risk Estimates in the Life Span Study of Atomic Bomb Survivors.

In the Life Span Study cohort of atomic bomb survivors, differences in urbanicity between high-dose and low-dose survivors could confound the association between radiation dose and adverse outcomes. We obtained data on the population distribution in Hiroshima and Nagasaki before the 1945 bombings and quantified the impact of adjustment for population density on radiation risk estimates for mortality (1950-2003) and incident solid cancer (1958-2009). Population density ranged from 4,671 to 14,378 people/km2 in the urban region of Hiroshima and 5,748 to 19,149 people/km2 in the urban region of Nagasaki. Radiation risk estimates for solid cancer mortality were attenuated by 5.1% after adjustment for population density, but those for all-cause mortality and incident solid cancer were unchanged. There was no overall association between population density and adverse outcomes, but there was evidence that the association between density and mortality differed according to age at exposure. Among survivors who were 10-14 years of age in 1945, there was a positive association between population density and risk of all-cause mortality (per 5,000-people/km2 increase, relative risk = 1.053, 95% confidence interval: 1.027, 1.079) and solid cancer mortality (per 5,000-people/km2 increase, relative risk = 1.069, 95% confidence interval: 1.025, 1.115). Our results suggest that radiation risk estimates from the Life Span Study are not sensitive to unmeasured confounding by urban-rural differences.

The incidence of leukemia, lymphoma and multiple myeloma among atomic bomb survivors: 1950-2001.

A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This article presents analyses of radiation effects on leukemia, lymphoma and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose-response relationship and, to the extent the data allowed, to investigate variation in the excess risks with gender, attained age, exposure age and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a nonlinear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this nonlinearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence that the radiation-associated excess leukemia risks, especially for acute myeloid leukemia, had persisted throughout the follow-up period out to 55 years after the bombings. As in earlier analyses, there was a weak suggestion of a radiation dose response for non-Hodgkin lymphoma among men, with no indication of such an effect among women. There was no evidence of radiation-associated excess risks for either Hodgkin lymphoma or multiple myeloma.

Ionizing radiation exposure and the development of soft-tissue sarcomas in atomic-bomb survivors.

BACKGROUND: Very high levels of ionizing radiation exposure have been associated with the development of soft-tissue sarcoma. The effects of lower levels of ionizing radiation on sarcoma development are unknown. This study addressed the role of low to moderately high levels of ionizing radiation exposure in the development of soft-tissue sarcoma. METHODS: Based on the Life Span Study cohort of Japanese atomic-bomb survivors, 80,180 individuals were prospectively assessed for the development of primary soft-tissue sarcoma. Colon dose in gray (Gy), the excess relative risk, and the excess absolute rate per Gy absorbed ionizing radiation dose were assessed. Subject demographic, age-specific, and survival parameters were evaluated. RESULTS: One hundred and four soft-tissue sarcomas were identified (mean colon dose = 0.18 Gy), associated with a 39% five-year survival rate. Mean ages at the time of the bombings and sarcoma diagnosis were 26.8 and 63.6 years, respectively. A linear dose-response model with an excess relative risk of 1.01 per Gy (95% confidence interval [CI]: 0.13 to 2.46; p = 0.019) and an excess absolute risk per Gy of 4.3 per 100,000 persons per year (95% CI: 1.1 to 8.9; p = 0.001) were noted in the development of soft-tissue sarcoma. CONCLUSIONS: This is one of the largest and longest studies (fifty-six years from the time of exposure to the time of follow-up) to assess ionizing radiation effects on the development of soft-tissue sarcoma. This is the first study to suggest that lower levels of ionizing radiation may be associated with the development of soft-tissue sarcoma, with exposure of 1 Gy doubling the risk of soft-tissue sarcoma development (linear dose-response). The five-year survival rate of patients with soft-tissue sarcoma in this population was much lower than that reported elsewhere.

Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure.

Thyroid cancer risk following exposure to ionizing radiation in childhood and adolescence is a topic of public concern. To characterize the long-term temporal trend and age-at-exposure variation in the radiation-induced risk of thyroid cancer, we analyzed thyroid cancer incidence data for the period from 1958 through 2005 among 105,401 members of the Life Span Study cohort of Japanese atomic-bomb survivors. During the follow-up period, 371 thyroid cancer cases (excluding those with microcarcinoma with a diameter <10 mm) were identified as a first primary among the eligible subjects. Using a linear dose-response model, the excess relative risk of thyroid cancer at 1 Gy of radiation exposure was estimated as 1.28 (95% confidence interval: 0.59-2.70) at age 60 after acute exposure at age 10. The risk decreased sharply with increasing age-at-exposure and there was little evidence of increased thyroid cancer rates for those exposed after age 20. About 36% of the thyroid cancer cases among those exposed before age 20 were estimated to be attributable to radiation exposure. While the magnitude of the excess risk has decreased with increasing attained age or time since exposure, the excess thyroid cancer risk associated with childhood exposure has persisted for >50 years after exposure.

Radiation and smoking effects on lung cancer incidence by histological types among atomic bomb survivors.

While the risk of lung cancer associated separately with smoking and radiation exposure has been widely reported, it is not clear how smoking and radiation together contribute to the risk of specific lung cancer histological types. With individual smoking histories and radiation dose estimates, we characterized the joint effects of radiation and smoking on type-specific lung cancer rates among the Life Span Study cohort of Japanese atomic bomb survivors. Among 105,404 cohort subjects followed between 1958 and 1999, 1,803 first primary lung cancer incident cases were diagnosed and classified by histological type. Poisson regression methods were used to estimate excess relative risks under several interaction models. Adenocarcinoma (636 cases), squamous-cell carcinoma (330) and small-cell carcinoma (194) made up 90% of the cases with known histology. Both smoking and radiation exposure significantly increased the risk of each major lung cancer histological type. Smoking-associated excess relative risks were significantly larger for small-cell and squamous-cell carcinomas than for adenocarcinoma. The gender-averaged excess relative risks per 1 Gy of radiation (for never-smokers at age 70 after radiation exposure at age 30) were estimated as 1.49 (95% confidence interval 0.1-4.6) for small-cell carcinoma, 0.75 (0.3-1.3) for adenocarcinoma, and 0.27 (0-1.5) for squamous-cell carcinoma. Under a model allowing radiation effects to vary with levels of smoking, the nature of the joint effect of smoking and radiation showed a similar pattern for different histological types in which the radiation-associated excess relative risk tended to be larger for moderate smokers than for heavy smokers. However, in contrast to analyses of all lung cancers as a group, such complicated interactions did not describe the data significantly better than either simple additive or multiplicative interaction models for any of the type-specific analyses.

Radiation dose and cataract surgery incidence in atomic bomb survivors, 1986-2005.

PURPOSE: To examine the incidence of clinically important cataracts in relation to lens radiation doses between 0 and approximately 3 Gy to address risks at relatively low brief doses. MATERIALS AND METHODS: Informed consent was obtained, and human subjects procedures were approved by the ethical committee at the Radiation Effects Research Foundation. Cataract surgery incidence was documented for 6066 atomic bomb survivors during 1986-2005. Sixteen risk factors for cataract, such as smoking, hypertension, and corticosteroid use, were not confounders of the radiation effect on the basis of Cox regression analysis. Radiation dose-response analyses were performed for cataract surgery incidence by using Poisson regression analysis, adjusting for demographic variables and diabetes mellitus, and results were expressed as the excess relative risk (ERR) and the excess absolute risk (EAR) (ie, measures of how much radiation multiplies [ERR] or adds to [EAR] the risk in the unexposed group). RESULTS: Of 6066 atomic bomb survivors, 1028 underwent a first cataract surgery during 1986-2005. The estimated threshold dose was 0.50 Gy (95% confidence interval [CI]: 0.10 Gy, 0.95 Gy) for the ERR model and 0.45 Gy (95% CI: 0.10 Gy, 1.05 Gy) for the EAR model. A linear-quadratic test for upward curvature did not show a significant quadratic effect for either the ERR or EAR model. The linear ERR model for a 70-year-old individual, exposed at age 20 years, showed a 0.32 (95% CI: 0.09, 0.53) [corrected] excess risk at 1 Gy. The ERR was highest for those who were young at exposure. CONCLUSION: These data indicate a radiation effect for vision-impairing cataracts at doses less than 1 Gy. The evidence suggests that dose standards for protection of the eye from brief radiation exposures should be 0.5 Gy or less.

Protecting privacy of shared epidemiologic data without compromising analysis potential.

OBJECTIVE: Ensuring privacy of research subjects when epidemiologic data are shared with outside collaborators involves masking (modifying) the data, but overmasking can compromise utility (analysis potential). Methods of statistical disclosure control for protecting privacy may be impractical for individual researchers involved in small-scale collaborations. METHODS: We investigated a simple approach based on measures of disclosure risk and analytical utility that are straightforward for epidemiologic researchers to derive. The method is illustrated using data from the Japanese Atomic-bomb Survivor population. RESULTS: Masking by modest rounding did not adequately enhance security but rounding to remove several digits of relative accuracy effectively reduced the risk of identification without substantially reducing utility. Grouping or adding random noise led to noticeable bias. CONCLUSIONS: When sharing epidemiologic data, it is recommended that masking be performed using rounding. Specific treatment should be determined separately in individual situations after consideration of the disclosure risks and analysis needs.

Exposure to ionizing radiation and development of bone sarcoma: new insights based on atomic-bomb survivors of Hiroshima and Nagasaki.

BACKGROUND: Radiation-induced bone sarcoma has been associated with high doses of ionizing radiation from therapeutic or occupation-related exposures. However, the development of bone sarcoma following exposure to lower doses of ionizing radiation remains speculative. METHODS: A cohort analysis based on the Life Span Study (n = 120,321) was performed to assess the development of bone sarcoma in atomic-bomb survivors of Hiroshima and Nagasaki followed from 1958 to 2001. The excess relative risk per gray of ionizing radiation absorbed by the bone marrow was estimated. Additional subject demographic, survival, and clinical factors were evaluated. RESULTS: Nineteen cases of bone sarcoma (in eleven males and eight females) were identified among the 80,181 subjects who met the inclusion criteria, corresponding to an incidence of 0.9 per 100,000 person-years. The mean ages at the time of the bombing and at diagnosis were 32.4 and 61.6 years, respectively. The mean bone marrow dose was 0.43 Gy. Osteosarcoma was the most commonly identified bone sarcoma. The most common bone sarcoma site was the pelvis. The overall unadjusted five-year survival rate was 25%. A dose threshold was found at 0.85 Gy (95% confidence interval, 0.12 to 1.85 Gy), with a linear dose-response association above this threshold. The linear slope equaled an excess relative risk of 7.5 per Gy (95% confidence interval, 1.34 to 23.14 per Gy) in excess of 0.85 Gy. CONCLUSIONS: On the basis of what we believe is one of the longest and largest prospective studies assessing the development of bone sarcoma in individuals exposed to ionizing radiation, it appears that the development of radiation-induced bone sarcoma may be associated with exposure to much lower doses of ionizing radiation than have previously been reported. Such new insights may potentially improve bone sarcoma prevention measures and broaden our understanding of the role of ionizing radiation from various sources on the development of malignant tumors. This study stresses the need to become increasingly aware of the various health risks that may be attributable to even low levels of ionizing radiation exposure. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions to Authors for a complete description of levels of evidence.

Biomarkers of radiosensitivity in a-bomb survivors pregnant at the time of bombings in hiroshima and nagasaki.

Purpose. There is evidence in the literature of increased maternal radiosensitivity during pregnancy. Materials and Methods. We tested this hypothesis using information from the atomic-bomb survivor cohort, that is, the Adult Health Study database at the Radiation Effects Research Foundation, which contains data from a cohort of women who were pregnant at the time of the bombings of Hiroshima and Nagasaki. Previous evaluation has demonstrated long-term radiation dose-response effects. Results/Conclusions. Data on approximately 250 women were available to assess dose-response rates for serum cholesterol, white blood cell count, erythrocyte sedimentation rate, and serum hemoglobin, and on approximately 85 women for stable chromosome aberrations, glycophorin A locus mutations, and naïve CD4 T-cell counts. Although there is no statistically significant evidence of increased radiosensitivity in pregnant women, the increased slope of the linear trend line in the third trimester with respect to stable chromosome aberrations is suggestive of an increased radiosensitivity.

Radiation and smoking effects on lung cancer incidence among atomic bomb survivors.

While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958-1999. Individual smoking history information and the latest radiation dose estimates were used to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers, lung cancer risks increased with the amount and duration of smoking and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31-1.00) for nonsmokers with a female : male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity and is best described by the generalized interaction model rather than a simple additive or multiplicative model.

Papillary microcarcinoma of the thyroid among atomic bomb survivors: tumor characteristics and radiation risk.

BACKGROUND: : Radiation exposure is an established cause of clinical thyroid cancer, but little is known about radiation effects on papillary microcarcinoma (PMC) of the thyroid, a relatively common subclinical thyroid malignancy. Because the incidence of these small thyroid cancers has been increasing, it is important to better understand them and their relation to radiation. METHODS: : PMCs were identified in a subset of 7659 members of the Life Span Study of atomic bomb survivors who had archived autopsy or surgical materials. We conducted a pathology review of these specimens and evaluated the histological features of the tumors and the association between PMCs and thyroid radiation dose. RESULTS: : From 1958 to 1995, 458 PMCs were detected among 313 study subjects. The majority of cancers exhibited pathologic features of papillary thyroid cancers. Overall, 81% of the PMCs were of the sclerosing variant and 91% were nonencapsulated, psammoma bodies that occurred in 13% and calcification was observed in 23%. Over 95% had papillary or papillary-follicular architecture and most displayed nuclear overlap, clear nuclei, and nuclear grooves. Several of these features increased with increasing tumor size, but no association was found with radiation dose. A significant radiation-dose response was found for the prevalence of PMCs (estimated excess odds ratio/Gy = 0.57; 95% confidence interval, 0.01-1.55), with the excess risk observed primarily among women. CONCLUSIONS: : Exposure to low-to-moderate doses of ionizing radiation appears to increase the risk of thyroid PMCs, even when exposure occurs during adulthood. Cancer 2010. (c) 2010 American Cancer Society.

Cardiovascular disease risk among atomic bomb survivors exposed in utero, 1978-2003.

Given the well-documented association of in utero radiation exposure with childhood cancer and developmental impairments, the possibility of effects on adult onset diseases is an important issue. The objectives of the present study were to examine the effects of atomic bomb radiation dose on the incidence of hypertension, hypercholesterolemia and cardiovascular disease (myocardial infarction and stroke) among survivors exposed in utero and to compare their risk estimates with those of survivors exposed in childhood (<10 years old) at the time of the bombing. A total of 506 participants exposed in utero and 1,053 participants exposed in childhood were followed during 1978-2003 with biennial clinical examinations. There were no significant radiation dose effects for any diseases in the entire in utero-exposed cohort or in trimester-of-exposure subgroups, though there was a suggestion of an increased risk when fatal and nonfatal cardiovascular disease cases were combined. Positive radiation dose effects were found for hypertension and cardiovascular disease in the childhood-exposure cohort, but there were no statistically significant differences in the relative risks when we compared the two cohorts. Since the in utero cohort was under age 60 at the latest examination, continued follow-up is needed to document cardiovascular disease risk more fully.