Japanese Atomic Bomb Survivors Research Articles

Human-mouse comparison of the multistage nature of radiation carcinogenesis in a mathematical model.

Mouse models are vital for assessing risk from environmental carcinogens, including ionizing radiation, yet the interspecies difference in the dose response precludes direct application of experimental evidence to humans. Herein, we take a mathematical approach to delineate the mechanism underlying the human-mouse difference in radiation-related cancer risk. We used a multistage carcinogenesis model assuming a mutational action of radiation to analyze previous data on cancer mortality in the Japanese atomic bomb survivors and in lifespan mouse experiments. Theoretically, the model predicted that exposure will chronologically shift the age-related increase in cancer risk forward by a period corresponding to the time in which the spontaneous mutational process generates the same mutational burden as that the exposure generates. This model appropriately fitted both human and mouse data and suggested a linear dose response for the time shift. The effect per dose decreased with increasing age at exposure similarly between humans and mice on a per-lifespan basis (0.72- and 0.71-fold, respectively, for every tenth lifetime). The time shift per dose was larger by two orders of magnitude in humans (7.8 and 0.046 years per Gy for humans and mice, respectively, when exposed at ~35% of their lifetime). The difference was mostly explained by the two orders of magnitude difference in spontaneous somatic mutation rates between the species plus the species-independent radiation-induced mutation rate. Thus, the findings delineate the mechanism underlying the interspecies difference in radiation-associated cancer mortality and may lead to the use of experimental evidence for risk prediction in humans.

Assessing the impact of neutron relative biological effectiveness on all solid cancer mortality risks in the Japanese atomic bomb survivors

Purpose Risk analyses, based on relative biological effectiveness (RBE) estimates for neutrons relative to gammas, were performed; and the change in the curvature of the risk to dose response with increasing neutron RBE was analyzed using all solid cancer mortality data from the Radiation Effect Research Foundation (RERF). Results were compared to those based on incidence data. Materials and methods This analysis is based on RERF mortality data with separate neutron and gamma doses for colon doses, from which organ averaged doses could be calculated. A model for risk ratio variation with RBE was developed. Results The best estimate of the neutron RBE considering mortality data was 200 (95% confidence interval (CI): 50–1010) for colon dose using the weighted-dose approach and for organ averaged dose 110 (95% CI: 30–350). The ERR risk ratios for all solid cancers combined, for the best fitting neutron RBE estimate and the neutron RBE of 10 result in a ratio of 0.54 (95% CI: 0.17–0.85) for colon dose and 0.55 (95% CI: 0.18–0.87) for organ averaged dose. The risk to dose response curvature became significantly negative (concave down) with increasing RBE, at a neutron RBE of 170 using colon dose and at an RBE of 90 using organ averaged dose for males when fitting a linear-quadratic dose response. For females, the curvature decreased toward linearity with increasing neutron RBE and remained significantly positive until RBE of 80 and 40 using colon and organ averaged dose, respectively. For higher neutron RBEs, no significant conclusion could be drawn about the shape of the dose–response curve. Conclusions Application of neutron RBE values higher than 10 results in substantially reduced cancer mortality risk estimates and a significant reduction in curvature of the risk to dose responses for males. Using mortality data, the best fitting neutron RBE is much higher than when incidence data is used. The neutron RBE ranges covered by the overlap in the CIs from both the mortality and incidence analyses are 50–190 using colon dose and in all cases, the best fitting neutron RBE and lower 95% CI are higher than the value of 10 traditionally applied by the RERF. Therefore, it is recommended to consider uncertainties in neutron RBE values when calculating radiation risks and discussing the shape of dose responses using Japanese A-bomb survivors data.

Radiation exposure and leukaemia risk among cohorts of persons exposed to low and moderate doses of external ionising radiation in childhood.

Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards. We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

Radiation-induced bystander effect and its clinical implications.

For many years, targeted DNA damage caused by radiation has been considered the main cause of various biological effects. Based on this paradigm, any small amount of radiation is harmful to the organism. Epidemiological studies of Japanese atomic bomb survivors have proposed the linear-non-threshold model as the dominant standard in the field of radiation protection. However, there is increasing evidence that the linear-non-threshold model is not fully applicable to the biological effects caused by low dose radiation, and theories related to low dose radiation require further investigation. In addition to the cell damage caused by direct exposure, non-targeted effects, which are sometimes referred to as bystander effects, abscopal effects, genetic instability, etc., are another kind of significant effect related to low dose radiation. An understanding of this phenomenon is crucial for both basic biomedical research and clinical application. This article reviews recent studies on the bystander effect and summarizes the key findings in the field. Additionally, it offers a cross-sectional comparison of bystander effects caused by various radiation sources in different cell types, as well as an in-depth analysis of studies on the potential biological mechanisms of bystander effects. This review aims to present valuable information and provide new insights on the bystander effect to enlighten both radiobiologists and clinical radiologists searching for new ways to improve clinical treatments.

Discussion of uncertainties and the impact of different neutron RBEs on all solid cancer radiation incidence risks obtained from the Japanese A-bomb survivor data.

The most recent publicly available data on all solid cancer incidence from the Life Span Study (LSS) of Japanese A-bomb survivors provides colon dose contributions weighted with a relative biological effectiveness (RBE) of 10 for neutrons, relative to gammas. However, there is evidence from several investigations that the neutron RBE for A-bomb survivors may be higher than 10. The change in the shape of the corresponding dose-response curves was evaluated by Hafner and co-workers in a previous study by applying sex-specific linear-quadratic dose models to previous LSS data for all solid cancer incidence that include separate neutron and gamma absorbed doses for several organs, in contrast to the most recent data. The resulting curvature change became significantly negative for males at an RBE of 140 for colon, 100 for liver, and 80 for organ averaged dose. For females, the corresponding RBE values were 110, 80, and 60 for colon, liver, and organ averaged doses. The present study compares three different methods to calculate the 95% confidence intervals in an analysis of the curvature with increasing RBE. Further, the impact of a higher neutron RBE on the work of the International Commission on Radiological Protection, and the importance of including uncertainties and performing sensitivity analysis of different parameters in radiation risk assessment are discussed.

Low-Dose Extrapolation Factors Implied by Mortality and Incidence Data from the Japanese Atomic Bomb Survivor Life Span Study Data.

Assessment of the effect of low dose and low-dose-rate exposure depends critically on extrapolation from groups exposed at high dose and high-dose rates such as the Japanese atomic bomb survivor data, and has often been achieved via application of a dose and dose-rate effectiveness factor (DDREF). An important component of DDREF is the factor determining the effect of extrapolation of dose, the so-called low-dose extrapolation factor (LDEF). To assess LDEF models linear (or linear quadratic) in dose are often fitted. In this report LDEF is assessed via fitting relative rate models that are linear or linear quadratic in dose to the latest Japanese atomic bomb survivor data on solid cancer, leukemia and circulatory disease mortality (followed from 1950 through 2003) and to data on solid cancer, lung cancer and urinary tract cancer incidence. The uncertainties in LDEF are assessed using parametric bootstrap techniques. Analysis is restricted to survivors with <3 Gy dose. There is modest evidence for upward curvature in dose response in the mortality data. For leukemia and for all solid cancer excluding lung, stomach and breast cancer there is significant curvature (P < 0.05). There is no evidence of curvature for circulatory disease (P > 0.5). The estimate of LDEF for all solid cancer mortality is 1.273 [95% confidence intervals (CI) 0.913, 2.182], for all solid cancer mortality excluding lung cancer, stomach cancer and breast cancer is 2.183 (95% CI 1.090, >100) and for leukemia mortality is 11.447 (95% CI 2.390, >100). For stomach cancer mortality LDEF is modestly raised, 1.077 (95% CI 0.526, >100), while for lung cancer, female breast cancer and circulatory disease mortality the LDEF does not much exceed 1. LDEF for solid cancer incidence is 1.186 (95% CI 0.942, 1.626) and for urinary tract cancer is 1.298 (95% CI <0, 7.723), although for lung cancer LDEF is not elevated, 0.842 (95% CI 0.344, >100).

Assessing the impact of different neutron RBEs on the all solid cancer radiation risks obtained from the Japanese A-bomb survivors data

Purpose Development of a model characterizing risk variation with RBE to investigate how the incidence risk for all solid cancers combined varies with higher neutron RBEs and different organ dose types. Material and methods The model is based on RERF data with separate neutron and gamma dose information. Results For both additive and multiplicative linear excess risks per unit organ averaged dose, a reduction of 50% in the risk coefficient per weighted dose arises when a neutron RBE of 110 is used instead of 10. Considering risk per unit liver dose, this reduction occurs for an RBE of 130 and for risks per unit colon dose for an RBE of 190. The change in the shape of the dose response curve when using higher neutron RBEs is evaluated. The curvature changed and became significantly negative for males at an RBE of 140 for colon dose, 100 for liver dose and 80 for organ averaged dose. For females this is the case at an RBE of 110, 80 and 60, respectively. Conclusions Uncertainties in neutron RBE values should be considered when radiation risks and the shape of dose responses are deduced from cancer risk data from the atomic bomb survivors.

The risk of cancer following high, and very high, doses of ionising radiation

It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.

Total-Body Irradiation Is Associated With Increased Incidence of Mesenchymal Neoplasia in a Radiation Late Effects Cohort of Rhesus Macaques (Macaca mulatta)

Cancer is a severe delayed effect of acute radiation exposure. Total-body irradiation has been associated with an increased risk of solid cancer and leukemia in Japanese atomic bomb survivors, and secondary malignancies, such as sarcoma, are a serious consequence of cancer radiation therapy. The radiation late effects cohort (RLEC) of rhesus macaques (Macaca mulatta) is a unique resource of more than 200 animals for studying the long-term consequences of total-body irradiation in an animal model that closely resembles humans at the genetic and physiologic levels. Using clinical records, clinical imaging, histopathology, and immunohistochemistry, this retrospective study characterized the incidence of neoplasia in the RLEC. Since 2007, 61 neoplasms in 44 of 239 irradiated animals were documented (18.4% of the irradiated population). Only 1 neoplasm was diagnosed among the 51 nonirradiated controls of the RLEC (2.0%). The most common malignancies in the RLEC were sarcomas (38.3% of diagnoses), which are rare neoplasms in nonirradiated macaques. The most common sarcomas included malignant nerve sheath tumors and malignant glomus tumors. Carcinomas were less common (19.7% of diagnoses), and consisted primarily of renal cell and hepatocellular carcinomas. Neoplasia occurred in most major body systems, with the skin and subcutis being the most common site (40%). RNA analysis showed similarities in transcriptional profiles between RLEC and human malignant nerve sheath tumors. This study indicates that total-body irradiation is associated with an increased incidence of neoplasia years following irradiation, at more than double the incidence described in aging, nonirradiated animals, and promotes tumor histotypes that are rarely observed in nonirradiated, aging rhesus macaques.

The Incidence Risk for Primary Glaucoma and Its Subtypes following Chronic Exposure to Ionizing Radiation in the Russian Cohort of Mayak Nuclear Workers.

Simple SummaryGlaucoma is a leading cause of irreversible blindness worldwide and also represents one of the normal tissue complications following radiation therapy involving ocular radiation exposure. It has widely been considered that such secondary glaucoma occurs at fractionated high dose (several tens of Gy). In contrast, this study is the first to report that normal-tension glaucoma (a subtype of primary open-angle glaucoma) occurs in radiation workers at a chronic dose of >1 Gy. Such elevated risk of radiogenic normal-tension glaucoma, if confirmed in other cohorts, has significant implications for normal tissue complications in radiotherapy patients receiving ocular radiation exposure, and for ocular radiation protection in radiation workers.Secondary glaucoma is a typical normal tissue complication following radiation therapy involving ocular radiation exposure at high fractionated dose (several tens of Gy). In contrast, recent studies in acutely exposed Japanese atomic bomb survivors showed a significantly increased risk for normal-tension glaucoma (NTG, a subtype of primary open-angle glaucoma) at much lower dose, but such information is not available in any other cohorts. We therefore set out to evaluate the incidence of risk for primary glaucoma and its subtypes in a Russian cohort of Mayak Production Association nuclear workers who received chronic radiation exposure over many years. Of these, we found a significantly increased relative risk (RR) of NTG incidence (RR = 1.88 95% confidence intervals (CI): 1.01, 3.51; p = 0.047) in workers exposed to gamma rays at cumulative brain absorbed dose above >1 Gy. We observed the linear relationship between NTG incidence and brain absorbed gamma dose with an excess relative risk per unit brain absorbed dose of 0.53 (95% CI: 0.01, 1.68; p < 0.05), but not for any other subtypes nor for total primary glaucoma. Such elevated risk of radiogenic NTG incidence, if confirmed in other cohorts, has significant implications for normal tissue complications in radiotherapy patients receiving ocular radiation exposure, and for ocular radiation protection in radiation workers.

Biological Effects of Neutron Radiation: An Overview

Exposure of human body to neutrons occurs in radiotherapy using high-energy radiations. This review summarizes knowledges related to biological effects of neutrons, including those obtained in recent projects in Japan and Europe. A study of Japanese atomic bomb survivors with recently revised dosimetry indicated very high relative biological effectiveness (RBE) of 25-80 (as point estimates) regarding cancer risk. Animal studies indicate RBE of 2-100 or even higher regarding cancer induction, which seem to have a peak around ～1 MeV. Evidence suggests that these values depend on the age and sex. Reported RBE regarding the effects on the lens of the eye is in a similar range and sometimes very high. Regarding other tissue reactions, reported RBE values range from 2-10. Experiments at the cellular level have reported RBE of 1-5 regarding cell killing, 2-20 regarding induction of mutations (with a peak at ～1 MeV), and ～1 regarding induction of DNA double strand breaks. A simulation study predicted that the RBE of induction of complex DNA breaks peaks at ～1 MeV with a value of ～17. The complex breaks produced are likely to be far less in amount than simple DNA breaks, leading to a subtle increase in the yield of total DNA breaks; however, these complex damages may be very efficient in inducing mutations and cancer. Thus, the combination of the yield of complex DNA damage and its efficacy in inducing cancer is considered to underlie the high RBE of neutrons regarding cancer risk.

Bespoke Instruments: A new tool for addressing unmeasured confounders.

Suppose that an investigator is interested in quantifying an exposure-disease causal association in a setting where the exposure, disease, and some potential confounders of the association of interest have been measured. However, there remains concern about residual confounding of the association of interest by unmeasured confounders. We propose an approach to account for residual bias due to unmeasured confounders. The proposed approach uses a measured confounder to derive a "bespoke" instrumental variable that is tailored to the study population and is used to control for bias due to residual confounding. The approach may provide a useful tool for assessing and accounting for bias due to residual confounding. We provide a formal description of the conditions for identification of causal effects, illustrate the method using simulations, and provide an empirical example concerning mortality among Japanese atomic bomb survivors.

Cancer risk following low doses of ionising radiation – Current epidemiological evidence and implications for radiological protection

Recent studies suggest that every year worldwide about a million patients might be exposed to doses of the order of 100 mGy of low-LET radiation, due to recurrent application of radioimaging procedures. This paper presents a synthesis of recent epidemiological evidence on radiation-related cancer risks from low-LET radiation doses of this magnitude. Evidence from pooled analyses and meta-analyses also involving epidemiological studies that, individually, do not find statistically significant radiation-related cancer risks is reviewed, and evidence from additional and more recent epidemiological studies of radiation exposures indicating excess cancer risks is also summarized. Cohorts discussed in the present paper include Japanese atomic bomb survivors, nuclear workers, patients exposed for medical purposes, and populations exposed environmentally to natural background radiation or radioactive contamination. Taken together, the overall evidence summarized here is based on studies including several million individuals, many of them followed-up for more than half a century. In summary, substantial evidence was found from epidemiological studies of exposed groups of humans that ionizing radiation causes cancer at acute and protracted doses above 100 mGy, and growing evidence for doses below 100 mGy. The significant radiation-related solid cancer risks observed at doses of several 100 mGy of protracted exposures (observed, for example, among nuclear workers) demonstrate that doses accumulated over many years at low dose rates do cause stochastic health effects. On this basis, it can be concluded that doses of the order of 100 mGy from recurrent application of medical imaging procedures involving ionizing radiation are of concern, from the viewpoint of radiological protection.

Overview of epidemiological studies of nuclear workers: opportunities, expectations, and limitations ∗ ∗ Based upon an invited presentation in Special Session 9 of the IRPA15 Virtual Congress, January–February 2021.

Epidemiological studies of those exposed occupationally to ionising radiation offer an important opportunity to directly check the assumptions underlying the international system of radiological protection against low-level radiation exposures. Recent nuclear worker studies, notably the International Nuclear Workers Study (INWORKS) and studies of the Mayak workforce in Russia, provide powerful investigations of a wide range of cumulative photon doses received at a low dose-rate over protracted periods, and broadly confirm radiation-related excess risks of leukaemia and solid cancers at around the levels predicted by standard risk models derived mainly from the experience of the Japanese atomic-bomb survivors acutely exposed principally to gamma radiation. However, the slope of the dose-response for solid cancers expressed in terms of the excess relative risk per unit dose, ERR/Gy, differs between INWORKS and Mayak, such that when compared with the slope derived from the atomic-bomb survivors, INWORKS does not provide obvious support for the use in radiological protection of a dose and dose-rate effectiveness factor greater than one whereas the Mayak workforce apparently does. This difference could be a chance effect, but it could also point to potential problems with these worker studies. Of particular concern is the adequacy of recorded doses received in the early years of operations at older nuclear installations, such as the potential for ‘missed’ photon doses. A further issue is how baseline cancer rates may influence radiation-related excess risks. There is scope for a considerable increase in the statistical power of worker studies, with longer follow-up capturing more deaths and incident cases of cancer, and further workforces being included in collaborative studies, but the difficulties posed by dosimetry questions should not be ignored and need to be the subject of detailed scrutiny.

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.

Mortality among medical radiation workers in the United States, 1965–2016

Background Estimates of radiation risks following prolonged exposures at low doses and low-dose rates are uncertain. Medical radiation workers are a major component of the Million Person Study (MPS) of low-dose health effects. Annual personal dose equivalents, H P(10), for individual workers are available to facilitate dose-response analyses for lung cancer, leukemia, ischemic heart disease (IHD) and other causes of death. Materials and methods The Landauer, Inc. dosimetry database identified 109,019 medical and associated radiation workers first monitored 1965–1994. Vital status and cause of death were determined through 2016. Mean absorbed doses to red bone marrow (RBM), lung, heart, and other organs were estimated by adjusting the recorded H P(10) for each worker by scaling factors, accounting for exposure geometry, the energy of the incident photon radiation, sex of the worker and whether an apron was worn. There were 4 exposure scenarios: general radiology characterized by low-energy x-ray exposure with no lead apron use, interventional radiologists/cardiologists who wore aprons, nuclear medicine personnel and radiation oncologists exposed to high-energy photon radiation, and other workers. Standardized mortality ratio (SMR) analyses were performed. Cox proportional hazards models were used to estimate organ-specific radiation risks. Results Overall, 11,433 deaths occurred (SMR 0.60; 95%CI 0.59,0.61), 126 from leukemia other than chronic lymphocytic leukemia (CLL), 850 from lung cancer, and 1654 from IHD. The mean duration of monitoring was 23.7 y. The excess relative rate (ERR) per 100 mGy was estimated as 0.10 (95% CI −0.34, 0.54) for leukemia other than CLL, 0.15 (0.02, 0.27) for lung cancer, and −0.10 (–0.27, 0.06) for IHD. The ERR for lung cancer was 0.16 (0.01, 0.32) among the 55,218 male workers and 0.09 (–0.19, 0.36) among the 53,801 female workers; a difference that was not statistically significant (p-value = 0.23). Conclusions Medical radiation workers were at increased risk for lung cancer that was higher among men than women, although this difference was not statistically significant. In contrast, the study of Japanese atomic bomb survivors exposed briefly to radiation in 1945 found females to be nearly 3 times the radiation risk of lung cancer compared with males on a relative scale. For medical workers, there were no statistically significant radiation associations with leukemia excluding CLL, IHD or other specific causes of death. Combining these data with other cohorts within the MPS, such as nuclear power plant workers and nuclear submariners, will enable more precise estimates of radiation risks at relatively low cumulative doses.

Mortality from leukemia, cancer and heart disease among U.S. nuclear power plant workers, 1957–2011

Background The aim of the Million Person Study of Low-Dose Health Effects (MPS) is to examine the level of radiation risk for chronic exposures received gradually over time and not acutely as was the case for the Japanese atomic bomb survivors. Nuclear power plant (NPP) workers comprise nearly 15 percent of the MPS. Leukemia, selected cancers, Parkinson’s disease, ischemic heart disease (IHD) and other causes of death are evaluated. Methods and material The U.S. Nuclear Regulatory Commission’s Radiation Exposure Information and Reporting System (REIRS) and the Landauer, Inc. dosimetry databases identified 135,193 NPP workers first monitored 1957–1984. Annual personal dose equivalents [Hp(10)] were available for each worker. Radiation records from all places of employment were sought. Vital status was determined through 2011. Mean absorbed doses to red bone marrow (RBM), esophagus, lung, colon, brain and heart were estimated by adjusting the recorded Hp(10) for each worker by scaling factors, accounting for exposure geometry and energy of the incident gamma radiation. Standardized mortality ratios (SMR) were calculated. Radiation risks were estimated using Cox proportional hazards models. Results Nearly 50% of workers were employed for more than 20 years. The mean duration of follow-up was 30.2 y. Overall, 29,124 total deaths occurred, 296 from leukemia other than chronic lymphocytic leukemia (CLL), 3382 from lung cancer, 140 from Parkinson’s disease and 5410 from IHD. The mean dose to RBM was 37.9 mGy (maximum 1.0 Gy; percent >100 mGy was 9.2%), 43.2 mGy to lung, 43.7 mGy to colon, 33.2 mGy to brain, and 43.9 mGy to heart. The SMRs (95% CI) were 1.06 (0.94; 1.19) for leukemia other than CLL, 1.10 (1.07; 1.14) for lung cancer, 0.90 (0.76; 1.06) for Parkinson’s disease, and 0.80 (0.78; 0.82) for IHD. The excess relative risk (ERR) per 100 mGy for leukemia other than CLL was 0.15 (90% CI −0.001; 0.31). For all solid cancers the ERR per 100 mGy (95% CI) was 0.01 (–0.03; 0.05), for lung cancer −0.04 (–0.11; 0.02), for Parkinson’s disease 0.24 (–0.02; 0.50), and for IHD −0.01 (–0.06; 0.04). Conclusion Prolonged exposure to radiation increased the risk of leukemia other than CLL among NPP workers. There was little evidence for a radiation association for all solid cancers, lung cancer or ischemic heart disease. Increased precision will be forthcoming as the different cohorts within the MPS are combined, such as industrial radiographers and medical radiation workers who were assembled and evaluated in like manner.

Methodological improvements to meta-analysis of low dose rate studies and derivation of dose and dose-rate effectiveness factors.

Epidemiological studies of cancer rates associated with external and internal exposure to ionizing radiation have been subject to extensive reviews by various scientific bodies. It has long been assumed that radiation-induced cancer risks at low doses or low-dose rates are lower (per unit dose) than those at higher doses and dose rates. Based on a mixture of experimental and epidemiologic evidence the International Commission on Radiological Protection recommended the use of a dose and dose-rate effectiveness factor for purposes of radiological protection to reduce solid cancer risks obtained from moderate-to-high acute dose studies (e.g. those derived from the Japanese atomic bomb survivors) when applied to low dose or low-dose rate exposures. In the last few years there have been a number of attempts at assessing the effect of extrapolation of dose rate via direct comparison of observed risks in low-dose rate occupational studies and appropriately age/sex-adjusted analyses of the Japanese atomic bomb survivors. The usual approach is to consider the ratio of the excess relative risks in the two studies, a measure of the inverse of the dose rate effectiveness factor. This can be estimated using standard meta-analysis with inverse weighting of ratios of relative risks using variances derived via the delta method. In this paper certain potential statistical problems in the ratio of estimated excess relative risks for low-dose rate studies to the excess relative risk in the Japanese atomic bomb survivors are discussed, specifically the absence of a well-defined mean and the theoretically unbounded variance of this ratio. A slightly different method of meta-analysis for estimating uncertainties of these ratios is proposed, motivated by Fieller's theorem, which leads to slightly different central estimates and confidence intervals for the dose rate effectiveness factor. However, given the uncertainties in the data, the differences in mean values and uncertainties from the dose rate effectiveness factor estimated using delta-method-based meta-analysis are not substantial, generally less than 70%.

Radiation effects on atherosclerosis in atomic bomb survivors: a cross\u2010sectional study using structural equation modeling

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [− 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Risk of cancer associated with low-dose radiation exposure: comparison of results between the INWORKS nuclear workers study and the A-bomb survivors study

The Life Span Study (LSS) of Japanese atomic bomb survivors has served as the primary basis for estimates of radiation-related disease risks that inform radiation protection standards. The long-term follow-up of radiation-monitored nuclear workers provides estimates of radiation-cancer associations that complement findings from the LSS. Here, a comparison of radiation-cancer mortality risk estimates derived from the LSS and INWORKS, a large international nuclear worker study, is presented. Restrictions were made, so that the two study populations were similar with respect to ages and periods of exposure, leading to selection of 45,625 A-bomb survivors and 259,350 nuclear workers. For solid cancer, excess relative rates (ERR) per gray (Gy) were 0.28 (90% CI 0.18; 0.38) in the LSS, and 0.29 (90% CI 0.07; 0.53) in INWORKS. A joint analysis of the data allowed for a formal assessment of heterogeneity of the ERR per Gy across the two studies (P = 0.909), with minimal evidence of curvature or of a modifying effect of attained age, age at exposure, or sex in either study. There was evidence in both cohorts of modification of the excess absolute risk (EAR) of solid cancer by attained age, with a trend of increasing EAR per Gy with attained age. For leukemia, under a simple linear model, the ERR per Gy was 2.75 (90% CI 1.73; 4.21) in the LSS and 3.15 (90% CI 1.12; 5.72) in INWORKS, with evidence of curvature in the association across the range of dose observed in the LSS but not in INWORKS; the EAR per Gy was 3.54 (90% CI 2.30; 5.05) in the LSS and 2.03 (90% CI 0.36; 4.07) in INWORKS. These findings from different study populations may help understanding of radiation risks, with INWORKS contributing information derived from cohorts of workers with protracted low dose-rate exposures.