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Takahashi I.,Radiation Effects Research Foundation RERF | Shimizu Y.,Radiation Effects Research Foundation RERF | Grant E.J.,Radiation Effects Research Foundation RERF | Cologne J.,Radiation Effects Research Foundation RERF | And 2 more authors.
Radiation Research | Year: 2017

Based on the findings from the Radiation Effects Research Foundation's studies of the cohort of Japanese atomic bomb survivors, it has been reported that total-body irradiation at 0.5-1.0 Gy could be responsible for increased rates of mortality from broad-based categories of cardiovascular disease (CVD), i.e., stroke and heart disease. However, CVD consists of various subtypes that have potentially different radiation dose responses, as well as subtype-specific risks that have not been fully evaluated. Potential problems with changes in the coding rules for the International Classification of Diseases (ICD) and the underlying causes and trends in CVD mortality in Japan also need to be considered. The goal of this study was to clarify the radiation risk of subtype-specific heart disease over different time periods. Radiation dose response was examined for mortality from several heart disease subtypes in 86,600 members of the Life Span Study (LSS) cohort during 1950-2008. These subtypes included ischemic heart disease (IHD), valvular heart disease (VHD), hypertensive organ damage (HOD) and heart failure (HF). Individual radiation doses ranged between 0 and 4 Gy. In addition to analyses for the total period, we examined specific periods, 1950-1968, 1969-1980, 1981-1994 and 1995-2008, corresponding to major developments in medical technologies and ICD code revisions. We observed significant positive associations between radiation dose and mortality from heart disease overall in 1950-2008 excess relative risk or ERR/Gy (95% CI) = 0.14 (0.06, 0.22). Subtype-specific ERRs also positively increased with dose: 0.45 (0.13, 0.85) for VHD, 0.36 (0.10, 0.68) for HOD and 0.21 (0.07, 0.37) for HF, respectively. No significant departure from linearity was shown for the dose-response model. Although there was no evidence for a threshold in a model function, the lowest dose ranges with a statistically significant dose response were 0-0.7 Gy for heart disease overall and VHD, 0-1.5 Gy for HOD and 0-0.4 Gy for HF. No significant association between radiation exposure and IHD was observed in any model, although a quadratic model fit the best. The risk of HOD and rheumatic VHD increased significantly in the earliest periods ERR/Gy = 0.59 (0.07, 1.32) and 1.34 (0.24, 3.16), respectively.The risk of nonrheumatic VHD increased with calendar time and was significant in the latest period ERR/Gy = 0.75 (0.02, 1.92). The risk of IHD, especially for myocardial infarction, tended to be elevated in the most recent period after 2001, where cautious interpretation is needed due to the uncertain validity of death diagnosis. Radiation risks of heart disease mortality in the LSS appeared to vary substantially among subtypes, indicating possible differences in radiation-induced pathogenesis. Trends in CVD rates in Japan during the long observation period may also impact risk analyses. © 2017 by Radiation Research Society.

PubMed | U.S. National Institute on Aging, RERF, Hiroshima University, Duke University and 2 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Ionizing radiation (IR) is a major source of cellular damage and the immediate cellular response to IR has been well characterized. But the long-term impact of IR on cell function and its relationship with aging are not known. Here, we examined the IR effects on telomere length and other biomarkers 50 to 68 years post-exposure (two time points per person) in survivors of the atomic bombing at Hiroshima during WWII. We found that telomere length of leukocytes was inversely correlated with the dose of IR (p=0.008), and this effect was primarily found in survivors who were exposed at younger ages; specifically those <12 years old (p=0.0004). Although a dose-related retardation of telomere shortening with age was observed in the cross-sectional data, longitudinal follow-up after 11 years did not show IR exposure-related alteration of the rate of telomere shortening with age. In addition, IR diminished the associations between telomere length and selected aging biomarkers that were observed in survivors with no dose. These included uric acid metabolism, cytokines, and blood T cell counts. These findings showed long-lasting detrimental effects of IR on telomere length of leukocytes in both dose- and age-at-exposure dependent manner, and on alterations of biomarkers with aging.

Adams M.J.,University of Rochester | Grant E.J.,Radiation Effects Research Foundation RERF | Kodama K.,Radiation Effects Research Foundation RERF | Shimizu Y.,Radiation Effects Research Foundation RERF | And 4 more authors.
Radiation Research | Year: 2012

Whole-body and thoracic ionizing radiation exposure are associated with increased cardiovascular disease (CVD) risk. In atomic bomb survivors, radiation dose is also associated with increased hypertension incidence, suggesting that radiation dose may be associated with chronic renal failure (CRF), thus explaining part of the mechanism for increased CVD. Multivariate Poisson regression was used to evaluate the association of radiation dose with various definitions of chronic kidney disease (CKD) mortality in the Life Span Study (LSS) of atomic bomb survivors. A secondary analysis was performed using a subsample for whom self-reported information on hypertension and diabetes, the two biggest risk factors for CRF, had been collected. We found a significant association between radiation dose and only our broadest definition of CRF among the full cohort. A quadratic dose excess relative risk model [ERR/Gy 2 = 0.091 (95% CI: 0.05, 0.198)] fit minimally better than a linear model. Within the subsample, association was also observed only with the broadest CRF definition [ERR/Gy 2 = 0.15 (95% CI: 0.02, 0.32)]. Adjustment for hypertension and diabetes improved model fit but did not substantially change the ERR/Gy 2 estimate, which was 0.17 (95% CI: 0.04, 0.35). We found a significant quadratic dose relationship between radiation dose and possible chronic renal disease mortality that is similar in shape to that observed between radiation and incidence of hypertension in this population. Our results suggest that renal dysfunction could be part of the mechanism causing increased CVD risk after whole-body irradiation, a hypothesis that deserves further study. © 2012 by Radiation Research Society. All rights of reproduction in any form reserved.

Takahashi I.,Radiation Effects Research Foundation RERF | Takahashi I.,Hiroshima University | Furukawa K.,Radiation Effects Research Foundation RERF | Ohishi W.,Radiation Effects Research Foundation RERF | And 3 more authors.
Vascular Health and Risk Management | Year: 2013

Peripheral arterial disease (PAD) generally remains under-recognized, mainly due to the specialized technical skills required to detect the low values of the ankle-brachial index (ABI). As a simpler and faster alternative to the standard method using continuous-wave Doppler ultrasound, we evaluated automated oscillometric ABI measurement by VP-2000 with an elderly cohort of 113 subjects (age range, 61 to 88 years). The standard deviation in ABIs measured by the Doppler method was statistically greater than that measured by the oscillometric method for each of the two legs (P, 0.001). Correlations in ABIs between the two methods were 0.46 for the left leg and 0.61 for the right leg; this result appears to have been caused by inter observer variation in the Doppler ABI measurements. While the trend showing greater differences between average oscillometric- and Doppler-ABIs was significant at the lower ABI ranges, there was little indication of differences in measurements having an average ABI. 1.1. The difference between the methods was suggestively larger in subjects who were smokers than in non-smokers (P = 0.09), but the difference was not affected by other potential atherosclerotic risk factors, including age at examination (P. 0.50). A larger difference at lower ABIs led to better PAD detection by the Doppler method compared to the oscillometric method (sensitivity = 50%, specifcity = 100%), although the overall agreement was not small (Cohen's Kappa = 0.65). Our findings indicate that oscillometric devices can provide more accurate estimation of the prevalence of PA D in elderly individuals than the conventional Doppler method. © 2013 Takahashi et al, publisher and licensee Dove Medical Press Ltd.

Takahashi I.,Radiation Effects Research Foundation RERF | Takahashi I.,Hiroshima University | Abbott R.D.,Radiation Effects Research Foundation RERF | Ohshita T.,Hiroshima University | And 7 more authors.
BMJ Open | Year: 2012

Objective: Use of medical radiotherapy has increased markedly in recent decades. Whether the consequence includes an increased risk of cardiovascular disease remains to be determined. The purpose of this study was to examine the association between radiation exposure and the incidence of stroke among Japanese atomic bomb survivors. Design: A prospective follow-up study. Setting and participants: Radiation exposure from the atomic bombing was assessed in 9515 subjects (34.8% men) with 24-year follow-up from 1980. Subjects were free of prevalent stroke when follow-up began. Outcome measures: Stroke events and the underlying cause of death were reviewed to confirm the first-ever stroke. Subtypes (ischaemic and haemorrhagic events) were categorised based on established criteria according to the definitions of typical/atypical stroke symptoms. Results: Overall mean radiation dose (6SD) in units of gray (Gy) was 0.3860.58 (range: 0-3.5). During the study period, 235 haemorrhagic and 607 ischaemic events were identified. For men, after adjusting for age and concomitant risk factors, the risk of haemorrhagic stroke rose consistently from 11.6 to 29.1 per 10 000 person-years as doses increased from <0.05 to ≥2 Gy (p=0.009). Incidence also rose within the dose range <1 Gy (p=0.004) with no dose threshold. In women, the risk of haemorrhagic stroke rose with increasing radiation exposure but not until doses reached a threshold of 1.3 Gy (95% CI 0.5 to 2.3). Among women, for doses <1.3 Gy, differences in stroke risk were modest (13.5 per 10 000 person-years), while it increased to 20.3 per 10 000 person-years for doses that ranged from 1.3 to <2.2 Gy and to 48.6 per 10 000 person-years for doses that were higher (p=0.002). In both sexes, dose was unrelated to ischaemic stroke. Conclusion: While the risk of haemorrhagic stroke increases with rising radiation exposure for both sexes, effects in women are less apparent until doses exceed a threshold at 1.3 Gy.

PubMed | Public Health England, Fukushima Medical University, Oita University of Nursing and Health Sciences, Federal office for Radiation Protection and 11 more.
Type: Congresses | Journal: Radiation and environmental biophysics | Year: 2015

The biological effects on humans of low-dose and low-dose-rate exposures to ionizing radiation have always been of major interest. The most recent concept as suggested by the International Commission on Radiological Protection (ICRP) is to extrapolate existing epidemiological data at high doses and dose rates down to low doses and low dose rates relevant to radiological protection, using the so-called dose and dose-rate effectiveness factor (DDREF). The present paper summarizes what was presented and discussed by experts from ICRP and Japan at a dedicated workshop on this topic held in May 2015 in Kyoto, Japan. This paper describes the historical development of the DDREF concept in light of emerging scientific evidence on dose and dose-rate effects, summarizes the conclusions recently drawn by a number of international organizations (e.g., BEIR VII, ICRP, SSK, UNSCEAR, and WHO), mentions current scientific efforts to obtain more data on low-dose and low-dose-rate effects at molecular, cellular, animal and human levels, and discusses future options that could be useful to improve and optimize the DDREF concept for the purpose of radiological protection.

Takahashi I.,Radiation Effects Research Foundation RERF
Journal of radiological protection : official journal of the Society for Radiological Protection | Year: 2013

Two longitudinal cohort studies of Japanese atomic bomb survivors-the life span study (LSS) and the adult health study (AHS)-from the Radiation Effects Research Foundation (RERF) indicate that total body irradiation doses less than 1 Gy are associated with an increased risk of cardiovascular disease (CVD), but several questions about this association remain.In particular, the diversity of heart disease subtypes and the high prevalence of other risk factors complicate the estimates of radiation effects. Subtype-specific analyses with more reliable diagnostic criteria and measurement techniques are needed. The radiation effects on CVD risk are probably tissue-reaction (deterministic) effects, so the dose-response relationships for various subtypes of CVD may be nonlinear and therefore should be explored with several types of statistical models.Subpopulations at high risk need to be identified because effects at lower radiation doses may occur primarily in these susceptible subpopulations. Whether other CVD risk factors modify radiation effects also needs to be determined. Finally, background rates for various subtypes of CVD have historically differed substantially between Japanese and Western populations, so the generalisability to other populations needs to be examined.Cardiovascular disease mechanisms and manifestations may differ between high-dose local irradiation and low-dose total body irradiation (TBI)-microvascular damage and altered metabolism from low-dose TBI, but coronary artery atherosclerosis and thrombotic myocardial infarcts at high localised doses. For TBI, doses to organs other than the heart may be important in pathogenesis of CVD, so data on renal and liver disorders, plaque instability, microvascular damage, metabolic disorders, hypertension and various CVD biomarkers and risk factors are needed. Epidemiological, clinical and experimental studies at doses of less than 1 Gy are necessary to clarify the effects of radiation on CVD risk.

Kodama K.,Radiation Effects Research Foundation RERF | Ozasa K.,Radiation Effects Research Foundation RERF | Okubo T.,Radiation Effects Research Foundation RERF
Journal of Radiological Protection | Year: 2012

With the aim of accurately assessing the effects of radiation exposure in the Japanese atomic-bomb survivors, the Radiation Effects Research Foundation has, over several decades, conducted studies of the Life Span Study (LSS) cohort, comprising 93 000 atomic-bomb survivors and 27 000 controls. Solid cancer: the recent report on solid cancer incidence found that at age 70 years following exposure at age 30 years, solid cancer rates increase by about 35% Gy -1 for men and 58%Gy -1 for women. Age-at-exposure is an important risk modifier. In the case of lung cancer, cigarette smoking has been found to be an important risk modifier. Radiation has similar effects on first-primary and second-primary cancer risks. Finally, radiation-associated increases in cancer rates appear to persist throughout life. Leukaemia: the recent report on leukaemia mortality suggests that radiation effects on leukaemia mortality persisted for more than 50 years. Moreover, significant dose-response for myelodysplastic syndrome was observed in Nagasaki LSS members even 40-60 years after radiation exposure. Future perspective: given the continuing solid cancer increase in the survivor population, the LSS will likely continue to provide important new information on radiation exposure and solid cancer risks for another 15-20 years, especially for those exposed at a young age. © 2012 IOP Publishing Ltd.

Kodama K.,Radiation Effects Research Foundation RERF | Ozasa K.,Radiation Effects Research Foundation RERF | Katayama H.,Radiation Effects Research Foundation RERF | Shore R.E.,Radiation Effects Research Foundation RERF | Okubo T.,Radiation Effects Research Foundation RERF
Radiation Protection Dosimetry | Year: 2012

To determine late health effects of radiation in atomic bomb survivors, the Radiation Effects Research Foundation has been conducting studies on the Life Span Study (LSS) population, which consists of 93 000 atomic bomb survivors and 27 000 controls. A recent report on the incidence of solid cancers estimates that at the age of 70 y, after exposure at the age of 30 y, solid-cancer rates increase by about 35 % per Gy for men and 58 % per Gy for women. The age-at-exposure is an important risk modifier. Furthermore, it seems that radiation-associated increases in cancer rates persist throughout life. In addition, radiation has similar effects upon first-primary and second-primary cancer risks. A recent report on leukemia mortality suggested that the effect of radiation on leukemia mortality persisted for more than five decades. In addition, a significant dose-response for myelodysplastic syndrome is found in Nagasaki LSS members 40-60 y after radiation exposure. In view of the nature of the continuing increase in solid cancers, the LSS should continue to provide important new information on cancer risks, as most survivors still alive today were exposed to the atomic bomb radiation under the age of 20 y and are now entering their cancer-prone years. © World Health Organization 2012. All rights reserved.

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