Estimated Excess Relative Risk Research Articles

Further analysis of incidence of multiple myeloma among atomic-bomb survivors, 1950 to 1994.

Multiple myeloma (MM) predominantly occurs in older persons and its diagnosis depends on pathological and laboratory findings. Epidemiological studies have provided inconsistent results on relationship between radiation exposure and MM. The Life Span Study (LSS) of atomic bomb (A-bomb) survivors has not shown a statistically significant radiation risk for MM. We studied previously reported MM cases diagnosed between 1950 and 1994 in the LSS and assessed diagnostic certainty based on histological and clinical features. Among 122 incident MM cases, 67 were classified as definite, 23, probable and 32, undetermined. The incidence rate increased with attained age and was highest in the oldest age group of over 70 years. For definite MM, Poisson regression dose response analysis showed an elevated, though not statistically significant, radiation risk with an estimated excess relative risk (ERR) per Gy of 0.44 (95%CI:<-0.02, 2.4), which was markedly higher than the previously reported ERR/Gy of -0.02 (95% CI: -0.24,0.75) that included cases with undetermined diagnostic certainty. The present case series included 24 persons with MM diagnosed after participating in M-protein screening offered to a clinical subset of the LSS members. Exclusion of screen-detected cases led to a higher radiation risk estimate, which was not statistically significant. A large number of young survivors exposed before age 20 years were younger than 70 years in the current follow-up period, but will reach ages with rapidly increasing MM rates. Future follow-up data with improved diagnostic certainty will improve understanding of long-term effects of radiation exposure on MM in this cohort.

The Effect of Prostate-Specific Antigen (PSA) Test on Radiation Risk Estimate for Prostate Cancer Incidence among Atomic-Bomb Survivors.

Following our previous report on the radiation dose-response for prostate cancer incidence rates in the Life Span Study (LSS) cohort of atomic bomb survivors, we reevaluated the radiation-related risk adjusting for differences in baseline cancer incidence rates among three subsets of the LSS cohort defined by the timing of their first participation in biennial health examinations offered to the Adult Health Study (AHS) sub-cohort members and prostate-specific-antigen (PSA) testing status for AHS participants: 1. non-AHS participants, 2. AHS participants before receiving PSA test, and 3. AHS participants after receiving PSA test. We found a 2.9-fold increase in the baseline incidence rates among AHS participants after receiving PSA test. After adjusting for the PSA-testing-status effects on the baseline rates the estimated excess relative risk (ERR) per Gy was 0.54 (95% CI: 0.15, 1.05), which was almost identical to the previously reported unadjusted ERR estimate (0.57, 95% CI: 0.21, 1.00). The current results confirmed that, while the PSA testing among AHS participants increased the baseline incidence rates, it did not impact the radiation risk estimate, strengthening the previously reported dose-response relationship for prostate cancer incidence in the LSS. As the use of PSA tests continue in screening and medical settings, analyses of possible effects of PSA testing should be an important aspect of future epidemiological studies of the association between radiation exposure and prostate cancer.

Статистические связи с дозой облучения и оценка радиационных рисков неонкологических заболеваний эндокринной системы ликвидаторов чернобыльской аварии с учётом возможных ошибок в постановке и регистрации диагнозов

The paper provides research on statistical relationship between endocrine diseases registered in the Chernobyl liquidators and radiation dose they received. Data of clinical and epidemiological observations accumulated at the National Radiation Epidemiological Register (NRER) for the period from 1986 to 2020 were used for analysis. The cohort contained 41,979 liquidators with 107,713 established diagnoses included in the ICD-10 Е00-E90 blocks. Statistical relationship between radiation doses and endocrine diseases was investigated with the use of statistical methods. Statistical Data Mining methods free of apriori guesses for probable doses and diagnoses distribution, models of dose-effect (disease) relationship were used for analysis of statistical relationship between radiation dose and the diagnoses structure. Statistically significant relationship between radiation doses and diagnoses were found in the blocks E01 (iodine deficiency), E04 (goiter), E06 (thyroiditis), E11 (type II diabetes mellitus). Relationships between radiation dose and diagnosis were also found in the E01.2 block (endemic goiter, caused due to iodine deficiency) and in E04.0 block (non-toxic diffuse goiter). Existence of identified statistical relationship is supported with the estimates of excess relative risk (ERR) and the relative risk (RR). The threshold relationship between RR and radiation dose with threshold of 0.3 Gy shows that radiation effect on human endocrine system is a deterministic effect (tissue reactions). Quantitative risks estimates for endocrine diseases in the liquidators are stable in relation to the diagnostic specificity index up to 90%. The general statistic Data Mining method to search relationship between a disease diagnosis and radiation dose is useful for the diseases identification in order to estimate radiation risk with conventual radiation epidemiology approaches.

Incidence of lymphoid neoplasms among atomic bomb survivors by histological subtype, 1950 to 1994

AbstractEpidemiological data have provided limited and inconsistent evidence on the relationship between radiation exposure and lymphoid neoplasms. We classified 553 lymphoid neoplasm cases diagnosed between 1950 and 1994 in the Life Span Study cohort of atomic bomb survivors into World Health Organization subtypes. Mature B-cell neoplasms represented 58%, mature T-cell and natural killer (NK)-cell neoplasms 20%, precursor cell neoplasms 5%, and Hodgkin lymphoma (HL) 3%, with the remaining 15% classified as non-Hodgkin lymphoid (NHL) neoplasms or lymphoid neoplasms not otherwise specified. We used Poisson regression methods to assess the relationship between radiation exposure and the more common subtypes. As in earlier reports, a significant dose response for NHL neoplasms as a group was seen for males but not females. However, subtype analyses showed that radiation dose was strongly associated with increased precursor cell neoplasms rates, with an estimated excess relative risk per Gy of 16 (95% Confidence interval: 7.0, >533) at age 50. The current data based primarily of tissue-based diagnoses suggest that the association between radiation dose and lymphoid neoplasms as a group is largely driven by the radiation effect on precursor cell neoplasms while presenting no evidence of a radiation dose response for major categories of mature cell neoplasms, either B- or T-/NK-cell, or more specific disease entities (diffuse large B-cell lymphoma, plasma cell myeloma, adult T-cell leukemia/lymphoma) or HL.

Radiation Risk Analysis of Neuropsychiatric Disorders in Ukrainian Chornobyl Catastrophe Liquidators.

Goal: To explore the possible impact of ionizing radiation in the pathophysiology of neuropsychiatric disorders amongst clean-up workers of the Chornobyl catastrophe (liquidators).Design, object, and methods: Retrospective-prospective study (1987–2015) of liquidators from the State Register of Ukraine (SRU) with radiation doses records and Clinical-Epidemiological Register (CER) of the State Institution ≪National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine≫ (NRCRM). Moreover, cohort and cross-sectional studies of the randomized sample of liquidators from the CER (exposed group, 198 subjects) were examined. Internal control group included the liquidators irradiated in doses <50.0 mSv (42 persons). All subjects were assessed by a detailed clinical examination and a battery of standardized neuropsychiatric scales, psychometric, and neuropsychological tests. Descriptive and variation statistics, non-parametric criteria, regression-correlation analysis, survival analysis by Kaplan & Meier, and risk analysis were used.Results: Exposed group vs. control group showed cognitive disorders in 99 (50.0%) vs. 20 (18.1%), (P = 0.04); affective disorders in 96 (48.3%) vs. 36 (32.7%) (P = 0.007), and stress-related disorders in 115 (58.4%) vs. 8 (7.3%) (P < 0.001). In the main group exposed to ≥50 mSv vs. internal control group (exposed to <50 mSv), affective disorders were present, respectively, in 89 (56.4%) vs. 7 (19.1%) (P < 0.001), and stress-related disorders in 98 (62.8%) vs. 17 (40.4%) (P = 0.009). Relative risks (RR) and 95% confidential intervals (95%CI) of Incidence of some neuropsychiatric disorders in liquidators of 1986–1987 related to internal control (doses <50 mSv) were as follows: organic psychosis (RR = 3.15; 95% CI: 2.6; 3.7); non-psychotic organic brain damage (RR = 1.99; 95% CI: 1.6; 2.5); acute (RR = 1.40, 95% CI: 1.3; 1.5), and chronic cerebrovascular disorders (RR = 1.23; 95% CI 1.0;1.5). Neuropsychiatric diseases show a strong, increasing, and approximately quadratic statistically significant (Pv < 0.001) relationship with individual dose, yielding an estimated excess relative risk ERR = 2.76 Sv−2 (95% CI 1.06–7.15).Conclusions: Liquidators have an excess of cognitive, affective, and stress-related disorders. The risk of diseases rises with radiation dose. Radiation risks are revealed for organic psychoses, non-psychotic organic brain damage, acute and chronic cerebrovascular pathology.

Risk of Prostate Cancer Incidence among Atomic Bomb Survivors: 1958-2009.

Epidemiological evidence for a radiation effect on prostate cancer risk has been inconsistent and largely indicative of no or little effect. Here we studied prostate cancer incidence among males of the Life Span Study cohort of atomic bomb survivors in a follow-up from 1958 to 2009, eleven years more than was previously reported. During this period there were 851 incident cases of prostate cancer among 41,544 male subjects, doubling the total number of cases in the cohort. More than 50% of the cases were diagnosed among those who were less than 20 years of age at the time of the bombings and who were at, or near, the ages of heightened prostate cancer risks during the last decade of follow-up. In analyses of the radiation dose response using Poisson regression methods, we used a baseline-rate model that allowed for calendar period effects corresponding to the emergence of prostate-specific antigen screening in the general population as well as effects of attained age and birth cohort. The model also allowed for markedly increased baseline rates among the Adult Health Study participants between 2005 and 2009, a period during which a prostate-specific antigen test was included in Adult Health Study biennial health examinations. We found a significant linear dose response with an estimated excess relative risk (ERR) per Gy of 0.57 (95% CI: 0.21, 1.00, P = 0.001). An estimated 40 of the observed cases were attributed to radiation exposure from the bombings. There was a suggestion of the ERR decreasing with increasing age at exposure (P = 0.09). We found no indication of effects of smoking, alcohol consumption and body mass index on the baseline risk of prostate cancer. The observed dose response strengthens the evidence of a radiation effect on the risk of prostate cancer incidence in the atomic bomb survivors.

Радиационный риск заболеваемости и смертности от лейкоза в объединенной когорте работников атомной отрасли России и Великобритании

Purpose: The estimation of the radiation risk of leukemia incidence and mortality for occupational exposure.&#x0D; Material and methods: The study was conducted in the pooled cohort comprised 45,817 workers from the two enterprises; 23,443 radiation workers first employed in 1947–2002 from the Sellafield plant (Great Britain) and 22,774 workers from the Mayak PA (Russia) first employed at the main plants in 1948–1982. The period of follow-up was terminated at the end of 2008 for Mayak workers who were Ozyorsk city residents, and at the end of 2005 for Sellafield workers and Mayak workers who had migrated from Ozyorsk.&#x0D; Results: Comparable radiation risk estimates of leukemia incidence and mortality were found among Mayak PA and Sellafield workers as for the whole dose range and separate dose intervals. Averaged by attained age estimate of excess relative risk per 1 Gy of external gamma-dose was 3.0 (95 % CI: 1.3–6.3) under the assumption of the linear dose–effect model. The quadratic model with attained age modification showed the best quality of fit. Risk estimates were statistically significant in the dose range 0.15–1.5 Gy. There was no evidence of any relationship between leukemia risks and accumulated red bone marrow dose of internal alpha-exposure due to incorporated Pu-239.&#x0D; Conclusion: Preliminary analysis of the pooled cohort data has demonstrated the feasibility and efficiency of a research project looking at leukemia risks in a joint cohort of Mayak and Sellafield workers. The current study provides further evidence about the already well established link between external-gamma exposure and leukemia risk. However, it fails to provide any firm further evidence about the absence or presence of relationship between plutonium exposure and leukemia risk.

Mammary Chain Irradiation in Left-Sided Breast Cancer: Can We Reduce the Risk of Secondary Cancer and Ischaemic Heart Disease with Modern Intensity-Modulated Radiotherapy Techniques?

Introduction: The aim of the present study was to estimate the impact of the addition of internal mammary chain (IMC) irradiation in node-positive left-sided breast cancer (BC) patients undergoing regional nodal irradiation (RNI) and comparatively evaluate excess relative and absolute risks of radiation-induced lung cancer/BC and ischaemic heart disease for intensity-modulated radiotherapy (IMRT) versus 3D conformal radiotherapy (3D-CRT). Methods: Four treatment plans were created (3D-CRT and IMRT –/+ IMC) for each of the 10 evaluated patients, and estimates of excess relative risk (ERR) and 10-year excess absolute risk (EAR) were calculated for radiation-induced lung cancer/BC and coronary events using linear, linear-exponential and plateau models. Results: The addition of IMC irradiation to RNI significantly increased the dose exposure of the heart, lung and contralateral breast using both techniques, increasing ERR for secondary lung cancer (58 vs. 44%, p = 0.002), contralateral BC (49 vs. 31%, p = 0.002) and ischaemic heart disease (41 vs. 27%, p = 0.002, IMRT plans). IMRT significantly reduced the mean cardiac dose and mean lung dose as compared to 3D-CRT, decreasing ERR for major coronary events (64% 3D-CRT vs. 41% IMRT, p = 0.002) and ERR for secondary lung cancer (75 vs. 58%, p = 0.004) in IMC irradiation, without a significant impact on secondary contralateral BC risks. Conclusion: Although IMC irradiation has been shown to increase survival rates in node-positive BC patients, it increased dose exposure of organs at risk in left-sided BC, resulting in significantly increased risks for secondary lung cancer/contralateral BC and ischaemic heart disease. In this setting, the adoption of IMRT seems advantageous when compared to 3D-CRT.

Benchmarking risk predictions and uncertainties in the NSCR model of GCR cancer risks with revised low let risk coefficients

We report on the contributions of model factors that appear in projection models to the overall uncertainty in cancer risks predictions for exposures to galactic cosmic ray (GCR) in deep space, including comparisons with revised low LET risks coefficients. Annual GCR exposures to astronauts at solar minimum are considered. Uncertainties in low LET risk coefficients, dose and dose-rate modifiers, quality factors (QFs), space radiation organ doses, non-targeted effects (NTE) and increased tumor lethality at high LET compared to low LET radiation are considered. For the low LET reference radiation parameters we use a revised assessment of excess relative risk (ERR) and excess additive risk (EAR) for radiation induced cancers in the Life-Span Study (LSS) of the Atomic bomb survivors that was recently reported, and also consider ERR estimates for males from the International Study of Nuclear Workers (INWORKS). For 45-y old females at mission age the risk of exposure induced death (REID) per year and 95% confidence intervals is predicted as 1.6% [0.71, 1.63] without QF uncertainties and 1.64% [0.69, 4.06] with QF uncertainties. However, fatal risk predictions increase to 5.83% [2.56, 9.7] based on a sensitivity study of the inclusion of non-targeted effects on risk predictions. For males a comparison using LSS or INWORKS lead to predictions of 1.24% [0.58, 3.14] and 2.45% [1.23, 5.9], respectively without NTEs. The major conclusion of our report is that high LET risk prediction uncertainties due to QFs parameters, NTEs, and possible increase lethality at high LET are dominant contributions to GCR uncertainties and should be the focus of space radiation research.

Meta-analysis of published excess relative risk estimates.

A meta-analytic summary effect estimate often is calculated as an inverse-variance-weighted average of study-specific estimates of association. The variances of published estimates of association often are derived from their associated confidence intervals under assumptions typical of Wald-type statistics, such as normality of the parameter. However, in some research areas, such as radiation epidemiology, epidemiological results typically are obtained by fitting linear relative risk models, and associated likelihood-based confidence intervals are often asymmetric; consequently, reasonable estimates of variances associated with study-specific estimates of association may be difficult to infer from the standard approach based on the assumption of a Wald-type interval. Here, a novel method is described for meta-analysis of published results from linear relative risk models that uses a parametric transformation of published results to improve on the normal approximation used to assess confidence intervals. Using simulations, it is illustrated that the meta-analytic summary obtained using the proposed approach yields less biased summary estimates, with better confidence interval coverage, than the summary obtained using the more classical approach to meta-analysis. The proposed approach is illustrated using a previously published example of meta-analysis of epidemiological findings regarding circulatory disease following exposure to low-level ionizing radiation.

Evaluation of statistical modeling approaches for epidemiologic studies of low-dose radiation health effects

Purpose A substantial body of epidemiologic literature addresses risks associated with occupational radiation exposure but comparing results between studies is often difficult as different statistical models are commonly used. It is unclear whether different methods produce similar results for estimates of radiation risk when applied to the same data. The goal of this study was to compare the radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. Materials and methods For brevity, this methods paper presents the results from one cohort, the Nuclear Power Plant workers (NPP), though the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. Results Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. Conclusions As computational power is no longer the burden today as it has been in the past, the results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation.

LEUKEMIA INCIDENCE AND MORTALITY OF RECOVERY OPERATION WORKERS OF THE CHERNOBYL ACCIDENT: ASSESSMENT OF RADIATION RISKS FOR THE FOLLOW-UP PERIOD OF 1986–2014

Leukemia incidence in the cohort of Russian male recovery operation workers (liquidators) was estimated at 78110 people for the follow-up period 1986-2014. The average age of the liquidators at the time of entry into the zone of works for liquidation of the Chernobyl accident was 34 years. Radiation risk of leukemia incidence (with the exception of chronic lymphocytic leukemia) was analyzed for liquidators who had official data on the individual dose of external gamma radiation of the entire body accumulated over the period of work. During the follow-up period, 157 cases of leukemia were detected (with the exception of chronic lymphocytic leukemia). Collection and verification of data of hemoblastoses cases among persons exposed to radiation exposure was carried out according to a specially developed algorithm. The average dose of the liquidators was 108 mGy. During the period 1986–1997 was established a statistically significant (p&lt;0.05) linear dose dependence of the leukemia incidence with an excess relative risk of ERR/Gy=4.17 (90% CI: 0.18, 13.24). From 1998 until the end of the follow-up period, as well as for the entire follow-up period (from 1986 to 2014), no statistically significant estimates of excess relative risk were found. For mortality, no statistically significant estimates of excess relative risk and relative risk were found for any of the observation periods. The obtained estimates of the radiation risk of morbidity indicate that a statistically significant excess leukemia incidence of liquidators, which may be associated with external gamma irradiation, is manifested in the first decade after exposure.

Direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999–2010

A causal relationship between protracted exposure to low-dose rate radiation and health effects remains unclear despite extensive international studies of nuclear workers. One potential reason is that radiation epidemiological studies that adjust for tobacco smoking, which heavily influences mortality, have been limited. In the present study, we examined radiation-related cancer risk by directly assessing the possible confounding effect of smoking, using data from two questionnaire surveys performed among Japanese nuclear workers in 1997 and 2003. Mortality follow-up was carried out for 71 733 male respondents for an average of 8.2 years during the observation period of 1999–2010. The mean cumulative dose was 25.5 mSv at the end of the follow-up period. Estimates of excess relative risk per Sv (ERRs/Sv) were obtained by Poisson regression. By adjusting for smoking directly on the basis of a linear dose-response model, we quantified the confounding effects of smoking on radiation risks. Statistically significant ERRs/Sv were found for all causes, all diseases, all non-cancer diseases, and liver cancer: 0.97 (90% confidence interval: 0.23, 1.78), 1.32 (0.40, 2.34), 1.87 (0.47, 3.49), and 4.78 (0.09, 11.68), respectively, without adjustment for smoking. However, the ERRs/Sv were no longer statistically significant after adjustment for smoking: 0.45 (−0.22, 1.19), 0.77 (−0.08, 1.72), 1.28 (−0.03, 2.79), and 3.89 (−0.46, 10.34), respectively. The ERRs/Sv for all cancers excluding leukaemia and lung cancer were not significant before adjustment for smoking, but declined after adjustment for smoking. The present study demonstrates that in this cohort of workers, smoking heavily distorts radiation risk estimates of mortality. The possibility of confounding by smoking depends on how strongly smoking is correlated with radiation exposure. If a correlation between smoking and radiation dose is suggested, smoking is an important confounder when assessing the radiation and health risks.

Lung Cancer Risk from Plutonium: A Pooled Analysis of the Mayak and Sellafield Worker Cohorts.

In this study, lung cancer risk from occupational plutonium exposure was analyzed in a pooled cohort of Mayak and Sellafield workers, two of the most informative cohorts in the world with detailed plutonium urine monitoring programs. The pooled cohort comprised 45,817 workers: 23,443 Sellafield workers first employed during 1947-2002 with follow-up until the end of 2005 and 22,374 Mayak workers first employed during 1948-1982 with follow-up until the end of 2008. In the pooled cohort 1,195 lung cancer deaths were observed (789 Mayak, 406 Sellafield) but only 893 lung cancer incidences (509 Mayak, 384 Sellafield, due to truncated follow-up in the incidence analysis). Analyses were performed using Poisson regression models, and were based on doses derived from individual radiation monitoring data using an updated dose assessment methodology developed in the study. There was clear evidence of a linear association between cumulative internal plutonium lung dose and risk of both lung cancer mortality and incidence in the pooled cohort. The pooled point estimates of the excess relative risk (ERR) from plutonium exposure for both lung cancer mortality and incidence were within the range of 5-8 per Gy for males at age 60. The ERR estimates in relationship to external gamma radiation were also significantly raised and in the range 0.2-0.4 per Gy of cumulative gamma dose to the lung. The point estimates of risk, for both external and plutonium exposure, were comparable between the cohorts, which suggests that the pooling of these data was valid. The results support point estimates of relative biological effectiveness (RBE) in the range of 10-25, which is in broad agreement with the value of 20 currently adopted in radiological protection as the radiation weighting factor for alpha particles, however, the uncertainty on this value (RBE = 21; 95% CI: 9-178) is large. The results provide direct evidence that the plutonium risks in each cohort are of the same order of magnitude but the uncertainty on the Sellafield cohort plutonium risk estimates is large, with observed risks consistent with no plutonium risk, and risks five times larger than those observed in the Mayak cohort.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

BackgroundAnalyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour.MethodsGAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 – 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy.ResultsFor all solid cancer incidence, RR estimated from 0 – 100 mGy and 0 – 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 – 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort.ConclusionNon-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0191-3) contains supplementary material, which is available to authorized users.

Mortality among military participants at the 1957 PLUMBBOB nuclear weapons test series and from leukemia among participants at the SMOKY test

Health effects following low doses of ionizing radiation are uncertain. Military veterans at the Nevada test site (NTS) during the SMOKY atmospheric nuclear weapons test in 1957 were reported to be at increased risk for leukemia in 1979, but this increase was not evaluated with respect to radiation dose. The SMOKY test was one of 30 tests in 1957 within the PLUMBBOB test series. These early studies led to public laws where atomic veterans could qualify for compensation for presumptive radiogenic diseases.A retrospective cohort study was conducted of 12219 veterans at the PLUMBBOB test series, including 3020 at the SMOKY nuclear test. Mortality follow-up was through 2010 and observed causes of death were compared with expected causes based on general population rates. Radiation dose to red bone marrow was based on individual dose reconstructions, and Cox proportional hazards models were used to evaluate dose response for all leukemias other than chronic lymphocytic leukemia (non-CLL leukemia).Vital status was determined for 95.3% of the 12 219 veterans. The dose to red bone marrow was low (mean 3.2 mGy, maximum 500 mGy). Military participants at the PLUMBBOB nuclear test series remained relatively healthy after 53 years and died at a lower rate than the general population. In contrast, and in comparison with national rates, the SMOKY participants showed significant increases in all causes of death, respiratory cancer, leukemia, nephritis and nephrosis, and accidents, possibly related in part to lifestyle factors common to enlisted men who made up 81% of the SMOKY cohort.Compared with national rates, a statistically significant excess of non-CLL leukemia was observed among SMOKY participants (Standardized Mortality Ratio  =  1.89, 95% 1.24–2.75, n  =  27) but not among PLUMBBOB participants after excluding SMOKY (SMR  =  0.87, 95% 0.64–1.51, n  =  47). Leukemia risk, initially reported to be significantly increased among SMOKY participants, remained elevated, but this risk diminished over time. Despite an intense dose reconstruction, the risk for leukemia was not found to increase with increasing levels of radiation dose to the red bone marrow. Based on a linear model, the estimated excess relative risk per mGy is  −0.05 (95% CI -0.14, 0.04). An explanation for the observed excess of leukemia remains unresolved but conceivably could be related to chance due to small numbers, subtle biases in the study design and/or high tobacco use among enlisted men. Larger studies should elucidate further the possible relationship between fallout radiation, leukemia and cancer among atomic veterans.

Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies.

Studies have causally linked external thyroid radiation exposure in childhood with thyroid cancer. In 1995, investigators conducted relative risk analyses of pooled data from seven epidemiologic studies. Doses were mostly <10 Gy, although childhood cancer therapies can result in thyroid doses >50 Gy. We pooled data from 12 studies of thyroid cancer patients who were exposed to radiation in childhood (ages <20 years), more than doubling the data, including 1,070 (927 exposed) thyroid cancers and 5.3 million (3.4 million exposed) person-years. Relative risks increased supralinearly through 2-4 Gy, leveled off between 10-30 Gy and declined thereafter, remaining significantly elevated above 50 Gy. There was a significant relative risk trend for doses <0.10 Gy (P < 0.01), with no departure from linearity (P = 0.36). We observed radiogenic effects for both papillary and nonpapillary tumors. Estimates of excess relative risk per Gy (ERR/Gy) were homogeneous by sex (P = 0.35) and number of radiation treatments (P = 0.84) and increased with decreasing age at the time of exposure. The ERR/Gy estimate was significant within ten years of radiation exposure, 2.76 (95% CI, 0.94-4.98), based on 42 exposed cases, and remained elevated 50 years and more after exposure. Finally, exposure to chemotherapy was significantly associated with thyroid cancer, with results supporting a nonsynergistic (additive) association with radiation.

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.

Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy.

Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta-analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30–1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1–2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran's Q statistic (P < 0.001), which may be partly accounted for by age at exposure.

Risks of circulatory diseases among Mayak PA workers with radiation doses estimated using the improved Mayak Worker Dosimetry System 2008

The new Mayak Worker Dosimetry System 2008 (MWDS-2008) was published in 2013 and supersedes the Doses-2005 dosimetry system for Mayak Production Association (PA) workers. It provides revised external and internal dose estimates based on the updated occupational history data. Using MWDS-2008, a cohort of 18,856 workers first employed at one of the main Mayak PA plants during 1948-1972 and followed up to 2005 was identified. Incidence and mortality risks from ischemic heart disease (IHD) (International Classification of Diseases (ICD)-9 codes 410-414) and from cerebrovascular diseases (CVD) (ICD-9 codes 430-438) were examined in this cohort and compared with previously published risk estimates in the same cohort based on the Doses-2005 dosimetry system. Significant associations were observed between doses from external gamma-rays and IHD and CVD incidence and also between internal doses from alpha-radiation and IHD mortality and CVD incidence. The estimates of excess relative risk (ERR)/Gy were consistent with those estimates from the previous studies based on Doses-2005 system apart from the relationship between CVD incidence and internal liver dose where the ERR/Gy based on MWDS-2008 was just over three times higher than the corresponding estimate based on Doses-2005 system. Adjustment for smoking status did not show any effect on the estimates of risk from internal alpha-particle exposure.