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Background: Although high doses of ionizing radiation have long been linked to circulatory disease, evidence for an association at lower exposures remains controversial. However, recent analyses suggest excess relative risks at occupational exposure levels

Background: The cause-of-death register at the Southern Urals Biophysics Institute (SUBI), Ozyorsk, Russia, was established to document the number and causes of deaths in the Mayak workers cohort, which includes all persons (N = 22,377) employed at Mayak nuclear facility between 1948 and 1982. Most workers were occupationally exposed to high doses of ionizing radiation and have been shown to have increased risks of various chronic diseases including cancer.Objectives: To investigate the quality of cause of death coding in the SUBI register.Methods: A random sample of 246 deaths (~1% of the total) was coded independently at the SUBI and the Danish Cancer Society using the International Classification of Diseases 9 (ICD-9). Proportions of matching codes were calculated.Results: Overall, 233 deaths (95%) were identically classified using the ICD-9 main category matching. Excluding mismatches that were considered to be incorrectly coded during validation, the validity of the register increased to 98%. Using the specific ICD-9 first three-digit matching, 182 deaths were identically coded (74%) and the respective validity of the register was 85%. There were also some non-resolvable discrepancies demonstrating limitations of assigning one code for each death or using language-adapted ICD-9 version.Conclusions: This validation study was an important quality check of a register used for mortality follow-up in a highly influential epidemiological study on radiation-related health effects. The results of the inter-institutional comparison were generally favourable; however, since the comparison revealed individual mismatches and some systematically differing coding practices, it is essential to repeat it on a regular basis in order to maintain a high quality. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. It has been known for some considerable time that radiation is associated with excess risk of CVD. A recent systematic review of radiation and CVD highlighted substantial inter-study heterogeneity in effect, possibly a result of confounding or modifications of radiation effect by non-radiation factors, in particular by the major lifestyle/environmental/medical risk factors and latent period., Methods: We assessed effects of confounding by lifestyle/environmental/medical risk factors on radiation-associated CVD and investigated evidence for modifying effects of these variables on CVD radiation dose-response, using data assembled for a recent systematic review., Results: There are 43 epidemiologic studies which are informative on effects of adjustment for confounding or risk modifying factors on radiation-associated CVD. Of these 22 were studies of groups exposed to substantial doses of medical radiation for therapy or diagnosis. The remaining 21 studies were of groups exposed at much lower levels of dose and/or dose rate. Only four studies suggest substantial effects of adjustment for lifestyle/environmental/medical risk factors on radiation risk of CVD; however, there were also substantial uncertainties in the estimates in all of these studies. There are fewer suggestions of effects that modify the radiation dose response; only two studies, both at lower levels of dose, report the most serious level of modifying effect., Conclusions: There are still large uncertainties about confounding factors or lifestyle/environmental/medical variables that may influence radiation-associated CVD, although indications are that there are not many studies in which there are substantial confounding effects of these risk factors., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The aim of the present study was to assess the risk of primary central nervous system (CNS) tumour incidence in a cohort of 22,377 Mayak Production Association workers chronically exposed to ionising radiation. There were 96 primary CNS tumours, including 42 cases of glioma and 44 cases of meningioma, registered during the whole follow-up period (1948-2018). The study demonstrated that the risk of primary CNS tumour incidence was associated with sex, attained age, calendar period, tall body height, age at the beginning of exposure, and facility type. There was no association found between risk of CNS tumour incidence and body mass index, smoking (males) and alcohol consumption status. The study did not find an effect of the total external gamma radiation dose absorbed in the brain on risk of CNS tumour incidence irrespective of whether an adjustment for the total external neutron dose absorbed in the brain was included or not. Excess relative risk per 1 Gy of external gamma brain dose was 0.05 (95% confidence interval (CI) -0.30; 0.70) for all CNS tumours, -0.18 (95% CI -; 0.44) for gliomas, and 0.38 (95% CI -0.32; 2.08) for meningiomas without adjustment for total neutron brain dose. There was no effect modification by sex, attained age, age at hire or facility., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Specimens of lung adenocarcinoma (AdCa) from Russian nuclear workers ( n  = 54) exposed to alpha particles and gamma rays and from individuals non-exposed to radiation ( n  = 21) were examined using immunohistochemistry. Estimated significant associations with alpha dose were negative for Ki-67 and collagen IV in AdCa. Associations with gamma-ray dose were negative for tissue inhibitor of matrix metalloproteinase 2 and caspase 3 and positive for matrix metalloproteinase 2 and leukemia inhibiting factor in AdCa. The findings provide some evidence supporting alterations in apoptosis, cell proliferation and extracellular matrix in lung tissues affected by chronic radiation exposure that can contribute to radiogenic cancerogenesis.

The study aimed to estimate threshold doses and their uncertainties for some human health effects after short-term high dose-rate radiation exposure by quantile technique and the effective dose threshold technique based on distribution functions. The relative uncertainty (U) of the threshold dose was estimated using the error propagation technique. The quantile technique provided statistically significant estimates of threshold doses for acute radiation syndrome onset (0.44 ± 0.12 Gy, U = 143%) and lethality (1.84 ± 0.44 Gy, U = 117%) but relative uncertainties were high. The effective threshold dose technique provided statistically significant and more precise threshold dose estimates for acute radiation syndrome onset (0.73 ± 0.02 Gy, U = 18%) and lethality (6.83 ± 0.08 Gy, U = 36%), as well as agranulocytosis (3.51 ± 0.03 Gy, U = 16%) and vomiting onset in the prodromal period (1.54 ± 0.02 Gy, U = 16%). Threshold doses estimated for the change in the peripheral blood neutrophil and leukocyte counts during the first days after short-term high dose-rate radiation exposure were not statistically significant., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To systematically review and perform a meta-analysis of radiation associated risks of cardiovascular disease in all groups exposed to radiation with individual radiation dose estimates., Design: Systematic review and meta-analysis., Main Outcome Measures: Excess relative risk per unit dose (Gy), estimated by restricted maximum likelihood methods., Data Sources: PubMed and Medline, Embase, Scopus, Web of Science Core collection databases., Eligibility Criteria for Selecting Studies: Databases were searched on 6 October 2022, with no limits on date of publication or language. Animal studies and studies without an abstract were excluded., Results: The meta-analysis yielded 93 relevant studies. Relative risk per Gy increased for all cardiovascular disease (excess relative risk per Gy of 0.11 (95% confidence interval 0.08 to 0.14)) and for the four major subtypes of cardiovascular disease (ischaemic heart disease, other heart disease, cerebrovascular disease, all other cardiovascular disease). However, interstudy heterogeneity was noted (P<0.05 for all endpoints except for other heart disease), possibly resulting from interstudy variation in unmeasured confounders or effect modifiers, which is markedly reduced if attention is restricted to higher quality studies or those at moderate doses (<0.5 Gy) or low dose rates (<5 mGy/h). For ischaemic heart disease and all cardiovascular disease, risks were larger per unit dose for lower dose (inverse dose effect) and for fractionated exposures (inverse dose fractionation effect). Population based excess absolute risks are estimated for a number of national populations (Canada, England and Wales, France, Germany, Japan, USA) and range from 2.33% per Gy (95% confidence interval 1.69% to 2.98%) for England and Wales to 3.66% per Gy (2.65% to 4.68%) for Germany, largely reflecting the underlying rates of cardiovascular disease mortality in these populations. Estimated risk of mortality from cardiovascular disease are generally dominated by cerebrovascular disease (around 0.94-1.26% per Gy), with the next largest contribution from ischaemic heart disease (around 0.30-1.20% per Gy)., Conclusions: Results provide evidence supporting a causal association between radiation exposure and cardiovascular disease at high dose, and to a lesser extent at low dose, with some indications of differences in risk between acute and chronic exposures, which require further investigation. The observed heterogeneity complicates a causal interpretation of these findings, although this heterogeneity is much reduced if only higher quality studies or those at moderate doses or low dose rates are considered. Studies are needed to assess in more detail modifications of radiation effect by lifestyle and medical risk factors., Systematic Review Registration: PROSPERO CRD42020202036., Competing Interests: Competing interest: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: AJE has received speaker fees from Ionetix; has received consulting fees from WL Gore & Associates; has received authorship fees from Wolters Kluwer Healthcare–UpToDate; and has received grants to his institution from Attralus, Canon Medical Systems, Eidos Therapeutics, GE Healthcare, Pfizer, Roche Medical Systems, WL Gore & Associates, and XyloCor Therapeutics; none of these are related to the present work. Otherwise no other authors declare any competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Heart diseases are one of the main causes of death. The incidence risks were assessed for various types of heart diseases (HDs) in a cohort of Russian nuclear workers of the Mayak Production Association (PA) who had been chronically occupationally exposed to external gamma and/ or internal alpha radiation. The study cohort included all workers (22,377 individuals) who had been hired at the Mayak PA during 1948-1982 and followed up until 31 December 2018. The mean gamma-absorbed dose to the liver (standard deviation) was 0.43 (0.63) Gy, and the mean alpha-absorbed dose to the liver was 0.25 (1.19) Gy. Excess relative risk (ERR) per unit liver-absorbed dose (Gy) was calculated based on maximum likelihood. At the end of the follow-up, 559 chronic rheumatic heart disease (CRHD), 7722 ischemic heart disease (IHD) [including 2185 acute myocardial infarction (AMI) and 3976 angina pectoris (AP)], 4939 heart failure (HF), and 3689 cardiac arrhythmia and conduction disorder (CACD) cases were verified in the study cohort. Linear model fits of the gamma dose response for HDs were best once adjustments for non-radiation factors (sex, attained age, calendar period, smoking status and alcohol consumption) and alpha dose were included. ERR/Gy in males and females was 0.17 (95% confidence intervals: 0.10, 0.26) and 0.23 (0.09, 0.38) for IHD; 0.18 (0.09, 0.29) and 0.26 (0.08, 0.49) for AP; - 0.01 (n/a, 0.1) and - 0.01 (n/a, 0.27) for AMI; 0.27 (0.16, 0.40) and 0.27 (0.10, 0.49) for HF; 0.32 (0.19, 0.46) and 0.05 (- 0.09, 0.22) for CACD; 0.73 (- 0.02, 2.40) and - 0.12 (- 0.50, 0.69) for CRHD, respectively. Sensitivity analyses demonstrated the persistence of a significant dose-response regardless of exclusion/inclusion of adjustments for known potential non-radiation confounders (smoking, alcohol consumption, body mass index, hypertension, diabetes mellitus), and it was only the magnitude of the risk estimate that varied. The risks of HD incidence were not modified with sex (except for the CACD risk). This study provides evidence for a significant association of certain types of HDs with cumulative dose of occupational chronic external exposure to gamma radiation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

For improvement of the radiation protection system it is crucial to know the factors that modify the radiation dose-response relationship. One of such key factors is the ionizing radiation dose rate. There are, however, very few studies that examine the impact of the dose rate on radiogenic risks observed in human cohorts exposed to radiation at various dose rates. Here we investigated the impact of the dose rate (in terms of the recorded annual dose) on ischemic heart disease (IHD) mortality among Russian nuclear workers chronically exposed to radiation. We observed significantly increased excess relative risks (ERR) of IHD mortality per unit of external gamma-ray absorbed dose accumulated at higher dose rates (0.005-0.050 Gy/year). The present findings provide evidence for the association between radiation dose rate and ERRs of IHD mortality in occupationally chronically exposed workers per unit total dose. IHD mortality risk estimates considerably increased with increasing duration of uninterrupted radiation exposure at high rates. The present findings are consistent with other studies and can contribute to the scientific basis for recommendations on the radiation protection system., (© 2023. The Author(s).)

This paper reports on the findings from the study of mortality from diseases of the circulatory system (DCS) in Russian nuclear workers of the Mayak Production Association (22 377 individuals, 25.4% female) who were hired at the facility between 1948 and 1982 and followed up until the end of 2018. Using the AMFIT module of the EPICURE software, relative risks (RRs) and excess RRs per unit absorbed dose (ERR/Gy) for the entire Mayak cohort, the subcohort of workers who were residents of the dormitory town of Ozyorsk and the subcohort of migrants from Ozyorsk were calculated based on maximum likelihood. The mean cumulative liver absorbed gamma-ray dose from external exposure was 0.45 (0.65) Gy (mean (standard deviation)) for men and 0.37 (0.56) Gy for women. The mean cumulative liver absorbed alpha dose from internal exposure to incorporated plutonium was 0.18 (0.65) Gy for men and 0.40 (1.92) Gy for women. By the end of the follow-up, 6019 deaths with DCS as the main cause of death were registered among Mayak Production Association workers (including 3828 deaths in the subcohort of residents and 2191 deaths in the subcohort of migrants) over 890 132 (622 199/267 933) person-years of follow-up. The linear model that took into account non-radiation factors (sex, attained age, calendar period, smoking status and alcohol drinking status) and alpha radiation dose (via adjusting) did not demonstrate significant associations of mortality from DCS, ischaemic heart disease (IHD) and cerebrovascular disease with gamma-ray exposure dose in the entire cohort, the resident subcohort or the migrant subcohort (either in men or women). For the subcohort of residents, a significant association with gamma dose was observed for mortality from ischaemic stroke in men with ERR/Gy = 0.43 (95% CI 0.08; 0.99); there were no significant associations with liver absorbed gamma dose for any other considered outcomes. As for internal exposure, for men no significant associations of mortality from any DCS with liver absorbed alpha dose were observed, but for women positive associations were found for mortality from DCS (the entire cohort and the resident subcohort) and IHD (the entire cohort). No significant associations of mortality from various types of DCS with neutron dose were observed either in men or women, although neutron absorbed doses were recorded in only 18% of the workers., (© 2022 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

Incidence risks for cerebrovascular diseases (CeVD) and some types of stroke in a cohort of 22,377 Russian Mayak nuclear workers chronically exposed to ionising radiation and followed up until the end of 2018 are reported. Among total 9469 cases of CeVD, 2078 cases were strokes that included 262 hemorrhagic strokes (HS) and 1611 ischemic strokes (IS). Data evaluation was performed with categorical and dose-response analyses estimating the relative risk (RR) and excess relative risk (ERR) per unit cumulative liver absorbed dose of external gamma-ray or internal alpha-particle exposure based on a linear model utilizing the AMFIT module of the EPICURE software. CeVD incidence was found to be significantly associated with cumulative radiation dose: ERR/Gy was 0.37 (95% confidence interval (CI) 0.27, 0.47) in males and 0.47 (95% CI 0.31, 0.66) in females for external exposure, and 0.31 (95% CI 0.11, 0.59) in males and 0.32 (95% CI 0.11, 0.61) in females for internal exposure. When the model for the analysis of external radiation effect did not include an adjustment for alpha radiation dose (and vice versa), the radiogenic risk estimate increased notably both for males and for females. In contrast, exclusion from or inclusion in the model of additional adjustments for non-radiation factors did not notably change the risk estimates. ERR/Gy of external gamma dose for CeVD incidence significantly decreased with increasing attained age (males and females) and duration of employment (females). No significant associations of either stroke or its types with cumulative gamma-ray dose of external exposure or alpha-particle dose of internal exposure were found., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

Recently, several compilations of individual radiation epidemiology study results have aimed to obtain direct evidence on the magnitudes of dose-rate effects on radiation-related cancer risks. These compilations have relied on meta-analyses of ratios of risks from low dose-rate studies and matched risks from the solid cancer Excess Relative Risk models fitted to the acutely exposed Japanese A-bomb cohort. The purpose here is to demonstrate how choices of methodology for evaluating dose-rate effects on radiation-related cancer risks may influence the results reported for dose-rate effects. The current analysis is intended to address methodological issues and does not imply that the authors recommend a particular value for the dose and dose-rate effectiveness factor. A set of 22 results from one recent published study has been adopted here as a test set of data for applying the many different methods described here, that nearly all produced highly consistent results. Some recently voiced concerns, involving the recalling of the well-known theoretical point-the ratio of two normal random variables has a theoretically unbounded variance-that could potentially cause issues, are shown to be unfounded when aimed at the published work cited and examined in detail here. In the calculation of dose-rate effects for radiation protection purposes, it is recommended that meta-estimators should retain the full epidemiological and dosimetric matching information between the risks from the individual low dose-rate studies and the acutely exposed A-bomb cohort and that a regression approach can be considered as a useful alternative to current approaches., (© 2021. The Author(s).)

The incidence risk of non-melanoma skin cancer (NMSC), in particular basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), was investigated in a cohort of workers of the Russian nuclear facility, the Mayak Production Association (PA), who had been occupationally exposed to low dose-rate ionizing radiation over prolonged periods. The study cohort included all workers who had been hired at the enterprise in 1948-1982 and followed up to 31.12.2018 (22,377 individuals, 25% of females). The mean cumulative skin absorbed dose of external gamma-ray exposure was 0.50 ± 0.73 Gy (the range of 0.00-8.84 Gy); the mean cumulative skin absorbed dose of neutron exposure was 0.002 ± 0.004 Gy (the range of 0.0000002-0.153 Gy). Relative risk and excess relative risk per unit skin absorbed dose of external exposure (RR and ERR/Gy) were estimated using AMFIT module of EPICURE software. Over the entire follow-up period 295 (84.8%) BCC, 48 (13.8%) SCC and 5 (1.4%) skin appendage cell carcinomas (SACC) were registered among NMSC in members of the study cohort. A significant linear association of the BCC incidence with the cumulative skin absorbed dose of external gamma-ray exposure was observed: ERR/Gy = 0.57 (95% CI 0.24, 1.06). Inclusion of an adjustment for neutron dose in the model resulted in a modest reduction of the BCC risk estimate [ERR/Gy = 0.55 (95% CI 0.23, 1.03)]. No significant association was revealed for SCC incidence with cumulative skin absorbed dose of external gamma-ray exposure [ERR/Gy = 0.14 (95% CI - 0.23, 0.91)]; inclusion of the neutron dose adjustment in the model did not modify the estimated SCC risk. No modification of the BCC and SCC incidence risks by sex, age at hire, attained age and facility type was observed.

Purpose: There are well-known correlations between high and moderate doses (>0.5 Gy) of ionizing radiation exposure and circulatory system damage, also between radiation and posterior subcapsular cataract. At lower dose correlations with circulatory disease are emerging in the Japanese atomic bomb survivors and in some occupationally exposed groups, and are still to some extent controversial. Heterogeneity in excess relative risks per unit dose in epidemiological studies at low (<0.1 Gy) and at low-moderate (>0.1 Gy, <0.5 Gy) doses may result from confounding and other types of bias, and effect modification by established risk factors. There is also accumulating evidence of excess cataract risks at lower dose and low dose rate in various cohorts. Other ocular endpoints, specifically glaucoma and macular degeneration have been little studied. In this paper, we review recent epidemiological findings, and also discuss some of the underlying radiobiology of these conditions. We briefly review some other types of mainly neurological nonmalignant disease in relation to radiation exposure., Conclusions: We document statistically significant excess risk of the major types of circulatory disease, specifically ischemic heart disease and stroke, in moderate- or low-dose exposed groups, with some not altogether consistent evidence suggesting dose-response non-linearity, particularly for stroke. However, the patterns of risk reported are not straightforward. We also document evidence of excess risks at lower doses/dose-rates of posterior subcapsular and cortical cataract in the Chernobyl liquidators, US Radiologic Technologists and Russian Mayak nuclear workers, with fundamentally linear dose-response. Nuclear cataracts are less radiogenic. For other ocular endpoints, specifically glaucoma and macular degeneration there is very little evidence of effects at low doses; radiation-associated glaucoma has been documented only for doses >5 Gy, and so has the characteristics of a tissue reaction. There is some evidence of neurological detriment following low-moderate dose (∼0.1-0.2 Gy) radiation exposure in utero or in early childhood.

The International Commission on Radiological Protection (ICRP) has considered for over 60 years that the lens of the eye is among the most radiosensitive tissues, and has recommended dose limits for the lens to prevent occurrence of vision impairing cataracts (VICs). Epidemiological evidence that doses much lower than previously thought produce cataracts led ICRP to recommend reducing dose threshold for VICs and reducing an occupational equivalent dose limit for the lens in 2011, when only a single threshold of 0.5 Gy was recommended. On the basis of epidemiological evidence, ICRP assumed progression of minor opacities into VICs and no dose rate effect. This contrasts with previously recommended separate thresholds for minor opacities and VICs, and for different exposure scenarios. Progression was assumed based on similar risks of cataracts and cataract surgery in Japanese atomic bomb survivors. The absence of dose rate effect derived from the observed similar thresholds for protracted exposures in Chernobyl cleanup workers and in atomic bomb survivors. Since 2011, there has been an increasing body of epidemiological evidence relating to cataracts and other ocular diseases ( i.e. glaucoma and macular degeneration), particularly at low doses and low dose rates. This review paper gives an overview of the scientific basis of the 2011 ICRP recommendation, discusses the plausibility of these two assumptions in the light of emerging scientific evidence, and considers the radiosensitivity of the lens among ocular structures.

Stomach cancer is a widespread health condition associated with environmental and genetic factors. Contribution of ionizing radiation to stomach cancer etiology is not sufficiently studied. This study was aimed to assess an association of the stomach cancer incidence risk with doses from occupational radiation exposure in a cohort of workers hired at main Mayak production association facilities in 1948-1982 taking into account non-radiation factors including digestive disorders. The study cohort comprised 22,377 individuals and by 31.12.2013 343 stomach cancer diagnoses had been reported among the cohort members. Occupational stomach absorbed doses were provided by the Mayak Worker Dosimetry System- 2008 (MWDS-2008) for external gamma ray exposure and by the Mayak Worker Dosimetry System- 2013 (MWDS-2013) for internal exposure to plutonium. Excess relative risks (ERR) per Gy for stomach cancer were estimated using the Poisson's regression. Analyses were run using the AMFIT module of the EPICURE software. The stomach cancer incidence risk in the study cohort was found to be significantly associated with the stomach absorbed dose of gamma rays: ERR/Gy = 0.19 (95% CI: 0.01, 0.44) with a 0 year lag, and ERR/Gy = 0.20 (95% CI: 0.01, 0.45) with a 5 year lag. To estimate the baseline risk, sex, attained age, smoking status and alcohol consumption, chronic diseases (peptic ulcer, gastritis and duodenitis) were taken into account. No modifications of the radiogenic risk by non-radiation factors were found in the study worker cohort. No association of the stomach cancer incidence risk with internal exposure to incorporated plutonium was observed., Competing Interests: The authors have declared that no competing interests exist.

Background: Patients receiving radiotherapy demonstrate cognitive deficits, impairment of neurogenesis and neurovascular damage developing as late side effects of radiation exposure to the head. In light of the increasing use of diagnostic radiological procedures, epidemiological data raise concerns about possible harmful effects of low-level radiation on the human brain. A series of studies of chronically exposed Russian nuclear workers have provided information on risks of cancer and non-cancer diseases., Methods: This study aimed to assess the risk of Parkinson's-disease (PD) incidence in a cohort of workers occupationally exposed to chronic radiation. The cohort comprised workers of a Russian nuclear production facility who were first employed in 1948-1982 and followed up until the end of 2013 (22 377 individuals; 25% female). Using the AMFIT module of EPICURE software, relative risk and excess relative risk per unit dose (ERR/Gy) were calculated based on maximum likelihood., Results: A linear association was found between PD incidence and cumulative γ-dose after adjusting for sex and attained age [ERR/Gy = 1.02 (95% confidence interval, 0.59 to 1.63, p = 5.44 × 10-5)]. The ERR/Gy of external radiation for PD incidence was stable after adjusting for neutron dose (ERR/Gy = 1.03; 95% confidence interval: 0.59 to 1.67, p = 6.86 × 10-5). The risk increased with increasing lag period and decreased notably after adjusting for body mass index, smoking and alcohol consumption. Additional adjustments for hypertension, gout, gastric ulcer, head injuries with loss of awareness and diabetes mellitus did not affect the risk estimate., Conclusions: This study is the first to suggest that PD is associated with prolonged occupational external γ-ray exposure., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

A registry for chronic radiation syndrome (CRS), a deterministic effect of chronic exposure to external and/or internal radiation at doses and dose rates exceeding thresholds for tissue reactions, was established within a medical and dosimetry database known as 'Clinics', of the Southern Urals Biophysics Institute at the Federal Medical and Biological Agency of Russia. It includes 2068 CRS cases: 1517 (73.4%) in males and 551 (26.6%) in females. The majority of workers (97.9%) diagnosed with CRS at one of the main facilities of the first Russian nuclear enterprise, Mayak Production Association, were hired in the period 1948-1954. On the date of CRS diagnosis, the mean cumulative red bone marrow (RBM) absorbed doses from external gamma rays were 1.1 ± 0.66 Gy in males and 1.0 ± 0.58 Gy (±standard deviation) in females, with mean annual doses of 0.46 ± 0.33 Gy and 0.38 ± 0.22 Gy, respectively, and maximum annual doses of 0.67 ± 0.46 Gy and 0.55 ± 0.34 Gy, respectively. The frequency of CRS cases significantly increased with the increasing cumulative and mean annual RBM absorbed doses from external gamma rays. The paper presents the structure and descriptive characteristics of the CRS registry as well as prospects for its use.

Glaucoma is a major cause of visual impairment, and secondary glaucoma manifested as neovascular glaucoma has long been known to occur following high-dose fractionated radiation therapy. In contrast, little is known as to whether ionizing radiation exposure causes primary glaucoma, except that a single study in Japanese atomic bomb survivors has reported a significantly increase risk. Therefore, the effect of lower dose and lower dose rate remains unclear. Here we report that in Russian Mayak Production Association workers occupationally exposed to chronic radiation for prolonged periods, incidence of total primary glaucoma and primary open-angle glaucoma is significantly associated with various non-radiation factors (sex, attained age, and cataract diagnosed prior to glaucoma), but neither with cumulative dose from external γ-rays nor with cumulative neutron dose nor with the unweighted sum of cumulative γ and neutron doses. The present results suggest for the first time that chronic radiation exposure does not cause primary glaucoma, although the analyses need to be made in other cohorts exposed at various dose and dose rate.

In this study, the risk of cataract removal surgery was assessed in a cohort of workers occupationally exposed to ionizing radiation over a prolonged period. The study cohort includes 22,377 workers of the Mayak Production Association (about 25% of whom are females) first employed at one of the main facilities in 1948-1982, who were followed up to the end of 2008. Dose estimates used in the study are provided by the Mayak Worker Dosimetry System 2008. The mean cumulative dose from external γ-rays [personal dose equivalent H p (10)] is 0.54 ± 0.76 Sv for males and 0.44 ± 0.65 Sv for females. The mean cumulative doses from neutrons (personal dose equivalent H p (10) n ) were 0.034 ± 0.080 Sv for males and 0.033 ± 0.092 Sv for females. Relative risks and excess relative risks per unit dose were calculated based on maximum likelihood. Among 4,177 workers diagnosed with a verified diagnosis of senile cataract, 701 lens removal surgeries (16.7%) were performed by the end of the follow-up period. The risk of cataract removal surgery was shown to be significantly associated with non-radiation factors such as sex, attained age, smoking, an ocular comorbidity (e.g., glaucoma), and a somatic comorbidity (e.g., diabetes mellitus). There was no significant association of cataract removal surgery with external γ-dose regardless of inclusion of the neutron dose adjustment with either linear or non-linear models. It is concluded that cataract removal surgery rate may not be a highly sensitive and specific indicator that could serve as a surrogate for radiation-related cataracts.

Glaucoma is a group of optic neuropathies causing optic nerve damage and visual field defects, and is one of the leading causes of blindness. Nearly a century has passed since the first report of glaucoma manifested following ionizing radiation therapy of cancers. Nevertheless, associations between glaucoma and radiation exposures, a dose response relationship, and the mechanistic underpinnings remain incompletely understood. Here we review the current knowledge on manifestations and mechanisms of radiogenic glaucoma. There is some evidence that neovascular glaucoma is manifest relatively quickly, within a few years after high-dose and high dose-rate radiotherapeutic exposure, but little evidence of excess risks of glaucoma after exposure to much lower doses or dose rates. As such, glaucoma appears to have some of the characteristics of a tissue reaction effect, with a threshold of at least 5 Gy but possibly much higher., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study is the first to report cataract type specific risks in a cohort of Russian Mayak Production Association workers following chronic occupational exposure to ionizing radiation. In this retrospective cohort study, 22,377 workers (females 25.4%) first employed in 1948-1982 were followed up till the end of 2008. All cataract subtypes were significantly dependent on sex, attained age, diabetes mellitus, myopia and glaucoma. For each of posterior subcapsular (PSC), cortical and nuclear cataracts, the risk of cataract incidence significantly linearly increased with increasing radiation dose. Excess relative risk per unit effective dose (ERR/Sv) from external γ-rays based on the linear model was 0.91 [95% confidence intervals (CIs) 0.67, 1.20] for PSC, 0.63 (95% CIs 0.49, 0.76) for cortical, and 0.47 (95% CIs 0.35, 0.60) for nuclear cataracts. For all three types of cataracts, exclusion of an adjustment for neutron dose as well as inclusion of additional adjustments for body mass index and smoking index decreased ERR/Sv of external γ-rays. Inclusion of an additional adjustment for glaucoma, however, modestly increased incidence risks for cortical and nuclear cataracts, but not PSC cataracts. Inclusion of an adjustment for diabetes mellitus decreased ERR/Sv of external γ-rays only for PSC incidence. Both males and females had increased risks for all three types of cataracts, but ERR/Sv was significantly higher in females than in males (p < 0.001), particularly for PSC cataracts. The results suggest that chronic occupational radiation exposure significantly increases risks of PSC, cortical and nuclear cataracts, and that such risks are higher in females than in males.

Recently an increasing trend in skin cancer rates has been observed in various populations including those exposed to different radiation types. Risk and dose-response following prolonged radiation exposure remain unclear. The present study was aimed to assess skin melanoma (SM) and non-melanoma skin cancer (NMSC) incidence risks in a cohort of workers occupationally exposed to ionizing radiation at low dose rates over prolonged periods. The study cohort included workers of a Russian nuclear production facility, Mayak Production Association (PA), who were first employed in 1948-1982 and followed up till the end of 2013 (the total of 22,377 individuals with 25% of females). Using AMFIT module of EPICURE software, relative risk and excess relative risk per unit dose (RR and ERR/Sv) were calculated. 60 SM and 294 NMSC cases were registered in members of the study cohort. SM and NMSC incidence was dependent on sex, attained age, age at first employment at the enterprise, type of facility, education level and was not dependent on calendar period of first employment, calendar period of diagnosis, duration of employment, smoking and alcohol consumption statuses. The risk of NMSC incidence was found to be significantly increased in workers occupationally exposed to ionizing radiation at cumulative doses above 2.0 Sv (RR = 2.52; 95% CI: 1.60, 3.97) compared to a reference dose category (0-0.05 Sv). NMSC incidence was found to be significantly associated with cumulative external gamma-dose with ERR/Sv of 0.49 (95% CI: 0.22, 0.90) without an adjustment for neutron dose and 0.51 (95% CI: 0.22, 0.93) while adjusted for neutron dose. Results of the analysis did not reveal a significant association of SM incidence with cumulative dose from external gamma-rays with ERR/Sv of 0.22 (95% CI: -0.29, 1.46) not including a neutron dose adjustment and of 0.15 (95% CI: -0.41, 1.31) while adjusted for dose from neutron exposure., Competing Interests: The authors have declared that no competing interests exist.

This study aimed to identify immunological biomarkers for prolonged occupational radiation exposure and thus studied a random sample of the Mayak Production Association worker cohort (91 individuals). The control group included 43 local individuals never employed at the Mayak Production Association. To identify biomarkers, two groups of workers were formed: the first one included workers chronically exposed to external gamma rays at cumulative doses of 0.5-3.0 Gy (14 individuals); the second one included workers exposed to combined radiation-external gamma rays at doses ranging from 0.7 to 5.1 Gy and internal alpha radiation from incorporated plutonium with 0.3-16.4 kBq body burden (77 individuals). The age range of the study individuals was 66-91 y. Peripheral blood serum protein concentrations of cytokines, immunoglobulins, and matrix metalloproteinase-9 were analyzed using enzyme-linked immunoassay following the manufacturer's protocol. Flow cytometry was used to analyze levels of various lymphocyte subpopulations. The findings of the current study demonstrate that some immunological characteristics may be considered as biomarkers of prolonged chronic radiation exposure for any radiation type (in the delayed period after the exposure) based on fold differences from controls: M immunoglobulin fold differences were 1.75 ± 0.27 (p = 0.0001) for external gamma-ray exposure and 1.50 ± 0.27 (p = 0.0003) for combined radiation exposure; matrix metalloproteinase-9 fold differences were 1.5 ± 0.22 (p = 0.008) for external gamma-ray exposure and 1.69 ± 0.24 (p = 0.00007) for combined radiation exposure; A immunoglobulin fold differences were 1.61 ± 0.27 (p = 0.002) for external gamma-ray exposure and 1.56 ± 0.27 (p = 0.00002) for combined radiation exposure; relative concentration of natural killer cell fold differences were 1.53 ± 0.23 (p = 0.01) for external gamma-ray exposure and 1.35 ± 0.22 (p = 0.001) for combined radiation exposure; and relative concentration of T-lymphocytes fold differences were 0.89 ± 0.04 (p = 0.01) for external gamma-ray exposure and 0.95 ± 0.05 (p = 0.003) for combined radiation exposure. Based on fold differences from controls, interferon-gamma (3.50 ± 0.65, p = 0.031), transforming growth factor-beta (2.91 ± 0.389, p = 0.026), and relative blood serum levels of T-helper cells (0.90 ± 0.065, p = 0.02) may be used as immunological markers of chronic external gamma-ray exposure. Moreover, there was a significant inverse linear association of relative concentration of T-helper cells with dose from external gamma rays accumulated over an extended period.

Mortality from circulatory disease (CD), ischemic heart disease (IHD) and cerebrovascular disease (CeVD) was investigated in relationship to cumulative doses of external gamma radiation and internal alpha radiation to the liver from deposited plutonium over long follow-up periods in two large cohorts of nuclear workers: the Russian Mayak Worker Cohort (MWC) and the UK Sellafield Worker Cohort (SWC). The MWC comprised 22,374 workers (74.6% males) with 5,123 CD deaths registered during 842,538 person-years of follow-up, while the SWC comprised 23,443 workers (87.8% males) with 2,322 CD deaths registered during 602,311 person-years of follow-up. Dose estimates for external gamma radiation and internal alpha radiation to the liver were calculated via a common methodology, in accordance with an agreed protocol. The mean cumulative external H p (10) dose was 0.52 Sv for the MWC and 0.07 Sv for the SWC, while the mean cumulative internal dose was 0.19 Gy for the MWC and 0.01 Gy for the SWC. Categorical relative risks (RR) and excess relative risks (ERR) per unit dose were estimated for each cohort and for the pooled cohort when appropriate. The dose responses for CD, IHD and CeVD in relationship to internal alpha-particle dose did not differ significantly from the null for either the MWC, the SWC or the pooled plutonium worker cohort. The ERR/Sv estimates in relationship to external exposure were significantly raised for both cohorts (marginally so for the MWC) for CD and IHD (but not for CeVD), but differed significantly between the two cohorts, the estimate for the SWC being approximately ten times greater than that for the MWC. Examination of the ERR/Sv estimates for two periods of first employment at the two facilities revealed that the significant heterogeneity was confined to the earlier sub-cohorts, and that the estimates for the later sub-cohorts were compatible. The two sub-cohorts for the later first-employment periods were pooled, producing risk estimates that were raised, but not significantly so: ERR/Sv for CD, IHD and CeVD of 0.22 (95% CI: -0.01, 0.49), 0.22 (95% CI: -0.06, 0.57) and 0.24 (95% CI: -0.17, 0.80), respectively. The reasons for the complex pattern of results found in this study are unclear. Among potential explanations are the influence of differences in background CD mortality rates, an effect of other occupational factors, substantial uncertainties in doses, particularly during earlier periods of operations, as well as confounding and/or modifying factors that were not taken into account in the current analysis.

Hypermethylation of СpG islands in the promoter regions of several genes with basic protective function in blood leukocytes of individuals exposed to ionizing radiation long time ago (2-46 years), and differential effects of age and radiation exposure on hypermethylation was reported in our previous work. To validate these results, epigenetic modifications were assessed in an independent series of 49 nuclear industry workers from the "Mayak" facility (67-84 years old at sampling) with documented individual accumulated doses from the prolonged external γ-radiation exposure (95.9-409.5 cGy, end of work with radiation:0.3-39 years ago), and in 50 non-exposed persons matched by age. In addition to the genes analyzed before (RASSF1A, p16/INK4A, p14/ARF, GSTP1), four additional loci were analyzed: TP53, ATM, SOD3, ESR1. The frequency of individuals displaying promoter methylation of at least one of the 8 genes (71.4%) was significantly higher in exposed group as compared to the control group (40%), p = .002, OR = 3.75. A significantly elevated frequency of individuals with hypermethylated СpG islands in GSTP1, TP53, SOD3 promoters was revealed among exposed subjects as compared to the control group (p = .012, OR = 8.41; p = .041, OR = 4.02 and p = .009, OR = 3.42, respectively). A similar trend (p = .12, OR = 3.06) was observed for the p16/INK4A gene. As a whole, p16/INK4A and GSTP1 promoter hypermethylation in irradiated subjects from both previously and currently analyzed groups was pronounced. Thus, the direction of the effects was fully confirmed, suggesting the result reproducibility. No statistically significant correlation between promoter methylation and individual radiation dose was found. Further studies are required to create an array of blood epigenetic markers of radiation exposure associating with premature aging and age-related diseases and to accurately evaluate radiation-added effect across the range of doses., Synthesis: The results of studies of epigenetic changes in two independent samples of irradiated subjects indicated the significance of radiation factor in the induction of hypermethylation of CpG islands in gene promoters that is revealed in blood cells years and decades after exposure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We propose a stochastic model for use in epidemiological analysis, describing the age-dependent development of atherosclerosis with adequate simplification. The model features the uptake of monocytes into the arterial wall, their proliferation and transition into foam cells. The number of foam cells is assumed to determine the health risk for clinically relevant events such as stroke. In a simulation study, the model was checked against the age-dependent prevalence of atherosclerotic lesions. Next, the model was applied to incidence of atherosclerotic stroke in the cohort of male workers from the Mayak nuclear facility in the Southern Urals. It describes the data as well as standard epidemiological models. Based on goodness-of-fit criteria the risk factors smoking, hypertension and radiation exposure were tested for their effect on disease development. Hypertension was identified to affect disease progression mainly in the late stage of atherosclerosis. Fitting mechanistic models to incidence data allows to integrate biological evidence on disease progression into epidemiological studies. The mechanistic approach adds to an understanding of pathogenic processes, whereas standard epidemiological methods mainly explore the statistical association between risk factors and disease outcome. Due to a more comprehensive scientific foundation, risk estimates from mechanistic models can be deemed more reliable. To the best of our knowledge, such models are applied to epidemiological data on cardiovascular diseases for the first time.

Individual doses from external γ-rays were estimated using biological dosimetry based on limited samplings (n₁= 15 and n₂ 12 individuals) which comprised the Mayak workers group with acute radiation sickness (ARS). The following primary data were used for calculation as initial parameters: estimated dose from ex- ternal γ-rays based on physical dosimetry methods - D (Gy); time before first vomiting - T (h); number of lymphocytes in peripheral blood on a second day after acute radiation exposure - L (10⁹/1); number of neutrophils in blood during first hours after accidental radiation exposure - N(10⁹/). A number of mathe- matical models used for dose estimation were verified: power-law dependence of the absorbed dose from ex- ternal γ-rays (D) on time before first vomiting (7), exponential dependence of D on the number of lympho- cytes in peripheral blood (L), dependence of D on the number of neutrophils in peripheral blood (N) and complex models forD association with Tand L parameters as well as-with Tand Nparameters. The biological dosimetry technique based on a complex approach was shown to provide the best agreement with physical dosimetry methods for individual assessment of doses from external γ-rays.

Aim: to assess the relative risk (RR) of senile cataract in a cohort of workers occupationally exposed to external gamma-rays over a long time period., Material and Methods: The RR of cataract development was studied in a cohort of nuclear workers that were first employed in 1948-1982 and followed up till the end of 2008 (n=22,377; females, 25.4%). The mean age at initial employment was 24.9 years. The mean cumulative gamma-ray dose was 0.54 Sv in males and 0.44 Sv in females. The analysis performed with EPICURE software provided RR estimates for cataract incidence in relation to a number of non-radiation and radiation factors., Results: The RR of senile cataract increased with the attained age of the workers. The RR was significantly higher in males during the 2006-2008 period as compared to the 1996-2005 period. The RR was significantly higher in workers that were diagnosed with glaucoma and high myopia as compared to those that were not. The risk of senile cataract increased with the external gamma-ray dose and was the highest in workers who had formerly been exposed to doses above 2.00 Sv. The RR of senile cataract showed no dependency on sex, age at initial employment, smoking status, alcohol consumption, or diabetes mellitus., Conclusion: The incidence of senile cataract in the cohort under study was found to depend on both non-radiation and radiation factors.

Aim: To assess mortality from circulatory diseases (CD) in a cohort of workers exposed occupationally to chronic radiation in relation to external and internal exposure, by taking into account known non-radiation risk factors (RFs), such as smoking (including smoking index), alcohol consumption, hypertension, and body mass index., Subjects and Methods: Mortality from CD (ICD-10: I00 - I99) was studied in a cohort of 22,377 nuclear power plant («Mayak» Production Association) workers exposed occupationally to chronic radiation. The study was based on the individual dose estimates of external and internal exposure taken from the new Mayak workers dosimetry system 2008 (MWDS-2008). The quantitative characteristics of smoking (smoking index) were used for the first time to assess the risk for CD in the cohort of workers exposed to chronic radiation., Results: There was a statistically significant linear relationship between CD mortality and external gamma-dose after adjusting for the non-radiation RFs; the excess relative risk per unit dose (ERR/Gy) was 0.05 (95% confidence interval (CI): 0 to 0.11). Introducing an additional adjustment for internal alpha-dose resulted in a twofold increase in ERR/Gy=0.10 (95% CI: 0.02 to 0.21). There was a statistically significant increasing trend in CD mortality with the elevated absorbed dose from internal alpha-radiation in the liver (ERR/Gy=0.27; 95% CI: 0.12 to 0.48). However, ERR/Gy decreased and lost its statistical significance after adjusting for external gamma-dose., Conclusion: The results of this study are in good agreement with risk estimates obtained in the Japanese cohort of atomic bomb survivors and in the cohorts of occupationally exposed workers.

This is the first study of cataract incidence in a cohort of Mayak Production Association workers first employed at one of the main facilities in 1948-1982 and followed up till the end of 2008 (22,377 workers). Principal advantages of the study are the large size of the cohort, long-term follow-up and sufficient statistical power, available results of annual eye examinations over the entire follow-up period and detailed information on non-radiation confounders. Individual measured doses from external γ-rays and neutrons used in the analyses were provided by the Mayak Worker Dosimetry System 2008 (MWDS-2008). Relative risk (RR) and excess relative risk (ERR) per unit dose (Gy) were calculated based on maximum likelihood using the AMFIT module of the EPICURE software. The RR of cataract incidence was found to be the highest in workers exposed at doses above 2.0 Gy. A significant linear association of cataract incidence with cumulative dose from external γ-rays was found with ERR/Gy equal to 0.28 (95% confidence intervals: 0.20, 0.37). The results obtained varied slightly with inclusion of additional adjustments for non-radiation factors (smoking index, hypertension, glaucoma and body mass index). Adjusting for the dose from neutrons gave a considerable increase in ERR/Gy for cataract incidence., Competing Interests: The authors have declared that no competing interests exist.

An association between polymorphic variants of key genes of base excision repair (BER) and lung cancer was studied in "Mayak" workers occupationally exposed to prolonged external y-rays and internal α-radiation from incorporated (239)Pu. The study was "case-control". The group of "cases" consists of 75 "Mayak" workers with the verified diagnosis of "lung cancer". At the moment of diagnosis the mean total absorbed dose from external y-rays to whole body was 1.19 Gy; the mean total absorbed dose from internal α-radiation due to incorporated (239)Pu in lung was 0.31 Gy. The group of "controls" includes "Mayak" workers matched by sex and birth year without lung cancer and other cancers during the study period (141 individuals). Increased lung cancer risk was revealed in workers-carriers of homozygous minor genotype of genes OGG] Ser326Cys (OR - 4.67, p = 0.007), APEI Asp148Glu (OR = 1.82, p = 0.063) and XRCC1 Gln399Arg (OR = 2.86, p = 0.026). Increased lung cancer risk was revealed in carriers of different pairwise combinations of minor genotypes of the studied genes of BER or in carriers of pairwise combinations with one homozygous minor mm-genotype and the other homozygous major ww genotype. Thus, OR of lung cancer in carriers of pairwise genotypes of mm genes OGG] Ser326Cys and APE] Asp 148Glu was 12.17.

Quantification of biological effects (cancer, other diseases, and cell damage) associated with exposure to ionising radiation has been a major issue for the International Commission on Radiological Protection (ICRP) since its foundation in 1928. While there is a wealth of information on the effects on human health for whole-body doses above approximately 100 mGy, the effects associated with doses below 100 mGy are still being investigated and debated intensively. The current radiological protection approach, proposed by ICRP for workers and the public, is largely based on risks obtained from high-dose and high-dose-rate studies, such as the Japanese Life Span Study on atomic bomb survivors. The risk coefficients obtained from these studies can be reduced by the dose and dose-rate effectiveness factor (DDREF) to account for the assumed lower effectiveness of low-dose and low-dose-rate exposures. The 2007 ICRP Recommendations continue to propose a value of 2 for DDREF, while other international organisations suggest either application of different values or abandonment of the factor. This paper summarises the current status of discussions, and highlights issues that are relevant to reassessing the magnitude and application of DDREF.

In this study the incidence risk of lower extremity arterial disease (LEAD; international classification of diseases version 9 code 440.2) was assessed in a cohort of workers occupationally exposed to radiation over a prolonged period. The study cohort includes 22,377 workers of the Mayak Production Association (25% of whom are females) first employed at one of the main facilities in 1948-1982 and followed up to the end of 2008. Dose estimates used in the study are provided by Mayak Worker Dosimetry System 2008. The mean total dose from external gamma-rays is 0.54 Gy for males and 0.44 Gy for females. The mean absorbed liver dose from internal alpha-radiation due to incorporated plutonium is 0.23 Gy in males and 0.44 Gy in females. Relative risks and excess relative risks per unit dose (ERR/Gy) are calculated based on maximum likelihood. A total of 943 cases of LEAD are registered in the study cohort during the follow-up of 512,801 person-years. A significant association of LEAD incidence with total dose from external gamma-rays (based on a linear model) was revealed, and the ERR/Gy is 0.27 (95% confidence interval (CI) 0.11; 0.48). It turned out that a linear-exponential model provides a better fit of the data (∆AIC = 9.957). Inclusion of an adjustment for internal alpha-radiation dose resulted in the reduction of the ERR/Gy to 0.19 (95% CI 0.05; 0.39), but the risk remains significant. No association of LEAD incidence with dose from internal alpha-radiation was found in the study worker cohort. It is concluded that this study provides evidence for an association of LEAD incidence with dose from external gamma-rays taking non-radiation factors into account.

This study was aimed to compare mFISH and mBAND techniques in assessment of the yield of chromosomal aberrations induced by high-LET ionizing radiation. The study group included Mayak workers (46 individuals), for whom the yield of chromosomal aberrations was assessed using two methods: mFISH and mBAND. It was shown that both methods are applicable for biological indication of internal α-radiation exposure. Nevertheless, in case when the source of ionizing radiation is unknown or in terms of a mixed exposure, mFISH appeared as more informative technique that allows identification of markers both external γ-rays (translocations) and internal α-radiation (complex chromosomal rearrangements).

The results of the epidemiological research of the last decade demonstrate the increased risk of circulatory system diseases in the cohorts of people exposed to professional, anthropogenic or medical irradiation, which causes the development of atherosclerosis of the vessels. It was shown that ionizing radiation is one of the promoters of the development of atherosclerosis.

Background: The city of Ozyorsk (Southern Urals) was created as a secret city in 1945 and is a closed city until today. It housed workers of the earliest and one of the country's largest nuclear facilities. Workers of the nuclear reactors, radiochemical or reprocessing plants were exposed to high levels of ionising radiation in the early years of operation and possibly further exposed from inhalation of plutonium aerosols., Methods: The cause-of-death registry of Ozyorsk received paper copies of original death certificates of all deaths of residents of the city. Data were analysed for recent mortality rates (1998-2010) and time trends in age-standardised mortality rates between 1953 and 2010 of main groups of causes of deaths, in particular cancer., Results: Comparing workers of the three main plant types with the remainder of the Ozyorsk residents, and with national figures, all-cause mortality rates were lowest among workers, with ratios compared to national figures of 0.65 (men) and 0.56 (women), and compared to the other residents of 0.77 (men) and of 0.74 (women). For cancer overall, the differences were smaller in men (ratio between workers and national figures of 0.86) and there were no differences in women (ratio of 1.00), but ratios differed by cancer type. Most cancer deaths were however least common in the workers, including leukaemia. Over the last 60 years, all-cause mortality has gradually increased among men in all three groups but was stable among women, whereas cancer death rates have slightly declined in both sexes., Conclusions: Healthy worker effect, relatively better living conditions in Ozyorsk and healthier lifestyles may explain the lower mortality rates in Ozyorsk. Overall mortality time trends in Ozyorsk were similar to the entire country. No apparent radiation-related effects were seen in this population-level analysis, but the radiation-related risks can be better addressed in individual-level studies.

The aim of this study was to apply the fluorescence in situ hybridization (FISH) translocation assay in combination with chromosome painting of peripheral blood lymphocytes for retrospective biological dosimetry of Mayak nuclear power plant workers exposed chronically to external gamma radiation. These data were compared with physical dose estimates based on monitoring with badge dosimeters throughout each person's working life. Chromosome translocation yields for 94 workers of the Mayak production association were measured in three laboratories: Southern Urals Biophysics Institute, Leiden University Medical Center and the former Health Protection Agency of the UK (hereinafter Public Health England). The results of the study demonstrated that the FISH-based translocation assay in workers with prolonged (chronic) occupational gamma-ray exposure was a reliable biological dosimeter even many years after radiation exposure. Cytogenetic estimates of red bone marrow doses from external gamma rays were reasonably consistent with dose measurements based on film badge readings successfully validated in dosimetry system "Doses-2005" by FISH, within the bounds of the associated uncertainties.

Objective: Incidence and mortality from ischaemic heart disease (IHD) was studied in an extended cohort of 22,377 workers first employed at the Mayak Production Association during 1948-82 and followed up to the end of 2008., Methods: Relative risks and excess relative risks per unit dose (ERR/Gy) were calculated based on the maximum likelihood using Epicure software (Hirosoft International Corporation, Seattle, WA). Dose estimates used in analyses were provided by an updated "Mayak Worker Dosimetry System-2008"., Results: A significant increasing linear trend in IHD incidence with total dose from external γ-rays was observed after having adjusted for non-radiation factors and dose from internal radiation {ERR/Gy = 0.10 [95% confidence interval (CI): 0.04 to 0.17]}. The pure quadratic model provided a better fit of the data than did the linear one. No significant association of IHD mortality with total dose from external γ-rays after having adjusted for non-radiation factors and dose from internal alpha radiation was observed in the study cohort [ERR/Gy = 0.06 (95% CI: <0 to 0.15)]. A significant increasing linear trend was observed in IHD mortality with total absorbed dose from internal alpha radiation to the liver after having adjusted for non-radiation factors and dose from external γ-rays in both the whole cohort [ERR/Gy = 0.21 (95% CI: 0.01 to 0.58)] and the subcohort of workers exposed at alpha dose <1.00 Gy [ERR/Gy = 1.08 (95% CI: 0.34 to 2.15)]. No association of IHD incidence with total dose from internal alpha radiation to the liver was found in the whole cohort after having adjusted for non-radiation factors and external gamma dose [ERR/Gy = 0.02 (95% CI: not available to 0.10)]. Statistically significant dose effect was revealed in the subcohort of workers exposed to internal alpha radiation at dose to the liver <1.00 Gy [ERR/Gy = 0.44 (95% CI: 0.09 to 0.85)]., Conclusion: This study provides strong evidence of IHD incidence and mortality association with external γ-ray exposure and some evidence of IHD incidence and mortality association with internal alpha-radiation exposure., Advances in Knowledge: It is the first time the validity of internal radiation dose estimates has been shown to affect the risk of IHD incidence.

Mortality from circulatory diseases (CD) (ICD-9 codes 390-459) was studied in an extended Mayak worker cohort, which included 22,377 workers first employed at the Mayak Production Association in 1948-1982 and followed up to the end of 2008. The enlarged cohort and extended follow-up as compared to the previous analyses provided an increased number of deaths from CD and improved statistical power of this mortality study. The analyses were based on dose estimates provided by a new Mayak Worker Dosimetry System 2008 (MWDS-2008). For the first time in the study of non-cancer effects in this cohort quantitative smoking data (smoking index) were taken into account. A significant increasing trend for CD mortality with increasing dose from external gamma-rays was found after having adjusted for non-radiation factors; the excess relative risk per unit dose (ERR/Gy) was 0.05 (95% confidence interval (CI):  >0, 0.11). Inclusion of an additional adjustment for dose from internal alpha-radiation to the liver resulted in a two-fold increase of ERR/Gy = 0.10 (95% CI: 0.02, 0.21). A significant increasing trend in CD mortality with increasing dose from internal alpha-radiation to the liver was observed (ERR/Gy = 0.27, 95% CI: 0.12, 0.48). However the ERR/Gy decreased and lost its significance after adjusting for dose from external gamma-rays. Results of the current study are in good agreement with risk estimates obtained for the Japanese LSS cohort as well as other studies of cohorts of nuclear workers.

A detailed analysis of cerebrovascular diseases (CeVD) for the cohort of workers at Mayak Production Association (PA) is presented. This cohort is especially suitable for the analysis of radiation induced circulatory diseases, due to the detailed medical surveillance and information on several risk factors. The risk after external, typically protracted, gamma exposure is analysed, accounting for potential additional internal alpha exposure. Three different endpoints have been investigated: incidence and mortality from all cerebrovascular diseases and incidence of stroke. Particular emphasis was given to the form of the dose-response relationship and the time dependence of the radiation induced risk. Young attained age was observed to be an important, aggravating modifier of radiation risk for incidence of CeVD and stroke. For incidence of CeVD, our analysis supports a dose response sub-linear for low doses. Finally, the excess relative risk per dose was confirmed to be significantly higher for incidence of CeVD compared to CeVD mortality and incidence of stroke. Arguments are presented for this difference to be based on a true biological effect.

mFISH analysis of chromosome aberration profiles of 47 and 144 h lymphocyte cultures following exposure to 193 mGy α-particle radiation confirmed that the frequency of stable aberrant cells and stable cells carrying translocations remains constant through repeated cell divisions. Age-specific rates and in vitro dose-response curves were used to derive expected translocation yields in nine workers from the Mayak nuclear facility in Russia. Five had external exposure to γ-radiation, two of whom also had exposure to neutrons, and four had external exposure to γ-radiation and internal exposure to α-particle radiation from incorporated plutonium. Doubts over the appropriateness of the dose response used to estimate translocations from the neutron component made interpretation difficult in two of the workers with external exposure, but the other three had translocation yields broadly in line with expectations. Three of the four plutonium workers had translocation yields in line with expectations, thus supporting the application of the recently derived in vitro α-particle dose response for translocations in stable cells. Overall this report demonstrates that with adequate reference in vitro dose-response curves, translocation yield has the potential to be a useful tool in the validation of red bone marrow doses resulting from mixed exposure to external and internal radiation.