Biomarkers of Atherosclerotic Vascular Disease in Workers Chronically Exposed to Ionizing Radiation.

ABSTRACT: It is well established that cohorts of individuals exposed to ionizing radiation demonstrate increased risks of cardio- and cerebrovascular diseases. However, mechanisms of these radiation-induced diseases developing in individuals exposed to ionizing radiation remain unclear. To identify biomarkers of the atherosclerotic vessel damage in workers chronically exposed to ionizing radiation, this study considered 49 workers of the Russian nuclear production facility-the Mayak Production Association (mean age of 68.73 ± 6.92 years)-and 38 unexposed individuals (mean age of 68.84 ± 6.20 y) who had never been exposed to ionizing radiation (control). All workers were chronically exposed to combined radiation (external gamma rays and internal alpha particles). The mean cumulative liver absorbed dose from external gamma-ray exposure was 0.18 ± 0.12 Gy; the mean cumulative liver absorbed dose from internal alpha-particles was 0.14 ± 0.21 Gy. Levels of biomarkers in blood serum of the study participants were measured using the ELISA method. Elevated levels of apolipoprotein B, superoxide dismutase, monocyte chemoattractant protein 1, vascular cell adhesion protein 1, and a decreased level of endothelin-1 were observed in blood serum of Mayak PA workers chronically exposed to combined radiation compared to control individuals. A significant positive correlation was demonstrated between the vascular cell adhesion protein 1 level and cumulative liver absorbed doses from external gamma radiation and internal alpha radiation. Findings of the study suggest that molecular changes in blood of individuals occupationally exposed to ionizing radiation (combined internal exposure to alpha particles and external exposure to gamma rays) may indicate dyslipidemia, oxidative stress, inflammation, and endothelial dysfunction involved in atherosclerosis development.

Risk of skin cancer by histological type in a cohort of workers chronically exposed to ionizing radiation.

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.

Occupational exposure to chronic ionizing radiation increases risk of Parkinson's disease incidence in Russian Mayak workers.

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.

Risk of malignant skin neoplasms in a cohort of workers occupationally exposed to ionizing radiation at low dose rates.

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.

Immunological Markers of Chronic Occupational Radiation Exposure.

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.

Expression of blood serum proteins and lymphocyte differentiation clusters after chronic occupational exposure to ionizing radiation.

This study aimed to assess effects of chronic occupational exposure on immune status in Mayak workers chronically exposed to ionizing radiation (IR). The study cohort consists of 77 workers occupationally exposed to external gamma-rays at total dose from 0.5 to 3.0 Gy (14 individuals) and workers with combined exposure (external gamma-rays at total dose range 0.7-5.1 Gy and internal alpha-radiation from incorporated plutonium with a body burden of 0.3-16.4 kBq). The control group consists of 43 age- and sex-matched individuals who never were exposed to IR, never involved in any cleanup operations following radiation accidents and never resided at contaminated areas. Enzyme-linked immunoassay and flow cytometry were used to determine the relative concentration of lymphocytes and proteins. The concentrations of T-lymphocytes, interleukin-8 and immunoglobulins G were decreased in external gamma-exposed workers relative to control. Relative concentrations of NKT-lymphocytes, concentrations of transforming growth factor-ß, interferon gamma, immunoglobulins A, immunoglobulins M and matrix proteinase-9 were higher in this group as compared with control. Relative concentrations of T-lymphocytes and concentration of interleukin-8 were decreased, while both the relative and absolute concentration of natural killers, concentration of immunoglobulins A and M and matrix proteinase-9 were increased in workers with combined exposure as compared to control. An inverse linear relation was revealed between absolute concentration of T-lymphocytes, relative and absolute concentration of T-helpers cells, concentration of interferon gamma and total absorbed dose from external gamma-rays in exposed workers. For workers with incorporated plutonium, there was an inverse linear relation of absolute concentration of T-helpers as well as direct linear relation of relative concentration of NKT-lymphocytes to total absorbed red bone marrow dose from internal alpha-radiation. In all, chronic occupational IR exposure of workers induced a depletion of immune cells in peripheral blood of the individuals involved.