Siberian Group Of Chemical Enterprises Research Articles

ANALYSIS OF CANCER INCIDENCE AMONG EMPLOYEES OF SIBERIAN GROUP OF CHEMICAL ENTERPRISES

Background. One of the main directions in the field of ensuring radiation safety of “nuclear legacy” facilities is the assessment of radiation effects and most significant radiogenic risks in employees of nuclear enterprises and their descendants.Objective. Analysis of the cancer incidence among employees of the Siberian Group of Chemical Enterprises (SGCE) exposed to ionizing radiation in the course of their professional activities.Material and Methods. The actual values and standardized estimated risks of developing cancer among the SGCE workers occupationally exposed to ionizing radiation were calculated using generally accepted methods based on the information of the regional medical dosimetry registry of Seversk Biophysical Research Center of FMBA, containing updated data on all SGCE employees diagnosed with cancer (period from 01.01.1950 to 31.12.2015 inclusive). The control group consisted of workers who were not occupationally exposed to ionizing radiation.Results. Among the male personnel of the SGCE, the highest incidence of cancer of the digestive, respiratory, and skin organs (including melanoma) was observed in patients aged 50–59 and 70–79 years. Among the female workers, the highest cancer incidence was in the age group 40–49 years; cancer of the gastrointestinal tract, genital tract and breast was the most common. The cancer incidence rate in the SGCE workers who occupationally exposed to ionizing radiation was not higher that that observed in the control group. The median age of male cancer patients occupationally exposed to ionizing radiation was significantly lower than the median age of male cancer patients of the control group. In female cancer patients, a significant difference in the median age of cancer diagnosis was found only in relation to skin cancer. Both male and female SGCE personnel occupationally exposed to ionizing radiation was at high risk of certain cancers: among male patients – cancer of the mesothelium and soft tissues, genital organs, eyes and brain, as well as multiple primary tumors; among female patients – cancer of lips, oral cavity, pharynx, digestive system, respiratory system, skin (including melanoma), mesothelium, soft tissues, breast, urinary tract, lymphatic and hematopoietic tissues, as well as multiple primary tumors.Conclusion. The data obtained will allow determination of the main directions for assessing the health risks of personnel of radiation hazardous facilities and the formation of a set of measures aimed at improving the system of protection and improving the health of workers at radiation hazardous enterprises and the extension of their working longevity.

Methylation of Promoters of Apoptosis-Related Genes in Blood Lymphocytes of Workers Exposed to Occupational External Irradiation.

We studied the effect of technogenic radiation on the degree of promoter methylation in genes involved in apoptosis in blood lymphocytes of workers exposed to long-term γ-radiation during their professional activities. Blood samples for the analysis were obtained from 11 conventionally healthy men aged from 54 to 71 years (mean 66 years), workers of the Siberian Group of Chemical Enterprises working experience from 27 to 40 years (mean 30 years); the external exposure dose was 175.88 mSv (158.20-207.81 mSv). In all examined subjects, the degree of methylation of the promoters of apoptosis-related genes ranged from 0.22 to 50.00%. A correlation was found between the degree of methylation of BCLAF1 promoters (p=0.035) with the age of workers, BAX promoters (p=0.0289) with high content of aberrant cells, and APAF1 promoters (p=0.0152) with increased number of dicentric chromosomes. A relationship was found between the dose of external irradiation and the degree of methylation of gene promoters of BAD (p=0.0388), BID (р=0.0426), and HRK (р=0.0101) genes.

ПРЕДИКТОРЫ РАЗВИТИЯ ОСТРОГО ИНФАРКТА МИОКАРДА ДЛЯ ПЕРСОНАЛА ТРУДОСПОСОБНОГО ВОЗРАСТА НА РАДИАЦИОННО-ОПАСНЫХ ПРОИЗВОДСТВАХ

Purpose: To examine the predictors of acute myocardial infarction development and to evaluate the relationship of the radiation component (external γ-radiation) with the probability of developing acute myocardial infarction in workers of radiation-dangerous plants working age (under 60 for men, 55 for women), by the example of the Siberian Group of Chemical Enterprises personnel. 
 Material and methods: The work is based on the results of a prospective population study (1998–2013). The diagnosis of acute myocardial infarction was verified in 540 people of working age (34 women and 506 men). For each case selected control (n = 1,080) among the employees of the Siberian Group of Chemical Enterprises, passed periodic medical examination in the study period. Every person was described by means of 46 variables including characteristics of social status, a number of risk factors, associated diseases, biochemical indices including the level of general cholesterol, the main clinical data, cumulative dose of external radiation and the amount of 239Pu content in an organism. 
 Results: It was determined that in the group of the personnel of working age the most important traditional predictors of acute myocardial infarction, less important factor in the pathogenesis of the disease are conditions of the individual accumulation of a dose, but not the magnitude of the total external doses in the evaluation range. 
 Conclusion: To improve the system of preventive measures aimed at reducing the level of morbidity and mortality from acute myocardial infarction, it is recommended to form risk groups taking into account the most significant predictors of this disease (age, systolic blood pressure, smoking). For the personnel of radiation dangerous plants working age insignificant conditions for the formation of radiation dose (age of first exposure, the rate of accumulation of radiation dose, duration of exposure) under conditions of trouble-free operation of the equipment. 
 Active measures for the diagnosis of coronary heart disease and targeted correction of detected somatic disorders for the prevention of acute vascular catastrophes are expedient for workers of radiation hazardous industries from 40 to 60 years with an individual risk of acute myocardial infarction less than 50 % using the model described below.

Descriptive characteristics of occupational exposures and medical follow-up in the cohort of workers of the Siberian Group of Chemical Enterprises in Seversk, Russia

Purpose To date, only a few studies have examined long-term health risks of exposures in the uranium processing industry and reported contradictory results, necessitating further research in this area. This is the first description of a cohort of ∼65,000 uranium processing workers (20.6% women) of the Siberian Group of Chemical Enterprises (SGCE) in Seversk, Russia, first employed during 1950-2010. Methods SGCE is one of the largest and oldest uranium processing complexes in the world. SGCE workers at the Radiochemical, Plutonium, Sublimate and Enrichment plants were exposed to a combination of internal and external radiation, while workers at the Support Facility were primarily exposed to non-radiation factors. Results Mean cumulative gamma-ray dose based on individual external dosimetry was 28.3 millisievert. About 4,000 workers have individual biophysical survey data that could be used for estimation of organ doses from uranium. SGCE workers were followed up for mortality and cancer incidence during 1950-2013 (vital status known for 80.8% of workers). The SGCE computerized database contains information on the results of regular medical examinations, and on smoking, alcohol and other individual characteristics. Conclusions The SGCE cohort is uniquely suited to examine long-term health risks of exposures to gamma-radiation and long-lived radionuclides in uranium processing workers.

РОЛЬ МЕТИЛИРОВАНИЯ BAK1 В ИНДУКЦИИ ХРОМОСОМНЫХ АБЕРРАЦИЙ ПРИ ХРОНИЧЕСКОМ НИЗКОИНТЕНСИВНОМ ВНЕШНЕМ ОБЛУЧЕНИИ

Purpose: To study the relationship between the methylation status of the Bаk1 promoter and the frequency of chromosomal aberrations in human blood lymphocytes under chronic low-intensity external ionizing radiation.
 Material and methods: The study was performed on 41 people (31 men and 10 women, aged from 36 to 83 years) who are former or current employees of the Siberian Group of Chemical Enterprises, who have been exposed or haven't been exposed to chronic low-intensity external radiation in the course of their professional activities. The workers included in the study were divided into two groups: the first – 15 people who did not have exposure, the second – 26 people who had external exposure (gamma radiation, total dose 89–716 mSv). Whole blood was used to isolate DNA and evaluate chromosomal aberrations in lymphocytes. The methylation status of the Bаk1 promoter was determined using methylsensitive PCR, which was performed after pretreatment of the isolated DNA with methylsensitive AoxI restrictase. The obtained quantitative data were analyzed using the Statistica 10. The differences were considered statistically significant at p ≤ 0.05.
 Results: The methylation status of the Bаk1 promoter in the study groups does not differ (p = 0.18). The study of the effect of external radiation dose on the methylation status of the Bak1 promoter showed that the unmethylated promoter prevails in workers with an average radiation dose of 273.37 ± 43.82 mSv, while the methylated promoter – in workers with an average radiation dose of 183.63 ± 20.58 mSv (p = 0.03). The unmethylated promoter Bаk1 is associated with an increased frequency of chromatid fragments in the blood lymphocytes of group 2 workers (p = 0.03).
 Conclusion: The status of methylation of the Bаk1 promoter in human blood lymphocytes under chronic low-intensity ionizing radiation does not change, but it is observed to depend on the radiation dose and is associated with an increased frequency of chromosomal aberrations (chromatid fragments). Thus, the unmethylated Bаk1 promoter prevails when the external radiation dose is increased. An increase in the frequency of chromatid fragments is associated with an unmethylated Bаk1 promoter. In addition, exposure to chronic low-intensity external radiation is accompanied by a decrease in the frequency of chromosomal fragments in the blood lymphocytes of workers of the Siberian Group of Chemical Enterprises.

Факторы влияния на состояние здоровья взрослого населения, проживающего в зоне действия предприятия атомной индустрии

Purpose: Development of the basic directions of a modern strategy for protecting the health of the adult population living in the activity zone of nuclear industry enterprises (using the example of the Seversk population).
 Material and methods: The object of the study was the population of the city of Seversk, formed around the Siberian Group of Chemical Enterprises. The subject of the study was demographic indicators; disability; incidence of malignant neoplasms, diseases of the circulatory system, injuries and accidents); socio-economic, behavioral and technological risk factors affecting the occurrence of major diseases. 
 Results: It was established that by the end of the study period (1970–2017), the studied population was in a state of natural population decline due to a decrease in the birth rate and an increase in mortality, while the mortality rate exceeded the birth rate.
 During the period under review, the primary incidence of malignant neoplasia significantly increased; at the same time, the incidence of cardiovascular diseases, as well as the frequency of injuries and poisoning, decreased. Among the adult population of Seversk, behavioral factors (the habit of smoking, regular use of alcohol, a sedentary lifestyle, lack of regular physical activity) are more common than socio-economic (living conditions, financial situation) risk factors. Important risk factors are incorrect assessment by citizens of their own health and the reasons for its violation. Among Siberian Group of Chemical Enterprises workers exposed to tekhnogenic risk factor (long-term occupational exposure), there is an increased risk of cancer death of all localizations taken together, respiratory and digestive organs; bones, joints, mesothelium, soft tissues and genitals. At the same time, the risk of oncological mortality during irradiation was not exceeded in the range of small doses of (up to 100 mSv), and for any of the localization of malignant neoplasms this effect is not dose-dependent.
 Conclusion: The data obtained made it possible to specify and substantiate the basic directions of the modern strategy for protecting the health of the adult population living in the activity zone of nuclear industry enterprises (using the example of the Seversk population).

Delayed Changes in the Frequency of Unstable Chromosomal Aberrations and the CNA-Genetic Landscape of Blood Leukocytes in People Exposed to Long-Term Occupational Irradiation

Abstract—The results of a study of delayed changes in the frequency of unstable chromosomal aberrations and the CNA- and LOH-genetic landscape of blood leukocytes in healthy employees at the main facilities of the Siberian Group of Chemical Enterprises exposed to external irradiation are presented. In 2014, 11 persons with de novo induced mosaic deletions and amplifications associated with dicentric and/or ring chromosomes (markers for individual radiosensitivity) were detected. Three years later, the frequency levels of chromosomal aberrations were compared. In 2017 the frequency of aberrant cells had increased by 1.7 times compared to 2014, the frequency of the chromosomal type aberrations had doubled, the frequency of pair fragments had a more than fourfold increase, and the frequency of dicentrics had almost doubled. The mosaic deletion in employee no. 1490 (3q12.3–13.11) identified in 2014 persisted until 2017. Mosaic amplifications identified in 2014 were preserved in five out of six employees (nos. 178, 203, 450, 1620, and 1792). Moreover, we identified that the CNstate in employee no. 450 had increased 1.5 times by 2017. The mosaic amplification of the short arm of the third chromosome in employee no. 278 had been eliminated by 2017. Other changes in the CNA and LOH-genetic landscape were not detected. Thus, these data indicate the formation of self-sustained bone marrow clones, whose descendants produce a population of aberrant cells in the blood of irradiated individuals. Further research into the preservation of chromosomal aberrations and CNA is needed, as well as studies aimed at detecting the clones of aberrant cells in the bone marrow.

Полногеномное ассоциативное исследование связи полиморфных локусов с повышенной частотой хромосомных аберраций у лиц, подвергавшихся длительному радиационному воздействию

Purpose: To conduct genome wide association study of the association of 750,000 SNPs and an increased frequency of different types of chromosomal aberrations, induced by chronic irradiation in the dose range of 100–300 mSv.
 Material and methods: The study was conducted among Siberian Group of Chemical Enterprises healthy employees (n = 37) exposed to professional external γ-radiation in a dose range of 100–300 mSv. The de novo induced CNVs were previously detected in these persons. Mean dose – 188.8 ± 8.3 mSv, median – 185 mSv, interquartile range – 147.8–218.7 mSv, min – 103.4 mSv, max – 295.8 mSv. Genotyping of DNA samples from 37 employees was carried out by microarray CytoScan™ HD Array (Affymetrix, USA), containing 750,000 SNP-markers of 36,000 genes. The standard cytogenetic analysis was performed in the entire examined group.
 Results: We analyzed the association of these SNPs with the frequencies of aberrant cells and following chromosomal aberrations: single chromatid fragments, chromatid exchanges, paired fragments, dicentrics, rings, and translocations. We have found that 8 SNPs (rs10779468, rs158735, rs158710, rs158712, rs11131536, rs528170, rs9533572, rs10512439) are associated with the frequency of aberrant cells.
 Conclusion: We have discovered polymorphic variants that are associated with an increased frequency of aberrant cells in workers of Siberian Group of Chemical Enterprises exposed to irradiation at a dose of 100–300 mSv. This polymorphic variants can be considered as potential markers of individual radiosensitivity. To confirm identified associations, further validation studies on an extended sample of people exposed to radiation are needed.

Descriptive characteristics of the cohort of workers from the Siberian Group of Chemical Enterprises (SGCE)

Author(s): Karpov, Andrey; Takhauov, Ravil; Zerenkov, Andrey; Dolgopolov, Yuriy; Izmestev, Konstantin; Blinov, Aleksey; Zablotska, Lydia

Радиоэкологическое обследование наземных и водных экосистем в районе размещения АО «СХК»

Радиоэкологическое обследование наземных и водных экосистем в районе размещения АО «СХК»

Different patterns of allelic imbalance in sporadic tumors and tumors associated with long-term exposure to gamma-radiation

The study aimed to reveal cancer related mutations in DNA repair and cell cycle genes associated with chronic occupational exposure to gamma-radiation in personnel of the Siberian Group of Chemical Enterprises (SGCE). Mutations were analyzed by comparing genotypes of malignant tumors and matched normal tissues of 255 cancer patients including 98 exposed to external gamma-radiation (mean dose 128.1±150.5mSv). Also a genetic association analysis was carried out in a sample of 149 cancer patients and 908 healthy controls occupationally exposed to gamma-radiation (153.2±204.6mSv and 150.5±211.2mSv, respectively). Eight SNPs of genes of DNA excision repair were genotyped (rs13181, rs1052133, rs1042522, rs2305427, rs4244285, rs1045642, rs1805419 and rs1801133). The mutation profiles in heterozygous loci for selected SNP were different between sporadic tumors and tumors in patients exposed to radiation. In sporadic tumors, heterozygous genotype Arg/Pro of the rs1042522 SNP mutated into Arg/0 in 15 cases (9.6%) and 0/Pro in 14 cases (8.9%). The genotype Lys/Gln of the rs13181 SNP mutated into Lys/0 and 0/Gln in 9 and 4 cases, respectively. In tumors of patients exposed to low-level radiation, the rs1042522 Arg/0 mutated genotype was found in 12 cases (12.1%), while in 2 cases (2%) 0/Pro mutation was observed. Finally, the rs13181 0/Gln mutated genotype was observed in 15 cases (16,5%) . Thus, our study showed the difference in patterns of allelic imbalance in tumors appeared under low-level radiation exposure and spontaneous tumors for selected SNPs. This suggests different mechanisms of inactivation of heterozygous genotypes in sporadic and radiation-induced tumors.

The bank of biological samples representing individuals exposed to long-term ionizing radiation at various doses.

Collection and storage of biological specimens in biobanks aims to obtain and preserve samples of different kinds for biological and medical studies. Here we present a description of the Bank of Biological Materials (BBM) housed by the Seversk Biophysical Research Centre (SBRC; Seversk, Russia). The main goal of maintaining the BBM is to collect and store biological samples suitable for genetic studies of people exposed to long-term ionizing radiation. Currently, the collection includes 19,194 biological specimens obtained from 8105 donors, of whom 42.3% are diagnosed with malignant neoplasms, 28.7% are healthy residents of the city of Seversk, 18.8% are healthy employees of the Siberian Group of Chemical Enterprises (SGCE), and 10.2% are patients diagnosed with acute myocardial infarction. The donors were enrolled using the Regional Medical and Dosimetric Register database created by the SBRC. For each donor, DNA specimens were extracted from peripheral blood and tissues and cell suspensions for cytogenetic analysis were prepared routinely. The BBM's unique collection is suitable primarily for studies of individual radiosensitivity of humans (IRH), and genetic aspects of the pathophysiology of common human diseases, especially in populations exposed to long-term low-dose ionizing radiation.

The Risk of Acute Myocardial Infarction and Arterial Hypertension in a Cohort of Male Employees of a Siberian Group of Chemical Enterprises Exposed to Long-Term Irradiation

During the period from 1998 to 2007, a prospective cohort study of acute myocardial infarction morbidity cases as well as a "case-control" study of arterial hypertension was carried out. The risk of acute myocardial infarction was assessed as well as arterial hypertension; the dose-response relationship and the role of radiation in the mechanism of acute myocardial infarction as well as arterial hypertension development were studied. As a result of this study, a statistically significant increased risk of acute myocardial infarction among the male staff at the Siberian Group of Chemical Enterprises [standardized relative risk = 1.16 (1.04; 1.29)] exposed to external irradiation in comparison with employees unexposed to ionizing radiation was observed. A significant increase in the risk of acute myocardial infarction was observed at external radiation dose accumulation of more than 300 mSv [standardized relative risk = 1.46 (1.09; 1.91)]. The increase in arterial hypertension risk has been established among the analyzed group of employees exposed to long-term irradiation in the absence of the linear dependence of risk, based on cumulative dose of external γ-irradiation [risk due to external radiation dose in the range of 7.3-21.3 mSv = 1.6 (0.96; 2.51) and in the range of external radiation dose 21.4-68.5 mSv = 1.7 (1.04; 2.67) for 68.6-864 mSv = 1.6 (1.01; 2.57)]. This led to the conclusion that radiation can act also as a factor that might potentiate the negative effects of the "traditional" risk factors in the pathogenesis of acute myocardial infarction and hypertension.

Possible ways of improving the health management system of male staff at atomic industry enterprises

Oncological morbidity among the male workers of the Siberian Group of Chemical Enterprises (SGCE) in 1970—2005 was studied. Increased related risk (in comparison with the standard) of malignant neoplasms of resiratory and digestive tract, urinary ways and genitals was found. On the basis of the received results proposals on perfection of system of health protection of the man's personnel of the enterprises of nuclear branch are made.

The association gene polymorphisms with risk of cancer in long-term «low-dose» y-irradiation exposure

The association of 13 biallelic polymorphisms of genes hOGG1 977C G, XPD1 2251A C, XPG1 3310G C, XRCC1:580C T, 839G A, 1196GA GSTT1 («+»/«-»), GSTM1 («+»/«-»), CYP2C19 681G A, NOS3: -665CT, 774С T, 894G T, VNTRint4 with risk of development of malignant new growths (MNG) in conditions of "low-dose" ionizing irradiation was investigated. In 1 group of irradiated patients of malignant new growths there are 96 persons, in 2 group of non-irradiated patients of MNG - 135 persons, in 3 control group - 148 healthy irradiated workers of the Siberian Group of Chemical Enterprises. By means of procedure FDR it is shown that only polymorphic variants of gene CYP2C19681G* are authentically associated with risk of occurrence of MNG against an irradiation. 1 genotype consisting of a combination of 5 polymorphic loci is selected. Frequency of occurrence of this genotype in 1 group makes 16,9 % (14/83), in 2 group - 1,0 % (1/100), in 3 group - 0,84 % (1/119). At its carriers in conditions of low-dose irradiation more than in 20 times the risk of occurrence of MNG (OR between 1 and 3 groups (95 % CI) = 24,14 (3,21-502,64) increases; p = 0,0000581, taking into account the correction of Bonferroni р = 0,01046).

Evaluation of long-term effects of low doses of ionising radiation (the role of the regional medicodosimetric register of SGCE personnel and population of Seversk)

The purpose of the research: to develop the optimal model of the creation of a medicodosimetric register, to carry out research on the dynamics of morbidity and mortality rate indices in personnel of the Siberian Group of Chemical Enterprises (SGCE) and to evaluate the long term effects of low doses of ionising radiation (IR). Materials and methods: the database of the Regional Medicodosimetric Register (RMDR) of SGCE personnel includes information about personnel, dosimetric and the medical character of the disease. We have completed forming the cohorts of reactor production (RP) and radiochemical production (RCP) workers. The cited data testify that most RP and RCP workers received registered cumulative doses of external radiation lower than 500 mSv ('low doses'), so further analysis will help us to understand the IR effects on the health of workers under study.

DNA and radiobiological material bank of persons exposed to ionising radiation

The structure of the DNA and radiobiological material bank of the Seversk Biophysical Research Center is described. Workers of the Siberian Group of Chemical Enterprises (SGCE) and their relatives are the subjects of the storage. Cytogenetic analysis, including Gbanding, is being performed for the participants. Currently, the bank contains 700 DNA and blood samples of workers of SGCE, 123 DNA and blood samples of cancer cases, about 500 DNA samples of children from Seversk city, and 100 blood samples of SGCE workers who survived acute myocardial infarction. DNA and blood accumulation is still in progress, but by this time, it is ready for large scale scientific projects devoted to the study of the genetic basis of individual radiosensitivity and consequences of low dose irradiation effect on the human genome.

Experimental Determination of the Spent Graphite Radioactive Contamination at Plutonium-Production Reactors of the Siberian Group of Chemical Enterprises (TOMSK-7)

Spent graphite from decommissioned plutonium-production uranium-graphite reactors is contaminated with radionuclides, and this graphite represents an important fraction of the radioactive wastes accumulated by the Russian nuclear power industry. To select proper ways and dates for the management of graphite, the information regarding the composition and level of the graphite contamination is required.In the paper, results are presented that were obtained in studies carried out at the I-1, EI-2, and ADE-3 reactors of the Siberian Group of Chemical Enterprises (Russia) in 1996-1999. The main feature of the studies is a wide-scale sampling from the graphite piles of the aforementioned reactors followed by complex assays of their radioactive contamination.The analyses performed for the large number of graphite samples made it possible to obtain a detailed picture of the pile contamination, to study radionuclide distributions over the piles, to construct schemes for evaluation of radionuclide stockpiles, and to evaluate stockpiles of several radionuclides including 14C, 3H, 90Sr, 241Am, 244Cm, 238,239,240,241Pu, 137,134Cs, and 60Co.