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The objective of this work was to study the expression of the TBX21, RORC, GATA3, NFKB1, MAPK8, and STAT3 genes responsible for the regulation of the differentiation of various T-helper subpopulations in individuals chronically exposed to radiation. The object of the study was peripheral blood cells obtained from 120 persons chronically exposed to radiation in a wide range of doses on the Techa River. The mean cumulative absorbed dose to red bone marrow in the examined exposed individuals was 742.7 ± 78.6 mGy (dose range, 73.5-3516.1 mGy); in the comparison group, 17.4 ± 2.2 mGy (dose range, 0.0-55.5 mGy). The subpopulation composition of T-helpers (Th1, Th2, and Th17) was analyzed by flow cytofluorometry. The relative mRNA content of the TBX21, RORC, GATA3, NFKB1, MAPK8, and STAT3 genes was estimated by real-time PCR. The study made it possible to note a decrease in the relative number of T-helpers 2 in the populations of T-helpers of the central memory in the group of chronically exposed persons compared to the comparison group. In the population of T-helpers of the central memory, a statistically significant increase in the relative number of T-helpers 1 was shown, depending on the accumulated absorbed dose to red bone marrow. No changes in mRNA expression of the studied genes were observed. The analysis of the correlation between the expression of GATA3, MAPK8, STAT3, RORC, and TBX21 mRNA and the relative number of cells in subpopulations of T-helper types 1, 2, and 17 in the examined people did not reveal statistically significant patterns., (© 2024. Pleiades Publishing, Ltd.)

Circulating T-lymphocytes are used as "natural biodosimeters" for estimating radiation doses, since the frequency of chromosomal aberrations induced in them is proportional to the accumulated dose. Moreover, stable chromosomal aberrations (translocations) are detected years and decades after exposure. Internal incorporation of radionuclides often leads to non-uniform exposure, which resulted in difficulties in the application of retrospective biodosimetry using T-lymphocytes. Some properties of T-lymphocytes complicate retrospective biodosimetry in this case: (1) the thymic production of T-cells depends significantly on age, the maximum is observed in early childhood; (2) the "lymphocyte-dosimeter" accumulates changes (translocations) while circulating through the body. The objective of this paper is to describe the technical characteristics of the model of age dynamics and T-cell biokinetics and approaches to assessing the dose to circulating lymphocytes under various exposure scenarios. The model allows to quantify the fractions of T-lymphocytes that were formed before and after exposure. The model takes into account the time fractions that circulating lymphocytes spend in various lymphoid organs. Age-related thymic involution was also considered. The model predicts that after internal exposure to 90 Sr, the doses to T-lymphocytes can differ significantly from the doses to the bone marrow and other tissues. For uniform external γ-exposure, and for internal exposure due to non-bone -seeking radionuclides (for example, 144 Ce), predicted doses to T-lymphocytes are very close to bone marrow doses. The model allows to quantify the correction factors for FISH-based doses to obtain doses to organs and tissues., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Methylation of the CpG islands of gene promoter regions is the most common epigenetic modification involved in the regulation of gene expression. A number of studies have shown that ionizing radiation can cause both hyper- and hypomethylation of DNA. Aberrant methylation affects cellular processes and can lead to the development of various pathological states. In the literature, there are few studies on the methylation status of human DNA a long time after radiation exposure. Here, the methylation level of CpG islands of the promoter regions of apoptosis genes (BCL2, ATM, MDM2, CDKN1A, STAT3, and NFKB1), and also its influence on apoptosis of peripheral blood lymphocytes in chronically exposed persons were studied. Residents of the South Ural region who were chronically exposed to radiation (after discharges of radioactive wastes into the Techa river by the "Mayak Production Association" in 1949-1956) were included in the study. It was established that the proportion of individuals with hypermethylated BCL2 gene promoter among the exposed people was statistically significantly higher than in the control group. The percentage of methylation of the ATM gene promoter weakly positively correlated with dose and age characteristics. Differences in the frequency of lymphocyte apoptosis in exposed individuals with a hypo- or hypermethylated ATM gene promoter were also established. The data indicate that, in the long-term, after chronic low intensity radiation exposure at low and medium doses, epigenetic modifications of the genome occur, which are manifested as changes in methylation of promoter regions of BCL2 and ATM genes.

Transcriptional activity of genes involved in maintaining genetic homeostasis (genes for repair, cell cycle and apoptosis: TP53, MDM2, ATM, BAX, BCL-2, CDKN1A, OGG1, XPC, PADI4, MAPK8, NF-KB1, STAT3, GATA3) was studied in chronically exposed persons with an increased intensity of early and late stages of apoptosis and necrosis of peripheral blood lymphocytes. The object of this study was peripheral blood mononuclear cells obtained from 132 chronically exposed residents of the Techa riverside villages. The mean accumulated dose to red bone marrow was 426.4 ± 48.2 mGy (1.3-2930.0 mGy), to thymus and peripheral immune organs, 58.9 ± 7.9 mGy (0.1-489.0 mGy). The study was performed more than 60 years after the onset of exposure, the average age of exposed persons was 68 ± 0.6 years (55-86 years). The study of apoptotic and necrotic death of peripheral blood lymphocytes was based on the presence of phosphatidylserine on the cell membrane surface, as well as on its permeability for DNA-intercalating dye. Evaluation of the relative content of mRNA genes for repair, cell cycle, and apoptosis was carried out using real-time PCR. An increased relative content of PADI4 gene mRNA was registered in the group of chronically exposed persons with the increased intensity of early apoptosis (p = 0.006). Modulation of the relative content of mRNA of the TP53 (p = 0.013) and BCL-2 (p = 0.021) genes was detected in the group of chronically exposed individuals with the increased intensity of the late stage of apoptosis. A statistically signif icant increase in the transcriptional activity of the TP53 gene was observed in the group of chronically exposed persons with the increased intensity of peripheral blood lymphocyte necrosis in the long-term period (p = 0.015). In the course of the study it was noted that exposed people with increased intensity of apoptosis, f irst of all, demonstrate changes in the transcriptional activity of apoptotic genes. These data are consistent with current views on the activation of programmed cell death., (Copyright © AUTHORS.)

This paper is devoted to the issue of medical care provision to the residents of the Techa riverside settlements affected by long-term radiation exposure. The river was contaminated due to operational and accidental releases of liquid radioactive waste (LRW) by the 'Mayak' Production Association from 1949 to 1956. Contamination of the river and its floodplain with radionuclides, including long-lived 90 Sr and 137 Cs, caused long-term external and internal exposure of the population, predominantly of the bone marrow. Protective countermeasures (resettlement of residents, introduction of restrictions on the use of the river and floodplain, construction of wells, etc) did not manage to prevent relatively high exposure doses to the population. The mean dose value of bone marrow exposure in residents of the riverside settlements was 0.35 Gy, whereas the maximum values were up to 7.92 Gy. The first medical examinations by mobile teams of the Moscow Institute of Biophysics were started approximately two years after the onset of LRW releases. Since 1955, exposed residents have been followed up and are undergoing medical treatment at the Clinic of the Urals Research Center for Radiation Medicine of the Federal Medical and Biological Agency (URCRM). This center was established in response to the necessity to study the biological effects of the combined external γ-exposure and exposure due to 90 Sr in order to arrange medical care for the exposed population. The URCRM Clinic focuses on the provision of hematological care since cases of chronic radiation syndrome were registered among the exposed population in the early period, and increased leukemia incidence has been observed in the long-term period., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

The process of nuclear weapons production from 1949 to 1987 was accompanied by the generation of a great amount of radioactive waste. Waste processing operations and controls on discharges at this time were not to the same standard as today. Because of this, vast areas of the Urals region of Russia surrounding the Mayak Production Association (MPA) were exposed to routine and accidental radioactive contamination. The greatest contribution to the contamination was gas aerosol emissions from the MPA in the 1950s (total activity 38 PBq, mainly 131 I), releases of liquid radioactive waste into the Techa River from 1949 to 1956 (total activity 115 PBq, including long-lived 90 Sr and 137 Cs) and accidental atmospheric releases as a result of the thermochemical explosion of the storage tank for liquid radioactive waste in 1957 (74 PBq, relatively short-lived radionuclides being the main contributors). Protective measures helped to relieve the pressing problem of population safety in the 1950s and 1960s, but they led to the appearance of new sources of contamination in the territory surrounding the MPA-Lake Karachay (total activity of beta-emitters 4400 PBq) and the Techa Cascade of Reservoirs (TCR; total activity 8 PBq). Owing to natural radioactive decay and rehabilitation measures, the radiation situation in the East Urals Radioactive Trace (EURT) has improved considerably over the years. Economic activity has been partially restored in these territories. Only the most contaminated territory of the East Urals Radioactive Reserve cannot be used for any economic activities up to the present day. Marked non-uniformity of radioactive contamination of the EURT and the Techa River floodplain, as well as radionuclide washout from Lake Karachay and the TCR into the underground waters and the Techa River require on-going radioecological monitoring, management and regulatory supervision., (© 2021 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights reserved.)

The review presents the results of a retrospective analysis of early markers of chronic radiation syndrome (CRS) in residents of the Techa riverside settlements. Mean values of postnatal red bone marrow doses calculated with the Techa River Dosimetry System-2016D were 698.8 ± 18.2 mGy, and maximum values reached 3 603.9 mGy. The clinical picture of the initial CRS stage was characterized by a set of non-specific functional changes that included not only hematopoietic but also immune, neurological, endocrine, and visceral disorders. CRS signs developed in a certain sequence. The earliest CRS signs were: increase of olfactory and taste thresholds, decrease of sensitivity to vibration and changes of systemic immunity. These were registered prior to hematopoietic changes typical of CRS. All initial organ changes related to CRS were functional in nature, mild or moderate, and transient. Early changes induced by chronic exposure in nervous, immune, and endocrine systems permit to consider CRS at early stages as a stereotype dysregulation pathology primarily based on radiation-induced disorders in regulatory systems. Disorders of circulatory, digestive, and other organs at early stages of CRS are secondary and their function restores spontaneously when the exposure stops. If exposure is continuous at doses sufficient for development of morphological tissue changes (dystrophy, fibrosis, hypoplasia and others), the CRS course becomes progressive and irreversible. The paper also describes the specific clinical manifestations of early stage of CRS in children.

The present study is based on a retrospective analysis of archive data of the Clinical Department of the Urals Research Center for Radiation Medicine that has been established to examine and treat accidentally exposed residents of the Urals Region. All individuals included in this study were examined by an ophthalmologist. The study of cataract incidence has been conducted retrospectively for the period from 1951 till 2000 among chronically exposed residents of the Techa riverside villages (6343 persons). Individual accumulated absorbed doses to soft tissues (analogue of eye dose) reached 1.18 Gy (mean 0.12 Gy) while for 88.9% of the study group the dose did not exceed 0.1 Gy. There was no evidence of the influence of low-dose and low-dose rate on cataract incidence. Excess relative risk of cataract formation per 1 Gy was 0.40 (95% CI -0.43; 1.47). It is noted that 15% of all excess cases were registered in persons with soft tissue dose above 0.3 Gy, though their fraction among all examined persons was only 4.1%. Risk of cataract development significantly increased in exposed individuals with retinal angiosclerosis, diabetes and arterial hypertension.

This paper presents an overview of the nuclear accident that occurred at the Mayak Production Association (PA) in the Russian Federation on 29 September 1957, often referred to as 'Kyshtym Accident', when 20 MCi (740 PBq) of radionuclides were released by a chemical explosion in a radioactive waste storage tank. 2 MCi (74 PBq) spread beyond the Mayak PA site to form the East Urals Radioactive Trace (EURT). The paper describes the accident and gives brief characteristics of the efficacy of the implemented protective measures that made it possible to considerably reduce doses to the exposed population. The paper also provides retrospective dosimetry estimates for the members of the EURT Cohort (EURTC) which comprises approximately 21 400 people. During the first two years after the accident a decrease in the group average leukocyte (mainly due to neutrophils and lymphocytes) and thrombocyte count was observed in the population. At later dates an increased excess relative risk of solid cancer incidence and mortality was found in the EURTC.

Health effects of in utero exposure to ionizing radiation, especially among adults, are still unclear. The aim of this study was to analyze cancer risk in a cohort of subjects exposed in utero due to releases of nuclear waste into the Techa River in the Southern Urals, taking into account additional postnatal exposure. Analysis for solid cancer was based on 242 cases among 10,482 cohort members, accumulating 381,948 person-years at risk, with follow-up from 1956-2009, while analysis for hematological malignancies was based on 26 cases among 11,070 persons, with 423,502 person-years at risk, with follow-up from 1953-2009. Mean doses accumulated in soft tissues and in red bone marrow during the prenatal period were 4 mGy and 30 mGy, respectively. Additional respective mean postnatal doses received by cohort members were 11 and 84 mGy. Poisson regression analysis was used to estimate the excess relative risk (ERR) of cancer incidence related to in utero and postnatal doses. No association was observed for in utero exposure with solid cancer risk [ERR per 10 mGy: -0.007; 95% confidence interval (CI): <-0.107; 0.148] or with hematological malignancy risk (ERR/10 mGy: -0.011; 95% CI: <-0.015; 0.099). However, ERR of solid cancer increased significantly with increasing postnatal dose (ERR/10 mGy: 0.11; 95% CI: 0.04; 0.22). The very wide confidence intervals in these ERR results are similar to those of studies performed on the LSS cohort and the offspring of the Mayak Female Worker Cohort, as well as case-control studies of effects after in utero medical exposure. There were limitations of this study, with decreased statistical power, due to the low prenatal doses received by most of the cohort members, the small number of cancer cases and the absence of cohort members over the age of 59 years (living cohort members had reached 49-59 years of age). Further aging of the cohort and extension of the follow-up period will enhance the statistical power of this study in the future. There is a shortage of cohort studies reporting on the effects of prenatal radiation exposure, as well as information on chronic exposure during the prenatal period. Therefore, further research of this unique cohort will be a useful addition to the published literature on this subject, and a valuable means of elucidating the long-term effects of low-dose radiation exposure in the fetus.

Background: It is scientifically uncertain whether in utero exposure to low-dose ionising radiation increases the lifetime risk of haematological malignancies., Methods: We pooled two cohorts from the Southern Urals comprising offspring of female workers of a large nuclear facility (the Mayak Production Association) and of women living in areas along the Techa River contaminated by nuclear accidents/waste from the same facility, with detailed dosimetry., Results: The combined cohort totalled 19 536 subjects with 700 504 person-years at risk over the period of incidence follow-up, and slightly more over the period of mortality follow-up, yielding 58 incident cases and 36 deaths up to age 61 years. Risk was increased in subjects who received in utero doses of ⩾80 mGy (excess relative risk (ERR): 1.27; 95% confidence interval (CI): -0.20 to 4.71), and the risk increased consistently per 100 mGy of continuous exposure in utero (ERR: 0.77; CI: 0.02 to 2.56). No association was apparent in mortality-based analyses. Results for leukaemia and lymphoma were similar. A very weak positive association was observed between incidence and postnatal exposure., Conclusions: In summary, the results suggest a positive association between in utero exposure to ionising radiation and risk of haematological malignancies, but the small number of outcomes and inconsistent incidence and mortality findings preclude firm conclusions.

Release of liquid radioactive waste into the Techa River from the Mayak Production Association during 1949-1956 resulted in a significant exposure of about 30000 people who lived in downstream settlements. The residents were exposed to internal and external radiation. The article discusses the capability of two methods that were used 50 years after the termination of radioactive discharges for the dose reconstruction, namely EPR measurements of tooth enamel, and FISH measurements of stable chromosome aberrations in circulating lymphocytes. The Main issue in the application of these methods for the dose reconstruction was local irradiation from strontium radioisotopes incorporated in teeth and bones. The EPR and FISH assays were supported by measurements of the 90Sr content in the skeleton and teeth in order to estimate and subtract internal doses from incorporated 89, 90Sr. The resulting dose estimates obtained from EPR and FISH mea- surements were found to be consistent The settlement-averaged values in the upper-Techa Region varied from 550-570 mGy to 130-160 mGy and showed a reduction with the distance from the release site. The EPR- and FISH-based dose estimates were in agreement with the doses calculated with the dosimetry system TRDS that uses data on radionuclide contamination of the Techa River floodplain and individual residential histories.

At present volumetric activity of β-emitting radionuclides in water at various locations of the Techa River ranges from 5 to 40-Bq/L; a specific activity of β-emitting radionuclides in the bottom sediments at various locations ranges 10 Ito 106 Bq/kg dry weight. A significant increase of the erythroblast content in blood as compared to that in the roach from the reference watercourse (the Miass River) was observed during spawning in the spring. Due to this fact the number of erythrocytes was equal to that in the control animals under chronic radiation exposure at the dose rates of 0.9 and 16 μGy/day, and was insufficient at the dose rate of 108 gGy/day. During summer feeding no changes in the indexes of erythropoiesis in roach were observed under chronic radiation exposure at the dose rate of 0.9 μGy/day; the number of erythrocytes in the peripheral blood declines when the dose rates are 16 and 108 μGy/day. When performing a regression analysis, we revealed a dose-rate-dependent decrease in the absolute number of erythrocytes, normocytes, polychromatocytes, dividing and non-dividing erythroid cells in the peripheral blood of roach from the Techa River and an increase of a relative number of normochromatophylic erythrocytes.

Analysis of recently available archive materials regarding the liquid radioactive waste storage and reprocessing at the "Mayak" Production Association in 1949-1956 has led to a more accurate reconstruction of radionuclide releases into the Techa River. Radionuclide concentrations in the Techa River water, bottom sediments and floodplain soils in 1949-1951 were reconstructed with the use of a purposely-developed Techa River model. Model calculations agree with the measurements of the specific activity in the river water and bottom sediments conducted since 1951. The model output for the (90)Sr concentration in the river water shows a good agreement with the retrospective estimates derived from (90)Sr measurements in teeth and the whole body of the Techa riverside residents. Modeled (137)Cs-contamination of the floodplain shows agreement with the values reconstructed from (137)Cs measurements in the floodplain soils obtained in later years. Reconstructed contamination levels by radionuclides in the Techa River water and floodplain are being used to refine internal and external doses and risk estimates of late effects in the population chronically exposed to radiation.

This paper presents an overview of radiobiological dependences governing the occurrence of tissue (organ) reactions that determine the outcomes of chronic exposure to low-LET ionizing radiation (IR) in humans. The mechanisms involved in the development of tissue reactions (TRs) to long-term exposures to IR and radioadaptation are considered. The overview describes the reactions of the haematopoietic, immune, nervous, reproductive and endocrine systems, lungs, skin and crystalline lens to chronic radiation exposure, which are of fundamental importance in view of radiation protection. It is shown that the individual's physiological tissue (organ) reserve, and also that induced by radiation exposure at low-dose rates are of great significance in the context of TR development., (© World Health Organisation 2016. All rights reserved. The World Health Organization has granted Oxford University Press permission for the reproduction of this article.)

Empirical data on the behavior of radionuclides in aquatic ecosystems are needed for radioecological modeling, which is commonly used for predicting transfer of radionuclides, estimating doses, and assessing possible adverse effects on species and communities. Preliminary studies of radioecological parameters including distribution coefficients and concentration ratios, for (90)Sr and (137)Cs were not in full agreement with the default values used in the ERICA Tool and the RESRAD BIOTA codes. The unique radiation situation in the Techa River, which was contaminated by long-lived radionuclides ((90)Sr and (137)Cs) in the middle of the last century allows improved knowledge about these parameters for river systems. Therefore, the study was focused on the evaluation of radioecological parameters (distribution coefficients and concentration ratios for (90)Sr and (137)Cs) for the Techa River and the Miass River, which is assumed as a comparison waterbody. To achieve the aim the current contamination of biotic and abiotic components of the river ecosystems was studied; distribution coefficients for (90)Sr and (137)Cs were calculated; concentration ratios of (90)Sr and (137)Cs for three fish species (roach, perch and pike), gastropods and filamentous algae were evaluated. Study results were then compared with default values available for use in the well-known computer codes ERICA Tool and RESRAD BIOTA (when site-specific data are not available). We show that the concentration ratios of (137)Cs in whole fish bodies depend on the predominant type of nutrition (carnivores and phytophagous). The results presented here are useful in the context of improving of tools for assessing concentrations of radionuclides in biota, which could rely on a wider range of ecosystem information compared with the process limited the current versions of ERICA and RESRAD codes. Further, the concentration ratios of (90)Sr are species-specific and strongly dependent on Ca(2+) concentration in water. The universal characteristic allows us to combine the data of fish caught in the water with different mineralization by multiplying the concentration of Ca(2+). The concentration ratios for fishes were well-fitted by Generalized Logistic Distribution function (GLD). In conclusion, the GLD can be used for probabilistic modeling of the concentration ratios in freshwater fishes to improve the confidence in the modeling results. This is important in the context of risk assessment and regulatory., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

As a result of operation of the Mayak Production Association (Mayak PA), Chelyabinsk Oblast, Russia, an enterprise for production and separation of weapon-grade plutonium in the Soviet Union, ecosystems of a number of water bodies have been radioactively contaminated. The article presents information about the current state of ecosystems of 6 special industrial storage reservoirs of liquid radioactive waste from Mayak PA: reservoirs R-3, R-4, R-9, R-10, R-11 and R-17. At present the excess of the radionuclide content in the water of the studied reservoirs and comparison reservoirs (Shershnyovskoye and Beloyarskoye reservoirs) is 9 orders of magnitude for (90)Sr and (137)Cs, and 6 orders of magnitude for alpha-emitting radionuclides. According to the level of radioactive contamination, the reservoirs of the Mayak PA could be arranged in the ascending order as follows: R-11, R-10, R-4, R-3, R-17 and R-9. In 2007-2012 research of the status of the biocenoses of these reservoirs in terms of phytoplankton, zooplankton, bacterioplankton, zoobenthos, aquatic plants, ichthyofauna, avifauna parameters was performed. The conducted studies revealed decrease in species diversity in reservoirs with the highest levels of radioactive and chemical contamination. This article is an initial descriptive report on the status of the biocenoses of radioactively contaminated reservoirs of the Mayak PA, and is the first article in a series of publications devoted to the studies of the reaction of biocenoses of the fresh-water reservoirs of the Mayak PA to a combination of natural and man-made factors, including chronic radiation exposure., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The purpose of the present research was to estimate the intensity of the apoptotic death of lymphocytes during the period of carcinogenic effect realization in the residents of the Techa riverside villages. The investigation included analyses of the frequency of lymphocytes at the early and late stages of apoptosis and necrosis of peripheral blood lymphocytes using the method of FITC Annexin V, lymphocyte counts at the stage of DNA fragmentation using the TUNEL method, and the number of CD95(+)-lymphocytes. In the capacity of additional tests, loading tests involving in vitro irradiation at the dose of 1 Gy of a suspension of lymphocytes and incubations for 5 and 24 hours were used. Activation of the initial apoptotic and necrotic death of peripheral blood lymphocytes was revealed in the persons chronically exposed to low-intensity radiation within the range from 0.01 to 4.23 Gy. Exposed patients demonstrated a decrease in the number of CD95(+)-cells as compared to unexposed patients. The results of the cell death studies in the persons residing in the Techa riverside villages testify indirectly to the genomic instability of the peripheral blood lymphocytes.

Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all-solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites.

Objective: To assess the cognitive status in persons exposed to ionizing radiation in prenatal period., Material and Methods: The study included in-utero exposed people (n = 77), and the comparison group (n = 73), which consisted of people who lived in the territories of the Chelyabinsk Oblast that were not radioactive. The following methods were used: clinical, clinical-psychological (Mini-Mental State Examination (MMSE), the WAIS test, the proverb interpretation task, neurophysiological (EEG) methods, laboratory-based methods (cholesterol, high and low-density lipoproteins, triglycerides, cortisol, melatonin), and methods of statistical data processing., Results and Conclusion: The number of people with non-psychotic mental disorders with the prevalence of organic mental disorders (cognitive and asthenic) was significantly higher among in-utero exposed subjects. A neurophysiological study revealed more severe changes in the bioelectric brain activity with the presence of pathological and theta-rhythms in exposed persons. The clinical-psychological study revealed a significant decrease in the analytic/synthetic ability in exposed people and significantly lower level of the general and verbal IQ. These changes were accompanied by higher levels of cortisol and melatonin which led to the activation and tension of the adaptation mechanisms in in-utero exposed subjects.

A biologically motivated dynamical model of the lymphocytopoietic system in irradiated humans is applied here to analyze the data obtained under hematological examinations of residents of Techa riverside villages. Those people were exposed to chronic irradiation with varying dose rates, due to the radioactive contamination of the river basin by the Mayak Production Association. Modeling studies revealed the relationship between the dynamics of the lymphocytopoietic system in the examined individuals and the variation of dose rate over the considered period of time. It is found that the developed model is capable of reproducing the decreased level of blood lymphocyte concentration observed during the period of maximum radiation exposure, the recovery processes in the system observed during the period of decreasing dose rate, as well as the enhanced mitotic activity of bone marrow precursor cells in this hematopoietic lineage observed during the entire period under consideration. Mechanisms of these effects of chronic irradiation on the human lymphocytopoietic system are elucidated based on the applied model. The results obtained demonstrate the efficiency of the developed model in the analysis, investigation, and prediction of effects of chronic irradiation with varying dose rate on the human lymphocytopoietic system. In particular, the developed model can be used for predicting any radiation injury of this vital system in people exposed to chronic irradiation due to environmental radiological events, such as anthropogenic radiation accidents or radiological terroristic attacks.

A profound approach to the analysis of clinical data on the dynamics of major hematopoietic lineages (granulocytopoietic, thrombocytopoietic, and erythrocytopoietic systems) in chronically irradiated humans is proposed. It is based on recently developed mathematical models of these systems in humans, which enable one to study and interpret clinical hematological data. The developed approach is applied to the analysis of statistically processed clinical data, which were obtained under hematological examinations of residents of Techa riverside villages. These people were exposed to chronic irradiation with varying dose rate due to the radioactive contamination of the river basin by the Mayak Production Association. In the course of modeling studies, the relationship between the dynamics of aforementioned systems in examined individuals and the variation of chronic exposure dose rate over the considered period of time is revealed. It is found that the models are capable of reproducing common regularities and peculiarities of the dynamics of systems on hand, including the decreased stationary levels of blood cell concentrations during the period of maximum radiation exposure, the recovery processes during the period of decrease of exposure dose rate, and the prevalence of younger bone marrow granulocytopoietic cells over more mature ones during the entire period. The mechanisms of such effects of chronic irradiation on the hematopoietic lineages are revealed on the basis of modeling studies. All this testifies to the efficiency of employment of the developed models in the analysis, investigation, and prediction of effects of chronic irradiation on human hematopoietic system.

Background: Little is known about leukaemia risk following chronic radiation exposures at low dose rates. The Techa River Cohort of individuals residing in riverside villages between 1950 and 1961 when releases from the Mayak plutonium production complex contaminated the river allows quantification of leukaemia risks associated with chronic low-dose-rate internal and external exposures., Methods: Excess relative risk models described the dose-response relationship between radiation dose on the basis of updated dose estimates and the incidence of haematological malignancies ascertained between 1953 and 2007 among 28 223 cohort members, adjusted for attained age, sex, and other factors., Results: Almost half of the 72 leukaemia cases (excluding chronic lymphocytic leukaemia (CLL)) were estimated to be associated with radiation exposure. These data are consistent with a linear dose response with no evidence of modification. The excess relative risk estimate was 0.22 per 100 mGy. There was no evidence of significant dose effect for CLL or other haematopoietic malignancies., Conclusion: These analyses demonstrate that radiation exposures, similar to those received by populations exposed as a consequence of nuclear accidents, are associated with long-term dose-related increases in leukaemia risks. Using updated dose estimates, the leukaemia risk per unit dose is about half of that based on previous dosimetry.

This paper presents the results of a cytogenetic study conducted among residents of the Techa Riverside communities (Southern Urals, Russia) exposed in the early 1950s as a result of releases of liquid radioactive wastes from the Mayak plutonium-production facility. The study was performed 50-60 years after the beginning of the exposure for those individuals who were predominantly exposed to strontium radioisotopes ((89,90)Sr) through drinking contaminated river water and consumption of local foodstuff. Standard cytogenetic methods were used for evaluation of the frequency of unstable chromosome aberrations in exposed persons as well as in persons from the control group who were of similar age and sex, living in similar socio-economic conditions in non-contaminated territories of the Southern Urals. The exposure doses were reconstructed for the studied donors using the Techa River Dosimetry System developed in 2009. The doses of internal exposure from ingested radionuclides were evaluated using individual or family in vivo measurements of (90)Sr-body burden. Individual cumulative absorbed doses in red bone marrow (RBM) in the studied persons varied in the range of 0.01-4.4Gy. A significantly higher level of unstable chromosome aberrations (UCA) in T-cells was observed in the group of exposed individuals as compared to control group. The highest UCA level was detected in the individuals who were suspected of having chronic radiation syndrome., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Our understanding of cancer risk from ionizing radiation is largely based on studies of populations exposed at high dose and high dose rates. Less certain is the magnitude of cancer risk from protracted, low-dose and low-dose-rate radiation exposure. We estimated the dose-response relationship for solid cancer mortality in a cohort of 29,730 individuals who lived along the Techa River between 1950 and 1960. This population was exposed to both external γ radiation and internal (90)Sr, (137)Cs and other radionuclides after the release of radioactive waste into the river by the Mayak Radiochemical Plant. The analysis utilized the latest individualized doses from the Techa River Dosimetry System (TRDS) 2009. We estimated excess relative risks (ERRs) per Gy for solid cancer mortality using Poisson regression methods with 95% confidence intervals (CIs) and P values based on likelihood ratio tests. Between 1950 and 2007, there were 2,303 solid cancer deaths. The linear ERR/Gy = 0.61 (95%; CI 0.04-1.27), P = 0.03. It is estimated that approximately 2% (49.7) of solid cancers deaths were associated with the radiation exposure. Our results, based on 2,303 solid cancer deaths and more than 50 years of follow-up, support an increased risk of solid cancer mortality following protracted radiation exposure from the Techa River contamination. The wide confidence interval of our estimate reflects the challenges of quantifying and describing the shape of the dose-response relationship in the low dose range. Nevertheless, the risk estimates provide important information concerning health risks from whole-body radiation exposure that can occur from accidents that result in wide-scale environmental contamination.

Presented in the manuscript are the results of an analytic study on the chronic radiation syndrome (CRS) among 940 residents of the Techa riverside villages. The uniqueness of this pathology is associated with the fact that, so far, this clinical entity has mainly been observed among Mayak PA workers and residents of the Techa riverside villages. The analyses of CRS cases identified among a population characterised by significant heterogeneity in terms of age, baseline health status and other radiosensitivity modification factors presents a considerable scientific and practical interest. It has been shown that a long-term total exposure at doses in excess of the threshold organ dose in people causes primarily functional changes (neutropaenia, thrombocytopaenia, vegetative dysfunction and asthenia) which, if the exposure continues, are transformed into organic changes (bone marrow hypoplasia, organic damage to the nervous system). If the dose rate decreases below the threshold, a complete repair of the functional changes is observed, while organic alterations may persist for a long time.

This research has been conducted to study the activity of apoptosis of peripheral blood lymphocytes (PBLs) and the frequency of CD3-/CD4+ PBLs in people who have suffered chronic low-intensity radiation exposure. An increase in the frequency of apoptotic cells (TUNEL) is demonstrated in the group of exposed individuals relative to the control group. The frequency of mutations in the gene of the T-cell receptor in the exposed individuals is also elevated. Analyses of the mean values of apoptosis and CD3-CD4+ PBLs in different dose subgroups have found an increase in the proportion of cells with mutant T-cell receptors against the background of a decrease in the frequency of apoptotic cells in the range of low and medium radiation doses.

Liquid radioactive waste from the Mayak Production Association (Chelyabinsk Region, Russia) is contained in industrial reservoirs (R-11, R-10, R-4, R-17, and R-9) that have different levels of radioactive contamination, increased from R-11 to R-17. A study of the ecosystems in these reservoirs was performed in 2009 to determine if there was any association with the level of contamination. No significant change in the status of biota was found in the reservoir with the lowest radionuclide concentrations (R-11) in comparison to other reservoirs in the region with a similar geography that are unaffected by radioactive contamination. In reservoir R-10, changes in the zoobenthos indices were registered. In reservoir R-4, changes in the zoobenthos and zooplankton communities were registered. In reservoir R-17, there was no ichthyofauna, but strong changes in the phytoplankton, zooplankton, and zoobenthos communities were registered. In reservoir R-9, under the conditions of the heaviest radioactive contamination of water ecosystems in the biosphere, there was no ichthyofauna, and phytoplankton and zooplankton consisted of almost a monoculture of cyanobacteriae and rotifers.

In this paper we present a new multiple-pathway stochastic model of carcinogenesis with potential of predicting individual incidence risks on the basis of biomedical measurements. The model incorporates the concept of intracellular barrier mechanisms in which cell malignization occurs due to an inefficient operation of barrier cell mechanisms, such as antioxidant defense, repair systems, and apoptosis. Mathematical formalism combines methodological innovations of mechanistic carcinogenesis models and stochastic process models widely used in studying biodemography of aging and longevity. An advantage of the modeling approach is in the natural combining of two types of measures expressed in terms of model parameters: age-specific hazard rate and means of barrier states. Results of simulation studies allow us to conclude that the model parameters can be estimated in joint analyses of epidemiological data and newly collected data on individual biomolecular measurements of barrier states. Respective experimental designs for such measurements are suggested and discussed. An analytical solution is obtained for the simplest design when only age-specific incidence rates are observed. Detailed comparison with TSCE model reveals advantages of the approach such as the possibility to describe decline in risk at advanced ages, possibilities to describe heterogeneous system of intermediate cells, and perspectives for individual prognoses of cancer risks. Application of the results to fit the SEER data on cancer risks demonstrates a strong predictive power of the model. Further generalizations of the model, opportunities to measure barrier systems, biomedical and mathematical aspects of the new model are discussed., (Copyright © 2012. Published by Elsevier Inc.)

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of 'practical' threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye. Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40-50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower. A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1-1.2, and in a few cases 1.5-2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors. Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further., (Copyright © 2012. Published by Elsevier Ltd.)

A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950-1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose-effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose-rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia).

A new model of the hematopoietic system for humans chronically exposed to ionizing radiation allows for quantitative description of the initial hematopoiesis inhibition and subsequent increase in the risks of late stochastic effects such as leukemia. This model describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the three blood cell types (leukocytes, erythrocytes, and platelets). The model parameters are estimated from the results of other experiments. They include the steady-state numbers of hematopoietic stem cells and peripheral blood cell lines for an unexposed organism, amplification parameters for each blood cell line, parameters describing the proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity in respect to cell death and non-lethal cell damages. The dynamic model of hematopoiesis is applied to the data on a subcohort of the Techa River residents with hematological measurements (e.g., blood counts) performed in 1950-1956 (which totals to about 3,500 exposed individuals). Among well-described effects observed in these data are the slope values of the dose-effect curves describing the hematopoietic inhibition and the dose rate patterns of the fractions of cytopenic states (e.g., leukopenia, thrombocytopenia). The model has been further generalized by inclusion of the component describing the risk of late stochastic effects. The risks of the development of late effects (such as leukemia) in population groups with specific patterns of early reactions in hematopoiesis (such as leukopenia induced by ionizing radiation) are investigated using simulation studies and compared to data.

The major goal of this study is to investigate and quantitatively describe the nature of the relationship between the characteristics of chronic exposure to ionizing radiation and specific patterns of hematopoiesis reduction. The study is based on about 3,200 hemograms taken for inhabitants of the Techa riverside villages over the years 1951-1956, i.e., the period characterized by a gradual decrease in dose rates. The mean cumulative red bone marrow dose was 333.6 + or - 4.6 mGy. The approach to statistical analyses involved both empirical methods and modeling (generalized linear models and logistic regressions). The results of the analyses highlighted a gradual increase in the frequency of cytopenias with dose rate. The impact of exposure on hematopoiesis reduction patterns was found to be more substantial than that of age and health status. Dose rates resulting in a two-fold increase in the frequency of cytopenias have been estimated.

Unlabelled: The present paper focuses on the analysis of data resulting from 50-y studies involving assessment of the hemopoiesis state in Techa riverside residents chronically exposed to radiation and evaluation of the bone tissue status for people with Sr incorporation at late time after the intakes., Conclusions: 1. In the late period after the start of chronic radiation exposure (50 y later) only a few individuals with red bone marrow doses reaching about 1.8 Gy (mean dose of 0.66 Gy) had a marked peripheral blood leucopenia, and the incidence of neutropenia, lymphopenia and thrombocypenia in the exposed group did not exceed that noted in the control group. The results of our observations indicate the spontaneous recovery of the hemopoietic system of residents of the Techa riverside villages. Thus, the adaptation mechanisms of hemopoiesis to the long-term chronic exposure in the range of low to intermediate doses are sufficiently effective; 2. About half of the people with Sr incorporation and the control group have changes in bone tissue expressed by different stages of osteoporosis. Age is a determinative factor of bone tissue involution in women while some tendency of Sr influence on the intensity of osteoporosis is revealed in the male group.

The major goal of this study was to identify and quantitatively describe the association between the characteristics of chronic (low-dose rate) exposure to (low LET) ionizing radiation and cellularity of peripheral blood cell lines. About 3,200 hemograms (i.e., spectra of blood counts) obtained over the years of maximal exposure to ionizing radiation (1950-1956) for inhabitants of the Techa River were used in analyses. The mean cumulative red bone marrow dose (with standard errors), calculated using Techa River Dosimetry System-2000, was 333.6 +/- 4.6 mGy (SD = 259.9 mGy, max = 1151 mGy) to the year 1956. The statistical approach included both empirical methods for estimating frequencies of cytopenic states of the investigated blood cell lines (e.g. neutrophile, platelets, erythrocyte, etc.), and regression methods, including generalized linear models and logistic regressions which allowed taking into account confounding factors (e.g., attained age, age at maximal exposure, presence of concomitant diseases, and demographic characteristics). The results of the analyses demonstrated hematopoiesis inhibition manifested by a decrease in peripheral blood cellularity and an increase in the frequency of cytopenia in all blood cell lines (leukocytes, including lymphocytes, monocytes, neutrophiles, as well as platelets and erythrocytes). The intensity of hematopoiesis inhibition in the period of maximal exposures is determined by the combined influence of the dose rate and cumulative dose. The contribution of specific confounding factors was quantified and shown to be much less important than dose characteristics. The best predictor among dose characteristics was identified for each blood cell line. A 2-fold increase in dose rate is assumed to be a characteristic of radiosensitivity and a quantitative characteristic of the effect.

Germline mutation at eight minisatellite loci has been studied among the irradiated families from the Techa River population and non-exposed families from the rural area of the Chelyabinsk and Kurgan Oblasts. The groups were matched by ethnicity, parental age, occupation and smoking habit. A statistically significant 1.7-fold increase in mutation rate was found in the germline of irradiated fathers, whereas maternal germline mutation rate in the exposed families was not elevated. Most of the minisatellite loci showed an elevated paternal mutation rate in the exposed group, indicating a generalised increase in minisatellite germline mutation rate in the Techa River population. These data suggest that the elevated minisatellite mutation rate can be attributed to radioactive exposure. The spectra of paternal mutation seen in the unexposed and exposed families were indistinguishable.

Residents living on the banks of the Techa River in the Southern Urals region of Russia were exposed to radioactive contamination from the Mayak plutonium production and separation facility that discharged liquid radioactive waste into this river. This paper describes the methods used to establish and follow the Extended Techa River Cohort (ETRC), which includes almost 30,000 people living along the Techa River who were exposed to a complex mixture of radionuclides, largely 90Sr and 137Cs. The system of regular follow-up allows ascertainment of vital status, cause of death and cancer incidence. With over 50 years of follow-up and over 50% deceased, the ETRC now provides a valuable opportunity to study a wide range of health effects, both early and late, associated with protracted internal and external radiation exposures. The wide range of doses allows analysis of the nature of the dose-response relationship based on internal comparisons. Other features of the cohort are the high proportion (40%) exposed under age 20, and the inclusion of both sexes. The limitations of the study include loss to follow-up due to difficulties in tracing some cohort members and migration and incomplete ascertainment of cause of death.