Modeling hematopoietic system response caused by chronic exposure to ionizing radiation

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).     

Status of hemapoiesis in residents of the Techa riverside villages in the period of maximum radiation exposure. Report 1. Evaluation of the cellular composition of peripheral blood and the role of comorbidities in the oppression of hemapoiesis

Residents of the Techa riverside villages chronically exposed to ionizing radiation (the average dose rate in 1951-1956 was 0.047 Gy/year, the maximum reached 2.44 Gy/year) developed marked changes in the cellular composition of peripheral blood. The maximum reduction of peripheral blood counts occurred in the years 1951-1953, after which the beginning of the restoration of cellularity to the control level was observed. The dose rate at this point (1956) was about 0.02 Gy/year. The factors of radiation and non-radiation nature (gender, the age at the onset of exposure, health related disorders) in different combinations affect the number of peripheral blood cells. The influence of dose rate of a chronic radiation exposure on a platelet count takes precedence over other factors. The factors of gender and dose rate determine the number of erythrocytes in exposed persons. The changes accompanying the health status and dose rate significantly affect the number of neutrophils. The influence of comorbidity, age and dose rate on the number of monocytes was noted. A lymphocyte count was mainly determined by the age at the onset of exposure and concomitant diseases. A joint influence of chronic radiation exposure and concomitant diseases increases a mutual action on erythro- and thrombocytopoiesis. The decrease of the dose rate was followed by a gradual predominance of the somatic disease influence on leukocyte (neutrophils, lymphocytes and monocytes) counts.     

Evaluation of external exposures of the population of Ozyorsk,Russia, with luminescence measurements of bricks

Recently discovered historical documents indicate that large releases of noble gases (mainly ⁴¹Ar and radioactive isotopes of Kr and Xe) from the Mayak Production Association (MPA) over the period from 1948 to 1956 may have caused considerable external exposures of both, inhabitants of Ozyorsk and former inhabitants of villages at the upper Techa River. To quantify this exposure, seven brick samples from three buildings in Ozyorsk, located 8–10 km north-northwest from the radioactive gas release points, were taken. The absorbed dose in brick was measured in a depth interval of 3–13 mm below the exposed surface of the bricks by means of the thermoluminescence (TL) and the optically stimulated luminescence (OSL) method. Generally, luminescence properties using TL were more favorable for precise dose determination than using OSL, but within their uncertainties the results from both methods agree well with each other. The absorbed dose due to natural radiation was assessed and subtracted under the assumption of the bricks to be completely dry. The weighted average of the anthropogenic dose for all samples measured by TL and OSL is 10 ± 9 and 1 ± 9 mGy, respectively. An upper limit for a possible anthropogenic dose in brick that would not be detected due to the measurement uncertainties is estimated at 24 mGy. This corresponds to an effective dose of about 21 mSv. A similar range of values is obtained in recently published dispersion calculations that were based on reconstructed MPA releases. It is concluded that the release of radioactive noble gases from the radiochemical and reactor plants at Mayak PA did not lead to a significant external exposure of the population of Ozyorsk. In addition, the study demonstrates the detection limit for anthropogenic doses in ca. 60-year-old bricks to be about 24 mGy, if luminescence methods are used.     

Status of hemapoiesis in residents of the Techa riverside villages in the period of maximum radiation exposure. Report 2. Influence of exposure dose and dose rate of red bone marrow as well as modifying factors on the frequency of cytopenia and cytosis

The purpose of this study is a retrospective estimation of the influence of dose and dose rate of the red bone marrow chronic radiation exposure in combination with various modifying factors (gender, age, comorbidity) on the frequency of deviations from normal values of the results of peripheral blood investigation in humans exposed on the Techa River. The results of investigation show that humans chronically exposed to radiation can develop marked changes in the cellular composition of peripheral blood characterized by a tendency to cytopenia (signs of the decompensation of hemopoiesis). The tendency to cytopenia can be identified earlier in the lymphoid germ, and later in platelet and erythroid lines. A high lability of granulocytes under the influence of various, often infectious, factors is the cause of the lack of statistically significant differences in terms of frequency of neutropenia. Several non-radiation factors (gender, age, health status) in combination with radiation exposure could have a modifying influence on hematopoiesis, which contributed to the disruption of adaptation processes and the development of conditions characterized by a tendency to cytopenias in exposed individuals. The red bone marrow dose rate reduction resulted in a gradual decrease in the frequency of erythrocytopenia, thrombocytopenia, neutropenia and lymphocytopenia in the group of exposed population. Increased frequencies of erythrocytosis, thrombocytosis, lymphocytosis, monocytosis and neutrophilia were observed when the median dose rate was reduced to the level of 0.024 Gy/year (in the year 1956), which could be regarded as activation of regenerative processes in hematopoiesis.     

On an evaluation of external dose values in the Techa River Dosimetry System (TRDS) 2000

Absorbed doses were determined by thermoluminescence (TL) measurements for bricks from a height of 6 m from the south-western wall of the former mill in Metlino that faced the Techa river. Measurements of the internal beta-radiation and alpha-radiation in the brick samples and of radionuclide activities in soil samples from the Techa river valley were performed. The absorbed dose in bricks due to the natural radiation was derived and subtracted from the total dose in order to obtain the absorbed dose in the bricks caused by anthropogenic sources. The results were combined with results from two previous studies. The absorbed dose in the bricks due to the radiation field after relocation of the Metlino population in 1956 was derived from dose rates in air measured in front of the sampling locations in 1996/1997. Based on these dose rates the dose to bricks was calculated by means of conversion factors from the literature. The absorbed dose accumulated in the bricks in the period 1949–1956 was nearly 80% of the total dose that had been determined by TL measurements. Previously derived conversion factors were applied to obtain an estimate of the gamma dose in air at the former shore of the Techa river. An uncertainty and sensitivity analysis was performed with the program package Crystal Ball. Care was taken to treat statistical and systematic uncertainties separately and to take parameter correlations into account. The resulting distribution for the gamma dose accumulated in the period 1949–1956 at the Techa river shore has a median value of 32 Gy with a 95% confidence interval of 21–45 Gy. This study confirms the corresponding value of 26.6 Gy that is used in the Techa River Dosimetry System (TRDS) 2000.     

Nonlinear ionizing radiation-induced changes in eye lens cell proliferation,cyclin D1 expression and lens shape

Elevated cataract risk after radiation exposure was established soon after the discovery of X-rays in 1895. Today, increased cataract incidence among medical imaging practitioners and after nuclear incidents has highlighted how little is still understood about the biological responses of the lens to low-dose ionizing radiation (IR). Here, we show for the first time that in mice, lens epithelial cells (LECs) in the peripheral region repair DNA double strand breaks (DSB) after exposure to 20 and 100 mGy more slowly compared with circulating blood lymphocytes, as demonstrated by counts of γH2AX foci in cell nuclei. LECs in the central region repaired DSBs faster than either LECs in the lens periphery or lymphocytes. Although DSB markers (γH2AX, 53BP1 and RAD51) in both lens regions showed linear dose responses at the 1 h timepoint, nonlinear responses were observed in lenses for EdU (5-ethynyl-2′-deoxy-uridine) incorporation, cyclin D1 staining and cell density after 24 h at 100 and 250 mGy. After 10 months, the lens aspect ratio was also altered, an indicator of the consequences of the altered cell proliferation and cell density changes. A best-fit model demonstrated a dose-response peak at 500 mGy. These data identify specific nonlinear biological responses to low (less than 1000 mGy) dose IR-induced DNA damage in the lens epithelium.     

Pilot study of the Urals population by tooth electron paramagnetic resonance dosimetry

During 1949–1956, about 76 × 10⁶ m³ of radioactive liquid waste containing a total activity of 10¹⁷ Bq was discharged into the Techa River by the first Russian industrial nuclear facility Mayak. As a consequence, the population living in the river valley received considerable internal and external radiation doses. The results of a first application of electron paramagnetic resonance (EPR) of tooth enamel for a retrospective individual dose evaluation of the residents of the Techa riverside are presented. Three main contributions to the dose absorbed in tooth enamel have been considered: external exposure mainly from the Techa River sediments, internal exposure mainly due to ⁹⁰Sr; and background radiation including all other sources of exposure except the Techa River. The teeth of 86 inhabitants of the town Kamensk-Uralskii were analysed to determine the age-dependent contribution of the background radiation to the enamel dose. For 22 residents of the middle and lower Techa riverside, measurements of the ⁹⁰Sr whole-body content and EPR measurements of the absorbed dose in enamel were used to establish a correlation between these two quantities. Finally, absorbed doses in the enamel of five residents of the upper Techa riverside were determined by the EPR method. Contributions of the background radiation and the internal ⁹⁰Sr contamination were subtracted to determine the external exposure of the residents.     

Verification of external exposure assessment for the upper Techa riverside by luminescence measurements and Monte Carlo photon transport modeling

An area located in the Southern Urals was contaminated in 1949–1956 as a result of radioactive waste releases into the Techa river by the Mayak Production Association. The external dose reconstruction of the Techa river dosimetry system (TRDS-2000) for the exposed population is based on an assessment of dose rates in air (DRA) obtained by modeling transport and deposition of radionuclides along the river for the time before 1952 and by gamma dose rate measurements since 1952. The aim of this paper is to contribute to a verification of the TRDS-2000 external dose assessment. Absorbed doses in bricks from a 130-year-old building in the heavily exposed Metlino settlement were measured by a luminescence technique. By the autumn of 1956 the population of Metlino had been evacuated, and then a water reservoir was created at the village location, which led to a change in the radioactive source geometry. Radiation transport calculations for assumed environmental sources before and since 1957 were performed with the MCNP Monte Carlo code. In combination with TRDS-2000 estimates for annual dose rates in air at the shore of the Techa river for the period 1949–1956 and contemporary dose rate in air measurements, absorbed doses in bricks were calculated. These calculations were performed deterministically with best estimates of the modeling parameters and stochastically by propagating uncertainty distributions through the calculation scheme. Assessed doses in bricks were found to be consistent with measured values within the uncertainty bounds, while their best estimates were approximately 15% lower than the luminescence measurements.An erratum to this article can be found at     

Dual-energy contrast-enhanced digital mammography: Glandular dose estimation using a Monte Carlo code and voxel phantom

PurposeTo estimate the mean glandular dose of contrast enhanced digital mammography, using the EGSnrc Monte Carlo code and female adult voxel phantom.MethodsAutomatic exposure control of full field digital mammography system was used for the selection of the X-ray spectrum and the exposure settings for dual energy imaging. Measurements of the air-kerma and of the half value layers were performed and a Monte Carlo simulation of the digital mammography system was used to compute the mean glandular dose, for breast phantoms of various thicknesses, glandularities and for different X-ray spectra (low and high energy).ResultsFor breast phantoms of 2.0–8.0 cm thick and 0.1–100% glandular fraction, CC view acquisition, from AEC settings, can result in a mean glandular dose of 0.450 ± 0.022 mGy −2.575 ± 0.033 mGy for low energy images and 0.061 ± 0.021 mGy – 0.232 ± 0.033 mGy for high energy images. In MLO view acquisition mean glandular dose values ranged between 0.488 ± 0.007 mGy – 2.080 ± 0.021 mGy for low energy images and 0.065 ± 0.012 mGy – 0.215 ± 0.010 mGy for high energy images.ConclusionThe low kV part of contrast enhanced digital mammography is the main contributor to total mean glandular breast dose. The results of this study can be used to provide an estimated mean glandular dose for individual cases.     

External dose reconstruction for the former village of Metlino (Techa River,Russia) based on environmental surveys,luminescence measurements,and radiation transport modelling

In the first years of its operation, the Mayak Production Association, a facility part of the Soviet nuclear weapons program in the Southern Urals, Russia, discharged large amounts of radioactively contaminated effluent into the nearby Techa River, thus exposing the people living at this river to external and internal radiations. The Techa River Cohort is a cohort intensely studied in epidemiology to investigate the correlation between low-dose radiation and health effects on humans. For the individuals in the cohort, the Techa River Dosimetry System describes the accumulated dose in human organs and tissues. In particular, organ doses from external exposure are derived from estimates of dose rate in air on the Techa River banks which were estimated from measurements and Monte Carlo modelling. Individual doses are calculated in accordance with historical records of individuals’ residence histories, observational data of typical lifestyles for different age groups, and age-dependent conversion factors from air kerma to organ dose. The work here describes an experimentally independent assessment of the key input parameter of the dosimetry system, the integral air kerma, for the former village of Metlino, upper Techa River region. The aim of this work was thus to validate the Techa River Dosimetry System for the location of Metlino in an independent approach. Dose reconstruction based on dose measurements in bricks from a church tower and Monte Carlo calculations was used to model the historic air kerma accumulated in the time from 1949 to 1956 at the shoreline of the Techa River in Metlino. Main issues are caused by a change in the landscape after the evacuation of the village in 1956. Based on measurements and published information and data, two separate models for the historic pre-evacuation geometry and for the current geometry of Metlino were created. Using both models, a value for the air kerma was reconstructed, which agrees with that obtained in the Techa River Dosimetry System within a factor of two.     

Biological effects induced by doses of mammographic screening

PurposeMammography is the diagnostic imaging practice used in screening to detect early lesions suspected of malignancy. It uses a low energy X-ray beam in which a low dose in the order of 2–3 mGy is delivered to patient breast cells. However, it has been speculated that it could lead to significant cell damage, when compared to conventional X-ray. We investigated the biological effects of low doses, with mean glandular doses (MGDs) of 2.5 mGy and 2.5 + 2.5 mGy, on mammary cells in vitro.MethodsWe used the non-tumorigenic cell line (MCF-10A) and two tumor cells lines (MCF-7 and MDA-MB-231). Colony formation, apoptosis, and double-strand DNA breaks (DSBs) were quantified.ResultsThe selected MGD regimens did not alter the formation of colonies by any of the cell lines. MCF-7 cells exhibited a markedly increase in apoptosis, 24 h after the single-dose protocol; MCF-10A cells underwent apoptosis only after 72 h, with both irradiation regimens, while MDA-MB-231 cells (highly invasive and metastatic) were not susceptible to apoptosis. The detection of γH2AX histone in the nuclei of irradiated cells showed that the double-dose resulted in increase of DSBs, especially in tumor cell lines.ConclusionsAlthough the health benefits of early breast screening remain indisputable, our future perspective is to better understand the biological basis for the effects of low dose radiation on breast cells and to investigate if and under what conditions there would be a risky situation in repeated mammography screening, in both asymptomatic and symptomatic women.     

Evaluation of anthropogenic dose distribution amongst building walls at the Metlino area of the upper Techa River region

This paper presents the results of an effort to evaluate anthropogenic doses in bricks from old buildings located on the banks of the Techa River. The river area was contaminated in 1949–1956 as a result of radioactive waste releases by the Mayak plutonium facility (Southern Urals, Russia). Absorbed doses were determined by luminescence measurements of quartz extracted from the near-surface layers of bricks sampled in 1991–1997 from three remained buildings (a mill, a granary and a church). These buildings are located in the former residence area of Metlino, which was the settlement located closest to the release site (residents of Metlino were relocated from the contaminated river in 1956). The measured anthropogenic dose in the three buildings was found to be comparable: minimum values were equal to 0.5–0.9 Gy and maximum values amounted to about 3–4 Gy. Unfortunately, the geometry of gamma-exposure of the brick samples changed significantly in 1956 as a result of creation of an artificial reservoir downstream of the Metlinsky pond. Since luminescence data provide absorbed dose in the investigated samples accumulated over the whole period of irradiation, for interpretation of the data obtained it is important to know the exposure geometry for the period of maximal exposure, which was in the early 1950s. In 2005, archival data describing configuration of contaminated water streams and shorelines (which were the main sources of gamma-irradiation) were published. Comparison of these data with the results of the luminescence study presented here showed that the bricks with the highest thermoluminescence (TL)-based doses faced contaminated shores and were located close to them. In contrast, the bricks with lower values of measured dose were opposite to contaminated shores and/or being shielded. This demonstrates that the luminescence method allowed reconstruction of the anthropogenic dose distribution in the former settlement center. The obtained results suggest new options for further luminescence studies in Metlino aimed at the reconstruction of the external exposures of the affected population.     

Effect of low-level radiation on the death of male germ cells

Hormetic and adaptive responses induced by low-level radiation in hematopoietic and immune systems have been observed, as shown by stimulatory effects on cell growth and resistance to subsequent radiation-induced cytogenetic damage. However, in terms of cell death by apoptosis, the effects of low-level radiation are controversial: Some studies showed decreased apoptosis in response to low-level radiation while others showed increased apoptosis. This controversy may be related to the radiation doses or dose rates and also, more importantly, to the cell types. Testes are one of the most radiosensitive organs. The loss of male germ cells after exposure to ionizing radiation has been attributed to apoptosis. In the present study, the effects of low-level radiation at doses up to 200 mGy on mouse male germ cells in terms of apoptosis and the expression of apoptosis-related proteins were examined at different times after whole-body exposure of mice to low-level radiation. In addition, the effect of pre-exposure to low-level radiation on subsequent cell death induced by high doses of radiation was examined to explore the possibility of low-level radiation-induced adaptive response. The results showed that low-level radiation in the dose range of 25-200 mGy induced significant increases in apoptosis in both spermatogonia and spermatocytes, with the maximal effect at 75 mGy. The increased apoptosis is most likely associated with Trp53 protein expression. Furthermore, 75 mGy low-level radiation given pre-irradiation led to an adaptive response of seminiferous germ cells to subsequent high-level radiation-induced apoptosis. These results suggest that low-level radiation induces increased apoptosis in male germ cells but also induces a significant adaptive response that decreases cell death after a subsequent high-dose irradiation.     

Chronic low-dose exposure in the Techa River Cohort: risk of mortality from circulatory diseases

The aim of the present study was to analyze the mortality from circulatory diseases for about 30,000 members of the Techa River cohort over the period 1950–2003, and to investigate how these rates depend on radiation doses. This population received both external and internal exposures from ⁹⁰Sr, ⁸⁹Sr, ¹³⁷Cs, and other uranium fission products as a result of waterborne releases from the Mayak nuclear facility in the Southern Urals region of the Russian Federation. The analysis included individualized estimates of the total (external plus internal) absorbed dose in muscle calculated based on the Techa River Dosimetry System 2009. The cohort-average dose to muscle tissue was 35 mGy, and the maximum dose was 510 mGy. Between 1950 and 2003, 7,595 deaths from circulatory diseases were registered among cohort members with 901,563 person years at risk. Mortality rates in the cohort were analyzed using a simple parametric excess relative risk (ERR) model. For all circulatory diseases, the estimated excess relative risk per 100 mGy with a 15-year lag period was 3.6 % with a 95 % confidence interval of 0.2–7.5 %, and for ischemic heart disease it was 5.6 % with a 95 % confidence interval of 0.1–11.9 %. A linear ERR model provided the best fit. Analyses with a lag period shorter than 15 years from the beginning of exposure did not reveal any significant risk of mortality from either all circulatory diseases or ischemic heart disease. There was no evidence of an increased mortality risk from cerebrovascular disease (p > 0.5). These results should be regarded as preliminary, since they will be updated after adjustment for smoking and alcohol consumption.     

Preliminary FISH-based assessment of external dose for residents exposed on the Techa River

This paper presents the results of a feasibility cytogenetic study using the fluorescence in situ hybridization (FISH) translocation assay for residents of villages located on the Techa River (Southern Urals, Russia) contaminated with liquid radioactive wastes from the Mayak plutonium facility in 1949-1956. The study was conducted with two groups of donors that differed in their main pathways of exposure. The first group comprised 18 residents of the middle Techa region who were exposed predominantly from ingestion of radionuclides (mostly (89,90)Sr) via the river water and local foodstuffs. The second group included 20 residents of Metlino, the closest village to the site of releases, who were exposed to external γ radiation from the contaminated river bank and exposed internally from dietary intake of radionuclides. A significant linear dependence between the radiation-induced translocation frequency and individual red bone marrow dose from incorporated (89,90)Sr, calculated with the Techa River Dosimetry System (TRDS), was found in the first group of donors. This allowed us to take the contribution of (89,90)Sr to the total radiation-induced translocation frequency into account for the second group of donors and to analyze translocations resulting from external γ-ray exposure. Individual doses from external exposure derived from the corrected translocation frequency for the second group of donors (Metlino residents), using a linear dose-response coefficient of 0.015 translocation/cell/Gy recommended by Edwards et al. in 2005, were shown to vary up to 2.1 Gy, with an average value of 0.48 Gy, which was in agreement with TRDS-based external dose estimates for Metlino residents.     

Fetal dose assessment for the offspring of the Techa Riverside residents

Massive releases of fission products from the plutonium facility Mayak (Southern Urals, Russia) resulted in the contamination of the Techa river and its floodlands (1949–1956). The results of long-term studies of exposure populations have been used for different purposes of retrospective dosimetry. The riverside residents were exposed via various pathways and their progeny were exposed in utero both to external radiation and to internal radiation from radionuclides ingested by the mothers prior to conception and during pregnancy. Fetal doses due to ⁹⁰Sr from the maternal skeleton were estimated and compared with doses from other pathways. Individual red bone marrow (RBM) doses to the late fetuses were calculated on the basis of ⁹⁰Sr contents measured in the maternal skeleton and the ⁹⁰Sr transfer coefficients (TC) to the fetal skeleton were determined on the basis of the Techa river data. Two values of TC were assumed depending on the mothers’ maturation status in the period of maximum releases: TC=0.2 for group 1 (adulthood of mothers in 1950) and TC=0.02 for group 2 (mothers not yet in menarche age in 1950). Fetal doses in both groups that resulted from the different TC values varied by a factor of about 5–8. Furthermore, the fetal RBM doses due to ⁹⁰Sr from the maternal skeleton were found to depend on the distances from the site of release and the time after major ⁹⁰Sr intake. The average fetal RBM doses in the population of the upper, middle and lower Techa riverside regions were close to the ratio 3:2:1 and 20 years after the onset of contamination, the fetal doses have decreased by a factor of about 3–5. The distance from the site of release determined the relative contribution of different pathways to the fetal dose. For the settlements that are located closest to the site of release, the external exposure was of major concern up to the date of evacuation. For the non-evacuated settlements, the contribution of internal doses was higher and after 1956, external exposure is assumed to be negligible. From 1956 on, ⁹⁰Sr that has been transferred from the maternal skeleton was practically the single source of in utero exposure. Received: 8 December 2000 / Accepted: 1 July 2001     

Low-dose/dose-rate γ radiation depresses neural differentiation and alters protein expression profiles in neuroblastoma SH-SY5Y cells and C17.2 neural stem cells

The effects of low doses of ionizing radiation on cellular development in the nervous system are presently unclear. The focus of the present study was to examine low-dose γ-radiation-induced effects on the differentiation of neuronal cells and on the development of neural stem cells to glial cells. Human neuroblastoma SH-SY5Y cells were exposed to (137)Cs γ rays at different stages of retinoic acid-induced neuronal differentiation, and neurite formation was determined 6 days after exposure. When SH-SY5Y cells were exposed to low-dose-rate γ rays at the onset of differentiation, the number of neurites formed per cell was significantly less after exposure to either 10, 30 or 100 mGy compared to control cells. Exposure to 10 and 30 mGy attenuated differentiation of immature C17.2 mouse-derived neural stem cells to glial cells, as verified by the diminished expression of glial fibrillary acidic protein. Proteomic analysis of the neuroblastoma cells by 2D-PAGE after 30 mGy irradiation showed that proteins involved in neuronal development were downregulated. Proteins involved in cell cycle and proliferation were altered in both cell lines after exposure to 30 mGy; however, the rate of cell proliferation was not affected in the low-dose range. The radiation-induced attenuation of differentiation and the persistent changes in protein expression is indicative of an epigenetic rather than a cytotoxic mechanism.