Model of age-dependent dynamics and biokinetics of T-cells as natural biodosimeters.

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 90Sr, 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, 144Ce), 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.

In utero exposure to radiation and haematological malignancies: pooled analysis of Southern Urals cohorts.

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.

Incidence and Mortality of Solid Cancers in People Exposed In Utero to Ionizing Radiation: Pooled Analyses of Two Cohorts from the Southern Urals, Russia.

BACKGROUND: Previous studies have shown that acute external in utero exposure to ionizing radiation can increase cancer risk. It is not known whether chronic exposure at low dose rates, including due to radionuclide intake, influences the lifetime risk of solid cancers in the offspring. The objective of this study was to investigate solid cancer risk after in utero irradiation. METHODS: Cancer incidence and mortality over a 60-year period (from January 1950 to December 2009) were analyzed in the Urals Prenatally Exposed Cohort (UPEC). The cohort comprised in utero exposed offspring of Mayak Production Association female workers and of female residents of Techa River villages. Some of the offspring also received postnatal exposure, either due to becoming radiation workers themselves or due to continuing to live in the contaminated areas of the Techa River. The mortality analyses comprised 16,821 subjects (601,372 person-years), and the incidence analyses comprised 15,813 subjects (554,411 person-years). Poisson regression was used to quantify the relative risk as a function of the in utero soft tissue dose (with cumulative doses up to 944.9 mGy, mean dose of 14.1 mGy in the pooled cohort) and the postnatal stomach dose for solid cancer incidence and mortality. RESULTS: When a log-linear model was used, relative risk of cancer per 10 mGy of in utero dose was 0.99 (95% confidence interval (CI) = 0.96 to 1.01) based on incidence data and 0.98 (CI = 0.94 to 1.01) based on mortality data. Postnatal exposure to ionizing radiation was positively associated with the solid cancer risk in members of the UPEC, with a relative risk of 1.02 per 10mGy CI = 1.00 to 1.04). CONCLUSIONS: No strong evidence was found that chronic low-dose-rate exposure of the embryo and fetus increased the risk of solid cancers in childhood or in adulthood. For both incidence and mortality, a tendency towards a decreased relative risk was noted with increasing doses to soft tissues of the fetus. Further follow-up will provide more precise radiation risk estimates of solid cancer as cohort members are approaching their 60s and cancer becomes more common.

Modeling analysis of the lymphocytopoiesis dynamics in chronically irradiated residents of Techa riverside villages.

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.

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 (90)Sr, (89)Sr, (137)Cs, 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.

Adaptive response of blood lymphocytes as a marker of hemopoiesis status in exposed persons.

After the onset of a long-term low dose rate radiation exposure (55-60 y later) of the Techa riverside residents within a range of individual red bone marrow (RBM) doses from 0.01 to 1.79 Gy, it was established that there was an obvious association between the type of reaction manifested by peripheral blood lymphocytes to small dose irradiation in vitro (adaptive potential) and the RBM cell composition (during the period of the major exposure), as well as the peripheral blood cell composition (at a late time period coincident with the studies of induced radioresistance). The nature of these dependencies observed in chronically exposed individuals differs from that revealed in the controls. Based on the results of the study, it can be suggested that the capacity for adaptive response shown by peripheral blood lymphocytes donated by exposed persons at late time after exposure can be regarded as a biological marker of the functional state of the hemopoietic stem cell pool.

Apoptosis of peripheral blood lymphocytes and mutations in the gene of the T-cell receptor in survivors of chronic radiation exposure.

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.

Status of ecosystems in radioactive waste reservoirs of the Mayak Production Association in 2009.

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.

New stochastic carcinogenesis model with covariates: an approach involving intracellular barrier mechanisms.

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.

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).

Modeling deterministic effects in hematopoietic system caused by chronic exposure to ionizing radiation in large human cohorts.

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.

Early hematopoietic effects of chronic radiation exposure in humans.

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.

Long-term cellular effects in humans chronically exposed to ionizing radiation.

The aim of the study was to investigate hematopoietic injury and recovery in residents of the Techa riverside villages who had been chronically exposed to radiation as a result of the activities of the Mayak Nuclear Facility, and evaluate late effects from chronic, low-dose radiation exposures. Whole blood samples were drawn from 338 unexposed individuals resident in noncontaminated villages, and 692 individuals chronically exposed externally (to primarily gamma radiation) and internally from Sr since 1949 at decreasing dose-rates which have currently reached the background levels. The mean cumulative dose in the exposed cohort was 0.62 Gy over the years 1949 to 2008 using the Techa River Dosimetry System (TRDS) 2000. The frequency of chromosome aberrations and mutations in peripheral lymphocytes, and other aspects indicative of cellular and molecular repair of radiation damage, were measured. The subjects were divided into two study groups: (a) 171 individuals who during the early exposure period (where the highest dose-rates were prevalent) were noted to manifest leucopenia and/or were diagnosed with chronic radiation syndrome (CRS), and (b) 521 exposed individuals without cytopenia and CRS. The first group demonstrated an increased frequency of micronuclei, dicentric chromosomes, somatic mutations (CD3-CD4+cells) in lymphocytes, and mutations in the TP53 gene. In addition, they demonstrated a lower Cu/Zn-SOD concentration, a significantly increased concentration of nitric oxide, and a greater apoptotic frequency in peripheral blood lymphocytes compared to exposed individuals without leucopenia. Similar to the unexposed individuals, the second group demonstrated "background levels" of mutational frequencies several years after their exposures, but they did show an increased number of cells with delayed cell cycles based on Chk-2 concentrations compared to the unexposed population. The data are consistent with the idea that a chronic radiation exposure within a dose range from 0.01 Gy to 1.96 Gy results in more severe late hematopoietic effects in a select cohort of highly radiosensitive individuals, rather than an overall increase in late effects in cells of each exposed individual. The authors state that radiation-exposed subjects demonstrating CRS showed an activation of barrier anti-oxidative stress mechanisms at late periods after radiation exposure, apparently in response to a more severe radiation damage than subjects exposed to similar radiation doses but not demonstrating CRS. Finally, the persistence of chromosome aberrations and somatic mutations in the CRS cohort is indicative of an exhaustion of the anti-oxidative stress mechanisms responding for so many years after the exposure, leading to genomic instability.

Late effects in hemopoiesis and bone tissue among people with incorporated osteotropic isotope 90Sr.

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.

Early hematopoiesis inhibition under chronic radiation exposure in humans.

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.

Leukemia incidence among people exposed to chronic radiation from the contaminated Techa River, 1953-2005.

Beginning in 1950, people living on the banks of the Techa River received chronic low-dose-rate internal and external radiation exposures as a result of releases from the Mayak nuclear weapons plutonium production facility in the Southern Urals region of the Russian Federation. The Techa River cohort includes about 30,000 people who resided in riverside villages sometime between 1950 and 1960. Cumulative red bone marrow doses range up to 2 Gy with a mean of 0.3 Gy and a median of 0.2 Gy. Between 1953 and 2005, 93 first primary cases of leukemia, including 23 cases of chronic lymphatic leukemia (CLL), were ascertained among the cohort members. A significant linear dose-response relationship was seen for leukemias other than CLL (P < 0.001), but not for CLL. The estimated excess relative risk per Gy is 4.9 (95% confidence interval (CI): 1.6; 14.3) for leukemias other than CLL and less than 0 (95% upper bound 1.4) for CLL.

Minisatellite germline mutation rate in the Techa River population.

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.

Electron paramagnetic resonance and fluorescence in situ hybridization-based investigations of individual doses for persons living at Metlino in the upper reaches of the Techa River.

Waterborne releases to the Techa River from the Mayak Production Association in Russia during 1949-1956 resulted in significant doses to persons living downstream; the most contaminated village was Metlino, about 7 km from the site of release. Internal and external doses have been estimated for these residents using the Techa River Dosimetry System-2000 (TRDS-2000); the primary purpose is to support epidemiological studies of the members of the Extended Techa River Cohort. Efforts to validate the calculations of external and internal dose are considered essential. One validation study of the TRDS-2000 system has been performed by the comparison of calculated doses to quartz from bricks in old buildings at Metlino with those measured by luminescence dosimetry. Two additional methods of validation considered here are electron paramagnetic resonance (EPR) measurements of teeth and fluorescence in situ hybridization (FISH) measurements of chromosome translocations in circulating lymphocytes. For electron paramagnetic resonance, 36 measurements on 26 teeth from 16 donors from Metlino were made at the GSF-National Research Center for Environment and Health (16 measurements) and the Institute of Metal Physics (20 measurements); the correlation among measurements made at the two laboratories has been found to be 0.99. Background measurements were also made on 218 teeth (63 molars, 128 premolars, and 27 incisors). Fluorescence in situ hybridization measurements were made for 31 residents of Metlino. These measurements were handicapped by the analysis of a limited number of cells; for several individuals no stable translocations were observed. Fluorescence in situ hybridization measurements were also made for 39 individuals believed to be unexposed. The EPR- and FISH-based estimates agreed well for permanent residents of Metlino: 0.67 +/- 0.21 Gy and 0.48 +/- 0.18 Gy (mean +/- standard error of the mean), respectively. Results of the two experimental methods also agreed well with the estimates derived from the use of the TRDS-2000. For all persons investigated according to each technique, the EPR-measured dose to enamel was 0.55 +/- 0.17 Gy, and the TRDS-2000 prediction for the dose to enamel for these individuals is 0.55 +/- 0.07 Gy. The fluorescence in situ hybridization-based dose, 0.38 +/- 0.10 Gy, compared well to the TRDS-2000 prediction of external dose, 0.31 +/- 0.03 Gy, to red bone marrow for these persons. Validation of external doses at the remaining villages is an active area of investigation.