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.

Uncertainty of stochastic parametric approach to bone marrow dosimetry of 89,90Sr.

The objective of this study is to evaluate the uncertainties of the dosimetric modeling of active marrow (AM) exposure from bone-seeking 89,90Sr. The stochastic parametric skeletal dosimetry (SPSD) model was specifically developed to study the long-term effects resulting from chronic 89,90Sr exposure in populations of the radioactively contaminated territories of the Southern Urals region of the Russian Federation. The method permits the evaluation of the dose factors (DF(AM ← TBV) and DF(AM ← CBV)), which convert the radionuclide activity concentration in trabecular (TBV) and cortical (CBV) bone volumes into dose rate in the AM, and their uncertainties. The sources of uncertainty can be subdivided into inherent uncertainties related to the individual variability of the simulated objects and introduced uncertainties related to model simplifications. Inherent uncertainty components are the individual variability of bone chemical composition, bone density, bone micro- and macro-architecture as well as AM distribution within the skeleton. The introduced uncertainties may result from the stylization of bone segment geometry, assumption of uniform cortical thickness, restriction of bone geometry and the selection of the applied voxel resolution. The inherent uncertainty depends on a number of factors of influence. Foremost, it is the result of variability of AM distribution within the skeleton. Another important factor is the variability of bone micro- and macro-architecture. The inherent uncertainty of skeletal-average dose factors was found to be about 40-50%. The introduced uncertainty associated with the SPSD model approach does not exceed 16% and mainly depends on the error of bone-shape stylization. The overall inherent and introduced uncertainties of DF(AM ← TBV) and DF(AM ← CBV) are below 55% and 63%, respectively. The results obtained will be incorporated into the stochastic version of the Techa River Dosimetry System (TRDS-2016MC) that provides multiple realizations of the annual doses for each cohort member to obtain both a central estimate of the individual dose and information on the dose uncertainty.

Stochastic parametric skeletal dosimetry model for humans: General approach and application to active marrow exposure from bone-seeking beta-particle emitters.

The objective of this study is to develop a skeleton model for assessing active marrow dose from bone-seeking beta-emitting radionuclides. This article explains the modeling methodology which accounts for individual variability of the macro- and microstructure of bone tissue. Bone sites with active hematopoiesis are assessed by dividing them into small segments described by simple geometric shapes. Spongiosa, which fills the segments, is modeled as an isotropic three-dimensional grid (framework) of rod-like trabeculae that "run through" the bone marrow. Randomized multiple framework deformations are simulated by changing the positions of the grid nodes and the thickness of the rods. Model grid parameters are selected in accordance with the parameters of spongiosa microstructures taken from the published papers. Stochastic modeling of radiation transport in heterogeneous media simulating the distribution of bone tissue and marrow in each of the segments is performed by Monte Carlo methods. Model output for the human femur at different ages is provided as an example. The uncertainty of dosimetric characteristics associated with individual variability of bone structure was evaluated. An advantage of this methodology for the calculation of doses absorbed in the marrow from bone-seeking radionuclides is that it does not require additional studies of autopsy material. The biokinetic model results will be used in the future to calculate individual doses to members of a cohort exposed to 89,90Sr from liquid radioactive waste discharged to the Techa River by the Mayak Production Association in 1949-1956. Further study of these unique cohorts provides an opportunity to gain more in-depth knowledge about the effects of chronic radiation on the hematopoietic system. In addition, the proposed model can be used to assess the doses to active marrow under any other scenarios of 90Sr and 89Sr intake to humans.

Individual doses for super cohort members exposed to atmospheric radioiodine from the Mayak releases with an emphasis on prenatal doses.

Time-dependent thyroid doses were reconstructed for 45,837 members of the Southern Urals Population Exposed to Radiation Cohort (SUPER-C) living in the region around the Mayak Production Association facilities in Russia from 131I released to the atmosphere from all relevant exposure pathways. The dose calculations are implemented in a Monte Carlo framework that produces best estimates and stochastic realizations of dose time-histories. The arithmetic mean thyroid dose from 131I for SUPER-C members was 195 mGy; the median was 61 mGy. Overall, 131I-thyroid doses for about 3.6% of SUPER-C members were larger than 1 Gy. For children born in 1940-1950, the dose was about 10% higher than in previous studies because doses during the prenatal period for 9,117 individuals are included in the current work. Half of the individuals born in the region in 1950-1960 who remained in the study domain through 1972 received 9.4% or more of their total dose during the prenatal period. SUPER-C members residing in areas contaminated by discharges of liquid radioactive releases into the Techa River or the Kyshtym Accident in 1957 received 80% of their thyroid dose from airborne 131I emissions.

Local bone-marrow exposure: how to interpret the data on stable chromosome aberrations in circulating lymphocytes? (some comments on the use of FISH method for dose reconstruction for Techa riverside Residents).

The method of fluorescence in situ hybridization (FISH) applied to peripheral blood T lymphocytes is used for retrospective dose estimation, and the results obtained from the analysis of stable chromosomal aberrations are usually interpreted as a dose accumulated in the red bone marrow (RBM). However, after local internal exposure of the RBM, doses derived from FISH were found to be lower than those derived from direct measurements of radionuclides accumulated in the bodies of exposed persons. These results were obtained for people residing near the Techa River contaminated by 89,90Sr (beta-emitters) in 1949-1956 (Chelyabinsk Oblast, Russia). A new analysis has been performed of the combined results of FISH studies (n = 178) undertaken during 1994-2012 for persons living on the Techa Riverside. Analysis confirms the lower slope of the translocation yield per Gy (8.0 ± 0.7 × 10-3) for Techa residents in comparison with FISH data for donors with external exposures (11.6 ± 1.6 × 10-3, Tawn et al., Radiat Res 184(3):296-303, 2015). It was suggested that some portion of T cells remained unexposed, because they represented the descendants of T cell progenitors, which had migrated to the thymus before the start of 89,90Sr intakes. To clarify this problem, the dynamics of T-cell Genera (TG), combining all descendants of specific T-cell progenitor reaching the thymus, was considered. Rates of TGs produced by RBM over different age periods of human life were estimated with the use of the mathematic model of T-cell homeostasis (Bains, Mathematical modeling of T-cell homeostasis. A thesis submitted for the degree of Doctor of Philosophy of the University College London. http://discovery.ucl.ac.uk/20159/1/20159.pdf , 2010). The rate of TG loss during the lifetime was assumed to be very small in comparison with production rate. The recirculation of mature T lymphocytes in contaminated RBM was taken into account. According to our model estimates, at the time of blood sampling, the fraction of exposed T lymphocytes (whose progenitors were irradiated) ranged from 20 to 80% depending on the donors' age at the start of exposure to 89,90Sr. Dose to T lymphocytes, estimated from FISH studies, should be about 0.6-0.9 of RBM dose for residents of the upper Techa region and about 0.4-0.8 in the middle Techa region. Our results could explain the lower value of translocation yield per Gy obtained for Techa residents. The approaches for further model improvement and validation are discussed in this paper.

Calculations of individual doses for Techa River Cohort members exposed to atmospheric radioiodine from Mayak releases.

Time-dependent thyroid doses were reconstructed for over 29,000 Techa River Cohort members living near the Mayak production facilities from 131I released to the atmosphere for all relevant exposure pathways. The calculational approach uses four general steps: 1) construct estimates of releases of 131I to the air from production facilities; 2) model the transport of 131I in the air and subsequent deposition on the ground and vegetation; 3) model the accumulation of 131I in environmental media; and 4) calculate individualized doses. The dose calculations are implemented in a Monte Carlo framework that produces best estimates and confidence intervals of dose time-histories. Other radionuclide contributors to thyroid dose were evaluated. The 131I contribution was 75-99% of the thyroid dose. The mean total thyroid dose for cohort members was 193 mGy and the median was 53 mGy. Thyroid doses for about 3% of cohort members were larger than 1 Gy. About 7% of children born in 1940-1950 had doses larger than 1 Gy. The uncertainty in the 131I dose estimates is low enough for this approach to be used in regional epidemiological studies.

Reconstruction of radionuclide intakes for the residents of East Urals Radioactive Trace (1957-2011).

The East Urals Radioactive Trace (EURT) was formed after a chemical explosion in the radioactive waste-storage facility of the Mayak Production Association in 1957 (Southern Urals, Russia) and resulted in an activity dispersion of 7.4 × 1016 Bq into the atmosphere. Internal exposure due to ingestion of radionuclides with local foodstuffs was the main factor of public exposure at the EURT. The EURT cohort, combining residents of most contaminated settlements, was formed for epidemiological study at the Urals Research Center for Radiation Medicine, Russia (URCRM). For the purpose of improvement of radionuclide intake estimates for cohort members, the following data sets collected in URCRM were used: (1) Total ß-activity and radiochemical measurements of 90Sr in local foodstuffs over all of the period of interest (1958-2011; n = 2200), which were used for relative 90Sr intake estimations. (2) 90Sr measurements in human bones and whole body (n = 338); these data were used for average 90Sr intake derivations using an age- and gender-dependent Sr-biokinetic model. Non-strontium radionuclide intakes were evaluated on the basis of 90Sr intake data and the radionuclide composition of contaminated foodstuffs. Validation of radionuclide intakes during the first years after the accident was first carried out using measurements of the feces ß-activity of EURT residents (n = 148). The comparison of experimental and reconstructed values of feces ß-activity shows good agreement. 90Sr intakes for residents of settlements evacuated 7-14 days after the accident were also obtained from 90Sr measurements in human bone and whole body. The results of radionuclide intake reconstruction will be used to estimate the internal doses for the members of the EURT cohort.

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.

Body Potassium Content and Radiation Dose from 40K for the Urals Population (Russia).

Long-term whole-body monitoring of radionuclides in residents of the Urals Region has been performed at the Urals Research Center for Radiation Medicine (URCRM, Chelyabinsk). Quantification of 40K was achieved by measuring the 40K photopeak with four phoswich detectors in whole body counter SICH-9.1M. The current study presents the results of 40K measurements in 3,651 women and 1,961 t-test; U-test men aged 11-90; measurements were performed in 2006-2014. The residents belonged to two ethnic groups, Turkic (Tatar, Bashkir) and Slavs (mainly Russian). The levels of 40K-body contents depend upon gender, age, and body mass. Significant ethnic-differences were not found in 40K-body contents and 40K concentrations in terms of Bq per kg of body weight (in groups homogenous by age and gender). Both 40K-body contents and concentrations were significantly higher in men than in women in all age-groups; the difference was about 25%. The measured 40K-body content in men of 20-50 years was about 4200 Bq (134 g of K) and about 3000 Bq (95 g of K) in women. By the age of 80 these values decreased to 3200 Bq (102 g of K) in men and 2500 Bq (80 g of K) in women. Annual dose rates were maximal in the age group of 20-30 years- 0.16 mGy/y for men and 0.13 mGy/y for women. Further, the dose-rates decreased with age and in the groups of 60-80 years were 0.13 mGy/y for men and 0.10 mGy/y for women. Within groups homogeneous by age and gender, individual dose rates are described by a normal statistical distribution. The coefficient of variation ranges from 9 to 14%, and on the average is 12.5%. Doses from naturally occurring 40K accumulated over 70 years were found to be 9.9 mGy for men and 8.3 mGy for women; over 90 years - 12.5 and 10.4 mGy.

Fetal organ dosimetry for the Techa River and Ozyorsk Offspring Cohorts, part 2: radionuclide S values for fetal self-dose and maternal cross-dose.

One of the many objectives of the European Union's SOLO (Epidemiological Studies of Exposed Southern Urals Populations) project is to quantify the radiation dose-response following chronic in utero exposures to ionizing radiation. The project is presently conducting a pooled analysis of two cohorts of individuals born to exposed mothers-the Techa River Offspring Cohort (TROC) and the Ozyorsk Offspring Cohort (OOC). The TROC includes the offspring of mothers with external exposures to contaminated riverbanks and internal ingestions of (89)Sr, (90)Sr/(90)Y, and (137)Cs/(137m)Ba, while the OOC includes the offspring of mothers with external exposures seen within the Mayak plutonium production facilities and internal inhalation of (239)Pu and possibly (131)I. In the present study, a newly created Urals-based series of fetal and maternal models is employed to assess S values for all seven radionuclides. Among all fetal ages, S values ranged in magnitude from 10(-14) to 10(-10) Gy per Bq-s for fetal source organs and from 10(-18) to 10(-14) Gy per Bq-s from maternal source organs, depending upon particle type, particle energy, and fetal age. For a given radionuclide and fetal age, S values for fetal source organs were approximately two orders of magnitude higher than for maternal source organs. Little variation in S values was observed among fetal source organs, while variations of over 100 % with respect to the mean were observed for maternal source organs near the fetus. S value variations from maternal cross-fire were highly dependent on fetal position and separation distance from the maternal source organ. These radionuclide S values have been coupled with biokinetic models for use in cohort dose assessment within the SOLO project.

Fetal organ dosimetry for the Techa River and Ozyorsk offspring cohorts, part 1: a Urals-based series of fetal computational phantoms.

The European Union's SOLO (Epidemiological Studies of Exposed Southern Urals Populations) project aims to improve understanding of cancer risks associated with chronic in utero radiation exposure. A comprehensive series of hybrid computational fetal phantoms was previously developed at the University of Florida in order to provide the SOLO project with the capability of computationally simulating and quantifying radiation exposures to individual fetal bones and soft tissue organs. To improve harmonization between the SOLO fetal biokinetic models and the computational phantoms, a subset of those phantoms was systematically modified to create a novel series of phantoms matching anatomical data representing Russian fetal biometry in the Southern Urals. Using previously established modeling techniques, eight computational Urals-based phantoms aged 8, 12, 18, 22, 26, 30, 34, and 38 weeks post-conception were constructed to match appropriate age-dependent femur lengths, biparietal diameters, individual bone masses and whole-body masses. Bone and soft tissue organ mass differences between the common ages of the subset of UF phantom series and the Urals-based phantom series illustrated the need for improved understanding of fetal bone densities as a critical parameter of computational phantom development. In anticipation for SOLO radiation dosimetry studies involving the developing fetus and pregnant female, the completed phantom series was successfully converted to a cuboidal voxel format easily interpreted by radiation transport software.

Increase in accumulation of strontium-90 in the maternal skeleton during pregnancy and lactation: analysis of the Techa River data.

The unique contamination of the Techa River (Southern Urals, Russia) in the 1950s by long-lived (90)Sr allows investigation of the accumulation of bone-seeking elements in humans. This study is based on information compiled at the Urals Research Center for Radiation Medicine (Chelyabinsk, Russia) over a long period of time. It includes the results of in vivo measurements of (90)Sr-body burden with a whole body counter (WBC), data on personal medical examinations and residence and family histories. Data on 185 women from two Techa riverside villages Muslyumovo and Brodokalmak were selected. The settlements differ in terms of (90)Sr diet intake (higher in Muslyumovo than in Brodokalmak) and ethnicity (residents were mainly Slavs in Brodokalmak and Turkic in Muslyumovo). Results of a total of 555 WBC measurements performed in 1974-1997 were available for the women studied; maximum measured values reached 40 kBq/body. The women from each settlement were subdivided into three groups according to their childbearing history: pregnancy and lactation occurred (1) during the period of maximal (90)Sr intake (1950-1951); (2) after the period of maximal intake and (3) before this period or women who were childless. An increase was found in accumulation of (90)Sr in maternal skeleton during pregnancy and lactation (group 1) by a factor of 1.5-2 in comparison with non-pregnant, non-lactating women. This result was found in both Muslyumovo and Brodokalmak samples. An increase in accumulation of toxic elements in pregnant/lactating women is associated with increased radiation/toxic doses and risk for the women's health.

Does the cortical bone resorption rate change due to 90Sr-radiation exposure? Analysis of data from Techa Riverside residents.

The Mayak Production Association released large amounts of (90)Sr into the Techa River (Southern Urals, Russia) with peak amounts in 1950-1951. Techa Riverside residents ingested an average of about 3,000 kBq of (90)Sr. The (90)Sr-body burden of approximately 15,000 individuals has been measured in the Urals Research Center for Radiation Medicine in 1974-1997 with use of a special whole-body counter (WBC). Strontium-90 had mainly deposited in the cortical part of the skeleton by 25 years following intake, and (90)Sr elimination occurs as a result of cortical bone resorption. The effect of (90)Sr-radiation exposure on the rate of cortical bone resorption was studied. Data on 2,022 WBC measurements were selected for 207 adult persons, who were measured three or more times before they were 50-55 years old. The individual-resorption rates were calculated with the rate of strontium recirculation evaluated as 0.0018 year(-1). Individual absorbed doses in red bone marrow (RBM) and bone surface (BS) were also calculated. Statistically significant negative relationships of cortical bone resorption rate were discovered related to (90)Sr-body burden and dose absorbed in the RBM or the BS. The response appears to have a threshold of about 1.5-Gy RBM dose. The radiation-induced decrease in bone resorption rate may not be significant in terms of health. However, a decrease in bone remodeling rate can be among several causes of an increased level of degenerative dystrophic bone pathology in exposed persons.

Reconstruction of (90)Sr intake for breast-fed infants in the Techa riverside settlements.

The Techa River (Southern Urals, Russia) was contaminated as a result of radioactive releases by the Mayak plutonium production facility during 1949-1956. The persons born after the onset of the contamination have been identified as the "Techa River Offspring Cohort" (TROC). The TROC has the potential to provide direct data on health effects in progeny that resulted from exposure of a general parent population to chronic radiation. The purpose of the present investigation is the estimation of (90)Sr intake from breast milk and river water in the period from birth to 6 months of life, necessary for an infant dose calculation. The investigation is based on all available data concerning radioactive contamination due to global fallouts and Mayak releases in the Southern Urals where extensive radiometric and radiochemical investigations of human tissues and environmental samples were conducted during the second half of the twentieth century. The strontium transfer factor from mother's daily diet to breast milk was estimated as 0.05 (0.01-0.13) d L(-1). Based on this transfer factor and data on (90)Sr water contamination, the average total (90)Sr intake for an infant born in the middle Techa River region was found to be equal to 60-80 kBq in 1950-1951. For the same period, calculations of (90)Sr intake using ICRP models gave values of 70-100 kBq. From 1952 onwards, the differences in intakes calculated using the two approaches increased, reaching a factor of 2-3 in 1953. The Techa River data provide the basis for improving and adapting the ICRP models for application to Techa River-specific population.

Age dependencies of 90Sr incorporation in dental tissues: comparative analysis and interpretation of different kinds of measurements obtained for residents on the Techa River.

Human teeth have been considered as dosimeters for decades. Methods include the in vivo measurement of 90Sr/90Y in teeth with a tooth-beta counter, the radiochemical determination of 90Sr in whole teeth, and the measurement of dose in teeth by use of electron paramagnetic resonance. Presented in this paper are results of 2,514 tooth-beta counter measurements, 334 radiochemical measurements, and 218 electron paramagnetic resonance measurements for residents living in settlements along the Techa River. All three kinds of measurements indicate a sharp peak that corresponds to the uptake of 90Sr by tooth tissue. The results can be interpreted in terms of an intake function for 90Sr only if the period of calcification of each individual tooth is considered--such detail on a tooth-by-tooth basis is presented in this paper. The conclusion is reached that the tooth-beta counter data are the most reliable in terms of reconstruction of 90Sr intake; this is due in part to the fact that the tooth-beta counter measures four teeth (all at position 1) with essentially the same time periods of mineralization and because there are a large number of tooth-beta counter measurements. The main utility of electron paramagnetic resonance measurements is considered to be the validation of estimates of external dose; but for this purpose teeth with 90Sr taken up into enamel must be avoided.