Radiation sensitivity of human and murine peripheral blood lymphocytes,stem and progenitor cells

Immunodeficiency is a severe side effect of radiation therapy, notably at high radiation doses. It may also impact healthy individuals exposed to environmental ionizing radiation. Although it is believed to result from cytotoxicity of bone marrow cells and of immunocompetent cells in the peripheral blood, the response of distinct bone marrow and blood cell subpopulations following exposure to ionizing radiation is not yet fully explored. In this review, we aim to compile the knowledge on radiation sensitivity of immunocompetent cells and to summarize data from bone marrow and peripheral blood cells derived from mouse and human origin. In addition, we address the radiation response of blood stem and progenitor cells. The data indicate that stem cells, T helper cells, cytotoxic T cells, monocytes, neutrophils and, at a high degree, B cells display a radiation sensitive phenotype while regulatory T cells, macrophages, dendritic cells and natural killer cells appear to be more radioresistant. No conclusive data are available for basophil and eosinophil granulocytes. Erythrocytes and thrombocytes, but not their precursors, seem to be highly radioresistant. Overall, the data indicate considerable differences in radiosensitivity of bone marrow and blood normal and malignant cell populations, which are discussed in the light of differential radiation responses resulting in hematotoxicity and related clinical implications.     

A novel fast kilovoltage switching dual-energy CT with deep learning: Accuracy of CT number on virtual monochromatic imaging and iodine quantification

PurposeA novel fast kilovoltage switching dual-energy CT with deep learning [Deep learning based-spectral CT (DL-Spectral CT)], which generates a complete sinogram for each kilovolt using deep learning views that complement the measured views at each energy, was commercialized in 2020. The purpose of this study was to evaluate the accuracy of CT numbers in virtual monochromatic images (VMIs) and iodine quantifications at various radiation doses using DL-Spectral CT.Materials and methodsTwo multi-energy phantoms (large and small) using several rods representing different materials (iodine, calcium, blood, and adipose) were scanned by DL-Spectral CT at varying radiation doses. Images were reconstructed using three reconstruction parameters (body, lung, bone). The absolute percentage errors (APEs) for CT numbers on VMIs at 50, 70, and 100 keV and iodine quantification were compared among different radiation dose protocols.ResultsThe APEs of the CT numbers on VMIs were <15% in both the large and small phantoms, except at the minimum dose in the large phantom. There were no significant differences among radiation dose protocols in computed tomography dose index volumes of 12.3 mGy or larger. The accuracy of iodine quantification provided by the body parameter was significantly better than those obtained with the lung and bone parameters. Increasing the radiation dose did not always improve the accuracy of iodine quantification, regardless of the reconstruction parameter and phantom size.ConclusionThe accuracy of iodine quantification and CT numbers on VMIs in DL-Spectral CT was not affected by the radiation dose, except for an extremely low radiation dose for body size.     

A new cortical thickness mapping method with application to an in vivo finite element model

Finite element modelling of musculoskeletal systems, with geometrical structures constructed from computed tomography (CT) scans, is a useful and powerful tool for biomechanical studies. The use of CT scans from living human subjects, however, is still limited. Accurate reconstruction of thin cortical bone structures from CT scans of living human subjects is especially problematic, due to low CT resolution that results from mandatory low radiation doses and/or involuntary movements of the subject. In this study, a new method for mapping cortical thickness is described. Using the method, cortical thickness measurements of a coxal (pelvis) bone obtained from CT scans of a cadaver were mapped to the coxal geometry as obtained through CT scans of a live human subject, resulting in accurate cortical thickness while maintaining geometric fidelity of the live subject. The mapping procedure includes shape-preserving parameterisation, mesh movement and interpolation of thickness using a search algorithm. The methodology is applicable to modelling of other bones where accurate cortical thickness is needed and for which such data exist.     

Mortality of monkeys after exposure to fission neutrons and the effect of autologous bone marrow transplantation.

In order to assess the risk of exposure to ionizing radiation in man, and to evaluate the results of therapeutic measures, the mortality of rhesus monkeys irradiated with X-rays and fission neutrons and the effect of autologous bone marrow transplantation have been investigated. The LD50/30d values for X- and neutron-irradiated monkeys amount to 525 and 260 rad respectively, resulting in an r.b.e. of approximately 2 for the occurrence of the bone marrow syndrome. Protection of the animals by autologous bone marrow transplantation was observed up to doses of 860 rad of X-rays and 440 rad of fission neutrons. After both fission-neutron irradiation and X-irradiation in the lowest range of lethal doses, the bone marrow syndrome was found to occur without the concurrent incidence of the intestinal syndrome. The studies indicate that, for humans accidentally exposed to what would otherwise be lethal doses of fast neutrons, bone marrow transplantation may be beneficial.     

An EGS4 based Monte Carlo code for the calculation of organ equivalent dose to a modified Yale voxel phantom.

Organ or tissue equivalent dose, the most important quantity in radiation protection, cannot be measured directly. Therefore it became common practice to calculate the quantity of interest with Monte Carlo methods applied to so-called human phantoms, which are virtual representations of the human body. The Monte Carlo computer code determines conversion coefficients, which are ratios between organ or tissue equivalent dose and measurable quantities. Conversion coefficients have been published by the ICRP (Report No. 74) for various types of radiation, energies and fields, which have been calculated, among others, with the mathematical phantoms ADAM and EVA. Since then progress of image processing, and of clock speed and memory capacity of computers made it possible to create so-called voxel phantoms, which are a far more realistic representation of the human body. Voxel (Volume pixel) phantoms are built from segmented CT and/or MRI images of real persons. A complete set of such images can be joined to a 3-dimensional representation of the human body, which can be linked to a Monte Carlo code allowing for particle transport calculations. A modified version of the VOX_TISS8 human voxel phantom (Yale University) has been connected to the EGS4 Monte Carlo code. The paper explains the modifications, which have been made, the method of coupling the voxel phantom with the code, and presents results as conversion coefficients between organ equivalent dose and kerma in air for external photon radiation. A comparison of the results with published data shows good agreement.     

Generating and using patient-specific whole-body models for organ dose estimates in CT with increased accuracy: Feasibility and validation

The estimation of patient dose using Monte Carlo (MC) simulations based on the available patient CT images is limited to the length of the scan. Software tools for dose estimation based on standard computational phantoms overcome this problem; however, they are limited with respect to taking individual patient anatomy into account. The purpose of this study was to generate whole-body patient models in order to take scattered radiation and over-scanning effects into account. Thorax examinations were performed on three physical anthropomorphic phantoms at tube voltages of 80 kV and 120 kV; absorbed dose was measured using thermoluminescence dosimeters (TLD). Whole-body voxel models were built as a combination of the acquired CT images appended by data taken from widely used anthropomorphic voxel phantoms. MC simulations were performed both for the CT image volumes alone and for the whole-body models. Measured and calculated dose distributions were compared for each TLD chip position; additionally, organ doses were determined.MC simulations based only on CT data underestimated dose by 8%–15% on average depending on patient size with highest underestimation values of 37% for the adult phantom at the caudal border of the image volume. The use of whole-body models substantially reduced these errors; measured and simulated results consistently agreed to better than 10%.This study demonstrates that combined whole-body models can provide three-dimensional dose distributions with improved accuracy. Using the presented concept should be of high interest for research studies which demand high accuracy, e.g. for dose optimization efforts.     

Organ doses from radiation therapy in atomic bomb survivors

Previous surveys of radiation therapy among the Life Span Study (LSS) population at the Radiation Effects Research Foundation (RERF) revealed that 1,670 (1.4%) of the LSS participants received radiation treatments before 1984. The data on therapeutic radiation doses are indispensable for studying the relationship between radiation treatments and subsequent cancer occurrences. In this study, the radiation treatments were reproduced experimentally to determine the scattered radiation doses. The experiments were conducted using a female human phantom and various radiation sources, including a medium-voltage X-ray machine and a (60)Co gamma-ray source. Doses were measured using thermoluminescence dosimetry and ionization chambers. Radiation doses were determined for the salivary glands, thyroid gland, breast, lung, stomach, colon, ovary and active bone marrow. The results have been used for documenting the organ doses received by patients in previous surveys. The contribution of therapeutic irradiation to the occurrence of chromosome aberrations was studied using data on doses to active bone marrow from both radiation treatments and atomic bomb exposures in 26 RERF Adult Health Study participants. The results suggest that radiation treatments contributed to a large part of their frequencies of stable-type chromosome aberrations. The therapeutic radiation doses determined in the present study are available for investigating the effects of therapeutic irradiation on the subsequent primary cancers among atomic bomb survivors who received radiation treatments.     

Monte Carlo evaluation of occupational exposure during uterine artery embolization

PurposeUterine fibroids affect women mainly of childbearing age, an alternative for the treatment of these fibroids is uterine artery embolization (UAE), a minimally invasive procedure which uses fluoroscopy, providing radiation doses often high, due to the fact that professionals remain in the room throughout the procedure. In this work, equivalent and effective doses were evaluated for the main physician, for the assistant and for the patient during the UAE procedure.MethodsDoses were calculated using computer simulation with the Monte Carlo Method, and virtual anthropomorphic phantoms, in a typical scenario of interventional radiology with field sizes of 20 × 20, 25 × 25 and 32 × 32 cm², tube voltages of 70, 80, 90 and 100 kV, and projections of LAO45, RAO45 and PA.ResultsThe results showed that the highest doses received by the professionals were for the LAO45 projection with 32 × 32 cm² field size and 100 kV tube voltage, which is in accordance with the existing literature. The highest equivalent doses, without the protective equipment, were in the eyes, skin, breast and stomach for the main physician, and for the assistant they were in the eyes, breast, thyroid and skin. When she used the protective equipment, the highest equivalent doses for the main physician were on the skin, brain, bone marrow and bone surface, and for the assistant they were on the skin, brain, red bone marrow and bone surface.ConclusionsEffective doses increased up to 3186% for the main physician, and 2462% for the assistant, without protective equipment, thus showing their importance.     

A voxel-based head-and-neck phantom built from tomographic colored images.

Recent progress in computer speed and medical imaging has made possible the development of a new family of anthropomorphic models, based on a volume elements (voxels) approach to phantom design. Such phantoms can represent details of the anatomical structures of the human body more realistically. Tomographic images (CT or MRI) contain the basic information for the construction of voxel-based phantoms. Use of voxel-based phantoms has its most significant application in the planning of individual patients therapy. To be implemented, results must be obtained in a reasonably short period of time. The segmentation of organs and tissues is a critical step in this process. This article presents a new approach in the construction of voxel-based phantoms that was implemented to simplify the segmentation process of organs and tissues, reducing the time used in this procedure. A voxel-based head and neck phantom, called MCvoxEL, was built using this new approach. The volumes and masses of the segmented organs and tissues were compared with data published by other investigators.     

Interplanetary crew exposure estimates for the August 1972 and October 1989 solar particle events

Using the coupled neutron-proton space radiation transport computer code (BRYNTRN), estimates of human exposure in interplanetary space, behind various thicknesses of aluminum shielding, are made for the large solar proton events of August 1972 and October 1989. A comparison of risk assessment in terms of total absorbed dose for each event is made for the skin, ocular lens, and bone marrow. Overall, the doses associated with the August 1972 event were higher than those with the October 1989 event and appear to be more limiting when compared with current guidelines for dose limits for missions in low Earth orbit and more hazardous with regard to potential acute effects on these organs. Both events could be life-threatening if adequate shielding is not provided.     

Response kinetics of radiation-induced micronucleated reticulocytes in human bone marrow culture

The frequency of micronucleated reticulocytes (MN-RETs) in the bone marrow or peripheral blood is a sensitive indicator of cytogenetic damage. While the kinetics of MN-RET induction in rodent models following irradiation has been investigated and reported, information about MN-RET induction of human bone marrow after radiation exposure is sparse. In this report, we describe a human long-term bone marrow culture (LTBMC), established in three-dimensional (3D) bioreactors, which sustains long-term erythropoiesis. Using this system, we measured the kinetics of human bone marrow red blood cell (RBC) and reticulocyte (RET) production, as well as the kinetics of human MN-RET induction following radiation exposure up to 6Gy. Human bone marrow established in the 3D bioreactor demonstrated an average percentage of RBCs among total viable cells peaking at 21% on day 21. The average percentage of RETs among total viable cells reached a maximum of 11% on day 14, and remained above 5% by day 28, suggesting that terminal erythroid differentiation was still active. Time- and dose-dependent induction of MN-RET by gamma radiation was observed in the human 3D LTBMC, with peak values occurring at approximately 3 days following 1Gy irradiation. A trend towards delayed peak to 3-5 days post-radiation was observed with radiation doses ≥2Gy. Our data reveal valuable information on the kinetics of radiation-induced MN-RET of human bone marrow cultured in the 3D bioreactor, a synthetic bioculture system, and suggest that this model may serve as a promising tool for studying MN-RET formation in human bone marrow, thereby providing opportunities to study bone marrow genotoxicity testing, mitigating agent effects, and other conditions that are not ordinarily feasible to experimental manipulation in vivo.     

Retrospective biodosimetry among United States radiologic technologists

Measurement of chromosome translocations in peripheral blood lymphocytes has been used to quantify prior exposure to ionizing radiation, including for workers exposed to low, chronic doses. We assessed translocation frequencies in a subset of U.S. radiologic technologists to substantiate ionizing radiation dose estimates developed for 110,418 technologists who worked between 1916 and 1984. From 3,441 cohort members known to have begun working before 1950, we selected a sample of 152, stratified by estimated cumulative dose, over-sampling from higher-dose categories and excluding persons with a prior cancer diagnosis, a personal or family history of chromosomal instability disorders, or a current history of smoking. Estimates of film-badge dose ranged from less than 10 cSv to more than 30 cSv. Blood samples, obtained in 2004, were analyzed by fluorescence in situ hybridization (FISH) whole chromosome painting by simultaneously labeling chromosomes 1, 2 and 4 in red and 3, 5 and 6 in green. Translocations were scored in 1800 well-spread metaphase cells and expressed per 100 cell equivalents (CE) per person. Linear Poisson regression models with allowance for overdispersion were used to assess the relationship between estimated occupational red bone marrow absorbed dose in cGy and translocation frequency, adjusted for age, gender and estimated red bone marrow absorbed dose score from personal diagnostic procedures. We observed 0.09 excess translocations per 100 CE per cGy red bone marrow dose (95% CI: -0.01, 0.2; P = 0.07), which is similar to the expected estimate based on previous cytogenetic studies (0.05 excess translocations per 100 CE per cGy). Despite uncertainty in the estimates of occupational red bone marrow absorbed doses, we found good general agreement between the doses and translocation frequencies, lending support to the credibility of the dose assessment for this large cohort of U.S. radiologic technologists.     

Relative biological effectiveness and dose rate effect of tritiated water on chromosomes in human lymphocytes and bone marrow cells

Tritriated water (HTO) is a major toxic effluent from the nuclear power industry, that is released into the environment in large quantities. The low dose radiation effect and dose rate effect of HTO on human lymphocytes and bone marrow cells have not been well studied. The present study was therefore undertaken to investigate the HTO dose-response relationship for chromosomal aberrations in human lymphocytes and bone marrow cells at low in vitro radiation doses ranging from 0.1 to 1 Gy. Lymphocytes (G₀ stage) and bone marrow cells were incubated for 10–150 min with HTO at a dose rate of 2cGy/min (555 MBq/ml). The relative biological effectiveness (RBE) of HTO was calculated with respect to ₆₀Co γ-rays for the induction of dicentric and centric ring chromosomes at low radiation doses. The RBE value for HTO β-rays relative to ⁶⁰Co γ-rays was 2.7 for lymphocytes and 3.1 for chromatid aberrations in bone marrow cells. Lymphocytes were also chronically exposed to HTO for 6.7–80 h at dose rates of 0.5 cGy/min (138.5 MBq/ml) and 0.02 cGy/min (5.6 MBq/ml). There was a 71.5% decrease in the yield of dicentrics and centric rings at the dose rate of 0.02 cGy/min, indicating a clear dose rate effect of HTO. The RBE value for HTO relative to ¹³⁷Cs γ-rays was 2.0 at a dose rate of 0.02 cGy/min, suggesting that low HTO dose rates produce no increase of the RBE values and that the values may be constant between 2 and 3 within these dose rates. These results should prove useful in assessment of the health risk for humans exposed to low levels of HTO.     

Canine models of bone marrow transplantation

Progress in experimental bone marrow transplantation in dogs has provided for the direct transfer of research data to the clinical setting and the therapeutic application of marrow grafting to a variety of human diseases. Animal models of total body irradiation, engraftment and graft-versus-host disease are still needed to solve the existing clinical problems of marrow transplantation. Therefore, work in various canine model systems continues to be of interest. Pet dogs with spontaneously occurring lymphomas are used to study the clinical parameters necessary for applying the technique of transplanting their own marrow (autologous), in conjunction with high dose radiation and/or chemotherapy, to human patients with cancer. A major consideration in the successful transplantation of donor bone marrow (allogeneic) is overcoming histocompatibility barriers to assure engraftment and the prevention of graft-versus-host disease, a major limiting aspect of clinical marrow transplantation. Chemicals, radiation, radiotherapeutic techniques, antisera and monoclonal antibodies have been and continue to be developed in laboratory bred dogs. These approaches suppress the immune system either nonspecifically by ablation of immune reactive tissue, or specifically by affecting certain types of immune reactive cells. Parameters such as clinical effectiveness (engraftment or prevention of graft-versus-host disease), immune reconstitution and undesirable side affects in long-term survivors are all used to determine whether new technology can be transferred from preclinical canine studies to human bone marrow transplantation protocols.     

Monte Carlo simulation of the dose distribution of ICRP adult reference computational phantoms for acquisitions with a 320 detector-row cone-beam CT scanner

PurposeThe purpose of this study was to develop and validate a Monte Carlo (MC) simulation tool for patient dose assessment for a 320 detector-row CT scanner, based on the recommendations of International Commission on Radiological Protection (ICRP). Additionally, the simulation was applied on four clinical acquisition protocols, with and without automatic tube current modulation (TCM).MethodsThe MC simulation was based on EGS4 code and was developed specifically for a 320 detector-row cone-beam CT scanner. The ICRP adult reference phantoms were used as patient models. Dose measurements were performed free-in-air and also in four CTDI phantoms: 150 mm and 350 mm long CT head and CT body phantoms. The MC program was validated by comparing simulations results with these actual measurements acquired under the same conditions. The measurements agreed with the simulations across all conditions within 5%. Patient dose assessment was performed for four clinical axial acquisitions using the ICRP adult reference phantoms, one of them using TCM.ResultsThe results were nearly always lower than those obtained from other dose calculator tools or published in other studies, which were obtained using mathematical phantoms in different CT systems. For the protocol with TCM organ doses were reduced by between 28 and 36%, compared to the results obtained using a fixed mA value.ConclusionsThe developed simulation program provides a useful tool for assessing doses in a 320 detector-row cone-beam CT scanner using ICRP adult reference computational phantoms and is ready to be applied to more complex protocols.     

External radiation doses from <Superscript>137</Superscript>Cs to frog phantoms in a wetland area: in situ measurements and dose model calculations

For assessment of external radiation doses to frogs in a wetland area contaminated with ¹³⁷Cs, frog phantoms were constructed from polymethyl methacrylate (PMMA). The frog phantoms contained thermoluminescence (TL) chips and were used in situ at two study sites to measure doses. To test if higher doses are received by the sensitive skin of frogs, extra-thin TL chips were applied close to the surface of the frog phantoms. In addition, the measured doses were compared with those calculated on the basis of soil sample data from the wetland multiplied with dose-conversion coefficients from the US Department of Energy’s RESRAD-BIOTA code and from the ERICA assessment tool. Measured doses were generally lower than those calculated to ellipsoids used to model frogs. Higher doses were measured at the frog phantoms’ surfaces in comparison to inner parts at one of the two sites indicating that the frogs’ thin skin could receive a higher radiation dose than expected. In the efforts to assure protection of non-human biota, in situ measurements with phantoms provide valuable dose information and input to dose models in site-specific risk assessments of areas contaminated with radionuclides.     

Osteosarcoma development following single inhalation exposure to americium-241 in beagle dogs

Young, mature Beagle dogs underwent single inhalation exposure to respirable aerosols of 241AmO2 to determine the radiation dose distribution to tissues. The dogs were serially sacrificed to assess the clearance of 241Am from the lung, the rate of translocation to internal organs, the pattern of retention in the organs, and the rates and modes of excretion. Americium dioxide was relatively soluble in the lung, leading to the translocation of significant quantities of 241Am to bone and liver, thus delivering radiation doses to these tissues nearly equal to that received by the lung. Osteoblastic osteosarcomas developed in four dogs surviving more than 1000 days after exposure. Histologically, all of the osteosarcomas were associated with areas of radiation osteodystrophy characterized by bone infarction, peritrabecular new bone formation, marrow fibrosis, and microresorptive cavities. The retention and translocation of inhaled 241Am in dogs is similar to that of man, indicating that 241Am inhaled by humans may potentially result in significant risk of bone tumor development.     

The experimental evaluation of antiradiation effectiveness of beta-estradiol on survival rates and bone marrow hemopoiesis of X-ray irradiated mice

The study was aimed at evaluating the radioprotective effectiveness of beta-estradiol following its prophylactic administration in conditions of acute irradiation. Evaluation of the radioprotective efficiency was performed by studying the 30-day survival rate, life expectancy, the structure of irradiated mice death, the bone marrow hematopoiesis using the method of exogenous colony formation. The prophylactic use of beta-estradiol at doses of 20 and 40 mg/kg 5 days before irradiation has been established to protect the exposed mice against radiation death induced by X-rays at doses LD50-90/30, thus increasing their survival rate by 17-58%, and to favor the reduced expression of post radiation disorders of bone marrow hematopoiesis.     

Comparison of specific absorbed fractions (SAF) in the Brazilian adult male and the reference man phantoms.

The mathematical phantom of the Brazilian man was developed because many anatomical differences exist between South Americans, Europeans and North Americans. The objective of this work was to compare specific absorbed fractions (SAF) obtained for a model of the Brazilian adult male with those for the reference adult calculated by Snyder et al. in 1974 and to evaluate the importance of these new values in calculating radiation doses in diagnosis and therapy. The length and mass of the total body for the Brazilian man phantom were obtained from tables provided by the Brazilian government (IBGE) in which the masses of organs were measured atautopsy. Monte Carlo methods (using the ALGAM-97 computer code) were applied to calculate SAF for internal organs and the total body. The mathematical phantom designed by Snyder et al. represents very closely Reference Man, as defined in ICRP publication 23. SAF for the whole body were not more than 15% different between the two phantoms. The differences between both models are more significant for individual organs. When the source organ is the lung and red marrow is the target, for initial photon energy of 10 keV, the results obtained indicate that marrow receives 64% more dose in Brazilian model than in the Reference Man model. Eighty tables were made for 97 distinct organs (target-source) and the comparison made between the, Brazilian man and Reference man.