RESUMEN
This study aimed to identify immunological biomarkers for prolonged occupational radiation exposure and thus studied a random sample of the Mayak Production Association worker cohort (91 individuals). The control group included 43 local individuals never employed at the Mayak Production Association. To identify biomarkers, two groups of workers were formed: the first one included workers chronically exposed to external gamma rays at cumulative doses of 0.5-3.0 Gy (14 individuals); the second one included workers exposed to combined radiation-external gamma rays at doses ranging from 0.7 to 5.1 Gy and internal alpha radiation from incorporated plutonium with 0.3-16.4 kBq body burden (77 individuals). The age range of the study individuals was 66-91 y. Peripheral blood serum protein concentrations of cytokines, immunoglobulins, and matrix metalloproteinase-9 were analyzed using enzyme-linked immunoassay following the manufacturer's protocol. Flow cytometry was used to analyze levels of various lymphocyte subpopulations. The findings of the current study demonstrate that some immunological characteristics may be considered as biomarkers of prolonged chronic radiation exposure for any radiation type (in the delayed period after the exposure) based on fold differences from controls: M immunoglobulin fold differences were 1.75 ± 0.27 (p = 0.0001) for external gamma-ray exposure and 1.50 ± 0.27 (p = 0.0003) for combined radiation exposure; matrix metalloproteinase-9 fold differences were 1.5 ± 0.22 (p = 0.008) for external gamma-ray exposure and 1.69 ± 0.24 (p = 0.00007) for combined radiation exposure; A immunoglobulin fold differences were 1.61 ± 0.27 (p = 0.002) for external gamma-ray exposure and 1.56 ± 0.27 (p = 0.00002) for combined radiation exposure; relative concentration of natural killer cell fold differences were 1.53 ± 0.23 (p = 0.01) for external gamma-ray exposure and 1.35 ± 0.22 (p = 0.001) for combined radiation exposure; and relative concentration of T-lymphocytes fold differences were 0.89 ± 0.04 (p = 0.01) for external gamma-ray exposure and 0.95 ± 0.05 (p = 0.003) for combined radiation exposure. Based on fold differences from controls, interferon-gamma (3.50 ± 0.65, p = 0.031), transforming growth factor-beta (2.91 ± 0.389, p = 0.026), and relative blood serum levels of T-helper cells (0.90 ± 0.065, p = 0.02) may be used as immunological markers of chronic external gamma-ray exposure. Moreover, there was a significant inverse linear association of relative concentration of T-helper cells with dose from external gamma rays accumulated over an extended period.
Asunto(s)
Biomarcadores/sangre , Rayos gamma/efectos adversos , Reactores Nucleares , Exposición Profesional/análisis , Exposición a la Radiación/efectos adversos , Traumatismos por Radiación/diagnóstico , Anciano , Anciano de 80 o más Años , Carga Corporal (Radioterapia) , Estudios de Casos y Controles , Estudios de Cohortes , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Traumatismos por Radiación/sangre , Traumatismos por Radiación/etiologíaRESUMEN
Since controlled clinical studies on drug administration for the acute radiation syndrome are lacking, clinical data of human radiation accident victims as well as experimental animal models are the main sources of information. This leads to the question of how to compare and link clinical observations collected after human radiation accidents with experimental observations in non-human primate (NHP) models. Using the example of granulocyte counts in the peripheral blood following radiation exposure, approaches for adaptation between NHP and patient databases on data comparison and transformation are introduced. As a substitute for studying the effects of administration of granulocyte-colony stimulating factor (G-CSF) in human clinical trials, the method of mathematical modeling is suggested using the example of G-CSF administration to NHP after total body irradiation.
Asunto(s)
Síndrome de Radiación Aguda/tratamiento farmacológico , Síndrome de Radiación Aguda/inmunología , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Macaca mulatta , Liberación de Radiactividad Peligrosa , Síndrome de Radiación Aguda/diagnóstico , Animales , Bases de Datos Factuales , Relación Dosis-Respuesta en la Radiación , Humanos , Estudios Longitudinales , Masculino , Dosis de Radiación , Protectores contra Radiación/uso terapéutico , Especificidad de la Especie , Factores de Tiempo , Resultado del Tratamiento , Irradiación Corporal Total/efectos adversosRESUMEN
We examined the association of gene expression with noncancer chronic disease outcomes in Mayak nuclear weapons plant workers who were exposed to radiation due to their occupation. We conducted a cross-sectional study with selection based on radiation exposure status of Mayak plant workers living in Ozyorsk who were alive in 2011 and either exposed to: combined incorporated Plutonium-239 ((239)Pu) and external gamma-ray exposure (n = 82); external gamma-ray exposure alone (n = 18); or were unexposed (n = 50) of Ozyorsk residents who provided community-based professional support for plant personnel and who were alive in 2011. Peripheral blood was taken and RNA was isolated and then converted into cDNA and stored at -20°C. In a previous analysis we screened the whole genome for radiation-associated candidate genes, and validated 15 mRNAs and 15 microRNAs using qRT-PCR. In the current analysis we examined the association of these genes with 15 different chronic diseases on 92 samples (47 males, 45 females). We examined the radiation-to-gene and gene-to-disease associations in statistical models stratified by gender and separately for each disease and exposure. We modeled radiation exposure as gamma or (239)Pu on both the continuous and categorical scales. Unconditional logistic regression was used to calculate odds ratios (OR), 95% confidence intervals (CI), and the concordance for genes that were significantly associated with radiation exposure and a specific disease outcome were identified. Altogether 12 mRNAs and 9 microRNAs appeared to be significantly associated with 6 diseases, including thyroid diseases (3 genes, OR: 1.2-5.1, concordance: 71-78%), atherosclerotic diseases (4 genes, OR: 2.5-10, concordance: 70-75%), kidney diseases (6 genes, OR: 1.3-8.6, concordance: 69-85%), cholelithiasis (3 genes, OR: 0.2-0.3, concordance: 74-75%), benign tumors [1 gene (AGAP4), OR: 3.7, concordance: 81%] and chronic radiation syndrome (4 genes, OR: 2.5-4.3, concordance: 70-99%). Further associations were found for systolic blood pressure (6 genes, OR: 3.7-10.6, concordance: 81-88%) and body mass index [1 gene (miR-484), OR: 3.7, concordance: 81%]. All associations were gender and exposure dependent. These findings suggest that gene expression changes observed after occupational prolonged radiation exposures may increase the risk for certain noncancer chronic diseases.
Asunto(s)
Enfermedad Crónica/epidemiología , Regulación de la Expresión Génica/efectos de la radiación , MicroARNs/biosíntesis , Exposición Profesional , Relación Dosis-Respuesta en la Radiación , Femenino , Rayos gamma , Humanos , Masculino , Plantas de Energía Nuclear , ARN Mensajero/biosíntesis , Traumatismos por Radiación , Federación de RusiaRESUMEN
We evaluated gene expression in the peripheral blood of Mayak workers in relationship to occupational chronic exposure to identify permanent post-exposure signatures. The Mayak workers had experienced either a combined exposure to incorporated (239)Pu and external gamma rays (n = 82) or exposure to external gamma rays (n = 18). Fifty unexposed individuals served as controls. Peripheral blood was collected and then the RNA was isolated, converting it into cDNA and stored at -20°C. In a previous study at stage I, we screened the mRNA and microRNA transcriptome using 40 of the 150 samples and identified 95 mRNAs and 45 microRNAs. In stage II of this study, we now validated our 140 candidate genes using the qRT-PCR technique for the remaining 92 blood samples (18 samples were lost due to methodological reasons). We analyzed associations of normalized gene expression values in linear models separately for both exposure types (continuous and categorical scales) and adjusted for exposure age as well as stratified by gender. After further adjustment for confounders such as chronic non-cancer diseases or age at biosampling, mostly binary (on/off) dose-to-gene relationships were found for 15 mRNAs and 15 microRNAs, of which 8 mRNAs and 6 microRNAs remained significant after Bonferroni correction. Almost all of them were associated with plutonium incorporation and gender. Our study provides mRNA and microRNA gene expression changes dependent on the exposure type and gender, which occur and seem to persist after chronic radiation exposures supporting the concept of permanent post-exposure signatures.
Asunto(s)
Rayos gamma/efectos adversos , Expresión Génica/efectos de la radiación , Exposición Profesional , Plutonio/efectos adversos , Anciano , Anciano de 80 o más Años , Femenino , Genoma Humano , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , ARN Mensajero/sangre , TranscriptomaRESUMEN
The release of radioactive material due to accidents or terroristic actions can result in radioactive contamination of the environment and may lead to intake and incorporation of radionuclides with the consequence of prolonged radiation exposure. In this case, a decision about countermeasures must be carried out as soon as possible to reduce the resulting radiation dose. In order to be prepared for such a scenario, an Assessment and Documentation System has been developed to support the rapid assessment of internal exposures and to assist in decision making. Radionuclide distributions, excretion rates, and resulting exposures have been calculated on the basis of a reference scenario. The documentation of the results in the form of tables and graphs allows the easy and quick interpretation of measurements in terms of exposure and intake. The system in its present status gives information about possibilities of countermeasures; it is the intention of the next steps of development to give advice on the basis of estimated avertable doses.
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Exposición a Riesgos Ambientales/análisis , Monitoreo de Radiación/métodos , Radioisótopos/análisis , Toma de Decisiones , Especificidad de Órganos , Radioisótopos/farmacocinéticaRESUMEN
The authors evaluated gene expression in the peripheral blood in relation to occupational exposure in Mayak workers to find out about the existence of a permanent post exposure signature. Workers were exposed to combined incorporated ²³9Pu and external gamma rays (n = 82) or to external gamma rays only (n = 18), and 50 unexposed individuals served as controls. Peripheral blood was taken from workers older than 70 y. RNA was isolated, converted into cDNA, and stored at -20°C. A two-stage study design was performed focusing on examinations on the transcriptional (mRNA) and post-transcriptional level (microRNA). In the first stage, 40 samples were identified for screening purposes and selection of candidate genes. For examinations on the transcriptional level, whole genome microarrays and qRT-PCR were employed on the post-transcriptional level (667 microRNAs). Candidate genes were assessed by (1) introducing a twofold difference in gene expression over the reference group and (2) showing a significant p-value using the Kruskal-Wallis test. From 42,545 transcripts of the whole genome microarray, 376 candidate genes (80 up-regulated and 296 down-regulated relative to the reference group) were selected. Expression of almost all of these genes (70-98%) appeared significantly associated with internal ²³9Pu and to a lesser extent were associated with external gamma-ray exposure (2-30%). Associations in the same direction were found for 45 microRNAs. Although both exposures led to modulations of different gene sets in different directions, the authors could detect no differences in gene set enrichment analysis.
Asunto(s)
Plantas de Energía Nuclear , Exposición Profesional/efectos adversos , Liberación de Radiactividad Peligrosa , Transcriptoma/efectos de la radiación , Adolescente , Adulto , Estudios de Cohortes , Femenino , Genoma Humano/genética , Genoma Humano/efectos de la radiación , Genómica , Humanos , Masculino , MicroARNs/genética , Biosíntesis de Proteínas/efectos de la radiación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto JovenRESUMEN
Chromosome aberration (translocation) yield was investigated by mFISH in peripheral blood lymphocytes of Mayak Production Association (PA) workers with prolonged occupational exposure to ionizing radiation (IR). A dose threshold for cytogenetic indication of a prolonged occupational radiation exposure was estimated for Mayak PA workers using functions of dose distributions. Two limits were estimated for the indication of IR exposure to workers with a prolonged external gamma-ray exposure: These are a background translocation yield of N0 = 0.812 ± 0.149% and a dose threshold of indication D0 estimated to be approximately 1 Gy.
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Aberraciones Cromosómicas/efectos de la radiación , Hibridación Fluorescente in Situ , Plantas de Energía Nuclear , Liberación de Radiactividad Peligrosa , Valores Limites del Umbral , Anciano , Femenino , Humanos , Masculino , Probabilidad , Factores de TiempoRESUMEN
The aim of this paper is to compare and contrast the needs for biodosimetry for initial triage for military forces and civilian populations when there are radiation exposures that involve potentially a large number of persons. Several differences in the likely scenarios for exposure of military forces include a greater likelihood of having higher rates of significant exposures, inhomogeneous exposures, significant doses from neutrons, and combined injury. Measurements will be able to begin sooner than for exposures in civilian settings because medical facilities usually are an integral part of the way military forces are deployed. It also will be very feasible to have personnel that will be trained and equipped specifically for rapid deployment to assess dose. As a consequence, the most appropriate biodosimetry techniques will include features that are not present or are less important for civilian settings; i.e., the need for changes that become measureable very soon after the radiation is received, the ability to complete measurements in very close proximity to the subjects (so samples do not need to be transported out and results returned), increased capability of resolving homogeneity of the exposure, ability to be carried out in an injured person, capability of determining whether neutrons have made a significant contribution to dose, and the ability to rely on more sophisticated equipment and trained personnel to carry out the measurements at the point of care.
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Personal Militar , Liberación de Radiactividad Peligrosa , Radiometría/métodos , Defensa Civil , Exposición a Riesgos Ambientales/análisis , Humanos , Recuento de Leucocitos , Incidentes con Víctimas en Masa , ProbabilidadRESUMEN
A key difficulty in developing countermeasures against radiation-induced health impairments is the clear lack of controlled clinical studies, due to the relatively low number of radiation victims worldwide. Instead, established and accepted animal models, as well as the recommendations of national and international expert panels and committees, are the main sources of information. Therefore, the development of countermeasures requires comparison of data from many sources and accumulation of information consistent with the U. S. Food and Drug Administration's "Animal Rule." A new approach is the comparative analysis of human data from the SEARCH (System for Evaluation and Archiving of Radiation Accidents based on Case Histories) database and data from nonhuman primate (NHP) animal model studies. The SEARCH database contains 824 clinical cases from 81 radiation accidents in 19 countries. This exceptional collection of clinical data from accidentally radiation-exposed persons is analyzed regarding clinical signs and symptoms of radiation-induced health impairments. To analyze the time course of radiation syndromes, clinical parameters common to the SEARCH and NHP databases have to be assigned into comparable categories of clinical severity for each species. The goal is to establish a method for comparison of human and NHP data, validate the NHP data as a surrogate for human efficacy/clinical studies, and open a way for the extraction of diagnostic and treatment methods for humans after radiation exposure according to relevant regulations.
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Primates , Traumatismos por Radiación/etiología , Traumatismos por Radiación/terapia , Liberación de Radiactividad Peligrosa , Investigación Biomédica Traslacional , Animales , Bases de Datos Factuales , Relación Dosis-Respuesta en la Radiación , Exposición a Riesgos Ambientales/efectos adversos , Humanos , Irradiación Corporal Total/efectos adversosRESUMEN
The March 2011 radiation accident in Fukushima, Japan, is a textbook example of a radiation accident of global significance. In view of the global dimensions of the accident, it is important to consider the lessons learned. In this context, emphasis must be placed on consequences for planning appropriate medical management for radiation accidents including, for example, estimates of necessary human and material resources. The specific characteristics of the radiation accident in Fukushima are thematically divided into five groups: the exceptional environmental influences on the Fukushima radiation accident, particular circumstances of the accident, differences in risk perception, changed psychosocial factors in the age of the Internet and globalization, and the ignorance of the effects of ionizing radiation both among the general public and health care professionals. Conclusions like the need for reviewing international communication, interfacing, and interface definitions will be drawn from the Fukushima radiation accident.
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Medicina de Emergencia , Plantas de Energía Nuclear , Liberación de Radiactividad Peligrosa , Animales , Actitud Frente a la Salud , Ambiente , Humanos , Japón , Médicos , Psicología , Liberación de Radiactividad Peligrosa/psicología , RiesgoRESUMEN
Radiation accidents are fortunately infrequent occurrences, but since their consequences can be very serious as in the Chernobyl and the Fukushima nuclear accidents, medical management of radiation accidents is of great importance. Besides several other tasks, medical management of radiation accidents is one of the key tasks of the Bundeswehr Institute of Radiobiology. Within a Task Force Unit for medical chemical, biological, radiological, and nuclear (CBRN) Defense, the institute provides designated personnel who will perform clinical investigations on the scene and will liaise with the institute, where different methods for biological dosimetry and dose reconstruction will be performed. The most important aspects of efficient medical management of radiation accidents are diagnosis of radiation-induced health damage, determination of the cause, dealing with contamination/incorporation, pathophysiological and therapeutic principles, preparatory planning, national and international cooperation and training. Military and non-military institutions have to work closely together when it comes to radiation accidents and since national resources are limited and could be exhausted, international networks can help to ensure medical treatment for radiation accident victims.
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Liberación de Radiactividad Peligrosa , Radiobiología , Accidente Nuclear de Fukushima , Humanos , Cooperación InternacionalRESUMEN
Fortunately radiation accidents are infrequent occurrences, but since they have the potential of large scale events like the nuclear accidents of Chernobyl and Fukushima, preparatory planning of the medical management of radiation accident victims is very important. Radiation accidents can result in different types of radiation exposure for which the diagnostic and therapeutic measures, as well as the outcomes, differ. The clinical course of acute radiation syndrome depends on the absorbed radiation dose and its distribution. Multi-organ-involvement and multi-organ-failure need be taken into account. The most vulnerable organ system to radiation exposure is the hematopoietic system. In addition to hematopoietic syndrome, radiation induced damage to the skin plays an important role in diagnostics and the treatment of radiation accident victims. The most important therapeutic principles with special reference to hematopoietic syndrome and cutaneous radiation syndrome are reviewed.
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Síndrome de Radiación Aguda/etiología , Síndrome de Radiación Aguda/terapia , Liberación de Radiactividad Peligrosa , Síndrome de Radiación Aguda/fisiopatología , Sistema Hematopoyético/efectos de la radiación , HumanosRESUMEN
Radiation exposure leads to a risk for long-term deterministic and stochastic late effects. Two individuals exposed to protracted photon radiation in the radiological accident at the Lilo Military site in Georgia in 1997 received follow-up treatment and resection of several chronic radiation ulcers in the Bundeswehr Hospital Ulm, Germany, in 2003. Multi-parameter analysis revealed that spermatogenetic arrest and serum hormone levels in both patients had recovered compared to the status in 1997. However, we observed a persistence of altered T-cell ratios, increased ICAM1 and beta1-integrin expression, and aberrant bone marrow cells and lymphocytes with significantly increased translocations 6 years after the accident. This investigation thus identified altered end points still detectable years after the accident that suggest persistent genomic damage as well as epigenetic effects in these individuals, which may be associated with an elevated risk for the development of further late effects. Our observations further suggest the development of a chronic radiation syndrome and indicate follow-up parameters in radiation victims.
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Liberación de Radiactividad Peligrosa , Moléculas de Adhesión Celular/metabolismo , Aberraciones Cromosómicas , ADN/genética , Reparación del ADN/genética , Regulación de la Expresión Génica/efectos de la radiación , Georgia (República) , Humanos , Hibridación Fluorescente in Situ , Masculino , Radiometría , Piel/metabolismo , Piel/efectos de la radiación , Factores de TiempoRESUMEN
OBJECTIVE: The objective of this review is to provide a scientific justification for using the pattern of changes of granulocytes, platelets, and lymphocytes within the first few days after an accidental whole-body exposure to ionizing radiation as a convincing indicator of the severity of its effect on the hematopoietic stem cell pool. METHOD: The availability of the SEARCH database system (System for Evaluation and Archiving of Radiation Accidents based on Case Histories) allowed us to analyze the "early" blood cell changes after accidental whole-body radiation exposure in more than 100 patients and to assign them to severity of effect code H4 and H3, described in the METREPOL approach. RESULTS: A specific pattern of blood cell changes (granulocytes, platelets, lymphocytes) within the first 5 to 8 days after exposure is compatible with the assumption of an irreversible damage of the stem cell pool distributed throughout the skeletal bone marrow designated as H4. Distinguishable from this pattern is a blood cell response pattern characterized by an "abortive recovery," which can be explained by the "injured cell hypothesis," allowing to assign these patients to a severity-of-effect-code H3, H2, or H1 compatible with the assumption of a "reversible" damage to the stem cell pool. Biomathematical models allow one to correlate the blood cell change patterns with the extent of damage to the stem cell pool. CONCLUSION: Patterns of change in peripheral blood cell counts indicate the effect of radiation on the hematopoietic stem cell pool, and have the potential to predict autochthonous regeneration.