Hemopoietic response to low dose-rates of ionizing radiation shows stem cell tolerance and adaptation.

Chronic exposure of mammals to low dose-rates of ionizing radiation affects proliferating cell systems as a function of both dose-rate and the total dose accumulated. The lower the dose-rate the higher needs to be the total dose for a deterministic effect, i.e., tissue reaction to appear. Stem cells provide for proliferating, maturing and functional cells. Stem cells usually are particularly radiosensitive and damage to them may propagate to cause failure of functional cells. The paper revisits 1) medical histories with emphasis on the hemopoietic system of the victims of ten accidental chronic radiation exposures, 2) published hematological findings of long-term chronically gamma-irradiated rodents, and 3) such findings in dogs chronically exposed in large life-span studies. The data are consistent with the hypothesis that hemopoietic stem and early progenitor cells have the capacity to tolerate and adapt to being repetitively hit by energy deposition events. The data are compatible with the "injured stem cell hypothesis", stating that radiation-injured stem cells, depending on dose-rate, may continue to deliver clones of functional cells that maintain homeostasis of hemopoiesis throughout life. Further studies perhaps on separated hemopoietic stem cells may unravel the molecular-biology mechanisms causing radiation tolerance and adaptation.

Radiation accident preparedness: a European approach to train physicians to manage mass radiation casualties.

Mass casualties after radiation exposure pose an enormous logistical challenge for national health services worldwide. Successful medical treatment of radiation victims requires that a plan for medical radiation accident management be established, that the plan be tested in regular exercises, and that it be found to be effective in the management of actual victims of a radiological incident. These activities must be provided by a critical mass of clinicians who are knowledgeable in the diagnosis and management of radiation injury. Here, we describe efforts to provide education to physicians engaged in clinical transplantation. Following intensive discussion among European experts at the International Center for Advanced Studies in Health Sciences and Services, University of Ulm, Germany, an advanced training program on "radiation syndromes" was developed for physicians with experience in the management of patients with pancytopenia and multi-organ failure occurring in a transplant setting. The first European advanced training course using this educational tool took place at Oberschleissheim, Germany, on 28-30 November 2007. Small group discussions and practical exercises were employed to teach general principles and unique features of whole body radiation exposure. Topics included the biological effects of contamination, incorporation of radionuclides, clinical consequences of exposure to radiation, and approaches to medical management. Recommendations resulting from this initial educational experience include (1) provision of funding for attending, conducting and updating the curriculum, and (2) development of an educational program that is harmonized among European and non-European experts in medical management of mass casualties from a radionuclear incident.

Computer-assisted severity of effect assessment of hematopoietic cell renewal after radiation exposure based on mathematical models.

After accidental radiation exposure, one of the most significant health impairments is the partial or complete failure of the blood forming systems. Depending on the degree of damage, a suitable therapy must be prepared in time. This requires the assessment of the degree of damage of the blood-forming system and, in particular, of the stem-cell pool. A new approach for assessing the degree of hematopoietic impairment based on dynamic reactions of blood counts immediately following radiation exposure is presented. Cell kinetic mathematical models of blood cell turnover, neural networks, and expert-assessed clinical data records of historical radiation accidents are combined to provide a method for automatic classification of patients and to assign them to clinically related categories of severity. Using this computer-assisted approach, it is possible to distinguish those patients that are likely to restore their blood-cell formation autochthonously from those that need stem-cell transplantation.

Stem cells, multiorgan failure in radiation emergency medical preparedness: a U.S./European Consultation Workshop.

The concern of the public regarding terrorist actions involving nuclear emergencies resulted in the reopening of the discussion regarding the best ways to cope with the inevitable health impairments. Medical experts from the US and from Europe considered it of importance to harmonize at an international level the diagnostic and therapeutic approaches regarding the radiation-induced health impairments. The present contribution is the result of the first U.S./European Consultation Workshop addressing approaches to radiation emergency preparedness and assistance, which was held recently at Ulm University, Ulm, Germany. Discussions dealt with the assessment of the extent of damage after total body exposure and, in particular, the quantity and quality of the damage to the hematopoietic stem cell pool. Secondly, the pathogenesis of the multiorgan failure was considered because of the organ-to-organ interactions. Thirdly, approaches were considered to harmonize the "triage-methods" used on an international level using the "Response Category" approach as developed for the European Communities. These discussions lead to the conclusion that there is a strong need for continuing education of physicians, nurses, and support personnel to address the issues posed by the management of patients suffering from radiation syndromes. Finally, the discussions expressed the need for more international cooperation in research and development of more refined methods to treat patients with any type of radiation syndromes.

Thyroid examination in highly radiation-exposed workers after the Chernobyl accident.

CONTEXT: Radioactive contamination from the Chernobyl nuclear accident that happened on the morning of 26th April 1986 had a major impact on thyroid health in the Belarus region. OBJECTIVE: Observational study of a cohort of 99 adults, most strongly exposed to ionizing radioactivity. DESIGN, SETTING AND PATIENTS: Observational study performed between 1998 and 2000. The cohort comprised 99 workers (92 male) of the Chernobyl nuclear power plant. Examination including physical examination, ultrasonography of the thyroid gland and measurement of serum free thyroxin (fT(4)), free triiodothyronine (fT(3)) and TSH. Anti-thyroperoxidase (anti-TPO), antithyroglobulin (anti-Tg) antibodies and thyroid stimulating immunoglobulin were also determined. MAIN OUTCOME MEASURES: The impact of exposure to high-dose radiation, including radioactive iodine, on the thyroid gland was examined. RESULTS: Levels of fT(4) in all probands were within the normal World Health Organization-defined range. Elevated levels of fT(3) were found in two workers (2%), high titres of anti-TPO and anti-Tg antibodies were present in four subjects (4%). Mild hypothyroidism was present in one patient. Enlargement of the thyroid gland was observed in 17 workers (17%). There was no evidence of clinically overt thyroid cancer. CONCLUSIONS: The Chernobyl accident showed surprisingly little impact on the thyroid in a cohort of workers strongly exposed to radiation. Our data suggest an age-dependent heterogeneity in response to the short-lived radioiodine isotopes and favours long-term follow-up analysis.

Hematopoietic cell renewal systems: mechanisms of coping and failing after chronic exposure to ionizing radiation.

On the occasion of the first international workshop on systems radiation biology we review the role of cell renewal systems in maintaining the integrity of the mammalian organism after irradiation. First, 11 radiation emergencies characterized by chronic or protracted exposure of the human beings to ionizing irradiation were "revisited". The data provide evidence to suggest that at a daily exposure of about 10-100 mSv, humans are capable of coping with the excess cell loss for weeks or even many months without hematopoietic organ failure. Below 10 mSv/day, the organisms show some cellular or subcellular indicators of response. At dose rates above 100 mSv/day, a progressive shortening of the life span of the irradiated organism is observed. To elucidate the mechanisms relevant to tolerance or failure, the Megakaryocyte-thrombocyte cell renewal system was investigated. A biomathematical model of this system was developed to simulate the development of thrombocyte concentration as a function of time after onset of chronic radiation exposure. The hematological data were taken from experimental chronic irradiation studies with dogs at the Argonne National Laboratory, USA. The results of thrombocyte response patterns are compatible with the notion of an "excess cell loss" (compared to the steady-state) in all proliferative cell compartments, including the stem cell pool. The "excess cell loss" is a function of the daily irradiation dose rate. Once the stem cell pool is approaching an exhaustion level, a "turbulence region" is reached. Then it takes a very little additional stress for the system to fail. We conclude that in mammalian radiation biology (including radiation medicine), it is important to understand the physiology and pathophysiology of cell renewal systems in order to allow predicting the development of radiation induced lesions.

Radiation-induced late effects in two affected individuals of the Lilo radiation accident.

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.

Pathophysiological principles underlying the blood cell concentration responses used to assess the severity of effect after accidental whole-body radiation exposure: an essential basis for an evidence-based clinical triage.

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.

Nuclear terrorism: the role of hematology in coping with its health consequences.

PURPOSE OF REVIEW: This review reports on a novel approach to use blood cell change patterns after accidental whole body radiation exposure (to be expected as a consequence of nuclear terrorism) as reliable indicators of effect and as an aid to plan therapeutic measures. RECENT FINDINGS: There is growing concern about the potential of nuclear terrorism. Several scenarios are being discussed. In all of them one finds elements that mimic the experience gained in assessing and treating humans who were exposed to ionizing radiation in radiation accidents. This experience leads to diagnostic and therapeutic measures laid down in a recently published Manual on the Acute Radiation Syndrome. The European Bone Marrow Transplantation Group (EBMT) together with the Institut de Radioprotection et de Sûreté Nucléaire (IRSN) in Paris and the University of Ulm published a consensus paper to use 'response categories' based on organ-specific gradings of severity as indicators of the severity of health impairments. SUMMARY: The implication of this review is obvious: the medical staff confronted suddenly with the challenge of clinically managing an irradiated person will find all scientifically based recommendations in order to cope with the evolving problems on a scientific-pathophysiology driven approach.

Medical management principles for radiation accidents.

The medical management of radiation accidents requires intensive planning and action. This article looks at the medical management of recent radiation accidents to derive principles for structuring and organizing the treatment of patients who may have radiation-induced health impairments. Although the radiation accidents in Tokai-mura, Japan and Lilo, Georgia were small-scale accidents, they illustrate important and characteristic symptoms and clinical developments. There are lessons to be learned and conclusions to be drawn for the military medical officers concerned with problems of medical management after radiation accidents.

Hematopoietic cell renewal as the limiting factor in low-level radiation exposure: diagnostic implications and therapeutic options.

In some radiation accidents, exposure doses are delivered over days or even months. In all cases the organ system most relevant to a patient's survival is the hematopoietic tissue. There appears to be a threshold of approximately 10 mSv per day above which hematopoietic effects become apparent and hematopoietic failure may occur. Experimental observations in dogs demonstrate that exposure to chronic gamma-irradiation may be tolerated for over a year if the daily dose does not exceed 7 mSv to 18 mSv. The pathophysiological mechanisms are being studied by hematological measures and biomathematical models. The results are in accordance with the assumption of excess cell loss and progressive diminution of the stem cell pool over time until a "turbulence region," with an increased probability of system failure, is approached. Diagnostic procedures require a thorough hematological assessment that includes the stem cell compartment. Therapeutic options include administration of hematopoietic growth factors and stem cell transplantation.