Internal contamination by radionuclides may occur through inhalation, ingestion and absorption through the skin or subcutaneous tissue. The clinical management of internalized radionuclides requires the integration of clinical signs and symptoms with dose estimates in biological tissues obtained from the face, nose, sputum, urine, faeces and/or skin. The assessment of ingested radionuclides includes bioassays of urine and faeces, and if available, whole body counting for radionuclides that emit penetrating x-rays or gamma-rays. An estimate of intake dose may be made at the time of initial patient evaluation by measuring radioactivity, converting counts/minute to depositions/minute with a specific gamma-ray constant, and comparing the amount to its annual limit on intake, clinical decision guide or derived reference level. Since nobody dies from internal contamination per se, medically unstable patients should be stabilized before addressing internal contamination. Whenever possible, internal contaminants should be physically removed as soon as possible after exposure. For inhaled internal contaminants, radionuclide-specific therapy may include the administration of an ion exchange resin (i.e. Prussian blue, PB) or chelating agent (i.e. diethylenetriamine pentaacetate, DTPA, that binds to radioactive plutonium, americium, and curium), or the physical removal of insoluble particles with a high activity radionuclide (192Ir, 90Sr, 210Po) by bronchioalveolar lavage. Decorporation with PB, DTPA and other agents is used to enhance excretion. The treatment of wounds contaminated with an actinide includes gentle irrigation, surgical excision of contaminated tissue and DTPA. The averted dose (i.e. the total effective dose averted by therapy) may be calculated for each exposure route.
Special Issue Concerning Medical Management after High-Dose Radiation Exposures
Guest Editors
Jack Valentin, Consultant, and Karolinska Institute, Stockholm, Sweden
Leif Stenke, Karolinska Institute, and Karolinska University Hospital, Stockholm, Sweden
Scope
High doses of ionising radiation (say, 0.5 Gy or more) will cause significant harm to the human body. Various kinds of medical treatment can reduce the harmful effects of a high-dose event and increase the probability of survival. While high-dose events keep recurring, cases in any given country are rare. Furthermore, most past events have caused high doses only to one or relatively few person(s) per event. The average physician has never seen, let alone treated, a victim of a high dose of radiation.
Because high-dose radiation events are rare, education and training regarding the symptoms and possible treatments tend to be at a disadvantage when universities plan their curriculum. Radiological protection experts, medical physicists, and medical staff are all insufficiently educated and trained in this area. However, not only do the rare events continue to occur, but possible malevolent events could lead to high doses to many victims ??and the possibility of exposures from a new nuclear weapon explosion (intentional or otherwise) cannot be excluded.
In order to address these problems, the Journal of Radiological Protection is organising a Special Issue intended to provide a state-of-the-art overview of the medical management of radiation injuries, covering as far as possible all relevant kinds of harm and treatment. The intention is to satisfy the needs long felt by all kinds of radiation experts for an accessible yet reliable and accurate summary of the medical effects of ionising radiation and the current methods to manage such effects.
Editorial
Papers
Medical management of acute radiation syndrome
View article, Medical management of acute radiation syndrome
PDF, Medical management of acute radiation syndrome
Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.
Open access
Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
View article, Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
PDF, Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
A major radiological or nuclear emergency may, apart from causing a substantial loss of life and physical damage, also put a substantial strain on affected societies with social, economic and political consequences. Although such emergencies are relatively uncommon, it is now being increasingly recognised that their subsequent psychosocial impact can be widespread and long lasting. Mental health effects, such as depression, anxiety and post-traumatic stress disorder, are highly represented in a population affected by a radiation disaster. In order to reach the majority of the people affected by radiation accidents, we need to be aware of how to distribute relevant and accurate information related to both short- and long-term medical effects. Effective risk communication is associated with improved compliance with any given recommendations. It is important to protect the public from physical radiation damage, but it is also essential to take into account the social and mental health effects that radiation disasters may induce. This article provides a brief review of recent reporting on the psychological consequences after a major radiation emergency.
Open access
The risk of cancer following high, and very high, doses of ionising radiation
View article, The risk of cancer following high, and very high, doses of ionising radiation
PDF, The risk of cancer following high, and very high, doses of ionising radiation
It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.
Responding to radiation accidents: what more do we need to know?
View article, Responding to radiation accidents: what more do we need to know?
PDF, Responding to radiation accidents: what more do we need to know?
A short review of the various types of radiation incidents and accidents that have occurred is used to provide a context for discussing the findings on medical management of the victims of such incidents and accidents reported in a recent Special Issue of the Journal of Radiological Protection. The review demonstrates that accidents and incidents giving rise to high radiation doses may involve over-exposure of a single individual, a few individuals, or very large numbers. In general, these exposures will be relatively short-term, ranging from a few seconds to a few days, but chronic situations resulting in high exposures can occur. Some of these exposures may be highly localised, whereas others may result in almost uniform whole-body irradiation. This diversity of situations means that it is not feasible to have a single protocol for the diagnosis and treatment of over-exposed individuals. If the over-exposures are limited to one or a few individuals, these can be addressed on a case-by-case basis. However, where large numbers have been exposed or may have been exposed, there is a need to implement a rapid and effective system of triage. Furthermore, this system is likely to have to be implemented by individuals who have little or no direct experience of radiation-induced injuries. For those individuals who may have been significantly exposed, the key consideration is not to determine the radiation dose that they have received, but to establish their present clinical status and how it is likely to develop with time. There is at most a very limited role for bone-marrow transplantation in the treatment of acute radiation syndrome, whereas there are good arguments for administering various treatments to boost bone marrow function together with other supportive interventions, e.g. in control of infections and handling both fluid loss and bleeding. However, there is concern that the focus to date has been only on the licencing of drugs related to the management of haematopoietic effects. Although a great deal is known about the diagnosis and treatment of injuries arising from high dose exposures, this knowledge is biased towards situations in which there is relatively uniform, external whole-body exposure. More attention needs to be given to assessing the implications of various inhomogeneous exposure regimes and to developing medical countermeasures optimised for addressing the complex, multi-organ effects likely to arise from such inhomogeneous exposures.
Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
View article, Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
PDF, Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
Mesenchymal stromal cells (MSCs) are a stem cell product with good safety that demonstrate significant clinical efficacy in the treatment of different pathologies, including radiation diseases (e.g. radiological burns, pelvic radiation disease). While the first results for some first human applications for the treatment of radiation disease suggest benefit, larger trials with clinically important endpoints are needed before definitive conclusions can be drawn. However, the supply and cost of MSCs remain the two main limitations for this innovative therapeutic product. Exosomes (EXOs), a stem cell product associated with MSC therapy, have shown promising efficacy and safety in humans. MSC-EXO therapeutics represent a promising next-generation approach for treating radiation diseases involving a primary (major) inflammatory component. Provided that conditions for MSC-EXO production and bio-banking are agreed in the near future, the transition to industrial production of MSC-EXOs will be possible, and this is required to initiate well-controlled clinical trials for approval by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).
Open access
The acute radiation syndrome—need for updated medical guidelines
View article, The acute radiation syndrome—need for updated medical guidelines
PDF, The acute radiation syndrome—need for updated medical guidelines
The major immediate and severe medical consequences in man following exposure to high doses of ionising radiation can be summarised within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the World Health Organization published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.
The METREPOL criteria—are they still relevant?
View article, The METREPOL criteria—are they still relevant?
PDF, The METREPOL criteria—are they still relevant?
The medical management of radiation accidents manual on the acute radiation syndrome proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.
Cutaneous and local radiation injuries
The threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionising radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome, a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation or an improvised nuclear detonation (IND), a nuclear power plant incident, or an encounter with a radioactive dispersal or exposure device. These incidents may also result in a radiation-combined injury; a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognising the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.
Open access
Early molecular markers for retrospective biodosimetry and prediction of acute health effects
View article, Early molecular markers for retrospective biodosimetry and prediction of acute health effects
PDF, Early molecular markers for retrospective biodosimetry and prediction of acute health effects
Radiation-induced biological changes occurring within hours and days after irradiation can be potentially used for either exposure reconstruction (retrospective dosimetry) or the prediction of consecutively occurring acute or chronic health effects. The advantage of molecular protein or gene expression (GE) (mRNA) marker lies in their capability for early (1–3 days after irradiation), high-throughput and point-of-care diagnosis, required for the prediction of the acute radiation syndrome (ARS) in radiological or nuclear scenarios. These molecular marker in most cases respond differently regarding exposure characteristics such as e.g. radiation quality, dose, dose rate and most importantly over time. Changes over time are in particular challenging and demand certain strategies to deal with. With this review, we provide an overview and will focus on already identified and used mRNA GE and protein markers of the peripheral blood related to the ARS. These molecules are examined in light of 'ideal' characteristics of a biomarkers (e.g. easy accessible, early response, signal persistency) and the validation degree. Finally, we present strategies on the use of these markers considering challenges as their variation over time and future developments regarding e.g. origin of samples, point of care and high-throughput diagnosis.
Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot.
41 S391)
View article, Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot. 41 S391)
PDF, Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot. 41 S391)
Prevention and management of infections after exposure to ionising radiation
View article, Prevention and management of infections after exposure to ionising radiation
PDF, Prevention and management of infections after exposure to ionising radiation
Ionising radiation impacts many organ systems, each of which comprises a level of immunity to infectious disease. Bone marrow toxicity after radiation results in a predisposition to leukopenia and subsequent susceptibility to bacterial, viral, and fungal infections. Radiation-induced damage to mucosal, integumentary, and solid organ structures disrupts additional lines of innate defense. Over the past three decades, much progress has been made in effective antimicrobial prophylaxis, resulting in decreased infectious complications and improved survival. Vaccination schedules following myeloablative radiation have become highly regimented and treatment of overt infectious complications is largely standardised. In this article, we discuss consequences, prevention, and management of infections following exposure to ionising radiation.
High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
View article, High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
PDF, High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500–800 mGy, subclinical hypothyroidism has been detected in 3%–6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.
Open access
United States medical preparedness for nuclear and radiological emergencies
View article, United States medical preparedness for nuclear and radiological emergencies
PDF, United States medical preparedness for nuclear and radiological emergencies
With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of 11 September, which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG's efforts to plan for the unthinkable have centred on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.
Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
View article, Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
PDF, Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
Cells exposed to ionizing radiation have a wide spectrum of DNA lesions that include DNA single-strand breaks, DNA double-strand breaks (DSBs), oxidative base damage and DNA-protein crosslinks. Among them, DSB is the most critical lesion, which when mis-repaired leads to unstable and stable chromosome aberrations. Currently, chromosome aberration analysis is the preferred method for biological monitoring of radiation-exposed humans. Stable chromosome aberrations, such as inversions and balanced translocations, persist in the peripheral blood lymphocytes of radiation-exposed humans for several years and, therefore, are potentially useful tools to prognosticate the health risks of radiation exposure, particularly in the hematopoietic system. In this review, we summarize the cytogenetic follow-up studies performed by REAC/TS (Radiation Emergency Assistance Center/Training site, Oak Ridge, USA) on humans exposed to internal and external radiation. In the light of our observations as well as the data existing in the literature, this review attempts to highlight the importance of follow-up studies for predicting the extent of genomic instability and its impact on delayed health risks in radiation-exposed victims.
Combined injury: irradiation with skin or bone wounds in rodent models
View article, Combined injury: irradiation with skin or bone wounds in rodent models
PDF, Combined injury: irradiation with skin or bone wounds in rodent models
A radiation combined injury is defined as an injury that occurs in the setting of irradiation, such as those expected after a nuclear accident, radiation dispersal device release (a 'dirty bomb'), or a nuclear weapon detonation. There is much research on irradiation-associated burns and their healing, but there is less known about other injuries sustained in the context of irradiation. Animal models are limited in their correlations to clinical situations but can support research on specific questions about injuries and their healing. Mouse models of irradiation with skin or bone wounds are validated as highly reproducible and quantitative. They show dose-dependent impairment of wound healing, with later recovery. Irradiation-induced delay of bone wound healing was mitigated to different extents by single doses of gramicidin S-nitroxide JP4-039, a plasmid expressing manganese superoxide dismutase, amifostine/WR2721, or the bifunctional sulfoxide MMS-350. These models should be useful for research on mechanisms of radiation dermal and osseous damage and for further development of new radioprotectors. They also provide information of potential relevance to the effects of clinical radiation therapies.
Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
View article, Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
PDF, Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
A collection of powerful diagnostic tools have been developed under the umbrellas of NATO for ionising radiation dose assessment (BAT, WinFRAT) and estimate of acute health effects in humans (WinFRAT, H-Module). We assembled a database of 191 ARS cases using the medical treatment protocols for radiation accident victims (n = 167) and the system for evaluation and archiving of radiation accidents based on case histories (n = 24) for training purposes of medical personnel. From 2016 to 2019, we trained 39 participants comprising MSc level radiobiology students in an on-site teaching class. Enforced by the covid-19 pandemic in 2020 for the first time, an online teaching of nine MSc radiobiology students replaced the on-site teaching. We found that: (a) limitations of correct diagnostic decision-making based on clinical signs and symptoms were experienced unrelated to the teaching format. (b) A significant performance decrease concerning online (first number in parenthesis) versus on-site teaching (reference and second number in parenthesis) was seen regarding the estimate time (31 vs 61 cases per hour, two-fold decrease, p = 0.005). Also, the accurate assessment of response categories (89.9% vs 96.9%, p = 0.001), ARS (92.4% vs 96.7%, p = 0.002) and hospitalisation (93.5% vs 97.0%, p = 0.002) decreased by around 3%–7%. The performances of the online attendees were mainly distributed within the lower quartile performance of on-site participants and the 25%–75% interquartile range increased 3–7-fold. (c) Comparison of dose estimates performed by training participants with hematologic acute radiation syndrome (HARS) severity mirrored the known limitations of dose alone as a surrogate parameter for HARS severity at doses less than 1.5 Gy, but demonstrated correct determination of HARS 2–4 and support for clinical decision making at dose estimates >1.5 Gy, regardless of teaching format. (d) Overall, one-third of the online participants showed substantial misapprehension and insecurities of elementary course content that did not occur after the on-site teaching.
Open access
Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
View article, Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
PDF, Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
Generally, intentional exposure of pregnant women is avoided as far as possible in both medical and occupational situations. This paper aims to summarise available information on sources of radiation exposure of the embryo/foetus primarily in medical settings. Accidental and unintended exposure is also considered. Knowledge on the effects of radiation exposure on the developing embryo/foetus remains incomplete—drawn largely from animal studies and two human cohorts but a summary is provided in relation to the key health endpoints of concern, severe foetal malformations/death, future cancer risk, and future impact on cognitive function. Both the specific education and training and also the literature regarding medical management of pregnant females is in general sparse, and consequently the justification and optimisation approaches may need to be considered on a case by case basis. In collating and reviewing this information, several suggestions for future basic science research, education and training, and radiation protection practice are identified.
Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
View article, Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
PDF, Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.
Basic concepts of radiation emergency medicine
View article, Basic concepts of radiation emergency medicine
PDF, Basic concepts of radiation emergency medicine
Nuclear and radiological accidents are not frequent but may lead to major consequences in the population. For the health systems, the need to handle a large number of victims will probably remain as an exception. However, a high number of affected victims can be expected in some terrorist scenarios. In addition, medical accidents in radiotherapy, fluoroscopy and diagnostic radiology have increased the number of patients with severe radiation injuries considerably, especially in developed countries. Given the increased use of ionising radiation for industrial and medical purposes and new technological applications emerging, the number of accidents may increase in the future. Consequently, the early identification and adequate management of these emergencies is a priority, as well as the need for medical preparedness, requiring knowledge about various emergency scenarios and planning appropriate responses to them before they occur. Unfortunately, medical professionals have a substantial knowledge gap in identifying and treating injured persons affected by ionising radiation. As managing radiation accidents is a very challenging process, exercises must be carried out to organise a well-trained multidisciplinary group of professionals to manage any radiation accident properly. Efforts on a continuously updated guidance system should be developed. In addition, new approaches to foster sustainable interdisciplinary and international cooperative networks on radiation injuries are necessary. Lessons learned from past nuclear and radiological emergencies have significantly contributed to strengthening scientific knowledge and increasing the available medical information on the effects of ionising radiation in the human body. In this context, radiation emergency medicine has emerged as a discipline that contributes to the diagnosis, treatment, medical follow-up and prognosis of persons affected by radiation injuries in a nuclear or a radiological emergency. In this paper, we review some relevant concepts related to the medical preparedness and multidisciplinary response required to attend to persons affected by these emergencies.
Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
View article, Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
PDF, Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
Recent advances in medical countermeasures (MCMs) has been dependent on the Food and Drug Administration (FDA) animal rule (AR) and the final guidance document provided for industry on product development. The criteria outlined therein establish the path for approval under the AR. The guidance document, along with the funding and requirements from the federal agencies provided the basic considerations for animal model development in assessing radiation effects and efficacy against the potential lethal effects of acute radiation injury and the delayed effects of acute exposure. Animal models, essential for determining MCM efficacy, were developed and validated to assess organ-specific, potentially lethal, radiation effects against the gastrointestinal (GI) and hematopoietic acute radiation syndrome (H-ARS), and radiation-induced delayed effects to lung and associated comorbidities of prolonged immune suppression, GI, kidney and heart injury. Partial-body irradiation models where marginal bone marrow was spared resulted in the ability to evaluate the concomitant evolution of multiple organ injury in the acute and delayed effects in survivors of acute radiation exposure. There are no MCMs for prophylaxis against the major sequelae of the ARS or the delayed effects of acute exposure. Also lacking are MCMs that will mitigate the GI ARS consequent to potentially lethal exposure from a terrorist event or major radiation accident. Additionally, the gap in countermeasures for prophylaxis may extend to mixed neutron/gamma radiation if current modelling predicts prompt exposure from an improvised nuclear device. However, progress in the field of MCM development has been made due to federal and corporate funding, clarification of the critical criteria for efficacy within the FDA AR and the concomitant development and validation of additional animal models. These models provided for a strategic and tactical approach to determine radiation effects and MCM efficacy.
Treatment of radiological contamination: a review
View article, Treatment of radiological contamination: a review
PDF, Treatment of radiological contamination: a review
After nuclear accidents, people can be contaminated internally via ingestion, inhalation and via intact skin or wounds. The assessment of absorbed, committed doses after internal exposure is based on activity measurement by in vivo or in vitro bioassay. Estimation of dose following internal contamination is dependent on understanding the nature and form of the radionuclide. Direct counting methods that directly measure γ-rays coming from within the body or bioassay methods that measure the amount of radioactive materials in urine or feces are used to estimate the intake, which is required for calculating internal exposure doses. The interpretation of these data in terms of intake and the lifetime committed dose requires knowledge or making assumptions about a number of parameters (time, type of exposure, route of the exposure, physical, biological and chemical characteristics) and their biokinetics inside the body. Radioactive materials incorporated into the body emit radiation within the body. Accumulation in some specific organs may occur depending on the types of radioactive materials. Decorporation therapy is that acceleration of the natural rate of elimination of the contaminant will reduce the amount of radioactivity retained in the body. This article presents an overview of treatment of radiological contamination after internal contamination.
Open access
Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
View article, Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
PDF, Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects.
Specific features of medical care provision to the population of the Techa riverside settlements
View article, Specific features of medical care provision to the population of the Techa riverside settlements
PDF, Specific features of medical care provision to the population of the Techa riverside settlements
This paper is devoted to the issue of medical care provision to the residents of the Techa riverside settlements affected by long-term radiation exposure. The river was contaminated due to operational and accidental releases of liquid radioactive waste (LRW) by the 'Mayak' Production Association from 1949 to 1956. Contamination of the river and its floodplain with radionuclides, including long-lived 90Sr and 137Cs, caused long-term external and internal exposure of the population, predominantly of the bone marrow. Protective countermeasures (resettlement of residents, introduction of restrictions on the use of the river and floodplain, construction of wells, etc) did not manage to prevent relatively high exposure doses to the population. The mean dose value of bone marrow exposure in residents of the riverside settlements was 0.35 Gy, whereas the maximum values were up to 7.92 Gy. The first medical examinations by mobile teams of the Moscow Institute of Biophysics were started approximately two years after the onset of LRW releases. Since 1955, exposed residents have been followed up and are undergoing medical treatment at the Clinic of the Urals Research Center for Radiation Medicine of the Federal Medical and Biological Agency (URCRM). This center was established in response to the necessity to study the biological effects of the combined external γ-exposure and exposure due to 90Sr in order to arrange medical care for the exposed population. The URCRM Clinic focuses on the provision of hematological care since cases of chronic radiation syndrome were registered among the exposed population in the early period, and increased leukemia incidence has been observed in the long-term period.
Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
View article, Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
PDF, Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons and γ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose of γ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.
How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
View article, How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
PDF, How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
High-dose radiation exposures of humans occur every year around the world, and may lead to harmful tissue reactions. This review aims to look at the available information sources that can help answering the question of how often these events occur yearly on a global scale. In the absence of comprehensive databases of global occurrence, publications on radiation accidents in all uses of radiation and on rates of high-dose events in different medical uses of radiation have been reviewed. Most high-dose radiation exposures seem to occur in the medical uses of radiation, reflecting the high number of medical exposures performed. In therapeutic medical uses, radiation doses are purposely often given at levels known to cause deterministic effects, and there is a very narrow range in which the medical practitioner can operate without causing severe unacceptable outcomes. In interventional medical uses, there are scenarios in which the radiation dose given to a patient may reach or exceed a threshold for skin effects, where this radiation dose may be unavoidable, considering all benefits and risks as well as benefits and risks of any alternative procedures. Regardless of if the delivered dose is unintended, unnecessary or unavoidable, there are estimates published of the rates of high-dose events and of radiation-induced tissue injuries occurring in medical uses. If this information is extrapolated to a global scenario, noting the inherent limitations in doing so, it does not seem unreasonable to expect that the global number of radiation-induced injuries every year may be in the order of hundreds, likely mainly arising from medical uses of radiation, and in particular from interventional fluoroscopy procedures and external beam radiotherapy procedures. These procedures are so frequently employed throughout the world that even a very small rate of radiation-induced injuries becomes a substantial number when scaled up to a global level.
Open access
Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
View article, Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
PDF, Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
The accepted generic multiple-parameter and early-response biodosimetry and dosimetry assessment approach for suspected high-dose radiation (i.e. life-threatening) exposure includes measuring radioactivity associated with the exposed individual (if appropriate); observing and recording prodromal signs/symptoms; obtaining serial complete blood counts with white-blood-cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the 'gold standard' dicentric assay (premature chromosome condensation assay for exposures >5 Gy photon acute doses equivalent), measurement of proteomic biomarkers and gene expression assays for dose assessment; bioassay sampling, if appropriate, to determine radioactive internal contamination; physical dose reconstruction, and using other available opportunistic dosimetry approaches. Biodosimetry and dosimetry resources are identified and should be setup in advance along with agreements to access additional national, regional, and international resources. This multifaceted capability needs to be integrated into a biodosimetry/dosimetry 'concept of operations' for use in a radiological emergency. The combined use of traditional biological-, clinical-, and physical-dosimetry should be use in an integrated approach to provide: (a) early-phase diagnostics to guide the development of initial medical-management strategy, and (b) intermediate and definitive assessment of radiation dose and injury. Use of early-phase (a) clinical signs and symptoms, (b) blood chemistry biomarkers, and (c) triage cytogenetics shows diagnostic utility to predict acute radiation injury severity.
Medical management: major lessons learned from the Chernobyl accident (the review)
View article, Medical management: major lessons learned from the Chernobyl accident (the review)
PDF, Medical management: major lessons learned from the Chernobyl accident (the review)
Thirty-five years have passed since the moment of the disaster at the Chernobyl nuclear power plant. It is quite a sufficient period to assess the correctness of the organisation of medical care for victims, to summarise the results of monitoring the health status of various groups of persons involved in the accident, including its direct participants. Radiation from a massive source of relatively uniform gamma radiation and a heterogeneous source of beta radiation can cause affected people to develop acute radiation syndrome (ARS) of varying severity, including non-curable forms of the disease ARS developed in 134 patients; 28 patients from 134 with ARS died in a short time (100 d) after exposure. Among the patients whose disease ended in death, 2/3 of the outcome could be due to radiation skin lesions (19 people). Treatment of ARS varying severity, which was combined with common skin burns with beta radiation, requires long-term specialised treatment. The experience of treating this group of patients has demonstrated that the indications for bone marrow transplantation in the curable form of ARS are limited. The percentage of victims who have absolute indications for allogeneic bone marrow transplantation and in whom this procedure will lead to an improved prognosis for life is very small. Recovery of own myelopoiesis and survival are possible after whole-body irradiation from 6 to 8 Gy, which was found after rejection of haploidentical human leucocyte antigen transplantation, as well as in patients who did not use bone marrow transplantation due to the absence of a corresponding donor. Patients who have undergone ARS need lifelong medical supervision and the provision of necessary medical care.
Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
View article, Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
PDF, Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
My task is to consider whether haematopoietic cell transplants would be considered appropriate today in persons with features like victims of high-dose and dose-rate ionizing radiations after the Chernobyl nuclear power facility accident in 1986 given knowledge and experience gained over the past 35 years. First I consider the conceptual bases for considering an intervention appropriate and then the metric for deciding whether a transplant is appropriate in similar persons. Data needed to support this decision-making process include estimates of dose, dose-rate, dose uniformity, synchronous or metachronous injuries, donor availability and alternative interventions. Many of these co-variates have substantial uncertainties. Fundamental is a consideration of potential benefit-to-risk and risk-to-benefit ratios under conditions of substantial inaccuracy and imprecision. The bottom line is probably fewer transplants would be done and more victims would receive molecularly-cloned haematopoietic growth factors.
Papers
Medical management of acute radiation syndrome
View article, Medical management of acute radiation syndrome
PDF, Medical management of acute radiation syndrome
Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.
Open access
Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
View article, Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
PDF, Mental health and psychosocial consequences linked to radiation emergencies—increasingly recognised concerns
A major radiological or nuclear emergency may, apart from causing a substantial loss of life and physical damage, also put a substantial strain on affected societies with social, economic and political consequences. Although such emergencies are relatively uncommon, it is now being increasingly recognised that their subsequent psychosocial impact can be widespread and long lasting. Mental health effects, such as depression, anxiety and post-traumatic stress disorder, are highly represented in a population affected by a radiation disaster. In order to reach the majority of the people affected by radiation accidents, we need to be aware of how to distribute relevant and accurate information related to both short- and long-term medical effects. Effective risk communication is associated with improved compliance with any given recommendations. It is important to protect the public from physical radiation damage, but it is also essential to take into account the social and mental health effects that radiation disasters may induce. This article provides a brief review of recent reporting on the psychological consequences after a major radiation emergency.
Open access
The risk of cancer following high, and very high, doses of ionising radiation
View article, The risk of cancer following high, and very high, doses of ionising radiation
PDF, The risk of cancer following high, and very high, doses of ionising radiation
It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.
Responding to radiation accidents: what more do we need to know?
View article, Responding to radiation accidents: what more do we need to know?
PDF, Responding to radiation accidents: what more do we need to know?
A short review of the various types of radiation incidents and accidents that have occurred is used to provide a context for discussing the findings on medical management of the victims of such incidents and accidents reported in a recent Special Issue of the Journal of Radiological Protection. The review demonstrates that accidents and incidents giving rise to high radiation doses may involve over-exposure of a single individual, a few individuals, or very large numbers. In general, these exposures will be relatively short-term, ranging from a few seconds to a few days, but chronic situations resulting in high exposures can occur. Some of these exposures may be highly localised, whereas others may result in almost uniform whole-body irradiation. This diversity of situations means that it is not feasible to have a single protocol for the diagnosis and treatment of over-exposed individuals. If the over-exposures are limited to one or a few individuals, these can be addressed on a case-by-case basis. However, where large numbers have been exposed or may have been exposed, there is a need to implement a rapid and effective system of triage. Furthermore, this system is likely to have to be implemented by individuals who have little or no direct experience of radiation-induced injuries. For those individuals who may have been significantly exposed, the key consideration is not to determine the radiation dose that they have received, but to establish their present clinical status and how it is likely to develop with time. There is at most a very limited role for bone-marrow transplantation in the treatment of acute radiation syndrome, whereas there are good arguments for administering various treatments to boost bone marrow function together with other supportive interventions, e.g. in control of infections and handling both fluid loss and bleeding. However, there is concern that the focus to date has been only on the licencing of drugs related to the management of haematopoietic effects. Although a great deal is known about the diagnosis and treatment of injuries arising from high dose exposures, this knowledge is biased towards situations in which there is relatively uniform, external whole-body exposure. More attention needs to be given to assessing the implications of various inhomogeneous exposure regimes and to developing medical countermeasures optimised for addressing the complex, multi-organ effects likely to arise from such inhomogeneous exposures.
Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
View article, Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
PDF, Mesenchymal stromal cells in the regeneration of radiation-induced organ sequelae: will they make the difference?
Mesenchymal stromal cells (MSCs) are a stem cell product with good safety that demonstrate significant clinical efficacy in the treatment of different pathologies, including radiation diseases (e.g. radiological burns, pelvic radiation disease). While the first results for some first human applications for the treatment of radiation disease suggest benefit, larger trials with clinically important endpoints are needed before definitive conclusions can be drawn. However, the supply and cost of MSCs remain the two main limitations for this innovative therapeutic product. Exosomes (EXOs), a stem cell product associated with MSC therapy, have shown promising efficacy and safety in humans. MSC-EXO therapeutics represent a promising next-generation approach for treating radiation diseases involving a primary (major) inflammatory component. Provided that conditions for MSC-EXO production and bio-banking are agreed in the near future, the transition to industrial production of MSC-EXOs will be possible, and this is required to initiate well-controlled clinical trials for approval by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).
Open access
The acute radiation syndrome—need for updated medical guidelines
View article, The acute radiation syndrome—need for updated medical guidelines
PDF, The acute radiation syndrome—need for updated medical guidelines
The major immediate and severe medical consequences in man following exposure to high doses of ionising radiation can be summarised within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the World Health Organization published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.
The METREPOL criteria—are they still relevant?
View article, The METREPOL criteria—are they still relevant?
PDF, The METREPOL criteria—are they still relevant?
The medical management of radiation accidents manual on the acute radiation syndrome proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.
Cutaneous and local radiation injuries
The threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionising radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome, a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation or an improvised nuclear detonation (IND), a nuclear power plant incident, or an encounter with a radioactive dispersal or exposure device. These incidents may also result in a radiation-combined injury; a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognising the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.
Open access
Early molecular markers for retrospective biodosimetry and prediction of acute health effects
View article, Early molecular markers for retrospective biodosimetry and prediction of acute health effects
PDF, Early molecular markers for retrospective biodosimetry and prediction of acute health effects
Radiation-induced biological changes occurring within hours and days after irradiation can be potentially used for either exposure reconstruction (retrospective dosimetry) or the prediction of consecutively occurring acute or chronic health effects. The advantage of molecular protein or gene expression (GE) (mRNA) marker lies in their capability for early (1–3 days after irradiation), high-throughput and point-of-care diagnosis, required for the prediction of the acute radiation syndrome (ARS) in radiological or nuclear scenarios. These molecular marker in most cases respond differently regarding exposure characteristics such as e.g. radiation quality, dose, dose rate and most importantly over time. Changes over time are in particular challenging and demand certain strategies to deal with. With this review, we provide an overview and will focus on already identified and used mRNA GE and protein markers of the peripheral blood related to the ARS. These molecules are examined in light of 'ideal' characteristics of a biomarkers (e.g. easy accessible, early response, signal persistency) and the validation degree. Finally, we present strategies on the use of these markers considering challenges as their variation over time and future developments regarding e.g. origin of samples, point of care and high-throughput diagnosis.
Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot.
41 S391)
View article, Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot. 41 S391)
PDF, Corrigendum: Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident (2021 J. Radiol. Prot. 41 S391)
Prevention and management of infections after exposure to ionising radiation
View article, Prevention and management of infections after exposure to ionising radiation
PDF, Prevention and management of infections after exposure to ionising radiation
Ionising radiation impacts many organ systems, each of which comprises a level of immunity to infectious disease. Bone marrow toxicity after radiation results in a predisposition to leukopenia and subsequent susceptibility to bacterial, viral, and fungal infections. Radiation-induced damage to mucosal, integumentary, and solid organ structures disrupts additional lines of innate defense. Over the past three decades, much progress has been made in effective antimicrobial prophylaxis, resulting in decreased infectious complications and improved survival. Vaccination schedules following myeloablative radiation have become highly regimented and treatment of overt infectious complications is largely standardised. In this article, we discuss consequences, prevention, and management of infections following exposure to ionising radiation.
High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
View article, High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
PDF, High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy
Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500–800 mGy, subclinical hypothyroidism has been detected in 3%–6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.
Open access
United States medical preparedness for nuclear and radiological emergencies
View article, United States medical preparedness for nuclear and radiological emergencies
PDF, United States medical preparedness for nuclear and radiological emergencies
With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of 11 September, which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG's efforts to plan for the unthinkable have centred on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.
Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
View article, Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
PDF, Cytogenetic follow-up studies on humans with internal and external exposure to ionizing radiation
Cells exposed to ionizing radiation have a wide spectrum of DNA lesions that include DNA single-strand breaks, DNA double-strand breaks (DSBs), oxidative base damage and DNA-protein crosslinks. Among them, DSB is the most critical lesion, which when mis-repaired leads to unstable and stable chromosome aberrations. Currently, chromosome aberration analysis is the preferred method for biological monitoring of radiation-exposed humans. Stable chromosome aberrations, such as inversions and balanced translocations, persist in the peripheral blood lymphocytes of radiation-exposed humans for several years and, therefore, are potentially useful tools to prognosticate the health risks of radiation exposure, particularly in the hematopoietic system. In this review, we summarize the cytogenetic follow-up studies performed by REAC/TS (Radiation Emergency Assistance Center/Training site, Oak Ridge, USA) on humans exposed to internal and external radiation. In the light of our observations as well as the data existing in the literature, this review attempts to highlight the importance of follow-up studies for predicting the extent of genomic instability and its impact on delayed health risks in radiation-exposed victims.
Combined injury: irradiation with skin or bone wounds in rodent models
View article, Combined injury: irradiation with skin or bone wounds in rodent models
PDF, Combined injury: irradiation with skin or bone wounds in rodent models
A radiation combined injury is defined as an injury that occurs in the setting of irradiation, such as those expected after a nuclear accident, radiation dispersal device release (a 'dirty bomb'), or a nuclear weapon detonation. There is much research on irradiation-associated burns and their healing, but there is less known about other injuries sustained in the context of irradiation. Animal models are limited in their correlations to clinical situations but can support research on specific questions about injuries and their healing. Mouse models of irradiation with skin or bone wounds are validated as highly reproducible and quantitative. They show dose-dependent impairment of wound healing, with later recovery. Irradiation-induced delay of bone wound healing was mitigated to different extents by single doses of gramicidin S-nitroxide JP4-039, a plasmid expressing manganese superoxide dismutase, amifostine/WR2721, or the bifunctional sulfoxide MMS-350. These models should be useful for research on mechanisms of radiation dermal and osseous damage and for further development of new radioprotectors. They also provide information of potential relevance to the effects of clinical radiation therapies.
Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
View article, Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
PDF, Training of clinical triage of acute radiation casualties: a performance comparison of on-site versus online training due to the covid-19 pandemic
A collection of powerful diagnostic tools have been developed under the umbrellas of NATO for ionising radiation dose assessment (BAT, WinFRAT) and estimate of acute health effects in humans (WinFRAT, H-Module). We assembled a database of 191 ARS cases using the medical treatment protocols for radiation accident victims (n = 167) and the system for evaluation and archiving of radiation accidents based on case histories (n = 24) for training purposes of medical personnel. From 2016 to 2019, we trained 39 participants comprising MSc level radiobiology students in an on-site teaching class. Enforced by the covid-19 pandemic in 2020 for the first time, an online teaching of nine MSc radiobiology students replaced the on-site teaching. We found that: (a) limitations of correct diagnostic decision-making based on clinical signs and symptoms were experienced unrelated to the teaching format. (b) A significant performance decrease concerning online (first number in parenthesis) versus on-site teaching (reference and second number in parenthesis) was seen regarding the estimate time (31 vs 61 cases per hour, two-fold decrease, p = 0.005). Also, the accurate assessment of response categories (89.9% vs 96.9%, p = 0.001), ARS (92.4% vs 96.7%, p = 0.002) and hospitalisation (93.5% vs 97.0%, p = 0.002) decreased by around 3%–7%. The performances of the online attendees were mainly distributed within the lower quartile performance of on-site participants and the 25%–75% interquartile range increased 3–7-fold. (c) Comparison of dose estimates performed by training participants with hematologic acute radiation syndrome (HARS) severity mirrored the known limitations of dose alone as a surrogate parameter for HARS severity at doses less than 1.5 Gy, but demonstrated correct determination of HARS 2–4 and support for clinical decision making at dose estimates >1.5 Gy, regardless of teaching format. (d) Overall, one-third of the online participants showed substantial misapprehension and insecurities of elementary course content that did not occur after the on-site teaching.
Open access
Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
View article, Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
PDF, Radiation exposures in pregnancy, health effects and risks to the embryo/foetus—information to inform the medical management of the pregnant patient
Generally, intentional exposure of pregnant women is avoided as far as possible in both medical and occupational situations. This paper aims to summarise available information on sources of radiation exposure of the embryo/foetus primarily in medical settings. Accidental and unintended exposure is also considered. Knowledge on the effects of radiation exposure on the developing embryo/foetus remains incomplete—drawn largely from animal studies and two human cohorts but a summary is provided in relation to the key health endpoints of concern, severe foetal malformations/death, future cancer risk, and future impact on cognitive function. Both the specific education and training and also the literature regarding medical management of pregnant females is in general sparse, and consequently the justification and optimisation approaches may need to be considered on a case by case basis. In collating and reviewing this information, several suggestions for future basic science research, education and training, and radiation protection practice are identified.
Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
View article, Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
PDF, Role of molecularly-cloned hematopoietic growth factors after acute high-dose radiation exposures
Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.
Basic concepts of radiation emergency medicine
View article, Basic concepts of radiation emergency medicine
PDF, Basic concepts of radiation emergency medicine
Nuclear and radiological accidents are not frequent but may lead to major consequences in the population. For the health systems, the need to handle a large number of victims will probably remain as an exception. However, a high number of affected victims can be expected in some terrorist scenarios. In addition, medical accidents in radiotherapy, fluoroscopy and diagnostic radiology have increased the number of patients with severe radiation injuries considerably, especially in developed countries. Given the increased use of ionising radiation for industrial and medical purposes and new technological applications emerging, the number of accidents may increase in the future. Consequently, the early identification and adequate management of these emergencies is a priority, as well as the need for medical preparedness, requiring knowledge about various emergency scenarios and planning appropriate responses to them before they occur. Unfortunately, medical professionals have a substantial knowledge gap in identifying and treating injured persons affected by ionising radiation. As managing radiation accidents is a very challenging process, exercises must be carried out to organise a well-trained multidisciplinary group of professionals to manage any radiation accident properly. Efforts on a continuously updated guidance system should be developed. In addition, new approaches to foster sustainable interdisciplinary and international cooperative networks on radiation injuries are necessary. Lessons learned from past nuclear and radiological emergencies have significantly contributed to strengthening scientific knowledge and increasing the available medical information on the effects of ionising radiation in the human body. In this context, radiation emergency medicine has emerged as a discipline that contributes to the diagnosis, treatment, medical follow-up and prognosis of persons affected by radiation injuries in a nuclear or a radiological emergency. In this paper, we review some relevant concepts related to the medical preparedness and multidisciplinary response required to attend to persons affected by these emergencies.
Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
View article, Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
PDF, Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule
Recent advances in medical countermeasures (MCMs) has been dependent on the Food and Drug Administration (FDA) animal rule (AR) and the final guidance document provided for industry on product development. The criteria outlined therein establish the path for approval under the AR. The guidance document, along with the funding and requirements from the federal agencies provided the basic considerations for animal model development in assessing radiation effects and efficacy against the potential lethal effects of acute radiation injury and the delayed effects of acute exposure. Animal models, essential for determining MCM efficacy, were developed and validated to assess organ-specific, potentially lethal, radiation effects against the gastrointestinal (GI) and hematopoietic acute radiation syndrome (H-ARS), and radiation-induced delayed effects to lung and associated comorbidities of prolonged immune suppression, GI, kidney and heart injury. Partial-body irradiation models where marginal bone marrow was spared resulted in the ability to evaluate the concomitant evolution of multiple organ injury in the acute and delayed effects in survivors of acute radiation exposure. There are no MCMs for prophylaxis against the major sequelae of the ARS or the delayed effects of acute exposure. Also lacking are MCMs that will mitigate the GI ARS consequent to potentially lethal exposure from a terrorist event or major radiation accident. Additionally, the gap in countermeasures for prophylaxis may extend to mixed neutron/gamma radiation if current modelling predicts prompt exposure from an improvised nuclear device. However, progress in the field of MCM development has been made due to federal and corporate funding, clarification of the critical criteria for efficacy within the FDA AR and the concomitant development and validation of additional animal models. These models provided for a strategic and tactical approach to determine radiation effects and MCM efficacy.
Treatment of radiological contamination: a review
View article, Treatment of radiological contamination: a review
PDF, Treatment of radiological contamination: a review
After nuclear accidents, people can be contaminated internally via ingestion, inhalation and via intact skin or wounds. The assessment of absorbed, committed doses after internal exposure is based on activity measurement by in vivo or in vitro bioassay. Estimation of dose following internal contamination is dependent on understanding the nature and form of the radionuclide. Direct counting methods that directly measure γ-rays coming from within the body or bioassay methods that measure the amount of radioactive materials in urine or feces are used to estimate the intake, which is required for calculating internal exposure doses. The interpretation of these data in terms of intake and the lifetime committed dose requires knowledge or making assumptions about a number of parameters (time, type of exposure, route of the exposure, physical, biological and chemical characteristics) and their biokinetics inside the body. Radioactive materials incorporated into the body emit radiation within the body. Accumulation in some specific organs may occur depending on the types of radioactive materials. Decorporation therapy is that acceleration of the natural rate of elimination of the contaminant will reduce the amount of radioactivity retained in the body. This article presents an overview of treatment of radiological contamination after internal contamination.
Open access
Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
View article, Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
PDF, Medical consequences of radiation exposure of the bronchi—what can we learn from high-dose precision radiation therapy?
The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects.
Specific features of medical care provision to the population of the Techa riverside settlements
View article, Specific features of medical care provision to the population of the Techa riverside settlements
PDF, Specific features of medical care provision to the population of the Techa riverside settlements
This paper is devoted to the issue of medical care provision to the residents of the Techa riverside settlements affected by long-term radiation exposure. The river was contaminated due to operational and accidental releases of liquid radioactive waste (LRW) by the 'Mayak' Production Association from 1949 to 1956. Contamination of the river and its floodplain with radionuclides, including long-lived 90Sr and 137Cs, caused long-term external and internal exposure of the population, predominantly of the bone marrow. Protective countermeasures (resettlement of residents, introduction of restrictions on the use of the river and floodplain, construction of wells, etc) did not manage to prevent relatively high exposure doses to the population. The mean dose value of bone marrow exposure in residents of the riverside settlements was 0.35 Gy, whereas the maximum values were up to 7.92 Gy. The first medical examinations by mobile teams of the Moscow Institute of Biophysics were started approximately two years after the onset of LRW releases. Since 1955, exposed residents have been followed up and are undergoing medical treatment at the Clinic of the Urals Research Center for Radiation Medicine of the Federal Medical and Biological Agency (URCRM). This center was established in response to the necessity to study the biological effects of the combined external γ-exposure and exposure due to 90Sr in order to arrange medical care for the exposed population. The URCRM Clinic focuses on the provision of hematological care since cases of chronic radiation syndrome were registered among the exposed population in the early period, and increased leukemia incidence has been observed in the long-term period.
Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
View article, Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
PDF, Medical management of heavily exposed victims: an experience at the Tokaimura criticality accident
A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons and γ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose of γ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.
How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
View article, How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
PDF, How often does it happen? A review of unintended, unnecessary and unavoidable high-dose radiation exposures
High-dose radiation exposures of humans occur every year around the world, and may lead to harmful tissue reactions. This review aims to look at the available information sources that can help answering the question of how often these events occur yearly on a global scale. In the absence of comprehensive databases of global occurrence, publications on radiation accidents in all uses of radiation and on rates of high-dose events in different medical uses of radiation have been reviewed. Most high-dose radiation exposures seem to occur in the medical uses of radiation, reflecting the high number of medical exposures performed. In therapeutic medical uses, radiation doses are purposely often given at levels known to cause deterministic effects, and there is a very narrow range in which the medical practitioner can operate without causing severe unacceptable outcomes. In interventional medical uses, there are scenarios in which the radiation dose given to a patient may reach or exceed a threshold for skin effects, where this radiation dose may be unavoidable, considering all benefits and risks as well as benefits and risks of any alternative procedures. Regardless of if the delivered dose is unintended, unnecessary or unavoidable, there are estimates published of the rates of high-dose events and of radiation-induced tissue injuries occurring in medical uses. If this information is extrapolated to a global scenario, noting the inherent limitations in doing so, it does not seem unreasonable to expect that the global number of radiation-induced injuries every year may be in the order of hundreds, likely mainly arising from medical uses of radiation, and in particular from interventional fluoroscopy procedures and external beam radiotherapy procedures. These procedures are so frequently employed throughout the world that even a very small rate of radiation-induced injuries becomes a substantial number when scaled up to a global level.
Open access
Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
View article, Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
PDF, Early-response multiple-parameter biodosimetry and dosimetry: risk predictions
The accepted generic multiple-parameter and early-response biodosimetry and dosimetry assessment approach for suspected high-dose radiation (i.e. life-threatening) exposure includes measuring radioactivity associated with the exposed individual (if appropriate); observing and recording prodromal signs/symptoms; obtaining serial complete blood counts with white-blood-cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the 'gold standard' dicentric assay (premature chromosome condensation assay for exposures >5 Gy photon acute doses equivalent), measurement of proteomic biomarkers and gene expression assays for dose assessment; bioassay sampling, if appropriate, to determine radioactive internal contamination; physical dose reconstruction, and using other available opportunistic dosimetry approaches. Biodosimetry and dosimetry resources are identified and should be setup in advance along with agreements to access additional national, regional, and international resources. This multifaceted capability needs to be integrated into a biodosimetry/dosimetry 'concept of operations' for use in a radiological emergency. The combined use of traditional biological-, clinical-, and physical-dosimetry should be use in an integrated approach to provide: (a) early-phase diagnostics to guide the development of initial medical-management strategy, and (b) intermediate and definitive assessment of radiation dose and injury. Use of early-phase (a) clinical signs and symptoms, (b) blood chemistry biomarkers, and (c) triage cytogenetics shows diagnostic utility to predict acute radiation injury severity.
Medical management: major lessons learned from the Chernobyl accident (the review)
View article, Medical management: major lessons learned from the Chernobyl accident (the review)
PDF, Medical management: major lessons learned from the Chernobyl accident (the review)
Thirty-five years have passed since the moment of the disaster at the Chernobyl nuclear power plant. It is quite a sufficient period to assess the correctness of the organisation of medical care for victims, to summarise the results of monitoring the health status of various groups of persons involved in the accident, including its direct participants. Radiation from a massive source of relatively uniform gamma radiation and a heterogeneous source of beta radiation can cause affected people to develop acute radiation syndrome (ARS) of varying severity, including non-curable forms of the disease ARS developed in 134 patients; 28 patients from 134 with ARS died in a short time (100 d) after exposure. Among the patients whose disease ended in death, 2/3 of the outcome could be due to radiation skin lesions (19 people). Treatment of ARS varying severity, which was combined with common skin burns with beta radiation, requires long-term specialised treatment. The experience of treating this group of patients has demonstrated that the indications for bone marrow transplantation in the curable form of ARS are limited. The percentage of victims who have absolute indications for allogeneic bone marrow transplantation and in whom this procedure will lead to an improved prognosis for life is very small. Recovery of own myelopoiesis and survival are possible after whole-body irradiation from 6 to 8 Gy, which was found after rejection of haploidentical human leucocyte antigen transplantation, as well as in patients who did not use bone marrow transplantation due to the absence of a corresponding donor. Patients who have undergone ARS need lifelong medical supervision and the provision of necessary medical care.
Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
View article, Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
PDF, Is there a role for haematopoietic cell transplants after radiation and nuclear accidents?
My task is to consider whether haematopoietic cell transplants would be considered appropriate today in persons with features like victims of high-dose and dose-rate ionizing radiations after the Chernobyl nuclear power facility accident in 1986 given knowledge and experience gained over the past 35 years. First I consider the conceptual bases for considering an intervention appropriate and then the metric for deciding whether a transplant is appropriate in similar persons. Data needed to support this decision-making process include estimates of dose, dose-rate, dose uniformity, synchronous or metachronous injuries, donor availability and alternative interventions. Many of these co-variates have substantial uncertainties. Fundamental is a consideration of potential benefit-to-risk and risk-to-benefit ratios under conditions of substantial inaccuracy and imprecision. The bottom line is probably fewer transplants would be done and more victims would receive molecularly-cloned haematopoietic growth factors.
Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.
A major radiological or nuclear emergency may, apart from causing a substantial loss of life and physical damage, also put a substantial strain on affected societies with social, economic and political consequences. Although such emergencies are relatively uncommon, it is now being increasingly recognised that their subsequent psychosocial impact can be widespread and long lasting. Mental health effects, such as depression, anxiety and post-traumatic stress disorder, are highly represented in a population affected by a radiation disaster. In order to reach the majority of the people affected by radiation accidents, we need to be aware of how to distribute relevant and accurate information related to both short- and long-term medical effects. Effective risk communication is associated with improved compliance with any given recommendations. It is important to protect the public from physical radiation damage, but it is also essential to take into account the social and mental health effects that radiation disasters may induce. This article provides a brief review of recent reporting on the psychological consequences after a major radiation emergency.
It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.
A short review of the various types of radiation incidents and accidents that have occurred is used to provide a context for discussing the findings on medical management of the victims of such incidents and accidents reported in a recent Special Issue of the Journal of Radiological Protection. The review demonstrates that accidents and incidents giving rise to high radiation doses may involve over-exposure of a single individual, a few individuals, or very large numbers. In general, these exposures will be relatively short-term, ranging from a few seconds to a few days, but chronic situations resulting in high exposures can occur. Some of these exposures may be highly localised, whereas others may result in almost uniform whole-body irradiation. This diversity of situations means that it is not feasible to have a single protocol for the diagnosis and treatment of over-exposed individuals. If the over-exposures are limited to one or a few individuals, these can be addressed on a case-by-case basis. However, where large numbers have been exposed or may have been exposed, there is a need to implement a rapid and effective system of triage. Furthermore, this system is likely to have to be implemented by individuals who have little or no direct experience of radiation-induced injuries. For those individuals who may have been significantly exposed, the key consideration is not to determine the radiation dose that they have received, but to establish their present clinical status and how it is likely to develop with time. There is at most a very limited role for bone-marrow transplantation in the treatment of acute radiation syndrome, whereas there are good arguments for administering various treatments to boost bone marrow function together with other supportive interventions, e.g. in control of infections and handling both fluid loss and bleeding. However, there is concern that the focus to date has been only on the licencing of drugs related to the management of haematopoietic effects. Although a great deal is known about the diagnosis and treatment of injuries arising from high dose exposures, this knowledge is biased towards situations in which there is relatively uniform, external whole-body exposure. More attention needs to be given to assessing the implications of various inhomogeneous exposure regimes and to developing medical countermeasures optimised for addressing the complex, multi-organ effects likely to arise from such inhomogeneous exposures.
Mesenchymal stromal cells (MSCs) are a stem cell product with good safety that demonstrate significant clinical efficacy in the treatment of different pathologies, including radiation diseases (e.g. radiological burns, pelvic radiation disease). While the first results for some first human applications for the treatment of radiation disease suggest benefit, larger trials with clinically important endpoints are needed before definitive conclusions can be drawn. However, the supply and cost of MSCs remain the two main limitations for this innovative therapeutic product. Exosomes (EXOs), a stem cell product associated with MSC therapy, have shown promising efficacy and safety in humans. MSC-EXO therapeutics represent a promising next-generation approach for treating radiation diseases involving a primary (major) inflammatory component. Provided that conditions for MSC-EXO production and bio-banking are agreed in the near future, the transition to industrial production of MSC-EXOs will be possible, and this is required to initiate well-controlled clinical trials for approval by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA).
The major immediate and severe medical consequences in man following exposure to high doses of ionising radiation can be summarised within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the World Health Organization published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.
The medical management of radiation accidents manual on the acute radiation syndrome proposed a successful strategic approach to diagnosing and treating acute radiation syndrome: the response category concept. Based on clinical and laboratory parameters, this approach aimed to assess damage to critical organ systems as a function of time, categorising different therapeutical approaches. After 20 years of its publication, the following paper attempts to provide a broad overview of this important document and tries to respond if proposed criteria are still relevant for the medical management of radiation-induced injuries. In addition, a critical analysis of its limitations and perspectives is proposed.
The threat of a large-scale radiological or nuclear (R/N) incident looms in the present-day climate, as noted most recently in an editorial in Scientific American (March 2021). These large-scale incidents are infrequent but affect large numbers of people. Smaller-scale R/N incidents occur more often, affecting smaller numbers of people. There is more awareness of acute radiation syndrome (ARS) in the medical community; however, ionising radiation-induced injuries to the skin are much less understood. This article will provide an overview of radiation-induced injuries to the skin, deeper tissues, and organs. The history and nomenclature; types and causes of injuries; pathophysiology; evaluation and diagnosis; current medical management; and current research of the evaluation and management are presented. Cutaneous radiation injuries (CRI) or local radiation injuries (LRI) may lead to cutaneous radiation syndrome, a sub-syndrome of ARS. These injuries may occur from exposure to radioactive particles suspended in the environment (air, soil, water) after a nuclear detonation or an improvised nuclear detonation (IND), a nuclear power plant incident, or an encounter with a radioactive dispersal or exposure device. These incidents may also result in a radiation-combined injury; a chemical, thermal, or traumatic injury, with radiation exposure. Skin injuries from medical diagnostic and therapeutic imaging, medical misadministration of nuclear medicine or radiotherapy, occupational exposures (including research) to radioactive sources are more common but are not the focus of this manuscript. Diagnosis and evaluation of injuries are based on the scenario, clinical picture, and dosimetry, and may be assisted through advanced imaging techniques. Research-based multidisciplinary therapies, both in the laboratory and clinical trial environments, hold promise for future medical management. Great progress is being made in recognising the extent of injuries, understanding their pathophysiology, as well as diagnosis and management; however, research gaps still exist.
Radiation-induced biological changes occurring within hours and days after irradiation can be potentially used for either exposure reconstruction (retrospective dosimetry) or the prediction of consecutively occurring acute or chronic health effects. The advantage of molecular protein or gene expression (GE) (mRNA) marker lies in their capability for early (1–3 days after irradiation), high-throughput and point-of-care diagnosis, required for the prediction of the acute radiation syndrome (ARS) in radiological or nuclear scenarios. These molecular marker in most cases respond differently regarding exposure characteristics such as e.g. radiation quality, dose, dose rate and most importantly over time. Changes over time are in particular challenging and demand certain strategies to deal with. With this review, we provide an overview and will focus on already identified and used mRNA GE and protein markers of the peripheral blood related to the ARS. These molecules are examined in light of 'ideal' characteristics of a biomarkers (e.g. easy accessible, early response, signal persistency) and the validation degree. Finally, we present strategies on the use of these markers considering challenges as their variation over time and future developments regarding e.g. origin of samples, point of care and high-throughput diagnosis.
Ionising radiation impacts many organ systems, each of which comprises a level of immunity to infectious disease. Bone marrow toxicity after radiation results in a predisposition to leukopenia and subsequent susceptibility to bacterial, viral, and fungal infections. Radiation-induced damage to mucosal, integumentary, and solid organ structures disrupts additional lines of innate defense. Over the past three decades, much progress has been made in effective antimicrobial prophylaxis, resulting in decreased infectious complications and improved survival. Vaccination schedules following myeloablative radiation have become highly regimented and treatment of overt infectious complications is largely standardised. In this article, we discuss consequences, prevention, and management of infections following exposure to ionising radiation.
Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500–800 mGy, subclinical hypothyroidism has been detected in 3%–6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.
With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of 11 September, which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG's efforts to plan for the unthinkable have centred on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.
Cells exposed to ionizing radiation have a wide spectrum of DNA lesions that include DNA single-strand breaks, DNA double-strand breaks (DSBs), oxidative base damage and DNA-protein crosslinks. Among them, DSB is the most critical lesion, which when mis-repaired leads to unstable and stable chromosome aberrations. Currently, chromosome aberration analysis is the preferred method for biological monitoring of radiation-exposed humans. Stable chromosome aberrations, such as inversions and balanced translocations, persist in the peripheral blood lymphocytes of radiation-exposed humans for several years and, therefore, are potentially useful tools to prognosticate the health risks of radiation exposure, particularly in the hematopoietic system. In this review, we summarize the cytogenetic follow-up studies performed by REAC/TS (Radiation Emergency Assistance Center/Training site, Oak Ridge, USA) on humans exposed to internal and external radiation. In the light of our observations as well as the data existing in the literature, this review attempts to highlight the importance of follow-up studies for predicting the extent of genomic instability and its impact on delayed health risks in radiation-exposed victims.
A radiation combined injury is defined as an injury that occurs in the setting of irradiation, such as those expected after a nuclear accident, radiation dispersal device release (a 'dirty bomb'), or a nuclear weapon detonation. There is much research on irradiation-associated burns and their healing, but there is less known about other injuries sustained in the context of irradiation. Animal models are limited in their correlations to clinical situations but can support research on specific questions about injuries and their healing. Mouse models of irradiation with skin or bone wounds are validated as highly reproducible and quantitative. They show dose-dependent impairment of wound healing, with later recovery. Irradiation-induced delay of bone wound healing was mitigated to different extents by single doses of gramicidin S-nitroxide JP4-039, a plasmid expressing manganese superoxide dismutase, amifostine/WR2721, or the bifunctional sulfoxide MMS-350. These models should be useful for research on mechanisms of radiation dermal and osseous damage and for further development of new radioprotectors. They also provide information of potential relevance to the effects of clinical radiation therapies.
A collection of powerful diagnostic tools have been developed under the umbrellas of NATO for ionising radiation dose assessment (BAT, WinFRAT) and estimate of acute health effects in humans (WinFRAT, H-Module). We assembled a database of 191 ARS cases using the medical treatment protocols for radiation accident victims (n = 167) and the system for evaluation and archiving of radiation accidents based on case histories (n = 24) for training purposes of medical personnel. From 2016 to 2019, we trained 39 participants comprising MSc level radiobiology students in an on-site teaching class. Enforced by the covid-19 pandemic in 2020 for the first time, an online teaching of nine MSc radiobiology students replaced the on-site teaching. We found that: (a) limitations of correct diagnostic decision-making based on clinical signs and symptoms were experienced unrelated to the teaching format. (b) A significant performance decrease concerning online (first number in parenthesis) versus on-site teaching (reference and second number in parenthesis) was seen regarding the estimate time (31 vs 61 cases per hour, two-fold decrease, p = 0.005). Also, the accurate assessment of response categories (89.9% vs 96.9%, p = 0.001), ARS (92.4% vs 96.7%, p = 0.002) and hospitalisation (93.5% vs 97.0%, p = 0.002) decreased by around 3%–7%. The performances of the online attendees were mainly distributed within the lower quartile performance of on-site participants and the 25%–75% interquartile range increased 3–7-fold. (c) Comparison of dose estimates performed by training participants with hematologic acute radiation syndrome (HARS) severity mirrored the known limitations of dose alone as a surrogate parameter for HARS severity at doses less than 1.5 Gy, but demonstrated correct determination of HARS 2–4 and support for clinical decision making at dose estimates >1.5 Gy, regardless of teaching format. (d) Overall, one-third of the online participants showed substantial misapprehension and insecurities of elementary course content that did not occur after the on-site teaching.
Generally, intentional exposure of pregnant women is avoided as far as possible in both medical and occupational situations. This paper aims to summarise available information on sources of radiation exposure of the embryo/foetus primarily in medical settings. Accidental and unintended exposure is also considered. Knowledge on the effects of radiation exposure on the developing embryo/foetus remains incomplete—drawn largely from animal studies and two human cohorts but a summary is provided in relation to the key health endpoints of concern, severe foetal malformations/death, future cancer risk, and future impact on cognitive function. Both the specific education and training and also the literature regarding medical management of pregnant females is in general sparse, and consequently the justification and optimisation approaches may need to be considered on a case by case basis. In collating and reviewing this information, several suggestions for future basic science research, education and training, and radiation protection practice are identified.
Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.
Nuclear and radiological accidents are not frequent but may lead to major consequences in the population. For the health systems, the need to handle a large number of victims will probably remain as an exception. However, a high number of affected victims can be expected in some terrorist scenarios. In addition, medical accidents in radiotherapy, fluoroscopy and diagnostic radiology have increased the number of patients with severe radiation injuries considerably, especially in developed countries. Given the increased use of ionising radiation for industrial and medical purposes and new technological applications emerging, the number of accidents may increase in the future. Consequently, the early identification and adequate management of these emergencies is a priority, as well as the need for medical preparedness, requiring knowledge about various emergency scenarios and planning appropriate responses to them before they occur. Unfortunately, medical professionals have a substantial knowledge gap in identifying and treating injured persons affected by ionising radiation. As managing radiation accidents is a very challenging process, exercises must be carried out to organise a well-trained multidisciplinary group of professionals to manage any radiation accident properly. Efforts on a continuously updated guidance system should be developed. In addition, new approaches to foster sustainable interdisciplinary and international cooperative networks on radiation injuries are necessary. Lessons learned from past nuclear and radiological emergencies have significantly contributed to strengthening scientific knowledge and increasing the available medical information on the effects of ionising radiation in the human body. In this context, radiation emergency medicine has emerged as a discipline that contributes to the diagnosis, treatment, medical follow-up and prognosis of persons affected by radiation injuries in a nuclear or a radiological emergency. In this paper, we review some relevant concepts related to the medical preparedness and multidisciplinary response required to attend to persons affected by these emergencies.
Recent advances in medical countermeasures (MCMs) has been dependent on the Food and Drug Administration (FDA) animal rule (AR) and the final guidance document provided for industry on product development. The criteria outlined therein establish the path for approval under the AR. The guidance document, along with the funding and requirements from the federal agencies provided the basic considerations for animal model development in assessing radiation effects and efficacy against the potential lethal effects of acute radiation injury and the delayed effects of acute exposure. Animal models, essential for determining MCM efficacy, were developed and validated to assess organ-specific, potentially lethal, radiation effects against the gastrointestinal (GI) and hematopoietic acute radiation syndrome (H-ARS), and radiation-induced delayed effects to lung and associated comorbidities of prolonged immune suppression, GI, kidney and heart injury. Partial-body irradiation models where marginal bone marrow was spared resulted in the ability to evaluate the concomitant evolution of multiple organ injury in the acute and delayed effects in survivors of acute radiation exposure. There are no MCMs for prophylaxis against the major sequelae of the ARS or the delayed effects of acute exposure. Also lacking are MCMs that will mitigate the GI ARS consequent to potentially lethal exposure from a terrorist event or major radiation accident. Additionally, the gap in countermeasures for prophylaxis may extend to mixed neutron/gamma radiation if current modelling predicts prompt exposure from an improvised nuclear device. However, progress in the field of MCM development has been made due to federal and corporate funding, clarification of the critical criteria for efficacy within the FDA AR and the concomitant development and validation of additional animal models. These models provided for a strategic and tactical approach to determine radiation effects and MCM efficacy.
After nuclear accidents, people can be contaminated internally via ingestion, inhalation and via intact skin or wounds. The assessment of absorbed, committed doses after internal exposure is based on activity measurement by in vivo or in vitro bioassay. Estimation of dose following internal contamination is dependent on understanding the nature and form of the radionuclide. Direct counting methods that directly measure γ-rays coming from within the body or bioassay methods that measure the amount of radioactive materials in urine or feces are used to estimate the intake, which is required for calculating internal exposure doses. The interpretation of these data in terms of intake and the lifetime committed dose requires knowledge or making assumptions about a number of parameters (time, type of exposure, route of the exposure, physical, biological and chemical characteristics) and their biokinetics inside the body. Radioactive materials incorporated into the body emit radiation within the body. Accumulation in some specific organs may occur depending on the types of radioactive materials. Decorporation therapy is that acceleration of the natural rate of elimination of the contaminant will reduce the amount of radioactivity retained in the body. This article presents an overview of treatment of radiological contamination after internal contamination.
The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects.
This paper is devoted to the issue of medical care provision to the residents of the Techa riverside settlements affected by long-term radiation exposure. The river was contaminated due to operational and accidental releases of liquid radioactive waste (LRW) by the 'Mayak' Production Association from 1949 to 1956. Contamination of the river and its floodplain with radionuclides, including long-lived 90Sr and 137Cs, caused long-term external and internal exposure of the population, predominantly of the bone marrow. Protective countermeasures (resettlement of residents, introduction of restrictions on the use of the river and floodplain, construction of wells, etc) did not manage to prevent relatively high exposure doses to the population. The mean dose value of bone marrow exposure in residents of the riverside settlements was 0.35 Gy, whereas the maximum values were up to 7.92 Gy. The first medical examinations by mobile teams of the Moscow Institute of Biophysics were started approximately two years after the onset of LRW releases. Since 1955, exposed residents have been followed up and are undergoing medical treatment at the Clinic of the Urals Research Center for Radiation Medicine of the Federal Medical and Biological Agency (URCRM). This center was established in response to the necessity to study the biological effects of the combined external γ-exposure and exposure due to 90Sr in order to arrange medical care for the exposed population. The URCRM Clinic focuses on the provision of hematological care since cases of chronic radiation syndrome were registered among the exposed population in the early period, and increased leukemia incidence has been observed in the long-term period.
A criticality accident occurred at the uranium conversion plant in Tokaimura, Ibaraki Prefecture, Japan on 30 September 1999. When uranyl nitrate was overloaded to a critical mass level, uncontrolled fission reaction occurred. A procedure was carried out according to the JCO manual, although not an officially approved manual. Three workers were heavily exposed to neutrons and γ-rays produced by nuclear fission, and they subsequently developed acute radiation syndrome (ARS). The average doses to the whole body of the three workers were approximately 25, 9, and 3 GyEq (biologically equivalent dose of γ-exposure), respectively; dose distribution analysis later revealed extreme heterogeneity of these doses in two workers. They were triaged according to the predicted clinical needs. Two of these workers developed severe bone marrow failure and received haematopoietic stem cell transplantation: one with peripheral stem cell transplantation from his Human Leukocyte Antigen compatible sister and the other with umbilical cord blood transplantation. The graft was initially successful in both workers; autologous haematopoietic recovery was observed after donor/recipient mixed chimerism in one of them. Despite of all medical efforts available including haematopoietic stem cell transplantation, investigational drugs, skin graft, two workers died of multiple organ involvement and failure 83 and 211 days after the accident, respectively. Clinically as well as pathologically, the direct cause of death was deemed to be intractable gastrointestinal (GI) bleeding in one, and thoraco-abdominal compartment syndrome due to dermal fibrosis/sclerosis in the other. The third worker also developed bone marrow suppression but was treated with granulocyte colony-stimulating factor. He recovered without major complications and is now under periodical medical follow-up. These experiences suggest that treatment of bone marrow is not a limiting factor for saving the life of ARS victims severely exposed. Successful treatment of other organs such as lungs, skin, and GI tract is also essential. Furthermore, the whole-body dose may not always reflect the prognosis of ARS victims because of the nature of accidental exposure, heterogenous exposure.
High-dose radiation exposures of humans occur every year around the world, and may lead to harmful tissue reactions. This review aims to look at the available information sources that can help answering the question of how often these events occur yearly on a global scale. In the absence of comprehensive databases of global occurrence, publications on radiation accidents in all uses of radiation and on rates of high-dose events in different medical uses of radiation have been reviewed. Most high-dose radiation exposures seem to occur in the medical uses of radiation, reflecting the high number of medical exposures performed. In therapeutic medical uses, radiation doses are purposely often given at levels known to cause deterministic effects, and there is a very narrow range in which the medical practitioner can operate without causing severe unacceptable outcomes. In interventional medical uses, there are scenarios in which the radiation dose given to a patient may reach or exceed a threshold for skin effects, where this radiation dose may be unavoidable, considering all benefits and risks as well as benefits and risks of any alternative procedures. Regardless of if the delivered dose is unintended, unnecessary or unavoidable, there are estimates published of the rates of high-dose events and of radiation-induced tissue injuries occurring in medical uses. If this information is extrapolated to a global scenario, noting the inherent limitations in doing so, it does not seem unreasonable to expect that the global number of radiation-induced injuries every year may be in the order of hundreds, likely mainly arising from medical uses of radiation, and in particular from interventional fluoroscopy procedures and external beam radiotherapy procedures. These procedures are so frequently employed throughout the world that even a very small rate of radiation-induced injuries becomes a substantial number when scaled up to a global level.
The accepted generic multiple-parameter and early-response biodosimetry and dosimetry assessment approach for suspected high-dose radiation (i.e. life-threatening) exposure includes measuring radioactivity associated with the exposed individual (if appropriate); observing and recording prodromal signs/symptoms; obtaining serial complete blood counts with white-blood-cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the 'gold standard' dicentric assay (premature chromosome condensation assay for exposures >5 Gy photon acute doses equivalent), measurement of proteomic biomarkers and gene expression assays for dose assessment; bioassay sampling, if appropriate, to determine radioactive internal contamination; physical dose reconstruction, and using other available opportunistic dosimetry approaches. Biodosimetry and dosimetry resources are identified and should be setup in advance along with agreements to access additional national, regional, and international resources. This multifaceted capability needs to be integrated into a biodosimetry/dosimetry 'concept of operations' for use in a radiological emergency. The combined use of traditional biological-, clinical-, and physical-dosimetry should be use in an integrated approach to provide: (a) early-phase diagnostics to guide the development of initial medical-management strategy, and (b) intermediate and definitive assessment of radiation dose and injury. Use of early-phase (a) clinical signs and symptoms, (b) blood chemistry biomarkers, and (c) triage cytogenetics shows diagnostic utility to predict acute radiation injury severity.
Thirty-five years have passed since the moment of the disaster at the Chernobyl nuclear power plant. It is quite a sufficient period to assess the correctness of the organisation of medical care for victims, to summarise the results of monitoring the health status of various groups of persons involved in the accident, including its direct participants. Radiation from a massive source of relatively uniform gamma radiation and a heterogeneous source of beta radiation can cause affected people to develop acute radiation syndrome (ARS) of varying severity, including non-curable forms of the disease ARS developed in 134 patients; 28 patients from 134 with ARS died in a short time (100 d) after exposure. Among the patients whose disease ended in death, 2/3 of the outcome could be due to radiation skin lesions (19 people). Treatment of ARS varying severity, which was combined with common skin burns with beta radiation, requires long-term specialised treatment. The experience of treating this group of patients has demonstrated that the indications for bone marrow transplantation in the curable form of ARS are limited. The percentage of victims who have absolute indications for allogeneic bone marrow transplantation and in whom this procedure will lead to an improved prognosis for life is very small. Recovery of own myelopoiesis and survival are possible after whole-body irradiation from 6 to 8 Gy, which was found after rejection of haploidentical human leucocyte antigen transplantation, as well as in patients who did not use bone marrow transplantation due to the absence of a corresponding donor. Patients who have undergone ARS need lifelong medical supervision and the provision of necessary medical care.
My task is to consider whether haematopoietic cell transplants would be considered appropriate today in persons with features like victims of high-dose and dose-rate ionizing radiations after the Chernobyl nuclear power facility accident in 1986 given knowledge and experience gained over the past 35 years. First I consider the conceptual bases for considering an intervention appropriate and then the metric for deciding whether a transplant is appropriate in similar persons. Data needed to support this decision-making process include estimates of dose, dose-rate, dose uniformity, synchronous or metachronous injuries, donor availability and alternative interventions. Many of these co-variates have substantial uncertainties. Fundamental is a consideration of potential benefit-to-risk and risk-to-benefit ratios under conditions of substantial inaccuracy and imprecision. The bottom line is probably fewer transplants would be done and more victims would receive molecularly-cloned haematopoietic growth factors.