Reference values of electrographic and cardiac ultrasound parameters in Russian healthy children and adolescents.

Between 2009 and 2013, a large cross-sectional study on the health consequences of the Chernobyl nuclear accident was performed in the contaminated and uncontaminated territories of the Bryansk Oblast (Russian Federation). The objective of this work was to confirm or refute a possible association between childhood cardiac arrhythmia and a chronic exposure to caesium-137. As part of this study, a large number of electrocardiographic and cardiac ultrasound parameters were collected from 18,152 children aged 2-18 years including 12,512 healthy ones not contaminated with caesium-137. It seemed therefore relevant for us to share in a second publication these medical data based on healthy and uncontaminated children with the scientific community because of the large quantities and the limited availability of such kind of data. In the present study, relating to electrocardiographic parameters, the measurements performed fully reflect the expected evolution of the paediatric electrocardiogram between 5 and 18 years of age. Thus, the median values were generally quite close to those available in the literature. In contrast, differences in the 2nd and 98th percentiles were notable and could be explained in particular by the type of equipment used, the number of subjects included in the study and racial disparities. As for echocardiographic parameters, the evolution of the measured values in age groups is consistent with what was expected considering factors such as growth. In comparison with other scientific studies that have investigated these echocardiographic parameters, some differences by age groups have been identified. The ethnic factor truly appears to be a relevant feature to consider. In view of the results, it appeared essential to the authors to approach the methodological conditions of the scientific studies already published on the topic to be truly comparable and thus to provide a reliable answer on a topic for which real expectations in terms of medical care are required.

Radiation-induced lens opacities: Epidemiological, clinical and experimental evidence, methodological issues, research gaps and strategy.

In 2011, the International Commission on Radiological Protection (ICRP) recommended reducing the occupational equivalent dose limit for the lens of the eye from 150 mSv/year to 20 mSv/year, averaged over five years, with no single year exceeding 50 mSv. With this recommendation, several important assumptions were made, such as lack of dose rate effect, classification of cataracts as a tissue reaction with a dose threshold at 0.5 Gy, and progression of minor opacities into vision-impairing cataracts. However, although new dose thresholds and occupational dose limits have been set for radiation-induced cataract, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological and mechanistic evidence at doses under 2 Gy. Since the release of the 2011 ICRP statement, the Multidisciplinary European Low Dose Initiative (MELODI) supported in April 2019 a scientific workshop that aimed to review epidemiological, clinical and biological evidence for radiation-induced cataracts. The purpose of this article is to present and discuss recent related epidemiological and clinical studies, ophthalmic examination techniques, biological and mechanistic knowledge, and to identify research gaps, towards the implementation of a research strategy for future studies on radiation-induced lens opacities. The authors recommend particularly to study the effect of ionizing radiation on the lens in the context of the wider, systemic effects, including in the retina, brain and other organs, and as such cataract is recommended to be studied as part of larger scale programs focused on multiple radiation health effects.

Hto, Tritiated Amino Acid Exposure and External Exposure Induce Differential Effects on Hematopoiesis and Iron Metabolism.

The increased potential for tritium releases from either nuclear reactors or from new facilities raises questions about the appropriateness of the current ICRP and WHO recommendations for tritium exposures to human populations. To study the potential toxicity of tritium as a function of dose, including at a regulatory level, mice were chronically exposed to tritium in drinking water at one of three concentrations, 10 kBq.l-1, 1 MBq.l-1 or 20 MBq.l-1. Tritium was administered as either HTO or as tritiated non-essential amino acids (TAA). After one month's exposure, a dose-dependent decrease in red blood cells (RBC) and iron deprivation was seen in all TAA exposed groups, but not in the HTO exposed groups. After eight months of exposure this RBC decrease was compensated by an increase in mean globular volume - suggesting the occurrence of an iron deficit-associated anemia. The analysis of hematopoiesis, of red blood cell retention in the spleen and of iron metabolism in the liver, the kidneys and the intestine suggested that the iron deficit was due to a decrease in iron absorption from the intestine. In contrast, mice exposed to external gamma irradiation at equivalent dose rates did not show any change in red blood cell numbers, white blood cell numbers or in the plasma iron concentration. These results showed that health effects only appeared following chronic exposure to concentrations of tritium above regulatory levels and the effects seen were dependent upon the speciation of tritium.

Repeated KI Prophylaxis in Case of Prolonged Exposure to Iodine Radioisotopes: Pharmacokinetic Studies in Adult Rats.

PURPOSE: To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case of prolonged exposure to radioactive iodine. METHODS: The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters. RESULTS: A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KI between 174 and 1190 µg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showed that the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decrease in iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses. CONCLUSION: Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.

DO MULTIPLE ADMINISTRATIONS OF STABLE IODINE PROTECT POPULATION CHRONICALLY EXPOSED TO RADIOACTIVE IODINE: WHAT IS PRIODAC RESEARCH PROGRAM (2014-22) TEACHING US?

Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here.

In vivo animal studies help achieve international consensus on standards and guidelines for health risk estimates for chronic exposure to low levels of tritium in drinking water.

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Cytogenetic damage analysis in mice chronically exposed to low-dose internal tritium beta-particle radiation.

The aim of this study was to carry out a comprehensive examination of potential genotoxic effects of low doses of tritium delivered chronically to mice and to compare these effects to the ones resulting from equivalent doses of gamma-irradiation. Mice were chronically exposed for one or eight months to either tritiated water (HTO) or organically bound tritium (OBT) in drinking water at concentrations of 10 kBq/L, 1 MBq/L or 20 MBq/L. Dose rates of internal ß-particle resulting from such tritium treatments were calculated and matching external gamma-exposures were carried out. We measured cytogenetic damage in bone marrow and in peripheral blood lymphocytes (PBLs) and the cumulative tritium doses (0.009 - 181 mGy) were used to evaluate the dose-response of OBT in PBLs, as well as its relative biological effectiveness (RBE). Neither tritium, nor gamma exposures produced genotoxic effects in bone marrow. However, significant increases in chromosome damage rates in PBLs were found as a result of chronic OBT exposures at 1 and 20 M Bq/L, but not at 10 kBq/L. When compared to an external acute gamma-exposure ex vivo, the RBE of OBT for chromosome aberrations induction was evaluated to be significantly higher than 1 at cumulative tritium doses below 10 mGy. Although found non-existent at 10 kBq/L (the WHO limit), the genotoxic potential of low doses of tritium (>10 kBq/L), mainly OBT, may be higher than currently assumed.

Is exposure to ionising radiation associated with childhood cardiac arrhythmia in the Russian territories contaminated by the Chernobyl fallout? A cross-sectional population-based study.

OBJECTIVE: To investigate childhood cardiac arrhythmia and chronic exposure to caesium-137 (137Cs) resulting from the Chernobyl accident. DESIGN: Prospective cross-sectional study using exposed/unexposed design conducted in the Bryansk region from May 2009 to May 2013 on children selected on the basis of 137Cs soil deposition: control territories ([137Cs]<37 kBq per square metre, where children were considered as unexposed) and contaminated territories ([137Cs]>555 kBq per square metre, where children were considered as exposed). SETTING: Russian territories affected by the Chernobyl fallout (Bryansk region). PARTICIPANTS: This cross-sectional study included 18 152 children aged 2-18 years and living in the Bryansk region (Russia). MAIN OUTCOME MEASURES: All children received three medical examinations (ECG, echocardiography and 137Cs whole-body activity measurement) and some of them were given with a 24-hour Holter monitoring and blood tests. RESULTS: Cardiac arrhythmia was diagnosed in 1172 children living in contaminated territories and 1354 children living in control territories. The crude prevalence estimated to 13.3% in contaminated territories was significantly lower than in control territories with 15.2% over the period 2009-2013 (P<0.001). Considering 137Cs whole-body burden as exposure, cardiac arrhythmia was found in 449 contaminated children and 2077 uncontaminated children, corresponding to an estimated crude prevalence of 14.5% and 14.2%, respectively, which does not differ significantly (P=0.74). Also, we investigated the association between territory, exposure to 137Cs and cardiac arrhythmia: the adjusted OR was not significant (0.90 with 95% CI 0.81 to 1.00; P=0.06) for the territory. For 137Cs whole-body burden, the ORs close to 1 did not reach statistical significance (P for trend=0.97). CONCLUSION: This study does not observe an association between cardiac arrhythmia and 137Cs deposition levels in the Bryansk region exposed to Chernobyl fallout. The suspected increase of cardiac arrhythmia in children exposed to Chernobyl fallout is not confirmed.

Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat.

BACKGROUND: A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. METHODS: Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. RESULTS: hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (-58% and -26% respectively), followed by a delayed decrease of TPO mRNA expression (-33%) in conjunction with a stimulation of PDS mRNA expression (+62%). CONCLUSION: we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones.

Optimal KI Prophylactic Dose Determination for Thyroid Radiation Protection After a Single Administration in Adult Rats.

A dose-response study was performed in adult rats to select an optimal stable potassium iodide (KI) dose which could be implemented in repeated prophylaxis, in case of prolonged exposure to radioactive iodine. Increasing doses of KI were given orally to rats 1 hour before internal exposure simulated by I-125 injection. I-125 incorporation in the thyroid was measured by γ-spectrometry, and KI protection effect was modeled by pharmacological functions. The measurement method by inductively coupled plasma mass spectrometry previously developed for the quantification of stable iodine in urine was adapted to correlate KI effect with its distribution in the thyroid. More than 75% blockade of iodine I-125 incorporation in the thyroid was achieved for KI single doses above 0.5 to 0.7 mg/kg. Stable iodine content in the thyroid 24 hours after KI administration displayed a biphasic response, with a maximum level for a dose around 1 mg/kg. Besides, the urinary excretion of stable iodine is described by a sigmoid function. The change in the rate of iodine excretion for doses above 1 mg/kg KI suggests a body overload in iodine and corroborates a possible saturation of the thyroid. The results show that 1 mg/kg KI could be regarded as an optimal dose for thyroid protection.

Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop.

In recent years, there has been increasing concern over the possibility of a radiological or nuclear incident occurring somewhere in the world. Intelligence agencies frequently report that terrorist groups and rogue nations are seeking to obtain radiological or nuclear weapons of mass destruction. In addition, there exists the real possibility that safety of nuclear power reactors could be compromised by natural (such as the tsunami and subsequent Fukushima accident in Japan in March, 2011) or accidental (Three Mile Island, 1979 and Chernobyl, 1986) events. Although progress has been made by governments around the world to prepare for these events, including the stockpiling of radiation countermeasures, there are still challenges concerning care of patients injured during a radiation incident. Because the deleterious and pathological effects of radiation are so broad, it is desirable to identify medical countermeasures that can have a beneficial impact on several tissues and organ systems. Cellular therapies have the potential to impact recovery and tissue/organ regeneration for both early and late complications of radiation exposure. These therapies, which could include stem or blood progenitor cells, mesenchymal stromal cells (MSCs) or cells derived from other tissues (e.g., endothelium or placenta), have shown great promise in treating other nonradiation injuries to and diseases of the bone marrow, skin, gastrointestinal tract, brain, lung and heart. To explore the potential use of these therapies in the treatment of victims after acute radiation exposure, the National Institute of Allergy and Infectious Diseases co-sponsored an international workshop in July, 2015 in Paris, France with the Institut de Radioprotection et de Sûreté Nucléaire. The workshop included discussions of data available from testing in preclinical models of radiation injury to different organs, logistics associated with the practical use of cellular therapies for a mass casualty incident, as well as international regulatory requirements for authorizing such drug products to be legally and readily used in such incidents. This report reviews the data presented, as well as key discussion points from the meeting.

Multidisciplinary European low dose initiative: an update of the MELODI program.

PURPOSE: This paper provides an update and summary on the organization of European research in the field of low dose risk and radiation protection. To address declining resources and competence in radiation protection and related research across European countries, a High Level and Expert Group (HLEG) was established in 2007. The HLEG identified key policy and scientific questions to be addressed through a strategic research agenda for low dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). Dr Bill Morgan closely followed the European low dose programme and chaired the international Advisory Boards of DoReMi Network of Excellence and the MELODI platform. CONCLUSION: The MELODI research platform is dedicated to low dose ionizing radiation risk. In 2010, MELODI was founded as a registered association with 15 members. As of September 2016, the association´s membership increased to 46. A major activity of MELODI is the establishment and updating of a long-term Strategic Research Agenda (SRA) for research on low dose risk in Europe. The SRA is intended to guide the priorities for national and European research programmes and the preparation of competitive calls at the European level. A key priority for radiation protection research is to improve health risk estimates for exposures corresponding to the dose limits for occupational exposures and to reference levels for the exposure of the population in emergency situations.

Tritium ( 3 H) Retention In Mice: Administered As HTO, DTO or as 3 H-Labeled Amino-Acids.

The objective of this study was to compare the biokinetics of injected H-labeled light (HTO) and heavy (DTO) water in CBA/CaJ mice and to compare the organ distribution and/or body content of H administered by chronic ingestion for 1 mo to C57Bl/6J mice, as either H-labeled water or H-labeled amino acids (glycine, alanine and proline). HTO and DTO were administered to CBA/CaJ mice by single intraperitoneal injection and body retention was determined for up to 384 h post-injection. Tritium-labeled water or H-labeled amino acids were given to C57Bl/6J mice ad libitum for 30 d in drinking water. Body content and organ distribution of H during the period of administration and subsequent to administration was determined by liquid scintillation counting. No differences were found between the biokinetics of HTO and DTO, indicating that data generated using HTO can be used to help assess the consequences of H releases from heavy water reactors. The results for H-water showed that the concentration of radionuclide in the mice reached a peak after about 10 d and dropped rapidly after the cessation of H administration. The maximum concentration reached was only 50% of that in the water consumed, indicating that mice receive a significant fraction of their water from respiration. Contrary to the findings of others, the pattern of H retention following the administration of a cocktail of the labeled amino acids was very little different from that found for the water. This is consistent with the suggestion that most of the ingested amino acids were rapidly metabolized, releasing water and carbon dioxide.

Environmentally Relevant Chronic Low-Dose Tritium and Gamma Exposures do not Increase Somatic Intrachromosomal Recombination in pKZ1 Mouse Spleen.

The toxicity of tritium is a public health concern given its presence and mobility in the environment. For risk predictions using radiological protection models, it is essential to allocate an appropriate radiation weighting factor (WR). This in turn should be consistent with the observed relative biological effectiveness (RBE) of tritium beta radiation. Although the International Commission on Radiological Protection (ICRP) currently recommends a WR of 1 for the calculation of committed effective dose for X rays, gamma rays and electrons of all energies, including tritium energies, there are concerns that tritium health risks are underestimated and that current regulatory tritium drinking water standards need revision. In this study, we investigated potential cytotoxic and genotoxic effects in mouse spleen after one month and eight months of chronic exposure to low-dose tritiated water (HTO). The dose regimes studied were designed to mimic human chronic consumption of HTO at levels of 10 kBq/l, 1 MBq/l and 20 MBq/l. The total doses from these radiation exposures ranged from 0.01 to 180 mGy. We also compared the biological effects of exposure to HTO with equivalent exposure to external whole-body 60Co gamma rays. Changes in spleen weight and somatic intrachromosomal recombination (DNA inversions) in spleen tissue of pKZ1Tg/+ mice were monitored. Our results showed no overall changes in either spleen organ weights and no increase mouse splenic intrachromosomal recombination frequencies, indicating that current drinking water standards for tritium exposure in the form of HTO are likely to be adequately protective against cytotoxic and genotoxic damage in spleen. These results demonstrate no evidence for cytotoxicity or genotoxicity in mouse spleen following chronic exposures to HTO activities (or equivalent gamma doses) up to 20 MBq/L.

The First Meeting of the WHO Guideline Development Group for the Revision of the WHO 1999 Guidelines for Iodine Thyroid Blocking.

The meeting held in May 2014 in Würzburg, Germany, discussed the scope of the revision of the 1999 WHO guidelines for iodine thyroid blocking (ITB) by following the WHO handbook for guideline development. This article describes the process and methods of developing the revised, evidence-based WHO guidelines for ITB following nuclear and radiological accidents, the results of the kick-off meeting as well as further steps taken to complete the revision.

Managing Internal Radiation Contamination Following an Emergency: Identification of Gaps and Priorities.

Following a radiological or nuclear emergency, first responders and the public may become internally contaminated with radioactive materials, as demonstrated during the Goiânia, Chernobyl and Fukushima accidents. Timely monitoring of the affected populations for potential internal contamination, assessment of radiation dose and the provision of necessary medical treatment are required to minimize the health risks from the contamination. This paper summarizes the guidelines and tools that have been developed, and identifies the gaps and priorities for future projects.

Improved communication, understanding of risk perception and ethics related to ionising radiation.

In Europe today, institutions, media and the general public exchange information about ionizing radiation and associated risks. However, communication about ionising radiation with the general public has to be further improved, as has been previously highlighted by international responses to the 2011 accident in Japan. This article reports the main activities and findings in this field from the following three FP7 projects: EAGLE, PREPARE and OPERRA and discussed by a broad spectrum of stakeholders at the conference RICOMET 2015. These projects, among other aims, also investigate how communication about ionising radiation in different fields could be improved and harmonised, how radiological risks are perceived, how to encourage ethical considerations in all fields of nuclear applications and what kind of transdisciplinary research is needed. The projects relate to several domains; the first relates to education, training and communication, the second to nuclear emergency preparedness and response, and the third to research and development in the radiation protection field. Incorporation of stakeholder engagement activities such as the RICOMET conference broadens social and ethical aspects and takes them into account during coordination activities as well as during core scientific and nuclear research and development performed in the projects. These activities offered opportunities for moving closer to a citizen-centred ideal of risk communication in particular and nuclear research and development in general.

Mass Casualty Decontamination in a Chemical or Radiological/Nuclear Incident with External Contamination: Guiding Principles and Research Needs.

Hazardous chemical, radiological, and nuclear materials threaten public health in scenarios of accidental or intentional release which can lead to external contamination of people.  Without intervention, the contamination could cause severe adverse health effects, through systemic absorption by the contaminated casualties as well as spread of contamination to other people, medical equipment, and facilities.  Timely decontamination can prevent or interrupt absorption into the body and minimize opportunities for spread of the contamination, thereby mitigating the health impact of the incident.  Although the specific physicochemical characteristics of the hazardous material(s) will determine the nature of an incident and its risks, some decontamination and medical challenges and recommended response strategies are common among chemical and radioactive material incidents.  Furthermore, the identity of the hazardous material released may not be known early in an incident.  Therefore, it may be beneficial to compare the evidence and harmonize approaches between chemical and radioactive contamination incidents.  Experts from the Global Health Security Initiative's Chemical and Radiological/Nuclear Working Groups present here a succinct summary of guiding principles for planning and response based on current best practices, as well as research needs, to address the challenges of managing contaminated casualties in a chemical or radiological/nuclear incident.

Low-dose ionising radiation and cardiovascular diseases--Strategies for molecular epidemiological studies in Europe.

It is well established that high-dose ionising radiation causes cardiovascular diseases. In contrast, the evidence for a causal relationship between long-term risk of cardiovascular diseases after moderate doses (0.5-5 Gy) is suggestive and weak after low doses (<0.5 Gy). However, evidence is emerging that doses under 0.5 Gy may also increase long-term risk of cardiovascular disease. This would have major implications for radiation protection with respect to medical use of radiation for diagnostic purposes and occupational or environmental radiation exposure. Therefore, it is of great importance to gain information about the presence and possible magnitude of radiation-related cardiovascular disease risk at doses of less than 0.5 Gy. The biological mechanisms implicated in any such effects are unclear and results from epidemiological studies are inconsistent. Molecular epidemiological studies can improve the understanding of the pathogenesis and the risk estimation of radiation-induced circulatory disease at low doses. Within the European DoReMi (Low Dose Research towards Multidisciplinary Integration) project, strategies to conduct molecular epidemiological studies in this field have been developed and evaluated. Key potentially useful European cohorts are the Mayak workers, other nuclear workers, uranium miners, Chernobyl liquidators, the Techa river residents and several diagnostic or low-dose radiotherapy patient cohorts. Criteria for informative studies are given and biomarkers to be investigated suggested. A close collaboration between epidemiology, biology and dosimetry is recommended, not only among experts in the radiation field, but also those in cardiovascular diseases.