Key outcome summaries of the scientific programme of the IRPA15 congress.

This special issue of JRP includes a selection of research papers and review articles presented at the 15th Congress of the International Radiation Protection Association (IRPA15) as chosen by the scientific committee. All invited journal contributions are suitably expanded beyond the initial conference presentations to meet the criteria for a full journal article and include (a) presentation within a comprehensive radiological protection context and (b) additional data/interpretation. Published contributions address a wide spectrum of scientific topics and concepts to further develop the radiation protection (RP) system. They are based on scientific evidence and available experience in a wide spectrum of applications of the protection system. The IRPA is the international voice of the RP profession. It promotes excellence in RP by providing benchmarks of good practice, enhancing professional competence, and encourages the application of the highest standards of professional conduct, skills and knowledge for the benefit of individuals and society. Within the overarching theme of the conference 'Bridging RP Culture and Science-Widening Public Empathy' IRPA15 provided an invaluable opportunity to discuss and strengthen the relations between RP culture and science, and share developing scientific knowledge and related experience in RP among members of the scientific community, between representatives of key international organizations, including ICRP, IAEA, WHO, and NEA but also with the public. Some discussions focused on the rationale of available RP programmes and priorities, with an opportunity to identify and further develop key scientific issues of the current RP system as well as key processes for the interaction between members of the scientific community and society. The scientific programme of IRPA15 included eight topics and four thematic areas. The topical areas were: Underpinning Science; Dosimetry and Measurement; the System of Protection; Standards and Regulation; Practical Implementation-Medical Sector, as well as Industry and Research; Emergency Preparedness and Response; Existing Exposures and Non-ionizing Radiation. The thematic areas addressed were: Ethics; Communication and Public Understanding; RP Culture; Human Capital and Competency.

Development of operational intervention levels for events with release of radionuclides.

An essential part of a protection strategy for radiological emergencies is the development of national dose criteria and of operational intervention levels (OILs) to decide about protective measures for all ten scenarios Germany is preparing. For the process of planning and implementing such protection strategies as required by the German Radiation Protection Law the Federal Ministry BMU has commissioned the German Radiation Protection Commission (SSK) to recommend dose criteria and OILs for emergency response measures. OILs link a chosen dose criterion for a protective action with a suitable measurement of the contamination situation such as ambient dose rate (µSv h-1), contamination level on surfaces (Bq cm-2) or activity content (Bq g-1, Bq cm-3). This link should adequately model the exposure of persons during a defined exposure period (e.g. seven days, one year) caused by the measured contamination. Dose calculations to quantify OILs should apply assumptions and parameter values that are in tendency realistic and not unduly conservative. OILs have been developed for the following emergency response actions based on radiation measurements:Sheltering on the basis of dose rate (µSv h-1) and contamination level(Bq cm-2).Evacuation on the basis of dose rate (µSv h-1) and contamination level(Bq cm-2).Establishing a radiological hazard area to implement access andcontamination control on the basis of dose rate (µSv h-1) and contaminationlevel (Bq cm-2).Contamination control and possibly decontamination of persons and objects(items, goods, vehicles, etc) based on contamination level (Bq cm-2).A set of precautionary early actions: warning the population not toconsume freshly contaminated food and agricultural measures to reducefood contamination based on dose rate (µSv h-1).Application of maximum permitted levels of radioactive contamination offood and feed (Bq kg-1) according to Euratom Regulation.

Dose limits for occupational exposure to ionising radiation and genotoxic carcinogens: a German perspective.

This paper summarises the view of the German Commission on Radiological Protection ("Strahlenschutzkommission", SSK) on the rationale behind the currently valid dose limits and dose constraints for workers recommended by the International Commission on Radiological Protection (ICRP). The paper includes a discussion of the reasoning behind current dose limits followed by a discussion of the detriment used by ICRP as a measure for stochastic health effects. Studies on radiation-induced cancer are reviewed because this endpoint represents the most important contribution to detriment. Recent findings on radiation-induced circulatory disease that are currently not included in detriment calculation are also reviewed. It appeared that for detriment calculations the contribution of circulatory diseases plays only a secondary role, although the uncertainties involved in their risk estimates are considerable. These discussions are complemented by a review of the procedures currently in use in Germany, or in discussion elsewhere, to define limits for genotoxic carcinogens. To put these concepts in perspective, actual occupational radiation exposures are exemplified with data from Germany, for the year 2012, and regulations in Germany are compared to the recommendations issued by ICRP. Conclusions include, among others, considerations on radiation protection concepts currently in use and recommendations of the SSK on the limitation of annual effective dose and effective dose cumulated over a whole working life.

CHERNOBYL THYROID CANCER: 30 YEARS OF FOLLOW-UP OVERVIEW.

A substantial increase of the thyroid cancer incidence has been observed after the Chernobyl accident in the whole of Belarus and Ukraine, and the four most affected oblasts of the Russian Federation among those exposed as children or adolescents. The dominant risk factor was the thyroid exposure by 131I resulting from the ingestion of milk. A minimum latency period for the identification of the thyroid cancer incidence of 4-5 years has been observed. The cancer incidence among males who were 10 years old at the time of the accident was more than a factor of 4 lower than among females. The incidence data in this age group registered during the period 1991-2015 continuously increased with time to approach a number of 20.000 thyroid cancer cases at the end of this period. From a scientific point of view there is an obligation to pursue programs for long-term medical follow up of the most affected populations. The lessons learned during the past 30 years should be used to improve the standards and criteria for emergency preparedness and response.

Radiological Protection Issues Arising During and After the Fukushima Nuclear Reactor Accident-Memorandum of TG 84 of ICRP.

Observations and lessons identified after the Fukushima accident have been collected and assessed by ICRP Task Group 84. Together with the observations of other expert organizations, they are being used to further develop the current system of protection. While many of the established protection criteria remain valid, improvements are needed in three areas. Key issues related to the need of planning for long-term protective actions (criteria for returning home, dealing with waste) have to be implemented as important elements of the national protection strategies during the preparedness stage. The justification of disruptive protective actions and the protection of vulnerably groups of the population need to be reconsidered to avoid unpleasant imbalances and outcomes. The coexistence of radiation-induced health effects and health effects with social determinants requires consideration of both aspects in decision-making and response.

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban-an oral, direct Factor Xa inhibitor.

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2-3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

Radiological protection issues arising during and after the Fukushima nuclear reactor accident.

Following the Fukushima accident, the International Commission on Radiological Protection (ICRP) convened a task group to compile lessons learned from the nuclear reactor accident at the Fukushima Daiichi nuclear power plant in Japan, with respect to the ICRP system of radiological protection. In this memorandum the members of the task group express their personal views on issues arising during and after the accident, without explicit endorsement of or approval by the ICRP. While the affected people were largely protected against radiation exposure and no one incurred a lethal dose of radiation (or a dose sufficiently large to cause radiation sickness), many radiological protection questions were raised. The following issues were identified: inferring radiation risks (and the misunderstanding of nominal risk coefficients); attributing radiation effects from low dose exposures; quantifying radiation exposure; assessing the importance of internal exposures; managing emergency crises; protecting rescuers and volunteers; responding with medical aid; justifying necessary but disruptive protective actions; transiting from an emergency to an existing situation; rehabilitating evacuated areas; restricting individual doses of members of the public; caring for infants and children; categorising public exposures due to an accident; considering pregnant women and their foetuses and embryos; monitoring public protection; dealing with 'contamination' of territories, rubble and residues and consumer products; recognising the importance of psychological consequences; and fostering the sharing of information. Relevant ICRP Recommendations were scrutinised, lessons were collected and suggestions were compiled. It was concluded that the radiological protection community has an ethical duty to learn from the lessons of Fukushima and resolve any identified challenges. Before another large accident occurs, it should be ensured that inter alia: radiation risk coefficients of potential health effects are properly interpreted; the limitations of epidemiological studies for attributing radiation effects following low exposures are understood; any confusion on protection quantities and units is resolved; the potential hazard from the intake of radionuclides into the body is elucidated; rescuers and volunteers are protected with an ad hoc system; clear recommendations on crisis management and medical care and on recovery and rehabilitation are available; recommendations on public protection levels (including infant, children and pregnant women and their expected offspring) and associated issues are consistent and understandable; updated recommendations on public monitoring policy are available; acceptable (or tolerable) 'contamination' levels are clearly stated and defined; strategies for mitigating the serious psychological consequences arising from radiological accidents are sought; and, last but not least, failures in fostering information sharing on radiological protection policy after an accident need to be addressed with recommendations to minimise such lapses in communication.

State of the art in research into the risk of low dose radiation exposure--findings of the fourth MELODI workshop.

The fourth workshop of the Multidisciplinary European Low Dose Initiative (MELODI) was organised by STUK-Radiation and Nuclear Safety Authority of Finland. It took place from 12 to 14 September 2012 in Helsinki, Finland. The meeting was attended by 179 scientists and professionals engaged in radiation research and radiation protection. We summarise the major scientific findings of the workshop and the recommendations for updating the MELODI Strategic Research Agenda and Road Map for future low dose research activities.

Oscillometric estimation of central blood pressure: validation of the Mobil-O-Graph in comparison with the SphygmoCor device.

BACKGROUND: Hypertension is a major risk factor for a wide range of cardiovascular diseases and is typically identified by measuring blood pressure (BP) at the brachial artery. Although such a measurement may accurately determine diastolic BP, systolic BP is not reflected accurately. Current noninvasive techniques for assessing central aortic BP require additional recording of an arterial pressure wave using a high-fidelity applanation tonometer. Within one measurement cycle, the Mobil-O-Graph BP device uses brachial oscillometric BP waves for a noninvasive estimation of central BP. We therefore validated the Mobil-O-Graph against the SphygmoCor device, which is widely known as the commonly used approach for a noninvasive estimation of central BP. METHODS: For each individual, we compared three readings of the central BP values obtained by the Mobil-O-Graph and SphygmoCor device consecutively. One hundred individuals (mean age 56.1 ± 15.4 years) were recruited for measurement.Differences between the central BP values of the test device and the SphygmoCor device were calculated for each measurement. RESULTS: The mean difference (95% confidence interval) for the estimated central systolic BP between both devices was -0.6 ± 3.7 mmHg. Comparison of the central BP values measured by the two devices showed a statistically significant linear correlation (R=0.91, P<0.0001). The mean between-method difference was 0.50 mmHg for central systolic BP estimation. The intrarater reproducibility between both the devices was also comparable. Bland and Altman analyses showed that the mean differences (95% confidence interval) between repeated measurements were 1.89 (0.42-3.36) mmHg and 1.36 (-0.16 to 2.83) mmHg for the SphygmoCor and the Mobil-O-Graph device, respectively. Thus, neither of these differences was statistically significantly different from 0. The limits of agreement were -16.34 to 19.73 and -15.23 to 17.17 mmHg for the SphygmoCor and the Mobil-O-Graph device, respectively. CONCLUSION: Oscillometric noninvasive estimation of central BP with the Mobil-O-Graph BP device is as effective as using the well-established SphygmoCor applanation tonometry device. In comparison, the Mobil-O-Graph combines the widespread benefits of brachial BP measurement and also provides central BP within one measurement.

Preparing a scientific report to the general assembly on 'exposures due to the nuclear accident following the Great East-Japan earthquake and tsunami'.

At its 58th session in May 2011, the United Nations Committee on the Effects of Atomic Radiation (UNSCEAR) decided to carry out, once sufficient information was available, a full assessment of the levels of exposure and radiation risks attributable to the Fukushima accident. It envisages a preliminary document for consideration at its 59th session in May of 2012 and a more complete report for the 60th session of the Committee in 2013. This paper summarises the aims and objectives of the project, the scope, the working arrangements as well as the relation of the work to other activities.

Childhood leukemia--risk factors and the need for an interdisciplinary research agenda.

The International Agency for Research on Cancer (IARC) has classified high as well as low-frequency fields as "possibly carcinogenic to humans" (Group 2B). For high frequency fields the recent assessment is based mainly on weak positive associations described in some epidemiological studies between glioma and acoustic neuroma and the use of mobile and other wireless phones. Also for lowfrequency fields the evidence is based on epidemiological findings revealing a statistic association between childhood leukemia (CL) and low-level magnetic fields. The basic findings are already 10 years old. They have since been supported by further epidemiological studies. However, the knowledge on the main/crucial question of causality has not improved. This fact and in addition the small, but statistically significant increased incidence of CL in the surrounding of German nuclear power plants have motivated the German Office for Radiation Protection (BfS) to work toward a better understanding of the main causes of CL. A long-term strategic research agenda has been developed which builds on an interdisciplinary, international network and aims at clarifying the aetiology of childhood acute lymphoblastic leukemia.

Evaluation of the efficacy and safety of rivaroxaban using a computer model for blood coagulation.

Rivaroxaban is an oral, direct Factor Xa inhibitor approved in the European Union and several other countries for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is in advanced clinical development for the treatment of thromboembolic disorders. Its mechanism of action is antithrombin independent and differs from that of other anticoagulants, such as warfarin (a vitamin K antagonist), enoxaparin (an indirect thrombin/Factor Xa inhibitor) and dabigatran (a direct thrombin inhibitor). A blood coagulation computer model has been developed, based on several published models and preclinical and clinical data. Unlike previous models, the current model takes into account both the intrinsic and extrinsic pathways of the coagulation cascade, and possesses some unique features, including a blood flow component and a portfolio of drug action mechanisms. This study aimed to use the model to compare the mechanism of action of rivaroxaban with that of warfarin, and to evaluate the efficacy and safety of different rivaroxaban doses with other anticoagulants included in the model. Rather than reproducing known standard clinical measurements, such as the prothrombin time and activated partial thromboplastin time clotting tests, the anticoagulant benchmarking was based on a simulation of physiologically plausible clotting scenarios. Compared with warfarin, rivaroxaban showed a favourable sensitivity for tissue factor concentration inducing clotting, and a steep concentration-effect relationship, rapidly flattening towards higher inhibitor concentrations, both suggesting a broad therapeutic window. The predicted dosing window is highly accordant with the final dose recommendation based upon extensive clinical studies.

A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks.

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim(®) and MoBi(®) capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug-drug, or drug-metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach.

The European strategy on low dose risk research and the role of radiation quality according to the recommendations of the "ad hoc" High Level and Expert Group (HLEG).

Health effects of exposures at low doses and/or low dose rates are recognized as requiring intensive research activity to answer several questions. To address these issues at a strategic level in Europe, with the perspective of integrating national and EC efforts (in particular those within the Euratom research programmes), a "European High Level and Expert Group (HLEG) on low dose risk research" was formed and carried out its work during 2008. The Group produced a report published by the European Commission in 2009 and available on the website http://www.hleg.de . The more important research issues identified by the HLEG were as follows: (a) the shape of dose-response for cancer; (b) the tissue sensitivities for cancer induction; (c) the individual variability in cancer risk; (d) the effects of radiation quality (type); (e) the risks from internal radiation exposure; and (f) the risks of, and dose response relationships for, non-cancer diseases. In this paper, the radiation quality issues are especially considered, since they are closely linked to health problems and related radioprotection in space and in emerging radiotherapeutic techniques (i.e., hadrontherapy). The peculiar features of low-fluence, high-LET radiation exposures can question in particular the validity of the radiation-weighting factor (w ( R )) approach. Specific strategies are therefore needed to assess such risks. A multi-scale/systems biology approach, based on mechanistic studies coordinated with molecular-epidemiological studies, is considered essential to elucidate differences and similarities between specific effects of low- and high-LET radiation.

Noninvasive detection of lung cancer by analysis of exhaled breath.

BACKGROUND: Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless. METHODS: Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers. RESULTS: Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS-results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons. CONCLUSION: GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important.

Determination of volatile organic compounds in exhaled breath of patients with lung cancer using solid phase microextraction and gas chromatography mass spectrometry.

BACKGROUND: Analysis of exhaled breath is a promising diagnostic method. Sampling of exhaled breath is non-invasive and can be performed as often as considered desirable. There are indications that the concentration and presence of certain of volatile compounds in exhaled breath of lung cancer patients is different from concentrations in healthy volunteers. This might lead to a future diagnostic test for lung cancer. METHODS: Exhaled breath samples from 65 patients with different stages of lung cancer and undergoing different treatment regimes were analysed. Mixed expiratory and indoor air samples were collected. Solid phase microextraction (SPME) with carboxen/polydimethylsiloxane (CAR/PDMS) sorbent was applied. Compounds were analysed by means of gas chromatography (GC) and mass spectrometry (MS). RESULTS: The method we used allowed identification with the spectral library of 103 compounds showing at least 15% higher concentration in exhaled breath than in inhaled air. Among those 103 compounds, 84 were confirmed by determination of the retention time using standards based on the respective pure compound. Approximately, one third of the compounds detected were hydrocarbons. We found aromatic hydrocarbons, alcohols, aldehydes, ketones, esters, ethers, sulfur compounds, nitrogen-containing compounds and halogenated compounds. Acetonitrile and benzene were two of 10 compounds which correlated with smoking behaviour. A comparison of results from cancer patients with those of 31 healthy volunteers revealed differences in the concentration and presence of certain compounds. The sensitivity for detection of lung cancer patients based on eight different compounds not seen in exhaled breath of healthy volunteers was 51% and the specificity was 100%. These eight potential markers for detection of lung cancer are 1-propanol, 2-butanone, 3-butyn-2-ol, benzaldehyde, 2-methyl-pentane, 3-methyl-pentane, n-pentane and n-hexane. CONCLUSIONS: SPME is a relatively insensitive method and compounds not observed in exhaled breath may be present at a concentration lower than LOD. The main achievement of the present work is the validated identification of compounds observed in exhaled breath of lung cancer patients. This identification is indispensible for future work on the biochemical sources of these compounds and their metabolic pathways.

Single-institution results of primary external-beam radiation for the treatment of t1-t3 prostate cancer.

PURPOSE: To evaluate survival and toxicity rates after primary external-beam radiation for the treatment of prostate cancer. PATIENTS AND METHODS: Data of 306 patients treated with conformal external beam radiation between 1996 and 2001 were collected. These were evaluated in terms of overall, cause-specific and disease-free survival as well as toxicity. Furthermore, an investigation of possible risk factors was performed. RESULTS: Toxicity rates compared favorably with other series with 5.2% RTOG 1-2 and no RTOG > 2 long-term side effects. Actuarial 5-year overall survival rates with and without biochemical failure were 77% versus 78%, cancer-specific survival was 85.41% versus 100%, and disease-free survival was 71.54%, respectively. Potential risk factors for cancer-related death were biochemical failure, initial serum prostate-specific antigen (PSA) and Gleason score. CONCLUSION: Toxicity rates were found to be surprisingly low compared to other series, which is likely due to low daily dose and consistent MR-based treatment planning. In terms of survival, no significant differences to other trials could be observed. Initial PSA and Gleason score were significant predictors for treatment outcome in terms of survival.