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.

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.

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.

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.

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.

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.

Thyroid artery erosion by esophageal cancer: management with interventional radiology.

Management of upper gastrointestinal bleeding because of erosion of vessels by esophageal cancer may be challenging. We present herein the angiographic images of a 49-year-old patient who was admitted with massive bleeding from a tumor-eroded inferior thyroid artery. Attempts to control the bleeding by means of flexible endoscopy and insertion of a Sengstaken-Blakemore tube had failed. The diagnosis was impressively demonstrated by multislice computed tomography with intravenous contrast in the arterial phase and multiplanar reconstructions (computed tomography angiography) and by digital subtraction angiography. The bleeding was successfully treated with superselective catheterization and coiling of the eroded vessel.

Diguanosine pentaphosphate: an endogenous activator of Rho-kinase possibly involved in blood pressure regulation.

OBJECTIVE: Rho-kinase activity is increased in cardiovascular disease and in the pathophysiology of hypertension. Few endogenous factors are known that activate the Rho-kinase pathway. Stimulation of P2Y receptors activates the Rho-kinase pathway. Recently identified diguanosine pentaphosphate (Gp5G) possibly activates P2Y receptors. In this study, Gp5G was identified and quantified in human plasma. The influence of Gp5G on vascular tone was studied. METHODS: Gp5G in human plasma was purified to homogeneity by several steps. Gp5G was quantified and identified by matrix-assisted laser desorption/ionization mass spectrometry and enzymatic analysis. The vasoactive effects of Gp5G were studied in the isolated perfused rat kidney and after intra-aortic application. Activation of Rho-kinase was measured using western blot analysis. RESULTS: The plasma level of Gp5G in healthy donors is 9.47 +/- 4.97 nmol/l. Gp5G increases contractile responses induced by angiotensin II in a dose-dependent way [ED50 (-log mol) angiotensin II: 10.9 +/- 0.1; angiotensin II plus Gp5G (100 nmol/l): 11.5 +/- 0.1]. P2 receptor antagonists inhibited the Gp5G-induced increase in angiotensin II vasoconstriction. MRS2179, a selective P2Y1 receptor antagonist, had no effect on Gp5G-mediated angiotensin II potentiation. Rho-kinase inhibition by Y27632 abolished the Gp5G-induced increase of contractile responses to angiotensin II. Concentrations of 10 nmol/l Gp5G activated the translocation of RhoA from the cytosolic to the membranous fraction indicating the activation of Rho-kinase. The intra-aortic application of 100 pmol Gp5G significantly increased mean arterial blood pressure by 13.5 +/- 4.2 mmHg. CONCLUSION: Gp5G is an endogenous activator of Rho-kinase, which might affect vascular tone control by Rho-kinase at physiological levels. Gp5G activates P2Y4&6 receptors, and might play a role in physiological and pathophysiological vascular tone control.

Prophylaxis of contrast material-induced nephropathy in patients in intensive care: acetylcysteine, theophylline, or both? A randomized study.

PURPOSE: To prospectively compare the protective effect of acetylcysteine, theophylline, and both agents combined in patients who are admitted to the intensive care unit with at least one risk factor for contrast material-induced nephropathy and who receive at least 100 mL of iodinated contrast medium. MATERIALS AND METHODS: Institutional ethics review board approval and informed consent were obtained. A total of 91 patients (mean age, 58.5 years+/-14.8 [standard deviation]; 31 women, 60 men; 150 examinations) were admitted to the intensive care unit with at least one risk factor for contrast-induced nephropathy and received either (a) 200 mg theophylline 30 minutes before contrast medium administration (group T), (b) 600 mg acetylcysteine twice daily on the day of and (if possible) the day before the examination (group A), or (c) both agents combined (group AT). The primary endpoint for this study was the incidence of contrast-induced nephropathy (chi2 test). RESULTS: Groups T, A, and AT were comparable with regard to baseline creatinine levels and the amount of contrast medium administered. The incidence of contrast-induced nephropathy in groups T, A, and AT was 2%, 12%, and 4%, respectively, and was significantly lower in group T than in group A (P=.047). There was no significant difference in the incidence of contrast-induced nephropathy between groups A and AT (P=.148) or between groups T and AT (P=.53). For group A, serum creatinine did not change after 12, 24, or 48 hours compared with baseline. Creatinine levels in group T decreased 12 hours (1.19 mg/dL+/-0.58; P=.008) and 48 hours (1.16 mg/dL+/-0.55; P=.034) after contrast material injection compared with baseline (1.25 mg/dL+/-0.61). In group AT, creatinine significantly decreased 24 hours (1.21 mg/dL+/-0.74; P=.003) and 48 hours (1.17 mg/dL+/-0.69; P<.001) after contrast material injection compared with baseline (1.28 mg/dL+/-0.74). Group A had significantly higher maximal increases in creatinine than groups T and AT (P=.014). CONCLUSION: For prophylaxis of contrast-induced nephropathy in patients who are admitted to the intensive care unit and who receive 100 mL or more of contrast medium, theophylline is superior to acetylcysteine.

Role of adhesion molecules in the induction of restenosis after angioplasty in the lower limb.

OBJECTIVE: The adhesion molecules P selectin, E selectin, intercellular adhesion molecule, vascular cellular adhesion molecule (VCAM), and monocyte chemoattractant protein 1 play a important role in the development of arteriosclerotic lesions and are considered main contributors to restenosis after angioplasty. We expected that the serum levels of these markers would increase in the early phase of the first few weeks after angioplasty. METHODS: We assessed prospectively the levels of soluble forms of adhesion molecules on the day before and then 24 hours and 2 and 4 weeks after angioplasty in arteries of the lower limb by using enzyme-linked immunosorbent assays. We investigated the distribution pattern of these markers in 44 patients (25 male and 19 female; age, 67.7 +/- 8.5 years [mean +/- SD]) presenting with intermittent claudication (Fontaine stage IIb). Twelve patients (27.3%) underwent diagnostic angiography, 32 (72.2%) received interventional treatment, 22 (68.8%) received balloon angioplasty, and 10 (31.2%) required stent placement. RESULTS: Ten (31.3%) of the treated patients developed restenosis within 6 months. These patients had significantly higher levels of P selectin (P = .034), E selectin (P = .006), and VCAM (P = .050) at all time points. E selectin, VCAM, and monocyte chemoattractant protein 1 levels increased between 24 hours and 4 weeks after angiographic procedures, thus indicating that the angiographic procedure itself leads to activation and inflammation of the endothelium. CONCLUSIONS: This study emphasizes a meaningful role of the adhesion molecules E selectin, P selectin, and VCAM as interesting contributors to restenosis formation after percutaneous transluminal angioplasty.