Group Radiation Risk - Projects

Mission: Assessment of personalized health risks from radiation exposure for clinics and population

The Research Group Radiation Risk investigates health risks from exposures to ionizing radiation. Models of carcinogenesis and cardiovascular diseases are developed and applied for assessment of radiation-induced risk. These models can be used in all areas of exposure to ionising radiation.  Research is focused on risk assessment for medical therapeutic and diagnostic procedures.

PASSOS: Personalised assessment of late health risks after exposure to ionising radiation and guidance for radiation applications in medicine

Project title: PASSOS: Personalisierte Abschätzung von Spätfolgen nach Strahlenexposition und Orientierungshilfe für Strahlenanwendungen in der Medizin
Period: 1 January 2013 - 31 December 2016
Funding institution: Federal Ministry of Education and Research, Kompetenzverbund Strahlenforschung (KVSF)
Total budget: 2.780.000 €
Coordinator: Dr.  Markus Eidemüller
Scientific personnel: Dr. Markus Eidemüller, Dr. Alexander Ulanowski, Dr. Cristoforo Simonetto, Dr. Pavel Kundrat, Noemi Castelletti, Elena Shemiakina und Dr. Denise Güthlin
Number of partner institutions: 9
Link: PASSOS

The aim of PASSOS is the assessment of the risk of cancer and cardiovascular diseases after medical radiation exposure taking into account individual patient factors. Applications of breast cancer therapy and cardiac diagnostic procedures are investigated. In both application cases PASSOS concentrates on diseases with good prognosis, i.e. with expected survival times of many years. Therefore the assessment of late health risks after exposure is of high relevance from a medical, societal and socio-economic viewpoint.

For different procedures of breast cancer treatment and cardiac diagnostics the dose distribution in the organs is calculated, taking into account individual properties of the patients. Risk models including individual risk factors for all cancer sites and cardiovascular diseases must be developed. A particular challenge lies in the large range of exposures from low (10 mGy) to therapeutic doses (> 4 Gy).

A software package for the assessment of late health risks with two modes of operation will be developed, one for given organ dose distributions, and one for different radiation applications for breast cancer and cardiac diseases. The aim is to provide guidance to medical doctors for the personalised choice of different therapy and diagnostic procedures.

Contact person: Dr. Markus Eidemüller

CONCERT

Project title: CONCERT - European Joint Programme for the Integration of Radiation Protection Research
Period: 1 June 2015 - 31 Mai 2020
Funding organisation: European Commission
Scientific personnel: Dr. Markus Eidemüller
Links: CONCERT, MELODI, DoReMi, HLEG
Documents: MELODIE SRA (09/2016), DoReMi TRA (03/2016), HLEG Report (01/2009)

The ‘CONCERT-European Joint Programme for the Integration of Radiation Protection Research’ under Horizon 2020 is operating as an umbrella structure for the research initiatives jointly launched by the radiation protection research platforms MELODI, ALLIANCE, NERIS and EURADOS. CONCERT is a co-fund action that aims at attracting and pooling national research efforts with European ones in order to make better use of public R&D resources and to tackle common European challenges in radiation protection more effectively by joint research efforts in key areas.

Back in 2009, the European High Level and Expert Group (HLEG) identified key policies and scientific questions to be addressed through a Strategic Research Agenda (SRA) for low dose radiation risks. Subsequently, institutions active in radiation protection research in Europe have founded the European Research Platform MELODI. Major outcome of MELODI is the development of an SRA in low dose risk research and the recommendation of short to medium term research priorities. Similar activities in the fields of radioecology and nuclear emergency preparedness led to the establishment of the research platforms ALLIANCE and NERIS, respectively. Today CONCERT is in a position, to integrate the research efforts off all these platforms (EURADOS as a long-standing organisation joined the platform family) under one umbrella structure, to jointly address common research needs in radiation protection and to organize funding of research projects.

Based on the platform SRAs and joint programming, CONCERT will develop research priorities, align them with priorities from participating Member States and will seek further input from society and stakeholders. It will reach out to engage the wider scientific community in its projects, aiming to answer the needs in radiation protection for the public, occupationally exposed people, patients in medicine, and the environment.

Contact person: Dr. Markus Eidemüller

CONFIDENCE

Period: 1 January 2017 - 31 December 2019
Funding organisation: European Commission
Scientific personnel: Dr. Alexander Ulanowski, Elena Shemiakina
Link: CONFIDENCE

Within the Task 2.3 “Health risk assessment” of the CONFIDENCE project, the radiation-associated risk of malignant diseases following accidental exposures for all solid cancer, thyroid cancer, female breast cancer, and leukemia are studied and modelled. Given plausible emergency contamination and population exposure scenarios, a user-friendly software tool will be developed and will allow for quick lifetime risk projections for the affected population groups. Robust phenomenological risk models, compatible to those recently applied by WHO for assessing health effects of the Fukushima accident, will be used for lifetime risk calculations with thorough consideration of associated uncertainties. Distributions of doses, uncertainties of the risk model parameters, aggregation of the risk models using methods of Multi-Model Inference (MMI), transfer of risk predictions from epidemiological cohorts to target populations, stochastic consideration of latency effects – all these will contribute to plausibility of risk estimates and will be increasing confidence of the lifetime risk projections for relevant European populations. A path will be sought to integrate the developed risk assessment software tool into existing assessment and decision-support systems.

Contact person: Dr. Alexander Ulanowski

ProZES

Project title: Quantitative assessment of radiation risk from individual exposure scenarios, part 2
Period: 1 February 2013 - 31 December 2015
Funding organisation: German Federal Office for Radiation Protection
Budget: 403,180 €
Scientific personnel: Dr. Alexander Ulanowski, Fr. Elena Shemiakina, Dr. Denise Güthlin, Dr. Jan Christian Kaiser, Dr. Markus Eidemüller
Link: ProZES (BfS Website)

The project is focused on development of the methodology and the software tool ProZES for assessment of personalized causal link between cancer and preceding radiation exposure. The actual project continues the work done in the 1st phase (see Completed projects (2011-2014) 'Radio-epidemiological tables'), extends the current tool to cover the full list of cancers and to include effects related to high-LET radiations along with effects of cancer latency, exposure dose rates and others. The assigned share, AS, is defined as the probability that the observed cancer of an individual is caused by previous radiation exposure, and is expressed as AS=radiation-induced incidence rate / total incidence rate.

The cancer risk models are an essential part of ProZES. Most of the models have been newly developed or re-evaluated from cohort data. Risk models for low-LET radiation are mainly been based on the incidence data of the atomic bomb survivors of Hiroshima and Nagasaki (LSS cohort), the worldwide largest study on radiation-induced cancer risk. For lung cancer after radon exposure, separate risk models have been implemented for exposure in mines and indoor exposure. ProZES includes dedicated radiation risk models for the most frequent types of radiation-induced cancers, including cancers for the lung, female breast, colon, stomach, and thyroid. Risk models for other cancers have been developed for groups of functionally similar cancer sites.

The calculation of the individual assigned share from the risk models is faced with several methodological issues. Risk from a Japanese population must be transferred to a current Western population. The method of multi-model inference is applied to account for different possible dose dependencies and reduce possible selection bias. Monte-Carlo methods are used to account for different sources of uncertainties. ProZES is developed as Windows stand-alone program with graphical user interface in German and English.

Contact person: Dr. Markus Eidemüller

Software tool
Fig. 1: Screenshot of the software tool ProZES

Kompetenzverbund Strahlenforschung (KVSF): Joint Research Project LET: Simulation of high-LET effects by focused low-LET irradiation

Project title: KVSF - Joint Research Project LET: Simulation of high-LET effects by focused low-LET irradiation
Period: 1 June 2013 - 31 May 2017
Funding organization: Federal German Ministry of Education and Research
Budget: 238.179 €
Scientific personnel: Dr. Werner Friedland, Dr. Pavel Kundrát und Dr. Elke Schmitt
Partner institutions: Universität der Bundeswehr München (Coordinator), University Hospital Klinkum rechts der Isar, GSI Helmholtzzentrum für Schwerionenforschung GmbH

Mimicking high-LET particle tracks with sub-micrometer focused beams of relatively low-LET protons represents a novel experimental tool to assess in detail the mechanisms of radiation-induced biological effects. In particular, the method allows separating the influence of damage complexity on a nanometer scale from spatial lesion distribution on micrometer scale, which are closely interwoven in conventional studies. Biological effects in terms of DNA damage, chromosome aberrations, and cell killing by high-LET carbon ions, protons and other light ions focused to about 0.5 μm spots or homogeneously distributed will be compared. The experiments performed at the SNAKE ion microbeam facility of the Munich Technical University will be closely linked with simulations using the local effect model (LEM; Department of Biophysics at the GSI Helmholtzzentrum) and the biophysical simulation program package PARTRAC (Institute of Radiation Protection, Helmholtz Zentrum München). The experiments will benchmark the models and guide their refinements. The models will inform the experiments on spatial and temporal scales and endpoints where additional data would mostly improve the understanding of the underlying mechanisms.

Within the project, the present simulations on repaired, misrepaired and unrejoined DNA double-strand breaks in PARTRAC will be extended to a cell killing model. Simulations with PARTRAC and the LEM will be compared regarding initial radiation effects and their implications for radiotherapy with ions. The results will allow a more precise description of the effects of high-LET radiation both for tumor therapy with ion beams as well as for risk estimation in the course of radiation accidents, for aircrew members and for manned space flights.

Contact person: Dr. Werner Friedland

EpiRadBio: Cancer risks after exposure to ionizing radiation with cumulated doses in the order of 100 mSv or below

Project title: Combining epidemiology and radiobiology to assess cancer risks in the breast, lung, thyroid and digestive tract after exposures to ionizing radiation with cumulated doses in the order of 100 mSv or below (EpiRadBio)
Period: 1 April 2011 - 31 March 2015
Funding institution: European Commission
Total budget: 9.400.000 €
Coordinator: Dr. Peter Jacob
Scientific personnel: Dr. Peter Jacob, Dr. Markus Eidemüller, Dr. Pavel Kundrat, Dr. Sascha Zöllner und Dr. Ignacio Zaballa
Number of partner institutions: 17
Link: EpiRadBio

Recent epidemiological studies suggest that cancer risk after exposures with doses comparable to the dose limits for occupationally exposed workers may be larger than assumed by ICRP in the derivation of these limits ( Highlight: Cancer risk after low dose exposure ). The value of cancer risk from such exposures and its dependence on tissue, radiation type and individual factors is largely unknown.

The innovative approach proposed here combines epidemiology and radiobiology in order to quantify cancer risks after low-dose or low-dose-rate exposures to ionizing radiation. Key factors of radiation induced carcinogenesis such as genomic instability will be measured in cancer tissues and blood samples from members of the following radio-epidemiological cohorts: French Hemangioma Cohort, Mayak Worker Cohort ( Highlight: Mayak ), and thyroid cancer cases after the Chernobyl accident . Inter-cellular communication after exposure to low-dose radiation exposure and its influence on apoptosis, cell proliferation, differentiation and genomic instability will be explored with 2D cell cultures and 3D tissue models. This includes research on stem cells, which will be isolated from healthy human breast tissue.

The results of the radiobiological studies will be integrated in the development of models of carcinogenesis for evaluation of major epidemiological cohorts: Atomic Bomb Survivors, French-Swedish-Italian Thyroid Cancer Cohort, Mayak Worker Cohort, Swedish Hemangioma Cohort, UkrAm Cohort on thyroid cancer after the Chernobyl accident, and UK National Registry for Radiation Workers. Cancer risk will be determined for the breast, lung, thyroid and the digestive tract after low-dose-rate exposure to low-LET radiation (external gamma radiation and internal radiation from 131I) and to high-LET radiation (alpha-particles from incorporated plutonium).

Lifetime cancer risks including individual risk factors will be calculated to establish a new basis for deriving dose limits and estimating cancer risks including those from medical diagnostic exposures.

Contact person: Dr. Peter Jacob

DoReMi - Integrating Low Dose Research

Project title: DoReMi - Low Dose Research towards Multidisciplinary Integration
Period: 1 January 2010 - 31 December 2015
Funding organisation: European Commission
Total budget: 5,414,780 €
Scientific personnel: Dr. Markus Eidemüller, Dr. Peter Jacob, Dr. Pavel Kundrat and PD Dr. Helmut Schöllnberger
Links: DoReMi, MELODI, HLEG
Documents: DoReMi TRA (09/2010), MELODIE SRA (09/2011), HLEG Report (01/2009)

Although much is known about the effects of exposure to ionising radiation, considerable uncertainties and divergent views remain about the health effects at low doses. To integrate European research programmes in this area, the European High Level and Expert Group (HLEG) recommended the establishment of a Multidisciplinary European Low Dose Research Initiative (MELODI) that would create a platform for low dose research under a jointly agreed Strategic Research Agenda (SRA). The research agenda would focus on the key policy questions to be addressed and provide a road map for such research in the coming years and decades.

In 2010, a Network of Excellence called DoReMi was launched by the Euratom FP7 programme. DoReMi will act as operational tool for the development of the MELODI platform over six years, 2010-2015. The joint programme for research focuses on the areas identified by the HLEG as the most promising in terms of adressing/resolving the key policy questions, namely: the shape of dose response curve for cancer, individual susceptibilities and non-cancer effects. Radiation quality, tissue sensitivities and internal exposures will be addressed as cross cutting themes within the three main research areas.

One of the early activities of DoReMi is to develop a Transitional Research Agenda (TRA) with a short to medium scale, focusing on goals that are feasible to achieve within the 6 year project and areas where barriers need to be removed in order to proceed to the longer term strategic objectives. The TRA is the first step in the roadmap of joint European low dose risk research programme. It describes a methodology to identify research lines, how priorities are set and how the research strategy will be implemented. The TRA provides details and some refinement of the scientific questions addressed, the actual research issues covered and a forecast of forthcoming additional research needs. The Roadmap and a Call plan give an initial view of identified future research priorities and likely further developments.

Contact person: Dr. Markus Eidemüller

Projects before 2015

Development of cardiovascular diseases after radiation exposure at low doses

Project title: Development of cardiovascular diseases after radiation exposure at low doses
Period: 1 November 2011 - 31 October 2014
Funding organisation: German Federal Office for Radiation Protection
Budget: 469,000 €
Scientific personnel: Dr. Cristoforo Simonetto and PD Dr. Helmut Schöllnberger

In recent years, mounting scientific evidence has suggested that high doses of ionising radiation have a harmful influence on the development of cardiovascular diseases. In this project, several important and new data sets will be analysed that refer to the cohort of Mayak Production Association workers who were exposed to external gamma and internal alpha radiation. One of the reasons the Mayak Worker Cohort is so important is that the workers were irradiated at low dose rates, i.e. they were exposed to protracted radiation. In contrast to the survivors of the atomic bomb, the exposure situation of the Mayak workers is therefore more comparable to that of the general population.

This project investigates the influence of ionising radiation on the development of cardiovascular diseases in humans. Empirical and mechanistic mathematical models are fitted to the most recent epidemiological data of the Mayak workers, which will be provided by the Southern Urals Biophysics Institute . The fitting of the empirical models will provide the form of the dose-response relationships. The technique to be used for this is multi-model inference , an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. The model fits using a stochastic mechanistic model for atherosclerosis developed in our group enable the determination which parts of the disease process can be influenced by ionising radiation. Parallel to these modelling studies, proteomic analyses of tissue samples of Mayak workers with different exposure doses will be carried out at the Institute of Radiobiology of the Helmholtz Zentrum München. The findings of the proteomic analyses will be integrated into the mechanistic models. The aim is to achieve an improved quantitative description of radiation-induced cardiovascular risk.

Contact person: Dr. Cristoforo Simonetto

ProCardio: Mathematical modeling of radiation-induced circulatory disease

Project title: Cardiovascular risk from exposure to low-dose and low-dose-rate ionizing radiation (ProCardio)
Period: 1 October 2011 - 30 September 2014
Funding organisation: European Commission
Budget: 155,000 €
Scientific personnel: PD Dr. Helmut Schöllnberger
Number of partner institutions: 12

In recent years, mounting scientific evidence has suggested that high doses of ionising radiation have a harmful influence on the development of cardiovascular diseases. This project will investigate the influence of low, medium and high doses of ionising radiation on the development of cardiovascular diseases in humans. One of the most important data sets used to evaluate the risks from exposure to ionising radiation are those from the Life Span Study (LSS), i.e. the data of the atomic bomb survivors.

Within the workpackage treated by our Research Group the latest LSS mortality data for cerebrovascular and cardiovascular diseases will be analysed. Different parametric and categorical models will be fitted to the data to investigate the shape of the dose-response relationships. The technique to be used for this is multi-model inference, an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice.

Contact person: PD Dr. Helmut Schöllnberger

DoReMi - Task INITIUM

Project title: Track structure and initial events: an integrated approach to assess the issue of radiation quality dependence
Period: 1 February 2012- 31 January 2014
Funding institution: European Commission
Budget: 85.300 €
Scientific personnel: Dr. Werner Friedland, Dr. Pavel Kundrát und Dr. Elke Schmitt
Partner institutions: University of Pavia, Italy (Coordinator), Institute of Radiation Biology of Helmholtz Zentrum München

In order to assess the differences in biological effects of radiation of different qualities it is necessary to know the differences in spatial and temporal distributions of the initial interactions with matter. The INITIUM project extends and uses the well-established physical-biological Monte Carlo modelling tool PARTRAC to investigate in four tasks different aspects of initial damage formation and its progression in order to improve predictions of the relative biological effectiveness (RBE) of different radiation qualities, and to integrate modelling with experiments to investigate non-DNA targeted effects at the cellular level:
The first task investigates how the damage to DNA from low-energy beta-emitting radionuclides depends on the region within the cell where the material is located depending on the chemical-molecular form of the radionuclide. The second task involves extending PARTRAC to cover light ions and nuclei in the low-energy regime down to full stopping. This improves estimations of ion-induced in vivo radiation effects and opens opportunities for understanding the neutron RBE variation with energy. The third task uses track structure modelling and differential equations to investigate the relationship between individual DNA double-strand breaks (DSB) and the appearance of detectable ionising radiation-induced foci (IRIF) over a range of different radiation qualities. The objective is to provide reliable information on the time evolution of DSB formation and repair from experimental studies using IRIF method. The fourth task is exploratory work investigating implications of non-DNA targeted effects in cellular response to radiation from different qualities. The objective is to test via experiments and simulations the hypothesis that - beyond genomic DNA - mitochondria are important initial targets of biological effects from low dose ionising radiation.

Contact person: Dr. Werner Friedland

Radio-epidemiological tables

Project title: Quantitative assessment of radiation risk from individual exposure scenarios
Period: 1 November 2009 - 31 October 2012
Funding organisation: German Federal Office for Radiation Protection
Budget: 301312 €
Scientific personnel: Dr. Peter Jacob and Dr. Alexander Ulanovsky

Cancer of an occupationally exposed person often leads to the question, whether the disease is related to the radiation exposure. Generally, other factors like smoking, nutrition, genetic predisposition or viruses interact with radiation in the causation of cancer. Thus a share of causation can be assigned to radiation (the term 'probability of causation', which is often used, is less appropriate). Currently our working group develops software that calculates for arbitrary exposure histories the assigned share of causation for a cancer case.

The project is the first part of a larger project. This first part focuses on the methodology and the development of a computer program for cancer after exposure to low-LET radiation of those organs, in which cancer appears frequently or which have a relatively high radiosensitivity. These are the colon, the lung, the stomach and the female breast. The risk assessments are based on analyses of cancer incidence data for the atomic bomb survivors from Hiroshima and Nagasaki. Multi-model inference is used to derive risks coefficients that are relatively independent of the assumptions made in the models. In order to include individual risk factors for breast cancer, other studies than the atomic bomb survivors will be taken into account. Current data on cancer risks in Germany are used in the transfer of radiation risk coefficients from the atomic bomb survivors to a cancer case in Germany. A number of sources for uncertainty are taken into account including the limited knowledge of cancer risk from exposures with low doses or low dose rates. The final result of the software is the probability distribution for the contribution of the radiation exposure to the development of the cancer case (see table).

Table: Example of a probability distribution for a relation between a colon cancer of a male at age 70 and an exposure starting at age 20 and lasting for 30 years with annual colon doses of 3 mGy (total dose of 90 mGy). In the example it can be excluded with 99% probability that the radiation exposure contributed more than 24% to the genesis of the disease. With 50% probability is can be excluded that the radiation exposure contributed more than 9% to the genesis of the disease.

Probability: 50% 90% 95% 99%
that the radiation exposure contributed to the cancerogenesis less than:  9% 13% 15% 24%

Contact person: Dr. Peter Jacob

Kompetenzverbund Strahlenforschung (KVSF): 3D/4D architecture of chromosomal break point regions in nuclei after radiation exposure of normal and cancer cells

Project title: KVSF - 3D/4D architecture of chromosomal break point regions in nuclei after radiation exposure of normal and cancer cells
Period: 1 October 2010 - 30 September 2013
Funding organization: BMU/BfS
Budget: 184.929 €
Scientific personnel: Dr. Pavel Kundrat and Dr. Werner Friedland
Partner institutions: Universities of Heidelberg (Coordinator), Darmstadt and Munich (LMU and Universität der Bundeswehr)

Mechanisms of double strand break induction will be studied experimentally and by computer models within this project in relation to structural changes of certain chromatin regions of the cell nucleus. Various cell types will be characterized regarding the conformation and spatial structure of the chromatin and investigated after low-dose irradiation for various radiation qualities.

The hypothesis will be tested that certain chromatin regions have a higher probability for radiation-induced oncogenic translocations. To this end, specific models of the chromatin structure within the cell nucleus will be calibrated by high-resolution optical microscopy with fluorescent markers. These model developments will be used for improved DNA target models in PARTRAC and its DNA repair module. The repair module will be refined regarding calculations after low-dose irradiations, predictions of types of chromosomal aberrations and their experimental detectability.

The project is aimed at developing a mechanistic model of radiation response that contributes significantly to the estimation of carcinogenic radiation effects. Advances and developments in the experimental as well as in the simulation methods will deliver many data and techniques for a better understanding of radiation response mechanism and processes.

Contact person: Dr. Werner Friedland

Kompetenzverbund Strahlenforschung (KVSF): Individual Radiation Sensitivity and Genomic Instability

Project title: KVSF - Individual Radiation Sensitivity and Genomic Instability
Period: 1 January 2009 - 31 December 2011
Funding organisation: Federal Ministry of Education and Research
Budget: 252,449 €
Scientific personnel: Dr. Markus Eidemüller and Dr. Peter Jacob

Epidemiological studies show a clear evidence for an increase of cancer cases after exposure to radiation with doses above 100 mGy. Since carcinogenesis is a stochastic process, for each individual cancer it is not possible to derive clear evidence for an association with former radiation exposure.

Radiation could cause a genomic instability in healty tissue or pre-cancerous cells. This could be an important factor in radiation-induced carcinogenesis. To analyse possible consequences of radiation-induced genomic instability, mathematical models of carcinogenesis are extended to include potential mechanisms of genomic instability. Suitable epidemiolgical cohorts are then analysed with these models and consequences for the radiation risk estimated.

Between individuals exists a variability of radiation-induced cancer risk that is poorly understood. This question is of particular importance in radiation therapy where acute exposure can lead to strong treatment complication. Furthermore the appearance of therapy-associated secondary tumors poses a threat that can be very much dependent on the individual susceptibility. The Swedish hemangioma cohort is analysed together with breast cancer data from the mothers and sisters. From a comparison of familial predisposition and cancer risk after radiation exposure the variability of the individual/familial risk is estimated.

Contact person: Dr. Markus Eidemüller