Impact of the measurement conditions and compression paddle on mammography dosimeter response.

The effect of mammography measurement conditions was investigated to evaluate their impact on measurement uncertainties in clinical practice. The most prominent physical X-ray beam quantities i.e., - air kerma, half-value layer, and X-ray tube voltage - were examined by measuring the response of two ionization chambers and six X-ray multimeters (XMMs) of different models. Measurements were performed using several anode/filter combinations and both with and without the compression paddle in the X-ray beam. Maximum differences of higher than 6 % were found for all quantities when the dosimeter displayed value was compared with the reference value or the variation within the clinical anode/filter combinations Mo/Mo and Mo/Rh were considered. The study showed that the calibration procedure with the W/Al anode/filter combination was reliable only for ionization chambers, and the response of XMMs varies in such a way that the calibration coefficient cannot be predicted between various measurement conditions used in calibration and clinical practices. XMM calibrations are typically performed without a compression paddle in the beam, and the response of the XMM changes when radiation quality is slightly altered. If XMM specific data is not available, based on this study, an additional uncertainty of 2 % (k = 1) could be used as a typical estimate, at least for air kerma measurements. XMMs should be used for clinical measurements in mammography only with correct settings. If the correct settings are not available, the XMMs should not be used or used only with extreme caution.

Staff eye lens dose in interventional radiology and cardiology in Finland.

PURPOSE: The aim of this study was to investigate the eye lens and whole-body radiation doses to interventional radiology and cardiology staff in two Finnish hospitals. METHODS: Simultaneous measurements of personal dose equivalent quantities Hp(3) and Hp(10) were conducted in clinical conditions during different radiological and cardiological interventional procedures. In order to study the feasibility to estimate eye lens dose with Hp(10) measured over the protective apron or thyroid shield, the ratio between measured Hp(3) and Hp(10) was investigated. RESULTS AND CONCLUSIONS: Applying the obtained ratio on Hp(10) records from national dose register showed that only a small number of interventional radiologists and cardiologists in Finland may exceed eye lens equivalent dose levels of 20 mSv per year or 100 mSv in five consecutive years, but likely do not exceed 50 mSv in a single year. For the most Finnish interventionalists, the eye lens dose is well below 10 mSv per year. Nurses and radiographers assisting in interventions are, on average, less exposed than interventionalists, and will not exceed 20 mSv per year. Based on our results, Hp(10) measured over the protective apron or thyroid shield provides a conservative estimate of the eye lens dose for interventional radiologists and cardiologists, provided that appropriate protective glasses are used.

CONTEMPORARY RADIATION DOSES IN INTERVENTIONAL CARDIOLOGY: A NATIONWIDE STUDY OF PATIENT SKIN DOSES IN FINLAND.

In contemporary interventional cardiology, for typical elderly patients, the most severe radiation-related harm to patients can be considered to come from skin exposures. In this paper, maximum local skin doses in cardiological procedures are explored with Gafchromic film dosimetry. Film and reader calibrations and reading were performed at the Secondary Standards Dosimetry Laboratory of the Radiation and Nuclear Safety Authority (STUK), and data were gathered from seven hospitals in Finland. As alert levels for early transient erythema, 200 Gycm2 kerma area product (KAP) and 2000 mGy air kerma levels for transcatheter aortic valve implantations (TAVI) procedures are proposed. The largest doses were measured in TAVI (4158.8 mGy) and percutaneous coronary interventions (PCI) (941.68 mGy). Accuracies of the GE DoseWatch and Siemens CareMonitor skin dose estimates were reasonable, but more results are needed to reliably assess and validate the tools' capabilities and reliabilities. Uncertainty of the Gafchromic dosimetry was estimated as 9.1% for a calibration with seven data points and 19.3% for a calibration with five data points.

Automated scoring of dicentric chromosomes differentiates increased radiation sensitivity of young children after low dose CT exposure in vitro.

PURPOSE: Automated detection of dicentric chromosomes from a large number of cells was applied to study age-dependent radiosensitivity after in vitro CT exposure of blood from healthy donors. MATERIALS AND METHODS: Blood samples from newborns, children (2-5 years) and adults (20-50 years) were exposed in vitro to 0 mGy, 41 mGy and 978 mGy using a CT equipment. In this study, automated scoring based on 13,000-31,000 cells/dose point/age group was performed. Results for control and low dose points were validated by manually counting about 26,000 cells/dose point/age group. RESULTS: For all age groups, the high number of analyzed cells enabled the detection of a significant increase in the frequency of radiation induced dicentric chromosomes in cells exposed to 41 mGy as compared to control cells. Moreover, differences between the age groups could be resolved for the low dose: young donors showed significantly increased risk for induced dicentrics at 41 mGy compared to adults. CONCLUSIONS: The results very clearly demonstrate that the automated dicentric scoring method is capable of discerning radiation induced biomarkers in the low dose range (<100 mGy) and thus may open possibilities for large-scale molecular epidemiology studies in radiation protection.

Age-dependent differences in DNA damage after in vitro CT exposure.

PURPOSE: Age dependent radiation sensitivity for DNA damage after in vitro blood exposure by computer tomography (CT) was investigated. MATERIALS AND METHODS: Radiation biomarkers (dicentrics and gammaH2AX) in blood samples of newborns, children under five years and adults after sham exposure (0 mGy), low-dose (41 mGy) and high-dose (978 mGy) in vitro CT exposure were analyzed. RESULTS: Significantly higher levels of dicentric induction were found for the single and combined newborns/children group compared to adults, by a factor of 1.48 (95% CI 1.30-1.68), after exposure to 978 mGy. Although a significant dose response for damage induction and dose-dependent repair was found, the gammaH2AX assay did not show an age-dependent increase in DNA damage in newborns/children compared to adults. This was the case for the gammaH2AX levels after repair time intervals of 30 minutes and 24 hours, after correcting for the underlying background damage. For the low dose of 41 mGy, the power of the dicentric assay was also not sufficient to detect an age-dependent effect in the sample size investigated. CONCLUSION: A 1.5-fold increased level of dicentric aberrations is detected in newborns and children under five years after 1 Gy radiation exposure.

Capabilities of the RENEB network for research and large scale radiological and nuclear emergency situations.

PURPOSE: To identify and assess, among the participants in the RENEB (Realizing the European Network of Biodosimetry) project, the emergency preparedness, response capabilities and resources that can be deployed in the event of a radiological or nuclear accident/incident affecting a large number of individuals. These capabilities include available biodosimetry techniques, infrastructure, human resources (existing trained staff), financial and organizational resources (including the role of national contact points and their articulation with other stakeholders in emergency response) as well as robust quality control/assurance systems. MATERIALS AND METHODS: A survey was prepared and sent to the RENEB partners in order to acquire information about the existing, operational techniques and infrastructure in the laboratories of the different RENEB countries and to assess the capacity of response in the event of radiological or nuclear accident involving mass casualties. The survey focused on several main areas: laboratory's general information, country and staff involved in biological and physical dosimetry; retrospective assays used, the number of assays available per laboratory and other information related to biodosimetry and emergency preparedness. Following technical intercomparisons amongst RENEB members, an update of the survey was performed one year later concerning the staff and the available assays. CONCLUSIONS: The analysis of RENEB questionnaires allowed a detailed assessment of existing capacity of the RENEB network to respond to nuclear and radiological emergencies. This highlighted the key importance of international cooperation in order to guarantee an effective and timely response in the event of radiological or nuclear accidents involving a considerable number of casualties. The deployment of the scientific and technical capabilities existing within the RENEB network members seems mandatory, to help other countries with less or no capacity for biological or physical dosimetry, or countries overwhelmed in case of a radiological or nuclear accident involving a large number of individuals.

RENEB biodosimetry intercomparison analyzing translocations by FISH.

PURPOSE: In the framework of RENEB, several biodosimetry exercises were conducted analyzing different endpoints. Among them, the analysis of translocations is considered the most useful method for retrospective biodosimetry due to the relative stability of their frequency with post irradiation time. The aim of this study was to harmonize the accuracy of translocation-based biodosimetry within the RENEB consortium. MATERIALS AND METHODS: An initial telescoring exercise analyzing FISH metaphase images was done to harmonize chromosome aberration descriptions. Then two blind intercomparison exercises (IE) were performed, by sending irradiated blood samples to each partner. Samples were cultured and stained by each partner using their standard protocol and translocation frequency was used to produce dose estimates. RESULTS: The coefficient of variation in the 1st IE (CV = 0.34) was higher than in the 2nd IE (CV = 0.16 and 0.23 in the two samples analyzed), for the genomic frequency of total translocations. Z-score analysis revealed that eight out of 10 and 17 out of 20 dose estimates were satisfactory in the 1st and 2nd IE, respectively. CONCLUSIONS: The results obtained indicate that, despite the problems identified in few partners, which can be corrected, the RENEB consortium is able to carry out retrospective biodosimetry analyzing the frequency of translocations by FISH.

The second gamma-H2AX assay inter-comparison exercise carried out in the framework of the European biodosimetry network (RENEB).

PURPOSE: Within the EU RENEB project, seven laboratories have taken part in training and harmonisation activities to strengthen triage gamma-H2AX-based radiation exposure assessment. This has culminated in a second triage biodosimetry exercise. MATERIALS AND METHODS: Whole blood and separated lymphocyte samples were homogenously irradiated with 60Co gamma rays at 0.5, 2.5 (blind samples), 0 and 2 Gy (reference samples). Following post-exposure incubations of 4 and 24 h, 16 samples were shipped on ice packs to each partner. The samples were stained and scored for gamma-H2AX foci, using manual and/or automated fluorescence microscope scoring strategies. Dose estimates were obtained and used to assign triage categories to the samples. RESULTS: Average dose estimates across all the laboratories correlated well with true doses. The most accurate assignment of triage category was achieved by manual scoring of the 4-h blood and lymphocyte samples. Only three samples out of a total of 46 were miscategorized in a way that could have adversely effected the clinical management of a radiation casualty. CONCLUSIONS: This inter-comparison exercise has demonstrated that following a recent acute radiation exposure, the gamma-H2AX assay could be a useful triage tool that can be successfully applied across a network of laboratories.

Web based scoring is useful for validation and harmonisation of scoring criteria within RENEB.

PURPOSE: To establish a training data set of digital images and to investigate the scoring criteria and dose assessment of the dicentric assay within the European network of biodosimetry (RENEB), a web based scoring inter-comparison was undertaken by 17 RENEB partners. MATERIALS AND METHODS: Two sets of 50 high resolution images were uploaded onto the RENEB website. One set included metaphases after a moderate exposure (1.3 Gy) and the other set consisted of metaphases after a high dose exposure (3.5 Gy). The laboratories used their own calibration curves for estimating doses based on observed aberration frequencies. RESULTS: The dose estimations and 95% confidence limits were compared to the actual doses and the corresponding z-values were satisfactory for the majority; only the dose estimations from two laboratories were too low or too high. The coefficients of variation were 17.6% for the moderate and 11.2% for the high dose. Metaphases with controversial results could be identified for training purposes. CONCLUSIONS: Overall, the web based scoring of the two galleries by the 17 laboratories produced very good results. Application of web based scoring for the dicentric assay may therefore be a relevant strategy for an operational biodosimetry assistance network.

RENEB - Running the European Network of biological dosimetry and physical retrospective dosimetry.

PURPOSE: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios. RESULTS: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015. CONCLUSIONS: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects.

RENEB intercomparisons applying the conventional Dicentric Chromosome Assay (DCA).

PURPOSE: Two quality controlled inter-laboratory exercises were organized within the EU project 'Realizing the European Network of Biodosimetry (RENEB)' to further optimize the dicentric chromosome assay (DCA) and to identify needs for training and harmonization activities within the RENEB network. MATERIALS AND METHODS: The general study design included blood shipment, sample processing, analysis of chromosome aberrations and radiation dose assessment. After manual scoring of dicentric chromosomes in different cell numbers dose estimations and corresponding 95% confidence intervals were submitted by the participants. RESULTS: The shipment of blood samples to the partners in the European Community (EU) were performed successfully. Outside the EU unacceptable delays occurred. The results of the dose estimation demonstrate a very successful classification of the blood samples in medically relevant groups. In comparison to the 1st exercise the 2nd intercomparison showed an improvement in the accuracy of dose estimations especially for the high dose point. CONCLUSIONS: In case of a large-scale radiological incident, the pooling of ressources by networks can enhance the rapid classification of individuals in medically relevant treatment groups based on the DCA. The performance of the RENEB network as a whole has clearly benefited from harmonization processes and specific training activities for the network partners.

EPI-CT: in vitro assessment of the applicability of the γ-H2AX-foci assay as cellular biomarker for exposure in a multicentre study of children in diagnostic radiology.

PURPOSE: To conduct a feasibility study on the application of the γ-H2AX foci assay as an exposure biomarker in a prospective multicentre paediatric radiology setting. MATERIALS AND METHODS: A set of in vitro experiments was performed to evaluate technical hurdles related to biological sample collection in a paediatric radiology setting (small blood sample volume), processing and storing of blood samples (effect of storing blood at 4°C), the reliability of foci scoring for low-doses (merge γ-H2AX/53BP1 scoring), as well as the impact of contrast agent administration as potential confounding factor. Given the exploratory nature of this study and the ethical constraints related to paediatric blood sampling, blood samples from adult volunteers were used for these experiments. In order to test the feasibility of pooling the γ-H2AX data when different centres are involved in an international multicentre study, two intercomparison studies in the low-dose range (10-500 mGy) were performed. RESULTS: Determination of the number of X-ray induced γ-H2AX foci is feasible with one 2 ml blood sample pre- and post-computed tomography (CT) scan. Lymphocyte isolation and fixation on slides is necessary within 5 h of blood sampling to guarantee reliable results. The possible enhancement effect of contrast medium on the induction of DNA DSB in a patient study can be ruled out if radiation doses and the contrast agent concentration are within diagnostic ranges. The intercomparison studies using in vitro irradiated blood samples showed that the participating laboratories, executing successfully the γ-H2AX foci assay in lymphocytes, were able to rank blind samples in order of lowest to highest radiation dose based on mean foci/cell counts. The dose response of all intercomparison data shows that a dose point of 10 mGy could be distinguished from the sham-irradiated control (p = 0.006). CONCLUSIONS: The results demonstrate that it is feasible to apply the γ-H2AX foci assay as a cellular biomarker of exposure in a multicentre prospective study in paediatric CT imaging after validating it in an in vivo international pilot study on paediatric patients.

Operational guidance for radiation emergency response organisations in Europe for using biodosimetric tools developed in EU MULTIBIODOSE project.

In the event of a large-scale radiological emergency, the triage of individuals according to their degree of exposure forms an important initial step of the accident management. Although clinical signs and symptoms of a serious exposure may be used for radiological triage, they are not necessarily radiation specific and can lead to a false diagnosis. Biodosimetry is a method based on the analysis of radiation-induced changes in cells of the human body or in portable electronic devices and enables the unequivocal identification of exposed people who should receive medical treatment. The MULTIBIODOSE (MBD) consortium developed and validated several biodosimetric assays and adapted and tested them as tools for biological dose assessment in a mass-casualty event. Different biodosimetric assays were validated against the 'gold standard' of biological dosimetry-the dicentric assay. The assays were harmonised in such a way that, in an emergency situation, they can be run in parallel in a network of European laboratories. The aim of this guidance is to give a concise overview of the developed biodosimetric tools as well as how and when they can be used in an emergency situation.

Occupational exposure to 131I-a case study.

In a laboratory in a company manufacturing radiopharmaceuticals, a laboratory technician was contaminated with I. The employee was preparing I capsules for thyroid carcinoma treatment. The employee was wearing two pairs of protective gloves and, when changing gloves, noticed a rupture in the right inner glove but no visible rupture in the outer glove. Only 3-4 h later, routine monitoring revealed heavy contamination of the back of the right hand. Immediate actions to decontaminate the hand were taken on-site. Stable iodine was not administered. On the next day, besides persisting heavy contamination of the hand, I was also detected in the thyroid gland. Based on original measurements on-site and later follow-up at STUK, including surface contamination measurements and whole body counting, the original I activity on the hand was estimated at 12 MBq and the superficial skin dose at 33 Gy, affecting a skin area of about 10 cm. The thyroid dose was estimated at 430 mGy. Eleven days after the incident, the skin was dry and slightly desquamated. After 15 d, the skin was intact with no desquamation left. No further signs of skin damage have occurred. Cytogenetic analysis of circulating lymphocytes indicated a slight elevation of chromosomal aberrations.

Multibiodose radiation emergency triage categorization software.

In this note, the authors describe the MULTIBIODOSE software, which has been created as part of the MULTIBIODOSE project. The software enables doses estimated by networks of laboratories, using up to five retrospective (biological and physical) assays, to be combined to give a single estimate of triage category for each individual potentially exposed to ionizing radiation in a large scale radiation accident or incident. The MULTIBIODOSE software has been created in Java. The usage of the software is based on the MULTIBIODOSE Guidance: the program creates a link to a single SQLite database for each incident, and the database is administered by the lead laboratory. The software has been tested with Java runtime environment 6 and 7 on a number of different Windows, Mac, and Linux systems, using data from a recent intercomparison exercise. The Java program MULTIBIODOSE_1.0.jar is freely available to download from http://www.multibiodose.eu/software or by contacting the software administrator: MULTIBIODOSE-software@gmx.com.

Assessment of targeted and non-targeted responses in cells deficient in ATM function following exposure to low and high dose X-rays.

Radiation sensitivity at low and high dose exposure to X-rays was investigated by means of chromosomal aberration (CA) analysis in heterozygous ATM mutation carrier and A-T patient (biallelic ATM mutation) lymphoblastoid cell lines (LCLs). Targeted and non-targeted responses to acutely delivered irradiation were examined by applying a co-culture system that enables study of both directly irradiated cells and medium-mediated bystander effects in the same experimental setting. No indication of radiation hypersensitivity was observed at doses of 0.01 Gy or 0.1 Gy for the ATM mutation carrier LCL. The A-T patient cells also did not show low-dose response. There was significant increase in unstable CA yields for both ATM mutation carrier and A-T LCLs at 1 and 2 Gy, the A-T cells displaying more distinct dose dependency. Both chromosome and chromatid type aberrations were induced at an increased rate in the irradiated A-T cells, whereas for ATM carrier cells, only unstable chromosomal aberrations were increased above the level observed in the wild type cell line. No bystander effect could be demonstrated in any of the cell lines or doses applied. Characteristics typical for the A-T cell line were detected, i.e., high baseline frequency of CA that increased with dose. In addition, dose-dependent loss of cell viability was observed. In conclusion, CA analysis did not demonstrate low-dose (≤100 mGy) radiosensitivity in ATM mutation carrier cells or A-T patient cells. However, both cell lines showed increased radiosensitivity at high dose exposure.

Profiling of low molecular weight proteins in plasma from locally irradiated individuals.

In studies reported in the 1960s and since, blood plasma from radiation-exposed individuals has been shown to induce chromosome damage when transferred into lymphocyte cultures of non-irradiated persons. This effect has been described to occur via clastogenic factors, whose nature is still mostly unknown. We have previously examined clastogenic factors from irradiated individuals by looking at plasma-induced DNA damage in reporter cells. Plasma was tested from ca. 30 locally exposed clinical patients receiving fractionated radiation treatment, as well as from three radiological accident victims exposed in 1994, albeit sampled 14 years post-accident. In the current work, proteome changes in the plasma from all subjects were examined with 2D gel electrophoresis-based proteomics techniques, in order to evaluate the level of protein expression with respect to the findings of a clastogenic factor effect. No differences were observed in protein expression due to local radiation exposure (pre- vs post-exposure). In contrast, plasma from the radiation accident victims showed alterations in the expression of 18 protein spots (in comparison with plasma from the control group). Among these, proteins such as haptoglobin, serotransferrin/transferrin, fibrinogen and ubiquitin-60S ribosomal protein L40 were observed, none of them likely to be clastogenic factors. In conclusion, the proteomics techniques applied were unable to identify changes in the proteome of the locally irradiated patients, whereas such differences were observed for the accident victims. However, association with the clastogenic effect or any specific clastogenic factor remains unresolved and thus further studies with more sensitive techniques are warranted.

Inter- and intra-laboratory comparison of a multibiodosimetric approach to triage in a simulated, large scale radiation emergency.

PURPOSE: The European Union's Seventh Framework Programme-funded project 'Multi-disciplinary biodosimetric tools to manage high scale radiological casualties' (MULTIBIODOSE) has developed a multiparametric approach to radiation biodosimetry, with a particular emphasis on triage of large numbers of potentially exposed individuals following accidental exposures. In November 2012, an emergency exercise took place which tested the capabilities of the MULTIBIODOSE project partners. The exercise described here had a dual purpose: Intercomparison of (i) three biodosimetric assays, and (ii) the capabilities of the seven laboratories, with regards to provision of triage status for suspected radiation exposed individuals. MATERIALS AND METHODS: Three biological dosimetry tools - the dicentric, micronucleus and gamma-H2AX (the phosphorylated form of member X of histone H2A, in response to DNA double-strand breaks) foci assays - were tested, in addition to provision of the triage status results (low exposure: < 1 Gy; medium exposure: 1-2 Gy; high exposure: > 2 Gy) by the MULTIBIODOSE software. The exercise was run in two modes: An initial triage categorisation of samples (based on the first dose estimates for each assay received from each laboratory) followed by collation of the full set of estimated doses (all the results from all modes of each assay carried out by the participating laboratories) calculated using as many modes of operation as possible of the different assays developed during the project. Simulated acute whole body and partial body exposures were included. RESULTS: The results of the initial triage categorisation and the full comparison of assays and methods within and between laboratories are presented here. CONCLUSIONS: The data demonstrate that the MULTIBIODOSE approach of applying multiparametric tools to radiation emergencies is valid and effective.

Manual versus automated γ-H2AX foci analysis across five European laboratories: can this assay be used for rapid biodosimetry in a large scale radiation accident?

The identification of severely exposed individuals and reassurance of the 'worried well' are of prime importance for initial triage following a large scale radiation accident. We aim to develop the γ-H2AX foci assay into a rapid biomarker tool for use in accidents. Here, five laboratories established a standard operating procedure and analysed 100 ex vivo γ-irradiated, 4 or 24h incubated and overnight-shipped lymphocyte samples from four donors to generate γ-H2AX reference data, using manual and/or automated foci scoring strategies. In addition to acute, homogeneous exposures to 0, 1, 2 and 4Gy, acute simulated partial body (4Gy to 50% of cells) and protracted exposures (4Gy over 24h) were analysed. Data from all laboratories could be satisfactorily fitted with linear dose response functions. Average yields observed at 4h post exposure were 2-4 times higher than at 24h and varied considerably between laboratories. Automated scoring caused larger uncertainties than manual scoring and was unable to identify partial exposures, which were detectable in manually scored samples due to their overdispersed foci distributions. Protracted exposures were detectable but doses could not be accurately estimated with the γ-H2AX assay. We conclude that the γ-H2AX assay may be useful for rapid triage following a recent acute radiation exposure. The potentially higher speed and convenience of automated relative to manual foci scoring needs to be balanced against its compromised accuracy and inability to detect partial body exposures. Regular re-calibration or inclusion of reference samples may be necessary to ensure consistent results between laboratories or over long time periods.

Ionizing radiation biomarkers for potential use in epidemiological studies.

Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100mSv and/or 0.1mSvmin(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.