Biokinetics and Internal Dosimetry of Tritiated Steel Particles.

Decommissioning fission and fusion facilities can result in the production of airborne particles containing tritium that could inadvertently be inhaled by workers directly involved in the operations, and potentially others, resulting in internal exposures to tritium. Of particular interest in this context, given the potentially large masses of material involved, is tritiated steel. The International Commission on Radiological Protection (ICRP) has recommended committed effective dose coefficients for inhalation of some tritiated materials, but not specifically for tritiated steel. The lack of a dose coefficient for tritiated steel is a concern given the potential importance of the material. To address this knowledge gap, a "dissolution" study, in vivo biokinetic study in a rodent model (1 MBq intratracheal instillation, 3-month follow-up) and associated state-of-the-art modelling were undertaken to derive dose coefficients for model tritiated steel particles. A committed effective dose coefficient for the inhalation of 3.3 × 10-12 Sv Bq-1 was evaluated for the particles, reflecting an activity median aerodynamic diameter (AMAD) of 13.3 µm, with the value for a reference AMAD for workers (5 µm) of 5.6 × 10-12 Sv Bq-1 that may be applied to occupational inhalation exposure to tritiated steel particles.

Cancer risk from chronic exposures to chemicals and radiation: a comparison of the toxicological reference value with the radiation detriment.

This article aims at comparing reference methods for the assessment of cancer risk from exposure to genotoxic carcinogen chemical substances and to ionizing radiation. For chemicals, cancer potency is expressed as a toxicological reference value (TRV) based on the most sensitive type of cancer generally observed in animal experiments of oral or inhalation exposure. A dose-response curve is established by modelling experimental data adjusted to apply to human exposure. This leads to a point of departure from which the TRV is derived as the slope of a linear extrapolation to zero dose. Human lifetime cancer risk can then be assessed as the product of dose by TRV and it is generally considered to be tolerable in a 10-6-10-4 range for the public in a normal situation. Radiation exposure is assessed as an effective dose corresponding to a weighted average of energy deposition in body organs. Cancer risk models were derived from the epidemiological follow-up of atomic bombing survivors. Considering a linear-no-threshold dose-risk relationship and average baseline risks, lifetime nominal risk coefficients were established for 13 types of cancers. Those are adjusted according to the severity of each cancer type and combined into an overall indicator denominated radiation detriment. Exposure to radiation is subject to dose limits proscribing unacceptable health detriment. The differences between chemical and radiological cancer risk assessments are discussed and concern data sources, extrapolation to low doses, definition of dose, considered health effects and level of conservatism. These differences should not be an insuperable impediment to the comparison of TRVs with radiation risk, thus opportunities exist to bring closer the two types of risk assessment.

Analysis of the association between ionizing radiation and mortality in uranium workers from five plants involved in the nuclear fuel production cycle in France.

PURPOSE: The aim is to investigate associations between mortality and exposure to ionizing radiation in a cohort of uranium workers with potential for internal and external radiation exposures. METHODS: Workers employed for at least 6 months between 1958 and 2006 in five plants involved in the French nuclear fuel cycle were included and followed up between 1968 and 2013. Cause-specific standardized mortality ratios were calculated. Analyses of associations between individual cumulative radiation dose (both internal and external, lagged by 5-15 years) and mortality were conducted using Poisson regression. RESULTS: The cohort includes 4541 workers. The mean cumulative external dose was 11.12 mGy. Mean cumulative internal doses ranged, depending on modelling hypotheses, from 0.05 to 0.09 mGy (liver) and from 4.22 to 10.90 mGy (lung). At the end of the follow-up, 838 workers were deceased and 28 lost to follow-up. A healthy worker effect was observed. The risk of prostate and lung cancers mortality was significantly higher for workers exposed to cumulative external dose above 50 mGy compared to non-exposed, but these associations were based only on three cases and became non-significant, although of similar magnitude, after adjustment for smoking. Associations with internal dose showed no consistent pattern. CONCLUSIONS: For the first time, a study was conducted in a French cohort of uranium workers with a complete reconstruction of internal dose. Results are preliminary and must be interpreted with caution because of the limited cohort size and significant sources of uncertainty. Future steps of this study will overcome these limitations.

Circulatory disease in French nuclear fuel cycle workers chronically exposed to uranium: a nested case-control study.

OBJECTIVES: There is growing evidence of an association between low-dose external γ-radiation and circulatory system diseases (CSDs), yet sparse data exist about an association with chronic internal uranium exposure and the role of non-radiation risk factors. We conducted a nested case-control study of French AREVA NC Pierrelatte nuclear workers employed between 1960 and 2005 to estimate CSD risks adjusting for major CSD risk factors (smoking, blood pressure, body mass index, total cholesterol and glycaemia) and external γ-radiation dose. METHODS: The study included 102 cases of death from CSD and 416 controls individually matched on age, gender, birth cohort and socio-professional status. Information on CSD risk factors was collected from occupational medical records. Organ-specific absorbed doses were estimated using biomonitoring data, taking into account exposure regime and uranium physicochemical properties. External γ-radiation was measured by individual dosimeter badges. Analysis was conducted with conditional logistic regression. RESULTS: Workers were exposed to very low radiation doses (mean γ-radiation dose 2 and lung uranium dose 1 mGy). A positive but imprecise association was observed (excess OR per mGy 0.2, 95% CI 0.004 to 0.5). Results obtained after adjustment suggest that uranium exposure might be an independent CSD risk factor. CONCLUSIONS: Our results suggest that a positive association might exist between internal uranium exposure and CSD mortality, not confounded by CSD risk factors. Future work should focus on numerous uncertainties associated with internal uranium dose estimation and on understanding biological pathway of CSD after protracted low-dose internal radiation exposure.

Risk of Lung Cancer Mortality in Nuclear Workers from Internal Exposure to Alpha Particle-emitting Radionuclides.

BACKGROUND: Carcinogenic risks of internal exposures to alpha-emitters (except radon) are poorly understood. Since exposure to alpha particles-particularly through inhalation-occurs in a range of settings, understanding consequent risks is a public health priority. We aimed to quantify dose-response relationships between lung dose from alpha-emitters and lung cancer in nuclear workers. METHODS: We conducted a case-control study, nested within Belgian, French, and UK cohorts of uranium and plutonium workers. Cases were workers who died from lung cancer; one to three controls were matched to each. Lung doses from alpha-emitters were assessed using bioassay data. We estimated excess odds ratio (OR) of lung cancer per gray (Gy) of lung dose. RESULTS: The study comprised 553 cases and 1,333 controls. Median positive total alpha lung dose was 2.42 mGy (mean: 8.13 mGy; maximum: 316 mGy); for plutonium the median was 1.27 mGy and for uranium 2.17 mGy. Excess OR/Gy (90% confidence interval)-adjusted for external radiation, socioeconomic status, and smoking-was 11 (2.6, 24) for total alpha dose, 50 (17, 106) for plutonium, and 5.3 (-1.9, 18) for uranium. CONCLUSIONS: We found strong evidence for associations between low doses from alpha-emitters and lung cancer risk. The excess OR/Gy was greater for plutonium than uranium, though confidence intervals overlap. Risk estimates were similar to those estimated previously in plutonium workers, and in uranium miners exposed to radon and its progeny. Expressed as risk/equivalent dose in sieverts (Sv), our estimates are somewhat larger than but consistent with those for atomic bomb survivors.See video abstract at, http://links.lww.com/EDE/B232.

Ionizing radiation biomarkers in epidemiological studies - An update.

Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30-60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.

Optimization of Routine Monitoring of Workers Exposed to Plutonium Aerosols.

In case of incidental confinement failure, mixed oxide (MOX) fuel preparation may expose workers to plutonium aerosols. Due to its potential toxicity, occupational exposure to plutonium compounds should be kept as low as reasonably achievable. To ensure the absence of significant intake of radionuclides, workers at risk of internal contamination are monitored by periodic bioassay planned in a routine monitoring programme. From bioassay results, internal dose may be estimated. However, accurate dose calculation relies on known exposure conditions, which are rarely available when the exposure is demonstrated by routine monitoring only. Therefore, internal dose calculation is subject to uncertainty from unknown exposure conditions and from activity measurement variability. The present study calculates the minimum detectable dose (MDD) for a routine monitoring programme by considering all plausible conditions of exposure and measurement uncertainty. The MDD evaluates the monitoring quality and can be used for optimization. Here, MDDs were calculated for the monitoring of workers preparing MOX fuel. Uncertain parameters were modelled by probability distributions defined according to information provided by experts of routine monitoring, of workplace radiological protection and of bioassay analysis. Results show that the current monitoring is well adapted to potential exposure. A sensitivity study of MDD highlights high dependence on exposure condition modelling. Integrating all expert knowledge is therefore crucial to obtain reliable MDD estimates, stressing the value of a holistic approach to worker monitoring.

Concerted Uranium Research in Europe (CURE): toward a collaborative project integrating dosimetry, epidemiology and radiobiology to study the effects of occupational uranium exposure.

The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.

Doses and lung cancer risks from exposure to radon and plutonium.

PURPOSE: Epidemiological studies of the French uranium miners and the plutonium workers at the Mayak nuclear facility have provided excess relative risk (ERR) estimates per unit absorbed lung dose from alpha radiation. The aim of this paper was to review these two studies and to derive values of the relative biological effectiveness (RBE) of alpha particles for the induction of lung cancer. MATERIALS AND METHODS: We examined and compared the dosimetry assumptions and methodology used in the epidemiological studies of uranium miners and the plutonium workers. Values of RBE were obtained by comparing risk coefficients including comparison of lifetime risks for a given population. To do this, preliminary calculations of lifetime risks following inhalation of plutonium were carried out. RESULTS AND CONCLUSIONS: Published values of risk per unit dose following inhalation of radon progeny and plutonium were in agreement despite the very different dose distributions within the lungs and the different ways the doses were calculated. Values of RBE around 10-20 were obtained by comparing ERR values, but with wide uncertainty ranges. Comparing lifetime risks gave similar values (10, 19 and 21). This supports the use of a radiation weighting factor of 20 for alpha particles for radiation protection purposes.

Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA.

PURPOSE: To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). MATERIALS AND METHODS: Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. RESULTS: The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf), respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. CONCLUSIONS: The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. RESULTS of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms.

Collective dosimetry to distinguish occupational exposure to natural uranium from alimentary uranium background in bioassay measurements.

PURPOSE: To assess occupational exposure from uranium bioassay results which are low and impacted by dietary intakes. MATERIAL AND METHODS: First, the bioassay results of a group of workers exposed to UO2 were compiled along with results of a control group. A Bayesian approach was developed to account for dietary intakes in the calculation of the committed effective dose from occupational exposure of a group of workers. RESULTS: Significant differences in uranium bioassay between the exposed and control groups were found establishing an occupational contamination of the exposed group of workers. Because uranium alimentary excretion estimated from the control group is very variable leading to unreliable individual dose assessment, a collective dosimetric approach was chosen. Applying the Bayesian method, all annual committed effective doses for the exposed group were estimated to be below 0.5 mSv with 95% confidence. CONCLUSIONS: The Bayesian method presented here is well designed to derive best estimate and dose distribution for a group of workers when a contamination is difficult to discriminate from a natural background or alimentary excretion.

Absorption of americium compounds in the respiratory tract.

PURPOSE: To improve the dosimetry of incorporated americium (Am) and to contribute to radiation protection by characterizing the absorption kinetics of inhaled Am compounds. MATERIAL AND METHODS: In vitro dissolution tests, animal experiments and human contamination cases published in the literature were reviewed. The data were analyzed with biokinetic models consistent with the current publications of the International Commission on Radiological Protection. RESULTS: Material-specific dissolution parameter values with consequent assignment to absorption Types are proposed as well as representative central values for the different chemical forms of Am. CONCLUSIONS: The absorption of Am oxide is consistent with the moderate absorption Type M while Am nitrate appears more soluble. Am associated with plutonium oxide usually follows its slow absorption Type S. However, the large variability observed stresses the value of investigating the specific absorption kinetics for Am compounds which represent a significant risk of internal exposure.

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.

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.

Risk of lung cancer mortality in relation to lung doses among French uranium miners: follow-up 1956-1999.

The aim of this study was to assess the risk of lung cancer death associated with cumulative lung doses from exposure to α-particle emitters, including radon gas, radon short-lived progeny, and long-lived radionuclides, and to external γ rays among French uranium miners. The French "post-55" sub-cohort included 3,377 uranium miners hired from 1956, followed up through the end of 1999, and contributing to 89,405 person-years. Lung doses were calculated with the ICRP Human Respiratory Tract Model (Publication 66) for 3,271 exposed miners. The mean "absorbed lung dose" due to α-particle radiation was 78 mGy, and that due to the contribution from other types of radiation (γ and ß-particle radiation) was 56 mGy. Radon short-lived progeny accounted for 97% of the α-particle absorbed dose. Out of the 627 deaths, the cause of death was identified for 97.4%, and 66 cases were due to lung cancer. A significant excess relative risk (ERR) of lung cancer death was associated with the total absorbed lung dose (ERR/Gy = 2.94, 95% CI 0.80, 7.53) and the α-particle absorbed dose (4.48, 95% CI 1.27, 10.89). Assuming a value of 20 for the relative biological effectiveness (RBE) of α particles for lung cancer induction, the ERR/Gy-Eq for the total weighted lung dose was 0.22 (95% CI: 0.06, 0.53).

Dose conversion factors for radon: recent developments.

Epidemiological studies of the occupational exposure of miners and domestic exposures of the public have provided strong and complementary evidence of the risks of lung cancer following inhalation of radon progeny. Recent miner epidemiological studies, which include low levels of exposure, long duration of follow-up, and good quality of individual exposure data, suggest higher risks of lung cancer per unit exposure than assumed previously by the International Commission on Radiological Protection (ICRP). Although risks can be managed by controlling exposures, dose estimates are required for the control of occupational exposures and are also useful for comparing sources of public exposure. Currently, ICRP calculates doses from radon and its progeny using dose conversion factors from exposure (WLM) to dose (mSv) based on miner epidemiological studies, referred to as the epidemiological approach. Revision of these dose conversion factors using risk estimates based on the most recent epidemiological data gives values that are in good agreement with the results of calculations using ICRP biokinetic and dosimetric models, the dosimetric approach. ICRP now proposes to treat radon progeny in the same way as other radionuclides and to publish dose coefficients calculated using models, for use within the ICRP system of protection.

The CONRAD approach to biokinetic modeling of DTPA decorporation therapy.

Diethylene Triamine Pentaacetic Acid (DTPA) is used for decorporation of plutonium because it is known to be able to enhance its urinary excretion for several days after treatment by forming stable Pu-DTPA complexes. The decorporation prevents accumulation in organs and results in a dosimetric benefit, which is difficult to quantify from bioassay data using existing models. The development of a biokinetic model describing the mechanisms of actinide decorporation by administration of DTPA was initiated as a task in the European COordinated Network on RAdiation Dosimetry (CONRAD). The systemic biokinetic model from Leggett et al. and the biokinetic model for DTPA compounds of International Commission on Radiological Protection Publication 53 were the starting points. A new model for biokinetics of administered DTPA based on physiological interpretation of 14C-labeled DTPA studies from literature was proposed by the group. Plutonium and DTPA biokinetics were modeled separately. The systems were connected by means of a second order kinetics process describing the chelation process of plutonium atoms and DTPA molecules to Pu-DTPA complexes. It was assumed that chelation only occurs in the blood and in systemic compartment ST0 (representing rapid turnover soft tissues), and that Pu-DTPA complexes and administered forms of DTPA share the same biokinetic behavior. First applications of the CONRAD approach showed that the enhancement of plutonium urinary excretion after administration of DTPA was strongly influenced by the chelation rate constant. Setting it to a high value resulted in a good fit to the observed data. However, the model was not yet satisfactory since the effects of repeated DTPA administration in a short time period cannot be predicted in a realistic way. In order to introduce more physiological knowledge into the model several questions still have to be answered. Further detailed studies of human contamination cases and experimental data will be needed in order to address these issues. The work is now continued within the European Radiation Dosimetry Group, EURADOS.