Evaluation of uncertainties in lung measurement of actinides due to non-uniform distribution of activity in lungs.

Various parameters can introduce uncertainties in the lung activity measurements of actinides. In this study, uncertainties due to non-uniform distribution of activity in the lungs are evaluated. To study the effect of non-uniform distribution, lungs of ICRP male thorax voxel and resized phantoms are divided into upper and lower parts of both right and left lungs as well as into anterior and posterior lung regions. Simulation of uniform and non-uniform distribution of activity in lungs is carried out using thorax voxel phantoms in FLUKA for Phoswich and an array of three HPGe detectors for 18-238keV photons. Source sampling for non-uniform distribution of activity is carried out by selecting the source points by varying the weightage to 0.4, 0.5, 0.6 and 1 in different parts of lungs. Uncertainties in lung activity estimation at different energies are quantified in the form of scattering factors (SFs) which are geometric standard deviations. The SFs due to non-uniform distribution of activity of the order of 0.4-0.6 in different parts of the lungs are found to be ~ 1.25 for Phoswich and HPGe array detectors above 18keV.

Skin absorption of actinides: influence of solvents or chelates on skin penetration ex vivo.

PURPOSE: To evaluate skin penetration and retention of americium (Am) and plutonium (Pu), in different chemical forms relevant to the nuclear industry and to treatment by chelation. MATERIALS AND METHODS: Percutaneous penetration of different Am and Pu forms were evaluated using viable pig skin with the Franz cell diffusion system. The behavior of the complex Pu-tributyl phosphate (Pu-TBP), Am or Pu complexed to the chelator Diethylene triamine pentaacetic acid (DTPA) and the effect of dimethyl sulfoxide (DMSO) was assessed. Radioactivity was measured in skin and receiver compartments. Three approaches were used to visualize activity in skin including the recent iQID technique for quantification. RESULTS: Transfer of Am was 24-fold greater than Pu and Pu-TBP complex penetration was enhanced by 500-fold. Actinide-DTPA transfer was greater than the Am or Pu alone (17-fold and 148-fold, respectively). The stratum corneum retained the majority of activity in all cases and both DMSO and TBP enhanced skin retention of Am and Pu, respectively. Histological and bioimaging data confirmed these results and the iQID camera allowed the quantification of skin activity. CONCLUSIONS: Skin penetration and fixation profiles are different depending on the chemical actinide form. Altered behavior of Pu-TBP and actinide-DTPA complexes reinforces the need to address decontamination protocols.

Analysis methodology and development of a statistical tool for biodistribution data from internal contamination with actinides.

The aim of this work was to develop a computational tool that integrates several statistical analysis features for biodistribution data from internal contamination experiments. These data represent actinide levels in biological compartments as a function of time and are derived from activity measurements in tissues and excreta. These experiments aim at assessing the influence of different contamination conditions (e.g. intake route or radioelement) on the biological behavior of the contaminant. The ever increasing number of datasets and diversity of experimental conditions make the handling and analysis of biodistribution data difficult. This work sought to facilitate the statistical analysis of a large number of datasets and the comparison of results from diverse experimental conditions. Functional modules were developed using the open-source programming language R to facilitate specific operations: descriptive statistics, visual comparison, curve fitting, and implementation of biokinetic models. In addition, the structure of the datasets was harmonized using the same table format. Analysis outputs can be written in text files and updated data can be written in the consistent table format. Hence, a data repository is built progressively, which is essential for the optimal use of animal data. Graphical representations can be automatically generated and saved as image files. The resulting computational tool was applied using data derived from wound contamination experiments conducted under different conditions. In facilitating biodistribution data handling and statistical analyses, this computational tool ensures faster analyses and a better reproducibility compared with the use of multiple office software applications. Furthermore, re-analysis of archival data and comparison of data from different sources is made much easier. Hence this tool will help to understand better the influence of contamination characteristics on actinide biokinetics. Our approach can aid the optimization of treatment protocols and therefore contribute to the improvement of the medical response after internal contamination with actinides.

Siderocalin-mediated recognition, sensitization, and cellular uptake of actinides.

Synthetic radionuclides, such as the transuranic actinides plutonium, americium, and curium, present severe health threats as contaminants, and understanding the scope of the biochemical interactions involved in actinide transport is instrumental in managing human contamination. Here we show that siderocalin, a mammalian siderophore-binding protein from the lipocalin family, specifically binds lanthanide and actinide complexes through molecular recognition of the ligands chelating the metal ions. Using crystallography, we structurally characterized the resulting siderocalin-transuranic actinide complexes, providing unprecedented insights into the biological coordination of heavy radioelements. In controlled in vitro assays, we found that intracellular plutonium uptake can occur through siderocalin-mediated endocytosis. We also demonstrated that siderocalin can act as a synergistic antenna to sensitize the luminescence of trivalent lanthanide and actinide ions in ternary protein-ligand complexes, dramatically increasing the brightness and efficiency of intramolecular energy transfer processes that give rise to metal luminescence. Our results identify siderocalin as a potential player in the biological trafficking of f elements, but through a secondary ligand-based metal sequestration mechanism. Beyond elucidating contamination pathways, this work is a starting point for the design of two-stage biomimetic platforms for photoluminescence, separation, and transport applications.

Assessment of uncertainties in the lung activity measurement of low-energy photon emitters using Monte Carlo simulation of ICRP male thorax voxel phantom.

Assessment of intake due to long-lived actinides by inhalation pathway is carried out by lung monitoring of the radiation workers inside totally shielded steel room using sensitive detection systems such as Phoswich and an array of HPGe detectors. In this paper, uncertainties in the lung activity estimation due to positional errors, chest wall thickness (CWT) and detector background variation are evaluated. First, calibration factors (CFs) of Phoswich and an array of three HPGe detectors are estimated by incorporating ICRP male thorax voxel phantom and detectors in Monte Carlo code 'FLUKA'. CFs are estimated for the uniform source distribution in lungs of the phantom for various photon energies. The variation in the CFs for positional errors of ±0.5, 1 and 1.5 cm in horizontal and vertical direction along the chest are studied. The positional errors are also evaluated by resizing the voxel phantom. Combined uncertainties are estimated at different energies using the uncertainties due to CWT, detector positioning, detector background variation of an uncontaminated adult person and counting statistics in the form of scattering factors (SFs). SFs are found to decrease with increase in energy. With HPGe array, highest SF of 1.84 is found at 18 keV. It reduces to 1.36 at 238 keV.

Study of the distribution of actinides in human tissues using synchrotron radiation micro X-ray fluorescence spectrometry.

This study aims at evaluating the capabilities of synchrotron radiation micro X-ray fluorescence spectrometry (SR micro-XRF) for qualitative and semi-quantitative elemental mapping of the distribution of actinides in human tissues originating from individuals with documented occupational exposure. The investigated lymph node tissues were provided by the United States Transuranium and Uranium Registries (USTUR) and were analyzed following appropriate sample pre-treatment. Semi-quantitative results were obtained via calibration by external standards and demonstrated that the uranium concentration level in the detected actinide hot spots reaches more than 100 µg/g. For the plutonium hot spots, concentration levels up to 31 µg/g were found. As illustrated by this case study on these unique samples, SR micro-XRF has a high potential for this type of elemental bio-imaging owing to its high sensitivity, high spatial resolution, and non-destructive character.

Monte Carlo simulation of skull and knee voxel phantoms for the assessment of skeletal burden of low-energy photon emitters.

In case of internal contamination due to long-lived actinides by inhalation or injection pathway, a major portion of activity will be deposited in the skeleton and liver over a period of time. In this study, calibration factors (CFs) of Phoswich and an array of HPGe detectors are estimated using skull and knee voxel phantoms. These phantoms are generated from International Commission of Radiation Protection reference male voxel phantom. The phantoms as well as 20 cm diameter phoswich, having 1.2 cm thick NaI (Tl) primary and 5cm thick CsI (Tl) secondary detector and an array of three HPGe detectors (each of diameter of 7 cm and thickness of 2.5 cm) are incorporated in Monte Carlo code 'FLUKA'. Biokinetic models of Pu, Am, U and Th are solved using default parameters to identify different parts of the skeleton where activity will accumulate after an inhalation intake of 1 Bq. Accordingly, CFs are evaluated for the uniform source distribution in trabecular bone and bone marrow (TBBM), cortical bone (CB) as well as in both TBBM and CB regions for photon energies of 18, 60, 63, 74, 93, 185 and 238 keV describing sources of (239)Pu, (241)Am, (238)U, (235)U and (232)Th. The CFs are also evaluated for non-uniform distribution of activity in TBBM and CB regions. The variation in the CFs for source distributed in different regions of the bones is studied. The assessment of skeletal activity of actinides from skull and knee activity measurements is discussed along with the errors.

Radionuclide decorporation: matching the biokinetics of actinides by transdermal delivery of pro-chelators.

The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device ("dirty bomb") has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40-45% Miglyol® 840, and 15-20% ethyl cellulose were spiked with [(14)C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an (241)Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of (241)Am in a dose-dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile.

Actinide chelation: biodistribution and in vivo complex stability of the targeted metal ions.

Because of the continuing use of nuclear fuel sources and heightened threats of nuclear weapon use, the amount of produced and released radionuclides is increasing daily, as is the risk of larger human exposure to fission product actinides. A rodent model was used to follow the in vivo distribution of representative actinides, administered as free metal ions or complexed with chelating agents including diethylenetriamine pentaacetic acid (DTPA) and the hydroxypyridinonate ligands 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). Different metabolic pathways for the different metal ions were evidenced, resulting in intricate ligand- and metal-dependent decorporation mechanisms. While the three studied chelators are known for their unrivaled actinide decorporation efficiency, the corresponding metal complexes may undergo in vivo decomposition and release metal ions in various biological pools. This study sets the basis to further explore the metabolism and in vivo coordination properties of internalized actinides for the future development of viable therapeutic chelating agents.

Bone as target organ for metals: the case of f-elements.

The skeleton is a target organ for most metals. This leads to their bioaccumulation, either as storage of useful oligoelements or as a protection against damage by toxic elements. The different events leading to their accumulation in this organ, under constant remodeling, are not fully understood, nor the full subsequent impact on bone metabolism. This lack of knowledge is particularly true for lanthanides and actinides, whose use has been increasing over recent decades. These metals, known as f-elements, present chemical similarities and differences. After a comparison of the biologically relevant physicochemical properties of lanthanides and actinides, and a brief reminder of the main events of bone metabolism, this review considers the results published over the past decade regarding the interaction between bones and f-elements. Emphasis will be given to the molecular events, which constitute the basis of the most recent toxicological studies in this domain but still need further investigation. Ionic exchanges with the inorganic matrix, interactions with bone proteins, and cellular mechanism disturbances are mainly considered in this review.

Treatment of actinide exposures: a review of Ca-DTPA injections inside CEA-COGEMA plants.

Calcium diethylenetriamine pentacetate (Ca-DTPA) has been used for medical treatment of plutonium and americium contaminations in the CEA and COGEMA plants from 1970 to 2003. This paper is a survey of the injections Ca-DTPA administered as a chelating molecule and it will be a part of the authorisation process for Ca-DTPA by intravenous administration. Out of 1158 injections administered to 469 persons, 548 events of possible or confirmed contamination were reported. These employees were followed by occupational physicians according to the current French regulations. These incidents took place at work, were most often minor, not requiring follow-up treatment. The authors present (1) a synthesis of the most recent findings. Due to its short biological half-time and its limited action in the blood, Ca-DTPA does not chelate with plutonium and americium as soon as these elements are deposited in the target organs. It justifies an early treatment, even in cases of suspected contamination followed by additional injections if necessary (2) data concerning these 1158 injections (route of contamination, dosage, adverse effects, etc.) The authors also investigated a study on the efficacy of the product on a group of persons having received five or more injections. These results were compared with the efficacy estimated theoretically. Dosages and therapeutic schemes were proposed based on these observations. This synthesis is the result of a collective work having mobilised the occupational medicine departments, the medical laboratories inside a working group CEA-COGEMA-SPRA.

Limits of DPUI application associated with the number of particles within actinide aerosols.

Dose per unit intake (DPUI) of radionuclides is obtained using International Commission on Radiological Protection (ICRP) models. After inhalation exposure, the first model calculates the fraction of activity deposited within the different regions of the respiratory tract, assuming that the aerosol contains an infinite number of particles. Using default parameters for workers, an exposure to one annual limit of intake (ALI) corresponds to an aerosol of 239PuO2 containing approximately 1 x 10(6) particles. To reach such an exposure, very low particle number might be involved especially for compounds having a high specific activity. This study provides examples of exposures to actinide aerosols for which the number of particles is too low for a standard application of the ICRP model. These examples, which involve physical studies of aerosols collected at the workplace and interpretation of bioassay data, show that the number of particles of the aerosol can be the main limit for the application of DPUI after inhalation exposure.

Uncertainties in estimation of intakes of actinides for dose reconstruction cases.

Intakes and doses arising from exposure to actinides must be reconstructed from historical bioassay data for the purposes of worker compensation and for epidemiology studies. The usual default assumption is that a series of urine activities is the result of a constant chronic intake. In reality, the urine activities will most likely arise from a random sequence of discrete intakes. In order to investigate the accuracy of the constant chronic assumption, we have created virtual urine datasets using Monte Carlo modelling and these were used as input to the code IMBA(1). Comparisons of estimated intakes with those used as input allow the uncertainties in the procedure to be estimated. The effects of incorrect assumptions about the scattering factors, activity median aerodynamic diameter (AMAD) and solubility can also be examined. The results show that the constant chronic assumptions leads to remarkably reliable estimates of intake, even for datasets generated by just a few intakes per year. The estimate of intake is fairly robust against mis-assignment of scattering factor and AMAD. However, as is well-known, the correct assignment of solubility is crucial in obtaining reliable estimates of intake and dose.

MEDOR, a didactic tool to support interpretation of bioassay data after internal contamination by actinides.

A didactic software, MEthodes DOsimètriques de REférence (MEDOR), is being developed to provide help in the interpretation of biological data. Its main purpose is to evaluate the pertinence of the application of different models. This paper describes its first version that is focused on inhalation exposure to actinide aerosols. With this tool, sensitivity analysis on different parameters of the ICRP models can be easily done for aerosol deposition, in terms of activity and particle number, actinide biokinetics and doses. The user can analyse different inhalation cases showing either that dose per unit intake cannot be applied if the aerosol contains a low number of particles or that an inhibition of the late pulmonary clearance by particle transport can occur which contributes to a 3-4 fold increase in effective dose as compared with application of default parameters. This underlines the need to estimate systematically the number of deposited particles, as well as to do chest monitoring as long as possible.

[The parameters of clearance of industrially significant alpha-emitters from the lungs of mammals].

Results of assessment of biokinetic parameters of change in the burden of significant alpha-emitters in the lungs of mammals in various times after inhalation intake (Qt(lung)) were generalized. 1740 Wistar rats of both sex with the initial age of 2-2.5 months and 143 mature mongrel dogs used in 23 and 3 animal tests, respectively, were involved in this work. The analysis of experimental data resulted in selection of three groups of chemically soluble compounds of alpha-emitters that differ in the rate of radionuclide clearance from the lung as well as in integral doses. Stable complex compounds of quadrivalent and of hexavalent nuclides and non-complex salts of quinquivalent and of hexavalent 237Np were assigned to the group of soluble compounds of 239Pu and 237Np. A three-component exponential model of change in Qt(lung) with the prevalence of fast and of intermediate phases (55%, T(eff) = 0.41 days and 35%, T(eff) = 18.1 days respectively) and the presence of a slow clearance phase (10%, T(eff) = 206 days) was developed for these compounds. Complex compounds of quadrivalent 239Pu and 237Np unstable in the environment of pH and of body temperature, their non-complex salts of mineral acids in ionic or polymer form, and submicron plutonium dioxide (SMD = 0.07 mkm) were assigned to the group of relatively soluble compounds includes. An exponential model with 2-3 components with the prevalence of intermediate and of slow clearance phases (71%, T(eff) = 19.3 days and 22%, T(eff) = 169 days respectively) was developed for compounds of this group. The third group of the compounds is presented based on the soluble 241Am compounds that could be typical for stable trivalent compounds of rare-earth and transuranium radionuclides. Their biokinetics is described by a 3-4-component exponential model with the fast phase prevailing (96.7%, T(eff) < or = 6.8 days), and with intermediate (2.6%, T(eff) = 69 days) and with slow (0.7%, T(eff) = 1040 days) phases being negligible. Physical chemicas and biological processes determining nuclides biokinetics in lungs are discussed.

Monte Carlo modelling of a voxel head phantom for in vivo measurement of bone-seeker nuclides.

Whole-body counters (WBCs) are used for the assessment of the internal contamination of actinides in the human body. WBCs require adequate calibration procedures that rely on the use of suitable calibration phantoms. A previous study carried out at the ENEA-Radiation Protection Institute was aimed at designing a head calibration phantom in which a heterogeneous distribution of 241Am point sources could satisfactorily approximate an assumed homogeneous contamination throughout the head bones. Suitable correction factors for the WBC detection efficiencies were evaluated with Monte Carlo. The present paper summarises the main aspects and implications of an advanced modelling technique based on a VOXEL approach. The methodology could be extended to other bone-seeker radionuclides.

The contribution of chemical speciation to internal dosimetry.

Speciation studies refer to the distribution of species in a particular sample or matrix. These studies are necessary to improve the description, understanding and prediction of trace element kinetics and toxicity. In the case of internal contamination with radionuclides, speciation studies could help to improve both the biokinetic and dosimetric models for radionuclides. There are different methods to approach the speciation of radionuclides in a biological system, depending on the degree of accuracy needed and the level of uncertainties accepted. Among them, computer modelling and experimental determination are complementary approaches. This paper describes what is known about speciation of actinides in blood, GI tract, liver and skeleton and of their consequences in terms of internal dosimetry. The conclusion is that such studies provide very valuable data and should be targeted in the future on some specific tissues and biomolecules.

The United States Transuranium and Uranium Registries as sources for actinide dosimetry and bioeffects.

The United States Transuranium and Uranium Registries (USTUR) has analysed tissues collected at autopsies of over 300 former radiation workers from actinide processing sites throughout the US, in addition to collecting the medical and radiation exposure histories of those workers. These data are included in a large USTUR database and they are available to research scientists throughout the world, either as public records or through collaborative projects with the USTUR. The USTUR also operates the National Human Radiobiological Tissue Repository (NHRTR), in which portions of tissue samples collected at autopsy are kept. These samples, frozen at -70 degrees C, may be used for molecular studies of the effects of radiation. Medical and radiation exposure histories of the tissue donors are available, as are the results of radiochemical analyses of adjacent portions of the samples. These materials are available to researchers who have collaborative agreements with the USTUR, which can be established by accessing USTUR staff members through the website, http://www.ustur.wsu.edu.

Application of Monte Carlo calculations to calibration of anthropomorphic phantoms used for activity assessment of actinides in lungs.

This paper reports on a new utility for development of computational phantoms for Monte Carlo calculations and data analysis for in vivo measurements of radionuclides deposited in tissues. The individual parameters of each worker can be acquired for an exact geometric representation of his or her anatomy, which is particularly important for low-energy gamma ray emitting sources such as thorium, uranium, plutonium and other actinides. The software discussed here enables automatic creation of an MCNP input data file based on computed tomography (CT) scanning data. The utility was first tested for low- and medium-energy actinide emitters on Livermore phantoms, the mannequins generally used for lung counting, in order to compare the results of simulation and measurement. From these results, the utility's ability to study uncertainties in in vivo calibration were investigated. Calculations and comparison with the experimental data are presented and discussed in this paper.