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International audience; Purpose To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case ofprolonged exposure to radioactive iodine.Methods The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters.Results A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KIbetween 174 and 1190 μg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showedthat the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decreasein iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses.Conclusion Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.

Individual monitoring of workers exposed to the risk of intake of actinides requires suitable methods for measuring low level of excreted activity. The current protocols used for actinides analysis in bioassay are usually complicated and highly time consuming. In this work, a protocol based on the microwave digestion of urines followed by the separation of actinides using calix[6]arene-based chromatography columns and their measurement by a quadrupole ICP-MS is developed and validated, for the first time, on urine samples containing the three actinides, U, Pu and Am. With this protocol, the total analysis time is about 2 days, including the mineralization of urine and the chromatographic separation of actinides. Detection limits of actinides in urine are determined and compared to those obtained after “dilute and shoot” ICP-MS analysis or after alpha spectrometry measurement.

15th Coordination and Planning Meeting of the World-Health-Organization's Radiation-Emergency-Medical-Preparedness-and-Assistance-Network (WHO-REMPAN), Geneva, SWITZERLAND, JUL 03-05, 2017; Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here.

International audience; Background : In the context of a nuclear reactor accident, thyroid is the main target organ of radioactive iodines. To avoid as much as possible thyroid disorders or even cancer development, it is recommended to administer a single dose of potassium iodide to people at risk of exposure. Nevertheless, the Fu-kushima Dai-ichi disaster has pointed out many questions about the conditions of stable iodine prophylaxis implementation highlighting the need for reflection further revision of the actual "iodine doctrine". Therefore, providing useful data is required notably through the implementation of animal experiments to strengthen current knowledge and to edit new recommendations. Methods : Urinary iodine constitutes a very good indicator to investigate the function of thyroid, its interpretation demands reliable analyses. Prior to perform animal experiments, two calibration methods were designed by our lab and compared together (standard addition and external calibration) to assess the urinary concentration of stable iodine in urine by ICP-MS. They were validated based on several key parameters especially linearity, accuracy and limits of detection (LOD) and quantification (LOQ). Results : The results were nicely satisfying. Indeed, both calibration methods have indicated very good coefficients of correlations, accuracies with low expanded relative uncertainties were obtained. The estimated LOD in the sample for standard addition method and external calibration were fully acceptable, 0.39 µg·L −1 and 0.35 µg·L −1 , respectively. All performance criteria have been thus fulfilled successfully. The established methods were proven to be accurate, robust and sensitive. Once validated, both calibration methods were applied to rat urine samples and the results of z-score and Wilcoxon W test concluded that there were no statistically significant differences between both methods.

International audience; A method based on the coupling of a calixarene column used for the preconcentration of actinides to a quadrupole ICP-MS was developed for the separation of actinides and their on-line detection. First, a flow injection system was developed for aqueous U, Pu and Am on-line ICP-MS analysis. Then, chromatography parameters such as the column diameter and flow rates were optimised using the theoretical plate model. The detection limits achieved are 0.6 ng (7 μBq) for 238U, 16 pg (37 mBq) for 239Pu and 0.21 pg (27 mBq) for 241Am. The signal improvement achieved by this coupling method was discussed and compared to "dilute and shoot" analysis. Finally, this method was validated on certified reference materials of 238U, 239Pu and 241Am, at concentration levels close to the detection limits. © The Royal Society of Chemistry 2016.

International audience; No emergency decontamination treatment is currently available in the case of radiological skin contamination by uranium compounds. First responders in the workplace or during an industrial nuclear accident must be able to treat internal contamination through skin. For this purpose, a calixarene nanoemulsion was developed for the treatment of intact skin or superficial wounds contaminated by uranium, and the decontamination efficiency of this nanoemulsion was investigated in vitro and ex vivo. The present work addresses the in vivo decontamination efficiency of this nanoemulsion, using a rat model. This efficiency is compared to the radio-decontaminant soapy water currently used in France (Trait rouge®) in the workplace. The results showed that both calixarene-loaded nanoemulsion and non-loaded nanoemulsion allowed a significant decontamination efficiency compared to the treatment with soapy water. Early application of the nanoemulsions on contaminated excoriated rat skin allowed decreasing the uranium content by around 85% in femurs, 95% in kidneys and 93% in urines. For skin wounded by microneedles, mimicking wounds by microstings, nanoemulsions allowed approximately a 94% decrease in the uranium retention in kidneys. However, specific chelation of uranium by calixarene molecules within the nanoemulsion was not statistically significant, probably because of the limited calixarene-to-uranium molar ratio in these experiment conditions. Moreover, these studies showed that the soapy water treatment potentiates the transcutaneous passage of uranium, thus making it bioavailable, in particular when the skin is superficially wounded. © 2016 Elsevier Ireland Ltd

For a few years, the biological effects on ecosystems and the public of the bioaccumulation of radionuclides in situations of chronic exposures have been studied. This work, in keeping with the ENVIRHOM French research program, presents the uranium microdistribution by secondary ion mass spectrometry (SIMS) technique in the renal cortex of rats following chronic exposure to this low level element in the drinking water (40 mg/L) as a function to exposure duration (6, 9, 12, and 18 months). The SIMS mass spectra and 238U+ ion images produced with a SIMS CAMECA 4F-E7 show the kinetic of uranium accumulation in the different structures of the kidney. For the rats contaminated up to 12 months, the radioelement is mainly fixed in the proximal tubules; then after 18 exposure months, uranium is detected in all the segments of the nephron. This work has also shown that ion microscopy is an analytical method to detect trace elements and give elemental cartography at the micrometer scale.

Cutaneous contamination by radionuclides is a major concern in the nuclear industry. In case of skin exposure to uranium, no efficient emergency treatment is available to remove the actinide from the skin. For this purpose, we developed a nanoemulsion containing calixarene molecules displaying good chelating properties towards uranium. In this paper, we describe the ability of this formulation to trap uranium and limit its transfer from the cutaneous contaminated site into the blood. Uranium percutaneous diffusion kinetics was assessed with Franz cells over 24 h through intact and excoriated pig ear skin biopsies, after or without application of the nanoemulsion. Uranium distribution in the skin layers was analysed by SIMS microscopy. The results showed that prompt application of the calixarene nanoemulsion allows a 94% and 98% reduction of the amount of uranium diffused respectively through intact and excoriated skin. The formulation is still efficient in case of delayed application up to 30 minutes since the 24 h-uranium transfer through excoriated skin is reduced by 71%. Besides, no accumulation of uranium or uranium- calixarene chelate was observed in the different skin layers. In conclusion, this study demonstrated the efficiency of the calixarene nanoemulsion, which can be regarded as a promising treatment for uranium cutaneous contamination. © 2011 Elsevier B.V.

Thorium is a natural alpha-emitting element occurring in various ores and has numerous industrial applications. Routine monitoring of potentially exposed workers is generally achieved through radiobioassay (urine and faeces). The procedures currently used for analysing actinides such as thorium in urine require lengthy chemical separation associated with long counting times by alpha-spectrometry due to low activity levels. Thus, their main drawback is that they are time-consuming, which limits the frequency and flexibility of individual monitoring. In this context, this study developed new radiochemical procedures based on the use of tertbutylcalix[6]arenes bearing three carboxylic acid groups or three hydroxamic acid groups. These previous works demonstrated that these macrocyclic molecules immobilised on an inert solid support are excellent extractants for uranium, plutonium and americium. In this study, the authors investigated the thorium extraction by calix[6]arene columns. Experiments were performed on synthetic solutions and on real urine samples. The influence of various parameters, such as the thorium solution pH and the column flow rate on thorium extraction, was studied. The results showed that both calix[6]arenes are efficient to extract thorium. Thorium extraction is quantitative from pH=2 for synthetic solution and from pH=3 for real urine samples. This study has demonstrated that the column flow rate is a crucial parameter since its value must not be too high to achieve the steady-state complexation equilibrium. Finally, these results will be compared with those obtained for other actinides (U, Pu and Am) and the conditions of actinides' separation will be discussed. © The Author 2010. Published by Oxford University Press. All rights reserved.

International audience; Uranium is naturally found in the environment, and its extensive use results in an increased risk of human exposure. Kidney cells have mainly been used as in vitro models to study effects of uranium exposure, and very little about the effects on other cell types is known. The aim of this study was to assess the impact of depleted uranium exposure at the cellular level in human kidney (HEK-293), liver (HepG2), and neuronal (IMR-32) cell lines. Cytotoxicity studies showed that these cell lines reacted in a roughly similar manner to depleted uranium exposure, responding at a cytotoxicity threshold of 300-500 μM. Uranium was localized in cells with secondary ion mass spectrometry technology. Results showed that uranium precipitates at subtoxic concentrations (>100 μM). With this approach, we were able for the first time to observe the soluble form of uranium in the cell at low concentrations (10-100 μM). Moreover, this technique allows us to localize it mainly in the nucleus. These innovative results raise the question of how uranium penetrates into cells and open new perspectives for studying the mechanisms of uranium chemical toxicity.

International audience; Actinides determination in urine samples is part of the analyses performed to monitor internal contamination in case of an accident or a terrorist attack involving nuclear matter. Mineralisation is the first step of any of these analyses. It aims at reducing the sample volume and at destroying all organic compounds present. The mineralisation protocol is usually based on a wet ashing step, followed by actinides co-precipitation and a furnace ashing step, before redissolution and the quantification of the actinides by the appropriate techniques. Amongst the existing methods to perform the actinides co-precipitation, alkali-earth (typically calcium) precipitation is widely used. In the present work, the extraction of uranium(VI), plutonium(IV) and americium(III) from the redissolution solutions (called "mineralised urines") on calix[6]arene columns bearing hydroxamic groups was investigated as such an extraction is a necessary step before their determination by ICP-MS or alpha spectrometry. Difficulties were encountered in the transfer of uranium(VI) from raw to mineralised urines, with yield of transfer ranging between 0% and 85%, compared to about 90% for Pu and Am, depending on the starting raw urines. To understand the origin of such a difficulty, the speciation of uranium (VI) in mineralised urines was investigated by computer simulation using the MEDUSA software and the associated HYDRA database, compiled with recently published data. These calculations showed that the presence of phosphates in the "mineralised urines" leads to the formation of strong uranyl-phosphate complexes (such as UO2HPO4) which compete with the uranium (VI) extraction by the calix[6]arene bearing hydroxamic groups. The extraction constant of uranium (VI) by calix[6]arene bearing hydroxamic groups was determined in a 0.04 mol L-1 sodium nitrate solution (log K=4.86±0.03) and implemented in an extraction model taking into account the speciation in the aqueous phase. This model allowed to simulate satisfactorily the experimental uranium extraction data and to support the preliminary conclusions about the role of the phosphates present in mineralised urines. These calculations also showed that the phosphate/calcium ratio is a key parameter as far as the efficiency of the uranium (VI) extraction by the calix[6]arene columns is concerned. It predicted that the addition of CaCl2 in mineralised urines would release uranium (VI) from phosphates by forming calcium (II)-phosphate complexes and thus facilitate the uranium (VI) extraction on calix[6]arene columns. These predictions were confirmed experimentally as the addition of 0.1 mol L-1 CaCl2 to a mineralised urine containing naturally a high concentration of phosphate (typically 0.04 mol L-1) significantly increased the percentage of uranium (VI) extraction on the calix[6]arene columns. © 2015 Elsevier B.V. All rights reserved.

International audience; The present work aims at studying the decontamination efficacy of a calixarene-loaded nanoemulsion on two ex vivo wounded skin models mimicking superficial stings or cuts contaminated with uranium, and on a third model using excoriation. The decontaminating formulation was compared with the currently used radio-decontaminating soapy water (Trait rouge®) treatment. Moreover, to assess skin damage potentially induced by the undiluted nanoemulsion, in vitro toxicity studies were conducted on an in vitro reconstructed human epidermis, coupled with three different toxicity tests [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide, lactate dehydrogenase, and interleukin-1-α]. This work demonstrated not only a significant decontamination activity of the calixarene nanoemulsion on wounded skin, ranging from 92% to 94% of the applied uranium solution according to the ex vivo model used, but also the absence of side effects of this promising treatment. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

An oil-in-water cleansing emulsion containing calixarene molecule, an actinide specific chelating agent, was formulated in order to improve the decontamination of uranium from the skin. Commonly commercialized cosmetic ingredients such as surfactants, mineral oil, or viscosifying agents were used in preparing the calixarene emulsion. The formulation was characterized in terms of size and apparent viscosity measurements and then was tested for its ability to limit uranyl ion permeation through excoriated pig-ear skin explants in 24-h penetration studies. Calixarene emulsion effectiveness was compared with two other reference treatments consisting of DTPA and EHBP solutions. Application of calixarene emulsion induced the highest decontamination effect with an 87% decrease in uranium diffusion flux. By contrast, EHBP and DTPA solutions only allowed a 50% and 55% reduction of uranium permeation, respectively, and had the same effect as a simple dilution of the contamination by pure water. Uranium diffusion decrease was attributed to uranyl ion-specific chelation by calixarene within the formulation, since no significant effect was obtained after application of the same emulsion without calixarene. Thus, calixarene cleansing emulsion could be considered as a promising treatment in case of accidental contamination of the skin by highly diffusible uranium compounds.Health Phys. 105(4):000-000; 2013 © 2013 Health Physics Society.

Context: Since no specific treatment exists in case of cutaneous contamination by radionuclides such as uranium, a nanoemulsion comprising calixarene molecules, known for their good chelation properties, was previously designed. However, this fluid topical form may be not suitable for optimal application on the skin or wounds. Objective: To develop a texturing pharmaceutical form for the treatment of wounded skins contaminated by uranium. Materials and methods: The formulations consisted in oil-in-water (O/W) nanoemulsions, loaded with calixarene molecules. The external phase of the initial liquid nanoemulsion was modified with a combination of thermosensitive gelifying polymers: Poloxamer and HydroxyPropylMethylcellulose (HPMC) or methylcellulose (MC). These new formulations were characterized then tested by ex vivo experiments on Franz cells to prevent uranyl ions diffusion through excoriated pig ear skin explants. Results: Despite strong changes in rheological properties, the physico-chemical characteristics of the new nanoemulsions, such as the size and the zeta potential as well as macroscopic aspect were preserved. In addition, on wounded skin, diffusion of uranyl ions, measured by ICP-MS, was limited to less than 5% for both HPMC and MC nanoemulsions. Conclusions: These results demonstrated that a hybrid formulation of nanoemulsion in hydrogel is efficient to treat uranium skin contamination. © 2014 Informa Healthcare USA, Inc.

The general population is chronically exposed to uranium (234U, 235U, and 238U) and polonium (210Po) mainly through day-to-day food and beverage intake. The measurement of these naturally-occurring radionuclides in drinking water is important to assess their health impact. In this work the applicability of calix[6]arene-derivatives columns for uranium analysis in drinking water was investigated. A simple and effective method was proposed on a specific column called AQUALIX, for the separation and preconcentration of U from drinking water. This procedure is suitable for routine analysis and the analysis time is considerably shortened (around 4 h) by combining the separation on AQUALIX with fast ICP-MS measurement. This new method was tested on different French bottled waters (still mineral water, sparkling mineral water, and spring water). Then, the case of simultaneous presence of uranium and polonium in water was considered due to interferences in alpha spectrometry measurement. A protocol was proposed using a first usual step of spontaneous deposition of polonium on silver disc in order to separate Po, followed by the uranium extraction on AQUALIX column before alpha spectrometry counting. © 2013 Elsevier B.V.

cited By 14; This work aims to evaluate the efficiency of a calixarene emulsion for uranium extraction from a contaminated solution prior to apply such a delivery system to uranium skin decontamination. For this purpose, various experimental parameters that can influence the efficiency of the calixarene emulsion on uranium extraction were determined. The results show that the calixarene nanoemulsion effect can be observed after a very short time of contact with uranium-contaminated solution (5. min) and that it is still efficient in case of small volumes of contaminated solution. The pH of the contaminated solution was found to be the most important parameter affecting the calixarene nanoemulsion efficiency with a dramatic reduction of the uranium extraction rate in case of acidification of the contaminated medium. This lack of efficiency can be overcome by buffering the nanoemulsion continuous phase. The obtained results reveal that the calixarene nanoemulsion could represent a promising system for the emergency treatment of uranium cutaneous contamination. © 2010 Elsevier B.V.

Tetraorganothallium ate complexes have been prepared and reacted with enones to afford either the [1,2] or [1,4] addition product. Mixed ate complexes display high levels of chemoselectivity in the transfer of one of their ligands.

In this work the applicability of calix[6]arene columns for actinides analysis in urine samples and drinking water was investigated. A radiochemical procedure has been developed for U, Pu, Am analysis in urine. A simple and effective method has also been proposed on a specific column named AQUALIX, for the separation and preconcentration of U from drinking water. These procedures are suitable for routine analysis and require a considerably reduced number of steps of sample treatment as compared to current procedures. © 2009 Akadémiai Kiadó, Budapest, Hungary.

Accidental cutaneous contamination by actinides such as uranium occurring to nuclear power plant workers can lead to their dissemination in other tissues and induce severe damages. Until now, no specific emergency treatment for such contamination has been developed. The aim of the present work was to formulate a tricarboxylic calix[6]arene molecule, known to exhibit good affinity and selectivity for complexing uranium, within a topical delivery system for the treatment of skin contamination. Since calixarene was shown to reduce oil/water interfacial tension, we have designed an oil-inwater nanoemulsion, taking advantage of the small droplet size offering a high contact surface with the contaminated aqueous medium. Characterization of the calixarene nanoemulsion was performed by determination of the oily droplet size, zeta potential and pH, measured as a function of the calixarene concentration. The obtained results have confirmed the surface localization of calixarene molecules being potentially available to extract uranyl ions from an aqueous contaminated solution. In a preliminary experiments, the calixarene nanoemulsion was used for the removal of free uranium from an aqueous contaminated solution. Results showed that the calixarene nanoemulsion extracted up to 80 ± 5% of uranium, which demonstrates the potential interest of this delivery system for uranium skin decontamination. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association.

The microdistribution of uranium in the gills of freshwater bivalve Corbicula fluminea following chronic direct exposure to this radioelement has been investigated using the SIMS technique. Different exposure levels and exposure durations have been studied. The SIMS mass spectra and 238U+ ion images produced with a SIMS CAMECA 4F-E7 show an U accumulation with the lower aqueous U concentration (20 μg/L) and the influence of the exposure levels on the bioaccumulation capacities. Furthermore, the ionic images display a heterogeneous distribution of uranium within the gill structure whatever the exposure conditions are. This study, in keeping with the ENVIRHOM French research program, was led to the conclusion that ion microscopy is an appropriate analytical method for trace elements and can give elemental cartography in a biological tissue section. © 2009 Elsevier B.V. All rights reserved.

Individual monitoring of workers exposed to a risk of internal contamination with actinides is achieved through in vivo measurements (anthroporadiametry) and in vitro measurements (urine and feces). The procedures currently used for analyzing actinides in urine require lengthy separation associated with long counting times by alpha spectrometry due to low activity levels. Their main drawback is thus that they are time-consuming, which limits the frequency and flexibility of individual monitoring. In this context, the aim of this work, carried out by the Radiochemistry Laboratory at the Institute for Radiological Protection and Nuclear Safety (IRSN), is to propose alternative radiochemical procedures for the analysis of actinides U, Pu and Am in urine. In order to selectively extract actinides from urines, it is of interest to use calix[n]arene molecules. Indeed, the preorganized structure of these macrocyclic molecules is suitable for the complexation of ions and they can be easily functionalized to be more specific. Thus, the p-tertbutylcalix[6]arenes bearing three carboxylic acid groups or three hydroxamic acid groups are excellent extractants for uranium, and they have also a very good affinity for plutonium and americium. The extraction of actinides by these calixarene has been studied experimentally, and also by computational study for uranium. From these results, a new radiochemical procedure has been proposed for U, Pu, Am analysis in urine. For an application to bioassays laboratories, it was decided to immobilize the calix[6]arene molecules on an inert solid support, for implementation with a chromatographic column. This technique makes it possible to combine the extraction performances of the calix[6]arenes with the practical advantages of the chromatographic column. Consequently, this new radiochemical is well suited for routine analysis. Furthermore, the actinides separation is quantitative and reproducible, and is faster and easier than the current procedures.