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The use of animals in chemical testing and hazard assessment can be reduced using New Approach Methods or NAMs. In vitro human models have been successfully developed to measure the acute toxicity of drugs and environmental pollutants. In this study, we introduce the use of 3D model of the human bronchial epithelium to assess the repeated exposure to xenobiotics. The human lung epithelial cell line Calu-3 was exposed to silver nanoparticles at the air-liquid interface every 2 to 3 days during 12 days to mimic repeated exposure to inhaled particles. The biological effects of a single versus repeated exposure to silver nanoparticles were compared to determine whether transient, decreasing or increasing cellular responses were observed when exposing non-proliferating cells multiple times to a xenobiotic. Our results showed a stronger induction of the cellular response to metal stress after repeated exposure, and a stable oxidative stress response after a single or repeated exposure. While the epithelial barrier integrity was not affected, sustained translocation of silver was observed in the basal medium after each exposure. On the apical side, the proteomic analysis of the mucus revealed changes in the secreted protein profiles associated with the epithelial immune response after multiple exposure to silver nanoparticles that were unseen after a single exposure. These results demonstrate that it is possible and necessary to take into account the adaptive response of human cells using advanced NAMs to assess the toxicity of chemicals or environmental pollutants when chronic exposure is likely to occur.

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.

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.

Background A single dose of potassium iodide (KI) is recommended to reduce the risk of thyroid cancer during nuclear accidents. However in case of prolonged radioiodine exposure, more than one dose of KI may be necessary. This work aims to evaluate the potential toxic effect of repeated administration of KI. Methods Adult Wistar rats received an optimal dose of KI 1 mg/kg over a period of 1, 4 or 8 days. Results hormonal status (TSH, FT4) of treated rats was unaffected. Contrariwise, a sequential Wolff-Chaikoff effect was observed, resulting in a prompt decrease of NIS and MCT8 mRNA expression (−58% and −26% respectively), followed by a delayed decrease of TPO mRNA expression (−33%) in conjunction with a stimulation of PDS mRNA expression (+62%). Conclusion we show for the first time that repeated administration of KI at 1 mg/kg/24h doesn't cause modification of thyroid hormones level, but leads to a reversible modification of the expression of genes involved in the synthesis and secretion of thyroid hormones.

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

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.

The aim of this study is to propose a single modeling structure to describe both plutonium and americium decorporation by DTPA, which is based on hypotheses mostly validated by experimental data. Decorporation efficacy of extracellular retention depends on the concentration ratio of DTPA vs. actinides and varies in each compartment according to the amount of biological ligands and their affinity for actinides. By contrast, because the relatively long residence time of DTPA after its cell internalization and the stability of actinide-DTPA complexes, intracellular decorporation efficacy is mainly controlled by a DTPA/actinide ratio, which is specific to each retention compartment. Although the affinity of DTPA is much lower for americium than for plutonium, a larger decorporation of americium can be obtained, which is explained by different biological ligands and/or their affinity for the actinide. Altogether, these results show that the relative contribution of intra vs. extracellular decorporation varies depending on the actinide, the chemical form of radionuclides, the galenic formulation of DTPA, and the treatment schedule.

Modelling Pu/Am decorporation by DTPA. A new tool has been developed to optimize DTPA efficacy as concerns reduction of effective dose after 239 Pu wound. For example, the simulations show, for moderately soluble compounds (type M), a 1/3 decrease of effective dose is obtained after repeated early treatment (24 i.v. for 4 months), whereas a decrease by a factor 5 can be reached if treatments continue for 5 years at 2 week interval. By contrast, for poorly soluble compounds (type S), negligible efficacy is observed after early treatments, and a 3 time decrease of dose is obtained for treatments performed at 2 week interval for 50 years. Some of the hypotheses retained for modelling DTPA decorporation are validated from new experimental data published recently, and structure of a new model which can be applied both to Pu and Am is reported, taking into account urinary and faecal excretion, structure being suitable for different doses of DTPA and using various galenic forms.

International audience; The possibility of accidents in the nuclear industry or of nuclear terrorist attacks makes the development of new decontamination strategies crucial. Among radionuclides, actinides such as uranium and plutonium and their different isotopes are considered as the most dangerous contaminants, plutonium displaying mostly a radiological toxicity whereas uranium exhibits mainly a chemical toxicity. Contamination occurs through ingestion, skin or lung exposure with subsequent absorption and distribution of the radionuclides to different tissues where they induce damaging effects. Different chelating agents have been synthesized but their efficacy is limited by their low tissue specificity and high toxicity. For these reasons, several groups have developed smart delivery systems to increase the local concentration of the chelating agent or to improve its biodistribution. The aim of this review is to highlight these strategies. © 2015 Elsevier B.V.

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.

International audience; Secure components are subject to physical attacks whose aim is to recover the secret information that they store. Most of works which aim to protect these components generally consist in developing protections (or countermeasures) taken one by one. But this ``countermeasure-centered'' approach drastically decreases the performances of the whole chip in terms of power and speed. Our work is complementary and consists in re-organising a given set of existing countermeasures in order to optimise both the security and the availability of the circuit without reducing its global performances. The proposed solution is based on a double-processor architecture and on mechanisms to parametrise the hardware and software countermeasures. One processor embeds the state-of-the-art set of countermeasures and executes the application code. The second processor, much smaller, applies the strategy of security (i.e the response of the circuit when a security event arises), but without sharing sensitive data with the first processor. We show that our approach enables the secure circuit's designer to easily fine tune the strategy of security, for example, of Pay-TV applications and could, in the future, be used to optimise dynamically the trade-off between performance and security.

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.

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.

Cellular internalisation of DTPA appears negligible. Thus, a fast urinary excretion of Pu-DTPA is observed after treatments, but a slow excretion also occurs, explained by Pu-DTPA retention within the interstitium (2.5% of Pu-DTPA, half-life 1 week). One day after 14C-DTPA i.v., 1-2% of the activity was retained in perfused soft tissues, demonstrating its cellular internalisation, whereas blood DTPA was 0.025%. Encapsulation of DTPA has been proposed to improve its cellular internalisation, and a nearly total liver decorporation was obtained using stealth® 100 nm-liposomes. This study estimates intracellular decorporation of Pu by different DTPA formulations. First, a biokinetic study was performed after Pu-DTPA i.v., to help interpretation of decorporation data. About 99% of Pu was excreted via urines for the first 3 days, followed by residual excretion. Similar Pu activities were measured in skeleton, liver, kidneys and urine of day 7 (0.1%). These values, quite different than those measured after Pu-citrate i.v., demonstrated the great stability of Pu-DTPA, in extra and intracellular environments. When DTPA solutions were given i.v., 1 hour after Pu-citrate i.v., both fast and slow excretion (half-life 3-4 days) of Pu-DTPA were observed. The ratio between fast and slow excretions increased with DTPA dosage and, at similar dosage, this ratio was much lower after pulmonary insufflation of dry DTPA powder than after i.v.. Therefore, fast excretion depends on DTPA concentration in blood, whereas slow excretion, associated with intracellular DTPA, depends on total DTPA administered. This was confirmed after specific liver or lung contamination. Then, most of the urinary decorporation involved a slow process observed for 1 month. Moreover, half-life of slow excretion appeared to vary depending on tissues. In a last experiment, a treatment was performed 1 day before Pu-citrate i.v. (30 and 300µmol.kg-1). A decorporation similar to a standard treatment (30µmol.kg-1, i.v. at+1h) was observed for the highest dosage (~50%), whereas a 25 % decorporation was obtained for the lowest dosage. Altogether, these results underline the importance of intracellular DTPA in the decorporation process which will be discuss in terms of modelling and radioprotection.

The aim of the study was to demonstrate that decorporation of 238Pu is achieved more efficiently by an optimized liposomal formulation of diethylene triamine pentaacetic acid (DTPA) than by the usual free DTPA treatment. The optimized formulation consisted of polyethylene glycol-coated stealth liposomes with a mean diameter of 100 nm (SL-100 nm). Rats were intravenously injected with various Pu-phytate salt solutions in order to test different contamination conditions (activity and salt concentration) impacting liver kinetics and skeletal uptake of Pu. All treatments were given intravenously 1 h after contamination. Efficiency was evaluated 24 h, 7, 16 or 30 days later through their ability to promote Pu elimination and to reduce Pu burden in the skeleton and liver, the main organs of Pu deposition and radiotoxicological effects. Whatever the conditions of contaminations, a single injection of SL-100 nm (3.2 micromol kg(-1) DTPA) boosted urinary elimination of Pu to above 90% of the injected dose. In addition, liposomes strongly and significantly reduced the Pu burden of the liver and skeleton even 30 days after a single treatment: a dose of 0.3 micromol kg(-1) induced the same skeletal Pu reduction as four injections of free DTPA (30 micromol kg(-1)). A log dose-effect relation was found with SL-100 nm DTPA and Pu excretion in urine or Pu burden in the studied organs (liver, femurs, spleen and kidneys). This efficacy was attributed to an optimized targeting of DTPA to the main Pu retention organs and especially the liver.

The aim of the present study was to develop an efficient DTPA liposome formulation designed for plutonium decorporation. DTPA was encapsulated in conventional (CL) and polyethylene glycol-coated stealth liposomes (SL) prepared by extrusion followed by the freeze-thawing method and sizing from around 100 to 800 nm. DTPA encapsulation percentages were approximately 30% in CL of any size but dropped from 48% to 7% as the diameter of SL was reduced. The pharmacokinetics of [(14)C]-DTPA encapsulated in large and small vesicles was evaluated in rats after a single intravenous administration. Both liposomal composition and size reduction had a significant impact on pharmacokinetic parameters, inducing a marked increased in exposure of the body to DTPA and its delayed excretion. DTPA distribution was moderate in liver but enhanced in spleen and bone and was dose-dependent, especially when SL of 100 nm were given. In conclusion, small and stealth(R) vesicles have interesting properties in delivering DTPA to contaminated tissues.