Intranasal exposure to uranium results in direct transfer to the brain along olfactory nerve bundles.

AIMS: Uranium olfactory uptake after intranasal exposure raises some concerns for people potentially exposed to airborne radionuclide contamination as the brain could be a direct target for these contaminants. A model of nasal instillation was used to elucidate the transport mechanisms of uranium to the brain and to map its localization. METHODS: Increasing concentrations of depleted uranium containing solutions were instilled in the nasal cavity of adult male rats. Uranium concentrations were measured using inductively coupled plasma-mass spectrometry (ICP-MS) 4 h after instillation. Olfactory neuroepithelium cytoarchitecture was studied using immunohistochemistry experiments. Secondary ion mass spectrometry (SIMS) microscopy was performed to localize uranium in the olfactory system. RESULTS: ICP-MS analyses showed a frontal accumulation of uranium in the olfactory bulbs associated with a smaller increase in more caudal brain regions (frontal cortex, hippocampus and cerebellum). Uranium concentrations in the olfactory bulbs do not reach a saturation point. Olfactory nerve bundle integrity is not affected by uranium as revealed by immunohistochemistry. SIMS microscopy allowed us to show that uranium localization is mainly restricted to the olfactory neuroepithelium and around olfactory nerve bundles. It is subsequently detected in the olfactory nerve layer of the olfactory bulb. DISCUSSION: These results suggest the existence of a transcellular passage from the mucosa to the perineural space around axon bundles. Uranium bypasses the blood brain barrier and is conveyed to the brain via the cerebrospinal fluid along the olfactory nerve. Future studies might need to integrate this new contamination route to assess uranium neurotoxicity after nasal exposure.

Molecular, cellular, and tissue impact of depleted uranium on xenobiotic-metabolizing enzymes.

Enzymes that metabolize xenobiotics (XME) are well recognized in experimental models as representative indicators of organ detoxification functions and of exposure to toxicants. As several in vivo studies have shown, uranium can alter XME in the rat liver or kidneys after either acute or chronic exposure. To determine how length or level of exposure affects these changes in XME, we continued our investigation of chronic rat exposure to depleted uranium (DU, uranyl nitrate). The first study examined the effect of duration (1-18 months) of chronic exposure to DU, the second evaluated dose dependence, from a level close to that found in the environment near mining sites (0.2 mg/L) to a supra-environmental dose (120 mg/L, 10 times the highest level naturally found in the environment), and the third was an in vitro assessment of whether DU exposure directly affects XME and, in particular, CYP3A. The experimental in vivo models used here demonstrated that CYP3A is the enzyme modified to the greatest extent: high gene expression changed after 6 and 9 months. The most substantial effects were observed in the liver of rats after 9 months of exposure to 120 mg/L of DU: CYP3A gene and protein expression and enzyme activity all decreased by more than 40 %. Nonetheless, no direct effect of DU by itself was observed after in vitro exposure of rat microsomal preparations, HepG2 cells, or human primary hepatocytes. Overall, these results probably indicate the occurrence of regulatory or adaptive mechanisms that could explain the indirect effect observed in vivo after chronic exposure.

Chronic exposure to low concentrations of strontium 90 affects bone physiology but not the hematopoietic system in mice.

The aim of this work was to delineate the effects of chronic ingestion of strontium 90 ((90) Sr) at low concentrations on the hematopoiesis and the bone physiology. A mouse model was used for that purpose. Parent animals ingested water containing 20 kBq l(-1) of (90) Sr two weeks before mating. Offspring were then continuously contaminated with (90) Sr through placental transfer during fetal life, through lactation after birth and through drinking water after weaning. At various ages between birth and 20 weeks, animals were tested for hematopoietic parameters such as blood cell counts, colony forming cells in spleen and bone marrow and cytokine concentrations in the plasma. However, we did not find any modification in (90) Sr ingesting animals as compared with control animals. By contrast, the analysis of bone physiology showed a modification of gene expression towards bone resorption. This was confirmed by an increase in C-telopeptide of collagen in the plasma of (90) Sr ingesting animals as compared with control animals. This modification in bone metabolism was not linked to a modification of the phosphocalcic homeostasis, as measured by calcium, phosphorus, vitamin D and parathyroid hormone in the blood. Overall these results suggest that the chronic ingestion of (90) Sr at low concentration in the long term may induce modifications in bone metabolism but not in hematopoiesis.

Chronic exposure to natural uranium via drinking water affects bone in growing rats.

BACKGROUND: Bone is the main site of uranium accumulation after long term contamination. Several studies describe that at high dose of exposure, uranium impairs bone growth. Nevertheless little is known about the effects of chronic exposure at low doses of this radionuclide on bone, especially when ingested via drinking water, which is considered as the main exposure pathway for the public. METHODS: In this study, male rats were exposed to natural uranium in drinking water for a 9 month period, either at 40 mg l(-1) starting just after birth (post-natal model) or starting at 3 months of age (adult model). RESULTS: In the post-natal model at 40 mg l(-1), three-dimensional microtomography analysis showed that NU decreased significantly the cortical bone diameter in NU-contaminated rats. Bone histomorphometry analysis also showed a significant increase of the osteoid thickness in trabecular bone of the femur of NU-contaminated rats. In addition, mRNA expression in trabecular bone of genes involved in osteoblast differentiation (OSX, BMP2, RUNX2), bone remodeling (TRAP, OCN), bone mineralization (BSP, OPN, DMP1), calcium transport (TRPV5) as well as vitamin D receptor (VDR) was significantly decreased in this model. In contrast, in the adult model, no morphometric, cellular and molecular changes were observed in bone. GENERAL SIGNIFICANCE: This study showed for the first time that NU at this concentration has no detectable effect in adult bone while it significantly affects growing bone, which thus appears more sensitive to low dose contamination by this radionuclide.

Uranium microdistribution in renal cortex of rats after chronic exposure: a study by secondary ion mass spectrometry microscopy.

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.

Biokinetics of 90Sr after chronic ingestion in a juvenile and adult mouse model.

The aim of our study was to define the biokinetics of (90)Sr after chronic contamination by ingestion using a juvenile and adult murine model. Animals ingested (90)Sr by drinking water containing 20 kBq l(-1) of (90)Sr. For the juvenile model, parents received (90)Sr before mating and their offspring were killed between birth and 20 weeks of ingestion. For the adult model, (90)Sr ingestion started at 9 weeks of age and they were killed after different ingestion periods up to 20 weeks. The body weight, food and water consumption of the animals were monitored on a weekly basis. Before killing and sampling of organs, animals were put in metabolic cages. (90)Sr in organs and excreta was determined by liquid scintillation ß counting. Highest (90)Sr contents were found in bones and were generally higher in females than in males, and (90)Sr retention varied according to the skeletal sites. An accumulation of (90)Sr in the bones was observed over time for both models, with a plateau level at adult age for the juvenile model. The highest rate of (90)Sr accumulation in bones was observed in early life of offspring, i.e. before the age of 6 weeks. With the exception of the digestive tract, (90)Sr was below the detection limit in all other organs sampled. Overall, our results confirm that (90)Sr mainly accumulates in bones. Furthermore, our results indicate that there are gender- and age-dependent differences in the distribution of (90)Sr after low-dose chronic ingestion in the mouse model. These results provide the basis for future studies on possible non-cancerous effects during chronic, long-term exposure to (90)Sr through ingestion in a mouse model, especially on the immune and hematopoietic systems.

Influence on the mouse immune system of chronic ingestion of 137Cs.

The aim of this work was to determine the possible occurrence of damage to the immune system during the course of chronic ingestion of (137)Cs. BALB/C mice were used, with (137)Cs intake via drinking water at a concentration of 20 kBq l(-1). Adults received (137)Cs before mating and offspring were sacrificed at various ages between birth and 20 weeks. Phenotypic analysis of circulating blood cells and thymocytes did not show any significant modification of immune cell populations in animals ingesting (137)Cs as compared with control animals, with the exception of a slight increase in Treg percentage at the age of 12 weeks. Functional tests, including proliferative response to mitogens such as phytohaemagglutinin, response to alloantigens in mixed lymphocyte reaction and immunoglobulin response to vaccine antigens such as tetanus toxin and keyhole limpet haemocyanin did not show any significant functional modification of the immune system in (137)Cs-ingesting animals as compared with control animals. Overall, our results suggest that chronic ingestion of a low concentration of (137)Cs in drinking water in the long term does not have any biologically relevant effect on the immune system.

Brain accumulation of inhaled uranium in the rat depends on aerosol concentration, exposure repetitions, particle size and solubility.

A rostro-caudal gradient of uranium (U) in the brain has been suggested after its inhalation. To study the factors influencing this mapping, we first used 30-min acute inhalation at 56 mg/m3 of the relatively soluble form UO4 in the rat. These exposure parameters were then used as a reference in comparison with the other experimental conditions. Other groups received acute inhalation at different concentrations, repeated low dose inhalation of UO4 (10 exposures) or acute low dose inhalation of the insoluble form UO2. At 24 h after the last exposure, all rats showed a brain U accumulation with a rostro-caudal gradient as compared to controls. However, the total concentration to the brain was greater after repeated exposure than acute exposure, demonstrating an accumulative effect. In comparison with the low dose soluble U exposure, a higher accumulation in the front of the brain was observed after exposure to higher dose, to insoluble particles and following repetition of exposures, thus demonstrating a dose effect and influences of solubility and repetition of exposures. In the last part, exposure to ultrafine U particles made it possible to show 24 h after exposure the presence of U in the brain according to a rostro-caudal gradient. Finally, the time-course after exposure to micronic or nanometric U particles has revealed greater residence times for nanoparticles.

Distribution of soluble uranium in the nuclear cell compartment at subtoxic concentrations.

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.

Biodistribution of (137)Cs in a mouse model of chronic contamination by ingestion and effects on the hematopoietic system.

The aim of this work was to define the possible occurrence of hematological changes during the course of a chronic ingestion of (137)Cs. A mouse model was used, with ingestion through drinking water with a cesium concentration of 20 kBq l(-1). Ingestion started in parent animals before mating, and (137)Cs intake and its effect on the hematopoietic system was studied in offspring at various ages between birth and 20 weeks. (137)Cs content was measured in various organs, indicating that (137)Cs was distributed throughout the organism including lympho-hematopoietic organs, i.e., femurs, spleen and thymus. However, we did not observe any effect on the hematopoietic system, whatever the parameter used. In fact, blood cell counts, mononuclear cell counts and progenitor frequency in bone marrow and spleen, and Flt3-ligand, Erythropoietin, G-CSF and SDF-1 concentration in plasma remained unchanged when compared to control animals. Moreover, phenotypic analysis did not show any change in the proportions of bone marrow cell populations. These results indicate that, although (137)Cs was found in all organs implicated in the hematopoietic system, this did not induce any changes in bone marrow function.

Hto, Tritiated Amino Acid Exposure and External Exposure Induce Differential Effects on Hematopoiesis and Iron Metabolism.

The increased potential for tritium releases from either nuclear reactors or from new facilities raises questions about the appropriateness of the current ICRP and WHO recommendations for tritium exposures to human populations. To study the potential toxicity of tritium as a function of dose, including at a regulatory level, mice were chronically exposed to tritium in drinking water at one of three concentrations, 10 kBq.l-1, 1 MBq.l-1 or 20 MBq.l-1. Tritium was administered as either HTO or as tritiated non-essential amino acids (TAA). After one month's exposure, a dose-dependent decrease in red blood cells (RBC) and iron deprivation was seen in all TAA exposed groups, but not in the HTO exposed groups. After eight months of exposure this RBC decrease was compensated by an increase in mean globular volume - suggesting the occurrence of an iron deficit-associated anemia. The analysis of hematopoiesis, of red blood cell retention in the spleen and of iron metabolism in the liver, the kidneys and the intestine suggested that the iron deficit was due to a decrease in iron absorption from the intestine. In contrast, mice exposed to external gamma irradiation at equivalent dose rates did not show any change in red blood cell numbers, white blood cell numbers or in the plasma iron concentration. These results showed that health effects only appeared following chronic exposure to concentrations of tritium above regulatory levels and the effects seen were dependent upon the speciation of tritium.

Effects of repeated potassium iodide administration on genes involved in synthesis and secretion of thyroid hormone in adult male rat.

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.

In vivo animal studies help achieve international consensus on standards and guidelines for health risk estimates for chronic exposure to low levels of tritium in drinking water.

Existing and future nuclear fusion technologies involve the production and use of large quantities of tritium, a highly volatile, but low toxicity beta-emitting isotope of hydrogen. Tritium has received international attention because of public and scientific concerns over its release to the environment and the potential health impact of its internalization. This article provides a brief summary of the current state of knowledge of both the biological and regulatory aspects of tritium exposure; it also explores the gaps in this knowledge and provides recommendations on the best ways forward for improving our understanding of the health effects of low-level exposure to it. Linking health effects specifically to tritium exposure is challenging in epidemiological studies due to high uncertainty in tritium dosimetry and often suboptimal cohort sizes. We therefore argued that limits for tritium in drinking water should be based on evidence derived from controlled in vivo animal tritium toxicity studies that use realistically low levels of tritium. This article presents one such mouse study, undertaken within an international collaboration, and discusses the implications of its main findings, such as the similarity of the biokinetics of tritiated water (HTO) and organically bound tritium (OBT) and the higher biological effectiveness of OBT. This discussion is consistent with the position expressed in this article that in vivo animal tritium toxicity studies carried out within large, multi-partner collaborations allow evaluation of a great variety of health-related endpoints and essential to the development of international consensus on the regulation of tritium levels in the environment. Environ. Mol. Mutagen. 59:586-594, 2018. © 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

Modifications of inflammatory pathways in rat intestine following chronic ingestion of depleted uranium.

The environmental contamination by dispersion of depleted uranium (DU) might result in its chronic ingestion of DU by local populations. The aim of this study was to determine if chronic ingestion of DU at low doses induces inflammatory reactions in intestine, first biological system exposed to uranium after ingestion. Experiments were performed with rats receiving uranium in drinking water (40 mg/l) during 3, 6, or 9 months. Several parameters referring to prostaglandin, histamine, cytokine, and nitric oxide (NO) pathways were assessed in ileum. Concerning the prostaglandin pathway, a twofold increase in gene expression of cyclooxygenase of type 2 was noted after 6 months, with no changes in prostaglandins levels. At the same time, a decrease in mast cell number was observed without any changes in histamine levels. Experiments on cytokines showed increased gene expression of interleukin (IL)-1beta and IL-10 at 6 months, and decreased messenger RNA level of CCL-2. This change was associated with decreased macrophage density. An opposite effect of DU was induced on neutrophils, since increased number was observed at 3 (x1.7) and 9 months (x3). The results obtained on NO pathway seemed to indicate that DU exposure inhibited this pathway (decreased endothelial NO synthase messenger RNA, inductive NO synthase activity and NO(2)(-)/NO(3)(-) levels) at 6 months. In conclusion, this study demonstrated that chronic ingestion of DU-induced time-dependent modifications of inflammatory pathways, notably in terms of immune cell content. The ultimate effects of DU contamination might be pathogenic by suppressing defense mechanisms or inducing hypersensitivity. Further experiments should be thus performed to determine real consequences on intestinal response to oral antigens.

Immune System Modifications Induced in a Mouse Model of Chronic Exposure to (90)Sr.

Strontium 90 ((90)Sr) remains in the environment long after a major nuclear disaster occurs. As a result, populations living on contaminated land are potentially exposed to daily ingesting of low quantities of (90)Sr. The potential long-term health effects of such chronic contamination are unknown. In this study, we used a mouse model to evaluate the effects of (90)Sr ingestion on the immune system, the animals were chronically exposed to (90)Sr in drinking water at a concentration of 20 kBq/l, for a daily ingestion of 80-100 Bq/day. This resulted in a reduced number of CD19(+) B lymphocytes in the bone marrow and spleen in steady-state conditions. In contrast, the results from a vaccine experiment performed as a functional test of the immune system showed that in response to T-dependent antigens, there was a reduction in IgG specific to tetanus toxin (TT), a balanced Th1/Th2 response inducer antigen, but not to keyhole limpet hemocyanin (KLH), a strong Th2 response inducer antigen. This was accompanied by a reduction in Th1 cells in the spleen, consistent with the observed reduction in specific IgG concentration. The precise mechanisms by which (90)Sr acts on the immune system remain to be elucidated. However, our results suggest that (90)Sr ingestion may be responsible for some of the reported effects of internal contamination on the immune system in civilian populations exposed to the Chernobyl fallout.

Metabolomics reveals dose effects of low-dose chronic exposure to uranium in rats: identification of candidate biomarkers in urine samples.

INTRODUCTION: Data are sparse about the potential health risks of chronic low-dose contamination of humans by uranium (natural or anthropogenic) in drinking water. Previous studies report some molecular imbalances but no clinical signs due to uranium intake. OBJECTIVES: In a proof-of-principle study, we reported that metabolomics is an appropriate method for addressing this chronic low-dose exposure in a rat model (uranium dose: 40 mg L-1; duration: 9 months, n = 10). In the present study, our aim was to investigate the dose-effect pattern and identify additional potential biomarkers in urine samples. METHODS: Compared to our previous protocol, we doubled the number of rats per group (n = 20), added additional sampling time points (3 and 6 months) and included several lower doses of natural uranium (doses used: 40, 1.5, 0.15 and 0.015 mg L-1). LC-MS metabolomics was performed on urine samples and statistical analyses were made with SIMCA-P+ and R packages. RESULTS: The data confirmed our previous results and showed that discrimination was both dose and time related. Uranium exposure was revealed in rats contaminated for 9 months at a dose as low as 0.15 mg L-1. Eleven features, including the confidently identified N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide and 4-hydroxyphenylacetylglycine, discriminated control from contaminated rats with a specificity and a sensitivity ranging from 83 to 96 %, when combined into a composite score. CONCLUSION: These findings show promise for the elucidation of underlying radiotoxicologic mechanisms and the design of a diagnostic test to assess exposure in urine, in a dose range experimentally estimated to be above a threshold between 0.015 and 0.15 mg L-1.

The neurotoxicology of uranium.

The brain is a target of environmental toxic pollutants that impair cerebral functions. Uranium is present in the environment as a result of natural deposits and release by human applications. The first part of this review describes the passage of uranium into the brain, and its effects on neurological functions and cognitive abilities. Very few human studies have looked at its cognitive effects. Experimental studies show that after exposure, uranium can reach the brain and lead to neurobehavioral impairments, including increased locomotor activity, perturbation of the sleep-wake cycle, decreased memory, and increased anxiety. The mechanisms underlying these neurobehavioral disturbances are not clearly understood. It is evident that there must be more than one toxic mechanism and that it might include different targets in the brain. In the second part, we therefore review the principal mechanisms that have been investigated in experimental models: imbalance of the anti/pro-oxidant system and neurochemical and neurophysiological pathways. Uranium effects are clearly specific according to brain area, dose, and time. Nonetheless, this review demonstrates the paucity of data about its effects on developmental processes and the need for more attention to the consequences of exposure during development.

Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice.

After Chernobyl and Fukushima Daï Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFα, MCP-1, IFNγ) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content.

Unexpected lack of deleterious effects of uranium on physiological systems following a chronic oral intake in adult rat.

Uranium level in drinking water is usually in the range of microgram-per-liter, but this value may be as much as 100 to 1000 times higher in some areas, which may raise question about the health consequences for human populations living in these areas. Our purpose was to improve knowledge of chemical effects of uranium following chronic ingestion. Experiments were performed on rats contaminated for 9 months via drinking water containing depleted uranium (0.2, 2, 5, 10, 20, 40, or 120 mg/L). Blood biochemical and hematological indicators were measured and several different types of investigations (molecular, functional, and structural) were conducted in organs (intestine, liver, kidneys, hematopoietic cells, and brain). The specific sensitivity of the organs to uranium was deduced from nondeleterious biological effects, with the following thresholds (in mg/L): 0.2 for brain, >2 for liver, >10 for kidneys, and >20 for intestine, indicating a NOAEL (No-Observed-Adverse-Effect Level) threshold for uranium superior to 120 m g/L. Based on the chemical uranium toxicity, the tolerable daily intake calculation yields a guideline value for humans of 1350 µg/L. This value was higher than the WHO value of 30 µg/L, indicating that this WHO guideline for uranium content in drinking water is very protective and might be reconsidered.

Inhalation of uranium nanoparticles: respiratory tract deposition and translocation to secondary target organs in rats.

Uranium nanoparticles (<100 nm) can be released into the atmosphere during industrial stages of the nuclear fuel cycle and during remediation and decommissioning of nuclear facilities. Explosions and fires in nuclear reactors and the use of ammunition containing depleted uranium can also produce such aerosols. The risk of accidental inhalation of uranium nanoparticles by nuclear workers, military personnel or civilian populations must therefore be taken into account. In order to address this issue, the absorption rate of inhaled uranium nanoparticles needs to be characterised experimentally. For this purpose, rats were exposed to an aerosol containing 107 particles of uranium per cm³ (CMD=38 nm) for 1h in a nose-only inhalation exposure system. Uranium concentrations deposited in the respiratory tract, blood, brain, skeleton and kidneys were determined by ICP-MS. Twenty-seven percent of the inhaled mass of uranium nanoparticles was deposited in the respiratory tract. One-fifth of UO2 nanoparticles were rapidly cleared from lung (T(½)=2.4 h) and translocated to extrathoracic organs. However, the majority of the particles were cleared slowly (T(½)=141.5 d). Future long-term experimental studies concerning uranium nanoparticles should focus on the potential lung toxicity of the large fraction of particles cleared slowly from the respiratory tract after inhalation exposure.