Evolution of the percutaneous penetration and distribution of uranyl nitrate as a function of skin-barrier integrity: an in vitro assessment.

As recommended by OECD Guidelines, percutaneous penetration studies consider intact skin, but rarely injured skin. Recent years have witnessed a growing concern for these two types of dermal exposure in the industry, particularly in the nuclear industry. The aim of this study was to show that a method based on an in vitro device can be used to realistically assess how skin-barrier alterations caused by occupational accidents can modify the percutaneous penetration and distribution of radionuclides, particularly uranium. Wounds encountered in the nuclear industry (i.e., nitric acid burns and abrasion) were simulated on hairless rat skin. Skin-barrier alterations were characterized by means of a histological study and by measuring transepidermal water loss (TEWL) and skin thickness. The percutaneous penetration of uranyl nitrate through intact or injured skin biopsies was then measured in vitro. The maximum uranium flux values obtained for intact skin, skin abrasion with stratum corneum removal, and skin exposed to 2 N HNO(3), 5 N HNO(3), and 14 N HNO(3) were, respectively, 0.6 +/- 0.02, 1.2 +/- 0.03, 1.2 +/- 0.04, 42.0 +/- 1.0, and 174.0 +/- 8.7 ng.cm(-2).h(-1). These results demonstrated that the percutaneous absorption of uranium increased with the increased impairment of the stratum corneum. TEWL, combined with maximum uranium flux values measured in vitro, yielded a good prediction of the percutaneous penetration of uranium through injured skin, previously observed in vivo. To conclude, this in vitro assay provides a conservative estimate of the percutaneous diffusion of uranium through intact or injured skin, making it a good alternative method for toxicological studies and risk assessments.

Water-sediment interactions for Hyalella azteca exposed to uranium-spiked sediment.

Data on the toxicity of uranium in sediments to Hyalella azteca and the effect of overlying water chemistry are limited. This study exposed H. azteca to sediments spiked with U (0-10,000 microg U/g dry weight) and five different overlying waters, which varied independently in hardness and alkalinity. Water pH had a major effect on U bioavailability and uptake by H. azteca. Uranium toxicity was higher when overlying water pH was low, while desorption of U into the overlying water increased with increasing pH. There appears to be little effect of Ca on U uptake, other than its influence on U speciation. Experiments with caged animals indicate that U accumulation and toxicity occur mainly through the dissolved phase rather than the solid phase. Uranium bioaccumulation is a more reliable indicator of U toxicity than U concentration in water or sediment. Uranium bioaccumulation in the H. azteca and U adsorption to sediment can be satisfactorily explained using saturation models.

Acute exposure of uranyl nitrate causes lipid peroxidation and histopathological damage in brain and bone of Wistar rat.

Although the kidneys are the main target organs for uranium (U) toxicity, recent studies have shown that U can cross the blood-brain barrier to accumulate in the brain. Uranyl nitrate (U-238)induced oxidative damage was investigated in brain and bone of Wistar rats after intraperitoneal injection of uranyl nitrate at acute doses either nephrotoxic (576 microg of U/kg body weight) or subnephrotoxic (144 microg U/kg body weight). The health effects of U administration at 576 microg of U/kg body weight were seen in terms of decrease in food intake and no gain in body weight compared to respective controls. These alterations were correlated with increased lipid peroxidation as measured by thiobarbituric acid reactive substances in rat brain and bone. However, at lower dosage of U (144 microg U/kg body weight), no significant lipid peroxidation was observed in brain and bone. Histological examination of U-treated (576 microg of U/kg body weight) rat brain tissues showed marked and diffuse cystic degeneration and a similar pattern in histological alterations was observed in kidneys in treated animals; whereas no significant histological change was observed in rat brains and kidney treated with a lower dose of U (144 microg U/kg body weight). It is concluded that administration of U at an acute nephrotoxic dose caused oxidative stress in brain and bone manifested as lipid peroxidation and histopathological damage.

Absorption, accumulation and biological effects of depleted uranium in Peyer's patches of rats.

The digestive tract is the entry route for radionuclides following the ingestion of contaminated food and/or water wells. It was recently characterized that the small intestine was the main area of uranium absorption throughout the gastrointestinal tract. This study was designed to determine the role played by the Peyer's patches in the intestinal absorption of uranium, as well as the possible accumulation of this radionuclide in lymphoid follicles and the toxicological or pathological consequences on the Peyer's patch function subsequent to the passage and/or accumulation of uranium. Results of experiments performed in Ussing chambers indicate that the apparent permeability to uranium in the intestine was higher (10-fold) in the mucosa than in Peyer's patches ((6.21+/-1.21 to 0.55+/-0.35)x10(-6)cm/s, respectively), demonstrating that the small intestinal epithelium was the preferential pathway for the transmucosal passage of uranium. A quantitative analysis of uranium by ICP-MS following chronic contamination with depleted uranium during 3 or 9 months showed a preferential accumulation of uranium in Peyer's patches (1355% and 1266%, respectively, at 3 and 9 months) as compared with epithelium (890% and 747%, respectively, at 3 and 9 months). Uranium was also detected in the mesenteric lymph nodes ( approximately 5-fold after contamination with DU). The biological effects of this accumulation of depleted uranium after chronic contamination were investigated in Peyer's patches. There was no induction of the apoptosis pathway after chronic DU contamination in Peyer's patches. The results indicate no change in the cytokine expression (Il-10, TGF-beta, IFN-gamma, TNF-alpha, MCP-1) in Peyer's patches and in mesenteric lymph nodes, and no modification in the uptake of yeast cells by Peyer's patches. In conclusion, this study shows that the Peyer's patches were a site of retention for uranium following the chronic ingestion of this radionuclide, without any biological consequences of such accumulation on Peyer's patch functions.

Radiation protection by deferiprone in animal models.

The effectiveness of deferiprone (L1) in removing depleted uranium (DU) and protecting animals from radiation exposure was examined. Rats that had received 2 mg/kg DU via intramuscular injection were orally administered 100, 200 or 400 mg/kg L1 for 3 days. In all of the groups, significant increases in urinary DU excretion and decreases in DU concentration in the injected muscle were observed, indicating that L1 combined with DU and DU was excreted in the urine. No significant increase in the amount of DU in the excreta or decrease in DU concentration in organs other than the muscles was found. As a preliminary test, the effectiveness of L1 in reducing radiation damage was examined in mice injected with 400 mg/kg L1 and rats administered orally with 200 and 400 mg/kg L1 before and just after x-ray exposure. The results were inconclusive.

In vitro evaluation of percutaneous diffusion of uranyl nitrate through intact or excoriated skin of rat and pig.

At the present time, the International Commission on Radiological Protection (ICRP) has not published any model concerning internal radioactive contamination by uptake from wounds. The aims of our work were to determine the time available to treat contamination of intact or wounded skin before a significant uptake of uranium occurred and to evaluate the consequences of incomplete decontamination on uranium uptake. The kinetics of percutaneous diffusion of uranium through intact or excoriated skin and its distribution in skin layers were evaluated using an in vitro technique. Our data demonstrated a dramatic increase of uranium percutaneous diffusion through excoriated skin compared with intact skin. Significant uptake of uranium through excoriated skin occurred in only 30 min, indicating that there is only a short interval available to treat a contaminated wound effectively. Moreover, in the case of an incompletely decontaminated superficial wound, viable epidermis behaved as a reservoir for uranium that remained bioavailable. At the present time, potential uptake of uranium and perhaps other radionuclides through intact or wounded skin is not adequately taken into account by radiological protection agencies. Our results emphasize the need for further study and modeling of uptake of radionuclides through intact or wounded skin.

Role of alveolar macrophages in precipitation of mineral elements inhaled as soluble aerosols.

The lysosomes of several varieties of cells such as the tubular proximal cell of the kidney and the alveolar macrophage have the ability to concentrate and precipitate several elements inhaled in water-soluble form, usually as phosphate. The mechanism involved is attributed to the high acid phosphatase activity of lysosomes and can be considered as an in vivo Gomori reaction. Among the elements studied, most of them are chemotoxic or radiotoxic (Cr; group IIIA: Al, Ga, In; rare earths: La, Ce, Tm; actinides: Th, U). In the lung macrophage, this mechanism of intralysosomal concentration and precipitation may prevent the diffusion of these toxic elements through the alveolar membrane.

The clearance of uranium after deposition of the nitrate and bicarbonate in different regions of the rat lung.

This study investigated the tissue distribution and excretion of uranium after its deposition as either the nitrate or bicarbonate in the three regions of the respiratory system of the rat. Results confirm the recommendations of ICRP that uranyl nitrate and bicarbonate should be treated as class D compounds; but imply that some of the parameters used in the ICRP lung model are not applicable to soluble uranium compounds.