Incorporation and distribution of uranium in rats after a contamination on intact or wounded skin.

Uranium uptake can occur accidentally by inhalation, ingestion, injection, or absorption through intact or wounded skin. Intact or wounded skin routes of absorption of uranium have received little attention. The aims of our work were (1) to evaluate the influence of the type of wound contamination on the short term distribution and excretion of uranium in rats and (2) to generate data to assess the time available to treat contamination of intact or wounded skin before significant uptake of uranium occurs. Biokinetic data presented in the present paper are based on an in vivo rat model. This study shows that a significant uptake of a uranyl nitrate solution through intact skin can occur within the first 6 h of exposure. Absorption of a uranyl nitrate solution through excoriated skin is significant after only 30 min of exposure. After a 24-h exposure, uranium uptake through intact skin and excoriated skin represents about 0.4% and 38% of the initial deposit of uranium, respectively. Contaminated serious chemical skin burns induced by HNO3 or NaOH are paradoxically less important in terms of uranium uptake risk because 99% of the incorporated uranium remains trapped at the wound site and its incorporation is delayed for at least 6 h after the beginning of contamination. These results confirm that the biokinetics of a given physicochemical form of uranium incorporated after wound contamination depend largely on the physiological evolution of the considered wound. Each type of wound, with its corresponding biokinetics of a uranium species, is a particular case.

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.

Effect of DTPA on the nephrotoxicity induced by uranium in the rat.

The only treatment proposed after human contamination with MOX (mixed oxide of uranium and plutonium) is diethylenetriaminepentaacetic acid (DTPA), because plutonium is considered to be the major risk. However, both DTPA and uranium are nephrotoxic at high dosages and DTPA has been shown to increase in vitro the cytotoxicity induced by uranium on cultured epithelial tubular cells. This work aimed to test this effect in vivo. Rats were injected with subtoxic (57 microg kg(-1)) to toxic (639 microg kg(-1)) amounts of uranium as nitrate at 0 h, they received two DTPA injections (30 micromol kg(-1)) at 2 min and 24 h and were euthanased at 48 h. The nephrotoxic effects were evaluated by measurement of the body weight gain, food and water intake, measurement of biochemical parameters in urine and blood, and histological examination of one kidney. The main result was that DTPA did not increase the nephrotoxicity induced by uranium in the range of concentrations tested, which was inconsistent with the in vitro results.

The cytogenetic dosimetry of recent accidental overexposure.

When accidental exposure to ionizing radiations is suspected, optimal choice of a treatment strategy requires, in addition to information about the clinical signs and physical dosimetry, a determination by biological parameters of the dose received. The scoring of unstable chromosomal aberrations in peripheral blood lymphocytes is the current reference method. Preparation of these samples depends on the goal sought--an exact assessment of several irradiations or rapid triage in the case of a large-scale accident. Moreover, some adaptation may be necessary if the irradiation is either heterogenous or not recent. Despite the robustness and adaptability of this procedure, conventional cytogenetics remains a tedious and time-consuming technique, and it requires specialized staff. Scoring micronuclei in binucleated lymphocytes may be an easier, simpler altemative to a dicentric assay. This paper, which is based on the experience acquired by the IPSN in recent years in expert assessment of suspected radiations, has as its goal to provide a succinct technical guideline of these different approaches, as they are adapted to suspected recent irradiation and triage.

Biochemical indicators of whole-body gamma-radiation effects in the pig.

PURPOSE: Validation of the pig as an experimental animal model for dose assessment after ionizing irradiation. MATERIALS AND METHODS: The evolution of haematological and biochemical parameters was followed for up to 7 days after irradiation in pigs exposed to whole-body 60Co gamma-radiation at doses between O and 6 Gy. RESULTS: Some biochemical indicators showed significant variations: amylase, LDH, alkaline and acid phosphatases, ALT and iron. None of the studied parameters alone presents a reliable dose-effect relationship; however, there was evidence that the combination of lymphocyte and neutrophil counts and the determination of LDH, ALT, AST and urea levels allowed some dose determination, independent of time, if blood samples were taken within 7 days post-irradiation. CONCLUSION: The results confirm the main problems of biochemical dosimetry. However, the pig model could represent a useful alternative to the non-human primate in radiobiology research, especially in the case of partial-body exposure. A multiparametric approach to dose assessment seems to be possible in the pig model. Confirmation should be carried out using blood samples from patients undergoing radiotherapy treatment.

Characterization of the response of human bone marrow endothelial cells to in vitro irradiation.

Endothelial cell dysfunction is a classic consequence of radiation damage. Bone marrow endothelial cells (BMEC) are a critical component of the stroma in the regulation of haemopoiesis. In animal models, radiation-induced injury of BMEC has been described and a role for BMEC in haemopoietic regeneration after irradiation has been suggested. However, functions of BMEC involved in the haemopoietic regeneration have not been assessed. Therefore we studied the functional response of human BMEC to irradiation using the transformed human BMEC line (TrHBMEC) irradiated with 2. 5 or 10Gy. Our results showed a time- and a dose-dependent increase in damage to irradiated TrHBMEC measured by a decreased number of adherent cells which correlated with increased apoptosis and augmented release of soluble ICAM-1 and von Willebrand factor. 2 Gy irradiated TrHBMEC expressed more ICAM-1 on their surface than non-irradiated cells, whereas no change in VCAM-1, E-selectin and PECAM-1 expression was observed. An increased production of G-CSF, GM-CSF, IL-8, IL-6, IL-1alpha, IL-11, MIP-1alpha and SCF and no production of LIF, TNF-alpha, TPO and IL-3 by 2 Gy irradiated TrHBMEC was observed. The haemopoietic supportive function of TrHBMEC was not altered after a 2 Gy exposure. These results suggest that although radiation induces endothelial cell damage, irradiated cells still support the proliferation and the differentiation of CD34+ haemopoietic cells.

Role of alveolar macrophage lysosomes in metal detoxification.

The intracellular behaviour of different toxic mineral elements inhaled as soluble aerosols or as insoluble particles was studied in the rat by electron microscopy, electron probe microanalysis, and electron microdiffraction. This study showed that, after inhalation, aerosols of soluble elements like cerous chloride, chromic chloride, uranyl nitrate, and aluminium chloride, are concentrated in the lysosomes of alveolar macrophages and are precipitated in the lysosomes in the form of insoluble phosphate, probably due to the activity of acid phosphatase (intralysosomial enzyme). Also, after inhalation of crystalline particles that are insoluble or poorly soluble in water such as the illites (phyllosilicates), ceric oxides (opaline), and industrial uranium oxides (U3O8), the small crystals are captured by the alveolar macrophage lysosomes and transformed over time into an amorphous form. This structural transformation is associated with changes in the chemical nature of particles inhaled in the oxide form. Microanalysis of amorphous deposits observed after inhalation of uranium or ceric oxides has shown that they contain high concentrations of phosphorus associated with the initial elements cerium and uranium. These different processes tend to limit the diffusion of these toxic elements within the organism, whether they are inhaled in soluble form or not.

Role of alveolar macrophages in the dissolution of two different industrial uranium oxides.

This study was aimed at assessing and understanding some mechanisms involved in the intracellular particle transformation of two uranium oxides (U3O8 and UO2 + Umetal) produced by a new isotopic enrichment plant using laser technology. Instillations were conducted on rats with both uranium compounds and alveolar macrophages were harvested at different dates and prepared in order to be studied using transmission electron microscopy and electron energy loss spectrometry (EELS). The presence of particles in the cells was observed from the first day after instillation, and crystalline needles of uranyl phosphate appeared in the cytoplasm of the cells. These needles were more numerous after instillation with the mixture UO2 + Umetal than after administration of U3O8 and may be correlated with the higher solubility of UO2 + Umetal observed in vitro. The formation of insoluble needles in lysosomes is consistent with the insolubilisation of uranium observed after phagocytosis by alveolar macrophages.