Low doses of uranium and osteoclastic bone resorption: key reciprocal effects evidenced using new in vitro biomimetic models of bone matrix.

Uranium is widely spread in the environment due to its natural and anthropogenic occurrences, hence the importance of understanding its impact on human health. The skeleton is the main site of long-term accumulation of this actinide. However, interactions of this metal with biological processes involving the mineralized extracellular matrix and bone cells are still poorly understood. To get a better insight into these interactions, we developed new biomimetic bone matrices containing low doses of natural uranium (up to 0.85 µg of uranium per cm2). These models were characterized by spectroscopic and microscopic approaches before being used as a support for the culture and differentiation of pre-osteoclastic cells. In doing so, we demonstrate that uranium can exert opposite effects on osteoclast resorption depending on its concentration in the bone microenvironment. Our results also provide evidence for the first time that resorption contributes to the remobilization of bone matrix-bound uranium. In agreement with this, we identified, by HRTEM, uranium phosphate internalized in vesicles of resorbing osteoclasts. Thanks to the biomimetic matrices we developed, this study highlights the complex mutual effects between osteoclasts and uranium. This demonstrates the relevance of these 3D models to further study the cellular mechanisms at play in response to uranium storage in bone tissue, and thus better understand the impact of environmental exposure to uranium on human bone health.

Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity.

Natural uranium (U), which is present in our environment, exerts a chemical toxicity, particularly in bone where it accumulates. Generally, U is found at oxidation state +VI in its oxocationic form [Formula: see text] in aqueous media. Although U(VI) has been reported to induce cell death in osteoblasts, the cells in charge of bone formation, the molecular mechanism for U(VI) effects in these cells remains poorly understood. The objective of our study was to explore U(VI) effect at doses ranging from 5 to 600 µM, on mineralization and autophagy induction in the UMR-106 model osteoblastic cell line and to determine U(VI) speciation after cellular uptake. Our results indicate that U(VI) affects mineralization function, even at subtoxic concentrations (<100 µM). The combination of thermodynamic modeling of U with EXAFS data in the culture medium and in the cells clearly indicates the biotransformation of U(VI) carbonate species into a meta-autunite phase upon uptake by osteoblasts. We next assessed U(VI) effect at 100 and 300 µM on autophagy, a survival process triggered by various stresses such as metal exposure. We observed that U(VI) was able to rapidly activate autophagy but an inhibition of the autophagic flux was observed after 24 h. Thus, our results indicate that U(VI) perturbs osteoblastic functions by reducing mineralization capacity. Our study identifies for the first time U(VI) in the form of meta-autunite in mammalian cells. In addition, U(VI)-mediated inhibition of the autophagic flux may be one of the underlying mechanisms leading to the decreased mineralization and the toxicity observed in osteoblasts.

Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome.

Natural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg·L(-1) for male rats and 40 mg·L(-1) for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L(-1) NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L(-1) NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

Calculation of internal dose from ingested soil-derived uranium in humans: Application of a new method.

The aim of the present study was to determine the internal dose in humans after the ingestion of soil highly contaminated with uranium. Therefore, an in vitro solubility assay was performed to estimate the bioaccessibility of uranium for two types of soil. Based on the results, the corresponding bioavailabilities were assessed by using a recently published method. Finally, these bioavailability data were used together with the biokinetic model of uranium to assess the internal doses for a hypothetical but realistic scenario characterized by a daily ingestion of 10 mg of soil over 1 year. The investigated soil samples were from two former uranium mining sites of Germany with (238)U concentrations of about 460 and 550 mg/kg. For these soils, the bioavailabilities of (238)U were quantified as 0.18 and 0.28 % (geometric mean) with 2.5th percentiles of 0.02 and 0.03 % and 97.5th percentiles of 1.48 and 2.34 %, respectively. The corresponding calculated annual committed effective doses for the assumed scenario were 0.4 and 0.6 µSv (GM) with 2.5th percentiles of 0.2 and 0.3 µSv and 97.5th percentiles of 1.6 and 3.0 µSv, respectively. These annual committed effective doses are similar to those from natural uranium intake by food and drinking water, which is estimated to be 0.5 µSv. Based on the present experimental data and the selected ingestion scenario, the investigated soils-although highly contaminated with uranium-are not expected to pose any major health risk to humans related to radiation.

Radiological and chemical toxicity due to ingestion of uranium through drinking water in the environment of Bangalore, India.

Groundwater samples collected from 96 bore wells in the study area (city of Bangalore) were analysed for concentration of natural uranium using laser-induced fluorimetry. The risk to the population of the region associated with radiological and chemical toxicity of uranium due to its ingestion through drinking water over a lifetime was estimated. The concentration of uranium was found to be in the range 0.136 to 2027.5 µg L(-1) with an average value of 92.42 µg L(-1). In the present study, about 61% of the samples show concentrations of uranium within the safe limit of 30 µg L(-1) as set by the world health organisation. The radiological risk estimated as lifetime cancer risk is in the range 4.3 × 10(-7) to 6.4 × 10(-3) with an average of 2.9 × 10(-4). The chemical toxicity risk measured as lifetime average daily dose is found to range from 0.005 to 75.42 µg kg(-1) d(-1). The reference dose estimated as 1.12 µg kg(-1) d(-1) was used to assess the chemical toxicity. The results indicate that the chemical toxicity due to ingestion of uranium through drinking water is of more concern than the radiological toxicity. The present study, being the first of its kind in this region, will augment the database of uranium in groundwater.

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.

The ex-vivo intestinal absorption rate of uranium is a two-phase function of supply.

The concentration-dependent absorption behaviour of uranium was investigated with surviving intestinal segments of rat jejunums, using an ex-vivo model. The results showed a monotonic slightly nonlinear increase in absorption as uranium concentrations increased. This trend was observed over the entire concentration range tested. In the lower concentration range a slower linear ascent was observed while a steeper linear ascent was found for the higher concentration range. Statistical fit was only slightly poorer for an exponential function in the range of lower values and a logarithmic function in the range of higher values. The proportion of uranium absorbed expressed as percent of uranium concentrations in the perfusion solutions followed a monotonically increasing trend from 20 to around 200 µg/l uranium in the perfusion solutions, which thereafter appears to reach a plateau, as further increase towards concentrations around 400 µg/l is not substantial. The uranium concentration administered had no effect on the vitality and consequently the functionality of the intestinal segments, measured in terms of active glucose transport. The results imply that uranium concentrations of more than 20 µg/l in drinking water, for example, could lead to elevated absorption rates and thus to higher internal exposures to consider when setting of Guideline values in this concentration range.

Monte Carlo simulation of enriched uranium in the lungs of thorax voxel phantom for assessment of enrichment and its effect on dose.

In-vivo lung monitoring is an important technique for the assessment of internal dose of radiation workers handling actinides. At BARC, counting efficiencies (CEs) of detection systems used for estimation of natural uranium in the lungs are evaluated using realistic thorax physical phantoms or computational voxel phantoms. The quantification of 238U and 235U in lungs is done using CEs determined at 63.3 keV and 185.7 keV photon energies respectively. These CEs can also be used for assessment of enriched uranium in the lungs of the workers. In this study, spectra are generated for HPGe array detectors using Monte Carlo simulations of various enriched uranium compositions distributed in the lungs of thorax voxel phantom. A methodology is developed to predict the 235U enrichment from lung spectrum analysis using the ratio of net counts in 185.7 keV and 63.3 keV energy regions. It is possible to estimate enrichments in the range of 2%-30% using the developed method with less than ±9% error. Finally, effect of 235U enrichment on dose assessment using lung monitoring method is studied.

Chronic oral depleted uranium leads to reproductive damage in male rats through the ROS-hnRNP A2/B1-COX-2 signaling pathway.

Depleted uranium (DU) is widely used in civil and military activities. The testis is one of the target organs of DU chronic toxicity. In this study, male SD rats were chronically exposed to DU by 3, 30, 300 mg U/kg through oral intake. After 6 months and 12 months of exposure, it was found that DU could lead to increased oxidative stress levels, decreased glutathione S-transferases (GSTs) expression, resulting in testicular injury and decreased serum testosterone (T) level in rats. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) expression increases with the increase of DU exposure dose. After upregulation of hnRNP A2/B1 expression, the GC-1 cell injury caused by DU is aggravated, suggesting that hnRNP A2/B1 may play an important role in the reproductive toxicity of DU. At the same time, 12 months after chronic oral exposure to DU, the expression level of cyclooxygenase-2 (COX-2) and proinflammatory factor prostaglandin E2 (PGE2) in testicular tissue were increased, and the level of hnRNP A2/B1 caused by DU was decreased by reactive oxygen scavenger N-acetylcysteine (NAC). As hnRNP A2/B1 is a COX-2 regulator, DU may lead to the upregulation of hnRNP A2/B1 expression through the increase of oxidative stress level in germ cells, which in turn leads to the increase of COX-2 and PGE2 level, and ultimately result in the reproductive toxicity. In this study, the regulation mechanism of the ROS-hnRNP A2/B1-COX-2 pathway on DU-induced reproductive damage in male rats was hypothesized, providing a new target for the prevention and treatment of chronic poisoning of DU.

French cohort of the uranium processing workers: mortality pattern after 30-year follow-up.

OBJECTIVE: To investigate mortality among nuclear workers with potential internal exposure to uranium. METHODS: The cohort included 2,709 workers employed at the AREVA NC Pierrelatte plant for at least 6 months (72,787 person-years). This plant processed uranium enrichment during the period 1960-1996 and chemical conversion since 1980. Mortality was compared to the national and regional mortality rates available for the period 1968-2005. For causes of death of interest with respect to occupational exposure, mortality trends according to occupational characteristics were assessed. RESULTS: As expected, an important healthy worker effect (all causes SMR = 0.55 (95% CI: 0.50-0.61), n = 411; all cancers SMR = 0.70 (95% CI: 0.60-0.81), n = 193) was observed. Among cancer sites a priori related to uranium exposure, only mortality for lymphatic cancer was increased among potentially exposed workers (SMR = 1.49 (95% CI: 0.68-2.82); n = 9). An important increase in mortality from pleural cancer was observed (SMR = 2.85 (95% CI: 0.93-6.66), n = 5); none of the deceased workers were exposed to radiation whereas all handled asbestos. CONCLUSION: In spite of limited statistical power, results show consistency with previous studies of nuclear workers potentially exposed to uranium. Further investigation based on more precise uranium exposure data should allow the estimation of uranium hazard effects among this cohort.

Modifications of the expression of genes involved in cerebral cholesterol metabolism in the rat following chronic ingestion of depleted uranium.

Depleted uranium results from the enrichment of natural uranium for energetic purpose. Its potential dispersion in the environment would set human populations at risk of being contaminated through ingestion. Uranium can build up in the brain and induce behavior disorders. As a major constituent of the myelin sheath, cholesterol is essential to brain function, and several neurological pathologies result from a disruption of cholesterol metabolism. To assess the effect of a chronic contamination with depleted uranium on cerebral cholesterol metabolism, rats were exposed to depleted uranium for 9 months through drinking water at 40 mg/l. The study focuses on gene expression. Cholesterol-catabolizing enzyme CYP46A1 displayed a 39% increase of its messenger RNA (mRNA) level. 3-Hydroxy-3-methylglutamyl CoA synthase gene expression rose from 91%. Concerning cholesterol transport, mRNA levels of scavenger receptor-B1 and adenosine triphosphate-binding cassette transporter A1 increased by 34% and that of apolipoprotein E by 75%. Concerning regulation, gene expression of nuclear receptors peroxisome proliferator-activated receptors alpha and gamma increased by 46% and 36% respectively, whereas that of retinoid-X-receptor decreased by 29%. In conclusion, a chronic internal contamination with depleted uranium does not affect the health status of rats but induces molecular changes in the dynamic equilibrium of the cerebral cholesterol pool.

Renal dysfunction induced by long-term exposure to depleted uranium in rats.

Depleted uranium (DU) is a kind of radioactive heavy metal which can enter into the body via inhalation (aerosols), ingestion (drinking and eating) and wounds (embedded), and causes chemical and/or radiation-induced toxicities. In this study, male Sprague Dawley rats were surgically implanted in gastrocnemius muscle with DU fragments at three dose levels (low-dose, medium-dose and high-dose), with biologically inert tantalum (Ta) fragments served as controls. At 1 day, 7 days, and 3, 6, and 12 months after implantation, the rats were euthanized and tissue samples were collected, and uranium levels were measured in a variety of tissues by inductively coupled plasma-mass spectrometry (ICP-MS) to analyze the dynamic changes and distribution of uranium in rats. Thereafter, at 3, 6 and 12 months after implantation, the rats were euthanized after the collection of 24 h urine, blood and kidney samples were collected for analysis of DU-induced renal histopathologic changes and renal dysfunction. It was observed that DU concentrations in all the DU implanted groups were higher than that in Ta control group, and DU concentrations in the kidney increased with the implanted times, peaked at the 90 days after implantation, with a high correlation to the implanted DU doses, and then began to decrease gradually and slowly, and the DU concentrations in kidney still maintained at a relatively high level even at the 360 days after implantation. Otherwise, chronic DU contamination could induce the pathological changes of renal glomeruli, tubules and mesenchyme, such as interstitial fibrosis, enlarged interstice of renal tubular epithelial cells, tumefactions and necrosis of epithelial cells, shrinkage and disappearance of cavity of Bowman's capsule. By TEM, it was shown that the basement membrane of glomerulus was incrassated, mitochondrial of kidney proximal tubule had visible tumefaction and became bigger, and the mitochondrial cristae became shorter and disorderly in alignment. Compared to the control group, it was found that there was significant increase in the DU implantation group in terms of their blood urea nitrogen (BUN) and serum creatinine, urinary beta2-microglobulin (beta2-MG) and albumin, with a high correlation to the implanted DU dosage and periods. It was concluded that DU could accumulate in kidneys for a long period, and causes kidney injury by the toxic chemical/radioactive action such as renal dysfunction and structural damage.

Efficacy of oral and intraperitoneal administration of CBMIDA for removing uranium in rats after parenteral injections of depleted uranium.

The efficacy of oral administration of the chelating agent catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) for removing uranium from rats after intraperitoneal (i.p.) and intramuscular (i.m.) injections of depleted uranium (DU) was examined and the results with those by the i.p. injection of CBMIDA were compared. In Experiment 1, after a single i.p. injection of 8 mg kg(-1) of DU of rat's body weight, 35 8-week-old male rats were divided into seven groups consisting of five rats each. Three groups were administered with CBMIDA 240, 720 or 1200 mg kg(-1) of rat's body weight orally once a day, and three other groups received an i.p. injection of 240, 480 or 720 mg kg(-1) CBMIDA for 3 d, starting 30 min after DU injection on the first day. One DU group received no CBMIDA. The remaining five intact rats were used as a control group. Rats were killed 6 d after DU injection. In Experiment 2, the 35 male rats that received a single i.m. injection of 8 mg kg(-1) DU were divided into seven groups, and the rats of each group received the same doses of CBMIDA on the same schedules of treatment as those described in Experiment 1. The results obtained in Experiment 1 indicated that orally administered CBMIDA significantly increased the excretion of uranium at doses of 720 and 1200 mg kg(-1) and decreased uranium concentrations, particularly in the kidney, at all the doses tested, and the effects were almost equal to those of the i.p. injection. The lack of increases in creatinine and blood urea nitrogen in serum indicated that CBMIDA is efficacious in preventing the renal dysfunction caused by uranium. In Experiment 2, oral administration of CBMIDA significantly increased uranium excretion and significantly decreased uranium concentrations, particularly in the kidneys, at all the doses tested, and the effects were almost equal to those of the i.p. injection. However, these effects of CBMIDA on the i.m.-injected DU were lower than those of the i.p.-injected DU in Experiment 1. These results indicated that oral administration of CBMIDA has almost the same efficacy as that administered by the parenteral route. Additional study is necessary to obtain satisfactory effects for the clinical use of CBMIDA, particularly for wounds contaminated accidentally with uranium.

The mechanism of acute renal failure after uranyl nitrate.

Administration of 25 mg/kg uranyl nitrate (UN) to rats leads to a brief period of polyuria followed by progressive oliguria with death at 5 days. Factors that determine glomerular filtration rate (GFR) were examined in control Munich-Wistar rats (n equals 16) and 2 h after either 15 mg/kg (n equals 8) or 25 mg/kg (n equals 7) of UN (i.v.) utilizing direct measurements of hydrostatic and oncotic pressures and plasma flow. Total kidney GFR was reduced to 47% of control in the low dose group and to 21% in the high dose group. The simultaneous nephron filtration rate (sngfr) was 28.6 plus or minus 0.8 nl/min/g kidney wt in control, 29.1 plus or minus 1.0 in the low dose group, and 18.1 plus or minus 1.2 (P less than 0.001) in the higher dose group. This disparity in UN effect upon GFR and sngfr was due to tubular back-diffusion of solute through damaged epithelia beyond the early proximal tubule as demonstrated by microinjection of inulin and mannitol in the proximal tubule. Inulin "leak" persisted at 6 h after UN when tubular pressure had returned to normal. Comparison of sngfr measured in early vs. late proximal tubule revealed no difference after high dose UN, suggesting no significant leak of inulin from the early proximal tubule, and that the decreased sngfr was due to primary reductions in ultrafiltration. Nephron plasma flow was equal to control at both doses of UN. Also directly measured hydrostatic pressure gradient across the glomerular capillary was not changed. The effective filtration pressure achieved equilibrium in control of animals but became significantly positive at the efferent end of the capillary at both doses of UN and increased. Total glomerular permeability (LpA) was progressively reduced from control (0.089 plus or minus 0.005 nl/s/g kidney wt/mm Hg) at low dose UN (0.047 plus or minus 0.013) and high dose 0.024 plus or minus 0.003 nl/s/g kidney wt/mm Hg). Therefore UN decreases GFR by two mechanisms: (1) tubular damage leading to back-diffusion of solutes and (b) a primary reduction in sngfr due to reduced LpA.

Chronic exposure to uranium leads to iron accumulation in rat kidney cells.

After it is incorporated into the body, uranium accumulates in bone and kidney and is a nephrotoxin. Although acute or short-term uranium exposures are well documented, there is a lack of information about the effects of chronic exposure to low levels of uranium on both occupationally exposed people and the general public. The objective of this study was to identify the distribution and chemical form of uranium in kidneys of rats chronically exposed to uranium in drinking water (40 mg uranium liter(-1)). Rats were killed humanely 6, 9, 12 and 18 months after the beginning of exposure. Kidneys were dissected out and prepared for optical and electron microscope analysis and energy dispersive X-ray (XEDS) or electron energy loss spectrometry (EELS). Microscopic analysis showed that proximal tubule cells from contaminated rats had increased numbers of vesicles containing dense granular inclusions. These inclusions were composed of clusters of small granules and increased in number with the exposure duration. Using XEDS and EELS, these characteristic granules were identified as iron oxides. Uranium was found to be present as a trace element but was never associated with the iron granules. These results suggested that the mechanisms of iron homeostasis in kidney could be affected by chronic uranium exposure.

Radiological impact of dietary intakes of naturally occurring radionuclides on Pakistani adults.

Daily dietary intakes of three naturally occurring long-lived radionuclides (232)Th, (238)U and (40)K were estimated for the adult population of Pakistan using neutron activation analysis (NAA), inductively coupled plasma mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS), respectively. The daily intakes of (232)Th ranged from 4 to 29 mBq, (238)U ranged from 17 to 82 mBq and (40)K ranged from 51 to 128 Bq. The geometric means of these intakes were 10 mBqd(-1) for (232)Th, 33 mBqd(-1) for (238)U and 78.5 Bqd(-1) for (40)K. The measured values give annual committed effective doses of 0.80, 0.53 and 178.75 microSvyr(-1) for (232)Th, (238)U and (40)K, respectively to Pakistani population. The net radiological impact of these radionuclides is 180.08 microSvyr(-1). This value gives cancer risk factor of 4.5 x 10(-4) and loss of life expectancy of 0.87 days only. Whereas ICRP cancer risk factor for general public is 2.5 x 10(-3) and total risk involve from the all natural radiation sources based on global average annual radiation dose of 2.4 mSvyr(-1) is 6.0 x 10(-3). The estimated cancer risk shows that probability of increase of cancer risk from daily Pakistani diet is only a minor fraction of ICRP values. Therefore, the diet does not pose any significant health hazard and is considered radiologically safe for human consumption.

Evaluation of the effect of implanted depleted uranium (DU) on adult rat behavior and toxicological endpoints.

In 2002, the Naval Health Research Center Toxicology Detachment began a study to determine the effects of surgically implanted depleted uranium (DU) pellets on adult rat (e.g., P1 generation) health and reproduction. In this report, the effect of implanted DU on adult rat behavior and health is described. Adult Sprague-Dawley (SD) rats, 8 wk of age, were surgically implanted with 0, 4, 8, 12, or 20 DU pellets (1 x 2 mm); 20 DU pellets of size 1 x 2 mm approximates to 0.22 kg (0.5 lb) of DU in a 70-kg (154 lb) person. Control animals were implanted with 12 or 20 tantallum (Ta) pellets. The animals were then housed for up to 150 d postimplantation or 20% of an assumed 2-yr life span for rats. The concentration of uranium in urine directly correlated with the number of implanted DU pellets, indicating that DU was migrating into the body from the implanted pellets. Three male and 4 female animals died during the 150-d period of causes apparently not related to DU implantation. Behavioral testing found no definitive evidence of neurobehavioral perturbations associated with DU implantation. Uranium translocated to tissues known to sequester uranium (bone, teeth, and kidneys), but uranium concentrations varied considerably within each dose group and did not follow a dose-response pattern as anticipated. Serum chemistry values were within normal ranges for the SD rat. However, alanine aminotransferase measurements were significantly lower for rats implanted with 20 DU pellets as compared to sham surgery controls but not when compared to animals implanted with Ta pellets only. Phosphate measurements were significantly lower for female rats implanted with 20 DU pellets as compared to both sham surgery controls and animals implanted with Ta pellets only. Monocyte ratios were higher in adult rats implanted with 20 DU pellets as compared to sham surgery controls but not when compared to animals implanted with 20 Ta pellets. Mean platelet volume was found to be significantly lower for rats implanted with 20 DU pellets as compared to sham surgery controls but not when compared to animals implanted with 20 Ta pellets. Gross necropsy found no obvious tissue abnormalities in implanted rats, and the weights of major tissues did not differ between Ta- and DU-implanted animals. Histopathologic analysis of major tissues from animals implanted with 0 pellets, 20 Ta pellets, or 20 DU pellets found no differences between treatment groups. The findings of this study indicate that implantation of up to 20 DU pellets in adult rats did not have a significant negative impact on their general health and neurobehavioral capacities when assessed after 150 d of pellet implantation. However, the growing body of data on the potential health effects associated with DU exposure warrants further studies involving higher embedded DU body burdens in conjunction with longer surveillance periods postimplantation.

Effects of pH on du intake and removal by CBMIDA and EHBP.

The effects of pH on deleted uranium (DU) and DU removal by chelating agents, catechol-3,6-bis(methyleneiminodiacetic acid) (CBMIDA) and ethane-1-hydroxy-1,1-bisphoshonate (EHBP) in rats were examined. Ninety male Wistar rats, 8 wk old, were divided into six groups of 15 rats. Rats of five groups were each preinjected intraperitoneally with 8 mg kg(-1) DU in pH 1, 3, 5, 7, and 10 solutions. In each pH group, five rats were injected intraperitoneally with 240 mg kg(-1) CBMIDA, and the other five with 10 mg kg(-1) EHBP; the remaining five were used as the corresponding group with no chelating agent. One group was kept as the control (no injected DU) group, which consisted of five intact, five with CBMIDA, and five with EHBP administration. Chelating agents were administered for 3 d. Rats were injected with the DU 30 min prior to treatment with chelating agents on the first day. The gathered data indicated that the DU toxicity varied according to differences in pH; in addition, at pH 7, when varied DU-complexes formed, the DU toxicity including renal dysfunction increased, and the DU removal effects of chelating agents were not obtained. Both CBMIDA and EHBP were effective in excreting DU, reducing DU concentrations in organs, and preventing DU-induced toxicity, and CBMIDA was superior to EHBP, particularly in the prevention of renal dysfunction. These results indicate that the excretion and distribution of soluble DU changes and the removal effects of chelating agents according to pH differs, indicating that the treatment with chelating agent should begin in the DU-contaminated person as early as possible after an accident.

Uranium dose assessment: a Bayesian approach to the problem of dietary background.

Workers are routinely monitored by urinalysis for exposure to uranium at Los Alamos National Laboratory. Urine samples are analysed by alpha spectroscopy for 234U, 235U and 238U. Interpretation of the data is complicated by the presence of natural uranium in the workers' drinking water and diet. Earlier methods used drinking water samples to estimate the dietary component in urine excretion. However, there proved to be insufficient correlation between drinking water concentration and excretion rate. Instead, an iterative calculation is used to identify a typical excretion rate for each individual in the absence of occupational intakes. Bayesian dose-assessment methods, first developed for plutonium bioassay at Los Alamos, have been adapted for uranium. These methods, coupled with an algorithm for identifying each individual's baseline level of uranium from environmental sources, yield improved reliability in the identification of occupational intakes.

Dose assessment for inhalation intakes in complex, energetic environments: experience from the US Capstone study.

Because of the lack of existing information needed to evaluate the risks from inhalation exposures to depleted uranium (DU) aerosols of US soldiers during the 1991 Persian Gulf War, the US Department of Defense funded an experimental study to measure the characteristics of DU aerosols created when Abrams tanks and Bradley fighting vehicles are struck with large-caliber DU penetrators, and a dose and risk assessment for individuals present in such vehicles. This paper describes some of the difficulties experienced in dose assessment modelling of the very complex DU aerosols created in the Capstone studies, e.g. high concentrations, heterogeneous aerosol properties, non-lognormal particle size distributions, triphasic in vitro dissolution and rapid time-varying functions of both DU air concentration and particle size. The approaches used to solve these problems along with example results are presented.