Pulmonary toxicity, genotoxicity, and carcinogenicity evaluation of molybdenum, lithium, and tungsten: A review.

Molybdenum, lithium, and tungsten are constituents of many products, and exposure to these elements potentially occurs at work. Therefore it is important to determine at what levels they are toxic, and thus we set out to review their pulmonary toxicity, genotoxicity, and carcinogenicity. After pulmonary exposure, molybdenum and tungsten are increased in multiple tissues; data on the distribution of lithium are limited. Excretion of all three elements is both via faeces and urine. Molybdenum trioxide exerted pulmonary toxicity in a 2-year inhalation study in rats and mice with a lowest-observed-adverse-effect concentration (LOAEC) of 6.6 mg Mo/m3. Lithium chloride had a LOAEC of 1.9 mg Li/m3 after subacute inhalation in rabbits. Tungsten oxide nanoparticles resulted in a no-observed-adverse-effect concentration (NOAEC) of 5 mg/m3 after inhalation in hamsters. In another study, tungsten blue oxide had a LOAEC of 63 mg W/m3 in rats. Concerning genotoxicity, for molybdenum, the in vivo genotoxicity after inhalation remains unknown; however, there was some evidence of carcinogenicity of molybdenum trioxide. The data on the genotoxicity of lithium are equivocal, and one carcinogenicity study was negative. Tungsten seems to have a genotoxic potential, but the data on carcinogenicity are equivocal. In conclusion, for all three elements, dose descriptors for inhalation toxicity were identified, and the potential for genotoxicity and carcinogenicity was assessed.

Oxygen-supplementing mesoporous polydopamine nanosponges with WS2 QDs-embedded for CT/MSOT/MR imaging and thermoradiotherapy of hypoxic cancer.

Multifunctional nanoplatforms with flexible architectures and tumor microenvironment response are highly anticipated within the field of thermoradiotherapy. Herein, the multifunctional nanoplatforms for thermoradiotherapy have been successfully constructed by the embedding of tungsten disulfide quantum dots (WS2 QDs) into mesoporous polydopamine nanosponges (MPDA NSs), followed by integration with manganese dioxide (MnO2). MPDA-WS2@MnO2, the resultant nanoplatforms, exhibit radiosensitization enhanced behavior and a capacity for responsive oxygen self-supplementation. The ingenious mesoporous structure of MPDA NSs serves as reservoir for the assembly of WS2 QDs to form MPDA-WS2 nanoparticles (NPs), in which WS2 QDs provide the radiation enhancement effect, whereas the MPDA NSs framework endows the MPDA-WS2@MnO2 with an excellent photothermal capability. Additionally, the integration of the MnO2 component works to decompose the tumor-overexpressed H2O2 and alleviate tumor hypoxia subsequently, which has been demonstrated to enhance radiotherapy performance considerably. Meanwhile, the prepared MPDA-WS2@MnO2 nanoplatforms have been evaluated as trimodality contrast agents for computed tomography (CT), multispectral optoacoustic tomography (MSOT), and tumor microenvironment-responsive T1-weighted magnetic resonance (MR) imaging that have the potential for real-time guidance and monitoring during cancer therapy. More importantly, when subjected to near infrared (NIR) laser irradiation and X-ray exposure, the tumor is found to be inhibited significantly through the process of combined thermoradiotherapy. The design concepts of embedding WS2 QDs into MPDA NSs and oxygen self-supplementing hold great potential for multimodal imaging-guided thermoradiotherapy of hypoxic cancer.

Uptake Kinetics and Trophic Transfer of Tungsten from Cabbage to a Herbivorous Animal Model.

This investigation builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the most important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail's hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. This offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.

Tungsten (W) bioavailability in paddy rice soils and its accumulation in rice (Oryza sativa).

The aim of this study was to investigate the accumulation characteristics of tungsten (W) by different indica rice cultivars from the soil and to assess the potential risks to human health via dietary intake of W in rice consumption. A total of 153 rice (ear) samples of 15 cultivars and the corresponding surface soil samples were collected from 7 cities in Fujian Province of southeastern China. The available soil W were extracted using H2C2O4·2H2O-(NH4)2C2O4·H2O at pH 3.3). Results showed that the total soil W ranged from 2.03 mg kg-1 to 15.34 mg kg-1 and available soil W ranged from 0.03 mg kg-1 to 1.61 mg kg-1. The W concentration in brown rice varied from 7 µg kg-1 to 283 µg kg-1 and was significantly correlated with the available soil W. The highest mean TFavail (transfer factor based on available soil W) was 0.91 for Te-you 627 (hybrid, indica rice), whereas the lowest was 0.08 for Yi-you 673 (hybrid, indica rice). The TFavail decreased with the increase in available soil W, clay content, and cation exchange capacity. The consumption of the brown rice produced from the investigated areas in some cultivars by the present study may cause risks to human health.

Renal-Clearable Ultrasmall Coordination Polymer Nanodots for Chelator-Free 64Cu-Labeling and Imaging-Guided Enhanced Radiotherapy of Cancer.

Developing tumor-homing nanoparticles with integrated diagnostic and therapeutic functions, and meanwhile could be rapidly excreted from the body, would be of great interest to realize imaging-guided precision treatment of cancer. In this study, an ultrasmall coordination polymer nanodot (CPN) based on the coordination between tungsten ions (WVI) and gallic acid (W-GA) was developed via a simple method. After polyethylene glycol (PEG) modification, PEGylated W-GA (W-GA-PEG) CPNs with an ultrasmall hydrodynamic diameter of 5 nm were rather stable in various physiological solutions. Without the need of chelator molecules, W-GA-PEG CPNs could be efficiently labeled with radioisotope 64Cu2+, enabling positron emission tomography (PET) imaging, which reveals efficient tumor accumulation and rapid renal clearance of W-GA-PEG CPNs upon intravenous injection. Utilizing the radio-sensitizing function of tungsten with strong X-ray absorption, such W-GA-PEG CPNs were able to greatly enhance the efficacy of cancer radiotherapy in inhibiting the tumor growth. With fast clearance and little long-term body retention, those W-GA-PEG CPNs exhibited no appreciable in vivo toxicity. This study presents a type of CPNs with excellent imaging and therapeutic abilities as well as rapid renal clearance behavior, promising for further clinic translation.

Original Research: Evaluation of pulmonary response to inhaled tungsten (IV) oxide nanoparticles in golden Syrian hamsters.

Extensive industrial and military uses of tungsten have raised the possibilities of human occupational and environmental exposure to nanoparticles of this metal, with concomitant health concerns. The goal of this study was to investigate the potential mechanism of pulmonary toxicity associated with inhaled tungsten (IV) oxide nanoparticles (WO3 NPs) in Golden Syrian Hamsters. Animals exposed to WO3 NPs via inhalation were divided into three groups - control and two treatment groups exposed to either 5 or 10 mg/m3 of aerosolized WO3 NPs for 4 h/day for four days. A long-term exposure study (4 h/day for eight days) was also carried out using an additional three groups. Pulmonary toxicity assessed by examining changes in cell numbers, lactate dehydrogenase activity, alkaline phosphatase activity, total protein content, TNF-α, and HMGB1 levels in bronchoalveolar lavage fluids showed a significant difference when compared to control (P < 0.05). The molecular mechanism was established by assessing protein expression of cathepsin B, TXNIP, NLRP3, ASC, IL-1ß and caspase-1. Western blot analysis indicated a 1.5 and 1.7 fold changes in NLRP3 in treatment groups (5 mg/m3, P < 0.05 and 10 mg/m3, P < 0.01, respectively), whereas levels of cathepsin B were 1.3 fold higher in lung tissue exposed to WO3 NPs suggesting activation of inflammasome pathway. Morphological changes studied using light and electron microscopy showed localization of nanoparticles and subsequent perturbation in airway epithelia, macrophages, and interstitial areas of alveolar structures. Results from the current study indicate that inhalation exposure to WO3 NPs may induce cytotoxicity, morphological changes, and lung injury via pyroptotic cell death pathway caused by activation of caspase-1.

Tungsten Promotes Sex-Specific Adipogenesis in the Bone by Altering Differentiation of Bone Marrow-Resident Mesenchymal Stromal Cells.

Tungsten is a naturally occurring metal that increasingly is being incorporated into industrial goods and medical devices, and is recognized as an emerging contaminant. Tungsten preferentially and rapidly accumulates in murine bone in a concentration-dependent manner; however the effect of tungsten deposition on bone biology is unknown. Other metals alter bone homeostasis by targeting bone marrow-derived mesenchymal stromal cell (MSC) differentiation, thus, we investigated the effects of tungsten on MSCsin vitroandin vivoIn vitro, tungsten shifted the balance of MSC differentiation by enhancing rosiglitazone-induced adipogenesis, which correlated with an increase in adipocyte content in the bone of tungsten-exposed, young, male mice. Conversely, tungsten inhibited osteogenesis of MSCsin vitro; however, we found no evidence that tungsten inhibited osteogenesisin vivo Interestingly, two factors known to influence adipogenesis are sex and age of mice. Both female and older mice have enhanced adipogenesis. We extended our study and exposed young female and adult (9-month) male and female mice to tungsten for 4 weeks. Although tungsten accumulated to a similar extent in young female mice, it did not promote adipogenesis. Interestingly, tungsten did not accumulate in the bone of older mice; it was undetectable in adult male mice, and just above the limit of detect in adult female mice. Surprisingly, tungsten enhanced adipogenesis in adult female mice. In summary, we found that tungsten alters bone homeostasis by altering differentiation of MSCs, which could have significant implications for bone quality, but is highly dependent upon sex and age.

Material Decomposition in Dual-Energy Computed Tomography Separates High-Z Elements From Iodine, Identifying Potential Contrast Media Tailored for Dual Contrast Medium Examinations.

OBJECTIVE: The aim of this study was to determine the potential of different high-Z elements to act as contrast media (CMs) alongside iodine (I) in dual-CM, dual-energy (DE) computed tomography examinations. METHODS: Gadolinium (Gd), tantalum (Ta), wolfram (W), gold (Au), and bismuth (Bi) in addition to I were examined at all available kilovolt settings in a DE computed tomography scanner. Dual-energy ratios were calculated by dividing attenuation at low kilovolt by attenuation at high kilovolt. Dual-energy data sets were loaded into material decomposition software to evaluate separation of the elements from I. RESULTS: The DE ratios of Ta, W, and Au ranged between 0.9 and 1.2, being considerably lower than I at 1.9 to 2.6. These elements were completely separated from I using material decomposition. Gadolinium and Bi were more similar to I at 1.4 to 1.9. However, separation was nearly complete for Bi and suboptimal for Gd. CONCLUSIONS: Tantalum, W, and Au are ideal candidates for dual-CM examinations, whereas Bi is a slightly weaker candidate.

Dissolution and biodurability: Important parameters needed for risk assessment of nanomaterials.

Biopersistence and biodurability have the potential to influence the long-term toxicity and hence pathogenicity of particles that deposit in the body. Therefore, biopersistence and biodurability are considered to be important parameters needed for the risk assessment of particles and fibres. Dissolution, as a measure of biodurability, is dependent on the chemical and physical properties (size, surface area, etc.) of particles and fibres and also of the suspension medium including its ionic strength, pH, and temperature. In vitro dissolution tests can provide useful insights as to how particles and fibres may react in biological environments; particles and fibres that release ions at a higher rate when suspended in vitro in a specific simulated biological fluid will be expected to do so when they exist in a similar biological environment in vivo. Dissolution of particles and fibres can follow different reaction kinetics. For example, the majority of micro-sized particles and fibres follow zero-order reaction kinetics. In this case, although it is possible to calculate the half-time of a particle or fibre, such calculation will be dependent on the initial concentration of the investigated particle or fibre. Such dependence was eliminated in the shrinking sphere and fibre models where it was possible to estimate the lifetimes of particles and fibres as a measure of their biodurability. The latter models can be adapted for the dissolution studies of nanomaterials. However, the models may apply only to nanomaterials where their dissolution follows zero-order kinetics. The dissolution of most nanomaterials follows first-order kinetics where dependence on their initial concentration of the investigated nanomaterials is not required and therefore it is possible to estimate their half-times as a measure of their biodurability. In dissolution kinetics for micro-sized and nano-sized particles and fibres, knowledge of dissolution rate constants is necessary to understand biodurability. Unfortunately, many studies on dissolution of nanoparticles and nanofibres do not determine the dissolution rates and dissolution rate constants. The recommendation is that these parameters should be considered as part of the important descriptors of particle and fibre physicochemical properties, which in turn, will enable the determination of their biodurability.

Microneedle-assisted microparticle delivery by gene guns: experiments and modeling on the effects of particle characteristics.

Microneedles (MNs) have been shown to enhance the penetration depths of microparticles delivered by gene gun. This study aims to investigate the penetration of model microparticle materials, namely, tungsten (<1 µm diameter) and stainless steel (18 and 30 µm diameters) into a skin mimicking agarose gel to determine the effects of particle characteristics (mainly particle size). A number of experiments have been processed to analyze the passage percentage and the penetration depth of these microparticles in relation to the operating pressures and MN lengths. A comparison between the stainless steel and tungsten microparticles has been discussed, e.g. passage percentage, penetration depth. The passage percentage of tungsten microparticles is found to be less than the stainless steel. It is worth mentioning that the tungsten microparticles present unfavourable results which show that they cannot penetrate into the skin mimicking agarose gel without the help of MN due to insufficient momentum due to the smaller particle size. This condition does not occur for stainless steel microparticles. In order to further understand the penetration of the microparticles, a mathematical model has been built based on the experimental set up. The penetration depth of the microparticles is analyzed in relation to the size, operating pressure and MN length for conditions that cannot be obtained in the experiments. In addition, the penetration depth difference between stainless steel and tungsten microparticles is studied using the developed model to further understand the effect of an increased particle density and size on the penetration depth.

Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

Upper lobe-dominant pulmonary fibrosis showing deposits of hard metal component in the fibrotic lesions.

We present a 54-year-old man employed in the field of hard metal manufacturing who complained of progressive dyspnea and weight loss. His chest radiograph showed bilateral fibrosis predominantly distributed in the upper lobes with bilateral pleural effusions, and a strong reduction in lung volume. Lung histopathology showed apical cap-like fibrosis but no giant cell interstitial pneumonia. Electron probe microanalysis detected tungsten deposits in the fibrotic region: we therefore considered this to be a case of hard metal disease. Hard metal disease should be considered as one possibility in the differential diagnosis of upper lobe-dominant pulmonary fibrosis.

Tungsten effects on phosphate-dependent biochemical pathways are species and liver cell line dependent.

Tungsten, in the form of tungstate, polymerizes with phosphate, and as extensive polymerization occurs, cellular phosphorylation and dephosphorylation reactions may be disrupted, resulting in negative effects on cellular functions. A series of studies were conducted to evaluate the effect of tungsten on several phosphate-dependent intracellular functions, including energy cycling (ATP), regulation of enzyme activity (cytosolic protein tyrosine kinase [cytPTK] and tyrosine phosphatase), and intracellular secondary messengers (cyclic adenosine monophosphate [cAMP]). Rat noncancerous hepatocyte (Clone-9), rat cancerous hepatocyte (H4IIE), and human cancerous hepatocyte (HepG2) cells were exposed to 1-1000 mg/l tungsten (in the form of sodium tungstate) for 24 h, lysed, and analyzed for the above biochemical parameters. Cellular ATP levels were not significantly affected in any cell line. After 4 h, tungsten significantly decreased cytPTK activity in Clone-9 cells at >or= 18 mg/l, had no effect in H4IIE cells, and significantly increased cytPTK activity by 70% in HepG2 cells at >or= 2 mg/l. CytPTK displayed a slight hormetic response to tungsten after 24-h exposure yet returned to normal after 48-h exposure. Tungsten significantly increased cAMP by over 60% in Clone-9 cells at >or= 100 mg/l, significantly increased cAMP in H4IIE cells at only 100 mg/l, and significantly increased cAMP in HepG2 cells between 1-100 mg/l but at much more modest levels (8-20%). In conclusion, these data indicate that tungsten produces complex results that must be carefully interpreted in the context of their respective animal models, as well as the phenotype of the cell lines (i.e., normal vs. cancerous).

Influence of artificial gastric juice composition on bioaccessibility of cobalt- and tungsten-containing powders.

The dissolution of metal-containing particles in the gastric compartment is poorly understood. The purpose of this study was to elucidate the influence of artificial gastric juice chemical composition on bioaccessibility of metals associated with ingestion-based health concerns. Dissolution rates were evaluated for well-characterized feedstock cobalt, tungsten metal, and tungsten carbide powders, chemically bonded pre-sintered (spray dryer material) and post-sintered (chamfer grinder) cemented tungsten carbide materials, and an admixture of pure cobalt and pure tungsten carbide, prepared by mechanically blending the two feedstock powders. Dissolution of each study material was evaluated in three different formulations of artificial gastric juice (from simplest to most chemically complex): American Society of Testing Materials (ASTM), U.S. Pharmacopoeia (USP), and National Institute for Occupational Safety and Health (NIOSH). Approximately 20% of cobalt dissolved in the first dissolution phase (t(1/2) = 0.02 days) and the remaining 80% was released in the second long-term dissolution phase (t(1/2) = 0.5 to 1 days). Artificial gastric juice chemical composition did not influence dissolution rate constant values (k, g/cm(2)day) of cobalt powder, either alone or as an admixture. Approximately 100% of the tungsten and tungsten carbide that dissolved was released in a single dissolution phase; k-values of each material differed significantly in the solvents: NIOSH > ASTM > USP (p<0.05). The k-values of cobalt and tungsten carbide in pre- and post-sintered cemented tungsten carbide powders were significantly different from values for the pure feedstock powders. Solvent composition had little influence on oral bioaccessibility of highly soluble cobalt and our data support consideration of the oral exposure route as a contributing pathway to total-body exposure. Solvent composition appeared to influence bioaccessibility of the low soluble tungsten compounds, though differences may be due to variability in the data associated with the small masses of materials that dissolved. Nonetheless, ingestion exposure may not contribute appreciably to total body burden given the short residence time of material in the stomach and relatively long dissolution half-times of these materials (t(1/2) = 60 to 380 days).

Bioavailability of tungsten and associated metals in calcareous soils in the vicinity of an ancient metalliferous mine in the Corbières area, southwestern France.

The mobility and bioavailability of tungsten and associated metals are examined in calcareous soils and subsequent bioaccumulation by four species of plants is determined. Apparent bioavailability of metalliferous cations indicated by accepted monitoring methods and actual bioaccumulation is compared using regression analysis. Two soil extraction procedures were used without significant correlation between the methods at all stages, with the exception of copper and arsenic. More importantly, perhaps, the bioaccumulation by various tissues of Buxus sempervirens did not significantly correlate for the majority of target metals for each extraction procedure. Possible accumulation of toxic cations by a dying tree species was also examined. The availability of tungsten and associated metals in calcareous soils was compared with previous investigations on acidic soils, resulting in confirmation that tungsten in particular, in naturally occurring ores, is more readily mobilized under alkaline conditions.

Disposition and clearance of tungsten after single-dose oral and intravenous exposure in rodents.

Tungsten (W) has been nominated for study to the National Toxicology Program (NTP) because of reported associations between concentrations of W in drinking water and childhood leukemia. The disposition of W (administered as sodium tungstate dihydrate in water) in plasma, liver, kidneys, uterus, femur, and intestine of rodents (Sprague-Dawley rats and C57BL/6N mice) was characterized after exposures by oral gavage (1, 10, or 100 mg/kg) or intravenous (1 mg/kg) administration. Each tissue (or plasma) was collected and analyzed by inductively coupled plasma mass spectrometry at 1, 2, 4, or 24 h after dose administration. W was observed in plasma and all tissues after both gavage and i.v. administration. In rats, concentrations in plasma and most tissues peaked at 4 h. In mice, concentrations in plasma and most tissues peaked at 1 h. Although the amount of W in each matrix decreased significantly by 24 h, there was W remaining in several tissues, especially at the higher doses.

ATSDR evaluation of health effects of tungsten and relevance to public health.

The Agency for Toxic Substances and Disease Registry prepares toxicological profiles, as part of its mandate, on hazardous chemicals found at Comprehensive Environmental Response, Compensation, and Liability Act National Priorities List sites that have the greatest public health impact. These profiles comprehensively summarize toxicological and environmental information. This article constitutes the release of portions of the Toxicological Profile for tungsten. The primary purpose of this article is to provide public health officials, physicians, toxicologists and other interested individuals and groups with an overall perspective on the toxicology of tungsten. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

Effects of tungsten on environmental systems.

Tungsten is a metal with many industrial and military applications, including manufacturing of commercial and military ammunition. Despite its widespread use, the potential environmental effects of tungsten are essentially unknown. This study addresses environmental effects of particulate and soluble forms of tungsten, and to a minor extent certain tungsten alloy components, present in some munitions formulations. Dissolution of tungsten powder significantly acidifies soils. Tungsten powder mixed with soils at rates higher than 1% on a mass basis, trigger changes in soil microbial communities resulting in the death of a substantial portion of the bacterial component and an increase of the fungal biomass. It also induces the death of red worms and plants. These effects appear to be related with the soil acidification occurring during tungsten dissolution. Dissolved tungsten species significantly decrease microbial yields by as much as 38% for a tungsten media concentration of 89 mg l(-1). Soluble tungsten concentrations as low as 10(-5) mg l(-1), cause a decrease in biomass production by 8% which is possibly related to production of stress proteins. Plants and worms take up tungsten ions from soil in significant amounts while an enrichment of tungsten in the plant rhizosphere is observed. These results provide an indication that tungsten compounds may be introduced into the food chain and suggest the possibility of development of phytoremediation-based technologies for the cleanup of tungsten contaminated sites.

Recombinant Rhodobacter capsulatus xanthine dehydrogenase, a useful model system for the characterization of protein variants leading to xanthinuria I in humans.

Rhodobacter capsulatus xanthine dehydrogenase (XDH) forms an (alphabeta)2 heterotetramer and is highly homologous to homodimeric eukaryotic XDHs. The crystal structures of bovine XDH and R. capsulatus XDH showed that the two proteins have highly similar folds. We have developed an efficient system for the recombinant expression of R. capsulatus XDH in Escherichia coli. The recombinant protein shows spectral features and a range of substrate specificities similar to bovine milk xanthine oxidase. However, R. capsulatus XDH is at least 5 times more active than bovine XDH and, unlike mammalian XDH, does not undergo the conversion to the oxidase form. EPR spectra were obtained for the FeS centers of the enzyme showing an axial signal for FeSI, which is different from that reported for xanthine oxidase. X-ray absorption spectroscopy at the iron and molybdenum K-edge and the tungsten LIII-edge have been used to probe the different metal coordinations of variant forms of the enzyme. Based on a mutation identified in a patient suffering from xanthinuria I, the corresponding arginine 135 was substituted to a cysteine in R. capsulatus XDH, and the protein variant was purified and characterized. Two different forms of XDH-R135C were purified, an active (alphabeta)2 heterotetrameric form and an inactive (alphabeta) heterodimeric form. The active form contains a full complement of redox centers, whereas in the inactive form the FeSI center is likely to be missing.

Degradation of tungsten coils implanted into the subclavian artery of New Zealand white rabbits is not associated with local or systemic toxicity.

OBJECTIVE: To assess whether corrosion of tungsten coils is related to residual shunting and to evaluate whether elevated tungsten serum levels are associated with local or systemic toxicity. METHODS: Tungsten coils (SPI, Balt, France) were implanted into the subclavian artery of New Zealand white rabbits leading to a residual high-flow shunt in 5/10 rabbits. Serial serum tungsten levels, complete blood count and clinical chemistry were analysed prior to the implantation as well as 15 min, 2 and 4 months thereafter. After 4 months the rabbits underwent repeat angiography before they were sacrificed and the internal organs were evaluated histopathologically. RESULTS: Mean tungsten levels rose from 0.48 microg/l prior to the implantation to 12.4 microg/l 4 months post-implantation. The rise in serum tungsten levels was neither associated with residual shunting present at the time of implantation nor with residual shunting at the time of explantation. One animal had to be sacrificed because of non-resolving palsy of the upper extremity. The remaining animals had an uneventful clinical course with no signs of toxicity of the elevated tungsten levels. Histological examination revealed no evidence of local or systemic toxicity of the tungsten coils. CONCLUSION: Tungsten coils corrode and lead to a steady increase in serum tungsten levels starting as early as 15 min after implantation. Residual shunting does not seem to influence the kinetics of corrosion of tungsten coils. Despite markedly elevated serum tungsten levels 4 months after implantation degradation of tungsten coils is not associated with local or systemic toxicity.