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.

Concentrations of Trace Elements in Hemodialysis Patients: A Prospective Cohort Study.

BACKGROUND: Low concentrations and excessive concentrations of trace elements have been commonly reported in hemodialysis patients, but available studies have several important limitations. STUDY DESIGN: Random sample of patients drawn from a prospective cohort. SETTING & PARTICIPANTS: 198 incident hemodialysis patients treated in 3 Canadian centers. MEASUREMENTS: We used mass spectrometry to measure plasma concentrations of the 25 elements at baseline, 6 months, 1 year, and 2 years following enrollment in the cohort. We focused on low concentrations of zinc, selenium, and manganese and excessive concentrations of lead, arsenic, and mercury; low and excessive concentrations of the other 19 trace elements were treated as exploratory analyses. Low and excessive concentrations were based on the 5th and 95th percentile plasma concentrations from healthy reference populations. RESULTS: At all 4 occasions, low zinc, selenium, and manganese concentrations were uncommon in study participants (≤5.1%, ≤1.8%, and ≤0.9% for zinc, selenium, and manganese, respectively) and a substantial proportion of participants had concentrations that exceeded the 95th percentile (≥65.2%, ≥74.2%, and ≥19.7%, respectively). Almost all participants had plasma lead concentrations above the 95th percentile at all time points. The proportion of participants with plasma arsenic concentrations exceeding the 95th percentile was relatively constant over time (9.1%-9.8%); the proportion with plasma mercury concentrations that exceeded the 95th percentile varied between 15.2% and 29.3%. Low arsenic, platinum, tungsten, and beryllium concentrations were common (>50%), as were excessive cobalt, manganese, zinc, vanadium, cadmium, selenium, barium, antimony, nickel, molybdenum, lead, and chromium concentrations. CONCLUSIONS: There was no evidence that low zinc, selenium, or manganese concentrations exist in most contemporary Canadian hemodialysis patients. Some patients have excessive plasma arsenic and mercury concentrations, and excessive lead concentrations were common. These findings require further investigation.

Toxicological assessment of nano and micron-sized tungsten oxide after 28days repeated oral administration to Wistar rats.

Tungsten oxide (WO3) nanoparticles (NPs) are being used in various applications. However, the health consequences of WO3 NPs exposure have not been explored extensively. Hence, the goal of this study was to evaluate the toxicity of WO3 NPs and their microparticles (MPs) after 28days repeated oral administration in Wistar rats. The particles were characterised by transmission electron microscopy (TEM), dynamic light scattering (DLS), laser Doppler velocimetry (LDV), Brunner-Emmett-Teller (BET), X- ray diffraction (XRD), and inductively coupled plasma optical emission spectrometer (ICP-OES). Genotoxicity was determined using comet assay in blood and liver and micronucleus test in bone marrow. Biochemical parameters such as aspartate aminotransferase and alanine aminotransferase in serum and reduced glutathione content, catalase and lipid peroxidation in liver tissue were determined. Histopathological changes in tissues were documented. Biodistribution of tungsten (W) in rat's blood, urine, feces and tissues were analysed. The mean size of WO3 NPs and MPs by TEM was 52±2.97nm, and 5.73±7.58µm and morphology were spherical in both the particles. DLS of NPs was 195.6nm. XRD and BET data of WO3 NPs and MPs showed a hexagonal and tetragonal crystal structure and surface area of 19.33 and 15.15(m2/g), respectively. The results revealed a significant increase in DNA damage and micronuclei, a difference in biochemical levels and histopathological alterations after exposure to 1000mg/kg dose of WO3 NPs. W biodistribution was detected in all the tissues in a dose and organ-dependent manner in both the particles. The highest amount of W was found in the liver and lowest in the brain of the treated rats. The tested NPs were found to have little toxicity hazard.

Biological monitoring of welders' exposure to chromium, molybdenum, tungsten and vanadium.

BACKGROUND: Welders are exposed to a number of metallic elements during work. Bioaccessability, that is important for element uptake, has been little studied. This study addresses bioaccessability and uptake of chromium (Cr), molybdenum (Mo), tungsten (W) and vanadium (V) among welders. METHODS: Bioaccessability of Cr, Mo, V and W was studied in airborne particulate matter collected by personal sampling of the workroom air among shipyard welders by using the lung lining fluid simulant Hatch solution. Associations between concentrations of Hatch soluble and non-soluble elements (Hatchsol and Hatchnon-sol) and concentrations of the four elements in whole blood, serum, blood cells and urine were studied. RESULTS: Air concentrations of the four elements were low. Only a small fraction of Cr, V and W was Hatchsol, while similar amounts of Mo were Hatchsol and Hatchnon-sol. Welders (N=70) had statistically significantly higher concentrations of all four elements in urine and serum when compared to referents (N=74). Highly statistically significant associations were observed between urinary W and Hatchsol W (p<0.001) and serum V and Hatchsol V (p<0.001), in particular when air samples collected the day before collection of biological samples were considered. CONCLUSIONS: Associations between Hatchsol elements in air and their biological concentrations were higher than when Hatchnon-sol concentrations were considered. Associations were generally higher when air samples collected the day before biological sampling were considered as compared to air samples collected two days before.

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.

Biospeciation of tungsten in the serum of diabetic and healthy rats treated with the antidiabetic agent sodium tungstate.

It is known that oral administration of sodium tungstate preserves the pancreatic beta cell function in diabetic rats. Healthy and streptozotocin-induced diabetic rats were treated with sodium tungstate for one, three or six weeks, after which the species of W in serum, were analysed. An increase in serum W with treatment time was observed. After six weeks, the serum W concentration in diabetic rats (70 mg L(-1)) was about 4.6 times higher than in healthy specimens. This different behaviour was also observed for Cu accumulation, while the Zn pattern follows the contrary. The patterns observed in the retention of Cu and Zn may be attributable to a normalization of glycaemia. The speciation analysis of W was performed using 2D separations, including an immunoaffinity packing and a SEC (Size Exclusion Chromatography) column coupled to an ICP-MS (Inductively Coupled Plasma Mass Spectrometry) for elemental detection. Ultrafiltration data together with SEC-ICP-MS results proved that around 80% of serum W was bound to proteins, the diabetic rats registering a higher W content than their healthy counterparts. Most of the protein-bound W was due to a complex with albumin. An unknown protein with a molecular weight higher than 100 kDa was also found to bind a small amount of W (about 2%). MALDI-TOF (Matrix-Assisted Laser Desorption Ionization Time-of-Flight) analysis of the desalted and concentrated chromatographic fractions confirmed albumin as the main protein bound to tungstate in rat serum, while no binding to transferrin (Tf) was detected. The interaction between glutathione and W was also evaluated using standard solutions; however, the formation of complexes was not observed. The stability of the complexes between W and proteins when subjected to more stringent procedures, like those used in proteomic methodologies (denaturing with urea or SDS, boiling, sonication, acid media, reduction with ß-mercaptoethanol (BME) or DTT (dithiotreitol) and alkylation with iodoacetamide (IAA), was also evaluated. Our results indicate that the stability of the complexes between W and proteins is not too high enough to remain unaltered during protein separation by SDS-PAGE in denaturing and reducing conditions. However, the procedures for in-solution tryptic digestion and for ESI-MS analysis in MeOH/H(2)O/with 0.1% formic acid could be used for protein identification without large loss of binding between W and proteins.

Biological monitoring of tungsten (and cobalt) in workers of a hard metal alloy industry.

OBJECTIVES: To evaluate a combined biomonitoring approach based on both cobalt and tungsten determination in workers of the hard metal alloy sector. METHODS: We enrolled 55 workers from a factory producing cutting tools for carpentry. Combined workroom air and biological monitoring of both cobalt and tungsten relied on inductively coupled plasma mass spectrometry determinations. Metals were determined on plasma, blood and urine samples. Urine samples from 34 unexposed subjects were also analyzed. RESULTS: Tungsten was determined in every collected sample. Workers showed significantly higher urinary tungsten levels than controls (pre-shift values of 4.12 vs. 0.06 microg/l on average; P < 0.0005). Both airborne and biological levels of tungsten prevailed among workers involved in wet-grinding activities. The element was excreted at higher urinary levels than cobalt and showed lower circulating (blood, plasma) concentrations. Exposure-dose relationships were apparent for tungsten biomarkers. CONCLUSIONS: Obtained results may contribute to the development of biomarkers of exposure to tungsten. The association of such biomarkers to traditional determinations of cobalt in blood and/or urine may substantially improve the exposure assessment of workers employed in cemented carbide industries.

Urinary and serum metal levels as indicators of embedded tungsten alloy fragments.

Novel metal formulations are being used with increasing frequency on the modern battlefield. In many cases the health effects of these materials are not known, especially when they are embedded as fragments. Imaging techniques, although useful for determining location, provide no information regarding the composition of embedded fragments. In this report, we show that laboratory rats implanted with weapons-grade tungsten alloy (tungsten, nickel, and cobalt) pellets demonstrate significant increases in both urinary and serum levels of tungsten, nickel, and cobalt, which indicates that such measurements can provide information on the composition of embedded fragments. We also propose that, in addition to the requirements promulgated by the recent directive on analysis of metal fragments removed from Department of Defense personnel (Health Affairs policy 07-029), urine and blood/serum samples should be collected from personnel and analyzed for metal content. Such measurements could yield information on the composition of retained fragments and provide the basis for further treatment options.

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.

Validation of an inductively coupled plasma-mass spectrometry method to quantify tungsten in human plasma. Determination of percentage binding to plasma proteins.

BACKGROUND: The aim of this paper was to validate an inductively coupled plasma-mass spectrometry (ICP-MS) method to quantify tungsten in human plasma and to study its percentage binding to plasma proteins. METHODS: This method was validated with respect to accuracy, precision, selectivity and limits of quantification and of detection according to Good Laboratory Practice Guidelines. Calibration curves were obtained in the range 10-500 ng/ml. The extent of plasma protein binding was determined by ultrafiltration in the range 40-2000 ng/ml. RESULTS: A significant matrix effect was observed. The linearity of this method was statistically proven. Precision ranged from 0.76% to 6.49%, and accuracy from 97% to 102%. The lower limit of quantification (LLOQ) was 10 ng/ml. The mean percentage of unbound fraction was 89%. CONCLUSIONS: The results obtained indicate that the method described fulfills the accuracy and precision requirements necessary to carry out pharmacokinetic studies in man.

Dissolution of tungsten coils does not produce systemic toxicity, but leads to elevated levels of tungsten in the serum and recanalization of the previously occluded vessel.

AIM: To evaluate the failure of mechanically detachable spirals produced from tungsten (MDS, Balt, Montmorency, France) and the toxicity of elevated levels of tungsten in the serum subsequent to their implantation. METHODS: We reviewed findings in 21 patients in whom tungsten coils had been used to occlude pathologic vessels, aneurysms and fistulas between 1996 and 1999. We achieved clinical follow-up, and measured renal and hepatic function, in 14 of the 21 patients. RESULTS: Decreased radiopacity of the coils was observed in 9 of 13 patients who had follow-up fluoroscopy during repeat cardiac catheterization. Repeat angiography of the vessel occluded by the coil was performed in 7 patients, 5 of whom showed recanalization. Levels of tungsten in the serum were analyzed 6 to 35 months after implantation of coils in 8 patients. The mean concentration was 6.43 micrograms/l, with a range from 2 to 14.4 micrograms/l, normal values being less than 0.2 microgram/l. CONCLUSION: Tungsten coils may dissolve over time and lead to markedly elevated levels of tungsten in the serum, with recanalization of previously occluded vessels. Despite lack of clinical and laboratory data in patients with elevated levels of tungsten in the serum, our study suggests that the clinical use of mechanically detachable coils produced from tungsten should no longer be recommended.

Hematological effects and metal residue concentrations following chronic dosing with tungsten-iron and tungsten-polymer shot in adult game-farm mallards.

The U.S. Fish and Wildlife Service required a chronic dosing study that assessed the health and reproductive effects of tungsten-iron and tungsten-polymer shot in adult game-farm mallards (Anas platyrhynchos) prior to granting permanent approval of the shot for waterfowl hunting. Herein, we present the effects of tungsten-iron and tungsten-polymer shot on various hematologic parameters and metal residue concentrations in the femur, liver, kidneys, and gonads. Thirty-two-bird groups (sexes equal) of adult mallards were dosed orally with eight #4 steel shot (control), eight #4 tungsten-iron shot, or eight #4 tungsten-polymer shot on days 0, 30, 60, 90, and 120 of a 150 day trial (26 January 1998 to 25 June 1998). An additional 12 mallards (sexes equal) received eight #4 lead shot (positive control) on day 0 of the study. Lead-dosed mallards had significantly decreased hematocrit, hemoglobin concentration, and whole-blood delta aminolevulinic acid dehydratase activity on day 7, as well as significant changes in a number of plasma chemistry parameters compared to ducks in the control, tungsten-iron, or tungsten-polymer groups. Mallards dosed with tungsten-iron or tungsten-polymer shot had occasional significant differences in hematocrit and plasma chemistry values when compared to control mallards over the 150 day period, but these changes were not considered to be indicative of deleterious effects. Low concentrations of tungsten were detected in gonad and kidney samples from males and females and in liver samples from females dosed with tungsten-polymer shot. Tungsten was also detected in femur samples from tungsten-polymer-dosed mallards. Higher concentrations of tungsten were detected in femur, liver, kidney, and gonad samples from tungsten-iron-dosed ducks. Tungsten-iron or tungsten-polymer shot repeatedly administered to adult mallards did not cause adverse hematological effects during the 150 day trial. Concentrations of tungsten in the femur, liver, kidneys, and gonads were generally higher in tungsten-iron-dosed ducks when compared to tungsten-polymer-dosed ducks.

Pharmacokinetics of sodium tungstate in rat and dog: a population approach.

Sodium tungstate has been found to correct hyperglycemia in insulin- and noninsulin-dependent models of diabetes when administered in drinking fluid with a low degree of toxicity; thus, it provides a potential treatment for diabetes. In the present report, pharmacokinetic studies with sodium tungstate were carried out in the Sprague-Dawley rat and beagle dog. This drug was administered either i.v. (8.97 mg/kg in rat; 25 and 50 mg/kg in dog) or orally in the form of solution (35.9 and 107.7 mg/kg in rat; 25 and 50 mg/kg in dog). Tungsten was quantified using an inductively coupled plasma method. Pharmacokinetic parameters were estimated using a population approach. Sodium tungstate followed first order kinetics, and plasma concentration-versus-time data were adequately described by a two-compartment model. In rat, bioavailability was high (92%), whereas it was lower in dog (approximately 65%). The total volume of distribution expressed by unit of body weight was much higher when the animal was smaller (0.46 l/kg in rat versus 0.23 l/kg in dog). The total body clearance normalized by weight, 0.19 l/h/kg in rat versus 0.043 l/h/kg in dog, changed as for the volume of distribution. The elimination half-life was two times higher in dog (approximately 4 h) than in rat (approximately 1.7 h). In the range of 35.9 to 107.7 mg/kg after oral administration in rat and 25 to 50 mg/kg after oral and i.v. administration in dog, tungsten plasma concentrations increased in proportion to dose.

Endovascular embolization of varicoceles: resorption of tungsten coils in the spermatic vein.

PURPOSE: To investigate whether resorption of tungsten coils occurs in patients with varicoceles treated by endovascular embolization of the spermatic vein. METHODS: Patients who had previously had varicocele embolization were requested by letter to attend the radiology department. Blood levels of tungsten were compared with a group of controls. Fluoroscopic images of the coils were taken and compared with those obtained during the original procedures. RESULTS: Nineteen patients attended, whose procedure had been done 19-57 months previously (mean 40 months). Blood levels of tungsten were raised in 18 patients compared with the controls. Radiographic evidence of loss of substance of the coils was seen in four patients. CONCLUSION: Tungsten coil resorption occurs in varicocele embolization. In view of the unknown long-term effects of raised blood tungsten levels and the availability of alternative embolization agents, we feel that it is unwise to persist in the use of tungsten coils in this application.

Multielement determination of metals in biological specimens of hard metal workers: a study carried out by neutron activation analysis.

Multielemental analysis, using neutron activation, was carried out on the urine, whole blood, pubic hair and toenails of thirty subjects occupationally exposed to hard metal dusts. A high concentration of Co, W and Cr was observed in all samples analysed. The concentrations determined, when subjected to statistical analysis using pattern recognition techniques (e.g. cluster analysis), indicated a positive correlation, at p = 0.001, for the pair (Co, W) in urine and blood, as well as a possible influence of Cr on this pair.