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Carcinogenicity classification of vanadium pentoxide and inorganic vanadium compounds, the NTP study of carcinogenicity of inhaled vanadium pentoxide, and vanadium chemistry.

It is argued that, because of inherent weaknesses in design and procedure, the U.S. National Toxicology Program study of the carcinogenicity of inhaled vanadium pentoxide does not provide adequate evidence to support the classification by regulatory authorities of vanadium pentoxide as a Group 2B (possible) human carcinogen. The extension by one regulatory authority of the carcinogenicity classification for vanadium pentoxide to cover all vanadium compounds is also questioned. Such an extension implies that the toxic effect of some unknown vanadium species is more powerful than that of any oxygen species generated from the oxygen atoms in vanadium pentoxide, and that vanadium in any form can be converted in vivo to an undefined toxic species. There is no experimental or theoretical basis supporting this hypothesis. For oxygen-containing compounds like vanadium pentoxide, there is a need for some form of toxicity classification related to their oxygen content since it is likely to be the most reactive component of such compounds. For all particulates, such as those of crystalline vanadium pentoxide, the special toxicity of particulates, and especially nanoparticles, also needs separate consideration and classification.

Aerosols↗

Vanadium metabolism in sheep. II. Effect of dietary vanadium on performance, vanadium excretion and bone deposition in sheep.

Sixteen ram lambs were fed 0, 50 or 200 ppm supplemental vanadium daily as NH4VO3 for 90 d and coccygeal vertebrae were sampled at 0, 15, 30, 60 and 90 d after the imposition of dietary treatments. Vertebral vanadium content was elevated (P less than .05) after exposure to 200 ppm added vanadium in the diet of 15 d, but nonsignificant increases occurred thereafter. Increasing dietary vanadium increased bone ash vanadium concentration from .4 to 1.7 and 3.8 ppm in sheep fed 0, 50 and 200 ppm supplemental vanadium, respectively. In a balance study, urinary concentrations of the element also were related directly to dietary intake. A trend toward elevated urine volume with increased intake of vanadium was also observed.

Absorption↗

The distribution and half-life for retention of vanadium in the organs of normal and diabetic rats orally fed vanadium(IV) and vanadium(V).

The concentration of vanadium in organs of diabetic rats that had been fed vanadium, either as V(IV) or V(V), in their drinking water has been determined. The kidney was found to have the highest concentration, about 185 nmol/g wet tissue. This averages about three times higher than for the liver or spleen, for which concentrations were comparable. The lung, blood plasma, and blood cells tended to have the lowest accumulations of vanadium. A time-course study indicated that the half-life for elimination of vanadium from the bodies of vanadium-fed rats is about 12 d.

Animals↗

A vanadium and iron cluster accumulates on VnfX during iron-vanadium-cofactor synthesis for the vanadium nitrogenase in Azotobacter vinelandii.

The vnf-encoded nitrogenase from Azotobacter vinelandii contains an iron-vanadium cofactor (FeV-co) in its active site. Little is known about the synthesis pathway of FeV-co, other than that some of the gene products required are also involved in the synthesis of the iron-molybdenum cofactor (FeMo-co) of the widely studied molybdenum-dinitrogenase. We have found that VnfX, the gene product of one of the genes contained in the vnf-regulon, accumulates iron and vanadium in a novel V-Fe cluster during synthesis of FeV-co. The electron paramagnetic resonance (EPR) and metal analyses of the V-Fe cluster accumulated on VnfX are consistent with a VFe7-8Sx precursor of FeV-co. The EPR spectrum of VnfX with the V-Fe cluster bound strongly resembles that of isolated FeV-co and a model VFe3S4 compound. The V-Fe cluster accumulating on VnfX does not contain homocitrate. No accumulation of V-Fe cluster on VnfX was observed in strains with deletions in genes known to be involved in the early steps of FeV-co synthesis, suggesting that it corresponds to a precursor of FeV-co. VnfX purified from a nifB strain incapable of FeV-co synthesis has a different electrophoretic mobility in native anoxic gels than does VnfX, which has the V-Fe cluster bound. NifB-co, the Fe and S precursor of FeMo-co (and presumably FeV-co), binds to VnfX purified from the nifB strain, producing a shift in its electrophoretic mobility on anoxic native gels. The data suggest that a precursor of FeV-co that contains vanadium and iron accumulates on VnfX, and thus, VnfX is involved in the synthesis of FeV-co.

Azotobacter vinelandii↗

The vanadium-iron protein of vanadium nitrogenase from Azotobacter chroococcum contains an iron-vanadium cofactor.

N-Methylformamide extracts of acid-treated precipitated VFe protein of the V-nitrogenase of Azotobacter chroococcum are yellow-brown in colour and contain vanadium, iron and acid-labile sulphur in the approximate proportions 1:6:5. E.p.r. spectra of the extracts exhibit a weak signal with g values near 4.5, 3.6 and 2.0 characteristic of an S = 3/2 metal-containing centre. The N-methylformamide extracts activated the MoFe protein polypeptides from mutants of nitrogen-fixing bacteria unable to synthesize FeMoco, the active centre of Mo-nitrogenase. The active hybrid protein exhibited the characteristic substrate-reducing phenotype associated with the VFe protein except that it could not reduce N2 to NH3. The above data are interpreted as demonstrating the existence of an iron- and vanadium-containing cofactor, FeVaco, within the VFe protein. It is suggested that nitrogen fixation requires specific interactions between FeVaco or FeMoco and their respective polypeptides. The biosynthesis of these cofactors is discussed.

Azotobacter↗

The intensity of vanadium(V)-induced cytotoxicity and morphological transformation in BALB/3T3 cells is dependent on glutathione-mediated bioreduction to vanadium(IV).

Cytotoxicity and morphological transformation has been studied in BALB/3T3 Cl A31-1-1 mouse embryo cells for ammonium vanadate [vanadium(V)] and vanadyl sulphate [vanadium(IV)] alone or in combination with diethylmaleate (DEM), a cellular glutathione (GSH)-depleting agent. Cells exposed for 24 h to 10(-5) M vanadium(V) alone or in combination with 3 x 10(-6) M DEM showed the characteristic hyperfine EPR signal of vanadium(IV), which was more obvious in the case of exposure to vanadium(V) alone. This suggests that the amount of vanadium(V) reduced to vanadium(IV) decreased in GSH-depleted cells. While vanadium(IV) at concentrations of 3 x 10(-6) M and 10(-5) M was not transforming in the cells, vanadium(V) showed neoplastic transforming activity (P < 0.025 and P < 0.001 for the two doses, respectively) in comparison to controls (vanadium unexposed cells). Cytotoxicity and morphological transformation in cells exposed to vanadium(V) in combination with 3 x 10(-6) M DEM were significantly more intensive (P < 0.005 and P < 0.01 for the two doses of vanadate tested) compared to the corresponding values observed in cells exposed to vanadium(V) alone. This suggests that the final transforming activity response is dependent on the intracellular GSH-mediated mechanism of reduction of vanadium(V) to vanadium(IV): (i) the extent to which vanadium(V) should be bioreduced to less toxic vanadium(IV) via intracellular GSH is a key point in determining the intensity of the observed neoplastic action; (ii) the carcinogenic potential of vanadium(V) should be strictly dependent on its intracellular persistence which could lead to changes in normal metabolic patterns of vanadium(V) in the oxidized form due to lack of GSH-mediated reduction.

3T3 Cells↗

Speciation of vanadium(IV) and vanadium(V) using ion-exchange chromatography and ICP-AES.

A speciation method for vanadium(IV) and vanadium(V) is presented that uses a combination of HPLC and ICP-AES. In this method, 1 mM HNO3 solution and 100 mM HNO3 solution were applied in sequence as eluent. A vanadium(IV) and vanadium(V) mixture was injected into a HPLC anion-exchange column; and vanadium(IV) cation was then eluted by 1 mM HNO3, while vanadium(V) oxoacid anion was trapped on the column. After this separation, vanadium(V) was eluted as a cation from the column by 100 mM HNO3. Vanadium was detected by ICP-AES. In this separation, about 15% of vanadium(V) interfered with vanadium(IV), and trace vanadium(IV) interfered with vanadium(V). This interference could be estimated by simple calculation based on standard observations, and the speciation of vanadium(IV) and vanadium(V) was performed. The lower determination limit was 1 microgram/mL, which is insufficient to speciate vanadium sampled by conventional sampling methods in a working environment. However, impurity of the other valent vanadium species in a vanadium(V) reagent can be determined by the present method, which should be valuable in precisely assessing the toxicities of vanadium species.

Chromatography, High Pressure Liquid↗

Serum and urinary vanadium of workers processing vanadium pentoxide.

Serum and urinary vanadium concentrations were investigated in eight men exposed to vanadium pentoxide dust. The creatinine-adjusted urinary vanadium concentrations were found to correlate with serum vanadium concentrations (r = 0.81), but not with the vanadium contents of factory air. The urinary vanadium excretion decreased significantly with the time the workers spent out of exposure. At the beginning of their summer holidays the serum vanadium concentration of the workers was 393 +/- 223 (S.D.) nmol/l and the urinary excretion of vanadium 73 +/- 50 nmol/mmol of creatinine. Three days after exposure the urinary excretion of vanadium was 46 +/- 24 nmol/mmol of creatinine. On the 16th day of their holidays vanadium could be detected in the serum (225 +/- 83 nmol/l) and in the urine (48 +/- 26 nmol/mmol of creatinine) of the workers. Eight family members of the exposed had less vanadium in urine (32 +/- 17 nmol/mmol of creatinine). These results suggest that most of the absorbed vanadium is excreted in the urine within one day after a long-term moderate exposure to vanadium dust.

Adult↗

Vanadium respiration by Geobacter metallireducens: novel strategy for in situ removal of vanadium from groundwater.

Vanadium can be an important contaminant in groundwaters impacted by mining activities. In order to determine if microorganisms of the Geobacteraceae, the predominant dissimilatory metal reducers in many subsurface environments, were capable of reducing vanadium(V), Geobacter metallireducens was inoculated into a medium in which acetate was the electron donor and vanadium(V) was the sole electron acceptor. Reduction of vanadium(V) resulted in the production of vanadium(IV), which subsequently precipitated. Reduction of vanadium(V) was associated with cell growth with a generation time of 15 h. No vanadium(V) was reduced and no precipitate was formed in heat-killed or abiotic controls. Acetate was the most effective of all the electron donors evaluated. When acetate was injected into the subsurface to enhance the growth and activity of Geobacteraceae in an aquifer contaminated with uranium and vanadium, vanadium was removed from the groundwater even more effectively than uranium. These studies demonstrate that G. metallireducens can grow via vanadium(V) respiration and that stimulating the activity of Geobacteraceae, and hence vanadium(V) reduction, can be an effective strategy for in situ immobilization of vanadium in contaminated subsurface environments.

Anaerobiosis↗

A new dinuclear vanadium(V)-citrate complex from aqueous solutions. Synthetic, structural, spectroscopic, and pH-dependent studies in relevance to aqueous vanadium(V)-citrate speciation.

Vanadium interactions with low molecular mass binders in biological fluids entail the existence of vanadium species with variable chemical and biological properties. In the course of efforts to elucidate the chemistry related to such interactions, we have explored the oxidative chemistry of vanadium(III) with the physiologically relevant tricarboxylic citric acid. Aqueous reactions involving VCl(3) and anhydrous citric acid, at pH approximately 7, resulted in blue solutions. Investigation into the nature of the species arising in those solutions revealed, through UV/visible and EPR spectroscopies, oxidation of vanadium(III) to vanadium(IV). Further addition of H(2)O(2) resulted in the oxidation of vanadium(IV) to vanadium(V), and the isolation of a new vanadium(V)-citrate complex in the form of its potassium salt. Analogous reactions with K(4)[V(2)O(2)(C(6)H(4)O(7))(2)].6H(2)O and H(2)O(2) or V(2)O(5) and citrate at pH approximately 5.5 afforded the same material. Elemental analysis pointed to the molecular formulation K(4)[V(2)O(4)(C(6)H(5)O(7))(2)].5.6H(2)O (1). Complex 1 was further characterized by FT-IR and X-ray crystallography. 1 crystallizes in the triclinic space group P(-)1, with a = 11.093(4) A, b = 9.186(3) A, c = 15.503(5) A, alpha = 78.60(1) degrees, beta = 86.16(1) degrees, gamma = 69.87(1) degrees, V = 1454.0(8) A(3), and Z = 2. The X-ray structure of 1 reveals the presence of a dinuclear vanadium(V)-citrate complex containing a V(V)(2)O(2) core. The citrate ligands are triply deprotonated, and as such they bind to vanadium(V) ions, thus generating a distorted trigonal bipyramidal geometry. Binding occurs through the central alkoxide and carboxylate groups, with the remaining two terminal carboxylates being uncoordinated. One of those carboxylates is protonated and contributes to hydrogen bond formation with the deprotonated terminal carboxylate of an adjacent molecule. Therefore, an extended network of hydrogen-bonded V(V)(2)O(2)-core-containing dimers is created in the lattice of 1. pH-dependent transformations of 1 in aqueous media suggest its involvement in a web of vanadium(V)-citrate dinuclear species, consistent with past solution speciation studies investigating biologically relevant forms of vanadium.

Journal Article↗

Cellular retention, cytotoxicity and morphological transformation by vanadium(IV) and vanadium(V) in BALB/3T3 cell lines.

Cytotoxicity, morphological transformation and cellular retention have been studied in BALB/3T3 Cl A 31-1-1 cells for ammonium or sodium vanadate [vanadium(V)] and for vanadyl sulphate [vanadium(IV)]. A morphological transformation focus assay showed transforming activity for vanadium(V) (P less than 0.005 at concentrations of 3 x 10(-6) or higher) while vanadium(IV) was not transforming in the cells. Cytotoxicity was higher for vanadium(V) than for vanadium(IV); this was particularly clear at doses from 5 x 10(-6) to 5 x 10(-5) M. The cellular retention of both vanadate and vanadyl compounds at 24, 48 and 72 h incubation was similar. At concentrations lower than 10(-6) M vanadate, the retention was linear with the dose, while at higher exposures the vanadium taken up by the cells levelled off or slightly decreased. Exposure to 10(-6) M and 10(-5) M vanadium(V) for 3 and 24 h as well as to 10(-6) M for 48 and 72 h yielded greater than 94% vanadium in the cytosol, but exposure to a toxic dose (10(-5) M) for 48 and 72 h yielded 20% vanadium associated with cellular organelles, which suggests that some sites in the cytosol become saturated with vanadium. The corresponding gel-filtration experiments indicate that a redistribution of the element among the cytosol components occurs with time.

Animals↗

Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used.

In the present investigation, the effects of oral administration of sodium metavanadate, sodium orthovanadate and vanadyl sulphate to alleviate some signs of diabetes in streptozotocin-treated rats have been evaluated. Streptozotocin-induced diabetic rats drank aqueous solutions (NaCl, 80 mM) containing sodium metavanadate (0.15 mg/ml), sodium orthovanadate (0.23 mg/ml), or vanadyl sulphate pentahydrate (0.31 mg/ml) for 28 days. The vanadium-treated animals were compared to controls, either diabetic or nondiabetic, receiving drinking water containing NaCl (80 mM) only. Daily food and fluid intake were significantly decreased in the vanadium-treated animals relative to diabetic controls. Also, vanadium treatment reduced the level of hyperglycemia in diabetic rats, with sodium metavanadate being the most effective of the vanadium compounds tested. However, daily vanadium intake was significantly lower in the animals receiving sodium metavanadate. Signs of toxicity were observed in all vanadium-treated animals as evidenced by some deaths, decreased weight gain, and increased serum concentrations of urea and creatinine. Moreover, vanadium was detected in all tissues analyzed. Although some signs of diabetes were improved by vanadium treatment, because of the severe toxic side effects noted in all of the vanadium-treated animals, it seems evident that oral vanadium administration is not a suitable therapy of diabetes mellitus in streptozotocin-diabetic rats.

Administration, Oral↗

Reactivity investigation of dinuclear vanadium(IV,V)-citrate complexes in aqueous solutions. A closer look into aqueous vanadium-citrate interconversions.

Well-known vanadium(IV)- and vanadium(V)-citrate complexes have been employed in transformations involving vanadium redox as well as nonredox processes. The employed complexes include K(2)[V(2)O(4)(C(6)H(6)O(7))(2)] x 4H(2)O, K(4)[V(2)O(4)(C(6)H(5)O(7))(2)] x 5.6H(2)O, K(2)[V(2)O(2)(O(2))(2)(C(6)H(6)O(7))(2)] x 2H(2)O, K(4)[V(2)O(2)(C(6)H(4)O(7))(2)] x 6H(2)O, K(3)[V(2)O(2)(C(6)H(4)O(7))(C(6)H(5)O(7))] x 7H(2)O, (NH(4))(4)[V(2)O(2)(C(6)H(4)O(7))(2)] x 2H(2)O, and (NH(4))(6)[V(2)O(4)(C(6)H(4)O(7))(2)] x 6H(2)O. Reactions toward hydrogen peroxide at different vanadium(IV,V):H(2)O(2) ratios were crucial in delineating the routes leading to the interconversion of the various species. Equally important thermal transformations were critical in showing the linkage between pairs of dinuclear vanadium-citrate peroxo as well as nonperoxo complexes, for which the important vanadium(V)-assisted oxidative decarboxylation, leading to reduction of vanadium(V) to vanadium(IV), seemed to be a plausible pathway in place for all the cases examined. FT-IR spectroscopy and X-ray crystallography were instrumental in the identification of the arising products of all investigated reactions. Collectively, the data support the existence of chemical links between different and various structural forms of dinuclear vanadium(IV,V)-citrate complexes in aqueous media. Furthermore, in corroboration of past studies, the examined interconversions lend credence to the notion that the involved species are active participants in the respective aqueous distributions of the metal ion in the presence of the physiological ligand citrate. The concomitant significance of structure-specific species relating to soluble and potentially bioavailable forms of vanadium is mentioned.

Journal Article↗

Urinary vanadium as a biological indicator of exposure to vanadium.

Vanadium was determined in urine and blood of two workers (Worker Nos. 1 and 2 with direct exposure to vanadium pentoxide) and 13 fellow workers (with indirect or no vanadium exposure), and the results were compared by means of personal and stationary sampling of vanadium in air. Worker No. 1, a foreman with the heaviest exposure to vanadium, had a green tongue, complained of frequent productive coughing, and excreted 47 to 124 ng/ml vanadium in his late morning and mid-afternoon urine. Worker No. 2, a helper to the foreman with less exposure, had no green tongue or subjective complaints, and excreted no vanadium at a measurable level even in his mid-shift urine. No vanadium was detected in urine samples from other workers, nor in blood from all workers including Worker Nos. 1 and 2. Application of inductively coupled plasma emission spectrometry to measurement of vanadium in biological materials is discussed.

Adult↗

Toxicology of vanadium compounds in diabetic rats: the action of chelating agents on vanadium accumulation.

The possible use of vanadium compounds in the treatment of diabetic patients is now being evaluated. However, previously to establish the optimal maximum dose for diabetes therapy, it should be taken into account that vanadium is a highly toxic element to man and animals. The toxic effects of vanadium are here reviewed. The tissue vanadium accumulation, which would mean an additional risk of toxicity following prolonged vanadium administration is also discussed. Recently, it has been shown that coadministration of vanadate and TIRON, an effective chelator in the treatment of vanadium intoxication, reduced the tissue accumulation of this element, decreasing the possibility of toxic side effects derived from chronic vanadium administration without diminishing the hypoglycemic effect of vanadium. However, previously to assess the effectiveness of this treatment in diabetic patients, a critical reevaluation of the antidiabetic action of vanadium and its potential toxicity is clearly needed.

Animals↗

Vanadium-binding proteins (vanabins) from a vanadium-rich ascidian Ascidia sydneiensis samea.

Since the beginning of the last century, it has been known that ascidians accumulate high levels of a transition metal, vanadium, in their blood cells, although the mechanism for this curious biological function remains unknown. Recently, we identified three vanadium-binding proteins (vanabins), previously denoted as vanadium-associated proteins (VAPs) [Zool. Sci. 14 (1997) 37], from the cytoplasm fraction of vanadium-containing blood cells (vanadocytes) of the vanadium-rich ascidian Ascidia sydneiensis samea. Here, we describe the cloning, expression, and analysis of the metal-binding ability of vanabins. Recombinant proteins of two independent but related vanabins, vanabin1 and vanabin2, bound to 10 and 20 vanadium(IV) ions with dissociation constants of 2.1x10(-5) and 2.3x10(-5) M, respectively. The binding of vanadium(IV) to these vanabins was inhibited by the addition of copper(II) ions, but not by magnesium(II) or molybdate(VI) ions. Vanabins are the first proteins reported to show specific binding to vanadium ions; this should provide a clue to resolving the problem regarding the selective accumulation of vanadium in ascidians.

Amino Acid Sequence↗

Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution.

AIMS: Vanadium is currently undergoing clinical trials as an oral drug in patients with noninsulin-dependent diabetes mellitus. Furthermore, vanadium occurs in elevated concentrations in the blood of patients receiving intravenous albumin solutions containing large amounts of the metal ion as an impurity. The present study was performed to examine the pharmacokinetics of vanadium in humans following a single intravenous (i.v.) dose of a commercial albumin solution containing a high amount of vanadium. METHODS: The study was conducted in five healthy volunteer subjects who received intravenously 90 ml of a commercial 20% albumin infusion solution containing 47.6 micro g vanadium as an impurity. Vanadium concentrations in serum and urine were determined by electrothermal atomic absorption spectrometry. RESULTS: Vanadium serum concentrations after i.v. administration were measured for 31 days. The data could be fitted by a triexponential function corresponding formally to a three-compartment model. There was an initial rapid decrease in serum concentrations with half-lives of 1.2 and 26 h. This was followed by a long-terminal half-life time of 10 days. The terminal phase accounted for about 80% of the total area under the serum concentration-time curve (AUC). The mean apparent volume of distribution of the central compartment was found to be 10 l. The volume of distribution at steady state was 54 l, and total clearance was 0.15 l h(-1). Vanadium was mainly excreted by the kidneys. About 52% of the dose was recovered in the urine after 12 days. CONCLUSIONS: This study provides data on vanadium pharmacokinetics in healthy humans.

Adult↗

Serum and urinary vanadium of vanadium-exposed workers.

In this investigation the environment of vanadium workers was studied. It was found that low concentrations of vanadium (0.01--0.04 mg/m3) in the air do not correlate with vanadium serum levels or its urinary excretion. The results, however, suggest that values of vanadium in serum and urine samples reflect absorption of vanadium because vanadium could not be detected in the urine of referents. In higher vanadium exposure (0.2--0.5 mg/m3), the concentration in the air inhaled remaining unknown due to the use of dust masks, urinary vanadium excretion and serum vanadium level decreased significantly with exposure-free time.

Air Pollutants↗