Vanadium Toxicity Research Articles

Preface

Knowledge of the chemistry and biochemistry of vanadium has increased enormously since the early 1980s, particularly that of vanadium(III), (IV), and (V). This led to remarkable developments in the understanding and recognition of the properties of vanadium compounds. A consequence of these new insights has been numerous applications of vanadium complexes ranging from therapeutics to catalysis and from new materials to green chemistry. Many of the more recent advances were presented at the 6th International Vanadium Symposium held 17‚Äì19 July 2008 in Lisbon, Portugal.The conference included 56 oral communications and 52 poster presentations. The following 12 papers are a selection from the oral communications presented. This conference attracted over 100 participants from 27 countries and 4 continents. The inorganic chemistry of vanadium, application of vanadium chemistry in catalysis and organic synthesis, and biological aspects of vanadium chemistry were discussed in invited lectures as well as in poster communications.The Vanadium Award, a prize first introduced at the 4th International Vanadium Symposium held in 2004 in Szeged, Hungary to recognize an outstanding contributor to the advancement of vanadium science, was awarded in 2008 to Prof. Toshikazu Hirao of the Osaka University, Japan, and his contribution is the first paper presented herein.The additional contributions that embody this issue are mostly papers covering aspects related to catalytic applications of vanadium compounds, including their use as functional models of vanadiumdependent haloperoxidases. Electron transfer in oxo and non-oxo vanadium complexes, the use of NMR to characterize the complexes, and synthesis of new polyoxovanadates are the subjects of other papers included.We look forward to the 7th International Vanadium Symposium to be held in Japan in 2010, where additional studies on the role of vanadium in life, the vanadium nutritional essentiality, vanadium toxicity, and vanadium therapy, as well as new contributions to the use of vanadium compounds in catalysis, including "green chemical" industrial applications, will certainly be presented.João Costa PessoaConference Chair

Green Tea Drinking Reduces the Effects of Vanadium Poisoning in Rat Kidney

Transitional metals, as vanadium, are known to exert noxious effects by generating oxidative stress. Addition of antioxidants in the diet could decrease the cytotoxic effect related to the oxidative stress. The present study, carried out in rats, is a contribution to explore mechanisms underlying vanadium toxicity and possible protective effects of green tea Camellia sinensis which is known to be rich in antioxidant compounds (polyphenols...). Chronic intoxication by vanadium given in drinking water was found to induce histological structure changes of renal glomeruli and tubules, but indicators of nephrotoxicity (serum creatinine and urea, urinary pH) were not perturbed. Vanadium accumulation was found to be decreased in (T+V) group, and renal histological changes were not observed. The ability of catechins to chelate metal ions, and perhaps vanadium, could explain protective effects of herbal green tea. Intraperitoneal administration of vanadium to rats (V) was found to induce an increase of lipid peroxidation levels in kidney, that was lowered in rats (T+V) drinking herbal tea. This effect was partly due to a tea-induced decrease of basal lipid peroxidation level in kidney tissues. Similar HSP72 underexpression and HSP73 overexpression were found in (V) and (T+V) rats. Vanadium-induced HSP70 underexpression was discussed in relation to the ability of the metal to inactivate some phosphatases, resulting in phosphorylation and transcriptional activity changes of heat shock factor 1 (HSF1). Besides, two forms of GRP94 (96, 98kD) were immunodetected, that appeared inversely regulated by vanadium, but not by herbal tea. This suggests that vanadium can disrupt reticulum endoplasmic function resulting in GRP94 phosphorylation and/or glycosylation changes.

Effective control of blood glucose status and toxicity in streptozotocin-induced diabetic rats by orally administration of vanadate in an herbal decoction

Vanadium compounds have been well recognized for hypoglycemic effects, but questions remain on gastrointestinal disturbance and possible tissue vanadium accumulation thus slowing the acceptance of vanadium compounds as diabetic therapeutic agents. Our intestinal permeability and toxicity studies of vanadium compounds have suggested that the co-administration of vanadate with Salvia miltiorrhiza Bunge decoction could benefit the therapeutic use of hypoglycemic vanadium compounds. In the present paper, we tested the hypoglycemic effects of vanadate ingested in an aqueous extract of S. Bunge using a streptozocin (STZ)-induced diabetic rat model. Oral administration of vanadate in S. Bunge herbal decoction produced a stable (free of hypoglycemic shock) and long-lasting (∼70 day) control of blood glucose status. Effective protection of animal organs from hyperglycemic damage was also observed. As expected, the herbal extract significantly alleviated vanadium toxicity, i.e. GI stress and metal accumulation. In addition, the result suggesting that vanadium-induced amelioration of the diabetic state appears to be secondary to the preservation of a functional portion of the pancreatic β-cells which initially survived STZ-toxicity. These studies provide new insight into the therapeutic treatment of diabetics with vanadium compounds.

Vanadium-enriched chickpea sprout ameliorated hyperglycemia and impaired memory in streptozotocin-induced diabetes rats

Vanadium compounds have been recognized for their hypoglycemic effects; however, potential short and long-term vanadium toxicity has slowed the acceptance for therapeutic use. In the present work, three batches of vanadium-enriched chickpea sprout (VCS) were prepared by incubating chickpea seeds in presence of 200, 100, and 50 microg/ml of sodium orthovanadate (SOV). The effects of oral administration of chickpea sprout (CS) and VCS food for 8 weeks on streptozotocin-induced (STZ) diabetic rats were investigated. Both CS and VCS food was found to ameliorate some hyperglycemic symptoms of the diabetic rats, i.e. improve lipid metabolism, decrease blood glucose level, prevent body weight loss, and reduce impairment of diabetic related spatial learning and memory. Serum insulin was substantially elevated in treated diabetic rats, which is probably one important reason for the hypoglycemic effect. Compared with CS alone, VCS100 food exhibited remarkably enhanced effectiveness in alleviating diabetes induced hyperglycemia and memory loss. Moreover, vanadium-enriched chickpeas appeared to abolish the vanadium induced toxicity associated with administration of this metal for diabetes during the 8-week study period. This study suggested further work of the vanadium speciation in CS and novel hypoglycemic mechanism for the antidiabetic activity of vanadium agents. Vanadium containing (VCS) food could be a dietary supplement for the diabetic status.

Biological response of primary rat calvarial cell by surface treatment of Ti-8Ta-8Nb alloy

Purpose: Ti-6Al-4V alloy is widely used as an implant material because of its good biocompatibility and good mechanical property compared with commercial pure titanium. Otherwise, toxicity of aluminum and vanadium in vivo has been reported. Ti-8Ta-3Nb alloy is recently developed in the RD38:595-602)

Ｔｉ‐６Ａｌ‐７Ｎｂ合金粉末によるＭＩＭプロセスの最適化

Ti-6Al-7Nb alloy has been developed for more suitable biomaterial in place of Ti-6Al-4V alloy because of vanadium toxicity to human body. In this study, the metal injection molding process was applied to produce the Ti-6Al-7Nb alloy compacts using alloy powder. For comparison, the mixed elemental powders of Ti, Al and Nb, and pre-alloyed powders of Ti-Al and Al-Nb were also used. The effects of sintering conditions on the microstructures, relative density and mechanical properties of injection molded compacts were investigated. Sintered compacts using alloy powder showed relatively higher mechanical properties than the compacts using mixed powder. Eventually, the compacts using alloy powder were improved to be 900 MPa of tensile strength with 15% of elongation, which are comparable to the properties of wrought materials.

Preclinical Evaluation of a Dual-Acting Microbicidal Prodrug WHI-07 in Combination with Vanadocene Dithiocarbamate in the Female Reproductive Tract of Rabbit, Pig, and Cat

The mucosal safety of the combination antiretroviral spermicide,WHI-07 [5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxy alaninyl phosphate] and vanadocene dithiocarbamate (VDDTC), was evaluated in 3 different animal models. Twenty-seven NZW rabbits in four subgroups were exposed intravaginally to a gel-microemulsion (GM) with and without three dose levels of WHI-07 plus VDDTC (0.5+0.06%, 1.0+0.12% and 2.0+0.25%) or 4% nonoxynol-9 (N-9; Conceptrol) for 14 consecutive days. Ten nonestrus gilts (Duroc) in three subgroups received either a single or daily intravaginal application of GM with and without 2.0% WHI-07 plus 0.25% VDDTC or 2.0% benzalkonium chloride (BZK)-containing gel for 6 and 4 consecutive days, respectively. Five cats received a single intravaginal application of GM incorporating 2.0% WHI-07 plus 0.25% VDDTC. Genital tract histopathology was performed in the pig and rabbit at the end of dosing period but after 18 weeks post-dosing in the cat. Porcine cervicovaginal lavage (CVL) fluid was obtained for up to 72 hours after a single exposure and changes in the levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma, and TNF-alpha) were quantitated by a multiplexed chemiluminescence-based immunoassay. Rabbit vaginal tissues were evaluated for localized cellular inflammation and in situ apoptosis by immunohistochemical staining for CD45, nuclear factor (NF)-kappa B, and terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick-end labeling (TUNEL) using confocal laser scanning microscopy (CLSM), respectively. Vanadium content in selected organs and body fluids from rabbits and pigs was determined by atomic absorption spectroscopy. When compared with 4% N-9 (total irritation score 13-14 out of a possible 16), none of the rabbits given WHI-07 plus VDDTC intravaginally, developed histological alterations such as epithelial erosion, edema, leukocyte influx or vascular congestion characteristic of inflammation (total irritation score 4-6). CD45 and NF-kappa B immunoreactivity was limited to cells within the vascular lumen of both control and WHI-07 plus VDDTC-treated vaginal tissues. TUNEL assay revealed lack of increased apoptotic cells in vaginal mucosa exposed to increasing concentrations of WHI-07 plus VDDTC. Basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) in porcine CVL were unaffected by intravaginal exposure to WHI-07 plus VDDTC when compared with BZK used as a positive control. Endpoint histology of the reproductive tract from cats and pigs after a single or repeated intravaginal exposure to WHI-07 plus VDDTC, respectively, revealed lack of irritation/inflammation in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues, and underlying/surrounding muscles. Vanadium was not preferentially incorporated into rabbit or porcine tissues and body fluids at levels above 1 microg/g. Based on comparative histologic data and surrogate markers for inflammation, repeated intravaginal administration of WHI-07 plus VDDTC via a gel-microemulsion did not result in vaginal irritation, mucosal toxicity, or systemic absorption of vanadium. Therefore, the combined use of WHI-07 and VDDTC via gel-microemulsion appears safe for topical use as a prophylactic anti-HIV microbicide.

Amelioration of vanadium-induced testicular toxicity and adrenocortical hyperactivity by vitamin E acetate in rats

Vanadium toxicity is a challenging problem to the health professionals and a cutting-edge medical problem. Vanadium has been recognized as industrial hazards that adversely affect human and animal reproductive health. Since testicular function is exquisitely susceptible to reactive-oxygen species, the present study elucidates the possible involvement of oxidative stress in vanadium-induced testicular toxicity and the prophylactic effects of vitamin E acetate against such adverse effects of vanadium. The study also characterizes the effects of vanadium on rat adrenal steroidogenesis and determines the underlying mechanisms of testicular and adrenal interactions in response to vanadium exposure. Significantly reduced sperm count associated with decreased serum testosterone and gonadotropins level in the vanadium-injected group of rats compared to control substantially proves the ongoing damaging effects of vanadium-induced ROS on developing germ cells. This is in turn reflected in the appreciable increase in testicular lipid peroxidation level and decline in the activities of steroidogenic and antioxidant enzymes. However, oral administration of vitamin E acetate could protect testes from the toxic effects of vanadium. Vanadium also results in adrenocortical hyperactivity, as evidenced by the elevated secretion of glucocorticoids, adrenal gland hypertrophy and increased activity of adrenal Delta(5)3beta-HSD. However, reversibility of these alterations in adrenocortical activities was vividly reflected after vitamin E acetate supplementation. All these studies reveal that oxidative stress is the major mechanism of health deterioration and that vanadium can act as a stressor metal causing chronic stress effects through excitation of hypothalamo-pituitary-adrenal axis. However antioxidant support by vitamin E acetate may provide significant protection.

Electrochemical Corrosion of the Ti-xAl-yFe Alloys Fabricated by Direct Metal Deposition in Hanks Solution

A problem addressed of toxicity of vanadium in the Ti-6Al-4V used as biomedical implant has been. Combinatorial library of the new type of titanium alloys composed of non-toxic elements, such as Ti, Al, and Fe with lower modulus of elasticity and greater corrosion resistance has been fabricated by direct metal deposition technique. The resistance to electrochemical corrosion in Hanks solution of each titanium based alloy was tested cyclic voltammetry and polarization method.

Reduction of oxidative stress induced vanadium toxicity by complexing with a flavonoid, quercetin: A pragmatic therapeutic approach for diabetes

Vanadium compounds are known to lower blood glucose level in diabetes but are associated with toxicity. In vitro cytotoxicity of VOSO(4) and bis(quercetinato) oxovanadium(IV) (BQOV) was examined in CHO cells. Both the agents showed time and dose dependent increase in ROS generation however it was relatively less in BQOV. Moreover, VOSO(4) also caused higher necrosis. Hypoglycemic potential of VOSO(4) and BQOV was tested in streptozotocin-induced diabetic Balb/c mice. A marked difference was observed in the hypoglycemic action of VOSO(4) and BQOV treated mice that lasted only for about 6 h in VOSO(4) as against 24 h in BQOV. Comparison of acute toxicity of the compounds in normal Balb/c mice revealed negligible nephrotoxicity of BQOV. Kidney analyses of VOSO(4) treated animals' revealed high ROS generation and tubular necrosis. Similarly serum levels of urea and creatinine were elevated in these animals indicating kidney dysfunction. No such abnormality was observed in BQOV treated animals. Reduced nephrotoxicity of BQOV could be due to increased catalase activity found in the kidney of BQOV treated animals and BQOV's radical scavenging activity. The data clearly demonstrates immense hypoglycemic activity and reduced toxicity of BQOV thus making the conjugate a suitable candidate for therapeutic utility.

Toxicity and Hazard of Vanadium to Mallard Ducks (Anas platyrhynchos) and Canada Geese (Branta canadensis)

A recent Canada goose (Branta canadensis) die-off at a petroleum refinery fly ash pond in Delaware was attributed to vanadium (V) toxicity. Because of the paucity of V toxicity data for wild birds, a series of studies was undertaken using the forms of V believed to have resulted in this incident. In 7-d single oral dose trials with mallard drakes (Anas platyrhynchos), the estimated median lethal dose (LD50) for vanadium pentoxide was 113 mg/kg body weight, while the LD50 for sodium metavanadate was 75.5 mg/kg. Sodium metavanadate was found to be even more potent (LD50 = 37.2 mg/kg) in male Canada geese. The most distinctive histopathological lesion of both forms of V was lympho-granulocytic enteritis with hemorrhage into the intestinal lumen. Vanadium accumulation in liver and kidney was proportional to the administered dose, and predictive analyses based on these data suggest that V concentrations of 10 μg/g dry weight (dw) in liver and 25 μg/g dw in kidney are associated with mortality (>90% confidence that exposure is >LD50) in mallards acutely exposed to sodium metavanadate. Chronic exposure to increasing dietary concentrations of sodium metavanadate (38.5 to 2651 ppm) over 67 d resulted in V accumulation in liver and kidney (25.2 and 13.6 μg/g dw, respectively), mild intestinal hemorrhage, blood chemistry changes, and evidence of hepatic oxidative stress in mallards, although some of these responses may have been confounded by food avoidance and weight loss. Dietary exposure of mallards to 250 ppm sodium metavanadate for 4 wk resulted in modest accumulation of V in liver and kidney (<5 μg/g dw) and mild intestinal hemorrhage. Based on these data and other observations, it is unlikely that chronic low-level dietary exposure to V poses a direct lethal hazard to wildlife. However, point sources, such as the V-laden fly ash pond encountered by geese at the petroleum refinery in Delaware, may pose a significant hazard to water birds.

Vanadium induced ultrastructural changes and apoptosis in male germ cells

Vanadium is a transition metal that is emitted to the atmosphere during combustion of fossil fuels. In the environment, vanadium occurs in the (V) oxidized form, but in the body it is found exclusively in the (IV) oxidized form. Vanadium tetraoxide is an inorganic chemical species in the (IV) oxidized form that has been shown to induce toxic effects in vitro and in vivo. The reproductive toxicity of vanadium in males was studied through monitoring germ cell apoptosis during spermatogenesis. We analyzed ultrastructural damage, and testosterone and progesterone concentrations following vanadium tetraoxide administered to male mice for 60 days. Spermatogenesis stages I–III and X–XII frequently showed apoptotic germ cells in control and treated animals; vanadium tetraoxide treatment induced an increase in the number of germ cell apoptosis in stages I–III and XII at 9.4 and 18.8 mg/kg, respectively. Although spermatogenesis is regulated by testosterone, in our study this hormone level was not modified by vanadium administration; thus, germ cell death was not related with testosterone concentration. At the ultrastructural level, we observed inclusion structures that varied as to location and content in the Sertoli and germ cells.

Preface

Abstract The following 10 papers are selections from the 4th International Symposium on Chemistry and Biological Chemistry of Vanadium held 3-5 September 2004 in Szeged, Hungary. This conference attracted over 110 participants from 25 countries and 4 continents. Plenary and invited lectures as well as posters discussed the inorganic chemistry of vanadium, vanadium chemistry in catalysis and organic synthesis, and biological aspects of vanadium chemistry. A new feature was introduced: the presentation of the Vanadis Award. The purpose of the Vanadis Award is to recognize an outstanding contributor to the advancement of vanadium science. The award will be presented at each International Vanadium Symposium prior to a lecture to be given by the recipient. It is awarded on the basis of contributions to a discipline or combination of disciplines of vanadium science, and is presented to an investigator who has produced innovative research with impact on the direction of the field. The nominee is selected on the basis of the following criteria: (1) Innovative research: A history of development or expansion of techniques and procedures and discovery of new chemical, biochemical, biological, technological, or pharmaceutical systems; (2) Development of new applications in one or more of the following areas: chemistry, biochemistry, biology, pharmaceutical science, materials science, and nanotechnology; (3) Wide-ranging influence of the nominee's work on the research of others in one or more disciplines; (4) History of highquality and -impact publications; and (5) Service of the nominee to progress, application, and exploration of vanadium in science. The recipient of the first Vanadis Award is Prof. Debbie C. Crans of Colorado State University, whose award address is the first contribution to be presented herein. The additional contributions begin with papers covering various aspects of the inorganic chemistry of vanadium. These papers are followed by descriptions of recent results in the use of vanadium compounds to further organic synthesis, and on the catalytic behavior of interesting vanadium complexes. The final selection includes papers dealing with the role of vanadium in haloperoxidases, or as insulin-mimetic compounds, which may be orally administered replacements of insulin injections. A tremendous increase in studies of aqueous vanadium chemistry over the past decade has been driven by the need to comprehend the diverse biological effects of vanadium. Examples of the rich array of data and concepts needed to explain the biological role of vanadium are given by models of the vanadium-containing haloperoxidase enzyme activity. However, this selection of papers from the 4th International Vanadium Symposium indicates that basic inorganic studies and a wide range of applications of vanadium chemistry to fundamental chemical problems of synthesis, reactivity, and catalysis are not lacking. Indeed, we look forward to the 5th International Vanadium Symposium to be held in San Francisco, CA USA in the fall of 2006, where additional fundamental studies linked to the need to better understand vanadium nutritional essentiality, vanadium toxicity, vanadium therapy, and vanadium catalysis, including "green chemical" industrial applications will be presented. Kenneth Kustin and Tamas Kiss Conference Editors

Acute toxicity of vanadium to the threespine stickleback,Gasterosteus aculeatus

Vanadium is widely distributed, occurring in many types of minerals, coal, and petroleum. Anthropogenic sources of vanadium originate from the production, processing, and wastes of these materials. The aquatic toxicity of vanadium to fish species is not well characterized. This study focused on the three-spined stickleback, Gasterosteus aculeatus, a small and widely distributed euryhaline species of fish. The three-spined stickleback is used as an effluent-monitoring species in both Canada and the United States. Five 96-h static renewal acute toxicity tests were performed in moderately hard water with adult fish. The geometric mean and range of the five 96-h LC(50)s based on measured concentrations of total vanadium in the test solution were 3.17 and 2.35-4.07 mg V/L, respectively. A conservative estimation of a safe concentration of vanadium that would not affect survival of adult three-spined sticklebacks over a 96-h exposure period in moderately hard water is approximately 0.30 mg V/L. A comparison with other fish species previously tested suggests that the three-spined stickleback is intermediate in sensitivity to vanadium. Information reported from this study may be useful in effluent toxicity identification evaluations and ecological risk assessments related to vanadium.

Peracute vanadium toxicity in cattle grazing near a vanadium mine.

Animals may act as bioindicators for potential human health problems associated with mining and refining. Eight cattle died after a vanadium mine dam collapsed close to the area in which they were grazing. Necropsies were conducted on five cattle. Affected animals had shown a watery bloody diarrhea, red urine and listlessness before collapsing. On necropsy (n = 5) there was a moderate bilateral multifocal granulomatous-like conjunctivitis. The most prominent lesions were eosinophillic granulomatous-like inflammation of the thymus, mediastinal and mesenteric lymph nodes, oesophagus, abomasum and colon. There was also marked hyperaemia of the abomasal mucosa with petechiation. Pulmonary and tracheal haemorrhage was also present. Histopathology showed severe inflammatory cell infiltration (mainly eosinophils with lesser numbers of neutrophils and macrophages) of lymphoid tissue associated with the thymus, lymph nodes, esophagus, abomasum, colon and conjunctiva. There were also areas of tissue necrosis, congested blood vessels and haemorrhage. Conjunctival lesions point to a systemic rather than a local effect as the cattle in this case died following ingestion rather than inhalation of vanadium. The causal relationship between intoxication and death is conventionally based on the level of that toxin present in tissues at necropsy. The variability in demonstrating vanadium in biological samples may have been due to the rapid excretion of vanadium by the living animal, or the solubility of the salts, which results in the substance leaching into the fluid portion of the samples. Cross-reactions with colorimetric tests for arsenic should also be noted.

Effect of radiation-degraded chitosan on plants stressed with vanadium

The toxicity of vanadium (V) and the effect of chitosan has been investigated on soybean, rice, wheat and barley. Wheat and barley were sensitive to V than rice and soybean but all seedlings of these plants were damaged at 2.5 μg/ml V (in VCl 3). These damages were reduced by application of radiation-degraded chitosan. The recovery of growth and reduction of V levels in seedlings were obtained by the treatments with 10–100 μg/ml chitosan irradiated at 70–200 kGy of γ-rays in 1% solution. The reductions of V and Fe contents in plants were due to the ability of chitosan to form chelate complexes with metals in solution. The result of BAS analysis shows that the absorption and transportation of 48V to the leaf from root was suppressed with irradiated chitosan. Therefore, it can be concluded that chitosan irradiated at suitable doses (ca. 100 kGy) is effective as plant growth promoters and heavy metal eliminators in crop production.

Intravaginal Toxicity Studies of a Gel-Microemulsion Formulation of Spermicidal Vanadocenes in Rabbits

Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. We investigated the toxicity potential of intravaginally administered gel-microemulsion formulation of two representative vanadocenes, vanadocene acetylacetonato monotriflate (VDACAC) and vanadocene dithiocarbamate (VDDTC), in the rabbit model. New Zealand White rabbits in subgroups of three were exposed intravaginally to a gel-microemulsion with and without 0.1 or 0.25% VDACAC and VDDTC for 10 consecutive days. The doses of vanadocenes used were nearly 500- to 1250-fold and 2000- to 5000-fold higher than their respective in vitro spermicidal EC50 values. Animals were euthanized on day 11 and vaginal tissues were evaluated for local toxicity by histopathology, cell proliferating activity by immunohistochemical detection of proliferating cell nuclear antigen (PCNA), and in situ apoptosis by the terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick end-labeling (TUNEL) assay and confocal laser scanning microscopy (CLSM). Blood was analyzed for clinical chemistry profiles. Vanadium content in selected organs and body fluids was determined by atomic absorption spectroscopy. None of the rabbits given 0.1% VDACAC and VDDTC intravaginally developed epithelial ulceration, edema, leukocyte influx, or vascular congestion characteristic of inflammation. Only minimal to moderate irritation was observed at 0.25% VDACAC and VDDTC. A significant decrease in epithelial and stromal PCNA expression was observed in the 0.25% dose group. However, TUNEL assay and CLSM revealed no staining in the vaginal epithelium and only minimal nonspecific staining in the stroma. Repetitive intravaginal application of 0.1 or 0.25% VDACAC and VDDTC had no adverse effects on clinical chemistry profiles. Vanadium was not incorporated into rabbit tissues and body fluids at levels above 1 μg/g. Thus, intravaginal administration of VDACAC and VDDTC at concentrations nearly 500 and 2000 times higher than their respective in vitro spermicidal EC50 values did not induce marked vaginal irritation, mucosal toxicity, or systemic absorption of vanadium in the rabbit model. The lack of significant mucosal or systemic toxicity of intravaginal vanadocenes observed may have particular clinical utility as a new class of contraceptive agents.

Salinity Dependence of Vanadium Toxicity against the Brackish Water Hydroid Cordylophora caspia

Vanadium, an abundant metal, enters the environment through natural rock weathering or by combustion of oil products. A third pathway is the leaching of vanadium-rich building materials. Stones made from steel industry residual slags, so-called slag stones, contain rather large amounts of vanadium. The increasing use of these slag stones in riverbank reinforcement has therefore led to increased interest in the toxicity of vanadium to aquatic organisms. The aim of the study was to determine the toxicity of vanadium to the brackish water hydroid Cordylophora caspia and the effect of vanadium on the membrane-bound enzyme Na, K-ATPase at various salinities. EC50 values for population growth inhibition were determined from 1.74 to 7.96 mg L−1 vanadium, depending on salinity. The maximum inhibition of population growth by vanadium was observed at low salinities. Correspondingly, maximum Na, K-ATPase inhibition was also measured at low salinities and decreased with increasing salinity. The present study suggests that the observed inhibition of population growth of C. caspia caused by vanadium-contaminated rearing water is due to the vanadium-induced inhibition of phosphatases.

Insulin-like effects of vanadium: basic and clinical implications

Most mammalian cells contain vanadium at a concentration of about 20 nM, the bulk of which is probably in the reduced vanadyl (+4) form. Although this trace element is essential and should be present in the diet in minute quantities, no known physiological role for vanadium has been found thus far. In the late 1970s the vanadate ion was shown to act as an efficient inhibitor of Na +, K +-ATPase as well as of other related phosphohydrolases. In 1980 vanadium was reported to mimic the metabolic effects of insulin in rat adipocytes. During the last decade, vanadium has been found to act in an insulin-like manner in all three main target tissues of the hormone, namely skeletal muscles, adipose, and liver. Subsequent studies revealed that the action of vanadium salts is mediated through insulin-receptor independent alternative pathway(s). The investigation of the antidiabetic potency of vanadium soon ensued. Vanadium therapy was shown to normalize blood glucose levels in STZ-rats and to cure many hyperglycemia-related deficiencies. Therapeutic effects of vanadium were then demonstrated in type II diabetic rodents, which do not respond to exogenously administered insulin. Finally, clinical studies indicated encouraging beneficial effects. A major obstacle, however, is overcoming vanadium toxicity. Recently, several organically chelated vanadium compounds were found more potent and less toxic than vanadium salts in vivo. Such a newly discovered organic chelator of vanadium is described in this review.

Vanadium and diabetes. What about vanadium toxicity?

Recently, Poucheret et al. [1] reviewed some key aspects of vanadium in relation to its insulin-mimetic, antihyperglycemic and antihypertensive effects. It was stated that vanadyl sulfate is effective orally when administered by either single dose or chronic doses, whereas bismaltolato-oxovanadium IV (BMOV) is 2–3 times more potent than vanadyl sulfate and has shown less toxicity. However, throughout the article no specific details on the toxic effects of vanadyl sulfate in STZdiabetic animals are reported. Although the authors reviewed a long list of in vivo beneficial effects of vanadium in STZdiabetes and in other models of diabetes, no toxic effects of vanadium compounds were included. In spite of the lack of information about the potential toxic effects of this element, Poucheret and associates [1] indicated that BMOV did not affect body weight gain in control rats for the first 10 weeks when compared to vanadyl sulfate, which is important regarding some concerns expressed in the literature about vanadium toxicity. On the other hand, when the authors reviewed the clinical studies on vanadium and diabetes, they stated that these investigations have been promising, with diarrhoea being the main side effect observed. We have also reviewed these reports and a summary of side effects is shown in Table 1. While the only common toxic effect was mild gastrointestinal disturbance, the main concern with these studies is the very short period of vanadium administration, with a maximum of 4 weeks [2–5]. With regard to it, the authors of one of the clinical studies [4] remarked that although there is few information relative to the long-term effects of vanadium salts in humans, in previous studies in which 125 mg/day of diammonium oxy-tartrato vanadate were administered for about 5 months to patients with coronary artery disease, it was found that half of these subjects experienced abdominal pain, anorexia and weight loss [6]. An additional concern with long-tern vanadium use is its known tissue accumulation. Although oral administration of vanadyl sulfate (0.5 mg/kg/day) for 12 weeks did not affect blood cells, viscosity or biochemical parameters relating to liver and kidney function in weight training athletes [7], the authors of the study emphasized the possibility that vanadium might accumulate in some tissues such as bone and kidney, which would be a cause for concern particularly since weight training athletes tend to use oral vanadyl sulfate repeatedly in cycles of up to 3 months [7]. In a recent review on the biological actions and potential as pharmacological agents of vanadium compounds, Tsiani