Physiological Effects and Toxicity

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The total body pool of vanadium is low; depending on the source of information, it varies between ca. 0.1 and 1 mg (Wenning and Kirsch 1988; Leonard and Gerber 1994), corresponding to an approximate concentration of c = 0.03-0.3 pM. The average vanadium concentration in blood is 2.3 pg L"1 (c = 45 nM) (Leuschner et al. 1994). Vanadium contents in food are typically around 30 pg V kg"1 food (Wenning and Kirsch 1988), while drinking water commonly contains less than 10 pg L"1 (c < 0.2 pM) (Cohen 1996). In basaltic volcanic areas, the concentration can go up by an order of magnitude. Breathable air contains 0.25-75 ng V m"3 in rural areas, and 60-300 ng m"3 in urban settings (Cohen 1996). The daily overall intake, dominated by dietary sources, amounts to 0.01-2 mg vanadium (Cohen 1996; Scior et al. 2005). Less than 1% of this remains absorbed: vanadium, in particular in its oxidation state +IV, is effectively excreted through feces and urine. The no-effect level is an intake of about 10 mg kg"1 day"1; hence, normal diet-related exposure to vanadium does not affect our health.

High exposure risks (>30 mg m-3 in the breathable air), coupled with potentially severe health problems, go along with the mining and milling of vanadium containing ores, the production of vanadium metal, vanadium oxides used in redox catalysis and batteries (Tracey et al. 2007), and fly ashes from oil firing. The latter problem arises from the sometimes high amounts of vanadium (present as vanadyl porphyrins) in crude oil; cf. Sect. 11.3. The worldwide industrial emission of vanadium into the atmosphere totaled 71,000 tons per year in 1995 (Nriagu and Pirrone 1998), which may be extrapolated to 85,000 tons in 2010. This compares to an estimated world-wide emission of vanadium from natural sources (continental dust, volcanic activity, forest fires) of approximately 10 tons per year.

The toxicity of vanadium compounds is generally low. Orally applied, pentavalent compounds (vanadates) are more toxic than tetravalent compounds (vanadyl) because the latter form almost insoluble VO(OH)2 in the gastro-intestinal tract. In the US, vanadyl sulfate VOSO4 is a common supplement, in daily doses up to 60 mg, for athletes for an alleged increase their muscle mass (Barceloux 1999). Vanadium pentoxide V2O5, the main aerial contaminant, is potentially mutagenic and terato-genic. In mice, V2O5 causes pulmonary inflammation and tumor promotion (Rondini et al. 2010). In rats, vanadium compounds cause DNA cleavage, likely as a results of the intermittent formation of reactive hydroxyl radicals (Sakurai 1994); (11.4) in Sect. 11.2. Vanadium oxides may therefore be considered "suspected carcinogenic compounds" for humans: In workers exposed to the inhalation of V2O5, its metabolites cause oxidation of DNA, affect DNA repair, and induce the formation of tumor-associated antigens (Ehrlich et al. 2008). On the other hand, vanadium compounds such as sodium vanadate, VO(acac)2 (acac = acetylacetonate(1-)), and VO(maltolate)2 (bis(maltolato-oxidovanadium(IV), BMOV) inhibit the proliferation of hepatoma cells to a higher extent than of hepatic cells, which is paralleled by lower levels of ROS in hepatoma than in hepatic cells (Wang et al. 2010).

Human vanadium poisoning symptoms are mainly restricted to the conjunctivae and respiratory system, renal and gastrointestinal irritation. Exposure can thus give rise to conjunctivitis, rhinitis, pulmonary inflammation resulting in bronchitis and asthma-like diseases, and dysfunctions of the digestive system. The limit value for immediate danger to health for an average human is about 7 mg V in the case of intravenous application, and 35 mg V m-3 in breathing air. The following compilation lists selected official exposure limits (MAC) and LD50/LC50 values. MAC refers to the maximum allowable concentration at the workplace (40-h week, 8-h time-weighted average). LD50 and LC50 indicate the level of a harmful substance (in mg per kg body weight) causing the death of 50% of the test animals by oral (LD) or inhalative (LC) administration, respectively.

A biological threshold limit of 50 pg V g-1 of creatinine in urine collected at the end of the work week has been adopted in the US. Vanadium is also toxic for aquatic organisms: LD50 values are 4.8 mg L_1 for soft water, and 30 mg-1 for hard water. The lower toxicity in hard water reflects the formation of sparingly soluble calcium vanadates.

Irritation of the conjunctivae and pulmonary systems either directly by vanadium oxides (V2O5, V2O4, V2O3) and/or the oxidovanadium moieties VO2+, VO3+, and VO2+ formed by solubilization of the oxides in the physiological systems goes along with the generation of reactive oxygen species (H2O2, and the radicals O2.~ and *OH), considered to be the actual agents responsible for tissue impairment, either by oxidative damage and/or intervention with the phosphoryla-tion of signaling and transcription pathways (Rondini et al. 2010). In hepatic cells, N-acetylcysteine can ameliorate this (indirect) cytotoxicity (Wang et al. 2010). While oxidovanadium species are usually considered to generate ROS, they can also consume ROS, e.g., in the course of the oxidation of vanadyl to vanadate(V) reversal of (11.4) in Sect. 11.2. Further, trivanadate V3O93~, and VO2+, complexed to sylicylidenehydrazide ligands, have been shown to consume alkylating toxins (Hamilton et al. 2006; Fautch et al. 2009), thus preventing DNA alkylation and, concomitantly, cancer risk.

Physiological effects of vanadium applied in the form of vanadate or simple vanadium complexes also arise from its direct intervention with phosphatases, phosphorylation enzymes, kinases, ribonucleases, and the phosphate metabolism in general (Tracey et al. 2007; McLauchlan et al. 2010). These interventions go back to the structural similarity between vanadate VO(OH)3~/H2VO4~ and phosphate HPO42~ on the one hand (cf. also Sect. 11.1), and the ability of the transition metal vanadium to enlarge its coordination sphere and thus to form stable penta-and hexa-coordinated coordination compounds on the other hand. In contrast, penta-coordinated phosphorus only exists as a transitory species in, e.g., phospha-tase reactions. In Fig. 11.4, this is pictured for the pentavalent transition state formed in the course of the phosphoester cleavage by a phosphatase with histidine in the active center, and the inhibition of this hydrolysis through the build-in of vanadate into the active site of the enzyme. The awareness of the role of vanadate as a phosphatase inhibitor goes back to the discovery of the switch-off of the Na+, K+-pump by sodium vanadate (Cantley et al. 1977). Trace amounts of vanadium have since been proposed to be an essential regulatory nutrient for most if not all living beings. The omnipresence of oxidic vanadium in soil, and of vanadate in the aqueous medium, has likely provoked an adaption - in terms of beneficial use - to vanadium already in the primordial development of life (Rehder 2008b). This is also suggested by the similarity of the active centers of vanadate-dependent haloperoxidases and vanadate-inhibited phosphatases (2 in Fig. 11.3). Interestingly, vanadate-inhibited phosphatases can exhibit some haloperoxidase activity (Tanaka et al. 2002).

The vanadate-phosphate analogy (Stankiewicz and Tracey 1995; Crans et al. 2004; Steens et al. 2009) is also the key to the potency, in the treatment of diabetes mellitus, of vanadate, vanadyl and simple vanadium compounds such as BMOV and its ethyl analog, b/s(ethylmaltolato)oxidovanadium BEOV. Here, vanadium acts as a regulator of glucose homeostasis and inhibits free fatty acid release.

^ (Phosphatase)

and N

Pentavalent Transition State

(Phosphatase)

Fig. 11.4 Hydrolysis of the phospho-ester bond catalyzed by purple acid phosphatase via a pentavalent transition state (top), and inhibition of the phosphatase by vanadate (bottom left) (Rehder 2010; modified). For the active center see also 2 in Fig. 11.3, Sect. 11.3

The active species likely is vanadate H2VO4~, a key "end-products" in physiological turn-over of vanadium compounds (vide infra). The mode of action possibly is by inhibition of a protein tyrosine phosphatase at the cytosolic site of the cellular insulin receptor and/or the activation of a tyrosine kinase in the signaling path (Sakurai et al. 2006). So far, BEOV has been the only vanadium compound to be subjected to clinical tests (phase II). The tests have, however, been abandoned due to renal problems with some of the probands.

Other beneficial modes of action of vanadate compounds, as tested ex vivo (with cell cultures) and, in part, in vivo (with animals) include the treatment of certain cancer forms (such as leukemia, Ehrlich ascites tumors, carcinomas of the lungs, prostate, testes, ovaria, and liver), amoebiasis (Maurya et al. 2006), tuberculosis, HIV, and herpes. VO2+ complexed to sugars such as the disaccharide trehalose promotes both, glucose consumption in osteoblasts and inhibition of the proliferation of tumoral osteoblasts (Barrio et al. 2003; Etcheverry et al. 2009).

11.5 Uptake, Speciation, Excretion, and Detoxification

The main pathways for uptake, speciation, distribution, and excretion of vanadium compounds are illustrated in Fig. 11.5. Dietary vanadium may be vanadate, vanadyl (VO2+), e.g., in the form of VOSO4, or vanadium compounds with organic ligands (symbolized {V} in Fig. 11.5), such as VO(acac)2 and BEOV. Inhaled vanadium species, mainly ingested by the pulmonary tissue, commonly are particulate vanadium oxides (V2O5, V2O4, V2O3) or essentially oxidic vanadium minerals. Basic

Effect H2s Wine
Fig. 11.5 Pathways of vanadium compounds taken in via nutrition or inhalation. {V} stands for any vanadium compound other than vanadate and bare vanadyl, VOx for any vanadium oxide and particulate vanadium minerals

dietary vanadium species will be oxidatively converted to vanadate(V) in the oral cavity, transformed to decavanadate or even VO2+ (Sect. 11.1) in the acidic medium of the stomach, and reconverted to vanadate and vanadyl under the slightly alkaline and reducing conditions in the small intestines. Vanadium complexes may or may not survive the medial conditions of the gastrointestinal tract. In case they are unstable under the conditions prevailing there (such as the low pH in the stomach), decomposition and generation of vanadate/vanadyl takes place. Once transferred into the blood, most of the vanadium is complexed by transferrin (Tf) and apoTf. The complexation constant for the binding of VO2+ to apoTf, as defined by (11.12), is 10~147 (Kiss etal. 2006), i.e., only those complex {V} species survive the transport through the blood which are thermodynamically more stable than VO2+-Tf, or whose degradation is kinetically hampered. VO2+-Tf can be taken up by the cells via endo-cytosis; vanadate may also directly enter the cells through phosphate channels. Once arrived within the tissue cells, even stable complexes will be converted to basic inorganic vanadium compounds. Given the commonly reducing conditions in the cytosol, provided by reductants such as NAD(P)H, FADH2, glutathione, ascorbate, and catecholamines, the predominant cytosolic species likely is VO2+, stabilized to some extent by coordination to cytosolic constituents capable of ligating vanadium (and here again, glutathione and ascorbate come in; Rehder et al. 2002). Where VO2+ becomes involved in the production of ROS (11.1), or where ROS are formed from other sources, vanadate(V) H2VO4~ will form.

The retention time of vanadium in tissue is up to 30 min (Yasui et al. 2002). Part of the vanadium is, however, stored in the bones, where it's half-life is 4-5 days (Setyawati et al. 1998): VO2+ is absorbed to the bone surface, while H2VO4~ is incorporated in the hydroxyapatite lattice, where it can replace phosphate

(Rehder 2008a; Etcheverry et al. 2009). The final excretion of resorbed vanadium is essentially via the kidneys, i.e., most of the vanadium is recovered in the urine.

Vanadium concentrations in serum after intravenous injection to humans in the form of vanadate in a 20% albumin infusion (containing a total amount of 47.6 pg V) declined rapidly within a few hours (<30% after 24 h). Subsequently, serum vanadium concentrations dropped more slowly, approaching zero after a month (Heinemann et al. 2003). In general, vanadium's toxicological and pharmacological potential very much depends on the mode of vanadium intake/application (intravenous, subcutaneous, oral, inhalation, absorption through mucosae), individual response, and modulating factors such as age, sex, exercise, stress, and the nutritional state (Thompson et al. 1998).

While global anthropogenic vanadium emission is not likely to constitute a significant health risk, local exposure of workers in industrial enterprises processing vanadium ores and compounds can result in severe health problems caused by vanadium toxication (see Sect. 11.4). Also, local increase of vanadium contents in soil, originating from the deposition of vanadium oxides in the course of industrial activities or excessive local burning of fossil fuels, may cause a potential health problem for the population in the respective area. Vanadium may further be mobilized from its deposits, and thus arrive in surface and ground water, eventually ending up in drinking water. Mobilization can come about by solubilization of oxidic vanadium, i.e., the formation of water-soluble vanadate, in particular in acidic soils, and by complexation and thus solubilization of vanadyl VO2+ in non-oxic environments by siderophores, humic acids, and other organic constituents with suitable ligand properties. Even at vanadium levels <15 pg L-1, the notification level set for drinking water by the US Environmental Protection Agency, accumulation of vanadium up to 2% by weight in the corrosion deposits in lead drinking water pipes can occur - a potential reservoir for human exposure by municipal water systems, if this vanadium becomes re-mobilized by alterations in the drinking water characteristics (Gerke et al. 2009).

The formation of vanadinite, PbCl2 3Pb3[VVO4]2, orPb5[VO4]3Cl for short, and the re-mobilization of vanadate can be formulated as depicted in the equilibrium (11.13), the Pb2+ ions being delivered via, e.g., divalent lead (hydroxy)carbonates and lead phosphate in the lead pipe. Equation (11.13) also demonstrates that remobilization of vanadate from insoluble vanadinite takes place as the medium becomes sufficiently acidic. At higher phosphate concentrations, chloropyro-morphite Pb5[PO4]3Cl is more stable than vanadinite (Gerke et al. 2009); excess phosphate thus can destabilize vanadinite. Hence, while the formation of vanadinite deposits in the pipe scales is a means of detoxification, a decrease of pH or the presence of excess phosphate (such as provided by orthophosphate-based corrosion inhibitors) can result in re-toxification of drinking water (11.14).

5Pb2+ + 3H2VO4- + Cl- ^ Pb5 [VO4]3Cl # + 6H+ (11.13) Pb5 [VO4]3Cl + 3HPO42- + 3H+ ! Pb5 [PO4]3Cl # + 3H2VO4- (11.14)

Fig. 11.6 Compounds which have been employed in animal studies to successfully mask vanadium: (—)Catechin (4), the disodium salt of Tiron (5), the Ca,Na2 salt of EDTA (6) and deferoxamine mesylate (7)

Fig. 11.6 Compounds which have been employed in animal studies to successfully mask vanadium: (—)Catechin (4), the disodium salt of Tiron (5), the Ca,Na2 salt of EDTA (6) and deferoxamine mesylate (7)

Most cases of vanadium toxication will recover on removal from exposure and symptomatic treatment. In case of vanadium ingestion, application of ascorbic acid, followed by 2,3-mercapto-1-propanol in a later stage has been recommended (International Programme on Chemical Safety, Health and Safety Guide, no. 42, 1990). Both agents are likely to effect reduction of vanadium(V) to vanadium(IV), which transforms into insoluble and hence essentially harmless vanadyl hydroxides in the small intestines. By extrapolation from animal studies (mice, rats, rabbits, calves), treatment of toxic effects related to vanadium might be achieved by drinking green tea (Soussi et al. 2009), or by treatment with chelating agents such as ethylenediaminetetraacetate (EDTA) (Domingo et al. 1986; Gummow et al. 2006), deferoxamine mesylate (Domingo et al. 1986), or 4,5-dihydroxy-1,3-benzene disulphonate (Tiron) (Shrivastava et al. 2007); Fig. 11.6. Green tea from Camellia sinensis contains oligophenols such as catechins (4 in Fig. 11.6), which can act as antioxidants and as chelators for metal ions such as VO2+, VO3+, and VO2+. Similarly, Tiron (5) combines these two properties, while EDTA (6) and deferoxamine (7 in Fig. 11.6) are strong chelating agents, which are also used in masking other metal ions.

11.6 Conclusion

The categorization of vanadium, by the WHO and national health organizations, as mutagenic, teratogenic, and potentially cancerogenic affords special awareness in handling this element, and precautions when exposed to it. In the light of the potential hazards, the approval, in North America, of vanadyl sulfate as a food additive ("vanadyl fuel") consumed by athletes for a putative increase of the muscle mass appears to be an unorthodox issue. On the other hand, since less than 1% of bare vanadyl VO2+ is absorbed, its adverse effect should be minimal.

On a general basis, exposure to vanadium present in the environment (drinking water, food, aerial dust) is a negligible problem. Acute vanadium poisoning has so far only been observed with workers directly exposed to inhalation of vanadium oxide at the working place, and with animals injected or fed high doses of vanadium compounds. As far as workplace exposure is concerned, a maximum allowable concentration (MAC value) of 0.05 g V m~3 has been assessed. The increasing use of vanadium compounds in catalysis (e.g., V2O4 in the production of sulfuric acid, vanadate esters and ester chlorides in polymerization catalysis), in silver vanadium oxide batteries, and in vanadium steels, may henceforward increase the contamination, by vanadium, of water resources and the atmosphere. Oncoming developments for industrial applications of vanadium include vanadiumoxide-based nanotubes, -rods and -wires, metal-organic frameworks (MOFs), composite vanadates/silicates, and large polyoxidometalates (POMs). Another source for potentially increasing vanadium pollution and hence increasing health hazards is the burning of petrol and other fossil fuels, which can contain high amounts of porphyrinogenic vanadium compounds. Finally, remobilization of vanadate from vanadinite accumulating in the scales of lead water pipes, is a potential problem. For the decontamination of soil and wet areas containing an overload of vanadium (V), bacteria which reduce VV (V2O5, vanadate) to insoluble vanadyl hydroxide are an option. Geobacter metallireducens and Shewanella oneidensis are promising candidates.

As is common with elements which, at higher doses and under specific conditioning are toxic, beneficial effects, e.g., the treatment of cancer, amoebiasis, and diabetes mellitus may come in. Bis(ethylmaltolato)oxidovanadium(IV), BEOV, has been a bearer of hope in this respect for the treatment of diabetes for a couple of years. This potential insulin-enhancing drug has faced a draw-back on occasion of clinical phase II tests - which fact does not imply that similar vanadium compounds, or novel developments based on vanadium will be more successful and hence beneficial.

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