This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization.

Concise International Chemical
Assessment Document 29

VANADIUM PENTOXIDE AND
OTHER INORGANIC VANADIUM COMPOUNDS

First draft prepared by
Dr M. Costigan and Mr R. Cary, Health and Safety Executive, Liverpool, United Kingdom,
and
Dr S. Dobson, Centre for Ecology and Hydrology, Huntingdon, United Kingdom

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization
Geneva, 2001

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Vanadium pentoxide and other inorganic vanadium compounds.
(Concise international chemical assessment document ; 29)
1.Vanadium compounds - adverse effects 2.Risk assessment
3.Environmental exposure I.International Programme on Chemical Safety
II.Series
ISBN 92 4 153029 4 (NLM Classification: QV 290)
ISSN 1020-6167

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TABLE OF CONTENTS

FOREWORD

1. EXECUTIVE SUMMARY

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

3. ANALYTICAL METHODS

3.1 Workplace air monitoring

3.2 Biological monitoring

3.3 Environmental monitoring

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

5.1 Chemical speciation of vanadium

5.2 Essentiality of vanadium

5.3 Bioaccumulation

5.4 Leaching and bioavailability in soils

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

6.1 Environmental levels

6.1.1 Air

6.1.2 Surface waters and sediments

6.1.3 Biota

6.1.4 Soil

6.2 Human exposure

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS

8.1 Single exposure

8.1.1 Vanadium pentoxide

8.1.2 Other pentavalent vanadium compounds

8.1.3 Tetravalent vanadium compounds

8.1.4 Trivalent vanadium compounds

8.2 Irritation and sensitization

8.3 Effects of inhaled vanadium compounds on the respiratory tract

8.4 Other short-term exposure studies

8.4.1 Vanadium pentoxide

8.4.2 Other pentavalent vanadium compounds

8.4.3 Tetravalent vanadium compounds

8.5 Medium-term exposure

8.5.1 Vanadium pentoxide and other pentavalent vanadium compounds

8.5.2 Tetravalent vanadium compounds

8.6 Long-term exposure and carcinogenicity

8.6.1 Vanadium pentoxide and other pentavalent vanadium compounds

8.6.2 Tetravalent vanadium compounds

8.7 Genotoxicity and related end-points

8.7.1 Studies in prokaryotes

8.7.1.1 Vanadium pentoxide

8.7.1.2 Other pentavalent vanadium compounds

8.7.1.3 Tetravalent vanadium compounds

8.7.1.4 Trivalent vanadium compounds

8.7.2 In vitro studies in eukaryotes

8.7.2.1 Vanadium pentoxide

8.7.2.2 Other pentavalent vanadium compounds

8.7.2.3 Tetravalent vanadium compounds

8.7.2.4 Trivalent vanadium compounds

8.7.3 Sister chromatid exchange

8.7.4 Other in vitro studies

8.7.4.1 Vanadium pentoxide

8.7.4.2 Other pentavalent vanadium compounds

8.7.4.3 Tetravalent vanadium compounds

8.7.5 In vivo studies in eukaryotes (somatic cells)

8.7.5.1 Vanadium pentoxide

8.7.5.2 Other pentavalent vanadium compounds

8.7.5.3 Tetravalent vanadium compounds

8.7.6 In vivo studies in eukaryotes (germ cells)

8.7.6.1 Vanadium pentoxide

8.7.6.2 Other pentavalent and tetravalent vanadium compounds

8.7.7 Supporting data

8.8 Reproductive toxicity

8.8.1 Effects on fertility

8.8.1.1 Vanadium pentoxide and other pentavalent vanadium compounds

8.8.1.2 Tetravalent vanadium compounds

8.8.2 Developmental toxicity

8.8.2.1 Vanadium pentoxide

8.8.2.2 Other pentavalent vanadium compounds

8.8.2.3 Tetravalent vanadium compounds

8.9 Immunological and neurological effects

8.9.1 Vanadium pentoxide

8.9.2 Other pentavalent vanadium compounds

8.9.3 Tetravalent vanadium compounds

9. EFFECTS ON HUMANS

9.1 Studies on volunteers

9.1.1 Vanadium pentoxide

9.1.2 Other pentavalent vanadium compounds

9.1.3 Tetravalent vanadium compounds

9.2 Clinical and epidemiological studies for occupational exposure

9.2.1 Vanadium pentoxide

9.2.2 Tetravalent vanadium compounds

9.3 Epidemiological studies for general population exposure

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

10.1 Aquatic environment

10.2 Terrestrial environment

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–response assessment

11.1.2 Criteria for setting tolerable intakes or guidance values for vanadium pentoxide

11.1.3 Sample risk characterization

11.1.4 Uncertainties

11.2 Evaluation of environmental effects

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

APPENDIX 1 — SOURCE DOCUMENTS

APPENDIX 2 — CICAD PEER REVIEW

APPENDIX 3 — CICAD FINAL REVIEW BOARD

INTERNATIONAL CHEMICAL SAFETY CARDS

RÉSUMÉ D’ORIENTATION

RESUMEN DE ORIENTACIÓN

FOREWORD

Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals.

International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the protection of human health and on emergency action. They are produced in a separate peer-reviewed procedure at IPCS. They may be complemented by information from IPCS Poison Information Monographs (PIM), similarly produced separately from the CICAD process.

CICADs are concise documents that provide sum maries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their complete ness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn.

The primary objective of CICADs is characteri zation of hazard and dose–response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based.

Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encour aged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characteriza tion are provided in CICADs, whenever possible. These examples cannot be considered as representing all pos sible exposure situations, but are provided as guidance only. The reader is referred to EHC 1701 for advice on the derivation of health-based tolerable intakes and guidance values.

While every effort is made to ensure that CICADs represent the current status of knowledge, new informa tion is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new informa tion that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.

Procedures

The flow chart shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world — expertise that is required to produce the high- quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk Assess ment Steering Group advises the Co-ordinator, IPCS, on the selection of chemicals for an IPCS risk assessment, whether a CICAD or an EHC is produced, and which institution bears the responsibility of the document production, as well as on the type and extent of the international peer review.

The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS and one or more experienced authors of criteria documents in order to ensure that it meets the specified criteria for CICADs.

The draft is then sent to an international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers’ comments.

A consultative group may be necessary to advise on specific issues in the risk assessment document.

The CICAD Final Review Board has several important functions:

– to ensure that each CICAD has been subjected to an appropriate and thorough peer review;

– to verify that the peer reviewers’ comments have been addressed appropriately;

– to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and

– to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

Flow Chart

1. EXECUTIVE SUMMARY

This CICAD on vanadium pentoxide and other inorganic vanadium compounds was based on a review of human health concerns (primarily occupational) prepared by the United Kingdom’s Health and Safety Executive (HSE, in press). This review focuses on exposures via routes relevant to occupational settings, but it also contains environmental information. Data identified as of November 1998 were covered. A further literature search was performed up to May 1999 to identify any additional information published since this review was completed. An Environmental Health Criteria monograph (IPCS, 1988) was used as a source document for environmental information. As no more recent source document was available for environmental fate and effects, the literature was searched for additional information. Information on the nature of the peer review and availability of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Helsinki, Finland, on 26–29 June 2000. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Cards on vanadium trioxide (ICSC 0455) and vanadium pentoxide (ICSC 0596), produced by the International Programme on Chemical Safety (IPCS, 1999a,b), have also been reproduced in this document.

Vanadium (CAS No. 7440-62-2) is a soft silvery- grey metal that can exist in a number of different oxida tion states: -1, 0, +2, +3, +4, and +5. The most common commercial form is vanadium pentoxide (V2O5; CAS No. 1314-62-1), and this exists in the pentavalent state as a yellow-red or green crystalline powder.

Vanadium is an abundant element with a very wide distribution and is mined in South Africa, Russia, and China. During the smelting of iron ore, a vanadium slag is formed that containvanadium pentoxide, which is used for the production of vanadium metal. Vanadium pentox ide is also produced by solvent extraction from uranium ores and by a salt roast process from boiler residues or residues from elemental phosphate plants. During the burning of fuel oils in boilers and furnaces, vanadium pentoxide is present in the solid residues, soot, boiler scale, and fly ash.

Atmospheric emissions from natural sources have been estimated at 8.4 tonnes per annum globally (range 1.5–49.2 tonnes). By far the most important source of environmental contamination with vanadium is combus tion of oil and coal; about 90% of the approximately 64 000 tonnes of vanadium that are emitted to the atmos phere each year from both natural and anthropogenic sources comes from oil combustion.

The environmental chemistry of vanadium is com plex. In minerals, the oxidation state of vanadium may be +3, +4, or +5. Dissolution in water rapidly oxidizes V3+ and V4+ to the pentavalent state, the most usual form of the metal in the environment. Vanadate, the pentavalent species in solution, may polymerize (mainly to dimeric and trimeric forms), particularly at higher concentrations of the salts. Within tissues of organisms, V3+ and V4+ predominate because of largely reducing conditions; in plasma, V5+ predominates.

Vanadium is probably essential to enzyme systems that fix nitrogen from the atmosphere (bacteria) and is concentrated by some organisms (tunicates, some poly chaete annelids, some microalgae), but its function in these organisms is uncertain. Whether vanadium is essential to other organisms remains an open question. There is no evidence of accumulation or biomagnifica tion in food chains in marine organisms, the best studied group.

There is very limited leaching of vanadium through soil profiles.

Higher levels of vanadium have been reported in air close to industrial sources and oil fires. Representa tive deposition rates are 0.1–10 kg/ha per annum for urban sites affected by strong local sources, 0.01– 0.1 kg/ha per annum for rural sites and urban ones with no strong local source, and <0.001–0.01 kg/ha per annum for remote sites.

Most surface fresh waters contain less than 3 µg vanadium/litre; higher levels of up to about 70 µg/litre have been reported in areas with high geochemical sources. Data on levels of vanadium in surface water close to industrial activity are few; most reports suggest levels approximately the same as the highest natural ones. Seawater concentrations in the open ocean range from 1 to 3 µg/litre, and sediment concentrations range from 20 to 200 µg/g; the highest levels are in coastal sediments.

A few organisms concentrate vanadium, with up to 10 000 µg/g in ascidians and 786 µg/g in polychaete annelids. Most other organisms contain generally less than 50 µg/g and usually much lower concentrations.

Estimates of total dietary intake of humans range from 11 to 30 µg/day. Levels in drinking-water range up to 100 µg/litre. Some groundwater sources supplying potable water show concentrations above 50 µg/litre. Levels in bottled spring water may be higher.

In humans, there is limited toxicokinetic information suggesting that vanadium is absorbed following inhalation and is subsequently excreted via the urine with an initial rapid phase of elimination, followed by a slower phase, which presumably reflects the gradual release of vanadium from body tissues. Following oral administration, tetravalent vanadium is poorly absorbed from the gastrointestinal tract. There were no dermal studies available.

In inhalation and oral studies in laboratory animals, absorbed vanadium in either pentavalent or tetravalent states is distributed mainly to the bone, liver, kidney, and spleen, and it is also detected in the testes. The main route of vanadium excretion is via the urine. The pattern of vanadium distribution and excretion indicates that there is potential for accumulation and retention of absorbed vanadium, particularly in the bone. There is evidence that tetravalent vanadium has the ability to cross the placental barrier to the fetus.

The one acute inhalation study available reported an LC67 of 1440 mg/m3 (800 mg vanadium/m3) following a 1-h exposure of rats to vanadium pentoxide dust. Oral studies in rats and mice resulted in LD50 values in the range 10–160 mg/kg body weight for vanadium pentox ide and other pentavalent vanadium compounds, while tetravalent vanadium compounds have LD50 values in the range 448–467 mg/kg body weight. No information is available concerning dermal toxicity.

Eye irritation has been reported in studies in vanadium workers. No skin irritation was reported in 100 human volunteers following skin patch testing with 10% vanadium pentoxide, although patch testing in workforces has produced two isolated reactions. No clear information is available from animal studies with regard to the potential of vanadium compounds to produce skin or eye irritation or skin sensitization.

In a group of human volunteers, a single 8-h exposure to 0.1 mg vanadium pentoxide dust/m3 caused delayed but prolonged bronchial effects involving exces sive production of mucus. At 0.25 mg/m3, a similar pattern of response was seen, with the addition of cough for some days post-exposure. Exposure to 1.0 mg/m3 produced persistent and prolonged coughing after 5 h. A no-effect level for bronchial effects was not identified in this study.

Repeated inhalation exposure to the dust and fume of vanadium pentoxide is associated with irritation of the eyes, nose, and throat. Wheeze and dyspnoea are commonly reported in workers exposed to vanadium pentoxide dust and fume. Overall, there are insufficient data to reliably describe the exposure–response relation ship for the respiratory effects of vanadium pentoxide dust and fume in humans.

Pentavalent and tetravalent forms of vanadium have produced aneugenic effects in vitro in the presence and absence of metabolic activation. There is evidence that these forms of vanadium as well as trivalent vana dium can also produce DNA/chromosome damage in vitro, both positive and negative results having emerged from the available studies. The weight of evidence from the available data suggests that vanadium compounds do not produce gene mutations in standard in vitro tests in bacterial or mammalian cells.

In vivo, both pentavalent and tetravalent vanadium compounds have produced clear evidence of aneuploidy in somatic cells following exposure by several different routes. The evidence for vanadium compounds also being able to express clastogenic effects is, as with in vitro studies, mixed, and the overall position on clasto genicity in somatic cells is uncertain. A positive result was obtained in germ cells of mice receiving vanadium pentoxide by intraperitoneal injection. However, the underlying mechanism for this effect (aneugenicity; clastogenicity) is uncertain. It is also unclear how these findings can be generalized to more realistic routes of exposure or to other vanadium compounds.

The nature of the genotoxicity database on vanadium pentoxide and other vanadium compounds is such that it is not possible to clearly identify the threshold level, for any route of exposure relevant to humans, below which there would be no concern for potential genotoxic activity.

No useful information is available on the carcinogenic potential of any form of vanadium via any route of exposure in animals2 or in humans.

A fertility study in male mice, involving exposure to sodium metavanadate in drinking-water, suggests the possibility that oral exposure of male mice to sodium metavanadate at 60 and 80 mg/kg body weight directly caused a decrease in spermatid/spermatozoal count and in the number of pregnancies produced in subsequent matings. However, significant general toxicity (decreased body weight gain) was also evident at 80 mg/kg body weight.

There are a number of developmental studies on pentavalent and tetravalent vanadium compounds, and a consistent observation is that of skeletal anomalies. Interpretation of these studies is difficult because of unconventional routes of exposure and evidence of maternal toxicity that may itself contribute to the effects seen in pups.

The toxicological end-points of concern for humans are genotoxicity and respiratory tract irritation. Since it is not possible to identify a level of exposure that is without adverse effect, it is recommended that levels be reduced to the extent possible.

Acute LC50 values for aquatic organisms range from 0.2 to about 120 mg/litre, with the majority lying between 1 and 12 mg/litre. More ecotoxicologically relevant end-points were development of oyster larvae (significantly reduced at 0.05 mg vanadium/litre) and reproduction of Daphnia (21-day no-observed-effect concentration at 1.13 mg/litre). There are few terrestrial studies. Most plant studies have been on hydroponic cultures where effects occurred at 5 mg/litre and higher; these studies are difficult to interpret in relation to plants growing in soil.

Concentrations in environmental media are sub stantially lower than reported toxic concentrations. Few data are available on concentrations at specific industrial sites, and it is not possible to conduct a risk assessment on this basis. However, reported concentrations appear to be similar to the highest natural concentrations, suggesting that risk would be low. Local measurements must be carried out to assess risk in any particular circumstance.

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES

Vanadium can exist in a number of different oxidation states: -1, 0, +2, +3, +4, and +5. The most common commercial form of vanadium is vanadium pentoxide (V2O5), in which vanadium is in the +5 oxidation state. Other forms of vanadium in the +5 oxidation state mentioned in this review derive from the vanadate ion (VO3) and include ammonium meta vanadate (NH4VO3), sodium metavanadate (NaVO3), and sodium orthovanadate (Na3VO4). Compounds in the +4 oxidation state are derived from the vanadyl ion (VO2+) — for example, vanadyl dichloride (VOCl2) and vanadyl sulfate (VOSO4). Compounds containing vanadium in the +3 oxidation state include vanadium oxide (V2O3). Table 1 provides some physicochemical properties of vanadium compounds that are referred to in this review.

Vanadium (CAS No. 7440-62-2) is a soft silvery- grey metal with a relative molecular mass of 50.9.

Vanadium pentoxide (CAS No. 1314-62-1) is the most commonly used vanadium compound and exists in the pentavalent state as a yellow-red or green crystalline powder of relative molecular mass 181.9. Other common synonyms include vanadic anhydride and divanadium pentoxide.

Vapour pressures (and hence Henry’s law con stants) and octanol/water partition coefficients are not available for vanadium compounds.

3. ANALYTICAL METHODS

3.1 Workplace air monitoring

Airborne monitoring is largely based on measure ment of vanadium, rather than vanadium pentoxide. The Health and Safety Executive has published MDHS 91 Metals and metalloids in workplace air by X-ray fluorescence spectrometry (HSE, 1998). This method can be used for measuring vanadium and vanadium compounds in workplace air, but no method performance data are available for vanadium.

The US National Institute of Occupational Safety and Health (NIOSH, 1994) and the US Occupational Safety and Health Administration (OSHA, 1991) have published methods that are suitable for measuring vanadium and vanadium compounds in workplace air. Both are generic methods for metals and metalloids in which samples are collected by drawing air through a membrane filter mounted in a cassette-type filter holder, dissolved in acid on a hotplate, and analysed by induc tively coupled plasma – atomic emission spectrometry (ICP-AES). For both methods, the lower limit of the working range is approximately 0.005 mg/m3 for a 500- litre air sample, although these methods are not widely available.

3.2 Biological monitoring

The measurement of vanadium in end-of-shift urine samples is appropriate for biological monitoring of vanadium exposure and has been widely used to monitor occupational exposure to vanadium compounds in a number of industrial activities (Angerer & Schaller, 1994).

Table 1: Physical/chemical properties of vanadium and selected inorganic vanadium compounds.

Compound

CAS number

Molecular / atomic mass

Melting point
(°C)

Boiling point
(°C)

Solubility (g/litre)

Cold water (20–25 °C)

Hot water

Other solvents

Vanadium, V

7440-62-2

50.942

1890 ± 10; 1917

3380

Insoluble

Insoluble

Not attacked by hot or cold hydrochloric acid or cold sulfuric acid, but soluble in hydrofluoric acid, nitric acid, and aquaregia

Vanadium pentoxide, V2O5

1314-62-1

181.9

690

1750

8

No data

Soluble in acid/alkali; insoluble in absolute alcohol

Sodium meta vanadate, NaVO3

13718-26-8

121.93

No data

No data

211

388
(at 75 °C)

No data

Sodium ortho-vanadate, Na3VO4

13721-39-6

183.91

850–856

No data

Soluble

No data

Soluble in alcohol

Ammonium meta-vanadate, NH4VO3

7803-55-6

116.98

200 (decomposes)

No data

58

Decomposes

Soluble in ammonium carbonate

Vanadium oxytri-chloride, VOCl3

7727-18-6

 

 

 

Soluble, decomposes

No data

Soluble in alcohol, ether, acetic acid

Vanadyl sulfate, VOSO4

27774-13-6

 

 

 

Very soluble

No data

No data

Vanadyl oxydi-chloride, VOCl2

10213-09-9

 

 

 

Decomposes

No data

Soluble in dilute nitric acid

Vanadium trioxide, V2O3

1314-34-7

 

 

 

Slightly soluble

Soluble

Soluble in nitric acid, hydrofluoric acid, alkali

Vanadium is eliminated in the urine with a half-life of 15–40 h (Sabbioni & Moroni, 1983). Pre-shift and post-shift urine vanadium levels measured at the beginning and the end of a working week will, therefore, give a measure of daily absorption and accumulated dose from exposures over the preceding days. A further study of workers exposed to vanadium pentoxide (Kawai et al., 1989) demonstrated the utility of measuring mid-shift urinary vanadium as an indicator of exposure. Blood vanadium levels were also determined but offered no advantage over urine measurements. As non-invasive sampling is normally preferred for routine biological monitoring, the measurement of vanadium in urine is generally recommended.

In biological monitoring studies of occupational vanadium exposure, urinary levels of vanadium asso ciated with airborne exposures have been measured (see Table 4 in section 6.2).

Urinary vanadium may be determined accurately by several analytical techniques (Hauser et al., 1998; HSE, in press). Electrothermal atomic absorption spectrophotometry (AAS), with pre-concentration by chelation and solvent extraction, is the most widely used analytical method for the determination of vanadium in urine, and validated methods have been described in the literature. This analytical method gives typical detection limits of 0.1 µg/litre for vanadium in urine, with analytical precisions of 11% relative standard deviation at 1 µg/litre and 4% at 10 µg/litre.

3.3 Environmental monitoring

Various methods have been described for analysis of vanadium in air, surface waters, and biota (e.g., Ahmed & Banerjee, 1995). Flameless AAS (NIOSH, 1977) gives a detection limit of 1 ng/ml in air, corresponding to an absolute sensitivity of 0.1 ng vanadium. ICP-AES has a working range of 5–2000 µg/m3 for a 500-litre air sample (NIOSH, 1994). Direct aspiration and graphite furnace AAS methods for determining vanadium compounds in water were reported in US EPA (1983). The detection limits for these two methods are 200 and 4 µg/litre, respectively (US EPA, 1986). Instru mental neutron activation analysis gave detection limits of 0.01 µg/g in the context of sea mammal tissues (Mackey et al., 1996). The instrumental detection limit was 0.1 ng/ml using inductively coupled plasma – mass spectrometry (Saeki et al., 1999).

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

Vanadium is a relatively abundant element with a very wide distribution; however, workable deposits are very rare. Vanadium occurs in the minerals vanadinite, chileite, patronite, and carnotite. It constitutes about 0.01% of the crust of the Earth (Budavari et al., 1996). It is derived mainly from titaniferous magnetites containing 1.5–2.5% vanadium pentoxide, which are mined in South Africa, Russia, and China (HSE, in press). During the smelting of iron ore, a vanadium slag is formed that contains 12–24% vanadium pentoxide, which is used for the production of vanadium metal. Worldwide produc tion of vanadium was stable at just over 27 000 tonnes per annum between 1976 and 1990. Estimated produc tion in 1990 was 30 700 tonnes, comprising approxi mately 15 400 tonnes from South Africa, 4100 tonnes from China, 8200 tonnes from the former USSR, 2100 tonnes from the USA, and under 900 tonnes from Japan (Hilliard, 1992). Vanadium pentoxide is also produced by solvent extraction from uranium ores and by a salt roast process from boiler residues or residues from elemental phosphate plants. Ferrovanadium can be obtained from vanadium pentoxides or vanadium slags by the alumino-thermic process.

All crude oils contain metallic impurities, includ ing vanadium, which is present as an organometallic complex. The vanadium concentration in the oils varies greatly, depending on their origin. The concentration of vanadium in crude oil ranges from 3 to 260 µg and in residual fuel oil from 0.2 to 160 µg/g (NAS, 1974). During the burning of fuel oils in boilers and furnaces, the vanadium is left behind as vanadium pentoxide in the solid residues, soot, boiler scale, and fly ash. The vana dium content of these residues varies from less than 1% up to almost 60%. Vanadium is also present in coal, typically at a concentration between 14 and 56 ppm (mg/kg).

Vanadium is used in the United Kingdom in cer- tain ferrovanadium alloys, being added in relatively small proportions at the refining stage of steelmaking. Titanium-boron-aluminium (TiBAl) rod, containing less than 1% vanadium, is used by the secondary aluminium industry as a grain refiner. The hard metals industry uses small amounts of vanadium carbide in the production of tungsten carbide tool bits. Pure vanadium, imported from outside the United Kingdom, is used in very small quan tities for research purposes.

Vanadium pentoxide is used as the catalyst for a variety of gas-phase oxidation processes, particularly the conversion of sulfur dioxide to sulfur trioxide during the manufacture of sulfuric acid. The most frequently used vanadium pentoxide catalyst contains 4–6% vanadium as vanadium pentoxide on a silica base.

Vanadium pentoxide is also used in some pigments and inks used in the ceramics industry to impart a colour ranging from brown to green. Pigments and inks are made containing up to about 15% vanadium pentoxide, the higher-concentration ones being supplied in an oil base rather than as a dry powder.

Vanadium pentoxide can be used as a colouring agent and to provide ultraviolet filtering properties in some glasses. Normally, the vanadium content in the batch materials is less than 0.5%.

Atmospheric emissions of vanadium from natural sources have been estimated at 8.4 tonnes per annum globally (range 1.5–49.2 tonnes). Natural sources, in order of importance, are continental dusts, volcanoes, seasalt spray, forest fires, and biogenic processes (Nriagu, 1990).

By far the most important source of environmental contamination with vanadium is combustion of oil, with coal combustion as the second most important. Of the estimated total global emissions from both natural and anthropogenic sources of 64 000 tonnes per annum to the atmosphere, 58 500 tonnes come from oil combustion, with more than 33 500 tonnes of this accounted for by the developing economies in Asia and just under 14 500 tonnes by Eastern Europe and the former USSR. There are considerable regional variations in vanadium emissions. For example, emissions to the Great Lakes area fell between 1980 and 1995, whereas those to the Mediterranean basin have continued to rise, dominated by emissions from a few countries (Turkey 20%, Egypt 19%, and Lebanon 15% of the total) (Nriagu & Pirrone, 1998).

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION,
AND TRANSFORMATION

5.1 Chemical speciation of vanadium

The chemistry of vanadium is extremely complex, and the reader is referred elsewhere for detailed dis cussion of the origin, speciation, bioaccumulation, and complex-forming chemistry of the metal related to the environment and biological systems (Crans et al., 1998). A simple summary of vanadium chemistry is presented here.

Under environmental conditions, vanadium may exist in oxidation states +3, +4, and +5. V3+ and V4+ act as cations, but V5+, the most common form in the aquatic environment, reacts both as a cation and anionically as an analogue of phosphate.

In minerals, the oxidation state of vanadium may be +3, +4, or +5, but all mineral dissolution rapidly oxidizes V3+ and V4+ to the pentavalent state. Dry weathering produces dusts that may be distributed over great distances; deposition of dust into water will also lead to exclusively pentavalent vanadium. Vanadium is a non-volatile metal, and atmospheric transport is via particulates. In fuel oils and coal, vanadium is present as very stable porphyrin and non-porphyrin complexes (Yen, 1975; Fish & Komlenic, 1984) but is emitted as oxides when these fossil fuels are burned. The native oxides are sparingly soluble in water but undergo hydrolysis to generate "vanadate" in solution. Vanadate is often used as a generalized term for vanadium species in solution. Speciation of vanadium in solution is com plex and highly dependent on vanadium concentration. Under most common environmental conditions of pH and redox potential, and at the low concentrations reported for vanadium in natural waters, the vanadate is largely monomeric. At higher concentrations, such as those used in toxicity testing, dimeric and trimeric forms may predominate, and this can have an effect on how the vanadium compounds interact with biological systems (Crans et al., 1998).

Within tissues in organisms, V3+ and V4+ predom inate because of largely reducing conditions; in plasma, however, which is high in oxygen, V5+ is formed (Crans et al., 1998).

5.2 Essentiality of vanadium

Vanadium has been characterized as a constituent of several enzyme systems and complexes within living organisms. Nitrogen-fixing bacteria and cyanobacteria contain nitrogenases, which catalyse the reduction of atmospheric nitrogen to ammonia. The best characterized nitrogenase is molybdenum-dependent, and its detailed structure has been published (Chan et al., 1993). Although it has been known for a long time (Bortels, 1936) that vanadium could substitute for molybdenum as a trace element in nitrogen-fixing bacteria, only recently has it been studied in detail. The structure of the vanadium-dependent enzyme is not fully known but is assumed to be similar to the molybdenum–iron protein (Chan et al., 1993). The vanadium enzyme has been shown to function under conditions of low molybdenum, but it may also operate under all conditions; genetic variants lacking the molybdenum–iron enzyme and relying exclusively on the vanadium–iron enzyme are known.

Vanadium-dependent haloperoxidases have been found in marine macroalgae and also in a lichen and fungus. Amavadin, a complex molecule centred on vanadium, is found in fungi of the genus Amanita; its function is not known, but it may act as a mediator in electron transfer. In ascidians (Tunicata; Protochordata), commonly called sea squirts, it has been suggested that vanadium interacts with tunichromes, oligopeptides that are the building blocks of the tunic. In fan worms (Polychaeta; Annelida), a function for vanadium in oxygen absorption and storage has been suggested.

Recent reviews on the role of vanadium in biologi cal systems include those by Rehder & Jantzen (1998), Wever & Hemrika (1998), Chasteen (1990), and Sigel & Sigel (1995), where details of the chemistry of vanadium in biological systems can be found.

Whether vanadium is an essential trace element for mammals remains an open question. Deficiency states have been described for goats and chicks, consisting of reproductive anomalies and deleterious effects on bone growth (Nielsen & Uthus, 1990). However, there is disagreement on results, and, if vanadium is essential, requirement levels of the order of a few nanograms per day are likely (Mackey et al., 1996).

5.3 Bioaccumulation

Ascidians have been known to accumulate large residues of vanadium since a first report in 1911 (Henze, 1911). The metal accumulates in blood cells (vanado cytes). The highest reported concentration is 350 mmol/ litre in the blood cells of Ascidia gemmata (Michibata et al., 1991), a concentration factor above that in seawater of 107. Recent reviews of accumulation and the signifi cance of vanadium in these organisms include those by Kustin & Robinson (1995), Michibata (1996), and Michibata & Kanamori (1998). Recently (Ishii et al., 1993), high vanadium accumulation was demonstrated for polychaetes of the genus Pseudopotamilla; poly chaetes of other genera did not accumulate the metal. Pseudopotamilla occelata showed concentrations in whole soft body ranging from 320 to 1350 mg/kg dry weight. Distribution, speciation, and possible physio logical roles of the metal are discussed in Ishii (1998).

Apart from the specific accumulators mentioned above, organisms generally do not concentrate or accu mulate vanadium from environmental media to a high degree, and there is no indication of biomagnification in food chains. Miramand & Fowler (1998) reviewed reported levels of vanadium in marine organisms and calculated concentration factors for components of a typical marine food chain based on average seawater concentrations of 2 ng/g. Concentration factors for primary producers ranged from 40 to 560, for primary consumers from 40 to 150, for secondary consumers from approximately 20 to 150, and for tertiary con sumers from approximately 2 to 400. Although vana dium concentrations are higher in sediment than in open seawater, only one study has attempted to quantify uptake from sediment using 48V; the ragworm Nereis diversicolor accumulated vanadium from the sediment with a low transfer factor of about 0.02 (Miramand, 1979). Using labelled food, assimilation coefficients have been calculated for several marine organisms. For the carnivorous invertebrates Marthasterias glacialis, Sepia officianalis, Carcinus maenus, and Lysmata seticaudata, assimilation coefficients of 88% (Miramand et al., 1982), 40% (Miramand & Fowler, 1998), 38%, and 25% (Miramand et al., 1981) were reported, respectively. Biological half-lives in the same organisms were 57, 7, 10, and 12 days, respectively. A high proportion of the vanadium was present in the digestive gland (63– 98.8%). For a single fish species (Gobius minutus), assimilation was much lower, at 2–3%, with a half-life of 3 days (Miramand et al., 1992), and accumulation was also low in a bivalve feeding on suspended matter (Mytilus galloprovincialis), at 7%, with a half-life of 7 days (Miramand et al., 1980). Comparison of uptakes via food and directly from water showed that inverte brates accumulated much of the vanadium from food (Miramand & Fowler, 1998). Recent studies on bioaccu mulation of vanadium in pinnipeds and cetaceans in Swedish (Frank et al., 1992), northern Pacific (Saeki et al., 1999), and Alaskan/Atlantic (Mackey et al., 1996) waters have shown a correlation of residues with age, comparable to other metal residues. Liver showed the highest accumulation of the metal of all tissues analysed. However, bone, which might be expected to accumulate the element, was not analysed. Alaskan sea mammals showed the highest levels, ranging up to 1.2 µg/g wet weight. The authors suggest a unique dietary source, a unique geochemical source, or anthropogenic input to the Alaskan marine environment as possible explanations (Mackey et al., 1996).

Marine biota are thought to contribute to the sedimentation of vanadium from seawater via shells, faecal pellets, and moult. Coastal sediments appear to be a sink for vanadium (Miramand & Fowler, 1998).

5.4 Leaching and bioavailability in soils

A field study conducted over 30 months examined movement of vanadium added to the top 7.5 cm of coastal plain soil and its availability to bean plants. Less than 3% of applied metal moved down the soil profile. Extractable concentrations decreased over the first 18 months of the study and remained constant thereafter. Uptake of vanadium into the roots and upper parts of the bean plants did not change significantly between 18 months and the end of the experiment but was reduced during the initial period, suggesting reduced bioavailability over time as a result of binding to soil materials (Martin & Kaplan, 1998).

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

6.1 Environmental levels

A very substantial literature exists on environmen tal levels of vanadium. The metal has been monitored in geographical areas with naturally high occurrence of the metal (mainly volcanic regions) where local water con tributes to drinking supplies, and vanadium has been used to monitor general industrial contamination, since it is a common component of oil and coal. In addition, accumulation of the metal has been studied intensively for marine organisms, since vanadium is known to accumulate in a few species (section 5). In this section, representative levels are presented. The reader is referred to several recent reviews for more detailed coverage of the literature in each of the subsections following.

6.1.1 Air

Earlier measurements of vanadium in air were reviewed by Schroeder et al. (1987); most measurements were performed in the 1970s, with a few in the early 1980s. A review of later measurements and comparison with the earlier review were conducted by Mamane & Pirrone (1998). The ranges they reported are presented in Table 2, together with reported concentrations down wind of the Kuwait oil fires in 1991–1992. The ranges are very large, and there is no simple explanation for the variation; possible causes are reviewed by Mamane & Pirrone (1998), although they can draw no firm conclu sions.

Table 2: Ranges of concentrations of vanadium in air.

Area

Atmospheric concentration (ng/m3)

Reference

Urban air
Rural air
Remote areasa

0.4–1460
2.7–97
0.001–14

Schroeder et al., 1987

Urban air
Rural air
Remote areas

0.5–1230
0.4–500
0.01–2

Mamane & Pirrone, 1998

Dhahran, Saudi Arabia, during Kuwait oil fires

2.4–1170 (in the PM10 fraction)

Sadiq & Mian, 1994

a Includes the Arctic and oceanic islands in the Atlantic and Pacific.

Vanadium in air from oil combustion tends to be in smaller particulate fractions. In arid areas with dust storms, high levels of vanadium have been reported; here, particle size tends to be much larger (Mamane & Pirrone, 1998).

Bulk precipitation concentration ranges have been reported at 4.1–13 µg/litre for the rural United Kingdom (Galloway et al., 1982) and 0.12–0.65 µg/litre (mean 0.45 µg/litre) in Switzerland (Atteia, 1994). Wet deposition in an area of New England remote from anthropogenic input showed concentrations of vanadium ranging from 0.2 to 1.16 µg/litre (average 0.67 µg/litre) and in Bermuda ranging from 0.049 to 0.111 µg/litre (average 0.096 µg/litre) (Church et al., 1984). Ice and snow levels in northern Norway and Alaska were 0.31 and 0.13 µg/litre, respectively (Galloway et al., 1982), and two ice core levels in Greenland were reported at 0.022 and 0.016 µg/litre. Levels in rain ranged from 1.1 to 46 µg/litre for rural and urban sites in North America and Europe (Galloway et al., 1982).

Based on these reported concentrations, Mamone & Pirrone (1998) calculated representative total depo sition rates of vanadium at 0.1–10 kg/ha per annum for urban sites affected by strong local sources, 0.01– 0.1 kg/ha per annum for rural sites and urban ones with no strong local source, and <0.001–0.01 kg/ha per annum for remote sites.

6.1.2 Surface waters and sediments

Most surface fresh waters contain less than 3 µg vanadium/litre (Hamada, 1998). The vanadium content of water from the Colorado River basin (USA) ranged from 0.2 to 49.2 µg/litre, with the highest levels associ ated with uranium–vanadium mining (Linstedt & Kruger, 1969). A wider survey of Wyoming, Idaho, Utah, and Colorado in the USA showed vanadium concentrations of 2.0–9.0 µg/litre (Parker et al., 1978). Unfiltered water from the source area of the Yangtze River in China con tained between 0.24 and 64.5 µg/litre, whereas concen trations in filtered water ranged from 0.02 to 0.46 µg/li tre (Zhang & Zhou, 1992). The highest levels reported are in surface waters in the area of Mount Fuji in Japan. Two springs had 14.8 and 16.4 µg/litre, and five river samples showed between 17.7 and 48.8 µg/litre (Hamada, 1998).

Data on concentrations of vanadium in wastewater and local surface water are few, and studies are old; reliability for present-day operations is questionable. A single concentration of 2 mg/litre for surface water from 1961, reported in IPCS (1988), seems much higher than other more recent reports, where levels of up to 60 µg/litre in industrial areas seem more likely.

Seawater concentrations have been reviewed by Miramand & Fowler (1998). Most reported concentra tions in the open ocean have been in the range 1–3 µg/litre, with the highest reported value at 7.1 µg/litre. Sedi ment concentrations range from 20 to 200 µg/g dry weight, with higher levels in coastal sediments.

6.1.3 Biota

Ranges of concentrations of vanadium in marine organisms are given in Table 3, based on a review of the literature in Miramand & Fowler (1998), where the original references can be found. The ranges include values from areas of likely local contamination from industrial sources. With the exception of ascidians (tunicates), some annelids, and molluscs, concentrations of vanadium in marine organisms are low. The range for planktonic species is heavily influenced by a single study showing accumulation up to 290 mg/kg dry weight; this was mainly into shells of planktonic forms of molluscs. Generally, planktonic organisms show concentrations of vanadium around 1 mg/kg.

There are fewer data for freshwater organisms. The most comprehensive study of organisms was conducted in the Mount Fuji area of Japan, where concentrations in organisms from water with high (43.4 µg/litre) and lower (0.72 or 0.4 µg/litre) concentrations of vanadium were compared. Water plants from the high-vanadium area contained 21.8 ± 11.3 µg/g dry weight of the metal (range 5.6–43.7 µg/g), compared with 0.79 ± 0.52 µg/g (range 0.22–1.91 µg/g) in the low-vanadium area. A green microalga in the high-concentration area contained the highest reported concentration of the metal, at 118– 168 µg/g dry weight. The vanadium concentration in rainbow trout (Oncorhynchus mykiss) farmed in water from these areas was measured: bone concentrations were 0.87, 4.77, and 17.2 µg/g and kidney concentra tions were 0.43, 2.38, and 4.63 µg/g for water concen trations of 0.72, 43.4, and 82.7 µg/litre, respectively. In all cases, muscle concentrations were low and did not differ between areas (0.016–0.024 µg/g) (Hamada, 1998). A pooled sample of 279 larval razorback sucker (Xyrauchen texanus) from the Green River in Utah, USA, showed a vanadium concentration of 1.7 mg/kg dry weight. The Green River receives irrigation drainage and typically shows higher concentrations of a range of elements compared with the input streams (Hamilton et al., 2000).

Table 3: Concentrations of vanadium in marine organisms.a

Organism

Concentration of vanadium
(mg/kg dry weight)

Phytoplankton

1.5–4.7

Zooplankton

0.07–290

Macroalgae

0.4–8.9

Ascidians

25–10 000

Annelids

0.7–786

Other invertebrates

0.004–45.7

Fish

0.08–3

Mammals

<0.01–1.04 (fresh weight)

a From Miramand & Fowler (1998).

A single study detected vanadium in 19 out of 120 canvasback ducks (Aythya valisineria) wintering in Louisiana, USA; the maximum concentration in duck liver was 0.94 µg/g dry weight (Custer & Hohman, 1994). The mean vanadium concentration in four species of Japanese waterfowl ranged from 3.69 to 8.11 µg/g dry weight in kidney and from 0.39 to 3.69 µg/g in liver tissue (Mochizuki et al., 1999).

6.1.4 Soil

At distances of 600–2400 m from a metallurgical plant producing vanadium pentoxide, to a depth of 10 cm, the surface layer of the soil contained 18–136 mg vanadium/kg dry weight (Lener et al., 1998). The back ground concentration for the area is not stated, although levels at 600 m from the plant are clearly elevated com pared with those at greater distances. Concentrations in soil globally are very variable. Schacklette et al. (1971) found concentrations in soils in the USA ranging from <7 to 500 mg/kg, with the median at around 60 mg/kg and the 90th percentile at 130 mg/kg. The average worldwide soil concentration is around 100 mg/kg (Hopkins et al., 1977).

6.2 Human exposure

The quantitative data available to the authors of this document are restricted mainly to the occupational environment (HSE, in press). Information on control measures has been derived from industry sources in the United Kingdom.

The main activity where workers can be exposed to vanadium in the United Kingdom is the cleaning of oil-fired boilers and furnaces where vanadium pentoxide is a major component of the boiler residues. It is estimated that 1000 workers in the United Kingdom are employed by specialist boiler maintenance contractors, although they probably spend less than 20% of their time cleaning oil-fired boilers. Measured vanadium exposures (total inhalable fraction) can approach 20 mg/m3 (during task), but can be lower than 0.1 mg/m3. The lowest results are obtained where wet cleaning methods are used. Respira tory protective equipment is usually worn during boiler cleaning operations.

Handling of catalysts in chemical manufacturing plants is carried out by specialist contractors. Fewer than 50 workers in the United Kingdom are exposed to vana dium pentoxide during such activities. Exposure depends on the type of operations being carried out. During the removal and replacement of the catalyst, exposures can be between 0.01 and 0.67 mg/m3. Sieving of the catalyst can lead to higher exposures, and results of between 0.01 and 1.9 mg/m3 (total inhalable vanadium) have been obtained. Air-fed respiratory protective equipment is normally worn during catalyst removal and replacement and sieving.

Fewer than 200 workers in the United Kingdom are exposed to vanadium during the manufacture of ferrovanadium alloys and TiBAl rod. The limited exposure data available indicate exposures below the limit of detection of 0.01 mg/m3. No data have been found to quantify exposures during the manufacture of TiBAl rod.

There are fewer than 50 workers who are exposed to vanadium compounds in the United Kingdom during the manufacture of vanadium-containing pigments for the ceramics industry. Exposure is controlled by the use of local exhaust ventilation, and measured data indicate that levels are normally below 0.2 mg/m3 (total inhalable fraction).

Occupational exposure data are also available from Finland, including personal monitoring data from a range of work processes in a vanadium refining plant (Kivilu oto, 1981). Generally, two samples were taken per per son over a 2-month period. The mean respirable fraction (particle size 5 µm or less) of the dust was 20%. The highest values (expressed as total inhalable vanadium) were obtained in the laboratory (range 0.25–4.7 mg/m3, mean shift length exposure 1.7 mg/m3) and the smelting room (0.055–0.47 mg/m3, mean 0.21 mg/m3), but were usually much lower for other processes (around 0.002– 0.18 mg/m3, mean 0.005–0.037 mg/m3).

Table 4: Biological monitoring studies of occupational vanadium exposure.

Industry

Sample matrix

No. of subjects

Measured air V (mg/m3) (TWA)

Urine V (µg/litre)
(range)

Reference

V2O5 production

Urine

58

Up to 5

28.3 (3–762)

Kucera et al., 1992

Boiler cleaning

Urine

4

2.3–18.6
(0.1–6.3)

2–10.5

White et al., 1987

Incinerator workers

Urine

43

Not known

<0.1–2

Wrbitsky et al., 1995

Boiler cleaners

Urine

10 (-RPE)a
10 (+RPE)

Not known

92 (20–270)
38

Todaro et al., 1991

Boiler cleaners

Urine

30

0.04–88.7

(0.1–322)

Smith et al., 1992

V alloy production

Urine

5

Not known

3.6 (0.5–8.9)

Arbouine, 1990

Pigment manufacture

Urine

8

Not known

2.3 (0.8–6.3)

Arbouine, 1990

V2O5 staining

Urine

2

(<0.04–0.13)

<4–124

Kawai et al., 1989

Unexposed (general population)

Urine

213 012

 

0.22 (0.07–0.5)
<0.4
<0.1

Kucera et al., 1992
White et al., 1987
Smith, 1992

a RPE = respiratory protective equipment.

Biological monitoring studies of occupational vanadium exposure also indicate the magnitude of airborne exposures (Table 4). A further recent example is detailed (Kucera et al., 1992, 1994, 1998; see also sections 7 and 9): a group of workers from the Czech Republic involved in the manufacture of vanadium pentoxide from slag rich in vanadium for periods of 0.5–33 years (mean duration of exposure 9.2 years) was exposed to airborne vanadium concentrations of 0.016– 4.8 mg/m3. Urinary vanadium content was 3.02–769 ng/ ml, compared with 0.066–53.4 ng/ml in controls. In blood, vanadium levels were 3.1–217 ng/ml, compared with 0.032–0.095 ng/ml in controls. The vanadium content in the hair of exposed and non-exposed persons was in the range of 0.103–203 mg/kg and 0.009– 3.03 mg/kg, respectively, and the vanadium content in the fingernails was in the range of 0.260–614 mg/kg and 0.017–16.5 mg/kg, respectively. Determinations of the vanadium content were carried out by both radiochemi cal and instrumental neutron activation analyses in all instances.

Estimates given in IPCS (1988) for total dietary intake of the general population in food range from 11 to 30 µg/day (adults). The mean vanadium concentration in drinking-water in Cleveland, USA, was 5 µg/litre, with a maximum of 100 µg/litre (Strain et al., 1982). Wells close to a vanadium slag processing plant in the Czech Republic showed concentrations ranging from 0.01 to 0.44 µg/litre; the local municipal supply contained 0.01 µg/litre (Lener et al., 1998). Groundwater in the vicinity of Mount Fuji in Japan contains high vanadium levels from leaching of larval flows rich in the metal; measured concentrations in deep wells were between 89 and 147 µg/litre, levels higher than those measured in spring water (Hamada, 1998). A sample of drinking- water from Kanagawa Prefecture in Japan contained a vanadium concentration of 22.6 µg/litre, the highest value in a survey of Japanese cities and 21 cities in the USA (Tsukamoto et al., 1990). The water here was influenced by Mount Fuji groundwater. Groundwater in the region of Mount Etna in Sicily has been used as a source of drinking-water. The western basin showed the highest levels of vanadium; 33% of samples had concen trations between non-detectable and 20 µg/litre, 54% between 20 and 50 µg/litre, and 13% higher than 50 µg/ litre (Giammanco et al., 1996). Older studies summar ized in IPCS (1988) report drinking-water concentrations up to 70 µg/litre, although the majority of samples con tained less than 10 µg/litre, and in many the metal was undetectable. Levels in bottled waters from mineral springs may contain much higher levels of vanadium; one study of bottled waters from Switzerland reported a range of 4–290 µg/litre (Schlettwein-Gzell & Mommsen- Straub, 1973).

The mean concentration of vanadium in cigarettes was 1.11 ± 0.35 µg/g, and the mean concentration in cigarette smoke was 0.33 ± 0.06 µg/g (Adachi et al., 1998).

Following the major contamination of the marine environment with oil in the Gulf War, levels of vanadium in seafood (six species of fish and two species of shrimp) were measured. Mean daily consumption of seafood by people in five districts of Kuwait ranged from 0.15 to 1.16 g seafood/kg body weight; the mean vanadium content of seafood edible tissues ranged from 0.48 to 1.48 µg/g dry weight (Bu-Olayan & Al-Yakoob, 1998).

7. COMPARATIVE KINETICS AND METABOLISM IN
LABORATORY ANIMALS AND HUMANS

Human exposure data suggest that vanadium (chemical form unknown) is absorbed following inhala tion exposure to 0.03–0.77 mg vanadium/m3 and is sub sequently excreted via the urine with an initial rapid phase of elimination, followed by a slower phase, which presumably reflects the gradual release of vanadium from body tissues (Kiviluoto et al., 1981a).

Following oral administration of 50–125 mg/day, ammonium vanadyl tartrate (tetravalent vanadium) is poorly absorbed from the gastrointestinal tract in humans (Dimond et al., 1963). Less than 1% of the administered dose was eliminated in the urine within the first 24 h post-administration. No other information is available in humans.

Groups of two rats were exposed to ammonium metavanadate (pentavalent vanadium, median mass aerodynamic diameter [MMAD] 0.32 µm) at a concen tration of 2 mg/m3 for 8 h/day for 4 days (Cohen et al., 1996b). There was a tendency for vanadium to accumu late in the lung; lung levels increased by around 44% over the first 2 days, followed by an additional 10% on each of days 3 and 4. Twenty-four hours after the final exposure, lung vanadium levels decreased by about 39% (from 27 to 17 µg/g lung).

Intratracheal studies in animals (Oberg et al., 1978; Conklin et al., 1982; Rhoads & Sanders, 1985; Sharma et al., 1987) indicate that vanadium, from either vana dium pentoxide or other pentavalent and tetravalent vanadium compounds, is absorbed to a significant extent from the lungs. Following intratracheal instillation of 40 µg vanadium pentoxide, 72% of the administered dose was absorbed from the lungs within 11 min (Rhoads & Sanders, 1985). The remaining 28% was absorbed over 2 days. Forty per cent of the administered dose was retained within the carcass after 14 days (12% in bones), and 40% was eliminated via urine and faeces. Similar results were obtained by the other authors.

Oral studies (Parker & Sharma, 1978; Conklin et al., 1982; Ramanadham et al., 1991; summarized by HSE, in press) indicate that vanadium compounds are poorly absorbed from the gastrointestinal tract (approx imately 3% of the administered dose).

No dermal studies are available.

Absorbed vanadium in either pentavalent or tetra valent states is distributed mainly to the bone (around 10–25% of the administered dose 3 days after admin istration) and to a lesser extent to the liver (about 5%), kidney (about 4%), and spleen (about 0.1%), while small amounts are also detected in the testes (about 0.2%) (Sabbioni et al., 1978; Ramanadham et al., 1991; Sanchez et al., 1998; HSE, in press). Distribution studies in which rats received a total of approximately 224 and 415 mg vanadium pentoxide/kg in drinking-water over a period of 1 and 2 months indicated that the vanadium content (assessed in 13 specific tissues) was greatest in the kidneys, spleen, tibia, and testes (Kucera et al., 1990). Similar distribution was seen in a study conducted using vanadyl sulfate (tetravalent vanadium) (Kucera et al., 1990). Further evidence for the distribution of vana dium to testes comes from genotoxicity studies in germ cells (section 8.7) and reproductive studies (section 8.8).

The main route of vanadium excretion is via the urine (HSE, in press). Following oral (drinking-water) administration of vanadyl sulfate (tetravalent vanadium), the half-time for elimination via urine in rats was calcu lated to be around 12 days (this is in contrast to the initial short half-time seen in humans, presumably reflecting post-exposure clearance from the bloodstream, followed by a more gradual release from other body compartments). The pattern of vanadium distribution and excretion indicates that there is potential for accumu lation and retention of absorbed vanadium, particularly in the bone. One oral study in which groups of 22 preg nant mice received vanadyl sulfate pentahydrate at doses of 0, 38, 75, or 150 mg/kg body weight per day by oral gavage (Paternain et al., 1990) indicates that tetravalent vanadium has the ability to cross the placental barrier to the fetus.

8. EFFECTS ON LABORATORY MAMMALS AND
IN VITRO TEST SYSTEMS

Where data on vanadium pentoxide are lacking, information on properties of other pentavalent or tetra valent vanadium compounds is utilized. There is no toxicological information on elemental vanadium and negligible information on the trivalent forms.

In this section, reference is made to a review of the toxicity of vanadium compounds (including vanadium pentoxide) by Sun (1987). However, it has not been possible to trace the majority of the primary references from which the review is constructed, and so it has not been possible to perform a critical evaluation of the quality of the information presented.

8.1 Single exposure

8.1.1 Vanadium pentoxide

The one acute inhalation study available reported an LC67 of 1.44 mg/litre (1440 mg/m3) following a 1-h exposure of rats to vanadium pentoxide dust (US EPA, 1992). Additional inhalation data are cited in the MAK (1992) review. Two out of four rabbits exposed to 205 mg/m3 for 2 h (30% of particles had a diameter less than 5 µm) died within 12–24 h. Clinical signs of toxicity included respiratory distress, "mucosal irri tation" (tissues unstated), and diarrhoea.

Further information relating to single inhalation exposures is presented in section 8.3. No information on single exposures via the dermal route is available.

Oral studies in rats and mice demonstrate greater toxicity of vanadium as oxidation state increases. The review by Sun (1987) cites a study by Yao et al. (1986b) in which rat oral LD50 values for vanadium pentoxide in the range 86–137 mg/kg body weight are reported. Clinical signs of toxicity included lethargic behaviour, lacrimation, and diarrhoea, and histological examination revealed necrosis of liver cells and cloudy swelling of renal tubules. The dose–response characteristics of these effects were not described.

A further review of vanadium pentoxide cites oral LD50 values of around 10 mg/kg body weight for rats and 23 mg/kg body weight for mice (MAK, 1992). No fur ther details are available.

For mice, oral LD50 values for vanadium pentoxide were in the range 64–117 mg/kg body weight (Yao et al., 1986b). Similarly, an oral LD50 of 64 mg/kg body weight for vanadium pentoxide administered to male rabbits was reported. For both rabbits and mice, the signs of toxicity reported were the same as those observed in rats.

8.1.2 Other pentavalent vanadium compounds

Groups of 10 male rats received aqueous sodium metavanadate by gavage (Llobet & Domingo, 1984). The LD50 value reported was 98 mg/kg body weight. No deaths were reported at 39 mg sodium metavanadate/kg body weight. Clinical signs of toxicity reported were decreased locomotor activity, paralysis of the hind legs, and decreased sensitivity to pain. At the highest doses (not clearly defined), intense diarrhoea, irregular res piration, and increased cardiac rhythm and ataxia were reported. The effects had mostly disappeared in sur vivors at 48 h after treatment. No histopathology was performed.

The MAK (1992) review cites rat oral LD50 values in the range 18–160 mg/kg body weight for ammonium metavanadate. No further details are available.

An oral LD50 value of 75 mg/kg body weight in male mice was reported for sodium metavanadate (Llobet & Domingo, 1984). No deaths were reported at 41 mg/kg body weight. Clinical signs of toxicity reported were the same as those seen in rats.

8.1.3 Tetravalent vanadium compounds

An oral LD50 value of 448 mg/kg body weight in male rats exposed to vanadyl sulfate pentahydrate was reported (Llobet & Domingo, 1984). No deaths were reported at 296 mg/kg body weight. Signs of toxicity were similar to those reported following treatment with sodium metavanadate, although to a lesser degree.

For mice, the oral LD50 value reported for vanadyl sulfate pentahydrate was 467 mg/kg body weight (Llobet & Domingo, 1984). No deaths were reported at 186 mg/kg body weight. Clinical signs of toxicity reported were the same as those seen in rats.

A study by Paternain et al. (1990) investigating developmental toxicity in mice reported an LD50 for vanadyl sulfate pentahydrate of 450 mg/kg body weight.

8.1.4 Trivalent vanadium compounds

The MAK (1992) review cites a rat oral LD50 value of 350 mg/kg body weight and a mouse LD50 value of around 23 mg/kg body weight for vanadium trichloride and a mouse oral LD50 of 130 mg/kg body weight for vanadium trioxide. No further details are available.

8.2 Irritation and sensitization

No information is available from animal studies with regard to the potential of vanadium compounds to induce skin or eye irritation.

The primate inhalation studies by Knecht et al. 1992 (see section 8.3) also included an unconventional evaluation of skin sensitization; this investigation gave a negative response for immediate and delayed skin reactions to vanadium only or in combination with a carrier protein.

8.3 Effects of inhaled vanadium compounds on the respiratory tract

Presumably owing to the serious nature and rapid onset of the respiratory effects that have been observed in humans in occupational settings (see also section 9), the following series of single and repeated inhalation studies was conducted in an attempt to further elucidate the possible mechanisms and dose–response relation ships.

A study by Knecht et al. (1985) investigated pulmonary responses to inhaled vanadium pentoxide dust and sodium vanadate aerosols (thought to contain the polymeric vanadium species most likely to be present in the respiratory mucosa after inhalation of vanadium pentoxide) in a group of 16 cynomolgus monkeys. The study design attempted to simulate exposure patterns and their consequences in humans. Animals were given sequential exposures to 0, 19, and 39 mg vanadium/m3 in the form of sodium vanadate aerosol (characteristics not reported) for 1 min, at 30-min intervals (duration unclear). Two weeks later, the animals were exposed, whole body, to 0.5 and then to 5.0 mg vanadium pentoxide dust/m3 (0.28 and 2.8 mg vanadium/m3; particle size 0.59–0.61 µm) for 6 h, with a 1-week interval between the two exposures. Pulmonary function was evaluated before any exposures began and then immediately after exposure to sodium vanadate and 18–21 h after exposure to vanadium pentoxide. The reason for this pattern of investigating was that experi ence in humans suggested that respiratory effects had appeared approximately 1 day after exposure to vanadium pentoxide; the pulmonary investigations made immediately after sodium vanadate exposure were explained on the basis that it was known that inhalation of soluble zinc salt can produce an immediate irritant response. Bronchoalveolar lavage (BAL) was performed pre-exposure and following exposure to 5.0 mg vana dium pentoxide/m3.

Evidence of slight impairment of pulmonary func tion was reported following the single 6-h inhalation of 5.0 mg vanadium pentoxide dust/m3, but not 0.5 mg/m3. This was based on statistically significant decreases in peak expiratory flow rate (PEFR; median 89% of base line values), forced expiratory volume (FEV0.5; 95% of baseline values), and forced expiratory flow (FEF50; 92% of baseline values), these changes giving an indication of airflow limitation in the large central airways; a statis tically significant decrease in FEF25 (77% of baseline values), which gives an indication of airflow limitation in the peripheral airways; and statistically significant increases in functional residual volume (FRV; 124% of baseline values), residual volume (133% of baseline values), closing volume (127% of baseline values), and the percentage rise in nitrogen at 25% vital capacity (VC; 167% of baseline values), an indication of narrowing of the dependent, peripheral small airways. No significant changes were reported in forced vital capacity (FVC), total lung capacity (TLC), or diffusion capacity for carbon monoxide (DL50), indicating the absence of parenchymal dysfunction. However, although statistically significant, the magnitude of the observed changes was small.

BAL analysis revealed statistically significant increases in numbers of polymorphonuclear leukocytes and decreases in mast cells following exposure to 5.0 mg vanadium pentoxide/m3. Numbers of macrophages and lymphocytes were unaltered by exposure.

Another study in monkeys by Knecht et al. (1992) compared bronchial reactivity following challenge with vanadium pentoxide dust, both before and after sub chronic exposure to vanadium pentoxide dust. Both before and after subchronic exposure, the animals underwent 6-h whole-body challenges with vanadium pentoxide aerosol (stated to be "generally 1–5 micro metres") at concentrations of 0.5 and 3.0 mg/m3 (0.28 and 1.68 mg vanadium/m3), separated by a 2-week interval. Two weeks later, the animals were challenged with methacholine to assess non-specific bronchial reactivity. The subchronic exposure regime involved exposure to vanadium pentoxide 6 h/day, 5 days/week, for 26 weeks. Two vanadium pentoxide-exposed groups (n = 9 each) received equal weekly exposures (concen tration × time) with different exposure profiles. One vanadium pentoxide-exposed group received a constant concentration of 0.1 mg/m3 (0.06 mg vanadium/m3) for 3 days/week and an exposure at a constant concentration of 1.1 mg/m3 (0.62 mg vanadium/m3) for 2 days/week. The other vanadium pentoxide-exposed group received a constant daily concentration of 0.5 mg/m3. A control group (n = 8) received filtered, conditioned air. The animals were allowed a 2-week recovery period before being retested as before.

Blood cytological and immunological analysis was carried out before both sets of acute challenges with vanadium pentoxide. Pulmonary function testing was carried out pre-exposure, the day after each acute challenge with vanadium pentoxide, and immediately after challenge with methacholine. BAL fluid was collected for cytological and immunological analysis before each series of challenges and after challenge with 3.0 mg/m3.

Respiratory distress developed in three monkeys from the subchronic exposure group, which received the intermittent peaks of 1.1 mg vanadium pentoxide/m3, characterized by audible wheezing and coughing, which occurred only on peak exposure days during the first few weeks of exposure. Pre-subchronic exposure provocation challenges with vanadium pentoxide produced statis tically significant changes in average flow resistance (RL; mean, 103% and 114% of baseline values at 0.5 and 3.0 mg/m3, respectively) and FVC (96% and 97% of baseline values, respectively) at both dose levels used, while statistically significant differences were observed only at 3.0 mg/m3 for FEF50/FVC (99% and 87% of baseline values, respectively) and residual volume (RV; 105% and 114% of baseline values, respectively), which indicates an obstructive pattern of impaired pulmonary function. No statistically significant change in dynamic compliance (CLdyn) was observed.

At the second challenge, after subchronic expo sure, the pattern of findings was similar to that from the first challenge, but none of the changes was statistically significantly different from baseline values, nor was there any statistically significant difference between the controls, the "peak" exposure group, or the "constant" group. Large, statistically significant increases in RL and FEF50/FVC were observed following challenge with methacholine, but this reactivity was not significantly increased following subchronic exposure to vanadium pentoxide.

A significant increase in the total number of respiratory cells in BAL fluid was observed following pre-subchronic exposure challenge with 3.0 mg vana dium pentoxide/m3. The increase in the total number of cells occurred through a highly significant increase in the number of neutrophils (393% of baseline values). The number of eosinophils recovered from the lung was also increased (170% of baseline values), while the numbers of lymphocytes, macrophages, and mast cells were not. Significant challenge responses were not observed for total protein, albumin, leukotriene C4, or the immuno globulins IgG and IgE, despite the significant cellular response to vanadium pentoxide challenge. A similar pattern of cellular and immunological response was observed after subchronic exposure. Post-exposure challenge responses for neutrophils were greater than 400% of baseline values. A post-exposure trend (statistically significant for eosinophils) towards decreased responses was observed in the vanadium pentoxide-exposed groups as compared with the control group. The number of circulating neutrophils and eosinophils in venous blood was not affected by sub chronic vanadium pentoxide exposure. Similarly, serum immunoglobulins were unchanged throughout the study.

8.4 Other short-term exposure studies

Oral studies are described below; no dermal studies are available.

8.4.1 Vanadium pentoxide

Short-term immunotoxicity studies are described briefly in section 8.9.1.

8.4.2 Other pentavalent vanadium compounds

Groups of 10 male rats received 0, 5, 10, and 50 ppm (mg/litre) sodium metavanadate in drinking- water for 3 months, which corresponded to 0, 2.1, 4.2, and 21 ppm vanadium. This intake was equivalent to about 0, 0.3, 0.6, and 3 mg sodium metavanadate/kg body weight per day, assuming 350 g body weight and 20 ml/day water consumption (Domingo et al., 1985). Limited numbers of animals were selected for liver and renal function tests and organ weight analysis (liver, kidneys, heart, spleen, and lungs only). Histological examination was performed on only three animals of each group.

There was no effect on weight gain, consumption of water, urine volume, or urinary protein levels during the treatment period. No significant difference was reported in the relative organ weights of the groups. Plasma concentrations of urea, uric acid, and creatinine were reported to be within the normal range for all groups of animals, except in 50 ppm animals, in which urea and uric acid values were significantly greater than in concurrent controls. No effect on liver function was apparent from the results. Dose-dependent histological changes, including hypertrophy and hyperplasia in the white pulp of spleen, corticomedullary microhaemor rhagic foci in kidneys, and mononuclear cell infiltration, mostly perivascular, in lungs, were apparent in all treated animals. Hence, no no-observed-adverse-effect level (NOAEL) could be derived from this study, although changes at the lowest exposure level were considered by the authors to be minimal.

Groups of eight male rats were administered 0 or about 9.7 mg vanadium/kg body weight per day as ammonium metavanadate via the drinking-water for 12 weeks (Dai et al., 1995). Before the start of the study and at weeks 1, 2, 4, 8, and 12 following vanadium treat ment, haematological indices (haematocrit, haemoglobin concentration, erythrocyte count, leukocyte count, plate let count, reticulocyte count, and erythrocyte osmotic fragility) of the peripheral blood were investigated in all animals. There were no other investigations. No differ ence in food intake or body weight was apparent between the groups. There were no differences in haematological parameters between the groups.

Groups of 15–16 male and female rats were admin istered 0, 1.5, or 5–6 mg vanadium/kg body weight per day as ammonium metavanadate in drinking-water for 4 weeks (Zaporowska et al., 1993). No differences in external appearance or locomotor behaviour were reported between the groups. Body weight increase in the treated groups was lower than in control animals, but this was not dose-related. Slight, but statistically signif icant, decreases in erythrocyte number and haemoglobin concentration (top dose only, all about 10% less than control) were observed. Similarly, a slight but statis tically significant decrease in haematocrit was reported in treated males (mean value was 98% of controls). No significant differences in leukocyte numbers were reported between the groups. No clinically significant changes in biochemical parameters were reported. Overall, the changes were slight.

Groups of 12–13 male and female Wistar rats were administered 0 or about 13 mg ammonium metavana date/kg body weight per day in drinking-water for 4 weeks (Zaporowska & Wasilewski, 1992). Investigations included water and food consumption, body weight, and a range of haematological parameters; there were no further investigations conducted.

There was a marked decrease in water consumption with concomitant decreases in food consumption and body weight gain. Although there were statistically significant reductions in some of the haematological parameters measured (as above), it is impossible to draw any conclusions regarding the toxicological significance due to the limited study design and confounding due to impaired water consumption (which may have been related to unpalatability).

Groups of 12 male Sprague-Dawley rats received 0, 4, 8, or 16 mg aqueous sodium metavanadate/kg body weight per day by oral gavage for 8 weeks (Sanchez et al., 1998). Investigations were limited to body weight, open field activity, avoidance of electrical stimulus (recorded over a 3-week period, starting after the 8-week treatment period), and a limited range of tissues removed for analysis of vanadium content (see section 7).

Reduced body weight gain was noted only at 16 mg/kg body weight per day (20% lower than controls). There was no observable effect on rearing counts. However, a statistically significant reduction in total distance travelled in the open field activity investigation (recorded 3 weeks after cessation of treatment only) was recorded in the first 5 min at 8 and 16 mg/kg body weight per day, but not at 5–10 or 10– 15 min. Decreased avoidance compared with controls was noted among all vanadium-exposed animals over 3 consecutive days, although there was no clear dose– response relationship and no indication of other results for the 3-week testing period. Hence, this would seem to be a rather selective presentation of results. There was no discussion of whether or not the transient nature of the reduction in total distance travelled could have been related to other factors such as palatability that may have affected behaviour and movement. Also, given the extremely limited range of observations, substantial interindividual variation, and absence of histopathology, it is impossible to draw any firm conclusions from this study.

Short-term immunotoxicity studies are described briefly in section 8.9.2.

8.4.3 Tetravalent vanadium compounds

As previously described for sodium metavanadate (section 8.4.2), Dai et al. (1995) also investigated the potential effect of 7.7 mg vanadium/kg body weight per day as vanadyl sulfate (+4) and 9.2 mg vanadium/kg body weight per day in the form of bis(maltolato)oxo vanadium (+4) on haematological parameters. No difference in food intake or body weight was apparent between the groups (control and vanadium in valency states +4 and +5). There were no differences in haema tological parameters between the groups.

Short-term immunotoxicity studies are described briefly in section 8.9.3.

8.5 Medium-term exposure

8.5.1 Vanadium pentoxide and other pentavalent vanadium compounds

Medium-term oral and dermal exposures to vanadium pentoxide have not been studied.

Groups of six male rats received 0, 10, or 40 µg/ml as sodium metavanadate (about 0, 0.6, or 2.4 mg/kg body weight per day, assuming 20 ml water consumed per day and 350 g body weight) in drinking-water for 210 days (Boscolo et al., 1994). In the second experi ment, groups of six male rats received 0 or 1 µg sodium metavanadate/ml (approximately 0.06 mg/kg body weight per day using the same assumptions) in drinking- water for 180 days. Investigations included urinalysis, haemodynamic measurements, and histopathology.

No treatment-related effect on cardiovascular function was reported. Histopathological investigation showed no change in the brain, liver, lungs, heart, or blood vessels of treated animals. An increase (5 times greater than controls) in urinary kininase I (measured to assess arterial hypertension) and II (twice control values) activities was reported in treated rats at 40 µg/ml, although the significance of this is unclear. No effect was reported on urinary excretion of creatinine, total nitro gen, protein, or sodium. Urinary potassium decreased with dose, whereas urinary calcium was reduced at 10 µg/ml only. Again, this study did not reveal any clearly toxicologically significant changes attributable to vanadium exposure.

8.5.2 Tetravalent vanadium compounds

There are no data available.

8.6 Long-term exposure and carcinogenicity

8.6.1 Vanadium pentoxide and other pentavalent vanadium compounds

Long-term oral and dermal exposures to vanadium pentoxide and other pentavalent vanadium compounds have not been studied.

In a study conducted by Yao et al. (1986a) and cited by Sun (1987), groups of 62–84 male and female mice were exposed to 0, 0.5, 2, or 8 mg vanadium pentoxide dust/m3 (particle size not reported) for 4 h/day for 1 year. "Papillomatous and adenomatous tumours" in the lungs were reported in 2 of 79 and 3 of 62 mice at 2 and 8 mg/m3, respectively. No tumours were reported in controls or at 0.5 mg/m3. No further information is available.

8.6.2 Tetravalent vanadium compounds

Long-term inhalation and dermal exposures to tetravalent vanadium compounds have not been studied.

As part of a study related to the investigation of diabetes, groups of 8–23 male Wistar rats received approximately 0, 34, 54, or 90 mg vanadyl sulfate/kg body weight per day in drinking-water for up to 52 weeks (Dai & McNeill, 1994; Dai et al., 1994a,b). Investigations were extensive and included blood biochemistry, haematology, blood pressure and pulse rate, ophthalmoscopy, organ weights, and microscopic pathology. The only adverse effect observed was reduced body weight gain (around 33% reduction at 90 mg/kg body weight per day and 10% at 34 and 54 mg/kg body weight per day).

8.7 Genotoxicity and related end-points

8.7.1 Studies in prokaryotes

8.7.1.1 Vanadium pentoxide

Only very limited data are available (see section 8.7.7).

8.7.1.2 Other pentavalent vanadium compounds

There are no data available.

8.7.1.3 Tetravalent vanadium compounds

There are no data available.

8.7.1.4 Trivalent vanadium compounds

One Ames test has been performed with vanadium (+3) trichloride. Negative results were obtained, in the presence and absence of metabolic activation, at concen trations between 1 and 200 µg/plate with Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 and Escherichia coli WP2uvrA (JETOC, 1996).

8.7.2 In vitro studies in eukaryotes

8.7.2.1 Vanadium pentoxide

Vanadium pentoxide was added, at concentrations of 0, 2, 4, and 6 µg/ml (0, 1, 2, and 3 µg vanadium/ml), in replicate experiments, to cultures of human lympho cytes (Roldan & Altamirano, 1990). Cells were incu bated in the absence of metabolic activation with vana dium pentoxide for 48 h. A minimum of 100 well-spread first-division metaphases were analysed for structural and numerical aberrations (polyploid only).

Mitotic index was statistically significantly decreased (74, 41, and 42% of control value at 2, 4, and 6 µg/ml, respectively). The frequency of structural chro mosome aberrations did not increase in the presence of vanadium pentoxide. However, a statistically significant increase in the frequency of polyploid cells was reported at all dose levels, which did not show a clear dose– response relationship (4/226, 10/224, 8/200, and 10/218, respectively). This study also reported a dose-related increase in the number of cells with "satellite associa tions" (a tendency for satellite-bearing chromosomes to lie side by side, with their satellite regions facing each other). This finding, along with the induction of poly ploidy, is indicative of vanadium pentoxide exerting its effects at the level of spindle formation.

The potential of vanadium pentoxide exposure to induce micronuclei and centromere-positive micronuclei in vitro was investigated in Chinese hamster V79 cells, in the absence of metabolic activation (Zhong et al., 1994). Studies of cytotoxicity were performed in cells exposed to concentrations of vanadium pentoxide up to 12 µg/ml (6.7 µg vanadium/ml) for 24 h. In each group, the numbers of mononucleated and binucleated cells per 1000 cells were determined for cell cycle kinetics. The investigation of centromere-positive micronuclei was performed in cells cultured with vanadium pentoxide concentrations of 0, 1, 2, or 3 µg/ml (0, 0.6, 1.1, or 2.2 µg vanadium/ml) for 24 h. Binucleated cells were scored and numbers of micronuclei determined.

Cytotoxic effects of vanadium pentoxide, as defined by a reduced number of binucleated cells, were apparent at all doses. A dose-related, statistically significant increase in micronucleus induction was reported at all vanadium dose levels tested (2.4, 4.2, 6.2, and 7.6% of cells, for solvent control, 1, 2, and 3 µg/ml, respectively). This dose–response relationship was also observed in the numbers of centromere-positive micro nuclei (49, 70, 82, and 89% of micronuclei, respec tively).

Induction of gene mutation at the HPRT locus was investigated following exposure of Chinese hamster V79 cells, in the absence of metabolic activation, to 0, 1, 2, 3, or 4 µg vanadium pentoxide/ml (0, 0.6, 1.1, 1.7, or 2.2 µg vanadium/ml) for 24 h (Zhong et al., 1994). No significant increase in the frequency of gene mutation was reported following treatment with vanadium pentoxide.

8.7.2.2 Other pentavalent vanadium compounds

Human lymphocyte cells were incubated in the absence of metabolic activation for 24 h with sodium metavanadate, ammonium metavanadate, and sodium orthovanadate at concentrations of 0, 2.5, 5, 10, 20, 40, 80, or 160 µmol/litre (approximately 0, 0.13–8.0 µg vanadium/ml), and the induction of structural and numerical chromosome aberrations was investigated (Migliore et al., 1993).

The highest dose of vanadium compounds used, 160 µmol/litre, was found to be toxic to the cells in all studies. There was no significant difference in the incidences of chromosome aberrations (excluding gaps, although the nature of the aberrations was not defined) induced by any of the three compounds, for any of the dose levels used. A statistically significant number of hypoploid cells (missing chromosomes) was reported at all doses following treatment with sodium metavanadate and sodium orthovanadate and at the top two doses with ammonium metavanadate. No significant increases in the numbers of hyperploid or polyploid cells were reported.

Chinese hamster ovary cells were exposed to 0, 4, 8, or 16 µg ammonium metavanadate/ml (0, 1.7, 3.3, or 6.7 µg vanadium/ml) for 2 h in the presence and absence of metabolic activation, and then for a further 22 h in fresh medium (Owusu-Yaw et al., 1990). At least 100 metaphases per flask were scored for chromosome aberrations (experiment carried out in duplicate).

Significant increases were reported in the numbers of chromosome aberrations (excluding gaps) induced compared with solvent control values in both the presence and absence (up to 8 times controls in each case) of metabolic activation. The positive controls gave appropriate responses.

Migliore et al. (1993) investigated the potential of three pentavalent vanadium compounds — sodium metavanadate, ammonium metavanadate, and sodium orthovanadate — to induce micronuclei in human lymphocytes in vitro. The aneugenic potential was investigated using fluorescence in situ hybridization (FISH), the number of micronuclei with fluorescent spots (centromere-positive micronuclei) being reported. The final concentrations tested were 0 and 2.5–160 µmol/litre (approximately 0 and 0.13–8.0 µg vanadium/ml) in all experiments, apart from the study involving in situ hybridization, where only 0, 10, 40, and 80 µmol/litre (approximately 0, 0.5, 2.1, and 4.2 µg vanadium/ml) were used. Cells were incubated with the test substances for 48 h. Two thousand binucleated cells (when possible), 100 clear first metaphases, and 25 clear second metaphases were analysed for micronuclei.

The highest dose of vanadium used, 160 µmol/li tre, was found to be toxic to the cells in all studies. Ammonium metavanadate (up to 6% at the highest dose), sodium metavanadate (up to 4.6% at the highest dose), and sodium orthovanadate (up to 2.4% at the highest dose) all induced a dose-related, statistically significant number of micronuclei at 10 µmol/litre and above, although the increases were in general relatively small. Dose-related decreases in the number of binucleated cells were also reported for all compounds, which could be due to general toxicity or specific inhibition of cell cytokinesis. A dose-related increase in the number of micronuclei was reported in the cells used for the FISH technique, although the increases were, as before, relatively small. Statistically significant increases in the numbers of centromere-positive micronuclei were reported at all dose levels for all the compounds, which were comparable with the positive control values.

The ability of ammonium metavanadate to induce mutations, with exogenous metabolic activation, at the HPRT locus in V79 cells in Chinese hamster ovary was investigated using concentrations of 0, 5, 10, 20, 25, 40, and 50 µmol/litre (Cohen et al., 1992). No treatment- related increase in mutation frequency was reported, with testing up to cytotoxic concentrations of ammonium metavanadate.

Ammonium metavanadate induced both mitotic gene conversion and reverse point mutation in the D7 strain of Saccharomyces cerevisiae at dose levels of between 80 and 210 mmol/litre in both the presence and absence of metabolic activation (Bronzetti et al., 1990).

Cell transformation and gap junctional intercellu lar communication were assessed in Syrian hamster embryo cells exposed to 0, 0.2, 0.4, 1.9, 2.3, or 6.9 µmol sodium orthovanadate/litre (Rivedal et al., 1990; Kerckaert et al., 1996). A marked increase in cell trans formation was noted only at the highest concentration, although there were no effects on cloning efficiency, indicating a positive result for genotoxicity in this system. There was no observed effect on gap junctional intercellular communication.

8.7.2.3 Tetravalent vanadium compounds

Migliore et al. (1993) also investigated the ability of vanadyl sulfate to induce structural and numerical chromosome aberrations in human lymphocytes in the absence of exogenous metabolic activation. No signifi cant difference in the incidence of chromosome aberra tions (excluding gaps) was induced. A statistically significant number of hypoploid cells was reported at the top three doses (20–80 µmol/litre).

Owusu-Yaw et al. (1990) also exposed Chinese hamster ovary cells to 6, 12, or 24 µg vanadyl sulfate/ml (1.9, 3.7, or 7.4 µg vanadium/ml) for investigation of chromosome aberrations. Significant increases in induction of chromosome aberrations were reported in both the presence (up to 6 times controls) and absence (up to 13 times controls) of metabolic activation.

Migliore et al. (1993) also investigated the potential of vanadyl sulfate to induce micronuclei in human lymphocytes. Dose-related decreases in the number of binucleated cells were also reported, although these were less pronounced than those observed with pentavalent vanadium compounds. A dose-related, statistically significant increase in the number of micronuclei was reported at 10 µmol/litre and above, although the increases were in general relatively small. Statistically significant increases in the numbers of centromere-positive micronuclei were reported at all dose levels.

Vanadyl sulfate induced no convertants or rever tants in the D7 strain of S. cerevisiae at dose levels of between 420 and 1000 mmol/litre in both the presence and absence of metabolic activation (Galli et al., 1991). Also, no mutagenic activity was detected in hamster V79 cells at dose levels between 0 and 7.5 mmol/litre in both the presence and absence of metabolic activation.

No mutagenic activity was detected in hamster V79 cells at dose levels between 0 and 7.5 mmol vanadyl sulfate/litre in both the presence and absence of meta bolic activation (Galli et al., 1991).

Vanadyl chloride did not produce an increased incidence of transformations in the C3H10T1/2 mouse fibroblast cell line at dose levels up to 5 µg/ml (Doran et al., 1998).

8.7.2.4 Trivalent vanadium compounds

Using protocols similar to that previously ascribed to these authors, Chinese hamster ovary cells were exposed to 12 or 18 µg vanadium oxide/ml (8.2 or 12.2 µg vanadium/ml) (Owusu-Yaw et al., 1990). Significant increases in induction of chromosome aberrations were reported in both the presence (up to 4 times controls) and absence (up to 6 times controls) of metabolic activation.

8.7.3 Sister chromatid exchange

Vanadium pentoxide did not increase incidences of sister chromatid exchange, while studies with other pentavalent, tetravalent, and trivalent compounds did, in a number of different cell systems, over a range of concentrations (0.3–19.2 µg/ml) (Owusu-Yaw et al., 1990; Roldan & Altamirano, 1990; Migliore et al., 1993; Zhong et al., 1994).

8.7.4 Other in vitro studies

8.7.4.1 Vanadium pentoxide

A study by Rojas et al. (1996) investigated the induction of DNA strand breaks in human lymphocytes by vanadium pentoxide using the Comet assay. At dose levels of 0.5, 5.5, and 546 µg vanadium pentoxide/ml, a statistically significant increase in DNA migration was reported, indicating the DNA-damaging potential of vanadium pentoxide. There was no cytotoxicity detected.

8.7.4.2 Other pentavalent vanadium compounds

Chinese hamster V79 cells and human leukaemic T-lymphocyte (MOLT4) cells were exposed to ammo nium metavanadate to investigate the formation of DNA–protein cross-links (Cohen et al., 1992). Dose- related increases in cross-links were reported following 24-h exposure to ammonium metavanadate in both cell types.

Ammonium vanadate gave positive results in a transformation assay in BALB/3T3 mouse embryo cells at doses of 5 and 10 µmol/litre (Sabbioni et al., 1993).

8.7.4.3 Tetravalent vanadium compounds

Vanadyl sulfate gave negative results in a trans formation assay in BALB/3T3 mouse embryo cells at doses of 5 and 10 µmol/litre (Sabbioni et al., 1993). For this study and the above-mentioned work on ammonium metavanadate by these authors (section 8.7.4.2), cyto toxicity, as evidenced by about a 50% reduction in colony-forming efficiency compared with controls, was seen at a concentration of 5 µmol/litre.

8.7.5 In vivo studies in eukaryotes (somatic cells)

8.7.5.1 Vanadium pentoxide

Only very limited data are available (see section 8.7.7).

8.7.5.2 Other pentavalent vanadium compounds

Ciranni et al. (1995) investigated the ability of sodium orthovanadate and ammonium metavanadate to induce chromosome aberration and aneuploidy in the bone marrow of male mice. Male mice (three per experimental group or four per control group) were administered a single dose, intragastrically, of either 0 or 75 mg sodium orthovanadate/kg body weight (21 mg vanadium/kg body weight) or 50 mg ammonium meta vanadate/kg body weight (42 mg vanadium/kg body weight) dissolved in sterile water. Groups of animals were sacrificed at 24 and 36 h post-dose.

Although increases in chromosome aberrations were reported after 36 h with sodium orthovanadate and ammonium metavanadate, these were not statistically significant. No increases were seen at 24 h. Clear and statistically significant increases in cells with hypoploidy and with hyperploidy were apparent at one or both sampling times with both vanadium compounds. Statistically significant, dose-related increases in cells with hypoploidy were reported following treatment with sodium orthovanadate and ammonium metavanadate. Statistically significant increases in cells with hyperploidy were reported 24 h post-treatment with sodium orthovanadate and at both 24 and 36 h post-treatment with ammonium metavanadate. No significant induction of polyploidy was reported.

Groups of 3–4 male mice were administered a single dose, intragastrically, of either 0 or 75 mg sodium orthovanadate/kg body weight (21 mg vanadium/kg body weight) or 50 mg ammonium metavanadate/kg body weight (42 mg vanadium/kg body weight) dissolved in sterile water (Ciranni et al., 1995). Bone marrow cells were sampled at 6, 12, 18, 24, 30, 36, 42, 48, and 72 h post-treatment and assessed for induction of micronuclei.

Polychromatic erythrocyte/normochromatic erythrocyte (PCE/NCE) ratios were lower in the test animals (down to 50% of control values at some time points), indicating that the vanadium compounds had reached the bone marrow and expressed cytotoxicity. Compared with negative controls, there was a small but statistically significant increase (at least twice control values) in the percentage of PCEs with micronuclei for sodium orthovanadate at 24, 30, and 48 h and with ammonium metavanadate at 18, 24, and 30 h.

8.7.5.3 Tetravalent vanadium compounds

Ciranni et al. (1995) also investigated the ability of vanadyl sulfate to induce chromosome aberration and aneuploidy in the bone marrow of male mice. Male mice were administered a single dose, intragastrically, of 0 or 100 mg vanadyl sulfate/kg body weight (0 or 31 mg vanadium/kg body weight). A statistically significant increase in the number of aberrant cells (excluding gaps) was found at 24 and 36 h (4.3 and 2.7%, respectively, compared with 0.6% in negative controls). Statistically significant increases in cells with hypoploidy were reported following treatment at both sampling times and in cells with hyperploidy 24 h post-treatment. No significant induction of polyploidy was reported.

Groups of male mice were administered a single dose of 0 or 100 mg vanadyl sulfate/kg body weight (0 or 31 mg vanadium/kg body weight) intragastrically (Ciranni et al., 1995). There was a small but statistically significant increase (at least twice control values) in the percentage of PCEs with micronuclei at 6, 12, 18, 24, 30, 36, and 48 h.

8.7.6 In vivo studies in eukaryotes (germ cells)

8.7.6.1 Vanadium pentoxide

As part of a larger study (not performed to current standard Organisation for Economic Co-operation and Development [OECD] guidelines) to investigate other reproductive and genotoxic end-points, a dominant lethal-type assay was reported by Altamirano-Lozano et al. (1996). On the basis of deaths reported following repeated administration of 17 mg vanadium pentoxide/kg body weight by intraperitoneal injection in a previous study by the same authors, male mice (15–20 per group) received 0 or 8.5 mg vanadium pentoxide/kg body weight in saline by intraperitoneal injection every third day for 60 days. From day 61, each male had five over night matings with two untreated females, and successful copulation was determined by the presence of a copulation plug or sperm in the vagina.

A statistically significantly reduced body weight in treated animals at the end of the treatment period was reported (79% of control value). The study did not refer to any other signs of toxicity in male mice. Whereas 34 of 40 (85%) of the females mated with controls became pregnant, the rate for the treated group was 33% (10/30). There was a statistically significant reduction in implan tation sites per dam for the treatment groups compared with controls (10.9 and 5.8 in the control and treated groups, respectively). A statistically significant increase in the number of resorptions per litter (0.2 and 2.0 in the control and treated groups, respectively) and a statis tically significant reduction in the number of live fetuses per litter (10.5 and 3.4 in the control and treated groups, respectively) were apparent in the vanadium pentoxide group. There was no statistically significant difference in the numbers of dead fetuses per litter. Post-implantation loss (number of dead fetuses per number of liveborn pups) was approximately 10 times greater in the treat ment group than in controls (0.41 and 0.04, respec tively).

Given that vanadium pentoxide is poorly absorbed following oral exposure and well absorbed and widely distributed when inhaled, the use of the intraperitoneal route in this assay is considered a valid surrogate for relevant exposure routes in this instance. Overall, while this study is of limited quality in view of the non- standard protocol, poor reporting, and clearly reduced pregnancy rate in females mated with treated males, the clear increases in resorptions per litter and post- implantation losses in the vanadium pentoxide group are indicative of a dominant lethal effect.

8.7.6.2 Other pentavalent and tetravalent vanadium compounds

There are no data available.

8.7.7 Supporting data

The following studies cited in a review prepared by Sun (1987) have been included here as they provide further supporting evidence of genotoxic activity of vanadium pentoxide. However, no firm conclusions can be drawn from the results due to the limited reporting.

An Ames test using S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 is briefly reported (Si et al., 1982). Vanadium pentoxide at 0, 50, 100, and 200 µg/plate was tested in both the absence and presence of S9 mix. The numbers of induced revertants at all test levels were less than 2-fold greater than control numbers; hence, vanadium pentoxide gave a negative result under the conditions of the test.

In an E. coli reversion assay using strains WP2, WP2uvrA, CM891 (base pair substitutions), ND-160, and MR 102 (frameshift mutations) (Si et al., 1982), vanadium pentoxide was tested at concentrations of 0, 10, 50, 100, 500, 1000, and 2000 µg/plate in both the presence and absence of S9. A highly significant, dose- related increase in the number of revertants was reported at 10, 50, and 100 µg/plate in strains WP2, WP2uvrA, and CM891 in both the presence and absence of S9. Above these dose levels, vanadium pentoxide produced toxicity. No significant increase was reported in strains ND-160 and MR 102.

Vanadium pentoxide did not increase incidences of sister chromatid exchange in vitro over a range of concentrations (0.3–30 µg/ml) (Sun, undated).

Bone marrow micronucleus tests on vanadium pentoxide via the intraperitoneal, subcutaneous, inhalation, and oral routes in mice are briefly reported (Si et al., 1982; Yang et al., 1986b,c; Sun et al., undated). A statistically significant increase (approximately doubled) in the frequency of micronucleus formation was reported at all dose levels in mice administered 0, 0.2 (or 0.7), 2, or 6 mg vanadium pentoxide/kg body weight intra peritoneally daily for 5 days. A positive result was also reported in mice following subcutaneous administration of 0.25, 1.0, or 4.0 mg vanadium pentoxide/kg body weight, 6 days/week, for 5 weeks, although no further details were provided. An increase in the frequency of micronuclei was reported following exposure of mice to 0, 0.5, 2.0, or 8.0 mg vanadium pentoxide dust/m3 (no details of dust characteristics given). No increase in induction of micronuclei was reported in mice orally administered 1, 3, 6, or 11 mg vanadium pentoxide/kg body weight in a 3% starch suspension for 6 weeks.

8.8 Reproductive toxicity

8.8.1 Effects on fertility

8.8.1.1 Vanadium pentoxide and other pentavalent vanadium compounds

No fertility studies are available on vanadium pentoxide.

Groups of 24 male mice received sodium meta vanadate in drinking-water for 64 days at concentrations of 0, 20, 40, 60, or 80 mg/kg body weight per day (Llobet et al., 1993). At the end of the exposure period, each group was divided into two subgroups: a group of 8 animals for a mating trial and a group of 16 animals for pathology and sperm examinations (utilizing postmortem samples). In the fertility study, each male was mated with two untreated females for 4 days. The females were sacrificed 10 days after the end of the mating period and their uterine contents examined.

A 13% reduction in male body weight was appar ent in the 80 mg/kg body weight group, compared with the controls, immediately after the exposure period. Decreases relative to the controls in the number of pregnant females were reported in some of the vanadium-treated group, but no dose–response relationship was observed. No information was given on mating behaviour. There were no significant differences between the groups regarding the numbers of implan tations, early or late resorptions, or dead or live fetuses. In males, no significant differences were observed in testes weights. Absolute epididymis weight was reduced at 80 mg/kg body weight (88% of control value), although no difference was observed in relative weight, reflecting the reduced body weight in animals of this dose group. A significant 30% reduction in spermatid count was reported at 80 mg/kg body weight, and a significant decrease in spermatozoal count was reported at 60 and 80 mg/kg body weight, although this was not clearly dose-related (99%, 104%, 56%, and 69% of control values in the 20, 40, 60, and 80 mg/kg body weight groups, respectively). There were no significant differences in sperm motility or sperm abnormalities between the groups. No histopathological changes were reported between the groups.

This study suggests the possibility that oral expo sure of male mice to sodium metavanadate at 60 and 80 mg/kg body weight directly caused a decrease in spermatid/spermatozoal count and in the number of pregnancies produced in subsequent matings. However, the results are not convincing, and significant general toxicity, reflected in decreased body weight gain, was also evident at 80 mg/kg body weight. Overall, the results do not provide convincing evidence that oral exposure to sodium metavanadate produced specific fertility effects in this study.

8.8.1.2 Tetravalent vanadium compounds

No data are available.

8.8.2 Developmental toxicity

8.8.2.1 Vanadium pentoxide

Groups of 18–21 pregnant Wistar rats received 0, 1, 3, 9, or 18 mg vanadium pentoxide/kg body weight per day in vegetable oil by oral gavage on days 6–15 of gestation (Yang et al., 1986a). Animals were sacrificed on day 20 of gestation and the uterine contents exam ined. The numbers of implantations, resorptions, and live and dead fetuses were recorded. Fetuses were examined for gross anomalies, and fetal body weight and length were measured. One-third were subsequently examined for visceral abnormalities, and two-thirds for skeletal abnormalities.

Statistically significant decreases in maternal body weight gain were reported in animals of the 9 and 18 mg/kg body weight groups (75% and 40% of control values, respectively). No treatment-related increases in the numbers of resorptions or dead fetuses were observed, although the results were not reported on a per litter basis. Fetal body weight, body length, and tail length were all statistically significantly decreased in the top dose group (87%, 92%, and 94% of control values, respectively).

Delayed occipital ossification (top-dose animals) and non-ossification or delayed ossification of the sternum (all dose groups) were reported; however, these results were not given on a per litter basis, and so their significance is unclear. It was also observed that skeletal abnormalities were statistically significantly increased in the top two dose groups, but again these findings were not reported on a per litter basis. No visceral abnormal ities were reported.

Although the reported increase in skeletal abnor malities at 18 mg/kg body weight is a concern, inter pretation is hindered by the evidence of significant maternal toxicity. Furthermore, bearing in mind the nature of the abnormalities seen and data not having been related to the litter as a unit, no decision can be made regarding the reliability of the reported findings.

8.8.2.2 Other pentavalent vanadium compounds

Groups of 20 mated, presumed pregnant, rats were administered 0, 5, 10, or 20 mg sodium metavanadate/kg body weight (0, 2.1, 4.2, and 8.4 mg vanadium/kg body weight) in distilled water, intragastrically, on days 6–14 of gestation (Paternain et al., 1987). The fetuses were removed on day 20 by caesarean section.

No information regarding maternal toxicity was reported. The numbers of litters produced were 14, 14, 12, and 8 at 0, 5, 10, and 20 mg/kg body weight, respec tively. There was no statistical difference in the numbers per litter of corpora lutea, implantations, resorptions, or live fetuses between the groups. A non-dose-related increase in the number of abnormal fetuses was reported. No visceral or skeletal abnormalities were reported. Although fetal dermal haemorrhage (haematoma) in the facial area, dorsal area, thorax, and extremities was reported, this is a common background finding in developmental toxicology studies and is not considered to be an indicator of specific developmental toxicity. Hydrocephaly was reported in 2 of 98 fetuses at 20 mg/kg body weight compared with none in other groups. No significant difference was reported for fetal body weight or body length. Overall, there is no clear evidence of direct developmental toxicity following exposure to sodium metavanadate.

Groups of 18–20 pregnant mice were administered 0, 7.5, 15, 30, or 60 mg sodium orthovanadate/kg body weight (0, 2.1, 4.2, 8.3, or 16.6 mg vanadium/kg body weight) in deionized water by oral gavage on days 6–15 of pregnancy (Sanchez et al., 1991). The animals were sacrificed on day 18 of pregnancy.

Severe maternal toxicity resulted from the dosing with 30 and 60 mg/kg body weight (4/18 and 17/19 dams, respectively, died as a result of treatment). The two remaining dams at 60 mg/kg body weight were not included in the final evaluation. Body weight gain was significantly reduced (approximately 20%) at 15 mg/kg body weight. However, no significant difference was reported at the end of the study. No differences were reported in final body weight, gravid uterine weight, or corrected body weight. There were no differences in the number of total implants per dam, number of live fetuses per dam, sex ratio, average fetal body weight, or the number of stunted fetuses. There were also no differ ences between the groups in the incidences of skeletal or visceral abnormalities. There was some evidence of delayed ossification at 30 mg/kg body weight; this is considered to be a secondary consequence of the pronounced maternal toxicity produced at this dose level. Overall, sodium orthovanadate did not produce developmental toxicity in this thorough investigation.

8.8.2.3 Tetravalent vanadium compounds

Groups of 22 pregnant mice were administered vanadyl sulfate pentahydrate at 0, 37.5, 75, or 150 mg/kg body weight per day by gavage on days 6–15 of gestation (Paternain et al., 1990). The animals were sacrificed on day 18 of gestation. Three fetuses from each dam were used for whole-body analyses of vanadium. After external examination, one-third of the remaining fetuses were examined for visceral abnormalities and the rest for skeletal abnormalities.

Over the study period, there was a dose-related decrease in body weight gain down to 62% of control values at 150 mg/kg body weight, with no corresponding difference in food consumption. Final body weights were significantly reduced (81%, 83%, and 80% of controls, respectively), and corrected body weights, minus the gravid uterine weight, were also significantly reduced (88%, 84%, and 83% of controls, respectively). There were no differences in the mean numbers of total implants per dam, live fetuses per dam, late resorptions per dam, or dead fetuses per dam. Fetal body weight was significantly reduced at all dose levels (87%, 87%, and 79% of control values, respectively), as was fetal body length (97%, 85%, and 82% of control values, respec tively). The major dose-related effects externally were increased incidence of cleft palate (an abnormality with a significant background incidence in mice) at 75 and 150 mg/kg body weight (4 fetuses in 3 litters and 58 fetuses in 12 litters, respectively) and micrognathia at 37.5, 75, and 150 mg/kg body weight (2 fetuses in 1 litter, 3 fetuses in 1 litter, and 12 fetuses in 3 litters, respectively). The only visceral abnormality reported was hydrocephaly at 75 and 150 mg/kg body weight (2 fetuses in 2 litters and 4 fetuses in 3 litters, respec tively). Delayed ossification was reported in all groups, including controls.

The effects on fetal development (cleft palate, micrognathia, hydrocephaly) reported in this study occurred in the presence of significant maternal toxicity as defined by decreased body weight gain. It is possible that the fetal effects were secondary to maternal toxicity. Unfortunately, the study did not include a dose level at which there was no maternal toxicity.

A number of other studies have been reported in which vanadium compounds have been administered via intraperitoneal, subcutaneous, and intravenous routes (Carlton et al., 1982; Wide, 1984; Sun, 1987; Zhang et al., 1991, 1993a,b; Gomez et al., 1992; Bosque et al., 1993). Effects were observed on the developing fetus, including (but not in every report) increased skeletal abnormalities, increased numbers of resorbed/dead fetuses, increased incidences of delayed ossification, and decreased fetal body weight and length. However, given the routes of exposure used, no conclusion can be drawn from these studies in relation to the potential develop mental toxicity of vanadium compounds in humans exposed occupationally.

8.9 Immunological and neurological effects

8.9.1 Vanadium pentoxide

Groups of 6–8 female rats received a solution of 0, 0.042, or 0.42 mg vanadium pentoxide in phosphate- buffered saline by single intratracheal administration (Pierce et al., 1996). Cells were collected by BAL and subsequently lysed for RNA isolation. Hybridization studies were conducted to determine the expression of cytokines. BAL indicated a significant, dose-related influx of neutrophils in the lungs, and the Northern blot analysis demonstrated increased mRNA expression of macrophage inflammatory protein-2 and another cyto kine, KC. The results demonstrate an inflammatory response in the lungs associated with exposure to vanadium pentoxide.

Groups of 10 male Wistar rats received vanadium pentoxide in drinking-water for a period of 6 months at concentrations of 0, 1, or 100 mg vanadium/litre. Simi larly, 10 male and 10 female ICR mice were given 0 or 6 mg vanadium pentoxide/kg body weight by gavage, 5 days/week for 6 weeks. The study focused on assessing the immunotoxicity of vanadium and recorded the weight of the spleen and thymus, spleen cellularity, leukocyte count in peripheral blood, indicators of non-specific immunity (phagocytosis, natural killer cell activity), and humoral as well as cell-mediated immunity (Mravcova et al., 1993).

The study demonstrated an enlargement of the spleen in rats exposed to vanadium at a concentration of 100 mg/litre, the same finding as in mice, although with diminished spleen cellularity in mice. Thymus weight was not influenced. The leukocyte count in peripheral blood was increased significantly in both rats and mice. In rats and mice, a decrease in phagocytosis, which was dose-dependent in rats, was found. In exposed mice, there appeared signs of intense response to mitogens and high stimulation of B-cells in the plaque-forming cells assay. Activation of T- and B-cells and the magnitude of the response to concanavalin A indicate potential vanadium-related hypersensitivity.

There are no data specifically relating to neuro logical end-points.

8.9.2 Other pentavalent vanadium compounds

Male rats (numbers not given) were exposed nose only 8 h/day for 4 days to atmospheres containing either filtered air or approximately 2 mg vanadium/m3 in the form of ammonium metavanadate aerosol (0.32 µm MMAD) (Cohen et al., 1996a,b). Twenty-four hours after the final exposure, BAL was performed on the rats. Cells gathered in this process were used to assess the effects of vanadium on tumour necrosis factor alpha (TNF-alpha) production, radical oxygen ion production, interferon-gamma-induced Class II/I-A antigen expression, and phagocytic activity.

There was no significant difference in the numbers of alveolar macrophages in the BAL fluid taken from exposed and control animals. Induced production of TNF-alpha by these macrophages was decreased following vanadium exposure, as was the ability to increase cell surface Class II/I-A antigen expression induced by interferon-gamma. The ability of the macrophages to produce radical oxygen anions in response to stimulation was also reduced following vanadium exposure. The report suggests that vanadium exposure could alter host immunocompetence through an inhibitory effect on macrophage function.

Groups of 6–8 female rats received a solution of 0, 0.021, or 0.21 mg sodium metavanadate in phosphate- buffered saline by single intratracheal administration (Pierce et al., 1996). Procedures were as with the work on vanadium pentoxide (section 8.9.1).

Results were similar to those obtained with vana dium pentoxide, but occurred earlier and lasted longer. The results demonstrate an inflammatory response, more potent than with vanadium pentoxide, associated with exposure to sodium metavanadate.

There are no data specifically relating to neuro logical end-points.

8.9.3 Tetravalent vanadium compounds

As part of the study summarized above (sections 8.9.1 and 8.9.2), groups of 6–8 female rats received a solution of 0, 0.021, or 0.21 mg vanadyl sulfate in phosphate-buffered saline by single intratracheal administration (Pierce et al., 1996). Procedures were as with the work on vanadium pentoxide (section 8.9.1).

Results were similar to those obtained with vanadium pentoxide, but occurred earlier and lasted longer than with either vanadium pentoxide or sodium metavanadate, indicating that, in this assay, this substance was the most potent in an inflammatory response.

There are no data specifically relating to neurological end-points.

9. EFFECTS ON HUMANS

9.1 Studies on volunteers

9.1.1 Vanadium pentoxide

Nine healthy volunteers were exposed to vanadium pentoxide dust (98% <5 µm) in an exposure chamber (Zenz & Berg, 1967). Each subject underwent a complete physical evaluation, chest X-ray, haematological and urine analysis, and pulmonary function tests prior to and immediately after exposure.Two volunteers were exposed to 0.1 mg/m3 for 8 h. No symptoms occurred during or immediately after exposure. Within 24 h, considerable mucus had formed. This was easily cleared by slight coughing, increased after 48 h, subsided within 72 h, and completely disappeared after 4 days. Five volunteers were exposed to 0.25 mg/m3 for 8 h. All developed a loose, productive cough the following morning. All subjects had stopped coughing by the tenth day. Physical examination revealed nothing of clinical significance, and pulmonary function tests showed no change compared with pre-exposure values. Two volunteers were exposed to 1 mg vanadium pentoxide dust/m3 for 8 h. Sporadic coughing developed after 5 h, and more frequent coughing developed by the end of the 7th hour. Persistent cough remained for 8 days. Chest examinations revealed clear lung fields, and no differ ences were reported in pulmonary function tests per formed before, immediately after, or once weekly for 3 weeks after exposure. Three weeks after the initial exposure, the same volunteers were accidentally exposed to a heavy cloud of vanadium pentoxide dust (unknown concentration) for a 5-min period while waiting for another test, resulting in marked coughing (which per sisted for about 1 week), production of sputum, rales, and expiratory wheezes. Pulmonary function was alleged to be normal, although the reliability of this claim is considered doubtful in view of the severity of the clinical observations.

9.1.2 Other pentavalent vanadium compounds

Five male medical students received an oral administration of 100 or 125 mg diammonium oxy- tartratovanadate/day (approximately 1.7 mg/kg body weight per day, assuming 70 kg body weight) for 6 weeks (Curran et al., 1959). No overt evidence of toxicity was reported in any of the men. No change in complete blood counts, including platelets, routine urinalyses, blood urea nitrogen, blood glucose, serum cholesterol esters, serum alkaline phosphatase, serum transaminase, or serum bilirubin was reported throughout the study. No further investigations were conducted.

9.1.3 Tetravalent vanadium compounds

Vanadyl sulfate is apparently used by some weight- training athletes in an attempt to improve performance, as it has been claimed to lower blood cholesterol levels. A double-blind trial by Fawcett et al. (1996, 1997) investigated the effects of administration of vanadyl sulfate on haematological indices, blood viscosity, and biochemistry in weight-training athletes. The treatment group (11 males; 4 females) was orally administered 0.5 mg/kg body weight per day for 12 weeks, and a control group (12 males; 4 females) received placebo capsules. At the end of the study, there were no significant differences between the groups in terms of body weight, blood pressure, standard haematological indices, blood viscosity, or standard blood biochemistry measurements.

A group of 12 volunteers received 75 mg diammonium vanadotartrate/day orally for 2 weeks, followed by 125 mg/day for the remaining 5.5 months (Somerville & Davies, 1962). Two subjects withdrew due to "toxic gastrointestinal effects."

There was no significant effect on serum cholesterol levels. However, five patients had persistent upper abdominal pain, anorexia, nausea, and weight loss. These symptoms improved when dosing was stopped or reduced. Five men developed "green tongue" and one other pharyngitis with marginal ulceration of the tongue.

A group of six subjects was administered 50– 125 mg ammonium vanadyl tartrate/day orally for 45– 94 days (Dimond et al., 1963). No haematological or biochemical indication of toxicity and no effect on circulating lipids were reported. There were no other investigations conducted.

9.2 Clinical and epidemiological studies for occupational exposure

9.2.1 Vanadium pentoxide

Eye irritation has been reported in studies in vanadium workers (see Lewis, 1959; Zenz et al., 1962; Lees, 1980; Musk & Tees, 1982). Patch testing in workforces has produced two isolated reactions, although no skin irritation was reported in 100 human volunteers follow ing skin patch testing with 10% vanadium pentoxide in petrolatum. The underlying reason for the skin responses in workers is unclear (Motolese et al., 1993).

Zenz et al. (1962) reported on 18 workers exposed to varying degrees to vanadium pentoxide dust (mean particle size <5 µm) in excess of 0.5 mg/m3 (apparently measured over a 24-h period) during a pelletizing process. Three of the most heavily exposed men devel oped symptoms, including sore throat and dry cough. Examination of each on the third day revealed markedly inflamed throats and signs of intense persistent coughing, but no evidence of wheezing or rales. The three men also reported "burning eyes," and physical examination revealed slight conjunctivitis. Upon resumption of work after a 3-day exposure-free period, the symptoms returned within 0.5–4 h, with greater intensity than before, despite the use of respiratory protective equip ment. After 2 weeks of the process, all 18 workers, including those primarily assigned to office and labora tory duties, developed symptoms and signs of varying degrees, including nasopharyngitis, hacking cough, and wheezing. This study confirms that vanadium pentoxide exposure can produce respiratory and also eye irritation.

Lees (1980) reported signs of respiratory irritation (cough, respiratory wheeze, sore throat, rhinitis, and nosebleed) and eye irritation in a group of 17 boiler cleaners. However, as there was no control group and it was unclear whether other compounds were present, no conclusions can be drawn regarding the cause or significance of these symptoms. However, the findings are compatible with other studies on inhalation of vanadium pentoxide.

A study by Kiviluoto (1980), using a respiratory questionnaire, chest radiography, and tests of ventilatory function (FVC and FEV1), investigated 63 men who had worked at a factory refining vanadium pentoxide from magnetite ore for at least 4 months. These men were matched for age and smoking habit with 63 workers at a magnetite ore mine in the same area, presumably not exposed or negligibly exposed to vanadium pentoxide.

Overall, on the basis of pulmonary function tests and a questionnaire of respiratory symptomatology, there were no indications of vanadium-induced ill-health in this workforce.

A further study, in which haematological and biochemical analyses were performed, is reported in the same group of workers as above by Kiviluoto et al. (1981b). All the haematological results were within reference values, and there were no statistical differences between the groups. Although there were significant differences between control and exposed groups in serum concentrations of albumin, chloride ions, bilirubin, conjugated bilirubin, and urea, these were not clinically significant, as the magnitude of change was small, subject to interindividual variation, and liable to have arisen by chance.

Levy et al. (1984) studied respiratory tract irritation in a group of 74 boilermakers. Vanadium pentoxide fume in air was measured from various parts of the boiler and ranged between 0.05 and 5.3 mg/m3 (time period of measurement not stated). The boilermakers worked 10 h/day, 6 days/week, and reported symptoms after only a couple of days.

The incidence of respiratory tract symptomatology was high, a finding that is compatible with other studies on inhalation of vanadium pentoxide. However, it is difficult to draw firm conclusions from this study due to the potential for mixed exposures to have occurred (e.g., especially sulfur dioxide, but also chromium, nickel, copper, iron oxide, and carbon monoxide), and also no control group was utilized for comparison.

A study by Lewis (1959) investigated 24 men exposed to vanadium pentoxide for at least 6 months from two different centres. These were age-matched with 45 control subjects from the same areas. The level of exposure to vanadium pentoxide was between 0.2 and 0.92 mg/m3 (0.11 and 0.52 mg vanadium/m3; time period of measurement not stated). In the exposed group, 62.5% complained of eye, nose, and throat irritation (6.6% in control), 83.4% had a cough (33.3% in control), 41.5% produced sputum (13.3% in control), and 16.6% complained of wheezing (0% in control). Physical findings included wheezes, rales, or rhonchi in 20.8% (0% in controls), injection (i.e., hyperaemia) of the pharynx and nasal mucosa in 41.5% (4.4% in controls), and "green tongue" in 37.5% (0% in controls).

It is not clear what levels or duration of exposure were experienced by the workers who presented with symptoms. However, the findings reinforce the picture of exposure to vanadium pentoxide causing eye and respira tory tract effects.

A group of 69 workers in the Czech Republic was exposed for periods ranging from 0.5 to 33 years (mean duration of exposure 9.2 years) in the manufacture of vanadium pentoxide from slag rich in vanadium (Kucera et al., 1994). The concentration of vanadium in the ambient air at the work sites was 0.016–4.8 mg/m3. For comparison, a group of 33 adult subjects not exposed to vanadium was investigated to assess the influence of such exposure. The authors stated that there were no symptoms of adverse health effects related to vanadium reported in the workers, although it was unclear what investigations had been conducted to support this assertion.

Huang et al. (1989) conducted a clinical and radio logical investigation of 76 workers in a ferrovanadium works, who had worked in the plant between 2 and 28 years. In the exposed group, out of 71 examined, 89% had a cough (10% in controls), expectoration was seen in 53% (15% in controls), 38% were short of breath (0% in controls), and 44% had respiratory harshness or dry sibilant rale (0% in controls). Of 66 of the exposed group examined, hyposmia or anosmia was reported in 23% (5% in controls), congested nasal mucosa in 80% (13% in controls), erosion or ulceration of the nasal septum in 9% (0% in controls), and perforation of the nasal septum in 1 subject (0 in controls). Chest X-rays of all 76 exposed subjects revealed 68% with increased, coars ened, and contorted bronchovascular shadowing (23% in controls).

While exposure to vanadium compounds may have contributed to the clinical findings and symptoms reported, no firm conclusion can be drawn from this study in this regard, as mixed exposures are likely to have occurred, including possibly to hexavalent chro mium used in alloy production or chromium plating (some of the effects described, particularly nasal septum perforation, are consistent with chromium toxicity).

The case histories of four men were reported by Musk & Tees (1982). One worker was exposed to large amounts of dry ammonium vanadate dust over a 6-h period while shovelling powder into a bin. Within 2 h of commencing work, retro-orbital headache, epiphora (tears), dry mouth, and green discoloration of the tongue were reported. There was a marked green discoloration of the skin of the fingers (despite the use of gloves), scrotum, and upper legs. His nose was reported to be stuffy, and he was lethargic. The next day, his testicles were swollen and tender, and, on the third day after exposure, he developed wheezing, dyspnoea, and a cough productive of green sputum. He had several small haemoptyses over the following 2 weeks. Wheezing and dyspnoea persisted for about 1 month; chest symptoms were at their worst 3 weeks after the incident. On examination 6 weeks after the last exposure, he was asymptomatic, with the exception of a partially blocked left nostril and the reddened appearance of nasal mucosa. Chest examination revealed no abnormality. Pulmonary function assessment showed normal lung volume, forced expiratory flow rate, and gas transfer. He had a mild eosinophilia of the peripheral blood.

The other three workers also reported broadly similar findings (e.g., green discoloration of the tongue and skin, respiratory difficulties) associated with exposure to vanadium pentoxide.

In a further study of workers exposed to vanadium pentoxide, one worker exposed to up to 0.1 mg/m3 for 30 min/day on a regular basis displayed the characteristic "green tongue" associated with vanadium exposure (Kawai et al., 1989). This effect was not observed in the two other workers regularly working with vanadium pentoxide (albeit at much lower levels). The limited number of samples and people in this study precluded any assessment of a dose–response relationship for "green tongue."

A similar, but slight, impairment of pulmonary function (FEV1 reduced by less than 4%) was observed over a 4-week work period in a prospective study of a group of 26 boilermakers with personal exposures to around 0.0016–0.032 mg/m3 "vanadium" (form unspec ified) (Hauser et al., 1995). However, no firm conclu sions can be drawn owing to the mixed exposures that were likely to have been encountered and the small magnitude of the reported change. There was also a lack of exposure–response relationship.

Similarly, green tongue and irritation of the upper respiratory tract were reported in a group of 10 boiler maintenance workers (Todaro et al., 1991). Urinary vanadium levels were recorded, but there was no report ing of air monitoring values or indication of other substances that may have been present. A small range of blood biochemistry parameters was recorded for up to 2 years after a change in the work (which presumably led to reduced exposure), but no changes were observed. Overall, no useful conclusions can be drawn from this study.

A link between workers exposed to vanadium and asthma/bronchial hyperresponsiveness has been claimed (Irsigler et al., 1999). However, less than 1% of workers showed bronchial hyperresponsiveness. Although it was reported that some of these worked in a part of the factory with the highest vanadium exposures, it is unclear how many other men also worked there but were unaffected by exposure. Indeed, details of the numbers of men in various parts of the factory were not given. Also, the previous medical histories of the affected men are unclear. There does not appear to be a comparison with a suitably matched control group. Thus, no mean ingful conclusions can be drawn from this study.

9.2.2 Tetravalent vanadium compounds

There are no data available.

9.3 Epidemiological studies for general population exposure

Early correlational studies relating general concen trations of vanadium in the environment to mortality figures are summarized in IPCS (1988); no cause–effect relationships can be established from these studies, which give conflicting results. A single epidemiological study, where individual exposure could be assessed, has been conducted of general population exposure to dusts generated by a plant processing vanadium-rich slag. It is estimated that an area with a radius of 3 km was exposed to the dust from a plant in Mnisek in the Czech Republic; the population in this area was 4850. The study concen trated on children aged between 10 and 12 years, with sampling conducted over 2 years. Venous blood, saliva, hair, and fingernail clippings were collected from the children. Dust aerosol, ambient air, soil, and drinking- water were analysed from the local environment. Health status was assessed based on haematological parameters (blood cell and platelet counts, haematocrit, mean cor puscular volume, and haemoglobin), specific immunity (IgA, IgE, IgG, secretory IgA, IgM, transferrin, alpha-1- antitrypsin, beta-2-microglobulin), cellular immunity (phagocytosis of peripheral leukocytes, stimulation of T- lymphocyte mitogenic activity), cytogenic analysis (frequency of chromosome aberrations in peripheral lymphocytes, sister chromatid exchange), and serum lipids (cholesterol, triglycerides). Children from the exposed groups had lower red blood cell counts than controls, a decrease in levels of serum and secretory IgA, and a seasonal decrease in IgG. Marked differences between groups were seen in natural cell-mediated immunity, with significantly higher mitotic activity of T- lymphocytes in children from the immediate vicinity of the plant. A higher incidence of viral and bacterial infections was registered in children from the exposed locality. However, the study could not control for confounding by exposures to compounds other than vanadium. Cytogenetic analysis revealed no genotoxic effects. Vanadium levels in hair were elevated in children living close to the plant. In another group living farther away, those with parent(s) working at the plant had higher levels in hair than those whose parent(s) did not, indicating exposure in the home from dust trans ferred on working clothes (Kucera et al., 1992). The overall conclusion reached was that long-term exposure to vanadium had no negative impact on health; differ ences observed were within the range of normal values in all cases (Lener et al., 1998).

10. EFFECTS ON OTHER ORGANISMS
IN THE LABORATORY AND FIELD

10.1 Aquatic environment

The toxicity of vanadium to aquatic organisms is summarized in Table 5.

In six of seven lakes studied, the addition of vanadium at concentrations in the 2–165 × 10–7 mol/litre range decreased photosynthetic rates of phytoplankton. Simple correlation analysis revealed that only biomass and proportion of cyanobacteria were significantly correlated (P < 0.05) with the response to vanadium. The authors concluded that lakes characterized by high phytoplankton biomass, high proportion of cyano bacteria, and low proportion of Bacillariophyta and Chrysophyta are most vulnerable to inhibition of photosynthesis by vanadium (Nalewajko et al., 1995).

Ringelband & Karbe (1996) found that population growth in the brackish water hydroid Cordylophora caspia was significantly impaired at 2 mg vanadium/litre over a 10-day exposure period.

Fichet & Miramand (1998) observed a significant reduction in the development of normal oyster (Crassos trea gigas) larvae exposed to 0.05 mg vanadium/litre for 48 h. A significant reduction in pluteus development in urchin (Paracentrotus lividus) larvae was found at 0.1 mg/litre, but not at 0.05 mg/litre, over the same time period. In 8-day exposures, significant mortality was observed in brine shrimp (Artemia salina) larvae at 0.25 mg/litre.

Van der Hoeven (1991) found a 21-day no- observed-effect concentration (NOEC), based on off spring production in Daphnia magna, of 1.13 mg vanadium/litre.

Stendahl & Sprague (1982) reported weight- adjusted 7-day LC50s ranging from 1.9 to 6 mg vana dium/litre in tests at various levels of total hardness (30, 100, and 355 mg/litre) and pH (5.5–8.8). Toxicity decreased from low to high hardness by an average factor of 1.8. Toxicity was greatest at pH 7.7, and the predominating ion H2VO4 was apparently the most toxic one.

Hilton & Bettger (1988) fed juvenile rainbow trout (Oncorhynchus mykiss) a diet containing sodium ortho vanadate at concentrations ranging from 10.2 to 8960 mg vanadium/kg diet for 12 weeks. All levels of supple mented vanadium significantly reduced growth and feeding response in the trout. Feed avoidance and significantly increased mortality were reported at >493 mg/kg diet.

10.2 Terrestrial environment

Cannon (1963) reported detrimental effects on plants at aqueous vanadium concentrations of 10– 20 mg/litre; however, higher concentrations can be tolerated by legumes that use vanadium in the nitrogen fixation process.

The growth of flax and cabbage was reduced at a vanadium concentration of 0.5 mg/litre (nutrient solu tion), especially under conditions of low iron and phos phorus (Warington, 1954; Hara et al., 1976).

Vanadium can induce iron deficiency chlorosis (Cannon, 1963) and affect trace element nutrition (Warington, 1954; Wallace et al., 1977). Hewitt (1953) found that 5 mg vanadium/litre in hydroponic medium caused iron deficiency chlorosis in sugar beet plants, and growth was reduced by 30–50%.

In soil, the concentration of vanadium causing toxic effects in plants may range between 10 and 1300 mg/kg, depending on plant species, the form of vanadium, and soil type (Hopkins et al., 1977). Kaplan et al. (1990) found that vanadium concentrations of 80 mg/kg caused significant reductions in Brassica biomass in sandy soil; however, concentrations of up to 100 mg/kg had no effect in loamy sand. The differential response was attributed to greater accumulation of vanadium by plants grown in sand. Similarly, significant reductions in dry matter yield of shoots and roots of soybean were observed at 30 mg/kg in fluvo-aquic soil, whereas no effect was found at 75 mg/kg in oxisols derived from red sandstones in China (Wang & Liu, 1999).

Table 5: Toxicity of vanadium compounds to aquatic organisms.

Organism

End-point

Concentration (mg/litre)

Reference

Marine algae

 

 

 

Green alga Dunaliella marina

15-day LC50

0.5

Miramand & Ünsal, 1978

Marine diatom

Diatom Asterionella japonica

15-day LC50

2

Miramand & Ünsal, 1978

Freshwater invertebrates

Water flea Daphnia magna

48-h LC50

3.1

Allen et al., 1995

 

48-h LC50

4.1

Beusen & Neven, 1987

 

23-day LC50

2

Beusen & Neven, 1987

Naidid oligochaete Pristina leidyi

48-h LC50

30.8

Smith et al., 1991

Marine invertebrates

Hydroid Cordylophora caspia

10-day LC50

5.8

Ringelband & Karbe, 1996

Worm Nereis diversicolor

9-day LC50

10

Miramand & Ünsal, 1978

Mussel Mytilus galloprovincialis

9-day LC50

35

Miramand & Ünsal, 1978

Crab Carcinus maenus

9-day LC50

65

Miramand & Ünsal, 1978

Brine shrimp Artemia salina (larvae)

9-day LC50

0.2–0.3

Miramand & Fowler, 1998

Sea urchin Arbaccia lixula (pluteus)

72-h LC100

0.5

Miramand & Fowler, 1998

Freshwater fish

Rainbow trout Oncorhynchus mykiss

96-h LC50

6.4–22

Giles et al., 1979

(juvenile)

96-h LC50

11.4

Giles & Klaverkamp, 1982

(eyed egg)

96-h LC50

118

Giles & Klaverkamp, 1982

 

96-h LC50

5.2–13.2

Stendahl & Sprague, 1982

 

7-day LC50

2.4–5.6

Sprague et al., 1978

 

11-day LC50

1.99

Sprague et al., 1978

 

14-day LC50

1.95

Giles et al., 1979

Chinook salmon Oncorhynchus tshawytscha

96-h LC50

16.5

Hamilton & Buhl, 1990

Brook trout Salvelinus fontinalis

96-h LC50

7–24

Ernst & Garside, 1987

Flag fish Jordanella floridae (adult)

96-h LC50

11.2

Holdway & Sprague, 1979

(larvae)

28-day LC50

1.1–1.9

Holdway & Sprague, 1979

Colorado squawfish Ptychocheilus lucius (fry)

96-h LC50

7.8

Hamilton, 1995

(juvenile)

96-h LC50

3.8–4.3

Hamilton, 1995

Razorback sucker Xyrauchen texanus (fry)

96-h LC50

8.8

Hamilton, 1995

(juvenile)

96-h LC50

3.0–4.0

Hamilton, 1995

Bonytail Gila elegans (fry)

96-h LC50

5.3

Hamilton, 1995

(juvenile)

96-h LC50

2.2–5.1

Hamilton, 1995

Flannelmouth sucker Catostomus latipinnis (larvae)

96-h LC50

11.5

Hamilton & Buhl, 1997

Goldfish Carassius auratus

144-h LC50

2.5–8.1

Knudtson, 1979

Guppy Poecilia reticulata

96-h LC50

8

Beusen & Neven, 1987

 

144-h LC50

0.4–1.1

Knudtson, 1979

Zebrafish Brachydanio rerio

96-h LC50

4

Beusen & Neven, 1987

Freshwater teleost Nuria denricus

96-h LC50

2.6

Abbasi, 1998

Marine fish

Dab Limanda limanda

96-h LC50

27.8

Taylor et al., 1985

11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–response assessment

In animals, pentavalent vanadium has been shown to accumulate in the lung following repeated exposure. There is information suggesting that inorganic vanadium compounds are absorbed following inhalation and subsequently excreted via the urine with an initial rapid phase of elimination, followed by a slower phase, which presumably reflects the gradual release of vanadium from body tissues.

Oral studies indicate that vanadium compounds are poorly absorbed from the gastrointestinal tract. No dermal studies are available.

Absorbed vanadium in either pentavalent or tetravalent states is distributed mainly to the bone, liver, kidney, and spleen, and it is also detected in the testes. The main route of vanadium excretion is via the urine. The pattern of vanadium distribution and excretion indicates that there is potential for accumulation and retention of absorbed vanadium, particularly in the bone. One oral study indicates that tetravalent vanadium has the ability to cross the placental barrier to the fetus.

An LC67 of 1440 mg/m3 (800 mg vanadium/m3) has been reported following 1-h inhalation exposure of rats to vanadium pentoxide dust. Oral studies in rats and mice produced LD50 values in the range 10–160 mg/kg body weight (6–90 mg/kg body weight as vanadium) for vanadium pentoxide and other pentavalent vanadium compounds, whereas tetravalent vanadium compounds have LD50 values in the range 448–467 mg/kg body weight (90–94 mg/kg body weight as vanadium). No information is available concerning dermal toxicity.

Eye irritation has been reported in studies in vanadium workers. Patch testing in workforces has produced two isolated reactions. No skin irritation was reported in 100 human volunteers following skin patch testing with 10% vanadium pentoxide. No information is available from animal studies with regard to the potential of vanadium compounds to produce skin or eye irrita tion. Overall, the potential for vanadium and vanadium compounds to produce skin irritation on direct contact is unclear. No conventional animal skin sensitization studies have been reported.

The effects on the respiratory tract of single and repeated inhalation exposure (and combinations thereof) to pentavalent vanadium compounds have been investigated or reported in animals and humans. The data are of variable quality. No studies are available on tetra valent forms of vanadium.

Inhalation studies in primates reported changes in pulmonary function and inflammatory cell parameters following a 6-h exposure to 3 or 5 mg vanadium pentox ide aerosol/m3 (1.7 or 2.8 mg vanadium/m3). Subchronic exposure did not lead to an exacerbation of this acute responsivity or to a cellular immune response as mea sured in BAL fluid and also in serum. Furthermore, subchronic exposure to up to 0.5 mg/m3 (0.28 mg vanadium/m3) did not enhance bronchial reactivity to vanadium pentoxide or methacholine. Respiratory distress developed in three animals from a group of nine exposed to the intermittent peaks of 1.1 mg vanadium pentoxide/m3 (0.62 mg/m3 vanadium) for 2 days/week. A concentration of 1.0 mg vanadium pentoxide/m3 (0.56 mg vanadium/m3) did not produce respiratory tract toxicity in rats and mice following exposure for 6 h/day, 5 days/week, for 13 weeks. At 2 mg vanadium pentoxide/m3 (1 mg vanadium/m3) and above, dose-related toxicity to the respiratory tract has been observed in rodents, including hyperplasia and metaplasia of the respiratory epithelium and lung fibrosis and inflamma tion.

A study in human volunteers showed that a single 8-h exposure to 0.1 mg vanadium pentoxide dust/m3 leads to delayed but prolonged bronchial effects involv ing excessive production of mucus. The mechanism underlying this response is uncertain, as no subjective irritant symptoms were reported during exposure. At 0.25 mg/m3, a similar pattern of response was seen, with the addition of cough for some days post-exposure. Exposure to 1.0 mg/m3 produced persistent and pro longed coughing after 5 h. A no-effect level for bronchial effects was not identified in this study.

The workplace studies available lack information on the nature and extent of past occupational exposure and provide only limited information on exposures at the time of the study. There is the likelihood that mixed exposures may have occurred, although the appearance of green coloration of the tongue indicates that exposure to vanadium pentoxide is likely. The generally poor- quality data available indicate that repeated inhalation exposure to the dust and fume of vanadium pentoxide is associated with irritation of the eyes, nose, and throat. Wheeze and dyspnoea are commonly reported in work ers exposed to vanadium pentoxide dust and fume. Overall, there are insufficient data to reliably describe the exposure–response relationship for the respiratory effects of vanadium pentoxide dust and fume in humans.

Oral studies involving repeated exposure, although of poor quality, are available for both pentavalent and tetravalent forms of vanadium in both humans and animals, although vanadium pentoxide has not been studied. No dermal studies are available, although it is not expected that vanadium will be absorbed across the skin to any significant extent. The limitations of the repeated oral dosing studies are such that it is not pos sible to characterize a dose–response relationship for the toxicity of any form of vanadium in animals or in humans; one study in rats produced evidence of spleen and kidney toxicity with a drinking-water intake of 2.1 ppm (mg/litre) vanadium and above, as sodium metavanadate.

Pentavalent and tetravalent forms of vanadium have produced aneugenic effects in vitro. There is evi dence that these forms of vanadium as well as trivalent vanadium can also produce DNA/chromosome damage in vitro, both positive and negative results having emerged from the available studies. The weight of evidence from the available data suggests that vanadium compounds do not produce gene mutations in standard in vitro tests in bacterial or mammalian cells.

In vivo, both pentavalent and tetravalent vanadium compounds have produced clear evidence of aneuploidy in somatic cells. There is some limited evidence for vanadium compounds also being able to express clasto genic effects. Only one study is available on the potential of vanadium compounds to produce germ cell mutagen icity. A positive result was obtained in mice receiving vanadium pentoxide by intraperitoneal injection, indicat ing the potential for vanadium to act as a germ cell mutagen. However, the underlying mechanism for this effect (aneugenicity; clastogenicity) is uncertain. It is also unclear how these findings can be generalized to more realistic routes of exposure or to other vanadium compounds.

Although aneugenicity is, in principle, a form of genotoxicity that can have an identifiable threshold, the nature of the mutagenicity database on vanadium com pounds is such that it is not possible to clearly identify the threshold level, for any route of exposure relevant to humans, below which there would be no concern for potential mutagenic activity.

No useful information is available regarding the carcinogenic potential of any form of vanadium via any route of exposure in animals3 or in humans.

The potential for vanadium compounds to exert effects on fertility has been very poorly investigated. A fertility study in male mice involving exposure to sodium metavanadate in drinking-water suggests the possibility that oral exposure of male mice to sodium metavanadate at 60 and 80 mg/kg body weight directly caused a decrease in spermatid/spermatozoal count and in the number of pregnancies produced in subsequent matings. However, significant general toxicity, reflected in decreased body weight gain, was also evident at 80 mg/kg body weight.

There are a number of developmental studies on pentavalent and tetravalent vanadium compounds, and a consistent observation is that of skeletal anomalies. Interpretation of these studies is difficult because of unconventional routes of exposure and evidence of maternal toxicity that may itself contribute to the effects seen in pups.

11.1.2 Criteria for setting tolerable intakes or guidance values for vanadium pentoxide

The toxicological end-points of concern are genotoxicity and respiratory tract irritation. Vanadium pentoxide is considered to be a somatic and germ cell mutagen, and there is some, although not conclusive, evidence to indicate the involvement, at least in part, of aneugenicity. It is not possible to clearly identify the threshold level, for any route of exposure relevant to humans, below which there would be no concern for potential genotoxic activity. In addition, repeated inhalation exposure to the dust and fume of vanadium pentoxide is associated with irritation of the eyes, nose, and throat and impaired pulmonary function. Similarly, there are insufficient data to reliably describe the exposure–response relationship for the respiratory effects of vanadium pentoxide dust and fume in humans. Since it is not possible to identify a level of exposure that is without adverse effect, it is recommended that levels be reduced to the extent possible.

11.1.3 Sample risk characterization

Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encour aged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characteriza tion are provided in CICADs, whenever possible. These examples cannot be considered as representing all pos sible exposure situations, but are provided as guidance only. The reader is referred to EHC 170 (IPCS, 1994) for advice on the derivation of health-based tolerable intakes and guidance values.

The scenario chosen as a specific example is occu pational exposure in the United Kingdom. There are only two forms of vanadium of occupational significance in the United Kingdom — vanadium metal (impure and alloyed forms) and vanadium pentoxide. No toxicology data are available on metallic vanadium (valency state 0). There is no means of extrapolating data from vanadium compounds to predict the properties of vanadium metal. Therefore, in the absence of a hazard assessment on vanadium metal, no risk assessment can be per formed.

The other occupationally relevant form is vana dium pentoxide. Vanadium pentoxide is a demonstrable somatic and presumed germ cell mutagen and produces an unusual profile of respiratory tract effects. Delayed and persistent respiratory effects (production of mucus and cough) have been reported following human expo sure to 0.1 mg vanadium pentoxide dust/m3, although no threshold was established for these effects. Impaired pulmonary function is reported following repeated exposure to vanadium pentoxide dust and fume, and there are insufficient data to reliably describe the exposure–response relationship for the respiratory effects in humans. Thus, toxicity to the respiratory tract will be a concern at all levels of occupational exposure.

Inhalation is the dominant route of concern for vanadium pentoxide exposure. There is substantial absorption of inorganic vanadium compounds following inhalation exposure. Given the genotoxic properties of vanadium and the inability to identify a threshold, there is concern at every level of exposure.

There are no oral exposure data on vanadium pentoxide.

Following dermal exposure, it is unlikely that skin irritation or sensitization will be of concern in humans. Given the green staining of the skin that is occasionally seen as a result of excessive exposure to vanadium pentoxide, it would seem that there is potential for some, perhaps limited, dermal absorption. However, there are no data relating to potential systemic toxicity via dermal exposure. Given the overall lack of information in relation to dermal exposure, it is not possible to assess the risks to human health following exposure by this route.

11.1.4 Uncertainties

Overall, the toxicokinetic and toxicological data base on vanadium and vanadium pentoxide is limited, and attempts to utilize information from other inorganic vanadium compounds are not entirely satisfactory. Of particular concern is the limited understanding of the potential for dermal absorption and the potential long- term effects as a result of sequestration in body tissues such as bone. Furthermore, the significance of effects seen in developmental toxicity studies using vanadium pentoxide is not well understood. At present, studies are generally poorly reported or poorly conducted. Skeletal anomalies have been seen in a number of studies with pentavalent and tetravalent vanadium compounds, although it is difficult to ascertain the role of the severe maternal toxicity that has also been evident. It is plausible that the skeletal anomalies in pups may be related to the disturbance of calcium balance (Younes & Strubelt, 1991) and interference with phosphate metabolism.

11.2 Evaluation of environmental effects

Vanadium is found in both fresh water and sea water in a natural background range of approximately 1–3 µg/litre. Locally high concentrations of the metal, up to about 70 µg/litre, have been reported in fresh waters, often associated with leaching from volcanic lava flows and uranium deposits. Data on concentrations in surface waters influenced by industrial waste are few, but mainly fall within the natural range (up to about 65 µg/litre). A single early reported concentration in surface waters receiving industrial waste of 2 mg/litre may be unreli able.

Vanadium is an essential trace element in some organisms (e.g., nitrogen-fixing bacteria). Its essentiality in other organisms (e.g., for humans and other mammals) remains an open question.

Vanadium is bioaccumulated by a few species of biota, notably ascidians and some polychaete annelids. Most organisms show low concentrations of the metal. There is no evidence for biomagnification in food chains in marine organisms; there are no data for freshwater organisms.

Toxicity values for vanadium in freshwater and marine organisms generally range between 0.2 and 120 mg/litre. Reports of sublethal effects at around 10 µg/litre for algal photosynthesis, 50 µg/litre for oyster larval development, and 1130 µg/litre for Daphnia reproduction have been reported.

For natural waters, most toxic effects of vanadium occur only at concentrations substantially higher than those reported in the field. Most reported concentration in industrial areas are also substantially lower than those required to produce adverse effects. A single, possibly unreliable, older high value for an industrial scenario does exceed toxic concentrations (Fig. 1).

Figure 1

There are insufficient data on toxicity to terrestrial organisms to draw risk conclusions.

There are too few data to assess risk in specific industrial contexts.

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

A published review of vanadium is available (IPCS, 1988). Information on international hazard classification and labelling is included in the Inter national Chemical Safety Cards (ICSCs 0455 and 0596) reproduced in this document. The World Health Organization’s air quality guideline for vanadium is 1 µg/m3, which is based on a lowest-observed-adverse- effect level (LOAEL) of 20 µg/m3 from studies on occupationally exposed individuals, using an overall uncertainty factor of 20 (WHO, 1987).

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Zhang T, Yang Z, Zeng C, Gou X (1993b) A study on developmen tal toxicity of vanadium pentoxide in Wistar rats. Hua Hsi I Ko Ta Hsueh Hsueh Pao, 24:92–96.

Zhong B, Gu Z, Wallace W, Whong W, Ong T (1994) Genotoxicity of vanadium pentoxide in Chinese hamster V79 cells. Mutation research, 321:35–42.

APPENDIX 1 — SOURCE DOCUMENTS

HSE (in press) Vanadium pentoxide. Health and Safety Executive. Sudbury, Suffolk, HSE Books (Risk Assessment Document EH72/XX)

The author’s draft version is initially reviewed internally by a group of approximately 10 Health and Safety Executive experts, mainly toxicologists, but also involving other relevant disciplines, such as epidemiology and occupational hygiene. The toxicology section of the amended draft is then reviewed by toxicologists from the United Kingdom Department of Health. Subsequently, the entire Risk Assessment Document is reviewed by a tripartite advisory committee to the United Kingdom Health and Safety Commission, the Working Group for the Assessment of Toxic Chemicals (WATCH). This committee comprises experts in toxicology, occupational health, and hygiene from industry, trade unions, and academia.

The members of the WATCH committee at the time of the peer review were:

Mr Steve Bailey (Independent Consultant)

Professor Jim Bridges (Robens Institute, Guildford)

Mr Robin Chapman (Chemical Industries Association)

Dr Hilary Cross (Trade Unions Congress)

Mr David Farrar (Independent Consultant)

Dr Tony Fletcher (Trade Unions Congress)

Dr Ian Guest (Chemical Industries Association)

Dr Alastair Hay (Trade Unions Congress)

Dr Len Levy (Institute for Environment and Health, Leicester)

Dr Tony Mallet (Chemical Industries Association)

Mr Alan Moses (Chemical Industries Association)

Mr Jim Sanderson (Independent Consultant)

Dr Anne Spurgeon (Institute of Occupational Health, Birmingham)

IPCS (1988) Vanadium. Geneva, World Health Organization, International Programme on Chemical Safety, 170 pp. (Environmental Health Criteria 81)

A WHO Task Group on Environmental Health Criteria for Vanadium met in Moscow, USSR, from 30 March to 3 April 1987. The Task Group reviewed and revised the draft criteria document and made an evaluation of the risks for human health and the environment from exposure to vanadium

Copies of this document may be obtained from:

International Programme on Chemical Safety
World Health Organization
Geneva, Switzerland

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on vanadium pentoxide and other inorganic vanadium compounds was sent for review to institutions and organizations identified by IPCS after contact with IPCS national contact points and Participating Institutions, as well as to identified experts. Comments were received from:

M. Baril, International Programme on Chemical Safety/ Institut de Recherche en Santé et en Sécurité du Travail du Québec, Montreal, Quebec, Canada

R. Benson, Drinking Water Program, US Environmental Protection Agency, Denver, CO, USA

T. Berzins, National Chemicals Inspectorate, Solna, Sweden

R. Chhabra, Department of Health and Human Services, Research Triangle Park, NC, USA

P. Edwards, Protection of Health Division, Department of Health, London, United Kingdom

R. Hertel, Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany

M. Kiilunen, Finnish Institute of Occupational Health, Helsinki, Finland

J. Lener, National Institute of Public Health, Prague, Czech Republic

I. Mangelsdorf, Fraunhofer Institute, Hanover, Germany

H. Nagy, National Institute for Occupational Safety and Health, Washington, DC, USA

E. Ohanian, Office of Water, US Environmental Protection Agency, Washington, DC, USA

S.A. Soliman, Alexandria University, El-Shatby, Alexandria, Egypt

M. Sun, School of Public Health, West China University of Medical Sciences, Chengdu, Sichuan, People’s Republic of China

W.F. ten Berge, DSM, Heerlen, The Netherlands

P. Yao, Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Ministry of Health, Beijing, People’s Republic of China

K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umvelt und Gesundheit, Neuherberg, Oberschleissheim, Germany

APPENDIX 3 — CICAD FINAL REVIEW BOARD

Helsinki, Finland, 26–29 June 2000

Members

Mr H. Ahlers, Education and Information Division, National Institute for Occupational Safety and Health, Cincinnati, OH, USA

Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden

Dr R.M. Bruce, Office of Research and Development, National Center for Environmental Assessment, US Environmental Protection Agency, Cincinnati, OH, USA

Mr R. Cary, Health and Safety Executive, Liverpool, United Kingdom (Rapporteur)

Dr R.S. Chhabra, General Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Dr H. Choudhury, National Center for Environmental Assessment, US Environmental Protection Agency, Cincinnati, OH, USA

Dr S. Dobson, Centre for Ecology and Hydrology, Monks Wood, Abbots Ripton, United Kingdom (Chairman)

Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA

Dr R.F. Hertel, Federal Institute for Health Protection of Consumers and Veterinary Medicine, Berlin, Germany

Ms K. Hughes, Priority Substances Section, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada

Dr G. Koennecker, Chemical Risk Assessment, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany

Ms M. Meek, Existing Substances Division, Environmental Health Directorate, Health Canada, Ottawa, Ontario, Canada

Dr A. Nishikawa, Division of Pathology, Biological Safety Research Centre, National Institute of Health Sciences, Tokyo, Japan

Dr V. Riihimäki, Finnish Institute of Occupational Health, Helsinki, Finland

Dr J. Risher, Agency for Toxic Substances and Disease Registry, Division of Toxicology, US Department of Health and Human Services, Atlanta, GA, USA

Professor K. Savolainen, Finnish Institute of Occupational Health, Helsinki, Finland (Vice-Chairman)

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan

Dr S. Soliman, Department of Pesticide Chemistry, Faculty of Agriculture, Alexandria University, Alexandria, Egypt

Ms D. Willcocks, National Industrial Chemicals Notification and Assessment Scheme, Sydney, NSW, Australia

Observer

Dr R.J. Lewis (representative of European Centre for Ecotoxicology and Toxicology of Chemicals), Epidemiology and Health Surveillance, ExxonMobil Biomedical Sciences, Inc., Annandale, NJ, USA

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary)

Dr P.G. Jenkins, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

Dr M. Younes, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland

INTERNATIONAL CHEMICAL SAFETY CARDS

VANADIUM TRIOXIDE ICSC:0455

VANADIUM PENTOXIDE ICSC:0596

RÉSUMÉ D’ORIENTATION

Ce CICAD consacré au pentoxyde de vanadium et à d’autres dérivés minéraux du vanadium repose sur un bilan des problèmes sanitaires (principalement en milieu professionnel) préparé par le Health and Safety Executive du Royaume-Uni (HSE, sous presse). Ce document vise principalement les voies d’exposition à prendre en considération sur les lieux de travail, mais contient également des informations relatives à l’environnement. La bibliographie utilisée va jusqu’à novembre 1998. Un dépouillement complémentaire de la litterature à été effectué jusqu’à mai 1999 afin de recueillir toutes données supplémentaires publiées après l’achèvement de ce document. En ce qui concerne les données environnementales, on a utilisé la monographie publiée dans la série Critères d’hygiène de l’environne ment (IPCS, 1988). Comme on ne disposait d’aucun document plus récent sur le devenir et les effets environnementaux de ces composés, il a été procédé à une recherche bibliographique afin d’obtenir un complément d’information. Des renseignements sur la nature de l’examen par des pairs et sur les sources documentaires existantes sont données à l’appendice 1. L’appendice 2 contient des informations sur l’examen par des pairs du présent CICAD. Ce CICAD a été approuvé en tant qu’évaluation internationale lors de la réunion du Comité d’évaluation finale qui s’est tenue à Helsinki (Finlande) du 26 au 29 juin 2000. La liste des participants à cette réunion figure à l’appendice 3. Les fiches internationales sur la sécurité chimique du trioxyde (ICSC 0455) et du pentoxyde de vanadium (ICSC 0596) établies par le Programme international sur la sécurité chimique (IPCS, 1999a,b) sont également reproduites dans le présent CICAD.

Le vanadium (No CAS 7440-62-2) est un métal ductile, de couleur gris-argent, qui peut exister sous divers degrés d’oxydation : -1, 0, +2, +3, +4 et +5. Sa forme commerciale la plus courante est le pentoxyde V2O5 (No CAS 1314-62-1) correspondant à la valence +5 et qui se présente sous la forme d’une poudre cristalline qui peut être jaune, rouge ou verte.

Le vanadium est un élément abondant et très largement répandu. Le minerai est extrait en Afrique du Sud, en Russie et en Chine. Lors de la fusion du minerai de fer, il se forme un laitier contenant du pentoxyde de vanadium que l’on utilise pour la production du métal. On prépare également le pentoxyde de vanadium en l’extrayant par solvant des minerais d’uranium ou par grillage des sels présents dans les résidus de chaudières ou dans ceux des usines de production de phosphore élémentaire. La combustion des huiles lourdes dans les chaudières et les fours conduit à la formation de résidus solides, de suie, de tartre et de cendres volantes qui contiennent du pentoxyde de vanadium.

On estime que chaque année, quelque 8,4 tonnes de vanadium sont libérées dans l’atmosphère à partir de sources naturelles (valeurs extrêmes : 1,5-49,2 tonnes). La source de pollution de l’environnement par le vanadium qui est de loin la plus importante est constituée par la combustion du pétrole et du charbon; environ 90 % des quelque 64 000 tonnes de vanadium libérées dans l’atmosphère chaque année par des phénomènes naturels ou par l’activité humaine ont en effet cette source pour origine.

Dans l’environnement, le vanadium offre une chimie complexe. Dans les minéraux, le degré d’oxy dation du vanadium peut être de +3, +4 ou +5. Par dissolution dans l’eau, V3+ et V4+ sont rapidement oxydés au degré +5, qui constitue la forme la plus commune du vanadium dans l’environnement. En solution, cette forme correspond aux vanadates, qui peuvent se polymériser

(pour donner principalement des dimères et des trimères), en particulier en solution concentrée. Dans les tissus, ce sont les formes V3+ et V4+ qui prédominent, du fait que le milieu est largement réducteur; dans le plasma, c’est V5+ qui prédomine.

Le vanadium est probablement essentiel pour les systèmes enzymatiques qui fixent l’azote atmosphérique (bactéries) et il est concentré par certains organismes comme les tuniciers, quelques annélidés de la classe des polychètes et certaines algues microscopiques. On ne sait cependant pas avec certitude quelle est sa fonction chez ces organismes. La question de savoir si le vanadium est essentiel pour d’autres organismes reste posée. Rien n’indique qu’il s’accumule ou subisse une bioamplifi cation dans la chaîne alimentaire des organismes marins, qui constituent le groupe le mieux étudié.

Le lessivage du vanadium dans les différents profils pédologiques est très limité.

On a signalé la présence de fortes concentrations de vanadium dans l’air à proximité de sources indus trielles et de feux d’hydrocarbures. En ce qui concerne les dépôts, des valeurs annuelles de 0,1 à 10 kg/ha sont caractéristiques des zones urbaines où sont implantées des sources importantes de vanadium; ces valeurs vont de 0,01 à 0,1 kg/ha par an dans les zones rurales ou urbaines où n’existent pas de sources de vanadium et s’abaissent à <0,001-0,01 kg/ha par an dans les régions reculées.

Dans la plupart des eaux douces de surface, la concentration du vanadium est inférieure à 3 µg/litre; des valeurs plus élevées, pouvant atteindre 70 µg/litre ont été relevées dans des zones où existent d’importantes sources géochimiques. On ne possède guère de données sur la teneur en vanadium des eaux proches de sites industriels; la plupart des publications font état de valeurs correspondant sensiblement aux concentrations naturelles les plus fortes. Les concentrations pélagiques vont de 1 à 3 µg/litre, dans les sédiments, la concen tration va de 20 à 200 µg/g, les valeurs les plus élevées étant relevées dans la zone littorale.

Quelques organismes concentrent le vanadium, et la concentration de ce métal peut atteindre 10 000 µg/g chez les ascidies et 786 µg/g chez les polychètes. Chez la plupart des êtres vivants, la concentration est, d’une façon générale, inférieure à 50 µg/g et habituellement beaucoup plus faible.

L’exposition par la voie alimentaire est estimée chez l’Homme à 11-30 µg par jour. Dans l’eau de boisson, la concentration va jusqu’à 100 µg/litre. Dans certaines nappes souterraines qui alimentent les sources d’eau potable, on a relevé des concentrations de vanadium supérieures à 50 µg/litre. L’eau minérale en bouteille peut en contenir davantage.

On possède des données toxicocinétiques limitées selon lesquelles chez l’Homme, le vanadium est résorbé après inhalation puis excrété dans l’urine, l’élimination se faisant en deux phases, une phase initiale rapide puis une phase plus lente qui correspond vraisemblablement à la libération progressive du vanadium retenu dans les tissus. Après administration par voie orale, le vanadium IV est mal résorbé dans les voies digestives. On ne dispose pas d’études sur l’absorption percutanée.

L’expérimentation animale montre qu’après exposition par la voie respiratoire ou orale le vanadium absorbé sous des formes correspondant aux degrés d’oxydation IV ou V se répartit principalement dans les os, le foie, les reins et la rate. On en a également décelé la présence dans les testicules. La principale voie d’excrétion est la voie urinaire. Le mode de distribution et d’excrétion du vanadium montre qu’une fois résorbé, le métal peut s’accumuler et être retenu, notamment dans les os. Il a également été montré que le vanadium tétravalent est capable de franchir la barrière foeto- placentaire.

Dans la seule étude de toxicité aiguë par inhalation qui soit disponible, on a obtenu une CL67 de 1440 mg/m3 (800 mg de vanadium par m3) pour des rats exposés pendant 1 h à de la poussière de pentoxyde de vanadium. L’exposition de rats et de souris par la voie orale a permis d’obtenir une DL50 qui se situait entre 10 et 160 mg/kg de poids corporel dans le cas du pentoxyde et d’autres dérivés du vanadium V, alors qu’avec les dérivés du vanadium IV, les valeurs étaient comprises entre 448 et 467 mg/kg de poids corporel. On ne dispose d’aucune donnée sur la toxicité du vanadium par la voie percutanée.

Des études sur des travailleurs de l’industrie du vanadium ont mis en évidence des cas d’irritation oculaire. Chez 100 volontaires à qui on avait posé un timbre cutané contenant 10 % de pentoxyde de vanadium, on n’a pas constaté d’irritation cutanée, mais un test analogue effectué sur des travailleurs a donné lieu a deux réactions isolées. L’expérimentation animale n’a permis de dégager aucun résultat clair concernant le pouvoir irritant oculaire ou cutané des composés du vanadium ou leur action sensibilisatrice au niveau de l’épiderme.

Dans un groupe de volontaires exposés pendant 8 h à de la poussière contenant 0,1 mg de vanadium par m3, on a observé des effets retardés mais prolongés sur les bronches qui se manifestaient notamment par une production excessive de mucus. A la concentration de 0,25 mg/m3, la réaction était analogue, avec en plus de la toux qui s’est prolongée pendant les quelques jours suivant l’exposition. A la concentration de 1,0 mg/m3, la toux est devenue permanente au bout de cinq heures et s’est maintenue longtemps. Il ne ressort de cette étude aucune valeur de la dose maximale sans effet bronchique.

L’inhalation répétée de vapeurs et de poussières de pentoxyde de vanadium entraîne une irritation des yeux, du nez et de la gorge. Chez les travailleurs exposés à ces vapeurs et à ces poussières, on observe couramment une respiration sifflante et de la dyspnée. Globalement , on ne dispose pas de données suffisantes pour établir de façon fiable une relation exposition-réponse relative aux effets respiratoires des poussières et des vapeurs de vanadium chez l’Homme.

Les dérivés correspondant aux valences 4 et 5 du vanadium ont des effets aneugènes in vitro en présence ou en l’absence d’activation métabolique. On est fondé à penser que ces dérivés ainsi que ceux du vanadium III sont capables de provoquer des lésions de l’ADN et des chromosomes in vitro, mais les études existantes donnent à cet égard des résultats qui sont tantôt positifs, tantôt négatifs. Il semble, à la lumière des données disponibles, que les composés du vanadium ne soient pas mutagènes , à en juger par les tests classiques de mutagénicité in vitro sur des cellules bactériennes ou mammaliennes.

In vivo, une aneuploïdie des cellules somatiques s’observe clairement après exposition à des dérivés du vanadium IV et du vanadium V selon différentes voies. Comme dans le cas des études in vitro, les tests destinés à mettre en évidence des effets clastogènes donnent des résultats mitigés et dans l’ensemble, on reste dans l’incertitude quand au pouvoir clastogène du vanadium vis-à-vis des cellules somatiques. Par contre, on a obtenu un résultat positif dans le cas des cellules germinales de souris à qui on avait injecté du pentoxyde de vanadium par voie intrapéritonéale. Le mécanisme qui est à la base de ces effets (aneugènes et clastogènes) n’est pas connu avec certitude. On ignore également dans quelle mesure ces résultats peuvent être étendus à d’autres voies d’exposition et à d’autres dérivés du vanadium.

Etant donné la nature de la base de données sur la génotoxicité du pentoxyde de vanadium et d’autres dérivés de cet élément, il n’est pas possible de définir sans ambiguité le seuil au-dessous duquel, quelle que soit la voie d’exposition à prendre en considération chez l’Homme, il n’y aurait pas lieu de craindre un risque d’activité génotoxique.

On ne possède aucune information utile sur le pouvoir cancérogène du vanadium chez l’Homme ou l’animal, sous quelque forme et par quelque voie d’exposition que ce soit. 4

Une étude de fécondité sur des souris mâles dont l’eau de boisson contenait du métavanadate de sodium, incite à penser que l’exposition des animaux à ce composé aux doses de 60 et 80 mg/kg de poids corporel a été la cause directe d’une diminution du nombre de spermatides et de spermatozoïdes ainsi que du nombre de grossesses consécutives à l’accouplement de ces mâles avec des souris femelles. Il est vrai toutefois, qu’à la dose de 80 mg/kg p.c., la toxicité générale du composé était également évidente (diminution du gain de poids).

Un certain nombre d’études ont été consacrées à l’action des composés du vanadium IV et V sur le développement. Elles révèlent systématiquement la présence d’anomalies du squelette. Les résultats de ces études sont difficiles à interpréter car les voies d’exposition étaient inhabituelles et la toxicité manifeste des composés pour les mères a pu influer sur les effets constatés dans la progéniture.

Chez l’Homme les points d’aboutissement de l’action toxique à prendre en considération sont la génotoxicité et l’irritation des voies respiratoires. Comme il n’est pas possible de définir le seuil de concentration à partir duquel il n’y a plus d’effets toxiques, il est recommandé de réduire le plus possible le niveau d’exposition.

Pour les organismes aquatiques, les valeurs de la CL50 vont de 0,2 à environ 120 mg/litre, la majorité des valeurs se situant entre 1 et 12 mg par litre. D’une point de vue écotoxicologique, il serait plus judicieux de prendre en considération l’action sur le développement des huîtres (sensiblement réduit à 0,05 mg de vanadium par litre) et sur la reproduction des daphnies (concen tration sans effet observable à 21 jours : 1,13 mg/litre). Peu d’études ont été consacrés aux organismes terrestres. La plupart de celles qui portent sur des végétaux concernent des cultures hydroponiques sur lesquelles on observe des effets à partir de 5 mg/litre. Les résultats de ces études sont difficiles à transposer aux plantes cultivées en pleine terre.

Dans les divers compartiments de l’environnement, la concentration est sensiblement inférieure aux valeurs toxiques. On ne possède que peu de données sur la concentration au voisinage des sites industriels et il n’est pas possible de procéder à une évaluation du risque sur cette base. Quoi qu’il en soit, les valeurs dont il est fait état semble correspondre aux concentrations naturelles les plus fortes, ce qui indique que le risque devrait être faible. Des mesures sur les lieux mêmes s’imposent dans chaque cas particulier.

RESUMEN DE ORIENTACIÓN

Este CICAD sobre el pentóxido de vanadio y otros compuestos inorgánicos de vanadio se basó en un examen de los problemas relativos a la salud humana (fundamentalmente profesionales) preparado por la Dirección de Salud y Seguridad del Reino Unido (HSE, en prensa). Este examen se concentra en las vías de exposición de interés para el entorno ocupacional, pero contiene también información sobre el medio ambiente. Figuran los datos identificados hasta noviembre de 1998. Se realizó una ulterior búsqueda bibliográfica hasta mayo de 1999 para localizar cualquier información nueva que se hubiera publicado desde la terminación del examen. Se utilizó una monografía de los Criterios de Salud Ambiental (IPCS, 1988) como documento original para la información ambiental. Puesto que no se disponía de documentos originales más recientes sobre el destino y los efectos en el medio ambiente, se realizó una búsqueda bibliográfica para obtener más información. La información acerca del carácter del examen colegiado y la disponibilidad de los documentos originales figura en el apéndice 1. La información sobre el examen colegiado de este CICAD aparece en el apéndice 2. Este CICAD se aprobó como evaluación internacional en una reunión de la Junta de Evaluación Final celebrada en Helsinki (Finlandia) del 26 al 29 de junio de 2000. La lista de participantes en esta reunión figura en el apéndice 3. Las Fichas internacionales de seguridad química sobre el trióxido de vanadio (ICSC 0455) y el pentóxido de vanadio (ICSC 0596), prepara das por el Programa Internacional de Seguridad de las Sustancias Químicas (IPCS, 1999a,b), también se reproducen en el presente documento.

El vanadio (CAS Nş 7440-62-2) es un metal gris plateado suave que puede existir en varios estados de oxidación diferentes: -1, 0, +2, +3, +4 y +5. La forma comercial más común es el pentóxido de vanadio (V2O5; CAS Nş 1314-62-1) y en este estado pentavalente es un polvo cristalino rojo-amarillento o verde.

El vanadio es un elemento abundante, con una distribución muy amplia; se extrae en Sudáfrica, Rusia y China. Durante la fusión de la mena de hierro se forma escoria de vanadio con pentóxido de vanadio, que se utiliza para la producción de vanadio metálico. El pentóxido de vanadio se obtiene también por extracción con disolventes a partir de menas de uranio y mediante un proceso de calcinación de las sales de los residuos de las calderas o de los residuos de las instalaciones de fosfato elemental. Durante la combustión de fueloil en calderas y hornos, hay pentóxido de vanadio en los residuos sólidos, el hollín, las incrustaciones de las calderas y las cenizas volátiles.

Las emisiones atmosféricas a partir de fuentes naturales en todo el mundo se han estimado en 8,4 tone ladas al año (gama de 1,5-49,2 toneladas). La fuente más importante de contaminación ambiental por vanadio es con diferencia la combustión de petróleo y de carbón; alrededor del 90% de las aproximadamente 64 000 tone ladas de vanadio que se liberan en la atmósfera cada año a partir de fuentes tanto naturales como antropogénicas procede de la combustión del petróleo.

La química del vanadio en el medio ambiente es compleja. En los minerales, el estado de oxidación del vanadio puede ser +3, +4 ó +5. La disolución en agua oxida rápidamente el V3+ y el V4+ al estado pentavalente, que es la forma más común del metal en el medio ambiente. El vanadato, compuesto pentavalente en solución, se puede polimerizar (principalmente a las formas diméricas o triméricas), en particular a concen traciones más altas de las sales. En los tejidos de los organismos predominan el V3+ y el V4+, debido en gran parte a las condiciones de reducción; en el plasma predomina el V5+.

El vanadio es probablemente esencial para los sistemas enzimáticos que fijan el nitrógeno de la atmós fera (bacterias) y lo concentran algunos organismos (tunicados, algunos anélidos poliquetos, algunas micro algas), pero no se conoce bien su función en estos organismos. Sigue siendo una cuestión abierta si el vanadio es o no esencial para otros organismos. No hay pruebas de acumulación o bioamplificación en las cadenas alimentarias de los organismos marinos, que forman el grupo mejor estudiado.

Hay una lixiviación muy limitada del vanadio a través de los perfiles del suelo.

Se han notificado niveles más altos de vanadio en el aire próximo a fuentes industriales e incendios de hidrocarburos. Las tasas de deposición representativas son de 0,1-10 kg/ha al año para zonas urbanas afectadas por fuentes locales importantes, de 0,01-0,1 kg/ha al año para las zonas rurales y urbanas que no tienen una fuente local importante y <0,001-0,01 kg/ha al año para las zonas remotas.

La mayor parte de las aguas superficiales dulces contienen menos de 3 µg de vanadio/litro; se han notificado niveles más altos, de hasta unos 70 µg/litro, en zonas con fuentes geoquímicas grandes. Los datos sobre los niveles de vanadio en aguas superficiales próximas a actividades industriales son escasos; la mayoría de los informes parecen indicar niveles aproximadamente iguales a los naturales más elevados. Las concentraciones en el agua marina en mar abierta oscilan entre 1 y 3 µg/litro y en los sedimentos van de 20 a 200 µg/g; los niveles más altos se observan en los sedimentos costeros.

Algunos organismos concentran vanadio en can tidades que ascienden hasta 10 000 µg/g en las ascidias y 786 µg/g en los anélidos poliquetos. La mayoría de los organismos suelen contener menos de 50 µg/g y normal mente concentraciones mucho más bajas.

Las estimaciones de la exposición total de las personas en los alimentos oscilan entre 11 y 30 µg/día. Los niveles en el agua de bebida ascienden hasta 100 µg/litro. Algunas fuentes de agua freática que abastecen de agua potable muestran concentraciones superiores a 50 µg/litro. Los niveles en el agua de manantial embotellada pueden ser más altos.

En las personas, la limitada información tóxico cinetica disponible parece indicar que se absorbe vanadio tras la inhalación y luego se excreta en la orina con una fase inicial de eliminación rápida, seguida de una fase más lenta, que posiblemente se debe a la eliminación gradual de vanadio de los tejidos del organismo. Tras la administración oral, la absorción de vanadio tetravalente a partir del sistema gastrointestinal es escasa. No se disponía de estudios cutáneos.

En estudios de inhalación y de administración oral en animales de laboratorio, el vanadio absorbido en los estados pentavalente o tetravalente se distribuye funda mentalmente en los huesos, el hígado, el riñón y el bazo, y también se detecta en los testículos. La vía principal de excreción del vanadio es a través de la orina. Su pauta de distribución y excreción indica que es posible la acumulación y retención del vanadio absorbido, sobre todo en los huesos. Hay pruebas de que el vanadio tetravalente puede atravesar la barrera placentaría y llegar al feto.

En el único estudio de inhalación aguda disponible se notificó una CL67 de 1440 mg/m3 (800 mg de vanadio/m3) tras la exposición de ratas a polvo de pentóxido de vanadio durante una hora. En estudios de administración oral en ratas y ratones se obtuvieron valores de la DL50 del orden de 10-160 mg/kg de peso corporal para el pentóxido de vanadio y otros com puestos de vanadio pentavalente, mientras que para los compuestos de vanadio tetravalente los valores de la DL50 son del orden de 448-467 mg/kg de peso corporal. No hay información relativa a la toxicidad cutánea.

En estudios realizados con trabajadores del vana dio se ha notificado irritación ocular. No se informó de irritación cutánea en 100 voluntarios humanos tras la prueba del parche cutáneo con un 10% de pentóxido de vanadio, aunque la prueba del parche realizada en los trabajadores produjo dos reacciones aisladas. No hay información clara disponible de estudios en animales con respecto al potencial de los compuestos de vanadio para producir irritación cutánea u ocular o bien sensi bilización cutánea.

En un grupo de voluntarios humanos, una expo sición aislada de ocho horas a 0,1 mg de polvo de pentóxido de vanadio/m3 produjo efectos bronquiales retardados, pero prolongados, con una producción excesiva de moco. Con 0,25 mg/m3 se observó una pauta de respuesta semejante, con la adición de tos durante algunos días después de la exposición. La exposición a 1,0 mg/m3 produjo una tos persistente y prolongada después de cinco horas. En este estudio no se identificó un nivel sin efectos para los trastornos bronquiales.

La exposición por inhalación repetida al polvo y el humo de pentóxido de vanadio está asociada con la irritación de los ojos, la nariz y la garganta. En los trabajadores expuestos al polvo y el humo de pentóxido de vanadio se suelen notificar jadeo y disnea. En con junto, no hay datos suficientes que permitan describir de manera fidedigna la relación exposición-respuesta para los efectos respiratorios del polvo y el humo de pen tóxido de vanadio en las personas.

Las formas pentavalentes y tetravelentes del vanadio han provocado efectos aneugénicos in vitro con activación metabólica y sin ella. Hay pruebas de que estas formas de vanadio, así como el vanadio trivalente, también pueden producir in vitro daños en el ADN/ cromosomas, habiéndose obtenido en los estudios disponibles resultados tanto positivos como negativos. El valor probatorio de los datos disponibles parece indicar que los compuestos de vanadio no producen mutaciones genéticas en pruebas normalizadas in vitro en células de bacterias o de mamíferos.

In vivo, tanto los compuestos de vanadio penta valentes como los tetravalentes han dado pruebas manifiestas de aneuploidía de las células somáticas tras la exposición mediante varias vías diferentes. Las pruebas de que los compuestos de vanadio también pueden producir efectos clastogénicos son desiguales, al igual que en los estudios in vitro, y la posición global sobre la clastogenicidad en las células somáticas es incierta. Se obtuvo un resultado positivo en células germinales de ratones a los que se administró pentóxido de vanadio por inyección intraperitoneal. Sin embargo, hay dudas acerca del mecanismo en el que se basa este efecto (aneugenicidad; clastogenicidad). Tampoco está claro cómo se pueden generalizar estos resultados a vías de exposición más realistas o a otros compuestos de vanadio.

Las características de la base de datos sobre la genotoxicidad del pentóxido de vanadio y otros com puestos de vanadio son tales que no es posible identi ficar claramente el nivel umbral para ninguna vía de exposición de interés para el ser humano por debajo del cual no habría que preocuparse por la posible actividad genotóxica.

No se dispone de información útil sobre el potencial carcinogénico de ninguna de las formas de vanadio por ninguna de las vías de exposición para los animales5 o las personas.

Un estudio de la fecundidad en ratones machos, con exposición al metavanadato de sodio en el agua de bebida, parece indicar la posibilidad de que la expo sición oral de los ratones machos a este compuesto a concentraciones de 60 y 80 mg/kg de peso corporal causara directamente una disminución del recuento de espermátidas/espermatozoides y del número de gesta ciones tras el apareamiento. Sin embargo, también se pudo observar una toxicidad general significativa (disminución del aumento del peso corporal) a 80 mg/kg de peso corporal).

Hay algunos estudios sobre los efectos de los compuestos de vanadio pentavalente o tetravalente en el desarrollo, con una observación sistemática de anoma lías esqueléticas. La interpretación de estos estudios es difícil, debido a las vías de exposición no tradicionales utilizadas y a que hay pruebas de toxicidad materna, la cual podría contribuir por sí misma a los efectos detec tados en las crías.

Los efectos toxicológicos finales motivo de pre ocupación para las personas son la genotoxicidad y la irritación de las vías respiratorias. Puesto que no es posible determinar un nivel de exposición sin efectos adversos, se recomienda reducir los niveles en la medida de lo posible.

Los valores de la CL50 para la toxicidad aguda de organismos acuáticos oscila entre 0,2 y unos 120 mg/li tro, aunque para la mayoría están entre 1 y 12 mg/litro. Otros efectos finales importantes desde el punto de vista ecotoxicológico se observaron en el desarrollo de las larvas de ostras (reducción significativa con 0,05 mg de vanadio/litro) y en la reproducción de Daphnia (con centración sin efectos observados en 21 días con 1,13 mg/litro). Son pocos los estudios terrestres. La mayoría de los estudios en plantas se han realizado en cultivos hidropónicos, donde se detectaron efectos a concentraciones de 5 mg/litro y superiores; estos estudios son difíciles de interpretar en relación con las plantas cultivadas en el suelo.

Las concentraciones en los compartimentos del medio ambiente son notablemente inferiores a las concentraciones tóxicas notificadas. Se dispone de pocos datos sobre las concentraciones en lugares industriales específicos y no es posible realizar una evaluación del riesgo sobre esta base. Sin embargo, las concentraciones notificadas parecen ser semejantes a las naturales más altas, lo que parece indicar que el riesgo sería bajo. Se deben realizar mediciones locales para evaluar el riesgo en cualquier circunstancia determinada.

FOOTNOTES:

1 International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: derivation of guidance values for health-based exposure limits. Geneva, World Health Organization (Environmental Health Criteria 170)

2 The authors of this document are aware that a 2-year inhala tion bioassay in rodents has recently been completed at the US National Toxicology Program. However, results are not avail able at this time.

3 The authors of this document are aware that a 2-year inhala tion bioassay in rodents has recently been completed at the US National Toxicology Program. However, results are not avail able at this time.

4 Les auteurs de ce document ont connaissance d’une étude au cours de laquelle on a fait inhaler pendant 2 ans des dérivés du vanadium à des rongeurs. Cette étude vient de s’achever aux Etats-Unis dans le cadre du National Toxicology Program et les résultats n’en sont pas encore disponibles.

5 Los autores de este documento tienen conocimiento de que recientemente se ha completado en el Programa Nacional de Toxicología de los Estados Unidos una biovaloración por inhalación de dos años en roedores. Sin embargo, en este momento no están disponibles todavía los resultados.



    See Also:
       Toxicological Abbreviations