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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 Note that the layout and pagination of this pdf file are not identical to the printed CICAD 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
Transcript

This report contains the collective views of an international group of experts and does notnecessarily represent the decisions or the stated policy of the United Nations EnvironmentProgramme, the International Labour Organization, or the World Health Organization.

Concise International Chemical Assessment Document 29

VANADIUM PENTOXIDE ANDOTHER INORGANIC VANADIUM COMPOUNDS

Note that the layout and pagination of this pdf file are not identical to the printed CICAD

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

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

World Health OrganizationGeneva, 2001

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint ventureof 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 thescientific basis for assessment of the risk to human health and the environment from exposure tochemicals, through international peer review processes, as a prerequisite for the promotion of chemicalsafety, and to provide technical assistance in strengthening national capacities for the sound managementof chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) wasestablished 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 andResearch, and the Organisation for Economic Co-operation and Development (ParticipatingOrganizations), following recommendations made by the 1992 UN Conference on Environment andDevelopment to strengthen cooperation and increase coordination in the field of chemical safety. Thepurpose of the IOMC is to promote coordination of the policies and activities pursued by the ParticipatingOrganizations, jointly or separately, to achieve the sound management of chemicals in relation to humanhealth 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 assessment3.Environmental exposure I.International Programme on Chemical SafetyII.Series

ISBN 92 4 153029 4 (NLM Classification: QV 290) ISSN 1020-6167

The World Health Organization welcomes requests for permission to reproduce or translate itspublications, in part or in full. Applications and enquiries should be addressed to the Office of Publications,World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information onany changes made to the text, plans for new editions, and reprints and translations already available.

©World Health Organization 2001

Publications of the World Health Organization enjoy copyright protection in accordance with theprovisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the Secretariat of the World Health Organizationconcerning the legal status of any country, territory, city, or area or of its authorities, or concerning thedelimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products aredistinguished by initial capital letters.

The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany,provided financial support for the printing of this publication.

Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10

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TABLE OF CONTENTS

FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3. ANALYTICAL METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

3.1 Workplace air monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.2 Biological monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.3 Environmental monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . . . . . . . . . . . . . . . . . . . . 9

5.1 Chemical speciation of vanadium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95.2 Essentiality of vanadium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95.3 Bioaccumulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

5.4 Leaching and bioavailability in soils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6.1 Environmental levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.1.1 Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106.1.2 Surface waters and sediments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.1.3 Biota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.1.4 Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

6.2 Human exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS ANDHUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . 14

8.1 Single exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.1.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8.1.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.1.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.1.4 Trivalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8.2 Irritation and sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158.3 Effects of inhaled vanadium compounds on the respiratory tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168.4 Other short-term exposure studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

8.4.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178.4.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178.4.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

8.5 Medium-term exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188.5.1 Vanadium pentoxide and other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188.5.2 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

8.6 Long-term exposure and carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.6.1 Vanadium pentoxide and other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

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8.6.2 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7 Genotoxicity and related end-points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

8.7.1 Studies in prokaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7.1.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7.1.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7.1.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7.1.4 Trivalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

8.7.2 In vitro studies in eukaryotes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198.7.2.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

8.7.2.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208.7.2.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218.7.2.4 Trivalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

8.7.3 Sister chromatid exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218.7.4 Other in vitro studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

8.7.4.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218.7.4.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218.7.4.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

8.7.5 In vivo studies in eukaryotes (somatic cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.7.5.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.7.5.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.7.5.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

8.7.6 In vivo studies in eukaryotes (germ cells) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.7.6.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228.7.6.2 Other pentavalent and tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

8.7.7 Supporting data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238.8 Reproductive toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

8.8.1 Effects on fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238.8.1.1 Vanadium pentoxide and other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . 238.8.1.2 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

8.8.2 Developmental toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248.8.2.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248.8.2.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248.8.2.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

8.9 Immunological and neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

8.9.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258.9.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268.9.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

9. EFFECTS ON HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

9.1 Studies on volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269.1.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269.1.2 Other pentavalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279.1.3 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

9.2 Clinical and epidemiological studies for occupational exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279.2.1 Vanadium pentoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279.2.2 Tetravalent vanadium compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

9.3 Epidemiological studies for general population exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

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10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

10.1 Aquatic environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3010.2 Terrestrial environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

11. EFFECTS EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

11.1 Evaluation of health effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 11.1.1 Hazard identification and dose–response assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 11.1.2 Criteria for setting tolerable intakes or guidance values for vanadium pentoxide . . . . . . . . . . . . . . . . . . 33 11.1.3 Sample risk characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

11.1.4 Uncertainties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3411.2 Evaluation of environmental effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

APPENDIX 1 — SOURCE DOCUMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

APPENDIX 2 — CICAD PEER REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

INTERNATIONAL CHEMICAL SAFETY CARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

RÉSUMÉ D’ORIENTATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

RESUMEN DE ORIENTACIÓN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

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FOREWORD

Concise International Chemical AssessmentDocuments (CICADs) are the latest in a family ofpublications from the International Programme onChemical Safety (IPCS) — a cooperative programme ofthe World Health Organization (WHO), the InternationalLabour Organization (ILO), and the United NationsEnvironment Programme (UNEP). CICADs join theEnvironmental Health Criteria documents (EHCs) asauthoritative documents on the risk assessment ofchemicals.

International Chemical Safety Cards on therelevant chemical(s) are attached at the end of theCICAD, to provide the reader with concise informationon the protection of human health and on emergencyaction. They are produced in a separate peer-reviewedprocedure at IPCS. They may be complemented byinformation from IPCS Poison Information Monographs(PIM), similarly produced separately from the CICADprocess.

CICADs are concise documents that provide sum-maries of the relevant scientific information concerningthe potential effects of chemicals upon human healthand/or the environment. They are based on selectednational or regional evaluation documents or on existingEHCs. Before acceptance for publication as CICADs byIPCS, these documents undergo extensive peer reviewby internationally selected experts to ensure theircompleteness, accuracy in the way in which the originaldata are represented, and the validity of the conclusionsdrawn.

The primary objective of CICADs is characteri-zation of hazard and dose–response from exposure to achemical. CICADs are not a summary of all available dataon a particular chemical; rather, they include only thatinformation considered critical for characterization of therisk posed by the chemical. The critical studies are,however, presented in sufficient detail to support theconclusions drawn. For additional information, thereader should consult the identified source documentsupon which the CICAD has been based.

Risks to human health and the environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but are

provided as guidance only. The reader is referred to EHC1701 for advice on the derivation of health-basedtolerable intakes and guidance values.

While every effort is made to ensure that CICADsrepresent the current status of knowledge, new informa-tion is being developed constantly. Unless otherwisestated, CICADs are based on a search of the scientificliterature to the date shown in the executive summary. Inthe event that a reader becomes aware of new informa-tion that would change the conclusions drawn in aCICAD, the reader is requested to contact IPCS to informit of the new information.

Procedures

The flow chart shows the procedures followed toproduce a CICAD. These procedures are designed totake advantage of the expertise that exists around theworld — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and otherdata that are necessary for assessing risks to humanhealth and/or the environment. The IPCS Risk Assess-ment Steering Group advises the Co-ordinator, IPCS, onthe selection of chemicals for an IPCS risk assessment,whether a CICAD or an EHC is produced, and whichinstitution bears the responsibility of the documentproduction, as well as on the type and extent of theinternational peer review.

The first draft is based on an existing national,regional, or international review. Authors of the firstdraft are usually, but not necessarily, from the institutionthat developed the original review. A standard outlinehas been developed to encourage consistency in form.The first draft undergoes primary review by IPCS andone or more experienced authors of criteria documents inorder to ensure that it meets the specified criteria forCICADs.

The draft is then sent to an international peerreview by scientists known for their particular expertiseand by scientists selected from an international rostercompiled by IPCS through recommendations from IPCSnational Contact Points and from IPCS ParticipatingInstitutions. Adequate time is allowed for the selectedexperts to undertake a thorough review. Authors arerequired to take reviewers’ comments into account andrevise their draft, if necessary. The resulting second draft

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

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S E L E C T I O N O F H I G H Q U A L I T YN A T I O N A L / R E G I O N A L

A S S E S S M E N T D O C U M E N T ( S )

CICAD PREPARATION FLOW CHART

F I R S T D R A F T

P R E P A R E D

REVIEW BY IPCS CONTACT POINTS/SPECIALIZED EXPERTS

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

SELECTION OF PRIORITY CHEMICAL

1 Taking into account the comments from reviewers.2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments.3 Includes any revisions requested by the Final Review Board.

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER),PREPARATION

OF SECOND DRAFT 1

P R I M A R Y R E V I E W B Y I P C S

( REVISIONS AS NECESSARY)

Vanadium pentoxide and other inorganic vanadium compounds

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is submitted to a Final Review Board together with thereviewers’ comments.

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

The CICAD Final Review Board has severalimportant functions:

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

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

– to provide guidance to those responsible for thepreparation of CICADs on how to resolve anyremaining issues if, in the opinion of the Board, theauthor has not adequately addressed all commentsof the reviewers; and

– to approve CICADs as international assessments.

Board members serve in their personal capacity, not asrepresentatives of any organization, government, orindustry. They are selected because of their expertise inhuman and environmental toxicology or because of theirexperience in the regulation of chemicals. Boards arechosen according to the range of expertise required for ameeting and the need for balanced geographicrepresentation.

Board members, authors, reviewers, consultants,and advisers who participate in the preparation of aCICAD are required to declare any real or potentialconflict of interest in relation to the subjects underdiscussion at any stage of the process. Representativesof nongovernmental organizations may be invited toobserve the proceedings of the Final Review Board.Observers may participate in Board discussions only atthe invitation of the Chairperson, and they may notparticipate in the final decision-making process.

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1. EXECUTIVE SUMMARY

This CICAD on vanadium pentoxide and otherinorganic vanadium compounds was based on a reviewof human health concerns (primarily occupational)prepared by the United Kingdom’s Health and SafetyExecutive (HSE, in press). This review focuses onexposures via routes relevant to occupational settings,but it also contains environmental information. Dataidentified as of November 1998 were covered. A furtherliterature search was performed up to May 1999 toidentify any additional information published since thisreview was completed. An Environmental Health Criteriamonograph (IPCS, 1988) was used as a source documentfor environmental information. As no more recent sourcedocument was available for environmental fate andeffects, the literature was searched for additionalinformation. Information on the nature of the peer reviewand availability of the source documents is presented inAppendix 1. Information on the peer review of thisCICAD is presented in Appendix 2. This CICAD wasapproved as an international assessment at a meeting ofthe Final Review Board, held in Helsinki, Finland, on26–29 June 2000. Participants at the Final Review Boardmeeting are listed in Appendix 3. The InternationalChemical Safety Cards on vanadium trioxide (ICSC 0455)and vanadium pentoxide (ICSC 0596), produced by theInternational 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 commoncommercial form is vanadium pentoxide (V2O5; CAS No.1314-62-1), and this exists in the pentavalent state as ayellow-red or green crystalline powder.

Vanadium is an abundant element with a very widedistribution and is mined in South Africa, Russia, andChina. During the smelting of iron ore, a vanadium slagis formed that containvanadium pentoxide, which is usedfor the production of vanadium metal. Vanadium pentox-ide is also produced by solvent extraction from uraniumores and by a salt roast process from boiler residues orresidues from elemental phosphate plants. During theburning of fuel oils in boilers and furnaces, vanadiumpentoxide is present in the solid residues, soot, boilerscale, and fly ash.

Atmospheric emissions from natural sources havebeen estimated at 8.4 tonnes per annum globally (range1.5–49.2 tonnes). By far the most important source ofenvironmental 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 anthropogenicsources 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 ofthe metal in the environment. Vanadate, the pentavalentspecies in solution, may polymerize (mainly to dimericand trimeric forms), particularly at higher concentrationsof the salts. Within tissues of organisms, V3+ and V4+

predominate because of largely reducing conditions; inplasma, V5+ predominates.

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

There is very limited leaching of vanadium throughsoil profiles.

Higher levels of vanadium have been reported inair close to industrial sources and oil fires. Representa-tive deposition rates are 0.1–10 kg/ha per annum forurban sites affected by strong local sources, 0.01–0.1 kg/ha per annum for rural sites and urban ones withno strong local source, and <0.001–0.01 kg/ha per annumfor remote sites.

Most surface fresh waters contain less than 3 µgvanadium/litre; higher levels of up to about 70 µg/litrehave been reported in areas with high geochemicalsources. Data on levels of vanadium in surface waterclose to industrial activity are few; most reports suggestlevels approximately the same as the highest naturalones. Seawater concentrations in the open ocean rangefrom 1 to 3 µg/litre, and sediment concentrations rangefrom 20 to 200 µg/g; the highest levels are in coastalsediments.

A few organisms concentrate vanadium, with up to10 000 µg/g in ascidians and 786 µg/g in polychaeteannelids. Most other organisms contain generally lessthan 50 µg/g and usually much lower concentrations.

Estimates of total dietary intake of humans rangefrom 11 to 30 µg/day. Levels in drinking-water range upto 100 µg/litre. Some groundwater sources supplying

Vanadium pentoxide and other inorganic vanadium compounds

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potable water show concentrations above 50 µg/litre.Levels in bottled spring water may be higher.

In humans, there is limited toxicokinetic informa-tion suggesting that vanadium is absorbed followinginhalation and is subsequently excreted via the urinewith an initial rapid phase of elimination, followed by aslower phase, which presumably reflects the gradualrelease of vanadium from body tissues. Following oraladministration, tetravalent vanadium is poorly absorbedfrom the gastrointestinal tract. There were no dermalstudies available.

In inhalation and oral studies in laboratory animals,absorbed vanadium in either pentavalent or tetravalentstates is distributed mainly to the bone, liver, kidney,and spleen, and it is also detected in the testes. The mainroute of vanadium excretion is via the urine. The patternof vanadium distribution and excretion indicates thatthere is potential for accumulation and retention ofabsorbed vanadium, particularly in the bone. There isevidence that tetravalent vanadium has the ability tocross the placental barrier to the fetus.

The one acute inhalation study available reportedan LC67 of 1440 mg/m3 (800 mg vanadium/m3) following a1-h exposure of rats to vanadium pentoxide dust. Oralstudies in rats and mice resulted in LD50 values in therange 10–160 mg/kg body weight for vanadium pentox-ide and other pentavalent vanadium compounds, whiletetravalent vanadium compounds have LD50 values inthe range 448–467 mg/kg body weight. No information isavailable concerning dermal toxicity.

Eye irritation has been reported in studies invanadium workers. No skin irritation was reported in100 human volunteers following skin patch testing with10% vanadium pentoxide, although patch testing inworkforces has produced two isolated reactions. Noclear information is available from animal studies withregard to the potential of vanadium compounds toproduce skin or eye irritation or skin sensitization.

In a group of human volunteers, a single 8-hexposure to 0.1 mg vanadium pentoxide dust/m3 causeddelayed but prolonged bronchial effects involving exces-sive production of mucus. At 0.25 mg/m3, a similarpattern of response was seen, with the addition of coughfor 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 identifiedin this study.

Repeated inhalation exposure to the dust and fumeof vanadium pentoxide is associated with irritation of theeyes, nose, and throat. Wheeze and dyspnoea arecommonly reported in workers exposed to vanadium

pentoxide dust and fume. Overall, there are insufficientdata to reliably describe the exposure–response relation-ship for the respiratory effects of vanadium pentoxidedust and fume in humans.

Pentavalent and tetravalent forms of vanadiumhave produced aneugenic effects in vitro in the presenceand absence of metabolic activation. There is evidencethat these forms of vanadium as well as trivalent vana-dium can also produce DNA/chromosome damage invitro, both positive and negative results having emergedfrom the available studies. The weight of evidence fromthe available data suggests that vanadium compoundsdo not produce gene mutations in standard in vitro testsin bacterial or mammalian cells.

In vivo, both pentavalent and tetravalent vanadiumcompounds have produced clear evidence of aneuploidyin somatic cells following exposure by several differentroutes. The evidence for vanadium compounds alsobeing able to express clastogenic effects is, as with invitro studies, mixed, and the overall position on clasto-genicity in somatic cells is uncertain. A positive resultwas obtained in germ cells of mice receiving vanadiumpentoxide by intraperitoneal injection. However, theunderlying mechanism for this effect (aneugenicity;clastogenicity) is uncertain. It is also unclear how thesefindings can be generalized to more realistic routes ofexposure or to other vanadium compounds.

The nature of the genotoxicity database on vana-dium pentoxide and other vanadium compounds is suchthat it is not possible to clearly identify the thresholdlevel, for any route of exposure relevant to humans,below which there would be no concern for potentialgenotoxic activity.

No useful information is available on the carcino-genic potential of any form of vanadium via any route ofexposure in animals1 or in humans.

A fertility study in male mice, involving exposureto sodium metavanadate in drinking-water, suggests thepossibility that oral exposure of male mice to sodiummetavanadate at 60 and 80 mg/kg body weight directlycaused a decrease in spermatid/spermatozoal count andin the number of pregnancies produced in subsequentmatings. However, significant general toxicity (decreasedbody weight gain) was also evident at 80 mg/kg bodyweight.

1 The authors of this document are aware that a 2-yearinhalation bioassay in rodents has recently beencompleted at the US National Toxicology Program.However, results are not available at this time.

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There are a number of developmental studies onpentavalent and tetravalent vanadium compounds, and aconsistent observation is that of skeletal anomalies.Interpretation of these studies is difficult because ofunconventional routes of exposure and evidence ofmaternal toxicity that may itself contribute to the effectsseen in pups.

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

Acute LC50 values for aquatic organisms rangefrom 0.2 to about 120 mg/litre, with the majority lyingbetween 1 and 12 mg/litre. More ecotoxicologicallyrelevant end-points were development of oyster larvae(significantly reduced at 0.05 mg vanadium/litre) andreproduction of Daphnia (21-day no-observed-effectconcentration at 1.13 mg/litre). There are few terrestrialstudies. Most plant studies have been on hydroponiccultures where effects occurred at 5 mg/litre and higher;these studies are difficult to interpret in relation to plantsgrowing in soil.

Concentrations in environmental media are sub-stantially lower than reported toxic concentrations. Fewdata are available on concentrations at specific industrialsites, and it is not possible to conduct a risk assessmenton this basis. However, reported concentrations appearto be similar to the highest natural concentrations,suggesting that risk would be low. Local measurementsmust be carried out to assess risk in any particularcircumstance.

2. IDENTITY AND PHYSICAL/CHEMICALPROPERTIES

Vanadium can exist in a number of differentoxidation states: !1, 0, +2, +3, +4, and +5. The mostcommon commercial form of vanadium is vanadiumpentoxide (V2O5), in which vanadium is in the +5oxidation state. Other forms of vanadium in the +5oxidation state mentioned in this review derive from thevanadate ion (VO3

–) and include ammonium meta-vanadate (NH4VO3), sodium metavanadate (NaVO3), andsodium orthovanadate (Na3VO4). Compounds in the +4oxidation state are derived from the vanadyl ion (VO2+)— for example, vanadyl dichloride (VOCl2) and vanadylsulfate (VOSO4). Compounds containing vanadium in the+3 oxidation state include vanadium oxide (V2O3). Table 1

provides some physicochemical properties of vanadiumcompounds 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 themost commonly used vanadium compound and exists inthe pentavalent state as a yellow-red or green crystallinepowder of relative molecular mass 181.9. Other commonsynonyms include vanadic anhydride and divanadiumpentoxide.

Vapour pressures (and hence Henry’s law con-stants) and octanol/water partition coefficients are notavailable 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. TheHealth and Safety Executive has published MDHS 91Metals and metalloids in workplace air by X-rayfluorescence spectrometry (HSE, 1998). This method canbe used for measuring vanadium and vanadiumcompounds in workplace air, but no method performancedata are available for vanadium.

The US National Institute of Occupational Safetyand Health (NIOSH, 1994) and the US OccupationalSafety and Health Administration (OSHA, 1991) havepublished methods that are suitable for measuringvanadium and vanadium compounds in workplace air.Both are generic methods for metals and metalloids inwhich samples are collected by drawing air through amembrane 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 theworking range is approximately 0.005 mg/m3 for a 500-litreair sample, although these methods are not widelyavailable.

3.2 Biological monitoring

The measurement of vanadium in end-of-shift urinesamples is appropriate for biological monitoring ofvanadium exposure and has been widely used to monitoroccupational exposure to vanadium compounds in anumber of industrial activities (Angerer & Schaller,1994).

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

Solubility (g/litre)

CompoundCAS

numberMolecular/

atomic massMelting

point (°C)Boiling

point (°C)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 orcold hydrochloric acidor cold sulfuric acid,but soluble inhydrofluoric acid, nitricacid, and aquaregia

Vanadiumpentoxide,V2O5

1314-62-1 181.9 690 1750 8 No data Soluble in acid/alkali;insoluble in absolutealcohol

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

Ammoniummeta-vanadate,NH4VO3

7803-55-6 116.98 200 (decom-poses)

No data 58 Decomposes Soluble in ammoniumcarbonate

Vanadiumoxytrichloride,VOCl 3

7727-18-6 Soluble,decomposes

No data Soluble in alcohol,ether, acetic acid

Vanadylsulfate,VOSO4

27774-13-6

Very soluble No data No data

Vanadyloxydichloride,VOCl 2

10213-09-9

Decomposes No data Soluble in dilute nitricacid

Vanadiumtrioxide, V2O3

1314-34-7 Slightlysoluble

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 andpost-shift urine vanadium levels measured at thebeginning and the end of a working week will, therefore,give a measure of daily absorption and accumulateddose from exposures over the preceding days. A furtherstudy of workers exposed to vanadium pentoxide (Kawaiet al., 1989) demonstrated the utility of measuring mid-shift urinary vanadium as an indicator of exposure.Blood vanadium levels were also determined but offeredno advantage over urine measurements. As non-invasive sampling is normally preferred for routinebiological monitoring, the measurement of vanadium inurine is generally recommended.

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

Urinary vanadium may be determined accuratelyby several analytical techniques (Hauser et al., 1998;HSE, in press). Electrothermal atomic absorption

spectrophotometry (AAS), with pre-concentration bychelation and solvent extraction, is the most widely usedanalytical method for the determination of vanadium inurine, and validated methods have been described in theliterature. This analytical method gives typical detectionlimits of 0.1 µg/litre for vanadium in urine, with analyticalprecisions of 11% relative standard deviation at 1 µg/litreand 4% at 10 µg/litre.

3.3 Environmental monitoring

Various methods have been described for analysisof 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 toan absolute sensitivity of 0.1 ng vanadium. ICP-AES hasa working range of 5–2000 µg/m3 for a 500-litre air sample(NIOSH, 1994). Direct aspiration and graphite furnaceAAS methods for determining vanadium compounds inwater were reported in US EPA (1983). The detectionlimits for these two methods are 200 and 4 µg/litre,respectively (US EPA, 1986). Instrumental neutronactivation analysis gave detection limits of 0.01 µg/g in

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the context of sea mammal tissues (Mackey et al., 1996).The instrumental detection limit was 0.1 ng/ml usinginductively coupled plasma – mass spectrometry (Saekiet al., 1999).

4. SOURCES OF HUMAN ANDENVIRONMENTAL EXPOSURE

Vanadium is a relatively abundant element with avery wide distribution; however, workable deposits arevery rare. Vanadium occurs in the minerals vanadinite,chileite, patronite, and carnotite. It constitutes about0.01% of the crust of the Earth (Budavari et al., 1996). Itis derived mainly from titaniferous magnetites containing1.5–2.5% vanadium pentoxide, which are mined in SouthAfrica, Russia, and China (HSE, in press). During thesmelting of iron ore, a vanadium slag is formed thatcontains 12–24% vanadium pentoxide, which is used forthe production of vanadium metal. Worldwide produc-tion of vanadium was stable at just over 27 000 tonnesper annum between 1976 and 1990. Estimated productionin 1990 was 30 700 tonnes, comprising approximately15 400 tonnes from South Africa, 4100 tonnes fromChina, 8200 tonnes from the former USSR, 2100 tonnesfrom the USA, and under 900 tonnes from Japan (Hilliard,1992). Vanadium pentoxide is also produced by solventextraction from uranium ores and by a salt roast processfrom boiler residues or residues from elementalphosphate plants. Ferrovanadium can be obtained fromvanadium pentoxides or vanadium slags by the alumino-thermic process.

All crude oils contain metallic impurities, includingvanadium, which is present as an organometalliccomplex. The vanadium concentration in the oils variesgreatly, depending on their origin. The concentration ofvanadium in crude oil ranges from 3 to 260 µg/g and inresidual fuel oil from 0.2 to 160 µg/g (NAS, 1974). Duringthe burning of fuel oils in boilers and furnaces, thevanadium is left behind as vanadium pentoxide in thesolid 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 smallproportions at the refining stage of steelmaking.Titanium-boron-aluminium (TiBAl) rod, containing lessthan 1% vanadium, is used by the secondary aluminiumindustry as a grain refiner. The hard metals industry usessmall amounts of vanadium carbide in the production oftungsten 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 avariety of gas-phase oxidation processes, particularlythe conversion of sulfur dioxide to sulfur trioxide duringthe manufacture of sulfuric acid. The most frequentlyused 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 colourranging from brown to green. Pigments and inks aremade containing up to about 15% vanadium pentoxide,the higher-concentration ones being supplied in an oilbase rather than as a dry powder.

Vanadium pentoxide can be used as a colouringagent and to provide ultraviolet filtering properties insome glasses. Normally, the vanadium content in thebatch materials is less than 0.5%.

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

By far the most important source of environmentalcontamination with vanadium is combustion of oil, withcoal combustion as the second most important. Of theestimated total global emissions from both natural andanthropogenic sources of 64 000 tonnes per annum tothe atmosphere, 58 500 tonnes come from oilcombustion, with more than 33 500 tonnes of thisaccounted for by the developing economies in Asia andjust under 14 500 tonnes by Eastern Europe and theformer USSR. There are considerable regional variationsin vanadium emissions. For example, emissions to theGreat Lakes area fell between 1980 and 1995, whereasthose to the Mediterranean basin have continued to rise,dominated by emissions from a few countries (Turkey20%, Egypt 19%, and Lebanon 15% of the total) (Nriagu& Pirrone, 1998).

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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, andcomplex-forming chemistry of the metal related to theenvironment and biological systems (Crans et al., 1998).A simple summary of vanadium chemistry is presentedhere.

Under environmental conditions, vanadium mayexist in oxidation states +3, +4, and +5. V3+ and V4+ act ascations, but V5+, the most common form in the aquaticenvironment, reacts both as a cation and anionically asan analogue of phosphate.

In minerals, the oxidation state of vanadium may be+3, +4, or +5, but all mineral dissolution rapidly oxidizesV3+ and V4+ to the pentavalent state. Dry weatheringproduces dusts that may be distributed over greatdistances; deposition of dust into water will also lead toexclusively pentavalent vanadium. Vanadium is a non-volatile metal, and atmospheric transport is viaparticulates. In fuel oils and coal, vanadium is present asvery stable porphyrin and non-porphyrin complexes(Yen, 1975; Fish & Komlenic, 1984) but is emitted asoxides when these fossil fuels are burned. The nativeoxides are sparingly soluble in water but undergohydrolysis to generate “vanadate” in solution. Vanadateis often used as a generalized term for vanadium speciesin solution. Speciation of vanadium in solution is com-plex and highly dependent on vanadium concentration.Under most common environmental conditions of pHand redox potential, and at the low concentrationsreported for vanadium in natural waters, the vanadate islargely monomeric. At higher concentrations, such asthose used in toxicity testing, dimeric and trimeric formsmay predominate, and this can have an effect on how thevanadium 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 (Cranset al., 1998).

5.2 Essentiality of vanadium

Vanadium has been characterized as a constituentof several enzyme systems and complexes within livingorganisms. Nitrogen-fixing bacteria and cyanobacteriacontain nitrogenases, which catalyse the reduction of

atmospheric nitrogen to ammonia. The best characterizednitrogenase is molybdenum-dependent, and its detailedstructure has been published (Chan et al., 1993).Although it has been known for a long time (Bortels,1936) that vanadium could substitute for molybdenum asa trace element in nitrogen-fixing bacteria, only recentlyhas it been studied in detail. The structure of thevanadium-dependent enzyme is not fully known but isassumed to be similar to the molybdenum–iron protein(Chan et al., 1993). The vanadium enzyme has beenshown to function under conditions of low molybdenum,but it may also operate under all conditions; geneticvariants lacking the molybdenum–iron enzyme andrelying exclusively on the vanadium–iron enzyme areknown.

Vanadium-dependent haloperoxidases have beenfound in marine macroalgae and also in a lichen andfungus. Amavadin, a complex molecule centred onvanadium, is found in fungi of the genus Amanita; itsfunction is not known, but it may act as a mediator inelectron transfer. In ascidians (Tunicata; Protochordata),commonly called sea squirts, it has been suggested thatvanadium interacts with tunichromes, oligopeptides thatare the building blocks of the tunic. In fan worms(Polychaeta; Annelida), a function for vanadium inoxygen 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 vanadiumin biological systems can be found.

Whether vanadium is an essential trace element formammals remains an open question. Deficiency stateshave been described for goats and chicks, consisting ofreproductive anomalies and deleterious effects on bonegrowth (Nielsen & Uthus, 1990). However, there isdisagreement on results, and, if vanadium is essential,requirement levels of the order of a few nanograms perday are likely (Mackey et al., 1996).

5.3 Bioaccumulation

Ascidians have been known to accumulate largeresidues 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 etal., 1991), a concentration factor above that in seawaterof 107. Recent reviews of accumulation and the signifi-cance of vanadium in these organisms include those byKustin & Robinson (1995), Michibata (1996), andMichibata & Kanamori (1998). Recently (Ishii et al., 1993),high vanadium accumulation was demonstrated for

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polychaetes of the genus Pseudopotamilla; polychaetesof other genera did not accumulate the metal.Pseudopotamilla occelata showed concentrations inwhole soft body ranging from 320 to 1350 mg/kg dryweight. Distribution, speciation, and possible physio-logical roles of the metal are discussed in Ishii (1998).

Apart from the specific accumulators mentionedabove, organisms generally do not concentrate or accu-mulate vanadium from environmental media to a highdegree, and there is no indication of biomagnification infood chains. Miramand & Fowler (1998) reviewedreported levels of vanadium in marine organisms andcalculated concentration factors for components of atypical marine food chain based on average seawaterconcentrations of 2 ng/g. Concentration factors forprimary producers ranged from 40 to 560, for primaryconsumers from 40 to 150, for secondary consumers fromapproximately 20 to 150, and for tertiary consumers fromapproximately 2 to 400. Although vanadiumconcentrations are higher in sediment than in openseawater, only one study has attempted to quantifyuptake from sediment using 48V; the ragworm Nereisdiversicolor accumulated vanadium from the sedimentwith a low transfer factor of about 0.02 (Miramand, 1979).Using labelled food, assimilation coefficients have beencalculated for several marine organisms. For thecarnivorous invertebrates Marthasterias glacialis,Sepia officianalis, Carcinus maenus, and Lysmataseticaudata, assimilation coefficients of 88% (Miramandet al., 1982), 40% (Miramand & Fowler, 1998), 38%, and25% (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 thevanadium was present in the digestive gland (63–98.8%).For a single fish species (Gobius minutus), assimilationwas much lower, at 2–3%, with a half-life of 3 days(Miramand et al., 1992), and accumulation was also lowin a bivalve feeding on suspended matter (Mytilusgalloprovincialis), at 7%, with a half-life of 7 days(Miramand et al., 1980). Comparison of uptakes via foodand directly from water showed that invertebratesaccumulated much of the vanadium from food(Miramand & Fowler, 1998). Recent studies on bioaccu-mulation of vanadium in pinnipeds and cetaceans inSwedish (Frank et al., 1992), northern Pacific (Saeki et al.,1999), and Alaskan/Atlantic (Mackey et al., 1996) watershave shown a correlation of residues with age,comparable to other metal residues. Liver showed thehighest accumulation of the metal of all tissues analysed.However, bone, which might be expected to accumulatethe element, was not analysed. Alaskan sea mammalsshowed the highest levels, ranging up to 1.2 µg/g wetweight. The authors suggest a unique dietary source, aunique geochemical source, or anthropogenic input to

the Alaskan marine environment as possibleexplanations (Mackey et al., 1996).

Marine biota are thought to contribute to thesedimentation of vanadium from seawater via shells,faecal pellets, and moult. Coastal sediments appear to bea 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 ofcoastal plain soil and its availability to bean plants. Lessthan 3% of applied metal moved down the soil profile.Extractable concentrations decreased over the first18 months of the study and remained constant thereafter.Uptake of vanadium into the roots and upper parts of thebean plants did not change significantly between18 months and the end of the experiment but wasreduced during the initial period, suggesting reducedbioavailability over time as a result of binding to soilmaterials (Martin & Kaplan, 1998).

6. ENVIRONMENTAL LEVELS ANDHUMAN EXPOSURE

6.1 Environmental levels

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

6.1.1 Air

Earlier measurements of vanadium in air werereviewed by Schroeder et al. (1987); most measurementswere performed in the 1970s, with a few in the early1980s. A review of later measurements and comparisonwith the earlier review were conducted by Mamane &Pirrone (1998). The ranges they reported are presented inTable 2, together with reported concentrations down-wind of the Kuwait oil fires in 1991–1992. The ranges arevery large, and there is no simple explanation for the

Vanadium pentoxide and other inorganic vanadium compounds

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Table 2: Ranges of concentrations of vanadium in air.

Area

Atmosphericconcentration

(ng/m3) Reference

Urban airRural airRemote areasa

0.4–14602.7–97

0.001–14

Schroeder et al., 1987

Urban airRural airRemote areas

0.5–12300.4–5000.01–2

Mamane & Pirrone,1998

Dhahran, SaudiArabia, duringKuwait oil fires

2.4–1170 (inthe PM10

fraction)

Sadiq & Mian, 1994

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

variation; possible causes are reviewed by Mamane &Pirrone (1998), although they can draw no firm conclu-sions.

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

Bulk precipitation concentration ranges have beenreported at 4.1–13 µg/litre for the rural United Kingdom(Galloway et al., 1982) and 0.12–0.65 µg/litre (mean 0.45µg/litre) in Switzerland (Atteia, 1994). Wet deposition inan area of New England remote from anthropogenicinput showed concentrations of vanadium ranging from0.2 to 1.16 µg/litre (average 0.67 µg/litre) and in Bermudaranging from 0.049 to 0.111 µg/litre (average 0.096µg/litre) (Church et al., 1984). Ice and snow levels innorthern Norway and Alaska were 0.31 and 0.13 µg/litre,respectively (Galloway et al., 1982), and two ice corelevels in Greenland were reported at 0.022 and 0.016µg/litre. Levels in rain ranged from 1.1 to 46 µg/litre forrural 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 forurban sites affected by strong local sources, 0.01–0.1 kg/ha per annum for rural sites and urban ones withno strong local source, and <0.001–0.01 kg/ha per annumfor remote sites.

6.1.2 Surface waters and sediments

Most surface fresh waters contain less than 3 µgvanadium/litre (Hamada, 1998). The vanadium content ofwater from the Colorado River basin (USA) ranged from0.2 to 49.2 µg/litre, with the highest levels associatedwith uranium–vanadium mining (Linstedt & Kruger,

1969). A wider survey of Wyoming, Idaho, Utah, andColorado in the USA showed vanadium concentrationsof 2.0–9.0 µg/litre (Parker et al., 1978). Unfiltered waterfrom the source area of the Yangtze River in China con-tained between 0.24 and 64.5 µg/litre, whereas concentra-tions in filtered water ranged from 0.02 to 0.46 µg/litre(Zhang & Zhou, 1992). The highest levels reported are insurface waters in the area of Mount Fuji in Japan. Twosprings had 14.8 and 16.4 µg/litre, and five river samplesshowed between 17.7 and 48.8 µg/litre (Hamada, 1998).

Data on concentrations of vanadium in wastewaterand local surface water are few, and studies are old;reliability for present-day operations is questionable. Asingle concentration of 2 mg/litre for surface water from1961, reported in IPCS (1988), seems much higher thanother more recent reports, where levels of up to 60 µg/li-tre in industrial areas seem more likely.

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

6.1.3 Biota

Ranges of concentrations of vanadium in marineorganisms are given in Table 3, based on a review of theliterature in Miramand & Fowler (1998), where theoriginal references can be found. The ranges includevalues from areas of likely local contamination fromindustrial sources. With the exception of ascidians(tunicates), some annelids, and molluscs, concentrationsof vanadium in marine organisms are low. The range forplanktonic species is heavily influenced by a singlestudy showing accumulation up to 290 mg/kg dryweight; this was mainly into shells of planktonic forms ofmolluscs. Generally, planktonic organisms showconcentrations of vanadium around 1 mg/kg.

There are fewer data for freshwater organisms. Themost comprehensive study of organisms was conductedin the Mount Fuji area of Japan, where concentrations inorganisms from water with high (43.4 µg/litre) and lower(0.72 or 0.4 µg/litre) concentrations of vanadium werecompared. Water plants from the high-vanadium areacontained 21.8 ± 11.3 µg/g dry weight of the metal (range5.6–43.7 µg/g), compared with 0.79 ± 0.52 µg/g (range0.22–1.91 µg/g) in the low-vanadium area. A greenmicroalga in the high-concentration area contained thehighest reported concentration of the metal, at 118–168µg/g dry weight. The vanadium concentration in rainbowtrout (Oncorhynchus mykiss) farmed in water from theseareas was measured: bone concentrations

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Table 3: Concentrations of vanadium in marine organisms.a

OrganismConcentration 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).

were 0.87, 4.77, and 17.2 µg/g and kidney concentrationswere 0.43, 2.38, and 4.63 µg/g for water concentrations of0.72, 43.4, and 82.7 µg/litre, respectively. In all cases,muscle concentrations were low and did not differbetween areas (0.016–0.024 µg/g) (Hamada, 1998). Apooled sample of 279 larval razorback sucker (Xyrauchentexanus) from the Green River in Utah, USA, showed avanadium concentration of 1.7 mg/kg dry weight. TheGreen River receives irrigation drainage and typicallyshows higher concentrations of a range of elementscompared with the input streams (Hamilton et al., 2000).

A single study detected vanadium in 19 out of120 canvasback ducks (Aythya valisineria) wintering inLouisiana, USA; the maximum concentration in duckliver was 0.94 µg/g dry weight (Custer & Hohman, 1994).The mean vanadium concentration in four species ofJapanese waterfowl ranged from 3.69 to 8.11 µg/g dryweight 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 metallurgicalplant producing vanadium pentoxide, to a depth of10 cm, the surface layer of the soil contained 18–136 mgvanadium/kg dry weight (Lener et al., 1998). The back-ground concentration for the area is not stated, althoughlevels at 600 m from the plant are clearly elevated com-pared with those at greater distances. Concentrations insoil 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 andthe 90th percentile at 130 mg/kg. The average worldwidesoil concentration is around 100 mg/kg (Hopkins et al.,1977).

6.2 Human exposure

The quantitative data available to the authors ofthis document are restricted mainly to the occupationalenvironment (HSE, in press). Information on controlmeasures has been derived from industry sources in theUnited Kingdom.

The main activity where workers can be exposed tovanadium in the United Kingdom is the cleaning of oil-fired boilers and furnaces where vanadium pentoxide is amajor component of the boiler residues. It is estimatedthat 1000 workers in the United Kingdom are employedby specialist boiler maintenance contractors, althoughthey probably spend less than 20% of their time cleaningoil-fired boilers. Measured vanadium exposures (totalinhalable fraction) can approach 20 mg/m3 (during task),but can be lower than 0.1 mg/m3. The lowest results areobtained where wet cleaning methods are used. Respira-tory protective equipment is usually worn during boilercleaning operations.

Handling of catalysts in chemical manufacturingplants is carried out by specialist contractors. Fewerthan 50 workers in the United Kingdom are exposed tovanadium pentoxide during such activities. Exposuredepends 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. Sievingof the catalyst can lead to higher exposures, and resultsof between 0.01 and 1.9 mg/m3 (total inhalable vanadium)have been obtained. Air-fed respiratory protectiveequipment is normally worn during catalyst removal andreplacement and sieving.

Fewer than 200 workers in the United Kingdom are

exposed to vanadium during the manufacture offerrovanadium alloys and TiBAl rod. The limitedexposure data available indicate exposures below thelimit of detection of 0.01 mg/m3. No data have beenfound to quantify exposures during the manufacture ofTiBAl rod.

There are fewer than 50 workers who are exposedto vanadium compounds in the United Kingdom duringthe manufacture of vanadium-containing pigments forthe ceramics industry. Exposure is controlled by the useof local exhaust ventilation, and measured data indicatethat levels are normally below 0.2 mg/m3 (total inhalablefraction).

Occupational exposure data are also available fromFinland, including personal monitoring data from a rangeof work processes in a vanadium refining plant (Kivilu-oto, 1981). Generally, two samples were taken per personover a 2-month period. The mean respirable fraction

Vanadium pentoxide and other inorganic vanadium compounds

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Table 4: Biological monitoring studies of occupational vanadium exposure.

IndustrySamplematrix 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)a10 (+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

Pigmentmanufacture

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 (generalpopulation)

Urine 213 012 0.22 (0.07–0.5)<0.4<0.1

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

a RPE = respiratory protective equipment.

(particle size 5 µm or less) of the dust was 20%. Thehighest 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 smeltingroom (0.055–0.47 mg/m3, mean 0.21 mg/m3), but wereusually much lower for other processes (around 0.002–0.18 mg/m3, mean 0.005–0.037 mg/m3).

Biological monitoring studies of occupationalvanadium exposure also indicate the magnitude ofairborne exposures (Table 4). A further recent example isdetailed (Kucera et al., 1992, 1994, 1998; see also sections7 and 9): a group of workers from the Czech Republicinvolved in the manufacture of vanadium pentoxide fromslag rich in vanadium for periods of 0.5–33 years (meanduration of exposure 9.2 years) was exposed to airbornevanadium concentrations of 0.016–4.8 mg/m3. Urinaryvanadium content was 3.02–769 ng/ml, compared with0.066–53.4 ng/ml in controls. In blood, vanadium levelswere 3.1–217 ng/ml, compared with 0.032–0.095 ng/ml incontrols. The vanadium content in the hair of exposedand non-exposed persons was in the range of 0.103–203mg/kg and 0.009–3.03 mg/kg, respectively, and thevanadium content in the fingernails was in the range of0.260–614 mg/kg and 0.017–16.5 mg/kg, respectively.Determinations of the vanadium content were carried outby both radiochemical and instrumental neutronactivation analyses in all instances.

Estimates given in IPCS (1988) for total dietaryintake of the general population in food range from 11 to30 µg/day (adults). The mean vanadium concentration indrinking-water in Cleveland, USA, was 5 µg/litre, with amaximum of 100 µg/litre (Strain et al., 1982). Wells close

to a vanadium slag processing plant in the CzechRepublic showed concentrations ranging from 0.01 to0.44 µg/litre; the local municipal supply contained0.01 µg/litre (Lener et al., 1998). Groundwater in thevicinity of Mount Fuji in Japan contains high vanadiumlevels from leaching of larval flows rich in the metal;measured concentrations in deep wells were between 89and 147 µg/litre, levels higher than those measured inspring water (Hamada, 1998). A sample of drinking-waterfrom Kanagawa Prefecture in Japan contained avanadium concentration of 22.6 µg/litre, the highestvalue in a survey of Japanese cities and 21 cities in theUSA (Tsukamoto et al., 1990). The water here wasinfluenced by Mount Fuji groundwater. Groundwater inthe region of Mount Etna in Sicily has been used as asource of drinking-water. The western basin showed thehighest 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/li-tre (Giammanco et al., 1996). Older studies summarized inIPCS (1988) report drinking-water concentrations up to70 µg/litre, although the majority of samples containedless than 10 µg/litre, and in many the metal wasundetectable. Levels in bottled waters from mineralsprings may contain much higher levels of vanadium;one study of bottled waters from Switzerland reported arange of 4–290 µg/litre (Schlettwein-Gzell & Mommsen-Straub, 1973).

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

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

7. COMPARATIVE KINETICS ANDMETABOLISM 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 rapidphase of elimination, followed by a slower phase, whichpresumably reflects the gradual release of vanadium frombody tissues (Kiviluoto et al., 1981a).

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

Groups of two rats were exposed to ammoniummetavanadate (pentavalent vanadium, median massaerodynamic 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% oneach of days 3 and 4. Twenty-four hours after the finalexposure, 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 etal., 1987) indicate that vanadium, from either vanadiumpentoxide or other pentavalent and tetravalent vanadiumcompounds, is absorbed to a significant extent from thelungs. Following intratracheal instillation of 40 µgvanadium pentoxide, 72% of the administered dose wasabsorbed from the lungs within 11 min (Rhoads &Sanders, 1985). The remaining 28% was absorbed over 2days. Forty per cent of the administered dose wasretained within the carcass after 14 days (12% in bones),and 40% was eliminated via urine and faeces. Similarresults were obtained by the other authors.

Oral studies (Parker & Sharma, 1978; Conklin et al.,1982; Ramanadham et al., 1991; summarized by HSE, inpress) indicate that vanadium compounds are poorlyabsorbed from the gastrointestinal tract (approximately3% of the administered dose).

No dermal studies are available.

Absorbed vanadium in either pentavalent or tetra-valent states is distributed mainly to the bone (around10–25% 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 smallamounts are also detected in the testes (about 0.2%)(Sabbioni et al., 1978; Ramanadham et al., 1991; Sanchezet al., 1998; HSE, in press). Distribution studies in whichrats received a total of approximately 224 and 415 mgvanadium pentoxide/kg in drinking-water over a period of1 and 2 months indicated that the vanadium content(assessed in 13 specific tissues) was greatest in thekidneys, spleen, tibia, and testes (Kucera et al., 1990).Similar distribution was seen in a study conducted usingvanadyl sulfate (tetravalent vanadium) (Kucera et al.,1990). Further evidence for the distribution of vanadiumto 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 theurine (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 theinitial short half-time seen in humans, presumablyreflecting post-exposure clearance from the bloodstream,followed by a more gradual release from other bodycompartments). The pattern of vanadium distributionand excretion indicates that there is potential foraccumulation and retention of absorbed vanadium,particularly in the bone. One oral study in which groupsof 22 pregnant mice received vanadyl sulfatepentahydrate at doses of 0, 38, 75, or 150 mg/kg bodyweight per day by oral gavage (Paternain et al., 1990)indicates that tetravalent vanadium has the ability tocross the placental barrier to the fetus.

8. EFFECTS ON LABORATORYMAMMALS 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 notoxicological information on elemental vanadium andnegligible information on the trivalent forms.

Vanadium pentoxide and other inorganic vanadium compounds

15

In this section, reference is made to a review of thetoxicity of vanadium compounds (including vanadiumpentoxide) by Sun (1987). However, it has not beenpossible to trace the majority of the primary referencesfrom which the review is constructed, and so it has notbeen possible to perform a critical evaluation of thequality of the information presented.

8.1 Single exposure

8.1.1 Vanadium pentoxide

The one acute inhalation study available reportedan LC67 of 1.44 mg/litre (1440 mg/m3) following a 1-hexposure 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 to205 mg/m3 for 2 h (30% of particles had a diameter lessthan 5 µm) died within 12–24 h. Clinical signs of toxicityincluded respiratory distress, “mucosal irritation”(tissues unstated), and diarrhoea.

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

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

A further review of vanadium pentoxide cites oralLD50 values of around 10 mg/kg body weight for rats and23 mg/kg body weight for mice (MAK, 1992). No furtherdetails are available.

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

8.1.2 Other pentavalent vanadium compounds

Groups of 10 male rats received aqueous sodiummetavanadate by gavage (Llobet & Domingo, 1984). TheLD50 value reported was 98 mg/kg body weight. Nodeaths were reported at 39 mg sodium metavanadate/kgbody weight. Clinical signs of toxicity reported weredecreased 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 werereported. The effects had mostly disappeared in sur-vivors at 48 h after treatment. No histopathology wasperformed.

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

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

8.1.3 Tetravalent vanadium compounds

An oral LD50 value of 448 mg/kg body weight inmale rats exposed to vanadyl sulfate pentahydrate wasreported (Llobet & Domingo, 1984). No deaths werereported at 296 mg/kg body weight. Signs of toxicitywere similar to those reported following treatment withsodium metavanadate, although to a lesser degree.

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

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

8.1.4 Trivalent vanadium compounds

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

8.2 Irritation and sensitization

No information is available from animal studieswith regard to the potential of vanadium compounds toinduce skin or eye irritation.

The primate inhalation studies by Knecht et al.1992 (see section 8.3) also included an unconventionalevaluation of skin sensitization; this investigation gave anegative response for immediate and delayed skinreactions to vanadium only or in combination with acarrier protein.

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8.3 Effects of inhaled vanadiumcompounds on the respiratory tract

Presumably owing to the serious nature and rapidonset of the respiratory effects that have been observedin humans in occupational settings (see also section 9),the following series of single and repeated inhalationstudies was conducted in an attempt to further elucidatethe possible mechanisms and dose–response relation-ships.

A study by Knecht et al. (1985) investigatedpulmonary responses to inhaled vanadium pentoxidedust and sodium vanadate aerosols (thought to containthe polymeric vanadium species most likely to be presentin the respiratory mucosa after inhalation of vanadiumpentoxide) in a group of 16 cynomolgus monkeys. Thestudy design attempted to simulate exposure patternsand their consequences in humans. Animals were givensequential exposures to 0, 19, and 39 mg vanadium/m3 inthe form of sodium vanadate aerosol (characteristics notreported) 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 twoexposures. Pulmonary function was evaluated beforeany exposures began and then immediately afterexposure to sodium vanadate and 18–21 h after exposureto vanadium pentoxide. The reason for this pattern ofinvestigating was that experience in humans suggestedthat respiratory effects had appeared approximately 1day after exposure to vanadium pentoxide; thepulmonary investigations made immediately after sodiumvanadate exposure were explained on the basis that itwas known that inhalation of soluble zinc salt canproduce an immediate irritant response. Bronchoalveolarlavage (BAL) was performed pre-exposure and followingexposure to 5.0 mg vanadium pentoxide/m3.

Evidence of slight impairment of pulmonary func-tion was reported following the single 6-h inhalation of5.0 mg vanadium pentoxide dust/m3, but not 0.5 mg/m3.This was based on statistically significant decreases inpeak expiratory flow rate (PEFR; median 89% of baselinevalues), forced expiratory volume (FEV0.5; 95% ofbaseline values), and forced expiratory flow (FEF50; 92%of baseline values), these changes giving an indicationof airflow limitation in the large central airways; a statis-tically significant decrease in FEF25 (77% of baselinevalues), which gives an indication of airflow limitation inthe peripheral airways; and statistically significantincreases in functional residual volume (FRV; 124% ofbaseline values), residual volume (133% of baselinevalues), 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 ofthe dependent, peripheral small airways. No significantchanges were reported in forced vital capacity (FVC),total lung capacity (TLC), or diffusion capacity forcarbon monoxide (DL50), indicating the absence ofparenchymal dysfunction. However, althoughstatistically significant, the magnitude of the observedchanges was small.

BAL analysis revealed statistically significant

increases in numbers of polymorphonuclear leukocytesand decreases in mast cells following exposure to 5.0 mgvanadium pentoxide/m3. Numbers of macrophages andlymphocytes were unaltered by exposure.

Another study in monkeys by Knecht et al. (1992)compared bronchial reactivity following challenge withvanadium pentoxide dust, both before and after sub-chronic exposure to vanadium pentoxide dust. Bothbefore and after subchronic exposure, the animalsunderwent 6-h whole-body challenges with vanadiumpentoxide aerosol (stated to be “generally 1–5 micro-metres”) at concentrations of 0.5 and 3.0 mg/m3 (0.28 and1.68 mg vanadium/m3), separated by a 2-week interval.Two weeks later, the animals were challenged withmethacholine to assess non-specific bronchial reactivity.The subchronic exposure regime involved exposure tovanadium pentoxide 6 h/day, 5 days/week, for 26 weeks.Two vanadium pentoxide-exposed groups (n = 9 each)received equal weekly exposures (concentration × time)with different exposure profiles. One vanadiumpentoxide-exposed group received a constantconcentration of 0.1 mg/m3 (0.06 mg vanadium/m3) for3 days/week and an exposure at a constantconcentration of 1.1 mg/m3 (0.62 mg vanadium/m3) for 2days/week. The other vanadium pentoxide-exposedgroup received a constant daily concentration of 0.5mg/m3. A control group (n = 8) received filtered,conditioned air. The animals were allowed a 2-weekrecovery period before being retested as before.

Blood cytological and immunological analysis wascarried out before both sets of acute challenges withvanadium pentoxide. Pulmonary function testing wascarried out pre-exposure, the day after each acutechallenge with vanadium pentoxide, and immediatelyafter challenge with methacholine. BAL fluid wascollected for cytological and immunological analysisbefore each series of challenges and after challenge with3.0 mg/m3.

Respiratory distress developed in three monkeysfrom the subchronic exposure group, which received theintermittent peaks of 1.1 mg vanadium pentoxide/m3,characterized by audible wheezing and coughing, which

Vanadium pentoxide and other inorganic vanadium compounds

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occurred only on peak exposure days during the first fewweeks of exposure. Pre-subchronic exposureprovocation challenges with vanadium pentoxideproduced statistically significant changes in averageflow resistance (RL; mean, 103% and 114% of baselinevalues at 0.5 and 3.0 mg/m3, respectively) and FVC (96%and 97% of baseline values, respectively) at both doselevels used, while statistically significant differenceswere observed only at 3.0 mg/m3 for FEF50/FVC (99% and87% of baseline values, respectively) and residualvolume (RV; 105% and 114% of baseline values,respectively), which indicates an obstructive pattern ofimpaired pulmonary function. No statistically significantchange in dynamic compliance (CLdyn) was observed.

At the second challenge, after subchronic expo-sure, the pattern of findings was similar to that from thefirst challenge, but none of the changes was statisticallysignificantly different from baseline values, nor wasthere any statistically significant difference between thecontrols, the “peak” exposure group, or the “constant”group. Large, statistically significant increases in RL andFEF50/FVC were observed following challenge withmethacholine, but this reactivity was not significantlyincreased following subchronic exposure to vanadiumpentoxide.

A significant increase in the total number ofrespiratory cells in BAL fluid was observed followingpre-subchronic exposure challenge with 3.0 mg vana-dium pentoxide/m3. The increase in the total number ofcells occurred through a highly significant increase inthe number of neutrophils (393% of baseline values).The number of eosinophils recovered from the lung wasalso increased (170% of baseline values), while thenumbers of lymphocytes, macrophages, and mast cellswere not. Significant challenge responses were notobserved for total protein, albumin, leukotriene C4, or theimmunoglobulins IgG and IgE, despite the significantcellular response to vanadium pentoxide challenge. Asimilar pattern of cellular and immunological responsewas observed after subchronic exposure. Post-exposurechallenge responses for neutrophils were greater than400% of baseline values. A post-exposure trend(statistically significant for eosinophils) towardsdecreased responses was observed in the vanadiumpentoxide-exposed groups as compared with the controlgroup. The number of circulating neutrophils andeosinophils in venous blood was not affected by sub-chronic vanadium pentoxide exposure. Similarly, serumimmunoglobulins were unchanged throughout thestudy.

8.4 Other short-term exposure studies

Oral studies are described below; no dermalstudies are available.

8.4.1 Vanadium pentoxide

Short-term immunotoxicity studies are describedbriefly in section 8.9.1.

8.4.2 Other pentavalent vanadium compounds

Groups of 10 male rats received 0, 5, 10, and50 ppm (mg/litre) sodium metavanadate in drinking-waterfor 3 months, which corresponded to 0, 2.1, 4.2, and 21ppm vanadium. This intake was equivalent to about 0,0.3, 0.6, and 3 mg sodium metavanadate/kg body weightper day, assuming 350 g body weight and 20 ml/daywater consumption (Domingo et al., 1985). Limitednumbers of animals were selected for liver and renalfunction tests and organ weight analysis (liver, kidneys,heart, spleen, and lungs only). Histological examinationwas performed on only three animals of each group.

There was no effect on weight gain, consumptionof water, urine volume, or urinary protein levels duringthe treatment period. No significant difference wasreported in the relative organ weights of the groups.Plasma concentrations of urea, uric acid, and creatininewere reported to be within the normal range for allgroups of animals, except in 50 ppm animals, in whichurea and uric acid values were significantly greater thanin concurrent controls. No effect on liver function wasapparent from the results. Dose-dependent histologicalchanges, including hypertrophy and hyperplasia in thewhite pulp of spleen, corticomedullary microhaemor-rhagic foci in kidneys, and mononuclear cell infiltration,mostly perivascular, in lungs, were apparent in all treatedanimals. Hence, no no-observed-adverse-effect level(NOAEL) could be derived from this study, althoughchanges at the lowest exposure level were considered bythe authors to be minimal.

Groups of eight male rats were administered 0 orabout 9.7 mg vanadium/kg body weight per day asammonium metavanadate via the drinking-water for12 weeks (Dai et al., 1995). Before the start of the studyand at weeks 1, 2, 4, 8, and 12 following vanadium treat-ment, haematological indices (haematocrit, haemoglobinconcentration, erythrocyte count, leukocyte count,platelet count, reticulocyte count, and erythrocyteosmotic fragility) of the peripheral blood were investi-gated in all animals. There were no other investigations.No difference in food intake or body weight was appar-ent between the groups. There were no differences inhaematological 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 perday as ammonium metavanadate in drinking-water for4 weeks (Zaporowska et al., 1993). No differences in

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external appearance or locomotor behaviour werereported between the groups. Body weight increase inthe treated groups was lower than in control animals, butthis was not dose-related. Slight, but statistically signif-icant, decreases in erythrocyte number and haemoglobinconcentration (top dose only, all about 10% less thancontrol) were observed. Similarly, a slight but statis-tically significant decrease in haematocrit was reportedin treated males (mean value was 98% of controls). Nosignificant differences in leukocyte numbers werereported between the groups. No clinically significantchanges in biochemical parameters were reported.Overall, the changes were slight.

Groups of 12–13 male and female Wistar rats wereadministered 0 or about 13 mg ammonium metavanadate/kg body weight per day in drinking-water for 4 weeks(Zaporowska & Wasilewski, 1992). Investigationsincluded water and food consumption, body weight, anda range of haematological parameters; there were nofurther investigations conducted.

There was a marked decrease in water consumptionwith concomitant decreases in food consumption andbody weight gain. Although there were statisticallysignificant reductions in some of the haematologicalparameters measured (as above), it is impossible to drawany conclusions regarding the toxicological significancedue to the limited study design and confounding due toimpaired water consumption (which may have beenrelated to unpalatability).

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

Reduced body weight gain was noted only at16 mg/kg body weight per day (20% lower thancontrols). There was no observable effect on rearingcounts. However, a statistically significant reduction intotal distance travelled in the open field activityinvestigation (recorded 3 weeks after cessation oftreatment only) was recorded in the first 5 min at 8 and 16mg/kg body weight per day, but not at 5–10 or 10–15 min. Decreased avoidance compared with controlswas noted among all vanadium-exposed animals over3 consecutive days, although there was no clear dose–response relationship and no indication of other resultsfor the 3-week testing period. Hence, this would seem tobe a rather selective presentation of results. There wasno discussion of whether or not the transient nature of

the reduction in total distance travelled could have beenrelated to other factors such as palatability that mayhave affected behaviour and movement. Also, given theextremely limited range of observations, substantialinterindividual variation, and absence of histopathology,it is impossible to draw any firm conclusions from thisstudy.

Short-term immunotoxicity studies are describedbriefly 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 thepotential effect of 7.7 mg vanadium/kg body weight perday as vanadyl sulfate (+4) and 9.2 mg vanadium/kgbody weight per day in the form of bis(maltolato)oxo-vanadium (+4) on haematological parameters. Nodifference in food intake or body weight was apparentbetween the groups (control and vanadium in valencystates +4 and +5). There were no differences in haema-tological parameters between the groups.

Short-term immunotoxicity studies are describedbriefly in section 8.9.3.

8.5 Medium-term exposure

8.5.1 Vanadium pentoxide and otherpentavalent vanadium compounds

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

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

No treatment-related effect on cardiovascularfunction was reported. Histopathological investigationshowed no change in the brain, liver, lungs, heart, orblood vessels of treated animals. An increase (5 timesgreater than controls) in urinary kininase I (measured toassess arterial hypertension) and II (twice controlvalues) activities was reported in treated rats at 40 µg/ml,although the significance of this is unclear. No effectwas reported on urinary excretion of creatinine, totalnitrogen, protein, or sodium. Urinary potassiumdecreased with dose, whereas urinary calcium was

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reduced at 10 µg/ml only. Again, this study did notreveal any clearly toxicologically significant changesattributable to vanadium exposure.

8.5.2 Tetravalent vanadium compounds

There are no data available.

8.6 Long-term exposure andcarcinogenicity

8.6.1 Vanadium pentoxide and otherpentavalent vanadium compounds

Long-term oral and dermal exposures to vanadiumpentoxide and other pentavalent vanadium compoundshave not been studied.

In a study conducted by Yao et al. (1986a) andcited by Sun (1987), groups of 62–84 male and femalemice were exposed to 0, 0.5, 2, or 8 mg vanadiumpentoxide dust/m3 (particle size not reported) for 4 h/dayfor 1 year. “Papillomatous and adenomatous tumours” inthe lungs were reported in 2 of 79 and 3 of 62 mice at 2and 8 mg/m3, respectively. No tumours were reported incontrols or at 0.5 mg/m3. No further information isavailable.

8.6.2 Tetravalent vanadium compounds

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

As part of a study related to the investigation ofdiabetes, groups of 8–23 male Wistar rats receivedapproximately 0, 34, 54, or 90 mg vanadyl sulfate/kg bodyweight per day in drinking-water for up to 52 weeks (Dai& McNeill, 1994; Dai et al., 1994a,b). Investigations wereextensive and included blood biochemistry,haematology, blood pressure and pulse rate,ophthalmoscopy, organ weights, and microscopicpathology. The only adverse effect observed wasreduced body weight gain (around 33% reduction at90 mg/kg body weight per day and 10% at 34 and54 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 section8.7.7).

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 thepresence and absence of metabolic activation, at concen-trations between 1 and 200 µg/plate with Salmonellatyphimurium 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 concentrationsof 0, 2, 4, and 6 µg/ml (0, 1, 2, and 3 µg vanadium/ml), inreplicate experiments, to cultures of human lymphocytes(Roldan & Altamirano, 1990). Cells were incubated in theabsence of metabolic activation with vanadiumpentoxide for 48 h. A minimum of 100 well-spread first-division metaphases were analysed for structural andnumerical aberrations (polyploid only).

Mitotic index was statistically significantlydecreased (74, 41, and 42% of control value at 2, 4, and 6µg/ml, respectively). The frequency of structural chro-mosome aberrations did not increase in the presence ofvanadium pentoxide. However, a statistically significantincrease in the frequency of polyploid cells was reportedat 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-relatedincrease in the number of cells with “satellite associa-tions” (a tendency for satellite-bearing chromosomes tolie side by side, with their satellite regions facing eachother). This finding, along with the induction of poly-ploidy, is indicative of vanadium pentoxide exerting itseffects at the level of spindle formation.

The potential of vanadium pentoxide exposure toinduce micronuclei and centromere-positive micronucleiin vitro was investigated in Chinese hamster V79 cells, inthe absence of metabolic activation (Zhong et al., 1994).Studies of cytotoxicity were performed in cells exposedto concentrations of vanadium pentoxide up to 12 µg/ml(6.7 µg vanadium/ml) for 24 h. In each group, thenumbers of mononucleated and binucleated cells per1000 cells were determined for cell cycle kinetics. Theinvestigation of centromere-positive micronuclei was

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performed in cells cultured with vanadium pentoxideconcentrations of 0, 1, 2, or 3 µg/ml (0, 0.6, 1.1, or 2.2 µgvanadium/ml) for 24 h. Binucleated cells were scored andnumbers of micronuclei determined.

Cytotoxic effects of vanadium pentoxide, asdefined by a reduced number of binucleated cells, wereapparent at all doses. A dose-related, statisticallysignificant increase in micronucleus induction wasreported 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 alsoobserved in the numbers of centromere-positive micro-nuclei (49, 70, 82, and 89% of micronuclei, respectively).

Induction of gene mutation at the HPRT locus wasinvestigated following exposure of Chinese hamster V79cells, 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 µgvanadium/ml) for 24 h (Zhong et al., 1994). No significantincrease in the frequency of gene mutation was reportedfollowing treatment with vanadium pentoxide.

8.7.2.2 Other pentavalent vanadium compounds

Human lymphocyte cells were incubated in theabsence of metabolic activation for 24 h with sodiummetavanadate, ammonium metavanadate, and sodiumorthovanadate at concentrations of 0, 2.5, 5, 10, 20, 40,80, or 160 µmol/litre (approximately 0, 0.13–8.0 µgvanadium/ml), and the induction of structural andnumerical 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 allstudies. There was no significant difference in theincidences of chromosome aberrations (excluding gaps,although the nature of the aberrations was not defined)induced by any of the three compounds, for any of thedose levels used. A statistically significant number ofhypoploid cells (missing chromosomes) was reported atall doses following treatment with sodium metavanadateand sodium orthovanadate and at the top two doseswith ammonium metavanadate. No significant increasesin the numbers of hyperploid or polyploid cells werereported.

Chinese hamster ovary cells were exposed to 0, 4,

8, or 16 µg ammonium metavanadate/ml (0, 1.7, 3.3, or 6.7µg vanadium/ml) for 2 h in the presence and absence ofmetabolic activation, and then for a further 22 h in freshmedium (Owusu-Yaw et al., 1990). At least 100metaphases per flask were scored for chromosomeaberrations (experiment carried out in duplicate).

Significant increases were reported in the numbersof chromosome aberrations (excluding gaps) inducedcompared with solvent control values in both thepresence and absence (up to 8 times controls in eachcase) of metabolic activation. The positive controls gaveappropriate responses.

Migliore et al. (1993) investigated the potential ofthree pentavalent vanadium compounds — sodiummetavanadate, ammonium metavanadate, and sodiumorthovanadate — to induce micronuclei in humanlymphocytes in vitro. The aneugenic potential wasinvestigated using fluorescence in situ hybridization(FISH), the number of micronuclei with fluorescent spots(centromere-positive micronuclei) being reported. Thefinal concentrations tested were 0 and 2.5–160 µmol/litre(approximately 0 and 0.13–8.0 µg vanadium/ml) in allexperiments, apart from the study involving in situhybridization, where only 0, 10, 40, and 80 µmol/litre(approximately 0, 0.5, 2.1, and 4.2 µg vanadium/ml) wereused. Cells were incubated with the test substances for48 h. Two thousand binucleated cells (when possible),100 clear first metaphases, and 25 clear secondmetaphases were analysed for micronuclei.

The highest dose of vanadium used, 160 µmol/litre,was found to be toxic to the cells in all studies.Ammonium metavanadate (up to 6% at the highestdose), sodium metavanadate (up to 4.6% at the highestdose), and sodium orthovanadate (up to 2.4% at thehighest dose) all induced a dose-related, statisticallysignificant number of micronuclei at 10 µmol/litre andabove, although the increases were in general relativelysmall. Dose-related decreases in the number ofbinucleated cells were also reported for all compounds,which could be due to general toxicity or specificinhibition of cell cytokinesis. A dose-related increase inthe number of micronuclei was reported in the cells usedfor the FISH technique, although the increases were, asbefore, relatively small. Statistically significant increasesin the numbers of centromere-positive micronuclei werereported at all dose levels for all the compounds, whichwere comparable with the positive control values.

The ability of ammonium metavanadate to inducemutations, with exogenous metabolic activation, at theHPRT locus in V79 cells in Chinese hamster ovary wasinvestigated 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 ammoniummetavanadate.

Ammonium metavanadate induced both mitoticgene conversion and reverse point mutation in the D7strain of Saccharomyces cerevisiae at dose levels of

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between 80 and 210 mmol/litre in both the presence andabsence of metabolic activation (Bronzetti et al., 1990).

Cell transformation and gap junctional intercellularcommunication were assessed in Syrian hamster embryocells exposed to 0, 0.2, 0.4, 1.9, 2.3, or 6.9 µmol sodiumorthovanadate/litre (Rivedal et al., 1990; Kerckaert et al.,1996). A marked increase in cell transformation wasnoted only at the highest concentration, although therewere no effects on cloning efficiency, indicating apositive result for genotoxicity in this system. There wasno observed effect on gap junctional intercellularcommunication.

8.7.2.3 Tetravalent vanadium compounds

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

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

Migliore et al. (1993) also investigated the potentialof vanadyl sulfate to induce micronuclei in humanlymphocytes. Dose-related decreases in the number ofbinucleated cells were also reported, although thesewere less pronounced than those observed withpentavalent vanadium compounds. A dose-related,statistically significant increase in the number ofmicronuclei was reported at 10 µmol/litre and above,although the increases were in general relatively small.Statistically significant increases in the numbers ofcentromere-positive micronuclei were reported at all doselevels.

Vanadyl sulfate induced no convertants or rever-tants in the D7 strain of S. cerevisiae at dose levels ofbetween 420 and 1000 mmol/litre in both the presenceand absence of metabolic activation (Galli et al., 1991).Also, no mutagenic activity was detected in hamster V79cells at dose levels between 0 and 7.5 mmol/litre in boththe presence and absence of metabolic activation.

No mutagenic activity was detected in hamster V79cells 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 increasedincidence of transformations in the C3H10T1/2 mousefibroblast cell line at dose levels up to 5 µg/ml (Doran etal., 1998).

8.7.2.4 Trivalent vanadium compounds

Using protocols similar to that previously ascribedto these authors, Chinese hamster ovary cells wereexposed to 12 or 18 µg vanadium oxide/ml (8.2 or 12.2 µgvanadium/ml) (Owusu-Yaw et al., 1990). Significantincreases in induction of chromosome aberrations werereported in both the presence (up to 4 times controls)and absence (up to 6 times controls) of metabolicactivation.

8.7.3 Sister chromatid exchange

Vanadium pentoxide did not increase incidences ofsister chromatid exchange, while studies with otherpentavalent, tetravalent, and trivalent compounds did, ina number of different cell systems, over a range of con-centrations (0.3–19.2 µg/ml) (Owusu-Yaw et al., 1990;Roldan & Altamirano, 1990; Migliore et al., 1993; Zhonget al., 1994). 8.7.4 Other in vitro studies

8.7.4.1 Vanadium pentoxide

A study by Rojas et al. (1996) investigated theinduction of DNA strand breaks in human lymphocytesby vanadium pentoxide using the Comet assay. At doselevels of 0.5, 5.5, and 546 µg vanadium pentoxide/ml, astatistically significant increase in DNA migration wasreported, indicating the DNA-damaging potential ofvanadium 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 ammoniummetavanadate to investigate the formation ofDNA–protein cross-links (Cohen et al., 1992). Dose-related increases in cross-links were reported following24-h exposure to ammonium metavanadate in both celltypes.

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

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8.6.4.3 Tetravalent vanadium compounds

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

8.7.5 In vivo studies in eukaryotes (somaticcells)

8.7.5.1 Vanadium pentoxide

Only very limited data are available (see section8.7.7).

8.7.5.2 Other pentavalent vanadium compounds

Ciranni et al. (1995) investigated the ability ofsodium orthovanadate and ammonium metavanadate toinduce chromosome aberration and aneuploidy in thebone marrow of male mice. Male mice (three perexperimental group or four per control group) wereadministered a single dose, intragastrically, of either 0 or75 mg sodium orthovanadate/kg body weight (21 mgvanadium/kg body weight) or 50 mg ammonium meta-vanadate/kg body weight (42 mg vanadium/kg bodyweight) dissolved in sterile water. Groups of animalswere sacrificed at 24 and 36 h post-dose.

Although increases in chromosome aberrationswere reported after 36 h with sodium orthovanadate andammonium metavanadate, these were not statisticallysignificant. No increases were seen at 24 h. Clear andstatistically significant increases in cells withhypoploidy and with hyperploidy were apparent at oneor both sampling times with both vanadium compounds.Statistically significant, dose-related increases in cellswith hypoploidy were reported following treatment withsodium orthovanadate and ammonium metavanadate.Statistically significant increases in cells with hyper-ploidy were reported 24 h post-treatment with sodiumorthovanadate and at both 24 and 36 h post-treatmentwith ammonium metavanadate. No significant inductionof polyploidy was reported.

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

Polychromatic erythrocyte/normochromaticerythrocyte (PCE/NCE) ratios were lower in the testanimals (down to 50% of control values at some timepoints), indicating that the vanadium compounds hadreached the bone marrow and expressed cytotoxicity.Compared with negative controls, there was a small butstatistically significant increase (at least twice controlvalues) in the percentage of PCEs with micronuclei forsodium orthovanadate at 24, 30, and 48 h and withammonium metavanadate at 18, 24, and 30 h.

8.7.5.3 Tetravalent vanadium compounds

Ciranni et al. (1995) also investigated the ability ofvanadyl sulfate to induce chromosome aberration andaneuploidy in the bone marrow of male mice. Male micewere administered a single dose, intragastrically, of 0 or100 mg vanadyl sulfate/kg body weight (0 or 31 mg vana-dium/kg body weight). A statistically significant increasein the number of aberrant cells (excluding gaps) wasfound at 24 and 36 h (4.3 and 2.7%, respectively, com-pared with 0.6% in negative controls). Statistically sig-nificant increases in cells with hypoploidy were reportedfollowing treatment at both sampling times and in cellswith hyperploidy 24 h post-treatment. No significantinduction of polyploidy was reported.

Groups of male mice were administered a singledose of 0 or 100 mg vanadyl sulfate/kg body weight (0 or31 mg vanadium/kg body weight) intragastrically(Ciranni et al., 1995). There was a small but statisticallysignificant increase (at least twice control values) in thepercentage 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 currentstandard Organisation for Economic Co-operation andDevelopment [OECD] guidelines) to investigate otherreproductive and genotoxic end-points, a dominantlethal-type assay was reported by Altamirano-Lozano etal. (1996). On the basis of deaths reported followingrepeated administration of 17 mg vanadium pentoxide/kgbody weight by intraperitoneal injection in a previousstudy by the same authors, male mice (15–20 per group)received 0 or 8.5 mg vanadium pentoxide/kg body weightin saline by intraperitoneal injection every third day for60 days. From day 61, each male had five overnightmatings with two untreated females, and successfulcopulation was determined by the presence of a copula-tion plug or sperm in the vagina.

A statistically significantly reduced body weight intreated animals at the end of the treatment period was

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reported (79% of control value). The study did not referto any other signs of toxicity in male mice. Whereas 34 of40 (85%) of the females mated with controls becamepregnant, 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 comparedwith controls (10.9 and 5.8 in the control and treatedgroups, respectively). A statistically significant increasein the number of resorptions per litter (0.2 and 2.0 in thecontrol and treated groups, respectively) and a statis-tically significant reduction in the number of live fetusesper litter (10.5 and 3.4 in the control and treated groups,respectively) were apparent in the vanadium pentoxidegroup. There was no statistically significant difference inthe numbers of dead fetuses per litter. Post-implantationloss (number of dead fetuses per number of livebornpups) was approximately 10 times greater in the treatmentgroup than in controls (0.41 and 0.04, respectively).

Given that vanadium pentoxide is poorly absorbedfollowing oral exposure and well absorbed and widelydistributed when inhaled, the use of the intraperitonealroute in this assay is considered a valid surrogate forrelevant exposure routes in this instance. Overall, whilethis study is of limited quality in view of the non-standard protocol, poor reporting, and clearly reducedpregnancy rate in females mated with treated males, theclear increases in resorptions per litter and post-implantation losses in the vanadium pentoxide group areindicative of a dominant lethal effect.

8.7.6.2 Other pentavalent and tetravalent vanadiumcompounds

There are no data available. 8.7.7 Supporting data

The following studies cited in a review prepared bySun (1987) have been included here as they providefurther supporting evidence of genotoxic activity ofvanadium pentoxide. However, no firm conclusions canbe 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 200µg/plate was tested in both the absence and presence ofS9 mix. The numbers of induced revertants at all testlevels were less than 2-fold greater than controlnumbers; hence, vanadium pentoxide gave a negativeresult under the conditions of the test.

In an E. coli reversion assay using strains WP2,WP2uvrA, CM891 (base pair substitutions), ND-160, andMR 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 andabsence of S9. A highly significant, dose-relatedincrease in the number of revertants was reported at 10,50, and 100 µg/plate in strains WP2, WP2uvrA, andCM891 in both the presence and absence of S9. Abovethese dose levels, vanadium pentoxide producedtoxicity. No significant increase was reported in strainsND-160 and MR 102.

Vanadium pentoxide did not increase incidences of

sister chromatid exchange in vitro over a range of con-centrations (0.3–30 µg/ml) (Sun, undated).

Bone marrow micronucleus tests on vanadiumpentoxide via the intraperitoneal, subcutaneous, inhala-tion, and oral routes in mice are briefly reported (Si et al.,1982; Yang et al., 1986b,c; Sun et al., undated). Astatistically significant increase (approximately doubled)in the frequency of micronucleus formation was reportedat all dose levels in mice administered 0, 0.2 (or 0.7), 2, or6 mg vanadium pentoxide/kg body weight intra-peritoneally daily for 5 days. A positive result was alsoreported in mice following subcutaneous administrationof 0.25, 1.0, or 4.0 mg vanadium pentoxide/kg bodyweight, 6 days/week, for 5 weeks, although no furtherdetails were provided. An increase in the frequency ofmicronuclei was reported following exposure of mice to0, 0.5, 2.0, or 8.0 mg vanadium pentoxide dust/m3 (nodetails of dust characteristics given). No increase ininduction of micronuclei was reported in mice orallyadministered 1, 3, 6, or 11 mg vanadium pentoxide/kgbody 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 pentavalentvanadium compounds

No fertility studies are available on vanadiumpentoxide.

Groups of 24 male mice received sodium meta-vanadate in drinking-water for 64 days at concentrationsof 0, 20, 40, 60, or 80 mg/kg body weight per day (Llobetet al., 1993). At the end of the exposure period, eachgroup was divided into two subgroups: a group of8 animals for a mating trial and a group of 16 animals forpathology and sperm examinations (utilizing postmortemsamples). In the fertility study, each male was mated withtwo untreated females for 4 days. The females weresacrificed 10 days after the end of the mating period andtheir uterine contents examined.

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A 13% reduction in male body weight was appar-ent in the 80 mg/kg body weight group, compared withthe controls, immediately after the exposure period.Decreases relative to the controls in the number ofpregnant females were reported in some of the vana-dium-treated group, but no dose–response relationshipwas observed. No information was given on matingbehaviour. There were no significant differencesbetween the groups regarding the numbers of implan-tations, early or late resorptions, or dead or live fetuses.In males, no significant differences were observed intestes weights. Absolute epididymis weight was reducedat 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 thisdose group. A significant 30% reduction in spermatidcount was reported at 80 mg/kg body weight, and asignificant decrease in spermatozoal count was reportedat 60 and 80 mg/kg body weight, although this was notclearly dose-related (99%, 104%, 56%, and 69% ofcontrol values in the 20, 40, 60, and 80 mg/kg bodyweight groups, respectively). There were no significantdifferences in sperm motility or sperm abnormalitiesbetween the groups. No histopathological changes werereported between the groups.

This study suggests the possibility that oral expo-sure of male mice to sodium metavanadate at 60 and80 mg/kg body weight directly caused a decrease inspermatid/spermatozoal count and in the number ofpregnancies produced in subsequent matings. However,the results are not convincing, and significant generaltoxicity, reflected in decreased body weight gain, wasalso evident at 80 mg/kg body weight. Overall, theresults do not provide convincing evidence that oralexposure to sodium metavanadate produced specificfertility 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 perday in vegetable oil by oral gavage on days 6–15 ofgestation (Yang et al., 1986a). Animals were sacrificed onday 20 of gestation and the uterine contents examined.The numbers of implantations, resorptions, and live anddead fetuses were recorded. Fetuses were examined forgross anomalies, and fetal body weight and length weremeasured. One-third were subsequently examined forvisceral abnormalities, and two-thirds for skeletalabnormalities.

Statistically significant decreases in maternal bodyweight gain were reported in animals of the 9 and18 mg/kg body weight groups (75% and 40% of controlvalues, respectively). No treatment-related increases inthe numbers of resorptions or dead fetuses wereobserved, although the results were not reported on aper litter basis. Fetal body weight, body length, and taillength were all statistically significantly decreased in thetop dose group (87%, 92%, and 94% of control values,respectively).

Delayed occipital ossification (top-dose animals)and non-ossification or delayed ossification of thesternum (all dose groups) were reported; however, theseresults were not given on a per litter basis, and so theirsignificance is unclear. It was also observed that skeletalabnormalities were statistically significantly increased inthe top two dose groups, but again these findings werenot 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 significantmaternal toxicity. Furthermore, bearing in mind the natureof the abnormalities seen and data not having beenrelated to the litter as a unit, no decision can be maderegarding the reliability of the reported findings.

8.8.2.2 Other pentavalent vanadium compounds

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

No information regarding maternal toxicity wasreported. 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 numbersper litter of corpora lutea, implantations, resorptions, orlive fetuses between the groups. A non-dose-relatedincrease in the number of abnormal fetuses was reported.No visceral or skeletal abnormalities were reported.Although fetal dermal haemorrhage (haematoma) in thefacial area, dorsal area, thorax, and extremities wasreported, this is a common background finding indevelopmental toxicology studies and is not consideredto be an indicator of specific developmental toxicity.Hydrocephaly was reported in 2 of 98 fetuses at20 mg/kg body weight compared with none in othergroups. No significant difference was reported for fetalbody weight or body length. Overall, there is no clearevidence of direct developmental toxicity followingexposure to sodium metavanadate.

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Groups of 18–20 pregnant mice were administered0, 7.5, 15, 30, or 60 mg sodium orthovanadate/kg bodyweight (0, 2.1, 4.2, 8.3, or 16.6 mg vanadium/kg bodyweight) in deionized water by oral gavage on days 6–15of pregnancy (Sanchez et al., 1991). The animals weresacrificed on day 18 of pregnancy.

Severe maternal toxicity resulted from the dosingwith 30 and 60 mg/kg body weight (4/18 and 17/19 dams,respectively, died as a result of treatment). The tworemaining dams at 60 mg/kg body weight were notincluded in the final evaluation. Body weight gain wassignificantly reduced (approximately 20%) at 15 mg/kgbody weight. However, no significant difference wasreported at the end of the study. No differences werereported in final body weight, gravid uterine weight, orcorrected body weight. There were no differences in thenumber of total implants per dam, number of live fetusesper dam, sex ratio, average fetal body weight, or thenumber of stunted fetuses. There were also no differ-ences between the groups in the incidences of skeletalor visceral abnormalities. There was some evidence ofdelayed ossification at 30 mg/kg body weight; this isconsidered to be a secondary consequence of thepronounced maternal toxicity produced at this doselevel. Overall, sodium orthovanadate did not producedevelopmental toxicity in this thorough investigation.

8.8.2.3 Tetravalent vanadium compounds

Groups of 22 pregnant mice were administeredvanadyl sulfate pentahydrate at 0, 37.5, 75, or 150 mg/kgbody weight per day by gavage on days 6–15 of gesta-tion (Paternain et al., 1990). The animals were sacrificedon day 18 of gestation. Three fetuses from each damwere used for whole-body analyses of vanadium. Afterexternal examination, one-third of the remaining fetuseswere examined for visceral abnormalities and the rest forskeletal abnormalities.

Over the study period, there was a dose-relateddecrease in body weight gain down to 62% of controlvalues at 150 mg/kg body weight, with no correspondingdifference in food consumption. Final body weights weresignificantly reduced (81%, 83%, and 80% of controls,respectively), and corrected body weights, minus thegravid uterine weight, were also significantly reduced(88%, 84%, and 83% of controls, respectively). Therewere no differences in the mean numbers of totalimplants per dam, live fetuses per dam, late resorptionsper dam, or dead fetuses per dam. Fetal body weight wassignificantly reduced at all dose levels (87%, 87%, and79% of control values, respectively), as was fetal bodylength (97%, 85%, and 82% of control values, respec-tively). The major dose-related effects externally wereincreased incidence of cleft palate (an abnormality with asignificant background incidence in mice) at 75 and

150 mg/kg body weight (4 fetuses in 3 litters and58 fetuses in 12 litters, respectively) and micrognathiaat 37.5, 75, and 150 mg/kg body weight (2 fetuses in1 litter, 3 fetuses in 1 litter, and 12 fetuses in 3 litters,respectively). The only visceral abnormality reportedwas 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 studyoccurred in the presence of significant maternal toxicityas defined by decreased body weight gain. It is possiblethat the fetal effects were secondary to maternal toxicity.Unfortunately, the study did not include a dose level atwhich there was no maternal toxicity.

A number of other studies have been reported inwhich vanadium compounds have been administered viaintraperitoneal, 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 skeletalabnormalities, increased numbers of resorbed/deadfetuses, increased incidences of delayed ossification,and decreased fetal body weight and length. However,given the routes of exposure used, no conclusion can bedrawn from these studies in relation to the potentialdevelopmental toxicity of vanadium compounds inhumans exposed occupationally.

8.9 Immunological and neurologicaleffects

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 andsubsequently lysed for RNA isolation. Hybridizationstudies were conducted to determine the expression ofcytokines. BAL indicated a significant, dose-relatedinflux of neutrophils in the lungs, and the Northern blotanalysis demonstrated increased mRNA expression ofmacrophage inflammatory protein-2 and another cyto-kine, KC. The results demonstrate an inflammatoryresponse in the lungs associated with exposure tovanadium pentoxide.

Groups of 10 male Wistar rats received vanadiumpentoxide in drinking-water for a period of 6 months atconcentrations of 0, 1, or 100 mg vanadium/litre. Simi-larly, 10 male and 10 female ICR mice were given 0 or

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6 mg vanadium pentoxide/kg body weight by gavage,5 days/week for 6 weeks. The study focused onassessing the immunotoxicity of vanadium and recordedthe weight of the spleen and thymus, spleen cellularity,leukocyte count in peripheral blood, indicators of non-specific immunity (phagocytosis, natural killer cellactivity), and humoral as well as cell-mediated immunity(Mravcova et al., 1993).

The study demonstrated an enlargement of thespleen in rats exposed to vanadium at a concentration of100 mg/litre, the same finding as in mice, although withdiminished spleen cellularity in mice. Thymus weightwas not influenced. The leukocyte count in peripheralblood was increased significantly in both rats and mice.In rats and mice, a decrease in phagocytosis, which wasdose-dependent in rats, was found. In exposed mice,there appeared signs of intense response to mitogensand high stimulation of B-cells in the plaque-formingcells assay. Activation of T- and B-cells and themagnitude of the response to concanavalin A indicatepotential 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 noseonly 8 h/day for 4 days to atmospheres containing eitherfiltered air or approximately 2 mg vanadium/m3 in theform of ammonium metavanadate aerosol (0.32 µmMMAD) (Cohen et al., 1996a,b). Twenty-four hours afterthe final exposure, BAL was performed on the rats. Cellsgathered in this process were used to assess the effectsof vanadium on tumour necrosis factor alpha (TNF-")production, radical oxygen ion production, interferon-(-induced Class II/I-A antigen expression, and phagocyticactivity.

There was no significant difference in the numbersof alveolar macrophages in the BAL fluid taken fromexposed and control animals. Induced production ofTNF-" by these macrophages was decreased followingvanadium exposure, as was the ability to increase cellsurface Class II/I-A antigen expression induced byinterferon-(. The ability of the macrophages to produceradical oxygen anions in response to stimulation wasalso reduced following vanadium exposure. The reportsuggests that vanadium exposure could alter hostimmunocompetence through an inhibitory effect onmacrophage 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 onvanadium 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, morepotent than with vanadium pentoxide, associated withexposure 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 (sections8.9.1 and 8.9.2), groups of 6–8 female rats received asolution of 0, 0.021, or 0.21 mg vanadyl sulfate inphosphate-buffered saline by single intratrachealadministration (Pierce et al., 1996). Procedures were aswith the work on vanadium pentoxide (section 8.9.1).

Results were similar to those obtained with vana-dium pentoxide, but occurred earlier and lasted longerthan with either vanadium pentoxide or sodium meta-vanadate, indicating that, in this assay, this substancewas the most potent in an inflammatory response.

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

9. EFFECTS ON HUMANS

9.1 Studies on volunteers

9.1.1 Vanadium pentoxide

Nine healthy volunteers were exposed to vanadiumpentoxide dust (98% <5 µm) in an exposure chamber(Zenz & Berg, 1967). Each subject underwent a completephysical evaluation, chest X-ray, haematological andurine analysis, and pulmonary function tests prior to andimmediately after exposure.Two volunteers were exposedto 0.1 mg/m3 for 8 h. No symptoms occurred during orimmediately after exposure. Within 24 h, considerablemucus had formed. This was easily cleared by slightcoughing, increased after 48 h, subsided within 72 h, andcompletely disappeared after 4 days. Five volunteerswere exposed to 0.25 mg/m3 for 8 h. All developed aloose, productive cough the following morning. Allsubjects had stopped coughing by the tenth day.Physical examination revealed nothing of clinicalsignificance, and pulmonary function tests showed nochange compared with pre-exposure values. Twovolunteers were exposed to 1 mg vanadium pentoxide

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dust/m3 for 8 h. Sporadic coughing developed after 5 h,and more frequent coughing developed by the end ofthe 7th hour. Persistent cough remained for 8 days.Chest examinations revealed clear lung fields, and nodifferences were reported in pulmonary function testsperformed before, immediately after, or once weekly for3 weeks after exposure. Three weeks after the initialexposure, the same volunteers were accidentally exposedto a heavy cloud of vanadium pentoxide dust (unknownconcentration) for a 5-min period while waiting foranother test, resulting in marked coughing (which per-sisted for about 1 week), production of sputum, rales,and expiratory wheezes. Pulmonary function was allegedto be normal, although the reliability of this claim isconsidered doubtful in view of the severity of the clinicalobservations.

9.1.2 Other pentavalent vanadium compounds

Five male medical students received an oraladministration of 100 or 125 mg diammonium oxy-tartratovanadate/day (approximately 1.7 mg/kg bodyweight per day, assuming 70 kg body weight) for6 weeks (Curran et al., 1959). No overt evidence oftoxicity was reported in any of the men. No change incomplete blood counts, including platelets, routineurinalyses, blood urea nitrogen, blood glucose, serumcholesterol esters, serum alkaline phosphatase, serumtransaminase, or serum bilirubin was reportedthroughout the study. No further investigations wereconducted.

9.1.3 Tetravalent vanadium compounds

Vanadyl sulfate is apparently used by someweight-training athletes in an attempt to improveperformance, as it has been claimed to lower bloodcholesterol levels. A double-blind trial by Fawcett et al.(1996, 1997) investigated the effects of administration ofvanadyl sulfate on haematological indices, bloodviscosity, and biochemistry in weight-training athletes.The treatment group (11 males; 4 females) was orallyadministered 0.5 mg/kg body weight per day for 12weeks, and a control group (12 males; 4 females) receivedplacebo capsules. At the end of the study, there were nosignificant differences between the groups in terms ofbody weight, blood pressure, standard haematologicalindices, blood viscosity, or standard blood biochemistrymeasurements.

A group of 12 volunteers received 75 mg diammo-nium vanadotartrate/day orally for 2 weeks, followed by125 mg/day for the remaining 5.5 months (Somerville &Davies, 1962). Two subjects withdrew due to “toxicgastrointestinal effects.”

There was no significant effect on serum choles-terol levels. However, five patients had persistent upper

abdominal pain, anorexia, nausea, and weight loss.These symptoms improved when dosing was stopped orreduced. Five men developed “green tongue” and oneother 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 orbiochemical indication of toxicity and no effect oncirculating lipids were reported. There were no otherinvestigations conducted.

9.2 Clinical and epidemiological studiesfor occupational exposure

9.2.1 Vanadium pentoxide

Eye irritation has been reported in studies in vana-dium workers (see Lewis, 1959; Zenz et al., 1962; Lees,1980; Musk & Tees, 1982). Patch testing in workforceshas produced two isolated reactions, although no skinirritation was reported in 100 human volunteers followingskin patch testing with 10% vanadium pentoxide inpetrolatum. The underlying reason for the skinresponses in workers is unclear (Motolese et al., 1993).

Zenz et al. (1962) reported on 18 workers exposedto varying degrees to vanadium pentoxide dust (meanparticle size <5 µm) in excess of 0.5 mg/m3 (apparentlymeasured over a 24-h period) during a pelletizingprocess. Three of the most heavily exposed men devel-oped symptoms, including sore throat and dry cough.Examination of each on the third day revealed markedlyinflamed throats and signs of intense persistentcoughing, but no evidence of wheezing or rales. Thethree men also reported “burning eyes,” and physicalexamination revealed slight conjunctivitis. Uponresumption of work after a 3-day exposure-free period,the symptoms returned within 0.5–4 h, with greaterintensity than before, despite the use of respiratoryprotective equipment. After 2 weeks of the process, all 18workers, including those primarily assigned to office andlaboratory duties, developed symptoms and signs ofvarying degrees, including nasopharyngitis, hackingcough, and wheezing. This study confirms thatvanadium pentoxide exposure can produce respiratoryand also eye irritation.

Lees (1980) reported signs of respiratory irritation

(cough, respiratory wheeze, sore throat, rhinitis, andnosebleed) and eye irritation in a group of 17 boilercleaners. However, as there was no control group and itwas unclear whether other compounds were present, noconclusions can be drawn regarding the cause or signifi-cance of these symptoms. However, the findings arecompatible with other studies on inhalation of vanadiumpentoxide.

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A study by Kiviluoto (1980), using a respiratoryquestionnaire, chest radiography, and tests ofventilatory function (FVC and FEV1), investigated 63men who had worked at a factory refining vanadiumpentoxide from magnetite ore for at least 4 months.These men were matched for age and smoking habit with63 workers at a magnetite ore mine in the same area,presumably not exposed or negligibly exposed tovanadium pentoxide.

Overall, on the basis of pulmonary function tests

and a questionnaire of respiratory symptomatology,there were no indications of vanadium-induced ill-healthin this workforce.

A further study, in which haematological andbiochemical analyses were performed, is reported in thesame group of workers as above by Kiviluoto et al.(1981b). All the haematological results were withinreference values, and there were no statistical differencesbetween the groups. Although there were significantdifferences between control and exposed groups inserum concentrations of albumin, chloride ions, bilirubin,conjugated bilirubin, and urea, these were not clinicallysignificant, as the magnitude of change was small,subject to interindividual variation, and liable to havearisen by chance.

Levy et al. (1984) studied respiratory tract irritationin a group of 74 boilermakers. Vanadium pentoxide fumein air was measured from various parts of the boiler andranged between 0.05 and 5.3 mg/m3 (time period ofmeasurement not stated). The boilermakers worked10 h/day, 6 days/week, and reported symptoms afteronly a couple of days.

The incidence of respiratory tract symptomatologywas high, a finding that is compatible with other studieson inhalation of vanadium pentoxide. However, it isdifficult to draw firm conclusions from this study due tothe potential for mixed exposures to have occurred (e.g.,especially sulfur dioxide, but also chromium, nickel,copper, iron oxide, and carbon monoxide), and also nocontrol group was utilized for comparison.

A study by Lewis (1959) investigated 24 menexposed to vanadium pentoxide for at least 6 monthsfrom two different centres. These were age-matched with45 control subjects from the same areas. The level ofexposure to vanadium pentoxide was between 0.2 and0.92 mg/m3 (0.11 and 0.52 mg vanadium/m3; time period ofmeasurement not stated). In the exposed group, 62.5%complained of eye, nose, and throat irritation (6.6% incontrol), 83.4% had a cough (33.3% in control), 41.5%produced sputum (13.3% in control), and 16.6% com-plained of wheezing (0% in control). Physical findingsincluded wheezes, rales, or rhonchi in 20.8% (0% in

controls), injection (i.e., hyperaemia) of the pharynx andnasal mucosa in 41.5% (4.4% in controls), and “greentongue” in 37.5% (0% in controls).

It is not clear what levels or duration of exposurewere experienced by the workers who presented withsymptoms. However, the findings reinforce the picture ofexposure to vanadium pentoxide causing eye andrespiratory tract effects.

A group of 69 workers in the Czech Republic was

exposed for periods ranging from 0.5 to 33 years (meanduration of exposure 9.2 years) in the manufacture ofvanadium pentoxide from slag rich in vanadium (Kuceraet al., 1994). The concentration of vanadium in theambient air at the work sites was 0.016–4.8 mg/m3. Forcomparison, a group of 33 adult subjects not exposed tovanadium was investigated to assess the influence ofsuch exposure. The authors stated that there were nosymptoms of adverse health effects related to vanadiumreported in the workers, although it was unclear whatinvestigations had been conducted to support thisassertion.

Huang et al. (1989) conducted a clinical and radio-logical investigation of 76 workers in a ferrovanadiumworks, who had worked in the plant between 2 and28 years. In the exposed group, out of 71 examined, 89%had a cough (10% in controls), expectoration was seen in53% (15% in controls), 38% were short of breath (0% incontrols), and 44% had respiratory harshness or drysibilant rale (0% in controls). Of 66 of the exposed groupexamined, hyposmia or anosmia was reported in 23% (5%in controls), congested nasal mucosa in 80% (13% incontrols), erosion or ulceration of the nasal septum in9% (0% in controls), and perforation of the nasal septumin 1 subject (0 in controls). Chest X-rays of all 76exposed subjects revealed 68% with increased, coars-ened, and contorted bronchovascular shadowing (23%in controls).

While exposure to vanadium compounds may havecontributed to the clinical findings and symptomsreported, no firm conclusion can be drawn from thisstudy in this regard, as mixed exposures are likely tohave occurred, including possibly to hexavalent chro-mium used in alloy production or chromium plating(some of the effects described, particularly nasal septumperforation, are consistent with chromium toxicity).

The case histories of four men were reported byMusk & Tees (1982). One worker was exposed to largeamounts of dry ammonium vanadate dust over a 6-hperiod while shovelling powder into a bin. Within 2 h ofcommencing work, retro-orbital headache, epiphora(tears), dry mouth, and green discoloration of the tongue

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were reported. There was a marked green discoloration ofthe skin of the fingers (despite the use of gloves),scrotum, and upper legs. His nose was reported to bestuffy, and he was lethargic. The next day, his testicleswere swollen and tender, and, on the third day afterexposure, he developed wheezing, dyspnoea, and acough productive of green sputum. He had several smallhaemoptyses over the following 2 weeks. Wheezing anddyspnoea persisted for about 1 month; chest symptomswere at their worst 3 weeks after the incident. Onexamination 6 weeks after the last exposure, he wasasymptomatic, with the exception of a partially blockedleft nostril and the reddened appearance of nasalmucosa. Chest examination revealed no abnormality.Pulmonary function assessment showed normal lungvolume, forced expiratory flow rate, and gas transfer. Hehad a mild eosinophilia of the peripheral blood.

The other three workers also reported broadlysimilar findings (e.g., green discoloration of the tongueand skin, respiratory difficulties) associated withexposure to vanadium pentoxide.

In a further study of workers exposed to vanadiumpentoxide, one worker exposed to up to 0.1 mg/m3 for30 min/day on a regular basis displayed thecharacteristic “green tongue” associated with vanadiumexposure (Kawai et al., 1989). This effect was notobserved in the two other workers regularly workingwith vanadium pentoxide (albeit at much lower levels).The limited number of samples and people in this studyprecluded any assessment of a dose–responserelationship for “green tongue.”

A similar, but slight, impairment of pulmonaryfunction (FEV1 reduced by less than 4%) was observedover a 4-week work period in a prospective study of agroup of 26 boilermakers with personal exposures toaround 0.0016–0.032 mg/m3 “vanadium” (form unspec-ified) (Hauser et al., 1995). However, no firm conclusionscan be drawn owing to the mixed exposures that werelikely to have been encountered and the small magnitudeof the reported change. There was also a lack ofexposure–response relationship.

Similarly, green tongue and irritation of the upperrespiratory tract were reported in a group of 10 boilermaintenance workers (Todaro et al., 1991). Urinaryvanadium levels were recorded, but there was no report-ing of air monitoring values or indication of othersubstances that may have been present. A small range ofblood biochemistry parameters was recorded for up to2 years after a change in the work (which presumably ledto reduced exposure), but no changes were observed.Overall, no useful conclusions can be drawn from thisstudy.

A link between workers exposed to vanadium andasthma/bronchial hyperresponsiveness has been claimed(Irsigler et al., 1999). However, less than 1% of workersshowed bronchial hyperresponsiveness. Although itwas reported that some of these worked in a part of thefactory with the highest vanadium exposures, it isunclear how many other men also worked there but wereunaffected by exposure. Indeed, details of the numbersof men in various parts of the factory were not given.Also, the previous medical histories of the affected menare unclear. There does not appear to be a comparisonwith 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 generalpopulation exposure

Early correlational studies relating general concen-trations of vanadium in the environment to mortalityfigures are summarized in IPCS (1988); no cause–effectrelationships can be established from these studies,which give conflicting results. A single epidemiologicalstudy, where individual exposure could be assessed, hasbeen conducted of general population exposure to dustsgenerated by a plant processing vanadium-rich slag. It isestimated that an area with a radius of 3 km was exposedto 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, withsampling conducted over 2 years. Venous blood, saliva,hair, and fingernail clippings were collected from thechildren. Dust aerosol, ambient air, soil, and drinking-water were analysed from the local environment. Healthstatus was assessed based on haematologicalparameters (blood cell and platelet counts, haematocrit,mean corpuscular volume, and haemoglobin), specificimmunity (IgA, IgE, IgG, secretory IgA, IgM, transferrin,"-1-antitrypsin, $-2-microglobulin), cellular immunity(phagocytosis of peripheral leukocytes, stimulation of T-lymphocyte mitogenic activity), cytogenic analysis(frequency of chromosome aberrations in peripherallymphocytes, sister chromatid exchange), and serumlipids (cholesterol, triglycerides). Children from theexposed groups had lower red blood cell counts thancontrols, a decrease in levels of serum and secretoryIgA, and a seasonal decrease in IgG. Marked differencesbetween groups were seen in natural cell-mediatedimmunity, with significantly higher mitotic activity of T-lymphocytes in children from the immediate vicinity ofthe plant. A higher incidence of viral and bacterialinfections was registered in children from the exposedlocality. However, the study could not control for

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confounding by exposures to compounds other thanvanadium. Cytogenetic analysis revealed no genotoxiceffects. Vanadium levels in hair were elevated in childrenliving close to the plant. In another group living fartheraway, those with parent(s) working at the plant hadhigher levels in hair than those whose parent(s) did not,indicating exposure in the home from dust transferred onworking clothes (Kucera et al., 1992). The overallconclusion reached was that long-term exposure tovanadium had no negative impact on health; differencesobserved were within the range of normal values in allcases (Lener et al., 1998).

10. EFFECTS ON OTHER ORGANISMS INTHE LABORATORY AND FIELD

10.1 Aquatic environment

The toxicity of vanadium to aquatic organisms issummarized in Table 5.

In six of seven lakes studied, the addition ofvanadium at concentrations in the 2–165 ×10–7 mol/litrerange decreased photosynthetic rates of phytoplankton.Simple correlation analysis revealed that only biomassand proportion of cyanobacteria were significantlycorrelated (P < 0.05) with the response to vanadium. Theauthors concluded that lakes characterized by highphytoplankton biomass, high proportion of cyano-bacteria, and low proportion of Bacillariophyta andChrysophyta are most vulnerable to inhibition ofphotosynthesis by vanadium (Nalewajko et al., 1995).

Ringelband & Karbe (1996) found that populationgrowth in the brackish water hydroid Cordylophoracaspia was significantly impaired at 2 mg vanadium/litreover a 10-day exposure period.

Fichet & Miramand (1998) observed a significantreduction in the development of normal oyster (Crassos-trea gigas) larvae exposed to 0.05 mg vanadium/litre for48 h. A significant reduction in pluteus development inurchin (Paracentrotus lividus) larvae was found at0.1 mg/litre, but not at 0.05 mg/litre, over the same timeperiod. In 8-day exposures, significant mortality wasobserved in brine shrimp (Artemia salina) larvae at0.25 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 mgvanadium/litre.

Stendahl & Sprague (1982) reported weight-adjusted 7-day LC50s ranging from 1.9 to 6 mg vanadium/litre in tests at various levels of total hardness (30, 100,and 355 mg/litre) and pH (5.5–8.8). Toxicity decreasedfrom low to high hardness by an average factor of 1.8.Toxicity was greatest at pH 7.7, and the predominatingion 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 mgvanadium/kg diet for 12 weeks. All levels of supple-mented vanadium significantly reduced growth andfeeding response in the trout. Feed avoidance andsignificantly increased mortality were reported at>493 mg/kg diet.

10.2 Terrestrial environment

Cannon (1963) reported detrimental effects onplants at aqueous vanadium concentrations of 10–20 mg/litre; however, higher concentrations can betolerated by legumes that use vanadium in the nitrogenfixation process.

The growth of flax and cabbage was reduced at avanadium 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 mediumcaused iron deficiency chlorosis in sugar beet plants,and growth was reduced by 30–50%.

In soil, the concentration of vanadium causingtoxic effects in plants may range between 10 and1300 mg/kg, depending on plant species, the form ofvanadium, and soil type (Hopkins et al., 1977). Kaplan etal. (1990) found that vanadium concentrations of80 mg/kg caused significant reductions in Brassicabiomass in sandy soil; however, concentrations of up to100 mg/kg had no effect in loamy sand. The differentialresponse was attributed to greater accumulation ofvanadium by plants grown in sand. Similarly, significantreductions in dry matter yield of shoots and roots ofsoybean were observed at 30 mg/kg in fluvo-aquic soil,whereas no effect was found at 75 mg/kg in oxisolsderived from red sandstones in China (Wang & Liu,1999).

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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

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11. EFFECTS EVALUATION

11.1 Evaluation of health effects

11.1.1 Hazard identification and dose–responseassessment

In animals, pentavalent vanadium has been shownto accumulate in the lung following repeated exposure.There is information suggesting that inorganic vanadiumcompounds are absorbed following inhalation andsubsequently excreted via the urine with an initial rapidphase of elimination, followed by a slower phase, whichpresumably reflects the gradual release of vanadium frombody tissues.

Oral studies indicate that vanadium compoundsare poorly absorbed from the gastrointestinal tract. Nodermal studies are available.

Absorbed vanadium in either pentavalent ortetravalent 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 excretionindicates that there is potential for accumulation andretention of absorbed vanadium, particularly in the bone.One oral study indicates that tetravalent vanadium hasthe ability to cross the placental barrier to the fetus.

An LC67 of 1440 mg/m3 (800 mg vanadium/m3) hasbeen reported following 1-h inhalation exposure of ratsto vanadium pentoxide dust. Oral studies in rats andmice produced LD50 values in the range 10–160 mg/kgbody weight (6–90 mg/kg body weight as vanadium) forvanadium pentoxide and other pentavalent vanadiumcompounds, whereas tetravalent vanadium compoundshave LD50 values in the range 448–467 mg/kg bodyweight (90–94 mg/kg body weight as vanadium). Noinformation is available concerning dermal toxicity.

Eye irritation has been reported in studies invanadium workers. Patch testing in workforces hasproduced two isolated reactions. No skin irritation wasreported in 100 human volunteers following skin patchtesting with 10% vanadium pentoxide. No information isavailable from animal studies with regard to the potentialof vanadium compounds to produce skin or eye irrita-tion. Overall, the potential for vanadium and vanadiumcompounds to produce skin irritation on direct contact isunclear. No conventional animal skin sensitizationstudies have been reported.

The effects on the respiratory tract of single andrepeated inhalation exposure (and combinations thereof)

to pentavalent vanadium compounds have beeninvestigated or reported in animals and humans. Thedata are of variable quality. No studies are available ontetravalent forms of vanadium.

Inhalation studies in primates reported changes inpulmonary function and inflammatory cell parametersfollowing a 6-h exposure to 3 or 5 mg vanadium pentox-ide aerosol/m3 (1.7 or 2.8 mg vanadium/m3). Subchronicexposure did not lead to an exacerbation of this acuteresponsivity 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 mgvanadium/m3) did not enhance bronchial reactivity tovanadium pentoxide or methacholine. Respiratorydistress developed in three animals from a group of nineexposed to the intermittent peaks of 1.1 mg vanadiumpentoxide/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 tracttoxicity in rats and mice following exposure for 6 h/day, 5days/week, for 13 weeks. At 2 mg vanadium pentoxide/m3 (1 mg vanadium/m3) and above, dose-related toxicityto the respiratory tract has been observed in rodents,including hyperplasia and metaplasia of the respiratoryepithelium and lung fibrosis and inflammation.

A study in human volunteers showed that a single8-h exposure to 0.1 mg vanadium pentoxide dust/m3

leads to delayed but prolonged bronchial effects involv-ing excessive production of mucus. The mechanismunderlying this response is uncertain, as no subjectiveirritant symptoms were reported during exposure. At 0.25mg/m3, a similar pattern of response was seen, with theaddition of cough for some days post-exposure. Expo-sure to 1.0 mg/m3 produced persistent and prolongedcoughing after 5 h. A no-effect level for bronchial effectswas not identified in this study.

The workplace studies available lack informationon the nature and extent of past occupational exposureand provide only limited information on exposures at thetime of the study. There is the likelihood that mixedexposures may have occurred, although the appearanceof green coloration of the tongue indicates that exposureto vanadium pentoxide is likely. The generally poor-quality data available indicate that repeated inhalationexposure to the dust and fume of vanadium pentoxide isassociated 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 theexposure–response relationship for the respiratoryeffects of vanadium pentoxide dust and fume in humans.

Vanadium pentoxide and other inorganic vanadium compounds

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Oral studies involving repeated exposure, althoughof poor quality, are available for both pentavalent andtetravalent forms of vanadium in both humans andanimals, although vanadium pentoxide has not beenstudied. No dermal studies are available, although it isnot expected that vanadium will be absorbed across theskin to any significant extent. The limitations of therepeated oral dosing studies are such that it is not pos-sible to characterize a dose–response relationship for thetoxicity of any form of vanadium in animals or inhumans; one study in rats produced evidence of spleenand kidney toxicity with a drinking-water intake of2.1 ppm (mg/litre) vanadium and above, as sodiummetavanadate.

Pentavalent and tetravalent forms of vanadiumhave produced aneugenic effects in vitro. There is evi-dence that these forms of vanadium as well as trivalentvanadium can also produce DNA/chromosome damagein vitro, both positive and negative results havingemerged from the available studies. The weight of evi-dence from the available data suggests that vanadiumcompounds do not produce gene mutations in standardin vitro tests in bacterial or mammalian cells.

In vivo, both pentavalent and tetravalent vanadiumcompounds have produced clear evidence of aneuploidyin somatic cells. There is some limited evidence forvanadium compounds also being able to express clasto-genic effects. Only one study is available on thepotential of vanadium compounds to produce germ cellmutagenicity. A positive result was obtained in micereceiving vanadium pentoxide by intraperitonealinjection, indicating the potential for vanadium to act asa germ cell mutagen. However, the underlyingmechanism for this effect (aneugenicity; clastogenicity)is uncertain. It is also unclear how these findings can begeneralized to more realistic routes of exposure or toother vanadium compounds.

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

No useful information is available regarding thecarcinogenic potential of any form of vanadium via anyroute of exposure in animals1 or in humans.

The potential for vanadium compounds to exerteffects on fertility has been very poorly investigated. Afertility study in male mice involving exposure to sodiummetavanadate in drinking-water suggests the possibilitythat oral exposure of male mice to sodium metavanadateat 60 and 80 mg/kg body weight directly caused adecrease in spermatid/spermatozoal count and in thenumber of pregnancies produced in subsequent matings.However, significant general toxicity, reflected indecreased body weight gain, was also evident at80 mg/kg body weight.

There are a number of developmental studies onpentavalent and tetravalent vanadium compounds, and aconsistent observation is that of skeletal anomalies.Interpretation of these studies is difficult because ofunconventional routes of exposure and evidence ofmaternal toxicity that may itself contribute to the effectsseen in pups.

11.1.2 Criteria for setting tolerable intakes orguidance values for vanadium pentoxide

The toxicological end-points of concern aregenotoxicity and respiratory tract irritation. Vanadiumpentoxide is considered to be a somatic and germ cellmutagen, and there is some, although not conclusive,evidence to indicate the involvement, at least in part, ofaneugenicity. It is not possible to clearly identify thethreshold level, for any route of exposure relevant tohumans, below which there would be no concern forpotential genotoxic activity. In addition, repeatedinhalation exposure to the dust and fume of vanadiumpentoxide is associated with irritation of the eyes, nose,and throat and impaired pulmonary function. Similarly,there are insufficient data to reliably describe theexposure–response relationship for the respiratoryeffects of vanadium pentoxide dust and fume in humans.Since it is not possible to identify a level of exposurethat is without adverse effect, it is recommended thatlevels be reduced to the extent possible.

11.1.3 Sample risk characterization

Risks to human health and the environment willvary considerably depending upon the type and extentof exposure. Responsible authorities are stronglyencouraged to characterize risk on the basis of locallymeasured or predicted exposure scenarios. To assist thereader, examples of exposure estimation and riskcharacterization are provided in CICADs, wheneverpossible. These examples cannot be considered asrepresenting all possible exposure situations, but areprovided as guidance only. The reader is referred to EHC170 (IPCS, 1994) for advice on the derivation of health-based tolerable intakes and guidance values.

1 The authors of this document are aware that a 2-yearinhalation bioassay in rodents has recently beencompleted at the US National Toxicology Program.However, results are not available at this time.

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The scenario chosen as a specific example is occu-pational exposure in the United Kingdom. There are onlytwo forms of vanadium of occupational significance inthe United Kingdom — vanadium metal (impure andalloyed forms) and vanadium pentoxide. No toxicologydata are available on metallic vanadium (valency state 0).There is no means of extrapolating data from vanadiumcompounds to predict the properties of vanadium metal.Therefore, in the absence of a hazard assessment onvanadium metal, no risk assessment can be performed.

The other occupationally relevant form is vana-dium pentoxide. Vanadium pentoxide is a demonstrablesomatic and presumed germ cell mutagen and producesan unusual profile of respiratory tract effects. Delayedand persistent respiratory effects (production of mucusand cough) have been reported following human expo-sure to 0.1 mg vanadium pentoxide dust/m3, although nothreshold was established for these effects. Impairedpulmonary function is reported following repeatedexposure to vanadium pentoxide dust and fume, andthere are insufficient data to reliably describe theexposure–response relationship for the respiratoryeffects in humans. Thus, toxicity to the respiratory tractwill be a concern at all levels of occupational exposure.

Inhalation is the dominant route of concern forvanadium pentoxide exposure. There is substantialabsorption of inorganic vanadium compounds followinginhalation exposure. Given the genotoxic properties ofvanadium and the inability to identify a threshold, thereis concern at every level of exposure.

There are no oral exposure data on vanadiumpentoxide.

Following dermal exposure, it is unlikely that skinirritation or sensitization will be of concern in humans.Given the green staining of the skin that is occasionallyseen as a result of excessive exposure to vanadiumpentoxide, it would seem that there is potential for some,perhaps limited, dermal absorption. However, there areno data relating to potential systemic toxicity via dermalexposure. Given the overall lack of information in relationto dermal exposure, it is not possible to assess the risksto 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 inorganicvanadium compounds are not entirely satisfactory. Ofparticular concern is the limited understanding of thepotential for dermal absorption and the potential long-

term effects as a result of sequestration in body tissuessuch as bone. Furthermore, the significance of effectsseen in developmental toxicity studies using vanadiumpentoxide is not well understood. At present, studies aregenerally poorly reported or poorly conducted. Skeletalanomalies have been seen in a number of studies withpentavalent and tetravalent vanadium compounds,although it is difficult to ascertain the role of the severematernal toxicity that has also been evident. It is plaus-ible that the skeletal anomalies in pups may be related tothe 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 approximately1–3 µg/litre. Locally high concentrations of the metal, upto about 70 µg/litre, have been reported in fresh waters,often associated with leaching from volcanic lava flowsand uranium deposits. Data on concentrations in surfacewaters influenced by industrial waste are few, but mainlyfall within the natural range (up to about 65 µg/litre). Asingle early reported concentration in surface watersreceiving industrial waste of 2 mg/litre may be unreliable.

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

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

Toxicity values for vanadium in freshwater andmarine organisms generally range between 0.2 and120 mg/litre. Reports of sublethal effects at around10 µg/litre for algal photosynthesis, 50 µg/litre for oysterlarval development, and 1130 µg/litre for Daphniareproduction have been reported.

For natural waters, most toxic effects of vanadiumoccur only at concentrations substantially higher thanthose reported in the field. Most reported concentrationin industrial areas are also substantially lower than thoserequired to produce adverse effects. A single, possiblyunreliable, older high value for an industrial scenariodoes exceed toxic concentrations (Fig. 1).

Vanadium pentoxide and other inorganic vanadium compounds

35

-1

0

1

2

3

4

5

6

Lo

g c

on

cen

trat

ion

of v

anad

ium

(µg

/litr

e)

Normal range for surface waters

Highest reportedconcentration in natural water

Single reported concentrationfor industrial waters(reliability uncertain)

10

10

10

10

10

10

10

10Figure 1. Range of reported toxic concentrations of vanadium compared with concentrations in water. Triangles represent

reported LC50 values for a range of organisms in seawater and fresh water, squares represent the 21-day NOEC for Daphniamagna reproduction, and circles represent the LOEC for the development of oyster larvae.

There are insufficient data on toxicity to terrestrialorganisms to draw risk conclusions.

There are too few data to assess risk in specificindustrial contexts.

12. PREVIOUS EVALUATIONS BYINTERNATIONAL BODIES

A published review of vanadium is available (IPCS,1988). Information on international hazard classificationand labelling is included in the International ChemicalSafety Cards (ICSCs 0455 and 0596) reproduced in thisdocument. The World Health Organization’s air qualityguideline for vanadium is 1 µg/m3, which is based on alowest-observed-adverse-effect level (LOAEL) of 20µg/m3 from studies on occupationally exposedindividuals, using an overall uncertainty factor of 20(WHO, 1987).

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APPENDIX 1 — SOURCE DOCUMENTS

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

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

The members of the WATCH committee at the time of thepeer 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 HealthOrganization, International Programme onChemical Safety, 170 pp. (Environmental HealthCriteria 81)

A WHO Task Group on Environmental Health Criteria forVanadium met in Moscow, USSR, from 30 March to 3 April1987. The Task Group reviewed and revised the draft criteriadocument and made an evaluation of the risks for human healthand the environment from exposure to vanadium

Copies of this document may be obtained from:

International Programme on Chemical SafetyWorld Health OrganizationGeneva, Switzerland

APPENDIX 2 — CICAD PEER REVIEW

The draft CICAD on vanadium pentoxide and otherinorganic vanadium compounds was sent for review toinstitutions and organizations identified by IPCS after contactwith 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 duTravail du Québec, Montreal, Quebec, Canada

R. Benson, Drinking Water Program, US EnvironmentalProtection 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 ofHealth, London, United Kingdom

R. Hertel, Federal Institute for Health Protection ofConsumers 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, GermanyH. Nagy, National Institute for Occupational Safety and

Health, Washington, DC, USAE. Ohanian, Office of Water, US Environmental

Protection Agency, Washington, DC, USAS.A. Soliman, Alexandria University, El-Shatby,

Alexandria, EgyptM. Sun, School of Public Health, West China University of

Medical Sciences, Chengdu, Sichuan, People’sRepublic of China

W.F. ten Berge, DSM, Heerlen, The NetherlandsP. 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 Umveltund Gesundheit, Neuherberg, Oberschleissheim,Germany

Vanadium pentoxide and other inorganic vanadium compounds

43

APPENDIX 3 — CICAD FINAL REVIEWBOARD

Helsinki, Finland, 26–29 June 2000

Members

Mr H. Ahlers, Education and Information Division, NationalInstitute 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, NationalCenter for Environmental Assessment, US EnvironmentalProtection Agency, Cincinnati, OH, USA

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

Dr R.S. Chhabra, General Toxicology Group, National Instituteof 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, USEnvironmental Protection Agency, Washington, DC, USA

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

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

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

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

Dr A. Nishikawa, Division of Pathology, Biological SafetyResearch 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 HumanServices, Atlanta, GA, USA

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

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

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

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

Observer

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

Secretariat

Dr A. Aitio, International Programme on Chemical Safety, WorldHealth 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

Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 1999

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

VANADIUM TRIOXIDE 0455March 1998

CAS No: 1314-34-7RTECS No: YW3050000UN No: 3285EC No:

Divanadium trioxideVanadium sesquioxideVanadic oxideVanadium(III) oxideV2O3

Molecular mass: 149.9

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Combustible under specificconditions. Gives off irritating ortoxic fumes (or gases) in a fire.

NO open flames. In case of fire in the surroundings:all extinguishing agents allowed.

EXPLOSION

EXPOSURE PREVENT DISPERSION OF DUST!

Inhalation Sore throat. Cough. Labouredbreathing. Weakness.

Local exhaust or breathingprotection.

Fresh air, rest. Half-uprightposition. Refer for medicalattention.

Skin Dry skin. Redness. Protective gloves. Remove contaminated clothes.Rinse skin with plenty of water orshower.

Eyes Redness. Safety goggles, or eye protection incombination with breathingprotection if powder.

First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Headache. Vomiting. Weakness. Do not eat, drink, or smoke duringwork.

Induce vomiting (ONLY INCONSCIOUS PERSONS!). Giveplenty of water to drink. Refer formedical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into containers; ifappropriate, moisten first to prevent dusting.Carefully collect remainder, then remove to safeplace (extra personal protection: P3 filter respiratorfor toxic particles).

SymbolR:S:UN Hazard Class: 6.1UN Pack Group: III

Do not transport with food andfeedstuffs.

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61G65c Separated from food and feedstuffs.

Melting point: 1970�CDensity: 4.87 g/cm3 at 18�C

Solubility in water: poor

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

© IPCS 1999

0455 VANADIUM TRIOXIDE

IMPORTANT DATA

Physical State; AppearanceBLACK POWDER, TURNS GRADUALLY INTO INDIGO-BLUECRYSTALS OF VANADIUM TETROXIDE (V2O4) ONEXPOSURE TO AIR.

Chemical DangersThe substance decomposes on heating or on burningproducing irritating and toxic fumes (vanadium oxides).

Occupational Exposure LimitsTLV not established. MAK not established.

Routes of ExposureThe substance can be absorbed into the body by inhalation ofits aerosol and by ingestion.

Inhalation RiskEvaporation at 20�C is negligible; a harmful concentration ofairborne particles can, however, be reached quickly.

Effects of Short-term ExposureThe aerosol irritates the eyes, the skin and the respiratory tract.Inhalation of high concentrations of aerosol of this substancemay cause conjunctivitis, rhinitis and bronchitis. The effectsmay be delayed. See Notes.

Effects of Long-term or Repeated ExposureThe substance may have effects on the respiratory tract,resulting in chronic rhinitis and chronic bronchitis.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

NOTES

Depending on the degree of exposure, periodic medical examination is indicated. The symptoms of acute exposure do not becomemanifest until 1-6 days. Also consult ICSC # 0596 Vanadium pentoxide.

ADDITIONAL INFORMATION

Prepared in the context of cooperation between the InternationalProgramme on Chemical Safety and the European Commission

© IPCS 2000

SEE IMPORTANT INFORMATION ON THE BACK.

IPCSInternationalProgramme onChemical Safety

VANADIUM PENTOXIDE 0596October 1999

CAS No: 1314-62-1RTECS No: YW2450000 (dust)UN No: 2862EC No: 023-001-00-8

Divanadium pentoxideVanadic anhydrideVanadium(V)oxideV2O5

Molecular mass: 181.9

TYPES OFHAZARD/EXPOSURE

ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING

FIRE Not combustible. In case of fire in the surroundings:all extinguishing agents allowed.

EXPLOSION

EXPOSURE PREVENT DISPERSION OF DUST!STRICT HYGIENE!

Inhalation Sore throat. Cough. Burningsensation. Shortness of breath.Laboured breathing. Wheezing.

Ventilation, local exhaust, orbreathing protection.

Fresh air, rest. Half-upright position.Refer for medical attention.

Skin Redness. Burning sensation. Pain. Protective gloves. Remove contaminated clothes.Rinse skin with plenty of water orshower.

Eyes Pain. Redness. Conjunctivitis. Safety goggles, or eye protection incombination with breathingprotection if powder.

First rinse with plenty of water forseveral minutes (remove contactlenses if easily possible), then taketo a doctor.

Ingestion Abdominal cramps. Diarrhoea.Drowsiness. Nausea.Unconsciousness. Vomiting.

Do not eat, drink, or smoke duringwork. Wash hands before eating.

Induce vomiting (ONLY INCONSCIOUS PERSONS!). Giveplenty of water to drink. Refer formedical attention.

SPILLAGE DISPOSAL PACKAGING & LABELLING

Sweep spilled substance into containers; ifappropriate, moisten first to prevent dusting.Carefully collect remainder, then remove to safeplace. (Extra personal protection: P3 filter respiratorfor toxic particles). Do NOT let this chemical enterthe environment.

T SymbolN SymbolR: 20/22-37-40-48/23-51/53-63S: (1/2-)36/37-38-45-61UN Hazard Class: 6.1UN Pack Group: III

Do not transport with food andfeedstuffs.

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61G64c Separated from food and feedstuffs.

Boiling point (decomposes): 1750°CMelting point: 690°C

Relative density (water = 1): 3.4Solubility in water, g/100 ml: 0.8

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible for the use which might be made of this information

©IPCS 2000

0596 VANADIUM PENTOXIDE

IMPORTANT DATA

Physical State; AppearanceYELLOW TO RED CRYSTALLINE POWDER OR SOLID INVARIOUS FORMS.

Chemical dangersUpon heating, toxic fumes are formed. Reacts with combustiblesubstances.

Occupational exposure limitsTLV (respirable dust or fume, as V2O5): 0.05 mg/m3 (TWA)(ACGIH 1999).MAK: 0.05 mg/m3; (1996).

Routes of exposureThe substance can be absorbed into the body by inhalation ofits aerosol and by ingestion.

Inhalation riskEvaporation at 20°C is negligible; a harmful concentration ofairborne particles can, however, be reached quickly whendispersed.

Effects of short-term exposureThe aerosol of this substance irritates the eyes, the skin andthe respiratory tract. Inhalation of high concentrations maycause lung oedema, bronchitis, bronchospasm. The effectsmay be delayed.

Effects of long-term or repeated exposureLungs may be affected by inhalation of high concentrations ofdust or fumes. The substance may cause greenish-blackdiscolouration of the tongue.

PHYSICAL PROPERTIES

ENVIRONMENTAL DATA

The substance is harmful to aquatic organisms.

NOTES

Depending on the degree of exposure, periodic medical examination is indicated.The symptoms of lung oedema often do not become manifest until a few hours have passed and they are aggravated by physicaleffort. Rest and medical observation are therefore essential.Immediate administration of an appropriate spray, by a doctor or a person authorized by him/her, should be considered.

ADDITIONAL INFORMATION

Concise International Chemical Assessment Document 29

48

RÉSUMÉ D’ORIENTATION

Ce CICAD consacré au pentoxyde de vanadium età d’autres dérivés minéraux du vanadium repose sur unbilan des problèmes sanitaires (principalement en milieuprofessionnel) préparé par le Health and SafetyExecutive du Royaume-Uni (HSE, sous presse). Cedocument vise principalement les voies d’exposition àprendre en considération sur les lieux de travail, maiscontient également des informations relatives àl’environnement. La bibliographie utilisée va jusqu’ànovembre 1998. Un dépouillement complémentaire de lalitterature à été effectué jusqu’à mai 1999 afin de recueillirtoutes données supplémentaires publiées aprèsl’achèvement de ce document. En ce qui concerne lesdonnées environnementales, on a utilisé la monographiepubliée dans la série Critères d’hygiène de l’environne-ment (IPCS, 1988). Comme on ne disposait d’aucundocument plus récent sur le devenir et les effetsenvironnementaux de ces composés, il a été procédé àune recherche bibliographique afin d’obtenir uncomplément d’information. Des renseignements sur lanature de l’examen par des pairs et sur les sourcesdocumentaires existantes sont données à l’appendice 1.L’appendice 2 contient des informations sur l’examen pardes pairs du présent CICAD. Ce CICAD a été approuvéen tant qu’évaluation internationale lors de la réunion duComité d’évaluation finale qui s’est tenue à Helsinki(Finlande) du 26 au 29 juin 2000. La liste des participantsà cette réunion figure à l’appendice 3. Les fichesinternationales sur la sécurité chimique du trioxyde(ICSC 0455) et du pentoxyde de vanadium (ICSC 0596)établies par le Programme international sur la sécuritéchimique (IPCS, 1999a,b) sont également reproduitesdans le présent CICAD.

Le vanadium (No CAS 7440-62-2) est un métalductile, de couleur gris-argent, qui peut exister sousdivers degrés d’oxydation : !1, 0, +2, +3, +4 et +5. Saforme commerciale la plus courante est le pentoxydeV2O5 (No CAS 1314-62-1) correspondant à la valence +5et qui se présente sous la forme d’une poudre cristallinequi peut être jaune, rouge ou verte.

Le vanadium est un élément abondant et trèslargement répandu. Le minerai est extrait en Afrique duSud, en Russie et en Chine. Lors de la fusion du mineraide fer, il se forme un laitier contenant du pentoxyde devanadium que l’on utilise pour la production du métal.On prépare également le pentoxyde de vanadium enl’extrayant par solvant des minerais d’uranium ou pargrillage des sels présents dans les résidus de chaudièresou dans ceux des usines de production de phosphoreélémentaire. La combustion des huiles lourdes dans leschaudières et les fours conduit à la formation de résidussolides, de suie, de tartre et de cendres volantes quicontiennent du pentoxyde de vanadium.

On estime que chaque année, quelque 8,4 tonnesde vanadium sont libérées dans l’atmosphère à partir desources naturelles (valeurs extrêmes : 1,5-49,2 tonnes). Lasource de pollution de l’environnement par le vanadiumqui est de loin la plus importante est constituée par lacombustion du pétrole et du charbon; environ 90 % desquelque 64 000 tonnes de vanadium libérées dansl’atmosphère chaque année par des phénomènesnaturels ou par l’activité humaine ont en effet cettesource pour origine.

Dans l’environnement, le vanadium offre unechimie complexe. Dans les minéraux, le degré d’oxydationdu vanadium peut être de +3, +4 ou +5. Par dissolutiondans l’eau, V3+ et V4+ sont rapidement oxydés au degré+5, qui constitue la forme la plus commune du vanadiumdans l’environnement. En solution, cette formecorrespond aux vanadates, qui peuvent se polymériser(pour donner principalement des dimères et destrimères), en particulier en solution concentrée. Dans lestissus, ce sont les formes V3+ et V4+ qui prédominent, dufait que le milieu est largement réducteur; dans le plasma,c’est V5+ qui prédomine.

Le vanadium est probablement essentiel pour lessystèmes enzymatiques qui fixent l’azote atmosphérique(bactéries) et il est concentré par certains organismescomme les tuniciers, quelques annélidés de la classe despolychètes et certaines algues microscopiques. On nesait cependant pas avec certitude quelle est sa fonctionchez ces organismes. La question de savoir si levanadium est essentiel pour d’autres organismes resteposée. Rien n’indique qu’il s’accumule ou subisse unebioamplification dans la chaîne alimentaire desorganismes marins, qui constituent le groupe le mieuxétudié.

Le lessivage du vanadium dans les différentsprofils pédologiques est très limité.

On a signalé la présence de fortes concentrationsde vanadium dans l’air à proximité de sources indus-trielles et de feux d’hydrocarbures. En ce qui concerneles dépôts, des valeurs annuelles de 0,1 à 10 kg/ha sontcaractéristiques des zones urbaines où sont implantéesdes sources importantes de vanadium; ces valeurs vontde 0,01 à 0,1 kg/ha par an dans les zones rurales ouurbaines où n’existent pas de sources de vanadium ets’abaissent à <0,001-0,01 kg/ha par an dans les régionsreculées.

Dans la plupart des eaux douces de surface, laconcentration du vanadium est inférieure à 3 µg/litre; desvaleurs plus élevées, pouvant atteindre 70 µg/litre ontété relevées dans des zones où existent d’importantessources géochimiques. On ne possède guère de donnéessur la teneur en vanadium des eaux proches de sitesindustriels; la plupart des publications font état de

Vanadium pentoxide and other inorganic vanadium compounds

49

valeurs correspondant sensiblement aux concentrationsnaturelles les plus fortes. Les concentrations pélagiquesvont de 1 à 3 µg/litre, dans les sédiments, la concen-tration va de 20 à 200 µg/g, les valeurs les plus élevéesétant relevées dans la zone littorale.

Quelques organismes concentrent le vanadium, etla concentration de ce métal peut atteindre 10 000 µg/gchez les ascidies et 786 µg/g chez les polychètes. Chez laplupart des êtres vivants, la concentration est, d’unefaçon générale, inférieure à 50 µg/g et habituellementbeaucoup plus faible.

L’exposition par la voie alimentaire est estiméechez l’Homme à 11-30 µg par jour. Dans l’eau de boisson,la concentration va jusqu’à 100 µg/litre. Dans certainesnappes souterraines qui alimentent les sources d’eaupotable, on a relevé des concentrations de vanadiumsupérieures à 50 µg/litre. L’eau minérale en bouteille peuten contenir davantage.

On possède des données toxicocinétiques limitéesselon lesquelles chez l’Homme, le vanadium est résorbéaprès inhalation puis excrété dans l’urine, l’élimination sefaisant en deux phases, une phase initiale rapide puisune phase plus lente qui correspond vraisemblablementà la libération progressive du vanadium retenu dans lestissus. Après administration par voie orale, le vanadiumIV est mal résorbé dans les voies digestives. On nedispose pas d’études sur l’absorption percutanée.

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

Dans la seule étude de toxicité aiguë par inhalationqui soit disponible, on a obtenu une CL67 de 1440 mg/m3

(800 mg de vanadium par m3) pour des rats exposéspendant 1 h à de la poussière de pentoxyde devanadium. L’exposition de rats et de souris par la voieorale a permis d’obtenir une DL50 qui se situait entre 10et 160 mg/kg de poids corporel dans le cas du pentoxydeet d’autres dérivés du vanadium V, alors qu’avec lesdérivés du vanadium IV, les valeurs étaient comprisesentre 448 et 467 mg/kg de poids corporel. On ne disposed’aucune donnée sur la toxicité du vanadium par la voiepercutanée.

Des études sur des travailleurs de l’industrie duvanadium ont mis en évidence des cas d’irritationoculaire. Chez 100 volontaires à qui on avait posé untimbre cutané contenant 10 % de pentoxyde devanadium, on n’a pas constaté d’irritation cutanée, maisun test analogue effectué sur des travailleurs a donnélieu a deux réactions isolées. L’expérimentation animalen’a permis de dégager aucun résultat clair concernant lepouvoir irritant oculaire ou cutané des composés duvanadium ou leur action sensibilisatrice au niveau del’épiderme.

Dans un groupe de volontaires exposés pendant 8h à de la poussière contenant 0,1 mg de vanadium par m3,on a observé des effets retardés mais prolongés sur lesbronches qui se manifestaient notamment par uneproduction excessive de mucus. A la concentration de0,25 mg/m3, la réaction était analogue, avec en plus de latoux qui s’est prolongée pendant les quelques jourssuivant l’exposition. A la concentration de 1,0 mg/m3, latoux est devenue permanente au bout de cinq heures ets’est maintenue longtemps. Il ne ressort de cette étudeaucune valeur de la dose maximale sans effetbronchique.

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

Les dérivés correspondant aux valences 4 et 5 du

vanadium ont des effets aneugènes in vitro en présenceou en l’absence d’activation métabolique. On est fondé àpenser que ces dérivés ainsi que ceux du vanadium IIIsont capables de provoquer des lésions de l’ADN et deschromosomes in vitro, mais les études existantesdonnent à cet égard des résultats qui sont tantôtpositifs, tantôt négatifs. Il semble, à la lumière desdonnées disponibles, que les composés du vanadium nesoient pas mutagènes , à en juger par les tests classiquesde mutagénicité in vitro sur des cellules bactériennes oumammaliennes.

In vivo, une aneuploïdie des cellules somatiquess’observe clairement après exposition à des dérivés duvanadium IV et du vanadium V selon différentes voies.Comme dans le cas des études in vitro, les tests destinésà mettre en évidence des effets clastogènes donnent desrésultats mitigés et dans l’ensemble, on reste dansl’incertitude quand au pouvoir clastogène du vanadiumvis-à-vis des cellules somatiques. Par contre, on aobtenu un résultat positif dans le cas des cellulesgerminales de souris à qui on avait injecté du pentoxyde

Concise International Chemical Assessment Document 29

50

de vanadium par voie intrapéritonéale. Le mécanisme quiest à la base de ces effets (aneugènes et clastogènes)n’est pas connu avec certitude. On ignore égalementdans quelle mesure ces résultats peuvent être étendus àd’autres voies d’exposition et à d’autres dérivés duvanadium.

Etant donné la nature de la base de données sur lagénotoxicité du pentoxyde de vanadium et d’autresdérivés de cet élément, il n’est pas possible de définirsans ambiguité le seuil au-dessous duquel, quelle quesoit la voie d’exposition à prendre en considération chezl’Homme, il n’y aurait pas lieu de craindre un risqued’activité génotoxique.

On ne possède aucune information utile sur lepouvoir cancérogène du vanadium chez l’Homme oul’animal, sous quelque forme et par quelque voied’exposition que ce soit.1

Une étude de fécondité sur des souris mâles dontl’eau de boisson contenait du métavanadate de sodium,incite à penser que l’exposition des animaux à cecomposé aux doses de 60 et 80 mg/kg de poids corporela été la cause directe d’une diminution du nombre despermatides et de spermatozoïdes ainsi que du nombrede grossesses consécutives à l’accouplement de cesmâles avec des souris femelles. Il est vrai toutefois, qu’àla dose de 80 mg/kg p.c., la toxicité générale du composéétait également évidente (diminution du gain de poids).

Un certain nombre d’études ont été consacrées àl’action des composés du vanadium IV et V sur ledéveloppement. Elles révèlent systématiquement laprésence d’anomalies du squelette. Les résultats de cesétudes sont difficiles à interpréter car les voiesd’exposition étaient inhabituelles et la toxicité manifestedes composés pour les mères a pu influer sur les effetsconstatés dans la progéniture.

Chez l’Homme les points d’aboutissement del’action toxique à prendre en considération sont lagénotoxicité et l’irritation des voies respiratoires. Commeil n’est pas possible de définir le seuil de concentration àpartir duquel il n’y a plus d’effets toxiques, il estrecommandé de réduire le plus possible le niveaud’exposition.

Pour les organismes aquatiques, les valeurs de laCL50 vont de 0,2 à environ 120 mg/litre, la majorité desvaleurs se situant entre 1 et 12 mg par litre. D’une point

de vue écotoxicologique, il serait plus judicieux deprendre en considération l’action sur le développementdes huîtres (sensiblement réduit à 0,05 mg de vanadiumpar 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 organismesterrestres. La plupart de celles qui portent sur desvégétaux concernent des cultures hydroponiques surlesquelles on observe des effets à partir de 5 mg/litre.Les résultats de ces études sont difficiles à transposeraux plantes cultivées en pleine terre.

Dans les divers compartiments de l’environnement,la concentration est sensiblement inférieure aux valeurstoxiques. On ne possède que peu de données sur laconcentration au voisinage des sites industriels et iln’est pas possible de procéder à une évaluation durisque sur cette base. Quoi qu’il en soit, les valeurs dontil est fait état semble correspondre aux concentrationsnaturelles les plus fortes, ce qui indique que le risquedevrait être faible. Des mesures sur les lieux mêmess’imposent dans chaque cas particulier.

1 Les auteurs de ce document ont connaissance d’uneétude au cours de laquelle on a fait inhaler pendant 2 ansdes dérivés du vanadium à des rongeurs. Cette étudevient de s’achever aux Etats-Unis dans le cadre duNational Toxicology Program et les résultats n’en sontpas encore disponibles.

Vanadium pentoxide and other inorganic vanadium compounds

51

RESUMEN DE ORIENTACIÓN

Este CICAD sobre el pentóxido de vanadio y otroscompuestos inorgánicos de vanadio se basó en unexamen de los problemas relativos a la salud humana(fundamentalmente profesionales) preparado por laDirección de Salud y Seguridad del Reino Unido (HSE,en prensa). Este examen se concentra en las vías deexposición de interés para el entorno ocupacional, perocontiene también información sobre el medio ambiente.Figuran los datos identificados hasta noviembre de 1998.Se realizó una ulterior búsqueda bibliográfica hasta mayode 1999 para localizar cualquier información nueva quese hubiera publicado desde la terminación del examen. Seutilizó una monografía de los Criterios de SaludAmbiental (IPCS, 1988) como documento original para lainformación ambiental. Puesto que no se disponía dedocumentos originales más recientes sobre el destino ylos efectos en el medio ambiente, se realizó unabúsqueda bibliográfica para obtener más información. Lainformación acerca del carácter del examen colegiado y ladisponibilidad de los documentos originales figura en elapéndice 1. La información sobre el examen colegiado deeste CICAD aparece en el apéndice 2. Este CICAD seaprobó como evaluación internacional en una reunión dela Junta de Evaluación Final celebrada en Helsinki(Finlandia) del 26 al 29 de junio de 2000. La lista departicipantes en esta reunión figura en el apéndice 3. LasFichas internacionales de seguridad química sobre eltrióxido de vanadio (ICSC 0455) y el pentóxido devanadio (ICSC 0596), preparadas por el ProgramaInternacional de Seguridad de las Sustancias Químicas(IPCS, 1999a,b), también se reproducen en el presentedocumento.

El vanadio (CAS Nº 7440-62-2) es un metal gris

plateado suave que puede existir en varios estados deoxidación diferentes: !1, 0, +2, +3, +4 y +5. La formacomercial más común es el pentóxido de vanadio (V2O5;CAS Nº 1314-62-1) y en este estado pentavalente es unpolvo cristalino rojo-amarillento o verde.

El vanadio es un elemento abundante, con unadistribución muy amplia; se extrae en Sudáfrica, Rusia yChina. Durante la fusión de la mena de hierro se formaescoria de vanadio con pentóxido de vanadio, que seutiliza para la producción de vanadio metálico. Elpentóxido de vanadio se obtiene también por extraccióncon disolventes a partir de menas de uranio y medianteun proceso de calcinación de las sales de los residuos delas calderas o de los residuos de las instalaciones defosfato elemental. Durante la combustión de fueloil encalderas y hornos, hay pentóxido de vanadio en losresiduos sólidos, el hollín, las incrustaciones de lascalderas y las cenizas volátiles.

Las emisiones atmosféricas a partir de fuentesnaturales en todo el mundo se han estimado en 8,4 tone-ladas al año (gama de 1,5-49,2 toneladas). La fuente másimportante de contaminación ambiental por vanadio escon 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 añoa partir de fuentes tanto naturales como antropogénicasprocede de la combustión del petróleo.

La química del vanadio en el medio ambiente es

compleja. En los minerales, el estado de oxidación delvanadio puede ser +3, +4 ó +5. La disolución en aguaoxida rápidamente el V3+ y el V4+ al estado pentavalente,que es la forma más común del metal en el medioambiente. El vanadato, compuesto pentavalente ensolución, se puede polimerizar (principalmente a lasformas diméricas o triméricas), en particular a concen-traciones más altas de las sales. En los tejidos de losorganismos predominan el V3+ y el V4+, debido en granparte a las condiciones de reducción; en el plasmapredomina el V5+.

El vanadio es probablemente esencial para lossistemas 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 estosorganismos. Sigue siendo una cuestión abierta si elvanadio es o no esencial para otros organismos. No haypruebas de acumulación o bioamplificación en lascadenas alimentarias de los organismos marinos, queforman el grupo mejor estudiado.

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

Se han notificado niveles más altos de vanadio enel aire próximo a fuentes industriales e incendios dehidrocarburos. Las tasas de deposición representativasson de 0,1-10 kg/ha al año para zonas urbanas afectadaspor fuentes locales importantes, de 0,01-0,1 kg/ha al añopara las zonas rurales y urbanas que no tienen unafuente local importante y <0,001-0,01 kg/ha al año paralas zonas remotas.

La mayor parte de las aguas superficiales dulcescontienen menos de 3 µg de vanadio/litro; se hannotificado niveles más altos, de hasta unos 70 µg/litro,en zonas con fuentes geoquímicas grandes. Los datossobre los niveles de vanadio en aguas superficialespróximas a actividades industriales son escasos; lamayoría de los informes parecen indicar nivelesaproximadamente iguales a los naturales más elevados.Las concentraciones en el agua marina en mar abiertaoscilan entre 1 y 3 µg/litro y en los sedimentos van de 20a 200 µg/g; los niveles más altos se observan en lossedimentos costeros.

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

Las estimaciones de la exposición total de laspersonas en los alimentos oscilan entre 11 y 30 µg/día.Los niveles en el agua de bebida ascienden hasta100 µg/litro. Algunas fuentes de agua freática queabastecen de agua potable muestran concentracionessuperiores a 50 µg/litro. Los niveles en el agua demanantial embotellada pueden ser más altos.

En las personas, la limitada información tóxico-cinetica disponible parece indicar que se absorbevanadio tras la inhalación y luego se excreta en la orinacon una fase inicial de eliminación rápida, seguida deuna fase más lenta, que posiblemente se debe a laeliminación gradual de vanadio de los tejidos delorganismo. Tras la administración oral, la absorción devanadio tetravalente a partir del sistema gastrointestinales escasa. No se disponía de estudios cutáneos.

En estudios de inhalación y de administración oralen animales de laboratorio, el vanadio absorbido en losestados 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 deexcreción del vanadio es a través de la orina. Su pauta dedistribución y excreción indica que es posible laacumulación y retención del vanadio absorbido, sobretodo en los huesos. Hay pruebas de que el vanadiotetravalente puede atravesar la barrera placentaría yllegar al feto.

En el único estudio de inhalación aguda disponiblese notificó una CL67 de 1440 mg/m3 (800 mg de vanadio/m3) tras la exposición de ratas a polvo de pentóxido devanadio durante una hora. En estudios de administraciónoral en ratas y ratones se obtuvieron valores de la DL50

del orden de 10-160 mg/kg de peso corporal para elpentóxido de vanadio y otros compuestos de vanadiopentavalente, mientras que para los compuestos devanadio tetravalente los valores de la DL50 son del ordende 448-467 mg/kg de peso corporal. No hay informaciónrelativa a la toxicidad cutánea.

En estudios realizados con trabajadores del vana-dio se ha notificado irritación ocular. No se informó deirritación cutánea en 100 voluntarios humanos tras laprueba del parche cutáneo con un 10% de pentóxido devanadio, aunque la prueba del parche realizada en lostrabajadores produjo dos reacciones aisladas. No hayinformación clara disponible de estudios en animales conrespecto al potencial de los compuestos de vanadio paraproducir irritación cutánea u ocular o bien sensibilizacióncutánea.

En un grupo de voluntarios humanos, una expo-sición aislada de ocho horas a 0,1 mg de polvo depentóxido de vanadio/m3 produjo efectos bronquialesretardados, pero prolongados, con una producciónexcesiva de moco. Con 0,25 mg/m3 se observó una pautade respuesta semejante, con la adición de tos durantealgunos días después de la exposición. La exposición a1,0 mg/m3 produjo una tos persistente y prolongadadespués de cinco horas. En este estudio no se identificóun nivel sin efectos para los trastornos bronquiales.

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

Las formas pentavalentes y tetravelentes delvanadio han provocado efectos aneugénicos in vitrocon activación metabólica y sin ella. Hay pruebas de queestas formas de vanadio, así como el vanadio trivalente,también pueden producir in vitro daños en el ADN/cromosomas, habiéndose obtenido en los estudiosdisponibles resultados tanto positivos como negativos.El valor probatorio de los datos disponibles pareceindicar que los compuestos de vanadio no producenmutaciones genéticas en pruebas normalizadas in vitroen células de bacterias o de mamíferos.

In vivo, tanto los compuestos de vanadio penta-valentes como los tetravalentes han dado pruebasmanifiestas de aneuploidía de las células somáticas trasla exposición mediante varias vías diferentes. Laspruebas de que los compuestos de vanadio tambiénpueden producir efectos clastogénicos son desiguales,al igual que en los estudios in vitro, y la posición globalsobre la clastogenicidad en las células somáticas esincierta. Se obtuvo un resultado positivo en célulasgerminales de ratones a los que se administró pentóxidode vanadio por inyección intraperitoneal. Sin embargo,hay dudas acerca del mecanismo en el que se basa esteefecto (aneugenicidad; clastogenicidad). Tampoco estáclaro cómo se pueden generalizar estos resultados a víasde exposición más realistas o a otros compuestos devanadio.

Las características de la base de datos sobre lagenotoxicidad 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 deexposición de interés para el ser humano por debajo delcual no habría que preocuparse por la posible actividadgenotóxica.

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No se dispone de información útil sobre elpotencial carcinogénico de ninguna de las formas devanadio por ninguna de las vías de exposición para losanimales1 o las personas.

Un estudio de la fecundidad en ratones machos,con exposición al metavanadato de sodio en el agua debebida, parece indicar la posibilidad de que la exposiciónoral de los ratones machos a este compuesto aconcentraciones de 60 y 80 mg/kg de peso corporalcausara directamente una disminución del recuento deespermátidas/espermatozoides y del número de gesta-ciones tras el apareamiento. Sin embargo, también sepudo observar una toxicidad general significativa(disminución del aumento del peso corporal) a 80 mg/kgde peso corporal).

Hay algunos estudios sobre los efectos de loscompuestos de vanadio pentavalente o tetravalente en eldesarrollo, con una observación sistemática de anoma-lías esqueléticas. La interpretación de estos estudios esdifícil, debido a las vías de exposición no tradicionalesutilizadas y a que hay pruebas de toxicidad materna, lacual 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 lairritación de las vías respiratorias. Puesto que no esposible determinar un nivel de exposición sin efectosadversos, se recomienda reducir los niveles en la medidade lo posible.

Los valores de la CL50 para la toxicidad aguda deorganismos 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 vistaecotoxicológico se observaron en el desarrollo de laslarvas de ostras (reducción significativa con 0,05 mg devanadio/litro) y en la reproducción de Daphnia (con-centración sin efectos observados en 21 días con1,13 mg/litro). Son pocos los estudios terrestres. Lamayoría de los estudios en plantas se han realizado encultivos hidropónicos, donde se detectaron efectos aconcentraciones de 5 mg/litro y superiores; estosestudios son difíciles de interpretar en relación con lasplantas cultivadas en el suelo.

Las concentraciones en los compartimentos delmedio ambiente son notablemente inferiores a lasconcentraciones tóxicas notificadas. Se dispone de

pocos datos sobre las concentraciones en lugaresindustriales específicos y no es posible realizar unaevaluación del riesgo sobre esta base. Sin embargo, lasconcentraciones notificadas parecen ser semejantes a lasnaturales más altas, lo que parece indicar que el riesgosería bajo. Se deben realizar mediciones locales paraevaluar el riesgo en cualquier circunstancia determinada.

1 Los autores de este documento tienen conocimiento deque recientemente se ha completado en el ProgramaNacional de Toxicología de los Estados Unidos unabiovaloración por inhalación de dos años en roedores.Sin embargo, en este momento no están disponiblestodavía los resultados.

THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

Azodicarbonamide (No. 16, 1999)Benzoic acid and sodium benzoate (No. 26, 2000)Benzyl butyl phthalate (No. 17, 1999)Biphenyl (No. 6, 1999)2-Butoxyethanol (No. 10, 1998)Chloral hydrate (No. 25, 2000)Crystalline silica, Quartz (No. 24, 2000)Cumene (No. 18, 1999)1,2-Diaminoethane (No. 15, 1999)3,3'-Dichlorobenzidine (No. 2, 1998)1,2-Dichloroethane (No. 1, 1998)2,2-Dichloro-1,1,1-trifluoroethane (HCFC-123) (No. 23, 2000)Diphenylmethane diisocyanate (MDI) (No. 27, 2000)Ethylenediamine (No. 15, 1999)Ethylene glycol: environmental aspects (No. 22, 2000)2-Furaldehyde (No. 21, 2000)HCFC-123 (No. 23, 2000)Limonene (No. 5, 1998)Manganese and its compounds (No. 12, 1999)Methyl chloride (No. 28, 2000)Methyl methacrylate (No. 4, 1998)Mononitrophenols (No. 20, 2000)Phenylhydrazine (No. 19, 2000)N-Phenyl-1-naphthylamine (No. 9, 1998)1,1,2,2-Tetrachloroethane (No. 3, 1998)1,1,1,2-Tetrafluoroethane (No. 11, 1998)o-Toluidine (No. 7, 1998)Tributyltin oxide (No. 14, 1999)Triglycidyl isocyanurate (No. 8, 1998)Triphenyltin compounds (No. 13, 1999)

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