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 www.ep a.gov/iris

TOXICOLOGICAL REVIEW 

OF

VANADIUM PENTOXIDE 

(V2O5)

(CAS No. 1314-62-1) 

In Support of Summary Information on the 

Integrated Risk Information System (IRIS)

July 2011

NOTICE

This document is an Interagency Science Consultation draft. This information is distributed 

solely for the purpose of pre-dissemination peer review under applicable information quality 

guidelines. It has not been formally disseminated by EPA. It does not represent and should not 

be construed to represent any Agency determination or policy. It is being circulated for review 

of its technical accuracy and science policy implications.

U.S. Environmental Protection Agency 

Washington, DC.
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DISCLAIMER

 This document is a preliminary draft for review purposes only. This information is 

distributed solely for the purpose of pre-dissemination peer review under applicable information 

quality guidelines. It has not been formally disseminated by EPA. It does not represent and 

should not be construed to represent any Agency determination or policy. Mention of trade 

names or commercial products does not constitute endorsement or recommendation for use. 
DRAFT - DO NOT CITE OR QUOTE iii 

CONTENTS – TOXICOLOGICAL REVIEW OF VANADIUM PENTOXIDE 

(CAS No. 1314-62-1) 

AUTHORS, CONTRIBUTORS, AND REVIEWERS ........................................................... xiii

1. INTRODUCTION .................................................................................................................... 1

2. CHEMICAL AND PHYSICAL INFORMATION ............................................................... 3

3. TOXICOKINETICS ................................................................................................................. 6

3.1 Absorption ............................................................................................................................ 6

3.1.1 Inhalation Exposure ................................................................................................. 6

3.1.2 Oral Exposure ................................................................................................................ 7

3.1.3 Dermal Exposure ..................................................................................................... 8

3.1.4 Other Routes of Exposure ....................................................................................... 8

3.2 Distribution ........................................................................................................................... 8

3.2.1 Inhalation Exposure ................................................................................................. 8

3.2.2 Oral Exposure .......................................................................................................... 9

3.2.3 Dermal Exposure ................................................................................................... 10

3.2.4 Other Routes of Exposure ..................................................................................... 11

3.3 Metabolism ......................................................................................................................... 11

3.4 Elimination and Excretion .................................................................................................. 11

3.4.1 Inhalation Exposure ............................................................................................... 11

3.4.2 Oral Exposure ........................................................................................................ 12

3.4.3 Dermal Exposure ................................................................................................... 12

3.4.4 Other Routes of Exposure ..................................................................................... 12

3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models .......... 12

3.5.1 Animal-to-Human Extrapolations ......................................................................... 12

4. HAZARD IDENTIFICATION ............................................................................................. 14

4.1. STUDIES IN HUMANS – EPIDEMIOLOGY, CASE REPORTS, CLINICAL 

CONTROLS ..................................................................................................................... 14

4.1.1 Oral Exposure ............................................................................................................... 14

4.1.2 Inhalation Exposure ...................................................................................................... 14

4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 

ANIMALS – ORAL AND INHALATION ...................................................................... 31

4.2.1. Oral Exposure ........................................................................................................ 31

4.2.1.1. Subchronic Studies ................................................................................................ 31

4.2.1.2 Chronic Studies ..................................................................................................... 32

4.2.2. Inhalation Exposure ............................................................................................... 33
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4.2.2.1 Subchronic Studies ................................................................................................ 33

4.2.2.2 Chronic Studies ..................................................................................................... 43

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES – ORAL, INHALATION, 

INTRAPERITONEAL AND INJECTION ....................................................................... 53

4.3.1. Oral Studies ........................................................................................................... 53

4.3.2. Inhalation Studies .................................................................................................. 54

4.3.3. Intraperitoneal and Injection Studies .................................................................... 55

4.4 OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES ......................................... 57

4.4.1 Acute and Short-Term Studies ...................................................................................... 57

4.4.1.1 Acute Studies .......................................................................................................... 57

4.4.1.2. Short-term Studies ................................................................................................. 59

4.4.2 Immunological Endpoints ............................................................................................. 61

4.4.2.1 Human Studies ....................................................................................................... 61

4.4.2.2 Animal Studies ........................................................................................................ 64

4.4.3 Neurological Endpoints ................................................................................................ 65

4.4.3.1 Human Studies ....................................................................................................... 66

4.4.3.2 Animal Studies ....................................................................................................... 66

4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF 

ACTION FOR PULMONARY FIBROSIS AND CANCER ........................................... 68

4.5.1 Genotoxicity .................................................................................................................. 68

4.5.1.1 Human Studies ........................................................................................................ 68

4.5.1.2 Laboratory in vivo and in vitro studies ................................................................... 71

4.5.2 Mechanisms of Inflammation and Fibrosis ................................................................... 78

4.5.3 Mechanisms of Hyperplasia and Carcinogenicity ......................................................... 82

4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS ....................................................... 86

4.6.1. Oral ........................................................................................................................ 86

4.6.1.1 Acute ....................................................................................................................... 86

4.6.1.2 Subchronic .............................................................................................................. 88

4.6.1.3 Chronic .................................................................................................................... 88

4.6.2. Inhalation ............................................................................................................... 88

4.6.2.1 Acute and Short-term .............................................................................................. 89

4.6.2.2 Subchronic ............................................................................................................ 90

4.6.2.3 Chronic .................................................................................................................... 91

4.6.3 Mode of Action Information ......................................................................................... 98

4.6.3.1 Pulmonary Toxicity .............................................................................................. 98

4.6.3.2 Neurotoxicity ........................................................................................................ 100

4.6.3.3 Reproductive Toxicity .......................................................................................... 100

4.7. EVALUATION OF CARCINOGENICITY ..................................................................... 101

4.7.1 Summary of Overall Weight of Evidence ................................................................ 101

4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence .......................... 101
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4.7.3. Mode of Action Information ............................................................................... 102

4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES ................................................. 103

4.8.1. Possible Childhood Susceptibility ....................................................................... 103

4.8.2. Possible Gender Differences ............................................................................... 103

4.8.3. Other Susceptible Populations ............................................................................ 103

5. DOSE-RESPONSE ANALYSIS .......................................................................................... 106

5.1. ORAL REFERENCE DOSE (RfD) .................................................................................. 106

5.1.1 Methods of Analysis ................................................................................................... 108

5.1.2 RfD Derivation – Including Application of Uncertainty Factors (UF) ....................... 109

5.1.2. Previous RfD Assessment ................................................................................... 110

5.2. INHALATION REFERENCE CONCENTRATION (RfC) ............................................. 111

5.2.1 Choice of Principal Study and Critical Effect with Rationale and Justification ......... 111

5.2.2 Methods of Analysis ................................................................................................ 113

5.2.3 RfC Derivation- Including Application of Uncertainty Factors (UFs) .................... 119

5.2.4. Previous RfC Assessment ................................................................................... 120

5.3 UNCERTAINTIES IN THE INHALATION REFERENCE CONCENTRATION (RfC) 120

5.4. CANCER ASSESSMENT ............................................................................................... 123

5.4.1 Choice of Study/Data – with Rationale and Justification ........................................ 123

5.4.2 Dose-Response Data ................................................................................................ 124

5.4.3 Dose Adjustments and Extrapolation Methods ........................................................ 124

5.4.4 Inhalation Unit Risk ................................................................................................. 127

5.4.5 Oral Cancer Slope Factor .......................................................................................... 127

5.4.6 Uncertainties in Cancer Risk Values ....................................................................... 127

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE 

RESPONSE ............................................................................................................................... 132

6.1 Human Hazard Potential .................................................................................................... 132

6.2. Dose Response .................................................................................................................. 136

6.2.1 Noncancer.................................................................................................................... 136

6.2.2 Cancer.......................................................................................................................... 138

7. REFERENCES ...................................................................................................................... 140
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LIST OF TABLES 

Table 2-1. Valence states and water solubility of various vanadium compounds. .................. 4

Table 2-2: Chemical and physical properties of Vanadium Pentoxide .................................... 5

Table 4–1. Hematological results of oral vanadium pentoxide exposure in rats (Mountain 

et al. 1953). ................................................................................................................................... 32

Table 4-2. Body Weight Gain and Lung Weights in Rats (F344/N) Exposed to Vanadium 

Pentoxide by Inhalation for 3 Months (Values are Means±Standard Error) (NTP, 2002) . 35

Table 4-3. Selected Hematology Parameters in Rats (F344/N) Exposed to Vanadium 

Pentoxide by Inhalation for 3 Months (NTP, 2002) ................................................................. 35

Table 4-4. Incidences of Selected Nonneoplastic Lesions of the Lung and Nose in Rats 

(F344/N) Exposed to Vanadium Pentoxide by Inhalation for 3 Months (NTP, 2002) .......... 37

Table 4-5. Body Weight Gain and Lung Weights in Mice (B6C3F1) Exposed to Vanadium 

Pentoxide by Inhalation for 3 Months (Values are Means±Standard Error) (NTP, 2002) . 40

Table 4-6. Incidences of Selected Nonneoplastic Lesions of the Lung in Mice (B6C3F1) 

Exposed to Vanadium Pentoxide by Inhalation for 3 Months (NTP, 2002) .......................... 41

Table 4-7. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to 

Particulate Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) ................................. 44

Table 4-8. Incidences of Respiratory Tumors in Rats Exposed to Vanadium Pentoxide in a 

2 Year Inhalation Study (NTP, 2002)a ...................................................................................... 47

Table 4-9. Selected Nonneoplastic Lesions of the Respiratory System in Mice Exposed to 

Vanadium Pentoxide in a 2 Year Inhalation Study (NTP, 2002) .......................................... 48

Table 4-10. Incidences of Respiratory Tumors in Mice Exposed to Vanadium Pentoxide in 

the 2 Year Inhalation Study (NTP, 2002) ................................................................................. 51

Table 4 -11. Lung tumor multiplicity in MCA-Treated mice exposed to V2O5 by 

pharyngeal aspiration (Rondini et al. 2010). a,b ........................................................................ 52

Table 4-12. Genotoxicity Data Following Exposure to Vanadium Pentoxide ....................... 74

Table 4-13: Summary of Noncancer Results of Repeat-Dose Studies for Oral Exposure of 

Experimental Animals to Vanadium Pentoxide ....................................................................... 86

Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation 

Exposure of Vanadium Pentoxide ............................................................................................. 92

Table 5–1. Hematological results of oral vanadium pentoxide exposure in rats (Mountain 

et al. 1953). ................................................................................................................................. 107

Table 5-2 Human equivalence dose conversion by BW3/4 for RfD derivation. ................... 109

Table 5-3. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to 

Particulate Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) ............................... 114
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Table 5-4: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year 

Inhalation Studies in Rats (NTP, 2002) .................................................................................. 116

Table 5-5: Candidate PODs for Vanadium Pentoxide Derived from NTP Studies (2002) 

through BMDS Modeling. ........................................................................................................ 116

Table 5-6: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation in 

Female Rats, NTP (2002) .......................................................................................................... 118

Table 5-7: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Female Rats, NTP (2002) ............................................................. 119

Table 5-8. Incidences of Respiratory Tumors in Mice Exposed to Vanadium Pentoxide in 

the 2 Year Inhalation Study (NTP, 2002) ............................................................................... 123

Table 5-9: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year 

Inhalation Studies (NTP, 2002) ................................................................................................ 125

Table 5- 10. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar 

Adenoma and Carcinoma in Male Mice, NTP (2002). .......................................................... 126

Table 5-11. Summary of uncertainty in the vanadium pentoxide cancer risk assessment.

..................................................................................................................................................... 129

Table B-1: Candidate PODs for Vanadium Pentoxide Derived from NTP Studies (2002) 

through BMDS Modeling. ........................................................................................................ 154

Table B-2: Trend Tests on the Selected Data Sets from the 2-Year Inhalation Studies in 

Rats (NTP, 2002) ....................................................................................................................... 156

Table B-3: Average Life Time Animal Body Weight of Rats in the 2-Year Inhalation 

Studies of Vanadium Pentoxide (NTP, 2002) ......................................................................... 157

Table B-4: RDDRs for Different Concentration/Sex Group in the 2-Year Inhalation Studies 

of Vanadium Pentoxide (NTP, 2002) ....................................................................................... 157

Table B-5: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year 

Inhalation Studies (NTP, 2002) ................................................................................................ 158

Table B-6: Benchmark Modeling Results for Incidence of Lung Alveolar Epithelium 

Hyperplasia in Male Rats, NTP (2002) ................................................................................... 159

Table B-7: Benchmark Modeling Results for Incidence of Lung Chronic Active 

Inflammation in Male Rats, NTP (2002) ................................................................................ 162

Table B-8: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation in 

Male Rats, NTP (2002) ............................................................................................................. 164

Table B-9: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Male Rats, NTP (2002) ................................................................. 167

Table B-10: Benchmark Modeling Results for Incidence of Nose Goblet Cell, Respiratory 

Epithelium, Hyperplasia in Male Rats, NTP (2002) .............................................................. 169

Table B-11: Benchmark Modeling Results for Incidence of Lung Alveolar Epithelium 

Hyperplasia in Female Rats, NTP (2002) ............................................................................... 172
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Table B-12: Benchmark Modeling Results for Incidence of Lung Chronic Active 

Inflammation in Female Rats, NTP (2002) ............................................................................. 174

Table B-13: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation 

in Female Rats, NTP (2002) ..................................................................................................... 176

Table B-14: Benchmark Modeling Results for Incidence of Larynx Respiratory 

Epithelium, Epiglottis, Hyperplasia in Female Rats, NTP (2002) ........................................ 179

Table B-15: Benchmark Modeling Results for Incidence of Larynx Respiratory 

Epithelium, Epiglottis, Hyperplasia in Female Rats, NTP (2002) ........................................ 181

Table C- 1. Summary of Candidate PODs and Cancer Slope Factors. ............................... 185

Table C-2: Trend Tests on the Inhalation Carcinogenesis Data Sets in Mice from the 2-

Year Inhalation Studies (NTP, 2002) ...................................................................................... 185

Table C-3: Average Life Time Animal Body Weight of Mice for 2-Year Inhalation Studies 

of Vanadium Pentoxide (NTP, 2002) ....................................................................................... 186

Table C-4: RDDRs for Different Concentration/Sex Group of Mice in the 2-Year 

Inhalation Studies of Vanadium Pentoxide (NTP, 2002) ...................................................... 187

Table C-5: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year 

Inhalation Studies (NTP, 2002) ................................................................................................ 187

Table C-6: BMR Estimation for Male and Female Mice Data Sets. .................................... 188

Table C- 7. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar 

Adenoma and Carcinoma in Male Mice, NTP (2002). .......................................................... 189

Table C- 8. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar 

Adenoma and Carcinoma in Male Mice after Dropping the Highest Concentration, NTP 

(2002). ......................................................................................................................................... 191

Table C- 9. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar 

Adenomas and Carcinomas with All Four Concentrations in Female Mice, NTP (2002). 193

Table C- 10. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar 

Adenoma and Carcinoma in Female Mice after Dropping the Highest Concentration, NTP 

(2002). ......................................................................................................................................... 194

Table C- 11. Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Male Mice 

Exposed to Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002). .......................... 197

Table C- 12. Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Female Mice 

Exposed to Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002). .......................... 201
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LIST OF FIGURES

Figure 2-1. Vanadium pentoxide structure ................................................................................ 3

Figure 4-1: Genomics of V2O5-Induced Bronchitis (reprinted with permission from Ingram 

et al., (2007) Respir. Res. Apr 25;8(1):34) ............................................................................... 82
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LIST OF ACRONYMS AND ABBREVIATIONS

BMC benchmark concentration 

BMCL benchmark concentration (lower limit) 

BMD benchmark dose 

BMDL benchmark dose (lower limit) 

BMDS benchmark dose software 

BMR benchmark response 

bw body weight 

cc cubic centimeters 

CD caesarean delivered 

CERCLA Comprehensive Environmental Response, Compensation and 

Liability Act of 1980 

CNS central nervous system 

cu.m cubic meter 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

g grams 

GI gastrointestinal 

HED human equivalent dose 

HEC human equivalent concentration 

Hgb hemoglobin 

i.m. intramuscular 

i.p. intraperitoneal 

IRIS Integrated Risk Information System 

IUR inhalation unit risk 

i.v. intravenous 

kg kilogram 

L liter 

LOAEL lowest-observed-adverse-effect level 

LOAEL[ADJ] LOAEL adjusted to continuous exposure duration 

LOAEL[HEC] LOAEL adjusted for dosimetric differences across species to a human 

m meter 

MCL maximum contaminant level 

MF modifying factor 

mg milligram 
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mg/kg milligrams per kilogram 

mg/L milligrams per liter 

MRL minimal risk level 

MTD maximum tolerated dose 

NAAQS National Ambient Air Quality Standards 

NMMAPS National Morbidity, Mortality, and Air Pollution Study 

NOAEL no-observed-adverse-effect level 

NOAEL[ADJ] NOAEL adjusted to continuous exposure duration 

NOAEL[HEC] NOAEL adjusted for dosimetric differences across species to a human 

NOEL no-observed-effect level 

OSF oral slope factor 

PBPK physiologically based pharmacokinetic 

ppb parts per billion 

ppm parts per million 

PPRTV Provisional Peer Reviewed Toxicity Value 

RBC red blood cell(s) 

RCRA Resource Conservation and Recovery Act 

RDDR Regional deposited dose ratio (for the indicated lung region) 

RfC inhalation reference concentration 

RfD oral reference dose 

RGDR Regional gas dose ratio (for the indicated lung region) 

SCE sister chromatid exchange 

SDWA Safe Drinking Water Act 

sq.cm. square centimeters 

TSCA Toxic Substances Control Act 

UF uncertainty factor 

μg microgram 

μmol micromoles 

VOC volatile organic compound 
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FOREWORD

The purpose of this Toxicological Review is to provide scientific support and rationale 

for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to vanadium 

pentoxide. It is not intended to be a comprehensive treatise on the chemical or toxicological 

nature of vanadium pentoxide, and does not address other vanadium compounds. 

 The intent of Section 6, Major Conclusions in the Characterization of Hazard and Dose 

Response, is to present the major conclusions reached in the derivation of the reference dose, 

reference concentration and cancer assessment, where applicable, and to characterize the overall 

confidence in the quantitative and qualitative aspects of hazard and dose response by addressing 

the quality of data and related uncertainties. The discussion is intended to convey the limitations 

of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk 

assessment process. 

For other general information about this assessment or other questions relating to IRIS, 

the reader is referred to EPA’s IRIS Hotline at (202) 566-1676 (phone), (202) 566-1749 (fax), or 

hotline.iris@epa.gov (email address). 
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AUTHORS, CONTRIBUTORS, AND REVIEWERS

CHEMICAL MANAGER/AUTHOR

Maureen R. Gwinn, Ph.D., DABT 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

IRIS CO-LEAD/AUTHOR

Kathleen Newhouse, M.S. 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

CO-AUTHORS 

Gillian Backus, Ph.D.* 

Northern Virginia Community College 

Sterling, VA. 20164 

Yuyang Christine Cai, M.S., PMP 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

Sanjivani Diwan, Ph.D.* 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

Barbara Glenn, Ph.D. 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

Kathleen Raffaele, Ph.D. 
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Office of Solid Waste and Emergency Response 

US Environmental Protection Agency 

Washington, D.C. 20460 

Suryanarayana V. Vulimiri, D.V.M., Ph.D., DABT 

National Center for Environmental Assessment 

US Environmental Protection Agency 

Washington, D.C. 20460 

*Former EPA employee 
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1. INTRODUCTION 

This document presents background information and justification for the Integrated Risk 

Information System (IRIS) Summary of the hazard and dose-response assessment of vanadium 

pentoxide. IRIS Summaries may include oral reference dose (RfD) and inhalation reference 

concentration (RfC) values for chronic and other exposure durations, and a carcinogenicity 

assessment. 

The RfD and RfC, if derived, provide quantitative information for use in risk assessments 

for health effects known or assumed to be produced through a nonlinear (presumed threshold) 

mode of action. The RfD (expressed in units of mg/kg-day) is defined as an estimate (with 

uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human 

population (including sensitive subgroups) that is likely to be without an appreciable risk of 

deleterious effects during a lifetime. The inhalation RfC (expressed in units of mg/m3

) is 

analogous to the oral RfD, but provides a continuous inhalation exposure estimate. The 

inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for 

effects peripheral to the respiratory system (extrarespiratory or systemic effects). Reference 

values are generally derived for chronic exposures (up to a lifetime), but may also be derived for 

acute (≤24 hours), short-term (>24 hours up to 30 days), and subchronic (>30 days up to 10% of 

lifetime) exposure durations, all of which are derived based on an assumption of continuous 

exposure throughout the duration specified. Unless specified otherwise, the RfD and RfC are 

derived for chronic exposure duration. 

The carcinogenicity assessment provides information on the carcinogenic hazard 

potential of the substance in question, and quantitative estimates of risk from oral and inhalation 

exposures may be derived. The information includes a weight-of-evidence judgment of the 

likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic 

effects may be expressed. Quantitative risk estimates may be derived from the application of a 

low-dose extrapolation procedure. If derived, the oral slope factor is a plausible upper bound on 

the estimate of risk per mg/kg-day of oral exposure. Similarly, an inhalation unit risk is a 

plausible upper bound on the estimate of risk per μg/m3

 air breathed. 

Development of these hazard identification and dose-response assessments for vanadium 

pentoxide has followed the general guidelines for risk assessment as set forth by the National 

Research Council (1983). EPA Guidelines and Risk Assessment Forum technical panel reports 

that may have been used in the development of this assessment include the following: Guidelines 

for the Health Risk Assessment of Chemical Mixtures (U.S. EPA, 1986a), Guidelines for 

Mutagenicity Risk Assessment (U.S. EPA, 1986b), Recommendations for and Documentation of 
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Biological Values for Use in Risk Assessment (U.S. EPA, 1988), Guidelines for Developmental 

Toxicity Risk Assessment (U.S. EPA, 1991), Interim Policy for Particle Size and Limit 

Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of 

Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 

1994b), Use of the Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995), 

Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996), Guidelines for 

Neurotoxicity Risk Assessment (U.S. EPA, 1998), Science Policy Council Handbook: Risk 

Characterization (U.S. EPA, 2000a), Benchmark Dose Technical Guidance Document (U.S. 

EPA, 2000b), Supplementary Guidance for Conducting Health Risk Assessment of Chemical 

Mixtures (U.S. EPA, 2000c), A Review of the Reference Dose and Reference Concentration 

Processes (U.S. EPA, 2002), Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), 

Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens 

(U.S. EPA, 2005b), Science Policy Council Handbook: Peer Review (U.S. EPA, 2006a), and A 

Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 

2006b). 

The literature search strategy employed for this compound was based on the Chemical 

Abstracts Service Registry Number (CASRN) and at least one common name. Any pertinent 

scientific information submitted by the public to the IRIS Submission Desk was also considered 

in the development of this document. The relevant literature was reviewed through May 2011. 

Portions of this document were developed under a Memorandum of Understanding with 

the Agency for Toxic Substances and Disease Registry (ATSDR) as part of a collaborative effort 

in the development of human health toxicological assessments. 
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2. CHEMICAL AND PHYSICAL INFORMATION

As an element, vanadium (V) exists in several oxidation states from -1 to +5. Vanadium 

(CASRN 7440-62-2) is a soft silver-grey metal commonly found in ores, tars, coals and oils and 

is used as an alloy in steel (WHO, 1988). The focus of this toxicological review is on vanadium 

pentoxide (CASRN 1314-62-1), but a short description of chemistry of vanadium and related 

compounds is given below for clarification. 

The chemistry of vanadium is complex; the valence state of vanadium can shift 

depending on pH and other factors. In the body, there is an interconversion of two oxidation 

states of vanadium, the tetravalent form, vanadyl (V+4), and the pentavalent form, vanadate 

(V+5). Vanadate is considered more toxic than vanadyl because vanadate is reactive with a 

number of enzymes and is a potent inhibitor of the Na+K+-ATPase of plasma membranes 

(Harris et al. 1984; Patterson et al. 1986). 

Figure 2-1. Vanadium pentoxide structure 

Generally, V3+ and V4+ predominate in body tissues while V5+ predominates in plasma 

(IPCS, 2001). Vanadium pentoxide (V2O5), sodium metavanadate (NaVO3), sodium 

orthovanadate (Na3VO4), and ammonium metavanadate (NH4VO3) all contain vanadium in the 

+5 oxidation state. Of these compounds, V2O5 is the only compound that is covalently bonded. 

Vanadium compounds differ in their physicochemical properties which influence their 

solubility under different pH conditions and their accessibility and availability in biological 

systems [reviewed in (Assem and Levy 2009)]. An acidic pH favors tetravalent state (V+4) 

keeping it as vanadyl, while an alkaline pH prefers pentavalent state (V+5) as vanadate (Crans et 

al . 2004). In the case of oral ingestion, vanadium compounds are exposed to a range of pH 

solutions in the digestive tract starting from the stomach (pH typically between 1-3.5) followed 

by the small intestine (pH around 8). Bruyere et al. (1999) state that at pH between 1.3 and 3.3 

the predominate form of vanadium is VO2+ and at higher pH the form is VO(OH)3. When the pH 

is high V(5+) (e.g. VO4(OH)3) and polymerized vanadium is predominant (HnV10O29(n-6))(Bruyere 

et al . 1999). At physiological pH vanadium compounds have been shown to exist in monomeric 

tetravalent [VO(OH)3]

-

 and dimeric [(VO)2(OH)5]

-

 forms, as well as pentavalent (H2VO4

-

) forms 
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4

[reviewed in (Assem and Levy 2009)]. Thus, the valence of a vanadium compound will depend 

on the pH. 

The solubility of different vanadium compounds in water between 20 and 25oC differs 

among different valences as shown in Table 2-1 (HSDB 2009; IPCS 2001). The elemental 

vanadium (V0) is insoluble in water. The tetravalent (V+4) compound vanadyl sulfate (VOSO4) 

is highly soluble 534.64 g/L (Rahman and Skyllas-Kazacos 1998), while the pentavalent 

vanadium compounds (V+5), such as vanadium pentoxide (V2O5) is less soluble (8 g/L). Other 

vanadium compounds such as sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4) 

and ammonium metavanadate (NH4VO3) have solubility of 211 g/L, 100 g/L, 58 g/L, 

respectively (IPCS 2001). Furthermore, the rate (distinguished from the solubility – an 

equilibrium or thermodynamic parameter) of dissolution of various vanadium compounds may 

vary, resulting in different concentrations of specific forms of vanadium. It seems a reasonable 

hypothesis that these various forms of vanadium will be absorbed differently, which may result 

in different physiological effects. For example, V(5+

) compounds can mimic phosphate and can 

inhibit phosphatases (Assem and Levy 2009). 

Table 2-1. Valence states and water solubility of various vanadium compounds. 

Vanadium compound Formula CASRN 

Valenc

y 

Solubility (g/L) at 20–25°C 

(HSDB 2009; IPCS 2001) 

Vanadium V 7440-62-2 0 Insoluble 

 Vanadium pentoxide V2O5 1314-62-1 +5 8 

 Sodium m-vanadate NaVO3 13718-26-8 +5 211 

 Sodium o-vanadate Na3VO4 13721-39-6 +5 100 

 Ammonium m-vanadate NH4VO3 7803-55-6 +5 

58 (IPCS 2001); 5.2 at 15o

C (HSDB 

2009) 

 Vanadium oxytrichloride VOCl3 7727-18-6 +5 

Soluble, decomposes in presence of 

moisture into vanadic acid and HCl. 

 

 Vanadyl sulfate VOSO4 27774-13-6 +4 

535 at 20o

C 

(Rahman and Skyllas-Kazacos 1998) 

 Vanadium tetrachloride VCl4 7632-51-1 +4 Decomposes 

 Vanadyl oxydichloride VOCl2 10213-09-9 +3 Decomposes 

 Vanadium trioxide V2O3 1314-34-7 +3 Slightly soluble 

Adapted from (Assem and Levy 2009). 

This Toxicological Review focuses exclusively on vanadium pentoxide (V2O5, CASRN 

1314-62-1) (Figure 2-1), the most common form of vanadium used commercially. Vanadium 
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5

pentoxide exists in the pentavalent state as a yellow-red powder (Table 2-2) (OSHA 2007). 

Table 2-2: Chemical and physical properties of Vanadium Pentoxide 

Characteristic Information Reference 

Chemical name Vanadium Pentoxide 

Synonym(s) Vanadium oxide, vanadic anhydride dust, 

divanadium pentaoxide, divanadium pentoxide, 

vanadium pentaoxide 

OSHA 2007 

Chemical 

formula 

V2O5 CAS 

CASRN 1314-62-1 CAS 

Molecular weight 181.9 

Color Yellowish-red powder 

Yellow to rust-brown orthorhombic powder 

Yellow-orange powder or dark gray flakes 

dispersed in air 

OSHA 2007 

O’Neil 2001; NIOSH 

2005 

Melting point 690 °C OSHA 2007 

Boiling point 1750 °C OSHA 2007 

Density at 18 °C 3.357 ChemFinder.com, HSDB 

2008, Lewis, 1997. 

Odor threshold: Odorless OSHA 2007, NIOSH 

2005. 

Solubility: 

 Water 

 

 Organic 

solvents 

 8 g/L (20 °C) 

 10 g/L (20 °C) 

Soluble in alkalies, concentrated acids, insoluble in 

alcohol 

OSHA 2007 

ChemFinder.com 

O’Neil 2001; HSDB, 

2008 

Vapor pressure 0 mm Hg HSDB 2008 

Specific Gravity 3.4 g/cm3 NTP 2008 

Flash point Not applicable, Non-combustible OSHA 2007 

Conversions: 

 ppm to mg/m3

 mg/m3

 to ppm 

1 ppm = 7.44 mg/m3

1 mg/m3

 = 0.134 ppm 

Calculated 

Calculated 
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3. TOXICOKINETICS

Toxicokinetics of vanadium pentoxide have been investigated in limited studies 

described below and reviewed by Cooper (2007). Toxicokinetics of several other vanadium 

compounds have been evaluated in animal models and are reviewed elsewhere (Sabbioni et al. 

1996; Barceloux 1999; Mukherjee et al. 2004; ATSDR 2009). Vanadium pentoxide is rapidly 

absorbed by both inhalation and oral exposures through lungs and the gastrointestinal tract, 

respectively, although the amount absorbed through the gastrointestinal tract is low. Laboratory 

animal studies show vanadium pentoxide is mainly distributed following inhalation and oral 

exposure to the bone, lungs, liver and kidney. Elimination of vanadium pentoxide has been 

studied only following inhalation exposure, and is mainly through the urine. 

3.1 Absorption 

3.1.1 Inhalation Exposure 

Several occupational studies indicate that absorption can occur in humans following 

inhalation exposure. An increase in urinary vanadium levels was found in workers 

occupationally exposed to <1 ppm (<7.44mg/m3) of vanadium compounds, including vanadium 

pentoxide (Gylseth et al. 1979; Kiviluoto et al. 1981a; Lewis 1959; NIOSH 1983), with the 

majority excreted in urine within one day post long-term or moderate exposure to vanadium dust 

(Kiviluoto et al. 1981a). The vanadium concentration in serum was higher than the 

nonoccupationally exposed controls following exposure to vanadium pentoxide dust (Kiviluoto 

et al. 1981b). 

Indirect evidence of absorption of vanadium in animals is indicated in studies involving 

inhalation exposure or intratracheal administration. In rats and mice exposed to 0.28–2.2 mg 

vanadium/m3

 as vanadium pentoxide1 for 14 days or 2 years (6 hours/day, 5 days/week), 

marginal increases in blood vanadium levels were observed, suggesting that vanadium pentoxide 

was poorly absorbed or rapidly cleared from the blood (NTP 2002; Dill et al. 2004); in the 2-year 

studies by NTP (2002), the increase in blood vanadium levels were concentration-related, 

although not statistically significant. Intratracheal studies suggest that vanadium pentoxide is 

1

Many studies describe exposures in terms of concentration of vanadium, particularly when describing exposure to 

mixtures. When possible, a concentration is given as amounts of vanadium pentoxide. As listed here (mg 

vanadium/m3

 as vanadium pentoxide) shows exposure was to vanadium pentoxide, with data shown here in 

concentration of vanadium. 
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7

readily absorbed through the lungs. The greatest absorption of a radioactive dose, 48V, was 

found to occur 5 minutes after administration in albino rats (gender not specified) (Roshchin et 

al. 1980). Most of the vanadium, i.e., 80 and 85% of the tetravalent (V4+) and pentavalent (V5+) 

forms of vanadium, respectively, cleared from the lungs 3 hours after intratracheal exposure in 

male abino rats (Edel and Sabbioni 1988). After 3 days, 90% of vanadium pentoxide was 

eliminated from the lungs of female rats following intratracheal instillation (Conklin et al. 1982). 

 In an intratracheal instillation study in female Fischer rats 50% was cleared in 18 minutes, and 

the rest within a few days (Rhoads and Sanders 1985). 

Wallenborn et. al. (2007) analyzed the components of a complex particulate matter 

mixture into its metal components and tracked the absorption of different metals in different 

tissues following a single intratracheal dose in rats. Healthy male Wistar rats were instilled with 

a single intratracheal dose of combustion particulate matter (PM) containing a moderate amount 

of transition metals, including vanadium. The composition of vanadium in the PM was 62.95 

μg/mg, with 7.18 μg/mg in the water soluble fraction, 26.50 μg/mg in the acid soluble fraction 

and 29.27 μg/mg in the insoluble fraction. According to calculations, of the 196.63 μg/rat of 

vanadium instilled (theoretical), 110.32 μg/rat was measured in lung 4-hrs post-instillation and 

62.76 μg/rat was measured in lung 24-hrs post-instillation. In the plasma and lung, vanadium 

was significantly elevated 4-hr post-instillation (130,000 ng V/g lung tissue, and 350 ng V/g 

plasma) compared to 24-hrs (60,000 ng V/g lung tissue, and 110 ng V/g plasma, respectively) 

suggesting rapid uptake of water-soluble vanadium. The vanadium component of PM was 

tracked to lung, plasma, heart and liver and was significantly increased compared to controls at 

both 4- and 24-hrs post-instillation compared to saline controls. This study permitted detectable 

changes in component metals of a complex mixture in various organs and provides evidence that 

metals dissociate from particulate matter and translocate to various target organs, depending on 

solubility (Wallenborn et al 2007). 

3.1.2 Oral Exposure 

No studies were available in the published literature regarding the rate and extent of 

absorption in humans after oral exposure to vanadium pentoxide. 

The absorption of vanadium through the gastrointestinal tract of animals is low. Less 

than 0.1% of an intragastric dose was detectable in the blood of albino rats at 15 minutes postexposure, and less than 1% at 1 hour (Roshchin et al. 1980). Similarly, only 2.6% of an orally 

administered radiolabeled dose of vanadium pentoxide was absorbed 3 days after exposure in 

female Fischer rats (Conklin et al. 1982). Vanadium was reported in tissues and urine of male 
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8

albino rats within hours after a single oral dose (Edel and Sabbioni 1988), suggesting that it is 

rapidly absorbed. Young rats that consumed vanadium in the drinking water and feed were 

found to have higher tissue vanadium levels 21 days after birth than they did 115 days after birth 

(Edel et al. 1984). The data suggest that there is a higher absorption of vanadium in these young 

animals due to a greater nonselective permeability of the undeveloped intestinal barrier. Thus, 

age of the rodents appears to play an important role in the absorption of vanadium in the 

gastrointestinal tract. 

3.1.3 Dermal Exposure 

No specific studies were available in the published literature regarding absorption in 

humans or animals after dermal exposure to vanadium pentoxide, although absorption by this 

route is generally considered to be very low (WHO 1988). Vanadium is a metal with low 

solubility, therefore absorption through the skin is thought to be minimal. 

3.1.4 Other Routes of Exposure 

No studies were available in the published literature regarding the nature and extent of 

absorption in humans after other routes of exposure to vanadium pentoxide. 

 

3.2 Distribution 

Distribution was measured from autopsy cases with unknown routes of exposure. 

Vanadium has been detected in the lungs (in 52% of the cases) and intestines (in 16% of the 

cases) of humans with no known occupational exposure, collected from autopsy data and 

reviewed in Schroeder et al. (1963). In the gastrointestinal tract, it was primarily found in the 

ileum (37%), cecum (45.1%), sigmoid colon (15.9%), and rectum (26.2%). Most positive 

samples had 0.01μg or less per g of tissue. The heart, aorta, brain, kidney, muscle, ovary, and 

testes were found to have no detectable vanadium concentrations. 

3.2.1 Inhalation Exposure 

There are limited data on the distribution of vanadium in workers; serum vanadium levels 

in workers were highest within a day after inhalation exposure followed by a rapid decline in 

levels upon cessation of exposure (Gylseth et al. 1979; Kiviluoto et al. 1981b). Analytical 

studies have shown low levels of vanadium in human kidneys and liver, with even less in brain, 
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9

heart, and milk. Higher levels were detected in hair, bone, and teeth (Byrne and Kosta 1978). 

Inhalation exposure and intratracheal administration studies have examined the distribution of 

vanadium in rodents. In F344 rats chronically exposed to 0.56 or 1.1 mg vanadium/m3 as 

vanadium pentoxide (6 hours/day, 5 days/week), vanadium lung burdens peaked after 173 days 

of exposure and declined until 542 days; lung levels never reached steady state (NTP 2002). In 

contrast, lung burdens appeared to reach steady state by exposure day 173 in rats exposed to 0.28 

mg vanadium/m3

 (NTP 2002). Similarly, lung burdens did not reach steady state in B6C3F1 

mice exposed to 1.1 or 2.2 mg vanadium/m3

 as vanadium pentoxide, 6 hours/day, 5 days/week 

for 542 days (NTP 2002). Rather, lung burdens peaked near day 54 and declined through day 

535. Steady state was achieved in mice exposed to 0.56 mg vanadium/m3

 during the first 26 

days of exposure. 

Vanadium is found to have a two-phase lung clearance after a single acute exposure in 

both male Wistar rats and female Fischer rats (Oberg et al. 1978; Rhoads and Sanders 1985). 

The initial phase is rapid with a large percentage of the absorbed dose distributed to most organs 

and blood 24 hours postexposure, followed by a slower clearance phase. Vanadium is 

transported mainly in the plasma. It is found in appreciable amounts in the blood initially and 

only at trace levels 2 days after exposure (Roshchin et al. 1980). The pentavalent and tetravalent 

forms of vanadium compounds were found to have similar distribution patterns in male albino 

Sprague-Dawley rats (Edel and Sabbioni 1988). Three hours after exposure to the pentavalent or 

tetravalent form, 15–17% of the absorbed dose was found in the lung, 2.8% in the liver, and 2% 

in the kidney (Edel and Sabbioni 1988). After intratracheal instillation of pentavalent vanadium, 

retention of vanadium was observed in lungs, liver, kidneys, bone, testes and spleen with 

clearance at different timepoints post-exposure with little to no retention observed in stomach, 

intestines, heart or trachea (Edel and Sabbioni 1988). This is similar to the distribution seen 

following inhalation and oral exposure. 

3.2.2 Oral Exposure 

No studies were available in the published literature regarding distribution in humans 

after oral exposure to vanadium pentoxide. 

Acute studies with rats showed the highest vanadium concentration in the skeleton. Male 

rats had approximately 0.05% of the administered 48V in bones, 0.01% in the liver, and <0.01% 

in the kidney, blood, testis, or spleen after 24 hours (Edel and Sabbioni 1988). Other authors 

who found that the bone had the greatest concentration of radiolabeled vanadium, followed by 

the kidney (Roshchin et al. 1980), noted similar findings. Conklin et al. (1982) reported that 
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10

after 3 days, 25% of the absorbed vanadium pentoxide was detectable in the skeleton and blood 

of female Fischer rats. 

Oral exposure for an intermediate duration produced the highest accumulation of 

vanadium in the kidney. In young male rats at 3 weeks of age, the kidneys, heart, and lungs had 

the highest levels immediately following exposure (Edel et al. 1984). Vanadium in the kidney, 

liver, and lung decreased significantly at 115 days of age. There was an accumulation in muscle 

and fat, related to the growing mass of the tissues with age. The higher levels of vanadium in the 

young rat tissues may be due to the higher retention capacity of the undeveloped tissues, or a 

greater permeability of the intestinal wall. Adult rats exposed to 5 or 50 ppm vanadium in the 

drinking water for 3 months had the highest vanadium levels in the kidney, followed by bone, 

liver, and muscle (Parker and Sharma 1978). The retention in bone may have been due to 

phosphate displacement. All tissue levels plateaued at the third week of exposure. A possible 

explanation for the initially higher levels in the kidney during intermediate-duration exposure is 

the daily excretion of vanadium in the urine. When the treatment is stopped, levels decrease in 

the kidney. At the cessation of treatment, vanadium mobilized rapidly from the liver and slowly 

from the bones. Other tissue levels decreased rapidly after oral exposure was discontinued. 

Thus, retention of vanadium was much longer in the bones (Edel et al. 1984; Parker and Sharma 

1978). 

Radike et al. (2002) assessed the distribution of various metals, including vanadium, in 

female B6C3F1 mice. Mice ingested either (1) a metal mixture containing Chromium (Cr), 

Cadmium (Cd), Arsenic (As), Nickel (Ni) and Vanadium (V) in drinking water or (2) a metal 

mixture containing Cr, Cd, As, Ni, and V in NIH-31 feed. In water and feed, the calculated 

vanadium concentration in the mixture was 45 ppm and 1.105 ppm, respectively. Measured 

vanadium levels in the small intestine were 10 ppm at 5 weeks and 14 ppm at 8 weeks, and were 

significantly higher compared to controls than any other metal constituent in the small intestine. 

Mainly, vanadium pentoxide is distributed to bone (10-25% of administered oral dose), liver 

(~5%), and kidney (~4%). In addition, vanadium levels in the kidneys and the femur were 

significantly greater than in controls at 4, 8, 12, 16, and 24 week following oral dosing. 

Vanadium levels in small intestine and kidneys were lower in mice given vanadium as part of a 

heterogeneous metal mixture in feed vs. water (Radike et al. 2002). 

3.2.3 Dermal Exposure 

No studies were available in the published literature regarding distribution in humans or 

animals after dermal exposure to vanadium. 
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11

3.2.4 Other Routes of Exposure 

After intraperitoneal administration to rats, vanadium is distributed to all organs. After 

24 hours, the highest concentrations were found in the bones and kidney, although initial levels 

were highest in the kidney (Roshchin et al. 1980; Sharma et al. 1980). 

3.3 Metabolism 

Vanadium is an element, and as such, is not metabolized. In the oxygenated blood, it 

circulates as a polyvanadate (isopolyanions containing pentavalent vanadium) but in tissues, it is 

retained mainly as the vanadyl cation (cationic form of tetravalent vanadium). Depending on the 

availability of reducing equivalents (such as reduced glutathione GSH, NADPH, NADH) and 

oxygen, vanadium may be reduced, reoxidized, and/or undergo redox cycling (Byczkowski and 

Kulkarni 1992). 

3.4 Elimination and Excretion 

3.4.1 Inhalation Exposure 

Occupational studies showed that urinary vanadium levels significantly increased in 

vanadium pentoxide exposed workers (Gylseth et al. 1979; Kiviluoto et al. 1981a; Lewis 1959; 

NIOSH 1983; Zenz et al. 1962). Male and female workers exposed to 0.1–0.19 mg/m3 vanadium 

in a manufacturing company, had significantly higher urinary levels (20.6 μg/L) than the 

nonoccupationally exposed control subjects (2.7 μg/L) (NIOSH 1983). The correlation between 

ambient vanadium levels and urinary levels of vanadium is difficult to determine from these 

epidemiological studies (Kiviluoto et al. 1981b). In most instances, no other excretion routes 

were monitored. Analytical studies have shown very low levels in human milk (Byrne and 

Kosta 1978). Evidence from animal studies supports the occupational findings. Vanadium 

administered intratracheally to rats was reported to be excreted predominantly in the urine 

(Oberg et al. 1978) at levels twice that found in the feces (Rhoads and Sanders 1985). Three 

days after intratracheal exposure to radiolabeled vanadium pentoxide, 40% of the recovered 48V 

dose was cleared in the urine while 30% remained in the skeleton, and 2–7% was in the lungs, 

liver, kidneys, or blood (Conklin et al. 1982). 

 In female rats exposed to 0.56 or 1.1 mg vanadium/m3

 as vanadium pentoxide for 16 days 
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12

(6 hours/day, 5 days/week), lung clearance half-times during an 8-day recovery period were 4.42 

and 4.96 days, respectively (NTP 2002). In mice similarly exposed to 1.1 or 2.2 mg 

vanadium/m3 as vanadium pentoxide, lung clearance half-times were 2.55 and 2.40 days, 

respectively (NTP 2002). In contrast to the 16-day exposure data, the lung clearance half-times 

in female rats exposed to 0.28, 0.56, or 1.1 mg vanadium/m3 for 2 years (6 hours/day, 5 

days/week) were 37.3, 58.6, and 61.4 days, respectively (NTP 2002). In mice, the half-times 

were 6.26, 10.7, and 13.9 days at 0.56, 1.1, and 2.2 mg vanadium/m3

 exposure levels (NTP 

2002). 

 After intratracheal instillation of pentavalent vanadium, clearance from lungs was 

initially rapid (3h) but with some vanadium (2% original dose) remaining at 12 d post-exposure. 

All other tissues eliminated 98-99% of original dose by 3h post-exposure (Edel and Sabbioni 

1988). Epidemiological studies and animal studies suggest that elimination of vanadium 

following inhalation exposure is primarily in the urine. 

3.4.2 Oral Exposure 

No studies were available published literature regarding excretion in humans or 

laboratory animals after oral exposure to vanadium pentoxide. 

3.4.3 Dermal Exposure 

No studies were available published literature regarding excretion in humans or 

laboratory animals after dermal exposure to vanadium pentoxide. 

3.4.4 Other Routes of Exposure 

No studies were available published literature regarding excretion in humans or 

laboratory animals after other routes of exposure to vanadium pentoxide. 

3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

No PBPK models for vanadium pentoxide are available. 

3.5.1 Animal-to-Human Extrapolations 

There are no relevant data available to evaluate potential toxicokinetic differences 
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13

between humans and laboratory animals. Similar effects have been reported in humans and 

animals following inhalation or oral exposure to vanadium pentoxide; however, this conclusion 

is based on the limited human toxicity data. In absence of data to the contrary, rats or mice 

appear to be valid models for extrapolation to humans. 
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14

4. HAZARD IDENTIFICATION

4.1. STUDIES IN HUMANS – EPIDEMIOLOGY, CASE REPORTS, CLINICAL 

CONTROLS 

4.1.1 Oral Exposure 

 

Few relevant studies investigating the effects of acute, subchronic or chronic oral 

exposure to vanadium pentoxide in humans were identified in the peer-reviewed literature. One 

study, Kucera et al. (1992), measured vanadium in the hair and blood of children exposed to 

vanadium by accidental drinking of contaminated water near a vanadium pentoxide plant. 

Vanadium levels in the hair did not differ significantly for the control and exposed groups. An 

increase in vanadium concentrations was found in the blood of exposed children (median: 0.078 

μg/L) compared to control children (median: 0.042 μg/L). No exposure-response relationship 

could be quantified. These results suggest that the vanadium levels in blood, but not hair is a 

sensitive or suitable indicator of environmental exposure. 

4.1.2 Inhalation Exposure 

 

Health effects of inhalation exposure to vanadium pentoxide and other vanadium 

compounds reported by case studies and epidemiological investigations include respiratory tract 

irritation, bronchitis (often called boilermakers’ bronchitis), airway obstruction, chest pain, 

rhinitis, pharyngitis, laryngitis and conjunctivitis in workers exposed to vanadium-containing 

dust during vanadium processing (Sjöberg, 1951; Sjöberg, 1956; Zenz et al., 1962; Kiviluoto et 

al., 1979; Kiviluoto, 1980; Kiviluoto et al., 1981; Musk and Tees, 1982; Irsigler et al., 1999) or 

to fuel-oil ash containing vanadium during cleaning and maintenence of oil-burning boilers 

(Williams, 1952; Sjöberg, 1955; Lees, 1980; Ross, 1983; Levy et al., 1984; Hauser et al., 1995a; 

Hauser et al., 1995b; Woodin et al., 1998; Woodin et al., 1999; Woodin et al., 2000; Hauser et 

al., 2001; Kim et al., 2004). Most of these studies did not quantify the inhalation exposure 

specifically to vanadium pentoxide, although it was the primary exposure in vanadium pentoxide 

production. Exposures to residual oil fly ash (ROFA) involves a mixture of pollutants including 

elemental vanadium, vanadium oxides, vanadium pentoxide, vanadium sulphates, particulate 

matter and other metal constituents (Hauser et al., 1995b). Vanadium pentoxide is a major 
DRAFT - DO NOT CITE OR QUOTE 

15

constituent of ROFA and the studies of health effects among boilermakers evaluated models in 

relation to vanadium content of respirable particulate matter. Therefore, these papers serve to 

inform the assessment of the nature and scope of the health response to vanadium pentoxide. 

More recently, epidemiology studies evaluated the metals content of ambient particulate matter 

(PM) and found that communities in the United States with higher vanadium content in PM have 

higher PM-related risk of mortality or hospitalizations for cardiovascular or respiratory disease 

(Lippmann et al., 2006; Dominici et al., 2007; Bell et al., 2009; Patel et al., 2009; Lagorio et al., 

2006). Because exposures to vanadium, not vanadium pentoxide, were evaluated in the studies 

of ROFA or PM air pollution, information to characterize the exposure-response relationship 

between inhaled vanadium pentoxide alone and adverse health effects in humans is limited. 

Moreover, both ROFA and PM are mixtures with several components that also may contribute to 

observed health effects. 

4.1.2.1 Controlled Human Exposure Study 

 Zenz and Berg (1967) exposed nine volunteers to vanadium pentoxide dust to evaluate 

respiratory effects. Volunteers (gender not reported) were exposed to 0.1 mg/m3 (n=2), 

0.25 mg/m3 (n=5) or 1 mg/m3 (n=2) vanadium pentoxide in an environmental chamber for 8 hrs; 

no control group was included in this study. Particle size analysis revealed that 98% of particles 

had a diameter <0.5 μm. Post-exposure assessments of chest x-ray, blood, urine, nasal smear 

samples and pulmonary function were compared with baseline values determined for each 

subject prior to exposure. All subjects were observed for clinical symptoms for 11-19 months 

after exposure. Subjects exposed to 1 mg/m3 vanadium pentoxide developed sporadic cough 

after 5 hrs of exposure, which progressed to persistent cough during the last 3 hrs of exposure 

and continued for 8 days. No other signs of respiratory irritation were observed. Results of 

pulmonary function tests and chest x-ray 1, 2 and 3 weeks after exposure were similar to 

baseline (data not reported). Hematology and urinalysis parameters were not affected by 

exposure (data not reported). Nasal smears obtained 24 hrs, 72 hrs and 1 week after exposure 

were negative for eosinophilia. Three weeks after the initial exposure, two of the subjects were 

accidentally exposed to a “heavy cloud” of vanadium pentoxide dust (concentration not reported) 

for 5 minutes. Within 16 hrs of exposure, both subjects developed a “marked” productive cough 

with rales and expiratory wheeze, which continued for 1 week. However, pulmonary function 

test results were comparable to baseline (data not reported). Blood and nasal smear samples 

were negative for eosinophilia. Subjects in the 0.25 mg/m3

 exposure group developed a “loose” 

productive cough on the day after exposure, which lasted for 7-10 days. No additional 
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16

symptoms were observed and post-exposure pulmonary function and laboratory tests were 

comparable to baseline results (data not reported). Subjects exposed to 0.1 mg/m3 developed 

“considerable” mucus formation within 24 hrs after exposure, lasting for 4 days. No other 

symptoms or positive findings for pulmonary function or laboratory tests were observed. No 

treatment-related symptoms or clinical findings were reported for any subject during the 

11-19 months post-treatment period. 

4.1.2.2 Occupational Exposure during Vanadium Pentoxide Mining and Processing 

Respiratory and other symptoms have been documented among workers employed at 

facilities producing and processing vanadium pentoxide (Sjöberg, 1951; Sjöberg, 1956; Zenz et 

al., 1962; Kiviluoto et al., 1979; Kiviluoto, 1980; Kiviluoto et al., 1981a; Musk and Tees, 1982; 

Irsigler et al., 1999). Sjöberg (1951) reviewed earlier reports of symptoms among workers 

exposed to vanadium pentoxide and described symptoms among 36 employees (foremen, 

workers, builders/repairers) at a V2O5 production factory in Falun, Sweden that began operation 

in 1946. The employees experienced symptoms on one or multiple occasions while under his 

medical surveillance between 1947 and 1950. Symptoms generally persisted an average of 13 

days. Air samples in different parts of the vanadium pentoxide facility were found to contain 

dust concentrations of 0.6 – 86.9 mg/m3

 during pulverization of iron ore slag with a vanadium 

content of 4.8 to 7.5%. A significant proportion of the dust consisted of small, respirable 

particles (22% < 8μ, 39% < 12μ). Although vanadium pentoxide concentrations in air were not 

reported, vanadium was detected in the blood and urine of 23 and 27 individuals, respectively. 

Sjöberg (1956) reported the main findings of his medical surveillance, including those of 

a thorough examination of the cohort in October, 1948, comparing them to an external referent 

population, a group of 703 workers from mines and sawmills in northern Sweden followed 

during the same time period and examined using the same methods. The authors assumed that 

the comparison population was exposed only to inert dust, however no sampling data was 

reported. The main symptoms of the upper respiratory tract were nasal irritation and/or nasal 

catarrh (inflammation of mucus membranes; 42% versus 20% among unexposed) and throat 

dryness and pain (86% versus 8% among unexposed). These symptoms were reported to be 

more prevalent at the final examination in 1948 and included acute and chronic pathological 

changes in the nose and pharynx. Lower respiratory tract symptoms included cough with no 

sputum (61%), cough with sputum (39%), wheezing (86%) and shortness of breath (75%). In 

the comparison group, prevalence of coughing and shortness of breath was 4% and 24%, 

respectively. Bronchoscopy, measured in five individuals, revealed no severe changes in four 
DRAFT - DO NOT CITE OR QUOTE 

17

cases and mild chronic bronchitis in one person. Acute changes in the lungs indicative of 

pneumonitis were noted in five workers. Spirometric measures were reported to be higher than 

those of the comparison group. A decrease in hemoglobin levels (7.8 ± 2.36% compared to 3.0 ± 

2.07%) and red blood cell count was observed, particularly among workers who were 

permanently or frequently employed at the plant during the observation period, although levels 

remained within normal limits. The authors did not observe leucopenia or eosnophilia in blood 

samples. Six cases of dermatitis were observed, and one person had a positive response to a 

patch test with a sodium vanadate solution. Finally, weakness and fatigue were reported to be 

common symptoms after heavy exposure to dust, and symptoms of a neurasthenic character were 

noted in some cases. 

Six workers with persistent symptoms were re-examined in December, 1953 to January, 

1954 (Sjöberg, 1956). Reported symptoms included cough and wheezing (N=5), and dyspnea 

and fatigue (N=6). Clinical measurements and blood pressure were normal including sinuses, 

circulating eosinophils, erythrocyte sedimentation rate, and radiographic examination of the 

lungs and heart revealed no evidence of pneumoconiosis. Lung function measures had increased 

which the authors attributed to differences in technique. However, bronchoscopic examination 

and biopsy of bronchial mucosa showed evidence of chronic bronchitis (N=5). 

Two additional published case summaries described symptoms that appeared among 

workers after the start of new plant operations producing vanadium pentoxide pellets (N=18) 

(Zenz et al., 1962) or refining vanadium pentoxide (N=4) (Musk and Tees, 1982). Both 

exposures were to dry vanadium pentoxide powder at high concentrations (> 0.5 mg/m3

). 

Symptoms similar to those reported by Sjöberg (1956) appeared by the end of the first day of 

exposure including eye and throat irritation and cough with sputum, and persisted 2 – 4 weeks 

after exposure ended. Lung function tests revealed reversible airflow obstruction in 3 of the 4 

case histories reported by Musk and Tees, and bronchial reactivity to histamine was 

demonstrated in two of the four. One individual with a family history of asthma and positive 

skin prick tests to common allergens, continued to experience wheezing for 8 weeks. Zenz et al 

(1962) did not find reductions in airflow among the 18 men examined. 

Kiviluoto et al. (1979; 1980; 1981a, b) published a series of reports regarding an 

investigation in 1975 of respiratory symptoms and clinical findings among employees (process 

workers, repairmen, foremen, and a laboratory worker) at a factory making vanadium pentoxide 

from magnetite ore. A total of 79 men employed at the vanadium factory ≥ 4 months were 

eligible and 63 men, aged 19-52 years, who were not on holiday or sick leave were enrolled 

(80% participation rate). A referent group of 63 men living in the same area were selected from 

workers at the magnetite ore mine (concentrating plant, the mine, the repair shop, and the office) 
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18

and matched for age (within 2 years) and smoking habit (within 5 cigarettes/day). Vanadium dust 

concentrations at various sites measured on 8 days over 2 shifts in March-May 1976, were 0.012 

mg/m3 ranging between 0.002 (LOD) and 0.043 mg/m3. Vanadium concentrations in the 

breathing zone were 0.028 mg/m3

 (TWA) with a range of 0.002 – 0.42 mg/m3. Higher 

concentrations were found where grinding and packing of smelt were conducted (TWA (range): 

2.3 mg/m3

 (one sample) and 0.13 mg/m3 (0.02 – 0.37). Air monitoring results were not reported 

for the referent population. Urinary vanadium concentrations among the exposed averaged 0.26 

± 0.17 umol/L (18 hour excretion), while concentrations among the referent group did not 

exceed the < 0.04 umol/L limit of detection (LOD). 

Clinical assessments were conducted by health personnel with no knowledge of exposure 

status. The occurrence of wheeze differed by exposure. Workers who reported wheezing were 

twice as likely to work in the vanadium factory (p<0.05) (Kiviluoto, 1980). Prevalence of nasal 

catarrh, cough, phlegm, or other respiratory symptoms did not differ between the exposed and 

referent groups. Spirometric measurements (FVC, FEV1, adjusted for height), obtained at the 

end of workers’ summer holidays, did not differ between the exposed and referent groups 

(p>0.01) and were not related to duration of exposure to vanadium dust (p>0.1). Inflammation 

was observed in nasal smears and these results are discussed in the section on immunological 

endpoints (Section 4.2.1). Nonfasting serum chemistry parameters, analyzed in May – June, 

1975, when vanadium concentrations were higher (0.2-0.5 mg/m3) were compared between 16 

exposed and 16 referent subjects. Among the several serum chemistry parameters tested, the 

difference between the exposed and referent groups for serum albumin, chloride, urea, bilirubin 

and conjugated bilirubin were statistically significant, although no values were outside the range 

of reference values. Hematological results (nonfasting) for 63 exposed and 16 referents, 

analyzed in March – May, 1976, when vanadium concentrations were lower (0.01-0.04 mg/m3), 

did not vary by exposure group (p>0.05). In addition, there were no differences noted for serum 

cholesterol, serum triglyceride, or leukocyte differential. 

Irsigler et al. (1999) evaluated the clinical histories of 40 men, who were employed at a 

vanadium pentoxide production plant in South Africa, and were referred by the plant’s medical 

staff for more detailed medical assessment because of persistence of respiratory symptoms 

(cough, breathing difficulty, wheezing) between October 1995 – October 1997. Twelve men, 

aged 19 – 60 years with bronchial hyperresponsiveness to inhaled histamine or exercise 

challenge (out of 40 men referred) were selected for analysis along with 12 men, aged 24 – 54, 

who were referred and did not have bronchial hyperresponsiveness, matched by age and 

smoking. The authors concluded that the asthma symptoms and bronchial reactivity had 

occurred as a result of vanadium exposure because all were free of current symptoms or a 
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19

previous history of asthma when they began employment at the plant. Bronchial reactivity was 

determined by the repeated inhalation of histamine at successively doubled doses until a 

decrease of 20% or greater in FEV1 was measured (Histamine PC20 FEV1). A PC20 > 8 mg/ml 

was considered to be normal. Alternatively, an exercise challenge consisting of free tread mill 

running indoors for 6 minutes was used to assess bronchial reactivity. A positive test was 

defined as a decrease of 200 ml or a 15% or greater fall in FEV1. Vanadium pentoxide 

concentrations in air from area samples were < 0.15 mg/m3 in the mills, kiln, leaching, and 

pollution control areas, 1.53 mg/m3

 in the fusion precipitation area, and 0.057 mg/m3 in the 

ferrovanadium area. Concentrations of SO2 and NH3 were above their recommended 

occupational limits in the kiln area. Vanadium pentoxide in spot urine samples was detected in 

10 of the 12 workers with bronchial reactivity (5.2 – 180 μg/g creatinine) and was above a level 

considered to be toxic in 3 individuals (> 50 μg/g creatinine). Levels in the 12 referent men 

ranged between 12.0 – 55 μg/g creatinine, with one person above 50 μg/g creatinine. Among 9 

subjects who returned for a follow-up examination after 5 to 23 months with no vanadium 

pentoxide exposure, 8 still exhibited bronchial reactivity. Atopy was ruled out as a primary 

cause because 5 individuals with positive skin prick allergy tests were equally distributed in the 

reactive and nonreactive groups. In addition, no evidence of viral upper respiratory tract 

infection was found in the study subjects, and 10 cigarette smokers were also distributed equally 

in both groups. Work tasks did not appear to be different between the two groups. This small 

study was not informative regarding associations between vanadium pentoxide exposure and 

bronchial reactivity. Although the group with bronchial reactivity had two subjects with high 

urine vanadium levels, differences in biomarker levels or job site between groups were not 

analyzed statistically, and the sample size and study design were not adequate to determine an 

association of vanadium pentoxide exposure with bronchial reactivity. 

4.1.2.3 Occupational Exposure during Cleaning and Maintenance of Oil-Fired Boilers 

Vanadium pentoxide is present in significant amounts along with other vanadium oxides, 

vanadium sulphate and metals in ash that accumulate in oil- and coal-fired boilers, as well as 

other fuel types used in boilers. Several reports of case histories and epidemiology studies of 

boilermakers involved in the construction, cleaning and maintenance of oil-fired boilers have 

described upper and lower respiratory symptoms similar to those reported among workers 

processing vanadium pentoxide (Williams, 1952; Sjöberg, 1955; Lees, 1980; Ross, 1983; Levy 

et al., 1984; Hauser et al., 1995a; Hauser et al., 1995b; Woodin et al., 1998; Woodin et al., 1999; 

Woodin et al., 2000; Hauser et al., 2001; Kim et al., 2004). Additional health parameters have 
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20

been investigated including pulmonary function (Lees, 1980; Levy et al., 1984; Hauser et al., 

1995a; Woodin et al., 1999; , biomarkers of inflammation in nasal fluid (Hauser et al., 1995b; 

Woodin et al., 1998), and autonomic cardiac function (Magari et al., 2002). Studies have 

investigated acute effects occurring after jobs cleaning or overhauling boilers lasting a few days 

to several weeks and chronic conditions among boilermakers who had worked in that occupation 

for several years. 

Several case summaries described the health response of workers cleaning oil-fired 

boilers in Great Britain (Williams, 1952; Ross, 1983), Sweden (Sjöberg, 1955), and Canada 

(Lees, 1980). Two case series reports described exposure to dust during cleaning jobs of a few 

days to one week during 1946 – 1953. The onset of symptoms, including rhinorrhoea, sneezing, 

eye irritation, sore throat, and chest pain, began within 1 to 12 hours (Williams, 1952; Sjoberg, 

1955). Symptoms with a delayed onset of 6 – 24 hours included a dry cough becoming 

paroxysmal and productive in some workers, wheezing, dyspnea upon exertion, and fatigue 

(Williams, 1952; Sjoberg, 1955). Bronchial irritation, bronchitis, and the development of rales 

in regions of the lung of some of the workers also were reported. Some workers also developed 

a greenish-black coating on the tongue. Symptoms were reported to persist for 3 days to one 

week after exposure was ended. Concentrations of vanadium pentoxide particles (10-20 μ in 

diameter) in the air inside the boilers during cleaning were 17 – 85 mg/m3

. 

Lees (1980) reported on a clinical evaluation of 17 men occupationally exposed to 

bottom ash from cleaning the boiler of an oil-fired electricity generating station. Personal 

sampling in the breathing zone of four of the men indicated a mean time weighted average of 

523 μg/m3 (0.52 mg/m3) for dust under 10μ. Vanadium content in the bottom ash and crusted 

deposits was 15.3% and 24.2 – 35%, respectively. The men wore cartridge filter type respirators 

during the cleaning operation, however subsequent testing documented that they leaked up to 

9%. The air concentrations of vanadium pentoxide were not specifically reported. Symptoms 

and lung function after exposure were compared to health status assessed before exposure began. 

 A medical history and clinical examination, performed before work began and the day after, 

indicated symptoms similar to those described in earlier reports, including cough with sputum, 

respiratory wheeze, and sore throat reported in 77%, 53%, and 41% of the men, respectively. 

Serial spirometry measurements at 24 hour intervals showed reductions with the lowest mean 

FVC and FEV1 values at postexposure days 3 and 2, respectively, compared to baseline (percent 

of baseline: 88.6% and 86.6%, respectively; p<0.05). Reductions in forced mid-expiratory flow 

of 9-31% also were recorded. These measures had returned to preexposure levels after 4 weeks. 

 No details were provided regarding the years the study was conducted and the characteristics of 

the men under study. 
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21

In 1981, the Occupational Safety and Health Administration conducted an investigation 

of work-related bronchitis among 100 boilermakers exposed to vanadium pentoxide during an oil 

to coal conversion of a utility company power plant in western Massachusetts (Levy et al., 

1984). The conversion occurred over the course of approximately 6 weeks, October 15 – 

November 30, with most of the men working 10 hour days, six days per week. Air samples 

obtained in the boiler at approximately 4 weeks during the conversion indicated vanadium 

pentoxide fume concentrations of 0.05 – 5.3 mg/m3

. Concentrations of chromium, nickel, and 

fumes of copper and iron oxide were stated to be within acceptable limits. Nitrogen dioxide and 

hydrogen sulfide were not detected. Low concentrations of carbon dioxide (<5 ppm) and ozone 

(< 0.1 ppm) were measured. Sulfur dioxide (< 1 ppm) was measured in the boiler during 

welding operations and outside the boiler (1 – 35 ppm) when expansion joints were cut with a 

torch. 

In early December, a questionnaire was distributed to all 100 workers through the union 

president and responses were received from 55 men over the next two months. All of the 

respondents, aged 23 – 60 years, reported symptoms, with over half describing cough with 

sputum (85%), sore throat (76%), dyspnea on exertion (71%), chest pain or discomfort (65%), 

headache (56%), runny nose or sneezing (56%), wheezing (55%) and tiredness (51%). The 

median time to onset was 7 days with clustering at 0 – 4 days and 6 – 8 days. When the 

questionnaires were completed, symptoms had resolved or were improving in 41 of the 55 

respondents. Although three-fourths of the respondents stated that they had used a respirator 

over half the time when in the boiler, more than half stated that the respirator used was a paper 

mask. Respondents had been boilermakers a median of 10 years. Pulmonary function tests were 

performed on 35 individuals after they visited a physician. Median FVC was 87% of predicted, 

but was < 80% of predicted in 5 of 27 individuals. Median FEV1 was 93% of predicted, but was 

< 80% of predicted in 8 of 27 men. Median FEV1/FVC was 79% of predicted. Median FEF25-

75% among 24 workers tested was 57% of predicted with only 4 of 24 above 80% of predicted. 

FEF25-75% was not correlated with smoking history among the 69% of workers for whom this 

information was obtained. 

The symptoms and effects on lung function are consistent with previous reports of 

occupational exposures during the cleaning and maintenance of boilers that had burned oil 

contaminated with vanadium pentoxide. A marked deficit in pulmonary function, particularly in 

FEF, was observed in some of the workers. However, pulmonary function was assessed in only 

60% of respondents by several different health providers. In addition, this study is limited by a 

lack of baseline information on health status or comparison to a comparable occupational group, 

a relatively low response among the exposed workers, and data collection days to weeks after 
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exposure was discontinued. 

A subsequent study of lung function among boilermakers before and after four weeks of 

work overhauling an oil-fired boiler did not observe an association with respirable vanadium 

dust concentrations (Hauser et al., 1995a). A total of 36 out of 80 eligible workers completed a 

baseline test, and 26 completed a postexposure test. The men averaged 42.5 years of age (27 – 

60) and 16.9 years on the job (6 months – 35 years). Daily exposure estimates were developed 

for each subject based on work diaries detailing tasks and locations and personal sampling. 

Between 1 and 10 hour time weighted average sampling was available for 15% of the total 

number of study days and these data were applied to the task/location information to assign 

exposure levels for PM10 and vanadium dust for each worker. Lung function values were 

analyzed in relation to three exposure indices for the exposure period; average or peak 

concentrations, and concentrations on the day of the postexposure test. Average, peak and mean 

day-of vanadium concentrations in particulate matter < 10 μm (range) were estimated to be 12.2 

± 9.1 μg/m3 (2.2 – 31.3), 20.2 ± 11.4 μg/m3 (2.2-32.2) and 12.1 ± 10.9 (1.6-31.1), respectively. 

For the spirometric measures, the largest value from three acceptable curves was used in the 

analysis. Reductions in several lung function measures were observed over the average of 27 

±4.1 days between the baseline and postexposure tests that were statistically significant. FEV1, 

FVC, and FEF25-75% decreased by an average of 140 ± 160 ml (range: -390-420), 140 ± 200 ml 

(range: -580-320) and 270 ± 450 ml/s (range: -1170-870), respectively. Each lung function 

index was adjusted by dividing the change by the average of the pre- and post-exposure value. 

The adjusted value was analyzed for associations with exposure in multiple linear regression 

models adjusting for age and current smoking status. Peak PM10 was inversely associated with 

adjusted ΔFEV1 (p=0.03), ΔFEV25%, (p=0.07), ΔFEV50%, (p=0.01), ΔFVC (p=0.01), but not 

ΔFEV25-75%, (p=0.23) and ΔFEV75% (p=0.43). However, mean, peak, and day-of respirable 

vanadium dust concentrations were not associated with any spirometric indices (the data were 

not presented). PM10 and vanadium dust exposure also were not related to bronchial reactivity as 

measured with methacholine challenge tests before and after the overhaul. The authors noted 

that the concentrations of vanadium dust were low and the variation in the range of 

concentrations may not have been wide enough to detect a relation with lung function in this 

small sample. Alternatively, the deficits in lung function may have been caused by a different 

constituent in PM10. 

Woodin et al (1998, 1999, 2000) described in a series of reports a prospective clinical 

study that evaluated health measures among 18 boilermakers and compared them to 11 utility 

workers involved in the overhaul of a large, oil-fired boiler over a six week period from midMay, 1995 to late-June, 1995. The men had volunteered for the study and did not have allergic 
DRAFT - DO NOT CITE OR QUOTE 

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symptoms two weeks prior to or during the overhaul. Data from one person who presented with 

cold or flu symptoms at one of the clinical assessments were excluded. All were white men aged 

26 – 61 years and were employed a mean of 20.5 years (range: 3 – 39). Vanadium and PM10

exposure was calculated for each subject for each work day using information on task duration 

and location and use of personal protective equipment from job diaries, and PM10 or vanadium 

concentrations from personal exposure monitors in the breathing zone. Personal and stationary 

sampling of PM10 (< 10 μm) was conducted over 10 – 12 hour shifts in major work areas in and 

around the boiler. Environmental concentrations were compared before and during the boiler 

overhaul, and between the two occupational groups. Utility workers did not enter the boiler 

during the overhaul. Vanadium levels before the boiler work was comparable for boilermakers 

and utility workers (geometric mean (SD) μg/m3

: 1.2 (1.4) and 1.1 (1.2), respectively). During 

the boiler work, vanadium levels rose to a geometric mean (SD) of 8.9 (2.3) μg/m3 inside the 

boiler but did not change appreciably outside the boiler (geometric mean (SD) μg/m3

: 1.4 (1.6) 

(p < 0.001)). Exposure estimates were adjusted for the type of protective gear worn and its 

duration to calculate individual daily dose. The daily dose to the upper and lower airway was 

estimated using values for minute volume, penetration and deposition rates, and particle size. 

Quartiles of lung vanadium dose (μg) were ≤ 0.90, > 0.90 - ≤ 5.30, > 5.30 - ≤ 22.30 and > 22.30. 

 Quartiles of nasal vanadium dose (μg) were ≤ 2.50, > 2.50 - ≤ 23.20, > 23.20 - ≤ 68.30 and > 

68.30. 

The workers recorded symptoms five times per day in a log and scored them for severity 

with a numerical score from 0 to 3. The highest severity score for each day was used in the 

analysis. Incidence of upper airway symptoms (nasal congestion/irritation, throat irritation) was 

67% (12/18) among boilermakers and 36% (4/11) among utility workers. The incidence of 

lower airway symptoms (chest tightness, wheeze, cough, and sputum production) was 72% 

(13/18) among boilers and 27% (3/11) among utility workers. Robust regression models of 

lower airway maximum severity scores and average symptom frequency in relation to quartiles 

of lung vanadium dose indicated a dose-related increase. Maximum lower airway severity 

scores were increased by 0.47 (p=0.01), 0.86 (p<0.01) and 0.24 (0.10) in quartiles of lung 

vanadium dose 2, 3, and 4 compared to 1. Average lower airway frequency was increased by 

0.19 (p=0.02), 0.39 (p<0.01) and 0.14 (0.07) in quartiles of lung vanadium dose 2, 3, and 4 

compared to 1. The regression models were adjusted for current smoking. 

Lung function was assessed on three occasions: before the overhaul, during the overhaul 

(before the shift on the last day) and 2 weeks after the work ended (Woodin et al., 1999). The 

highest value from three acceptable curves obtained during each test was used in repeated 

measures analysis of variance to test for differences over time. No changes in the four airflow 
DRAFT - DO NOT CITE OR QUOTE 

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measures, FEF25, FEF50, FEF75, and MMEF, were observed over the course of the study. Mean 

(SD) FEV1 (l) values before, during and after the overhaul were 3.73 (0.61), 3.76 (0.54) and 3.65 

(0.42), respectively. Mean (SD) FVC (l) values before, during and after the overhaul were 5.01 

(0.67), 4.94 (0.61) and 4.92 (0.55), respectively. Change in lung function from the beginning to 

the end of the overhaul was not associated with upper or lower airway dose levels of either 

vanadium or PM10 when assessed in linear regression models adjusting for smoking and age. In 

addition, mean dose estimates were not different between individuals who experienced a loss of 

either FEV1 or FVC > 100 ml or those who experienced no change or an increase (two-sample ttest). 

Boilermakers were exposed to higher PM10 concentrations compared to utility workers 

both before (geometric mean (SD): 0.40 (1.60) versus 0.10 (2.70), p < 0.05) and during the 

overhaul (geometric mean (SD): 0.47 (1.90) versus 0.13 (4.00), p < 0.001). In contrast to the 

elevations in vanadium concentrations measured during the overhaul, PM10 concentrations did 

not increase appreciably (p > 0.05). During the boiler overhaul, ozone concentrations increased 

somewhat outside the boiler, but did not change inside the boiler. The authors considered the 

levels of other metals (cadmium, chromium, manganese, lead, arsenic, and nickel) to be low. All 

samples were 1-3 orders of magnitude below the 1996 TLV, and no significant changes were 

observed during the overhaul. Analyses of lung function and other pollutants were not reported. 

Reductions in lung function over two years were investigated by Hauser et al. (2001) in a 

longitudinal study of boilermaker construction workers exposed to combustion particles from 

multiple sources including powerplants (oil, coal, natural gas), trash incinerators, paper mill 

incinerators and other industrial sources with boiler, vessels and tanks requiring maintenance and 

repair. A total of 118 boilermakers from Local 29 of the International Brotherhood of 

Boilermakers, Iron Shipbuilders, Blacksmiths, Forgers and Helpers (81% of those contacted) 

were followed between 1997 and 2000. Participants completed spirometry, a modified 

American Thoracic Society questionnaire on respiratory symptoms, and a work history 

questionnaire at baseline and two annual follow-up visits. The male cohort averaged 42.6 years 

of age (range: 20.5 – 56.5 years) and 97% were Caucasian. Technicians used standardized 

techniques and the same equipment to conduct spirometry testing for all workers during the 

study. Each worker, after some days off work, performed 3 – 7 forced vital capacity maneuvers 

to obtain at least three acceptable curves between 9:00 am and 2:00 pm on testing days. Baseline 

FEV1 and FVC were 90% and 94% of predicted. The nine participants who were lost to followup had a lower mean baseline FEV1 compared to those who remained in the study (84% 

compared to 91.2% predicted). The number of years worked as a boilermaker was a statistically 

significant predictor of annual FEV1 (-33.5 ml/years worked (95% CI:-45.9 - -21.1)). In 
DRAFT - DO NOT CITE OR QUOTE 

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generalized estimating equations adjusting for age, baseline FEV1 and cigarette smoking status, 

the number of hours worked at gas-fired powerplants in the previous year was inversely related 

to annual FEV1 (-9.8 ml/100 hours worked (95% CI: -16.0 - -3.5). Adjusted models analyzing 

the number of hours worked at oil and gas-fired powerplants also showed FEV1 reductions, 

however the associations were not statistically significant. Statistically significant reductions in 

annual FEV1 also were observed among boilermakers who had ever worked at a coal, oil or gasfired powerplant in models evaluating each fuel type separately. This study provides evidence of 

long-term declines in lung function among boilermakers exposed to combustion particles from 

several fuel types. The study did not estimate exposure to individual substances however, and 

no conclusions can be drawn regarding a role for vanadium compounds. 

The effect of occupational PM2.5 concentrations and metals components on cardiac 

autonomic function during a work shift was studied among a panel of 39 boilermaker 

construction workers (Magari et al., 2002). The group of apprentice and journeyman 

boilermakers was an average of 38 years old (18 – 59 years) and had worked an average of 13 

years (0 – 40 years) in that occupation. Metals concentrations over an 8 – 10 hour work shift 

were determined from particle samples (< 2.5 μm) collected using personal monitors, and heart 

rate was monitored using a five-lead Holter monitor during the same period. Heart rate 

variability was estimated as the mean of 5 minute average SDNN (standard deviation of the 

normal-to-normal intervals). Vanadium concentrations (corrected for blank filter metal content) 

were skewed with a mean of 0.76 ± 1.96 μg/m3

 and a median of 0.13 ± 1.96 μg/m3 (range 0 – 

11.62). Fifteen of 48 personal samples were above the limit of detection for vanadium (0.00859 

μg/m3

). Average PM2.5 concentrations were 1.16 ± 1.61 μg/m3 with a median of 0.56 ± 1.96 

μg/m3 (range 0.09 – 7.76). Vanadium concentrations during the shift were associated with a 3.98 

msec (95% CI: 1.64 – 6.32) increase in SDNN index per μg/m3 in mixed effects regression 

models with a random effect for each study subject and fixed covariates for smoking status, age, 

and mean heart rate. Lead also was associated with an increase in SDNN index (11.3 

msec/μg/m3

, 95% CI: 2.88 – 19.73).2 In contrast to earlier studies in this cohort that observed a 

decrease in SDNN measures, average PM2.5 concentrations were not associated with SDNN 

index in this study (-0.77 msec/μg/m3, 95% CI: -2.36 – 2.81). Vanadium concentrations were 

not correlated with either lead or PM2.5 indicating that these pollutants were not likely to be 

confounders of the association of heart rate variability with vanadium. No associations with 

heart rate variability were observed for the other analyzed metals including nickel, chromium, 

2 These effect estimates for vanadium and lead were reported as such in the abstract and Table 4, but were transposed 

in the text of the Results. 
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26

manganese, or copper. It is possible that the observation of an increase in heart rate variability 

with unit increases in vanadium and lead concentrations was the result of the temporal 

framework chosen for the analysis (e.g., averages over the work shift) rather than other time 

frames for exposure and SDNN averages. Indeed, a subsequent study examining changes in a 

different index of autonomic cardiac function, rMSSD (square root of the mean squared 

differences of successive intervals), averaged over the night-time hours (0:00 – 7:00), found an 

inverse association with average work shift concentrations of the PM2.5 metal, manganese 

(Cavallari et al., 2008). The authors did not report on the results of analyses for vanadium. The 

biological significance of the association of vanadium with increases in heart rate variability is 

unclear. All-cause mortality has been associated with decreased heart rate variability measured 

at baseline in longitudinal studies (Dekker et al., 1997). However, the effect on heart rate 

variability indicates that vanadium exposure may alter autonomic function. Alternatively, the 

observed association may have been due to chance. 

In summary, case series, cross-sectional and longitudinal studies of occupational 

exposure to vanadium pentoxide or vanadium in residual oil fuel ash over a few days to several 

weeks reported symptoms of upper and lower respiratory tract irritation including headache, 

runny nose or sneezing, sore throat, cough with sputum, dyspnea on exertion, chest pain or 

discomfort, wheezing and tiredness (Sjöberg, 1951; Sjöberg, 1956; Zenz et al., 1962; Kiviluoto 

et al., 1979; Kiviluoto, 1980; Musk and Tees, 1982; Williams, 1952; Sjöberg, 1955; Lees, 1980; 

Ross, 1983; Levy et al., 1984; Woodin et al., 2000). Some symptoms began after a few hours 

while the onset of other symptoms occurred after one to several days. Vanadium pentoxide 

concentrations in production facilities where the studies were conducted varied by work location 

from 0.06 mg/m3 in the ferrovanadium area to 1.53 mg/m3 in the fusion precipitation area at one 

facility (Irsigler et al., 1999) and > 0.5 mg/m3 at a pilot-plant operation (Zenz et al., 1962). 

Concentrations of vanadium pentoxide inside the boiler during a cleaning operation were 85 

mg/m3

 (Sjoberg, 1955) and ranged from 0.05 – 5.3 mg/m3 during conversion of a power plant 

from coal to oil (Levy et al., 1984). 

The frequency and severity of symptoms were associated with vanadium among 

boilermakers exposed to relatively low ambient concentrations. Upper airway symptom severity 

scores (nasal congestion/irritation, throat irritation) increased across quartiles of estimated 

vanadium dose in the nose and the elevation was statistically significant in the third quartile 

compared to the first quartile in regression models adjusted for smoking (Woodin et al., 2000). 

Increases in lower airway symptom frequency and severity (chest tightness, wheeze, cough, and 

sputum production) were associated in a dose-related manner with estimates of lung vanadium 

dose. During the boiler overhaul, geometric mean respirable vanadium dust concentrations (SD) 
DRAFT - DO NOT CITE OR QUOTE 

27

were 8.9 (2.3) μg/m3 (0.009 mg/m3). 

Vanadium concentrations in respirable particles (< 10 μm) inside the boiler during an 

overhaul (geometric mean (SD): 8.9 (2.3) μg/m3) associated with increased upper and lower 

respiratory symptoms among boilermakers were not related to deficits in pulmonary function. 

Pulmonary function declines (FEV1, FVC, FEF25%-75%) over the course of a boiler overhaul were 

reported among boilermakers (Lees, 1980; Levy et al., 1984; Hauser et al., 1995a; Woodin et al., 

1999). However, those studies with more systematic and detailed reporting of methods and 

results observed no association of FEV1, FVC or flow measures with average vanadium 

concentrations in PM10 (Mean (SD): 12.2 (9.1) μg/m3

) or estimates of vanadium or PM10 dose in 

nasal passages or the lung (Hauser et al., 1995a; Woodin et al., 1999). Peak PM10 exposure (the 

highest concentration (1 – 10 hour TWA) reached on any day during the overhaul) (Mean (SD): 

4.25 (1.58) mg/m3) was inversely associated with ΔFEV1, ΔFEV50%, and ΔFVC, however peak 

vanadium concentrations (Mean (SD): 20.3 (11.4) μg/m3

) were not. 

The authors reported that concentrations of respirable vanadium dust were relatively low 

and there may not have been enough variation in exposure to allow detection of an association 

with the small changes in pulmonary function that occurred during the overhaul. Uncertainties 

in the exposure estimates, particularly inside the boiler, also may have prevented detection of 

associations between vanadium exposure and pulmonary function. The authors reported that 

they obtained fewer air samples inside the boiler where wearing the monitor was uncomfortable. 

 Consequently, exposure and dose estimates for these locations may be more uncertain compared 

to other locations. The cohort had worked in this occupation an average of 20 years and may 

represent a healthy, less susceptible population. In addition to vanadium, boilermakers are 

exposed to increases in the levels of other metals during boiler overhauls including nickel, 

chromium and manganese (Liu et al., 2005). The observed pulmonary function declines amng 

boilermakers may be explained by exposure to other ROFA constituents.

4.1.2.4 Exposure to PM2.5 Vanadium in Ambient Air 

Vanadium is a constituent of ambient particulate generated by oil combustion. Recent 

studies of the short-term health effects of particulate matter and its constituents have found 

higher risks of mortality and hospitalization in locations with a higher fractional content of 

vanadium, nickel and elemental carbon in PM (Dominici et al., 2007; Bell et al., 2009). 

Lippmann et al (2006) evaluated the impact of average concentrations of 16 PM2.5

components across 60 U.S. communities on the association between the daily change in PM10

concentration on daily all-cause mortality risk in those communities. Community-specific 
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28

mortality risk estimates per daily change in PM10 concentrations were obtained from the 

National Morbidity, Mortality, and Air Pollution Study (NMMAPS) database for the years 1987 

– 1994. Annual average concentrations for PM constituents were obtained for 2000-2003 from 

the PM2.5 speciation network. The authors used weighted linear regression to evaluate for each 

chemical constituent whether annual average concentration altered the association between PM10

concentration on the previous day and mortality risk. The constituents, nickel and vanadium, 

were found to increase PM10 mortality risk. 

These results were re-evaluated and extended by Dominici and colleagues (2007) using 

NMMAPS data for 90 communities from 1987 – 2000 and data on PM2.5 composition for 187 

U.S. counties for 2000 - 2005. A total of 69 U.S. communities in the NMMAPS database also 

had data on PM2.5 composition and were included in this analysis. Using a Bayesian hierarchical 

regression model to estimate the association between the l-day lag PM10 mortality risk and 

average county-level PM constituent concentrations, counties with high average concentrations 

of nickel and vanadium had higher PM10 mortality risk with a one-day lag. When the three 

counties that comprise the NMMAPS New York community were excluded from the analysis, 

the effect of nickel and vanadium was much weaker and lost statistical significance. The authors 

stated that the three New York counties had nickel and vanadium concentrations that were 8.9 

and 3.4 times higher than the other counties in the analysis. 

Bell et al (2009) used a Bayesian hierarchical regression model to evaluate the effect of 

PM2.5 chemical constituents as percent of PM2.5 total mass on PM2.5 associated cardiovascular 

and respiratory hospital admissions by county and season for 106 U.S. counties during 1999 - 

2005. Counties with a population 200,000 or greater for which data on PM and constituent 

concentrations were available were selected. Models were adjusted for day of the week, 

seasonality, long-term trends using a smoothing function, daily temperature and dew point 

temperature, as well as the previous three days temperature and dew point temperature. Countyand season-specific PM2.5 relative risk for cardiovascular and respiratory hospital admissions 

were higher in counties and seasons with a nickel, vanadium or elemental carbon fraction of total 

PM2.5 in the 75th compared to the 25th percentile. The effect of these PM constituents was 

statistically significant. The average concentration of vanadium across the counties was 0.003 

μg/m3 (range: 0.001-0.01) with an interquartile range of 0.001 μg/m3. The interquartile range as 

percent of PM2.5 total mass was 0.01%. Each interquartile range increase in the fraction of PM2.5

total mass for vanadium was associated with a 27.5% (95% posterior interval: 10.6 - 44.4) 

increase in PM2.5 associated cardiovascular hospitalizations and a 392% (95% posterior interval: 

46.3 – 738) increase in PM2.5 associated respiratory hospitalizations. Associations also were 

observed for elemental carbon and nickel, and effect estimates were not always stable in 
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29

multipollutant models. 

The finding that communities with a higher fractional content of vanadium, nickel and 

elemental carbon in ambient particulate matter have a higher risk of mortality and hospital 

admissions related to daily change in PM2.5 concentration is intriguing and indicates the need for 

further research on the contribution of fuel oil combustion to regional and local air pollution, and 

the contribution of specific metals, including possibly vanadium pentoxide to elevated health 

risks. The time series study design used in these investigations evaluates exposure-disease 

associations at the county level and therefore, individual-level assessments of exposure and the 

impact of possible confounders is not possible. However, Bell et al (2009) investigated whether 

county-level indicators of socioeconomic status, racial composition, and degree of urbanization 

could be alternative explanations for the observed effect modification by PM2.5 constituents and 

concluded that this was not the case. 

Ambient concentrations of PM2.5 and PM2.5 fractions of nickel, vanadium, zinc and 

elemental carbon were evaluated in relation to respiratory symptoms among young Dominican 

and African American children, aged 3 – 24 months, followed as part of a birth cohort study in 

Northern Manhattan and the South Bronx in New York City between 1998 and 2007 (Patel et al., 

2009). Among 653 24 month old children with questionnaire data (90% of total enrolled) 3-

month average ambient vanadium concentrations were associated with an increase in the 

presence of wheeze during the cold and flu season (September 1 – March 31). After adjusting 

for elemental carbon, NO2, copper, and iron, an interquartile range increase (0.003 μg/m3) in 

three-month average vanadium concentrations was associated with a 31% increased probability 

of wheeze during the cold season (p<0.0003). When not stratified by season, an IQR increase in 

vanadium concentration was associated with a 14% increased probability of wheeze (p=0.08). 

However, when the highest 5% of vanadium concentrations were excluded, the association of 

wheeze with vanadium lost significance in the multipollutant model. Vanadium concentrations 

were not associated with cough. Twenty-four hour average ambient concentrations of PM2.5 and 

PM2.5 fractions of nickel, vanadium, zinc and elemental carbon, measured every third day at two 

stationary sites in the Bronx, were obtained from the New York State Department of 

Environmental Conservation. Exposure levels were assigned to each subject by calculating 3-

month moving average concentrations of each pollutant based on each follow-up questionnaire 

date and the previous three months. Exposures were assigned to each subject’s address using 

inverse-distance weighted concentrations from the two stationary monitors. Associations were 

evaluated using generalized additive mixed effects models and a first-order autoregressive 

correlation structure to account for correlation between the up to 8 repeated observations for 

each individual. The models also adjusted for sex, ethnicity, postnatal ETS exposure, and a 
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30

smoothed term for calendar time using natural cubic splines. Other pollutants also were 

associated with increased probability of wheeze (nickel) or cough (elemental carbon, NO2) 

during the cold/flu season or wheeze in other months (NO2). PM2.5 mass concentrations were 

not related to an increase in probability of symptoms. 

The interpretation of the multi-pollutant models for vanadium is complicated because 

other PM constituents are correlated with vanadium concentrations resulting in less stable risk 

estimates. Nickel was not evaluated in the same model with vanadium for this reason. The 

association with vanadium was independent of the association with NO2, a marker for traffic 

emissions, and the authors suggested that oil combustion for space heating may contribute to the 

observed respiratory symptoms in the very young children in this study. Although vanadium 

cannot be singled out as the responsible agent for the probability of wheeze observed in this 

study, the association is consistent with the respiratory symptoms observed among boilermakers 

with exposure to high levels of residual oil fuel ash for periods of days to weeks. 

The effect of the metal content of ambient PM2.5 on lung function also was evaluated in a 

time-series panel study of 29 patients with chronic obstructive lung disease, asthma, or ischemic 

heart disease in Rome, Italy in the spring and winter of 1999 (Lagorio et al., 2006). Outpatients 

of the Pneumology and Cardiology Departments of the Catholic University Hospital in Rome 

who met eligibility requirements for COPD (N=11), asthma (N=11) or ischemic heart disease 

(N=7), and who lived in census tracts less than 2 kilometers from one of six air monitoring 

stations were selected for the study. The subjects volunteered to conduct repeated clinical 

examinations for two one-month periods. Pulmonary function testing was conducted according 

American Thoracic Society guidelines, and measures were expressed as the percentage of 

predicted based on subject-specific age, height and weight. An average of 15, 24 and 9 

observations were obtained from each participant in the COPD, ischemic heart disease and 

asthma panels, respectively. Daily average PM2.5 concentrations were calculated based on 

measurements obtained at two fixed site monitors set up for the study. PM content of cadmium, 

chromium, iron, nickel, lead, platinum, vanadium and zinc was calculated as the ratio of the 

metal content in each PM sample to the air volume collected during the sampling. The mean 24-

hour PM2.5 concentrations during the spring and winter of 1999 were 18.2 ± 5.0 μg/m3

 and 36.7 

± 24.1 μg/m3, respectively. The mean 24-hour vanadium concentrations during the spring and 

winter of 1999 were 2.4 ± 1.6 ng/m3

 and 1.1 ± 0.52 μg/m3, respectively. Vanadium was not 

associated with daily change in percent predicted pulmonary function among subjects with 

asthma, ischemic heart disease, or COPD in generalized estimating equations models. Models 

adjusted for season (all), daily mean temperature (all), relative humidity (all), day of the week 

(COPD, IHD) and ß-2 agonist use (asthma). Although the repeated measures design was a 
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31

 

strength of the study, the number of subjects in each disease panel was small, and may not have 

been large enough to detect an association with the very low vanadium concentrations analyzed. 

 

4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 

ANIMALS – ORAL AND INHALATION 

4.2.1. Oral Exposure 

4.2.1.1. Subchronic Studies 

 No animal studies that have comprehensively examined histopathological, biochemical 

and clinical endpoints of subchronic oral exposure were identified from the available literature. 

Mountain et al. (1953) evaluated the effects of subchronic exposure of rats to dietary vanadium 

pentoxide on body weight gain, erythrocyte count, hemoglobin and cystine content of hair. 

Groups of 5 male Wistar rats were fed diets containing 0, 25, 50, 500 or 1000 ppm of vanadium 

incorporated in the form of pentoxide for 103 days (25 and 50 ppm groups; “low-exposure” 

groups) or 75 days (500 and 1000 ppm groups; “high-exposure” groups). After 35 days of 

treatment, dietary vanadium levels of the “low-exposure” groups were increased to 100 and 

150 ppm, resulting in average daily doses of 0, 74.5, 116, 500, and 1000 ppm (0, 5.9, 9.2, 39, or 

79 mg/kg-day)3

 of vanadium resulting in a doses of 0, 10.5, 16.4, 69.6, or 141.0 mg/kg-day of 

vanadium pentoxide.4

 At the end of treatment, body weight gain, liver weight, and cystine 

content of hair were measured in all groups, erythrocyte count and hemoglobin level were 

measured in control and “low-exposure” groups, and relative liver weight was measured in 

control and 69.6 mg/kg-day groups. Average body weights of animals at the conclusion of the 

study were not reported, though average weight gain in grams/rat was reported. Compared to 

control, average body weight gain was increased in the 10.5 mg/kg-day and 16.4 mg/kg-day 

groups (54 and 45% increase) and decreased in the 69.6 mg/kg-day group (66%) and 141.0 

mg/kg-day group (no gain in body weight over the study period). The increase in body weight 

gain at the low-exposure levels was not explained and statistical significance or standard 

deviations were not reported for any result. Relative liver weight in the 69.6 mg/kg-day group 

3 Calculation: mg/kg-day = ppm(mg of compound per kg food) x mg food consumed/day x 1/kg body weight (using 

reference food consumption rate of 0.0217 kg/day [U.S. EPA, 1988] and average body weight of 0.275 kg for male 

rats [Mountain et al., 1953]). 

4

 Conversion from mg/kg – d of vanadium to amount vanadium pentoxide: [(mg/kg-d vanadium)(MW vanadium 

pentoxide, 181.9)]/(2xMW vanadium, 101.9). 
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32

was statistically significantly increased compared to control, reported as a ratio of liver 

weight/body weight (3.86 compared to 3.51, p < 0.05, F ratio in analysis of variance). Data on 

relative liver weight were not reported for other dose groups. A dose-dependent decrease in 

erythrocyte count (12.8 and 21.3%) was observed over the duration of the study, in rats exposed 

to 10.5 mg/kg-day and 16.4 mg/kg-day vanadium pentoxide respectively, compared to controls 

(3.8% decrease) (Table 4-1). A 20-30% decrease in erythrocyte count is considered biologically 

significant, however, no statistical analysis was reported by the study authors, and no measure of 

variance (SE or SD) was given for the means. Data were not reported for high dose groups. 

Hemoglobin levels decreased 4.6% and 10.5%, respectively, in the 10.5 and 16.4 mg/kg-day 

groups over the duration of the study compared to 3.9% in controls. Cystine content of hair 

significantly decreased in a non-dose dependent manner in all vanadium pentoxide treatment 

groups compared to controls with the exception of the lowest exposure group. The biological 

significance of decreased hair cystine content is not established; though the researchers 

speculated that vanadium may have inhibited enzymes, such as sulfotransferases, that decreased 

the availability of cystine for hair growth. This study observed potentially dose-related changes 

in erythrocytes, body weight gain, and liver weight in treated animals. However, no statistical 

analysis was performed for the decrease in erythrocytes and body weight gain and no degree of 

variance was reported (precluding statistical analysis for this review), therefore, a NOAEL or 

LOAEL could not be determined from this study. However, compared to hematological data for 

Wistar rats (Wright et al., 2009; Charles River 2008), the observed decrease in erythrocyte 

counts observed in this study is outside of the reference range for the historical controls and thus 

is believed to be a clinically significant finding. 

Table 4–1. Hematological results of oral vanadium pentoxide exposure in rats (Mountain et al. 

1953). 

Control 10.5 mg/kg-day 16.4 mg/kg-day 

Red Cell Count (M/mm3) 

Start 8.0 7.8 8.0 

Finish (103 days) 7.7 6.8 6.3 

Percent change between start and 

finish of expt (%) 

3.8 12.8 21.3 

Hemoglobin, % 

Start 15.6 15.2 15.3 

Finish (103 days) 15.0 14.5 13.7 

Percent change between start and 

finish of expt (%) 

3.9 4.6 10.5 

4.2.1.2 Chronic Studies 
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A 2.5-year dietary study on vanadium in rats (strain not described) was previously used 

as the basis of the chronic RfD (Stokinger et al., 1953). The results were summarized in Patty's 

Industrial Hygiene and Toxicology, 3rd ed., 1981. In this chronic study, an unspecified number 

of rats were exposed to dietary levels of 10 or 100 ppm vanadium (about 17.9 or 179 ppm 

vanadium pentoxide; 1.41 and 14. 1 mg/kg-day )5

 for 2.5 years. Endpoints evaluated were 

limited to growth rate, survival, and hair cystine content. The study did not assess 

comprehensive toxicity endpoints. Hair cystine content was significantly decreased in exposed 

animals, compared to controls but no values were given. This study reports the oral NOAEL 

upon which an RfD can be derived as 17.9 ppm (1.41 mg/kg - day) vanadium pentoxide. 

However, the biological significance of decreased hair cystine is unclear and is not specific to 

vanadium pentoxide exposure. No additional oral chronic exposure studies in animals were 

identified in the published literature.

4.2.2. Inhalation Exposure 

4.2.2.1 Subchronic Studies 

The 3-month exposure studies in F344/N rats were conducted to evaluate the cumulative 

toxic effects of subchronic inhalation exposure to vanadium pentoxide (NTP, 2002). Chemical 

identity and purity of vanadium pentoxide was evaluated prior to the beginning of and following 

the conclusion of all assays. Groups of 10 male and 10 female rats were exposed (whole-body 

exposure) to aerosols of vanadium pentoxide at concentrations of 0, 1, 2, 4, 8 or 16 mg/m3, 6 hrs 

per day, 5 days/week for 3 months. Additional groups of 10 male and 10 female rats were 

exposed to 4, 8 or 16 mg/m3

 for 12 (females) or 13 (males) weeks to investigate effects of 

exposure on cardiovascular function, pulmonary function and pulmonary inflammation. Clinical 

findings were recorded weekly and animals were weighed weekly and at the end of the study. 

Blood and urine were collected from core study rats at study termination. Blood was also 

collected from cardiopulmonary physiology study rats on days 4 and 23 for hematology and 

clinical chemistry determinations. Necropsy and histopathological evaluations (light microscopy 

of comprehensive tissues6

) were performed on all main study rats exposed to 0, 2 (male rats 

5

 Converted to ppm vanadium pentoxide by [(ppm vanadium)(MW vanadium pentoxide, 181.9)]/(2xMW vanadium, 

101.9). No information given on average rat weights so cannot be converted to mg/kg-day directly. Conversions 

based on data from subchronic study from same group (Moutain et al., 1953). Calculation: mg/kg-day =ppm(mg of 

compound per kg food) x mg food consumed/day x 1/kg body weight (usingreference food consumption rate of 

0.0217 kg/day [U.S. EPA, 1988] and average body weight of 0.275 kg for male rats [Mountain et al., 1953]) 6

 Complete histopathology was performed on 0, 8 (rats only), and 16 mg/m3 rats and mice. In addition to gross 
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only), 4, 8 or 16 (female rats only) mg/m3

 at the completion of the study. Sperm motility and 

vaginal cytology evaluations were analyzed from all core study rats. 

Seven male rats and three female rats exposed to 16 mg/m3 vanadium pentoxide died 

during the study (NTP, 2002). Abnormal breathing, emaciation, lethargy, abnormal posture and 

ruffled fur were observed in male and female rats exposed to concentrations of 8 mg/m3 and 

higher. Diarrhea and nasal/eye discharge were also observed in some rats exposed to 16 mg/m3

. 

Weight gain and absolute and relative lung weights are summarized in Table 4-2. Weight gain 

over the 3-month treatment period was significantly decreased compared to control in males 

exposed to 4 (6% decrease), 8 (10% decrease) and 16 (60% decrease) mg/m3 and in females 

exposed to 16 mg/m3 (30% decrease). Absolute lung weights were significantly increased in 

males exposed to concentrations of 2 mg/m3

 and greater and in females exposed to 4 mg/m3 and 

greater. Relative lung weights were significantly greater than control in males exposed to 2 

(16% increase), 4 (30% increase), 8 (51% increase) or 16 (145% increase) mg/m3 and in females 

exposed to 4 (19% increase), 8 (76% increase) or 16 (117% increase) mg/m3. Other organ 

weight differences were considered to be related to body weight decreases. 

Results of hematology assessments following 3-months of inhalation exposure are 

presented in Table 4-3. Erythrocyte count was significantly increased in the 8 and 16 mg/m3

groups and hematocrit was significantly increased in the 16 mg/m3 group in male and female 

rats. Hemoglobin was increased significantly only in females exposed to 16 mg/m3. 

Microscopic evaluation of the red blood cell morphology detected increased polychromasia and 

hypochromia in rats in the 16 mg/m3 groups (data not presented). Significantly decreased mean 

cell hemoglobin concentrations were observed in males exposed to 8 and 16 mg/m3

 and in 

females exposed to 4, 8, and 16 mg/m3. Reticulocyte count was significantly increased in males 

and females exposed to 16 mg/m3. Mean cell volume was significantly decreased, indicative of 

microcytosis, in male rats at concentrations of 2 mg/m3

 and above and in female rats at 

concentrations of 4 mg/m3

 and above. The observed hematological changes, including 

erythrocytosis, are consistent with pulmonary lesions that reduce pulmonary oxygen transfer, 

resulting in tissue hypoxia and stimulation of erythropoiesis by increased renal production of 

erythropoietin. Erythrocyte microcytosis is consistent with ineffective erythropoiesis, suggestive 

lesions and tissue masses, the following tissues were examined in the 3 month studies: adrenal gland, bone with 

marrow, brain, clitoral gland, esophagus, gallbladder (mice only), heart and aorta, large intestine (cecum, colon and 

rectum), small intestine (duodenum, jejunum, and ileum), kidney, larynx, liver, lung and mainstream bronchi, lymph 

nodes (mandibular, mediastinal, mesenteric, and bronchial), mammary gland (except mail mice), nose, ovary, 

pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, skin, spleen, stomach 

(forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid gland, trachea, urinary 

bladder, and uterus. The lung of rats and mice and nose of rats in all remaining exposure groups and the thymus in 8 

mg/m3

 mice were also examined. 
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of altered iron metabolism and heme/hemoglobin production. 

Table 4-2. Body Weight Gain and Lung Weights in Rats (F344/N) Exposed to Vanadium Pentoxide 

by Inhalation for 3 Months (Values are Means±Standard Error) (NTP, 2002) 

Parameter 

Exposure 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Male Rats

Weight gain 

during 3-

month 

exposure 

period (g) 

197±6 202±5 180±5 173±8a 161±5a 1±9a

Absolute 

lung weight 

(g) 

2.38±0.17 2.56±0.11 2.65±0.07 2.93±0.09a 3.26±0.13a 1.98±0.10b

Relative lung 

weight 

6.77±0.36 7.40±0.28 7.83±0.19

a

 

8.88±0.22a

 10.20±0.30a 16.60±0.33a

Female Rats 

Weight gain 

during 3-

month 

exposure 

period (g) 

87±3 88±4 96±4 83±3 77±4 25±7a

Absolute 

lung weight 

(g) 

1.65±0.11c

 

1.58±0.04 1.92±0.12b

 

1.95±0.08b ,c 2.16±0.06a 2.16±0.12a

Relative lung 

weight 

8.37±0.58c 7.84±0.16 9.23±0.53 10.00±0.38b,c 11.48±0.33a 18.15±1.06a

a

Significantly different from control by William’s or Dunnett’s test (p≤ 0.01) b

Significantly different from control by William’s or Dunnett’s test (p≤ 0.05) c

n = 9 

Table 4-3. Selected Hematology Parameters in Rats (F344/N) Exposed to Vanadium Pentoxide by 

Inhalation for 3 Months (NTP, 2002)a

Parameter 

Exposure 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Male Rats

Number 9 9 10 9 10 3 

Erythrocytes 

(106

/μL) 

9.2±0.1 9.0±0.1 9.1±0.1 9.3±0.2 9.7±0.2b

 15.1±0.3c

Reticulocytes 0.2 0.22±0.03 0.19±0.02 0.23±0.03 0.25±0.02 0.8 ±0.08 b
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Table 4-3. Selected Hematology Parameters in Rats (F344/N) Exposed to Vanadium Pentoxide by 

Inhalation for 3 Months (NTP, 2002)a

Parameter 

Exposure 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

(106/μL) ±0.02 

Hematocrit (%) 48.5±0.6 47.7±0.5 47.6±0.6 48.7±0.9 49.9±0.7 71.2±2.8b

Hemoglobin (g/dL) 15.8±0.1 15.5±0.1 15.5±0.2 15.9±0.2 16.1±0.2 20.4±0.8 

Mean cell volume 

(fL) 

52.9±0.2 52.9±0.1 52.3±0.1b 52.2±0.2b 51.3±0.2c 46.8±1.0c

Mean cell 

hemoglobin (pg) 

17.3±0.2 17.2±0.1 17.1±0.1 17.1±0.02 16.5±0.2c 13.4±0.4c

Female Rats 

Number 10 10 9 10 10 6 

Erythrocytes 

(106/μL) 

8.0±0.1 7.8±0.1 8.2±0.2 8.3±0.1 8.6±0.1b 12.5±0.34c

Reticulocytes 

(106/μL) 

0.15 ± 

0.02 

0.17 ± 

0.01 

0.17 ± 

0.01 

0.16 ± 

0.02 

0.17 ± 

0.02 

0.45 ± 

0.08c

Hematocrit (%) 45.8±0.5 44.3±0.4 46.1±1.2 46.4±0.4 47.2±0.6 60.8±1.4c

Hemoglobin (g/dL) 15.5±0.2 15.0±0.1 15.5±0.2 15.6±0.1 15.8±0.1 18.2±0.3c

Mean cell volume 

(fL) 

56.9±0.1 56.9±0.1 56.6±0.1 55.8±0.1c 55.0±0.2c 48.7±0.6c

Mean cell 

hemoglobin (pg) 

19.3±0.2 19.3±0.2 19.0±0.2 18.7±0.2c 18.5±0.2c 14.6±0.3c

a

Values are means±standard error 

b

Significantly different from control (p≤ 0.05) c

Significantly different from control (p≤ 0.01) 

Sporadic alterations in clinical chemistry and urinalysis variables were observed at 

various time-points in exposed males and females; however, no dose- or duration-related pattern 

of effect was observed. Occasional changes in serum liver enzyme activities were not consistent 

with hepatocellular injury. 

Vanadium pentoxide exposure did not affect reproductive endpoints in males (sperm 

count, spermatid heads, sperm motility), but it did increase estrous cycle length by 10% in 

females exposed to 8 mg/m3, but not to 16 mg/m3, and reduced the number of cycling females in 

surviving rats in the 16 mg/m3

 group (percent reduction not reported) (NTP 2002). 

Complete histopathological assessments were performed on rats exposed to 0, 8 and 

16 mg/m3

 for 3 months; only nonneoplastic lesions of the lung and nose were related to 

treatment (NTP, 2002). Results of histopathological evaluations of lung and nasal tissue from 

male and female rats exposed to 1, 2, 4, 8 and 16 mg/m3

 for 3 months are summarized in Table 
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4-4. Significant increases in the incidences of epithelial hyperplasia of the lung were observed in 

male and female rats exposed to concentrations of 2 mg/m3 or greater, compared to controls. 

Epithelial hyperplasia occurred in the distal airways and associated alveolar ducts and alveoli. 

Inflammation and fibrosis were significantly increased in males (2 mg/m3

 or greater) and females 

(4 mg/m3

 or greater). In the nasal compartment, incidences of hyperplasia and metaplasia of the 

respiratory epithelium were significantly increased in males exposed to 8 or 16 mg/m3

 and in 

females exposed to 4 mg/m3 or greater. Nasal hyperplasia and metaplasia was localized to 

respiratory epithelium on the ventral portion of the nasal septum, the vomeronasal organ, and, to 

a lesser extent, the ventral lateral walls of the anterior portion of the nasal cavity. Nasal 

inflammation was significantly increased in males and females exposed to 16 mg/m3. 

Cardiopulmonary assessments were conducted in groups of 4-10 male and female rats 

exposed to 0, 4, 8 and 16 mg/m3 for 3 months (NTP, 2002). No treatment-related changes in 

cardiovascular function, as assessed by blood pressure (systolic, diastolic and mean), heart rate 

and electrocardiogram, were observed in rats exposed to 4 or 8 mg/m3

. Decreased heart rate and 

diastolic, systolic and mean blood pressure observed in male and female rats exposed to 

16 mg/m3

 were considered to be a reflection of the poor condition of the animals, and 

complicated by anesthesia. Significant exposure-related decreases in pulmonary function (as 

assessed by respiratory rate, tidal and minute volume, expiratory resistance, vital and total 

capacity, diffusing capacity, and dynamic and peak compliance) were observed at all 

concentrations of vanadium pentoxide-exposed male and female rats. Observed changes in 

impaired capacity to diffuse carbon monoxide and reduced static and dynamic lung volumes at 

exposure concentrations of 4 mg/m3

 and greater suggest a restrictive lesion. Changes in forced 

expiratory maneuvers in rats exposed to 16 mg/m3 suggest the presence of an obstructive 

disease. Pulmonary function results may indicate obstructive disease or may reflect the 

deteriorating condition of the 16 mg/m3 rats, since histopathological finding in lungs of rats 

exposed to 8 and 16 mg/m3

 were similar. Taken together, results of pulmonary function tests 

indicate that a presence of restrictive injury in male and female rats exposed to concentrations of 

4 mg/m3 or greater, while an obstructive lung injury may have been present in rats exposed to 

16 mg/m3. 

Table 4-4. Incidences of Selected Nonneoplastic Lesions of the Lung and Nose in Rats (F344/N) 

Exposed to Vanadium Pentoxide by Inhalation for 3 Months (NTP, 2002) 

Lesion Location 

and Type 

Numbers of Animals with Lesions (Avg Severity Score) 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Male Ratsa
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Table 4-4. Incidences of Selected Nonneoplastic Lesions of the Lung and Nose in Rats (F344/N) 

Exposed to Vanadium Pentoxide by Inhalation for 3 Months (NTP, 2002) 

Lesion Location 

and Type 

Numbers of Animals with Lesions (Avg Severity Score) 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Lung

Epithelium, 

hyperplasia 

0 0 10b (2.0) 10b (3.0) 10b (3.6) 10b (3.3) 

Inflammation 0 0 9b (1.0) 10b (1.0) 10b (1.6) 10b (2.1) 

Fibrosis 0 0 2 (1.0) 10b (1.9) 10b (3.2) 10b (3.1) 

Bronchiole, 

exudates 

0 0 0 0 7b (1.0) 8b (1.4) 

Nose

Epithelium, 

hyperplasia 

0 0 0 1 (1.0) 10b (1.2) 10b (2.0) 

Epithelium, 

squamous 

metaplasia 

0 0 0 1 (1.0) 10b (1.2) 10b (1.8) 

Inflammation 0 0 0 0 0 7b (1.6) 

Female Ratsa

Lung

Epithelium, 

hyperplasia 

0 0 10b (1.3) 10b (2.9) 10b (3.5) 10b (3.2) 

Inflammation 0 0 0 10b (1.0) 10b (1.9) 10b (1.2) 

Fibrosis 0 0 0 10b (1.0) 10b (2.9) 10b (3.2) 

Bronchiole, 

exudates 

0 0 0 0 10b (1.0) 8b (1.1) 

Nose

Epithelium, 

hyperplasia 

0 0 0 10b (1.0) 10b (1.8) 10b (2.7) 

Epithelium, 

squamous 

metaplasia 

0 0 0 8b (1.0) 10b (1.8) 10b (2.8) 

Inflammation 0 0 0 0 1 (1.0) 9b (1.6)) a

10 animals per treatment group; numbers in parentheses indicate average severity grade of lesions in affected 

animals: 1=minimal, 2=mild, 3=moderate, 4=marked 

b

Significantly different from control by Fisher exact test (p≤ 0.01) 

BAL fluid was analyzed for markers of pulmonary inflammation in rats exposed to 0, 4, 8 

and 16 mg/m3

 for 3 months (NTP, 2002). Concentration-related increases were observed in the 

total numbers of cells, lymphocytes, neutrophils and protein recovered in BAL fluid from rats 
DRAFT - DO NOT CITE OR QUOTE 

39

exposed to vanadium pentoxide at concentrations of 4 and 8 mg/m3, demonstrating a pulmonary 

inflammatory response in male and female rats. These endpoints also were increased in the 

16 mg/m3 group, but to a lesser extent, vanadium pentoxide was overtly toxic at this dose. 

 Results of this study show that inhalation exposure of male and female rats to vanadium 

pentoxide aerosol for 3 months produced adverse effects on the hematological system and the 

lung (NTP, 2002). Microcytic erythrocytosis, which was possibly secondary to impaired 

pulmonary function, was observed at concentrations of 2 mg/m3

 and greater in males and 

4 mg/m3

 and greater in females. Absolute and relative lung weights were significantly increased 

compared to controls at concentrations of 4 mg/m3

 and greater in females and 2 mg/m3 and 

greater and 4 mg/m3 and greater, respectively, in males. The incidence of nonneoplastic lesions 

of the nose was increased in male and female rats at concentrations of 8 mg/m3

 and greater and 

4 mg/m3

 and greater, respectively, and the incidence of nonneoplastic lesions of the lung was 

increased in male and female rats 2 mg/m3

 and greater. Results of pulmonary function tests 

consistent with restrictive lung disease were observed at concentrations of 4 mg/m3 and greater. 

Based on decreased erythrocyte size in male rats and nonneoplastic lung lesions in male and 

female rats, the NOAEL and LOAEL values identified for 3-month inhalation exposure to 

vanadium pentoxide aerosols were 1 and 2 mg/m3, respectively. 

Three-month exposure studies in B6C3F1 mice were conducted to evaluate the toxicity of 

subchronic inhalation exposure to vanadium pentoxide (NTP, 2002). Groups of 10 male and 

10 female mice were exposed (whole-body exposure) to vanadium pentoxide aerosols at 

concentrations of 0, 1, 2, 4, 8 or 16 mg/m3

, 6 hrs per day, 5 days/week for 3 months. Particle 

size given in mass median aerodynamic diameter (MMAD) ± geometric standard deviation 

(GSD) for each dose groups was as follows: 1 mg/m3

=1.2±2.8; 2 mg/m3=1.1±2.8; 

4 mg/m3=1.2±2.8; 8 mg/m3=1.0±2.9; 16 mg/m3=1.2±2.8. Clinical findings were recorded 

weekly. Animals were weighed weekly and at the end of the study. All study animals were 

necropsied. Histopathological examinations of lungs were performed in all mice in the 0, 1, 2, 4, 

8 or 16 mg/m3

 groups and of thymus in all mice in the 0, 8 or 16 mg/m3 groups. At the end of 

the 3-month exposure period, samples for sperm motility and vaginal cytology evaluations were 

collected from mice exposed to 0, 4, 8 or 16 mg/m3. Complete histopathological examination 

was performed in mice in the control and 16 mg/m3 groups. Assessments of cardiopulmonary 

function, pulmonary inflammation (analysis of pulmonary lavage), and hematological parameters 

were not conducted in mice.

One male mouse in the 16 mg/m3

 group died before the end of the study. Other than 

appearing thin, no other signs of toxicity were reported (NTP, 2002). No other treatment-related 

clinical findings were observed in any other mice in any treatment group. Weight gain and 
DRAFT - DO NOT CITE OR QUOTE 

40

absolute and relative lung weights are summarized in Table 4-5. Weight gain over the 3-month 

treatment period was significantly decreased compared to control in males exposed to 8 (6% 

decrease) and 16 (10% decrease) mg/m3 and in females exposed to 4 (11% decrease), 8 (10% 

decrease) and 16 (12% decrease) mg/m3

. Absolute lung weights were significantly increased 

compared to control at concentrations of 2 mg/m3

 and higher in males and 4 mg/m3 and higher in 

females. Relative lung weights were significantly greater than control in males exposed to 4 

(33% increase), 8 (43% increase) or 16 (82% increase) mg/m3 and in females exposed to 4 (62% 

increase), 8 (63% increase) or 16 (101% increase) mg/m3

. Other organ weight differences were 

considered to be related to decreases in body weight by the researchers. The epididymal 

spermatozoal motility of males exposed to 8 or 16 mg/m3

 was significantly decreased by 13 and 

5%, respectively. No treatment-related effects were observed for assessments of estrous cycle 

(estrous cycle length and number of cycling females). 

Table 4-5. Body Weight Gain and Lung Weights in Mice (B6C3F1) Exposed to Vanadium 

Pentoxide by Inhalation for 3 Months (Values are Means±Standard Error) (NTP, 2002) 

Parameter 

Exposure 

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Male Mice

Weight gain 

during 3-month 

exposure period 

(g) 

8.4±0.9 7.4±0.8 8.2±0.6 7.7±0.5 6.2±0.2a 5.6±0.7b

Absolute lung 

weight (g) 

0.2±0.01 0.2±0.01 0.3±0.01b 0.3±0.01b 0.3±0.01b 0.4±0.01b

Relative lung 

weight 

7.0±0.2 6.9±0.2 7.8±0.3 9.3±0.2b 10.0±0.3b 12.7±0.4b

Female Mice 

Weight gain 

during 3-month 

exposure period 

(g) 

9.7±1.0 10.0±1.0 8.1±0.4 5.8±0.5b 6.1±0.4b 5.4±0.3b

Absolute lung 

weight (g) 

0.2±0.01 0.3±0.01 0.3±0.01 0.3±0.02b 0.4±0.02b 0.4±0.02b

Relative lung 

weight 

8.1±0.5 8.8±0.3 9.7±0.5 13.2±0.9b 13.2±0.6b 16.3±0.52b

a

Significantly different from control by William’s test (p≤ 0.05) 

b

Significantly different from control by William’s test (p≤ 0.01)
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41

Results of histopathological evaluations of lung tissue from male and female mice 

exposed to 0, 1, 2, 4, 8 and 16 mg/m3 for 3 months are summarized in Table 4-6 (NTP, 2002). 

Epithelial hyperplasia was observed in male and female mice exposed to concentrations of 

2 mg/m3

 and above; lesion severity increased with increasing exposure concentration. 

Hyperplasia involved alveolar and, to a lesser extent, bronchiolar epithelium. Inflammation was 

characterized by multiple foci of a mixed cellular infiltrate oriented around blood vessels and 

bronchioles and was observed in male mice exposed to 4 mg/m3

 and above and in female mice 

exposed to 2 mg/m3

 and above. Infiltrate was composed primarily of macrophages with 

abundant cytoplasm and fewer lymphocytes and neutrophils. Histopathological evaluations of 

the thymus of male and female mice exposed to 0, 8 and 16 mg/m3

 for 3 months showed 

lymphoid depletion in mice exposed to 16 mg/m3

 (males: control, 0/9; 8 mg/m3, 0/8; 16 mg/m3, 

2/7; females: 0/9, 0/9, 1/10). 

The lung was identified as the most sensitive target organ in the 3-month inhalation study 

in mice (NTP, 2002). Based on increases in absolute lung weights at concentrations of 2 mg/m3

and greater (males) and inflammation of the respiratory epithelium at concentrations of 2 mg/m3

and greater (males and females), NOAEL and LOAEL values were identified as 1 and 2 mg/m3, 

respectively. 

Table 4-6. Incidences of Selected Nonneoplastic Lesions of the Lung in Mice (B6C3F1) Exposed to 

Vanadium Pentoxide by Inhalation for 3 Months (NTP, 2002) 

Lesion Type 

Numbers of Animals with Lesionsa

Control 1 mg/m3 2 mg/m3 4 mg/m3 8 mg/m3 16 mg/m3

Male

Number 10 10 10 10 10 10 

Inflammation 0 1 (1.0) 3 (1.0) 4b (1.0) 10c (2.0) 10c (2.0) 

Epithelium, 

hyperplasia 

0 1 (1.0) 4b (1.0) 5b (1.0) 10c (1.3) 10c (3.0) 

Female 

Number 10 9 10 9 10 10 

Inflammation 0 1 (1.0) 7c (1.0) 9c (1.9) 10c (1.9) 10c (2.5) 

Epithelium, 

hyperplasia 

0 0 6c (1.0) 9c (1.5) 10c (1.5) 10c (2.5) 

a

Numbers in parentheses indicate average severity grade of lesions in affected animals: 1=minimal, 2=mild, 

3=moderate, 4=marked 

b

Significantly different from control by Fisher exact test, p≤ 0.05 c

Significantly different from control by Fisher exact test, p≤ 0.01 

In a study using cynomolgus monkeys, weekly provocation challenges (single 6-hr 
DRAFT - DO NOT CITE OR QUOTE 

42

exposures to 0.5 or 3.0 mg/m3) with inhaled vanadium pentoxide aerosol for six weeks produced 

statistically significant pulmonary responses, prior to a subchronic exposure (6 hrs/day, 5 

days/week for 26 weeks) (Knecht et al., 1992). The subchronic exposure was divided into three 

groups; one group (n=8) was exposed to filtered, conditioned air and two exposed groups (n=8 

each) received nominally equal weekly vanadium pentoxide exposures (concentration x time) 

with different exposure profile. The peak exposure group received an actual concentration of 

0.16 ± 0.01) mg/m3 (0.1 mg/m3 nominal) vanadium pentoxide on Mondays, Wednesdays and 

Fridays and 1.38 ± 0.07) mg/m3

 (1.1 mg/m3 nominal) vanadium pentoxide on Tuesdays and 

Thursdays, and the constant exposure group received a constant daily actual concentration of 

0.57 ± 0.03) mg/m3

 (0.5 mg/m3 nominal). The constant exposure regimen corresponded to a 

continuous exposure of 0.10 mg/m3

 after adjusting for exposure protocol (0.57 mg/m3 x 6/24 x 

5/7). The peak exposure regimen averaged to a slightly higher continuous exposure of 0.12 

mg/m3

 after adjusting for exposure protocol. Vanadium pentoxide particle size was determined 

weekly during challenges and biweekly during exposures. Average particle size for the 

subchronic constant exposure group was 3.15 μm (MMAD), with a GSD of 3.25 μm. Particle 

sizes (MMAD ± GSD) for the peak exposure group were 3.17 ± 2.48 and 3.10 ± 2.45 for the 0.1 

mg/m3 and 1.1 mg/m3 exposures, respectively. Pulmonary function tests, cytological and 

immunological analyses of blood and bronchiolar lavage fluid, and skin sensitivity tests were 

conducted before the pre- and post-exposure provocation challenges. Immunological analyses 

are described in Section 4.4.1.2. Pulmonary function tests and bronchiolar lavage fluid analyses 

were also performed one day after the provocation challenges. Cytological endpoints included 

complete and differential blood cell counts and leukotriene C4 levels. Pulmonary function 

endpoints included total pulmonary resistance (RL), forced expiratory flow (FEF), forced vital 

capacity (FVC), residual volume (RV) and dynamic lung compliance (CLdyn). Respiratory 

distress, characterized by audible wheezing and coughing, occurred in 3 out of 8 monkeys from 

the peak exposure group on peak exposure days during the first few weeks of the 26-week 

exposure; the responses developed within 3-4 hrs of exposure and occasionally required early 

removal of the affected monkeys from the exposure chamber. Impaired pulmonary function 

accompanied pre-exposure provocation challenges with V2O5 at 3.0 mg/m3

 and was 

characterized by a 14% increase in RL and 13% decrease in FEV50/FVC accompanied by a 14% 

increase in RV and 3% decrease in FVC. Pulmonary function and other study endpoints were 

not significantly different between the three exposure groups (control, peak and constant) at 

either challenge concentration when the monkeys were rechallenged following subchronic 

exposure. The authors suggested that the absence of increased pulmonary reactivity to vanadium 

pentoxide following subchronic inhalation may be attributed to the development of tolerance. 
DRAFT - DO NOT CITE OR QUOTE 

43

 

The study establishes a subchronic NOAEL[ADJ] of 0.10 mg/m3 (continuous exposure) for 

pulmonary function. No subchronic LOAEL was established. However, an apparent acute, but 

reversible, LOAEL of 1.38 mg/m3 is established based on the respiratory distress observed at 

1.38 mg/m3

 at an early time point. 

 Hematological effects of vanadium pentoxide were assessed in male CD-1 mice that were 

exposed by whole-body inhalation for 1 hr/day, 2 days/week for up to 12 weeks (GonzalezVillalva et al., 2006). A 0.02 M aqueous solution of vanadium pentoxide was aerosolized 

generating a reported average vanadium of 1436 μg/m3

 (1.44 mg/m3 V ), as measured by filters 

following the 12 weeks exposure. This study did not provide reliable exposure information, thus 

exposure concentrations in mg/m3 could not be determined. Groups of 8 exposed mice and 8 

vehicle control mice (inhaling deionized water droplets) were evaluated after 24 hrs and weekly 

for 12 weeks. Evaluations consisted of a complete blood count and morphological examination 

of platelets. Platelet count was significantly increased in the exposed mice on weeks 3-12; 

counts increased from week 3 to a maximum at week 9 and subsequently declined, but still 

remained above controls (quantitative data inadequately reported). The morphology 

examinations showed the presence of giant platelets at unspecified longer exposure times. The 

study establishes an apparent LOAEL for increased platelet count and altered platelet 

morphology from short-term intermittent exposure to vanadium pentoxide at 2.56 mg/m3

. A 

continuous exposure equivalent concentration cannot be estimated with any confidence, as the 

intermittency of the exposure protocol is extreme. 

4.2.2.2 Chronic Studies 

The toxicity of chronic inhalation exposure to particulate aerosols of vanadium pentoxide 

was assessed in groups of 50 male and 50 female F344/N rats exposed (whole-body exposure) at 

concentrations of 0, 0.5, 1 or 2 mg/m3

 6 hrs/day, 5 days/week for 104 weeks (Ress et al., 2003; 

NTP, 2002). Body weights and clinical findings were recorded throughout the exposure period. 

Necropsy and comprehensive histopathological evaluation7

 were performed on all animals. No 

clinical findings related to vanadium pentoxide exposure were observed. Mean body weights of 

females exposed to 2 mg/m3

 were marginally less (3-6%; statistical significance not reported) 

7 In addition to gross lesions and tissue masses, the following tissues were examined in the 2-yr bioassay: adrenal 

gland, bone with marrow, brain, clitoral gland, esophagus, gallbladder (mice only), heart and aorta, large intestine 

(cecum, colon and rectum), small intestine (duodenum, jejunum, and ileum), kidney, larynx, liver, lung and 

mainstream bronchi, lymph nodes (mandibular, mediastinal, mesenteric, and bronchial), mammary gland (except 

mail mice), nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, 

skin, spleen, stomach (forestomach and glandular), testis (with epididymis and seminal vesicle), thymus, thyroid 

gland, trachea, urinary bladder, and uterus. 
DRAFT - DO NOT CITE OR QUOTE 

44

than that of controls throughout the 2-year study; mean body weights of exposed male rats were 

similar to controls throughout the study. The percent survival of male and female rats for the 

entire 104-week exposure period ranged from 52-58% in male rats and 30-40% in female rats. 

The percent survival of controls was 40% for male rats and 28% for female rats (Table 4-7). No 

infection was reported in this study that may account for these survival rates; however, these 

survival rates are comparable to historical rates of survival for male and female F344/N rats. 

The incidences of nonneoplastic lesions of the respiratory tract in male and female rats 

are summarized in Table 4-7 (Ress et al., 2003; NTP, 2002). In male rats, the incidences of 

nonneoplastic lesions of the lungs (alveolar and bronchiolar epithelial hyperplasia and alveolar 

histiocyte infiltration), larynx (inflammation and epiglottis degeneration, hyperplasia and 

squamous metaplasia) and nose (goblet cell hyperplasia) were significantly increased compared 

to controls in all vanadium pentoxide exposure groups. In female rats, the incidences of 

nonneoplastic lesions of the lungs (interstitial fibrosis and alveolar histiocyte infiltration) and 

larynx (inflammation and epiglottis degeneration and hyperplasia) were significantly increased 

compared to control in all vanadium pentoxide exposure groups. In general, the incidences and 

severity ratings of respiratory lesions increased with exposure level. No treatment-related 

histopathological findings were observed in other tissues. A LOAEL of 0.5 mg/m3

 was 

established for nonneoplastic lesions of the respiratory tract in male and female rats; a NOAEL 

was not identified. 

Table 4-7. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to 

Particulate Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) 

Lesion Type and Locationa

Exposure Group 

Control 0.5 mg/m3 1 mg/m3 2 mg/m3

Male Rats 

Percent survivald 40 58 52 54 

Lung 

Number of animals examined) 50 49 48 50 

Alveolar epithelium, hyperplasia 7 (2.3) 24b (2.0) 34b (2.0) 49b (3.3) 

Bronchiole epithelium, 

hyperplasia 

3 (2.3) 17b (2.2) 31b (1.8) 48b (3.3) 

Alveolar epithelium, squamous 

metaplasia 

1 (1.0) 0 0 21b (3.6) 

Bronchiole epithelium, squamous 

metaplasia 

0 0 0 7b (3/7) 

Inflammation, chronic active 5 (1.6) 8 (1.8) 24b (1.3) 42b (2.4) 

Interstitial, fibrosis 7 (1.4) 7 (2.0) 16c (1.6) 38b (2.1) 

Alveolus, histiocyte infiltration 22 (1.3) 40b (2.0) 45b (2.3) 50b (2.1) 
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45

Table 4-7. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to 

Particulate Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) 

Lesion Type and Locationa

Exposure Group 

Control 0.5 mg/m3 1 mg/m3 2 mg/m3

Larynx 

Number of animals examined 49 50 50 50 

Inflammation, chronic 3 (1.0) 20b (1.1) 17b (1.5) 28b (1.6) 

Epiglottis epithelium, 

degeneration 

0 22b (1.1) 23b (1.1) 33b (1.5) 

Epiglottis epithelium, hyperplasia 0 18b (1.5) 34b (1.5) 32b (1.9) 

Epiglottis epithelium, squamous 

metaplasia 

0 9b (1.7) 16b (1.8) 19b (1.9) 

Nose 

Number of animals examined 49 50 49 48 

Goblet cell, hyperplasia 4 (1.8) 15b (1.8) 12c (2.0) 17b (2.1) 

Female Rats 

Percent survivald 28 40 34 30 

Lung 

Number of animals examined 49 49 50 50 

Alveolar epithelium, hyperplasia 4 (1.0) 8 (1.5) 21b (1.2) 50b (3.1) 

Bronchiole epithelium, 

hyperplasia 

6 (1.5) 5 (1.6) 14c (1.3) 48b (3.0) 

Alveolar epithelium, squamous 

metaplasia 

0 0 0 6c (3.0) 

Bronchiole epithelium, squamous 

metaplasia 

0 0 0 1 (2.0) 

Inflammation,chronic active 10 (1.5) 10 (1.1) 14 (1.2) 40b (1.7) 

Interstitial, fibrosis 19 (1.4) 7b (1.3) 12 (1.6) 32b (1.4) 

Alveolus, histiocyte infiltration 26 (1.4) 35c (1.3) 44b (2.0) 50b (1.9) 

Larynx 

Number of animals examined 50 49 49 50 

Inflammation, chronic 8 (1.8) 26b (1.5) 27b (1.3) 38b (1.4) 

Epiglottis epithelium, 

degeneration 

2 (1.0) 33b (1.2) 26b (1.3) 40b (1.5) 

Epiglottis epithelium, hyperplasia 0 25b (1.4) 26b (1.3) 33b (1.5) 

Epiglottis epithelium, squamous 

metaplasia 

2 (2.0) 7 (1.9) 9 (1.7) 16b (1.4) 

Nose 

Number of animals examined 50 50 50 50 

Goblet cell, hyperplasia 13 (2.0) 19 (2.0) 16 (1.9) 30b (2.0) a

Number of animals with lesion; numbers in parentheses indicate average severity grade of lesions in affected animals: 

1=minimal, 2=mild, 3=moderate, 4=marked b

Significantly different from control by the Poly-3 test (p< 0.01) c

Significantly different from control by the Poly-3 test (p< 0.05) d

Nonneoplastic lesions observed at time of sacrifice; percent survival consistent with historical controls for F344 rats in NTP 
DRAFT - DO NOT CITE OR QUOTE 

46

studies. 

The NTP (2002) and Ress et. al. (2003) studies also conducted analysis of neoplasms in 

rats exposed to vanadium pentoxide by inhalation for 2-years, using the protocol described 

above. Compared to concurrent controls, the incidences of alveolar/bronchiolar adenoma, 

alveolar/bronchiolar carcinoma or combined alveolar/bronchiolar adenoma or carcinoma were 

not significantly different (Poly-3 test) for male or female rats. Compared to historical controls, 

alveolar/bronchiolar adenoma in 0.5 and 2 mg/m3

 males and 0.5 mg/m3 females, 

alveolar/bronchiolar carcinoma in 0.5 and 2 mg/m3

 males, and combined alveolar/bronchiolar 

carcinoma in 0.5, 1 and 2 mg/m3

 males and in 0.5 mg/m3 females were statistically significantly 

different (see Table 4-8 footnotes). 

NTP (2002) and Ress et al. (2003) concluded that exposure to vanadium pentoxide 

caused alveolar and bronchiolar adenomas and carcinomas in male rats because incidence 

exceeded historical controls. The marginal increase in lung neoplasms observed in female rats 

was statistically significant only in the 0.5 mg/m3 exposure group. This increase was not 

definitively attributed to vanadium pentoxide exposure since the tumors were observed only at 

the lowest dose and no dose-response was evident. 
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Table 4-8. Incidences of Respiratory Tumors in Rats Exposed to Vanadium Pentoxide in a 2 Year 

Inhalation Study (NTP, 2002)a

Tumor Type 

Exposure Group 

Historical 

Control 

Control 0.5 mg/m3 1 mg/m3 2 mg/m3

Male Rats 

Number of animals examined 1054 50 49 48 50 

Alveolar/bronchiolar 

adenomab

18 (10%) 4 (8%) 8 (16%)c 5 (10%) 6 (12%)c

Alveolar/bronchiolar 

carcinomad

8 (4%) 0 (0%) 3 (6%)c 1 (2%) 3 (6%)c

Alveolar/bronchiolar adenoma 

or carcinomae

26 (10%) 4 (8%) 10 (20%)c 6 (12%)c 9 (18%)c

Female Rats 

Number of animals examined 1050 49 49 50 50 

Alveolar/bronchiolar 

adenomaf

12 (4%) 0 (0%) 3 (6%)c 1 (2%) 0 (0%) 

Alveolar/bronchiolar 

carcinoma 

0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (2%) 

Alveolar/bronchiolar adenoma 

or carcinomag

14 (4%) 0 (0%) 3 (6%)c 1 (2%) 1 (2%) 

a

Numbers in parentheses indicate percent incidence; particle size mass mean aerodynamic diameter + geometric 

standard deviation (MMAD±GSD): 0.5 mg/m3

=1.2±2.9; 1 mg/m3=1.2±2.9; 2 mg/m3=1.3±2.9 

b

Historical incidence of alveolar/bronchiolar adenoma male F344/N rats fed in inhalation chamber controls given 

NIH-07 diet. 

c

Incidence exceeds historical control (statistical comparison between NTP (2002) data and historical data not 

conducted) 

d

Historical incidence of alveolar/bronchiolar carcinoma of male F344/N rats fed in inhalation chamber controls given 

NIH-07 diet. 

e

Historical incidence of combined alveolar/bronchiolar adenoma or carcinoma male F344/N rats fed in inhalation 

chamber controls given NIH-07 diet. 

f

Historical incidence of alveolar/bronchiolar adenoma female F344/N rats fed in inhalation chamber controls given 

NIH-07 diet. 

g

Historical incidence of combined alveolar/bronchiolar adenoma or carcinoma female F344/N rats fed in inhalation 

chamber controls given NIH-07 diet. 

NTP (2002) and Ress et. al. (2003) also reported the toxicity of chronic exposure to 

vanadium pentoxide in mice. Groups of 50 male and 50 female B6C3F1 mice were exposed 

(whole-body exposure) to vanadium pentoxide particulate aerosol concentrations of 0, 1, 2 or 

4 mg/m3

, 6 hrs per day, 5 days/week, for 104 weeks (Ress et al., 2003; NTP, 2002). Particle 

MMAD±GSD for each dose group was reported as follows: 1 mg/m3

=1.3±2.9; 

2 mg/m3=1.2±2.9; 4 mg/m3=1.2±2.9. Body weights and clinical findings were recorded 
DRAFT - DO NOT CITE OR QUOTE 

48

throughout the exposure period. Necropsy and comprehensive histopathological evaluation were 

performed on all animals and analysis of both non neoplastic and neoplastic lesions was 

performed. Many mice exposed to vanadium pentoxide were thin and exhibited abnormal 

breathing, particularly those exposed to 2 or 4 mg/m3

 vanadium pentoxide (specific incidence 

data not reported). Mean body weights were generally less than control in males exposed to 

4 mg/m3

 (decreases of 5-15%) and in females for all exposure groups (1 mg/m3, decreases of 

4-10%; 2 mg/m3, decreases of 14-20%; and 4 mg/m3, decreases of 4-19%) (Statistical 

significance not reported). The number of mice surviving for the entire 104-week exposure 

period was similar to control (78% for male mice and 76% for female mice) for all exposure 

groups for female mice and for males in the 1 and 2 mg/m3 groups, but survival was significantly 

decreased in male mice exposed to 4 mg/m3

 (50% survival rate)(Table 4-9). 

The incidences of nonneoplastic lesions of the respiratory tract in male and female mice 

are summarized in Table 4-9 (Ress et al., 2003; NTP, 2002). In male mice, the incidences of 

nonneoplastic lesions of the lungs (hyperplasia of the alveolar and bronchiole epithelium, 

inflammation, alveolus histiocyte infiltration), larynx (squamous metaplasia of the epiglottis) and 

nose (olfactory and respiratory epithelium degeneration in males and olfactory epithelial 

degeneration and atrophy in females) were significantly increased compared to control in all 

vanadium pentoxide exposure groups. Incidences of interstitial fibrosis were significantly 

increased in male and female mice exposed to 2 or 4 mg/m3

. In general, the incidences and 

severity ratings of lesions increased with exposure level and matched the types of lesions 

observed in rats. No treatment-related histopathological findings were observed in other tissues. 

The LOAEL of 1 mg/m3 was established for nonneoplastic lesions of the respiratory tract in male 

and female mice; a NOAEL was not identified. 

Table 4-9. Selected Nonneoplastic Lesions of the Respiratory System in Mice Exposed to 

Vanadium Pentoxide in a 2 Year Inhalation Study (NTP, 2002) 

Lesion Type and Locationa

Exposure Group 

Control 1 mg/m3 2 mg/m3 4 mg/m3

Male Mice 

Percent survival 78 66 72 50b

Lung 

Number of animals examined 50 50 50 50 

Alveolar epithelium, 

hyperplasia 

3 (3.0) 41c (2.2) 49c (3.3) 50c (3.9) 

Bronchiole epithelium, 

hyperplasia 

0 15c (1.0) 37c (1.1) 46c (1.7) 

Inflammation, chronic 6 (1.5) 42c (1.5) 45c (1.6) 47c (2.0) 

Alveolus, histiocyte 10 (2.4) 36c (2.4) 45c (2.6) 49c (3.0) 
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49

infiltration 

Interstitial, fibrosis 1 (1.0) 6 (1.7) 9c (1.2) 12c (1.7) 

Larynx 

Number of animals examined 49 50 48 50 

Epiglottis epithelium, 

squamous metaplasia 

2 (1.0) 45c (1.0) 41c (1.0) 41c (1.0) 

Nose 

Number of animals examined 50 50 50 50 

Inflammation, suppurative 16 (1.3) 11 (1.4) 32c (1.2) 23b (1.3) 

Olfactory epithelium, atrophy 6 (1.0) 7 (1.6) 9 (1.3) 12 (1.2) 

Olfactory epithelium, 

degeneration 

1 (1.0) 7b (1.0) 23b (1.1) 30c (1.2) 

Respiratory epithelium, 

degeneration 

8 (1.1) 22c (1.0) 38c (1.2) 41c (1.4) 

Bronchial Lymph Node 

Number of animals examined 40 38 36 40 

Hyperplasia 7 (2.1) 7 (2.4) 12 (2.1) 13 (2.2) 
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Female Mice 

Percent survival 76 64 60 64 

Lung 

 Number of animals examined 50 50 50 50 

Alveolar epithelium, 

hyperplasia 

31c (1.6) 38c (2.0) 50c (3.3) 

Bronchiole epithelium, 

hyperplasia 

0 12c (1.0) 34c (1.0) 48c (1.5) 

Inflammation, chronic 0 37c (1.3) 39c (1.8) 49c (2.0) 

Alveolus, histiocyte 

infiltration 

4 (1.0) 34c (2.4) 35c (2.4) 45c (2.7) 

Interstitial, fibrosis 0 1 (2.0) 4b (2.5) 8c (1.5) 

Larynx 

Number of animals examined 50 50 49 50 

Epiglottis epithelium, 

squamous metaplasia 

0 39c (1.0) 45c (1.0) 44c (1.1) 

Nose 

Number of animals examined 50 50 50 50 

Inflammation, suppurative 19 (1.1) 14 (1.2) 32c (1.2) 30c (1.3) 

Olfactory epithelium, atrophy 2 (1.5) 8b (1.3) 5 (1.0) 14c (1.3) 

Olfactory epithelium, 

degeneration 

11 (1.2) 23c (1.0) 34c (1.2) 48c (1.3) 

Respiratory epithelium, 

degeneration 

35 (1.3) 39 (1.5) 46c (1.7) 50c (1.8) 

Bronchial Lymph Node 

(Number of animals 

examined) 

39 40 45 41 

Hyperplasia 3 (2.0) 13c (1.8) 14c (2.3) 20c (2.3) a

Number of animals with lesion; numbers in parentheses indicate average severity grade of lesions in affected 

animals: 1=minimal, 2=mild, 3=moderate, 4=marked 

b

Significantly different from control by the Poly-3 test (p< 0.05) c

Significantly different from control by the Poly-3 test (p< 0.01) 

The incidences of tumors of the respiratory tract in male and female mice exposed to vanadium 

pentoxide for 2 years are summarized in Table 4-10 (Ress et al., 2003; NTP, 2002). The 

incidences of alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma and combined 

alveolar/bronchiolar adenoma or carcinoma were significantly increased in all groups of exposed 

female mice. In male mice, the incidences of alveolar/bronchiolar carcinoma and combined 

alveolar/bronchiolar adenoma or carcinoma were significantly increased compared to control in 

all vanadium pentoxide treatment groups and alveolar/bronchiolar adenoma was significantly 

increased in the 2 mg/m3

 group. 
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Table 4-10. Incidences of Respiratory Tumors in Mice Exposed to Vanadium Pentoxide in the 2 

Year Inhalation Study (NTP, 2002) 

Tumor Typea

Exposure Group 

Historical 

Control 

Control 1 mg/m3 2 mg/m3 4 mg/m3

Male Mice 

Number of animals examined 1071 50 50 50 50 

Alveolar/bronchiolar 

adenomab

201 (19%) 13 (26%) 16 (32%) 26c

(53%) 

15 (30%) 

Alveolar/bronchiolar 

carcinoma 

97(9%) 12 (24%) 29c (58%) 30c

(60%) 

35c (70%) 

Alveolar/bronchiolar 

adenoma or carcinoma 

285 (26.8%) 22 (28%) 42c (84%) 43c

(86%) 

43c (86) 

Female Mice 

Number of animals examined 1075 50 50 50 50 

Alveolar/bronchiolar 

adenoma 

67 (6.3%) 1 (2%) 17c (34%) 23c

(46%) 

19c (38%) 

Alveolar/bronchiolar 

carcinoma 

43 (–3.9%) 0 (0%) 23c (46%) 18c

(36%) 

22c (44%) 

Alveolar/bronchiolar 

adenoma or carcinoma 

109 (–

10.1%) 

1 (2%) 32c (64%) 35c

(70%) 

32c (64%) 

a

Number of animals with tumor; numbers in parentheses indicate percent incidence; particle size mass mean aerodynamic 

diameter + geometric standard deviation (MMAD±GSD): 1 mg/m3

= 1.3±2.9; 2 mg/m3= 1.2±2.9; 4 mg/m3=1.2±2.9 b

Historical incidence of alveolar/bronchiolar adenoma male B6C3F1 mice fed in inhalation chamber controls given NIH-07 diet. c

Significantly different from control by the Poly-3 test (p≤0.01) 

A recent study has examined the effect of vanadium pentoxide exposure by aspiration 

(Rondini et al. 2010). Rondini et al (2010) examined the induction of pulmonary inflammation 

and tumor promotion in three different mice strains (A/J, BALB/c and C57BL/6J) following 

oropharyngeal aspiration exposure. This study was designed to test the hypothesis that 

vanadium pentoxide acts as a tumor promoter in exposed rodents. Three mouse strains were 

used to further understand potential susceptibility to these effects. These particular mouse 

strains were selected because of their known differential susceptibility to chronic pulmonary 

inflammation and carcinogenesis: A/J mice are sensitive, BALB/C are intermediate and 

C57BL/6J are resistant. The experiment was designed to measure vanadium pentoxide tumor 

promotion following tumor initiation by 3-methylcholanthrene (MCA). All experimental mice 

were exposed to MCA (10ug/g bw in corn oil; intraperitoneal injection) in week 1, followed by 5 

weekly aspirations of either V2O5 (4 mg/kg) or PBS. Tumor incidence was measured at 20 

weeks post-MCA exposure. Statistically significant lung tumor increases were observed in A/J 

and BALB/C mice as compared to the MCA-treated control (p≤0.05; Table 4 – 11). Differences 

were also observed between strains, with A/J mice showing increased tumorigenicity in response 
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52

to vanadium pentoxide. In the absence of MCA, V2O5 was not sufficient to initiate 

tumorigenesis in this study. C57BL/6J had no tumors following exposure (data not shown). To 

evaluate the strain differences in inflammation, mice were aspirated with V2O5 (4 mg/kg bw) 4 

times weekly, with BALF collected at 6hr, 1d, 3d, 6d, and 21d following the last aspiration. 

Cellular infiltrates and protein content was compared, and lungs were snap-frozen for 

histopathology. Increased pulmonary inflammation and hyperpermeability was increased in all 

exposed strains in a similar pattern as the tumor induction, with greater increases observed in A/J 

mice than in BALB/C. C57BL/6J showed the least amount of increase in all parameters 

compared to all mouse strains. All results returned to baseline at 21 days post-exposure. The 

results of PMN increases were confirmed by histopathology in A/J and C57BL/6J mice. Further 

analysis was performed to measure inflammatory chemokine production (KC, MIP-2, MCP-1) 

and transcription factor activity (NFkB, c-Fos) and signaling pathway activation (MAPK). Like 

the increased inflammatory markers above, increased levels of KC and MCP-1 were observed in 

A/J and BALB/C mice as compared to the C57BL/6J mice. Similar strain differences were 

observed for the transcription activity of NFkB and c-Fos and the MAPK signaling activity in 

A/J mice as compared to C57BL/6J (BALB/C were not analyzed). 

Table 4 -11. Lung tumor multiplicity in MCA-Treated mice exposed to V2O5 by pharyngeal 

aspiration (Rondini et al. 2010). a,b

PBS Control V2O5

A/J 3.3 ± 0.75 

(n=4) 

10 ± 1.4 

(n=15) 

BALB/C 0.78 ± 0.28 

(n=8) 

2.2 ± 0.36 

(n=12) a

No tumors were observed in C57BL/6J mice. 

b

Number of animals for each treatment in parantheses. 

In summary, the identified noncancer health effects following occupational exposure via 

inhalation to vanadium pentoxide in humans include respiratory irritation, cough and bronchitis; 

inhalation exposure in animals results in multiple health effects, including pulmonary 

inflammation, lung and nasal hyplerplasia and pulmonary fibrosis. Vanadium pentoxide 

exposure for two years was associated with a wide spectrum of nonneoplastic pulmonary lesions 

in both rats and mice, ranging from hyperplasia to inflammation, fibrosis, and metaplasia. 

Lesions were detected in the lung, larynx, and nose in both rats and mice exposed to vanadium 

pentoxide. Bronchial lymph node changes were detected in mice exposed to vanadium 

pentoxide. There are currently no human epidemiology studies that examined carcinogenesis 

following exposure to vanadium pentoxide. However, there is clear evidence of carcinogenicity 
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53

 

in male and female mice exposed to vanadium pentoxide, and some evidence of carcinogenicity 

in male rats, based on observations of alveolar and bronchiolar neoplasms that exceeded 

historical controls in groups exposed to vanadium pentoxide (NTP 2002). A more recent study 

has also shown lung tumor promotion in sensitive mouse strains (Rondini et al. 2010). 

4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES – ORAL, INHALATION, 

INTRAPERITONEAL AND INJECTION 

4.3.1. Oral Studies 

Vanadium pentoxide delivered orally to weanling rats (10 to 200 μmol/kg) for three days 

produced a significant increase in alkaline phosphatase activity and DNA content in the 

diaphysis of femoral bones, and suggests that vanadium pentoxide may be linked to bone 

formation in the developing rat (Yamaguchi et. al., 1989). Yamaguchi et al. (1989) examined 

the potential effects of vanadium pentoxide on bone metabolism. Weanling male Wistar rats 

were exposed to 1.8 to 36.4 mg/kg (10 to 200 μmol/kg)8

 vanadium pentoxide orally 1 hr 

following an oral injection of 15.3 μmol Zn/100g) for three times at 24-h intervals. The highest 

dose vanadium pentoxide tested (200 μmol/kg) led to death in four of nine rats (cause of death 

not described). Authors state that administration of zinc as well blocked these deaths. All rats 

were killed 24h following the last vanadium administration, and blood immediately removed by 

cardiac puncture. Statistically significant increases were observed in serum from high-dose rats 

for calcium (27.3 – 36.4 mg/kg; p < 0.05) and decreased for phosphorus (36.4 mg/kg; p < 0.01). 

Administration of zinc completely prevented these serum changes. Femurs were also 

immediately removed. The diaphysis and epiphysis were used for alkaline phosphatase 

measures (right femur) and DNA content analyses (left femur). Alkaline phosphatase activity 

was significantly increased at the lowest dose tested (1.8 mg/kg; p< 0.05) and peaked at 3.6 

mg/kg. Further increasing doses led to decreases in alkaline phosphatase activity. A similar 

pattern was observed for bone DNA content, with statistically significant increases at 1.8 – 18.1 

mg/kg (p < 0.05), but decreased at higher doses. Although the authors state the interaction of 

vanadium and zinc led to an increase in bone calcium, based on the data presented in the figures 

in this publication, vanadium administration did not lead to alterations of bone calcium. Overall, 

this study shows an increase in both DNA content and alkaline phosphatase activity in weanling 

male rats following oral administration of vanadium pentoxide, suggesting a possible role of 

vanadium in increased bone growth. 

8

 Conversion factor: μmol = 0.1819 mg 
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Mravcova et. al (1993) assessed the extent of vanadium pentoxide accumulation in the 

bones of rats following 6 month exposure (full study description in 4.4.4.2). Vanadium 

accumulated in the epiphyseal cartilage of the tibia in rats with significantly higher 

concentrations of vanadium in the tibia and incisors of weanling rats compared to adults. 

However, no dose response data for these endpoints was reported. 

4.3.2. Inhalation Studies 

Investigations of the reproductive and developmental toxicity of subchronic or chronic 

inhalation exposure to vanadium pentoxide are limited to two studies. Mussali-Galante et. al 

(2005), used immunohistochemistry to assess the amount of gamma tubulin accumulating within 

somatic and testicular germ cells. Mussali-Galante et al. (2005) exposed 60 male CD-1 mice to 

inhaled vanadium pentoxide (0.02M, apparently aqueous solution containing aerosolized 

vanadium pentoxide) for 1 hr two times a week for 12 weeks. Avila-Costa et. al. (2004), 

investigators from the same laboratory, used the same protocol and reported that droplets of the 

vanadium pentoxide mixture had average diameters of 0.5 – 5 μm (Avila-Costa et. al., 2004). 

Thirty-six control animals inhaled only vehicle (deionized water). Groups of three exposed 

animals and three control animals were sacrificed per week for 12 weeks. Results indicated 

accumulation of vanadium pentoxide in testes (Mussali-Galante et al., 2005). Moreover, gamma 

tubulin was significantly decreased in testicular samples exposed to vanadium pentoxide 

compared to control, starting after the first week of exposure. Changes in gamma tubulin may 

suggest changes in microtubule-involved function, such as cell division, which may impact 

spermatogenesis. Responses were duration-dependent, with the lowest percentages of 

immunoreactive cells occurring at the end of the exposure period; values at week 12 ranged from 

1.2% for germ cells and 1.5% for Sertoli cells to 10.1% for Leydig cells (compared to 87-88% in 

controls) (Mussali-Galante et. al., 2005). 

Fortoul et al. (2007) analyzed testes for ultrastructural changes, testosterone 

concentration, and vanadium tissue concentration, using the same protocol as that reported above 

(Mussali-Galante et al 2005). No overt toxicity or changes in body or testicular weight were 

observed. Histopathological analysis revealed necrotic cell death in spermatocytes (25%) and 

Sertoli cells (15%) at weeks 5-6 in vanadium-exposed animals. Spermatocytes exhibited 

cytoplasmic vacuolation, nuclear distortion and intercellular edema in response to vanadium 

pentoxide exposure. Spermatogonia (40% necrosis during weeks 6-7) were the most susceptible 

cell type, followed by spermatocytes and Sertoli cells. Moreover, vanadium pentoxide 

concentrations increased dramatically after one week of exposure and remained consistently 

elevated (avg concentration 0.05 μg/g dry tissue in controls, 1.63 μg/g dry tissue in exposed 
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55

animals, 33 times higher). Concentrations of testosterone were highly variable and not 

statistically significant. 

Vanadium pentoxide exposure did not affect reproductive endpoints in male rats (sperm 

count, spermatid heads, sperm motility), but it did increase estrous cycle length by 10% in 

female rats exposed to 8 mg/m3, but not to 16 mg/m3, and reduced the number of cycling females 

in surviving rats in the 16 mg/m3

 group (percent reduction not reported). The epididymal 

spermatozoal motility of male mice exposed to 8 or 16 mg/m3 was significantly decreased by 13 

and 5%, respectively. No treatment-related effects were observed for assessments of estrous 

cycle in female mice (estrous cycle length and number of cycling females) (NTP 2002). 

4.3.3. Intraperitoneal and Injection Studies 

Male and female reproductive endpoints were evaluated in young rats following 

intraperitoneal administration of vanadium pentoxide (Altamirano et al., 1991). Newborn male 

and female rats were injected with 0 or 12.5 mg/kg vanadium pentoxide in saline on every 

second day from birth to age 21 days; groups sizes were 5 (treated males) or 9 (male and female 

controls and treated females). Males were sacrificed at 55 days of age and the females were 

sacrificed on the day of first vaginal estrus. Other groups of females were injected with 0 or 12.5 

mg/kg-day vanadium pentoxide (n = 10 and 6, respectively) from age 21 days to the day of first 

vaginal estrus, at which time they were sacrificed. Reported endpoints in the males consisted of 

absolute weights of testes, prostate, seminal vesicles, adrenals, pituitary, thymus, liver, kidneys 

and submandibular glands. The only effects in treated males were statistically significant 

increases in seminal vesicle, thymus and submandibular gland weights (20.1, 29.5 and 19.2% 

higher than controls, respectively). Endpoints evaluated in the females included body weight, 

absolute organ weights (ovaries, uterus, adrenals, pituitary, thymus, liver, kidneys and 

submandibular glands), age at vaginal opening, number of ova in oviducts and ovulation rate. 

The only effects in treated females occurred in the group treated from 21 days of age; these 

consisted of statistically significant increases in body weight (14.3% higher than controls) and 

increased weights of thymus, submandibular gland and liver (31.1, 15.8 and 28.4% above control 

weights, respectively). 

Fertility and sperm assessments were also performed in male CD-1 mice following 

intraperitoneal administration of vanadium pentoxide (Altamirano-Lozano et al., 1996). In the 

fertility assessment, groups of 20 and 15 male mice were injected with 0 and 8.5 mg/kg 

vanadium pentoxide in saline, respectively, every 3rd day for 60 days and mated 24 hrs after the 

last injection. Statistically significant effects in the treated group included reduced fertility rate 

in males (33% compared to 85% in controls), reduced numbers of implantation sites (avg = 5.8 
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56

compared to 10.88 in controls), reduced numbers of live fetuses (3.4 compared to 10.53 in 

controls) and increased number of resorptions per dam (2.00 compared to 0.24 average 

resorptions in controls). In the sperm assessment, 20 males were injected with 8.5 mg/kg 

vanadium pentoxide every 3 days for up to 60 days with groups of 5 evaluated after 10, 20, 30, 

40, 50 or 60 days of treatment. Statistically significant effects included reduced sperm motility 

after ≥10 days, reduced sperm count and increased percentage of abnormal sperm after ≥20 days, 

decreased absolute testicular weight after ≥50 days (relative weight not reported), and decreased 

body weight after 60 days. 

Developmental toxicity was evaluated in groups of 13 or 15 female CD-1 mice that were 

administered 0 or 8.5 mg/kg vanadium pentoxide in distilled water, respectively, by 

intraperitoneal injection on days 6-15 of gestation (Altamirano-Lozano et al., 1993). No 

maternal toxicity was reported (endpoints not specified). Developmental toxicity endpoints were 

assessed on gestation day 18. The endpoints included the number of implants, resorptions, and 

live fetuses. For all fetuses, weight, sex, and external malformations were noted. For two-thirds 

of the fetuses, skeletal abnormalities were also recorded. Internal soft-tissue examinations do 

not appear to have been conducted. The treated group had statistically significant increases in 

the number of litters with abnormal fetuses (9/15 compared to 3/13 in controls), number of 

abnormal fetuses (15/149 compared to 3/124), and number of fetuses with short limbs (8/149 

compared to 0/124 in controls). Additionally, the numbers of ossification centers in forelimbs 

and hindlimbs were significantly reduced in the treated fetuses. 

 Zhang et al. (1991a) evaluated the developmental toxicity in NIH mice following 

intraperitoneal injection of 5 mg/kg-day vanadium pentoxide on days 1-5, 6-15, 7, 8, 9, 10, 11 or 

14-17 of gestation. There were no adverse effects on preimplantation or implantation, 

developmental toxicity, or premature births. Increased frequencies of resorption or fetal death 

were observed for gestation days 6-15, 7 and 14-17. Delayed ossification (sites not specified) 

was observed for gestation days 6-15, 8, 10 and 14-17. In a second study, Zhang et al. (1993a) 

evaluated developmental toxicity in Wistar rats following intraperitoneal injection of 0.33, 1.0 or 

3.0 mg/kg-day on days 6-15 of gestation. Decreased placental weight and increases in embryofetus mortality and external or skeletal malformations (unspecified) occurred at 1.0 and 3.0 

mg/kg-day. Maternal toxic symptoms (unspecified), decreased maternal weight gain during 

treatment and fetal growth retardation were observed at 3.0 mg/kg-day. In the third study, Zhang 

et al. (1993b) evaluated developmental toxicity in Wistar rats following intraperitoneal injection 

of vanadium pentoxide in doses of 3 mg/kg-day on days 6-15 of gestation or 5 mg/kg-day on 

days 9, 10, 11 or 9-12 of gestation. Effects in rats exposed on gestation days 6-15 and 9-12 

included decreased maternal weight gain, increased fetal mortality, decreased fetal weight and 
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57

re test). 

 

crown-rump length, delayed ossification of unspecified bones, and increased incidences of 

subcutaneous hemorrhage, wavy ribs, and dilation of lateral ventricles and renal pelvis. Effects 

in rats exposed on a single day of gestation included subcutaneous hemorrhage and unspecified 

visceral anomalies following exposure on days 9, 10 and 11, and increased fetal mortality and 

delayed ossification of unspecified bones following exposure on day 10. Additional study 

details were not available. Overall, the three studies identified an intraperitoneal developmentaltoxicity LOAEL for vanadium pentoxide of 1 mg/kg-day (Zhang et al., 1991a, 1993a,b). 

 One study examined the effects of vanadium pentoxide (1.1mg/kg in distilled water) 

following tail vein injection in a total of 20 pregnant NMRI mice (data pooled from three studies 

with 6-10 mice each) (Wide 1984). Injections were performed before implantation or on 

gestation day 3 or 8, and animals were euthanized on gestation day 17 (two days before 

parturition. Pre-implantation exposure had no effect on the fetuses as regards number per litter, 

weight, or external and internal morphology. Exposure to vanadium pentoxide on gestation day 

3 or 8 did not lead to significant changes in resorption frequencies, fetal weights or frequencies 

of fetal hemorrhages as compared to controls. However, the number of fetuses defined as having 

less mature skeletons9

 by the authors was significantly greater in mice given vanadium 

pentoxide on gestation day 8, but not gestation day 3 (p < 0.001, chi squa

 Although the intraperitoneal and tail vein injection studies show the potential of 

vanadium pentoxide to cause reproductive and developmental effects in rodents, the studies are 

of little use in the quantitation of vanadium pentoxide toxicity, as equivalent oral or inhalation 

exposures cannot be established. 

4.4 OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES 

4.4.1 Acute and Short-Term Studies 

4.4.1.1 Acute Studies 

 4.4.1.1.1 Oral 

According to the Concise International Chemical Assessment Document 29 (WHO-IPCS, 

CICAD 29, 2001), rat oral LD50 values for vanadium pentoxide range from 86-137 mg/kg body 

weight (Yao et. al., 1986 as cited in WHO-IPCS, 2001). A rat oral LD50 value of 10 mg/kg body 

weight was reported in IARC Monographs, volume 86 (IARC, 2006) in a study by Lewis et al. 

9

 No ossification of three of four elements examined (supraoccipital bone, sternum, metatarsalia, and all caudal 

vertebrae). 
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58

(2000). Lewis et al. (2000) also reported a mouse oral LD50 value at 23 mg/kg body weight. 

Clinical signs of acute toxicity included lethargy, excessive tearing (lacrimation), and diarrhea 

but dose-response data was not reported (Yao et. al., 1986 as cited in WHO-IPCS, 2001). 

Histopathological analysis revealed liver necrosis and swelling of renal tubules. Other studies 

(WHO-IPCS, 2001) have identified LD50s of ~10 mg/kg body weight in rats and 23 mg/kg body 

weight in mice. An oral LD50 at 64 mg/kg body weight in rabbits was established (WHO-IPCS, 

2001). Signs of toxicity in rabbits mimicked those reported for rats. 

 4.4.1.1.2 Inhalation 

 A 1-hr inhalation exposure to vanadium pentoxide dust in rats led to an LC67 of 1.44 

mg/L (1440 mg/m3

) (US EPA, 1992). Clinical signs of toxicity included respiratory difficulty, 

irritation of mucosa, and diarrhea (WHO-IPCS, 2001). Knecht et al. (1985) reported air flow 

restriction, as measured by pulmonary function tests, in sixteen adult male cynomolgus monkeys 

(Macaca fasicularis) exposed to vanadium pentoxide by whole-body inhalation at 5.0 mg/m3

 for 

6 hrs but not at the lower dose tested (0.5 mg/m3

). From this study, a LOAEL of 5.0 mg/m3 and 

a NOAEL of 0.5 mg/m3

 were established. The lung was also identified as a target organ in 

response to acute inhalation exposure to vanadium pentoxide. Following a baseline 

measurement of pulmonary function, each of sixteen male cynomolgus monkeys were exposed 

to aerosols of 0.5 mg/m3 vanadium pentoxide by whole-body inhalation for 6 hrs (Knecht et al., 

1985). One week later, these monkeys were exposed to aerosols of 5 mg/m3

 vanadium pentoxide 

by whole-body inhalation for 6 hrs. Effects on airway function were evaluated in monkeys by 

comprehensive pulmonary function tests (PFTs) performed 24 hours post-exposure to 0.5 and 

5 mg/m3 and on pulmonary inflammation by analysis of bronchiolar lavage (BAL) fluid in 

monkeys performed after exposure to 5 mg/m3. Significant changes in pulmonary function 

parameters compared to baseline values were observed only following exposure to 5 mg/m3

 as 

follows: 16% increase in pulmonary resistance; 11% decrease in peak expiratory flow rate; 

5-22% decreases in forced expiratory flow maneuvers; 33% increase in residual volume; and 

24% increase in forced residual capacity. Results are consistent with air-flow limitation in both 

small peripheral and large central airways. An increase (approximately 87%; data presented 

graphically) in the total number of cells recovered in BAL fluid was observed 1 day after 

exposure to 5 mg/m3

 vanadium pentoxide. The increase in BAL fluid total cell number was 

primarily due to a marked increase (approximately 425%; data presented graphically) in the 

number of polymorphonuclear leukocytes. Results suggest that pulmonary inflammation and 

release of bronchoconstrictive mediators from inflammatory cells may play a role in vanadium 
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59

pentoxide-induced air-flow restriction. An acute (single 6-hr exposure) LOAEL for vanadium 

pentoxide of 5 mg/m3 for pulmonary function in monkeys was established in this study, with a 

NOAEL of 0.5 mg/m3. 

A study in male CD-1 mice (n = 48) by Avila-Costa et al. (2006) noted significantly 

impaired performance on memory tasks, significantly decreased dendritic spine length, and 

significant increases in percentages of necrotic cells in the hippocampus compared to controls 

following a 1 hr inhalation exposure to 0.02 M (2.5 mg/m3

 as Vanadium) vanadium pentoxide (p 

< 0.05). The dose-response relationship for these effects could not be evaluated, since only one 

dose was tested, and a NOAEL could not be established.

4.4.1.2. Short-term Studies 

4.4.1.2.1 Inhalation and Aspiration 

The primary noncancer health effect of short-term inhalation exposure in humans is 

respiratory irritation where 100 workers were reportedly exposed to 0.05 to5.3 mg/m3

 vanadium 

for 10 hr/day, 6 days/week, for 4 weeks (Levy et al., 1984). A LOAEL of 0.05 mg/m3

 was 

established. However, dose-response was not systematically measured, there were no controls, 

and exposure due to vanadium pentoxide could not be directly correlated to effects. The primary 

noncancer health effects of short term inhalation exposure in animals include increased 

pulmonary inflammation, and dose-related decreases in body weight and relative lung weight in 

rodents (NTP, 2002). 

Results of the NTP (2002) study in rats and mice provide evidence of toxicity to the 

upper and lower respiratory tract, including increased lung weight, inflammation, nonneoplastic 

lesions, and decreased pulmonary function following 13-day or 16-day inhalation exposure to 

vanadium pentoxide. A significant increase in pulmonary inflammation and histiocytic infiltrate 

of minimal to mild severity was observed in female rats (assessments not made in male rats) 

exposed to vanadium pentoxide for 13 days, with a LOAEL of 1 mg/m3

; a NOAEL was not 

established. Similar results were observed for female mice (assessments not made in male mice) 

exposed for 13 days, with a LOAEL of 2 mg/m3 for minimal to mild epithelial hyperplasia and 

inflammation; a NOAEL was not established. 

Male rats (22/group) and female mice (50/group) were also assessed for pulmonary 

inflammation (bronchiolar lavage analysis) and systemic immunotoxicity (pulmonary 

bacteriocidal activity) following exposure to 0, 4, 8, and 16 mg/m3

 vanadium pentoxide for 16-

days (NTP, 2002). Observed effects included significant alterations in the percentage of 
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60

recoverable bronchial lavage cells (macrophages and neutrophils) (LOAEL of 8 , mg/m3 and 

NOAEL of 4 mg/m3.), and increased lung protein and lysozyme in male rats (LOAEL of 4 

mg/m3). No NOAEL was established. In female mice exposed to vanadium pentoxide for 16 

days, there was a localized inflammatory response in the lungs based on increase in 

lymphocytes, protein and lysozymes at all concentrations; the NOAEL was not established. A 

significant decrease in the percentage of macrophages from bronchiolar lavage fluid led to a 

LOAEL of 8 mg/m3

 and a NOAEL of 4 mg/m3. These responses, NOAEL, and LOAELs are 

commensurate with those observed in the 3-month study in rats and mice of both genders (NTP, 

2002). Thus, the lowest concentrations at which adverse effects were observed were 1 and 2 

mg/m3 (LOAEL) for lung inflammation in female rats and mice, respectively, exposed to 

vanadium pentoxide for 13-days. 

An additional 5 male and 5 female mice were exposed by inhalation to vanadium 

pentoxide for 6 hrs per day, 5 days a week for 16-days at concentrations of 0, 2, 4, 8, 16, or 32 

mg/m3

 (NTP, 2002). All male mice exposed to 32 mg/m3 died before study completion. Body 

weight was significantly decreased in male and female mice at 16 and 32 mg/m3, respectively. 

Absolute lung weights were significantly increased in a dose-dependent manner in males at ≥ 4 

mg/m3, and relative lung weight were significantly increased in males at ≥ 2 mg/m3. Among 

females both absolute and relative lung weights increased in all exposure groups establishing the 

LOAEL of 2 mg/m3; no NOAEL was established. 

Additional groups of 40-60 female mice were exposed to 0, 2, 4 or 8 mg/m3 for 6 hrs per 

day, 5 days per week for 16 days (NTP, 2002). The nonneoplastic lung lesions noted on day 6 

and 13 consisted of hyperplasia of the alvelolar and bronchiolar epithelium at all exposure levels. 

 Increase in severity of lesions was correlated with increasing concentration and time. The 

LOAEL for nonneoplastic lung lesions was 2 mg/m3

. A NOAEL was not established. 

A duration-dependent decrease in the number of immunoreactive TH+ neurons (AvilaCosta et al., 2004) after 4 weeks and increased quantities in metalloproteinase (MMP)-2 and 

MMP-9 in CNS after 8 weeks in male mice (Colin-Barenque et. al. 2008) following twice 

weekly, one hour inhalation exposure to 5.13 mg/m3

 vanadium pentoxide were suggestive of 

disruption of blood-brain barrier . 

Turpin et al. (2010) exposed male AKR mice to vanadium pentoxide by intranasal 

aspiration following exposure to respiratory syncytial virus (RSV) to determine if pre-exposure 

to the virus exacerbated the vanadium pentoxide-induced lung inflammation and fibrosis. 

Animals were exposed intranasally to RSV (6 x 105 PFU in 100ul PBS) on day -1 and day 8, 

then exposed intranasally to V2O5 (4mg/kg in 50ul PBS) on day 0 and day 7. One hour before 

euthanasia, animals were given BrdU (50 mg/kg) by i.p. for analyzing cell proliferation in 
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bronchus-associated lymphoid tissue (BALT). Lungs were lavaged with PBS and BALF 

collected for analyzing differential cell counts (neutrophils, macrophages and lymphocytes). 

Total RNA from lung was analyzed by real time RT-PCR for mRNAs coding for pro-fibrogenic 

growth factors TGF-β-1, connective tissue growth factor (CTGF), platelet-derived growth factorC (PDGF-C) and collagen Col1A2, anti-fibrogenic type I interferons-alpha (IFN-α) and -beta 

(IFN-β) and IFN-inducible chemokines CXCL9 and CXCL10. 

Lung sections stained with Masson’s trichrome staining to show collagen had an 

inflammation score of two, representing mild fibrosis with vanadium pentoxide exposure alone. 

 However, vanadium pentoxide-induced fibrotic response was less severe in the lungs of mice 

which received either pre- or post-RSV exposure, and no difference observed in pre- or postRSV alone and the negative controls. In addition, BALF from mice exposed to vanadium 

pentoxide alone or with RSV-post exposure had significantly higher total cell count compared to 

RSV pre-exposure, RSV pre-exposure plus vanadium pentoxide or controls. In particular, 

vanadium pentoxide alone caused a significant increase in the levels of neutrophils and 

lymphoctyes compared to controls. Both pre- and post-exposure to RSV led to a decrease in the 

severity of V2O5-induced fibrosis, and gene expression analysis showed decreases in several 

pro-fibrinogenic genes associated with innate immunity. 

The acute and short-term studies described here support those results describe previously 

in the subchronic and chronic studies, and suggest progressive lung effects from vanadium 

pentoxide exposure. These further support that the lung is the most sensitive organ to vanadium 

pentoxide exposure. 

4.4.2 Immunological Endpoints 

4.4.2.1 Human Studies 

 Some of the early case series observed dermatitis among affected workers employed at 

vanadium pentoxide processing facilities (Sjöberg, 1951; Zenz et al., 1962). Zenz et al. (1962) 

observed that respiratory symptoms, such as conjunctivitis, nasopharyngitis, hacking cough, fine 

rales, and wheezing recurred with greater severity when work resumed after three days of no 

exposure, even with the use of respirators, perhaps indicating immune system involvement. 

 Kiviluoto published a series of reports regarding an investigation in 1975 of respiratory 

symptoms and clinical findings among employees (process workers, repairmen, foremen, and a 

laboratory worker) at a factory making vanadium pentoxide from magnetite ore (Kiviluoto, 1980; 

Kiviluoto et al., 1979; Kiviluoto et al., 1981a). A higher proportion of the exposed group (N = 

63) had an elevated number of neutrophils in nasal smears compared to the referent group (N = 
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63) who were employed at the magnetite ore mine and matched to the exposed by age and 

smoking habit (35% versus 7%, p<0.001, N=55 pairs). In biopsies of the nasal mucosa, a higher 

proportion in the exposed groups had elevated plasma cells and round cells (26% versus 0%, 

p<0.05, N=57 pairs and 48% versus 29%, p<0.05, N=56, respectively). The prevalence of 

elevated numbers of eosinophils did not vary by exposure, leading the authors to conclude that 

the cytological and histological response in the vanadium-exposed group was an irritant, not 

allergic response. Vanadium concentrations in the breathing zone averaged 0.028 mg/m3

 (TWA) 

with a range of 0.002 – 0.42 mg/m3

. Higher concentrations were found where grinding and 

packing of smelt were conducted (TWA (range): 2.3 mg/m3

 (one sample) and 0.13 mg/m3 (0.02 – 

0.37). 

 Motolese et. al. (1993) assessed whether exposure to vanadium pentoxide in the ceramics 

industry was associated with contact dermatitis or contact sensitization. One hundred and twentysix enamellers and sixty-four decorators from five ceramics factories were tested for contact 

sensitization using skin patch testing after exposure to a variety of substances, including 

vanadium pentoxide. Among the 190 workers under study, twenty-two individuals were found to 

have dermatitis and 17 reported having had skin lesions in the past. One worker responded with a 

positive skin patch test indicating sensitization to a 10% solution of vanadium pentoxide. 

 A pilot study using nasal lavage to evaluate an inflammatory response to fuel oil ash 

exposure, did not find an association of several exposure indices of vanadium or PM10 exposure 

with counts or percentages of polymorphonuclear cells, eosinophils, and epithelial cells (Hauser 

et al., 1995b). Thirty-six out of 50 volunteers with no symptoms of cold or flu provided a nasal 

lavage sample both at baseline after at least 36 hours away from work and after 72 hours of 

exposure at a local electric company. A total of 19 boilermakers involved in the overhaul of a 

large oil-fired boiler and 18 utility workers, full-time employees of the power company with 

lower exposure to fuel oil ash, were studied. Daily exposure estimates for PM10 (< 10 μm) and 

vanadium (adjusted for filter extraction efficiency) were assigned to each individual using data 

from personal air sampling (1 – 10 hour TWA) and a self-completed work diary completed by 

each participant listing tasks and job locations during the day. A total of 29 task/location 

exposure categories were identified, but only 3 or fewer samples were available to estimate 

concentrations at 23 of them. Environmental PM10 concentrations based on personal sampling 

were 50 to 4510 μg/m3

. Concentrations of respirable vanadium dust were 0.10 to 139.2 μg/m3. 

Compared to baseline, the number of polymorphonuclear cells/ml recovered nasal fluid (adjusted 

by dividing the change by the mean of the baseline and postexposure value) increased by 40% 

(SD 100%, p < 0.05) with a range of -89% - 200%. The adjusted number of epithelial cells/ml 

recovered nasal fluid increased by 26.7% (SD 81.4%, p > 0.05) with a range of -83% - 200%. 
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Regression models controlled for age and smoking. Models did not control for ozone levels or 

respirator use. The wide variation in the change in cell counts after exposure, especially among 

nonsmokers, and the small number of subjects may have precluded the detection of an 

association with vanadium or particulate exposure. Alternatively, the authors considered the 

levels of vanadium dust to be low, possibly not enough to cause inflammation in these workers. 

 Woodin et. al (1998) analyzed nasal lavage fluid from 18 boilermakers before, during, 

and after the overhaul of a large, oil-fired boiler over a six week period from mid-May, 1995 to 

late-June, 1995. Biomarkers of upper airway inflammation in nasal lavage fluid were more 

prevalent among boilermakers during the overhaul compared to 11 utility workers (Woodin et al., 

1998). Interleukin-8 (pg/ml) levels increased from a mean of 93.7 pg/ml (22.6-235.0) before the 

overhaul to 140.9 pg/ml (32.4-307.0) during the overhaul (p < 0.05), and decreased to levels 

comparable to those before the overhaul two weeks later (mean (range): 89.0 pg/ml (20.3-75.0)). 

Interleukin-8 levels among utility workers did not change substantially during the overhaul (mean 

(range): 69.2 (24.6-104.5), 58.5 (14.3-108.4) and 47.5 (12.8–74.7), respectively. 

Myeloperoxidase levels also increased among boilermakers during the overhaul, but not among 

utility workers. Among boilermakers, myeloperoxidase levels (ng/ml) were 22.7 (2.0-72.8), 33.9 

(2.0-103.0) and 24.2 (3.9-58.1) before, during and after the overhaul, respectively (before versus 

during: p < 0.05). Among utility workers, myeloperoxidase levels were 25.6 (10.1-47.6), 27.2 

(4.9-66.2) and 25.6 (4.9-51.7), respectively. Mean IL-6 and eosinophilic cationic protein levels 

did not change during the overhaul work suggesting that the inflammatory response was not due 

to an allergy or respiratory infection. During the boiler work, vanadium levels rose to a 

geometric mean (SD) of 8.9 (2.3) μg/m3 inside the boiler but did not change appreciably outside 

the boiler where the utility workers were located (geometric mean (SD) μg/m3: 1.4 (1.6) (p < 

0.001)). However, vanadium concentrations in nasal lavage fluid were not associated with levels 

of either IL-8 or myeloperoxidase using Spearman’s Rank Order Correlation Test. 

 Hauser et. al. (2002) reported on a prospective cohort study of 118 boilermaker 

construction workers (see Section 4.1.2). The participants provided information on their work at 

oil, gas and coal-fired powerplants in annual work history questionnaires, but exposure to specific 

components in the combustion particles were not quantified. Spirometry was used to measure 

lung function. Among the cohort, 6 workers reported having asthma diagnosed by a physician 

and 18 workers reported having symptoms of chronic bronchitis. Workers with asthma or chronic 

bronchitis experienced greater reductions in annualFEV1 associated with the number of hours 

worked at gas or coal-fired powerplants during the year compared to the other workers. The 

generalized estimating equation models adjusted for age and smoking status, and interaction 

terms were statistically significant. In contrast, models adjusting for age, baseline FEV1, and 
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cigarette smoking status did not find a similar effect of airway responsiveness, measured by 

methacholine challenge, on exposure-related reductions in FEV1. The annual reduction in FEV1

associated with the number of hours worked at gas, oil or coal-fired powerplants was similar 

between workers with and without reactive airways. 

 In conclusion, case studies of occupational exposure to vanadium pentoxide dust or 

ROFA have reported individuals with dermatitis, positive skin patch reactions and bronchial 

reactivity, although this does not appear to be a common occurence. Although increases in the 

numbers of inflammatory cells in nasal smears or nasal lavage fluid have been observed in 

exposed workers, no associations were observed in relation to estimates of respirable vanadium 

dust or vanadium concentrations in nasal fluid. The authors did not report increases in 

eosinophils suggesting that the inflammation was due to irritation and was not an allergic 

response. 

4.4.2.2 Animal Studies 

 Pinon-Zarate et. al. (2008) exposed 112 male CD1 mice to ~1.4 mg/m3 vanadium 

pentoxide by inhalation for 1 hr/day, 2x a day, for 12 weeks as measured by filters following 

exposure. This study did not provide reliable exposure information, thus exposure concentrations 

in mg/m3

 could not be more specfically determined. Spleen weight and histology were 

determined. B-lymphocytes in the spleen were identified by immunohistochemical staining for 

CD19 (a cell surface marker which acts as a co-receptor for other CD markers). In addition, eight 

control and eight vanadium pentoxide-treated mice were immunized with Hepatitis B Surface 

antigen, a well-known T-cell dependent antigen. Avidity to the resulting antibody was measured. 

 Spleen weight of vanadium-pentoxide exposed animals increased significantly and peaked at 9 

weeks, and then decreased significantly. Splenic germinal centers were significantly increased in 

vanadium pentoxide-treated mice and contained a significantly increased number of CD19+ cells 

compared to controls. The authors suggest that vanadium pentoxide does not act as a direct 

antigen and does not induce a “host humoral response”. These data suggest that vanadium 

pentoxide may affect the avidity of antibodies – the ability of antibodies to bind effectively to 

substrates (affinity) and to engage multiple epitopes of the antigen at once. 

Mravcova et al (1993) conducted experiments to determine effects of subchronic 

exposure to low doses of vanadium pentoxide on the immune system. Weanling and adult male 

and female Wistar rats (n= 10 per group) were given vanadium pentoxide in drinking water (0, 1, 

100 mg/L or 0, 0.14, 14 mg/kg-day) for 6 months. Also, male and female ICR mice (groups of 

10) were given vanadium pentoxide (0 or 6 mg/kg-day) by gavage 5x a week for 6 weeks. 
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Immunotoxicity endpoints included spleen and thymus weight, spleen cellularity, number of 

peripheral white blood cells, phagocytosis and natural killer cell activity, the extent of plaqueforming cells being converted to T-dependent antigen, and several cell-mediated immunity 

endpoints (Concanavalin A (ConA), pokeweed mitogen responsiveness (PWM), and 

phytohemagglutinin responsiveness (PHA) assays). Of these endpoints, spleen weight was 

significantly elevated over controls at 14 mg/kg-day in rats. The ConA and PHA assays 

illustrated significant cell-mediated immune activation at 1 mg/L in rats over control (3 and 2.5 

times higher than control values, respectively) but statistical significance was not indicated or 

reported. At the high dose (14 mg/kg-day vanadium), ConA and PHA assay results were close 

to control values. Thus, no dose-response pattern was detected. The low dose response may be 

a transient or compensatory response. Results of other endpoints were not reported. No 

significant differences in these parameters were reported in mice. The authors suggested that the 

high Con A response of T suppressor cells indicate that vanadium pentoxide may induce 

hypersensitivity responses at low doses. 

Immunological endpoints were also analyzed as part of a pulmonary study using 

cynomolous monkeys weekly provocation challenges (single 6-hr exposures to 0.5 or 3.0 

mg/m3

). Inhaled vanadium pentoxide aerosol for six weeks produced statistically significant 

pulmonary responses, prior to a subchronic exposure (6 hrs/day, 5 days/week for 26 weeks) 

(Knecht et al., 1992; study details in Sec 4.2.2.1). Immunological analyses of blood and 

bronchiolar lavage fluid, and skin sensitivity tests were conducted before the pre- and postexposure provocation challenges. Bronchiolar lavage fluid analyses were also performed one 

day after the provocation challenges. Cytological endpoints included complete and differential 

blood cell counts and leukotriene C4 levels. Immunological endpoints included total IgE, total 

IgG, albumin and total protein. The skin sensitivity tests assessed immediate and delayed 

responses to intradermal injections of vanadium pentoxide-monkey serum albumin conjugate. 

BAL fluid analysis showed a significant influx of inflammatory cells (polymorphonuclear 

leukocytes) into the lung. Other study endpoints were not significantly different between the 

three exposure groups (control, peak and constant) at either challenge concentration when the 

monkeys were rechallenged following subchronic exposure. 

 In summary, immunological effects of vanadium pentoxide exposure have not been 

comprehensively studied. The studies described here have not shown a statistically significant 

response in the endpoints tested, however, some effects were observed. These results are 

therefore inconclusive. 

4.4.3 Neurological Endpoints 
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4.4.3.1 Human Studies 

 No studies on the neurological effects of vanadium pentoxide were reported in humans. 

 4.4.3.2 Animal Studies 

Pazynich (1966) exposed 33 male albino rats (species not specified) to 0.027 mg/m3

 or 

0.002 mg/m3

 aerosolized vanadium pentoxide “round the clock” for 70 days. A third group of 

rats served as control. The animals were evaluated for general condition, body weight, motor 

chromaxy of antagonistic muscles, whole blood cholinesterase activity, and oxyhemoglobin 

content. Motor chromaxy of extensor muscles decreased significantly (p<0.01) while that of 

flexor muscles increased (p<0.001) in animals exposed to 0.027 mg/m3

. Blood cholinesterase 

levels were statistically significantly reduced after exposure to 0.027 mg/m3

 and the reduction 

persisted throughout the 90-day recovery period. There was a statistically significant reduction 

in venous oxyhemoglobin in rats from the 0.027 mg/m3. Recovery was observed after 20 days. 

No difference in these parameters was reported in the 0.002 mg/m3

 group compared to controls. 

These results suggest a LOAEL of 0.027 mg/m3

 for hematological and CNS effects in albino rats 

with a NOAEL of 0.002 mg/m3

. 

Three recent studies by Avila-Costa et al. (2004, 2005, 2006) found morphological 

changes in the central nervous system following inhalation exposure to vanadium pentoxide. 

Male CD-1 mice (n=48) were exposed to vanadium pentoxide by whole-body inhalation for 1 

hr/day, 2 days/week for up to 8 weeks (Avila-Costa et al., 2004, 2005). Particle size was not 

reported in either study. The exposure concentration was reported as 0.02 M (Avila-Costa et al., 

2004, 2005, 2006) or “2.5 mg/m3 V” (Avila-Costa et al., 2005). The same group of investigators 

(Gonzalez-Villalva et al., 2006; Mussali-Galante et al., 2005) using the same exposure protocol 

reported that the 0.02 M solution generated an average chamber concentration of 2.5 mg/m3

, as 

vanadium metal (MW = 50.94), corresponding to 2.57 mg/m3 vanadium pentoxide (MW = 

181.9). The number of immunoreactive-TH+

 neurons in the substantia nigra region of the basal 

ganglia in the mesencephalon (Avila-Costa et. al., 2004) and the morphology of the blood-brain 

barrier (Avila-Costa et. al., 2005) were assessed at the end of each week for up to 8 weeks of 

exposure. No clinical signs of toxicity were reported in either study. A duration-dependent 

decrease in the number of immunoreactive-TH+ neurons was observed from week 3 (decrease of 

approximately 30%; data presented graphically) through week 8 (decreased by approximately 

63%; data presented graphically) of exposure (Avila-Costa et al., 2004). Morphological changes 

to the blood-brain barrier (cilia loss, cell sloughing and ependymal cell layer detachment) were 
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also observed starting at one week and increasing with duration of exposure (Avila-Costa et al., 

2005). 

Using a similar protocol, Avila-Costa et al. (2006) assessed the effects of vanadium 

pentoxide on memory and morphology of hippocampal neurons in male CD-1 mice that were 

exposed by whole-body inhalation for 1 hr/day, 2 days/week for up to 4 weeks. Groups of 6 

exposed mice and 6 vehicle control mice (inhaling deionized water droplets) were evaluated 

after 24 hrs and weekly for 4 weeks. No clinical signs or body weight changes were observed. 

Spatial memory was tested using a modified Morris water maze task that was learned preexposure. Performance on this test, as assessed by latency (swimming time) to locate a hidden 

platform, was significantly impaired in the exposed mice at all time points in an increasing, timerelated manner. Pyramidal neurons from the hippocampus CA1 region were evaluated for 

cytological and ultrastructural changes, because impairment in spatial memory is frequently seen 

following damage to this region of the brain. The cytological analysis assessed numbers of 

dendritic spines in the hippocampal cells; results showed a significant loss of dendritic spines in 

the exposed mice at all time points; the loss increased with time, in a manner that correlated with 

the memory impairments. The ultrastructural analysis showed a significantly increased 

percentage of necrotic hippocampal cells at all time points, with a maximum of 33% after 4 

weeks of exposure; other findings included hyperdense postsynaptic terminals and edema in 

mitochrondria, dendrites, dendritic spines and presynaptic terminals. These three studies 

establish a LOAEL for morphological changes to the central nervous system accompanied by 

behavioral effects following acute and short-term intermittent exposure to vanadium pentoxide at 

concentrations of 2.56 mg/m3

 two times per week, for 1-hr duration/exposure. 

 Colin-Barenque et al. (2008) investigated whether the vanadium pentoxide-mediated 

disruption of the blood-brain barrier was associated with the activation of matrix 

metalloproteinases (MMPs), protein degrading enzymes that are involved in tissue remodeling. 

Male CD-1 mice (n= 20 per group) were exposed to 0.02 M (2.56 mg/m3

) aerosolized vanadium 

pentoxide in deionized water or deionized water alone for 1 hr two times a week for up to four 

weeks. Five mice were sacrificed from each group, per time point (24 h, 1, 2 and 4 weeks). The 

presence of matrix metalloproteinase (MMP) was determined by gel zymography. In the 

olfactory bulb, MMP-2 was not different between vanadium pentoxide treated mice and controls, 

regardless of time point. MMP-9 was significantly elevated (300% and ~420%) in vanadium 

pentoxide-exposed mice compared to controls at 2 and 4 weeks, respectively. Both MMP-2 and 

MMP-9 were detected in the prefrontal cortex; MMP-2 was not different between controls and 

treated animals at any time point, but , MMP-9 was significantly elevated over control values at 1, 

2 and 4 weeks of exposure (150%, ~175%, and 250% of control values, respectively). In the 
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hippocampus, MMP-9 from vanadium pentoxide-treated mice was significantly elevated over 

controls after 1, 2 and 4 weeks of exposure (200%, 340%, and ~370%) while MMP-2 in exposed 

animals was significantly increased at 4 weeks (~150% over controls). In the striatum, MMP-9 

from exposed mice was significantly elevated over that of controls after 4 weeks of exposure; 

MMP-2 levels from exposed mice were significantly elevanted over control values after 2 (160%) 

and 4 weeks (~250%) of exposure, but were not documented at earlier time points. These 

findings suggest that vanadium-induced increases in MMP’s in different parts of CNS occur in 

association with dendritic spine loss as well as neuronal death, and could be related to blood-brain 

barrier disruption. 

4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF 

ACTION FOR PULMONARY FIBROSIS AND CANCER 

The preceding paragraphs have highlighted the main noncancer and cancer health effects that 

result from exposure to vanadium pentoxide. Noncancer effects in the lung range from 

histiocytic infiltration and alveolar inflammation, to hyperplasia of alveolar epithelium and 

pulmonary fibrosis. These endpoints exist in a plausible biological response continuum—from 

inflammation to reparative hyperplasia, to fibrosis. These effects also display a temporal and 

dose-response continuum, ranging from inflammatory and hyperplastic responses that occur at 

earlier time points (13 and 16 days) and at lower doses (2 mg/m3

) to fibrosis that occurs at later 

time points (3 months) and at higher doses (4 mg/m3

). Inflammation and hyperplasia are 

biologically relevant as precursor events to pulmonary fibrosis. Several investigators have 

systematically investigated the molecular mechanisms underlying vanadium pentoxide-induced 

pulmonary inflammation and fibrosis. These studies are summarized below. 

4.5.1 Genotoxicity 

The genotoxicity assays of vanadium pentoxide are summarized in Table 4-12. 

4.5.1.1 Human Studies 

Two studies investigated mutagenic activity in humans exposed to vanadium pentoxide 

(Ehrlich et al 2008; Ivancsits et al 2002). The in vivo genotoxicity of vanadium pentoxide in 

lymphocytes and whole blood leukocytes obtained from 49 male workers exposed to vanadium 

pentoxide at a processing plant was compared to 12 non-exposed controls (Ivancsits et al., 2002). 

 The average exposure duration for workers was 12.4 years. Workers reported using protective 
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masks at least occasionally. Measurements or estimates of worker exposure to vanadium 

pentoxide were not reported, although exposure to vanadium was confirmed through 

measurement of serum and urine vanadium. No significant differences between vanadiumexposed and control workers were observed for DNA strand breaks (as assessed by alkaline 

comet assay), 8-hydroxy-2'deoxyguanosine (8-OHdG),an oxidized DNA base common 

indicative of oxidative stress or the frequency of sister chromatid exchange (SCE) in leukocytes. 

 When normal human leukocytes or human fibroblasts were cultured in vitro and exposed to 

vanadate (25-500 μg/L), both whole blood cells and isolated non-proliferating lymphocytes 

exhibited a significant increase in DNA migration in the alkaline comet assay compared to nonexposed cells only at the highest doses tested (250-500 μg/L). Cultured human fibroblasts, 

however, exhibited a dramatic dose-dependent increase in DNA migration after vanadate 

treatment at lower concentrations as well (as low as 0.5 μg/L) and suggest that fibroblasts are 

more sensitive to DNA damage in the presence of vanadate than are blood cells when exposed in 

vitro (Ivancsitis et al. 2002). 

Ehrlich et al (2008) investigated the impact of inhaled vanadium pentoxide on DNA 

stability in vanadium production workers (n= 52) compared to non-exposed jail wardens (n=52) 

during October 2004 – May 2005. All subjects studied were male, and were exposed for their 

entire 8-hr shift while wearing protective masks. However, the duration of exposure and 

concentration of the inhaled vanadium was not determined. The median concentration (25th – 

75th percentile) of vanadium in plasma was 7-fold higher in exposed workers compared to the 

unexposed reference group. Leukocytes were then assayed (Comet assay) for DNA damage, and 

endogenous levels of oxidized purines and pyrimidines were determined. No differences in 

DNA migration by exposure were noted in leukocytes under standard conditions, demonstrating 

that exposure is not associated with increases in single- and double-strand breaks. However, 

increases were observed in both oxidized purine (7% increase, p = 0.02) and pyrimidine (33% 

increase, p = 0.002) formation in exposed individuals. Moreover, DNA damage induced by 

bleomycin was 25% greater in leukocytes from the exposed workers (p < 0.0001) and DNA 

repair after bleomycin administration was less evident (p < 0.0001). The extent of micronuclei 

formation, necrosis and apoptosis was determined in isolated lymphocytes using the CBMN Cyt 

assay. The number of micronuclei was 2.5 fold higher in 24 workers than 23 non-exposed 

referents (p = 0.01). The frequency of nucleoplasmic bridges and nuclear buds (which indicate 

evidence of misrepaired DNA breaks and gene amplification, respectively) were significantly 

increased (7-fold and 3-fold) over controls. Numbers of necrotic and apoptotic cells were 

increased by 55% and 50% respectively in exposed workers. Together, these results suggest that 

occupational exposure to inhaled vanadium pentoxide may affect DNA stability by increasing 
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levels of oxidized bases and affecting DNA repair. Age, body mass index and smoking habit 

(cigarettes/day) were similar between the two groups. Folate levels also were similar but 

vitamin B6 and B12 levels were lower among the unexposed indicating that the effects on DNA in 

the exposed were not due to vitamin deficits. 

Kim and colleagues (2004) assessed the cross-shift change in urine levels of 8-hydroxy2’-deoxyguanosine (8-OHdG), a marker of DNA repair of oxidative DNA damage, over a 5-day 

period in 1999 among a group of 20 boilermakers involved in the overhaul of oil-fired boilers at 

a power plant (74% of eligible). Median total PM2.5 8-hour TWA concentration, measured using 

personal exposure monitoring, was 0.44 mg/m3

 (Q25% - Q75%: 0.29 – 0.76 mg/m3). Total 

vanadium 8-hour TWA concentration, including vanadium oxides, was 1.23 μg/m3 (Q25% - Q75%: 

0.47 – 3.53 μg/m3

). The workers were 18 – 59 years old (mean ± SD: 45.5 ± 12.0) and had been 

employed as boilermakers for 0.04 to 40 years ((mean ± SD: 21.7 ± 12.9). The mean cross-shift 

change in creatinine adjusted 8-OHdG levels in urine was 1.88 μg/g creatinine (SD 0.74). Preshift levels, measured an average of two days away from work, were significantly different from 

post-shift levels (p = 0.02). In linear mixed regression models, a 1 mg/m3

 increase in total PM2.5

8-hour TWA concentration was associated with an increase in urinary 8-OHdG concentrations of 

1.67 μg/g creatinine (95% CI: 0.21 – 3.14), adjusting for urinary cotinine, chronic bronchitis 

status, and age. A 1 μg/m3 increase in PM2.5 vanadium concentration was associated with an 

increase in urinary 8-OHdG concentrations of 0.23 μg/g creatinine (95% CI: 0.04 – 0.42) in a 

model with the same covariates. PM2.5 manganese, nickel and lead concentrations also were 

associated with 8-OHdG levels in urine when analyzed separately in similar models. The 

concentrations of the metals were correlated (0.52 < r < 0.92) and so the association with 

vanadium may not have been independent of the associations with the other metals. However, 

the finding of oxidative DNA injury and repair among healthy boilermakers is consistent with 

similar reports among vanadium pentoxide workers. 

Another marker of oxidative DNA damage, 7-hydro-8-oxo-2’-deoxyguanosine (8-

oxodG), was assessed in relation to water soluble transition metal content in ambient PM2.5

among male and female nonsmoking students, 20 – 33 years of age, living in central Copenhagen 

(Sorensen et al., 2005). Personal samples of PM2.5 were collected over two days twice during 

one year, once during summer and once during autumn. Median (interquartile range) 

concentrations of PM2.5 were 20.1 μg/m3

 (13.1 – 27.7) in November and 12.6 μg/m3 (9.4 – 24.3) 

in August. The median (interquartile range) concentration of vanadium in PM2.5 was 3.0 (0.3 – 

4.7) in November and 3.2 (1.4 – 5.7) in August. Of 66 participating students, 32 provided 

measurements for both seasons. Median (interquartile range) levels of 8-OxodG in lymphocytes 

(per 105 dG) were 0.55 (0.34 – 0.78) and 0.58 (0.47 – 0.70) in November and August, 
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respectively. Vanadium and chromium concentrations in aqueous suspensions of PM2.5 were 

associated with the 8-oxodG concentration in lymphocytes in mixed regression models with 

subject as a random factor and adjusting for PM2.5 mass and season. A 1 μg/L increase in either 

vanadium or chromium was associated with a 1.9% (95% CI: 0.6 – 3.3) or 2.2% (95% CI: 0.8 – 

3.5) increase in 8-oxodG concentrations in lymphocytes, respectively. Platinum, nickel, copper, 

and iron were not associated with 8-oxodG concentration in lymphocytes and no metals were 

associated with 8-oxodG concentration in urine. This study suggests that metal content of 

ambient fine particulate matter increases oxidative DNA damage in lymphocytes and that 

vanadium may be one of the responsible agents along with other metal constituents in particulate 

air pollution at levels common in urban settings. 

Three other studies demonstrated a genotoxic effect of vanadium pentoxide on primary 

human lymphocytes in vitro (Rojas et al. 1996; Ramirez et al. 1997; Roldan and Altamirano 

1990). These studies examined chromosomal aberrations and aneuploidy by fluorescence in situ 

hybridization (FISH) and SCE assays, as well as DNA damage by the comet assay. Cells 

exposed to vanadium pentoxide had significantly increased DNA migration indicative of DNA 

damage at all doses tested in primary human leukocytes (p<0.05) and in the high doses in three 

of four donor lymphocyte cell strains (p<0.05). Vanadium pentoxide (0 – 0.1uM) lead to an 

increase in aneuploidy with some interindividual variation observed in four primary human 

lymphocyte cell strains (Ramirez et al. 1997). An increase in aneuploidy was observed in one 

primary human cell strain exposed to vanadium pentoxide (0 – 6ug/ml) but no chromosomal 

aberrations were observed (Roldan and Altamirano 1990). 

4.5.1.2 Laboratory in vivo and in vitro studies 

Vanadium pentoxide produced gene mutations in two bacterial test systems (Bacillus 

subtilus and Escherichia coli) (Kada et. al., 1980, Kanematsu et. al., 1980); although negative 

results were reported by NTP (2002) in a reverse mutation assay in Salmonella typhimurium 

(TA97,TA98,TA100, TA102,TA1535 with or without metabolic activation). Negative results 

were also reported in a gene mutation assay in Chinese hamster V79 fibroblast cells (Zhong et 

al., 1994). However, DNA damage and/or aneuploidy was observed in all in vitro studies 

performed in primary human cells (Ivancsits et al. 2002; Kleinsasser et al. 2003; Ramirez et al. 

1997; Rojas et al. 1996; Roldan and Altamirano 1990). Positive results were observed for DNA 

strand breaks in cultured human lymphocytes (Rojas et. al, 1996) at high doses of vanadate 

(Ivancsits et. al, 2002) and in cultured human fibroblasts at lower, more environmentally relevant 

doses of vanadate (0.5 μg/L) (Ivancsits et. al., 2002). Positive results have been noted for 
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72

aneuploidy (Ramirez et. al., 1997), and polyploidy (Roldan and Altamirano et. al., 1990). 

Negative results were reported for chromosomal aberrations (Roldan and Altamirano et. al., 

1990). In Chinese hamster V79 lung fibroblast cells, positive results were observed for 

micronuclei formation (Zhong et. al., 1994), altered mitosis (Zhong et. al., 1994), and cell 

transformation in Syrian hamster embryo cells (Kerckaert et al., 1996) at concentrations that 

were not cytotoxic. Negative results were reported for sister chromatid exchanges and gene 

mutations in vanadium pentoxide-treated Chinese hamster V79 firbroblast cells (Zhong et. al., 

1994). 

One study evaluated the genotoxicity of vanadium pentoxide in primary human cell 

cultures. Kleinsasser et. al. (2003) took mucosal biopsies from inferior nasal turbinates and blood 

samples from seventeen healthy volunteers. Isolated lymphocytes and mucosal cells were 

cultured and exposed to 0, 0.06, 0.12, 0.24, and 0.47 mM vanadium pentoxide in vitro for 1hr. 

Mucosal cells and lymphocytes were assessed for DNA migration by the Comet assay. Extent of 

migration was measured qualitatively (image analysis) and quantitatively (“Olive Tail Moment” 

method). DNA migration was not significantly different in exposed human nasal mucosal cells 

compared to controls. However, DNA migration appeared to increase dose-dependently in 

exposed human lymphocytes compared to controls (p = 0.001). Cytotoxicity was limited in both 

cell types at all doses as measured by trypan blue exclusion assay. These results suggest that 

human lymphocytes, but not nasal mucosal cells demonstrate genotoxic damage (single strand 

breaks and/or alkali-labile damage) in response to vanadium pentoxide. 

Experimental data in animals provide evidence of some types of genotoxicity following 

in vivo exposure to vanadium pentoxide. Vanadium pentoxide administered for 3 months by 

inhalation to male and female mice (1, 2, 4, 8 or 16 mg/m3

) did not increase the frequency of 

micronucleated normochromatic erythrocytes in peripheral blood (NTP, 2002). Additional 

details of exposure are provided in the NTP (2002) study summary (see Section 4.2.1.2). 

Genotoxicity was evaluated in male CD-1 mice following single intraperitoneal injections of 

5.75, 11.5 or 23 mg/kg vanadium pentoxide (Altamirano-Lozano et al., 1993, 1996). Exposure 

caused no treatment-related effects on mitotic index, average generational time or sister 

chromatid exchanges in bone marrow cells (Altamirano-Lozano et al., 1993), although all doses 

induced DNA damage in testicular germ cells (Altamirano-Lozano et al., 1996). 

Altamirano-Lozano et al. (1999) assessed DNA damage in male CD-1 mice 24 hrs following 

single intraperitoneal injections of 0, 23.0, 11.5 or 5.75 mg/kg vanadium pentoxide 

(corresponding approximately to the LD50, 1

/2 LD50 and 1/4 LD50, respectively). Comet test 

results show the number of cells with DNA damage (primarily single strand breaks and alkali 
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73

labile damage) was increased in liver, kidney, lung, spleen and heart, although increases did not 

exhibit dose-dependence. No evidence of DNA damage was observed in bone marrow. 

In summary, the evidence for mutagenicity in humans is limited. There are few studies 

examining genotoxicity in humans in vivo, with equivocal results. Ivancsits et. al. (2002) 

reported no differences in DNA strand breaks, oxidative damage, or sister chromatid exchange 

frequency in leukocytes between control and vanadium pentoxide-exposed workers. Ehrlich et. 

al., (2008) noted changes in DNA stability and DNA repair in leukocytes of occupationallyexposed workers as compared to controls. Studies have demonstrated a genotoxic effect of 

vanadium pentoxide on human cells in vitro. Ivancsits et al. (2002) demonstrated significant 

increases in DNA damage as measured by the Comet assay in both leukocytes and fibroblasts but 

with different dose sensitivity, while Kleinsasser et. al (2003) noted DNA migration differences 

occurred dose-dependently in peripheral blood lymphocytes but not in nasal mucosa. Earlier 

studies in human lymphocyte cultures also demonstrated increased aneuploidy (Ramirez et al. 

1997; Rojas et al. 1996) and DNA damage (Roldan and Altamirano 1990) following exposure to 

vanadium pentoxide. Thus, vanadium pentoxide-induced mutagenicity may occur at doses 

higher than those measured in these occupational exposures, may be tissue-specific and may be 

associated with oxidative stress rather than direct DNA damage. 

In vitro tests in bacterial and yeast systems provide mixed evidence of vanadium 

pentoxide-induced mutagenicity. In general, classic gene mutation assays were negative, as 

were tests that assessed sister chromatid exchange and other chromosomal aberrations. DNA 

strand breaks (Rojas et al., 1996; Ivancsits et. al., 2002) and micronuclei formation (Zhong et. 

al., 1994) were indicated in some studies in cultured cells but were dependent on cell type. 

Fibroblasts appear to be more sensitive to vanadium exposure in vitro than are blood cells. 

Similarly, experimental data from animal studies is equivocal. NTP (2002) reported that the 

frequency of micronucleated normochromatic erythrocytes in peripheral blood was not increased 

in exposed compared to control mice. However, a number of studies by Altamirano-Lozano et 

al. (1993, 1996, 1999) have noted DNA damage in specific target tissues in vanadium pentoxidetreated mice. It should be noted that Altamirano-Lozano et al (1993) consistently used 

intraperitoneal injection as the route of exposure for these studies. 
Table 4-12. Genotoxicity Data Following Exposure to Vanadium Pentoxide 

Test System/Species Results Exposure Dose Effects 

In vivo Human 49 exposed male workers at vanadium pentoxide processing plant; 12 nonexposure controls 

_ avg 12.4y not reported - 

exposure confirmed through blood and urine measurements of vanadium 

Genotoxicity measured in isolated lymphocytes and whole blood leukocytes. Study also examined in vitro exposure (below). 

C

_ D

(

_ S

ce

52 exposed workers; 52 non-exposed workers (jail wardens) 

- inhalation not reported - 

8hr shift, protective masks; exposure confirmed through blood levels of vanadium 

Genotoxicity was measured in isolated leukocytes by Comet assay, with no increases in single- and double-DNA strand breaks observed. However, increases were observed in oxidized purines and pyrimidine formation in exposed workers. CBMN Cyt assay demonstrated increased MN induction, nucleoplasmic bridges and nuclear bud formation. Necrosis and apoptosis levels were also increased in 

exposed individuals. 

C

+ M

inon

Laboratory Animals 

Male CD-1 mice (n 

= 4) 

+ intraperitoneal 

injection, 

sacrificed 24h 

post injection 

0, 5.75, 11.5, 

23 μg/g bw 

DNA damage was observed in all tissues examined except for bone marrow. This included liver, kidney, lung, spleen, and heart. 

Male CD-1 mice (n 

= 2) 

+ intraperitoneal 

injection, 

sacrificed 24h 

post injection 

0, 5.75, 11.5, 

23 μg/g bw 

As part of a larger study on reprotoxicity, DNA damage in sperm cells was analyzed. Significant increases were observed in a dose-dependent manner (p <0.05). 

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74
Male CD-1 mice (n 

= 4) 

- intraperitoneal 

injection, 

sacrificed 24h 

post injection 

0, 5.75, 11.5, 

23 μg/g bw 

Analysis of sister chromatid exchange demonstrated no effect of vanadium pentoxide exposure in this 

study. 

B6C3F1 mice (M, F) + inhalation, 

2yr 

0, 1,2, or 4 

mg/m3

DNA was isolated from lung tumros and normal tissue from exposed animals. Of the 20 tumors analyzed, 13 had either K-ras mutations or LOH at chromosome 6 or both. 

B6C3F1 mice (M, F) + inhalation, 

2yr 

0, 1,2, or 4 

mg/m3 Analysis of frequency of micronuclei in peripheral blood normochromatic erythrocytes demonstrated 

on effect of vanadium pentoxide exposure in this study. 

In vitro 

primary human 

lymphocytes 

+ 25 – 500 

μg/L 

V2O5 exposure led to significant increase in DNA migration as measured by Comet assay at the highest doses tested (250 - 500ug/L) for whole blood lymphocytes and leukocytes, and at all doses tested in cultured fibroblasts (p values not given). 

C

primary human 

whole blood 

leukocytes 

+ 

cultured human 

fibroblasts 

+ 

primary human 

lymphocytes 

+ 

0 – 47 mM 

Exposure to vanadium pentoxide led to a dosedependent increase in DNA migration in lymphocytes but not in mucosal cells. 

primary human nasal 

mucosal cells 

- 

primary human 

lymphocytes 

+ 0 - 0.1 μM 

Vanadium pentoxide lead to an increase in aneuploidy with some interindividual variation observed between the four primary cell strains. Disruption of spindle formation may be due to interaction with microtubules. 

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75
primary human 

lymphocytes (n=4) 

+ 

24h 

0.3, 30, 3000 

μM 

Cells exposed to vanadium pentoxide had significantly increased DNA migration at all doses tested in the leukocytes (p < 0.05) and in the high doses in lymphocytes for three of the four donors (p < 0.05). DNA repair occurred generally within in 45 min post-exposure. 

C

primary human 

lymphocytes (n = 1) 

- 

72h 

0, 2, 4, 6 

μg/ml 

Vanadium pentoxide exposed cells had an increase in aneuploidy and a decrease in mitotic index, with no changes in SCE or chromosomal aberrations. 

+ 

Syrian Hamster 

Embryo cells 

+ 0, 24h, 7d 0 to 0.875 

μg/ml 

Vanadium pentoxide exposed cells were positive at 7d exposure but not at 24h, similar to other tumorpromotion chemicals studied by this group. 

tr

Chinese hamster 

V79 cells 

+ 24h 0, 1, 3, 6, 9, 

12 μg/ml 

Vanadium pentoxide exposure led to increased MN induction (p < 0.005), apparently due to damage to the spindle apparatus but no significant increases in mutations or SCE. 

M

- - 

Bacterial systems 

Bacillus subtilis positive 

with and 

without 

activation 

Study details not available. r

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77

Escherichia coli positive 

without 

activation 

(not tested 

with 

activation) 

Study details not available. g

Salmonella 

typhimurium 

Salmonella typhimurium (TA97,TA98,TA100, TA102,TA1535 with or without metabolic activation) 

All strains negative with and without activation (both hamster and rat S9 fractions) 48 h 

0 - 333 μg/plate 

No increase in revertant colonies was observed following exposure. g
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4.5.2 Mechanisms of Inflammation and Fibrosis 

Increases in markers of pulmonary inflammation have been observed in the BAL fluid of 

rats and susceptible mice following intratracheal instillation exposure to vanadium pentoxide 

(Pierce et al. 1996; Bonner et al. 2002). These include macrophage inflammatory protein-2 

(MIP-2), keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and IL-8. Further, the 

increased expression of prostaglandin-generating enzymes cyclooxygenases (COX) and 

prostaglandin E synthases have been associated with exposure to vanadium pentoxide (Bonner et 

al 2002; Pierce et al 1996), further suggesting increased inflammation. 

Pierce et. al. (1996) investigated the ability of several vanadium compounds to increase 

mRNA levels of cytokines in bronchoalveolar lavage (BAL) fluid. Female CD rats received 42 

or 420 μg of vanadium pentoxide or phosphate-buffered saline (PBS) by intratracheal 

instillation. BAL fluid was recovered one hr to ten days after exposure. Significant neutrophil 

influx was observed after 24 hrs exposure to vanadium pentoxide and peaked at 48-hr postexposure with 20% neutrophils. MIP-2 mRNA expression levels were significantly elevated in 

vanadium pentoxide-treated rats compared to controls at early time points (1 hr to 48 hrs) 

suggesting pulmonary inflammation. 

Pro-inflammatory prostaglandins such as PGE2 produced by the enzymes COX-1 and 

COX-2, and PGE synthase mediate tissue homeostasis and/or known to be associated with 

various inflammatory diseases. Bonner et. al. (2002) assessed the role of COX-1 and COX-2 

enzymes in vanadium pentoxide-induced pulmonary inflammatory and fibrotic responses using 

6-8 month-old male and female mice (of a hybrid C57BL/6J and 129/Ola genotype) that were 

deficient in either COX-1 (COX1-/-) or COX-2 (COX2-/-) enzyme. These COX-deficient mice 

and genotype-matched controls (wildtype) were instilled with 50 μL of saline (n = 3 to 4) or 

1mg/kg vanadium pentoxide in saline (n = 5 to 6). Lungs were lavaged at 1, 3, 6, or 15 days 

post-instillation and BAL fluid was collected and analyzed for tumor necrosis factor-alpha 

(TNF-α) and prostanoids (e.g., PGE2) by ELISA. Lungs were removed and preserved for 

histopathology, hydroxyproline assay, or COX immunoblotting. Histopathology showed marked 

inflammation and increased injury in COX2-/- mice compared to wild-type and COX1-/- mice 3 

days following vanadium pentoxide instillation. Hydroxyproline content was not different in 

wildtype or COX1-/- mice in response to vanadium pentoxide compared to saline-instilled 

controls. Hydroxyproline content in vanadium pentoxide-exposed COX2-/- mice was increased 

twofold compared to saline-instilled COX2-/- mice suggesting enhancement of lung fibrosis 

following vanadium pentoxide exposure. PGE2 levels increased from ~500 pg/mL in salineinstilled wildtype mice to ~1000 pg/mL in vanadium pentoxide-treated wildtype mice at 24 hrs 
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but not at other time points. The PGE2 level in saline-treated COX1-/- mice was ~10 pg/mL and 

about ~225 pg/mL after 24 hrs of vanadium pentoxide. PGE2 levels were ~200 pg/mL at 24 hrs 

in saline-treated COX2-/- mice and did not differ significantly from vanadium pentoxide-treated 

COX2-/- mice regardless of time point. This study suggests that vanadium pentoxide-induced 

inflammation may also be at least partially mediated by prostaglandins such as PGE2 generated 

by COX-2. 

Myofibroblasts, the principal proliferating cells that produce collagen, are involved in 

fibrogenic response of lungs following exposure to pulmonary irritants. Bonner et. al. (2000) 

observed that proliferating myofibroblasts were the principle cell type that contributed to the 

observed fibrosis. Male Sprague-Dawley rats weighing ~200 g received intratreacheal 

instillation of sterile saline or 1 mg/kg vanadium pentoxide. Rats were additionally injected with 

BrdU (50 mg/kg, i.p.) one hr prior to sacrifice. Sacrifice occurred at 3, 6, and 15 days after 

vanadium pentoxide instillation. Excised lung tissue was assessed morphometrically and by 

immunohistochemistry for vimentin and desmin, two biomarkers for myofibroblasts and smooth 

muscle cells, respectively. Trichrome staining was used to assess collagen levels, an indicator of 

the extent of fibrosis. Vanadium pentoxide exposure induced thickening of the desmin-positive 

bronchiolar smooth muscle cell layer by day 6 post exposure and were identified as 

myofibroblasts. A 2.3-fold increase in airway smooth muscle cell nuclear profile, suggesting 

increase in smooth muscle cell proliferation was due to hyperplasia. Serial sections of the 

peribronchiolar region stained positive for vimentin and desmin, and were mainly 

myofibroblasts. The thickness of the subepithelial trichrome-positive layer was 3.1-3.9-fold 

higher at day 15 in vanadium pentoxide vs. control samples. The peak appearance of 

peribronchiloar myofibroblasts occurred at day 6 and declined by day 15. A thickened collagen 

ring was apparent by day 15 in vanadium pentoxide-exposed samples compared to controls. 

Rice et. al. (1999) using both in vitro and in vivo models showed that myofibroblasts do 

proliferate in response to vanadium pentoxide, and are dependent on platelet-derived growth 

factor (PDGF) and epidermal growth factor (EGF). Rat lung myofibroblasts were isolated from 

exposed male Sprague-Dawley rats, as stated in Bonner (1998) above, and were grown to 

confluency. Cultures were incubated for 24 hrs with increasing concentrations of one of two 

inhibitors of the PDGF-R (AG1296) and EGF-R (AG1478), respectively, at a concentration of 

100 μmol/L. Autophosphorlyation of PDGF-R and EGF-R in vitro was specifically blocked by 

AG1296 and AG1478, respectively. Tritiated [3

H] thymidine uptake, a measure of mitogenesis, 

was blocked by selective inhibition of PDGF- and EGF- receptors. An in vivo study was carried 

out at the same time. Male Sprague-Dawley rats were treated with AG1296 or AG1478 (50 

mg/kg) by intraperitoneal injection 1 hr prior to intratracheal instillation of vanadium pentoxide 
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(1 mg/kg) and again two days after vanadium pentoxide was administered. Rats were sacrificed 

3, 6, and 15 days after instillation and lungs were preserved for bromodeoxyuridine (BrdU) 

immunohistochemistry and hydroxyproline assays to measure DNA replication and cell division, 

respectively. Quantitation of BrdU-labeled cells in the nuclei of rat lung tissue was significantly 

reduced in vanadium pentoxide-treated animals that had received injections of AG1296 and 

AG1478, compared to vanadium pentoxide treated animals that were injected with vehicle alone. 

 Vanadium pentoxide treatment induced a five-fold increase in lung hydroxyproline content, an 

indicator of lung collagen and potentially fibrosis, 15 days after instillation. Prior and posttreatment with AG1296 reduced hydroxyproline content in vanadium pentoxide-treated animals 

to quantities similar to saline-instilled animals. Pre- and post-treatments with AG1478 reduced 

hydroxyproline content by ~50%, but were still significantly higher than in saline-instilled 

controls. 

Two recent studies examined the mechanism of inflammation in mice (Rondini et al. 

2010; Turpin et al. 2010). Rondini et al (2010) examined the effect of exposure to vanadium 

pentoxide in three mouse strains of varying susceptibility to lung cancer (A/J, BALB/C and 

C57BL/6J) in an initiation/promotion model (full study description in Section 4.2.2.2). 

Significantly higher transcriptional activity was observed for NFkB (A/J mice; peaked at 1 day 

post-treatment) and AP-1 (A/J and B6 mice; peaked at 6 hrs post-treatment) compared to PBScontrols, the activities in the order of A/J mice > B6 mice; in vanadium pentoxide-treated mice. 

 Overall, the differential inflammatory responses observed in the three strains of mice appear to 

positively correlate with increased levels of chemokines, such as keratinocyte-derived 

chemokine (KC) and monocyte chemotactic protein-1 (MCP-1), and increased binding of 

transcriptional factors NFκB and AP-1 (c-Fos), and sustained activation of MAP kinases 

(MAPKs) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) suggesting inflammation 

as a major response in mice. Turpin et al. (2010) examined pulmonary inflammation and fibrosis 

following intranasal aspiration exposure to vanadium pentoxide with and without respiratory 

syncytial virus (RSV) exposure (full study description in Section 4.4.1.2). In this study, 

vanadium pentoxide exposure also caused a significant increase in cell proliferation in the 

airways and lung parenchyma, lung mRNAs for TGF-β-1, CTGF, PDGF-C, Col1A2, and 

mRNAs for IFN-α and -β and IFN-inducible chemokines CXCL9 and CXCL10 compared to 

controls. Pre- or post-treatment with RSV caused a significant reduction in the all mRNAs. 

Together, results from this study showed that vanadium pentoxide induces inflammatory and 

fibrogenic response in mouse lung and these effects were suppressed by RSV infection. 

To elucidate the potential cell signaling cascades associated with these endpoints, AntaoMenezes et. al. (2008) investigated the role of the signaling molecule, signal transducer and 
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activator of transcription (STAT)-1 in vanadium pentoxide-induced pulmonary fibrosis. Their 

work identified another inflammatory molecule, interferon-beta (IFN-β), as a mediator of 

vanadium pentoxide-induced STAT-1 activation in normal human lung fibroblasts. Briefly, 

confluent, quiescent cultures of human lung fibroblasts were either placed in serum-free defined 

medium (SFDM) or SFDM supplemented with 10 μg/cm2 vanadium pentoxide. Neutralizing 

anti-IFN-α and anti-IFN-β antibodies were used to quench activity of IFN-α and IFN-β and the 

ratio of phosphor-STAT-1 to STAT-1 was then measured by quantitative RT-PCR or Western 

blot. Vanadium pentoxide-induced STAT-1 activation could be inhibited by a broad spectrum 

NADPH inhibitor at 24 hr. Vanadium pentoxide induced significant IFN-β expression after 18 

and 24 hrs. This effect was nearly completely abolished by addition of the NAPDH inhibitor. 

Activation of STAT-1 (as measured by a ratio of phosphor-STAT1 to total STAT-1) was 

significantly decreased by addition of neutralizing IFN-β antibodies and also by addition of a 

Janus Associated Kinase (JAK) inhibitor. In summary, STAT-1 was activated in response to 

vanadium pentoxide exposure, and was linked to IFN-β as its primary mediator. This study 

identifies a putative signaling pathway leading to expression of genes that control proliferation 

of myofibroblasts. 

 Ingram et. al. (2007) performed gene array analysis to determine a list of candidate genes 

altered by exposure to vanadium pentoxide. Normal human lung fibroblasts were exposed to 10 

μg/cm2

 vanadium pentoxide or saline in vitro. RNA from cells was harvested 1, 4 8, 12, and 24 

hrs post-treatment. Labeled cRNA hybridized to the Affymetrix Human Genome Array U133A 

2.0 gene chip was used to assess gene expression at various time points up to 24 hrs of exposure. 

 About 300 genes were found to be upregulated in response to vanadium pentoxide including 

inflammatory and immunomodulatory genes. Over 1,000 genes were downregulated in response 

to vanadium pentoxide including genes from the ubiquitin cycle and cell cycle genes. A dozen 

genes were confirmed by RT-PCR and included growth factors (heparin-binding EGF-like 

growth factor [HB-EGF], vascular endothelial cell growth factor [VEGF], and connective tissue 

growth factor [CTGF]), chemokines (IL-8, CXCL9, CXCL10), oxidative response genes 

(superoxide dismutase [SOD]2, pipecolic acid oxidase [PIPOX], oxidative stress response 

[OXR]1) and DNA-binding proteins (growth arrest specific [GAS]1, STAT1). The gene array 

analysis thus confirms that a number of mitogens, growth factors, chemokines, cytokines, 

oxidative response genes, and DNA-binding proteins are all critical to the formation of 

fibroproliferative lesions in response to vanadium pentoxide exposure in vitro (Figure 4-1). 
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Figure 4-1: Genomics of V2O5-Induced Bronchitis (reprinted with permission from Ingram 

et al., (2007) Respir. Res. Apr 25;8(1):34) 

Together, these results indicate that proliferating myofibroblasts are the primary cell type 

associated with vanadium pentoxide-induced pulmonary fibrosis, and that cellular proliferation 

depends on activated mitogens such as PDGF and EGF, in addition to HB-EGF. The STAT-1 

and MAPKinase pathways may play key roles in this process. Moreover, fibroproliferative 

lesions contain collagen. 

4.5.3 Mechanisms of Hyperplasia and Carcinogenicity 

Molecular events underlying the mechanism of reparative hyperplasia and carcinogenesis 

have been documented. Bonner et. al. (1998) exposed male Sprague-Dawley rats to vanadium 

pentoxide or sterile saline by intratracheal instillation at 1 mg/kg. Animals were sacrificed at 3, 

6 and 15 days after instillation. Lungs were preserved and analyzed for PDGFR-α by 

immunohistochemical analysis and morphometry for fibroproliferative lesions. Smooth muscle 

thickening was observed beneath ciliated epithelial cells, as indicated by increased desmin 

localization, on day 6 in exposed samples. Trichrome staining revealed increased collagen 

deposition around bronchioles in vanadium-pentoxide exposed samples. The thickness of the 

subepithelial layer increased by 3.1 to 3.9 fold at day 15 after instillation of vanadium pentoxide, 

determined by morphometric techniques. 

Platelet-derived growth factor (PDGF) is a mitogen and chemoattractant for fibroblasts. 
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Male Sprague-Dawley rats were intratracheally instilled with sterile saline or 2 mg/kg of 

vanadium pentoxide (Bonner et al 1998). Tissues were harvested at 24, 48, and 72 hr post 

exposure as well as at 6 and 15 days. Pulmonary myofibroblasts and alveolar macrophages were 

isolated. Isolated total lung RNA was assessed for quantitation of PDGF by Northern blot 

analysis. PDGF-receptor alpha mRNA and protein expression were significantly elevated in 

vanadium pentoxide exposed animals compared to controls at 24 and 48 hrs. PDGF-receptor 

beta was not significantly elevated over controls at any time points. Confluent cultures of lung 

myofibroblasts were stimulated with vanadium pentoxide. Similarly, cultures of lung 

macrophages were stimulated with vanadium pentoxide. Levels of PDGF in myofibroblasts 

were not affected by direct stimulation by vanadium pentoxide, but were affected by a factor 

released by vanadium pentoxide stimulated macrophages, and were associated with interleukin 

(IL)-1B, an inflammatory cytokine. Together, these results suggest that hyperplasia occurs 

under the control of inflammatory mediatiors such as IL-1B that can recruit mitogens such as 

PDGF that can stimulate growth of myofibroblasts, the main cell type involved in the 

development of fibrotic lesions. 

Zhang et al (2001a) investigated the ability of vanadium pentoxide to induce heparinbinding epidermal growth factor-like growth factor (HB-EGF) (another mitogen) in vitro, using 

normal human bronchial epithelial cells (NHBECs). Mature cultures of NHBECs were 

incubated with vanadium pentoxide at 0, 1, 10 and 50 μg/cm3

 for 3 hrs. Total RNA was then 

isolated and RT-PCR was used to quantitate HB-EGF. HB-EGF mRNA was significantly and 

dose-dependently increased in response to vanadium pentoxide compared to controls. In a 

second time course study, (using only the high dose 50 μg/cm3 of vanadium pentoxide) the peak 

of HB-EGF induction occurred after 3hrs of exposure and persisted until 8 hrs of exposure. 

In a follow-up study, Ingram et al. (2003) similarly showed a peak induction of HB-EGF 

in quiescent cultured human lung fibroblasts exposed to 10 μg/cm2 vanadium pentoxide at 3 hrs. 

 Quiescent cultured human lung fibroblasts were exposed for 3 hrs to 0, 10, 30 or 100 μg/cm2

vanadium pentoxide. HB-EGF RNA was isolated and detected by Northern blot. HB-EGF was 

significantly elevated in a dose-dependent manner in vanadium pentoxide-exposed fibroblasts 

compared to controls. Stimulating human lung fibroblasts with H2O2 (10 μM) similarly induced 

HB-EGF, with a peak mRNA expression at 1hr post exposure. HB-EGF protein expression 

peaked at 6 hr post--exposure, as measured by Western blot. Quiescent human lung fibroblasts 

stimulated with 10 μg/cm2

 vanadium pentoxide were found to initially quench spontaneous H2O2

production (at early time points) and then boost H2O2 production at a peak of 12 hrs post 

exposure. To assess the role of extracellular signal-regulated protein kinase (ERK), and the p38 

subunit of mitogen-activated protein (MAP) kinase in vanadium pentoxide induced HB-EGF 
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production, Ingram et al (2003) exposed quiescent confluent human lung fibroblast cells in 

culture to 500 μM H2O2 or 10 μg/cm2 vanadium pentoxide for 15 min, 30 min, 1 hr, 3 hr, 6 hr or 

24 hr. Cell lysates were collected and Western blot was performed for the phosphorylated form 

of ERK or total ERK protein or for the phosphorylated p38 subunit of MAPkinase and total p38. 

 Peak phosphorylated ERK occurred at 30 min post exposure to H2O2. Vanadium-induced 

increases to p-ERK were biphasic, with one peak at 30 min post-exposure and the next at 24 hr 

post-exposure. Phosphorylated p38 was similarly maximally elevated at 30 min post-treatment 

with H2O2 and 24 hrs post treatment with vanadium pentoxide. Thus, this study suggests that 

HB-EGF expression occurs as a result of activation of the MAPKinase and ERK pathways. 

NTP (2002) and Ress et al. (2003) concluded that exposure to vanadium pentoxide 

caused alveolar and bronchiolar adenomas and carcinomas in male and female mice and there is 

some evidence of carcinogenicity in male rats, based on observations of alveolar and bronchiolar 

neoplasms in groups exposed to vanadium pentoxide that exceeded historical controls. The body 

of evidence that has investigated the mode of action (MOA) underlying cancer effects due to 

exposure of vanadium pentoxide is not as well characterized as mechanisms underlying noncancer fibrotic effects. However, loss of heterozygosity (LOH) and DNA damage has been 

documented. 

Using mouse lung tumor tissues from the NTP (2002) chronic inhalation study from mice 

exposed to 0, 1, 2 or 4 mg/m3

 vanadium pentoxide, Zhang et. al. (2001b), observed LOH on 

chromosome 6 (in the region of the K-ras gene) in 17 of 19 vanadium pentoxide-induced mouse 

tumor samples. Moreover, 29 of 40 (73%) vanadium pentoxide-induced murine 

adenocarcinomas from the 2002 NTP study had mutations in Kras2. The Kras2 mutations 

typically were the result of either a GAÆAT transition or a GAÆTA transversion in the second 

base of codon 12 (Zhang et. al., 2001b). To determine the effect of the K-ras mutations and 

LOH on activated MAP kinase, Devereux et al (2002), used tissues from the NTP (2002) 2-year 

carcinogenicity study in female and male B6C3F1 mice to isolate protein from 17 vanadium 

pentoxide-induced alveolar and bronchiolar carcinomas, one spontaneous carcinoma, and two 

normal (untreated) lung tissue samples. Levels of total MAP kinase and activated MAP kinase 

were assessed by probing isolated lung protein for total and phosphorylated MAP kinase with 

anti-phospho-MAP kinase antibody in all samples. Only qualitative analysis was reported. 

Total MAP kinase was not different between normal tissue and lung tumor tissue. Activated 

MAP kinsase was elevated in five of six tumors that had both LOH and K-ras mutations, and 

was barely detectable in all seven tumors examined where no K-ras mutations were detected. 

Four of five tumors with K-ras mutations but were not positive for LOH had elevated 

phosphorylated MAP kinase levels. However, these results should be interpreted cautiously as 
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85

LOH was difficult to detect due to interference from infiltrating lymphocytes. In summary, 

mouse tumor tissue excised from mice used in the NTP 2002 study showed LOH in the region of 

the k-ras oncogene location in 17 or 19 samples tested. However, the signaling events, and 

specifically the role of the MAPkinase pathway, associated with this oncogenic mutation remain 

unclear. 

Pierce et al. (1996) identified proinflammatory cytokines associated with vanadium 

pentoxide exposure. Pierce et al. (1996) reported increased mRNA expression of macrophage 

inflammatory protein (MIP-2) and keratinocyte-derived cytokine (KC) in bronchiolar lavage 

(BAL) fluid in vanadium pentoxide-treated female CD rats compared to controls at early time 

points (1 hr to 48 hrs). 

In summary, hyperplastic responses following exposure to vanadium pentoxide are 

associated with increased expression of various mitogens such as PDGF and HB-EGF. 

Moreover, PDGF activation may be dependent on inflammatory mediators such as IL-1B. HBEGF expression is dependent on activation of the MAPKinase and ERK signaling pathways. 

No information is available concerning the rat neoplasm data. Indeed, the marginal increase in 

lung neoplasms observed in female rats was not statistically significant. It is not known whether 

lung neoplasms from male rats exhibit elevated activated MAP kinase or whether the rat tumors 

have increased K-ras mutation and LOH on chromosome 6. 
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4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS 

4.6.1. Oral 

 Limited studies have been published examining the effects following oral exposure to 

vanadium pentoxide. Table 4-13 presents a summary of the noncancer results for the subchronic 

and chronic oral studies of vanadium pentoxide toxicity in experimental animals. 

4.6.1.1 Acute 

The only acute studies available report oral LD50 values in rats that range from ~10-137 

mg/kg body weight and 64 mg/kg-body weight in mice depending on the source (Yao et. al., 

1986b and CICAD 29, 2001). Clinical signs of toxicity included lethargy, excessive tearing 

(lacrimation), and diarrhea. Histopathological analysis revealed liver necrosis and swelling of 

renal tubules. No acute dose-response studies are available for any animal species. 

Table 4-13: Summary of Noncancer Results of Repeat-Dose Studies for Oral Exposure of 

Experimental Animals to Vanadium Pentoxide 

Species 

(sex) 

Avg Daily 

Dose 

(mg/kg-day) 

Exposure 

Duration 

and 

Route 

Response 

at LOAEL 

NOAEL 

(mg/kgday) 

LOAEL 

(mg/kg/day)

Comments Reference

Wistar 

Rat 

(male) 

0, 10.5, 

16.4, 69.6, 

141.0 

mg/kg-day 

(correspond

s to 0, 74.5a

, 

116.1b

, 500 

and 1000 

ppm) 

103days 

in food 

Decreased 

erythrocyt

e count 

10.5 

mg/kgday 

16.4 mg/kgday Dietary 

exposure 

was 

increased 

at day 35 

of study 

(from 25 to 

100 and 

from 50 to 

150 ppm) 

(See notes 

below) 

Mountain 

et al., 

1953 

0, 10.5, 

16.4, 69.6, 

141.0 

mg/kg-day 

(correspond

s to 0, 74.5a

, 

116.1b

, 500 

and 1000 

ppm) 

103 days 

in food 

Decreased 

relative 

liver 

weight 

-- 69.6 mg/kgday 
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87

Table 4-13: Summary of Noncancer Results of Repeat-Dose Studies for Oral Exposure of 

Experimental Animals to Vanadium Pentoxide 

0, 10.5, 

16.4, 69.6, 

141.0 

mg/kg-day 

(correspond

s to 0, 74.5a, 

116.1b

, 500 

and 1000 

ppm) 

103 days 

in food 

Decreased 

Hair 

Cystine 

10.5 

mg/kgday 

16.4 mg/kgday 

Rat 

(male) 

1.41 and 

14.1 mg/kgday 

(correspond

s to 17.9 and 

179 ppm) 

2.5 yrs in 

food 

Decreased 

Hair 

Cystine 

1.41 

mg/kgday 

14.1 mg/kgday Study 

published 

in Patty’s 

Industrial 

Hygiene 

and 

Toxicology 

3rd ed. 

1981 

Original 

data not 

available. 

Stokinger 

et. al., 

1953 

a

 Represents an average dose based on 25 ppm for 35 days, and 100 ppm for 68 days 

b

 Represents an average dose based on 50 ppm for 35 days and 150 ppm for 68 days. 

. 

 
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4.6.1.2 Subchronic 

Data on toxicity following subchronic oral exposure to vanadium pentoxide are 

extremely limited. No comprehensive studies outlining toxic effects in response to vanadium 

pentoxide in humans have been reported. The primary noncancer health effects of subchronic 

oral exposure in animals include changes in relative liver weight, decreased erythrocyte count 

and hemoglobin counts, and decreased hair cystine content (Mountain et. al., 1953) in rats. 

Erythrocyte count and hemoglobin decreases are correlated and cannot be considered as separate 

effects. The hematological parameters were measured at low dose exposure levels. Relative 

liver weights were only measured for control and in the highest dose (69.6 mg/kg-day) group. 

Changes in hair cystine were measured in all dose groups but the biological significance of this 

effect is unknown; changes in hair cystine content may serve as a biomarker of exposure, rather 

than as an indication of an adverse effect. From these data, and using standard conversions for 

body weight and food consumption for Wistar rats, the NOAEL of 74.5 ppm was converted to 

10.5 mg/kg-day for decreased erythrocyte count. 

4.6.1.3 Chronic 

 No studies reporting chronic exposure to vanadium pentoxide in humans are available in 

the published literature. Chronic animal studies evaluating effects of oral exposure to vanadium 

pentoxide are limited. Previously, a study based on a 2.5 yr dietary exposure to vanadium 

(Stokinger et. al., 1953 reported in Patty’s Industrial Hygiene and Toxicology, 3rd Ed., 1981.) 

utilized hair cystine as the critical effect, since hair cystine was significantly decreased (no 

details provided regarding the percent decrease or dose-response) in exposed rats and this change 

may reflect changes to enzymatic pathways. However, comprehensive toxicity endpoints were 

not evaluated, and the number and strain of rats used was not reported in this 1953 study. 

Decreased hair cystine may or may not be a biologically relevant effect. Decreased hair cystine 

may not be related to vanadium exposure, but rather an effect of poor nutritional status, as a 

result of an aversion to vanadium pentoxide in the feed. EPA has been unable to gain access to 

the raw data. No additional oral chronic exposure studies in animals were identified in the 

literature. 

4.6.2. Inhalation 

 Table 4-20 presents a summary of the noncancer results for the acute subchronic and 

chronic studies of vanadium pentoxide toxicity in humans and experimental animals. The 
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identified noncancer health effects following occupational exposure to vanadium pentoxide in 

humans include respiratory irritation, airway obstruction, chest pain, bronchitis and similar 

effects; inhalation exposure in animals results in multiple health effects, including pulmonary 

inflammation, lung and nasal hyplerplasia, pulmonary fibrosis, changes in nervous system 

structure and function, and reproductive/developmental effects (Table 4-14). The most 

comprehensive animal studies evaluated toxicity following inhalation of vanadium pentoxide in 

F344/N rats and B6C3F1 mice (NTP, 2002); these studies included acute, short-term, subchronic 

and chronic duration exposures and multiple toxicological endpoints. In those studies, the lung 

was identified as the most sensitive organ. The reported neurotoxic effects appear after as little 

as a single one hour exposure to inhaled vanadium pentoxide; although multiple effects were 

identified that increased in severity with increased duration of exposure, the studies were 

conducted using only one exposure level. Thus, a no-effect level for neurotoxicity could not be 

determined. Major data gaps also exist for studies on developmental toxicity, reproductive 

toxicity, and immunotoxicity following inhalation exposure to vanadium pentoxide, although 

effects have been seen in available studies (some of which used an exposure paradigm similar to 

that used for neurotoxicity studies). 

4.6.2.1 Acute and Short-term 

 The primary identified noncancer health effect following acute inhalation exposure in 

humans is respiratory irritation, cough, and mucus formation. A human controlled exposure 

study (n = 100) performed by Zenz and Berg (1967) reported respiratory irritation, cough, and 

mucus formation in humans exposed to vanadium pentoxide at 0, 0.1, 0.5, and 1.0 mg/m3

, for 8 

hrs. A NOAEL of 0.5 mg/m3

 was established. These effects are confirmed in male monkeys 

exposed to vanadium pentoxide at 0.5 or 5.0 mg/m3

 for 6 hrs (Knecht et. al., 1985). Air flow 

restriction, as measured by pulmonary function tests, was reported at 5.0 mg/m3 (LOAEL); the 

NOAEL was 0.5 mg/m.3 Moreover, a WHO-IPCS (CICAD) document (2001) reports a 1-hr 

inhalation exposure to vanadium pentoxide dust in rats led to an LC67 of 1.44 mg/L (1440 

mg/m3

). Clinical signs of toxicity included respiratory difficulty, increased respiratory tract 

mucus production, and irritation of the eyes, nose, and throat (WHO-IPCS, 2001, section 11.1.1). 

 Neurotoxicity has also been observed in mice following a single inhalation exposure; AvilaCosta et al. (2006) noted significant changes in brain morphology and impairment in memory in 
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90

male CD-1 mice compared to controls following a single 1 hr exposure to 0.02 M (2.5 mg/m3 V 

) inhaled vanadium pentoxide. 

Respiratory irritation was observed following short-term inhalation exposure in humans. 

100 workers were reportedly exposed to 0.05 to5.3 mg/m3

 vanadium for 10 hr/day, 6 days/week, 

for 4 weeks (Levy et al., 1984). A LOAEL of 0.05 mg/m3

 was established. However, doseresponse was not systematically measured, there were no controls, and exposure to vanadium 

pentoxide could not be directly correlated to effects. The primary noncancer health effects of 

short term inhalation exposure in animals include increased pulmonary inflammation, and doserelated decreases in body weight and relative lung weight in rodents (NTP, 2002). 

4.6.2.2 Subchronic 

No comprehensive subchronic studies have evaluated inhalation effects in humans. The 

primary noncancer health effects of subchronic inhalation exposure in animals include 

nonneoplastic lung and nasal lesions (NTP, 2002), hematological parameter changes (NTP, 

2002), decreased pulmonary function in male monkeys (Knecht et al., 1992), morphological 

changes to the CNS (Avila-Costa et al., 2004; 2005; 2006), increased platelet counts (GonzalezVillalva et al., 2006), and testicular malformation (Mussali-Galante et al., 2005; Fortoul et al., 

2007). The NTP (2002) study evaluated pulmonary and nasal endpoints in both male and female 

rats and mice after 3 months exposure to vanadium pentoxide at 0, 1, 2, 4, 8 and 16 mg/m3

. 

Lung inflammation, lung hyperplasia and increased relative lung weight were observed at similar 

low doses in rats and mice. A LOAEL of 2.0 and NOAEL of 1.0 mg/m3

 were established. In 

addition, rats exhibited bronchiolar exudates, microcytic erythrocytosis, lung fibrosis, and nasal 

lesions. Associated LOAELs and NOAELs were established and are listed in Table 4-20. Body 

weight loss and increased absolute lung weight were reported in mice and resulted in a LOAEL 

of 8.0 mg/m3

 and NOAEL of 4.0 mg/m3. An increased absolute and relative lung weight 

LOAEL was set at 4.0 mg/m3

 and 2.0 mg/m3 for these lesions observed in mice. In summary, 

rats appear to be more sensitive to inhalation exposure to vanadium pentoxide than mice, based 

on the occurrence of a wider variety of nonneoplastic lesions throughout the respiratory tract. 

Knecht et. al. (1992) observed that inhaled vanadium pentoxide leads to adverse lung 

effects by measuring decreased pulmonary function in male monkeys exposed to vanadium 

pentoxide at 0.1, 0.5, or 1.1 mg/m3

 for 26 weeks (6 hrs/day, 5 days/week). A LOAEL of 0.5 

mgm3

 and a NOAEL of 0.1 mg/m3 was established. Pulmonary function parameters were 

reversible and did not repeat following subsequent challenge. 

Selected hematology parameters (number of erythrocytes and reticulocytes and percent 
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91

hematocrit) were significantly altered in male and female rats at the highest dose level (NTP, 

2002). A LOAEL of 16.0 mg/m3 and a NOAEL of 8.0 mg/m3 were established. Other effects 

such as increased platelet count following 12 weeks and altered testicular morphology following 

20 weeks were tested at only one dose (5.13 mg/m3

). 

4.6.2.3 Chronic 

 Limited information is available specific to the vanadium pentoxide exposure levels in 

human studies. Respiratory and other symptoms have been documented among workers 

employed at facilities producing and processing vanadium pentoxide (Sjoberg, 1951; Sjoberg, 

1956; Zenz et al., 1962; Kiviluoto et al., 1979; Kiviluoto, 1980; Kiviluoto et al., 1981a; Musk 

and Tees, 1982; Irsigler et al., 1999). Similar effects were observed in occupational studies of 

boilermakers involved in the construction, cleaning and maintenance of oil-fired boilers 

(Williams, 1952; Sjoberg, 1955; Lees, 1980; Ross, 1983; Levy et al., 1984; Hauser et al., 1995a; 

1995b; 2001; Woodin et al., 1998; 1999; 2000; Kim et al., 2004). Noncancer health effects of 

chronic inhalation exposure in animals included nonneoplastic pulmonary lesions in male and 

female rats and mice exposed to vanadium pentoxide for 2 yrs at 0, 0.5, 1.0 and 2.0 mg/m3

 and 0, 

1.0, 2.0, and 4.0 mg/m3

, respectively (NTP, 2002). Increased incidence of alveolar and 

bronchiolar epithelial hyperplasia in male rats, alveolar histiocyte infiltration, laryngeal 

inflammation, and epiglottis epithelial degeneration, hyperplasia, and squamous metaplasia in 

male and female rats, and goblet cell hyperplasia in nasal compartments in male rats were 

reported. Based on these findings, the lowest dose for which a LOAEL could be established in 

rats was 0.5 mg/m3. Additional findings observed in females included increased interstitial 

fibrosis. No NOAEL was established. In both male and female mice, increased incidences of 

pulmonary inflammation, and hyperplasia were reported. Increased incidences of nasal olfactory 

and/or respiratory epithelium degeneration, and epiglottis metaplasia were reported 1.0 mg/m3 

(LOAEL) in both male and female mice. The lung fibrosis and nasal inflammation were noted at 

≥ 2 mg/m3

 in both sexes. In general, the incidence and severity of pulmonary lesions increased 

with increasing dose. No treatment-related histopathological lesions were observed in other 

evaluated tissues. Interstitial fibrosis was significantly elevated in exposed male and female 

mice compared to controls at 2 and 4 mg/m3

. No treatment-related findings were observed in 

other tissues. 
Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide 

Species 

(sex) 

Avg 

Daily 

Dose 

(mg/m3) 

Exposure 

Duration 

Response at LOAEL NOAEL 

(mg/m3) 

LOAEL 

(mg/m3) 

Commen

Acute Exposure 

Monkey (male) 

0.5 or 5.0 mg/m3

6 hrs (single exposure) 

Air-flow restriction (measured by pulmonary function tests) 

0.5a 5.0 

Human (not reported) 

0, 0.1, 0.5, 1.0 mg/m3

8 hrs (single exposure) 

Respiratory irritation, cough, mucus formation 

0.5 1.0 Small sample siz

Mouse (male) 

2.56 mg/m3

1 hr (single exposure) 

Impaired performance in spatial memory, decreased dendritic spines increased percentage of necrotic cells in hippocampus 

--- 2.56 Only one dose te

Short-term Exposure 

Rat and mice (female) 

0, 1, 2, 4 mg/m3

13 days, 6 hrs/day, 5 days/week 

Histiocytic infiltrate and lung inflammation (rats); alveolar and bronchial hyperplasia (mice) 

-- 1.0 

(rats) 2.0 (mice) 

No study performmale rats or mic

Rat (male) 

0, 4, 8, 16, 32 mg/m3

16 days, 6 hr/day, 5 day/week 

BALFluid analysis: increased neutrophilia and decreased macrophage infiltration Significant increase in total cell count 

8.0 4 

16.0 8 

Sample size = 22 Rats exposed to were emaciated, rats died in the 3

group, 

Mouse (male) Mouse (female) 

0, 2, 4, 8, 16, 32 mg/m3

16 days, , 6 hr/day, 5  day/week 

Absolute lung weight Relative lung weightDecreased percentage of macrophages in BAL Fluid 

2.0 --4.0 

4.0 2.08.0 

Sample size = 5 sex. All male mi32 mg/m3Sample size 40-6

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Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide 

Increased protein leakage into BAL Fluid and increased lymphocytes 

- - 4.0 Females only. 

Mouse (male) 

2.56 mg/m3

30 days (1 hr, 2 times a week for up to 4 weeks) 

Changes in matrix metalloproteinase levels in multiple regions of the brain 

-- 2.56 Signficant increa

occurred after 1 exposure. Only olevel was used. 

Human (not reported) 

Range of 0.05 to 5.3 mg/m3

4 weeks, 10 hr/day, 6 days/week 

Respiratory irritation -- 0.05b Dose and respon

not systematicalmeasured, vanadpentoxide exposaccurate 

Subchronic Exposure 

Mouse (male) 

2.56 mg/m3

8 weeks, 1 hr, 2 times/week 

Morphological changes to CNS (cilia loss, increased cell sloughing, ependymal cell layer detachment, decreased dendritic spines in hippocampus and substantia nigra, increased cell loss, decreased performance in Morris water maze) 

--- 2.56 No clinical signs 

toxicity or other toxicologic endpwere reported 

Mouse (male) 

2.56 mg/m3

12 week,(1 hr/day, 2 days/weeks) 

Increased platelet counts and altered platelet morphology 

-- 2.56 

Mouse (male) 

2.56 mg/m3

12 weeks (1 hr 2 times per week) 

Decreased gamma globulin in testes, Increased cell death in spermatogonia 

-- 2.56 Only one dose u

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Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide 

Monkey (male) 

0.1, 0.5, or 1.1 mg/m3

26 weeks (6 hrs per day, 5 days per week) 

Impaired pulmonary function 0.1 0.5 Exposures occur

alternate days foof animals (som0.1 or 1.1 mg/malternate days, wsecond group waexposed to a conconcentration (0mg/m3) for all 5 Pulmonary functparameters were reversible and direappear followisubsequent chall26 animals totalper group. 

Rat (both) and mouse (both) 

0, 1, 2, 4, 8, 16 mg/m3

3 months (6 hr/day, 5 days/week) 

Lung hyperplasia 1.0 2.0 

Rat (both) 0, 1, 2, 4, 

8, 16 mg/m3

3 months (6 hr/day, 5 days/week) 

Lung fibrosis 2.0 4.0 

Rat (male) 

Microcytic erythrocytosis, lung inflammation, and , lung epithelial hyperplasia, 

1.0 2.0 

Mouse (male) 

0, 1, 2, 4, 8, 16 mg/m3

3 months (6 hr/day, 5 days/week) 

Lung inflammation 2.0 4.0 

Mouse (female) 

1.0 2.0 

Rat 0, 1, 2, 4, 3 months (6 Nasal hyperplasia and 4.0 8.0 

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Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide 

(male) 8, 16 

mg/m3

hr/day, 5days/week) 

squamous metaplasia, body 

Rat weight gain (female) 

2.0 4.0 

Rat  and mouse (male) Rat and Mouse (female) 

0, 1, 2, 4, 8, 16 mg/m3

3 months (6 hr/day, 5 days/week)

Body weight loss 4.0 

2.0 

8.0 4.0 

Rat and Mouse (male) Rat and Mouse (female) 

0, 1, 2, 4, 8, 16 mg/m3

0, 1, 2, 4, 8, 16 mg/m3

3 months (6 hr/day, 5 days/week) 3 months (6 hr/day, 5 days/week) 

Increased Relative lung weight Increased absolute lung weight 

2.0 1.0 2.0 

4.0 2.0 4.0 

Rat (both) 0, 1, 2, 4, 

8, 16 mg/m3

3 months (6 hr/day, 5 days/week) 

Increased levels of hematological parameters 

8.0 16.0 

Chronic Exposure 

Rat (male) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung hyperplasia, histiocytic infiltration, epiglottis degeneration, , hyperplasia and squamous metaplasia, chronic inflammation of the larynx, , goblet cell hyperplasia 

-- 0.5 No other clinica

or altered surviv

Rat (female) 

Interstititial fibrosis, and histiocytic infiltration, epiglottis degeneration, hyperplasia, and squamous 

-- 0.5 

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Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide 

metaplasia, chronic inflammation of the larynx 

Rat (female) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung inflammation 1.0 2.0 No other clinica

or altered surviv

Rat (female) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung hyperplasia 0.5 1.0 No other clinica

or altered surviv

Mouse (both) 

0, 1, 2, 4 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung inflammation, and hyperplasia 

-- 1.0 Mice reported as 

survival significdecreased in ma4 mg/m3

Rat (female) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung squamous metaplasia of alveolar and bronchiolar epithelium 

1.0 2.0 No other clinica

or altered surviv

Rat  (male) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung fibrosis 0.5 1.0 No other clinica

or altered surviv

Mouse (both) 

0, 1, 2, 4 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Lung fibrosis 1.0 2.0 Mice reported as 

survival significdecreased in ma4 mg/m3

Rat (male) 

0, 0.5, 1, 2 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Nasal olfactory degeneration and respiratory degeneration 

0.5 No other clinica

or altered surviv

Mouse (both) 

0, 1, 2, 4 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Nasal inflammation 1.0 2.0 

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Table 4-14: Summary of Noncancer Results of Repeat-Dose Studies for Inhalation Exposure of Vanadium Pentoxide Mouse (both) 

0, 1, 2, 4 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Nasal olfactory degeneration and respiratory degeneration 

- - 1.0 

Mouse (both) 

0, 1, 2, 4 mg/m3

2 yrs (6 hr/day, 5 days/week) 

Epiglottis metaplasia -- 1.0 

a Single exposures not adjusted for continuous exposure b Not adjusted for continuous exposure because of the highly intermittent exposure protocol (1 hr/day, 2 days/week) 
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4.6.3 Mode of Action Information 

There is currently insufficient evidence to establish the mode of action for vanadium 

pentoxide toxicity. However, the limited data to inform the mechanisms of various non-cancer 

health effects (pulmonary toxicity, neurotoxicity and reproductive toxicity) following inhalation 

exposure to vanadium pentoxide are summarized below. 

4.6.3.1 Pulmonary Toxicity 

The mechanism of action underlying the formation of pulmonary fibroproliferative 

lesions has been linked to inflammation, leading to regenerative hyperplastic responses, as 

evidenced by the presence of mitogens and observed smooth muscle thickening. Oxidative 

stress has also been implicated. Oxidative stress induced directly or indirectly by vanadium 

pentoxide may work in combination with vanadium pentoxide-induced inflammatory responses 

to activate signaling molecules such as ERK 1 or 2 and p38 kinase that lead to induction to 

growth factors and generation of fibrotic lesions. These potential modes of action are supported 

by a limited number of mechanistic analyses of inflammation and fibrosis following exposure to 

vanadium pentoxide. 

Inflammation. Pierce et. al. (1996) identified proinflammatory cytokines associated with 

vanadium pentoxide exposure. Oxidative stress has been implicated in the mechanism 

underlying vanadium pentoxide induced pulmonary injury. All species of vanadium may 

participate in redox cycling and can generate reactive oxygen species (Carter et. al.1997). 

Intracellular and extracellular H2O2 production increases significantly after 18 hr exposure to 

vanadium pentoxide compared to controls (Antao-Menezes et. al. 2008). Vanadium pentoxide 

induced significant IFN-β expression after 18 and 24 hrs but could be inhibited by catalase, an 

inhibitor of H2O2. Oxidative stress was also a suggested mechanism underlying STAT-1 

activation, since addition of either an NAPDH inhibitor or a xanthine oxidase inhibitor ablated 

STAT-1 activation in cells exposed to vanadium pentoxide (Antao-Menezes et. al. 2008). 

Moreover, spontaneous hydrogen peroxide generation by fibroblasts was depleted within 

minutes by addition of vanadium pentoxide (Ingram et. al. 2003). In addition, vanadium can 

contribute to inhibition of protein tyrosine phosphatases through the generation of reactive 

oxygen species (Zhang et. al. 2001). It is possible that hydrogen peroxide and vanadium 

pentoxide reacted to form peroxovanadium intermediates and/or ROS that led to the production 

of HB-EGF in fibroblasts. Oxidative stress could also be inducing ERK and p38 kinase that lead 
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99

to the production of HB-EGF (Ingram et. al. 2003) or by ROS-mediated competitive inhibition 

of protein tyrosine phosphatases (Zhang et. al., 2001, Samet et. al., 1999). Gene array analysis 

and subsequent confirmation by PCR revealed that various oxidative stress genes such as 

superoxide dismutase (SOD2), pipecolic acid oxidase (PIPOX), and oxidative stress response 

(OXR1) were altered by vanadium pentoxide exposure (Ingram et. al., 2007). Thus vanadium 

pentoxide-mediated production of ROS may lead to oxidative stress and induce downstream 

signaling events that result in activation of mitogens and proinflammatory cytokines that 

contribute to the formation of fibroproliferative lesions in the lung. 

Fibrosis. Bonner et al. has published numerous studies describing the mechanism 

underlying the formation of fibroproliferative lesions in response to vanadium pentoxide 

exposure. Specifically, smooth muscle thickening and increased collagen deposition was 

observed beneath ciliated epithelial cells in vanadium pentoxide-exposed male Sprague-Dawley 

rats (Bonner et. al. 1998). Further, proliferating myofibroblasts were the principle cell type that 

contributed to the observed fibrosis (Bonner et. al. 2000). Using both in vitro and in vivo

models, Rice et. al. (1999) showed that inhibition of autophosphorylation of tyrosine kinases 

reduced vanadium pentoxide-induced pulmonary fibrosis, thus implicating the tyrosine kinases 

as key signaling mediators underlying the mechanism of PDGF release and ultimately, 

fibrinogenesis. 

Zhang et. al. (2001) and Ingram et. al. (2003) identified a second mitogen, heparinbinding epidermal growth factor-like growth factor (HB-EGF) as an important mediator of 

vanadium pentoxide-induced injury in vitro in normal human bronchial epithelial cells 

(NHBECS). Further, two signaling molecules (ERK and the p38 subunit of MAPkinase) were 

activated in response to vanadium pentoxide (Ingram et. al. 2003). Gene array analysis 

confirmed the importance of HB-EGF and IL-8 in vanadium pentoxide-induced lung injury and 

identified several new candidate genes including growth factors (VEGF, and CTGF), 

chemokines (CXCL9, CXCL10), oxidative response genes (SOD2, PIPOX, OXRI) and DNAbinding proteins (GAS1, STAT1) (Ingram et. al., 2007). 

Bonner et. al. (2003) has also reported that fibroproliferative lesions are resolved and 

repair initiated in response to vanadium pentoxide. Their work illustrates that mice deficient in 

prostaglandins (PG) such as the enzyme cyclooxygenase (COX)-2, are protected from vanadium 

pentoxide-induced fibroproliferative lesions and indicate the potential important role of 

cyclooxygenases in mitigating vanadium pentoxide induced injury. Antao-Menezes et. al. 

(2008) characterized the role of STAT-1 in vanadium pentoxide pulmonary fibrosis. Their work 

identified Interferon-beta (IFN-β) as a mediator of vanadium pentoxide-induced STAT-1 

activation in normal human lung fibroblasts, and linked STAT-1 activation with STAT-1 
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dependent production of a chemokine, CXCL10, that was identified in the Ingram et. al. (2007) 

gene array analysis (Figure 4-1). Thus fibroblasts appear to synthesize IFN-β that activates 

STAT-1. STAT-1 activation simultaneously causes growth arrest and increases levels of 

CXCL10 which then diminish fibrinogenesis, as a negative feedback loop. In summary, 

vanadium pentoxide stimulated production of IFN-β activates signaling pathways that lead to the 

resolution of fibrosis after vanadium pentoxide induced injury. 

4.6.3.2 Neurotoxicity 

The mechanism(s) underlying nervous system toxicity in response to vanadium pentoxide 

is not well-characterized. A duration-dependent decrease in the number of immunoreactive TH+ 

neurons and morphological changes to the blood-brain barrier were observed in response to 

vanadium pentoxide. It has been suggested that blood-brain barrier disruption may be related to 

brain region-specific changes in metalloproteinases (MMP-2 and MMP-9) that have been seen 

following vanadium pentoxide exposure (Colin-Barenque et. al. 2008), however more work is 

needed to fully characterize these findings. 

4.6.3.3 Reproductive Toxicity 

Limited studies of vanadium pentoxide have examined reproductive and developmental 

toxicity. Short-term oral exposures in weanling rats demonstrated a potential effect on bone 

growth as measured by serum calcium concentrations and bone alkaline phosphatase activity 

(Yamaguchi et al. 1989). Reproductive effects due to vanadium pentoxide inhalation exposure 

included morphological changes to spermatogonia, spermatocytes and Sertoli cells (Fortoul et. 

al., 2007). Estrous cycle length was increased in female rats but not mice following inhalation 

exposure at high doses, while decreased spermatozoal motility was observed in male mice but 

not male rats at high doses (NTP 2002). Excess vanadium pentoxide was found to accumulate in 

the testes following inhalation exposure (Mussali-Galante et al., 2005). Moreover, significant 

decreases in gamma globulin were observed in testicular samples exposed to vanadium 

pentoxide (Mussali-Galante et al., 2005). Decreased gamma-globulin levels may lead to changes 

in microtubule formation that would impact spermatogenesis. Injection studies described by 

Wide (1984) demonstrated decreased ossification in fetuses exposed to vanadium pentoxide in 

utero. Determination of a specific mode of action for reproductive toxicity is not possible due to 

the limited studies examining these effects. 
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4.7. EVALUATION OF CARCINOGENICITY 

4.7.1 Summary of Overall Weight of Evidence 

 Under the U.S. EPA Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 2005a) 

vanadium pentoxide is “likely to be carcinogenic to humans” by the inhalation route of exposure 

based on inhalation studies in male rats and male and female mice (NTP 2002). No studies 

evaluating the carcinogenic potential in humans exposed to inhaled vanadium pentoxide were 

identified. No studies suitable for evaluation of the oral carcinogenic potential for vanadium 

pentoxide were located in the published literature. There was clear evidence of carcinogenesis in 

both male and female mice based on the statistically significant and dose-related increased 

incidence of alveolar/bronchiolar tumors (NTP, 2002; Ress et al., 2003). There was some 

evidence of carcinogenic activity in male rats and equivocal evidence in female rats (NTP, 

2002). Although the incidence of bronchiolar tumors in vanadium-pentoxide-treated rats was not 

significantly increased compared to control, tumor incidence was elevated relative to historical 

control in most treatment groups in male rats and some treatment groups in female rats (Table 4-

8). No other tumor type was significantly increased in either rats or mice in this study. These 

results are supported by a recent study by Rondini et al (2010) also showed increased lung 

tumors in male mice (A/J, BALB/C) following exposure to vanadium pentoxide along with an 

initiator (MCA). 

 U.S. EPA’s Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 2005a) indicate for 

that for tumors occurring at a site other than the initial point of contact, the weight of evidence 

for carcinogenic potential may apply to all routes of exposure that have not been adequately 

tested at sufficient doses. An exception occurs when there is convincing information (e.g., 

toxicokinetic data) that absorption does not occur by other routes. Information available on the 

carcinogenic effects of V2O5 via the inhalation route is limited to examination of the respiratory 

tumors. Information on the carcinogenic effects of V2O5 via the oral and dermal routes in 

humans or animals is absent. Based on the observance of only portal-of-entry tumors (respiratory 

tumors) following inhalation exposure, and in the absence of information to establish a mode of 

action, this cancer descriptor applies only to the inhalation route of exposure. Therefore, V2O5 is 

“likely to be carcinogenic to humans” by the inhalation route of exposure, and the database has 

“inadequate information to assess carcinogenic potential” via the oral or dermal route. 

4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence 

 Few studies are available that assess the carcinogenic potential of vanadium pentoxide. 
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Although both epidemiology and laboratory animal studies show similar respiratory tract 

toxicity, there are currently no epidemiology studies available in the published literature 

examining carcinogenicity. 

 Only two published laboratory animal studies provide evidence for the carcinogenic 

potential of vanadium pentoxide (NTP 2002; Rondini et al., 2010). Vanadium pentoxide has 

been shown to induce pulmonary tumors following inhalation exposure in a study performed by 

NTP (NTP 2002). F344 rats (50/sex/group) and B6C3F1 mice (50/sex/group) were exposed to 

vanadium pentoxide particles for six hours a day, five days per week for two years. Rats were 

exposed to 0.5, 1.0, or 2.0 mg/m3

 of vanadium pentoxide, with mice exposed to 1.0, 2.0 or 4.0 

mg/m3 of vanadium pentoxide. Lung tumors were observed in male and female rats, but 

incidence exceeded historical controls in male rats only (Table 4-15). Both male and female 

mice showed statistically significant increases in lung tumors as compared to controls (p ≤ 0.01). 

 These increases were observed in both sexes at all doses, with 50% of the male mice in the 

highest exposure group dying before the end of the study. Survival rates in all other exposed 

groups for both rats and mice was not significantly different from controls. Both rats and mice 

showed other lesions of the respiratory tract, including inflammation, fibrosis and hyperplasia 

(Tables 4-7, 4-9). Decreased body weight gain was observed as early as 3 months post-exposure 

in the high dose groups of all exposed animals. 

 Along with the NTP study (2002), a recent study by Rondini et al (2010) examined 

tumor promotion of vanadium pentoxide in three different mice strains. Lung tumors were 

observed in two of three mouse strains 20 weeks after MCA tumor initiation, followed by 

exposure (only males exposed) to V2O5 (4 mg/kg, 5 times weekly) (Table 4-11). A/J and 

BALB/C male mice showed increases in lung tumors following exposure to both MCA (initiator) 

and V2O5, but not V2O5 alone, suggesting V2O5 works as a tumor promoter. 

4.7.3. Mode of Action Information 

The U.S. EPA (2005a) Guidelines for Carcinogen Risk Assessment defines mode of 

action (MOA) as a sequence of key events and processes, starting with the interaction of an 

agent with a cell, proceeding through operational and anatomical changes, and resulting in 

cancer formation. Examples of possible modes of carcinogenic action include mutagenic, 

mitogenic, anti-apoptotic (inhibition of programmed cell death), and cytotoxic mechanisms with 

reparative cell proliferation and immunologic suppression. There is insufficient information to 

establish a carcinogenic mode of action for bronchiolar tumors observed in animals following 

inhalation exposure to vanadium pentoxide. 
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4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES 

4.8.1. Possible Childhood Susceptibility 

 There are no reports of childhood susceptibility due to exposure to vanadium pentoxide. 

There are also no reports indicating increased susceptibility in developings, however the data on 

developmental effects of vanadium pentoxide are very limited (see discussion of data gaps 

below). Young rats that consumed vanadium in the drinking water and feed were found to have 

higher tissue vanadium levels 21 days after birth than they did 115 days after birth (Edel et al. 

1984). The data suggest that there is a higher absorption of vanadium in these young animals 

due to a greater nonselective permeability of the undeveloped intestinal barrier. Thus, age of the 

rodents appears to play an important role in the absorption of vanadium in the gastrointestinal 

tract. Mravcova et. al (1993) assessed the extent of vanadium pentoxide accumulation in the 

bones of rats following 6 month exposure. Vanadium accumulated in the epiphyseal cartilage of 

the tibia in rats with significantly higher concentrations of vanadium in the tibia and incisors of 

weanling rats compared to adults. However, no dose response data for these endpoints was 

reported. 

4.8.2. Possible Gender Differences 

Reports of gender differences are limited to the carcinogenicity data from NTP, 2002 

where clear evidence of carcinogenicity was reported in male and female mice exposed to 

vanadium pentoxide, and some evidence of carcinogenicity was reported in male rats, based on 

observations of alveolar and bronchiolar neoplasms that exceeded historical controls in groups 

exposed to vanadium pentoxide. The number of neoplasms in female rats was not higher than 

that observed in historical controls and thus, a relationship between neoplasms and vanadium 

pentoxide could not be established in female rats (NTP, 2002 and Ress, 2002). Thus, increased 

tumor incidence in rats is equivocal overall, but the lack of any increase in females may suggest 

a gender-related increase in susceptibility in males. It is unknown whether this observed 

difference is applicable to humans. There are no reported differences for response to vanadium 

pentoxide between genders for either animals or humans for any non-cancer endpoint. 

4.8.3. Other Susceptible Populations 

 No data exists on the role of genetic polymorphisms in differentially susceptible human 

populations in response to vanadium pentoxide exposure. In mice, research suggests that all 

strains have an inflammatory response to vanadium pentoxide exposure, but the severity of 
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inflammation varies greatly from strain to strain. Such variability in response suggests that a 

genetic component may contribute to the severity of vanadium pentoxide-induced pulmonary 

inflammation and tumorigenicity in mice (Rondini et al., 2010). The NTP study (2002) used 

B6C3F1 mice in all of their exposure protocols for 16-day, 3 month, and 2 yr exposure studies. 

Pulmonary fibrosis was observed in this hybrid strain. 

Kyono et. al. (1999) used a rat model of acute bronchiolitis (Br) to investigate whether 

animals with pre-existing lung conditions would be differentially susceptible to inhaled 

vanadium pentoxide. Compared to exposed normal rats, Br rats exhibited delayed recovery 

from pre-existing lesions and exacerbated lung inflammation. Sensitive rats also showed 

reductions in the deposition and clearance rates of inhaled particles. 

Rondini et al (2010) examined the effect of exposure to vanadium pentoxide in three 

mouse strains of varying susceptibility to lung cancer (A/J, BALB/C and C57BL/6J) in an 

initiation/promotion model (full study description in Section 4.2.2.2). Three mouse strains were 

used to further understand potential susceptibility to these effects. These particular mouse 

strains were selected because of their known differential susceptibility to chronic pulmonary 

inflammation and carcinogenesis: A/J mice are sensitive, BALB/C are intermediate and 

C57BL/6J are resistant. Statistically significant lung tumor increases were observed in A/J and 

BALB/C mice as compared to the MCA-treated control (p≤0.05; Table 4 – 11). Differences 

were also observed between strains, with A/J mice showing increased tumorigenicity in response 

to vanadium pentoxide. In the absence of MCA, V2O5 was not sufficient to initiate tumorigenesis 

in this study. C57BL/6J had no tumors following exposure (data not shown). 

Overall, the differential inflammatory responses observed in the three strains of mice 

appear to positively correlate with increased levels of chemokines, such as keratinocyte-derived 

chemokine (KC) and monocyte chemotactic protein-1 (MCP-1), and increased binding of 

transcriptional factors NFκB and AP-1 (c-Fos), and sustained activation of MAP kinases 

(MAPKs) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2) suggesting inflammation 

as a major response in mice. Turpin et al. (2010) examined pulmonary inflammation and fibrosis 

following intranasal aspiration exposure to vanadium pentoxide with and without respiratory 

syncytial virus (RSV) exposure (full study description in Section 4.4.1.2). In this study, 

vanadium pentoxide exposure also caused a significant increase in cell proliferation in the 

airways and lung parenchyma, lung mRNAs for TGF-β-1, CTGF, PDGF-C, Col1A2, and 

mRNAs for IFN-α and -β and IFN-inducible chemokines CXCL9 and CXCL10 compared to 
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controls. Pre- or post-treatment with RSV caused a significant reduction in the all mRNAs. 

Together, results from this study showed that vanadium pentoxide induces inflammatory and 

fibrogenic response in mouse lung and these effects were suppressed by RSV infection. 
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5. DOSE-RESPONSE ANALYSIS 

5.1. ORAL REFERENCE DOSE (RfD) 

Only two studies exist on human oral exposure to vanadium pentoxide, and neither 

examined health effects related to this exposure. Two studies measured cystine levels in hair and 

fingernails and vanadium levels in urine (Kucera et al., 1994) or blood (Kucera et al., 1992) 

following oral exposure to vanadium pentoxide. Kucera et al. (1994) detected vanadium in urine 

of workers from a Czechoslovakian vanadium pentoxide production plant, however, it is 

expected that these urinary levels of vanadium resulted from multiple exposure routes. Kucera et 

al. (1992) measured vanadium in the hair and blood of children and the blood of adults 

potentially exposed through ingestion of vanadium-contaminated drinking water (concentration 

range: 0.001-0.1 mg/L). Vanadium concentrations in water supply wells exceeded the maximum 

permissible limit in drinking water (0.01 mg/L) with the contamination continuing over 2 years. 

Significantly increased vanadium concentrations were found in blood of exposed children 

compared to unexposed children and adults, whereas vanadium levels in hair of exposed children 

(adults not measured) were no different from the control group. No exposure-response 

relationship could be determined for either endpoint, and changes in hair cystine levels have not 

been correlated with adverse health effects. Additional studies of workers occupationally 

exposed to vanadium pentoxide exist, although it is presumed that these workers were exposed 

by multiple routes, inhalation was likely the primary route of exposure (Sjöberg, 1951; Sjöberg, 

1956; Zenz et al., 1962; Kiviluoto et al., 1979; Kiviluoto, 1980; Kiviluoto et al., 1981b; Musk 

and Tees, 1982; Irsigler et al., 1999). 

Mountain et al. (1953) is the only published, peer-reviewed study that evaluated the 

effects of subchronic oral vanadium pentoxide exposure in laboratory animals. Male Wistar rats 

(5/group; 200 – 350 gm bw) were exposed to vanadium pentoxide for 103 days using average 

daily doses of 0, 10.5, 16.4, 69.6, 141.0 mg/kg-day vanadium pentoxide in feed. Changes were 

observed in body weight gain, erythrocyte count, hemoglobin, and cystine content of hair. Other 

endpoints of toxicity were not reported. 

The study authors reported increased body weight gain in the low exposure groups (0 – 

16.4 mg/kg-day) and decreased body weight gain in the highest exposure group (141.0 mg/kgday). However, these data were not accompanied by any explanation, statistical analysis, or 

measures of variability (SE or SD). Cystine content of hair was significantly decreased 

compared to control at doses ≥ 16.4 mg/kg-day vanadium pentoxide. Alterations in hair cystine 

levels can be associated with dietary changes or altered health status (Kleinfeld et al. 1961). The 
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authors speculated that vanadium may have inhibited enzymes, such as sulfur transferases, that 

decreased the availability of cystine for hair growth. However, data to support a relationship 

between decreased hair cystine levels and adverse health outcomes are not available in the 

published literature. Thus, the biological significance of decreased hair cystine content is 

unclear. 

Table 5–1. Hematological results of oral vanadium pentoxide exposure in rats (Mountain et al. 

1953). 

Control 10.5 mg/kg-day 16.4 mg/kg-day 

Red Cell Count (M/mm3) 

Start 8.0 7.8 8.0 

Finish (103 days) 7.7 6.8 6.3 

Percent change between start and 

finish of expt (%) 

3.8 12.8 21.3 

Hemoglobin, % 

Start 15.6 15.2 15.3 

Finish (103 days) 15.0 14.5 13.7 

Percent change between start and 

finish of expt (%) 

3.9 4.6 10.5 

Relative liver weight increases and decreases in erythrocytes and hemoglobin levels were 

also reported by Mountain et al. (1953). Mean relative liver weights, reported as a ratio of liver 

weight to body weight, were statistically significantly elevated above controls at 69.6 mg/kg-day 

(i.e., 3.51 ± 0.06 versus 3.86 ± 0.07). Liver weight data were not reported for other doses. 

Apparent dose-related decreases in RBC count (21.3%) and hemoglobin concentration (10.5%) 

were observed in the 10.5 and 16.4 mg/kg-day vanadium pentoxide dose groups compared to 

controls (Table 5-1). No statistical analysis was performed by the study authors on these data, 

and no measure of variance was reported, precluding independent statistical analysis. The 

effects on RBC count and hemoglobin concentration observed in this oral study are consistent 

with the hematological effects observed in a 3-month inhalation study of vanadium pentoxide in 

rats (NTP, 2002). Decreases in mean cell volume (MCV) and mean cell hemoglobin (MCH) 

accompanied by erythrocyte microcytosis were suggestive of altered iron metabolism and 

heme/hemoglobin production following vanadium pentoxide inhalation exposure. Based on the 

dose-related decreases in RBC count in the oral study supported by the hematological effects 

observed in the inhalation study, decreased RBC count was selected as the critical effect. 

Although a dose-related decrease in RBC count was seen at 10.5 and 16.4 mg/kg-day 

vanadium pentoxide (12.8% and 21.3%, respectively) in the Mountain et al. (1953) study, the 

magnitude of this change is considered biologically significant only at 16.4 mg/kg-day, which 
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EPA thus identified as the LOAEL. The lowest dose of 10.5 mg/kg-day was then identified by 

EPA as a NOAEL. 

5.1.1 Methods of Analysis 

 The most sensitive endpoint following oral exposure to vanadium pentoxide is decreased 

RBC count with a NOAEL of 10.5 mg/kg-day vanadium pentoxide (Mountain et. al., 1953). 

Because the study authors reported the decrease in RBC count as a mean with no measure of 

variability (SE or SD), this continuous endpoint could not be subjected to benchmark dose 

(BMD) modeling. Therefore, the NOAEL of 10.5 mg/kg-day is identified as the point of 

departure (POD) for use in deriving the RfD for vanadium pentoxide. 

 The Agency endorses a hierarchy of approaches to derive human equivalent oral 

exposures from data from laboratory animal species, with the preferred approach being 

physiologically based toxicokinetic modeling (U.S. EPA, 2011). Other approaches may include 

using some chemical-specific information, without a complete physiologically based 

toxicokinetic model. In lieu of data to support either of these types of approaches, body weight 

scaling to the 3⁄4 power (i.e., BW3/4) is endorsed as a general default to extrapolate toxicologically 

equivalent doses of orally administered agents from all laboratory animals to humans for the 

purpose of deriving an oral Reference Dose (RfD). In general, the use of BW3/4 scaling is 

considered appropriate for deriving an oral RfD when the observed effects are associated with 

the parent compound or a stable metabolite, not related to a portal-of-entry effect, and not related 

to developmental endpoints. Use of BW3/4 scaling in combination with consideration of a 

reduced interspecies uncertainty factor, UFA, is recommended as the Agency default approach. 

No physiologically based toxicokinetic modeling information exists for vanadium 

pentoxide. The selected critical effect (decreased red blood cell counts) is associated with the 

parent compound, is not considered a portal-of-entry effect and was observed in mature rats. 

Therefore, consistent with U.S. EPA guidance (U.S. EPA, 2011), the POD identified in rats (i.e., 

10.5 mg/kg-day) is converted to a human equivalent dose (HED) through application of a 

dosimetric adjustment factor (DAF) derived as follows: 

 DAF = (BWa

1/4 / BWh1/4), 

 where 

DAF = dosimetric adjustment factor 

 BWa = animal body weight 

 BWh = human body weight 
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 Using a BWa of 0.25 kg for rats and a BWh of 70 kg for humans, the resulting DAF is 

0.244. Applying this DAF to the POD identified in rats yields a HED of 2.56 mg/kg-day as 

follows: 

 HED = Laboratory animal dose (mg/kg-day) x DAF 

 = 10.5 mg/kg-day x 0.244 

 = 2.56 mg/kg-day 

Table 5-2 Human equivalence dose conversion by BW3/4 for RfD derivation. 

Species BWa

1/4 / BWh1/4 = DAF HED UFs RfD 

(mg/kg-day)

Rat 

(0.25kg) 0.25kg1/4 ÷ 70kg1/4 = 0.244 

10.5 mg/kgd x 0.244 = 

2.56 mg/kgd 

Total = 3000 

UFA = 3 

UFH = 10 

UFS = 10 

UFD = 10 

 2.56 ÷ 3000

= 8.5 x 10-4 

a. Using the BWa 0.25 kg for rats and BWh 70 kg for humans, and multiplying it by the NOAEL of 10.5 mg/kg-d 

from Mountain et al. (1953). 

5.1.2 RfD Derivation – Including Application of Uncertainty Factors (UF) 

 

The NOAEL of 10.5 mg/kg-day for decreased RBC count in male rats (Mountain et. al., 

1953) was used as the POD to derive an RfD. The application of uncertainty factors to the POD, 

converted to a HED, results in a composite uncertainty factor of 3,000 covering four areas of 

uncertainty: 3 for interspecies extrapolation from animals to humans (UFA); 10 for human 

intraspecies variability (UFH), 10 for extrapolation from a subchronic to a chronic study (UFS), 

and 10 for database insufficiencies (UFD). No UF is needed for extrapolation from a LOAEL to 

NOAEL because a NOAEL was used to identify the POD (US EPA, 2002). 

An interspecies uncertainty factor, UFA, of 3 (100.5 = 3.16, rounded to 3) was applied to 

account for uncertainty in extrapolating from laboratory animals to humans (i.e., interspecies 

variability). This interspecies uncertainty factor is comprised of two separate but equal sources 

of uncertainty, toxicokinetic and toxicodynamic differences between animals and humans. For 

vanadium pentoxide, toxicokinetic uncertainty was accounted for by calculation of a human 

equivalent dose (HED) through application of a dosimetric adjustment factor (DAF) as outlined 

in the U.S. EPA guidance on the use of BW3/4 scaling in the derivation of the oral RfD (U.S. 
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EPA, 2011). As the toxicokinetic differences are thus accounted for, only the toxicodynamic 

uncertainty remains, and an UFA of 3 is retained to account for this residual uncertainty. 

An intraspecies uncertainty factor, UFH, of 10 for intraspecies differences (human 

variability) was used to account for potentially susceptible individuals in the absence of 

quantitative information on the variability of response in humans. 

An UFS of 10 for extrapolation from a subchronic to chronic study is applied because a 

subchronic study was used for the POD. 

An UFL for LOAEL to NOAEL extrapolation was not used because a NOAEL was 

identified from the principal study and used as the POD. 

An UFD of 10 was used for database insufficiencies due to the lack of a developmental 

toxicity study and a multi-generation reproductive study for V2O5 by the oral route. Studies 

using alternate routes of exposure (intraperitoneal) have indicated adverse reproductive and 

developmental effects in response to vanadium pentoxide, including statistically significant 

increases in seminal vesicle, thymus and submandibular gland weights in male mice and body 

weight, thymus, submandibular gland, and liver weights in female mice (Altamirano et al., 1991) 

as well as reduced fertility (Altamirano-Lozano et al., 1996). No physiologically based 

toxicokinetic models are available for conducting a route-to-route extrapolation. 

Therefore, the RfD for vanadium pentoxide is calculated as follows: 

RfD = NOAELHED ÷ UF 

= 2.56 mg/kg-day ÷ 3000 

= 0.000085 mg/kg-day or 9E-04 mg/kg-day 

Note: Because vanadium exists in several different valence states, all of which are not 

equivalent toxicologically (WHO-IPCS, 2001), the values generated here apply to vanadium 

pentoxide and should not be applied to other vanadium compounds. 

5.1.2. Previous RfD Assessment 

U.S. EPA previously derived a chronic reference dose (RfD) of 9 x 10-3 mg/kg-day for 

vanadium pentoxide based on a 2.5-year dietary NOAEL of 0.89 mg/kg-day vanadium pentoxide 

for decreased hair cystine content that was entered on the IRIS database in 1987 (U.S. EPA, 

1987; Stokinger et. al., 1953 reported in Patty’s Industrial Hygiene and Toxicology, 3rd Ed., 

1981). Limited details were provided, and this study is not available for analysis. The rats 

(number and species unspecified) were exposed to dietary levels of vanadium pentoxide (0.89 or 

8.9 mg/kg-day for 2.5 yrs) and assessed for growth rate, survival, and hair cystine content. Of 
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the endpoints reported in the book chapter, decreased hair cystine was selected as the critical 

effect with a NOAEL of 0.89 mg/kg-day. Upon further analysis of this study as described in 

Section 5.1.1, it was determined to be inadequate for use in deriving an RfD. 

5.2. INHALATION REFERENCE CONCENTRATION (RfC) 

5.2.1 Choice of Principal Study and Critical Effect with Rationale and Justification 

 The available human and animal data identify the respiratory tract as the primary target 

for chronic exposure to vanadium pentoxide. Irritation of the upper and lower respiratory tract 

has been reported in several acute, subchronic and chronic occupational and case studies of 

workers exposed to vanadium pentoxide in fuel-oil ash and vanadium dust (Woodin et al., 2000; 

Irsigler et al., 1999; Woodin et al., 1999; Hauser et al., 1995; Levy et al., 1984; Musk and Tees, 

1982; Kiviluoto, 1980; Lees, 1980; Kiviluoto et al., 1979; Zenz et al., 1962; Sjöberg, 1955; 

Vintinner et al., 1955; Williams, 1952, Lewis, 1959). These results are supported by effects 

observed in rodents, including inflammation, hyperplasia, and fibrosis. Although subchronic 

occupational exposure studies provide supportive evidence for the respiratory tract as a target for 

inhaled vanadium pentoxide, studies often failed to quantify vanadium pentoxide concentration 

as a constituent in an inhaled mixture. Thus, the available occupational exposure studies are not 

suitable as the basis for the RfC. 

 The toxicity database for inhalation exposure in laboratory animals includes two chronic 

studies (Knecht et al., 1992; NTP, 2002). A 6 month cynomologus monkey study (Knecht et al., 

1992) exposed monkeys (n=8) to vanadium pentoxide aerosol (0.5 or 3.0 mg/m3

) for 6 hrs/day, 5 

days/week for 26 weeks. This study was not selected as the principal study due to limitations in 

the number of test animals, study duration and number of doses used. 

Results of the NTP (2002) study in rats and mice provide evidence of toxicity to the 

upper and lower respiratory tract, including increased lung weight, inflammation, histological 

lesions, and decreased pulmonary function following a 3-month inhalation exposure to vanadium 

pentoxide. Pulmonary lesions were observed in F344/N rats (10 male and 10 female) and 

B6C3F1 mice (10 male and 10 female) exposed for 3 months, with NOAEL and LOAEL values 

of 1 and 2 mg/m3

, respectively, for minimal to mild epithelial hyperplasia (Tables 4-4 and 4-6). 

Other observed endpoints include increased lung bronchiolar exudate, lung fibrosis, altered nasal 

morphology, and increased nasal inflammation observed in rats. Significant exposure-related 

decreases in pulmonary function were also observed in male and female rats, with a LOAEL of 

4 mg/m3 (pulmonary function not assessed in mice) (NTP, 2002). Other effects identified from 
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the NTP (2002) 3 month inhalation study are the erythrocytosis , body weight and lung weight 

changes. Erythrocytosis was observed in male and female rats exposed to inhaled vanadium 

pentoxide for 3 months; hematological endpoints were not examined in mice (NTP, 2002). The 

NOAELs for mild erythrocytosis were 1 mg/m3

 in male rats and 2 mg/m3 in female rats. The 

erythrocytosis is considered to be a secondary effect arising from the primary lung lesions and 

was not considered as a critical effect. 

Abnormal breathing, emaciation, and lethargy were observed in male and female rats 

exposed to concentrations of 8 mg/m3

 or higher (NOAEL 4 mg/m3, LOAEL 8 mg/m3) in 

response to vanadium pentoxide after 3 months of exposure. Final body weight was statistically 

significantly decreased as compared to the respective controls at 16 mg/m3

 in male rats (60%) 

and male mice (10%); 8 mg/m3

 in male rats (10%) and mice (6%); 16 mg/m3 in female rats 

(30%) and female mice (12%); 8 mg/m3

 in female mice (10%); and 4 mg/m3 in female mice 

(11%). Thus, a NOAEL of 4 mg/m3

 and a LOAEL of 8 mg/m3 suggested for body weight loss 

and associated behavioral changes in rats and male mice. Relative lung weights were 

significantly increased in male and female rats (4 mg/m3

) following 3-months inhalation 

exposure to vanadium pentoxide. Similarly, relative lung weights were significantly increased in 

male and female mice starting at 4 mg/m3. 

Other studies identified morphological changes to the central nervous system (CNS) in 

male mice exposed to vanadium pentoxide for up to 8 weeks (Avila-Costa et al., 2004, 2005). 

Avila-Costa et al. (2004, 2005) also reported morphological changes in the substantia nigra 

region of the basal ganglia and the blood-brain barrier in male mice exposed to 1.4 mgV/m3

 for 

up to 8 weeks; effects on central nervous system function or other comprehensive endpoints 

were not reported. Using the same dose regimen (1.4 mgV/m3

 two times a week for up to one 

month) Avila Costa et. al. (2006) reported a time-dependent loss of dendritic spines, necroticlike cell death, and morphological changes to the hippocampal region and that these changes 

may be related to the associated spatial memory loss. Morphological changes in the CNS 

reported by Avila-Costa et al. (2004; 2005; 2006) were not considered as the critical effect due 

to lack of information on the exposure-response relationship for morphological changes to the 

central nervous system, as only one exposure level was tested. Moreover, the lung appears to be 

the most sensitive target to inhalation exposure to vanadium pentoxide. 

Results of the NTP (2002) study in rats and mice provide evidence of toxicity to the 

upper and lower respiratory tract, including increased lung weight, inflammation, histological 

lesions, and decreased pulmonary function following 3-month inhalation exposure to vanadium 

pentoxide. Though body weights and a complete necropsy and histological analysis were 

performed, adverse effects in other target organs were not identified in the chronic exposure 
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study. The series of effects described in the NTP (2002) bioassay and supporting studies from 

the available inhalation database reflect a dose-response with increase in severity with vanadium 

pentoxide concentration, and a progression of respiratory effects (infiltration of macrophages, 

inflammation, hyperplastic response, fibrosis). Based on the dose-response and temporal 

relationship of effects throughout the course of the 2-year study, and the concordance with 

effects seen in humans, the NTP (2002) study is selected as the critical study. The 2-year 

exposure study in F344/N rats and B6C3F1 mice (50/sex/group) (NTP, 2002) examined the 

effects of chronic inhalation (0, 0.5, 1 or 2mg/m3

 in rats and 0, 1, 2, 4 mg/m3 in mice for 6hrs/d, 

5d/wk, 104 weeks) of vanadium pentoxide. The NTP (2002) observed nonneoplastic lesions of 

the respiratory tract in male and female rats and mice. Numerous lesions of the upper and lower 

respiratory tract were observed in male and female rats and mice at the lowest exposure 

concentrations tested. Specifically, epiglottis epithelial hyperplasia in male and female rats 

(LOAELs of 0.5 mg/m3

), and alveolar and bronchiolar hyperplasia was observed in male rats 

(LOAELs of 0.5 mg/m3) and in male and female mice (1 mg/m3); NOAELs were not identified 

(Tables 4-7 and 4-9). Other histological lesions observed at a LOAEL of 0.5 mg/m3 include 

multiple lesions in the nose and larynx of male and female rats including epiglottis epithelial 

degeneration, hyperplasia, and squamous metaplasia in both sexes and nasal goblet cell 

hyperplasia in males. In male and female mice, histological lesions also occurred in the larynx 

and nasal tissues at 1 mg/m3; it should be noted that 0.5 mg/m3 was not used as a dose in mice. 

In mice exposed to 1 mg/m3

, lesions were observed in the nose, bronchioles and lung of male 

mice and the nose, larynx, bronchioles and lung of female mice. Chronic, active inflammation 

and interstitial fibrosis was observed in male rats at a LOAEL of 1 mg/m3

 (NOAEL 0.5 mg/m3). 

The NTP (2002) chronic study is well-designed, well-controlled, and well-reported. Numerous 

toxicological endpoints were assessed. As with the subchronic exposure studies, results of this 

two-year inhalation study identify the upper and lower respiratory tract as the target for chronic 

inhalation exposure to vanadium pentoxide. The nasal and laryngeal lesions observed by NTP 

(2002) are among the most sensitive effects observed and were observed in both sexes of rats 

and mice (Table 5-3). Irritation of the upper and lower respiratory tract has been reported in 

several occupational and case studies of workers exposed for days or weeks to vanadium 

pentoxide in fuel-oil ash and vanadium dust (Sjöberg, 1951; Sjöberg, 1956; Zenz et al., 1962; 

Kiviluoto et al., 1979; Kiviluoto, 1980; Kiviluoto et al., 1981a, b; Musk and Tees, 1982; Irsigler 

et al., 1999). Therefore, NTP (2002) was selected as the principal study, with effects on the 

upper and lower respiratory tract selected as the critical effects. 

5.2.2 Methods of Analysis 
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To analyze the concentration response effect of vanadium pentoxide, the reported 

concentrations of vanadium pentoxide were converted to human equivalent concentrations prior 

to any modeling (Table 5.4, Appendix B). The Methods for Derivation of Inhalation Reference 

Concentrations and Application of Inhalation Dosimetry (hereafter referred to as the RfC 

Methodology) recommends converting the POD[ADJ] to a human equivalent concentration (HEC) 

(U.S. EPA, 1994b). The RfC Methodology separates gases into three categories based on their 

water solubility and reactivity with tissues in the respiratory tract, and recommends the use of 

regional deposited dose ratios (RDDRs) for converting to HECs for particles (e.g., vanadium 

pentoxide). RDDRs were calculated for rats with the RDDR computer program (U.S. EPA, 

1994) using mean body weights for male and female rats and the average particle size 

MMAD±GSD of 1.24±1.89 for rats as reported by NTP (2002). Human equivalent concentration 

(HEC) conversions (in mg vanadium pentoxide/m3

) were calculated by multiplying Conc[ADJ] by 

the pulmonary RDDR for lesions in the lung, or the extrathoracic RDDR for lesions in the larynx 

and nose and are summarized in Table 5-4. Duration-adjusted exposure concentrations 

(Conc[ADJ]) of 0.09, 0.18 and 0.36 mg/m3

, corresponding to nominal exposure concentrations of 

0.5, 1 and 2 mg/m3

, were calculated to account for continuous ambient exposure: 

Conc[ADJ] = Conc × 6/24 × 5/7 

HECs were calculated by multiplying Conc[ADJ] by the extrathoracic RDDR for lesions of 

the larynx in female rats (Appendix B, Table B-5). 

Table 5-3. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to Particulate 

Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) 

Lesion Type and Locationa

Exposure Group 

Control 

(% 

incidence) 

0.5 mg/m3

(% 

incidence) 

1 mg/m3 

(% 

incidence) 

2 mg/m3

(% 

incidence) 

Male Rats 

Percent survival (%) 40 58 52 54 

Lung 

Number of animals examined 50 49 48 50 

Alveolar epithelium, hyperplasia 7 (14) 24b (49) 34b (71) 49b (98) 

Bronchiole epithelium, 

hyperplasia 

3 (6) 17b (35) 31b (65) 48b (96) 

Inflammation, chronic active 5 (10) 8 (16) 24b (50) 42b (84) 
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Table 5-3. Selected Nonneoplastic Lesions of the Respiratory System in Rats Exposed to Particulate 

Aerosols of Vanadium Pentoxide for 2 Years (NTP, 2002) 

Lesion Type and Locationa

Exposure Group 

Control 

(% 

incidence) 

0.5 mg/m3

(% 

incidence) 

1 mg/m3 

(% 

incidence) 

2 mg/m3

(% 

incidence) 

Interstitial, fibrosis 7 (14) 7 (14) 16c (33) 38b (76) 

Alveolus, histiocyte infiltration 22 (44) 40b (82) 45b (94) 50b (100) 

Larynx 

Number of animals examined 49 50 50 50 

Inflammation, chronic 3 (6) 20b (40) 17b (34) 28b (56) 

Epiglottis epithelium, 

degeneration 

0 (0) 22b (44) 23b (46) 33b (66) 

Epiglottis epithelium, hyperplasia 0 (0) 18b (36) 34b (68) 32b (64) 

Epiglottis epithelium, squamous 

metaplasia 

0 (0) 9b (18) 16b (32) 19b (38) 

Nose 

Number of animals examined 49 50 49 48 

Goblet cell, hyperplasia 4 (8) 15b (30) 12c (24) 17b (35) 

Female Rats 

Percent survival (%) 28 40 34 30 

Lung 

Number of animals examined 49 49 50 50 

Alveolar epithelium, hyperplasia 4 (8) 8 (16) 21b (42) 50b (100) 

Bronchiole epithelium, 

hyperplasia 

6 (12) 5 (10) 14c (28) 48b (96) 

Inflammation,chronic active 10 (20) 10 (20) 14 (28) 40b (80) 

Interstitial, fibrosis 19 (39) 7b (14) 12 (24) 32b (64) 

Alveolus, histiocyte infiltration 26 (53) 35c (71) 44b (88) 50b (100) 

Larynx 

Number of animals examined 50 49 49 50 

Inflammation, chronic 8 (16) 26b (53) 27b (55) 38b (76) 

Epiglottis epithelium, 

degeneration 

2 (4) 33b (67) 26b (53) 40b (80) 

Epiglottis epithelium, hyperplasia 0 (0) 25b (51) 26b (53) 33b (66) 

Epiglottis epithelium, squamous 

metaplasia 

2 (4) 7 (14) 9 (18) 16b (32) 

Nose 

Number of animals examined 50 50 50 50 

Goblet cell, hyperplasia 13 (26) 19 (38) 16 (32) 30b (60) 

a

Number of animals with lesion; numbers in parantheses indicate percent incidence compared to control. 
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b

Significantly different from control by the Poly-3 test, p≤ 0.01 c

Significantly different from control by the Poly-3 test, p≤ 0.05 

Table 5-4: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year Inhalation 

Studies in Rats (NTP, 2002) 

Concentration 

as Reported a

(mg/m3) 

Continuous 

Exposure 

Adjustment 

Factor b

RDDR c Human Equivalent 

Concentration d (mg/m3

) 

Extrathoraci

c Pulmonary Extrathoracic Pulmonary

Male Rats (F344/N) 

0 0.179 0.516 0.496 0.00 0.00 

0.5 0.179 0.530 0.494 0.05 0.04 

1 0.179 0.520 0.495 0.09 0.09 

2 0.179 0.503 0.498 0.18 0.18 

Female Rats (F344/N) 

0 0.179 0.263 0.524 0.00 0.00 

0.5 0.179 0.259 0.524 0.02 0.05 

1 0.179 0.263 0.524 0.05 0.09 

2 0.179 0.245 0.524 0.09 0.19 a

 “Toxicology and carcinogenesis studies of vanadium pentoxide in F344/N rats and B6C3F1 Mice”, NTP, 2002. 

b

 “Continuous Exposure Adjustment Factor” = (6/24) * (5/7); animals were exposed to vanadium pentoxide 6 hours 

per day and 5 days per week. c

 Please refer to Appendix Table B-4. 

d

 “Human Equivalent Concentration” = “Concentration as Reported” * “Continuous Exposure Adjustment Factor ” 

* “RDDR” 

To determine the POD for derivation of the RfC, benchmark dose modeling was 

conducted on lesions observed in both male and female rats in the NTP study (2002; chronic 

lung inflammation, alveolar epithelium hyperplasia, chronic inflammation of the larynx, 

respiratory epithelial hyperplasia of the larynx and nose) with the best-fitting model selected for 

each endpoint (Appendix B). 

 As shown in Table 5-5, the lowest BMCL[HEC] of 0.003 mg/m3

 was observed for chronic 

inflammation of the larynx of female rats, indicating that the larynx was the most sensitive target 

for chronic inhalation exposure to vanadium pentoxide. Thus, it was chosen as the POD for the 

basis of the RfC calculation. 

Table 5-5: Candidate PODs for Vanadium Pentoxide Derived from NTP Studies (2002) through 

BMDS Modeling. 

Endpoint Selected BM HEC b
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Model a R 

(Extr

a 

Risk)

BMC

(mg/m3

) 

BMCLc

(mg/m3

) 

(Candidate 

POD) 

Male F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia Probit 0.1 0.016 0.013 

Chronic Active Inflammation Logistic 0.1 0.035 0.029 

Larynx 

Chronic Inflammation LogLogistic 0.1 0.017 0.012 

Respiratory Epithelium, Epiglottis, 

Hyperplasia LogLogistic 0.1 0.008 0.006 

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia LogLogistic 0.1 0.044 0.026 

Female F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia Gamma 0.1 0.076 0.063 

Chronic Active Inflammation 

Multistage 

(Stage3) 0.1 0.080 0.048 

Larynx 

Chronic Inflammation LogLogistic 0.1 0.005 0.003 

Respiratory Epithelium, Epiglottis, 

Hyperplasia LogLogistic 0.1 0.004 0.003 

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia 

Multistage 

(Stage2) 0.1 0.038 0.014 

a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

Degeneration of the epiglottis epithelium was not selected for BMD modeling because 

the incidence of this lesion did not exhibit dose-dependence, with the same incidence observed 

in the low and high dose groups. Epithelial squamous metaplasia was not selected for BMD 

modeling because the incidence of this lesion was not significantly different from control at the 

low- and mid-dose groups; thus, other lesions of the larynx were more sensitive endpoints. In all 

vanadium pentoxide groups, lesion severity was classified as minimal to mild. 

Modeling was performed using the Benchmark Dose Modeling Software (BMDS; 

Version 2.1.2) (U.S. EPA, 2000b). Biological and statistical considerations were taken into 

account in the selection of a benchmark response (BMR) level for all data sets. In the absence of 

information indicating what magnitude of inflammatory changes in the larynx and epiglottis are 
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considered biologically significant, the benchmark response (BMR) of 10% increase in extra risk 

was used as the basis for the BMC (BMC10), with the BMCL10 representing by the 95% lower 

confidence limit on the BMC10 (US EPA 2000b). Following the model selection steps outlined in 

the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the best-fitting model was 

selected. Biological and statistical considerations were taken into account in the selection of a 

benchmark response (BMR) level for this data set. Statistically, a 10% level of response is 

intended to represent a response level near the lower range of detectable observations in typical 

studies conducted with 50 animals per dose group (U.S. EPA, 2000b). 

 Results of the BMDS modeling for chronic inflammation of the larynx in female rats are 

summarized in Table 5-6, and for epiglottis hyperplasia in Table 5-7. As assessed by the 

chi-square goodness-of-fit test, several models demonstrated adequate goodness of fit p-value ≥

0.1 and good visual fit (Appendix B). In accordance with the draft Benchmark Dose Technical 

Guidance (US EPA, 2000b), the LogLogistic model was selected as the best fitting model. The 

BMC10 and BMCL10 were estimated as 0.005 and 0.003 mg/m3.

Table 5-6: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation in Female 

Rats, NTP (2002) 

Model a 

Goodness of Fit 

BMR 

HEC c 

PValue AIC b 

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/

m3) 

BMC

Ld

(mg/m

3

) 

LogLogistic 0.46 242.0 -0.88 -0.13 

Extra 

Risk 

10% 

0.005 0.003 

LogProbit 0.27 243.6 -0.89 -0.02 0.003 0.000 

Gamma 

0.19 243.7 1.58 -0.57 

0.007 0.006 

Multistage 0.013 0.011 e 

 (Stage1) 

0.014 0.011 

Weibull 

Probit 0.03 247.5 

1.99 

1.99 

Logistic 0.03 247.6 

1.97 

1.97 

a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 
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Table 5-7: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR 

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m

3

) 

BMCLd

(mg/m3) 

LogLogist

ic 0.30 205.3 1.53 0.000 

Extra 

Risk 

10% 

0.004 0.003 

LogProbit 0.78 204.2 -0.57 0.000 0.000 failed 

Gamma 

0.01 212.3 2.85 0.000 0.006 0.005 

Multistage e 

(Stage1) 

Weibull 

Probit 0.00 234.6 3.258 3.258 0.016 0.013 

Logistic 0.00 235.3 -3.295 3.174 0.016 0.014 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

5.2.3 RfC Derivation- Including Application of Uncertainty Factors (UFs) 

Benchmark dose modeling of incidence data for chronic inflammation of the larynx in 

female rats yielded the BMCL10 of 0.003 mg/m3. A total UF of 300 was applied to the BMCL10

of 0.003 mg/m3: 3 for interspecies extrapolation from animals to humans (UFA); 10 for human 

interspecies variability (UFH), and 10 for database insufficiencies (UFD). An uncertainty factor 

(UFS) was not applied for extrapolation of subchronic to chronic study as data was used from a 

chronic 2-yr study. 

 An UF of 3 (101/2 = 3.16, rounded to 3) was applied for interspecies extrapolation (UFA) 

to account for uncertainty in extrapolating from laboratory animals to humans (i.e., interspecies 

variability). This uncertainty factor is comprised of two separate and equal areas of uncertainty 

to account for differences in the toxicokinetics and toxicodynamics of animals and humans. In 

this assessment, toxicokinetic uncertainty was accounted for by the calculation of a human 

equivalent concentration by the application of a dosimetric adjustment factor as outlined in the 

RfC methodology (U.S. EPA, 1994). As the toxicokinetic differences are thus accounted for, 

only the toxicodynamic uncertainties remain, and a UF of 3 is retained to account for this 

residual uncertainty. 
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An UFH of 10 for intraspecies differences (human variability) was used to account for 

potentially susceptible individuals in the absence of quantitative information or information on 

the variability of response in humans. Considering the pulmonary effects of V2O5, individuals 

with pre-existing respiratory disorders may be more susceptible to inhaled vanadium pentoxide. 

An UFL for LOAEL to NOAEL extrapolation was not used because the current approach 

is to address this factor as one of the considerations in selecting a BMR for BMD modeling (US 

EPA 2000b; 1994b). In this case, a BMR of a 10% increase in the incidence of chronic 

inflammation of the larynx and epithelial hyperplasia of the epiglottis was selected under the 

assumption that it represents a minimal, biologically significant change. 

An UFD of 10 was used for database insufficiencies due to the lack of a developmental 

toxicity study and a multi-generation reproductive study for V2O5 by the inhalation route. 

Studies using alternate routes of exposure (intraperitoneal) have indicated adverse reproductive 

and developmental effects in response to vanadium pentoxide, including statistically significant 

increases in seminal vesicle, thymus and submandibular gland weights in male mice and body 

weight, thymus, submandibular gland, and liver weights in female mice (Altamirano et al., 1991) 

as well as reduced fertility (Altamirano-Lozano et al., 1996). No pharmacokinetic models are 

available for conducting a route-to-route extrapolation. 

The chronic RfC for vanadium pentoxide is calculated as follows: 

RfC = BMCL10 ÷ UF 

= 0.003 mg/m3 ÷ 300 

= 0.00001 mg/m3 or 1E-05 mg/m3 

Note: Because vanadium exists in several different valence states, all of which are not 

equivalent toxicologically (WHO-IPCS, 2001), the values generated here apply to vanadium 

pentoxide and should not be applied to other vanadium compounds. 

5.2.4. Previous RfC Assessment 

 An inhalation assessment for V2O5 was not previously available on IRIS. 

5.3 UNCERTAINTIES IN THE INHALATION REFERENCE CONCENTRATION (RfC) 

The following discussion identifies uncertainties associated with the subchronic and 

chronic RfCs. As presented earlier in this section, EPA standard practices and RfC guidance 

(U.S. EPA 1994a,b, 1995, 2002b) were followed in applying an uncertainty factor approach to a 
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point of departure (POD). A BMDL10 approach was used for derivation of the chronic RfC. 

Factors accounting for uncertainties associated with a number of steps in the analyses were 

adopted to account for extrapolating from an animal bioassay to human exposure, a diverse 

human population of varying susceptibilities, and to account for database insufficiencies. These 

extrapolations are carried out with standard approaches given the paucity of experimental and 

human data on vanadium pentoxide to inform individual steps. 

An adequate range of animal toxicology data is available for the inhalation hazard 

assessment of vanadium pentoxide, as described in Section 4. Included in these studies are shortterm, subchronic, and chronic bioassays in rats, as well as a range of supporting genotoxity studies. 

Toxicity associated with inhalation exposure to vanadium pentoxide is observed in reproductive 

organs, the CNS, and particularly in the respiratory system, including a range of nasal and 

pulmonary nonneoplastic lesions such as pulmonary inflammation, tissue morphology changes, and 

development of pulmonary fibrosis. Recent mechanistic studies have investigated vanadium 

pentoxide-induced pulmonary fibrosis and have contributed to some understanding of a putative 

mode of action for pulmonary fibrosis in response to vanadium pentoxide. 

In addition to respiratory effects, immunological and neurological effects have been seen 

following vanadium pentoxide exposure in experimental animals. An inhalation study using 

vanadium pentoxide (12 weeks, 1.4 mg/m3

) in male mice noted altered immune status, including 

a temporary increase in spleen weight, and alterations in antibody avidity following exposure to 

vanadium pentoxide (Pinon-Zarate et. al. 2008). This in part supports the results of an earlier 

oral study (6 months, 0 – 14 mg/kg-day in drinking water) in rats that also observed increased 

spleen weight (Mravcova et al., 1993). Several recent studies document neurotoxic 

morphological and behavioral effects (decreased dendritic spine length and increased necrosis in 

neural cells) in animals following inhalation exposure to vanadium pentoxide (Avila-Costa et al., 

2004; 2005; 2006; Colin-Barenque et al., 2008). Though these immune and neurological effects 

occurred at a low dose (1.4 mg/m3

), in most cases only one dose was tested and precludes 

formation of an adequate dose-response. 

For derivation of the chronic RfC for vanadium pentoxide, a two-year inhalation study in rats 

and mice (NTP, 2002) was selected as the principal study and inflammation of the larynx and 

epithelial hyperplasia of the epiglottis were selected as the critical effects. Lung hyperplasia, nasal 

inflammation, and lung fibrosis were also sensitive effects. Inflammation of the larynx and 

epithelial hyperplasia were selected as the critical effects because they are sensitive indicators of 

vanadium pentoxide-induced respiratory toxicity and yielded the lowest POD. 

The selection of the benchmark dose model for the quantitation of the RfC does not lead to 

significant uncertainty in estimating the POD since benchmark effect levels were within the range of 
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experimental data for chronic inflammation of the larynx. However, the selected model, the loglogistic model, while the best fitting model, is not the only model that adequately describes the data. 

 Other models could be selected to yield more extreme results, both higher and lower than those 

included in this assessment. 

Extrapolating from animals to humans entails further issues and uncertainties as the 

magnitude of the effect and the effect itself associated with the concentration at the point of 

departure in rodents are extrapolated to human response. Pharmacokinetic models are useful in 

examining species differences in pharmacokinetics; however, a PBPK model for vanadium 

pentoxide was not available. Therefore, toxicokinetic species differences were addressed by the 

determination of a HEC through inhalation dosimetry adjustments (as described in the RfC 

methodology, U.S. EPA, 1994b). A UF of 3 was applied to account for the remaining 

toxicokinetic uncertainties in the extrapolation from rats and humans. 

Information was unavailable for quantitative assessment of toxicokinetic or toxicodynamic 

differences between animals and humans, so the three-fold uncertainty factor (UF) was used to 

account for uncertainty in extrapolating from laboratory animals to humans in the derivation of the 

subchronic and chronic RfC values. 

Heterogeneity among humans is another uncertainty associated with the RfC. In the absence 

of vanadium pentoxide-specific data on human variation, an uncertainty factor of 10 was applied to 

account for uncertainty associated with variation in the human population in the derivation of the 

subchronic and chronic RfCs. The range of human response to vanadium pentoxide may be larger or 

smaller. Vanadium pentoxide-specific data to examine the potential magnitude of over- or 

underestimation are not available. 

No NOAEL was identified in the NTP, 2002 study for either the subchronic or chronic 

RfCs. Effects in this study were found at the lowest exposure concentrations measured, 

therefore, the LOAEL determined for this study for both subchronic and chronic effects does not 

indicate where a threshold of effects would lie and the data provided in the study is not sufficient 

for a dose response analysis. The data were amenable to BMD analysis and a BMCL was used 

so the UF for LOAEL to NOAEL extrapolation is not applicable. The selected critical effect was 

observed in longer term studies (3-months and 2-yrs) at similar doses and appeared to be a 

persistent and sensitive effect. 

Data gaps have been identified that are associated with uncertainties specific to the 

developmental and reproductive toxicities of vanadium pentoxide following inhalation exposure. 

Studies that used intraperitoneal injection to study pregnant rats exposed to vanadium pentoxide 

suggest that exposure to the developing fetus may have adverse health effects. However, no 

inhalation studies have assessed the risk to the developing fetus. The database also does not 
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include a comprehensive multigenerational reproductive study to help establish the full range of 

developmental endpoints and thus represents a gap in the database. To account for the lack of 

inhalation developmental studies and for the lack of multigenerational reproductive toxicity 

studies to establish the range of toxicities across development, a full uncertainty factor of 10 was 

applied to the chronic RfC derivations. 

 Overall confidence in the chronic RfC is medium. Confidence in the principal study 

(NTP, 2002) is high. It is a well-conducted study that used rats and mice, an adequate number of 

animals, and exposure at a range of doses. Multiple toxicity endpoints were assessed. However, 

confidence in the overall database is medium. The NTP study is the only chronic animal study 

available. Recent mechanistic studies have investigated vanadium pentoxide-induced pulmonary 

fibrosis and have contributed to a better understanding of a putative mode of action for 

pulmonary fibrosis in response to vanadium pentoxide. Health effects reported among workers 

exposed to vanadium pentoxide and other vanadium compounds in dust are consistent with 

effects observed in experimental studies. Reflecting high confidence in the principal study and 

medium confidence in the database, confidence in the RfC is medium. 

5.4. CANCER ASSESSMENT 

 

5.4.1 Choice of Study/Data – with Rationale and Justification 

 The 2-year NTP (2002) inhalation cancer bioassay reported an increased incidence of 

alveolar/bronchiolar adenomas or carcinomas in male F344/N rats and equivocal evidence of 

carcinogenic activity of vanadium pentoxide in female F344/N rats at the high dose. Male and 

female B6C3F1 mice had even greater incidences of these lesions, with a statistically 

significantly increased incidence of alveolar/bronchiolar adenomas or carcinomas in both male 

and female B6C3F1 mice following inhalation exposure to ≥ 1 mg/m3

 of vanadium pentoxide 

(NTP, 2002) (Table 5-8). These tumor types are considered relevant to humans. Human data on 

the carcinogenic potential of inhalation exposure to vanadium pentoxide are not available. There 

are no human or laboratory animal data to determine the carcinogenicity of vanadium pentoxide 

by the oral or dermal route. 

Table 5-8. Incidences of Respiratory Tumors in Mice Exposed to Vanadium Pentoxide in the 2 

Year Inhalation Study (NTP, 2002) 

Exposure Group 
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Tumor Typea Historical 

Control (% 

Historical 

Control) 

Control 1 mg/m3 2 mg/m3 4 mg/m3

Male Mice 

Number of animals examined 1071 50 50 50 50 

Alveolar/bronchiolar 

adenomab

201 (19%) 13 (26%) 16 (32%) 26c

(53%) 

15 (30%) 

Alveolar/bronchiolar 

carcinoma 

97(9%) 12 (24%) 29c (58%) 30c

(60%) 

35c (70%) 

Alveolar/bronchiolar 

adenoma or carcinoma 

285 (26.8%) 22 (28%) 42c (84%) 43c

(86%) 

43c (86) 

Female Mice 

Number of animals examined 1075 50 50 50 50 

Alveolar/bronchiolar 

adenoma 

67 (6.3%) 1 (2%) 17c (34%) 23c

(46%) 

19c (38%) 

Alveolar/bronchiolar 

carcinoma 

43 (3.9%) 0 (0%) 23c (46%) 18c

(36%) 

22c (44%) 

Alveolar/bronchiolar 

adenoma or carcinoma 

109 (10.1%) 1 (2%) 32c (64%) 35c

(70%) 

32c (64%) 

a

Number of animals with tumor; numbers in parentheses indicate percent incidence; particle size mass mean aerodynamic 

diameter + geometric standard deviation (MMAD±GSD): 1 mg/m3

= 1.3±2.9; 2 mg/m3= 1.2±2.9; 4 mg/m3=1.2±2.9 b

Historical incidence of alveolar/bronchiolar adenoma male B6C3F1 mice fed in inhalation chamber controls given NIH-07 diet. c

Significantly different from control by the Poly-3 test (p≤0.01) 

5.4.2 Dose-Response Data 

 Data on the incidences of alveolar/bronchiolar adenomas or carcinomas in male and 

female mice from the NTP (2002) study were used for cancer dose-response assessment. These 

data are shown in Table 5-9. 

5.4.3 Dose Adjustments and Extrapolation Methods 

 

 The NTP (2002) 2-year carcinogenicity study in mice was used for the derivation of an 

inhalation unit risk, based on the dose-response relationship for alveolar/bronchiolar neoplasms 

(adenoma and carcinoma). 

Using the RDDR computer program, as specified in the RfC guidelines (U.S. EPA, 

1994b), HECs (in mg/m3

) were calculated at each exposure level for male and female mice using 

mean body weights for males and females reported by NTP (2002) and the average particle size 

MMAD±GSD of 1.26±1.87 as reported by NTP (2002). HECs were calculated by multiplying 

Conc[ADJ] by the RDDR for male and female mice (Table 5-9). 
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Table 5-9: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year Inhalation 

Studies (NTP, 2002) 

Concentration as 

Reported a (mg/m3) 

Continuous Exposure 

Adjustment Factor b

RDDR c HEC d (mg/m3

) 

Pulmonary Pulmonary 

Male Mice (B6C3F1) 

0 0.179 1.168 0.00 

1 0.179 1.168 0.21 

2 0.179 1.168 0.42 

4 0.179 1.134 0.81 

Female Mice (B6C3F1) 

0 0.179 1.168 0.00 

1 0.179 1.143 0.20 

2 0.179 1.077 0.38 

4 0.179 1.023 0.73 a

 “Toxicology and carcinogenesis studies of vanadium pentoxide in F344/N rats and B6C3F1 Mice”, NTP, 2002. 

b

 “Continuous Exposure Adjustment Factor” = (6/24) * (5/7); animals were exposed to vanadium pentoxide 6 hours 

per day and 5 days per week. c

 Please refer to Appendix Table C-4. 

d

 HEC=Human Equivalent Concentration = “Concentration as Reported” * “Continuous Exposure Adjustment 

Factor ” * “RDDR”.

 

According to the U.S. EPA Guidelines for Carcinogen Risk Assessment (US EPA, 

2005a), for each tumor response, a POD from the observed data should be estimated to mark the 

beginning of extrapolation to lower doses. The POD is an estimated dose near the lower end of 

the observed range without significant extrapolation to lower doses.10 Since all non-control 

concentrations from the NTP carcinogenesis studies (2002) showed a plateau response, the data 

set provided limited information about the concentration-response relationship because the 

complete range of response from background to maximum must occur somewhere below the 

lowest dose. Therefore, a BMR based on the response at the control concentration and the first 

non-control concentration was calculated (Table C-6), and then used for estimation of POD 

(BMCL, extra risk of 0.71 for male mice, 0.67 for female mice). 

Modeling was performed using the Benchmark Dose Modeling Software (BMDS; 

Version 2.1.2) developed by the National Center for Environmental Assessment (U.S. EPA, 

2000b). The incidence of alveolar/bronchiolar adenomas and carcinomas in mice were 

combined; males and females were modeled separately (Table 5-10).Models were run using the 

 

10 If the POD is above some data points, it can fail to reflect the shape of the concentration-response curve at the 

lowest doses and can introduce bias into subsequent extrapolations. However, if the POD is far below all observed 

data points, it can introduce model uncertainty and parameter uncertainty that increase with the distance between the 

data and the POD. Use of a POD at the lowest level supported by the data seeks to balance these considerations. 
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default restrictions on parameters built into the BMD software. Goodness-of-fit was evaluated 

using the Chi-square statistic calculated by the BMDS program. Acceptable global goodness of 

fit was a p-value greater than or equal to 0.1. Each data set was first fitted with the dichotomous 

multi-stage cancer model; if the goodness-of-fit p-value was < 0.05, other dichotomous models 

were fitted; if still no model showed adequate goodness of fit p-value ≥ 0.05, the highest dose 

was dropped for further modeling. 

Table 5- 10. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar Adenoma 

and Carcinoma in Male Mice, NTP (2002). 

Model a

Goodness of Fit 

BM

R 

HEC 

PValu

e

AIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3) 

BMCLc

(mg/m3) 

Primary Cancer Models 

MultistageCancer Stage 

1,2 and 3 

0.01 207.

0 2.05 0.72 

Extr

a 

Risk 

71% 

0.532 0.379 

Other Dichotomous Models 

LogLogistic 0.19 200.

6 -1.42 0.04 

Extr

a 

Risk 

71% 

0.360 0.208 

LogProbit 0.88 199.

6 0.13 -0.06 0.146 failed 

Gamma 0.01 207.

0 2.05 0.72 0.532 0.379 Weibull 

Logistic 0.00 209.

4 2.15 0.96 0.609 0.447 

Probit 0.00 210.

4 2.19 -1.54 0.654 0.495 

a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

The BMDS modeling results for models meeting goodness-of-fit criteria are summarized 

in Appendix C. For incidence data in male mice, the log-logistic model was the only model that 

met goodness-of-fit criteria when all three dose groups were included, predicting BMC71 and 

BMCL71 values of 0.360 and 0.208 mg/m3

, respectively (Appendix C). The multi-stage model fit 

the incidence data for male mice when the high dose was dropped, predicting BMC71 and 

BMCL71 values of 0.306 and 0.220 mg/m3

, respectively. 
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None of the dichotomous models fit tumor incidence data for female mice when all three 

dose groups were included. One model (log-logistic) fit the incidence data for female mice when 

the high dose was dropped, predicting BMC67 and BMCL67 values of 0.237 and 0.161 mg/m3, 

respectively. 

The BMCL71 of 0.208 mg/m3 for male mice was selected as the point of departure (POD) 

for derivation of the inhalation unit risk as as this was the only model fit when including all 

doses for analysis of lung tumor formation following inhalation exposure to vanadium pentoxide. 

5.4.4 Inhalation Unit Risk 

 Data to support a mode of action for the carcinogenicity of vanadium pentoxide are 

insufficient, although some data suggest that either a mutagenic or a cytotoxic and reparative 

proliferation mode of action is operative. In the absence of such data, extrapolation from the 

point of departure to lower doses was conducted by using a linear approach. 

 The inhalation unit risk represents an upper bound, continuous lifetime exposure risk 

estimate and is calculated as BMR/BMCL [0.71/(0.208 mg/m3

)]. The HEC BMCL71 for extra 

risk of alveolar/bronchiolar adenomas or carcinomas in male B6C3F1 mice exposed to vanadium 

pentoxide results in an inhalation unit risk of 3.4 (mg/m3

)

–1. This value was derived by linear 

extrapolation to the origin from the point of departure of 0.208 mg/m3 and represents an upperbound estimate. 

5.4.5 Oral Cancer Slope Factor 

 No human data or animal studies relevant to the carcinogenicity of vanadium pentoxide 

following oral exposure were located in the published literature. Therefore, an oral cancer slope 

factor is not derived. 

5.4.6 Uncertainties in Cancer Risk Values 

 Extrapolation of study data to estimate potential risks to human populations from 

exposure to vanadium pentoxide has engendered some uncertainty in the results. Several types 

of uncertainty may be considered quantitatively, but other important uncertainties cannot be 

considered quantitatively. Section 5.4.5.1 and Table 5-11 summarize principal uncertainties. 

 Carcinogenicity due to chronic exposure of vanadium pentoxide was observed in two 

species (NTP, 2002), with the carcinogenicity more definitive in mice than in rats, particularly 

female rats, where the increased incidence of neoplasms did not exceed what would be expected 

due to spontaneous tumor formation. Similarly, spontaneous tumors were observed in male rats 
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at control levels, though tumor incidence increased in male rats in response to exposure to 

vanadium pentoxide. The confidence in the database is low. Respiratory tract carcinogenicity 

was reported in two rodent species (i.e., mice and rats) in awell-conducted NTP study (2002) and 

supported by a study in mice (Rondini et al., 2010). Human variability in response to vanadium 

pentoxide is unknown and, humans occupationally exposed to vanadium pentoxide are often 

simultaneously exposed to other valence states of vanadium and to other inhaled environmental 

toxicants simultaneously. Genotoxicity is equivocal and no further mode of action information 

is available. Overall confidence in the inhalation unit risk is low. 

 Choice of low-dose extrapolation approach. The Mode of Action (MOA) is a key 

consideration in clarifying how risks should be estimated for low-dose exposure. A linear lowdose extrapolation approach was used to estimate human carcinogenic risk associated with 

vanadium pentoxide exposure due to the unavailability of data that supports any specific mode of 

carcinogenic action of vanadium pentoxide. 

Dose metric. Vanadium exists in the +5 valence state in vanadium pentoxide. Other 

valence states ranging from -1 to +5 exist. Frequently, vanadium exposures involve a mixture of 

vanadium compounds ranging mostly from +3 to +5 valence state. The carcinogenic potential of 

other valence states of vanadium has not been established. It is not known whether vanadium 

pentoxide dissociates to other valence states with known carcinogenic potential or whether some 

other valence state or some combination of +5 and other valence states is responsible for the 

observed toxicity. If the actual carcinogenic moiety is proportional to administered exposure, 

then use of administered exposure as the dose metric is the preferred choice. 

Statistical uncertainty at the point of departure. Parameter uncertainty can be assessed 

through confidence intervals. Each description of parameter uncertainty assumes that the 

underlying model and associated assumptions are valid. For the log-logistic cancer model 

applied to the male mice data, there is a reasonably small degree of uncertainty at a 71% increase 

in tumor incidence (the point of departure for linear low-dose extrapolation). 

Bioassay selection. The study by NTP (2002) was selected for development of an 

inhalation unit risk. This was a well-designed study, conducted in both sexes in two species with 

an adequate number of animals per dose group. The number of test animals allocated among the 

two dose levels and an untreated control group was adequate, with examination of appropriate 

toxicological endpoints in both sexes of rats and mice. Both genders of mice exhibited a 

statistically significant increased incidence of lung tumors. 

Choice of species/gender: The inhalation unit risk for vanadium pentoxide was quantified 

using the tumor incidence data for male mice which was more amenable to BMD modeling than 

tumor incidence in female mice. In addition, lung neoplasm incidence was reported in male and 
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female rats, though neither gender of rat was as sensitive as mice. A 71% tumor incidence level 

was observed in female mice at the lowest exposure level (1 mg/m3), suggesting that lower doses 

may have revealed more information about low dose region of the dose response curve. Male 

mice demonstrated a high background rate of lung tumors, with spontaneous lung neoplasms 

observed in male mice at control levels (up to 28% of male mice). Tumor incidence increased 

significantly (84%) at the lowest dose level tested (1 mg/m3). While these incidence response 

rates were higher in male mice than those of the females at the comparable exposure level, 

suggesting greater sensitivity of the male mice, there is no information concerning the doseresponse relationships at lower exposure levels.In other words, the behavior of vanadium 

pentoxide at 1.0 mg/m3 in male mice may not inform the tumor response to vanadium pentoxide 

at lower exposures. 

 Relevance to humans. In the absence of direct human data, the most appropriate animal 

bioassays to use in the derivation of cancer risk values are chronic (i.e., lifetime) studies in two 

species of rodents. The inhalation unit risk was derived from the combined tumor incidence of 

lung adenomas and carcinomas in male mice. The information investigating the mode of action 

of the lung tumors observed in the chronic animal bioassay, however, is limited. The 

genotoxicity studies provide inadequate evidence of a genotoxic mode of action, and there are 

inadequate data to support alternative mode-of-action hypotheses. 

Human population variability. The extent of inter-individual variability in animals for 

vanadium pentoxide metabolism has not been characterized. Strain differences in the response 

to vanadium pentoxide-induced pulmonary fibrosis in rodents suggests a genetic component to 

susceptibility. Moreover, humans occupationally exposed to vanadium pentoxide are often 

simultaneously exposed to other valence states of vanadium and to other inhaled environmental 

toxicants simultaneously. This lack of understanding about potential differences in metabolism 

and susceptibility across exposed human populations thus represents a source of uncertainty. 

Table 5-11. Summary of uncertainty in the vanadium pentoxide cancer risk assessment. 

Consideration/ 

 Approach 

Impact on 

inhalation unit 

risk Decision Justification 
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Consideration/ 

 Approach 

Impact on 

inhalation unit 

risk Decision Justification 

Low-dose 

extrapolation 

procedure 

Departure from 

EPA’s Guidelines 

for Carcinogen 

Risk Assessment 

POD paradigm, if 

justified, could ↓

or ↑ slope factor 

an unknown 

extent 

Log-logistic 

cancer model 

to determine 

POD, linear 

low-dose 

extrapolation 

from POD 

Available MOA data do not inform 

selection of dose-response model. 

Dose metric Alternatives 

could ↑ or ↓ slope 

factor by an 

unknown extent 

Used 

administered 

exposure 

Experimental evidence supports a role of 

other valence states of vanadium in the 

body on health effects, but no data exists 

to support carcinogenicity due to other 

forms of vanadium. 

Cross-species 

scaling 

Alternative 

methods could ↓

or ↑ inhalation 

unit risk [e.g., 

3.5-fold ↓

(scaling by BW) 

or ↑ 2-fold 

(scaling by BW2/3

)] 

RDDR RDDR software was used to adjust for 

toxicokinetic differences in inhalation 

dosimetry. 

Statistical 

uncertainty at 

POD 

↓ slope factor if 

MLE used rather 

than lower bound 

on POD 

LEC (method 

for calculating 

reasonable 

upper bound 

slope factor) 

Lower bound is 95% confidence interval 

on administered exposure. 

Bioassay Alternatives 

could ↑ or ↓ slope 

factor by an 

unknown extent 

NTP study Alternative bioassays were unavailable. 

Species /gender 

combination 

Human risk could 

↓ or ↑, depending 

on relative 

sensitivity 

Male mice 

lung cancer 

There are no MOA data to inform 

extrapolation approach for any choice. It 

was assumed that humans are as sensitive 

as the most sensitive rodent gender/species 

tested; true correspondence is unknown. 

The carcinogenic response occurs across 

genders and species. 
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Consideration/ 

 Approach 

Impact on 

inhalation unit 

risk Decision Justification 

Human 

relevance of 

mouse tumor 

data 

Human relevance 

of mouse tumor 

data could ↓ slope 

factor 

Lung tumors in 

mice are 

relevant to 

human 

exposure 

Vanadium pentoxide may be carcinogenic 

through an unknown mode of action. 

Human 

population 

variability in 

metabolism and 

response/ 

sensitive 

subpopulations 

Low-dose risk ↑

to an unknown 

extent 

Considered 

qualitatively 

No data to support range of human 

variability/sensitivity. 
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6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE 

RESPONSE

6.1 Human Hazard Potential 

Vanadium is a metal commonly found in ores, tars, coals and oils and is used as an alloy in 

steel. The toxicity of vanadium depends on its valence state, which can range from -1 to +5, 

depending on pH and other factors. Vanadium pentoxide (V2O5), sodium metavanadate 

(NaVO3), and ammonium metavanadate (NH4VO3) all contain vanadium in the +5 oxidation 

state. This Toxicological Review focuses exclusively on vanadium pentoxide (V2O5), the most 

common form of vanadium used commercially. In addition, V2O5 is the only compound that is 

covalently bonded. Occupational exposure to vanadium pentoxide occurs primarily via 

inhalation of dust generated during vanadium processing and fuel-oil ash generation during 

cleaning of oil-burning boilers and furnaces.

Toxicokinetics of orally administered vanadium pentoxide is not available in humans. 

Kucera et. al. (1992) attempted to measure vanadium in the hair of children who had been 

exposed to vanadium in drinking water, but exposure could not be tied to vanadium pentoxide 

specifically. Oral toxicokinetic studies in animals are limited. One study investigated the 

toxicokinetics of components of various metals, including vanadium, in female B6C3F1 mice 

(Radike et al., 2002). In this study, vanadium was detected in small intestine, kidney and the 

femur. Similarly, there are a few studies that evaluated the toxicokinetics of inhaled vanadium, 

but there are no data in humans. Occupational studies of inhaled vanadium pentoxide indicate 

that vanadium is absorbed by humans, and levels in blood and urine rapidly declined following 

exposure (Kiviluoto et al., 1981b). Results of toxicokinetics studies of inhaled or intratracheally 

administered vanadium pentoxide in rats show that vanadium pentoxide is absorbed from the 

lung, undergoes a wide distribution to liver, kidney, bone, blood, gastrointestinal tract, and 

ovary, and is eliminated primarily in the urine (NTP 2002; Dill et al., 2004; Roshchin et al., 

1980). 

The animal oral toxicity database reported decreased hair cystine (Mountain et. al., 1953, 

Stokinger et. al., 1953), hematological effects, including a decrease in RBC and hemoglobin 

(Mountain et. al., 1953), and a variety of reproductive and developmental effects following 

exposure to vanadium pentoxide (Altamirano et. al., 1993; Zhang et. al., 1993). 

Studies of human exposure to inhaled vanadium pentoxide include primarily 

occupational reports and one controlled human exposure study. Several case study summaries 

reported upper and lower respiratory tract irritation and inflammation among workers with 
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inhalation exposure to vanadium pentoxide and other vanadium compounds in dust during 

vanadium processing or to fuel oil ash during cleaning and maintenence of oil burning boilers 

(section 4.1.2). However, the chemical composition of the fuel-oil ash and vanadium dust or 

exposure measurements for vanadium pentoxide generally were not reported. Thus, in many 

cases, specific relationships between vanadium pentoxide and adverse respiratory effects cannot 

be definitively determined. Sjöberg (1955) published seven case reports of vanadium-induced 

bronchitis in workers cleaning boilers where the concentrations of vanadium pentoxide particles 

(10-20 μ in diameter) in the air were 2 – 85 mg/m3

. Self-reported respiratory symptoms 

included cough, rhinitis, wheeze, sore throat, and conjunctivitis. All symptoms resolved by two 

weeks post-exposure, but would reappear upon re-exposure. Of 100 workers occupationally 

exposed to vanadium pentoxide fume (0.05 – 5.3 mg/m3

) via an oil-to-coal power plant 

conversion, 74 reported severe respiratory tract irritation (Levy et al., 1984). Estimated daily 

nasal and lung dose of vanadium was associated with incidence and severity of upper airway 

symptoms (nasal congestion/irritation, throat irritation) and lower airway symptoms (chest 

tightness, wheeze, cough, and sputum production) in a dose-related manner in a prospective 

clinical study of boilermakers and utility workers involved in the overhaul of a large, oil-fired 

boiler over a six week period (Woodin et al., 1998, 1999, 2000). Geometric mean concentrations 

of vanadium (9-10 hour shifts) measured in the breathing zone ranged from 1.1 – 8.9 μg/m3

. 

Reductions in pulmonary function were measured among boilermakers with exposure to fly ash 

for weeks or years, however an association with vanadium has not been established (Woodin et 

al., 1999; Hauser et al., 1995a; 2001).There are no reported cases of cancer in workers examined 

over sufficient latency period as a result of exposure to vanadium pentoxide. 

 Respiratory effects in experimental animals are well documented and include lesions in 

the nasal compartment, larynx, and lung. In addition to respiratory effects observed in animals 

(NTP, 2002; Knecht et. al., 1985, 1992), there are some animal studies documenting changes to 

spermatogenesis and testicular ultrastructural changes (Mussali-Galante et. al., 2005) and CNS 

effects (Colin-Barenque et. al., 2007; Avila-Costa et. al., 2004, 2005, 2006) in response to 

inhaled vanadium pentoxide. Following repeated inhalation to vanadium pentoxide, the 

respiratory system is the most sensitive target for noncancer toxicity in rats and mice. Short term 

inhalation exposure (13-days) in F344 rats and B6C3F1 mice was associated with histiocytic 

infiltration at 1.0 mg/m3, and short-term and subchronic inhalation exposure (3 month) in F344 

rats and B6C3F1 mice was associated with increased lung epithelial hyperplasia and 

inflammation at 2.0 mg/m3 (NTP, 2002). Long term exposure (2yr) in F344 rats and B6C3F1 

mice similarly resulted in increased incidence of respiratory toxicity and carcinogenicity (NTP, 

2002). Lung inflammation was observed at 1.0 mg/m3

 and lung hyperplasia was observed at 2.0 
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mg/m3 in female rats. Lung inflammation and hyperplasia were observed at 1.0 mg/m3 in both 

male and female mice. In male and female mice, nonneoplastic lesions also occurred in the 

larynx (squamous metaplasia of epiglottis epithelium) and nasal tissues (degeneration and 

atrophy of olfactory epithelium and degeneration of respiratory epithelium) at 1 mg/m3

; it should 

be noted that 1 mg/m3

 was the lowest dose in mice. In mice exposed to 1 mg/m3, lesions were 

observed in the nose, bronchioles and lung of male mice and the nose, larynx, bronchioles and 

lung of female mice. Chronic, active inflammation and interstitial fibrosis was observed in male 

rats at a LOAEL of 1 mg/m3 (NOAEL 0.5 mg/m3). The nasal and laryngeal lesions appear to be 

among the most sensitive effects observed at the lowest dose tested. Moreover, multiple lesion 

types were observed in both sexes of rats and thus, the LOAEL of 0.5 mg/m3

 for nasal and 

laryngeal lesions was selected as the critical effect. 

 Reproductive and developmental studies reveal various altered endpoints in response to 

vanadium pentoxide via oral and inhalation routes. Vanadium pentoxide delivered orally to 

weanling rats for three days caused a significant increase in alkaline phosphatase activity and 

DNA content in the diaphysis of femoral bones suggesting that vanadium pentoxide may be 

linked to bone formation in the developing rat (Yamaguchi et. al., 1989). Mussali-Galante et. al., 

(2005) identified accumulation of vanadium pentoxide in the testes after 1 week of inhalation 

exposure in male CD-1 mice (0.02M or 1.4 mg V/m3). Gamma tubulin was significantly 

decreased in testes exposed to vanadium pentoxide and may suggest changes in microtubule 

function that may impact spermatogenesis. In a follow-up study, Fortoul et. al. (2007) reported 

necrotic cell death in spermatogonia and increased nuclear distortion in spermatocytes in male 

CD-1 mice exposed by inhalation to vanadium pentoxide (0.02M or 1.4 mg V/m3). 

 A number of intraperitoneal studies have evaluated reproductive and developmental 

endpoints. Common reproductive effects include increased reproductive organ weights in male 

rats (Altamirano et. al., 1991), increased incidence of apoptotic spermatogonia in male mice 

(Aragon et. al., 2005) and reduced sperm motility, reduced sperm count, and increased numbers 

of abnormal sperm in male CD1 mice (Altamirano-Lozano et. al., 1996). In developmental 

studies, reduced ossification in the developing fore and hindlimbs of fetuses have been reported 

in response to intraperitoneal exposure to vanadium pentoxide during gestation days 6-15 in 

pregnant CD-1 mice (Altamirano-Lozano et. al., 1993) and Wistar rats (Zhang et. al., 1993a, b). 

Other reported effects range from reduced fetal weight and increased placenta weight. 

The genotoxicity database for vanadium pentoxide is limited. The evidence for 

genotoxicity in humans is limited. There are few studies examining genotoxicity in humans in 

vivo, with equivocal results. Ivancsits et. al. (2002) reported no differences in DNA strand 

breaks, oxidative damage, or sister chromatid exchange frequency in leukocytes between control 
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and vanadium pentoxide-exposed workers. Ehrlich et. al., (2008) noted changes in DNA 

stability and DNA repair in leukocytes of occupationally-exposed workers as compared to 

controls. Studies have demonstrated a genotoxic effect of vanadium pentoxide on human cells in 

vitro. Ivancsits et al. (2002) demonstrated significant increases in DNA damage as measured by 

the Comet assay in both leukocytes and fibroblasts but with different dose sensitivity, while 

Kleinsasser et. al (2003) noted DNA migration differences occurred dose-dependently in 

peripheral blood lymphocytes but not in nasal mucosa cells. Earlier studies in human 

lymphocyte cultures also demonstrated increased aneuploidy (Ramirez et al. 1997; Rojas et al. 

1996) and DNA damage (Roldan and Altamirano 1990) following exposure to vanadium 

pentoxide. Thus, vanadium pentoxide-induced mutagenicity may occur at doses higher than 

those measured in these occupational exposures, may be tissue-specific and may be associated 

with oxidative stress rather than direct DNA damage. Experimental data in animals provide 

evidence of some types of genotoxicity following in vivo exposure to vanadium pentoxide. 

Vanadium pentoxide administered by inhalation to mice or rats did not increase the frequency of 

micronucleated normochromatic erythrocytes in peripheral blood (NTP, 2002). Genotoxicity 

assessed in male CD-1 mice following intraperitoneal injection caused no treatment related 

effects in mitotic index, average generational time, or sister chromatid exchange (AltamiranoLozano et. al., 1993). However, DNA damage was detected in six organs from vanadium 

pentoxide-treated mice via intraperitoneal injection (Altamirano-Lorano et. al., 1999). Vanadium 

pentoxide produced gene mutations in two bacterial test systems (Kada et. al., 1980; Kanematsu 

et. al., 1980) but negative results in the NTP (2002) study. Vanadium pentoxide produced DNA 

strand breaks, aneuploidy, and micronuclei induction but did not produce chromosomal 

aberrations or sister chromatid exchange in various cell lines (Ivancsits et al. 2002; Kleinsasser 

et al. 2003; Ramirez et al. 1997; Rojas et al. 1996; Roldan and Altamirano 1990; Zhong et al., 

1994). 

 Most of the effects of vanadium pentoxide are thought to be produced by the parent 

compound, primarily by inducing cell damage and pulmonary fibrosis (NTP, 2002, Bonner et. 

al., 1998, Bonner et. al., 2000). Pulmonary fibrosis is mediated either directly by vanadium 

pentoxide-induced changes to cell signaling molecules or via vanadium pentoxide-induced 

oxidative stress that induces cellular changes leading to fibrosis (Bonner et. al., 1998, Rice et. 

al., 1999, Ingram et. al., 2003). It is possible that pulmonary fibrosis could be a key event 

leading to eventual tumorigenesis. 

 Vanadium pentoxide is “likely carcinogenic to humans” by the inhalation route of 

exposure under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a). Existing 

cancer data comes from two animal species (mice, rats) reported in one well-characterized study 
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(NTP, 2002). Increased incidence of pulmonary adenomas and carcinomas were observed in 

male and female mice exposed to vanadium pentoxide for 2 years. There is evidence of 

carcinogenicity in male rats exposed to vanadium pentoxide for 2 years, as respiratory tumor 

incidence exceeded that in historical controls. In female rats, the incidence of respiratory 

tumorigenesis in response to vanadium pentoxide did not exceed historical controls. Tumor 

incidence has not been documented in humans. 

Information available on the carcinogenic effects of V2O5 via the inhalation route is 

limited to examination of the respiratory tumors. Information on the carcinogenic effects of 

V2O5 via the oral and dermal routes in humans or animals is absent. Based on the observance of 

only respiratory tumors following inhalation exposure, and in the absence of information to 

establish a mode of action, this cancer descriptor applies only to the inhalation route of exposure. 

Therefore, the database has “inadequate information to assess carcinogenic potential” of V2O5 

via the oral or dermal route. 

The mode of action underlying tumorigenicity in rats and mice has not been established. 

The genotoxicity database for vanadium pentoxide is equivocal, including both positive and 

negative studies for mutation, DNA damage and chromosomal aberrations. A nongenotoxic 

mode of action hypothesis involving hyperplasia and development of fibrotic pulmonary lesions 

is supported by the presence of hyperplastic lesions and pulmonary fibrosis at earlier time points 

and at lower doses. However, the dose-response relationship is not robust and a clear 

relationship linking these effects to the tumor response has not been established. It is unknown 

whether cytotoxicity may be a required precursor event for vanadium pentoxide-induced cell 

proliferation. Sufficient data regarding a plausible dose response and temporal progression from 

cytotoxicity to hyperplasia to fibrosis to tumorigenesis are not available. 

6.2. Dose Response 

6.2.1 Noncancer 

Limited studies are available examining the toxicity of vanadium pentoxide following 

oral exposure in humans or laboratory animals. Decreased RBC count and hemoglobin was 

observed following subchronic oral exposure to vanadium pentoxide in rats (Mountain et. al. 

1953). The authors reported the decrease of RBC as a mean with no measure of variability 

between animals, therefore the continuous data was not amenable to BMD modeling. Derivation 

of an RfD was based on a NOAEL of 10.5 mg/kg-d for the critical effect decreased RBC counts 

and divided by a total UF of 3000, 3 to represent interspecies toxicodynamic uncertainties, 10 for 

interhuman variability in the absence of quantitative information on the variability of response in 
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humans, 10 for extrapolation from subchronic to chronic study and 10 for database deficiencies 

to arrive at the chronic RfD of 9 x 10 -4 mg/kg-day. 

Confidence in the principal study for derivation of the RfD (Mountain et al., 1953) is 

low. Mountain et al. (1953) is a well-conducted study with numerous doses, but is a subchronic 

study with a small sample size (n = 5) for one species of rodents (Wistar rat), using one gender 

(male), limited endpoints and time points. Confidence in the critical effect is medium. 

Hematological effects have been documented in other rodent species in response to inhaled 

vanadium pentoxide (NTP, 2002). However, confidence in the overall database is low. 

Mountain et al. (1953) is the single relevant peer-reviewed study for derivation of the chronic 

RfD. Thus, overall confidence in the chronic RfD is low. 

Pulmonary effects have been documented in numerous species, including humans and 

primates, in response to inhaled vanadium pentoxide. Inflammation and histiocytic infiltrate are 

common hallmarks of initial vanadium-induced pulmonary injury. The database also includes 

occupational (inhalation) and laboratory animal (inhalation and oral) studies demonstrating 

possible immunotoxicity following exposure to vanadium pentoxide. In addition, the database 

includes studies of neurotoxicity and reproductive and developmental toxicity studies following 

inhalation exposure to vanadium pentoxide in rodents. Overall, the lung is the most sensitive 

target for noncancer toxicity in rats and mice following chronic inhalation exposure to vanadium 

pentoxide. Nonneoplastic lung lesions (specifically laryngeal lesions) were selected as the most 

sensitive endpoint from a well-conducted chronic study (NTP, 2002; 2-year rodent bioassay). 

The chronic inflammation of the larynx and epithelial hyperplasia of the epiglottis in rats were 

chosen as critical effects because they are the most sensitive effects and the most proximal to 

route of exposure (inhalation). These effects were observed in both male and female rats and 

mice.

The dose-response pattern for laryngeal lesions (NTP, 2002) was amenable to BMD 

modeling and was used for derivation of the chronic RfC. Two laryngeal lesions were selected 

for modeling because they had the lowest Regional Deposited Dose Ratio (RDDR) value and 

corresponding BMCL[HEC]. In accordance with U.S. EPA Benchmark Dose methodology 

(2000b), a benchmark response (BMR) of 10% increase in extra risk was selected to represent a 

minimally adverse level. All available dichotomous models were fit to the incidence data for 

chronic inflammation and for epithelial hyperplasia of the epiglottis. The model with the lowest 

Akaike’s Information Criteria (AIC) value was considered to provide a superior fit. Benchmark 

dose modeling of incidence data for chronic inflammation of the larynx and epithelial 

hyperplasia of the epiglottis in female rats yielded the same BMCL10 of 0.003 mg/m3

. The 

shared BMCL10 of 0.003 mg/m3

 for either chronic inflammation of the larynx or epithelial 
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hyperplasia of the epiglottis was divided by a total UF of 300, 3 to represent interspecies 

toxicodynamic uncertainties, 10 for interhuman variability in the absence of quantitative 

information on the variability of response in humans, and 10 for database deficiencies to arrive at 

the chronic RfC of 1 x 10 -5 mg/m3

. 

Confidence in the principal study for derivation of the RfC (NTP, 2002) is high. NTP 

(2002) is a well-conducted study with numerous doses, a large sample size of two species of 

rodents, using both genders, numerous endpoints and time points. Confidence in the critical 

effect is high. Pulmonary effects have been documented in numerous species, including humans 

and primates, in response to inhaled vanadium pentoxide. Laryngeal lesions are a relevant 

proximal portal of entry target tissue for inhalation exposure and serves as an indicator of 

vanadium pentoxide-induced pulmonary injury. However, confidence in the overall database is 

medium. NTP (2002) remains the single relevant study for use in the derivation of the chronic 

RfC. Thus, overall confidence in the chronic RfC is medium. 

6.2.2 Cancer 

There are no studies identifying cancer effects in following oral exposure to vanadium 

pentoxide in either humans or animals, or following inhalation exposure in humans. 

Under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), the database 

for vanadium pentoxide indicates that it is “likely to be carcinogenic to humans” via the 

inhalation route of exposure. This determination is based predominantly on the NTP (2002) 

study, which found positive evidence of lung tumors in both sexes of mice and male rats after 

chronic vanadium pentoxide inhalation exposure. This weight of evidence conclusion takes into 

consideration the NTP (2002) cancer bioassay, the available human studies, and other laboratory 

animal studies. Information available on the carcinogenic effects of V2O5 via the inhalation route 

is limited to examination of the respiratory tumors. Information on the carcinogenic effects of 

V2O5 via the oral and dermal routes in humans or animals is absent. Based on the observance of 

only respiratory tumors following inhalation exposure, and in the absence of information to 

establish a mode of action, this cancer descriptor applies only to the inhalation route of exposure. 

Therefore, the database has “inadequate information to assess carcinogenic potential” of V2O5 

via the oral or dermal route. 

The increased incidence of lung tumors in male mice observed in the NTP (2002) 104 

week inhalation study was used to calculate the inhalation unit risk for vanadium pentoxide. The 

calculated cancer inhalation unit risk for vanadium pentoxide is 3.4 ug/m3

 for the development of 

alveolar/bronchiolar adenomas or carcinomas in male B6C3F1 mice. This value was derived 

from BMCL10, the 95% lower bound on the dose associated with 71% extra cancer risk of 
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139

respiratory carcinoma in male B6C3F1 mice, by dividing the BMR (0.71) by the BMCL10, and 

represents the upper bound, continuous lifetime exposure estimate of cancer potency. The 

BMCL10, lower 95% bound on exposure at 71% risk, is 2.08 x 10-1 mg/m3 and the slope of the 

linear extrapolation from the BMCL to the origin = 0.71/2.08 x 10-1 mg/m3

 = 3.4 (mg/m3)

-1. A 

linear low-dose extrapolation approach was used to estimate human carcinogenic risk associated 

with vanadium pentoxide exposure due to a lack of data that supports any specific mode of 

carcinogenic action of vanadium pentoxide. Therefore, the derived inhalation unit risk to 

vanadium pentoxide is 3.4 per mg/m3

. 

 Areas of uncertainty exist for this cancer assessment. The log-logistic model was selected 

to model lung tumor incidence in male mice; however, it is unknown how well this model or the 

linear low-dose extrapolation predicts low-dose risks for vanadium pentoxide. The selected 

model, while the best fitting model, is not the only model that adequately describes the data. 

Other models could conceivably be selected to yield different results consistent with the 

observed data, both higher and lower than those included in this assessment. The human 

equivalent inhalation unit risks estimated from the statistically significant increase in lung 

tumors ranged from 1.4 mg/m3

 in male mice to 4.2 mg/m3 in female mice. These tumors are 

considered to be relevant to humans. As there is no information to inform which species or 

gender of animals would be most applicable to humans, the most sensitive group was selected 

for the basis of the inhalation unit risk. 
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140

7. REFERENCES 

ACGIH. (1991). Vanadium pentoxide. In:eds. Cincinnati, OH: American Conference of 

Governmental Industrial Hygienists, 1677-1682. 

Altamirano-Lozano, M; Alvarez-Barrera, L; Basurto-Alcántara, F; et al. (1996) Reprotoxic and 

genotoxic studies of vanadium pentoxide in male mice. Teratogenesis, Carcinogenesis, 

and Mutagenesis 16:7-17. 

Altamirano-Lozano, M; Alvarez-Barrera, L; Roldán-Reyes, E. (1993) Cytogenetic and 

teratogenic effects of vanadium pentoxide on mice. Med Sci Res 21:711-713. 

Altamirano-Lozano, M; Roldán, E; Bonilla, E; et al. (1998) Effect of metal compounds on boar 

sperm motility in vitro. Advances in Experimental Medicine and Biology 444:105-110; 

discussion 110-111. 

Altamirano-Lozano, M; Valverde, M; Alvarez-Barrera, L; et al. (1999) Genotoxic studies of 

vanadium pentoxide (V(2)O(5)) in male mice. II. Effects in several mouse tissues. 

Teratogenesis, Carcinogenesis, and Mutagenesis 19:243-255. 

Altamirano, M; Ayala, ME; Flores, A; et al. (1991) Sex differences in the effects of vanadium 

pentoxide administration to prepubertal rats. Med Sci Res 19:825-826. 

Antao-Menezes, A; Turpin, EA; Bost, PC; et al. (2008) STAT-1 signaling in human lung 

fibroblasts is induced by vanadium pentoxide through an IFN-beta autocrine loop. 

Journal of Immunology 180:4200-4207. 

Aragon, MA; Ayala, ME; Fortoul, TI; et al. (2005) Vanadium induced ultrastructural changes 

and apoptosis in male germ cells. Reproductive Toxicology 20:127-134. 

Assem, FL; Levy, LS. (2009) A review of current toxicological concerns on vanadium pentoxide 

and other vanadium compounds: gaps in knowledge and directions for future research. 

Journal of Toxicology and Environmental Health, Part B: Critical Reviews 12:289-306. 

ATSDR (2009) Draft toxicological profile for vanadium. Atlanta, GA. U.S. Department of 

Health and Human Services Public Health Service, Agency for Toxic Substances and 

Disease Registry http://www.atsdr.cdc.gov/toxprofiles/tp.asp?id=276&tid=50 

Avila-Costa, MR; Colín-Barenque, L; Zepeda-Rodríguez, A; et al. (2005) Ependymal epithelium 

disruption after vanadium pentoxide inhalation A mice experimental model. 

Neuroscience Letters 381:21-25. 

Avila-Costa, MR; Fortoul, TI; Niño-Cabrera, G; et al. (2006) Hippocampal cell alterations 

induced by the inhalation of vanadium pentoxide (V(2)O(5)) promote memory 
DRAFT - DO NOT CITE OR QUOTE 

141

deterioration. NeuroToxicology 27:1007-1012. 

Avila-Costa, MR; Montiel Flores, E; Colin-Barenque, L; et al. (2004) Nigrostriatal modifications 

after vanadium inhalation: an immunocytochemical and cytological approach. 

Neurochemical Research 29:1365-1369. 

Barceloux, DG. (1999) Vanadium. Journal of Toxicology - Clinical Toxicology 37:265-278. 

Bell, M; Ebisu, K; Peng, R; et al. (2009) Hospital Admissions and Chemical Composition of 

Fine Particle Air Pollution. American Journal of Respiratory and Critical Care Medicine 

179:1115-1120. 

Bonner, JC; Lindroos, PM; Rice, AB; et al. (1998) Induction of PDGF receptor-alpha in rat 

myofibroblasts during pulmonary fibrogenesis in vivo. American Journal of Physiology 

274:L72-L80. 

Bonner, JC; Rice, AB; Ingram, JL; et al. (2002) Susceptibility of cyclooxygenase-2-deficient 

mice to pulmonary fibrogenesis. The American Journal of Pathology 161:459-470. 

Bonner, JC; Rice, AB; Moomaw, CR; et al. (2000) Airway fibrosis in rats induced by vanadium 

pentoxide. American Journal of Physiology: Lung Cellular and Molecular Physiology 

278:L209-L216. 

Byczkowski, JZ; Kulkarni, AP. (1992) Vanadium redox cycling, lipid peroxidation and cooxygenation of benzo(a)pyrene-7,8-dihydrodiol. Biochim Biophys Acta 1125:134-141. 

Byrne, AR; Kosta, L. (1978) Vanadium in foods and in human body fluids and tissues. Science 

of the Total Environment 10:17-30. 

Carter, JD; Ghio, AJ; Samet, JM; et al. (1997) Cytokine production by human airway epithelial 

cells after exposure to an air pollution particle is metal-dependent. Toxicology and 

Applied Pharmacology 146:180-188. 

Charles River (2008) Wistar Rat Hematology Available at: 

http://www.criver.com/SiteCollectionDocuments/rm_rm_r_Wistar_rat_hematology_2008

.pdf

Colin-Barenque, L; Martinez-Hernandez, MG; Baiza-Gutman, LA; et al. (2008) Matrix 

metalloproteinases 2 and 9 in central nervous system and their modification after 

vanadium inhalation. Journal of Applied Toxicology 28:718-723. 

Colín-Barenque, L; Martínez-Hernández, MG; Baiza-Gutman, LA; et al. (2007) Matrix 

metalloproteinases 2 and 9 in central nervous system and their modification after 

vanadium inhalation. Journal of Applied Toxicology 28:718-723. 

Conklin, AW; Skinner, SC; Felten, TL; et al. (1982) Clearance and distribution of intratracheally 
DRAFT - DO NOT CITE OR QUOTE 

142

instilled vanadium compounds in the rat. Toxicol Lett 11:199-203. 

Cooper, RG. (2007) Vanadium pentoxide inhalation. Indian J Occup Environ Med 11:97-102. 

Dekker, JM; Schouten, EG; Klootwijk, P; et al. (1997) Heart rate variability from short 

electrocardiographic recordings predicts mortality from all causes in middle-aged and 

elderly men. The Zutphen Study. American Journal of Epidemiology 145:899-908. 

Devereux, TR; Holliday, W; Anna, C; et al. (2002) Map kinase activation correlates with K-ras 

mutation and loss of heterozygosity on chromosome 6 in alveolar bronchiolar carcinomas 

from B6C3F1 mice exposed to vanadium pentoxide for 2 years. Carcinogenesis 23:1737-

1743. 

Dill, JA; Lee, KM; Mellinger, KH; et al. (2004) Lung deposition and clearance of inhaled 

vanadium pentoxide in chronically exposed F344 rats and B6C3F1 mice. Toxicological 

Sciences 77:6-18. 

Dominici, F; Peng, RD; Ebisu, K; et al. (2007) Does the effect of PM10 on mortality depend on 

PM nickel and vanadium content? A reanalysis of the NMMAPS data. Environmental 

Health Perspectives 115:1701-1703. 

Duve, RN; Chandra, JP; Singh, SB. (1981) Open digestion modification of AOAC method for 

determination of mercury in fish. Journal of the Association of Official Analytical 

Chemists 64:1027-1029. 

Edel, J; Pietra, R; Sabbioni, E; et al. (1984) Disposition of vanadium in rat tissues at different 

age. Chemosphere 13:87-93. 

Edel, J; Sabbioni, E. (1988) Retention of intratracheally instilled and ingested tetravalent and 

pentavalent vanadium in the rat. J Trace Elem Electrolytes Health Dis 2:23-30. 

Ehrlich, VA; Nersesyan, AK; Hoelzl, C; et al. (2008) Inhalative exposure to vanadium pentoxide 

causes DNA damage in workers: Results of a multiple end point study. Environmental 

Health Perspectives 116:1689-1693. 

Fortoul, TI; Bizarro-Nevares, P; Acevedo-Nava, S; et al. (2007) Ultrastructural findings in 

murine seminiferous tubules as a consequence of subchronic vanadium pentoxide 

inhalation. Reproductive Toxicology 23:588-592. 

González-Villalva, A; Fortoul, TI; Avila-Costa, MR; et al. (2006) Thrombocytosis induced in 

mice after subacute and subchronic V2O5 inhalation. Toxicology and Industrial Health 

22:113-116. 

Gylseth, B; Leira, HL; Steinnes, E; et al. (1979) Vanadium in the blood and urine of workers in a 

ferroalloy plant. Scand J Work Environ Health 5:188-194. 
DRAFT - DO NOT CITE OR QUOTE 

143

Hauser, R; Eisen, EA; Pothier, L; et al. (2001) A prospective study of lung function among 

boilermaker construction workers exposed to combustion particulates. American Journal 

of Industrial Medicine 39:454-462. 

Hauser, R; Eisen, EA; Pothier, L; et al. (2002) Spirometric abnormalities associated with chronic 

bronchitis, asthma, and airway hyperresponsiveness among boilermaker construction 

workers. Chest 121:2052-2060. 

Hauser, R; Elreedy, S; Hoppin, JA; et al. (1995a) Upper airway response in workers exposed to 

fuel oil ash: nasal lavage analysis. Occupational and Environmental Medicine 52:353-

358. 

Hauser, R; Elreedy, S; Hoppin, JA; et al. (1995b) Urinary vanadium as a biological indicator of 

exposure to vanadium. Occupational and Environmental Medicine 52:353?358. 

HSDB (2008) Vanadium pentoxide, In: National Library of Medicine,. Hazardous Substances 

Databank, Available at: http://toxnet.nlm.nih.gov 

IARC (2006) Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and 

vanadium pentoxide, In: International Agency for Research on Cancer. pp.1-294, Lyon, 

France Available at: 

Ingram, JL; Antao-Menezes, A; Turpin, EA; et al. (2007) Genomic analysis of human lung 

fibroblasts exposed to vanadium pentoxide to identify candidate genes for occupational 

bronchitis. Respiratory Research 8:34. 

Ingram, JL; Rice, AB; Santos, J; et al. (2003) Vanadium-induced HB-EGF expression in human 

lung fibroblasts is oxidant dependent;and requires MAP kinases. American Journal of 

Physiology: Lung Cellular and Molecular Physiology 284:L774-L782. 

Irsigler, GB; Visser, PJ; Spangenberg, PAL. (1999) Asthma and chemical bronchitis in 

vanadium plant workers. American Journal of Industrial Medicine 35:366-374. 

Ivancsits, S; Pilger, A; Diem, E; et al. (2002) Vanadate induces DNA strand breaks in cultured 

human fibroblasts at doses relevant to occupational exposure. Mutation Research 519:25-

35. 

Kada, T; Hirano, K; Shirasu, Y. (1980). Screening of environmental chemical mutagens by the 

rec-assay system with Bacillus subtilis. In: de Serres, FJ.Hollaender, A eds. Chemical 

Mutagens: Principles and Methods for their Detection New York: Plenum, 149-173. 

Kanematsu, N; Hara, M; Kada, T. (1980) Rec assay and mutagenicity studies on metal 

compounds. Mutat Res 77:109-116. 
DRAFT - DO NOT CITE OR QUOTE 

144

Kerckaert, GA; LeBoeuf, RA; Isfort, RJ. (1996) Use of the Syrian hamster embryo cell 

transformation assay for determining the carcinogenic potential of heavy metal 

compounds. Fundamental and Applied Toxicology 34:67-72. 

Kim, JY; Mukherjee, S; Ngo, LC; et al. (2004) Urinary 8-hydroxy-2'-deoxyguanosine as a 

biomarker of oxidative DNA damage in workers exposed to fine particulates. 

Environmental Health Perspectives 112:666-671. 

Kiviluoto, M. (1980) Observations on the lungs of vanadium workers. Occupational and 

Environmental Medicine 37:363-366. 

Kiviluoto, M; Pakarinen, A; Pyy, L. (1981b) Clinical laboratory results of vanadium-exposed 

workers. Archives of Environmental and Occupational Health 36:109-113. 

Kiviluoto, M; Pyy, L; Pakarinen, A. (1979) Serum and urinary vanadium of vanadium-exposed 

workers. Scandinavian Journal of Work, Environment and Health 5:362-367. 

Kiviluoto, M; Pyy, L; Pakarinen, A. (1981a) Serum and urinary vanadium of workers processing 

vanadium pentoxide. International Archives of Occupational and Environmental Health 

48:251-256. 

Kleinsasser, N; Dirschedl, P; Staudenmaier, R; et al. (2003) Genotoxic effects of vanadium 

pentoxide on human peripheral lymphocytes and mucosal cells of the upper aerodigestive 

tract. International Journal of Environmental Health Research 13:373-379. 

Knecht, EA; Moorman, WJ; Clark, JC; et al. (1992) Pulmonary reactivity to vanadium pentoxide 

following subchronic inhalation exposure in a non-human primate animal model. Journal 

of Applied Toxicology 12:427-434. 

Knecht, EA; Moorman, WJ; Clark, JC; et al. (1985) Pulmonary effects of acute vanadium 

pentoxide inhalation in monkeys. American Review of Respiratory Disease 132:1181-

1185. 

Kucera, J; Byrne, AR; Mravcová, A; et al. (1992) Vanadium levels in hair and blood of normal 

and exposed persons. Science of the Total Environment 115:191-205. 

Kucera, J; Lener, J; Mnuková, J. (1994) Vanadium levels in urine and cystine levels in 

fingernails and hair of exposed and normal persons. Biological Trace Element Research 

43-45:327-334. 

Kyono, H; Serita, F; Toya, T; et al. (1999) A new model rat with acute bronchiolitis and its 

application to research on the toxicology of inhaled particulate matter. Industrial Health 

37:47-54. 

Lagorio, S; Forastiere, F; Pistelli, R; et al. (2006) Air pollution and lung function among 

susceptible adult subjects: a panel study. Environmental Health 5:11. 
DRAFT - DO NOT CITE OR QUOTE 

145

Lees, RE. (1980) Changes in lung function after exposure to vanadium compounds in fuel oil 

ash. British Journal of Industrial Medicine 37:253-256. 

Levy, BS; Hoffman, L; Gottsegen, S. (1984) Boilermakers bronchitis: respiratory tract irritation 

associated with vanadium pentoxide exposure during oil-to-coal conversion of a power 

plant. Journal of Occupational and Environmental Medicine 26:567-570. 

Lewis, CE. (1959) The biological effects of vanadium. II. The signs and symptoms of 

occupational vanadium exposure. AMA Arch Ind Health 19:497-503. 

Lewis, RJ, Sr ed. 1997. Hawley's Condensed Chemical Dictionary. New York, NY: John Wiley 

& Sons, Inc., p. 1163. 

Lippmann, M; Ito, K; Hwang, JS; et al. (2006) Cardiovascular effects of nickel in ambient air. 

Environmental Health Perspectives 114:1662-1669. 

Magari, SR; Schwartz, J; Williams, PL; et al. (2002) The association of particulate air metal 

concentrations with heart rate variability. Environmental Health Perspectives 110:875-

880. 

Motolese, A; Truzzi, M; Giannini, A; et al. (1993) Contact dermatitis and contact sensitization 

among enamellers and decorators in the ceramics industry. Contact Dermatitis 28:59-62. 

Mountain, JT; Delker, LL; Stokinger, HE. (1953) Studies in vanadium toxicology; reduction in 

the cystine content of rat hair. A M A Arch Ind Hyg Occup Med 8:406-411. 

Mravcova, A; Jirova, D; Janci, H; et al. (1993) Effects of orally administered vanadium on the 

immune system and bone metabolism in experimental animals. Science of the Total 

Environment Suppl Pt 1:663-669. 

Mukherjee, B; Patra, B; Mahapatra, S; et al. (2004) Vanadium--an element of atypical biological 

significance. Toxicology Letters 150:135-143. 

Musk, AW; Tees, JG. (1982) Asthma caused by occupational exposure to vanadium compounds. 

Medical Journal of Australia 1:183-184. 

Mussali-Galante, P; Rodriguez-Lara, V; Hernandez-Tellez, B; et al. (2005) Inhaled vanadium 

pentoxide decrease gamma-tubulin of mouse testes at different exposure times. 

Toxicology and Industrial Health 21:215-222. 

NIOSH (1983) Health hazard evaluation report HETA 80-096-1359, Eureka Company, 

Bloomington, IL. Washington, DC: U.S. Department of Health and Human Services, 

National Institute of Occupational Safety and Health, PB85163574. 
DRAFT - DO NOT CITE OR QUOTE 

146

NIOSH (2005) Vanadium dust, In: NIOSH Pocket Guide to Chemical Hazard (DHHS (NIOSH) 

Publication No. 2005-149), National Institute for Occupational Safety and Health, 

Department of Health and Human Services, pp.328, Cincinnati, OH Available at: 

http://www.cdc.gov/niosh/npg/npgd0653.html 

NRC (National Research Council). (1983) Risk assessment in the federal government: Managing 

the process. Washington, DC. National Academies Press Available from: 

http://www.nap.edu/openbook.php?isbn=0309033497 

NTP (2002) NTP toxicology and carcinogensis studies of vanadium pentoxide (CAS No.;1314-

62-1) in F344/N rats and B6C3F1 mice (inhalation), In: National Toxicology Program. 

pp.1-343, Washington, DC Available at: 

http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr507.pdf

NTP (2008) Chemical Information Review Document for Oral Exposure to Tetravalent and 

Pentavalent Vanadium Compounds, In: National Toxicology Program, National Institute 

of Environmental Health Sciences, National Institutes of Health, U.S. Department of 

Health and Human Services. pp.p. 5, Research Triangle Park, NC Available at: http://ntpserver.niehs.nih.gov/ntp/htdocs/Chem_Background/ExSumPdf/NIEHS_Vanadium_comp

ounds_508.pdf 

Oberg, SG; Parker, RD; Sharma, RP. (1978) Distribution and elimination of an intratracheally 

administered vanadium compound in the rat. Toxicology 11:315-323. 

O'Neal, SG; Rhoads, DB; Racker, E. (1979) Vanadate inhibition of sarcoplasmic reticulum 

Ca2+-ATPase and other ATPases. Biochem Biophys Res Commun 89:845-850. 

OSHA (2007) Occupational Safety and Health Guideline for Vanadium Pentoxide Dust, In: 

Occupational Safety and Health Administration. Washington, DC. U.S.Department of 

Labor. Available at: 

http://www.osha.gov/SLTC/healthguidelines/vanadiumpentoxidedust/recognition.html 

Parker, RD; Sharma, RP. (1978) Accumulation and depletion of vanadium in selected tissues of 

rats treated with vanadyl sulfate and sodium orthovanadate. J Environ Pathol Toxicol 

2:235-245. 

Patel, MM; Hoepner, L; Garfinkel, R; et al. (2009) Ambient metals, elemental carbon, and 

wheeze and cough in New York City children through 24 months of age. American 

Journal of Respiratory and Critical Care Medicine 180:1107-1113. 

Pazynich, VM. (1966) Maximum permissible concentration of vanadium pentoxide in the 

atmosphere. Gigiena i Sanitariia 317-9:6-12. 

Pierce, LM; Alessandrini, F; Godleski, JJ; et al. (1996) Vanadium-induced chemokine mRNA 
DRAFT - DO NOT CITE OR QUOTE 

147

expression and pulmonary inflammation. Toxicology and Applied Pharmacology 138:1-

11. 

Pinon-Zarate, G; Rodriguez-Lara, V; Rojas-Lemus, M; et al. (2008) Vanadium pentoxide 

inhalation provokes germinal center hyperplasia and suppressed humoral immune 

responses. Journal of Immunotoxicology 5:115-122. 

Radike, M; Warshawsky, D; Caruso, J; et al. (2002) Distribution and accumulation of a mixture 

of arsenic, cadmium, chromium, nickel, and vanadium in mouse small intestine, kidneys, 

pancreas, and femur following oral administration in water or feed. Journal of 

Toxicology and Environmental Health, Part A: Current Issues 65:2029-2052. 

Ramirez, P; Eastmond, DA; Laclette, JP; et al. (1997) Disruption of microtubule assembly and 

spindle formation as a mechanism for the;induction of aneuploid cells by sodium arsenite 

and vanadium pentoxide. Mutation Research 386:291-298. 

Ress, NB; Chou, BJ; Renne, RA; et al. (2003) Carcinogenicity of inhaled vanadium pentoxide in 

F344/N rats and B6C3F1 mice. Toxicological Sciences 74:287-296. 

Rhoads, K; Sanders, CL. (1985) Lung clearance, translocation, and acute toxicity of arsenic, 

beryllium, cadmium, cobalt, lead, selenium, vanadium, and ytterbium oxides following 

deposition in rat lung. Environ Res 36:359-378. 

Rice, AB; Moomaw, CR; Morgan, DL; et al. (1999) Specific inhibitors of platelet-derived 

growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary 

fibrosis in rats. Am J Pathol 155:213-221. 

Rojas, E; Valverde, M; Herrera, LA; et al. (1996) Genotoxicity of vanadium pentoxide evaluate 

by the single cell gel electrophoresis assay in human lymphocytes. Mutation Research 

359:77-84. 

Roldán, RE; Altamirano, LM. (1990) Chromosomal aberrations, sister-chromatid exchanges, 

cell-cycle kinetics and satellite associations in human lymphocyte cultures exposed to 

vanadium pentoxide. Mutation Research 245:61-65. 

Rondini, EA; Walters, DM; Bauer, AK. (2010) Vanadium pentoxide induces pulmonary 

inflammation and tumor promotion in a strain-dependent manner. Particle and Fibre 

Toxicology 7:9. 

Roshchin, AV; Ordzhonikidze, EK; Shalganova, IV. (1980) Vanadium--toxicity, metabolism, 

carrier state. J Hyg Epidemiol Microbiol Immunol 24:377-383. 

Ross, DS. (1983) Case study: exposure to vanadium pentoxide. Occupational health; a journal 

for occupational health nurses 35:67-71. 

Sabbioni, E; Kueera, J; Pietra, R; et al. (1996) A critical review on normal concentrations of 
DRAFT - DO NOT CITE OR QUOTE 

148

vanadium in human blood, serum, and urine. Science of the Total Environment 188:49-

58. 

Schroeder, HA; Balassa, JJ; Tipton, IH. (1963) Abnormal Trace Metals in Man--Vanadium. J 

Chronic Dis 16:1047-1071. 

Sharma, RP; Oberg, SG; Parker, RD. (1980) Vanadium retention in rat tissues following acute 

exposures to different dose levels. J Toxicol Environ Health 6:45-54. 

Sjoberg, SG. (1951) Health hazards in the production and handling of vanadium pentoxide. 

AMA Archives of Industrial Hygiene and Occupational Medicine 3:631-646. 

Sjoberg, SG. (1955) Vanadium bronchitis from cleaning oil-fired boilers. AMA Archives of 

Industrial Health 11:505-512. 

Sjoberg, SG. (1956) Vanadium dust, chronic bronchitis and possible risk of emphysema: a 

follow-up investigation of workers at a vanadium factory. Journal of Internal Medicine 

154:381-386. 

Sorensen, M; Schins, RPF; Hertel, O; et al. (2005) Transition metals in personal samples of 

PM25 and oxidative stress in human volunteers. Cancer Epidemiology Biomarkers and 

Prevention 14:1340-1343. 

Stokinger, HE; Wagner, WD; Mountain, JT; et al. (1953) Unpublished results. Division of 

Occupational Health, Cincinnati, OH. (Cited in Patty's Industrial Hygiene and 

Toxicology, 3rd ed., 1981). 

Turpin, EA; Antao-Menezes, A; Cesta, MF; et al. (2010) Respiratory syncytial virus infection 

reduces lung inflammation and fibrosis in mice exposed to vanadium pentoxide. 

Respiratory Research 11:20. 

U.S. EPA (Environmental Protection Agency). (1986a) Guidelines for the health risk assessment 

of chemical mixtures. Federal Register 51(185):34014-34025. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1986b) Guidelines for mutagenicity risk assessment. Federal Register 

51(185):34006-34012. Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1988) Recommendations for and documentation of biological values for use in risk 

assessment. Prepared by the Environmental Criteria and Assessment Office, Office of 

Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and 

Emergency Response, Washington, DC; EPA 600/6-87/008. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1991) Guidelines for developmental toxicity risk assessment. Federal Register 

56(234):63798-63826. Available from: <http://www.epa.gov/iris/backgr-d.htm>. 
DRAFT - DO NOT CITE OR QUOTE 

149

U.S. EPA. (1994a) Interim policy for particle size and limit concentration issues in inhalation 

toxicity studies. Federal Register 59(206):53799. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1994b) Methods for derivation of inhalation reference concentrations and application 

of inhalation dosimetry. Office of Research and Development, Washington, DC; 

EPA/600/8-90/066F. Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1995) Use of the benchmark dose approach in health risk assessment. Risk 

Assessment Forum, Washington, DC; EPA/630/R-94/007. Available from: 

<http://cfpub.epa.gov/ncea/raf/recordisplay.cfm?deid=42601>. 

U.S. EPA. (1996a) Guidelines for reproductive toxicity risk assessment. Federal Register 

61(212):56274-56322. Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (1987) Vanadium Pentoxide. IRIS Assessment. Available from: 

http://www.epa.gov/iris/subst/0125.htm. 

U.S. EPA. (1998) Guidelines for neurotoxicity risk assessment. Federal Register 63(93):26926-

26954. Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2000a) Science policy council handbook: risk characterization. Office of Science 

Policy, Office of Research and Development, Washington, DC; EPA 100-B-00-002. 

Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2000b) Benchmark dose technical guidance document [external review draft]. Risk 

Assessment Forum, Washington, DC; EPA/630/R-00/001. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2000c) Supplementary guidance for conducting for health risk assessment of 

chemical mixtures. Risk Assessment Forum, Washington, DC; EPA/630/R-00/002. 

Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2002) A review of the reference dose and reference concentration processes. Risk 

Assessment Forum, Washington, DC; EPA/630/P-02/0002F. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2005a) Guidelines for carcinogen risk assessment. Risk Assessment Forum, 

Washington, DC; EPA/630/P-03/001B. Available from: 

<http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2005b) Supplemental guidance for assessing susceptibility from early-life exposure 

to carcinogens. Risk Assessment Forum, Washington, DC; EPA/630/R-03/003F. 

Available from: <http://www.epa.gov/iris/backgrd.html>. 
DRAFT - DO NOT CITE OR QUOTE 

150

U.S. EPA. (2006a) Science policy council handbook: peer review. Third edition. Office of 

Science Policy, Office of Research and Development, Washington, DC; EPA/100/B06/002. Available from: <http://www.epa.gov/iris/backgrd.html>. 

U.S. EPA. (2006b) A Framework for Assessing Health Risk of Environmental Exposures to 

Children. National Center for Environmental Assessment, Washington, DC, EPA/600/R05/093F. Available from: 

<http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158363>. 

U.S. EPA. (2011) Recommended Use of Body Weight3⁄4 at the Default Method in Derivation of 

the Oral Reference Dose. Risk Assessment Forum, Office of the Science Advisor, 

Washington, DC, EPA/100/R11/0001. Available from: 

http://www.epa.gov/raf/publications/pdfs/recommended-use-of-bw34.pdf

Vintinner, FJ; Vallenas, R; Carlin, CE; et al. (1955) Study of the health of workers employed in 

mining and processing of vanadium ore. AMA Arch Ind Health 12:635-642. 

Wallenborn, JG; McKee, JK; Schladweiler, MC; et al. (2007) Systemic translocation of 

particulate matter-associated metals following a single intratracheal instillation in rats. 

Journal of Toxicological Sciences 98:231-239. 

WHO-IPCS (2001) Vanadium pentoxide and other inorganic vanadium compounds, In: Concise 

International Chemical Assessment Document 29, World Health Organization, Geneva, 

Switzerland Available at: http://www.inchem.org/documents/cicads/cicads/cicad29.htm 

WHO (1988) Vanadium, In: WHO Regional Publ, pp.361-371, Copenhagen Available at: 

Wide, M. (1984) Effect of short-term exposure to five industrial metals on the embryonic and 

fetal development of the mouse. Environmental Research 33:47-53. 

Williams, N. (1952) Vanadium poisoning from cleaning oil-fired boilers. British Journal of 

Industrial Medicine 9:50-55. 

Woodin, MA; Hauser, R; Liu, Y; et al. (1998) Molecular markers of acute upper airway 

inflammation in workers exposed to fuel-oil ash. American Journal of Respiratory and 

Critical Care Medicine 158:182-187. 

Woodin, MA; Liu, Y; Hauser, R; et al. (1999) Pulmonary function in workers exposed to low 

levels of fuel-oil ash. Journal of Occupational and Environmental Medicine 41:973-980. 

Woodin, MA; Liu, Y; Neuberg, D; et al. (2000) Acute respiratory symptoms in workers exposed 

to vanadium-rich fuel-oil ash. American Journal of Industrial Medicine 37:353-363. 

Wright, JR; Yates, AJ; Shah, NT; Neff JC; et al. (2009) Hematological characteristics of the BB 

Wistar rat. Veterinary Clinical Pathology 12:9-13. 
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151

Yamaguchi, M; Oishi, H; Suketa, Y. (1989) Effect of vanadium on bone metabolism in weanling 

rats: zinc prevents the toxic effect of vanadium. Research in Experimental Medicine 

189:47-53. 

Zenz, C; Bartlett, JP; Thiede, WH. (1962) Acute vanadium pentoxide intoxication. Archives of 

Environmental and Occupational Health 5:542-546. 

Zenz, C; Berg, BA. (1967) Human responses to controlled vanadium pentoxide exposure. 

Archives of Environmental and Occupational Health 14:709-712. 

Zhang, L; Rice, AB; Adler, K; et al. (2001a) Vanadium stimulates human bronchial epithelial 

cells to produce heparin-binding epidermal growth factor-like growth factor: a mitogen 

for lung fibroblasts. American Journal of Respiratory Cell and Molecular Biology 

24:123-131. 

Zhang, T; Gou, X; Yang, Z. (1991a) A study on developmental toxicity of vanadium pentoxide 

in NIH mice. Hua Xi Yi Ke Da Xue Xue Bao 22:192-195. 

Zhang, T; Gou, X; Yang, Z. (1993b) A study of teratogenicity and sensitive period of vanadium 

pentoxide in Wistar rats. Hua Xi Yi Ke Da Xue Xue Bao 24:202-205. 

Zhang, T; Yang, Z; Li, S; et al. (1991b) Transplacental passage of vanadium after treatment with 

vanadium pentoxide in Wistar rat. Hua Xi Yi Ke Da Xue Xue Bao 22:296-299. 

Zhang, T; Yang, Z; Zeng, C; et al. (1993a) A study on developmental toxicity of vanadium 

pentoxide in Wistar rats. Hua Xi Yi Ke Da Xue Xue Bao 24:92-96. 

Zhang, Z; Wang, Y; Vikis, HG; et al. (2001b) Wildtype Kras2 can inhibit lung carcinogenesis in 

mice. Nature Genetics 29:25-33. 

Zhong, BZ; Gu, ZW; Wallace, WE; et al. (1994) Genotoxicity of vanadium pentoxide in Chinese 

hamster V79 cells. Mutation Research 321:35-42. 
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APPENDIX A - SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC 

COMMENTS AND DISPOSITION 

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APPENDIX B - BENCHMARK CONCENTRATION MODELING OF INHALATION 

STUDIES IN RATS FROM NTP, 2002 

To derive the RfC for vanadium pentoxide, inhalation toxicity effects observed in rats 

(NTP, 2002) were modeled to estimate the candidate PODs. Five endpoints in both male and 

female rats (Table B-2) were selected because of two reasons: 

• The study in rats was designed with lower concentrations of vanadium pentoxide; 

• The results showed both biological significance and statistically significant 

trends. 

Each data set was fitted with the dichotomous models available in EPA BMDS (version 

2.1.2). Following the model selection steps outlined in the draft Benchmark Dose Technical 

Guidance (US EPA, 2000b), the best-fitting model for each data set was used to estimate the 

candidate POD, which was the BMCL at the selected BMR as 10% extra risk. 

The highlights of the benchmark dose modeling results are: 

• The POD value of 0.003 mg/m3

, from two endpoints in female rats, was the lowest 

POD derived and used for the calculation of RfC. The two endpoints were larynx 

chronic inflammation and larynx respiratory epithelium epiglottis hyperplasia. 

• All candidate PODs and the selected models are summarized in Table B-1. 
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Table B-1: Candidate PODs for Vanadium Pentoxide Derived from NTP Studies (2002) through 

BMDS Modeling. 

Endpoint Selected 

Model a

BM

R 

(Extr

a 

Risk)

HEC b

BMC

(mg/m3

) 

BMCLc

(mg/m3

) 

(Candidate 

POD) 

Male F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia Probit 0.1 0.016 0.013 

Chronic Active Inflammation Logistic 0.1 0.035 0.029 

Larynx 

Chronic Inflammation LogLogistic 0.1 0.017 0.012 

Respiratory Epithelium, Epiglottis, 

Hyperplasia LogLogistic 0.1 0.008 0.006 

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia LogLogistic 0.1 0.044 0.026 

Female F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia Gamma 0.1 0.076 0.063 

Chronic Active Inflammation 

Multistage(Stag

e3) 0.1 0.080 0.048 

Larynx 

Chronic Inflammation LogLogistic 0.1 0.005 0.003 

Respiratory Epithelium, Epiglottis, 

Hyperplasia LogLogistic 0.1 0.004 0.003 

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia 

Multistage(Stag

e2) 0.1 0.038 0.014 

a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose 

Technical Guidance (2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

B.1. TREND TESTS ON THE INHALATION DATA SETS FOR BMDS MODELING 

Ten inhalation toxicology data sets in rats were selected because of the lower 

concentrations of vanadium pentoxide administrated (as compared to mice), the significantly 

biologically adverse effects observed and the statistical significance reported by NTP (2002). A 

Cochran-Armitage test was conducted to confirm the significance of the statistical trend for the 

selected data sets (Table B-2) before modeling. 
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Table B-2: Trend Tests on the Selected Data Sets from the 2-Year Inhalation Studies in Rats (NTP, 

2002) 

Endpoint 

Concentration as Reported 

(mg/m3

) a Trend Test b

0.0 0.5 1.0 2.0 Z -Score p-value 

Incidence c in Male F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia d 7/50 24/49 35/48 50/50 8.83 <0.0001

Chronic Active Inflammation 5/50 8/49 24/48 42/50 8.36 <0.0001

Larynx 

Chronic Inflammation 3/49 20/50 17/50 28/49 4.79 <0.0001

Respiratory Epithelium, Epiglottis 

Hyperplasia 0/49 18/50 34/50 32/49 -6.56 <0.0001

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia 4/49 15/50 12/49 17/48 2.68 0.0037

 Incidence c in Female F344/N Rats 

Lung 

Alveolar Epithelium Hyperplasia d 7/49 8/49 21/50 50/50 9.53 <0.0001

Chronic Active Inflammation 10/49 10/49 14/50 40/50 6.71 <0.0001

Larynx 

Chronic Inflammation 8/50 26/49 27/49 37/50 5.38 <0.0001

Respiratory Epithelium, Epiglottis 

Hyperplasia 0/50 25/49 26/49 33/50 -5.98 <0.0001

Nose 

Goblet Cell, Respiratory Epithelium, 

Hyperplasia 13/50 19/50 16/50 30/50 3.46 0.0003

a

 Concentrations are as reported by NTP (2002). 

b

 One-sided Cochran-Armitage trend test. 

c

 Incidence=(number of animals affected)/(number of animals examined). 

d

 This data set was calculated by combining the incidences of alveolar epithelium hyperplasia 

and bronchiole epithelium hyperplasia. 

 

B.2. DOSE CONVERSION 

In the toxicology and carcinogenesis studies reported by NTP (2002), rats (F344/N) were 

exposed to vanadium pentoxide through inhalation. To analyze the concentration response effect 

of vanadium pentoxide, the reported concentrations of vanadium pentoxide were converted to 

human equivalent concentrations before any modeling and extrapolation. 

First, the average life time animal body weights of rats were estimated based on the mean 

body weight at different weeks (Table B-3). Secondly, following the Methods for Derivation of 
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157

Inhalation Reference Concentrations and Application of Inhalation Dosimetry (US EPA, 1994b), 

RDDRs (regional deposited dose ratios) were calculated with the RDDR program designed by 

US EPA (1994). Although six regional RDDRs were reported by the RDDR program for each 

concentration/sex group, only two regional RDDRs (i.e. Extrathoracic and Pulmonary) are 

relevant to the selected endpoints, which are summarized in Table B-4. Then, the human 

equivalent concentration for each concentration/sex group was calculated from the reported 

concentration in rats by multiplying the continuous exposure adjustment factor and RDDR 

(Table B-5). For endpoints in the lung, the pulmonary RDDR was applied; for endpoints in the 

larynx and nose, the extrathoracic RDDR was applied. 

Table B-3: Average Life Time Animal Body Weight of Rats in the 2-Year Inhalation Studies of 

Vanadium Pentoxide (NTP, 2002) 

Vanadium Pentoxide 

Concentration as 

Reported (mg/m3

) 

 Mean Animal Body Weight a (g) Average Life 

Time Animal 

Body Weight b 

(g) 

1-13 

weeks 

14-52 

weeks 

53-104 

weeks 

Male Rats (F344/N) 

0 238 411 504 440 

0.5 241 422 513 449 

1 242 414 508 443 

2 233 404 494 432 

Female Rats (F344/N) 

0 151 227 326 269 

0.5 150 229 319 266 

1 150 227 326 269 

2 147 217 308 256 a

 As reported in Table 11-12 of the NTP report (2002). 

b “Average Life Time Animal Body Weight” = ( “Mean Body Weight 1-13 Weeks” * 13 +“ 

Mean Body Weight 14 -52 Weeks” * 39 + “Mean Body Weight 53-104 Weeks” * 52) /104 

Table B-4: RDDRs for Different Concentration/Sex Group in the 2-Year Inhalation Studies of 

Vanadium Pentoxide (NTP, 2002) 

Vanadium 

Pentoxide 

Concentration as 

Reported (mg/m3) 

Average Life 

Time Animal 

Body Weight a 

(g) 

Average 

MMAD 

b

Average 

GSD c

RDDR d

Extrathoraci

c Pulmonary

Male Rats (F344/N) 

0 440 

1.24 1.89 

0.516 0.496 

0.5 449 0.530 0.494 

1 443 0.520 0.495 
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2 432 0.503 0.498 

Female Rats (F344/N) 

0 269 

1.24 1.89 

0.263 0.524 

0.5 266 0.259 0.524 

1 269 0.263 0.524 

2 256 0.245 0.524 a

 All average life time animal body weights were calculated in Table B-3. 

b

 MMAD =mass median aerodynamic diameter; calculated based on the MMADs reported for 2-year studies (NTP, 

2002) . 

c GSD = geometric standard deviation; calculated based on the GDSs reported for 2-year studies (NTP, 2002) . 

d

 RDDR = regional deposited dose ratio; calculated with the RDDR program (V.2.3. US EPA); 

Table B-5: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year Inhalation 

Studies (NTP, 2002) 

Concentration 

as Reported a

(mg/m3) 

Continuous 

Exposure 

Adjustment 

Factor b

RDDR c Human Equivalent 

Concentration d (mg/m3) 

Extrathoraci

c Pulmonary Extrathoracic Pulmonary

Male Rats (F344/N) 

0 0.179 0.516 0.496 0.00 0.00 

0.5 0.179 0.530 0.494 0.05 0.04 

1 0.179 0.520 0.495 0.09 0.09 

2 0.179 0.503 0.498 0.18 0.18 

Female Rats (F344/N) 

0 0.179 0.263 0.524 0.00 0.00 

0.5 0.179 0.259 0.524 0.02 0.05 

1 0.179 0.263 0.524 0.05 0.09 

2 0.179 0.245 0.524 0.09 0.19 a

 “Toxicology and carcinogenesis studies of vanadium pentoxide in F344/N rats and B6C3F1 Mice”, NTP, 2002. 

b

 “Continuous Exposure Adjustment Factor” = (6/24) * (5/7); animals were exposed to vanadium pentoxide 6 hours 

per day and 5 days per week. 

c

 Please refer to Appendix Table B-4. 

d

 “Human Equivalent Concentration” = “Concentration as Reported” * “Continuous Exposure Adjustment Factor ” 

* “RDDR” 

B.3. BMDS MODELING FOR INHALATION DATA SETS 

Each selected inhalation data set was fitted with all the standard dichotomous models 

available in EPA BMDS (version 2.1.2.). Following the model selection steps outlined in the 

Benchmark Dose Technical Guidance (US EPA, 2000b), the best-fitting model was used to 

estimate the candidate POD for each endpoint, which was the BMCL at the selected BMR as 

10% extra risk. 
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The selected models and candidate PODs for all endpoints are summarized in Table B-1. 

Data Set 1: Incidence of Lung Alveolar Epithelium Hyperplasia in Male Rats, NTP (2002) 

Summary 

 All three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

differences from the control as reported. The severity of these nonneoplastic lesions increased 

from mild to moderate as reported when the concentration of vanadium pentoxide increased. 

The Cochran-Armitage test confirmed the statistically significant trend with Z score as 8.83 and 

one-sided p-value as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the combined incidence was used as the BMR to determine the 

POD. The goodness of fit, BMC and BMCL for each model are summarized in Table B-6. 

Five models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 

Based on the draft Benchmark Dose Technical Guidance (U.S. EPA, 2000b), the Probit model 

was selected as the model for POD computation. The BMCL10 of this model was 0.013 mg/m3 

and regarded as one of the candidate PODs. 

Table B-6: Benchmark Modeling Results for Incidence of Lung Alveolar Epithelium Hyperplasia in 

Male Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValue AIC b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

Probit 0.53 170.0 -0.70 -0.23 

Extra 

Risk 

10% 

0.016 0.013 

Logistic 0.38 171.0 -0.87 -0.20 0.016 0.013 

Multistage e 

(Stage3) 0.43 171.3 -0.50 -0.08 0.011 0.007 

Weibull 0.18 172.7 -0.90 -0.15 0.019 0.010 

Gamma 0.13 173.6 -1.05 -0.10 0.021 0.009 

LogProbit 0.06 175.1 -1.31 0.67 0.026 0.016 

LogLogisti

c 

0.04 176.4 -1.38 0.67 0.025 0.015 

a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. 

e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 
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160

 ==================================================================== 

 Probit Model. (Version: 3.2; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLungAlBrEpHyperplasia\NTP_2002_Lung 

Alveolar Bronchiole Combined Epithelium Hyperplasia_Probit_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLungAlBrEpHyperplasia\NTP_2002_Lung 

Alveolar Bronchiole Combined Epithelium Hyperplasia_Probit_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = CumNorm(Intercept+Slope*Dose), 

 where CumNorm(.) is the cumulative normal distribution function 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is not restricted 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 background = 0 Specified 

 intercept = -1.04337 

 slope = 20.1821 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 -0.78 

 slope -0.78 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -1.02981 0.180284 -1.38316 -0.676464 

 slope 20.0578 2.82623 14.5184 25.5971 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -82.2383 4 

 Fitted model -82.9994 2 1.52225 2 0.4671 

 Reduced model -133.424 1 102.372 3 <.0001 

 AIC: 169.999 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1515 7.577 7.000 50 -0.228 

 0.0441 0.4423 21.673 24.000 49 0.669 

 0.0884 0.7713 37.023 35.000 48 -0.695 

 0.1779 0.9944 49.721 50.000 50 0.530 

 Chi^2 = 1.26 d.f. = 2 P-value = 0.5316 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0155483 

 BMDL = 0.0129496 
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161

 0

 0.2

 0.4

 0.6

 0.8

 1

 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 0.18

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

11:00 09/10 2010

BMDL BMD

 

Probit
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162

Data Set 2: Incidence of Lung Chronic Active Inflammation in Male Rats, NTP (2002) 

Summary 

 Two concentration groups (1 and 2 mg/m3) showed statistically significant difference 

from the control group as reported. The severity increased from minimal to mild as reported 

when the concentration of vanadium pentoxide increased. The Cochran-Armitage test confirmed 

the statistically significant trend with Z score as 8.36 and one-sided p-value as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-7. 

All models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 

Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the Logistic model 

was selected as the model for POD computation. The BMCL10 of this model was 0.029 mg/m3 

and regarded as one of the candidate PODs. 

Table B-7: Benchmark Modeling Results for Incidence of Lung Chronic Active Inflammation in 

Male Rats, NTP (2002) 

Model a

Goodness of Fit 

BM

R 

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3) 

BMCLd

(mg/m3)

Logistic 0.40 192.

5 -0.92 -0.92 

Extr

a 

Risk 

10% 

0.035 0.029 

Probit 0.37 192.

7 -1.00 -1.00 0.032 0.027 

LogProbit 0.67 192.

8 0.29 -0.26 0.046 0.032 

LogLogist

ic 0.60 192.9 -0.34 -0.34 0.045 0.031 

Gamma 0.40 193.

3 0.58 -0.52 0.042 0.027 

Weibull 0.27 193.

9 -0.75 -0.75 0.038 0.024 

Multistage 

e

 (Stage2) 0.24 194.0 0.88 -0.66 0.040 0.019 

a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 
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163

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLungChronicActiveInflammation\NTP_20

02_Lung Chronic Active Inflammation_Logistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLungChronicActiveInflammation\NTP_20

02_Lung Chronic Active Inflammation_Logistic_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = 1/[1+EXP(-intercept-slope*dose)] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is not restricted 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 background = 0 Specified 

 intercept = -2.2183 

 slope = 21.8588 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept slope 

 intercept 1 -0.82 

 slope -0.82 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 intercept -2.29582 0.320666 -2.92431 -1.66732 

 slope 23.0148 3.22048 16.7027 29.3268 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -93.3159 4 

 Fitted model -94.2613 2 1.8908 2 0.3885 

 Reduced model -132.664 1 78.6961 3 <.0001 

 AIC: 192.523 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0915 4.574 5.000 50 0.209 

 0.0441 0.2174 10.654 8.000 49 -0.919 

 0.0884 0.4350 20.880 24.000 48 0.908 

 0.1779 0.8578 42.892 42.000 50 -0.361 

 Chi^2 = 1.84 d.f. = 2 P-value = 0.3976 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0345486 

 BMDL = 0.0285337 
DRAFT - DO NOT CITE OR QUOTE 

164

 0

 0.2

 0.4

 0.6

 0.8

 1

 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 0.18

Fraction Affected

dose

Logistic Model with 0.95 Confidence Level

11:24 09/10 2010

BMDL BMD

 

Logistic

Data Set 3: Incidence of Larynx Chronic Inflammation in Male Rats, NTP (2002) 

Summary 

 Three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

difference from the control group as reported. The severity increased from minimal to about mild 

as reported when the concentration of vanadium pentoxide increased. The Cochran-Armitage test 

confirmed the statistically significant trend with Z score as 4.79 and one-sided p-value as 

<0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-8. 

Only one model demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 

 Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the LogLogistic 

model was selected as the model for POD computation. The BMCL10 of this model was 0.012 

mg/m3 and regarded as one of the candidate PODs. 

Table B-8: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation in Male 

Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

LogLogistic 0.12 229.1 1.63 -0.27 Extra 

Risk 

10% 

0.017 0.012 

LogProbit 0.09 229.8 -1.37 -0.01 0.005 0.000 

Multistage e 

(Stage1) 0.05 230.7 2.14 -0.65 0.023 0.017 
DRAFT - DO NOT CITE OR QUOTE 

165

Gamma 

Weibull 

Probit 0.01 234.8 2.45 2.45 0.043 0.036 

Logistic 0.01 235.2 2.43 2.43 0.046 0.038 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLarynxChronicInflammation\NTP_2002_L

arynx Chronic Inflammation_LogLogistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLarynxChronicInflammation\NTP_2002_L

arynx Chronic Inflammation_LogLogistic_0.1.plt 

 ==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.0612245 

 intercept = 1.9744 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.53 

 intercept -0.53 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0712314 * * * 

 intercept 1.9037 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -110.451 4 

 Fitted model -112.55 2 4.19924 2 0.1225 

 Reduced model -127.371 1 33.8403 3 <.0001 

 AIC: 229.101 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0712 3.490 3.000 49 -0.272 

 0.0473 0.2951 14.754 20.000 50 1.627 

 0.0929 0.4278 21.390 17.000 50 -1.255 
DRAFT - DO NOT CITE OR QUOTE 

166

 0.1796 0.5789 28.366 28.000 49 -0.106 

 Chi^2 = 4.31 d.f. = 2 P-value = 0.1162 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0165573 

 BMDL = 0.0117279 

 0

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 0.18

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

13:22 09/10 2010

BMDL BMD

 

Log-Logistic

Data Set 4: Incidence of Larynx Respiratory Epithelium, Epiglottis, Hyperplasia in Male 

Rats, NTP (2002) 

Summary 

Three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

difference from the control group as reported. The severity increased slightly when the 

concentration of vanadium pentoxide increased. The Cochran-Armitage test confirmed the 

statistically significant trend with Z score as -6.56 and one-sided p-value as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-9. 

Both LogLogistic and LogProbit models demonstrated adequate goodness of fit p-value ≥

0.1 and good visual fit, but the BMC/BMCL ratio in LogProbit was infinite, which was not 

acceptable. Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the 

LogLogistic model was selected as the model for POD computation. The BMCL10 of this model 

was 0.006 mg/m3 and regarded as one of the candidate PODs. 
DRAFT - DO NOT CITE OR QUOTE 

167

Table B-9: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Male Rats, NTP (2002) 

Model a

Goodness of Fit 

BM

R 

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3) 

BMCLd

(mg/m3)

LogLogist

ic 0.27 197.3 1.56 0.000 

Extr

a 

Risk 

10% 

0.008 0.006 

LogProbit 0.14 199.

3 1.60 0.000 0.007 0.000 

Gamma 

0.04 201.

5 -2.12 0.000 0.013 0.010 

Multistage e 

(Stage1) 

Weibull 

Probit 0.00 226.

4 3.16 1.180 0.031 0.027 

Logistic 0.00 227.

1 3.05 1.078 0.032 0.027 

a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLarynxEpiglottisHyperplasia\NTP_2002

_Larynx Epiglottis Hyperplasia_LogLogistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsLarynxEpiglottisHyperplasia\NTP_2002

_Larynx Epiglottis Hyperplasia_LogLogistic_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0 

 intercept = 2.65432 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 
DRAFT - DO NOT CITE OR QUOTE 

168

 intercept 

 intercept 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0 * * * 

 intercept 2.66112 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -95.6454 4 

 Fitted model -97.6263 1 3.96181 3 0.2656 

 Reduced model -134.962 1 78.6325 3 <.0001 

 AIC: 197.253 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0.000 49 0.000 

 0.0473 0.4038 20.190 18.000 50 -0.631 

 0.0929 0.5706 28.532 34.000 50 1.562 

 0.1796 0.7200 35.279 32.000 49 -1.043 

 Chi^2 = 3.93 d.f. = 3 P-value = 0.2694 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.00776335 

 BMDL = 0.00584847 

 0

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 0.18

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

13:40 09/10 2010

BMDL BMD

 

Log-Logistic

Data Set 5: Incidence of Nose Goblet Cell, Respiratory Epithelium, Hyperplasia in Male 

Rats, NTP (2002) 

Summary 

 Three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

difference from the control group as reported. The severity increase slightly as reported when the 
DRAFT - DO NOT CITE OR QUOTE 

169

concentration of vanadium pentoxide increased. The Cochran-Armitage test confirmed the 

statistically significant trend with Z score as 2.68 and one-sided p-value as 0.0037. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-10. 

Five models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit, but 

LogProbit model failed to compute a reasonable BMCL. Based on the draft Benchmark Dose 

Technical Guidance (U.S. EPA, 2000), the LogLogistic model was selected as the model for 

POD computation. The BMCL10 of this model was 0.026 mg/m3 and regarded as the one of the 

candidate PODs. 

Table B-10: Benchmark Modeling Results for Incidence of Nose Goblet Cell, Respiratory 

Epithelium, Hyperplasia in Male Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

LogLogistic 0.16 213.2 1.66 1.656 

Extra 

Risk 

10% 

0.044 0.026 

LogProbit 0.31 212.8 -0.83 -0.003 0.002 failed 

Gamma 

0.12 213.7 1.75 1.75 0.052 0.033 Multistage e 

(Stage1) 

Weibull 

Probit 0.08 214.9 1.787 -0.155 0.077 0.056 

Logistic 0.07 215.0 1.78 -0.128 0.081 0.060 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsNoseGobletEpiHyperplasia\NTP_2002_La

rynx Goblet Hyperplasia _LogLogistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerMaleRats\MaleRatsNoseGobletEpiHyperplasia\NTP_2002_La

rynx Goblet Hyperplasia _LogLogistic_0.1.plt 

 ==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 
DRAFT - DO NOT CITE OR QUOTE 

170

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.0816327 

 intercept = 1.21717 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.72 

 intercept -0.72 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.110444 * * * 

 intercept 0.926382 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -102.873 4 

 Fitted model -104.611 2 3.47486 2 0.176 

 Reduced model -109.105 1 12.4644 3 0.00595 

 AIC: 213.221 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1104 5.412 4.000 49 -0.643 

 0.0473 0.2054 10.270 15.000 50 1.656 

 0.0929 0.2794 13.691 12.000 49 -0.539 

 0.1796 0.3881 18.627 17.000 48 -0.482 

 Chi^2 = 3.68 d.f. = 2 P-value = 0.1590 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0439982 

 BMDL = 0.026051 
DRAFT - DO NOT CITE OR QUOTE 

171

 0

 0.1

 0.2

 0.3

 0.4

 0.5

 0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 0.18

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

14:08 09/10 2010

BMDL BMD

 

Log-Logistic

Data Set 6: Incidence of Lung Alveolar Epithelium Hyperplasia in Female Rats, NTP 

(2002) 

Summary 

Two concentration groups (1 and 2 mg/m3

) showed statistically significant difference 

from the control as reported. The severity of these nonneoplastic lesions increased from minimal 

to moderate as reported when the concentration of vanadium pentoxide increased. The CochranArmitage test confirmed the statistically significant trend with Z score as 9.53 and one-sided pvalue as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the combined incidence was used as the BMR to determine the 

POD. The goodness of fit, BMC and BMCL for each model are summarized in Table B-11. 

Five models demonstrated adequate goodness of fit p-value ≥ 0.1, but the extreme 

curvature of LogLogistic model did not reelect in the observed data. Based on the draft 

Benchmark Dose Technical Guidance (US EPA, 2000b), the Gamma model was selected as the 

model for POD computation. The BMCL10 of this model was 0.063 mg/m3 and regarded as one 

of the candidate PODs. 
DRAFT - DO NOT CITE OR QUOTE 

172

Table B-11: Benchmark Modeling Results for Incidence of Lung Alveolar Epithelium Hyperplasia 

in Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

Gamma 0.89 156.2 0.37 -0.12 

Extra 

Risk 

10% 

0.076 0.063 

LogLogisti

c 

0.96 155.9 0.20 0.00 0.086 0.070 

Weibull 0.91 157.9 0.08 -0.01 0.071 0.053 

LogProbit 0.78 157.9 0.20 0.00 0.085 0.068 

Multistage 

(Stage 3) 0.46 158.1 0.87 -0.24 0.055 0.041 

Logistic 0.00 168.1 2.34 -0.78 0.035 0.028 

Probit 0.00 168.4 2.32 -1.11 0.031 0.025 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Gamma Model. (Version: 2.15; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLungAlBrEpHyperplasia\NTP_2002_L

ung Alveolar Bronchiole Combined Epithelium Hyperplasia_Gamma_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLungAlBrEpHyperplasia\NTP_2002_L

ung Alveolar Bronchiole Combined Epithelium Hyperplasia_Gamma_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response]= background+(1-background)*CumGamma[slope*dose,power], 

 where CumGamma(.) is the cummulative Gamma distribution function 

 Dependent variable = Response 

 Independent variable = Dose 

 Power parameter is restricted as power >=1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial (and Specified) Parameter Values 

 Background = 0.156863 

 Slope = 139.011 

 Power = 16.8546 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Power 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Slope 

Background 1 -0.32 

 Slope -0.32 1 

 Parameter Estimates 
DRAFT - DO NOT CITE OR QUOTE 

173

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.151066 0.03605 0.080409 0.221723 

 Slope 169.414 9.58875 150.621 188.208 

 Power 18 NA 

NA - Indicates that this parameter has hit a bound 

 implied by some inequality constraint and thus 

 has no standard error. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -75.9175 4 

 Fitted model -76.0968 2 0.358619 2 0.8358 

 Reduced model -135.531 1 119.227 3 <.0001 

 AIC: 156.194 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1511 7.402 7.000 49 -0.160 

 0.0468 0.1523 7.462 8.000 49 0.214 

 0.0936 0.4286 21.431 21.000 50 -0.123 

 0.1871 0.9973 49.864 50.000 50 0.369 

 Chi^2 = 0.22 d.f. = 2 P-value = 0.8945 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0756821 

 BMDL = 0.0626004 

 0

 0.2

 0.4

 0.6

 0.8

 1

 0 0.05 0.1 0.15

Fraction Affected

dose

Gamma Multi-Hit Model with 0.95 Confidence Level

14:40 09/10 2010

BMDL BMD

 

Gamma Multi-Hit

Data Set 7: Incidence of Lung Chronic Active Inflammation in Female Rats, NTP (2002) 

Summary 

One concentration group (2 mg/m3) showed statistically significant difference from the 

control group as reported. The severity did not change much when the concentration of 

vanadium pentoxide increased. The Cochran-Armitage test confirmed the statistically significant 

trend with Z score as 6.71 and one-sided p-value as <0.0001. 
DRAFT - DO NOT CITE OR QUOTE 

174

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-12. 

Five models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 

Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the Multistage 

(Stage3) model was selected as the model for POD computation. The BMCL10 of this model 

was 0.048 mg/m3 and regarded as one of the candidate PODs. 

Table B-12: Benchmark Modeling Results for Incidence of Lung Chronic Active Inflammation in 

Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

Multistage e 

 (Stage3) 

0.82 212.9 -0.51 -0.51 

Extra 

Risk 

10% 

0.080 0.048 

LogProbit 1.00 214.5 0.00 0.00 0.094 0.068 

Gamma 0.99 214.5 -0.01 0.00 0.094 0.063 

LogLogisti

c 

0.97 214.5 -0.03 0.00 0.094 0.065 

Weibull 0.94 214.5 -0.06 0.01 0.094 0.059 

Logistic 0.04 218.8 1.64 -0.48 0.040 0.033 

Probit 0.03 219.4 -1.71 -0.62 0.037 0.031 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Multistage Model. (Version: 3.2; Date: 05/26/2010) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLungChronicActiveInflammation\NT

P_2002_Lung Chronic Active Inflammation_Multi3_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLungChronicActiveInflammation\NT

P_2002_Lung Chronic Active Inflammation_Multi3_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP( 

 -beta1*dose^1-beta2*dose^2-beta3*dose^3)] 

 The parameter betas are restricted to be positive 

 Dependent variable = Response 

 Independent variable = Dose 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Total number of parameters in model = 4 

 Total number of specified parameters = 0 
DRAFT - DO NOT CITE OR QUOTE 

175

 Degree of polynomial = 3 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 Background = 0.17928 

 Beta(1) = 0 

 Beta(2) = 0 

 Beta(3) = 214.579 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Beta(1) -Beta(2) 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Beta(3) 

Background 1 -0.41 

 Beta(3) -0.41 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.186734 * * * 

 Beta(1) 0 * * * 

 Beta(2) 0 * * * 

 Beta(3) 206.262 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -104.257 4 

 Fitted model -104.451 2 0.389305 2 0.8231 

 Reduced model -130.861 1 53.209 3 <.0001 

 AIC: 212.903 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1867 9.150 10.000 49 0.312 

 0.0468 0.2037 9.983 10.000 49 0.006 

 0.0936 0.3132 15.659 14.000 50 -0.506 

 0.1871 0.7896 39.478 40.000 50 0.181 

 Chi^2 = 0.39 d.f. = 2 P-value = 0.8246 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.079938 

 BMDL = 0.0483842 

 BMDU = 0.0900697 

Taken together, (0.0483842, 0.0900697) is a 90% two-sided confidence 

interval for the BMD 
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176

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0.9

 0 0.05 0.1 0.15

Fraction Affected

dose

Multistage Model with 0.95 Confidence Level

15:28 09/10 2010

BMDL BMD

 

Multistage

Data Set 8: Incidence of Larynx Chronic Inflammation in Female Rats, NTP (2002) 

Summary 

Three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

difference from the control group as reported. The severity did not change much when the 

concentration of vanadium pentoxide increased. The Cochran-Armitage test confirmed the 

statistically significant trend with Z score as 5.38 and one-sided p-value as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-13. 

Five models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 

Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the LogLogistic 

model was selected as the model for POD computation. The BMCL10 of this model was 0.003 

mg/m3 and regarded as one of the candidate PODs. 

Table B-13: Benchmark Modeling Results for Incidence of Larynx Chronic Inflammation in 

Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

LogLogistic 0.46 242.0 -0.88 -0.13 

Extra 

Risk 

10% 

0.005 0.003 

LogProbit 0.27 243.6 -0.89 -0.02 0.003 0.000 

Gamma 

Multistage 0.19 243.7 1.58 -0.57 0.007 0.006 e 

 (Stage1) 
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177

Weibull 

Probit 0.03 247.5 1.99 1.99 0.013 0.011 

Logistic 0.03 247.6 1.97 1.97 0.014 0.011 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLarynxChronicInflammation\NTP_20

02_Larynx Chronice Inflammation_LogLogistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLarynxChronicInflammation\NTP_20

02_Larynx Chronice Inflammation_LogLogistic_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.16 

 intercept = 3.2396 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.54 

 intercept -0.54 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.166778 * * * 

 intercept 3.19725 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -118.217 4 

 Fitted model -118.997 2 1.55893 2 0.4587 

 Reduced model -137.233 1 38.0314 3 <.0001 

 AIC: 241.994 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.1668 8.339 8.000 50 -0.129 

 0.0231 0.4678 22.925 26.000 49 0.881 

 0.0470 0.6123 30.001 27.000 49 -0.880 
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178

 0.0875 0.7347 36.735 37.000 50 0.085 

 Chi^2 = 1.57 d.f. = 2 P-value = 0.4553 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.00454158 

 BMDL = 0.00312534 

 0

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0.9

 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

16:29 09/10 2010

BMDL BMD

 

Log-Logistic

Data Set 9: Incidence of Larynx Respiratory Epithelium, Epiglottis, Hyperplasia in Female 

Rats, NTP (2002) 

Summary 

Three concentration groups (0.5, 1 and 2 mg/m3) showed statistically significant 

difference from the control group as reported. The severity did not change much when the 

concentration of vanadium pentoxide increased. The Cochran-Armitage test confirmed the 

statistically significant trend with Z score as -5.98 and one-sided p-value as <0.0001. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-14. 

Both LogLogistic and LogProbit models demonstrated adequate goodness of fit p-value ≥

0.1 and good visual fit, but LogProbit model failed to compute a reasonable BMCL. Based on 

the draft Benchmark Dose Technical Guidance (U.S. EPA, 2000), the LogLogistic model was 

selected as the model for POD computation. The BMCL10 of this model was 0.003 mg/m3 and 

regarded as one of the candidate PODs. 
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179

Table B-14: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BM

R 

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3) 

BMCLd

(mg/m3)

LogLogist

ic 0.30 205.3 1.53 0.000 

Extr

a 

Risk 

10% 

0.004 0.003 

LogProbit 0.78 204.2 -0.57 0.000 0.000 failed 

Gamma 

0.01 212.3 2.85 0.000 0.006 0.005 

Multistage e 

(Stage1) 

Weibull 

Probit 0.00 234.6 3.258 3.258 0.016 0.013 

Logistic 0.00 235.3 -3.295 3.174 0.016 0.014 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLarynxEpiglottisHyperplasia\NTP_

2002_Larynx Epiglottis Hyperplasia_LogLogistic_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsLarynxEpiglottisHyperplasia\NTP_

2002_Larynx Epiglottis Hyperplasia_LogLogistic_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Response 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0 

 intercept = 3.38546 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -background -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 intercept 

 intercept 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0 * * * 

 intercept 3.3735 * * * 
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180

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -99.8781 4 

 Fitted model -101.66 1 3.56345 3 0.3126 

 Reduced model -134.962 1 70.1671 3 <.0001 

 AIC: 205.32 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0000 0.000 0.000 50 0.000 

 0.0231 0.4029 19.743 25.000 49 1.531 

 0.0470 0.5781 28.329 26.000 49 -0.674 

 0.0875 0.7186 35.929 33.000 50 -0.921 

 Chi^2 = 3.65 d.f. = 3 P-value = 0.3022 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.00380772 

 BMDL = 0.0028644 

 0

 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

11:10 09/16 2010

BMDL BMD

 

Log-Logistic

Data Set 10: Incidence of Nose Goblet Cell, Respiratory Epithelium, Hyperplasia in Female 

Rats, NTP (2002) 

Summary 

One concentration groups (2 mg/m3

) showed statistically significant difference from the 

control group as reported. The severity did not change much when the concentration of 

vanadium pentoxide increased. The Cochran-Armitage test confirmed the statistically significant 

trend with Z score as 3.46 and one-sided p-value as 0.0003. 

Seven dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this 

data set. A 10% extra risk of the incidence was used as the BMR to determine the POD. The 

goodness of fit, BMC and BMCL for each model are summarized in Table B-15. 

All models demonstrated adequate goodness of fit p-value ≥ 0.1 and good visual fit. 
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181

Based on the draft Benchmark Dose Technical Guidance (US EPA, 2000b), the Multistage 

(Stage2) model was selected as the model for POD computation. The BMCL10 of this model 

was 0.014 mg/m3 and regarded as one of the candidate PODs. 

Table B-15: Benchmark Modeling Results for Incidence of Larynx Respiratory Epithelium, 

Epiglottis, Hyperplasia in Female Rats, NTP (2002) 

Model a

Goodness of Fit 

BMR

HEC c

PValueAIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3

) 

BMCLd

(mg/m3

) 

Multistage 

(Stage2) 0.43 258.3 -0.90 -0.896 

Extra 

Risk 

10% 

0.038 0.014 

Logistic 0.33 258.9 -1.252 0.586 0.024 0.018 

Probit 0.32 258.9 -1.273 0.564 0.023 0.018 

Weibull 

( Quantal 

Linear) 

0.22 259.7 -1.45 0.337 0.019 0.012 

LogLogisti

c 

0.28 259.8 0.78 -0.027 0.064 0.014 

Gamma 0.28 259.8 0.77 -0.005 0.063 0.014 

LogProbit 0.28 259.8 0.765 -0.001 0.062 0.015 a

 Selected (best-fitting) model shown in first row, in boldface type. 

b

 AIC=Akaike Information Criterion. 

c

 HEC=Human Equivalent Concentration. 

d

 BMCL= the lower bound of BMCat 95% confidence level. e

 For Multistage model, up to 3 stages were tested. Only the model with the lowest AIC and lowest stage was 

reported here. 

BMDS output file 

 ==================================================================== 

 Multistage Model. (Version: 3.2; Date: 05/26/2010) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsNoseGobletEpiHyperplasia\NTP_200

2_Nose Goblet Hyperplasia_Multi2_0.1.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002NonCancerFemaleRats\FemaleRatsNoseGobletEpiHyperplasia\NTP_200

2_Nose Goblet Hyperplasia_Multi2_0.1.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background + (1-background)*[1-EXP( 

 -beta1*dose^1-beta2*dose^2)] 

 The parameter betas are restricted to be positive 

 Dependent variable = Response 

 Independent variable = Dose 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Total number of parameters in model = 3 

 Total number of specified parameters = 0 

 Degree of polynomial = 2 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 
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182

 Default Initial Parameter Values 

 Background = 0.270822 

 Beta(1) = 0 

 Beta(2) = 75.6009 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -Beta(1) 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 Background Beta(2) 

Background 1 -0.59 

 Beta(2) -0.59 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.276279 * * * 

 Beta(1) 0 * * * 

 Beta(2) 71.2588 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -126.318 4 

 Fitted model -127.169 2 1.70254 2 0.4269 

 Reduced model -133.292 1 13.9479 3 0.002977 

 AIC: 258.338 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.2763 13.814 13.000 50 -0.257 

 0.0231 0.3033 15.167 18.000 50 0.872 

 0.0470 0.3815 19.077 16.000 50 -0.896 

 0.0875 0.5806 29.030 30.000 50 0.278 

 Chi^2 = 1.71 d.f. = 2 P-value = 0.4262 

 Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.0384521 

 BMDL = 0.0135524 

 BMDU = 0.0544996 

Taken together, (0.0135524, 0.0544996) is a 90% two-sided confidence 

interval for the BMD 
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 0.1

 0.2

 0.3

 0.4

 0.5

 0.6

 0.7

 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09

Fraction Affected

dose

Multistage Model with 0.95 Confidence Level

16:49 09/10 2010

BMDL BMD

 

Multistage
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184

APPENDIX C - BENCHMARK CONCENTRATION MODELING OF COMBINED 

LUNG ALVEOLAR AND BRONCHIOLAR TUMOR DATA SETS FROM NTP 

STUDIES (2002) 

To derive the cancer slope factor of vanadium pentoxide, combined alveolar/bronchiolar 

adenoma and carcinoma data sets in B6C3F1 mice (Table C-2) by NTP (2002) were selected 

because of their biological and statistical significance. 

The highlights of the benchmark concentration modeling results are: 

• Cancer slope factor: 

The cancer slope factor was estimated as 3.4 per mg/m3

 after linear extrapolation. The 

selected model for each data set, the candidate PODs and the calculation of cancer slope factor 

are summarized in Table C-1. 

• BMDS modeling: 

Each data set was firstly fitted with the recommended dichotomous model, multistagecancer model, through EPA BMDS (version 2.1.2); if the goodness of fit p-value < 0.05, other 

dichotomous models available in EPA BMDS (version 2.1.2) were used; if still no model 

showed adequate goodness of fit p-value ≥ 0.05, the highest dose was dropped for further 

modeling. Following the general model selection steps outlined in the draft Benchmark Dose 

Technical Guidance (U.S. EPA, 2000), the best-fitting model was selected for each data set to 

estimate the candidate POD, which was the BMCL at the pre-determined BMR. 

• BMR: 

Since all the non-control concentrations showed essentially a plateau response, the tumor 

data sets provided limited information about the concentration-response relationship. So, BMR 

for each data set was calculated based on the response at the control and the first non-control 

concentration groups. 

• Multistage Weibull (MSW) time-to-tumor modeling: 

Since the survival curves reported by NTP (2002) showed a high percentage of deaths 

(22-46%) at the end of 2-year studies across the different concentrations groups, MSW time-totumor model was also used with these data sets. However, no adequate fit was noticed for either 

male or female mice data set. 
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Table C- 1. Summary of Candidate PODs and Cancer Slope Factors. 

Animal 

BMR 

(Extra 

Risk) a

HEC b Cancer 

Slope 

Factor d 

(per 

mg/m3

) 

BMC

(mg/m3

) 

BMCLc

(Candidate 

POD, mg/m3

) 

 Male B6C3F1

Mice 0.71 0.360 0.208 3.4 

Female B6C3F1 

Mice 0.67 0.237 0.161 4.2 

a

 BMR was calculated based on the response at the control concentration and the first non-control concentration 

(Table C-6). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

d Cancer Slope Factor = BMR/BMCL, as linear extrapolation was used. 

C.1. TREND TESTS BEFORE MODELING 

Two inhalation carcinogenesis data sets were selected because of the biological and the 

statistical significance reported by NTP (2002). Cochran-Armitage test was conducted to 

confirm the significance of the statistical trend for the selected data sets (Table C-2) before 

modeling. 

Table C-2: Trend Tests on the Inhalation Carcinogenesis Data Sets in Mice from the 2-Year 

Inhalation Studies (NTP, 2002) 

Endpoint Concentration as Reported (mg/m3

) a Trend Test b

0.0 1.0 2.0 4.0 Z -Score p-value 

Incidence c in Male B6C3F1 Mice 

Lung 

Alveolar/Bronchiolar 

Adenoma and 

Carcinoma 

22/50 42/50 43/50 43/50 4.14 <0.0001

Incidence c in Female B6C3F1 Mice 

 Lung 

Alveolar/Bronchiolar 

Adenoma and 

Carcinoma 

1/48 32/47 35/48 32/49 5.19 <0.0001

a

 Concentrations are as reported by NTP (2002). 

b

 One-sided Cochran-Armitage trend test. 

c

 Incidence = (number of animals with alveolar/bronchiolar adenoma and/or carcinoma)/(animal sample size). Only 

the animals alive at 52 weeks or when the first tumor appeared, whichever was earlier, was counted toward the 

sample size. 

C.2. DOSE CONVERSION 

In the carcinogenesis studies reported by NTP (2002), mice (B6C3F1) were exposed to 
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186

vanadium pentoxide through inhalation. To analyze the concentration response effect, the 

reported concentrations of vanadium pentoxide were converted to human equivalent 

concentrations before any modeling and extrapolation. 

Firstly, the average life time animal body weights of rats were estimated based on the 

mean body weight at different weeks (Table C-3). Secondly, following the US EPA inhalation 

methods (1994), RDDRs (regional deposited dose ratio) were calculated with the RDDR 

program designed by US EPA (1994) and summarized in Table C-4. Then, the human equivalent 

concentration for each concentration/sex group was calculated from the reported concentration in 

mice by multiply the continuous exposure adjustment factor and the pulmonary RDDR (Table C5). 

Table C-3: Average Life Time Animal Body Weight of Mice for 2-Year Inhalation Studies of 

Vanadium Pentoxide (NTP, 2002) 

Vanadium Pentoxide 

Concentration as 

Reported (mg/m3) 

 Mean Animal Body Weight a (g) Average Life 

Time Animal 

Body Weight b 

(g) 

1-13 

weeks 

14-52 

weeks 

53-104 

weeks 

Male Mice (B6C3F1) 

0 30.8 46.7 54.1 48.9 

1 30.5 47.0 52.9 48.3 

2 30.3 45.4 51.4 46.9 

4 29.8 43.7 46.1 43.6 

Female Mice (B6C3F1) 

0 25.5 42.7 56.1 47.7 

1 24.9 40.9 50.7 44.2 

2 24.8 36.8 44.8 39.7 

4 24.5 34.2 40.1 36.3 a

 As reported in Table 20-21of the NTP report (2002). 

b “Average Life Time Animal Body Weight” = ( “Mean Body Weight 1-13 Weeks” * 13 +“ Mean Body Weight 14 -

52 Weeks” * 39 + “Mean Body Weight 53-104 Weeks” * 52) /104 
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187

Table C-4: RDDRs for Different Concentration/Sex Group of Mice in the 2-Year Inhalation Studies 

of Vanadium Pentoxide (NTP, 2002) 

Vanadium Pentoxide 

Concentration as 

Reported (mg/m3) 

Average Life 

Time Animal 

Body Weight a

 (g) 

Average 

MMAD 

b

Average 

GSD c

RDDR d

Pulmonary 

Male Mice (B6C3F1) 

0 48.9 e

1.26 1.87 

1.168 e

1 48.3 e 1.168 e

2 46.9 e 1.168 e

4 43.6 1.134 

Female Mice (B6C3F1) 

0 47.7 e

1.26 1.87 

1.168 e

1 44.2 1.143 

2 39.7 1.077 

4 36.3 1.023 a

 Average life time animal body weight of each concentration/sex group was calculated in Table C-3. 

b

 MMAD =mass median aerodynamic diameter; calculated based on the MMADs reported for 2-year studies (NTP, 

2002) . 

c GSD = geometric standard deviation; calculated based on the GDSs reported for 2-year studies (NTP, 2002) . 

d

 RDDR = regional deposited dose ratio; calculated with the RDDR program from USA EPA (1994); 

e Since the average life time animal body weight was out of the mice weight range (17-46g) accepted by RDDR 

program (V.2.3, US EPA), 46g was used to calculate the corresponding RDDRs. 

Table C-5: Human Equivalent Concentrations of Vanadium Pentoxide in the 2-Year Inhalation 

Studies (NTP, 2002) 

Concentration as 

Reported a

(mg/m3

) 

Continuous 

Exposure 

Adjustment 

Factor b

RDDR c HEC d 

(mg/m3) 

Pulmonary Pulmonary 

Male Mice (B6C3F1) 

0 0.179 1.168 0.00 

1 0.179 1.168 0.21 

2 0.179 1.168 0.42 

4 0.179 1.134 0.81 

Female Mice (B6C3F1) 

0 0.179 1.168 0.00 

1 0.179 1.143 0.20 

2 0.179 1.077 0.38 

4 0.179 1.023 0.73 a

 “Toxicology and carcinogenesis studies of vanadium pentoxide in F344/N rats and B6C3F1 Mice”, NTP, 2002. 

b

 “Continuous Exposure Adjustment Factor” = (6/24) * (5/7); animals were exposed to vanadium pentoxide 6 hours 

per day and 5 days per week. c

 Please refer to Appendix Table C-4. 
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188

d

 HEC=Human Equivalent Concentration = “Concentration as Reported” * “Continuous Exposure Adjustment 

Factor ” * “RDDR” 

C.3. BMR CALCULATION 

Since all non-control concentrations from the NTP carcinogenesis studies (2002) showed 

essentially a plateau response, the data set provided limited information about the concentrationresponse relationship because the complete range of response from background to maximum 

must occur somewhere below the lowest dose, thus the BMD may be just below the first dose or 

orders of magnitudes lower. So, a BMR estimated based on the response at the control 

concentration and the first non-control concentration was calculated (Table C-6), and then used 

for estimation of BMCL. 

Table C-6: BMR Estimation for Male and Female Mice Data Sets. 

Animal P(Control) a

P(1st Noncontrol 

Concentration)

b

Calculated BMR 

(Extra Risk) c

 Male B6C3F1 Mice 0.44 0.84 0.71 

Female B6C3F1 

Mice 0.02 0.68 0.67 a

 The combined alveolar/bronchiolar adenoma and carcinoma incidence in the control group. 

b

 The combined alveolar/bronchiolar adenoma and carcinoma incidence in the 1st non-control concentration group. c

 Calculated BMR = [P(1st Non-control Concentration) - P(Control)]/[1- P(Control)]. 

C.4. BMDS MODELING FOR INHALATION CARCINOGENESIS DATA SETS 

Each data set was firstly fitted with dichotomous multistage-cancer model provided in 

EPA BMDS (version 2.1.2); if the goodness of fit p-value < 0.05, other dichotomous models 

available in EPA BMDS (version 2.1.2) were fitted; if still no model showed adequate goodness 

of fit p-value ≥ 0.05, the highest dose was dropped for further modeling. 

Following the general model selection steps outlined in the draft Benchmark Dose 

Technical Guidance (U.S. EPA, 2000), the best-fitting model was selected for each data set to 

estimate the candidate POD, which was the BMCL at the calculated BMR for each data set. 

The selected models and candidate PODs for all endpoints are summarized in Table C-1. 

Lung Tumor Data Set 1: Combined Incidence of Alveolar/Bronchiolar Adenoma and 

Carcinoma in Male Mice, NTP (2002). 

Summary 

The Cochran-Armitage test confirmed the statistically significant trend with Z score as 

4.14 and one-sided p-value as <0.0001. 
DRAFT - DO NOT CITE OR QUOTE 

189

Because all the non-control concentrations showed a similar effect, a BMR as 71% extra 

risk was calculated and used to estimate the POD. The goodness of fit, BMC and BMCL for each 

model are summarized in Table C- 7 and C-8. 

Since the primary cancer model (Multistage-cancer) did not show an adequate fit, six 

other dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this data set. 

Two models demonstrated adequate goodness of fit p-value ≥ 0.05 and good visual fit, but 

LogProbit model failed to compute a reasonable BMCL. Based on the draft Benchmark Dose 

Technical Guidance (U.S. EPA, 2000), the LogLogistic model was selected and BMCL71 of this 

model was 0.208 mg/m3

. 

Further BMD modeling was performed for comparison purposes. Since the primary 

cancer model (Multistage-cancer) did not show adequate fit with all doses, the highest 

concentration was dropped for further modeling. After dropping the high dose, the primary 

cancer model (Multistage-cancer) demonstrated adequate goodness of fit p-value ≥ 0.05 and 

good visual fit. 

Table C- 7. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar Adenoma 

and Carcinoma in Male Mice, NTP (2002). 

Model a

Goodness of Fit 

BM

R 

HEC 

PValu

e

AIC 

b

Largest 

Scaled 

Residual 

Scaled 

Residual of 

Interest 

BMC

(mg/m3) 

BMCLc

(mg/m3) 

Primary Cancer Models 

MultistageCancer Stage 

1,2 and 3 

0.01 207.

0 2.05 0.72 

Extr

a 

Risk 

71% 

0.532 0.379 

Other Dichotomous Models 

LogLogistic 0.19 200.

632 -1.42 0.04 

Extr

a 

Risk 

71% 

0.360 0.208 

LogProbit 0.88 199.

6 0.13 -0.06 0.146 failed 

Gamma 0.01 207.

0 2.05 0.72 0.532 0.379 Weibull 

Logistic 0.00 209.

4 2.15 0.96 0.609 0.447 

Probit 0.00 210.

4 2.19 -1.54 0.654 0.495 

a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 
DRAFT - DO NOT CITE OR QUOTE 

190

BMDS output file 

==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\MaleMiceTumor4DosesAllModel\NTP_2002_MaleMiceTum

or4DosesAllModels_LogLogistic_0.71.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\MaleMiceTumor4DosesAllModel\NTP_2002_MaleMiceTum

or4DosesAllModels_LogLogistic_0.71.plt 

==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Effect 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 4 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.44 

 intercept = 1.9384 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.58 

 intercept -0.58 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.451808 * * * 

 intercept 1.91813 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -96.7763 4 

 Fitted model -98.3159 2 3.07913 2 0.2145 

 Reduced model -112.467 1 31.3814 3 <.0001 

 AIC: 200.632 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.4518 22.590 22.000 50 -0.168 

 0.2100 0.7744 38.719 42.000 50 1.110 

 0.4200 0.8580 42.898 43.000 50 0.041 
DRAFT - DO NOT CITE OR QUOTE 

191

 0.8100 0.9159 45.793 43.000 50 -1.423 

 Chi^2 = 3.29 d.f. = 2 P-value = 0.1934 

 Benchmark Dose Computation 

Specified effect = 0.71 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.359607 

 BMDL = 0.208416 

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0.9

 1

 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

15:37 09/20 2010

BMDL BMD

 

Log-Logistic

Table C- 8. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar Adenoma 

and Carcinoma in Male Mice after Dropping the Highest Concentration, NTP (2002). 

Model a

Goodness of Fit 

BMR 

HEC 

PValue AIC b

Largest 

Scaled 

Residual

Scaled 

Residual 

of 

Interest 

BMC

(mg/m3

) 

BMCLc

(mg/m3

) 

Primary Cancer Models 

MultistageCancer 

Stage 1,2 

and 3 

0.12 159.5 1.19 

Extra 

Risk 

71% 

0.310 0..220 

Other Dichotomous Models 

LogLogistic 0.43 157.7 0.52 

Extra 

Risk 

71% 

0.260 0.140 

Gamma 0.12 159.5 1.19 0.310 0.220 Weibull 

Probit 0.04 161.5 -1.03 0.340 0.270 

Logistic 0.05 160.1 -1.09 0.330 0.250 

LogProbit NA 159.1 0.00 0.190 failed a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 
DRAFT - DO NOT CITE OR QUOTE 

192

==================================================================== 

 Multistage Cancer Model. (Version: 1.9; Date: 05/26/2010) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\MaleMiceTumor3DosesAllModel\NTP_2002_MaleMiceTumor3Dose

sAllModels_MultiCanc1_0.71.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\MaleMiceTumor3DosesAllModel\NTP_2002_MaleMiceTumor3Dose

sAllModels_MultiCanc1_0.71.plt 

 Thu Feb 17 17:24:36 2011 

==================================================================== 

 The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP( 

 -beta1*dose^1)] 

 The parameter betas are restricted to be positive 

 Dependent variable = Effect 

 Independent variable = Dose 

 Total number of observations = 3 

 Total number of records with missing values = 0 

 Total number of parameters in model = 2 

 Total number of specified parameters = 0 

 Degree of polynomial = 1 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 Default Initial Parameter Values 

 Background = 0.535297 

 Beta(1) = 3.3007 

 Asymptotic Correlation Matrix of Parameter Estimates 

 Background Beta(1) 

Background 1 -0.6 

 Beta(1) -0.6 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 Background 0.461149 * * * 

 Beta(1) 4.04221 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -76.5282 3 

 Fitted model -77.7667 2 2.47711 1 0.1155 

 Reduced model -89.871 1 26.6857 2 <.0001 

 AIC: 159.533 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.4611 23.057 22.000 50 -0.300 

 0.2100 0.7694 38.471 42.000 50 1.185 

 0.4200 0.9013 45.067 43.000 50 -0.980 

 Chi^2 = 2.45 d.f. = 1 P-value = 0.1172 

 Benchmark Dose Computation 

Specified effect = 0.71 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.306237 

 BMDL = 0.220508 

 BMDU = 0.471328 

Taken together, (0.220508, 0.471328) is a 90 % two-sided confidence 

interval for the BMD 

Multistage Cancer Slope Factor = 3.21985 
DRAFT - DO NOT CITE OR QUOTE 

193

 0.3

 0.4

 0.5

 0.6

 0.7

 0.8

 0.9

 1

 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4

Fraction Affected

dose

Multistage Cancer Model with 0.95 Confidence Level

17:34 02/17 2011

BMDL BMD

 

Multistage Cancer

Linear extrapolation

Lung Tumor Data Set 2: Combined Incidence of Alveolar/Bronchiolar Adenoma and 

Carcinoma in Female Mice, NTP (2002). 

Summary 

 The Cochran-Armitage test confirmed the statistically significant trend with Z score as 

5.19 and one-sided p-value as <0.0001. 

Because all the non-control concentrations showed a similar effect, a BMR as 67% extra 

risk was calculated and used to determine the POD. The goodness of fit, BMC and BMCL for 

each model are summarized in Table C-9 and C-10. 

Since the primary cancer model (Multistage-cancer) did not show an adequate fit, six 

other dichotomous models available in EPA BMDS (version 2.1.2.) were fitted to this data set. 

Only one model demonstrated adequate goodness of fit p-value ≥ 0.05, however, it failed to 

compute BMC and BMCL. So, the highest concentration was dropped for further modeling. 

After dropping the highest dose, the primary cancer model (Multistage-cancer) still did 

not show an adequate fit. Then six other dichotomous models available in EPA BMDS (version 

2.1.2.) were tried. Only the LogLogistc model demonstrated adequate goodness of fit p-value ≥

0.05 and good visual fit. Based on the draft Benchmark Dose Technical Guidance (U.S. EPA, 

2000), the LogLogistic model was selected and BMCL67 of this model was 0.161 mg/m3

. 

Table C- 9. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar Adenomas 

and Carcinomas with All Four Concentrations in Female Mice, NTP (2002). 

Model a Goodness of Fit BMR HEC 
DRAFT - DO NOT CITE OR QUOTE 

194

PValue AIC b

Largest 

Scaled 

Residual

Scaled 

Residual 

of 

Interest 

BMC

(mg/m3

) 

BMCLc

(mg/m3

) 

Primary Cancer Models 

MultistageCancer Stage 

1,2 and 3 

0.00 218.8 -3.90 1.33 

Extra 

Risk 

67% 

0.435 0.359 

Other Dichotomous Models 

LogProbit 0.72 192.6 0.62 -999.00 

Extra 

Risk 

67% 

Failed d Failed d

LogLogistic 0.00 202.7 -2.87 0.52 0.351 0.255 

Gamma 0.00 218.8 -3.90 1.33 0.435 0.359 Weibull 

Logistic 0.00 239.4 -4.00 -2.62 0.657 0.532 

Probit 0.00 239.6 -3.97 -2.48 0.670 0.553 

a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

Table C- 10. BMDS Modeling Results for Combined Incidence of Alveolar/Bronchiolar Adenoma 

and Carcinoma in Female Mice after Dropping the Highest Concentration, NTP (2002). 

Model a

Goodness of Fit 

BMR

HEC 

PValue AIC b

Largest 

Scaled 

Residual

Scaled 

Residual 

of 

Interest 

BMC

(mg/m3

) 

BMCLc

(mg/m3

) 

Primary Cancer Models 

MultistageCancer Stage 

1,2 and 3 

0.06 132.2 1.42 1.42 

Extra 

Risk 

67% 

0.264 0.213 

Other Dichotomous Models 

LogLogistic 0.37 129.453 -0.67 0.60 

Extra 

Risk 

67% 

0.237 0.161 

Gamma 0.06 132.2 1.42 1.42 0.264 0.213 Weibull 

Probit 0.00 145.9 3.00 -1.85 0.309 0.272 

Logistic 0.00 146.5 2.84 -1.99 0.303 0.263 

LogProbit NA 130.7 0.00 0.00 0.190 failed a

 Selected model is the best-fitting model for the data set based on the draft Benchmark Dose Technical Guidance 

(2000). 

b

 HEC=Human Equivalent Concentration. 

c

 BMCL= the lower bound of BMCat 95% confidence level. 

BMDS output file 
DRAFT - DO NOT CITE OR QUOTE 

195

 ==================================================================== 

 Logistic Model. (Version: 2.13; Date: 10/28/2009) 

 Input Data File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\FemaleMiceTumor3DosesAllModels\NTP_2002_FemaleMiceTumor

3DosesAllModels_LogLogistic_0.67.(d) 

 Gnuplot Plotting File: 

C:\USEPA\BMDS212\Data\V2O5\NTP_2002Cancer\FemaleMiceTumor3DosesAllModels\NTP_2002_FemaleMiceTumor

3DosesAllModels_LogLogistic_0.67.plt

 ==================================================================== 

 The form of the probability function is: 

 P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))] 

 Dependent variable = Effect 

 Independent variable = Dose 

 Slope parameter is restricted as slope >= 1 

 Total number of observations = 3 

 Total number of records with missing values = 0 

 Maximum number of iterations = 250 

 Relative Function Convergence has been set to: 1e-008 

 Parameter Convergence has been set to: 1e-008 

 User has chosen the log transformed model 

 Default Initial Parameter Values 

 background = 0.0208333 

 intercept = 2.36858 

 slope = 1 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -slope 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 background intercept 

background 1 -0.14 

 intercept -0.14 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 background 0.0210689 * * * 

 intercept 2.14725 * * * 

 slope 1 * * * 

* - Indicates that this value is not calculated. 

 Analysis of Deviance Table 

 Model Log(likelihood) # Param's Deviance Test d.f. P-value 

 Full model -62.3295 3 

 Fitted model -62.7264 2 0.79377 1 0.373 

 Reduced model -98.9486 1 73.2384 2 <.0001 

 AIC: 129.453 

 Goodness of Fit 

 Scaled 

 Dose Est._Prob. Expected Observed Size Residual 

 ------------------------------------------------------------------------ 

 0.0000 0.0211 1.011 1.000 48 -0.011 

 0.2000 0.6391 30.036 32.000 47 0.596 

 0.3800 0.7698 36.952 35.000 48 -0.669 

 Chi^2 = 0.80 d.f. = 1 P-value = 0.3699 

 Benchmark Dose Computation 

Specified effect = 0.67 

Risk Type = Extra risk 

Confidence level = 0.95 

 BMD = 0.23715 

 BMDL = 0.160575 
DRAFT - DO NOT CITE OR QUOTE 

196

 0

 0.2

 0.4

 0.6

 0.8

 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35

Fraction Affected

dose

Log-Logistic Model with 0.95 Confidence Level

16:29 09/21 2010

BMDL BMD

 

Log-Logistic

C.5. EXTRAPOLATION METHOD AND INHALATION CANCER SLOPE FACTOR 

As explained in Chapter 5, linear extrapolation was applied in this assessment and BMCL

at the calculated BMR was regarded as POD. The inhalation cancer slope factor was the upperbound estimation of risk and calculated as BMR/BMCL. It was used to estimate the lifetime lung 

tumor risk in human for vanadium pentoxide exposure through inhalation. Data are summarized 

in Table C-1. 

C.6. MSW TIME-TO-TUMOR MODELING OF THE INHALATION 

CARCINOGENESIS DATA SETS 

Multistage Weibull Time-to-tumor modeling was also used to model these data sets 

because the survival curves reported by NTP (2002) showed a high percentage (22-46%) of 

deaths at the end of 2-year studies across the different concentrations groups. The individual 

animal data was obtained through the NTP website and summarized according to concentration 

and week of death (Table C-11). 

Based on the results, MSW time-to-tumor model was not recommended to derive cancer 

slope factor for these data sets because of two reasons: 

• The visual fit near the 1st non-control concentration was not adequate. 

• The parameters, including c, beta_0 and beta_1, were very close to the initial values, 

which suggested the model was non-convergence. 

. 

Lung Tumor Data Set 1: Combined Incidence of Alveolar/Bronchiolar Adenomas and 
DRAFT - DO NOT CITE OR QUOTE 

197

Carcinomas in Male Mice, NTP (2002). 

Table C- 11. Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Male Mice Exposed to 

Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002). 

Human 

Equivalent 

Concentration 

(mg/m3

)

Week of 

Death 

Response Category for 

Alveolar/Bronchiolar 

Adenoma and/or Carcinoma 

b

Number of 

Animals 

0.0 

2 C 1 

26 C 1 

72 C 1 

89 C 1 

92 C 1 

95 C 1 

97 C 1 

98 C 2 

99 C 1 

101 C 1 

102 C 1 

104 C 6 

104 I 1 

105 C 31 

0.21 

3 C 3 

64 C 1 

75 I 1 

76 I 1 

81 I 1 

83 I 1 

86 C 1 

87 I 1 

91 I 1 

93 I 1 

94 I 2 

95 C 1 

101 I 1 

103 I 1 

104 I 8 

104 C 1 

105 C 11 

105 I 13 
DRAFT - DO NOT CITE OR QUOTE 

198

Table C- 11. Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Male Mice 

Exposed to Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002). (Continued) 

Human 

Equivalent 

Concentration 

(mg/m3) 

Week of 

Death 

Response Category for 

Alveolar/Bronchiolar 

Adenoma and/or Carcinoma 

b

Number of 

Animals 

0.42 

36 C 1 

39 C 1 

40 I 1 

45 I 1 

50 C 1 

59 C 1 

70 C 1 

72 I 1 

76 I 1 

82 C 1 

83 I 1 

91 I 1 

92 I 1 

95 I 1 

95 C 1 

99 I 1 

101 I 2 

101 C 1 

104 I 7 

105 I 17 

105 C 7 

0.81 

36 C 1 

68 I 1 

77 I 1 

79 I 1 

79 C 1 

81 C 1 

81 I 1 

87 C 2 

91 I 1 

93 I 1 

98 I 1 

99 C 1 

101 I 2 

104 I 7 

104 C 3 

105 I 16 

105 C 9 
DRAFT - DO NOT CITE OR QUOTE 

199

a

 Concentration was the original doses reported in the publication from NTP(2002). No adjustment was applied. 

b

 Categories of response: “C”=Neither carcinoma nor adenoma was detected when the subject was removed from the 

study due to scheduled sacrifice or unscheduled death; “I”= carcinoma and/or adenoma were detected when the 

subjected was removed from the study due to scheduled sacrifice or unscheduled death. 

MSW Time-to-tumor output 

======================================================================= 

 Multistage Weibull Model. (Version: 1.6.1; Date: 11/24/2009) 

 Solutions are obtained using donlp2-intv, (c) by P. Spellucci 

 Input Data File: V2O5_NTP_MaleMiceHEC_Poly1.(d) 

 ======================================================================= 

 V2O5_NTP_MaleMiceHEC 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 The form of the probability function is: 

 P[response] = 1-EXP{-(t - t_0)^c * 

 (beta_0+beta_1*dose^1)} 

 The parameter betas are restricted to be positive 

 Dependent variable = CONTEXT 

 Independent variables = DOSE, TIME 

 Total number of observations = 200 

 Total number of records with missing values = 0 

 Total number of parameters in model = 4 

 Total number of specified parameters = 1 

 Degree of polynomial = 1 

 User specifies the following parameters: 

 t_0 = 0 

 Maximum number of iterations = 64 

 Relative Function Convergence has been set to: 2.22045e-016 

 Parameter Convergence has been set to: 1.49012e-008 

 Default Initial Parameter Values 

 c = 1.05882 

 t_0 = 0 Specified 

 beta_0 = 0.0054829 

 beta_1 = 0.0193401 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -c -t_0 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 beta_0 beta_1 

 beta_0 1 -0.61 

 beta_1 -0.61 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 c 1 NA 

 beta_0 0.00720175 0.00201449 0.00325342 0.0111501 

 beta_1 0.0252605 0.00794841 0.00968191 0.0408391 

NA - Indicates that this parameter has hit a 

 bound implied by some inequality constraint 

 and thus has no standard error. 

 Log(likelihood) # Param AIC 

 Fitted Model -101.116 3 208.233 

 Data Summary 

 CONTEXT 

 C F I U Total Expected Response 

 DOSE 

 0 28 0 22 0 50 25.86 

 0.21 8 0 42 0 50 35.33 

 0.42 7 0 43 0 50 41.53 

 0.81 7 0 43 0 50 46.15 

 Benchmark Dose Computation 
DRAFT - DO NOT CITE OR QUOTE 

200

Risk Response = Incidental 

Risk Type = Extra 

Specified effect = 0.71 

Confidence level = 0.9 

Time = 104 

 BMD = 0.471196 

 BMDL = 0.390136 

 BMDU = 0.716564 

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.00

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.21

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.42

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.81

Time

Probability

Incidental Risk: V2O5_NTP_MaleMiceHEC_Poly1
DRAFT - DO NOT CITE OR QUOTE 

201

Lung Tumor Data Set 2: Combined Incidence of Alveolar/Bronchiolar Adenoma and 

Carcinoma in Female Mice, NTP (2002). 

Table C- 12. Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Female Mice Exposed to 

Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002).

Human 

Equivalent 

Concentration 

(mg/m3

) 

Week of 

Death 

Response Category for 

Alveolar/Bronchiolar 

Adenoma and/or Carcinoma 

b

Number of 

Animals 

0.00 

2 C 1 

26 C 1 

72 C 1 

89 C 1 

92 C 1 

95 C 1 

97 C 1 

98 C 2 

99 C 1 

101 C 1 

102 C 1 

104 C 6 

104 I 1 

105 C 31 

0.20 

3 C 3 

64 C 1 

75 I 1 

76 I 1 

81 I 1 

83 I 1 

86 C 1 

87 I 1 

91 I 1 

93 I 1 

94 I 2 

95 C 1 

101 I 1 

103 I 1 

104 I 8 

104 C 1 

105 C 11 

105 I 13 
DRAFT - DO NOT CITE OR QUOTE 

202

Table C-12 . Grouped Data for MSW Time-to-tumor Modeling; B6C3F1 Female Mice 

Exposed to Vanadium Pentoxide by Inhalation for 2 Years (NTP, 2002). (Continued) 

Human 

Equivalent 

Concentration 

(mg/m3) 

Week of 

Death 

Response Category for 

Alveolar/Bronchiolar 

Adenoma and/or Carcinoma 

b

Number of 

Animals 

0.38 

36 C 1 

39 C 1 

40 I 1 

45 I 1 

50 C 1 

59 C 1 

70 C 1 

72 I 1 

76 I 1 

82 C 1 

83 I 1 

91 I 1 

92 I 1 

95 I 1 

95 C 1 

99 I 1 

101 I 2 

101 C 1 

104 I 7 

105 I 17 

105 C 7 

0.73 

36 C 1 

68 I 1 

77 I 1 

79 I 1 

79 C 1 

81 C 1 

81 I 1 

87 C 2 

91 I 1 

93 I 1 

98 I 1 

99 C 1 

101 I 2 

104 I 7 

104 C 3 

105 I 16 
DRAFT - DO NOT CITE OR QUOTE 

203

105 C 9 a

 Concentration was the original one reported in the publication from NTP(2002). No adjustment was applied. 

b

 Categories of response: “C”=Neither carcinoma nor adenoma was detected when the subject was removed from the 

study due to scheduled sacrifice or unscheduled death; “I”= carcinoma and/or adenoma were detected when the 

subjected was removed from the study due to scheduled sacrifice or unscheduled death. 

MSW Time-to-tumor output 

======================================================================= 

 Multistage Weibull Model. (Version: 1.6.1; Date: 11/24/2009) 

 Solutions are obtained using donlp2-intv, (c) by P. Spellucci 

 Input Data File: V2O5_NTP_FemaleMiceHEC_Poly1.(d) 

======================================================================= 

 V2O5_NTP_FemaleMiceHEC 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

 The form of the probability function is: 

 P[response] = 1-EXP{-(t - t_0)^c * 

 (beta_0+beta_1*dose^1)} 

 The parameter betas are restricted to be positive 

 Dependent variable = CONTEXT 

 Independent variables = DOSE, TIME 

 Total number of observations = 200 

 Total number of records with missing values = 0 

 Total number of parameters in model = 4 

 Total number of specified parameters = 1 

 Degree of polynomial = 1 

 User specifies the following parameters: 

 t_0 = 0 

 Maximum number of iterations = 64 

 Relative Function Convergence has been set to: 2.22045e-016 

 Parameter Convergence has been set to: 1.49012e-008 

 Default Initial Parameter Values 

 c = 1.125 

 t_0 = 0 Specified 

 beta_0 = 0.000224032 

 beta_1 = 0.0144984 

 Asymptotic Correlation Matrix of Parameter Estimates 

 ( *** The model parameter(s) -t_0 

 have been estimated at a boundary point, or have been specified by the user, 

 and do not appear in the correlation matrix ) 

 c beta_0 beta_1 

 c 1 -0.93 -1 

 beta_0 -0.93 1 0.93 

 beta_1 -1 0.93 1 

 Parameter Estimates 

 95.0% Wald Confidence Interval 

 Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit 

 c 1.12496 0.770137 -0.384483 2.6344 

 beta_0 0.000224043 0.000862599 -0.00146662 0.00191471 

 beta_1 0.0144991 0.0511302 -0.0857143 0.114712 

 Log(likelihood) # Param AIC 

 Fitted Model -109.298 3 224.597 

 Data Summary 

 CONTEXT 

 C F I U Total Expected Response 

 DOSE 

 0 49 0 1 0 50 1.94 

 0.2 18 0 32 0 50 19.95 

 0.38 15 0 35 0 50 30.09 

 0.73 18 0 32 0 50 42.08 

 Benchmark Dose Computation 

Risk Response = Incidental 

Risk Type = Extra 

Specified effect = 0.67 
DRAFT - DO NOT CITE OR QUOTE 

204

Confidence level = 0.9 

Time = 104 

 BMD = 0.411511 

 BMDL = 0.339589 

 BMDU = 0.516352 

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.00

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.20

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.38

Time

Probability

0 20 40 60 80 100

0.0 0.4 0.8

Dose = 0.73

Time

Probability

Incidental Risk: V2O5_NTP_FemaleMiceHEC_Poly1