## DRAFT

TOXICOLOGICAL PROFILE FOR

VANADIUM

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service Agency for Toxic Substances and Disease Registry

September 2009ii VANADIUM



### DISCLAIMER

The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry.

This information is distributed solely for the purpose of pre dis semination public comment under applicable information quality guidelines. It has not been formally disseminated by the Agency for Toxic Substances and Disease Registry. It does not represent and should not be construed to represent any agency determinat ion or policy.

***DRAFT FOR PUBLIC COMMENT***iii VANADIUM



### UPDATE STATEMENT

A Toxicological Profile for Vanadium was released in 1992. This present edition supersedes any previously released draft or final profile.

Toxicological profiles are revised and republished as necessary. For informa tion regarding the update status of previously released profiles, contact ATSDR at:

Agency for Toxic Substances and Disease Registry Division of Toxicology and Environmental Medicine/Applied Toxicology Branch

1600 Clifton Road NE Mailstop F-62 Atlanta, G eorgia 30333

***DRAFT FOR PUBLIC COMMENT***iv VANADIUM



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***v



### FOREWORD

This toxicological profile is prepared in accordance with guidelines developed by the Agency for

Toxic Substances and Disease Registry (A TSDR) and the Environmental Protection Agency (EPA). The
original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised

and republished as necesslll)'.

The A TSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects

information for these toxic substances described therein. Each peer-reviewed profile identifies and reviews

the key literature that describes a substance's toxicologic properties. Other pertinent literature is also
presented, but is described in less detail than the key studies. The profile is not intended to be an
exhaustive document; more comprehensive sources of specialty information are referenced.

The focus of the profiles is on health and toxicologic information. Each toxicological profile begins

with a public health statement that describes, in nontechnical language, a substance's relevant toxicological
properties. Following the public health statement is information concerning levels of significant human

exposure and, where known, significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summlll)'. Data needs that are of significance to protection of public health are identified by A TSDR and EPA.

Each profile includes the following:

(A) The examination, summlll)', and interpretation of available toxicologic information and
epidemiologic evaluations on a toxic substance to ascertain the levels of significant human

exposure for the substance and the associated acute, subacute, and chronic health effects;

(B) A determination of whether adequate information on the health effects of each substance is

available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and

(C) Where appropriate, identification of toxicologic testing needed to identifY the types or levels of

exposure that may present significant risk of adverse health effects in humans.

The principal audiences for the toxicological profiles are health professionals at the Federal, State,

and local levels; interested private sector organizations and groups; and members of the public. We pIan to

revise these documents in response to public comments and as additional data become available.

Therefore, we encourage comments that will make the toxicological profile series of the greatest use.

Comments should be sent to:

Agency for Toxic Substances and Disease Registry

Division of Toxicology and Environmental Medicine

1600 Clifton Road, N.E.

Mail Stop F-62

Atlanta, Georgia 30333VI

The toxicological profiles are developed under the Comprehensive Environmental Response,
Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section

I 04(i)(1) directs the Administrator of ATSDR to "

... effectuate and implement the health related

authorities" of the statute. This inCludes the preparation of toxicological profiles for hazardous substances

most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. Section 104(i)(3) of

CERCLA, as amended, directs the Administrator of A TSDR to prepare a toxicological profile for each

substance on the list. In addition, A TSDR has the authority to prepare toxicological profiles for substances

not found at sites on the National Priorities List, in an effort to "

... establish and maintain inventory of

literature, research, and studies on the health effects oftoxic substances" under CERCLA Section

I 04(i)(1 XB), to respond to requests for consultation under section 104(iX 4), and as otherwise necessary to

support the site-specific response actions conducted by ATSDR.

This profile reflects ATSDR's assessment of all relevant toxicologic testing and information that

has been peer-reviewed. Staffs of the Centers for Disease Control and Prevention and other Federal

scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and is being made available for public review. Final responsibility for the contents

and views expressed in this toxicological profile resides with ATSDR. 

# V

Howard Frumkin, M.D., Dr. P.H. Thomas R. Frieden, M.D., M.P.H.

Director, National Center for Environmental Administrator, Agency for Toxic Substances and
Health/Agency for Toxic Substances and Disease Disease Registry
Registryvii VANADIUM



### QUICK REFERENCE FOR HEALTH CARE PROVIDERS

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluati on, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast

answers to ofte n-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Public Health Statement : The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance’s relevant toxicologic properties in a nontechnical, question-and- answer format, and it includes a review of the general health effects observed following exposure.

Chapter 2: Relevance to Public Health : The Relevance to Public Health Section evaluates, interprets

, and assesses the significance of toxicity data to human health.

Chapter 3: Health Effects : Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section.

NOTE : Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure.

Pediatrics : Four new sections have been added to each Toxicological Profile to address child health

issues:

Section 1.6 How Can (Chemical X) Affect Children?

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?

Section 3.7 Children’s Susceptibility

Section 6.6 Exposures of Children

Other Sections of Interest:

Section 3.8 Biomarkers of Exposure and Effect

Section 3.11 Methods for Redu cing Toxic Effects

ATSDR Information Center

Phone: 1-800- CDC

- INFO (800 -232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178

E- mail: cdcinfo@cdc.gov Internet : http://www.atsdr.cdc.gov

The following additional material can be ordered through the ATSDR Information Center:

Case Studies in Environmental Medicine: Taking an Exposure History

— The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide
Toxicity ; and numerous chemical- specific case studies.

***DRAFT FOR PUBLIC COMMENT***viii VANADIUM

Managing Hazardous Materials Incidents is a three

- volu me set of recommendations for on

- scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are planning guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume III— Medical Management Guidelines for Acute Chemical Exposure s— is a guide for health care professionals treating patients exposed to hazardous materials.

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances.

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, injury, and disability related to the interactions between people and their environment outside the workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta,

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015.

The National Institute for Occupational Safety and Health (NIOSH) conducts research o n occupational diseases and injuries, responds to requests for assistance by investigating problems of health and safety in the workplace, recommends standards to the Occupational Safety and Health Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998

• Phone: 800 -35- NIOSH.

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for biomedical research on the effects of chemical, physical, and biologic environmental agents on human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, Research Triangle Park, NC 27709 • Phone: 919-541-3212.

Referrals

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of cl inics in the United States to provide expertise in occupational and environmental issues. Contact: AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976

• FAX: 202 -347-4950 • e- mail: AOEC@AOEC.ORG • Web Page: http://www.aoec. org/.

The American College of Occupational and Environmental Medicine (ACOEM) is an association of physicians and other health care providers specializing in the field of occupational and environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266.

***DRAFT FOR PUBLIC COMMENT***ix VANADIUM



### CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHOR(S):

Jessilynn Taylor, M.S. , CDR USPHS Sam Keith, M.S. , CHP Larry Cseh, M.S.A., R.S. , CPT USPHS ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA

Lisa Ingerman, Ph.D., DABT Lara Chappell, Ph.D. Jennifer Rhoades, B.A. Amy Hueber, M.L.S. SRC, Inc., North Syracuse, NY

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points.

2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to

substance- specific Minimal Risk Levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs.

3. Data Needs Review. The Applied Toxicology Branch reviews data needs sections to assure consistency across profiles and adherence to instructions in the Guidance.

4. Green Border Review. Green Border review assures the consistency with ATSDR policy.

***DRAFT FOR PUBLIC COMMENT***x VANADIUM



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***xi VANADIUM



### PEER REVIEW

A peer review panel was asse mbled for vanadium. The panel consisted of the following members:

1. Janusz Z. Byczkowski, Ph.D., DABT, Independent Consultant, Fairborn, O hio;

2. David Dorman , Ph.D., D.V.M., DABT, Associate Dean for Research and Graduate Studies , North

Carolina State University , Raleigh, North Carolina; and

3. Anna Fan, Ph.D., DABT, Chief, Pesticide and Environmental Toxicology Branch, Office of

Environmental Health Hazard Assessment

, California Environmental Protection Agency

, Oakland/Sacramento , C alifornia.

These experts collectively have knowledge of vanadium's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity wit h the conditions for peer review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrati ve record for this compound.

The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR.

***DRAFT FOR PUBLIC COMMENT***xii VANADIUM



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***xiii VANADIU M



### CONTENTS

DISCLAIMER

................................................................................................ .............................................. ii

UPDATE STATEMENT

............................................................................................................................. iii

FOREWORD

................................................................................................ ................................................ v QUICK REFERENCE FOR HEALTH CARE PROVIDERS

.................................................................... vii

CONTRIBUTOR S

................................................................................................ ....................................... ix

PEER REVIEW

................................................................................................ ........................................... xi

CONTENTS

................................................................................................ ............................................... xiii

LIST OF FIGURES

................................................................................................ .................................. xvii

LIST OF TABLES

................................................................................................ ..................................... xix

1. PUBLIC HEALTH STATEMENT

.......................................................................................................... 1

1.1 WHAT IS VANADIUM?

............................................................................................................. 1

1.2 WHAT HAPPENS TO VANADIUM WHEN IT ENTERS THE ENVIRONMENT?

................ 2

1.3 HOW MIGHT I BE EXPOSED TO VANADIUM?

.................................................................... 3

1.4 HOW CAN VANADIUM ENTER AND LEAVE MY BODY?

................................................. 4

1.5 HOW CAN VANADIUM AFFECT MY HEALTH?

.................................................................. 5

1.6 HOW CAN VANADIUM AFFECT CHILDREN?

...................................................................... 6

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO VANADIUM?

................. 6

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN

EXPOSED TO VANADIUM?

..................................................................................................... 7

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH?

.................................................................................................. 7

1.10 WHERE CAN I GET MORE INFORMATION?

......................................................................... 8

2. RELEVANCE TO PUBLIC HEALTH

................................................................................................. 11

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO VANADIUM IN THE

UNITED STATES

................................................................................................ .................................. 11

2.2 SUMMARY OF HEALTH EFFECTS

....................................................................................... 12

2.3 MINIMAL RISK LEVELS (MRLs)

........................................................................................... 13

3. HEALTH EFFECTS

.............................................................................................................................. 25

3.1 INTRODUCTION

...................................................................................................................... 25

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

.................................... 25

3.2.1 Inhalation Exposure

............................................................................................................ 26

3.2.1.1 Death

............................................................................................................................... 26

3.2.1.2 Systemic Effects

.............................................................................................................. 27

3.2.1.3 Immunological and Lymphoreticular Effects

................................................................. 41

3.2.1.4 Neurological Effects

....................................................................................................... 41

3.2.1.5 Reproductive Effects

....................................................................................................... 41

3.2.1.6 Developmental Effects

.................................................................................................... 42

3.2.1.7 Cancer

............................................................................................................................. 42

3.2.2 Oral Exposure

..................................................................................................................... 44

3.2.2.1 Death

............................................................................................................................... 44

3.2.2.2 Systemic Effects

.............................................................................................................. 44

3.2.2.3 Immunological and Lymphoreticular Effects

................................................................. 64

3.2.2.4 Neurological Effects

....................................................................................................... 64

3.2.2.5 Reproductive Effects

....................................................................................................... 65

3.2.2.6 Developmental Effects

.................................................................................................... 65

3.2.2.7 Cancer

............................................................................................................................. 66

***DRAFT FOR PUBLIC COMMENT***3.2.3 Dermal Exposure................................................................................................................. 66

3.2.3.1 Death

............................................................................................................................... 66

3.2.3.2 Systemic Effects

.............................................................................................................. 66

3.2.3.3 Immunological and Lymphoreticular Effects

................................................................. 66

3.2.3.4 Neurological Effects

....................................................................................................... 66

3.2.3.5 Reproductive Effects

....................................................................................................... 66

3.2.3.6 Developmental Effects

.................................................................................................... 66

3.2.3.7 Cancer

............................................................................................................................. 66

3.3 GENOTOXICITY

....................................................................................................................... 66

3.4 TOXICOKINETICS

................................................................................................................... 72

3.4.1 Absorption

........................................................................................................................... 72

3.4.1.1 Inhalation Exposure

........................................................................................................ 72

3.4.1.2 Oral Exposure

................................................................................................................. 73

3.4.1.3 Dermal Exposure............................................................................................................. 73

3.4.2 Distribution

......................................................................................................................... 73

3.4.2.1 Inhalation Exposure

........................................................................................................ 73

3.4.2.2 Oral Exposure

................................................................................................................. 74

3.4.2.3 Dermal Exposure............................................................................................................. 77

3.4.2.4 Other Routes of Exposure

............................................................................................... 77

3.4.3 Metabolism

......................................................................................................................... 77

3.4.4 Elimination and Excre tion

.................................................................................................. 77

3.4.4.1 Inhalation Exposure

........................................................................................................ 77

3.4.4.2 Oral Exposure

................................................................................................................. 78

3.4.4.3 Dermal Exposure............................................................................................................. 78

3.4.5 Physiologically Based Pharmacok inetic (PBPK)/Pharmacodynamic (PD) Models

........... 78

3.5 MECHANISMS OF ACTION

.................................................................................................... 80

3.5.1 Pharmacokinetic Mechanisms

............................................................................................. 80

3.5.2 Mechanisms of Toxicity

...................................................................................................... 82

3.5.3 Animal

- to -Human Extrapolations

....................................................................................... 82

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS

........................... 82

3.7 CHILDREN’S SUSCEPTIBILITY

............................................................................................ 83

3.8 BIOMARKERS OF EXPOSURE AND EFFECT

...................................................................... 85

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Vanadium

...................................... 86

3.8.2 Biomarkers Used to Characterize Effects Caused by Vanadium

........................................ 87

3.9 INTERACTIONS WITH OTHER CHEMICALS

...................................................................... 87

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

................................................ 87

3.11 METHODS FOR REDUCING TOXIC EFFECTS

.................................................................... 88

3.11.1 Reducing Peak Absorption Following Exposure

................................................................ 88

3.11.2 Reducing Body Burden

....................................................................................................... 88

3.11.3 Interfering with the Mechanism of Action for Toxic Effects

.............................................. 89

3.12 ADEQUACY OF THE DATABA SE

......................................................................................... 90

3.12.1 Existing Information on Health Effects of Vanadium

........................................................ 90

3.12.2 Identification of Data Needs

............................................................................................... 92

3.12.3 Ongoing Studies

.................................................................................................................. 99

4. CHEMICAL AND PHYSICAL INFORMATION

.............................................................................. 101

4.1 CHEMICAL IDENTITY

.......................................................................................................... 101

4.2 PHYSICAL AND CHEMICAL PROPERTIES

....................................................................... 101

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

.......................................................... 107

5.1 PRODUCTION

......................................................................................................................... 107 xiv VANADIUM

***DRAFT FOR PUBLIC COMMENT***5.2 IMPORT/EXPORT

................................................................................................................... 113

5.3 USE

................................................................................................ ........................................... 113

5.4 DISPOSAL

............................................................................................................................... 113

6. POTENTIAL FOR HUMAN EXPOSURE

......................................................................................... 115

6.1 OVERVIEW

............................................................................................................................. 115

6.2 RELEASES TO THE ENVIRONMENT

................................................................................. 117

6.2.1 Air

................................................................................................ ..................................... 118

6.2.2 Water

................................................................................................ ................................. 123

6.2.3 Soil

................................................................................................ .................................... 123

6.3 ENVIRONMENTAL FATE

..................................................................................................... 124

6.3.1 Transport and Partitioning

................................................................................................ 124

6.3.2 Transformation and Degradation

...................................................................................... 127

6.3.2.1 Air

................................................................................................ ................................. 127

6.3.2.2 Water

............................................................................................................................. 128

6.3.2.3 Sediment and Soil

......................................................................................................... 128

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

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

6.4.1 Air

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

6.4.2 Water

................................................................................................ ................................. 131

6.4.3 Sediment and Soil

............................................................................................................. 133

6.4.4 Other Environmental Media

.............................................................................................. 136

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

....................................... 139

6.6 EXPOSURES OF CHILDREN

................................................................................................ 142

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

............................................. 144

6.8 ADEQUACY OF THE DATABASE

....................................................................................... 145

6.8.1 Ide ntification of Data Needs

............................................................................................. 145

6.8.2 Ongoing Studies

................................................................................................................ 148

7. ANALYTICAL METHODS

................................................................................................................ 149

7.1 BIOLOGICAL MATERIALS

.................................................................................................. 151

7.2 ENVIRONMENTAL SAMPLES

............................................................................................. 153

7.3 ADEQUACY OF THE DATABASE

....................................................................................... 153

7.3.1 Identification of Data Needs

............................................................................................. 157

7.3.2 Ongoing Studies

................................................................................................................ 157

8. REGULATIONS, ADVISORIES, AND GUIDELINES

..................................................................... 159

9. REFERENCES

................................................................................................ .................................... 165

10. GLOSSARY

................................................................................................ ...................................... 201

APPENDICES

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS

............................................................. A-1

B. USER’S GUIDE

................................................................................................ .................................. B-1
C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

...................................................................... C-1

D. INDEX

................................................................................................ ................................................ D-1 xv VANADIUM

***DRAFT FOR PUBLIC COMMENT***xvi VANADIUM



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM xvii



### LIST OF FIGURES

3-1. Levels of Significant Exposure to Vanadium and Compounds

- Inhalation

...................................... 34

3-2. Levels of Significant Exposure to Vanadium and Compounds

- Oral

................................................ 56

3-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance

...................................................................................................... 81

3-4. Existing Information on Health Effects of Vanadium and Compounds

............................................. 91

6-1. Frequency of NPL Sites with Vanadium Contamination

................................................................. 116

***DRAFT FOR PUBLIC COMMENT***VANADIUM xviii



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***xix VANADIU M



### LIST OF TABLES

2-1. Lung Effects Observed in Rats Exposed to Vanadium Pentoxide 6 H ours/day, 5 Days/week for

6 or 13 Days, 3 Months, or 2 Years

.................................................................................................... 17

2- 2. Hematological Effects in Rats Exposed to Ammonium Metavanadate for 4 Weeks

......................... 23

3-1. Levels of Significant Exposure to Vana dium and Compounds

- Inhalation

...................................... 28

3-2. Incidence of Lung Tumors in Rats and Mice Exposed to Vanadium Pentoxide for 2 Years

............. 43

3-3. Levels of Significant Exposure to Vanadium and Compounds

- Oral

................................................ 45

3-4. Genotoxicity of Vanadium and Compounds In Vitro

......................................................................... 67

3-5. Genotoxicity of Vanadium and Compounds In Vivo

.......................................................................... 70

3-6. Vanadium Elimination Half- Times in Various Organs in Rats Ex posed t o 8.2 mg Vanadium/kg/day for 1 Week

............................................................................................................. 76

4-1. Chemical Identity of Vanadium and Compounds............................................................................. 102

4-2. Physical and Chemical Properties of Vanadium and Compounds

................................................... 104

5-1. Facilities that Produce, Process, or Use Vanadium (Except When Contained in an Alloy)

............. 108

5-2. Facilities that Produce, Process, or Use Vanadium Compounds

...................................................... 110

5-3. Current U.S. Manufactur ers of Vanadium and Selected Vanadium Compounds

............................. 112

6- 1. Releases to the Environment from Facilities that Produce, Proces s, or Use Vanadium (Except

When Contained in an Alloy)

........................................................................................................... 119

6- 2. Release s to the Environment from Facilities that Produce, Process, or Use Vanadium Compounds

................................................................................................ ....................................... 121

6-3. Vanadium Levels in Food

................................................................................................................. 137

6-4. Estimated Daily Vanadium Intake

.................................................................................................... 140

7- 1. Analytical Methods for Determining Vanadium in Biological Materials

........................................ 152

7-2. Analytical Methods for Determining Vanadium in Environmental Samples

................................... 154

8-1. Regulations, Advisories, and Guidelines Applicable to Vanadium and Compounds

....................... 161

***DRAFT FOR PUBLIC COMMENT***xx VANADIUM



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***1 VANADIUM



## 1. PUBLIC HEALTH STATEMENT

This public health statement tells you about vanadium and the effects of exposure to it.

The Environme ntal Protection Agency (EPA) identifies the most serious hazardous waste sites in the

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long

- term

federal clean -up activities. Vanadium has been found in at least 319 of the 1,699 current or former NPL

sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility

exists that the number of sites at which vanadium is found may increase in the future as more sites are

evaluated. This information is important because these sites may be sources of exposure and exposure to

this substance may be harmful.

When a substance is released either from a large area, such as an industrial plant, or from a container,

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing,

eating, or drinking the substance, or by skin contact.

If you a re exposed to vanadium, many factors will determine whether you will be harmed. These factors

include the dose (how much), the duration (how long), and how you come in contact with it. You must

also consider any other chemicals you are exposed to and you r age, sex, diet, family traits, lifestyle, and

state of health.

1.1 WHAT IS VANADIUM?

Description Vanadium is a naturally occurring element. It is widely distributed in the earth’s crust at an average concentration of approximately 100 mg/kg

. Vanad ium is found in about

65 different minerals

.

Depending on its form, vanadium can be a

gray

- white metal or light gray or white lustrous powder. Pure vanadium is a bright white, soft,

and ductile metal

.

***DRAFT FOR PUBLIC COMMENT***2 VANADIUM

1. PUBLIC HEALTH STATEMENT

Uses

• Vanadium metal

• Vanadium pentoxide

• Vanadyl sulfate and sodium metavanadate Vanadium is used in producing rust

- resistant, spring, and high

- speed tool steels. It is an important carbide stabilizer in making steels

.

Vanadium pentoxide is used in ceramics and as a catalyst as well as in the production of superconductive magnets

.

Vanadyl sulfate and sodium metavanadate

have been used in dietary supplements

.

For more information on the physical and chemical properties of vanadium and its production, disposal

and use, see Chapters 4 and 5.

1.2 WHAT HAPPENS TO VANADIUM WHEN IT ENTERS THE ENVIRONMENT?

Sources Vanadium occurs naturally in soil, water, and

air. Natural sources of atmospheric vanadium
include continental dust, marine aerosol, and

volcanic emissions

.

Releases of vanadium to the environment are mainly associated with industrial sources, especially oil refineries and power plants using

vanadium rich fuel oil and coal

. Global human

made atmospheric releases of vanadium h as been estimated to be greater than vanadium

releases due to natural sources. Natural releases to water and soil are far greater overall

than human

- made releases to the atmosphere

.

***DRAFT FOR PUBLIC COMMENT***3 VANADIUM

1. PUBLIC HEALTH STATEMENT

Break down

• Air

• Water and soil Vanadium cannot be destroyed in the environment. It can only change its form or become attached or separated from airborne particulate, soil, particulate in water, and

sediment.

Vanadium particles in the air settle to the ground or are washed out of the air by rain. Smaller particles, such as those emitted from

oil

- fuel ed power plants, may stay in the air for longer times and are more likely to be transported farther away from the site of

release

.

The transport and partitioning of vanadium in water and soil is influenced by many factors including acidity of the water or soil and the presence of particulate s . Vanadium can either be dissolved in water as dissolved ions or may

become a d sorbed to particulate matter

.

1.3 HOW MIGHT I BE EXPOSED TO VANADIUM?

Food

– primary source of exposure Most foods have naturally occurring low concentrations of vanadium. Seafood generally contains higher concentrations of vanadium than

meat from land animals

.

Daily intakes of vanadium from food ranging from

0.0 1 to 0.0 2 mg have been reported

. Average vanadium concentrations in tap water are approximately 0.001 mg /L . Assuming that you drink approximately 2 L of water a day , a daily intake of approximately 0.002 m g of vanadium from tap water can be estimated for adults

.

Vanadium also may be found in various commercial nutritional supplements and multivitamins in amounts ranging from 0.0004 to 12.5 mg, depending on the serving size recommended by the manufacturer

. Consumption of some vanadium

- containing supplements may result in intakes of vanadium

that would exceed intakes from food and water.

Populations in areas with high levels of residual fuel oil consumption may also be exposed to

above

- background levels of vanadium, both from increased particulate deposition upon food crops and soil in the vicinity of power plants

.

***DRAFT FOR PUBLIC COMMENT***4 VANADIUM

1. PUBLIC HEALTH STATEMENT

Air Most people take in very little vanadium from breathing. The general population may also be exposed to airborne vanadium through inhalation, particularly in areas where use of residual fuel oils for energy production is high

.

Individuals exposed to cigarette smoke may also be exposed to higher than background levels of

vanadium. Approximately 0.0004 mg of vanadium is given off by in the smoke of one cigarette

.

Water and soil Vanadium concentrations in surface water can range from approximately 0. 04 to 220 μg/L depending on geographical location

.

For more information on how you might be exposed to vanadium, see Chapter 6.

1.4 HOW CAN VANADIUM ENTER AND LEAVE MY BODY?

Enter your body

• Inhalation

• Ingestion

• Dermal contact Some of the vanadium you breathe will enter your body through your lungs; however, we do

not know how much will enter.

A small amount of vanadium in food and water (3

– 20%) will enter your body through the digestive tract. The vanadium compounds you are exposed to will determine how much is

absorbed.

We do not know how much vanadium will enter your body through your skin. It is likely that very little will pass through the skin.

For more information about how vanadium enters and leaves your body, see Chapter 3.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 5

1. PUBLIC HEALTH STATEMENT

1.5 HOW CAN VANADIUM AFFECT MY HEALTH?

This section looks at studies concerning potential health effects in animal and human studies.

Workers

• Inhalation Breathing air with vanadium pentoxide can result in coughing which can last a number of days after exposure

.

Laboratory animals

• Inhalation Damage to the lungs, throat, and nose have been observed in rats and mice exposed to vanadium pentoxide

.

Humans Nausea, mild diarrhea, and stomach cramps

• Oral have been reported in people taking sodium metavanadate or vanadyl sulfate for the experimental treatment of diabetes

.

Stomach cramps were also reported in a study of people taking about 13 mg vanadium/day.

Laboratory animals

• Oral A number of effects have been found in rats and mice ingesting several vanadium compounds. The effects include:

• Decreases in number of red blood cells

• Increased blood pressure

• Mild neurological effects

Cancer Lung cancer has been found in mice exposed to vanadium pentoxide.

The International Agency for Research on Cancer (IARC) has determined that vanadium is possibly carcinogenic to humans.

For more information on health effects in people and animals after breathing, eating, or touching

vanadium, see Chapter 3.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 6

1. PUBLIC HEALTH STATEMENT

1.6 HOW CAN VANADIUM AFFECT CHILDREN?

This section discusses potential health effects in humans from exposures during the period from

conception to maturity at 18 years of age.

Effects in children The health effects seen in children from exposure to toxic levels of vanadium are expected to be similar to the effects seen in

adults. We do not know if children will be more sensitive to vanadium toxicity than adults.

Birth defects We do not know whether vanadium can cause birth defects in people.

Studies in animals exposed during pregnancy

have shown that vanadium can cause decreases in growth and increases in the

occurrence of birth defects. These effects are usually observed at levels which cause effects

in the mother.

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO VANADIUM?

Food Vanadium is a naturally occurring element that is widely distributed in the environment. I t is found in many foods , typically in small amounts. You cannot avoid exposure to vanadium.

Exposure to the levels of vanadium that ar e naturally present in food and water are not

considered to be harmful.

Consumer products Consumption of some vanadium

- containing supplements may result in intakes of vanadium

that would exceed intakes from food and water. You should check with your physician before taking supplements containing vanadium to determine if such supplements are appropriate for you.

As a precaution, such products should have

child

- proof caps or should be kept out of reach of children so that children will not accidentally

in gest them.

***DRAFT FOR PUBLIC COMMENT***7 VANADIUM

1. PUBLIC HEALTH STATEMENT

Air Individuals exposed to cigarette smoke may also be exposed to higher

- than

- background levels of vanadium. Avoiding exposure to cigarette smoke may reduce exposure of you and your family to vanadium.

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO

VANADIUM?

Detecting exposure All people have small amounts of vanadium in their bodies. It can be measured in many tissues and fluids including blood, urine, and

hair.

Measuring exposure Measurements of vanadium concentrations in blood and urine can tell you whether you have been exposed to larger

- than

- normal amounts of

vanadium. B lood and urinary vanadium levels

are considered the most reliable indicators of occupational exposure to vanadium

.

Measuring the concentration of vanadium in breathing air, drinking water, and food can help in determining how much vananium you are exposed to.

Measuring vanadium levels in hair is not a good indicator of occupational or environmental exposure to vanadium

.

For more information on ways to tell whether you have been exposed to vanadium see Chapters 3 and 7.

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO

PROTECT HUMAN HEALTH?

The federal government develops regulations and recommendations to protect public health. Regulations

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic

substances. Recommendations provide valuable guidelines to protect public health, but cannot be

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop

rec ommendations for toxic substances.

***DRAFT FOR PUBLIC COMMENT***8 VANADIUM

1. PUBLIC HEALTH STATEMENT

Regulations and recommendations can be expressed as “not

- to

- exceed” levels. These are levels of a toxic

substance in air, water, soil, or food that do not exceed a critical value. This critical value is usually based

o n levels that affect animals; they are then adjusted to levels that will help protect humans. Sometimes

these not- to

- exceed levels differ among federal organizations because they used different exposure times

(an 8-hour workday or a 24-hour day), different animal studies, or other factors.

Recommendations and regulations are also updated periodically as more information becomes available.

For the most current information, check with the federal agency or organization that provides it.

Some regulations a nd recommendations for vanadium include the following:

Workplace air OSHA set a legal limit of 0.5 mg/m 3 for vanadium pentoxide respirable dust averaged

over an 8

- hour work day. A limit of 0.1 mg/m 3

for vanadium pentoxide fume has also been

established.

1.10 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or

environmental quality department, or contact ATSDR at the address and phone number below.

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous

substances.

Toxicological profiles are also available on

- line at www.atsdr.cdc. gov and on CD-ROM. You may

request a copy of the ATSDR ToxProfiles TM CD

- ROM by calling the toll -free information and technical

assistance number at 1 -800- CDCINFO (1 -800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing

to:

Agency for Toxic Substa nces and Disease Registry Division of Toxicology and Environmental Medicine

1600 Clifton Road NE Mailstop F-62 Atlanta, GA 30333

Fax: 1 -770-488-4178

***DRAFT FOR PUBLIC COMMENT***9 VANADIUM

1. PUBLIC HEALTH STATEMENT

Organizations for

- profit may request copies of final Toxicological Profiles from the following:

National Technical Information Service (NTIS) 5285 Port Royal Road Springfield, VA 22161

Phone: 1 -800-553-6847 or 1-703-605-6000

Web site: http://www.ntis.gov/

***DRAFT FOR PUBLIC COMMENT***10 VANADIUM

1. PUBLIC HEALTH STATEMENT



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***11 VANADIUM



### 2. RELEVANCE TO PUBLIC HEALTH

2.1 BACKGROUN D AND ENVIRONMENTAL EXPOSURES TO VANADIUM IN THE

UNITED STATES

Vanadium is the 22 nd most abundant element in the earth’s crust with an average concentration of

100 ppm. It exists in oxidation states ranging from -1 to +5 with 3+, 4+, and 5+ being the most common

oxidation states. Va nadium is primarily used in the production of rust -resistant, spring, and high- speed

tool steels; vanadium pentoxide is used in ceramics. Vanadium is released to the environment by

continental dust, marine aerosols, volcanic emissions, and the combustion of coal and petroleum crude

oils. It is naturally released into water and soil as a result of weathering of rock and soil erosion.

Ambient air concentrations of vanadium are low, with urban areas having higher concentratio ns. Average

vanadium concentrations were 3.0–3.7 ng/m 3 in urban areas of Illinois ; in rural areas, the vanadium

concentrations were 0.8 –1.2 ng/m 3 . Higher vanadium levels have been measured in the eastern United

States due to the high density of oil fired power plants using vanadium- rich residual fuel oil. An average

vanadium air concentration of 620 ng/m 3 was measured in Eastern cities compared to 11 ng/m 3 in cities

throughout the United States. Vanadium residence time in the environment is inversely related to the

particle size. In water, vanadium is converted from trivalent forms to pentavalent forms. The levels of

vanadium in surface water range from 0. 04 to 104 μg/L . Vanadium levels of 1.2–1.0 μg/L were

measured in tap water samples collected in several U.S. states

.

Food is the primary route of exposure for the general population; foods with the highest vanadium content

include ground parsley, freeze-dried spinach, wild mushrooms, and oysters. Vanadium in food is mainly

ingested as VO 2+ (va nadyl, V 4+ ) or HVO 4 2- (vanadate , V 5+ ). Estimates of dietary vanadium intake range

from 0.09 to 0.34 μg/kg/day in adults. Humans are potentially exposed to a variety of vanadium

compounds, the most common being vanadium pentoxide, sodium metavanadate, sodium orthovanadate,

vanadyl sulfate, and ammonium metavanadate. Organic anthropogenic vanadium compounds, such as

bis(maltolato) oxyvanadium (IV) or vanadyl acetyl acetonate, are used in the treatment of diabetes and

cancer; these compounds have differen t toxicokinetic properties than inorganic vanadium compounds and

are not discussed in this toxicological profile.

Although there is some evidence to suggest that vanadium is an essential nutrient, a functional role for

vanadium in humans has not been es tablished ; increases in abortion rates and decreased milk production

have been observed in vanadium-deprived goats . Vanadium mimics insulin and stimulates cell

proliferation and differentiation. In animal models, particularly streptozotoxin-induced di abetes in rats,

***DRAFT FOR PUBLIC COMMENT***12 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

vanadium has been shown to normalize blood glucose and lipid levels, improve insulin sensitivity, and

prevent or reverse secondary complications such as cardiomyopathy, cataract development, and impaired

antioxidant status.

2.2 SUMMARY OF HEALTH EFFECTS

The general population can be exposed to vanadium primarily through oral (ingestion of vanadium in

food) and inhalation routes of exposure. Based on occupational exposure studies, human experimental

studies, and studies in laboratory a nimals, the respiratory tract following inhalation exposure and the

gastrointestinal tract, hematological system, and developing organism following oral exposure are th e

primary target s of toxicity.

Adverse respiratory effects have been reported in humans and animals exposed to vanadium compounds

at concentrations much higher than those typically found in the environment. Although the available data

in humans are limited, signs of airway irritation (e.g., coughing, wheezing, sore throat) have been

reporte d in subjects acutely exposed to 0.6 mg vanadium/m 3 and in workers exposed to vanadium

pentoxide dust . These effects have persisted for days to weeks after exposure termination and are often

not associated with alterations in lung function. Studies in laboratory animals provide strong support that

the respiratory tract is the most sensitive target following inhalation exposure to vanadium. A variety of

lung lesions including alveolar/bronchiolar hyperplasia, inflammation, and fibrosis have been observed in

rats and mice exposed to vanadium pentoxide ; the severity of the lesions is related to concentration and

duration. The lung effects have been observed following acute exposure to 0.56 mg vanadium/m 3 and

chronic exposures to 0.28 mg vanadium/m 3 and h ave been observed after 2 days of exposure. Longer

duration exposures also result in inflammation and hyperplasia in the larynx and hyperplasia in nasal

goblet cells. These histological alterations result in restrictive impairments in lung function; resp iratory

distress is observed at vanadium pentoxide concentrations of ≥4.5 mg vanadium/m 3

.

Other sensitive targets of vanadium toxicity include the gastrointestinal system following oral exposure

and hematological system following inhalation or oral exposure. Symptoms of gastrointestinal irritation

(diarrhea, cramps, nausea) have been observed in humans following bolus administration of sodium

metavanadate or vanadyl sulfate; it appears that with repeated exposure, humans develop a tolerance to

these effe cts. Diarrhea has also been observed in rats and mice orally exposed to lethal doses of

vanadium. Microcytic erythrocytosis (evidenced by decreases in hematocrit, hemoglobin, and mean cell

volume and increases in reticulocytes and nucleated erythrocytes) has been observed in rats exposed to

***DRAFT FOR PUBLIC COMMENT***13 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

1.1 mg vanadium/m 3 as vanadium pentoxide for at least 4 days . Hematological effects, including

decreases in erythrocyte levels, decreases in hemoglobin, and increases in reticulocytes have also been

observed in rats orally exposed to 1.18 mg vanadium/kg/day as ammonium metavanadate for 4 weeks

.

Information on the potential of vanadium to induce developmental effects in humans is limited, but

developmental effects have been observed in laboratory animals. Decreases in pup growth have been

observed at maternal doses of ≥2.1 mg vanadium/kg/day . At higher doses, decreases in pup survival and

gross, skeletal, and visceral malformations and anomalies have been reported; marked decreases in

maternal body weight are also observed at these dose levels.

No studies have examined the carcinogenic potential of vanadium in humans. An increase in lung

carcinoma incidence has been observed in mice chronically exposed to vanadium pentoxide ; there is also

marginal evidence for lung cancer in male rats (incidence of carcinoma was higher than historical controls

but not concurrent controls). Carcinogenicity has not been adequately assessed in laboratory animals

following oral exposure. One study classified vanadium pentoxide in group 2B (possibly carcinogenic to

humans) based on inadequate evidence in humans and sufficient evidence in animals. The Department of

Health and Human Services and EPA have not classified carcinogenicity of vanadium.

2.3 MINIMAL RISK LEVELS (MRLs)

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for vanadium. An

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive

health effect(s) for a specific duration within a given route of exposure. MRLs are based on

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate

methodology does not exist to develop MRLs for dermal exposu re.

Although methods have been established to derive these types of levels (Barnes and Dourson 1988; EPA

1990), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional

uncertainties inherent in the application of th e procedures to derive less than lifetime MRLs. As an

example, acute inhalation MRLs may not be protective for health effects that are delayed in development

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic

***DRAFT FOR PUBLIC COMMENT***14 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

bronchitis. As these kinds of health effects data become available and methods to assess levels of

significant human exposure improve, these MRLs will be revised.

Inhalation MRLs

Acute -Duration Inhalation MRL

**•** An MRL of 0.0008 mg vanadium/m 3 has been derived for acute-duration inhalation exposure (14 days or less) to vanadium pentoxide dust.

Data on acute toxicity of vanadium in humans are limited to an experimental study in which a small

number of subjects were exposed to vanadium pentoxide dust for 8 hours (Zenz and Berg 1967). A

persistent cough lasting for 8 days developed in two subjects exposed to 0.6 mg vanadium/m 3 ; at 0.1 mg

vanadium/m 3 , a productive cough without any subjective complaints or impact on work or home activities

were observed in five subjects. The available studies in laboratory animals focused on potential

respiratory tract effects. Impaired lung function, characterized as airway obstructive changes (increased

resistance and decreased airflow), was observed in monkeys exp osed to 2.5 or 1.7 mg vanadium/m 3 as

vanadium pentoxide for 6 hours (Knecht et al. 1985, 1992); the highest no- observed

- adverse

- effect level

(NOAEL) for this effect was 0.34 mg vanadium/m 3 . In female rats exposed to 0.56 mg vanadium/m 3

6 hours/day, 5 days /week for 13 days, minimal inflammation and histiocytic infiltration were observed

(NTP 2002). Alveolar and bronchiolar epithelial hyperplasia and inflammation were observed in the

lungs of mice similarly exposed to 1.1 mg vanadium/m 3 as vanadium pentoxid e (NTP 2002). Although

the Knecht et al. (1985, 1992) or NTP (2002) studies did not include examination of potential end points

outside of the respiratory tract, longer

- duration studies have identified the respiratory tract as the most

sensitive target of toxicity (NTP 2002). The NTP (2002) rat study was selected as the basis of the acute

duration inhalation MRL.

In th e NTP (2002) study, groups of male and female F344 rats received whole-body exposure to 0, 1, 2,

or 4 mg vanadium pentoxide/m 3 (0, 0.56, 1.1, or 2.2 mg vanadium/m 3 ) as particulate aerosols 6 hours/day,

5 days/week. On days 6 and 13, 10 rats/group were kill ed and a histopathological examination of the

lungs was conducted. Four rats per group were kille d for examination of the onset and ex tent of lung

lesions after 1, 2, 5, 10, or 16 days of exposure. Hyperplasia of alveolar epithelium and bronchiole

epithelium were observed in 100% of the female rats exposed to 1.1 or 2.2 mg vanadium/m 3 for 6 or

13 days. Significant increases in the inci dence of histiocytic infiltrate and inflammation were observed in

rats exposed to 1.1 or 2.2 mg vanadium/m 3 for 6 or 13 days and in rats exposed to 0.56 mg vanadium/m 3

for 13 days. A significant increase in fibrosis was observed in rats exposed to 2.2 mg vanadium/m 3 for

***DRAFT FOR PUBLIC COMMENT***15 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

13 days. No histopathological alterations were observed in the four female rats killed after 1 day of

exposure; by day 2, inflammation and histiocytic infiltrates (increased number of alveolar macrophages)

were observed in the rats exposed to 2.2 mg vanadium/m 3 . Hyperplasia of the alveolar and bronchiolar

epidthelium was first observed on day 5 in rats exposed to 1.1 or 2.2 mg vanadium/m 3

.

A benchmark dose (BMD) approach was considered for derivation of the acute

- duration inhalation MRL ;

however, the fit was not considered adequate due to the limited amount of information from the study on

the shape of the exposure -response curve for lung inflammation ; more information regarding the BMD

analysis is presented in Appendix A. A NOAEL/lowes t- observed

- adverse

- effect level (LOAEL)

approach was used to derive the MRL. The LOAEL of 0.56 mg vanadium/m 3 for lung inflammation was

selected as the point of departure for the MRL. This LOAEL was converted to a human equivalent

concentration (LOAEL HEC ) of 0.073 mg vanadium/m 3 (see Appendix A for more information on the

calculation of the LOAEL HEC ) and divided by an uncertainty factor of 90 (3 for use of a minimal LOAEL,

3 for animal to human extrapolation using dosimetric adjustments, and 10 for human variability),

resulting in an acute -duration inhalation MRL of 0.0008 mg vanadium/m 3

.

Intermediate

- Duration Inhalation MRL

The available data on the toxicity of vanadium following intermediate -duration inhalation exposure are

limited to several rat and m ouse studies (NTP 2002) involving exposure to vanadium pentoxide for

6 hours/day, 5 days/week . These studies demonstrate that the respiratory tract is the most sensitive target

of toxicity. S igns of respiratory distress (rapid respiration, difficulty breathing) have been observed in

rats exposed to 4.4 mg vanadium/m 3 as vanadium pentoxide for at least 4 weeks (NTP 2002). A 3-month

exposure resulted in increased incidences of lung lesions in rats and mice and nasal lesions in rats. Lung

effects included alveolar and bronchiolar epithelial hyperplasia, histiocytic infiltrates, inflammation, and

fibrosis. A NOAEL of 0.56 mg vanadium/m 3 was identified in both species. At 1.1 mg vanadium/m 3

, epithelial hyperplasia and inflammation (male rats and female mice only) were observed. In mice, the

severity of the lesions was graded as minimal. In rats, the epithelial hyperplasia was graded as mild in

males and minimal to mild in females and the inflammation was graded as mild. These data suggest that

at a given air concentration, rats are more sensitive than mice based on the severity of the lesions. In both

species, the severity of the lesions increased with increasing concentrations. Significant alterations in

pulmonary function suggestive of a restrictive disease were observed in rats exposed to 2.2 or 4.4 mg

vanadium/m 3 ; lung function tests were not performed in mice. Nasal effects in rats included hyperplasia

and squamous metaplasia of the respiratory epithelium and inflammation. The NOAEL and LOAEL for

***DRAFT FOR PUBLIC COMMENT***16 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

nasal effects were 2.2 and 4.5 mg vanadium/m 3 in males and 1.1 and 2.2 mg vanadium/m 3 in females. In

ad dition to the respiratory tract effects, mild microcytic erythrocytosis was observed in rats exposed to

≥1.1 mg vanadium/m 3

.

The lowest LOAEL identified in intermediate

- duration studies is 1.1 mg vanadium/m 3 for lung epithelial

hyperplasia and inflammatio n in rats exposed 6 hours/day, 5 days/week for 13 weeks (NTP 2002); the

NOAEL for these effects is 0.56 mg vanadium/m 3 . However, this NOAEL is the same as the LOAEL for

lung inflammation in rats exposed for 13 days (NTP 2002). As summarized in Table 2-1, lung

inflammation was observed in rats exposed to 0.56 mg vanadium/m 3 for 6 days (not significant), 13 days,

and 2 years. Although the three studies were conducted for the National Toxicology Program (NTP), the

13- week study was conducted at a different laboratory using the same strain of rats and vanadium

pentoxide dusts with similar particles sizes as the acute and chronic studies. An explanation for the

inconsistent findings is not apparent from the available data. Because an intermediate -duration inhalation

MRL based on the NOAEL identified in the 13-week study would be higher than the acute-duration

inhalation MRL, the database is not considered adequate for derivation of an intermediate-duration

inhalation MRL. However, it would be expected that the acute -duration inhalation MRL would be

protective of intermediate -duration exposure to vanadium.

Chronic

- Duration Inhalation MRL

**•** An MRL of 0.0001 mg vanadium/m 3 has been derived for chronic- duration inhalation exposure (1 year or longer) to vanadium p entoxide dust.

Two -year rat and mouse studies conducted by NTP (2002) examined the chronic toxicity of inhaled

vanadium pentoxide 6 hours/day, 5 days/week for 2 years . At the lowest concentration tested in rats

(0.28 mg vanadium/m 3 ), lung (increases in t he incidence of alveolar and bronchiolar epithelial

hyperplasia), larynx (degeneration and hyperplasia of the epiglottis epithelium), and nasal (goblet cell

hyperplasia in respiratory epithelium) effects were observed. Similar lung and larynx effects were

observed in mice at the lowest concentration tested (0.56 mg vanadium/m 3 ). The nasal effects observed

in mice exposed to 0.56 mg vanadium/m 3 included goblet cell hyperplasia in the respiratory epithelium

and nasal olfactory epithelial atrophy and hyaline degeneration. In addition to these effects, a significant

increase in alveolar/bronchiolar carcinoma incidence was also observed in mice exposed to ≥0.56 mg

vanadium/m 3 . In male rats, an increased combined incidence of alveolar/bronchiolar adenoma or

carcinoma was also observed; however, the incidence was not significantly higher than concurrent

***DRAFT FOR PUBLIC COMMENT***17 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH



### Table 2

- 1. Lung Effects Observed in Rats Exposed to Vanadium

Pentoxide 6 H ours/day, 5 D ays/week for 6 or

13 D ays, 3 M onths, or 2 Y ears

mg vanadium/ m 3

Ai r concentration 0 0.28 0.56 1.1 2.2 4.5 9.0

6- Day study

Alveolar hyperplasia 0/10 0/10 10/10 a 8/10 a (1.4) (1.1) b

Bronchiole 1/10 (1.0) 0/10 10/10 a (1.7) 10/10 a
hyperplasia (1.8)

Histiocytic infiltrate 2/10 (1.0) 6/10 (1.3) 10/10 a (1.4) 10/10 a
( 1.8)

Inflammation 0/10 3/10 (1.0) 10/10 a (1.5) 10/10 a
(2.5)

13

- Day study

Alveolar hyperplasia 0/10 3/10 (1.0) 10/10 a (1.0) 10/10 a
(2.0)

Bronchiole 0/10 0/10 10/10 a (1.0) 10/10 a
hyperplasia (1.8)

Histiocytic infiltrate 0/10 10/10 a 10/10 a (1.9) 10/10 a
(1.3) (2.2)

Inflammation 0/10 8/10 (1.3) 10/10 a (1.7) 10/10 a
(2.0)

Fibrosis 0/10 0/10 0/10 6/10 a (1.5)

3- Month study (males)

Epithelial hyperplasia 0/10 0/10 10/10 a (2.0) 10/10 a 10/10 a 10/10 a
(3.0) (3.6) (3.3)

Inflammation 0/10 0/10 9/10 a (1.0) 10/10 a 10/10 (1.6) 10/10 a
(1.0) (2.1)

Fibrosis 0/10 0/10 2/10 (1.0) 10/10 a 10/10 a 10/10 (3.1) (1.9) (3.2)

3

- Month study (females)

Epithelial hyperplasia 0/10 0/10 10/10 a (1.3) 10/10 a 10/10 a 10/10 a
(2.9) (3.5) (3.2)

Inflammation 0/10 0/10 0/10 10/10 a 10/10 a 10/10 a
(1.0) (1.9) (1.2)

Fibrosis 0/10 0/10 0/10 10/10 a 10/10 a 10/10 a
(1.0) (2.9) (3.2)

***DRAFT FOR PUBLIC COMMENT***18 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH



### Table 2

- 1. Lung Effects Observed in Rats Exposed to Vanadium

Pentoxide 6 H ours/day, 5 D ays/week for 6 or

13 D ays, 3 M onths, or 2 Y ears

mg vanadium/ m 3

Ai r concentration 0 0.28 0.56 1.1 2.2 4.5 9.0

Alveolar hyperplasia

Bronchiole hyperplasia

Inflammation

Fibrosis

Histiocyte infiltration

Alveolar hyperplasia

Bronchiole hyperplasia

Inflammation

Fibrosis

Histiocyte infiltration 2

- Year study (males)

7/50 (2.3) 24/49 a 34/48 a 49/50 a (3.3) (2.0) (2.0)

3/50 (2.3) 17/49 a 31/48 a 49/50 a (3.3) (2.2) (1.8)

5/50 (1.6) 8/49 (1.8) 24/48 a 42/50 a (2.4) (1.3)

7/50 (1.4) 7/49 (2.0) 16/48 a 38/50 a (2.1) (1.6)

22/50 40/49 a 45/48 a 50/50 a (3.3) (1.3) (2.0) (2.3)

2- Year study (females)

4/49 (1.0) 8/49 (1.8) 21/50 a 50/50 a (3.1) (1.2)

6/49 (1.5) 5/49 (1.6) 14/50 a 48/50 a (3.0) (1.3)

10/49 10/49 (1.1) 14/50 (1.2) 40/50 a (1.7) (1.5)

19/49 7/49 a (1. 3) 12/50 (1.6) 32/50 a (1.4) (1.4)

26/49 35/49 a 44/50 a 50/50 a (1.9) (1.4) (1.3) (2.0)

a p ≤0.05

b Average severity grade of lesions in affected animals: 1=minimal; 2=mild, 3=moderate; 4=marked

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***19 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

controls, but was higher than historical controls. Because the rat study identified a lower LOAEL for

lung, larynx, and nasal effects, it was selected as the basis of a chronic -duration inhalation MRL.

In the NTP (2002) study, groups of 50 male and 50 female F344 rats were exposed to 0, 0.5, 1, or 2 mg

vanadium pentoxide/m 3 (0, 0.28, 0.56, and 1.1 mg vanadium/m 3 ) 6 hours/day, 5 days/week for 104 weeks.

No significant alterations in survival or body weight gain were observed in the vanadium-exposed rats.

Alveolar histio cytic infiltrates were observed in males and females exposed to ≥0.28 mg vanadium/m 3

. Significant increases in the incidence of hyperplasia of the alveolar and bronchiolar epithelium were

observed in males exposed to ≥0.28 mg vanadium/m 3 and females expos ed to ≥0.56 mg vanadium/m 3

. Squamous metaplasia was observed in alveolar epithelium of males and females exposed to 1.1 mg

vanadium/m 3 and in the bronchiolar epithelium of males exposed to 1.1 mg vanadium/m 3 . Chronic

inflammation was observed in males ex posed to 0.56 or 1.1 mg vanadium/m 3 and females exposed to

1.1 mg vanadium/m 3 and interstitial fibrosis was observed in males exposed to 1.1 mg vanadium/m 3 and

females exposed to 0.28 or 1.1 mg vanadium/m 3 . An increased incidence of brownish pigment in al veolar

macrophages was observed in males exposed to 1.1 mg vanadium/m 3 and females exposed to 0.56 or

1.1 mg vanadium/m 3 ; this effect was considered to be of little biological relevance. Chronic

inflammation, degeneration and hyperplasia of the epiglottis were observed in the larynx of males and

females exposed to ≥0.28 mg vanadium/m 3 ; squamous metaplasia of the epiglottis respiratory epithelium

was also observed in males exposed to ≥0.28 mg vanadium/m 3 and in females exposed to 1.1 mg

vanadium/m 3 . Goblet cell hyperplasia of the nasal respiratory epithelium was observed in males exposed

to ≥0.28 mg vanadium/m 3 and in females exposed to 1.1 mg vanadium/m 3

.

BMD analyses of the incidence data for alveolar and bronchiolar epithelial hyperplasia, chronic

inflammation of the larynx, degeneration of epiglottis respiratory epithelium, and hyperplasia of nasal

respiratory epithelial goblet cells in male rats were used to determine the point of departure for the MRL.

As described in greater detail in Appendix A, the BMCL 10 values for these effects were 0.09, 0.10, 0.07,

0.04, and 0.16 mg vanadium/m 3 , respectively.

These BMCL 10 values were converted to a human equivalent concentrations (as described in detail in

Appendix A); the BMCL HEC values were 0.008, 0.017, 0.005, 0.003, and 0.012 mg vanadium/m 3 for

alveolar epithelial hyperplasia, bronchiolar epithelial hyperplasia, chronic inflammation of the larynx,

degeneration of epiglottis respiratory epithelium, and hyperplasia of nasal respiratory epithelial goblet

c ells, respectively. The BMCL HEC of 0.003 mg vanadium/m 3 for degeneration of epiglottis respiratory

epithelium was selected as the point of departure. This value was divided by an uncertainty factor of

***DRAFT FOR PUBLIC COMMENT***20 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

30 (3 for animal to human extrapolation with dosimetric adjustment and 10 for human variability),

resulting in a chronic-duration inhalation MRL of 0.0001 mg vanadium/m 3

.

Oral MRLs

Acute

- Duration Oral MRL

Gastrointestinal effects (diarrhea, cramps, nausea, and vomiting) have been observed in diabetic patie nts

administered vanadyl sulfate or sodium metavanadate capsules as a supplement to their diabetes treatment

(Boden et al. 1996; Cusi et al. 2001; Goldfine et al. 1995). The gastrointestinal effects subsided within

the first couple of weeks of exposure. The concentrations in the capsules ranged from 16 to 24 mg and

daily doses ranged from 0.35 to 0.66 mg vanadium/kg/day. A small number of studies in laboratory

animals have examined the acute toxicity of vanadium following oral exposure. Significant incr eases in

reticulocyte levels in peripheral blood and polychromatophilic erythroblasts in the bone marrow were

observed in rats exposed to 27.72 mg vanadium/kg/day as ammonium metavanadate in drinking water for

2 weeks (Zaporowska and Wasilewski 1989). The remaining nonlethality studies reported developmental

effects in the offspring of rats and mice administered 7.5 –8.4 mg vanadium/kg/day via gavage during

gestation (Paternain et al. 1987, 1990; Sanchez et al. 1991). The observed developmental effects included

decreases in fetal growth, increases in resorptions, and gross, visceral, and skeletal malformations and

anomalies.

Although the human studies identified the lowest LOAEL values, they were not considered suitable as the

basis of an MRL. These studies used a small number of diabetic subjects (5

– 10 subjects per study) and

no control group. The lowest LOAEL identified in an animal study is 7.5 mg vanadium/kg/day for

developmental effects (Paternain et al. 1990). In this study, significant increases in early resorptions,

decreases in fetal body weight and length, and increases in the incidence of soft tissue anomalies/

malformations (hematomas in facial area, neck, and dorsal area, cleft palate), and skeletal defects

(delayed ossification of supraoccipital bone, carpus, tarsus, and sternebrae) were observed in the offspring

of Swiss mice administered via gavage 7.5 mg vanadium/kg/day as vanadyl sulfate on gestation days 6

–

15. This dose was also associated with significant decreases in maternal body weight gain (during

gestation days 6 –15, the dams gained 46% less weight than controls); no significant alterations in food

intake were observed. Because 7.5 mg vanadium/kg/day is a serious LOAEL in the dams (ATSDR

defines serious effects as those that evoke failure in a biological system and can lead to morbidity or

mortality), this study is not suitable for derivation of an acute

- duration oral MRL. It is ATSDR ’s policy

to not use a LOAEL for serious health effects as the basis of an MRL.

***DRAFT FOR PUBLIC COMMENT***21 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

Intermediate

- Duration Oral MRL

**•** An MRL of 0.01 mg vanadium/kg/day has been derived for intermediate- duration oral exposure (15–364 days) to vanadium.

Two human studies have examined the oral toxicity of vanadium. No significant alterations in

hematological parameters, liver function (as measured by serum enzymes), cholesterol and triglyceride

levels, kidney function (as measured by blood urea nitrogen), body weight, or blood pressure were

observed in subjects administered via capsule 0.12 or 0.19 mg vanadium as ammonium vanadyl tartrate or

vanadyl sulfate for 6 –12 weeks (Dimond et al. 1963; Fawcett et al. 1997). Studies in laboratory anim als

have identified several sensitive effects including alterations in erythrocyte and reticulocyte levels,

increased blood pressure, neurobehavioral alterations, and developmental toxicity. The lowest LOAEL

identified in an intermediate- duration study wa s 0.12 mg vanadium/kg/day for increases in blood pressure

observed in rats exposed to sodium metavanadate in drinking water for 210 days (Boscolo et al. 1994);

several other studies by these investigators have reported similar effects at higher doses (Carmag nani et

al. 1991, 1992). However, other studies have not found significant alterations in blood pressure at higher

doses (Bursztyn and Mekler 1993; Sušić and Kentera 1986, 1988). Significant decreases in erythrocyte

levels have been observed in rats expo sed to 1.18 mg vanadium/kg/day as ammonium metavanadate in

drinking water for 4 weeks (Zaporowska et al. 1993); at higher concentrations, decreases in hemoglobin
and increases in reticulocyte levels have been observed (Ścibior 2005; Ścibior et al. 2006; Za porowska

and Wasilewski 1990, 1991, 1992a, 1992b; Zaporowska et al. 1993). However, other intermediateduration studies have not found significant alterations at doses as high as 9.7 mg vanadium/kg/day (Dai et

al. 1995; Mountain et al. 1953). At 1.72 mg vanadium/kg/day, impaired performance on neurobehavioral

tests (open field and active avoidance tests) was observed in rats exposed to administered sodium

metavanadate for 8 weeks (Sanchez et al. 1998). No other studies have examined the neurotoxic potent ial

of vanadium. As with acute-duration exposure, the developing organism is a sensitive target of vanadium

toxicity. Decreases in pup body weight and length were observed in the offspring of rats administered

2.1 mg vanadium/kg/day as sodium metavanadat e for 14 days prior to mating and throughout gestation

and lactation (Domingo et al. 1986). At higher doses (6, 10, or 12 mg vanadium/kg/day), decreases in

pup survival, and increases in the occurrence of gross, visceral, or skeletal malformations and anomalies

were observed (Elfant and Keen 1987; Morgan and El-Tawil 2003; Poggioli et al. 2001).

The animal database suggests that the most sensitive targets of vanadium toxicity are blood pressure,

erythroctyes, nervous system, and the developing organism with LOAEL values of 0.12, 1.18, 1.72, and

***DRAFT FOR PUBLIC COMMENT***22 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

2.1 mg vanadium/kg/day, respectively. Two approaches for derivation of an intermediate-duration oral

MRL were considered. In the first approach, the NOAEL of 0.12 mg vanadium/kg/day identified in the

Fawcett et al. (1997) study was used as the point of departure for the MRL. The Fawcett et al. (1997)

study was selected over the Dimond et al. (1963) study, which identified a slightly higher NOAEL

(0.19 mg vanadium/kg/day) because more subjects ( six subjects in Di mond study compared to 15–

16 subjects in Fawcett study) were examined and the results of the study are described in greater detail.

In the Fawcett et al. (1997) study, groups of men and women enrolled in a weight training program for at

least 1 year were administered capsules containing 0 (11 men and 4 women) or 0.12 mg vanadium/kg/day

as vanadyl sulfate trihydrate (12 men and 4 women) for 12 weeks. Fasting blood samples were collected

at 0 and 12 weeks and analyzed for hematological (erythrocyte count, hemoglobin, hematocrit, mean cell

volume, mean cell hemoglobin, platelet count, and total and differential leukocyte count) and serum

chemistry (cholesterol, high density lipoprotein, triglycerides, albumin, total protein, total and direct

bilirubin, alkali ne phosphatase, alanine amino- transferase) parameters. Body weight and blood pressure

were measured at weeks 4, 8, and 12. No significant alterations in blood pressure, body weight, or

hematological or clinical chemistry parameters were found. Using the NOAEL of 0.12 mg vanadium/kg/

day and an uncertainty factor of 10 for human variability, the MRL would be 0.01 mg vanadium/kg/day.

Several animal studies were also considered as the basis of an MRL. Although an increase in blood

pressure was observed at the lowest adverse effect l evel (0.12 mg vanadium/kg/day; Boscolo et al. 1994),

this end point was not selected as the basis for an intermediate -duration oral MRL. This effect has not

been consistently observed among rat studies and no alterations in blood pressure were observed in a

study of healthy adults exposed to 0.12 mg vanadium/kg/day for 12 weeks (Fawcett et al. 1997). The

next highest LOAEL of 1.18 mg vanadium/kg/day for a decrease in erythrocyte levels in rats (Zaporowski

et al. 1993) was considered as the principal study for the MRL. In the Zaporowski et al. (1993) study,

groups of 2-month- old male and female Wistar rats (15 –16/sex/group) were exposed to ammonium

metavanadate in drinking water for 4 weeks at doses of 0, 1.18, and 4.93 mg vanadium/kg/day (males) or

1.50 and 6.65 mg vanadium/kg/day (females). No alterations in behavior or motor activity were

observed. A significant decrease in water consumption (14% less than controls) was observed in males

exposed to 4.93 mg vanadium/kg/day. No significant alterations in body weight gain were observed. As

summarized in Table 2 -2, alterations in erythrocyte, hemoglobin, hematocrit, and reticulocyte levels were

observed. This study identified a minimal LOAEL of 1.18 mg vanadium/kg/day for decreases in

erythrocyte and hematocrit levels in male rats. The alteration in erythrocyte levels was considered

minimally adverse because the magnitude of the change was small (approximately 11%). Dividing this

***DRAFT FOR PUBLIC COMMENT***23 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH



### Table 2

- 2. Hematological Effects in Rats Exposed to Ammonium Metavanad ate

for 4 Weeks

Dose (mg vanadium/kg/day)

Males 0 1.18 4.93

Erythrocytes (x10 12 /dm 3 ) 8.32 7.38 a 7.47 b

Hemoglobin (mmol/L) 9.37 8.94 8.65 a

Hematocrit (L) 0.48 0.47 b 0.47 a

Reticulocytes (%) 2.55 2.64 3.82 b

Females 0 1.50 6.65

Erythrocytes (x1 0 12 /dm 3 ) 8.24 7.38 c 7.12 c

Hemoglobin (mmol/L) 9.41 8.76 8.72 a

Hematocrit (L) 0.48 0.47 0.47

Reticulocytes (%) 2.55 2.91 3.64 b

a Significantly different from control group ( p<0.01 )

b Significantly different from control group ( p<0.0 5)

c Significantly d ifferent from control group ( p<0.0 01)

Source: Zaporowska et al. 1993

***DRAFT FOR PUBLIC COMMENT***24 VANADIUM

2. RELEVANCE TO PUBLIC HEALTH

minimal LOAEL by an uncertainty factor of 300 (3 for the use of a minimal LOAEL, 10 for animal to

human extrapolation, and 10 for human variability) results in an MRL of 0.004 mg vana dium/kg/day.

Although an MRL based on the Zaporwska et al. (1993) rat study would be approximately 3 times lower

than an MRL based on the Fawcett et al. (1997) human study, the Fawcett et al. (1997) study was selected

as the basis of the intermediate -dur ation oral MRL because greater confidence was given to an MRL

based on a reliable human study. Thus, the intermediate -duration oral MRL is 0.01 mg vanadium/kg/day.

Chronic

- Duration Oral MRL

No studies examining the chronic toxicity of vanadium in humans were identified. Although several

laboratory animal studies have examined chronic toxicity, most tested low doses and did not find effects.

No adverse effects were observed in rats and mice exposed to 0.7 or 4.1 mg vanadium/kg/day,

respectively, as vana dyl sulfate in drinking water for 2 –2.5 years (Schroeder et al. 1970; Schroeder and

Balassa 1967). In rats exposed to 28 mg vanadium/kg/day as vanadyl sulfate in drinking water, a 20%

decrease in body weight gain was observed; no alterations in lungs, hea rt, liver, or kidneys

histopathology, hematological parameters, or blood pressure were observed at 19 mg vanadium/kg/day

(Dai and McNeill 1994; Dai et al. 1994a, 1994b). Because the most sensitive target of vanadium toxicity

following chronic- duration ora l exposure have not been identified, the animal studies that mostly

identified free

- standing NOAEL values were not considered suitable for derivation of an MRL.

***DRAFT FOR PUBLIC COMMENT***25 VANADIUM



### 3. HEALTH EFFECTS

3.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and

other interested individuals and groups with an overall perspective on the toxicology of vanadium. It

contains descriptions and evaluations of toxicological studies and epidemiological investigations and

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

Elemental vanadium does not occur in nature; however, vanadium compounds exist in over 50 different

mineral ores and in association with fossil fuels. It has six oxidation states (1-, 0, 2+, 3+, 4+, and 5+) of

which 3+, 4+, and 5+ are the most common. The toxicologically significant compounds are vanadium

pentoxide (V 2 O 5 ), sodium metavanadate (NaVO 3 ), sodium orthovanadate (Na 3 VO 4 ), vanadyl sulfate

(VOSO 4 ), and ammonium vanadate (NH 4 VO 3 ). Vanadium pentoxide dust is usually encountered in

occupational settings, and humans would be exposed via the inhalation route. Organic vanadium

compounds, such as bis(maltolato)oxyvanadium (IV), bis(ethylmaltolato)oxyvanadium (IV), and vanadyl

acetyl acetonate, have been synthesized for use in the treatment of diabetes and cancer. Because these

compounds likely have different toxicokinetic properties from inorganic vanadium compounds, they are

not included in this toxicological profile.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health p rofessionals and others address the needs of persons living or working near

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation,

oral, and dermal) and then by health effect (death, systemic, immunologi cal, neurological, reproductive,

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure

periods: acute (14 days or less), intermediate (15 –364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in

figures. The points in the figures showing no- observed

- adverse

- effect levels (NOAELs) or lowest

observed

- adverse

- effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies.

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress

***DRAFT FOR PUBLIC COMMENT***26 VANADIUM

3. HEALTH EFFECTS

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death,

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a

considerable amount of judgment may be required in establishing whether an end point should be

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the

Agency has establis hed guidelines and policies that are used to classify these end points. ATSDR

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between

"less serious" and "serious" effects. The distinction between "less ser ious" effects and "serious" effects is

considered to be important because it helps the users of the profiles to identify levels of exposure at which

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not

the effects vary with dose and/or duration, and place into perspective the possible significance of these

effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and

figures may differ depend ing on the user's perspective. Public health officials and others concerned with

appropriate actions to take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

3.2.1 Inhalation Exposure

3.2.1.1 Death

No studies were located regarding death in humans aft er inhalation exposure to vanadium.

Increases in mortality have been observed in several studies of laboratory animals exposed to vanadium

pentoxide. Deaths occurred in rabbits exposed to 114 mg vanadium/m 3 for 1 hour, but not in rabbits

exposed to 43 mg vanadium/m 3 (Sjöberg 1950). Exposure to 18 mg vanadium/m 3 as vanadium pentoxide

resulted in death in three of five rats exposed for 6 days (NTP 2002). Intermediate- duration exposure

resulted in deaths in rats exposed to 9 mg vanadium/m 3 and mice exposed to 18 mg vanadium/m 3 (NTP

***DRAFT FOR PUBLIC COMMENT***27 VANADIUM

3. HEALTH EFFECTS

2002). A decrease in survival was observed in mice chronically exposed to 2.2 mg vanadium/m 3 (NTP

2002). The LOAEL values are recorded in Table 3-1 and plotted in Figure 3-1.

3.2.1.2 Systemic Effects

The highest NOAEL valu es and all reliable LOAEL values for each species and duration category are

recorded in Table 3 -1 and plotted in Figure 3-1.

Respiratory Effects. Although a number of studies have reported respiratory effects in humans

exposed to vanadium, in particular vanadium pentoxide, very few provide reliable quantitative exposure

data. In an experimental study, persistent coughing lasting 8 days after exposure termination was

observed in two subjects exposed to 0.6 mg vanadium/m 3 for 8 hours; no alterations in lung function

(lung function parameters assessed: forced vital capacity, 0.5 and 1 second forced expiratory volume,

maximal expiratory flow, 200–1,200 cc flow rate, maximal midexpiratory time, and forced inspiratory

vital capacity) were observed (Zenz and B erg 1967). At 0.1 mg vanadium/m 3 , five subjects reported

productive coughing without other subjective complaints, alterations in lung function, or changes in daily

activities; this concentration level was considered a NOAEL. Workers exposed to a range of vanadium

pentoxide dust levels for as little as 1 day (Levy et al. 1984; Musk and Tees 1982; Thomas and Stiebris

1956; Zenz et al. 1962) or as long as ≥ 6 years (Irsigler et al. 1999; Lewis 1959; NIOSH 1983; Sjöberg

1956; Vintinner et al. 1955; Wyers 1946), show mild respiratory distress, such as cough, wheezing, chest

pain, runny nose, or sore throat. One study of chronically-exposed workers showed increased neutrophils

in the nasal mucosa (Kiviluoto 1980; Kiviluoto et al. 1979b, 1981a). More severe pathology has not been

reported. Symptoms are reversible within days or weeks after exposure ceases. Data were not located to

assess the relationship of exposure level or duration to severity of response. Chest x-rays and pulmonary

function tests were normal in most cases. Chronic effects were infrequently reported. In a study of

40 vanadium pentoxide workers with persistent respiratory symptoms (Irsigler et al. 1999), 12 were found

to have bronchial hyperresponsiveness to inhaled histamine or exercise cha llenge. No significant

alterations in baseline lung function were found. The mean urine vanadium level (assessed via spot urine

samples) in the hyperresponsive group was 52.7 μg/g creatinine compared to 30.7 μg/g creatinine in

12 matched subjects with pe rsistent respiratory symptoms and without bronchial hyperreactivity;

statistical comparisons of the two groups were not made. Five to 23 months after removal from exposure,

bronchial hyperreactivity was still present in nine of the subjects, although the response was less severe in

five of them and more severe in one subject.

***DRAFT FOR PUBLIC COMMENT***8114120.342.51300.281.71070.561231.1109181159Table 3-1 Levels of Significant Exposure to Vanadium - InhalationExposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormCommentsACUTE EXPOSUREDeath1Rabbit 1 d114 (2/4 died)Sjoberg 19507 hr/dVANADIUM PENTOXIDE(NS)Systemic2Monkey 6 hrResp 0.34 M2.5 M (impaired lung function)Knecht et al. 1985(Cynomolgus)(NS)VANADIUM PENTOXIDE3Monkey 6 hrResp 0.28 M1.7 M (impaired lung function)Knecht et al. 1992(Cynomolgus)VANADIUM PENTOXIDE4Rat 6 hr/dbResp0.56 F (histiocytic infiltrate andNTP 20025 d/wk(Fischer- 344)inflammation in lungs)VANADIUM PENTOXIDE6 or 13 d5Mouse 6 hr/dResp1.1 F (hyperplasia of alveolarNTP 20025 d/wk(B6C3F1)and bronchioleepithelium andinflammation in lungs)6 or 13 dVANADIUM PENTOXIDEINTERMEDIATE EXPOSUREDeath6Rat 6 hr/d18 M (3/5 males died)NTP 20025 d/wk(Fischer- 344)16 dVANADIUM PENTOXIDE7Rat 6 hr/d9 (7/10 males and 3/10NTP 20025 d/wk(Fischer- 344)3 mofemales died)VANADIUM PENTOXIDE118181290.621081.12.24.5991120.561.14.54.54.54.54.54.54.59Table 3-1 Levels of Significant Exposure to Vanadium - Inhalation(continued)Exposure/Duration/aFrequencyKey toSpecies(Route)Figure (Strain)8Mouse(B6C3F1)Systemic9Monkey(Cynomolgus)10Rat(Fischer- 344)11Rat(Fischer- 344)6 hr/d5 d/wk16 d6 hr/d5 d/wk26 wk6 hr/d5 d/wk16 d6 hr/d5 d/wk3 moSystemRespRespBd WtRespCardioGastroMusc/skelHepaticRenalDermalBd WtLOAELReferenceNOAEL Less SeriousSerious(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormComments18 M (5/5 males died)NTP 2002VANADIUM PENTOXIDE0.62 M (audible wheezing andKnecht et al. 1992coughing in 3/8VANADIUM PENTOXIDEmonkeys)1.12.2 (localized inflammatoryNTP 2002response)VANADIUM PENTOXIDE4.59 (12-13% decreased body 9 (25-40% decreased bodyweight gain)weight gain)0.561.1 (epithelial hyperplasiaNTP 2002and inflammation inVANADIUM PENTOXIDElungs)4.54.54.54.54.54.54.59 (30-60% decreased bodyweight gain)1171.12.29181200.561.199994.591102.21191811492.24.5Table 3-1 Levels of Significant Exposure to Vanadium - Inhalation(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormComments12Mouse 6 hr/dResp 1.12.2 (lung inflammation)NTP 20025 d/wk(B6C3F1)16 dVANADIUM PENTOXIDEBd Wt918(28% decreased bodyweight gain)13Mouse 6 hr/dResp 0.561.1 (lung inflammation andNTP 20025 d/wk(B6C3F1)epithelial hyperplasia)3 moVANADIUM PENTOXIDECardio 9Gastro 9Hepatic 9Renal9Bd Wt 4.5 F 9 F(12% decreased bodyweight gain)Immuno/ Lymphoret14Rat 6 hr/d2.2 (decr phagocytosis andNTP 20025 d/wk(Fischer- 344)16 dincr bactericidal activity)VANADIUM PENTOXIDE15Mouse 6 hr/d18NTP 20025 d/wk(B6C3F1)16 dVANADIUM PENTOXIDEReproductive16Rat 6 hr/d9 M4.5 F (increased estrous cycleNTP 20025 d/wk(Fischer- 344)3 molength)VANADIUM PENTOXIDE2.2 F1242.294.51262.21160.281.11.11.11.11.11.1Table 3-1 Levels of Significant Exposure to Vanadium - Inhalation(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormCommentsMouse 6 hr/d172.2 M4.5 M (decreased epididymalNTP 20025 d/wk(B6C3F1)3 mospermatozoa motility)VANADIUM PENTOXIDE9 FCHRONIC EXPOSUREDeath18Mouse 6 hr/d2.2 M (decreased survival inNTP 20025 d/wk(B6C3F1)2 yrmales)VANADIUM PENTOXIDESystemic19Rat 6 hr/dcResp0.28 (hyperplasia of alveolarNTP 20025 d/wk(Fischer- 344)2 yrand bronchiolarVANADIUM PENTOXIDEepithelium, degenerationand hyperplasia ofepiglottis epithelium, andgoblet cell hyperplasia innasal respiratoryepithelium)Cardio 1.1Gastro 1.1Musc/skel 1.1Hepatic 1.1Renal 1.1Bd Wt 1.11250.562.22.22.22.22.20.561.12.21280.28Table 3-1 Levels of Significant Exposure to Vanadium - Inhalation(continued)LOAELReferenceNOAEL Less SeriousSeriousSystem(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormCommentsResp0.56(hyperplasia and chronicNTP 2002inflammation in lungs;VANADIUM PENTOXIDEsquamous metaplasia ofepiglottis epithelium andnasal respiratoryepithelium; atrophy anddegeneration of nasalolfactory epithelium)Cardio 2.2Gastro 2.2Hepatic 2.2Renal 2.2Dermal 2.2Bd Wt 0.56 1.1(15-20% decreased body 2.2 (20-29% decreased bodyweight gain)weight gain)0.28 M (lung tumor incidenceNTP 2002higher than historicalVANADIUM PENTOXIDEcontrols)Exposure/Duration/aFrequencyKey to Species(Route)Figure (Strain)20Mouse6 hr/d5 d/wk(B6C3F1)2 yrCancer21Rat 6 hr/d5 d/wk(Fischer- 344)2 yr1270.5622Table 3-1 Levels of Significant Exposure to Vanadium - Inhalation(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/m3) (mg V/m3)(mg V/m3)Chemical FormCommentsMouse 6 hr/d0.56 (alveolar/bronchiolarNTP 20025 d/wk(B6C3F1)2 yrcarcinoma)VANADIUM PENTOXIDEa The number corresponds to entries in Figure 3-1b Used to derive an acute-duration inhalation minimal risk level (MRL) of 0.0008 mg vanadium/m3; concentration adjusted for intermittent exposure (6 hours/24 hours, 5 days/7days), multiplied by the Regional Deposited Dose Ratio (RDDR) of 0.732 for the thoracic region, and divided by an uncertainty factor of 90 (3 for the use of a minimal LOAEL, 3 forextrapolation from animals to human with dosimetric adjustment, and 10 for human variability).c Used to derive a chronic-duration inhalation MRL of 0.0001 mg vanadium/m3 calculated using benchmark dose analysis. The BMCL10 of 0.04 mg vanadium/m3 was adjusted forintermittent exposure (6 hours/24 hours, 5 days/7 days), multiplied by the RDDR of 0.423 for the extrathoracic region, and divided by an uncertainty factor of 30 (3 for extrapolationfrom animals to humans with dosimetric adjustment and 10 for human variability).Bd Wt = body weight; Cardio = cardiovascular; d = day(s); F = Female; Gastro = gastrointestinal hr = hour(s); Immuno/Lymphoret = immunological/lymphoreticular; LOAEL =lowest-observed-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk= week(s); yr = year(s)0.0001 0.001

0.01

0.1 1

10 100 1000 Death

1h Respiratory

2k

2k 3k 3k

5m

4r mg V/m 3 

### Figure 3-1 Levels of Significant Exposure to Vanadium - Inhalation

Acute (≤14 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer SystemicVANADIUM3. HEALTH EFFECTS34***DRAFT FOR PUBLIC COMMENT***0.1 1 10 100 Death

8m 6r

7r Respiratory

9k 12m 12m

13m

13m 10r 10r

11r

11r Cardiovascular

13m

11r Gastrointestinal

13m

11r Musculoskeletal

11r Hepatic

13m

11r Renal

13m

11r Dermal

11r Body Weight

12m

12m

13m 13m 10r 10r

10r 11r

11r Immuno/Lymphor

15m

14r Reproductive

17m

17m 17m

16r 16r

16r mg V/m3 

### Figure 3-1 Levels of Significant Exposure to Vanadium - Inhalation (Continued)

Intermediate (15-364 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer SystemicVANADIUM3. HEALTH EFFECTS35***DRAFT FOR PUBLIC COMMENT***0.0001 0.001

0.01

0.1 1

10 Death

18m Respiratory

20m

19r Cardiovascular

20m

19r Gastrointestinal

20m

19r Musculoskeletal

19r Hepatic

20m

19r Renal

20m

19r Dermal

20m Body Weight

20m

20m 20m 19r Cancer *

22m

21r mg V /m 3 

### Figure 3-1 Levels of Significant Exposure to Vanadium - Inhalation (Continued)

Chronic (≥365 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer Systemic

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint.VANADIUM3. HEALTH EFFECTS36***DRAFT FOR PUBLIC COMMENT***37 VANADIUM

3. HEALTH EFFECTS

Animal data support the human findings and provide additional evidence that vanadium compounds are

respiratory toxicants. S igns of respiratory distre ss, impaired lung function, increased pulmonary

reactivity, and histological alterations in the lungs, larynx, and nasal cavity have been observed in

laboratory animals. Rapid respiration during the exposure period was observed in rats exposed to 9.0 mg

vanadium/m 3 as vanadium pentoxide for 16 days or 4.5 mg vanadium/m 3 for 4 weeks. In rats exposed to

9.0 mg vanadium/m 3 for 9 weeks, abnormal respiration was also observed during periods between

vanadium exposures (NTP 2002). Audible wheezing and coughing were observed in monkeys exposed to

0.62 mg vanadium/m 3 for 6 hours; respiratory symptoms were not observed at 0.14 or 0.028 mg

vanadium/m 3 as vanadium pentoxide (Knecht et al. 1992).

Decreases in pulmonary function were observed in rats exposed to ≥2.2 m g vanadium/m 3 6 hours/day,

5 days/week for 13 weeks (NTP 2002). Exposure to 2.2 or 4.5 mg vanadium/m 3 resulted in alterations

characterized as restrictive based on reduced lung compliance, changes in breathing measurements,

impaired capacity to diffuse ca rbon monoxide, reduced static and dynamic lung volumes, and exaggerated

airflow. The changes in breathing mechanics, static lung volumes, and forced expiratory maneuvers

observed at 9.0 mg vanadium/m 3 were suggestive of an obstructive lung disease; howeve r, the

investigators noted that these alterations may have been due to the deteriorating condition of the rats

rather than an obstructive disease. Increased pulmonary resistance was observed in monkeys 1 day after a

6-hour exposure to 2.8 mg vanadium/m 3 (Knecht et al. 1985). Pulmonary reactivity, as evidenced by an

obstructive pattern of impaired pulmonary function, was also observed in monkeys following a 6-hour

exposure to 1.7 mg vanadium/m 3 as vanadium pentoxide (Knecht et al. 1992); an increase in the total

number of inflammatory cells present in the lungs was also observed. A similar degree of pulmonary

reactivity was observed when the monkeys were re

- challenged with methacholine following a 26- week

exposure to 0.28 mg vanadium/m 3 (6 hours/day, 5 day s/week). Pulmonary reactivity was not

significantly affected by a provocation challenge with 0.28 mg vanadium/m 3 before or after the 26- week

exposure (Knecht et al. 1992).

NTP (2002) conducted a series of studies to evaluate the toxicity of vanadium pentoxide in rats and mice

exposed 6 hours/day, 5 days/week for acute, intermediate, and chronic durations. Histological alterations

were observed in the lungs, larynx, and nose. In the lungs, hyperplasia of alveolar and bronchiolar

epithelium occurred at 1.1 mg vanadium/m 3 in rats and mice exposed for 6, 13, or 90 days, 0.28 mg

vanadium/m 3 in rats exposed for 2 years, and 0.56 mg vanadium/m 3 in mice exposed for 2 years. Lung

inflammation and histiocytic infiltration (alveolar macrophages) were observed at similar concentrations

in the acute, intermediate, and chronic duration studies. Fibrosis was also observed in rats exposed to

***DRAFT FOR PUBLIC COMMENT***38 VANADIUM

3. HEALTH EFFECTS

2.2 mg vanadium/m 3 for 13 or 90 days or 0.28 mg vanadium/m 3 for 2 years and in mice exposed to 1.1 mg

vanadium/m 3 for 2 years. In both species, the severity of the lung lesions increased with increasing

exposure duration and vanadium pentoxide exposure level. NTP (2002) also conducted several studies to

examine the time course of the lung lesions. In rats exposed to 2.2 mg vanadium/m 3 , histiocytic infiltrates

and inflammation were observed after 2 days of exposure and alveolar and bronchiolar epithelial

hyperplasia were first observed after 5 days of exposure to 1.1 or 2.2 mg vanadium/m 3 . In rats exposed to

0.56 mg vanadium/m 3

, hyperplasia was only observed in a few animals after 542 days of exposure;

however, at the end of the 2- year study, there was a significant increase in the incidence at this exposure

level. In mice, lung lesions were not observed after 1 or 2 days of exp osure. Bronchiolar epithelial

hyperplasia and inflammation were observed after 5 days of exposure to 2.2 mg vanadium/m 3 . At the

lower exposure levels, lung lesions were observed after 12 days of exposure to 1.1 mg vanadium/m 3 and

54 days of exposure to 0 .56 mg vanadium/m 3

.

The nasal effects observed in rats consisted of hyperplasia and squamous metaplasia of respiratory

epithelium at 2.2 mg vanadium/m 3 for 13 weeks, inflammation at 9.0 mg vanadium/m 3 for 13 weeks, and

goblet cell hyperplasia of the res piratory epithelium at 0.28 mg vanadium/m 3 for 2 years. In mice exposed

to vanadium pentoxide for 2 years, the nasal effects included suppurative inflammation at 1.1 mg

vanadium/m 3 , olfactory epithelium atrophy at 0.56 mg vanadium/m 3 , hyaline degeneration of olfactory

and respiratory epithelium at 0.56 mg vanadium/m 3

, and squamous metaplasia of respiratory epithelium at

0.56 mg vanadium/m 3 . Chronic exposure also resulted in damage to the larynx; degeneration and

hyperplasia of the epiglottis epithelium we re observed in rats exposed to 0.28 mg vanadium/m 3 and

squamous metaplasia of epiglottis epithelium was observed in rats exposed to 1.1 mg vanadium/m 3 and

mice exposed to 0.56 mg vanadium/m 3

.

Cardiovascular Effects. Workers exposed chronically to van adium pentoxide dusts at incompletely

documented exposure levels had normal blood pressure values (Vintinner et al. 1955). No other

cardiovascular parameters were investigated in this study, but another study revealed normal

electrocardiograms in vanadium workers (Sjöberg 1950).

No significant alterations in heart rate, blood pressure, or electrocardiogram readings were observed in

rats exposed to 4.5 mg vanadium/m 3 as vanadium pentoxide 6 hours/day, 5 days/week for 13 weeks (NTP

2002). Decreases in heart rate and blood pressure were found in rats exposed to 9.0 mg vanadium/m 3 ;

however, this was attributed to the poor condition of the animals rather than a direct cardiotoxic effect.

No histological alterations were observed in the hearts of rats exposed to 4.5 or 1.1 mg vanadium/m 3

***DRAFT FOR PUBLIC COMMENT***39 VANADIUM

3. HEALTH EFFECTS

6 hours/day, 5 days/week for 13 weeks or 2 years, respectively, or mice exposed to 9.0 or 2.2 mg

vanadium/m 3 for 13 weeks or 2 years, respectively (NTP 2002).

Gastrointestinal Effects. No gastrointestinal complaints were re ported by subjects exposed to 0.6 or

0.1 mg vanadium/m 3 vanadium pentoxide dusts for 8 hours (Zenz and Berg 1967). Workers exposed to

vanadium in oil-burner ashes also did not show gastrointestinal symptoms (Sjöberg 1950). One study

found that workers ex posed chronically to vanadium dusts in factories sometimes complained of nausea

and vomiting (Levy et al. 1984), but these symptoms can have a number of causes (such as exposure to

other substances) and cannot be directly attributed to the vanadium. No hi stological alterations were

observed in the gastrointestinal tract of rats exposed to 4.5 or 1.1 mg vanadium/m 3 as vanadium pentoxide

6 hours/day, 5 days/week for 13 weeks or 2 years, respectively, or mice exposed to 9.0 or 2.2 mg

vanadium/m 3 for 13 weeks or 2 years, respectively, (NTP 2002).

Hematological Effects. No hematological alterations were observed in humans following acute

(Zenz and Berg 1967) or occupational exposure (Kiviluoto et al. 1981a; Sjöberg 1950; Vintinner et al.

1955) to vanadium d usts.

During the first 23 days of a 13-week study, minimal erythrocyte microcytosis (as evidenced by decreases

in hematocrit values, hemoglobin, mean cell volume, and mean cell hemoglobin ) was observed in rats

exposed to vanadium pentoxide 6 hours/day, 5 days/week (NTP 2002). The alterations in hematocrit and

hemoglobin were observed after 4 days of exposure to 1.1 mg vanadium/m 3 , mean cell volume and mean

cell hemoglobin were decreased after 23 or 90 days of exposure to 2.2 mg vanadium/m 3 . At 13 weeks,

the microcytosis was replaced by erythrocytosis (as evidenced by increases in hemoglobin, hematocrit,

nucleated erythrocytes, and reticulocytes) in rats exposed to 4.5 or 9.0 mg vanadium/m 3

.

Musculoskeletal Effects. Muscular strength was not altered in one study of workers exposed to

vanadium pentoxide (Vintinner et al. 1955). No significant histological alterations were observed in the

bone or muscle following a 13- week or 2 -year exposure of rats to 9.0 or 1.1 mg vanadium/m 3 as

vanadium pentoxide, r espectively, or mice to 9.0 or 2.2 mg vanadium/m 3 , respectively.

Hepatic Effects. Workers exposed chronically to 0.01–0.5 mg/m 3 of vanadium dusts had normal

serum levels of four enzymes (serum alkaline phosphatase, alanine aminotransferase (ALT) , aspar tate

aminotransferase (AST) , and lactate dehydrogenase) that are commonly used to detect possible liver

damage (Kiviluoto et al. 1981a).

***DRAFT FOR PUBLIC COMMENT***40 VANADIUM

3. HEALTH EFFECTS

Significant increases in serum ALT levels were observed in rats exposed to 4.5 mg vanadium/m 3

6 hours/day, 5 days/week for 13 weeks (NTP 2002). However, this alteration was not considered to be

biologically relevant because it was not associated with histological alterations in the liver. No

histological alterations were observed in the livers of rats exposed to 4.5 or 1.1 mg vanadium/m 3 as

vanadium pentoxide 6 hours/day, 5 days/week for 13 weeks or 2 years, respectively, or mice exposed to

9.0 or 2.2 mg vanadium/m 3 for 13 weeks or 2 years, respectively (NTP 2002).

Renal Effects. Workers exposed chronically to 0.01–0.5 mg/m 3 of vanadium dusts had normal serum

levels of electrolytes, creatinine, and urea, suggesting no alterations in renal function (Kiviluoto et al.

1981b). Workers in other studies of chronic exposure to vanadium had normal urine levels of substances

used to detect kidney disease (casts, protein levels, urea) (Sjöberg 1950; Vintinner et al. 1955).

Significant increases in serum urea nitrogen concentration were observed in male rats exposed to 4.5 mg

vanadium/m 3 for 13 weeks and females exposed to 2.2 mg vanadium/m 3 for 23 days (but not after

13 weeks of exposure) (NTP 2002). However, because decreases in total protein and creatinine

concentration were also observed, the urea nitrogen alteration was attributed to decreased body weight

rather than an ef fect on renal clearance. A decrease in overnight urine volumes and increase in urine

specific gravity were observed in rats exposed to 2.2 mg vanadium/m 3 for 13 weeks (NTP 2002). No

alterations in urine volume or specific gravity were observed in urine samples collected after a 16 -hour

water deprivation period, suggesting that the alterations observed in the overnight urine sample were

reflective of dehydration rather than altered kidney function. No histological alterations were observed in

the kidneys of rats exposed to 4.5 or 1.1 mg vanadium/m 3 as vanadium pentoxide 6 hours/day,

5 days/week for 13 weeks or 2 years, respectively, or mice exposed to 9.0 or 2.2 mg vanadium/m 3 for

13 weeks or 2 years, respectively (NTP 2002).

Dermal Effects. No increas es in the occurrence of dermatitis were observed in vanadium pentoxide

workers (Vintinner et al. 1955); increases in skin rashes were observed in some workers (NIOSH 1983).

No histological alterations of the skin were observed in rats and mice following i ntermediate - or chronicduration exposure to vanadium pentoxide (NTP 2002).

Ocular Effects. Workers chronically exposed to vanadium dusts in factories had slight to moderate

eye irritation (Levy et al. 1984; Lewis 1959; Sjöberg 1950; Thomas and Stiebris 1956; Vintinner et al.

1955). Brief exposure to vanadium dust can also cause conjunctivitis (Zenz et al. 1962).

***DRAFT FOR PUBLIC COMMENT***41 VANADIUM

3. HEALTH EFFECTS

Body Weight Effects. Workers exposed to vanadium ore dust reported weight loss (Vintinner et al.

1955). Significant d ecreases in body weight gain have been observed in rats and mice exposed to

vanadium pentoxide (6 hours/day, 5 days/week) for intermediate or chronic durations (NTP 2002). The

LOAELs were 9.0 mg vanadium/m 3 for rats exposed for 16 or 90 days, 18 mg vanadium/m 3 for mice

ex posed for 16 days, 9.0 mg vanadium/m 3 for mice exposed for 90 days, and 1.1 mg vanadium/m 3 for

mice exposed for 2 years. At lower concentrations, the decreases were within 10% of the controls.

Marked decreases in body weight gain (approximately 30% or h igher) were observed at lethal

concentrations.

3.2.1.3 Immunological and Lymphoreticular Effects

The only human data located found that workers chronically exposed to unspecified levels of vanadium

dusts in factories showed no significant signs of allergic reactions on the skin or in the respiratory system

(Sjöberg 1950). This, however, cannot be considered to be an adequate evaluation of immunological

function. Systemic immunity was evaluated in rats and mice exposed to vanadium pentoxide 6 hours/da y,

5 days/week for 16 days (NTP 2002). Significant decreases in in vitro phagocytosis and increases in vivo

bactericidal activity were observed in rats exposed to ≥ 2.2 mg vanadium/m 3

. No adverse effect on the

response to Klebsiella pneumoniae or to the i nfluenza virus were observed in mice exposed to 18 mg

vanadium/m 3

.

3.2.1.4 Neurological Effects

Most workers exposed to vanadium dusts did not report major adverse neurological signs (Sjöberg 1956;

Vintinner et al. 1955). However, some workers complained of dizziness, depression, headache, or

tremors of the fingers and arms (Levy et al. 1984; Vintinner et al. 1955), which may or may not have been

specifically due to vanadium exposure. No histological alterations were observed in the nervous system

following a 13- week or 2

- year exposure of rats to 4.5 or 1.1 mg vanadium/m 3 , respectively, or mice to

9.0 or 2.2 mg vanadium/m 3 , respectively (NTP 2002). Because the NTP (2002) study did not assess

neurological function, these NOAELs are not listed in Tab le 3 -1 or Figure 3-1.

3.2.1.5 Reproductive Effects

No studies were located regarding the reproductive effects in humans after inhalation exposure to

vanadium. There are limited data on the potential reproductive toxicity of vanadium in animals follow ing

***DRAFT FOR PUBLIC COMMENT***42 VANADIUM

3. HEALTH EFFECTS

inhalation exposure. No histological alterations were observed in rats exposed to 9.0 mg vanadium/m 3 as

vanadium pentoxide for 3 months or 1.1 mg vanadium/m 3 for 2 years or in mice exposed to 9.0 mg

vanadium/m 3 for 3 months or 2.2 mg vanadium/m 3 for 2 years (NTP 2002). No significant alterations in

sperm count, motility, or concentration were observed in rats exposed to 9.0 mg vanadium/m 3 for

3 months (NTP 2002). In females exposed to 4.5 mg vanadium/m 3 as vanadium pentoxide for 3 months,

significant increases in estrous cycle length were observed (NTP 2002); at 9.0 mg vanadium/m 3 , the

number of cycling females was significantly reduced. No studies examined reproductive function.

3.2.1.6 Developmental Effects

No studies were located regarding the developmental effects in humans or animals after inhalation

exposure to vanadium.

3.2.1.7 Cancer

No studies were located regarding the carcinogenicity in humans after inhalation exposure to vanadium.

NTP (2002) examined the carcinogenic potential of vanadium in rats and mice exposed to vanadium

pentoxide 6 hours/day, 5 days/week for 2 years. Increases in the incidence of alveolar/bronchiolar

adenoma, carcinoma, or the combined incidences of adenoma and carcinoma were observed in male rats.

As i ndicated in Table 3

- 2, the incidences of these tumors were not statistically different from controls;

however, the incidence of adenomas at 0.28 mg vanadium/m 3 and combined incidence of adenoma and

carcinoma at 0.56 or 1.1 mg vanadium/m 3 were greater than historical control levels. Due to the rarity of

these tumors, NTP considered the increases in adenoma and carcinoma observed in male rats to be related

to vanadium pentoxide exposure. In female rats, no significant increases in lung tumors were observed.

In the 0.28 mg vanadium/m 3 group, the incidence of alveolar/bronchiolar adenoma exceeded the historical

control range. NTP (2002) noted that this may be related to vanadium pentoxide exposure; however,

because it was only observed at the lowest vanadium pentoxide concentration, a clear relationship

between lung neoplasms and vanadium pentoxide could not be determined in female rats. In male mice,

significant increases in the incidence of alveolar/bronchiolar carcinoma and the combined incidence of

alveo lar/bronchiolar adenoma and carcinoma were observed at 0.56, 1.1, and 2.2 mg vanadium/m 3 ; an

increased incidence of alveolar/bronchiolar adenoma was observed at 1.1 mg vanadium/m 3 . In female

mice, the incidences of alveolar/bronchiolar adenoma or carcinoma and the combined incidence of

adenoma and carcinoma were significantly elevated in the 0.56, 1.1, and 2.2 mg vanadium/m 3 groups. As

presented in Table 3 -2 , the tumor incidences in the male and female mice were not concentration

- related

. Based on vanadium lung burden studies in female rats and mice exposed to vanadium pentoxide, NTP

***DRAFT FOR PUBLIC COMMENT***43 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 2. Incidence of Lung Tumors in Rats and Mice Exposed to Vanadium

Pentoxide for 2 Years a

Concentration (mg vanadium/m 3 )

0 0.28 0.56 1.1

Rats

Male

Al veolar/bronchiolar adenoma, multiple 0/50 2/49 0/48 0/50

Alveolar/bronchiolar adenoma (includes multiple) b 4/50 8/49 5/48 6/50

Alveolar/bronchiolar carcinoma, multiple 0/50 1/49 0/48 0/50

Alveolar/bronchiolar carcinoma (includes multiple) c 0/50 3 /49 1/48 3/50

Alveolar/bronchiolar adenoma or

carcinoma d 4/50 10/49 6/48 9/50

Female

Alveolar/bronchiolar adenoma 0/49 3/49 1/50 0/50

Alveolar/bronchiolar carcinoma 0/49 0/49 0/50 1/50

Alveolar/bronchiolar adenoma or carcinoma 0/49 3/49 1/50 1/50

Mice 0 0.56 1.1 2.2

Male

Alveolar/bronchiolar adenoma, multiple 1/50 1/50 11/50 e 5/50

Alveolar/bronchiolar adenoma (includes 13/50 16/50 26/50 e 15/50 multiple)

Alveolar/bronchiolar carcinoma, multiple 1/50 10/50 e 16/50 e 13/50 e

Alveolar/bronchiolar carcinoma (includes 12/50 29/50 30/50 35/50 multiple)

Alveolar/bronchiolar adenoma or carcinoma 22/50 42/50 e 43/50 e 43/50 e

Female 0 0.28 0.56 1.1

Alveolar/bronchiolar adenoma, multiple 0/50 3/50 5/50 e 6/50 e

alveolar/bronc hiolar adenoma (includes 1/50 17/50 e 23/50 e 19/50 e
multiple)

Alveolar/bronchiolar carcinoma, multiple 0/50 9/50 e 5/50 e 5/50 e

Alveolar/bronchiolar carcinoma (includes 0/50 23/50 e 18/50 e 22/50 e
multiple)

Alveolar/bronchiolar adenoma or carcinoma 1/ 50 32/50 e 35/50 e 32/50 e

a Animals were exposed for 6 hours/day, 5 days/week

b Historical incidence for 2

- year studies with controls given NTP

- 2000 diet (mean ±standard deviation): 4.2±3.5%, range 0

– 12%; with inhalation chamber controls given NIH

- 07 diet: 1.7±2.4%, range 0

– 10%

c Historical incidence for NTP

- 2000: diet 0.4±0.8%, range 0

– 2%; NIH

- 07 diet: 0.8±1.2%, range 0

– 10%

d Historical incidence for NTP

- 2000: diet 4.5±3.9%, range 0

– 14%; NIH

- 07 diet: 2.5±2.6%, range 0

– 10%

e p ≤0.01

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***44 VANADIUM

3. HEALTH EFFECTS

(2002) estimated that the total vanadium lung “doses” were 130, 175, and 308 μg vanadium in rats

exposed to 0.28, 0.56, or 1.1 mg vanadium/m 3 for 540 days and 153, 162, and 225 μg vanadium in mice

exposed to 0.56, 1.1, or 2.2 mg vanadium/m 3 for 553 days. In both species, the similarity of the total dose

at the two lower concentrations (total lung doses of 130 and 175 μg vanadium in rats exposed to 0.28 and

0.56 mg vanadium/m 3 and 153 and 162 μg vanadium in mice exposed to 0.56 and 1.1 mg vanadium/m 3 )

provides a partial explanation for the flat dose-response curve for lung tumors. NTP (2002) also

suggested that the differences in lung tumor responses between the rats and mice may be due to finding

that mice received considerably more vanadium on a body weight basis than rats.

3.2.2 Oral Exposure

3.2.2.1 Death

No studies were located regarding death in humans after oral exposure to vanadium.

The 14- day LD 50 values for sodium metavanadate are 41 mg vanadium/kg in rats and 31.2 mg vanadium/

kg in mice (Llobet and Domingo 1984). Deaths have been reported in rat dams exposed to 17 mg

vanadium/kg/day as sodium orthovanadate on gestation days 6–15 (Sanchez et al. 1991) and in rats

exposed to 22.06 or 24.47 mg vanadium/kg/day as ammonium metavan adate for 4 weeks (Zaporowska

and Wasilewski 1989, 1990). Although the cause of death was not determined, marked decreases in body

weight, food intake, and water consumption and increases in the occurrence of diarrhea were observed in

animals dying early. Chronic exposures of up to 19 mg vanadium/kg as vanadyl sulfate in food or water

did not affect mortality in rats or mice (Dai et al. 1994a, 1994b; Schroeder and Balassa 1967; Schroeder et

al. 1970).

3.2.2.2 Systemic Effects

The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and

duration category are recorded in Table 3-3 and plotted in Figure 3-2.

No studies were located regarding musculoskeletal or dermal/ocular effects in humans or animals

following oral e xposure to vanadium.

Respiratory Effects. No studies were located regarding respiratory effects in humans after oral

exposure to vanadium. Rats receiving sodium metavanadate in the drinking water for 3 months had

***DRAFT FOR PUBLIC COMMENT***2641253169178727.7227.651037.5244.28.4Table 3-3 Levels of Significant Exposure to Vanadium - OralExposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormCommentsACUTE EXPOSUREDeath1Rat 1 d41 (LD50)Llobet and Domingo 19841 x/dSODIUM METAVANADATE(GW)2Mouse once31 (LD50)Llobet and Domingo 1984(GW)SODIUM METAVANADATE3Mouse Gd 6-1517 F (17/19 dams died)Sanchez et al. 1991(Swiss)(G)SODIUM ORTHOVANADATESystemic4Rat 2 wkHemato27.72 M (increased reticulocytes,Zaporowska and Wasilewski(Wistar)(W)1989increasedpolychromatophilicAMMONIUMerythroblasts in boneMETAVANADATEmarrow)Bd Wt 27.65 FMouse Gd 6-155Bd Wt7.5 F (46% decrease inPaternain et al. 1990(Swiss)(G)maternal weight gain)VANADYL SULFATEDevelopmental6Rat Gd 6-144.28.4 (facial hemorrhages)Paternain et al. 1987(G)SODIUM METAVANADATE687.5704.28.38924.479122.06300.190.190.19Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormComments7Mouse Gd 6-157.5 F (increased earlyPaternain et al. 1990(Swiss)(G)resorptions, decreasedVANADYL SULFATEfetal growth, increasedsoft tissue and skeletaldefects)8Mouse Gd 6-154.28.3 (decreased number ofSanchez et al. 1991(Swiss)(G)ossified sacrococcygealSODIUM ORTHOVANADATEvertebrae)INTERMEDIATE EXPOSUREDeathRat 4 or 8 wk924.47 M (10/32 animals died byZaporowska and Wasilewski(Wistar)(W)1989week 4)AMMONIUMMETAVANADATE10Rat 4 wk22.06 M (12/20 rats died)Zaporowska and Wasilewski(Wistar)(W)1990AMMONIUMMETAVANADATESystemic11Human 45-68 dHemato 0.19Dimond et al. 1963(C)AMMONIUM VANADYLTARTRATEHepatic 0.19Renal 0.19790.120.120.120.129312.12.1763131724.70.124.7Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormComments12Human dailyCardio 0.12Fawcett et al. 199712 wkVANADYL SULFATE(C)bHemato 0.12Hepatic 0.12Bd Wt 0.1213Rat 10 wkHemato 1 F2.1 F (decreased hemoglobinAdachi et al. 2000(Wistar)(F)and hematocrit,SODIUM METAVANADATEincreased reticulocyte)Bd Wt 2.1 F14Rat 60 dCardio31 M (decreased aortaAkgun-Dar et al. 2007(Swiss)(G)diameter)VANADYL SULFATEMetab 31 Md15Rat 210 dResp 4.7 MBoscolo et al. 1994(Sprague-(W)SODIUM METAVANADATEDawley)Cardio0.12 M (increased bloodpressure)Hepatic 4.7 M7522227312741.2779.79.7787.67.6102610431Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)LOAELReferenceNOAEL Less SeriousSeriousSystem(mg/kg/day) (mg/kg/day)(mg/kg/day)Chemical FormCommentsCardio 22 MBursztyn and Mekler 1993SODIUM METAVANADATEMetab 22 MCardio12 M (increased bloodCarmagnani et al. 1991pressure and heart rate)SODIUM METAVANADATECardio1.2 M (increased bloodCarmagnani et al. 1992pressure)SODIUM METAVANADATEHemato 9.7 MDai et al. 1995AMMONIUMMETAVANADATEBd Wt 9.7 MHemato 7.6 MDai et al. 1995VANADYL SULFATEBd Wt 7.6 MBd Wt6 F(19% decrease inElefant and Keen 1987maternal body weightSODIUM METAVANADATEgain)Bd Wt 31 MJain et al. 2007VANADYL SULFATEaKey toFigure16171819202122Species(Strain)Rat(Sabra)Rat(SpragueDawley)Rat(SpragueDawley)Rat(Wistar)Rat(Wistar)Rat(SpragueDawley)Rat(Wistar)Exposure/Duration/Frequency(Route)4 wk(W)7 mo(W)7 mo(W)12 wk(W)12 wk(W)Gd 0- Ld 21(F)60 d(G)216.66.6301063.426.84818.358.358210.69201010113Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormComments23Rat 75 or 103 dHemato 6.6 MMountain et al. 1953(Wistar)(F)VANADIUM PENTOXIDEBd Wt 6.6 M30 M (53% decrease in bodyweight gain)Rat 8 wk24Bd Wt 3.42 M6.84 M (10% decrease in bodySanchez et al. 1998(Sprague-(G)weight gain)SODIUM METAVANADATEDawley)25Rat 6 wkHemato8.35 M (increased erythrocyteScibior 2005(Wistar)(W)levels)SODIUM METAVANADATEBd Wt 8.35 M26Rat 6 wkHemato10.69 M (decreased erythrocyteScibior et al. 2006(Wistar)(W)and hemoglobin levels)SODIUM METAVANADATE27Rat 2 moCardio10 M (increased ventricularSusic and Kentera 1986(Long- Evans)(F)pressure)AMMONIUMMETAVANADATE28Rat 7.4 wkMetab 13 MYao et al. 1997(Sprague-(W)VANADYL SULFATEDawley)8824.479022.068319.738419.7319.738512.99Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/FrequencyNOAEL Less SeriousSeriousReference(Route)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormComments4 or 8 wkHemato24.47 M (decreased erythroctyes,Zaporowska and Wasilewski(W)increased reticulocytes)1989AMMONIUMMETAVANADATE4 wkHemato22.06 M (decreased erythrocyte,Zaporowska and Wasilewski(W)increased reticulocyte)1990AMMONIUMMETAVANADATE4 wkHemato19.73 M (decreased hemoglobinZaporowska and Wasilewski(W)and erythrocyte and1991increased reticulocyte)AMMONIUMMETAVANADATE4 wkGastro19.73 (diarrhea)Zaporowska and Wasilewski(W)1992aAMMONIUMMETAVANADATEHemato19.73 M (decreased hemoglobinand erythrocyte andincreased reticulocyte)4 wkHemato12.99 M (decreased hemoglobinZaporowska and Wasilewski(W)and erythrocyte and1992bincreased reticulocyte)AMMONIUMMETAVANADATEaKey to SpeciesFigure (Strain)29Rat(Wistar)30Rat(Wistar)31Rat(Wistar)32Rat(Wistar)33Rat(Wistar)861.184.93801.89412.11001.721346.84148.4Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormComments34Rat 4 wkHemato1.18 M (decreased erythrocyteZaporowska et al. 1993(Wistar)(W)levels)AMMONIUMMETAVANADATEBd Wt 4.93 M35Rabbit 24, 129,Hemato1.8 (decreased erythrocyteKasibhatla and Rai 1993or 171 d(NS)levels)Not Reported(W)Immuno/ Lymphoret36Rat 10 wk1 F2.1 F (decreased B-cell, IgG,Adachi et al. 2000(Wistar)(F)and IgM levels)SODIUM METAVANADATENeurological37Rat 8 wk1.72 M (impaired performanceSanchez et al. 1998(Sprague-(G)on neurobehavioral tests)SODIUM METAVANADATEDawley)38Rat daily6.84 M (impaired response inSanchez et al. 19998 wk(Sprague-active avoidance tests)SODIUM METAVANADATEDawley)(GW)Reproductive39Rat 60 d8.4Domingo et al. 1986(Sprague-(GW)SODIUM METAVANADATEDawley)9631981012971725132.1666Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/FrequencyNOAEL Less SeriousSeriousReference(Route)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormComments60 d31 M (decreased fertility,Jain et al. 2007(G)sperm count, andVANADYL SULFATEmotility)M: 70 d F:14 d10 M (decreased fertility)Morgan and El-Tawil 2003premating,mating,AMMONIUMgestation,12 F (decreased fertility)METAVANADATElactation(W)64 d17 M25 M (decreased fertility andLlobet et al. 1993(W)spermatozoa count)SODIUM METAVANADATE60 d2.1 (reduced pup weight andDomingo et al. 1986(G)length)SODIUM METAVANADATEGd 0- Ld 216 (decreased pup survivalElefant and Keen 1987(F)and body weight)SODIUM METAVANADATEaKey to SpeciesFigure (Strain)40Rat(Wistar)41Rat(SpragueDawley)42Mouse(Swiss)Developmental43Rat(SpragueDawley)44Rat(SpragueDawley)9910127110480.7504.1490.54Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormCommentsRat M: 70 d F:14 d4510 M (decreased viability,Morgan and El-Tawil 2003premating,(Sprague-mating,increased gross, skeletalAMMONIUMDawley)gestation,and visceral anomalies,METAVANADATEdecreased pup bodylactationweight)(W)12 F(decreased viability,increased gross, skeletaland visceral anomalies,decreased pup bodyweight)46Rat Gd 19- Ld 25,10(decreased pup survival)Poggioli et al. 2001pups exposed(Wistar)until pnd 100VANADYL SULFATE(W)CHRONIC EXPOSUREDeath47Rat 2.5 yr0.7Schroeder et al. 1970(W)VANADYL SULFATE48Mouse 2 yr4.1Schroeder and Balassa 1967(F)VANADYL SULFATE49Mouse 2.5 yr0.54Schroeder and Mitchner 1975(W)VANADYL SULFATE921919191919172819150.70.7164.14.14.14.14.1170.54Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aFrequencyReferenceKey to SpeciesNOAEL Less SeriousSerious(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormCommentsSystemic50Rat 52 wkResp19 MDai and McNeill 1994; Dai et(Wistar)(W)al. 1994a, 1994bVANADYL SULFATECardio 19 MHemato 19 MHepatic 19 MRenal 19 M(dfBd Wt 17 M 28 M (20% decrease in bodyweight gain)Metab 19 M51Rat 2.5 yrRenal 0.7Schroeder et al. 1970(W)VANADYL SULFATEBd Wt 0.752Mouse 2 yrResp 4.1Schroeder and Balassa 1967(F)VANADYL SULFATECardio 4.1Hemato 4.1Renal 4.1Bd Wt 4.153Mouse 2.5 yrBd Wt 0.54Schroeder and Mitchner 1975(W)VANADYL SULFATE524.1Table 3-3 Levels of Significant Exposure to Vanadium - Oral(continued)Exposure/LOAELDuration/aKey to SpeciesFrequencyNOAEL Less SeriousSeriousReference(Route)Figure (Strain)System(mg V/kg/day) (mg V/kg/day)(mg V/kg/day)Chemical FormCommentsImmuno/ Lymphoret54Mouse 2 yr4.1Schroeder and Balassa 1967(F)VANADYL SULFATEa The number corresponds to entries in Figure 3-2b Used to derive an intermediate-duration oral MRL of 0.01 mg vanadium/kg/day; dose divided by an uncertainty factor of 10 for human variability.Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; d = day(s); (F) = feed; F = Female; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day; (GW) = gavage inwater; Hemato = hematological; Immuno/Lymphoret = immunological/lymphoreticular; Ld = lactation day; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level;M = male; Metab = metabolic; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; pnd = post-natal day; Resp = respiratory; (W) = drinking water; wk =week(s); x = time(s); yr = year(s)1 10 100 Death

2m

3m 1r Hematological

4r Body Weight

5m 4r Developmental

7m 8m

8m 6r

6r mg V /kg/day 

### Figure 3-2 Levels of Significant Exposure to Vanadium - Oral

Acute (≤14 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer SystemicVANADIUM3. HEALTH EFFECTS56***DRAFT FOR PUBLIC COMMENT***0.01 0.1 1

10 100 Death

9r 10r Respiratory

15r Cardiovascular

12 14r

15r 16r

17r

18r 27r Gastrointestinal

32r Hematological

11

12 13r 13r 19r

20r 23r 25r 26r 29r 30r 31r 32r

33r

34r 35h Hepatic

11

12 15r Renal

11 Body Weight

12 13r 19r

20r

21r 22r 23r

23r

24r 24r 25r

34r Metabolic

14r

16r

28r Immuno/Lymphor

36r 36r Neurological

37r 38r Reproductive

42m 42m

39r 40r

41r 41r mg V /kg/day 

### Figure 3-2 Levels of Significant Exposure to Vanadium - Oral (Continued)

Intermediate (15-364 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer Developmental

43r 44r 45r 45r 46r SystemicVANADIUM3. HEALTH EFFECTS57***DRAFT FOR PUBLIC COMMENT***0.1 1 10 100 Death

48m

49m 47r Respiratory

52m 50r Cardiovascular

52m 50r Hematological

52m 50r Hepatic

50r Renal

52m 50r

51r Body Weight

52m

53m 50r 50r

51r Metabolic

50r Immuno/Lymphor

54m mg V /kg/day 

### Figure 3-2 Levels of Significant Exposure to Vanadium - Oral (Continued)

Chronic (≥365 days)

c-Cat d-Dog r-Rat p-Pig q-Cow -Humans k-Monkey m-Mouse h-Rabbit a-Sheep f-Ferret j-Pigeon e-Gerbil s-Hamster g-Guinea Pig n-Mink o-Other Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals Cancer Effect Level-Humans LOAEL, More Serious-Humans LOAEL, Less Serious-Humans NOAEL - Humans LD50/LC50 Minimal Risk Level for effects other than Cancer SystemicVANADIUM3. HEALTH EFFECTS58***DRAFT FOR PUBLIC COMMENT***59 VANADIUM

3. HEALTH EFFECTS

mon onuclear cell infiltration, mostly perivascular, in the lungs; the investigators noted that the effects

were more evident at the highest dose level (3.5 mg vanadium/kg/day), but incidence data were not

reported (Domingo et al. 1985).

Cardiovascular Effect s. No significant alterations in systolic or diastolic blood pressure were

observed in adults exposed to 0.12 mg vanadium/kg/day as vanadyl sulfate for 4, 8, or 12 weeks via

capsules taken at mealtime (Fawcett et al. 1997).

Several studies have exami ned the effects of vanadium on blood pressure in laboratory animals. The

results are inconsistent; however, differences in the methods used to measure blood pressure and the

strains of rats tested complicate cross study comparisons. Significant increases in systolic, diastolic,

and/or mean blood pressure were observed in Sprague

- Dawley rats exposed to 0.12 –12 mg vanadium/

kg/day as sodium metavanadate in drinking water for 180– 210 days (measured in femoral artery of

anesthetized rats; Boscolo et al. 1994), in Sprague- Dawley rats exposed to 1.2

– 12 mg vanadium/kg/day as

sodium metavanadate in drinking water for 7 months (mea sured in the aorta of anesthetized rats;

Carmagnani et al. 1991, 1992), and Long-Evans rats exposed to 10 mg vanadium/kg/day as ammonium

vanadate in the diet for 60 days (measured in ventricle of anesthetized rats; Sušić and Kentera 1986). In

contrast, no alterations in blood pressure were observed in rats exposed to 10 mg vanadium/kg/day as

ammonium vanadate in the diet for 60 days (Long- Evans rats, measured in femoral artery; Sušić and

Kentera 1986), 22 mg vanadium/kg/day as sodium metavanadate in drinki ng water for 4 weeks (Sabra

rats, measured via tail cuff; Bursztyn and Mekler 1993), 32 mg vanadium/kg/day as vanadyl sulfate in

drinking water for 52 weeks (Wistar rats, measured via tail cuff; Dai and McNeill 1994), or 63 mg

vanadium/kg/day as sodium met avanadate in the diet for 24 weeks (Long

- Evans rats, measured via tail

cuff or femoral artery; Sušić and Kentera 1988). Studies in compromised animals have also found

alterations in blood pressure. Increases in arterial blood pressure (measured via tail cuff) were observed

in salt -induced hypertensive rats exposed to 22 mg vanadium/kg/day as sodium metavanadate in drinking

water for 4 weeks compared to hypertensive controls (Bursztyn and Mekler 1993). Similar increases in

blood pressure (measured via tai l cuff) were observed in uninephrectomized rats exposed to 6 mg

vanadium/kg/day as sodium metavanadate in the diet for 18 weeks (Sušić and Kentera 1988) or 5 mg

vanadium/kg/day as sodium orthovanadate in the diet (Steffen et al. 1981). Alterations in the renin

angiotensin

- aldosterone system and alterations in urinary excretion of electrolytes observed in the

Boscolo et al. (1994) study provide suggestive evidence that altered renal function may play a role in

vanadium-induced hypertension. Significant inc reases in plasma renin activity, plasma aldosterone

levels, and increases in kallikrein (enzyme that releases vasodilating kinins from plasma proteins), and

***DRAFT FOR PUBLIC COMMENT***60 VANADIUM

3. HEALTH EFFECTS

kininases I and II activities were observed in rats exposed to 1.2 or 4.7 mg vanadium/kg/day as sod ium

metavanadate in the drinking water for 7 months.

Other alterations in the cardiovascular system included significant decreases in aorta diameter and the

aorta tunica intima thickness in rats administered 31 mg vanadium/kg/day as vanadyl sulfate via ga vage

for 60 days (Akgün -Dar et al. 2007) and an increase in heart rate in rats exposed to 12 mg vanadium/kg/

day as sodium metavanadate in drinking water for 7 months (Carmagnani et al. 1991, 1992), but not in

rats exposed to ≤4.7 mg vanadium/kg/day as sod ium metavanadate in drinking water for 7 months

(Boscolo et al. 1994; Carmagnani et al. 1992) or 10 mg vanadium/kg/day as ammonium vanadate in the

diet for 2 months (Sušić and Kentera 1986).

Gastrointestinal Effects. The limited data available for assessing gastrointestinal effects suggest

that exposure to vanadium may cause mild gastrointestinal irritation. Intestinal cramping and diarrhea

were observed in subjects exposed to an average dose of 0.19 mg vanadium/kg/day as ammonium

vanadyl tartrate admi nistered via capsules for 45–68 days (Dimond et al. 1963). Several clinical studies

investigating the efficacy and mechanism of action of sodium metavanadate and vanadyl sulfate for the

treatment of diabetes mellitus have found mild gastrointestinal effec ts (Boden et al. 1996; Cusi et al.

2001; Goldfine et al. 1995). Mild diarrhea was reported by 4/10 insulin- and noninsulin-dependent

diabetes patients administered 0.66 mg vanadium/kg/day as sodium metavanadate as capsules

administered 3 times/day (0.26 mg vanadium/kg at breakfast and lunch and 0.13 mg vanadium/kg at

dinner) for 14 days (Goldfine et al. 1995); another subject reported nausea and vomiting that subsided

when the dose was decreased to 0.13 mg vanadium/kg 3 times/day. In another study of eight noninsulin

dependent diabetics administered 0.35 mg vanadium/kg/day as vanadyl sul fate as capsules 2 times/day for

4 weeks, diarrhea and abdominal cramps were reported during the first week of treatment, but not

reported thereafter (Boden et al. 1996). Similarly, insulin -independent diabetics reported diarrhea and

abdominal discomfort during the first 2 weeks of exposure to vanadyl sulfate (Cusi et al. 2001). The

initial dose of 0.2 mg vanadium/kg/day administered presumably as capsules 2 times/day was increased

every 2 –3 days and reached 0.6 mg vanadium/kg/day by week 2. Several animal studies have reported

diarrhea in rats exposed to ≥8.35 mg vanadium/kg/day as sodium metavanadate or ammonium
metavanadate (Ścibior 2005; Zaporowska and Wasilewski 1989, 1990, 1992a); the diarrhea was often

observed at doses associated with marked decreases in food intake and water consumption.

Hematological Effects. No alterations in reticulocyte or platelet counts (Dimond et al. 1963) or

erythrocyte, hemoglobin, hem atocrit, or platelet levels (Fawcett et al. 1997) were observed in adults

***DRAFT FOR PUBLIC COMMENT***61 VANADIUM

3. HEALTH EFFECTS

exposed to 0.19 mg vanadium/kg/day as ammonium vanadyl tartrate for 6–10 weeks or 0.12 mg

vanadium/kg/day as vanadyl sulfate for 12 weeks, respectively.

A series of studies conducte d by Zaporowska and associates examined the hematotoxicity of ammonium

metavanadate administered in drinking water to rats for acute or intermediate durations. A 2- week

exposure to 27.72 mg vanadium/kg/day resulted in significant increases in reticulocyte levels and

increases in the percentage of polychromatophilic erythroblasts in the bone marrow in male rats

(Zaporowska and Wasilewski 1989); a nonsignificant increase in erythrocytes was also observed at this

dose level. Exposures to 12.99–24.47 mg vanad ium/kg/day for 4 weeks resulted in decreases in

erythrocyte levels and hemoglobin levels and increases in reticulocyte levels (Zaporowska and

Wasilewski 1989, 1990, 1991, 1992a, 1992b). However, death and decreases in body weight gain, food

intake, and wa ter consumption were also observed at these dose levels. Similar effects were observed in
rats exposed to 8.35 or 10.69 mg vanadium/kg/day as sodium metavanadate for 6 weeks (Ścibior 2005;

Ścibior et al. 2006). One study in this series tested lower concentration s which did not result in frank

toxicity. Sign ificant decreases in erythrocyte and hematocrit levels were o bserved in rats exposed to

1.18 or 4.93 mg vanadium/kg/day as ammonium metavanadate for 4 weeks (Zaporowska et al. 1993);

significant increases in reticulocyte levels were observed at 4.93 mg van adium/kg/day. The decreases in

erythrocyte levels were small (approximately 11% less than controls) and not dose

- related. Decreases in

hemoglobin and hematocrit and increases in reticulocytes were observed in rats exposed to 2.1 mg

vanadium/kg/da y as sodium metavanadate for 10 weeks (Adachi et al. 2000a) and decreases in

erythrocyte counts were observed in rabbits exposed to 1.8 mg vanadium/kg/day of an unknown

metavanadate compound for 24 days (Kasbhatla and Rai 1993). However, other investigators have not

found hematological alterations in rats exposed to 19 mg vanadium/kg/day as vanadyl sulfate for 1 year

(Dai and McNeill 1994), 9.7 mg vanadium/kg/ day as ammonium metavanadate for 12 weeks (Dai et al.

1995), 7.6 mg vanadium/kg/day as vanadyl sulfate for 12 weeks (Dai et al. 1995), or 6.6 mg

vanadium/kg/day as vanadium pentoxide for 10– 15 weeks (Mountain et al. 1953). As suggested by

Ścibior et al. (2006), the differences may be due to the duration of exposure, compound administered, or

age of the animals.

Hepatic Effects. No significant alterations in serum AST , cholesterol, triglyceride, phospholipid,

and/or bilirubin levels were observed in humans administered, via capsules, 0.19 mg vanadium/kg as

ammonium vanadyl tartrate for 45–68 days (Dimond et al. 1963) or 0.12 mg vanadium/kg/day as vanadyl

sulfate for 12 weeks (Fawcett et al. 1997).

***DRAFT FOR PUBLIC COMMENT***62 VANADIUM

3. HEALTH EFFECTS

Several studies in laboratory animals examining cholesterol and triglyceride levels (Adachi et al. 2000a;

Dai et al. 1994a) or serum enzyme levels ( ALT or AST ) (Adachi et al. 2000a; Dai et al. 1994b; Yao et al.

1997) have not found biologically relevant alterations. The highest NOAEL values for these effects are

13 mg vanadium/kg/day (Yao et al. 1997) following intermediate-duration exposure and 19 mg

vanadium/kg/day following chronic-duration exposure (Dai et al. 1994a, 1994b). No histological

alterations were observed in the livers of rats exposed to 3.5 mg vanadium/kg/day as sodium

metavanadate in drinking water for 3 months (Domingo et al. 1985), 4.7 mg vanadium/kg/day as sodium

metavanadate in drinking water for 210 days (Boscolo et al. 1994), or 19 mg vanadium/kg/day as vandyl

sulfate in drinking wate r for 1 year (Dai et al. 1994b).

Renal Effects. Humans given 0.19 mg vanadium/kg as ammonium vanadyl tartrate capsules for 45–

68 days did not show any changes in urinalysis for albumin, hemoglobin, or formed elements. Blood urea

nitrogen levels were a lso unchanged (Dimond et al. 1963).

There are limited data on the renal toxicity of vanadium compounds. Narrowing of the lumen of the

proximal tubules was observed in rats exposed to 4.7 or 12 mg vanadium/kg/day as sodium metavanadate

in drinking water for 7 months (Boscolo et al. 1994; Carmagnani et al. 1991); however, neither study

reported the incidence of the lesion or statistical significance. Similarly, corticomedullar micro

hemorrhagic foci were observed in the kidneys of rats exposed to sodium me tavanadate in drinking water

for 3 months (Domingo et al. 1985); the investigators noted that the effect was more evident at the highest

dose (3.5 mg vanadium/kg/day), but incidence data or statistical analyses were not included in the paper.

This study a lso found significant increases in serum total protein, urea, and uric acid levels in rats

exposed to 3.5 mg vanadium/kg/day. No statistically significant increases in the incidence of histological

alterations were observed in rats exposed to 19 mg vanadi um/kg/day as vanadyl sulfate in drinking water

for 1 year (Dai et al. 1994b). No histological alterations were observed in the kidneys of rats exposed to

0.7 mg vanadium/kg/day (Schroeder et al. 1970) as vanadyl sulfate in drinking water for 2.5 years or in

mice exposed to 4.1 mg vanadium/kg/day as vanadyl sulfate in the diet for 2 years (Schroeder and Balassa

1967).

Body Weight Effects. No significant alterations in body weight were observed in adults exposed to

0.12 mg vanadium/kg/day as vanadyl su lfate administered via capsules for 12 weeks (Fawcett et al.

1997). Numerous studies have reported significant decreases in body weight gain in rats or mice exposed

to vanadium compounds. In general, intermediate-duration exposure to <10 mg vanadium/kg/day did not

result in >10% decreases in body weight gain (Adachi et al. 2000a; Dai et al. 1995; Sanchez et al. 1998;

***DRAFT FOR PUBLIC COMMENT***63 VANADIUM

3. HEALTH EFFECTS

Ścibior 2005; Zaporwska et al. 1993). At higher concentrations, a considerable amount of variability in

the magnitude of decreases in body weight gain was observed. Decreases of 12

– 15% were observed in

rats or mice exposed to 10.69, 13, 20.93, 22.06, or 33 mg vanadium/kg/day as vanadyl sulfate,
ammonium metavanadate, or sodium metavanadate in drinking water (Llobet et al. 1993; Ścibior et al

. 2006; Yao et al. 1997; Zaporowski and Wasilewski 1989, 1990). However, decreases of ≥37% were

observed in rats exposed to 12.99 or 19.73 mg vanadium/kg/day as ammonium vanadate in drinking water

(Zaporowski and Wasilewski 1991, 1992a, 1992b); these decr eases in body weight gain were

accompanied by marked decreases in food intake and water consumption. A severe decrease in body

weight gain (54%) and weight loss were observed in rats exposed to 30 or 55 mg vanadium/kg/day,

respectively, as vanadium pentox ide for 75 days (Mountain et al. 1953). In contrast, no alterations in

body weight gain were observed in rats exposed to 22 mg vanadium/kg/day as sodium metavanadate in

drinking water (Bursztyn and Mekler 1993) or administered via gavage at 31 mg vanadium /kg/day as

vanadyl sulfate (Akgün -Dar et al. 2007; Jain et al. 2007). Significant decreases in maternal weight gain

have been observed in rats exposed to 6 mg vanadium/kg/day as sodium metavanadate (Elfant and Keen

1997) and mice administered 7.5 mg vanadium/kg/day as vanadyl sulfate (Paternain et al. 1990).

Following chronic exposure, a 20% decrease in body weight gain was observed in rats exposed to vanadyl

sulfate in drinking water for 1 year (Dai et al. 1994a). No alterations in body weight gain were observed

in mice exposed to 4.1 or 0.54 mg vanadium/kg/day as vanadyl sulfate (Schroeder and Balassa 1967;

Schroeder and Mitchener 1975) or rats exposed to 0.7 mg vanadium/kg/day as vanadyl sulfate (Schroeder

et al. 1970).

It is likely that the decreases in body weight in a number of these studies are secondary to decreases in

water consumption (possibly due to palatability). D ecreases in food intake and body weight gain have

been observed in rats placed on a water restricted diet (Crampton and Lloyd 195 4) ; young rats were

particularly sensitive to the effect (2 -month- old rats were used in the Zaporowski and Wasilewski

studies). Thus, LOAELs for decreases in body weight gain in drinking water studies reporting decreases

in water consumption (possibly due to palatability) are not presented in Table 3-3 or Figure 3- 2; similarly,

LOAELs were not listed for studies that did not report whether there was an effect on drinking water

consumption.

Metabolic Effects. No studies were located regarding metabolic effects in healthy humans after oral

exposure to vanadium. No significant alterations in blood glucose or insulin levels were observed in rats

exposed to 22 mg vanadium/kg/day as sodium metavanadate in drinking water for 4 weeks (Bursztyn and

Mekler 199 3), rats administered 31 mg vanadium/kg/day as vanadyl sulfate for 60 days (Akgün- Dar et al.

***DRAFT FOR PUBLIC COMMENT***64 VANADIUM

3. HEALTH EFFECTS

2007), or rats exposed to 19 mg vanadium/kg/day as vanadyl sulfate in drinking water for 1 year (Dai et

al. 1994a). Additionally, no alterations in the response t o an oral glucose tolerance test were observed in

rats exposed to 13 mg vanadium/kg/day as vanadyl sulfate in drinking water for 7.4 weeks (Yao et al.

1997).

3.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological effects in humans after oral exposure to vanadium.

Minimal information on immunological effects in animals was located. Mice exposed to 0.13, 1.3, or

6.5 mg vanadium/kg/day as sodium orthovanadate in the drinking water for 6 weeks showed a doserela ted, but nonsignificant, decrease in the antibody -forming cells in the spleen when challenged with

sheep erythrocytes (Sharma et al. 1981). The number of plaques formed was 46, 69, and 78%,

respectively, lower than the response in the controls; the invest igators noted that statistical significance

was not achieved due to the large variation in the control group. Decreases in B- cell levels and IgG and

IgM levels were observed in rats exposed to 2.1 mg vanadium/kg/day as sodium metavanadate in the diet

for 10 weeks (Adachi et al. 2000a). Mild spleen hypertrophy and hyperplasia were seen in rats exposed to

sodium metavanadate in the drinking water for 3 months (Domingo et al. 1985); the investigators noted

that the effects were more evident at the highest do se (3.5 mg vanadium/kg/day), but incidence data were

not reported. The highest NOAEL values and all reliable LOAEL values for immunological effects in

each species and duration category are recorded in Table 3 -3 and plotted in Figure 3-2.

3.2.2.4 Neuro logical Effects

No studies were located regarding neurological effects in humans after oral exposure to vanadium. Data

on the neurotoxicity of vanadium are limited to two studies in rats. In one study, decreases in travelling

distance and horizontal movement in an open field test and poorer avoidance performance and higher

latency period in an active avoidance test were observed in rats administered 1.72 mg vanadium/kg/day as

sodium metavanadate for 8 weeks (Sanchez et al. 1998). In the second study, n o alterations in travelling

distance or vertical movements were observed in an open field test in rats administered 6.84 mg

vanadium/kg/day as sodium metavanadate for 8 weeks (Sanchez et al. 1999). A decrease in the number

of avoidance responses to conditioned stimuli and increases in the latency period were also observed in

these rats. Th ese LOAEL value s are recorded in Table 3 -3 and Figure 3-2.

***DRAFT FOR PUBLIC COMMENT***65 VANADIUM

3. HEALTH EFFECTS

3.2.2.5 Reproductive Effects

No studies were located regarding reproductive effects in humans after oral exposure to vanadium.

Decreases in fertility have been observed in female rats mated to unexposed males (Ganguli et al. 1994b;

Morgan and El- Tawil 2003) and in male rats or mice mated with unexposed females (Jain et al. 2007;

Llobet et al. 1993; Morgan an d El

- Tawil 2003). The lowest LOAEL values for decreased fertility are

12 and 10 mg vanadium/kg/day for females and males, respectively (Morgan and El -Tawil 2003). No

alterations in fertility were observed in male and female rats administered 8.4 mg vanad ium/kg/day as

sodium metavanadate (Domingo et al. 1986). Decreases in sperm count and motility have also been

observed in rats administered 31 mg vanadium/kg/day as vanadyl sulfate for 60 days (Jain et al. 2007).

This NOAEL value and reliable LOAEL value s are recorded in Table 3 -3 and plotted in Figure 3-2.

3.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans after oral exposure to vanadium. A

variety of fetal malformations/anomalies have been observed in animals following gestational exposure to

vanadium. Exposure on gestation days 6– 14 or 6

– 15 resulted in increases in facial hemorrhages

(Paternain et al. 1987), hematomas in facial, neck, and dorsal areas (Paternain et al. 1990), and delayed

ossification (Paternain et al. 1990; Sanchez et al. 1991); the rat and mouse dams were administered 7.5–

8.3 mg vanadium/kg/day as vanadyl sulfate, sodium metavanadate, or sodium orthovanadate. One study

also reported increases in early resorptions and decreases in fe tal growth in the offspring of mice

administered 7.5 mg vanadium/kg/day as vanadyl sulfate (Paternain et al. 1990); marked decreases in

maternal body weight were also observed at this dose level. Vanadium exposure throughout gestation and

lactation result ed in decreases in pup body weight and length at ≥2.1 mg vanadium/kg/day (Domingo et

al. 1986; Elfant and Keen 1987; Morgan and El-Tawil 2003). Increases in stillbirths and decreases in pup

survival were observed at 6 mg vanadium/kg/day (Elfant and Keen 1987); this dose level was associated

with decreases in maternal food intake and body weight. Increases in gross, skeletal, and visceral

anomalies were observed in the offspring of rats exposed to 12 mg vanadium/kg/day as ammonium

metavanadate (Morgan and El

- Tawil 2003); similar effects were observed in unexposed dams mated with

males exposed to 10 mg vanadium/kg/day (Morgan and El-Tawil 2003). In rats exposed to 10 mg

vanadium/kg/day as vanadyl sulfate in drinking water during gestation and lactation and exposed until

postnatal day 100, significant decreases in survival were observed (Poggioli et al. 2001). This study also

found significant decreases in the number of rearings in an open field test and no alterations in locomotor

activity or working memory . A two -generation, one-dose study in rats showed altered lung collagen

metabolism in fetuses of adults with lifetime exposure (Kowalska 1988). The toxicological significance

***DRAFT FOR PUBLIC COMMENT***66 VANADIUM

3. HEALTH EFFECTS

of this finding is also not known. Reliable LOAEL values from these studies ar e recorded in Table 3 -3

and plotted in Figure 3-2.

3.2.2.7 Cancer

No studies were located that specifically studied cancer in humans or animals after oral exposure to

vanadium. However, some studies designed to test other end points noted no increase in tumor frequency

in rats and mice chronically exposed to 0.5– 4.1 mg vanadium/kg as vanadyl sulfate in drinking water

(Schroeder and Balassa 1967; Schroeder and Mitchener 1975; Schroeder et al. 1970). Although results of

these oral studies were negative for carcinogenicity, they were inadequate for evaluating carcinogenic

effects because insufficient numbers of animals were used, it was not determined whether or not a

maximum tolerated dose was achieved, a complete histological examination was not performed, and only

one exposure dose per study was evaluated.

3.2.3 Dermal Exposure

No studies were located regarding the following health effects in humans or animals after dermal

exposure to vanadium:

3.2.3.1 Death

3.2.3.2 Systemic Effects

3.2.3.3 Immunological and Lymphoreticular Effects

3.2.3.4 Neurological Effects

3.2.3.5 Reproductive Effects

3.2.3.6 Developmental Effects

3.2.3.7 Cancer

3.3 GENOTOXICITY

The in vitro and in vivo data on the genotoxicity of vanadium compounds a re summarized in Tables 3 -4

and 3-5, respectively. In workers exposed to vanadium pentoxide, no alterations in the occurrence of

sister chromatid exchange (Ivancsits et al. 2002) or deoxyribonucleic acid ( DNA ) strand breaks (Ehrlich

et al. 2008; Ivancsits et al. 2002) were observed; however, an increase in micronuclei formation was

observed in lymphocytes (Ehrlich et al. 2008). Similarly, increases in the micronuclei formation were

observed in mouse bone marrow cells following oral exposure to vanadyl sul fate (Ciranni et al. 1995;

***DRAFT FOR PUBLIC COMMENT***67 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 4. Genotoxicity of Vanadium and Compounds **In Vitro**

Results

With Without Species (test system) End point activation activation Reference Form

Bacillus subtilis Recombination repair No data + Kada et al. 1980 V 2 O 5

+ VOCl 2

+ NH 4 VO 3

B

. subtilis Recombination repair No data + Kanematsu et al. V 2 O 5

+ 1980 VOCl 2

+ NH 4 VO 3

Escherichia coli Gene mutation No data

C Kanematsu et al. V 2 O 5

C 1980 NH 4 VO 3 Salmonella typhimurium Gene mutation No data

C Kanematsu et al. V 2 O 5

C 1980 NH 4 VO

S. typhimurium Gene mutation

C C NTP 2002 V 2 O 5 Saccharomyces cerevisiae Induction of diploid No data + Sora et al. 1986 VOSO 4 spores

S. cerevisiae Reverse point + + Bronzetti et al. NH 4 VO 3 mutation 1990

S. cerevisiae Mitotic gene + + Bronzetti et al. NH 4 VO 3 conversion 1990

Mouse erythroleukemia DNA repair No data + Foresti et al. NaVO 3 cells 2001

Mouse 3T3 and 3T6 cells DNA synthesis No data + Smith 1983 Na 3 VO 4 VOSO 4 Chinese hamster ovary DNA protein crosslinks No data + Cohen et al

. NH 4 VO 3 cells 1992

Hamster V79 fetal lung hprt mutation No data + Cohen et al. NH 4 VO 3 fibroblasts frequency 1992

Chinese hamster V79 cells hprt mutation No data + Klein et al. 1994 NH 4 VO 3 frequency

Chinese hamster V79 cells gpt mutation No data

C K lein et al. 1994 NH 4 VO 3 frequency

Chinese hamster V79 cells hprt mutation No data

C Zhong et al. V 2 O 5 frequency 1994

Syrian hamster ovary cells Micronuclei formation No data

C Gibson et al. V 2 O 5 1997

Chinese hamster V79 cells Micronuclei formation No data + Zhon g et al. V 2 O 5 1994

Chinese hamster ovary Sister chromatid + + Owusu

- Yaw et VOSO 4 cells exchange + + al. 1990 V 2 O 3

+ + NH 4 VO 3

Chinese hamster V79 cells Sister chromatid No data

C Zhong et al. V 2 O 5 exchange 1994

***DRAFT FOR PUBLIC COMMENT***68 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 4. Genotoxicity of Vanadium and Compounds **In Vitro**

Results

With Without Species (test system) End point activation activation Reference Form

Chinese hamster V79 cells Chromosomal No data + Zhong et al. V 2 O 5 aberr ations 1994

Chinese hamster ovary Chromosomal + + Owusu

- Yaw et VOSO 4 cells aberrations + + al. 1990 V 2 O 3

+ + NH 4 VO 3

Human tumor cells Colony formation No data + Hanauske et al. <0.1 pM V

1987

Human tumor cells Colony f ormation No data

C Hanauske et al. >0.1 pM V

1987

Human leukocytes DNA strand break No data + Birnboim 1988 Na 3 VO 4

Human fibroblasts DNA strand break No data + Ivancsits et al. V 2 O 5 2002

Human erythrocytes, DNA strand break No data

C

C Ivanc sits et al. V 2 O 5 lymphocytes 2002

Human nasal epithelial DNA strand break No data Kleinsasser et al. V 2 O 5 cells 2003

Human lymphocytes DNA strand break No data + Kleinsasser et al. V 2 O 5 2003

Human lymphocytes DNA strand break No data + Wozniak and VOSO 4 Blasiak 2004

Human cervical cancer DNA strand break No data + Wozniak and VOSO 4 cells (HeLa) Blasiak 2004

Human lymphocytes DNA strand break No data ± Rojas et al. 1996 V 2 O 5 Human leukocytes DNA strand break No data + Rojas et al. 1996 V 2 O 5 Human lymphocy tes Chromosomal No data + Migliore et al. NH 4 VO 3 , aberrations + 1993 NaVO 3 , + Na 3 VO 4 , + VOSO 4 Human lymphocytes Structural No data

C Roldán and V 2 O 5 chromosomal Altamirano 1990

aberrations

Human lymphocytes Numerical No data + Roldán and V 2 O 5 chromosomal Altamirano 1990

aberrations

Human lymphocytes Sister chromatid No data

C

C

C

C

C Roldán and V 2 O 5 exchange Altamirano 1990

Human lymphocytes Sister chromatid No data exchange Migliore et al. NH 4 VO 3 , 1993 NaVO 3 , Na 3 VO 4 , VOSO 4

***DRAFT FOR PUBLIC COMMENT***69 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 4. Genotoxicity of Vanadium and Compounds **In Vitro**

Results

With Without Species (test system) End point activation activation Reference Form

Human lymphocytes Micro nuclei formation No data + Migliore et al. Na 3 VO 4 , + 1995 VOSO 4

Human lymphocytes Micronuclei formation No data + Migliore et al. NH 4 VO 3 , + 1993 NaVO 3 , + Na 3 VO 4 , + VOSO 4

C = negative result; + = positive result; ± = weakly positive; DNA = deoxyribonucleic acid; hprt = hypoxanthine phosphoribosyltransferase; NaVO 3 = sodium metavanadate; Na 3 VO 4 = sodium orthovanadate; NH 4 VO 3 = ammonium
metavanadate; V 2 O 5 = vanadium pentoxide; V 2 O 3 = vanadium trioxide; VOSO 4 = vanadyl sulfate; VOCl 2 = vanadyl

dichloride

***DRAFT FOR PUBLIC COMMENT***70 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 5. Genotoxicity of Vanadium and Compounds **In Vivo**

Exposure Species (test system) End point Route Result Reference Form

Human leukocytes Sister chromatid Inhalation

C Ivancsits et al. V 2 O 5 exchange (occupational) 2002

Human l ymphocytes Sist er chromatid Inhalation

C Ivancsits et al. V 2 O 5 exchange (occupational) 2002

Human l ymphocytes Micronuclei formation Inhalation + Ehrlich et al. V 2 O 5 (occupational) 2008

Human leukocytes DNA strand breaks Inhalation

C Ivancsits et al. V 2 O 5 (occupational) 2002

Human l ymphocytes DNA strand breaks Inhalation

C Ivancsits et al. V 2 O 5 (occupational) 2002

Human l ymphocytes DNA strand breaks Inhalation

C Ehrlich et al. V 2 O 5 (occupational) 2008

CD

- 1 mouse bone marrow Micronuclei formation Drinking water

C Villa ni et al. 2007 VOSO 4

CD

- 1 mouse blood Micronuclei formation Drinking water ± Villani et al. 2007 VOSO 4 reticulocytes

CD

- 1 mouse bone marrow Micronuclei formation Gavage + Ciranni et al. VOSO 4

+ 1995 Na 3 VO 4

+ NH 4 VO 3

B6C3F1 mouse Micronucle i formation Inhalation

C NTP 2002 V 2 O 5 erythrocytes

CD

- 1 mouse bone marrow Chromosome Gavage + Ciranni et al. VOSO 4 aberrations + 1995 Na 3 VO 4

+ NH 4 VO 3

CD

- 1 mouse bone marrow DNA damage Drinking water

C Villani et al. 2007 VOSO 4

CD

- 1 mouse testis cells DNA damage D rinking water

C Villani et al. 2007 VOSO 4

C = negative result; + = positive result; ± = weakly positive; DNA = deoxyribonucleic acid; V 2 O 5 = vanadium pentoxide;

VOSO 4 = vanadyl sulfate; Na 3 VO 4 = sodium orthovanadate; NH 4 VO 3 = ammonium metavanadate

***DRAFT FOR PUBLIC COMMENT***71 VANADIUM

3. HEALTH EFFECTS

Villani et al. 2007), sodium orthovanadate (Ciranni et al. 1995), or ammonium metavanadate (Ciranni et

al. 1995); however no increases in micronuclei formation were observed in mouse erythrocytes following

intermediate duration inhalation exposure to vanadium pentoxide (NTP 2002). Increases in chromosomal

aberrations were also observed in mouse bone marrow following a single gavage exposure to vanadyl

sulfate, sodium orthovanadate, or ammonium metavanadate (Ciranni et al. 1995). As with the vanadium

worker s, DNA damage was not observed in mouse bone marrow or testis cells following intermediate

duration exposure to vanadyl sulfate in drinking water.

Conflicting results have been found for genotoxicity tests in prokaryote assays. Impaired recombination

rep air were found in Bacillus subtilis following exposure to vanadium pentoxide, vanadyl dichloride, or

ammonium metavanadate (Kada et al. 1980; Kanematsu et al. 1980). No alterations in gene mutation

frequency were found in Escherichia coli or Salmonella typhimurium for vanadium pentoxide

(Kanematsu et al. 1980; NTP 2002) or ammonium metavanadate (Kanematsu et al. 1980). In

nonmammalian eukaryotes, increases in reverse point mutations and mitotic gene conversion were found

in Saccharomyces cerevisiae (Bronz etti et al. 1990). In general, alterations in DNA repair, synthesis,

formation of cross links or strand breaks, and gene mutation frequency were observed in mammalian cells

for vanadium pentoxide, ammonium metavanadate, vanadyl sulfate, sodium orthovanadate (Birnboim

1988; Cohen et al. 1992; Foresti et al. 2001; Ivancsits et al. 2002; Klein et al. 1994; Kleinsasser et al.

2003; Rojas et al. 1996; Smith 1983; Wozniak and Blasiak 2004; Zhong et al. 1994). In vitro human data

suggest cell

- specific difference s in the ability of vanadium compounds to induce DNA strand breaks.

DNA strand breaks were found in fibroblasts and lymphocytes (Ivancsits et al. 2002; Kleinsasser et al.

2003; Wozniak and Blasiak 2004) but not in erythrocytes or nasal epithelial cells (Ivancsits et al. 2002;

Kleinsasser et al. 2003). Increases in the occurrence of chromosomal aberrations were observed in

Chinese hamster V79 cells exposed to vanadium pentoxide (Zhong et al. 1994), Chinese hamster ovary

cells exposed to vanadyl sulfate, va nadium trioxide, or ammonium metavanadate (Owusu- Yaw et al.

1990), and human lymphocytes exposed to ammonium metavanadate, sodium metavanadate, sodium

orthovanadate, vanadium pentoxide, or vanadyl sulfate (Migliore et al. 1993; Roldán and Altamirano

1990). An increase in sister chromatid exchange was found in Chinese hamster ovary cells exposed to

vanadyl sulfate, vanadium trioxide, or ammonium metavanadate (Owusu

- Yaw et al. 1990), but not in

Chinese hamster V79 cells exposed to vanadium pentoxide (Zhong et al. 1994) or human lymphocytes

exposed to vanadium pentoxide, ammonium metavanadate, sodium metavanadate, sodium orthovanadate,

or vanadyl sulfate (Migliore et al. 1993; Roldán and Altamirano 1990). Increases in micronuclei

formation were also found in Chinese hamster V79 cells exposed to vanadium pentoxide (Zhong et al.

1994) and in human lymphocytes exposed to sodium orthovanadate, vanadyl sulfate, ammonium

***DRAFT FOR PUBLIC COMMENT***72 VANADIUM

3. HEALTH EFFECTS

metavanadate, or sodium metavanadate (Migliore et al. 1993, 1995), but not in Syrian hamster ova ry cells

exposed to vanadium pentoxide (Gibson et al. 1997). Thus, the available data provide evidence that

vanadium compounds are genotoxic, both clastogenic effects and DNA damage have been observed in in

vitro and in vivo studies.

3.4 TOXICOKINETICS

3.4.1 Absorption

3.4.1.1 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 exposed to <1 ppm of vanadium (Gyl seth et

al. 1979; Kiviluoto et al. 1981b; Lewis 1959; NIOSH 1983). The vanadium concentration in serum was

also reported to be higher than the nonoccupationally exposed controls following exposure to vanadium

pentoxide dust (Kiviluoto et al. 1981b).

In direct evidence of absorption after inhalation 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/m 3 as vanadium pentoxide 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); in the 2- year studies, the increase in blood

vanadium levels were somewhat concentration

- related. Intratracheal studies suggest that soluble

vanadium compounds are readily absorbed through the lungs. Initial pulmonary clearance is rapid in rats.

There was rapid 100% absorption of vanadium in rats receiving radiolabeled vanadyl chloride (Conklin et

al. 1982). The greatest absorption of a radioactive dose, 48 V, was found to occur 5 minutes after

administration (Roshchin et al. 1980). Most of the vanadium, 80 and 85% of the tetravalent (V4+) and

pentavalent (V5+) forms of vanadium, respectively, cleared from the lungs 3 hours after intratracheal

exposure (Edel and Sabbioni 1988). After 24 hours, >50% of vanadyl oxychloride was cleared from the

lungs of male rats (Oberg et al. 1978), and at 3 days, 90% of vanadium pentoxide was eliminated from the

lungs of female rats (Conklin et al. 1982). In another study 50% was cleared in 18 minutes, and the rest

within a few days (Rhoads and Sanders 1985).

***DRAFT FOR PUBLIC COMMENT***73 VANADIUM

3. HEALTH EFFECTS

3.4.1.2 Oral Exposure

No studies were located regarding the rate and extent of absorption in humans after oral exposure to

vanadium.

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 rats at 15 minutes postexposure, and less tha n 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 rats (Conklin et al. 1982). In contrast, 16.5%

of vanadium was absorbed in rats exposed to sodium metavanadate in the diet for 7 days (Adachi et al.

2000b). Vanadium was reported in tissues and urine within hours after a single (Edel and Sabbioni 1988)

and repeated oral exposure in rats (Bogden et al. 1982; Parker and Sharma 1978), 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 hig her absorption of vanadium in these young animals due to a greater

nonselective permeability of the undeveloped gastro intestinal barrier.

3.4.1.3 Dermal Exposure

No specific studies were located regarding absorption in humans or animals after dermal e xposure to

vanadium, although absorption by this route is generally considered to be very low (WHO 1988).

Absorption through the skin is thought to be quite minimal due to its low lipid/water solubility.

3.4.2 Distribution

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 (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%). The heart, aorta, brain, kidney, muscle, ovary, and testes were found to

have no detectable vanadium concentrations. Bone was not tested.

3.4.2.1 Inhalation Exposure

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

were highest within a day after exposure followed by a rapid decline in levels upon cessation of exposure

***DRAFT FOR PUBLIC COMMENT***74 VANADIUM

3. HEALTH EFFECTS

(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, heart, and milk. Higher levels were detected in hair,

bone, and teeth (Byrne and Kosta 1978). Inhalation exposure and intratracheal administration studies in

laboratory animals have examined the distribution of vanadium. In rats chronically exposed to 0.56 or

1.1 mg vanadium/m 3 as vanadium pentoxide (6 hours/day, 5 days/week), vanadium lung burdens peaked

after 173 days of exposure and declined for the remainder of the study (day 542) ; lung burden 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/m 3 (NTP 2002). Similarly, lung burdens did not

reach steady state in mice expose d to 1.1 or 2.2 mg vanadium/m 3 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/m 3 during the firs t 26 days of

exposure. These data suggest that vanadium is cleared more rapidly from the lungs of mice compared to

rats.

Vanadium is rapidly distributed in tissues of rats after acute intratracheal administration. Within

15 minutes after exposure to 0 .36 mg/kg vanadium oxychloride, radiolabeled vanadium was detectable in

all organs except the brain. The highest concentration was in the lungs, followed by the heart and kidney.

The other organs had low levels. Maximum concentrations were reached in mo st tissues between 4 and

24 hours (Oberg et al. 1978). Vanadium is found to have a two- phase lung clearance after a single acute

exposure (Oberg et al. 1978; Rhoads and Sanders 1985). The initial phase is rapid with a large percentage

of the absorbed dos e 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 (Ro shchin et al. 1980). The pentavalent and

tetravalent forms of vanadium compounds were found to have similar distribution patterns (Edel and

Sabbioni 1988). Three hours after intratracheal exposure to the pentavalent or tetravalent form, 15 –17%

of the abs orbed dose was found in the lung, 2.8% in the liver, and 2% in the kidney (Edel and Sabbioni

1988). Although levels in the kidney are high after exposure, the bone had greater retention of vanadium.

Skeletal levels of vanadium peaked 1 –3 days postexposure (Conklin et al. 1982; Rhoads and Sanders

1985; Roshchin et al. 1980) and have been reported to persist after 63 days (Oberg et al. 1978).

3.4.2.2 Oral Exposure

No studies were located regarding distribution in humans after oral exposure to vanadiu m.

***DRAFT FOR PUBLIC COMMENT***75 VANADIUM

3. HEALTH EFFECTS

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

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

kidney, blood, testis, or spleen after 24 hours (Edel and Sabbioni 1988). Similar findings were noted by

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

by the kidney (Roshchin et al. 1980). Conklin et al. (1982) reported that after 3 days, 25% o f the

absorbed vanadium pentoxide was detectable in the skeleton and blood of female rats. In female rats

exposed to sodium metavanadate in the diet for 7 days, the highest concentrations of vanadium were

found in bone, followed by the spleen and kidney (Adachi et al. 2000b); the lowest concentration was

found in the brain. As summarized in Table 3-6, vanadium elimination half- times in various tissues were

3.57–15.95 or 3.18–13.50 days following a 1-week exposure to 8.2 mg vanadium/kg/day as sodium

metava nadate or vanadyl sulfate, respectively, administered in a liquid diet (Hamel and Duckworth 1995).

Although the elimination half

- times were longer in rats administered sodium metavanadate compared to

vanadyl sulfate, no statistical comparisons were made.

Oral exposure for an intermediate duration produced the highest accumulation of vanadium in the kidney.

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 decre ased rapidly after oral exposure was discontinued. Thus, retention of

vanadium was much longer in the bones (Edel et al. 1984; Parker and Sharma 1978).

In rats exposed to approximately 100 mg/L vanadium in drinking water as vanadyl sulfate or ammonium

me tavanadate for 12 weeks, significant increases, as compared to controls, in bone, kidney, and liver

vanadium levels were observed; no alterations in vanadium muscle levels were found (Thompson et al.

2002). The highest concentration of vanadium was found in the bone, followed by the kidney and liver.

Tissue vanadium concentrations were significantly higher in rats exposed to ammonium metavanadate as

compared to animals exposed to vanadyl sulfate.

***DRAFT FOR PUBLIC COMMENT***76 VANADIUM

3. HEALTH EFFECTS



### Table 3

- 6 . Vanadium Elimination Half

- Times in Various Organs in Rats Exposed

to 8. 2 mg Vanadium/kg/day for 1 Week

Half

- time (days)

Organ Sodium m etavanadate Vanadyl s ulfate

Liver 3.57 3.18

Kidney 3.92 3.27

Fat 4.06 5.04

Lung 5.52 4.45

Muscle 6.11 4.49

Heart 7.03 5.05

Spleen 9.13 5.15

Brain 11.17 9 .17

Testes 15.95 13.50

Source: Hamel and Duckworth 1995

***DRAFT FOR PUBLIC COMMENT***77 VANADIUM

3. HEALTH EFFECTS

3.4.2.3 Dermal Exposure

No studies were located regarding distribution in humans and animals after dermal exposure to vanadium.

3.4.2.4 Other Routes of Exposure

After intraperitoneal a dministration 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). This is similar to the distribution seen following

inhalation and oral exposure.

3.4.3 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 t issues

, it is retained mainly as the

vanadyl cation (cationic form of tetravalent vanadium). Depending on the availability of reducing

equivalents (such as reduced glutathione-SH, NADPH, NADH) and oxygen, vanadium may be reduced,

reoxidized, and/or underg o redox cycling (Byczkowski and Kulkarni 19 98).

3.4.4 Elimination and Excretion

3.4.4.1 Inhalation Exposure

Occupational studies showed that urinary vanadium levels significantly increased in exposed workers

(Gylseth et al. 1979; Kiviluoto et al . 1981b; Lewis 1959; NIOSH 1983; Zenz et al. 1962). Male and

female workers exposed to 0.1 –0.19 mg/m 3 vanadium in a manufacturing company, had signif icantly

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 stud ies (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

adm inistered 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 exposure to

vanadium pentoxide, 40% of the 48 V dose was excret ed, mostly in the urine while 30% remained in the

skeleton (5 days after exposure) (Conklin et al. 1982).

***DRAFT FOR PUBLIC COMMENT***78 VANADIUM

3. HEALTH EFFECTS

In female rats exposed to 0.56 or 1.1 mg vanadium/m 3 as vanadium pentoxide for 16 days (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/m 3 , lung clearance half

times were 2.55 and 2.40 days, respectively (NTP 2002). In contrast to the 16-day exposure data, the

lun g clearance half -times in female rats exposed to 0.28, 0.56, or 1.1 mg vanadium/m 3 for 2 years

(6 hours/day, 5 days/week) were 37.3, 58.6, and 61.4 days, respectively (NTP 2002). In mice, the halftimes were 6.26, 10.7, and 13.9 days at 0.56, 1.1, and 2.2 mg vanadium/m 3 exposure levels (NTP 2002).

These data suggest that vanadium is more rapidly cleared from the lungs following a short exposure

period compared to longer periods.

3.4.4.2 Oral Exposure

No studies were located regarding excretion in hum ans after oral exposure to vanadium.

Since vanadium is poorly absorbed in the gastrointestinal tract, a large percentage of vanadium is excreted

unabsorbed in the feces in rats following oral exposure. More than 80% of the administered dose of

ammonium m etavanadate or sodium metavanadate accumulated in the feces after 6 or 7 days (Adachi et

al. 2000b; Patterson et al. 1986). After 2 weeks of exposure, 59.1±18.8% of sodium metavanadate was

found in the feces (Bogden et al. 1982). However, the principal r oute of excretion of absorbed vanadium

is through the kidney in animals. Approximately 0.9% of ingested vanadium was excreted in the urine of

rats exposed to sodium metavanadate in the diet for 7 days (Adachi et al. 2000b). An elimination halftime of 11 .7 days was estimated in rats exposed to vanadyl sulfate in drinking water for 3 weeks

(Ramanadham et al. 1991).

3.4.4.3 Dermal Exposure

No studies were located regarding excretion in humans or animals after dermal exposure to vanadium.

3.4.5 Physi ologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and

disposition of chemical substances to quantitatively describe the relationships among critical biological

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various

***DRAFT FOR PUBLIC COMMENT***79 VANADIUM

3. HEALTH EFFECTS

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based

pharmacodynamic (PBPD) models use mathematical descriptions of the dose

- re sponse function to

quantitatively describe the relationship between target tissue dose and toxic end points.

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to

delineate and characterize the relationships betwee n: (1) the external/exposure concentration and target

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from

route to route, between species, and between subpopulations within a species. The biological basis of

PBPK models results in more meaningful extrapol ations than those generated with the more conventional

use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance

specific physicochemical parameters, and species

- specific physiological and biological parameters. The

numerical estimates of these model parameters are incorporated within a set of differe ntial and algebraic

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations

provides the predictions of tissue dose. Computers then provide process simulations based on these

solutions.

The structure a nd mathematical expressions used in PBPK models significantly simplify the true

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are

adequately described, however, this simplification is desirable because data are often unavailable for

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of

PBPK models in risk a ssessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in

***DRAFT FOR PUBLIC COMMENT***80 VANADIUM

3. HEALTH EFFECTS

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste

sites) based on the results of studies where doses were higher or were administered in differe nt species.

Figure 3- 3 shows a conceptualized representation of a PBPK model.

If PBPK models for vanadium exist, the overall results and individual models are discussed in this section

in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.

No PBPK models for vanadium were located.

3.5 MECHANISMS OF ACTION

3.5.1 Pharmacokinetic Mechanisms

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 ). Vanadium can reversibly bind to transferrin protein in

the blood and then be taken up into erythrocytes. Vanadate is considered more toxic than vanadyl

because vanadate is reactive with a number of enzymes a nd is a potent inhibitor of the Na+K+- ATPase of

plasma membranes (Harris et al. 1984; Patterson et al. 1986). There is a slower uptake of vanadyl into

erythrocytes compared to the vanadate form. Five minutes after an intravenous administration of

radiolabeled vanadate or vanadyl in dogs, 30% of the vanadate dose and 12% of the vanadyl dose is found

in erythrocytes (Harris et al. 1984). It is suggested that this difference in uptake is due to the time

required for the vanadyl form to be oxidized to vanada te. When V +4 or V +5 is administered intravenously,

a balance is reached in which vanadium moves in and out of the cells at a rate that is comparable to the

rate of vanadium removal from the blood (Harris et al. 1984). Initially, vanadyl leaves the blood more

rapidly than vanadate, possibly due to the slower uptake of vanadyl into cells (Harris et al. 1984). Five

hours after administration, blood clearance is essentially identical for the two forms. A decrease in

glutathione

- SH , NADPH, and NADH occurs wi thin an hour after intraperitoneal injection of sodium

vanadate in mice (Bruech et al. 1984). It is believed that the redox cycling of vanadium V +5 /V +4

, depending on the local availability of oxygen in tissues, depletes reducing equivalents th at are necessary

for activity of cytochrome P -450.

Vanadium in the plasma can exist in a bound or unbound form (Bruech et al. 1984). Vanadium as

vanadyl (Patterson et al. 1986) or vanadate (Harris and Carrano 1984) reversibly binds to human serum

transferrin at tw o metal -binding sites on the protein. With intravenous administration of vanadate or

vanadyl, there is a short lag time for vanadate binding to transferrin, but at 30 hours, the association is

***DRAFT FOR PUBLIC COMMENT***GI

Tract 81 VANADIUM

3. HEALTH EFFECTS



### Figure 3 -3

. Conceptual Representation of a Physiologically B ased Pharmacokinetic (PBPK) Model for a

Hypothetical Chemical Substance

Inhaled chemical Exhaled chemical

Ingestion Lungs

Liver

V

max

K

m A

V R

E Fat T

N E

O R

U Slowly I

S perfused A

tissues L

Richly B perfused L B tissues O L Feces O O

D O Kidney D

Urine

Skin

Chemicals contacting skin

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation.

Source: adapted from Krishnan and Andersen 1994

***DRAFT FOR PUBLIC COMMENT***82 VANADIUM

3. HEALTH EFFECTS

identical for the two vanadium forms (Harris et al. 1984). The vanadium- transfer rin binding is most

likely to occur with the vanadyl form as this complex is more stable (Harris et al. 1984). The transferrin

bound vanadium is cleared from the blood at a slower rate than unbound vanadium in rats, which explains

a biphasic clearance pattern (Sabbioni and Marafante 1978). The metabolic pathway appears to be

independent of route of exposure (Edel and Sabbioni 1988).

3.5.2 Mechanisms of Toxicity

In vitro studies (as reviewed by Barceloux 1999; Etcheverry and Cortizo 1998; Harland and Harden

Williams 1994; Léonard and Gerber 1994; Mukherjee et al. 2004) have shown that vanadium acts as a

phosphate analog and, as such, interferes with various ATPases, phosphatases, and phosph ate

- transfer

enzymes. Vanadium has been shown to inhibit Na+K+ ATPase, Ca2+ATPase, H+K+ATPase,

K+ATPase, Ca+Mg+ATPase, dynein ATPase, actomyosin ATPase, acid and alkaline phosphatases,

glucose-6-phosphatase, ribonuclease, phosphodiesterase, and phosphotryosyl- phosphatase. It has also

been shown to stimulate tyrosine kinase phosph or ylase, NADPH oxidase, and adenylate cyclase.

Additionally, vanadium has been shown to have insulin- mimetic properties, particularly the ability to

stimulate glucose uptake and oxidation and glycogen synthesis, and the ability to induce cell proliferation.

The effect of vanadium on various enzymes may be responsible for the diverse effects observed in

animals exposed to vanadium. However, little information is available regarding the mechanism of

vanadium toxicity in vivo

.

3.5.3 Animal -to- Human Extrapolations

There are little data available to evaluate potential toxicokinetic differences between humans and

laboratory animals. Similar effects have been reported in humans and animals following inhalation or

oral exposure to vanadium; 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.

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals

with this type of activity are most commonly referred to as endocrine disru ptors . However, appropriate

terminology to describe such effects remains controversial. The terminology endocrine disruptors

, initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to

***DRAFT FOR PUBLIC COMMENT***83 VANADIUM

3. HEALTH EFFECTS

develop a screening program for “...certain substances [which] may have an effect produced by a

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a

panel called the Endocrine Disruptors Screening and Testing Advisory Committee ( EDSTAC), and in

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine

disruptors . In 1999, the National Academy of Sciences released a report that referred to these same types

of chemicals as hormonally active a gents . The terminology endocrine modulators has also been used to

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to

the health of humans, aquatic animals, and wildlife. However, others think that endocrine- active

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are

similar in structure and action to endogenous estrogen. Although the public hea lth significance and

descriptive terminology of substances capable of affecting the endocrine system remains controversial,

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or

elimination of natural hor mones in the body responsible for maintaining homeostasis, reproduction,

development, and/or behavior (EPA 1997b). Stated differently, such compounds may cause toxicities that

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering,

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994;

Giwercman et al. 19 93; Hoel et al. 1992).

No in vivo or in vitro studies were located regarding endocrine disruption in humans and/or animals after

exposure to vanadium.

3.7 CHILDREN’S SUSCEPTIBILITY

This section discusses potential health effects from exposures during the period from conception to

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation.

Relevant animal and in vitro models are also discussed.

***DRAFT FOR PUBLIC COMMENT***84 VANADIUM

3. HEALTH EFFECTS

Children are not small adults. They differ from adults in their exposures and may differ in their

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children.

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less

susceptible than adults to health effects, and the relationship may change with developmental age

(Guzelian et al . 1992; NRC 1993). Vulnerability often depends on developmental stage. There are

critical periods of structural and functional development during both prenatal and postnatal life, and a

particular structure or function will be most sensitive to disruptio n during its critical period(s). Damage

may not be evident until a later stage of development. There are often differences in pharmacokinetics

and metabolism between children and adults. For example, absorption may be different in neonates

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example,

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek

1966; Widdowson and Dickerson 1964). The infant also has an immature blood- brain barrier (Adinolfi

1985; Johanson 1980) and probably an immature blood- testis barrier (Setchell and Waites 1975). Many

xenobiotic metabolizing enzymes have distinctive developme ntal patterns. At various stages of growth

and development, levels of particular enzymes may be higher or lower than those of adults, and

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and

Kearns 1997; NR C 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of

the parent compound to its toxic form or in detoxification. There may also be differences in excretion,

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948).

Children and adults may differ in their capacity to repair damage from chemical insults. Children also

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly

relevant to cancer.

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others

may decrease susceptibility to the same chemical. For example, although infants breathe more air per

kilogram of body weight than adults breathe, this difference might be somewhat counterb alanced by their

***DRAFT FOR PUBLIC COMMENT***85 VANADIUM

3. HEALTH EFFECTS

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar

absorption (NRC 1993).

There are limited data on the toxicity of vanadium in children. One study examined the influence of age

on the r enal toxicity of vanadium in male rats administered 10 mg/kg/day sodium orthovanadate via

intraperitoneal injection for 8 days. Similar morphological effects were observed in the kidneys of

22-day-old rats and 62-day- old rats; however, the effects were more severe in the older rats (de la Torre et

al. 1999). The difference in lesion severity is likely due to the significantly lower renal vanadium

concentration in the young rats.

Edel et al. (1984) examined age-related changes in the distribution of vanadium in rats exposed to

background levels of vanadium. At 21 days of age, the highest concentrations of vanadium (ng

vanadium/g wet weight) were found in the kidney, heart, lung, brain, and liver. By 115 days of age, the

highest concentration was in the femur; levels in the heart, lung, brain, spleen, and muscle were

approximately 3–4 times lower. The concentrations of vanadium in the kidney, liver, and lungs

significantly decreased with increasing age of the rat. The investigators suggested several mechanisms

th at may be responsible for the age

- related changes in vanadium tissue concentration , including higher

gastrointestinal absorption of vanadium in young rats, which may be due to increased bioavailability of

vanadium in breast milk compared to the di et , or a higher vanadium retention capacity in undeveloped

tissue due to a greater affinity or lower elimination rate.

As discussed in Section 3.2, a number of developmental effects including decreases in growth, increases

in malformation and anomalies, and death have been observed in developmental toxicity studies

(Domingo et al. 1986; Elfant and Keen 1987; Morgan and El-Tawil 2003; Paternain et al. 1990); however

most of these effects occurred at doses associated with significant maternal toxicity.

3. 8 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC

1989).

The N ational Report on Human Exposure to Environmental Chemicals provides an ongoing assessment

of the exposure of the U.S. population to environmental chemicals using biomonitoring. This report is

***DRAFT FOR PUBLIC COMMENT***86 VANADIUM

3. HEALTH EFFECTS

available at http://www.cdc.gov/exposurereport/. The biomonit oring data for vanadium from this report

is discussed in Section 6.5. A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the

product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is

measure d within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure

are generally the substance itself, substance

- specific metabolites in readily obtainable body fluid(s), or

excreta. However, several factors can confound the use a nd interpretation of biomarkers of exposure.

The body burden of a substance may be the result of exposures from more than one source. The

substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels

of phenol ca n result from exposure to several different aromatic compounds). Depending on the

properties of the substance (e.g., biologic half -life) and environmental conditions (e.g., duration and route

of exposure), the substance and all of its metabolites may have left the body by the time samples can be

taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly

found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium).

Biomar kers of exposure to vanadium are discussed in Section 3.8.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an

organism that, depending on magnitude, can be recognized as an established or potential health

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung

capacity. Note that these markers are not often substance specific. They also may not be directly

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused

by vanadium are discussed in Section 3.8.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are

discussed in Se ction 3.10, Populations That Are Unusually Susceptible.

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Vanadium

Several biomarkers of exposure have been identified for vanadium but none of them can be used to

quantitatively determine exposu re levels. Elevated levels of vanadium have been found in the serum

***DRAFT FOR PUBLIC COMMENT***87 VANADIUM

3. HEALTH EFFECTS

(Gylseth et al. 1979; Kiviluoto et al. 1981b ) and urine ( Gylseth et al. 1979; Kiviluoto et al. 1981b; Lewis

1959; NIOSH 1983; Zenz et al. 1962 ) of exposed workers. However, relationships between exposure

levels and serum or urine vanadium levels have not been established. Some vanadium workers develop a

characteristic green tongue, as a result of direct accumulation of the vanadium dusts on the tongue (Lewis

1959). One report from the 1 950s states that vanadium exposure was associated with decreased cystine

content in the fingernails of vanadium workers (Mountain et al. 1955). However, alterations in cystine

levels can also be associated with dietary changes and with other disease states, so this is not specific for

vanadium exposure. No other commonly measured cellular changes have been identified with vanadium

exposure.

3.8.2 Biomarkers Used to Characterize Effects Caused by Vanadium

The primary effects of inhalation exposure to v anadium dusts are coughing, wheezing, and other

respiratory difficulties. These effects, however, are not specific to vanadium and can be found following

inhalation of many types of dusts.

3.9 INTERACTIONS WITH OTHER CHEMICALS

Vanadium in the drinking water of mice had no influence on tumor induction by the known carcinogen

1,2-dimethylhydrazine given by subcutaneous injection (Kingsnorth et al. 1986), but dietary vanadium

did decrease mammary tumors in mice caused by 1

- methyl -1-nitrosourea administ ered concurrently

(Thompson et al. 1984). The latter effect may have been due to interaction with DNA.

The combination of manganese and vanadium or of nickel and vanadium administered to pregnant mice

caused some alterations in behavioral development of the pups as compared to either element

administered alone (Hoshishima et al. 1983). Oral administration of vanadium in rats interfered with

copper metabolism, probably by inhibiting the intestinal absorption of copper (Witkowska et al. 1988).

3.10 POPU LATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to vanadium than will most persons

exposed to the same level of vanadium in the environment. Reasons may include genetic makeup, age,

health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These

parameters result in reduced detoxification or excretion of vanadium, or compromised function of organs

***DRAFT FOR PUBLIC COMMENT***88 VANADIUM

3. HEALTH EFFECTS

affected by vanadium. Populations who are at greater risk due to their unusually high exposure to

vanadium are discussed in Section 6.7, Populations with Potentially High Exposures.

No unusually susceptible populations have been identified, but persons with pre-existing respiratory

disorders such as asthma or ch ronic obstructive pulmonary disease (COPD) may be expected to have

increased adverse effects from breathing vanadium dusts. Due to the insulin

- mimetic effects of

vanadium, individuals with hypoglycemia may be unusually susceptible to exposure to high leve ls of

vanadium.

3.11 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of

exposure to vanadium. However, because some of the treatments discussed may be experime ntal and

unproven, this section should not be used as a guide for treatment of exposures to vanadium. When

specific exposures have occurred, poison control centers and medical toxicologists should be consulted

for medical advice. The following texts provide specific information about treatment following exposures

to vanadium:

Haddad LM, Winchester JF. 1990. Clinical management of poisoning and drug overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Company, 1033.

Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. 2nd ed. Beltsville, MD: Bradford Communications Corporation, 406-407.

3.11.1 Reducing Peak Absorption Following Exposure

There is no known treatment to decrease absorption after inhaling vanadium and/or its compounds.

Following oral exposure, dilution with water or milk is one way to decrease overall absorption (Stutz and

Janusz 1988). To decrease gastrointestinal absorption, especially for organic vanadium compounds, it has

been suggested that activated charcoal be ingested. If vanadium gets onto the skin, washing the

contaminated area with soapy water has been advised. For ocular exposure, it is suggested that the eyes

be flushed with large amounts of saline or water (Stutz and Janusz 1988).

3.11.2 Reducing Body Burden

Several studies have evaluated the effectiveness of chelating agents in reducing vanadium body burden.

Significant increases in urinary excretion of vanadium were observed in r odents treated with ascorbic acid

***DRAFT FOR PUBLIC COMMENT***89 VANADIUM

3. HEALTH EFFECTS

(Domi ngo et al. 1990), tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) (Domingo et al. 1990;

Gomez et al. 1991), deferoxamine mesylate (Gomez et al. 1988, 1991), or 2-mercaptosuccinic (Domingo

et al. 1990) following intramuscular injection of vanadyl sulfate (Domingo et al. 1990) or 6- week oral

exposure to sodium metavanadate or vanadyl sulfate (Gomez et al. 1991). Administration of EDTA,

2-mercaptosuccinic or tiron also significantly reduced kidney vanadium levels (Domingo et al. 1990) and

tiron reduced spleen and kidney vanadium levels (Gomez et al. 1991). Administration of calcium

disodium EDTA resulted in increases in urinary excretion of vanadium in calves exposed to high levels of

dietary vanadium (Gummow et al. 2006); however, no difference in vanadium excretion was observed

after vanadium exposure was terminated. Other studies have examined the potential of chelating agents

to reduce toxicity. Humans or animals with vanadium poisoning have not been helped by the chelating

agent dimercaprol (BAL), which is often effective in lessening the toxicity of other metals (Lusky et al.

1949). Intraperitoneal injections of ascorbic acid and of ethylene diamine tetraacetate (EDTA) reduced

vanadium-induced morbidity in mice and rats (Jones and Basinger 1983; Mitchell and Floyd 1954).

Administration of tiron 0, 24, 48, or 72 hours after pregnant mice received a 25 mg/kg sodium

metavanadate intraperitoneal injection on gestation day 12 resulted in significant reductions in vanadiuminduced abortions, early deliveries, fetal deaths, and incidence of reduced ossification (Domingo et al.

1993a). Administration of tiron after a 6- week exposure to sodium metavanadate reverted the vanadium

induced impairment in performance on neurobehavioral tests (Sanchez et al. 1999). Co -exposure to

calcium disodium EDTA did not significantly alter the toxicity of ingested vanadium in calves (Gummow

et al. 2006).

3.11.3 Interfering with the Mechanism of Action for Toxic Effects

There are limited data on treatments which interf ere with the mechanism of action for vanadium toxicity.

Moderate to severe morphological alterations (average severity score of 3.0) were observed in the kidneys

25 days after rats were administered 1 mg vanadium/kg/day as ammonium metavanadate via

subcut aneous injection (Al -Bayati et al. 2002). Administration of the antifibrotic agent, pirfenidone, for

41 days after exposure termination resulted in a decrease in the severity of the kidney lesions; the lesions

were scored as very mild with a severity scor e of 1.42. Although the mechanism associated with the

reduction in toxicity was not determined, it is possible that the pirfenidone-induced reduction in collagendeposition in the kidney may have contributed to the diminished toxicity. Chandra et al. (2007a)

demonstrated a reduction in testes toxicity in rats administered 0.4 mg vanadium/kg/day as sodium

metavanadate via intraperitoneal injection for 26 days and 50 or 100 mg/kg vitamin E acetate

simultaneously in the diet compared to rats administered vanadium only. The likely mechanism is that

***DRAFT FOR PUBLIC COMMENT***90 VANADIUM

3. HEALTH EFFECTS

vitamin E interrupts the chain reactions of lipid peroxidation and scavenges ROS generated during the

univalent reduction of molecular oxygen and normal activity of oxidative enzymes; thus its prevents the

detrimen tal effect of vanadium on testis by inhibiting the oxidative stress.

3.12 ADEQUACY OF THE DATABASE

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of vanadium is available. Where adequate information is not

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the

init iation of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of vanadium.

The following categories of possible data needs have been identified by a joint team of scientis ts from

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance- specific research agenda will be proposed.

3.12.1 Existing Information on Health Effects of Vanadium

The existing data on health effects of in halation, oral, and dermal exposure of humans and animals to

vanadium are summarized in Figure 3 -4. The purpose of this figure is to illustrate the existing

information concerning the health effects of vanadium. Each dot in the figure indicates that one or more

studies provide information associated with that particular effect. The dot does not necessarily imply

anything about the quality of the study or studies, nor should missing information in this figure be

interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying

Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and

Disease Registry 1989), is substance

- specific information necessary to conduct comprehensive public

health assessments. Generally, ATSDR defines a data gap more broadly as any substance

- specific

information missing from the scientific literature.

Data are available from humans regarding acute, intermediate, and chronic inhalation exposure to

vanadium pentoxide and on immunologic and neurologic effects, primarily from case studies of factory

***DRAFT FOR PUBLIC COMMENT***VANADIUM 91

3. HEALTH EFFECTS

***DRAFT FOR PUBLIC COMMENT*** 

### Figure 3 -4 . Existing Information on Health Effects of Vanadium and Compounds

Inhalation

Oral

Dermal

Human

Inhalation

Oral

Dermal

Animal

Existing Studies Systemic

o r et

i c hp

y m L a l e c / e nt t gi i a o c t i v e d c l g i c o h e l o u n i n d p m x i c e t m u r o e l o r o o t o re a ut e r u c e t o c r m p e e ev n D A I n I m R G e n h D C a C N

Systemic c

r et

i oh

e Ly m

p

/ e t al

i c

o uc t i v n g i c m e di

at o c l g e o p x i c d o t h a ni n l t e r m r o u ur o pr o e l o m ot c e D

e r A

c u t e N e na I R e n C

h m ev n G e I D C92 VANADIUM

3. HEALTH EFFECTS

workers. Data regarding acute effects are available from volunteers who ingested am monium vanadyl

tartrate in capsules for intermediate periods. No human dermal data were located.

Data are available regarding the effects of inhalation of vanadium pentoxide in rats, mice, and monkeys

following acute, intermediate, and chronic exposures. Data are available in humans orally exposed to

vanadyl sulfate or ammonium metavanadate. Data are available following acute, intermediate, and

chronic oral exposures in animals, including information on death (from ammonium metavanadate,

sodium metavana date, or vanadyl sulfate), systemic toxicity (from vanadyl sulfate, sodium metavanadate,

sodium orthovanadate, or ammonium metavanadate), immunological (from sodium orthovanadate),

neurological (from vanadium pentoxide), developmental (from vandyl sulfate, sodium orthovanadate,

ammonium metavanadate, or sodium metavanadate), and reproductive effects (from sodium

metavanadate, ammonium metavanadate, or vanadyl sulfate). No animal dermal data were located.

3.12.2 Identification of Data Needs

Acute

- Durat ion Exposure. Information on the acute toxicity of inhaled vanadium in humans is

limited to the finding of symptoms of respiratory irritation (persistent coughing) in a small number of

subjects exposed to vanadium pentoxide dust for 8 hours (Zenz and Berg 1967). Several animal studies

confirm that the respiratory tract is the most sensitive target of vanadium toxicity (Knecht et al. 1985,

1992; NTP 2002). These studies only examined the respiratory tract; however, longer duration studies

have confirmed the respiratory tract as the most sensitive target following inhalation exposure. At lower

concentrations, the observed effects included lung inflammation and alveolar and bronchiolar epithelial

hyperplasia in rats and mice exposed to vanadium pentoxide for 6 or 13 days (NTP 2002); the severity of

the lung effects increased with increasing vanadium concentrations. Impaired lung function was reported

in monkeys exposed to fairly low concentrations of vanadium pentoxide for 6 hours (Knecht et al. 1985,

199 2). The animal data were sufficient to derive an acute -duration inhalation MRL for vanadium based

on lung inflammation in rats (NTP 2002).

There are limited data on human toxicity following ingestion of vanadium; gastrointestinal effects

(diarrhea, cra mps, nausea, vomiting) have been reported in patients given vanadium supplement as part of

a diabetes treatment plan (Boden et al. 1996; Cusi et al. 2001; Goldfine et al. 1995). However, these

studies are limited by the small number of subjects and the la ck of control groups. A small number of

studies in laboratory animals have examined the acute toxicity of vanadium following oral exposure. At

the lowest doses tested, marked developmental toxicity (decreases in fetal growth, increases in resorptions

***DRAFT FOR PUBLIC COMMENT***93 VANADIUM

3. HEALTH EFFECTS

and gross, visceral, and skeletal malformations and anomalies) was observed in rat and mouse offspring

(Paternain et al. 1987, 1990; Sanchez et al. 1991). In adult rats, hematological effects (including

increases in reticulocyte levels and polychromatophilic erythroblasts in bone marrow) were observed at

higher doses than the developmental effects (Zaporowska and Wasilewski 1989). The database was

considered inadequate for derivation of an acute-duration oral MRL due to the limitations in the human

studies a nd the serious effects observed at the lowest animal dose tested. At the lowest adverse effect

level, a 46% decrease in weight gain (considered a serious health effect) was observed in the rat dams

(Paternain et al. 1990); it is ATSDR policy to not use se rious LOAELs as the basis of an MRL.

Additional studies which examine a variety of end points are needed to identify the most sensitive effect

following acute oral exposure. These additional studies might provide a suitable basis for an acute

duration ora l MRL.

No dermal exposure studies were identified in humans or animals. Studies are needed to establish the

potential toxicity of vanadium compounds applied to the skin.

Intermediate

- Duration Exposure. No human studies examined the toxicity of vanadium following

intermediate -duration inhalation exposure. Animal data come from 16-day and 13- week exposure studies

in rats and mice (NTP 2002). These studies clearly identify the respiratory tract as the most sensitive

target of toxicity. At low concentr ations of vanadium pentoxide, alveolar and bronchiolar epithelial

hyperplasia were observed in both species. At higher concentrations, nasal effects were also observed.

Although the NTP (2002) study is a high quality study which identified NOAEL and LOAE L values for a

sensitive end point, an intermediate -duration inhalation MRL was not derived because the NOAEL value

was the same as the LOAEL for lung inflammation in rats exposed to vanadium pentoxide for 13 days

(NTP 2002). An explanation for the incons istent findings is not apparent from the available data. An

additional study designed to examine respiratory effects after various exposure durations may provide

insight into the inconsistent findings of the NTP study and may be useful for derivation of a n MRL.

Data on the toxicity of vanadium following intermediate-duration oral exposure come from two human

studies and a number of animal studies. The human studies examined a number of potential end points in

subjects exposed to relatively low doses of v anadium for 6– 12 weeks; no adverse effects were observed

(Dimond et al. 1963; Fawcett et al. 1997). Animal studies have identified several sensitive effects

including hematological alterations (decreased erythrocyte levels and increased reticulocyte levels)
(Ścibior 2005; Ścibior et al. 2006; Zaporowska and Wasilewski 1990, 1991, 1992a, 1992b; Zaporowska

et al. 1993), increased blood pressure (Boscolo et al. 1994; Carmagnani et al. 1991, 1992), alterations in

***DRAFT FOR PUBLIC COMMENT***94 VANADIUM

3. HEALTH EFFECTS

neurobehavioral performance tests (Sanchez et a l. 1998), and developmental toxicity (Domingo et al.

1986; Elfant and Keen 1987; Morgan and El- Tawil 2003; Poggioli et al. 2001). However, the findings

are inconsistent and a cause of the conflicting results has not been identified. Additional animal stu dies

examining hematological, blood pressure, and neurological end points are needed to support the findings

of the animal studies. An intermediate -duration oral MRL based on the NOAEL identified in one of the

human studies (Fawcett et al. 1997) was derived.

No dermal exposure studies were identified in humans or animals. Studies utilizing several vanadium

compounds would be useful for assessing the potential dermal toxicity of vanadium.

Chronic

- Duration Exposure and Cancer. Sufficient information is available in occupationally

exposed humans to identify the respiratory system as a target organ following chronic inhalation exposure

(Lewis 1959; NIOSH 1983; Sjöberg 1956; Vintinner et al. 1955; Wyers 1946). Two- year rat and mouse

studies (NTP 2002) con firm the identification of the respiratory tract as the most sensitive target of

inhaled vanadium pentoxide. At the lowest concentrations tested, histological alterations in the lungs

(alveolar and bronchiolar epithelial hyperplasia), larynx (degeneration and hyperplasia of epiglottis

epithelium), and nasal cavity (goblet cell hyperplasia) were observed. The NTP (2002) rat study was used

as the basis of a chronic

- duration inhalation MRL for vanadium.

No studies examining the chronic oral toxicity of vana dium in humans were identified. Several studies

have examined chronic oral toxicity in rats and mice (Dai and McNeill 1994; Dai et al. 1994a, 1994b;

Schroeder and Balassa 1967; Schroeder et al. 1970); however, the doses tested did not result in adverse

effects, with the exception of a decrease in body weight gain, and the most sensitive targets of vanadium

toxicity following chronic exposure have not been identified. Additional studies examining a variety of

end points, including potential hematological a nd cardiovascular effects (sensitive targets following

intermediate -duration exposure), are needed to identify sensitive targets and establish dose- response

relationships.

Data are not available to determine target organs in humans from chronic dermal e xposure. Dermal

exposure studies which could be used to identify targets of toxicity and dose- response relationships are

needed.

No studies were located regarding the carcinogenicity in humans after inhalation, oral, or dermal exposure

to vanadium. Si gnificant increases in the incidence of lung tumors (alveolar/bronchiolar adenoma and/or

***DRAFT FOR PUBLIC COMMENT***95 VANADIUM

3. HEALTH EFFECTS

carcinoma) were observed in mice exposed to airborne vanadium pentoxide for 2 years (NTP 2002).

Suggestive evidence of lung carcinogenicity was also observed in male rats chronically exposed to

vanadium pentoxide (NTP 2002). Although several oral studies did not find increases in tumor frequency

in rats or mice exposed to vanadyl sulfate in drinking water (Schroeder and Balassa 1967; Schroeder and

Mitchener 1975; Schr oeder et al. 1970), these studies were considered inadequate for carcinogenicity

assessment due to the small number of animals tested, low doses (maximum tolerated dose was not

achieved), incomplete histological examination, and the use of one exposure dose per study. No studies

examined the potential carcinogenicity of vanadium following dermal exposure. Additional studies are

needed to evaluate the potential carcinogenicity of vanadium following oral and dermal exposure.

Genotoxicity. In vivo genoto xicity assays have been conducted in vanadium pentoxide workers

(Ehrlich et al. 2008; Ivancsits et al. 2002), in mice exposed to airborne vanadium pentoxide (NTP 2002),

in mice exposed to vanadyl sulfate in drinking water (Villani et al. 2007), and in mice administered a

gavage dose of vanadyl sulfate, ammonium metavanadate, or sodium orthovanadate (Ciranni et al. 1995).

Most of the in vitro genotoxicity assays have been conducted in mammalian systems, although there are

also mutagenicity assays in culture d bacteria (Kada et al. 1980; Kanematsu et al. 1980; NTP 2002) and

yeast (Bronzetti et al. 1990; Sora et al. 1986). In mammalian systems, mutagenicity (Cohen et al. 1992),

DNA damage (Birnboim 1988; Foresti et al. 2001; Ivancsits et al. 2002; Kleinsasser et al. 2003; Rojas et

al. 1996; Smith 1983; Wozniak and Blasiak 2004), and clastogenicity (Gibson et al. 1997; Migliore et al.

1993, 1995; Owusu-Yaw et al. 1990; Roldán and Altamirano 1990; Zhong et al. 1994) have been

observed. In general these studies p rovide evidence that vanadium compounds damage DNA and induce

clastogenic alterations. However, there are a number of inconsistencies in the results and additional

studies are needed.

Reproductive Toxicity. No studies were located regarding the repr oductive effects in humans after

inhalation, oral, or dermal exposure to vanadium. Following inhalation exposure, alterations in estrous

cycle were observed in female rats exposed to vanadium pentoxide for 3 months (NTP 2002); no

alterations in sperm characteristics were observed. Studies examining reproductive function are needed to

evaluate whether the alterations observed in female rats would result in impaired fertility. Decreases in

male and/or female fertility were observed in rats and mice orally exposed to vanadium (Ganguli et al.

1994b; Jain et al. 2007; Llobet et al. 1993; Morgan and El-Tawil 2003). Dermal exposure studies are

needed to evaluate whether the reproductive system is also a target of toxicity for this route.

***DRAFT FOR PUBLIC COMMENT***96 VANADIUM

3. HEALTH EFFECTS

Developmental Toxicity

. The potential developmental toxicity of vanadium has not been assessed in

humans. Oral exposure studies in animals provide evidence that developmental toxicity is a sensitive end

point. The observed effects include decreases in fetal/pup growth, incr eased mortality, and increases in

gross, skeletal, and visceral malformations and anomalies (Domingo et al. 1986; Elfant and Keen 1987;

Morgan and El-Tawil 2003; Paternain et al. 1987, 1990; Poggioli et al. 2001). Most of these effects

occurred at doses a ssociated with decreases in maternal food intake and body weight. Additional studies

utilizing doses not associated with maternal toxicity would be useful in determining whether the observed

effects are secondary to maternal toxicity or whether the developing organism is a primary target. No

studies were located regarding the developmental effects in animals after inhalation or dermal exposure to

vanadium. Studies are needed to determine whether developmental toxicity would also be a sensitive

target fol lowing inhalation or dermal exposure.

Immunotoxicity. Data regarding the immunotoxicity of vanadium in humans are limited to a study of

vanadium workers which did not find signs of allergic reactions on the skin or in the respiratory tract

(Sjöberg 195 0). No alterations in immune response to bacteria and/or viruses were observed in mice

exposed to airborne vanadium pentoxide for 16 days (NTP 2002) ; an altered response was observed in

rats . An altered response to sheep red blood cells in mice exposed to sodium orthovanadate in drinking

water for 6 weeks (Sharma et al. 1981) and decreases in B

- cell, IgG, and IgM levels in rats exposed to

sodium metavanadate in the diet for 10 weeks (Adachi et al. 2000a) were observed. No dermal exposure

studies examinin g immunological end points were identified. Although the animal data provide some

suggestive evidence of immunotoxicity, additional inhalation and oral exposure studies testing a full

immunology battery are needed to establish the potential of vanadium to induce immunotoxicity.

Neurotoxicity. Some workers exposed to vanadium dust complained of dizziness, depression,

headache, or tremors of the fingers and arms (Levy et al. 1984; Vintinner et al. 1955); however, these

effects may not have been specifica lly due to vanadium exposure. Neurotoxicity was not evaluated in

humans following oral or dermal exposure. In animals, alterations in performance on neurobehavioral

tests were observed in rats orally exposed to sodium metavanadate (Sanchez et al. 1998 , 1999). No

histological alterations in the nervous system were observed in rats or mice exposed to airborne vanadium

pentoxide (NTP 2002). Neurotoxicity potential was not assessed in animals following dermal exposure.

Additional studies performing a compl ete neurological battery of tests are needed to fully evaluate the

potential of vanadium to induce neurotoxicity, particularly since the Sanchez et al. (1998) study provides

suggestive evidence that this may be a sensitive target following oral exposure.

***DRAFT FOR PUBLIC COMMENT***97 VANADIUM

3. HEALTH EFFECTS

Epidemiological and Human Dosimetry Studies. Studies of health effects on people who have

inhaled vanadium in the workplace clearly show that the target organ is the respiratory system (Domingo

et al. 1985; Levy et al. 1984; Lewis 1959; Musk and Tees 1982; NIOSH 1983; Sjöberg 1950, 1956;

Thomas and Stiebris 1956; Vintinner et al. 1955; Wyers 1946; Zenz and Berg 1967; Zenz et al. 1962).

The dose-response relationship is not known, because exposure levels are not well quantified. Further

information on e xposure levels associated with respiratory effects would be useful. However, people

living near hazardous waste sites are unlikely to come in contact with amounts of vanadium dusts large

enough to cause adverse health effects. Further epidemiological stu dies may be useful in revealing

adverse health effects in people living near boiler ash dumps. Additional information on potentially

susceptible populations, such as those people with asthma or other respiratory problems, would be useful.

There are limit ed data regarding the oral toxicity of vanadium in humans. Studies in diabetics have

shown that bolus administration can result in symptoms of gastrointestinal irritation (Boden et al. 1996;

Cusi et al. 2001; Goldfine et al. 1995). Two studies in healthy individuals (Dimond et al. 1963; Fawcett

et al. 1997) examined a wide variety of potential targets of vanadium toxicity. However, both studies

used a small number of subjects and additional studies are needed to evaluate the long

- term toxicity of

vanadium in humans, particularly since vanadium is present in a number of nutritional supplements and

there is a potential for human exposure. An intermediate- duration oral study (Fawcett et al. 1997) which

found no adverse effects in subjects administered vanady l sulfate via capsules was used as the basis of an

MRL.

Biomarkers of Exposure and Effect.

Exposure. Biomarkers specific for exposure to vanadium include the presence of vanadium in the urine

(Gylseth et al. 1979; Kiviluoto et al. 1981b; Lewis 1959; NIOSH 1983; Zenz et al. 1962) and serum

( Gylseth et al. 1979) and a green discoloration of the tongue (Lewis 1959), the latter resulting from the

direct accumulation of vanadium pentoxide. Further studies would be helpful in correlating urinary or

ser um vanadium levels with exposure levels. Vanadium can also be measured in the hair (Stokinger et al.

1953), and studies could be performed to determine if a correlation exists between levels of vanadium in

hair and exposure levels. In the 1950s, decreased cystine content of the hair or fingernails was described

as a possible biomarker of exposure (Mountain et al. 1955). However, this is not specific for vanadium

since other factors, such as diet or disease, can also affect cystine content.

***DRAFT FOR PUBLIC COMMENT***98 VANADIUM

3. HEALTH EFFECTS

Effect. Ther e are no specific biomarkers of effects. It is possible that further biochemical studies might

show specific effects. For example, it is possible that specific effects may be seen on lung cells, which

can be examined by lavage.

Absorption, Distribution, Metabolism, and Excretion. Data are available from human and

animal studies regarding the kinetics of vanadium following inhalation and oral exposure. Specific data

from dermal exposure are lacking; although significant absorption of vanadium by this route in humans is

unlikely (WHO 1988), data are needed to confirm this hypothesis. No animal studies were located that

evaluated absorption efficiency following inhalation exposure, although NTP (2002) reported marginal,

but concentration- related, increa ses in blood vanadium in rats exposed to vanadium pentoxide for 14 days

or 2 years. Additionally, information is available from intratracheal exposures (Conklin et al. 1982; Edel

and Sabbioni 1988; Oberg et al. 1978; Rhoads and Sanders 1985). Oral exposu re studies suggest that

approximately 3–17% of ingested vanadium is absorbed and that absorption efficiency may vary among

vanadium compounds (Adachi et al. 2000b; Conklin et al. 1982). Intratracheal administration and oral

exposure suggest similar patter ns of distribution and excretion (Adachi et al. 2000b; Conklin et al. 1982;

Ramanadham et al. 1991; Rhoads and Sanders 1985) for the two routes of exposure. Additional studies

are needed to provide information on the toxicokinetic properties of vanadium f ollowing inhalation and

dermal exposure. Additionally, there are limited data comparing the absorption and distribution of

various vanadium compounds; inhalation, oral, and dermal exposure studies are needed to evaluate

whether there are compound- specific differences.

Comparative Toxicokinetics. Animal data (Conklin et al. 1982; Oberg et al. 1978; Rhoads and

Sanders 1985; Roshchin et al. 1980) and limited human (Dimond et al. 1963; Gylseth et al. 1979;

Schroeder et al. 1963) data are available on the k inetics of vanadium. There is little reason to believe that

vanadium toxicokinetics would differ between animals and humans. The data indicate that the kinetics

are similar in both. However, as with any particulate substance, extrapolations on inhalatio n absorption

rates from animals to humans would be difficult. Studies are available in humans, rats, mice, and dogs.

Methods for Reducing Toxic Effects. No vanadium- specific information on reducing the

absorption of vanadium following inhalation, oral, or dermal exposure were identified; such information

would be useful in the treatment of persons who may have been exposed to vanadium and/or its

compounds near hazardous waste sites. Several animal studies have explored the use of chelating agents

fo r reducing the vanadium body burden. Administration of ascorbic acid, tiron, deferoxamine mesylate,

or 2- mercaptosuccinic have been shown to increase urinary excretion of vanadium or reduce kidney levels

***DRAFT FOR PUBLIC COMMENT***99 VANADIUM

3. HEALTH EFFECTS

(Domingo et al. 1990; Gomez et al. 1988, 1991), and EDTA and tiron have been shown to reduce toxicity

(Domingo et al. 1993a; Jones and Basinger 1983; Mitchell and Floyd 1954; Sanchez et al. 1999),

presumably by reducing the body burden. There is some evidence that pirfenidone (an antifibrotic agent)

(Al -Bayati et al. 2002) and vitamin E (Chandra et al. 2007a) may interfere with the mechanism of

vanadium toxicity. Additional data are needed, particularly studies examining methods for reducing the

toxicity of inhaled vanadium.

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and

developmental effects expressed either prenatally or during childhood, are discussed in detail in the

Developmental Toxicity subsection above.

There are limited data on the susceptibility of children to vanadium toxicity. No human or animal studies

examined possible age -related differences in toxicity following inhalation, oral, or dermal exposure. An

intraperitoneal study found decreases in the severity of renal lesions in young rats (2 2 days of age)

compared to older rats (62 days of age) (de la Torre et al. 1999). Additional studies are needed to

evaluate if there are age

- related differences in vanadium toxicity or toxicokinetic properties.

Child health data needs relating to expos ure are discussed in Section 6.8.1, Identification of Data Needs:

Exposures of Children.

3.12.3 Ongoing Studies

No ongoing studies examining the toxicity or toxicokinetics of vanadium were identified.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 100

3. HEALTH EFFECTS



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 101



### 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Vanadium is a naturally occurring element that appears in group 5(B5) of the periodic table (Lide 2008).

Vanadium is widely distributed in the earth’s crust at an average concentration of 100 ppm

(appr oximately 100 mg/kg), similar to that of zinc and nickel (Byerrum 1991). Vanadium is the 22 nd most

abundant element in the earth’s crust (Baroch 2006). Vanadium is found in about 65 different minerals;

carnotite, roscoelite, vanadinite, and patronite are important sources of this metal along with bravoite and

davidite (Baroch 2006, Lide 2008). It is also found in phosphate rock and certain ores and is present in

some crude oils as organic complexes (Lide 2008). Table 4 -1 lists common synonyms and other pertinent

identification information for vanadium and representative vanadium compounds.

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Vanadium is a gray metal with a body

- centered cubic crystal system. It is a member of the first transition

series. Because of its high melting point, it is referred to as a refractory metal (Baroch 2006). When

highly pure, it is a bright white metal that is soft and ductile. It has good structural strength and a lowfission neutron cross section. Vanadium has good corrosion resistance to alkalis, sulfuric and

hydrochloric acid, and salt water; however, the metal oxidizes readily above 660 °C (Lide 2008). The

chemistry of vanadium compounds is related to the oxidation state of the vanadium (Woolery 2005).

Vanadium has oxidation states of +2, +3, +4, and +5. When heated in air at different temperatures, it

oxidizes to a brownish black trioxide, a blue black tetraoxide, or a reddish orange pentoxide. It reacts

with chlorine at fairly low temperatures (180 °C) forming vanadium tetrachloride and with carbon and

nitrogen at high temperatures forming VC and VN, respectively. The pure metal in massive form is

relatively inert toward oxygen, nitrogen, and hydrogen at room temperature (HSDB 2009). Vanadium

pentoxide is an industrially important vanadium compound (Lide 2008). Table 4- 2 lists important

physical and chemical properties of vanadium and vanadium compounds.

***DRAFT FOR PUB LIC COMMENT***VANADIUM 102

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 1. Chemical Identity of Vanadium and Compounds a

Characte ristic Vanadium Vanadium pentoxide Vanadyl sulfate

Synonym(s) Vanadium, elemental Vanadium oxide; Vanadic sulfate; vanadium(V) oxide; vanadium oxide vanadic anhydride; sulfate divanadium pentoxide

Registered trade name(s)

Chemical formula V V 2 O 5 VOS O 4

Identification numbers:

CAS registry 7440

- 62 -2 1314

- 62 -1 27774

- 13 -6

EINECS 231

- 171 -1 215

- 239 -8 248

- 652 -7

RTECS b YW1355000 YW2450000 YW1925000

EPA hazardous waste No data P120 No data

OHM/TADS No data No data No data

DOT/UN/NA/IM DG s hipping No data UN2862 UN2931

HSDB 1022 1024 1026

NCI No data No data No data

***DRAFT FOR PUBLIC COMMENT***VANADIUM 103

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 1. Chemical Identity of Vanadium and Compounds a

Sodium Ammonium

Characteristic metavanadate Sodium orthovanadate metavanadate

Synonym(s) Sodium vanadate(V); Sodium o

- vanadate; Ammonium vanadic acid, sodium pervanadate; vanadate(V);

monosodium sodium vanadium oxide; ammonium vanadic(II) acid, trisodium monovanadate;

salt ammonium vanadium
oxide; ammoni um vanadium trioxide;

vanadic a ci d,

ammonium salt

Registered trade name(s)

Chemical formula NaVO 3 Na 3 V O 4 NH 4 VO 3

Identification numbers:

CAS registry 13718

- 26

- 8 13721

- 39

- 6 7803

- 55

- 6

EINECS 237

- 272

- 7 237

- 287

- 9 232

- 261

- 3

RTECS b YW1050000 YW1120000 YW0875000

EPA hazardous waste No data No data P119

OHM/TADS No data No data No data

DOT/UN/NA/IM DG shipping No data No data UN2859

HSDB No data No data 6310

NCI No data No data No data

a All in formation obtained from ChemIDPlus 2009 and HSDB 2 009, except where noted.

b RTECS 200 9

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency;

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances

***DRAFT FOR PUBLIC COMMENT***VANADIUM 104

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 2. Physical and Chemical Properties of Vanadium and Compounds a

Vanadyl sulfate Property Vanadium Vanadium pento xide dihydrate

Molecular weight 50.9415 181.88 199.035 c

Color Light gray or white lustrous powder, fused Yellow to rust

- brown orthorhombic cryst als. Blue crystalline powder c
hard lumps or body

- Yellow

- orange powder or centered cubic crystals. dark

- gray flakes dispersed Pure vanadium is bright in air. Yellow to red white, soft and ductile. crystalline powder.

Physical state Solid b Solid b Solid

Melting point 1,910 °C 690 °C

Boiling point 3,407 °C 1,750 °C (decomposes)

Density at 18.7 °C 6.11 3.357 No data

Odor No data Odorless No data

Odor threshold:

Water No data No data No data

Air No data No data No data

Solubility:

W ater Insoluble 1 g dissolves in S oluble in water c
approximately 125 mL

water

O ther solvent s Soluble in nitric, Soluble in concentrated No data hydrofluoric, and acids, alkalies; insoluble in

concentrated sulfuric alcohol acids; attacked by alkali, forming water

soluble vanadates

Partition coefficients:

Log K

ow No data No data No data

Log K

oc No data No data No data

Vapor pressure 2.34 x 10 - 2 mm Hg at No data No data 1,916 °C (e xtrapolated )

Henry's law constant No data No data No data

Autoignition temperature No data No data No data

Flashpoint No data No data No data

Flammability limits No data No data No data

Conversion factors No data No data No data

Explosive limits No data No data No data

***DRAFT FOR PUBLIC COMMENT***VANADIUM 105

4. CHEMICAL AND PHYSICAL INFORMATION



### Table 4

- 2. Physical and Chemical Properties of Vanadium and Compounds a

Sodium Ammonium Property metavanadate Sodium orthovanadate metavanadate

Molecular weight 121.830 c 183.909 c 116.98

Color Colorless, monoclinic, prismat ic crystals or pale

- green crystalline
powder b Colorless, hexagonal
prisms b White or slightly yellow, crystalline powder

Physical state Solid Solid Solid

Melting point 630 °C b 850

– 866 °C b 200 °C

Boiling point No data No data No data

Density No data No da ta 2.326 g/cm 3

Odor No data No data No data

Odor threshold:

Water No data No data No data

Air No data No data No data

Solubility:

W ater 21 g/100 g water at

25 °C c Soluble in water c Slightly soluble in cold

water

O ther Solvents No data Inso luble in ethanol c Insoluble in alcohol,
ether, ammonium

chloride

Partition coefficients:

Log K

ow No data No data No data

Log K

oc No data No data No data

Vapor pressure No data No data No data

Henry's law constant No data No data No data

Autoigni tion temperature No data No data No data

Flashpoint No data No data No data

Flammability limits Noncombustible b No data Nonflammable b

Conversion factors No data No data No data

Explosive limits No data No data No data

a All information obtained from H SDB 2009, except where noted.

b Lewis 2007

c Lide 2008

d Vanadyl sulfate pentahydrate

- Ethereal blue solid; readily soluble in water

***DRAFT FOR PUBLIC COMMENT***VANADIUM 106

4. CHEMICAL AND PHYSICAL INFORMATION



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 107



### 5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.1 PRODUCTION

TRI information is available in the TRI database on facilities that manufacture or process vanadium

(except when contained in an alloy) and vanadium compounds for Release Year 2007, in accordance with

Sectio n 313 of the Emergency Planning and Community Right- to -Know Act (Title III of the Superfund

Amendments and Reauthorization Act of 1986) (TRI07 2009).

Seven U.S. firms produced ferrovanadium, vanadium pentoxide, vanadium metal, and vanadium-bearing

chemicals or specialty alloys by processing materials such as petroleum residues, spent catalysts, utility

ash, and vanadium-bearing pig iron slag (USGS 2009a).

Vanadium occurs in uranium-bearing minerals of Colorado, in the copper, lead, and zinc vanadates of

Africa, and with certain phosphatic shales and phosphate rocks in the western United States. Commercial

production from petroleum ash holds promise as an important source of vanadium. It is a constituent of

titaniferous magnetites that are widely distribu ted in Russia, South Africa, Finland, People’s Republic of

China, eastern and western United Sates, and Australia. The vanadium deposits from sulfide and

vanadate ores in the Peruvian Andes have been depleted. Most reserves are in deposits where vanadium

would be a by- product or co -product with other minerals, including phosphate, titanium, iron, and

petroleum (Baroch 2006). High-purity ductile vanadium can be obtained by reduction of vanadium

chloride with magnesium or with magnesium

- sodium mixtures. M uch of the vanadium metal now being

produced is made by calcium reduction of V 2 O 5 in a pressure vessel (Lide 2008).

World mine production reported for 2008 (in metric tons) was: China, 20,000; Russia, 16,000; South

Africa, 23,000; and other countries, 1,000, or about 60,000 metric tons for the world (USGS 2009a).

Table 5- 1 lists the facilities in each state that manufacture or process vanadium (except when contained in

an alloy), the intended use, and the range of maximum amounts of this material that are stored on site.

Table 5-2 lists the facilities in each state that manufacture or process vanadium compounds, the intended

use, and the range of maximum amounts of this material that are stored on site. The data listed in

Tables 5-1 and 5- 2 are derived f rom the Toxics Release Inventory (TRI07 2009). Only certain types of

facilities were required to report (EPA 2005b). Therefore, this is not an exhaustive list.

Current U.S. manufacturers of vanadium and selected vanadium compounds are given in Table 5-3.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 108

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL



### Table 5

- 1 . Facilities that Produce, Process, or Use Vanadium (Except When

Contained in a n Alloy)

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

AL 7 100 49,999,999 1, 2, 3, 5, 7 , 12, 13, 14

AR 4 0 99,999 1, 5, 13, 14

AZ 5 10,000 9,999,999 1, 2, 3, 4, 5, 6, 12, 13, 14

CA 12 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14

CT 2 10,000 999,999 1, 4, 5, 9, 12

FL 8 0 999,999 1, 4, 5, 9, 10, 12, 13, 14

GA 1 1,000,000 9,999,999 1, 11, 13

ID 3 100,000 999,999 1, 3, 5, 12

IL 9 0 999,999 1, 5, 7, 12, 13

IN 3 0 999,999 8, 10, 14

KS 4 100 999,999 1, 5, 11, 12, 14

KY 6 0 99,999 1, 5, 7, 8, 11, 12

LA 7 0 999,999 1, 2, 3, 6, 7, 10, 12, 13, 14

MD 3 0 99,999 1, 5

MI 2 1,000 99,999 2, 5, 7, 8, 11, 14

MO 1 1,000 9,999 12

MS 3 10,000 999,999 2, 3, 8, 10

NC 1 1,000 9,999 8

ND 1 100,000 999,999 1, 5, 12

NE 3 10,000 99,999 1, 3, 4, 5, 9, 12, 13

NJ 1 10,000 99,999 2, 13

NM 2 10,000 9,999,999 12

NY 3 100 999,999 1, 5, 6

OH 14 0 9, 999,999 1, 3, 4, 5, 7, 8, 11, 12, 13, 14

OK 2 10,000 99,999 1, 5, 11, 14

PA 8 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 12

PR 1 0 0 0

SC 10 0 999,999 1, 3, 4, 5, 6, 9, 12, 13

TN 4 100 9,999 1, 2, 3, 5, 9, 13, 14

TX 24 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 0, 11, 12, 13, 14

VA 3 0 99,999 1, 2, 5, 12, 13, 14

WI 1 1,000 9,999 7, 8

***DRAFT FOR PUBLIC COMMENT***VANADIUM 109

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL



### Table 5

- 1 . Facilities that Produce, Process, or Use Vanadium (Except When

Contained in a n Alloy)

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

WV 2 1,000 99,999 10, 12

WY 2 10,000 99,999 10, 12

a Post office state abbreviations used

b Amounts on site reported by facilities in each state

c Activities/Uses:

1. Produce 6. Impurity 11. Chemical Processing Aid

2. Import 7. Reactant 12. Manufacturing Aid

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses

4. Sale/Distribution 9. Article Component 14. Process Im purity

5. Byproduct 10. Repackaging

Source: TRI07 2009 (Data are from 2007)

***DRAFT FOR PUBLIC COMMENT***VANADIUM 110

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL



### Table 5

- 2 . Facilities that Produce, Process, or Use Vanadium Compounds

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

AL 25 0 9 99,999 1, 3, 4, 5, 7, 8, 9, 12, 13, 14

AR 16 0 999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

AZ 19 1,000 99,999,999 1, 3, 4, 5, 6, 9, 10, 12, 13, 14

CA 28 0 49,999,999 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14

CO 21 100 999,999 1, 4, 5, 9, 12, 13, 14

CT 5 100 9,999 1, 4, 5, 9, 12, 13

DE 10 0 999,999 1, 2, 5, 9, 10, 12, 13

FL 51 0 9,999,999 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14

GA 27 0 49,999,999 1, 3, 4, 5, 7, 9, 10, 12, 13, 14

HI 1 100 999 1, 5

IA 14 0 999,999 1, 3, 4, 5, 9, 12, 13, 14

ID 11 0 49,999,999 1, 2, 3, 5, 6, 10, 14

IL 45 0 999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 13, 14

IN 52 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

KS 19 0 999,999 1, 3, 4, 5, 9, 10, 12, 13, 14

KY 23 0 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14

LA 50 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

MA 10 1,000 99,999 1, 2, 5, 9, 11, 12, 13, 14

MD 16 0 999,999 1, 4, 5, 6, 7, 9, 12, 13, 14

ME 7 0 99,999 1, 5, 12, 13

MI 37 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14

MN 10 100 999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 12, 13, 14

MO 21 0 999,999 1, 3, 5, 9, 10, 12, 13, 14

MS 14 0 9,999,999 1, 2, 3, 4, 5, 8, 9, 10, 13, 14

MT 5 100 999,999 1, 5, 9, 12, 14

NC 32 0 9,999,999 1, 2, 3, 4, 5, 7, 9, 12, 13, 14

ND 6 10,000 999,999 1, 5, 9 , 12, 13, 14

NE 9 10,000 999,999 1, 3, 4, 5, 9, 12, 13

NH 7 0 999,999 1, 5, 9

NJ 20 100 999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14

NM 8 1,000 999,999 1, 3, 4, 5, 9, 12, 13, 14

NV 22 0 499,999,999 1, 2, 3, 5, 6, 9, 10, 12, 13, 14

NY 21 0 999,999 1 , 2, 3, 4, 5, 6, 7, 9, 12, 13, 14

OH 46 0 9,999,999 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

OK 14 1,000 99,999 1, 3, 4, 5, 8, 9, 10, 11, 12, 13, 14

OR 3 1,000 99,999 1, 3, 4, 5, 9, 14

PA 59 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

***DRAFT FOR PUBLIC COMMENT***VANADIUM 111

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL



### Table 5

- 2 . Facilities that Produce, Process, or Use Vanadium Compounds

Minimum Maximum

Number of amount on site amount on site

State a facilities in pounds b in pounds b Activities and uses c

PR 8 0 99,999 1, 2, 5, 10, 13

SC 18 0 9,999,999 1, 3, 4, 5, 7, 8, 9, 12, 13, 14

SD 2 10,000 99,999 1, 5, 9, 13, 14

TN 25 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14

TX 69 0 9,999,999 1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14

UT 26 100 49,99 9,999 1, 2, 3, 4, 5, 7, 9, 10, 11, 12, 13, 14

VA 21 0 999,999 1, 3, 4, 5, 8, 9, 10, 12, 13, 14

VI 1 100,000 999,999 10, 14

WA 3 10,000 999,999 1, 3, 4, 5, 9, 12, 13

WI 17 0 999,999 1, 3, 4, 5, 9, 12, 13, 14

WV 26 0 999,999 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 14

a Post office state abbreviations used

b Amounts on site reported by facilities in each state

c Activities/Uses:

1. Produce 6. Impurity 11. Chemical Processing Aid 2. Import 7. Reactant 12. Manufacturing Aid 3. Onsite use/processing 8. Formulation Compo nent 13. Ancillary/Other Uses

4. Sale/Distribution 9. Article Component 14. Process Impurity 5. Byproduct 10. Repackaging

Source: TRI07 2009 (Data are from 2007)

***DRAFT FOR PUBLIC COMMENT***VANADIUM 112

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL



### Table 5

- 3 . Current U.S. Manufacturers of Vanadium and Selected Vanadium Compounds a

Company Location

Vanadium

International Specialty Alloys New Castle, Pennsylvania

Vanadium pentoxide

Denison Mines (USA) Corp. Blanding, Utah

Gulf Chemical & Metallurgical Corp. Freeport, Texas

Stratcor, Inc. Hot Springs, Ari zona
Vanadyl sulfate

The Shepherd Chemical Co. Cincinnati, Ohio

Shieldalloy Metallurgical Corp.; Specialty Products Division Cambridge, Ohio

Stratcor, Inc. Hot Springs, Arizona

Sodium metavanadate

Denison Mines (USA) Corp. Blanding, Utah

Shieldall oy Metallurgical Corp.; Specialty Products Division Cambridge, Ohio

Sodium orthovanadate

Shieldalloy Metallurgical Corp.; Specialty Products Division Cambridge, Ohio

Ammonium metavanadate

Denison Mines (USA) Corp. Blanding, Utah

Shieldalloy Metallur gical Corp.; Specialty Products Division Cambridge, Ohio

Stratcor, Inc. Hot Springs, Arizona

a Stanford Research Institute (SRI 200 8 ), except where otherwise noted. SRI reports production of chemicals produced in commercial quantities (defined as exceed ing 5,000 pounds or $10,000 in value annually) by the companies listed.

b USGS 2009b

***DRAFT FOR PUBLIC COMMENT***VANADIUM 113

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2 IMPORT/EXPORT

Import sources of ferrovanadium from 2004 to 2007 were 76% of the Czech Republic, 7% from

Swaziland, 6% from Canada, 6% from the Republic of Korea and 5% from other sources. Vanadium

pentoxide import sources in this same time period were 59% from South Africa, 20% from China, 18%

from Russia, and 3% from other sources (USGS 2009a).

5.3 USE

Vanadium is used in producing rust- resistant, spring, and high- speed tool steels. It is an important

carbide stabilizer in making steels. About 80% of the vanadium produced is used as ferrovanadium as a

steel additive. Vanadium foil is used as a bonding agent in cladding titanium to steel. Vanadium

pentox ide is used in ceramics and as a catalyst as well as in producing a superconductive magnet with a

field of 175,000 gauss (Lide 2008). Metallurgical use as an alloying agent for iron and steel accounted

for approximately 92% of domestic vanadium consumption in 2008 (USGS 2009a).

Vanadium, as elemental vanadium or vanadyl sulfate, also may be found in various commercial

nutritional supplements and multivitamins (NLM 2009). V anadyl sulfate and sodium metavanadate ha ve

been used in supplements for individual s with diabetes

, as well by weight training athletes ( Barceloux

1999; IOM 2001; Smith et al. 2008).

5.4 DISPOSAL

Waste material contaminated with vanadium should be disposed of in a manner not hazardous to

employees. The disposal method must confor m to applicable local, state, and federal regulations and

must not constitute a hazard to the surrounding population or environment. Chemical precipitation has

been investigated as a possible wastewater treatment technology for vanadium (EPA 1982).

Approximately 8.8x10 5 and 7.0x10 5 pounds of vanadium (except when contained in an alloy) and

vanadium compounds, respectively, were reported for on-site disposal and other releases in 2007. On- site

disposal or other releases include emissions to the air, disc harges to bodies of water, disposal at the

facility to land, and disposal in underground injection wells. Approximately 1.2x10 6 and 9.6x10 6 pounds

of vanadium (except when contained in an alloy) and vanadium compounds, respectively, were reported

for off -site disposal and other releases in 2007. An off- site disposal or other release is a discharge of a

***DRAFT FOR PUBLIC COMMENT***VANADIUM 114

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

toxic chemical to the environment that occurs as a result of a facility’s transferring a waste containing a

TRI chemical off

- site for disposal or other rel ease (TRI07 2009). The TRI data should be used with

caution because only certain types of facilities are required to report (EPA 2005b). This is not an

exhaustive list.

Some tool steel scrap was recycled mainly for its vanadium content, and vanadium was recycled from

spent chemical process catalysts; however, these two sources together accounted for only a small

percentage (USGS 2009a).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 115



### 6. POTENTIAL FOR HUMAN EXPOSURE

6.1 OVERVIEW

Vanadium has been identified in at least 319 of the 1,699 hazardou s waste sites that have been proposed

for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number of sites

evaluated for vanadium is not known. The frequency of these sites can be seen in Figure 6 -1. All of

these sites are located within the United States.

Vanadium is widely distributed in the earth’s crust at an average concentration of 100 ppm

(approximately 100 mg/kg), similar to that of zinc and nickel (Byerrum 1991). Vanadium is the 22 nd most

abundant element in the earth’s crust (Baroch 2006). There are about 65 different vanadium-containing

minerals; carnotite, roscoelite, vanadinite, and patronite are important sources of this metal along with

bravoite and davidite (Baroch 2006; Lide 2008). It is also found in ph osphate rock and certain ores and is

present in some crude oils as organic complexes (Lide 2008).

Vanadium is released naturally to the atmosphere by the formation of continental dust, marine aerosols,

and volcanic emissions. Vanadium is a constituent of nearly all coal and petroleum crude oils. Eastern

U.S. coal has an average vanadium content of approximately 30 ppm, while coal from western states has

average content of 15 ppm, and coal from the interior portion of the United States contains an avera ge

vanadium concentration of 34 ppm (Byerrum et al. 1974). The average vanadium content of bituminous

and anthracite coal is 30 and 125 ppm, respectively (Byerrum et al. 1974). The most important

anthropogenic sources of vanadium include the combustion of fossil fuels, particularly residual fuel oils,

which constitute the single largest overall release of vanadium to the atmosphere. While the levels of

vanadium in residual fuel oil vary by source, levels of 1–1,400 ppm have been reported (Byerrum et al.

1974). Natural gas and distillate fuel oils contain very low or undetectable levels (<0.05 ppm) of

vanadium and are not considered a significant source of vanadium to the environment, except in the case

of large accidental spills. The natural release of vanadium to water and soils occurs primarily as a result

of weathering of rocks and soil erosion. This process usually involves the conversion of the less-soluble

trivalent form to the more soluble pentavalent form. Deposition of atmospheric vanadium is also an

important source both near and far from industrial plants burning residual fuel oils rich in vanadium.

Other anthropogenic sources include leachates from mining tailings, vanadium- enriched slag heaps,

municipal sewage sludge, and certain fertilize rs. Natural releases to water and soil are far greater overall

than anthropogenic releases to the atmosphere.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 116

6. POTENTIAL FOR HUMAN EXPOSURE



### Figure 6

- 1. Frequency of NPL Sites with Vanadium Contamination

***DRAFT FOR PUBLIC COMMENT***VANADIUM 117

6. POTENTIAL FOR HUMAN EXPOSURE

Ambient atmospheric levels of vanadium are generally low (parts per trillion range) in rural and remote

areas and greater in urban locations; however, vanadium levels in both rural and urban locations in the

eastern United States tend to be significantly higher than in other areas throughout the country,

particularly during winter months. A high density of oil fired power plants that consume vanadium-rich

residual fuel oil stretching from southern New York to North Carolina are likely to be the greatest

potential source of the high vanadium levels observed in the eastern United Sta tes (Polissar et al. 2001).

In 2007, the Department of Energy reported that nearly 80% of the residual fuel oil consumed for power

generation was purchased in the East Coast districts (DOE 2008).

The general population is exposed to background levels of vanadium primarily through ingestion of food.

Vanadium in food is mainly ingested as VO 2+ (vanadyl, V 4+ ) or HVO 4 2- (vanadate) (Sepe et al. 2003).

Vanadium , as elemental vanadium or vanadyl sulfate , is also found in some dietary supplements and

multivitam ins; consumption of some vanadium- containing supplements may result in intakes of vanadium

that would exceed those from food. Workers in industries processing or using vanadium compounds are

commonly exposed to higher than background levels of vanadium as vanadium oxides via the inhalation

pathway. Exposure to vanadium oxides through inhalation may also be of importance in urban areas,

particularly in the northeastern United States where large amounts of residual fuel oil are burned. Other

populations possibly exposed to higher-than-background levels, include those ingesting foodstuffs

contaminated by vanadium-enriched soil, fertilizers, or sludge. Populations in the vicinity of vanadiumcontaining hazardous waste sites may also be exposed to higher than background levels. Individuals

exposed to cigarette smoke may also be exposed to higher-than-background levels of vanadium.

6.2 RELEASES TO THE ENVIRONMENT

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of

facilities are required to report (EPA 2005b). This is not an exhaustive list. Manufacturing and

processing facilities are required to report information to the TRI only if they employ 10 or more full- time

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011,

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.),

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities

***DRAFT FOR PUBLIC COMMENT***VANADIUM 118

6. POTENTIAL FOR HUMAN EXPOSURE

primarily engaged in solvents recovery services on a contract or fee basi s); and if their facility produces,

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI

chemical in a calendar year (EPA 2005b).

6.2.1 Air

Estimated releases of 8.1x10 4 pounds (~37 metric tons) of vanadium (except when contained in an alloy)

to the atmosphere from 49 domestic manufacturing and processing facilities in 2007, accounted for about

3.8% of the estimated total environmental releases from facilities required to report to the TRI (TRI07

2009). Estimated releases of 6.0x10 5 pounds (~270 metric tons) of vanadium compounds to the

atmosphere from 520 domestic manufacturing and processing facilities in 2007, accounted for about 1.4%

of the estimated total environmental releases from facilities required to report to the TRI (TRI07 2009).

These releases are summarized in Tables 6 -1 and 6-2.

Natural sources of atmospheric vanadium include continental dust, marine aerosol, and volcanic

emissions (Byerrum et al. 1974; Van Zinderen Bakker and Jaworski 1980; Zoller et al. 1973). The

quantities entering the atmosphere from each of these sources are uncertain; however, continental dust is

believed to account for the largest portion of naturally emitted atmospheric vanadium followed by marine

aerosols. Contributions from volcanic emissions are believed to be negligible when compared with the

other two sources (Zoller et al. 1973).

Combustion of heavy fuels, especially in oil-fired power plants, refineries, and industrial boilers, and coal

are the major source of anthropogenic emissions of vanadium into the atmosphere (Mamane and Pirrone

1998; Sepe et al. 2003). Global anthropogenic atmospheric emission of vanadium as been estimated to be

2.1x10 5 metric tons (MT)/year, 3 times higher than vanadium releases due to natural sources. However,

other estimates indicated that anthropogenic releases of particulate -bound vanadium (9x10 4 MT/year)

were more similar to releases due natural sources, such as continental or volcanic dusts, which have

releases of 7x10 4 and 1x10 4 MT/year, respectively) (Mamane and Pirrone 1998).

Fuel oils may contain vanadium in concentrations ranging from 1 to 1,400 ppm, depending on their origin

(Byerrum et al. 1974). During the combustion of residual oils organovanadium compounds found in fuel

oils are oxidized and transformed into various compounds (e.g., vanadium pentoxide, vanadium tetroxide,

vanadium trioxide, and vanadium dioxide). These compounds are emitted as fly ash into the atmosphere

(Mamane and Pirrone 1998).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 119

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 1 . Releases to the Environment from Facilities that Produce, Process, or

Use Vanadium (Except When Contained in a n Alloy) a

Reported amounts released in pounds per year b

Total release

On

- and

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k off

- site

AL 1 17,181 0 0 3,436 0 20,617 0 20,617

AR 2 6 0 0 0 1,739 6 1,739 1,745

AZ 2 77 0 0 187,092 0 187,167 2 187,169

CA 4 252 310 0 127,011 5 76,332 51,246 127,578

ID 1 38 0 0 244,713 0 244,751 0 244,751

IL 1 0 0 0 3,068 0 0 3,068 3,068

KS 3 5,709 0 0 102,300 608,717 11,009 705,717 716,726

KY 1 14 0 0 0 0 14 0 14

LA 2 140 5,152 0 56,388 0 5,292 56,388 61,680

MO 1 0 0 0 0 20 0 20 20

MS 1 0 0 0 131,300 0 0 131,300 131,300

ND 1 48,088 0 0 86,381 0 90,782 43,687 134,469

NE 1 140 0 0 13,000 0 13,140 0 13,140

NY 1 0 0 0 949 64,880 0 65,828 65,828

OH 6 1,614 1,674 2 138,507 26,328 48,265 119,860 168,125

PA 3 3,279 0 0 5 35,104 3,284 35,104 38,388

PR 1 0 0 0 0 0 0 0 0

SC 1 1,000 1,972 0 107 0 3,079 0 3,079

TN 1 10 0 0 1,512 274 10 1,786 1,796

TX 12 3,212 19,799 0 17,938 5 25,004 15,950 40,954

VA 1 83 15 0 4,108 4 98 4,112 4,210

WV 1 0 0 0 52,255 0 52,255 0 52,255

***DRAFT FOR PUBLIC COMMENT***VANADIUM 120

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 1 . Releases to the Environment from Facilities that Produce, Process, or

Use Vanadium (Except When Contained in a n Alloy) a

Reported amounts released in pounds per year b

Total release

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k On

- and

off

- site

WY

Total 1

49 201

81,043 0

28,922 0

2 100,057

1,270,126 0

737,076 100,258

881,362 0

1,235,808 100,258

2 ,117,170

a The TRI data should be used with caution since only certain types of facilities are required to report. This is not an

exhaustive list. Data are rounded to nearest whole number.

b Data in TRI are maximum amounts released by each facility.

c Pos t office state abbreviations are used.

d Number of reporting facilities.

e The sum of fugitive and point source releases are included in releases to air by a given facility.

f Surface water discharges, waste water treatment

- (metals only), and publicly owned treatment works ( POTWs) (metal and metal compounds).

g Class I wells, Class II

- V wells, and underground injection.

h Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on

- site landfills, land treatment, surface impoundments, other land disposal, other landfills.

i Storage only, solidification/stabilization (metals only), other off

- site management, transfers to waste broker for disposal, unknown

j The sum of all releases of the chemical to air, land, water, and underground injection wells.

k Total amount of chemical transferred off

- site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI07 2009 (Data are from 2007)

***DRAFT FOR PUBLIC COMMENT***VANADIUM 121

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 2 . Releases to the Environment from Facilities that Pro duce, Process, or

Use Vanadium Compounds a

Reported amounts released in pounds per year b

Total release

On

- and

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k off

- site

AL 21 14,224 9,379 0 1,694,971 27 1,711,492 7,109 1,718,601

AR 8 16,188 169,170 0 1,709,832 1,858 1,895,125 1,923 1,897,048

AZ 7 1,099 0 0 244,363 0 245,462 0 245,462

CA 13 187 1,052 0 86,238 15 994 86,498 87,492

CO 10 1,375 119 0 303,890 7,052 163,631 148,805 312,436

CT 2 0 0 0 20,009 0 0 20,009 20,009

DE 4 1,743 17,501 0 428,513 179,436 56,244 570,949 627,193

FL 21 54,752 1,481 33,315 4,958,132 28,031 1,785,451 3,290,260 5,075,711

GA 15 27,261 20,059 0 1,873,231 0 1,881,251 39,300 1,920,551

IA 7 1,571 5 0 173,500 12,644 168,976 18,744 187,720

ID 2 3,819 1,405 0 616,407 1,620 621,632 1,620 623,252

IL 22 28,755 10,927 0 418,991 321 341,886 117,108 458,994

IN 29 19,920 12,250 0 3,311,659 18,648 2,693,285 669,192 3,362,477

KS 8 11,820 1 0 259,993 0 271,382 432 271,814

KY 23 20,580 21,751 0 3,198,893 124,137 3, 054,104 311,257 3,365,361

LA 24 147,927 55,994 0 332,235 6,722 436,791 106,087 542,878

MA 4 4,938 2,491 0 64,314 0 38,274 33,469 71,743

MD 8 5,704 1,597 0 159,347 260,048 56,863 369,833 426,697

ME 2 1,500 4,662 0 21,274 0 27,436 0 27,436

MI 17 6,036 7 ,869 0 832,882 2,358 622,845 226,300 849,145

MN 5 2,070 863 0 392,039 3,182 277,956 120,198 398,154

MO 11 6,124 25 0 262,566 0 268,310 405 268,715

MS 8 1,037 67,469 1,261,497 2,701,215 0 4,030,172 1,046 4,031,218

MT 2 2,832 10 0 215,880 12,930 218,722 12,930 231,652

NC 20 15,186 8,878 0 1,373,808 15,355 1,350,201 63,027 1,413,228

ND 3 1,115 0 0 143,171 679 136,742 8,223 144,965

NE 3 2,615 0 0 78,511 0 81,126 0 81,126

NH 3 1,075 0 0 10,380 0 2,975 8,480 11,455

NJ 7 1,638 16,250 0 5,018 6,300 17,638 11,568 29,206

NM 5 1,971 830 0 490,597 0 493,398 0 493,398

NV 5 17 0 0 2,201,622 0 2,201,639 0 2,201,639

NY 9 20,512 3,276 0 585,147 247,051 551,640 304,346 855,986

OH 26 106,896 1,139 1,810 2,159,259 162,350 1,793,794 637,660 2,431,454

OK 10 2,842 11 0 126,270 0 77,723 51,400 129,123

***DRAFT FOR PUBLIC COMMENT***VANADIUM 122

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 2 . Releases to the Environment from Facilities that Pro duce, Process, or

Use Vanadium Compounds a

Reported amounts released in pounds per year b

Total release

On

- and

State c RF d Air e Water f UI g Land h Other i On

- site j Off

- site k off

- site

OR 1 305 0 0 9,900 0 10,205 0 10,205

PA 29 13,634 1,127 0 1,499,090 550 936,936 577,465 1,514,401

PR 1 0 0 0 0 0 0 0 0

SC 16 4,754 4,227 0 276,695 322 263,725 22,274 285,999

SD 1 104 0 0 17,100 0 13,104 4,100 17,204

TN 15 3,931 30,351 0 1,508,290 0 1,268,104 274,468 1,542,572

TX 33 25,734 6,258 11,292 1,652,925 120,018 1,642,602 173,625 1,816,227

UT 9 1,021 1,000 0 284,148 28,151 285,391 28,929 314,320

VA 16 4,059 5,687 0 693,368 38,974 632,757 109,331 742,088

VI 1 37 8,387 0 24,878 0 11,990 21,312 33,302

WA 1 387 182 0 96,659 0 97,228 0 97,228

WI 14 4,914 868 0 577,355 131,721 106,054 608,803 714,857

WV 15 4,775 991 0 2,085,660 38,000 1,681,804 447,622 2,129,425

WY 4 1,913 0 0 244,462 0 176,966 69,409 246,375

Total 520 600,897 495,542 1,307,914 40,424,686 1,448,501 34,702,024 9,575,516 44,277,540

a The TRI data should be used with caution since only certain types of facilities are required to report. This is not an

exhaustive list. Data are rounded to nearest whole number.

b Data in TRI are maximum amounts released by each facility.

c Post office state abbreviations are used.

d Number of reporting facilities.

e The sum of fugitive and point source releases are included in releases to air by a given facility.

f S urface water discharges, waste water treatment

- (metals only), and publicly owned treatment works ( POTWs) (metal and metal compounds).

g Class I wells, Class II

- V wells, and underground injection.

h Resource Conservation and Recovery Act (RCRA) subtitle C lan dfills; other on

- site landfills, land treatment, surface impoundments, other land disposal, other landfills.

i Storage only, solidification/stabilization (metals only), other off

- site management, transfers to waste broker for disposal, unknown

j The sum of all releases of the chemical to air, land, water, and underground injection wells.

k Total amount of chemical transferred off

- site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI07 2009 (Data are from 2007)

***DRAFT FOR PUBLIC COMMENT***VANADIUM 123

6. POTENTIAL FOR HUMAN EXPOSURE

Vana dium has not been identified in air collected at current or former NPL hazardous waste sites where

vanadium was detected in some environmental media (HazDat 2007).

6.2.2 Water

Estimated releases of 2.9x10 4 pounds (~13 metric tons) of vanadium (except when contained in an alloy)

to surface water from 49 domestic manufacturing and processing facilities in 2007, accounted for about

1.4% of the estimated total environmental releases from facilities required to report to the TRI (TRI07

2009). Estimated r eleases of 5.0x10 5 pounds (~230 metric tons) of vanadium compounds to surface water

from 520 domestic manufacturing and processing facilities in 2007, accounted for about 1.1% of the

estimated total environmental releases from facilities required to report to the TRI (TRI07 2009). These

releases are summarized in Tables 6 -1 and 6-2.

Natural sources of vanadium release to water include wet and dry deposition, soil erosion, and leaching

from rocks and soils. The largest amount of vanadium release occurs na turally through water erosion of

land surfaces. It has been estimated that approximately 32,300 tons of vanadium are dissolved and

transported to the oceans by water, and an additional 308,650 tons are thought to be transported in the

form of particulate and suspended sediment (Van Zinderen Bakker and Jaworski 1980).

Anthropogenic releases to water and sediments are far smaller than natural sources (Van Zinderen Bakker

and Jaworski 1980). Such sources of vanadium in water may include leaching from the re sidue of ores

and clays, vanadium- enriched slags, urban sewage sludge, and certain fertilizers, all of which are

subjected to rain and groundwater drainage, as well as leachate from ash ponds and coal preparation

wastes (Byerrum et al. 1974; Van Zinderen Bakker and Jaworski 1980). Leaching may potentially occur

from landfills and from the airborne particulate matter that is deposited in areas with high residual fuel oil

combustion, although neither of these release sources is documented.

Vanadium has been identified in groundwater and surface water at 224 and 129 sites, respectively, of the

319 NPL hazardous waste sites where it was detected in some environmental media (HazDat 2007).

6.2.3 Soil

Estimated releases of 1.3 million pounds (~580 metric tons) of vanadium (except when contained in an

alloy) to soils from 49 domestic manufacturing and processing facilities in 2007, accounted for about 60%

***DRAFT FOR PUBLIC COMMENT***VANADIUM 124

6. POTENTIAL FOR HUMAN EXPOSURE

of the estimated total environmental releases from facilities required to report to the TRI (TRI07 2009).

An additional 2 pounds (~0.9 kilograms) of vanadium were released via underground injection (TRI07

2009). Estimated releases of 40 million pounds (~1.8x10 4 metric tons) of vanadium compounds to soils

from 520 domestic manufacturing and processing facil ities in 2007, accounted for about 91% of the

estimated total environmental releases from facilities required to report to the TRI (TRI07 2009). An

estimated 1.3 million pounds (~590 metric tons) of vanadium compounds were released via underground

injecti on from 520 domestic manufacturing and processing facilities in 2007, accounted for about 3.0% of

the estimated total environmental releases from facilities required to report to the TRI (TRI07 2009).

These releases are summarized in Tables 6 -1 and 6-2.

Natural releases of vanadium to soil result from weathering of rock -bearing vanadium minerals,

precipitation of vanadium particulate from the atmosphere, deposition of suspended particulate from

water, and plant and animal wastes. The largest amount of va nadium released to soil occurs through the

natural weathering of geological formations (Byerrum et al. 1974; Van Zinderen Bakker and Jaworski

1980).

Anthropogenic releases of vanadium to soil are less widespread than natural releases and occur on a

smaller scale. These include the use of certain fertilizers containing materials with a high vanadium

content such as rock phosphate (10 –1,000 mg/kg vanadium), superphosphate (50–2,000 mg/kg

vanadium), and basic slag (1,000–5,000 mg/kg vanadium) (Van Zinderen B akker and Jaworski 1980) as

well as disposal of industrial wastes such as slag heaps and mine tailings. Additional release to the

environment may also result from the disposal of vanadium-containing wastes in landfills, although this

has not been specific ally documented, and from wet and dry deposition of airborne particulate,

particularly in areas with high levels of residual fuel oil combustion (Byerrum et al. 1974).

Vanadium has been identified in soil at 172 sites and in sediment at 44 sites collected from 319 NPL

hazardous waste sites, where vanadium was detected in some environmental media (HazDat 2007).

6.3 ENVIRONMENTAL FATE

6.3.1 Transport and Partitioning

The global biogeochemical cycling of vanadium is characterized by releases to the atmosphere, water, and

land by natural and anthropogenic sources, long-range transportation of particles in both air and water,

wet and dry deposition, adsorption, and complexing. Vanadium generally enters the atmosphere as an

***DRAFT FOR PUBLIC COMMENT***VANADIUM 125

6. POTENTIAL FOR HUMAN EXPOSURE

aerosol. From natural sour ces, vanadium is probably in the form of mineral particles; it has been

suggested that these may frequently be in the less

- soluble trivalent form (Byerrum et al. 1974; Zoller et al.

1973). From human- made sources, almost all of the vanadium released to the atmosphere is in the form

of simple or complex vanadium oxides (Byerrum et al. 1974).

The size distribution of vanadium-bearing particles in the atmosphere is substantially altered during longrange transportation (Zoller et al. 1973). Natural sources of vanadium, as well as man

- made sources such

as ore

- processing dust, tend to release large particles that are more likely to settle near the source.

Smaller particles, such as those emitted from oil

- fueled power plants, have a longer residence time in the

atmosphere and are more likely to be transported farther away from the site of release (Zoller et al. 1973).

Vanadium transported within the atmosphere is eventually transferred to soil and water on the earth's

surface by wet and dry deposition and dissolution in sea water (Duce and Hoffman 1976; Van Zinderen

Bakker and Jaworski 1980). Eventually, in the course of biogeochemical movement between soil and

water, these particulates are adsorbed to hydroxides or associated with organic compounds and are

deposited on the sea bed (WHO 1988).

Deposition rates ranging from 20.5 to 84.9 μg/cm 2 /day of vanadium were reported in urban dust collected

between March and September 2002 from six locations Adapazarí, Turkey (Dundar 2006). Vanadium is

considered a marke r of air pollution emitted from residual oil and coal combustion (Mamane and Pirrone

1998).

The transport and partitioning of vanadium in water and soil is influenced by pH, redox potential, and the

presence of particulate. In fresh water, vanadium generally exists in solution as the vanadyl ion (V 4+ )

under reducing conditions and the vanadate ion (V 5+ ) under oxidizing conditions, or as an integral part of,

or adsorbed onto, particulate matter (Wehrli and Stumm 1989). The chemical formulas of the vanadyl

species most commonly reported in fresh water are VO 2+ and VO(OH) + , and the vanadate species are

- H 2 VO 4 and HVO 4 2- (Wehrli and Stumm 1989). The partitioning of vanadium between water and

sediment is strongly influenced by the presence of particulate in the water. Both vanadate and vanadyl

species are known to bind strongly to mineral or biogenic surfaces by adsorption or complexing (Wehrli

and Stumm 1989). Thus, vanadium is transported in water in one of two ways: solution or suspension. It

has been estimated that only 13% is transported in solution, while the remaining 87% is in suspension

(WHO 1988).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 126

6. POTENTIAL FOR HUMAN EXPOSURE

Upon entering the ocean, vanadium in suspension or adsorbed and/or absorbed onto particulate is

deposited upon the sea bed (WHO 1988). The fate of the remaining dissolved vanadium is more

complex. Only about 0.001% of vanadium entering the oceans is estimated to persist in soluble form

(Byerrum et al. 1974). Ads orption /absorption and biochemical processes are thought to contribute to the

extraction of vanadium from sea water (WHO 1988). Adsorption to organic matter as well as to

manganese oxide and ferric hydroxide, demonstrated by the high particle- water partition coefficient of

5.7x10 5 L/kg for the adsorption of manganese oxide in sea water, results in the precipitation of the

dissolved vanadium (Wehrli and Stumm 1989; WHO 1988). Biochemical processes are also of

importance in the partitioning from sea water to sediment (WHO 1988). Some marine organisms, in

particular the ascidians (sea squirts), b ioconcentrate vanadium very efficiently, attaining body

concentrations approximately 10,000 times greater than the ambient sea water (Byerrum et al. 1974).

Upon the death of the organism, the body burden adds to the accumulation of vanadium in silt (WHO

1988). The extent to which either bioconcentration or adsorption dominates is uncertain (WHO 1988).

In general, marine plants and invertebrates contain higher levels of vanadium than terrestrial plants and

animals. In the terrestrial environment, bioconcentration is more commonly observed amongst the lower

plant phyla than in the higher, seed

- producing phyla. The vanadium levels in terrestrial plants are

dependent upon the amount of water-soluble vanadium available in the soil, pH, and growing conditions.

It has been found that the uptake of vanadium into the above-ground parts of many plants is low, although

root concentrations have shown some correlation with levels in the soil (Byerrum et al. 1974). Certain

legumes, such as Astralagus preussi , have been shown to be vanadium accumulators. Vanadium is

believed to replace molybdenum as a specific catalyst in nitrogen fixation (Cannon 1963), and the root

nodules of these plants may contain vanadium levels three times greater than those of the surrounding soil

(Byerrum et al. 1974). Of the few plants known to actively accumulate vanadium, Amanita muscaria , a

poisonous mushroom, has been demonstrated to contain levels up to 112 ppm (dry weight). Vanadium

appears to be present in all terrestrial animals, b ut, in vertebrates, tissue concentrations are often so low

that detection is difficult. The highest levels of vanadium in terrestrial mammals are generally found in

the liver and skeletal tissues (Van Zinderen Bakker and Jaworski 1980; WHO 1988). No data are

available regarding biomagnification of vanadium within the food chain, but human studies suggest that it

is unlikely; most of the 1 –2% vanadium that appears to be absorbed by humans following ingestion is

rapidly excreted in the urine with no evidence of long-term accumulation (Fox 1987).

The form of vanadium present in the soil is determined largely by the parent rock. Ferric hydroxides and

solid bitumens (organic) constitute the main carriers of vanadium in the sedimentation process. Iron acts

***DRAFT FOR PUBLIC COMMENT***VANADIUM 127

6. POTENTIAL FOR HUMAN EXPOSURE

as a carrier for trivalent vanadium due to the high affinity between trivalent vanadium and trivalent iron,

and is responsible for its diffusion through molten rocks where it becomes trapped during crystallization.

The mobility of vanadium in soils is affec ted by the pH of the soil. Relative to other metals, vanadium is

fairly mobile in neutral or alkaline soils, but its mobility decreases in acidic soils (Van Zinderen Bakker

and Jaworski 1980). Similarly, under oxidizing, unsaturated conditions, some mobility is observed, but

under reducing, saturated conditions, vanadium is immobile (Van Zinderen Bakker and Jaworski 1980).

In a 30-month field study to examine the movement of metal ions through a profile of an acidic loamy

sand soil from the Upper Coastal Plain (South Carolina), <3% of the applied vanadium , as dissolved salt

(vanadyl sulfate), was found to move below the surface 7.5 cm region (Martin and Kaplan 1998).

Buchter et al. (1989) reported log K d values for various metal ions in 11 soils from 7 s tates in the U.S.

(Louisiana, South Carolina, Hawaii, Iowa, New Hampshire, New Mexico, and Florida). Log K d values

for vanadium (applied as ammonium vanadate) ranged from 1.035 in Calciorthid soil from New Mexico

(pH 8.5, 0.44% total organic carbon [TOC], 70.0% sand, 19.3% silt, 10.7% clay) to 3.347 in Kula soil

from Hawaii (pH 5.9, 6.62% TOC, 73.7% sand, 25.4% silt, 0.9% clay).

6.3.2 Transformation and Degradation

As an element, vanadium cannot be degraded in the environment, but may undergo variou s precipitation

or ligand exchange reactions. Vanadium in compounds may undergo oxidation- reduction reactions under

various environmental conditions. Vanadium can be complexed by various ligands present in the

environment (e.g., fulvic and humic acids). Despite forming complexes with organic matter, it is

generally not incorporated into organic compounds. Thus, transformation occurs primarily between

various inorganic compounds during its movement through the environment, and biotransformation is not

co nsidered to be an important environmental fate process. Vanadium can exist in many different

oxidation states, ranging from -2 to +5; however, under environmental conditions, vanadium can exist in

the +3, +4, or +5 oxidation states, with the +5 oxidation state being the most prevalent under most

environmental conditions (Crans et al. 1998).

6.3.2.1 Air

Vanadium-containing particulates emitted to the atmosphere from anthropogenic sources are frequently

simple or complex oxides (Byerrum et al. 1974) o r may be associated with sulfates (Zoller et al. 1973).

Generally, lower oxides formed during combustion of coal and residual fuel oils, such as vanadium

trioxide, undergo further oxidation to the pentoxide form, often before leaving the stacks (EPA 1985a).

The average residence time for vanadium in the atmosphere is unknown as the particle size varies

***DRAFT FOR PUBLIC COMMENT***VANADIUM 128

6. POTENTIAL FOR HUMAN EXPOSURE

considerably. An estimated residence time of about 1 day has been proposed for the settling of fly ash

vanadium pentoxide when associated with hydrogen su lfate (EPA 1985a).

6.3.2.2 Water

Vanadium entering water by leaching from vanadium -containing rocks is rapidly oxidized from lesssoluble vanadium(III) to more-soluble vanadium(V), which is the most common oxidation state of

vanadium found in surface waters (Byerrum et al. 1974; Crans et al. 1998). In water, vanadium can

undergo hydrolytic reactions, forming oligomeric anionic species. The equilibrium of vanadium(V) in

solution is sensitive to vanadium concentration, pH, ionic strength, and oxidation-reduction potential

(Crans et al. 1998). The species of vanadium most likely to be found in sea water are (H 2 V 4 O 13 ) 4-

,

HVO 4 2- , and VO 3- (Van Zinderen Bakker and Jaworski 1980). Vanadium(III) is only found in very

reducing environments or is complexed to organic ligands (Crans et al. 1998). Vanadium is continuously

precipitated from sea water by ferric hydroxides and organic matter (WHO 1988) and forms sediments on

the seabed.

6.3.2.3 Sediment and Soil

There are about 65 different vanadium-containing minerals (Baroch 2006; Lide 2008). The main

vanadium- containing minerals include carnotite, cuprodescloizite, descloizite, mottramite, patronite,

roscoelite, and vanadinite (Crans et al. 1998). Vanadium exists in its +3 to +5 oxidation states in these

minerals. Vanadium(V) is more soluble and is easily leached from soils into water. The vanadium

oxides, carnotite, cuprodescloizite, descloizite, mottramite, and vanadinite, are mostly vanadium(V)

minerals and comprise most of the vanadium- containing min erals. Roscoelite contains vanadium(III),

and the exact chemical composition of patronite is not known (Crans et al. 1998). Weathering of rocks

and minerals during soil formation may extract vanadium in the form of a complex anion that may remain

in the soil or enter the hydrosphere. Vanadium remains in the soil after being precipitated from the

weathering solution. This can be brought about by precipitation with polyvalent cations such as divalent

calcium and divalent copper, by binding with organic complexing agents, adsorbing onto anion

exchangers such as clay particles in the soil, and coprecipitating and adsorbing to hydrous ferric oxide in

the soil (Van Zinderen Bakker and Jaworski 1980). In the presence of humic acids, mobile metavanadate

anions can be converted to the immobile vanadyl cations resulting in local accumulation of vanadium

(Van Zinderen Bakker and Jaworski 1980).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 129

6. POTENTIAL FOR HUMAN EXPOSURE

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to vanadium depends in part on the reliability of

supporting analytical data from environmental samples and biological specimens. Concentrations of

vanadium in unpolluted atmospheres and in pristine surface waters are often so low as to be near the

limits of curr ent analytical methods. In reviewing data on vanadium levels monitored or estimated in the

environment, it should also be noted that the amount of chemical identified analytically is not necessarily

equivalent to the amount that is bioavailable. The anal ytical methods available for monitoring vanadium

in a variety of environmental media are detailed in Chapter 7.

6.4.1 Air

Levels of vanadium measured in ambient air vary widely between rural and urban locations, time of

season, and geographical locati on. In general, urban locations often tend to have greater atmospheric

levels of vanadium as compared to rural sites since there is a larger density of combustion sources capable

of emitting particulate matter containing vanadium to the environment. Swee t et al. (1993) reported

average vanadium concentrations of 3.0 and 3.0 ng/m 3 (fine particles, <2.5 μm) and 3.7 and 3.0 ng/m 3

(coarse particles, 2.5

– 10 μm) in samples of inhalable particulate matter collected over a 3

- year sampling

period in southeast Chic ago and East St. Louis Illinois, respectively. Average vanadium concentrations in

fine and coarse particulate matter collected from a rural site in Bondville, Illinois were 0.8 and 1.2 ng/m 3

, respectively (Sweet et al. 1993). Aerosol sampling (PM 2.5 frac tion) was conducted from 1988 to 1995 at a

rural location in Underhill, Vermont (Polissar et al. 2001). A geometric mean concentration of

0.82 ng/m 3 was reported for vanadium, with seasonal maxima occurring during the winter and spring

months and minimum concentrations observed during the summer months. A factor analysis method

applied to the data determined that the most likely sources of the vanadium were oil fired power plants

predominantly located in eastern Virginia, Pennsylvania, southern New York, New Jersey, Maryland, and

Delaware (Polissar et al. 2001). Measurements obtained at five different rural sites in northwestern

Canada were found have average vanadium concentrations of 0.72 ng/m 3 (range 0.21–1.9 ng/m 3 ) (Zoller

et al. 1973). Between the years 1965 and 1969, average ambient vanadium concentrations in rural air in

the United States ranged from <1 to 40 ng/m 3 (Byerrum et al. 1974), although some rural areas may have

levels as high as 64 ng/m 3 due to localized burning of fuel oils with a high vanadium content (WHO

1988). Vanadium concentrations in air samples collected from a rural forest in Denmark that received

heavy deposition from European cities were 11.5 and 4.4 ng/m 3 in samples from 1979 to 1980 and 2002

to 2005, respectively (Hovmand et al. 2008).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 130

6. POTENTIAL FOR HUMAN EXPOSURE

Northeastern locations in the United States typically have high er atmospheric levels of vanadium as

compared to other regions of the country. U.S. cities were divided into two groups based on the levels of

vanadium present in the atmosphere and geographic location (Zoller et al. 1973). The first group of cities

is widely distributed throughout the United States and is characterized by ambient air vanadium

concentrations that range from 3 to 22 ng/m 3 , with an average concentration of 11 ng/m 3 (approximately

20 times that of remote areas). Cities in the second group, primarily located in the northeastern United

States, had vanadium concentrations in air that ranged from 150 to 1,400 ng/m 3 with an average of

620 ng/m 3 (Zoller et al. 1973). T he variation is attributed to the use of large quantities of residual fuel oil

for the generation of heat and electricity, particularly during winter months

Atmospheric levels of vanadium at remote sites tend to be low er since both natural and anthropogenic

emissions are typically negligible. Vanadium concentrations measured over the South Pole ranged from

0.001 to 0.002 ng/m 3 (WHO 1988) and are frequently 2 orders of magnitude smaller than those over the

ocean at middle latitudes (WHO 1988). For exampl e, vanadium concentrations in air measurements taken

at nine rural sites located in the Eastern Pacific averaged 0.1 ng/m 3 (range 0.02–0.8 ng/m 3 ). Atmospheric

aerosols were collected from Mt. Everest in May –June, 2005; vanadium concentrations ranged from

0.9 to 3.8 ng/m 3 , with a mean of 1.4 ng/m 3 (Cong et al. 2008). Vanadium concentrations at other remote

locations of 0.044 and 0.0039 ng/m 3 were reported for Greenland, 1988 –1989 and Terra Nova Bay,

Antarctica, 2000 –2001, respectively (Cong et al. 2008; Mosher et al. 1993).

Vanadium was detected in exhaust aerosol collected from the Elbtunnel, a major highway tunnel in

Hamburg, Germany, at an average concentration of 14.8 ng/m 3 (range: 7.6– 36.9 ng/m 3 ) (Dannecker et al.

1990). Fine atmospheric particulat e PM 2.5 (particles with diameters of <2.5 μm) were collected from

November 2000 to September 2001 in Guaynabo, Puerto Rico, an urban industrialized area, and in

Fajardo, Puerto Rico, a less polluted reference site (Figueroa et al. 2006). Vanadium concentr ations in the

PM 2.5 were 40 and 1.4 ng/m 3 for Guaynabo and Fajardo, respectively. Mean urban vanadium

concentrations in winter and summer air (fine and course particulate combined) collected from the

Birmingham University campus, Edgbaston, United Kingdom in January-February 1992 and July- August

1992 were 11.2 and 3.5 ng/m 3 , respectively. Vanadium concentrations were higher in the fine particle

fraction, 7.6 and 2.3 ng/m 3 (winter and summer), as compared to the coarse particle samples, 3.6 and

1.2 ng/m 3 (winter and summer) (Harrison et al. 1996). Mean vanadium concentrations in air samples

from a central Copenhagen street (January –March 1992 and February–March 1993) and a city park

(January –March 1992) were reported to be 12 and 10 ng/m 3 , respectively (Ni elsen 1996). Smith et al.

(1996) reported mean vanadium concentrations in air samples collected from a city site, a rural site, and

***DRAFT FOR PUBLIC COMMENT***VANADIUM 131

6. POTENTIAL FOR HUMAN EXPOSURE

an industrial site in Lahore, Pakistan in 1992 –1993 of 127, 161, and 253 ng/m 3 , respectively. Mean

vanadium concentrations in air samples of 10, 180, and 110 ng/m 3 were reported in Karachi, Pakistan;

Calcutta, India; and Bombay, India, respectively ( Smith et al. 1996)

. Schroeder et al. (1987) reported

concentration ranges of vanadium associated with particulate matter in the atmosphere: 0.001–14 ng/m 3

(remote areas); 2.7 –97 ng/m 3 (rural); 10 –130 ng/m 3 (urban Canada); 0.4 –1,460 ng/m 3 (urban United

States); 11 –73 ng/m 3 (urban Europe); and 1.7–180 ng/m 3 (urban other).

Vanadium and nickel were measured in air particulate samples collected during and after the Kuwait oil

fires (from March 1991 to July 1992) at Dhahran, Saudi Arabia (Sadiq and Mian 1994). Vanadium

concentrations ranged from not detected to 1,165.8 ng/m 3 in the inhalable (PM 10 , <10 μm) and from not

detected to 160.26 ng/m 3 in the total suspended particulate. The minimum vanadium concentration was

found in samples collected in December 1991 and gradually increased through May 1992.

Air sampling in homes in two New York counties in the winter of 1986 measured var ious contaminants in

the indoor air (Koutrakis et al. 1992). Mean vanadium concentrations in indoor air of non-source homes

(no kerosene heaters, wood stoves, or cigarette smokers), wood -burning homes, kerosene heater homes,

and smoking homes were 5, 4, 6, and 6 ng/m 3 , respectively. Miguel et al. (1995) reported vanadium

concentrations in samples of indoor air from non- industrial office workplaces and restaurants in the cities

of Sao Paulo and Rio de Janeiro, Brazil in the summer of 1993 ranging from less than the detection limit

to 0.360 μg/m 3 . Kinney et al. (2002) reported mean winter and summer vanadium concentrations of

9.49 and 4.17 ng/m 3 in indoor air (particle-associated) in 38 homes sampled in 1999 in the West Central

Harlem section of New York Ci ty. A mean vanadium concentration of 0.8 ng/m 3 was reported inside

patrol cars of ten nonsmoking North Carolina State Highway Patrol troopers during 25 work days (3 pm

to midnight shift) during August–October of 2001 (Riediker et al. 2003).

6.4.2 Water

Levels of vanadium in fresh water illustrate geographic variations produced by differences in effluents

and leachates, from both anthropogenic and natural sources, entering the water table. Vanadium

concentrations in water can range from approximately 0.2 to >100 μg/L depending on geographical

location (Sepe et al. 2003). Vanadium was detected in 3,387 of 3,625 surface water samples recorded in

the STORET database for 2007–2 008 at concentrations ranging from 0.04 to 104 μg/L in samples where

vanadium was detected (EPA 2009a). Measurements of vanadium in such natural fresh waters as the

Animas, Colorado, Green, Sacramento, San Joaquin, and San Juan Rivers, as well as some fre sh water

***DRAFT FOR PUBLIC COMMENT***VANADIUM 132

6. POTENTIAL FOR HUMAN EXPOSURE

supplies in Wyoming, range from 0.3 to 200 μg/L (Byerrum et al. 1974; Van Zinderen Bakker and

Jaworski 1980). The presence of naturally occurring uranium ores resulted in rivers in the Colorado

Plateau containing vanadium concentrations of up to 70 μg/L, and in Wyoming, vanadium concentrations

in water were found to range from 30 to 220 μg/L (Byerrum et al. 1974).

Taylor et al. (2001) reported vanadium concentrations of <0.05 μg/L in water collected in June and

September 1994 from the Alamosa River, Colorado and 6.2 μg/L in water collected in September 1992

from Big Arsenic Spring, New Mexico. Saleh and Wilson (1999) reported various metal concentrations

in surface water from the Houston Ship Channel, Texas; vanadium concentrations ranged from 4.062 to

115.600 μg/L in samples from Buffalo Bayou and the Washburn Tunnel, respectively. Coal mining

activity in the west

- central region of Indiana has resulted in a number of sites where surface waters are

contaminated with acidic mine drainage. Surfa ce water samples collected from 12 locations in west

central Indiana that have been contaminated with acidic mine drainage were reported to contain vanadium

at concentrations ranging from 0.17 to 0.66 mg/L (Allen et al. 1996). Kennish (1998) reported vanadium

concentration s ranging from 1.0 to 38 nmol/L (0.05– 1.9 μg/L) in wa ters from U.S. estuaries and

32 nmol/L (1.6 μg/L) in U.S. coastal marine waters.

Levels in sea water are considerably lower than those in fresh water because much of the vanadium is

precipitated (Byerrum et al. 1974; Van Zinderen Bakker and Jaworski 1980). Vanadium concentrations

measured usually average 1

– 3 μg/L (Sepe et al. 2003; Van Zinderen Bakker and Jaworski 1980), although

levels as high as 29 μg/L have been reported (Byerrum e t al. 1974). The total content of vanadium in sea

water has been estimated to be 7.5x10 12 kg (7.5x10 9 metric tons) (Byerrum et al. 1974). Mean vanadium

concentrations ranging from 2.08 to 2.60 μg/L were reported in seawater samples collected along the

Sa udi coast of the Arabian Gulf (Sadiq et al. 1992b).

Fiorentino et al. (2007) measured vanadium concentrations in groundwater collected from the southwest

of the Province of Buenos Aires, Argentina; all samples contained vanadium, and concentrations ranged

from 0.05 to 2.47 mg/L. Groundwater samples collected from 104 monitoring wells from shallow

aquifers beneath an industrial city in the Eastern Province of Saudi Arabia contained vanadium

concentrations that ranged from 0.04 to 55.69 μg/L, with a mean concentration of 7.46 μg/L (Sadiq and

Alam 1997).

Vanadium is on the EPA Drinking Water Contaminant Candidate List (CCL). The contaminants on this

list are known or anticipated to occur in public water systems; however, they are currently not regulated

***DRAFT FOR PUBLIC COMMENT***VANADIUM 133

6. POTENTIAL FOR HUMAN EXPOSURE

by existing national primary drinking water regulation. Research in ongoing to determine whether

regulations are needed (EPA 2008b).

Mean vanadium concentrations in tap water collected from homes participating a dietary study in EPA

Region V (Indiana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin) for the National Human

Exposure Assessment Survey (NHEXAS) were 1.2 and 1.0 μg/L, respectively, in samples collected after

running the water at high velocity for 3 minutes (flushed tap water) and after there h ad been no usage of

any tap water or toilet in the home for the previous 4 hours (standing tap water) (Thomas et al. 1999).

As part of the National Water- Quality Assessment Program of the U.S. Geological Survey (USGS), water

samples were collected durin g 1991–2004 from domestic wells (private wells used for household drinking

water) for analysis of drinking- water contaminants . Vanadium was detected in 452 of 662 samples, with

a median concentration of 1.29 μg/L ( USGS 2009c ).

Lagerkvist et al. (1986) su mmarized older reports from the 1960s and 1970s regarding vanadium

concentrations in drinking water. One report stated th at 91% of drinking water samples analyzed from

U.S. sources had vanadium concentrations below 10 μg/L , with an average concentration of 4.3 μg/L . In

another report, the typical vanadium concentrations in drinking water were about 1 μg/L

.

6.4.3 Sediment and Soil

Vanadium is widely distributed in the earth’s crust at an average concentration of 100 ppm

(approximately 100 mg/kg) (Byerrum 1991). The level of vanadium measured in soil is closely related to

the parent rock type (Van Zinderen Bakker and Jaworski 1980; Waters 1977). A range of 3– 310 mg/kg

has been observed, with tundra podsols and clays exhibiting the highest concentration, 100 and

300 mg/kg, respectively (Byerrum et al. 1974). The average vanadium content of soils in the United

States is 200 mg/kg (Byerrum et al. 1974) and seems to be most abundant in the western United States,

especially the Colorado Plateau (Cannon 1 963; Grayson 1983).

Gallagher et al. (2008) measured various metal concentrations in soils collected during the summer of

2005 from a site in Jersey City, New Jersey on the west bank of Upper New York Bay. This land was

originally an intertidal mud flat and a salt marsh that was filled during 1860– 1919 with material

consisting of mostly debris from construction projects and refuse from New York City. It was used as a

railroad yard until 1967. The site was then transferred to the New Jersey Division of P arks and Forestry

***DRAFT FOR PUBLIC COMMENT***VANADIUM 134

6. POTENTIAL FOR HUMAN EXPOSURE

in 1970. Vanadium concentrations in soil collected from this site ranged from below the detection limit

(<0.01 μg/g) to 317 μg/g, with a median value of 56.4 μg/g (Gallagher et al. 2008). Metal concentrations

were measured in two alluvial soils from the lower Mississippi River Delta. Median vanadium

concentrations of 3.2 and 3.8 μg/g were reported in freshly deposited alluvium soil from Bonnet Carré

Spillway and in urban soil samples from New Orleans, respectively (Mielke at el. 2000).

Various trace elements were measured in 13 surface soils collected from southwestern Saskatchewan,

Canada (Mermut et al. 1996). Fertilizers and pesticides are the two major anthropogenic sources of trace

elements in the Canadian Prairies. Vanadium conc entrations ranged from 31.75 mg/kg in Hatton soil (0–

13 cm, pH 6.2, 1.32% organic content [OC], 6% clay) to 180.06 mg/kg in Sceptre soil (90–105 cm, pH

8.0, 0.85% OC, 73% clay). Clay soils were found to contain more vanadium that other soils (Mermut et

al . 1996). Vanadium concentrations in 16 soil samples collected in May 2000 in the vicinity of a cement

plant in Catalonia, Spain ranged from 5.6 to 12.4 mg/kg dry weight. These values were generally lower

than vanadium levels found in urban areas (Schuhma cher et al. 2002). The geometric mean vanadium

concentrations in 112 samples street dust and 40 samples of urban soil collected in Aviles, Northern Spain

were 28.1 (range 25.0–34.0) and 34.1 (22.0–67.0) μg/g, respectively (Ordóñez et al. 2003).

Metal co ntamination was determined in soil samples collected from 10 locations in the Hafr Al Batin

Area (Saudi Arabia) near the Saudi/Kuwaiti border following the Gulf War (1990–1991) (Sadiq et al.

1992a). Oil burning in Kuwait, atmospheric fallout of particulat es form the use of explosives in the Gulf

War, and other war-related ground activities created air pollution problems in the countries neighboring

Kuwait. Vanadium concentrations in soil ranged from 2 mg/kg collected at the most distant sampling site

from the Kuwaiti border (15–25 cm depth) to 59 mg/kg collected from a sampling site near the border (0–

5 cm depth). Vanadium concentrations in soil samples were found to decrease with increasing distance

from the border (Sadiq et al. 1992a). Various metal concentrations were determined in 25 surface soil

samples from Surat, India, an industrial area. Vanadium concentrations ranged from 141.9 to

380.6 mg/kg with a mean 284.8 mg/kg (Krishna and Govil 2007).

Mean vanadium concentration of 44 and 82 mg/kg were reported in the sediments of Lake Huron and

Lake Superior. Vanadium was detected in sediment samples from the Georgian Bay and North Channel

(Lake Huron) at mean concentrations of 67 and 66 mg/kg, respectively (International Joint Commission

1978). Heit et al. (1984) reported vanadium concentrations in Rocky Mountain Lake sediments of

27.3 and 15 mg/kg dry weight in Lake Husted surface (0– 2 cm) and subsurface sediments, respectively,

and 35 and 32.8 mg/kg dry weight in Lake Louise surface and subsurface sediments, respectively.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 135

6. POTENTIAL FOR HUMAN EXPOSURE

Vanadium concentrations of 55 and 43 mg/kg dry weight were reported in surface sediments from Lake

Haiyaha and The Loch, two other Rocky Mountain lakes. Total vanadium concentrations of 136 and

222 mg/kg dry weight were reported i n sediment samples from the Texas City channel and Ashtabula

River, Ohio (Engler 1979).

Four sediment cores collected January 1996 from Central Park Lake New York City, New York were

analyzed for various metals including vanadium; average vanadium concen trations ranged from 87 μg/g

at a depth of 44–47 cm to 665 μg/g at a depth of 12–14 cm (Chillrud et al. 1999). In 1966, approximately

35% of the residual fuel oil used in New York City was from Venezuela. Vanadium is enriched in the

sulfur-rich petroleum from Venezuela. Comparison of the approximate year of deposition to vanadium

concentration in the sediment for Central Park Lake showed that vanadium levels in sediments from

Central Park Lake were found to decrease after restrictions on sulfur content o f fuel oils used in New

York City were introduced starting in 1966. The average vanadium concentration peaks at 665 μg/g in

sediments from 12 to 14 cm depth, which correlates with approximately with the mid 1960s (Chillrud et

al. 1999). Trace metal conce ntrations were measured in sediment cores collected in February 1992 from

the Gulf of Mexico; the average vanadium concentration was 47.78 μg/g and ranged from 15.6 to

117.5 μg/g (Macias

- Zamora et al. 1999). Metal concentrations were measured in sediment collected

during early and late autumn of 1993 and 1994 from 16 locations in Lake Erie, the Niagara River, and

Lake Ontario; vanadium concentrations ranged from 6.0 to 31.1 μg/kg dry weight in these sediment

samples (Lowe and Day 2002).

Vanadium concentrations in surface sediments collected during 1988–1991 from the Great Astrolabe

Lagoon, Fiji ranged from 2 to 726 mg/kg dry weight. This lagoon, which encompasses a number of small

volcanic islands, is considered to be a pristine marine environment with m inimal human impact in this

study (Morrison et al. 1997).

A diesel oil spill occurred in April 2002 from a pipeline on the Pacific side of Mexico, in Salina Cruz into

the San Pedro stream, Xadani estuary, and the Superior Lagoon mouth (Salazar- Coria et al . 2007).

Vanadium concentrations in sediment collected after the spill during the dry and rainy seasons were

110.5 and 123.0 mg/kg dry weight at the San Pedro site, 95.4 and 148.9 mg/kg dry weight at the Piedra

Estuary, 113.3 and 107.7 mg/kg dry weight at the Xadani estuary, and <5.0 mg/kg dry weight at Superior

Lagoon, respectively. Vanadium concentrations in a reference site, upstream from the spill were below

the limit of detection, <5.0 mg/kg dry weight.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 136

6. POTENTIAL FOR HUMAN EXPOSURE

Chemical contamination was measured in sedim ent from the Shuaiba Industrial Area (SIA), a coastal area

in Kuwait that receives industrial effluent (Beg et al. 2001). The SIA contains a petrochemical company,

three refineries, two power desalination plants, a melamine company, an industrial gas corporation, a

paper products company, and other smaller industrial plants, as well as a large harbor. Vanadium

concentrations were reported to range from 9.8 to 146.0 mg/kg dry weight in sediment from Shuaiba

coastal area (Beg et al. 2001).

6.4.4 Other En vironmental Media

The majority of foods have naturally occurring low concentrations of vanadium, many of them ≤1 ng/g

(Byrne and Kosta 1978). Food items containing the highest levels of vanadium include ground parsley

(1,800 ng/g dry weight), freeze- dried spinach (533

– 840 ng/g), wild mushrooms (50–2,000 ng/g dry

weight), and oysters (455 ng/g wet weight) (Byrne and Kosta 1978). Intermediate levels are found in food

types such as certain cereals (ranging from 0.7 ng/g in maize to 30 ng/g in Macedonian rice), fish (ranging

from 3.5 ng/g in mackerel to 28 ng/g in freeze -dried tuna), and liver (ranging from 7.3 ng/g in beef to

38 ng/g in chicken) (Byrne and Kosta 1978). In general, seafoods have been found to be higher in

vanadium than terrestrial animal tissues (WHO 1988). Vanadium concentrations in cow milk ranging

from about 0.2 to 10 μg/kg also have been reported in older reports from the late 1970s and early 1960s,

respectively (Lagerkvist et al. 1986). Pennington and Jones (1987) surveyed 234 foods from a 1984

collectio n of the FDA’s Total Diet Study for various trace elements including vanadium. Sixty-four

percent of the Total Diet Foods had vanadium concentrations of <0.5 μg/100 g and 88% had vanadium

concentrations of <2 μg/100 g. Foods with the highest vanadium con centrations included breakfast

cereals, canned fruit juices, fish sticks, several vegetables, sweeteners, wine, and beer. The data from this

survey are summarized in Table 6 -3.

Vanadium, as elemental vanadium or vanadyl sulfate, also may be found in vari ous commercial nutritional

supplements and multivitamins ; vanadium concentration can range from 0.0004 to 12.5 mg in these

supplements depending on the serving size recommended by the manufacturer (NLM 2009). Vanadium

has been used in supplements for indi viduals with diabetes ; i ntakes of 30 –150 mg/day for vanadyl sulfate

(9 –47 mg V/day) and 125 mg/day for sodium metavanadate (52 mg V/day) have been reported (IOM

2001; Smith et al. 2008).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 137

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 3. Vanadium Levels in Food

Mean Range

Food item (μg /100 g)

Adult foods

Milk, yogurt, and cheese 0.1 0

– 0.6

Meat, fish, and poultry 1.0 0

– 11.9

Eggs 0.3 0.2

– 0.4

Nuts 0.6 0.2

– 1.0

Legumes 0.1 0

– 0.3

Grains and grain products 2.3 0– 14.7

Fruits and fruit juices 0.6 0– 7.1

Vegetables 0.6 0

– 7.2

Mix ed dishes and soups 0.6 0– 2.0

Desserts 0.9 0– 2.9

Sweeteners 2.3 0.4

– 4.7

Fats and sauces 0.3 0

– 0.6

Beverages 0.7 0– 3.3

Infant foods

Formulas 0.1 0– 0.2

Meat and poultry 0.5 0

– 0.8

Cereals 1.6 1.2

– 2.0

Fruit and juices 1.6 0– 13.4

Vegetables 0 .4 0

– 1.1

Mixed dishes 0.2 0

– 0.6

Custard 0.2 No data

Source: Pennington and Jones 1987

***DRAFT FOR PUBLIC COMMENT***VANADIUM 138

6. POTENTIAL FOR HUMAN EXPOSURE

Gummow et al. (2005) reported a study that looked at the commonly consumed tissues and milk

concentrations of vanadium in cattle in South Africa that were extensively farmed over a 5 -year period

(1999–2004) in an area adjacent to a vanadium processing plant that was known to have higher-thannormal background levels of vanadium. The group of cattle included two groups, one group of 10 cattle

that was farmed adjacent to the mine, with an average exposure of 1 ,229 mg V/day, and another group of

20 cattle that was farmed 2 –3 km from the first group with an exposure about half that of the high

exposure group (mean=532 mg V/day). Cattle in the trial were monitored ov er a 5

- year period and six

cohorts of animals were slaughtered over this period. Concentrations of vanadium in commonly

consumed tissues (liver, kidney, fillet, and triceps) ranged from <0.05 to 11.51 mg/kg (wet- weight) in

triceps and liver, respectively , over both groups . The median concentrati on of vanadium in milk was

0.23 mg/kg (range: <0.05 –1.92 mg/kg) over both groups. Concentrations of vanadium in tissues from the

group raised adjacent to the mine and those raised 2

– 3 km away were not differentiat ed in the

presentation of the data.

Concentrations of various metals, including vanadium, were measured in samples of six fish species

collected during 1997 and 1998 along the coast of the Adriatic Sea. Vanadium concentrations (μg/kg

fresh weight) were 45.3–74.4 (anchovy), <4.0–4.8 (angler), <4.0 (hake), 6.7–29.8 (mackerel), 11.8–

32.4 (red mullet), and <4.0–2.9 (sole) (Sepe et al. 2003).

Vanadium is found in almost all coals used in the United States, with levels ranging from extremely low

to 10 g/kg ( Byerrum et al. 1974; WHO 1988). Eastern U.S. coal has an average content of 30 ppm,

western coal has an average content of 15 ppm, and coal from the interior contains an average of 34 ppm

(Byerrum et al. 1974). The average vanadium content of bituminous and anthracite coal is 30 and

125 ppm, respectively (Byerrum et al. 1974).

Vanadium is usually the most abundant trace metal found in petroleum samples (Amorim et al. 2007).

Vanadium concentrations in petroleum may be as high as 1,500 mg/kg, while some crude oils contain

<0.1 mg/kg. Vanadium occurs predominantly as the vanadyl ion (VO 2+ ) in the form of organometallic

complexes with porphyrins. Vanadyl porphyrins originated from the formation of crude oil; the vanadyl

ion was substituted for magnesium ion (Mg 2+ ) in the chlorophylls of plants. Other vanadium complexes

in petroleum include non-porphyrin and organic acid complexes (Hovmand et al. 2008). Mamane and

Pirrone (1998) reported that residual fuel oils manufactured from U.S. crude oils contain 25–50 ppm of

vanadium. Venezuelan, Middle Eastern, and North African residual oils have vanadium concentrations of

200–300, 10– 20, and 50 –90 ppm, respectively. Vanadium is highly enriched relative to other elements in

***DRAFT FOR PUBLIC COMMENT***VANADIUM 139

6. POTENTIAL FOR HUMAN EXPOSURE

heavy fuel oils due to vanadium porph yrins. Because of this, vanadium is used as a marker for emissions

from fuel oil combustion (Mamane and Pirrone 1998).

Vanadium concentrations ranging from 0.49 to 5.33 μg/g in were measured in 45 different brands of

whole unsmoked cigarettes. Mean vana dium concentrations of 1.11, 0.67, 0.09, and 0.33 μg/cigarette in

whole unsmoked cigarettes, ash, filter, and smoke of six different brands of cigarettes, respectively

(Adachi et al. 1998a).

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Food is the main source of vanadium intake for humans (Lagerkvist et al. 1986). Higher dietary intake

levels are possible when food is grown in soil contaminated with greater than background levels of

vanadium. Vanadium in food is mainly ingested as VO 2+ (vanadyl, V 4+ ) or HVO 4 2- (vanadate) (Sepe et al.

2003). Byrne and Kučera (1991) reported a daily intake of vanadium of 10 –20 μg. The dietary intake of

vanadium estimated from the combined total intake of solids and liquids from a dietary study in EPA

Region V (Ind iana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin) for the NHEXAS was

0.34 μg/kg of body weight/day (Thomas et al. 1999). Pennington and Jones (1987) surveyed 234 foods

from a 1984 collection of the FDA’s Total Diet Study for various trace elements including vanadium.

Based on this survey, estimated daily intakes of vanadium ranged from 6.2 μg/day for 60–65- year -old

females to 18.3 μg/day for 25 –30- year

- old males. Table 6

- 4 summarizes the estimated daily intakes of

vanadium for the various age gro ups in this study.

Various metal concentrations were determined in foods (meat, fish and seafood, pulses [lentil, bean],

cereals, vegetables, fruits, tubers, whole milk, yogurt, eggs, and sugar) purchased from local markets,

supermarkets, and grocery stor es in zones of Tarragona County (Catalonia, Spain) near a hazardous waste

incinerator, which has been operating since 1999 (Bocio et al. 2005). A dietary intake for vanadium of

28.9 μg/day was estimated for an average adult man (70 kg body weight) in Tarragona County (Catalonia,

Spain). Fish and seafood (hake, sardine, and mussels) were the only foods that contributed to this value;

vanadium was not detected in any other foods that were surveyed. The detection limit for vanadium in

this study was 0.25 μg/g (Bocio et al. 2005). Sepe et al. (2003) reported an 11–34% contribution to the

daily vanadium ingestion from fish collected during 1997 and 1998 along the coast of the Adriatic Sea for

the population in this area.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 140

6. POTENTIAL FOR HUMAN EXPOSURE



### Table 6

- 4

. Estimated Daily Vanadium Intake

Age group Intake (μg/day)

6

– 11 Months 6.7

2 Years 6.5

14

– 16 Years, female 7.1

14

– 16 Years, male 11.0

25

– 30 Years, female 8.1

25

– 30 Years, male 18.3

60

– 65 Years, female 6.2

60

– 65 Years, male 10.6

Source: Penningt on and Jones 1987

***DRAFT FOR PUBLIC COMMENT***VANADIUM 141

6. POTENTIAL FOR HUMAN EXPOSURE

Gummow et al. (2005) estimated dietary intakes of vanadium from the consumption of cattle in South

Africa that were raised over a 5

- year period (1999 –2004) in an area adjacent to a vanadium processing

plant that was known to have higher-than-normal background levels of vanadium. The median potential

daily intakes of vanadium in the diet of humans consuming beef from these cattle were estimated to be

1.9, 1.8, 2.9, and 1.2 μg/kg body weight/day for consuming fillet, triceps, liver, and kidney, respectively.

The median potential daily intake of vanadium from drinking milk of these cattle was estimated to be

4.6 μg/kg body weight/day (Gummow et al. 2005).

As compared to food, drinking water is a less important source of vanadium exposure for the general

population. Thomas et al. (1999) reported mean vanadium concentrations of 1.2 and 1.0 μg/L in flushed

tap water and standing tap water samples from Indiana, Illinois, Michigan, Minnesota, Ohio, and

Wisconsin, respectively. Assuming a daily intake of 2 L of water (EPA 1988) , a daily intake of

approximately 2 μg of vanadium from tap water can be estimated.

Vanadium is present in many dietary supplements, including multivitamin and mineral supplement

formulations, as well as products mark eted for weight control, bodybuilding, and diabetes control (NTP

2008) . The National Library of Medicine’s (NLM’s) Dietary Supplements L abel Database lists

>100 products containing vanadium (NLM 2009). Many of these products contain <10 μg of vanadium.

Some of these products contain up to 12.5 mg of vanadium depending on the serving size recommended

by the manufacturer . Three containing vanadyl sulfate are also listed on the NLM’s Dietary Supplements

Label Database, containing 0.01–1.66 mg of vanadyl su lfate (0.003 –0.52 mg vanadium) depending on the

serving size recommended by the manufacturer (NLM 2009) . According to the Third National Health

and Nutrition Examination Survey on supplement use of vanadium, the median intake of supplement

vanadium by adults was approximately 9 μg/day (IOM 2001). Vanadium has been used in supplements

for individuals with diabetes. Intakes of 30–150 mg/day for vanadyl sulfate (9 –47 mg V/day) and

125 mg/day for sodium metavanadate (52 mg V/day) have been reported (IOM 2001; Smith et al. 2008).

Vanadyl sulfate supplements have been used as well by weight training athletes at levels up to 60 mg/day

(18.6 mg V/day) ( Barceloux 1999). Consumption of some vanadium -containing supplements may result

in intakes of vanadium that wo uld exceed those from food and water.

The general population may also be exposed to airborne vanadium through inhalation, particularly in

areas where use of residual fuel oils for energy production is high (Zoller et al. 1973). Assuming air

concentrati ons of approximately 50 ng/m 3 , Byrne and Kosta (1978) estimated a daily intake of 1 μg

vanadium, assuming an average inhalation rate of 20 m 3 /day. In addition, cigarette smoke can contribute

***DRAFT FOR PUBLIC COMMENT***VANADIUM 142

6. POTENTIAL FOR HUMAN EXPOSURE

vanadium exposure. Koutrakis et al. (1992) estimated an emission rate for vanadium from cigarette

smoke of 373 ng/cigarette ; approximately 0.04 μg of vanadium is given off by in the smoke of one

cigarette

.

Lin et al. (2004) reported vanadium concentrations in the blood of 52 Taiwanese college students (19–

42 years ol d). None of these students had occupational exposure to vanadium and five of the students (all

male) were smokers. The average vanadium concentration in was 0.42 ng/mL in all students, with a

range of 0.01–1.20 ng/mL. The average vanadium concentration in blood for the female students was

0.37 ng/L and the average concentration for nonsmoking male students was 0.44 ng/L; the average for the

five smokers was 0.47 ng/mL. Concentrations of vanadium in human blood reported in the literature

range from 0.032 to 0.095 n g/mL (Kučera et al. 1992; Lin et al. 2004; Sabbioni et al. 1996). The average

vanadium concentration in blood of individuals that have occupational exposure is 33.2 (3.10–217)

ng/mL (Lin et al. 2004). Sabbioni et al. (1996) surveyed the literature for reports on vanadium

determination in human blood, serum, and urine and reported that vanadium concentrations in blood

and/or serum ranged from 0.45– 18.4 nmol/L (0.022 –0.937 μg/L) and concentrations in urine ranged from

4.16– 15.7 nmol/L (0.212 –0.800 μg/L). Normal concentrations of vanadium in blood and serum were

reported to be around 1 nmol/L (0.05 μg/L) and around 10 nmol/L (0.5 μg/L) for urine. Nixon et al.

(2002) reported similar values for vanadium concentrations of 0.05 and 0.24 μg/L in serum and urine,

respectively, in healthy individuals from a literature survey. Vanadium concentrations ranging from 30 to

160 μg/kg have been reported in hair (Fernandes et al. 2007; Kučera et al. 1992). No functional role for

vanadium in higher animals or humans has been identified (IOM 2001).

6.6 EXPOSURES OF CHILDREN

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susc eptibility.

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways.

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults.

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths,

***DRAFT FOR PUBLIC COMMENT***VANADIUM 143

6. POTENTIAL FOR HUMAN EXPOSURE

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children

also are closer to the gr ound, and they do not use the judgment of adults to avoid hazards (NRC 1993).

Similar to adults, dietary intake of vanadium through the ingestion of food is the primary exposure route

for children. This route of exposure is particularly relevant when the food is contaminated with soil

because soil contains an average of about 10,000 times as much vanadium as is found in many biological

materials (Byrne and Kosta 1978). Since young children tend to ingest soil and dust during daily

activities, children ma y be exposed to vanadium through the ingestion of soil or dust. Cigarette smoke

can contribute vanadium exposure of children. Approximately 0. 04 μ g of vanadium is given off by in the

smoke of one cigarette (Koutrakis et al. 1992).

Blood and hair samples were collected from 23 children living in the vicinity of a metallurgical plant

producing vanadium pentoxide (V 2 O 5 ) approximately 20 km from Prague, Czechoslovakia (Kučera et al.

1992). These children may have been expos ed to vanadium due to contamination of well water. A

control group consisted of 17 children from a nonpolluted rural area about 30 km from Prague. Median

vanadium concentrations in hair samples from the exposed and control groups did not differ significantly,

and were 98 and 88 μg/kg, respectively. The median vanadium concentration in the blood of the exposed

children and the children in the control group were 0.078 and 0.042 μg/L, respectively, and were

considered significantly different (Kučera et al. 1992).

Concentrations of vanadium in human breast milk of 0.46, 0.27, 0.21, 0.11, 0.69, and 0.13 μg/g have been

reported in samples from Nigeria, Za ire, Guatemala, Hungary, Philippines, and Sweden, respectively

(Nriagu et al. 1992). Ikem et al. (2002) reported mean vanadium concentrations of 0.001, 0.002, and

0.003 μg/mL in milk-based liquid formulas from the United Kingdom, milk based powdered formu las

from the United States, and soy-based powder formulas from the United States, respectively. Vanadium

was not detected in milk

- based powdered formulas from Nigeria and the United Kingdom. Daily intakes

of vanadium for infants in the United States were estimated to be 0.05, 3.5, and 2.8 μg/day for milk

- based

powder formulas, soy -based powder formulas, and hypoallergenic powder formulas from the United

States, respectively (Ikem et al. 2002).

Pennington and Jones (1987) reported concentrations in infant foods that ranged from 0.1 μg/100 g in

formulas to 1.6 μg/100 g in cereals, fruits, and juices. Daily intakes of vanadium of 6.7, 6.5, 7.1, and

11.6 μg/day for children aged 6– 11 months, 2 years, 14

– 16 years (female), and 14

– 16 years (male),

***DRAFT FOR PUBLIC COMMENT***VANADIUM 144

6. POTENTIAL FOR HUMAN EXPOSURE

respective ly, were estimated based on this food survey. A summary of these data are found in Tables 6-3

and 6-4.

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Populations consuming foods grown in soils supplemented with fertilizers or sludge containing vanad ium

or in soils naturally high in vanadium content may be exposed to concentrations higher than background

levels. This is due primarily to surface deposition.

Populations in areas with high levels of residual fuel oil consumption may also be exposed t o above

background levels of vanadium, both from increased particulate deposition upon food crops and soil in

the vicinity of power plants and higher ambient air levels (Zoller et al. 1973). Cities in the northeastern

United States frequently fall into th is category, where ambient air levels often range from 150 to

1,400 ng/m 3 (Zoller et al. 1973).

Personal exposure measurements were conducted on 18 boilermakers and 11 utility workers before and

during a 3- week overhaul of a large oil -fired power plant (Liu et al. 2005). Utility workers included

mechanics, welders, laborers, painters, precipitator operators, work crew supervisors, and laboratory

workers. During the overhaul, boilermakers worked both inside and outside the boiler and were more

likely to be exposed to ash. Utility workers worked outside the boiler in adjacent areas and had little

direct contact with the ash. Time

- weighted average exposures for the boilermakers and the utility

workers were 1.20 and 1.10 μg/m 3 , respectively, before the overhaul work and 8.9 and 1.4 μg/m 3

, respectively, during the overhaul work (Liu et al. 2005).

Full -shift, personal breathing sampling was conducted on nine employees working in the finishing and

cut-off areas (torch cutting, pneumatic hammer, water blast, and the five finishing workstations) of a

titanium investment casting plant in Redmond, Oregon during July 7–10, 2003. Respirable vanadium

pentoxide concentrations ranged from 0.0005 to 0.0089 mg/m 3 , with the highest measurement of

0.123 mg/m 3 in the torc h cutting area (NIOSH 2004).

Vanadium, as elemental vanadium or vanadyl sulfate, may be found in various commercial nutritional

supplements and multivitamins; vanadium concentration can range from 0.0004 to 12.5 mg in these

supplements depending on the serving size recommended by the manufacturer (NLM 2009). Vanadium

supplements have be used and studied as supplements for diabetic individuals. Intakes of 30–150 mg/day

***DRAFT FOR PUBLIC COMMENT***VANADIUM 145

6. POTENTIAL FOR HUMAN EXPOSURE

for vanadyl sulfate (9–47 mg V/day) and 125 mg/day for sodium metavanadate (52 mg V/day) have been

reported (IOM 2001; Smith et al. 2008). Vanadyl sulfate supplements have been used as well by weight

training athletes at levels up to 60 mg/day (18.6 mg V/day) ( Barceloux 1999). Consumption of some

vanadium containing supplements may result in intakes of vanadium that would exceed that from food

and water.

6.8 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of t he Public Health Service) to assess whether

adequate information on the health effects of vanadium is available. Where adequate information is not

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research

designed to determine the health effects (and techniques for developing methods to determine such health

effects) of vanadium.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance -specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance- specific research agenda will be proposed.

6.8.1 Identification of Data Needs

Physical and Chemical Properties. The physical and chemical properties of vanadium and its

com pounds are reasonably well documented (see Tables 4-1 and 4-2). No data needs are indentified.

Production, Import/Export, Use, Release, and Disposal. According to the Emergency

Planning and Community Right- to -Know Act of 1986, 42 U.S.C. Section 11023, industries are required

to submit substance release and off -site transfer information to the EPA. The TRI, which contains this

information for 2007, became available in March of 2009. This database is updated yearly and should

provide a list of industri al production facilities and emissions.

Companies involved in the vanadium production industry (see Table 5-3), uses of vanadium and various

vanadium compounds (Lide 2008; USGS 2009a), and various sources of release are also available (see

Table 6-1). Th ere is little information available describing the amounts of vanadium consumed in each

***DRAFT FOR PUBLIC COMMENT***VANADIUM 146

6. POTENTIAL FOR HUMAN EXPOSURE

use category or the quantities recycled and disposed of within the United States. Few details were found

regarding the specific disposal methods used (HSDB 2009; USGS 2009a). Information in each of these

areas would provide an indication of the potential for human exposure as a result of disposal practices.

Environmental Fate. The relative contributions of natural (Byerrum et al. 1974; Zoller et al. 1973)

and anthropogenic sources (Byerrum et al. 1974; TRI07 2009) of vanadium to the different environmental

media are available. Partitioning between the various media is described, in particular from soil to water

and from water to sediment (Wehrli and Stumm 1989; WHO 1988), but specific coefficients are not

available in many studies. Information on the transport of vanadium within each media is available (Duce

and Hoffman 1976; Martin and Kaplan 1998; Wehrli and Stumm 1989; WHO 1988; Zoller et al. 1973).

Bioavailabi lity from Environmental Media. Occupational studies on the uptake of vanadium via

the inhalation route exist; however, data suggesting that this route is relevant with regard to hazardous

waste sites are lacking. Dermal absorption data are limited; how ever, it is likely that absorption via this

route is low since vanadium, like other metals, has low solubility in lipids (WHO 1988). The daily

intakes of vanadium from air, food, and water are generally small (Bocio et al. 2005; Thomas et al. 1999;

Zoller et al. 1973). Seafood or milk from cows raised in an area with vanadium contamination can be a

more significant dietary contribution of vanadium (Gummow et al. 2005; Sepe et al. 2003). No data

needs are identified.

Food Chain Bioaccumulation. The up take of vanadium in aquatic plants and animals is reasonably

well documented; levels of vanadium present in different species have been established (Byerrum et al.

1974; WHO 1988). Levels present in terrestrial plants (Byerrum et al. 1974; Cannon 1963) an d animals

(Van Zinderen Bakker and Jaworski 1980; WHO 1988) have been established for several species. Uptake

of vanadium by terrestrial plants grown on sludge-amended, or vanadium- containing fertilized fields has

been studied. Vanadium does not appear to concentrate in above-ground portions of terrestrial plants

(Byerrum et al. 1974). No data needs are identified.

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of vanadium

in contaminated media at hazardous waste site s are needed so that the information obtained on levels of

vanadium in the environment can be used in combination with the known body burden of vanadium to

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste

sites.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 147

6. POTENTIAL FOR HUMAN EXPOSURE

Estimates of human exposure to vanadium from food (Bocio et al. 2005; Byrne and Kosta 1978; Byrne

and Ku čera 1991; Gummow et al. 2005; Pennington and Jones 1987; Sepe et al. 2003; Thomas et al.

1999; WHO 1988), drinking water ( USGS 2009c ; Lagerkvist et al. 1986 ; Thomas et al. 1999), and air

(Byrne and Kosta 1978) are limited. Current information on emission levels from the combustion of

residual fuel oil would enable a more complete picture of populations potentially exposed to higher than

background ambient air levels. A data need is identified regarding vanadium levels found in

environmental media in the vicinity of hazardous waste sites.

Exposure Levels in Humans. Limited information was located describing levels of vanadium

present in human tissues for the general population (Byrne and Kosta 1978; F ernandes et al. 2007; Kučera

et al. 1992; Lin et al. 2004; Nixon et al. 2002; Sabbioni et al. 1996). Little information is available on

tissue levels found in populations near hazardous waste sites. A data need for vanadium levels in blood

samples of the general population and those residing near hazardous waste sites is identified.

This information is necessary for assessing the need to conduct health studies on these populations.

Exposures of Children. Measurements of the vanadium in blood and hair of children who have been

exposed to vanadium, as well as unexposed children, are limited (Kučera et al. 1992). Additional

information monitoring vanadium concentrations in children are needed. Specific data on the intake of

vanadium from food eaten by children and from their diet are also limited (Ikem et al. 2002; Pennington

and Jones 1987).

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data

Needs: Children’s Susceptibility.

Exposure Registrie s. No exposure registries for vanadium were located. This substance is not

currently one of the compounds for which a sub- registry has been established in the National Exposure

Registry. The substance will be considered in the future when chemical sel ection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates

the epidemiological research needed to assess adverse health outcomes that may be related to exposure to

this substance.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 148

6. POTENTIAL FOR HUMAN EXPOSURE

6. 8.2 Ongoing Studies

No long- term research studies on the environmental fate of vanadium were identified. No ongoing

studies or long -term research concerning occupational or general population exposures to vanadium were

identified (FEDRIP 2009).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 149



### 7. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting,

measuring, and/or monitoring vanadium, its metabolites, and other biomarkers of exposure and effect to

vanadium. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to

identify well

- established methods that are used as the standard methods of analysis. Many of the

analytical methods used for environmental samples are the methods approved by federal agencies and

organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other

methods presented in this chapter are those that are approved by groups such as the Association of

Official Anal ytical Chemists (AOAC) and the American Public Health Association (APHA).

Additionally, analytical methods are included that modify previously used methods to obtain lower

detection limits and/or to improve accuracy and precision.

Vanadium can be determined as the total metal, as well as in its different oxidation states (species). The

various oxidation states of vanadium can interconvert between the oxidation state depending on

conditions such as, oxidation-reduction potential, pH, and salinity. In natural waters, dissolved vanadium

exists as vanadium(IV) or vanadium(V) and these species have different toxic properties; therefore,

determination of the vanadium species present in a sample can be more important than the total vanadium

content of the sampl e in order to best evaluate human exposure (Pyrzyńska and Wierzbicki 2004).

Analytical techniques for the determination of species of vanadium include standard atomic spectroscopic

techniques and separations methods coupled with sensitive detectors. Sep aration methods include

capillary electrophoresis (CE) and liquid chromatography (LC). Atomic spectroscopic methods used for

the determination of vanadium include atomic absorption spectroscopy (AAS) with flame and graphite

tube atom izers, inductively coupled plasma optical emission spectrometry (ICP

- OES), inductively

coupled plasma mass spectrometry (ICP

- MS), x

- ray fluorescence spectrometry (XRF), and

spectrophotometric methods (Chen and Owens 2008).

Sample preparation is one of the most important steps in the analysis of vanadium in biological and

environmental samples. Direct analysis of vanadium species using atomic spectroscopic or separation

techniques is generally not feasible due to the relatively low concentrations of vana dium found in samples

as compared to other metals. In addition, the complexity of the matrices of biological and environmental

samples can interfere with the determination of vanadium species, and it is often necessary to remove the

matrices prior to vana dium analysis (Pyrzyńska and Wierzbicki 2004; Chen and Owens 2008).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 150

7. ANALYTICAL METHODS

The main methods for matrix removal are liquid-liquid extraction (LLE) and solid phase extraction (SPE).

LLE is based on the distribution of the analyte between two immiscible solvents and involves the

formation of an uncharged chemical species in the aqueous phase by chelation or ion- association of the

vanadium ion, followed by extraction into an organic solvent. Example of complexing reagents (chelates)

used to bind vanadium species include, vanadium(IV) with bis(salicylaldehyde) tetramethylethylene

diimine in a chloroform/water mixture, vanadium(V) with N-benzoyl-N-phenylhydroxylamine (BPHA) in

a chloroform/water mixture, and vanadium(V) with 2- (5

- bromo -2- pyridylazo) -5- (N -propyl-N-sulfopropylamino)-phenol (5- Br

- PAPS) in a xylene/water mixture. Each of these LLE steps was followed by

separation using liquid chromatography with UV detection. Other complexing agents that have been

studied include dibenzo -18- crown -6 and N-phenyl-(1,2-methanofullerene)-formohydroxamic acid

(PMFFA) (Chen and Owens 2008; Pyrzy ńska and Wierzbicki 2004).

SPE is based on the transfer of metal ions from an aqueous phase to the active sites of a solid phase.

Compared to LLE, SPE is simpler and more convenient to automate. It also uses less solvent and requires

fewer manipulations . Several ion

- exchange resins, functionalized cellulose sorbents, and chelating resins

have been studied for the selective preconcentration and separation of vanadium species. Cellulose

sorbent with phosphonic acid exchange groups gives excellent enrichment of vanadium(IV) and

vanadium(V) and can be simultaneously eluted using an ethylenediamine tetraacetic acid (EDTA)

solution. Other solid phases used to separate and preconcentrate vanadium species include Sephadex

DEAE A -25 with Eriochrome Cyanide R complexation, C 18 microcolumn or XAD -7 resin with

complexation using 2- (5 -bromo-2- pyridylazo) -5-diethylaminophenol or dithizone or 8-hydroxyquinoline

(8

- HQ), and Chelex 100 (Chen and Owens 2008; Pyrzyńska and Wierzbicki 2004).

Vanadium concentrations in biological and environmental samples are typically very low, and vanadium

analysis requires powerful analytical methods. Analytical methods with sufficient sensitivity include

neutron activation analysis (NAA), electrothermal atomic absorption spectrometry ( ETAAS), inductively

coupled plasma atomic emission spectrometry (ICP

- AES), ICP -MS, and some UV-vis spectrophotometric

methods (Pyrzyńska and Wierzbicki 2004). ETAAS is routinely used for the determination of trace

concentrations of vanadium. ICP- MS has better sensitivity than ETAAS; however, interference from the

sample matrix can complicate the analysis. The species 16 O 35 Cl + and 34 S 16 OH + from the sample matrix

can overlap with the most abundant isotope of vanadium at m/z = 51 (Nixon et al. 2002; Pyrzyńska and

Wierzbicki 2004).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 151

7. ANALYTICAL METHODS

Due to the low levels of vanadium that are typically found in biological and environmental samples, c are

must be exercised during sample handling in order to avoid contamination. Vanadium may be found in

disposable steel needles, collection vials, storage containers, and chemicals and reagents (Kučera and

Sabbioni 1998).

7.1 BIOLOGICAL MATERIALS

Met hods for determination of vanadium in biological samples are summarized in Table 7-1.

NAA has been widely used to measure trace elements (including vanadium) in biological samples (Allen

and Steinnes 1978; Lavi and Alfassi 1988; Martin and Chasteen 1988; Mousty et al. 1984). In NAA, the

sample is bombarded with neutrons, and the element of interest is made radioactive. The amount of the

element present in the sample is then determined by measurement of the radioactivity or radioactive

decay products. When 51 V is bombarded with neutrons, it becomes 52 V (half -life 3.75 minutes and

γ emission of 1.433 MeV). The resultant γ emission is detected with an efficient detector with high

spectral resolution such as a well

- type germanium detector combined with a multichannel analyzer. The

concentration of vanadium is determined through its short-lived half- life of 52 V (Seiler 1995). Detection

limits of low - to sub- ppb (μg/L) levels of vanadium in blood and urine samples have been obtained (Allen

and Steinnes 1978; Lavi and Alfassi 1988; Mousty et al. 1984). The advantages of the NAA technique

are its sensitivity and multi

- elemental capability. The disadvantages of this technique include its high

cost and the limited availability of nuclear facilities for NAA anal ysis (Seiler 1995).

Sabbioni et al. (1996) surveyed the literature for reports on vanadium determination in human blood,

serum, and urine. Many analytical methods have been used to determine vanadium concentrations in

blood, serum, and urine samples, including spectrography, colorimetry, catalytic reactions, XRF, particle

induced x- ray emission (PIXE), ICP -AES, isotope dilution mass spectrometry (ID- MS), graphite furnace

AAS (GF

- AAS), and NAA. Only ID

- MS, NAA, and GF -AAS can determine vanadium concentrat ions at

levels of a few picograms (pg) of vanadium; GF -AAS and NAA are used most frequently (Ku čera and

Sabbioni 1998; Nixon et al. 2002; Sabbioni et al. 1996).

Nixon et al. (2002) reported the use of a Dynamic Reaction Cell TM ICP

- MS (DRC

- ICP

- MS) for the

analysis of vanadium in serum and urine. Generally, Zeeman graphite furnace atomic absorption

spectrometry (ZGFAAS) and NAA are routinely used for the determination of vanadium in urine and

serum. While ICP -MS as been routinely used to determine heavy metal concentrations in blood, serum,

***DRAFT FOR PUBLIC COMMENT***VANADIUM 152

7. ANALYTICAL METHODS



### Table 7

- 1. Analytical Methods for Determining Vanadium in Biological Materials

Sample

matrix Preparation method Analytical

method Sample

detection limit Percent

recovery Reference

Blood/u rine Digest sample and evaporate; redissolve
in acid; extract with MIBK; evaporate;

redissolve in acid NAA ~1 μg/L (bloo d);

2– 4 μg/L (urine) No data Allen and Steinnes

1978

Urine Wet ashing with HNO 3 ; chelation with GFAAS 1 μg/L 96

– 100% Buchet et al. 1982

cupferron; extraction

into MIBK

Serum/urine Digestion in

H 2 SO 4 /HClO 4 /HNO 3 add KMnO 4 , sulfamic
acid, and HCl; extract

with BTA in benzene ETAAS 0.008 μg/L 90.3% (serum); 90.8% (urine) Ishida et al. 1989

Serum Coprecipitate sample

with lead nitrate or NAA 0.7 μg/L No data Lavi and Alfassi

1988 bismuth nitrate; dry

and irradiate

Blood Microwave digestion

with HNO 3 ICP

- MS 0.0078 μg/L No data Lin et al. 2004

Serum/u rine Dilution with 1% HNO 3 and addition of internal DRC

- ICP

MS 0.028 μg/L No data Nixon et al. 2002

standard

Hair Washing and drying of hair samples, followed by cryogenic grinding; powdered hair samples

pr epared as slurries in

mixtures of HNO 3 and a slurry stabilizer ETAAS 0.28

– 0.34 μg/L No data Fernandes et al.

2007

BTA = N

- benzoyl -N-(o- tolyl)hydroxylamine; DRC

- ICP

- MS = Dynamic Reaction Cell TM inductively coupled mass spectrometry; MIBK = methyl isobutyl ketone; NAA = neutron activation analysis

***DRAFT FOR PUBLIC COMMENT***VANADIUM 153

7. ANALYTICAL METHODS

and urine, and ICP-MS quantitation is at least an order of magnitude better than ZGFAAS for elements

such as arsenic, lead, selenium, and cadmium, interference from 16 O 35 Cl + , which is produced in the argon

plas ma of the instrument, has limited the use of ICP -MS for the determination of vanadium. In this study

it was found that with proper dynamic reaction cell conditions, OCl + interference can be eliminated. The

detection limit for vanadium (0.028 μg/L) was also found to be superior to that of ZGFAAS (1.9 μg/L)

(Nixon et al. 2002).

Fernandes et al. (2007) reported on a method to analyze hair samples using ETAAS. Samples were

powdered using cryogenic grinding and hair slurries contained nitric acid, Triton X-100 (a nonionic

surfactant), and water soluble tertiary amines. Limits of detection of 0.28 and 0.34 μg/L were reported

using longitudinal heating and transversal heating graphite furnace atomizers, respectively.

7.2 ENVIRONMENTAL SAMPLES

Standard met hods are available to measure vanadium concentrations in air, surfaces, water, soil, sediment,

and plant and animal tissue (EPA 1983a, 1983b, 1983c, 1994a, 1994b, 1997a, 2003a; NIOSH 2003a,

2003b, 2003c, 2003d; OSHA 2002; USGS 1987, 1993, 1996, 1998, 2006, 2007 ). Atomic spectroscopic

methods are generally used in these methods as well as ICP -MS and spectrophotometric methods.

NIOSH Method 7504 (1994) and OSHA Method ID-185 (1991) can be used to measure vanadium oxides

in air samples using XRF. Methods fo r determination of vanadium in environmental samples are

summarized in Table 7-2.

7.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether

adequate information on the health effects of vanadium is available. Where adequate information is not

available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research

designed to determine the health effects (and techniques for developing methods to determine such health

effects) of vanadium.

The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, a nd EPA. They are defined as substance-specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

***DRAFT FOR PUBLIC COMMENT***VANADIUM 154

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Methods for Determining Vanadium in Envi ronmental Samples

Sample Preparation Analytical detection Percent Sample matrix method method limit recovery Reference

Vanadium

Air Collect sample on ICP

- AES

MCE or PVC filter, followed by

HNO 3 / HClO 4 ashing

Air Collect sample on ICP

- AES

MCE or PVC filter, followed by aqua regia ashing

Air Collect sample on ICP

- AES
MCE filter, followed by hot

block/HC l/HNO 3 digestion

Wipes Wipe surface; ash ICP

- AES wipe with

HNO 3 /HClO 4

Air, w ipe, or b ulk D igest ion of filters ICAP

- AES

with HNO 3 /

H 2 SO 4 /H 2 O 2

Water Acid solubilization ICP

- MS

Water Sample is mixed AVICP

- AES

with HNO 3 /HCl

and heated

Water Acidified with FAAS

HNO 3

Water Acidified with GFAAS

HNO 3

Water Fi lter and ICP

- AES acidified samples

Water Fi lter and ICP

- MS acidified sample s 0.028 μg/filter

0.028 μg/filter

0.003 μg/mL

0.01 μg/ wipe

1.9 μg

0 .01 4 μ g/ L

0.2 μ g/ L

200 μ g/ L

4 μ g/ L

6 μ g/ L

0.08 mg/L 98.3

– 103.2% NIOSH 2003 a (MCE) ( Method 7300 )

102.5

– 108.3% (PVC)

101.3

– NIOSH 2003 b

106.0% ( Method 7301 ) (MCE)

77.8

– 96.1% (PVC)

No data NIOSH 2003 c (Method 7303)

No data NIOSH 2003d (Method 9102)

No da ta OSHA 2002 (Method ID

- 125G)

97

– 109.2% EPA 1997a (EPA Method 200.10)

93% EPA 2003 (EPA Method 200.5)

95

– 100% EPA 1983a, 1983b (EPA Method 286.1)

No data EPA 1983a, 1983c (EPA Method 286.2)

No data USGS 1987 (USGS

Method I

- 1472

- 87)

64

– 105% USGS 1998 (USGS

Method I

- 2477

- 92)

***DRAFT FOR PUBLIC COMMENT***VANADIUM 155

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Methods for Determining Vanadium in Envi ronmental Samples

Sample Preparation Analytical detection Percent Sample matrix method method limit recovery Reference

Water Treatment with an

a mmonium persulfate phosphoric acid reagent and g allic

acid solution

Water Fi lter and acidified samples

Water (filtered) Filtered (0.045 μm membrane); preserved with

HNO 3

Water Preserved with (unfiltered) HNO 3 followed by digestion

Water/waste Digestion with

water/ solid nitric and

wastes hydrochloric acid

Water/waste s Digestion with

nitric and hydrochloric acid

Water/waste Acid digestion

water/ solid

wastes

Soil/sediment Air

- dried and sieved; digestion

with HNO 3 using

a closed

- vessel

microwave digestion procedure

Animal tissue Acid digestion

Animal tissue Acid digestion Colorimetric

ICP

- OE S

ICP

- MS

ICP

- MS

ICP

- AES

ICP

- MS

ICP

- AES

ICP

- MS

ICP

- MS

ICP

- AES 1 μ g/ L

5 μ g/ L

0.05 μ g/ L

0.05 μ g/ L

3 μ g/ L

2.5 μ g/ L

5 μ g/ L

0.01 μ g/ L

0.06 μ g/ g

Not

calculatable No data USGS 1993 (USGS

Method I

- 2880)

98% USGS 1998 (USGS

Method I

- 4471

- 97)

No data USGS 2006 (USGS

Method I

- 2020

- 05)

No data USGS 2006 (USGS

Method I

- 4020

- 05)

84

– 104% EPA 1994a ( EPA

Method 200.7 )

74.9

– 113.4% EP A 1994b ( EPA

Method 200.8 )

No data EPA 200 7 (EPA Method 6010 C)

No data USGS 2006 (USGS

Method I

- 5020

- 05)

101% USGS 1996 (USGS

Method B

- 9001

- 95 [ICP

- MS])

96% USGS 1996 (USGS

Method B

- 9001

- 95 [ICP

- AES])

***DRAFT FOR PUBLIC COMMENT***VANADIUM 156

7. ANALYTICAL METHODS



### Table 7

- 2. Analytical Methods for Determining Vanadium in Envi ronmental Samples

Sample Preparation Analytical detection Percent Sample matrix method method limit recovery Reference

Biota Digestion wi th ICP

- MS 0.01 μ g/ L No data USGS 2006 (USGS

HNO 3 using a Method I

- 9020

- 05)

closed

- vessel

microwave digestion procedure

Vanadium o xides

Air Collect sample on XRD 4

– 28 μg No data NIOSH 1994 PVC filter, (V 2 O 5 ), 5

– ( Method 7504 )

d issolve filter in 62 μg (V 2 O 3 )

, THF ; redeposit on 7– 50.3 μg
silver filter ( NH 4 VO 3 )

Vanadium pentoxide

Air Collect sample on XR D 25 μ g at 65 s 163.4

– OSHA 1991
PVC filter, 190.2% (Method ID

- 185 )

d issolve filter in (r e spirable

THF ; suspension dust); 85.9

– is produced with 91.1% (f ine

the collected respirable

dust , which is dust)

transferred to

silver membrane

AVICP-AES = a xially viewed inductively coupled plasma

- atomic emission spectrometry ; EPA = Environmental Protection Agency ; FAAS = flame atomic absorption spectrometry; GFAAS : graphite furnace atomic abs orption spectrometry; ICAP -AES = i nductively c oupled a rgon p lasma -a tomic e mission s pectroscopy; ICP

- AES = inductively coupled plasma

- atomic emission spectroscopy ; ICP

- MS = inductively couples plasma

- mass spectrometry ; I CP -OES = ind uctively coupled plasma

- optical emission spectroscopy ; MCE = mixed cellulose ester ; NIOSH = National Institute for Occupational Safety and Health ; OSHA = Occupational Safety and Health

Administration ; PVC = polyvinyl chloride; THF = tetrahydrofuran; USGS = United States Geological Survey ; X RD = X- ray diffraction

***DRAFT FOR PUBLIC COMMENT***VANADIUM 157

7. ANALYTICAL METHODS

that all data needs discussed in this section must be filled. In the future, the identified data needs will be

evaluated and prioritized, and a substance- specific research agenda will be propose d.

7.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. Sensitive and selective

methods are available for the detection and quantitative measurement of vanadium after the sample matrix

in which it is contai ned as been properly treated. Atomic spectroscopic methods used for the

determination of vanadium include AAS with flame and graphite tube atomizers, ICP- OES, ICP

- MS,

XRF, and spectrophotometric methods (Chen and Owens 2008). No data needs are identified.

Exposure

. Methods exist to determine vanadium levels in environmental samples and human tissues.

While several biomarkers of exposure have been indentified, none of them can be used to quantitatively

determine exposure levels ( Rydzynski 2001). Kučera et al. (1998) reported that blood and urinary

vanadium levels are considered the most reliable indicators of occupational exposure to vanadium. No

data needs are identified.

Effect. No well -documented biomarkers of effect specif ic for vanadium have been report (Rydzynski

2001). The primary effects of exposure to vanadium dusts are coughing, wheezing, and other respiratory

difficulties; however, these effects are not specific to vanadium and can be found following inhalation of

many types of dusts (Rydzynski 2001). No data needs are identified.

Methods for Determining Parent Compounds and Degradation Products in Environmental

Media. Methods for determining vanadium in water, air, and waste samples with adequate selectivity

an d sensitivity are well developed and undergoing constant improvement. No data needs are identified.

7.3.2 Ongoing Studies

No ongoing studies regarding methods for measuring vanadium in biological and environmental samples

were located (FEDRIP 2009).

***DRAFT FOR PUBLIC COMMENT***VANADIUM 158

7. ANALYTICAL METHODS



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 159



### 8. REGULATIONS, ADVISORIES, AND GUIDELINES

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by

ATSDR health assessors and other responders to identify contaminants and potential health effects that

may be of concern at hazardous waste sites.

ATSDR has derived an acute -duration inhalation MRL of 0.0008 mg vanadium/m 3 based on a LOAEL of

0.56 mg vanadium/m 3 for lung inflammation in rats exposed to vanadium pentoxide 6 hours/day,

5 days/week for 13 days (NTP 2002). The MRL was derived by dividing the human equivalent

concentration of the LOAEL (0.073 mg vanadium/m 3 ) by an uncertainty factor of 90 (3 for use of a

minimal LOAEL, 3 for animal to human extrapolation with dosimetric adjustments, and 10 for human

variability).

ATSDR has derived a chronic -duration inhalation MRL of 0.0001 mg vanadium/m 3 based on a BMCL 10
of 0.04 mg vanadium/m 3 for degeneration of epiglottis respiratory epithelium of rats exposed to vanadium

pentox ide 6 hours/day, 5 days/week for 2 years (NTP 2002). The MRL was derived by dividing the

human equivalent concentration of the BMCL 10 (0.003 mg vanadium/m 3 ) by an uncertainty factor of 30

(3 for animal to human extrapolation with dosimetric adjustments and 10 for human variability).

ATSDR has derived an intermediate -duration oral MRL of 0.01 mg vanadium/kg/day based on a NOAEL

of 0.12 mg vanadium/kg/day for hematological and blood pressure effects in humans exposed to vanadyl

sulfate for 12 weeks (Fawcett et al. 1997) and an uncertainty factor of 10 for human variability.

IRIS (2009) has derived an oral reference dose (RfD) of 0.009 mg/kg/day for vanadium pentoxide based

on a NOAEL of 0.89 mg/kg/day for decreased hair cysteine levels in rats exposed to vanadium pentoxide

for 2.5 years (Stokinger et al. 1953) and an uncertainty factor of 100 (10 for extrapolation from animals to

humans and 10 to protect against unusually susceptible individuals).

EPA has not derived an inhalation reference concentration (RfC) for vanadium and vanadium compounds.

OSHA has required employers of workers who are occupationally exposed to vanadium peroxide to

institute engineering controls and work practices to reduce and maintain employee exposure at or below

permissible expos ure limits (PELs) (OSHA 2009). The employer must use engineering and work practice

***DRAFT FOR PUBLIC COMMENT***VA NADIUM 160

8. REGULATIONS AND ADVISORIES

controls to reduce exposures to not exceed 0.5 mg/m 3 for vanadium peroxide as respirable dust (as V 2 O 5 )

and 0.1 mg/m 3 as fume (as V 2 O 5 ) at any time (OSHA 2009).

Vanadium pentoxide, vanadyl sulfate dehydrate, and ammonium metavanadate are on the list of

chemicals appearing in “Toxic Chemicals Subject to Section 313 of the Emergency Planning and

Community Right- to -Know Act of 1986" and has been assigned a reportable quantity (RQ) limit of

1,000 pounds each (EPA 2009d). Vanadium pentoxide is also considered to be an extremely hazardous

substance (EPA 2009e). The RQ represents the amount of a designated hazardous substance which, when

released to the environment, must be repor ted to the appropriate authority.

The international and national regulations, advisories, and guidelines regarding vanadium and compounds

in air, water, and other media are summarized in Table 8-1.

***DRAFT FOR PUBLIC COMMENT***VA NADIUM 161

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. Regulations

, Advisories

, and Guidelines Applicable to Vanadium and Compounds

Agency Description Information Reference

INTERNATIONAL

Guidelines:

IARC Carcinogenicity classification IARC 2009

Vanadium pentoxide Group 2B a

WHO Air quality guidelines WHO 2000

Vanadium

TWA based on effects other than cancer or odor/annoyance using an averaging time of 24 hours 1 μg/m 3

Drinking water quality guidelines No data WHO 2006

NATIONAL

Regulations and

Guidelines:

a. Air

ACGIH TLV (8

- hour TWA) b

Vanadi um pentoxide (respirable fraction of dust or fume, as V 2 O 5 ) 0.05 mg/m 3 ACGIH 2008

TLV Basis Irritation and lung

AIHA ERPG values No AIHA 2008

EPA Second AEGL c hemical p riority l ist EPA 2008 a

Vanadium and compounds Yes c

Hazardous air pollutant No EPA 2 009b

42 USC 7412

NIOSH REL (15

- minute ceiling)

Vanadium pentoxide d

IDLH 0.05 mg/m 3

35 mg/m 3 NIOSH 2005

Target organ Eyes, skin, and respiratory system

OSHA PEL (ceiling limit) for general industry

Van adium pentoxide

Respirable dust (as V 2 O 5 )

Fume (as V 2 O 5 ) 0.5 mg/m 3

0.1 mg/m 3 OSHA 2009
29 CFR 1910.1000,

Table Z -1

b. Water

EPA Designated as hazardous substances

in accordance with Section 311(b)(2)(A)

of the Clean Water Act EPA 2009 h

40 CFR 116.4

Vanadium pentoxide Yes

Vanadyl sulfate dehydrate Yes

Drinking water contaminant candidate

list EPA 1998 b

***DRAFT FOR PUBLIC COMMENT***VA NADIUM 16 2

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. Regulations

, Advisories

, and Guidelines Applicable to Vanadium and Compounds

Agency Description Information Reference

Vanadium Yes 63 FR 10274

NATIONAL (cont.)

EPA Drinking water standards and health

advisories No EPA 2006a

National primary drinking water

standards No EP A 2003 b

National recommended water quality

criteria No EPA 2006b

Reportable quantities of hazardous substances designated pursuant to

Section 311 of the Clean Water Act EPA 2009c

40 CFR 117.3

Vanadium pentoxide 1,000 pounds

Vanadyl sulfate dehy drate 1,000 pounds

c. Food

FDA EAFUS e No FDA 2008

d. Other

ACGIH Carcinogenicity classification A4 f ACGIH 2008

Biological exposure indices (end of shift at end of workweek)

Vanadium in urine 50 μg/g creatinine

EPA Carcinogenicity c lassification No IRIS 2009

RfC No

RfD

Vanadium pentoxide 9x 10 - 3 mg/kg/day

Superfund, emergency planning, and community right

- to

- know

Designated CERCLA hazardous

substance and their reportable quanti ties EPA 2009d

40 CFR 302.4

Vanadiu m pentoxide g

Vanadyl sulfate dehydrate h

Ammonium metavanadate i 1,000 pounds

1,000 pounds

1,000 pounds

Effective date of toxic chemical EPA 200 9 f release reporting 40 CFR 372.65

Vanadium (except when contained in an alloy) 01/01/2000

Extremely hazardous substance and its threshold planning quantity

Vanadium pentoxide 100/10,000 pounds EPA 2009e
40 CFR 355, Appendix A

***DRAFT FOR PUBLIC COMMENT***VA NADIUM 163

8. REGULATIONS AND ADVISORIES



### Table 8

- 1. Regulations

, Advisories

, and Guidelines Applicable to Vanadium and Compounds

Agency Description Information Reference

NATIONAL (cont.)

TSCA chemical lists and reporting EPA 2009g periods 40 CFR 712.30

Vanadium, vanadium pe ntoxide, vanadyl sulfate dehydrate, sodium
metavanadate, sodium
orthovanadate, and ammonium

metavanadate

Effective date 07/11/2003

Reporting date 09/09/2003

DHHS Carcinogenicity classification No data NTP 2005

IOM Upper Tolerable Limit 1.8 mg/day IOM 2001

a Group 2B: possibly carcinogenic to humans

b Vanadium peroxide is included in the 2008 Notice of Intended Changes in which the substance and its corresponding values and notations for which the withdrawal of the Documentation and adopted TLV are proposed.

c Vanadium and compounds are included on the list of 371 priority chemicals that are acutely toxic and represent the selection of chemicals for AEGL development by the NAC/AEGL committee during the next several years.

d The REL applies to all vanadium compounds except vanadium metal and vanadium carbide.

e The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food

additives or listed or affirmed as GRAS.

f A4: not classifiable as a human car cinogen

g Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act and Section 3001 of the Resource Conservation and Recovery Act.

h Designated CERCLA hazardous substance pursuant to Section 311(b)(2) of the Clean Water Act.

i Designated CERCLA hazardous substance pursuant to Section 3001 of the Resource Conservation and Recovery

Act.

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response, Compensation, and Liability Act; CFR = Code of Federal Regulations; DHHS = Department of Health and Human Services; EAFUS = Everything Added to Food in the United States; EPA = Environmental Protec tion Agency;

ERPG = emergency response planning guidelines; FDA = Food and Drug Administration; FR = Federal Register;

GRAS = Generally Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; IOM = Institute of Medicien; NAC = National Advisory Council ; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit;

REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose;

TLV = threshold limit values; TSCA = Toxic Substances Control Act; TWA = time

- weighted average; USC = United

States Co de; WHO = World Health Organization

***DRAFT FOR PUBLIC COMMENT***VA NADIUM 164

8. REGULATIONS AND ADVISORIES



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***_______________________ VANADIUM 165



### 9. REFERENCES

Abbasi SA. 1981. Pollution due to vanadium and a new spot test for detection of traces of vanadium in water, plants, soils, and rocks. Int J Environ Stud 18:51-52.

Abbasi SA. 1987. Trace analysis of vanadium in environmental as its ternary complex with N-p methoxyphenyl-2-furylacrylohydroxamic acid and 3- (o -carboxyphenyl)-1-phenyltriazine-n-oxide. Anal

Lett 20:134 7-1361.

ACGIH. 2001. Vanadium pentoxide. In: Documentation of the threshold limit values and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*ACGIH. 2008. Vanadium pentoxide. In: Thresho ld limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

*Adachi A, Asai K, Koyama Y, et al. 1998a. Vanadium content of cigarettes. Bull Environ Contam Toxicol 61(2):276-280.

Adachi A, Asai K, Koyama Y, et al. 1998b. Determination of vanadium in cigarettes by atomic absorption spectrophotometry. Anal Lett 31(10):1769-1776.

*+Adachi A, Asai K, Koyama Y, et al. 2000a. Subacute vanadi um toxicity in rats. J Health Sci 46(6):503-508.

*Adachi A, Ogawa K, Tsushi Y, et al. 2000b. Balance, excretion and tissue distribution of vanadium in

rats after short -term ingestion. J Health Sci 46(1):59-62.

*Adinolfi M. 1985. The development of the human blood- CSF -brain barrier. Dev Med Child Neurol 27(4):532-537.

*Adlercreutz H. 1995. Phytoestrogens: Epidemiology and a possible role in cancer protection. Environ Health Perspect Suppl 103(7):103-112.

Agency for Toxic Substances and Disease Registry. 1989. Decision guide for identifying substancespecific data needs related to toxicological profiles; Notice. Fed Regist 54(174):37618 -37634.

Agency for Toxic Substances and Disease Registry. 1990. Biomarkers of organ damage or d ysfunction for the renal, hepatobiliary, and immune systems. Subcommittee on Biomarkers of Organ Damage and Dysfunction. Atlanta, GA: Agency for Toxic Substances and Disease Registry.

*Cited in text +Cited in supplemental document

***DRAFT FOR PUBLIC COMMENT***VANADIUM 166

9. REFERENCES

Agency for Toxic Substances and Disease Registry. 2007. Health consultation: Assessment of cancer incidence from the Louisiana tumor registry from 1988-2004. Calcasieu Parish, Louisiana. Atlanta, GA:

U.S. Department of Health and Human Service s, Agency for Toxic Substances and Disease Registry,

Division of Health Assessment and Consultation. http://www.atsdr.cdc.gov/HAC/pha/CalcasieuCancer/CalcasieuCancerHC92707.pdf . May 14, 2009.

Agrawal YK. 1975. Extraction and spectrophotometric determination of vanadium (V) with n-phenyl 2- naphthohydroxamic acid. Anal Chem 47:940-942.

*AIHA. 2008. Emergency Response Planning Guidelines (ERPG). Fairfax, VA: American Industrial Hygiene Association. http://www.aiha.org/1documents/Committees/ERP- er pglevels.pdf . May 19, 2009.

Aiton JF, Cramb G. 1985. The effects of vanadate on rabbit ventricular muscle adenylate cyclase and sodium pump activities. Biochem Pharmacol 34:1543-1548.

Akera T, Temma K, Takeda K. 1983. Cardiac actions of vanadium. Fed Proc 42:2984-2988.

*+Akgün -Dar K, Bolkent S, Yanardag R, et al. 2007. Vanadyl sulfate protects against streptozotocininduced morphological and biochemical changes in rat aorta. Cell Biochem Funct 25(6):603-609.

Al

- Bayati MA, Raabe OG, Giri SN, et al. 1991. Distribution of vanadate in the rat following subcutaneous and oral routes of administration. J Am Coll Toxicol 10(2):233-242.

*Al -Bayati MA, Xie Y, Mohr FC, et al. 2002. Effect of pirfenidone against vanadate-induced kidney

fibros is in rats. Biochem Pharmacol 64(3):517-525.

Alexandrova R, Alexandrov I, Nikolova E. 2002. Effect of orally administered ammonium vanadate on the immune response of experimental animals. Dokl Bulg Acad Nauk 55(3):69-72.

Alimonti A, Petrucci F, K rachler M, et al. 2000. Reference values for chromium, nickel and vanadium in urine of youngsters from the urban area of Rome. J Environ Monit 2(4):351-354.

*Allen RO, Steinnes E. 1978. Determination of vanadium in biological materials by radiochem ical neutron activation analysis. Anal Chem 50:1553-1555.

*Allen SK, Allen JM, Lucas S. 1996. Dissolved metal concentrations in surface waters from west

central Indiana contaminated with acidic mine drainage. Bull Environ Contam Toxicol 56:240-243.

Alliksaar T, Punning JM. 1998. The spatial distribution of characteristics fly- ash particles and trace metals in lake sediments and catchment mosses: Estonia. Water Air Soil Pollut 106(3 -4):219-239.

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(23):825-826.

Altamirano MA, Betancourt M, Roldan E. 1993a. Effects of caffeine on sister chromatid exchanges in human lymphocytes treated with v anadium pentoxide. 24th Annual Scientific Meeting of the Environmental Mutagen Society, Norfolk, Virginia, USA, April 17-22, 1993. Environ Mol Mutagen 21(suppl 22):2.

Altamirano -Lozano M, Alvarez- Barrera L, Basurto -Alcantara F, et al. 1996. Reprotox ic and genotoxic studies of vanadium pentoxide in male mice. Teratog Carcinog Mutagen 16(1):7-17.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 167

9. REFERENCES

Altamirano -Lozano M, Alvarez- Barrera L, Roldan -Reyes E. 1993b. Cytogenic and teratogenic effects of vanadium pentoxide on mice. Med Sci Res 21(19):711-713.

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. Teratog Carcinog Mutagen 19(4):243-255.

*Altman PL, Dittmer DS. 1974. Biological handbooks: Biology data book. Vol. III. 2nd ed. Bethesda, MD: Federation of American Societies of Experimental Biology.

Amiard JC, Journel R, Bacheley H. 2008. Influence of field and experimental exposure of mussels ( Mytilus sp.) to nickel and vanadium on metallothionein concentration. Comp Biochem Physiol C Toxicol Pharmacol 147(3):378-385.

*Amorim FA, Welz B, Costa AC, et al. 2007. Determination of vanadium in petroleum and petroleum products using atomic spectrometric techniques. Talanta 72(2):349-359.

*Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, reduction, and replacement. New York, NY: Marcel Dekker, Inc., 9-25.

*Andersen ME, Clewell HJ, Gargas ML, et al. 1987. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol 87(2):185 -205.

Aragon AM, Altamira no-Lozano M. 2001. Sperm and testicular modifications induced by subchronic treatments with vanadium (IV) in CD -1 mice. Reprod Toxicol 15(2):145-151.

Aragon MA, Ayala ME, Fortoul TI, et al. 2005. Vanadium induced ultrastructural changes and apoptos is in male germ cells. Reprod Toxicol 20(1):127-134.

Arbouine MW, Smith NJ. 1991. Determination of vanadium in urine and its application to biological monitoring of occupationally exposed workers. Atom Spectrosc 12(2):54-58.

Attia SM, Badary OA, Hamada FM, et al. 2005. Orthovanadate increased the frequency of aneuploid mouse sperm without micronucleus induction in mouse bone marrow erythrocytes at the same dose level. Mutat Res 583(2):158-167.

Avila

- Costa MR, Colin -Barenque L, Zepeda-Rodriguez A, et al. 2005. Ependymal epithelium disruption after vanadium pentoxide inhalation. A mice experimental model. Neurosci Lett 381(1-2):21-25.

Avila -Costa MR, Fortoul TI, Nino-Cabrera G, et al. 2006. Hippocampal cell alterations induced by the inhalation of vanadium pentoxide (V 2 O 5 ) promote memory deterioration. Neurotoxicology 27(6):1007-

1012.

Avila

- Costa MR, Montiel Flores E, Colin -Barenque L, et al. 2004. Nigrostriatal modifications after vanadium inhalation: An immunocytochemical and cytological approach. Neurochem Res 29(7):1365-

1369.

Azay J, Bres J, Krosniak M, et al. 2001. Vanadium pharmacokinetics and oral bioavailability upon single -dose administration of vanadyl sulfate to rats. Fundam Clin Pharmacol 15(5):313-324.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 168

9. REFERENCES

Barba nte C, Boutron C, Moreau AL, et al. 2002. Seasonal variations in nickel and vanadium in Mont Blanc snow and ice dated from the 1960s and 1990s. J Environ Monit 4(6):960-966.

*Barceloux DG. 1999. Vanadium. J Toxicol Clin Toxicol 37(2):265-278.

*Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. Regul Toxicol Pharmacol 8(4):471-486.

Barnes D, Bellin J, DeRosa C, et al. 1988. Reference dose (RfD): Description and use in health risk

assessment s. Appendix A: Integrated risk information system supportive documentation. Washington, DC: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment.

*Baroch EF. 2006. Vanadium and vanadium alloys. In: Kirk- Othmer encyclopedia of chemical technology. John Wiley & Sons, Inc. http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/vana.a01/current/pdf. May 12,

2009.

Barth A, Schaffer AW, Konnaris C, et al. 2002. Neurobehavioral effects of vanadium. J Toxi col Environ Health A 65(9):677-683.

*Beauge LA, Cavieres JJ, Glynn IM, et al. 1980. The effects of vanadate on the fluxes of sodium and potassium ions through the sodium pump. J Physiol 301:7-23.

*Beg MU, Al -Muzaini S, Saeed T, et al. 2001. Chemical contamination and toxicity of sediment from a coastal area receiving industrial effluents in Kuwait. Arch Environ Contam Toxicol 41:289-297.

*Berger GS, ed. 1994. Epidemiology of endometriosis. In: Endometriosis: Modern surgical management of endometriosis. New York, NY: Springer- Verlag, 3 -7.

*Birnboim HC. 1988. A superoxide anion induced DNA strand-break metabolic pathway in human leukocytes: Effects of vanadate. Biochem Cell Biol 66:374-381.

*Bocio A, Nadal M, Domingo JL. 2005. Human exposure to metals through the diet in Tarragona, Spain: Temporal trend. Biol Trace Elem Res 104(3):193-201.

*+Boden G, Chen X, Ruiz J, et al. 1996. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non- insulin -dependent diabetes mellitus. Metabolism 45(9):1130-1135.

*Bogden JD, Higashino H, Lavenhar MA, et al. 1982. Balance and tissue distribution of vanadium after short-term ingestion of vanadate. J Nutr 112:2279-2285.

Boice JD, Jr., Mumma MT, Blot WJ . 2007. Cancer and noncancer mortality in populations living near uranium and vanadium mining and milling operations in Montrose County, Colorado, 1950-2000. Radiat Res 167(6):711-726.

Bonner JC, Rice AB, Moomaw CR, et al. 2000. Airway fibrosis in rats induced by vanadium pentoxide. Am J Physiol Lung Cell Mol Physiol 278(1):L209-L216.

*+Boscolo P, Carmignani M, Volpe AR, et al. 1994. Renal toxicity and arterial hypertension in rats chronically exposed to vanadate. Occup Environ Med 51(7):500-503.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 169

9. REFERENCES

Brichard SM, Henquin JC. 1995. The role of vanadium in the management of diabetes. Trends Pharmacol Sci 16(8):265-270.

*Bronzetti G, Morichetti E, Della Croce C, et al. 1990. Vanadium: Genetical and biochemical investigations. Mutagenesis 5(3):293 -295.

Brooks SM. 1986. Pulmonary reactions to miscellaneous mineral dusts, man-made mineral fibers, and miscellaneous pneumoconioses. Washington, DC: U.S. Department of Health and Human Services, National Institute of Occupational Safety and Health, Division of Respiratory Disease Studies. Occupational respiratory diseases. DHHS (NIOSH) Publication No. 86-102.

Browning E. 1969. Toxicity of industrial metals. 2nd ed. New York, NY: Appleton-Century-Crofts,

340-343.

*Bruech M, Quintanilla ME, Legrum W, et al. 1984. Effects of vanadate on intracellular reduction equivalents in mouse liver and the fate of vanadium in plasma, erthrocytes, and liver. Toxicology 31:283-

295.

*Buchet JP, Knepper E, Lauwerys R. 1982. Determination of vanadium in urine by electrothermal atomic absorption spectrometry. Anal Chim Acta 136:243-248.

*Buchter B, Davidoff B, Amacher MC, et al. 1989. Correlation of Freundlich Kd and n retention parameters with soils and elements. Soil Sci 148(5):370-378.

Bu

- Olayan AH, Al -Yakoob S. 1998. Lead, nickel and vanadium in seafood: An exposure assessment for Kuwaiti consumers. Sci Total Environ 223(2-3):81-86.

Bu -Olayan AH, Subrahmanyam MN. 1998. Trace metal concentrations in the crab Macrophthalmus depressus and sediments on the Kuwait coast. Environ Monit Assess 53(2):297-304.

*+Bursztyn M, Mekler J. 1993. Acute hypertensive response to saline induced by vanadate, an insulinomimetic agent. J Hypertens 11(6):605-609.

Butte W, Heinzow B. 2002. Pollutants in house dust as indicators of indoor contamination. Rev Environ

Contam Toxicol 175:1-46.

*Byczkowski JZ, Kulkarni AP. 1998. Oxidative stress and pro-oxidant biological effects of vanadium. In: Nriagu JO, ed. Vanadium in the environment. Part 2: Health effects. Vol. 31. New York, NY: John Wiley & Sons, 235-264.

*Byerrum RU. 1991. Vanadium. In: Merian E, ed. Metals and their compounds in the environment. Weinheim, Germany: VCH, 1289-1297.

*Byerrum RU, Eckardt RE, Hopkin s LL, et al. 1974. Vanadium. Washington, DC: National Academy of Sciences, 19-45.

*Byrne AR, Kosta L. 1978. Vanadium in foods and in human body fluids and tissues. Sci Total Environ

10:17-30.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 170

9. REFERENCES

*Byrne AR, Kucera J. 1991. New data on levels of vanadium in man and his diet. In: Momcilovic B, ed. Trace elements in man and animals. Vol. 7. Copenhagen, Denmark: World Health Organisation (WHO), Regional Office for Europe, 25-18 to 25-20.

Cadene A, Gross R, Poucheret P, et al. 1996. Vanadyl s ulphate differently influences insulin response to glucose in isolated pancreas of normal rats after in vivo or in vitro exposure. Eur J Pharmacol 318(1):145-151.

Cam MC, Pederson RA, Brownsey RW, et al. 1993. Long- term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats. Diabetologia 36(3):218-224.

*Cannon HL. 1963. The biogeochemistry of vanadium. Soil Sci 98:196-204.

+Carlton BD, Beneke MB, Fisher GL. 1982. Assessment of the teratogenicity of ammonium vanadate using syr ian golden hamsters. Environ Res 29:256-262.

*+Carmignani M, Boscolo P, Volpe AR, et al. 1991. Cardiovascular system and kidney as specific targets of chronic exposure to vanadate in the rat: Functional and morphological findings. Arch Toxicol Suppl 14:124-127.

*+Carmignani M, Volpe AR, Porcelli G, et al. 1992. Chronic exposure to vanadate as factor of arterial hypertension in the rat: Toxicodynamic mechanisms. Arch Toxicol Suppl 15:117-120.

Caroli S, Forte G, Iamiceli AL, et al. 1999. D etermination of essential and potentially toxic trace elements in honey by inductively coupled plasma-based techniques. Talanta 50(2):327-336.

*Castranova V, Bowman L, Wright JR, et al. 1984. Toxicity of metallic ions in the lung: Effects on

alveola r macrophages and alveolar type II cells. J Toxicol Environ Health 13:845-856.

Chandra AK, Ghosh R, Chatterjee A, et al. 2007a. Amelioration of vanadium- induced testicular toxicity and adrenocortical hyperactivity by vitamin E acetate in rats. Mol Cel l Biochem 306(1-2):189-200.

Chandra AK, Ghosh R, Chatterjee A, et al. 2007b. Vanadium-induced testicular toxicity and its prevention by oral supplementation of zinc sulphate. Toxicol Mech Methods 17(4):175-187.

+Chanh PH. 1965. The comparative t oxicity of sodium chromate, molybdate, tungstate and metavanadate. II. Experiments on mice and rats. Arch Int Pharmacodyn Ther 157(1):109-114.

*ChemIDplus. 2009. Vanadium and vanadium compounds. ChemIDplus. Bethesda, MD: U.S. National Library of Medicine. http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp . May 21, 2009.

*Chen ZL, Owens G. 2008. Trends in speciation analysis of vanadium in environmental samples and biological fluids - a review. Anal Chim Acta 607(1):1-14.

*Chillrud SN, Bopp RF, Simpson HJ, et al. 1999. Twentieth century atmospheric metal fluxes into Central Park Lake, New York City. Environ Sci Technol 33(5):657-662.

Chiu NH, Moilanen LH. 2003. Evaluation of the oral reference dose for vanadium. Toxicol Sci 72(S1):29.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 171

9. REFERENCES

*Ciranni R, Antonetti M, Migliore L. 1995. Vanadium salts induce cytogenetic effects in in vivo treated mice. Mutat Res 343(1):53-60.

*Clewell HJ, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol

In d Health 1(4):111-131.

CLPSD. 1988. Contract laboratory program statistical database. Washington, DC: U.S. Environmental Protection Agency, Contract Laboratory Program.

Cohen MD, Becker S, Devlin R, et al. 1997. Effects of vanadium upon polyI-C: Induced responses in rat lung and alveolar macrophages. J Toxicol Environ Health 51(6):591 -608.

Cohen MD, Fukayama MY, Wei CI. 1991. Immunotoxicological studies of ammonium metavanadate in mice. In: Dillon HK, Ho MH, eds. Biological monitoring of exposure to chemicals: Metals. New York, NY: John Wiley and Sons, 127-144.

*Cohen MD, Klein CB, Costa M. 1992. Forward mutations and DNA-protein crosslinks induced by ammonium metavanadate in cultured mammalian cells. Mutat Res 269(1):141 -148.

Cohen MD, McManus TP, Yang Z, et al. 1996a. Vanadium affects macrophage interferon- gamma

binding and - inducible responses. Toxicol Appl Pharmacol 138(1):110 -120.

*+Cohen MD, Wei C, Tan H, et al. 1986. Effect of ammonium metavanadate on the murine immune response. J Toxicol Environ Health 19:279-298.

Cohen MD, Yang Z, Zelikoff JT, et al. 1996b. Pulmonary immunotoxicity of inhaled ammonium metavanadate in Fisher 344 rats. Fundam Appl Toxicol 33(2):254-263.

Colin -Barenque L, Avila- Costa M, D elgado V, et al. 2004. Mice olfactory bulb neuronal death after V2O5 inhalation. Toxicologist 78(1 -S):233.

*Cong Z, Kang S, Dong S, et al. 2008. Elemental and individual particle analysis of atmospheric aerosols from high Himalayas. Environ Monit Assess [Dec 13; Epub ahead of print.]

*Conklin AW, Skinner CS, Felten TL, et al. 1982. Clearance and distribution of intratracheally instilled vanadium-48 compounds in the rat. Toxicol Lett 11:199-203.

*Crampton EW, Lloyd LE. 1954. The effect of water restriction on the food intake and food efficiency of growing rats. J Nutr 54(2):221-224.

*Crans DC, Amin SS, Keramidas AD. 1998. Chemistry of relevance to vanadium in the environment. In: Nriagu JO, ed. Vanadium in the environment. Vol. 30. New York, NY: John Wiley & Sons, Inc.,

73-95.

Cui CT, Uriu -Adams JY, Tchaparian EH, et al. 2004. Metavanadate causes cellular accumulation of copper and decreased lysyl oxidase activity. Toxicol Appl Pharmacol 199(1):35-43.

*+Cusi K, Cukier S, DeFronzo RA, et al. 2001. Vanadyl sulfate improves hepatic and muscle insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab 86(3):1410-1417.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 172

9. REFERENCES

*+Dai S, McNeill JH. 1994. One- year treatment of non

- diabetic and streptozotocin

- diabetic rats wi th vanadyl sulphate did not alter blood pressure or haematological indices. Pharmacol Toxicol 74(2):110-

115.

*+Dai S, Thompson KH, McNeill JH. 1994a. One- year treatment of streptozotocin

- induced diabetic rats with vanadyl sulphate. Pharmacol Toxicol 74(2):101-109.

*+Dai S, Thompson KH, Vera E, et al. 1994b. Toxicity studies on one-year treatment of non- diabetic and streptozotocin-diabetic rats with vanadyl sulphate. Pharmacol Toxicol 75(5):265-273.

*+Dai S, Vera E, McNeill JH. 1995. Lack o f haematological effect of oral vanadium treatment in rats. Pharmacol Toxicol 76(4):263 -268.

*Dannecker W, Schroeder B, Stechmann H. 1990. Organic and inorganic substances in highway tunnel

exhaust air. Sci Total Environ 93:293-300.

De Cremer K, Cornelis R, Strijckmans K, et al. 2002. Fractionation of vanadium in urine of Wistar rats as a function of time after intraperitoneal injection. J Inorg Biochem 90(1-2):71-77.

*de la Torre A, Granero S, Mayayo E, et al. 1999. Effect of age on vanadium nephrotoxicity in rats. Toxicol Lett 105(1):75 -82.

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. Toxicol Sci 77(1):6-18.

*+Dimond EG, Caravaca J, Benchimol A. 1963. Excretion, toxicity, lipid effect in man. Am J Clin Nutr

12:49-53.

*DOE. 2008. Fuel oil and kerosene sales 2007. Washington, DC: U.S. Department of Energy, Energy Information Administration, Office of Oil and Gas.

Domingo JL. 1996. Vanadium: A review of the reproductive and developmental toxicity. Reprod Toxicol 10(3):175-182.

Domingo JL. 2000. Vanadium and diabetes. What about vanadium toxicity? Mol Cell Biochem 203(1- 2):185-187.

Domingo JL. 2002. V anadium and tungsten derivatives as antidiabetic agents: A review of their toxic effects. Biol Trace Elem Res 88(2):97 -112.

Domingo JL, Bosque MA, Luna M, et al. 1993a. Prevention by Tiron (sodium 4,5-dihydroxybenzene1,3-disulfonate) of vanadate- in duced developmental toxicity in mice. Teratology 48(2):133-138.

*Domingo JL, Gomez M, Llobet JM, et al. 1990. Chelating agents in the treatment of acute vanadyl sulphate intoxication in mice. Toxicology 62(2):203-211.

Domingo JL, Gomez M, Sanchez DJ, et al. 1992a. Tiron administration minimizes the toxicity of vanadate but not its insulin mimetic properties in diabetic rats. Life Sci 50(18):1311-1317.

Domingo JL, Gomez M, Sanchez DJ, et al. 1995. Toxicology of vanadium compounds in diabeti c rats: The action of chelating agents on vanadium accumulation. Mol Cell Biochem 153(1-2):233-240.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 173

9. REFERENCES

*+Domingo JL, Llobet JM, Tomas JM, et al. 1985. Short- term toxicity studies of vanadium in rats. J Appl Toxicol 5(6):418 -420.

*+Domingo JL, Paternan JM, Llobet JM, et al. 1986. Effects of vanadium on reproduction, gestation, parturition and lactation in rats upon oral administration. Life Sci 39:819-824.

Domingo JL, Sanchez DJ, Gomez M, et al. 1992b. Administration of vanadyl sulfate by gavage does not normalize blood glucose levels in streptozotocin-induced diabetic rats. Res Commun Chem Pathol Pharmacol 75(3):369-372.

Domingo JL, Sanchez DJ, Gomez M, et al. 1993b. Oral vanadate and tiron in treatment of diabetes

mellitus in rats: Im provement of glucose homeostasis and negative side -effects. Vet Hum Toxicol 35(6):495-500.

Domingo JL, Schuhmacher M, Agramunt MC, et al. 2001. Levels of metals and organic substances in blood and urine of workers at a new hazardous waste incinerator. Int Arch Occup Environ Health 74(4):263-269.

+Donaldson J, Hemming R, LaBella F. 1985. Vanadium exposure enhances lipid peroxidation in the kidney of rats and mice. Can J Physiol Pharmacol 63:196-199.

*Duce RA, Hoffman GL. 1976. Atmospheric vanadium transport to the ocean. Atmos Environ 10:989-

996.

Duffus JH. 2007. Carcinogenicity classification of vanadium pentoxide and inorganic vanadium compounds, the NTP study of carcinogenicity of inhaled vanadium pentoxide, and vanadium chemistry. Regul Toxicol Pharmacol 47(1):110-114.

*Dundar MS. 2006. Vanadium concentrations in settled outdoor dust particles. Environ Monit Assess 123(1-3):345-350.

Dutch Safety Institute. 1980. Vanadium tetrachloride. 2nd ed. Amsterdam, Holland: Dutch Association of Safety Exposure, Dutch Chemical Industry Association, 952.

*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.

*Edel J, Pietra R, Sabbioni E, et al. 1984. Disposition of vanadium in rat tissues at different age. Chemosphere 13:87-93.

*Ehrlich VA, Nersesyan AK, Atefie K, et al. 2008. Inhalative exposure to vanadium pentoxide causes DNA damage in workers: R esults of a multiple end point study. Environ Health Perspect 116(12):1689-

1693.

*+Elfant M, Keen CL. 1987. Sodium vanadate toxicity in adult and developing rats. Biol Trace Elem

Res 14:193-208.

*Engler RM. 1979. Bioaccumulation of toxic substances from contaminated sediments by fish and benthic organisms. In: Management of bottom sediments containing toxic substances. Washington, DC:

U.S. Environmental Protection Agency, 325-354.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 174

9. REFERENCES

* EPA. 1982. Management of hazardous waste leachate. Was hington, D.C.: U.S. Environmental Protection Agency, Office of Solid Wa ste and Emergency Response. PB91181578.

*EPA. 1983a. Methods for chem ical analysis of water and wastes. Washington, DC: U.S. Environmental Protection Agency, Office of Research a nd Development. EPA600479020.

*EPA. 1983b. Method 286.1. In: Methods for chemical analysis of water and wastes. Washington, DC:

U.S. Environmental Protection Agency, Office of Research and Development. EPA600479020.

*EPA. 1983c. Method 286.2. In: Methods for chemical analysis of water and wastes. Washington, DC:

U.S. Environmental Protection Agency, Office of Research and Development. EPA600479020.

EPA. 1983d. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 122

, Appendix D, Table V.

*EPA. 1985a. Health and environmental effects profile for vanadium pentoxide. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office. EPA600x85114.

EPA. 1985b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 302.4.

EPA. 1985c. U.S. Environmental Protection Agency. Fed Regist 50:50225-50228.

EPA. 1985d. Vanadium pentoxide. Washington, DC: U.S. Environmental Protection Agency. EPA

chemical profiles.

EPA. 1986c. Reference values for risk assessment. Final draft. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office, Office of Health and Environmental

Assessment. ECAOC1N477.

EPA. 1986a. Test methods for evaluating solid waste. Washington, DC: U.S. Environmental Protection Agency, Office of Solid Wasted and Emergency Response. Laboratory manual physical/chemical

methods. Vol. 1A.

EPA. 1986b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 117.3.

EPA. 1987a. Emergency planning and notification. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 355, Appendix A.

EPA. 1987b. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 264, Appendix 1x.

EPA. 1987c. U.S. Environmental Protection Agency. Fed Regist 52:21152-21208.

EPA. 1988. Recommendations for and documentation of biological values for use in risk assessment

. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office,

Office of Health and Environmental Assessment. EPA600687008.

EPA. 1989. Interim methods for development of inhalation reference doses. Cincinnati, OH: U.S.

Environmental Prote ction Agency, Environmental Criteria and Assessment Office, Office of Health and

Environmental Assessment. EPA600888066F.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 175

9. REFERENCES

*EPA. 1990. Interim methods for development of inhalation reference concentrations. Washington, DC:

U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Office of Research and Development. EPA600890066A. PB90238890.

*EPA. 1994a. Determination of metals and trace elements in water and wastes by inductively coupled plasma

- atomic emission spect rometry. Method 200.7. In: Methods for the determination of metals in environmental samples, Supplement 1. Cincinnati, OH: U.S. Environmental Protection Agency. http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=300036HL.txt . May 22, 2009.

*EPA. 1994b. Determination of trace elements in waters and wastes by inductively coupled plasma - mass spectrometry. Method 200.8. In: Methods for the determination of metals in environmental samples, Supplement 1. Cincinnati, OH: U.S. Environmental Protection Agen cy. http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=300036HL.txt . May 22, 2009.

*EPA. 1994c. Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Office of Research and Development, Washington DC. EPA600890066F.

EPA. 1995. Determination of background concentrations of inorganics in soils and sediments at hazardous waste sites. Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development. EPA540S96500.

*EPA. 1997a. Determination of trace elements in marine waters by on- line chelation preconcentration and inductively coupled plasma - mass spectrometry. Method 200.10. In: Methods for the determination

of chemical substances in marine and estuarine environmental matrice s. 2nd ed. Cincinnati, OH: National Exposure Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency. EPA600R97072. http://www.epa.gov/microbes/marinmet.pdf. May 22, 2009.

EPA. 1997b. Special report on environmental endocrine disruption: An effects assessment and analysis. Washington, DC: U.S. Environmental Protection Agency, Risk Assessment Forum.

EPA. 1998a. Automated Form R for Windows: User’s guide (RY97). Washington, DC: U.S.

Environmental Prote ction Agency, Office of Pollution Prevention and Toxics.

*EPA. 1998b. The drinking water contaminant candidate list. U.S. Environmental Protection Agency. Fed Regist 63:10274. http://www.gpoaccess.gov/fr/index.html . May 11, 2009.

*EPA. 2003a. Method 200.5: Determination of trace elements in drinking water by axially viewed inductively coupled plasma - atomic emission spectrometry Cincinnati, OH: U.S. Environmental Protection Agency, National Exposure Research Laboratory, Office of Research and Development. http://www.epa.gov/nerlcwww/m_200_5.pdf . May 23, 2009.

*EPA. 2003b. National primary drinking water regulations. Washington, DC: Office of Ground Water and Drinking Water, U.S. Environmental Protection Agency. http://www.epa.gov/safewater/contaminants/index.html . May 19, 2009.

*EPA. 2005a. Partition coefficients for metals in surface water, soil, and waste. Washington DC: U.S. Environmental Protection Agency, Office of Research and Development. EPA600R05074.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 176

9. REFERENCES

*EPA. 2005b. Toxic chemical release inventory reporting forms and instructions: Revised 2004 version. Section 313 of the Emergency Planning and Community Right- to -Know Act (Title III of the Superfund Amendments and Reauthorization Act of 1986). U.S. Environmental Prot ection Agency, Office of

Environmental Information. EPA260B05001.

*EPA. 2006a. Drinking water standards and health advisories. Washington, DC: Office of Water, U.S. Environmental Protection Agency. http://epa.gov/waterscience/criteria/drinking/. May 19, 2009.

*EPA. 2006b. National recommended water quality criteria. Washington, DC: Office of Water, Office of Science and Technology, U.S. Environmental Protection Agency. http://www.epa.gov/waterscience/criteria/wqcriteria.html . May 11, 2009.

*EPA. 2007. Method 6010C: Inductively coupled plasma- atomic emission spectrometry

. In: Test methods for evaluating solid waste, physical/chemical methods. U.S. Environmental Protection Agency, http://www.epa.gov/osw/hazard/testmethods/sw846/pdfs/6010c.pdf . August 10, 2009.

*EPA. 2008a . Acute exposure guideline levels (AEGLs). Second AEGL Chemical Priority List. Washington, DC: Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency. http://www.epa.gov/oppt/aegl/pubs/priority_2.htm. May 19, 2009.

*EPA. 2008b. Drinking water contaminant candidate list and regulatory determinations. U.S. Environmental Protection Agency. http://www.epa.gov/OGWDW/ccl/basicinformation.html . August 13,

2009.

*EPA. 2009a. Vanadium and vanadium compounds. Modernized STORET system: Regular results by project (stormodb): Characteristic search by CAS number. U.S. Environmental Protection Agency. http://www.epa.gov/storet/dbtop.html . April 23, 2009.

*EPA. 2009b. Hazardous air pollutants. Clean Air Act. U.S. Environmental Protection Agency. United States Code. 42 USC 7412. http://www.epa.gov/ttn/atw/orig189.html. May 19, 2009.

*EPA. 2009c. Reportable quantities of hazardous substances designated pursuant to Section 311 of the Clean Water Act. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 117.3. http://www.epa.gov/lawsregs/search/40cfr.html . May 20, 2009.

*EPA. 2009d. Superfund, emergency planning, and community right- to -know programs. Designation, reportable quantities, and notifications. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 302.4. http://www.epa.gov/lawsregs/search/40cfr.html . May 20, 2009.

*EPA. 2009e. Superfund, emergency planning, and community ri ght

- to -know programs. Extremely hazardous substances and their threshold planning quantities. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 355, Appendix A. http://www.epa.gov/lawsregs/search/40cfr.html

. May 20, 2009.

EPA. 2009f. Superfund, Emergency Planning, And Community Right- To -Know Programs. Toxic Chemical Release Reporting. U.S. Environmental Protection Agency. Code of Federal Regulations. 40

CFR 372.65. http://www.epa.gov/lawsregs/search/40cfr.html . May 11, 2009.

*EPA. 2009g. Toxic substances control act. Chemical lists and reporting periods. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 712.30. http://www.epa.gov/lawsregs/search/40cfr.html . May 20, 2009.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 177

9. REFERENCES

*EPA. 2009h. Design ated as hazardous substances in accordance with Section 311(b)(2)(A) of the Clean Water Act. U.S. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 116.4. http://www.epa.gov/lawsregs/search/40cfr.html . May 20, 2009.

*Etcheverry SB, Cortizo AM. 1998. Bioactivity of vanadium compounds on cells in culture. In: Nriagu JO, ed. Vanadium in the environment. Part I: Chemistry and biochemistry. John Wiley & Sons, Inc.,

359-394.

Faria de Rodriguez C, Gallo M, Marcano M, et al. 1998a. [Toxic effects of ammonium metavanadate on the growth and number of the offspring of Swiss albino mice.] Invest Clin 39(suppl 1):87-97. (Spanish)

Faria de Rodriguez C, Villalobos H, Nava de Leal C. 1998b. [Teratogenic effects of ammonium

metavanadate on the CNS of the offspring of albino rats. A histological and histochemical study]. Invest Clin 39(suppl 1):55 -85. (Spanish)

Fassett JD, Kingston HM. 1985. Determination of nanogram quantities of vanadium in biological material by isotope dilution thermal ionization mass spectrometry with ion counting detection. Anal

Chem 57:2474-2478.

*+Fawcett JP, Farquhar SJ, Thou T, et al. 1997. Oral vanadyl sulphate does not affect blood cells, viscosity or biochemistry in humans. Pharmacol Toxicol 80:202-206.

*FDA. 2008. Everything added to food in the United States (EAFUS). Washington, DC: U.S. Food and Drug Administration. http://vm.cfsan.fda.gov/~dms/eafus.html . May 19, 2009.

*FEDRIP. 2009. Vanadium. Federal Research in Progress database. Springfield, VA: National

Technical Information Service.

Feng X, Melander AP, Klaue B. 2000. Contribution of municipal waste incineration to trace metal deposition on the vicinity. Water Air Soil Pollut 119:295-316.

*Fernandes KG, Nogueira AR, Ne to JA, et al. 2007. Determination of vanadium in human hair slurries by electrothermal atomic absorption spectrometry. Talanta 71(3):1118-1123.

*Figueroa DA, Rodriguez- Sierra CJ, Jimenez -Velez BD. 2006. Concentrations of Ni and V, other heavy

metal s, arsenic, elemental and organic carbon in atmospheric fine particles (PM2.5) from Puerto Rico. Toxicol Ind Health 22(2):87-99.

*Fiorentino CE, Paoloni JD, Sequeira ME, et al. 2007. The presence of vanadium in groundwater of

southeastern extreme the Pampean region Argentina relationship with other chemicals. J Contam Hydrol 93(1-4):122-129.

*Fomon SJ. 1966. Body composition of the infant: Part 1: The male reference infant. In: Faulkner F, ed. Human development. Philadelphia, PA: WB Saunders, 239-246.

*Fomon SJ, Haschke F, Ziegler EE, et al. 1982. Body composition of reference children from birth to age 10 years. Am J Clin Nutr 35(suppl 5):1169- 1175.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 178

9. REFERENCES

*Foresti M, Scippa S, Mele F, et al. 2001. A short low- level exposure to metavanadate during a cell cycle

- specific interval of time is sufficient to permanently derange the differentiative properties of Mel cells. Mutagenesis 16(5):395 -400.

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. Reprod Toxicol 23(4):588-592.

Fortoul TI, Pinon

- Zarate G, Diaz

- Bech ME, et al. 2008. Spleen and bone marrow megakaryocytes as targets for inhaled vanadium. His tol Histopathol 23(11):1321-1326.

Fortoul TI, Pinon

- Zarate G, Gonzalez -Villalva A, et al. 2005. Spleen repercussions after chronic inhalation of vanadium pentoxide (V2O5) evaluated In mice. Toxicol Sci 84(1-S):236.

Fortoul TI, Quan

- Torres A, Sanch ez I, et al. 2002. Vanadium in ambient air: Concentrations in lung tissue from autopsies of Mexico City residents in the 1960s and 1990s. Arch Environ Health 57(5):446-

449.

*Fox MR. 1987. Assessment of cadmium, lead and vanadium status of large an imals as related to the

human food chain. J Anim Sci 65:1744-1752.

Fox PM, Doner HE. 2003. Accumulation, release, and solubility of arsenic, molybdenum, and vanadium in wetland sediments. J Environ Qual 32(6):2428-2435.

*+Franke KW, Moxon AL. 1937. The toxicity of orally ingested arsenic, selenium, tellurium, vanadium and molybdenum. J Pharmacol Exp Ther 61:89-102.

French RJ, Jones PJ. 1993. Role of vanadium in nutrition: Metabolism, essentiality and dietary considerations. Life Sci 52(4):339-346.

*Gallagher FJ, Pechmann I, Bogden JD, et al. 2008. Soil metal concentrations and vegetative assemblage structure in an urban brownfield. Environ Pollut 153(2):351-361.

Galli A, Giromini L, Del Carratore R, et al. 1990. Genotoxicity and effect of microsomal enzymes of vanadium compounds. Mutat Res 234:427-428.

+Ganguli S, Reuland DJ, Franklin LA, et al. 1994a. Effects of maternal vanadate treatment of fetal development. Life Sci 55(16):1267-1276.

*+Ganguli S, Reuland DJ, Franklin LA, et al. 1994b. Effect of vanadate on reproductive efficiency in normal and streptozocin- treated diabetic rats. Metabolism 43(11):1384 -1388.

Geyikoglu F, Turkez H. 2008. Boron compounds reduce vanadium tetraoxide genotoxicity in human lymphocytes. Environ Toxicol Pharmacol 26(3):342-347.

*Gibson DP, Brauninger R, Shaffi HS, et al. 1997. Induction of micronuclei in Syrian hamster embryo cells: Comparison of results in the SHE cell transformation assay for national toxicology program test

chemicals. Mutat Res 392(1 -2):61-70.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 179

9. REFERENCES

Gichner T, Cabrera Lopez G, Wagner ED, et al. 1994. Induction of somatic mutations in Tradescantia clone 4430 by three phenylenediamine isomers and the antimutagenic mechanisms of diethyldithiocarbamate and ammon ium meta -vanadate. Mutat Res 306(2):165-172.

*Giwercman A, Carlsen E, Keiding N, et al. 1993. Evidence for increasing incidence of abnormalities of the human testis: A review. Environ Health Perspect 101(supp 2):65-71.

*+Goldfine AB, Simonson DC, Folli F, et al. 1995. Metabolic effects of sodium metavanadate in

humans with insulin

- dependent and noninsulin -dependent diabetes mellitus in vivo and in vitro studies. J Clin Endocrinol Metab 80(11):3311-3320.

*Gomez M, Domingo JL, Llobet JM, et al. 1988. Effectiveness of chelation therapy with time after acute vanadium intoxication. J Appl Toxicol 8:439-444.

*Gomez M, Domingo JL, Llobet JM, et al. 1991. Effectiveness of some chelating agents on distribution and excretion of vanadium in rats after prolonged oral administration. J Appl Toxicol 11(3):195-198.

Gonzalez- Villalva A, Fortoul TI, Avila -Costa MR, et al. 2006. Thrombocytosis induced in mice after subacute and subchronic V2O5 inhalation. Toxicol Ind Health 22(3):113-116.

Gos wami A, Singh AK, Venkataramani B. 2004. Erratum to "8-hydroxyquinoline anchored to silica gel via new moderate size linker: Synthesis and applications as a metal ion collector for their flame atomic absorption spectrometric determination" [Erratum to: Talanta 60(2003) 1141-1154]. Talanta 62:863.

*Grayson M. 1983. Kirk-Othmer encyclopedia of chemical technology. 3rd ed. New York, NY: John Wiley & Sons, 688-704.

Gregurek D, Reimann C, Stumpfl EF. 1998. Trace elements and precious metals in snow samples from the immediate vicinity of nickel processing plants, Kola Peninsula, northwest Russia. Environ Pollut 102(2-3):221-232.

Gummow B, Bastianello SS, Botha CJ, et al. 1994. Vanadium air pollution: A cause of malabsorption and immunosupp ression in cattle. Onderstepoort J Vet Res 61(4):303 -316.

*Gummow B, Botha CJ, Noordhuizen JP, et al. 2005. The public health implications of farming cattle in areas with high background concentrations of vanadium. Prev Vet Med 72(3-4):281-290.

*Gummow B, Botha CJ, Williams MC. 2006. Chronic vanadium poisoning in calves and its treatment with calcium disodium ethylenediaminetetraacetate. Vet Res Commun 30(7):807-822.

Gupta VK, Tandon SG. 1973. N- arylhydroxamic acids as reagents for vanadiu m (V). Spectrophotometric determination of vanadium (V) with n-m- tolyl -p-methoxybenzohydroxamic acid.

Anal Chim Acta 66:39-48.

*Guzelian PS, Henry CJ, Olin SS. 1992. Similarities and differences between children and adults: Implications for risk as sessment. Washington, DC: International Life Sciences and Press Institute Press.

*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 FOR PUBLIC COMMENT***VANADIUM 180

9. REFERENCES

*Haddad LM, Winchester JF. 1990. Clinical management of poisoning and drug overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Company, 163, 332, 335-336, 524, 542-551, 964-965, 1029-1033,
1058-1059, 1076-1087, 1128-1129, 1209, 1214-1215, 1221, 1224, 1226-1227, 1235-1243, 1250-1252,
1290-1292, 1477-1451, 1481.

+Haider SS, Kashyap SK. 1989. Vanadium intoxication inhibits sulfhydryl -groups and glutathione in the

rat brain. Ind Health 27:23-25.

Haider SS, Abdel- Gayoum AA, el -Fakhri M, et al. 1998. Effect of selenium on vanadium toxicity in different regions of rat brain. Hum Exp Toxicol 17(1):23-28.

*Hamel FG, Duckworth WC. 1995. The relationship between insulin and vanadium metabolism in insulin target tissues. Mol Cell Biochem 153(1 -2):95-102.

Hame l FG, Solomon SS, Jespersen AS, et al. 1993. Alteration of tissue vanadium content in diabetes. Metabolism 42(12):1503-1505.

*Hanauske U, Hanauske A, Marshall MH, et al. 1987. Biphasic effect of vanadium salts on in vitro tumor colony growth. Int J Cell Cloning 5:170-178.

+Hansard SL, Ammerman CB, Henry RR, et al. 1982. Vanadium metabolism in sheep. I. Comparative and acute toxicity of vanadium compounds in sheep. J Anim Sci 55:344-349.

Hansen TV, Aaseth J, Skaug V. 1986. Hemolytic activity of vanadylsulphate and sodium vanadate. Acta Pharmacol Toxicol (Copenh) 59(suppl 7):562-565.

*Harland BF, Harden-Williams BA. 1994. Is vanadium of human nutritional importance yet? J Am Diet Assoc 94(8):891-894.

*Harris WR, Carrano CJ. 1984. Binding of vanadate to human serum transferrin. J Inorg Biochem

22:201-218.

*Harris WR, Friedman SB, Silberman D. 1984. Behavior of vanadate and vanadyl ion in canine blood. J Inorg Biochem 20:157-169.

*Harrison RM, Smith DJ, Luhana L. 1996. Source apportionment of atmospheric polycyclic aromatic hydrocarbons collected from an urban location in Birmingham, U.K. Environ Sci Technol 30(3):825-832.

Hauser R, Elreedy S, Hoppin JA, et al. 1995. Airway obstruction in boilermakers exposed to fuel oil ash. A prospective investigation. Am J Respir Crit Care Med 152:1478-1484.

*HazDat. 2009. Vanadium. HazDat Database: ATSDR’s Hazardous Substance Release and Health Effects Database. Atlanta, GA: Agency for Toxic Substances and Disease R egistry.

Heaton RW, Rahn KA, Lowenthal DH. 1990. Determination of trace elements, including regional tracers, in Rhode Island (USA) precipitation. Atmos Environ 24(1):147-154.

*Heit M, Klusek C, Baron J. 1984. Evidence of deposition of anthropog enic pollutants in remote Rocky

Mountain lakes. Water Air Soil Pollut 22:403-416.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 181

9. REFERENCES

Higashino H, Bogden JD, Lavenhar MA, et al. 1983. Vanadium, Na -K- ATPase, and potassium adaptation in the rat. Am J Physiol 244:F105 -F111.

Hilliard HE. 1987. Vanadium. In: The minerals yearbook - minerals and metals, 917 -927.

*Hoel DG, Davis DL, Miller AB, et al. 1992. Trends in cancer mortality in 15 industrialized countries, 1969-1986. J Natl Cancer Inst 84(5):313-320.

Hogan GR. 1990. Peripheral eryth rocyte levels, hemolysis and three vanadium compounds. Experientia 46(5):444-446.

Hope BK. 1997. An assessment of the global impact of anthropogenic vanadium. Biogeochem 37(1):1-

13.

*Hoshishima K, Shimai KS, Kano K. 1983. The combined administr ation of certain metals in trace dose upon the post natal development of behavior in mice. Dev Toxicol Environ Sci 11:529-532.

*Hovmand MF, Kemp K, Kystol J, et al. 2008. Atmospheric heavy metal deposition accumulated in

rural forest soils of souther n Scandinavia. Environ Pollut 155(3):537-541.

HSDB. 1992. Vanadim and vanadium compounds. Hazardous Substances Data Bank. National Library

of Medicine. http://toxnet.nlm.nih.gov.

*HSDB . 2009. Vanadium and vanadium compounds. Hazardous Substa nces Data Bank, National Library of Medicine. http://toxnet.nlm.nih.gov. May 21, 2009.

*IARC. 2006. Vanadium Pentoxide. In: IARC monographs on the evaluation of the carcinogenic risk

of chemicals to humans. Vol. 86: Cobalt in hard metals and cobal t sulfate gallium arsenide, indium phosphide and vanadium pentoxide. Lyon, France: International Agency for Research on Cancer, 227-

292.

*IARC. 2009. Agents Reviewed by the IARC Monographs. Volumes 1-99. Lyon, France: International Agency for Resea rch on Cancer. http://monographs.iarc.fr/ENG/Classification/index.php. May 19, 2009.

ICRP. 1975. Report of the task group on reference man. In: International commission on radiological protection. Vol. 23. New York, NY: Pergamon Press, 416.

*Ikem A, Nwankwoala A, Odueyungbo S, et al. 2002. Levels of 26 elements in infant formula from USA, UK, and Nigeria by microwave digestion and ICP-OES. Food Chem 77:439-447.

*International Joint Commission. 1978. Great Lakes water quality board - appendix E Status report on organic and heavy metal contaminants in the lakes Erie, Michigan, Huron and Superior basins. Windsor,

Ontario: International Joint Commission, Great Lakes Water Quality Board.

*IOM. 2001. Arsenic, boron, nickel, silicon, and vanadium. In: Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Acadamy Press, Food and Nutrition Board, Institute o f

Medicine. http://books.nap.edu/openbook.php?record_id=10026&page=502 . May 27, 2009.

*IRIS. 2009. Vanadium pentoxide. Integrated Risk Information System. Washington, DC: U.S. Environmental Protection Agency. http://www.epa.gov/iris/subst/index.html . May 11, 2009.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 182

9. REFERENCES

*Irsigler GB, Visser PJ, Spangenberg PA. 1999. Asthma and chemical bronchitis in vanadium plant workers. Am J Ind Med 35(4):366-374.

*Ishida O, Kihira K, Tsukamoto Y, et al. 1989. Improved determination of vanadium in biological fluids by electrothermal atomic absorption spectrometry. Clin Chem 35:127-130.

*Ivancsits S, Pilger A, Diem E, et al. 2002. Vanadate induces DNA strand breaks in cultured human fibroblasts at doses relevant to occupational exposure. Mutat Res 519(1-2):25-35.

*+Jain GC, Pareek H, Sharma S, et al. 2007. Reproductive toxicity of vanadyl sulphate in male rats. J Health Sci 53(1):137-141.

Jha AR, et al. 1979. A sensitive and selective spot test method for the detection of vanadium (V) in a

wat er sample. Int J Environ Stud 14:235-236.

*Johanson CE. 1980. Permeability and vascularity of the developing brain: Cerebellum vs. cerebral cortex. Brain Res 190(1):3-16.

*Jones MM, Basinger MA. 1983. Chelate antidotes for sodium vanadate and vanadyl sulfate

intoxication in mice. J Toxicol Environ Health 12:749-756.

*Kada T, Koichi H, Shirasu Y. 1980. Screening of environmental chemical mutagens by the rec- assay system with Bacillus subtilis. In: De Serres FJ, Hollaender A, eds. Chemcial mutagens: Principles and methods for their detection. Vol. 6. New York, NY: Plenum Press, 149-173.

*Kanematsu N, Hara M, Kada T. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat

Res 77:109-116.

Kanisawa M, Schroeder HA. 196 7. Life term studies on the effects of arsenic, germanium, tin, and vanadium on spontaneous tumors in mice. Cancer Res 27:1192-1195.

Kasibhatla U, Rai V. 1993a. Changes in the plasma levels of phosphatases and transaminases in rabbits following vanadium exposure. Pollut Res 12(1):19-27.

*+Kasibhatla U, Rai V. 1993b. Haematological changes following vanadium exposure. Geobios 20(2):85-95.

Kawai T, Seijji K, Watanabe T, et al. 1989. Urinary vanadium as a biological indicator of exposure to vanadium. Int Arch Occup Environ Health 61:283-287.

Keller RJ, Sharma RP. 1985. In vitro and in vivo effects of vanadate on K+- dependent phosphatase activities from subcellular fractions of brain, kidney, and liver. Toxicol Lett 26:9 -14.

Kellett RJ, Barker ED. 1989. The effect of vanadate on glucose transport and metabolism in rat small intestine. Biochim Biophys Acta 979:311-315.

*Kennish MJ. 1998. Trace metal- sediment dynamics in estuaries: Pollution assessment. Rev Environ

Contam Toxicol 155:69-110.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 183

9. REFERENCES

*Kingsnorth AN, LaMuraglia GM, Ross JS, et al. 1986. Vanadate supplements and 1,2-dimethylhydrazine induced colon cancer in mice: Increased thymidine incorporation without enhanced carcinogenesis. Br J Cancer 53:683-686.

*Kinney PL, Chillrud SN, Ramstrom S, et al. 2002. Exposures to multiple air toxics in New York City. Environ Health Perspect 110(suppl 4):539-546.

*+Kiviluoto M. 1980. Observations on the lungs of vanadium workers. Br J Ind Med 37:363-366.

Kiviluoto M, Pyy L, Pakarinen A. 1979a. Serum and urinary vanadium of vanadium-exposed workers.

Scand J Work Environ Health 5:362-367.

*Kiviluoto M, Pyy L, Pakarinen A. 1981a. Clinical laboratory results of vanadium-exposed workers.

Arch Environ Health 36:109-113.

*+Kiviluoto M, Pyy L, Pakarinen A. 1981b. Serum and urinary vanadium of workers processing vanadium pentoxide. Int Arch Occup Environ Health 48:251-256.

*+Kiviluoto M, Rasanen O, Rinne A, et al. 1979b. Effects of vanadium on the upper respir atory tract of workers in a vanadium factory: A macroscopic and microscopic study. Scand J Work Environ Health

5:50-58.

+Kiviluoto M, Rasanen O, Rinne A, et al. 1981c. Intracellular immunoglobulins in plasma cells of nasal biopsies taken from vanadium- exposed workers: A retrospective case control study by the peroxidase

antiperoxidase (PAP) method. Anat Anz 149:446-450.

*Klein CB, Kargacin B, Su L, et al. 1994. Metal mutagenesis in transgenic Chinese hamster cell lines. Environ Health Perspec t 102(suppl 3):63 -67.

*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. Int J Environ Health Res 13(4):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. J Appl Toxicol 12(6):427-434.

*+Knecht EA, Moorman WJ, Clark JC, et al. 1985. Pulmonary effects of acute vanadium pentoxide inhalation in monkeys. Am Rev Respir Dis 132:1181-1185.

Kobayashi K, Himeno S, Satoh M, et al. 2006. Pentavalent vanadium induces hepatic metallothionein through interleukin-6- dependent and -independent mechanisms. Toxicology 228(2-3):162-170.

*Komori M, Nishio K, Kitada M, et al. 1990. Fetus- specific expression of a form of cytochrome P -450 in human livers. Biochemistry 29(18):4430-4433.

Kordowiak AM, Goc A, Drozdowska E, et al. 2005. Sodium ortho vanadate exerts influence on liver golgi complexes from control and streptozotocin- diabetic rats. J Inorg Biochem 99(5):1083-1089.

Korn MG, Santos DS, Welz B, et al. 2007. Atomic spectrometric methods for the determination of

metals and metalloids in automotive fuels

- a review. Talanta 73(1):1 -11.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 184

9. REFERENCES

*Koutrakis P, Briggs SLK, Leaderer BP. 1992. Source apportionment of indoor aerosols in Suffolk and Onondaga counties, New York. Environ Sci Technol 26:521-527.

Kovacs -Huber G. 1982. Pesticide monitoring in Lake Balaton between 1978-1980. Hung J Ind Chem

10:57-75.

*+Kowalska M. 1988. The effect of vanadium on lung collagen content and composition in two successive generations of rats. Toxicol Lett 41:203 -208.

Krachler M, Mohl C, Emons H, et al. 2003. Atmospheric deposition of V, Cr, and Ni since the late glacial: Effects of climatic cycles, human impacts, and comparison with crustal abundances. Environ Sci Technol 37(12):2658-2667.

*Krishna AK, Govil PK. 2007. Soil contamination due to heavy metals from an industrial area of Surat, Gujarat, Western India. Environ Monit Assess 124(1-3):263-275.

*Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: Hayes AW, ed. Principles and met hods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149-

188.

*Krishnan K, Anderson ME, Clewell HJ, et al. 1994. Physiologically based pharmacokinetic modeling of chemical mixtures. In: Yang RSH, ed. Toxicology of chemical mixtures. Case studies, mechanisms, and novel approaches. San Diego, CA: Academic Press, 399-437.

Krishnan SS, Quittkat S, Crapper DR. 1976. Atomic absorption analysis for traces of aluminum and vanadium in biological tissue. A critical evaluation of the graphi te furnace atomizer. Can J Spectrosc

21:25-30.

*Kučera J, Byrne AR, Mravcova A, et al. 1992. Vanadium levels in hair and blood of normal and exposed persons. Sci Total Environ 115(3):191-205.

*Kučera J, Lener J, Mnukova J, et al. 1998. Vanadium exposure tests in human: Hair, nails, blood. In: Nriagu JO, ed. Vanadium in the environment, part 2: Health effects. New York, NY: John Wiley &
Sons, Inc., 55-74.

*Kučera J, Sabbioni E. 1998. Baseline vanadium levels in human blood, serum, and urine. In: Nriagu JO, ed. Vanadium in the environment, part 2: Health effects. New York, NY: John Wiley & Sons, Inc.,

75-90.

*Lagerkvist B, Nordberg GF, Vouk V. 1986. Vanadium. In: Friberg L, Nordberg GR, Vouk VB, et al.,

eds. Handbook on th e toxicology of metals. Vol. II: Specific metals. Amsterdam: Elsevier, 638 -663.

*Lavi N, Alfassi ZB. 1988. Determination of trace amounts of titanium and vanadium in human blood serum by neutron activation analysis: Coprecipitation with Pb/PDC/2 or Be/PDC/3. J Radioanal Chem

126:361-374.

+Lee KP, Gillies PJ. 1986. Pulmonary response and intrapulmonary lipids in rats exposed to bismuth orthovanadate dust by inhalation. Environ Res 40:115-135.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 185

9. REFERENCES

*Leeder JS, Kearns GL. 1997. Pharmacogenetic s in pediatrics: Implications for practice. Pediatr Clin North Am 44(1):55-77.

Lener J, Kucera J, Kodl M, et al. 1998. Health effects of environmental exposure to vanadium. In: Nriagu JO, ed. Vanadium in the environment, part 2: Health effects. New York, NY: John Wiley &
Sons, Inc., 1-20.

*Léonard A, Gerber GB. 1994. Mutagenicity, carcinogenicity and teratogenicity of vanadium compounds. Mutat Res 317(1):81-88.

Leopardi P, Villani P, Cordelli E, et al. 2005. Assessment of the in vivo genotoxicity of vanadate: Analysis of micronuclei and DNA damage induced in mice by oral exposure. Toxicol Lett 158(1):39-49.

*Leung H. 1993. Physiologically- based pharmacokinetic modelling. In: Ballantyne B, Marrs T, Turner P, eds. General and ap plied toxicology. Vol. 1. New York, NY: Stockton Press, 153-164.

*+Levy BS, Hoffman L, Gottsegan S. 1984. Boilermakers' bronchitis. J Occup Med 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. 2007. Hawley's condensed chemical dictionary. 15th ed. Hoboken, NJ: John Wiley &
Sons, Inc., 71, 1149, 1151.

*Lide DR. 2008. CRC handbook of chemistry and physics. 88th ed. Boca Raton, FL: CRC Press, 4-40,
4-90, 4-92, 4-98.

*Lin TS, Chang CL, Shen FM. 2004. Whole blood vanadium in Taiwanese college students. Bull Environ Contam Toxicol 73(5):781-786.

*Liu Y, Woodin MA, Smith TJ, et al. 2005. Exposure to fuel-oil ash and welding emissions during the overhaul of an oil-fired boiler. J Occup Environ Hyg 2(9):435-443.

*Livingston AL. 1978. Forage plant estrogens. J Toxicol Environ Health 4(2-3):301-324.

*+Llobet JM, Domingo JL. 1984. Acute toxicity of vanadium compounds in rats and mice. Toxicol Lett

23:227-231.

*+Llobet JM, Colomina MT, Sirvent JJ, et al. 1993. Reproductive toxicity evaluation of vanadium in male mice. Toxicology 80(2-3):199-206.

Llobet JM, Granero S, Torres A, et al. 1998. Biological monitoring of environmental pollution and human exposure to metals in Tarragona, Spain: III. Blood levels. Trace Elem Electrolytes 15(2):76-80.

Loring DH. 1979. Geochemistry of cobalt, nickel, chromium, and vanadium in the sediments of t he estuary and open gulf of St. Lawrence. Can J Earth Sci 16:1196-1209.

Lough GC, Schauer JJ, Park J, et al. 2005. Emissions of metals associated with motor vehicle roadways.

Environ Sci Technol 39:826 -836.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 186

9. REFERENCES

Lowe TP, Day DD. 2002. Metal concentr ations in zebra mussels and sediments from embayments and riverine environments of eastern Lake Erie, southern Lake Ontario, and the Niagara River. Arch Environ

Contam Toxicol 43:301-308.

*Lusky LM, Braun HA, Laug EP. 1949. The effect of BAL on experimental lead, tungsten, vanadium, uranium, copper and copper-arsenic poisoning. J Ind Hyg Toxicol 31:301-305.

*Macias

- Zamora JV, Villaescusa

- Celaya JA, Munoz -Barbosa A, et al. 1999. Trace metals in sediment cores from the Campeche shelf, Gulf of Mexi co. Environ Pollut 104(1):69-77.

Mackinson FW, Stricoff RS, Partridge LJ. 1978. NIOSH/OSHA- occupational health guidelines for chemical hazards. DHHS (NIOSH) Publication.

*Mamane Y, Pirrone N. 1998. Vanadium in the atmosphere. In: Nriagu JO, e d. Advances in environmental science and technology. Vanadium in the environment, Part 1: Chemistry and biochemistry. Vol. 30. New York, NY: John Wiley and Sons, 37-71.

*Martin DM, Chasteen ND. 1988. Vanadium. Methods Enzymol 158:402-421.

*Mar tin HW, Kaplan DI. 1998. Temporal changes in cadmium, thallium and vanadium mobility in soil and phytoavailability under field conditions. Water Air Soil Pollut 101(1-4):399-410.

*Mayr U, Butsch A, Schneider S. 1992. Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. Toxicology 74(2-3):135-149.

McCrindle CM, Mokantla E, Duncan N. 2001. Peracute vanadium toxicity in cattle grazing near a vanadium mine. J Environ Monit 3(6):580-582.

*Mermut AR, Jain JC, Song L, et al. 1996. Trace element concentrations of selected soils and fertilizers in Saskatchewan, Canada. J Environ Qual 25(4):845-853.

*Mielke HW, Gonzales CR, Smith MK, et al. 2000. Quantities and associations of lead, zinc, cadmium, manganese, chromium, nickel, vanadium, and copper in fresh Mississippi Delta alluvium and New

Orleans alluvial soils. Sci Total Environ 246:249-259.

*Migliore L, Bocciardi R, Macri C, et al. 1993. Cytogenetic damage induced in human lymphocytes by four vanadium compounds and micronucleus analysis by fluorescence in situ hybridization with a centromeric probe. Mutat Res 319(3):205-213.

Migliore L, Cocchi L, Macri C, et al. 1992. Cytogenetic effects induced in vitro and in vi vo by vanadium compounds. Mutat Res 271(2):175-176.

*Migliore L, Scarpato R, Falco P. 1995. The use of fluorescence in situ hybridization with a betasatellite DNA probe for the detection of acrocentric chromosomes in vanadium-induced micronuclei. Cytogenet Cell Genet 69(3-4):215-219.

Migliore L, Zotti -Martelli L, Scarpato R. 1999. Detection of chromosome loss and gain induced by griseofulvin, estramustine, and vanadate in binucleated lymphocytes using FISH analysis. Environ Mol Mutagen 34(1):6 4-68.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 187

9. REFERENCES

*Miguel AH, De Aquino Neto FR, Cardoso JN, et al. 1995. Characterization of indoor air quality in the cities of Sao Paulo and Rio de Janeiro, Brazil. Environ Sci Technol 29:338-345.

Miramand P, Fowler SW. 1998. Bioaccumulation and transfer of vanadium in marine organisms. In: Nriagu JO, ed. Advances in environmental science and technology. Vanadium in the environment, Part

1: Chemistry and biochemistry. Vol. 30. New York, NY: John Wiley and Sons, 167-197.

*Mitchell WG, Floyd EP. 1954. Ascorbic acid and ethylene diamine tetraacetate as antidotes in experimental vanadium poisoning. Proc Soc Exp Biol Med 85:206-208.

*+Morgan AM, El-Tawil OS. 2003. Effects of ammonium metavanadate on fertility and reproductive performance of adult male and female rats. Pharmacol Res 47(1):75 -85.

*Morrison RJ, Gangaiya P, Naqasima MR, et al. 1997. Trace metal studies in the Great Astrolabe Lagoon, Fiji, a pristine marine environment. Mar Pollut Bull 34(5):353-356.

*Morselli PL, Franco -Morselli R, Bossi L. 1980. Clinical pharmacokinetics in newborns and infants: Age

- related differences and therapeutic implications. Clin Pharmacokinet 5(6):485 -527.

Morton- Bermea O, Carrillo -Chavez A, Hernandez E, et al. 2004. Determination of meta ls for leaching experiments of mine tailings: Evaluation of the potential environmental hazard in the Guanajuato Mining District, Mexico. Bull Environ Contam Toxicol 73:770-776.

*Mosher BW, Winkler P, Jaffrezo JL. 1993. Seasonal aerosol chemistry at dye 3 greenland. Atmospheric Environment Part a General Topics 27(17 -18):2761-2772.

*+Mountain JT, Delker LL, Stokinger HE. 1953. Studies in vanadium toxicology. Reduction in the cystine content of rat hair. AMA Arch Ind Hyg Occup Med 8:406-411.

Mountain JT, Stockell FR, Stokinger HE. 1955. Studies in vanadium toxicology: III. Fingernail cystine as an early indicator of metabolic changes in vanadium workers. AMA Arch Ind Health 12:494-502.

*Mousty F, Omenetto N, Pietra R, et al. 1984. At omic

- absorption spectrometric, neutron -activation and radioanalytical techniques for the determination of trace metals in environmental, biochemical and toxicological research. Part I. Vanadium. Analyst 109:1451-1454.

Mravcova A, Jirova D, Janci H, e t al. 1993. Effects of orally administered vanadium on the immune system and bone metabolism in experimental animals. Sci Total Environ Suppl Pt 1:663-669.

*Mukherjee B, Patra B, Mahapatra S, et al. 2004. Vanadium- an element of atypical biological significance. Toxicol Lett 150(2):135 -143.

*+Musk AW, Tees JG. 1982. Asthma caused by occupational exposure to vanadium compounds. Med J

Aust 1:183-184.

Mussali -Galante P, Rodriguez- Lara V, Avila -Costa MR, et al. 2007. Mechanisms of vanadium to xicity. In: Fortoul TI, Avila- Costa MR, eds. Vanadium: Its impact on health. New York, NY: Nova Science Publishers, 7-19.

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. Toxicol Ind Health 21(9):215-222.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 188

9. REFERENCES

*NAS/NRC. 1989. Report of the oversight committee. Washington, DC: National Academy of Sciences, National Research Council, National Academy Press. Biologic markers in rep roductive toxicology.

Nava de Leal CA, Villalobos H, Faria de Rodriguez C. 1998. [Changes in female reproduction induced by ammonium metavanadate in Swiss albino mice]. Invest Clin 39(supp l):99-122. (Spanish)

+Naylor GJ, Smith AH, Bryce-Smith D, et al. 1984. Elevated vanadium content of hair and mania. Biol Psychiatry 19:759-764.

Nechay BR, Saunders JP. 1978. Inhibition by vanadium of sodium and potassium dependent adenosinetriphosphatase derived from animal and human tissues. J Environ Path ol Toxicol 2:247 -262.

Nielsen FH. 1995. Vanadium in mammalian physiology and nutrition. In: Sigel H, Sigel A, eds. Metal ions in biological systems. Vol. 31. New York, NY: Marcel Dekker, Inc., 543-573.

Nielsen T. 1996. Traffic contribution of polycyclic aromatic hydrocarbons in the center of a large city. Atmos Environ 30(20):3481-3490.

NIOSH. 1976. National occupational hazard survey (1970) database. Cincinnati, OH: U.S. department of Health and Human Services, National Institute of Occupational Safety and Health.

*+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. P B85163574.

NIOSH. 1984a. National occupational exposure survey (1980-1983) database. Cincinnati, OH: U.S. Department of Health and Human Services, National Institute of Occupational Safety and Health.

NIOSH. 1984b. NIOSH manual of analytical methods. Washington, DC: U.S. Department of Health and Human Services, National Institute of Occupational Safety and Health.

*NIOSH. 1994. Vanadium oxides. Method 7504. In: NIOSH manual of analytical methods. Centers for Disease Control, National Institute for Occupational Safety and Health, http://www.cdc.gov/niosh/nmam/pdfs/7504.pdf . May 26, 2009.

*NIOSH. 2003a. Elements by ICP (nitric/perchloric acid ashing). Method 7300. In: NIOSH manual of analytical methods. 4th ed. Centers for Disease Control, National Institute for Occupational Safety and

Health. http://www.cdc.gov/niosh/nmam/pdfs/7300.pdf . May 26, 2009.

*NIOSH. 2003b. Elements by ICP (aqua regia ashing). Method 7301. In: NIOSH manual of analytical methods. 4th ed. Centers for Disease Control, National Institute for Occupational Safety and Health. http://www.cdc.gov/niosh/nmam/pdfs/7301.pdf . May 26, 2009.

*NIOSH. 2003c. Elements by ICP (hot block/HCl/HNO3 digestion). Method 7303. In: NIOSH manual of analytical methods. 4th ed. Centers for Disease Control, National Institute for Occupational Safety

and Health. http://www.cdc.gov/niosh/nmam/pdfs/7303.pdf. May 26, 2009.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 189

9. REFERENCES

*NIOSH. 2003d. Elements on wipes. Method 9102. In: NIOSH manual of analytical methods. 4th ed. Centers for Disease Control, National Institute for Occupational Safety and Health, http://www.cdc.gov/niosh/nmam/pdfs/9102.pdf . May 26, 2009.

*NIOSH. 2004. NIOSH Health Hazard Evaluation Report: HETA No. 2003-0171-2925, PCC Schlosser, Redmond, Oregon. Cincinnati, OH: National Institute for Occupational Safety and Health.

*NIOSH. 2005. Vanadium pentoxide. NIOSH pocket guide to chemical hazards. Atlanta, GA: National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention. http://www.cdc.gov/niosh/npg/. May 19, 2009.

*Nixon DE, Neubauer KR, Eckdahl SJ, et al. 2002. Evaluation of a tunable bandpass reaction cell for an inductively coupled plasma mass spectrometer for the determination of chromium and van adium in serum and urine. Spectrochim Acta Part B 57:951-966.

*NLM. 2009. Vanadium. Bethesda, MD: U.S. National Library of Medicine, National Institutes of Health, Department of Health and Human Services. http://dietarysupplements.nlm.nih.gov/dietar y/ingredDetail.jsp?contain=Vanadium&id=1280 . June 17,

2009.

Novelli M, De Tata V, Fierabracci V, et al. 2005. Comparative study on the preventing effects of oral vanadyl sulfate and dietary restriction on the age- related glucose intolerance in rats. A ging Clin Exp Res 17(5):351-357.

*NRC. 1993. Pesticides in the diets of infants and children. Washington, DC: National Research Council. National Academy Press.

*Nriagu JO. 1992. Review: Toxic metal pollution in Africa. Sci Total Environ 121 :1 -37.

Nriagu JO, Pirrone N. 1998. Emissions of vanadium into the atmosphere. In: Nriagu JO, ed. Advances in environmental science and technology. Vanadium in the environment, Part 1: Chemistry and biochemistry. Vol. 30. New York, NY: John Wiley and Sons, 25-36.

*+NTP. 2002. NTP toxicology and carcinogenesis studies of vanadium pentoxide (CAS No. 1314-62-1) in F344/N rats and B6C3F1 mice (inhalation). Natl Toxicol Program Tech Rep Ser (507):1-343.

*NTP. 2005. Report on carcinogens, 11th edition. Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. http://ntp

server.niehs.nih.gov/ntp/roc/toc11.html. May 11, 2009.

*NTP. 2008. Chemical information review docu ment for oral exposure to tetravalent and pentavalent vanadium compounds. National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health,. http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background /

ExSumPdf/ NIEHS_Vanadium_compounds_508.pdf. August 3, 2009.

*Oberg SG, Parker R, Sharma RP. 1978. Distribution and elimination of an intratracheally administered vanadium compound in the rat. Toxicology 11:315-323.

*O'Neil MJ, Heckelman PE, Koch CB, eds. 2006. The merck index. 14th ed. Whitehouse Station, NJ: Merck & Co., Inc., 90, 4192, 1705-1706.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 190

9. REFERENCES

*Ordóñez A, Loredo J, Demiguel E, et al. 2003. Distribution of heavy metals in the street dusts and soils of an industrial city in northern Spain. Arch Environ Contam Toxicol 44:160-170.

*OSHA. 1991. Confirmation of vanadium pentoxide in workplace atmospheres. Occupational Safety and Health Administration. http://www.osha.gov/dts/sltc/methods/inorganic/id185/id185.html. April 7,

2009.

*OSHA. 2002. Metal and metalloid particulates in workplace atmospheres (ICP analysis). Occupational Safety and Health Administration. Division of Physical Measurements and Inorganic Analyses, OSHA

Technical Center. http://www.osha.gov/dts/sltc/methods/inorganic/id125g/id125g.pdf. May 23, 2009.

*OSHA. 2009. Toxic and Hazardous Substances. Occupational safety and health standards. Occupational Safety and Health Administration. Code of Federal Regulations. 29 CFR 1910.1000, Table

Z 1. http://www.osha.gov/comp-links.html . May 19, 2009.

Oster MH, Llobet JM, Domingo JL, et al. 1993. Vanadium treatment of diabetic Sprague- Dawley rats results in tissue vanadium accumulation and pro -oxidant effects. Toxicology 83(1-3):115-130.

OTA. 1990. Neurotoxicity: Identifying and controlling poisons of the nervous system. Washington, DC: Office of Technology Assessment.

*Owen GM, Brozek J. 1966. Influence of age, sex and nutrition on body composition during childhood and adolescence. In: Falkner F, ed. Human development. Philadelphia, PA: WB Saunders, 222-238.

*Owusu -Yaw J, Cohen MD, Fernando SY, et al. 1990. An assessment of the genotoxicity of vanadium. Toxicol Lett 50(2 -3):327-336.

Pantelica A, Salagean M, Schreiber H. 1998. Compara tive evaluation of some pollutants in the airborne particulate matter in Eastern and Western Europe: Two -city study, Bucharest- Stuttgart. AU

- CERCASOV V. Environ Pollut 101(3):331-337.

Parkash P, Gupta A. 1991. Cardiotoxic effects of vanadium as revealed through electrocardiogram. Indian J Ind Med 37(1):32-36.

*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.

Parr RM, Aras NK, Iyengar GV. 2006. Dietary intakes of essential trace elements: Results from total diet studies supported by the IAEA. J Radioanal Nucl Chem 270(1):155-161.

*+Paternain JL, Domingo JL, Gomez M, et al. 1990. Developmental tox icity of vanadium in mice after oral administration. J Appl Toxicol 10(3):181-186.

*+Paternain JL, Domingo JL, Llobet JM, et al. 1987. Embryotoxic effects of sodium metavanadate administered to rats during organogenesis. Rev Esp Fisiol 43(2):223-228.

*Patterson BW, Hansard SL, Ammerman CB, et al. 1986. Kinetic model of whole- body vanadium metabolism: Studies in sheep. Am J Physiol 251:R325-R332.

Paul KR, Gupta VK. 1982. Toxicology, solvent extraction and spectrophotometric determination of vanadium in complex materials. Am Ind Hyg Assoc J 43:529-532.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 191

9. REFERENCES

*Pennington JA, Jones JW. 1987. Molybdenum, nickel, cobalt, vanadium, and strontium in total diets. J

Am Diet Assoc 12:1644-1650.

Phillips T, Nechay BR, Heidelbaugh D. 1983. Vanadium: Chemistry and the kidney. Fed Proc

42:2969-2973.

Pierce LM, Alessandrini F, Godleski JJ, et al. 1996. Vanadium-induced chemokine mRNA expression and pulmonary inflammation. Toxicol Appl Pharmacol 138(1):1-11.

Pinon-Zarate G, Rodriguez- Lara V, R ojas -Lemus M, et al. 2005. Gender differences in spleen megakaryocyte features after chronic inhalation of vanadium [Abstract]. Toxicol Lett 158(suppl 1):S161.

Pinon-Zarate G, Rodriguez- Lara V, Rojas -Lemus M, et al. 2008. Vanadium pentoxide inhalation provokes germinal center hyperplasia and suppressed humoral immune responses. J Immunotoxicol 5(2):115-122.

*+Poggioli R, Arletti R, Bertolini A, et al. 2001. Behavioral and developmental outcomes of prenatal and postnatal vanadium exposure in the rat. Pharmacol Res 43(4):341-347.

*Polissar AV, Hopke PK, Poirot RL. 2001. Atmospheric aerosol over Vermont: Chemical composition

and sources. Environ Sci Technol 35:4604-4621.

*Poucheret P, Verma S, Grynpas MD, et al. 1998. Vanadium and diabetes. Mol Cell Biochem 188:73-

80.

Poulsen OM, Christensen JM, Sabbioni E, et al. 1994. Trace element reference values in tissues from inhabitants of the European community. V. Review of trace elements in blood, serum and urine and

critical evaluatio n of reference values for the Danish population. Sci Total Environ 141:197-215.

Poykio R, Maenpaa A, Peramaki P, et al. 2005. Heavy metals (Cr, Zn, Ni, V, Pb, Cd) in ligonberries ( Vaccinium vitis -idaea L .) and assessment of human exposure in two indu strial areas in the Kemi -Tornio Region, Northern Finland. Arch Environ Contam Toxicol 48:338-343.

Presley BJ. 1997. A review of arctic trace metal data with implications for biological effects. Mar Pollut Bull 35(7-12):226-234.

Pugazhenthi S, Kha ndelwal RL. 1990. Insulin like effects of vanadate on hepatic glycogen metabolism in nondiabetic and streptozocin- induced diabetic rats. Diabetes 39(7):821 -827.

*Pyrzyńska K, Wierzbicki T. 2004. Determination of vanadium species in environmental sa mples.

Talanta 64:823 -829.

Pytkowski B, Jagodzinska -Hamann L. 1996. Effects of in vivo vanadate administration on calcium exchange and contractile force of rat ventricular myocardium. Toxicol Lett 84(3):167-173.

Pyy L, Lajunen LH, Hakala E. 1983. Determination of vanadium in workplace air by DCP emission spectrometry. Am Ind Hyg Assoc J 44:609-614.

Quickert N, Zdrojewski A, Dubois L. 1974. The accurate measurement of vanadium in airborne particulates. Int J Environ Anal Chem 3:229-238.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 192

9. REFERENCES

*Ramanadham S, Heyliger C, Gresser MJ, et al. 1991. The distribution and half- life for retention of vanadium in the organs of normal and diabetic rats orally fed vanadium(IV) and vanadium(V). Biol Trace Elem Res 30(2):119 -124.

Rawal SB, Singh MV, Salhan A, et al. 1997. Influence of vanadium on acclimatization of humans to high altitude. Int J Biometeorol 40(2):95-98.

Reimann C, De Caritat P, Halleraker JH, et al. 1997. Rainwater composition in eight arctic catchments in northern Europe (Finland, Norway and Russia). Atmos Environ 31(2):159-170.

Ress NB, Chou BJ, Renne RA, et al. 2003a. Carcinogenicity of inhaled vanadium pentoxide in F344/N rats and B6C3F1 mice. Toxicol Sci 74(2):287-296.

Ress NB, Roycroft JH, Hailey JR, et al. 2003b. Toxic and carcinogenic effects in the lungs of rats and mice exposed to vanadium pentoxide by whole-body inhalation. Toxicol Sci 72(S-1):85.

*Rhoads K, Samders CL. 1985. Lung clearance, translocation, and acute toxicity of arsenic, beryllium,

cadm ium, cobalt, lead, selenium, vanadium and ytterbium oxides following deposition in rat lung.

Environ Res 36:359-378.

*Riediker M, Williams R, Devlin R, et al. 2003. Exposure to particulate matter, volatile organic compounds, and other air pollutants inside patrol cars. Environ Sci Technol 37:2084 -2093.

Ringelband U, Hehl O. 2000. Kinetics of Vanadium Bioaccumulation by the brackish water hydroid Cordylophora caspia (Pallas). Bull Environ Contam Toxicol 65(4):486-493.

Rodriguez- Mercado JJ, Ro ldan

- Reyes E, Altamirano -Lozano M. 2003. Genotoxic effects of vanadium(IV) in human peripheral blood cells. Toxicol Lett 144(3):359-369.

*Rojas E, Valverde M, Herrera LA, et al. 1996. Genotoxicity of vanadium pentoxide evaluate by the single cell g el electrophoresis assay in human lymphocytes. Mutat Res 359(2):77-84.

*Roldán RE, Altamirano LM. 1990. Chromosomal aberrations, sister- chromatid exchanges, cell

- cycle kinetics and satellite associations in human lymphocyte cultures exposed to vanadi um pentoxide. Mutat Res 245(2):61-66.

+Roschin IV. 1967. [Vanadium]. In: Izrael'son ZI, ed. [Toxicology of the rare metals]. Jerusalem: Israel Program for Scientific Translations, 52 -60. (Russian)

*+Roshchin AV, Ordzhonikidze EK, Shalganova IV. 1980. [Vanadium- toxicity, metabolism, carrier state]. J Hyg Epidemiol Microbiol Immunol 24:377-383. (Russian)

*RTECS. 2009. Vanadium and vanadium compounds. Registry of Toxic Effects on Chemical Substances. National Institute of Occupational Sa fety and Health. MDL Information Systems, Inc. May
26, 2009.

Rutzke MA, Gutenmann WH, Lisk DJ, et al. 2000. Toxic and nutrient element concentrations in soft tissues of zebra and guagga mussels from Lakes Erie and Ontario. Chemosphere 40:1353-1356.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 193

9. REFERENCES

*Rydzynski K. 2001. Vanadium, Niobium, and Tantalum. In: Bingham E, Cohrssen B, Powell CH, eds. Patty's toxicology. Vol. 3. 5th ed. New York, NY: John Wiley & Sons, Inc., 1-38.

*Sabbioni E, Marafante E. 1978. Metabolic patterns of vanadium in the rat. Bioinorg Chem 9:389-408.

*Sabbioni E, Kueera J, Pietra R, et al. 1996. A critical review on normal concentrations of vanadium in human blood, serum, and urine. Sci Total Environ 188(1):49-58.

*Sadiq M, Alam I. 1997. Metal concentrations in a shallow groundwater aquifer underneath petrochemical complex. Water Res 31(12):3089-3097.

*Sadiq M, Mian AA. 1994. Nickel and vanadium in air particulates at Dhahran (Saudi Arabia) during and after the Kuwait oil fires. Atmos Environ 28(13):2249-2253.

Sadiq M, Alam IA, Al-Mohanna H. 1992b. Bioaccumulation of nickel and vanadium by clams ( Meretrix

meretrix ) living in different salinities along the Saudi coast of the Arabian Gulf. Environ Pollut 76(3):225-231.

Sadiq M, AlThagafi KM, M ian AA. 1992a. Preliminary evaluation of metal contamination of soils from

the Gulf War activities. Bull Environ Contam Toxicol 46:633 -639.

*Salazar -Coria L, Amezcua- Allieri MA, Tenorio -Torres M, et al. 2007. Polyaromatic hydrocarbons (PAHs) and me tal evaluation after a diesel spill in Oaxaca, Mexico. Bull Environ Contam Toxicol 79(4):462-467.

Saldivar L, Espejel G, Sanchez I, et al. 2004. Study of vanadium, an experimental model in mice. Toxicol Appl Pharmacol 197(3):274-275.

*Saleh MA, W ilson BL. 1999. Analysis of metal pollutants in the Houston Ship Channel by inductively coupled plasma/mass spectrometry. Ecotoxicol Environ Saf 44:113-117.

*+Sanchez D, Ortega A, Domingo JL, et al. 1991. Developmental toxicity evaluation of orthov anadate in the mouse. Biol Trace Elem Res 30(3):219 -226.

*+Sanchez DJ, Colomina MT, Domingo JL. 1998. Effects of vanadium on activity and learning in rats. Physiol Behav 63(3):345-350.

*Sanchez DJ, Colomina MT, Domingo JL, et al. 1999. Prevention by sodium 4,5-dihydroxybenzene-1,3- disulfonate (tiron) of vanadium-induced behavioral toxicity in rats. Biol Trace Elem Res 69(3):249-259.

Sanchez DJ, Gomez M, Domingo JL, et al. 1992. Maternal and developmental toxicity of metavanadate in mice. In: Anastassopoulou J, Collery P, Etienne JC, eds. Metal ions in biology and medicine. Vol. 2. Paris: John Libbey Eurotext, 319-320.

*+Schroeder HA, Balassa JJ. 1967. Arsenic, germanium, tin and vanadium in mice: Effects on growth,

survival and tissue levels. J Nutr 92(2):245 -252.

*+Schroeder HA, Mitchener M. 1975. Life- term effects of mercury, methyl mercury, and nine other trace metals on mice. J Nutr 105(4):452-458.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 194

9. REFERENCES

*Schroeder HA, Balassa JJ, Tipton IH. 1963. Abnormal trace metals in man - vanadium. J Chronic Dis

16:1047-1071.

*+Schroeder HA, Mitchener M, Nason AP. 1970. Zirconium, niobium, antimony, vanadium and lead in rats: Life term studies. J Nutr 100(1):59 -68.

*Schroeder WH, Dobson M, Kane DM, et al. 1987. Toxic t race elements associated with airborne particulate matter: A review. JAPCA 37(11):1267 -1285.

*Schuhmacher M, Bocio A, Agramunt MC, et al. 2002. PCDD/F and metal concentrations in soil and herbage samples collected in the vicinity of a cement plant. Chemosphere 48:209-217.

*+Scibior A. 2005. Some selected blood parameters in rats exposed to vanadium and chromium via drinking water. Trace Elem Electrolytes 22(1):40 -46.

*+Scibior A, Zaporowska H, Ostrowski J. 2006. Selected haematological an d biochemical parameters of blood in rats after subchronic administration of vanadium and/or magnesium in drinking water. Arch Environ Contam Toxicol 51(2):287-295.

*Seiler HG. 1995. Analytical procedures for the determination of vanadium in biologic al materials. In: Sigel H, Sigel A, eds. Metal ions in biological systems. New York, NY: Marcel Dekker, Inc., 671-688.

Sella SM, Pereiranetto AD, Delestal LM. 2001. Trace metals in the atmosphere of Niteroi City, RJ,

Brazil. Bull Environ Contam To xicol 67:271-275.

Senesi GS, Baldassarre G, Senesi N, et al. 1999. Trace element inputs into soils by anthropogenic activities and implications for human health. Chemosphere 39(2):343-377.

*Sepe A, Ciaralli L, Ciprotti M, et al. 2003. Determination of cadmium, chromium, lead and vanadium in six fish species from the Adriatic Sea. Food Addit Contam 20(6):543-552.

*Setchell BP, Waites GMH. 1975. The blood testis barrier. In: Creep RO, Astwood EB, Geiger SR, eds. Handbook of physiology: Endocrinology V. Washington, DC: American Physiological Society,

143-172.

Shahin U, Yi SM, Paode RD, et al. 2000. Long-term elemental dry deposition fluxes measured around Lake Michigan with an automated dry deposition sampler. Environ Sci Technol 34:1887-1892.

*+Sharma RP, Bourcier DR, Brinkerhoff CR, et al. 1981. Effects of vanadium on immunologic functions. Am J Ind Med 2(2):91-99.

*Sharma RP, Oberg SG, Parker RD. 1980. Vanadium retention in rat tissues following acute exposures

to diffe rent dose levels. J Toxicol Environ Health 6:45 -54.

*Sheridan CJ, Pfleger RC, McClellan RO. 1978. Cytotoxicity of vanadium pentoxide on pulmonary alveolar macrophages from dog, rabbit, and rat: Effect on viability and effect on lipid metabolism. Ann Resp Inhalation Toxicol:294 -298.

Sheu CW, Rodriguez I, Lee JK. 1992. Proliferation and morphological transformation of BALB/3T3 cells by a prolonged treatment with sodium orthovanadate. Food Chem Toxicol 30(4):307-311.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 195

9. REFERENCES

Shimy TM. 1997. Distribution of selected trace metals and its relation with environmental pollution. Energy Sources 19(8):851 -860.

Shrivastava S, Jadon A, Shukla S. 2007. Effect of tiron and its combination with nutritional supplements against vanadium intoxication in female albino rats. J Toxicol Sci 32(2):185-192.

Shrivastava S, Jadon A, Shukla S, et al. 2007. Chelation therapy and vanadium: Effect on reproductive organs in rats. Indian J Exp Biol 45(6):515 -523.

Siemon H, Schneider H, Fuhrmann GF. 1982. Vanadium increases selective K+ -permeability in human erythrocytes. Toxicology 22:271-278.

Singh PP, Junnarkar AY. 1991. Behavioural and toxic profile of some essential trace metal salts in mice and rats. Indian J Pharmacol 23(3):153-159.

Sitprija V, Tun gsanga K, Tosukhowong P, et al. 1993. Metabolic problems in northeastern Thailand: Possible role of vanadium. Miner Electrolyte Metab 19(1):51 -56.

*+Sj öberg SG. 1950. Vanadium pentoxide dust: A clinical and experimental investigation on its effec t after inhalation. Stockholm: Esselte AB, 6-188.

*+Sjöberg SG. 1956. Vanadium dust, chronic bronchitis and possible risk of emphysema. Acta Med

Scand 154:381-386.

*Smith DJ, Harrison RM, Luhana L, et al. 1996. Concentrations of particulate airb orne polycyclic aromatic hydrocarbons and metals collected in Lahore, Pakistan. Atmos Environ 30(23):4031-4040.

*Smith JB. 1983. Vanadium ions stimulated DNA synthesis in Swill mouse 3T3 and 3T6 cells. Proc

Natl Acad Sci USA 80:6162-6166.

*Smith DM, Pickering RM, Lewith GT. 2008. A systematic review of vanadium oral supplements for glycaemic control in type 2 diabetes mellitus. Q J Med 101(5):351-358.

Soldi T, Riolo C, Alberti G, et al. 1996. Environmental vanadium distribution from an indus trial settlement. Sci Total Environ 181(1):45-50.

*Sora S, Carbone MLA, Pacciarini M, et al. 1986. Disomic and diploid meiotic products induced in Saccharomyuces cerevisiae by the salts of 27 elements. Mutagenesis 1(1):21 -28.

*SRI. 2008. Directory of chemical producers: United States. Menlo Park, CA: SRI Consulting, 912.

*+Steffen RP, Pamnani MB, Clough DL, et al. 1981. Effect of prolonged dietary administration of vanadate on blood pressure in the rat. Hypertension 3(3 Pt 2):I-173 to I-178.

*+Stokinger HE, Wagner WD, Mountain JT, et al. 1953. Unpublished results. Cincinnati, OH: Division of Occupational Health. (As cited in IRIS 2009).

*Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. 2nd ed. Beltsville, MD: Bradford Communications Corporation, 406-407.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 196

9. REFERENCES

*+Susic D, Kentera D. 1986. Effect of chronic vanadate administration on pulmonary circulation in the rat. Respiration 49:68-72.

*Susic D, Kentera D. 1988. Dependence of the hypertensive effect of chronic vanadate administration on renal excretory function in the rat. J Hypertens 6(3):199-204.

*Sweet CW, Vermette SJ, Landsberger S. 1993. Sources of toxic trace elements in urban air in Illinois. Environ Sci Technol 27(12 ):2502-2510.

Symanski HJ. 1983. Vanadium, alloys and compounds. In: Encyclopedia of occupational health and safety. Vol. II. Geneva, Switzerland: International Labour Office, 2240-2241.

Szakmary E, Naray M, Tatrai E, et al. 2003. Embryotoxic and teratogenic effect of vanadium pentoxide on rats and rabbits. Egeszsegtudomany 47(1-2):45-57.

*Taylor HE, Antweiler RC, Roth DA, et al. 2001. The occurrence and distribution of selected trace elements in the upper Rio Grande and tributaries in C olorado and northern New Mexico. Arch Environ

Contam Toxicol 41:410-426.

*+Thomas DL, Stiebris K. 1956. Vanadium poisoning in industry. Med J Aust 1:607-609.

*Thomas K, Colborn T. 1992. Organochlorine endocrine disruptors in human tissue. In: C olborn T, Clement C, eds. Chemically induced alterations in sexual and functional development: The wildlife/human connection. Princeton, NJ: Princeton Scientific Publishing, 365-394.

*Thomas KW, Pellizzari ED, Berry MR. 1999. Population- based dietary intakes and tap water concentrations for selected elements in the EPA region V national human exposure assessment survey (NHEXAS). J Expo Anal Environ Epidemiol 9:402-413.

*Thompson KH, Orvig C. 2006. Vanadium in diabetes: 100 years from Phase 0 to Phase I. J Inorg Biochem 100(12):1925-1935.

*Thompson HJ, Chasteen ND, Meeker LD. 1984. Dietary vanadyl (IV) sulfate inhibits chemicallyinduced mammary carcinogenesis. Carcinogenesis 5:849 -851.

Thompson KH, Leichter J, McNeill JH. 1993. St udies of vanadyl sulfate as a glucose

- lowering agent in

STZ -diabetic rats. Biochem Biophys Res Commun 197(3):1549-1555.

*Thompson KH, Tsukada Y, Xu Z, et al. 2002. Influence of chelation and oxidation state on vanadium bioavailability, and their effe cts on tissue concentrations of zinc, copper, and iron. Biol Trace Elem Res 86(1):31-44.

Toya T, Fukuda K, Takaya M, et al. 2001. Lung lesions induced by intratracheal instillation of vanadium pentoxide powder in rats. Ind Health 39(1):8-15.

*TRI 07. 2009. TRI explorer: Providing access to EPA’s toxics release inventory data. Washington, DC: Office of Information Analysis and Access. Office of Environmental Information. U.S. Environmental Protection Agency. Toxics Release Inventory. http://www.epa.gov/triexplorer/. April 7,

2009.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 197

9. REFERENCES

Trumbo P, Yates AA, Schlicker S, et al. 2001. Dietary reference intakes: Vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J

Am Diet Assoc 101(3):294-301.

Tunali S, Yanardag R. 2006. Effect of vanadyl sulfate on the status of lipid parameters and on stomach and spleen tissues of streptozotocin -induced diabetic rats. Pharmacol Res 53(3):271-277.

*USGS. 1987. Metals, atomic emission spectrometry, inductively coupled plasma (ICP). In: Methods for the determination of inorganic substances in water and fluvial sediments, techniques of water

resources investigations of the United States Geological Survey. Denver, CO: U.S. G eological Survey. http://infotrek.er.usgs.gov/pls/htmldb/f?p=119:38:8660777138310287::::P38_METHOD_ID:8896 . May 23, 2009.

*USGS. 1993. Vanadium, colorimetry, catalytic oxidation, automated-segmented flow. U.S. Geological Survey. http://pubs.er.usgs.gov/djvu/OFR/1993/ofr_93_125.djvu . May 26, 2009.

*USGS. 1996. Methods of analysis by the U.S. Geological Survey National Water Quality Laboratory - preparation procedure for aquatic biological material determined for trace metals. Denver, CO: U.S. Geological Survey, Department of the Interior. Open-File Report 96-362. http://nwql.usgs.gov/Public/pubs/OFR96-362/OFR96-362.pdf . May 22, 2009.

*USGS. 1998. Methods of analysis by the U.S. Geological Survey National Water Quality Laboratory -

determin ation of elements in whole- water digests using inductively coupled plasma

- optical emission spectrometry and inductively coupled plasma-optical emission spectrometry and inductively coupled plasma

- mass spectrometry. Denver, CO: U. S. Geological Survey. O pen- File Report 98 -165. http://pubs.er.usgs.gov/usgspubs/ofr/ofr98165 . May 22, 2009.

*USGS. 1999. Methods of analysis by the U.S. Geological Survey National Water Quality Laboratory - determination of dissolved arsenic, boron, lithium, selenium, strontium, thallium, and vanadium using inductively. Denver, CO: U.S. Geological Survey. Open- file report 99 -093. http://nwql.usgs.gov/Public/pubs/OFR99-093/OFR99-093.pdf . May 23, 2009.

*USGS. 2006. Determination of elements in natural- water, biota, sed iment, and soil samples using collision/reaction cell inductively - coupled plasma - mass spectrometry. U.S. Department of the Interior,

U.S. Geological Survey. http://pubs.usgs.gov/tm/2006/tm5b1/PDF/TM5-B1.pdf . May 22, 2009.

USGS. 2008. Vanadium. Mineral commodity summaries. U.S. Geological Survey. http://minerals.usgs.gov/minerals/pubs/commodity/vanadium/mcs-2008-vanad.pdf . May 21, 2009.

*USGS. 2009a. Vanadium. Mineral commodity summaries. U.S. Geological Survey. http://minerals.usgs.gov/m inerals/pubs/commodity/vanadium/mcs-2009-vanad.pdf . May 21, 2009.

*USGS. 2009b. 2007 Minerals yearbook. U.S. Department of the Interior, U.S. Geological Survey. http://minerals.usgs.gov/minerals/pubs/commodity/vanadium/myb1-2007-vanad.pdf . May 27, 2009.

*USGS. 2009c. Quality of water from domestic wells in principal aquifers of the United States, 1991- 2004. Reston, VA: U.S. Department of the Interior, U.S. Geological Survey. Scientific Investigations Report 2008-5227. http://pubs.usgs.gov/sir/2008/5227. August 3, 2009.

Vannetten C, Cann SAH, Morley DR, et al. 2000. Elemental and radioactive analysis of commercially

available seaweed. Sci Total Environ 255:169 -175.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 198

9. REFERENCES

*Van Zinderen Bakker, Jaworski JF. 1980. Effects of vanadium in the Canadian environment. Ottawa, Canada: National Research Council Canada, Associate Committee Scientific Criteria for Environmental Quality, 1-94.

Verma S, Cam MC, McNeill JH. 1998. Nutritional factors that can favorably influence the glucose/insulin sys tem: Vanadium. J Am Coll Nutr 17(1):11-18.

*Vieira I, Sonnier M, Cresteil T. 1996. Developmental expression of CYP2E1 in the human liver: Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238(2):476-483.

*Vil lani P, Cordelli E, Leopardi P, et al. 2007. Evaluation of genotoxicity of oral exposure to tetravalent vanadium in vivo. Toxicol Lett 170(1):11-18.

*+Vintinner FJ, Vallenas R, Carlin CE, et al. 1955. Study of the health of workers employed in mini ng and processing of vanadium ore. AMA Arch Ind Health 12:635-642.

*Vouk VB. 1979. Vanadium. In: Friberg L, Nordberg GR, Vouk VB, eds. Handbook on the toxicology of metals. New York, NY: Elsevier North Holland, 659-674.

*Waters MD. 1977. Toxicology of vanadium. In: Mehlam MA, Marzulli FN, Maibach HI, eds. Advances in Modern Toxicology. Vol. 2. New York, NY: Wiley, 147-189.

*Waters MD, Gardner DE, Coffin DL. 1974. Cytotoxic effects of vanadium on rabbit alveolar macrophages in vitro. Toxicol Appl Pharmacol 28:253-263.

Weast RC. 1969. Chemical rubber company handbook of chemistry and physics. 50th ed. Cleveland,
OH: CRC Press, Inc., B -144-B-145, 261.

*Wehrli B, Stumm W. 1989. Vanadyl in natural waters: Adsorption and hyd rolysis promote oxygenation. Geochim Cosmochim Acta 53:69-77.

*Wei C, Misra HP. 1982. Cytotoxicity of ammonium metavanadate to cultured bovine alveolar macrophages. J Toxicol Environ Health 9:995-1006.

*West JR, Smith HW, Chasis H. 1948. Glomeru lar filtration rate, effective renal blood flow, and maximal tubular excretory capacity in infancy. J Pediatr 32:10-18.

+Westenfelder C, Hamburger RK, Garcia ME. 1981. Effect of vanadate on renal tubular function in rats. Am J Physiol Renal Physiol 240(6):F522-F529.

WHO. 1987. Air quality guidelines for Europe. Copenhagen, Denmark: World Health Organization, Regional Office of Europe.

*WHO. 1988. Vanadium. In: Environmental health criteria 81. Geneva, Switzerland: World Health Organiz ation,

*WHO. 2000. Air quality guidelines. 2nd edition. Geneva, Switzerland: World Health Organization. http://www.euro.who.int/air/activities/20050223_4 . May 11, 2009.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 199

9. REFERENCES

WHO. 2001. Vanadium pentoxide and other inorganic vanadium compounds. Concise International

Chemical Assessment Document 29.

*WHO. 2006. Guidelines for drinking-water quality. 3rd edition. Geneva, Switzerland: World Health Organization.

*Widdowson EM, Dickerson JWT. 1964. Chemical composition of the body. In: Comar CL, Bronner F, eds. Mineral metabolism: An advance treatise. Vol. II. New York, NY: Academic Press, 1 -247.

+Wide M. 1984. Effect of short-term exposure to five industrial metals on the embryonic and fetal development of the mouse. Environ Res 33 (1):47 -53.

Windholz M. 1983. The Merck index. Rahway, NJ: Merck & Co., Inc., 82, 1417-1419.

*Witkowska D, Oledzka R, Markowska B. 1988. Effect of intoxication with vanadium compounds on copper metabolism in the rat. Bull Environ Contam Toxicol 40:309-316.

Woodin MA, Liu Y, Hauser R, et al. 1999. Pulmonary function in workers exposed to low levels of fueloil ash. J Occup Environ Med 41(11):973-980.

Woodin MA, Liu Y, Neuberg D, et al. 2000. Acute respiratory symptoms in workers expose d to vanadium-rich fuel-oil ash. Am J Ind Med 37(4):353-363.

*Woolery M. 2005. Vanadium compounds. In: Kirk- Othmer encyclopedia of chemical technology. John Wiley & Sons, Inc. http://mrw.interscience.wiley.com/emrw/9780471238966/kirk/article/vanawool.a01/current/pdf . May 27,

2009.

*Wozniak K, Blasiak J. 2004. Vanadyl sulfate can differentially damage DNA in human lymphocytes and HeLa cells. Arch Toxicol 78(1):7 -15.

*+Wyers H. 1946. Some toxic effects of vanadium pentoxide. Br J Ind Med 3:177 -182.

*+Yao J, Battell ML, McNeill JH. 1997. Acute and chronic response to vanadium following two methods of streptozotocin-diabetes induction. Can J Physiol Pharmacol 75(2):83-90.

*+Zaporowska H, Wasilewski W. 1989. Some selected peripheral blood and haemopoietic system indices in Wistar rats with chronic vanadium intoxication. Comp Biochem Physiol C Comp Pharmacol Toxicol 93C(1):175-180.

*+Zaporowska H, Wasilewski W. 1990. Some selected hematological indices in Wistar rats in the

van adium-ethanol interaction. Comp Biochem Physiol C Comp Pharmacol Toxicol 96(1):33-38.

*+Zaporowska H, Wasilewski W. 1991. Significance of reduced food and water consumption in rats intoxicated with vanadium. Comp Biochem Physiol C 99(3):349-352.

*+Zaporowska H, Wasilewski W. 1992a. Combined effect of vanadium and zinc on certain selected haematological indices in rats. Comp Biochem Physiol C 103(1):143-147.

*+Zaporowska H, Wasilewski W. 1992b. Haematological results of vanadium intoxicati on in Wistar rats. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 101C(1):57-61.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 200

9. REFERENCES

*+Zaporowska H, Wasilewski W, Slotwinska M. 1993. Effect of chronic vanadium administration in drinking water to rats. Biometals 6(1):3 -10.

*+Zenz C, Berg BA. 1967. Human responses to controlled vanadium pentoxide exposure. Arch Environ

Health 14:709-712.

*+Zenz C, Bartlett JP, Thiede WM, et al. 1962. Acute vanadium pentoxide intoxication. Arch Environ

Health 5:542-546.

*Zhong BZ, Gu ZW, Wallace WE, et al. 1994. Genotoxicity of vanadium pentoxide in Chinese hamster V79 cells. Mutat Res 321(1 -2):35-42.

Zhou D, Feng C, Lan Y, et al. 2007. Paired-control study on the effect of vanadium on neurobehavioral functions. Sichuan Da Xue Xue Bao Yi Xue Ban 38(3):468-470.

*Ziegler EE, Edwards BB, Jensen RL, et al. 1978. Absorption and retention of lead by infants. Pediatr Res 12(1):29-34.

*Zoller WH, Gordon GE, Cladney ES, et al. 1973. The sources and distribution of vanadium in the atmosphere. In: Advances in chemistry series no. 123. Trace elements in the environment. Washington DC: American Chemical Society, 31 -47.

Zychlinski L, Byczkowski JZ, Kulkarni AP. 1991. Toxic effects of long- term intratracheal administration of vanadium pentoxide in rats. Arch Environ Contam Toxicol 20(3):295-298.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 201



### 10. GLOSSARY

Absorption

— The taking up of liquids by solids, or of gases by solids or liquids.

Acute Exposure

— Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles.

Adsorption

— The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the surfaces of solid bodies or liquids with which they are in contact.

Adsorption Co efficient (K

oc )— The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)

— The amount of a chemical adsorbed by sediment o r soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or

sediment.

Benchmark Dose (BMD)

— Usually defined as the lower confidence limit on the dose that produces a specified magnitude of changes in a specified adverse response. For example, a BMD 10 would be the dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 10%. The BMD is determined by modeling the dose response curve in the region of the dose response relationship where biologically observable data are feasible.

Benchmark Dose Model

— A statistical dose

- response mo del applied to either experimental toxicological or epidemiological data to calculate a BMD.

Bioconcentration Factor (BCF)

— The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period.

Biomarkers

— Broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility.

Cancer Effect Level (CEL)

— The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control.

Carcinogen

— A chemical capable of inducing cancer.

Case

- Control Study

— A type of epidemiological study that examines the relationship between a particular outcome (disease or condition) and a variety of potential causative agents (such as toxic chemicals). In a case -controlled study, a group of people with a specified and well-defined outcome is identified and compared to a similar group of people without outcome.

Case Report

— Describes a single individual with a particular disease or exposure. These may suggest some potential topics for scientific research, but are not actual research studies.

Case Series

— Describes the experience of a small number of individuals with the same disease or exposure. These may suggest potential topics for scientific resea rch, but are not actual research studies.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 202

10. GLOSSARY

Ceiling Value

— A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure

— Exposure to a chemical for 365 days or more, as specified in the Toxicological

Profiles.

Cohort Study

— A type of epidemiological study of a specific group or groups of people who have had a common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are followed forward from exposure to outcome. At least one exposed group is compared to one unexposed

group.

Cross

- sectional Study

— A type of epidemiological study of a group or groups of people that examines the relationship between exposure and outcome to a chemical or to chemicals at one point in time.

Data Needs

— Subs tance -specific informational needs that if met would reduce the uncertainties of human

health assessment.

Developmental Toxicity— The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception ( either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism.

Dose

- Response Relationship

— The quantitative relationship between th e amount of exposure to a

toxicant and the incidence of the adverse effects.

Embryotoxicity and Fetotoxicity

— Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero
death.

Environmental Protection Agency (EPA) Health Advisory— An estimate of acceptable drinking water

levels for a ch emical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials.

Epidemiology

— Refers to the investigation of factors tha t determine the frequency and distribution of

disease or other health -related conditions within a defined human population during a specified period.

Genotoxicity

— A specific adverse effect on the genome of living cells that, upon the duplication of

affe cted cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific alteration of the molecular structure of the genome.

Half

- life

— A measure of rate for the time required to eliminate one half of a quantity of a chemical fr om the body or environmental media.

Immediately Dangerous to Life or Health (IDLH)

— The maximum environmental concentration of a contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or

irreversible health effects.

Immunologic Toxicity— The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 203

10. GLOSSARY

Immunological Effects

— Functional changes in the immune response.

Incidence

— The ratio of individuals in a population who develop a specified condition to the total number of individuals in that population who could have developed that condition in a specified time period.

Intermediate Exposure

— Exposure to a chemical for a duration of 15– 364 days, as specif ied in the Toxicological Profiles.

In Vitro

— Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo

— Occurring within the living organism.

Lethal Concentration (LO) (LC LO )— The lowest concentration of a chemical in air tha t has been reported

to have caused death in humans or animals.

Lethal Concentration (50) (LC 50 )— A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental anim al population.

Lethal Dose (LO) (LD Lo )— The lowest dose of a chemical introduced by a route other than inhalation that has been reported to have caused death in humans or animals.

Lethal Dose (50) (LD 50 )— The dose of a chemical that has been calculated to ca use death in 50% of a defined experimental animal population.

Lethal Time (50) (LT 50 )— A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population.

Lowest

- Obs erved

- Adverse

- Effect Level (LOAEL)

— The lowest exposure level of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects

— Represent morphological effects involving lymphatic tissues such as the lymph nodes, spleen, and thymus.

Malformations— Permanent structural changes that may adversely affect survival, development, or

function.

Minimal Risk Level (MRL)

— An estimate of daily human exposure to a hazardous substance that is likely to be without an appreciable risk of adverse noncancer health effects over a specified route and duration of exposure.

Modifying Factor (MF)

— A value (gre ater than zero) that is applied to the derivation of a Minimal Risk Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty

factors. The default value for a MF is 1.

Morbidity

— State of being diseased; morbidi ty rate is the incidence or prevalence of disease in a specific population.

Mortality— Death; mortality rate is a measure of the number of deaths in a population during a specified

interval of time.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 204

10. GLOSSARY

Mutagen

— A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s DNA. Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy

— The gross examination of the organs and tissues of a dead body to determine the cause of death or pathological conditions.

Neurotoxici ty

— The occurrence of adverse effects on the nervous system following exposure to a

chemical.

No

- Observed

- Adverse

- Effect Level (NOAEL)

— The dose of a chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not

considered to be adverse.

Octanol- Water Partition Coefficient (K

ow )— The equilibrium ratio of the concentrations o f a chemical

in n -octanol and water, in dilute solution.

Odds Ratio (OR)

— A means of measuring the association between an exposure (such as toxic substances and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence among subjects exposed to a particular risk factor divided by the incidence among subjects who were not exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the exposed group compared to the unexposed group.

Organophosphate or Organophosphorus Compound

— A phosphorus-containing organic compound and especially a pesticide that acts by inhibiting cholinesterase.

Permissible Exposure Limit (PEL)

— An Occupational Safety and Health Administration (OSHA) allowable exposure level in workplace air averaged over an 8 -hour shift of a 40-hour workweek.

Pesticide

— General classification of chemicals specifically developed and produced for use in the control of agricultural and public health pests.

Pharm acokinetics

— The dynamic behavior of a material in the body, used to predict the fate (disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.

Pharmacokinetic Model

— A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data

- based and physiologic ally -based. A data- based model divides the animal system into a series of compartments, which, in general, do not represent real, identifiable anatomic regions of the body, whereas the physiologically- based model compartments represent real anatomic regio ns of the body.

Physiologically Based Pharmacodynamic (PBPD) Model

— A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous

substance.

Physiologically Based Pharmacokinetic (PBPK) Model

— Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a

***DRAFT FOR PUBLIC COMMENT***VANADIUM 205

10. GLOSSARY

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly membrane permeabil ities. The models also utilize biochemical information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models.

Prevalence

— The number of cases of a disease or condition in a population at one point in time.

Prospective Study

— A type of cohort study in which the pertinent observations are made on events occurring after the start of the study. A group is followed over time.

q 1 *— The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q 1 * can be used to calculate an estimate of carcinogenic potency, the

incremental exce ss cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and μg/m 3 for air).

Recommended Exposure Limit (REL)

— A National Institute for Occupational Safety and Health (NIOSH) time

- weighted average (TWA) concentration for up to a 10 -hour workday during a 40-hour

workweek.

Reference Concentration (RfC)

— An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be wi thout an appreciable risk of deleterious noncancer health effects during a lifetime. The inhalation reference concentration is for continuous inhalation exposures and is appropriately expressed in units of mg/m 3 or ppm.

Reference Dose (RfD)

— An estimate ( with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the no

- observed

- adverse

- effect level (NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the ent ire database on the chemical. The RfDs are not applicable to

nonthreshold effects such as cancer.

Reportable Quantity (RQ)

— The quantity of a hazardous substance that is considered reportable under the Comprehensive Environmental Response, Compensation, a nd Liability Act (CERCLA). Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 24-hour period.

Reproductive Toxicity

— The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxi city may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system.

Retrospective Study

— A type of cohort study based on a group of persons known to have been exposed at some time in the past. Data are collected from routinely recorded events, up to the time the study is undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing records and/or examining survivo rs of the cohort.

Risk

— The possibility or chance that some adverse effect will result from a given exposure to a chemical.

***DRAFT FOR PUBLIC COMMENT***VANADIUM 206

10. GLOSSARY

Risk Factor

— An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or

inherited characteristic that i s associated with an increased occurrence of disease or other health

- related

event or condition.

Risk Ratio

— The ratio of the risk among persons with specific risk factors compared to the risk among persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed group compared to the unexposed group.

Short

- Term Exposure Limit (STEL)

— The American Conference of Governmental Industrial Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes continually. No more than four excursions are allowed per day, and there must be at least 60 minutes between exposure periods. The daily Threshold Limit Value- Time Weighted Average (TLV

- TWA) may

not be exceeded.

Standardized Mortality Ratio (SMR)

— A ratio of the observed number of deaths and the expected number of deaths in a specific standard population.

Target Organ Toxicity

— This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovasc ular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen

— A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)

— A n American Conference of Governmental Industrial Hygienists (ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a Time Weighted Average (TWA), as a Short -Term Exposure Limit (STEL), or as a ceiling limit (CL).

Time

- Weighted Average (TWA)

— An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek.

Toxic Dose (50) (TD 50 )— A calculated dose of a chemical, introduced by a route other than inhalation,

wh ich is expected to cause a specific toxic effect in 50% of a defined experimental animal population.

Toxicokinetic

— The absorption, distribution, and elimination of toxic compounds in the living organism.

Uncertainty Factor (UF)

— A factor used in operation ally deriving the Minimal Risk Level (MRL) or Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating fromdata obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved

- adverse

- effect level (LOAEL) data rather than no -obs erved

- adverse

- effect level (NOAEL) data. A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; however, a reduced UF of 3 may be used on a case -by- case basis, 3 being the approximate logarithmic average of 10 and 1.

Xenobiotic

— Any chemical that is foreign to the biological system.

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-1



### APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS

The Comprehensive Environmental Response, Compensation, and Liability Act (CER CLA) [42 U.S.C.

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99–

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological

profiles for each substance included on the priority list of hazardous substances; and assure the initiation

of a research program to fill identified data needs associated with the substances.

The toxicological profiles include an examination, summary, and interpretation of available toxicological

information and epidemiologic evaluations of a hazardous substance. During the development of

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration

of exposure. MRLs are based on noncancer he alth effects only and are not based on a consideration of

cancer effects. These substance

- specific estimates, which are intended to serve as screening levels, are

used by ATSDR health assessors to identify contaminants and potential health effects that ma y be of

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean -up or

action levels.

MRLs are derived for hazardous substances using the no

- observed

- adverse

- effect level/uncertainty factor

approach. They are below levels that might cause adverse health effects in the people most sensitive to

such chemical

- induced effects. MRLs are derived for acute (1

– 14 days), intermediate (15 –364 days), and

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently,

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical -induced end

point conside red to be of relevance to humans. Serious health effects (such as irreparable damage to the

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level

above the MRL does not mean that adverse health effects wil l occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-2

APPENDIX A

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants,

elderly, nutritionally or immunologically compromised) to the effects of hazardous sub stances. ATSDR

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons

may be particularly sensitive. Thus, the resulting MRL may be as much a s 100- fold below levels that

have been shown to be nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency- wide MRL

Workgroup reviews, with participation from other federal agencies and comments from the public. They

are subject to change as new information becomes available concomitant with updating the toxicological

profiles. Thus, MRLs in th e most recent toxicological profiles supersede previously published levels.

For additional information regarding MRLs, please contact the Division of Toxicology and

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE,

Mailstop F-62, Atlanta, Georgia 30333.

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-3

APPENDIX A



### MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Vanadium compounds

CAS Numbers: 7440-62-2

Date: August 2009

Profile Status: Pre -Public Comment, Final Draft

Route: [X] Inhalation [ ] Oral

Duration: [X] Acu te [ ] Intermediate [ ] Chronic Graph Key: 4 Species: Rat

Minimal Risk Level : 0.0008 [ ] mg/kg/day [X] mg vanadium/m 3

Reference : NTP. 2002. NTP toxicology and carcinogenesis studies of vanadium pentoxide (CAS No.

1314-62- 1) in F344/N rats and B6C3F1 mice (inhalation). Natl Toxicol Program Tech Rep Ser (507):1-

343.

Experimental design : Groups of 40–60 female F344 rats were exposed to 0, 1, 2, or 4 mg vanadium pentoxide/m 3 (0, 0.56, 1.1, and 2.2 mg vanadium/m 3 ) 6 hours/day, 5 days/week for 16 days. On days 6 and 13, 10 rats/group were kille d and a histopathological examination of the lungs was conducted. Four animals per group were kille d for examination of onset and extent of lung lesions on days 1, 2, 5, 10, and

16. The remaining animals were used to measure blood and lung concentrations of vanadium, lung

clearance half

- times, and cell proliferation rates.

Effect noted in study and corresponding doses : Hyperplasia of alveolar epithelium and bronchiole epithelium were observed in 100% of the female rats exposed to 1.1 or 2.2 mg vanadium/m 3 for 6 or 13 days. Significant increases in the incidence of histiocytic infiltrate and inflammation were observed in rats exposed to 1.1 or 2.2 mg vanadium/m 3 for 6 or 13 days and in rats exposed to 0.56 mg vanadium/m 3

for 13 days. A significant increase in fibrosis was observed in rats exposed to 2.2 mg vanadium/m 3 for

13 days. No histopathological alterations were observed in the four female rats killed after 1 day of exposure; by day 2, inflammation and histiocytic infiltrates (increased number of alveolar macrophages) were observed in the rats exposed to 2.2 mg vanadium/m 3 . Hyperplasia of the alveolar and bronchiolar epidthelium was first observed on day 5 in rats exposed to 1.1 or 2.2 mg vanadium/m 3

.

Dose and end point used for MRL derivation : Increase in the incidence of lung inflammation in rats exposed to 0.56 mg vanadium/m 3 as vanadium pentoxide for 13 days.

[ ] NOAEL [X] LOAEL

A BMD analysis was considered for determining the point of departure for the inflammation in female rats exposed to vanadium pentoxide for 13 days. All available dichotomous models in the EPA benchmark dose software ([BMDS] version 2.1) were fit to the incidence data for lung inflammation (0/10, 8/10, 10/10, and 10/10 in rats exposed to 0, 0.56, 1.1, or 2.2 mg vanadium/m 3 ) using the extra risk option. The multistage model was run for all polynomial degrees up to n-1 (where n is the number of dose groups including control). Adequate model fit is judged by three criteria: goodness-of- fit p- value (p>0.1), visual inspection of the dose- response curve, and scaled residual at the data point (except the control) closest to the predefined benchmark response (BMR). Among all the models providing adequate fit to the data, the lowest lower bound on the BMC (BMCL) is selected as the point of departure when the

difference between the BMDLs estimated from these models are more three -fold; otherwise, the BMCL from the model with the lowest AIC is chosen. In accordance with U.S. EPA (2000) guidance,

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-4

APPENDIX A

benchmark concentrations (BMCs) and BMCLs associated with an extra risk of 10% are calculated for all

models.



### Table A

- 1. Model Predictions for the Incidence of Inflammation in Female Rats Exposed to Vanadium Pentoxide 6 Hours/Day, 5 Days/Week for 13 Days

Model

Gamma b χ 2 Goodness of fit p

- value a

1.00 AIC

12.01 BMC 10 (mg V/m 3 )

0.33 BMCL 10 (mg V/m 3 )

0.02

Logistic 1.00 14.01 0.46 0.10

LogLogistic 1.00 12.01 0.46 0.01

LogProbit

Multistage c 1.00

0.93 14.01

12.69 0.42

0.03 0.03

0.02

Probit 1.00 14.01 0.38 0.09

W eibull b 1.00 14.01 0.25 0.02

Quantal

- linear 0.93 12.69 0.03 0.02

a Values <0.10 fail to meet conventional goodness

- of

- fit criteria

b Power restricted to ≥1

c Betas restricted to ≥0; 1

- degree polynomial

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the concentration associated with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-5

APPENDIX A



### Figure A

- 1. Fit of Gamma Model to Data on the Incidence of Inflammation in Female Rats Exposed to Va nadium Pentoxide for 13 Days

Gamma Multi

- Hit Model with 0.95 Confidence Level

Gamma Multi

- Hit

1

0.8ed 0.6ectfon Afiract

0.4F

0.2

0

BMDL BMD

0 0.5 1 1.5 2

dose

22:23 05/24 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

Although the data provide an adequate statistical fit, the estimated BMCL 10 of 0.02 mg vanadium/m 3

appears to be an overly conservative estimate of a no

- adverse

- effect level, which may be a reflection of the limited amount of information from the study on the shape of the exposure- response relationship (incidences of lung inflammation were 0/10 in controls and 8/10 at the lowest vanadium concentration). In a chronic-duration study conducted by NTP (2002), no significant alterations in the incidence of lung inflammation were observed in male and female rats exposed to 0.28 mg vanadium/m 3 ; the LOAEL for

lu ng inflammation was 0.56 mg vanadium/m 3 in males and 1.1 mg vanadium/m 3 in females.

Due to the low confidence in the BMCL 10 , a NOAEL/LOAEL approach was used to determine the point of departure for the acute MRL.

Uncertainty Factors used in MRL derivati on :

[X] 3 for use of a minimal LOAEL [X] 3 for extrapolation from animals to humans with dosimetric adjustment

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-6

APPENDIX A

[X] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose ? Not applicable.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose :

The duration-adjusted LOAEL of 0.1 mg vanadium/m 3 was converted to a human equivalent concentration (LOAEL HEC ) using the following equation:

LOAEL HEC = LOAEL AD J x RDDR TH LOAEL HEC = 0.1 mg vanadium/m 3 x 0.732

LOAEL HEC = 0.073 mg vanadium/m 3

where: The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal to the predicted inhalation particulate exposure concentration for a human. The RDDR program (EPA 1990) was used to calculate a multiplier of 0.732 for the thoracic region was determined using a default body weight of 0.124 kg (EPA 1994c) and a particle size MMAD of 1.2 μm with a geometric standard deviation of 1.9

Was a conversion used from intermittent to continuous exposure ? The LOAEL was adjusted for intermittent exposure as follows:

LOAEL ADJ = LOAEL x 6 hours/day x 5 days/week

LOAEL ADJ = 0.56 mg vanadium/m 3 x 6 hours/24 hours x 5 days/7 d ays LOAEL ADJ = 0.1 mg vanadium/m 3

Other additional studies or pertinent information that lend support to this MRL : Data on acute toxicity of vanadium in humans are limited to an experimental study in which a small number of subjects were exposed to vanadium pentoxide dust for 8 hours (Zenz and Berg 1967). A persistent cough lasting for 8 days developed in two subjects exposed to 0.6 mg vanadium/m 3 ; at 0.1 mg vanadium/m 3 , a productive cough without any subjective complaints or impact on work or home act ivities were observed in

5 subjects. The available studies in laboratory animals focused on potential respiratory tract effects. Impaired lung function characterized as airway obstructive changes (increased resistance and decreased airflow) were observed in monkeys exposed to 2.5 or 1.7 mg vanadium/m 3 as vanadium pentoxide for 6 hours (Knecht et al. 1985, 1992); the highest NOAEL for this effect was 0.34 mg vanadium/m 3

. Alveolar and bronchiolar epithelial hyperplasia and inflammation were observed in the lungs of mice exposed to 1.1 mg vanadium/m 3 6 hours/day, 5 days/week for 13 days (NTP 2002). Although the Knecht et al. (1985, 1992) or NTP (2002) studies did not include examination of potential end points outside of the respiratory tract, longer -durati on studies have identified the respiratory tract as the most sensitive target of toxicity (NTP 2002).

Agency Contact s (Chemical Manager s) : Jessilynn Taylor, Sam Keith, Larry Cseh

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-7

APPENDIX A



### MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Vanadium compounds

CA S Numbers: 7440-62-2

Date: August 2009

Profile Status: Pre -Public Comment, Final Draft

Route: [X] Inhalation [ ] Oral

Duration: [ ] Acute [ ] Intermediate [X] Chronic Graph Key: 19 Species: Rat

Minimal Risk Level : 0.0001 [ ] mg/kg/day [X] mg va nadium/m 3

Reference : NTP. 2002. NTP toxicology and carcinogenesis studies of vanadium pentoxide (CAS No. 1314-62-1) in F344/N rats and B6C3F1 mice (inhalation). Natl Toxicol Program Tech Rep Ser (507):1-

343.

Experimental design : Groups of 50 male and 50 female F344 rats were exposed to 0, 0.5, 1, or 2 mg vanadium pentoxide/m 3 (0, 0.28, 0.56, and 1.1 mg vanadium/m 3 ) 6 hours/day, 5 days/week for 104 weeks. The following parameters were used to assess toxicity: clinical observations, body weights (eve ry 4 weeks from week 5 to 89 and every 2 weeks from week 92 to 104), complete necropsy, and microscopic examination of major tissues and organs.

Effect noted in study and corresponding doses : No significant alterations in survival or body weight gain

wer e observed in the vanadium -exposed rats. A summary of selected non- neoplastic respiratory tract lesions is presented in Table A

- 2. Alveolar histiocytic infiltrates were observed in males and females exposed to ≥0.28 mg vanadium/m 3 . Significant increases in the incidence of hyperplasia of the alveolar and bronchiolar epithelium were observed in males exposed to ≥0.28 mg vanadium/m 3 and females exposed to ≥0.56 mg vanadium/m 3 . Squamous metaplasia was observed in alveolar epithelium of males

and females ex posed to 1.1 mg vanadium/m 3 and in the bronchiolar epithelium of males exposed to

1.1 mg vanadium/m 3 . Chronic inflammation was observed in males exposed to 0.56 or 1.1 mg

vanadium/m 3 and females exposed to 1.1 mg vanadium/m 3 and interstitial fibrosis was observed in males exposed to 1.1 mg vanadium/m 3 and females exposed to 0.28 or 1.1 mg vanadium/m 3 . An increased incidence of brownish pigment in alveolar macrophages was observed in males exposed to 1.1 mg

vanadium/m 3 and females exposed to 0.56 or 1.1 mg vanadium/m 3 ; this effect was considered to be of little biological relevance. Chronic inflammation, degeneration, and hyperplasia of the epiglottis were observed in the larynx of males and females exposed to ≥0.28 mg vanadium/m 3 ; squamous metaplasia of

t he epiglottis respiratory epithelium was also observed in males exposed to ≥0.28 mg vanadium/m 3 and in females exposed to 1.1 mg vanadium/m 3 . Goblet cell hyperplasia of the nasal respiratory epithelium was observed in males exposed to ≥0.28 mg vanadium/m 3 and in females exposed to 1.1 mg vanadium/m 3 . A positive trend for increased incidences of uterine stromal polyp was observed; NTP did not consider it to be related to vanadium pentoxide exposure. An increased incidence of nephropathy was observed in ma le rats exposed to 0.56 or 1.1 mg vanadium/m 3 ; NTP considered the finding to be of marginal biological significance because there was a lack of increase in severity, as compared to controls, and significant findings in female rats. No significant increase s in the incidence of lung neoplasms were observed; however, the incidence of alveolar/bronchiolar adenoma in males exposed to 0.28 mg vanadium/m 3 and alveolar/bronchiolar carcinoma or combined incidence of adenoma and carcinoma in males exposed to

0.28 or 1.1 mg vanadium/m 3 were higher than historical controls. These increases in lung tumors were considered to be related to vanadium pentoxide exposure.

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-8

APPENDIX A



### Table A

- 2. Selected Respiratory Tract Effects Observed in Rats Exposed to

Vanadium Pentoxide 6 Hours/ Day, 5 Days/Week for 2 Years

Air concentration (mg vanadium/m 3 ) 0 0.28 0.56 1.1

Males

Lungs

Alveolar hyperplasia 7/50 (2.3) 24/49 b (2.0) 34/48 b (2.0) 49/50 b (3.3)

Bronchiole hyperplasia 3/50 (2.3) 17/49 b (2.2) 31/48 b (1.8) 49/50 b (3.3)

Inflammation 5/50 (1.6) 8/49 (1.8) 24/48 b (1.3) 42/50 b (2.4)

Fibrosis 7/50 (1.4) 7/49 (2.0) 16/48 c (1.6) 38/50 b (2.1)

Histiocyte infiltration 22/50 (1.3) 40/49 b (2.0) 45/48 b (2.3) 50/50 b (3.3)

Larynx

Chronic inflammation 3/49 (1.0) 20/50 b (1.1) 17/50 b (1.5) 28/49 b (1.6)

Degeneration of epiglottis respiratory 0/49 22/50 b (1.1) 23/50 b (1.1) 33/50 b (1.5) epithelium

Hyperplasia of epiglottis respiratory 0/49 22/50 b (1.1) 23/50 b (1.1) 33/49 b (1.5) epithelium

Squamous metaplasia of epi glottis 0/49 18/50 b (1.5) 34/50 b (1.5) 32/49 b (1.9) respiratory epithelium

Nose

Hyperplasia of respiratory epithelium 4/49 (1.8) 15/50 b (1.8) 12/49 c (2.0) 17/48 b (2.1) goblet cell

Female

Lung

Alveolar hyperplasia 4/49 (1.0) 8/49 (1. 8) 21/50 b (1.2) 50/50 b (3.1)

Bronchiole hyperplasia 6/49 (1.5) 5/49 (1.6) 14/50 c (1.3) 48/50 b (3.0)

Inflammation 10/49 (1.5) 10/49 (1.1) 14/50 (1.2) 40/50 c (1.7)

Fibrosis 19/49 (1.4) 7/49 (1.3) 12/50 (1.6) 32/50 b (1.4)

Histiocyte infiltration 2 6/49 (1.4) 35/49 c (1.3) 44/50 b (2.0) 50/50 b (1.9)

Larynx

Chronic inflammation 8/50 (1.8) 26/49 b (1.5) 27/49 b (1.3) 37/50 b (1.4)

Degeneration of epiglottis respiratory 2/50 (1.0) 33/49 b (1.2) 26/49 b (1.2) 40/50 b (1.5) epithelium

Hyperplasia o f epiglottis respiratory 0/50 25/49 b (1.4) 26/49 b (1.3) 33/50 b (1.5) epithelium

Squamous metaplasia of epiglottis 2/50 (2.0) 7/49 (1.9) 7/40 (1/7) 16/50 b (1.4) respiratory epithelium

Nose

Hyperplasia of respiratory epithelium 13/50 (2.0) 18/50 (2.0) 16/50 (1.9) 30/50 b (2.0) goblet cell

a Average severity grade of lesions in affected animals: 1=minimal; 2=mild, 3=moderate; 4=marked

b p ≤0.01

c p ≤0.05

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A-9

APPENDIX A

Dose and end point used for MRL derivation : The human equivalent concentration of the BMCL 10 for degeneration of respiratory epithelium of the epiglottis, 0.003 mg vanadium/m 3 , was used as the point of departure for the chronic- duration inhalation MRL.

[ ] NOAEL [ ] LOAEL [X] BMCL 10

BMD analysis was used to determine the point of departure for select respiratory tract lesions in rats exposed to vanadium pentoxide for 2 years. A number of lesions were observed in m ale and female rats exposed to 0.28 mg vanadium/m 3 including hyperplasia of the alveolar and bronchiolar epithelium, chronic inflammation of the larynx, degeneration of the epiglottis, and hyperplasia of respiratory epithelial goblet cells. The incidence of these lesions in male rats were modeled using all available dichotomous models in the EPA BMDS (version 2.1) that were fit to the incidence data for alveolar hyperplasia, bronchial hyperplasia, using the extra risk option. The multistage model was run for all polynomial degrees up to n-1 (where n is the number of dose groups including control). Adequate model fit is judged by three criteria: goodness-of- fit p- value ( p>0.1), visual inspection of the dose- response curve, and scaled residual at the data p oint (except the control) closest to the predefined BMR. Among all the models providing adequate fit to the data, the lowest BMCL is selected as the point of departure when

the difference between the BMCLs estimated from these models are more three -fold; otherwise, the BMCL from the model with the lowest AIC is chosen. In accordance with U.S. EPA (2000) guidance,

BMCs and BMCLs associated with an extra risk of 10% are calculated for all models.

The results of the BMD analyses are presented in Table A -3 and Figures A-2 through A-6.



### Table A

- 3. Model Predictions for Respiratory Effects in Rats Exposed to

Vanadium Pentoxide for 2 Years

Model χ 2 Goodness of fit p

- value a AIC BMC 10 (mg V/m 3 ) BMCL 10 (mg V/m 3 )

Alveolar hyperplasia in male rats

Gamma b 0.25 183.50 0.12 0.04

Logistic 0.52 181.44 0.11 0.09

Log

- Logistic 0.08 185.40 NA NA

Log

- Probit 0.13 184.60 0.15 0.08

Multistage c 0.21 184.00 0.05 0.04

Probit 0.57 181.29 0.10 0.09

Weibull b 0.33 183.11 0.10 0.05

Quantal

- Linear 0.21 184.00 0.05 0.04

Bronchiolar hyperplasia in male rats

Gamma b 0.28 165.38 0.17 0.10

Logistic 0.60 163.19 0.15 0.12

Log

- Logistic 0.08 167.58 NA NA

Log

- Probit 0.12 166.67 0.19 0.13

Multistage c 0.56 164.51 0.13 0.07

Probit 0.71 162.87 0.14 0.12

Weibull b 0.45 164.73 0.15 0.09

Quantal

- linear 0.03 170.74

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 10

APPENDIX A



### Table A

- 3. Model Predictions for Respiratory Effects in Rats Exposed to

Vanadium Pentoxide for 2 Years

χ 2 Goodness BMC 10 BMCL 10 Model of fit p

- value a AIC (mg V/m 3 ) (mg V/m 3 )

Chronic inflammation in larynx of male rats

Gamma b 0.04 230.93 NA NA

Logistic 0.01 235.47 NA NA

Log

- Logistic 0.11 229.28 0.10 0.07

Log

- Probit 0.00 235.73 NA NA

Multistage c 0.04 230.93 NA NA

Probit 0.01 235.09 NA NA

Weibull b 0.04 230.93 NA NA

Quantal

- linear 0.04 230.93 NA NA

Degeneration of epiglottis respiratory epithelium in male rats

Gamma b 0.06 210.55 NA NA

Logistic 0.00 230.64 NA NA

Log

- Logistic 0.47 206.17 0.06 0.04

Lo g- Probit 0.01 214.79 NA NA

Multistage c 0.06 210.55 NA NA

Probit 0.00 229.81 NA NA

Weibull b 0.06 210.55 NA NA

Quantal

- linear 0.06 210.55 NA NA

Hyperplasia of nasal respiratory epithelial goblet cells in male rats

Gamma b 0.12 213.84 0.32 0.20

L ogistic 0.07 215.11 NA NA

Log

- Logistic 0.15 213.35 0.27 0.16

Log

- Probit 0.03 216.79 NA NA

Multistage c 0.12 213.84 0.32 0.20

Probit 0.07 214.97 NA NA

Weibull b 0.12 213.84 0.32 0.20

Quantal

- linear 0.12 213.84 0.32 0.20

a Values <0.10 fail to mee t conventional goodness

- of

- fit criteria

b Power restricted to ≥1

c Betas restricted to ≥0; 1

- degree polynomial

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the dose/concentration associated with the selected benchmark response; BMDL = 95% lower confidence limit on the BMD; NA = not applicable

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 11

APPENDIX A



### Figure A

- 2. Fit of Probit Model to Data on the Incidence of Alveolar Hyperplasia in Male Rats Exposed to Vanadium Pentoxide for 2 Years

Probit Model with 0.95 Confidence Level

Probit

1

0.8edect 0.6fon AfractiF

0.4

0.2

0 BMDL BMD

0 0.2 0.4 0.6 0.8 1

dose

23:03 05/24 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 12

APPENDIX A



### Figure A

- 3. Fit of Probit Model to Data on the Incidence of Bronchiolar Hyperplasia in Male Rats Exposed to Vanadium Pentoxide for 2 Years

Probit Model with 0.95 Confidence Level

Probit

1

0.8ed 0.6ectfon Afracti

0.4F

0.2

0

BMDL BMD

0 0.2 0.4 0.6 0.8 1

dose

23:18 05/24 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***

### Figure A

- 4. Fit of Log

- logistic Model to Data on the Incidence

Chronic Inflammation in Larynx of Male Rats Exposed to

Vanadium Pentoxide for 2 Years

Log

- Logistic Model with 0.95 Confidence Level

Log

- Logistic

0.7

0.6

0.5edectf

0.4on Af

0.3racti F

0.2

0.1

0

BMDL BMD VANADIUM A- 13

APPENDIX A

0 0.2 0.4 0.6 0.8 1

dose

09:24 05/26 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 14

APPENDIX A



### Figure A

- 5. Fit of Log

- logistic Model to Data on the Incidence of Degeneration of Epiglottis Respiratory Epithelium in Male Rats Exposed to Vanadium

Pentoxide for 2 Years

Log

- Logistic Model with 0.95 Confidence Level

Log

- Logistic

0.8

0.7

0.6

0.5edectf

0.4on Af iactr

0.3F

0.2

0.1

0

BMDL BMD

0 0.2 0.4 0.6 0.8 1

dose

09:53 05/26 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 15

APPENDIX A



### Figure A

- 6. Fit of Log

- logistic Model to Data on the Incidence of Hyperplasia of

Nasal Respiratory Epithelial Goblet Cells in Male Rats Exposed to Vanadium

Pentoxide for 2 Years

Log

- Logistic Model with 0.95 Confidence Level

Log

- Logistic

0.5

0.4edect
0.3fon AfiractF

0.2

0.1

0 BMDL BMD

0 0.2 0.4 0.6 0.8 1

dose

10:00 05/26 2009

BMCs and BMCLs indicated are associated with an extra risk of 10%, and are in units of mg vanadium/m 3

Source: NTP 2002

In summary, the lowest BMCL 10 values for alve olar epithelial hyperplasia, bronchiolar epithelial hyperplasia, laryngeal chronic inflammation, degeneration of epiglottis epithelium, and hyperplasia of nasal goblet cells were 0.09, 0.10, 0.07, 0.04, 0.16 mg vanadium/m 3 , respectively.

Uncertainty Fac tors used in MRL derivation :

[ ] 10 for use of a LOAEL [X] 3 for extrapolation from animals to humans with dosimetric adjustments [X] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose ? Not applicable.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose :

Human equivalent concentrations were calculated for each BMCL 10 using the following equation:

BMCL HEC = BMCL ADJ x RDDR

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 16

APPENDIX A

where:

The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal to the predicted inhalation particulate exposure concentration for a human. The RDDR program (EPA 1994c) was used to calculate a multiplier for th e different regions of the respiratory tract was determined using a default body weight of 0.380 kg (EPA 1994c) and a particle size MMAD of 1.2 μm with a geometric standard deviation of 1.9. The BMDL HEC values are presented in

Table A -4



### Table A

- 4. Summa ry of Human Equivalent Concentrations of BMCL Values for Rats Exposed to Vanadium Pentoxide for 2 Years

BMCL 10 BMCL ADJ a BMCL HEC Effect (mg vanadium/m 3 ) (mg vanadium/m 3 ) RDDR (mg vanadium/m 3 )

Alveolar epithelial 0.09 0.016 0.502 b 0.008 hyperplasia

Bron chiolar epithelial 0.10 0.018 0.971 c 0.017 hyperplasia

Laryngeal chronic 0.07 0.012 0.423 d 0.005

inflammation

Degeneration of epiglottis 0.04 0.0071 0.423 d 0.003 epithelium

Hyperplasia of nasal 0.16 0.029 0.423 d 0.012 goblet cells

a BMCL ADJ = BMCL 10 x 6 hours/24 hours x 5 days/7 days

b Pulmonary region

c Thoracic region

d Extrathoracic region

BMCL = b enchmark c oncentration, l ower confidence limit RDDR = regional deposited dose r atio

Source: NTP 2002

Was a conversion used from intermittent to continuous exposure ? The BMCL 10 was adjusted for intermittent exposure, as noted in Table A -4.

Other additional studies or pertinent information that lend support to this MRL : An increased combined

incidence of alveolar/bronchiolar adenoma or carcinoma was observ ed in male rats (NTP 2002). Although the incidence was not significantly higher than concurrent controls, it was higher than historical

controls and NTP considered it to be a vanadium- related effect.

In mice exposed to ≥0.56 mg vanadium/m 3 for 6 hours/day, 5 days/week for 2 years, significant increases in the incidence of alveolar and bronchiolar hyperplasia, chronic lung inflammation, squamous metaplasia of the respiratory epithelium of the epiglottis, goblet cell hyper plasia in the nasal respiratory epithelium and nasal olfactory epithelial atrophy, and hyaline degeneration were observed (NTP 2002). In addition to these effects, a significant increase in alveolar/bronchiolar carcinoma incidence was also observed in

mic e exposed to ≥0.56 mg vanadium/m 3

.

Agency Contact s (Chemical Manager s) : Jessilynn Taylor, Sam Keith, Larry Cseh

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 17

APPENDIX A



### MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Vanadium compounds

CAS Numbers: 7440-62-6

Date: August 2009

Profile Status: Pre -Public Comment, Final D raft

Route: [ ] Inhalation [X] Oral

Duration: [ ] Acute [X] Intermediate [ ] Chronic Graph Key: 12 Species: Human

Minimal Risk Level : 0.01 [X] mg vanadium/kg/day [ ] mg vanadium/m 3

Reference : Fawcett JP, Farquhar SJ, Thou T, et al. 1997. Oral vanadyl sulphate does not affect blood cells, viscosity or biochemistry in humans. Pharmacol Toxicol 80:202-206.

Experimental design : Groups of men and women enrolled in a weight training program for at least 1 year were administered capsules contain ing 0 (11 men and 4 women) or 0.5 mg/kg/day vanadyl sulfate trihydrate (0.12 mg vanadium/kg/day) (12 men and 4 women) for 12 weeks. Fasting blood samples were collected at 0 and 12 weeks and analyzed for hematological (erthyroctye count, hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin, platelet count, and total and differential leukocyte count) and serum chemistry (cholesterol, high density lipoprotein, triglycerides, albumin, total protein, total and direct bilirubin, alkaline phosphatase, ALT ) parameters. Body weight and blood pressure were measured at weeks 4, 8, and 12.

Effect noted in study and corresponding doses : No significant alterations in blood pressure, body weight, or hematological or clinical chemistry parameters were found.

Dose and end point used for MRL derivation : NOAEL of 0.12 mg vanadium/kg/day for hematological alterations and blood pressure.

[X] NOAEL [ ] LOAEL

Uncertainty Factors used in MRL derivation :

[ ] 10 for use of a LOAEL [ ] 10 for extrapolation fro m animals to humans [X] 10 for human variability

Was a conversion factor used from ppm in food or water to a mg/body weight dose ? No.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose : Not applicable

.

Was a conversion used from intermittent to continuous exposure ? Not applicable.

Other additional studies or pertinent information that lend support to this MRL : Studies in laboratory animals have identified several sensitive effects including alterat ions in erythrocyte and reticulocyte levels, increased blood pressure, neurobehavioral alterations, and developmental toxicity. Significant increases in blood pressure have been observed in rats exposed to 0.12 mg vanadium/kg/day for 210 days (Boscolo et al. 1994); increases in blood pressure have been observed at higher doses in several other

***DRAFT FOR PUBLIC COMMENT***VANADIUM A- 18

APPENDIX A

studies by these investigators (Carmagnani et al. 1991, 1992). In general, other studies have not found increases in blood pressure in rats exposed to doses as high as 31 mg vanadium/kg/day (Bursztyn and Mekler 1993; Sušić and Kentera 1986, 1988). Decreases in erythrocyte levels have been observed in rats exposed to 1.18 mg vanadium/kg/day as ammonium metavanadate in drinking water for 4 weeks (Zaporowska et al. 199 3); at higher concentrations, decreases in hemoglobin and increases in reticulocyte levels have been observed (Ścibior 2005; Ścibior et al. 2006; Zaporowska and Wasilewski 1990, 1991,

1992a, 1992b; Zaporowska et al. 1993). Decreases in pup body weight and length have been observed in the offspring of rats administered 2.1 mg vanadium/kg/day as sodium metavanadate for 14 days prior to mating and throughout gestation and lactation (Domingo et al. 1986). At higher doses (6, 10, or 12 mg vanadium/kg/day), dec reases in pup survival, and increases in the occurrence of gross, visceral, or skeletal malformations and anomalies were observed (Elfant and Keen 1987; Morgan and El-Tawil 2003; Poggioli et al. 2001).

Agency Contact s (Chemical Manager s) : Jessilynn Tay lor , Sam Keith, Larry Cseh

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-1



### APPENDIX B. USER'S GUIDE

Chapter 1

Public Health Statement

This chapter of the profile is a health effects summary written in non

- technical language. Its intended

audience is the general public, especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters i n the profile that will provide more information on the given topic.

Chapter 2

Relevance to Public Health

This chapter provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions:

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern t o humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous

waste sites?

The chapter covers end points in the same order that they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic).

In vitro data and data from parenteral routes (intramuscular, intravenou s, subcutaneous, etc.) are also considered in this chapter.

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently asse ss cancer potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed.

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Chapter 3 Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral

r outes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action, but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in h umans.

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-2

APPENDIX B

MRLs should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational

exposure.

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, "Relevance to Public Health," contains basic information known about the substance. Other sections such as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are Unusually Susceptible" provide important supplemental information.

MRL users should also understand the MRL derivation methodol ogy. MRLs are derived using a modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure.

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest no

- observed

- adverse

- effect level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a

lowest

- observed

- adverse

- effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance- specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables.

Chapter 3

Health Effects

Tables and Figures for Levels of Significant Exposure (LSE)

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, MRLs to humans for noncance r end points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure s cenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).

The legend s presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 3 -1 and Figure 3-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure.

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-3

APPENDIX B

LEGEN D See Sample LSE Table 3

- 1 (page B -6)

(1) Route of Exposure . One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. Typically

when sufficient da ta exist, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Tables 3 -1, 3-2, and 3- 3, respectively). LSE figures are li mited to the inhalation (LSE Figure 3 -1) and oral (LSE Figure 3- 2) routes. Not all substances will have data on each route of exposure and will not, therefore, have all five of the tables and figures.

(2) Exposure Period . Three exposure periods— acute (l ess than 15 days), intermediate (15– 364 days), and chronic (365 days or more)— are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick

reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure.

(3) Health Effect . The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18).

(4) Key to Figure . Eac h key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (a lso see the two "18r" data points in sample Figure 3-1).

(5) Species . The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent

human doses to derive an MRL.

(6) Exposure Frequency/Duration . The duration of the study and the weekly and daily exposure regimens are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation for 6 hours/day, 5 d ays/week, for 13 weeks. For a more complete review of the dosing regimen, refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 1981).

(7) System . This column further defines the systemic effects. These sy stems include respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated.

(8) NOAEL . A NOAEL is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system,

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see

footnote "b").

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-4

APPENDIX B

(9) LOAEL . A LOAEL is the lowest dose used in the study that caused a harmful health effect.

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from

Serious LOAELs.

(10) Reference . The complete reference citation is given in Chapter 9 of the profile.

(11) CEL . A CEL is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing

measurable cancer increases.

(12) Footnotes . Explanations of abbreviations or reference notes for data in the LSE tables are found

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to

derive an MRL of 0.005 ppm.

LEGEND See Sample Figure 3

- 1 (page B

- 7)

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposu re periods.

(13) Exposure Period . The same exposure periods appear as in the LSE table. In this example, health effects observed within the acute and intermediate exposure periods are illustrated.

(14) Health Effect . These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table.

(15) Levels of Exposure . Concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. Inhalation exposure is reported in mg/m 3 or ppm and oral exposure is reported in mg/kg/day.

(16) NOAEL . In this example, the open circle designated 18r identifies a NOAEL critical end point in the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of

0.005 ppm (see footnote "b" in the LSE table).

(17) CEL . Key number 38m is one of three studies for which CELs were derived. The diamond symbol refers to a CEL for the test species -mouse. The number 38 corresponds to the entry in the

LSE table.

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-5

APPENDIX B

(1 8) Estimated Upper -Bound Human Cancer Risk Levels

. This is the range associated with the upper

bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA's Human Health Assessment Group's upper -bound esti mates of the slope of the cancer dose response curve at low dose levels (q 1 *).

(19) Key to LSE Figure . The Key explains the abbreviations and symbols used in the figure.

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-6

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***1234**→**SAMPLETable3-1. Levels of Significant Exposure to [Chemical x]–Inhalation**→ →** ExposureKey tofrequency/figureaSpecies durationINTERMEDIATE EXPOSURE5 6Systemic**↓ ↓** NOAELSystem(ppm)7 8**↓ ↓** LOAEL (effect)Less serious(ppm)9**↓**Serious (ppm)Reference10**↓ →** **→**18Rat13 wkResp3b10 (hyperplasia)5 d/wkNitschke et al. 19816 hr/dCHRONIC EXPOSURECancer11**↓**38Rat18 mo20(CEL, multipleWong et al. 19825 d/wkorgans)7 hr/d39Rat 89–104 wk10(CEL, lung tumors,NTP 19825 d/wknasal tumors)6 hr/d40Mouse79–103 wk10(CEL, lung tumors, NTP 19825 d/wkhemangiosarcomas)6 hr/daThe number corresponds to entries in Figure 3-1.bUsed to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3ppm; dose adjusted for intermittent exposure and dividedby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).12VANADIUM B-7

APPENDIX B

***DRAFT FOR PUBLIC COMMENT***VANADIUM B-8

APPENDIX B



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-1



### APPENDIX C. ACRONYMS, ABBREVIATIONS , AND SYMBOLS

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AED atomic emission detect ion

AFID alkali flame ionization detector

AFOSH Air Force Office of Safety and Health

ALT alanine aminotransferase

AML acute myeloid leukemia

AOAC Association of Official Analytical Chemists

AOEC Association of Occupational and Environmental Clinics

AP alk aline phosphatase

APHA American Public Health Association

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry AWQC Ambient Water Quality Criteria

BAT best available technology

BCF bioconcentration factor

BEI Biological Exposure Index

BMD/C benchmark dose or benchmark concentration

BMD X dose that produces a X% change in response rate of an adverse effect

BMDL X 95% lower confidence limit on the BMD X BMDS Benchmark Dose Software

BMR benchmark response

BSC Boar d of Scientific Counselors

C centigrade

CAA Clean Air Act

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CELDS Computer-Environme ntal Legislative Data System

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

CL ceiling limit value

CLP Contract Laboratory Program

cm centimeter

CML chronic myelo id leukemia

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DHEW Department of Health, Education, and Welfare

DHHS Department of Health and Human Services

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DOL Departm ent of Labor

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-2

APPENDIX C

DOT

DOT/UN/

NA/IMDG

DWEL

ECD

ECG/EKG

EEG

EEGL

EPA

F

F 1 FAO

FDA

FEMA

FIFRA

FPD fpm

FR

FSH

g GC gd

GLC

GPC

HPLC

HRGC

HSDB

IARC

IDLH

ILO

IRIS

Kd kg kkg

K

oc K

ow L

LC

LC 50 LC Lo LD 50 LD Lo LDH

LH

LOAEL

LSE

LT 50

m
MA

MAL

mCi Department of Transportation Department of Transportation/United Nations/ North America/Intergovernmental Maritime Dangerous Goods Code drinking water exposure level electron capture detection

elect rocardiogram electroencephalogram Emergency Exposure Guidance Level Environmental Protection Agency

Fahrenheit

first

- filial generation Food and Agricultural Organization of the United Nations Food and Drug Administration

Fede ral Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act flame photometric detection feet per minute Federal Register follicle stimulating hormone

gram gas chromatography gestational day gas liqui d chromatography gel permeation chromatography high -performance liquid chromatography high resolution gas chromatography

Hazardous Substance Data Bank International Agency for Research on Cancer immediately dangerous to life a nd health International Labor Organization Integrated Risk Information System adsorption ratio kilogram

metric ton organic carbon partition coefficient

octanol- water partition coefficient

liter liquid chromatography lethal concentration, 50% kill lethal concentration, low lethal dose, 50% kill lethal dose, low lactic dehydrogenase luteinizing hormone

lowest

- observed

- adverse

- effect level Levels of Significant Exposure lethal time, 50 % kill

meter

trans,trans -muconic acid

maximum allowable level

millicurie

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-3

APPENDIX C

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

MFO mixed function oxidase

mg milligram

mL milliliter

mm millimeter
mmHg millimeters of mercury

mmol millimole mppcf millions of particles per cubic foot

MRL Minimal Risk Level MS mass spectrometry NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NATICH National Air Toxics Information Clearinghouse

NATO North At lantic Treaty Organization

NCE normochromatic erythrocytes

NCEH National Center for Environmental Health

NCI National Cancer Institute

ND not detected

NFPA National Fire Protection Association

ng nanogram NHANES National Health and Nutrition Examination Su rvey NIEHS National Institute of Environmental Health Sciences

NIOSH National Institute for Occupational Safety and Health

NIOSHTIC NIOSH's Computerized Information Retrieval System

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-obser ved

- adverse

- effect level

NOES National Occupational Exposure Survey

NOHS National Occupational Hazard Survey

NPD nitrogen phosphorus detection

NPDES National Pollutant Discharge Elimination System

NPL National Priorities List

NR not reported

NRC National R esearch Council

NS not specified

NSPS New Source Performance Standards

NTIS National Technical Information Service

NTP National Toxicology Program

ODW Office of Drinking Water, EPA

OERR Office of Emergency and Remedial Response, EPA

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System

OPP Office of Pesticide Programs, EPA

OPPT Office of Pollution Prevention and Toxics, EPA

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA

OR odds ratio

OSHA Occupational Safety and Health Admi nistration

OSW Office of Solid Waste, EPA

OTS Office of Toxic Substances

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-4

APPENDIX C

OW Office of Water

OWRS Office of Water Regulations and Standards, EPA

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic

PBPK physiologically based pharm acokinetic

PCE polychromatic erythrocytes

PEL permissible exposure limit

pg picogram

PHS Public Health Service

PID photo ionization detector pmol picomole

PMR proportionate mortality ratio ppb parts per billion ppm parts per million

ppt parts per trillion

PSNS pretreatment standards for new sources

RBC red blood cell

REL recommended exposure level/limit

RfC reference concentration

RfD reference dose

RNA ribonucleic acid RQ reportable quantity

RTECS Registry of Toxic Effects of Chemical Substances

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SGOT serum glutamic oxaloacetic transaminase

SGPT serum glutamic pyruvic transaminase

SIC standard industrial classification

SIM selected ion monitoring

SMCL secondary maximum contaminant level

SMR standardized mortality ratio

SNARL suggested no adverse response level

SPEGL Short- Term Public Emergency Guidance Level

STEL short term exposure limit

STORET Storage and Retrieval

TD 50 toxic dose, 50% specific toxic effect

TLV threshold limit value

TOC total organic carbon TPQ threshold planning quantity

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time

- weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-5

APPENDIX C

> greater than

≥ greater than or equal to

= equal to

< less than

≤ less than or equal to

% percent

α alpha β beta

γ gamma δ delta

μm micrometer

μg microgram

q 1 * cancer slope factor

– negative

+ positive (+) weakly positive result (–) weakly negative result

***DRAFT FOR PUBLIC COMMENT***VANADIUM C-6

APPENDIX C



### This page is intentionally blank.

***DRAFT FOR PUBLIC COMMENT***VANADIUM D-1



### APPENDIX D. INDEX

absorbed dose

................................................................................................ ........................................................ 74, 86

adsorbed

................................................................................................ ............................................................. 125, 126 adsorption

................................................................................................ .................................................. 124, 125, 126 alanine aminotransferase (see ALT)

............................................................................................................................ 39 ALT (see alanine aminotransferase)

................................................................................................................ 39, 40, 61

ambient air

................................................................................................ ..................................... 4, 129, 130, 144, 147 aspartate aminotransferase (se e AST)

.......................................................................................................................... 39 AST (see aspartate aminotransferase )

.................................................................................................................... 39, 61 bioavailability

................................................................................................ .............................................................. 85

bioconcentration

................................................................................................ ........................................................ 126

biomarker

................................................................................................ ......................................... 85, 86, 97, 149, 157

b ody w eight e ffects

................................................................................................ ................................................ 41, 62

breast milk

................................................................................................ ................................................... 85, 142, 143

cancer

................................................................................................ ................................ . 5, 11, 13, 25, 65, 68, 84, 161 carcinogen

................................................................................................ ............................................................ 87, 163 carcinogenic

................................................................................................ ................................... 5, 13, 25, 42, 66, 163 carcinogenicity

................................................................................................ .......................................... 13, 42, 66, 94

carcinoma

................................................................................................ ............................................ 13, 16, 42, 43, 94

cardiovascular

................................................................................................ .................................................. 38, 60, 94

c ardiovascular e ffects

................................................................................................ ...................................... 38, 59 , 94

chromosomal aberrations

................................................................................................ ................................ . 66, 68, 71

clearance

................................................................................................ .............................................. 40, 72, 74, 77, 81

death

................................................................................................ ...................................... 25, 26, 44, 61, 85, 90, 126 deoxyribonucleic acid (s ee DNA)

................................................................................................ ................................ 66

d ermal e ffects

................................................................................................ .............................................................. 40 developmental effects

.................................................................................................. 13, 20, 42, 65, 66, 85, 92, 95, 98

diabetes

.................................................................................................................... 5, 11, 20, 25, 60, 92, 113, 136, 141

DNA (see deoxyribonucleic acid)

............................................................................... 66, 67, 68, 69, 70, 71, 86, 87, 95

elimination half

- time

................................................................................................ ............................................. 75, 78

elimination rate

................................................................................................ ............................................................ 85

endocrin e

................................................................................................ ............................................................... 82, 83

fetus

................................................................................................ ............................................................................. 83 gastrointestinal effects

............................................................................................................................... 20, 39, 60, 92 general population

............................................................................................................. 4, 11, 12, 117, 141, 147, 148 genotoxic

................................................................................................ ............................................................... 25, 71 genotoxicity

................................................................................................ ..................................................... 66, 71, 95 groundwater

................................................................................................ ....................................................... 123, 132

half

- life

................................................................................................ ................................................................ 86, 151 hematological effects

................................................................................................ ................................ . 23, 39, 60, 92

h epatic e ffects

................................................................................................ ........................................................ 39, 61 immunolog ical

................................................................................................ ..................................... 25, 41, 64, 90, 96 immunological effects

................................................................................................ ................................................. 64

K

ow ................................................................................................ ..................................................................... 104, 105

LD 50

................................................................................................ ............................................................................. 44

metabolic effects

................................................................................................ .......................................................... 63

micronuclei

................................................................................................ ............................................................ 66, 71

milk

............................................................................................................ 11, 73, 77, 88, 136, 138, 139, 141, 143, 146

musculoskeletal e ffects

................................................................................................ ................................................ 39

neurobehavioral

................................................................................................ ................................... 21, 83, 89, 93, 96

n eurological e ffects

................................................................................................ ......................................5, 41, 64, 66

nuclear

................................................................................................ ....................................................................... 151

ocular effects

................................................................................................ ......................................................... 40, 44 pharmacodynamic

................................................................................................ ........................................................ 78

***DRAFT FOR PUBLIC COMMENT***VA NADIUM D-2

APPENDIX D

pharmacokinetic

................................................................................................ ......................................... 78, 79, 80 , 84

r enal e ffects

................................................................................................ ........................................................... 40, 62 reproductive effects

............................................................................................................................. 41, 64, 66, 92, 95 respiratory effects

................................................................................................ ................................ 12, 27, 44, 93, 96

retention

................................................................................................ ........................................................... 74, 75, 85 solubility

................................................................................................ .............................................................. 73, 146 systemic effects

................................................................................................ ............................................... 27, 44, 66

toxicokinetic

................................................................................................ ........................................ 11, 25, 82, 98, 99

tremors

................................................................................................ ................................................................... 41, 96

tumors

................................................................................................ ........................................................ 42, 44, 87, 94

***DRAFT FOR PUBLIC COMMENT***