vvEPA
EPA/635/R-20/112
IRIS Assessment Plan
www.epa.gov/iris
IRIS Assessment Plan for Oral Exposure to Vanadium and Compounds
(Scoping and Problem Formulation Materials)
July 2020
Integrated Risk Information System
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
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IRIS Assessment Plan for Vanadium Compounds
DISCLAIMER
This document is a public comment draft for review purposes only. This information is
distributed solely for the purpose of public comment. It has not been formally disseminated by
EPA. It does not represent and should not be construed to represent any Agency determination or
policy. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
CONTENTS
AUTHORS | CONTRIBUTORS | REVIEWERS vi
1. INTRODUCTION 1
2. SCOPING AND INITIAL PROBLEM FORMULATION 3
2.1. BACKGROUND 3
2.2. SCOPING SUMMARY 14
2.3. PROBLEM FORMULATION 15
2.4. PRELIMINARY LITERATURE SURVEY RESULTS 16
2.5. KEY SCIENCE ISSUES 33
3. OVERALL OBJECTIVE, SPECIFIC AIMS, AND DRAFT POPULATIONS, EXPOSURES,
COMPARATORS, AND OUTCOMES (PECO) CRITERIA 34
3.1. SPECIFIC AIMS 34
3.2. DRAFT PECO CRITERIA 35
REFERENCES 39
APPENDIX A. SURVEY OF EXISTING VANADIUM TOXICITY VALUES 44
APPENDIX B. LITERATURE SEARCH STRATEGIES 46
APPENDIX C. LITERATURE SEARCH AND SCREENING METHODS 49
APPENDIX D. PRELIMINARY LITERATURE SURVEY SUMMARY 51
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
TABLES
Table 1. Chemical identity and physiochemical properties of selected vanadium compounds as
curated by EPA's CompTox Chemicals Dashboard 7
Table 2. Details on derivation of the available health effect reference values for oral exposure to
vanadium compounds 10
Table 3. Details on additional oral reference values lacking derivation descriptions 13
Table 4. EPA program and regional office interest in a reassessment of vanadium compounds 14
Table 5. Summary of NOELs and LOELs from all multidose chronic animal studies that were not
included in the 1987 IRIS health effects assessment of vanadium, with doses
expressed as to (A) parts-per-million (ppm) vanadium or (B) mg/kg-day
vanadium 31
Table 6. Draft populations, exposures, comparators, outcomes (PECO) criteria for the vanadium
compounds assessment 35
Table 7. Major categories of "Potentially Relevant Supplemental Material" 37
Table A-l. Sources searched for human health reference values for vanadium 44
Table B-l. Literature search strategies for vanadium compounds 46
FIGURES
Figure 1. IRIS systematic review problem formulation and method documents 2
Figure 2. Available health effect reference values for oral exposure to vanadium compounds
(current as of May 2020) 9
Figure 3. Survey of human studies that met PECO criteria by study design and health systems
assessed 18
Figure 4. Tabular summary of study designs and exposure measurements used in human studies
that met PECO criteria 19
Figure 5. Survey of the vanadium compounds evaluated in the available animal studies, showing
the number of studies that evaluated each vanadium compound 21
Figure 6. Survey of animal studies that met PECO criteria by study design and species and health
systems assessed 22
Figure 7. Preliminary summary of multidose chronic animal studies 23
Figure 8. Preliminary summary of multidose subchronic animal studies 25
Figure 9. Preliminary summary of multidose reproductive and developmental animal studies 28
Figure D-l. Literature survey study flow selection diagram 51
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
ABBREVIATIONS
ATSDR Agency for Toxic Substances and Disease Registry
EPA Environmental Protection Agency
HERO Health and Environmental Research Online
IAP IRIS Assessment Plan
IARC International Agency for Research on Cancer
IRIS Integrated Risk Information System
CPAD Chemical and Pollutant Assessment Division
CPHEA Center for Public Health and Environmental Assessment
ORD Office of Research and Development
PBPK physiologically based pharmacokinetic
PECO populations, exposures, comparators, and outcomes
RfC reference concentration
RfD reference dose
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IRIS Assessment Plan for Vanadium Compounds
AUTHORS | CONTRIBUTORS | REVIEWERS
Assessment Team
Erin Yost, Ph.D. (co-Assessment Manager) U.S. EPA/ORD/CPHEA/CPAD
Kathleen Newhouse, M.S. (co-Assessment Manager)
Suryanarayana Vulimiri, Ph.D.
Elizabeth Radke, Ph.D.
Barbara Glenn, Ph.D.
Executive Direction
Wayne Cascio, M.D. (CPHEA Director) U.S. EPA/ORD/CPHEA
Samantha Jones, Ph.D. (CPHEA Associate Director)
Emma Lavoie, Ph.D. (CPHEA Senior Advisor)
Kristina Thayer, Ph.D. (CPAD Director)
James Avery, Ph.D. (CPAD Associate Director)
Belinda Hawkins, Ph.D. (CPAD Senior Science Advisor)
Andrew Kraft, Ph.D. (CPAD Senior Science Advisor)
Paul White, Ph.D. (CPAD Senior Science Advisor)
Janice Lee, Ph.D. (CPAD Toxic Effects Assessment Branch Chief)
Ravi Subramaniam, Ph.D. (CPAD Toxic Effects Assessment Branch Chief)
Contributors and Production Team
Hillary Hollinger
Ryan Jones
Vicki Soto
Dahnish Shams
Maureen Johnson
Brittany Schulz
Christine Cai
Audrey Galizia
Channa Keshava
Amanda Persad
Margaret Pratt
Robyn Blain
Katherine Duke
Alexandra Goldstone
Brandall Ingle
Alexander Lindahl
Carolyn Gigot
Andrew Greenhalgh
Rachel Lehmann
Krista Montgomery
Catheryne Chiang
Courtney Lemeris
HERO Librarian (ORAU)
HERO Director (U.S. EPA/ORD/CPHEA/CPAD)
Project Management Team (U.S. EPA/ORD/CPHEA/CPAD)
CPHEA Webmaster (U.S. EPA/ORD/CPHEA)
Reference Value Array Support (ORAU)
Systematic Review Support (U.S. EPA/ORD/CPHEA/CPAD)
Systematic Review Support (ICF)
Systematic Review Support (ORAU)
Systematic Review Support (University of Illinois)
Tableau Support (ICF)
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IRIS Assessment Plan for Vanadium Compounds
1. INTRODUCTION
The Integrated Risk Information System (IRIS) Program is undertaking a reassessment of
the health effects of vanadium and compounds. An assessment of oral exposure to vanadium and
compounds was identified as an Agency priority in December 2018 fhttps: //www.epa.gov/iris/iris-
program-outlookl. The IRIS Program announced the initiation of a vanadium and compounds
inhalation assessment in December 2019, which will be performed separately from the assessment
of oral exposure.
IRIS assessments provide high quality, publicly available information on the toxicity of
chemicals to which the public might be exposed. These assessments are not regulations but are
influential scientific information and provide a critical part of the scientific foundation for decisions
made in the Environmental Protection Agency (EPA) program and regional offices to protect public
health. IRIS assessments are also used by states and local health agencies, other federal agencies,
international health organizations, and other external stakeholders.
As part of the initial steps in assessment development, the IRIS Program undertakes scoping
and initial problem formulation activities. During scoping activities, the IRIS Program consults with
the EPA program and/or regional offices requesting the IRIS assessment to identify the nature of
the hazard characterization needed, the most important exposure pathways, and the level of detail
required to inform Agency decisions. A broad, preliminary literature survey may also be conducted
to assist in identifying the extent of the evidence and health effects that have been studied for the
chemical of interest. Based on the preliminary literature survey and the scope defined by the EPA,
the IRIS Program undertakes problem formulation activities to frame the scientific questions that
will be the focus of the assessment A summary of the IRIS Program's scoping and problem
formulation conclusions are contained in the IRIS Assessment Plan (IAP).
The IAP is followed by development of a Systematic Review Protocol, which presents
detailed methods for conducting the full systematic review and dose-response analysis, including
any adjustments made to the IAP in response to public input The IAP describes what will be
assessed, and the chemical-specific protocol describes how the assessment will be conducted.
Figure 1 displays the context of the IAP and Systematic Review Protocol in the systematic review
process.
This document presents the IAP for vanadium and compounds—a summary of the IRIS
Program's scoping and initial problem formulation conclusions. It describes the Agency need for
the assessment; objectives and specific aims of the assessment; draft Populations, Exposures,
Comparators, and Outcomes (PECO) criteria that outline the evidence considered most pertinent to
address the specific aims of the assessment; and identification of key areas of scientific complexity.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Brief background information on the uses and occurrence of vanadium and compounds, and the
potential for human exposure, is provided for context.
Systematic
Review Protocol
Literature
Inventory
Study
Evaluation
Data
Extraction
Derive Toxicity
Values
Integration
Assessment
Initiated
Select arte! Model
Studies
initial Problen
Formulation
literature
Search
Preliminary
Anal/sis Plan
Organize
Hazard Review
Assessment
Developed
Evidence Analysis
and Synthesis
Assessment
Plans:
What the
assessment
will cover
Protocols: How the assessment will be conducted (specific
procedures and approaches for each assessment component, with
rationale where needed)
Figure 1. IRIS systematic review problem formulation and method
documents.
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IRIS Assessment Plan for Vanadium Compounds
2. SCOPING AND INITIAL PROBLEM FORMULATION
2.1. BACKGROUND
Vanadium is a naturally occurring metal that is the 22nd most abundant element in the
earth's crust and is found in a variety of minerals and nearly all coal and petroleum crude oils. The
focus of this document is on oral exposure to vanadium and compounds and potential impacts on
human health. Although vanadium is not classified as an essential nutrient in mammals, it is
included in some multivitamins and dietary supplements fATSDR. 2012: IOM. 20011. Likely due to
its natural abundance, vanadium is present in human breast milk, although at relatively low levels
compared to other trace elements (Krachler et al.. 20001. It is also present at low concentrations in
the majority of foods, which serve as the major source of background vanadium exposure in the
general population fATSDR. 20121. The Institute of Medicine (IOM) Panel on Micro nutrients found
that the risk of adverse effects resulting from intake of vanadium from food was unlikely, whereas
increased risk was likely to result from chronic intake of supplements containing larger doses of
vanadium flOM. 20011. Inorganic vanadium compounds and organic vanadium-containing
compounds have also been studied as anti-diabetics (Trevino etal.. 2019: Smith etal.. 20081 and for
anticancer properties (Bishavee etal.. 20101. although these potential therapeutic applications
remain investigational at this time. Organic anthropogenic vanadium compounds synthesized to
treat diabetes and cancer are likely to have different toxicokinetic properties from inorganic
vanadium fATSDR. 20121. The primary source of environmental exposure to vanadium is from
inorganic vanadium compounds (see additional information below), and thus these are the primary
focus of this assessment (Section 3.2 describes that studies of exposure to organic anthropogenic
vanadium compounds will be tracked as potentially relevant supplemental material to reflect this
focus).
Natural releases of vanadium into water and soil occur due to weathering of rocks and
atmospheric deposition fSchlesinger etal.. 2017: ATSDR. 20121. Fossil fuel combustion is the
biggest anthropogenic source of vanadium to the atmosphere (Schlesinger etal.. 2017: ATSDR.
20121. and leachates from ores, slags, sewage sludge, fertilizers, and ash ponds and coal
preparation wastes contribute to anthropogenic release of vanadium into water and soil fATSDR.
20121. Increasing use of fossil fuels from unconventional sources (heavy oils, bitumen from tar
sands) that are richer in vanadium than conventional oil, as well as the increased mining of
vanadium to meet the demand for industrial applications such as steel production and vanadium
redox-flow batteries, could lead to an overall increase in vanadium releases fWattetal.. 2018:
Schlesinger etal.. 20171.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Vanadium has a complex chemistry, existing in the environment with a possible four
oxidation states (+2, +3, +4, +5), 23 species, and nine charges that include both anions and cations
fKelsall et al. 19931. Although it forms complexes with organic matter, vanadium is typically not
incorporated into organic compounds, and therefore transformation generally occurs between
various inorganic compounds during its transport through the environment fATSDR. 20121.
Speciation of inorganic vanadium compounds occurs as a complex function of factors including pH,
redox potential, and concentration. In water, vanadium occurs as oxygen-containing ions, with
vanadate species (+5) predominating under oxic conditions and high pH, vanadyl (+4) occuring
under suboxic conditions and low pH, and vanadium (+3) occuring under anoxic conditions
fGustafsson. 2019: Huang et al.. 20151. Vanadium (+2) is readily oxidized and unstable. As
expected, based on those conditions, vanadate (+5) and vanadyl (+4) are the prevailing vanadium
species in most natural waters fGustafsson. 20191. In the body, vanadium undergoes redox cycling
and speciation driven by factors such as pH, local availability of reducing equivalents (e.g.,
glutathione-SH, NADH), and complexation with biomolecules (NTP, 2008: Bvczkowski and
Kulkarni. 1996: Nielsen. 19951. Although ingested vanadium is likely reduced to vanadyl (+4) in
the acidic conditions of the stomach, it has been found that vanadate (+5) is absorbed more
effectively than vanadyl (+4) in the gastrointestinal tract The absorption of vanadium following
oral exposure is therefore expected to be influenced by the form of ingested vanadium as well as
residence time, conditions in the gastrointestinal tract, and speed of conversion fTrevino etal.
2019: Nielsen. 19951. It is generally reported that pentavalent vanadium is more toxic than
tetravalent vanadium fATSDR. 2012: NTP. 20081. In laboratory studies, vanadyl sulfate (VOSO4) is a
commonly studied tetravalent vanadium compound, and vanadium pentoxide (V2O5), sodium
metavanadate (NaVO;j], sodium orthovanadate (Na^VCUJ, and ammonium vanadate (NH4VO3) are
commonly studied pentavalent vanadium compounds (Table 1).
In 2016, the U.S. Environmental Protection Agency (EPA) included vanadium on the
drinking water Fourth Contaminant Candidate List (CCL 4), which is a list of contaminants that are
not currently subject to national primary drinking water regulations but are known or anticipated
to occur in public water systems. Contaminants listed on the CCL may require regulation under the
Safe Drinking Water Act (SD WA) if the Agency determines that the contaminant may have an
adverse effect on the health of persons; the contaminant is known to occur or there is substantial
likelihood that the contaminant will occur in public water systems with a frequency and at levels of
public health concern; and in the sole judgment of the Administrator, regulation of the contaminant
presents a meaningful opportunity for health risk reductions for persons served by public water
systems (Safe Drinking Water Act. 20191. Vanadium was monitored under EPA's Third Unregulated
Contaminant Monitoring Rule (UCMR3) from 2013 to 2015 and 3,625 out of 4,922 public water
systems (73.6%) detected vanadium at or above the minimum reporting level (2 |J.g/L). The data
show that 163 of these public water systems (3.3%) had results above the reference concentration
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
used in the UCMR 3 (21 (ig/L)1 (https://www.epa.gov/sites/production/files/2017-
02/documents/ucmr3-data-summary-january-2017.pdf). In December 2018, an Integrated Risk
Information System (IRIS) assessment of oral exposure to vanadium was identified by the EPA
Office of Water as a priority for an IRIS assessment(https://www.epa.gov/iris/iris-program-
outlook)).
Existing human health reference values for vanadium and compounds from federal, state,
and international agencies are depicted in Figure 2 (see Table 2 for a tabular summary, including
derivation details of the displayed values; current as of May 2020). IRIS published a health effects
assessment of vanadium and compounds in 1987, which includes a reference dose (RfD) for lifetime
oral exposure to vanadium pentoxide fU.S. EPA. 19871. The RfD was based on an unpublished
study by Stokinger et al. (19531 described in Patty's Industrial Hygiene and Toxicology (1981) in
which an unspecified strain of rats were fed vanadium pentoxide over a lifetime at levels of 10 and
100 ppm vanadium. An RfD of 0.009 mg/kg-day for vanadium pentoxide was derived based on the
no-observed-adverse-effect level (NOAEL) of 10 ppm vanadium (approximately 17.9 ppm
vanadium pentoxide) for decreased hair cystine content. The RfD was calculated by assuming that
rats eat food equivalent to 5% of their body weight and by applying an uncertainty factor (UF) of
100 (a factor of 10 for interspecies extrapolation and a factor of 10 to provide added protection for
unusually sensitive individuals). IRIS also reviewed the carcinogenicity data available for vanadium
and compounds and concluded that the weight of evidence classification for vanadium under the
1986 Guidelines for Carcinogen Risk Assessment (U.S. EPA. 19861 is Group D, not classifiable.
EPA also developed provisional peer-reviewed toxicity values (PPRTVs) for vanadium and
its soluble inorganic compounds other than vanadium pentoxide in 2009, including a chronic
provisional RfD (p-RfD) and subchronic p-RfD for vanadium. These values were based on kidney
histopathology in a 6-month study by Boscolo etal. (19941. in which rats were given sodium
metavanadate in drinking water at levels of 1,10, or 40 |ig/mL vanadium; EPA estimated that this
corresponded to doses of 0.12,1.2, or 4.7 mg/kg-day based on default drinking water and body
weight estimates. A subchronic p-RfD of 0.0007 mg/kg-day for vanadium was derived based on the
NOAEL of 0.12 mg/kg-day by adjusting upward by 0.1 mg/kg-day to account for likely background
exposure to vanadium in diet and by applying a UF of 300 (a factor of 10 for interspecies
extrapolation, a factor of 10 to protect unusually sensitive individuals, and a factor of 3 to account
for database deficiencies). A chronic p-RfD of 0.00007 mg/kg-day for vanadium was derived from
this same study by applying an additional UF of 10 to account for extrapolation to chronic exposure
duration. This assessment also concluded that there was "Inadequate Information to Assess [the]
1 The reference concentration for vanadium in drinking water used in the UCMR 3 was based on the ATSDR 1992
minimal risk level (MRL) of 0.003 mg/kg-day. The ATSDR 1992 Toxicological Profile for Vanadium is no longer
publicly available and has been replaced by ATSDR (2.012). The UCMR 3 reference concentration provides context
around the detection of a particular contaminant above the minimum reporting level and does not constitute an
"action level".
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IRIS Assessment Plan for Vanadium Compounds
Carcinogenic Potential" of vanadium based on the 2005 Guidelines for Carcinogen Risk Assessment
flJ.S. EPA. 20051.
Since the publication of these prior assessments by EPA, new information on the health
effects of vanadium and compounds has become available. The Agency for Toxic Substances and
Disease Registry (ATSDR) 2012 Toxicological Profile of Vanadium concluded that increased blood
pressure, hematological alterations, alterations in neurobehavioral tests, and developmental
toxicity were the most sensitive outcomes in laboratory animal studies following intermediate
duration (15-364 day) oral exposure to vanadium compounds, but noted that increased blood
pressure and hematological effects were not consistently observed across animal studies at higher
dose levels or in a 12-week controlled human trial fATSDR. 20121. More recently, NTP has
undertaken a series of studies in rats and mice on the health effects of oral (drinking water)
exposure to vanadyl sulfate and sodium metavanadate, which include evaluation of a range of
health outcomes and will provide additional information on the comparative toxicity of two
common vanadium oxidation states. These include 14-day studies in rats and mice (Roberts et aL
20161. a 13-week study in mice, and an extended developmental toxicity study in rats in which F1
offspring are exposed from gestation day (GD) 6 through 13 weeks post-weaning. NTP's
developmental and 13-week drinking water studies are expected to be posted by 2020, and interim
results are currently available
fhttps://ntp.niehs.nih.gov/ntp/results/pubs/posters/roberts sot20190300.pd0.
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IRIS Assessment Plan for Vanadium Compounds
Table 1. Chemical identity and physiochemical properties of selected vanadium compounds as curated by EPA's
CompTox Chemicals Dashboard
Name
Elemental
vanadium
Vanadyl sulfate
Sodium
metavanadate
Ammonium
metavanadate
Sodium
orthovanadate
Vanadium
pentoxide
CASRN
7440-62-2
27774-13-6
13718-26-8
7803-55-6
13721-39-6
1314-62-1
DTXSID3
2040282
4021428
3044336
1052533
2037269
2023806
Structure
V
0
^ - 11 -
V^O O S 0
II
0
O" Na+
1
j"j N^4
0^ ^0
Na
Cf
Na
0 \
0" Na
^ v
II II
0 0
Molecular weight
(g/mol)
50.942
163
121.928
116.978
183.907
181.878
Molecular formula
V
VOS04
NaVOs
NH4VO3
Na3V04
V2O5
Selected
Synonym(s)
Vanadium
(Oxido)vanadium(2+)
sulfate;
oxo(sulfato)vanadium;
oxovanadium(IV) sulfate;
vanadium oxide sulfate;
vanadium oxosulfate;
vanadium oxysulfate;
vanadium sulfate; vanadic
sulfate; vanadyl
monosulfate; vanadin(IV)
oxide sulfate
Sodium vanadate;
sodium
trioxidovanadate(l~);
sodium vanadium
oxide; sodium
vanadium trioxide;
vanadic acid,
monosodium salt;
sodium vanadate(V)
Ammonium
trioxovanadate(l~);
ammonium
tris(oxido)vanadate(l");
ammonium
monovanadate;
ammonium
vanadate(V); vanadic
acid, ammonium salt;
ammonium vanadium
oxide; ammonium
vanadium trioxide
Trisodium
tetraoxidovanadate
(3");
sodium vanadium
oxide, trisodium
vanadate, sodium
vanadate(V),
vanadic acid,
trisodium salt
Vanadium oxide;
mu-
oxido[tetrakis(oxido)
]divanadium;
divanadium
pentoxide; vanadic
anhydride;
vanadin(V) oxide;
vanadium(V) oxide
Water solubility
(mol/L)b
-
-
-
-
-
-
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IRIS Assessment Plan for Vanadium Compounds
Name
Elemental
vanadium
Vanadyl sulfate
Sodium
metavanadate
Ammonium
metavanadate
Sodium
orthovanadate
Vanadium
pentoxide
LogP: Octanol-
Waterb
--
--
-
--
--
--
Melting Point (°C)b
1.90e+3
--
630
--
858
690
Boiling Point (°C)b
3.00e+3
--
--
--
1.75e+3
Vapor Pressure
(mmHg)b
--
--
--
--
--
--
Bioconcentration
Factor13
4.36e+3
4.5
5.54
26.4
--
15.4
aDTXSIDs are unique substance identifiers used for curation by the EPA's Distributed Structure-Searchable Toxicity (DSSTox) project.
bExperimental average values for physiochemical properties are shown here. Median values and ranges for physiochemical properties are also provided on the
Chemicals Dashboard at https://comptox.epa.gov/dashboard/. If no experimental values were available on the Chemicals Dashboard, is shown.
This document is a draft for review purposes only and does not constitute Agency policy.
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Vanadium Oral Reference Values
o.i
Acute
0.01
i?
"O
2? 0.001
(D
DC
O
VI
O
O
0.00001
Short-Term
-- ATSDR-MRL(V and compouds)
EPA/HEASTRfD V,Os
0.0001
Subchronic
FPA/HFASTRfD IV sulfate!
Chronic
EPA/HEAST RfD (NaOjV)
x
EPA/HEASTRfD (V)
EPA/HEAST RfD (V sulfate)
d |
EPA/IRIS RfOVjOs
"q I
EPA/HEAST RfD (V)
RIVM pTDI (V and compounds) 81
I
EPA/HEASTRfD (NaQ3V) O"
EPA/PPRTV p-RfD*
EPA/PPRTV p-RfD" ~
M-
-f-
X ATSDR-MRL (2012)
I EPA/IRIS RfO (19S8)
~ EPA/HEASTRfD
(table updated 1997)
~ EPA/PPRTV p-RFD*
(2009)
• RIVM pTDI (2009)
10 100 1,000
Duration (Days)
10,000
100,000
*Appliesto vanadium and its soluble inorganic compounds,excludingvanadium pentoxide
Figure 2. Available health effect reference values for oral exposure to vanadium compounds (current as of May 2020).
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Table 2. Details on derivation of the available health effect reference values for oral exposure to vanadium
compounds3 (current as of May 2020; please consult citation source entities and other entities in Appendix Table A-l
for current values)
Reference
value
nameb
Duration
Compound
Reference
value
(mg/kg-day)
Health
effect
Point of
departure
Qualifier
Source
Uncertainty
factors0
Notes on
derivation
Review
status
EPARfD
(IRIS)d
Lifetime
(chronic)
Vanadium
pentoxide
0.009
Decreased
cystine in
hair of rats
0.89
mg/kg-day
NOAEL
amgfsT""
Total
UF = 100
UFa = 10
UFh = 10
NOAEL
Estimated6
Final
ru.s. EPA.
1987)
EPA
p-RFD
(PPRTV)f
Subchronic
Vanadium
and soluble
inorganic
compounds
(excluding
vanadium
pentoxide)
0.0007
Kidney
lesions in
male rats
exposed
for 6 mos.
0.12
mg/kg-day
0.22
mg/kg-day
NOAEL
NOAELadj
Boscolo et al.
Total
UF = 300
UFa = 10
UFh = 10
UFdb = 3
NOAEL
Adjusted®
Provisional
ru.s. EPA.
2009)
Chronic
0.00007
Total
UF = 3,000
UFa = 10
UFh = 10
UFs = 10
UFdb = 3
EPARfD
(HEAST)h
Subchronic
Chronic
Vanadium
0.007
0.007
Minor
serum
cholesterol
changes in
rats
0.7
mg/kg-day
NOAEL
Schroeder et
Total
UF = 100
UFa = 10
UFh = 10
NOAEL
Estimated'
Provisional
ru.s. EPA.
1997)
Subchronic
Chronic
Vanadium
sulfate
0.02
0.02
2.24
mg/kg-day
NOAEL
Subchronic
Vanadium
pentoxide
0.009
Adopted
IRIS
chronic
RfD
Adopted
IRIS
chronic
RfD
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Reference
value
nameb
Duration
Compound
Reference
value
(mg/kg-day)
Health
effect
Point of
departure
Qualifier
Source
Uncertainty
factors0
Notes on
derivation
Review
status
Subchronic
Sodium
meta-
vanadate
0.01
Impaired
kidney
function in
rats
1.3 mg/kg-
day
NOAEL
Dominso et
al. C19851
Total
UF = 100
UFa = 10
UFh = 10
NOAEL
Conversion
i
Provisional
ru.s. EPAl
Chronic
0.001
exposed
for 3 mos.
Total
UF = 1,000
UFa = 10
UFh = 10
UFs = 10
ATSDR-
MRL
Intermediate
(15-365
days)
Vanadium
and
compounds
0.01
No change
in blood
pressure,
body wt.,
or
hematologi
cal or
clinical
chemistry
parameter
s at
highest
dose in a
12-wk.
study
0.5
mg/kg-day
0.12
mg/kg-day
NOAEL
HeOsSV
NOAELV
Fawcett et al.
C19971
Total UF = 10
UFh = 10
NOAEL V
Calculated15
Final
fATSDR.
2012)
RIVM
pTDI
Chronic
Vanadium
and
compounds
0.002
Develop-
mental
effects in
rats
5
mg/kg-day
2.1
mg/kg-day
LOAEL
NaOsV
LOAELV
Dominso et
al. C19861
Total
UF = 1,000
UFa = 10
UFh = 10
UFl= 10
LOAEL V
Calculated1
Provisional
fTiesiema
and Baars.
2009)
aHealth effect reference values listed in Table 2 are shown in Figure 2.
bATSDR = Agency for Toxic Substances and Disease Registry; HEAST = Health Effects Assessment Summary Tables; MRL = Minimal Risk Level;
PPRTV = Provisional Peer-Reviewed Toxicity Value; RfD = Reference Dose; RIVM = Rijksinstituut voor Volksgezondheid en Milieu, The Netherlands Institute for
Public Health and the Environment; TDI = Tolerable Daily Intake.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
CUF = uncertainty factor; subscripts indicate the type of UF that was applied. UFh - inter-human variability; UFa - animal to human variability; UFl - LOAEL to
NOAEL adjustment; UFs - subchronic to chronic adjustment; UFdb - database uncertainty.
dThis RfD has been adopted as a state value by the Nevada Division of Environmental Protection.
The NOAEL was estimated based on the assumption that rats exposed to 10 ppm vanadium (17.85 ppm vanadium pentoxide) in food were consuming 5% of
their body weight in food per day.
The chronic p-RfD has been adopted as a state value by the Michigan Department of Environment, Great Lakes & Energy.
sThe NOAEL was adjusted upwards to account for possible additional vanadium exposure from the rats' basal diet.
hThe chronic RfD for sodium metavanadate has been adopted by the Nevada Division of Environmental Protection.
'The NOAEL was estimated for rats exposed to 5 ppm vanadium in the form of vanadyl sulfate in drinking water.
JRats were exposed to 10 ppm sodium metavanadate in their drinking water. Support documentation indicates that this exposure is equivalent to a dose rate of
0.55 mg vanadium/kg-day. While this is not explicitly stated anywhere in the text, 0.55 mg vanadium/kg-day equals 1.3 mg/kg-day sodium metavanadate, as
per the following molecular weight conversion. Thus, 1.3 mg/kg-day was likely used as the point of departure:
NOAEL NaV03 = NOAEL V x NaV03 M.W./V molar mass = 0.55 mg V/kg-day x 121.928 g NaV03/mol/50.942 g V/mol = 1.3 mg NaVOs/kg-day.
kNOAEL V = NOAEL V0S04-3H20 x Vmolar mass/V0S04-3H20 M.W. = 0.5 mg V0S04-3H20/kg-day x 50.942 g V/mol/217.041 g V0S04-3H20/mol = 0.12 mg
V/kg-day.
1 'LOAEL V = LOAEL NaVOs x V molar mass/NaVOs M.W. = 5 mg NAOsV/kg-day x 50.942 g V/mol/121.928 g NaVOs/mol = 2.1 mg V/kg-day.
2
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Table 3. Details on additional oral reference values lacking derivation descriptions3
Reference
value
nameb
Duration
Compound
Reference
value
(mg/kg-day)
Health
effect
Point of
departure
Qualifier
Source
Uncertaint
y factors
Notes on
derivation
Review
status
TCEQ RfD
Chronic
Vanadium
0.0018
NR
NR
NR
NR
RfD developed with
TCEQ's protocol
CTCEO.20121
Final
(TCEO,
20181
aHealth effect reference values listed in Table 3 are not shown in Figure 2 because they did not provide descriptions of how the value was derived.
bTCEQ = Texas Commission on Environmental Quality
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
1 2.2. SCOPING SUMMARY
2 During scoping, the IRIS Program met with EPA program and regional offices that had
3 interest in an IRIS assessment for vanadium and compounds to discuss specific assessment needs.
4 Table 4 provides a summary of input from this outreach.
Table 4. EPA program and regional office interest in a reassessment of
vanadium compounds
EPA program
or regional
office
Oral
Inhalation3
Statutes/regulations
Anticipated uses/interest
Office of Water
~
Safe Drinking Water Act
(SDWA) and Clean
Water Act (CWA)
The SDWA requires EPA to listb contaminants
that are currently not subject to any proposed
or promulgated National Primary Drinking
Water Regulation (NPDWR) but are known or
anticipated to occur in public water systems,
including vanadium. Contaminants listed on the
CCL may require future regulation under SDWA.
Under Section 304(a) of the CWA, EPA derives
recommended ambient water quality criteria
for the protection of human health. States and
tribes may use these values or other values in
their water quality standards to protect
designated uses.
Vanadium and compounds (oral) toxicological
information may be used to address risk under
the CWA and SDWA.
aThe IRIS Program announced the initiation of a vanadium and compounds (inhalation) assessment in December
2019. A separate IAP will be released regarding the inhalation assessment.
bEPA's Final Contaminant Candidate List (CCL) 4 lists vanadium.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
2.3. PROBLEM FORMULATION
Systematic review methods were used to identify a preliminary literature inventory for
vanadium and compounds. The ATSDR Toxicological Profile for Vanadium f AT SDR. 20121 was
selected as the starting point for the literature search because it is the most recent and
comprehensive review of health effects of vanadium and compounds published by a U.S. federal
government agency. All references from the 2012 ATSDR Toxicological Profile for Vanadium were
extracted by an EPA information specialist and stored in the Health and Environmental Research
Online (HERO) database fhttps://hero.epa.gov/hero/index.cfm/proiect/page/project id/23571.2
Database searches were then conducted on March 28, 2019 by an EPA information specialist in
three online databases (PubMed, Web of Science, Toxline)3 and repeated on March 9, 2020 to
identify records that had been published since the release of the 2012 ATSDR Toxicological Profile
for Vanadium. The year 2010 was selected as the start date for the literature search as a precaution
to capture records published near the last literature search date for the citations in the ATSDR
document.4 This literature search strategy is designed to be broad, but like any search strategy,
studies may be missed (e.g., studies published before 2010 that were not included in the ATSDR
document; cases where the specific chemical is not mentioned in title, abstract, or keyword content;
"grey" literature that is not indexed in the databases listed above). Thus, when additional
references that appeared to meet PECO criteria were identified through curation of references cited
in reviews or assessments, these references were annotated with respect to the source of the
record and screened using the same methods applied to the rest of the literature inventory. IRIS
encourages the identification of any additional missing studies by the public. All records were
stored in the HERO database. Draft PECO criteria (Populations, Exposures, Comparators,
Outcomes; see Table 6) were used to focus the research questions and guide screening to identify
relevant literature.
Studies that met PECO criteria were briefly summarized using DistillerSR5, and studies
which did not meet PECO criteria but contained potentially relevant supplemental material were
inventoried. For animal studies, the following information was captured: chemical form, study type
[acute (<24 hours), short term (1-30 days), subchronic (30-90 days), chronic (>90 days),
reproductive, developmental], duration of treatment, route, species, strain, sex, dose or
concentration levels tested, dose or concentration units, health system and specific endpoints
assessed, and a brief summary of findings at the health system level (null, no-observed-effect level
2EPA's HERO database provides access to the scientific literature behind EPA science assessments. The
database includes more than 600,000 scientific references and data from the peer-reviewed literature used
by EPA to develop its health assessment documents.
3The Toxline database was taken down and migrated to PubMed prior to the March 2020 literature search
update, so the Toxline search was only conducted in March 2019.
4Personal correspondence with ATSDR indicated that the final literature update for the 2012 Toxicological
Profile for Vanadium was conducted in August 2011.
5DistillerSR is a web-based systematic review software used to screen studies available at
https://www.evidencepartners.com/products/distillersr-systematic-review-software.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
[NOEL], or lowest-observed-effect level [LOEL] based on author-reported statistical significance
with an indication of which specific endpoints were affected). For human studies, the following
information was summarized: chemical form, population type (e.g., general population-adult,
occupational, pregnant women, infants and children), study type (e.g., controlled trial, cross-
sectional, cohort, case-control), short free text description of study population, sex, major route of
exposure (if known), description of how exposure was assessed, health system and specific
outcome assessed, and a summary of findings at the health system level based on author-reported
statistical significance (null or an indication of any associations found and a description of how the
exposure was quantified in the analysis). Studies were extracted into DistillerSR by one team
member and checked by at least one other team member. These study summaries are referred to
as literature surveys and are presented using Tableau visualization software
f https://www.tableau.com/].
These methods were implemented in accordance with EPA Quality Assurance policies and
procedures (Quality Policy Procedures6 and CIO 2105.0 (formerly 5360.1 A217). Detailed literature
search strategies (Appendix B), literature search and screening methods (Appendix C), and a
literature survey study flow selection diagram (Appendix D) are provided in the appendices at the
end of this document, and the preliminary literature survey results are described in the following
section. The results obtained from this systematic compilation of the evidence helped inform the
specific aims and key science issues that will be the focus of the assessment.
2.4. PRELIMINARY LITERATURE SURVEY RESULTS
The literature search and screening process identified 142 studies that met PECO criteria
(n = 48 human studies, n = 94 animal studies), and a total of 1,064 studies were tagged as
potentially relevant supplemental material. No PBPK models for vanadium or vanadium
compounds were identified.
Human studies: A preliminary survey of study designs and health systems assessed in the
human studies that met PECO criteria is provided in Figure 3 and a tabular summary is provided in
Figure 4. Human studies identified in the literature search included nine controlled trials that
administered vanadyl sulfate or sodium metavanadate directly to study participants. Of the
controlled human trials, seven were conducted in diabetic patients for the purpose of evaluating the
therapeutic effects of vanadium supplementation, with treatment durations of 2-6 weeks (Afkhami-
Arekani et al. 2008: Cusi etal. 2001: Goldfine et al. 2000: Boden etal. 1996: Halberstam etal.
1996: Cohen etal. "1995: Goldfine etal. 1995): one evaluated effects of vanadium supplementation
on insulin sensitivity in healthy adults, with a treatment duration of 7 days; and one evaluated
effects of vanadium supplementation in weight training athletes, with a treatment duration of
6U.S Environmental Protection Agency Procedures for Quality Policy:
https://www.epa.gOv/sites/production/files/2015-10/documents/21060.pdf
7Policy and Program Requirements for the Mandatory Agency -Wide Quality System:
https://www.epa.gov/sites/production/files/2015-09/documents/epa...order do 21050.pdf
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
1 12 weeks fFawcett et al, 19971. The literature search also identified 39 observational
2 epidemiology studies, which evaluated the association of health outcomes with total vanadium but
3 the specific form of vanadium was not determined. This included 37 studies (n = 13 case-control,
4 14 cross-sectional, and 10 cohort) in which vanadium exposure was evaluated using biomonitoring
5 of blood (whole blood, plasma, or serum), urine, hair, seminal plasma, cerebrospinal fluid, saliva, or
6 nails, but in which the route of exposure was unclear; and two ecological studies that evaluated the
7 association of human health outcomes with vanadium levels in soil, drinking water, or food.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Health System
controlled trial
case-control
cross-sectional
cohort
ecological Grand Total
Cancer
4
4
Cardiovascular
f
3
1
11
Dermal
1
1
Developmental
1
1
5
1 8
Endocrine
1
1
2
Gastrointestinal
7
7
Hematologic
3
1
4
Hepatic
1
1
Immune
1
1
1
3
Metabolic
8
2
1
11
Nervous
5
3
1 9
Other
1
1
Renal
1
1
2
Reproductive
3
1
4
Systemic/Whole Body
3
1
4
Grand Total
9
13
14
10
2 48
1 8
Figure 3. Survey of human studies that met PECO criteria by study design and health systems assessed.
Click here to view interactive version, which includes a more detailed description of study design and results. The
numbers indicate the number of studies that investigated a particular health system, not the number of studies that
observed an association with vanadium exposure. If a study evaluated multiple health outcomes, it is shown here multiple
times.
This document is a draft for review purposes only and does not constitute Agency policy,
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IRIS Assessment Plan for Vanadium Compounds
Health System
Chemical
Name
Population
Study Design
Sex
Reference
direct adminis
tration (oral)
Exposure Measurement / Biomonitoring Matrix
blood hair urine drinking water food
nails soil
Cancer
Vanadium
general population
case-control
both
Gomez-Tomas et al„ 2019
Lee etal., 2020
¦
¦
female
Tang etal., 2012
¦
occupational
case-control
both
Bai etal., 2019
¦
Cardiovascular
Sodium
metavanadate
general population
controlled trial
both
Afkhami-Ardekani et al., 2008
Goldfineet al., 1995
¦
¦
Vanadium
general population
cohort
both
Domingo-Relloso et al., 2019
¦
cross-sectional
both
Subrahmanyam et al., 2016
Wu etal., 2018
¦
¦
occupational
cross-sectional
both
Dai etal., 2019
¦
Vanadyl
sulfate
general population
controlled trial
both
Cohen etal., 1995
Cusi etal., 2001
Fawcett etal., 1997
Goldfineet al., 2000
Halberstam et al., 1996
i
¦
¦
¦
¦
Dermal
Vanadium
general population
case-control
male
Lai etal., 2013
¦ ¦
Developmental
Vanadium
general population
ecological
not reported
Yu and Zhang, 2011
¦ ¦
¦
children
cross-sectional
both
Tascilaretal., 2011
¦
pregnant women
case-control
female
Jiang et al., 2016
¦
cohort
both
Hu etal., 2018
¦
female
Hu etal., 2017
Zheng et al., 2014
¦
¦
infants
cohort
both
Sun etal., 2019
Zhou etal., 2019
¦
¦
Endocrine
Vanadium
children
cross-sectional
both
Kudabayeva et al., 2018
¦
pregnant women
cohort
female
Sun etal., 2019
¦
Gastrointestinal
Sodium
metavanadate
general population
controlled trial
both
Afkhami-Ardekani et al., 2008
Goldfine et al., 1995
¦
¦
Vanadyl
sulfate
general population
controlled trial
both
Boden etal., 1996
Cohen et al., 1995
Cusi etal., 2001
Goldfine et al., 2000
Halberstam et al., 1996
¦
¦
¦
¦
¦
Exposure Measurement:
¦ biomonitoring
¦ direct administration (oral)
¦ drinking water
¦ food
¦ soil
Figure 4. Tabular summary of study designs and exposure measurements used in human studies that met PECO
criteria (continued on following page). Click here to view interactive version, which includes a more detailed
description of study design and results.
This document is a draft for review purposes only and does not constitute Agency policy,
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IRIS Assessment Plan for Vanadium Compounds
Health System
Chemical Name
Population
Study Design
Sex
Reference
direct adminis
tration (oral)
Exposure Measurement / Biomonitoring Matrix
,, . cerebrospinal , .
blood ^ hair semen urine
fluid
saliva soil
Hematologic
Vanadium
children
cross-sectional
both
Lopez-Rodriguez et al., 2017
¦
Vanadyl sulfate
general population
controlled trial
both
Cohen et al., 1995
Fawcettetal., 1997
Halberstam et al., 1996
¦
¦
¦
Hepatic
Vanadyl sulfate
general population
controlled trial
both
Fawcettetal., 1997
¦
Immune
Vanadium
general population
cross-sectional
both
Pedro et al., 2019
¦
infants
cohort
both
Zhouetal., 2019
¦
Vanadyl sulfate
general population
controlled trial
both
Fawcett etal., 1997
¦
Metabolic
Sodium metavanadate
general population
controlled trial
both
Afkhami-Ardekani et al., 2008
Goldfine et al., 1995
¦
¦
Vanadium
general population
case-control
both
Li etal., 2017
Wang etal., 2014
¦
¦
pregnant women
cohort
female
Wang etal., 2020
¦
Vanadyl sulfate
general population
controlled trial
both
Boden etal., 1996
Cohen etal., 1995
Cusi etal., 2001
Goldfine et al., 2000
Halberstam et al., 1996
Jentjens and Jeukendrup, 2002
¦
¦
¦
¦
¦
¦
Nervous
Vanadium
general population
case-control
both
Roos etal., 2013
Squadrone et al., 2018
¦
¦
female
Nayloretal., 1984
¦
cross-sectional
both
Kihira etal., 2015
¦
children
case-control
both
Alqhazo and Rashaid, 2018
Skalnyetal., 2017
¦
¦
cross-sectional
both
Blaurock-Busch et al., 2012
¦
male
Tinkov et al., 2019
¦ ¦
ecological
both
Zahran etal., 2012
¦
Other
Vanadium
general population
cross-sectional
both
Inonuetal., 2019
¦
Renal
Vanadium
general population
cohort
both
Liu etal., 2020
¦
Vanadyl sulfate
general population
controlled trial
both
Fawcett etal., 1997
¦
Reproductive
Vanadium
general population
cross-sectional
female
Zheng etal., 2015
¦
male
Skalnaya etal., 2015
Wang etal., 2018
¦
¦ ¦
pregnant women
cohort
female
Jin etal., 2018
¦
Systemic/Whole
Sodium metavanadate
general population
controlled trial
both
Goldfine etal., 1995
¦
Body
Vanadium
pregnant women
cohort
female
Skalny etal., 2020
¦
Vanadyl sulfate
general population
controlled trial
both
Cohen etal., 1995
Goldfine et al., 2000
¦
¦
Exposure Measurement:
¦ biomonitoring
¦ direct administration (oral)
¦ soil
Figure 4 continued.
This document is a draft for review purposes only and does not constitute Agency policy,
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IRIS Assessment Plan for Vanadium Compounds
Animal studies: A preliminary survey of the types of vanadium compounds evaluated in
animal studies that met PECO criteria is shown in Figure 5, and a preliminary survey of study
designs, species, and health effects evaluated in the animal studies is provided in Figure 6. The
animal studies evaluated exposure to ammonium metavanadate, sodium metavanadate, sodium
orthovanadate, vanadyl sulfate, vanadium pentoxide, calcium orthovanadate, or calcium
pyrovanadate. Of these, vanadyl sulfate and sodium metavanadate were the most frequently
studied compounds. Two studies reported that animals were exposed to "ammonium vanadate"
(Susie and Kentera. 1986) and "sodium vanadate" (Sun etal.. 20141. which were inferred to be
ammonium metavanadate and sodium metavanadate (respectively) based on the synonyms
reported in Table 1 and are referred to accordingly here. Four studies reported that animals were
exposed to "vanadium" or "vanadate" but the specific chemical form was unclear. The majority of
studies were conducted in rats and mice, but data were also available in rabbits, cattle, goats, and
sheep. Among the 94 available animal studies, 23 included experiments in animal models of
diabetes that evaluated the therapeutic effects of vanadium compounds on diabetic symptoms.
Ammonium metavanadate
18
Calcium orthovanadate
1
Calcium pyrovanadate
1
Sodium metavanadate
31
Sodium orthovanadate
8
Vanadate
1
Vanadium
3
Vanadium pentoxide
4
Vanadyl sulfate
33
Grand Total
94
1 33
Figure 5. Survey of the vanadium compounds evaluated in the available
animal studies, showing the number of studies that evaluated each vanadium
compound. Click here to view interactive version, which includes a more detailed
description of study design and results. If study evaluated multiple types of
vanadium compounds, it is shown here multiple times.
Tabular summaries of the study designs and health effects evaluated in chronic, subchronic,
and reproductive or developmental studies that tested multiple dose levels are provided in
Figures 7, 8, and 9, respectively.8 In general, these study designs are preferred for toxicity value
derivation over acute/short-term studies or studies that test a single dose level (U.S. EPA. 2002).
although there may be circumstances where other study designs are more suitable. Figures are
organized by health outcomes evaluated. Diabetic animal models are not shown in Figures 7-9 but
are included in Figures 5 and 6 and in the interactive figures in Tableau.
8Dose levels shown in tabular summaries are those reported by the authors. For the assessment, doses
reported as concentrations in food or drinking water (e.g., ppm, |.ig/mL) will be converted to mg/kg-day.
This document is a draft for review purposes only and does not constitute Agency policy.
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acute
short-term
subchronic
chronic
reproductive
developmental
Grand
Health System
rat mouse
rat
mouse
sheep
rat
mouse cattle
goat
rat
mouse
rabbit cattle goat
rat mouse
rat
mouse
Total
ADME
1
8
1
1
1
1
3
2
16
Cancer
1
2
2
5
Cardiovascular
2
1
9
1 1
1
10
1 1
2
28
Dermal
1
1
Developmental
1
6
1
8
Endocrine
1
2
1
1
5
Gastrointestinal
1
1
2
Hematologic
6
8
1
5
20
Hepatic
1
6
3
4
3 1
1
2 1
4
22
Immune
6
2
7
3 1
2
2
21
Lymphatic
1
1
Metabolic
8
1
16
1 1
1
4
1
3
1
37
Musculoskeletal
1
1
1
1
4
Nervous
2
1
7
1
2
13
Ocular
1
1
Renal
3
3
5
2 1
5
3 1
3
24
Reproductive
1
1
1
1
8 2
2
14
Respiratory
1
2
2
1
2
7
Systemic/Whole Body
2 1
15
3
1
26
2 1
1
9
3
1 1
4 1
1
68
Urinary
1
1
Grand Total
2 1
17
3
1
34
4 1
1
15
3
111
9 2
9
2
94
1 26
Figure 6. Survey of animal studies that met PECO criteria by study design and species and health systems
assessed. Click here to view interactive version, which includes a more detailed description of study design and results.
The numbers indicate the number of studies that investigated a particular health system, not the number of studies that
observed an association with vanadium exposure. If a study evaluated multiple species, study designs, or health outcomes,
it is shown here multiple times.
This document is a draft for review purposes only and does not constitute Agency policy,
22 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Health System
Cancer
Cardiovascular
Chemical
Name
hh TirrniT
"itta'ja-iaaate
Vanadyl
rul^t"
fudhni
" etc* '3"adate
Species Sex
mouse male
¦at V">a
rat male
Dermal
Endocrine
Hematologic
Immune
Metabolic
Musculoskeletal
Renal
Sodium
ci tnovanadate
Vanadv'
sulfate
vanadum
pentOAide
Sodium
¦"tjt-, iadate
^">Ji i i
.i*"ho anadate
bod I u n
metavanacate
VanaduiT
pe itcx'ide
Variady-
sulfate
Vanadium
rSnlDXldi?
?odij~n
¦ iftrv, =naadt6
''Btiad/
-uha^
_>ndlU 11
rieta aiadaty
SiJlll 71
metavaiadate
Dosing Duration
30 wk
^20 d ;28 d tviti 15 ppm
t ler t'i 25 r ti ISO d)
r O1 n n'T
". rion
24 k
All dose
levels
n * n : n
catt'e
rat
cattle
• at
""
rat
--
:et
cattib
rat
^attie
rat
u
not
¦ . " t : :
male
75 d
_50 d
56 WK
reported
lut
'frDC. fe?
nnt
f6j: tec
ISO d 12
tlfc-r ..'it
,5 mon
_50 j
14 ,ii k
d
.in - p
_:3d)
10,
40
C in 40
2, .00
?noo
: 5 r
c _00,
200
: . 25
J..2
0 500,
^000
C, 100,
150
0, 3, 6, 9
C, 100.
200
0, 300
3000
0 100
150
0. 15/25
i1, - _on
0 \r 2
_5
_
. rOO
200.J
Dose
units
DDm V
ppm V
ug V/mt
jg 7 'tr i
p jrr
:prr V
ppm \
mg/kg-d
ppm V
pptr v
ppm V
DDm v
mg V/L
ppm V
mg/kg-d
"
ic VtpL
Reference
Kingrno'-th et m
a _9L>6
Tl .rrcsi.n et a I ,
1984
Eow'oatal
w -
: . " .t _
a ,lOQ2
S<*z carl
I- enteia, 1?S2
= ~ i;
Stefter-eta1 .
J 31
Shah etal. 2015 v
fuourtam etal
xQ'S 3
f.'ojt tair ft al
1952
Pa et a1., 18
Stiffen et ai.
1981
Sl:s-c and
ke~itei3 19SS
Mountain et al,,
_n"
Thrmpior et al..
r»"!a' lC 3 etal.
,q-r
Paietal., 2018 -
: ah Mt al. ioi5 P
2"?
Boecolu et al
Su:-c ard
e t:. ~ .
Route of Exposure:
'. - oral (diet)
81 oral (q3V3q©)
Figure 7. Preliminary summary of multidose chronic animal studies
(continued on following page). Click here to view interactive version, which
includes a more detailed description of study design and results.
This document is a draft for review purposes only and does not constitute Agency policy.
23 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Chemical
Health System Name
3odlum
Tietavanadate
Ammonium
metavanadate
Reproductive
Systemic/Whole
Body
Species Sex Dosing Duration
goat female 130 d
"1OUS0
S odium «*at
^etavanaaate
cattle
Urinary
Route of Exposure:
_ . —
L Ci a! tivater)
Sodium
¦"¦I t,io..anedate
vanadurr
peit?/ide
Vanacr, ¦
sui~ate
SodlJTi
"¦etc'.anaaate
t at
riali- 3 i i-
-- - 24 wk
female l?n d
All dose Dose
levels units
300,
-tins j
103 d
ISO d {23 d ''Vin 15 ipni
t isr 25 D ii 1 18u d i
~ " - '
" -00
20 n
5oo
lom
c _no
150
?pm •
0 10 20 p^rr V
ppm
ppm
? _5'25 L-nrrV
?, 10 40 jc c "ml
Reference
Tnpathi eta!.,
20 IS
Kings,"': -that
Sjs r =ind
kentera 1^5£
: 1 _:
Tnpathi et si.
201S
Staffer et at..
19 SI
L'Wntair et al.
-951
M jjrtair et al.
Thorrps^n et a I
: ; 2
Figure 7 continued.
This document is a draft for review purposes only and does not constitute Agency policy.
24 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Chemical
Health System Name
Annonium
Species Sex
Cardiovascular
Endocrine
Hepatic
netavaoaoate
Sodium
metavanadate
rat
female 35 a
e
Vanadyl sulfate goat
Sodium
metava "i a date
cattle-
Hematologic Sodium rat
metavanadate
cattle
Ammonium rat
metavanadate
Sodium rat
metavanadate
Sodium
catt'e
mouse male
orthovanadate
wanady sulfate mouse male
Route of Exposure:
Dosing All dose Dose
Duration levels units
0, 3,15,
30
0, 5,10,
50
d. non
cattle female 90 d
not
84 d
"e-ah 90 c
female 10 wk
renal e 90 c
female 5 wk
35 d
remale 1C wk
na« 3 mon
~ensl-e 9C c
13 wk
mg V/kg
ppm
0, 2.5,5 ppm V
0,1,2,3 ngV/d
2,5,5 pomV
"0
00
pDm V
1.5,5 ppm V
" ng V \c
7 1C
mglKc
?0
¦f
ICO
0, 5,10,
50
op it V
ppm
0,2,5.5 ppm V
0 ' _l0
'* mq V/L
51 *
10 ng/L
0.10.
Reference
*a io et a!.,
£019
Djmncoetal.,
_985
buriaet aI
2020
Zarqami et a1
2017
Gupta et a I,,
2020
Adacf i e: a
2000
Gupta et al,.
2020
Waic eta I.,
2016
Wa-.c, et al.,
2019
Adachi eo a-,.
2000
Domingo et al.,
1905
G jpta et al.,
2020
ICO, 50..
mq/L
viarma=>taL
.931
V I an et al„
2007
V.ban et al.,
2007
Figure 8. Preliminary summary of multidose subchronic animal studies
(continued on following pages). Click here to view interactive version, which
includes a more detailed description of study design and results.
This document is a draft for review purposes only and does not constitute Agency policy.
25 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Health
System
Immune
Lymphatic
Metabolic
Nervous
Renal
Chemical
Name
Sodium
neto anadate
Sodium
crtho'v anadate
Species Sex
rat finals
male
cattle ^en-le
mouse maie
Vanady sulfate nouse ria'e
Dosing
Duration
10 wk
3 mon
90 G
_3 tVK
j wk
Ail dose
levels
Dose
units
An mon tun-1
metaxanacate
rat
Soaium rat
metavanadate
rattle
Vanady sulfate goat
Sodium rat
metavanacate
femele
naie j mon
;emale 90 c
not
fpp:'t?c
"emalo
rna.e
o4 Li
10 wk
O ,«jIj
Wk
Amnion i urn rat
metavanadate
Sodium rat
metavanadate
cattle female
female 5 weeks
35C
7 : ~ :
Sodium
nouse ma'e
orrhiHciadate
vanadv ^Ifate mouse male
90 d
_3 wk
5 wk
0, t>0, 100 pom V
ppm
ppm V
0, 5, 10,
50
0, 2,5, 5
0,1 10
0._0 100
500. 1000
C, 3,15,
30
0, 5, .J)
50
¦^g v, l.
n-o'L
, U/L
•™>q V,'kg
ppm
0 50,100 rorr
C 4 1 S 2
16.4
0, G 5, 1.0,
mq/xq-d
t:
0. 3, ±5,
30
0. 5 10,
0 1 5 5
0 _0
50
€, 2.10
0, 10,100,
500 1000
y-L
mg V/ka
mg V/kg
com
ppm V
mg 7;L
~g/L
ng/L
Reference
Adach et a ,,
2000
Domingo etal.,
1935
G jfta *t al.
2020
Snarma et al .
19S1
i/il an et al,,
1007
Vil an et at,
2007
\A'ang ft ak.
;ni9
Domingo et al.,
19S5
G jpta et al.,
1:1:
larqami et al,.
201~
Adach et a,
2000
Sa^rnez et a .,
199,5
5 jr et al. 201T
: ! r" -
2016
Wang et el.,
2019
Domingo etal.,
1985
Gupta et al„
2020
5'-at ma et al,,
1981
711 an, et al.,
20u7
ViHan etal.,
2007
Route of Exposure:
J L r ell lUci.tl ,
Figure 8 continued.
This document is a draft for review purposes only and does not constitute Agency policy.
26 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Health
System
Chemical
Name
Species
Reproductive Vanadyl sulfate mouse
Dosing All dose Dose
Sex Duration levels units Reference
VfI arii et al,,
2007
Vilianietal.,
wk
rat
rat
. ^ Amnion mrr
Respiratory
¦Tietavanaaate
Sodium
•Tietavanaaate
. , Ammjniurr
Systemic/ _ , . rat
' metavanadate
Whole Body
Sodium
renale 35
metavanadate
rat
r - _
•s mon
:
10 wk
3 mon
cattle
Sodium
mouse
cithovanadate
vanad> Jtr. ret
Vanady. sulfate mouse
female 50 c
male i3w,k
male 60 o
rrirt'ip ^ -
goat
not
reported
84 d
0, 2. 10 "O/L
0, _0.100.
500.1000
0, 3, 15,
30
0, 5.10,
: .
G. 3.15
::
_
100,
, „ Vvc'io et a1,
-gV/kg £019
Domingo etal.
1985
Wang et ai.,
2019
Adachi et al,,
1000
0,5.10, Doi uncoet al
nir,
50 "r l^S",
C 4 1,3.2, , Sanchez eta..
4 IMS
G jpta et al.
2020
Sharma et al.,
1981
Tubafard etal
2010
Villani et al.,
2007
Villani etal.,
2007
Zarqarni et al.,
2017
ppm
mg V/kg
0. 50,100 pprr
spin
t 5 cpir V
_L
5".
0. 10, 40
.HQ SI, L
^g/Kg
0,2, _C mg/L
0,10, ^00
inn/i
500,1000 -
0,_,2,3 mgv-d
Route of Exposure:
Figure 8 continued.
This document is a draft for review purposes only and does not constitute Agency policy.
27 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Health System
Chemical
Name
Species
Sex
Dosing Duration
All dose
levels
Dose
units
Reference
Cardiovascular
Sodium
metavanadate
rat
both
cO c tFOmaiei -4 3
. - : "
i- lactaticr [FOferra'ei
. . 10,20
mg/kg-d
Domino;. et al.
XiiOO
i
Developmental
Sodium
nets a i a date
rat
both
6C <: FO it,alei 1** d
;r-diT-?t ig + r.estai. ?n
+ lactat'er i FO teira.ei
0. 5,10, 2l
D MM"1 etal.,
1986
¦
GD6-GD14
C 5,1C, 20
trig/kg
Paterncin et a",,
j.9S"
¦
Vanady sjlfate
mouse
both
G l,jd-,l.5
n, ?-, E" ~7C
150
i i-J
¦
Hepatic
Sodium
mete, a uchte
'at
both
6U FO ririli-i, _4d
p ^rrat n t n
+ l--tafrr imfen a m
0, 5,10, 20
mg/kg-d
Domingo etal.,
1986
¦
Vanadyl sulfate
mouse
female
(dam)
c-:m:
0, 37.5, 75,
150
mg/kg-d
Patemain etal.,
1990
¦
Immune
meta' n,ai6,i 14 d
G.dnidti.tj + aeotat.o.i
+ l?ctaticr rF0 tema ei
0, 5. 10, 20
mg/kg-d
Domingo etal.,
1986
¦
Van. , te
mouse
fern a
(dam)
GD6-15
:",5, 75,
150
ma/ka-d
Pate main eta!.,
i qqh
¦
Reproductive
Sodium
metavanadate
rat
both
* 1 a ztctior ! F0 f erra e i
0,5, _r,
¦"no/I* >3 d
Dunmrp et -4 ,
i966
¦
female
(dam)
6D6-GD14
0, 5,10, 20
mg/kg
Patemain et al.,
1987
¦
mouse
male
64 d
0 40
m
Sodium
orrhovanadate
rat
i
mg/mL
3c i_ j'i et al,,
1994a
Respiratory
Systemic/
Whole Body
•f 0 p-| ^ | Q
Vanadyl sulfate mouse , " G[
^dani
r> n q ?t;
_50
ig/Kg-c
Sodium
netdvanadate
Sodium
metavanadate
GO d ra.el, _4 1
rat both p'eti at ni cestat :n 0 5 10, 20 mg/kg-d
+ iaetaticr iFOtema si
P^tanain etal.,
_99 )
Domingo etal.,
1986
nouse male 64 d
0,20,40, ,, . Llobetetal.,
60., 80 m9/k9'd 1993
Route of Exposure;
iitai tga^ga)
¦ oral (water)
Figure 9. Preliminary summary of multidose reproductive and developmental
animal studies. Click here to view interactive version, which includes a more
detailed description of study design and results.
This document is a draft for review purposes only and does not constitute Agency policy.
28 DRAFT-DO NOT CITE OR QUOTE
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
IRIS Assessment Plan for Vanadium Compounds
Studies in progress by the National Toxicology Program: The interim results of NTP's
extended developmental study in rats and 13-week study in mice (currently available as a poster,9
with complete results expected to be published in 2020) were also considered for problem
formulation, as these studies were conducted by NTP following nomination by the EPA and
National Institute of Environmental Health Sciences and are intended to address data gaps related
to the oral toxicity of pentavalent and tetravalent vanadium compounds.10
In the developmental study, rat F1 offspring were initially exposed in utero and via breast
milk, and then continued to receive the same dose levels as their mothers via drinking water for 13
weeks following weaning. Moribundity of F0 dams was observed during parturition and lactation
in the 250 and 500 mg/L sodium metavanadate dose groups, with decreased maternal body
weights in proportion to dose. F1 pups exposed to sodium metavanadate had decreased survival
from postnatal days 1-10 in the 500 mg/L dose group, and F1 body weights at the end of the study
were found to be decreased in males at doses >125 mg/L and in females in the 500 mg/L dose
group. Conversely, no impacts on F0 or F1 survival or body weight were observed in rats exposed
to vanadyl sulfate. Analysis of total vanadium concentrations in plasma and urine of a subset of F1
rats at the end of the exposure period in the developmental study indicated higher absorption of
sodium metavanadate compared to vanadyl sulfate when consuming similar levels of vanadium,
which may explain the differential toxicity between these two compounds. The analysis of clinical
pathology, organ weight, and histopathology data from the developmental study is still ongoing.
Similarly, NTP's 13-week study in mice observed toxicity following exposure to sodium
metavanadate but not vanadyl sulfate. Mice exposed to sodium metavanadate had decreased body
weights (observed at doses of 500 mg/L in males and at 250 and 500 mg/L in females), decreased
thymus weights (observed at doses of 250 mg/L in males and 500 mg/L in females), increased
erythrocytes and reticulocytes (observed at 500 mg/L in males and females), and small decreases
in hematocrit and hemoglobin.
Comparison with studies used in the 1987 IRIS assessment: As described earlier in this
document, the 1987 IRIS RfD for vanadium pentoxide was based on a chronic (lifetime) NOAEL of
10 ppm vanadium for decreased hair cystine levels from the study in rats by Stokinger et al. (19531.
Decreased hair cystine content is a biomarker that has been associated with certain pathological
conditions in rodents and humans (Mountain et al.. 19531 but has limited interpretation with
respect to adversity and biological significance. For comparative purposes to provide an overview
of chronic health effects data that has become available since the 1987 IRIS vanadium health effects
assessment, Table 5 summarizes the study designs and NOELs/LOELs (reflecting only author-
reported statistical significance) in the chronic animal studies from the current literature inventory
that tested multiple dose levels of vanadium and which were not included in the 1987 IRIS
9https://ntp.niehs.nih.gov/ntp/resuIts/pubs/posters/roberts sot20190300.pdf.
10https://ntp. niehs.nih.gov/ getinvolved/nominate/summary/nm-
n20806.htm]?utm source=direct&utm medium=prod&utm campaign=ntpgoIinks&utm term=nm-n20806.
This document is a draft for review purposes only and does not constitute Agency policy.
29 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
1 assessment. Dose levels in this table are expressed as elemental vanadium to allow for comparison
2 across compounds. The author-reported NOELs in these studies ranged from 1 to 100 ppm
3 vanadium in drinking water and 3 to 6 ppm in diet. The author-reported LOELs ranged from 1 to
4 200 ppm vanadium in drinking water, 6 to 125.3 ppm vanadium in diet, and 0.078 mg/kg-day via
5 oral gavage.
6 Summary: The literature inventory includes a range of study designs and outcomes that are
7 potentially useful for hazard identification and/or dose-response analysis for vanadium and
8 compounds. Based on this preliminary literature survey, EPA anticipates conducting a systematic
9 review for any health effects associated with oral exposure to vanadium and compounds.
This document is a draft for review purposes only and does not constitute Agency policy.
30 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Table 5. Summary of NOELs and LOELs from all multidose chronic animal studies that were not included in the
1987 IRIS health effects assessment of vanadium, with doses expressed as to (A) parts-per-million (ppm)
vanadium or (B) mg/kg-day vanadium. NOELs and LOELs are based on author-reported statistical significance. Results
(bolded) from Stokinger et al. 1953 (used to derive the 1987 IRIS RfD) are shown for reference. Studies are ordered from
lowest to highest LOEL, followed by lowest to highest NOEL for studies that observed no effects within the tested dose
range.
A.
Reference3
Chemical name
Route
Species (Strain)
NOEL (ppm
vanadium)b
LOEL (ppm
vanadium)b
Effects summary at LOEL
Boscolo et al. (1994)°
Sodium
metavanadate
Drinking
water
Rat (Sprague-Dawley)
1
Increased systolic and diastolic blood
pressure, decreased plasma aldosterone,
decreased urinary kallikrein, decreased
urinary calcium. (Increased plasma renin
activity and increased urinary kininase 1 and II
observed at 10 ppm vanadium.)
Pal et al. (20181c
Sodium
metavanadate
Diet
Cattle (Karan Fries
[Tharparkarx Holstein
Friesian] crossbred
calves)
3
6
Increased insulin-like growth factor,
increased total triiodothyronine (T3),
increased total thyroxin (T4), increased bone
alkaline phosphatase, decreased bone
protein tyrosine phosphatase
Carmignani et al.
(1992)°
Sodium
metavanadate
Drinking
water
Rat (Sprague-Dawley)
10
Increased plasma renin activity, plasma
aldosterone, aortic blood pressure; urine
parameters (increased kallikrein levels,
kininase 1 and II levels, enkephalinase levels)
Mravcova et al.
(1993)c
Vanadium
pentoxide
Drinking
water
Rat (Wistar)
1
10
Increased spleen weight, decreased
phagocytosis
Stokinaer et al.
(19531c
Vanadium
pentoxide
Diet
Rat
10
100
Decreased hair cystine
Susie and Kentera
(19881d
Sodium
metavanadate
Diet
Rat (Long-Evans)
'
125.3
Decreased body weight, decreased cardiac
output, increased total peripheral resistance.
(Increased hematocrit and decreased plasma,
This document is a draft for review purposes only and does not constitute Agency policy.
31 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan for Vanadium Compounds
Reference3
Chemical name
Route
Species (Strain)
NOEL (ppm
vanadium)b
LOEL (ppm
vanadium)b
Effects summary at LOEL
blood and extracellular fluid volume
observed at 1253 ppm vanadium.)
Steffen et al. (1981)c
Sodium
orthovanadate
Drinking
water
Rat (Sprague-Dawley)
—
100
Increased systolic blood pressure, increased
relative heart weight. (Decreased body
weight gain at 200 ppm vanadium.)
Tripathi etal. (2018)c
Sodium
metavanadate
Diet
Goat (Alpine x Beetal
and Saanen x Beetal)
6
-
No change in final body weight, food intake,
milk yield, or milk composition
Kingsnorth et al.
(1986)c
Ammonium
metavanadate
Drinking
water
Mouse (CD-I)
20
-
No change in or survival or body weight gain
aCarmignani et al, (1992) was published in a book containing proceedings of the 31st Congress of the EUROTOX. All other studies were published in peer-
reviewed journals.
bl ppm = 1 mg/kg diet or 1 mg/L drinking water.
1 cStudies by Boscolo et al. (19941, Pal et al. (2018). Carmignani et al. (1992), Mravcova et al. (1993), Stokinger et al. (1953), Steffen et al. (1981), Tripathi et al.
2 (2018), and Kingsnorth et al. (1986) were interpreted as reporting dose levels for vanadium compounds in terms of elemental vanadium. Doses shown in this
3 table are those reported by the authors.
4 dSusic and Keiitera (1988) reported a LOEL of 300 ppm NaVOs. This was converted to elemental vanadium using the following molecular weight conversion:
5 LOEL V = LOEL NaVOs x V molar mass/NaVOs M.W. = 300 ppm NaVOs x 50.942 g V/mol/121.928 g NaVOs/mol = 125.3 ppm V
B.
Reference3
Chemical
name
Route
Species (Strain)
NOEL
(mg/kg-day
vanadium)
LOEL
(mg/kg-day
vanadium)
Effects summary at LOEL
Shah et al. (2016)e
Vanadyl sulfate
Gavage
Rat
0.078
Increased serum triglycerides, increased total
cholesterol, increased LDL-c, increased
VLDL-c, decreased HDL-c, decreased plasma
glucose, decreased serum insulin
6 'Shah et al. (2016) reported a LOEL of 0.25 mg VOSOVkg-day. This was converted to elemental vanadium using the following molecular weight conversion:
7 LOEL V = LOEL VOS04 x V molar mass/V0S04 M.W. = 0.25 mg VOS04/kg-day x 50.942 g V/mol/163 g VOS04/mol = 0.078 mg V/kg-day
This document is a draft for review purposes only and does not constitute Agency policy.
32 DRAFT-DO NOT CITE OR QUOTE
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
IRIS Assessment Plan for Vanadium Compounds
2.5. KEY SCIENCE ISSUES
Based on the preliminary literature survey, the following key scientific issues were
identified that warrant evaluation in this assessment.
• Kev science issue #1: Consideration of potential toxicity and toxicokinetic differences
across vanadium compounds. Differential absorption has been observed across inorganic
vanadium compounds. For instance, as described earlier in this document, studies in
progress by NTP preliminarily report that drinking water exposure to sodium
metavanadate (+5) in rats led to higher levels of vanadium in plasma and urine as compared
to vanadyl sulfate (+4) at similar vanadium exposure levels. This is consistent with reports
that vanadate (+5) is absorbed more readily in the gastrointestinal tract compared to
vanadyl (+4) (Trevino etal, 2019: Nielsen. 19951. Absorption may be correlated with
toxicity, as the effects observed by NTP were more pronounced following exposure to
sodium metavanadate compared to vanadyl sulfate. To address these apparent differences,
in addition to more fully characterizing the toxicokinetic differences across compounds
(including potential interconversion within the body), EPA plans to conduct separate
toxicity evaluations for different vanadium compounds where the evidence supports such
an analysis.
• Kev science issue #2: Consideration of vanadium speciation. Available information
indicates that vanadium in solution can readily interconvert between oxidation states and
will form different spectrums of species as a function of factors including pH, concentration,
and redox potential. For instance, tetravalent vanadium in drinking water is stable at acidic
pH but can convert to pentavalent species at neutral or basic pH fMutlu et al, 20171. Given
the apparent toxicokinetic (and, likely, toxicity) differences across vanadium compounds
(see Key Science Issue #1), study evaluations will, to the extent possible, consider factors
that could affect vanadium oxidation state and speciation in the available toxicity studies.
Speciation of vanadium at low environmental concentrations will also be of particular
interest
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1 3. OVERALL OBJECTIVE, SPECIFIC AIMS, AND
2 DRAFT POPULATIONS, EXPOSURES,
s COMPARATORS, AND OUTCOMES (PECO)
4 CRITERIA
5 The overall objectives of this assessment are to identify adverse human health effects of
6 exposure to vanadium and compounds and characterize exposure-response relationships for these
7 effects to support development of toxicity values. The evaluation conducted in this assessment will
8 utilize EPA guidance.11 The systematic review protocol will be disseminated after review of the
9 draft assessment plan and will reflect changes made to the specific aims, key science issues, and
10 PECO in response to public input. The systematic review protocol will also provide specific details
11 on the methods that will be used to carry out the specific aims outlined below.
12 3.1. SPECIFIC AIMS
13 • Identify epidemiological (i.e., human) and toxicological (i.e., experimental animal) literature
14 reporting effects of exposure to vanadium compounds as outlined in the PECO, and
15 inventory literature that is potentially relevant to the specific aims (e.g. toxicokinetic,
16 mechanistic). The AT SDR Toxicological Profile for Vanadium fATSDR. 2012] will serve as
17 the starting point for the literature search because it is the most recent and comprehensive
18 review of health effects of vanadium and compounds published by a US federal government
19 agency. Database searches will be conducted to identify records that had been published
20 since the literature was last searched for the 2012 ATSDR Toxicological Profile for
21 Vanadium.
22 • Conduct study evaluations (risk of bias and sensitivity) for individual epidemiological and
23 toxicological studies and (if identified in future literature searches) PBPK models.
24 • Extract data on relevant health outcomes from epidemiological and toxicological studies
25 included based on the study evaluation (full data extraction of low confidence studies may
26 not be performed for poorly studied health effects or for health effects on which extensive
27 medium and high confidence studies exist in the evidence base).
28 • Review and incorporate the available toxicokinetic and mechanistic information, as
29 warranted to support assessment decisions. The toxicokinetic analyses will focus primarily
nThe EPA guidelines have been developed over time and address the state of the science at the time they
were developed. Thus, evaluation methods may be updated as new science emerges, or when existing
guidelines are updated. EPA guidance documents can be found at: http: //www.epa.gov/iris/basic-
information-about-integrated-risk-information-svstem#guidance/
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IRIS Assessment Plan for Vanadium Compounds
1 on the key science issues identified in Section 2.5. The scope of the analysis of mechanistic
2 information will be determined by the complexity and confidence in the phenotypic
3 evidence in humans and animals, the likelihood of the analyses to affect evidence synthesis
4 conclusions for human health, and the directness or relevance of the available model
5 systems for understanding potential human health hazards.
6 • For each evidence stream (i.e., studies in humans, animal studies, and mechanistic or other
7 supplemental studies, as appropriate and depending on data availability), synthesize the
8 evidence across studies, assessing similar health outcomes using a narrative approach.
9 • For each health outcome, determine the strength of the evidence within and across evidence
10 streams to draw evidence integration judgments about the potential for vanadium and
11 compounds exposure to be hazardous to humans. Identify and discuss issues concerning
12 potentially susceptible populations and life stages.
13 • Derive oral toxicity values (e.g., reference doses [RfDs], cancer risk estimates for oral
14 exposure) as supported by the available data.
15 • Characterize uncertainties and identify key data gaps and research needs, such as
16 limitations of the evidence base, limitations of the systematic review, and consideration of
17 dose relevance and pharmacokinetic differences when extrapolating findings from higher
18 dose animal studies to lower levels of human exposure.
19 3.2. DRAFT PECO CRITERIA
20 The PECO is used to identify the evidence that addresses the specific aims of the assessment
21 as well as to focus the search terms and inclusion/exclusion criteria in a systematic review. The
22 draft PECO for vanadium and compounds (Table 6) was based on (1) nomination of the chemicals
23 for assessment, (2) discussions with scientists in the Office of Water to determine the scope of the
24 assessment that will best meet Agency needs, and (3) preliminary review of the health effects
25 literature for vanadium and compounds to identify the health hazards potentially associated with
26 oral exposure to vanadium and compounds and key areas of scientific complexity.
Table 6. Draft populations, exposures, comparators, outcomes (PECO) criteria
for the vanadium compounds assessment
PECO element
Evidence
Populations
Human: Anv population and lifestage (occupational or general population, including children,
women of childbearing age, and other sensitive populations).
Animal: Nonhuman mammalian animal species (whole organism) of anv lifestage (including
preconception, in utero, lactation, peripubertal, and adult stages).
Exposures
Relevant forms: Any form of vanadium. The focus will be on soluble inorganic vanadium
compounds that are relevant for environmental exposures, including the vanadium compounds
shown in Table 1 (e.g.,vanadyl sulfate, sodium metavanadate, sodium orthovanadate,
ammonium metavanadate, vanadium pentoxide). Studies of organic anthropogenic vanadium
compounds that are synthesized for pharmacologic uses [e.g., bis(maltolato)oxyvanadium (VI)],
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PECO element
Evidence
vanadium nanomaterials, and vanadium alloys that otherwise meet PECO criteria will be tracked
through full text screening for evidence mapping purposes and tagged as "potentially relevant
supplemental information," but a full systematic review will not be performed for these
compounds and they will not be considered for reference value derivation.
Human: Any exposure to vanadium compound(s) via the oral route, including exposure via
breastmilk. Studies will also be included if biomarkers of vanadium exposure are evaluated (e.g.,
measured vanadium levels in tissues or bodily fluids) but the exposure route is unclear. Other
exposure routes, including inhalation, will be tagged as "potentially relevant supplemental
information."
Animal: Anv exposure to vanadium compound(s) via the oral route, including exposure via
breastmilk. Studies involving exposures to mixtures will be included only if they include an arm
with exposure to vanadium compound(s) alone; otherwise, they will be tagged as potentially
relevant supplemental material. Other exposure routes, including inhalation, dermal, or
injection, will be tagged as "potentially relevant supplemental information."
Comparators
Human: A comparison or referent population exposed to lower levels (or no exposure/exposure
below detection limits), or exposure for shorter periods of time, or cases versus controls.
However, worker surveillance studies are considered to meet PECO criteria even if no referent
group is presented. Case reports describing findings in 1- 3 people in non-occupational or
occupational settings will be tagged as "potentially relevant supplemental information."
Animal: A concurrent control group exposed to vehicle-onlv treatment or untreated control.
Outcomes
All health outcomes (both cancer and noncancer).
PK/PBPK
models
Studies describing pharmacokinetic (PK) or physiologically based pharmacokinetic (PBPK) models
for any form of vanadium will be included.
Classical Pharmacokinetic (PK) or Dosimetry Model Studies: Classical PK or dosimetry modeling
usually divides the body into just one or two compartments, which are not specified by
physiology, where movement of a chemical into, between, and out of the compartments is
quantified empirically by fitting model parameters to ADME data. This category is for papers
that provide detailed descriptions of PK models, that are not a PBPK model.
Note: ADME studies often report classical PK parameters, such as bioavailability (fraction of an
oral dose absorbed), volume of distribution, clearance rate, and/or half-life or half-lives. If a
paper only provides such results in tables with minimal description of the underlying model or
software (i.e., uses standard PK software without elaboration), including "non-compartmental
analysis," it should only be listed as a supplemental material ADME study.
Physiologically-based Pharmacokinetic (PBPK) or Mechanistic Dosimetry Model Studies: PBPK
models represent the body as various compartments (e.g., liver, lung, slowly perfused tissue,
richly perfused tissue) in order to quantify the movement of chemicals or particles into and out
of the body (compartments) by defined routes of exposure, metabolism and elimination, and
thereby estimate concentrations in blood or target tissues.
1
2 In addition to the PECO criteria, studies containing supplemental material that are also
3 potentially relevant to the specific aims will be tracked during the literature screening process.
4 Table 7 presents major categories of supplemental material. The criteria are utilized to tag studies
5 during screening and to prioritize studies for consideration in the assessment based on likelihood
6 to impact assessment conclusions.
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It is important to emphasize that being tagged as supplemental material does not mean the
study is excluded from consideration in the assessment. The initial screening level distinctions
between a study meeting the PECO criteria and a supplemental study are often made for practical
reasons and the tagging structure in Table 7 is designed to ensure the supplemental studies are
categorized for easy retrieval during the course of developing the assessment Studies that meet
the PECO criteria are those that are most likely to be used to derive toxicity values and will thus
undergo individual level study evaluation and data extraction, as described in the protocol. For
evidence-rich topics this is most likely to be animal and epidemiological evidence. For most IRIS
assessments, identifying all available pharmacokinetic models is also considered critical and thus
those are generally included in the PECO criteria. In contrast, the impact on the assessment
conclusions of individual studies tagged as supporting material is often difficult to assess during the
screening phase of the assessment Studies tagged as supplemental may (1) become critical to the
interpretation of other evidence at the level of needing individual level study evaluation (e.g.,
genotoxicity studies when conducting a cancer MOA analysis is needed); (2) may be a single study
that contributes to a well-accepted scientific conclusion and does not need to be evaluated and
summarized at the individual study level (e.g., dioxin as an aromatic hydrocarbon receptor (AhR)
agonist); (3) provide key references for preparing certain sections in an IRIS assessment (e.g.,
background information on sources, production, or use; overview of toxicokinetics); or (4) provide
context for the decision to conduct the assessment or for the assessment conclusions (e.g.,
information on pathways and levels of exposure).
Table 7. Major categories of "Potentially Relevant Supplemental Material"
Category
Evidence
Mechanistic studies
Studies reporting measurements related to a health outcome that inform the
biological or chemical events associated with phenotypic effects, in both mammalian
and non-mammalian model systems, including in vitro, in vivo (by various routes of
exposure), ex vivo, and in silico studies.
Non-mammalian model
systems
Studies in non-mammalian model systems, e.g., fish, birds, C. elegans.
Non-oral route of
administration
Studies in which humans or animals (whole organism) were exposed via a non-oral
route (e.g., inhalation, injection, dermal exposure).
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Category
Evidence
ADME and toxicokinetic
Studies designed to capture information regarding absorption, distribution,
metabolism, and excretion, including toxicokinetic studies. These are primarily
controlled experiments, where defined exposures usually occur by intravenous, oral,
inhalation, or dermal routes, and the concentration of particles, a chemical, or its
metabolites in blood or serum, other body tissues, or excreta are then measured.
Such information may be helpful in deriving chemical-specific factors for animal-to-
human extrapolation and for updating or revising the parameters used in existing
PBPK models.
*Studies describing environmental fate and transport or metabolism in bacteria or
model systems not applicable to humans or animals should not be tagged.
Exposure characteristics
(no health outcome
assessment)
Exposure characteristic studies include data that are unrelated to toxicological
endpoints, but which provide information on exposure sources or measurement
properties of the environmental agent (e.g., demonstrate a biomarker of exposure).
Mixture studies
Mixture studies that are not considered PECO-relevant because they do not contain
an exposure or treatment group assessing only the chemical of interest.
Case reports
Case reports describing health outcomes after exposure will be tracked as potentially
relevant supplemental information when the number of subjects is <3.
Records with no original
data
Records that do not contain original data, such as other agency assessments,
informative scientific literature reviews, editorials or commentaries.
Conference
abstracts/abstract only
Records that do not contain sufficient documentation to support study evaluation
and data extraction.
Organic anthropogenic
vanadium compounds,
nanomaterials, and alloys
Studies of organic anthropogenic vanadium compounds, nanomaterials, and alloys
that otherwise meet PECO criteria. These studies were tracked through full text
screening for evidence mapping purposes, but a full systematic review will not be
performed for these compounds and they will not be considered for reference value
derivation.
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pentoxide (CASRN 7440-62-2 and others): Derivation of subchronic and chronic oral
RfDs [EPA Report]. (EPA/690/R-09/070F). Cincinnati, OH.
WattMliJjutrlLe^
il. KV: Rose. NL: Turner. SD: Spears. BM. (2018). Vanadium: A Re-Emerging
Environmental Hazard. Environ Sci Technol 52: 11973-11974.
httpi//dx.doi.o tcs.est,8b05560
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
APPENDIX A. SURVEY OF EXISTING VANADIUM
TOXICITY VALUES
1 Table A-l lists websites which were searched for relevant human health reference values
2 for vanadium and compounds, along with indications of the results of the search. In addition to
3 these sources, the ToxVal database on the Chemicals Dashboard
4 (https://comptox.epa.gov/dashboard/chemical_lists/T0XVAL_V5) was also searched for both
5 reference values and potential points of departure (PODs) for development of values. When values
6 were identified for vanadium, they are shown in Figure 2 and described in Table 2 if details were
7 provided on how the values were derived. When values were identified from sources that did not
8 provide derivation details, they are described in Table 3. The values in these tables are current as
9 of May 2020.
Table A-l. Sources searched for human health reference values for vanadium
Source3
Search results
Query and/or link
ATSDR
See Table 2
http://www.atsdr.cdc.gov/toxprofiles/index.asp
https://www.atsdr.cdc.gov/mrls/mrllist.asp
CalEPA
No values found
http://www.oehha.ca.gov/tcdb/index.asp
https://www.arb.ca.gov/toxics/healthval/healthval.htm
DWSHA
No values found
https://www.epa.gov/sites/production/files/2018-
03/documents/dwtable2018.pdf
Health Canada
No values found
https://www.canada.ca/en/services/health/publications/healthv-living.html
http://publications.gc.ca/site/archivee-
archived.html?url=http://publications.gc.ca/collections/collection 2012/sc-
hc/H 128-l-ll-638-eng.pdf
http://publications.gc.ca/site/archivee-
archived.html?url=http://publications.gc.ca/collections/Collection/H46-2-96-
194E.pdf
HEAST
See Table 2
http://epa-heast.ornl.gov/heast.php
https://nepis.epa.gov/Exe/ZvPDF.cgi/200000GZ. PDF?Dockev=200000GZ. PDF
IRIS
See Table 2
http://www.epa.gov/iris/
ITER
2 records
found; no
unique values
https://toxnet.nlm.nih.gov/newtoxnet/iter.htm
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Source3
Search results
Query and/or link
MlEGLE
PPRTV value
was adopted as
state value (see
Table 2)
https://www.michigan.gov/documents/dea/dea-rrd-chem-
CleanupCriteriaTSD 527410 7.pdf
MDH
No values found
https://www.health.state.mn. us/communities/environment/risk/guidance/g
w/table.html
NHMRC
No values found
https://www.nhmrc.gov.au/about-us/publications/australian-drinking-water-
guidelines
NY DEC
No values found
https://www.dec.nv.gov/docs/remediation hudson pdf/techsuppdoc.pdf
OPP
No search
results found
https://iaspub.epa.gov/apex/pesticides/f?p=chemicalsearch:l
PPRTV
See Table 2
https://www.epa.gov/pprtv/provisional-peer-reviewed-toxicitv-values-pprtvs-
assessments
RIVM
See Table 2
https://www.rivm.nl/bibliotheek/rapporten/711701092.pdf
No values found
https://www.rivm.nl/bibliotheek/rapporten/711701025.pdf
TCEQ
See Table 3
https://www.tcea.texas.gov/remediation/trrp/trrppcls.html
WHO
Environmental
Health Criteria
document
available; no
reference
values found
http://www.who.int/ipcs/publications/ehc/en/
aATSDR = Agency for Toxic Substances and Disease Registry; CalEPA = California Environmental Protection Agency;
DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IRIS = Integrated Risk Information System; ITER = International Toxicity Estimates for Risk; MDH = Minnesota
Department of Health; Ml EGLE = Michigan Department of Environment, Great Lakes & Energy; NHMRC = National
Health and Medical Research Council; NY DEC = New York State Department of Environmental Conservation;
OPP = Office of Pesticide Programs; PPRTV = Provisional Peer-Reviewed Toxicity Values; RIVM = Rijksinstituut voor
Volksgezondheid en Milieu, The Netherlands Institute for Public Health and the Environment; TCEQ = Texas
Commission on Environmental Quality; WHO = World Health Organization.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
APPENDIX B. LITERATURE SEARCH STRATEGIES
Table B-l. Literature search strategies for vanadium compounds
Source
Search strategy
Number of
records
ATSDR
Toxicological
Profile for
Vanadium (2012)
References pulled from ATSDR document
363
WOS
3/28/2019
3/9/2020
((TS="Ammonium metavanadate" ORTS="Ammonium monovanadate" OR
TS="Ammonium trioxovanadate" ORTS="Monosodium trioxovanadate" OR
TS="Oxosulfatovanadium pentahydrate" ORTS="Sodium metavanadate" OR
TS="Sodium o-vanadate" ORTS="Sodium orthovanadate" ORTS="Sodium
pervanadate" ORTS="Sodium tetraoxovanadate" ORTS="Sodium
trioxovanadate" ORTS="Sodium vanadate" ORTS="Trisodium
orthovanadate" ORTS="Trisodium tetraoxovanadate" ORTS="Trisodium
vanadate" OR TS="Vanadic sulfate" OR TS="vanadium" OR TS="Vanadyl
sulfate" ORTS="Vanadic" OR TS="Vanadin" ORTS="sodium peroxyvanadate"
ORTS="Vanadyl sulfate pentahydrate" OR TS="Ammonium vanadate" OR
TS="Divanadium trioxide" ORTS="Sodium hexavanadate") AND PY=(2010-
2019))
((TS="Sodium tetravanadate" ORTS="Sodium vanadite" ORTS="Sulfovanadic
acid" ORTS="vanadium salt" ORTS="Tetrachlorovanadium" OR
TS="Trichlorooxo vanadium" OR TS="Trichlorooxovanadium" OR
TS="Trichlorooxovanadium oxide" OR TS="Vanadic acid" OR TS="Vanadic
oxide" OR TS="Vanadious" OR TS="Vanadosulfuric acid" OR TS="Vanadyl
chloride" OR TS="Vanadyl trichloride" OR TS="Divanadium pentaoxide" OR
TS="Divanadium pentoxide" OR TS="Vanadic acid anhydride" OR
TS="Vanadic anhydride" OR TS="Vanadin(V) oxide" OR TS="Vanadium dust"
OR TS="Vanadium fume" OR TS="Vanadium oxide" OR TS="Vanadium
pentaoxide" ORTS="Vanadium pentoxide") AND PY=(2010-2019))
((TS="Vanadium" AND (TS="chloride" ORTS="dichloride" ORTS="oxide" OR
TS="oxychloride" ORTS="oxytrichloride" ORTS="sesquioxide" OR
TS="sulfate" ORTS="sulphate" ORTS="tetrachloride" ORTS="trichloride" OR
TS="trioxide")) AND PY=2010-2019)
24,878
PUBMED
3/28/2019
3/9/2020
«(7440-62-2[rn] OR 00J9J9XKDE[rn] OR 27774-13-6[rn] OR 6DU9Y533FA[rn]
OR 13718-26-8[rn] OR 13721-39-6[rn] OR 7803-55-6[rn] OR FL85PX638G[rn]
OR 12439-96-2[rn] OR "Ammonium metavanadate"[tw] OR "Ammonium
monovanadate"[tw] OR "Ammonium trioxovanadate"[tw] OR "Monosodium
trioxovanadate"[tw] OR "Oxosulfatovanadium pentahydrate"[tw] OR
"Sodium metavanadate"[tw] OR "Sodium o-vanadate"[tw] OR "Sodium
orthovanadate"[tw] OR "Sodium pervanadate"[tw] OR "Sodium
tetraoxovanadate"[tw] OR "Sodium trioxovanadate"[tw] OR "Sodium
4,888
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IRIS Assessment Plan for Vanadium Compounds
Source
Search strategy
Number of
records
vanadate"[tw] OR "Trisodium orthovanadate"[tw] OR "Trisodium
tetraoxovanadate"[tw] OR "Trisodium vanadate"[tw] OR "Vanadic
sulfate"[tw] OR vanadium[tw] OR "Vanadyl sulfate"[tw] OR Vanadic[tw] OR
Vanadin[tw] OR "sodium peroxyvanadate"[tw] OR "Vanadyl sulfate
pentahydrate"[tw] OR 16785-81-2[rn] OR 12436-28-l[rn] OR 12058-74-l[rn]
OR 64082-34-4[rn] OR 10580-52-6[rn] OR 7718-98-l[rn] OR 1314-34-7[rn]
OR 7632-51-l[rn] OR 11115-67-6[rn] OR 7727-18-6[rn] OR "Ammonium
vanadate"[tw] OR "Divanadium trioxide"[tw] OR "Sodium hexavanadate"[tw]
OR "Sodium tetravanadate"[tw] OR "Sodium vanadite"[tw] OR "Sulfovanadic
acid"[tw] OR "vanadium salt"[tw] OR Tetrachlorovanadium[tw] OR
"Trichlorooxo vanadium"[tw] ORTrichlorooxovanadium[tw] OR
"Trichlorooxovanadium oxide"[tw] OR "Vanadic acid"[tw] OR "Vanadic
oxide"[tw] OR Vanadious[tw] OR "Vanadosulfuric acid"[tw] OR "Vanadyl
chloride"[tw] OR "Vanadyl trichloride"[tw] OR 1314-62-l[rn] OR
"Divanadium pentaoxide"[tw] OR "Divanadium pentoxide"[tw] OR "Vanadic
acid anhydride"[tw] OR "Vanadic anhydride"[tw] OR "Vanadin(V) oxide"[tw]
OR "Vanadium dust"[tw] OR "Vanadium fume"[tw] OR "Vanadium oxide"[tw]
OR "Vanadium pentaoxide"[tw] OR "Vanadium pentoxide"[tw]) OR
(Vanadium[tw] AND (chloride[tw] OR dichloride[tw] OR oxide[tw] OR
oxychloride[tw] OR oxytrichloride[tw] OR sesquioxide[tw] OR sulfate[tw] OR
sulphate[tw] OR tetrachloride[tw] OR trichloride[tw] OR trioxide[tw]))) AND
("2010"[PDAT] : "3000"[PDAT]))
TOXLINE
3/28/2019
@SYN0+@AND+@OR+(@TERM+@rn+7440-62-2+@TERM+@rn+27774-13-
6+@TERM+@rn+13718-26-8+@TERM+@rn+13721-39-
6+@TERM+@rn+7803-55-6+@TERM+@rn+12439-96-
2+@TERM+@rn+16785-81-2+@TERM+@rn+12436-28-
l+@TERM+@rn+12058-74-l+@TERM+@rn+64082-34-
4+@TERM+@rn+10580-52-6+@TERM+@rn+7718-98-l+@TERM+@rn+1314-
34-7+@TERM+@rn+7632-51-l+@TERM+@rn+11115-67-
6+@TE RM+@rn+7727-18-6+@TERM+@rn+1314-62-
l)+@RANGE+yr+2010+2019+@NOT+@org+pubmed+pubdart+nih
@SYNO+@AND+@OR+(FL85PX638G+6DU9Y533FA+OOJ9J9XKDE+"Ammoniu
m+metavanadate"+"Ammonium+monovanadate"+"Ammonium+trioxovanad
ate"+"Monosodium+trioxovanadate"+"Oxosulfatovanadium+pentahydrate"+
"Sodium+metavanadate"+"Sodium+o-
vanadate"+"Sodium+orthovanadate"+"Sodium+pervanadate"+"Sodium+tetr
aoxovanadate"+"Sodium+trioxovanadate"+"Sodium+vanadate"+"Trisodium+
orthovanadate"+"Trisodium+tetraoxovanadate"+"Trisodium+vanadate"+"Va
nadic+sulfate"+vanadium+"Vanadyl+sulfate"+Vanadic+Vanadin+"sodium+pe
roxyvanadate"+"Vanadyl+sulfate+pentahydrate"+"Ammonium+vanadate"+"
Divanadium+trioxide"+"Sodium+hexavanadate"+"Sodium+tetravanadate"+"
Sodium+vanadite"+"Sulfovanadic+acid"+"vanadium+salt"+"Trichlorooxo+van
adium"+Tetrachlorovanadium+Trichlorooxovanadium+"Trichlorooxovanadiu
m+oxide"+"Vanadic+acid"+"Vanadium+dust"+"Vanadium+fume"+"Vanadiu
m+oxide"+"Vanadium+pentaoxide"+"Vanadium+pentoxide"+"Vanadic+oxide
"+Vanadious+"Vanadosulfuric+acid"+"Vanadyl+chloride"+"Vanadyl+trichlori
de"+"Divanadium+pentaoxide"+"Divanadium+pentoxide"+"Vanadic+acid+an
15
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
Source
Search strategy
Number of
records
hydride"+"Vanadic+anhydride"+"Vanadin+V+oxide")+@RANGE+yr+2010+20
19+@NOT+@org+pubmed+pubdart+nih
@SYNO+@AND+vanadium+@OR+(chloride+dichloride+oxide+oxychloride+o
xytrichloride+sesquioxide+sulfate+sulphate+tetrachloride+trichloride+trioxid
e)+@RANGE+yr+2010+2019+@NOT+@org+pubmed+pubdart+nih
TOTAL
25,988 unique items were discovered using this search strategy.
25,988
This document is a draft for review purposes only and does not constitute Agency policy.
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
IRIS Assessment Plan for Vanadium Compounds
APPENDIX C. LITERATURE SEARCH AND
SCREENING METHODS
All references were pulled from the 2012 ATSDR Toxicological Profile for Vanadium, and
database searches were conducted to identify records that had been published since the release of
the ATSDR document. The databases listed below were searched for records published between
2010-2020. 2010 was selected as the start date as a precaution to capture records published near
the last literature search date for the citations in the ATSDR document
• PubMed (National Library of Medicine)
• Web of Science (Thomson Reuters)
• ToxLine (National Library of Medicine)
The literature search was conducted by an EPA information specialist on March 28, 2019,
and an update to the database searches was performed on March 9, 2020. All records were stored
in the HERO database. Because the number of records retrieved was large, records were imported
into SWIFT Review software (https://www.sciome.com/swift-review/; see also (Howard etal..
2016)) to identify those most likely applicable to human health. In brief, SWIFT Review has pre-set
literature search filters that were developed by information specialists that can be applied to
separate studies that may present a health outcome from those that likely do not (e.g., exposure
only, analytical methods). The filters function like a typical search strategy, where studies are
tagged as belonging to a certain category based on terms appearing in title, abstract, keyword or
medical subject headings (MeSH) fields content. The records identified in the literature search for
vanadium were filtered using tags in SWIFT Review for lines of evidence (human, animal, in vitro).
The details of the search strategies that underlie the filters are available at
https://hawcprd.epa.gov/media/attachment/SWIFT-Review Search Strategies.pdf. Studies not
retrieved using these filters were not considered further. Studies that included one or more of the
search terms in the title, abstract, keyword, or MeSH fields were exported as a RIS file for screening
in DistillerSR as described below.
The subset of studies identified using the SWIFT Review filters was imported into
DistillerSR for title/abstract and full-text screening. Four additional records that appeared to meet
PECO criteria were identified through curation of references cited in the review article by Bishavee
etal. (2010): these additional records were also uploaded into DistillerSR, annotated with respect
to source of the record, and screened using the same methods described below. Both title/abstract
and full-text screening were conducted by two independent reviewers. Records that met PECO
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
1 criteria (Table 6) during title and abstract screening were considered for full-text screening. At
2 both the DistillerSR title/abstract and full-text review levels, screening conflicts were resolved by
3 discussion between the primary screeners with consultation by a third reviewer (if needed) to
4 resolve any remaining disagreements. For citations with no abstract, the articles were initially
5 screened based on all or some of the following: title relevance (title should indicate clear
6 relevance), and page numbers (articles two pages in length or less were assumed to be conference
7 reports, editorials, or letters). During title/abstract or full-text level screening in DistillerSR,
8 studies that did not meet the PECO criteria, but which could provide supporting information were
9 categorized (or "tagged") as supplemental information according to the categories listed in Table 7.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Vanadium Compounds
APPENDIX D. PRELIMINARY LITERATURE SURVEY
SUMMARY
2012 ATSDR
Toxicological Profile
for Vanadium,
n = 363
Database Searches (2010 - 2020),
n = 25,632 after duplicate removal
r ">
PubMed
(n = 4,888)
WOS ToxLine
(n = 24,878) (n = 15)
i i
.
n
= 25,988 records after duplicate removal
\
SWIFT Review software
Identification of potentially relevant studies based on application of SWIFT-Review evidence
stream and health outcome tags, n = 3,287
n = 4 additional records identified through curation of references
cited in a review article (Bishayee et al. 2010)
I
TITLE AND ABSTRACT SCREENING
Sum of excluded or supplemental (n= 2,935)
FULL TEXT SCREENING
Sum of excluded or supplemental (n= 214}
Full-Text Screening
{n = 356)
Title & Abstract Screening
(n = 3,291)
Tagged as Supplemental (n= 816)
Excluded (n= 2,119)
Tagged as Supplemental (n= 188)
Excluded (n= 26)
Studies meeting PECO criteria {n = 142)
• Human health effects studies (n = 48)
• Animal health effect studies (n = 94)
• PBPK models (n = 0)
Studies meeting PECO criteria that also
reported mechanistic or ADME
information (n= 60)
Tagged as Supplemental (n= 1,064 total)
mechanistic (n = 543), non-mammalian
model (n = 17), ADME (n = 96), non-oral
route of administration (n = 172), exposure
characteristics (n = 135), mixture studies (n
= 43), case studies (n = 6), no original data (n
= 98), abstract only (n = 18), PECO-relevant
studies of organic anthropogenic vanadium
compounds (n = 55)
Figure D-l. Literature survey study flow selection diagram. Click here to view
interactive visualization of results of the title/abstract and full text screening.
This document is a draft for review purposes only and does not constitute Agency policy,
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