#ll.	United States
Environmental Protection
^^LbI M % Agency
EPA/690/R-09/070F
Final
9-30-2009
Provisional Peer-Reviewed Toxicity Values for
Vanadium and Its Soluble Inorganic Compounds Other
Than Vanadium Pentoxide
(CASRN 7440-62-2 and Others)
Derivation of Subchronic and Chronic Oral RfDs
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Commonly Used Abbreviations
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
animal to human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete to complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL to NOAEL uncertainty factor
UFS
subchronic to chronic uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
VANADIUM AND ITS SOLUBLE INORGANIC COMPOUNDS OTHER THAN
VANADIUM PENTOXIDE (CASRN 7440-62-2 and others)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1)	U.S. EPA's Integrated Risk Information System (IRIS).
2)	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. EPA's Superfund
Program.
3)	Other (peer-reviewed) toxicity values, including
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal review by
two U.S. EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all U.S. EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or
external parties who may choose of their own initiative to use these PPRTVs are advised that
Superfund resources will not generally be used to respond to challenges of PPRTVs used in a
context outside of the Superfund Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the U.S. EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The U.S. Environmental Protection Agency's (U.S. EPA) Integrated Risk Information
System (IRIS) (U.S. EPA, 2008) contains a file for vanadium pentoxide describing a chronic
RfD and containing a message about assessing its carcinogenicity—but no chronic RfC. IRIS
currently contains no files for elemental vanadium or other vanadium compounds. The Drinking
Water Standards and Health Advisories list (U.S. EPA, 2006) does not include an RfD for any
vanadium compound. The Health Effects Assessment Summary Table (HEAST; U.S. EPA,
1997) lists subchronic and chronic oral RfDs of 7 x 10"3 mg/kg-day for vanadium and
2	x 102 mg/kg-day for vanadium sulfate. RfDs for both vanadium and vanadium sulfate were
based on a chronic study in which rats were exposed to 5 mg/L vanadium as vanadyl sulfate for
their lifetimes (Schroeder et al., 1970), as derived in U.S. EPA (1987). A total UF of 100 was
used to derive the RfDs. The Agency for Toxic Substance and Disease Registry (ATSDR, 1992)
derived an intermediate-duration oral minimal risk level (MRL) for vanadium of
3	x 10"3 mg/kg-day based on a NOAEL of 0.3 mg/kg-day in a 3-month drinking water study in
rats by Domingo et al. (1985); renal and respiratory effects (renal hemorrhagic foci and
pulmonary vascular infiltration) were seen at higher doses (0.6 mg/kg-day). A total UF of 100,
reflecting UFs of 10 each for interspecies extrapolation and intraspecies variability, was applied
to the NOAEL. ATSDR (1992) does not derive a chronic oral MRL.
Neither IRIS (U.S. EPA, 2008) nor the HEAST (U.S. EPA, 1997) reports an RfC for
vanadium. ATSDR (1992) derived an acute-duration inhalation MRL of 0.0002 mg/m3 for
vanadium based on a study of human exposure to vanadium pentoxide, but it does not provide
inhalation MRLs for other vanadium compounds. The American Conference of Governmental
Industrial Hygienists (ACGIH, 2007) lists a time weighted average-threshold limit value
(TWA-TLV) of 0.05 mg V205/m3 for vanadium pentoxide dust or fume (respirable fraction),
with a "notice of intended change" to 0.02 mg V/m3 (inhalable fraction) based on upper and
lower respiratory tract irritation. The National Institute for Occupational Safety and Health
(NIOSH, 2008) lists a recommended exposure limit (REL) of 0.05 mg V/m3 for vanadium
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pentoxide dust or fume as a 15-minute ceiling value. NIOSH includes a note that this REL
applies to all vanadium compounds except vanadium metal and vanadium carbide—for which a
REL of 1 mg/m3 TWA and 3 mg/m3 short-term exposure limit (STEL) applies (by analogy to
ferrovanadium dust). The Occupational Safety and Health Administration (OSHA, 2008)
permissible exposure limit (PEL) applicable to vanadium pentoxide is a ceiling of
0.1 mg V205/m3 for fume and 0.5 mg V205/m3 for dust.
An assessment of the carcinogenicity of vanadium is not available on IRIS
(U.S. EPA, 2008), in the HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and
Health Advisories list (U.S. EPA, 2006). The Chemical Assessments and Related Activities
(CARA) list (U.S. EPA, 1991, 1994) includes a Health Effects Assessment (HEA) for vanadium
and compounds (U.S. EPA, 1987) that assigned vanadium to cancer weight-of-evidence Group D
(Not Classifiable as to Human Carcinogenicity) based on inconclusive animal data (under
U.S. EPA 1986 Guidelines for Carcinogen Risk Assessment). Vanadium has not been evaluated
under the U.S. EPA (2005) Guidelines for Cancer Risk Assessment. Vanadium is not included
in the 11th Report on Carcinogens available from the National Toxicology Program (NTP, 2005).
The International Agency for Research on Cancer (IARC, 2008) has not evaluated vanadium for
potential carcinogenicity. For vanadium pentoxide, ACGIH (2007) has posted notice of intended
change in cancer notation from A4 (Not Classifiable) to A3 (Confirmed Animal Carcinogen).
To identify toxicological information pertinent to the derivation of provisional toxicity
values, literature searches were conducted from 1960s through December 2007 using the
following databases: MEDLINE, TOXLINE, BIOSIS, TSCATS1/2, CCRIS, DART/ETIC,
GENETOX, HSDB, RTECS, and Current Contents (prior 6 months). Vanadium pentoxide
(CASRN 1314-62-1) was excluded from the search because it has both an IRIS record and a
separate PPRTV document. In addition to searching for vanadium and its subheadings in these
databases, the following vanadium compounds were specifically included as search terms:
vanadyl sulfate (CASRN 27774-13-6), sodium metavanadate (CASRN 13718-26-8), sodium
orthovanadate (CASRN 13721-39-6), ammonium vanadate (CASRN 7803-55-6), vanadium
sulfate (CASRN 16785-81-2), sodium hexavanadate (CASRN 12436-28-1), sodium
tetravanadate (CASRN 1258-74-1), vanadious (4+) acid, disodium salt (CASRN 64082-34-4),
vanadium dichloride (CASRN 10580-52-6), vanadium trioxide (CASRN 1314-34-7), and
vanadium tetrachloride (CASRN 7632-51-1). Review documents by U.S. EPA (1987), ATSDR
(1992), the World Health Organization (WHO, 1988, 2001), and Rydzynski (2001) were also
consulted for relevant information. An updated literature search on PubMed was performed on
August 17, 2009.
REVIEW OF PERTINENT DATA
Vanadium Compounds Assessed
As noted above, vanadium pentoxide is the subject of both an IRIS record and a separate
PPRTV document, which should be used in the toxicity assessment of this particular vanadium
compound.
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Although vanadium has six oxidation states (-1,0, +2, +3, +4, and +5), the most stable
oxidation state is +4 (Rydzynski, 2001). In the environment, vanadium is bound to a variety of
elements including oxygen, sodium, sulfur, and chloride; in commerce, vanadium is often used
in an iron alloy (ferrovanadium) (Rydzynski, 2001). The literature searches identified toxicity
data for the following inorganic compounds: vanadyl sulfate (+4), sodium metavanadate (+5),
sodium orthovanadate (+5), and ammonium metavanadate (+5). Table 1 shows the CASRNs,
molecular formulas, molecular weights, and vanadium mass fractions for these compounds.
These compounds all exhibit some solubility in water (Rydzynski, 2001; ATSDR, 1992) and,
thus, can be considered representative of soluble tetravalent and pentavalent vanadium
compounds.
Table 1. Soluble Inorganic Vanadium Compounds Considered in this PPRTV
Compound
Chemical
Formula
Vanadium
Valence
Molecular
Weight
(g/mol)
Vanadium
Mass
Fraction"
Vanadium
V
various
50.94
1.0
Vanadyl sulfate trihydrate
V0S04-(H20)3
+4
217.06
0.235
Vanadyl sulfate pentahydrate
V0S04-(H20)5
+4
253.10
0.201
Ammonium metavanadate or ammonium
vanadate
nh4vo3
+5
116.99
0.435
Sodium metavanadate or sodium vanadate
NaV03
+5
121.93
0.418
Sodium orthovanadate or sodium vanadium
oxide
Na3V04
+5
183.91
0.277
aMolecular weight of vanadium divided by molecular weight of compound.
In recent years, organic vanadium compounds have been synthesized in an effort to
enhance the lipophilicity and biological uptake of vanadium for use in treating diabetes and/or
cancer. Toxicity data for three organic vanadium compounds were located:
bis(maltolato)oxyvanadium(IV) (BMOV), bis(ethylmaltolato)oxyvanadium(IV) (BEOV), and
vanadyl acetyl acetonate. Because these compounds have been developed as pharmaceutical
agents and are believed to have different absorption and/or toxicokinetic properties than soluble
inorganic vanadium salts, they are not considered in this review.
There are three early studies of human exposure to vanadium (Curran et al., 1959;
Dimond et al., 1963; and Sommerville and Davies, 1962) that employed compounds reported as
"ammonium vanadyl tartrate" and "diammonium oxy-tartrato vanadate" or "diammonium
vanado-tartrate." Information provided on the chemical form in the studies is limited to the
names and the valence state (+4) for the latter compound (reported by Sommerville and Davies,
1962). Reliable chemical structures and valence states for these compounds have not been
located; however, the tartrate component is an organic moiety. Given that the compounds
administered in these studies are unknown, it is difficult to estimate vanadium doses from the
reported doses of the compounds. Further, because the compounds used in these studies were
likely organic in nature and may have exhibited different bioavailability than inorganic vanadium
salts, these studies have been excluded from consideration in this review.
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Oral exposures to either vanadyl or vanadate result in internal exposures to a mixture of
vanadyl and vanadate complexes as a result of reduction/oxidation (redox) reactions that occur in
the gastrointestinal tract as well as in the blood and tissues (Rydzynski, 2001; Etcheverry and
Cortizo, 1998). Available information suggests that conditions in extracellular fluid favor the
formation of vanadate, while intracellular (cytosolic) conditions favor the vanadyl redox state
(Rydzynski, 2001). As a result of these physiological interconversions, there is no firm
toxicological basis for distinguishing dose-response relationships for these two forms given the
currently available data: while toxicology studies can be categorized based on whether humans
or animals were exposed to vanadyl or vanadate compounds, target organs and tissues are likely
exposed to a mix of these ions. For the purpose of this review, exposure to either the vanadyl or
vanadate form is treated as biologically equivalent. Therefore, exposure estimates in all of the
toxicity studies have been converted to equivalent vanadium doses for the purpose of
dose-response assessment.
In summary, this PPRTV document applies to soluble inorganic vanadyl (+4) and
vanadate (+5) compounds other than vanadium pentoxide, which is the subject of an IRIS review
and separate PPRTV document. Data are not available to assess the toxicity of insoluble
compounds or compounds in which vanadium exists in higher or lower valence states. Organic
vanadium compounds are expected to exhibit different toxicokinetic properties than inorganic
compounds and should be assessed independently if necessary. Finally, vanadyl and vanadate
exposures are considered biologically equivalent (on the basis of equivalent vanadium dose) for
the purpose of this review.
Human Studies
The possibility that vanadium may be an essential element for humans remains an
unanswered question. Etcheverry and Cortizo (1998) reported that deficiencies in vanadium
intake could be associated with alterations in bone structure and development, changes in plasma
cholesterol, and changes in reproductive performance. However, WHO (2001) considered the
issue unresolved and noted that, if vanadium is essential, required levels are very low (in the
range of nanograms per day).
Oral Exposure
Fawcett et al. (1997) administered tablets of vanadyl sulfate trihydrate at a dose of
0.5 mg/kg-day (0.1 mg V/kg-day) for 12 weeks to weight trainers. The treatment and control
groups each included 15 males and 5 females. The control group received a daily placebo.
Subjects in the control and treatment groups were matched with respect to gender, age, height,
weight, and weight-training program (e.g., intensity, schedule). Of those starting the study,
11 males and 4 females in the treatment group and 12 males and 4 females in the control group
completed the study. There were two males that withdrew from the study because of
self-reported side effects (tiredness and/or aggressiveness while weight training); these two
subjects were unremarkable with respect to endpoints assessed in this study. There were four
subjects that withdrew because of training-related injuries and three subjects withdrew for other
reasons not related to health. Blood pressure was measured and blood samples collected
periodically during the exposure period for evaluation of hematology (differential cell counts and
blood viscosity tests) and serum chemistry (plasma alanine aminotransferase [ALT] and alkaline
phosphatase [ALP], albumin, bilirubin, cholesterol, creatinine, high-density lipoprotein, total
protein, triglyceride, and urea). No differences were observed between the treatment and control
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groups for the following endpoints: body weight, systolic and diastolic blood pressure,
hematology or serum chemistry (all data shown). Without corroborating information, the
toxicological relevance of the self-reported symptoms of (tiredness and aggressiveness) is
uncertain. The administered dose (0.1 mg V/kg-day) is considered a freestanding NOAEL with
respect to the endpoints assessed in the study.
In a study designed to evaluate the safety of vanadyl sulfate as a diabetes treatment,
Boden et al. (1996) administered 50 mg capsules of vanadyl sulfate twice daily (100 mg/day) for
4-8 weeks to four men and four women with noninsulin-dependent diabetes mellitus. The
specific form of vanadyl sulfate was not reported; assuming vanadyl trihydrate, the
corresponding dose of vanadium would be 0.34 mg V/kg-day in men and 0.39 mg V/kg-day in
females of average body weight (70 kg and 60 kg, respectively). Of the eight patients, four men
and two women were treated with placebo for 4 weeks after the end of vanadium treatment to
provide reference data. Patients self-monitored their glucose using a glucometer and were
examined weekly at a hospital, where blood was drawn for complete blood count, serum
chemistry (glucose, insulin, blood urea nitrogen [BUN], fatty acids, vanadium content), liver and
kidney function tests, and urinalysis (urinary nitrogen). Self-reported symptoms were recorded
at that time. Glycemic control was assessed during and after the exposure period. Of the eight
patients, four reported diarrhea with abdominal cramps and/or flatulence, one reported flatulence
alone, and one reported slight nausea. Diarrhea lasted for 11 days in one patient but had abated
after the first week in the others. Vanadyl sulfate treatment resulted in statistically significant
(p < 0.05) decreases in fasting glucose concentration and hepatic glucose output during
hyperinsulinemia. There were no effects on total body glucose uptake, glycogen synthesis,
glycolysis, carbohydrate oxidation, or lipolysis during the euglycemic-hyperinsulenemic clamps.
The study authors reported that weekly blood counts, urinalysis, and liver function tests were not
affected by treatment (data not shown). A LOAEL of 0.34-0.39 mg V/kg-day is identified from
these data based on gastrointestinal symptoms; no NOAEL is identified.
Goldfine et al. (2000) also investigated the use of vanadyl sulfate to treat
noninsulin-dependent diabetes mellitus. Participants in the study were 16 diabetes patients
(11 males and 5 females) between the ages of 18 and 65 who did not have active cardiovascular,
pulmonary, renal, or hepatic disease. After 12 weeks of monitoring to derive baseline
information, the subjects were given vanadyl sulfate by tablet at doses of 75, 150, or 300 mg/day
for 6 weeks. Based on individual body weights reported in the study and assuming that the
trihydrate form of vanadyl sulfate was used, doses are 0.12-0.23, 0.28-0.45, and
0.43-1.14 mg V/kg-day in the 75, 150, and 300 mg/day groups. Blood glucose was monitored
throughout the study (other tests of glycemic control were also administered) and the patients
were given physical examinations, blood tests (electrolytes, BUN, creatinine, complete blood
count), liver and thyroid function tests and urine tests biweekly. To assess lipid peroxidation,
levels of thiobarbituric acid-reactive substances in the serum were measured. Ambulatory blood
pressure was measured 4 weeks after exposure was terminated. The patients were monitored for
2 additional weeks. Although patients exposed to the lowest dose range did not experience any
gastrointestinal symptoms, several patients at the next dose reported complaints and all patients
at the high dose reported cramping, abdominal discomfort, and/or diarrhea. The study authors
reported that no other signs of toxicity were observed and blood tests and urinalysis did not
indicate toxicity (data not shown). Systolic, diastolic, and mean arterial pressure were not
changed by exposure nor was heart rate. Insulin sensitivity and glycemic control were not
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dramatically improved in this study. A LOAEL of 0.28-0.45 mg V/kg-day is identified from this
study based on gastrointestinal symptoms; the NOAEL is in the range of
0.12-0.23 mg V/kg-day.
Cusi et al. (2001) gave a group of 11 patients (four men and seven women, mean age
59 years) with type 2 diabetes doses of 150 mg vanadyl sulfate each day for 6 weeks after a
2-week period of exposure to increasing doses up to 150 mg/day (exposure regimen during
run-up not reported). Assuming that vanadyl sulfate was in the trihydrate form, the estimated
doses (during the 6-week period) are 0.5 mg V/kg-day in males and 0.6 mg V/kg-day in females
(based on default body weights of 70 and 60 kg, respectively). Measures of glycemic control
were assessed throughout the exposure period. Effects reported in the subjects included diarrhea
(4/11) and abdominal discomfort (2/11). According to the authors, blood chemistry, complete
blood count, and urinalysis were not affected by treatment (data not shown), nor was bone
mineral density (measured in three subjects) or body weight. Measures of 24-hour ambulatory
blood pressure and mean heart rate were not affected by treatment (data shown). Glycemic
control was significantly improved. This study suggests a LOAEL of
0.5-0.6 mg V/kg-day based on gastrointestinal symptoms; a NOAEL could not be identified.
Inhalation Exposure
The few studies examining human exposure to vanadium compounds (other than
vanadium pentoxide) via inhalation (Woodin et al., 2000; Sorensen et al., 2005; Zhou et al.,
2007) do not specify the form of vanadium exposure; in these studies, coexposure to other
compounds could not be ruled out. Woodin et al. (2000) found increases in self-reported upper
and lower airway respiratory symptoms in 18 boilermaker workers exposed to vanadium
compared with 11 utility worker control subjects. The study authors correlated these symptoms
with estimated vanadium doses to the lung and upper airway in all but the highest exposure
quartile; the authors attributed the high-dose reversal to a possible healthy worker effect.
Sorensen et al. (2005) observed a positive association between levels of
7-hydro-8-oxo-2'-deoxyguanosine (a measure of DNA damage) in lymphocytes of 49 students in
Copenhagen and concentrations of both vanadium and chromium in PM2.5 samples.
Concentrations of platinum, nickel, copper, and iron were not related to the measures of DNA
damage. Based on the English abstract of a paper published in Chinese, 106 workers with
exposure to vanadium were reported to exhibit more negative moods as well as poorer
performance on neurobehavioral tests (Santa Ana dexterity, Benton visual retention and pursuit
aiming) than unexposed workers (Zhou et al., 2007). The average concentration of vanadium in
the air of the exposed workers ranged from 0.034 to 0.805 mg/m3; however, the form of
vanadium is not specified. No further information is presented in the abstract.
A case report documented symptoms of metal-fume fever in a worker exposed to a
vanadium catalyst, vanadyl pyrophosphate (Vandenplas et al., 2002). After exhibiting symptoms
in the work environment, the individual was assessed by a physician under controlled conditions
of exposure to the vanadium catalyst. Forced vital capacity and forced expiratory volume were
decreased and fever and peripheral blood neutrophilia were observed. Concentrations of
vanadium to which the individual was exposed in the workplace or under the challenge
conditions were not reported.
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Animal Studies
Only a few of the available laboratory animal studies provide information on the levels of
vanadium in the basal diet and none of the studies considered dietary input to total vanadium
dose. Kanisawa and Schroeder (1967), along with Schroeder et al. (1970), reported the
concentration of vanadium in their basal diet as 3.2 mg V/kg food. Elfant and Keen (1987)
reported a concentration of 1 mg V/kg in a "purified" diet. Finally, Scibior et al. (2006)
measured the concentration of vanadium in their standard chow to be 0.45 mg V/kg. For a
dietary concentration of 1 mg V/kg, the vanadium dose to rats and mice would be in the range of
0.1 to 0.2 mg V/kg-day (assuming default values for subchronic exposure in female
Sprague-Dawley and B6C3F1 mice; U.S. EPA, 1988). This estimate may not be representative
of all commercial laboratory animal feeds used in the studies included in this review. Because
exposure to vanadium in the basal diet was not taken into account in any of the studies, doses
reported in this review may be underestimated to some degree. Further, low-level exposure to
vanadium among controls increases the uncertainty in findings of effect at doses near the
estimated control dose.
Oral Exposure
Subchronic Studies—Domingo et al. (1985) exposed male Sprague-Dawley rats to
sodium metavanadate for 12 weeks. A control group consisted of 10 rats given free access to
drinking water without added vanadate. There were three treatment groups that consisted of
10 rats/group exposed to drinking water to which 5, 10, or 50 mg/L sodium metavanadate
(2, 4, or 21 mg V/L) had been added. Vanadium doses estimated for this review based on
reported water consumption and body weight (of the high-concentration group only) were 0.3,
0.6, and 3.0 mg V/kg-day. Body weight was measured weekly, while food consumption, water
intake, and urine volume were assessed daily. At sacrifice, blood was collected from five rats for
serum chemistry determinations (AST, ALT, total protein, bilirubin, creatinine, urea, uric acid,
glucose, and cholesterol). Selected organs (liver, kidneys, heart, spleen, and lung) from all
animals were weighed. Microscopic examination of the heart, kidney, liver, lung, spleen, and
stomach was performed on 3 rats/group. Body-weight gain was significantly (p < 0.05)
increased (42%) over controls in the high-dose group (3.0 mg V/kg-day) during the first 2 weeks
of exposure, but not thereafter; actual body weights are not reported. Food and water intake
were not affected in the high-dose group. The authors indicated that body weight, food
consumption, and water intake were not affected in other treatment groups (data not shown).
Urine volume was greater than controls in the high-dose group during the first month (58% to
2-fold higher; p < 0.05), but not during the remainder of the study. Compared to the control
values, plasma protein, urea, and uric acid concentrations were significantly higher (31%, 28%,
and 2-fold, respectively; p < 0.05) in the 3.0 mg V/kg-day treatment group but not in other
treatment groups. Organ weights were not affected by treatment (data shown). The
histopathology findings are summarized qualitatively as mild changes in the kidney
(hemorrhagic foci in the corticomedullary region), spleen (hypertrophy and hyperplasia), and
lungs (perivascular mononuclear cell infiltration). The authors reported that these changes
occurred in all treatment groups, but they are described as "more evident" in the
3.0 mg V/kg-day treatment group. Incidences of these effects are not reported. Given the
authors' report of histopathology and clinical chemistry findings in the low-dose group, even
though only three animals were examined, 3.0 mg V/kg-day is considered to be a LOAEL.
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A number of studies examined the beneficial effects of vanadium exposure on diabetic rats1.
Most of the studies examined few or no toxicological endpoints and used doses of
10 mg V/kg-day or greater. Those studies that did examine a few toxicological endpoints,
included a nondiabetic treatment group, and exposed the animals for at least 28 days are
summarized in Table 2. The studies shown in the table indicate that doses of 12 mg V/kg-day
and higher result in body weight reductions of at least 10%, often accompanied by marked
reductions in fluid intake. The reduced fluid intake may reflect an organoleptic effect of
vanadium compounds administered in drinking water. Although body-weight reductions can be
related to reduced fluid intake, studies that have observed reduced body weight or body weight
gain with dietary or gavage administration of vanadium (e.g., Sanchez et al., 1991, 1998, 1999;
Paternain et al., 1990; Elfant and Keen, 1987) suggest that this may be a toxic effect of the
element rather than resulting from reduced fluid intake. Thus, the body-weight decrement of at
least 10% observed at a dose of 12 mg V/kg-day (Cam et al., 1993) indicates that this dose is a
LOAEL.
Most of the studies that examined only effects in diabetic animals are not summarized
here—primarily because the studies demonstrated improvements in diabetes-related effects,
rather than any toxic effects of vanadium exposure. However, one study examining effects of
vanadium exposure in diabetic animals bears special consideration because it identifies enhanced
toxicity in the vanadium-treated animals when compared with both nondiabetic and diabetic
controls. Domingo et al. (1991) exposed groups of 10 streptozotocin-induced diabetic male
Sprague-Dawley rats to three different forms of vanadium: sodium metavanadate (150 mg/L),
sodium orthovanadate (230 mg/L), and vanadyl sulfate pentahydrate (310 mg/L) in the drinking
water for 28 days. Based on body weights and fluid intake measurements, the authors estimated
vanadium doses of 22.7, 15.6, and 6.1 mg V/kg-day for vanadyl sulfate, sodium orthovanadate,
and sodium metavanadate, respectively. Sodium chloride (80 mM) was added to the water to
inhibit gastrointestinal effects of vanadium. Both diabetic and nondiabetic control groups
(10/group) were included for comparison. Mortality, body weight, food and fluid intake and
blood glucose were monitored throughout the exposure period. After exposure ended, blood
samples were collected for analysis of hematocrit, glucose, urea, creatinine, AST and ALT.
1A chronic study that included a broader range of toxicological endpoints is discussed under Chronic Studies
(published in three papers: Dai et al., 1994a,b; Dai and McNeill, 1994).
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Table 2. Studies of Effects in Streptozotocin-induced Diabetic and Nondiabetic Rats Exposed to Vanadium
Reference
Number and
Sex of Rats
Vanadium
Compound
Administered
Duration
Dose"
Vanadium
(mg V/kg-day)
Significant Adverse Effects
Cametal., 1993
11-16 males
per group
Vanadyl sulfate in
drinking water
5 months
12b (nondiabetic)
18-20 (diabetic)
Decreased body weight (14%), fluid intake (40%) and food intake (up
to 10%) in treated nondiabetic rats relative to control nondiabetic rats.
Thompson et al.,
1993
10-16 males
per group
Vanadyl sulfate in
drinking water
Up to 12
weeks
36 (nondiabetic)
102 (diabetic)
Decreased body weight (30%), decreased fluid intake (54%) in treated
nondiabetic rats relative to control nondiabetic rats.
Decreased body weight (11%) in treated diabetic rats relative to
diabetic controls.
Yao et al., 1997
5-6 males per
group
Vanadyl sulfate in
drinking water
7 weeks
13 (nondiabetic)
24 or 29
(diabetic)
Decreased body-weight gain (14%), decreased fluid intake (34%) in
treated nondiabetic rats relative to control nondiabetic rats.
Tunali and
Yanardag, 2006;
Akgiin-Dar et al.,
2007
5-13 males per
group
Vanadyl sulfate via
daily gavage
60 days
24 b
Lower body weight (11%), increased serum glucose and
phospholipids, increased aortic lipid peroxidation, decreased stomach
and aortic glutathione, decreased aortic diameter and aortic tunica
intima thickness in treated nondiabetic rats relative to control
nondiabetic rats.
Decreased tunica muscularis thickness (in aorta) in treated diabetic
rats relative to both diabetic and nondiabetic controls.
aDoses estimated by authors except where indicated.
bDoses estimated for this review based on default body weight and fluid intake (U.S. EPA, 1988). Cam et al. (1993) reported using the trihydrate form of vanadyl sulfate.
Tunali and Yanardag (2006) and Akgiin-Dar et al. (2007) did not report the form administered; it was assumed to be the trihydrate for the purpose of dose estimation.
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In each of the groups exposed to sodium metavanadate and vanadyl sulfate, 3/10 rats
died, while 2/10 diabetic rats treated with sodium orthovanadate died (Domingo et al., 1991). By
comparison, no control nondiabetic rats died and 1/10 control diabetic rats died. Food and fluid
intake in the groups exposed to sodium metavanadate and vanadyl sulfate were increased relative
to the nondiabetic controls, but were lower than those of diabetic controls. Relative weight gain
was significantly lower in diabetic controls than in nondiabetic controls (8.2% vs. 24% over
study duration). However, the vanadium-treated rats lost weight over the exposure period (3.2%,
4.8%), and 7.2% losses in the groups exposed to vanadyl sulfate, sodium orthovanadate and
sodium metavanadate, respectively; p < 0.05 relative to both diabetic and nondiabetic control
groups). Thus, in this study, vanadium treatment enhanced the adverse effect of diabetes on
body-weight gain. In addition, vanadium treatment (all forms) resulted in significantly
(p < 0.05) higher serum urea concentrations relative to both diabetic and nondiabetic control
groups. Treatment with vanadyl sulfate also increased the serum creatinine level relative to both
control groups. This study suggests a LOAEL of 6.1 mg V/kg-day for body-weight losses in
diabetic rats. Although mortality was observed in diabetic rats treated with vanadium (3/10 in
the group exposed to 6.1 mg V/kg-day), it is not clear whether the deaths were attributable to the
disease or the treatment; one death also occurred in the untreated diabetic group. A NOAEL
cannot be determined.
A follow-up study assessing whether Tiron (sodium 4,5-dihydroxybenzene-l,3-
disulfonate, a chelating agent) would mitigate the toxicity of vanadium in diabetic rats, provided
some confirmation of these findings (Domingo et al., 1992). A group of 10
streptozotocin-induced diabetic rats was given sodium metavanadate at a concentration of
200 mg/L in the drinking water for 5 weeks, with or without Tiron; nondiabetic and diabetic
control groups were included. The same parameters as in the earlier study were monitored. The
authors estimated a vanadium dose of 23.2 mg V/kg-day in the group without Tiron exposure.
As with the previous study, exposure to sodium metavanadate in diabetic rats resulted in
body-weight loss (5%) while weight gains of 28% and 8.1%> were seen in untreated nondiabetic
and diabetic groups (respectively). The decrement was significantly different from both
untreated groups at/? < 0.01. In addition, serum urea was increased relative to both control
groups (10.9 mmol/L vs. 6.3 and 8.2 mmol/L in nondiabetic and diabetic controls), while serum
creatinine was not. Tiron administration did not ameliorate the effect of vanadium on
body-weight gain, but did reduce serum urea concentrations. A LOAEL of 23.2 mg V/kg-day is
identified from this study based on body-weight losses in treated diabetic rats.
A series of papers reported hematological effects of exposure to ammonium
metavanadate (Gorski and Zaporowska, 1982; Zaporowska and Wasilewski 1989, 1990, 1991,
1992a,b; Zaporowska and Scibior, 1999). With few exceptions, the study protocols are largely
the same. In most studies, 2-month old Wistar rats (either male or male and female) were
exposed to ammonium metavanadate in drinking water provided ad libitum, typically for
4 weeks. Some studies examined the interaction of vanadium with another toxicant (ethanol or
zinc), but some also provided data on exposure to the vanadium compound alone; in all cases, a
single concentration of ammonium vanadate was used. Vanadium concentrations in the drinking
water ranged from 50-300 mg/L, resulting in doses ranging from 7-29 mg V/kg-day in the
various studies. Body weight, fluid intake, and food consumption were monitored during the
exposure period. At sacrifice (at the end of exposure), the following hematological parameters
were assessed: erythrocyte, reticulocyte, and total and differential leukocyte counts, hematocrit
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[Hct], hemoglobin [Hgb], leukocyte composition in bone marrow and frequency of
polychromatophilic erythrocytes in peripheral blood and bone marrow. A few other evaluations
were conducted in individual studies. Zaporowska and Wasilewski (1992a) also examined the
osmotic resistance of erythrocytes and the activities of glucose-6-phosphate dehydrogenase and
lactate dehydrogenase in erythrocytes. Zaporowska and Scibior (1999) assessed the phagocytic
activity of neutrophils and the activities of myeloperoxidase and alkaline phosphatase in the
neutrophils. Based on the abstracts of papers published in Polish, Gorski and Zaporowska
(1982) also examined the histopathology of liver and kidneys, and Zaporowska (1987) evaluated
kidney histopathology.
Table 3 provides an overview of the study designs and results. Mortality occurred at
doses of 13 mg/kg-day and higher in this series of papers. In general, the studies consistently
demonstrated significantly depressed body-weight gain, food intake and fluid intake, decreased
erythrocyte counts and hemoglobin concentrations and increased reticulocytes and
polychromatophilic erythrocytes in exposed animals. Sporadic effects were observed on
leukocytes or leukocyte composition and no effects on erythrocyte enzyme activities were
reported. Abstracts from two studies (Gorski and Zaporowska, 1982; Zaporowska, 1987, both
published in Polish) reported renal histopathology (parenchymatous degeneration with vacuolar
degeneration and tubular casts) at doses of 9-29 mg V/kg-day, but the incidences of the renal
effects are not given. Gorski and Zaporowska (1982) also reported parenchymatous
degeneration of the liver. Neither study has been translated for this review. Taken together,
these studies identify a FEL of 13 mg/kg-day based on mortality (Zaporowska and
Wasilewski, 1992a).
In contrast to the other publications in this series, Zaporowska et al. (1993) used more
than one concentration of ammonium metavanadate and also used lower doses that were not
associated with mortality. Groups of 15-16 Wistar rats of each sex were given concentrations of
0, 10, or 50 mg V/L as ammonium metavanadate in drinking water for 4 weeks. Fluid intake
was measured daily and body weight recorded weekly; based on these measures, the authors
estimated doses of 1.2 or 5 mg V/kg-day in males and 1.5 or 7 mg V/kg-day in females. Food
intake was also monitored daily during exposure. Blood was drawn (presumably at sacrifice at
the end of exposure, although this is not specified) for hematology (erythrocyte count [RBC],
leukocyte count [WBC], Hgb, Hct, leukocyte composition, polychromatophilic erythrocytes, and
reticulocytes in peripheral blood) and erythrocyte enzyme activity determinations
(catalase,glucose-6-phosphate dehydrogenase, lactate dehydrogenase and S-aminolevulinic acid
dehydratase). Maiondialdehyde (MDA), glutathione (GSH) and L-ascorbic acid content of
erythrocytes were also measured. At these doses, there was no mortality. Although body-weight
gain was lower in exposed groups than in controls (as much as 9% lower at the high dose), the
differences are not statistically significant. Food intake was not affected by treatment and fluid
intake was decreased only in high-dose males (14% lower than controls,/* < 0.001). Statistically
significant—but modest—changes in erythrocyte count, hemoglobin concentration, and
hematocrit are shown in Table 4. In addition to these changes, the percentage of reticulocytes
was significantly increased at the high dose in both sexes (data presented graphically, p < 0.05).
There was no effect on leukocyte composition or enzyme activity in erythrocytes. While MDA
tended to be increased and GSH decreased in exposed animals, the changes are not statistically
significant. However, the concentration of L-ascorbic acid in the plasma of male rats was
reduced at both doses (24% and 37% below controls; p < 0.05). The high dose in this study is
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Table 3. Studies of Hematologic Effects in Rats Exposed to Ammonium Metavanadate in Drinking Water
Reference
Number
and Sex
of Rats
Cone.
Vanadium
(mg V/L)
Duration
Dose3
(mg V/kg-
day)
Significant Effects
Gorski and
Zaporowska, 1982
Published in Polish.
5-13
males per
group
0, 200
1,2, or 3
months
29b
Based on English abstract and tables only: decreased body-weight gain, decreased
erythrocyte count, hemoglobin, and hematocrit; in "single cases," parenchymatous
degeneration of liver and kidney, with vacuolar degeneration of kidney and tubular
casts.
Zaporowska, 1987
Published in Polish.
15 (sex
not given)
per group
0, 50, 100,
200
4 weeks
9, 12, 23b
Based on English abstract and tables only: decreased body-weight gain at high dose;
"renal tubule cylinders" at mid- and high doses.
Zaporowska and
Wasilewski, 1989
10-18 per
sex per
group
0, 300
2, 4, or
8 weeks
21-29
Mortality0 (6/16 and 2/14 males after 4 and 8 weeks; 2/13, 4/16, and 2/13 females
after 2, 4, and 8 weeks), transient diarrhea in "some" rats, decreased body-weight
gain, decreased food and water intake, decreased erythrocyte count and hemoglobin
concentration, increased number polychromophilic erythroblasts.
Zaporowska and
Wasilewski, 1990
10-21 per
sex per
group
0, 300
4 weeks
22-27
Mortality0 (6/21 males and 6/21 females), diarrhea, decreased body-weight gain,
decreased food and water intake, decreased erythrocyte count, increased reticulocyte
count, increased number polychromatophilic erythrocytes, decreased lymphocytes
and plasma cells in bone marrow.
Zaporowska and
Wasilewski, 1991
10-11
males per
group
0, 300
4 weeks
20
Decreased body-weight gain, fluid intake, food intake, erythrocyte count, and
hemoglobin concentration. Increased reticulocytes and polychromatophilic
erythrocytes in peripheral blood.
Zaporowska and
Wasilewski, 1992a
12-13 per
sex per
group
0, 150
4 weeks
13
Mortality0 (1/12 males); transient diarrhea (2 rats); decreased body-weight gain,
food intake, fluid intake, erythrocytes, hemoglobin count; increased leukocyte
count; decreased osmotic resistance of erythrocytes; increased reticulocytes,
polychromatophilic erythrocytes, neutrophils and lymphocytes in peripheral blood.
Zaporowska and
Wasilewski, 1992b
12—14 per
sex per
group
0, 300
4 weeks
20-26
Mortality0 (2/13 males and 3/14 females); frequent diarrhea; decreased body-weight
gain, food intake and fluid intake; decreased erythrocyte count and hemoglobin
concentration; increased reticulocytes and polychromatophilic erythrocytes in
peripheral blood and/or bone marrow.
Zaporowska and
Scibior, 1999
10-13
males per
group
0, 150
4 weeks
12
Decreased body-weight gain, food intake and fluid intake; decreased phagocytic
activity of neutrophils.
aDoses estimated by authors based on fluid intake and body weight except where indicated
bDoses estimated for this review based on default body weight and fluid intake (U.S. EPA, 1988)
°No control animals died in any study
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considered a LOAEL (5 mg V/kg-day in males and 7 mg V/kg-day in females) based on a
9% decrease in body-weight gain (albeit not significantly decreased from controls, and possibly
related to reduced fluid intake) and modest hematology changes. The low dose
(1.2 mg V/kg-day in males and 1.5 mg V/kg-day in females) is considered a NOAEL; the
statistically significant hematology changes observed at this dose are not considered
toxicologically significant.
Table 4. Hematologic Effects in Rats Exposed to Ammonium Metavanadate
for 4 Weeks3
Parameter
Control
10 mg V/L
50 mg V/L
Males
1.2 mg V/kg-day
5 mg V/kg-day
Erythrocytes (x 1012/dm3)
8.32 ±0.17
7.38 ±0.20 b
7.47 ± 0.27 c
Hemoglobin (mmol/L)
9.37 ±0.19
8.94 ±0.28
8.65 ± 0.26c
Hematocrit (%)
0.48 ±0.001
0.47 ± 0.004c
0.47 ± 0.003 b
Females
1.5 mg V/kg-day
7 mg V/kg-day
Erythrocytes (x 1012/dm3)
8.24 ±0.10
7.38 ± 0.14 d
7.12 ± 0.17 d
Hemoglobin (mmol/L)
9.41 ±0.12
8.76 ±0.30
8.72 ± 0.20c
"Zaporowska et al., 1993
bp < 0.01
0Significantly different from control, p < 0.05
d/?< 0.001
In recent papers by the same group of investigators, sodium metavanadate was used as
the test material in studies comparing the effects of vanadium alone or in combination with
chromium or magnesium. Scibior (2005) administered sodium metavanadate in the drinking
water to a group of 11 male Wistar rats at a concentration of 100 mg V/L; a group of
16 untreated rats served as controls. Food and fluid intake were measured daily and body weight
recorded weekly during the 6-week exposure period. After exposure ended, blood was collected
for hematology (RBC, Hct, Hgb, mean corpuscular volume [MCV], mean corpuscular
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], and WBC) and
assessment of the total antioxidant status of erythrocytes. Based on measured body weight and
fluid intake, the authors estimated the vanadium intake to be 8 mg V/kg-day. While total
body-weight gain was reduced in the vanadium-exposed group (about 9% less than controls), the
difference is not statistically significant. In treated rats, both food and fluid intake were reduced
compared to controls (13% and 32% less than controls, respectively; p < 0.05). Modest—but
statistically significant (p < 0.05)—effects observed with exposure include the following:
increased erythrocyte count (in contrast to earlier studies that showed a decrease; 10% higher
than controls) and decreased MCH (12% lower) and MCHC (4% lower). No other statistically
significant effects were observed in the parameters evaluated. A LOAEL of 8 mg V/kg-day is
identified for these data based on a 9% decrease in body-weight gain (albeit not significantly
decreased from controls, and possibly related to reduced food and fluid intake) and hematology
changes; no NOAEL can be determined.
Scibior et al. (2006) exposed male Wistar rats (12/group) to sodium metavanadate at a
concentration of 0 or 125 mg V/L in the drinking water for 6 weeks. Based on fluid intake and
body weight measurements, the authors estimated the average vanadium intake to be
11 mg V/kg-day in the exposed group. Evaluations were similar to those of previous studies and
included body-weight gain, food and fluid intake, hematology (RBC, WBC, Hgb, Hct, MCV,
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MCH, MCHC, and red-cell distribution width), leukocyte composition of peripheral blood
smears, phagocytic activity of neutrophils in whole blood, erythrocyte concentrations of
L-ascorbic acid and malondialdehyde, and the total antioxidant status of the plasma. In this
study, significant (p < 0.05) effects of treatment included a 15% decline in body-weight gain,
along with 6% and 30% decreases in food and fluid intakes (respectively). Erythrocyte count
was decreased by 6%, while hemoglobin concentration was depressed by 10.6% compared to
controls (p < 0.05). MCV and MCH were reduced by 4% and 6%, respectively (p < 0.05).
Leukocyte count and leukocyte composition of peripheral blood were not affected by treatment.
The plasma concentration of L-ascorbic acid was decreased (26%,p < 0.05), while
malondialdehyde content of erythrocytes was increased (78% ,p< 0 .05). Based on data
presented in tables, there are no statistically significant changes in Hct, MCHC, red-cell
distribution width, or phagocytic activity of neutrophils with exposure. A LOAEL of
11	mg V/kg-day is identified for these data based on a 15% decrease in body-weight gain
(possibly related to reduced food and fluid intake) and hematology changes; no NOAEL can be
determined.
In contrast to the studies published by Zaporowska and collaborators, Dai et al. (1995)
observed no effects on hematology parameters in groups of eight male Wistar rats exposed to
ammonium metavanadate (140 mg/L) and vanadyl sulfate (260 mg/L) in the drinking water for
12	weeks. An additional group of eight rats received untreated water. Body weight, food intake,
and fluid intake were measured before exposure and on Weeks 1, 2, 4, 8, and 12 of treatment.
These data were used by the authors to estimate vanadium doses of 0.19 and
0.15 mmol V/kg-day for ammonium metavanadate and vanadyl sulfate, respectively; these
values correspond to dose estimates of 9.7 and 7.6 mg V/kg-day, respectively. Blood samples
were collected on the same schedule as body weight measurements for evaluation of Hct, Hgb,
RBC, WBC, platelet count, differential leukocyte count, reticulocyte percentage and erythrocyte
osmotic fragility tests. No other evaluations were performed. Vanadium in the drinking water
led to significantly (p < 0.05) reduced fluid intake, regardless of the compound administered
(data presented graphically). However, food intake and body weight were not affected by
exposure and there was no statistically significant effect on any hematology parameter at any
time (data shown graphically). This study identifies freestanding NOAELs of 9.7 and
7.6 mg V/kg-day (for ammonium metavanadate and vanadyl sulfate, respectively) for
hematologic effects in male rats.
Adachi et al. (2000) exposed groups of seven female Wistar rats to sodium metavanadate
in the diet for 10 weeks. Concentrations of 0, 50, or 100 ppm (0, 21, or 42 ppm V) were
incorporated into the diet. Food intake and body weight were measured weekly; vanadium doses
calculated for this review based on food intake (14 g/day) and body weight (0.260 kg) roughly
estimated from graphical presentation of these data are 1.1 and 2.3 mg V/kg-day. After exposure
was terminated, the animals were sacrificed and blood was collected for hematology (RBC,
WBC, platelet count, reticulocyte count, Hgb, cell number, immunoglobulin levels) and serum
chemistry (AST, ALT, cholinesterase [ChE], ALP). Thiobarbituric acid levels (a measure of
lipid peroxidation) were determined in the liver, kidney, and spleen, while vanadium and
metallothionein (a metal-binding protein) contents of the liver and kidney were also assayed.
Histopathology was not assessed. Statistically significant decreases (p < 0.05) in body weight
were observed at both doses after 3 weeks of exposure; however, the body-weight decrements at
termination were less than 10% (approximately 5% and 7% lower than controls) at both doses.
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Food intake was not affected by exposure. Hematology and serum chemistry data were
presented graphically with statistical analysis of differences from control. ALT, ChE, and ALP
levels were significantly (p < 0.05) decreased at both doses. Although AST levels were reduced
by more than half at both doses, the difference was significantly different from control only at
the high dose. A decrease in serum liver enzymes is not considered to be of toxicological
significance. Hemoglobin content and hematocrit were slightly reduced at both doses (p < 0.05),
but erythrocyte count was not affected. Based on visual inspection of the graphs, the Hgb
decrease was about 4% at both doses, and Hct was decreased from about 51% to about 49%.
Platelet and reticulocyte counts were increased, while leukocyte counts were decreased at the
high dose only. The decrease in leukocytes was primarily a result of reduced lymphocyte counts,
specifically B cells. Plasma levels of immunoglobulin G (IgG) and IgM were also reduced at the
high dose. Lipid peroxidation, as measured by thiobarbituric acid content, was increased in the
kidney at the high dose only. Metallothionein content of the kidney is very slightly statistically
significantly (p < 0.05) higher in the exposed groups relative to controls; there was no difference
in the liver. Given the minimal changes in hematology and small body-weight decrease (-7%),
the high dose (2.3 mg V/kg-day) is considered a NOAEL.
Kasibhatla and Rai (1993) administered vanadium in drinking water to rabbits (strain and
sex not given) in a study evaluating limited hematology parameters. Rabbits (4/dose) were
exposed to concentrations of 0, 20, 40, or 80 ppm vanadium for 171, 171, 129, or 24 days,
respectively. The test material was characterized as "metavanadate." These exposure levels
correspond to doses of about 3.3, 6.7, and 13.8 mg V/kg-day based on measured body weights
and default values for water intake (U.S. EPA, 1988). An untreated control group received tap
water. Body weights were recorded at irregular intervals. Blood samples were collected
periodically for evaluation of erythrocyte and leukocyte counts, hemoglobin concentration and
packed cell volume. The authors reported clinical signs including diarrhea, conjunctivitis,
weakness, white nasal secretions, and loss of appetite in exposed rabbits, but no information on
incidences or doses is provided. Body weights were generally lower in the treated groups, but
the authors' statistical analysis indicated significantly reduced body weights only in the low-dose
group; thus, this finding appears to be spurious. The authors also reported statistically significant
(p < 0.05) reductions in erythrocyte count, hemoglobin concentration, and packed cell volume in
the treated animals. However, the hematology data show decreasing numbers of treated rabbits
over time, without explanation. It is not clear whether the missing animals died or were
otherwise removed from the study. The poor reporting in this study precludes determination of
effect levels.
Steffen et al. (1981) observed increased blood pressure in renally compromised rats
exposed to vanadium. Groups of 20 adult male uninephrectomized Sprague-Dawley rats were
given rat chow containing 100-ppm vanadium and either tap water or a 1% solution of sodium
chloride to drink for 9 weeks. Based on default values for food intake and body weight
(U.S. EPA, 1988), the dose for this experiment was estimated to be 9 mg V/kg-day. Control
groups of the same size were given untreated rat chow (which contained 0.3-ppm vanadium)
with one of the two fluid options. Fluid intake, urine volume, and urinary sodium concentration
were measured daily. Body weights and systolic blood pressure (measured by tail cuff) were
measured weekly. Upon sacrifice at the end of exposure, heart weights were recorded. There
was one rat exposed to vanadium and sodium chloride that died at Week 3 of exposure; cause of
death was not noted. Body-weight gain was lower in the vanadium-treated groups than in the
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corresponding control groups, with statistically significant (p < 0.05) reductions after the
4th week of treatment. Based on visual examination of the data presented graphically, body
weights of the treated groups at termination were about 12% lower than corresponding control
body weights. The authors reported that vanadium treatment did not alter water consumption,
urine volume, or urinary excretion of sodium (data on sodium excretion shown) compared with
corresponding control groups. In the vanadium-exposed group consuming tap water, blood
pressure was increased over the tap-water control group after the 3rd week of exposure (p < 0.05).
Blood pressure data are presented graphically; based on visual examination of the data, systolic
blood pressure approached 150 mm Hg in the vanadium-tap water group, compared with a value
of <130 mm Hg in the tap-water controls. Though blood pressure measures were higher in
vanadium-treated rats consuming sodium chloride, the difference from the sodium chloride
control group is not statistically significant. Heart weight was not affected by vanadium
treatment (data not shown). These data suggest a LOAEL of 9 mg V/kg-day based on decreased
body weight. Although one rat died in the first experiment, there are no other indications of
severe toxicity that would suggest that the death was related to treatment.
Susie and Kentera (1986) assessed the effects of vanadium administration on pulmonary
circulation in adult male Long-Evans rats. After 2 months of exposure to ammonium vanadate in
the diet (300 ppm or about 130-ppm vanadium assuming that the administered form was
ammonium metavanadate), pulmonary and systemic blood pressure and cardiac output were
measured and pulmonary and systemic vascular resistances were calculated from these
measurements. Blood pressure was measured directly using a femoral artery cannula in
anaesthetized animals. Using default values for food consumption and body weight
(U.S. EPA, 1988), this dietary concentration is estimated to result in a dose of about
12 mg V/kg-day. Arterial blood was collected for assessment of hematocrit (timing not
reported), but the results are not reported. After the exposure period, the rats were sacrificed and
hearts removed for determination of left and right ventricular weights. Body weight, heart rate,
mean femoral artery pressure, cardiac output, and total peripheral resistance were not affected by
exposure (data shown). Significant (p < 0.05) increases in right ventricular systolic and mean
pressures, as well as the calculated pulmonary vascular resistance, were observed with exposure
(data presented graphically). The right ventricles of exposed rats were slightly enlarged, as
shown by increased relative weight compared to controls (5 %,p< 0 .05). These data suggest a
LOAEL of 12 mg V/kg-day based on pulmonary hypertension.
Susie and Kentera (1988) compared the hypertensive effects of sodium metavanadate in
normal and partially nephrectomized Long-Evans rats. Groups of 18-24 male rats were fed diets
containing 0-, 300-, or 3000-ppm sodium metavanadate for 24 weeks. The authors estimated
doses of 5 and 47 mg sodium metavanadate per rat per day, corresponding to doses of
approximately 4.4 and 42 mg V/kg-day (assuming a body weight of 0.472 kg for male
Long-Evans rats [U.S. EPA, 1988a]). A separate group of 38 rats was subjected to partial
nephrectomy followed by exposure to either the control diet or a diet with 300-ppm sodium
vanadate (calculated to deliver a dose of 4.5-mg sodium metavanadate per rat per day, or
4.0 mg V/kg-day). Measurements of systolic blood pressure, heart rate, and body weight were
recorded biweekly and renal function (plasma creatinine concentration, 24-hour creatinine
clearance, urinary sodium excretion, and urinary output) was assessed in eight randomly chosen
rats per group during Weeks 5 and 6. After exposure was terminated, groups of six randomly
selected rats per group were selected for determination of hematocrit as well as plasma and
extracellular fluid volumes. The remaining animals were used for measurement of blood
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pressure, cardiac output, and total peripheral resistance. The animals were then sacrificed for
removal of hearts and measurement of left and right ventricular weights. Body weights were
significantly lower at both doses in the nonnephrectomized rats (p < 0.001 by t-test performed
for this review), but they did not exceed a 7% decrease from control body weight in either group.
The authors indicated that food intake was not affected by exposure (data not shown). Graphical
and tabular presentation of data indicated that systolic blood pressure, heart rate, and mean
arterial pressure were unchanged by vanadium treatment in nonnephrectomized rats. Statistically
significant (p < 0.05) changes observed in nonnephrectomized rats at the end of exposure
included decreased cardiac output and increased total peripheral resistance at both doses and
increased hematocrit and decreased extracellular fluid volume at the high dose (see Table 5). In
partially nephrectomized rats, systolic blood pressure, mean arterial pressure, and total peripheral
resistance were significantly increased by exposure; other parameters were not affected by
exposure. The authors indicated that the increase in resistance resulted from a vasoconstrictive
effect of vanadium. In rats with intact kidneys, the increased peripheral resistance was offset by
a reduction in cardiac output and blood pressure remained stable. In partially nephrectomized
rats, there was no compensatory reduction in cardiac output; thus, an increase in blood pressure
was observed. Renal function was not modified by vanadium exposure in any of the groups of
rats, based on the parameters measured (data shown). These data indicate a LOAEL of
4 mg V/kg-day based on increased blood pressure in partially nephrectomized rats. A NOAEL
cannot be determined.
Table 5. Significant Changes in Cardiovascular Parameters in Rats Exposed to Sodium
Metavanadate for 24 Weeks3




4 mg V/kg-day
47 mg V/kg-day
Parameter
Control
(300 ppm)
(3000 ppm)
Nonnephrectomized rats
Cardiac output (mL/min per 100 g)
25.6 ± 1.2
22.2 ± 0.6b
21.2 ± 0.9b
Total peripheral resistance (mm Hg/mL per min per lOOg)
4.44 ±0.12
5.41 ± 0.23 c
5.82 ± 0.31c
Hematocrit
41.9 ±0.7
43.5 ±0.5
45.5 ± 1.3b
Extracellular fluid volume (mL/lOOg)
17.0 ±0.3
15.9 ±0.4
12.9 ± 0.3d
Partially nephrectomized rats
Mean arterial pressure (mm Hg)
112 ± 4
134 ± 3d
NA
Total peripheral resistance (mm Hg/mL per min per lOOg)
4.11 ±0.29
5.15 ± 0.25b
NA
aSusic and Kentera, 1988
bSignificantly different from control, p < 0.05
cp < 0.01
dp< 0.001
Van Vleet et al. (1981; Van Vleet and Boon, 1980) exposed groups of six male pigs to
ammonium metavanadate in feed (0 or 200 mg V/kg) for 10 weeks. The dose estimated for this
review was 10 mg V/kg-day based on the average body weight reported in the study (12 kg) and
assuming a feed consumption rate of 0.6 kg feed/day (Brooks et al., 1984; U.S. EPA, 1988). The
authors indicated that food consumption was decreased in the treatment group relative to controls
(data not reported); therefore, the calculated dose may overestimate the actual dose in the
treatment group. Endpoints assessed include clinical signs, weekly body weight measurements,
blood glutathione peroxidase activity, gross necropsy, and microscopic histopathology
assessment of heart, kidney, liver, lung, skeletal muscle, stomach, and "other organs with
lesions." There were two deaths in the treatment group (33% mortality): one death on Day 60 of
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exposure and one on Day 65. Clinical signs observed in treated pigs (and not in controls) were
emaciation, rough hair coats, diarrhea, and blood in feces (incidences not reported). Body
weights were markedly lower in the treatment group compared to the control group (one-third to
one-half of control values; significantly lower at/? < 0.05) throughout the exposure period; this
decrease may have been associated with the reduction in food consumption. Blood glutathione
peroxidase concentrations were not different from controls. The histopathology assessment
revealed no abnormalities in the control group and the following findings in the treatment group:
ulceration of the large intestine (4/4 surviving pigs), bladder cystitis (2/4), periportal infiltration
of mononuclear leukocytes in liver (3/4) and necrosis of the heart atria (2/4). The dose used in
this study (10 mg V/kg-day) is a FEL based on mortality and emaciation.
Chronic Studies—There were three multiyear bioassays of vanadium published in the
1960s and 1970s that have been identified in the literature searches; none of the studies met
current standards for assessment of chronic toxicity and/or carcinogenicity.
Kanisawa and Schroeder (1967) exposed white Swiss mice (53 treated, 198 controls; sex
not specified) to vanadyl sulfate in the drinking water at a concentration of 5 mg V/L from birth
until natural death. The dose estimated for this review is 1 mg V/kg-day based on default values
for body weight and water intake (U.S. EPA, 1988). The group sizes are not specified. Survival
and body weight were monitored. Upon death, the animals were examined for gross lesions and
the heart, lung, kidney, liver, spleen, and abnormal organs were examined microscopically. The
authors emphasized that the tumor data reflected only tumors visible under a magnifying lens
since serial sections for histopathology evaluation were not performed. The authors reported that
neither survival nor body weight were affected by vanadium treatment (data not shown). Tumor
incidences were grouped across sex for reporting. Based on the tabulated results, exposure to
vanadium did not increase the incidence of any individual tumor type or the total incidences of
"pre-tumorous lesions," benign, or malignant tumors (grouped across target organ). However,
statistical analysis of the individual tumor data is precluded by the absence of group size
information. These data are not adequate to define effect levels for chronic exposure.
Schroeder et al. (1970) exposed Long-Evans rats to vanadyl sulfate in drinking water
from weaning through natural death (up to 45 months in this study). The treatment group
consisted of 61 female and 52 male rats that had free access to drinking water to which 5 mg/L
vanadium was added. Controls (54 female, 52 males) were exposed to water without added
vanadium. Doses estimated for this review based on reported body weights and default fluid
intakes (U.S. EPA, 1988) are 0.7 and 0.9 mg V/kg-day in males and females, respectively. Body
weight was measured weekly until 6 weeks of age and then monthly thereafter; at the same
times, blood pressure was recorded and blood collected for assessment of serum glucose levels.
Upon death, animals were necropsied, hearts were removed and weighed, and grossly visible
tumors and other lesions were described. An outbreak of pneumonia during this study led to the
deaths of 17 treated males, 17 treated females, 19 control males, and 12 control females; the
timing of the outbreak was not reported. No differences were observed in the following
endpoints: life span and longevity, body weight, blood pressure (measured with arterial cannula
in anesthetized animals), urine protein and glucose, and gross tumor incidence (all data other
than urine protein were shown). This study found significant (p < 0.05) differences between the
treatment and control groups in the following endpoints: increased fasting plasma glucose
concentrations (21%) in treated females, increased fasting plasma cholesterol concentrations
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(18%) in treated males and decreased fasting cholesterol concentrations (41%) in treated
females. Absolute and relative heart weights were 18 and 15% lower (respectively) in treated
males relative to controls, while female heart weights were higher (4 and 5% higher for absolute
and relative weights, respectively). No treatment-related increases in tumor formation were
found. Microscopy was performed on "some" tissues; however, a comprehensive microscopy
evaluation apparently was not performed or not reported. No microscopic lesions were reported
for any animals, although the histological evaluations performed in this study were not adequate
to detect any but the most severe lesions. However, a LOAEL of 0.7 mg V/kg-day can be
established for increased fasting plasma glucose and cholesterol levels and decreased heart
weights.
Using a study design similar to that above, Schroeder and Michener (1975) exposed
groups of Swiss mice (54/sex) to vanadyl sulfate in drinking water (5 mg V/L) for their lifetimes;
controls (54/sex) were given untreated water. The dose estimated for this review based on
reported body weights and default estimates of fluid intake (U.S. EPA, 1988) was 1 mg V/kg-day
in both sexes. The toxicological evaluations are the same as reported by Schroeder et al. (1970).
Significant differences between the treatment and control groups included increased body weight
in treated males and increased life span and longevity in treated males and females. A gross
assessment of tumors and microscopy of "some" tissues revealed no treatment-related increases
in tumor incidence. The limitations in the histological evaluations performed in this study
preclude the identification of effect levels from these data.
Steffen et al. (1981) exposed groups of uninephrectomized rats (group sizes not reported)
to dietary concentrations of 100- or 200-ppm vanadium (as sodium orthovanadate) for 56 weeks.
Based on default values for food intake and body weight (U.S. EPA, 1988), the doses for this
experiment are estimated to be 7 and 14 mg V/kg-day. Body weights and systolic blood pressure
(measured by tail cuff) were measured weekly. Upon sacrifice at the end of exposure, heart
weights were recorded, and tail artery norepinephrine content was measured. There were two
rats given 14 mg V/kg-day that died "early in the experiment"; neither timing nor cause of death
was reported (Steffen et al., 1981). In the 14 mg V/kg-day group, body weights were
significantly (p < 0.05) below controls beginning at Week 20 of treatment; based on graphical
presentation of the data, terminal body weight in this group was about 13% below that of
controls. Body weight was not significantly different from controls in the low-dose group. In
both groups of vanadium-treated rats, systolic blood pressure was significantly (p < 0.05)
increased over controls, in a dose-dependent fashion, after the first 1-2 months of treatment.
Increases of up to 10 and 25 mm Hg were seen in the low- and high-dose groups, respectively.
Plasma vanadium concentration measured at sacrifice correlated strongly with the last measure
of systolic blood pressure (r = 0.71 ,p< 0 .001), bolstering evidence for the apparent relationship
with exposure. The low dose (7 mg V/kg-day) is a freestanding LOAEL for increased blood
pressure in uninephrectomized rats.
Dai et al. (1994a,b; Dai and McNeill, 1994) exposed groups of nondiabetic and diabetic
(streptozocin-induced) male Wistar rats to vanadyl sulfate in drinking water for 1 year. The
three publications each reported findings of different endpoints. A control group consisted of
eight rats given free access to water without added vanadate. There were three treatment groups
that consisted of 8 rats/group exposed to water to which vanadyl sulfate was added; the
exposures (mg vanadyl sulfate/L) were as follows: treatment group 1500 mg/L for 52 weeks;
treatment group 2500 mg/L for 1 week followed by 750 mg/L for 51 weeks; treatment group
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3500 mg/L for 1 week followed by 750 mg/L for 1 week, followed by 1250 mg/L for 50 weeks.
Food intake, fluid intake, and body weight were recorded every 3-5 weeks throughout the
treatment period. On the basis of these measures, the authors estimated the doses of vanadyl
sulfate to be 34, 54, and 90 mg/kg-day (8, 13, and 21 mg V/kg-day, using the molecular weight
for the trihydrate form) in nondiabetic rats. In diabetic rats, vanadyl sulfate treatment was
adjusted up or down in order to control blood glucose or prevent diarrhea and weight loss. The
authors estimated vanadyl sulfate doses of 73 to 165 mg/kg-day (17 to 39 mg V/kg-day) at
different time points in the diabetic rats. The general condition of the animals—especially the
occurrence of diarrhea or cataracts—was assessed during treatment. Nonfasting blood glucose
was measured weekly for the first month and then every 2-4 weeks thereafter. Fasting blood
glucose, insulin, triglycerides and cholesterol were measured every 3 months during treatment.
The following measurements were made after 3, 6, 9, and 12 months of exposure: blood pressure
(measured with a tail cuff sensor in conscious animals), pulse rate, hematocrit and plasma
concentrations of AST, ALT, and urea. Most animals were sacrificed after the exposure period;
however, three control nondiabetic rats, eight treated nondiabetic rats, and five treated diabetic
rats were monitored for 16 untreated weeks prior to sacrifice. At sacrifice, a hematology
assessment (Hgb, RBC, total and differential WBC, platelet count, reticulocyte count) was
conducted and the following organs were weighed and examined microscopically: adrenal, brain,
heart, kidney, liver, lung, pancreas, spleen, testis, and thymus.
In nondiabetic rats, 1/8 animals treated at the highest dose died of unknown causes after
18 weeks of exposure (Dai et al., 1994a). Neither food nor fluid intake was significantly affected
by exposure to vanadyl sulfate (data shown graphically). However, body weight gain was
reduced in a dose-related manner in treated nondiabetic animals relative to control nondiabetic
animals. Based on visual inspection of data presented graphically, the body weight decrements
at termination were approximately 10% in the low- and mid-dose groups and 20% in the
high-dose group; statistical analysis of the data was not presented. Other than body weight data,
most information on the nondiabetic treated rats was pooled across the three treatment groups
(the authors indicated that there were no differences among the three groups). Vanadyl sulfate
treatment did not affect blood or plasma glucose levels, plasma triglycerides, or cholesterol
levels, but significantly lowered plasma insulin levels compared with controls at Weeks 12 and
25 (data presented graphically; p-walue not reported). No significant changes were observed in
the treatment group relative to the control group for the following endpoints: systolic blood
pressure, pulse rate, hematology endpoints and relative organ weights (Dai et al., 1994a; Dai and
McNeill, 1994). Plasma ALT and urea concentrations are significantly (p < 0.05) higher
(<2-fold higher based on data presented graphically) in the nondiabetic treatment group relative
to the corresponding control group after 3 months of exposure but not after 6, 9, 12, or
16 months of exposure (data presented graphically).
Histopathology findings included a high incidence of glomerular and tubular
degeneration and interstitial cell infiltration and fibrosis of the kidney in the nondiabetic control
group: 3/5 (60%) at the end of exposure and 2/3 (66%) at 16 weeks postexposure, for a combined
incidence of 5/8 (63%) for the two assessment times (Dai et al., 1994b). Despite this high
incidence in controls, which was probably age- and/or husbandry-related, the treated animals (all
three treatment groups pooled) had a higher incidence: 15/15 (100%, p = 0.053) at the end of the
exposure, 7/8 (88%,p = 0.049) 16 weeks postexposure and a combined incidence of 22/23 (96%;
p = 0.043) (based on Fisher exact test performed for this review). These results are consistent
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with the higher plasma urea concentrations in the treatment group. No other histopathology
findings are significantly increased with exposure to vanadyl sulfate. Based on the reduced body
weight in the low-dose group (-10% lower than controls at termination), and possibly renal
pathology, a LOAEL of 8 mg V/kg-day is identified for nondiabetic rats; no NOAEL can be
determined.
Vanadyl sulfate treatment of diabetic rats improved or prevented a number of adverse
effects seen in untreated diabetic rats, including: mortality; increased food and fluid intake;
hypoinsulinemia; polydipsia; cataract formation; elevations of serum glucose, ALT, urea,
triglycerides and cholesterol; bradycardia; decreased leukocyte count; increased relative organ
weights and occurrence of megacolon (Dai et al., 1994a,b; Dai and McNeill, 1994). No
improvement was seen in body-weight gain, which was markedly lower in both untreated and
vanadyl sulfate-treated rats than in both control and treated nondiabetic rats. At the end of
exposure, body weights were about 30% lower in both groups of diabetic rats when compared
with nondiabetic controls (based on graphical presentation of data). Likewise, renal effects that
were significantly increased in diabetic controls (compared with nondiabetic controls), including
vacuolation of tubular epithelial cells and renal cell tumors, occurred at similar frequency in
vanadyl sulfate-treated diabetic rats. As vanadium treatment was not associated with adverse
effects in diabetic rats, the dose to this group (17 to 39 mg V/kg-day) is considered a NOAEL in
diabetic rats.
Carmignani et al. (1991) exposed male Sprague-Dawley rats to sodium metavanadate in
drinking water for 7 months beginning at weaning. Groups of 10 rats were exposed to water to
which 0 or 100 mg V/L was added. The calculated dose was 12 mg V/kg-day, based on default
values for fluid intake and body weight (U.S. EPA, 1988). At the end of exposure, blood
pressure was measured (with an arterial cannula in anesthetized animals), urinalysis was
performed on a 24-hour urine collection and both light and electron microscopic evaluation of
the heart and kidney were performed. Systolic and diastolic blood pressure were significantly
(p < 0.05) elevated in the treatment group compared to the control group (systolic: control
122 mmHg, treatment group 144 mmHg; diastolic: control 95 mmHg, treatment 115 mmHg), as
was heart rate (control 239 beats per minute, treatment 288 beats per minute). According to the
authors, the urinalysis revealed no difference in urine osmolality, nitrogen, protein, or ionized
calcium between the treatment and control group (data not shown). Urinary sodium and
potassium excretion were significantly elevated (83% and >3-fold higher, respectively; p < 0.05)
in the treatment group compared to the control group. The histopathology assessment revealed
narrowing of the renal proximal tubules, which contained amorphous protein material and
swollen mitochondria, in the treatment group. The incidences of these changes in treated and
control animals are not reported. No changes were noted in the hearts of the treatment group
relative to the control group. A LOAEL of 12 mg V/kg-day is identified based on the increased
blood pressure and kidney histopathology. A NOAEL cannot be identified.
Investigators from the same laboratory (Boscolo et al., 1994) conducted further
experiments with male Sprague-Dawley rats exposed to sodium metavanadate in drinking water.
Groups of six rats were exposed to water containing 1, 10, or 40 mg V/L for 180, 210, and
210 days, respectively, in two experiments. Each experiment had a separate control group
receiving untreated water for the same duration. Doses estimated for this review based on
default estimates of fluid intake and body weight (U.S. EPA, 1988) were 0.12, 1.2, or
4.7 mg V/kg-day. The following endpoints were assessed: blood pressure (measured with an
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arterial cannula in anesthetized animals); heart rate; plasma renin activity, plasma aldosterone,
urinary kallikrein activity and urinary Kininase I and II activities (indicators of status of the
renin-angiotensin-aldosterone system); urinalysis (creatinine, total nitrogen, proteins, sodium,
potassium, and calcium); and microscopic examination of blood vessels, brain, heart, kidney,
liver, and lung. Histochemical analysis of the Na+, K+-ATPase activity was assessed in the
kidneys of high dose and control rats. Statistically significant changes in the measured
parameters are shown in Table 6. Significantly higher (p < 0.05) systolic and diastolic blood
pressures were observed in all treatment groups relative to the control group. The magnitude of
the increase did not appear to be dependent on dose level. Plasma renin activity, plasma
aldosterone concentration, and urinary kallikrein, Kininase I, and Kininase II were significantly
elevated in the 1.2 and 4.7 mg V/kg-day treatment groups relative to controls, suggesting
stimulation of the renin-angiotensin-aldosterone system at these exposure levels. In addition,
Kininase I activity was doubled at 0.12 mg V/kg-day, although not statistically significant. In
contrast, Kininase II activity and plasma aldosterone were significantly reduced at the low dose.
The histological assessment revealed narrowing of the lumen and amorphous casts in renal
proximal tubules and a decrease in histochemically detected Na+, K+-ATPase activity in injured
tubules in the 4.7 mg V/kg-day treatment group. The authors also reported hydropic
degeneration (swelling of the cells) in proximal, distal, and straight tubules. The incidences of
the latter effect were not reported; however, the authors indicated that these changes were "less
evident" at 1.2 mg V/kg-day and absent at 0.12 mg V/kg-day. These data suggest a LOAEL of
0.12 mg V/kg-day based on increased blood pressure (>20 mm Hg increase in both systolic and
diastolic measures) and stimulation of the renin-angiotensin-aldosterone system. A NOAEL for
increased blood pressure cannot be determined. However, a NOAEL for kidney effects
(histopathology) is established at 0.12 mg V/kg-day, with a LOAEL at 1.2 mg V/kg-day.
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Table 6. Significant Effects on Cardiovascular Parameters
in Male Rats Exposed to Sodium Metavanadate3
Parameter
Controlb
0.12 mg
V/kg-day
(180 days)
1.2 mg V/kg-
day
(210 days)
4.7 mg V/kg-day
(210 days)
Systolic blood pressure (mm Hg)
108 ±5C
106 ±7
130 ±4d
137 ±5d
132 ±4d
Diastolic blood pressure (mm Hg)
84	±4
85	±5
106 ± 3d
112 ± 5d
114 ±7d
Plasma renin activity (ng/mL/h)
13.4 ±3.4
10.3 ±2.7
10.6 ±2.4
47.5 ± 14.9d
40.6 ± 12.4d
Plasma aldosterone (pg/mL)
264 ± 22
188 ±57
158 ±lld
554 ±160d
265 ±61
Kallikrein (nM/mg creatinine)
8.02 ± 1.90
8.43 ± 0.96
4.36 ± 0.60d
13.67 ±2.54d
11.72 ±0.80d
Kininase I (nM x 10~3 of hydrolyzed
substrate/mg creatinine)
27.6 ±5.4
32.0 ±4.2
56.8 ±25.3
129.9 ± 14.9d
156.8 ±9.1d
Kininase II (nM x 10"3 of hydrolyzed
substrate/mg creatinine)
2.23 ±0.33
1.83 ±0.26
2.30 ±0.31
2.63 ± 0.13d
3.92 ± 4.08d
Urinary potassium excretion
1 l(mEq/g creatinine)
113 ± 25
118 ± 14
106 ±6
169 ±18d
221 ±28d
aBoscolo et al., 1994
bFirst result is for 180-day control group; second is for 210-day control group.
°Mean ± standard error of the mean
dSignificantly different from corresponding control, p < 0.05
Reproductive Studies—Effects on reproductive success have been reported with
preconception exposure to vanadium compounds. Domingo et al. (1986) administered daily
gavage doses of 0, 5, 10, or 20 mg/kg-day sodium metavanadate (2.1, 4.2, or 8.4 mg V/kg-day)
to male and female Sprague-Dawley rats (20/sex/dose). Male rats received daily doses for
60 days after which they were mated to female rats that had received the same doses 14 days
prior to mating. Dosing of females continued through gestation. Half of the females were
sacrificed on gestation day (GD) 14 for assessment of the number of corpora lutea, total
implantations, resorptions, and living and dead fetuses. The remaining dams were continued on
the exposure regimen through weaning of their pups (postnatal day [PND] 21). Evaluations of
offspring included viability, body-weight gain, body and tail lengths and clinical signs on
PND 1, 4, and 21. Results for pups were pooled across litters. Upon sacrifice of pups at
weaning, the weights of heart, lungs, spleen, liver, kidneys, and testicles were recorded. The
authors reported that maternal toxicity was not evident in the treated dams, but did not specify
the endpoints measured to assess maternal effects. No significant differences between the
treatment and control groups were observed in the various indicators of reproductive success
assessed at sacrifice on GD 14 (data shown). A significant decrease (p < 0.05) in pup growth
occurred in all treatment groups compared to the control group, as indicated by deficits in whole
litter weight and pup body weight, head-to-rump length, tail length, and relative kidney and liver
weights (organ-/body-weight ratios). Body weight per litter was significantly decreased in the
high-dose group on PND 4 and the mid- and high-dose groups on PND 21. Table 7 shows the
changes in pup growth parameters (pooled across litters) observed on PND 1, 4, and 21. At the
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high dose, significant (p < 0.05) decreases in relative heart (males only) and spleen weights (both
sexes) were also observed. These data suggest a developmental toxicity LOAEL of
2.1 mg V/kg-day based on growth retardation in pups; a developmental NOAEL was not
identified. Due to the lack of information on maternal endpoints evaluated, effect levels for
systemic toxicity cannot be determined
Table 7. Significant Effects on Growth Parameters (Pooled Across Litters) in Pups of
Dams Exposed to Sodium Metavanadate3

Parameter
Control
2.1 mg V/kg-day
4.2 mg V/kg-day
8.4 mg V/kg-day
Males
Body weight PND 1 (g)
7.9 ± 0.9(63)b
7.0 ± 1.1° (57)
6.5±0.9° (77)
6.7±0.6° (48)
Body weight PND 4 (g)
11.7 ± 1.3 (63)
9.6 ± 1.8° (57)
9.7 ± 1.2° (63)
8.9 ± 0.8° (40)
Body weight PND 21 (g)
42.0 ±8.3(57)
34.3 ± 7.9° (56)
33.7 ± 10.8° (35)
33.6 ± 7.6° (38)
Body length PND 1 (mm)
56.8 ±3.5
54.2 ± 3.6d
53.4 ± 3.4e
53.1 ± 3.0e
Body length PND 4 (mm)
67.1 ±3.4
62.0 ± 4.4°
64.7 ± 3.6°
62.2 ± 2.5°
Body length PND 21 (mm)
119.1 ± 6.1
108.0 ± 10.0C
102.8 ± 16.2°
104.8 ± 10.8C
Tail length PND 4 (mm)
30.4 ±2.4
23.9 ± 3.4°
25.8 ± 3.8°
23.6 ± 2.3°
Relative liver weight (g/lOOg BW)
5.12 ±0.58
4.72 ± 0.56d
4.63 ± 0.40d
4.57 ± 0.54d
Females
Body weight PND 1 (g)
7.6 ±0.9 (54)
6.8 ± 1.0° (58)
6.4 ± 0.9° (62)
6.5 ± 0.6° (43)
Body weight PND 4 (g)
11.2 ± 1.9 (53)
9.5 ± 1.6° (58)
9.3 ± 1.4° (48)
8.8 ± 1.1° (39)
Body weight PND 21 (g)
41.0 ±6.7 (51)
32.5 ± 6.3° (53)
29.7 ± 7.2° (20)
32.1 ± 8.8° (38)
Body length PND 1 (mm)
55.5 ±3.4
53.6 ± 3.7e
52.4 ± 3.9°
52.0 ± 2.6°
Body length PND 4 (mm)
65.5 ±3.0
61.4 ± 3.8°
63.0 ± 3.7°
61.5 ± 3.3°
Body length PND 21 (mm)
119.7 ±6.9
105.5 ± 11.3°
100.9 ± 11.7°
104.4 ± 11.3°
Tail length PND 4 (mm)
30.7 ±2.4
25.1 ±3.1°
26.2 ± 3.8°
24.3 ± 2.5°
Tail length PND 21 (mm)
70.4 ±8.0
66.3 ± 7.0d
68.9 ±9.5
61.0 ± 6.0°
Relative liver weight (g/lOOg BW)
5.53 ±0.45
5.04 ± 0.80d
5.01 ± 0.75d
4.72 ± 0.63e
Relative kidney weight (g/lOOg BW)
1.56 ±0.17
1.38 ± 0.22d
1.45 ± 0.20d
1.32 ± 0.16e
aDomingo et al, 1986
''Mean ± SD (number of animals)
><0.001
dSignificantly different from control, p < 0.05
><0.01
Llobet et al. (1993) exposed male Swiss mice to sodium metavanadate in drinking water
for 64 days prior to mating for 4 days with unexposed females. There were four treatment
groups that consisted of 24 mice per group given water to which 100, 200, 300, or 400 mg/L
sodium metavanadate was added. The authors reported the doses as 20, 40, 60, or 80 mg/kg-day
sodium metavanadate, which correspond to calculated vanadium doses of 8.4, 17, 25, or
33 mg V/kg-day. The control group consisted of 24 mice given water without added vanadate.
Dams were killed 10 days after mating (GD 10-14) and their uteri were examined to evaluate
pregnancy outcomes. Endpoints assessed included body weights; reproductive success,
including the number of implantations, early or late resorptions and dead or live fetuses; testis
and epididymis weights; and sperm counts, motility, and morphology. Body weights in the
33 mg V/kg-day group were significantly lower than in the control group (13%,/? < 0.05). The
absolute (but not relative) epididymis weight was reduced by treatment (12%, p < 0.01). There
was no difference in the absolute or relative testis weight between the control and treatment
groups. A lower number of successful impregnations occurred in the 25 and 33 mg V/kg-day
dose groups compared to the control group (43.8% and 62.5%, respectively, compared with
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81.3% in controls; p < 0.01). There were no differences in the number of resorptions or fetal
mortality. Outcomes related to sperm included: lower spermatozoa counts in the 25 and
33 mg V/kg-day groups relative to the control group (44% and 31% lower, respectively); a lower
spermatid count in the 33 mg V/kg-day group (30%,p < 0.01) and no significant difference in
sperm motility or morphology between control and treatment groups. These data indicate a
LOAEL of 25.1 mg V/kg-day based on reproductive effects in treated male mice (decreased
spermatozoa counts and reduced fecundity); the NOAEL is 17 mg V/kg-day.
In a study comparing reproductive effects of vanadium in diabetic and nondiabetic rats,
Ganguli et al. (1994a) administered concentrations of 0, 250, or 500 mg/L sodium orthovandate
(-69 or 138 mg V/L) with 0.45% normal saline in the drinking water of female Sprague-Dawley
rats. There were six groups of 15 rats/dose that were used (three groups each of nondiabetic and
streptozocin-induced diabetic rats). The authors reported that the animals were mated to
untreated males at the commencement of treatment (Day 1); however, the balance of the
treatment regimen was not described, so the duration of treatment is not known. Body weight,
fluid intake, and urine glucose were measured daily; however, data on body weight and fluid
intake are not reported or described. In the absence of information on the treatment schedule, it
is not possible to estimate doses with any degree of confidence. Pregnant dams were sacrificed
one day after giving birth; those treated females that did not become pregnant or failed to deliver
were sacrificed for examination of uteri and ovaries. At birth, the total number of pups and total
body weight were recorded. In contrast to the findings discussed previously (Dai et al., 1994a,b;
Dai and McNeill, 1994), vanadium was severely toxic to diabetic rats; 7/15 females exposed to
500 mg/L died before Day 15 of treatment and the remainder had severe diarrhea and lack of
appetite; these animals were sacrificed humanely. Mortality also occurred at the low dose in
diabetic rats (3/15). No deaths occurred in controls. In high-dose nondiabetic rats,
moderate-o-severe diarrhea was observed in 12/15 rats; this effect was not reported in low-dose
nondiabetic rats. The rate of conception was significantly (p < 0.05) reduced by vanadium
exposure in both diabetic and nondiabetic rats. When compared with nondiabetic controls, the
rate of conception is reduced by 13% and 20% at 250 and 500 mg/L (respectively) in nondiabetic
rats and by 7%, 33%, and 47% in 0, 250, and 500 mg/L (respectively) diabetic groups. Ability to
carry a pregnancy to term was also compromised by vanadium exposure, significantly so in the
diabetic animals. Compared with nondiabetic controls, nondiabetic treated animals exposed to
250 and 500 mg/L were 30% and 84% (respectively) less likely to carry pregnancy to term. In
diabetic animals, fewer than 10% of animals at the low dose carried pregnancy to term; as the
high-dose group was sacrificed early, there are no data on this endpoint. Effect levels cannot be
determined from these data since duration of treatment is unknown and doses could not be
estimated.
Faria de Rodriguez et al. (1998a) conducted three experiments to evaluate the effects of
exposure to vanadium on the development of the central nervous system in albino rats. This
study was published in Spanish and translated for this review. Groups of four female rats were
used in all experiments. In the first experiment, three groups were exposed to 0, 100, or 200 ppm
ammonium metavanadate (43.5 or 87 ppm V) in the drinking water from weaning until mating;
treatment was discontinued during mating and gestation. Doses estimated for this review based
on default values of water intake and body weight (U.S. EPA, 1988) were 7 and
15 mg V/kg-day. From each group, two dams were sacrificed at GD 20, while the other two
were allowed to deliver. Litters were sacrificed at birth for gross examination of external and
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internal malformations and the CNS was removed for microscopic examination and
histochemical assessment of glycosaminoglycans. In another experiment, two groups of
neonates whose mothers had been exposed to 100-ppm ammonium metavanadate from 37 days
of age until mating were exposed to concentrations of 0 or 100 ppm via lactation until weaning
and then via drinking water until mating. As with the first experiment, half of each group was
sacrificed at GD 20 and half after delivery; evaluation of litters was also the same. In the final
experiment, newborn rats of untreated mothers were exposed via lactation and then via drinking
water to 0 or 200 ppm ammonium metavanadate. All rats of the final experiment were permitted
to deliver. Females in all of the control groups delivered litters averaging from 5-11 offspring
each. All four rats exposed to 7 mg V/kg-day in the first experiment became pregnant,
delivering an average of 11 offspring per litter. At 15 mg V/kg-day, one rat died, one delivered a
litter of 11 offspring, and the other 2 did not become pregnant. In the second experiment, of four
rats exposed to 7 mg V/kg-day from birth to mating, only two became pregnant and delivered
litters, averaging six offspring each. Similarly, in the third experiment, exposure to
15 mg V/kg-day resulted in only 2/4 females delivering litters (4 and 10 offspring each). No
gross external malformations were observed in any of the groups. Data on the microscopic
examination of brains were grouped across the experiments, so a dose-response relationship
could not be discerned. Of the 81 brains obtained from the offspring of treated animals,
13 exhibited unilateral hypoplasia of the olfactory bulb and one exhibited unilateral hypoplasia
of the cerebral hemisphere; the remaining brains were characterized as normal. Microscopic
effects on the olfactory bulbs (for example, thinning or disorganization of the glomerular layer)
were also seen in the brains of animals with grossly observable effects; the incidences of specific
effects were not reported. All brains of control offspring were normal both macroscopically and
microscopically. Histochemical studies indicate that exposure to 15 mg V/kg-day increased the
glucosaminoglycan content—specifically those of a low grade of sulfation. Effect levels cannot
be determined from these data due to the lack of incidence data, the grouping of effect
information across treatment groups, and incomplete reporting.
Faria de Rodriguez et al. (1998b) exposed male and female Swiss albino mice to
ammonium metavanadate from birth until the animals were mated. This study was published in
Spanish and translated for this review. The test compound was administered in drinking water to
mothers so that the offspring were exposed via lactation until weaning, when they were
continued on the same exposure via drinking water (0, 100, or 200 ppm) until mating. These
concentrations correspond to 43.5 and 87 ppm vanadium or dose estimates of 15 and
30 mg V/kg-day (males) and 14 and 28 mg V/kg-day (females) based on default values2 for body
weight and water intake (U.S. EPA, 1988). The animals' body weight, body length, and tail
length were measured weekly. At maturity, the males and females of each exposure group were
mated with same-treated mice or cross-mated with untreated mice to evaluate separately the
effects on each gender. Numbers of offspring, as well as weight and length of offspring, were
assessed after successful mating. The authors reported the results of statistical analysis of the
parameters, but did not report the data for any endpoints. In addition, results for the same
exposure level were grouped across sex. The authors reported that there were no
treatment-related differences in body weight of the parents. Body length of treated mice was
significantly (p < 0.05) reduced with exposure to 28-30 mg V/kg-day, and tail length was
significantly lower at both exposure levels when compared with control animals. In contrast,
neither weight nor length of offspring was affected in any of the matings. Further, the number of
2Assuming body weight and water intake at weaning.
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offspring was higher in the exposure groups than in the control group. Effect levels cannot be
determined from these data due to inconsistent outcomes and poor reporting.
The same group of investigators conducted additional experiments on female Swiss
albino mice (Nava de Leal et al., 1998). This study was also published in Spanish and translated
for this review. Ammonium metavanadate was administered in drinking water at concentrations
of 0, 100, or 200 ppm (0, 43.5, or 87 ppm vanadium) at various times as shown in Table 8. Dose
estimates calculated for this review are 11 or 23 mg V/kg-day based on default values3 for body
weight and water intake (U.S. EPA, 1988). In each experiment, exposure was suspended during
8 days of mating with untreated males (ratio of 1 female to 2 males) and during gestation. After
mating, the mice were housed individually and weighed twice weekly. Pregnant mice were
allowed to deliver; pregnancy rates and number of offspring were recorded. Those mice that
failed to become pregnant were sacrificed 21 days after mating for evaluation of the following
parameters: uterine and ovarian weights; corpora lutea counts and histopathology examination of
the ovaries. The reporting of results was limited by some inconsistencies and apparent
typographical errors. As Table 8 shows, the pregnancy rate was significantly reduced from
controls in 2/3 groups (CI and F1C, but not A2) exposed to 23 mg V/kg-day but not in any group
exposed to 11 mg V/kg-day. The absence of an effect on pregnancy rate in Group A2 (exposed
to 23 mg V/kg-day from weaning until mating) contrasts with the findings in Group CI (exposed
to 11 mg V/kg-day until first mating and then to 23 mg V/kg-day from parturition until second
mating) and suggests that cumulative exposure may be an important factor in the effects of
vanadium on mating success. In the statistical analysis of litter sizes, groups exposed for
different time periods to the same concentration were combined (details unclear). The results
shown in Table 8 indicate that litter size is significantly smaller in mice exposed to
23 mg V/kg-day compared with controls (p-value not given). A similar approach was used to
compare the numbers of corpora lutea; this analysis also showed a reduced average number of
corpora lutea in mice exposed to 23 mg V/kg-day compared with untreated controls. Corpora
lutea were counted only in mice that failed to become pregnant, which may have biased the
findings.
3Assuming body weight and water intake for subchronic exposure.
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Table 8. Exposures, Group Sizes, and Pregnancy Outcomes Among Mice Exposed to

Ammonium Metavanadate3




Dose (mg
No.
Pregnancy
Average
Group
Exposure Period
V/kg-day)
Mice
Rate (%)
Litter Size
Al
Weaning to adulthood (mating)
0
8
NRb
13


11
12
50
13
A2
Weaning to adulthood
0
8
50
9


23
12
66.6
8
B
Weaning to adulthood
0
8
75
11


11
12
83.3
9
B1
Second mating of Group B; no exposure
0
6
100
10

between matings
11
10
100
10
FIB
Offspring of Group B
0
9
66.6
NR


11
26
73
NR
C
Weaning to adulthood
0
8
75
9


11
12
83.3
10
CI
Mice Group C that successfully became
0
6
100
9

pregnant; exposed from parturition until
23
10
20 c
3

second mating




F1C
Offspring of Group C; exposed via lactation
0
8
65
12

until weaning and drinking water until
23
24
0C
0

adulthood




aNava de Leal et al., 1998
bNot reported
Significantly different from control, p < 0.0001
Microscopic examination of the ovaries from mice that failed to become pregnant showed
histopathology associated with exposure to vanadium (Nava de Leal et al., 1998). Most (94%)
samples of ovaries from control mice that failed to become pregnant were reportedly normal. In
contrast, ovaries of mice exposed to 11 mg V/kg-day (Groups Al and B) exhibited fewer
follicles and/or follicular atresia (absence of follicles due to degeneration); the follicles that were
seen were enlarged and conferred a "polycystic aspect" on the ovaries. Histopathology findings
in the ovaries of mice exposed to 23 mg V/kg-day (Groups A2, CI, and F1C) were more
pronounced, including absence of mature follicles and corpora lutea, marked follicular atresia,
thickening of the external theca, loss of ovarian parenchymal architecture, cellular
disaggregation, and cytoplasmic vacuolation in granulosa lutein cells. The authors reported the
incidences of these findings in the ovaries of mice that did not become pregnant; however, the
overall incidences of these effects in treated mice were not available, as histopathology was not
assessed in mice that became pregnant. Ovarian histopathology changes in mice exposed to
11 mg V/kg-day suggest that this dose may be a LOAEL, despite the lack of effect on pregnancy
success; however, the absence of data on overall incidences in the treated and control groups
(including those that became pregnant), in addition to reporting problems, precludes definition of
reliable effect levels for this study.
Morgan and El-Tawil (2003) also assessed the effects of vanadium exposure on
reproductive success. Groups of 10 male and 20 female Sprague-Dawley rats were given
ammonium metavanadate at concentrations of 0 or 200 mg/L (87 mg V/L) in the drinking water.
Based on default values of water intake and body weight (U.S. EPA, 1988), the dose is estimated
to be 28 and 30 mg V/kg-day in males and females, respectively. Exposed male rats were treated
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for 70 days prior to mating with untreated females; exposed females were treated for 14 days
premating and during mating, gestation, and lactation (total of 61 days). During premating, the
estrous cycles of females were monitored. Maternal body weights were recorded at the end of
gestation. Half of each group of females was sacrificed on GD 20, while the other half, along
with their pups, was sacrificed after weaning on PND 21. Gravid uterine and placental weights
were recorded. Males were sacrificed after mating for assessment of body, testes, epididymis,
prostate, and seminal vesicle weights. Reproductive parameters assessed in the study included:
gestation duration; signs of dystocia; numbers of corpora lutea, implantation sites, resorptions,
pre- and postimplantation losses; live and dead fetuses; fetal body weight at birth and on PND 4,
7, 14, and 21 and fetal survival during lactation. During lactation, pups were examined for
learning and memory responses; however, the specific methods and endpoints were not
described. All pups were examined for gross malformations at sacrifice; two-thirds were
examined for skeletal abnormalities and the remainder for visceral abnormalities. Exposure to
ammonium metavanadate resulted in profound effects on reproductive success and offspring
development, regardless of whether males or females were treated. Statistically significant
adverse effects are reported for nearly every reproductive parameter assessed, including maternal
body, uterine and placental weights; litter parameters; viability of offspring at birth; pup body
weight during lactation and incidences of gross, visceral and skeletal malformations. In addition,
fewer treated females exhibited normal estrous cycles; treatment of females also resulted in
reduced survival and viability indices of offspring. Body weight of treated males was not
affected, but testes, epididymis, prostate gland and seminal vesicle weights were significantly
(p < 0.05) reduced by exposure. Few offspring were produced in the treated groups (20 and 35
in the offspring of treated males and females, respectively, compared with 216 controls). Those
that were produced had a high frequency of gross, visceral, and skeletal anomalies. Data were
reported using the fetus, rather than the litter, as the unit of statistical analysis, so it is not
possible to assess the litter distribution of effects. These data suggest a freestanding LOAEL of
28 mg V/kg-day for reproductive toxicity in rats.
Developmental Studies—Elfant and Keen (1987) exposed groups of at least 14 pregnant
Sprague-Dawley rats to diets containing 0- or 75-ppm vanadium (as sodium metavanadate)
throughout pregnancy and lactation. Based on default values for body weight and food intake4
(U.S. EPA, 1988), the dose of vanadium was around 7 mg/kg-day. Maternal weight and food
intake were recorded daily. When the dams gave birth, live and dead pups were counted. Pup
weights were recorded at birth and every second day thereafter until PND 21. Sacrifice of both
dams and pups was performed at PND 21, whereupon brain, kidney, spleen, pancreas, heart,
thymus, and testes were weighed. Liver samples were collected for analysis of lipid peroxidation
products (reduced glutathione, thiobarbituric acid reactivity, and superoxide dismutase activity).
The authors reported that both food intake and body-weight gain were lower in the
exposed dams (statistical analysis not reported); at parturition, the cumulative weight gain
appeared to be about 25% lower in exposed animals relative to controls based on visual
examination of body-weight gain data presented graphically (Elfant and Keen, 1987). Data on
food intake are not reported. The percentage of pups born alive was smaller in exposed dams
(about 80%) than in controls (about 90%) and survival to weaning was also lower (about 40% vs.
about 70%) in controls based on visual examination of data presented graphically and without
4Default values for body weight and food intake are uncertain estimates of weight and intake for pregnant animals,
but they do provide an approximate estimate of dose in the absence of study-specific data on these parameters.
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statistical analysis). The cumulative weight gain of the surviving pups was lower in exposed
offspring; at weaning, mean body weights of exposed pups were about 34% lower than controls
(data shown graphically and without statistical analysis). Pups of exposed dams were reported to
exhibit diarrhea, seborrhea, lethargy, staggered gaits, and ocular exudate (incidences not
reported). The relative weights of the liver, brain, and testes were higher in exposed vs. control
pups (18%, 36%), and 15%,p< 0.05). Reductions in body-weight gain among exposed pups
complicate the interpretation of these organ weight changes. Thiobarbituric acid reactivity was
elevated in whole cell homogenates from the livers of both dams and pups exposed to vanadium;
reduced glutathione was lower in exposed pups than in control pups but was not affected in
dams. The latter findings suggest increases in lipid peroxidation with vanadium exposure that
may contribute to developmental toxicity. These data indicate a maternal and developmental
LOAEL of about 7 mg/kg-day based on reduced maternal food intake and weight gain, as well as
reduced pup survival, body weight, growth and clinical signs in pups. A NOAEL cannot be
identified.
The effects of sodium metavanadate on development were further studied by
Paternain et al. (1987). Groups of 20 pregnant Sprague-Dawley rats were treated with sodium
metavanadate via gavage at doses of 0, 5, 10, or 20 mg/kg-day during GD 6-15. Equivalent
doses of vanadium were 2, 4, and 8 mg V/kg-day. On GD 20, the uteri were opened by
Caesarean section for examination of corpora lutea, implantations, live and dead fetuses, and
resorptions. Placental weights were recorded and fetal body weight, body length, and tail length
were measured. Gross abnormalities were assessed in all fetuses; half were examined for
skeletal abnormalities and half were examined for visceral anomalies. The paper does not report
any evaluation of maternal toxicity parameters. At the high dose, fewer litters were produced
than in controls or in other dose groups (14, 14, 12, and 8 in control, 2, 4, and 8 mg V/kg-day
groups, respectively), but the decrease is not statistically significant. The numbers of resorptions
were increased and numbers of live fetuses decreased at both 4 and 8 mg V/kg-day; however,
these differences were also not statistically significant. A slight—but statistically significant—
decrease in tail length was observed at 2 and 8 mg V/kg-day (4- 5%,/> < 0 .01), but not at
4 mg V/kg-day; there was no apparent dose-response relationship. The authors reported that the
incidences of skeletal and visceral abnormalities were not affected by treatment (data not
shown). A higher percentage of fetuses in the high-dose group exhibited facial (18%>) and dorsal
(10%>) hemorrhages when compared with controls (2% for facial and 2% for dorsal); however, a
litter-based comparison between the groups is not presented. The authors characterized the
4 mg V/kg-day dose as a NOAEL for developmental effects on the basis of the hemorrhages
observed at the high dose. However, the lack of information on the litter distribution of fetuses
with hemorrhages precludes a reliable determination of effect levels from these data. Further, as
maternal parameters were not evaluated, no determination of maternal effect levels can be made.
Paternain et al. (1990) administered gavage doses of 0, 37.5, 75, or 150 mg/kg-day
vanadyl sulfate pentahydrate (7.5, 15, or 30 mg V/kg-day) to female Swiss mice on GD 6-15.
The control group included 20 mice and the treatment groups consisted of 16 or 20 mice per
group. Body weight and food consumption were recorded daily and observations for morbidity
and mortality were also made daily. Dams were killed on GD 18 and fetuses harvested by
Caesarean section; dams were then examined for gross pathology. The following litter
parameters were evaluated: number of implants, number of resorptions, and number of live and
dead fetuses. Fetal sex, weight, and length were noted. Pups were examined for external,
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visceral, and skeletal abnormalities. Treatment did not result in mortality or clinical signs, and
food consumption was not different between the treatment and control groups. A significant
(p < 0.05) decrease in body-weight gain of the dams occurred in all treatment groups during the
treatment period (46%, 53%, and 59% below controls at low, mid-, and high doses, respectively).
At termination, body weights corrected for gravid uterine weights were reduced at 15 and
30 mg V/kg-day (16% below controls at both doses; p < 0.05). At these doses, absolute liver and
kidney weights were also reduced proportionate to the body weight decrements. A significant
(p < 0.05) increase in early resorptions occurred in all treatment groups relative to the control
group (2-6 fold higher, without a clear dose-response relationship). Fetal body weights were
significantly lower (13-21 %,p< 0 .001) in all treatment groups compared to the control group.
The following external and internal soft-tissue abnormalities were observed at significantly
elevated incidences (with litter as unit of statistical measure, p < 0.05) in fetuses of treated dams:
hematomas of the dorsal area (all dose levels), hematomas of the facial area and neck (15 and
30 mg V/kg-day only), anophthalmia/microphthalmia (15 mg V/kg-day), cleft palate, and
micrognathia (30 mg V/kg-day). The incidences of litters with external defects (grouped across
type) were 2/20, 8/20, 11/20, and 17/20 in control, low, mid-, and high doses, respectively; these
were significantly (p < 0.05) elevated above control at all dose levels. While the incidences of
soft tissue abnormalities (exclusively hydrocephaly) were increased at the mid- and high-dose,
the increases were not statistically significant. However, the incidence of skeletal defects were
increased at all doses (4/20, 9/16, 15/20, 20/20 affected litters in control through high dose;
p < 0.05 for all treatment groups). The skeletal abnormalities consisted of poorly ossified
supraoccipital bone, carpus, tarsus and sternebrae, as well as bipartite sternebrae and irregular
ribs. These data indicate a freestanding LOAEL of 7.5 mg V/kg-day for both maternal toxicity
(reduced body-weight gain during treatment) and developmental toxicity (increased resorptions,
skeletal malformations, and growth delays).
In a later study by the same laboratory, Sanchez et al. (1991) administered daily gavage
doses of 0, 7.5, 15, 30, or 60 mg/kg-day sodium orthovanadate (equivalent to 0, 2.1, 4.2, 8.3, or
17 mg V/kg-day) to groups of 14-20 pregnant Swiss mice on GD 6-15. Maternal appearance,
body weight and food consumption were recorded daily. The dams were sacrificed on GD 18 for
evaluation of body weight, liver and kidney weights, gravid uterine weight, and uterine
parameters (numbers of implants, early and late resorptions, live and dead fetuses). Live fetuses
were weighed, sexed, and examined grossly for abnormalities; two-thirds were then prepared for
skeletal examination and one-third for visceral examination. Exposure to doses of 8.3 or
17 mg V/kg-day proved to be lethal; 4/18 dams dosed at 8.3 mg V/kg-day died, while 17/19
given the high dose died. Body-weight gain during treatment was reduced at 8.3 mg V/kg-day
(30%) less than controls, p < 0.01) and not at lower doses. Food consumption was significantly
(p < 0.05) reduced at the beginning of treatment at both 4.2 and 8.3 mg V/kg-day. Body weight
at termination, corrected for gravid uterine weight, was unaffected at any dose. Relative kidney
weight was slightly—but statistically significantly—increased at 8.3 mg V/kg-day; however, the
body-weight reduction at this dose may have contributed to the increased relative kidney weight.
Litter parameters were not affected by exposure; at 8.3 mg V/kg-day, one litter contained no
viable implants, but the incidence of litters with resorptions was not significantly increased.
External and visceral malformations were not increased in exposed groups relative to controls;
however, the numbers of litters containing fetuses with incompletely ossified sacrococcygeal
vertebrae, forelimb and hindlimb proximal phalanges were increased at 8.3 mg V/kg-day. The
authors identified the low dose (2.1 mg V/kg-day) as a NOAEL for maternal toxicity,
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presumably considering the decreased food consumption at 4.2 mg V/kg-day. Given the
evidence for frank effects at the next higher dose (mortality at 8.3 mg V/kg-day), the decrease in
food consumption is considered potentially indicative of toxicity and is used to define the
4.2 mg V/kg-day dose as a LOAEL. The authors considered the 4.2 mg V/kg-day dose to be a
NOAEL for developmental effects. For the purpose of this review, the LOAEL for
developmental toxicity is 8.3 mg V/kg-day based on increases in the incidence of litters with
incomplete skeletal ossification.
Ganguli et al. (1994b) exposed female Sprague-Dawley rats to 250 mg/L sodium
orthovanadate (-69 mg V/L) added to drinking water on GD 10-20. The study compared the
effects of treatment in diabetic (streptozocin-induced) and nondiabetic rats. The doses
(calculated for this review based on reported fluid intakes and estimated body weight5 of 250 g)
were 7.5 and 17 mg V/kg-day in the nondiabetic and diabetic treatment groups, respectively.
The treatment groups consisted of 11 diabetic and 7 nondiabetic pregnant females; the control
groups consisted of 6 diabetic and 5 nondiabetic pregnant females given water without the
addition of vanadate. Endpoints examined in dams included blood and urine glucose
concentrations and fluid intake. On GD 20, the animals were sacrificed; the number of live pups
and the pups' weights were recorded. Maternal uteri, ovaries, and placentas were examined
grossly. Vanadium treatment was lethal in diabetic pregnant rats; only 6/11 dams survived until
termination. No deaths occurred in other groups. Intake of drinking water was significantly
decreased by vanadium treatment in both nondiabetic and diabetic rats. Fluid intake in the
nondiabetic treatment group was approximately half that of the corresponding control group; in
diabetic treated rats, fluid intake was about one-third that of the diabetic controls, who had
significantly higher water intake than nondiabetic controls. Blood glucose was significantly
decreased in vanadium-treated diabetic rats (p = 0.006), but the levels were still above those of
nondiabetic rats. Urine glucose was not affected by vanadium exposure. Statistical analysis is
not reported, and only data on pooled litters are reported; thus, a statistical group comparison
cannot be made. Nevertheless, the outcomes included a lower average number of live fetuses on
GD 20 (6.71 vs. 9.6 in treated vs. control nondiabetic rats and 5.5 vs. 11.3 in treated vs. control
diabetic rats) and lower average pup mass in nondiabetic rats (3.60 vs. 4.02 g in treated vs.
control) but not in diabetic rats (statistical analysis not reported). These data suggest that
17 mg V/kg-day is an FEL based on maternal mortality in the treated diabetic rats. Other effect
levels cannot be determined due to poor reporting of data and limited endpoints evaluated.
Poggioli et al. (2001) assessed the effects of prenatal and postnatal exposure to vanadyl
sulfate on the growth and behavior of Wistar rats. Concentrations of 0 or 300 mg/L of vanadyl
sulfate (corresponding to 70 mg V/L according to the authors) were administered in the drinking
water along with 5 g/L NaCl to reduce gastrointestinal effects of vanadium. An untreated control
group received water without vanadyl sulfate or NaCl. Dams were exposed beginning three days
before the last day of pregnancy and continued until weaning; thus, the pups were exposed
during 3 days of gestation and via lactation until weaning. Litters were culled to 8-10 pups
1	day after birth and at weaning the groups were again reduced to 10/sex/dose. After weaning,
the pups were given the same drinking water as their mothers until they were 100 days of age.
Body weight was recorded at regular intervals and food and water intake were measured at
2	months of age. Based on recorded water intake, the vanadium dose was estimated by the
authors to be about 10 mg V/kg-day. Neurobehavioral assessments were performed at 1 month
5The starting weights were 210-230 g; however, ending body weights were not reported.
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of age (locomotor activity and open field evaluation of ambulation, rearing, grooming and
defecation) and 100 days of age (memory test assessing time spent exploring new and familiar
objects). Survival to weaning was significantly reduced by vanadyl sulfate treatment when
compared with either the NaCl or untreated controls (61% in treated vs. 100% and 94% in NaCl
and untreated controls, respectively; p < 0.0001). Neither food nor water intake was affected by
exposure. Body weights were significantly lower than untreated controls beginning at weaning
(PND 25) in the vanadyl sulfate group. However, body weights were also reduced in the NaCl
group, so the effect of vanadium exposure cannot be distinguished. Locomotor activity was not
different among the groups (data shown). In contrast, the open field evaluation revealed
significantly (p < 0.05) fewer outer ambulation (ambulation in the outer area of the cage), rearing
and grooming events and increased defecation in treated male rats when compared with the NaCl
group; the treated males also exhibited reduced rearing events compared with untreated controls.
The memory test revealed similar impairment in both the NaCl and vanadium exposure groups,
which the authors attributed to NaCl exposure rather than vanadium (as the effect was similar in
both). A LOAEL of 10 mg V/kg-day is identified based on reduced survival to weaning; a
NOAEL cannot be identified.
Neurotoxicity
Sanchez et al. (1998) exposed male Sprague-Dawley rats to daily gavage doses of sodium
metavanadate at dose levels of 0, 1.7, 3.4, or 6.8 mg V/kg-day for 8 weeks (12 animals per
group). Endpoints assessed include body-weight gain and two neurobehavioral assessments:
open-field activity and active avoidance (electric shock with auditory and light stimulus as the
conditioned stimulus). Body-weight gains were significantly lower (10% below controls at the
end of the exposure period, p < 0.05) in the 6.8 mg V/kg-day group relative to the control group.
Open-field activity was lower in the 3.4 and 6.8 mg V/kg-day groups relative to the control
group—but only during the first of three testing sessions (p < 0.05, data presented graphically).
Similarly, acquisition of the avoidance response to the conditioned stimulus was significantly
lower in all treatment groups (p < 0.05; about one-half as many avoidance responses and
latencies about twice that of the control group based on graphical presentation of the data)—but
only during the last of three sessions. Neither parameter exhibited a clear dose-response
relationship; the magnitude of change from control was similar at all doses.
These investigators also conducted a follow-up study designed to evaluate whether the
chelating agent Tiron would ameliorate the effects of vanadium exposure on behavior
(Sanchez et al., 1999). Groups of 10 male Sprague-Dawley rats were given daily gavage doses
of water or aqueous sodium metavanadate at a dose of 6.84 mg V/kg-day for 8 weeks. There
were two groups that were also given Tiron via i.p. injection at two different doses. Body weight
was measured daily. After the end of exposure, open-field activity and active avoidance were
assessed as in the previous study. The authors indicated that body weight was not affected by
treatment (data not shown). Graphical presentation of the data indicated no effect of exposure on
open field motor activity but significant (p < 0.05) inhibition of active avoidance.
Administration of Tiron mitigated the effects of sodium metavanadate on both of these
endpoints.
Immunotoxicity
The limited data on immunotoxicity of vanadium suggest little or no adverse effect on
this endpoint. Alexandrova et al. (2002) assessed humoral and cellular immune responses in
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BALB/c mice and Wistar rats (both sexes) exposed to ammonium vanadate. Exposure to
ammonium vanadate in the drinking water (0.5 mg/L or 0.2 mg V/L) for 40 or 200 days (about 6
or 28 weeks) stimulated both humoral and immune responses, as measured by increases (above
control values) in the number of antibody-synthesizing cells in the spleen after challenge with
sheep erythrocytes, the titers of serum agglutinins and haemolysins (humoral response) and the
migration of spleen cells and peritoneal macrophages in vitro (cellular response). In contrast to
the results of Alexandrova et al. (2002), Sharma et al. (1981) observed a decrease (albeit not
statistically significant) in antibody-producing cells in the spleen of male Swiss-Webster mice
exposed to concentrations of 0, 1, 10, or 50 mg/L vanadium (as sodium orthovanadate) in the
drinking water for up to 13 weeks. No treatment-related effects were observed on delayed
hypersensitivity reaction and immunoglobulin levels (IgG, IgA, and IgM) were not affected by
exposure. Both Alexandrova et al. (2002) and Sharma et al. (1981) observed increased DNA
synthesis in splenic lymphocytes treated with vanadium and cultured in the presence of some
mitogens (phytohemagglutinin and pokeweed) but not others (bacterial lipopolysaccharide),
when compared with cells not treated with vanadium.
Inhalation Exposure
No subchronic or chronic animal studies of inhalation exposure to vanadium compounds
(other than vanadium pentoxide) have been identified in the literature search.
Other Studies
Toxicokinetics
In the United States, exposure to vanadium primarily occurs through dietary sources.
Estimates of the daily intake of vanadium in the diet are in the range of 10-30 jag V/day or
0.0001 to 0.0004 mg V/kg-day for an adult man (WHO, 2001). Few studies are available on the
absorption of vanadium from the gastrointestinal tract in humans or experimental animals;
however, existing data suggest a relatively low fractional absorption. WHO (2001) estimated the
gastrointestinal absorption of vanadium to be about 3% of the administered dose based on animal
studies. Therefore, a relatively small absolute difference in gastrointestinal absorption between
rodents and humans could result in a large error in the equivalent dose extrapolation. There are
no studies that allow a direct comparison of the absorption of vanadium when administered as
vanadyl or vanadate compounds.
Once absorbed, vanadium is distributed primarily to the bone, with smaller amounts
distributing to the kidney, liver, spleen, muscle, and testes (ATSDR, 1992; WHO, 2001;
Rydzynski, 2001). Vanadium stored in bone is retained much longer than in other tissues, from
which vanadium is rapidly excreted (ATSDR, 1992; Rydzynski, 2001). Urine appears to be the
major excretory route for absorbed vanadium, while unabsorbed vanadium is excreted in the
feces (ATSDR, 1992; WHO, 1988, 2001).
In blood, vanadyl and vanadate ions are interconverted through redox reactions that may
involve glutathione, cysteine, ascorbate, and possibly other components of plasma and cytosol
(Rehder and Jantzen, 1998). Vanadium in blood partitions between plasma and erythrocytes. In
beagle dogs administered single intravenous injections of vanadyl sulfate or ammonium
vanadate, approximately 30-45% of the vanadium in blood was associated with erythrocytes and
approximately 80% of vanadium in serum was associated with transferrin (Harris et al., 1984).
Albumin also participates as a protein ligand for vanadyl and vanadate in plasma
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(Chasteen et al., 1986a,b). Vanadyl and vanadate form complexes with a variety of intracellular
proteins including ATPases, calmodulin, kinases and phosphatases, ribonucleases and nucleic
acids (Rehder and Jantzen, 1998). The redox state of the cytosol favors the intracellular
reduction of vanadate to vanadyl, whereas the oxidation of vanadyl to vanadate is favored in
plasma; the interconversion occurs in minutes (Etcheverry and Cortizo, 1998).
Antineoplastic Studies
Vanadium has been tested as an antineoplastic agent in animal models of colon, liver, and
mammary carcinogenesis. All of the studies of this effect that were identified in the literature
searches were conducted by a single laboratory. In all of the studies, vanadium was administered
as ammonium monovanadate to rats at a concentration of 0.5 ppm in drinking water. Vanadium
coadministration reduced the number of aberrant crypt foci (a preneoplastic lesion in colon
cancer) in rats treated with 1,2-dimethylhydrazine and resulted in fewer colon tumors
(Kanna et al., 2003, 2004, 2005). Mechanistic data collected in these studies showed that
vanadium treatment reduced the number of DNA-protein cross-links and evidence of DNA
damage in colon cells, reduced the PCNA index, decreased the frequency of chromosomal
aberrations and increased glutathione S-transferase and cytochrome p450 levels when compared
with rats treated with carcinogen alone (Kanna et al., 2003, 2004, 2005). Similar findings were
observed in rat models of hepatocarcinogenesis. In rats treated with 2-acetylaminofluorene
(2-AAF) or diethyl nitrosamine (DEN) and subsequently given vanadium, relative liver weight,
incidence of gamma glutamyl transpeptidase (GGT)-positive foci, nodular incidence, number of
liver nodules and multiplicity of nodules were reduced compared with treatment with the
carcinogen alone (Chakraborty et al., 2005; 2006a,b,c; 2007a,b). Vanadium treatment reduced
the frequency of modified DNA bases, DNA damage, and chromosomal aberrations; reduced the
expression of metallothionein (a metalloprotein associated with neoplastic cell growth) and
Ki-67 nuclear antigen; and increased the expression of p53 tumor suppressor (Chakraborty et al.,
2005; 2006a,b,c; 2007a,b). Further evidence of a potential antineoplastic effect of vanadium was
provided in studies of rat mammary carcinogenesis. Vanadium treatment reduced the incidence,
total number, multiplicity and size of mammary tumors in rats pretreated with
7,12-dimethylbenz(a)anthracene (Ray et al., 2004; 2005a,b; 2006). Ray et al. (2006) used
immunohistochemical analysis to show that vanadium exposure increased apoptosis in mammary
tissues; p53 and Bax genes were upregulated, while the antiapoptotic protein Bcl2 was
downregulated by vanadium. In studies performed in another laboratory, a vanadium-cysteine
complex was effective in prolonging survival, reducing the rate of benzo(a)pyrene-induced
leiomyosarcoma growth, and inducing some tumor remission when given to male rats beginning
on the day a palpable tumor was observed (Evangelou et al., 1997; Liasko et al., 1998).
Mechanistic
Etcheverry and Cortizo (1998) reviewed the action of vanadium on cells in culture. Their
review indicated that vanadate acts as an analogue of phosphate, resulting in the modification
(stimulation or inhibition) of several enzymes involved in phosphate metabolism. In in vitro
systems, vanadium compounds have been shown to inhibit Na+K+ ATPase, Ca2+ ATPase,
H+K+ ATPase, H+-ATPase, K+ATPase, Ca+Mg+ATPase, dynein ATPase, actomysosin
ATPase, protein tyrosine phosphatase, glutamine dehydrogenase, acid and alkaline phosphatases,
glucose-6-phosphatase, phosphofructokinase, alanine aminotransferase, aspargine
aminotransferase, ribonuclease, phosphodiesterase, phosphotyrosyl-phosphatase, while
stimulating phospholipase C, adenyl cyclase, mitogen-activated protein kinases,
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phosphatidylinositol 3-kinase, NADPH oxidase, glycogen synthase, lipoprotein lipase, and
tyrosine kinase phosphorylase (Etcheverry and Cortizo, 1998; Rydzynski, 2001). In addition,
vanadium is a strong mitogen, inducing cell proliferation in a number of different systems
(including fibroblasts, Leydig cells, and bone cells); the mechanism for this effect may be related
to the inhibition of protein tyrosine phosphatases (Etcheverry and Cortizo, 1998). The effects of
vanadium on various enzymes, which, in turn, affect many systems, may be responsible for the
diverse effects seen in vivo—including modulation of diabetes, renal effects, reproductive and
developmental toxicity and cardiovascular effects. In a recent review, Coderre and
Srivastava (2004) proposed a potential mechanism of action for the cardiovascular effects of
vanadium. In the proposed scheme, vanadium inhibition of protein tyrosine phosphatases results
in the intracellular release of calcium and activation of phosphatidylinositol 3-kinase (PI3K) and
p38-mitogen activated protein kinase (p38 MAPK) signaling pathways; these effects, in turn,
stimulate smooth muscle contraction and glucose uptake (Coderre and Srivastava, 2004).
Vanadium causes contraction of several types of smooth muscles, including gastric and vascular
smooth muscle (Coderre and Srivastava, 2004). The effects of vanadium on smooth muscle
contraction and glucose uptake may help to explain the in vivo modulation of blood pressure by
vanadium. The authors noted that vanadium has exerted both vasodilation and vasoconstriction
effects in different systems; thus, the action of vanadium on blood pressure may vary with dose,
duration, and model system (Coderre and Srivastava, 2004).
Genotoxicity
Genotoxicity testing of soluble inorganic vanadium salts have primarily given positive
results for mutagenicity and clastogenicity (especially numerical chromosomal aberrations). In
the Bacillis subtilis Rec" mutagenicity screening assay, ammonium metavanadate gave a positive
result (greater inhibition of the Rec" strain than the wild type Rec+ strain) at a concentration of
0.3 M (Kanematsu et al., 1980). However, spot mutation tests with Escherichia coli (B/r WP2
and WP2) and Salmonella typhimurium (TA1535, TA100, TA98, TA1537, and TA1538) were
negative for this compound (Kanematsu et al., 1980). Ammonium metavanadate induced mitotic
gene conversion and reverse point mutations in Saccharomyces cerevisia (strain D7) when tested
at concentrations from 80-210 nM with and without S9 (Bronzetti et al., 1990). Greater numbers
of conversions and mutations were observed in the absence of S9, suggesting that the
metabolism of ammonium metavanadate may detoxify the compound. In a study of cultured
Chinese hamster V79 and V79-derived hprt~lgpt+ transgenic G12 cells, ammonium metavanadate
exposure resulted in weak, but concentration-related increases in hprt mutations in V79 cells and
in gpt mutations in G12 variants when the cells were exposed for 24 hours at concentrations from
5-50 |iM (Cohen et al., 1992; Klein et al., 1994). Owusu-Yaw et al. (1990) reported that
vanadyl sulfate and ammonium metavanadate both induced significant (p < 0.01) increases in the
frequency of sister chromatid exchanges (SCE) in Chinese hamster ovary (CHO) cells treated
with and without S9. Concentrations resulting in increases in SCE were about 6 and 2 |ig V/mL
for vanadyl sulfate and ammonium metavanadate, respectively. These compounds also induced
dose-related increases in the frequency of chromosomal aberrations at concentrations near those
causing cytotoxicity. Cytotoxic concentrations (TC50s) were 23 and 16 |ig V/mL for vanadyl
sulfate and ammonium metavanadate, respectively (Owusu-Yaw et al., 1990). In human
lymphocytes cultured in vitro, sodium metavanadate, sodium orthovanadate and ammonium
metavanadate and vanadyl sulfate resulted in increased frequencies of micronuclei and numerical
chromosomal aberrations (primarily hypoploidy) at doses as low as 5 uM (Migliore et al., 1993).
SCEs were induced at higher doses (Migliore et al., 1993).
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In vivo studies in mice indicated that vanadyl sulfate (100 mg/kg body weight), sodium
orthovanadate (75 mg/kg) and ammonium metavanadate (50 mg/kg) administered by gavage all
increased the frequency of micronucleated polychromatic erythrocytes (2- to 3-fold increase over
controls) (Ciranni et al., 1995). The frequencies of hypoploid (missing chromosomes) and
hyperploid (having an excess of chromosomes) cells were also increased by both compounds.
Only vanadyl sulfate exposure resulted in a statistically significant (p < 0.05) increase (up to
7-fold above control values) in structural chromosomal aberrations (Ciranni et al., 1995). Mice
exposed for 5 months to sodium orthovanadate in drinking water were observed to exhibit
statistically significant increases in bone marrow micronuclei (at exposure concentrations of 750
or 1500 mg/L) as well as evidence of DNA damage in splenocytes (measured by comet assay, at
a concentration of 1500 mg/L)—but not in bone marrow cells, testis cells or epididymal sperm
(Leopardi et al., 2005). In another study, oral exposure to drinking water containing vanadyl
sulfate (2-1000 mg/L) did not increase the frequency of micronuclei in bone marrow
polychromatic erythrocytes in male CD-I mice exposed for 5 weeks (Villani et al., 2007). In
reticulocytes from these same mice, the frequency of micronuclei was slightly increased at some
exposure levels, but there was no dose-response relationship (Villani et al., 2007).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES FOR VANADIUM AND COMPOUNDS
Equal intakes of vanadium in any of the forms considered (vanadyl sulfate, sodium
metavanadate, sodium orthovanadate, and ammonium metavanadate) were treated as
toxicologically equivalent for the purpose of deriving provisional oral toxicity values on the
following basis: (1) there is very little quantitative information about the gastrointestinal
absorption of vanadium and no evidence that the absorption of vanadium will be substantially
affected by the form of vanadium ingested for this set of compounds and (2) although there is
evidence for pharmacologic specificity of the actions of vanadate and vanadyl ions in various
biochemical systems, these forms are rapidly (within minutes) interconverted in the body in
oxidation-reduction reactions that take place in the intracellular and extracellular compartments
(Etcheverry and Cortizo, 1998; Mendz, 1998; Rydzynksi, 2001).
A total of four studies of humans exposed to vanadium compounds for brief durations (up
to 12 weeks) are available; Table 9 provides an overview of the findings in these studies. Of
these, three studies were of patients with diabetes. All of the studies used vanadyl sulfate in
tablet form. Endpoints assessed in the studies included body weight, gastrointestinal symptoms,
hematology, glycemic control, serum chemistry parameters, urinalysis, liver, kidney or thyroid
function tests, and blood pressure. None of the studies reported significant effects on any
endpoint other than gastrointestinal symptoms. Of particular note is the apparently normal
kidney function and the absence of a blood pressure effect at daily doses as high as 0.5 to
1.1 mg V/kg-day. However, the exposure groups were small, no histopathology was possible,
and often no referent population is included. While the individual studies are limited, the human
studies collectively provide a short-term human LOAEL of approximately 0.3 mg V/kg-day in
humans based on symptoms of gastrointestinal distress, including diarrhea, cramping, and
discomfort. The NOAEL for these effects is approximately 0.1 mg V/kg-day based on the
available studies. Gastrointestinal effects (severe diarrhea) have also been observed in rats
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exposed to vanadium in drinking water (Zaporowska and Wasilewski, 1989, 1990, 1992a,b;
Ganguli et al., 1994b); in rabbits exposed via drinking water (Khasibhatla and Rai, 1993) and in
pigs exposed via the diet (Van Vleet et al., 1981; Van Vleet and Boon, 1980), providing support
for the observed relationship between vanadium exposure and diarrhea in humans. The doses
resulting in diarrhea in laboratory animals were in the 5-20 mg V/kg-day range. Studies in rats
and mice indicate that vanadium exposure may be associated with effects on body weight,
hematology, kidney function, blood pressure and reproduction. Animal studies that meet
minimum criteria for possible use in deriving subchronic or chronic provisional RfDs (e.g., effect
levels could clearly be identified) are summarized in Table 10. It should be noted that some of
the LOAELs shown in Table 10 were identified for effects in partially nephrectomized rats
(Steffen et al., 1981; Susie and Kentera, 1988) or in diabetic rats (Domingo et al., 1991, 1992).
Table 9. Human Studies of Oral Exposure to Vanadium Compounds
Study
Description
Dose
(mg V/
kg-day)
Vanadium
Form
Administered
NOAEL
(mg V/
kg-day)
LOAEL
(mg V/
kg-day)
Responses at
the LOAEL
Comments
Reference
Human, 4 M
and 7 F
Tablet, daily
for 6 weeks
after 2-week
run-up
0.5 (M)
0.6 (F)
Vanadyl
sulfate
(assumed
trihydrate)
NA
0.5 (M)
0.6 (F)
Gastrointestinal
symptoms
Patients
with type 2
diabetes
Cusi et al.,
2001
Human, 11 M
and 5 F
Tablet, daily
for 6 weeks
0.12-0.23
0.28-0.45
0.43-1.14
Vanadyl
sulfate
(assumed
trihydrate)
0.12-0.23
0.28-0.45
Gastrointestinal
symptoms
Patients
with type 2
diabetes
Goldfine et al.,
2000
Human, 12-13
M and 4 F
Tablet, daily
for 12 weeks
0,0.1
Vanadyl
sulfate
trihydrate
0.1
NA
None
Weight
trainers
Fawcett et al.,
1997
Human, 4 M
and 4 F
Tablet, daily
for 4-8 weeks
0.34 (M)
0.39 (F)
Vanadyl
sulfate
(assumed
trihydrate)
NA
0.34 (M)
0.39 (F)
Gastrointestinal
symptoms
Patients
with type 2
diabetes
Boden et al.,
1996
Effects on blood pressure have been associated with vanadium exposure, although the
available studies provide conflicting results. Boscolo et al. (1994) found a significant increase in
systolic and diastolic blood pressure in rats exposed to 0.12, 1.2, or 4.7 mg V/kg-day as sodium
metavanadate in the drinking water for 6 months. Carmignani et al. (1991) reported similar
findings at a dose of 12 mg V/kg-day (as sodium metavanadate in drinking water). The increases
in blood pressure are not corroborated by the Schroeder et al. (1970) chronic rat study or the
Dai et al. (1994b) 52-week study in rats. Steffen et al. (1981) and Susie and Kentera (1988)
reported increases in blood pressure in partially nephrectomized rats exposed to sodium
orthovanadate and sodium metavanadate (respectively). In addition to these subchronic and
chronic studies, a shorter-term study reported increased blood pressure in lean Zucker rats
exposed to vanadium in the drinking water (about 10 mg V/kg-day) for 25 days (Hopfner et al.,
1999). Several differences in the studies need to be taken into consideration in cross-study
comparisons; Table 11 shows the major differences, which include the form of vanadium
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Table 10. Animal Studies of Oral Exposure to Vanadium Compounds
Study Description
Dose
(mg V/kg-
day)
Vanadium Form
Administered
NOAEL
(mg V/kg-
day)
LOAEL
(mg V/kg-
day)
Responses at the LOAEL
Comments
Reference
Shorter-term
Male Sprague-Dawley rats
(10/group) were exposed via
drinking water for 28 days
0,6.1, 15.6,
22.7
Sodium
metavanadate,
sodium
orthovanadate,
vanadyl sulfate
NA
6.1
Body-weight loss in diabetic
rats
No nondiabetic treatment
group
Domingo etal., 1991
Male Sprague-Dawley rats
(10/group) were exposed via
drinking water for 5 weeks
0, 23.2
Sodium
metavanadate
NA
23.2
Body-weight loss in diabetic
rats
No nondiabetic treatment
group
Domingo et al., 1992
Male and female Wistar rats
(15-16/sex/group) were
exposed via drinking water
for 4 weeks
0, 1.2, 5
(males)
0, 1.5,7
(females)
Ammonium
metavanadate
1.2 (males);
1.5 (females)
5 (males);
7 (females)
Reduced body weight (with
reduced fluid intake) and
hematology changes

Zaporowska et al.,
1993
Subchronic
Male Sprague-Dawley rats
(20/group) were exposed via
the diet for 9 weeks
0, 9
Sodium
orthovanadate
NA
9
Decreased weight gain and
increased blood pressure in
uninephrectomized rats

Steffenetal., 1981
Male weanling pigs (6) were
exposed via drinking water
for 12 weeks
0, 10
Ammonium
metavanadate
NA
10
(PEL)
Emaciation and mortality

Van Vleet, 1981
Male Sprague-Dawley rats
(10/group) were exposed via
drinking water for 12 weeks
0,0.3,0.6,3.0
Sodium
metavanadate
NA
(0.6, ATSDR,
1992)
0.3-3.0
(indeterminate
)
Mild changes in the kidney
(hemorrhagic foci in the
corticomedullary region),
spleen (hypertrophy and
hyperplasia) and lungs
(perivascular mononuclear
cell infiltration)
Occurring in all treatment
groups, but "more evident"
in the high-dose group.
Clear AEL at 3 mg/kg-day.
Domingo et al., 1985
Male Long-Evans rats
(15/group) were exposed via
the diet for 2 months
0, 12
Ammonium
metavanadate
NA
12
Pulmonary hypertension

Susie and Kentera,
1986
Male Wistar rats (8/group)
were exposed via drinking
water for 12 weeks
0, 7.7, 9.7
Ammonium
metavanadate,
vanadyl sulfate
7.7, 9.7
NA
No effects on food intake,
body weight, hematology
Fluid intake was reduced at
this dose
Dai et al., 1995
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Table 10. Animal Studies of Oral Exposure to Vanadium Compounds
Study Description
Dose
(mg V/kg-
day)
Vanadium Form
Administered
NOAEL
(mg V/kg-
day)
LOAEL
(mg V/kg-
day)
Responses at the LOAEL
Comments
Reference
Female Wistar rats (7/group)
were exposed via the diet for
10 weeks
0, 1.1, or 2.3
Sodium
metavanadate
2.3
NA
Small changes in hematology
and body weight were not
considered toxicologically
significant

Adachi et al., 2000
Male Wistar rats
(11-16/group) were exposed
via drinking water for 6
weeks
0, 8
Sodium
metavanadate
NA
8
Reduced body weight gain
(possibly related to reduced
food and fluid intake);
hematologic effects

Scibior, 2005
Male Wistar rats (12/group)
were exposed via drinking
water for 6 weeks
0, 11
Sodium
metavanadate
NA
11
Reduced body weight gain
(possibly related to reduced
food and fluid intake);
hematologic effects

Scibior et al., 2006
Intermediate
Male Long-Evans rats
(12-24/group) were exposed
via the diet for 24 weeks
0, 4.4, 42
Sodium
metavanadate
NA
4.4
Increased blood pressure in
partially nephrectomized rats
Blood pressure not affected
in rats with intact kidneys
Susie and Kentera,
1988
Male Sprague-Dawley rats
(10/group) were exposed via
drinking water for 7 months
0, 12
Sodium
metavanadate
NA
12
Increased blood pressure,
kidney histopathology

Carmignani et al.,
1991
Male Wistar rats (12/group)
were exposed via drinking
water for 5 months
0, 12
Vanadyl sulfate
NA
12
Decreased body weight in
treated nondiabetic rats
relative to nondiabetic
controls

Cametal., 1993
Male Sprague-Dawley rats
(6/group) were exposed via
drinking water for 180 or
210 days
0,0.12, 1.2,
4.7
Sodium
metavanadate
NA
0.12
Increased blood pressure,
stimulation of the renin-
angiotensin-aldosterone
system, and kidney
histopathology

Boscolo et al., 1994
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Table 10. Animal Studies of Oral Exposure to Vanadium Compounds
Study Description
Dose
(mg V/kg-
day)
Vanadium Form
Administered
NOAEL
(mg V/kg-
day)
LOAEL
(mg V/kg-
day)
Responses at the LOAEL
Comments
Reference
Chronic
Long-Evans rats were
exposed via drinking water
from weaning through
natural death (up to 45
months)
0, 0.7 (males),
d 0.9
(females)
Vanadyl sulfate
NA
NA
No effects observed
Histological evaluations
inadequate to detect any but
the most severe lesions;
effect levels cannot be
determined
Schroeder et al.,
1970
Male Sprague-Dawley rats
(>20/group) were exposed
via diet for 56 weeks
0, 7, 14
Sodium
orthovanadate
NA
7
Increased blood pressure in
uninephrectomized rats

Steffenetal., 1981
Male Wistar rats (8/group)
were exposed via drinking
water for 52 weeks
0, 8, 13 or 21
Vanadyl sulfate
NA
8
Reduced body-weight gain
Diabetic and nondiabetic
rats
Daietal., 1994a,b;
Dai and McNeill,
1994
Reproductive
Male and female Sprague-
Dawley rats (20/sex/group)
were exposed via drinking
water for 60 (M) or 14 (F)
days premating and during
gestation and lactation (F)
0,2.1,4.2, 8.4
Sodium
metavanadate
NA
2.1 (offspring)
Growth retardation in pups
Maternal effect levels could
not be identified due to lack
of information on endpoints
assessed
Domingo et al., 1986
Male and female Sprague-
Dawley rats (10 M and 20
F/group) were exposed via
drinking water for 70 days
(M) or through premating,
mating, gestation and
lactation (61 days, F)
0 or 28 (M) or
30 (F)
Ammonium
metavanadate
NA
28
Effects on reproductive
success, litter parameters,
postnatal growth, male
reproductive organ weights
and skeletal malformations

Morgan and El-
Tawil, 2003
Male Swiss mice (24/group)
were exposed via drinking
water for 64 days prior to
mating
8.4, 17, 25.1
or 33.4
Sodium
metavanadate
17
25.1
Decreased spermatozoa
counts and reduced fecundity

Llobetetal., 1993
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Table 10. Animal Studies of Oral Exposure to Vanadium Compounds
Study Description
Dose
(mg V/kg-
day)
Vanadium Form
Administered
NOAEL
(mg V/kg-
day)
LOAEL
(mg V/kg-
day)
Responses at the LOAEL
Comments
Reference
Developmental
Pregnant Sprague-Dawley
rats (14/group) were
exposed via the diet
throughout pregnancy and
lactation
0,7
Sodium
metavanadate
NA
7 (maternal
and develop-
mental)
Reduced food intake and
weight gain (maternal);
reduced pup survival, body
weight, growth and clinical
signs (developmental)

Elfant and Keen,
1987
Pregnant Swiss mice
(16-20/group) were exposed
via
daily gavage on GD 6-15
0,7.5, 15.1 or
30.2
Vanadyl sulfate
pentahydrate
NA
7.5 (maternal
and develop-
mental)
Reduced body-weight gain
(maternal)
Increased resorptions, growth
deficits, external and skeletal
abnormalities (developmental)

Paternainetal., 1990
Pregnant Swiss mice
(14-18/group) were exposed
via
daily gavage on GD 6-15
0,2.1,4.2, 8.3
or 16.6
Sodium
orthovanadate
2.1	(maternal)
4.2	(develop-
mental)
4.2	(maternal)
8.3	(develop-
mental)
Reduced food consumption
(maternal)
Delayed skeletal ossification
(developmental)
Maternal deaths occurred at
8.3 mg V/kg-day
Sanchez et al., 1991
Male and female Wistar rats,
(8-10/group) were exposed
via drinking water from 3
days before birth until 100
days of age
0, 10
Vanadyl sulfate
NA
10
Reduced survival to weaning

Poggioli et al., 2001
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administered, the method of administration, the renal status of the affected animals, the strain of
the affected animals and the method by which blood pressure was measured. All the blood
pressure increases were from exposure to the vanadate; there were no blood pressure increases in
the only two studies that used the vanadyl salt. Given the rapid interconversion of the two forms
in plasma and cytosol, this discrepancy cannot be explained. Blood pressure was generally
increased by 20-25 mm Hg over a 100-fold dose range within and among studies; this is
particularly noted for the companion studies of Carmignani et al. (1991) and Boscolo et al.
(1994) in which an interaction with thiopentane cannot be ruled out. Except for the shortest
study of 25 days (Hopfner et al., 1999), there is no apparent exposure-duration effect on the
magnitude of the blood pressure increase from exposure to vanadium for 9 to 56 weeks. No
effects on blood pressure were observed in the human studies at doses as high as
0.5-1 mg V/kg-day (Boden et al., 1996; Fawcett et al., 1997; Goldfine et al., 2000; Cusi et al.,
2001). Overall, these studies establish a NOAEL of at least 0.3 mg V/kg-day for blood pressure
effects in humans for short-term exposure (6 weeks).
Table 11. Comparison Among Studies in which Blood Pressure was Measured
Study
Observed
Effect on
Blood
Pressure"
Magnitude
of Effect
(mm Hg)
Form and Method of
Vanadium
Administration
Renal Status and
Strain of Affected
Animals
Method of Blood
Pressure
Measurement
Boscolo et al.,
1994
Increase at
>0.12 mg
V/kg-day
25
(not dose-
related)
Na metavanadate in
drinking water for
6 months
Intact Sprague-
Dawley rats
Arterial cannula
under thiopentane
anesthesia
Carmignani et
al., 1991
Increase at
12 mg V/kg-
day
22
Na metavanadate in
drinking water for
7 months
Intact Sprague-
Dawley rats
Arterial cannula
under thiopentane
anesthesia
Steffen et al.,
1981
Increase at
9 mg V/kg-
day
20
Na metavanadate in
diet for 9 weeks
Uninephrectomized
Sprague-Dawley
rats
Tail cuff in
conscious animals
Steffen et al.,
1981
Increase at 7,
14 mg V/kg-
day
10, 25
Na metavanadate in
diet for 56 weeks
Uninephrectomized
Sprague-Dawley
rats
Tail cuff in
conscious animals
Hopfner et al.,
1999
Increase at
10 mg V/kg-
day
15
Na orthovanadate in
drinking water for
25 days
Intact lean Zucker
rats
Tail cuff in
conscious animals
Susie and
Kentera, 1988
Increase at
4.4 mg V/kg-
day
22
Na orthovanadate in
diet for 24 weeks
Partially
nephrectomized
Long-Evans rats
Arterial cannula
under nembutal
anesthesia
Susie and
Kentera, 1988
None at
42 mg V/kg-
day
0
Na orthovanadate in
diet for 24 weeks
Intact Long-Evans
rats
Arterial cannula
under nembutal
Dai et al., 1994b
None at
21 mg V/kg-
day
0
Vanadyl sulfate in
drinking water for
1 year
Intact Wistar rats
Tail cuff in
conscious animals
Schroeder et al.,
1970
None at
0.7 mg V/kg-
day
0
Vanadyl sulfate in
drinking water for
45 months
Intact Long-Evans
rats
Anaesthetized
animals; method
not specified
aEffect observed at lowest dose tested in all positive studies
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Studies conducted by Susie and Kentera (1988) in which several cardiovascular
endpoints were assessed provide some information as to why vanadium exposure may increase
blood pressure in some animals and not in others. In rats with intact kidneys exposed to doses up
to 42 mg V/kg-day, a vanadium-related increase in peripheral resistance was offset by a
reduction in cardiac output and blood pressure remained stable (no effect on blood pressure was
observed). In partially nephrectomized rats, there was no compensatory reduction in cardiac
output; thus, an increase in blood pressure was observed (Susie and Kentera, 1988). Thus, one
potential explanation as to why blood pressure was not increased in every study is that
compensatory mechanisms may serve to modulate the effect on blood pressure. If so, then
individuals with health conditions that compromise these compensatory mechanisms (e.g.,
impaired renal function) may be at greater risk from vanadium exposure, although this
hypothesis must be considered somewhat speculative.
Limited mechanistic information also supports a potential relationship between vanadium
exposure and blood pressure changes. Boscolo et al. (1994) showed that vanadium exposure can
modify plasma levels of proteins involved in blood pressure homeostasis. In this study, exposure
to sodium metavanadate at doses of 1.2 or 4.7 mg V/kg-day resulted in increases in plasma renin
activity (an enzyme that converts angiotensin to angiotensin I, a precursor to the vasoconstrictor
angiotensin II) and aldosterone (a hormone involved in saltwater balance), as well as increases
in urinary excretion of kallikrein (an enzyme that releases vasodilating kinins from plasma
proteins) and kininases I and II (enzymes that break down kinins). The effects on the
renin-angiotensin-aldosterone system are consistent with the observed increases in blood
pressure.
Several studies (Domingo et al., 1985; Gorski and Zaporowska, 1982; Zaporowska, 1987;
Dai et al., 1994a,b; Dai and McNeill, 1994) have indicated that the kidney is a primary target
organ of vanadium toxicity in male rats. Among these, the study identifying effects at the lowest
dose was Domingo et al. (1985). This study reported histopathologic changes in kidneys of rats
exposed to sodium metavanadate in drinking water at dosages of 0.3 mg V/kg-day and higher.
However, as previously noted, this study is limited in that only three animals per exposure group
were actually subjected to a histopathological assessment and the results are summarized without
a qualitative or quantitative reporting of incidence and severity. As a result, it is difficult to
verify that the observed effects were clearly increased by exposure. Boscolo et al. (1994)
reported hydropic degeneration in the kidneys of rats exposed to sodium metavanadate at a dose
of 1.2 mg V/kg-day (in drinking water) for 1 year, with additional histopathologic changes
(narrowing of the lumen and appearance of amorphous casts in the renal proximal tubules) at the
next higher dose (4.7 mg V/kg-day). The latter changes were also observed by
Carmignini et al. (1991) at a drinking water dose of 12 mg V/kg-day for 1 year.
Dai et al. (1994a,b; Dai and McNeill, 1994) reported an increased incidence of glomerular and
tubular degeneration, with interstitial cell infiltration and fibrosis in the kidneys of rats exposed
to vanadyl sulfate in the drinking water at doses of 8-21 mg V/kg-day for a year. Limited
information provided in English abstracts of two Polish studies (Gorski and Zaporowska, 1982;
Zaporowska, 1987) suggested renal histopathology in rats exposed to 12-29 mg V/kg-day as
ammonium metavanadate. Of all of these studies, only Boscolo et al. (1994) identified an
unequivocal NOAEL for kidney effects.
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Clinical chemistry changes indicative of renal effects have also been reported in a
number of animal studies, although similar changes have not been observed in human studies
(Fawcett et al., 1997; Boden et al., 1996). Increases in plasma urea concentrations have been
observed at a dose of 3.0 mg V/kg-day in rats treated with sodium metavanadate
(Domingo et al., 1985) and at higher doses in a number of studies (Domingo et al., 1991, 1992;
Dai et al., 1994a,b; Dai and McNeill, 1994). Serum creatinine was higher in diabetic rats
exposed to 6.1-22.7 mg V/kg-day as sodium metavanadate (Domingo et al., 1991) but not in a
follow-up study in which diabetic rats were exposed to 23.2 mg V/kg-day as sodium
metavanadate (Domingo et al., 1992). Susie and Kentera (1988) observed no changes in
indicators of renal function (plasma creatinine, 24-hour creatinine clearance, urinary sodium
excretion, and urine output) in normal and partially nephrectomized Long-Evans rats exposed to
4.4 or 42 mg V/kg-day as sodium metavanadate. Boscolo et al. (1994) observed increased
potassium excretion after rats were exposed to sodium metavanadate at 1.2 and 4.7 mg V/kg-day,
but no changes in urinary creatinine, nitrogen, proteins, sodium, or calcium. It should be noted
vanadium was administered in drinking water in all of the studies that indicated clinical
chemistry changes related to renal function. A number of studies have shown reductions in fluid
intake, including marked reductions at doses of >10 mg V/kg-day, when vanadium is
incorporated into the drinking water of rats. Thus, the changes in renal function parameters may
have been influenced to an unknown degree by decreases in fluid intake, particularly at the
higher exposure levels. No changes in renal function were observed in the human studies at
doses as high as 0.5-1 mg V/kg-day (Boden et al., 1996; Fawcett et al., 1997;
Goldfine et al., 2000; Cusi et al., 2001). Overall, these studies establish aNOAEL of at least
0.3 mg V/kg-day for overt kidney effects in humans for short-term exposure (6 weeks).
Limited mechanistic information in animals also provides some support for potential
renal toxicity after vanadium exposure. Adachi et al. (2000) measured higher levels of lipid
peroxidation products in the kidneys of rats exposed to 2.3 mg V/kg-day. Boscolo et al. (1994)
reported reductions in Na+ K+ ATPase in the kidneys of rats exposed to 4.7 mg V/kg-day as
sodium metavanadate; vanadium is known to inhibit the sodium-potassium ATPase
(Etcheverry and Cortizo, 1998; Rydzynski, 2001). In addition, studies of vanadium distribution
after oral exposure indicate that higher levels of vanadium are observed in the kidneys than in
other organs, providing support for this organ as a potential target of vanadium toxicity.
Available data also supports a finding of reproductive and developmental toxicity
associated with vanadium exposure. Effects observed in the available studies (see Table 10),
conducted in both rats and mice, include diminished fertility, reduced offspring viability, growth
retardation of offspring and skeletal malformations (Morgan and El-Tawil, 2003;
Poggioli et al., 2001; Llobet et al., 1993; Sanchez et al., 1991; Paternain et al., 1990;
Elfant and Keen, 1987; and Domingo et al., 1986). In addition to the studies shown in the table,
several other studies are not suitable for derivation of provisional toxicity values, but they do
contribute to the overall database for reproductive and developmental toxicity. There were three
studies published in Spanish that provide suggestive evidence that vanadium exposure (as
ammonium metavanadate) may result in histopathologic changes in the ovaries
(Nava de Leal et al., 1998), effects on the developing central nervous system (especially the
olfactory bulbs; Faria de Rodriguez et al., 1998a) and growth delays (Faria de Rodriguez
et al., 1998b). In a study with poorly-reported information on the treatment regimen,
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Ganguli et al. (1994b) reported reduced rate of conception and reduced ability to carry pregnancy
to term in rats exposed to sodium orthovanadate.
Subchronic p-RfD
Data pertinent to the derivation of a subchronic p-RfD for vanadium include short-term
human studies, short-term (4-5 weeks) and subchronic animal studies, and reproductive and
developmental toxicity studies. In addition, several studies of slightly longer duration
(5-7 months) have some bearing on the subchronic p-RfD because of the kidney and blood
pressure endpoints. Blood pressure and kidney effects were fairly common among the rat
studies. Kidney toxicity was implied in the Domingo et al. (1985) 3-month study at doses as low
as 0.3 mg/kg-day, although it was not clear as to whether this was a LOAEL; ATSDR (1992)
determined that the 0.6 mg/kg-day exposure level was a NOAEL. Subsequent to that
determination, Boscolo et al. (1994) found mild kidney lesions in rats after a 6-month exposure
to 1.2 mg/kg-day, but none at 0.12 mg/kg-day. The most sensitive effect found by
Boscolo et al. (1994) was increased blood pressure at 0.12 mg/kg-day; although a 6-month study
is somewhat longer than subchronic, the findings are relevant to the subchronic p-RfD
assessment because they establish a much lower LOAEL for this effect. All the kidney and
blood-pressure effects occurred in male rats, but there was no direct indication that the kidney
toxicity in any of these studies was a result of a2U-globulin accumulation. The relevant studies
apparently did not test for the presence of a2u-globulin. However, as vanadium binds readily to
proteins and is a protease inhibitor, accumulation of a2U-globulin in the proximal tubule cells,
leading to tissue necrosis, is plausible. The hemorrhagic foci in the corticomedullary region
described by Domingo et al. (1985) could indicate proximal tubule necrosis. However, the
criteria for establishing an a2u-globulin mode of action have not been met. The human studies
collectively identify a NOAEL of at least 0.3 mg V/kg-day for increased blood pressure and
overt kidney toxicity, the most sensitive effects in rats; neither of these effects was observed for
some subjects at dose levels of 0.5 to 1.1 mg V/kg-day. The human studies, however, were not
considered for use in deriving the subchronic RfD. These studies are of short duration, used
small numbers of subjects, and are not capable of detecting sub-clinical kidney damage—
identifying a portal-of-entry effect (gastrointestinal distress) as the only adverse effect. Given no
evidence of systemic effects in the human subjects, many of which were diabetic, the male rat
may be particularly susceptible to kidney and blood pressure effects from vanadium exposure.
Accordingly the increased blood pressure reported by Boscolo et al. (1994) at the lowest dose
level (0.12 mg V/kg-day) is discounted as a basis for the pRfD, but the kidney effects remain
relevant for consideration as the basis for the subchronic p-RfD.
The lowest reproductive/developmental toxicity LOAEL is 2.1 mg V/kg-day for growth
retardation in the offspring of rats exposed prior to mating (Domingo et al., 1986); a NOAEL is
not established. A clear dose-response relationship is reported in both sexes of offspring for a
number of growth-related endpoints measured at several postnatal times. Benchmark dose
modeling is rejected because the data were pooled across litters, BMD models could not be fit to
most of the data, and it is not clear whether those endpoints that were fit successfully were the
most sensitive. Therefore, only the LOAEL of 2.1 mg V/kg-day is considered as a potential
POD for the subchronic p-RfD.
The NOAEL of 0.12 mg V/kg-day based on kidney histopathology at 1.2 mg V/kg-day in
the 6-month rat study of Boscolo et al. (1994) provides the most appropriate basis for the
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subchronic p-RfD. However, given exposure to vanadium in the diet, the NOAEL is adjusted
upward by 0.1 mg/kg-day, which is the lower end of the range of likely dietary exposure
discussed previously in this document. The subchronic p-RfD is derived as follows:
Subchronic p-RfD = NOAEL UF
= 0.22 mg V/kg-day -^300
= 0.0007 mg V/kg-day or 7 x 10"4 mg/kg-day
The composite UF of 3000 is composed of the following:
•	A full UF of 10 is used to account for interspecies extrapolation to account for
potential pharmacokinetic and pharmacodynamic differences between rats and
humans.
•	A full UF of 10 is used to account for potentially susceptible individuals in the
population in the absence of information on the variability of response to
vanadium developmental toxicity in humans.
•	A partial UF of 3 (10°5) is used to account for database deficiencies—in
particular the lack of a reproductive toxicity study.
Confidence in the key study (Boscolo et al., 1994) is low. The study does not examine
the factors that would determine whether the kidney effects in male rats were a result of
a2u-globulin accumulation. Confidence in the database is medium. The toxicological database
for oral exposure to vanadium includes human studies, several subchronic studies, several
reproductive and developmental toxicity studies and limited studies of immunotoxicity and
neurotoxicity. However, the majority of the subchronic studies evaluate limited endpoints; there
are no comprehensive bioassays of subchronic duration. Although several studies reported
kidney and blood pressure effects in male rats, none of them examined the factors that would
determine whether the kidney effects were a result of a2U-globulin accumulation. The
reproductive toxicity database does not include any adequate standard multigeneration studies.
The available 2-generation studies (Faria de Rodriguez et al., 1998a; Nava de Leal et al., 1998)
were limited by poor reporting or pooling of data across treatment groups; however, the results
provided suggestive evidence for reproductive toxicity. Likewise, two short-term studies of
neurotoxicity (Sanchez et al., 1998, 1999) provide suggestive evidence for an effect of vanadium
exposure on avoidance response, but neither study conducted comprehensive tests of
neurobehavioral endpoints. Low confidence in the subchronic p-RfD follows.
Chronic p-RfD
Kanisawa and Schroeder (1967) and Schroeder et al. (1970; Schroeder and
Michener, 1975) conducted chronic mouse and rat studies; however, the histopathologic
assessment in these studies included only gross morphologic evaluations after natural deaths of
the animals and would not have detected more subtle histopathologic lesions, particularly kidney
lesions. Thus, these studies are inappropriate as critical studies for the chronic p-RfD. The
lowest LOAEL of the remaining relevant endpoints is 1.2 mg V/kg-day for kidney pathology in
male rats after a 6-month exposure to sodium metavanadate in drinking water (Boscolo et al.,
1994), the basis for the subchronic p-RfD. As the human studies would not have revealed
subclinical tissue damage and were of short duration, chronic kidney damage would be of
concern. Therefore, kidney toxicity is selected as the critical effect, with a LOAEL of
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1.2 mg V/kg-day and NOAEL of 0.12 mg V/kg-day established in the Boscolo et al. (1994) rat
study. As for the subchronic p-RfD, the NOAEL is adjusted to 0.22 mg/kg-day to account for
dietary exposure. The chronic p-RfD is derived as follows:
Chronic p-RfD = NOAEL - UF
= 0.22 mg V/kg-day - 3000
= 0.00007 mg V/kg-day or 7 x 10"5 mg/kg-day
The composite UF of 3000 is composed of the following:
•	A full UF of 10 is used to account for interspecies extrapolation to account for
potential pharmacokinetic and pharmacodynamic differences between rats and
humans.
•	A full UF of 10 is used to account for potentially susceptible individuals in the
population in the absence of information on the variability of human response to
vanadium.
•	A partial UF of 3 (10°5) is used to account for database deficiencies as per the
subchronic p-RfD.
•	A full UF of 10 is used to account for extrapolation to chronic exposure duration
from a subchronic study.
Confidence in the key study (Boscolo et al., 1994) is low. The study focused on the
blood pressure and kidney effects of vanadium; it did not address a comprehensive suite of
endpoints. In addition, the issue of a2u-globulin accumulation was not addressed. Confidence in
the database is medium as for the subchronic p-RfD. The chronic studies are of limited utility.
Low confidence in the chronic p-RfD follows.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR VANADIUM AND COMPOUNDS
There are no inhalation data with which to derive subchronic or chronic p-RfCs for
vanadium compounds.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR VANADIUM AND COMPOUNDS
There are no human data on the potential carcinogenicity of soluble inorganic vanadium
compounds, nor are there adequate animal carcinogenicity bioassays; thus, under the
U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, there is "Inadequate Information
to Assess [the] Carcinogenic Potential" of vanadium. In early carcinogenicity bioassays of
vanadium, no increases in tumor incidence were observed in rats or mice exposed chronically
(Kanisawa and Schroeder, 1967; Schroeder et al., 1970; Schroeder and Michener, 1975).
However, these studies are limited in several ways: there is limited histopathology evaluation,
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and tumor findings are not reported by target organ. In addition, the study in rats (Schroeder et
al., 1970) is hampered by significant animal loss due to a pneumonia outbreak. A number of
studies in rats have indicated that vanadium may exert an antineoplastic effect in chemical
carcinogenesis, reducing the number and/or incidence of leiomyosarcomas and tumors of the
liver, colon, and mammary glands in rats (Evangelou et al., 1997; Liasko et al., 1998; Ray et al.,
2004, 2005a,b, 2006; Chakraborty et al., 2005, 2006a,b,c, 2007a,b; Kanna et al., 2003, 2004,
2005).	Mechanistic information supporting the potential antineoplastic effect includes evidence
that vanadium can induce apoptosis in mammary tumor cells both in vitro and in vivo (Ray et al.,
2006).	Limited genotoxicity data have shown that vanadium can induce mutations in yeast and
mammalian cells (Bronzetti et al., 1990; Cohen et al., 1992; Klein et al., 1994). In mammalian
cells cultured in vitro, vanadium increased the SCE frequency at noncytotoxic concentrations
(Owusu-Yaw et al., 1990). Vanadium has induced micronuclei and/or numerical chromosomal
aberrations (hypoploidy or hyperploidy) in mice treated in vivo (Ciranni et al., 1995;
Leopardi et al., 2005; Villani et al., 2007).
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