Toxicity Profiles
Formal Toxicity Summary for VANADIUM
NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 1. INTRODUCTION
- 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
DECEMBER 1991
Prepared by: Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
EXECUTIVE SUMMARY
Vanadium is a metallic element that occurs in six oxidation states and numerous inorganic compounds. Some of the more important compounds are vanadium pentoxide (V2O5), sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4), vanadyl sulfate (VOSO4), and ammonium vanadate (NH4VO3). Vanadium is used primarily as an alloying agent in steels and non-ferrous metals (ATSDR, 1990). Vanadium compounds are also used as catalysts and in chemical, ceramic or specialty applications.
Vanadium compounds are poorly absorbed through the gastrointestinal system (0.5-2% of dietary amount) (NRCC, 1980; ICRP, 1960; Byrne and Kosta, 1978), but slightly more readily absorbed through the lungs (20-25%) (ICRP, 1960; Davies and Bennett, 1983). Absorbed vanadium is widely distributed in the body, but short-term localization occurs primarily in bone, kidneys, and liver (Vouk, 1979; Roshchin et al., 1980; Parker et al., 1980; Sharma et al., 1980; Wiegmann et al., 1982). In the body, vanadium can undergo changes in oxidation state (interconversion of vanadyl (+4) and vanadate (+5) forms) and it can also bind with blood protein (transferin) (Harris et al., 1984). Vanadium is excreted primarily in the feces following oral exposures and primarily in the urine following inhalation exposures (Tipton et al., 1969; ATSDR, 1990).
The toxicity of vanadium depends on its physico-chemical state; particularly on its valence state and solubility. Based on acute toxicity, pentavalent NH4VO3 has been reported to be more than twice as toxic as trivalent VCl3 and more than 6 times as toxic as divalent VI2. Pentavalent V2O5 has been reported to be more than 5 times as toxic as trivalent V2O3 (Roschin, 1967). In animals, acutely toxic oral doses cause vasoconstriction, diffuse desquamative enteritis, congestion and fatty degeneration of the liver, congestion and focal hemorrhages in the lungs and adrenal cortex (Gosselin et al., 1984). Minimal effects seen after subchronic oral exposures to animals include diarrhea, altered renal function, and decreases in erythrocyte counts, hemogloblin, and hematocrit (Domingo et al., 1985; Zaporowska and Wasilewski, 1990). In humans, intestinal cramps and diarrhea may occur following subchronic oral exposures. These studies indicate that for subchronic and chronic oral exposures the primary targets are the digestive system, kidneys, and blood.
Reference Doses (RfD) for chronic oral exposures are: 0.007 mg/kg/day for vanadium; 0.009 mg/kg/day for vanadium pentoxide; 0.02 mg/kg/day for vanadyl sulfate; and 0.001 mg/kg/day for sodium metavanadate (U.S. EPA, 1987, 1991a,b). The subchronic RfDs for these compounds are the same as the chronic RfDs, except for sodium metavanadate, which is 0.01 mg/kg/day (U.S. EPA, 1987, 1991a,b).
Inhalation exposures to vanadium and vanadium compounds result primarily in adverse effects to the respiratory system (Sax, 1984; ATSDR, 1990). In laboratory studies, minimal effects (throat irritation and coughing) occurred after an 8-hr exposure to 0.1 mg V/m3 (Zenz and Berg, 1967). In studies on workers occupationally exposed to vanadium, the most common reported symptoms were: irritation of the respiratory tract, conjunctivitis, dermatitis, cough, bronchospasm, pulmonary congestion, and bronchitis (Symanski, 1939; Sjoberg, 1950, 1951, 1955, 1956; Vintinner et al., 1955; Lewis 1959; Tebrock and Machle, 1968; Roshchin, 1968; Kiviluoto et al., 1981b). Quantitative data are; however, insufficient to derive a subchronic or chronic inhalation Reference Concentration (RfC) for vanadium or vanadium compounds.
There is little evidence that vanadium or vanadium compounds are reproductive toxins or teratogens. There is also no evidence that any vanadium compound is carcinogenic; however, very few adequate studies are available for evaluation. Vanadium has not been classified as to carcinogenicity by the U.S. EPA (1991a).
1. INTRODUCTION
Vanadium (V) is a metal that occurs in six oxidation states and numerous chemical forms. From a toxicological standpoint, the most important inorganic vanadium compounds are vanadium pentoxide (V2O5), sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4), vanadyl sulfate (VOSO4), and ammonium vanadate (NH4VO3) (ATSDR, 1990).
About 97% of the total production of vanadium is used as an alloying agent in steels and non-ferrous metals such as copper, aluminum and titanium (ATSDR, 1990). Vanadium may also have applications as an intermetallic compound (V3Ga) for superconductor applications (Baroch, 1983). Vanadium compounds are also used as catalysts or in chemical, ceramic or specialty applications (Rosenbaum, 1983). Minor uses include applications as color modifiers in mercury-vapor lamps, as driers in paints and varnish, and as corrosion inhibitors in flue-gas scrubbers (Rosenbaum, 1983).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Absorption of vanadium into the body depends on the chemical composition of the compound containing the vanadium, as well as on the species exposed and the route of exposure. In humans, vanadium salts are poorly absorbed from the gastrointestinal tract (Curran and Burch, 1967). Estimates of the extent of gastrointestinal absorption of dietary vanadium are 0.5 to 2% (NRCC, 1980; ICRP, 1960, 1981). In rats, gastrointestinal absorption of vanadium amounted to 2.6% following oral dosing with vanadium pentoxide or vanadium oxydichloride and 17.5% following oral dosing with sodium orthovanadate (Conklin et al., 1982; Sollenberger, 1981; Wiegmann et al., 1982).
Because atmospheric vanadium would most likely be present in particulate form, deposition in the lungs will be greatest for particles in the submicron size range (Waters, 1977). In humans, a pulmonary retention value of 35% and a blood absorption value of 20% have been used to determine whole body burden of vanadium (Davies and Bennett, 1983). ICRP (1960) estimated that 26% of soluble vanadium is absorbed through the lungs. Studies in rats have shown that intratracheally instilled vanadium compounds such as V2O5 and VOCl2 disappear rapidly from the lungs; Conklin et al. (1982) reported a 40% loss of V2O5 in 1 hr and 90% after 3 days; Oberg et al. (1978) reported a >50% loss of VOCl2 in one day; Rhoads and Sanders (1985) reported a two-phase exponential loss model for V2O5 with 72% of the dose cleared from the lungs in the first phase (t½ = 11 min), 28% in the second phase (t½ = 1.8 days), and Edel and Sabbioni (1988) reported 80-85% clearance of tetravalent and pentavalent forms of vanadium within 3 hr.
Although it has been shown that vanadium (as aqueous solutions of vanadate salts) can be absorbed through the skin of experimental animals, uptake of vanadium through skin contact with airborne particulate matter is considered to be only a minor source of human exposure (NRC, 1974).
2.2. DISTRIBUTION
Absorbed vanadium is widely distributed in the body, but short-term localization occurs primarily in bone, kidneys, and liver, and possibly also in the spleen and lungs (Vouk, 1979; Roshchin et al., 1980; Parker et al., 1980; Sharma et al., 1980; Wiegmann et al., 1982).
2.2.1. Human
Concentrations of vanadium in human tissues have been reported to range from 0 to 12 µg/g (Scanlon, 1975). On a wet weight basis, concentrations of 19-140 ng/g in lung, 4.5-40 ng/g in liver, 30 ng/g in brain, 0.45-10 ng/g in muscle, 400 ng/g in lymph nodes, 200 ng/g in testes, 2.6-3.3 ng/g in kidney, and 3.0-3.2 ng/g in thyroid have been reported (Hamilton et al., 1972/73; Byrne and Kosta, 1978). In a study of workers at a metallurgic plant, the median vanadium concentration in the blood was 2.9 µg/L (Thurauf et al., 1979). In a study of workers in a ferroalloy plant, vanadium blood levels averaged 20.2 nmol/L in nonexposed or low exposure workers, and 35.7 nmol/L in moderate and high exposure workers (Gylseth et al., 1979). Kiviluoto et al. (1981a) reported vanadium levels of 393 ± 223 nmol/L in serum of workers exposed to TWAs of 0.03-0.77 mg V/m3.
2.2.2. Animal
Acute oral exposure to vanadium compounds results in rapid tissue distribution, particularly to bone (ATSDR, 1990). Intermediate exposures result in low levels in bone, kidneys, liver and lungs (ATSDR, 1990). Long-term dietary studies conducted on dogs revealed limited accumulation of vanadium in femoral epiphyses (1.2 to 1.5 ug/g) following 2.5 years on a diet containing 10 or 100 ppm vanadium added as vanadium pentoxide (Stokinger et al. unpublished, as reported in Stokinger, 1981). Uptake of vanadium was greater in the bones of rats than in bones of dogs exposed to the same dietary levels of vanadium. Tissue deposition of vanadium has been reported to be greater following dietary exposure to ammonium metavanadate than to vanadium pentoxide (Stokinger et al., 1981).
In rats, inhalation exposure to vanadium pentoxide (0.5 mg V/m3, 6 hr daily, for 6 mo) resulted in deposition of vanadium primarily in lungs (30 µg V/g), kidneys (0.8 µg V/g), and spleen (0.6 µg V/g) (Stokinger et al., 1981). Intratracheal instillation of vanadium pentoxide in the same species resulted in rapid transport to the blood, liver, and bone (Conklin et al., 1982), and deposition of 12% of the dose in the skeleton (Rhoads and Sanders, 1985). Intratracheal studies with VOCl2 also revealed rapid transport to blood, heart, spleen, liver, and kidneys, and relatively large deposition in the skeleton of rats (Oberg et al., 1978).
2.3. METABOLISM
In the body, vanadium can undergo changes in oxidation state and it can also form chemical complexes with blood proteins (ATSDR, 1990). Harris et al. (1984) followed the distribution of vanadium in blood cells and plasma of dogs injected i.v. with radiolabeled vanadyl chloride (+4 oxidation state) or ammonium vanadate (+5 oxidation state). A significant fraction of the vanadium was associated with red blood cells and 77% of the plasma vanadium was eventually bound to serum transferrin. Harris et al. (1984) noted that there is an interconversion of vanadyl and vanadate in the blood, probably with oxidation of the vanadyl transferrin complex taking place in the plasma, and reduction of vanadate to vanadyl ions occurring in red blood cells. Transferrin-bound vanadium may be exhanged with liver ferritin (Harris et al., 1984; Chasteen et al., 1986).
2.4. EXCRETION
2.4.1. Human
Excretion of vanadium depends on the exposure route and chemical form of the vanadium. Following oral administration of sodium metavanadate (12.5 mg/d for 12 days), 87.6% of the dose was recovered in the feces and the remainder (12.4%) in the urine (Proescher et al., 1917). The ratio of vanadium in urine to that in the diet was reported to be about 0.13 (Tipton et al., 1969).
Following inhalation exposures to vanadium compounds, urinary levels can be quite high. Workers occupationally exposed to vanadium dust (0.5 mg/m3) had detectable levels of vanadium in their urine for up to 2 weeks after the exposure ended (Zenz et al., 1962). Workers exposed to 0.1-0.19 mg/m3 vanadium in a manufacturing plant had significantly higher urinary levels of vanadium (20.6 µg/L) than non-exposed workers (2.7 µg/L) (Orris et al. 1983). Vanadium concentrations of 37.8 µg/L, median value (Thurauf et al., 1979), 46.7 µg/L, mean value (Lewis, 1959), and 200-500 µg/L, range (Gul'ko, 1956) have been reported for urine samples from other occupationally exposed workers. In a study of workers in a ferroalloy plant, vanadium concentrations in urine when adjusted for creatinine excretion, averaged 3.6 nmol/mmol creatinine for nonexposed workers and 15.2 nmol/mmol creatinine for exposed workers (Gylseth et al., 1979). Kiviluoto et al. (1981a) reported vanadium levels of 73 ±50 nmol/mmol of creatinine in urine of workers exposed to TWAs of 0.03-0.77 mg V/m3.
2.4.2. Animal
Because vanadium is poorly absorbed through the gastrointestinal tract, a large percentage of an ingested dose will be excreted unabsorbed in the feces; Patterson et al. (1986) reported that in rats, 80% of a dose of ammonium metavanadate was excreted in the feces over a period of 6 days. Of the absorbed vanadium, that fraction that is deposited in the liver is excreted rapidly, but that retained in bone is mobilized more slowly (Curran and Burch, 1967). Following inhalation exposure or intratracheal or intravenous injection, much of the absorbed vanadium is excreted in the urine (ATSDR, 1990). In rats, 32-40% of an intratracheal or intravenous dose was excreted in the urine in the first 3-4 days (Sabbioni and Marafante, 1978; Conklin et al., 1982). Excretion of vanadium in the urine may continue for up to 6 mo after chronic exposure is discontinued (Curran, unpublished).
3. NONCARCINOGENIC HEALTH EFFECTS
The toxicity of vanadium depends on its physico-chemical state; particularly on its valence state and solubility. Pentavalent vanadium is generally considered to be the most toxic form, regardless of whether it functions as an anion or cation (NRC, 1974). Based on relative median lethal doses, pentavalent ammonium vanadate (NH4VO3) has been reported to be more than twice as toxic as trivalent vanadium trifluoride (VCl3) and more than 6 times as toxic as divalent vanadium diiodide (VI2). Similarly, the pentavalent vanadium pentoxide (V2O5) was reported to be more than 5 times as toxic as the trivalent vanadium trioxide (V2O3). In in vitro tests on rabbit alveolar macrophages, V2O5 was more toxic than V2O3 which, in turn, was more toxic than VO2 (Waters et al., 1974).
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Vanadium pentoxide and sodium metavanadate have a toxicity rating of 5, equivalent to a probable lethal oral dose in humans of 5-50 mg/kg (Gosselin et al., 1984). The elemental metallic form is considered to be non-toxic.
3.1.1.2. Animal
Animals exposed to acutely toxic doses of vanadium compounds exhibit immediate distress, a hemorrhagic exudate from the nose, marked diarrhea, hindlimb paralysis, labored respiration, and convulsions that can lead to death (Gosselin et al., 1984). Pathologic effects include diffuse desquamative enteritis and congestion of lungs, liver, kidneys, adrenal cortex, brain, spinal cord, and bone marrow (Gosselin et al., 1984). Fatty degeneration of lungs and liver and focal hemorrhages in the lungs and adrenal cortex may also occur (Gosselin et al., 1984). High concentrations of vanadium compounds may cause irreversible damage to the kidneys (Kumar and Corder, 1980). Vanadium compounds have also been reported to be vasoconstricting agents affecting blood vessels of the lungs, spleen, kidneys, and intestine (Proescher et al., 1917; Erdmann et al., 1984). LD50 values for sodium metavanadate administered by gavage to rats and mice are 41 mg V/kg and 31 mg V/kg, respectively (ATSDR, 1990).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
Volunteers given 0.47-1.3 mg V/kg/day orally as ammonium vanadyl tartrate for three months, developed intestinal cramping and diarrhea, but no hematological abnormalities, no changes in serum chemistry indicative of adverse liver effects (glutamic oxaloacetic transferase, cholesterol, triglyceride, or phospholipid levels), and no changes in urine chemistry indicative of adverse renal effects (albumin, hemoglobin, BUN, or formed elements) (Dimond et al., 1963).
3.1.2.2. Animal
Sodium metavanadate at a concentration of 50 ppm in the drinking water of rats for three months resulted in slight increases in blood urea and uric acid and mild histopathological lesions in kidneys (corticomedullar microhaemorrhagic foci) and spleen (hypertrophy and hyperplasia in the white pulp) (Domingo et al., 1985). The exposure was equivalent to a daily dose level of 6.56 mg/kg/day or 2.74 mg V/kg/day. An exposure level of 10 ppm (1.32 mg/kg/day or 0.55 mg V/kg/day) was considered a NOAEL (U.S. EPA, 1987). The same compound added to the food of rats at levels of 25 and 50 ppm for 100 days had no effect on hemoglobin levels, but did cause dose-related decreases in growth as well as diarrhea at the highest dose (9.3 mg/kg/day) (Franke and Moxon, 1937). No other parameters of toxicity were evaluated.
Sodium orthovanadate in the diet of rats for six months caused no changes in heart rate or blood pressure, but did induce vasoconstriction (Susic and Kentera, 1988).
Ammonium vanadate (15 mg V/kg) in the diet of rats for 2 months resulted in increased right ventricular pressure and pulmonary hypertension (Susic and Kentera, 1986). The same compound administered in drinking water of rats (200 ppm vanadium) for two months resulted in decreased growth, decreased erythrocyte count, and reduced hemoglobin and hematocrit (Gorski and Zaporowska, 1983). Additional studies confirmed that vanadium in the drinking water of rats (300 ppm V for 4 weeks) caused a decrease in erythrocyte count and hemoglogin level (Zaporowska and Wasilewski, 1991). In addition, a relative increase in reticulocytes and polychromatophilic erythrocytes indicated an effect on erythrocyte maturation (Zaporowska and Wasilewski, 1991).
Vanadium pentoxide in the diet of male rats for 103 days (25 ppm for 35 days followed by 100 ppm for 68 days or 50 ppm for 35 days followed by 150 ppm for 68 days) resulted in a decrease in cystine content in hair and significant reductions in RBC count and hemoglobin in the high-dose group (Mountain et al., 1953).
3.1.3. Chronic Toxicity
3.1.3.1. Human
Information on the chronic oral toxicity of vanadium to humans was not available.
3.1.3.2. Animal
A vanadyl sulfate concentration of 5 µg/mL in drinking water, plus a vanadium level of 3.2 µg/g in the diet (4.1 mg V/kg total) of mice, was reported to cause no adverse effects over a lifetime exposure period (Schroeder and Balassa, 1967). In similar lifetime studies, rats and mice exhibited no adverse effects when exposed to 5 ppm vanadium (as vanadyl sulfate) in drinking water (Schroeder et al., 1970; Schroeder and Mitchner, 1975). The estimated dose levels were 0.7 mg V/kg/day for rats and 0.9 mg V/kg/day for mice.
Vanadium pentoxide in the diet of rats at levels of 10 and 100 ppm for their entire lifetime resulted in no significant toxicological effects except for a reduction in hair cystine content (Stokinger et al., 1953). The exposure level of 10 ppm was equivalent to 0.9 mg/kg/day of vanadium pentoxide (U.S. EPA, 1987).
3.1.4. Developmental and Reproductive Toxicity
3.1.4.1. Human
Information on the oral developmental and reproductive toxicity of vanadium to humans was not available.
3.1.4.2. Animal
Exposure of male and female rats before mating, and of female rats during gestation and lactation to sodium metavanadate by gavage (maximum of 8.4 mg V/kg/day) did not induce any adverse effects on fertility, reproduction, or parturition; however, doses of 4.2 mg V/kg/day significantly reduced pup size and body weight at birth and 21 days later (Domingo et al., 1986). Gavage doses of 8.4 mg V/kg/day, as sodium metavanadate, to pregnant rats on gestation days 6-14 did not result in embryolethality, teratogenicity or significant visceral or skeletal abnormalities; however, there was an increase in facial and dorsal hemorrhages (Paternain et al., 1987). In a two-generation study, altered lung collagen metabolism was seen in fetuses of adult rats receiving 2.8 mg V/kg, as sodium metavanadate in drinking water (Kowalska et al., 1988).
3.1.5. Reference Dose
Separate subchronic and chronic oral reference doses have been derived for vanadium, vanadium pentoxide, vanadyl sulfate, and sodium metavanadate (U.S. EPA, 1987, 1991a).
3.1.5.1. Subchronic
Vanadium
ORAL RfD: 0.007 mg/kg/day (U.S. EPA, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: NA
NOAEL: 0.7 mg/kg/day (rat), drinking water, lifetime
PRINCIPAL STUDY: Schroeder et al., 1970
COMMENTS: The NOAEL is derived from a lifetime single exposure level study in which rats were exposed to 5 ppm V, as vanadyl sulfate, in drinking water. The only reported effects were minor changes in serum chemistry. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Vanadium pentoxide
ORAL RfD: 0.009 mg/kg/day (U.S. EPA, 1991b)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 1
NOAEL: 0.89 mg/kg/day
PRINCIPAL STUDY: Stokinger et al., 1953
COMMENTS: The NOAEL is derived from a study in which rats received 10 or 100 ppm dietary vanadium pentoxide for 2.5 yr. The only change reported was a decrease in cystine levels in the hair of the exposed animals. The 10 ppm level was selected as a NOAEL. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Vanadyl sulfate
ORAL RfD: 0.02 mg/kg/day (U.S. EPA, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: NA
NOAEL: 2.24 mg/kg/day
PRINCIPAL STUDY: Schroeder et al., 1970, as reported in U.S. EPA, 1987
COMMENTS: The NOAEL is derived from a single exposure level study in which rats were exposed to 5 ppm V, as vanadyl sulfate, in drinking water for 2.5 yr for a lifetime. The only reported effects were minor changes in serum chemistry. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Sodium metavanadate
ORAL RfD: 0.01 mg/kg/day (U.S. EPA, 1987, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: NA
NOAEL: 1.32 mg/kg/day
PRINCIPAL STUDY: Domingo et al., 1985
COMMENTS: The NOAEL is derived from a study in which rats were given 0, 5, 10 and 50 ppm sodium metavanadate, in drinking water for 3 months. Impaired kidney function was seen at 50 ppm, and 10 ppm was considered a NOAEL. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
3.1.5.2. Chronic
Vanadium
ORAL RfD: 0.007 mg/kg/day (U.S. EPA, 1987, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: NA
NOAEL: 0.7 mg/kg/day (rat), drinking water, lifetime
PRINCIPAL STUDY: Schroeder et al., 1970
COMMENTS: The NOAEL is derived from a lifetime single exposure level study in which rats were exposed to 5 ppm V, as vanadyl sulfate, in drinking water. The only reported effects were minor changes in serum chemistry. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Vanadium pentoxide
ORAL RfD: 0.009 mg/kg/day (U.S. EPA, 1987, 1991b)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: 1
NOAEL: 0.89 mg/kg/day
CONFIDENCE:
Study: Low
Data Base: Low
RfD: Low
VERIFICATION DATE: 02/26/86
PRINCIPAL STUDY: Stokinger et al., 1953
COMMENTS: The NOAEL is derived from a study in which rats received 10 or 100 ppm dietary vanadium pentoxide for 2.5 yr. The only change reported was a decrease in cystine levels in the hair of the exposed animals. The 10 ppm level was selected as a NOAEL. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Vanadyl sulfate
ORAL RfD: 0.02 mg/kg/day (U.S. EPA, 1987, 1991a)
UNCERTAINTY FACTOR: 100
MODIFYING FACTOR: NA
NOAEL: 2.24 mg/kg/day
PRINCIPAL STUDY: Schroeder et al., 1970
COMMENTS: The NOAEL is derived from a single exposure level study in which rats were exposed to 5 ppm V, as vanadyl sulfate, in drinking water for 2.5 yr for a lifetime. The only reported effects were minor changes in serum chemistry. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans and a 10-fold uncertainty to protect sensitive individuals.
Sodium metavanadate
ORAL RfD: 0.001 mg/kg/day (U.S. EPA, 1987, 1991a)
UNCERTAINTY FACTOR: 1000
MODIFYING FACTOR: NA
NOAEL: 1.32 mg/kg/day
PRINCIPAL STUDY: Domingo et al., 1985
COMMENTS: The NOAEL is derived from a study in which rats were given 0, 5, 10 and 50 ppm sodium metavanadate, in drinking water for 3 months. Impaired kidney function was seen at 50 ppm, and 10 ppm was considered a NOAEL. The Uncertainty Factor of 100 is the product of a 10-fold uncertainty in extrapolating from laboratory animals to humans, a 10-fold uncertainty to extrapolate from a subchronic to chronic exposure, and a 10-fold uncertainty to protect sensitive individuals.
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
3.2.1.1. Human
In studies on humans, the acute toxic effects of inhaled vanadium were found to be limited to eye and respiratory tract irritation; there being no evidence of disturbances to the cardiovascular system, gastrointestinal tract, kidneys, blood, or CNS (Sax, 1984; ATSDR, 1990). Typical symptoms include coughing, wheezing, rhinorrhea, sore throat and chest pain (ATSDR, 1990). There is usually a latency period of 1-6 days before effects appear (Lagerkvist et al., 1986). In severe cases bronchospasms and bronchitis, accompanied by wheezing and dyspnea may occur, and bronchopneumonia may result from very high exposures (Lagerkvist et al., 1986)
NIOSH (1977) reported that respiratory irritation from inhalation of vanadium-containing dusts or fumes occurred at concentrations ranging from 0.1 to 85 mg/m3. At a concentration of about 1.0 mg/m3, vanadium dust caused coughing and throat irritation (Zenz and Berg, 1967). At a level of 0.1 mg/m3, an 8-hr exposure to vanadium pentoxide (0.06 mg V/m3) caused only mucus formation which was cleared by slight coughing that lasted 3-4 days (Zenz and Berg, 1967). A level of 0.06 mg V/m3 was considered a NOAEL for acute exposures by ATSDR (1990).
Lees (1980) reported that workers occupationally exposed (several hours per day for eight days) to vanadium-containing dust (as a component in fuel oil ash) exhibited significant decreases in several lung function tests including forced vital capacity, forced expiratory volume, and forced mid-expiratory flow. Lung functions returned to normal several weeks after the exposures ended.
There is some evidence that workers exposed to vanadium compounds become sensitized such that there is increased severity and more rapid onset of respiratory symptoms after multiple exposures (Zenz and Berg, 1967; Zenz et al., 1962; Roshchin, 1968).
3.2.1.2. Animal
Two of four rabbits died following 7 hr exposure to 114 mg V/m3, as V2O5; the exposures resulted in tracheitis, pulmonary edema and bronchopneumonia (Sjoberg, 1950).
Monkeys exposed to 2.8 mg V/m3, as V2O5, for 6 hr developed increased pulmonary resistance and had increased numbers of polymorphonuclear leucocytes in bronchoalveolar lavage fluid (Knecht et al., 1985). Exposure of rats to bismuth orthovanadate 6 hr/day for 2 weeks resulted in increases in lung weight and increased accumulation of alveolar macrophages, lung lipids and type II epithelial cells (Lee and Gillies, 1986). Rabbits exposed to vanadium pentoxide dust showed no evidence of adverse effects on cardiovasular or gastrointestinal systems, blood, spleen or brain; but they did exhibit conjunctivitis and some degree of fatty degeneration in the liver and kidneys (Sjoberg, 1950).
3.2.2. Subchronic Toxicity
3.2.2.1. Human
Information on the subchronic inhalation toxicity of vanadium and vanadium compounds to humans was not available.
3.2.2.2. Animal
Repeated inhalation of vanadium pentoxide (20-40 mg/m3, 1 hr/day, for several months) by rabbits resulted in chronic rhinitis and tracheitis, emphysema, patches of lung atelectasia, and bronchopneumonia (Sjoberg, 1950). Exposure of rabbits to vanadium trioxide aerosol (40-75 mg/m3, 2 hr/day, 9-12 months) resulted in sneezing, nasal discharge, dyspnea and tachypnea and sometimes bronchial asthma (Roshchin et al., 1964; Roshchin, 1967). Similar effects were seen in rabbits exposed under the same conditions to vanadium pentoxide concentrations of 8-18 mg/m3 or to vanadium carbide levels of 40-80 mg/m3, and also in rats exposed to vanadium pentoxide condensation aerosol (3-5 mg/m3, 2 hr/day, every second day for 3 months) and to vanadium pentoxide dust (10-40 mg/m3, 1 hr/day, for 4 months).
Stokinger et al. (1953) reported that a concentration of 0.5 mg V/m3 as vanadium pentoxide dust, 6 hr/day for 6 months caused no adverse effects in rats, dogs, guinea pigs, and rabbits.
Pazynich (1966) reported that albino rats exposed continuously for 70 days to 0.2 mg/m3 of vanadium pentoxide aerosol exhibited altered motor chronaxy of antagonistic muscles, decreased blood cholinesterase activity, reduced serum protein levels, including ß-globulins, reduced oxyhemoglobin, and also pathological changes in the lungs (congestion, hemorrhages, bronchitis), the liver (central vein congestion, hemorrhages, infilrates and degeneration), the kidneys (degeneration and necrosis of the epithelial cells of the convoluted tubules), and in the myocardial blood vessels (focal perivascular hemorrhages). No adverse effects were seen in rats exposed to 0.002 mg/m3.
Sugiura (1978) exposed rats and mice to 1-2 mg/m3 of vanadium pentoxide 6 hr/day for 3 months. At concentrations up to 0.4 mg/m3, no adverse effects were seen. At higher concentrations, the rats had decreased growth rates and enlarged lungs; whereas. mice had thickened alvelolar walls and congested lungs.
3.2.3. Chronic Toxicity
3.2.3.1. Human
Data on the effects of long term inhalation exposure to vanadium have been derived mainly from studies of workers occupationally exposed to vanadium pentoxide. The most frequently reported effects were irritation to the respiratory tract, conjunctivitis and dermatitis. Cough, bronchospasm, pulmonary congestion, and bronchitis are the most common symptoms, but rhinitis, pharyngitis, pneumosclerosis, asthma, and dyspnea have also been reported (Symanski, 1939; Sjoberg, 1950; Vintinner et al., 1955; Lewis 1959; Tebrock and Machle, 1968; Kiviluoto et al., 1981b; Sjoberg, 1956; Sjoberg, 1951, 1955; Roshchin, 1968). There is no clear evidence that chronic lung disease (emphysema, pneumoconiosis, fibrosis) results from long term exposure to vanadium compounds (NIOSH, 1977); however, it has been noted that cases of bronchial asthma and bronchitis have been reported with "sufficient frequency to warrant concern for decreased ventilatory function, and possibly, a progressively decreasing ventilatory function" (NIOSH, 1977). Bronchiopneumonia may possibly be a secondary complication caused by the effects of vanadium on respiratory mucosa (Sjoberg, 1955).
Evaluation of dose-response relationships from occupational exposure studies is difficult because of fluctuations in concentrations, lack of continuous monitoring, and potential exposure through routes other than inhalation. Generally, occupational exposures occur over wide concentration ranges, i.e., 0.05-5.58 mg/m3 (Sjoberg, 1950), 0.02-3.2 mg V/m3 (Tebrock and Machle, 1968), 0.004-2.116 mg V/m3 in ore dust and 0.018-58.82 mg V/m3 in vanadium pentoxide dust (Vintenner et al., 1955), and 0.012-2.3 mg V/m3 (time-weighted average exposures) for smelter workers (Kiviluoto et al., 1981a). Therefore, minimum effect levels are difficult to quantify. The lowest exposure levels at which there was an increased incidence of respiratory distress were those in the study of Lewis (1959) in which workers were exposed to vanadium pentoxide for an average duration of 2.5 years. In this study, vanadium concentrations in seven air samples ranged from 0.018-0.925 mg V/m3, but five of the measurements were 0.1-0.38 mg/m3. In another study, vanadium processing workers exposed to 0.1-0.3 mg/m3 had lowered serum cholesterol levels but no other adverse effects (Vintinner et al., 1955).
Most investigators have reported that long term occcupational exposure to vanadium compounds did not result in any gastrointestinal symptoms or adverse effects to the hemopoietic system, kidneys, liver, or nervous sytem (Symanski, 1939; Sjoberg, 1956: Kiviluoto et al., 1981a, 1981b). However, some workers chronically exposed to vanadium dust have reported dizziness, depression, headache, or tremors of the fingers and arms (Levy et al., 1984; Vintinner et al., 1955).
From the available pre-1974 clinical, experimental, and occupational exposure data, IIEQ (1974) concluded that clinical signs of severe chronic intoxication (hemoptysis, pneumonia, hacking cough, chest pain, lesions of the nose, and rales) occurred at vanadium pentoxide air concentrations of around 1000 µg/m3; clinical signs of subtle chronic intoxication (green tongue, cough, vascularization of the cornea, conjunctivitis, colic, respiratory tract irritation, mucus, and rhinorrhea) occurred at vanadium pentoxide concentrations of about 100 µg/m3 or less, and subclinical chronic intoxication resulting in metabolic disorders occurred at about 1-20 µg/m3. IIEQ (1974) considered reductions in body cystine levels (as measured in fingernails) to be a major subclinical effect of vanadium exposure. Other biochemical effects that may occur without clinical signs of toxicity include reductions in serum cholesterol, decreases in coenzyme A in liver and in coenzyme Q in mitochrondria and changes in activity of Na+-, K+-ATPase, Ca-ATPase, adenylate kinase, ribonuclease, phosphofructokinase, and glucose-6-phosphatase) (Lagerkvist et al., 1986).
3.2.3.2. Animal
Animal data indicate that chronic toxic effects on the respiratory system are similar to those seen in acute exposures. In addition, when the dose is sufficiently high or the exposure sufficiently long, systemic effects such as edema, hemorrhaging, and lesions can occur in the lungs, liver, and kidney.
Rabbits chronically exposed to vanadium pentoxide dust showed no evidence of adverse effects on the cardiovasular or gastrointestinal systems, blood, spleen or brain; but they did develop conjunctivitis and had some fatty degeneration in the liver and kidneys (Sjoberg, 1950). Fatty changes with partial cell necrosis were seen in the liver and kidneys of rats and rabbits exposed to vanadium pentoxide, trioxide and chloride (10-70 mg/m3, 2 hr/day, 9-12 mo) (Roshchin, 1968).
3.2.4. Developmental and Reproductive Toxicity
3.2.4.1. Human
Information on the developmental and reproductive toxicity of vanadium and vanadium compounds following inhalation exposure was not available.
3.2.4.2. Animal
Information on the developmental and reproductive toxicity of vanadium and vanadium compounds following inhalation exposure was not available.
3.2.5. Reference Concentration
A subchronic or chronic reference concentration for vanadium is not available at this time (U.S. EPA, 1991b).
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Stokinger et al. (1953) reported that a 10% solution of sodium metavanadate is a primary irritant to human skin. Saturated solutions of ammonium metavanadate (0.5%) and vanadium pentoxide (0.8% solution) did not irritate the skin. Sjoberg (1951) reported that several workers occupationally exposed to vanadium developed what appeared to be a contact dermatitis and that in one case, skin patch tests produced eczematous lesions indicative of an allergic reaction.
Proescher et al. (1917) estimated that 30 mg of sodium tetravanadate, injected intravenously, would be a fatal dose to a 70-kg man. Signs and symptoms of toxicity following a single intravenous injection of 100 mg vanadium pentoxide include nausea, vomiting, salivation, lacrimation, loss of pulse, and albumin and cylindrical casts in urine (Lagerkvist et al., 1986).
3.3.1.2. Animal
Administered to the eye of a rabbit, sodium orthovanadate caused a significant fall in intraocular pressure (Mittrag et al., 1984). The LD50 values for sodium metavanadate injected intrperitoneally is 0.11 mg V/kg in rats and 0.13 mg V/kg in mice (Chanh, 1965).
3.3.2. Subchronic Toxicity
3.3.2.1. Human
Information on the subchronic toxicity of vanadium or vanadium compounds to humans by other routes of exposure was not available.
3.3.2.2. Animal
Fatty changes were seen in the liver of rats following subcutaneous injections of ammonium vanadate (1 mg V/kg/day, for 30 days) (Kaku et al., 1971).
3.3.3. Chronic Toxicity
Information on the chronic toxicity of vanadium and vanadium compounds to humans or animals by other routes of exposure was not available.
3.3.4. Developmental and Reproductive Toxicity
3.3.4.1. Human
Information on the developmental and reproductive toxicity of vanadium or vanadium compounds to humans by other routes of exposure was not available.
3.3.4.2. Animal
There is no clear evidence that vanadium compounds are teratogenic to laboratory animals; however, in one study, exposure of pregnant Syrian golden hamsters to ammonium metavanadate (0, 0.47, 1.88, or 3.75 mg/kg injected i.p. on gestation days 5 through 10) resulted in a significant increase in fetal skeletal abnormalities (micrognathia, supernumerary ribs, and alternations in sternebral ossification) (Carlton et al., 1982). The number of malformed offspring was small, and there was no clear-cut dose/response relationship, thus, a definite assessment of teratogenicity was not possible. In this same study, there was also a decrease in the male-female fetal sex ratio, but no external and soft tissue anomalies. A delay in fetal skeletal ossification, but no implantation or teratogenic effects occurred in the offspring of mice injected with 0.15 mL of a 1 mM solution of vanadium pentoxide on day 8 of pregnancy (Wide, 1984). Exposure of female rats to 0.85 mg/kg of sodium metavanadate by subcutaneous injection on the 4th day of pregnancy resulted in an increase in preimplantation embryo mortality, but no teratogenic effects (Roshchin and Kazimov, 1980; Roshchin et al., 1980). However, in male rats dosed intraperitoneally (0.85 mg/kg/day of sodium metavanadate for 20 days), spermatogenesis was altered, sperm motility and osmotic resistance was reduced, the number of dead spermatozoa increased, and morphological damage to the seminiferous epithelium was observed. There was also a decrease in fertilization of females mated to exposed males and an increase in preimplantation embryo mortality.
In tests on pregnant rats, Hackett and Kelman (1983) found that vanadium accumulates in the placenta, preferentially concentrating in the membranes rather than in the fetus itself.
3.4. TARGET ORGANS/CRITICAL EFFECTS
Minimal effect levels and target organs may vary with the chemical form and oxidation state of the vanadium.
3.4.1. Oral Exposures
3.4.1.1. Primary Target Organ(s)
1. Gastrointestinal system: Diarrhea has been reported in humans and animals receiving ammonium vanadyl tartrate and sodium metavanadate, respectively.
2. Kidney: Slight changes in renal function as suggested by increases in blood urea nitrogen and uric acid have been reported in animals exposed to sodium metavanadate.
3. Blood: Decreases in erythrocytes, hemogloblin, or hematocrit have been reported in animals receiving ammonium vanadate or vanadium pentoxide.
3.4.1.2. Other Target Organ(s)
Other effects seen in animals chronically exposed to vanadium compounds include reduced growth rates in adults and fetuses (sodium metavanadate, ammonium vanadate), vasoconstriction (sodium orthovanadate), and facial and dorsal hemorrhages and altered lung collagen metabolism in fetuses (sodium metavanadate).
3.4.2. Inhalation Exposures
3.4.2.1. Primary Target Organ(s)
Respiratory system: Exposure to vanadium dusts can result in respiratory tract irritation. Bronchospasms and bronchitis, accompanied by wheezing and dysnea may occur, and bronchopneumonia may result from very high and prolonged exposures. The mechanism of vanadium's effect on the respiratory system is similar to that of other metals. Vanadium damages alveolar macrophages and affects lung clearance rates.
3.4.2.2. Other Target Organ(s)
1. Nervous System: Some workers chronically exposed to vanadium dust reported dizziness, depression, headache, or tremors of the fingers and arms.
2. Liver and Kidney: Limited animal data suggest that chronic exposure may lead to liver and kidney abnormalities.
Other effects seen in animals exposed to vanadium compounds include perivascular hemorrhages in myocardial vessels, altered muscle motor chronaxie, and changes in blood chemistry (vanadium pentoxide).
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
Citing a progress report submitted to the National Cancer Institute, Sax (1981) lists the carcinogenicity of vanadium as questionable (no other data available).
4.1.2. Animal
Kanisawa and Schroeder (1967) evaluated the carcinogenicity of vanadium in lifetime studies on Swiss mice. The test animals were given vanadyl sulfate in their drinking water (5 µg/mL water) and in their diet (3.2 µg/g feed) from the time they were 20-22 days old until death. NIOSH (1977) calculated that the total annual intake of vanadium in each animal would amount to 19.8 mg/100 g of body weight. There were no significant differences in the incidences of tumors (heart, lungs, kidneys, liver, spleen, and other organs were examined) between the exposed animals and the controls. Other studies using the same experimental procedures on both rats and mice also indicated that vanadium was not carcinogenic at a level of 5 µg vanadyl sulfate per mL of drinking water over a lifetime exposure (Schroeder and Balassa, 1967; Schroeder et al., 1970; Schroeder and Mitchner, 1975).
Stoner et al. (1976) evaluated the potential of various metallic compounds to induce lung adenomas in strain A mice. In one test group, mice were given 24 i.p. injections of vanadium (III) 2,4-pentanedione (total dose, 120, 60, or 24 mg/kg) over a 30-week period. The incidence of lung tumors was not significantly different from that of the controls.
Several studies have suggested that vanadium exhibits anti-carcinogenic activity. Thompson et al. (1984) reported that vanadyl sulfate inhibited murine mammary carcinogenesis by 1-methyl-1-nitrosourea in rats, and Djordjevic and Wampler (1985) reported that several vanadium complexes have antitumor activity against L1210 murine leukemia.
4.2. INHALATION EXPOSURES
4.2.1. Human
In a statistical study relating concentrations of air pollutants to mortality indices in Great Britain, Stocks (1960) found that together with arsenic and zinc, vanadium showed a weak correlation with lung cancer, and together with beryllium and molybdenum, showed correlations with other cancers in males. In a similar study conducted by Hickey et al. (1967), there was little correlation between lung cancer mortality and vanadium levels.
4.2.2. Animal
Information on the carcinogenicity of vanadium to animals after inhalation exposure was not available.
4.3. OTHER ROUTES OF EXPOSURE
Information on the carcinogenicity of vanadium to humans or animals from other routes of exposure was not available.
4.4. EPA WEIGHT-OF-EVIDENCE
The limited weight of evidence suggests that vanadium and vanadium compounds are not carcinogenic; however, few vanadium compounds have been adequately tested. Vanadium has not been classified as to carcinogenicity by the EPA. The NTP has approved vanadium pentoxide for carcinogenicity testing, but the results are yet not available (U.S. EPA, 1991b).
4.5. CARCINOGENICITY SLOPE FACTORS
Calculation of slope factors is not possible due to inadequate data.
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