SUMMARY

An Estimated Average Requirement (EAR) or Adequate Intake (AI) was not set for arsenic, boron, nickel, silicon, or vanadium. In the case of the vitamins and other minerals reviewed in this report, there are well-established studies typically based on observations from several laboratories. The data currently available for these vitamins and other minerals provide an understanding of the metabolic role of each and describe the consequences of their restriction in the diets of both laboratory animals and humans. There are also clearly defined, readily reproducible indicators in humans for these vitamins and other minerals that can be used to determine an EAR and calculate a Recommended Dietary Allowance, or to establish an AI. At present, such data do not exist for arsenic, boron, nickel, silicon, and vanadium.

In the case of arsenic, boron, nickel, silicon, and vanadium, there is evidence that they have a beneficial role in some physiological processes in some species. For boron, silicon, and vanadium, measurable responses of human subjects to variations in dietary intake have also been demonstrated. However, the available data are not as extensive (e.g., dose-response data are absent) and the responses are not as consistently observed as they are for the vitamins and other minerals. Thus, data are insufficient to determine an EAR for any of these minerals.

Estimates of dietary intakes of arsenic, boron, nickel, silicon, and vanadium by the North American adult population are available and could have been used to establish an AI. However, establishing an AI also requires a clearly defined, reproducible indicator in humans sensitive to a range of intakes. Indicators that meet this criterion for establishing an AI are not currently available for any of these minerals, and therefore no AI was set.

Notwithstanding, observations of deficiency effects (e.g., on growth and development) in multiple animal species and data from limited human studies suggest beneficial roles for arsenic, boron, nickel, silicon, and vanadium in human health. These data clearly indicate a need for continued study of these elements to determine their metabolic role, identify sensitive indicators, and more fully characterize specific functions in human health.

Estimates of Tolerable Upper Intake Levels (UL) were set for boron, nickel, and vanadium. The ULs for boron and vanadium are based on animal data and have been set for adults at 20 mg/day and 1.8 mg/day, respectively. The UL for nickel is 1 mg/day. There were insufficient data using the model described in Chapter 3 to set a UL for arsenic and silicon.

ARSENIC. BACKGROUND INFORMATION

FINDINGS BY LIFE STAGE AND GENDER GROUP

Because of the lack of human data to identify a biological role of arsenic in humans, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake were established.

INTAKE OF ARSENIC

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. Arsenic is currently under investigation for the treatment of leukemia (Look, 1998).

Arsenic occurs in both inorganic and organic forms, with the inorganic forms that contain trivalent arsenite (III) or pentavalent arsenate (V) being of the greatest toxicological significance (Chan and Huff, 1997). No data on the possible adverse effects of organic arsenic compounds in food were found. Because the organic forms are usually less toxic than the inorganic (ATSDR, 1998), adverse effects of inorganic forms are described. It is unclear whether risk assessments should be developed for specific groups of inorganic arsenic compounds.

RESEARCH RECOMMENDATIONS FOR ARSENIC

• A better understanding of species differences in biotransformation of arsenic and toxicity.
• The role of arsenic in methyl metabolism and genetic expression; identification of a reliable indicator of arsenic status in humans.
• Because relatively low serum arsenic concentrations have been associated with vascular diseases and central nervous system injury, more systematic investigation of the possible role of arsenic in these disorders.

BORON. BACKGROUND INFORMATION

FINDINGS BY LIFE STAGE AND GENDER GROUP

There is evidence supporting a biological role of boron in some microroganisms. In higher animals, boron has been shown to have a role in reproduction and development. The collective body of evidence, however, has yet to establish a clear biological function for boron in humans. Therefore, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake was established for boron.

INTAKE OF BORON

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects.

Hazard Identification

It should be noted that because some studies report doses of boron while others report doses of boric acid or borax, comparison of experiments is facilitated by expressing all doses as boron equivalents (e.g., boric acid dose × 0.175; borax dose × 0.113).

Adverse Effects

No data are available on adverse health effects from ingestion of large amounts of boron from food and water. According to case reports of poisoning incidents and accidental ingestions of boric acid and borax, these compounds exhibit low toxicity. Stokinger (1981) reported that the minimal lethal dose of boric acid from ingestion is 640 mg/kg/day. The potential lethal dose has been reported to be 15 to 20 g/day for adults and 3 to 6 g/day for infants; however, in an examination of 784 cases of boric acid ingestion, Litovitz and coworkers (1988) found minimal or no toxicity at these or higher intake levels. Initial symptoms include nausea, gastric discomfort, vomiting, and diarrhea. At higher doses, skin flushing, excitation, convulsions, depression, and vascular collapse have been reported.

Human Data. Most of the toxicity data on repeated administration of boron (as boric acid or borax) comes from studies in laboratory animals. However, from reports on the use of borates to treat epilepsy where doses between 1,000 mg/day of boric acid (2.5 mg/kg/ day) to 25 g/day of boric tartrate (24.8 mg/kg/day) were administered chronically, toxicity was expressed as dermatitis, alopecia, anorexia, and indigestion (Culver and Hubbard, 1996). On the basis of their review of the human data in adults, Culver and Hubbard (1996) reported no adverse effects at chronic intakes of 2.5 mg/ kg/day (about 1 g of boric acid). On the basis of nine cases involving infants (Gordon et al., 1973; O'Sullivan and Taylor, 1983), there does not appear to be an increased sensitivity of response to chronic exposure of boron compounds.

Genotoxicity. On the basis of existing data, genotoxicity is not an area of concern after exposure of humans to boron compounds (ATSDR, 1992; Dieter, 1994).

Reproductive and Developmental Effects in Animals. Although not observed in humans, animal studies have shown that high doses of borax or boric acid produce adverse effects in the testis and affect male fertility (IPCS, 1998). Also, adverse effects have been found in the developing fetus (Heindel et al., 1992; IPCS, 1998; Price et al., 1996a). Effects on the testis have been observed in three species—rats, mice, and dogs—after supplementation with boric acid or borates in feed or drinking water (Fail et al., 1990, 1991; Green et al., 1973; Ku et al., 1993; Lee et al., 1978; Weir and Fisher, 1972). The effects tend to be similar in all three species and include inhibition of spermiation (release of spermatozoa into seminiferous tubule), loss of germ cells, changes in epididymal sperm morphology and caput sperm reserves, testicular atrophy, and decreased serum testosterone levels. Doses of 29 mg/kg/day in dogs and 58.5 mg/kg/day in rats have resulted in adverse reproductive effects. A comparison of the lowest-observed-adverse-effect levels (LOAELs) and no-observed-adverse-effect levels (NOAELs) for the key studies on reproduction is given in Table 13-1.

TABLE 13-1

Ranking of Reproductive and Developmental Effects of Boron by Increasing Dose.

Pharmacokinetics. The pharmacokinetics of boron are very similar in animals and humans. There are several recent reviews of the available studies (Dourson et al., 1998; IPCS, 1998; Moore, 1997; Murray, 1998), and a summary of the key findings is presented here.

There is no evidence of boron accumulation in soft tissues of humans (Murray, 1998). In rats, boron increased more in bone than in plasma (Ku et al., 1991). Although methodological differences between studies preclude a clear-cut, cross-species comparison of blood boron concentrations in animals and humans at similar doses, IPCS (1998) reported a preliminary comparison between humans and rats after oral intakes of boron from diet or drinking water. Between 0.01 and 100 mg/kg/day, very similar blood levels were achieved at comparable intakes, further evidence that the kinetics of boron in humans and rats are alike.

Boron is rapidly excreted unchanged in the urine of humans and rodents regardless of the route of administration. In humans, the half-life for elimination was approximately 21 hours for both intravenously (Jansen et al., 1984a) and orally (Jansen et al., 1984b) administered boric acid. By using the data from Ku and coworkers (1991) and assuming first-order kinetics, the half-life in rats has been calculated in the range of 14 to 19 hours. As noted by Murray (1998) and Dourson and coworkers (1998), rats have mean glomerular filtration rates for boric acid three to four times that of humans, which could account for the small differences in blood (and, therefore, soft tissue) concentrations of boron noted by IPCS (1998).

Other Effects. Increased mortality was observed in mice fed dietary boric acid for periods of 13 weeks at boron levels of 563 mg/kg/day in females and 776 mg/kg/day in males (Dieter, 1994). Minimal to mild extramedullary hematopoiesis was noted at all doses for both sexes, and hyperkeratosis and hyperplasia of the forestomach also occurred at the highest doses for both sexes. Testicular atrophy or degeneration was observed at doses of 141 mg/kg/day. These findings confirmed the earlier studies by Weir and Fisher (1972) in which rats fed 88 mg/kg/day of boron as borax or boric acid for 90 days developed testicular atrophy.

Summary

Based on the considerations of causality, relevance, and the quality and completeness of the database in animals, reproductive and developmental effects were selected as the critical endpoint on which to base a UL for adults. Because no data are available on adverse reproductive effects in humans from the consumption of large amounts of boron from food and water, animal data were utilized to estimate the UL. The following factors support the use of the laboratory animal studies listed in Table 13-1 to assess the developmental and reproductive risks from boron exposure in humans: (1) boric acid has been shown to cause developmental effects in four species of animals, (2) the toxicity of boric acid and borax correlates with their elemental boron content under physiological conditions, (3) the organs that are sensitive to the acute systemic effects of boron in humans and animals are similar, (4) the pattern of tissue distribution and excretion of boron is similar in animals and humans, and (5) the chronic effects of boron observed in mice, rats, and dogs and the effective doses are similar.

Dose-Response Assessment

Adults

Data Selection. In the absence of human data pertaining to a dose-response relationship, the animal data sets reporting developmental abnormalities are shown in Table 13-1. The studies showing developmental abnormalities at the lowest levels of intake are in dogs (Weir and Fisher, 1972) and rats (Price et al., 1996b). However, the study in dogs was not used directly in this risk assessment of boron due to problems in the design (few animals per treatment group and lack of information on food intake). The study of Price and coworkers (1996b) is considered the critical study to assess the risks to humans from exposure to boron.

Identification of a NOAEL and LOAEL. In the study by Price and coworkers (1996b), boric acid was fed to time-mated rats (60 per treatment group) from gestational days 0 to 20 at dosages of 3.3, 6.3, 9.6, 13.3, or 25 mg/kg/day. Maternal body weight did not differ among groups during gestation or lactation, and weight gain was not affected by the amount of boron in the diet. The most sensitive parameter of developmental toxicity was decreased fetal weights at gestational day 20, with significantly decreased fetal weights found only in the 13.3 and 25 mg/kg/day groups. Thus, a NOAEL of 9.6 mg/kg/day and a LOAEL of 13.3 mg/kg/day were reported.

In an earlier study in rats using a very similar experimental design, Heindel and coworkers (1992) reported an increase in fetal malformations with boric acid at dosages of 13.6, 28.5, and 57.7 mg/ kg/day from gestational days 0 to 20. The most common malformations were enlargement of lateral ventricles in the brain, shortening of rib XIII, and wavy ribs. Although a LOAEL was found at the lowest dose tested (13.6 mg/kg/day), it is similar to the LOAEL of 13.3 mg/kg/day reported by Price and coworkers (1996b), a finding that provides additional support for the dose-response relationship for developmental toxicity as the critical effect.

Uncertainty Assessment. Five expert groups have assessed the risk to humans from boron using the NOAEL from Price and coworkers (1996b), and uncertainty factors (UFs) vary between 25 and 60 (Becking and Chen, 1998). There do not appear to be sufficient data to justify lowering the degree of uncertainty for extrapolating from experimental animals to humans from the 10 that is often used for nonessential chemicals. Thus, the usual value of 10 was selected. In view of the expected similarity in pharmokinetics among humans, however, a UF of 3 was chosen for intraspecies variability. These two UFs are multiplied to yield a UF of 30.

Derivation of a UL. The NOAEL for developmental effects in rats is 9.6 mg/kg/day. The UL for boron is calculated by dividing the NOAEL of 9.6 mg/kg/day by the UF of 30, resulting in an UL of 0.3 mg/kg/day. This value was multiplied by the average of the reference body weights for adult women, 61 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is rounded to 20 mg/day.

Boron UL Summary, Ages 19 Years and Older

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UL for Adults
≥ 19 years	20 mg/day of boron

Other Life Stage Groups

Infants. For infants, the UL was judged not determinable because of insufficient data on adverse effects in this age group and concern about the infant's ability to handle excess amounts. To prevent high levels of intake, the only source of intake for infants should be from food and formula.

Children and Adolescents. There are no reports of boron toxicity in children and adolescents. Given the dearth of information, the UL values for children and adolescents are extrapolated from those established for adults. Thus, the adult UL of 20 mg/day of boron was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1). Values have been rounded.

Pregnancy and Lactation. Because the UL is based on adverse reproductive effects in animals and because there are no reports of boron toxicity in lactating females, the UL for pregnant and lactating females is the same as that for the nonpregnant and nonlactating female.

Boron UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation

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UL for Infants
0–12 months	Not possible to establish; source of intake should be from food and formula only
UL for Children
1–3 years	3 mg/day of boron
4–8 years	6 mg/day of boron
9–13 years	11 mg/day of boron
UL for Adolescents
14–18 years	17 mg/day of boron
UL for Pregnancy
14–18 years	17 mg/day of boron
19–50 years	20 mg/day of boron
UL for Lactation
14–18 years	17 mg/day of boron
19–50 years	20 mg/day of boron

RESEARCH RECOMMENDATIONS FOR BORON

• The relationship between dietary boron and vitamin D metabolism; specifically, does boron influence the half-life of functional vitamin D metabolites and calcium metabolism as it relates to bone mineralization?
• The possible influence of boron on estrogen metabolism and function, particularly biological half-life, receptor-ligand interactions, and estrogen-inducible gene expression as related to bone mineral density.
• Studies of the possible role of boron in human neurophysiological and cognitive function that include delineation of a biochemical or other physiological basis for this function, in young as well as older populations.

NICKEL. BACKGROUND INFORMATION

FINDINGS BY LIFE STAGE AND GENDER GROUP

Nickel may serve as a cofactor or structural component of certain metalloenzymes and facilitate iron absorption or metabolism in microorganisms. No studies to determine the biological role of nickel in higher animals or humans have been reported. Therefore, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake was established for nickel.

INTAKE OF NICKEL

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving nickel under medical supervision.

Dose-Response Assessment

Adults

Data Selection. A subchronic rat gavage study (ABC, 1988) and a chronic rat dietary study (Ambrose et al., 1976) were considered most suitable for establishing an UL for human dietary exposure to soluble nickel salts.

Identification of a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest-Observed-Adverse-Effect Level (LOAEL). A NOAEL of 5 mg/kg/day was identified for both the 90-day subchronic gavage study (ABC, 1988) and the 2-year chronic dietary study (Ambrose et al., 1976) in rats.

In both cases, the NOAEL was established on the basis of decreased body weight gains and signs of systemic toxicity at higher dose levels. In the ABC (1988) study, groups of male and female CD rats were administered nickel chloride by water gavage at doses of 0, 5, 35, and 100 mg/kg/day for 3 months. On the basis of findings of decreased body weights, mortality, and clinical signs at higher doses, 5 mg/kg/day was concluded to be the NOAEL.

In the chronic study rats were administered nickel sulfate in the diet at doses of 0, 100, 1,000, or 2,500 ppm nickel (about 0, 5, 50, and 125 mg/kg/day) for a period of 2 years (Ambrose et al., 1976). Effects of treatment included reduced body weight gain in high-dose animals (125 mg/kg/day). Sporadic significant decreases in body weight gains were also recorded in the mid-dose group (50 mg/kg/day). Rats fed high- and mid-dose levels of nickel were reported to have significantly higher relative heart weights and lower relative liver weights. Although the study was suitable in design and conduct for use in establishing a UL for human dietary exposure to soluble nickel salts, poor survivorship in controls does raise some concern about its interpretability.

The results of three reproductive studies, one three-generation study (Schroeder and Mitchener, 1971) and two two-generation studies (RTI, 1988; Smith et al., 1993), suggest potential for fetotoxicity after oral exposure to soluble nickel salts. The lowest LOAEL identified by Smith and coworkers (1993) was 1.3 mg/kg/day of nickel based on the total number of dead pups and the percentage of dead pups per litter. The Schroeder and Mitchener (1971) study concluded that exposure to nickel at a concentration of 5 mg/L, or about 0.4 mg/kg body weight/day (assuming 8 ml/100 g body weight), was associated with increased neonatal death; however, these conclusions were based on the results of only five nonrandomized matings and therefore were not considered valid for use in determining a LOAEL for human dietary exposure to soluble nickel salts. In fact, all of the reproduction studies either were flawed or their interpretation was hampered by their statistical design and methodological and data-reporting limitations, as well as by inconsistencies in the reported dose-response relationships. As a result, these studies were not suitable for use in the establishment of a UL.

In summary, taken together, the oral subchronic and chronic rat studies support a NOAEL of 5 mg/kg body weight/day for soluble nickel salts. The selection of this NOAEL is in agreement with the NOAEL selected in the toxicological assessment of oral nickel exposure performed by the U.S. Environmental Protection Agency (EPA, 2000).

Uncertainty Assessment. When determining an uncertainty factor (UF) for nickel, several sources of uncertainty were selected to extrapolate from the NOAEL from the long-term rat study to the general population. The first UF of 10, which was used to extrapolate from the rat study to humans, incorporated uncertainties about the nature of the dose-response curve for nickel toxicity and uncertainties about the sensitivity of rats as compared with humans in respect to nickel toxicity. The second UF of 10 was to account for potential variation within the human population, especially in regard to the potential for nickel to induce hypersensitivity reactions in sensitive individuals. The third UF of 3 was introduced because of concerns raised by studies on reproductive effects, namely, that nickel may be a reproductive toxin at levels lower than the NOAEL observed for the chronic rat study. These three UFs were multiplied to yield the ultimate UF of 300 that would accommodate the general population including women who are pregnant or lactating.

Derivation of a UL. The NOAEL of 5 mg/kg body weight/day was divided by the UF of 300 to obtain a UL of 0.017 mg/kg body weight/day for adult humans. This figure was multiplied by the average of the reference body weights for adult women, 61 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is rounded down to 1.0 mg/day.

Nickel UL Summary, Ages 19 years and Older

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UL for Adults
≥ 19 years	1.0 mg/day of soluble nickel salts

Other Life Stage Groups

Infants. For infants, the UL was judged not determinable because of the lack of data on adverse effects in this age group and concern about the infant's ability to handle excess amounts. To prevent high levels of intake, the only source of intake for infants should be from food and formula.

Children and Adolescents. There are no reports of nickel toxicity in children and adolescents. The UL values for children and adolescents were extrapolated from those established for adults. Thus, the adult UL of 1.0 mg/day of soluble nickel salts was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1).

Pregnancy and Lactation. No data were found that could be used to identify a NOAEL or LOAEL and derive a UL for pregnant and lactating women. Therefore, the ULs for pregnant and lactating women are the same as for the nonpregnant and nonlactating women.

Nickel UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation

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UL for Infants
0–12 months	Not possible to establish; source of intake should be from food and formula only
UL for Children
1–3 years	0.2 mg/day of soluble nickel salts
4–8 years	0.3 mg/day of soluble nickel salts
9–13 years	0.6 mg/day of soluble nickel salts
UL for Adolescents
14–18 years	1.0 mg/day of soluble nickel salts
UL for Pregnancy
14–18 years	1.0 mg/day of soluble nickel salts
19–50 years	1.0 mg/day of soluble nickel salts
UL for Lactation
14–18 years	1.0 mg/day of soluble nickel salts
19–50 years	1.0 mg/day of soluble nickel salts

Special Considerations

Individuals with preexisting nickel hypersensitivity (from previous dermal exposure) and kidney dysfunction are distinctly susceptible to the adverse effects of excess nickel intake (Gawkrodger et al., 1986). These individuals may not be protected by the UL for nickel intake for the general population.

RESEARCH RECOMMENDATIONS FOR NICKEL

• Identification and clear characterization of a biochemical function for nickel in humans; identification of a reliable indicator of nickel status for use in future studies of nickel deficiency.
• Further exploration of the possible role of nickel in vitamin B₁₂ and folate metabolism, including whether nickel nutrition should be a concern for pregnant women or people at risk for cardiovascular disease.

SILICON. BACKGROUND INFORMATION

FINDINGS BY LIFE STAGE AND GENDER GROUP

Silicon appears to be involved in the formation of collagen and bone in animals. A biological role of silicon in humans has not yet been identified. Therefore, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake was established for silicon.

INTAKE OF SILICON

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects.

RESEARCH RECOMMENDATIONS FOR SILICON

• The physiological role of silicon and how this role relates to human health.
• The possible role of silicon in atherosclerosis and hypertension, several bone disorders, Alzheimer's disease, and other conditions common to the elderly because of the prevalence and cost of these disorders.
• The determination of a reliable indicator of silicon status.

VANADIUM. BACKGROUND INFORMATION

FINDINGS BY LIFE STAGE AND GENDER GROUP

In laboratory animals, vanadium mimics insulin (diminishes hyperglycemia and improves insulin secretion) and inhibits the activity of various enzymes. A deficiency of vanadium results in increased abortion rates. A biological role of vanadium in humans has not yet been identified. Therefore, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake was determined for vanadium.

INTAKE OF VANADIUM

TOLERABLE UPPER INTAKE LEVELS

The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well-controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxicity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to individuals who are receiving vanadium under medical supervision.

Hazard Identification

There is no evidence of adverse effects associated with vanadium intake from food, which is the major source of exposure to vanadium for the general population (Barceloux, 1999). There are data on adverse effects associated with vanadium intake from supplements and drinking water. Because the forms found in food and supplements are the same (i.e., tetravalent or vanadyl [VO₂+] and pentavalent or vanadate [VO₃–] forms), the UL value will apply to total vanadium intake from food, water, and supplements.

Most vanadium toxicity reports involve industrial exposure to high levels of airborne vanadium. The most toxic vanadium compound is vanadium pentoxide, but because vanadium pentoxide is not a normal constituent of food, supplements, or drinking water, it will not be considered in this review.

Weight training athletes use up to 60 mg/day of vanadyl sulfate supplements (or 18.6 mg of elemental vanadium) to improve performance (Barceloux, 1999). Furthermore, because vanadium may become useful in future treatment of diabetes, there is increased concern about its long-term toxicity.

Adverse Effects

Acute Toxicity. Acute vanadium poisoning has not been observed in humans. Acute poisoning from sodium vanadate in rats causes desquamative enteritis, mild liver congestion with fatty changes, and slight parenchymal degeneration of the renal convoluted tubules (Daniel and Lillie, 1938). In mice, a subcutaneous dose of 20 mg/ kg of ammonium metavanadate produced acute tubular necrosis by 6 to 7 hours postinjection (Wei et al., 1982).

Renal Toxicity. Evidence of renal toxicity associated with high vanadium intake in humans was not found. There is evidence of kidney effects in animals (Table 13-2). Domingo and coworkers (1985) found histopathological lesions of the kidney and increased plasma urea and uric acid concentrations in rats exposed to 50 μg/ mL in drinking water for 3 months. This finding suggests possible alterations in renal function. In a second study, Domingo and coworkers (1991) evaluated the toxicity of sodium metavanadate (0.15 mg/mL), sodium orthovanadate (0.23 mg/mL), and vanadyl sulfate pentahydrate (0.31 mg/mL) solutions given to diabetic rats for 28 days. In the vanadium-treated animals, they observed decreased weight gain and increased serum concentrations of urea and creatinine, as well as some deaths. A histopathological investigation was not performed.

TABLE 13-2

Animal Data on Vanadium-Induced Renal Toxicity, by Increasing Dose.

Boscolo and coworkers (1994) reported that the lumen of the proximal tubules was narrowed and contained amorphous material in rats fed 40 μg/mL of sodium metavanadate in drinking water for 6 or 7 months. Hydropic degeneration was also seen in some proximal and distal tubules and the loop of Henle. Because water intakes were not provided, this study could not be used to derive a dose. Acute tubular necrosis was observed in mice fed 20 mg/kg/day of ammonium metavanadate (Wei et al., 1982). The effect of supplemental vanadium intake on renal function needs further careful study.

Gastrointestinal Effects. There is human evidence of mild gastrointestinal effects (abdominal cramps, loose stool) primarily in patients with diabetes and animal evidence of more severe gastrointestinal effects (diarrhea, death) after ingestion of vanadium compounds (Boden et al., 1996; Dimond et al., 1963; Franke and Moxon, 1937; Goldfine et al., 1995). The human data are summarized in Table 13-3.

Hematological Effects. Vanadium compounds may cause anemia and changes in the leukocyte system. Animal studies of hemolytic activity of vanadium salts have conflicting results (Dai and McNeill, 1994; Dai et al., 1995; Hogan, 1990; Zaporowska and Wasilewski, 1992; Zaporowska et al., 1993). Fawcett and coworkers (1997) showed no effects of oral vanadyl sulfate (0.5 mg/kg body weight/day) on hematological indexes, blood viscosity, and biochemistry in a 12-week, double-blind, placebo-controlled trial in 31 athletes.

Cardiovascular Effects. Exposure to vanadate induced an increase in blood pressure and heart rate in rats (Carmignani et al., 1991; Steffen et al., 1981). Boscolo and coworkers (1994) showed an increase in arterial blood pressure following chronic exposure of rats to 1, 10, and 40 μg/mL of vanadium for 6 or 7 months. These changes were not dose-dependent.

Reproductive Effects. No evidence of reproductive abnormalities after ingestion in humans was found. Two animal studies evaluating the reproductive toxicity of vanadium have been reported: in one, Llobet and coworkers (1993) observed that at 60 and 80 mg/kg body weight/day, a significant decrease in pregnancy rate occurred; in the other, Domingo and coworkers (1986) found no effects on fertility or reproduction in rats gavaged up to 20 mg/kg body weight/day with sodium metavanadate.

TABLE 13-3

Human Data on Vanadium-Induced Gastrointestinal Effect, by Increasing Dose.

Other Adverse Effects. Other adverse effects associated with vanadium intake in humans include green tongue, fatigue, lethargy, and focal neurological lesions (Barceloux, 1999). These effects, however, have not been consistently observed or dose-related. No studies were found evaluating the genotoxicity in humans or animals after ingestion of vanadium, and no evidence was found showing carcinogenicity of vanadium compounds in animals or humans. The U.S. Environmental Protection Agency recently set an oral reference dose of 0.009 mg/kg/day for vanadium pentoxide based on decreased hair cystine content. This finding is from a chronic oral rat study described by Stokinger (1981). Because it is not clear that reduced hair cystine is an adverse effect, data on reduced hair cystine were judged not relevant to the derivation of a UL for elemental vanadium.

Summary

On the basis of the quality and completeness of the database and the strength of the causal association, renal toxicity was selected as the critical adverse effect on which to base a UL. The data on other effects such as hematological, cardiovascular, or reproductive effects are not consistent. While gastrointestinal effects appear to occur at lower doses in humans, the specificity of the observed effects and the dose-response relationship are not as clearly defined as the histopathological lesions and adverse kidney effects demonstrated in animals. While kidney effects have not been demonstrated in humans, excess vanadium has been shown in rats to accumulate in kidneys (Oster et al., 1993), and the evidence in different species (i.e., mice and rats) further supports a possible risk in humans. Because of the widespread use of high-dose (60 mg/day) supplemental vanadium by athletes and other subgroups (e.g., borderline diabetics) that are considered part of the apparently healthy general population (Barceloux, 1999), further research on vanadium toxicity is needed.

Dose-Response Assessment

Adults

Data Selection. The data in laboratory rats involving subchronic to chronic durations of intake were used to derive a UL. Studies that provided doses in units of concentration but provided no information on the body weights of the rats or the amount of water consumed were not used.

Identification of a No-Observed-Adverse-Effects Level (NOAEL) or Lowest-Observed-Adverse-Effects Level (LOAEL). A NOAEL of 0.8 mg/kg body weight/day and a LOAEL of 7.7 mg/kg body weight/day were determined on the basis of the results of Domingo and coworkers (1985). Vanadium could not be detected in the kidneys of animals receiving 5 μg/mL (or 0.8 mg/kg/day) (Table 13-2). Also, plasma urea, uric acid, and creatinine concentrations were within the normal range in this treatment group (Domingo et al., 1985). However, the study does not indicate whether there were kidney lesions at this level; therefore, whether this is a true NOAEL value for this study is uncertain. The same can be said for the treatment group given 10 μg/mL (or 1.5 mg/kg/day). The study does not provide enough detail about the findings at this dose level to ascertain whether it is a NOAEL or LOAEL.

The value of 7.7 mg/kg/day is the best estimate of a LOAEL from this data set. At this dose, there were evident lesions of the kidney and small, but significant, increases in plasma urea and uric acid. Furthermore, this LOAEL appears to be consistent with other studies (Boscolo et al., 1994; Domingo et al., 1991). Boscolo and coworkers (1994) failed to provide information on intakes (mg/kg/ day), and therefore the study was judged not useful for deriving a UL. Nevertheless, both Domingo and coworkers (1991) and Boscolo and coworkers (1994) showed a similar dose-response relationship. The study by Domingo and coworkers (1991) in diabetic rats provides results that are fairly consistent with their earlier study (Domingo et al., 1985). Although Domingo and coworkers (1991) tested different compounds of vanadium and used a shorter duration, they observed increased serum urea and creatinine concentrations at similar doses (6.1 and 22.7 mg/kg/day).

Uncertainty Assessment. In determining an uncertainty factor (UF) for vanadium, several sources of uncertainty were considered and combined into the final UF. The severity of kidney lesions justifies a UF higher than 1, and so a UF of 3 was selected to extrapolate from the LOAEL to the NOAEL. A UF of 10 was selected to extrapolate from laboratory animals to humans because no human and little animal data were available to use in the dose-response assessment. Another UF of 10 was selected for intraspecies variability. The three UFs are multiplied to yield an overall UF of 300 to extrapolate from the LOAEL in animals to derive a UL in humans.

Derivation of a UL. The LOAEL of 7.7 mg/kg/day was divided by a UF of 300 to obtain a UL of 0.026 mg/kg/day or 26 μg/kg/day for adult humans. This value was rounded and multiplied by the average of the reference body weights for adult men and women, 68.5 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is 1.78 mg/day (which was rounded to 1.8 mg/day).

Vanadium UL Summary, Ages 19 Years and Older

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UL for Adults
≥ 19 years	1.8 mg/day of elemental vanadium

Other Life Stage Groups

Given the severity of the critical effect for vanadium in adults, the lack of data on vanadium toxicity in other more sensitive life stage groups is of particular concern. Due to this lack of data, it was not possible to determine ULs for pregnant and lactating women, children, and infants. These individuals should be particularly cautious about consuming vanadium supplements. As indicated above, more research is needed on the renal effects of vanadium intake, particularly in these sensitive subgroups.

Vanadium UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation

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UL for Infants
0–12 months	Not possible to establish; source of intake should be from food and formula only
UL for Children
1–3 years	Not possible to establish; source of intake should be from food only
4–8 years	Not possible to establish; source of intake should be from food only
9–13 years	Not possible to establish; source of intake should be from food only
UL for Adolescents
14–18 years	Not possible to establish; source of intake should be from food only
UL for Pregnancy
14–18 years	Not possible to establish; source of intake should be from food only
19–50 years	Not possible to establish; source of intake should be from food only
UL for Lactation
14–18 years	Not possible to establish; source of intake should be from food only
19–50 years	Not possible to establish; source of intake should be from food only

Special Considerations

A review of the literature revealed no special subpopulations that are distinctly susceptible to the adverse effects of high vanadium intake.

RESEARCH RECOMMENDATIONS FOR VANADIUM

• Determination of the biochemical role of vanadium in both higher animals and humans and a reliable status indicator of vanadium for further work in humans.
• The efficacy and safety of the use of vanadium as a nutritional supplement.

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