Abstract

Oral human exposure to vanadium may occur due to its presence in food and drinking water and its use in dietary supplements. The most prevalent oxidation states of vanadium in food and drinking water have been characterized as tetravalent and pentavalent. Vanadyl sulfate and sodium metavanadate were selected as representative tetravalent (V⁴⁺) and pentavalent (V⁵⁺) test articles for these studies, respectively. To assess the potential for oral toxicity of vanadium compounds with differing oxidation states under similar test conditions, the 3-month National Toxicology Program (NTP) toxicity studies of sodium metavanadate and vanadyl sulfate in male and female Sprague Dawley (Hsd:Sprague Dawley^® SD^®) rats (including perinatal exposure) and in B6C3F1/N mice. Drinking water concentrations for sodium metavanadate (0, 31.3, 62.5, 125, 250, and 500 mg/L) and vanadyl sulfate (0, 21.0, 41.9, 83.8, 168, and 335 mg/L) were selected on the basis of previously published 14-day drinking water studies conducted as part of the NTP vanadium research program.

During the perinatal phase of the rat sodium metavanadate study, dams and pups exposed to the highest concentrations had lower survival. Moribund dams were removed beginning on gestation day 22, and select dams and pups continued to be removed due to moribundity or mortality throughout the lactation period. These removals collectively resulted in four litters in the 500 mg/L sodium metavanadate group available to populate the postweaning study. There were no effects on survival of vanadyl sulfate-exposed dams or pups.

In the perinatal and 3-month rat studies, 10 F₁ pups/sex/group were selected for continuation during the postweaning phase; all available pups (n = 12 or 13) were retained in the 500 mg/L group for the sodium metavanadate study. In the 3-month mouse studies, 10 animals per sex were assigned to each exposure group. Lower water consumption was observed in both rats and mice at the highest exposure concentrations for both test articles. Lower body weights were observed at the end of the 3-month studies in rats and mice exposed to sodium metavanadate and in mice exposed to vanadyl sulfate. Absolute thymus weights were decreased in male and female mice exposed to sodium metavanadate. Several other organ weight changes occurred in these studies and were considered secondary to body weight changes.

For rats and mice exposed to sodium metavanadate and mice exposed to vanadyl sulfate, hematological effects related to erythrocyte microcytosis, including decreased mean cell volume, were consistently observed. This response was more severe in mice, with corresponding reductions in hematocrit and hemoglobin as well as an erythrocytosis response, including increased erythrocytes and reticulocytes. In sodium metavanadate-exposed rats, decreased globulin and cholesterol were observed. Epithelial hyperplasia of the ileum was observed in rats and mice exposed to sodium metavanadate and vanadyl sulfate. This lesion was not observed in any control animals. Other sites of the small or large intestine, including the jejunum, were observed to have epithelial hyperplasia, but these observations were not consistent across test articles or sex/species.

Vanadium intake was calculated using the amount of vanadium in each test article (41.7% in sodium metavanadate and 31% in vanadyl sulfate), the exposure concentration, and the measured water consumption. In rats, the overall lowest-observed-effect levels (LOELs) for both sodium metavanadate and vanadyl sulfate align well with vanadium intake, indicating that total vanadium, rather than vanadium oxidation state, may be a driver for toxicity. In mice, however, the overall LOELs for both compounds and the LOELs for specific endpoints do not occur at the same calculated vanadium doses between test articles.

Sodium metavanadate and vanadyl sulfate were not mutagenic in several bacterial tester strains, with or without exogenous metabolic activation (S9 mix), and no biologically significant increases in micronucleated reticulocytes were seen in male and female rats and mice. An increase in the percentage of circulating immature erythrocytes (reticulocytes) was seen in male rats and in male and female mice when exposed to sodium metavanadate, whereas there were no changes in this population of cells in female rats. When exposed to vanadyl sulfate, increases in the percentage of reticulocytes were seen in male and female mice; however, no notable changes in this population of cells were observed in male and female rats.

Under the conditions of these studies, oral exposure to sodium metavanadate or vanadyl sulfate in drinking water resulted in hematological effects associated with erythrocyte microcytosis in rats (sodium metavanadate) and mice (sodium metavanadate and vanadyl sulfate), including erythrocytosis in male rats and in male and female mice. Epithelial hyperplasia of the ileum and other gastrointestinal sites was observed histologically, which was consistent for both test articles and across both sexes and species evaluated. In the sodium metavanadate studies, the LOELs were 125 mg/L in male and female rats, 31.3 mg/L in male mice, and 62.5 mg/L in female mice, based on changes in hematology (male rats and male and female mice) and epithelium hyperplasia in the ileum and jejunum (male and female rats). In the vanadyl sulfate studies, the LOELs were 168 mg/L in male and female rats and 83.8 mg/L in male and female mice, as indicated by epithelium hyperplasia in the ileum (male and female rats and mice) and hematology (female mice).

Synonyms for sodium metavanadate: sodium (meta)vanadate; sodium vanadate(V); vanadic acid, monosodium salt; sodium trioxovanadate; sodium vanadium oxide; monosodium trioxovanadate(1-); sodium vanadate; sodium trioxidovanadate(1-); sodium vanadium trioxide; vanadic acid (HVO₃), sodium salt (8Cl)

Synonyms for vanadyl sulfate: vanadium, oxo(sulfato(2-)-O)-; vanadium oxide sulphate; vanadic sulfate; oxovanadium(2+) sulfate; oxovanadium(IV) sulfate; vanadium(IV) oxysulfate; (oxido)vanadium(2+) sulfate; oxosulfatovanadium(IV); oxovanadium(IV) sulfate; vanadium oxide sulfate; vanadium oxosulfate; vanadium oxysulfate; vanadium sulfate; vanadyl monosulfate; vanadin(IV) oxide sulfate

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Contents

• Foreword
• Collaborators
• Contributors
• Peer Review
• Publication Details
• Acknowledgments
• Abstract
• Overview
• Introduction
  • Chemical and Physical Properties
  • Production, Use, and Human Exposure
  • Toxicity Assessments and Regulatory Status
  • Absorption, Distribution, Metabolism, and Excretion
  • Study Rationale
• Materials and Methods
  • Procurement and Characterization of Sodium Metavanadate and Vanadyl Sulfate
  • Preparation and Analysis of Dose Formulations
  • Animal Source
  • Animal Welfare
  • Exposure Selection Rationale
  • Three-month Studies
  • Statistical Methods
  • Quality Assurance Methods
  • Genetic Toxicology
• Results
  • Data Availability
  • Sodium Metavanadate
  • Vanadyl Sulfate
  • Genetic Toxicology
• Discussion
• References
• Appendix A. Chemical Characterization and Dose Formulation Studies
• Appendix B. Ingredients, Nutrient Composition, and Contaminant Levels in NIH-07 and NTP-2000 Rat and Mouse Ration
• Appendix C. Sentinel Animal Program
• Appendix D. Genetic Toxicology
• Appendix E. Supplemental Data