Notes on the Basis for the Proposed Revision of the Vanadium Rfd mark Smith, ors, April 2013 Vanadium Pentoxide

Notes on the Basis for the Proposed Revision of the Vanadium RfD

Mark Smith, ORS, April 2013
Vanadium Pentoxide.

IRIS RfD Value.

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  Last significant update: 06/30/1988 (last revised 12/01/1996 w. new contact info)
  
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  POD: Rat study (unpublished).
  
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  Value is for vanadium pentoxide.
  
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  9 X 10^-3 mg/kg/day
  
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    UF = 100
    
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    Confidence = low
    

Vanadium and Its Soluble Inorganic Compounds Other Than Vanadium Pentoxide.
PPRTV Value.
Derived because IRIS contains no files for elemental vanadium or other vanadium compounds.

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  Completed 9/30/2009. Considered many studies post 1988.
  
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  Applies to soluble inorganic vanadyl (+4) and vanadate (+5) compounds other than vanadium pentoxide for which the RfD (above) applies. Data are not available to assess the toxicity of insoluble compounds or compounds in which vanadium exists in higher or lower valence states.
  
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  POD: Rat study; kidney pathology.
  
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  Exposures converted to equivalent vanadium doses for the purpose of dose-response assessment.
  
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  7 × 10^-5 mg/kg-day
  
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    UF = 3000
    
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    Confidence = low
    

Key Supporting Information Excerpted From the EPA PPRTV Documentation
The Drinking Water Standards and Health Advisories list (U.S. EPA, 2006) does not include a RfD for any vanadium compound. The Health Effects Assessment Summary Table (HEAST; U.S. EPA, 1997) lists subchronic and chronic oral RfDs of 7 × 10^-3 mg/kg-day for vanadium and 2 × 10² mg/kg-day for vanadium sulfate. RfDs for both vanadium and vanadium sulfate were based on a chronic study in which rats were exposed to 5 mg/L vanadium as vanadyl sulfate for their lifetimes (Schroeder et al., 1970), as derived in U.S. EPA (1987). A total UF of 100 was used to derive the RfDs. The Agency for Toxic Substance and Disease Registry (ATSDR, 1992) derived an intermediate-duration oral minimal risk level (MRL) for vanadium of 3 × 10^-3 mg/kg-day based on a NOAEL of 0.3 mg/kg-day in a 3-month drinking water study in rats by Domingo et al. (1985); renal and respiratory effects (renal hemorrhagic foci and pulmonary vascular infiltration) were seen at higher doses (0.6 mg/kg-day). A total UF of 100, reflecting UFs of 10 each for interspecies extrapolation and intraspecies variability, was applied to the NOAEL. ATSDR (1992) did not derive a chronic oral MRL.

Although vanadium has six oxidation states (-1, 0, +2, +3, +4, and +5), the most stable oxidation state is +4 (Rydzynski, 2001). In the environment, vanadium is bound to a variety of elements including oxygen, sodium, sulfur, and chloride; in commerce, vanadium is often used in an iron alloy (ferrovanadium) (Rydzynski, 2001). The literature searches identified toxicity data for the following inorganic compounds: vanadyl sulfate (+4), sodium metavanadate (+5), sodium orthovanadate (+5), and ammonium metavanadate (+5). These compounds all exhibit some solubility in water (Rydzynski, 2001; ATSDR, 1992) and, thus, can be considered representative of soluble tetravalent and pentavalent vanadium compounds.

While the individual studies are limited, the human studies collectively provide a short-term human LOAEL of approximately 0.3 mg V/kg-day in humans based on symptoms of gastrointestinal distress, including diarrhea, cramping, and discomfort. The NOAEL for these effects is approximately 0.1 mg V/kg-day based on the available studies.
Chronic RfD Derivation
The lowest LOAEL of the remaining relevant endpoints is 1.2 mg V/kg-day for kidney pathology in male rats after a 6-month exposure to sodium metavanadate in drinking water (Boscolo et al., 1994), the basis for the subchronic p-RfD. As the human studies would not have revealed subclinical tissue damage and were of short duration, chronic kidney damage would be of concern. Therefore, kidney toxicity is selected as the critical effect, with a LOAEL of 1.2 mg V/kg-day and NOAEL of 0.12 mg V/kg-day established in the Boscolo et al. (1994) rat study. The NOAEL is adjusted to 0.22 mg/kg-day to account for dietary exposure. The chronic p-RfD is derived as follows:
Chronic p-RfD = NOAEL ÷ UF

= 0.22 mg V/kg-day ÷ 3000

= 0.00007 mg V/kg-day or 7 × 10^-5 mg/kg-day
The composite UF of 3000 is composed of the following:

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  A full UF of 10 is used to account for interspecies extrapolation to account for potential pharmacokinetic and pharmacodynamic differences between rats and humans.
  
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  A full UF of 10 is used to account for potentially susceptible individuals in the population in the absence of information on the variability of human response to vanadium.
  
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  A partial UF of 3 (100.5) is used to account for database deficiencies as per the subchronic p-RfD.
  
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  A full UF of 10 is used to account for extrapolation to chronic exposure duration from a subchronic study.
  

Confidence in the key study (Boscolo et al., 1994) is low. The study focused on the blood pressure and kidney effects of vanadium; it did not address a comprehensive suite of

endpoints. In addition, the issue of α2u-globulin accumulation was not addressed.