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EPA’s Response to Selected Interagency Comments on the Interagency Science 

Consultation Draft IRIS Toxicological Review of Vanadium Pentoxide

September 30, 2011

Purpose: 

The Integrated Risk Information System (IRIS) assessment development process of May 2009, 

includes two steps (Step 3 and 6) where White House offices and other federal agencies can 

comment on draft assessments. The following are EPA’s responses to selected major 

interagency review comments received during the Interagency Science Consultation step (Step 3) 

for the draft IRIS Toxicological Review of Vanadium Pentoxide (dated July 2011). All 

interagency comments provided were taken into consideration in revising the draft assessment 

prior to posting for public comment and external peer review. The complete set of interagency 

comments is attached as an appendix to this document.

For a complete description of the IRIS process, including Interagency Science Consultation, visit 

the IRIS website at www.epa.gov/iris. 

July 2011 Interagency Science Consultation Draft IRIS Assessment—Selected Comments 

and Responses: 

Topic #1: Clarification regarding the equation used to determine human equivalent oral 

doses from data in laboratory animal species for derivation of the RfD -NTP requested 

clarification on the use of the following equation to determine the dosimetric adjustment factor 

(DAF): DAF = (BWa

1/4 /BWh1/4) when the discussion focused on the use of body weight 3⁄4

scaling, not body weight1⁄4 scaling. 

EPA Response: In EPA’s Recommended Use of Body Weight3/4 as the Default Method 

in Derivation of the Oral Reference Dose (U.S. EPA, 2011), the Agency endorses body 

weight scaling to the 3⁄4 power (i.e., BW3/4) as a default to extrapolate toxicologically 

equivalent doses of orally administered agents from all laboratory animals to humans for 

the purpose of deriving an RfD under certain exposure conditions. A body of literature 

exists that generally supports an allometric relationship between BW3/4 and various 

physiological and biochemical processes, mostly related to kinetics, for a number of 

compounds across a reasonable number and range of species. Therefore, it is assumed 

that in general, an equal biological effect is obtained in an animal and a human when the 
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dose of a chemical (in mg) is expressed relative to body weight to the 3⁄4 power (i.e., 

BW3/4); represented by the following equation:

[mgH / BWH

3/4 ] = [mgA / BWA3/4 ]

where the subscripts “H” and “A” refer to human and animal, respectively. BW3/4 also 

can be represented as [BW1/1 / BW1/4], and this representation can then be substituted into 

the above equation:

[mgH / (BWH

1/1 / BWH1/4 )] = [mgA / (BWA1/1 / BWA1/4 )]

Solving this equation for [mgH / BWH], the human dose, yields the following:

[mgH / BWH] = [mgA / BWA] x [BWA / BWH]

1/4

Thus, to convert an animal dose (in mg/kg) to a toxicologically equivalent human dose 

(in mg/kg) using BW3/4 scaling, you multiply the animal dose by [BWA / BWH]

1/4, also 

known as the dosimetric adjustment factor or DAF, and this is what is represented in the 

DAF equation in the text of the Toxicological Review (Section 5.1.2).

Topic #2: Clarification of the discussion of the NTP (2002) study-NTP included several 

comments requesting clarification in the discussion of the 16 day, 13 week, and 2 year exposure 

studies reported in NTP (2002). For example, NTP requested that EPA note in the text that the 

historical databases referenced for comparison were different for males and females (e.g., 

databases for female rats fed NIH-07 diets versus male rats fed NTP-2000 diets). NTP suggested 

that the presentation of the respiratory tumor data following exposure to vanadium pentoxide for 

2 years shown in the tables should also be included in the text. NTP also requested clarification 

related to the reporting of the data from the 16 day study (i.e., presentation of results following

13 and 16 day exposures).

EPA Response: EPA has revised the text in the Toxicological Review to clarify which 

databases of historical controls were utilized for comparison with the NTP (2002) data. 

Additionally, EPA has included the tumor incidence data for both male and female rats 

exposed to vanadium pentoxide for 2 years in the text as requested by NTP. With regard to 

the 16 day study, NTP (2002) conducted three separate experiments utilizing a 16 day 

exposure to vanadium pentoxide, including the following: (1) an experiment in which male 
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rats and female mice were assessed for pulmonary inflammation and systemic 

immunotoxicity following exposure to 0, 4, 8, and 16 mg/m3 vanadium pentoxide for 

16 days; (2) an experiment in which five male and five female mice were exposed by 

inhalation to vanadium pentoxide for 6 hours per day, 5 days a week for 16 days at 

concentrations of 0, 2, 4, 8, 16, or 32 mg/m3; and (3) an experiment where an additional 

group of female mice were exposed to 0, 2, 4, or 8 mg/m3 for 6 hours per day, 5 days per 

week for 16 days and evaluated for nonneoplastic lung lesions on days 6 and 13. EPA 

augmented the Toxicological Review to clarify the presentation of the results of the 16 day 

studies. 
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Appendix

Comments on the Interagency Science Consultation Draft 

IRIS Toxicological Review of Vanadium Pentoxide
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National Institute of Environmental Health Sciences/National Toxicology Program

Comments on the Interagency Science Consultation Draft IRIS Toxicological 

Review of Vanadium Pentoxide (dated July 2011)

NIEHS/NTP

VANADIUM PENTOXIDE IRIS COMMENTS

August 1, 2011

Page 6 – When discussing NTP exposures prior to blood collection for vanadium 

analysis, consider changing to ...16 days or 2 years, as blood collection was part of a 16 

day study (will provide consistency with toxicity results)

Page 46 – When describing increases in neoplasms for rats exposed to vanadium 

pentoxide, please note that the historical control databases referenced were different for 

males and females. For females, a larger database in rats fed NIH-07 diet (which was 

used prior to NTP-2000 diet) was used as the historical control database. In addition, 

there was one lung tumor in each of the 1 and 2 mg/m3 groups, compared to 3 at 0.5 

mg/m3 and none in controls.

Page 47 – particle size is listed for mouse chronic (and prechronic) studies but not 

chronic/prechronic rat studies. The particle size is the same for both studies and should be 

listed as such.

Page 59 – when referring to “short term” inhalation studies in animals, please consider 

including the duration. In addition, it appears that increases in relative lung weight were 

observed in the short term NTP inhalation study.

Page 59 – It is unclear why 13-day and 16-day exposures are described. For example, the 

text indicates that non-neoplastic lesions were observed in the 13-day and 16-day (are 

these referring to the 16-day and 16-day special study animals?) studies. However, 

histopathology was not performed on the special study animals, so it is unclear which 

data are being described. In the last sentence of the last full paragraph, a 3 month study is 

mentioned and in the next sentence a 13-day study is mentioned. Are these referring to 
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the same study (13-weeks/3-monts vs. 13-days)? Interestingly, on the next page, the 16-

day special studies are described. Please clarify.

Page 84- in the second paragraph, it is indicated that exposure caused tumors... in mice, 

while “some evidence” was used to describe the level of evidence in male mice and 

female mice were not mentioned. Please consider standardizing the descriptions to either 

use or omit the NTP levels of evidence and a description of what the levels of evidence 

were based on (ex. Clear/statistically significant increases; some/increased over historical 

controls; equivocal/increased only at low dose and over a larger historical control 

database with a different diet...). 

Page 89 – it is unclear what study is being referred relative to neurotoxic effects (the NTP 

studies were described in the previous sentence).

Page 90 – similar to page 59, it is unclear why decreased lung weights are mentioned. 

Increased lung weights were observed.

Page 102 – The sentence in the middle of the second full paragraph (“...both sexes at all 

doses, with 50% of the male mice...”) is unclear. Was the intent to indicate that the 

deaths in males were due to increased tumors?

Page 103 – The sentence “Thus, the increased tumor incidence in rats equivocal 

overall,...” is incorrect. The male and female rat studies were two separate studies. In 

males, there was some evidence of carcinogenic activity while in females there was 

equivocal evidence.

Page 108 – It is unclear why in the DAF equation, body weights are raised to the 1⁄4 and 

not the 3⁄4 power.

Page 133 – 13 day exposure is mentioned again (see previous comments). In addition, the 

rat strain is the F344/N.

 
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Agency for Toxic Substances and Disease Registry (ATSDR) Comments on the 

Interagency Science Consultation Draft IRIS Toxicological Review of Vanadium 

Pentoxide (dated July 2011)

Date: August 2, 2011

From: Agency for Toxic Substances and Disease Registry

Subject: Comments on EPA’s Toxicological Review of Vanadium Pentoxide

To: Environmental Protection Agency

We appreciate the opportunity to review EPA’s Toxicological Review of 

Vanadium Pentoxide. Overall, we found the draft IRIS Toxicological Review and 

fact sheet well-written and concise. Studies of support within the document are 

sufficiently synthesized in a scientific manner to present the overall assessment of 

this substance as it relates to environmental health. The authors did a good job of 

stacking the evidence for the specific exposure and leading the reader to 

appropriate conclusions about vanadium pentoxide. 

One minor editorial comment: On Page 14, last sentence under Oral Exposure: 

there should be a comma after hair“...but not hair, is a sensitive...”