Draft Charge to External Reviewers for th e IRIS Toxicological Review of Vanadium

Pentoxide July 2011

The U.S. Environmental Protection Agency (EPA) is seeking an external peer review of the scientific basis supporting the human health assess ment of vanadium pentoxide that will appear on the Agency’s online database, the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by the EPA’s National Center for Environmenta l Assessment (NCEA) within the Office of Research and Developmen t (ORD). An existi ng IRIS assessment for vanadium pentoxide, which includes an oral refe rence dose (RfD), was posted on IRIS in 1987.

The current draft health assessment includes an RfD, an RfC and carcinogenicity assessment. Below is a set of charge questions that address scientific issues in the assessment of vanadium pentoxide. Please provide detaile d explanations for responses to the charge questions. Please consider the accuracy, objectivity, and transparen cy of EPA’s analyses and conclusions in your

review.

General Charge Questions :

1. Is the Toxicological Review logical, clear and concise? Has EPA clearly presented and synthesized the scientific eviden ce for noncancer and cancer hazard?

2. Please identify any additional studies that would be likely to make a significant impact on the conclusions of the Toxicological Review.

Chemical-Specific Charge Questions:

(A) Oral Reference Dose (RfD ) for Vanadium Pentoxide

1. A chronic RfD for vanadium pentoxide has been derived fro m the subchronic oral dietary study (Mountain et al., 1953) in Wi star rats. Please comment on whether the selection of this study as the principal study is sc ientifically supported and clea rly described. Please identify and provide the rationale for any ot her studies that should be sele cted as the principal study.

2. Decreased red blood cells in male Wistar rats were selected as the critical effect. Please

comment on whether the selection of this critical effect is scientifica lly supported and clearly described. Please identify and pr ovide the rationale for any other endpoints that should be

selected as the critical effect.

3. The NOAEL/LOAEL approach with dosimetri c adjustments for calculating the human equivalent dose was used to derive the POD. Please comment on whether this approach is scientifically supported and clearly described.4. Please comment on the rationale for the selecti on of the uncertainty factors (UFs) applied to

the POD for the derivation of the RfD. If ch anges to a UF are proposed, please identify and provide a rationale(s).

(B) Inhalation Reference Concentration (RfC) for Vanadium Pentoxide

1. A two-year bioassay of va nadium pentoxide in F344 rats (NTP, 2002) was selected as the

basis for the derivation of the RfC. Please comm ent on whether the selection of this study as the principal study is scientifically supported and clearl y described. Please id entify and provide the rationale for any other studies that shoul d be selected as the principal study.

2. Laryngeal lesions in female F344 rats were sel ected as the critical effect for the RfC. Please

comment on whether the selection of this critical effect is scientifica lly supported and clearly described. Please identify and pr ovide the rationale for any other endpoints that should be

selected as the critical effect.

3. Benchmark dose (BMD) modeling was conducted on the incidence of la ryngeal lesions in female F344 rats in conjunction with dosim etric adjustments for calculating the human equivalent concentration to derive the point of departure (POD). Has this approach been appropriately conducted and clearl y described? Is the benchmark response (BMR) selected for use in deriving the POD (i.e. A 10% extra risk of incidence of la ryngeal lesions) scientifically supported and clearl y described?

4. Please comment on the rationale for the selecti on of the uncertainty factors (UFs) applied to

the POD for the derivation of the RfC. Are the UFs scientifically supported and clearly described? If changes to the selected UFs are proposed, please identify and provide a rationale.

(C) Carcinogenicity of Vanadium Pentoxide

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment (www.epa.gov/iris/backgrd.html), vanadium pentoxide is “likely to be carcinogenic to humans” by the inhalation route of exposure. Is the cancer weight of evidence characterization scientifically supported and clearly described?

2. EPA has concluded that the available data do not support any specifi c mode of action for vanadium pentoxide-induced lung tumors in mice. Please comment on whether this determination is scientifically supported and clearly described. Please comment on data available for vanadium pentoxide that may support an alternativ e mode of action.

Oral Slope Factor (OSF)

3. An OSF was not derived due to lack of av ailable studies to char acterize the carcinogenic potential of vanadium pentoxide ad ministered via ingestion. Is the rationale for not deriving an OSF scientifically supported and clearly described? Pl ease identify and provide rationale for any

studies that should be sel ected as the principal study.Inhalation Unit Risk (IUR)

4. A two-year bioassay of va nadium pentoxide in B6C3F1 mi ce (NTP, 2002) was selected for

the derivation of an IUR. Please comment on wh ether the selection of th is study for quantitation is scientifically supported and cl early described. Please identify and provide the rationale for any other studies that should be selected for quantitation.

5. The incidence of respiratory tumors in B6C3F1 male mice was selected to serve as the basis for the quantitative inhalation cancer assessment. Please comment on whethe r this selection is scientifically supported and clea rly described. Please identify a nd provide the rationale for any other endpoints that should be selected to serve as the basis for the IUR.

6. The IUR was calculated by low-dose linear ex trapolation from the POD (i.e., the lower 95%

confidence limit on the concentratio n associated with 71% extra risk of respiratory tumors). Has the modeling been appropriately conducted and clearly described?