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Draft Charge to External Reviewers for the Toxicolo gical Review of Hexavalent Chromium April 2010

The U.S. Environmental Protection Agency (EPA) is s eeking an external peer review of the scientific basis supporting the human health assess ment of hexavalent chromium that will appear on the Agency’s online database, the Integrated Ris k Information System (IRIS). IRIS is prepared and maintained by the EPA’s National Cente r for Environmental Assessment (NCEA) within the Office of Research and Development (ORD) . An existing IRIS assessment for hexavalent chromium, which includes a chronic oral reference dose (RfD), a chronic inhalation reference concentration (RfC), and a carcinogenicit y assessment, was posted on IRIS in 1998.

The current draft health assessment includes a reas sessment of the noncancer and cancer health effects associated with the oral route of exposure (i.e., an RfD and oral slope factor) and a mode of action analysis for cancer across all routes of exposure. Below is a set of charge questions

that address scientific issues in the assessment of hexavalent chromium. Please provide detailed explanations for responses to the charge questions.

General Charge Questions :

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

2. Please identify any additional studies that wou ld make a significant impact on the conclusions of the Toxicological Review.

Chemical-Specific Charge Questions:

(A) Oral Reference Dose (RfD) for Hexavalent Chromi um

1. A two-year drinking water study of sodium dichr omate dihydrate in rats and mice (NTP, 2008) was selected as the basis for the derivation of the RfD. Please comment on whether the selection of this study as the principal study is s cientifically supported and clearly described. Please identify and provide the rationale for any o ther studies that should be selected as the principal study.

2. Diffuse epithelial hyperplasia in the duodenum of female mice was selected as the critical

effect for the RfD. Please comment on whether the selection of this critical effect is scientifically supported and clearly described. Pl ease identify and provide the rationale for any other endpoints that should be selected as the crit ical effect.

3. Benchmark dose (BMD) modeling was applied to th e incidence of diffuse epithelial hyperplasia in the duodenum of female mice to deriv e the point of departure (POD) for the RfD. Has the BMD modeling been appropriately conducted a nd clearly described? Is the benchmark response (BMR) selected for use in deriving the POD (i.e., a 10% increase in the incidence of diffuse epithelial hyperplasia) scientifically supp orted and clearly described?2

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. Are the UFs scientifically supported and clearly described in the document? If changes to the selec ted UFs are proposed, please identify and provide a rationale.

(B) Carcinogenicity of Hexavalent Chromium

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment ( www.epa.gov/iris/backgrd.htm l), hexavalent chromium is likely to be carcinogenic to humans by the oral route of exposure. Is the cancer weigh t of evidence characterization scientifically supported and clearly described?

2. A mutagenic mode of carcinogenic action by all routes of exposure is proposed for hexavalent

chromium. Please comment on whether this determina tion is scientifically supported and clearly

described. Please comment on data available for he xavalent chromium that may support an

alternative mode of action.

3. A two-year drinking water study in rats and mic e (NTP, 2008) was selected for the derivation of an oral slope factor. Please comment on whether the selection of this study for quantification is scientifically supported and clearly described. Please identify and provide the rationale for any other studies that should be considered.

4. The oral slope factor was calculated by linear extrapolation from the POD (i.e., the lower

95% confidence limit on the dose associated with 10 % extra risk of tumors of the small intestine in male mice). Has the modeling been appropriately conducted and clearly described?