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Draft Charge to External Reviewers for the Toxicological Review of Hexavalent Chromium 

April 2010 

The U.S. Environmental Protection Agency (EPA) is seeking an external peer review of the 

scientific basis supporting the human health assessment of hexavalent chromium 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 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 carcinogenicity assessment, was posted on IRIS in 1998. 

The current draft health assessment includes a reassessment 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 and cancer hazard? 

2. Please identify any additional studies that would make a significant impact on the conclusions 

of the Toxicological Review. 

Chemical-Specific Charge Questions: 

(A) Oral Reference Dose (RfD) for Hexavalent Chromium

1. A two-year drinking water study of sodium dichromate 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 scientifically supported and clearly described. 

Please identify and provide the rationale for any other 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. Please identify and provide the rationale for any 

other endpoints that should be selected as the critical effect. 

3. Benchmark dose (BMD) modeling was applied to the incidence of diffuse epithelial 

hyperplasia in the duodenum of female mice to derive the point of departure (POD) for the RfD. 

Has the BMD modeling been appropriately conducted and 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 supported and clearly described? 
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4. Please comment on the rationale for the selection 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 selected 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.html), hexavalent chromium is likely to be carcinogenic to humans 

by the oral route of exposure. Is the cancer weight 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 determination is scientifically supported and clearly 

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

alternative mode of action. 

3. A two-year drinking water study in rats and mice (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?