Draft Charge to External Reviewers for the IRIS Toxicological Review of Biphenyl 

July 2011 

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

scientific basis supporting the human health assessment of biphenyl 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 biphenyl includes 

an oral reference dose (RfD) (posted on IRIS in 1989) and a cancer weight-of-evidence 

descriptor (posted in 1991). 

The current draft health assessment includes an RfD and a carcinogenicity assessment. Below is 

a set of charge questions that address scientific issues in the assessment of biphenyl. Please 

provide detailed explanations for responses to the charge questions. Please consider the 

accuracy, objectivity, and transparency 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 evidence 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 Biphenyl

1. A developmental study of biphenyl in Wistar rats (Khera et al., 1979) 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. Developmental effects in Wistar rats (i.e., fetal skeletal anomalies) were selected as the 

critical effect for the RfD. EPA considers this effect to be adverse. Please comment on whether 

the characterization and 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 fetal skeletal anomalies in 

Wistar rats 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% extra risk of the incidence of fetal skeletal anomalies) 

scientifically supported and clearly described? 
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? If changes to the selected UFs are proposed, please identify and provide a rationale.

(B) Inhalation Reference Concentration (RfC) for Biphenyl

1. An RfC was not derived for biphenyl. Has the scientific justification for not deriving an RfC 

been clearly described in the document? Please identify and provide the rationale for any studies 

that should be selected as the principal study. 

(C) Carcinogenicity of Biphenyl

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment

(www.epa.gov/iris/backgrd.html), the database for biphenyl provides “suggestive evidence of 

carcinogenic potential” by all routes of exposure. Is the cancer weight of evidence 

characterization scientifically supported and clearly described? 

2. EPA has proposed a mode of action (MOA) for biphenyl-induced urinary bladder tumors in 

male rats involving sustained occurrence of calculi in the urinary bladder leading to transitional 

cell damage, sustained regenerative cell proliferation, and eventual promotion of spontaneously 

initiated tumor cells in the urinary bladder epithelium. Please comment on whether this analysis 

regarding the MOA for male rat urinary bladder tumors is scientifically supported and clearly 

described.

Oral Slope Factor (OSF) 

3. A two-year bioassay of biphenyl in BDF1 mice (Umeda et al., 2005) was selected for the 

derivation of an OSF. Please comment on whether the selection of this study for quantitation is 

scientifically supported and clearly described. Please identify and provide the rationale for any 

other studies that should be selected for quantitation. 

4. The incidence of liver tumors in female mice was selected to serve as the basis for the 

quantitative oral cancer assessment. Please comment on whether this selection is scientifically 

supported and clearly described. Please identify and provide the rationale for any other 

endpoints that should be selected to serve as the basis for the OSF.

5. The OSF was calculated by low-dose linear extrapolation from the POD (i.e., the lower 95% 

confidence limit on the dose associated with 10% extra risk of liver tumors). Has the modeling 

been appropriately conducted and clearly described? 

6. Please comment on the choice of the nonlinear threshold approach for the quantitative 

assessment of the carcinogenic potential of biphenyl associated with male rat urinary bladder 

tumors. Please comment on whether this approach is scientifically supported and clearly 

described. 
Inhalation Unit Risk (IUR) 

7. An IUR was not derived due to the lack of available studies to characterize the carcinogenic

potential of biphenyl administered via inhalation. Is the rationale for not deriving an IUR 

scientifically supported and clearly described? Please identify and provide the rationale for any 

studies that should be selected as the principal study.