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EPA Proposed Draft Charge to the Science Advisory Board for the 

IRIS Toxicological Review of Benzo[a]pyrene

June 2012

Introduction

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

basis supporting the draft Toxicological Review of Benzo[a]pyrene that will appear on the Agency’s 

online database, the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by 

EPA’s National Center for Environmental Assessment (NCEA) within the Office of Research and 

Development (ORD). An existing IRIS assessment for benzo[a]pyrene, which includes an evaluation 

of human cancer potential and an oral slope factor, was posted on the IRIS database in 1987.

IRIS is a human health assessment program that evaluates qualitative and quantitative health

information on effects that may result from exposure to specific chemical substances found in the

environment. Through the IRIS Program, EPA provides quality science-based human health

assessments to support the Agency’s regulatory activities. Combined with specific exposure

information, government and private entities use IRIS to help characterize public health risks of

chemical substances in site-specific situations in support of risk management decisions.

The external review draft Toxicological Review of Benzo[a]pyrene is based on a comprehensive 

review of the available scientific literature on the human and animal health effects of 

benzo[a]pyrene, and was developed according to guidelines and technical reports published by EPA 

(see Preamble). This draft IRIS assessment provides an overview of the data regarding the 

toxicokinetics of benzo[a]pyrene in humans and animals and characterizes the potential hazard 

posed by benzo[a]pyrene exposure for noncancer and cancer health effects. The draft assessment 

also includes a qualitative characterization of the human cancer potential. In addition, a chronic 

oral reference dose (RfD), inhalation reference concentration (RfC), oral and dermal slope factor, 

and inhalation unit risk are derived. 

Charge Questions

In April 2011, the National Research Council (NRC) released its “Review of the 

Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde.” In addition to 

offering comments specifically about EPA’s draft formaldehyde assessment, the NRC 

included comments and recommendations to improve IRIS documents generally. The IRIS 

Program’s implementation of the NRC recommendations is following a phased approach. 

Phase 1 of implementation has focused on a subset of the short-term recommendations, 

such as editing and streamlining documents, increasing transparency and clarity, and using 

more tables, figures, and appendices to present information and data in assessments. Phase 

1 also focused on assessments that had been near the end of the development process and 

close to final posting. The IRIS Program is now in Phase 2 of implementation, which 

addresses all of the short-term NRC recommendations. The Program is implementing all of 

these recommendations but recognizes that achieving full and robust implementation of 

certain recommendations will be an evolving process with input and feedback from the 

public, stakeholders, and external peer review committees. This phased approach is 

consistent with the NRC’s “Roadmap for Revision” as described in Chapter 7 of the 

formaldehyde review report. The NRC stated that “the committee recognizes that the 

changes suggested would involve a multi-year process and extensive effort by the staff at 
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the National Center for Environmental Assessment and input and review by the EPA Science 

Advisory Board and others.”

Below is a set of charge questions that address scientific issues in the draft IRIS Toxicological 

Review of Benzo[a]pyrene. The charge questions also seek feedback on whether the document is 

clear and concise, a central concern expressed in the NRC report. Please provide detailed 

explanations for responses to the charge questions. EPA will also consider the Science Advisory 

Board review panel’s comments on other major scientific issues specific to the hazard identification 

and dose-response assessment of benzo[a]pyrene. 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 health effects of 

benzo[a]pyrene?

2. Please identify any additional peer-reviewed studies from the primary literature that 

should be considered in the assessment of noncancer and cancer health effects of 

benzo[a]pyrene. 

Chemical-Specific Charge Questions:

(A) Hazard Identification 

Synthesis of Evidence 

1. A synthesis of the evidence for benzo[a]pyrene toxicity is provided in Section 1, Hazard 

Identification. Please comment on whether the available data have been clearly and 

appropriately synthesized for each toxicological effect. Please comment on whether the 

weight of evidence for hazard identification has been clearly described and scientifically 

justified.

Summary and Evaluation

1. Does EPA’s hazard assessment of non-cancer human health effects of benzo[a]pyrene 

clearly and objectively represent and synthesize the available scientific evidence to support 

its conclusions that benzo[a]pyrene poses a potential human health hazard for non-cancer 

toxicity to the immune system; the male and female reproductive systems; the developing 

fetus; and the nervous system in the developing fetus? 

2. Does EPA’s hazard assessment of the carcinogenicity of benzo[a]pyrene clearly and 

objectively represent and synthesize the available scientific evidence to support its 

conclusions that under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment, 

benzo[a]pyrene is determined to be carcinogenic to humans by all routes of exposure?

a. A mutagenic mode of action is proposed as the primary mode of action of 

benzo[a]pyrene carcinogenicity. Please comment on whether this determination is 

scientifically supported and clearly described. Please comment on data available for 
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benzo[a]pyrene that may support an alternative primary mode of action.

(B) Dose Response Analysis 

Oral reference dose (RfD) for benzo[a]pyrene

1. EPA’s dose-response analysis includes the development of candidate oral reference doses

(RfD) for non-cancer effects. Please comment on whether the evaluation and selection of 

studies and effects for the derivation of candidate RfDs is scientifically supported and 

clearly described. Specifically, please comment on the selection of the following studies and 

effects for dose-response analysis: 

a. Developmental toxicity-Chen et al. (2012) [neurodevelopmental impairment]; Jules 

et al. (2012) [cardiovascular effects];

b. Reproductive toxicity-Xu et al. (2010) [decreased ovarian weights];Mohamed et al. 

(2010) [decreased sperm count]; and Gao et al. (2011) [increased cervical 

hyperplasia]

c. Immunotoxicity-Kroese et al. (2001) [decreased thymus weights]; DeJong et al. 

(1999) [decreased IgM and IgA levels and number of B cells]

Please identify and provide the rationale for any other studies or effects that should be 

considered.

2. Benchmark dose (BMD) modeling was applied to derive points of departure (POD) for the 

candidate RfDs when possible. Has the BMD modeling been appropriately conducted and 

clearly described? Are the benchmark responses (BMR) selected for use in deriving the 

PODs scientifically supported and clearly described? When BMD modeling was not possible 

a NOAEL/LOAEL approach was used to calculate RfDs. Please comment on whether these

approaches are scientifically supported and clearly described.

3. Please comment on the rationale for the selection of the uncertainty factors (UFs) applied to 

the PODs for the derivation of the candidate RfDs. Are the UFs scientifically supported and 

clearly described? If changes to the selected UFs are proposed, please identify and provide 

a rationale.

4. Organ/system-specific RfDs were calculated based on developmental, reproductive and 

immune system toxicity data. These reference values may be useful for cumulative risk 

assessments that consider the combined effect of multiple agents acting on the same 

biological system. Please comment on whether the selection of these RfDs is scientifically 

supported and clearly described.

5. The proposed overall RfD chosen was based on neurodevelopmental impairment observed 

by Chen et al. (2012). Please comment on whether the selection of this RfD is scientifically 

supported and clearly described. 

Inhalation reference concentration (RfC) for benzo[a]pyrene

1. EPA’s dose-response analysis includes the development of candidate oral reference 

concentrations (RfC) for non-cancer effects. Please comment on whether the evaluation and 

selection of studies and effects for the derivation of candidate RfCs is scientifically 
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supported and clearly described. Specifically, please comment on the selection of the 

following studies and effects for dose-response analysis: 

a. Developmental toxicity-Archibong et al. (2002) [decreased fetal survival]; Wormley 

et al., (2004) [Decreased long term potentiation in hippocampus]

b. Reproductive toxicity-Archibong et al. (2008) [decreased testes weight and sperm 

count and motility]

Please identify and provide the rationale for any other studies or effects that should be 

considered.

2. Benchmark dose (BMD) modeling was attempted to derive points of departure (PODs) for 

the candidate RfCs but was not feasible. The NOAEL/LOAEL approach was used to derive 

the PODs for the candidate RfCs. Please comment on whether this approach is scientifically 

supported and clearly described. 

3. Please comment on the rationale for the selection 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.

4. Organ/system-specific RfCs were calculated based on developmental and reproductive 

toxicity data. These reference values may be useful for cumulative risk assessments that 

consider the combined effect of multiple agents acting on the same biological system. 

Please comment on whether the selection of these RfCs is scientifically supported and 

clearly described.

5. The proposed overall RfC chosen was based on decreased fetal survival observed by 

Archibong et al., (2002). Please comment on whether the selection of this RfD is 

scientifically supported and clearly described. 

Cancer risk estimates for benzo[a]pyrene

Oral Slope Factor (OSF)

1. A lifetime dietary study of benzo[a]pyrene in female mice (Beland and Culp, 1998) was 

selected for the derivation of the 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.

2. The incidence of tumors of the alimentary tract (forestomach, esophagus, tongue, and 

larynx) 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.

3. The OSF was calculated by linear extrapolation from the POD (i.e., the lower 95% 

confidence limit on the dose associated with 10% extra risk of alimentary tract tumors). 

Has the modeling been appropriately conducted and clearly described?

Inhalation Unit Risk (IUR)

1. A lifetime inhalation study of benzo[a]pyrene in Syrian hamsters (Thyssen et al., 1981) was 
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selected for the derivation of the IUR. 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.

2. The incidence of upper respiratory and upper digestive tract tumors (primarily larynx and 

pharynx tumors) in male hamsters was selected to serve as the basis for the quantitative 

inhalation 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 IUR.

3. The IUR was calculated by linear extrapolation from the POD (i.e., the lower 95% confidence 

limit on the concentration associated with 10% extra risk of laryngeal and pharyngeal 

tumors). Has the modeling been appropriately conducted and clearly described?

Dermal Slope Factor (DSF)

1. A lifetime study of benzo[a]pyrene in male C57L mice (Poel, 1959) and a 104-week study of 

benzo[a]pyrene in C3H/HeJ mice (Sivak et al., 1997) were selected for the derivation of a 

DSF based on increased incidence of skin tumors. 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.

2. The DSF was calculated by linear extrapolation from the POD (i.e., the lower 95% 

confidence limit on the concentration associated with 10% extra risk of skin tumors). Has 

the modeling been appropriately conducted and clearly described?

3. The DSF was adjusted to account for interspecies scaling between mice and humans. This 

cross-species adjustment was based on allometric scaling using body weight to the 3/4 

power. Under this approach, rodents and humans exposed to the same daily dose of a 

carcinogen, adjusted for BW3/4, would be expected to have equal lifetime risks of cancer. 

However, because there is no established methodology for cross-species extrapolation of 

dermal toxicity, several alternative approaches were evaluated (see Appendix H). Please 

comment on whether the selected interspecies scaling approach is scientifically supported 

and clearly described. Also, please comment on whether the alternative approaches 

presented are clearly described and whether any of these approaches should be selected as 

the recommended approach. Please identify and provide the rationale for any alternative 

approach that should be selected.