Draft Charge to External Reviewers for the IRIS Tox icological Review of Benzo[a]pyrene

June 2011

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 benzo[a]pyrene that will appear on the Agency’s online database, the Integrated Risk I nformation System (IRIS). IRIS is prepared and maintained by the EPA’s National Center for Env ironmental Assessment (NCEA) within the Office of Research and Development (ORD). An exist ing IRIS assessment for benzo[a]pyrene, which includes an oral reference dose (RfD) and car cinogenicity assessment, was posted on IRIS

in 1987.

The current draft health assessment includes an RfD , RfC, and carcinogenicity assessment. Below is a set of charge questions that address sci entific issues in the assessment of benzo[a]pyrene. Please provide detailed explanatio ns for responses to the charge questions. Please consider the accuracy, objectivity, and tran sparency 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 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 Benzo[a]pyrene

1. A 60 day toxicity study of benzo[a]pyrene in fe male Sprague-Dawley rats (Xu et al., 2010)

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 scientifica lly supported and clearly described. Please identify and provide the rationale for any other st udies that should be selected as the principal study.

2. Decreased ovary weight in female rats was selec ted as the critical effect for the derivation of

the RfD. Please comment on whether the selection o f this critical effect is scientifically supported and clearly described. Several additiona l studies are available which report low dose effects following oral benzo[a]pyrene exposure (see Table 5-1). Please identify and provide the rationale for any other endpoints that should be se lected as the critical effect.

3. Benchmark dose (BMD) modeling was applied to th e decrease in ovary weight in female Sprague-Dawley rats to derive the point of departur e (POD) for the RfD. Has the BMDmodeling been appropriately conducted and clearly d escribed? Is the benchmark response

(BMR) selected for use in deriving the POD (i.e. a 1 SD change in ovary weight) scientifically supported and clearly described? 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. Are the UFs scientifically supported and clearly described? If changes to the selected UFs are prop osed, please identify and provide a rationale.

(B) Inhalation Reference Concentration (RfC) for be nzo[a]pyrene

1. A developmental toxicity study (exposure on GD 11-20) of benzo[a]pyrene in F344 rats (Archibong et al., 2002) was selected as the basis for the derivation of the RfC. Please comment on whether the selection of this study as the princ ipal study is scientifically supported and clearly described. Please identify and provide the rationa le for any other studies that should be selected as the principal study.

2. Decreased fetal survival and decreased pup weig ht in rats was selected as the critical effect

for the derivation of the RfC. Please comment on w hether 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. The NOAEL/LOAEL approach was used to derive the POD for the RfC. Please comment on whether this approach is scientifically supported a nd 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 RfC. Are the UFs scientifically supported and clearly described? If changes to the selected UFs are prop osed, please identify and provide a rationale.

(C) Carcinogenicity of Benzo[a]pyrene

1. Under the EPA’s 2005 Guidelines for Carcinogen Risk Assessment , benzo[a]pyrene is determined to be carcinogenic to humans by all rout es of exposure. Is the cancer weight of evidence characterization scientifically supported and clearly described?

2. A mutagenic mode of action is proposed as the p rimary mode of action of benzo[a]pyrene carcinogenicity. Please comment on whether this de termination is scientifically supported and clearly described. Please comment on data availabl e for benzo[a]pyrene that may support an alternative primary mode of action.Oral Slope Factor (OSF)

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

selected for the derivation of an OSF. Please comm ent on whether the selection of this study for quantitation is scientifically supported and clearl y described. Please identify and provide the rationale for any other studies that should be sele cted for quantitation.

4. The incidence of tumors of the alimentary tract (forestomach, esophagus, tongue, and larynx)

in female mice was selected to serve as the basis f or the quantitative oral cancer assessment.

Please comment on whether this selection is scienti fically supported and clearly described. Please identify and provide the rationale for any o ther endpoints that should be selected to serve

as the basis for the OSF.

5. 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)

6. A lifetime inhalation study of benzo[a]pyrene i n Syrian hamsters (Thyssen et al., 1981) was

selected for the derivation of an IUR. Please comm ent on whether the selection of this study for quantitation is scientifically supported and clearl y described. Please identify and provide the rationale for any other studies that should be sele cted for quantitation.

7. The incidence of upper respiratory and upper di gestive tract tumors (primarily larynx and pharynx tumors) in male hamsters was selected to se rve as the basis for the quantitative

inhalation cancer assessment. Please comment on wh ether this selection is scientifically supported and clearly described. Please identify a nd provide the rationale for any other endpoints that should be selected to serve as the b asis for the IUR.

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

limit on the concentration associated with 10% extr a risk of laryngeal and pharyngeal tumors). Has the modeling been appropriately conducted and c learly described?

Dermal Slope Factor (DSF)

9. A 104-week study of benzo[a]pyrene in C3H/HeJ m ice (Sivak et al., 1997) was selected for

the derivation of a DSF. 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 quant itation.

10. The incidence of skin tumors in male mice was selected to serve as the basis for the quantitative dermal cancer assessment. Please comm ent on whether this selection is scientifically supported and clearly described. Pl ease identify and provide the rationale for any other endpoints that should be selected to serve as the basis for the DSF.11. The DSF was calculated by linear extrapolation from the POD (i.e. the lower 95%

confidence limit on the concentration associated wi th 10% extra risk of skin tumors). Has the modeling been appropriately conducted and clearly d escribed?

12. The DSF was adjusted to account for interspeci es scaling between mice and humans. This cross-species adjustment was based on allometric sc aling 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 BW 3/4 , would be expected to have equal lifetime risks of cancer. However, because there is no established methodology for cross-speci es extrapolation of dermal toxicity, several alternative approaches were evaluated (see Appendix H). Please comment on whether the selected interspecies scaling approach is scientifi cally supported and clearly described. Also, please comment on whether the alternative approache s presented are scientifically supported and clearly described. Please identify and provide the rationale for any alternative approach that

should be selected.