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Draft Charge to External Reviewers for the Developm ent of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) Mixtures for the IRIS Program September 2009

The U.S. Environmental Protection Agency (EPA) is s eeking an external peer review of the scientific basis supporting the document titled “Re lative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) Mixtures” tha t will appear on the Agency’s online database, the Integrated Risk Information System (I RIS). IRIS is prepared and maintained by the

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

Below is a set of charge questions that address sci entific issues in the document. Please provide detailed explanations for responses to the charge q uestions.

Chapter 1. Background, Scope of Work, and Relations hip to the Development of a PAH

Mixtures Health Assessment

1. Does the report provide adequate context for the us e of an RPF approach within a PAH

mixtures assessment?

Chapter 2. Rationale for Recommending an RPF Appro ach

2. Does the report provide adequate justification for including an RPF approach as a scientifically defensible method to assess the canc er risk associated with exposure to PAH

mixtures?

3. Is the list of 74 PAHs included in the initial lite rature search complete? Was the literature search sufficiently broad and inclusive? Has the s cientific rationale for the choice of PAHs included in the literature search been appropriatel y described? Are there other databases or

resources that should be included?

4. Benzo[a]pyrene (B[a]P) is utilized as the index com pound for the RPF approach. Has this scientific justification for this choice been appro priately described? Please identify and provide the rationale for alternative index compoun d(s) that should be considered.

5. Does the text adequately describe and evaluate the current weight of evidence supporting the assumption that PAHs as a chemical class have a sim ilar mode of action? Does the document adequately discuss the degree to which thi s hypothesis and other data support the assumption of additivity that is a key component of a RPF approach?

Chapter 3. Discussion of Previously Published RPF Approaches

6. Is the discussion of previously published RPF appro aches complete? Does it provide a meaningful background on how RPFs have been derived in the past, and the advantages and disadvantages of previous methods?2

Chapter 4. Evaluation of the Carcinogenicity of I ndividual PAHs

7. Is the database of primary literature relevant to t he RPF approach transparently and objectively described? Are the criteria used to se lect studies for inclusion in the assessment adequately described? Are there additional criter ia that should be considered?

8. The methodology for the derivation of RPFs includes only studies where at least one PAH

was tested at the same time as B[a]P. There are ot her studies available where a PAH was tested without concurrent testing of B[a]P, but whe re comparable B[a]P data are available from the same laboratory and test system. Should t hese data be used to estimate RPFs? Please discuss any advantages or disadvantages of e xcluding these data.

9. Tables of study summary information are used to sho w how studies were selected for use in dose-response assessment. Have the choices and assu mptions in making the selection been adequately described? Do the tables provide adequat e information to inform how the decisions were made? Were studies rejected or incl uded appropriately?

10. Do the sections describing different study types (e .g., 4.3.1-4.3.3) adequately explain the variety of methods used?

Chapter 5: Methods for Dose Response Assessment an d RPF Calculation

11. Is the scientific rationale for the dose-response m odeling approaches used in the derivation of RPFs adequaely described? Please describe alternat ive approaches (e.g., other model forms)

that should be considered.

12. For each individual dataset considered in the asses sment, the slope of the B[a]P doseresponse was calculated from the study-specific dat a. An alternative approach would be to pool the B[a]P data from different studies in the s ame test system and use a single B[a]P slope to calculate all RPFs for that test system. P lease comment on whether this alternative approach or additional approaches should be conside red.

13. The point of departure for slope estimation that ha s been used is the benchmark dose estimate (BMD) rather than the lower confidence limit on the benchmark dose (BMDL) as this

estimate is considered to be a more stable basis fo r comparison between the potencies of benzo[a]pyrene and the selected PAH. Has the ration ale been adequately described? Please comment on whether alternative approaches should be considered.

14. Is the process for calculating RPFs from the variou s datasets (e.g. multidose, single dose) adequately described? Are the special consideratio ns for RPF calculation (e.g. tumor bioassay data, cancer-related endpoint data) adequa tely described? Please describe alternative approaches that should be considered.

15. For bioassay data, mortalities that occurred prior to the appearance of the first tumor have not been taken into consideration, and an assumption ha s been made that the number of animals3

at risk for tumor development is equal to the total number of animals alive at the appearance of the first tumor. Has this rationale been adequat ely described? Please describe alternative approaches that should be considered.

Chapter 6: Selection of PAHs for Inclusion in Rela tive Potency Approach

16. A streamlined weight-of-evidence evaluation, in the form of a decision tree, is employed to assess whether a given PAH should be included or ex cluded from the RPF approach. Has the

scientific rationale for the decision tree been ade quatley described? Does the approach adequately consider the available information? Ple ase describe any data that conflicts with the conclusions of the decision tree for any given PAH.

17. Several studies have suggested that PAHs containing a bay or fjord region are more likely to be mutagenic and/or carcinogenic. Please comment o n how this or other structure-activity information should contribute to the weight of evid ence evaluation.

18. The weight of evidence analysis does not include da ta related to Ah-receptor binding, cytoxicity or tumor promotion. Should quantitative data for these endpoints be used in the derivation of RPFs? If so, please describe how the se data should be incorporated into the assessment (e.g., how would you modify the ranking framework to accommodate the data).

19. The assessment uses a “RPF detection limit” concept as a means of comparing positive and nonpositive (negative results) bioassays. Please co mment on whether the scientific justification for this concept has been adequately described. Does the approach used to estimate the “RPF detection limit” provide a meanin gful metric for this comparison?

20. Graphic arrays of the calculated RPFs (Figures 6-2 through 6-35) are presented as a means of representing the variability in RPFs from different data sources, the weight of evidence for carcinogenicity, and the basis for the selected RPF . Please comment on whether the figures are informative and adequately described. Is there other information that should be included in the figures? Are the narratives informative and complete?

Chapter 7: Derivation of Summary RPFs for selected PAHs

21. Summary RPFs were derived by averaging the RPFs cal culated from bioassay data for any PAH that had at least one RPF based on a bioassay. Please comment on the transparency and justification for this approach, and the discussion of alternative options for the estimation of the summary RPF. Please comment on the reporting o f the range of RPFs as a measure of variability instead of a confidence interval. Plea se comment on whether the data are adequate to support more precision in deriving the RPFs.

22. Please comment on whether the scientific rationale for the assignment of an RPF of zero for some PAHs is transparently and objectively describe d. Please comment on other data that

should be considered to assess whether an RPF of ze ro is appropriate. Please comment on whether the scientific rationale for assigning no R PF in the decision tree based on inadequate4

data for some PAHs is adequately described. Please comment on whether there are alternative methods for assigning RPFs to these PAH s.

23. Please comment on whether the approach provides ade quate distinction between PAHs with

RPFs of zero and PAHs with no selected RPF. And wh ether this distinction is useful for describing uncertainty in determining the cancer ri sk associated with PAH exposure.

24. Please comment on whether the scientific rationale for consideration of bioassay data versus cancer-endpoint data has been adequately described. Please comment on the use of tumor multiplicity data in the weight of evidence evaluat ions and for determination of the RPFs.

25. Please comment on whether the available data are ad equate to recommend exposure route- or target organ-specific RPFs.

26. The selected RPFs are characterized with confidence ratings. Please comment on whether the scientific rationale for the confidence ratings is appropriately described. Please describe alternative approaches to the confidence ratings th at should be considered.

Chapter 8. Uncertainties Associated with RPF Appro ach

27. Overall, does the report describe the scientific ra tionale for the methodology used to derive RPFs in a manner that is transparent and objective? Are the most important uncertainties

identified?

Appendices

28. Please comment on whether the information in the Ap pendices is adequate to allow independent verification of the calculated RPFs. If not, what additional information would be

useful?