STEP 3 IRIS INTERAGENCY COMMENTS

OMB Staff Working Comments on EPA’s Draft Relative Potency Factor (RPF) Approach for PAH Mixtures (page numbers refer to the redline dated September 2009) and Draft Charge to External Reviewers (dated September 2009) Under EPA’s IRIS Review Process.

General Science Comments:

 The new IRIS process (subtitle d the Assessment Development Pr ocess) is designed to cover the review of human health assessments deve loped within the IRIS program. The document provided for review provides “an approach to assessing cancer risks from exposure to PAH mixtures”, and it is not clear th at this “approach” is an assess ment (eg there is no assessment of individual carcinogenicity). Although we appreciate the opportunity for interagency review of such a document, we would like to better understand why IRIS is the appropriate venue for developing this approach.

 While EPA provides a rational for using an RPF approach as compared to other approaches, from the reading of the document it is not cl ear how EPA expects the approach to be used, and by whom, and therefore we believe more cl arity on how the approach should be applied would be useful for users and reviewers. This is particularly important as reviewers should be evaluating the approach in the context of its inte nded use. It is also unclear what routes of exposure these values are re levant to. In addition, we note that much of the in vivo data are derived from dermal, IP, and lung implantati on studies; how EPA app lies this data and approach in the context of inha lation and ingestion pathways is not clear in the document as written. Finally, we note that EP A’s quantitative cancer risk valu es for BaP, which serves as the reference PAH in this approach, were la st revised in 1994. How this RPF approach relates to use of the BaP cancer valu es should be clarified as well.

 As this is important guidance th at will have implications for assessing risk of many different PAH’s we would suggest that EPA have this reviewed through a Science Advisory Board Panel or similar body.

 EPA provides RPF values for PAH’s that are dete rmined to have potential carcinogenicity. It is unclear exactly what this term ‘potential ca rcinogenicity’ means, a nd this terminology does not appear on its face to be consistent with the weight of evidence descriptors provided in the EPA cancer guidelines. Further clarification of what EPA m eans by this terminology would be helpful. For example, does a higher RPF e quate to a higher potential carcinogenicity? In addition, in section 7.3, EPA stat es that all 23 PAHs are considered to be “carcinogenic by a mutagenic mode of action” and thus the suppl emental guidance for asse ssing susceptibility from early life exposure should be applie d. Has EPA sufficiently characterized the carcinogenicity of each of these 23 PAH’s to dete rmine that this is appropriate? For instance, EPA does not typically quantify cancer risk for chemicals for which there is only “suggestive evidence of carcinogenicity” (see cancer guidelines page 3-2). For some of the PAHs for which EPA has developed an RPF which is orde rs of magnitude less than one (eg 0.009 or 0.03), at least as currently writt en EPA does not appear to ha ve provided individual evidence of carcinogenicity. To support this statem ent, we believe an evaluation of the carcinogenicity of each or the 23 PAH compounds , similar to the cancer evaluation that is conducted using the recent EPA cancer guidelines , would be useful. We also recommend thatSTEP 3 IRIS INTERAGENCY COMMENTS

EPA have a specific charge question on the can cer descriptor EPA c hooses, and on applying the supplemental guidance to all the compounds for which a non-zero RPF is created.

 In Section 8, page xii notes th at “a description of uncertainties and limitations is crucial to interpretation of the RPF approach...” The discussion of uncertainti es in this section (beginning on page 197) could be enhanced by a specific discussion of limitations as well. EPA may want to consider changing the titl e of Section 8 to be “uncertainties and limitations”.

 The provided relative confiden ce rating for each derived RPF is very helpful and we appreciate EPA including this information, and we believe it would be useful if EPA could provide some suggested guidance on how this rati ng, as well as other ratings, should be used by the risk assessor. For instance, is there a s uggested mathematical approach that would give less weight to a RPF that is characterized as “very low” confidence? For example, the RPF for dibenz[a,c]anthracene is “very low”, yet the RPF value is the 5 th highest of all the RPF’s presented. Similarly the PAH with the highest RPF (60) has a ‘low’ confidence rating. Thus it is possible that at a specific site, a PAH, which has very low or low confidence, could be the quantitative driver in a risk analysis. We also suggest that EPA add a specific charge question on qualitative and quantit ative approaches that could be used to incorporate these confidence ratings into the risk analysis.

Specific Science Comments:

 Page v, and elsewhere, EPA states that biom arker studies measuring DNA adducts in humans were excluded. Please confirm whether this statement means that there are no dose-response information relating biomarkers of adducts to cancer endpoints.

 EPA states, page vi and elsewher e, that only studies with positive findings were used for the calculation of RPFs, while nega tive findings were used only in the weight of evidence (WOE) evaluation of potential carcinogenicity. It would be helpful for EPA to better elaborate on the rationale for not including nega tive studies in the RPF calculation even if they otherwise meet the appropriate quality cr iteria (or conversely, pleas e clarify if none of these studies met the qualifying criteria). If it is a methodol ogical limitation (e.g. how to consider or weight a zero value study), it would be helpful for EP A to have an explicit charge question that asks about possible approaches to using this information. We suggest that EPA also have a specific charge questi on that asks the expert panel if they agree with the approach of not using negative findings (fro m studies which meet the qualit y criteria) in the calculation of the RPF.

 Page vii, and elsewhere, EPA states that for data sets that included only a single dose or for those data sets for which no model fit was ach ieved, a point estimate RPF was calculated. We suggest EPA add a specific char ge question that takes commen t on this approach in these limited data cases. A discussion of this issue, and the impact it has on the RPFs (eg a statement of how many of the 23 values, a nd which ones are based on a point estimate) would be likely be very helpful to the peer reviewers. In add ition, it would be helpful to ask the expert reviewers about how this should, if it all, impact the relative conf idence rating given to the chemical.STEP 3 IRIS INTERAGENCY COMMENTS

 Page xii, the 5 th and 6 th columns in table 2 appear to be not consistent with the presentation in Table 1.

 Page 27 notes that the data are sufficient to classify a number of PAHs as “possibly carcinogenic to humans,” but for other PAHs the data are negative or equivocal. We believe it would be useful if EPA were to determine the carcinogenicity potent ial (using the weight of evidence descriptors in the 2005 Cancer Guid elines) for each of the PAHs for which an RPF is determined. If this is not possible, a good starting point would be clarification of which are “possibly carcinogenic” and which ha ve negative or equi vocal data. How this relates to the RPF value would also be helpful information.

 Page 28: should in vivo carcinogenicity assays be adde d to this bulleted list of study endpoints evaluated?

 Page 28, states that BaP is one of the mo st potent carcinogenic PAHs identified. The RPF approach identifies 5 PAHs with values >1, im plying that they are more potent than BaP. After calculating the RPFs, has EPA gone back through the existing available scientific literature to affirm that in f act these 5 compounds are expected to be more potent than BaP (and in some cases more than an order of magnit ude more potent)? We believe this would be helpful to validate the RPF approach.

 Page 31, line 9-18, please provide citations for each of the bulleted key events presented (similar to the citations provided on page 30).

 Page 33, line 4, are these data fo r PAHs or BaP? Please clarify.

 Page 39, the unlabelled figure provided above li ne 2 seems quite general. Is there a more detailed figure that shows the complexity of proteins binding the AHR (rather than just ARNT), as well as a more detailed list of mRNA’s up-regulated that could be provided and discussed? We also note that it would be helpful to provide citations for the sentences ending on lines 8 and 13.

 Page 43, lines 14-17, notes that r ecent studies have used QSAR to evaluate PAH structural features and mechanistic events related to carcinogenesis. Has EPA considered comparing the QSAR data and predictions to the results of the RPF approach for the 24 PAHs for which a RPF is provided? This type of cross-walk may provide useful validation of the RPF approach.

 Page 46, line 9, cites Schneider 2002 and the suggestion that RPF estimates be derived separately for different exposure pathways. Ha s EPA considered such an approach? If so, does EPA have a general idea of what imp act would this have on the derived RPF?

 Page 51, table 3-1 provides a very helpful comparison of RPF values derived by other agencies and also existing in the published literature. We believe tt would be extremelySTEP 3 IRIS INTERAGENCY COMMENTS

helpful and would facilitate understanding of the document if EPA added a column showing the values derived in the current approach.

 Page 58, line 4-10, provides a comparison of TEFs and RPFs. However, at this point in the document still may be unclear to readers how the RPFs should be applied (eg to what exposure routes and to what durations). More clarity here would be helpful.

 Page 60, line 5, states that the RPF method produ ces risk estimates that are significantly lower than those derived from epidemiology studies. Could a comparison be done with the epidemiology studies to determine if the relati ve rankings in RPF values are similar to the relative rankings of risk dete rmined from the epidemiology data? If so, we believe such a comparison would be useful and informative.

 Page 61, line 9-11, provides a lis t of studies that were excl uded from the database. We suggest EPA take specific comment on whethe r or not expert revi ewers agree with the determination to exclude these studies. EPA c ould add this question to the charge section which addresses chapter 4.

 Page 89, line 5, EPA refers to non-positive bioass ays. Please clarify if these means the BaP results were negative or the PAH test chemi cal results were negative. Are both options plausible?

 Page 108, we believe it would be helpful if EPA provided some discussion of the types of tumors that were included in the quantita tion. It appears that EPA treated benign and malignant tumors the same. We suggest adding a charge question for reviewers on this aspect of EPA’s approach. Perhaps a different appr oach would have EPA treating the tumors differently depending upon the specific type of tumor, its likelihood of progression to malignancy, and/or its relevance to humans (for some specific tumors expert reviewers have commented that the animal data are not rele vant). We suggest having a charge question which asks expert reviewers to comment on su ch alternative appro aches. These questions could be added to the section of the charge wh ich discusses chapter 5, and this treatment of the data should be discussed in th e uncertainty section in chapter 8.

 Page 108, line 34-38, discusses how EPA sequentially eliminated high-dose data groups in an effort to achieve adequate model fit. EPA st ates that these high-dose groups are not as informative and can be eliminated, with the jus tification that the lower dose is the region of interest. Did EPA develop an understanding of any data anomalies and a sound theoretical basis for either including or excluding them be fore looking at the le vel of the dose of the groups? We believe this step should have preceded—not foll owed—model fitting. If the model is fit first and then adjustments are made , the practice may be subject to the criticism, and we don’t believe from the write-up that EPA has provided a robust rationale for dropping data at the highest doses, especially for the explicit purpose of improvi ng the model fit. In practice, we believe it may be difficult to pred ict which levels may be useful from a policy perspective; therefore, the full dose-respons e relationship may be helpful for the risk manager who may need information across a wider range of dosages than just near the BMR. We suggest that EPA add an explicit charge question addressing this methodological issue.STEP 3 IRIS INTERAGENCY COMMENTS

Also, to inform the peer review, EPA could, perhaps in an appendix, provide information on the number of PAHs for which an RPF was de termined based on dropping high dose data. As a comparison, EPA could also provide inform ation using a point-estimate approach, with a charge question on the usefulness of this appr oach. Peer reviewers could also be asked to comment on the confidence rating of such values, as compared to values derived from a BMD approach.

 Page 110, line 1-6, EPA should clarify the ration ale for why they find the BMD to be more stable than the BMDL, in order to faci litate peer review of the rationale.

 Page 113, line 1-4 mentions that in several st udies the test conditions were not necessarily optimal for the selected PAHs. It may be useful to also discuss this in Section 8. It may also be helpful if EPA clarified how the test conditions impacted, if at all, the confidence ratings that were derived.

 Page 113, line 28, EPA states that a point estim ate approach using the peak response for the selected PAH was used. We suggest that a fuller discussion of the impacts of this approach may be helpful, and a charge question on this as pect of the approach may also be helpful.

 Page 114, line 18 states that PAHs with adequate evidence to suggest that they have little or no carcinogenic potential were assigned an RPF of 0. This suggests that the higher the RPF the greater the potential car cinogenicity. More discussion on how the RPF rating equates with the cancer weight of evidence descriptors in the cancer guidelines would be helpful. For example, does an RPF of zero mean that the co mpound has been determined to be “not likely to be carcinogenic”? For those which EPA eliminated from consideration, would the rating be something like “Inadequate Informati on to Assess Carcinogenic Potential”?

 Page 115, line 22, EPA states that when the data were considered adeq uate for a given PAH, it was selected for inclusion in the RPF approach. Further information on how EPA determined adequacy, and the cr iteria used, would be helpful.

 Page 116, EPA’s weight of evidence approach looks for positive result s in tumor bioassays but does not appear to consider the type of tumor, the location of the tumor or the potential relevance of the tumor to humans. If this is correct, discussion of this aspect of EPA’s approach and its potential impacts should be included in section 8 on uncertainties. EPA should also consider a ch arge question on this aspect of the approach.

 Page 118, it seems that EPA’s weight of eviden ce evaluation (figure 6- 1), is more of an examination of data sufficiency, rather than an evaluation of potenti al carcinogenicity. The evaluation seems to determine whether or not the PAH has a data set which allows the PAH to be included for evaluation, yet the evaluation does not determine what the relative ranking should be. More clarity here, a nd perhaps a possible name change for the evaluation may be helpful. As figures 6-2 through 6-35 do provi de helpful graphic arrays, which include presenting the RPF values as part of the weight of evidence evaluation, it might be helpful to have figure 6-1 mention the determination of the RPF as part of the evaluation process. MoreSTEP 3 IRIS INTERAGENCY COMMENTS

clarity on where the weight of evidence appro ach comes into play in determining potential carcinogenicity would be helpful.

 Page 189, we believe it would be very helpful to have a summary table which presents the inputs to the RPF derivation for each compound. Fo r instance, for each PAH, there could be columns which provide data on: # of positive bioassays, # of negative bioassays, # of positive studies on other endpoints, # of negative studie s on other endpoints. Such a table would allow a summary view of the strength of the dataset for each compound. This would also allow for comparison among the 26 compounds.

 Page 190, because for most of the PAHs (17/23) there were 3 or less RPFs derived, instead of presenting the range of RPFs, did EPA consider simply presenting all the RPF values in the table? This would be very helpful as it would make all the data availa ble and would let users and reviewers understand the full extent of how variable the R PF values may be for certain compounds.

 Page 190, line 17-19, mentions that calcula ting a weighted average might increase uncertainty. It would be helpful if EPA coul d explain why this might be the case, as we could imagine a method of weighting the studie s with more relevant exposure routes or perhaps higher quality data sets could be a promising approach.

 Page 191, line 3-5 discusses how when sepa rate RPFs where calculated for different endpoints in the same group of an imals, the higher va lue of the two RPFs was included in the calculation and the lower RPF was dropped. It woul d be useful to include discussion of why this approach was taken and its impacts on th e final derived RPFs. For example, it seems that EPA could have included th is lower RPF value in the rang e of RPF values derived for the PAH.

 Page 191, in the discussion of confidence rati ngs, we suggest EPA more clearly present which criteria and inputs led to which confiden ce ratings. A table would be useful here. For instance, it is not clear how the number of RPFs based on BMD modeling played into the confidence rating, nor is it clear how the numbe r of datasets helped determine the ranking. For instance, Fluoranthene has 6 datasets, 5 of which had RPFs based on BMD modeling. This is the highest number of BMD values for any compound, yet th e confidence rating is low. For example, this perhaps could have b een driven by the exposure route, or a hierarchy that EPA applied (eg exposure route then numbe r of studies, etc) when deriving confidence ratings. More clarity on this would be very useful.

 Page 197, line 34-37, EPA focuses discussion of improvements on the comprehensive review that was conducted. While this is very important, are there also methodological improvements in the derivations of the RFPs that EPA could also discuss?

 Page 198, in discussing uncertainties related to the dose-response, as noted above, this may be a good section in which to include discussion of EPAs approach of treating all tumors and all exposure routes equally. Similarly, EPA tr eated RPFs derived from point estimates andSTEP 3 IRIS INTERAGENCY COMMENTS

BMD modeling equal as well. It would also be he lpful, in this section, to have discussion of which decision points may lead to overesti mates of potency and which may lead to underestimates of potency. Page 202 mentions some of these aspects in bullets, but a discussion of impacts would be useful.

 Page 201, line 30-31, talks about situations wher e bioassays that did not include BaP data were considered. However, from previous text in the document, it appear ed that only studies that also included simultaneous BaP data were included for evaluati on. More clarification here would be helpful.

 Page 204, line 9, discussion of why EPA finds th at providing order of magnitude estimates was not considered superi or to providing simple means would be helpful.

 Page 205 provides a very helpful table of th e PAHs and their confidence ratings. See comments above on this issue.

 Page 212, line 18-21, EPA makes mention of the California RPF scheme which uses a hierarchy of bioassay data based on relevance of exposure route. Othe r than the preference for exposure routes that target the respiratory tr ack, EPA states that th e basis for prioritizing is not evident. It would be helpful if EPA could elaborate on why the agency did not employ a similar approach to th e California RPF method.

 Page 213, line 28, EPA states that the avai lable information provides “some support for cross-route extrapolation.” It is not clear what is meant by “some support.” This is an important issue as it provides the basis for dr awing data from multiple exposure routes. We suggest adding a charge question on this issue.

Comments on the draft Charge: (To be helpful, we have included some of the spec ific charge questions that were interspersed in the comments above to assi st with consolidation)

o In many cases, EPA asks if the scientific justification or criteria for a choice is appropriately described. Although it may be implied, EPA does not appear to ask the reviewers whether or not they are in agr eement with the scientific justification provided. While it is important that the re viewers comment on the transparency and clarity of the guidance, it would likely also be useful to explicitly ask that the reviewers comment on the scie ntific justifica tions presented. Below we suggest specific clarifications of a few questions; however, if EPA agrees with this general suggestion this change would apply to many of the questions not mentioned below.

o Since the development of Agency Informa tion Quality (IQ) guidelines required by statute, many agencies have been using char ge language that tracks with the standards of their own IQ guidelines. For example, such language often focuses on whether or not the information in question is accura te, clear, complete, transparently and objectively described, and scientifically just ified. We believe it may be useful forSTEP 3 IRIS INTERAGENCY COMMENTS

EPA to follow a similar approach and incor porate some of the language from your IQ guidelines into the formulati on of the charge questions.

 Chapter 1: Question 1 asks if the report provid es adequate context for the use of the RPF approach. It is unclear what is meant by this question. This could be strengthened by asking explicitly how RPFs should be used in asse ssing human health risk s and if there are any limitations in their use.

 Chapter 2:

o In Question 4 suggest asking if peer review ers agree with the choice of BaP as the index compound.

 Chapter 4:

o In Question 7 suggest asking reviewers if they agree with the criter ia used to select the studies for inclusion in the assessment.

o In Question 9 please clarify which tables are bein g referred to.

 Chapter 5:

o Suggest taking specific comment on the use of the multistage model as well as the determination to use the linear model for all datasets for which multi-dose continuous data was available.

o As mentioned above, suggest taking co mment on the decision to sequentially eliminate high dose groups to get the models to provide adequate fit.

o Suggest taking comment on EPAs approach for choosing the BMR based on using the observed response in BaP adjusted for background response.

o Section 5.4 discusses how a point estimate approach was used for data where only a single dose of BaP and other PAHs was av ailable. We suggest that EPA take comment on whether these single dose studies are robust enough to be used, and if so, how the single dose nature of the stud ies should be taken into account in the confidence rating and averaging appro ach used to derive the RPFs.

o Section 5.4 also mentions that statistical analysis was not always possible for each dose group and in these cases EPA chose the lowest dose that produced a near maximal change in the assay (the highes t dose in the linear portion of the doseresponse curve as identified visually). We suggest that EPA take comment on this aspect of the methodology. It may also be helpful to take comment on how these studies should be taken into account in th e confidence rating and averaging approach used to derive the RPFs.

o Suggest taking comment on the inclusion of RPF calculations from the newborn mouse assays. In particular, EPA may also want to ask for specific comments on its approach to handling gender and tumor diffe rences in the newborn mouse studies. We also note that section 5.6 is a bit unclear on how the data were treated in the end. Did EPA average the RPF values derived separa tely from the male and female mice, consistent with EPA’s approach of averaging RPFs?

 Chapter 6STEP 3 IRIS INTERAGENCY COMMENTS

o We suggest EPA should specifically as k reviewers to comment on how EPA implemented the decision tree approach. Fo r instance, do all the compounds included for RPFs belong and were the othe r compounds appropriately excluded?

 Chapter 7

o In Question 21, please clarify that the arit hmetic mean was used. It may also be helpful to take comment on other approaches in addition to the presentation of a range or confidence interval (for instance our comm ents above suggest that it may be just as easy to present all the data in some cases).

o As mentioned above, suggest taking specifi c comment on EPAs treatment of negative data when determining the RPF.

o It appears that EPA, when averaging RPFs does not ta ke into account route of exposure in the study. Suggest taking comment on this approach to get suggestions on how such information may or may not be useful.

o Suggest taking specific comment on the EP A approach, as described on page 191, where EPA uses only the higher value of mu ltiple RPFs from different endpoints in the same group of animals.

 Chapter 8

o In addition to asking if the most import ant uncertainties are identified, it may be helpful to ask the reviewers to comment on whether the most important limitations are identified.

o Suggest taking general comment on the fact that most PAHs evaluated included only 1-3 useable datasets and whether or not th is should impact how the data are used.

o Suggest taking specific comment on options for prioritizing RPFs (rather than averaging). Page 202, in the uncertainty disc ussion, states that th e current state of knowledge does not support a biological basis for prioritizing RPFs. It may be useful to get reviewers comments on this finding.

o Suggest taking comment on EPAs approach to providing a RPF for 1 PAH based on cancer-related endpoints only. It may also be helpful to ask peer reviewers to comment on how this value, which has a lo w confidence rating, should be used and considered by risk assessors and risk managers.