Page 1 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*1 GlobalBy requiring that the experiments be performedatthe same timein the same laboratory, EPA isexcluding the highest quality data (absent data fromhuman exposure), i.e., the whole animal cancerbioassays by the standard routes of exposure, i.e.,ingestion or inhalation.A logical extension of thisapproach would be to conclude that it is notappropriate to compare the cancer potenciesestimated from any of the NTP or other sets ofbioassays, as most of them were not conductedconcurrently. If such data were not appropriate tocompare and combine, the procedures generallyused by Federal regulatory agencies to comparecancer risks and estimate risks from exposure tomore than one carcinogen would also not beappropriate. Moreover, as the document is trying toestablish the relative cancer potency of the PAHs,itdoes not seem logical to exclude the cancerpotency data for the individual chemicals when theyare available. Finally, the relative potency estimatesfrom the cancer bioassays could be compared tothe relative potency estimates from other data, asagood indicator of whether the other data areproducing reasonable estimates.Exclusion of the whole animal cancer bioassaydata might encourage stakeholders, e.g.,industrial groups that have already filed otherdata quality challenges to do so in this case.Thus, it is recommended that the dataselection criteria should be modified and therelative potency factors (RPFs) re-estimated.Alternatively, as this document only addressesthe RPFs for carcinogenicity, the documentcould recommend that cancer potency factorsbased on bioassay data by the appropriateroute of exposure be used whenever chemicalspecific data are available, and that RPFs onlybe used in their absence. This approach hasthe advantage of making the documentevergreen, as well as being one suggested byan expert review panel that discussed therelated topic of TEFs for dioxin-like compounds(teleconference of 10/22/09 conducted byVersar on behalf of EPA’s Risk AssessmentForum).Please also note, the cancer bioassays thatwere used to estimate the RPFs included thosesuch as intraperitoneal and implantation thatare known to differ in their estimate of cancerpotency than those estimated from bioassaydata from oral or inhalation routes of exposure.S, MPage 2 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*2 Global The advisory report of EPA’s Science AdvisoryBoard (SAB, 2004; Review of EPA's DraftSupplemental Guidance for Assessing CancerSusceptibility from Early-Life Exposure toCarcinogens - A Report by the SupplementalGuidance for Assessing Cancer SusceptibilityReview Panel of the EPA SAB. At:http://yosemite.epa.gov/sab/sabproduct.nsf/WebReportsbyYearBOARD!OpenView&Start=1&Count=800&Expand=6#6 ) criticized the use of simple cancerpotency ratios, i.e., as estimated by q1*, for relativepotency estimates. In response, EPA developed amodel for determining the relative potency of cancerdata for its 2005 supplemental guidance to thecancer guidelines. This model is available on EPA’sweb site and was programmed in R, freeware alsoavailable on the internet. Use of this model wouldallow stakeholders to perform analyses that usedifferent data, e.g., to see if use of the wholeanimals bioassays excluded from EPA’s currentanalyses would change the RPFs.Given the amount of analyses that went intothis document, it would seem reasonable touse the more accurate relative potencyestimate model already developed by EPA (At:http://epa.gov/cancerguidelines/dataanalyses.htm).To quote from the SAB (2004)report:“Even assuming a full analysis as doneby Halmes et al. (2000) is not used here, thecomputation of the relative slope coefficientsfor juveniles and adults could have been doneon thelog-scalerather than thearithmeticscale. Since most models for cumulativeincidence for tumor onset assume a functionalform that includes an exponentiated dosefunction, changes in the point-of-departure fora fixed risk would better be reflected by acomparison of log-transformed data. The mathis as follows:P(dose)=1-[1-P(0)]exp(-slope*dose) [1]Hence{log[1-P(0)]-log[1-P(dose)]}/dose=slope [2]... For small P(dose) and small P(0), the EPAformula is approximately equal to [2]; formedium range P(dose) as we have here, theequations are not the same.ThisS, MPage 3 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*transformation is nonlinear so the resultingratios will be different[emphasis added].”3 Global While the points of departure (PODs) formany ofthe analyses are the ED10, as noted in thecomments on Appendix E, some of the PODs frompoint estimates appear to use much higherresponse levels, i.e., above the ED50. If this isanaccurate interpretation of the analysis, a linearextrapolation to low dose levels can not be used, asthis is a response level below which a “low levellinear” dose-response function can not be expected.If this interpretation of the analyses is incorrect,the document should be edited to prevent thisinterpretation. If the interpretation is correct,the analyses should be changed, and theRPFs reestimated.S, M4 ExecutiveSummaryPg. ivPara. 1See alsocomments forsection 2.8The actual requirements of using EPA’s dose-additivemodel (as described in the 1986 guidelines; Guidelinesfor Carcinogen Risk Assessment. U.S. EnvironmentalProtection Agency, Risk Assessment Forum,Washington, DC, 1986, at:http://epa.gov/cancerguidelines/guidelines-carcinogenrisk-assessment-1986.htm) are that the chemicalshave thesamemechanism of action; that they act aslower concentrations of the index chemical; that theydo notinteract toxicologically; and that (for themathematical derivation to work as presented) thelog(dose)-response curves must be parallel. [Thelatter requirement also requires that the chemicalshave the same efficacy, e.g., the same maximalresponse.] The guidelines allow for approximations,The document should be corrected and/orstate that these are approximations that areoften used in lieu of the stringent biological andmathematical requirements of the model.SPage 4 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*such as those stated in this document, but the actualrequirements are more stringent.Please note: the assumption about dose-responsecurves is consistent with EPA’s SAB’srecommendation to perform the analysis using anexponentiated dose function.5 ExecutiveSummaryPg. ivPara. 1These assumptions are not equivalent to additivity.When these conditions are present, additivity ofvarious types may be used, but so may other models,including dose-additivity within the dose-responsefunction to generate a dose-response surface (asmentioned in one reference in the text, but which isalso recommended by a number of experts in the riskassessment of mixtures of chemicals).The documents should be corrected to say thatthese approximations allow the assumption ofdose additivity and the RPF model.S6 ExecutiveSummaryPg. ivPara. 1See alsocomments forsection 2.8The assumption of lack of interaction at low levelsisoften made, but ignores the possibility of one of thechemicals being a strong antagonist. While this maybe a reasonable regulatory assumption, its limitationshave been demonstrated experimentally with mixturesof chemicals that are similar.Change to state that it is a reasonableregulatoryassumption to be health protective.S7 ExecutiveSummaryPg. vPara. 2See alsocomments forsection 2.8Studies of defined PAH mixtures should not beexcluded, as these will demonstrate the limitationsofthe method. In particular, such studies of similarchemicals often demonstrate that the dose-responsecurve of the mixture differs significantly from that ofthe index chemical, e.g., does not have the same slopeand/or is not equally efficacious.Available data on mixtures of knowncomposition should be added and used toestimate uncertainty, quantitatively, if possible.SPage 5 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*8 ExecutiveSummaryPg. viPara. 1stbulletSee alsocomments onAppendix GWhile simultaneous testing of BaP and other PAHs ispreferable, excluding other assays, especiallyin vivostudies, seems excessively restrictive.If no other data are available for that chemicalfor that endpoint, it would seem morereasonable to use the data with a qualifyingnotation that the estimate is likely to be lessaccurate. If the less reliable data is an outlierwhen all data are considered for the RPF, itcan be discarded later.S, M9 ExecutiveSummaryPg. viPara. 5thbullet and 3rdParagraphSee alsocomments onAppendix GEven when tumor incidence is 90% or greater, it isnotclear that multiplicity of tumors is informative.Thoughtempting to use such data (as dose-responseassessment for such data is of questionablerelevance), an increase in tumors with dose in a targetorgan is generally only used to increase the qualitativeweight of evidencefor carcinogenicity. These datashould not be used quantitatively without furtherjustification.Use of multiplicity of tumors for quantitativedose-response estimates is not a conventionalpractice and should be justified. Otherwise,these data should not be used in the analysis.S, M10 2.4Pg. 34Fig 2-3It is not clear whether this figure is proposing onemode of action that requires all of the key eventsin thefigure, or several potential modes of action that mayrequire one or more of the branches. If this is all onemode of action, does EPA anticipate that all pathwaysare active at all doses, or might different pathways beactive at different dose levels (cf. discussion onpg 42line 17 and following text)?Please clarify these issues. PAHs may beassumed to have a mutagenic MOA as BaPwas so named in EPA’s supplementalguidance (U.S. EPA. Supplemental Guidancefor Assessing Susceptibility from Early-LifeExposure to Carcinogens. U.S. EnvironmentalProtection Agency, Washington, DC,EPA/630/R-03/003F, 2005) and the othercarcinogenic PAHs by EPA’s implementationmemos (Communication II: Performing RiskAssessments that include CarcinogensDescribed in the Supplemental Guidance ashaving a Mutagenic Mode of Action. At:SPage 6 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*http://www.epa.gov/osa/spc/pdfs/cgiwg_communication_ii.pdf). In this case, however, thekey events posited in Figure 2-3 can not beassumed and should be proven using the MOAframework in EPA’s cancer guidelines.11 2.4Pg. 39Okey et al. (1994) is not in the reference list. Add to reference list. E12 2.4Pg. 40Line 29Please define “linear,” as many mathematicallyaccurate definitions exist, e.g., straight line, linearlyproportional to, and each variable existing only oncefor each power in the reduced form of the equation(i.e., the Hill equation is inherently nonlinear bythis lastdefinition).Please define “linear” here and, if useddifferently elsewhere, at all points where it isused. Alternatively, only use one definition oflinear in the document and use other terms,e.g., a straight line, for other circumstances.S13 2.4Pg. 42Line 25This paragraph asserts that there may be many MOAsfor PAHs. While not questioning that conclusion, noneof the MOAs are discussed using the framework inEPA’s 2005 cancer guidelines (U.S. EPA. Guidelinesfor Carcinogen Risk Assessment (2005). U.S.Environmental Protection Agency, Washington, DC,EPA/630/P-03/001F, 2005) – or any other framework.As such, the MOAs can not be considered to havebeen determined or established, as recognized by thenormal procedures. Simply asserting an MOA doesnot make it so. This is surprising, as the data are likelyto exist to do so.Use EPA’s 2005 cancer guidelines section ondetermining a mode of action forcarcinogenesis, and present the data in accordwith their MOA framework.S14 2.4Pg. 42No logic or data are provided for selecting the“primary mode of carcinogenic action.” Given theSelection of a primary mode of action – for allor some exposure conditions – requires moreS, MPage 7 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*Line 26previous paragraph, it is also likely that the MOAmay change with dose. If this is the primary MOA,itis not clear whether it is for the rodent bioassay,thehuman exposures, all exposure levels and routes, orsome other exposure(s). Determining an MOA isthe primary step in choosing a linear or nonlinearextrapolation for lower doses. Moreover, if differentMOAs primarily act at different levels of exposure,the logic for extrapolating from a high-dose MOA toa low-dose MOA should be presented, as the doseresponse functions are likely to vary substantially.than a simple assertion in one sentence.Please provide the data and logic behind thisassertion, the conditions of exposure for whichit is deemed appropriate should also beprovided. The data and logic as to why theother potential MOAs are not consideredprimary should be discussed as well.15 2.4Pg. 53Line 4The citation of USEPA 2009 is not in the referencelist. The entry for BaP states that the last revisionwas 12/10/1998; for benz[a]anthracene, 04/01/1997.Nor is there any such action mentioned for 2009 athttp://www.epa.gov/ncea/iris/recent.htm. EPA’sOffice of the Science Advisor issued animplementation memo on June 14, 2006 addressingthe use of PAHs using the 1993 provisionalguidance, which is cited in the document. Thereference lists the citation as 2008, but a searchofthat year in the url above as well as a search of the75 results for a search of the IRIS site for “PolycyclicAromatic Hydrocarbons” also did not disclose thisreference.As such a document would be most useful foran analysis of this document, the correctcitation, with a more specific url than that of theIRIS internet site, should be provided.Moreover, it would be useful to provideinformation on the authors and reviewers ofthis PAH document.E16 2.8GlobalAlthough the Executive Summary states that datafrom complex mixtures will not be used, the maindocument uses such data, e.g., in this section.References are also made throughout the documentThroughout the document, the text should bemodified to state that mixtures will not be usedto estimate the RPFs quantitatively. Moreimportantly, the document should also citeSPage 8 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*to studies where complex mixtures support theiranalyses, e.g., section 4.2 that includesepidemiological studies.those studies of mixtures of chemicals with asimilar mechanism of action where neitherdose- nor response-additivity was observed.17 2.8Pg. 46Line 30The sentence regarding dose additivity that beginsat the end of this line is illogical. If binary mixturesof PAHs “can exhibit antagonism, synergism, oradditivity...” more complex mixtures must alsoexhibit all of these interactions. Indeed there areexamples of such in the literature. Dose additivity ofPAHs is a reasonable, regulatory assumption as ascreening method – but it is not accurate.It is recommended that the independent clausethat begins this sentence be modified. Onesuggestion is, “It is reasonable to assume that,for regulatory, screening assessments, risks ofPAHs are additive,...”18 4.1Pg. 60-61Line 28 andfollowing textIt is unclear why mutagenicity, and not AhR binding,is considered relevant for estimating RPFs when aprevious section (2.6) discussed that the receptorbinding correlated better than mutagenicity with thecancer bioassays. If the RPFs are to vary withdose, e.g., by using the dose-response surfacemodel proposed, as mentioned on page 48, line 27,or if the document were to propose different RPFsfor different MOAs that occur at different doses, theuse of mutagenicity at lower doses might be able tobe justified, after the MOAs were established andthe approximate dose ranges for the MOAsestimated. Finally, it would appear that mutationswould be an indicator of dose and should use doseadditivity, rather than response additivity. Manyofthe attempts to relate mutagenic potency withcarcinogenic potency have demonstrated that this isnot a simple correlation.Although mutagenicity is a cancer-relatedendpoint, its selection for combining orcomparing directly with tumor data results in alogical inconsistency that should be resolved.There are several ways that this could beaccomplished, e.g., by determining a functionthat relates mutagenic potency for PAHs tocarcinogenic potency, and it is likely that theRPFs would need to be recalculated.Use of the AhR binding data would also likelyrequire use of a nonlinear extrapolation, asstandard receptor-binding data are inherentlynonlinear (e.g., Simon et al., 2009http://toxsci.oxfordjournals.org/cgi/reprint/kfp232). Finally, the logic for using responseadditivity rather than dose additivity formutagenicity as a precursor to cancer shouldbe justified, i.e., in contrast to the use ofS, MPage 9 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*mutagenicity as an endpoint by itself. Inparticular, if EPA believes that there arespecific mutations required for thecarcinogenicity, it would seem hard to assertthat a stochastic process is occurring, which isone of the assumptions for response additivity.19 4.3Pg. 89Para. 1Positive studies that did not follow the criteria forexcluding negative studies should also be excludedfrom the quantitative analysis. The same reasoningused to exclude the negative studies for quantitativeanalysis should exclude the positive studies from usequantitatively. In particular, if the animals wereobserved for less than 6 monthandwere positive, thepotency estimate from these studies is likely to varyfrom the potency estimate that would be estimatedfrom a two-year bioassay, i.e., the tumor incidencewould be expected to increase with increasedexposure time. Even if a time-to-tumor analysis wereused, the estimated potency from a longer study mightproduce a different cancer potency factor. Thus, suchpositive studies also should be only used for a weightof evidence determination, as they would be unlikely tofulfill the conditions for estimating a slope factor andtherefore, the associated RPF.Either clarify that these positive studies werenot used quantitatively, or re-estimate theRPFs without them as one method foruncertainty analysis.S, MPage 10 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*20 5.1Pg. 107Line 5Although use of number, i.e., multiplicity, of tumors is“discussed in Section 4.3,” neither there nor hereis therationale for the use of these data (other than that theyexist) explained or referenced. Indeed, the secondparagraph (line 15) states that, in many cases,incidence and multiplicity were either not correlated orinversely correlated. Justification for the use ofthesedata should be supplied.Use of multiplicity or tumors for a quantitativeanalysis of potency is a non-standardprocedure. As stated in this document, studieshave generally shown multiplicity to be anunreliable estimate of potency. These datashould not be used.S, M21 8.5Pg. 2092ndparagraphChemicals with a similar mode of action should becombined by dose additive methods according toEPA’s mixtures guidelines and guidance. Use ofresponse additivity for chemicals with similar modes ofaction seems contrary to the assumption in that modelthat the chemicals act independently.The use of response addition for chemicalswith a similar mode of action requires moreexplanation, especially with regard to EPA’sguidelines and guidance on this subject. Asthe document assumes a linear, no-thresholdmodel, the results are identical quantitatively.Nevertheless, the appropriate assumptions andmodels should be identified and justified.S22 8.5Pg. 209LastparagraphNo data will ever completely support the assumptionofadditivity, as it is a useful model that is sufficientlyaccurate for some purposes under some sets ofconditions.This paragraph should be rewritten to reflectthe reality of models rather than posit anunrealistic ideal that may raise expectationsthat can not be met.S23 Appendix DGeneralIt appears that most of these runs were performed in2005. The software has been modified since then.Would this make a difference in the result, especiallywith regard to whether the lower confidence limit isactually a two-sided, 95% confidence limit?If the changes in the software might changethe results, the data should be run again.S, MPage 11 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*24 Appendix EPg. E-2Relative potency usually is defined as the ratio ofthedoses required to produce the same effect. Given thatthe analyses were such that a dose to produce anequivalent effect, e.g., a BMR of 0.1, was alwaysestimated, the ratio of those doses can and shouldbeused without further calculation.Unnecessary conversions obfuscate the dataand in this case, the results should be thesame.S25 Appendix EPg. E-2Hoffmann and Wynder and other such studies in thetable should not be used. EPA’s cancer guidelinesallow the combination of cancers with papillomas, butpapillomas alone are not considered a positiveresponse for cancer.Recommend deleting these data from theanalysis. Given the wealth of data, there is noreason to use marginal data, e.g., Rice et al.on page E-3 where the type(s) of tumors were“unspecified”.S, M26 Appendix EPg. E-2LaVoie et al.: The same method should be used tocalculate the doses for all of the chemicals in oneanalysis. In this case, three of the chemicals used apoint estimate, and presumably the BMR for the fourth(which required dropping the highest dose to get thismethod to work) was also not a very good fit.Changing the method by which the doses areestimated within one study is likely to add unnecessaryuncertainty.Also, the use of a linear extrapolation at low doselevels is violated in some of the estimates made inthisdocument. These data appear to have beenextrapolated from a greater than80% response level,a response level below which a “low level linear” doseresponse function can not be expected.We suggest changing the calculation for BjF.The RPF needs to be estimated at a lowerresponse level. Using a straight lineextrapolation to the origin can only be justifiedfrom low BMRs, e.g., 10% or less. Thus, thecancer slope factor, i.e., the potency, will beincorrectly estimated, as will the relativepotency.S, MPage 12 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*27 Appendix EPg. E-5As stated previously, multiplicity of tumors isnotastandard method for quantifying cancer potency. Evenif this were a standard method, the process fordetecting the number of tumors would need to bevetted. Even for skin tumors, small tumors may bemissed, or tumors that have grown together may beincorrectly counted. Again, as most of these tumorsare only papillomas or unspecified, these data shouldnot be used anyway. Moreover, it appears that someof the data, e.g., Cavalieri et al.,1983, appear tobeused for both methods, thus double-counting andoverweighting these data.It is recommended that Table E-2 beeliminated, and the data not used forcalculating RPFs.S, M28 Appendix FPg. “G-1”The page number incorrect. The page number should be changed to F-1 E29 Appendix GPg. G-1Line 28By requiring that the experiments be performed at thesame time in the same laboratory, EPA is excludingthe highest quality data, i.e., the whole animal cancerbioassays. Moreover, a logical extension of thisapproach would be to state that it is not appropriate tocompare the cancer potencies estimated from any ofthe NTP or other sets of bioassays as most of themwere not conducted concurrently (as discussed inComment #1).This criterion for exclusion of data should bechanged, at a minimum for the cancerbioassays. As suggested before, the RPFmethod should only be used as a substitute forchemical-specific potencies. When relevant,chemical-specific data are available, they arepreferable to a model that, while useful, hasmore uncertainties and assumptions inherentin its use.S, MPage 13 of 14Department of Defense Comments on theDevelopment of a Relative Potency Factor (RPF) Approach for Polycyclic Aromatic Hydrocarbon (PAH) MixturesComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 28 October 2009*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*30 Appendix GPg. G-3Line 3Data from newborn animals should not be used inestimating RPFs, as EPA’s 2005 supplementalguidance demonstrates that newborns react to thesechemicals differently than the adults. These datamight be able to be used to estimate different cancerpotency for exposures to younger animals, as statedinEPA’s 2005 cancer guidelines and supplementalguidance.It is recommended that such data beeliminated from the RPF calculations, or if noother data are available, the resulting RPFsshould have an accompanying indicator.S, M31 Appendix GPg. G-6Line 18 andtext followingThis statement is puzzling, given that a quick PubMedsearch turned up the following citation for heterocyclicamines (HAs): Bogen KT 1994. Food Chem Toxicol.32(6):505-15. The abstract states, “Thus, in addition to82 tumor-type-specific potencies estimated for thesecompounds, 24 additional estimates of aggregatepotency (to induce one or more tumor types) weremade, using different methods to scale estimatedbioassay cancer potency to humans. The currentlyunknown potency of an additional cooked-food HAwas estimated using linear regressions of logcarcinogenic on log-mutagenic potency for the other10 HAs, some of which were highly significant (e.g.r =0.85, P < 0.004).” Also missing are citations fromseveral studies that found no or limited correlationsbetween cancer potency and mutagenic potency,including one by the National Academies.A more complete data search might be useful.Negative studies should also be cited.S32 G-2Pg. G-6This section could have been significantly reducedby consulting a special issue of Mutation Research(March 1992) that addressed it.E