# The Department of Defense is pleased to forward review comments

(attached) developed to support EPA’s Response to t he National

Research Council recommendations document “Health R isks from Dioxin

and Related Compounds Evaluation of the EPA Reasses sment." In

accordance with your guidance the EPA documents wer e distributed and

reviewed as a CLOSE HOLD task. The Department coor dinated its science

review with Service science representatives and oth er DoD experts.

The comments have been conveniently provided i n a standard format

matrix to assist the reader in cross referencing of the draft

documents. The comments generally fall into catego ries denoted as

Global, Major (M), and Science or methods (S). The review team agreed

that the comments marked as Major (M), when taken i n their totality,

bring to bear serious concerns of the outcome for t he assessment

overall. A sense of the Major issues found during the review follow:

- EPA exclusion of relevant data from a key s tudy to estimate

cancer risks.

- There exist a range of inconsistencies carr ied through the EPA

response that when taken collectively may call into question the

outcome of the assessment altogether (e.g., care to respond to NAS

consideration to treat dioxin as a threshold carcin ogen).

- There are areas of the EPA analysis that de viate from accepted

standard risk assessment practices as previously ou tlined in EPA

guidance and policy (e.g., use of non-standard lang uage leading to

redefinition of critical terms formulated in EPA ca ncer guidelines,

and use of assumptions about population risk to jus tify assumptions

about individual risk when developing cancer slope factors).

- Given EPA’s novel approaches used to develop cancer slope

factors for dioxin we look forward to further guida nce on how to use

these values to estimate probabilities of cancer in cidence from

exposure to dioxin; (e.g., specifically the slope f actors were based

upon cancer mortality instead of incidence; several different slope

factors associated with varying risk levels were de veloped for dioxin.

- Comprehensively, and in development of toxi city values for

assessing risk of dioxin we noted that the carcinog enic properties of

dioxin were not assessed using a reference dose met hod. Acknowledging

that this is EPA’s policy determination; the wealth of data presented

in response to the NRC review justifies harmonizati on of cancer and

non-cancer effects to develop a reference dose, and it is our opinion

# that it is not necessary to default to slope factor s for dioxin cancer

risk.

If there are any questions or if an EPA office is interested in

discussing any of these points please feel free to contact me directly.

The granting of the two-week extension was greatly appreciated and I

look forward to advancing your office expert commen ts to support the

Charge Questions as soon as possible.

Respectfully,

Robert (Bob) Boyd

Research Directorate (BioSystems)

Office of the Director, Defense Research & Engineer ingPage 1 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*1 Global,5-51, TextBox 5-1.Before addressing specific issues in EPA’sresponse, we would like to point out somereoccurring issues and inconsistencies noted inourreview. All of the implications of these findingsfor the qualitative and quantitative analyses andconclusions could not be determined during thetime allotted for this review. The major points arebriefly outlined in the following global comments.As but one example (explained in detail below),EPA’s “proof” in Text Box 5-1 is a logicaltautology, i.e., its assumptions include the premiseit intends to prove.The document to needs to be edited to thecritical analysis and responses so that itsauthors and editors can ensure logicalconsistency in at least the main text of thedocument. We recommend that severallogical inconsistencies, including a tautology,as well as the inconsistent use of definitionsthat deviate from EPA agency guidance becorrected. Before EPA releases this documentto the public,we strongly recommend that itcorrect these errors and the analyses thatdepend upon them.As dioxin risk is also thebasis for risks for a number of dioxin-likechemicals, it is especially critical that alldocuments related to the toxicity of dioxin beaccurate.S/M2 GlobalAlthough EPA says it accepts low-dosenonlinearity, it does not follow the procedurefor risk assessment that is presented in itscancer guidelines.For cancer, a publishedanalyses that demonstrates a dose-dependentmetabolism that results in nonlinearities at lowdoses appears to be supported. This conclusion isfurther confirmed by the calculation of exposuresassociated with specific risks, an unnecessary stepif the low-dose curve is linear as defined by EPA’scancer guidelines, i.e., risk is proportional toexposure. The approach for the dioxin cancerassessment does not use the approach in the EPA2005 cancer guidelines for chemicals for whichUnless compelling reasons are presented, werecommend that the cancer guidelines befollowed and the reference dose (RfD) methodbe used for establishing the cancer risks fordioxin. For dioxin, appropriatelyimplementing the conclusion that low-dosecancer risks are nonlinear has an additionaladvantage of harmonizing the U.S. assessmentwith those of other countries, e.g., Canada andthe European Union (EU). Estimating an RfDfrom the point of departure (POD) is expectedto change the estimated risks for dioxin anddioxin-like chemicals.S/MDeleted:Deleted:XXXXPage 2 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*there is evidence of low-dose nonlinearity, i.e., tocalculate an RfD.3 GlobalThe data set for TCDD is robust, and appearsto be a prime opportunity to harmonize thecancer and non-cancer risk assessment, yet thiswas not done. Since it is postulated that bothcancer and non-cancer endpoints are mediatedthrough Ahr interactions, this seems a reasonableapproach.Discussion relative to why cancer and noncancer benchmarks are not harmonized shouldbe included.S/M4 GlobalMultiple “oral slope factors” are presented thatwithout implementing guidance are not usefulfor many programs that utilize IRIS toxicityvalues.Because of the nonlinearities, thedocument presents separate “oral slope factors” fora series of cancer risk levels, though such slopefactors only have a logical meaning for linearextrapolations.This seems to be a new methodfor estimating risks, i.e., risk-specific, multiple,“oral slope factors”. We are not aware of any EPAdocument or review process that has evaluated thisnovel and major change in EPA’s riskassessment procedures.The presentation of risk-specific multiple slopefactors needs to be highly reconsidered. Weview this as a new risk assessment procedureand policy which should not be utilized on anad hocbasis without the appropriateprocedures for public comment and externalpeer review.If the multiple slope factors are retainedguidance for their use should be included in thedocument.S/M5 GlobalIt appears that the most relevant human datafor cancer risk assessment from its key studywere discarded.The document states that, forcancer risks, the epidemiological data are the keystudies, and selects one study for quantitativeanalysis. It also acknowledges that thepharmacokinetics (PK) and pharmacodynamics(PD) differ between chronic exposures withWe recommend that the dose-response curvefor cancer risks be based on those doses forwhich the cancers were found and be revisedaccordingly.We see these changes as necessary becausein our view it is not logical to state that thehigh and low doses have biologically distinctS/MDeleted:Deleted:XXXXPage 3 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*limited variation and high-level exposures due toaccidents. Nevertheless, the data from higherdoses were not used because they are notconsistent with the dose-response functions for thedata at the lower exposures – a natural andexpected consequence of the PK and PDdifferences at low and high doses that thedocument presents. This decision, however,eliminates the exposures where most of the cancerswere found, i.e., the data that should comprise thebasis for the dose-response function for cancer inhumans.EPA’s Science Advisory Board (SAB)cited these issues in its comments regardingEPA using this same procedure when EPAdiscarded the higher dose of the epidemiologicaldata in EPA’s draft assessment of ethyleneoxide.Furthermore, discarding the data from the higherexposure levels is not the same for epidemiologicalstudies as for animal bioassays. The usualprocedure for animal data, as practiced by EPA,rests on the assumption that the dose-responsefunction is the same at high and low doses – that isclearly not the case for this chemical. EPA hasalready presented data that demonstrates that thesame dose-response function would not beexpected to occur for dioxin. As such, the doseresponse function should be fit to those data wherethe cancers were found, i.e., the higher doses.processes and then to attempt to make thehigh and low doses conform to the samedose-response function.. By discardingmuch of the data, the power and quality of thestudy is also changed, this in turn,de factochanges the basis on which these data wereinitially selected by EPA as appropriate forestimating risks.Deleted:Deleted:XXXXPage 4 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*Finally, elimination of higher data points is not anunbiased decision, as a previously publishedanalysis (Crump et al., 2003 that is reviewed inthis EPA document) states that the slope of thedose-response function increased as each of thehighest dose groups were successively omitted.Crump et al. also state that the power of the studyis significantly reduced by omitting some of thehighest exposures. Thus, omitting some of thehigher exposures was already known to increasethe estimated risk while also increasing theuncertainty of the analysis by decreasing the powerof the studies observations.6 GlobalThe document redefines “linear” and“nonlinear” in a manner that is inconsistentwith EPA’s 2005 cancer guidelines, as well asinconsistent within the document.Theredefinitions are clear when they are presented(which is near the end of the document), but thesenew and non-standard definitions are not betransparent in the rest of the document, especiallywhen this document frequently refers to riskassessment methods in EPA’s cancer guidelinesthat have a much simpler and a different definitionof linear and nonlinear. The text presented onpage 5-49 does not well justify the departure fromthe cancer guidelines, and as the guidelines havebeen approved as all-agency guidelines, theyWe do not believe that fundamental riskassessment terminology should be redefinedin a chemical-specific document.Werecommend that terminology from the cancerguidelines be utilized consistently in thedocument.If the current redefined terms are retained inthe document their use needs to be betterjustified, used consistently in the document anddefinitions introduced early in the text.S/MDeleted:Deleted:XXXXPage 5 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*should not be ignored without a compelling reason.The assertion that “Linear above ThresholdModel” is linear directly conflicts with EPA’scancer guidelines,and violates their intent.. Thecancer guidelines are very explicit, as stated in thisdocument’s footnote on page 5-49, for thepurposes of the cancer guidelines, and hence forthe purposes of low-dose extrapolation,allthreshold models are nonlinear.Moreover, theterm “linear” is not used consistently in thisdocument.Several examples occur in section5.2.3.4.1.2., some of which are discussed in moredetail in the comments below. Furthermore, asthese definitions are presented at the end of thedocument, the reader can not be expected tounderstand the novel use of these common terms inthe prior sections. Therefore, as presented, we donot believe that the definitions are consistent withany of EPA’s previous definitions of these terms.Our interpretation of the cancer guidelines is :Any dose-response function for which low dosesare a straight line through the origin, i.e., nothreshold, are linear.All other dose-responsefunctions, specifically all functions with athreshold, are nonlinear.Consistent definitionsof critical terms is one purpose for developingguidelines and guidance. Frequently redefiningterms leads to confusion to the reader, as it isdifficult to determine which definitions are beingDeleted:Deleted:XXXXPage 6 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*used in a document, discussion, etc.7 GlobalAn inappropriate dataset was chosen for thechronic RfD.For noncancer risks, the documentconcludes that the human data are the mostrelevant. However, the studies selected do notmeet EPA’s criterion (page lvi) “for noncancer,information is required regarding the appropriatetime window of exposure that is relevant for aspecific, nonfatal health endpoint...” For achemical such as dioxin, where the documentstates that body burden or area under the curve(AUC) is the appropriate dose metric, there mustbe more than an acute exposure (as in theexposures for these studies) to attain the bodyburden. This has been the prior practice of EPA inestimating risks, e.g., that reproductive risks forthese chemicals are not based on the exposure on aparticular day, but rather are based on the averagedexposure that would lead to an estimated bodyburden. Furthermore, the analysis acknowledgesthat the biological and physiological parametersthat are associated with toxicity at acute and highlevels of exposure differ significantly from those atchronic levels of exposure. Thus, the Sevesostudies demonstrate the dangers of exposures thatmay occur during accidents; clearly, these levels ofexposure to dioxin should be avoided.However,Recommend that EPA retain the estimate basedon the acute exposures,and should label thisan RfD for acute exposures. EPA should usethe wealth of data it has presented to estimate achronic exposure RfD. Toxicologists and riskassessors – and EPA in the past, e.g., for waterquality – have made such distinctions.S/MDeleted:Deleted:XXXXPage 7 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*other epidemiological data, which aresupported by substantial data from laboratorystudies, just as clearly demonstrate that chronicexposure to lower levels of dioxin are moretolerated by mammals than effects from highlevel exposures due to accidents.8 GlobalWe disagree with the characterization forTCDD as “carcinogenic to humans” for alldoses; and believe that two classificationsshould be presented.The data as presented in thedocument strongly suggest that dioxin iscarcinogenic only at very high doses. As EPA’scurrent cancer guidelines allow for differentdescriptors for different exposures, we believe thatthis is a case where that option should beimplemented. Thus, we believe that dioxin shouldbe classified as “likely to be carcinogenic tohumans” at least for lower, chronic levels ofexposure. We also request further clarification ofthe response to the NAS’s request to “explainwhether this conclusion reflects a finding that thereis a strong association between dioxin exposureand human cancer or between dioxin exposure anda key precursor event of dioxin’s mode ofaction...,” on page 5-3. Stating that the EPA’sdecision is based on a “qualitative weight-ofevidence carcinogen classification” does notaccount for the many areas of concern, includinginconsistent tumor sites and several negativeepidemiology studies.The abundant data that demonstrate differenttoxicities at high and low exposure levels, bothacute and chronic should be utilized todifferentiate the descriptor for dioxin. Wesuggest that “carcinogenic to humans” belimited to very high exposures and that lowerexposures be classified as “likely to becarcinogenic to humans”.S/MDeleted:Deleted:XXXXPage 8 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*9 GlobalMuch discussion is devoted to the hazardousinteractions between TCDD and the Ahr; however,some of these interactions produce beneficialeffects (e.g. induction of CYP1A1 and MFOs).It would be useful to provide a briefbackground on the beneficial biologicalpurpose of the Ahr, and why it is conserved inmammals.E10Figure ES-2Figure 2-3Lvii2-234Although we agree with their inclusion, this figureis inconsistent with the inclusion of NTP studies,since they were not published in the peer-reviewedliterature. As such, inclusion of NTP studiesappears biased.Recommend changing the text in the firstdiamond to reflect study quality or endpointrelevance instead of a strict peer reviewcriterion.E11 3.3.1 3-5, line 11;3-56, Table3-3.The statement that, “TCDD is very slowlymetabolizedcompared to many other organiccompounds, with an elimination half life inhumans on the order of years following an initialperiod of distribution in the body” [bold text isoriginal] is outdated and inconsistent with the restof EPA’s document and models.As stated several times in the document, and aspublished data from EPA’s laboratories (Emond2005) states, for higher levels of exposure, i.e., thetypes of exposures on which the RfD is based, “thehalf-life is only weeks.” This is particularlyimportant as, in the footnote of Table 3-3, EPArepeats the assertion that the half-life in humans isgreater than 7 years for the doses used in theanimal bioassays, e.g., very high levels.By usinggreater than 7 years instead of weeks toestimate the human equivalent dose fromanimal bioassays, EPA will greatlyunderestimate theoriginal exposure andThe statement should be corrected to beconsistent with the data and other statements inthe document where EPA states that at low andchronic levels of exposure, the half-life is long,but at high and acute levels of exposure, thehalf-life is comparable to many chemicals andin the range of weeks.It appears that EPA has updated its conclusionsbased on more recent data, but has either notupdated its calculations or has not updated itstext. In either case, it is not clear which hasoccurred when such inconsistencies exist in themain text.Any calculations that are basedon this inaccurate statement should be reestimated before the document is releasedfor review.S/MDeleted:Deleted:XXXXPage 9 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*therefore greatly overestimate the potency ofthis chemical.Through the relative potency method (TEF), thetoxicity of a large number of chemicals isestimated in dioxin-equivalent doses. Thus, thisinaccurate estimation will have a larger effect onrisk assessments than for most chemicals.12 3-33Eq. 3-20Also5-51 line 50This is one of many discussions in the documentwhere the definition of linear from the cancerguidelines is not used, nor are the definitionspresented in section 5 used. As this sectiondescribes, a critical aspect of the Emond et al.PBPK model that was used is the induction of theenzyme CYP1A2. Production of this enzyme is “inthe form of a Hill-type function”. Inspection of theequation shows that the response is not linearlyproportional to dose. The various forms of the Hillequationare inherently nonlinearby allmathematical definitions of the term “linear” as, inits most reduced form, the independent variable(usually a form of dose or concentration) is presentmore than once with the same exponent.We recommend that he low-doseextrapolation be performed by the RfDprocedure, as stated in EPA’s 2005 cancerguidelines for nonlinear, low-dose functions.The dependence of the model on the Hillequation reinforces the conclusion of EPA andothers that the dose-response function isnonlinear.S/M13. 3-43 The PBPK model that was developed by EPAscientists was tested with data, both to optimize theparameters and (with different data) to test thepredictions. The “minor modifications” made byEPA for the purposes of the dioxin reassessmentdo not appear to have undergone any validationagainst actual data.Although this documentasserts that the changes have a small effect onIf the adjusted models have not been testedwith data and have not undergone sensitivityanalyses (neither is presented in thisdocument), the modified model should not beused.If, as asserted, the modifications makelittle difference in the results, changing themodel for no quantitative result can onlyincrease the uncertainty and lower theS/MDeleted:Deleted:XXXXPage 10 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*the results, this can not be accurate for allconditions, as even the original model has somelimitations as described in the sensitivityanalyses presented in the published papers.Indeed, this document uses the analyses in thepaper for the unmodified PBPK model for itsuncertainty analysis, rather than providinginformation on its modified model.confidence in the model.The data should bereanalyzed using the model as published and asvalidated. Alternatively, EPA may choose torepeat the validation studies of the originalmodel with its modifications to ensure that thestatements, e.g., about sensitivity on page 3-49are still accurate.14 4.2.4.2 4-15 Based upon the text, it appears modelfit wasdetermined through professional judgment ratherthan through statistical analyses. Regardless,specific criteria used for judging nominal fit arelacking.Recommend that clearer language regardingthe specific criteria used in judging nominal fitof dose response curves be provided.E15 Figure 4-4 4-51 The legend is sparse and the graphis difficult tointerpret. Magnitude of human variability reflectsstatic uncertainty value, and is not any reflection ofthe data. It is inconsistent to develop RfDs foreach study.Recommend either graphing endpoint-specificLOAEL and NOAEL values relative toBMD/BMDLs or the graph has little value.E16 5.1.2.1.1. 5-6,TemporalityTemporal responses between exposure and effectdo not infer causation. They are circumstantialand required at best. Neither is prolonged latencya requirement.Please note that exposure must precede effect,and that effect may manifest followingprolonged latency following exposure, but isnot necessarily a requirement.S17 5.1.2.2. 5-9SpecificityIt is stated that absence of specificity does notdetract from causal evidence, yet none is provided.In fact, it is stated throughout that the mechanismis poorly understood. Moreover, if tumorformation is tissue specific, and all cohorts areexposed in the same manner, it is not clear whatelse could explain the relatively weak increases inThe paragraph needs to be edited.Recommendseparating “mechanism” from “mode ofaction” (i.e. “mechanism of action”, see also p.5-14). The contradictions in the text need to beresolved. Acknowledge the insufficient humanepidemiological data and variability in animalresponse. Stronger causal data may be foundSDeleted:Deleted:XXXXPage 11 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*overall cancer incidences. Interesting relationshipsand hypotheses are presented, but more is neededfor any statements regarding causality.in the controlled animal data.18 5.1.2.3.4 5-18 It is stated that other studies havenot ruled outinvolvement of the Ahr in the mediation of adverseeffects, yet sections of the text cite studies inwhich Ahr negative knockout mice have shown toproduce adverse effects at high exposures(Fernandez-Salguero et al. 1996). Moreover, sinceit is recognized that the mechanism forcarcinogenicity is unknown, it cannot be stated thatAhR interactions are a necessary early event (seealso comment 2).Please modify the text accordingly. E19 5.2.2 5-22, line 18 The choice of the percent response, i.e., thebenchmark response or BMR, for the POD forextrapolation is not justified here, except to statethat, in the 2003 modeling, the choice made nodifference. According to EPA’s cancer guidelines,the POD should be “near the lower end of theobserved range, without significant extrapolationto lower doses.”We recommend tha the document justify theselection of an ED01based on the data in thestudy, not the properties of the dose-responsefunction that were selected.S20 5.2.3.2.6.8. 5-23 Bias in the blood-based measurecould occurthrough additional and unplanned exposures (e.g.through TCDD contaminated feed, as recognizedin the text).We recommend some recognition that thekinetics could be influenced from otheradditional TCDD exposures, particularly fromdata reported from early studies.E21 5.2.3.2.6.11 5-44 If it is postulated that TCDD acts as promoter (e.g.phorbal esters), the logic is unclear why the loglinear extrapolation is used.Please provide evidence that the dose responsecurve is not known at lower exposures. If so,the extrapolation to a BMDL01is probablyunsupported because of great variability at theSDeleted:Deleted:XXXXPage 12 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*tails. If data are available, then considermodifying the slope accordingly.22 5.2.3.3. 5-45 The BMDL provides the 95% confidence intervalsof the dose response data. As such, theyparameterize the variation of the model and do notrepresent “uncertainty”. Uncertainty, bydefinition, is what is not known.Recommend tephrasing to “variability”. E23 5.2.3.4.1.2.Low-doseextrapolation:threshold orno threshold?5-48 This section appears to be an attempt to redefine“linear” and “nonlinear” for EPA’s 2005 cancerguidelines. While the guidelines admit that thedefinition used is a “narrower sense than its usualmeaning in the field of mathematical modeling”,redefining the terms can only lead to confusion. Inparticular, including “Linear above ThresholdModel” as linear (page 5-50) is in direct conflictwith EPA’s cancer guidelines and violates theirintent. The cancer guidelines are very explicit. Asstated in this document’s footnote on page 5-49,for the purposes of the cancer guidelines, andhence for the purposes of low-dose extrapolation,all threshold models are nonlinear.Basic terminology from agency guidelinesshould not be redefined in a chemicalspecific document.Per the EPA cancerguidelines: Any dose-response function with athreshold is nonlinear for the purposes ofestimating low-dose cancer risks.S/M24 5.2.3.4.1.2. 5-50 The definitions presented hereof types of modelsare not useful as some dose-response functionswould fit more than one definition. The“threshold” model is part of three other models.As it is not clear if “linear above a threshold” isconsidered “linear”, the definition of “nonlinear” isalso not clear. If we assume that EPA intends theThe non-standard definitions presented in thissection do not consider the considerable effectthe presence of a threshold has on both riskassessment and risk perception and we believeshould not be used.One of the two mutually exclusive groups usedto divide carcinogens from EPA’s 2005S/MDeleted:Deleted:XXXXPage 13 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*“linear above a threshold” to be considered“linear”, then all of the definitions include the“zero at zero” model, as described in the paragraphafter the definitions.As not all dose-response functions are “zero atzero”, however, these definitions are confusing, asno one definition describes a coherent set ofmodels.By (1) redefining “linear” to include “linear abovea threshold” and (2) proposing that allclassifications of models include thresholds, thedocument proposed definitions that have no usefulfunction under current guidance. Prior to the 2005cancer risk guidelines, EPA assumed allcarcinogens had no threshold. EPA’s 2005guidelines divide carcinogens into twomathematically, mutually exclusive groups,“linear” and “nonlinear”, and present differentmethods for the risk assessment of each group. ByEPA’s standard definitions, all “linear” functionsmust not have a threshold, and all thresholdfunctions must be “nonlinear”. Some functionsthat do not have a threshold are also nonlinear.guidelines, “linear” or “nonlinear” should beused.25 5.2.3.4.1.2. 5-50 Traditionally, individual risks have been used inrisk assessment. Using population risks to imposeconditions on individual risks is not consistentwith current practice.According to EPA’s cancer guidelines, decisionsUnlike other IRIS documents, this documentconsiders population risks in addition to thestandard individual risks. We believe thatEPA should clearly state if it is intendingthis discussion to mark a change in policy.The document should also explain why or howS/MDeleted:Deleted:XXXXPage 14 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*regarding low-dose extrapolation proceduresdepend (in this case) on the existence of athreshold for the individual risk, not populationrisk.the lack of a population threshold would affectexistence of an individual threshold.Furthermore, the conclusions should not bebased on the limited number of examples thatconform to the thesis presented.26 5.2.3.4.1.2. 5-51, TextBox 5-1.The analysis in the text box doe no appear to becorrect. It is a logical tautology.The text states as its premise that each individualin the population has a threshold and that thisanalysis is to examine the resulting populationthreshold. However, by setting the limits ofintegration for the thresholds, T, from 0 toδ, EPAhas defined some members of the population tohave no threshold, i.e., T = 0 is the lower limit ofintegration.By assuming that some individualsin the population may not have a threshold forthis response, the population risk has beendefined to have no threshold.Thus, the rest ofthe “proof” is unnecessary.Furthermore, it assumed that the thresholds are“uniformly distributed”. A uniform distribution ishighly unlikely, as it assumes that the proportionof people with a given value for a threshold arealways the same, i.e., the number of people with athreshold at the 99thpercentile would be the sameas the number of people with a threshold at the 59thpercentile.By assuming a uniform distribution,it has been ensured that the probability ofIf the section on population risks is retained, itshould be edited to increase its validity.If part B of the text box is retained, a citation itshould provided for the fundamentalassumption that the response would belogarithmically proportional to dose near athreshold. Alternatively, EPA could clearlystate that, if this condition were true, then theanalysis might have utility, but that many doseresponse functions are not expected to havethis property.SDeleted:Deleted:XXXXPage 15 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*individuals in the population having a nothreshold is as likely as any other value for anindividual’s threshold.The assumption of a uniform distribution for T,along with the other assumptions in the example,ensures a biased estimate of the populationthreshold, unless the true threshold is less than orequal to the value of (δ−T). Assuming thatδissmall relative to T and that (as stated)δ> T,integrating between the limits of 0 andδwill resultin most of the probability mass for the distributionon T to be much less than T.For part A, assumes that the response isproportional to (δ−T). This is only accurate forthe case defined as “linear above a threshold”. If,for example, the response were proportional to(dose)2, then the integral would be of (δ−T)2, witha different outcome. Under these conditions, it isnot clear that the slope will be zero for thepopulation threshold.Part B appears tobe unnecessary. There is noapriorireason to believe that the response islogarithmically proportional to dose near thethreshold – or any other part of the dose-responsecurve. We assume that this function was usedbecause it is one of the few, in addition to thelinear above a threshold, for which the desiredproperty is true.Deleted:Deleted:XXXXPage 16 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*27 5.2.3.4.1.2. 5-51, line 51 The Hill equation is not linear at low doses. Thetangent to the Hill equation is used to estimate oneof the parameters. The equation is not a straightline for any value, although the linearapproximations for parts of the curve are useful forestimating some toxic parameters.The statements should be corrected to bemathematically accurate.S28 5.2.3.4.1.2. 5-51, line 52 The Michaelis-Mentenequation is not the linearform of the Hill equation. It is the form where theHill exponent is equal to 1.Statement needs to be corrected. S29 5.2.3.4.1.2. 5-51, line 53 The statement, “Linearity ... is a fundamentalconserved characteristic in living systems”requires a reference, we question its accuracy. Asnoted in many publications including EPA’sphysiologically based pharmacokinetic (PBPK)analysis presented in this document as well asEPA’s analysis of using (body weight)3/4, mostliving systems rely on an allometric scaling that isnot linear, even by the definitions presented herein.Moreover, many of the examples EPA presents inthis document assume that “living systems” arelog-linear that is not the same as linear.This assertion should be removed or provideexplanation why allometric scaling is notjustified for this chemical. The broad term“living systems” warrants better definition.S30 5.2.3.4.1.2. 5-52includingText Box 5-2.This very limited discussion of receptor binding isdependent on a very narrow set of conditions, notall of which would be expected for many of thewell studied receptors. The discussion, includingthat in the text box, assumes a Hill exponent of 1,i.e., the Michaelis-Menten equation. Many wellknown examples, e.g., hemoglobin, have receptorsfor which the Hill exponent is greater than one (inthat case, 4) and yet the basis for receptor bindingIn this discussion of receptor binding, equallyvalid alternative examples should be included.Such examples are readily available, but can beprovided upon request.SDeleted:Deleted:XXXXPage 17 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*analysis is still the law of mass balance. Volumes,e.g.,Methods in Enzymology, Volume 249, 1995,have been written on the possible variations thathave different properties than those assumed forthese examples.31 5.3 5-66.5-93, Table5-19.As stated, all of the epidemiology studies are basedon cause of death, and therefore, are related tocancermortality. EPA’s risk estimate procedures,are based on cancerincidence. Cancer incidence isalso the basis for several regulatory programs.Itappears, however, that EPA has neitheradjusted for the difference between cancerincidence and cancer mortality nor has itappended a qualifying note to its oral slopefactors.We expect that people will use the cancerpotency factors assuming that they are estimatingcancer incidence when they are estimating cancerdeaths. Note that, when data for both mortalityand incidence were available (Table 5-19., Becheret al.) “steeper dose-response [were] seen forcancer mortality”. Steeper dose-responsefunctions would result in higher cancer potencies.Ideally a slope factor useful for estimating theprobability of cancer incidence would bepresented in the document, as several Federaland State programs regulate carcinogens onthis basis, not mortality. The use of mortalitydata without adjustment should be justified,especially as the information it presentsindicates that mortality data may yield higherrisk estimates than the incidence data, at leastfor this chemical. EPA should ensure that itsoral slope factors clearly indicate that the riskestimates are for cancer mortality not cancerincidence. This is particularly important forsummary tables, e.g., Text Box ES-1 andEPA’s IRIS database.S/M32 Appendix B From our review of Appendix B, we believe thatthe criteria used to include or exclude studiesfrom the dose-response assessment may not beconsistently applied.Study selection andconclusions appeared to be based heavily onresults that showed positive associations. Forexample, in Table B-5 the Collins et al., 2009, isthe most recent study with study size and followAll studies should be evaluated on an equalbasis. All epidemiological studies havelimitations, and vague criteria should not beused to selectively include or exclude data.For example, if EPA believes that there shouldbe sufficient time between exposure andobservations for cancer to develop, it shoulddefine a time for this latent period. Ideally, theSDeleted:Deleted:XXXXPage 18 of 18Department of Defense Comments on theDraftEPA’s Response to “Health Risks from Dioxin and Related Compounds Evaluation of the EPAReassessment” Published by the National Research Council of the National Academies,January 2010Comments submitted by:Robert BoydOrganization: Department of DefenseDate Submitted: 03.26.2010*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(“Global” ifsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*up large enough to yield precise estimates of riskand ensure adequate statistical power. Individualserum samples with TCDD analyses available for280 former workers. Although the studydemonstrates an exposure-response relationshipwith TCDD, “The study found no associationbetween TDCC and death from most types ofcancer.” Nevertheless, this study was excludeddue to insufficient follow-up of cohort with noevaluation of possible latent effects.latent period should be chemical-specific. Fordioxin, where chemical accidents have,according to the document, led to someincrease in cancers, the period of time for thoseto become statistically above backgroundshould be sufficient for all studies. Similarly,as all of the worker cohorts had concurrentexposures to other chemicals, what were thequantitative criteria for inclusion or exclusion?If such information is not provided, thequalitative determination appears toosubjective.As has been suggested before and by others,EPA should consider using some of the metaanalytic techniques to combine results acrossstudies.Given the extensive resources EPAhas used to analyze virtually all of thereasonable data (animal and human), itwould seem appropriate to combine theresults to determine if the data areconsistent and, if they are, to reduce theuncertainty in the risk estimate.Deleted:Deleted:XXXX