Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*1GlobalThe draft toxicological review seems lengthy andcomplicated. Attempting to discern those data thathave been extracted for use in estimating EPA’snon-cancer and cancer toxicity values is difficult.The text, tables, and figures are neither clear nortransparent; some contain inaccuracies. Thedocument appears to contain logical inconsistenciesin different sections of the main text and appendicesthat seem to be disparate views among the authors.For this reason, some of the comments have beenpresented in an order other than that of their pagenumber.The document should contain a table or shortsummary of the major decisions and data usedquantitatively for deriving the cancer and noncancer risk values without reading all of thetext and appendices.E2GlobalThe document reads like an advocacy submission,rather than an unbiased review of the literature.Views and scientific opinions held by the majority ofthe experts and reports are dismissed without aclear presentation of their data and arguments,including misrepresentations of their statements anddata.Minority opinions and analyses should bepresented and appropriately defended – but soshould majority opinions. If both are presentedin an unbiased manner, regulatory decisionmakers and the public can determine the rangeof potential risks.S3GlobalThe bioassay data used for the oral cancer potencyfactor are from a batch of studies that expert panelshave determined are likely to be caused by infectionrather than exposure to the chemicals on test.Based on this finding, both the Food and DrugAdministration and the European Union (reaffirmedin 2009) have determined that the leukemias are notrelevant for human risk assessment. Furthermore,this analysis uses nonconventional techniques anda physiologically based pharmacokinetic (PBPK)model that has not been peer reviewed to calculateIf nonconventional risk assessment proceduresare used, the results of the standard EPAanalysis should also be presented. If peerreviewed models are modified, the results ofthe unmodified model should be presented.S/MPage 1 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*toxicity values.44.6.5.24-82, 3The European Foundation of Oncology andEnvironmental Sciences (ERF) studies have beenhighly controversial, for many reasons, not all ofwhich are sufficiently explained in this analysis.Some of them are discussed in the next fewcomments. For example, as this document states, 8of the chemicals tested have had high backgroundrates of lymphomas, and these occurred at thesame time period. The controversy about thecausal factor for the lymphomas is particularly anissue for the chemicals that were tested atapproximately the same time as the aspartamebioassay, which includes methanol.The analysis of high background ratespotentially due to an infection in the colonyshould be limited to those ERF studies duringthat time period.S54.6.5.24-82, 3The overall, historical rate of lymphomas in thecolony is irrelevant, if there was a temporal peakdue to a laboratory infection. Moreover, mostevaluators of bioassay data use the contemporarycontrols for the analysis. Use of historical controlsis primarily for the purposes of explaining why anassay should not be used, e.g., because thecontemporary controls are not consistent with thehistorical controls. In this case, historical averagesappear to be used to ignore the high values ofcontemporary controls.The inconsistent use of historical controlsshould be removed from the analysis.Moreover, as explained in a latter comment,the independent pathological review of thisissue – that has been accepted by U.S. FDAand the EU – should be presented as theopinion that reflects the view of the majority ofthe scientific community. If these authorscontinue to believe differently than other,independent evaluations of the primary data,then it should be clearly labeled as a minorityopinion.S64.6.5.24-83, 15This speculation about alternative causes of thehigh background is interesting, but conflicts with theprior assertions by these EPA authors that there isIt is not logical to assert in the space of threepages that (1) “only 8” of over 200 bioassayshave high background rates of lymphoma and(2) the ERF strain or study protocol producedSPage 2 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*not a high background of lymphomas.the high background rate. As the first does notaddress the issue raised by numerousacademic, Federal, and international scientists,i.e., a contemporaneous infection of the colony,it is recommended that only the latter bepresented. In that case, some data to supportthe assertion would be useful.74.6.5.24-87, 6While this document states that the conclusions ofthe European Food Safety Authority (EFSA) panelwere that,“the apparent compound-related increasein lymphomas and leukemias, may have beenincidental findings and, therefore, unrelated toaspartame.”, the conclusions of the PathologyWorking Group were much more definitive. Asreported on the National Cancer Institute’s webThe lack of a dose-response relationship,noted by the EFSA and in Table 4-27, is aclear indication that the chemical exposure isnot related to the effect.Since the regulatory toxicologists, pathologists,and risk assessors at FDA and the pathologists(mainly from NIEHS) agree, it seemscounterproductive for EPA scientists to revisitSpage(http://www.cancer.gov/cancertopics/factsheet/Risk/artificial-sweeteners)exactly the same data but without the slidesthat were available to the Pathology WorkingGroup.“Shortly before this most recent study of aspartameand cancer was published, the European FoodSafety Authority reviewed the recent animal dataand urged caution when interpreting results (TheEuropean Food Safety Authority 2006): "Theincreased incidence of lymphomas/leukemiasreported in treated rats was unrelated to aspartame,given the high background incidence of chronicinflammatory changes in the lungs and the lack of apositive dose-response relationship."Moreover, the FDA determined that the lymphomasSimilarly, since this document states that it cannot verify which metabolites of methanol areresponsible for the putative carcinogeniceffects, rehashing the Soffritti (ERF) studies ofMBTE and formaldehyde serves no purposeexcept, presumably, to “make the case” thatthe lymphomas are a result of chemicalexposures, contrary to the consensus ofnational and international expert panels. Asthese are not complete reviews of thecarcinogenicity of these chemicals, wePage 3 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*and leukemias were not relevant for humans anddid not use these findings to regulate aspartame.recommend that they be deleted.84.9.24-104Footnote 61 cites Curzan (2009) as a reference forcombining “lymphoblastic lymphomas, lymphocyticlymphomas, lympho-immunoblastic lymphomasand/or lymphoblastic leukemias as malignantlymphomas.” In contrast to this statement, theactual quotation from Curzan is as follows[emphasis added]: “The RF [Ramazzini Foundation]often combines the incidences of all cancers derivedfrom blood-forming cells for statistical evaluationand calls them “hemolymphoreticular tumors” (Table15). This is generally not considered appropriate,because different cancers are derived from differentcell types and do not share a common derivation.The cancer diagnoses included in the“hemolymphoreticular tumors” were histiocyticsarcoma, mononuclear leukemia, myeloid leukemia,lymphoblastic lymphoma, and lymphoimmunoblastic leukemia.”All references to other scientist’s conclusionsshould be re-checked for accuracy.S94.9.24-106, 9This document states that the lymphomas werechallenged,“because there is no indication that ERFused specific pathogen free (SPF) rats (Schoeb etal., 2009), and the protocol for the studiesconducted by the ERF (Soffritti et al., 2002c) isdifferent from 2-year bioassays conducted by NTPand NEDO.”Both of the stated reasons are notquite accurate. The challenge is that the mousecolony was infected, as demonstrated by the lungpathology, i.e., not at the site of exposure. The useTo be fully correct, we recommend that thestatement be edited. In particular, EPA shouldexplain why they used a study that did notfollow EPA guidelines to calculate the oralcancer potency.SPage 4 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*of a colony that was not reliably pathogen free is alikely cause of the infection. If there had not beensuch a strong indication of an infection, the lack ofspecific pathogen free rats would be of lessconcern. Also, the ERF protocols are not consistentwithEPA,OECD, orFDAguidelines, as well asNTP and NEDO guidelines.104.9.3Pgs. 4-110 –4-111EPA’s weight of the evidence is based on studiesthat have the same fundamental flaws and have notbeen repeated in other laboratories. Usingquestionable data to support a conclusion weakensEPA’s analysis.More robust and credible data should be usedto support conclusions.S114.9.3Pgs. 4-110 ­4-111The assumption of concordance between methanolmetabolites and formaldehyde concentrationcontradicts the later statements about (1) the lack ofknowledge about the relative concentrations of thevarious methanol metabolites in humans and (2) therapid metabolism of formaldehyde to formate.Moreover, if the lymphomas in both of these studieswere contaminated by the same infection (the mostwidely held opinion), then the finding of a correlationis more likely based on the infection. Basing acancer potency factor on an endpoint that has beenconsistently and repeatedly considered not to berelated to exposure to the chemicals on test, isdifficult to justify, except that it is the only data fromoral exposures that are positive.More robust and credible data should be usedto justify conclusions.S/M125.4.1.35-32, 5Although methanol metabolites gave the best fit ofthe three metrics, the conclusion in the appendix isThe text should be edited to reflect that none ofthe metrics fit the oral data well.SPage 5 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*that even this metric was not a good fit, especiallyfor the oral exposure data.135.4.1.35-32, 24As described in more detail in the comments onAppendix E, the use of a default interspeciesextrapolation factor after using a chemical-specificinterspecies PBPK adjustment is not appropriate.The points of departure for the extrapolationshould be recalculated without a doubleadjustment for allometric interspecies scaling.S/M145.4.1.35-33, 10Based on EPA’s cancer potency factor and datafrom FDA’s table on levels of methanol incarbonated beverages, a person drinking half a literof soda a day should have about a one-in-onethousand risk of cancer (Table 24. Methanol Levelsin Foods and Beverages. NTP-CERHR ExpertPanel Report On The Reproductive AndDevelopmental Toxicity Of Methanol, April 2002.)Information such as this should be includedsince it can be a useful reality check andbounding exercise. It can also inform thedecision-maker of the uncertainty inherent inthe calculations.S155.4.35-37Table 5-10EPA states that route-to-route extrapolation fromSoffriti et al. (2002a) study would increase inhalationPOD by about 4-fold.EPA states that the oral POD was based on the onlytumor type from Soffritti et al. (2002a) drinking waterstudy that had significantly increased (alllymphomas) while the inhalation POD was based onmost sensitive tumor response from NEDO(1985/2008b) study that had an increasedpheochromocytoma in female rats.If methanol is a systemic carcinogen, the two cancerpotencies, i.e., the two HEDs based on appropriatePBPK modeling, would be expected to be virtuallyidentical. Similarly, as the PBPK model and metricwere assumed to be the same for both routes ofPlease explain the unexpected significantdifference in types of cancers and cancerpotencies, other than that it was the data theyhad.SPage 6 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*exposure, the significant difference in types ofcancers observed is not expected.16B.1First page ofsection, line13EPA modified the existing model. The modifications,including all of the additional assumptions requiredfor these modifications, have not been peerreviewed. Lack of peer review of a PBPK model tohelp establish a toxicity value (for perchlorate) wasone of the reasons EPA’s Science Advisory Board(SAB) mentioned when it suggested that EPA recallits evaluation until the model was reviewed.Until EPA’s modifications are peer reviewed,results of using the other, already peerreviewed models should be presented. EPAshould not rely on the external peer review ofthis document to also peer review the model,as the latter can be an intensive effort itself.17B.1First page ofsection, line13EPA states,“Renal clearance is a minor pathwayand does not appreciably affect MeOH bloodkinetics.” Yet it added a renal compartment to thePBPK model and further states,“addition of abladder compartment ...impacts simulations forhuman urinary excretion.”(line 18-19) These twostatements appear to be contradictory. Since theyare in the summary of the PBPK model, the readeris left to infer that the bladder compartment isrequired but does not have a significant effect.Such a conclusion does not inspire confidence inthe model or those making the modification in themodel.The renal/bladder compartment should be keptin the model.S/MPage 7 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*18B.1Second pageof section,line 5Uncertainty factors (UFs) were applied to theinternal dose and then the human PBPK model wasused to estimate the human RfD. The humanequivalent NOAEL should be calculated using thePBPK model before the UFs are applied. As thePBPK model uses best estimate parameters, thebest of the internal dosenot the lower estimate onthe dose should be used in the model. Otherwise,the uncertainty due to, for example, variabilityamong people will be used with the best estimateparameters in the PBPK model.All iterations of the PBPK model should be runwith the data and parameters without addingthe UFs. The appropriate UFs should beapplied after the human-equivalent dose orconcentration is estimated in order to calculatean RfD or an RfC or a cancer potency.Please note that this is a major proceduralissue for estimating toxicity values, it is stronglyrecommended that other IRIS documents bereviewed to determine if this has been astandard practice.S/M19B.2.13rdpage ofsection, line27EPA states that the PBPK model“only describes therate of metabolism or conversion of MeOH to itsmetabolites. Distribution and metabolism offormaldehyde is not considered by the model, andthis model tracks neither formate nor formaldehyde.(The data that would be needed to parameterize orvalidate a specific description of either of thesemetabolites is not available).”The toxicokinetics described in Chapter 3 and thePBPK models in this appendix indicate that thekinetics of formation of formaldehyde and formate inhumans differs significantly from rodents. Indeed,mice differ from rats, and where data were lacking,the authors modified the human data to resemblemice rather than rats. For example, the human datawere “linearized” in Figure B-20, page 330), eventhough it was clearly nonlinear, and the modelrequired combining a fast and slow metabolism inWe recommend that if data are available tosupport this crucial issue, they should beclearly presented. Moreover, assumptions thatminimized the well-known differences in rodentand primate metabolism of methanol should beeliminated, and the toxicity values recalculatedbased on models and data that retain thesedifferences.S/MPage 8 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*order to fit the data, e.g., as described in Table B-1.The assumption that formaldehyde and/or formateare quantitatively the same “methanol metabolites”in the same ratios in rodents and primates is criticalto EPA’s analysis. However, the data presented byEPA repeatedly refute this assertion more thansupport it.20B.2.1First andsecondparagraphsbelow FigureB-1Even though a bladder compartment was requiredand added for the human PBPK model to fit thedata, nevertheless, the authors adjusted the valuegenerated by the model because they assert(without poving) that the model will not correctlyestimate this value. This results in estimating thelarger animal (human) to have an even larger riskthan that which they have gone to great lengths toestimate using a complex model for differences inkineticsAs stated at the beginning of this document, thedefault factor of BW3/4for interspecies adjustment isto be used in the absence of chemical-specific data.This is affirmed in EPA’s document on use of thisfactor for oral, non-cancer, interspeciesextrapolations, whose stated intent is to conformwith oral cancer, interspecies extrapolations. In thecase of methanol, not only is there an abundance ofAs there is no need for use of an interspeciesdefault factor for methanol, it is stronglyrecommended that all mention of this defaultfactor be eliminated from this document. Theanalyses that use chemical-specificadjustments as well as the default should bechanged to eliminate this second adjustmentfor interspecies differences. We recommendthat any analysis that only uses this defaultshould be eliminated from the document.The apparent lack of concern about applying adefault factor after already performing thesame adjustment on a chemical-specific basisraises concerns about analyses for otherchemicals. It is recommended that they bereexamined and adjusted if necessary.S/MPage 9 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*chemical-specific data, there are also several PBPKmodels – the preferred method for interspeciesextrapolation.21B.2.1GlobalThe authors assume that the PBPK model can berun without taking into account the existing level ofmethanol and formate in the blood due to normalhuman and rodent metabolism. This assumption issufficient to invalidate the “validity checks” andsensitivity models. The body does not distinguishthe source of these chemicals. For example, if thekinetics saturate at a blood level ofxand the normallevel in the body isx0, then the standard assumptionwould be that an exposure greater than (x-x0)would saturate the kinetics. The assumption madeby the EPA authors is that exposures would have toreachxbefore the kinetics are saturated, thusassuming saturation occurs at a higher level that isaccurate.We recommend that background level of achemical produced by the body must be takeninto account.S22B.2.2Table B-1In Table B-1, again the authors use BW3/4to scalethe parameters – and plan to use it again afterrunning the model.See comment page 294, line 35.SPage 10 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*23B.2.3.1First page ofsection, line21The sentences at the end of this paragraph seem tobe saying that absorption from the stomach issaturable and based on the volume of the stomach.The assertion is made that the stomach volume isproportional to body weight, rather than anallometric scaling of BW3/4, except that the value formice will be kept the same as rats, even though(according to Table B-1) rats are 10 times theweight of mice. The data won’t fit their assumptionwhen scaling from a 0.03 kg mouse to a 0.3 kg rat,but the authors assume that it will be accurate forscaling from the 0.3 kg rat to a 70 kg human, andthat it is appropriate to scale from a 0.03 kg mousewith a 0.3 kg rat’s stomach to a 70 kg human.This assumption should be changed toconform to the data. The toxicity values thatdepend on this assumption should berecalculated.S/M24B.2.3.1Text aboveFigure B-5The scientists who produced the data anddeveloped the model found that the volume ofdistribution varied with dose. However in thisToxicological Review of Methanol it was assumedthat the scientists running the experiments anddeveloping the model made an error when theywere dosing the animals without any proof that amistake was made by the scientists in thelaboratory. External peer reviewers of themanuscript, that was published, indicated thenecessity to modify the initial model based on thedata. This is a very significant comment that wasnot considered in this document.The peer-reviewed model and data should beused as presented unless EPA can presentdata that a laboratory mistake was made.S/M25B.2.3.4GlobalAs the analysis assumes that the concentration offormaldehyde or formate is the internal doseIf these assumptions are not accurate theeffects on the estimated toxicity values shouldSPage 11 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*responsible for adverse effects, this concentration isalso the correct metric on which to base theinterspecies conversion. As stated in thisparagraph, however, these concentrations are neverestimated. The analysis assumes that methanolclearance is equivalent to formaldehyde andformate production, but EPA states that “this has notbeen verified.”The limited data provided, the tablesin Chapter 3, do not appear to support thisassumption that is critical for the dose-responsemodeling. Moreover, Section 3.1 states that rodentshavetwopathways for formate metabolism, whileprimates have onlyone. Even if all of thesepathways are “fast” and kinetically “favorable” onecan not assume they are equivalent or that theyproduce equivalent ratios of all of the metabolites.Assuming the Tables 7-9 are actually Tables B-7 toB-9, these tables that are assumed to support thishypotheses have at least one value that is notaccurately reported (see comment below for pages386 & 387).be presented, as should calculations based onequally valid assumptions.26B.2.8.1GlobalIn this section, the authors appear to simply removethe second metabolism compartment from thehuman model as unnecessary at low doses. Asthey assert in the second page of text in the section,“A simple linear model is preferred over the use of aKm value that is high.”The authors of this analysismay prefer a simple model; the scientists whodeveloped the model and added this compartmentapparently disagree. Moreover, this “simplifyingThe results of using the model as intended bythe developers (that retains this knowndifference between rodent and humanmetabolism) should be presented.SPage 12 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*assumption” serves to make the human model morelike the rodent model, i.e., less accurate forportraying the interspecies differences that it wasdesigned to determine.27B.2.8.1Para.FollowingTable B-2Even if the previous statement about subtractingbackground were accurate, EPA did not simplysubtract the background. As stated in this section,the blood concentrations of the exposed population“were corrected by subtracting time-zero value forthe exposed groupplusa time dependent factorobtained by multiplying the slope of this regression(0.093 mg/L-hr) by the measurement time.”Clearly,the role and importance of background levels ofmethanol and formate are not as simple aspresented in this document.If non-standard processes are used, the resultsof standard processes should also bepresented.S28B.2.8.1Text followingTable B-3The authors state,“At greater than a 99.95%confidence level, using 2 metabolic rate constants(Km and VmaxC) is preferred over utilizing a singlerate constant.”The conclusion of this paragraph isthat the nonlinear Michaelis-Menten model must beused as the human equivalent concentrations, “arebeing conductedin a concentration range in whichthe nonlinearity has an impact.”The analysis presented here appears tocontradict the analysis presented on page 320.This logical inconsistency should be resolvedand the toxicity values that depend on it shouldbe recalculated, if necessary.S29B.2.8.1. andTable B-5Para.followingTable B-5After altering the PBPK model, the decision wasmade not to use this model and the actualconditions of the bioassay to determine the humanequivalent concentration, but rather to use analgebraic approximation and the assumption of acontinuous, 24-hour exposure for the interspeciesThe assumption of a 24-hour, continuousexposure to methanol needs to be justified, asthe animals were not exposed continuously,nor would people be expected to be exposedcontinuously.SPage 13 of 14Department of Defense Comments on theDraft Final Toxicological Review of Methanol, October 2009Comments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 23 November 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 & Line(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*conversion.30B.3.8Figure B-24,Table B-9If Figure B-24 is correctly labeled, then the Cmax for0.1 mg MeOH in a bolus should be almost 0.08instead of almost 0.06, as reported in Table B-9.Since a time-dependent dose for only one doselevel is provided, the rest of these data can not becritically evaluated.Please check the accuracy of the remainingdata since the only one presented appears tobe incorrect.S/M30B.2.9First page insectionThe text states: “Mouse, rat, and human MeOHPBPK models have been developed and calibratedto data in the open literature. The model simplifiesthe structure used by Ward et al. (1997) whileadding specific refinements (e.g., a standard lungcompartment and a two-compartment GI tract). ...The model fits to the mouse oral-route MeOH kineticdata using a consistent set of parameters (Figure B4) are reasonably good but not as good as fits to theinhalation data.”In the end, the fit wasn’t that good, especially for theoral data.The text should elaborate on whether the fitwould have been better if the model and datahad been used without changes.SPage 14 of 14