Department of Defense Comments on theDraft External Peer Review Charge for MethanolComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 20 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 &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*1A.1.We would prefer that the text “objectively and” beretained.Please retain “objectively” explicitly in thisquestion.S2B.1.& 2Several recent NAS reports have recommended thatrisk assessments move from the historical practiceof selecting one critical study to represent thequantitative analysis. It might be useful to ask thereviewers if they believe the results of the threeanalyses should be combined, and if so, how wouldthey recommend that they be combined.Suggest adding to the question: “Do yourecommend that the results from more than onestudy should be used quantitatively for doseresponse assessment, and if so, whattechniques would you recommend toaccomplish combine or compare the data?”S3B.3. firstbulletSome of the “subtraction from background”included a time-dependant change. We recommendthat this adjustment be specifically called-out forreview.We recommend that an additional sentence beadded to convey the following concept: “Someof the ‘subtraction from background’procedures included a time-dependant change,i.e., because the level of methanol in the bloodof control animals changed with time. Wasthis adjustment appropriate and was itperformed properly?”S/M4D.3. lastsentence.It is not clear whether “addressed” in the phrase“clearly described and addressed” asks thereviewers to consider if, given these issues, thesedata are appropriate for dose-response modeling forestimating human risks.We recommend changing “clearly describedand addressed” to “...clearly described andappropriately selected for dose-responsemodeling for estimation of human cancerrisks.”EPage 1 ofDepartment of Defense Comments on theDraft External Peer Review Charge for MethanolComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 20 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 &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*5D.4. firstsentenceOur interpretation of EPA’s toxicological review(TR) is that the clearance of metabolize methanolwas being used as a surrogate for the production offormaldehyde or formate and that it is possible(given the values in the text) to measure formate inthe blood. If this interpretation is accurate, werecommend editing the charge question to reflectthese facts.We recommend that the question be phrased inthe following manner: “If the metabolites ofmethanol cannot be measured in blood, i.e.,formaldehyde, or were not measured in blood,i.e., formate, is it appropriate to use clearanceof metabolized methanol as a surrogate? Isthere a procedure that might provide a betterestimate from this surrogate than assumingequivalence of the surrogate and theconcentration of the metabolite?”S/M6D.4. secondsentenceOur understanding from the TR is not thatmetabolism “may differ” among species but thatmetabolism in primates and rodents is known todiffer. As one major difference, the TR states thatmetabolism is a one-step process in rodents and atwo-step process in primates.Assuming our reading of the TR is accurate,we recommend that this sentence be revised toread, “The metric of formaldehyde productionis uncertain because: (1) metabolic processesare known to differ between rodents andprimates and metabolism is a one-step processin rodents and a two-step process in primates.[Note: we recommend both changes as thefirst, i.e., a different enzyme, might only affectrate while the second might affect the form,i.e., requiring a function rather than a constant,of any recommended conversion.]S/MPage 2 ofDepartment of Defense Comments on theDraft External Peer Review Charge for MethanolComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 20 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 &Paragraph(enter“Global” ifreportsection-wide)CommentSuggested Action, Revisionand References (if necessary)Category*7D.5. and D.7We noted that after the PBPK model was used forinterspecies extrapolation, the risk assessors alsoapplied the default interspecies extrapolation ofBW3/4 that had already been used to derive some ofthe parameters for the PBPK model. Werecommend that the external peer reviewers beasked to opine on this issue.Add the following to the end of this chargequestion. “Specifically, should the humanequivalent dose that has been derived from aPBPK model based on clearance of metabolitesbe further adjusted by the ratios of BW3/4 aswas done for methanol?”S/MPage 3 of