Page 1 of 3Department of Defense Comments on the ToxicologicalReview Of Formaldehyde Inhalation ToxicityComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 19 April 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 orGlobalCommentSuggested ActionCategory*1 Global Formaldehyde is a natural metabolite. The toxicityvalues in this document appear to be in the range ofnormal concentrations in the body and in foods. Ifformaldehyde is toxic at normally occurringconcentrations it seems that leukemia rates shouldbe much higher than they are.A reality check of formaldehyde in the diet andin healthy individuals compared with lifetimerisks of leukemia should be presented.Although an estimated 1 to 10 mg per dayingestion is cited (page 2-11), it is not inproximity to, nor compared with, neither theexisting data on risk of leukemia from allsources nor with the unit cancer risk of 8.1 ×10–2per ppm (6.6 × 10–5perμg/m3).S/M24.5.3.Global None of the hypothesized modes of action arepresented in the manner envisioned in the EPA’s2005 cancer guidelines. Moreover, none of the datarequired for a mode of action analysis are presentedin the discussion of the potential modes of action.Thus, it is not possible to judge if there are sufficientdata to support any or all of the modes of actionpresented.The assessment would be more defensible ifthe cancer guidelines were better adhered to.Not only does this procedure provide ascientifically defensible procedure forestablishing modes of action and causation,but it also is consistent with other methods fordetermining a mode of action. In particular,those modes of action for which no referencesare cited for the key events hypothesizedshould be deleted. EPA’s cancer guidelinesstate that mode-of-action analyses must bebased on data.SPage 2 of 3Department of Defense Comments on the ToxicologicalReview Of Formaldehyde Inhalation ToxicityComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 19 April 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 orGlobalCommentSuggested ActionCategory*34.5.3. 4-427The document does not present sufficientinformation to determine that the cancers have amutagenic mode of action. The observation ofpotential for systemic mutagenicity is necessary butnot sufficient for demonstrating a mutagenic modeof action at any particular site of carcinogenesis,ashas been discussed in EPA’s external review draftof a framework for mutagenic mode of action and inpeer-reviewed publications from those authors.Since demonstration of a mutagenic mode of actionchanges the risk estimates for early-life exposures,this determination is critical and must bedocumented appropriately.Recommend that the framework outlined in the2005 cancer guidelines be followed todetermine whether formaldehyde has amutagenic mode of action. If the relevant datato support the determination are available inthis document, they are not in the appropriatesection, and the analysis in that section isneither complete nor transparent with regard tothe criteria set forth in EPA’s cancer guidelines.S/M4 4.5.3 Global The data used, and the mode of actionhypothesized, for developing the cancer potency forformaldehyde is based primarily on very recent datafrom one laboratory. Possibly one of the modes ofaction, it is in conflict with current, evidence-basedmedical opinion. The current medical consensus isthat aplastic anemia is necessary for chemicallyinduced leukemia, as was discussed by Dr. BernardGoldstein at recent meetings (2009 SRA and 2010Navy and Marine Corps Public Health Centerannual meeting). As such, it would be expected tohave a threshold and thus to have a nonlinearextrapolation from the point of departure. (See also:Lu et al. 2010.Distribution of DNA Adducts Causedby Inhaled Formaldehyde is Consistent withInduction of Nasal Carcinoma but not Leukemia.Toxicol Sci. 2010 Feb 22 and Rava et al. 2009.Cause-specific Mortality in Populations Exposedand Unexposed to Outdoor Emissions ofFormaldehyde and Wood Dust: the Viadana study.(Epidemiol Prev. 33:176-83.) Furthermore, EPA’sWhile EPA’s hypothesized mode of action hassufficient support to be presented in thisdocument, the more universally accepted,evidence-based medical mode of action shouldalso be presented and a quantitative analysisfor risk assessment proffered. Otherwise, if thecurrent data are not replicated or if the weightof evidence continues to support the aplasticanemia basis for the mode of action, this fourvolume analysis would have to be withdrawnuntil such an analysis were done. By supplyingboth analyses, the IRIS document would bemore robust and allow decision makers to useeither value as more data become available.S/MPage 3 of 3Department of Defense Comments on the ToxicologicalReview Of Formaldehyde Inhalation ToxicityComments submitted by: Office of theSecretary of Defense Chemical andMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 19 April 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 orGlobalCommentSuggested ActionCategory*cancer guidelines recommends that modes of actionthat are biologically plausible be carried forwardquantitatively to the risk characterization sectionofthe risk assessment so that risk managers caninclude them in their evaluations. Certainly, thecurrent medical, evidence-based, consensusassessment qualifies.If the medical consensus is accurate,carcinogenesis requires killing of stem cells andtherefore is low-dose nonlinear. At a minimum, theanalysis should present both risk extrapolations, asthe Zhang et al. hypothesis may be shown not to beaccurate, and we don’t want to have to redo amultivolume assessment.4 4.5.3.1.1 4-443Line 28There are several Zhang et al. 2010’s in theliterature, and although this is a critical reference,none are in the reference list.References should be provided. E