Page 1 of 3 

Department of Defense Comments on the Toxicological Review Of Formaldehyde Inhalation To

Comments submitted by: Office of the Secretary of Defense Chemical and Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 19 April 201

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph or 

Global 

Comment Suggested Act

1 Global Formaldehyde is a natural metabolite. The toxicity 

values in this document appear to be in the range of normal concentrations in the body and in foods. If

formaldehyde is toxic at normally occurring concentrations it seems that leukemia rates should be much higher than they are. 

A reality check of formaldehydin healthy individuals comparerisks of leukemia should be pAlthough an estimated 1 to 10 ingestion is cited (page 2-11), proximity to, nor compared wiexisting data on risk of leukemsources nor with the unit canc10–2 per ppm (6.6 × 10–5 per μ

2 4.5.3. Global None of the hypothesized modes of action are

presented in the manner envisioned in the EPA’s 2005 cancer guidelines. Moreover, none of the datarequired for a mode of action analysis are presented 

in the discussion of the potential modes of action.

Thus, it is not possible to judge if there are sufficient 

data to support any or all of the modes of action presented. 

The assessment would be mothe cancer guidelines were beNot only does this procedure scientifically defensible proceestablishing modes of action abut it also is consistent with odetermining a mode of actionthose modes of action for whiare cited for the key events hyshould be deleted. EPA’s canstate that mode-of-action anabased on data. 
Page 2 of 3 

Department of Defense Comments on the Toxicological Review Of Formaldehyde Inhalation To

Comments submitted by: Office of the Secretary of Defense Chemical and Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 19 April 201

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph or 

Global 

Comment Suggested Act

3 4.5.3. 4-427 The document does not present sufficient 

information to determine that the cancers have a mutagenic mode of action. The observation of potential for systemic mutagenicity is necessary but not sufficient for demonstrating a mutagenic mode of action at any particular site of carcinogenesis, as has been discussed in EPA’s external review draft of a framework for mutagenic mode of action and in peer-reviewed publications from those authors. Since demonstration of a mutagenic mode of action changes the risk estimates for early-life exposures, this determination is critical and must be documented appropriately. 

Recommend that the framewo2005 cancer guidelines be foldetermine whether formaldehmutagenic mode of action. If to support the determination athis document, they are not in section, and the analysis in thneither complete nor transparthe criteria set forth in EPA’s c

4 4.5.3 Global The data used, and the mode of action 

hypothesized, for developing the cancer potency forformaldehyde is based primarily on very recent datafrom one laboratory. Possibly one of the modes of action, it is in conflict with current, evidence-based medical opinion. The current medical consensus is that aplastic anemia is necessary for chemically induced leukemia, as was discussed by Dr. Bernard Goldstein at recent meetings (2009 SRA and 2010 Navy and Marine Corps Public Health Center annual meeting). As such, it would be expected to have a threshold and thus to have a nonlinear extrapolation from the point of departure. (See also: 

Lu et al. 2010. Distribution of DNA Adducts Caused by Inhaled Formaldehyde is Consistent with Induction of Nasal Carcinoma but not Leukemia.

Toxicol Sci. 2010 Feb 22 and Rava et al. 2009. Cause-specific Mortality in Populations Exposed and Unexposed to Outdoor Emissions of Formaldehyde and Wood Dust: the Viadana study. (Epidemiol Prev. 33:176-83.) Furthermore, EPA’s 

While EPA’s hypothesized mosufficient support to be presendocument, the more universaevidence-based medical modalso be presented and a quanfor risk assessment profferedcurrent data are not replicated of evidence continues to suppanemia basis for the mode of volume analysis would have tuntil such an analysis were doboth analyses, the IRIS docummore robust and allow decisioeither value as more data bec
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Department of Defense Comments on the Toxicological Review Of Formaldehyde Inhalation To

Comments submitted by: Office of the Secretary of Defense Chemical and Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 19 April 201

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph or 

Global 

Comment Suggested Act

cancer guidelines recommends that modes of action that are biologically plausible be carried forward quantitatively to the risk characterization section of the risk assessment so that risk managers can include them in their evaluations. Certainly, the current medical, evidence-based, consensus assessment qualifies. If the medical consensus is accurate, carcinogenesis requires killing of stem cells and therefore is low-dose nonlinear. At a minimum, theanalysis should present both risk extrapolations, as the Zhang et al. hypothesis may be shown not to be accurate, and we don’t want to have to redo a multivolume assessment. 

4 4.5.3.1.1 4-443 

Line 28 

There are several Zhang et al. 2010’s in the literature, and although this is a critical reference, 

none are in the reference list. 

References should be provide