Dr. Preuss and Mr. Birchfield:

NASA thanks EPA for the opportunity to review and c omment on the draft IRIS risk assessment for Formal dehyde.

NASA’s review identified broad ongoing concerns ide ntified in recent IRIS draft risk assessments and s pecific technical issues. NASA suggests addressing the iden tified outstanding technical issues through detaile d questions provided in the Peer Review. NASA also notes that EPA’s approach and analysis does not correspond to the analysis and scientific conclusions targeting airb orne exposure to formaldehyde provided in the Natio nal Academy of Sciences report entitled, “Emergency and Continu ous Exposure Guidance Levels for Selected Submarine Contaminants”, Committee on Toxicology, National Re search Council (NRC), 2007 or in current models use d by EPA’s Office of Air and Radiation, applying Clean A ir Act requirements. We request EPA revisit these o utstanding issues by ensuring independent Peer Review of these concerns, specific technical issues and inconsiste ncies with conclusions reached in the 2007 NRC report.

Broad concerns and specific technical issues includ e: Setting of action levels at or below background lev els found in the environment



### • EPA sets the noncancer estimate and the age-adjuste d cancer slope factor that result in an equivalent air concentration of 1-3ppb. As noted in the NRC 2007 report, human breath has often been measured to contain levels in excess or 1-3 ppb, raising the qu estion of choice of an action level that is likely at or below the level found in the environment. EPA does not provide justification of setting of a level le ss or equal to normal thresholds of formaldehyde found in the human body.

Need for consistent regulation of chemicals in the environment/need for transparency in decision makin g:



### • In the draft IRIS risk assessment, EPA does not app ly the models suggested by the NRC 2007 report or internal EPA models utilized by the Agency’s Office of Air and Radiation. Given the large body of res earch on formaldehyde, NASA questions why EPA’s IRIS draf t not clearly detail the applicability of these established models and scientific understanding in the development of the IRIS draft. EPA needs to cl arify and support transparency in the development of IRIS draft risk assessments, especially when alternativ e approaches to established models are applied.



### • EPA needs to also clarify the hypothesis considered and the technical support for evaluation of formaldehyde under the EPA Cancer Guidelines and su pporting guidance. This discussion of the draft approach is of signficant concern to explain how un certainty is identified and addressed by EPA in thi s draft risk assessment.

Application of peer-reviewed literature to estimate non-cancer impacts:



### • In contrast to the EPA draft IRIS risk assessment r eliance on three co-critical studies, the NRC (2007 ) stated a strong preference for application of numer ous experimental studies of controlled human exposure to estimate short-term exposure levels. T he NRC cited, “ Thus, data from 22 clinical studies involving over 500 subjects form the most reliable basis for estimating health-protective short-term exposure levels for airborne formaldehyde”. EPA ne eds to detail why the IRIS draft does not follow th is recommendation and focuses on only 3 critical studi es.



### • Again, the NRC (2007) also identifies that irritat ion, based on the literature, is the first observed effect at 0.5-1ppm. In contrast, EPA does not address this N RC finding based on the literature and does not use this NRC finding in the establishment of the cRFC. EPA needs to explain why the NRC finding from the established literature was not applied in the setti ng of the proposed formaldehyde cRFC .



### • Based on the precedent of the NAS report on Perchlo rate (2005), robust human clinical data is superior to animal clinical data or ecological studies of human exposure. As with perchlorate, EPA is strongly encouraged to use human clinical data, including th e NOELs, as the basis of setting its cRFC for formaldehyde. Without use of this preferred data, t he proposed formaldehyde cRFC is not based on the most scientifically defensible data and this issue should be addressed more fully in the estimation of the cRFC and through evaluation by the Peer Review.

### • Potential cofounders were not or simply could not b e addressed in the three co-critical studies EPA us ed as the basis of the cRFC, raising significant conce rn over the application of these studies to set act ion levels. For example, Rumchev (2004) follows up the earlier paper determined to be co-critical by EPA w ith additional findings of statistically signficant ass ociations for other VOCs and particulate matter with asthma with the same study population. EPA , in the draft risk assessment, does not explain or address the implications of potential bias on the identifie d co-critical Rumchev (2002) paper or its impact on setting the draft cRFC.



### • EPA fails to provide the links of the associations identified chosen three co-critical papers to demonstrated reactions to formaldehyde exposure. Th is lack of clarification and causation is most concerning as EPA assumes that causation or trigger s for asthma, due to formaldehyde exposure, to be a t levels 1000 times lower that the first observed an d reversible effect, irritation. The draft IRIS ri sk assessment does not provide key defensible links to biological responses documented for formaldehyde

exposure.

Application of peer-reviewed literature in the esti mation of cancer risks:



### • EPA, as in the previous IRIS assessment, assumed a linear, low-dose extrapolation from the applicable point of departure. EPA does not in the draft IRIS risk assessment address or clarify its continue of a controversial and disputed approach. In the interes t of transparency, EPA is strongly encouraged to address this assumption and solicit Peer Review of use of this approach specifically on formaldehyde.



### • Use of the same linear, low-dose extrapolation appr oach used in the existing IRIS risk assessment for formaldehyde has been questioned as unsupportable b y the NRC. The NRC report (2007) summarizes its conclusions on the current IRIS value as, “ In rea lity, the risk is far lower. On the basis of the ev idence that the contributory mechanisms of action at high doses in rodents (that is, cytolethality and regeneration) would not occur at lower doses, the E PA unit risk factor for formaldehyde overestimates the risk at doses not associated with cytotoxicity (NRC, 2007., pg. 130). The NRC goes on to state, “T he available evidence, however, strongly suggests that the risk from formaldehyde at high doses in animal studies cannot be extrapolated to lower doses using the EPA’s approach. (NRC, 2007, pg. 131). The draf t IRIS risk assessment does not adequately respond to significant issue identified by the NRC in the development of the proposed action levels for forma ldehyde. EPA needs to clarify its position and requ est that the Peer Review evaluate the proposed EPA appr oach in light of the NRC findings on formaldehyde.



### • EPA finds that formation of DNA-protein-cross-links from formaldehyde exposure supports the draft’s findings that formaldehyde induces mutagenic action below levels that are cytotoxic. In contrast to EP A’s approach in the draft IRIS risk assessment, the NRC report (2007) and EPA’s Office of Air and Radiatio n (under the Clean Air Act), utilizing peer reviewed literature apply an alternative approach in models for low-dose carcinogenicity for formaldehyde exposure . The NRC report (2007, pg. 121) states that, “Although DNA-protein-cross-link formation might no t be directly relate to gene mutations at subcytotoxic doses, it has been used as a predictor of the probability of procarcinogenic mutation per cell division and has been incorporated in models for lo w-dose carcinogenicity in animals and humans.” EPA needs to detail its reasoning to not apply establis hed EPA models and NRC findings in the development of the IRIS cancer risk action levels. In addition, EP A should request the Peer Review evaluate EPA’s approach in the draft IRIS risk assessment against these alternative approaches and EPA models.



### • EPA uses human epidemiological data as its point of departure (POD) in the cancer assessment in the draft IRIS risk assessment. However, the NRC ident ified specific limitations with the primary study that found evidence of elevated levels of nasopharyngeal cancer or NPC (NRC, 2007, pg.122). Issues include d that the majority of the documented NPC cases were at one plant with most of the cases found in worker s with one year or less employment at the plant. The NCI study identified the signficant risk trend for NPC but was based on limited numbers of subjects. In a ddition, large cohort studies did not find any exce ss NPC cases. The draft IRIS risk assessment needs cl arification of these limitations, consideration of the impact of additional uncertainty and alternative ap proaches to establish the POD. EPA needs to request the Peer Review evaluate the EPA proposed establish ment of the POD, based on these studies and their documented limitations, and subsequent cancer asses sment values.NASA thanks EPA for the opportunity to review and c omment on the draft IRIS risk assessment for formal dehyde.

We request that EPA address the specific technical issues outlined above. To best ensure consideratio n of these outstanding issues, we request that the Peer Review evaluate EPA’s proposed risk assessment, methodolo gy, and supporting assumptions in light of the NRC report ( 2007) and EPA’s Office of Air and Radiation models and cancer assessment approaches.

Thank you. If you have any questions or need additi onal information or clarification, please contact m e.

Linda S. Wennerberg, Ph.D.

NASA HQ Suite 5E39 300 E Street, SW Washington, DC 20548-0001