data were limited by “…uncertainties of exposure assess- ment, possible confounding by other pollutants, and reli- ance on mortality data rather than incidence data….” Although EPA postulated a mutagenic mode of action for leukemia and other hematopoietic cancers, the evi- dence is very weak, particularly as it relates to low, envi- ronmental exposures with the NRC committee observing that “Although EPA postulated that formaldehyde could reach the bone marrow either as methanediol or as a byproduct of nonenzymatic reactions with glutathione, numerous studies…have demonstrated that systemic delivery of formaldehyde is highly unlikely at concentra- tions below those which overwhelm metabolism accord- ing to sensitive and selective analytic methods that can differentiate endogenous from exogenous exposures.” Additionally, while EPA suggested a mode of action in which hematopoietic cells in the nasal epithelium are affected by inhaled formaldehyde and return to the bone marrow the NRC committee considered this possibility and concluded, “As a result, EPA could only speculate that circulating hematopoietic stem cells that percolate through nasal capillary beds or nasal-associated lymphoid tissues may be the target cells for mutations and clastogenic effects that eventually result in lymphohemotopoietic cancers. Experimental evidence of this mechanism is lacking.” With respect to how data were selected and evaluated the committee stated that “EPA should revisit its argu- ments and include detailed descriptions of the criteria that were used to weigh evidence and assess causality.” The report also notes that EPA’s draft assessment “provides little discussion about how asthma could be caused or exacerbated by formaldehyde exposure” and that a study relied upon for development of the asthma RfC (i.e., Rumchev et al. 2002) “…most likely suffers from misclas- sification of infection-associated wheezing in young chil- dren as asthma.” On the issue of sensory irritation the NRC committee was critical of EPA for not including the controlled human studies and that “…EPA set aside the chamber and occupational studies too soon in the process.” As for the studies selected and relied upon (the study by Ritchie and Lehnen 1987 was rejected as invalid and “EPA should not have used it”) for establishing the RfC for sensory irritation the committed observed that “…study details…and study weaknesses (such as the limitations of the exposure assessments performed in the residential and occupational epidemiologic studies) were not thoroughly presented or critically evaluated in a consistent manner by EPA.” While the committee agreed that respiratory tract cancers were plausible since this is the first site of contact with inhaled formaldehyde they concluded that, “…the draft IRIS assessment does not present a clear framework for causal determinations and presents several conflicting statements that need to be resolved regarding a causal association between formaldehyde and respiratory tract cancers.” Finally, the committee was supportive of the biologically based dose response (BBRD) model devel- oped for risk assessment of formaldehyde induced nasal tumors and critical of EPA’s development “of alternative © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 691 models that yielded the most extreme deviations from the Conolly et al. (2004) low-dose extrapolations” which “produced unrealistically high added risks for humans at concentrations that have been observed in the environ- ment or occupationally exposed workers (100% incidence at concentrations as low as about 0.1-1 ppm).” B.Nasopharyngeal cancer (NPC) 1.Animal data Rat studies showing nasal tumors following chronic exposure to sufficient concentrations of formaldehyde provide support for the hypothetical possibility for the epidemiological findings of NPC (e.g., Kerns et al., 1983a, b; Tobe et al., 1989; Sellakumar et al., 1985; Feron et al., 1989). For example, in what is generally considered to be the definitive study of formaldehyde-induced nasal can- cer, rats were exposed by inhalation to formaldehyde at concentrations of 0, 0.7, 2, 6, 10, and 15 ppm for 2 years (Monticello et al., 1990). Nasal tumors occurred only at formaldehyde concentrations of 6 (1%), 10 (22%), and 15 (45%) ppm. Those concentrations are far in excess of tolerable irritant levels for humans and are sufficient to cause cytotoxicity of the rat nasal epithelium, with sub- sequent regenerative proliferation observed. Exposures at 6 ppm and above for a sufficient duration produce substantial toxicogenomic and histopathological der- rangements directly associated with the development of nasal tumors. 2.Mutagenicity data With respect to formaldehyde-induced nasal tumors in rats, a key issue is whether early mutations play an etiologic role in this process. Although in vitro studies demonstrate that formaldehyde is mutagenic in a num- ber of test systems (ATSDR, 1999; IARC, 2006), none of these studies have been conducted in whole tissues in the presence of formaldehyde dehydrogenase and other metabolizing enzymes. The lack of such metabolic capability suggests that in vitro studies are unlikely to mimic potential effects in rodents or humans with background endogenous formaldehyde concentrations and substantial detoxification capacity. Consequently, without the ability to metabolize formaldehyde, in vitro mutagenicity data may not provide an adequate basis for determining what role, if any, mutations might have played in the development of formaldehyde-induced rat nasal tumors. It is clearly established that sufficient doses of formaldehyde cause substantial cytotoxicity in nasal epithelial cells, double-stranded DNA breaks, and various DNA adducts that in sufficient quantity can lead to mutations and transformation. Unresolved, however, is whether dose-dependent, sub-cytotoxicity– induced mutations play an early etiologic role in tumor formation or appear only later in the tumorigenic pro- cess subsequent to frank cytotoxicity and regenerative proliferation. Consequently, for formaldehyde-induced nasal tumors in rats, it seems reasonable to also assume that if early mutations play an etiological role in the