712 R. Golden research with rodents. The remarkable concordance between cytotoxicity and regenerative proliferation has been augmented with toxicogenomic data showing clear evidence of dose-dependent transitions in genes most likely associated with tumor formation (including DNA repair genes) only at ≥6 ppm has several implications. First, in discussing the MOA for formaldehyde- induced nasal tumors, the US EPA/IRIS (2010a) assess- ment takes the position that mutations play a necessary early etiological role in nasal tumorigenesis, which is consistent with a presumption that a linear, no-threshold model must be used to assess potential risks. If this is cor- rect, one would expect to see toxicogenomic evidence of effects on DNA repair genes at the lowest formaldehyde doses tested (i.e., 0.7 and 2 ppm) over the course of up to 13 weeks of exposure, but this has not been reported (Andersen et al., 2008, 2010). The apparent reliance on single-dose nasal instillation studies (e.g., Hester et al., 2003, 2005) that report effects on DNA repair genes as the basis for presuming that early mutations play an etiologi- cal role in nasal tumorigenesis ignores the fact that the single formaldehyde dose by instillation up-regulated 3 times more genes that an inhalation dose of 15 ppm (Andersen et al., 2008). Second, the US EPA/IRIS assessment goes to great lengths (Appendices D, E, F, G, and H) to question the validity and/or utility of the substantial data pertaining to rat nasal tumorigenesis, including the toxicogenomic data (Andersen et al., 2008, 2010), and derived benchmark dose analyses (Thomas et al., 2008) of these data as well as the BBDR model (Conolly et al., 2003, 2004). Much of the analyses address the issue of uncertainty as this concept is now used. However, the body of available data is now able to explain with considerable certainty the MOA and dose- dependent sequence of events leading to nasal tumorigen- esis. The US EPA (2010a) analysis also fails to consider the inhaled concentrations required to enhance tissue formal- dehyde even in the proximal tissues of the nose. Third, it is worthwhile to point out that the formalde- hyde concentrations that produce tumors in rats (i.e., ≥6 ppm) are so irritating to human nasal tissue that they simply cannot be tolerated for a prolonged period of time. Due to this irritant potential, it is unlikely that any human could remain in the presence of formaldehyde at sustained concentrations (≥6 ppm). The lack of any nasal tissue histopathology (i.e., squamous metaplasia/ hyperplasia) in rats or monkeys following chronic inha- lation exposure to formaldehyde at <3 ppm also attest to the likely lack of such effects in humans exposed at the same concentrations. Indeed, the threshold limit value (TLV) of 5 ppm as a time-weighted average (TWA), which was in place from 1948 to 1962, was changed in 1963 to a ceiling (i.e., maximum instantaneous concentrations) and subsequently lowered to 2 ppm (ceiling) and eventu- ally to a ceiling of 0.3 ppm (Paustenbach et al., 1997). It is now well established that formaldehyde levels in the range of ≈5 ppm can produce the cytotoxicity and cellu- lar proliferation that are the obligatory precursor events in nasal carcinogenesis. This is supported by the INDEX (2005) report, which concluded, “A large body of data suggests an association between the cytotoxic, genotoxic, and carcinogenic effects of formaldehyde. The crucial role of tissue damage followed by hyperplasia and metaplasia of the nasal respiratory epithelium in formaldehyde car- cinogenesis has been demonstrated in a convincing way. Thus, formaldehyde in non-cytotoxic concentrations most probably cannot act as a complete carcinogen.” Substantial evidence on epidemiology, toxicology, and mode of action with formaldehyde calls into question the default that serves as the basis for US EPA’s current cancer 10−6 risk potency value for formaldehyde (0.08 ppb), a calcu- lation that assumes there is no threshold for nasal tumori- genesis and thus no safe level of exposure (IRIS, 1991). The most recent US EPA/IRIS (2010a) evaluation of formalde- hyde lowered the 10−6 risk value to 0.008 ppb (8 ppt), a level well below the range of formaldehyde measured in human breath (i.e., <0.5–2 ppb) or air concentrations in pristine rural locations. In fact, based on this value (i.e., 0.008 ppb), the range of exhaled formaldehyde in human breath would pose unacceptable cancer risks (i.e., >10−4). For all practi- cal purposes, this exposure recommendation suggests that talking to one another carries a potential cancer risk from exhaled formaldehyde in the breath. According to US EPA’s cancer risk assessment guidelines, the default assumption is meant to be used when there are no data establishing a mode of action inconsistent with low-dose linearity or the absence of a threshold (US EPA, 2005). The amount and consistency of the data that have been developed charac- terizing the MOA for formaldehyde-induced nasal tumors would appear to support departing from the no-threshold default assumption and applying a mode of action–based risk value. This position has been taken by numerous regu- latory or authoritative bodies in concluding that the form- aldehyde exposure concentration protective for sensory irritation is also protective for nasal cancer. Additional new data further challenge the current pre- sumption of no threshold for formaldehyde-induced nasal tumors in rodents and derivation of cancer risk values based on linear extrapolations from either animal or epidemiol- ogy data. A recent study by Moeller et al. (2010) determined the presence of endogenous and exogenous formalde- hyde-DNA adducts from nasal mucosa and bone marrow of cynomolgus macaques exposed to 1.9 and 6.1ppm of 13CD2-formaldehyde for 6 hours a day for 2 consecutive days. Both exogenous and endogenous formaldehyde- DNA adducts were readily detected and quantified in the nasal tissues of both exposure groups, with an exposure- dependent increase in exogenous formaldehyde-DNA adducts observed. In the nasal tissue DNA, exogenous formaldehyde-DNA adducts were present at 0.26± 0.04 and 0.41 ± 0.41 adducts/107 dG (N2-hydroxymethyl-dG) follow- ing the 1.9 and 6.1 ppm exposures, respectively, whereas endogenous adducts were present in the nasal DNA of all animals, with an average of 2.24± 0.50 adducts/107 dG. It is unlikely that any mechanism exists in which exogenous formaldehyde-DNA adducts formed following 1.9 or Critical Reviews in Toxicology