The remainder of this discussion provides a broad overview of the data and their implications on the three endpoints of primary concern in this review, i.e., sensory irritation, NPC, and leukemia. A.Sensory irritation For formaldehyde-induced sensory irritation, because the extensive controlled human exposure data have been widely accepted by numerous regulatory and authorita- tive entities, there is little dispute that these data accu- rately and quantitatively characterize human responses, including expected behavior in sensitive individuals and people with asthma. However, these results were not the primary basis for assessing human sensory irritation responses to formaldehyde. For instance, the US EPA/ IRIS (2010a) formaldehyde assessment established the reference concentrations (RfCs) for sensory irritation based on three “co-critical” residential and mobile home exposure studies (Ritchie and Lennen, 1987; Hanrahan et al., 1984; Liu et al., 1991) while marginalizing the con- trolled human volunteer chamber studies. They argue that the controlled human chamber studies are acute in nature, use few individuals, and include only healthy volunteers. However, deficiencies of the studies relied upon are not discussed. Because indoor air is a complex mixture of numerous chemicals (e.g., VOCs) and biologi- cal substances (e.g., fungal spores), which themselves produce irritant effects, any conclusions attributing such effects solely to formaldehyde in these types of environ- ments are suspect. With respect to the assertion that the controlled stud- ies are acute in nature (even though several span several weeks), ignore the results derived from human chamber studies that show that once symptoms are produced at a certain concentration, they are not enhanced with addi- tional exposure duration. Notably, the issue of Haber’s Law and the line of analysis upon which NAS (2007) relied to establish chronic exposure levels based on the controlled human exposure data is not mentioned in the Draft US EPA/IRIS Assessment. Importantly, Haber’s Law is not relevant for formaldehyde-induced irritation effects, an observation confirmed by Andersen et al. (2008, 2010) with toxicogenomic data demonstrating that continuing exposure at doses <2 ppm do not result in a progression of responses. The minimal response concen- tration of a family of seven sensitive response genes was essentially identical for 1, 4, and 13 weeks of exposure. The fact that the large body of controlled human expo- sure data has been reviewed and/or relied upon numer- ous times for establishing formaldehyde air levels to prevent the symptoms of sensory irritation by regulatory and authoritative bodies worldwide (e.g., US EPA, NAS, Canada’s Health Canada, Australia’s NICNAS, Germany’s 2 The OR of 14.41 in the abstract was incorrectly listed for “silversmithing” alone and should have been 7.31 as in the text for “silversmithing and other metal work” with the same 95% CI of 1.08–82.1 as shown in Table 4 of Marsh et al. (2007) (G. Marsh, personal communication). © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 711 BFR, OECD, WHO), attests to their validity and useful- ness. Consequently, the indoor air value established in this review of 0.1 ppm can be considered to be protective from the symptoms of sensory irritation for all individu- als, including children, asthmatics, and the elderly, for a lifetime of exposure. Since the data relied upon were derived exclusively from controlled human exposure studies, there is no justification for further “adjustments” by the use of uncertainty factors. In contrast, the US EPA/ IRIS RfCs for sensory irritation ranged from 9.5 to 23 ppb or 32 to 70 ppb incorporating an uncertainty factor (UF) of 3 or 1, respectively. As discussed in this review, because the studies investigating formaldehyde and sensory irri- tation in either residential or occupational environments involve numerous confounding co-exposures, there is substantial certainty that they are not a valid basis for reaching conclusions on the effects of exposure to form- aldehyde alone. B.Nasopharyngeal cancer (NPC) The epidemiology data causally linking formaldehyde exposure to the development NPC are equivocal with the findings from the NCI 10-plant study by Hauptmann et al. (2004) as the primary evidence for this associa- tion. The distribution of NPC cases over the 10 plants studied with five cases at 1 plant and the other four cases randomly distributed among the remaining 9 plants is inconsistent with a causal relationship to exposure. The lack of any increase in NPC in an additional 25,000 occupationally exposed workers, many of whom were exposed to higher formaldehyde levels than in the NCI cohort, also do not support a causal association (Coggon et al., 2003; Pinkerton et al., 2004). The multiple analyses of Plant 1 and the NCI cohort data by Marsh et al. (2002, 2005, 2007a, 2007b) also cast doubt on this association. Characterizations of these analyses in the US EPA/IRIS document are of interest. While noting the numerous analyses by Marsh and colleagues of Plant 1, US EPA/IRIS concludes that “…no convincing and consistent alterna- tive hypothesis of causation has been identified” (US EPA, 2010a, pp. 6–18). Marsh et al. (2007) showed that previous employment in metalworking industries was highly likely and could readily explain the NPC cases in Plant 1. Since all of the NPC cases in Plant 1 occurred after a relatively short time of employment at this facility, such a scenario is inconsistent with a causal relationship between NPC and formaldehyde. The US EPA/IRIS assessment cor- rectly notes a discrepancy between the Marsh et al. (2007) abstract and text in the OR for “silversmithing and other metal work.”2 Additionally, it is implied that mul- tiple comparisons in Marsh et al. (2007) may have led to the reported observation with silversmithing. This inter- pretation is incorrect, since this study was not an explor- atory “fishing expedition” type of analysis. The issue of previous employment was an a priori hypothesis that was tested with a limited number of comparisons. The proposed causal link between formaldehyde and NPC in humans is also inconsistent with the mechanistic