680 R. Golden for 22 hours/day, 7 days/week for 26 weeks, followed by histological examination of the lungs, trachea, and nasal turbinates. There was no incidence of monkeys with squamous metaplasia/hyperplasia in nasal turbinate epithelium at 0.98 ppm (Rusch et al. (1983). Due to differences in airway anatomy and airflow between rats and humans (e.g., rats are obligate nose breathers), tissue damage in humans requires form- aldehyde air concentrations even higher than those associated with tissue damage in rats (Kimbell et al., 2001; Conolly et al., 2004). As discussed below, the data documenting the lack of chronic formaldehyde-induced nasal histopathology at concentrations of 1 ppm or less challenge the derivation of Chronic Reference Exposure levels (RELs) or other regulatory guidance levels based on reports of nasal lesions (i.e., rhinitis, squamous meta- plasia or dysplasia) in occupationally exposed work- ers. Although these types of nasal lesions undoubtedly occurred as reported, the compelling lack of such lesions in both rats and monkeys following chronic exposure to formaldehyde alone (at concentrations far greater than would be achieved in an occupational setting) suggests that other co-exposures or levels of formaldehyde much higher than reported likely played contributory roles in such reports. C.Short- versus long-term exposure for formaldehyde- induced sensory irritation For formaldehyde-induced sensory irritation, there are essentially no meaningful differences between short-term and longer-term exposure (US EPA, 2004; NAS, 2007; Shusterman et al., 2006). As concluded by NAS (2007), “Formaldehyde irritation does not appear to follow Haber’s law (concentration [c] × exposure time [t] = response [k] for extrapolating between short-term and long-term toxicity levels. Generally, concentrations that do not produce short-term sensory irritation also do not produce sensory irritation after repeated exposure.” Also noted by NAS (2007) was that “The degree of sensory and irritant effects at lower exposure levels depends on concentration rather than duration.” This conclusion is based on test results derived from human chamber studies (and now confirmed by genomics data) that show that once symptoms are produced at a certain concentration, they are not enhanced with additional exposure time. It should be emphasized that this phe- nomenon (i.e., lack of time as a component) applies only to sensory irritation and not to tissue-damaging events such as cytotoxicity following exposure to higher concentrations. In addition, even for sensitive individ- uals, as concluded by Paustenbach et al. (1997), “The data indicated that below 1.0 ppm, if irritation occurs in some persons, the effects rapidly subside due to ‘accom- modation.’” This conclusion is essentially echoed by a more recent review, “Accommodation to low concentra- tions that cause short-term irritation has been reported; in such cases, irritation subsides with exposure dura- tion” (NAS, 2007). D.Exposure-response characterization of formaldehyde-induced sensory irritation It has long been appreciated that workplace exposure to sufficient levels of formaldehyde was associated with sensory irritation. However, with regulations in place to protect against such effects, the focus on non-occupational exposures has been more recent. Part of the initial rationale for the study of the possible adverse health effects of formaldehyde from exposure in the indoor residential environment began in the late 1960s and early 1970s as a result of the increased use of urea-formaldehyde foam insulation in homes and the use of formaldehyde-containing glues and adhesives in composite wood panels and particle board used in manufactured housing. This change in practice led to numerous studies all directed at determining the con- centrations of formaldehyde at which the symptoms of sensory irritation occurred, with the goal of first understanding exposure-response relationships and then using such data to establish exposure levels that would be protective for the most sensitive members of the population. These studies fall into several broad categories, including workplace, community (i.e., resi- dential), and controlled chamber studies. 1.Occupational and residential exposure studies With respect to workplace studies, many (and quite possibly most or all) are confounded to varying degrees by mixed exposures to wood dust, terpenes, and other airborne substances (e.g., Alexandersson and Hedenstierna, 1989); furniture lacquers, textiles, paint, plywood, polyethylene, and chipboard that con- tained formaldehyde (e.g., Nordman et al., 1985); or particulates, phenol, sodium hydroxide, and carbon monoxide (e.g., Horvath et al., 1988). Similarly, stud- ies investigating pulmonary function or nasal epithelial lesions (i.e., cytotoxicity such as squamous metaplasia or dysplasia) are also often confounded by simulta- neous exposure to particulates (and typically other chemicals as well), which may change the dynamics of detoxification and respiratory tract penetration due to surface adsorption/desorption. For example, as noted by ATSDR (1999), “Effect levels associated with formaldehyde-induced changes in pulmonary function variables in workers exposed to airborne formaldehyde concentrations generally less than 1 ppm…are not of suf- ficient magnitude to be of obvious clinical significance, have not been observed consistently across studies, and may be confounded, in some cases, by the presence of wood dust particulates which may facilitate transport of adsorbed formaldehyde to deeper regions of the respi- ratory tract compared with low-level exposure to form- aldehyde alone.” Eveninthestudiesinwhichmildnasalepitheliallesions have been observed in formaldehyde-exposed workers, there are questions concerning potential confounders that make it difficult to attribute reported effects to form- aldehyde alone. Examples of such confounded studies Critical Reviews in Toxicology