3.False positives in formaldehyde-induced sensory irritation A crucial distinction between controlled studies and those where responses are simply reported based on ambient exposure levels (whatever they might be) is that it is difficult (if not impossible) to reliably determine whether formaldehyde actually causes irritation at levels below about 1 ppm. This is because when some people are intentionally exposed to air with formaldehyde lev- els below 1 ppm and some are exposed to clean air (i.e., formaldehyde-free), 20–30% of those exposed to clean air will still report responses of sensory irritation (i.e., false positives) (Bender, 2002; OECD/SIDS, 2002). For exam- ple, after reviewing this large body of data, the Australian Indoor air exposure limit for formaldehyde 683 government (NICNAS, 2006) determined that “…chamber studies also found that some individuals begin to sense irritation from 0.5 ppm (0.6 mg/m3), although the response rate is often similar to that reported in controls. There is limited evidence that some individuals report sensory irri- tation as low as 0.25 ppm (0.3 mg/m3), however, the data is very unreliable. Therefore, the lowest observed effect level (LOEL) is considered to be 0.5 ppm.” Although there are no data specifically identifying different formaldehyde con- centrations below 1 ppm and the associated frequencies of false-positive reports of sensory irritation, it appears reasonable that such reports would be greater at 0.1 ppm than at 0.3 ppm, the consensus level below which sensory Table 1. Summary of authoritative or comprehensive evaluations and other relevant data on formaldehyde exposure concentrations associated with or protective from symptoms of sensory irritation or other adverse effects. Formaldehyde air concentration (ppm) Source Comment/observation 6−15 Monticello et al. 1996; Kerns et al. Chronic inhalation dose range required for the sustained cytotoxicity and 1983a, b; regenerative proliferation leading to development of nasal tumors. 1.0 0.9 0.75 0.7 0.5 0.3 0.2 0.1 0.08 TNO, 2003; Arts et al., 2006 “..… minimal/mild/slight eye irritation starts at levels of 1.0 ppm formaldehyde and higher.” EPA, 2004; Acute exposure “At 0.35 to 0.9 ppm, the subject’s subjective eye irritation responses ranged guideline level (AEGL) from none to slight, the same as their responses to clean air.” OSHA, 2006; (Occupational In effect for many years with no evidence of significant worker complaints of exposure standard)Noisel et al. sensory irritation. “The level of 0.75 ppm can be considered as a safe level that 2007 allows protecting virtually all workers.” Noisel et al. (2007) Noisel et al., 2007 “The level of 0.75ppm can be considered as a safe level that allows protecting virtually all workers.” Andersen et al., 2008, 2010 Inhaled concentration in rats that produces no significant toxicogenomic changes in nasal epithelial cells following 21 or 90 days of exposure. Lang et al., 2008 (most recent ““… the no-observed-effect level for subjective and objective eye irritation due controlled human study) EPA/ to formaldehyde exposure was 0.5 ppm in case of constant exposure level and NCEA 2005 0.3 ppm with peaks of 0.6 ppm in terms of short term peak exposures.”Clear threshold at 0.5 ppm for any effects (including odor) with an effective concentration at 1.5 ppm for moderate effects. US EPA/NCEA, 2005 Clear threshold at 0.5 ppm for any effects (including odor) with an effective concentration at 1.5 ppm for moderate effects. ATSDR, 1999, 2007 NAS, 2007 Most weight of evidence–based reviews conclude that 0.3 ppm is a reasonable WHO, 2010 ACGIH, 2001 MAK, and appropriate level below which symptoms of sensory irritation are unlikely 2006 OECD/SIDS, 2002 NICNAS, to occur, e.g., “…symptoms of eye and mucous membrane irritation at that 2005 concentration were not increased above control conditions in controlled chamber studies.” (NAS, 2007) and “Studies in the literature have reported a variety of responses induced by exposure to gaseous formaldehyde, generally beginning in the range of 0.3 to 0.5 ppm for eye irritation, the most sensitive endpoint. However, the severity of response at these levels is generally mild, and only a small portion of the population may respond.” (OECD/SIDS, 2002). SCOEL, 2008 “This especially considers possible interindividual differences in susceptibility to irritation by formaldehyde, which may be expected based on the entire body of data.” BfR, 2006; Health Canada, 2001, Partially derived from animal data, i.e., “The proposed level of 0.1 ppm is 2 2005; ASHRAE NASA/NAS, 2008 fold lower than the level derived from animal data by applying appropriate safety factors.” [emphasis in original]. 0.1 ppm (1 hour) = 1/5th of NOAEL (i.e., 0.5 ppm) for eye irritation. WHO, (2010); Wolkoff and Nielsen, “An air quality guideline of 0.1mg/m3 (0.08 ppm) is considered protective 2010 against both acute and chronic sensory irritation in the airways in the general population assuming a log normal distribution of nasal sensory irritation.” “Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies…. the guideline value of the WHO [of ]… 0.08 ppm FA, is considered preventive of carcinogenic effects in compliance with epidemiological findings.” WHO, 2010; Nielsen and Wolkoff, 2010 “Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies…the guideline value of the WHO [of ]…0.08 ppm FA, is considered preventive of carcinogenic effects in compliance with epidemiological findings.” © 2011 Informa Healthcare USA, Inc.