690 R. Golden H.Implications of Table 1 for non-cancer effects Table 1 is primarily a comprehensive compilation of the formaldehyde air concentrations that have been determined by numerous regulatory and/or authorita- tive entities as protective from the symptoms of sensory irritation as derived from the controlled human expo- sure data. The majority of the reviews of the controlled human exposure have determined that 0.3 ppm is a form- aldehyde exposure level below which the symptoms of sensory irritation are unlikely to occur. Although several entities have derived slightly lower values (i.e., 0.2, 0.1, and 0.08 ppm), it is clear that with most comprehensive evaluations clustering at 0.3 ppm that a formaldehyde level of 0.1 ppm as derived and justified in the present review represents a conservative and health-protective concentration for indoor air in residential dwellings. Even the OSHA standard of 0.75 ppm is protective for the symptoms of sensory irritation for the vast major- ity of individuals from occupational exposures. Because Haber’s Law does not apply to formaldehyde-induced sensory irritation, the value of 0.1 ppm derived in the present review provides an additional margin of pro- tection for a lifetime of 24/7 exposures. Importantly, because virtually all of the values listed in Table 1 have been derived from controlled human exposure data, which include sensitive individuals as well as asthmat- ics, there is no basis for the application or use of arbi- trary uncertainty factors to derive lower numbers. IV.Cancer effects A.Recent agency reviews of potential formaldehyde carcinogenicity In 2006, the International Agency for Research on Cancer (IARC) elevated formaldehyde into the category of a “known” human carcinogen based on a conclusion that nasopharyngeal cancer (NPC) was etiologically associ- ated with exposure. This was based primarily on the find- ings from a large 10-plant study conducted by the National Cancer Institute (NCI) involving more than 25,000 work- ers by Hauptmann et al. (2004). While expressing concern about a possible association with leukemia based on epidemiology data, IARC (2006) also expressed skepti- cism about this association because there was no known mechanism to explain how this might occur. Following the most recent formaldehyde meeting, IARC (2009) concluded that the evidence was sufficient to conclude that formaldehyde was also a “known” cause of leuke- mia. This change in listing presumably was related to data presented during the meeting that appeared to sup- port a hypothesized potential mode of action concern- ing formaldehyde-induced leukemia. Although IARC’s conclusions on leukemia were based substantially on an update of the NCI cohort by Beane Freeman et al. (2009), they were also supported by a misguided interpretation of formaldehyde toxicokinetics and a new study in Chinese workers by Zhang et al. (2010) in which it was reported that formaldehyde was associated with negative effects on blood counts and certain chromosomes in formaldehyde- exposed workers. Relevant aspects of the key epidemiol- ogy studies, the Chinese worker study, and mechanistic issues for both NPC and leukemia are discussed. An expert panel of the National Toxicology Program (NTP, 2009) concluded that formaldehyde should be listed as a “known human carcinogen” in the upcoming 12th Report on Carcinogens (RoC) for NPC, sinonasal can- cer and myeloid leukemia. It should be noted that IARC (2009), based on a review of the same epidemiology data, did not conclude that formaldehyde was “known” to cause sinonasal cancer, which is even rarer than NPC. The deci- sion of the NTP expert panel for NPC and myeloid leuke- mia was based on essentially the same epidemiology data as relied upon by IARC, the study by Zhang et al. (2010) in Chinese workers, and also included some discussion on possible mechanisms of formaldehyde-induced leukemia. Because of a number of controversial issues pertaining to the proposed listing by NTP, particularly for myeloid leu- kemia, at the time of this writing, it is not yet known if the 12th RoC, when finalized, will include this endpoint. The US Environmental Protection Agency (US EPA, 2010a) in its draft Integrated Risk Information System (IRIS) assessment of formaldehyde concluded that formaldehyde was etiologically associated with NPC, all forms of leukemia (i.e., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], acute lymphoid leuke- mia [ALL], and chronic lymphoid leukemia [CLL]) and Hodgkin’s lymphoma. As with the IARC and NTP deci- sions, this conclusion was also substantially based on the NCI cohort data (i.e., Beane Freeman et al., 2009), a study by Hauptmann et al. (2009) in embalmers, the Zhang et al. (2010) study in Chinese workers, as well as a meta-anal- ysis of the epidemiology data by Zhang et al. (2009). The IRIS review also concluded that neither animal data nor mode-of-action data were sufficient to support the epi- demiology findings for lymphohematopoieitc malignan- cies. Since all of these studies and issues are discussed in this review, other than for a few specific mechanistic and risk assessment-related issues, the conclusions of the US EPA/IRIS assessment will not be further analyzed. The draft EPA formaldehyde IRIS assessment was recently reviewed by a committee of the National Research Council (NRC) (NAS 2011). This review concluded that the assessment failed to support a causal association between formaldehyde and leukemia or other health problems. The NRC committee concluded that EPA’s claims that formaldehyde causes leukemia, myeloid leukemia or related hematopoietic cancers are not sup- ported in the EPA/IRIS assessment noting “As with the respiratory tract cancers, the draft IRIS assessment does not provide a clear framework for causal determinations. As a result, the conclusions appear to be based on a subjec- tive view of the overall data, and the absence of a causal framework for these cancers is particularly problematic given the inconsistencies in the epidemiologic data, the weak animal data, and the lack of mechanistic data.” In particular, the committee noted that the epidemiologic Critical Reviews in Toxicology