706 R. Golden potential carcinogenic effects of formaldehyde. Part of the problem concerns the endpoints and data sets from which to undertake such an exercise. Two widely disparate types of cancer, NPC and leukemia, have been determined to be causally associated with exposure to formaldehyde by IARC, NTP, and US EPA. However, despite the collective conclusions of these organizations, as summarized in this review, there is no biologically plausible explanation for how formal- dehyde might initiate the sequence of obligatory events required for chemical leukemogenesis, i.e., entry into the blood with subsequent transport to the bone mar- row with resulting myelotoxicity and pancytopenia as early precursors of subsequent leukemia. With no credible evidence that even high-dose formaldehyde exposure, whether by inhalation or ingestion, causes hematotoxicity, there appears to be no hypothetical pathway to the development of lymphohematopoietic malignancies. The lack of biological plausibility is also the most likely explanation for the highly equivocal body of epidemiology data that has been the subject of so much debate and controversy, i.e., reported posi- tive findings must be due to other factors, e.g., chance, errors in study design, confounding, etc. (see Table 5). This conclusion is certainly the case with the NCI cohort studies in which an unexplained deficit in leu- kemia mortality in the non-exposed and low-exposed groups can readily explain the reported findings for leukemia. Consequently, there is no basis for attempt- ing to calculate even a hypothetical safe exposure level for formaldehyde-induced leukemia. A formaldehyde vapor concentration of 0.1 ppm, which is protective for sensory irritation of the eyes, falls well below the exposure level (i.e., ≥6 ppm) that has been shown to initiate the sequence of events, i.e., cytotoxicity and regenerative proliferation with appro- priate accompanying dose-dependent transitions in toxicogenomic changes leading to nasopharyngeal cancer, the tumor that has long been of primary con- cern from the point of view of public health protection. The MOA for formaldehyde-induced nasal tumors in rodents is well characterized and now augmented with substantial toxicogenomic data demonstrating a clear no observed effect level (NOEL) for this event. This NOEL of 0.7 ppm produced no statistically significant gene changes with the evaluation criteria used (i.e., a 2-fold increase with a false discovery rate corrected p value <.05) in the 13-week study by Andersen et al. (2010), consistent with the lack of any other formalde- hyde-induced changes in nasal epithelial tissues at this concentration (i.e., cytotoxicity, regenerative prolifera- tion). Since chronic exposure at this concentration is clearly protective for the development of formalde- hyde-induced nasal tumors, the recommended indoor air level of 0.1 ppm would offer even a further margin of protection for this endpoint. The above logic has been endorsed by a number of regulatory and other standard-setting organizations that have evaluated the carcinogenic potential of formalde- hyde and determined that an indoor air exposure limit based on sensory irritation is adequate to protect human health from cancer risk. For example, Health Canada (2005) concluded that “…formaldehyde-induced carci- nogenicity appears to be a consequence of proliferative regeneration following cytotoxicity, and the risk of cancer associated with formaldehyde levels sufficiently low to prevent irritation and inflammatory responses appears therefore to be negligible.” A similar position was taken by the European Commission’s Scientific Committee on Occupational Exposure Limits (SCOEL, 2008), which stated, “It is generally considered that avoidance of sensory irritation of the eye and the upper respiratory tract would automatically imply a safety margin to avoid irritation- induced local cell proliferation.” Similarly, as noted by Germany’s Federal Institute for Risk Assessment (BfR, 2006), “In the absence of cytotoxicity and regenerative pro- cesses, the theoretical increase in tumor incidence caused by formaldehyde is practically non-relevant.” It should be pointed out that all of the above conclusions are based on the presumption that NPC is the endpoint of concern. However, a recent assessment by Nielsen and Wolkoff (2010), carried out using the framework of the WHO Indoor Air Quality Guideline development (2006–2009), reached the following more comprehensive conclusion concerning both NPC and leukemia, “For nasal can- cer in rats, the exposure–response relationship is highly non-linear, supporting a no-observed-adverse-effect level (NOAEL) that allows setting a guideline value…. Epidemiological studies reported no increased incidence of NPC in humans below a mean level of 1 ppm and peak levels below 4 ppm, consistent with results from rat stud- ies…. Rat studies indicate that cytotoxicity-induced cell proliferation (NOAEL at 1 ppm) is a key mechanism in development of nasal cancer…. Lymphohematopoietic malignancies are not observed consistently in animal studies and if caused by formaldehyde in humans, they are high-dose phenomenons with non-linear exposure– response relationships. Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignan- cies…the guideline value of the WHO [of ]…0.08 ppm FA, is considered preventive of carcinogenic effects in compli- ance with epidemiological findings.” V.Discussion The data summarized in this review cover a wide spec- trum of issues pertaining to formaldehyde chemistry, toxicokinetics, and potential adverse health effects. Although it was not the intent to exhaustively examine everything known about these issues, a number of key overarching messages are worth noting. Unlike most other chemicals, as a naturally occurring endogenous compound with substantial concentrations in the blood and all tissues and with prodigious metabolic capabili- ties in the nasal epithelium and upper respiratory tract, formaldehyde must be considered differently. Data in Critical Reviews in Toxicology