6.1 ppm exposures, which contribute less than the stan- dard deviation of identical endogenous formaldehyde- DNA adducts, could drive the biology that leads to nasal carcinogenesis in a non-threshold manner. Consequently, a formaldehyde vapor concentration of 0.1 ppm, which is protective for sensory irritation of the eyes, will also be far below the level that would initiate the sequence of events leading to nasal cancer, even in the most exposed tissues in the proximal epithelium of the nasal tract. C.Leukemia With respect to formaldehyde-induced leukemia, there remain substantial uncertainties concerning this associa- tion, in particular the questionable biological plausibility for this endpoint. As discussed, the epidemiology findings for leukemia are equivocal, with the significant mortality deficits for this endpoint in non- and low-exposed workers in the NCI cohort studies that are used for purposes of the internal comparisons substantially driving the reported results. Although the NCI cohort studies by Hauptmann et al. (2003) and the update by Beane Freeman et al. (2009) are discussed and substantially relied upon in the various evaluations, none of these critical reviews address the obvious problems and implications of the leukemia mortality deficits. As reported by Marsh et al. (2004) who reanalyzed the NCI cohort data (although this study was not cited in the US EPA/IRIS assessment), when the leu- kemia mortality in exposed workers was compared to local rates, there was no increase. Although the Zhang et al. (2010) study results in Chinese workers were clearly in conflict with the established chem- istry, biochemistry, and toxicokinetics of formaldehyde, they were uncritically accepted by IARC, NTP, and US EPA in their evaluations. In particular, the characterizations in the assessments by IARC and NTP of the biochemical data concerning methanediol with the implication that this formaldehyde hydration product might be a way that free formaldehyde could be transported and released at dis- tant sites were inappropriate. In addition, the assertion by Zhang et al. (2010) that a reported finding of aneuploidy, as demonstrated by increased monosomy 7 and trisomy 8 in healthy workers, was an early indication of future leu- kemia should have raised a flag, since there is no test in hematology or clinical medicine that is predictive of this disease. Furthermore, the literature on formaldehyde- induced mutations, both in vitro and in vivo, has not dem- onstrated that aneuploidy is a consequence of exposure. Instead, without considering any of the numerous meth- odological and interpretative issues as discussed in this review, this study was uncritically accepted as support for the equivocal epidemiology findings. Relevant data from the Zhang et al. (2010) study were recently obtained pursuant to a Freedom of Information Act (FOIA) request to NCI. A critical assessment of these data will be addressed in a separate publication. One aspect of the information obtained that requires minimum analysis concerns the number of cells that were counted as the basis for the key reported finding. Determination of monosomy © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 713 7 and trisomy 8 in exposed workers (N = 10) and controls (N = 12) was examined in cultured CFU-GM colony cells using fluorescence in situ hybridization (FISH) and as described by Zhang et al. (2010), “…all scorable metaphase spreads on each slide were analyzed, and a minimum of 150 cells per subject were counted.” Based on this analysis, it was reported that the frequency of monosomy 7 and trisomy 8 in exposed workers were significantly elevated compared to controls. From this it was concluded that formaldehyde exposure was “…associated with an increase in leukemia- specific chromosomal aneuploidy in the hematopoietic pro- genitor cells of the exposed workers.” However, the raw data obtained from NCI clearly has shown that far fewer cells were actually analyzed in the majority of cases than the minimum of 150 cells per subject, as stated. For monosomy 7, there were only 1 exposed and 4 control cases in which 150 cells were scored and for the remaining cases, the total number of cells counted ranged from 18 to 140. For trisomy 8, there were only 3 exposed and 3 controls in which 150 cells were scored, with the remaining cases reported cells counts ranging from 21 to 149. This deficiency has a sub- stantial effect on the reported differences between exposed and controls, since FISH assays are subject to correction for background and sensitivity errors and due to statistical limitations inherent in scoring of FISH assays, a minimum of 200 cells are typically required in order to report a valid result in a clinical setting. For example, although statisti- cally significant differences were reported for trisomy 8 (1.21% and 0.32% for exposed and unexposed subjects, respectively), if the analysis is limited to cases where >100 cells (but <150) are counted, the percentage with trisomy 8 is nearly identical (i.e., 1.04% and 0.94% for exposed and controls, respectively. This preliminary analysis of one of the major reported findings from the Zhang et al. (2010) study suggests that caution be used in relying on such data as the basis for any conclusions about the likelihood of formaldehyde-induced leukemia. Consequently, given the substantial uncertainties in the epidemiology data as well as the highly question- able biological plausibility that inhaled formaldehyde was capable of inducing leukemia, no attempt was made here to derive a formaldehyde exposure level that would be protective for leukemia. Unless other empirical data appear that would offset what is now known about the likelihood of formaldehyde-induced leukemia, it can be concluded that a formaldehyde concentration of 0.1 ppm would be protective for leukemia or cancer at any other site within the body. D.Chance as a potential source of uncertainty in epidemiology studies Because there appears to be a reasonable likelihood that both of the key epidemiology results reported (i.e., increased NPC and leukemia) could be false positives, it is illustrative to note a recent commentary by Boffetta et al. (2008) on false-positive results in cancer epide- miology studies. According to these authors (and using as examples some of the generic issues raised in this