values in [the US EPA/IRIS] document appear to be in the range of normal concentrations in the body and in foods. If formaldehyde is toxic at normally occurring concentra- tions it seems that leukemia rates should be much higher than they are,” the agency scientists observed that “A reality check of formaldehyde in the diet and in healthy individuals compared with lifetime risks of leukemia should be presented. Although an estimated 1 to 10 mg per day ingestion is cited (page 2–11), it is not in proximity to, nor compared with, either the existing data on risk of leukemia from all sources nor with the unit cancer risk of 8.1 × 10−2 per ppm (6.6 × 10−5 per μg/m 3)” (DOD, 2010). As previously noted, IARC (2006) was initially skep- tical concerning the reported epidemiology findings of an association between exposure to formaldehyde and leukemia due to the inability to identify a mode of action. Indeed, as discussed by IARC (2006), the idea that formaldehyde may cause leukemia “…raises a number of mechanistic questions, including the processes by which inhaled formaldehyde may reach a myeloid progenitor.” IARC continues, “…a clastogenic product of FA could conceivably be formed in the blood and circulate to the bone marrow although this has not been suggested in the literature.” And finally, “…it is possible that circulating myeloid progenitor stem cells could be the source of leu- kemia...such cells are present in the blood and plausibly could be exposed to formaldehyde in the respiratory tract vasculature; however, there is no known prototype for such a mechanism of leukemogenesis.” IARC (2006) appears to have addressed and ruled out many of the assumptions and critical issues pertaining to the biological plausibility of the mode of action proposed by DeVoney et al. (2006a, 2006b) and Zhang et al. (2009, 2010). The DeVoney et al. hypotheses has also been critically evaluated by Pyatt et al. (2008) with the conclusions that (1) there was no scientific support that the proposed MOA or any of its elements actually occurs, since there are no relevant supporting data; (2) the apparent speculation that inhaled formaldehyde would cause leukemia via this MOA was unsubstantiated; (3) formaldehyde does not fit the toxicological profile of a chemical capable of inducing leukemogenic transformation in humans; and (4) there is no biologically plausible mechanism to explain how a chemical with no documented hemato- or myelotoxicity could induce leukemia in animals or humans. 5.Chinese worker study Zhang et al. (2010) has brought additional attention to the issue of formaldehyde-induced myeloid leukemia. In this study, Chinese workers (43 exposed and 51 con- trols exposed to median formaldehyde concentrations of 1.28 ppm and 0.026 ppm, respectively) in two factories either producing or using formaldehyde-melamine resins were examined. Endpoints measured included complete blood counts and peripheral stem/progenitor cell colony formation (i.e., colony-forming units [CFUs]). In addition, myeloid progenitor cells were cultured from 10 exposed and 12 unexposed workers to quantify chromosome © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 703 changes, including monosomy 7 and trisomy 8, in meta- phase spreads of these cells. Using peripheral blood from study subjects, colony formation from circulating colony- forming unit (CFU)–granulocyte/macrophage (CFU-GM) progenitor cells was also investigated. A 20% decrease in colony formation from progenitor cells in formaldehyde- exposed workers was reported; however, this was not sta- tistically significant (p = .10). The major findings from the study were the significant difference between exposed and controls in red and white blood cell counts, although all measurements were in the normal clinical range and with the exposed group showing significantly increased frequencies of aneuploidy as reflected by monosomy 7 and trisomy 8 in metaphase spreads of cultured myeloid progenitor cells from peripheral blood. Zhang et al. (2010) interpreted the blood count results as evidence of early bone marrow toxicity (i.e., pancytopenia) and therefore consistent with other known leukemogens such as benzene. The findings of monosomy 7 and trisomy 8 were characterized as leukemia-specific changes also similar to that produced by benzene or therapy-induced AML. However, the reference (i.e., Rowley, 2000) cited by Zhang et al. (2010) as support for the statement that monosomy 7 and trisomy 8 “…are among the most fre- quent cytogenetic changes observed in myeloid leukemia and myelodysplastic syndromes” does not mention either of these aneuploidies. The Zhang et al. (2010) study appears to have method- ological and interpretative deficiencies that could under- mine the stated conclusions, including (1) chromosomes 7 and 8 are minimally relevant to leukemia and their count number in peripheral blood lymphocytes is not known (nor are any references cited in support of this) to have predictive value; (2) there is no accepted diagnos- tic test in clinical medicine, hematology, or hematopa- thology that can establish the presence of leukemia, or increased risk of developing leukemia, by detection of monosomy 7 or trisomy 8 in cultured myeloid progenitor cells from peripheral blood; (3) there are methodologi- cal questions whether the reported aneuploid effects in whatever cells where actually cultured were a reflection of in vivo events or were in vitro artifacts; (4) only infor- mation for chromosomes 7 and 8 were reported, whereas no information was provided for other chromosomes, translocations, or any of the common genetic lesions that are well established as associated with leukemia; (5) in the exposed and control individuals there was no assess- ment of the other common genetic abnormalities seen in AML, e.g., t(8;21), t(15:17), inv(16), or 11q23; and (6) chromosomes 7 and 8 are not typically involved in leuke- mia or therapy-related leukemia (e.g., Rowley and Olney, 2002). For example, as reported by Zheng et al. (2008), in 122 AML patients in China, none had monosomy 7 and only 4 had trisomy 8. A related question is whether formaldehyde induces aneuploidy, since the mutagenic mode of action of formaldehyde has been extensively characterized. Formaldehyde-induced mutations typically occur as