data must be unequivocal in demonstrating a causal association between exposure to formaldehyde and all forms of leukemia and non-Hodgkin’s lymphoma. In fact, as shown in this review, the available epidemiologic data do not support this conclusion. 3.Meta-analyses of leukemia data Several conflicting meta-analyses attest to the uncer- tainty of the formaldehyde-leukemia association. Collins and Lineker (2004) examined 18 epidemiology studies of workers exposed to formaldehyde where leukemia rates were reported and calculated meta-relative risk (mRR) values. The analysis stratified exposure according to occupation, thereby providing the ability to compare results based on formaldehyde exposure. There was a small increase in leukemia among embalmers (mRR = 1.6, 95% CI 1.2–6.0), and pathologists/anatomists (mRR = 1.4, 95% CI 1.0–1.9). However, in industrial workers, who have been reported to have the highest formaldehyde exposures, the mRR was 0.9 (95% CI 0.8–1.0). In a more recent meta-analysis, Zhang et al. (2008) assessed many of the same studies, although there was no stratification according to exposure. In this analysis the overall mRR for leukemia was 1.54 (95% CI 1.18–2.00), but it is not possible to ascertain if the RR would have been higher in the less-exposed cohorts compared to the more highly exposed cohorts, as reported by Collins and Lineker (2004). In the most recent meta-analysis of the data for both leukemia and NPC, Bachand et al. (2010) assessed all cohort, case-control, and proportional mortality (PMR) studies conducted to date. For leukemias the summary relative risk (RR) for cohort studies was 1.05 (95% CI 0.93– 1.20) and the summary odds ratio (OR) for case-control studies was 0.99 (95% CI 0.71–1.37). Although the sum- mary PMR was significantly elevated (PMR = 1.44, 95% CI 1.25–1.67), by design such studies are far less informative than cohort or case-control studies. Most importantly, based on cohort and case-control studies, no significant differences were seen by leukemia subtype, job type, publication period, or region. After excluding the single plant (Plant 1) with the cluster of NPC cases, the sum- mary cohort estimate for nasopharyngeal cancers was not elevated (RR = 0.72, 95% CI 0.40–1.28). Although the summary OR estimate was increased for case-control studies overall, it was not elevated when considering smoking-adjusted studies (OR = 1.10, 95% CI 0.80–1.50). The Bachand et al. (2010) meta-analysis was not cited in or considered by US EPA (2010a) in the IRIS assessment of formaldehyde even though it was available. The Zhang et al. (2009) was exclusively relied on as support for the findings reported by Beane Freeman et al. (2009). With respect to the three meta-analyses, some meth- odological issues may influence reported outcomes, including selection bias and inadequate consideration of the potential for heterogeneity. For example, of the three meta-analyses, both Collins and Lineker (2004) and Bachand et al. (2010) stratify and analyze the data based © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 701 on separate consideration of low-exposure (i.e., embalm- ers and anatomists) and high-exposure (i.e., industrial workers) occupations, whereas Zhang et al. (2009) does not. This stratification may be important because the high-exposure industries have, if anything, a lower collec- tive indication of effect than the low-exposure industries. Althugh Zhang et al. (2009) reported a significant effect across industries, they used what may be considered a subjective means of selecting and combining studies. Rather than using “ever exposed” or “never exposed” as metrics, Zhang et al. (2009) used different measures of exposure, selecting only one from each study even if sev- eral were examined, resulting in their selection of peak exposure for some studies, average exposure for others, cumulative exposure for still others, and exposure dura- tion for the balance. Moreover, when several categories or levels of exposure were examined, they took data from only the highest among them, and what constituted a “high” category also varied considerably among stud- ies, depending on how each study established grada- tions of exposure. As a consequence, the comparisons across studies are very heterogeneous, and it is not clear whether a comparable question was being examined in each case, which may lead to unreliable results in a meta- analysis. Because of the above issues, the conclusions from Zhang et al. (2009) should be interpreted with cau- tion, especially in view of their lack of concordance with other meta-analyses of essentially the same data set. Despite an abundance of epidemiological data, pos- sible conclusions concerning an etiological association between formaldehyde exposure and leukemia remain elusive. As a result, considerations of biological plausibil- ity are that much more important in attempting to shed light on this controversial issue. 4.Leukemia mode-of-action issues When IARC (2006) evaluated formaldehyde, there was skepticism about the reported leukemia findings (e.g., Hauptmann et al., 2003) because no mode of action had been identified to help explain how leukemia might have occurred. There is a detailed understanding of how chemicals cause leukemia (i.e., leukemogenesis) and several critical analyses demonstrate that formaldehyde is not one of those chemicals (Heck and Casanova, 2004; Golden et. al., 2006; Pyatt et al., 2008). In contrast, the chemicals that are known to cause leukemia (e.g., ben- zene and some cancer chemotherapeutic agents such as melphalan, chlorambucil, cyclophosphamide, nitrosou- rea, and topoisomerase inhibitors) share a number of common characteristics. They enter the systemic circu- lation, are distributed to the bone marrow, and induce pancytopenia and myelotoxicity. Most importantly, known human leukemogens also produce leukemia (or some variant lymphohematopoietic malignancy) when administered to rats or mice. In other words, chemical leukemogens produce a similar spectrum of effects in rodents and humans (Golden et al., 2006; Eastmond, 1997). None of these key fundamental characteristics of