700 R. Golden modeled exposure estimates (no formaldehyde mea- surements were available), mortality from myeloid leu- kemia was significantly increased with number of years of embalming (ptrend = .02) and increasing peak formal- dehyde exposure (ptrend = .036). Compared with subjects who performed fewer than 500 lifetime embalmings, myeloid leukemia mortality was elevated among those with more than 34 years of embalming (OR = 3.9, 95% CI 1.2–12.5, p = .012), with more than 3068 embalmings (OR = 3.0, 95% CI 1.0–9.2, p = .043). However, a key issue in the Hauptmann et al. (2009) study calls into ques- tion the rigor of their analysis and the likelihood that the reported results are correct. Because there was only one case of myeloid leukemia in the reference group of non-embalmers, risks for this condition were evaluated in a different comparison group consisting of individu- als who performed less than 500 lifetime embalmings in order to include five additional cases of myeloid leuke- mia in the reference group for purposes of risk assess- ment. As stated by the authors, “These represent more conservative but probably more reliable risk estimates for high-level exposure than those shown in Table 3.” A simple inspection of the ORs for myeloid leukemia in their Table 4 shows quite clearly that there is no significant trend, even though the ptrend values are reported as significant. However, in a footnote to Table 4, it is noted that “Trend tests for LHPM of non-lymphoid origin and myeloid leuke- mia are the same as those presented in Table 3.” In other words, none of the results presented in Table 4, which are described as “more reliable risk estimates” than those shown in Table 3, were actually tested for statistical sig- nificance. This substantial error calls into question the conclusions of this study. This issue was the subject of a Letter-to-the Editor of the Journal of the National Cancer Institute (JNCI) by Cole et al. (2010), which noted that “Surprisingly, the more reliable exposure–response analyses are not accompa- nied by their attendant P values. Even more perplexing is that they were accompanied by the P values obtained from the less reliable data…We are left with a study that is described as positive for a formaldehyde–myeloid leu- kemia association among embalmers but which provides little evidence of an overall excess of myeloid leukemia among them and whose most reliable data on exposure– response relationships were not tested for statistical significance.” In their response, Hauptmann et al. (2010) failed to address the key issue raised by Cole et al. (2010) of transferring the same p values from Table 3 to Table 4 without actually testing the findings presented in Table 4 for statistical significance. The findings reported by Hauptmann et al. (2009) are not new, since most of the previous studies on embalm- ers, pathologists, and anatomists have reported increased risk of leukemia. These findings have been attributed to either reporting bias, some exposure other than formaldehyde-related substances in the embalming, or to infectious agents (Harrington and Shannon, 1975; Walrath and Fraumeni, 1983, 1984; Stroup et al., 1986; Hayes et al., 1990). In the Hauptmann et al. (2009) study, formaldehyde exposure was never measured but rather inferred based on the number of embalming used as a surrogate. As noted by Hauptmann et al. (2009), embalm- ing fluids are complex mixtures including other chemi- cals along with formaldehyde, including isopropanol, ethylene glycol, methanol, phenol, and glutaraldehyde. In addition, these fluids often contain a variety of organic dyes (some of which may be mutagenic) used as color- ing agents and the mixture of chemicals in embalming fluids has changed over the years. Although the potential carcinogenicity of this mixture of chemicals is unknown, it is apparent that embalming involves exposure to more than just formaldehyde. Because the number of embalm- ings was one of the best predictors of risk of leukemia according to Hauptmann et al. (2009), it is possible that another component of embalming fluids is related to the increased risk to the extent that any increased risk was even demonstrated based on the issues pertaining to the reporting of results. Consequently, although there might be some equivo- cal evidence of a possible association between formal- dehyde exposure and myeloid leukemia, this evidence can hardly be characterized as “strong,” since three of the four studies (Coggon et al., 2003; Pinkerton et al., 2004; Beane Freeman et al., 2009) expressly state that there was not a statistically significant association and/ or exposure-response relationship between formalde- hyde exposure and myeloid leukemia. This consistent finding among three diverse studies, which collectively involved more than 50,000 occupationally exposed workers, calls into question the strength or confidence of the results of the fourth study (Hauptmann et al., 2009). Consequently, there is only a weak foundation for the NTP (2009) expert panel’s conclusion that there was “sufficient” evidence of an association between formal- dehyde exposure and myeloid leukemia. This is particu- larly evident because the largest of these studies (Beane Freeman et al., 2009) unequivocally does not show any significant association between formaldehyde exposure and myeloid leukemia in a cohort of more than 25,000 exposed workers. The recent US EPA (2010a) IRIS assessment of form- aldehyde goes beyond the conclusions of either IARC or NTP by concluding that there is a causal association between exposure to formaldehyde and all forms of leu- kemia, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), and chronic lymphoid leukemia (CLL) as well as Hodgkin’s lymphoma. As described in the US EPA (2005) cancer risk assessment guidelines, a weight-of-evidence evaluation for cancer requires consideration of existing human data, animal data, and mode-of-action data. As acknowledged in the IRIS (2010) assessment, there are neither animal data nor leukemia-specific empirical mode-of-action (MOA) data supporting a conclusion that formaldehyde causes any kind of lymphohematopoietic (LHP) malignancies. Consequently, the epidemiology Critical Reviews in Toxicology