formaldehyde would appear to provide the perfect candi- date. As a highly reactive, naturally occurring endogenous compound, with efficient metabolic mechanisms in place to protect against increases in concentrations in any tis- sues, there is a detailed understanding of formaldehyde- induced toxicity. Despite numerous epidemiology studies that have raised a specter of formaldehyde-induced NPC and leukemia, both endpoints now appear more likely to be false positives, as these findings are inconsistent with an ever-increasing body of data demonstrating that such effects simply cannot occur under any real-world expo- sure scenario. Why else would NAS, WHO, SCOEL, BfR, OECD, Health Canada, NICNAS, and for sensory irritation even US EPA (2005) reach conclusions essentially identi- cal to those reached in the present review? When ATSDR (2000) reviewed the carcinogenicity of polychlorinated biphenyls (PCBs), it took a common sense approach for assessing a large body of data by adopting a methodology in which the observed and expected mor- tality from each type of cancer in multiple occupational cohort mortality studies involving thousands of workers were compared to determine if there was a significant dif- ference. In essence, this approach asks the straightforward question—is there a discernable signal from a large body of data in highly exposed workers from many different plants of an increase in a particular type of cancer? When this approach is applied to what are clearly the three larg- est and longest followed formaldehyde-exposed occupa- tional cohorts where this method can be used (i.e., Beane Freeman et al., 2009; Coggon et al., 2003; and Pinkerton et al., 2004), encompassing more than 50,000 workers, the results are illuminating. For leukemia (Table 7), a total of 152 cases have been observed with 153 expected, whereas for NPC a total of 9 cases have been observed with 5 cases expected. Coggin et al. (2003) also assessed a subcohort of 4000 men with high exposure (>2 ppm); no cases of NPC were observed. Notably, the excess of NPC cases in the NCI cohort (Plant 1) quite reasonably attributable to other exposures now stand out even more starkly as unlikely related to formaldehyde. It is difficult to envision a scenario in which the 6 cases of NPC in the approxi- mately 7000 workers in Plant 1 were due to formaldehyde but not a single case of NPC occurred in the other 43,000 occupationally exposed workers. As shown in Table 7, the observed and expected mortality data for leukemia and NPC in more than 50,000 formaldehyde-exposed workers, followed in some cases for more than 60 years, illustrate quite clearly that even occupational exposure to formal- dehyde is not a cause of leukemia or NPC. This is further confirmation that an indoor air formaldehyde concentra- tion of 0.1 ppm, which is protective for the symptoms of sensory irritation, will also be protective for both leukemia and NPC, a conclusion consistent with other reviews. Rhomberg et al. (2011) recently completed a some- what different type of evaluation of essentially the same body of data as in the present review pertaining specifically to the issue of whether formaldehyde was capable of causing leukemia as suggested primarily by © 2011 Informa Healthcare USA, Inc. Indoor air exposure limit for formaldehyde 715 Table 7. Comparison of observed and expected leukemia and NPC mortality in formaldehyde-exposed workers. No. of Leukemia NPC Cohort Workers Observed Expectedb Observed Expected NCIa 25,600 116 ≈116 8 2 Coggin 14,000 12 13 1 2 Pinkerton 11,000 24 ≈24 0 1 Total 50,600 152 153 9 5 a: Beane Freeman et al. (2009) for leukemia and Hauptmann et al. (2004) for NPC. b: When only observed mortality was reported, the expected mortality was calculated by dividing the observed mortality by the SMR. the epidemiology studies. This evaluation involved the application of an explicit hypothesis-based weight-of-ev- idence approach to evaluating the large body of evidence regarding formaldehyde-induced leukemia, including all human, animal, and relevant mode-of-action data and how this large body of evidence informs an overall conclusion. Importantly, this approach explicitly consid- ered an often-overlooked aspect of weight-of-evidence evaluation by also addressing when causal explanations have been devised to account for results already in hand or when post hoc additions or modifications to hypoth- eses are constructed to explain what might otherwise be considered as contradictory findings. As concluded by Rhomberg et al., “Upon comparison of alternative propos- als regarding what causal processes may have led to the array of observations as we see them, we conclude that the case for a causal association is weak and strains biological plausibility. Instead, apparent association between form- aldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding.” Finally, the conclusions of the present review, those by Rhomberg et al. (2011) and now NAS (2011) are remark- ably congruent despite somewhat different approaches and goals. A central theme of these reviews revolves around how best to assess and weigh a substantial amount of evidence in order to reach valid conclusions. The final summary from the NRC committee addresses these overarching issues “…when the review of stud- ies used in the draft IRIS assessment of formaldehyde is compared with the current standard for evidence-based reviews and causal inference, limitations in each step used to generate the draft IRIS assessment are evident. For example, the methods are not clearly described, the review approaches are not transparent, and there is no indication that evidence-grading strategies were uniformly applied. In addition, the selection approach to identifying studies for RfC calculation appears ad hoc.” Acknowledgments The author would like to acknowledge Stewart Holm, Melvin Andersen, and the input from all the anonymous reviewers who provided valuable comments and insights that greatly aided in the revisions of this review paper.