714 R. Golden review), Table 5 illustrates some examples that could “… lead to the occurrence and reporting of false positives.” The issues summarized in Table 5 suggest that the NCI studies should have been more critically assessed by reviewing agencies instead of simply accepting the reported results. The numerous analyses (some of which have not been cited in review documents) of the NCI data set by Marsh and colleagues on both NPC and leukemia as iden- tified in Table 5 raise a number of relevant issues. The read- ers are left to assess the validity and biological plausibility of the purported causal association between formaldehyde exposure and the development of either NPC or leukemia. E.US EPA’s projected cancer risks from inhaled formaldehyde Based primarily on the NCI cohort studies on 25,000 exposed workers, the US EPA/IRIS (2010a) assessment con- cluded that exposure to formaldehyde caused all four types of leukemia (AML, CML, ALL, CLL), Hodgkin’s lymphoma, and NPC. Recognizing that it was not possible to extrapo- late potential risks based on the peak exposure metric, for leukemia and lymphoma, risk estimates were based on the RRs using the cumulative exposure metric (none of which were statistically significant) for both endpoints. Using data from the Surveillance, Epidemiology, and End Results (SEER) registry, crude upper bound projections of the number of people who would develop these cancers each year in the United States from exposure to formaldehyde were developed. Based on the SEER data, each year in the United States there are approximately 44,800 cases of leu- kemia (all types), 8500 cases of Hodgkin’s lymphoma, and about 2100 cases of NPC. Table 6 illustrates the US EPA/ IRIS cancer projections based on assumed exposures of 5 ppb and 20 ppb of formaldehyde (a common level found in indoor air) and the fraction of total yearly cases attributed to formaldehyde at these exposure levels. In addition, since the relationship between exposure to formaldehyde and disease is approximately proportional, the cases that might result from exposure to the ACGIH (i.e., 300 ppb) or OSHA (750 ppb) standards, which are 15 and 38 times more, respectively than 20 ppb, are included. In addi- tion, because formaldehyde is exhaled in the breath at an upper limit of ≈2 ppb, US EPA’s cancer projections would suggest that such levels could be the cause of 758/44,800, 136/8500, and 88/2100 yearly cases of leukemia, Hodgkin’s lymphoma, and NPC, respectively, in the United States. The cancer projections illustrated in Table 6 were criti- cized by scientists from one of the government agencies that reviewed the draft US EPA/IRIS prior to its release, i.e., “Given this large uncertainty [i.e., problems pertain- ing to the use of the peak exposure metric], and the lack of significance with any other metric, it seems premature at this time to use this [cumulative exposure] as a basis of cause and effect, and then to take the non-significant exposure trend for cumulative exposure and base an esti- mate of risk on it” (US CPSC, 2010). Becauseof thehighlyuncertainnature ofanyassociations between inhalation exposure to formaldehyde and either NPC or leukemia, no credible evaluation is possible for esti- mating likely incidence. This conclusion is particularly the case for leukemia, since the plausibility for this association appears to depend on a biologically implausible mode of action as well as ignoring the unequivocal demonstration that no inhaled formaldehyde is transported beyond the nasal epithelium to reach any distal sites in the body. VI.Conclusions If ever there were a compelling case for an evidence- based assessment of an extraordinarily large body of data, Table 5. Possible contributors leading to false positive results in NCI cohort studies. Generic issue Suggested examples Chance Statistically significant deficits in leukemia mortality in internal non- and low-exposed comparison groups that substantially influence RR calculations. This single issue alone, if properly addressed and accounted for, would appear to undermine any conclusion about a causal association between formaldehyde exposure and leukemia. Systematic errors in design Questionable reliance on an unconventional measure of exposure, (i.e., peak); all significant associations of study with leukemia mortality disappeared when assessed using cumulative number of peaks ≥4 ppm as a more appropriate metric of potential exposure. Analysis of study Failure to consider using an external comparison group in light of significant mortality deficits in internal groups; as shown by the Marsh et al. (2004) analysis, significant effects disappeared when this was done. In addition, the implications of >1000 deaths missed in the 1994 follow-up, and the substantial effects of these missed deaths on the RRs as shown in Table 2, should have been addressed. Inadequate accounting for Previous employment in occupations with exposure to known risk factors for NPC. confounding variables Table 6. Projected number of cases/year of leukemia, Hodgkin’s lymphoma, and NPC attributable to formaldehyde at various exposure levels. Endpoint Leukemia Hodgkin’s lymphoma NPC Incident number cases/ year in US 44,800 8500 2100 5 ppb 1900 564 220 Projected cases at various formaldehyde exposures 20 ppb 300 ppb 7580 Everyone? 1360 Everyone? 880 Everyone? 750 ppb Everyone? Everyone? Everyone? Critical Reviews in Toxicology