An IARC (International Agency for Research on
Cancer) working group categorized
formaldehyde as a human
carcinogen (Group 1) in 2004. A major component of the epidemiologic evidence evaluated by IARC to reach this decision was the analysis published by Hauptmann et al. [Hauptmann, M., Lubin, J. H., Stewart, P. A., Hayes, R. B., Blair, A. 2004. Mortality from solid
cancers among workers in
formaldehyde industries. Am. J. Epidemiol. 159, 1117-1130.] of the National Cancer Institute (NCI) historical cohort comprising industrial workers exposed to
formaldehyde in 10 U.S. plants. The NCI authors emphasized the relationship found between highest
formaldehyde peak exposure and death from
nasopharyngeal cancer (NPC). We performed two additional types of re-analyses of the NCI cohort data with focus on peak exposure and NPC mortality. The analyses were aimed at (1) investigating whether the model specification chosen by Hauptmann et al. (2004) was appropriate (interaction assessment) and (2) exploring the degree of instability of the risk estimates for NPC in relation to highest peak exposure (sensitivity analysis). Hauptmann et al. (2004) failed to account for an important interaction structure between plant group and the exposure variable that prohibits a generalization of
formaldehyde effects within the NCI cohort and, in particular, beyond the NCI cohort. In addition, our sensitivity analysis demonstrates considerable uncertainties in the risk estimates and points convincingly to instability problems particularly related to Plant 1. Even a simple sensitivity model taking only one additional death into account produced a variation of the risk estimates beyond the instability conveyed by standard confidence intervals. The results of our current reanalysis of the NCI study do not support NCI's suggestion of a causal association with
formaldehyde exposure and
nasopharyngeal cancer. The decision by the IARC working group to reclassify
formaldehyde as a Group 1 substance was clearly premature considering: (1) the missing evidence of an NPC excess from the large British and NIOSH cohort studies; (2) the absence of an association with
formaldehyde and NPC in the independent and expanded study of Plant 1; and (3) the mis-specified and non-robust internal analysis of the NCI cohort study brought to light in our current re-analysis. Thus, the 2004 IARC decision to reclassify
formaldehyde as a Group 1 substance should be reconsidered.