Commentary: mechanistic considerations for associations between formaldehyde exposure and nasopharyngeal carcinoma

The International Agency for Research on Cancer (IARC) has classified formaldehyde as a human carcinogen based, in part, on epidemiological evidence that formaldehyde increases the risk of nasopharyngeal carcinoma (NPC) [1-4]. This cancer exhibits remarkable geographical distribution that is posited to result from environmental factors, host genetic factors (i.e. race), and genetic variation in the gammaherpesvirus Epstein-Barr virus (EBV) that is widely believed to play a role in the etiology of NPC [5-9]. Mechanisms posited to explain formaldehyde carcinogenicity have invoked evidence for cytotoxicity, compensatory cell proliferation, and genotoxicity in animal bioassays [4,10-13]. However, mathematical models of the human respiratory passages indicate that the highest doses of formaldehyde are predicted to be above the hard palate, with relatively less vapor reaching the nasopharynx [14]. Histopathological samples from workers exposed to formaldehyde exhibit only mild nasal tissue pathology [4,15], suggesting that tissue damage might not occur in more distal regions. Thus, available data do not paint a coherent mechanism for formaldehyde to increase the risk of NPC, and moreover the association continues to be disputed [16-18].Few articles published on formaldehyde toxicity over the past decade have acknowledged that the class III alcohol dehydrogenase (ADH3), also termed formaldehyde dehydrogenase and S-nitrosoglutathione (GSNO) reductase, is a key mediator of the nitric oxide (NO)-related post-translational protein modification known as S-nitrosylation (Figure 1a) [19-24]. The S-nitrosylation of protein cysteine residues by NO and GSNO regulates a broad spectrum of cellular proteins and functions [25-36]. Dysregulation of nitrosothiol homeostasis has been implicated in diseases of the central nervous system, cardiovascular system, and lung [37-43]. We have previously described how ADH3 and nitrosothiols influence pulmonary physiology, and how formaldehyde might