Formaldehyde and glutaraldehyde and nasal cytotoxicity: Case study within the context of the 2006 IPCS human framework for the analysis of a cancer mode of action for humans

Formaldehyde and glutaraldehyde cause toxicity to the nasal epithelium of rats and mice upon inhalation. In addition, formaldehyde above certain concentrations induces dose-related increases in nasal tumors in rats and mice, but glutaraldehyde does not. Using the 2006 IPCS human framework for the analysis of cancer mode of action (MOA), an MOA for formaldehyde was formulated and its relevance was tested against the properties of the noncarcinogenic glutaraldehyde. These compounds produce similar patterns of response in histopathology and in genotoxicity tests (although formaldehyde has been much more extensively tested studied). The MOA is based on the induction of sustained cytotoxicity and reparative cell proliferation induced by formaldehyde at concentrations that also induce nasal tumors upon long-term exposure. Data on dose dependency and temporal relationships of key events are consistent with this MOA. While a genotoxic MOA can never be ruled out for a compound that is clearly genotoxic, at least in vitro, the nongenotoxic properties fundamental to the proposed MOA can explain the neoplastic response in the nose and may be more informative than genotoxicity in risk assessment. It is not yet fully explained why glutaraldehyde remains noncarcinogenic upon inhalation, but its greater inherent toxicity may be a key factor. The dual aldehyde functions in glutaraldehyde are likely to produce damage resulting in fewer kinetic possibilities (particularly for proteins involved in differentiation control) and lower potential for repair (nucleic acids) than would be the case for formaldehyde. While there have been few studies of possible glutaraldehyde-associated cancer, the evidence that formaldehyde is a human carcinogen is strong for nasopharyngeal cancers, although less so for sinonasal cancers. This apparent discrepancy could be due in part to the classification of human nasal tumors with tumors of the sinuses, which would receive much less exposure to inhaled formaldehyde. Evaluation of the human relevance of the proposed MOA of formaldehyde in rodents is restricted by human data limitations, although the key events are plausible. It is clear that the human relevance of the formaldehyde MOA in rodents cannot be excluded on either kinetic or dynamic grounds.