Thompson CM, Gentry R. An updated mode-of-action analysis for formaldehyde-induced nasal tumors in rodents: A case study using the IPCS MOA and human relevance frameworks. Poster at Society of Toxicology Annual Meeting, Baltimore, MD, March 2019.
Since discovery of nasal tumors following chronic inhalation exposure to formaldehyde in rats in the early nineteen eighties, formaldehyde has become one of the most studied chemicals with regard to research focused on pharmacokinetics and mode of action (MoA). Despite the ubiquitous endogenous presence of formaldehyde in cells and clear evidence for nonlinearities in inhalation dosimetry, toxicity, and tumor formation, some risk assessors continue to invoke low-dose linear extrapolation approaches based, in part, on concern for a mutagenic or genotoxic MoA. The MoA for nasal tumors was formally described in McGregor et al. (2006) using IPCS frameworks and again in US EPA (2010), albeit less formally. These two groups reached differing conclusions regarding the MoA and need for linear low-dose extrapolation in quantifying risk. Critical data informing the MoA of nasal tumors has been published over the past decade, facilitating an updated MoA analysis for nasal tumors. These new data include analytical results discerning endogenous and exogenous biomarkers of exposure to formaldehyde and negative results from in vivo genotoxicity assays in target tissues of rats, as well as in genetically susceptible mice (including a recent NIEHS study conducted in p53+/- mice). Herein, we conduct a MoA analysis with special emphasis on studies published over the past decade. These data support a MoA involving exceedance of intra- and extra-cellular barriers to formaldehyde exposure that result in elevations of formaldehyde within cells, elevations in formaldehyde that lead to cytotoxicity and adaptive responses, chronic regenerative cell proliferation, and induction of spontaneous mutations as a result of lifetime increases in cell replication. These key events ultimately lead to tumorigenesis in the rat nasal mucosa. The modified Hill criteria support dose and temporal concordance, consistency and specificity, and biological plausibility. In addition, weight of evidence comparisons are made to alternative MoAs such as a mutagenic MoA. These analyses support the use of non-linear risk assessment approaches such as reference concentration values. Additionally, results from biologically based dose-response (BBDR) modeling are in general agreement with this evaluation, providing support for the conclusions reached using the IPCS MoA framework.