Formaldehyde: integrating dosimetry, cytotoxicity, and genomics to understand dose-dependent transitions for an endogenous compound.

Formaldehyde (FA), an endogenous cellular aldehyde, is a rat nasal carcinogen. In this study, concentration and exposure duration transitions in FA mode of action (MOA) were examined with pharmacokinetic (PK) modeling for tissue formaldehyde acetal (FAcetal) and glutathione (GSH) and with histopathology and gene expression in nasal epithelium from rats exposed to 0, 0.7, 2, 6, 10, or 15 ppm FA 6 h/day for 1, 4, or 13 weeks. Patterns of gene expression varied with concentration and duration. At 2 ppm, sensitive response genes (SRGs)-associated with cellular stress, thiol transport/reduction, inflammation, and cell proliferation-were upregulated at all exposure durations. At 6 ppm and greater, gene expression changes showed enrichment of pathways involved in cell cycle, DNA repair, and apoptosis. ERBB, EGFR, WNT, TGF-beta, Hedgehog, and Notch signaling were also enriched. Benchmark doses for significantly enriched pathways were lowest at 13 weeks. Transcriptional and histological changes at 6 ppm and greater corresponded to dose ranges in which the PK model predicted significant reductions in free GSH and increases in FAcetal. Genomic changes at 0.7-2 ppm likely represent changes in extracellular FAcetal and GSH. DNA replication stress, enhanced proliferation, squamous metaplasia, and stem cell niche activation appear to be associated with FA carcinogenesis. Dose dependencies in MOA, high background FAcetal, and nonlinear FAcetal/GSH tissue kinetics indicate that FA concentrations below 1 or 2 ppm would not increase risk of cancer in the nose or any other tissue or affect FA homeostasis within epithelial cells.