Nasal Dosimetry of Formaldehyde: Modeling Site Specificity and the Effects of Preexposure

Abstract

The formation of DNA-protein cross-links (DPX) in the nose of F344 rats exposed to formaldehyde (HCHO) is site specific and depends on the prior exposure history of the animal if the exposures were to concentrations ≥6 ppm. The site specificity is interpreted in terms of a pharmacokinetic model in which the rate of DPX formation is proportional to the tissue concentration of HCHO. The model includes both saturable and nonsaturable elimination pathways, and it describes regional differences as being due to differences in nasal airflow rather than to differences in HCHO metabolism. Using a minimal number of adjustable parameters, the model accurately describes DPX formation in two nasal compartments [the lateral meatus (a high-frequency tumor site in a HCHO bioassay) and the medial and posterior meatuses (a low-frequency tumor site in the bioassay)] of F344 rats. The pharmacokinetics of DPX formation in preexposed rats is also describable in terms of the model. The effects of preexposure on DPX yields were predicted by recognizing that concentrations ≥6 ppm induce hyperplasia and squamous metaplasia, which increases the quantity of DNA, whereas concentrations ≤2 ppm do not increase the number of cells. The appropriate pharmacokinetic parameter was scaled in proportion to the quantity of DNA, and the predicted yields of DPX agreed well with experiment. The model suggests a close linkage between the pharmacokinetics of DPX formation and the results of fluid dynamics simulations. The two approaches provide complementary information that is important for an understanding of nasal dosimetry.