Comparison of Inhaled Formaldehyde Dosimetry Predictions with DNA–Protein Cross-Link Measurements in the Rat Nasal Passages

• Published in: Toxicology and applied pharmacology Vol. 143; no. 1; pp. 47 - 55
• Main Authors: Cohen Hubal, Elaine A., Schlosser, Paul M., Conolly, Rory B., Kimbell, Julia S.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.03.1997; Elsevier
• Subjects: Administration, Inhalation; Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Cross-Linking Reagents; DNA Adducts - analysis; DNA-Binding Proteins; Formaldehyde - administration & dosage; Formaldehyde - pharmacokinetics; Medical sciences; Models, Biological; Nasal Mucosa - metabolism; Rats; Rats, Inbred F344; Reproducibility of Results; Sensitivity and Specificity; Toxicology; Various organic compounds; Rat; Rodentia; Crosslinking; Uptake; Formaldehyde; Inhalation; Proteins; Toxicokinetics; Gases; Vertebrata; Mammalia; Absorption; Investigation method; Predictability; Animal; DNA; Nasal septum; Kinetics; Dosimetry; Diffusion; Mathematical model; Pharmacokinetics
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1996.8076

Kimbell and coworkers (Toxicol. Appl. Pharmacol.121,253–263, 1993) developed a computational fluid dynamics (CFD) model of a F344 rat nasal passage to quantify local wall mass flux (uptake rate) of inhaled chemical. To simulate formaldehyde uptake, Kimbellet al.assumed that mass transfer of formaldehyde from the air into the nasal lining was fast and complete. This was approximated in the CFD model by setting the formaldehyde concentration at the airway walls to zero. Experimental confirmation of formaldehyde mass-flux predictions is desirable if the CFD model is to be used for predicting formaldehyde dosimetry. The purpose of this study was to see if the CFD model predictions of formaldehyde mass flux are consistent with laboratory data on formaldehyde dosimetry. In this study, a mathematical model of the nasal lining was modified to link CFD dosimetry predictions for inhaled formaldehyde with measured tissue disposition of inhaled gas. This model treats the nasal lining as a single, well-stirred compartment, accounts for formaldehyde reaction via saturable and first-order pathways, and allows comparison of model-predicted DNA–protein cross-links (DPX) with regional DPX measured in formaldehyde-exposed rats. Effective Michaelis–Menten kinetic parameters (Vmax= 3040 μm/min andKm= 59 μm) and a pseudo-first-order rate constant for elimination of formaldehyde by nonsaturable pathways (kf= 6 min−1) were estimated (fit) using an average mass flux derived from experimentally measured uptake of formaldehyde. DPX predictions obtained using the estimated kinetic parameters and linking the CFD model to the nasal-lining model compared well with experimentally measured DPX. The close correlation between predicted and measured DPX in the rat nasal passage supports the CFD model predictions of formaldehyde mass flux at the level of resolution provided by the experimental data.