COMPARISON OF INHALED FORMALDEHYDE DOSIMETRY PREDICTIONS WITH DNA-PROTEIN CROSS-LINK MEASUREMENTS IN THE RAT NASAL PASSAGES

Kimbell and coworkers (Toxicol. Appl. Pharmacol. 121, 253-263, 1993) d eveloped a computational fluid dynamics (CFD) model of a F344 rat nasa l passage to quantify local wall mass flux (uptake rate) of inhaled ch emical. To simulate formaldehyde uptake, Kimbell et al. assumed that m ass transfer of formaldehyde from the air into the nasal lining was fa st 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 pu rpose of this study was to see if the CFD model predictions of formald ehyde mass flux are consistent with laboratory data on formaldehyde do simetry, In this study, a mathematical model of the nasal lining was m odified to link CFD dosimetry predictions for inhaled formaldehyde wit h measured tissue disposition of inhaled gas. This model treats the na sal lining as a single, well-stirred compartment, accounts for formald ehyde reaction via saturable and first-order pathways, and allows comp arison of model-predicted DNA-protein cross-links (DPX) with regional DPX measured in formaldehyde-exposed rats. Effective Michaelis-Menten kinetic parameters (V-max = 3040 mu M/min and K-m = 59 mu M) and a pse udo-first-order rate constant for elimination of formaldehyde by nonsa turable pathways (k(f) = 6 min(-1)) were estimated (fit) using an aver age mass flux derived from experimentally measured uptake of formaldeh yde. DPX predictions obtained using the estimated kinetic parameters a nd linking the CFD model to the nasal-lining model compared well with experimentally measured DPX. The close correlation between predicted a nd measured DPX in the rat nasal passage supports the CFD model predic tions of formaldehyde mass flux at the level of resolution provided by the experimental data. (C) 1997 Academic Press.