A Comparative Study of Regional Formaldehyde Uptake in the Nasal Passages of F344 Rats and Rhesus Monkeys. J. S. Kimbell, G. M. Kepler, E. A. Gross, E. A. Cohen Hubal, R. B. Conolly, and K. T. Morgan, Chemical Industry Institute of Toxicology, 6 Davis Drive, Research Triangle Park, NC 27709
In a study chronically exposing F344 rats to inhaled formaldehyde (HCHO), squamous cell carcinomas (SCC) were seen in the lateral wall of the anterior nasal passages at 6 ppm (Morgan et al., Toxicol. Appl. Pharmacol. 82:264-271, 1986). Accurate evaluation of the significance of these data for humans exposed to formaldehyde depends, in part, on realistic extrapolation of formaldehyde nasal dosimetry from rats to humans. As part of a research program designed to improve extrapolation methods, we have developed anatomically accurate, three-dimensional computer simulations of inspiratory airflow and regional dosimetry in the nasal airways of F344 rats and rhesus monkeys. Steady-state airflow and HCHO wall mass flux (the rate at which HCHO is delivered to the tissue from the air) were simulated in the anterior portion of the right side of the nasal passages of a male F344 rat (Kimbell et al., Toxicol. Appl. Pharmacol. 121:253-263, 1993) and in the right side of the entire nasal passages (excluding maxillary sinus) of a male rhesus monkey (Kimbell et al., J. Aerosol Med. 8:65, 1995). Volumetric airflow rates were set equal to estimated resting minute volumes for each animal. Nasal wall flux of HCHO was calculated assuming that the walls act as perfect sinks for inhaled HCHO (HCHO concentration set to zero at walls). Predictions were obtained for (1) HCHO flux into rat nasal passage walls in the SCC region and (2) any regions in primate nasal passages showing HCHO flux values equal to or greater than the rat SCC value. Computational mass balance errors were less than 1% for airflow and less than 5% for HCHO in simulations for both species. Simulations showed an anterior-to-posterior flux gradient in both species that was more shallow in the rhesus monkey. Overall HCHO uptake was predicted at 99% for the anterior F344 rat nasal passages and 88% for the entire rhesus nasal passages. Maximum flux occurred near the nostril in both species and was 5.3-fold higher in the rat than in the primate. Average overall flux was 2.5-fold higher in the rat than in the primate. Average and maximum flux values in the rat SCC region at 6 ppm were 5.2 and 26.7 pg/mm2/sec, respectively. Approximately 30% of the surface area modeled in each species showed flux values predicted to be in excess of the maximum in the rat SCC region. These simulations suggest that doses reach a higher peak in the rat nose than in the primate nose at equivalent inhaled concentrations of formaldehyde and that the primate receives higher doses in the posterior portions of the nose. Work is ongoing to confirm model predictions of HCHO uptake in the rhesus monkey and to determine effects of integrating flux over a physiological range of airflow rates. Sensitivity of model predictions to the apportionment of uptake between nasal and oral breathing in primates and to effects on uptake of cellular responses such as squamous metaplasia observed in HCHO-exposed rats will be studied. In summary, this work illustrates the use of anatomically realistic models for interspecies extrapolation of the nasal dosimetry of formaldehyde. This approach reduces the uncertainty associated with interspecies extrapolation of delivered dose, an important component of the risk assessment process.