Issues in Modeling Dosimetry in Rats and Primates

Abstract

Potential health risks to the human respiratory tract from inhalation exposure to chemicals must be determined, even when no human data are available. When respiratory tract responses in laboratory animals are site specific, interspecies differences in anatomy make accurate extrapolation of animal data to people difficult. A way of incorporating regional dose into the extrapolation process is needed so that potential response sites within the human respiratory tract can be identified. In this article, a strategy for understanding regional dosimetry in nasal toxicity is presented in which a mathematical dosimetry model is developed for the rat and extended to the primate and the human. Central to this strategy, the rat dosimetry model is described for the anterior nasal passages of the F344 rat (Kimbell et al., 1993a). Three-dimensional nasal airflow was simulated using a computer reconstruction of the nasal passages from serial step-sections. Regional formaldehyde gas (HCHO) concentration and uptake were calculated using simulated inspiratory airflow velocities, air-phase, diffusion, and uniformly-absorbing airway walls. Evidence was given supporting the hypothesis that airflow patterns are major determinants of regional HCHO dose. This example illustrates the dosimetry model structure underlying the proposed rat-primate-human strategy for understanding the role of regional dosimetry in nasal toxicity. Specific research needs for more accurate uptake simulation are also identified. The dosimetry modeling approach described here will be combined with other quantitative models incorporating tissue and airway lining factors to predict regional dose within the human respiratory tract for assessing risks to human health from inhalation exposures.