kind of study has advantages and limitations, as discussed in McClellan et al. (1992) and McConnell (1995) and briefly presented below.

INHALATION STUDIES

Experimental data are essential for providing basic information on the physiological and pathophysiological pulmonary responses to inhaled particles. Because various rodent species respond differently to selected inhaled materials, it is essential to consider numerous factors—such as anatomy and deposition patterns, physiology and macrophage clearance efficiency, biochemistry and inflammation and fibrogenic potential—when extrapolating the results of animal inhalation studies to humans. Therefore, knowledge of morphological and functional pulmonary characteristics is essential for full understanding of structure-function relationships among species but it is also necessary if one is to develop accurate risk estimates with regard to the toxicity of inhaled particles in exposed humans.

Several rodent species are commonly used in particle and fiber inhalation-toxicity studies designed to simulate human exposures and to evaluate lung responses to inhaled dusts. But experimental animals and humans differ with respect to lung anatomy and physiology and these differences influence particle deposition and corresponding lung-clearance responses. For example, humans have relatively symmetrical dichotomous airway branching that favors concentrated deposition on branch points, or bifurcations; rodents have highly asymmetric, monopodal branching that theoretically should reduce the tendency for concentrated deposition. Distal airways are fundamentally different between humans and rodents: humans have several generations of nonrespiratory bronchioles and three generations of respiratory bronchioles and alveolar ducts; guinea pigs and hamsters have poorly develop respiratory bronchioles, and mice and rats generally lack them. Humans and rodents have different pleural tissue anatomy. And rodents are obligate nasal breathers, whereas humans can favor oral breathing while speaking or during strenuous activity, thus permitting enhanced particle penetration to the lungs.

Several studies have used rats and hamsters as the primary species for assessing the chronic effects of inhaled fibers (Mast et al. 1994; Mast et al. 1995a; McConnell et al. 1999). Some have demonstrated clear



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