MORPHOMETRIC APPROACHES FOR EVALUATING PULMONARY TOXICITY IN MAMMALS - IMPLICATIONS FOR RISK ASSESSMENT

Recent advances in quantitative morphology provide all the tools neces sary to obtain structural information in the lung that can be quantifi ed and interpreted in the three-dimensional world of toxicology. Struc tural hierarchies of conducting airways and parenchyma of the lung pro vide: (1) numbers of cells per airway, lobe, or lung; (2) surface area s of cells, airways, and alveoli; (3) length of airways and vessels; a nd (4) volumes of cells, alveoli, airways, vessels, and individual lob es or the entire lung. Unbiased sampling of these subcompartments of t he lung requires fractionation of lobes or individual airways. Individ ual airways of proximal and distal generations are obtained by airway microdissection along one axial pathway and comparisons made between a irway generations. Vertical sections of selected airways are used to s ample epithelium and interstitium. Using this unbiased approach of qua ntitative morphology, we have shown that inhalation of low ambient con centrations of ozone ([O3]0.15 ppm) near or at the United States Natio nal Ambient Air Quality Standard (NAAQS) (0.12 ppm O3) induces signifi cant alterations in bronchiolar epithelium and interstitium in nonhuma n primates but not rats. The alterations do not appear to be concentra tion- or time-dependent, thereby bringing into question the current NA AQS that may be at or above the threshold for distal airway injury in primates. Unbiased morphometric methods are critical in a quantitative evaluation of toxicological injury of mammalian tracheobronchial airw ays.