title: Development of a short-term inhalation bioassay to assess pulmonary toxicity of inhaled particles: comparisons of pulmonary responses to carbonyl iron and silica.
abstract: This paper describes a short-term inhalation bioassay for evaluating the lung toxicity of inhaled particulate materials. To validate the method, rats were exposed for 6 hr or 3 days to various concentrations of either aerosolized alpha-quartz silica or carbonyl iron particles. Cells and fluids from groups of sham- and dust-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), and protein values were measured in BAL fluids at several time points postexposure. Cells were identified, counted, and evaluated for viability. Pulmonary macrophages (PM) were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for histopathology and transmission electron microscopy. Brief exposures to silica elicited a sustained granulocytic inflammatory response (primarily neutrophils) with concomitant increases in alkaline phosphatase, LDH, and protein in the lavage fluids (p less than 0.05). In addition, PM functional capacity was depressed (p less than 0.05) and histopathologic lesions were observed within 1 month after exposure. In contrast, 6-hr or 3-day exposures to CI produced no cellular, cytotoxic, or alveolar/capillary membrane permeability changes at any time postexposure. PM function was either enhanced or unchanged from controls. These data demonstrate that short-term, high-dose inhalation exposures of silica produce effects similar to those previously observed using intratracheal instillation or chronic inhalation models, and lend support to this method as a reliable short-term bioassay for evaluating the pulmonary toxicity and mechanisms associated with exposures to new and untested materials.
authors.affiliation: Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Company, Newark, Delaware 19714.
authors.forename: D B
authors.initials: DB
authors.lastname: Warheit
authors.forename: M C
authors.initials: MC
authors.lastname: Carakostas
authors.forename: M A
authors.initials: MA
authors.lastname: Hartsky
authors.forename: J F
authors.initials: JF
authors.lastname: Hansen
mesh_terms: D000280:Administration, Inhalation; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001992:Bronchoalveolar Lavage Fluid / Q000201:enzymology / Q000473:pathology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D005110:Extracellular Space / Q000201:enzymology / Q000378:metabolism; D054354:Iron Carbonyl Compounds; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D008854:Microscopy, Electron; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000633:toxicity*; D010316:Particle Size; D051381:Rats; D012822:Silicon Dioxide / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D015054:Zymosan / Q000494:pharmacology
chemical_list: D009942:Organometallic Compounds; D054354:Iron Carbonyl Compounds; D012822:Silicon Dioxide; D015054:Zymosan; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase