Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: evidence for biodegradability of inhaled fibrils.
Previous chronic inhalation studies have shown that high concentrations of Kevlar fibrils produced fibrosis and cystic keratinizing tumors in rats following 2-year inhalation exposures. The current studies were undertaken to evaluate mechanisms and to assess the toxicity of inhaled Kevlar fibrils relative to other reference materials. Rats were exposed to ultrafine Kevlar fibers (fibrils) for 3 or 5 days at concentrations ranging from 600-1300 fibers/cc (gravimetric concentrations ranging from 2-13 mg/m3). A complete characterization of the fiber aerosol and dose was carried out. These measurements included gravimetric concentrations, mass median aerodynamic diameter, fiber number, and count median lengths and diameters of the aerosol. Following exposures, cells and fluids from groups of sham- and fiber-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), protein, and N-acetyl glucosaminidase (NAG) values were measured in BAL fluids at several time points postexposure. Alveolar macrophages were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for deposition, cell labeling, retained dose, and lung clearance studies, as well as fiber dimensions (from digested lung tissue), histopathology, and transmission electron microscopy. Five-day exposures to Kevlar fibrils elicited a transient granulocytic inflammatory response with concomitant increases in BAL fluid levels of alkaline phosphatase, NAG, LDH, and protein. Unlike the data from silica and asbestos exposures where inflammation persisted, biochemical parameters returned to control levels at time intervals between 1 week and 1 month postexposure. Macrophage function in Kevlar-exposed alveolar macrophages was not significantly different from sham controls at any time period. Cell labeling studies were carried out immediately after exposure, as well as 1 week and 1 month postexposure. Increased pulmonary cell labeling was measured in terminal bronchiolar cells immediately after exposure but returned to control values 1 week later. Fiber clearance studies demonstrated a transient increase in the numbers of retained fibers at 1 week postexposure, with rapid clearance of fibers thereafter. The transient increase in the number of fibers could be due to transverse cleaving of the fibers, since the average lengths of retained fibers continued to decrease over time. In this regard, a progressive decrease in the mean lengths and diameters of inhaled fibers was measured over a 6-month postexposure period.(ABSTRACT TRUNCATED AT 400 WORDS)
Warheit
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DB
Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours and Co., Newark, Delaware 19714.
Kellar
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KA
Hartsky
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MA
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001673:Biodegradation, Environmental; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects; D008297:Male; D008855:Microscopy, Electron, Scanning; D010587:Phagocytosis / Q000187:drug effects; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000336:Aerosols; D002630:Chemotactic Factors; C039578:Kevlar Aramid fibers; D011108:Polymers; D011506:Proteins