title: Acute inhalation toxicity of polymeric diphenyl-methane 4,4'-diisocyanate in rats: time course of changes in bronchoalveolar lavage.
abstract: The early acute pulmonary response of Wistar rats exposed nose-only to respirable polymeric diphenylmethane 4,4'-diisocyanate (MDI) aerosol was examined. This study investigated the time course of the relationship between acute pulmonary irritation and ensuing disturbances of the air/blood barrier in rats exposed to concentrations of 0.7, 2.4, 8, or 20 mg MDI/m3. The duration of exposure was 6 h. The time-response relationship of MDI-induced acute lung injury was examined 0 h (directly after cessation of exposure), 3 h, 1 day, 3 days, and 7 days after exposure. Bronchoalveolar lavage (BAL) fluid was analyzed for markers indicative of injury of the bronchoalveolar region, i.e., angiotensin-converting enzyme, protein, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltranspeptidase, and sialic acid. Phosphatidylcholine and acid phosphatase were determined in BAL fluid and cells. Glutathione was determined in BAL fluid and lung tissue. This analysis revealed no latent period of effects except a transiently delayed influx of cells and increased lung weights on postexposure days 1 and 3. Markedly loaded BAL cells with phosphatidylcholine were observed on day 1 only. In most instances, changes returned to the level of the air exposed control on day 7, except increased glutathione in lung tissue. The findings suggest that the most sensitive markers of dysfunction of the air/blood barrier are angiotensin-converting enzyme and protein, including alkaline phosphatase. The statistically significant increase in intracellular phosphatidylcholine and decreased intracellular acid phosphatase on the exposure day suggest that increased amounts of phospholipids are phagocytized by alveolar macrophages, associated with protracted lysosomal catabolism. Partially glutathione-depleted rats exposed to 20 mg/m3 experienced a more pronounced increase in BAL protein than normal rats. In summary, this study suggests that respirable polymeric MDI aerosol interacts directly with the air/blood barrier causing increased extravasation of plasma constituents as a result of increased permeability of capillary endothelial cells. Overall, a transient dysfunction of the pulmonary epithelial barrier occurred at level as low as 0.7 mg/m3 and appears to be related a dysfunction of pulmonary surfactant. Nonprotein sulfhydryl constituents appear to play a role as portal-of-entry specific modifying factors.
authors.affiliation: Institute of Toxicology, Bayer AG, Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
authors.forename: J
authors.initials: J
authors.lastname: Pauluhn
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000336:Aerosols; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019570:Inhalation Exposure; D017953:Isocyanates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D008247:Lysosomes / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D011140:Polyurethanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000139:chemically induced* / Q000201:enzymology; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000336:Aerosols; D017953:Isocyanates; D010713:Phosphatidylcholines; D011140:Polyurethanes; D011663:Pulmonary Surfactants; C087867:polymeric 4,4'-diphenylmethane diisocyanate; D019328:Buthionine Sulfoximine; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D007703:Peptidyl-Dipeptidase A; D005978:Glutathione