Acute nose-only exposure of rats to phosgene. Part II. Concentration x time dependence of changes in bronchoalveolar lavage during a follow-up period of 3 months.
Groups of young adult male Wistar rats were acutely exposed to phosgene gas for either 30 or 240 min using a directed-flow nose-only mode of exposure. In 30-min exposed rats the concentrations were 0.94, 2.02, 3.89, 7.35, and 15.36 mg/m3, which relate to C x t products of 28.2, 60.6, 116.7, 220.5, and 460.8 mg/m3 x min. In 240-min exposed rats the concentrations were 0.96, 0.387, 0.786, 1.567, and 4.2 mg/m3, which relate C x t products of 47.0, 92.9, 188.6, 376, and 1008 mg/m3 x min. Six rats/group were sacrificed on postexposure days 1, 3, 7, 14, and 84, while the rats of the 1008 mg/m3 x min group where sacrificed on postexposure days 1, 7, 14, and 28. The focus of measurements was directed toward indicators of inflammatory response and increased transmucosal permeability in bronchoalveolar lavage (BAL), including lung weights. Lungs from rats sacrificed at the end of the postexposure period were additionally examined by histopathology. Mortality did not occur at any C x t product. The most pronounced changes were related to C x t-dependent increases in the following markers in BAL: protein, soluble collagen, polymorphonuclear leukocytes (PMN) counts, and alveolar macrophages with foamy appearance. These indicators were maximal on the first postexposure day, while total cell counts and alveolar macrophages containing increased phospholipids reached their climax around post-exposure day 3. At 1008 mg/m3 x min the most sensitive indicators in BAL, that is, protein, PMN, and collagen, resolved within 2 wk, whereas at lower C x t products they reached the level of the control by postexposure day 7. At 1008 mg/m3 x min (day 28), histopathology revealed a minimal to slight hypercellularity in terminal bronchioles with focal peribronchiolar inflammatory infiltrates and focal septal thickening. At lower C x t products (day 84) the rats from all groups were indistinguishable and Sirius red-stained lungs did not provide evidence of late-onset sequelae, such as fibrotic changes or collagen deposition. At similar C x t products the changes in BAL were slightly less pronounced using 30-min exposure periods when compared to 240-min exposure periods. In summary, the phosgene-induced transmucosal permeability caused a C x t-dependent increase of several BAL indicators, of which those of protein, PMN, and soluble collagen were most pronounced. Exposure intensities up to 116.7 mg/m3 x min did not cause changes different from those observed in controls, while at 188.6 mg/m3 x min distinct differences to the control existed. Despite the extensively increased airway permeability, histopathology did not provide evidence of lung tissue remodeling or irreversible sequelae.
Pauluhn
Jürgen
J
Institute of Toxicology, Bayer HealthCare, Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
D000280:Administration, Inhalation; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018893:Bronchoalveolar Lavage / Q000379:methods*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002452:Cell Count; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure / Q000009:adverse effects*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010705:Phosgene / Q000633:toxicity*; D010743:Phospholipids / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
D002619:Chemical Warfare Agents; D010743:Phospholipids; D010705:Phosgene; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase