Acute head-only exposure of dogs to phosgene. Part III. Comparison of indicators of lung injury in dogs and rats.
To better understand the relevance of phosgene-induced changes in bronchoalveolar lavage (BAL) fluid protein observed in acutely exposed rats, groups of beagle dogs were similarly exposed for 30 min to phosgene using a head-only mode of exposure. The actual exposure concentrations were 9, 16.5, and 35 mg/m3, with resultant C x t products of 270, 495, and 1050 mg/m3 x min. In rats, a C x t product of 270 mg/m3 x min caused a significant elevation of protein in the bronchoalveolar lavage (BAL) fluid, while the nonlethal threshold concentration (LCt01) was estimated to be 1075 mg/m3 x min. The endpoints examined in dogs focused on changes in BAL, lung weights, arterial blood gases, and lung histopathology approximately 24 h postexposure. Mortality did not occur at any C x t product. Increased lung weights and elevations in protein, soluble collagen, and polymorphonuclear leukocyte (PMN) counts in BAL were observed at 1050 mg/m3 x min with borderline changes at 495 mg/m3 x min. Following exposure to 1050 mg/m3 x min, the analysis of arterial blood gases provided evidence of a significantly decreased arterial pO2. Histopathology revealed a mild, although distinctive, inflammatory response at the bronchoalveolar level at 495 mg/m3 x min, whereas serofibrinous exudates and edema were observed at 1050 mg/m3 x min. The magnitude of effects correlated with the individual dogs' respiratory minute volume and breathing patterns (panting). Collectively, phosgene-induced indicators of acute lung injury appeared to be characterized best by protein in BAL fluid. With regard to both the inhaled dose and the associated increase of protein in BAL, the responses obtained in dogs appear to be more similar to humans. In contrast, elevations in BAL protein occurred in rats at three-fold lower concentrations when compared to dogs. The results of this study demonstrate that the magnitude of elevations of plasma exudate in BAL fluid following acute exposure to the pulmonary irritant phosgene is markedly more pronounced in rats when compared to the dog which is considered more human-like than rats. This is believed to be associated with the higher ventilation of small rodents and with rodent-specific sensory bronchopulmonary defense reflexes.
Pauluhn
Jürgen
J
Institute of Toxicology,Bayer HealthCare, Wuppertal, Germany. juergen.pauluhn@bayerhealthcare.com
D000280:Administration, Inhalation; D000818:Animals; D018893:Bronchoalveolar Lavage / Q000379:methods*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D019570:Inhalation Exposure / Q000009:adverse effects*; 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; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051381:Rats; D012119:Respiration / Q000187:drug effects*; D013045:Species Specificity
D002619:Chemical Warfare Agents; D010743:Phospholipids; D011506:Proteins; D010705:Phosgene