Phenyl isocyanate-induced asthma in rats following a 2-week exposure period

This study was conducted to assess the toxic effects of repeated inhalation exposures to phenyl isocyanate vapor in male Wistar rats. Rats were exposed to design concentrations of 0, 1, 4, 7, or 10 mg/m3 phenyl isocyanate air for 2 weeks (6 hr/day, 5 days/week). The rats were assessed for normal toxicologic parameters, and pulmonary function tests, blood gas measurements, and analysis of bronchoalveolar lavage fluid (BALF) parameters were utilized shortly after exposures as well as 2 months postexposure. The results indicated that rats exposed to 7 and 10 mg/m3 experienced decreased body weights, hypoactivity, hypothermia, signs of respiratory tract irritation, delayed onset of mortality, and changes in organ weights. In addition, pulmonary function tests demonstrated decreased forced expiratory flow rates and quasistatic lung compliance. Arterial blood gases showed an arterial hypoxemia and changes consistent with a pronounced venous-admixture-like perfusion, suggesting severe mismatch of the ventilation/perfusion relationship. Delayed onset of mortality appeared to be associated with respiratory acidosis and hypoxemia. Biochemical and cellular components in BALF complemented the results of the functional alterations. Remarkable changes were indicated by increased activities of the BALF parameters, gamma-GPT, protein, and sialic acid. Histopathological findings provided evidence of increased secretory cell activity and a concentration-dependent increase in goblet cell hyperplasia at concentrations of 4 mg/m3 and above. In rats exposed to 7 mg/m3 further findings consisted of intraluminal inflammation of airways, hypertrophia of bronchial smooth muscle, epithelial desquamation, and eosinophilia of the airways. A complete regression of morphological lesions was not found in the animals exposed to 4 mg/m3 and above at the 2-month postexposure time period. In conclusion, the damage to the airways comprise most of the features characteristic of chronic airway inflammation or asthma.