Altered lung function in rats after subacute exposure to n-butyl isocyanate

Abstract

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m³ air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m³ died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m³ a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasistatic compliance in rats exposed to 26 mg/m³. At the end of the observation period rats exposed to 6.2 and 15 mg/m³ air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship, Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m³ group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m³. Collectively, these results demonstrate obstructive and progressive lung disease with associated gas trapping and severe disturbance of the ventilation perfusion relationship which is considered to be the cause of delayed mortality. In terms of variability and sensitivity the increase in BALF parameters was most sensitive in indicating the diseased state of the lung.