Inhalation toxicity of 1,6-hexamethylene diisocyanate homopolymer (HDI-IC)aerosol: Results of single inhalation exposure studies

The early acute pulmonary response of female Wistar rats exposed nose-only to a mixture of 1,6-hexamethylene diisocyanate homopolymer (HDI-IC) aerosol was examined. This study was designed to investigate the time course of th e relationship between acute pulmonary irritation and ensuing disturbances of the air/blood barrier in rats exposed to concentrations of 3.9, 15.9, 54 .3, or 118.1 mg HDI-IC/m(3). The duration of exposure was 6 h, followed by serial sacrifices 0 h, 3 h, I day, 3 days, and 7 days postexposure. Concent rations were selected based on the results of a 4-h acute inhalation study in rats (LC50 = 462 mg/m(3)). Bronchoalveolar lavage (BAL) fluid was analyz ed for markers indicative of injury of the bronchoalveolar region, includin g phospholipids as proxy of altered surfactant homeostasis. Glutathione (GS H) was determined in BAL fluid and lung tissue. BAL cells with increased in tracellular phospholipids were observed on day 1 and especially day 3, with some residual increase on day 7. Increased intracellular phospholipids and activity of acid phosphatases appear to suggest that phagocytized phosphol ipids may transiently affect lysosomal function. Following exposure to 15.9 mg/m3, changes returned almost entirely to the level of the air-exposed co ntrol on day 7. Especially at higher exposure concentrations, lung weights and total number of cells in BAL were still statistically significantly ele vated at this time point. Experimental evidence suggests that markers indic ative of a dysfunction of the air/blood barrier, such as angiotensin-conver ting enzyme, total protein, and phospholipids engulfed by alveolar macropha ges, were most sensitive to probe this type of changes. Although GSH in BAL F was increased following exposure, there was an apparent depletion of tiss ue GSH immediately after cessation of exposure. In summary, this study sugg ests that respirable HDI-IC aerosol appears to cause a transient dysfunctio n of the air/blood barrier indicated by an increased extravasation of plasm a constituents. Despite the remarkable extent of effects observed, most cha nges were reversible within a postexposure period as short as 7 days. First evidence of increased leakage of pulmonary epithelial barrier was observed at 3.9 mg/m(3). With respect to changes of early markers of pulmonary epit helial barrier dysfunction, approximate to 3 mg HDI-IC/m3 was considered to be the threshold concentration for acute pulmonary irritation.