INHALATION TOXICITY OF AEROSOLIZED PENTAMIDINE ISETHIONATE IN RATS AND DOGS

The toxicity of inhaled aerosolized pentamidine isethionate solutions in rats and dogs was evaluated. Nose-only exposure equipment and a mas s mean aerodynamic particle size of less than or equal to 2 mu m were employed. Rats received either a single inhaled dose estimated at 0, 1 .4, 2.1, or 6.0 mg/kg/exposure day or 4 inhaled doses evenly spaced ov er 13 weeks estimated at 0, 0.35, 0.7, or 1.4 mg/kg/exposure day. Dogs were administered a single inhaled dose estimated at 0, 1.1, 3.4, or 5.0 mg/kg/exposure day. Rats administered a single inhaled dose of 6.0 mg/kg/exposure day exhibited respiratory distress. The lung-with-trac hea weights of these animals were elevated relative to controls. The h istopathology of acutely exposed rats consisted of dose-related neutro phil infiltration in the turbinates, larynx, and bronchi; erosion of e pithelium in the turbinates and larynx; thickening of the alveoli wall s with alveolar accumulation of mononuclear cells and neutrophils; and rhinitis. Rats in the highest dose group in the subchronic evaluation exhibited decreased body weight gains and reduced lung-with-trachea-t o-body weight ratios relative to controls. Hematology, clinical chemis try, and urinalysis values were within normal ranges. Microscopic pulm onary tissue changes were similar to those found in acute exposure wit h certain lesions (e.g., mucous cell hyperplasia) suggestive of a more chronic process. In addition, lung fibrosis was seen at the highest d ose. In dogs, pentamidine isethionate did not cause a change in the re spiratory minute volume (not measured in rats). Elevated lung-with-tra chea weights were noted in the high-dose females. Hematology, clinical chemistry, and urinalysis values were within normal ranges. Dose-rela ted lesions were loss of cilia, epithelial atrophy, and submucosal hem orrhage in the nasal cavity. Thus, the toxic responses in rats and dog s from inhaled pentamidine isethionate solution were limited to the re spiratory tract with lesions consistent with damage from direct contac t with an irritating or corrosive chemical. (C) 1994 Society of Toxico logy.