PULMONARY STRUCTURAL AND EXTRACELLULAR-MATRIX ALTERATIONS IN FISCHER-344 RATS FOLLOWING SUBCHRONIC PHOSGENE EXPOSURE

Phosgene, an acylating agent, is a very potent inducer of pulmonary ed ema. Subchronic effects of phosgene in laboratory animals are not well characterized, The purpose of the study was to elucidate potential lo ng-term effects on collagen and elastin metabolism during pulmonary in jury/recovery and obtain information about the concentration X time (C X T) behavior of low levels of phosgene. Male Fischer 344 rats (60 da ys old) were exposed either to clean air or phosgene, 6 hr/day: 0.1 pp m (5 days/week), 0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1 day/week), for 4 or 12 weeks, A group of rats was allowed clea n air recovery for 4 weeks after 12 weeks of phosgene exposure. This e xposure scenario was designed to provide Equal C X T product for all c oncentrations at one particular time point except for 0.1 ppm (50% C X T). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manne r. The increase in lung displacement volume was significant even at 0. 1 ppm phosgene at 4 weeks, Light microscopic level histopathology exam ination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene f ollowing 4 and 12 and 16 weeks (recovery), Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks, At 0.2 ppm phosgene, terminal br onchiolar thickening and inflammation appeared to be more prominent wh en compared to the 0.1 ppm group and changes in alveolar parenchyma we re minimal. At 1.0 ppm, extensive inflammation and thickening of termi nal bronchioles as well as alveolar walls were evident, Concentration rather than C X T seems to drive pathology response, Trichrome stainin g for collagen at the terminal bronchiolar sites indicated a slight in crease at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Who le-lung prolyl hydroxylase activity and hydroxyproline, taken as an in dex of collagen synthesis, were increased following 1.0 ppm phosgene e xposure at 4 as well as 12 weeks, respectively. Desmosine levels, take n as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group, Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups, Lung weight also remained significantly higher than the controls; however,desmosine and lung displacement volume in phosge ne-exposed animals were similar to controls. In summary, terminal bron chiolar and lung volume displacement changes occurred at very low phos gene concentrations (0.1 ppm). Phosgene concentration, rather than C X T product appeared to drive toxic responses, The changes induced by p hosgene (except of collagen) following 4 weeks were not further amplif ied at 12 weeks despite continued exposure, Phosgene-induced alteratio ns of matrix were only partially reversible after 4 weeks of clean air exposure. (C) 1997 Society of Toxicology.