Phosgene, an acylating agent, is a very potent inducer of
pulmonary edema. Subchronic effects of
phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on
collagen and
elastin metabolism during
pulmonary injury/recovery and obtain information about the concentration x time (C x T) behavior of low levels of
phosgene. Male Fischer 344 rats (60 days old) were exposed either to clean air or
phosgene, 6 hr/day: 0.1 ppm (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 clean air recovery for 4 weeks after 12 weeks of
phosgene exposure. This exposure scenario was designed to provide equal C x T product for all concentrations 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 manner. The increase in lung displacement volume was significant even at 0.1 ppm
phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm
phosgene following 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 bronchiolar thickening and
inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive
inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather than C x T seems to drive pathology response. Trichrome staining for
collagen at the terminal bronchiolar sites indicated a slight increase 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. Whole-lung
prolyl hydroxylase activity and
hydroxyproline, taken as an index of
collagen synthesis, were increased following 1.0 ppm
phosgene exposure at 4 as well as 12 weeks, respectively.
Desmosine levels, taken 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
phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low
phosgene concentrations (0.1 ppm).
Phosgene concentration, rather than C x T product appeared to drive toxic responses. The changes induced by
phosgene (except of
collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure.
Phosgene-induced alterations of matrix were only partially reversible after 4 weeks of clean air exposure.