O,S,S,-trimethyl phosphorodithioate-induced lung damage in rats and mice.

O,S,S,-Trimethyl phosphorodithioate (OSS) is a contaminant of various organophosphorus insecticides which induces delayed damage to rat lung bronchiolar and alveolar epithelial cells. Whether lung damage occurs in mice has not been tested. Changes in DNA synthesis, an index of cell division after the induction of damage, were monitored by measuring thymidine incorporation into pulmonary DNA. Mice, treated with 45 mg/kg OSS, exhibited a significant increase in pulmonary thymidine incorporation on Day 5. Maximal increases occurred on Days 7-10 and were followed by a gradual decline to control levels by Day 15. The labeling index of mouse lung cells, determined following autoradiography, exhibited a similar time course. Differential cell counts indicated that maximal division of type II cells occurred before that of interstitial cells, although interstitial cells were the predominant type labeled at all times. Pulmonary DNA synthesis was significantly increased in rats 2 days after treatment with 90 mg/kg OSS. Maximal thymidine incorporation was measured on Day 3, followed by a decline to control levels on Day 5. Thymidine incorporation into total lung DNA was dose related in both species. Maximal increases appeared after 45 and 90 mg/kg OSS in mice and rats, respectively. The histopathological changes in mouse lung tissue were similar, but somewhat less severe than those seen in rats. Rats exhibited a severe interstitial pneumonitis with type I alveolar cell destruction followed by type II cell proliferation. Mice exhibited a mild to moderate alveolitis with only slight damage to type I cells. Necrosis of bronchiolar Clara cells was evident in both species but was more extensive in rats. SKF 525a and piperonyl butoxide prevented OSS-induced increases in pulmonary DNA synthesis in rat lung suggesting that metabolic activation was necessary to elicit damage. Piperonyl butoxide treatments had no effect, however, on thymidine incorporation after OSS in mouse lung tissue, and the highest dose of SKF 525a had only a moderate inhibitory effect on this parameter while increasing animal mortality. These data indicate that systemic treatment with OSS results in damage to mouse, as well as rat, lung tissue at both the alveolar and bronchiolar levels.