Effects of administration of metabolic inducers and inhibitors on pulmonary toxicity and covalent binding by 1,1-dichloroethylene in CD-1 mice.

The administration of 1,1-dichloroethylene (1,1-DCE, 125 mg/kg ip) to CD-1 mice caused bronchiolar necrosis, which was accompanied by substantial covalent binding of radiolabeled compound and/or metabolite to lung. Lung injury and covalent binding were not modified by phenobarbital pretreatment. However, 3-methylcholanthrene provided a protective influence but failed to alter covalent binding to lung macromolecules. Prior administration with the metabolic inhibitors, piperonyl butoxide and SKF 525-A, produced differential effects. While piperonyl butoxide exacerbated bronchiolar injury by 1,1-DCE, covalent binding remained unaltered. In contrast, SKF 525-A protected from lung damage and significantly decreased covalent binding. Hepatic necrosis was relatively mild, and was not observed in all animals treated with 1,1-DCE. Although the hepatic lesion was not modified by phenobarbital, liver injury was slightly diminished by 3-methylcholanthrene. The inducers, piperonyl butoxide and SKF 525-A, enhanced liver necrosis, with the latter eliciting more severe effects than the former agent. Covalent binding to liver tissues was not significantly changed by pretreatment with either inducers or inhibitors. These results indicate that lack of an unequivocal correlation of cellular injury with covalent binding, but suggest that metabolism may be involved in the pneumotoxicity by 1,1-DCE. The influence and modification of lung injury by the liver, however, remain to be further elucidated.

Pulmonary toxicity of 1,1-dichloroethylene: correlation of early changes with covalent binding.

Administration of a single intraperitoneal dose of 1,1-dichloroethylene (125 mg/kg, 1,1-DCE) to mice resulted in bronchiolar injury with selective necrosis of Clara cells. Degenerative changes were manifest in Clara cells as early as 1 h following 1,1-DCE exposure, and were characterized by marked swelling of mitochondria and aggregation of chromatin against the nuclear membrane. Cell death was apparent at 2 h; by 8 h, areas of the bronchiolar epithelium were devoid of lining cells, and at 24 h, the majority of Clara cells were exfoliated. The residual epithelium consisted of flattened cells which formed a thin lining for the airway. Necrosis of Clara cells early in the course of 1,1-DCE exposure coincided with peak covalent binding of [14C]1,1-DCE and significant depression of components of the pulmonary mixed-function oxidase system; cytochrome P-450 and aryl hydrocarbon hydroxylase activity were markedly reduced but not depleted. Liver damage involving centrilobular hepatocytes was observed at 24 h in 30% of treated animals, and coincided with significant inhibition of aryl hydrocarbon hydroxylase activity; cytochrome P-450 content, however, remained unchanged. While changes in the liver evoked by 1,1-DCE were less striking, the results in lung demonstrate positive temporal correlations between structural damage, peak covalent binding and disturbances of monooxygenase enzymes.