The enhancement of paraquat toxicity in rats by 85% oxygen: lethality and cell-specific lung damage.

When rats were dosed s.c. with paraquat or diquat and then exposed to air or 85% oxygen, the lethality of paraquat was enhanced approximately 10-fold by 85% oxygen exposure, whereas the lethality of diquat was enhanced only 2-fold. This increase in toxicity was not caused by an increase in the lung concentration of either bipyridyl. The lungs of rats which had been dosed with paraquat (2·5 and 20 mg/kg) or diquat (10 and 20 mg/kg) and exposed to air or 85% oxygen were examined morphologically at various times up to 24 h after dosing. By 24 h after dosing, the extent of damage appeared to be generally similar for those doses of paraquat that killed the same proportion of animals when combined with air or 85% oxygen. The combination of 20 mg paraquat/kg and air exposure caused alveolar epithelial Type I and Type II cell damage. Following 2·5 mg paraquat/kg and 85% oxygen exposure or 20 mg diquat/kg and 85% oxygen exposure the Type II alveolar epithelial cells were more severely damaged than the Type I epithelial and endothelial cells. In contrast, there was no cell damage after 1 or 2 days of exposure to 85% oxygen alone, and when lung damage did develop after 4 days of exposure, it was the capillary endothelial cells which were primarily affected. Thus the toxic effects of paraquat to the Type II alveolar epithelial cells are enhanced by exposure to oxygen. The ability of the lung to accumulate paraquat was measured in lung slices that had been taken from rats dosed with paraquat or diquat and exposed to air or 85% oxygen for 2, 8 or 24 h. Paraquat accumulation was inhibited at times after dosing when the alveolar epithelial cells appeared to be damaged. This is consistent with the hypothesis that paraquat is primarily accumulated by the alveolar epithelial cells. We have concluded that (i) the toxic effects of paraquat to the alveolar epithelial cells of the lung are markedly enhanced when paraquat-treated rats are exposed to 85% oxygen, and (ii) the combination of low concentrations of paraquat (2·5 mg/kg) and 85% oxygen or high concentrations of diquat (20 mg/kg) and 85% oxygen damages the Type II alveolar epithelial cells.