SATURABLE METABOLISM AND THE ACUTE TOXICITY OF 1,1-DICHLOROETHYLENE

The toxic effects of single, oral doses of 1,1-dichloroethylene (1,1-DCE) are caused by its metabolites. When saturable, enzymatic production of a toxic intermediate regulates toxicity, the observed inhalation toxicity, at sufficiently high concentrations, will depend on the duration of exposure and be relatively independent of the ambient concentration. The inhalation toxicity of 1,1-DCE was examined in fasted male rats to ascertain its dependence on both 1,1-DCE concentration and the duration of exposure. Immature rats (100-150 g) were exposed to 200 ppm 1,1-DCE for durations up to 2 hr. Pentobarbital sleep times (PBST) were significantly increased after exposures as brief as 0.5 hr. Intubation of immature rats with 1,1-DCE produced extensive dilation and vacuolization of the endoplasmic reticulum (ER). While young rats were more susceptible to 1,1-DCE than older rats (> 200 g), extensive damage to the ER (the presumed site of 1,1-DCE metabolism) during exposure precluded their use in determining the inhalation dose-effect curves. With older rats, PBST were not increased during exposure. The concentration-mortality curve for 4-hr exposures increased sharply between 100 and 200 ppm, but was virtually flat (i.e., concentration independent) between 200 and 1000 ppm. The LT50 (the time of exposure required to kill half an exposed group at a given concentration) only varied between 4.1 and 2.4 hr as concentration increased from 200 to 1000 ppm. Failure of 1,1-DCE to adhere to a concentration × time relationship is further evidence of a role of saturable, enzymatic activation in the expression of its toxicity. © 1979.