Prediction of in vivo kinetic constants for metabolism of inhaled vapors from kinetic constants measured in vitro.

Benzene and toluene are metabolized by microsomal preparations in a closed metabolism flask. The Km values for benzene and toluene were 8.0 and 10.3 microM; the Vmax values were 17.2 and 20.8 nmol/g liver/min, respectively. By the use of a toxicokinetic model which acknowledges the potential for perfusion limitations on in vivo metabolism, the in vivo Km values (in terms of atmospheric concentration) for benzene and toluene were calculated based on the constants determined in vitro. The predicted in vivo constants were 0.20 and 0.21 mg/L, respectively. In vivo Km values experimentally determined by gas uptake techniques in the same strain of animal were 0.13 and 0.59 mg/L for benzene and toluene, respectively. For benzene predicted values and observed values for Km gave good correlation. The values for toluene did not correlate quite as well. The Vmax values predicted by direct conversion of the values obtained in vitro were 3.3 and 4.7 mg/kg/hr for benzene and toluene, respectively, and agreed well with the respective values observed in vivo of 2.2 and 4.6 mg/kg/hr. The model appeared capable of accurately predicting in vivo Km values from in vitro constants. Vmax values were predicted directly from in vitro constants.

Acute and chronic propylene glycol dinitrate exposure in the monkey.

Rhesus monkeys (Macaca mulatta) were exposed to propylene glycol 1,2-dinitrate (PGDN) vapors on either an acute (4-h) or chronic (125-d) schedule. During acute exposures, PGDN concentrations ranged from a low of 2 ppm (parts per million) to a high of 33 ppm. Free operant avoidance behavior and visual evoked responses were monitored and free operant avoidance was not affected at any dose level. The late positive (100-150 ms) wave of the visual evoked response increased 20% at 2 ppm and decreased 25% at concentrations up to 33 ppm. Although these changes were statistically different from control values, they were within the limits caused by distracting events (+/-40%), and might possibly have been caused by the irritating or distracting properties of the vapor. Other monkeys were exposed to successively increasing concentrations of PGDN vapors at 0.3-4.2 ppm. 23 h/d, for 125 d. Daily performance testing included alternating sessions of discrete-trial cued avoidance and free operant avoidance. Non of the PGDN concentrations had a discernible effect on either type of avoidance performance.

Oral toxicity of 1,1-dichloroethylene in the rat: effects of sex, age, and fasting.

Mortality curves for groups of fasted male rats treated with single, oral doses of 1,1-dichloroethylene (1,1-DCE, vinylidene chloride) were not monotonically increasing sigmoids, but were complex with maxima or extended plateaus in the region of dose between 100 and 700 mg of 1,1-DCE/kg. The exact shape was a function of the size (age) of the rat used. When groups of rats of various sizes were dosed with 50 mg/kg, mortality and hepatotoxicity were greatest for those groups whose average weight was between 100 and 150 g. Smaller and larger male rats were less susceptible to 1,1-DCE intoxication. The toxicity of 1,1-DCE was less severe in female rats and there was no significant effect of rat size on 1,1-DCE toxicity in females. In rats of both sexes the dose dependence of the hepatotoxic response was complex, possessing a threshold level, a region of precipitous increase, and a plateau, where larger doses were ineffective in increasing hepatotoxicity. The threshold in male rats of 100-150 g occurred near 50 mg/kg, and for females it was closer to 100 mg/kg. Considered in their entirety these data suggest that 1,1-DCE is metabolized to a toxic intermediate via some saturable pathway. Based on the effects of pretreatment with microsomal enzyme inhibitors and activators on 1,1-DCE toxicity in rats of various sizes, it appears that there are at least two microsomal reactions involved in 1,1-DCE metabolism.

Enhancement of 1,1-dichloroethylene toxicity by pretreatment of fasted male rats with 2,3-epoxypropan-1-ol.

The efficacy of pretreatment with various low molecular weight epoxides in increasing the toxicity of orally administered 1,1-dichloroethylene (1,1-DCE) has been determined in fasted male rats. Rats were dosed ip with either 2,3-epoxypropan-1-ol (EP), 1,1,1-trichloropropane-2,3-oxide (TCPO), styrene oxide (SO), cyclohexene oxide (CHO), butadiene monoxide (BMO) or the sulfhydryl reagent, diethylmaleate (DEM) 1 hr before intubation with 1,1-DCE. Increases in plasma aspartate transaminase (AsT) 24 hr after 1,1-DCE intubation were used as a measure of toxicity. In rats pretreated with 278 mg of EP/kg the acute LD50 of 1,1-DCE was reduced by a factor of 5 (to less than 40 mg/kg) and doses of 1,1-DCE as low as 12.5 mg/kg increased AsT levels. While 25 mg of 1,1-DCE/kg did not increase plasma AsT activities in naive rats, this dose did increase AsT levels in rats pretreated with 30 mg of EP/kg. The severity of 1,1-DCE toxicity in EP pretreated rats was greater in large, mature rats than in small, immature rats. On a molar basis the abilities of these various epoxides and DEM to exacerbate 1,1-DCE toxicity were related as follows: EP greater than SO greater than TCPO greater than CHO greater than DEM greater than BMO. These epoxides appeared to increase the toxicity of 1,1-DCE by interfering with the metabolism of a toxic product of the microsomal oxidation of 1,1-DCE.

Sulfolane-induced convulsions in rodents.

In rodents oral or parenteral administration of sulfolane (tetrahydrothiophene-1,1-dioxide) produced hyperactivity, followed by clonic-tonic convulsions. The analeptic effects of sulfolane were nearly additive with those of Metrazol. When injected simultaneously with pentobarbital, sulfolane decreased pentobarbital sleeping time in mice. But sulfolane increased sleeping time when the barbiturate was administered 1 hr after sulfolane.