Biphasic effects of 1,1,1-trichloroethane on the locomotor activity of mice: Relationship to blood and brain solvent concentrations

Despite the central nervous system (CNS) being a target of virtually all so lvents, few solvents have been thoroughly studied for their effects on unle arned animal behaviors. Of the solvents that have been studied, little is k nown about the relationship of exposure concentration to behavioral effect, and quantitative data relating the toxicologically important target organ (i.e., brain) dose to behavioral effect are almost non-existent. To examine the concentration- and time-dependency of effects of 1,1,1-trichloroethane (TRI) on behavior, male albino Swiss-Webster mice were exposed to TRI (500 -14,000 ppm) in static inhalation chambers for 30 min, during which locomot or activity was measured. Separate mice were exposed to the same concentrat ions under identical conditions for 6, 12, 18, 24, and 30 min, to determine blood and brain concentrations versus time profiles for TRI. This allowed for the relationships between blood and brain concentrations of TRI and loc omotor activity to be discerned. The lowest TRI, concentrations studied (50 0-2000 ppm) had no statistically significant effect on activity, intermedia te concentrations (4000-8000 ppm) increased activity immediately to levels that remained constant over time, and higher concentrations (10,000-14,000 ppm) produced biphasic effects, i.e., increases in activity followed by dec reases. 1,1,1-Trichloroethane concentrations in blood and brain approached steady-state equilibria very rapidly, demonstrated linear kinetics, and inc reased in direct proportion to one another. Locomotor activity increased mo nophasically (approximate to 3.5-fold) as solvent concentrations increased from approximately 50-150 mu g/g brain and mu g/ml blood. As concentrations exceeded the upper limit of this range, the activity level declined and ev entually fell below the control activity level at approximately 250 mu g/g brain and mu g/ml blood. Regression analyses indicated that blood and brain concentrations during exposure were strongly correlated with locomotor act ivity, as were measures of internal dose integrated over time. The broad ex posure range employed demonstrated that TRI, like some classical CNS depres sants, is capable of producing biphasic effects on behavior, supporting the hypothesis that selected solvents are members of the general class of CNS depressant drugs. By relating internal dose measures of TRI to locomotor ac tivity, our understanding of the effects observed and their predictive valu e may be enhanced.