Toxicological Sciences 56, 365-373 (2000)
Copyright © 2000 by the Society of Toxicology
Biphasic Effects of 1,1,1-Trichloroethane on the Locomotor Activity of Mice: Relationship to Blood and Brain Solvent Concentrations
* Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602–2352; and
Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, Virginia 23298–0813
Despite the central nervous system (CNS) being a target of virtually all solvents, few solvents have been thoroughly studied for their effects on unlearned animal behaviors. Of the solvents that have been studied, little is known 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 locomotor activity was measured. Separate mice were exposed to the same concentrations 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 locomotor activity to be discerned. The lowest TRI concentrations studied (500–2000 ppm) had no statistically significant effect on activity, intermediate 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 decreases. 1,1,1-Trichloroethane concentrations in blood and brain approached steady-state equilibria very rapidly, demonstrated linear kinetics, and increased in direct proportion to one another. Locomotor activity increased monophasically (
3.5-fold) as solvent concentrations increased from approximately 50–150 µg/g brain and µg/ml blood. As concentrations exceeded the upper limit of this range, the activity level declined and eventually fell below the control activity level at approximately 250 µg/g brain and µg/ml blood. Regression analyses indicated that blood and brain concentrations during exposure were strongly correlated with locomotor activity, as were measures of internal dose integrated over time. The broad exposure range employed demonstrated that TRI, like some classical CNS depressants, 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 activity, our understanding of the effects observed and their predictive value may be enhanced.
Key Words: 1,1,1-trichloroethane; methyl chloroform; locomotor activity; biphasic effects; internal dose; toxicokinetics..