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ToxSci Advance Access published online on June 23, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi242
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Published by Oxford University Press 2005.
Received May 19, 2005
Accepted June 21, 2005

Neurotoxicology

Momentary Brain Concentration of Trichloroethylene Predicts the Effects on Rat Visual Function

William K. Boyes 1*, Mark Bercegeay 1, Todd Krantz 2, Marina Evans 2, Vernon Benignus 3, and Jane Ellen Simmons 2

1 Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
2 Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
3 Human Studies Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina

* To whom correspondence should be addressed.
William K. Boyes, E-mail: boyes.william{at}epa.gov


  Abstract

The relationship between the concentration of trichloroethylene (TCE) in the brain and changes in brain function, indicated by the amplitude of steady-state pattern-elicited visual evoked potentials (VEP), was evaluated in Long-Evans rats. VEPs were recorded from visual cortex following stimulation of the eyes, and thus reflect the function of the afferent visual pathway and, in broad terms, may be indicative of overall brain function. The concentration of TCE in the brain at the time of VEP testing (i.e. momentary brain concentration) was hypothesized to predict the amplitude of the VEP across a range of inhalation concentrations, both during and after exposure. Awake restrained rats were exposed to clean air or TCE in the following combinations of concentration and duration: 500 ppm (4 hr); 1000 ppm (4 hr); 2000 (2 hr); 3000 ppm (1.3 hr); 4000 ppm (1 hr); and 5000 ppm (0.8 hr). VEPs were recorded several times during the exposure session, and afterward for experimental sessions of less than 4 hours total duration (i.e. concentrations from 2000-5000 ppm). The sample collection time for each VEP was about 1 min. Brain concentrations of TCE were predicted using a physiologically-based pharmacokinetic (PBPK) model. VEP waveforms were submitted to spectral analysis and the amplitude of the largest response component, occurring at twice the temporal stimulation rate (F2), was measured. Exposure to all air concentrations of TCE in the study reduced F2 amplitude. The reduction of F2 amplitude was proportional to momentary brain TCE concentration during and after exposure. A logistical function fit to the combined data from all exposure conditions described a statistically significant relationship with 95% confidence limits between brain TCE concentration and F2 amplitude. The results support the hypothesis that momentary brain concentration of TCE is an appropriate dose metric to describe the effects of acute TCE inhalation exposure on rat VEPs. The combination of the PBPK model predicting brain TCE concentration from the exposure conditions with the logistical function predicting F2 amplitude from the brain TCE concentration constitute a quantitative exposure-dose-response model describing an acute change in neurological function following exposure to an important hazardous air pollutant.


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