ToxSci Advance Access originally published online on December 19, 2008
Toxicological Sciences 2009 108(1):159-172; doi:10.1093/toxsci/kfn265
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Published by Oxford University Press 2008.
Acute Perchloroethylene Exposure Alters Rat Visual-Evoked Potentials in Relation to Brain Concentrations
* Neurotoxicology Division
Experimental Toxicology Division
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
1 To whom correspondence should be addressed at B105-05, Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: boyes.william{at}epa.gov.
Received November 4, 2008; accepted December 13, 2008
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Abstract |
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These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE in the brains of adult Long-Evans rats following inhalation exposure. The model was evaluated for performance against tissue concentrations from exposed rats (n = 40) and data from the published scientific literature. Visual function was assessed using steady-state pattern-elicited visual-evoked potentials (VEPs) recorded from rats during exposure to air or PCE in two experiments (total n = 84) with concentrations of PCE ranging from 250 to 4000 ppm. VEP waveforms were submitted to a spectral analysis in which the major response component, F2, occurring at twice the visual stimulation rate, was reduced in amplitude by PCE exposure. The F2 amplitudes were transformed to an effect-magnitude scale ranging from 0 (no effect) to 1 (maximum possible effect), and a logistical function was fit to the transformed values as a function of estimated concurrent brain PCE concentrations. The resultant function described a dose-response relationship between brain PCE concentration and changes in visual function with an ED10 value of approximately 0.684 mg/l and an ED50 value of approximately 46.5 mg/l. The results confirmed that visual function was disrupted by acute exposure to PCE, and the PBPK model and logistic model together could be used to make quantitative estimates of the magnitude of deficit to be expected for any given inhalation exposure scenario.
Key Words: neurotoxicity; PBPK model; volatile organic compound; organic solvent; visual-evoked potential.
This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA and approved for publication. Mention of trade names and commercial products does not constitute endorsement or recommendation for use.