ToxSci Advance Access originally published online on August 12, 2003
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Toxicological Sciences 76, 121-130 (2003)
Copyright © 2003 by the Society of Toxicology
NEUROTOXICOLOGY |
Dose-Based Duration Adjustments for the Effects of Inhaled Trichloroethylene on Rat Visual Function
* Neurotoxicology Division and
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and
Research Triangle Institute, Research Triangle Park, North Carolina 27709
Risk assessments often must consider exposures that vary over time or for which the exposure duration of concern differs from the available data, and a variety of extrapolation procedures have been devised accordingly. The present experiments explore the relationship(s) between exposure concentration (C) and time (t) to investigate procedures for assessing the risks of short-term solvent exposures. The first hypothesis tested was that the product of C x t would produce a constant health effect (Haber’s rule). The second hypothesis tested was that exposure conditions produce effects in proportion to the tissue concentrations created. Awake, adult, male Long-Evans (LE) rats were exposed to trichloroethylene (TCE) vapor in a head-only exposure chamber while pattern onset/offset visual evoked potentials (VEPs) were recorded. Exposure conditions were designed to provide C x t products of 0 ppm/h (0 ppm for 4 h) or 4000 ppm/h created through four exposure scenarios: 1000 ppm for 4 h; 2000 ppm for 2 h; 3000 ppm for 1.3 h; or 4000 ppm for 1h (n = 9–10/concentration). The amplitude of the VEP frequency double component (F2) was decreased significantly by exposure; this decrease was related to C but not to t or to the C x t product, indicating that Haber’s rule did not hold. The mean amplitude (± SEM in µV) of the F2 component in the control and treatment groups measured 4.4 ± 0.5 (0 ppm/4 h), 3.1 ± 0.5 (1000 ppm/4 h), 3.1 ± 0.4 (2000 ppm/2 h), 2.3 ± 0.3 (3000 ppm/1.3 h), and 1.9 ± 0.4 (4000 ppm/1 h). A physiologically based pharmacokinetic (PBPK) model was used to estimate the concentrations of TCE in the brain achieved during each exposure condition. The F2 amplitude of the VEP decreased monotonically as a function of the estimated peak brain concentration but was not related to the area under the curve (AUC) of the brain TCE concentration. In comparison to estimates from the PBPK model, extrapolations based on Haber’s rule yielded approximately a 6-fold error in estimated exposure duration when extrapolating across only a 4-fold change in exposure concentration. These results indicate that the use of a linear form of Haber’s rule will not predict accurately the risks of acute exposure to TCE, nor will an estimate of AUC of brain TCE. However, an estimate of the brain TCE concentration at the time of VEP testing predicted the effects of TCE across exposure concentrations and durations.
Key Words: Haber’s rule; physiologically based pharmacokinetic model; visual evoked potentials; neurotoxicity; organic solvents.
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