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QUANTITATIVE MODELING APPROACHES TO PREDICTING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS).
Citation:
BUSHNELL, P. J., W. K. BOYES, V. A. BENIGNUS, T. J. SHAFER, AND E. M. KENYON. QUANTITATIVE MODELING APPROACHES TO PREDICTING THE ACUTE NEUROTOXICITY OF VOLATILE ORGANIC COMPOUNDS (VOCS). Presented at EPA Computational Toxicology Forum, RTP, NC, May 21 - 23, 2007.
Description:
Lack of complete and appropriate human data requires prediction of the hazards for exposed human populations by extrapolation from available animal and in vitro data. Predictive models for the toxicity of chemicals can be constructed by linking kinetic and mode of action data utilizing a quantitative modeling framework. Volatile organic compounds (VOCs) comprise a class of chemicals suitable for developing such models because: (a) physiologically-based toxicokinetic (PBTK) models are well established for this chemical class; (b) the dose metric for the acute effects is known; and (c) information is available about the mode of action (MOA) for their acute effects (altered function of neuronal ion channels in the central nervous system). We have organized this information for VOCs into an exposure-dose-response (EDR) model, and have used this framework to develop dose-equivalence methods for several purposes. Dose equivalence (DE) methods involve quantitative comparisons of dose-effect functions that are either generated experimentally or derived from published data by means of meta-analysis. First, we showed that known relationships between exposure, dose, and effect for a well-studied compound (e.g., ethanol) can be used to estimate the costs of intoxication with another compound (e.g., toluene). Second, enough is known about toluene to use DE methods to compare its potency across species and functional endpoints in vivo. Third, given data on the potency of one VOC (e.g., toluene) in vitro and in vivo, the potency of other VOCs in vivo can be estimated from their in vitro potency and modeled internal doses. These approaches may be applied to longer duration exposures and chronic effects for VOCs, as well as to other chemical classes, when the MOA and dose metrics are known and PBTK models are available.