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EXPOSURE-DOSE-RESPONSE MODELING OF THE NEUROTOXIC EFFECTS OF ORGANIC SOLVENTS.
Citation:
Bushnell, P J., W K. Boyes, J E. Simmons, M V. Evans, W M. Oshiro, T E. Samsam, Q T. Krantz, T J. Shafer, V A. Benignus, AND T. L. Jackson. EXPOSURE-DOSE-RESPONSE MODELING OF THE NEUROTOXIC EFFECTS OF ORGANIC SOLVENTS. Presented at Society of Toxicology, Nashville, TN, 3/17/2002.
Description:
Risk assessments based on exposure to volatile organic compounds (VOCs) are hampered by the complexities of exposure scenarios, a lack of data regarding the mode of action of the VOCs, and uncertainties about extrapolating from animal data to human health risk. We are developing an approach to rationalize these assessments by (1) linking airborne exposure to internal dose via dosimetry modeling in rats; (2) investigating interactions of solvents with receptor systems in the CNS; and (3) comparing the relative sensitivities of rats and humans to the acute effects of VOCs. Physiologically-based pharmacokinetic (PBPK) models are being used to estimate the concentrations of VOCs in blood and brain of rats using a variety of exposure scenarios. Estimates of internal dose (concentrations of trichloroethylene or toluene in blood and brain) accurately predicted the effects of these VOCs on signal detection behavior and visual evoked potentials (VEPs). Mode of action studies are underway to identify critical neurochemical pathway(s) mediating the effects of toluene on signal detection behavior and VEPs, and to test the feasibility of in vitro tests of the acute neurotoxicity of VOCs. Parallel tests of signal detection in rats and humans inhaling toluene may yield a quantitative estimate of the relative sensitivities of the species, to facilitate extrapolation of toxicity in rats to the risk of adverse effects on human health. (This abstract does not necessarily reflect EPA policy.)