| Title: | Developing an exposure-dose-response model for the acute neurotoxicity of organic solvents: overview and progress on in vitro models and dosimetry |
| Author(s): | Bushnell PJ; Shafer TJ; Bale AS; Boyes WK; Simmons JE; Eklund C; Jackson TL; |
| Address: | "Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA" |
| Journal Title: | Environ Toxicol Pharmacol |
| DOI: | 10.1016/j.etap.2004.12.026 |
| ISSN/ISBN: | 1382-6689 (Print) 1382-6689 (Linking) |
| Abstract: | "We are developing an exposure-dose-response (EDR) model for volatile organic compounds (VOCs) to predict acute effects of VOCs on nervous system function from exposure data (concentration and duration of inhalation). This model contains both toxicokinetic and toxicodynamic components. One advantage of the EDR model will be its ability to relate in vitro effects of solvents on cellular ion channels (putative targets) to in vivo effects, using a combination of physiologically-based toxicokinetic (PBTK) modeling (to estimate VOC concentrations in the blood and brain) and in vitro studies to clarify the mode of action of the VOCs. Recent work in vitro has focused on quantifying the inhibitory effects of toluene, trichloroethylene (TCE) and perchloroethylene (PERC) on ion channel currents. All three VOCs inhibit current through voltage-sensitive calcium channels (VSCCs) in pheochromocytoma cells; PERC blocked calcium currents and altered the current-voltage relationship at lower concentrations than did toluene or TCE. Recombinant nicotinic acetylcholine receptors (nAChRs), expressed in Xenopus oocytes, were also inhibited by PERC and toluene in a concentration-dependent manner. PERC inhibited alpha7 receptors more than alpha4beta2 receptors in recombinant human and rat nAChRs. However, human and rat alpha7 receptors were equally sensitive to PERC and TOL. These in vitro studies will be used to identify an appropriate neuronal receptor system to serve as an index of acute effects of VOCs in vivo. The PBTK model incorporates physiological input parameters derived from radiotelemetered heart rate data from rats performing operant tests of cognitive and motor functions. These studies should improve predictions of target organ concentrations of inhaled VOCs in subjects actively performing behavioral tests over a range of physical activity levels" |
| Notes: | "PubMed-not-MEDLINEBushnell, Philip J Shafer, Timothy J Bale, Ambuja S Boyes, William K Simmons, Jane Ellen Eklund, Christopher Jackson, Trachette L eng Netherlands 2005/05/01 Environ Toxicol Pharmacol. 2005 May; 19(3):607-14. doi: 10.1016/j.etap.2004.12.026" |
