ToxSci Advance Access published online on August 13, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm203
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Published by Oxford University Press 2007.
Quantitative Comparisons of the Acute Neurotoxicity of Toluene in Rats and Humans
1 Human Studies Division 2 Neurotoxicology Division 3 Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA
Correspondence concerning this article should be addressed to: Vernon A. Benignus, Ph.D., Human Studies Division, Mail Code B105-06, US Environmental Protection Agency, Research Triangle Park, NC 27711, Tel: 919-541-1522, FAX: 919-541-4849, Email: benignus.vernon{at}epa.gov
Received May 9, 2007; revision received July 20, 2007; accepted July 30, 2007
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Abstract |
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The behavioral and neurophysiological effects of acute exposure to toluene are the most thoroughly explored of all the hydrocarbon solvents. Behavioral effects have been experimentally studied in humans and other species, e.g. rats. The existence of both rat and human dosimetric data offers the opportunity to quantitatively compare the relative sensitivity to acute toluene exposure. The purpose of this study was to fit dose-effect curves to existing data and to estimate the dose-equivalence equation (DEE) between rats and humans. The DEE gives the doses that produce the same magnitude of effect in the two species. Doses were brain concentrations of toluene estimated from PBPK models. Human experiments measuring toluene effects on choice reaction time (CRT) were meta-analyzed. Rat studies employed various dependent variables; amplitude of visual evoked potentials (VEP), signal detection (SIGDET) accuracy (ACCU) and reaction time (RT) and escape-avoidance behaviors (ES-AV). Comparison of dose-effect functions showed that human and rat sensitivity was practically the same for those two task regimens which exerted least control over the behaviors being measured (VEP in rats and CRT in humans) and the sensitivity was progressively lower for SIGDET RT, SIGDET ACCU and ES-AV behaviors in rats. These results suggested that the sensitivity to impairment by toluene depends on the strength of control over the measured behavior rather than on the species being tested. This interpretation suggests that (a) sensitivity to toluene would be equivalent in humans and rats if both species performed behaviors that were controlled to the same extent (b) the most sensitive tests of neurobehavioral effects would be those in which least control is exerted on the behavior being measured and (c) effects of toluene in humans may be estimated using the DEEs from rat studies despite differences in the amount of control exerted by the experimental regimen or differences in the behaviors under investigation.