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Approaches to extrapolating animal toxicity data on organic solvents to public health
Citation:
BUSHNELL, P. J., W. K. BOYES, T. J. SHAFER, A. BALE, AND V. A. BENIGNUS. Approaches to extrapolating animal toxicity data on organic solvents to public health. NEUROTOXICOLOGY. Intox Press, Inc, Little Rock, AR, 28(2):221-226, (2007).
Impact/Purpose:
Scientific Research
Description:
Developing predictive relationships between exposure and toxicity in humans is difficult because 1) available data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; 2) the specific neurotoxic endpoints measured in laboratory animals seldom translate into effects of concern in humans; and 3) the mode of action of the chemical is rarely understood. This paper describes two approaches for improving predictive exposure-effect relationships for acute exposure to toluene, a common volatile organic compound, using behavioral and physiological indices of toxicity. First, the relative sensitivities of rats and humans was studied using available published data, which included shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that changes in avoidance occur in rats at blood concentrations 25 times higher than changes reaction time in humans. In contrast, in vitro studies comparing neuronal targets from human- and rat-derived proteins indicated that the species do not differ in sensitivity to toluene. Analysis of dose-response relationships for other in vivo endpoints suggests that the apparent difference between rats and humans may be driven by the specific functions measured in the two species rather than by inherent differences in sensitivity to toluene. The second approach involves derivation of dose-equivalence relationships to compare the toxicity of related chemicals, and the application of these relationships to estimate the societal costs of exposure to the chemicals. For example, ethanol-induced changes in choice reaction time, whose societal costs have been estimated, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).
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Approaches to extrapolating animal toxicity data on organic solvents to public health