Bushnell Philip J, Boyes William K, Shafer Timothy J, Bale Ambuja S, Benignus Vernon A
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Neurotoxicology. 2007 Mar;28(2):221-6. doi: 10.1016/j.neuro.2006.03.013. Epub 2006 Mar 28.
Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific 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. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, 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).
将有机溶剂的急性神经毒性信息综合成人类暴露与效应之间的预测关系是困难的，因为：(1) 数据通常来自实验动物，而它们相对于人类对化学物质的敏感性未知；(2) 在实验动物中测量的特定终点很少能转化为人类关注的效应；(3) 化学物质的作用模式很少被理解。我们试图开发方法来估计有机溶剂暴露的危害和成本，重点关注甲苯对大鼠和人类的急性行为影响。现有的已发表数据包括大鼠的回避电击行为研究和人类的选择反应时间研究。对这些数据的荟萃分析表明，大鼠回避行为出现10%变化时的甲苯血药浓度比人类选择反应时间出现10%变化时的浓度高25倍。相比之下，我们对烟碱型乙酰胆碱受体的体外研究表明，人类和大鼠的受体对甲苯的敏感性没有差异。对大鼠视觉和认知功能的其他剂量反应关系分析表明，大鼠和人类之间的明显差异可能是由两个物种中测量的特定终点驱动的，而不是由对甲苯敏感性的内在差异驱动的。我们还探讨了剂量等效关系可用于比较两种化学物质社会成本的假设。例如，乙醇引起的选择反应时间变化（其社会成本是可估计的）可作为一个基准效应，用于估计控制有机溶剂暴露的货币效益。这种剂量等效方法适用于溶剂，因为这组数据满足基于单一效应的等效关系的三个重要假设：(1) 一个共同的剂量度量（大脑中化学物质的浓度）；(2) 一个共同的效应以提供一个联系变量（选择反应时间）；(3) 一个共同的作用模式（干扰神经元离子通道功能）。
