Neurotoxic Interactions of Different Forms of Mercury

描述(由申请人提供)：关于食用鱼类、牙科汞齐和疫苗中防腐剂的危害的报道引起了公众对汞暴露的担忧。尽管对这种担忧的科学支持可能很少，但我们对汞神经毒性的理解仍然存在相当大的差距，特别是关于不同物种的联合暴露，这是一种常见的情况。存在最大健康风险的两种形式是在鱼类和海洋哺乳动物中发现的甲基汞，以及在工业、化妆品和牙科汞齐中发现的金属汞蒸气。机理分析和有限的实验数据表明，联合暴露于这两种形式可能会增强其中任何一种形式的神经毒性，这对发育中的大脑来说是一个特别令人担忧的结果。由于联合暴露是如此常见，孕妇的检测表明，无机形式的汞占血液中汞的25%以上，因此该项目旨在更清楚地定义大脑发育的相关风险。怀孕的大鼠将同时通过吸入汞蒸气和饮用水中的甲基汞暴露。后代的神经行为测量将包括时间表控制的操作行为，以评估认知行为、动机和记忆；后肢张开作为运动功能的测试；以及运动活动，一种常见的神经行为状态测试。还将测量后代大脑中的汞浓度。研究将分阶段进行。(1)暴露水平本身就会产生轻微到中度的神经毒性和每种形式的可靠的剂量-效应函数。(2和3)在这里，我们确定特定浓度的蒸汽是否改变了甲基汞的剂量-效应函数，以及特定剂量的甲基汞是否改变了汞蒸汽的浓度-效应函数。这些结果将被用来通过基准剂量模型计算导致神经毒性指数变化10%和25%的蒸汽和甲基暴露。(4)将确定这些水平的综合影响。这些数据的获得为确定同时暴露于两种汞物种对神经行为发育的风险提供了坚实的基础。

DESCRIPTION (provided by applicant): Public anxieties about mercury exposure have been aroused by reports about the hazards of fish consumption, dental amalgams, and preservatives in vaccines. Although scientific support for such concerns may be tenuous, it is also true that sizable gaps remain in our understanding of mercury neurotoxicity, especially with respect to combined exposures to different species, a commonplace condition. The two forms that present the greatest health risks are methylmercury, found in fish and marine mammals, and metallic mercury vapor, found in industry, cosmetics, and dental amalgams. Mechanistic analyses and limited experimental data indicate that co-exposure to the two forms may enhance the neurotoxicity of either alone, an especially worrisome outcome for the developing brain. Because joint exposure is such a common occurrence, with assays in pregnant women indicating that the inorganic form accounts for more than 25% of mercury in blood, this project is designed to more clearly define the associated risks to brain development. Pregnant rats will be exposed concurrently to mercury vapor by inhalation and to methylmercury in drinking water. Neurobehavioral measures in the offspring will include schedule-controlled operant behavior to assess cognitive behavior, motivation, and memory; hindlimb splay as an assay for motor function; and locomotor activity, a common assay for neurobehavioral status. Mercury concentrations in offspring brains will also be measured. The research will proceed in stages. (1) Exposure levels will produce mild to moderate degrees of neurotoxicity and reliable dose-effect functions for each form by itself. (2 and 3) Here we determine if a specified concentration of vapor changes the dose-effect function for methylmercury and if a specified dose of methylmercury alters the concentration-effect function of mercury vapor. These results will be used to calculate, by Benchmark Dose modeling, vapor and methyl exposures inducing a 10% and 25% change in the neurotoxic indices. (4) The combined effects of these levels will be determined. The acquisition of these data offers a firm foundation for determining the risks to neurobehavioral development of concurrent exposures to both mercury species.