AL+3 TOXICITY:CONTRIBUTING FACTORS, AL FORM & CHELATION

申请人的长期目标是促进 了解铝（A1）毒理学的病因学和 制定预防和治疗战略。 的工作 在研究职业发展奖期间进行 将遵循几种研究途径。 一是确定 可能有助于吸收的因素的重要性 A1的积累。 这些研究正在进行中， 由NIH资助ES 2676支持。 急性生物利用度研究是 为了阐明A1型的作用， 肾功能受损、胃完整性改变和钙 缺乏对A1吸收和静脉药代动力学的影响 家兔 口服A1盐正在研究兔子肾脏 部分肾动脉结扎损伤，在兔维持 缺乏钙的饮食，在胃完整性受损的家兔中 阿司匹林混悬液和适当的对照兔。 进行血清A1的药代动力学分析。 结果 从急性研究将适用于亚慢性的设计 A1暴露研究，以确定影响 A1的药代动力学也影响A1的组织蓄积， 毒性 多种生理测量（行为、A1组织 水平和神经病理学）将用于确定毒性。 研究正在进行中，以阐明A1的机制， 吸收，使用离体大鼠肠道切片和原位灌注 大鼠肠制备。 研究也在进行中，以阐明 A1通过肾脏消除的机制，使用兔 肾皮质切片和Sperber鸡技术。 研究是 建议利用海马切片技术来确定 A_1对神经递质释放的影响 增强作用 这一结果可能解释了A1- 诱发神经行为毒性。 辛醇/水研究 分区系统建议，它可能是有用的，以确定 无A1螯合潜力的化合物与有A1螯合潜力的化合物 为了螯合A1，并且为了限定A1的亲水性，螯合剂 和A1螯合剂复合物。 测试的潜在A1螯合剂 在A1-负载的兔中评价体外体内A1- 螯合活性 利用这两种方法， 将对A1螯合剂进行测试，目标是口头识别 安全有效的A1螯合剂。 最后，为了确定化学物质 A1中毒的哺乳动物中A1的形式，建议进行研究 选择分离技术来确定化学物质 生物组织中A1的形态。

The long term objectives of the applicant are to contribute to the understanding of the etiology of aluminum (A1) toxicology and the development of prevention and treatment strategies. The work to be conducted during the Research Career Development Award will follow several avenues of research. One is to determine the significance of the factors that may contribute to the absorption and accumulation of A1. These studies are underway, being supported by NIH grant ES 2676. Acute bioavailability studies are being conducted to clarifying the roles of the form of A1, impaired renal function, altered gastic integrity, and calcium deficiency on A1 absorption and intravenous pharmacokinetics in rabbits. Oral A1 salts are being studied in rabbits renally impaired by partial renal artery ligation, in rabbits maintained on Ca-deficient diets, in rabbits with compromised stomach integrity produced by aspirin suspension, and in appropriate control rabbits. Pharmacokinetic analyses of serum A1 are conducted. Results from the acute studies will be applied to the design of sub-chronic A1 exposure studies to determine if the factors that influence the pharmacokinetics of A1 also influence A1 tissue accumulation and toxicity. Numerous physiological measures (behavior, A1 tissue levels, and neuropathology) will be used to determine toxicity. Studies are underway to elucidate the mechanisms by which A1 is absorbed, using isolated rat gut sections and the in situ perfused rat gut preparation. Studies are also underway to elucidate the mechanisms by which A1 is eliminated by the kidney, using rabbit renal cortex slices and the Sperber chicken technique. Studies are proposed to utilize the hippocampal slice technique to determine the influence of A1 on neurotransmitter release and on long term potentiation. The results may explain the mechanism of A1- induced neurobehavioral toxicity. Studies with an octanol/water partitioning system suggested that it may be useful to identify compounds with no A1 chelation potential vs. those with potential to chelate A1, and to define the hydrophilicity of A1, chelators and the A1 chelator complex. The potential A1 chelators tested in vitro were evaluated in the A1-loaded rabbit for in vivo A1- chelation activity. Using, these two approaches further potential A1 chelators will be tested, with the goal of identifying orally effective, safe A1 chelators. Finally, to determine the chemical forms of A1 in the A1-intoxicated mammal, studies are proposed to select separation techniques to determine the chemical speciation of A1 in biological tissue.