OCCUPATIONAL RISK REDUCTION BY RADIOTOXIN CHELATION

该项目的目标是开发能够对重离子产生影响的螯合剂 金属脱孔和降低放射性核素口服毒性的研究 这些螯合剂的应用。目前，职业暴露 用二乙烯三胺的钙和锌螯合物治疗个体- 五乙酸(DTPA)。DTPA形成高稳定性的螯合物，但 极强的亲水性，需要静脉给药，而且迅速 排泄物。在这个项目的前两年，我们设计了， 合成并测试了几类新的螯合化合物。从In开始 体外试验，几种二乙烯三胺(DT)和三乙烯四胺- 对基于(TT)的化合物进行了鉴定和体内测试。口服时 它们能非常有效地清除大鼠老化的241Am沉淀物。AM是 用作5f轨道元素的模型。具体来说，我们建议：1) 继续体内试验，以确定DT和TT的剂量和时间效应 基于螯合对Am和Pu的去除。排泄率将被确定，并 钚的组织定位化模式将通过中子诱导获得 放射自显影。其他类别的多氨基甲酸将被测试 在成功进行体外测试后。2)确定工作效率 DT和TT基络合物对非金属的脱孔作用 放线菌。这些海龟将结合铅和铁，初步研究将是 使用铅，这是一种重要的环境和职业毒素。 3)开发、合成和测试具有改良靶器官的海龟 专一性。为此，化学成分，一些类似于内源 底物，会附着在多胺基羧酸上。今年5月 提供相当大的治疗优势。4)确定器官和 口服海龟的组织分布。选择无线标记 将合成螯合物，并使用 生化和放射自显影方法。5)确定骨骼 长期(&gt；6年)螯合治疗(DTPA)对狗的影响。我们 从参与另一项研究的动物身上获得了完整的骨骼，并将 使用静态和动态组织形态计量学确定骨骼变化 方法：研究方法。这将为Long提供一些独特和实用的信息 定期螯合疗法。这些研究应该导致发展 可显著改进治疗方法的新型螯合剂 用来降低榄系元素、镧系元素和其他元素的毒性 金属。

The goal of this project is to develop chelating agents capable of heavy metal decorporation and to reduce radionuclide toxicity by the oral application of these chelators. At present, occupationally exposed individuals are treated with Ca- and Zn-chelates of diethylenetriamine- pentaacetic acid (DTPA). DTPA forms chelates with high stability but is strongly hydrophilic, requires parenteral administration and is rapidly excreted. In the first 2 years of this project, we have designed, synthesized and tested several classes of new chelation compounds. From in vitro testing, several diethylenetriamine-(DT) and triethylenetetramine- (TT) based compounds were identified and tested in vivo. When given orally they are very effective in removing aged 241Am deposits in rats. Am is used as a model of 5f-orbital elements. Specifically we propose to: 1) Continue in vivo testing to determine dose and time effects of DT and TT- based chelons on Am and Pu removal. Excretion rates will be determined and tissue localization patterns of Pu will be obtained by neutron-induced autoradiography. Other classes of polyaminocarboxylic acids will be tested following successful in vitro testing. 2) To determine the efficiency of DT- and TT-based chelons on the decorporation of metals other than actinides. These chelons will bind Pb and Fe and initial studies will be done with Pb, which is a significant environmental and occupational toxin. 3) To develop, synthesize and test chelons with improve target organ specificity. For this, chemical moieties, some analogous to endogenous substrates, will be attached to the polyaminocarboxylic acids. This may offer considerable therapeutic advantage. 4) To determine the organ and tissue distribution of orally administered chelons. Select radiolabeled chelons will be synthesized and their distribution determined using biochemical and autoradiographic methods. 5) To determine the skeletal effects of long term (>6 years) chelation treatment (DTPA) in dogs. We obtained complete skeletons from animals involved in another study and will determine skeletal changes using static and dynamic histomorphometric methods. This will provide some unique and practical information on long term chelation therapy. These studies should lead to the development of new chelation agents that may substantially improve therapeutic approaches for the reduction of toxicity from actinide, lanthanide and perhaps other metals.