BIOLOGICAL INDICATORS OF TOXICITY FROM SEMICONDUCTORS

拟议的研究重点是进一步划定 Ga、In或As的生物活性化学物种和早期生物 靶细胞损伤的指标。 这些研究将涉及体内 大鼠和仓鼠暴露于腹膜内滴注， 腹膜内注射Ga、InAs、GaAs或InAs。 目标组织 这些元素的浓度将被分成无机物， 大分子和细胞器成分使用各种分析和 生物化学方法学 这些数据将与金属或 涉及血红素扰动的混合物特异性生化反应 生物合成途径酶活性为了描述机制， 这些元素改变途径的敏感性和特异性 在血液、肝脏和肾脏中的个体或混合物基础上。 这些数据将与超微结构定量相关 血液、肝细胞和肾近曲小管细胞的形态计量分析 原位和组织血红素生物合成途径酶，以描绘 这些指标类别中哪一个是细胞损伤形式的最佳指标 Ga、In或As单独或混合物组合的化学物质。 为了进一步阐明 这些元素的细胞内化学物种，生物指示剂 和细胞损伤的机制，使用红细胞的体外研究， 将原代肝细胞和肾小管上皮细胞培养物 在项目的第二阶段进行。 这些研究报告将 使用Ga、In和As的稳定可溶化学形式进行。 结果 这些研究应该对必要的关系产生新的见解 Ga、In或As的特定细胞内化学物质之间， 对这些试剂的金属特异性生化反应和新的生物学活性 急性气管内滴注后靶细胞损伤的指标 这些元素的颗粒，单独或组合。

The proposed studies are focussed on further delineation between biologically active chemical species of Ga, In or As and early biological indicators of target cell injury. These studies will involve in vivo exposure of rats and hamsters to intratracheal instillations and intraperitoneal injections of Ga, In As, GaAs, or InAs. Target tissue concentrations of these elements will be fractioned into inorganic, macromolecular and organelle components using a variety of analytical and biochemical methodologies. These data will be correlated with metal or mixture-specific biochemical responses involving perturbations of heme biosynthetic pathway enzyme activities in order to delineate mechanisms, sensitivity and specificity of alterations in the pathway by these elements on an individual or mixture basis in blood, liver and kidney. These data will be quantitatively correlated with ultrastructural morphometric analyses of blood, liver cells and renal proximal tubule cells in situ and tissue heme biosynthetic pathway enzymes in order to delineate which of these indicator classes is the best indicator for cell injury form chemical species of Ga, In or As either alone or in mixture combinations. In order to further delineate mechanistic relationships between intracellular chemical species of these elements, the biological indicators and mechanisms of cell injury, in vitro studies using red blood cells and primary hepatocyte and renal tubule epithelial cell cultures will be conducted during the second phase of the project. These studies will be conducted using stable soluble chemical forms of Ga, In and As. Results of these studies should yield new insights into the necessary relationships between specific intracellular chemical species of Ga, In or As, early metal-specific biochemical responses to these agents and novel biological indicators of target cell injury following acute intratracheal instillation of particulates of these elements, either alone or in combination.