TOXICOLOGY OF DITHIOBIURET AND ENVIRONMENTAL AGENTS

2，4-二硫代缩二脲（DTB），具有广泛的特殊用途， 化工专业化 在大鼠和猫中，DTB产生延迟发作的肌肉 似乎是由于中央-外周远端轴突病引起的虚弱。 长期目标是描述大鼠DTB的神经病理学 和猫来确定它在神经系统中的作用部位和机制。 首先，建立产生神经毒性的条件， 目的是：开发一种用于评估虚弱程度的跑步机方法， 描述用于产生虚弱、进行 DTB同系物和DTB代谢物的结构-活性研究， 对神经病变的演变进行完整的形态学研究。 第二，确定DTB代谢和处置在 目的：建立高效液相色谱分离DTB的方法 和DTB代谢物，鉴定尿DTB代谢物，测量DTB血浆 清除率和尿排泄，并确定酶系统参与 DTB代谢。 第三，确定DTB神经毒性的机制， 大鼠的目的是：观察轴浆流是否受到抑制，确定是否 神经元产生能量的途径受到抑制，看看胆碱 乙酰转移酶活性降低，确定是否存在虚弱 继发于低氧血症或高血糖症，并开发DTB拮抗剂， 分析DTB的作用机制。 第四，确定 神经系统部位和作用机制，具体目标是： 确定躯体传入纤维是否存在电生理学变化 这可能与神经衰弱有关看看单突触脊髓反射 和初级传入反射被抑制（暗示中间神经元 和/或运动神经元损伤），确定DTB对频率依赖性 反射和递质转换，评估电生理特性 的运动神经元索马，评估DTB对运动轴突及其 终端，并确定是否烟碱受体的性质或机制， 将受体激活与肌肉膜电导变化联系起来， 改变了 这些研究对人类健康的应用是DTB 神经病变可能是人类某些神经病性疾病的模型， 拮抗剂最终可用于治疗这些疾病。

The 2, 4-Dithiobiuret (DTB), has a wide range of speciality uses in the chemical industry. In rats and cats DTB produces a delayed onset muscle weakness that appears to be due to a central-peripheral distal axonopathy. The long range objectives are to describe the neuropathology of DTB in rats and cats and determine it's nervous system sites and mechanisms of action. First, to establish conditions for producing neurotoxicity the specific aims are to: develop a treadmill method for assessing degrees of weakness, describe dosage regimens for the production of weakness, conduct structure-activity studies with DTB congeners and DTB metabolites, and conduct a complete morphologic study of the evolution of the neuropathy. Second, to determine the role of DTB metabolism and disposition in neurotoxicity the aims are to: develop a HPLC system for separating DTB and DTB metabolites, identify urinary DTB metabolites, measure DTB plasma clearance and urinary excretion, and identify enzyme systems involved in DTB metabolism. Third, to determine the mechanism of DTB neurotoxicity in rats the aims are to: see if axoplasmic flow is depressed, determine if neuronal energy-producing pathways are depressed, see if choline acetyltransferase activity is diminished, determine if weakness is secondary to hypoxemia or hyperglycemia, and develop DTB antagonists to pharmacologically dissect DTB's mechanism of action. Fourth, to determine nervous system sites, and mechanisms of action the specific aims are to: determine if electrophysiologic changes in somatic afferent fibers exist which can be linked to the weakness, see if monosynaptic spinal reflexes and primary afferent reflexes are depressed (suggestive of interneuron and/or motoneuron damage), identify effects of DTB on frequency dependent reflexes and transmitter turnover, evaluate electrophysiological properties of the motoneuron soma, assess DTB effects on motor axons and their terminals, and determine if nicotinic receptor properties or the mechanism which links receptor activation to muscle membrane conductance changes are altered. The application of these studies to human health is that DTB neuropathy may be a model for certain neuropathic diseases in man and DTB antagonists may ultimately be used in the treatment of these diseases.