FACTORS MODIFYING BEHAVIORAL TOXICITY OF LEAD AND PCB'S

改变铅和多氯联苯行为毒性的因素

• 批准号: 6340932
• 负责人: BARBARA J STRUPP
• 金额: $ 13.44万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-20 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340932
• 关键词: attention; chelation therapy; disease /disorder model; embryo /fetus toxicology; environmental contamination; halobiphenyl /halotriphenyl compound; hazardous substances; industrial waste; iron disorder; laboratory rat; lead; learning; long term memory; neuropsychological tests; neurotoxins; nonhuman therapy evaluation; sensory discrimination; sulfur aminoacid; toxicant interaction

Lead (Pb) is a frequently encountered pollutant from superfund sites, urban and agricultural soils, and other hazardous wastes which may be ingested or inhaled, particularly by children. There is increasing evidence that low-level Pb exposure and even slight elevations in blood lead (BPb) level in early childhood are associated with significant, enduring, cognitive neurobehavioral deficits, thereby creating a pressing need both to reduce exposure to Pb and to develop more effective means of treating children with even slightly elevated BPb levels. One promising new therapeutic chelating agent, dimercaptosuccinic acid (DMSA), is highly effective in reducing BPb and tissue Pb levels, can be administered orally on an outpatient basis, and does not cause the many side effects associated with current chelation therapy. To date, no studies have examined either the efficacy of this compound in alleviating Pb neurobehavioral toxicity or the possible behavioral teratogenicity of DMSA itself. Such studies are essential before the drug can be approved for widespread use; moreover, these studies can provide additional insight into the extent and duration of these deficits and the applicability of this model as a probe for assessment of neurotoxicants in hazardous wastes. The major purpose of the proposed studies is to determine if chelation with DMSA lessens the neurobehavioral deficits associated with rodent models of either childhood and adult Pb exposure. Separate groups of animals will be subjected to Pb exposure po via a regime already established as to BPb levels and neonastal deficits. Pb-exposed animals and controls will be euthanized before and after the three DMSA regimens so that performance in the battery of neurobehavioral measures can be correlated with both brain and blood Pb levels. This proposed study is a continuation of neurobehavioral Pb toxicity studies under the Cornell Superfund Basic Research and Education Program and parallels two studies recently funded by NIEHS to examine the efficacy of DMSA in alleviating the neurobehavioral toxicity of Pb - a multicenter pediatric trial (RFP NIH-ES 92-93) and a similar study using a non-human primate model. The proposed project will cooperatively provide important information about the efficacy of DMSA in alleviating (or exacerbating) Pb-induced cognitive dysfunction that will not be provided by either of the parallel studies and therefore should aid in interpretation of their results. They in turn provide technical services assisting evaluation of Pb mitigation. Briefly, this project, relative to the two parallel studies, would provide (1) dose-response information about DMSA in alleviating Pb- induced cognitive dysfunction; (2) determination of DMSA efficacy as a function of BPb level under conditions in which Pb exposure and DMSA treatment can be carefully controlled and monitored, and sociodemographic factors affecting cognition can be controlled; (3) the relationship between changes in neurobehavioral function and brain Pb levels; and (4) assessment of DMSA efficacy in alleviating neurobehavioral deficits in cases of adult Pb exposure.

铅是来自超级基金站点的一种常见污染物， 城市和农业土壤，以及其他可能是 吸入的摄取或吸入的，尤指被儿童吸入的有越来越多的 有证据表明，低水平的铅暴露和血液中的轻微升高 儿童早期铅(BPB)水平与显著、 持久的认知神经行为缺陷，从而产生一种压力 既需要减少铅的暴露，也需要开发更有效的方法 治疗即使是轻微升高的血铅水平的儿童。一 前景看好的新型治疗性螯合剂--二硫代丁二酸 (DMSA)，在降低血铅和组织铅水平方面非常有效，可以 在门诊基础上口服，不会导致许多 与目前的螯合疗法相关的副作用。到目前为止，没有 研究已经检验了这种化合物在缓解疾病方面的效果 铅的神经行为毒性或可能的行为致畸作用 DMSA本身。在药物获得批准之前，这样的研究是必不可少的 广泛使用；此外，这些研究还可以提供额外的 洞察这些赤字的程度和持续时间，以及 该模型作为评估神经毒物的探针的适用性 在危险废物中。 拟议研究的主要目的是确定螯合作用是否 使用DMSA可减轻与啮齿动物相关的神经行为缺陷 儿童和成人铅暴露的模型。不同的组 动物将受到铅暴露的影响，通过一个已经存在的制度 确定了血铅水平和新生儿缺乏症。接触铅的动物 而对照组将在三种DMSA方案之前和之后实施安乐死 因此，在一系列神经行为测量中的表现可以 与脑部和血铅水平相关。这项拟议的研究是 康奈尔大学神经行为铅中毒研究的继续 超级基金基础研究和教育计划及其平行的两项研究 最近由NIEHS资助，以检查DMSA在缓解 铅-a多中心儿科试验的神经行为毒性 NIH-ES 92-93)和一项使用非人类灵长类动物模型的类似研究。这个 提议的项目将合作提供关于以下方面的重要信息 DMSA对铅中毒的缓解(或加重)作用 认知功能障碍不会由任何一个平行的人提供 因此，这些研究应有助于解释其结果。他们 反过来，提供技术服务，协助评估铅的缓解。 简而言之，相对于这两项平行研究，该项目将 提供(1)DMSA缓解铅中毒的剂量反应信息 诱发认知功能障碍；(2)DMSA疗效的测定 铅暴露与DMSA联合作用下血铅水平的变化 治疗可以仔细控制和监测，社会人口学 影响认知的因素是可控的；(3) 神经行为功能变化与脑铅水平之间的关系；以及(4) DMSA对改善精神分裂症患者神经行为缺陷的疗效评价 成人铅暴露6例。