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: 6106346
• 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/6106346
• 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 (Pb) 是超级基金站点中经常遇到的污染物， 城市和农业土壤以及其他可能产生的危险废物 摄入或吸入，尤其是儿童。有越来越多 有证据表明，低水平的铅暴露，甚至血液中的轻微升高 儿童早期的铅 (BPb) 水平与显着的、 持久的认知神经行为缺陷，从而产生紧迫的 需要减少铅的暴露并开发更有效的方法 治疗 BPb 水平轻微升高的儿童。一 有前途的新型治疗螯合剂二巯基丁二酸 （DMSA），在降低 BPb 和组织 Pb 水平方面非常有效，可以 在门诊口服给药，不会引起许多 与当前螯合疗法相关的副作用。 迄今为止，没有 研究已经检验了该化合物在缓解 铅的神经行为毒性或可能的行为致畸性 DMSA 本身。在药物获得批准之前，此类研究是必不可少的 广泛使用；此外，这些研究可以提供额外的 深入了解这些赤字的程度和持续时间以及 该模型作为神经毒物评估探针的适用性 在危险废物中。 拟议研究的主要目的是确定螯合是否 DMSA 可减轻与啮齿动物相关的神经行为缺陷 儿童和成人铅暴露模型。分开的组 动物将通过已制定的制度接受铅暴露 确定了 BPb 水平和新生儿缺陷。接触铅的动物 对照组将在三种 DMSA 方案之前和之后被安乐死 这样神经行为测量的表现就可以 与大脑和血液中的 Pb 水平相关。这项拟议的研究是 康奈尔大学神经行为铅毒性研究的延续 超级基金基础研究和教育计划以及两项平行研究 最近由 NIEHS 资助检查 DMSA 在缓解 铅的神经行为毒性 - 一项多中心儿科试验 (RFP NIH-ES 92-93）以及使用非人类灵长类动物模型的类似研究。这 拟议项目将合作提供有关以下方面的重要信息 DMSA 在减轻（或加剧）Pb 诱导的 认知功能障碍不会由任何一个并行提供 研究，因此应该有助于解释其结果。他们 反过来提供技术服务协助评估铅减排。 简而言之，相对于两项平行研究，该项目将 提供 (1) 有关 DMSA 减轻 Pb- 的剂量反应信息 诱发认知功能障碍； (2) DMSA功效测定 Pb 暴露和 DMSA 条件下 BPb 水平的函数 可以仔细控制和监测治疗，并且社会人口统计学 影响认知的因素是可以控制的； (3)关系 神经行为功能和脑铅水平的变化之间；和（4） DMSA 缓解神经行为缺陷的功效评估 成人铅暴露案例。