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（Pb）是超级基金场地经常遇到的污染物， 城市和农业土壤，以及其他可能 摄入或吸入，尤其是儿童。人们日益 有证据表明，低水平的铅暴露，甚至血液中的轻微升高， 儿童早期铅（BPb）水平与 持久的，认知神经行为缺陷，从而创造了一个紧迫的 既需要减少铅暴露， 治疗那些血压稍高的孩子一 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 在门诊基础上口服给药，并且不会引起许多 与当前螯合疗法相关的副作用。 至今没有 研究已经检验了这种化合物在减轻 铅的神经行为毒性或可能的行为致畸性 DMSA本身。在药物被批准之前，这样的研究是必不可少的 广泛使用;此外，这些研究可以提供额外的 深入了解这些赤字的程度和持续时间， 该模型作为神经毒物评估探针的适用性 危险废物中。 拟议研究的主要目的是确定螯合作用是否 DMSA减轻了与啮齿动物相关的神经行为缺陷 儿童和成人铅暴露模型。组独立的 动物将通过一种已经存在的方案接受铅暴露 建立了BPb水平和消化道赤字。铅暴露动物 对照组将在三种DMSA方案之前和之后实施安乐死 这样在一系列神经行为测量中的表现就可以 与脑铅和血铅水平相关。这项拟议的研究是 在康奈尔大学继续进行神经行为铅毒性研究 超级基金基础研究和教育计划，并平行进行两项研究 最近由NIEHS资助，研究DMSA在减轻 铅对儿童神经行为毒性多中心研究 NIH-ES 92-93）和使用非人灵长类动物模型的类似研究。的 拟议项目将合作提供重要信息， DMSA缓解（或加剧）铅诱导的疗效 认知功能障碍，这将不会提供任何平行 研究，因此应有助于解释其结果。他们 反过来又提供技术服务，协助评估减少铅污染情况。 简言之，相对于两项平行研究，本项目将 提供（1）DMSA缓解铅中毒的剂量-反应关系信息。 诱导的认知功能障碍;（2）测定DMSA作为 在铅暴露和DMSA 治疗可以仔细控制和监测， 影响认知的因素是可控的;（3） 神经行为功能改变与脑铅水平之间的关系;（4） 评估DMSA在缓解神经行为缺陷方面的疗效 成人铅暴露病例。