BIOMARKERS OF EXPOSURE TO PULMONARY TOXICANTS

肺部有毒物质暴露的生物标志物

基本信息

批准号：
6239466
负责人：
ALAN R BUCKPITT
金额：
$ 15.6万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 1998-03-31
项目状态：
已结题

项目摘要

Numerous studies in laboratory animals have demonstrated the importance of respiratory epithelial cells as targets for both inhaled and ingested chemicals. There are, however, significant uncertainties in estimating the risks to humans from exposure to chemicals which are respiratory cytotoxicants in animals. These uncertainties are both species- and dose- related. The overall goals of the work proposed in this application are to develop markers of exposure, effect and susceptibility for chemicals which produce lung toxicity in animals. This work is based on the premise that the development of markers capable of signalling that an exposure has been at a level sufficient to result in cytotoxicity is dependent upon a complete understanding of essential biochemical and metabolic steps involved in toxicity in animals. Accordingly, this work will define the importance of specific protein and nonprotein targets of electrophilic intermediates to cytotoxic injury for three chemicals that produce focal injury to the respiratory epithelium by virtue of cytochrome P450 dependent metabolism. These chemicals are naphthalene, nitronaphthalene and trichloroethylene. The well established difference in sensitivity of various species and the highly focal nature of the injury within the respiratory system will be used as an experimental tool to indicate which protein adducts are important to toxicity. This will then guide the development of biomarkers which are closely related to the mechanism of toxicity. The specific aims of the work are to: (l) validate immunochemical methodology for determination of diastereomeric mercapturic acids of naphthalene as an index of the rate and stereochemistry of formation of naphthalene epoxides, (2) identify critical protein targets for reactive metabolites generated from naphthalene, nitronaphthalene, and trichloroethylene, (3) use the information obtained in (2) to develop markers which can be monitored in nasal lavage, bronchiolar lavage, blood or urine as indices of exposure, effect and susceptibility and (4) refine new systems capable of evaluating samples obtained from hazardous waste sites for the possible presence of pulmonary toxic chemicals. This work is intended to reduce the uncertainty inherent in current assessments of risks associated with human exposure to pulmonary toxic chemicals by developing methodologies that are capable of distinguishing exposures that occur at levels sufficient to cause toxicity from those that are without significant effect. These studies should also provide the tools necessary for determining whether the metabolic and biochemical factors which lead to toxicity in animals are operative in human lungs and whether there are significant interindividual differences in these metabolic and biochemical pathways with human populations.

大量实验动物研究表明了其重要性呼吸道上皮细胞作为吸入和摄入的目标化学品。然而，估算存在很大的不确定性接触呼吸道化学物质对人类造成的风险动物体内的细胞毒剂。这些不确定性既涉及物种又涉及剂量有关的。本申请中提出的工作的总体目标是开发化学品暴露、影响和敏感性的标记对动物产生肺毒性。这项工作是基于这样的前提开发能够发出暴露信号的标记物是否已处于足以导致细胞毒性的水平取决于在完全了解基本的生化和代谢的基础上涉及动物毒性的步骤。因此，这项工作将定义特定蛋白质和非蛋白质靶标的重要性亲电子中间体对三种化学物质的细胞毒性损伤通过以下方式对呼吸道上皮产生局灶性损伤细胞色素 P450 依赖性代谢。这些化学物质是萘、硝基萘和三氯乙烯。既定的差异不同物种的敏感性和高度聚焦的性质呼吸系统内的损伤将被用作实验工具表明哪些蛋白质加合物对毒性很重要。这将进而指导与其密切相关的生物标志物的开发毒性机制。这项工作的具体目标是： (l) 验证测定非对映异构体的免疫化学方法以萘的硫醇酸为指标的比率和萘环氧化物形成的立体化学，(2) 鉴定产生反应性代谢物的关键蛋白质靶标萘、硝基萘和三氯乙烯，(3) 使用 (2) 中获得的信息用于开发可在鼻腔灌洗、细支气管灌洗、血液或尿液作为暴露指标，效应和敏感性，以及（4）完善新系统，能够评估从危险废物场获取的样本是否可能存在存在肺部有毒化学物质。这项工作的目的是减少当前风险评估中固有的不确定性通过开发方法使人类接触肺部有毒化学物质能够区分发生在不同级别的暴露足以引起那些没有明显毒性的毒性影响。这些研究还应该提供必要的工具确定代谢和生化因素是否导致动物的毒性是否会作用于人的肺部，以及是否存在这些代谢和代谢方面存在显着的个体差异与人类的生化途径。