PROTEIN AND DNA ADDUCTS FOLLOWING LOW DOSE EXPOSURE BY ACCELERATOR MS

加速器 MS 低剂量照射后的蛋白质和 DNA 加合物

• 批准号: 6239478
• 负责人: KENNETH W TURTLETAUB
• 金额: $ 19.49万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6239478
• 关键词: DNA binding protein; adduct; arsenic; benzene; binding proteins; chemical carcinogen; dosage; environmental toxicology; gel electrophoresis; high performance liquid chromatography; industrial waste; laboratory mouse; macromolecule; mass spectrometry; method development; phenols; radiotracer; toluene; toxicant interaction; toxin metabolism; trichloroethylene

The scope of this proposal is to study the extent of benzene and trichloroethylene (TCE) macromolecular adduct formation, metabolism,a and interaction with other solvents at concentrations equivalent to human exposure levels outside the workplace. Benzene and TCE are important toxicants in the workplace and are ubiquitous in the environment. Most importantly, they are carcinogenic and are often found in combination with other potential carcinogens at wastesites and the behavior of chemicals in mixtures may differ substantially from pure compounds. Our goal for this project is to understand the relationship between chemical dose, the dose reaching the target issues and the resultant levels of macromolecular adducts that are formed at doses equivalent to those encountered around superfund waste sits. A second goal is to determine feasibility of measuring benzene and TCE metabolism in humans. Specifically, we will: 1. develop and validate methodology for ultra-low level measurement of TCE and benzene metabolism in rodents by accelerator mass spectrometry (AMS) in combination with HPLC and electrophoresis:" 2. identify the specific protein targets for benzene and TCE adduct formation in animal lymphocytes, hepatocytes, and plasma; 3. evaluate how xylene and toluene influence 14C-benzene metabolism in a murine model at low doses by AMS. The influence of these solvents on formation of DNA and protein adducts by AMS in target and non-target tissues will also be investigated: 4. compare how benzene and phenol, when administered in vivo, at low doses are metabolized. The extent of DNA and protein binding by these two compounds will be evaluated as well; and 5. determine how arsenic exposure influences 14C-benzene metabolism and macromolecular binding at exposure concentrations relevant for human environmental exposure. The results of this research project will be important for calculating the risk posed to humans by these compounds in the environment and will help pinpoint protein or DNA adducts that can be used for exposure assessments. This work will also lead to development of protocols for determining how benzene is metabolized at low dose and physiologically-based pharmacokinetic models relevant to determining the risk these compounds pose to the American public.

该提案的范围是研究苯和 三氯乙烯（TCE）大分子加合物的形成、代谢和 与人体浓度相当的其他溶剂相互作用 工作场所以外的暴露水平。 苯和TCE很重要 工作场所和环境中普遍存在有毒物质。 最多 重要的是，它们具有致癌性，并且经常与以下药物一起使用： 废物场中的其他潜在致癌物以及化学物质的行为 混合物可能与纯化合物有很大不同。 我们的目标是 项目是了解化学剂量、剂量之间的关系 达到目标问题和由此产生的大分子水平 加合物的形成剂量相当于周围遇到的剂量 超级基金浪费。 第二个目标是确定可行性 测量人体苯和三氯乙烯的代谢。 具体来说，我们将： 1. 开发并验证TCE超低水平测量方法 通过加速器质谱 (AMS) 测定啮齿类动物的苯代谢 结合HPLC和电泳：" 2. 确定苯和TCE加合物的特定蛋白质靶标 在动物淋巴细胞、肝细胞和血浆中形成； 3. 评估二甲苯和甲苯如何影响 14C-苯代谢 AMS 低剂量小鼠模型。 这些溶剂对 AMS 在靶标和非靶标中形成 DNA 和蛋白质加合物 组织也将被调查： 4. 比较苯和苯酚在低剂量体内给药时的表现 被代谢。 这两者结合 DNA 和蛋白质的程度 化合物也将被评估；和 5. 确定砷暴露如何影响 14C-苯代谢和 与人类相关的暴露浓度下的大分子结合 环境暴露。 该研究项目的结果对于计算 这些化合物在环境中对人类构成风险，并将有助于 精确定位可用于暴露评估的蛋白质或 DNA 加合物。 这项工作还将导致协议的开发，以确定如何 苯在低剂量和生理基础下代谢 与确定这些化合物的风险相关的药代动力学模型 向美国公众展示。