Mixture Toxicity: Evaluation of an Improved Methodology

混合物毒性：改进方法的评估

• 批准号: 6664874
• 负责人: DOUGLAS A DAWSON
• 金额: $ 8.04万
• 依托单位: ASHLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664874
• 关键词: Xenopus oocyte; bioassay; chemical addition; chemical kinetics; chemical reaction; chemical structure function; chemicals; dosage; embryo /fetus cell /tissue; evaluation /testing; molecular site; technology /technique development; toxicant interaction; toxicant screening; ultraviolet spectrometry

DESCRIPTION (provided by applicant): One of the fundamental principles of chemical mixture toxicity that remains to be clarified is whether there is a relationship between the type of combined effect obtained and the molecular site or sites of action of the agents. The work proposed in this application is designed to help determine whether such a relationship exists, thereby providing a more sound fundamental basis from which to perform more accurate risk assessments. The approach involves chemical mixture toxicity testing using the previously developed and evaluated frog embryo mixture toxicity assay. The chemicals evaluated in combination are osteolathyrogens, chemicals which inhibit lysyl oxidase (LO) catalyzed cross-linking reactions for developing connective tissue fibers. Osteolathyrogens have several potential sites of action: the LO active site, the organic cofactor for LO, chelation of copper from LO, and blockage of sites on the developing fibers where the normal cross-linking reactions take place. Through the use of UV-VIS spectrophotometry and spectrofluorimetry, each of twelve to fifteen osteolathyrogens will be examined for potential reactivity with the organic cofactor for LO and for their potential to chelate copper from the enzyme. The results of these studies will be compared with results from the mixture toxicity assay. Preliminary data suggests that mixture toxicity resembles the dose-addition combined effect, generally, but with results for some combinations being significantly different, statistically, from dose-addition - the combined effect expected for agents working at the same molecular site. By testing chemicals in two-, three- and four-chemical combinations that have been demonstrated to work at the same or at different molecular sites, it should be possible to evaluate the current theoretical framework for combined effect/site of actions models. Upon completion, the project should provide an answer as to whether there is a relationship between the type of combined effect obtained and the molecular site(s) of action of the agents.

描述（由申请人提供）：尚待澄清的化学混合毒性的基本原理之一是，获得的合并效应类型与分子位点或代理的作用位点之间存在关系。本应用程序中提出的工作旨在帮助确定是否存在这种关系，从而提供了更合理的基本依据，以进行更准确的风险评估。该方法涉及使用先前开发和评估的青蛙胚胎混合物毒性测定法测试化学混合物毒性测试。组合评估的化学物质是骨肌元元，这些化学物质是抑制赖氨酸氧化酶（LO）催化的交联反应的化学物质，以形成结缔组织纤维。骨触及元素具有多种潜在的作用部位：LO活性位点，用于LO的有机辅助因子，LO的铜螯合，以及发生正常交联反应的发育纤维上的位点的阻塞。通过使用UV-VIS分光光度法和光谱法，将检查十二至15个骨肌ro鼠中的每一种，以与有机辅助因子的潜在反应性，以使LO的LO及其潜在的潜力从酶中螯合。这些研究的结果将与混合毒性测定的结果进行比较。初步数据表明，混合物毒性通常类似于剂量加成的组合效应，但在统计学上，某些组合的结果与剂量增加的结果显着差异 - 在同一分子位点工作的药物预期的组合效果。通过在两种，三和四化学组合中测试化学物质，这些化学物质已证明在相同或不同的分子位点可起作用，应该可以评估目前的理论框架，以进行组合效应/作用模型的组合效果/位点。完成后，该项目应提供一个答案，即在获得的合并效应类型与代理的作用的分子位点之间存在关系。