NTP Database Summarization And Evaluation

NTP数据库总结与评估

• 批准号: 7007164
• 负责人: grace e kissling
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7007164
• 关键词: Caenorhabditis elegans; Rodentias; alternatives to animals in research; bioassay; biological models; carcinogen testing; chemical carcinogenesis; dioxins; fish; flow cytometry; halobiphenyl /halotriphenyl compound; information system analysis; mathematical model; statistics /biometry; toxicology information system

The goal of this project is to summarize, evaluate, and interpret data contained in NTP carcinogenicity databases. One recent evaluation involved analyzing and interpreting data from a study to determine if small fish could provide carcinogenicity information similar to the traditional rodent bioassays. In this set of studies, two species of fish were exposed to three chemicals known to be rodent carcinogens. Following a similar protocol as for rodents, fish were exposed to these chemicals for up to 16 months and necropsied at an interim or final time point. Several problems inherent to fish suggest that they will not be a good substitute for rodents in the bioassay. Fish that died early were consumed by other fish and not available for necropsy. One of the chemicals encouraged algae growth, and attempts to reduce the algae led to some fish deaths. Because of their similar appearances, males and females could not be separated, so reproduction during the study was possible, but could not be tracked. Nearly all of the tumors occurred in the liver and occasionally in the gallbladder, limiting the richness of the carcinogenicity information. Thus, until these logistical problems can be solved, the NTP bioassay will not benefit from using fish rather than rodents. An ongoing evaluation involves comparison of several dioxin-related compounds and their mixtures. Because these compounds are present together in the environment, humans are exposed to mixtures of these compounds, but the activity of these mixtures has been rarely investigated. The goal of our studies is to evaluate the World Health Organization?s (WHO) Toxic Equivalency Factor (TEF) values that estimate the relative toxicity of these compounds as compared with TCDD. We are completing studies in which rodents were exposed to various doses of TCDD, PCBs, PCDDs, PCDFs or mixtures of these compounds. Each study is being separately reported in the NTP Technical Report series, but in addition, the WHO TEFs will be incorporated into mathematical models to compare carcinogenic responses among compounds. In this way, we will be able to determine, for specific endpoints, whether the WHO TEF values are accurate, or whether adjustments in the relative potencies of these compounds need to be made. We will also be able to evaluate whether compounds have additive effects, synergistic effects, or antagonistic effects when present in mixtures. In another project, we are evaluating the possibilities of using the nematode, C. elegans, as a screening tool for assessing toxicological potential of chemicals. In this set of studies, we are using a high throughput system (flow cytometry) to measure growth, reproduction, and movement of the nematodes following exposure to varying doses of a wide range of chemicals. Because of the pilot study nature of this work, we are currently involved with developing experimental designs, resolving measurement issues, and evaluating methods for statistical analyses.

该项目的目的是总结，评估和解释NTP致癌性数据库中包含的数据。 最近的一项评估涉及分析和解释研究数据，以确定小鱼是否可以提供类似于传统啮齿动物生物测定的致癌性信息。在这组研究中，将两种鱼类暴露于已知是啮齿动物致癌物的三种化学物质。按照与啮齿动物相似的方案，将鱼类暴露于这些化学物质长达16个月的时间，并在临时或最终时间点进行死灵。鱼固有的几个问题表明，它们将无法代替生物测定中的啮齿动物。提前死亡的鱼被其他鱼类食用，无法用于尸检。其中一种化学物质鼓励藻类生长，并试图减少藻类导致一些鱼死亡。由于它们的外观类似，因此无法分离男性和女性，因此在研究过程中可以进行繁殖，但无法追踪。几乎所有的肿瘤都发生在肝脏中，偶尔发生在胆囊中，限制了致癌性信息的丰富性。因此，在解决这些后勤问题之前，NTP生物测定将不会从使用鱼而不是啮齿动物中受益。 正在进行的评估涉及比较几种与二恶英相关化合物及其混合物的比较。由于这些化合物存在于环境中，因此人类暴露于这些化合物的混合物中，但是这些混合物的活性很少进行研究。我们研究的目的是评估与TCDD相比，估计这些化合物相对毒性的世界卫生组织（谁）有毒等效因素（TEF）值。我们正在完成研究这些化合物的啮齿动物，PCB，PCDD，PCDF或混合物的各种剂量的研究。每项研究都在NTP技术报告系列中分别报告，但是此外，WHO TEF将被纳入数学模型中，以比较化合物之间的致癌反应。通过这种方式，我们将能够确定特定端点，WHO TEF值是否准确，或是否需要对这些化合物的相对效力进行调整。在混合物中存在时，我们还将能够评估化合物是否具有添加剂作用，协同作用或拮抗作用。 在另一个项目中，我们正在评估使用线虫秀丽隐杆线虫作为评估化学物质毒理潜力的筛查工具的可能性。在这组研究中，我们正在使用高吞吐量系统（流式细胞仪）来测量线虫暴露于不同剂量的多种化学物质后的生长，繁殖和运动。由于这项工作的试点研究性质，我们目前参与开发实验设计，解决测量问题以及评估统计分析的方法。