Quantitative dose-response characterization for liver carcinogenicity with non-mutagenic modes of action

非诱变作用模式下肝脏致癌性的定量剂量反应表征

• 批准号: 9892742
• 负责人: Kan Shao
• 金额: $ 15.31万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-13 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892742
• 关键词: Aryl Hydrocarbon Receptor; Award; Benchmarking; Biological; Carcinogens; Chemical Exposure; Chemicals; Complement; Data; Development Plans; Dose; Environmental Health; Evaluation; Event; Goals; Government; Guidelines; Health; Hepatocarcinogenesis; Human; Industry; Learning; Liver; Mediating; Mentors; Methodology; Methods; Modeling; Modernization; Mutagens; PPAR alpha; Pathway interactions; Preventive Medicine; Publishing; Research; Research Personnel; Research Project Grants; Research Proposals; Risk; Risk Assessment; Risk Estimate; Risk Management; Rodent; Science; Scientist; Series; Shapes; Source; Tetrachlorodibenzodioxin; Toxic effect; Toxicology; Training; Training Programs; Uncertainty; adverse outcome; cancer risk; carcinogenicity; career; career development; cytotoxicity; experience; improved; in vivo; innovation; novel; research and development; response; success; tool

PROJECT SUMMARY The goal of this K25 Mentored Quantitative Research Development Award project is to allow the PI to obtain systematic training in toxicology and prepare the PI to become an independent investigator. A research project complement the proposal’s comprehensive career development plan that promotes the PI’s research career. Human health risk assessment of chemical exposures is an important form of preventive medicine. Health risk assessment has been widely applied in both industry and government to evaluate the potential human toxicity of chemicals to properly protect human and environmental health. Modern toxicological science has provided scientists new tools to dissect and understand the biological adverse pathways underlying toxicity. This provides a great opportunity for risk assessment to characterize the dose-response relationship across the entire dose continuum (especially in the low-dose region) and may significantly improve the plausibility and accuracy of dose-response assessment. The long-term goal of this research is to develop a methodological framework that integrates mechanistic plausibility, experimental data, and uncertainty and variability into dose- response analysis in support of probabilistic carcinogen risk assessment. The objective of this project is to combine evidence from a sequence of events following a plausible mode of action to quantitatively characterize dose-response relationship across the entire dose continuum for liver carcinogenicity with non- mutagenic modes of action (MOAs). The central hypothesis is that liver carcinogens sharing the same MOA may have a similar shape of dose-response relationship which can be characterized by synthesizing evidence of a series of key and associative events. To achieve the objective, three specific aims will be pursued: (1) employ and improve existing framework to identify key and associative events with available data to understand mode of action of liver carcinogenesis; (2) develop a modeling framework to quantitatively integrate MOA information to characterize the dose-response relationship across the dose continuum; and (3) apply the framework to different non-mutagenic MOA for liver carcinogenicity and evaluate its feasibility and plausibility. The proposed methodological framework is highly innovative because it aims at quantitatively characterizing dose-response relationship across the whole dose continuum without dichotomizing the extrapolation method into linear vs. nonlinear (i.e., threshold). The success of the proposed methodological framework may revolutionarily change the current practice in dose-response assessment and significantly advance the science of chemical risk assessment by providing more scientifically plausible probabilistic risk estimation to support risk management.

项目总结 K25指导量化研究发展奖项目的目标是让PI获得 接受系统的毒理学培训，并为独立调查员做好准备。一个研究项目 补充提案的全面职业发展计划，以促进PI的研究职业生涯。 化学品暴露的人体健康风险评估是预防医学的一种重要形式。健康风险 评估已被广泛应用于工业和政府部门对潜在的人体毒性进行评估。 适当保护人类和环境健康的化学品。现代毒理学提供了 科学家们开发了新的工具来剖析和理解潜在毒性的生物不利途径。这 为风险评估提供了一个很好的机会，以表征整个 整个剂量连续谱(特别是在低剂量区)，并可能显著提高可信度和 剂量反应评估的准确性。这项研究的长期目标是发展一种方法论 将机械原理的合理性、实验数据以及不确定性和可变性整合到剂量中的框架- 响应分析，以支持概率致癌物风险评估。这个项目的目标是 结合一系列事件的证据，遵循看似合理的行动模式，以量化 描述在整个剂量连续体中肝致癌性的剂量-反应关系 诱变作用模式(MOA)。中心假设是肝脏致癌物质具有相同的MOA 可能具有相似的剂量-反应关系，这可以通过综合证据来表征 一系列关键事件和关联事件。为达致这个目标，我们会推行三个具体目标：(一) 利用并改进现有框架，以利用可用数据识别关键事件和关联事件 了解肝癌发生的作用模式；(2)建立一个模型框架，以定量集成 MOA信息，以描述整个剂量连续体的剂量-反应关系；以及(3)应用 建立不同的非致突变MOA的肝癌致癌性框架，并评价其可行性和合理性。 拟议的方法学框架具有很高的创新性，因为它的目标是量化描述 无二分外推法的全剂量连续谱剂量-效应关系 转换为线性与非线性(即，阈值)。拟议的方法学框架的成功可能 革命性地改变目前剂量反应评估的做法，显著促进科学发展 通过提供更科学合理的概率风险评估来支持化学品风险评估 风险管理。