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: 10318949
• 负责人: Kan Shao
• 金额: $ 15.27万
• 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/10318949
• 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.

项目摘要 K25指导定量研究开发奖项目的目标是允许PI获得 毒理学的系统培训，并准备成为PI成为独立研究者。 补充提案的全面职业发展计划，该计划促进了PI的研究生涯。 人类健康风险评估化学暴露是一种重要形式 评估哈斯在行业和政府中都应用了，以评估潜在的人类毒性 化学物质以适当保护人类和环境健康。 科学家的新工具可以剖析和理解弓形虫基础的生物不利途径。 为风险评估提供了一个很好的机会，以表征整个剂量的关系 整个剂量连续性（尤其是在低剂量区域），可能会显着提高形态性和 剂量反应评估的准确性。 将机理绘制，实验数据以及不确定性和可变性整合到剂量中的框架 支持概率的致癌风险评估的反应分析。 结合一系列事件的证据，按照合理的作用方式进行定量 表征整个剂量反应关系在整个剂量连续性的强制性中 诱变的作用模式（MOA）。 可能具有类似的剂量反应关系形状，可以通过合成证据来表征 在一系列关键事件中，要实现目标，三个特定的目标将倾向：（1） 使用并改进现有框架，以确定具有可行数据的密钥和关联事件 了解肝癌的模式；（2）开发一个建模框架 MOA信息表征整个剂量连续的剂量反应关系； 针对致癌性ATS的不同非毒素MOA的框架使其可行性和合理性。 支撑的方法学框架是高度创新的元素，因为它旨在定量化 在整个剂量连续体中的剂量反应关系，而没有二分法推外方法 在线性与非线性（即阈值）中 革命性地改变了剂量回应评估的当前实践，并显着提高了科学 通过提供更科学的合理概率估计来支持化学风险评估 风险管理。