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

项目摘要 这个K25指导定量研究开发奖项目的目标是让PI获得 系统的毒理学培训，使PI成为独立研究者。一个研究项目 补充提案的全面职业发展计划，促进PI的研究生涯。 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 评价已被广泛应用于工业和政府评估潜在的人类毒性 适当保护人类和环境健康。现代毒理学提供了 科学家们的新工具，剖析和了解潜在的毒性生物不良途径。这 为风险评估提供了一个很好的机会，以描述整个 整个剂量连续体（特别是在低剂量区域），并可显著改善可吸收性， 剂量反应评估的准确性。这项研究的长期目标是开发一种方法论， 该框架将机械可验证性、实验数据以及不确定性和可变性整合到剂量中， 支持概率致癌物风险评估的响应分析。该项目的目标是 联合收割机根据一种合理的作用模式从一系列事件中收集证据， 描述整个剂量连续体中肝脏致癌性的剂量-反应关系， 致突变作用模式（MOAs）。中心假设是肝脏致癌物具有相同的MOA 可能具有类似的剂量-反应关系，可以通过综合证据来表征 一系列关键和关联事件的记录为实现这一目标，将追求三个具体目标：（1） 采用和改进现有框架，利用现有数据确定关键和相关事件， 了解肝癌发生的作用模式;（2）建立一个模型框架， MOA信息，以表征整个剂量连续体的剂量-反应关系;以及（3）应用 不同非致突变MOA对肝脏致癌性的影响，并评价其可行性和可操作性。 拟议的方法框架具有高度创新性，因为它旨在从数量上描述 在整个剂量连续范围内的剂量-反应关系，无需对外推方法进行二分法 线性对非线性（即，阈值）。拟议方法框架的成功可能 彻底改变目前的剂量反应评估实践，并显著推进科学 通过提供更科学合理的概率风险估计来支持化学品风险评估 风险管理

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.