Developing Computational Models to Understand and Predict Adverse Human Health Effects Associated with Exposure to Environmental Chemicals

NIEHS的使命是发现环境如何影响人们，以促进更健康的生活。翻译毒理学司(DTT)通过开发和应用创新的、与人类有关的工具和战略来确定暴露在环境化学品中的危害的特征，领导毒理学的变革，为这一使命做出了贡献。DTT最近确定的战略调整的三个总体目标是：i)通过刻意应用翻译毒理学管道(TTP)，加快成为更具预测性、精确度和预防性的科学的进展；ii)提供基于证据的方法，以识别和了解当代和常见疾病的潜在环境因素；以及iii)提高我们进行和沟通基于物质的危险评估的能力，这些评估更具翻译性、创新性和响应性。DTT已经将开发和利用生物系统的多尺度计算模型的能力确定为关键需求。多尺度建模使用数学和计算来在不止一个尺度上定量地表示和模拟一个系统，同时在功能上链接这些尺度上的数学模型，包括原子、分子、细胞、器官、系统(例如，心血管、生殖等)、个体和(亚)种群。 这个项目的目的是进一步研究和开发DTT可以在其翻译毒理学管道(TTP)中使用的工具，以更好地预测急性和长期接触环境化学品及其混合物可能对人类健康造成的不利影响。根据这一机构间协议，研究计划涉及对先进计算方法的应用进行评估，这些方法整合了人类和啮齿动物生物学多个尺度上的数据并建立模型，以开始解决三个关键挑战，以便能够采用真正预测人类健康结果的安全评估范例：将性别视为生物变量；准确翻译跨生物尺度和物种之间的毒理学结果；表征个体间的生物变异性和易感性。

The mission of NIEHS is to discover how the environment affects people in order to promote healthier lives. The Division of Translational Toxicology (DTT) contributes to that mission by leading the transformation of toxicology through the development and application of innovative, human-relevant tools and strategies to characterize hazards presented by exposure to environmental chemicals. Three overarching objectives recently identified by DTT as part of its strategic realignment are to: i) accelerate progress toward becoming a more predictive, precise, and preventive science through the deliberate application of a Translational Toxicology Pipeline (TTP); ii) provide an evidence-based approach to identifying and understanding potential environmental contributors to contemporary and common diseases; and iii) improve our ability to conduct and communicate substance-based hazard evaluations that are more translational, innovative, and responsive. DTT has identified the ability to develop and utilize multi-scale computational models of biological systems as a critical need. Multiscale modeling uses mathematics and computation to quantitatively represent and simulate a system at more than one scale while functionally linking the mathematical models across these scales, which include atomic, molecular, cellular, organ, system (e.g., cardiovascular, reproductive, etc..), individual, and (sub)populations. The purpose of this project is to further the research and development of tools that DTT can use in its Translational Toxicology Pipeline (TTP) to better predict potential adverse human health effects caused by acute and chronic exposure to environmental chemicals and mixtures thereof. The research plan under this interagency agreement involves the assessment of the application of advanced computational approaches that integrate and model data across multiple scales of human and rodent biology to begin addressing three key challenges that must be overcome to enable the adoption of safety assessment paradigms that are truly predictive of human health outcomes: Accounting for sex as a biological variable; accurately translating toxicological findings across biological scales and between species; characterizing inter-individual biological variability and susceptibility