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。转化毒理学司（DTT）通过开发和应用创新的、与人类相关的工具和战略来描述暴露于环境化学品所带来的危害，从而领导毒理学的转变，从而有助于实现这一使命。作为其战略调整的一部分，DTT最近确定了三个总体目标：i)通过有意应用转化毒理学管道（TTP），加速成为一门更具预测性、准确性和预防性的科学；㈡提供以证据为基础的方法，查明和了解造成当代和常见疾病的潜在环境因素；iii)提高我们进行和交流基于物质的危害评估的能力，这些评估更具转译性、创新性和响应性。DTT已经确定了开发和利用生物系统的多尺度计算模型的能力，这是一个关键的需求。多尺度建模使用数学和计算在多个尺度上定量地表示和模拟系统，同时将这些尺度上的数学模型功能地联系起来，包括原子、分子、细胞、器官、系统（例如心血管、生殖等）、个体和（亚）群体。

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 will assess 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