NSMDS: Improving Material Safety through the Minimization of Oxidative Stress Potential: A mechanistic understanding of ROS generation in in vitro and in vivo systems

NSF化学部和环境保护局通过可持续分子设计和合成网络计划，支持耶鲁大学的Paul Anastas教授、William Jorgensen教授和埃文·比奇博士建立一个通过最大限度地减少氧化应激潜力来改善材料安全的网络。这个网络包括贝勒大学、乔治华盛顿大学和华盛顿大学的科学家，他们每个人都在推进该项目的目标方面发挥着关键作用。这个网络促进了合理设计化学品和材料以减少有害生物活动的科学。利用体内和体外的经验毒性数据，正在开发描述触发毒性反应的分子事件的计算模型。通过实验室和计算研究的迭代过程，正在为通过多种毒性途径引起氧化应激的可能性最小的分子创建设计指南(物理和化学性质参数)。这一战略包括基于与与活性氧物种(ROS)相关的毒性相关的化学品准备模型训练集；使用计算化学对导致氧化应激的化学途径进行建模和预测；对产生ROS的化学品在体内和体外的影响进行建模和测量；在计算机和实验结果中进行关联以制定最低ROS活性的设计参数。通过高级化学产生的化学品和材料是我们社会和经济的基础。然而，尽管所有优秀的毒理学帮助我们了解并在某些情况下预测了与工业化学品相关的毒性，但在回答基本的科学问题方面进展甚微，这些问题将使设计出对人类和环境危害更小的化学品成为可能。虽然绝大多数商业化学品不打算具有生物活性，但意外毒性在很大程度上是由于缺乏将功能功效与减少危险的设计相结合的指导方针。新的指导方针和设计工具有助于制定现有的化学产品，并指导安全替代品的创新。通过针对学生和专业化学家的教育活动，促进了对这些工具的接受和实施。其他努力力求通过提供一种按共同性质而不是逐案管理各类化学品的手段来为化学品政策提供信息，其总体目标是通过使用合理的化学品设计来促进创新，以减少或消除新材料的有毒影响。

With this award, the NSF Division of Chemistry and the Environmental Protection Agency, through a program of Networks for Sustainable Molecular Design and Synthesis, support Professors Paul Anastas and William Jorgensen and Dr. Evan Beach of Yale University in establishing a Network for Improving Material Safety through Minimization of Oxidative Stress Potential. This network includes scientists at Baylor University, George Washington University, and the University of Washington who each have critical roles to play in advancing the goals of the project. This network advances the science of rational design of chemicals and materials for reduced adverse biological activity. Utilizing empirical toxicity data, both in vivo and in vitro, computational models to describe molecular events that trigger toxic responses are being developed. Through an iterative process of laboratory and computational studies, design guidelines (physical and chemical property parameters) are being created for molecules with minimal potential to cause oxidative stress through multiple toxicity pathways. This strategy involves preparing model training sets based on chemicals relevant to toxicity associated with reactive oxygen species (ROS); using computational chemistry to model and predict chemical pathways that result in oxidative stress; modeling and measuring both in vivo and in vitro impacts of chemicals that generate ROS; and correlating in silico and experimental results to develop design parameters for minimal ROS activity.Chemicals and the materials created through advanced chemistry are the basis of our society and our economy. Yet, with all of the excellent toxicology that has helped us understand and in some cases predict toxicity associated with industrial chemicals, little progress has been made in answering the fundamental scientific questions that would allow for the design of chemicals with reduced hazard to humans and the environment. Although the vast majority of commercial chemicals are not intended to have biological activity, unintended toxicity is largely due to the lack of guidelines for coupling efficacy of function with design for reduced hazard. New guidelines and design tools aid in formulation of existing chemical products and guide innovation in safe alternatives. Acceptance and implementation of these tools are promoted by educational campaigns for students and professional chemists. Additional efforts seek to inform chemical policy by providing a means of managing classes of chemicals by common properties rather than on a case-by-case basis, with the overall goal to promote innovation through the use of rational chemical design to reduce or eliminate the toxic effects of new materials.