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

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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.