Toward designing safer chemicals.

![Figure][1] PHOTO: COURTESY OF JULIE ZIMMERMAN One year ago, an industrial coal-processing liquid contaminated the Elk River in West Virginia and affected the tap water of 15% of the state's population. The spill was declared a federal disaster, and ongoing investigations remain. Last month, a report assessing the water and health impacts of the Elk River spill pointed to the lack of a sound scientific approach for responding to and recovering from such incidents.[*][2] This year also marks 5 years since the Deepwater Horizon oil spill in the Gulf of Mexico, and last month brought the 30-year anniversary of the Bhopal gas tragedy that killed thousands, considered the world's worst industrial disaster. Despite our best efforts and intentions, human-made chemicals continue to be released into the environment, often with unquantified and potentially unquantifiable deleterious consequences. The questions posed to science are how to better understand the nature of synthetic substances in order to predict their potential adverse impacts on humans and the biosphere, and how do we design future substances to eliminate the need for engineered control systems. ![Figure][1] PHOTO: JOANNE WILCOX Until recently, descriptive toxicology characterized the impact of toxic substances on living organisms and ecosystems. Today, the emerging fields of mechanistic and molecular toxicology are evolving our understanding of how toxic exposure happens. We also now know that many of the physical and chemical properties that we impart to molecules to gain function and performance are linked to adverse consequences. Furthermore, improved knowledge about the human body's absorption, distribution, metabolism, and excretion of chemicals suggests a path toward reducing hazards through molecular design. These four criteria are enabling predictive modeling that uses the physicochemical properties and structural motifs of a chemical to provide insights into the transport and fate of chemicals in the environment, their metabolism and (bio)degradation, and their epidemiology. ![Figure][1] “…how do we design future substances to eliminate the need for engineered control systems.” PHOTO: CARLOS BARRIA/REUTERS However, associating the physical and chemical properties of a chemical with the mechanism of an adverse outcome is only a beginning. These associations require knowledge about large numbers of combinations of physicochemical properties. Although it is necessary to investigate chemicals individually, this is never the real-world situation. Chemicals interact in ways that can magnify or mitigate their effects, sometimes dramatically. All toxicological data to date must be considered with this limitation in mind. One of the greatest future challenges in safer chemical design is recognizing that the timing of dosing—not just the dose alone—is a critical factor in toxicity. Indeed, the adverse effects of chemical exposure on genes in one generation can be caused by exposures (doses) of prior generations, including during fetal and neonatal development. Do more data mean more knowledge? With the advent of high-throughput screening in efforts such as ToxCast by the U.S. Environmental Protection Agency and Tox21, a consortium of government agencies, private organizations, and university partners, there is an urgent need for new ways to mine, curate, store, and manage data in ways that can ultimately be used to design more benign products, processes, and systems. To begin to address these challenges, however, one area perhaps requires primary focus: transdisciplinarity. Research institutes, universities, industry, and funding and regulatory agencies (among other stakeholders) must cultivate a research ecosystem in which efforts are collaborative and knowledge is shared across disciplines, including pharmacology, (eco)toxicology, chemistry, modeling, and biostatistics. If traditional analyses can be coupled with integrated systems approaches, then the knowledge gained about the nature of complex systems may well lead to the design of chemicals that are compatible with life. [1]: pending:yes [2]: #fn-1