Objectives: In 2011, the U.S. Environmental Protection Agency initiated the NexGen project to develop a new paradigm for the next generation of risk science.Methods: The NexGen framework was built on three cornerstones: the availability of new data on toxicity pathways made possible by fundamental advances in basic biology and toxicological science, the incorporation of a population health perspective that recognizes that most adverse health outcomes involve multiple determinants, and a renewed focus on new risk assessment methodologies designed to better inform risk management decision making.Results: The NexGen framework has three phases. Phase I (objectives) focuses on problem formulation and scoping, taking into account the risk context and the range of available risk management decision-making options. Phase II (risk assessment) seeks to identify critical toxicity pathway perturbations using new toxicity testing tools and technologies, and to better characterize risks and uncertainties using advanced risk assessment methodologies. Phase III (risk management) involves the development of evidence-based population health risk management strategies of a regulatory, economic, advisory, community-based, or technological nature, using sound principles of risk management decision making.Conclusions: Analysis of a series of case study prototypes indicated that many aspects of the NexGen framework are already beginning to be adopted in practice.Citation: Krewski D, Westphal M, Andersen ME, Paoli GM, Chiu WA, Al-Zoughool M, Croteau MC, Burgoon LD, Cote I. 2014. A framework for the next generation of risk science. Environ Health Perspect 122:796–805; http://dx.doi.org/10.1289/ehp.1307260

Background:The Next Generation (NexGen) of Risk Assessment effort is a multi-year collaboration among several organizations evaluating new, potentially more efficient molecular, computational, and systems biology approaches to risk assessment. This article summarizes our findings, suggests applications to risk assessment, and identifies strategic research directions.Objective:Our specific objectives were to test whether advanced biological data and methods could better inform our understanding of public health risks posed by environmental exposures.Methods:New data and methods were applied and evaluated for use in hazard identification and dose–response assessment. Biomarkers of exposure and effect, and risk characterization were also examined. Consideration was given to various decision contexts with increasing regulatory and public health impacts. Data types included transcriptomics, genomics, and proteomics. Methods included molecular epidemiology and clinical studies, bioinformatic knowledge mining, pathway and network analyses, short-duration in vivo and in vitro bioassays, and quantitative structure activity relationship modeling.Discussion:NexGen has advanced our ability to apply new science by more rapidly identifying chemicals and exposures of potential concern, helping characterize mechanisms of action that influence conclusions about causality, exposure–response relationships, susceptibility and cumulative risk, and by elucidating new biomarkers of exposure and effects. Additionally, NexGen has fostered extensive discussion among risk scientists and managers and improved confidence in interpreting and applying new data streams.Conclusions:While considerable uncertainties remain, thoughtful application of new knowledge to risk assessment appears reasonable for augmenting major scope assessments, forming the basis for or augmenting limited scope assessments, and for prioritization and screening of very data limited chemicals.Citation:Cote I, Andersen ME, Ankley GT, Barone S, Birnbaum LS, Boekelheide K, Bois FY, Burgoon LD, Chiu WA, Crawford-Brown D, Crofton KM, DeVito M, Devlin RB, Edwards SW, Guyton KZ, Hattis D, Judson RS, Knight D, Krewski D, Lambert J, Maull EA, Mendrick D, Paoli GM, Patel CJ, Perkins EJ, Poje G, Portier CJ, Rusyn I, Schulte PA, Simeonov A, Smith MT, Thayer KA, Thomas RS, Thomas R, Tice RR, Vandenberg JJ, Villeneuve DL, Wesselkamper S, Whelan M, Whittaker C, White R, Xia M, Yauk C, Zeise L, Zhao J, DeWoskin RS. 2016. The Next Generation of Risk Assessment multiyear study—highlights of findings, applications to risk assessment, and future directions. Environ Health Perspect 124:1671–1682; http://dx.doi.org/10.1289/EHP233

We have developed a simulation model to quantify and characterize the response of the public health system and the impact of public health advisories in the event of an intentional contamination of the food supply. The model has three components: (1) definition of individual exposure over time and the outcomes of exposure, (2) definition of the geographical dispersal of exposures, and (3) response of the public health authorities to symptomatic individuals. The model explicitly considers the variation in the multiple interrelated facets of the response system, including differences among individuals' responses to exposure, variation between health care providers, and the subsequent processing of samples and confirmation of cases. To illustrate use of the model, case studies with Escherichia coli O157:H7 and Salmonella spp. in three categories of food vehicle were compared. The level of detail required to run the public health component of the model is not trivial. While some data may not be available for hazards of particular interest in potential bioterrorism events, the application of expert judgment permits comparisons between different agents, different system reactions, and other assumptions within the system. The model provides the capacity to study the impact of system changes, to compare scenarios and to quantify the benefits of improvement in terms of averted exposures and risk reduction, and constitutes a significant aid to understanding and managing these threats. Essentially, the model provides an explicit valuation of time saved in the identification and intervention in terrorist events in the food supply.

The report also calls for changes within the risk assessment process, including the enhanced role of problem formulation, the unification of non-cancer and cancer methods for deriving dose-response relationships, and cumulative risk assessment. The integration of these three driving concepts is discussed in this review expanding the strengths of these three frameworks and what they brought to the NexGen framework for risk science.