The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency

Abstract

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA's Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.

Keywords: ExpoCast; Tox21; ToxCast; cheminformatics; computational toxicology; exposure; high-throughput assays; predictive toxicology; risk assessment; toxicokinetics.

Figure 1.

Key elements of the EPA CompTox blueprint to obtain broader acceptance of the new approaches and application to higher tier regulatory decisions. The CompTox efforts will continue to emphasize the use of computational modeling and high-throughput approaches to connect and transform the traditional components in chemical risk assessment. Cross-cutting efforts in characterizing uncertainty and variability, development of software and information technology tools, outreach and training, and establishing scientific confidence enable translation to regulatory decision making.

Figure 2.

Tiered testing framework for hazard characterization. Tier 1 uses both chemical structure and broad coverage, high content assays across multiple cell types for comprehensively evaluating the potential effects of chemicals and grouping them based on similarity in potential hazards. For chemicals from Tier 1 without a defined biological target/pathway, a quantitative point-of-departure for hazard is estimated based on the absence of biological pathway or cellular phenotype perturbation. Chemicals from Tier 1 with a predicted biological target or pathway are evaluated Tier 2 using targeted follow-up assays. In Tier 3, the likely tissue, organ, or organism-level effects are considered based on either existing adverse outcome pathways (AOP) or more complex culture systems. Quantitative points-of-departure for hazard are estimated based on the AOP or responses in the complex culture system.

Figure 3.

Integrated strategy to model in vivo bioactivation and detoxification in a diverse range of in vitro assays. The extracellular approach generates metabolites in the media or buffer of in vitro assays and models the effects of hepatic metabolism on peripheral tissues. The intracellular approach generates metabolites inside the cell and models the effects of target tissue metabolism.