Abstract
BACKGROUND: The epigenome may be an important interface between environmental chemical exposures and human health. However, the links between epigenetic modifications and health outcomes are often correlative and do not distinguish between cause and effect or common-cause relationships. The Adverse Outcome Pathway (AOP) framework has the potential to demonstrate, by way of an inference- and science-based analysis, the causal relationship between chemical exposures, epigenome, and adverse health outcomes. OBJECTIVE: The objective of this work is to discuss the epigenome as a modifier of exposure effects and risk, perspectives for integrating toxicoepigenetic data into an AOP framework, tools for the exploration of epigenetic toxicity, and integration of AOP-guided epigenetic information into science and risk-assessment processes. DISCUSSION: Organizing epigenetic information into the topology of a qualitative AOP network may help describe how a system will respond to epigenetic modifications caused by environmental chemical exposures. However, understanding the biological plausibility, linking epigenetic effects to short- and long-term health outcomes, and including epigenetic studies in the risk assessment process is met by substantive challenges. These obstacles include understanding the complex range of epigenetic modifications and their combinatorial effects, the large number of environmental chemicals to be tested, and the lack of data that quantitatively evaluate the epigenetic effects of environmental exposure. CONCLUSION: We anticipate that epigenetic information organized into AOP frameworks can be consistently used to support biological plausibility and to identify data gaps that will accelerate the pace at which epigenetic information is applied in chemical evaluation and risk-assessment paradigms. https://doi.org/10.1289/EHP2322.