Editorial pubs.acs.org/crt
Pathway-Based Approaches for Environmental Monitoring and Risk Assessment
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AOPs may not be a panacea for all translational challenges in toxicology, we believe they will be useful for efficiently evaluating the hazards posed by untested environmental chemicals. Chemical Research in Toxicology (CRT) and Environmental Science & Technology (ES&T) have teamed together to create a Virtual Issue with articles from 2014 to 2016 that highlight the progress made in this field. The articles are organized into four categories that together describe the tremendous progress to formalize and implement mechanistic toxicology for risk assessment purposes. The collection starts with the ES&T Feature article “Are Adverse Outcome Pathways Here to Stay?” The CRT Perspectives article “Systems Toxicology: From Basic Research to Risk Assessment” provides an integrated view of the challenges of translating high-throughput toxicology to risk assessment. It emphasizes the importance of using AOPs as an integrative tool to organize empirical evidence in order to contextualize in vitro molecular initiating events (MIEs) via in vivo adverse outcomes for application to risk assessment. The first category in this Virtual Issue, Understanding AOPs (Adverse Outcome Pathways) of environmental chemicals, highlights the application of AOPs to improve the mechanistic understanding of toxicity pathways and the development of predictive tools targeting mainly human health. Various approaches to tackle hepatotoxicity highlight the diversity of approaches. Allen et al. (2014) proposed a unified approach for defining MIEs based on using QSARs and receptor activation. Once chemicals can be accurately mapped to MIEs, potential AOPs can be inferred. Mellor et al. (2016) implemented this approach by computationally identifying structural alerts for activators of nuclear receptors. If compounds weakly activate multiple receptors or evidence about specific early events is not conclusive, then MIEs cannot be defined, and using the AOP framework is difficult. If such chemicals disrupt the cellular homeostasis, then a range of stress response pathways can be activated. Wink et al. (2014) describe an innovative highcontent imaging framework to measure key events (KEs) in such stress response pathways to adverse hepatic outcomes. The second category, “mechanistic understanding for environmental assessment”, focuses on the application of pathway-based approaches for diverse types of wildlife from invertebrates to mammals. For example, molecular tools help to understand how honey bees are threatened by neonicotinoids and higher predators by anticoagulants. The third category, “AOP thinking informs environmental monitoring and assessment of mixture effects”, features applications for the monitoring of chemical mixtures and of water quality. Especially powerful are combinations of multiple methods as evidenced by a series of articles that assessed wastewater treatment plant effluents with transcriptomic and
nvironmental toxicologists supporting risk assessments of human or ecological health are responsible for generating data for possible adverse effects of a rapidly increasing number of substances. For example, the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program in Europe and the recent reauthorization of the Toxic Substances Control Act (TSCA) in the United States both explicitly mandate consideration of the environmental and health hazards of many thousands of chemicals. There is also an increasing emphasis on understanding the effects of existing chemical mixtures on human health and the environment. These new regulatory programs and monitoring initiatives highlight the necessity for identifying and developing novel, rapid approaches for assessing the hazards of substances Fortunately, these chemical evaluation challenges are occurring against a backdrop of evolving data collection and analysis techniques that enable the generation of biological information in manners previously considered unimaginable. For example, data from genomic technologies enable scientists to simultaneously probe chemical perturbations of hundreds of biological pathways in exposed organisms, and robotic highthroughput screening (HTS) technologies allow the rapid, costeffective measurement of effects of chemicals using in vitro assays representing a diversity of biological systems. In vitro bioassays have the potential to augment (or, in some instances, replace) the more costly, long-term in vivo toxicity test methods that historically have supported chemical risk assessments. Moreover, rapidly progressing bioinformatics approaches and advances in network and systems biology modeling enable an increasingly sophisticated understanding of the high-content data generated from genomic and/or HTS methodologies. Spurred by advances in HTS data generation, systems biology and systems toxicology aim to computationally reconstruct core components of molecular, cellular, and organ level networks that are responsible for normal functions/adverse outcomes. By using systems toxicology tools, it is feasible to use large-scale data-streams including metabolomics, genomics, and proteomics to develop an integrative, qualitative, and quantitative view of complex networks operative in cells. A major challenge relative to the use of these alternative data sources for regulatory purposes involves translation of the information into end points of direct applicability to risk assessment, that is, apical impacts of consequence (e.g., survival, development, and reproduction) in individuals and/or populations of concern or human disease. The adverse outcome pathway (AOP) framework was developed to meet this translation question through the identification and depiction of causal linkages between mechanistic in vitro or in vivo data and biological end points meaningful to risk assessment.1 The AOP concept has received considerable interest and support as a communication and organizational tool by research toxicologists and risk assessors throughout the world. Dozens of AOPs have been proposed thus far, and scores are being developed collaboratively by the toxicology community. While © 2016 American Chemical Society
Published: November 21, 2016 1789
DOI: 10.1021/acs.chemrestox.6b00321 Chem. Res. Toxicol. 2016, 29, 1789−1790
Chemical Research in Toxicology
Editorial
metabolomic tools and the combination of in vitro bioassays with chemical analysis, ideally in a quantitative way through mixture toxicity modeling. The fourth category, “linking exposure to effect”, starts off with the ES&T Feature article, “Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework,” Research articles highlight the link between exposure and effect. Applications range from using exposure models or pharmacokinetic information in conjunction with in vitro bioassays to prioritize chemicals all the way to applying in vitro assays to water samples and relating the detected chemicals and their computed mixture effect in in vitro assays to the measured biological effects in these samples. Vogs and Altenburger (2016) proposed to differentiate toxicokinetics from toxicodynamics and then relate the toxicodynamics to AOPs for a mechanistic interpretation of time-dependent effects in toxicity. This is a step toward quantitative AOPs. New trends are emerging in this area with increasing multidisciplinarity and breaking down the borders between human health and environmental risk assessment. Environmental Science & Technology and Chemical Research in Toxicology welcome future submissions of work in this area of research encompassing both human health and ecosystem health aspects, in particular studies with relevance to risk assessment and quantitative descriptions and modeling of toxicity pathways. This virtual issue can be found here: http://pubs.acs.org/ page/vi/adverse-outcome-pathways.html.
Gerald Ankley†,‡ Beate Escher§ Thomas Hartung*,∥ Imran Shah‡
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† Department of Fisheries, Wildlife and Conservation Biology, The University of Minnesota, St. Paul, Minnesota 55108, United States ‡ The U.S. Environmental Protection Agency, Research Triangle Park, Durham, North Carolina 27711, United States § National Research Centre for Environmental Toxicology, The University of Queensland, Coopers Plains, QLD 4108, Australia ∥ Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States
AUTHOR INFORMATION
Corresponding Author
*615 N. Wolfe Street, Room W7035, Baltimore, MD 21205. Phone: 410-614-4990. E-mail:
[email protected]. Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
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REFERENCES
(1) Ankley, G. T., Bennett, R. S., Erickson, R. J., Hoff, D. J., Hornung, M. W., Johnson, R. D., Mount, D. R., Nichols, J. W., Russom, C. L., Schmieder, P. K., Serrrano, J. A., Tietge, J. E., and Villeneuve, D. L. (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment. Environ. Toxicol. Chem. 29, 730−741.
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DOI: 10.1021/acs.chemrestox.6b00321 Chem. Res. Toxicol. 2016, 29, 1789−1790
