The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

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Abstract

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

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Most cited references 138

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Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment.

Gerald Ankley, Richard S. Bennett, Russell Erickson … (2010)

Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk-effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework.

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Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review

Kristina Thayer, Jerrold J. Heindel, John Bucher … (2012)

Background: There has been increasing interest in the concept that exposures to environmental chemicals may be contributing factors to the epidemics of diabetes and obesity. On 11–13 January 2011, the National Institute of Environmental Health Sciences (NIEHS) Division of the National Toxicology Program (NTP) organized a workshop to evaluate the current state of the science on these topics of increasing public health concern. Objective: The main objective of the workshop was to develop recommendations for a research agenda after completing a critical analysis of the literature for humans and experimental animals exposed to certain environmental chemicals. The environmental exposures considered at the workshop were arsenic, persistent organic pollutants, maternal smoking/nicotine, organotins, phthalates, bisphenol A, and pesticides. High-throughput screening data from Toxicology in the 21st Century (Tox21) were also considered as a way to evaluate potential cellular pathways and generate -hypotheses for testing which and how certain chemicals might perturb biological processes related to diabetes and obesity. Conclusions: Overall, the review of the existing literature identified linkages between several of the environmental exposures and type 2 diabetes. There was also support for the “developmental obesogen” hypothesis, which suggests that chemical exposures may increase the risk of obesity by altering the differentiation of adipocytes or the development of neural circuits that regulate feeding behavior. The effects may be most apparent when the developmental exposure is combined with consumption of a high-calorie, high-carbohydrate, or high-fat diet later in life. Research on environmental chemical exposures and type 1 diabetes was very limited. This lack of research was considered a critical data gap. In this workshop review, we outline the major themes that emerged from the workshop and discuss activities that NIEHS/NTP is undertaking to address research recommendations. This review also serves as an introduction to an upcoming series of articles that review the literature regarding specific exposures and outcomes in more detail.

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The Comparative Toxicogenomics Database's 10th year anniversary: update 2015

Allan Peter Davis, Cynthia Grondin, Kelley Lennon-Hopkins … (2014)

Ten years ago, the Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) was developed out of a need to formalize, harmonize and centralize the information on numerous genes and proteins responding to environmental toxic agents across diverse species. CTD's initial approach was to facilitate comparisons of nucleotide and protein sequences of toxicologically significant genes by curating these sequences and electronically annotating them with chemical terms from their associated references. Since then, however, CTD has vastly expanded its scope to robustly represent a triad of chemical–gene, chemical–disease and gene–disease interactions that are manually curated from the scientific literature by professional biocurators using controlled vocabularies, ontologies and structured notation. Today, CTD includes 24 million toxicogenomic connections relating chemicals/drugs, genes/proteins, diseases, taxa, phenotypes, Gene Ontology annotations, pathways and interaction modules. In this 10th year anniversary update, we outline the evolution of CTD, including our increased data content, new ‘Pathway View’ visualization tool, enhanced curation practices, pilot chemical–phenotype results and impending exposure data set. The prototype database originally described in our first report has transformed into a sophisticated resource used actively today to help scientists develop and test hypotheses about the etiologies of environmentally influenced diseases.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Journal ID (iso-abbrev): Environ. Health Perspect

Journal ID (publisher-id): EHP

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Electronic): 19 April 2016

Publication date (Print): November 2016

Volume: 124

Issue: 11

Pages: 1671-1682

Affiliations

[1 ]National Center for Environmental Assessment, U.S. Environmental Protection Agency (EPA), Washington, District of Columbia, USA

[2 ]ScitoVation, Research Triangle Park, North Carolina, USA

[3 ]National Health and Environmental Effects Research Laboratory, U.S. EPA, Duluth, Minnesota, USA

[4 ]Office of Chemical Safety and Pollution Prevention, U.S. EPA, Washington, District of Columbia, USA

[5 ]National Institute of Environmental Health Sciences, and

[6 ]National Toxicology Program, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA

[7 ]Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA

[8 ]Unité Modèles pour l’Écotoxicologie et la Toxicologie, Institut National de l’Environnement Industriel et des Risques, Verneuil en Halatte, France

[9 ]U.S. Army Engineer Research and Development Center, Research Triangle Park, North Carolina, USA

[10 ]Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA

[11 ]Department of Land Economy, University of Cambridge, Cambridge, England

[12 ]National Center for Computational Toxicology, and

[13 ]National Health and Environmental Effects Research Laboratory, U.S. EPA, Research Triangle Park, North Carolina, USA

[14 ]International Agency for Cancer Research, Lyon, France

[15 ]George Perkins Marsh Institute, Clark University, Worcester, Massachusetts, USA

[16 ]European Chemicals Agency, Annankatu, Helsinki, Finland

[17 ]McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada

[18 ]National Center for Environmental Assessment, U.S. EPA, Cincinnati, Ohio, USA

[19 ]National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA

[20 ]Risk Sciences International, Ottawa, Ontario, Canada

[21 ]Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA

[22 ]U.S. Army Engineer Research and Development Center, Vicksburg, Mississippi, USA

[23 ]Grant Consulting Group, Washington, District of Columbia, USA

[24 ]Environmental Defense Fund, Washington, District of Columbia, USA

[25 ]Education and Information Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Cincinnati, Ohio, USA

[26 ]National Center for Advancing Translational Sciences, NIH, DHHS, Bethesda, Maryland, USA

[27 ]Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, California, USA

[28 ]Gladstone Institutes, University of California, San Francisco, San Francisco, California, USA

[29 ]Systems Toxicology Unit, European Commission Joint Research Centre, Ispra, Italy

[30 ]Center for Effective Government, Washington, District of Columbia, USA

[31 ]Environmental Health Science and Research Bureau, Health Canada, Ottawa, Ontario, Canada

[32 ]Office of Environmental Health Hazard Assessment, California EPA, Oakland, California, USA

Author notes

[† ]Address correspondence to I. Cote, U.S. Environmental Protection Agency, Region 8, Room 8152, 1595 Wynkoop St., Denver, CO 80202-1129 USA. Telephone: (202) 288-9539. E-mail: cote.ila@ 123456epa.gov

Article

Publisher ID: EHP233

DOI: 10.1289/EHP233

PMC ID: 5089888

PubMed ID: 27091369

SO-VID: c155ad40-beab-4159-a380-ac43df544a42

License:

Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

History

Date received : 12 June 2015

Date revision received : 30 October 2015

Date accepted : 29 March 2016

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The Next Generation of Risk Assessment Multi-Year Study—Highlights of Findings, Applications to Risk Assessment, and Future Directions

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Abstract

Background:

Objective:

Methods:

Discussion:

Conclusions:

Citation:

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Global Health Next Generation Network

Most cited references 138

Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment.

Role of Environmental Chemicals in Diabetes and Obesity: A National Toxicology Program Workshop Review

The Comparative Toxicogenomics Database's 10th year anniversary: update 2015

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Cited by 32

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