USING
21ST CENTURY
SCIENCE
TO IMPROVE
RISK-RELATED
EVALUATIONS
Committee on Incorporating 21st Century Science into Risk-Based Evaluations
Board on Environmental Studies and Toxicology
Division on Earth and Life Studies
A Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by Contract EP-C-14-005, TO#0002 between the National Academy of Sciences and the US Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
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International Standard Book Number-13: 978-0-309-45348-6
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Digital Object Identifier: 10.17226/24635
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. Using 21st Century Science to Improve Risk-Related Evaluations. Washington, DC: The National Academies Press. doi: 10.17226/24635.
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COMMITTEE ON INCORPORATING 21ST CENTURY SCIENCE INTO RISK-BASED EVALUATIONS
Members
JONATHAN M. SAMET (Chair), University of Southern California, Los Angeles
MELVIN E. ANDERSEN, ScitoVation, Research Triangle Park, NC
JON A. ARNOT, ARC Arnot Research & Consulting, Toronto, ON
ESTEBAN BURCHARD, University of California, San Francisco
GEORGE P. DASTON, Procter & Gamble, Mason, OH
DAVID B. DUNSON, Duke University, Durham, NC
NIGEL GREENE, AstraZeneca, Waltham, MA
HEATHER B. PATISAUL, North Carolina State University, Raleigh
KRISTI PULLEN FEDINICK, Natural Resources Defense Council, Washington, DC
BEATE R. RITZ, University of California, Los Angeles
IVAN RUSYN, Texas A&M University, College Station
ROBERT L. TANGUAY, Oregon State University, Corvallis
JUSTIN G. TEEGUARDEN, Pacific Northwest National Laboratory, Richland, WA
JAMES M. TIEDJE, Michigan State University, East Lansing
PAOLO VINEIS, Imperial College London, UK
MICHELLE WILLIAMS, Harvard School of Public Health, Boston, MA
FRED WRIGHT, North Carolina State University, Raleigh
LAUREN ZEISE, California Environmental Protection Agency, Oakland
Staff
ELLEN K. MANTUS, Project Director
MARILEE SHELTON-DAVENPORT, Senior Program Officer
NORMAN GROSSBLATT, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE-CRAWFORD, Manager, Editorial Projects
IVORY CLARKE, Research Assistant
Sponsors
US ENVIRONMENTAL PROTECTION AGENCY
US FOOD AND DRUG ADMINISTRATION
NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1
Members
WILLIAM H. FARLAND (Chair), Colorado State University, Fort Collins
PRAVEEN AMAR, Independent Consultant, Lexington, MA
RICHARD A. BECKER, American Chemistry Council, Washington, DC
E. WILLIAM COLGLAZIER, American Association for the Advancement of Science, Washington, DC
DOMINIC M. DITORO, University of Delaware, Newark
DAVID C. DORMAN, North Carolina State University, Raleigh
CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY
ANNE FAIRBROTHER, Exponent (Retired), Philomath, OR
LINDA E. GREER, Natural Resources Defense Council, Washington, DC
WILLIAM E. HALPERIN, University of Medicine and Dentistry of New Jersey, Newark
STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY
ROBERT A. HIATT, University of California, San Francisco
PHILIP K. HOPKE, Clarkson University, Potsdam, NY
SAMEUL KACEW, University of Ottawa, Ontario
H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA
THOMAS E. McKONE, University of California, Berkeley
ROBERT PERCIASEPE, Center for Climate and Energy Solutions, Arlington, VA
MARK A. RATNER, Northwestern University, Evanston, IL
JOAN B. ROSE, Michigan State University, East Lansing
GINA M. SOLOMON, California Environmental Protection Agency, Sacramento
ROBERT M. SUSSMAN, Sussman and Associates, Washington, DC
DEBORAH L. SWACKHAMMER, University of Minnesota, St. Paul
PETER S. THORNE, University of Iowa, Iowa City
JOYCE S. TSUJI, Exponent, Inc., Bellevue, WA
Senior Staff
JAMES J. REISA, Senior Director
ELLEN K. MANTUS, Scholar and Director of Risk Assessment
RAYMOND A. WASSEL, Scholar and Director of Environmental Studies
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE-CRAWFORD, Manager, Editorial Projects
__________________
1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
Application of Modern Toxicology Approaches for Predicting Acute Toxicity for Chemical Defense (2015)
Review of California’s Risk-Assessment Process for Pesticides (2015)
Sustainability Concepts in Decision-Making: Tools and Approaches for the US Environmental Protection Agency (2014)
Rethinking the Components, Coordination, and Management of the US Environmental Protection Agency Laboratories (2014)
Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)
Review of the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)
Review of EPA’s Integrated Risk Information System (IRIS) Process (2014)
Review of the Environmental Protection Agency’s State-of-the-Science Evaluation of Nonmonotonic Dose-Response Relationships as They Apply to Endocrine Disruptors (2014)
Assessing Risks to Endangered and Threatened Species from Pesticides (2013)
Science for Environmental Protection: The Road Ahead (2012)
Exposure Science in the 21st Century: A Vision and a Strategy (2012)
A Research Strategy for Environmental, Health, and Safety Aspects of Engineered Nanomaterials (2012)
Macondo Well Deepwater Horizon Blowout: Lessons for Improving Offshore Drilling Safety (2012)
Feasibility of Using Mycoherbicides for Controlling Illicit Drug Crops (2011)
Improving Health in the United States: The Role of Health Impact Assessment (2011)
A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration (2011)
Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011)
Toxicity-Pathway-Based Risk Assessment: Preparing for Paradigm Change: A Symposium Summary (2010)
The Use of Title 42 Authority at the US Environmental Protection Agency: A Letter Report (2010)
Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene (2010)
Hidden Costs of Energy: Unpriced Consequences of Energy Production and Use (2009)
Contaminated Water Supplies at Camp Lejeune: Assessing Potential Health Effects (2010)
Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (2009)
Science and Decisions: Advancing Risk Assessment (2009)
Phthalates and Cumulative Risk Assessment: The Tasks Ahead (2008)
Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008)
Respiratory Diseases Research at NIOSH: Reviews of Research Programs of the National Institute for Occupational Safety and Health (2008)
Evaluating Research Efficiency in the US Environmental Protection Agency (2008)
Hydrology, Ecology, and Fishes of the Klamath River Basin (2008)
Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007)
Models in Environmental Regulatory Decision Making (2007)
Toxicity Testing in the 21st Century: A Vision and a Strategy (2007)
Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007)
Environmental Impacts of Wind-Energy Projects (2007)
Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007)
Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006)
New Source Review for Stationary Sources of Air Pollution (2006)
Human Biomonitoring for Environmental Chemicals (2006)
Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006)
Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006)
State and Federal Standards for Mobile-Source Emissions (2006)
Superfund and Mining Megasites: Lessons from the Coeur d’Alene River Basin (2005)
Health Implications of Perchlorate Ingestion (2005)
Air Quality Management in the United States (2004)
Endangered and Threatened Species of the Platte River (2004)
Atlantic Salmon in Maine (2004)
Endangered and Threatened Fishes in the Klamath River Basin: Causes of Decline and Strategies for Recovery (2004)
Cumulative Environmental Effects of Oil and Gas Activities on Alaska’s North Slope (2003)
Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002)
Biosolids Applied to Land: Advancing Standards and Practices (2002)
The Airliner Cabin Environment and the Health of Passengers and Crew (2002)
Arsenic in Drinking Water: 2001 Update (2001)
Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001)
Compensating for Wetland Losses Under the Clean Water Act (2001)
A Risk-Management Strategy for PCB-Contaminated Sediments (2001)
Acute Exposure Guideline Levels for Selected Airborne Chemicals (20 volumes, 2000-2016)
Toxicological Effects of Methylmercury (2000)
Strengthening Science at the US Environmental Protection Agency: Research-Management and Peer-Review Practices (2000)
Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000)
Ecological Indicators for the Nation (2000)
Waste Incineration and Public Health (2000)
Hormonally Active Agents in the Environment (1999)
Research Priorities for Airborne Particulate Matter (four volumes, 1998-2004)
The National Research Council’s Committee on Toxicology: The First 50 Years 1947-1997 (1997)
Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances (1996)
Upstream: Salmon and Society in the Pacific Northwest (1996)
Science and the Endangered Species Act (1995)
Wetlands: Characteristics and Boundaries (1995)
Biologic Markers (five volumes, 1989-1995)
Science and Judgment in Risk Assessment (1994)
Pesticides in the Diets of Infants and Children (1993)
Dolphins and the Tuna Industry (1992)
Science and the National Parks (1992)
Human Exposure Assessment for Airborne Pollutants: Advances and Opportunities (1991)
Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991)
Decline of the Sea Turtles: Causes and Prevention (1990)
Copies of these publications may be ordered from the National Academies Press
(800) 624-6242 or (202) 334-3313
www.nap.edu
Acknowledgments
This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report:
Hugh Barton, Pfizer Inc.
Kim Boekelheide, Brown University
Weihsueh Chiu, Texas A&M University
Graham Colditz, Washington University
Mark Cronin, Liverpool John Moores University
Richard Currie, Syngenta
Margaret Daniele Fallin, Johns Hopkins University
Charles Gallistel, Rutgers University
Kathryn Guyton, International Agency for Research on Cancer
Judy LaKind, LaKind Associates
Thomas McKone, University of California, Berkeley
Giovanni Parmigiani, Harvard University
David Reif, North Carolina State University
Craig Rowlands, Underwriters Laboratories
Maurice Whelan, DG Joint Research Centre
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Joseph Rodricks, Ramboll Environ, and Lynn Goldman, The George Washington University, who were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
The committee gratefully acknowledges the following for their presentations to the committee during open sessions: Christopher Austin, National Center for Advancing Translational Services; David Balshaw, National Institute of Environmental Health Sciences; Linda Birnbaum, National Institute of Environmental Health Sciences; Warren Casey, National Institute of Environmental Health Sciences; Suzanne Fitzpatrick, US Food and Drug Administration; James Jones, US Environmental Protection Agency; Robert Kavlock, US Environmental Protection Agency; Daniel Krewski, University of Ottawa; Michael Landa, US Food and Drug Administration; Chirag Patel, Harvard Medical School; Anton Simeonov, National Center for Advancing Translational Services; Russell Thomas, US Environmental Protection Agency, and David White, US Food and Drug Administration. The committee also thanks Tara Chu, University of Southern California, for compiling information on epidemiological studies that have investigated neurodevelopmental effects of air pollution.
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Acronyms and Abbreviations
ACToR | Aggregated Computational Toxicology Resource |
ADME | absorption, distribution, metabolism, and excretion |
AHR | aryl-hydrocarbon receptor |
AOP | adverse outcome pathway |
B[a]P | benzo[a]pyrene |
BPA | bisphenol A |
Cas9 | CRISPR associated protein 9 |
CC | collaborative cross |
CCS | collisional cross-section |
CDC | Centers for Disease Control and Prevention |
ChEMBL | Chemical European Molecular Biology Laboratory |
CPT | Continuous Performance Test |
CRISPR | clustered regularly interspaced short palidromic repeats |
DNT | developmental neurotoxicity |
DO | diversity outbred |
DSSTox | distributed structure-searchable toxicity |
ECHA | European Chemicals Agency |
ECVAM | European Centre for the Validation of Alternative Methods |
EFSA | European Food Safety Authority |
EPA | US Environmental Protection Agency |
ES21 | Exposure Science in the 21st Century: A Vision and a Strategy |
ESCAPE | European Study of Cohorts for Air Pollution Effects |
EURL | European Union Reference Laboratory for Alternatives to Animal Testing |
EWAS | exposome-wide association study |
ExpoCast | exposure forecasting |
FBS | fetal bovine serum |
FDA | US Food and Drug Administration |
FIFRA | Federal Insecticide, Fungicide, and Rodenticide Act |
GC | gas chromatography |
GPCR | G-protein coupled receptors |
GWAS | genome-wide association study |
HELIX | Human Early-Life Exposome Project |
HERCULES | Health and Exposome Research Center: Understanding Lifetime Exposures |
HMD | Human Metabolome Database |
HTS | high-throughput screening |
IARC | International Agency for Research on Cancer |
ICCVAM | Interagency Coordinating Committee on Validation of Alternative Methods |
IMS | ion-mobility spectrometry |
IOM | Institute of Medicine |
iPSC | induced pluripotent stem cell |
IRIS | Integrated Risk Information System |
IVIVE | in vitro–in vivo extrapolation |
LC | liquid chromatography |
LDL | low-density lipoprotein |
LUR | land-use regression |
MCMH | 4-methylcyclohexanemethanol |
MS/MS | tandem mass spectrometry |
NASA | National Aeronautics and Space Administration |
NCATS | National Center for Advancing Translational Sciences |
NHANES | National Health and Nutrition Examination Survey |
NHGRI | National Human Genome Research Institute |
NICEATM | NTP Interagency Center for the Evaluation of Alternative Toxicological Methods |
NIEHS | National Institute of Environmental Health Sciences |
NIH | National Institutes of Health |
NMR | nuclear magnetic resonance |
NOAEL | no-observed-adverse-effect level |
NOEL | no-observed-effect level |
NRC | National Research Council |
NTP | National Toxicology Program |
OECD | Organisation for Economic Co-operation and Development |
OED | oral equivalent dose |
PAH | polycyclic aromatic hydrocarbon |
PBPK | physiologically based pharmacokinetics |
PD | pharmacodynamics |
PhenX Toolkit | Phenotypes and Exposures ToolKit |
PM | particulate matter |
PPARγ | peroxisome proliferator-activated receptor gamma |
PPRTV | provisional peer reviewed toxicity value |
PXR | pregnane X receptor |
QSAR | quantitative structure–activity relationship |
QSPR | quantitative structure–property relationship |
RCPM | raven colored progressive matrices |
REACH | Registration, Evaluation, Authorisation, and Restriction of Chemicals |
RIX | recombinant inbred intercrosses |
rTK | reverse toxicokinetics |
RXR | retinoid X receptor |
SAP | Science Advisory Panel |
SAR | structure–activity relationship |
SEEM | systematic empirical evaluation of models |
SES | socioeconomic status |
SEURAT | Safety Evaluation Ultimately Replacing Animal Testing |
SHEDS-HT | Stochastic Human Exposure and Dose Simulation Model for High-Throughput |
SHEDS-MM | Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway |
STROBE | strengthening the reporting of observational studies in epidemiology |
TCDD | tetrachlorodibenzo-p-Dioxin |
TCE | tricloroethylene |
Tox21 | Toxicity Testing in the 21st Century: A Vision and a Strategy |
ToxCast | Toxicity Forecaster |
TTC | threshold of toxicological concern |
WHO | World Health Organization |
WPPSI | Wechsler Preschool and Primary Scale of Intelligence |
Contents
Toxicology in the 21st Century
Exposure Science in the 21st Century
The Committee’s Approach to Its Task
2 ADVANCES IN EXPOSURE SCIENCE
Major Advances in Exposure Science
Confidence Levels in Exposure Information and Assessment
Applications for Exposure Science
Challenges and Recommendations for Advancing Exposure Science
Predicting and Probing Interactions of Chemicals with Cellular Components
Tissue-Level and Organ-Level Response
Organism-Level and Population-Level Response
Challenges and Recommendations for Advancing Toxicology
Risk Assessment and Epidemiology
Epidemiology in the 21st Century
Challenges and Recommendations for Advancing Epidemiology
5 A NEW DIRECTION FOR RISK ASSESSMENT AND APPLICATIONS OF 21st CENTURY SCIENCE
A New Direction for Risk Assessment
Communicating the New Approaches
6 MODEL AND ASSAY VALIDATION AND ACCEPTANCE
Guidance on the Validation of In Vitro and Other New Test Methods
Challenges and Recommendations
7 INTERPRETATION AND INTEGRATION OF DATA AND EVIDENCE FOR RISK-BASED DECISION-MAKING
Data Interpretation and Key Inferences
Approaches for Evaluating and Integrating Data and Evidence
Challenges and Recommendations
B CASE STUDIES ON CHEMICAL ASSESSMENTS
C CASE STUDIES ON SITE-SPECIFIC ASSESSMENTS
D CASE STUDY ON ASSESSMENT OF NEW CHEMISTRIES
BOXES, FIGURES, AND TABLES
BOXES
1-1 Definitions of Various -Omics Terms
1-3 Agency Tasks and Decision-Making Contexts
2-1 Definitions of Selected Exposure Terms
2-2 Challenges in Estimating In Vitro Test Concentrations
2-3 High-Value Applications for Exposure Sciences
3-1 Using Zebrafish to Assess Behavior
5-1 Example of Multifactorial Nature of Disease
5-2 Uncertainty and Variability in Assessment
5-5 Two Examples of Exposure-Initiated Assessment
5-6 Case Studies: Site-Specific Assessments
5-7 Case Study: Assessment of New Chemistries
6-1 Summary of the Institute of Medicine Recommendations for Effective Biomarker Evaluation
6-2 Sources of OECD Guidance on Validation of Alternative Test Methods and Models
7-1 Data Analysis and Integration Terminology Used in This Report
7-2 Definitions of Component, Mechanism, and Pathway for This Report
7-4 Development of Best Statistical Practices for Analyzing Large Toxicity Datasets
7-5 Integrating and Evaluating Mechanistic Data in the International Agency for Research on Cancer
FIGURES
S-1 Approach to deriving health reference values when data on similar chemicals are available
2-1 Conceptual overview of the scope of and common methods for exposure science
2-4 Exposure measurements are made along multiple points in the source-to-outcome continuum
3-3 The exposure-to-outcome continuum with examples of cell responses
3-4 Exposure-to-outcome continuum with examples of tissue and organ effects
3-5 Generalized components of an organ-on-a-chip model
3-6 Exposure-to-outcome continuum with examples of organism and population-level responses
3-7 Molecular structures of (S)-thalidomide and (R)-thalidomide
3-8 Scenarios for conducting read-across
4-2 A study design for developing new hypotheses on causation of disease by exposure
5-6 Overview of approach and decisions for an exposure-initiated assessment
D-1 Metabolism of 1-O-β-glucuronide
E-2 Estimated dose–response curve for PXR activation and 95% credible interval for one chemical
TABLES
4-1 Advantages and Limitations of -Omics Technologies
7-1 Characteristics of Carcinogens
7-2 Examples of Inferences or Assumptions Needed to Use 21st Century Data in Various Analyses
B-2 Activity in ToxCast Assays for Selected Alkylphenols
C-1 Site-Specific Chemicals Identified by Targeted Chemistry Analysis
D-1 Chemical Structures and Selected Measured and Predicted Properties
D-2 Data from In Vitro Assay in Which Chemicals Had Activity Below 10 µM
USING
21ST CENTURY
SCIENCE
TO IMPROVE
RISK-RELATED
EVALUATIONS