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
International Standard Book Number-10: 0-309-45348-8
Digital Object Identifier: 10.17226/24635
Library of Congress Control Number: 2017930534

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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

Contents

SUMMARY

1 INTRODUCTION

Toxicology in the 21st Century

Exposure Science in the 21st Century

Terminology

The Committee and Its Task

The Committee’s Approach to Its Task

Organization of This Report

References

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

References

3 ADVANCES IN TOXICOLOGY

Predicting and Probing Interactions of Chemicals with Cellular Components

Cell Response

Tissue-Level and Organ-Level Response

Organism-Level and Population-Level Response

Incorporating Data Streams

Challenges and Recommendations for Advancing Toxicology

References

4 ADVANCES IN EPIDEMIOLOGY

Risk Assessment and Epidemiology

Epidemiology in the 21st Century

Epidemiology and -Omics Data

Challenges and Recommendations for Advancing Epidemiology

References

5 A NEW DIRECTION FOR RISK ASSESSMENT AND APPLICATIONS OF 21st CENTURY SCIENCE

A New Direction for Risk Assessment

Applications

Communicating the New Approaches

Challenges and Recommendations

References

6 MODEL AND ASSAY VALIDATION AND ACCEPTANCE

Guidance on the Validation of In Vitro and Other New Test Methods

Challenges and Recommendations

References

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

Uncertainties

Challenges and Recommendations

References

APPENDIXES

A BIOGRAPHICAL INFORMATION ON THE COMMITTEE ON INCORPORATING 21ST CENTURY SCIENCE INTO RISK-BASED EVALUATIONS

B CASE STUDIES ON CHEMICAL ASSESSMENTS

C CASE STUDIES ON SITE-SPECIFIC ASSESSMENTS

D CASE STUDY ON ASSESSMENT OF NEW CHEMISTRIES

E A BAYESIAN EXAMPLE: PREDICTING DOSE–RESPONSE RELATIONSHIPS FROM HIGH-THROUGHPUT DATA AND CHEMICAL STRUCTURE

BOXES, FIGURES, AND TABLES

BOXES

1-1 Definitions of Various -Omics Terms

1-2 Statement of Task

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

4-1 Using Legacy Studies

5-1 Example of Multifactorial Nature of Disease

5-2 Uncertainty and Variability in Assessment

5-3 Case Study: Alkylphenols

5-4 Case Study: Air Pollution

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

7-3 Causal Guidelines for Evaluating Associations of Health Effects and Components, Pathways, and Mechanisms

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

S-2 Multifactorial nature of disease illustrated by using the sufficient-component-cause model in which various overall mechanisms (I, II, and III) for a disease are represented as causal pies of various components

1-1 The risk-assessment process as defined by its four elements: hazard identification, dose–response assessment, exposure assessment, and risk characterization

2-1 Conceptual overview of the scope of and common methods for exposure science

2-2 A survey of measured blood concentrations shows that for the selected chemicals concentrations of pharmaceuticals and naturally present endogenous chemicals are similar and are generally higher than concentrations of environmental contaminants

2-3 Illustration of chemical distribution in an in vitro test system and illustration of the chemical depletion factor in a typical cell-based in vitro test system as a function of chemical partitioning properties

2-4 Exposure measurements are made along multiple points in the source-to-outcome continuum

2-5 Confidence increases with more complete characterization of the exposure pathway and associated exposure determinants

2-6 Alignment of exposures across experimental toxicity-testing systems can be achieved by understanding, measuring, and applying this information on the processes that control the time course of concentrations and delivery of chemicals and particles to target cells in each system

2-7 Data from nontargeted and targeted analysis of dust samples were used with toxicity data to rank chemicals for further analysis and testing

2-8 Workflow for nontargeted and targeted analysis of the house-dust exposome for chemical priority-setting and testing

3-1 Computational models and biological assays are shown with the exposure-to-outcome continuum to illustrate where the models and assays might be used to provide information at various points in the pathway

3-2 Exposure-to-outcome continuum with examples of types of interactions between biological molecules and chemicals

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

4-1 The meet-in-the-middle approach centers on investigating (A) the association between exposure and disease, (B) the relationship between exposure and biomarkers of exposure or effect, and (C) the relationship between disease and biomarkers of exposure or effect

4-2 A study design for developing new hypotheses on causation of disease by exposure

5-1 Multifactorial nature of disease illustrated with four mechanisms (M) that have various components (C) and lead to two outcomes (O)

5-2 Screening assessments could be used to estimate toxicity or predict exposure to rank chemicals for further testing or assessment

5-3 A comparison of the animal-based approach to derive reference values compared with an approach under development that uses in vitro batteries where a biological pathway for a specific outcome has been elucidated

5-4 Approach to deriving health reference values when data on structurally similar chemicals are available

5-5 Approach for deriving acceptable values when an appropriate analogue cannot be identified solely through comparisons of structure and physicochemical data

5-6 Overview of approach and decisions for an exposure-initiated assessment

7-1 Multifactorial nature of disease illustrated by the sufficient-component-cause model in which various overall mechanisms (I, II, and III) of a disease are represented as causal pies of various components

7-2 Determinants of variability in human response result from inherent and extrinsic factors that influence propagation of dose and responses along the source-to-outcome continuum

7-3 Correction for assay measurement error

C-1 Hypothetical distribution of unidentified analytes in environmental media and biomonitoring samples

C-2 GC, LC, and ion-mobility spectrometry—MS/MS platforms allow the use of multiple types of data—including isotopic signature, elution time, fragmentation pattern, ionization source, collision cross-sectional area, and physicochemical properties—to identify unknown chemicals

C-3 Biological read-across that provides an approach to assessing the hazard posed by complex mixtures

D-1 Metabolism of 1-O-β-glucuronide

E-1 Dose–response records of PXR activation for 969 chemicals represented in the AttaGene ToxCast Phase II data

E-2 Estimated dose–response curve for PXR activation and 95% credible interval for one chemical

E-3 The predicted dose–response curves and 95% credible intervals for PXR activation for two chemicals

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-1 Octanol–Water Partition Coefficients (K_OWS) and Chemical Similarity Scores (CSSs) of Selected Alkylphenols

B-2 Activity in ToxCast Assays for Selected Alkylphenols

B-3 Relevant Regulatory Questions and How -Omics Technologies Might Help to Answer Them in the Case of Lung Cancer

B-4 Study Design of Epidemiological Studies That Have Investigated Neurodevelopmental Effects of Air Pollution

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

D-3 Indoor Release (Scenario 1), Application (Scenario 2), and Ingestion (Scenario 3) Rates (mg/d) Corresponding to Selected In Vitro Bioactivity Data

USING
21ST CENTURY
SCIENCE
TO IMPROVE
RISK-RELATED
EVALUATIONS

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