TOXICITY-PATHWAY-BASED RISK ASSESSMENT
PREPARING FOR PARADIGM CHANGE
A Symposium Summary
Ellen Mantus, Rapporteur
NATIONAL RESEARCH COUNCIL
OF THE NATIONAL ACADEMIES
THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This project was supported by Contract No. EP-C-06-057 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences.
The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering.
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The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council.
PLANNING COMMITTEE FOR A SYMPOSIUM ON TOXICITY-PATHWAY-BASED RISK ASSESSMENT
Members
LORENZ RHOMBERG (Chair),
Gradient Corporation, Cambridge, MA
ELAINE FAUSTMAN,
University of Washington, Seattle
LYNN GOLDMAN,
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
MICHAEL LAWTON,
Pfizer Global Research and Development, Groton, CT
GEORGE LEIKAUF,
University of Pittsburgh, Pittsburgh, PA
JOEL POUNDS,
Pacific Northwest National Laboratory, Richland, WA
JOYCE TSUJI,
Exponent, Inc., Bellevue, WA
LAUREN ZEISE,
California Environmental Protection Agency, Oakland
Staff
ELLEN MANTUS, Project Director
NORMAN GROSSBLATT, Senior Editor
HEIDI MURRAY-SMITH, Associate Program Officer
KEEGAN SAWYER, Associate Program Officer
JOHN BROWN, Program Associate
Sponsor
U.S. ENVIRONMENTAL PROTECTION AGENCY
STANDING COMMITTEE ON RISK ANALYSIS ISSUES AND REVIEWS
Members
BERNARD GOLDSTEIN (Chair),
University of Pittsburgh, Pittsburgh, PA
FREDERÍC BOIS,
Institut National de l’Environnement Industriel et des Risques, France
MICHAEL BRAUER,
University of British Columbia, Vancouver, Canada
RICHARD CORLEY,
Pacific Northwest National Laboratory, Richland, WA
LINDA COWAN,
University of Oklahoma, Oklahoma City
KENNETH CRUMP,
Environ, Ruston, LA
LYNN GOLDMAN,
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
PHILIP LANDRIGAN,
Mount Sinai School of Medicine, New York, NY
THOMAS LOUIS,
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
NU-MAY RUBY REED,
California Environmental Protection Agency, Sacramento
LORENZ RHOMBERG,
Gradient Corporation, Cambridge, MA
JOYCE TSUJI,
Exponent, Inc., Bellevue, WA
Staff
ELLEN MANTUS, Project Director
HEIDI MURRAY-SMITH, Associate Program Officer
KEEGAN SAWYER, Associate Program Officer
JOHN BROWN, Program Associate
Sponsor
U.S. ENVIRONMENTAL PROTECTION AGENCY
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1
Members
ROGENE F. HENDERSON (Chair),
Lovelace Respiratory Research Institute, Albuquerque, NM
RAMÓN ALVAREZ,
Environmental Defense Fund, Austin, TX
TINA BAHADORI,
American Chemistry Council, Arlington, VA
MICHAEL J. BRADLEY,
M.J. Bradley & Associates, Concord, MA
DALLAS BURTRAW,
Resources for the Future, Washington, DC
JAMES S. BUS,
Dow Chemical Company, Midland, MI
JONATHAN Z. CANNON,
University of Virginia, Charlottesville
GAIL CHARNLEY,
HealthRisk Strategies, Washington, DC
RUTH DEFRIES,
Columbia University, New York, NY
RICHARD A. DENISON,
Environmental Defense Fund, Washington, DC
H. CHRISTOPHER FREY,
North Carolina State University, Raleigh
J. PAUL GILMAN,
Covanta Energy Corporation, Fairfield, NJ
RICHARD M. GOLD,
Holland & Knight, LLP, Washington, DC
LYNN R. GOLDMAN,
Johns Hopkins University, Baltimore, MD
JUDITH A. GRAHAM (retired),
Pittsboro, NC
HOWARD HU,
University of Michigan, Ann Arbor
ROGER E. KASPERSON,
Clark University, Worcester, MA
TERRY L. MEDLEY,
E.I. du Pont de Nemours & Company, Wilmington, DE
JANA MILFORD,
University of Colorado at Boulder, Boulder
DANNY D. REIBLE,
University of Texas, Austin
JOSEPH V. RODRICKS,
ENVIRON International Corporation, Arlington, VA
ROBERT F. SAWYER,
University of California, Berkeley
KIMBERLY M. THOMPSON,
Harvard School of Public Health, Boston, MA
MARK J. UTELL,
University of Rochester Medical Center, Rochester, NY
Senior Staff
JAMES J. REISA, Director
DAVID J. POLICANSKY, Scholar
RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
ELLEN K. MANTUS, Senior Program Officer for Risk Analysis
EILEEN N. ABT, Senior Program Officer
RUTH E. CROSSGROVE, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE, Manager, Editorial Projects
OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
The Use of Title 42 Authority at the U.S. Environmental Protection Agency (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 (2009)
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 (2008)
Evaluating Research Efficiency in the U.S. 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 Twenty-first 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 (2004)
Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (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 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 (seven volumes, 2000-2009)
Toxicological Effects of Methylmercury (2000)
Strengthening Science at the U.S. Environmental Protection Agency (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 (1997)
Carcinogens and Anticarcinogens in the Human Diet (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 (1991)
Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991)
Decline of the Sea Turtles (1990)
Copies of these reports may be ordered from the National Academies Press
(800) 624-6242 or (202) 334-3313
Preface
In 2007, the National Research Council (NRC) released a report titled Toxicity Testing in the 21st Century: A Vision and a Strategy. That report proposed a new paradigm for toxicity testing that envisioned evaluation of biologically significant perturbations in key toxicity pathways by using new methods in molecular biology, bioinformatics, and computational toxicology and a comprehensive array of in vitro tests based primarily on human biology. The revolution in toxicity testing is under way, and a large influx of new data is anticipated. The U.S. Environmental Protection Agency will need to be able to interpret the new data and therefore asked the Standing Committee on Risk Analysis Issues and Reviews to convene a symposium to stimulate discussion on the application of the new approaches and data in risk assessment. This summary provides an overview of the presentations and discussions that took place at that symposium.
This summary has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of the independent review is to provide candid and critical comments that will assist the institution in making its published summary as sound as possible and to ensure that the summary meets institutional standards of 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 thank the following for their review of this summary: Cynthia A. Afshari, Amgen, Inc.; Jonathan H. Freedman, Duke University; William B. Mattes, PharmPoint Consulting; and Joyce S. Tsuji, Exponent, Inc.
Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the summary before its release. The review of the summary was overseen by David L. Eaton, University of Washington. Appointed by the NRC, he was responsible for making certain that an independent examination of the summary was carried out in accordance with institutional procedures and that all review comments were
carefully considered. Responsibility for the final content of the summary rests entirely with the author and the institution.
The committee gratefully acknowledges those who made presentations or served on discussion panels at the symposium (see Appendix C for a list of speakers and affiliations). The committee is also grateful for the assistance of the NRC staff in preparing this summary. Staff members who contributed to the effort are Ellen Mantus, project director; Norman Grossblatt, senior editor; Heidi Murray-Smith, associate program officer; Keegan Sawyer, associate program officer; and Radiah Rose, editorial projects manager. I thank especially all the members of the planning committee for their efforts in the development of the program and the conduct of the symposium.
Lorenz Rhomberg, Chair
Planning Committee for a Symposium on
Toxicity-Pathway-Based Risk Assessment
Contents
TABLES AND FIGURES
TABLES
1 |
Options for Future Toxicity-Testing Strategies Considered by the NRC Committee on Toxicity Testing and Assessment of Environmental Agents, |
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2 |
Phased Development of ToxCast Program, |
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3 |
Types of ToxCast Assays, |
FIGURES
1 |
Components of the vision described in the report, Toxicity Testing in the 21st Century: A Vision and a Strategy, |
2 |
Perturbation of cellular response pathway, leading to adverse effects, |
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3 |
DNA sequencing output, |
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4 |
Throughput potential for data acquisition as related to levels of biologic organization, |
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5 |
Illustration of bioactivity profiling using high-throughput technologies to screen chemicals, |
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6 |
Overview of chemical registration for REACH, |
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7 |
Integration of new approaches for toxicology, |
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8 |
Dosimetry considerations in cell systems, |
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9 |
What do cells see? Protein adsorption by nanomaterials is a universal phenomenon in biologic systems, |
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10 |
Example of gene ontology for DNA metabolism, a biologic process, |
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11 |
Framework for interpretation of dose- and time-dependent genomic data, |
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12 |
Integrated data provide more comprehensive and accurate network reconstruction, |
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13 |
Illustration of the development of modular network models, |
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14 |
Interaction network that can be used to associate environmental factors with toxicity pathways and associated human diseases, |