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COMMITTEE TO REVIEW THE IRIS PROCESS
Members
JONATHAN M. SAMET (Chair), University of Southern California
SCOTT BARTELL, University of California, Irvine
LISA BERO, University of California, San Francisco
ANN BOSTROM, University of Washington
KAY DICKERSIN, Johns Hopkins School of Public Health, MD
DAVID C. DORMAN, North Carolina State University
DAVID L. EATON, University of Washington
JOE G. GARCIA, University of Arizona
MIGUEL HERNÁN, Harvard School of Public Health, MA
JAMES S. HOUSE, University of Michigan
MARGARET M. MACDONELL, Argonne National Laboratory, IL
RICHARD P. SCHEINES, Carnegie Mellon University, PA
LEONARD M. SIEGEL, Center for Public Environmental Oversight, CA
ROBERT B. WALLACE, University of Iowa College of Public Health
YILIANG ZHU, University of South Florida
Staff
ELLEN K. MANTUS, Project Director
KERI STOEVER, Research Associate
NORMAN GROSSBLATT, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE, Manager, Editorial Projects
IVORY CLARKE, Senior Program Assistant
Sponsors
U.S. ENVIRONMENTAL PROTECTION AGENCY
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1
Members
ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM
PRAVEEN AMAR, Clean Air Task Force, Boston, MA
RICHARD A. BECKER, American Chemistry Council, Washington, DC
MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA
JONATHAN Z. CANNON, University of Virginia, Charlottesville, VA
GAIL CHARNLEY, HealthRisk Strategies, Washington, DC
DOMINIC M. DI TORRO, University of Delaware, Newark, DE
DAVID C. DORMAN, North Carolina State University, Raleigh, NC
CHARLES T. DRISCOLL, JR., Syracuse University, Syracuse, NY
WILLIAM H. FARLAND, Colorado State University, Fort Collins, CO
LYNN R. GOLDMAN, George Washington University, Washington, DC
LINDA E. GREER, Natural Resources Defense Council, Washington, DC
WILLIAM E. HALPERIN, Rutgers University, Newark, NJ
STEVEN P. HAMBURG, Environmental Defense Fund, New York, NY
ROBERT A. HIATT, University of California, San Francisco, CA
PHILIP K. HOPKE, Clarkson University, Potsdam, NY
SAMUEL KACEW, University of Ottawa, Ontario, ON, Canada
H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA
THOMAS E. MCKONE, University of California, Berkeley, CA
TERRY L. MEDLEY, E.I. du Pont de Nemours & Company, Wilmington, DE
JANA MILFORD, University of Colorado, Boulder, CO
MARK A. RATNER, Northwestern University, Evanston, IL
JOAN B. ROSE, Michigan State University, East Lansing, MI
GINA M. SOLOMON, California Environmental Protection Agency, Sacramento, CA
PETER S. THORNE, University of Iowa, Iowa City, IA
JOYCE S. TSUJI, Exponent Environmental Group, Bellevue, WA
Senior Staff
JAMES J. REISA, Director
DAVID J. POLICANSKY, Scholar
RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies
ELLEN K. MANTUS, Senior Program Officer for Risk Analysis
SUSAN N.J. MARTEL, Senior Program Officer for Toxicology
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE, Manager, Editorial Projects
_____________________________
1This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.
OTHER REPORTS OF THE
BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY
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 (2010)
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 (seventeen volumes, 2000-2014)
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
www.nap.edu
Preface
In 2011, the National Research Council (NRC) released a report that reviewed the draft health assessment on formaldehyde produced by the US Environmental Protection (EPA) for its Integrated Risk Information System (IRIS). The report recommended improvements in the formaldehyde assessment and in the program responsible for producing the assessment. Congress directed EPA to implement the report’s recommendations and then asked the NRC to review the changes that EPA was making (or proposing to make) in response to the recommendations.
In the present report, the Committee to Review the IRIS Process first provides an overview of some general issues associated with IRIS assessments. It then addresses evidence identification and evaluation for IRIS assessments and discusses evidence integration for hazard evaluation and methods for calculating reference values and unit risks. It concludes with some overall recommendations and considerations for future directions.
This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC 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 report as sound as possible and to ensure that the report 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 report: Gary Ginsberg, Connecticut Department of Public Health; William Griffith, University of Washington; Thomas Hartung, Johns Hopkins Bloomberg School of Public Health; Gunnar Johanson, Karolinska Institute; Roderick Little, University of Michigan; Malcolm Macleod, University of Edinburgh; Peter McClure, SRC Environmental Science Center; Ana Navas-Acien, Johns Hopkins Bloomberg School of Public Health; Joseph Rodricks, ENVIRON; Ivan Rusyn, University of North Carolina at Chapel Hill; Christopher Schmid, Brown University; Kurt Straif, International Agency for Research on Cancer; and Joyce Tsuji, Exponent Environmental Group, Inc.
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 the report was overseen by the review coordinator, Danny Reible, Texas Tech University, and the review monitor, Mark Cullen, Stanford University. Appointed by the NRC, they were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution.
The committee gratefully acknowledges the following for their presentations to the committee during open sessions: Richard Atkinson, St. George’s University of London; David Budescu, Fordham University; Weihsueh Chiu, Vincent Cogliano, Glinda Cooper, Lynn Flowers, Samantha Jones, and Kenneth Olden, EPA; Chris Frey, North Carolina State University; Steve Goodman, Stanford University; Thomas Hartung and Karen Robinson, Johns Hopkins University; Jay Kadane, Carnegie Mellon University; Tim Lash, Emory University; George Leikauf, University of Pittsburgh; Malcolm MacLeod, University of Edinburgh; Lorenz Rhomberg,
Gradient Corporation; Joe Rodricks, ENVIRON; David Schwartz, University of Colorado; Kristina Thayer, NTP; Duncan Thomas, University of Southern California; Rusty Thomas, The Hamner Institutes for Health Sciences; Thomas Wallsten, University of Maryland; Tracey Woodruff, University of California, San Francisco; and Lauren Zeise, California EPA. The committee members also thank the staff of EPA for being so helpful in answering their numerous questions throughout the study process.
The committee is grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to the effort are Ellen Mantus, project director; Keri Stoever, research associate; James Reisa, director of the Board on Environmental Studies and Toxicology; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager of the Technical Information Center; Radiah Rose, manager of editorial projects; and Ivory Clarke, senior program assistant.
I especially thank the members of the committee for their efforts throughout the development of this report.
Jonathan M. Samet, Chair
Committee to Review the IRIS Process
Abbreviations
ADH1 | Alcohol Dehydrogenase |
ADME | Absorption, Distribution, Metabolism, and Excretion |
BEIR | Biological Effects of Ionizing Radiation |
BMD | Benchmark Dose |
BMDL | Benchmark Dose Lower-Confidence Limit |
BMDS | Benchmark Dose Software |
BUGS | Bayesian Inference Using Gibbs Sampling |
CAAC | Chemical Assessment Advisory Committee |
CAST | Chemical Assessment Support Team |
CCRIS | Chemical Carcinogenesis Research Information System |
CNS | Central Nervous System |
CONSORT | Consolidated Standards of Reporting Trials |
DNA | Deoxyribonucleic Acid |
ECVAM | European Centre for the Validation of Alternative Methods |
ED | Effective Dose |
ELISA | Enzyme-Linked Immunosorbent Assay |
EPA | US Environmental Protection Agency |
FDA | US Food and Drug Administration |
GENETOX | Genetic Toxicology |
GLP | Good Laboratory Practice |
GMP | Good Manufacturing Practice |
GRADE | Grading of Recommendations Assessment, Development and Evaluation |
HERO | Health & Environmental Research Online |
HIV | Human Immunodeficiency Virus |
HSDB | Hazardous Substances Data Bank |
IARC | International Agency for Research on Cancer |
ICCVAM | Interagency Coordinating Committee on the Validation of Alternative Methods |
IHAD | Integrated Hazard Assessment Database |
IOM | Institute of Medicine |
IRIS | Integrated Risk Information System |
LED | Lower Effective Dose |
LOAEL | Lowest Observed-Adverse-Effect Level |
MNP | Netherlands Environmental Assessment Agency |
NOAEL | No-Observed-Adverse-Effect Level |
NRC | National Research Council |
NTP | National Toxicology Program |
OHAT | Office of Hazard Assessment and Toxicology |
OPP | Office of Pesticide Programs |
PBPK | Physiologically Based Pharmacokinetic |
POD | Point of Departure |
PRISM | Planning Tool for Resource Integration, Synchronization, and Management |
QC | Quality Control |
RIVM | Netherlands National Institute for Public Health and the Environment |
RfC | Reference Concentration |
Contents
The Integrated Risk Information System and the 2011 Formaldehyde Report
Improvements in the Integrated Risk Information System
The Committee, Its Task, and Its Approach
General Recommendations in the 2011 National Research Council Formaldeyde Report
Response to the National Research Council Formaldehyde Report
Increasing Efficiency in the IRIS Process
Using Expert Judgment in the IRIS Process
3 PROBLEM FORMULATION AND PROTOCOL DEVELOPMENT
Consideration of Bias in Evidence Identification
Recommendations on Evidence Identification in the National Research Council Formaldeyde Report
Comments on Best Practices for Evidence Identification
Recommendations on Evidence Evaluation from the National Research Council Formaldeyde Report
Best Practices for Evaluating Evidence From Individual Studies
6 EVIDENCE INTEGRATION FOR HAZARD IDENTIFICATION
Evaluating Strengths and Weakness of Evidence
Organizing Principles for Integrating Evidence
7 DERIVATION OF TOXICITY VALUES
A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO REVIEW THE IRIS PROCESS
BOXES, FIGURES, AND TABLES
BOXES
3-1 Systematic-Review Protocol Elements
5-1 Recommendations from the National Research Council Formaldehyde Report on Evidence Evaluation
5-2 Aspects to Consider in Evaluating Study Quality as Listed in the Preamble for IRIS Assessments
5-3 Considerations for a Template for Evaluating an Epidemiologic Study
6-1 Recommendations on Evidence Integration from 2011 National Research Council Formaldehyde Report
7-2 Considerations in Deriving Toxicity Values
7-3 Standard Descriptors to Characterize Level of Confidence
8-1 Recommendations Directly Relevant to Current Revisions
FIGURES
S-1 Systematic review in the context of the IRIS process
1-2 Systematic review in the context of the IRIS process
3-1 The IRIS process; problem formulation and protocol development are highlighted
3-2 The risk-assessment, risk-management paradigm
4-1 The IRIS process; the evidence-identification step is highlighted
5-1 The IRIS process; the evidence-evaluation step is highlighted
5-2 Sample graphic display of risk-of-bias evaluations
6-1 The IRIS process; the hazard-identification process is highlighted
7-2 Derivation of toxicity values
7-3 Simple Bayesian framework for estimating human toxicity from results of an animal study
7-4 Bayesian framework for combining studies of different types
TABLES
1-1 Materials Received from the US Environmental Protection Agency
3-1 Outcomes for Consideration in Problem Formulation
5-1 Types of Biases and Their Sources
6-2 Categories of Carcinogenicity
6-3 Categories of Evidential Weight for Causality
6-5 Example Conversion of Quantitative Output to Qualitative Categorical Judgments
7-1 Definitions of Terms Related to Derivation of Toxicity Values