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REVIEW OF THE |
Committee to Review the Formaldehyde Assessment in the
National Toxicology Program 12th Report on Carcinogens
Board on Environmental Studies and Toxicology
Division on Earth and Life Studies
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 HHSP233201200024C between the National Academy of Sciences and the the Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project.
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COMMITTEE TO REVIEW THE FORMALDEHYDE
ASSESSMENT IN THE NTP 12TH ROC
Members
ALFRED O. BERG (Chair), University of Washington, Seattle
JOHN C. BAILAR III, University of Chicago (retired), Mitchellville, MD
A. JAY GANDOLFI, University of Arizona (retired), Tucson
DAVID KRIEBEL, University of Massachusetts, Lowell
JOHN B. MORRIS, University of Connecticut, Storrs
KENT E. PINKERTON, University of California, Davis
IVAN RUSYN, University of North Carolina, Chapel Hill
TOSHIHIRO SHIODA, Harvard Medical School and Massachusetts General Hospital, Boston
THOMAS J. SMITH, Harvard School of Public Health (retired), Boston, MA
MEIR WETZLER, Roswell Park Cancer Institute, University at Buffalo, State University of New York
LAUREN ZEISE, California Environmental Protection Agency, Oakland
PATRICK ZWEIDLER-MCKAY, The University of Texas M D Anderson Cancer Center, Houston
Staff
HEIDI MURRAY-SMITH, Project Director
KERI STOEVER, Research Associate
NORMAN GROSSBLATT, Senior Editor
MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center
RADIAH ROSE, Manager, Editorial Projects
RICARDO PAYNE, Program Coordinator
Sponsor
US DEPARTMENT OF HEALTH AND HUMAN SERVICES
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
GAIL CHARNLEY, HealthRisk Strategies, Washington, DC
DAVID C. DORMAN, Department of Molecular Biomedical Sciences, Raleigh, NC
CHARLES T. DRISCOLL, JR., Syracuse University, New York
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, 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
SAMUEL KACEW, University of Ottawa, Ontario
H. SCOTT MATTHEWS, Carnegie Mellon University, Pittsburgh, PA
THOMAS E. MCKONE, University of California, Berkeley
TERRY L. MEDLEY, E.I. du Pont de Nemours & Company, Wilmington, DE
JANA MILFORD, University of Colorado at Boulder, Boulder
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
DOMINIC M. DI TORO, University of Delaware Newark, DE
JOYCE S. TSUJI, Exponent, 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 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 (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 1981, The National Toxicology Program (NTP) first listed formaldehyde in the 2nd Report on Carcinogens (RoC) as “reasonably anticipated to be a human carcinogen”. In 2011, NTP upgraded the listing of formaldehyde in the 12th RoC to “known to be a human carcinogen”. Following the new listing, Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences (NAS) to independently review formaldehyde’s substance profile and listing in the 12th RoC (112th Congress, 1st Session; Public Law 112-74). This report presents the findings and conclusions of the committee formed in response to the congressional request.
To address its statement of task, the committee first conducted a peer review of the formaldehyde substance profile and listing in the 12th RoC. It considered literature available to NTP up to the publication of the 12th RoC (that is, literature published by June 10, 2011). The committee then conducted an independent assessment of formaldehyde and made a listing recommendation using the RoC listing criteria. In its independent assessment, the committee examined evidence published both before and after the publication of the 12th RoC. It considered presentations heard during its open-session meeting, comments submitted from the general public, and abstracts presented during conferences. It reviewed reports published by other authoritative bodies, and it examined primary literature, reviews, and meta-analyses that were publicly available in the peer-reviewed literature.
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 National Research Council 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 the report: Hugh Barton, Pfizer, Inc.; Harvey Checkoway, University of California, San Diego; David C. Dorman, North Carolina State University; Rogene F. Henderson; Lovelace Respiratory
Research Institute; Charles G. Mullighan, St. Jude Children’s Research Hospital; Neil Pearce, London School of Hygiene and Tropical Medicine; Elizabeth A. Platz, Johns Hopkins University; Joseph V. Rodricks, ENVIRON; Jonathan M. Samet, University of Southern California; Noah S. Seixas, University of Washington School of Public Health and Community Medicine; Michael J. Thirman, The University of Chicago Medicine; and Gerald N. Wogan, Massachusetts Institute of Technology.
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, Kenneth Ramos, University of Arizona, and the review monitor, Donald Mattison, Risk Sciences International. Appointed by the National Research Council, 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 Dr. Wanda Jones, U.S. Department of Health and Human Services, and Dr. John Bucher, National Toxicology Program, for making presentations to the committee. The committee appreciates all who supplied written documents or views to the committee during its open public session and throughout the study process.
The committee is also grateful for the assistance of the National Research Council staff in preparing this report. Staff members who contributed to the effort are Heidi Murray-Smith, project director; Ellen Mantus, senior program officer; 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 Ricardo Payne, program coordinator.
I especially thank the members of the committee for contributing their outstanding expertise, scientific focus, meticulous attention to detail, tireless hard work, and consistent good humor throughout the development of this report.
Alfred O. Berg, Chair
Committee to Review the
Formaldehyde Assessment in the
National Toxicology Program
12th Report on Carcinogens
Contents
Formaldehyde and the Report on Carcinogens
2 REVIEW OF THE FORMALDEHYDE PROFILE IN THE NATIONAL TOXICOLOGY PROGRAM 12th REPORT ON CARCINOGENS
Review of NTP’S Literature-Search Methods
Suggested Revisions for Future Editions of the Formaldehyde Listing in the Report on Carginogens
3 INDEPENDENT ASSESSMENT OF FORMALDEHYDE
Cancer Studies in Experimental Animals
B STATEMENT OF TASK FOR THE COMMITTEE TO REVIEW THE FORMALDEHYDE ASSESSMENT IN THE NTP 12th ROC
C EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC CARCINOGENICITY STUDIES
E GENOTOXICITY AND MUTAGENICITY SUMMARY TABLES
BOXES, FIGURES, AND TABLES
BOXES
1-1 Congressional Language Mandating the Report on Carcinogens
1-2 Listing Criteria for the Report on Carcinogens
3-1 Guidance from Various Agencies on the Use of Mechanistic and Other Relevant Data
D-1 Exclusion Criteria and Search Strategy for Human Studies
D-2 Exclusion Criteria and Search Strategy for Experimental-Animal Studies
D-4 Exclusion Criteria and Search Strategy for Immune Effects
FIGURES
1-1 Schematic of the review process for the 12th Report on Carcinogens
3-1 Summary of strong and moderately strong studies of formaldehyde and lymphohematopoietic cancers
D-1 Literature tree for human studies search
D-2 Literature tree for experimental-animal studies search
TABLES
1-1 Documents Pertaining to Formaldehyde That Were Available to or Written by NTP
2-1 Topic-Specific Search Terms Used in NTP’s Database Searches
3-1 Criteria Used to Assess Epidemiologic Studies for Hazard Assessment
3-2 Description of Epidemiologic Studies Reviewed by the Committee
3-3 Studies of Nasopharyngeal Cancer and Formaldehyde Exposure
3-4 Studies of Sinonasal Cancer and Formaldehyde Exposure
3-5 Lymphohematopoietic Cancers: Industrial Workers
3-6 Lymphohematopoietic Cancers: Funeral Workers, Embalmers, Pathologists, and Anatomists
3-8 Studies of Low Power for Detecting Malignancies
3-9 Nasal Squamous-Cell Carcinoma in Long-Term Inhalation Studies of Formaldehyde
3-11 Recent Studies of Hematologic Effects of Formaldehyde
3-12 Studies Grouped by Hematologic Effects
3-13 Transcriptomal Profiling Studies
C-1 Distinctions between Different Levels of Exposure
