REVIEW OF THE
Formaldehyde Assessment
IN THE National Toxicology Program
          12th Report on Carcinogens

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.

www.nap.edu



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page R1
REVIEW O F THE Formaldehy Ass yde sessme ent IN THE Nationa Toxicolo Prog E al ogy gram 12th Report on Carcinog gens Committee to Review the Formaldehy Assessm in the yde ment National Toxicology Prog N gram 12th R Report on Ca arcinogens Board on Environme n ental Studies and Toxico s ology Division on Earth and Lif Studies D E fe

OCR for page R1
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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 Insti- tute 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 opin- ions, 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. International Standard Book Number-13: 978-0-309-31227-1 International Standard Book Number-10: 0-309-31227-2 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334- 3313; http://www.nap.edu/. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

OCR for page R1
The Na ational Academy of Sciences is a private, nonp s profit, self-perpe etuating society of y distingu uished scholars engaged in scie entific and engin neering research dedicated to the h, furthera ance of science and technology and to their use for the general welfare. Upon the a authorit of the charter granted to it by the Congress in 1863, the Acade ty emy has a mand date that req quires it to advis the federal go se overnment on sc cientific and tech hnical matters. D Dr. Ralph J. Cicerone is preesident of the Na ational Academy of Sciences. y The Nattional Academy of Engineering was establishe in 1964, unde the charter of the y ed er Nationa Academy of Sciences, as a pa al S arallel organizattion of outstandi engineers. It is ing t autonom mous in its adm ministration and in the selection of its members sharing with t i s, the Nationa Academy of Sciences the res al S sponsibility for advising the feederal governmeent. The Naational Academy of Engineerin also sponsors engineering p y ng s programs aimed at d meeting national needs, encourages edu g ucation and reseearch, and recoggnizes the super rior achievements of engine eers. Dr. C. D. Mote, Jr., is pres M sident of the Nattional Academy of y ering. Enginee The Insstitute of Mediccine was established in 1970 by t National Ac the cademy of Scienc ces to secur the services of eminent memb of appropri ate professions in the examinati re o bers ion of polic matters perta cy aining to the heealth of the pub blic. The Institu acts under t ute the responsibility given to the National Ac t cademy of Sciennces by its congr ressional charter to r be an ad dviser to the fed deral governmen and, upon its o nt own initiative, to identify issues of o s medical care, research, and education. Dr. Victor J. Dz is president of the Institute of l zau t e Medicinne. The National Research Council was organized by the National Acade h o e emy of Sciences in s 1916 to associate the broad community of science and technology w the Academy o b y d with y’s purpose of furthering knowledge and advising the fe es ederal governme Functioning in ent. g accordaance with genera policies deter al rmined by the AAcademy, the Co ouncil has become the prin ncipal operating agency of both the National Aca a t ademy of Scienc and the Natio ces on- al Acaddemy of Enginee ering in providin services to th government, t public, and t ng he the the scientifi and engineer ic ring communitie The Council is administere jointly by bo es. l ed oth Academ and the Inst mies titute of Medicin Dr. Ralph J. Cicerone and D C. D. Mote, Jr., ne. Dr. are chai and vice chair, respectively, of the National Re ir , f esearch Council l. www.nati ional-academies.o org

OCR for page R1

OCR for page R1
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 v

OCR for page R1
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 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology. vi

OCR for page R1
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) vii

OCR for page R1
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 viii

OCR for page R1
Preface In 1981, The National Toxicology Program (NTP) first listed formalde- hyde 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 formalde- hyde’s substance profile and listing in the 12th RoC (112th Congress, 1st Ses- sion; 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 re- view of the formaldehyde substance profile and listing in the 12th RoC. It con- sidered 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 inde- pendent 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 con- sidered presentations heard during its open-session meeting, comments submit- ted from the general public, and abstracts presented during conferences. It re- viewed 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 ap- proved by the National Research Council Report Review Committee. The pur- pose 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 manu- script 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 ix

OCR for page R1
x Preface 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 Wash- ington School of Public Health and Community Medicine; Michael J. Thirman, The University of Chicago Medicine; and Gerald N. Wogan, Massachusetts In- stitute 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 Ra- mos, University of Arizona, and the review monitor, Donald Mattison, Risk Sci- ences 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. Depart- ment 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 ef- fort 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; Ra- diah Rose, manager of editorial projects; and Ricardo Payne, program coordina- tor. 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 re- port. Alfred O. Berg, Chair Committee to Review the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens x

OCR for page R1
Contents SUMMARY ...............................................................................................................3 1 INTRODUCTION ....................................................................................20 The Report on Carcinogens, 20 Formaldehyde and the Report on Carcinogens, 25 The Committee’s Task, 26 The Committee’s Approach, 26 Organization of the Report, 30 References, 30 2 REVIEW OF THE FORMALDEHYDE PROFILE IN THE NATIONAL TOXICOLOGY PROGRAM 12th REPORT ON CARCINOGENS .............................................................33 Carcinogenicity, 34 Properties, 53 Use, 53 Production, 54 Exposure, 54 Regulations and Guidelines, 54 Review of NTP’S Literature-Search Methods, 55 Suggested Revisions for Future Editions of the Formaldehyde Listing in the Report on Carginogens, 57 Summary and Conclusions, 57 References, 60 3 INDEPENDENT ASSESSMENT OF FORMALDEHYDE..................66 Cancer Studies in Humans, 67 Cancer Studies in Experimental Animals, 122 Toxicokinetics, 129 Mechanisms of Carcinogenesis, 136 Summary of Evidence, 163 Conclusions and Listing Recommendation, 165 References, 167 xi

OCR for page R1
xii Contents APPENDIXES A BIOGRAPHICAL INFORMATION ON THE COMMITTEE TO REVIEW THE FORMALDEHYDE ASSESSMENT IN THE NTP 12th ROC ...............................................................................................179 B STATEMENT OF TASK FOR THE COMMITTEE TO REVIEW THE FORMALDEHYDE ASSESSMENT IN THE NTP 12th ROC ........184 C EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC CARCINOGENICITY STUDIES ................................................................185 D LITERATURE-SEARCH STRATEGIES COMPLETED IN SUPPORT OF THE COMMITTEE’S INDEPENDENT ASSESSMENT OF FORMALDEHYDE .....................................................199 E GENOTOXICITY AND MUTAGENICITY SUMMARY TABLES ........207 BOXES, FIGURES, AND TABLES BOXES 1-1 Congressional Language Mandating the Report on Carcinogens, 22 1-2 Listing Criteria for the Report on Carcinogens, 23 3-1 Guidance from Various Agencies on the Use of Mechanistic and Other Relevant Data, 139 D-1 Exclusion Criteria and Search Strategy for Human Studies, 200 D-2 Exclusion Criteria and Search Strategy for Experimental-Animal Studies, 202 D-3 Exclusion Criteria and Search Strategy for Genotoxicity and Mutagenicity Mechanisms of Carcinogenesis, 203 D-4 Exclusion Criteria and Search Strategy for Immune Effects, 205 FIGURES 1-1 Schematic of the review process for the 12th Report on Carcinogens, 24 3-1 Summary of strong and moderately strong studies of formaldehyde and lymphohematopoietic cancers, 118 3-2 Summary of key findings from all studies that reported associations between formaldehyde and myeloid leukemia, 119 3-3 Schematic representation of the structure of the nasal mucosa of the respiratory epithelium and follicle-associated epithelium, 134 3-4 Model-based estimates of exogenous formaldehyde concentration in nasal tissues during inhalation exposure to 6 ppm formaldehyde, 135 D-1 Literature tree for human studies search, 201 D-2 Literature tree for experimental-animal studies search, 202 D-3 Literature tree for genotoxicity search, 204 D-4 Literature tree for immune-effects search, 206

OCR for page R1
Contents xiii TABLES 1-1 Documents Pertaining to Formaldehyde That Were Available to or Written by NTP, 27 2-1 Topic-Specific Search Terms Used in NTP’s Database Searches, 56 2-2 Suggested Revisions for the Formaldehyde Substance Profile and Background Document in Future Editions of the Report on Carcinogens, 58 3-1 Criteria Used to Assess Epidemiologic Studies for Hazard Assessment, 69 3-2 Description of Epidemiologic Studies Reviewed by the Committee, 70 3-3 Studies of Nasopharyngeal Cancer and Formaldehyde Exposure, 86 3-4 Studies of Sinonasal Cancer and Formaldehyde Exposure, 93 3-5 Lymphohematopoietic Cancers: Industrial Workers, 103 3-6 Lymphohematopoietic Cancers: Funeral Workers, Embalmers, Pathologists, and Anatomists, 111 3-7 Other Cancer Sites, 120 3-8 Studies of Low Power for Detecting Malignancies, 123 3-9 Nasal Squamous-Cell Carcinoma in Long-Term Inhalation Studies of Formaldehyde, 125 3-10 Summary of Published Studies on the Genotoxic and Mutagenic Effects of Formaldehyde in Test Systems and Organisms, 141 3-11 Recent Studies of Hematologic Effects of Formaldehyde, 148 3-12 Studies Grouped by Hematologic Effects, 153 3-13 Transcriptomal Profiling Studies, 158 C-1 Distinctions between Different Levels of Exposure, 188 C-2 Information Used to Evaluate Exposure Assessment Components of Epidemiologic Studies in Chapters 2 and 3, 196 E-1 DNA Adducts, 208 E-2 DNA–DNA Cross-Links, 209 E-3 DNA–Protein Cross-Links, 210 E-4 DNA Strand Breaks, 212 E-5 Mutations, 214 E-6 Sister-Chromatid Exchanges, 215 E-7 Micronuclei, 217 E-8 Chromosomal Aberrations, 219

OCR for page R1