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REVIEW O F THE Formaldehyyde Asssessmeent IN THEE Nationaal Toxicolo ogy Proggram 12th Report on Carcinoggens Committee to Review the Formaldehyyde Assessm ment in the National N Toxicology Prog gram 12th R Report on Caarcinogens n Environmeental Studiess and Toxicoology Board on Division D on Earth E and Liffe Studies

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

The Na ational Academy of Sciences iss a private, nonpprofit, self-perpeetuating societyy of distingu uished scholars engaged in scieentific and enginneering researchh, dedicated to the furtheraance of science and a technology and to their use for the general welfare. Upon the authoritty of the charter granted to it by the Congress in 1863, the Acadeemy has a manddate that req quires it to advisse the federal goovernment on sccientific and techhnical matters. D Dr. Ralph J. Cicerone is preesident of the Naational Academyy of Sciences. The Nattional Academy y of Engineering was establisheed in 1964, undeer the charter of the Nationaal Academy of Sciences, S as a paarallel organizattion of outstandiing engineers. Itt is autonom mous in its adm ministration and in i the selection of its memberss, sharing with tthe Nationaal Academy of Sciences S the ressponsibility for advising the feederal governmeent. The Naational Academy y of Engineerin ng also sponsorss engineering pprograms aimedd at meeting g national needs, encourages edu ucation and reseearch, and recoggnizes the superrior achievements of engineeers. Dr. C. D. Mote, M Jr., is pressident of the Nattional Academyy of Engineeering. The Insstitute of Mediccine was established in 1970 by tthe National Accademy of Sciencces to securre the services of o eminent memb bers of appropri ate professions in the examinatiion of policcy matters pertaaining to the heealth of the pubblic. The Instituute acts under tthe responsibility given to the t National Accademy of Sciennces by its congrressional charterr to be an addviser to the fed deral governmennt and, upon its oown initiative, too identify issuess of medicall care, research, and education. Dr. Victor J. Dzzau is presidentt of the Institutee of Medicinne. The National Research h Council was organized o by thee National Acadeemy of Sciencess in 1916 too associate the broad b community y of science andd technology w with the Academyy’s purposees of furthering knowledge and advising the feederal governmeent. Functioningg in accordaance with generaal policies deterrmined by the A Academy, the Coouncil has become the prin ncipal operating agency a of both the t National Acaademy of Sciencces and the Natioon- al Acaddemy of Engineeering in providin ng services to thhe government, tthe public, and tthe scientifiic and engineerring communitiees. The Councill is administereed jointly by booth Academ mies and the Insttitute of Medicin ne. Dr. Ralph J. Cicerone and D Dr. C. D. Mote, Jr., are chaiir and vice chair,, respectively, off the National Reesearch Councill. www.natiional-academies.oorg

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

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

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

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

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

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

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

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

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

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Many people in the United States are exposed to formaldehyde. Exposure can occur from environmental sources (for example, combustion processes, building materials, and tobacco smoke) or in occupational settings (for example, the furniture, textile, and construction industries). Formaldehyde exposure also has endogenous sources—it is produced intracellularly as a component of the one carbon pool intermediary metabolism pathway. Scientists have studied formaldehyde for decades to determine whether exogenous formaldehyde exposure may be associated with cancer in humans. In 1981, The National Toxicology Program (NTP) first listed formaldehyde in the 2nd Report on Carcinogens as "reasonably anticipated to be a human carcinogen". In 2011, NTP upgraded the listing of formaldehyde 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 to independently review formaldehyde's substance profile and listing. This report presents the findings and conclusions of the committee formed in response to the congressional request.

Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens concurs with NTP that there is sufficient evidence in studies that had adequate characterization of relevant exposure metrics to enable a strong conclusion about the association between formaldehyde exposure and cancer in humans. Additionally, the authoring committee independently reviewed the scientific evidence from studies in humans, experimental animals, and other studies relevant to the mechanisms of carcinogenesis and made level-of-evidence conclusions. This report finds clear and convincing epidemiologic evidence of an association between formaldehyde exposure and nasopharyngeal and sinonasal cancers in humans.

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