REVIEW OF THE ENVIRONMENTAL PROTECTION AGENCY’S DRAFT IRIS ASSESSMENT OF FORMALDEHYDE

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REVIEW OF THE ENVIRONMENTAL PROTECTION AGENCY’S DRAFT IRIS ASSESSMENT OF FORMALDEHYDE Committee to Review EPA’s Draft IRIS Assessment of Formaldehyde Board on Environmental Studies and Toxicology Division on Earth and Life Studies

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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 EP-C-09-003 between the National Academy of Sciences and U.S. Environmental Protection Agency. Any opinions, findings, conclu- sions, 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: 978-0-309-21193-2 International Standard Book Number-10: 0-309-21193-X Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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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. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the re- sponsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. 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 Na- tional 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. www.national-academies.org

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COMMITTEE TO REVIEW EPA’S DRAFT IRIS ASSESSMENT OF FORMALDEHYDE Members JONATHAN M. SAMET (Chair), University of Southern California, Los Angeles ANDREW F. OLSHAN (Vice-Chair), University of North Carolina at Chapel Hill JOHN BAILER, Miami University, Oxford, OH SANDRA J.S. BAIRD, Massachusetts Department of Environmental Protection, Boston HARVEY CHECKOWAY, University of Washington School of Public Health and Community Medicine, Seattle RICHARD A. CORLEY, Pacific Northwest National Laboratory, Richland, WA DAVID C. DORMAN, North Carolina State University, Raleigh CHARLES H. HOBBS, Lovelace Respiratory Research Institute, Albuquerque, NM MICHAEL D. LAIOSA, University of Wisconsin, Milwaukee IVAN RUSYN, University of North Carolina at Chapel Hill MARY ALICE SMITH, University of Georgia, Athens LESLIE T. STAYNER, University of Illinois, Chicago HELEN H. SUH, National Opinion Research Center, University of Chicago, IL YILIANG ZHU, University of South Florida, Tampa PATRICK A. ZWEIDLER-MCKAY, The University of Texas M. D. Anderson Cancer Center, Houston Staff ELLEN K. MANTUS, Project Director HEIDI MURRAY-SMITH, Program Officer KERI SCHAFFER, Research Associate NORMAN GROSSBLATT, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects PANOLA GOLSON, Program Associate Sponsor U.S. ENVIRONMENTAL PROTECTION AGENCY v

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM PRAVEEN AMAR, Northeast States for Coordinated Air Use Management, Boston, MA TINA BAHADORI, American Chemistry Council, Washington, DC 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 FRANK W. DAVIS, University of California, Santa Barbara 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, 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 PHILIP K. HOPKE, Clarkson University, Potsdam, NY HOWARD HU, University of Michigan, Ann Arbor ROGER E. KASPERSON, Clark University, Worcester, MA 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 FRANK O’DONNELL, Clean Air Watch, Washington, DC RICHARD L. POIROT, Vermont Department of Environmental Conservation, Waterbury DANNY D. REIBLE, University of Texas, Austin ROBERT F. SAWYER, University of California, Berkeley KATHRYN G. SESSIONS, Health and Environmental Funders Network, Bethesda, MD JOYCE S. TSUJI, Exponent Environmental Group, Bellevue, WA 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 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology. vi

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011) 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) vii

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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 (nine volumes, 2000-2010) 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

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Preface The U.S. Environmental Protection Agency (EPA) released noncancer and cancer assessments of formaldehyde for its Integrated Risk Information System (IRIS) in 1990 and 1991, respectively. The agency began reassessing formalde- hyde in 1998 and released a draft IRIS assessment in June 2010. Much research has been conducted since the original assessments, and scientists are currently debating the carcinogenic properties of formaldehyde and the ways that it might cause cancer. Given the complexity of the issues and the knowledge that the assessment will be used as the basis of regulatory decisions, EPA asked the Na- tional Research Council (NRC) to conduct an independent scientific review of the draft IRIS assessment. In this report, the Committee to Review EPA’s Draft IRIS Assessment of Formaldehyde first addresses some general issues associated with the draft IRIS assessment. The committee next focuses on questions concerning specific as- pects of the draft assessment, including derivation of the reference concentra- tions and the cancer unit risk estimates for formaldehyde. The committee closes with recommendations for improving the IRIS assessment of formaldehyde and provides some general comments on the IRIS development process. The present 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 independ- ent review is to provide candid and critical comments that will assist the institu- tion 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 confi- dential to protect the integrity of the deliberative process. We thank the follow- ing for their review of this report: Margit L. Bleecker, Center for Occupational and Environmental Neurology; Claude Emond, Université de Montréal; George L. Delclos, The University of Texas Health Science Center at Houston School of Public Health; Lynn R. Goldman, George Washington University; Ulrike Lud- erer, University of California, Irvine; Roger O. McClellan, Toxicology and Hu- man Health Risk Analysis; Martha S. Sandy, California Environmental Protec- ix

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x Preface tion Agency; Jeffrey D. Schroeter, The Hamner Institutes for Health Sciences; Susan J. Simmons, University of North Carolina, Wilmington; Joyce S. Tsuji, Exponent; Elizabeth W. Triche, Brown University; Clifford P. Weisel, Univer- sity of Medicine and Dentistry of New Jersey; Joseph L. Wiemels, University of California, San Francisco. 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 S. Ramos, University of Louisville Health Science Center, and the review monitor, Frank E. Speizer, Harvard Medical School and Harvard School of Public Health. Appointed by NRC, they were responsible for making certain that an independ- ent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsi- bility for the final content of the report rests entirely with the committee and the institution. The committee gratefully acknowledges Danielle DeVoney, Sue Makris, Peter Preuss, and Kathleen Raffaele, of the U.S. Environmental Protection Agency, and Bruce Fowler, of the Agency for Toxic Substances and Disease Registry, for making presentations to the committee. The committee is also grateful for the assistance of NRC staff in preparing this report. Staff members who contributed to the effort are Ellen Mantus, pro- ject director; Heidi Murray-Smith, program officer; Keri Schaffer, research as- sociate; James Reisa, director of the Board on Environmental Studies and Toxi- cology; Norman Grossblatt, senior editor; Mirsada Karalic-Loncarevic, manager, Technical Information Center; Radiah Rose, manager, editorial pro- jects; and Panola Golson, program associate. We thank especially the members of the committee for their efforts throughout the development of this report. Jonathan M. Samet, Chair Andrew F. Olshan, Vice-Chair Committee to Review EPA’s Draft IRIS Assessment of Formaldehyde

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Contents SUMMARY ...............................................................................................................3 1 INTRODUCTION ....................................................................................16 Formaldehyde and the Draft Assessment, 16 The Committee’s Task and Approach, 20 Organization of Report, 22 References, 23 2 REVIEW OF METHODS .......................................................................24 Review of the Methodology of the Draft IRIS Assessment of Formaldehyde, 25 Summary, 28 References, 28 3 TOXICOKINETICS AND MODES OF ACTION OF FORMALDEHYDE...........................................................................29 Toxicokinetics, 30 Carcinogenesis: Has a Mode of Action of Formaldehyde Been Identified?, 44 Use of a Biologically Based Dose-Response Model, 46 Conclusions and Recommendations, 58 References, 60 4 PORTAL-OF-ENTRY HEALTH EFFECTS ........................................64 Irritation, 65 Decreased Pulmonary Function, 71 Noncancer Respiratory Tract Pathology, 74 Asthma, 78 Respiratory Tract Cancers, 83 References, 88 xi

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xii Contents 5 SYSTEMIC HEALTH EFFECTS ..........................................................92 Immunotoxicity, 93 Neurotoxicity, 97 Reproductive and Developmental Toxicity, 102 Lymphohematopoietic Cancers, 108 References, 114 6 REFERENCE CONCENTRATIONS FOR NONCANCER EFFECTS AND UNIT RISKS FOR CANCER ...................................118 Formaldehyde Reference Concentrations, 119 Formaldehyde Unit Risks For Cancer, 133 Conclusions and Recommendations, 144 References, 146 7 A ROADMAP FOR REVISION ...........................................................151 Critical Revisions of the Current Draft IRIS Assessment of Formaldehyde, 151 Future Assessments and the IRIS Process, 152 References, 166 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO REVIEW EPA’S DRAFT IRIS ASSESSMENT OF FORMALDEHYDE ...............................................................................168 B WEIGHT-OF-EVIDENCE DESCRIPTIONS FROM U.S. ENVIRONMENTAL PROTECTION AGENCY GUIDELINES .........................................................................................174 BOXES, FIGURES, AND TABLES BOXES 1-1 Statement of Task, 20 FIGURES S-1 Illustration of potential process for identifying an RfC, 13 1-1 Formaldehyde chemical structure, 17 1-2 Formaldehyde concentration in various environments, 18 1-3 Timeline of the development of the draft IRIS assessment, 19 2-1 Elements of the IRIS process, 25 3-1 Schematic representation of the mammalian nasal epithelium, 32

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xiii Contents 4-1 Odds ratios for physician-diagnosed asthma in children associated with in-home formaldehyde concentrations in air, 82 5-1 Origins of lymphohematopoietic cancers, 109 5-2 Relative incidence and estimated annual new diagnoses of common lymphohematopoietic cancer subtypes in the United States, 110 6-1 Illustration of EPA’s process for deriving a reference concentration for formaldehyde, 120 6-2 Illustration of a potential process for identifying an RfC from a full database, 132 7-1 New IRIS assessment process, 154 7-2 Elements of the key steps in the development of a draft IRIS assessment, 155 7-3 Example of an article-selection process, 159 TABLES 3-1 Analysis of 3D CFD Models by Kimbell et al. (2001a,b) and Overton et al. (2001) for Rat, Monkey, and Human Airways, 41 3-2 Overview of the Conolly et al. BBDR Models, 48 3-3 Effects of Different Parameters on Predicted Results of the Conolly et al. BBDR Models, 52 6-1 Derivation of Candidate RfCs by EPA, 122 6-2 Cancer Unit Risk Estimates for Formaldehyde, 142 7-1 Criteria for Determining Causality, 157 7-2 Hierarchy for Classifying Strength of Causal Inferences on the Basis of Available Evidence, 157

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