REVIEW OF THE

Styrene Assessment

IN THE National Toxicology Program

     12th Report on Carcinogens

Committee to Review the Styrene 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

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
Committee to Review the Styrene 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

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 HHSP233201200025C between the National Academy of Sciences and 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 pro- vided support for this project. International Standard Book Number-13: 978-0-309-30178-7 International Standard Book Number-10: 0-309-30178-5 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 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. C. D. Mote, Jr., 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 responsibility 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. Victor J. Dzau 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 National 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. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

OCR for page R1

OCR for page R1
COMMITTEE TO REVIEW THE STYRENE ASSESSMENT IN THE NATIONAL TOXICOLOGY PROGRAM 12TH REPORT ON CARCINOGENS Members JANE E. HENNEY (Chair), Kansas City, MO JOHN C. BAILAR III, University of Chicago (retired), Mitchellville, MD ARTHUR P. GROLLMAN, State University of New York, Stony Brook JUDITH B. KLOTZ, Drexel University School of Public Health, Lawrenceville, NJ XIAOMEI MA, Yale University School of Public Health, New Haven, CT JOHN B. MORRIS, University of Connecticut, Storrs CHARLES G. PLOPPER, University of California Davis (retired), Chester STEPHEN M. ROBERTS, University of Florida, Gainesville IVAN RUSYN, University of North Carolina, Chapel Hill ELAINE SYMANSKI, University of Texas Health Science Center at Houston WEIQIANG (JOHN) ZHAO, Ohio State University, Columbus Consultant KEITH A. SOPER, Merck Research Laboratories, West Point, PA 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 TOXICOLOGYF1 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 Formaldehyde 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 (eighteen 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 2011, the National Toxicology Program (NTP) listed styrene as “rea- sonably anticipated to be a human carcinogen” in its 12th Report on Carcino- gens (RoC), marking the first time that the substance was listed in the RoC. Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences (NAS) to independently review the substance profile of styrene and its 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 re- view of the styrene substance profile and listing in the NTP 12th RoC. It consid- ered 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 styrene 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 disciplinary backgrounds and 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, evi- dence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative pro- cess. We thank the following for their review of the report: James S. Bus, Expo- nent; Samuel M. Cohen, University of Nebraska Medicine Center; Claude Emond, University of Montreal; William R. Fairweather, Flower Valley Con- sulting, Inc.; Mary Beth Genter, University of Cincinnati; Mark S. Goldberg, McGill University; Rogene F. Henderson, Lovelace Respiratory Research Insti- ix

OCR for page R1
x Preface tute; Richard D. Irons, Cinpathogen; Lawrence Loeb, University of Washington; Thomas M. Mack, University of Southern California; Roger O. McClellan, Tox- icology and Human Health Risk Analysis; Steven R. Tannenbaum, Massachu- setts Institute of Technology; and Martie Van Tongeren, Institute of Occupa- tional Medicine. Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the report’s conclu- sions or recommendations. They did not see the final draft of the report before its release. The review of the report was overseen by the review coordinator, David L. Eaton, University of Washington, and the review monitor, Mark Cul- len, Stanford University. Appointed by the National Research Council, they were responsible for making certain that an independent examination of the re- port was carried out in accordance with institutional procedures and that all re- view comments were carefully considered. Responsibility for the final content of the report rests entirely with the committee and the institution. The committee gratefully acknowledges Wanda Jones, of the US Depart- ment of Health and Human Services, and John Bucher, of the National Toxicol- ogy Program, for making presentations to the committee. The committee appre- ciates all who supplied written documents or views during its open public session and throughout the study process. The committee thanks Ileana D'An- drea, Marcello Noli, Giannina Satta, and Michela Ursi, of the University of Ca- gliari, Italy, for providing the translation of a study. The committee also thanks Keith Soper of Merck Research Laboratories for acting as a consultant to pro- vide the committee with input on targeted statistical questions. On behalf of the committee, I want to acknowledge the diligence of each National Research Council staff member. 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 thank members of the committee for their willingness to give their time, expertise, and energy to the task at hand. The members contributed greatly in their individual fields of scientific expertise. Moreover, all participated fully in the group’s rigorous review of the evidence and deliberations that led to the committee’s recommendations. Jane E. Henney, Chair Committee to Review the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens

OCR for page R1
Contents SUMMARY ...............................................................................................................3 1 INTRODUCTION ...........................................................................................18 The Report on Carcinogens, 18 Styrene, 20 The Committee’s Task, 24 The Committee’s Approach, 25 Organization of the Report, 28 References, 29 2 REVIEW OF THE STYRENE PROFILE IN THE NATIONAL TOXICOLOGY PROGRAM 12TH REPORT ON CARCINOGENS ........32 Carcinogenicity, 32 Properties, 45 Use, 46 Production, 46 Exposure, 46 Regulations and Guidelines, 47 Suggested Revisions for the Listing of Styrene in the Report on Carcinogens, 48 Conclusions, 49 References, 53 3 INDEPENDENT ASSESSMENT OF STYRENE .........................................57 Metabolism and Toxicokinetics, 59 Epidemiologic Studies, 64 Cancer Studies in Experimental Animals, 104 Mechanistic and Other Relevant Data, 116 Summary of Evidence and Conclusions, 141 References, 143 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO REVIEW THE STYRENE ASSESSMENT IN THE NTP 12th ROC ...............................................................................................160 xi

OCR for page R1
xii Contents B STATEMENT OF TASK OF THE COMMITTEE TO REVIEW THE STYRENE ASSESSMENT IN THE NTP 12th ROC ........................164 C DESCRIPTION OF THE NATIONAL TOXICOLOGY PROGRAM’S LITERATURE SEARCH ....................................................165 D LITERATURE SEARCH STRATEGY USED TO SUPPORT THE COMMITTEE’S INDEPENDENT ASSESSMENT OF STYRENE .........168 BOXES, FIGURES, AND TABLES BOXES 1-1 Congressional Language Mandating the Report on Carcinogens, 19 1-2 Listing Criteria for the Report on Carcinogens, 21 D-1 Exclusion Criteria and Search Strategy for Studies of the Metabolism of Styrene, 169 D-2 Exclusion Criteria and Search Strategy for Human Studies, 171 D-3 Exclusion Criteria and Search Strategy for Experimental Animal Studies, 173 D-4 Exclusion Criteria and Search Strategy for Studies of Genotoxicity and Related Mechanisms of Styrene, 174 D-5 Exclusion Criteria and Search Strategy for Immunosuppression Studies, 176 D-6 Exclusion Criteria and Search Strategy for Cytotoxicity Studies, 177 FIGURES 1-1 Schematic of the review process for the 12th Report on Carcinogens, 22 3-1 Primary metabolic pathways of styrene, 61 D-1 Literature tree for search of studies relevant to styrene metabolism, 170 D-2 Literature tree for search of studies relevant to humans, 172 D-3 Literature tree for search of studies relevant to experimental animals, 174 D-4 Literature tree for search of studies relevant to genotoxicity and mutagenicity, 175 D-5 Literature tree for search of studies relevant to styrene immunosuppression, 176 D-6 Literature tree for search of studies relevant to styrene cytotoxicity, 177 TABLES 1-1 Documents Pertaining to Styrene That Were Available to or Written by NTP, 26 2-1 Suggested Clarifications and Updates for the Styrene Substance Profile and Background Document in Future Editions of the Report on Carcinogens, 50

OCR for page R1
Contents xiii 3-1 Summary of Most Informative Epidemiologic Studies Related to Styrene Exposure and Cancer, 66 3-2 Summary of Observations for Lymphohematopoietic Cancers Combined, 78 3-3 Summary of Observations for Leukemia, 83 3-4 Summary of Observations for Non-Hodgkin Lymphoma, 87 3-5 Summary of Observations for Kidney Cancer, 93 3-6 Summary of Observations for Pancreatic Cancer, 98 3-7 Summary of Observations for Esophageal Cancer, 102 3-8 Summary of Observations for Lung, Bronchial, and Tracheal Cancers, 105 3-9 Lung-Tumor Incidence in CD-1 Mice Exposed to Styrene by Inhalation, 110 3-10 Lung-Tumor Incidence in B6C3F1 Mice Exposed to Styrene by Gavage, 111 3-11 Statistical Comparison of Mouse Lung Tumor Data from the 1979 NCI Study Using the Peto Test, 112 3-12 Studies of DNA Damage Associated with Styrene or Styrene-7,8-oxide (Including Adducts and Strand Breaks), 119 3-13 Studies of Sister-Chromatid Exchanges Associated with Styrene or Styrene-7,8-oxide, 121 3-14 Studies of Micronuclei Associated with Styrene or Styrene-7,8-oxide, 123 3-15 Studies of Chromosomal Aberrations Associated with Styrene or Styrene-7,8-oxide, 124 3-16 Summary of Genotoxic Effects of Styrene in Humans and Rodents, 126 3-17 Immune Effects of Inhalation or Intraperitoneal Exposure to Styrene in Animals, 131 3-18 Immune Effects of Inhalation Exposure to Styrene in Humans, 132 C-1 Topic-Specific Search Terms Used in the National Toxicology Program’s Literature Searches, 166

OCR for page R1