Arsenic in Drinking Water

Subcommittee on Arsenic in Drinking Water

Committee on Toxicology

Board on Environmental Studies and Toxicology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY PRESS
Washington, DC



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Arsenic in Drinking Water Subcommittee on Arsenic in Drinking Water Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, DC

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Page ii NATIONAL ACADEMY PRESS · 2101 Constitution Ave., N.W. · Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. 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. Bruce Alberts 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. William A. Wulf 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. Kenneth I. Shine 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. Bruce M. Alberts and Dr. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council. This project was supported by Cooperative Agreement No. CX825107-01-0 between the National Academy of Sciences and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Catalog Card Number 99-62141 International Standard Book Number 0-309-06333-7 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 1999 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Page iii Subcommittee on Arsenic in Drinking Water ROBERT A. GOYER, Chair, (emeritus) University of Western Ontario, London, Ont., Canada H. VASKEN APOSHIAN, University of Arizona, Tucson, Ariz. KENNETH G. BROWN, Kenneth G. Brown, Inc., Chapel Hill, N.C. KENNETH P. CANTOR, National Cancer Institute, Bethesda, Md. GARY P. CARLSON, Purdue University, West Lafayette, Ind. WILLIAM R. CULLEN, University of British Columbia, Vancouver, B.C., Canada GEORGE P. DASTON, The Procter & Gamble Company, Cincinnati, Ohio BRUCE A. FOWLER, University of Maryland Medical School, Baltimore, Md. CURTIS D. KLAASSEN, University of Kansas Medical Center, Kansas City, Kans. MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colo. WALTER MERTZ, (retired) Director of Beltsville Human Nutrition Research Center, Rockville, Md. R. JULIAN PRESTON, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. LOUISE M. RYAN, Harvard School of Public Health and Dana Farber Cancer Institute, Boston, Mass. ALLAN H. SMITH, University of California, Berkeley, Calif. MARIE E. VAHTER, Karolinska Institute, Stockholm, Sweden JOHN K. WIENCKE, University of California, San Francisco,Calif. Staff CAROL A. MACZKA, Director, Toxicology and Risk Assessment Program KULBIR S. BAKSHI, Program Director for the Committee on Toxicology MARGARET E. MCVEY, Project Director (prior to January 1998) RUTH E. CROSSGROVE, Editor MIRSADA KARALIC-LONCAREVIC, Information Specialist CATHERINE M. KUBIK, Senior Program Assistant LUCY V. FUSCO, Project Assistant Sponsor: U.S. Environmental Protection Agency

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Page iv

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Page v Committee on Toxicology BAILUS WALKER, JR., Chair, Howard University Medical Center, Washington, D.C. MELVIN E. ANDERSEN, Colorado State University, Denver, Colo. GERMAINE M. BUCK, State University of New York at Buffalo, Buffalo, N.Y. GARY P. CARLSON, Purdue University, West Lafayette, Ind. JACK H. DEAN, Sanofi Pharmaceuticals, Inc., Malverne, Pa. ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia, Pa. PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Ark. JUDITH A. GRAHAM, U.S. Environmental Protection Agency, Research Triangle Park, N.C. SIDNEY GREEN, Howard University, Washington, D.C. WILLIAM E. HALPERIN, National Institute for Occupational Safety and Health, Cincinnati, Ohio CHARLES H. HOBBS, Lovelace Respiratory Research Institute and Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.M. FLORENCE K. KINOSHITA, Hercules Incorporated, Wilmington, Del. MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colo. MORTON LIPPMANN, New York University School of Medicine, Tuxedo, N.Y. THOMAS E. MCKONE, University of California, Berkeley, Calif. ERNEST E. MCCONNELL, ToxPath, Inc., Raleigh, N.C. DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Md. GUNTER OBERDÖRSTER, University of Rochester, Rochester, N.Y. JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, N.Y. GEORGE M. RUSCH, AlliedSignal, Inc., Morristown, N.J. MARY E. VORE, University of Kentucky, Lexington, Ky. ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tenn.

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Page vi Staff CAROL A. MACZKA, Senior Program Director KULBIR S. BAKSHI, Program Director ABIGAIL STACK, Project Director SUSAN N.J. PANG, Research Associate RUTH E. CROSSGROVE, Publications Manager KATHRINE J. IVERSON, Manager, Toxicology Information Center CATHERINE M. KUBIK, Senior Program Assistant LINDA V. LEONARD, Senior Program Assistant LUCY V. Fusco, Project Assistant CHRISTINE E. PHILLIPS, Project Assistant

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Page vii Board on Environmental Studies and Toxicology GORDON ORIANS, Chair, University of Washington, Seattle, Wash. DONALD MATTISON, Vice Chair, March of Dimes, White Plains, N.Y. DAVID ALLEN, University of Texas, Austin, Tex. MAY R. BERENBAUM, University of Illinois, Urbana, Ill. EULA BINGHAM, University of Cincinnati, Ohio PAUL BUSCH, Malcolm Pirnie, Inc., White Plains, N.Y. PETER L. DEFUR, Virginia Commonwealth University, Richmond, Va. DAVID L. EATON, University of Washington, Seattle, Wash. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. JOHN GERHART, University of California, Berkeley, Calif. MARK HARWELL, University of Miami, Fla. ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, N.M. CAROL HENRY, American Petroleum Institute, Washington, D.C. BARBARA HULKA, University of North Carolina, Chapel Hill, N.C. DANIEL KREWSKI, Health Canada and University of Ottawa, Ont., Canada JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Mass. WARREN MUIR, Hampshire Research Institute, Alexandria, Va. CHARLES O'MELIA, Johns Hopkins University, Baltimore, Md. KIRK SMITH, University of California, Berkeley, Calif. MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Ruder Finn Inc., Washington, D.C. Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology CAROL A. MACZKA, Senior Program Director for Toxicology and Risk Assessment RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology LEE R. PAULSON, Program Director for Resource Management

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Page viii Commission on Life Sciences MICHAEL T. CLEGG, Chair, University of California, Riverside, Calif. PAUL BERG, Vice Chair, Stanford University, Stanford, Calif. FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, Ill. JOANNA BURGER, Rutgers University, Piscataway, N.J. SHARON L. DUNWOODY, University of Wisconsin, Madison, Wis. DAVID EISENBERG, University of California, Los Angeles, Calif. JOHN EMMERSON, Portland, Ore. NEAL FIRST, University of Wisconsin, Madison, Wis. DAVID J. GALAS, Chiroscience R&D Inc., Bothell, Wash. DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, Calif. ARTURO GOMEZ-POMPA, University of California, Riverside, Calif. COREY S. GOODMAN, University of California, Berkeley, Calif. HENRY HEIKKINEN, University of Northern Colorado, Greeley, Colo. BARBARA S. HULKA, University of North Carolina, Chapel Hill, N.C. HANS J. KENDE, Michigan State University, East Lansing, Mich. CYNTHIA KENYON, University of California, San Francisco, Calif. MARGARET G. KIDWELL, University of Arizona, Tucson, Ariz. BRUCE R. LEVIN, Emory University, Atlanta, Ga. OLGA F. LINARES, Smithsonian Tropical Research Institute, Miami, Fla. DAVID LIVINGSTON, Dana-Farber Cancer Institute, Boston, Mass. DONALD R. MATTISON, March of Dimes, White Plains, N.Y. ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, Calif. ROBERT T. PAINE, University of Washington, Seattle, Wash. RONALD R. SEDEROFF, North Carolina State University, Raleigh, N.C. ROBERT R. SOKAL, State University of New York, Stony Brook, N.Y. CHARLES F. STEVENS, The Salk Institute, La Jolla, Calif. SHIRLEY M. TILGHMAN, Princeton University, Princeton, N.J. JOHN L. VANDEBERG, Southwest Foundation for Biomedical Research, San Antonio, Tex. RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah MYRON F. UMAN, Acting Executive Director

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Page ix Other Reports of the Board on Environmental Studies and Toxicology Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998) Brucellosis in the Greater Yellowstone Area (1998) The National Research Council's Committee on Toxicology: The First 50 Years (1997) Toxicologic Assessment of the Army's Zinc Cadmium Sulfide Dispersion Tests (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 [Urinary Toxicology (1995), Immunotoxicology (1992), Neurotoxicology (1992), Pulmonary Toxicology (1989), Reproductive Toxicology (1989)] Review of EPA's Environmental Monitoring and Assessment Program (3 reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Waste Sites for Remedial Action (1994) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (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 Academy Press (800) 624-6242 (202) 334-3313 http://www.nap.edu

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Page x Preface IN 1976 under the Safe Drinking Water Act, the U.S. Environmental Protection Agency (EPA) proposed an interim maximum contaminant level (MCL) for arsenic in drinking water of 50 micrograms per liter (µg/L) as part of the National Interim Primary Drinking Water Standards. That standard will apply until EPA adopts a new MCL. As part of a periodic review process, EPA has been reviewing data on arsenic exposure and toxicity to determine the adequacy of the 50-µg/L MCL for protecting public health. To ensure a solid and unbiased scientific basis for its arsenic standard for drinking water and surface waters, EPA requested that the National Research Council (NRC) review and comment on the arsenic toxicity data base and evaluate the scientific validity of EPA's 1988 risk assessment for arsenic in drinking water. For this report, the Subcommittee on Arsenic in Drinking Water of the NRC's Committee on Toxicology reviewed EPA's characterization of existing human health risks from ingestion of arsenic found in drinking water and food; determined the adequacy of the current EPA MCL for protecting human health in the context of stated EPA policy; and identified priorities for research to fill data gaps. The subcommittee evaluated the Taiwanese epidemiological data for carcinogenic and noncarcinogenic health effects of arsenic exposure; compared effects of arsenic exposure demonstrated in other countries, including the United States, with those documented for Taiwanese populations; and reviewed data on toxicokinetics, metabolism, and mechanism and mode of action of arsenic to ascertain how these data could assist in assessing human health risks from arsenic exposures. In areas where the subcommittee concluded that EPA could improve the toxicity analysis and risk characterization, specific changes are recommended, and the implications of the changes for EPA's current MCL for arsenic are described in this report. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures

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Preface IN 1976 under the Safe Drinking Water Act, the U.S. Environmental Protec- tion Agency (EPA) proposed an interim maximum contaminant {eve! (MCL) for arsenic in drinking water of 50 micrograms per liter Age) as part of the National Interim Primary Drinking Water Standards. That standard will apply until EPA adopts a new MCL. As part of a periodic review process, EPA has been reviewing data on arsenic exposure and toxicity to determine the ade- quacy of the 50-,ug/L MCL for protecting public health. To ensure a solid and unbiased scientific basis for its arsenic standard for drinking water and surface waters, EPA requested that the National Research Council (NRC) review and comment on the arsenic toxicity data base and evaluate the scien- tific validity of EPA's 1988 risk assessment for arsenic in drinking water. For this report, the Subcommittee on Arsenic in Drinking Water of the NRC's Committee on Toxicology reviewed EPA's characterization of existing human health risks from ingestion of arsenic found in drinking water and food; determined the adequacy of the current EPA MCL for protecting human health in the context of stated EPA policy; and identified priorities for re- search to fill data gaps. The subcommittee evaluated the Taiwanese epidemio- logical data for carcinogenic and noncarcinogenic health effects of arsenic exposure; compared effects of arsenic exposure demonstrated in other coun- tries, including the United States, with those documented for Taiwanese populations; and reviewed data ontoxicokinetics, metabolism, end mechanism and mode of action of arsenic to ascertain how these data could assist in assessing human health risks from arsenic exposures. In areas where the subcommittee concluded that EPA could improve the toxicity analysis and risk characterization, specific changes are recommended, and the implications of the changes for EPA's current MCL for arsenic are described in this report. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures Xl

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Page xii approved by the NRC's Report Review Committee for reviewing NRC and Institute of Medicine reports. The purpose of this independent review is to provide candid and critical comments that will assist the NRC in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals, who are neither officials nor employees of the NRC, for their participation in the review of this report: Dean E. Carter, University of Arizona; Gerald F. Combs, Cornell University; K.S. Crump, Jr., Fred Hutchinson Cancer Research Center; John L. Emmerson of Portland, Oregon; Janet L. Greger, University of Wisconsin-Madison; Edward Harris, Texas A&M University; Ronald D. Hood, The University of Alabama; David A. Kalman, University of Washington; Karl T. Kelsey, Harvard School of Public Health; Harold H. Sandstead, University of Texas Medical Branch; Joyce S. Tsuji, Exponent; John E. Vanderveen of Rockville, Maryland; and Michael P. Waalkes, National Institute of Environmental Health Sciences. The individuals listed above have provided many constructive comments and suggestions. It must be emphasized, however, that responsibility for the final content of this report rests entirely with the authoring subcommittee and the NRC. The subcommittee gratefully acknowledges Charles Abernathy, Jeanette Wiltse, Herman Gibb, Denise Lewis, and David Thomas, all of the U.S. Environmental Protection Agency; Michael Bolger, U.S. Food and Drug Administration; Ruth Hund, American Water Works Association Research Foundation; Erik Olson and David Wallinga, Natural Resources Defense Council; Robert Fensterheim, Environmental Arsenic Council; Janice Yager, Electric Power Research Institute; Warner North, Decision Focus, Inc.; Raymond Grissom, Agency for Toxic Substances and Disease Registry; and Chien-Jen Chen, National Taiwan University; for providing background information or for making presentations to the subcommittee. In addition, Chris Le, University of Alberta, at the request of the subcommittee, contributed information on the collection and storage of urine samples for arsenic speciation. That information became an integral section of the report. We are grateful for the assistance of the NRC staff for preparing the report. Staff members who contributed to this effort are Paul Gilman, former executive director of the Commission on Life Sciences; James J. Reisa, director of the Board on Environmental Studies and Toxicology; Carol A. Maczka, the project director, who coordinated and contributed to the preparation of the subcommittee's report; Margaret M. McVey, former project

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Page xiii director; Ruth E. Crossgrove, editor; Mirsada Karalic-Loncarevic, information specialist; Lucy V. Fusco, project assistant; and Catherine M. Kubik, senior program assistant. Finally, I would like to thank all the members of the subcommittee for their dedicated efforts throughout the development of this report. ROBERT A. GOYER, M.D. Chair, Subcommittee on Arsenic in Drinking Water

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Page xiv Contents Executive Summary 1 1 Introduction 10 Background, 11 Scientific Controversies 12 Organization of this Report 13 References 14 2 The U.S. Environmental Protection Agency's 1988 Risk Assessment for Arsenic 16 Overview of the EPA 1988 Special Report 16 EPA's 1988 Risk Assessment: 10 Years Later 21 Summary 24 References 25 3 Chemistry and Analysis of Arsenic Species in Water and Biological Materials 27 Summary of Arsenic Compounds in Water and Food 27 Relevant Chemical Considerations 30 Analysis of Arsenic Compounds 35 Arsenic in Water 41 Arsenic in Food 46 Arsenic in Urine, Blood, Hair, and Nails 56 Summary and Conclusions 66 Recommendations 68 References 68 4 Health Effects of Arsenic 83

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Page xv Contents Executive Summary 1 1 Introduction 10 Background, 11 Scientific Controversies 12 Organization of this Report 13 References 14 2 The U.S. Environmental Protection Agency's 1988 Risk Assessment for Arsenic 16 Overview of the EPA 1988 Special Report 16 EPA's 1988 Risk Assessment: 10 Years Later 21 Summary 24 References 25 3 Chemistry and Analysis of Arsenic Species in Water and Biological Materials 27 Summary of Arsenic Compounds in Water and Food 27 Relevant Chemical Considerations 30 Analysis of Arsenic Compounds 35 Arsenic in Water 41 Arsenic in Food 46 Arsenic in Urine, Blood, Hair, and Nails 56 Summary and Conclusions 66 Recommendations 68 References 68 4 Health Effects of Arsenic 83

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Page xvi Cancer Effects 83 Noncancer Effects 101 Summary and Conclusions 130 Recommendations 133 References 133 5 Disposition of Inorganic Arsenic 150 Absorption 150 Biotransformation 151 Transportation, Distribution, and Elimination 159 Kinetic Model 164 Summary and Conclusions 165 Recommendations 167 References 167 6 Biomarkers of Arsenic Exposure 177 Arsenic in Urine 177 Arsenic in Blood 180 Arsenic in Hair and Nails 182 Summary and Conclusions 184 Recommendations 185 References 186 7 Mechanisms of Toxicity 193 Cancer Effects 193 Noncancer Effects 207 Summary and Conclusions 213 Recommendations 214 References 215 8 Variation in Human Sensitivity 229 Variation in Arsenic Metabolism 229 Nutritional Status 235 Summary and Conclusions 243 Recommendations 244 Reference 244 9 Essentiality and Therapeutic Uses 251 Definition of Essentiality 251 Evidence for Essentiality 252 Therapeutic Uses of Arsenic 257 Summary and Conclusions 259

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Page xvii Recommendations 260 Reference 260 10 Statistical Issues 264 A Review of Dose-Response Modeling and Risk Assessment 265 The EPA 1988 Analysis 267 Problems with Risk Assessment Based on Ecological Data 269 Internal-Cancer Data from Taiwan 273 Other Issues 284 Discussion 290 Summary and Conclusions 293 Recommendations 295 References 296 11 Risk Characterization 299 References 301 Addendum to Chapter 9 302 Addendum to Chapter 10 307

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