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METHYL BROM'DE RISK CHARA~ERI~TION ~ N CAL ~ F O R N ~ A Subcommittee for the Review of the Risk Assessment of Methyl Bromide Committee on Toxicology Board on Environmental Studies and Toxicology Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington, D.C.

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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. This project was supported by Agreement No. 98-0316 between the National Academy of Sciences and the California Department of Pesticide Regulation. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authoress and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-07087-2 Additional copies of this report are available from: National Academy Press 2101 Constitution Ave., NW Box 285 Washington, DC 20055 800-624-6242 202-334-33 13 (in the Washington metropolitan area) http://www.nap.edu Copyright 2000 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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~~ ~~: :~U National Academy of Sciences National Academy of Engineering Institute of Medicine National Research Council 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 M. 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.

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SUBCOMMITTEE ON METHYL BROMIDE CHARLES H. HOBBS (Chair), Lovelace Respiratory Research Institute, Albuquerque, New Mexico JANICE E. CHAMBERS, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi FRANK N. DOST, Professor Emeritus, Oregon State University, Corvallis, Oregon DALE B. HATTIS, Clark University, Worcester, Massachusetts MATTHEW C. KEIFER, University of Washington, Seattle, Washington UCRIKE LUDERER, University of California-Irvine, Irvine, California GLENN C. MILLER, University of Nevada, Reno, Nevada SYLVIA S. TALMAGE, Oak Ridge National Laboratory, Oak Ridge, Tennessee Staff ROBERTA M. WEDGE, Project Director EILEEN N. ABT, Research Associate ROBERT J. CROSSGROVE, Editor Lucy V. Fusco, Project Assistant MIRSADA KARALIC-LONCAREVIC, ~ nformation Specialist IV

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SUBCOMMITTEE ON METHYL BROMIDE CHARLES H. HOBBS (Chair), Lovelace Respiratory Research Institute, Albuquerque, New Mexico JANICE E. CHAMBERS, Mississippi State University, College of Veterinary Medicine, Mississippi State, Mississippi FRANK N. DOST, Professor Emeritus, Oregon State University, Corvallis, Oregon DALE B. HATTIS, Clark University, Worcester, Massachusetts MATTHEW C. KEIFER, University of Washington, Seattle, Washington UERIKE LUDERER, University of California-Irvine, Irvine, California GLENN C. MILLER, University of Nevada, Reno, Nevada SYLVIA S. TALMAGE, Oak Ridge National Laboratory, Oak Ridge, Tennessee Stay ROBERTA M. WEDGE, Project Director EILEEN N. ABT, Research Associate ROBERT J. CROSSGROVE, Editor MIRSADA KARALIC-LONCAREVIC, Information Specialist LUCY V. Fusco, Project Assistant Sponsor CALIFORNIA DEPARTMENT OF PESTICIDE REGULATION v

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COMMITTEE ON TOXICOLOGY BAILUS WALKER, JR. (Chair), Howard University Medical Center, Washington, D.C. MELVIN E. ANDERSEN, Colorado State University, Fort Collins, Colorado GERMAINE M. BUCK, State University of New York at Buffalo GARY P. CARLSON, Purdue University, West Lafayette, Indiana JACK H. DEAN, Sallow Pharmaceuticals, Inc., Malverne, Pennsylvania ROBERT E. FORSTER II, University of Pennsylvania, Philadelphia, Pennsylvania PAUL M.D. FOSTER, Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina DAVID W. GAYLOR, U S. Food and Drug Administration, Jefferson, Arkansas JUDITH A. GRAHAM, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 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, New Mexico FLORENCE K. KINOSHITA, Hercules Incorporated, Wilmington, Delaware MICHAEL J. KOSNETT, University of Colorado Health Sciences Center, Denver, Colorado MORTON LIPPMANN, New York University School of Medicine, Tuxedo, New York THOMAS E. MCKONE, University of California, Berkeley, California ERNEST E. MCCONNELL, ToxPath, Inc., Raleigh, North Carolina DAVID H. MOORE, Battelle Memorial Institute, Bet Air, Maryland GUNTER OBERDORSTER, University of Rochester, Rochester, New York JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, New York GEORGE M. RUSCH, AlliedSignal, Inc., Morristown, New Jersey MARY E. YORE, University of Kentucky, Lexington, Kentucky ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tennessee Stay KULBIR S. BAKSHI, Program Director SUSAN N.J. PANG, Program Officer ABIGAIE STACK, Program Officer RUTH E. CROSSGROVE, Publications Manager KATHRINE J. IVERSON, Manager, Toxicology Information Center LUCY V. Fusco, Project Assistant LEAH PROBST, Project Assistant Vl

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY GORDON ORGANS (Chair), University of Washington, Seattle, Washington DONALD MATTISON ~ Vice Chair), March of Dimes, White Plains, New York DAVID ALLEN, University of Texas, Austin, Texas INGRID C. BURKE, Colorado State University, Fort Collins, Colorado WILLIAM L. CHAMEIDES, Georgia Institute of Technology, Atlanta, Georgia JOHN Douse, University of Kansas Medical Center, Kansas City, Kansas CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, California JOHN GERHART, University of California, Berkeley, California J. PAUL OILMAN, Celera Genomics, Rockville, Maryland BRUCE D. HAMMOCK, University of California, Davis, California MARK HARWELL, University of Miami, Miami, Florida ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, Chemical Manufacturers Association, Arlington, Virginia BARBARA HULKA, University of North Carolina, Chapel Hill, North Carolina JAMES F. KITCHELL, University of Wisconsin, Madison, Wisconsin DANIEL KREWSKI, University of Ottawa, Ottawa, Ontario JAMES A. MACMAHON, Utah State University, Logan, Utah MARIO J. MOLINA, Massachusetts Institute of Technology, Cambridge, Massachusetts CHARLES O'MELIA, Johns Hopkins University, Baltimore, Maryland WILLEM F. PASSCHIER, Health Council of the Netherlands KIRK SMITH, University of California, Berkeley, California MARGARET STRAND, Oppenheimer Wolff Donnelly & Bayh, LLP, Washington, D.C. TERRY F. YOSIE, Chemical Manufacturers Association, Arlington, Virginia Senior Staff JAMES J. REISA, Director DAVID J. POLICA~SKY, 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 ROBERTA M. WEDGE, Program Director for Risk Analysis v'' . .

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COMMISSION ON LIFE SCIENCES MICHAEL T. CLEGG (Chair), University of California, Riverside, California PAUL BERG (Vice Chairg, Stanford University, Stanford, California FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOANNA BURGER, Rutgers University, Piscataway, New Jersey JAMES E. CLEAVER, University of California, San Francisco, California DAVID S. EISENBERG, University of California, Los Angeles, California JOHN L. EMMERSON, Fishers, Indiana NEAL L. FIRST, University of Wisconsin, Madison, Wisconsin DAVID J. GALAS, Keck Graduate Institute of Applied Life Science, Claremont, California DAVID V. GOEDDEL, Tularik, Inc., South San Francisco, California ARTURO GOMEZ-POMPA, University of California, Riverside, California COREY S. GOODMAN, University of California, Berkeley, California JON W. GORDON, Mount Sinai School of Medicine, New York, New York DAVID G. HOEL, Medical University of South Carolina, Charleston, South Carolina BARBARA S. HULKA, University of North Carolina, Chapel Hill, North Carolina CYNTHIA J. KENYON, University of California, San Francisco, California BRUCE R. LEVIN, Emory University, Atlanta, Georgia DAVID M. LIVINGSTON, Dana-Farber Cancer Institute, Boston, Massachusetts DONALD R. MATTISON, March of Dimes, White Plains, New York ELLIOT M. MEYEROWITZ, California Institute of Technology, Pasadena, California ROBERT T. PAINE, University of Washington, Seattle, Washington RONALD R. SEDEROFF, North Carolina State University, Raleigh, North Carolina ROBERT R. SOKAL, State University of New York, Stony Brook, New York CHARLES F. STEVENS, The Salk Institute for Biological Studies, La Jolla, California SHIRLEY M. TILGHMAN, Princeton University, Princeton, New Jersey RAYMOND L. WHITE, University of Utah, Salt Lake City, Utah Staff WARREN R. MUIR, Executive Director JACQUELINE K. PRINCE, Financial Officer BARBARA B. SMITH, Administrative Associate LAURA T. HOLLIDAY, Senior Program Assistant . . . v'''

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Copper in Drinking Water (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter: I. Immediate Priorities and a Long-Range Research Portfolio (1998~; II. Evaluating Research Progress and Updating the Portfolio (1999) Ozone-Forming Potential of Reformulated Gasoline (1999) Risk-Based Waste Classification in California (1999) Arsenic in Drinking Water (1999) 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 (5 reports, 1989- 1995) 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 ofthe Sea Turtles (1990) Copies of these reports may be orderedfrom the National Academy Press (800) 624-6242 or (202) 334-3313 www.nap.edu IX

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PREFACE information gathered at a public meeting held in Irvine, California, on October 4, ~ 999. The subcommittee wishes to thank the following members of the California Department of Pesticide Regulation Paul Gosselin, Acting Chief Deputy Director, Lori Lim, and Thomas Thongsinthusakfor providing the subcommittee with information on methyl bromide toxicology and exposure data and models, for their presentation at the public meeting, and for responding to follow up requests from the subcommittee members. We also gratefully acknowledge Vincent J. Piccirillo, NPC, Inc., Bill Walker, Environmental Working Group, and Amy Kyle, Consulting Scientist, for providing background information and for making presentations to the subcommittee, and Jodi Kuhn, Methyl Bromide Industry Pane! of the Chemical Manufacturers Association, for providing background materials as well. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures for reviewing NRC reports approved by the NRC's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist 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 content of the final report is the responsibility of NRC and the study subcommittee, and not the responsibility of the reviewers. 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 NRC, for their participation in the review of the report: Dana Barr, Centers for Disease Control and Prevention; David Dorman, Chemical Industry Institute of Toxicology; David Gaylor, National Center for Toxicological Research; Craig Harris, University of Michigan; John Morris, University of Connecticut; and P. Barry Ryan, Emory University. These reviewers 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 NRC. ~ am also grateful for the assistance of NRC staff in the preparation of this report. In particular, the subcommittee wishes to acknowledge Roberta Wedge, staff officer for the subcommittee, and Eileen Abt, research associate, with the Board on Environmental Studies and Toxicology. Other staff members who contributed to this effort are Robert Crossgrove, editor, Lucy Fusco, project assistant, and Kulbir Bakshi, program director for the Committee on Toxicology. Finally, ~ would like to thank the members of the subcommittee for their valuable expertise and dedicated efforts throughout the preparation of this report. Their efforts are much appreciated. Charles H. Hobbs, D.V.M. Chair, Subcommittee on the Review of the Risk Assessment for Methyl Bromide x

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Preface One of the most widely used pesticides in California is methyl bromide, a gas- eous fumigant that is used on a variety of crops primarily as a preplan" soil insecticide, on post-harvest commodities, and in some residences as a fumi- gant. Although methyl bromide is a recognized stratospheric ozone depleter and is scheduled to be phased out completely by 2005 under the United Na- tions Montreal Protocol, it continues to be of concern for the health of agricul- tural workers and exposed residents. The California Department of Pesticide Regulation (DPR) is responsible for the development of regulations that determine the site-specific permit con- ditions for the application of pesticides in the state. California is currently in the process of proposing new regulations for issuing methyl bromide permits that require submission of a worksite plan by the property operator, provide extra protection for children in nearby schools, establish minimum buffer zones around application sites, require that nearby residents receive prior noti- fication of the application of methyl bromide, and set new limits on hours that fumigation employees may work. To develop these regulations, the DPR pre- pared a risk-characterization document to evaluate the toxicity and exposure potential for workers and residents resulting from the inhalation of this pesti- cide. Under Section 57004 of the California Health and Safety Code, the scien- tific basis of the proposed regulations is subject to external peer review by the National Academy of Sciences, the University of California, or other similar institution of higher learning or group of scientists. This report addresses that regulatory requirement by reviewing the DPR risk-characterization document that supports the proposed regulations. The National Research Council (NRC), the operating arm of The National Academies, assigned the task of preparing this report to its Committee on Toxicology, which convened the subcommittee for the review of the risk as- Xl

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XI ! PREFA CE

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PREFA CE Xl l ~ ~ am also grateful for the assistance of NRC staff in the preparation of this report. In particular, the subcommittee wishes to acknowledge Roberta Wedge, staff officer for the subcommittee, and Eileen Abt, research associate, with the Board on Environmental Studies and Toxicology. Other staff mem- bers who contributed to this effort are Robert Crossgrove, editor, Lucy Fusco, project assistant, and Kulbir Bakshi, program director for the Committee on Toxicology. Finally, T would like to thank the members of the subcommittee for their valuable expertise and dedicated efforts throughout the preparation of this re- port. Their efforts are much appreciated. Charles H. Hobbs, D.V.M. Chair, Subcommittee on the Review of the Risk Assessment for Methyl Bromide

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Contents EXECUTIVE SUMMARY 1 INTRODUCTION Background, ~ California Regulations, 9 The Subcommittee's Task, 10 Organization of the Report, 11 2 TOXICOLOGY AND HAZARD IDENTIFICATION Pharmacokinetics, 13 Genotoxicity, 16 Acute Toxicity, 17 Subchronic Toxicity, 1 8 Chronic Inhalation and Oncogenicity, 20 Reproductive Toxicity, 23 Developmental Toxicity, 27 Neurotoxicity, 3 1 Selection of Critical Effects for Acute Toxicity, 32 3 EXPOSURE ASSESSMENT ..... Background, 35 Likely Exposure Scenarios, 36 Quality of Data Available for Characterizing Exposures, 39 Accuracy and Appropriateness of Available Modeling Tools, 46 Summary, 54 xv ......... 12 .. 35

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1 xvi CONTENTS 4 RISK CHARACTERIZATION ..... Risk Characterization Goals, 56 Hazard identification, 57 Exposure Assessment, 60 Margin-of-Exposure Analysis, 64 Uncertainty Issues, 66 Summary, 69 5 CONCLUSIONS AND RECOMMENDATIONS Toxicological Information, 70 Exposure Assessment, 72 Risk Characterization, 74 REFERENCES APPENDIX A Biographical Information on the Subcommittee for the Review of the Risk Assessment of Methyl Bromide . . APPENDIX B Public Access Materials ....... APPENDIX C Calculation of Air Exchange Rates .... 56 ..... 70 76 ........ 84 .. 87 90

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Methyl Bromide Risk Characterization in California

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