Toxicologic Assessment of Jet-Propulsion Fuel 8

Subcommittee on Jet-Propulsion Fuel 8

Committee on Toxicology

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL of the National Academies

THE NATIONAL ACADEMIES PRESS
Washington, D.C. www.nap.edu



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Toxicologic Assessment of Jet-Propulsion Fuel 8 Subcommittee on Jet-Propulsion Fuel 8 Committee on Toxicology Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL of the National Academies THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, D.C. 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 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 Contract No. DAMD17-99-C-9049 between the National Academy of Sciences and U.S. Department of Defense. 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. International Standard Book Number 0-309-08715-5 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 2003 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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. Wm. 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. 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 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. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council www.national-academies.org

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SUBCOMMITTEE ON JET-PROPULSION FUEL 8 MELVIN E. ANDERSEN (Chair), Colorado State University, Fort Collins, Colorado; currently at CIIT-Centers for Health Research, Research Triangle Park, North Carolina JANET M. BENSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico SCOTT W. BURCHIEL, University of New Mexico, Albuquerque RAKESH DIXIT, Merck Research Laboratory, West Point, Pennsylvania ROBERT G. FELDMAN, Boston University School of Medicine, Boston, Massachusetts SAM KACEW, University of Ottawa, Ottawa, Ontario, Canada NANCY I. KERKVLIET, Oregon State University, Corvallis MARTHA S. SANDY, California Environmental Protection Agency, Oakland WILLIAM M. VALENTINE, Vanderbilt University Medical Center, Nashville, Tennessee Staff ABIGAIL E. MITCHELL, Project Director NORMAN GROSSBLATT, Senior Editor KELLY CLARK, Assistant Editor MIRSADA KARALIC-LONCAREVIC, Research Assistant JESSICA BROCK, Senior Project Assistant

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COMMITTEE ON TOXICOLOGY BAILUS WALKER, JR. (Chair), Howard University Medical Center and American Public Health Association, Washington, D.C. MELVIN E. ANDERSEN, Colorado State University, Fort Collins EDWARD C. BISHOP, Parsons Corporation, Fairfax, Virginia GARY P. CARLSON, Purdue University, West Lafayette, Indiana JANICE E. CHAMBERS, Mississippi State University, Mississippi State LEONARD CHIAZZE, JR., Georgetown University, Washington, D.C. JUDITH A. GRAHAM, American Chemistry Council, Arlington, Virginia SIDNEY GREEN, Howard University, Washington, D.C. MERYL KAROL, University of Pittsburgh, Pittsburgh, Pennsylvania STEPHEN U. LESTER, Center for Health Environment and Justice, Falls Church, Virginia DAVID H. MOORE, Battelle Memorial Institute, Bel Air, Maryland CALVIN C. WILLHITE, State of California, Berkeley Staff KULBIR S. BAKSHI, Program Director SUSAN N.J. MARTEL, Senior Program Officer ABIGAIL E. MITCHELL, Program Officer KELLY CLARK, Assistant Editor AIDA NEEL, Senior Project Assistant TAMARA DAWSON, Project Assistant

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 GORDON ORIANS (Chair), University of Washington, Seattle JOHN DOULL (Vice Chair), University of Kansas Medical Center, Kansas City DAVID ALLEN, University of Texas, Austin THOMAS BURKE, Johns Hopkins University, Baltimore, Maryland JUDITH C. CHOW, Desert Research Institute, Reno, Nevada CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, California WILLIAM H. GLAZE, University of North Carolina, Chapel Hill SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, Virginia DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, Massachusetts ROGENE HENDERSON, Lovelace Respiratory Research Institute, Albuquerque, New Mexico CAROL HENRY, American Chemistry Council, Arlington, Virginia ROBERT HUGGETT, Michigan State University, East Lansing BARRY L. JOHNSON Emory University, Atlanta, Georgia JAMES H. JOHNSON, Howard University, Washington, D.C. JAMES A. MACMAHON, Utah State University, Logan PATRICK V. O’BRIEN, Chevron Research and Technology, Richmond, California DOROTHY E. PATTON, International Life Sciences Institute, Washington, D.C. ANN POWERS, Pace University School of Law, White Plains, New York LOUISE M. RYAN, Harvard University, Boston, Massachusetts JONATHAN M. SAMET, Johns Hopkins University, Baltimore, Maryland KIRK SMITH, University of California, Berkeley LISA SPEER, Natural Resources Defense Council, New York, New York G. DAVID TILMAN, University of Minnesota, St. Paul CHRIS G. WHIPPLE, Environ Incorporated, Emeryville, California LAUREN A. ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Senior Program Director for Applied Ecology RAYMOND A. WASSEL, Senior Program Director for Environmental Sciences and Engineering KULBIR BAKSHI, Program Director for the Committee on Toxicology ROBERTA M. WEDGE, Program Director for Risk Analysis K. JOHN HOLMES, Senior Staff Officer SUSAN N.J. MARTEL, Senior Staff Officer SUZANNE VAN DRUNICK, Senior Staff Officer RUTH E. CROSSGROVE, Managing Editor 1   This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) Ecological Dynamics on Yellowstone’s Northern Range (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 (2 reports; 2000, 2002) 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) Modeling Mobile-Source Emissions (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (3 reports, 1998-2001) Ozone-Forming Potential of Reformulated Gasoline (1999) Arsenic in Drinking Water (1999) 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 (5 reports, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (3 reports, 1994-1995) 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

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OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001) Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume 1 (2000), Volume 2 (2002) Review of the US Navy’s Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000) Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S. Navy Environmental Health Center’s Health-Hazard Assessment Process (2000) Review of the U.S. Navy's Exposure Standard for Manufactured Vitreous Fibers (2000) Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000) Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23, and HFC-404a (2000) Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2 (1999), Volume 3 (1999) Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998) Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996) Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3 (1996), Volume 4 (2000)

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Preface In the 1980s, the U.S. Department of Defense (DOD) selected jet-propulsion fuel 8 (JP-8) as its primary fuel. JP-8 is widely used by the military not only for aircraft, but also for ground vehicles and other equipment, such as generators, cooking stoves, and tent heaters. Military personnel can be exposed to JP-8 vapors and aerosols during a number of operational scenarios, including aircraft refueling and maintenance. To protect the health of its personnel, DOD recommended an interim permissible exposure level (PEL) of 350 mg/m3. The Air Force requested that the National Research Council (NRC) review the available toxicologic, epidemiologic, and other relevant data on JP-8 and evaluate independently the scientific basis of the DOD’s interim PEL of 350 mg/m3 for JP-8. The NRC assigned this project to the Committee on Toxicology (COT), which assembled the Subcommittee on Jet-Propulsion Fuel 8 to prepare this report. We thank the following Air Force personnel for providing valuable background information to the subcommittee: Brian Blazicko, Roger Gibson, John Hinz, David Mattie, James McDougal, and Richard Stotts. We also wish to express our gratitude to Geraldine Grant (George Mason University, Fairfax, Virginia), David Harris (University of Arizona, Tucson, Arizona), Glenn Ritchie (Geo-Centers, Inc., Wright-Patterson Air Force Base, Ohio), Mark Smulson (Georgetown University, Washington, D.C.), Steve Ullrich (M.D. Anderson Cancer Center, Houston, Texas), Russell White (Chevron Research

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and Technology Company, Richmond, California), and Mark Witten (University of Arizona, Tucson, Arizona) for providing background information to the subcommittee. We also thank Stephen Channel (U.S. Air Force), Thomas Neal (U.S. Air Force), and Kenneth Still (U.S. Navy) for their support of this project. This 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’s Report Review Committee. The purpose of this independent review is to provide candid, 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 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 for their review of this report: Edward Bishop, Parsons Engineering Sciences, Inc., Fairfax, Virginia; Judith Graham, American Chemistry Council, Arlington, Virginia; Karl Kelsey, Harvard School of Public Health, Boston, Massachusetts; Carole Kimmel, U.S. Environmental Protection Agency, Washington, D.C.; Kannan Krishnan, University of Montreal, Quebec, Canada; David Lawrence, New York State Department of Health, Albany, New York; Judith MacGregor, Toxicology Consulting Services, Arnold, Maryland; Ceinwen Schreiner, C & C Consulting in Toxicology, Meadowbrook, Pennsylvania; and Bailus Walker, Jr., Howard University Medical Center, Washington, D.C. Although the reviewers provided many constructive comments and suggestions, they were not asked to endorse the report’s conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Dean Carter, University of Arizona, Tucson, who was appointed by the NRC to ensure that an independent examination of this report was conducted 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 subcommittee and the institution. We are also grateful for the assistance of members of the NRC staff in the preparation of this report. The subcommittee acknowledges Abigail Mitchell, project director, and Kulbir Bakshi, program director of the Committee on Toxicology. Other staff members contributing to this report were James Reisa, director of the Board on Environmental Studies and Toxicology; Jessica Brock, senior project assistant; Norman Grossblatt, editor; and Kelly Clark, assistant editor.

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Finally, we thank all members of the subcommittee for their expertise and dedicated effort throughout the study. Melvin E. Andersen, PhD Chair, Subcommittee on Jet-Propulsion Fuel 8 Bailus Walker, Jr., PhD, MPH Chair, Committee on Toxicology

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Contents     Abbreviations   xix     Summary   1 1   Introduction   9     Summary of the 1996 National Research Council Report on Military Fuels   10     The Charge to the Subcommittee   11     The Subcommittee’s Approach to the Charge   11     Physical and Chemical Properties of JP-8   12     Organization of This Report   12     References   14 2   Dosimetry and Exposure Assessment of Jet-Propulsion Fuel 8   16     Background   16     Assessment of Occupational Exposure to JP-8   17     Measurement of Body Burden of JP-8   20     Protein Adducts as Surrogate Biomarkers of JP-8 Exposure   22     Factors That Modify Internal Dose of JP-8   22     Assessing Dosimetry in Toxicological Studies   24     Conclusions and Recommendations   26     References   27

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3   Toxicokinetics and Toxicodynamics of Jet-Propulsion Fuel 8   29     Benzene   30     Alkylbenzenes   30     C9-C13 Aliphatic and Aromatic Hydrocarbons   31     Physiologically Based Pharmacokinetic Models of Benzene, Nonane, and C9-C12 or C9-C17 Aliphatic Hydrocarbons   32     Toxicokinetics-Related Interactions Among Hydrocarbon Fuel Components   35     Toxicokinetic-Related Individual Susceptibility Factors   36     References   37 4   Effects of Jet-Propulsion Fuel 8 on the Respiratory Tract   41     Effects of Exposure to Jet Fuels and Kerosene in Humans   41     Effects of Exposure to Jet Fuels and Kerosene in Experimental Animals   45     Effects of In Vitro Exposure to JP-8   52     Conclusions and Recommendations   53     References   54 5   Effects of Jet-Propulsion Fuel 8 on the Nervous System   56     Summary of Studies Discussed in the 1996 National Research Council Report   56     Effects of Exposure to JP-8 in Humans   57     Effects of Exposure to JP-8 in Experimental Animals   61     Conclusions and Recommendations   67     References   68 6   Effects of Jet-Propulsion Fuel 8 on the Immune System   71     Immunosuppressive Effects of JP-8   71     Allergic Potential of JP-8   81     Autoimmune Effects of JP-8   82     Conclusions and Recommendations   82     References   83 7   Effects of Jet-Propulsion Fuel 8 on the Liver   86     Summary of Studies Discussed in the 1996 National Research Council Report   86     Effects of Exposure to JP-8 in Humans   88     Effects of Exposure to JP-8 in Experimental Animals   91     Effects of In Vitro Exposure to JP-8   97

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    Conclusions and Recommendations   97     References   98 8   Effects of Jet-Propulsion Fuel 8 on the Kidney   101     Summary of Studies Discussed in the 1996 National Research Council Report   101     Effects of Exposure to JP-8 in Humans   102     Effects of Exposure to JP-8 in Experimental Animals   106     Conclusions and Recommendations   110     References   111 9   Effects of Jet-Propulsion Fuel 8 on Reproduction and Development   113     Effects of Exposure to JP-8 in Humans   113     Effects of Exposure to JP-8 in Experimental Animals   114     Conclusions and Recommendations   120     References   121 10   Effects of Jet-Propulsion Fuel 8 on the Cardiovascular System   123     Summary of Studies Discussed in the 1996 National Research Council Report   123     Effects of Exposure to Jet Fuels in Humans   126     Effects of Exposure to JP-8 and Kerosene in Experimental Animals   127     Conclusions and Recommendations   128     References   128 11   Genotoxic Effects of Jet-Propulsion Fuel 8   130     Summary of Studies Discussed in the 1996 National Research Council Report   130     Genotoxicity in Humans   134     Genotoxicity Studies in Bacteria, Yeast, and Mammalian Cells In Vitro   135     In Vivo Genotoxicity Studies in Animals   136     Conclusions and Recommendations   137     References   138 12   Carcinogenic Effects of Jet-Propulsion Fuel 8   141     Summary of Studies Discussed in the 1996 National Research Council Report   141     Carcinogenicity Studies in Humans   148

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    Carcinogenicity Studies in Animals   148     Other Relevant Data   152     Conclusions and Recommendations   157     References   158 Appendix A.   Permissible Exposure Levels for Selected Military Fuel Vapors: Executive Summary (NRC 1996)   162 Appendix B.   JP-8 Final Risk Assessment: Executive Summary and Introduction(TIEHH 2001)   173 Appendix C.   Review of Tests Assessing Neurologic Function in Persons Exposed to Jet Fuels   201

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Abbreviations ACGIH American Conference of Governmental Industrial Hygienists ATSDR Agency for Toxic Substances and Disease Registry COT Committee on Toxicology CNS central nervous system DFM diesel fuel marine DNA deoxyribonucleic acid DOD U.S. Department of Defense FOB functional observation battery HDS hydrodesulfurized IARC International Agency for Research on Cancer JP-8 jet-propulsion fuel 8 LDH lactate dehydrogenase MDF middle distillate fraction MMAD mass mean aerodynamic diameter MN micronucleus NATO North Atlantic Treaty Organization NIOSH National Institute for Occupational Safety and Health NOAEL no-observed-adverse-effect level NRC National Research Council NTP National Toxicology Program

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OR odds ratio PEL permissible exposure level PB-PK model physiologically based pharmacokinetic model RD50 respiratory depression in 50% of the animals tested REL recommended exposure limit SCE sister chromatid exchange TOMM test of memory and motivation TWA time-weighted average UDS unscheduled DNA synthesis USAF U.S. Air Force

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Toxicologic Assessment of Jet-Propulsion Fuel 8

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