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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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