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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 ACADEM IES PRESS W ashington, D.C. ww w.nap.edu

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

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

S U B CO M M IT TE E ON J E T -P R O PU L SIO N F UEL 8 M E L VIN E. A N D E R S E N (Chair), Colorado State University, Fort Collins, Colorado; curre ntly at CIIT-C enters fo r Health Research , Resea rch T riangle P ark, N orth Carolina J ANET M . B E N S O N , Lovelace Respiratory Research Institute, Albuquerque, New Mexico S COTT W. B U R C H I E L, University of New Mexico, Albuquerque R A K ES H D IXIT , Merck Research L aboratory, W est Point, P ennsylva nia R OBERT G. F ELDM AN , Boston University School of Medicine, Boston, Ma ssachu setts S A M K A C E W , University of Ottawa, Ottawa, Ontario, Canada N ANCY I. K E R K V L IE T , Oregon State University, C orvallis M ARTHA S. S A N D Y , California Environmental Protection Agency, Oakland W I LL IA M M. V A LE N TIN E , Vanderbilt University Medical Center, Nashville, Tennessee Staff A BIGAIL E. M ITCHELL , Project Director N O R M AN G ROSSBLATT , Senior Editor K ELLY C L A R K , Assistant Editor M IRSADA K ARA LIC -L ON CAR EV IC , Research Assistant J ESSICA B R O C K , Senior Project Assistant v

C O M M IT TE E ON T O X I C O LO G Y B AILUS W A L K E R , J R . (Ch air), Howard University Medical Center and American Public Health Association, Washington, D.C. M E L VIN E. A N D E R S E N , Colorado State University, Fort Collins E D W A R D C. B I SH O P , Parsons Co rporation, Fairfax, Virginia G ARY P. C A R L SO N , Purdue University, West Lafayette, Indiana J A N I C E E. C H A M B E R S , Mississippi State U niversity, M ississippi State L E O N A RD C HIAZZE , J R ., Georgetown University, Washington, D.C. J U D IT H A. G RAHAM , Am erican C hem istry C oun cil, Arlington, Virginia S IDNEY G R E E N , Howard University, Washington, D.C. M ERYL K A R O L, Un iversity of Pittsburgh, Pittsburgh, Pennsylva nia S T E PH E N U. L E S T E R , Center for Health Environment and Justice, Falls Church, Virginia D A V ID H . M O O R E , Battelle Memorial Institute, Bel Air, Maryland C A LV IN C. W ILLHITE , State of California, Berkeley Staff K U L B I R S. B A K SH I , Program Director S U SA N N. J. M A R T E L , Senior Program Officer A BIGAIL E. M ITCHELL , Program Officer K ELLY C L A R K , Assistant Editor A IDA N E E L , Senior Project Assistant T AMARA D A W S O N , Project Assistant vi

B O A RD ON E NVIRONMEN TAL S T U D IE S AN D T O X I C O LO G Y 1 G O R DO N O R IA N S (Cha ir), University of Washin gton, Seattle J O H N D OULL (Vice Chair), Unive rsity of Kansas M edical Center, Kan sas City D A V ID A L L E N , University of Texas, A ustin T HOM AS B U R K E , Johns Hopkins University, Baltimore, Maryland J U D IT H C. C H O W , Desert Research Institute, Reno, Nevada C H R I ST O P H E R B. F IELD , Carnegie Institute of W ashin gton, Stanford , California W I LL IA M H . G LAZE , Un iversity of No rth C arolina, C hapel Hill S HE RRI W. G OODM AN , Center for N aval Analyses, Alexandria, Virginia D ANIEL S. G R E E N B A U M , Health Effects Institute, Cambridge, Massachu setts R O G E N E H E N D E R S O N , Lovelace Respiratory Research Institute, Albuquerque, New M exico C AROL H E N R Y , Am erican C hem istry C oun cil, Arlington, Virginia R OBERT H UGGETT , Michigan State University, East Lansing B ARRY L. J O H N S O N Em ory University, Atlanta, Georgia J AMES H . J O H N S O N , Howard University, Washington, D.C. J AMES A. M AC M A H O N , Utah State University, Logan P A T R IC K V. O’B R I E N , Chevron R esea rch and Technology, Richm ond , California D OROTH Y E. P A T TO N , International Life Sciences Institute, Washington, D.C. A N N P O W E R S , Pace U niversity School of La w, Wh ite Plains, New York L O U I SE M . R YAN , Harvard University, Bo ston, M assachusetts J O N AT H AN M . S A M E T , Johns Hopkins University, Baltimore, Maryland K I R K S MITH , University of California, Berkeley L ISA S P E E R , Natura l Resources Defen se Council, New Y ork, New York G. D A V ID T ILMAN , University of Minnesota, St. Paul C HRIS G. W HIPPLE , Environ Incorporated, Em eryville, C alifornia L A U RE N A. Z EISE , California Environmental Protection Agency, Oakland Senior Staff J AMES J. R EISA , Director D A V ID J. P O L I C AN S K Y , Associate Director and Senior Program Director for Applied Ecology R A Y MO N D A. W A S SE L , Senior Program Director for Environmental Sciences and Engineering K U L B I R B A K SH I , Program D irector for the Comm ittee on Toxicology R OBERTA M. W E D G E , Program Director for Risk Analysis K. J O H N H O L M E S , Senior Staff Officer S U SA N N.J. M A R T E L , Senior Staff Officer S U Z A N N E V A N D R U N I C K , Senior Staff Officer R U T H E. C ROSSGROVE , Managing Editor 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Tox icology. vii

O T H E R R E P O RT S O F TH E B O A RD ON E NVIRONMEN TAL S T U D IE S AN D T O X I C O LO G Y 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 N ational Research Coun cil’s Comm ittee 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 Environm ental Mon itoring and Assessm ent 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) Hum an 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 Acad emies Press (800) 624-6242 or (202) 334-3313 www.nap.edu viii

OTHER REPORTS OF THE C O M M IT TE E ON T O X I C O LO G Y Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Proced ures for D eveloping Acute Exp osure G uideline 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) Rev iew of the US N avy’s H um an H ealth Risk Assessme nt of the N aval A ir Facility at Atsugi, Japan (2000) Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S. Navy Environmental Health C enter’s Health-H azard Assessment Process (2000) Review of the U.S. Navy's Exposu re Standard for Man ufactured Vitreous Fibers (2000) Re-E valuation of D rinking-W ater G uidelines for D iisopropyl Methylph ospho nate (2000) Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC- 236fa, HFC-23, and HFC-404a (2000) Review of the U.S. Arm y’s H ealth Risk Assessm ents for O ral Exposure to Six Chemical-Warfare Agents (1999) Toxicity of M ilitary Sm okes and O bscurants, Vo lume 1(1997), Vo lume 2 (1999), Volume 3 (1999) Assessme nt of Exposu re-Respon se Fu nctions fo r Roc ket-Emission Toxicants (1998) Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCF C-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) ix

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 air- craft refueling and maintenance. To protect the health of its personnel, DOD recommended an interim permissible exposure level (PEL) of 350 mg/m 3. The Air Force requested that the National Research Council (NRC) re- view 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/m 3 for JP-8. The NR C assigned this project to the Comm ittee 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 back- ground information to the subcomm ittee: Brian Blazicko, Roger Gibson, John Hinz, David Mattie, James M cDougal, 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 (Georgetow n University, W ashington, D.C.), Steve Ullrich (M.D. Anderson Cancer Center, Houston, Texas), Russell White (Chevron Research xi

xii Preface and Technology Company, Richmond, California), and M ark Witten (Univer- sity of Arizona, Tucson, Arizona) for providing background information to the subcomm ittee. 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 Com mittee. The purpose of this independent review is to provide candid, critical com ments 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 comm ents and draft manu- script remain confidential to protect the integrity of the deliberative process. We wish to thank the fo llowing for their review of this report: Edward Bishop, Parsons Engineering Sciences, Inc., Fairfax, Virginia; Judith Graham, American Chemistry C ouncil, Arlington, Virginia; Karl Kelsey, Harvard School of Public Health, Boston, Massachusetts; C arole Kim mel, U.S. Envi- ronmental Protection Agency, Washington, D.C.; Kannan K rishnan, Univer- sity of Montreal, Quebec, Canada; David Lawrence, New York State Depart- ment of Health, Albany, New York; Judith MacGregor, Toxicology Consulting Services, Arnold, M aryland; Ceinwen Schreiner, C & C Consulting in Toxicol- ogy, Meadowbrook, Pennsylvania; and Bailus Walker, Jr., How ard University Medical Center, Washington, D.C. Although the reviewers provided many constructive comments and sug- gestions, they were not asked to endorse the report’s conclusions or recom- mend ations, 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 NR C to ensure that an independent exam i- nation of this report was conducted in accordance with institutional proce- dures 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 subcom mittee acknowledges Abigail Mitchell, project director, and Kulbir Bakshi, program director of the Committee on Toxicology. Other staff mem bers 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 ed itor.

Preface xiii 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

Contents Abbreviations xix Summ ary 1 1 Introduction 9 Sum mary of the 1996 National Research Council Report on Military Fuels 10 The Charge to the Subcommittee 11 The Subcom mittee’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 Stud ies 24 Conclusions and Recomm endations 26 References 27 xv

xvi Contents 3 Toxicokinetics and Toxicodynamics of Jet-Propulsion Fuel 8 29 Benzene 30 Alkylbenzenes 30 C9-C13 Aliphatic and A romatic Hydrocarbons 31 Physiologically Based Pharm acokinetic M odels of B enzene, Nonane, and C9-C12 or C9-C17 Aliphatic Hydrocarbons 32 Toxicokinetics-Related Interactions Am ong Hydrocarbon Fuel Com ponents 35 Toxicokinetic-Related Individual Susceptibility Factors 36 References 37 4 Effects of Jet-Propulsion Fuel 8 on the R espiratory Tract 41 Effects of Exposure to Jet Fuels and Kerosene in H umans 41 Effects of Exposure to Jet Fuels and Kerosene in Experimental Animals 45 Effects of In Vitro Exposure to JP-8 52 Conclusions and Recomm endations 53 References 54 5 Effects of Jet-Propulsion Fuel 8 on the Nervous System 56 Sum mary of Studies Discussed in the 1996 National Research Council Report 56 Effects of Exposure to JP-8 in Hum ans 57 Effects of Exposure to JP-8 in Experimental Anim als 61 Conclusions and Recomm endations 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 Recomm endations 82 References 83 7 Effects of Jet-Propulsion Fuel 8 on the Liver 86 Sum mary of Studies Discussed in the 1996 National Research Council Report 86 Effects of Exposure to JP-8 in Hum ans 88 Effects of Exposure to JP-8 in Experimental Animals 91 Effects of In Vitro Exposure to JP-8 97

Contents xvii Conclusions and Recomm endations 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 Hum ans 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 D evelopment 113 Effects of Exposure to JP-8 in Hum ans 113 Effects of Exposure to JP-8 in E xperimental Anim als 114 Conclusions and Recomm endations 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 Anim als 127 Conclusions and Recomm endations 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 Mamm alian Cells In Vitro 135 In Vivo G enotoxicity Studies in Animals 136 Conclusions and Recomm endations 137 References 138 12 Carcinogenic Effects of Jet-Propulsion Fuel 8 141 Sum mary of Studies Discussed in the 1996 National Research Council Report 141 Carcinogenicity Studies in Humans 148

xviii Contents Carcinogenicity Studies in Anim als 148 Other Relevant Data 152 Conclusions and Recomm endations 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 Ap pendix C. Review of Tests Assessing Neurologic Function in Persons Exposed to Jet Fuels 201

Abbreviations ACGIH Am erican Conference of Governmental Industrial Hygienists ATSDR Agency for Toxic Substances and D isease Registry COT Comm ittee 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 xix

xx Abbreviations OR odds ratio PEL permissible exposure level PB-PK m odel physiologically based pharmacokinetic model RD 50 respiratory depression in 50% of the animals tested REL recomm ended exposure limit SCE sister chromatid exchange TOMM test of memory and motivation TWA time-weighted average UDS unscheduled D NA synthesis USAF U.S. Air Force

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This report provides a critical review of toxicologic, epidemiologic, and other relevant data on jet-propulsion fuel 8, a type of fuel in wide use by the U.S. Department of Defense (DOD), and an evaluation of the scientific basis of DOD's interim permissible exposure level of 350 mg/m3

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