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 Chemical Warfare Agents
Biomedical and Psychological Effects, Medical
Countermeasures, and Emergency Response
Third Edition

Edited by
Brian J. Lukey
James A. Romano, Jr.
Harry Salem
CRC Press
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 “Under every peak is a mountain of support.”

This book is dedicated to three groups of people who were critical for its development.

Family:
Our families’ patience, support, and encouragement enabled us to bring together the many aspects of this finished product.
Florence Salem, who passed away on February 22, 2010, was Harry’s greatest inspiration and most ardent supporter.
Brian Lukey’s family (his wife Marita and three children Brianna, Tyler, and Camille).
James Romano’s family (his wife Candy [Grimes] and three grown children).
Harry Salem’s family (Jerry, Amy, Joel, Marshall, and Abby Rose) and his new wife and old friend Phyllis Salem and her
children Calla Knopman, Martin Knopman, Ronald Knopman, and Pamela Kaplan, and her grandson Jacob Knopman.

Chapter authors:
The contribution list identifies great colleagues who dedicated enormous efforts to
make this book come to fruition, and we thank them immensely.

Deceased friends:
Several of our good friends and distinguished colleagues have passed away since the last edition. They devoted their lives to the
advancement of research that focused on countermeasures to chemical warfare agents. The reputation of these great scientists
remains world renowned, and many of their accomplishments are captured in the chapters of this book. We are humbled by
their generous devotion to helping mankind best address the past, present, and future chemical warfare agent atrocities. We
are honored to have considered them as friends. We are truly proud to be standing on the shoulders of these giants:
Doug Cerosoli, Susan DeLeon, Bryan Ballantyne, Margaret Filbert, Frederick Sidell,
Bhupendra Doctor, Hendrik Benschop, Edson Albuquerque, and Steven Baskin
We especially want to recognize Dr. Satu Somani, a special friend who took the initiative to design, develop,
and edit the first edition of this book, on which the second and this third edition were developed. Although Dr.
Somani passed away on October 29, 2002, he remains a great source of inspiration to the editors.
Contents

Preface.....................................................................................................................................................................................................xi
Acknowledgments................................................................................................................................................................................. xiii
Editors.....................................................................................................................................................................................................xv
Contributors......................................................................................................................................................................................... xvii

Section I General
1. Brief History and Use of Chemical Warfare Agents in Warfare and Terrorism.....................................................................3
Harry Salem, Andrew L. Ternay, Jr., and Jeffery K. Smart

2. Chemistries of Chemical Warfare Agents.................................................................................................................................. 17

Terry J. Henderson, Ilona Petrikovics, Petr Kikilo, Andrew L. Ternay, Jr., and Harry Salem

3. Toxicokinetics of Nerve Agents....................................................................................................................................................39

Marcel J. van der Schans, Hendrik P. Benschop, and Christopher E. Whalley

4. Organization for the Prohibition of Chemical Weapons (OPCW): History, Mission, and Accomplishments....................59
Karen L. Mumy, William R. Howard, Ariel Parker, Jonathan Forman, and Expert Opinion by Gwyn Winfield

5. Chemical Weapons Holdings and Their Internationally Verified Destruction......................................................................71

John Hart and Thomas Stock

6. Syria’s Chemical Disposal Program............................................................................................................................................87

Al Mauroni and Timothy A. Blades

7. The Use of Chemical Warfare Agents during the Syrian Civil War..................................................................................... 103
Arik Eisenkraft and Avshalom Falk

8. U.S. CBRN Homeland Response and Civil Support...............................................................................................................123

Kelley J. Williams and Steven A. Schmitt

Section II Agent Effects

9. Mustard Vesicants....................................................................................................................................................................... 131
Rama Malaviya, Diane E. Heck, Robert P. Casillas, Jeffrey D. Laskin, and Debra L. Laskin

10. Health and Psychological Effects of Low-Level Exposure to Chemical Warfare Nerve Agents......................................... 145
Carl D. Smith, Kristin J. Heaton, James A. Romano, Jr., Maurice L. Sipos, and John H. McDonough

11. Inhalation Toxicology of Chemical Agents............................................................................................................................... 163

Stanley W. Hulet, Paul A. Dabisch, Robert L. Kristovich, Douglas R. Sommerville, and Robert J. Mioduszewski

12. Cyanides: Toxicology, Clinical Presentation, and Medical Management............................................................................. 181

Gary A. Rockwood, Gennady E. Platoff, Jr., and Harry Salem

13. The Structural Biology, Biochemistry, Toxicology, and Military Use of the Ricin Toxin and the Associated
Treatments and Medical Countermeasures for Ricin Exposure...........................................................................................203
Terry J. Henderson, George Emmett, Russell M. Dorsey, Charles B. Millard, Ross D. LeClaire, and Harry Salem

vii
viii Contents

14. Medical Countermeasures for Intoxication by Botulinum Neurotoxin.................................................................................227

Michael Adler, Ajay K. Singh, Nizamettin Gul, and Frank J. Lebeda

15. Incapacitating Agents and Technologies: A Review................................................................................................................245

Sidney A. Katz and Harry Salem

16. Screening Smokes: Applications, Toxicology, Clinical Considerations, and Medical Management..................................277
Lawrence A. Bickford and Harry Salem

Section III Protection

17. Personal Protective Equipment (PPE): Practical and Theoretical Considerations.............................................................303
Michael R. Jones

18. Pyridostigmine Protection from Nerve Agent Intoxication: Concept to FDA Approval.....................................................373
Michael Adler, James P. Apland, Sharad S. Deshpande, Irwin Koplovitz, and David E. Lenz

19. Hormesis: Using Preconditioning to Build Biological Shields—A Novel Approach for Enhancing Resilience to
Toxic Agents, Traumatic Illness/Injury, and Age-Related Degenerative Diseases..............................................................393
Edward J. Calabrese

Section IV Detection
20. Clinical Detection of Exposure to Chemical Warfare Agents................................................................................................401
Benedict R. Capacio, J. Richard Smith, Robert C. diTargiani, M. Ross Pennington, Richard K. Gordon,
Julian R. Haigh, John R. Barr, Brian J. Lukey, and Daniel Noort

21. Biomarkers for Organophosphate Poisoning: Physiological and Pathological Responses..................................................443

Arik Eisenkraft, Avshalom Falk, and Kevin G. McGarry, Jr.

22. Field Sensors: Military and Civilian......................................................................................................................................... 519

Kelley J. Williams and Juan Stevens

23. Application of Genomic, Proteomic, and Metabolomic Technologies to the Development of Countermeasures
against Chemical Warfare Agents.............................................................................................................................................523
Jennifer W. Sekowski and James F. Dillman, III

24. Nanomaterial-Based Sensors: Applications in Chemical Warfare Agent Detection and Identification............................ 539
Richard T. Agans, Madeleine C. DeBrosse, Richard L. Salisbury, and Saber M. Hussain

Section V Decontamination
25. Chemical Warfare Agent Decontamination from Skin...........................................................................................................549
Robert P. Chilcott, Brian J. Lukey, Harry F. Slife, Jr., Edward D. Clarkson, Charles G. Hurst,
and Ernest H. Braue, Jr.

26. Aircraft Decontamination and Mitigation............................................................................................................................... 559

William T. Greer, Jr., Angela M.G. Theys, William R. Davis, and Kenneth J. Heater

Section VI Treatment
27. Military Chemical Casualty Treatment...................................................................................................................................577
Timothy J. Byrne, Raymond Vazquez, Dan Boehm, Laukton Rimpel, and Charles G. Hurst
Contents ix

28. Pre-Hospital and Hospital Response to Toxicological Mass Casualty Events: The Israeli Approach...............................593
Arik Eisenkraft, Avshalom Falk, and Lion Poles

29. An Overview of the NIAID/NIH Chemical Medical Countermeasures Product Research and
Development Program................................................................................................................................................................ 615
David T. Yeung, Gennady E. Platoff, Jr., Jill R. Harper, and David A. Jett

30. Medical Management of Chemical Warfare Agents...............................................................................................................627

Stephen A. Pulley

31. Protein-Based Bioscavengers of Organophosphorus Nerve Agents.......................................................................................655

Moshe Goldsmith, Yacov Ashani, Tamara C. Otto, C. Linn Cadieux, and David S. Riddle

32. Oxime Research........................................................................................................................................................................... 681

Jiri Kassa

33. Brain-Penetrating Reactivators of Organophosphate-Inhibited Acetylcholinesterase........................................................697

Janice E. Chambers and Edward C. Meek

34. Nerve Agent–Induced Seizures and Status Epilepticus: Neuroprotective Strategies..........................................................703

Frederic Dorandeu, Karine Thibault, and Nina Dupuis

Section VII Predictive Modeling

35. Computational Modeling to Predict Human Toxicity.............................................................................................................723
Janet Moser, Douglas R. Sommerville, and George R. Famini

36. Lung-on-a-Chip........................................................................................................................................................................... 749

M. Tyler Nelson, Xinyu Lu, and Shuichi Takayama

37. Body-on-a-Chip for Pharmacology and Toxicology................................................................................................................ 763

Anthony Atala, Mahesh Devarasetty, Steven D. Forsythe, Russell M. Dorsey, Harry Salem, Thomas D. Shupe,
Aleksander Skardal, and Shay Soker

38. Animal Models.............................................................................................................................................................................773

Wenli Li and Juergen Pauluhn

39. Real-Time Physiological Data Collection and Analysis in Animal Inhalation Models:
Predictive and Diagnostic Implications.................................................................................................................................... 791
Benjamin Wong, Bryan J. McCranor, Rebecca Lewandowski, and Alfred M. Sciuto

40. Contextual Factors Influencing CBRN Leadership Decision Making..................................................................................803

Terry L. Oroszi

Index.....................................................................................................................................................................................................809
Preface

The first edition of this book, published in early 2001, focused on or terrorist group. Therefore, the second edition included epide-
chemical warfare agent toxicity at low levels. At that time, vari- miological or clinical studies of exposed or potentially exposed
ous review committees suggested that there were data gaps in populations, new treatment concepts and products, improved
our information about the low-level toxicity of chemical warfare organization of the national response apparatus in the United
agents. Epidemiological studies indicated then that more than States to address the potential for chemical warfare agent terror-
120,000 Gulf War veterans were suffering from many unex- ism, and improved diagnostic tests that enabled rapid diagnosis
plained illnesses and were seeking medical care. Among the and treatment.
putative explanations for these illnesses were exposure to nerve Many additional chemical warfare agent–related, worldwide
agents or pretreatment drugs. Many U.S. and British troops were events have occurred since 2007, which further highlight the
given pyridostigmine bromide as a pretreatment drug during the risk of chemical warfare agent use, the greatest being chemi-
2 weeks of the air and ground war to protect against possible cal warfare agent–related events during the Syrian uprising. It
exposure to nerve gas. One of the notable nerve gases suspected is important to recognize that advances in biotechnology, nano-
to be present during this first Gulf War was sarin. During this technology, genetic engineering, neurobiology, and computer
period, military personnel were under physical stress; some sciences, among others, may not only assist in the proliferation of
have argued for evidence of exposure to low levels of sarin. traditional chemical warfare agents but also stimulate the emer-
Certain factors such as stress, surroundings, and other chemical gence of nontraditional agents. Advances have also occurred in
agents can interact with the toxicity of chemical warfare agents. the delivery systems of these agents. While the use of chemi-
Consequently, the first book addressed many of those issues at cal warfare agents in terrorist activities appears to have been
that time. limited, this may not accurately reflect the potential for their
The second edition, published in 2007, took a much broader future use. Since the second edition, the chemical warfare agent
look at chemical warfare agent–related work/issues. Many community has worked hard to advance research for protection
changes had occurred in this area since that first edition, includ- and treatment, and developed/improved response approaches
ing the September 11 attacks and the Second Gulf War, which for individuals and definitive care. Consequently, in addition to
have created a sense of urgency to this field. Heightened terror- updating previous chapters, we added several new chapters that
ist threats underscored the need to readdress these issues. We address the Syrian War, chemical destruction, the Organisation
recognized that mustard gas, defoliants, and nerve gases were for the Prohibition of Chemical Weapons, biomarkers for chemi-
used in localized wars in the 1960s, 1970s, and 1980s. Chemical cal warfare agent exposure, field sensors, aircraft decontamina-
warfare agents, primarily categorized as lethal or incapacitating tion, lung/human on a chip, chemical warfare response decision
agents, possess the attractive quality of being easy and inexpen- making, and other research advancements. The chapters are
sive to synthesize on a large scale. A reasonable chemical-indus- written by world experts in their field, and we are very grateful
trial setup could be diverted to produce chemical warfare agents. for their contributions.
The agents are particularly terrifying because their toxic effects
are indiscriminate and thus affect not only military personnel Brian J. Lukey
but also the civilian population as a whole. The agents provide James A. Romano, Jr.
a substantial psychological edge to an otherwise weak military Harry Salem

xi
Acknowledgments

The editors wish to thank Lt. Correy Vigil and Donna M. Hoffman for helping with the preparation of this book, and Janet Stein and
the Edgewood Chemical Biological Center Library for all their help with obtaining key documents.

xiii
Editors

Col. (retired) Brian Lukey and his coeditor, Col. (retired) commander of the U.S. Army Medical Research and Materiel
James Romano, were previously commanders of the U.S. Army Command, Fort Detrick, Maryland, his position at retirement
Medical Research Institute of Chemical Defense (Aberdeen from the U.S. Army. He then joined Science Applications
Proving Ground, Maryland). The Institute is the Department of International Corporation as a senior principal life scientist in
Defense’s lead laboratory for medical chemical defense research. the fall of 2006.
Its mission is to discover and develop medical countermeasures In his research, he focused on the neurotoxicological effects of
to chemical warfare agents, to train and educate personnel in the chemical warfare agents and medical countermeasures to these
medical management of chemical casualties, and to provide sub- agents. Dr. Romano is the author of more than 100 papers in the
ject matter expertise in developing defense and national policy, areas of medical chemical defense and two successful textbooks:
and proper crisis management response. Chemical Warfare Agents: Toxicity at Low Levels (CRC Press,
2001) and Pharmacological Perspectives of Toxic Chemicals
Col (retired) Brian J. Lukey, PhD, received his bachelor of sci- and Their Antidotes (Springer-Verlag, 2004). He currently serves
ence in biology from Northern Kentucky University in 1980. He on the Homeland Security Subcommittee to the Environmental
earned a master’s degree in pharmacology in 1983 and a PhD in Protection Agency’s Board of Scientific Counselors.
toxicology in 1985 from the University of Louisville. In 1990, he Dr. Romano is married to Candy (Grimes) Romano, and
earned his master of science administration at Central Michigan they have three grown children. They reside in Middletown,
University. He was certified as a diplomate in general toxicology Maryland, which he describes as a far cry from his beloved New
by the American Board of Toxicology in 1993. York City–Jersey City roots.
Dr. Lukey is currently a senior civilian toxicologist for the U.S.
Air Force, Wright-Patterson Air Force Base. Due to the nature of Harry Salem, PhD, is chief scientist for Life Sciences at the
a military career, he has had numerous assignments in a variety U.S. Army Edgewood Chemical Biological Center, Aberdeen
of areas of medical research. These include managing programs Proving Ground, Maryland. Edgewood Chemical Biological
directed toward medical chemical warfare defense, forensic Center is a U.S. Army Research, Development, and Engineering
toxicology for drugs of abuse, occupational and environmental Command Laboratory and is the Army’s principal research and
health analytical procedures, and military operational medicine. development center for chemical and biological defense tech-
He has authored and coauthored more than 45 manuscripts and nology, engineering, and field operations. Edgewood Chemical
technical reports, and is the codeveloper of one patent. Biological Center has achieved major technological advances
Dr. Lukey is a highly decorated military officer, having for the warfighter and for our national defense, with a long and
been awarded the prestigious Medical Service Corps Award distinguished history of providing the Armed Forces with qual-
of Excellence, two Legion of Merits, and multiple Meritorious ity systems and outstanding customer service. Dr. Salem was
Service Medals, Army Commendation Medals, and Army previously the chief of the Toxicology Division and also the act-
Achievement Medals. He is a member of the Order of Military ing senior team leader for Biosciences at Edgewood. Prior to
Medical Merit and wears the Expert Field Medical Badge, that, he was employed in positions of increasing complexity and
Airborne Badge, Air Assault Badge, and German Troop Duty responsibility by the pharmaceutical and contract laboratory
Proficiency Badge. He and his wife, Marita, have three children, industries. His research interests and experience include inhala-
Brianna, Tyler, and Camille. They reside in Ohio and enjoy tion and general pharmacology and toxicology, and in vitro and
camping, fishing, bluegrass music, and family time. molecular toxicology.
Dr. Salem received a bachelor of arts degree from the
James A. Romano, Jr., PhD, was born in Jersey City, New University of Western Ontario in London, Ontario, Canada, a
Jersey. He received a bachelor of arts degree in psychology from bachelor of science in pharmacy from the University of Michigan
the College of the Holy Cross in 1966 and a PhD in experimental in Ann Arbor, and master’s and doctorate degrees in pharmacol-
psychology from Fordham University in 1975. He was certified ogy from the University of Toronto, Canada. He was certified as a
as a diplomate in general toxicology by the American Board of diplomate in general toxicology by the Academy of Toxicological
Toxicology in 1994. Sciences in 1985.
Dr. Romano was an instructor of psychology at Manhattan He has served in adjunct positions at the University of
College, Bronx, New York, from 1970 to 1975. Awarded tenure Pennsylvania, Temple University, Drexel University, and the
in 1976, from 1976 until 1978, he was an assistant professor of University of Maryland, and continues to be active as a visit-
psychology at Manhattan College. He entered the U.S. Army in ing professor at Rutgers University. He has been on the edi-
1978, and progressed as a scientist and manager into positions torial boards of several professional journals and has served
of increasingly greater responsibility to include commander, as editor-in-chief of the Journal of Applied Toxicology for
U.S. Army Medical Research Institute of Chemical Defense over 20 years. He has published 18 books, including three
(2000–2003), Aberdeen Proving Ground, Maryland, and deputy volumes of the International Encyclopedia of Pharmacology

xv
xvi Editors

and Therapeutics, which he coauthored, as well as over was awarded the Decoration for Meritorious Civilian Service
100 papers in scientific journals and chapters in books. Dr. in 1989 for his contributions to the field of toxicology.
Salem is an active member of many professional societies In 2001, Dr. Salem was awarded the Society of Toxicology
and has been elected a Fellow of the New York Academy of Congressional Science Fellowship, and he served as a science
Sciences, the American College of Clinical Pharmacology, advisor to Congressman Jim Greenwood. He became a Fellow
the American College of Toxicology, and the Academy of of the Royal Society of Chemistry in 2015, and was president of
Toxicological Sciences, where he served on the Professional the Stem Cell Specialty Section of the Society of Toxicology in
Standards Board and Board of Directors. He served as the 2017–2018.
chair of the Technical Committee of the Inhalation and He and his wife Phyllis reside in Elkins Park, Pennsylvania,
Respiratory Specialty Section of the Society of Toxicology close to his son Jerry and his wife Amy, his three grandchil-
and the Council of the International Society of Regulatory dren Joel, Marshall, and Abby Rose; his wife’s children Colla,
Toxicology and Pharmacology, and on the Advisory Board of Martin, Ron Knopman, and Pamela Kaplan, and her grandson
the Rocky Mountain Center for Homeland Defense. Dr. Salem Jacob Knopman.