i

MEDICAL ASPECTS OF CHEMICAL AND BIOLOGICAL WARFARE
ii

The Coat of Arms

1818

Medical Department of the Army

A 1976 etching by Vassil Ekimov of an

original color print that appeared in

The Military Surgeon, Vol XLI, No 2, 1917
iii

The first line of medical defense in wartime is the combat

medic. Although in ancient times medics carried the caduceus

into battle to signify the neutral, humanitarian nature of

their tasks, they have never been immune to the perils of

war. They have made the highest sacrifices to save the lives

of others, and their dedication to the wounded soldier is

the foundation of military medical care.
iv

Textbook of Military Medicine

Published by the

Office of The Surgeon General

Department of the Army, United States of America

Editor in Chief

Brigadier General Russ Zajtchuk, MC, U.S. Army

Director, Borden Institute

Commanding General

U.S. Army Medical Research and Materiel Command

Professor of Surgery

F. Edward Hébert School of Medicine

Uniformed Services University of the Health Sciences

Bethesda, Maryland

Managing Editor

Ronald F. Bellamy, M.D.

Colonel, MC, U.S. Army (Retired)

Borden Institute

Associate Professor of Military Medicine

Associate Professor of Surgery

F. Edward Hébert School of Medicine

Uniformed Services University of the Health Sciences

Bethesda, Maryland
v

The TMM Series

Part I. Warfare, Weaponry, and the Casualty

Medical Consequences of Nuclear Warfare

(1989)

Conventional Warfare: Ballistic, Blast, and Burn

Injuries (1991)

Military Psychiatry: Preparing in Peace for War

(1994)

War Psychiatry (1995)

Medical Aspects of Chemical and Biological

Warfare (1997)

Military Medical Ethics

Part II. Principles of Medical Command and Support

Military Medicine in Peace and War

Part III. Disease and the Environment

Occupational Health: The Soldier and the

Industrial Base (1993)

Military Dermatology (1994)

Military Preventive Medicine: Mobilization and

Deployment

Medical Aspects of Deployment to Harsh

Environments

Part IV. Surgical Combat Casualty Care

Anesthesia and Perioperative Care of the

Combat Casualty (1995)

Rehabilitation of the Injured Soldier

Military Surgery
vi

. . . .

Gas! GAS! Quick, boys!—An ecstasy of fumbling,

Fitting the clumsy helmets just in time;

But someone still was yelling out and stumbling

And flound’ring like a man in fire or lime . . .

Dim, through the misty panes and thick green light,

As under a green sea, I saw him drowning.

In all my dreams, before my helpless sight,

He plunges at me, guttering, choking, drowning.1

. . . .

—Wilfred Owen

The poetry, excerpted from Dulce et Decorum Est, was written by Lieutenant Wilfred Owen of the Royal

Army, who was killed in action in France on 4 November 1918.

“Gassed,” the frontispiece painting, shows the horror of chemical warfare in World War I as perceived by

the artist, Gilbert Rogers.2 As Keegan and Darracott observed, “Rogers was an officer of the Royal Army

Medical Corps commissioned to record medical work during the First World War. The subtitle to this

painting, “In Arduis Fidelis” (Faithful in Hardships), suggests the subject is a stretcher-bearer who has

succumbed to gas while transporting wounded.”3

1. Excerpted from Wilfred Owen. Dulce et decorum est. In: The Collected Poems of Wilfred Owen. Copyright © 1963 by Chatto &

Windus, Ltd. Reprinted by permission of New Directions Publishing: New York, NY.

2. Painting: Printed with permission from Imperial War Museum, London, England.

3. Keegan J, Darracott J. The Nature of War. New York, NY: Holt, Rinehart and Winston; 1981: 222.
vii

MEDICAL ASPECTS OF CHEMICAL

AND

 BIOLOGICAL WARFARE

Specialty Editors

FREDERICK R. SIDELL, M.D.

Chemical Casualty Consultant

ERNEST T. TAKAFUJI, M.D., M.P.H.

Colonel, Medical Corps, U.S. Army

DAVID R. FRANZ, D.V.M, PH.D.

Colonel, Veterinary Corps, U.S. Army

Borden Institute

Walter Reed Army Medical Center

Washington, D. C.

Office of The Surgeon General

United States Army

Falls Church, Virginia

United States Army Medical Department Center and School

Fort Sam Houston, Texas

United States Army Medical Research and Materiel Command

Fort Detrick, Frederick, Maryland

Uniformed Services University of the Health Sciences

Bethesda, Maryland

1997
viii

Editorial Staff: Lorraine B. Davis

Senior Editor

Colleen Mathews Quick

Associate Editor/Writer

This volume was prepared for military medical educational use. The focus of the information

is to foster discussion that may form the basis of doctrine and policy. The volume does not

constitute official policy of the United States Department of Defense.

Dosage Selection:

The authors and publisher have made every effort to ensure the accuracy of dosages cited herein.

However, it is the responsibility of every practitioner to consult appropriate information sources

to ascertain correct dosages for each clinical situation, especially for new or unfamiliar drugs and

procedures. The authors, editors, publisher, and the Department of Defense cannot be held

responsible for any errors found in this book.

Use of Trade or Brand Names:

Use of trade or brand names in this publication is for illustrative purposes only and does not

imply endorsement by the Department of Defense.

Neutral Language:

Unless this publication states otherwise, masculine nouns and pronouns do not refer exclusively

to men.

CERTAIN PARTS OF THIS PUBLICATION PERTAIN TO COPYRIGHT RESTRICTIONS.

ALL RIGHTS RESERVED.

NO COPYRIGHTED PARTS OF THIS PUBLICATION MAY BE REPRODUCED OR

TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL

(INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND

RETRIEVAL SYSTEM), WITHOUT PERMISSION IN WRITING FROM THE PUBLISHER OR

COPYRIGHT OWNER

Published by the Office of The Surgeon General at TMM Publications

Borden Institute

Walter Reed Army Medical Center

Washington, DC 20307-5001

Library of Congress Cataloging–in–Publication Data

Medical aspects of chemical and biological warfare / specialty

editors, Frederick R. Sidell, Ernest T. Takafuji, David R. Franz.

 p. cm. — (TMM series. Part I, Warfare, weaponry, and the

casualty)

Includes bibliographical references and index.

1. Medicine, Military. 2. Chemical warfare. 3. Biological

warfare. I. Sidell, Frederick R. II. Takafuji, Ernest T.

III. Franz, David R., D.V.M. IV. Series: Textbook of military

medicine. Part 1, Warfare, weaponry, and the casualty ; [v. 3].

[DNLM: 1. Chemical Warfare. 2. Biological Warfare. 3. Military

Medicine—methods. UH 390 T355 pt. 1 1997 v. 3]

RC971.T48 1989 vol 3

616.9’8023 s—dc21

[616.9’8023]

DNLM/DLC

for Library of Congress 97-22242

CIP

PRINTED IN THE UNITED STATES OF AMERICA

07, 06, 05, 04, 03, 02, 01, 00, 99, 98 5 4 3 2 1
ix

Contents

Foreword by The Surgeon General xi

Preface xiii

Patient Flow in a Theater of Operations xv

Medical Aftermath of the Persian Gulf War xvi

1. Overview: Defense Against the Effects of Chemical and Biological Warfare Agents 1

2. History of Chemical and Biological Warfare: An American Perspective 9

3. Historical Aspects of Medical Defense Against Chemical Warfare 87

4. The Chemical Warfare Threat and the Military Healthcare Provider 111

5. Nerve Agents 129

6. Pretreatment for Nerve Agent Exposure 181

7. Vesicants 197

8. Long-Term Health Effects of Nerve Agents and Mustard 229

9. Toxic Inhalational Injury 247

10. Cyanide Poisoning 271

11. Incapacitating Agents 287

12. Riot Control Agents 307

13. Field Management of Chemical Casualties 325

14. Triage of Chemical Casualties 337

15. Decontamination 351

16. Chemical Defense Equipment 361

17. Healthcare and the Chemical Surety Mission 397

18. Historical Overview of Biological Warfare 415

19. The U.S. Biological Warfare and Biological Defense Programs 425

20. Use of Biological Weapons 437

21. The Biological Warfare Threat 451

22. Anthrax 467

23. Plague 479
x

24. Tularemia 503

25. Brucellosis 513

26. Q Fever 523

27. Smallpox 539

28. Viral Encephalitides 561

29. Viral Hemorrhagic Fevers 591

30. Defense Against Toxin Weapons 603

31. Staphylococcal Enterotoxin B and Related Pyrogenic Toxins 621

32. Ricin Toxin 631

33. Botulinum Toxins 643

34. Trichothecene Mycotoxins 655

35. Medical Challenges in Chemical and Biological Defense for the 21st Century 677

Acronyms and Abbreviations 687

Index 691

To access USAMRIID’s contingency response and operational medicine and scientific consultation

capabilities, telephone 1-888-USA-RIID.

Interested readers can also find up-to-date information on the medical aspects of chemical and

biological warfare at the following internet locations:

The Medical NBC Information Server http://www.nbc-med.org

Medical Research and Materiel Command http://mrmc-www.army.mil

Medical Chemical Defense http://mrmc-www.army.mil/chemdef.html

Medical Biological Defense http://mrmc-www.army.mil/biodef.html

Medical Research Institute of Chemical Defense http://chemdef.apgea.army.mil

Medical Research Institute of Infectious Diseases http://www.usamriid.army.mil

(numeric) http://140.139.42.105
xi

Foreword

The thought of chemical and biological warfare terrifies us. What is it in the

human psyche that makes being attacked with conventional weapons—that kill

and maim—more acceptable than being attacked with molecules that alter the

body chemistry or with organisms that cause disease? For some, the wearing of

chemical protective clothing seems to exemplify our fear of an unknown agent

that we cannot see, do not understand, and think must be immoral.

World events have conspired to increase the threat of the use of chemical and

biological weapons. The end of the Cold War brought not only the hoped-for

change of swords into plowshares but also political and economic turbulence in

the former Soviet Union, unemployed and disenchanted weapons specialists

and scientists, the rise of religious fundamentalism in southwest Asia, statesponsored terrorism, and blurring of the lines between terrorism and traditional warfare.

In addition, the nature of war is changing. We no longer expect a war to last

years, as World War II did, but rather days, as we saw with the Persian Gulf

War. Worse, the weapons of war have also changed. Many countries do or could

possess chemical and biological agents—bypassing the tremendous financial

outlay required to acquire conventional weapons.

Until this decade, our military forces had not faced chemical and biological

weapons since World War I, and the prevailing attitude has been “out of sight,

out of mind.” The Persian Gulf War changed all that. Just the threat that such

weapons would be used was itself an effective weapon, as it required us to

expend tremendous logistical resources to supply our troops in the desert. Now

we know that we must master all relevant aspects of defense against chemical

and biological warfare. The Biological Weapons Convention, ratified in 1975,

did not slow the massive Soviet program, which continued until early 1992, nor

did it prevent the buildup in Iraq between 1985 and 1990. At this time, experts

are severely questioning whether verification of compliance with the treaty can

be certain. Similar concerns delayed ratification of the Chemical Weapons

Convention by the U.S. Senate; nevertheless, the senate ratified the treaty on 24

April 1997.

A primary value of the Textbook of Military Medicine series is to preserve the

lessons of past wars and, by so doing, demonstrate how current doctrine is built

on knowledge that was gained at so high a cost. Medical officers should read

this volume, Medical Aspects of Chemical and Biological Warfare, and learn its

lessons well. Civilians expect that we in the military will know how to manage

chemical and biological casualties. Indeed, if we do not, then who will? The

nation expects us to be prepared to defend against all attacks and will be

unforgiving of any incapacity on our part.

Lieutenant General Ronald R. Blanck

The Surgeon General

U.S. Army

May 1997

Washington, D. C.
xiii

Preface

Until recently, we in the United States have not given much thought to the

specter of chemical and biological warfare. Our fathers and grandfathers who

fought in World War I are almost all gone now, and the poet’s image of gassed

soldiers fumbling for their helmets has been considered merely a historical

footnote—if it is remembered at all. But forgetting is a luxury we can no longer

afford. In 1917, the Army War College stated:

The employment of poisonous gases as a means of offensive warfare has made it

imperative that medical officers should have some knowledge of the action of the

various gases that are likely to be met with and of rational lines of treatment which

may be adopted in cases of gas poisoning.1(p5)

Nothing has changed except the increased availability of chemical and biological weapons; now more than ever we must be able to both defend against attack

and manage chemical and biological casualties.

The good news is that the development of passive countermeasures for

chemical and biological defense (pretreatments, therapies, timely detectors,

effective protective equipment) has significantly reduced the threat to our

military forces. Although the biological defense countermeasures program is

not yet as advanced as its chemical counterpart, new developments in biotechnology have allowed us to take tremendous strides forward. In the meantime,

we can educate our healthcare providers now, at minimal cost and with great

potential benefit. One of the reasons that chemical and biological weapons are

considered so dangerous is that we medical officers, in our daily clinical

practice, hardly ever see patients whose conditions have any similarity to

casualties of chemical and some of the more exotic biological agents.

This textbook focuses on the management of casualties. Its publication may

be even more timely than we had expected, especially considering the increased

threat of terrorism—both foreign and domestic. Terrorist attacks at home and

abroad have heightened the interest of civilian healthcare providers and firstresponders, and of other governmental agencies such as the Federal Emergency

Management Agency and the Public Health Service that would be required to

respond in case of an attack on our own soil. These nonmilitary healthcare

providers will also find this textbook to be extremely useful.

The scientists who organized and are responsible for this textbook are

recognized worldwide as the foremost experts in the medical aspects of chemical and biological warfare. Their overriding goal is this: to produce a force that

understands the threats of chemical and biological weapons and how to respond to them, and, by understanding the threats, sustains fewer casualties.

Brigadier General Russ Zajtchuk

Medical Corps, U.S. Army

May 1997

Washington, D. C.

1. Army War College. Memorandum on Gas Poisoning in Warfare, With Notes on its Pathology and

Treatment. Washington, DC: Government Printing Office; 1917: 5.
xiv

The current medical system to support the U.S. Army at war is a

continuum from the forward line of troops through the continental United States; it serves as a primary source of trained replacements during the early stages of a major conflict. The system is

designed to optimize the return to duty of the maximum number

of trained combat soldiers at the lowest possible echelon. Farforward stabilization helps to maintain the physiology of injured

soldiers who are unlikely to return to duty and allows for their

rapid evacuation from the battlefield without needless sacrifice

of life or function.
xv

Medical Force 2000 (MF2K)

PATIENT FLOW IN A THEATER OF OPERATIONS

E: Echelon

EAC: Echelon Above Corps

FST: Forward Surgical Team

MASF: Mobile Aeromedical Staging Facility, USAF

Med Co: Medical Company

RTD: Return to Duty

ASF: Aeromedical Staging Facility, USAF

ASMB: Area Support Medical Battalion

ASMC: Area Support Medical Company

BAS: Battalion Aid Station

CM: Combat Medic

CONUS: Continental United States

CZ: Combat Zone

 BRIGADE

SUPPORT

AREA

CM

BAS

Med Co

MASF

Hospital

Med Co

ASMC/ASMB

ASMC/ASMB

xx

xxx

x

RTD

RTD

RTD

RTD

RTD

ECHELON ABOVE 

CORPS

 CORPS

SUPPORT

AREA

 DIVISION

SUPPORT

AREA

CZ

1st E

2nd E

3rd E

 CONUS 

FST

 UNIT

SUPPORT

AREA

ASF

Hospital

EAC

4th E
xvi

Medical Aftermath of the Persian Gulf War

The editors of the Textbook of Military Medicine are mindful that some veterans of

the Persian Gulf War (1990–1991) face continuing health problems. Although

readers might have hoped to find a discussion in this textbook devoted to the

illness known as Gulf War syndrome, the medical aftermath of that war is

incompletely understood. A formal academic treatment now would not only be

premature, it would soon be outdated.

One fact seems clear at this time (May 1997): the scientific community has not yet

reached a consensus on the medical consequences of serving in the Persian Gulf.

Most observers agree that some of the 697,000 U.S. soldiers who were deployed

there are sick and have wide-ranging symptoms, but the cause, or causes, have

not yet been established. Investigations into the etiology and epidemiology of

these illnesses have reached inconclusive and contradictory conclusions. Even

the popular name of the illness, Gulf War syndrome, is perhaps misleading

because the array of signs and symptoms does not fit the usual medical definition

of a syndrome: a set of symptoms that occur together; the sum of signs of any

morbid state; the aggregate of signs and symptoms associated with any morbid

process that constitute together the picture of the disease.

The level of scientific inquiry into the problem, already high, has increased in

recent months; we hope that these questions (particularly those pertaining to

etiology and epidemiology, and from there, treatment) can be answered soon.

Subsequent editions of this or other textbooks in this series will give the medical

aftermath of the Persian Gulf War the attention it deserves.
Overview: Defense Against the Effects of Chemical and Biological Warfare Agents

1

Chapter 1

OVERVIEW: DEFENSE AGAINST THE

EFFECTS OF CHEMICAL AND

BIOLOGICAL WARFARE AGENTS

FREDERICK R. SIDELL, M.D.*; AND DAVID R. FRANZ, D.V.M., PH.D.†

INTRODUCTION

HISTORICAL PRECEDENTS

INTRODUCTION TO CHEMICAL AND BIOLOGICAL AGENTS

IMPLICATIONS FOR THE MILITARY MEDICAL DEPARTMENTS

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014

†Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

2

INTRODUCTION

“Gas! Gas!” This warning cry, so common in

World War I, almost became real to U.S. forces again

as they prepared to liberate Kuwait in late 1990. The

threat of chemical, and even biological, warfare was

foremost in the minds of U.S. military personnel

during Operation Desert Shield, the preparation for

the Persian Gulf War. Iraq was known to have a

large stockpile of chemical weapons and had demonstrated during its conflict with Iran that it would

use them. It was not until after the Persian Gulf War

that the U.N. Special Commission on Iraq confirmed

that Saddam Hussein also had biological agents

loaded in weapons. The chemical and biological

threats were major concerns to those in the military medical departments who would be called on

to care for poisoned or infected casualties, possibly

in a chemically contaminated environment. Fortunately the ground war of the Persian Gulf War

(Operation Desert Storm) was brief, and even more

fortunately, our adversary did not employ these

weapons.

In the desert, during the fall and winter of

1990–1991, the threat of chemical warfare became very real to our military medical personnel.

The threat of biological warfare was no less feared.

The military medical departments realized that

medical personnel were not prepared to provide care to chemical or biological casualties

or to function in a contaminated environment. This

textbook should help accelerate the assimilation

of medical defense information in the next war;

in the past, such information has not been readily accessible. Two handbooks have also been prepared: Medical Management of Chemical Casualties

Handbook, Chemical Casualty Care Office, Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland (September 1994);

and Medical Management of Biological Casualties

Handbook, U.S. Army Medical Research Institute of

Infectious Diseases, Fort Detrick, Frederick, Maryland (March 1996).

Rapid and intense teaching programs helped prepare our medical healthcare providers, so

that by the onset of Operation Desert Storm,

they were as ready as any military medical personnel might be to go to war. Hundreds of thousands of troops were supplied with chemical

pretreatment and therapeutic agents and thousands were immunized against anthrax and the

botulinum toxins, the two most likely biological

battlefield threats.

Two lessons were learned from this conflict,

lessons that should never be forgotten by those

in the military. The first was that there are countries that have chemical and biological weapons,

and there are other countries that might obtain

or produce them. The second was that the U.S.

military medical departments must be prepared

at all times to treat both types of casualties. As

long as potential adversaries exist, the U.S. military might face a chemical or biological battlefield.

Military medical personnel of the United States

have not treated a chemical casualty on the battlefield for nearly 8 decades, and they have never

treated a biological casualty. Chemical agents have

not been used as weapons in a major war or in any

military conflict in which the United States has

been involved since World War I. Despite the recent dissolution of the Warsaw Pact, the breakup

of the Soviet Union, and other events that have

seemingly reduced the conventional military threat

to the United States, a textbook for military medical personnel on the management of chemical and

biological agent casualties is still urgently needed.

The breakup of the Soviet Union, and the consequent glut of biowarfare experts on the world employment market, may have actually increased the

threat of biological proliferation. In addition to the

recent experience in the Persian Gulf, a review of

other events of the past 2 decades bears out this conclusion (Exhibit 1-1).

EXHIBIT 1-1

RECENT TARGETS OF CHEMICAL OR

BIOLOGICAL AGENTS

Laos (mid to late 1970s; alleged)

Kampuchea (late 1970s and early 1980s; alleged)

Afghanistan (1980s; alleged)

Iran (1980s; Iran–Iraq War; confirmed)

Iraqi Kurds (1988; confirmed)
Overview: Defense Against the Effects of Chemical and Biological Warfare Agents

3

HISTORICAL PRECEDENTS

During the Arab–Israeli War (also called the Yom

Kippur War) of 1973, chemical weapons were not

used. While processing captured soldiers, however,

Israeli troops found that the Egyptians carried personal protective equipment, a decontamination kit

containing items unfamiliar to U.S. personnel, and

an antidote with which we were also unfamiliar.

This evidence suggested that the Egyptians were

prepared for a chemical battlefield, and the components of the antidote suggested that they were

prepared for the use of the nerve agent soman. (The

antidote was a mixture of three compounds: atropine, benactyzine, and the oxime, TMB4.) The U.S.

military soon issued the antidote to U.S. troops, only

to withdraw it about 5 years later.

In the mid to late 1970s, reports began to appear

that chemicals were being used against Hmong

tribesmen in Laos. The Hmong had been loyal to

the United States and had served this country

in many ways during the Vietnam War; it was

suggested that chemicals were being used against

the Hmong in retaliation. Investigations were

conducted by U.S. State Department personnel,

by a medical team sent by The U.S. Army Surgeon

General, and by international groups. Little definitive evidence was discovered, primarily because the

alleged attacks took place deep in Laos. The

victims took weeks to travel to Thailand to be

examined, and outsiders could not enter Laos to

examine the attack sites. The Hmong who reached

Thailand provided graphic accounts of attacks

by sprays and bombs from airplanes and how these

“smokes,” which were of all colors, killed many

in their villages. One member of the medical team

brought back a sample of a yellow substance on

the outer (barklike) layers of a bamboo culm (ie,

stalk); the sample had been given to him by a

Hmong, who claimed that the material had killed

many of his fellow villagers. This yellow substance,

along with samples from many other locations, later

became known as “yellow rain” (see Chapter 34,

Trichothecene Mycotoxins, which discusses yellow

rain in greater detail).

Moreover, in the late 1970s and early 1980s, allegations were made of chemical agent use against

refugees fleeing the barbaric conditions that existed

in Kampuchea at that time.1

 The clinical response

of the exposed humans did not fit what we understood about the effects of classic chemical agents.

Tearing and itching looked like the effects of tear

gas. Convulsions suggested nerve agents. But the

occurrence of internal hemorrhage and skin lesions

could not be explained. Analysis of a leaf sample

collected in Kampuchea 24 hours after an attack

implicated trichothecene mycotoxins, a family of

toxins produced by fungi but having characteristics more like chemical than biological agents.

In August 1981, based on limited physical evidence, the U.S. government announced that

trichothecene mycotoxins had been used—but the

findings were less than convincing to some in the

scientific community and the issue became extremely contentious. This controversy was never

totally resolved, and the question of which, if any,

agents were used against civilians was not answered. If mycotoxins were, in fact, used it was the

first recorded use of biological agents since before

World War II, when the Japanese used them against

the Chinese in the early 1940s.2

In the 1980s, Soviet troops battled Afghan rebels

protesting the communist Afghan regime. During

this lengthy conflict, frequent allegations were

made of the use of chemical agents against the Afghans. One of these chemicals, known as Blue-X,

was said to cause instant immobilization, the victim remaining in place for a number of hours before recovering. The use of other, more lethal agents

was also alleged, but again no definitive evidence

was found.

The most widespread and most open use of

chemical weapons on a battlefield in recent decades

was by Iraq in its conflict with Iran. This time the

evidence of chemical use was conclusive. Undetonated shells were sampled and their contents were

analyzed by several laboratories in Europe. A vesicant or blister agent (mustard) and a nerve agent

(tabun) were identified. About 100 Iranian soldiers

with chemical wounds were sent to European hospitals for care; their wounds were consistent with

vesicant (mustard) injury. A team appointed by the

U.N. secretariat went to Iranian battlefields and

hospitals and found chemical shells and patients

with chemical injuries. The public outcry at the use

of these weapons was less than overwhelming. Ignoring protests from the world community, Iraq

continued to use these agents.

Evacuating wounded soldiers to Europe not only

lessened the burden on the medical facilities in Iran

(although the number sent was a small fraction of

the total) and provided soldiers with good medical

care, but it also provided the rest of the world with

evidence that Iraq was using these weapons. In gen-
Medical Aspects of Chemical and Biological Warfare

4

eral, the casualties were sent privately, not through

governmental connections. Physicians in Europe

accepted the patients and assumed responsibility

for their care, usually in private hospitals (a situation that made a retrospective analysis of the care

rendered and the effectiveness of different treatment regimens difficult).

A similar situation enabled three physicians from

the U.S. Army medical community to examine several casualties from Iraq’s use of chemical weapons. On March 19, 1988, Iraqi airplanes bombed the

village of Halabja, in Iraq. The inhabitants were

Kurdish Iraqi citizens, a tribespeople who live in

the region where the borders of Turkey, Iran, and

Iraq meet. The casualties from this raid received

worldwide media attention. The chemical weapons

allegedly used were nerve agents, cyanide, and

mustard. The casualties were cared for by Iran, and

five of them (a man, a woman, and three young

children, all unrelated) were sent to the United

States for care by an Iranian physician living here.

On examination by three authors of chapters in this

textbook, the casualties were found to have skin

lesions and pulmonary pathological changes (as

determined by radiograph) consistent with mustard

exposure.

Other items in the news over the past decade

have suggested that the proliferation of chemical

and biological agents is greater than we might hope.

For example, numerous accounts claimed that Libya

had built a facility capable of chemical agent production at Rabta—Libya’s protestation that this facility was a pharmaceutical plant notwithstanding.

One report even noted that monthly production was

about 30 tons of mustard.

In 1979, an accident at a previously undetected

biological weapons plant in Sverdlovsk, Russia, surprised even the intelligence community.3

 At least

66 humans living or working downwind of the plant

died of pulmonary anthrax. Soviet troops quickly

attempted to decontaminate the facility and the city

following airborne release of anthrax spores, and

medical teams instituted preventive therapy, but the

message was clear. The Soviet biological warfare

program was thriving, more than 6 years after the

Soviet Union had signed the Biological Weapons

Convention.

In addition to their being used on the battlefield,

chemical and biological agents might also be used

in terrorist attacks. The nerve agent sarin was twice

used in Japan. The first incident, in Matsumoto in

June 1994, produced more than 200 casualties including 7 fatalities. In the second incident—in the

Tokyo subway system on 20 March 1995—5,510

people were taken to medical facilities or sought

medical assistance. About 20% of these were hospitalized, and 12 died. The cult that was accused of

both attacks was found to have a large facility for

manufacturing both chemical and biological agents.

In the face of overwhelming evidence, the Soviet

Union continued to officially deny having an offensive biological weapons program until 1992, when

Russian President Boris Yeltsin admitted publicly

to having maintained a program until March of that

year. Since then, visits by teams from the United

States and the United Kingdom to former biological warfare facilities under the Joint United States/

United Kingdom/Russia Trilateral Statement on

Biological Weapons have clearly documented the

capabilities to produce biological warfare agents in

massive quantities.

Verification of compliance with agreements such

as the Trilateral and with the chemical and biological weapons conventions are plagued by the “dualuse” nature of the facilities in which these agents

are developed and produced. A legitimate chemical facility can be converted fairly easily for the

manufacture of chemical agents. On threat of inspection by an international group, the facility can

readily be converted back to a legitimate use. The

dual-use nature of production facilities is even more

applicable to the production of biological agents.

Partly for this reason, chemical and biological weapons have been called “the poor man’s atom bomb.”

It has also been said that agents can be made in a

bathtub, which may be true to a limited extent for a

skilled microbiologist or chemist. Production of

even tactical quantities of these agents and their

deployment on the battlefield, however, is not a

trivial undertaking.

INTRODUCTION TO CHEMICAL AND BIOLOGICAL AGENTS

Chemical and biological agents differ in several

important ways. Chemical agents are typically manmade through the use of industrial chemical processes. Biological agents are either replicating

agents (bacteria or viruses) or nonreplicating materials (toxins or physiologically active proteins or

peptides) that can be produced by living organisms.

Some of the nonreplicating biological agents can

also be produced through either chemical synthesis, solid-phase protein synthesis, or recombinant

expression methods. Almost none of the biological

agents are dermally active (the mycotoxins are a
Overview: Defense Against the Effects of Chemical and Biological Warfare Agents

5

rare exception) and none are volatile. On the other

hand, most of the chemical agents are dermally active, volatile, or both.

Therefore, while many of the dermally active or

volatile chemical agents can be disseminated as liquids or aerosols, and the biological agents must be

dispersed as respirable aerosols (particles approximately 1–10 μm in diameter). Dispersing a respirable

aerosol on a battlefield requires a high-energy generating system to produce the small particle size,

appropriate weather conditions to assure that the

aerosol cloud stays near the ground, and adequate

infectivity or toxicity of the agent to produce the

desired effect. Except for infectivity, these are all

important practical requirements for the field use

of chemical, as well as biological, warfare agents.

In World War I, the use of chemical agents began

with the small-scale use of irritants (known today

as riot control agents). Chlorine, the first agent used

on a large scale, and phosgene caused large numbers of deaths. Cyanide was introduced in midwar,

but the agent that caused the greatest number of

casualties was the vesicant mustard, which was introduced late in the war. Cyanide, phosgene, and

mustard are still potential chemical weapons today.

In the period before World War II, German scientists synthesized the first nerve agents; during the

war, Germany had thousands of tons of nerve

agents stockpiled in munitions. The United States

and the Soviet Union captured the stockpiles and

manufacturing facilities late in the war, and they

began to manufacture and stockpile these agents.

Nerve agents are 15- to 100-fold more potent than

the chemical agents used in World War I. In the

1950s, the United States put the incapacitating compound BZ into munitions (which have been destroyed); late in that decade, the currently used riot

control agent CS was introduced for military use.

Military chemical agents are classified as “persistent” and “nonpersistent.” Persistent agents are

those with low volatility or which evaporate slowly.

Since they do not readily evaporate, they stay on

terrain, materiel, or equipment for days, weeks, or

months, depending on the weather. Chief among

the persistent agents are the vesicant mustard and

the nerve agent VX. Nonpersistent agents are those

that are volatile and hence evaporate quickly; they

are not expected to be present for more than several hours. The nonpersistent agents are phosgene,

cyanide, and the G series of nerve agents. Each type

has military advantages. Advancing troops might

disperse a nonpersistent agent ahead of their attack

to have the advantage of its effects on the enemy

and later to have uncontaminated terrain into which

to advance. A persistent agent might be used to contaminate terrain, supplies, and equipment, denying the enemy their use.

Biological weapons may contain either replicating or nonreplicating agents. Although hundreds

of naturally occurring bacteria, viruses, and toxins,

as well as “designer compounds,” could potentially

be considered agents by an aggressor, a finite number of these are actually useful as area weapons on

the battlefield. The agents’ utility is limited by ease

of production, stability, and infectivity (bacteria and

viruses), or toxicity/effectivity (toxins and other

physiologically active materials). Bacillus anthracis,

for example, is often touted as the best of bacterial

agents. Stability of the spore form and ease of production are its greatest strengths as weapons material. Among viral agents, Venezuelan equine encephalitis virus is easily grown to extremely high

titers, making it a potential incapacitating agent.

The bacterial agents that cause tularemia, Q fever,

and brucellosis are infective at extremely low doses

(1–10 organisms per person). Finally, the extraordinary toxicity (1,000- to 10,000-fold more toxic than

the classic nerve agents) of the staphylococcal enterotoxins as incapacitants and the botulinum toxins as lethal agents makes them candidates for

weaponization.

Most of the chemical compounds noted above

have characteristics that make them uniquely suited

to warfare. Closely related chemical substances,

however, and some of the threat agents, are found

throughout the civilian community. Unlike the

chemical warfare agents, which are not found in

nature, essentially all of the biological agents described are found in nature and cause the same or

very similar disease syndromes. Military medical

personnel might encounter persons exposed to the

organisms as endemic disease agents on remote

battlefields.

Similarly, civilians as well as military personnel

could be exposed during peacetime to commercial

chemicals closely related to chemical warfare

agents. Thousands of tons of cyanide, for example,

are manufactured annually for industrial use and

are shipped to users by truck and train throughout

the country. Phosgene is also manufactured in large

amounts and shipped cross-country. The nerve

agents are not available outside the military, but

they are closely related to most pesticides or insecticides that are sprayed on orchards or used by the

backyard rose gardener. The effects of these agricultural compounds are nearly identical to those of

nerve agents, and medical therapy is the same. The

incapacitating agent BZ (3-quinuclidinyl benzilate)
Medical Aspects of Chemical and Biological Warfare

6

is used in small amounts in research pharmacology

(where it is known as QNB). Also, BZ is pharmacologically related to anticholinergic drugs, which are

present in many over-the-counter preparations,

such as sleeping medications.

Unlike the chemical warfare agents, essentially

all of the biological agents described cause syndromes that mimic or are identical to naturally occurring diseases. Outbreaks of disease caused by

bacteria or viruses or isolated intoxications caused

by toxins may result in syndromes similar to those

seen in biological warfare attacks. In the case of

these agents, the route of exposure—universally via

the airways on the battlefield—may cause slightly

or significantly different clinical presentations. General principles of prophylaxis and therapy presented in this text, however, often apply. Although

the reader may initially think that the information

presented in this textbook is needed only in wartime, much of the contents will also be useful to the

physician in a busy emergency room.

On the battlefield, knowledge of the chemical or

biological agent threat and its medical and physical countermeasures can actually reduce the threat.

In World War I, the death rate for chemical casualties was about 3%. Data are not available for the

Iran–Iraq War, but informal reports indicate that the

death rate for those chemical casualties who reached

medical care was probably less than 5%, despite the

use of the highly toxic nerve agents against relatively unprotected troops. With well-trained troops

and well-prepared medical personnel, these figures

will be lower. For the chemical agents, real-time

detectors allow exploitation of the excellent individual physical protective mask, effective pretreatment, and therapy.

These countermeasures, in conjunction with

training of our forces, can make an enormous difference and actually serve as a deterrent to chemical agent use. A chemical attack on a battlefield will

not be the devastating event that some military

medical personnel fear. Soldiers will survive and

return to duty. For the biological agents, field detectors are still not responsive enough to allow timely

warning of a cloud moving across the battlefield. Although the mask is protective, adequate warning may

still be a problem. Knowledge of the meteorological

conditions necessary for effective deployment of biological and chemical agents can at least limit the time

during which a force must be on highest alert. In

addition, effective medical countermeasures (vaccines, drugs, and diagnostics) are available for many

of the agents of greatest concern. An integrated system of countermeasures for the chemical and biological agents can significantly reduce the threat by

raising the cost/benefit ratio for the would-be aggressor. If the agents are used, appropriate medical

care from well-informed medical care providers that

enables soldiers to survive could be the factor determining whether a battle is won or lost.

IMPLICATIONS FOR THE MILITARY MEDICAL DEPARTMENTS

From 18 January to 28 February 1991, 39 Iraqimodified SCUD missiles reached Israel.4

 Although

many were off target or malfunctioned, some of

them landed in and around Tel Aviv. Approximately

1,000 people were treated as a result of missile attacks,

but only 2 died. Anxiety was listed as the reason for

admitting 544 patients and atropine overdose for hospitalization of 230 patients. Clearly, these conventionally armed SCUDs were not effective mass casualty

weapons, yet they caused significant disruption to the

population of Tel Aviv. Approximately 75% of the casualties resulted from inappropriate actions or reactions on the part of the victims. Had one of the warheads contained a chemical or biological agent that

killed or intoxicated a few people, the “terror effect” would have been even greater.

The likelihood of such a weapon causing panic

among military personnel decreases, however,

when the leaders and troops become better educated regarding these agents. As General John J.

Pershing wrote after World War I: “Whether or not

gas will be employed in future wars is a matter of

conjecture. But the effect is so deadly to the unprepared that we can never afford to neglect the

question.”5(p623)

The experience in the Persian Gulf War reinforced

General Pershing’s warning. Despite the improvement in relations between the East and the West,

potential adversaries still exist—and potential adversaries have chemical and biological agents.

These agents have been used in recent years, and

probably will be used again on the battlefield or in

small, regional conflicts. They might also be used

in acts of terrorism within the United States, in

which case, by authority of Presidential Decision

Directive 39 (1995), the military will assist civilian

authorities and medical personnel.

Fortunately, U.S. troops and medical personnel

have not been involved in these attacks; it is hoped

that they never will be. We must be prepared, however. The purpose of this textbook is to assist in that

preparation.
Overview: Defense Against the Effects of Chemical and Biological Warfare Agents

7

REFERENCES

1. McDermott J. The Killing Winds. New York, NY: Arbor House; 1987: 49–60.

2. Williams P, Wallace D. Unit 731: Japan’s Secret Biological Warfare in World War II. New York, NY: The Free Press

(Macmillan); 1989: 65–70.

3. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science. 1994;266:1202–

1208.

4. Karsenty E, Shemer J, Alshech I, et al. Medical aspects of the Iraqi missile attacks on Israel. Isr J Med Sci.

1991;27:603–607.

5. Pershing JJ. Final report of General John J. Pershing. Annual Report. Vol 1, Part 1; 1919. Quoted by: Brown FJ.

Chemical Warfare. A Study in Restraints. Princeton, NJ: Princeton University Press; 1968: 623.
History of Chemical and Biological Warfare: An American Perspective

9

Chapter 2

HISTORY OF CHEMICAL AND BIOLOGICAL

WARFARE: AN AMERICAN PERSPECTIVE

JEFFERY K. SMART, M.A.*

INTRODUCTION

PRE–WORLD WAR I DEVELOPMENTS

WORLD WAR I

THE 1920S: THE LEAN YEARS

THE 1930S: THE GROWING THREAT OF CHEMICAL AND BIOLOGICAL

WARFARE

THE 1940S: WORLD WAR II AND THE NUCLEAR AGE

THE 1950S: HEYDAY OF THE CHEMICAL CORPS

THE 1960S: DECADE OF TURMOIL

THE 1970S: THE NEAR END OF THE CHEMICAL CORPS

THE 1980S: THE RETURN OF THE CHEMICAL CORPS

THE 1990S: THE THREAT MATERIALIZES

SUMMARY

*Command Historian, U.S. Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Maryland 21010-5423
Medical Aspects of Chemical and Biological Warfare

10

INTRODUCTION

Webster’s Ninth New Collegiate Dictionary defines

the term “chemical warfare,” first used in 1917,

as “tactical warfare using incendiary mixtures,

smokes, or irritant, burning, poisonous, or asphyxiating gases.” A working definition of a chemical agent is “a chemical which is intended for

use in military operations to kill, seriously injure,

or incapacitate man because of its physiological

effects. Excluded from consideration are riot control agents, chemical herbicides and smoke

and flame materials.”1(p1-1) Chemical agents were

usually divided into five categories: nerve agents,

vesicants, choking agents, blood agents, and

incapacitants.

Webster’s dictionary likewise defines “biological

warfare” as “warfare involving the use of living

organisms (as disease germs) or their toxic products against men, animals, or plants.” A working

definition of a biological agent is “a microorganism (or a toxin derived from it) which causes disease in man, plants or animals or causes deterioration of material.”2(p1-1) Biological warfare agents

were normally divided into three categories: antipersonnel, antianimal, and antiplant.

Prior to World War I, the United States had little

knowledge about the potential of chemical and biological warfare. Particularly in terms of preparing

soldiers for future wars, the possibility of chemical

or biological warfare went virtually unnoticed by

the U.S. Army. By the end of World War I, the situation had drastically changed. Chemical warfare

had been used against and by American soldiers

on the battlefield. Biological warfare had been used

covertly on several fronts. In an effort to determine

what had gone wrong with their planning and training, U.S. Army officers prepared a history of chemical and biological warfare. To their surprise, they

found numerous documented cases of chemical and

biological agents having been used or proposed to

influence the outcome of a battle or campaign. In

addition, they discovered that the technology to

protect against chemical and biological agents already existed, and, in some cases, was superior to

the equipment used during the war. In hindsight,

these officers realized that the army had failed to

recognize and prepare for these two already existing types of warfare.

[This chapter focuses primarily on the development of chemical and biological weapons and countermeasures to them, thus setting the stage for

Chapter 3, Historical Aspects of Medical Defense

Against Chemical Warfare, which concentrates on

medical aspects of chemical warfare. To avoid excessive duplication of material, protective equipment of the modern era is illustrated in Chapter 16,

Chemical Defense Equipment.—Eds.]

PRE–WORLD WAR I DEVELOPMENTS

The chemical agents first used in combat during

World War I were, for the most part, not recent discoveries. Most were 18th- and 19th-century discoveries. For example, Carl Scheele, a Swedish chemist, was credited with the discovery of chlorine in

1774. He also determined the properties and composition of hydrogen cyanide in 1782. Comte

Claude Louis Berthollet, a French chemist, synthesized cyanogen chloride in 1802. Sir Humphry

Davy, a British chemist, synthesized phosgene in

1812. Dichloroethylsulfide (commonly known as

mustard agent) was synthesized in 1822, again in

1854, and finally fully identified by Victor Meyer

in 1886. John Stenhouse, a Scotch chemist and inventor, synthesized chloropicrin in 1848.3

Many biological agents were naturally occurring

diseases thousands of years old. Others were generally discovered or recognized in the 19th and 20th

centuries. For example, plague was recognized

about 3,000 years ago. Smallpox was known in

China as early as 1122 BC. Yellow fever was first

described in the 1600s. Carlos Finlay, a Cuban

biologist, identified mosquitoes as the primary

carrier of yellow fever in 1881, while Walter Reed,

a U.S. Army physician, proved the agent to be a virus. Casimir-Joseph Davaine isolated the causative

organism of anthrax in 1863, followed by Robert

Koch, a German scientist, who obtained a pure culture of anthrax in 1876. Koch also discovered the

causative agent for cholera in 1883. Rocky Mountain spotted fever was first recognized in 1873;

Howard T. Ricketts, an American pathologist,

discovered the causative agent in 1907. Ricketts

also identified the causative organism of typhus in

1909. F. Loffler and W. Schutz identified glanders

in 1882. Sir David Bruce, a British pathologist, discovered the causative organism of brucellosis (it

was named after him) in 1887. Ricin toxin was identified in 1889. Tularemia was first described in

Tulare County, California (after which it was
History of Chemical and Biological Warfare: An American Perspective

11

named), in 1911, and the causative agent was identified the next year.3

Early Chemical Weaponization Proposals and Usage

There are numerous examples of chemical weapons used or proposed during the course of a campaign or battle. The Chinese used arsenical smokes

as early as 1000 BC. Solon of Athens put hellebore

roots in the drinking water of Kirrha in 600 BC. In

429 and 424 BC, the Spartans and their allies used

noxious smoke and flame against Athenian-allied

cities during the Peloponnesian War. About 200 BC,

the Carthaginians used Mandrake root left in wine

to sedate the enemy. The Chinese designed stink

bombs of poisonous smoke and shrapnel, along

with a chemical mortar that fired cast-iron stink

shells. Toxic smoke projectiles were designed and

used during the Thirty Years War. Leonardo da Vinci

proposed a powder of sulfide of arsenic and verdigris in the 15th century.3

During the Crimean War, there were several proposals to initiate chemical warfare to assist the Allies, particularly to solve the stalemate during the

siege of Sevastopol. In 1854, Lyon Playfair, a British chemist, proposed a cacodyl cyanide artillery

shell for use primarily against enemy ships. The

British Ordnance Department rejected the proposal

as “bad a mode of warfare as poisoning the wells

of the enemy.”4(p22) Playfair’s response outlined a

different concept, which was used to justify chemical warfare into the next century:

There was no sense in this objection. It is considered a legitimate mode of warfare to fill shells with

molten metal which scatters among the enemy, and

produced the most frightful modes of death. Why

a poisonous vapor which would kill men without

suffering is to be considered illegitimate warfare

is incomprehensible. War is destruction, and the

more destructive it can be made with the least suffering the sooner will be ended that barbarous

method of protecting national rights. No doubt in

time chemistry will be used to lessen the suffering

of combatants, and even of criminals condemned

to death.4(pp22–23)

There were other proposals for chemical warfare

during the Crimean War, but none were approved.

During the American Civil War, John Doughty, a

New York City school teacher, was one of the first

to propose the use of chlorine as a chemical warfare

agent. He envisioned a 10-in. artillery shell filled with

2 to 3 qt of liquid chlorine that, when released, would

produce many cubic feet of chlorine gas.

If the shell should explode over the heads of the

enemy, the gas would, by its great specific gravity,

rapidly fall to the ground: the men could not dodge

it, and their first intimation of its presence would

be by its inhalation, which would most effectually

disqualify every man for service that was within

the circle of its influence; rendering the disarming

and capturing of them as certain as though both

their legs were broken.5(p27)

As to the moral question of using chemical weapons, he echoed the sentiments of Lyon Playfair a

decade earlier:

As to the moral question involved in its introduction, I have, after watching the progress of events

during the last eight months with reference to it,

arrived at the somewhat paradoxical conclusion,

that its introduction would very much lessen the

sanguinary character of the battlefield, and at the

same time render conflicts more decisive in their

results.5(p33)

Doughty’s plan was apparently never acted

on, as it was probably presented to Brigadier General James W. Ripley, Chief of Ordnance, who

was described as being congenitally immune to

new ideas.5 A less-practical concept, proposed the

same year by Joseph Lott, was to fill a hand-pumped

fire engine with chloroform to spray on enemy

troops.6

The 1864 siege of Petersburg, Virginia, generated

several chemical warfare proposals. Forrest Shepherd proposed mixing hydrochloric and sulfuric

acids to create a toxic cloud to defeat the Confederates defending Petersburg.5

 Lieutenant Colonel

William W. Blackford, a Confederate engineer, designed a sulfur cartridge for use as a countertunnelling device.7

 The Confederates also considered using Chinese stink bombs against the Union

troops. Elsewhere, the same year, Union Army Captain E. C. Boynton proposed using a cacodyl glass

grenade for ship-to-ship fighting.5

 Other than possibly Blackford’s cartridge, none of the proposals

were used on the battlefield.

Two wars at the turn of the century also saw limited use of chemical weapons. During the Boer War,

British troops fired picric acid–filled shells, although to little effect.8

 During the Russo–Japanese

War, which was closely observed by those who

would plan World War I, Japanese soldiers threw

arsenal rag torches into Russian trenches.3

In 1887, the Germans apparently considered using lacrimators (tear agents) for military purposes.

The French also began a rudimentary chemical warfare program with the development of a tear gas
Medical Aspects of Chemical and Biological Warfare

12

grenade containing ethyl bromoacetate, and proposals to fill artillery shells with chloropicrin.9

Early Biological Warfare Proposals and Usage

There were many examples of proposed usage

or actual use of biological weapons on the battlefield. Hannibal hurled venomous snakes onto

the enemy ships of Pergamus at Eurymedon in 190

BC. Scythian archers used arrows dipped in blood

and manure or decomposing bodies in 400 BC. The

use of dead bodies as the carrier of the biological

agent proved particularly effective against

an enemy’s water supply. Barbarossa used this

tactic at the battle of Tortona in 1155. De Mussis, a

Mongol, catapulted bubonic plague–infected bodies into Caffa in 1346. The Spanish tried wine infected with leprosy patients’ blood against the

French near Naples in 1495. One of the more unique

attempts at biological warfare was initiated in 1650

by Siemenowics, a Polish artillery general, who put

saliva from rabid dogs into hollow spheres for firing against his enemies. The Russians cast plagueinfected bodies into Swedish-held Reval, Estonia,

in 1710.

The proposed use of biological weapons was not

limited to Europe and Asia. In 1763, during

Pontiac’s Rebellion in New England, Colonel Henry

Bouquet, a British officer, proposed giving the Indians at Fort Pitt, Pennsylvania, blankets infected

with smallpox. The disease, whether purposely disseminated or not, proved devastating to the Native

American population. A similar plan was executed

in 1785, when Tunisians threw plague-infected

clothing into La Calle, held by the Christians.

The 19th-century wars continued the same trend.

In 1861, Union troops advancing south into Maryland and other border states were warned not to

eat or drink anything provided by unknown civilians for fear of being poisoned. Despite the warnings, there were numerous cases where soldiers

thought they had been poisoned after eating or

drinking. Confederates retreating in Mississippi in

1863 left dead animals in wells and ponds to deny

water sources to the Union troops.

A more carefully planned use of biological weapons was attempted by Dr. Luke Blackburn, a future

governor of Kentucky, who attempted to infect

clothing with smallpox and yellow fever and then

sell it to unsuspecting Union troops. At least one

Union officer’s obituary stated that he died of smallpox attributed to Blackburn’s scheme. Yellow fever,

however, could not be transferred in this manner.

Since more soldiers died of disease during the Civil

War than were killed on the battlefield, the effectiveness of Blackburn’s work was difficult to judge.

Biological agents were also considered for

antianimal weapons during the 19th century. Louis

Pasteur, the French chemist and biologist usually

recognized for his humanitarian accomplishments,

also experimented with the use of salmonella as an

agent to exterminate rats. Others successfully used

chicken cholera to exterminate rabbits and dysentery to kill grasshoppers.3

Early Protective Devices

Parallel to the development and use of chemical

and biological weapons was the design of protective equipment for use against toxic chemicals and

biological agents. Although conventional protective

masks started appearing in the 19th century, the

earliest recorded mask proposal was written by

Leonardo da Vinci in the 15th century. He envisioned a fine cloth dipped in water for defense

Fig. 2-1. Theodore A. Hoffman patented this respirator

in 1866. It is representative of the already developing

protective mask designs of the post–American Civil War

era. Ironically, these masks were superior to the ad hoc

emergency masks used by the Allies after the Germans

began chemical warfare in World War I. Reprinted from

US Patent No. 58,255; 25 Sep 1866.
History of Chemical and Biological Warfare: An American Perspective

13

against a sulfide of arsenic and verdigris powder

he was proposing for a toxic weapon.10

The earliest known patent for a protective mask

in the United States was filed by Lewis P. Haslett in

1847. His design included a moistened woolen fabric mask with an exhaust.11 Benjamin I. Lane’s

patent in 1850 included an air tank, goggles, and a

rubber nose piece.12 John Stenhouse developed a

velvet-lined copper mask with a charcoal filter in

1854. The same year, George Wilson, a professor of

technology at the University of Edinburgh, proposed that the British Board of Ordnance issue charcoal masks to soldiers to protect them from bombs

employing suffocating or poisonous vapors during

the Crimean War.13

Between the American Civil War and World War

I, there were numerous additional patents and designs for protective devices that were used in industry, for fire fighting, and in mines. These included an improved mask by Lane, which had a

rubber facepiece with an exhaust; Theodore A.

Hoffman’s mask, which was made of cotton with

an elastic border to protect against aerosols (Figure

2-1); Samuel Barton’s mask with a metal-and-rubber facepiece, hood, goggles, and a charcoal filter;

and Charles A. Ash’s mask, which added an air supply for use by miners.3

Attempts to Control Chemical and Biological

Warfare

Most of the early attempts to control chemical

and biological warfare were bilateral or unilateral

agreements directed at the use of poisons. These

included the 1675 agreement between the French

and Germans, signed in Strassburg, to ban the use

of poison bullets, and U.S. Army General Order No.

100, issued in 1863 during the American Civil War,

which stated: “The use of poison in any manner, be

it to poison wells, or food, or arms, is wholly excluded from modern warfare.”14(p687)

The first international attempt to control chemical and biological weapons occurred in 1874, when

the International Declaration Concerning the Laws

and Customs of War was signed in Brussels and

included a prohibition against poison or poisoned

arms. The First Hague Peace Conference in 1899 also

banned the use of poisons and was ratified by the

United States. However, a separate proposition

stated: “The contracting Powers agree to abstain

from the use of projectiles the sole object of which

is the diffusion of asphyxiating gasses.”14(p685) Although 27 nations, including Germany, France, Russia, Austria-Hungary, and Great Britain, eventually

agreed to this additional statement, the United

States delegation declined to approve it.

Captain Alfred T. Mahan, a U.S. Navy delegate

plenipotentiary, gave three reasons for opposing the

additional restrictions: (1) currently used weapons

were despised as cruel and inhumane when first

introduced, (2) since there were no current chemical weapons stockpiles, it was too early to ban them,

and (3) chemical weapons were not any more inhumane than any other weapon. The 1907 Second

Hague Peace Conference retained the ban against

poisons.15

WORLD WAR I

When Europe was caught up in the crises of 1914

after the murder of Archduke Francis Ferdinand at

Sarajevo and the declarations of war among Austria-Hungary, Serbia, Germany, France, Russia, and

Great Britain that followed within a month, few

observers expected the 19th-century chemical and

biological paper proposals to be transformed into

actual battlefield operations. The United States, remaining neutral under the policy of President

Woodrow Wilson, certainly made no preparations

for chemical and biological warfare.

Early Allied Chemical Warfare Plans

With the outbreak of hostilities, both the French

and the British apparently considered, investigated,

and tested various chemical weapons at home and

on the battlefield. During the German invasion of

Belgium and France, the French used their ethyl

bromoacetate grenades against the Germans, but

with no noticeable effect. Although the grenades

were considered of no military worth, the French

apparently continued to consider the further use of

tear agents against the Germans.

In the early stages of the war, the British examined their own chemical technology for battlefield

use. They initially investigated tear agents also but

later turned to more toxic chemicals. In January

1915, several chemists at Imperial College successfully demonstrated ethyl iodoacetate as a tear gas

to the War Office by gassing a representative.

Another officer suggested using sulfur dioxide as a chemical weapon. Field Marshal Lord

Kitchener, Secretary of State for War, was not interested in the concept for the army but suggested trying the navy. At the Admiralty, the idea found a
Medical Aspects of Chemical and Biological Warfare

14

sympathetic ear in Winston Churchill in March

1915. The suggestion included a plan to use a sulfur dioxide cloud against the Germans, screen the

operation with smoke, and provide British troops a

gas-proof helmet. Churchill declined to accept the

sulfur dioxide plan but did put the officer in charge

of a committee the next month to discuss the use of

smoke on land and sea.9

German Chemical Warfare Plans

Possibly aware of the Allied interest in chemical

weapons, the Germans also examined their own

chemical technology for war applications. Their

strong dye industry and the technical knowledge

supplied by university professors in Berlin created

the right combination for pursuing the concept of

offensive chemical weapons. From the suggestion

of Professor Walther Nernst, a physical chemist at

the University of Berlin, or one of his colleagues,

the Germans filled 105-mm shells with dianisidine

chlorosulfate, a lung irritant, for use on the western front. To evade the 1899 international ban, the

Germans also put shrapnel in the shell so the “sole”

purpose was not gas dissemination.

On 27 October 1914, the Germans fired 3,000 of

these projectiles at the British near Neuve-Chapelle,

but with no visible effects. The explosive aspect of

the shells destroyed the chemical aspect. In fact, the

British were apparently unaware that they were the

victims of the first large-scale chemical projectile

attack.

The Germans continued researching chemical

shells, and by November 1914, Dr. Hans von

Tappen, assigned to the Heavy Artillery Department, designed a 150-mm howitzer shell containing 7 lb of xylyl bromide and a burster charge for

splinter effect (Figure 2-2). The Germans moved

these to the eastern front and experimented by firing more than 18,000 of the shells at Russian positions near Bolimov. In this case, the weather came

to the aid of the Russians by providing cold temperatures that prevented the vaporization of the gas.

The Germans tried the same shells again on the

western front at Nieuport in March 1915 with

equally unsuccessful results.9,14,16

Ypres, April 1915: The First Successful German

Chemical Attack

The concept of creating a toxic gas cloud from

chemical cylinders was credited to Fritz Haber of

the Kaiser Wilhelm Physical Institute of Berlin in

late 1914. Owing to shortages of artillery shells,

Fig. 2-2. The German 150-mm T-Shell, which mixed xylyl

bromide with an explosive charge. Note that the explosive charge was in the front and the chemical agent in

the rear compartment. This design is similar to the one

proposed in 1862 by John Doughty during the American

Civil War (see Figure 3-1). Reprinted from Army War

College. German Methods of Offense. Vol 1. In: Gas Warfare. Washington, DC: War Department; 1918: 59.

Haber thought a chemical gas cloud would negate

the enemy’s earthworks without the use of high

explosives. In addition, gas released directly from

its storage cylinder would cover a far broader area

than that dispersed from artillery shells. Haber selected chlorine for the gas since it was abundant in

the German dye industry and would have no prolonged influence over the terrain.

On 10 March 1915, under the guidance of Haber,

Pioneer Regiment 35 placed 1,600 large and 4,130

small cylinders containing a total of 168 tons of chlorine opposite the Allied troops defending Ypres,

Belgium. Haber also supplied the entire regiment

with Draeger oxygen breathing sets, used in mine

work, and a portion of the surrounding German

infantry with small pads coated with sodium thiosulfate. Once the cylinders were in place, the Germans then waited for the winds to shift to a westerly direction.9,14,17

The Germans believed this means of attack,

nonprojectile, was still within the guidelines of the
History of Chemical and Biological Warfare: An American Perspective

15

Hague ban and hoped the cylinders would produce

a potent cloud. The comments of General von

Deimling, commanding general of the German 15th

Corps in front of Ypres, written sometime after the

war, however, perhaps better reflect the reason for

initiating chemical warfare:

I must confess that the commission for poisoning

the enemy, just as one poisons rats, struck me as it

must any straight-forward soldier: it was repulsive

to me. If, however, these poison gases would lead

to the fall of Ypres, we would perhaps win a victory which might decide the entire war. In view of

such a high goal, personal susceptibilities had to

be silent.18(p5)

On 22 April 1915, the Germans released the gas

with mixed success. Initially, the Allied line simply

fell apart. This was despite the fact that the Allies

were aware of the pending gas attack, and British

airmen had actually spotted the gas cylinders in the

German trenches. The success of the attack was

more significant than the Germans expected, and

they were not ready to make significant gains despite the breakthrough. In addition, fresh Allied

troops quickly restored a new line further back. The

Allies claimed that 5,000 troops were killed in the

attack, but this was probably an inflated number

for propaganda purposes.18

The Germans used chlorine again at Ypres on 24

April 1915 and four more times during May 1915

(Figure 2-3). These additional attacks gained additional ground. As one British soldier stated:

Nobody appears to have realized the great danger

that was threatening, it being considered that the

enemy’s attempt would certainly fail and that

whatever gas reached our line could be easily

fanned away. No one felt in the slightest degree

uneasy, and the terrible effect of the gas came to us

as a great surprise.19(p3)

Another observer, in reflecting about the attack

at Ypres and the first major use of chemical warfare, wrote: “The most stupendous change in warfare

since gunpowder was invented had come, and come

to stay. Let us not forget that.”20(p3) Yet chemical

warfare failed to be decisive and the German attack

against Ypres was halted short of its objective.

Allied Chemical Warfare Retaliation

That same month, the British and the French began planning to retaliate with chemical weapons.

The Allied response to the chemical attacks evolved

into three general categories:

Fig. 2-3. A typical German chemical cylinder set up and

ready for discharge. The discharge from thousands of

cylinders created the gas cloud. Reprinted from Army

War College. German Methods of Offense. Vol 1. In: Gas

Warfare. Washington, DC: War Department; 1918: 14.

1. protective devices for the troops,

2. toxic gases of their own, and

3. weapons to deliver the toxic gases to the

enemy lines.

Shortly after the first chlorine attack, the Allies had

primitive emergency protective masks. In September, they launched their own chlorine attack against

the Germans at Loos (Figure 2-4). This initiated a

Fig. 2-4. A French cylinder attack on German trenches in

Flanders. The critical importance of the wind is apparent. Condensation of water vapor caused the cloudlike

appearance of the gas. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

16

deadly competition to develop better protective

masks, more potent chemicals, and long-range delivery systems to more widely disperse the agents.

The Germans quickly escalated to phosgene to

replace the less-effective chlorine. In May 1916, the

Germans started using trichloromethyl chloroformate (diphosgene), while the French tried hydrogen cyanide 2 months later and cyanogen chloride

the same year. In July 1917, the Germans introduced

mustard agent to provide a persistent vesicant that

could attack the body in places not protected by gas

masks. To further complicate defensive actions, both

sides mixed agents and experimented with camouflage materials to prevent quick identification.3

German Biological Warfare Plans

While the German chemical warfare program

was extensively documented after the war, the German use of biological weapons during World War I

unfortunately was poorly documented and much

debated. Apparently in 1915, the Germans initiated

covert biological warfare attacks against the Allies’

horses and cattle on both the western and the eastern fronts. In that year, they also allegedly used disease-producing bacteria to inoculate horses and

cattle leaving U.S. ports for shipment to the Allies.

Other attacks included a reported attempt to spread

plague in St. Petersburg, Russia, in 1915.3,21

The activities of German agents operating in the

United States in 1915 came to light after the war.

Erich von Steinmetz, a captain in the German navy,

entered the United States disguised as a woman.

He brought with him cultures of glanders to inoculate horses intended for the western front. After trying unsuccessfully, he posed as a researcher and

took the cultures to a laboratory, where it was determined the cultures were dead.

Anton Dilger was an American-educated surgeon

who specialized in wound surgery at Johns Hopkins

University, Baltimore, Maryland. After joining the

German army in 1914, he suffered a nervous breakdown and was sent to his parents’ home in Virginia

since the United States was still neutral in the war.

At the request of the German government, he

brought along strains of anthrax and glanders to

begin a horse-inoculation program. With his brother

Carl, he set up a laboratory in a private house in

Chevy Chase, Maryland, to produce additional

quantities of the bacteria.

The bacteria from “Tony’s lab” were delivered

to Captain Frederick Hinsch, who was using a house

at the corner of Charles and Redwood Streets in

Baltimore, Maryland. Hinsch inoculated horses in

Baltimore that were awaiting shipment to Europe.

Dilger also attempted to establish a second biological warfare laboratory in St. Louis, Missouri, but

gave up after a cold winter killed the cultures. Although the impact of these German agents’ activities was not determined, the year 1915 is considered to be the beginning of 20th-century antianimal

biological warfare.22

Additional biological attacks reportedly occurred

throughout the war. In 1916, a German agent with

intentions to spread a biological agent was arrested

in Russia. German agents also tried to infect horses

with glanders and cattle with anthrax in Bucharest

in 1916. In 1917, Germany was accused of poisoning wells in the Somme area with human corpses,

and dropping fruit, chocolate, and children’s toys

infected with lethal bacteria into Romanian cities.

German agents tried to infect horses with glanders

and cattle with anthrax in France. A more successful attack was the infection of some 4,500 mules with

glanders by a German agent in Mesopotamia. Another reported attack was with cholera in Italy. A

1929 report also accused the Germans of dropping

bombs containing “plague” over British positions

during the war. Many of these reports were of questionable authenticity and were vehemently denied

by the Germans. As had happened during the

American Civil War, the rampant spread of naturally occurring disease during World War I made

the impact of planned biological warfare attacks

impossible to determine.3,21

Pre-War Interest in the United States in

Chemical Warfare

The production and use of offensive chemical

weapons in the European war did not go completely

unnoticed in the United States. The combination of

the use of chemical warfare at Ypres in April, followed by the sinking of the Lusitania by a German

U-boat off the Irish coast on 7 May 1915, shocked

the nation. Americans began to take greater interest in the nature of warfare taking place in Europe

and elsewhere. In May 1915, President Woodrow

Wilson proposed that Germany halt chemical warfare in exchange for the British ending their blockade of neutral ports. Germany (and Great Britain)

refused to comply.

Helpful suggestions from armchair scientists

proved to be of little help to the army. The Army

and Navy Register of 29 May 1915 contained the following report:
History of Chemical and Biological Warfare: An American Perspective

17

Among the recommendations forwarded to the

Board of Ordnance and Fortifications there may be

found many suggestions in favor of the asphyxiation process, mostly by the employment of gases

contained in bombs to be thrown within the lines

of the foe, with varying effects from peaceful slumber to instant death. One ingenious person suggested a bomb laden to its full capacity with snuff,

which should be so evenly and thoroughly distributed that the enemy would be convulsed with

sneezing, and in this period of paroxysm it would

be possible to creep up on him and capture him in

the throes of the convulsion.23(p12)

By the fall of 1915, the War Department finally

became interested in providing American troops

with some form of a protective mask. By then, the

British already had the P helmet, a flannel bag

treated with sodium phenate and sodium hyposulfite that fitted over the head and was effective

against chlorine and phosgene gases. The Germans

were slightly ahead with a rubberized facepiece,

unbreakable eyepieces, and a drum canister.24

In the United States, the mask project was assigned to the Army Medical Department. The Medical Department sent several medical officers to Europe as observers, but accomplished little else. Since

the United States was not at war, no particular emphasis was placed on the project. Ultimately, all

major participants in World War I attempted to develop protective masks (Figure 2-5).

As relations with Germany declined over its unrestricted use of submarines, the war overtones did

energize several key civilians in the U.S. governFig. 2-5. A potpourri of World War I–vintage protective masks. This extraordinary

photograph gives some indication of the

great effort made by the warring parties to

develop an effective and practical (and frequently unsuccessful) defense against the

chemical warfare threat. Top row, left to

right: U.S. Navy Mark I mask; U.S. Navy

Mark II mask; U.S. CE mask; U.S. RFK mask;

U.S. AT mask; U.S. KT mask; U.S. model

1919 mask. Middle row, left to right: British

Black Veil mask; British PH helmet; British

BR mask; French M2 mask; French artillery

mask; French ARS mask. Bottom row, left

to right: German mask; Russian mask; Italian mask; British Motor Corps mask; U.S.

Rear Area mask; U.S. Connell mask. Photograph: Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

ment. One, Van H. Manning, Director of Bureau of

Mines, Department of the Interior, called together

his division chiefs on 7 February 1917 to discuss

how they could assist the government if the country was drawn into war. At this meeting, George S.

Rice suggested that the bureau might turn its experience in mine gas and rescue apparatus toward the

investigation of war gases and masks.

The next day, Manning sent a letter to Dr. C. D.

Walcott, Chairman of the Military Committee of the

National Research Council (NRC), which had been

created the year before, offering the Bureau’s services in creating a chemical warfare program for the

army. On 12 February 1917, Dr. Walcott replied to

Manning’s letter, stating that he would bring the

matter to the attention of the Military Committee.

Events, however, moved quicker than the

Military Committee. On 2 April 1917, President

Wilson addressed the U.S. Congress and called for

a declaration of war. The next day, the Military

Committee acted on Manning’s proposal and established the Subcommittee on Noxious Gases under

the chairmanship of the director of the Bureau of

Mines, and to include ordnance and medical officers from both the army and the navy, as well as two

members of the Chemical Committee of the NRC.

Their mission was to investigate noxious gases, the

generation of chemical warfare agents, and the

discovery of antidotes for war purposes. Three

days later the United States declared war on

Germany when congress approved the president’s

request.17,25,26
Medical Aspects of Chemical and Biological Warfare

18

The United States Organizes for Chemical

Warfare

The new Subcommittee on Toxic Gases got off to

a quick start. Within a short time, the subcommittee began organizing research into chemical agents

at universities and industries across the nation,

while mobilizing a large portion of the chemists in

the country. This initial phase was the groundwork

that later led to the establishment of the Chemical

Warfare Service, the forerunner of the Chemical

Corps. Thus the country’s civilian scientists, engineers, and chemistry professors rescued the army

from its unpreparedness for chemical warfare.

Eventually, the War Department also began to

plan for chemical warfare. The Medical Department

was assigned responsibility for chemical defense

and the Ordnance Department responsibility for

chemical munitions. The Corps of Engineers was

designated to provide engineers to employ the new

weapons. This diversified arrangement did not last

long.

When General John J. Pershing faced the task of

organizing the American Expeditionary Forces

(AEF) in France in the summer of 1917, he decided

to place responsibility for all phases of gas warfare

in a single military service, and he recommended

that the War Department at home do likewise. On 3

September 1917, the AEF established a centralized

Gas Service under the command of Lieutenant Colonel Amos A. Fries.25,26 The new organization had

many hurdles to overcome. The troops had virtually no chemical warfare equipment of U.S. design

and relied on the British and French to supply

equipment from gas masks to munitions.

U.S. Troops Introduced to Chemical Warfare

Despite the Allied support, the U.S. Army was

not ready for chemical warfare. For example, on 26

February 1918, the Germans fired 150 to 250 phosgene and chloropicrin projectiles against the Americans near Bois de Remieres, France. The first attack

occurred between 1:20 AM and 1:30 AM. There was a

blinding flash of light and then several seconds

elapsed before the projectiles reached their target.

Some exploded in the air and others on the ground.

A second and similar attack occurred about an hour

later. The attack and its casualties were recorded

by many observers, including the following selected

accounts27:

• A corporal saw the projectiles burst 10 ft in

the air with flash and smoke. As the shells

burst, he got his mask on without smelling

any gas. When he took his mask off an hour

and a half later, however, he could smell

gas.

• One private said the gas smelled like sour

milk and had a sharp odor. It hurt his eyes

and nose. Another private forgot to hold his

breath while putting on his mask. The gas

smelled sweet and he became sick to the

stomach and his lungs hurt. Still, he kept

his mask on for 4 hours.

• One man in panic stampeded and knocked

down two others who were adjusting their

masks. The panicked man rushed down the

trench screaming and made no attempt to

put on his respirator; he died shortly after

reaching the dressing station.

• Another man threw himself in the bottom

of the trench and began to scream. Two others, trying to adjust his respirator, had their

own pulled off and were gassed. The

screaming man was finally carried out of

the area but died not long after.

• An officer was gassed while shouting to the

men to keep their respirators on.

The Americans suffered 85 casualties with 8

deaths, approximately 33% of their battalion. The

problem was a lack of discipline. Because a good

American mask was not yet available, the soldiers

were issued two gas masks: a French M2, which was

comfortable but not extremely effective; and a British small-box respirator (SBR), which was effective

but uncomfortable with its scuba-type mouthpiece

and nose clip. At the first sign of gas, some of the

men could not find their gas masks in time. Others

were able to get their SBRs on, but then either removed their masks too quickly or decided to switch

to the more comfortable French mask and were

gassed in the process.27

An editorial later summed up the lesson learned

from this first fiasco:

A stack of standing orders a mile high will not discipline an army. Neither can you so train men at

the outbreak of hostilities that they can protect

themselves against the gas which will be used by

the enemy. We must train our Army to the last degree during peace.28(p2)

Creation of the Chemical Warfare Service

In the spring of 1918, the U.S. government began centralizing gas warfare functions in the War

Department under a senior Corps of Engineers of-
History of Chemical and Biological Warfare: An American Perspective

19

Fig. 2-6. Major General William L. Sibert was the first

commanding general of the U.S. Army Chemical Warfare Service. He had previously commanded the 1st Division in France in early 1918. Photograph: Chemical and

Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

ficer, Major General William L. Sibert (Figure 2-6).

When President Wilson transferred the research facilities that had been set up by the Bureau of Mines

to the War Department, the stage was set for the

inauguration of a new consolidated organization.

On 28 June 1918, the War Department formally established the Chemical Warfare Service (CWS) under Sibert as part of the National Army (ie, the wartime army, as distinguished from the regular army),

with full responsibility for all facilities and functions relating to toxic chemicals.

The CWS was organized into seven main divisions.

The Research Division was located at American

University, Washington, D. C. Most of the weapons

and agent research was conducted by this division

during the war. The Gas Defense Division was responsible for the production of gas masks and had

a large plant in Long Island City, New York. The

Gas Offense Division was responsible for the production of chemical agents and weapons, with its

main facility located at Edgewood Arsenal, Maryland. The Development Division was responsible

for charcoal production, and also pilot-plant work

on mustard agent production. The Proving Ground

Division was collocated with the Training Division

at Lakehurst, New Jersey. The Medical Division was

responsible for the pharmacological aspects of

chemical defense.

The offensive chemical unit for the AEF was the

First Gas Regiment, formerly the 30th Engineers.

This unit was organized at American University

under the command of Colonel E. J. Atkisson in

1917, and was sent to France in early 1918.17,25

The U.S. Army finally had an organization that

controlled offensive chemical production, defensive

equipment production, training, testing, and basic

research, along with a new chemical warfare unit,

the First Gas Regiment, under one general. This

organization helped lead the AEF to victory, although much of its work, including the construction of toxic gas–production and –filling plants and

gas mask factories, was only partially completed

by the end of the war.

Agent Production

Agent production and shell-filling were initially

assigned to the Ordnance Department and then to

the CWS. The primary facility was Edgewood

Arsenal, Maryland, erected in the winter of 1917–

1918. The plant was designed to have four shellfilling plants and four chemical agent production

plants. The first shell-filling plant filled 75-mm, 155-

mm, 4.7-in., and Livens projectiles with phosgene.

A second filling plant was added to fill 155-mm

shells with mustard agent or chloropicrin (Figure

2-7). Two additional shell-filling plants were started

but not completed before the end of the war.

The four agent production plants produced the

highest priority agents thought to be required for

the western front in 1917. These were chlorine, chloropicrin, phosgene, and mustard agent (Figure

2-8). By 1918, the first two were no longer critical

agents, although chlorine was used in the production of phosgene. Over 935 tons of phosgene and 711

tons of mustard agent were produced at the arsenal

by the end of the war. Government contractors also

produced these four agents and Lewisite, named after Captain W. Lee Lewis, a member of the CWS Research Division. The Lewisite, however, never reached

the front: it was dumped somewhere in the Atlantic

Ocean (ie, sea dumped) after the armistice.3,17,26

Chemical Weapons

During the war, the CWS used foreign technology for offensive weapons. The initial mode of of-
Medical Aspects of Chemical and Biological Warfare

20

fensive chemical attack was the portable chemical

cylinder, designed to hold 30 to 70 lb of agent. Soldiers simply opened a valve and hoped the wind

continued to blow in the right direction. The resulting cloud could drift many miles behind enemy

Fig. 2-8. Interior view of the Mustard Agent Production Plant at Edgewood Arsenal, Md. Photograph: Chemical and

Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

lines, or, if the wind changed, could gas friendly

troops.

The British improved on the delivery system,

developing the Livens projector, an 8-in. mortarlike

tube that shot or projected the cylinder into the

Fig. 2-7. Filling 75-mm artillery shells with mustard agent at Edgewood Arsenal, Md. Facilities designed to fill shells with

chemical agents were notoriously hazardous. Anecdotal reports from mustard shell-filling plants indicated that over several months, the entire labor force could be expected to become ill. These workers’ apparent nonchalance to the hazards of

mustard would not be tolerated by the occupational medicine standards of a later era (see Figure 2-31). Photograph: Chemical

and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

21

enemy’s lines (Figures 2-9 and 2-10). The range was

a respectable 1,700 yd, with a flight time of 25 seconds. There were several problems with the system.

Fig. 2-9. A battery of dug-in Livens projectors, with one

gas shell and its propellant charge shown in the foreground. Electrically controlled salvo firing was the usual

mode of operation. Emplacement was a slow process, and

it limited the surprise factor for attack. Photograph:

Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

Fig. 2-10. Sectionalized view of a Livens projectile. The

central tube contains a small explosive charge, which,

when detonated by the contact fuze, breaks the shell and

aids in the dissemination of the chemical agent. The usual

weight of the chemical agent was 30 lb; the shell weighed

an additional 30 lb. Photograph: Chemical and Biological Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.

Being electrically fired, a battery of Livens projectors required extensive preparation and could not

be moved once set up. Normally, a battery could

only be emplaced and fired once a day. This limited mobility required the element of surprise to

prevent the Germans from taking counter actions.

British 4-in. trench mortars, called Stokes mortars (Figure 2-11), provided a solution to some of

the problems with Livens projectors. The Stokes

mortar did not require extensive preparation and

could be moved as needed. Since it was not rifled,

the range was only 1,200 yd, which meant about a

14-second flight time. The small size of the shell

only held about 6 to 9 lb of agent, but experienced

gunners could fire 25 rounds per minute. American troops used both Livens projectors and Stokes

mortars during the war. Ordnance officers tried

making their own Stokes mortars, but none reached

the front before the end of the war.

In addition to the special chemical weapons, the

CWS fired chemical rounds from 75-mm, 4.7-in.,

155-mm, and larger-caliber guns. Many of these had

ranges of 5 to 10 miles, with payloads of as much

as 50 lb of agent. Owing to a shortage of shell parts

and the late completion of U.S. shell-filling plants,

U.S. troops primarily fired French phosgene and

mustard agent rounds.3,14,26

Biological Warfare Weapons

By 1918, the United States was apparently aware

of the German biological warfare program, but the

only agent examined was a toxin for retaliatory

Fig. 2-11. A complete Stokes mortar with ammunition and

accessories for firing. Photograph: Chemical and Biological Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

22

Fig. 2-12. Early attempts at collective protection during

World War I included the dugout blanket, which was

used to cover the doorways to dugouts. Reprinted from

Army War College. Methods of Defense Against Gas Attacks. Vol 2. In: Gas Warfare. Washington, DC: War Department; 1918: Figure 18.

purposes. Ricin, derived from castor beans, could

be disseminated two ways. The first involved adhering ricin to shrapnel bullets for containment in

an artillery shell. The results of this work were

stated in a technical report in 1918:

These experiments show two important points: (1)

easily prepared preparations of ricin can be made

to adhere to shrapnel bullets, (2) there is no loss in

toxicity of firing and even with the crudest method

of coating the bullets, not a very considerable loss

of the material itself. ... It is not unreasonable to

suppose that every wound inflicted by a shrapnel

bullet coated with ricin would produce a serious

casualty. ... Many wounds which would otherwise

be trivial would be fatal.29(p112)

The second involved the production of a ricin

dust cloud, but due to limited amounts of ricin being produced and the inefficient delivery via the

respiratory tract, little work seems to have been

pursued in this means of dissemination. Although

both approaches were laboratory tested, neither was

perfected for use in Europe before the end of the war.29

Protective Equipment

The early unsuccessful efforts to produce a

gas mask were resolved by CWS researchers at

American University and other CWS research facilities. In the spring of 1918, the CWS issued the

Richardson, Flory, and Kops (RFK) mask, which was

an improved version of the British SBR. Over 3 million were produced for U.S. troops. Late in 1918,

the CWS merged the best aspects of the RFK mask

with a French design that eliminated the scuba-type

mouthpiece. Designated the Kops Tissot Monro

(KTM) mask, only 2,000 were produced before the

end of the war.14,30–32 Humans were not the only creatures requiring protection against chemical agents:

the CWS developed protective masks for horses,

dogs, and carrier pigeons.

Other efforts at individual protection were not

very successful. Sag Paste derived its name from

Salve Antigas and was intended as an ointment that

would prevent mustard agent burns. It was made

of zinc stearate and vegetable oil and, for a short

period, provided some protection against large

doses of mustard agent. However, once the paste

absorbed the mustard, injuries occurred. In addition, there was the problem of an individual’s having to apply the paste to all the parts of his body

using his contaminated hands and while remaining on the battlefield. Over 900 tons of Sag Paste

was shipped to the AEF during the war.14,26

The early concerns with collective protection primarily concentrated on providing a group of soldiers a gas-proof place in the trenches where they

could remove the uncomfortable early gas masks.

To accomplish this objective, studies were conducted on blankets to hang over dugout doorways,

and various coatings or impregnates were examined

for agent resistance. The result was a regular cotton blanket treated with dugout-blanket oil, a special heavy oil (Figure 2-12). Over 35,000 such blankets were shipped to the AEF.26

For ventilation of the dugout, there was the special antigas fan known as the Canvas Trench Fan. A

1918 War College gas warfare manual dedicated

seven pages to the use of the fan, although all the

fan really did was disperse the gas (Figure 2-13).

Still, over 25,000 trench fans were sent to the

front.26,33

Decontamination

There was also the problem of cleaning up the

chemical agents after the gas attack. Mustard agent

was a significant problem when it came to decontaminating the ground. The Germans apparently

used chloride of lime to decontaminate the ground

after an explosion at Germany’s first mustard agent

factory in Adlershof. For the AEF, bleaching pow-
History of Chemical and Biological Warfare: An American Perspective

23

Fig. 2-13. Procedures for using the trench fan to remove chemical agents from trenches. The fan was a failure. Reprinted from Army War College. Methods of Defense Against Gas Attacks. Vol 2. In: Gas Warfare. Washington, DC: War

Department; 1918: Figure 25.

der (also known as chloride of lime or calcium hypochlorite) was the primary decontaminant during

the war. Obtained from the bleaching industry, this

white powder proved effective in neutralizing mustard agent on the ground. Almost 2,000 tons of bleaching powder was sent to the AEF during the war.

As for mustard-contaminated clothing, the recommendation was to expose it to the open air for

48 hours or longer if the weather was cold. A quicker

method was to leave the clothing inside a steam

disinfecting chamber for 3 hours, but steam chambers were normally not available to front line

troops.14,26,34

Detection and Alarms

The CWS also studied the critical need for chemical agent detectors and alarms. Initially, World War

I soldiers relied on their own senses (smell, and

throat and nose irritation) to detect chemicals. Eventually, the CWS was able to produce various dyes

that changed color when contaminated with mustard agent. Most of the formulas for the detector

paints, however, were British, and the CWS had

trouble duplicating their work.35

At least one organic detector was also studied.

One of the more interesting investigations was that

of using snails as detectors. U.S. Army scientists

reported that in the presence of mustard gas, snails

waved their tentacles wildly in the air and then

withdrew into their shells. When a prominent

French physiologist was asked about this, he burst

out laughing and said that French soldiers would

eat the snails first. A test was conducted using

French snails, but the conclusion was that the foreign snails were more conservative in their impulse

to wave their tentacles.36

Once chemical agents were detected, the alarm

was sounded by horns, rattles, bells, or whatever

loud noise was available. These alarms created

problems of their own, as the rattles often sounded

like machine-gun fire, and it was difficult to distinguish from other nonchemical alarms. By the end

of the war, the ability to detect chemical agents and

alert the troops was still in a very primitive state.

Gas Casualty Treatments

A month after the United States entered the war,

the U.S. Army War College issued Memorandum on

Gas Poisoning in Warfare with Notes on its Pathology

and Treatment,

37 a short manual for medical officers

written by a committee of consultant physicians and

physiologists. The memorandum directed that

“Rest is the most important point of all in the general treatment of gas casualties”37(p18) and recommended using morphia to calm gassed soldiers who

were too restless. Next in importance to rest were

oxygen; protection from cold; special stimulants or

drugs (particularly ampules of ammonia for inhalation, but also brandy in small sips, and pituitrin,

administered hypodermically every 3 h); venesec-
Medical Aspects of Chemical and Biological Warfare

24

tion (to relieve headaches); and removing “serous

exudate” from the lungs (by drinking water and

tickling the back of throat to produce vomiting; later

treatments included potassium iodide, atropine,

and steam tents with tincture benzoin compound).

The manual concluded by admitting: “Knowledge

on the various points discussed in this pamphlet is

still far from being stable.”37(p32)

The final version of the manual, issued in November 1918, made many changes to the original

and reflected battlefield experience. For example,

morphia was recognized as a “dangerous drug to

use when the respiration is seriously affected. Its

use should therefore be restricted to severe

cases.”38(p22) The most significant addition was information on mustard agent, which included sections for the treatment for the various organs exposed to the agent. For the skin, after cleaning the

mustard agent off a soldier with soap and water,

[a] dusting powder of zinc oxide mixed with boracic acid, chalk, and starch, or a calamine lotion

with lime water may be used after the bath to allay

skin irritation. The blisters may be evacuated by

pricking.38(p34)

The delayed action of mustard agent required

quick personnel decontamination actions. One solution was to bathe the soldiers thoroughly with

soap and water within half an hour of mustard

agent exposure. This was thought to prevent or

greatly reduce the severity of the mustard burns.

The army established degassing units that used a

5-ton truck with a 1,200-gal water tank, fitted with

heaters and piping to connect it to portable showers. A second truck held extra uniforms. Two degassing units were assigned to each division. After

the showers, the troops were give a drink of bicarbonate of soda water and then had their eyes, ears,

mouths, and noses washed with the soda water.38

Mustard agent was a significant problem for untrained soldiers. In September 1918, one Field Artillery general instructed his troops:

In view of the many casualties recently resulting

in other commands from German mustard gas, each

organization commander will take the following

precautions: (a) Each soldier will place a small piece

of soap in his gas mask container, (b) Each Chief of

Section will keep constantly on hand in each gunpit or gun position, two large bottles of soapy water—empty bottles may be purchased at wine shops

from Battery Fund, (c) In case of a gas attack, and

if opportunity permits, soapy water will be rubbed

under the arms and between the legs around the

scrotum, of soldiers affected, this serving to neutralize the pernicious effect of the gas. This effect

will be explained to the soldiers of each organization, who can only hope to prevent becoming casualties through the strictest gas discipline.39

Despite the many warnings, mustard agent

earned its designation of King of the Battlefield by

killing approximately 600 U.S. soldiers and injuring over 27,000.40

Lessons Learned

The armistice of November 1918 ended the

world’s first chemical and biological war. Of the

approximately 26 million casualties suffered by the

British, French, Russians, Italians, Germans, AustroHungarians, and the Americans, some 1 million

were gas casualties. Of the total 272,000 U.S. casualties, over 72,000 were gas casualties, or about one

fourth. Of the total U.S. gas casualties, approximately 1,200 either died in the hospital or were

killed in action by gas exposure. There were no casualties or deaths attributed to biological warfare.40

Thus the U.S. Army completed its introduction

to 20th-century chemical warfare. With the help of

the CWS, the army successfully recovered from its

early poor performance and survived repeated toxic

chemical attacks against its troops. Likewise, by the

end of the war, the First Gas Regiment and numerous U.S. artillery units successfully used toxic

chemical agents in retaliation and during offensive

operations.

At the end of the war, the United States could

proudly point to the best protective mask, abundant

munitions, and trained troops. The CWS had 1,680

officers and 20,518 enlisted personnel controlling

the army’s chemical warfare program.25

The only negative aspect was the dire prediction

of future chemical wars, as expressed by one U.S.

Army officer:

Gas was new and in an experimental stage throughout the war and hence the man who plans for future defense must consider the use of gas to have

been in its infancy. He must draw very few lessons

for the future use of gas based on past performances. He must only use those lessons as pointing the way and not as approaching a final result.

The firing of steel as shell passed its zenith with

the passing of the Argonne fight. Never again will

the world see such a hail of steel on battlefields,

but in its place will be concentrations of gas and

high explosives as much greater than the World

War as that was greater than the Civil War.41(p4)
History of Chemical and Biological Warfare: An American Perspective

25

In contrast, Fritz Haber, the Nobel laureate chemist who, more than anyone else, was responsible for

the development and fielding of chemical weapons

for use by Kaiser Wilhelm II’s army, downplayed the

importance of chemical warfare as a weapon of mass

destruction after the surprise was gone. In an interview published in New York in 1921, he concluded:

“Poison gas caused fewer deaths than bullets.”42(p10)

General John J. Pershing summed up his opinion of the new chemical warfare shortly after the

conclusion of World War I:

Whether or not gas will be employed in future wars

is a matter of conjecture, but the effect is so deadly

to the unprepared that we can never afford to neglect the question.43(p77)

THE 1920S: THE LEAN YEARS

The Chemical Warfare Service Made Permanent

Following the successful conclusion of World

War I, the U.S. Army almost immediately tried to

forget everything it had learned during the war

about being prepared for future chemical warfare.

The first major concern of the new CWS was to ensure that it survived demobilization. The army had

organized the CWS as a temporary war measure, a

part of the National Army only, and that temporary

existence was due to expire within 6 months after

the end of the war. This 6 months was later extended

to 30 June 1920. During hearings before the U.S.

Congress, Secretary of War Newton D. Baker testified, “We ought to defend our army against a gas

attack if somebody else uses it, but we ought not to

initiate gas.”44(p3) He and Chief of Staff General

Peyton C. March both used this philosophy to recommend both abolishing the CWS and outlawing

chemical warfare by a treaty.45

Even General Sibert, when asked about the need

for a permanent CWS and the possibility of chemical warfare in future wars, replied:

Based on its effectiveness and humaneness, [chemical warfare] certainly will be an important element

in any future war unless the use of it should be

prohibited by international agreement. As to the

probability of such action, I cannot venture an

opinion.46(p87)

To persuade congress to keep the CWS, several

prominent civilian and military leaders lobbied to

include a permanent chemical warfare organization.

Lieutenant Colonel Amos A. Fries, a CWS officer

and one of the strongest proponents of a permanent

organization, stressed the need for a central organization, one that covered all aspects of chemical

warfare (Figure 2-14). He drew on the lessons

learned from the previous war:

Had there been a Chemical Warfare Service in 1915

when the first gas attack was made, we would have

been fully prepared with gases and masks, and the

army would have been trained in its use. This

would have saved thousands of gas cases, the war

might easily have been shortened six months or

even a year, and untold misery and wasted wealth

might have been saved.47(p4)

Fig. 2-14. Amos A. Fries, shown here as a major general,

was chief of the Chemical Warfare Service between 1921

and 1929. “With his dynamic personality and extensive

contacts in Congress and the chemical industry, he quite

literally kept the CWS alive.” Quotation: Brown FJ.

Chemical Warfare—A Study in Restraints. Princeton, NJ:

Princeton University Press; 1968: 130. Photograph: Chemical and Biological Defense Command Historical Research

and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

26

He also stressed that both offensive and defensive

research must be conducted:

Just as developments in masks have gone on in the

past just so will they go in the future. Just as from

time to time gases were found that broke down or

penetrated existing masks, just so in the future will

gases be found that will more or less break down

or penetrate the best existing masks. Accordingly,

for thorough preparation, mask development must

be kept absolutely parallel with development in

poisonous and irritating gases. Mask development

cannot, however, be kept parallel unless those

working on masks know exactly what is going on

in the development of poisonous gases. Thus a nation that stops all investigation into poisonous

gases cannot hope to be prepared on the defensive

side should the time ever come when defense

against gas is needed.20(pp7–8)

Fries also disagreed with the premise that treaties could prevent chemical warfare:

Researches into poisonous gases cannot be suppressed. Why? Because they can be carried on in

out-of-the-way cellar rooms, where complete plans

may be worked out to change existing industrial

chemical plants into full capacity poisonous gas

plants on a fortnight’s notice, and who will be the

wiser?20(p3)

Although Fries was very persuasive and eloquent

in his comments, a young lieutenant, who published

the following poem in 1919, more graphically expressed the opinion of those who understood the

nature of chemical warfare:

There is nothing in war more important than gas

The man who neglects it himself is an ass

The unit Commander whose training is slack

Might just as well stab all his men in the back.48(cover iv)

The chemical warfare specialists won the argument. On 1 July 1920, the CWS became a permanent part of the Regular Army. Its mission included

development, procurement, and supply of all offensive and defensive chemical warfare material, together with similar functions in the fields of smoke

and incendiary weapons. In addition, the CWS was

made responsible for training the army in chemical

warfare and for organizing, equipping, training, and

employing special chemical troops (Figure 2-15).25,49

Despite the encouragement of permanent status

and surviving demobilization, the years after 1920

were lean (ie, austere) ones for the CWS, as indeed

they were for the army as a whole. The CWS was

authorized only 100 Regular Army officers but

never actually achieved that number. The low point

was 64 in 1923. Enlisted strength dropped to a low

of 261 in 1919 and averaged about 400 the rest of

the decade. Civilian employees numbered fewer

than 1,000. The low point in funding was in 1923,

when the amount was $600,000.25

After 1919, almost all the work of the CWS moved

to Edgewood Arsenal, Maryland, with only the

headquarters remaining in Washington, D. C.

Edgewood became the center of training, stockpiling, and research and development. Initially,

the CWS was authorized to train only its own troops

in all aspects of chemical warfare, while the

General Staff permitted only defensive training

for other army elements (Figure 2-16). The CWS

protested this limitation and finally in May 1930,

the Judge Advocate General ruled that both offensive and defensive training were allowed for all

troops.50

Leftover stocks of chemicals from World War I

were deemed sufficient for the army’s stockpile. In

1922, to comply with the Limitation of Arms Conference, the War Department ordered that “[t]he filling of all projectiles and containers with poisonous

gas will be discontinued, except for the limited

number needed in perfecting gas-defense appliances.”51 The CWS was only allowed to continue

limited research and development based on perceptions of future wars.51,52

To improve its standing with the taxpayers and

the growing pacifist movement, the CWS also expanded its research capabilities into nonmilitary

Fig. 2-15. The first temporary Chemical Warfare School

building at Edgewood Arsenal, Md., shortly after the end

of World War I. The school was later moved to a permanent structure. Photograph: Chemical and Biological

Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

27

Fig. 2-16. Soldiers wearing protective

clothing are firing 75-mm mustard

agent shells at Edgewood Arsenal,

Md., in 1928. Photograph: Chemical

and Biological Defense Command

Historical Research and Response

Team, Aberdeen Proving Ground, Md.

projects. These special projects included such activities as preserving wooden dock structures (1923)

and fighting boll weevils (1925–1927).53–55

New Chemical Weapons

In 1928, the CWS formalized the standardization

of chemical agents. Seven chemical agents and smokes

were selected as the most important. The seven, with

their symbols, were mustard agent (HS), methyldifluorarsine (MD), diphenylaminechlorarsine (DM),

chloroacetophenone (CN), titanium tetrachloride

(FM), white phosphorus (WP), and hexachlorethane

(HC). Phosgene (CG) and Lewisite (L) were considFig. 2-17. An experimental 4.2-in. chemical mortar, showing (1) the standard, (2) the barrel with the shock-absorbing mechanism, and (3) the tie rods connecting the standard to the baseplate. This weapon differed from the

Stokes mortar, its predecessor, in that it was easier to set

up and it was rifled; the spiral grooves can be seen on the

inside of the barrel at its muzzle. Photograph: Chemical

and Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

Fig. 2-18. The chemical weapons of the 1920s and 1930s.

From left to right: the 75-mm mustard shell; the 4.2-in.

white phosphorus shell; the M1 30-lb mustard bomb; the

Mk II 155-mm mustard shell; the Livens phosgene projectile; and the Mk I portable chemical cylinder. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving

Ground, Md.

ered of lesser importance. Chloropicrin (PS) and chlorine (Cl) were rated the least important.3

Delivery systems were also improved. As early

as 1920, Captain Lewis M. McBride experimented

with rifling the barrel of the Stokes mortar. In 1924,

a Stokes mortar barrel was rifled and tested. In truing the inside diameter of the 4-in. barrel preparatory to rifling, the bore was enlarged to 4.2 in. in

diameter. This work increased the range of the mortar from 1,100 yd to 2,400 yd. In 1928, the improved

mortar was standardized as the M1 4.2-in. chemical

mortar and became the CWS’s prized ground weapon

for the delivery of toxic chemical agents as well as

smoke and high explosives (Figures 2-17 and 2-18).26
Medical Aspects of Chemical and Biological Warfare

28

Fig. 2-19. A schematic diagram showing the M1 Service

Gas Mask. The M1 eliminated the nose clip and mouthpiece of the box respirators of World War I vintage. By

directing the incoming air over the eyepieces, it also

helped eliminate lens fogging. Photograph: Chemical and

Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

One much-discussed topic was the role that airplanes would take in the next chemical war. Fries

predicted:

The dropping of gas bombs of all kinds upon assembly points, concentration camps, rest areas and

the like, will be so fruitful a field for casualties and

for wearing down the morale of armies in the future that it will certainly be done and done on the

very first stroke of war.56(pp4–5)

To meet this need, the CWS standardized the M1

30-lb chemical bomb. It held only about 10 lb of

agent owing to its thick shell. As a test of the use of

airplanes in a chemical war, the CWS first demonstrated simulated chemical attacks against battleships in 1921.3,57

New Protective Equipment

The CWS concentrated, however, on defensive

work. After the war, the CWS continued working

on the KTM mask, which became known as the

Model 1919. In 1921, the mask officially became the

M1 Service Gas Mask (Figure 2-19); it had a rubber

facepiece and was available in five sizes.30,58 The hope

was to issue a protective mask to every soldier in the

army. One proponent described the reason why:

To put the matter briefly, a modern army which

enters on a campaign without respirators is

doomed from the outset. It is asking to be attacked

by gas, most certainly will be, and equally certainly

will be destroyed. A soldier without a respirator is

an anachronism.59(p129)

Biological Warfare Program

During the early 1920s, there were several suggestions from within the CWS that it undertake

more research into biological agents. Fries, who had

been promoted to major general and had replaced

Sibert as the Chief Chemical Officer in 1920, however, decided it was not profitable to do so. In 1926,

he wrote in the annual report of the CWS:

The subject of bacteriological warfare is one which

has received considerable notice recently. It should

be pointed out in the first place that no method for

the effective use of germs in warfare is known. It

has never been tried to any extent so far as is

known.60(p8)

The new League of Nations, which had been

quoted in the annual report, concluded the same:

[Biological] warfare would have little effect on the

actual issue of a war because of protective methods available; that filtering and chlorinating drinking water, vaccination, inoculation, and other methods

known to preventive medicine, would so circumscribe its effect as to make it practically ineffective.60(p8)

Chemical–Biological Warfare Use and Plans

Throughout the 1920s, rumors of chemical

warfare attacks plagued the world. Besides the

United States and the major World War I powers,

several other countries began to develop a chemical warfare capability. Some of the countries with

chemical weapons used them in their military operations. During the Russian Civil War and Allied

intervention in the early 1920s, both sides had

chemical weapons, and there were reports of iso-
History of Chemical and Biological Warfare: An American Perspective

29

lated chemical attacks. Later accounts3,21 accused

the British, French, and Spanish of using chemical

warfare at various times during the 1920s. One

country in particular attracted the attention of the

United States. As early as 1924, the CWS began to

take note of the growing Italian chemical warfare

capability. That was the year the Italians established

the Centro Chemico Militaire, a unified chemical

warfare service and began production of chemical

agents.61–63

Two events related to biological warfare probably went unnoticed by the Americans. In 1928, a

Japanese officer by the name of Shiro Ishii began

promoting biological warfare research and took a

2-year tour of foreign research establishments,

including the United States. After his tour, he

concluded that all the major powers were secretly

researching biological warfare. Although his conclusion was erroneous for the United States, it was

probably accurate for the Soviet Union. In 1929, the

Soviets reportedly established a biological warfare

facility north of the Caspian Sea.3,21,64,65

While the CWS struggled to survive and keep the

army ready for a chemical war, international attempts were made to prohibit chemical warfare. The

Treaty of Versailles, completed in 1919, prohibited

Germany from producing, storing, importing, or

using poisons, chemicals, and other chemical weapons. The treaty was not ratified by the United States.

A separate treaty with Germany did not mention

chemical warfare, but the United States agreed to

comply with the provisions of the Treaty of

Versailles in relation to poisonous gases.

Although the new League of Nations concluded

in 1920 that chemical warfare was no more cruel

than any other method of warfare used by combatants, the Limitation of Arms Conference, held in

Washington, D. C., in 1922, banned the use of poisonous gases except in retaliation. The United States

ratified the limitation, but France declined to ratify

the treaty and therefore it was never implemented.

This unsuccessful attempt was followed by the

1925 Geneva Protocol, which was signed by 28

countries, including the United States. This agreement condemned the use of gas and bacteriological

warfare. The U.S. Senate, however, refused to ratify

the Protocol and remained uncommitted by it. The

senate had apparently decided that chemical warfare was no more cruel than any other weapon and

therefore should not be banned. The general policy

of the U.S. government, however, still tended toward the discouragement of all aspects of chemical

warfare, but was tempered by a policy of preparedness should chemical warfare occur again.66–69

THE 1930S: THE GROWING THREAT OF CHEMICAL AND BIOLOGICAL WARFARE

Further international attempts to ban not only

the use of chemical weapons but also all research,

production, and training caused a response that

developed into a new U.S. policy on chemical warfare. The U.S. Army Chief of Staff, General Douglas

MacArthur, stated the policy in a letter to Secretary

of State Henry L. Stimson in 1932:

In the matter of chemical warfare, the War Department opposes any restrictions whereby the United

States would refrain from all peacetime preparation

or manufacture of gases, means of launching gases,

or defensive gas material. No provision that would

require the disposal or destruction of any existing

installation of our Chemical Warfare Service or of any

stocks of chemical warfare material should be incorporated in an agreement. Furthermore, the existence

of a War Department agency engaged in experimentation and manufacture of chemical warfare materials, and in training for unforeseen contingencies is

deemed essential to our national defense.45(p118)

There were no other major attempts to ban chemical and biological warfare during the 1930s.

New Chemical Agents and Weapons

The CWS continued to maintain stockpiles of the

key World War I–chemical agents during the 1930s.

Captain Alden H. Waitt, then Secretary of the

Chemical Warfare School at Edgewood Arsenal and

later Chief Chemical Officer, summed up the CWS’s

planning for the next war in 1935:

Foreign writers agree that at least for the first few

months of any war, should one occur within a few

years, the gases that were known at the end of the

World War would be used. Of these, the opinion is

unanimous that mustard gas would be the principal agent and the most valuable. Opinion in the

United States coincides with this.70(p285)

In 1937, Edgewood Arsenal rehabilitated their

mustard agent plant and produced 154 tons of mustard agent to increase their stockpile (Figure 2-20). The

same year, the phosgene plant was renovated for additional production, and the CWS changed phosgene

from substitute standard to standard (Figure 2-21).71
Medical Aspects of Chemical and Biological Warfare

30

The result of the CWS’s confidence in these selected agents was that the CWS missed the development of several key new agents. Waitt wrote:

Occasionally a statement appears in the newspapers that a new gas has been discovered superior

to any previously known. Such statements make

good copy, but not one of them has ever been verified. Today no gases are known that are superior

to those known during the World War. It is unlikely

that information about a new gas will be obtained

until it is used in war. The chemical agent is too

well adapted to secrecy. The only insurance against

surprise by a new gas is painstaking research to

find for ourselves every chemical agent that offers

promise for offensive or defensive uses. It seems

fairly safe to say that today mustard gas is still the

king of warfare chemicals and to base our tactical

schemes on that agent as a type.70(p285)

Yet already the reign of mustard agent was ending. In 1931, Kyle Ward, Jr., published an article

describing nitrogen mustard, a vesicant agent with

no odor. The CWS investigated the new substance

and found it to be less vesicant than sulfur mustard. The U.S. Army eventually standardized nitrogen mustard as HN-1, although it was the Germans

who took a great interest in the new vesicant.3

In 1936, German chemist Dr. Gerhart Schrader

of I. G. Farbon Company discovered an organophosphorus insecticide, which was reported to the

Chemical Weapons Section of the German military

prior to patenting. The military was impressed with

the effects of the compound on the nervous system

and classified the project for further research. The

military assigned various names to the new substance, including Trilon-83 and Le 100, but tabun

was the name that stuck. After World War II, the

CWS designated it GA, for “German” agent “A.”

Fig. 2-20. The Mustard Manufacturing Plant at Edgewood Arsenal, Md.

Photograph: Chemical and Biological

Defense Command Historical Research and Response Team, Aberdeen

Proving Ground, Md.

About 2 years later, Schrader developed a

similar agent, designated T-144 or Trilon-46 and

eventually called sarin, which was reportedly

5 times as toxic as tabun. The United States

later designated this agent GB. The Germans

assigned a large number of chemists to work

on these new nerve agents and began building a

pilot plant for production in 1939, the year World

War II started.3,72,73

Fig. 2-21. Interior view of the Phosgene Production Plant

at Edgewood Arsenal, Md. The low level of chemical

engineering technology apparent in this World War II–

era photograph is relevant to the problem of chemical

agent proliferation today. Elaborate, expensive equipment is not required for mass-producing the less-sophisticated chemical agents. Photograph: Chemical and Biological Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

31

During the 1930s, the CWS stockpiled the chemical weapons used by World War I ground forces in

preparation for a future war. These were primarily

Livens projectors, Stokes mortars, and portable cylinders. In addition, there were chemical shells for

75-mm, 105-mm, and 155-mm artillery pieces (Figures 2-22 and 2-23).

The production of the new 4.2-in. chemical mortar eventually made that weapon the key ground

delivery system for the CWS. Between 1928 and

1935, the army attempted to make the 4.2-in. mortar a mechanized weapon by mounting it on various vehicles (Figure 2-24). The CWS also began exFig. 2-22. A Field Artillery unit prepared for chemical war.

Both the men and the horses required protection against

the agents. Photograph: Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

Fig. 2-23. Battery D, 6th Field Artillery, firing a 75-mm

gun while in protective clothing at Edgewood Arsenal,

Md., in 1936. The overgarments of the 1920s were made

of rubberized cloth or cloth impregnated with substances

such as linseed oil. These overgarments were heavier and

hotter than today’s protective clothing. Note the lack of

overboots. Photograph: Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

Fig. 2-24. A 4.2-in. chemical mortar mounted on a light

cargo carrier in 1928. The carrier had a speed of 20 mph.

Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

periments in 1934 to make the mortar a more versatile weapon by testing high-explosive shells as an

alternative to chemical rounds.

In 1935, the improved M1A1 mortar was standardized. The M1A1 had an improved barrel and baseplate, and a new standard connected to the baseplate

by two tie-rods for support. The M1A1 had a maximum range of 3,200 yd (1.8 miles). Each shell held 5

to 7 lb of either phosgene, mustard agent, cyanogen

chloride, white phosphorus, or smoke agent.3,26

Additional new delivery systems also included

the first standardized chemical land mine for mustard agent in 1939. Designated the M1, this 1-gal

gasoline-type can held 9.9 lb of mustard agent and

required detonating cord to burst the can and disseminate the agent.74

For air delivery, the CWS standardized the first

good airplane smoke tank, the M10, in 1933. This tank

held 30 gal of mustard (320 lb), Lewisite (470 lb), or

smoke material. The system was rather simple. Electrically fired blasting caps shattered frangible seals in

the air inlet and the discharge line, which allowed air

and gravity to force the liquid out. The slipstream of

the plane then broke up the liquid into a spray.74

Biological Warfare Developments

While chemical warfare received some attention

during the 1930s, biological warfare received very

little. In 1933, Major Leon A. Fox, Medical Corps,
Medical Aspects of Chemical and Biological Warfare

32

Fig. 2-25. The Japanese UJI bacterial bomb, drawn from

sketches given to Lieutenant Colonel Murray Sanders,

Chemical Warfare Service, in 1945. Porcelain rather than

metal was used to form the “shell” because it could be

shattered by a much smaller explosive charge. This protected the biological agent, assuring that it would be subjected to less heat and pressure. Reprinted from Scientific and Technical Advisory Section, US Army Forces,

Pacific. Biological Warfare. Vol 5. In: Report on Scientific

Intelligence Survey in Japan. HQ, US Army Forces, Pacific;

1945: appended chart.

U.S. Army, wrote an article on bacterial warfare for

The Military Surgeon that began:

Bacterial warfare is one of the recent scare-heads

that we are being served by the pseudo-scientists

who contribute to the flaming pages of the Sunday

annexes syndicated over the Nation’s press.75(p189)

He then proceeded to point out the difficulties of

trying to weaponize biological agents. For example,

bubonic plague would create significant problems

for friendly troops as well as the enemy:

The use of bubonic plague today against a field

force, when the forces are actually in contact, is

unthinkable for the simple reason that the epidemic

could not be controlled. Infected personnel captured would provide the spark to set off possible

outbreaks of pneumonic plague in the ranks of the

captors. Infected rats would also visit and spread

the condition. An advance over terrain infected

with plague-bearing rats would be dangerous.

Therefore, except as a last desperate, despairing

hope of a rapidly retreating army, the use of plague

by forces in the field is not to be considered.75(p202)

After dismissing the causative organisms of malaria, yellow fever, anthrax, and other such agents,

he concluded:

I consider that it is highly questionable if biologic

agents are suited for warfare. Certainly at the

present time practically insurmountable technical

difficulties prevent the use of biologic agents as

effective weapons of warfare.75(p207)

The same year that Fox wrote his article, Germany began military training in offensive biological warfare and reportedly covertly tested Serratia

marcescens, considered a biological simulant, in the

Paris Metro ventilation shafts and near several

French forts. Three years later they conducted

antianimal experiments with foot and mouth disease at Luneburger Heide. The next year the German Military Bacteriological Institute in Berlin began developing anthrax as a biological weapon,

while the Agricultural Hochschule in Bonn examined the spraying of crops with bacteria.3,65

Even the future allies of the United States in

World War II were working on biological warfare

programs. By 1936, France had a large-scale biological warfare research program working on bacterial

and viral viability during storage and explosive

dispersal. The same year, Britain established a committee to examine offensive and defensive biological warfare issues. By 1940, the British chemical

laboratory at Porton Down had a biological warfare laboratory. Canada initiated biological warfare

research under Sir Frederick Banting at Connaught

Laboratories, Ile Grosse, and at Suffield in 1939. The

Canadians started work on anthrax, botulinum

toxin, plague, and psittacosis.3,65

One man who definitely thought differently from

Fox was Japan’s Ishii. In 1933, he set up an offensive biological warfare laboratory in occupied Manchuria, later designated Detachment 731, which

developed and tested a biological bomb within 3

years and also tested biological agents on Chinese

prisoners. Additional biological warfare facilities

were established in 1939, the same year that Japanese troops allegedly entered Russia to poison animals with anthrax and other diseases.
History of Chemical and Biological Warfare: An American Perspective

33

Fig. 2-26. In addition to the standard Service Gas Mask,

the Chemical Warfare Service also designed diaphragm

masks for speaking capability. Note the hood, which covered the skin of the head, face, and neck. The soldier also

wears chemically protective gloves. Since the uniform

was impregnated with a substance that hindered the penetration of mustard, in theory, no portion of his skin was

subject to mustard injury. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

By 1940, Ishii had developed and tested in the

field nine different kinds of biological bombs and

had produced over 1,600 bombs, although some had

been expended in research. The 40-kg Ha bomb,

filled with a mixture of shrapnel and anthrax spores,

and the 25-kg Type 50 UJI bomb, also filled with

anthrax spores, were considered the most effective

(Figure 2-25). His early discoveries that conventional bombs filled with biological agents failed to

disseminate the agent properly did, however, confirm some of Fox’s beliefs. The Japanese were able

to disseminate typhus rickettsia, cholera bacteria,

and plague-infested fleas through Ning Bo in China,

where 500 villagers died from plague epidemics. By

the beginning of World War II, Ishii was concentrating on the use of vectors such as the common

flea to carry the biological agents.3,64,76

New Defensive Equipment

The M1 gas mask design proved to be a reliable

choice for over a decade. In 1934, minor modifications to the head-harness straps and the mounting

of the eyepieces resulted in the M1A1 mask.

In 1935, the first major modification to the original design was introduced as the M1A2 mask. The

M1A2 was constructed from a flat rubber faceblank

with a seam at the chin. This design allowed the

mask to be issued in one universal size, although

the small and large sizes of the M1A1 continued in

production. This mask became the standard mask

for the army up to the beginning of World War II.

By 1937, Edgewood Arsenal was producing over

50,000 masks per year (Figure 2-26).30

Collective protection during the 1930s began the

advancement from the passive dugout blanket of

World War I to the modern mechanical systems.

Although most major powers initiated work on collective protection for troops in the field during the

1920s, the CWS did not standardize its first unit

until 1932. That year, the M1 Collective Protector, a

huge, 1,210-lb, fixed installation unit providing 200

cu ft of air per minute, was typed classified for use

primarily in coastal forts. The level of protection

was the same as that provided by the standard gas

mask canister.77

For decontamination, the CWS concentrated on

mustard agent decontaminants. Ordinary bleach,

used during World War I, was considered the most

effective but was corrosive to metals and had only

a 3-week storage life in the tropics (Figure 2-27).

Early work, starting in 1930, used simple tanks

filled with DR1 emulsion, a soap prepared with

magnesium carbonate, animal fat, and kerosene,

and designed primarily for ship decontamination.

The next development involved commercial items

such as insecticide sprayers, fire extinguishers, agricultural spreaders, and road sprinklers. The best

sprayer was the 3-gal Demustardizing Apparatus,

Commercial Type, standardized in 1938. The 11⁄2-qt

Demustardizing Apparatus was used for lighter

work. This fire extinguisher–type sprayer was recommended for standardization in 1937.

Agricultural spreaders and road sprinklers

proved less successful at disseminating the proper

amount of decontaminant. Just before the beginning

of World War II, the CWS also investigated the

power-driven demustardizing apparatus, which

was based on a commercial orchard sprayer with a

300-gal tank and an 8-hp engine.

In 1938, the CWS made the important discovery

of the decontaminating capability of the compound

RH-195, developed by the Du Pont Company, when
Medical Aspects of Chemical and Biological Warfare

34

Fig. 2-27. Cleaning up mustard agent

in the field with bleaching powder

and soil. The labor-intensive nature

of mustard decontamination is readily apparent. Note that the exercise

is being conducted in the winter; no

doubt the chemical protective garments shown here would have constituted a considerable thermal load.

Photograph: Chemical and Biological

Defense Command Historical Research and Response Team, Aberdeen

Proving Ground, Md.

mixed with acetylene tetrachloride. This combination was later designated Decontaminating Agent,

Non-Corrosive (DANC). DANC was a whitish powder that liberated chlorine more slowly than ordinary bleaching material and therefore was more

stable in storage. One gallon of DANC could decontaminate 15 sq yd of heavily contaminated soil.34

Italian–Ethiopian War

The first major use of chemical weapons after

World War I came in 1935 during the Italian–Ethiopian War. On 3 October 1935, Benito Mussolini

launched an invasion of Ethiopia from its neighbors

Eritrea, an Italian colony, and Italian Somaliland.

Ethiopia protested the invasion to the League of

Nations, which in turn imposed limited economic

sanctions against Italy. These sanctions, although

not crippling, put a deadline pressure on Italy to

either win the war or withdraw.

The initial Italian offensive from Eritrea was not

pursued with the proper vigor in Mussolini’s opinion, and the Italian commander was replaced. The

new commander, Marshal Pietro Badoglio, was ordered to finish the war quickly. He resorted to

chemical weapons to defeat the Ethiopian troops

led by Emperor Haile Selassie. Despite the Geneva

Protocol of 1925, which Italy had ratified in 1928

(and Ethiopia in 1935), the Italians dropped mustard bombs and occasionally sprayed it from airplane tanks. They also used mustard agent in powder form as a “dusty agent” to burn the unprotected

feet of the Ethiopians. There were also rumors of

phosgene and chloropicrin attacks, but these were

never verified.

The Italians attempted to justify their use of

chemical weapons by citing the exception to the

Geneva Protocol restrictions that referenced acceptable use for reprisal against illegal acts of war. They

stated that the Ethiopians had tortured or killed

their prisoners and wounded soldiers.78–90

Chemical weapons were devastating against the

unprepared and unprotected Ethiopians. With few

antiaircraft guns and no air force, the Italian aircraft ruled the skies. Selassie emotionally described

the nightmare to the League of Nations:

Special sprayers were installed on board aircraft

so they could vaporize over vast areas of territory

a fine, death-dealing rain. Groups of 9, 15, or 18

aircraft followed one another so that the fog issuing from them formed a continuous sheet. It was

thus that, as from the end of January 1936, soldiers,

women, children, cattle, rivers, lakes, and pastures

were drenched continually with this deadly rain.

In order more surely to poison the waters and pastures, the Italian command made its aircraft pass

over and over again. These fearful tactics succeeded. Men and animals succumbed. The deadly

rain that fell from the aircraft made all those whom

it touched fly shrieking with pain. All those who

drank poisoned water or ate infected food also succumbed in dreadful suffering. In tens of thousands

the victims of Italian mustard gas fell.83(pp151–152)

By May 1936, Italy’s army completely routed the

Ethiopian army. Italy controlled most of Ethiopia

until 1941 when British and other allied troops reconquered the country.

The U.S. Army closely followed the war and sent

Major Norman E. Fiske as an observer with the Italian army and Captain John Meade as an observer

with the Ethiopian army. Their different conclusions

as to the role of chemical warfare in the war reflected the sides they observed. Major Fiske thought

the Italians were clearly superior and that victory
History of Chemical and Biological Warfare: An American Perspective

35

for them was assured no matter what. The use of

chemical agents in the war was nothing more than

an experiment. He concluded:

From my own observations and from talking with

[Italian] junior officers and soldiers I have concluded that gas was not used extensively in the

African campaign and that its use had little if any

effect on the outcome.88(p20)

His opinion was supported by others who felt that

the Ethiopians had made a serious mistake in abandoning guerrilla operations for a conventional war.

Captain Meade, on the other hand, thought that

chemical weapons were a significant factor in winning the war. They had been used to destroy the

morale of the Ethiopian troops, who had little or

no protection, and to break up any attempts at concentration of forces. Captain Meade concluded:

It is my opinion that of all the superior weapons

possessed by the Italians, mustard gas was the most

effective. It caused few deaths that I observed, but

it temporarily incapacitated very large numbers

and so frightened the rest that the Ethiopian resistance broke completely.88(p20)

Major General J. F. C. Fuller, assigned to the Italian army, highlighted the Italian use of mustard

agent to protect the flanks of columns by denying

ridge lines and other key areas to the Ethiopians.

He concluded:

In place of the laborious process of picketing the

heights, the heights sprayed with gas were rendered unoccupiable by the enemy, save at the gravest risk. It was an exceedingly cunning use of this

chemical.85(p143)

Still another observer stated:

I think [where mustard] had [the] most effect was

on animals; the majority of the Ethiopian armies

consisted of a number of individual soldiers, each

with his donkey or mule on which he carried rations. These donkeys and mules ate the grass and

it killed them, and it was that which really broke

down morale more than anything.86(p81)

B. H. Liddell Hart, another military expert, compromised between the two schools of thought and

concluded:

The facts of the campaign point unmistakably to

the conclusion that mechanization in the broad

sense was the foundation on which the Italians’

military superiority was built, while aircraft, the

machine gun, and mustard gas proved the decisive

agents.87(p330)

All observers, however, seemed to agree that the

Italians would eventually have won whether chemical agents were used or not.

In general, the U.S. Army learned little new from

this war. The annual report for 1937 stated that

“situations involving the employment of chemical

agents have been introduced into a greater number

of problems.”89 The CWS Chemical Warfare School

concluded that “the use of gas in Ethiopia did not

disclose any new chemical warfare tactics,”90 but

only reconfirmed existing tactical use expectations.

The school also initiated a class for Army Air Corps

personnel (Figure 2-28).90 One senior air corps officer, perhaps noting the successful Italian use of

spray tanks, commented, “We want that course repeated again and again until all of our people are

thoroughly awake to the necessity for training and

preparation.”91(p153)

Japanese Invasion of China

The next war that drew the interest of chemical

warfare experts was the Japanese invasion of China

in 1937. The Japanese, in addition to their biological work, had an extensive chemical weapons program and were producing agent and munitions in

large numbers by the late 1930s. During the resulting war with China, Japanese forces reportedly beFig. 2-28. Aerial spraying of a Chemical Warfare School

class with tear gas during a training event. Photograph:

Chemical and Biological Defense Command Historical

Research and Response Team, Aberdeen Proving Ground,

Md.
Medical Aspects of Chemical and Biological Warfare

36

Fig. 2-29. The 150-mm German Nebelwerfer rocket projector was developed in the 1930s; one of its intended

uses was to disseminate chemical

agents. This fact was supposed to be

disguised by naming it the Nebelwerfer (literally “smoke-screen layer”).

As events transpired during World

War II, Nebelwerfers were used exclusively as rocket artillery, firing

high-explosive projectiles. Photograph: Chemical and Biological Defense Command Historical Research

and Response Team, Aberdeen Proving Ground, Md.

gan using chemical shells, tear gas grenades, and

lacrimatory candles, often mixed with smoke

screens.

By 1939, the Japanese reportedly escalated to

mustard agent and Lewisite. Against the untrained

and unequipped Chinese troops, the weapons

proved effective. The Chinese reported that their

troops retreated whenever the Japanese used just

smoke, thinking it was a chemical attack.21,92

Preparing for the Next War

After the Italian–Ethiopian War, the possibility

of war in Europe became the primary concern of

the U.S. Army. The CWS closely studied the chemical warfare capabilities of Germany and Italy, although it missed the German development of nerve

agents.

The United States, although largely isolationist

in policy, followed the declining political situation

in Europe and decided to begin a gradual improvement in its military posture. Official policy, however, was against the employment of chemical

warfare, and initially the CWS met with much resistance. President Franklin D. Roosevelt detested

chemical warfare and in 1937 refused to permit the

redesignation of the CWS as a corps. There was no

ongoing chemical warfare in Europe to learn from,

and public opinion continued to be solidly against

any use of chemical weapons. In addition, the issue of whether the CWS should field ground combat units, particularly chemical mortar battalions,

distracted policy makers and was only resolved by

the U.S. Army Chief of Staff, who finally approved

two battalions just before the beginning of World

War II.45

THE 1940S: WORLD WAR II AND THE NUCLEAR AGE

The start of World War II in 1939 and the rapid

collapse of France in the spring of 1940 stimulated

a major increase in the rate of American rearmament. Although no major use of chemical and biological agents occurred, rumors and reports of incidents of chemical and biological warfare attracted

the attention of intelligence officers. Although much

of Germany’s and Japan’s chemical and biological

weapons programs did not become known until

after the war, the actual threat was impressive.

During the war, Germany produced approximately 78,000 tons of chemical warfare agents. This

included about 12,000 tons of the nerve agent tabun,

produced between 1942 and 1945. Germany also

produced about 1,000 lb of sarin by 1945. The key

nerve agent weapons were the 105-mm and 150-mm

shells, the 250-kg bomb, and the 150-mm rocket. The

latter held 7 lb of agent and had a range of about 5

miles when fired from the six-barrel Nebelwerfer

launcher (Figure 2-29). Mustard agent, however,

was still the most important agent in terms of production, and the Germans filled artillery shells,

bombs, rockets, and spray tanks with the agent.

Phosgene, of somewhat lesser importance, was

loaded in 250- and 500-kg bombs. The Germans

were the greatest producers of nitrogen mustards

and produced about 2,000 tons of HN-3. This was

filled in artillery shells and rockets. They also had
History of Chemical and Biological Warfare: An American Perspective

37

a large number of captured chemical munitions

from France, Poland, USSR, Hungary, and other

occupied countries.3,26

Germany’s biological warfare program was much

less extensive than its chemical program. Most of

the Germans’ work was apparently with antipersonnel agents such as the causative organisms of

plague, cholera, typhus, and yellow fever. They also

investigated the use of vectors to attack animals and

crops.21,65

Japan produced about 8,000 tons of chemical

agents during the war. The Japanese loaded mustard agent, a mustard–Lewisite mixture, and phosgene in shells and bombs and gained experience in

their use during their attacks on China. They also

filled hydrogen cyanide in mortar and artillery

shells, and in glass grenades. Japan’s biological

warfare program was also in full swing by World

War II, and many weapons had been laboratoryand field-tested on humans.26

The possibility that massive chemical or biological attacks could happen any day kept CWS officers pushing for preparedness. A newspaper article

reflected the common prediction circulating in the

press:

European military authorities have predicted

that gas would be used in the present war, if at any

time the user could be sure of an immediate and

all-out success from which there could be no

retaliation.93(p37)

Major General William N. Porter (Figure 2-30),

the new chief of the CWS, warned that Hitler was

likely to use chemical weapons “at any moment.”

He also felt that “No weapon would be too bad to

stop or defeat Hitler”94(p31) and wanted to “fight fire

with fire in the event an enemy chooses to use poison gas.”95(p36)

Preparing for Chemical Warfare

During the massive 1941 training maneuvers, the

U.S. Army used a scenario that called for no first

use of chemical weapons by either side. Troops carried gas masks, but were to wear them only in areas designated as being under gas attack. Simulated

chemical agent attacks were made by placing signs

stating “Mustard Gas” in various areas and, in some

cases, using molasses residuum, a popular mustard

simulant. However, in the latter case, the army ran

into a serious problem of getting the stains out of

their uniforms. Despite this hitch, at least one participant concluded:

Fig. 2-30. Major General William N. Porter commanded

the Chemical Warfare Service during World War II. Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

There was clear evidence that distinct progress was

made during the maneuvers in arousing interest

in the use of chemical warfare means and methods

under battlefield conditions. As a result, a greater

portion of the command, staff, and rank and file

are undoubtedly more cognizant of how chemicals

might be used against them, and what countermeasures to take.96(p17)

While planning for a more traditional, Europeanstyle war, the CWS also monitored Japan’s use of

chemical weapons in China. U.S. Army interest in

chemical warfare preparation rose significantly,

since Japan was already employing chemical weapons.97

The CWS, however, found itself hardly prepared

to fight a major chemical war on the level of World

War I. Increased budgets and personnel helped with

war planning, but to actually field chemical weapons and build chemical stockpiles first required industrial mobilization and massive production.

The national emergency declared prior to the war

increased the size of the CWS to over 800 officers

and over 5,000 enlisted men, with civilian strength

keeping pace. Appropriations, which had already
Medical Aspects of Chemical and Biological Warfare

38

passed $2 million per year, jumped to $60 million

as successive military supplements increased the

fiscal 1941 budget. The CWS rapidly increased its

productive capacity and improved nationwide procurement district offices to expand its mobilization

basis.25

The Growth of the Chemical Warfare Service

When World War II finally engulfed the United

States on 7 December 1941, the transition to wartime conditions was much less sudden than in 1917,

primarily owing to the extensive mobilization activity of the preceding 2 years. Porter, who served

as the chief throughout the war, found under his

command not the skeletonized CWS of the 1930s

but a large and rapidly growing organization,

whose personnel numbered in the thousands,

physical facilities were scattered throughout the

eastern half of the country, and products were in

urgent demand by an army rapidly growing to

multimillion-man strength.

More than 400 chemical battalions and companies of varying types were activated during the

course of the war, and a large proportion of them

saw service overseas. Chemical mortar battalions

and companies, using high-explosive and smoke

shells in the 4.2-in. chemical mortars, gave close

artillery-type support to infantry units in every theater. Smoke generator battalions and companies

screened troop movements as well as fixed installations. Depot companies stored, maintained, and

issued material; processing companies kept up theater stocks of protective clothing; decontamination

companies backed up chemical defense postures;

and laboratory companies provided technical intelligence assessments of captured chemical material.

Chemical maintenance companies repaired and reworked equipment, performing especially critical

tasks in keeping the mortar units firing. Chemical

service units, organized to provide a broad spectrum of capabilities, performed most or all of the

service and logistical functions already mentioned

on a smaller scale where full-sized specialized companies were not authorized, or not available. Finally,

a full complement of chemical service units supported the operations of the Army Air Force, especially in the storage and handling of incendiary

bombs. In addition to the field organizations, each

theater, army group, and army headquarters had a

chemical staff in their headquarters elements.

The production and storage needs of a rapidly

growing military establishment could not be met

by Edgewood Arsenal alone. The CWS quickly constructed new installations: arsenals at Huntsville,

Alabama, Denver, Colorado, and Pine Bluff, Arkansas; a chemical/biological proving ground in Utah;

protective-clothing plants at Columbus, Ohio, Kansas City, Missouri, and New Cumberland, Pennsylvania; charcoal-filter plants at Zanesville and

Fostoria, Ohio; and impregnate factories at Niagara

Falls, New York, East St. Louis, Illinois, and Midland, Michigan.25,26

Chemical Agents

The CWS agent production initially concentrated

on the World War I agents. Approximately 146,000

tons of chemical agents was produced by the United

States between 1940 and 1945. Phosgene (CG) was

produced at Edgewood Arsenal; the new Huntsville

Arsenal; and the Duck River Plant owned by

Monsanto Chemical Company in Columbia, Tennessee. These plants produced about 20,000 tons of the

agent during the war. Mustard agent (HS) was produced at Edgewood Arsenal; Rocky Mountain Arsenal, Denver, Colorado; Pine Bluff Arsenal; and

Huntsville Arsenal (Figures 2-31 and 2-32). By the

end of the war, these plants produced over 87,000

tons of the agent. Lewisite (L) was produced at a

small pilot plant at Edgewood Arsenal and later at

Huntsville Arsenal, Pine Bluff Arsenal, and Rocky

Mountain Arsenal. Approximately 20,000 tons of the

agent was produced before the plants were shut

down in 1943. Cyanogen chloride (CK) was produced at the American Cyanamid Company plant

in Warners, New York, and at the Owl Plant in

Azusa, California. About 12,500 tons of the agent

was procured during the war. Hydrogen cyanide

(AC) was produced by Du Pont and the American

Cyanamid Company. Only about 560 tons of the

agent was procured by the CWS.

The leadership of the CWS took interest in the

nitrogen mustards after they learned that the Germans were producing it. HN-1 was produced at

Edgewood Arsenal in a small pilot plant and later

at Pine Bluff Arsenal, which produced about 100

tons of the agent. The British also investigated HN2 and HN-3, but the United States did not produce

the latter two agents.

Investigation of ways to improve the purity of

mustard agent resulted in the discovery that washing the agent with water and then distilling it produced a much more pure product. The new agent

was called distilled mustard agent (HD). Edgewood

Arsenal used a pilot plant to produce some of the

agent in 1944 and then a full-scale plant was completed at Rocky Mountain Arsenal the next year. By
History of Chemical and Biological Warfare: An American Perspective

39

Fig. 2-31. Interior view of the Mustard Agent Plant at

Edgewood Arsenal, Md., showing a soldier filling a 1-

ton container with the agent. The operator is wearing a

protective mask. Concerns regarding occupational hazards evidently dictated a higher standard of personal

protection than was apparent during World War I (see

Figure 2-7). Photograph: Chemical and Biological Defense Command Historical Research and Response Team,

Aberdeen Proving Ground, Md.

range of 4,400 yd, which was later increased to 5,600

yd by modifying the propellant in test firings at

Edgewood Arsenal in 1945. Despite a slow start, the

M2 series 4.2-in. chemical mortar rapidly became

the central weapon of the CWS, not only for chemical agent delivery if needed, but also for high-explosive, smoke, and white phosphorus rounds.

Over 8,000 chemical mortars were procured by the

CWS for chemical mortar battalions during the

war.3,26,98

The other offensive weapons for chemical agent

attack were to be delivered by either the artillery

or the air force. The artillery had available 75-mm,

the end of the war, over 4,600 tons of the agent was

produced.26

Chemical Weapons

The heart of the CWS offensive capability was

the chemical mortar. In December 1941, there were

only 44 chemical mortars on hand. This was quickly

corrected, as the demand for the versatile weapon

increased after each major usage. The continued

need for greater range, accuracy, durability, and

ease in manufacturing resulted in the improved M2

4.2-in. mortar in 1943. The M2 had a maximum

Fig. 2-32. Unloading mustard agent from 1-ton containers on flat cars at Pine Bluff Arsenal, Arkansas, in 1943.

Apparently unloading and loading mustard agent were

considered to constitute different hazards (see Figure 2-

31). Note that the operator is wearing a face shield, apron,

and gloves, but not a protective mask. Photograph:

Chemical and Biological Defense Command Historical

Research and Respeonse Team, Aberdeen Proving

Ground, Md.
Medical Aspects of Chemical and Biological Warfare

40

Fig. 2-35. The M2 series Service Mask. Photograph:

Chemical and Biological Defense Command Historical

Research and Response Team, Aberdeen Proving Ground, Md.

Fig. 2-33. Diagram of the M60 105-mm mustard shell,

with the cartridge case attached. Photograph: Chemical

and Biological Defense Command Historical Research

and Response Team, Aberdeen Proving Ground, Md.

Fig. 2-34. Open storage of M47 100-lb chemical bombs

on Guadalcanal Island in 1944. This important lesson is

frequently forgotten: it was necessary to take along the

full spectrum of chemical weaponry wherever U.S. troops

were deployed. Photograph: Chemical and Biological

Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.

105-mm, and 155-mm chemical rounds that were

filled primarily with mustard agent but that also

contained Lewisite (Figure 2-33). In 1945, the CWS

standardized the first chemical rockets: a 7.2-in.

version used phosgene and cyanogen chloride, fired

from a 24-barrel, multiple–rocket launcher platform;

and a smaller 2.36-in. cyanogen chloride–filled bazooka round.

The U.S. Army Air Force had 100-lb mustard

agent bombs (Figure 2-34); 500-lb phosgene or cyanogen chloride bombs; and 1,000-lb phosgene, cyanogen chloride, or hydrocyanic acid bombs. In

addition, the new M33 spray tank could hold 750

to 1,120 lb of mustard agent or Lewisite. None of

these chemical weapons were used on the battlefield during the war.3,99,100

The prepositioning of chemical weapons in forward areas in case of need resulted in one major

disaster and several near disasters. The one major

disaster occurred 2 December 1943, when the SS

John Harvey, loaded with 2,000 M47A1 mustard

agent bombs, was destroyed after a German air raid

at Bari Harbor, Italy. The only members of the crew

who were aware of the chemical munitions were

killed in the raid. As a result of the destruction of

the ship, mustard agent contaminated the oily water in the harbor and caused more than

600 casualties, in addition to those killed or injured

in the actual attack. The harbor clean-up took 3

weeks and used large quantities of lime as a

decontaminant.101

Defensive Equipment

At the beginning of the war, the CWS designed

and issued the M1 Training Mask, which used a

small, lightweight filter connected directly to the

facepiece. The facepiece was the first to use a fully

molded rubber faceblank. The original concept of a

training mask was that complete protection from

all chemical agents was not required; therefore,

there was no need for the state-of-the-art canisters.

However, soldiers liked the new facepieces enough

that the CWS standardized the M1 Training Mask

as the M2 Service Mask in 1941. The mask utilized

the original M1A2 mask’s M9A1 canister, which was

a bulky steel canister that, when combined with the

facepiece, weighed 5 lb (Figure 2-35). Over 8.4 mil-
History of Chemical and Biological Warfare: An American Perspective

41

lion of the M2 series masks were procured during

the war, but they were used only for training.

The existing M1 and M2 series protective masks,

with their molded rubber faceblanks and heavy

canisters, proved a significant problem for the military. First, there was a shortage of rubber during

World War II. Second, the weight of the mask with

canister needed to be reduced, particularly for amphibious assaults. The continued need for a lightweight combat mask resulted in the M3 series mask.

First standardized in August 1942, the M3 made

several changes to the M2 design. In the facepiece,

a nosecup covering the nose and mouth was added

to prevent lens fogging. The canister was modified

to be carried on the chest instead of the side; was

much lighter (the overall weight decreased to just

3.5 lb); and had a more efficient absorbent (Figure

2-36). Eventually, over 13 million M3 series masks

were procured during the war.

Production problems with the new molds, however, caused the CWS to issue the M4 series lightweight mask. This mask used a modified M2 series

facepiece with a nosecup to prevent lens fogging.

Only about 250,000 of the masks were produced.

By 1944, with a major invasion of Europe by U.S.

forces pending, the army requested a better assault

mask that was even lighter and less bulky than the

M3 series. To meet this requirement, the CWS returned to the original German World War I design,

which put the canister directly on the facepiece. The

Fig. 2-36. The M3 series lightweight gas mask. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving

Ground, Md.

result was the M5 Combat Mask, which was standardized in May 1944 (Figure 2-37). Due to the

shortage of rubber, the M5 mask was the first to use

synthetic rubber (neoprene) for the facepiece. This

mask eliminated the hose from canister to facepiece

by mounting the new M11 canister directly on the

cheek. The M11 canister used ASC Whetlerite charcoal, which proved better protection against hydrocyanic acid, a chemical agent discovered in a Japanese grenade shortly after the attack on Pearl Harbor

(Figure 2-38). Although the M5 weighed a mere

half-pound less than the M3, more than 500,000

were procured during the war. The U.S. soldiers

who landed at Normandy carried this mask with

them.

During the war, the CWS also initiated a major

civil defense program to protect civilians against

both chemical and biological weapons. Of particular concern were protective devices for children.

With the help of Walt Disney, a Mickey Mouse gas

mask was designed for children, in the hope that

they would not be frightened if they had to wear it,

and a tentlike protector was designed for infants.26,30,102–104

Fig. 2-37. The M5 Combat Service Mask, the first U.S.

mask with the canister placed directly on the cheek. The

M5 mask was part of the personal equipment of the

troops who landed at Normandy on 6 June 1944. Postwar tests indicated that it might have protected against

respiratory exposure to the nerve agent tabun if the Germans had chosen to use it against the invasion armada.

Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

42

Fig. 2-38. A Japanese frangible hydrocyanic acid grenade,

copper stabilized type. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

For collective protection, the CWS concentrated

on improving the bulky M1 Collective Protector for

field use. A somewhat lighter version, the M2, was

standardized in 1942. It provided the same amount

of air but weighed just over 600 lb. A still-lighter

version, the M3, was also standardized the same

year. It weighed only 225 lb and provided 50 cu ft

of air per minute.77

The CWS also tried to improve the detection capability for toxic chemical agents, particularly blister agents. The early war efforts included the M4

Vapor Detector Kit, which could detect even faint

concentrations of mustard agent; M5 liquid detector paint; M6 liquid detector paper; and the M7 detector crayon. These all proved relatively good for

detecting mustard and Lewisite. The development of

the M9 Chemical Agent Detector Kit in 1943 proved

to be one of the most significant developments of the

CWS during the war. Described in news releases as

being as “effective as a modern burglar alarm,”105 the

kit consisted of a sampling pump, four bottles of reagents, and six clips of detector tubes. The kit could

detect small amounts of mustard agent, phosgene,

and arsenicals by color changes. It was simple to

use and did not require a chemist to make the tests.

An improved version of the World War I orchard

sprayer decontamination apparatus was fielded to

provide ground and equipment decontamination.

It could also be used for plain water showers for

soldiers (Figure 2-39). For treatment of gas casualties, the CWS standardized the M5 Protective Ointment Kit. This kit came in a small, waterproof container and held four tubes of M5 Protective Ointment wrapped in cheesecloth and a tube of BAL

(British anti-Lewisite) Eye Ointment. The protective

ointment was used to liberate chlorine to neutralize vesicant agents on the skin. The BAL ointment

neutralized Lewisite in and around the eye by

changing it to a nontoxic compound. Over 25 million of the kits were procured for the army.26,35,105

Biological Warfare Program

The apparent use of cholera, dysentery, typhoid,

plague, anthrax, and paratyphoid by the Japanese

Fig. 2-39. The 400-gal decontaminating apparatus was also used to provide water showers for the troops on

Iwo Jima. Like the actual weapons,

all the associated paraphernalia of

chemical warfare had to go with the

deployed combat forces. Useful alternative work was found for decontamination apparatuses, however, in

contrast to the bombs shown in Figure 2-34. Photograph: Chemical and

Biological Defense Command Historical Research and Response Team,

Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

43

against Chinese troops finally led to an American

decision to conduct research and establish a retaliatory biological warfare capability. In response to

the potential threat, in 1941 (prior to the attack on

Pearl Harbor), Secretary of War Harry L. Stimson

asked the National Academy of Sciences to appoint

a committee to study biological warfare, appropriately named the Biological Warfare Committee. This

committee did not have time to prepare before the

war came. This left the army unprepared for the

threat of biological warfare by Japan.

Immediately following the attack on Pearl Harbor, the army’s Hawaiian Department took special

precautions against biological attack by both external enemies and local residents. Guards were placed

on the water supplies in Hawaii to protect against

sabotage by biological warfare, and daily checks for

chlorine content were made. Food production

plants were also guarded, and drinking fresh (but

not canned) milk, in particular, was banned. A general order was issued prohibiting the sale of poisons to the general public except under special circumstances.

In February 1942, the Biological Warfare Committee recommended that the United States should

take steps to reduce its vulnerability to biological

warfare. In response, Secretary Stimson recommended to President Roosevelt that a civilian organization should be established to accomplish the

mission. After the president approved the plan, the

War Research Service (WRS) was formed in August

1942 under the leadership of George W. Merck,

president of Merck Company, a pharmaceutical

company. The WRS was only a coordinating committee attached to the Federal Security Agency; it

used existing government and private institutions

for the actual work. It drew its scientific information from a committee of scientists from the National Academy of Sciences and the National Research Council.

In December 1943, U.S. intelligence reports predicted that Japan might use biological warfare. At

the same time, tests indicated that masks made in

the United States gave poor protection against simulated biological agents. In response to these threats,

the CWS (1) developed a special outlet-valve filter

for the masks and (2) rushed delivery of some

425,000 under special security conditions to the island of Saipan in case biological warfare actually

started.

In January 1944, the complete biological warfare

program was transferred from the WRS to the War

Department, and the WRS was abolished. The War

Department divided the biological warfare program

between the CWS and The U.S. Army Surgeon General. The CWS took responsibility for agent research

and production, foreign intelligence, and defensive

means. The Surgeon General was to cooperate with

the CWS on the defensive means. Merck, the former

leader of the WRS, became a special consultant to

the program.

This arrangement was modified in October 1944,

when the secretary of war established the U.S. Biological Warfare Committee with Merck as the chairman. The CWS assigned the biological warfare program to its Special Projects Division. At its peak,

this division had 3,900 army, navy, and civilian

personnel working on various programs.26,106

Initially, the army’s biological warfare program

was centered at Edgewood Arsenal. In April 1943,

Detrick Air Field near Frederick, Maryland, was

acquired by the CWS and was activated as Camp

Detrick. Four biological agent production plants

were started at Camp Detrick to meet the army’s

needs (Figure 2-40). Pilot Plant No. 1, activated in

October 1943 for the production of botulinum toxin,

was located in the Detrick Field hangar. Pilot Plant

No. 2, completed in March 1944, produced the anthrax simulant Bacillus globigii and actual anthrax

spores. Pilot Plant No. 3, completed in February

1945, produced plant pathogens. Pilot Plant No. 4

was completed in January 1945 and produced, in

embryonated eggs, the bacteria that cause brucellosis and psittacosis (Figure 2-41). Additional

smaller pilot plants were set up to explore the many

other antipersonnel, antianimal, and antiplant

agents examined in Camp Detrick’s laboratories.

The existing Vigo Ordnance Plant near Terre

Haute, Indiana, was also acquired by the CWS in

1944 for conversion into a biological agent– and

Fig. 2-40. The first biological warfare agent laboratory at

Camp Detrick, Md. Photograph: Chemical and Biological Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

44

Fig. 2-41. Camp Detrick, Md., 16 July 1945. These technicians at the Egg Plant are disinfecting and drilling eggs

prior to inoculating them with Brucella suis or Chlamydia

psittaci, the bacteria that cause brucellosis and psittacosis. Viral agents such as Venezuelan equine encephalitis

virus were also produced in eggs. This pilot facility had

incubator capacity for approximately 2,000 chicken eggs.

Depending on the agent being produced, eggs were incubated for approximately 1 to 10 days between inoculation and harvest. The work was done by hand, in assembly-line fashion, with little mechanical assistance.

Preparing biological warfare agents in this manner is a

labor-intensive process. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

weapon–production plant. This plant was divided

into four main subplants: agent production, munitions assembly, munition packaging and storage,

and the animal farm. Although the plant was considered ready to produce biological agents by the

summer of 1945, none were actually produced.

Weaponization of biological agents made tremendous progress, considering that the CWS started

from nothing. Anthrax was considered the most

important agent. Although no dissemination of anthrax in a weapon was accomplished in the United

States before the end of the war, anthrax simulant was

tested in large 100-lb and 115-lb bombs, and small 10-

lb bombs, shotgun shell (SS) bombs, and the 4-lb SPD

Mk I bomb. The smaller bombs, suitable for use in

larger cluster bombs, proved the most successful in

static tests. Only the SPD Mk I bomb was considered

ready for production, and the first and apparently only

large-scale munition order was placed at Vigo in June

1944 for production of 1 million of the bombs. The

order was canceled with the end of the war.

The U.S. Biological Weapons Program also targeted German and Japanese vegetable crops. Tests

of anticrop bombs included using spores of brown

spot of rice fungus and 2,4-dichlorophenoxyacetic

acid (known as VKA, for vegetable killer acid) in

the SPD Mk II bomb and a liquid (VKL, for vegetable

killer liquid) in the M-10 spray tank. Scientists also

worked on defoliants in the program.3,106

In 1944 and 1945, there was a sudden interest in

the possibility that Japan was attempting to attack

the United States by placing biological agents on

balloons that then floated across the ocean. In fact,

some 8,000 to 9,000 balloons were launched by Japan

against the United States, however, those recovered

in the United States contained only high-explosive

and incendiary bombs meant to start forest fires.

These balloons continued to turn up several years

after the war.26

U.S. Chemical Warfare Policy

President Roosevelt established a no-first-use

policy for chemical weapons early in the war. In

1943, this was reiterated in an official statement:

“We shall under no circumstances resort to the use

of such [chemical] weapons unless they are first

used by our enemies.”107(p6) The policy was backed

up by a statement of warning:

Any use of gas by any axis power, therefore, will

immediately be followed by the fullest possible

retaliation upon munition centers, seaports and

other military objectives throughout the whole extent of the territory of such axis country.107(pp6–7)

Neither Germany nor Japan chose to initiate

chemical warfare with the United States. The CWS

spent the war training troops; designing chemical,

incendiary, smoke, high explosive, and flame weapons, and protective equipment; and planning for a

chemical war that never occurred. It was a tremendous “just-in-case” effort.

Toward the end of the war with Japan, the combination of President Roosevelt’s death, the extremely costly battles of Iwo Jima and Okinawa, and

the planned invasion of the Japanese homeland led

the army to look at the possibility of initiating

chemical warfare to save American lives. One such

proposal began:

Our plan of campaign against the Japanese is one

which we think will bring the war against Japan to

the quickest conclusion and cut our cost in men and

resources to the minimum. Japan’s complete defeat

is assured providing we persevere in this plan, the

only question remaining being how long the war

will last and what the cost will be of achieving final victory. These questions will be answered not
History of Chemical and Biological Warfare: An American Perspective

45

alone by the tactics employed in the execution of

the plan but also by the weapons used. Gas is the

one single weapon hitherto unused which we can

have readily available and which assuredly can

greatly decrease the cost in American lives and

should materially shorten the war.108

The proposal concluded by recommending that the

president change the policy on no first use of chemical weapons and coordinate the plan with the British and Russians.108

The senior staff, however, concluded that chemical warfare would only complicate the invasion of

Japan and would not be a decisive weapon. In addition, coordinating and preparing America’s allies

for chemical warfare were also perceived as major

problems. The use of the atom bomb in 1945 effectively ended the discussion.45,109

Lessons Learned

The U.S. Army learned several lessons from this

nongas war that the CWS followed. Although perhaps more a finger-pointing exercise, the phrase

“had the United States been prepared for war in

1939, there would not have been a war”110(p24) was

taken as a self-evident truth. The CWS needed to

be a permanent organization that concentrated on

training, research and development, and chemical

warfare preparedness. This same lesson, from a

slightly different angle, was reflected in the words

of Under Secretary of War Kenneth C. Royall to the

chemical warfare specialists, “The better job you do

the less likely it is that you will have to put to actual use the products of your work.”111(p41)

Demobilization and the Creation of the

Chemical Corps

The army began demobilization activities almost

immediately on the president’s proclamation of the

end of hostilities. By early 1946, the CWS was effectively demobilized, and its military strength approached prewar levels. One observer commented:

“Gas warfare is obsolete! Yes, like the cavalry and

horsedrawn artillery, it is outmoded, archaic, and of

historical interest only. This is the atomic age!”112(p3)

To preserve the CWS from total disintegration,

Major General Porter, the chief of the CWS, made a

vigorous advocacy of the distinctive character and

important role of the CWS before an army board

considering postwar organization. The result was

the permanency long sought by the chemical program, a corps designation. The army finally agreed

that the CWS, along with the other Technical Services, should continue its existence as a distinct

entity in the peacetime army. On 2 August 1946,

Public Law 607 changed the name of the CWS to

the Chemical Corps.113

After World War II, as western defense became

increasingly based on the threatened use of nuclear

weapons, the Chemical Corps’s mission expanded

to include radiological protection as well as chemical and biological research and development. At the

same time, the Corps concentrated on producing

and fielding nerve agent weapons and the assorted

detection and decontamination equipment required.

Major General Alden H. Waitt, who replaced

Porter in November 1945, assessed the future of

chemical warfare in 1946:

The fact that toxic gas was not used in the late war

does not justify a conclusion that it will not be used

in the future. Gas has not been out-moded as a

weapon. The Germans developed new gases during World War II. The magnitude of their preparedness for gas warfare is indicated by the fact that

they had amassed more than a quarter of a million

tons of toxic gas; their failure to use this gas against

us is attributable largely to their fear of our retaliatory power. We cannot count upon other nations

refraining from the use of gas when it would serve

their purpose. There were numerous instances in

the late war in which the use of gas might have

had far-reaching results. Thus, there is no good reason for assuming that the considerations which

prevented the employment of gas in World War II

will prevail in the future.114

On the topic of biological warfare, he acknowledged

it as a new field that still required much work:

The tremendous potentialities of biological warfare

in the future demand that the necessary tactics and

employment in the field be worked out well in advance so that such means may be used immediately

and effectively once a decision to do so is made. It

is essential that Chemical Officers on the staffs of

divisions and higher units, including equivalent

Army Air Force elements, be in a position to advise their Commanders relative to the capability,

limitations and means of protection against this

new method of attack. Further, they must be able

to prepare suitable offensive and defensive plans

and to supervise such training of troops in these

methods as may be required.114

Demilitarization of Captured Weapons

Following the occupation of Germany and Japan,

the Allies initiated a sea-dumping and weapons

disposal program to eliminate the large stockpiles
Medical Aspects of Chemical and Biological Warfare

46

of captured chemical agents (Figure 2-42). Operation Davy Jones Locker involved sinking ships that

contained German weapons in the North Sea. However, not all the German weapons were destroyed.

Between 1945 and 1947, over 40,000 of the 250-kg

tabun bombs, over 21,000 mustard bombs of various sizes, over 2,700 nitrogen mustard rockets, and

about 750 tabun artillery shells of various sizes were

shipped to the United States. In addition to disposing of the enemy stockpiles, the United States also

dumped the U.S. Lewisite stockpile into the sea

during Operation Geranium in 1948.3,115

Post–World War II Developments

Although the late 1940s was not a time for many

dramatic developments, the Chemical Corps was

able to issue a new gas mask in 1947. Designated

the M9 series, it was an improved version of the

M5 mask (Figure 2-43). This mask utilized a superior synthetic rubber composition that worked better in cold weather than the neoprene of the earlier

mask.30

Fig. 2-42. Dumping weapons into the sea was not the

Allies’ only method of disposing of them. These 150-mm

German nitrogen mustard (HN-3) rockets are wired with

prima cord for destruction. Photograph: Chemical and

Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

Fig. 2-43. The M9 series gas mask. Photograph: Chemical and Biological Defense Command Historical Research

and Response Team, Aberdeen Proving Ground, Md.

In 1948, the army partially standardized sarin

and the year after, tabun. In 1948, the army also issued a new circular116 on G-series nerve agents and

a technical bulletin117 on the treatment of nerve

agent poisoning.3 The circular provided current information on detection, protection, and decontamination of nerve agents. For detection, the M9 and the

improved M9A1 detection kits, standardized in 1947,

could detect vapor after a complicated procedure:

To make test, tear off lead wrapper and heating pad.

Insert blue dot end of the glass tube into pump.

Slowly take 25 full pump strokes. Remove from

pump, and heat tube with matches or cigarette

lighter for about 5 seconds. (Avoid excessive heating of tube, since this will char contents of the tube

and invalidate the test results.) After tube is cool,

add liquid from blue bottle to unmarked end of the

tube. If gas is present, a blue ring will form in the

upper end of the tube.116

For droplets, the M5 detector paint and the M6 detector paper both turned from olive green to red.

None of the detectors provided any advance warning, and all merely confirmed the presence of the

agents after the fact.
History of Chemical and Biological Warfare: An American Perspective

47

For protection, the circular simply stated that the

current mask “gives protection for the eyes and respiratory tract and for the skin covered by the

facepiece.”116 Additional required items were impermeable clothing worn over a layer of ordinary clothing, rubber boots, and rubber gloves.

Decontamination of nerve agents was still a problem. DANC was not suitable. Bleach slurry and dilute water solutions of alkalies were reported as

effective decontaminants. Hot soapy water was also

recommended, while cold water only partially decontaminated the agents.116

The technical bulletin117 pointed out that contamination by nerve agents could come via breathing

the vapors or body contact with the liquid, and that

death could occur in a few minutes. The bulletin

then outlined the suggested treatment for exposures:

The treatment of poisoning is based essentially

upon the blocking of excessive nervous activity, due

to the direct effects of the poison and to apprehension, fear, physical activity, and external stimuli.

Quiet, reassurance, and gentle handling of the casualty are therefore essential. Atropine sulfate (1.0

mg) should be given by intravenous or intramuscular injection very promptly. This effectively

blocks the excessive activity of smooth muscle and

glands, and also controls convulsions.117

However, should this not work:

In the event of impending respiratory failure, all

drug therapy may be ineffective. Under such circumstances, artificial respiration may prove to be

the only life-saving procedure.117

How artificial respiration could be conducted in a

contaminated environment was not addressed.

Beginning of the Cold War

The declining relations with the Soviet Union

caused that country to become the number one intelligence target for chemical warfare preparations.

Intelligence reports noted with alarm that toward

the end of World War II, the Soviets had captured a

German nerve agent production facility and had

moved it back to their country.15,118

Other studies described the Soviets as ready to

conduct chemical attacks should open warfare

break out. In 1949, Waitt reported:

Intelligence reports indicate extensive preparation

for gas warfare by the USSR with current Soviet

superiority over the U.S. in this field as to stockpiles of gas munitions, currently operating war-gas

plant capacity, and Soviet ability to maintain this

superiority for at least 12 months after the start of

hostilities, assuming the U.S. gas warfare position

is not improved prior to M-Day.118

His recommendations were to increase chemical

training, replace the aging World War II–era equipment and munitions, and then achieve a much

higher state of readiness.118

One of the first Cold War actions that involved

the Chemical Corps was the Berlin Blockade in 1949.

Cold weather caused frost to build up on the airplanes flying to Berlin with supplies. The accepted

method of ice removal was to use brooms to sweep

the ice off. This slow and dangerous work was replaced by the corps’s using decontamination trucks

to spray isopropyl alcohol, which was used as a

deicer since glycerin was not readily available. A

large plane could be deiced in about 5 minutes, and

the corps was credited with keeping the airplanes

from being delayed by frost.119

THE 1950S: HEYDAY OF THE CHEMICAL CORPS

Korean War

In June 1950, with the onset of the Korean War,

the Chemical Corps participated in its first military

action. The corps quickly implemented an increased

procurement program to supply the army with a

retaliatory chemical capability and defensive equipment. Major General Anthony C. McAuliffe, the

new Chief of the Chemical Corps, concluded that

this ability was the number one lesson learned from

World War II:

It required the experiences of World War II to demonstrate that the most important basic factor in a

nation’s military strength is its war production

potential and ability to convert smoothly and

quickly its industry, manpower, and other economic resources.120(p284)

Within a short time, however, the army’s policy

on chemical warfare and the lessons learned from

the past were hotly disputed, particularly as the

military situation in Korea changed. First, the

Chemical Corps lost its high-visibility ground
Medical Aspects of Chemical and Biological Warfare

48

weapon, the 4.2-in. chemical mortar. Responsibility for research, development, procurement, storage, issue, and maintenance of all 4.2-in. mortars

and ammunition was transferred to the Ordnance

Department on 31 December 1947 by order of the

Chief of Staff, Department of the Army. The exception was the responsibility for chemical fillings for

mortar shells, which remained with the Chemical

Corps. This event represented the end of the Chemical Corps’s role in the development of the 4.2-in.

chemical mortar. In 1951, the Ordnance Department

completed the development of a new 4.2-in. (later

designated the 107-mm) mortar, the M30, to replace

the M2. The loss of the 4.2-in. mortar moved the

Chemical Corps away from being a combat arm and

left it a combat support arm.121

The action in Korea also brought up the subject

of whether to initiate chemical warfare to save lives.

Many of the Chemical Corps’s supporters favored

the use of chemical weapons as humane weapons

of war, particularly to offset the enemy’s superior

numbers. One writer, upset with negative public

opinion toward chemical weapons and the army’s

policy of retaliation only, wrote:

Has this concept and this attitude been reflected in

our military planning and our military preparations? If, in an effort to “make the most” of our

military expenditures we have failed to stock up

to the fullest requirements in the matter of toxic

weapons on the premise that such weapons “might

not be used again, as they were not used in World

War II,” we may have made a major military decision on the basis of a fatally unsound assumption.122(p3)

Another officer stated it much more bluntly:

The use of mustard, Lewisite and phosgene in the

vast quantities which we are capable of making and

distributing offers the only sure way of holding

Korea at the present time. We are not playing

marbles. We are fighting for our lives. Let’s use the

best means we have to overwhelm the enemy scientifically and intelligently.123(p3)

Again, however, neither side chose to initiate chemical and biological warfare and the corps supported

the war through its many other programs, particularly smoke and flame. Much as it had done during

World War II, the United States did not change its

policy about no first use of chemical weapons.

Although there were allegations by the North

Koreans and the Chinese that U.S. forces employed

chemical and biological weapons on the battlefield,

the Chemical Corps apparently did not use such

weapons. The corps did, however, use riot control

agents to quell riots of prisoners of war. In 1968, a

Czech general defected to the United States and

reported that U.S. prisoners of war were used for

biological tests by the Russians in North Korea. These

allegations have yet to be confirmed by the Russians

and were vigorously denied by the North Koreans.124

The Chemical Corps ended the Korean War in a

much stronger position than it faced after the end

of World War II. The corps reduced its units and

manpower somewhat, and terminated many of its

procurement contracts in the months following the

1953 armistice. Still, Major General Egbert F.

Bullene, the new Chief Chemical Officer summed

up the feeling of the corps about the Korean War

and the Cold War in general: “Today, thanks to Joe

Stalin, we are back in business.”125(p8)

Changes in the Chemical Corps

During the 1950s, the concept of warfare, and

chemical and biological warfare continued to

change radically. The phrase that one could “push

a button” to start a war became exceedingly popular. The lesson learned from the Korean War—the

concept of a limited war, fought without nuclear

weapons and possibly against satellite states, not

the “real enemy”—determined much of the army’s

planning. The fact, however, that two wars had

come and gone without the employment of chemical and biological weapons made it necessary for

successive Chief Chemical Officers to work continually to remind the army and the country that this

might not be the case again, and that the capabilities of the Chemical Corps constituted insurance

against the possibility of chemical or biological attack in the future.

Throughout the 1950s, the corps conducted several extensive studies to change its organization and

improve its training capabilities. One significant

improvement was the activation of a new training

center at Fort McClellan, Alabama, in 1951, which

offered more space and training options. The

Chemical School, after more than 30 years in Maryland, moved there early in 1952.3

The emphasis on individual training for chemical and biological warfare resulted in the elimination of the unit gas officers in 1954. Originally, an

officer or noncommissioned officer had been responsible for chemical and biological training and

readiness. With this change, the troop commanders assumed the responsibility and were expected

to include chemical and biological training in all

their field exercises and maneuvers.126
History of Chemical and Biological Warfare: An American Perspective

49

Nerve Agent Production and Development

In 1950, the Chemical Corps began construction of the first full-scale sarin production complex based on pilot plant work accomplished at

the Army Chemical Center, which had formerly

been called Edgewood Arsenal (Exhibit 2-1). The

production of sarin was a five-step process that

was divided between two sites. For the first two

steps of the process, the corps constructed a plant

at Muscle Shoals, Alabama, later designated Site

A or the Muscle Shoals Phosphate Development Works, which was completed in 1953. The last

three steps of the process were conducted at a

new plant at Rocky Mountain Arsenal, Colorado.

In 1951, the corps fully standardized sarin and

by 1953 was producing the agent. After only 4 years

of production, the plants stopped manufacturing

since the stockpile requirements for the agent

had been met. The plants then went into inactive

status with layaway planned. The related muniEXHIBIT 2-1

NAME CHANGES OF EDGEWOOD

ARSENAL

25 Oct 1917 Construction begun on a shellfilling plant called Gunpowder

Neck Reservation

2 Apr 1918 Gunpowder Neck Reservation

designated Gunpowder

Reservation

4 May 1918 Name changed from Gunpowder

Reservation to Edgewood Arsenal

10 May 1942 Name changed from Edgewood

Arsenal to Chemical Warfare

Center

2 Aug 1946 Name changed from Chemical

Warfare Center to Army Chemical

Center

1 Jan 1963 Name changed from Army

Chemical Center to Edgewood

Arsenal

1 July 1971 Edgewood Arsenal discontinued

as a separate installation and

designated Edgewood Area,

Aberdeen Proving Ground

tions filling plants also went into standby status a

year later.3,127

Part of the reason for the shut down of the sarin

plant was the development of a new nerve agent.

Chemists at Imperial Chemicals, Ltd., in the United

Kingdom, while searching for new insecticides,

came across compounds that were extremely toxic

to humans. The British shared the discovery with

the United States in 1953. The Chemical Corps examined the new compounds and determined that a

new series of nerve agents had been discovered that

were more persistent and much more toxic than the

G-series agents. This new series was designated the

V-series agents in 1955, because they were “venomous” in nature. These agents would enter the body

through the skin, thereby bypassing the protective

mask. They were 1,000-fold more toxic than sarin

when applied to the skin, and 2- to 3-fold more toxic

when inhaled. A drop the size of a pinhead on bare

skin could cause death within 15 minutes.3,128

The Chemical Corps gave top priority to the investigation of these compounds. Of the compounds investigated, VX was selected in 1957 for pilot plant

development and dissemination studies. It was standardized in December 1957. The annual report for that

year concluded: “The reign of mustard gas, which has

been called the King of Battle gases since it was first

used in July 1917, will probably come to an end.”129(p100)

The initial plan was to contract with private industry for a 10-ton per day production plant. A later

decision put the plant at the inactivated Dana

Heavy Water Plant of the Atomic Energy Commission at Newport, Indiana, within the Wabash River

Ordnance Works. A patent dispute that resulted in

a restraining order by the Chief Justice of the United

States and problems with contractors visiting the

new site delayed construction. Finally in 1959, Food

Machinery and Chemical Company, the low bidder,

got the contract and construction was planned for

1960. Shortly after the approval, the Chemical Corps

supplemented the contract to provide for a VX

weapon-filling plant.129,130

Chemical Weapons

During the 1950s, the Chemical Corps concentrated on the weaponization of sarin. For air delivery, the first items standardized in 1954 were the

1,000-lb M34 and M34A1 cluster bombs (Figure 2-

44). These clusters held 76 M125 or M125A1 10-lb

bombs, each containing 2.6 lb of sarin (Figure 2-45).

In 1959, the Chemical Corps standardized the

first nonclustered bomb, designated the MC-1 750-lb

sarin bomb. This was a modified general purpose
Medical Aspects of Chemical and Biological Warfare

50

Fig. 2-44. The M34 series sarin cluster bomb was the first

major nerve agent bomb standardized by the U.S. military after World War II. Photographs: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

demolition bomb, suitable for high-speed aircraft,

and held about 215 lb of sarin filling. For ground

delivery, the Chemical Corps standardized the

M360 105-mm and the M121 155-mm shells in 1954.

The smaller shell held about 1.6 lb of agent and the

larger about 6.5 lb.3,130

Although delivery systems for VX nerve agent

were initiated during the 1950s, no system was standardized. In addition, many of the sarin delivery

systems took longer to develop than planned and

some were never standardized.

Biological Agents

During the 1950s, the biological warfare program

was one of the most highly classified programs, owing to its nature and the ongoing Cold War, and

many of the details of the program have never been

declassified. The corps concentrated on standardizing the agents investigated during World War II

and weaponizing them at Fort Detrick, the Chemical Corps biological warfare center. The highest

priority was placed on the antipersonnel agents, as

the antianimal and antiplant programs both experienced major disruptions during the decade.

A number of antipersonnel agents were standardized during the early 1950s, but in 1953, Major General Bullene, Chief Chemical Officer, gave an overriding priority to the development of anthrax,

which had also been the highest-priority agent during World War II.

One of the more interesting stories was the standardization in 1959 of the yellow fever virus for use,

with a mosquito as vector. The virus came from an

individual in Trinidad who had been infected with

the disease during an epidemic in 1954. Scientists

inoculated rhesus monkeys with the serum to

propagate the virus. In tests conducted in Savannah, Georgia, and at the Avon Park Bombing Range,

Florida, uninfected mosquitoes were released by

airplane or helicopter. Within a day, the mosquitoes

had spread over several square miles and had bitten many people, demonstrating the feasibility of

such an attack. Fort Detrick’s laboratory was capable of producing half a million mosquitoes per

month and had plans for a plant that could produce

130 million per month.130

Fort Detrick, however, was limited in its production capability and required an expanded facility.

Since the World War II–era Vigo Plant, inactivated

in the postwar years, was not reopened (and was

eventually sold in 1958), Pine Bluff Arsenal was

selected to be the site of the new biological agent

Fig. 2-45. The M125 series sarin bomblet, which was contained in the M34 cluster bomb. Photograph: Chemical

and Biological Defense Command Historical Research

and Response Team, Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

51

production plant. The plant was designated the X201 Plant, later renamed the Production Development Laboratories, and was completed in 1954. This

plant could produce most of the agents standardized by the Chemical Corps, and could fill bombs

within 4 days after receipt of an order.

The antianimal program started off strong in 1952

when the Chemical Corps activated Fort Terry, on

Plum Island, New York, to study animal diseases. In

1954, however, the army terminated all antianimal

agent work with exception of rinderpest and the

completion of the foot-and-mouth disease research

facility. The Department of Agriculture then took

over the defensive aspects of the antianimal program, including Fort Terry, the same year.

The antiplant program made some progress

when, in 1955, wheat stem rust became the first

antiplant pathogen standardized by the Chemical

Corps for use primarily against cereal crops. Additional antiplant agents were standardized shortly

thereafter. In 1957, however, the army ordered the

corps to stop all antiplant research and development

since the air force, primarily, would be delivering

the agent. This was accomplished by 1958 with the

termination of the program. Then the decision was

reversed the next year after additional funding was

found. Fort Detrick had to restart the program,

which delayed any significant accomplishments for

some time. Fort Detrick also began to concentrate

more on the chemical defoliants, conducting the

first large-scale military defoliation effort at Fort

Drum, New York, using the butyl esters of 2,4-D

and 2,4,5-T, later designated Agent Purple.3,131

Biological Weapons

Although many biological agents were standardized and many delivery systems developed, only a

few biological weapons were standardized. The first

was the M114 4-lb antipersonnel bomb, which held

about 320 mL of Brucella suis (Figure 2-46). This was

a small, 21-in.-long tube with a 15⁄8-in. diameter,

similar to a pipe bomb. One hundred eight of the

M114s were clustered in the M33 500-lb cluster

bomb (Figure 2-47). The bombs were also tested at

Dugway Proving Ground, Utah, throughout the

1950s with various other fillings.

The M115 500-lb antiplant bomb was standardized in 1953 for the dissemination of wheat stem

rust. This filling consisted of dry particulate material adhered to a lightweight, dry carrier (ie, feathers). Thus, the bomb was normally referred to as

the feather bomb.

Fig. 2-47. The M33 500-lb biological cluster bomb, which

held 108 of the M114 bombs. Photograph: Chemical and

Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

Fig. 2-46. The M114 4-lb biological bomb was the first

biological weapon standardized by the U.S. military. Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

There were numerous other experimental delivery systems. The E61R4 half-pound antipersonnel

bomb held only about 35 mL of agent, but four of

the little bomblets produced twice the area coverage of one M114. The E133R3 750-lb cluster bomb

held 544 bomblets.

Copying the method the Japanese developed

during World War II, the Chemical Corps developed

the 80-lb antiplant balloon bomb. The bomb itself

was a cylinder 32 in. in diameter and 24 in. high

that served as the gondola of the balloon. Inside the

insulated gondola were five agent containers, each

holding feathers and an antiplant agent. The agent

containers were grouped around a chemical-type
Medical Aspects of Chemical and Biological Warfare

52

heater. A barometric and mechanical time mechanism opened the gondola at a preselected altitude,

releasing the agent.

Other delivery systems included spray tanks,

missiles, aerosol generators, drones, and marine

mines. Of these, the submarine mine was one of the

more covert forms of delivery. It was designed to

be fired from a torpedo tube, to sink to the bottom

for a specified period up to 2 hours, and then rise

to the surface and expel about 42 L of agent. After

dissemination of the agent, it scuttled itself.3,132

Although both simulants and small amounts of

live agents were used in open-air testing during the

1950s, for sheer size, Operation Large Area Coverage (LAC) covered the largest geographical area.

To test the feasibility of contaminating a large area

of the continent with biological organisms, in 1957

the Chemical Corps dropped a myriad of microscopic fluorescent particles of zinc cadmium sulfide

along a path from South Dakota to Minnesota. In

the first test, the air stream turned north and took

the bulk of the material into Canada. Still, a test station in New York was able to detect the particles.

In the second test in 1958, the particles were carried into the Gulf of Mexico. Special collectors were

located at 63 Civil Aeronautics Authority sites and

112 Weather Bureau stations. Over 2,200 samples

were mailed back to the corps from these sites.

Two additional tests covered from Ohio to Texas,

and from Illinois to Kansas. All demonstrated that

the particles were widely disseminated. Although

it had been only theoretical prior to this test, Operation LAC provided the first proof that biological agents were indeed potential weapons of mass

destruction.129

Medical Research on Human Volunteers

The Chemical Corps’s concern with the effects

of nerve and other chemical agents on soldiers led

to extensive studies to determine the dangers of

exposure and the proper kinds of treatment. This

program exposed soldiers to low levels of agents

to demonstrate the effects of treatment and to answer questions about how agents affect humans.

Prior to the 1950s, the use of humans in testing

had been conducted on a somewhat ad hoc basis,

with little documentation surviving. A more-formal

volunteer program was established at the Army

Chemical Center during the 1950s. This program

drew on local military installations and utilized a

specific consent procedure that ensured that each

volunteer was prebriefed and was truly a volunteer in the experiment. Between 1955 and 1975, over

6,000 soldiers participated in this program and were

exposed to approximately 250 different chemicals.133

Although biological agents had been tested on

animals, the question arose as to whether the same

agents would be effective on humans. In 1954, the

Chemical Corps received permission to use human

volunteers in the evaluation of biological agents.

The plan to assess the agents and vaccines, which

was approved by both the U.S. Army Surgeon General and the Secretary of the Army, was produced

at Fort Detrick. A medical school under contract

conducted most of the investigation. By 1955, the

corps had tested many of the known agents on the

volunteers in laboratory situations.

The army, however, also wanted to know the effects of biological agents in natural settings. After

receiving approval from the secretary of the army,

the first open-air test was conducted at Dugway

Proving Ground, Utah, where 30 volunteers were

exposed to an aerosol containing Coxiella burnetii,

the rickettsia that causes Q fever. These open-air

tests gave valuable data on the infectivity of biological warfare agents.134,135

The Incapacitant Program

During the 1950s, the Chemical Corps became

interested in developing chemical weapons that

incapacitated rather than killed its targets. In 1951,

the corps awarded a contract with the New York

State Psychiatric Institute to investigate the clinical

effects of mescaline and its derivatives. The contractor tested 6 derivatives, while the corps tested 35

derivatives. The results of the investigation indicated that mescaline and its derivatives would not

be practical as agents, because the doses needed to

bring about the mental confusion were too large.131

In 1955, the Chemical Corps formerly established

a new project called Psychochemical Agents. The

next year, the program was redesignated K-agents.

The objective was to develop a nonlethal but potent incapacitant that could be disseminated from

airplanes in all environments. The program was

conducted at the Army Chemical Center and examined nonmilitary drugs like lysergic acid (LSD) and

tetrahydrocannabinol (related to marijuana). None

of these drugs, however, were found to be of military worth.129,131,134,135

New Protective Equipment

The changing need for protective equipment created by the new threats of chemical, biological, and

radiological warfare was reflected in 1951, when the
History of Chemical and Biological Warfare: An American Perspective

53

Chemical Corps officially changed the name of all

its gas masks to “protective masks.” The M9A1

mask, standardized the same year, was the first to

be so designated.

Starting in 1952, the Chemical Corps began work

on a new mask to replace the M9 series. The corps

wanted a mask that was more reliable, suitable for

any face size and skin texture, and more comfortable in any climate. Utilizing previous work on

canisterless civilian masks and an earlier military

prototype, Dr. Frank Shanty, a young engineer assigned to the Army Chemical Center, thought of the

concept for a new mask on a late-night train to Cincinnati, Ohio. The final result was the M17 Protective Mask, the first canisterless military mask, which

was standardized in 1959. The new mask eliminated

the problem of having left- and right-handed masks,

weighed less, and had reduced breathing resistance.30

Other mask work included the first tank mask,

the M14, standardized in 1954 as part of the M8 3-

Man Tank Collective Protector. In 1959, the corps

standardized an improved head-wound mask, designated the M18, that allowed soldiers with head

wounds to wear protective masks in contaminated

environments.3

Chemical Agent Detection

The inability to instantly detect nerve agents and

sound an alarm to alert surrounding troops was the

primary concern of the Chemical Corps during the

1950s. Many detector kits from World War II were

updated to improve detection of nerve agents, but

these only provided confirmation, without providing advance warning.

The M5 Automatic G-Agent Fixed Installation

Alarm, standardized in 1958, was the first detector

and alarm for G-series agents. The unit could detect a G-series agent and sound an alarm in about

10 seconds. Unfortunately, the unit was 7 ft high

and 2 ft square. It was not suitable for the field and

was primarily used at Rocky Mountain Arsenal in

sarin production and filling plants.130

The M6 Automatic G-Agent Field Alarm, standardized also in 1958, was the first automatic electronic alarm for the detection of G-series agents for

field use. Owing to various problems, the alarm was

primarily used by the navy for dock monitoring.

The alarm was contained in a 24-lb aluminum case

approximately 7 in. wide by 15 in. high. The operation of the alarm was based on the color formed

when any G-series agent came into contact with a

combined solution of o-dianisidine and sodium

pyrophosphate peroxide. Design of the alarm provided that a drop of this combined solution was

placed on a paper tape, which was moved (every 5

min) under two sampling spots, one of which sampled

ambient air while the other acted as a monitor to minimize the effects of variations in light reflected from

the paper and fluctuations in electronics. The two

spots on the paper were viewed by two balanced

photo cells. If color developed on the sample side,

unbalance occurred between the cells and the

buzzer alarm triggered. As designed, it would function continuously unattended for a 12-hour period,

at which time it required fresh solutions and new

tape. One problem with the alarm was that it did

not function at temperatures below 32°F and therefore was not what the army needed.134,136

A secondary approach to detection and alarm

was the beginning of the remote sensing capability.

In 1954, the Chemical Corps began development of

a small, simple alarm commonly called LOPAIR

(long-path infrared) (Figure 2-48). The principle

behind the operation of this device was that the Gseries agents absorb certain portions of the infrared spectrum. Such a device would scan the atmosphere continuously in advance of troops and sound

a warning alarm when G-series agents were spotted. The prototype performed satisfactorily up to

about 300 yd, but it weighed over 250 lb and used

too much electrical power. An improved version

Fig. 2-48. A prototype long-path infrared (LOPAIR)

alarm, the E33 Area Scanning Alarm consisted of an infrared source, optical reflector, optical collecting system,

grating monochromator, and associated electronics. Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

54

reduced both the weight (to 34 lb) and the power

consumption. Its response time was 3 to 10 seconds.

A third version combined the best of each unit, with

a slight increase in weight but less power consumption, and a range of a quarter mile. Although the

corps worked continuously on this approach, it

would not come to completion for another 40

years.135

Decontamination

Although the Chemical Corps concentrated on

nerve agent programs during the 1950s, there was

one significant improvement for mustard agent

decontamination. In 1950, the corps standardized

super tropical bleach (STB) as the best decontaminant for persistent agents. The new bleach was

more stable in long-term storage, particularly in

temperature extremes, and was easier to spread

from a decontaminating apparatus, owing to its

more uniform consistency.137

Treatment for Nerve Agents

As a result of the introduction of nerve agents,

the Chemical Corps added atropine, an antidote to

G-series agent poisoning, to the World War II M5

Protective Ointment Set by replacing one of the four

ointment tubes. The modified kit was designated

the M5A1 Protective Ointment Set in 1950. Since

atropine had to be circulated by the blood stream

to overcome the effects of the G-series agent, it was

packaged in syrettes, small collapsible metal tubes

filled with a solution of atropine and fitted with a

hypodermic needle at one end. A soldier was required to jab the needle into his thigh muscle and

force the atropine out by squeezing the tube. Later

in the decade, the M5 ointment was also found to

be effective against V-series agents.74

Many soldiers, however, reportedly were afraid

to stick a needle into themselves. Therefore, a new

injector was developed: an aluminum tube, about

the size of a small cigar, containing a spring-driven

needle and cartridge containing atropine solution.

The soldier had simply to push the tube against his

thigh and pull a safety pin, and the spring drove

the needle into his leg. The new kit was standardized in 1959 as the M5A2 Protection and Detection

Set.130

The recognized need for respiratory support for

the apneic victim of nerve agent exposure resulted

in the development of a resuscitation device that

could be attached to the M9 series of protective

masks (Figure 2-49).

Fig. 2-49. With the advent of nerve agents and the recognition that they cause respiratory paralysis, the army saw

the need to develop first-aid methods capable of providing artificial ventilation on the battlefield. The M28 maskto-mouth resuscitator was one such development. It consisted of three parts: (1) a hose, which connected the

casualty and the rescuer; (2) a modified M9A1 protective mask; and (3) an anesthetist-type oronasal mask. The

expiratory valve of the M9A1 mask was removed and

replaced by the hose. The rescuer inhaled through a standard canister (out of sight in the photograph) and

exhaled into the hose. Positive pressure in the hose connecting the casualty and the rescuer opened a doubleacting, demand-type, inlet-and-expiration valve in the

oronasal mask. This allowed the rescuer’s exhaled breath

to enter the casualty’s lungs. The second canister (seen

on the casualty’s chest) protected the casualty from inhaling contaminated air when he began to breathe spontaneously. Note that none of the soldiers in this staged

photograph are protected against skin absorption. Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

The Growing Soviet Threat

The growing Soviet threat concerned the Chemical Corps and the U.S. Army throughout the decade.

Soviet Defense Minister Georgi Zhukov, while addressing the Communist Party Congress in Moscow

in 1956, warned: “[A]ny new war will be characterized by mass use of air power, various types of

rocket, atomic, thermo-nuclear, chemical and biological weapons.”138(p26)

In 1959, Major General Marshall Stubbs, the new

Chief Chemical Officer, assessed the growing Soviet chemical threat:

Soviet chemical weapons are modern and effective

and probably include all types of chemical muni-
History of Chemical and Biological Warfare: An American Perspective

55

tions known to the West, in addition to several dissemination devices peculiar to the Russians. Their

ground forces are equipped with a variety of protective chemical equipment and they are prepared

to participate in large scale gas warfare. They have

a complete line of protective clothing which will

provide protection in any gas situation and a large

variety of decontaminating equipment.139(pp8–9)

As for the biological threat, he added:

We can assume from available knowledge that they

are equally capable in biological warfare. The mass

of medical and technical reports published recently by their scientists indicates increased

activity in this area. Soviet microbiologists and

military authorities have conducted BW tests at

an isolated location over a long period of time. It

is also known that the Communists have conducted research and development leading to the

large scale production and storage of disease producing and toxic agents.139(p9)

He concluded: “I believe that I have given you

enough to make you aware that they pose a threat

to the free nations of the world.”139(p9)

THE 1960S: DECADE OF TURMOIL

In 1960, Major General Stubbs talked to various

groups around the country on the need for a greater

sense of urgency in attaining chemical, biological,

and radiological preparedness. Contending that—

to both military and civilian populations—the threat

of chemical and biological warfare was as great as

the threat of nuclear warfare, he quoted a Soviet

source who, in 1958, had described the next war as

being distinguished from all past wars in the mass

employment of military air force devices, rockets,

weapons; and various means of destruction such

as nuclear, chemical, and bacteriological weapons.

Stubbs also reported that the Soviets had about one

sixth of their total munitions in chemical weapons.140

In January 1961, Secretary of Defense Robert S.

McNamara initiated about 150 projects aimed at

giving him an appraisal of military capabilities. Two

of these—project 112 and project 80—had significant impact on the chemical and biological weapons program.

Project 112 had as its objective the evaluation of

chemical and biological weapons both for use as

strategic weapons and for limited war applications.

The result of this study was a recommendation to

highlight chemical and biological weapons and

particularly to increase long-term funding. In 1961,

these recommendations were basically approved for

immediate action by the deputy secretary of defense. One of the responses was the creation of

Deseret Test Center, Utah, which was intended for

extracontinental chemical and biological agent testing, including trials at sea, and arctic and tropical

environmental testing. The new center was jointly

staffed by the army, navy, and air force, with testing scheduled to begin in 1962.

Project 80 resulted in a committee to review the

organization of the army. The conclusion of this

committee was to eliminate the technical services

and distribute their functions to various elements

of the new army organization. Secretary of Defense

McNamara felt that the Chemical Corps’s knowledge, experience, and training was not being “infused” into the rest of the army. The problem

appeared to be that the combat troops were “structurally separated” from the Chemical Corps, particularly in the areas of research and development,

and training.141

The chemical training of combat troops was a

major concern. Colonel John M. Palmer, commanding the Chemical Corps Training Command, reflected on the problem in 1960:

The quickest way to reduce the effectiveness of a

military training program is to train without purpose or sense of urgency. Unfortunately, for

40 years an aimless approach has largely characterized unit chemical warfare training in the

U.S. Army.... Much of the Army still appears to visualize chemical warfare, and related biological

warfare training, as an annoying distraction from

normal combat training.142(p28)

Based on these problems, the Defense Department

ordered a far-reaching realignment of functions in

1962. Most of the Technical Service headquarters

establishments, including that of the Chemical

Corps, were discontinued, and their functions

merged into three field commands. Thus, the training mission of the Chief Chemical Officer was

assigned to the Continental Army Command; the

development of doctrine to the new Combat Development Command; and the logistical function, including all arsenals, laboratories, and proving

grounds, to the equally new Army Materiel Command (AMC).

The effects of the reorganization were quickly

felt. Within 2 years, the chemical warfare training

program had been improved significantly. One junior officer described the changes:
Medical Aspects of Chemical and Biological Warfare

56

We have set up special 40-hour or 80-hour schools

so that we can have a trained CBR [chemical-biological-radiological] officer and noncommissioned

officer in every company-sized unit. We have assigned a chemical officer down to brigade, and a

chemical operations sergeant down to battalion. We

set aside a certain number of hours annually for

classroom instruction for the troops. We set up special blocks of instruction for surveying and monitoring teams. We list CBR defense as a subject integrated into our training schedules, and ... we may

even throw tear gas grenades or other agents at

troops in the field.143(p16)

The same officer, however, concluded that even

more realistic field training was still required to

prepare soldiers for the modern battlefield with

nuclear weapons, nerve agents, and biological

weapons.143

Beginning of the Vietnam War

A growing guerrilla war in South Vietnam soon

made the army again reexamine its training program, chemical warfare readiness, and its no-firstuse policy. One observer stated in 1963: “After years

of almost total lack of interest, the United States has

taken up guerrilla warfare training as though it

were something new under the sun.”144(p12) As part

of that sudden interest, the role of chemical weapons again came under intense scrutiny and debate.

In 1963, one author stated: “The best way for the

U.S. to achieve its military aims in Southeast Asia

would be to rely on chemical warfare.”144(p12) He

described how soldiers could “sanitize” a particular area with gases and sprays that killed everything

from vegetation to humans.144

In 1966, a retired U.S. Army general suggested

that mustard gas be used as an invaluable weapon

for clearing Vietnamese tunnels. He thought the use

of low-lethality chemicals would save both American and Vietnamese lives by rendering the tunnels

useless.145

Other observers and authors also recommended

revising the no-first-use policy. Public opinion and

national policy opposing the use of toxic chemicals

apparently was the deciding factor against their

employment. The army did, however, utilize defoliants and nonlethal riot control agents in large

quantities. This caused a worldwide response that

required the army to quickly explain the differences

between lethal and nonlethal chemicals.

The expansion of hostilities in Vietnam caused a

gradual rise in the level of development and procurement of chemical warfare–related items. By virtue of their training and their specialized equipment, Chemical Corps personnel were able to make

a number of contributions, primarily in the areas

of riot control and flame weapons.

Yemen Civil War

While the United States was still involved in the

Vietnam War, another small war in the Middle East

brought the subject of chemical warfare back from

being only hypothetical. In 1962, Yemeni dissidents

overthrew the monarchy and declared a republic.

Royalist forces then retreated into the mountains

of northern Yemen and initiated a counterrevolt

against the republican forces. Egypt (which probably had had a hand in the revolt) recognized the

new republic and sent military forces to help defeat the royalist troops, who were supported by the

kingdoms of Saudi Arabia and later Jordan.146

Egyptian efforts to defeat the royalist forces

and destroy their civilian support bases proved particularly difficult in the mountainous terrain. Apparently growing impatient with the successful

royalist guerrilla tactics, the Egyptian air force

allegedly dropped chemical-filled bombs on proroyalist villages to terrorize or kill not only the local inhabitants but also, possibly, the royalists who

were hiding in caves and tunnels. The Egyptians

denied ever using chemical warfare during their

support of republican forces.

Most of the early accounts of chemical warfare

came from journalists in the area. The first reported

incident occurred in July 1963. This alleged attack

took place against the village of Al Kawma and

killed seven civilians. The United Nations investigated the allegation by sending an observation team

to Yemen, but their report concluded there was no

evidence of a chemical attack.147

Newspaper articles described additional chemical attacks taking place from 1963 to 1967, although

most disagreed on the dates, locations, and effects

of the attacks. The United States, involved in its own

controversy concerning the use of riot control agents

in Vietnam, took little notice of the reports.

Much like the progression of chemicals used

during World War I, the Egyptians allegedly started

with tear gases, which were meant to terrorize more

than kill; then progressed to mustard agents, which

caused more-serious casualties; and finally to nerve

agents, which were meant to kill large numbers

quickly. Prior to this, no country had ever used

nerve agents in combat. The combination of the use

of nerve agents by the Egyptians in early 1967 and

the outbreak of war between Egypt and Israel dur-
History of Chemical and Biological Warfare: An American Perspective

57

ing the Six-Day War in June, finally attracted world

attention to the events in Yemen.

In January 1967, an attack occurred on the Yemeni

village of Kitaf. During this air raid, bombs were

dropped upwind of the town and produced a graygreen cloud that drifted over the village. According

to newspaper accounts,148–152 95% of the population

up to 2 km downwind of the impact site died within

10 to 50 minutes of the attack. All the animals in

the area also died. The estimated total human casualties numbered more than 200. Still another attack was reported to have taken place on the town

of Gahar in May 1967 that killed 75 inhabitants.

Additional attacks occurred that same month on the

villages of Gabas, Hofal, Gadr, and Gadafa, killing

over 243 occupants.

Shortly after these attacks, the International Red

Cross examined victims, soil samples, and bomb

fragments, and officially declared that chemical

weapons, identified as mustard agent and possibly

nerve agents, had been used in Yemen. The Saudi

government protested the Egyptian use of chemical weapons to the United Nations. U Thant, Secretary-General of the United Nations, sought to

confirm the use of chemical weapons with the Egyptians, but they denied it. The United Nations

apparently took little further notice of the situation.

The civil war officially ended in 1970 with a political agreement between the republican and royalist

factions.

Egypt had been a signatory of the 1925 Geneva

Convention, which outlawed the use of chemical

weapons. Some accounts attributed the chemical

weapons to German scientists, usually described as

being former Nazis, who had been brought to Egypt

by President Nasser. Several sources reported that

the Soviet Union, through its friendship with Egypt,

used Yemen as a testing ground for its chemical research program. Other reports mentioned Communist China as being the supplier, while still other

accounts had Egypt using old chemical munitions

left behind from World War II stockpiles.147–154

Much of what the U.S. Army learned from the

Yemen Civil War was negative. Reports of possible

chemical use in certain areas of the world, particularly those inaccessible to official and technical observers, were difficult to confirm or even to condemn without accurate and verifiable information.

News reports alone proved informative but unreliable. Even samples from the alleged attacks apparently did not lead to further political or military

action. Most importantly, with the world distracted

by the Arab–Israeli Six-Day War and events in Vietnam, politics discouraged a universal condemnation and follow-up response. In effect, the world powers let the event pass much as they had when Italy

used chemical warfare against Ethiopia in the 1930s.

1967 Arab–Israeli Six-Day War

The 1967 Arab–Israeli Six-Day War was described

as having come very close to being the first major

war where both combatants openly used nerve

agents and biological warfare. Fearing a pending

attack from its Arab neighbors, on 5 June 1967, the

Israelis launched a preemptive strike against Jordan, Egypt, and Syria. This action included an invasion of the Sinai Peninsula, Jerusalem’s Old City,

Jordan’s West Bank, the Gaza Strip, and the Golan

Heights.

Reports soon appeared that the Egyptians allegedly had stored artillery rounds filled with nerve

agents in the Sinai Peninsula for use during a war.

The Israelis, reflecting on Egypt’s possible testing

of the weapons in Yemen earlier in the year, suddenly realized that their troops and cities were vulnerable to attack. The fact that chemical weapons

were not used during the war was possibly due to

the Israelis’ preemptive action or possibly to the

newspaper reports of the Yemen Civil War. The Israelis felt threatened enough to place frantic orders

for gas masks with Western countries. However, this

last-minute plea for gas masks and nerve agent antidote came too late to have prevented enormous

casualties if nerve agents had been employed. The

Egyptians, on the other hand, claimed that Israel

was preparing for biological warfare. A United

Nations–sponsored cease-fire ended the fighting on

10 June 1967, and the potential chemical–biological

war did not occur.84,148,149,155

Chemical Agents

While concern over the potential and actual use

of chemical agents grew during the 1960s, the

United States also continued its chemical agent production program. Construction of the United States’s

VX agent production plant at Newport, Indiana, was

completed in 1961, when the first agent was produced

(Figure 2-50). The production plant was only operated for 7 years, and it was placed in standby in 1968.3

The first and only incapacitating agent (excluding riot control agents) standardized by the army

completed development in 1962. Designated BZ, 3-

quinuclidinyl benzilate was a solid but was disseminated as an aerosol. The major problem with the

agent for military purposes was its prolonged time

of onset of symptoms. The estimate was 2 to 3 hours
Medical Aspects of Chemical and Biological Warfare

58

Fig. 2-50. The first three steps of VX nerve agent production were completed in these structures at Newport, Indiana. The technological level of chemical engineering

needed to make this agent is vastly more complicated

than that required to make mustard and phosgene during the World War I era. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md. Fig. 2-52. The M55 115-mm rocket could hold the nerve

agents VX or sarin. The problem was the aluminum warhead, which began leaking soon after production. Photograph: Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

before the enemy would become confused and

therefore vulnerable. This was a disappointment to

those hoping for a quick-use, nonlethal agent as an

alternative to lethal agents. A second problem was

its visible cloud of smoke during dissemination,

which limited the element of surprise.141

New Chemical and Biological Weapons

Having concentrated on nerve agent bombs during the 1950s, the Chemical Corps turned its attention to artillery, rocket, and other delivery systems

during the 1960s. In 1960, the corps standardized

the first nerve agent land mine, designated the M23

2-gal VX mine (Figure 2-51). This mine resembled

the conventional high-explosive land mine, but held

about 11.5 lb of agent. It was designed to be activated either by a vehicle’s running over it or by an

antipersonnel antitampering fuze.

In 1961, the Chemical Corps standardized two

new VX projectiles for artillery. The M121A1 was

an improved version of the earlier sarin round. Each

round held about 6.5 lb of agent. The M426 8-in.

sarin or VX projectile held more than 15.5 lb of

agent.3

The early 1960s was the peak of the nerve agent

rocket program. The program was first started at

the end of World War II to duplicate the German V2 missiles used against England. The United States

eventually developed both short-range and longrange rockets.

For short-range tactical support, the Chemical

Corps standardized the M55 115-mm rocket in 1960

(Figure 2-52). Described as the first significant

ground capability for the delivery of chemical

Fig. 2-51. The M23 VX land mine. Most of the interior

was to be filled with the nerve agent VX. Photograph:

Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

59

Fig. 2-53. A chemical warhead for the Honest John rocket.

It was designed to break apart and disperse the spherical bomblets of nerve agent. Photograph: Chemical and

Biological Defense Command Historical Research and

Response Team, Aberdeen Proving Ground, Md.

a slow (300 knots), remote-controlled, recoverable

drone that could hold over 200 lb of either nerve

agent or biological agents. It had a range of about

100 nautical miles and could disperse agent over

about 5 to 10 nautical miles. The SD-5 was an improvement that used a jet engine that gave it speeds

of over Mach 0.75 and a range of over 650 nautical

miles. The added horsepower allowed it to hold

about 1,260 lb of chemical or biological agent, which

was discharged through a tail nozzle.

The BZ program also reached weaponization status in the 1960s. In 1962, the Chemical Corps standardized the M43 750-lb BZ Bomb Cluster and the

M44 175-lb BZ Generator Cluster. The M43 held 57

M138 BZ bomblets. The M44 held three 50-lb thermal generators, each holding 42 BZ canisters.3

Biological Agents and Weapons

By the 1960s, the U.S. Biological Warfare Program

was in decline. Funding for the program gradually

decreased throughout much of the 1960s, from $38

million in 1966 to $31 million in 1969. In 1961, the

army announced that new biological agents would

be standardized in conjunction with munitions. This

proved a further limiting factor, as the demand for

biological munitions decreased.157

agents since the 4.2-in. chemical mortar, the M55

was loaded with 11 lb of VX or sarin nerve agent.

The range when fired from the M91 multiple rocket

launcher was over 6 miles. Each launcher held 45 rockets that could be fired simultaneously. The army initially approved 40,000 sarin-filled and 20,000 VX-filled

rockets, but many more were actually filled.3,156

For middle-range tactical support, the Chemical

Corps standardized the M79 sarin warhead for the

762-mm Honest John rocket in 1960 (Figure 2-53).

The rocket had a range of 16 miles, and the warhead held 356 M134 4.5-in. spherical bomblets, each

containing about 1 lb of sarin. A smaller warhead was

standardized in 1964 for the 318-mm Little John rocket,

which held 52 of the improved M139 4.5-in. spherical

bomblets, each holding 1.3 lb of sarin (Figure 2-54).

The first long-range rocket warhead was standardized the same year for the Sergeant missile system. The missile had a range of 75 miles and the

warhead held 330 M139 sarin bomblets. More developmental projects added chemical warheads to

other long-range missiles, such as the Pershing missile, which had a range of over 300 miles.

Development of rockets as delivery systems for

biological agents also reached its peak during the

1960s. The M210 warhead for the Sergeant missile

held 720 M143 bomblets. The M143 1-lb spherical

bomblet was smaller than the sarin version, being

only 3.4 in. in diameter. Each bomblet held about

212 mL of agent. If released at about 50,000 ft, the

dispersion of the bomblets would cover about 60

square miles.

In addition to the rocket program, the Chemical

Corps examined several drones for delivery of

chemical and biological agents. The SD-2 Drone was

Fig. 2-54. The M139 4.5-in. spherical sarin bomblet used

in the Little John rocket. The vanes on the outside of the

bomblet created a spin that then armed the impact fuze.

The explosive burster is in the center and sarin fills the

two outer compartments. Photograph: Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

60

Despite budget and development constraints, the

army continued to work on the antipersonnel

agents. The standardization of dry Pasteurella

tularensis was considered a significant improvement

over the liquid suspension used by most agents. Dry

agents were more adaptable to storage, shipping,

and logistical considerations. The research into drying methods for living agents was begun during the

Korean War. The method adopted for P tularensis

was to freeze droplets of a concentrated liquid culture with liquid Freon, drying the resultant pellets,

and reducing the product to a particle diameter of

about 5.5 μm by means of a milling operation. The

stabilizer used as a protective suspension contained

skim milk and sucrose. A gram of the packaged

product contained about 14.7 x 109 viable cells and

had a 3-year storage stability when stored in a dry

nitrogen atmosphere at –18°C.156

The antiplant program was resumed for the U.S.

Air Force in 1962. Agent production was conducted

at Pine Bluff Arsenal. Field tests of wheat stem rust

and rice blast disease were conducted at several

sites in the midwestern and southern United States

and on Okinawa. The same year, the Defense Department requested additional work on defoliation

and antiplant activities owing to the ongoing events

in southeast Asia. In 1962, the Chemical Corps initiated a crash project for the production of wheat

stem rust under Rocky Mountain Arsenal supervision. Other work included trying to find pathogens

suitable for use against the opium poppy crop.141

During the 1960s, the army conducted large-scale

tests using the biological simulant Bacillus globigii

(code name BG) at various places in the public domain to access the dangers of covert biological attacks. For example, in 1965, BG was tested at National Airport and the Greyhound Terminal in

Washington, D. C. In 1966, BG was disseminated in

New York City within the subway tubes and from

the street into the subway stations in mid Manhattan. The results confirmed that a similar real covert

attack would have infected a large number of people

during peak traffic periods.

The army also conducted antianimal testing using BG at several stockyards in Texas, Missouri,

Minnesota, South Dakota, Iowa, and Nebraska between 1964 and 1965. Antiplant testing using the

wheat stem rust fungus was also conducted at

Langdon, North Dakota, in 1960 and Yeehaw Junction, Florida, in 1968.157

By the 1960s, the army was in the process of developing vaccines for most of the biological agents

standardized or in development. A 1965 volunteer

consent form provides insight into the pertinent

agents (Exhibit 2-2). Attached to the consent form

for vaccines was an order to also administer selected

live agents to the participants.158,159

New Defensive Equipment

The most significant advancement in individual

protection was a new version of the M17 Protective

Mask, designated the M17A1, which introduced

two new concepts in 1966 that were long overdue.

The first was a resuscitation device for the mask,

which was required to allow soldiers to provide

artificial respiration without unmasking. Although

atropine injections were an effective antidote for the

anticholinesterase effects of nerve agents, artificial

respiration was required to counteract the effects

of the agent on the respiratory system.

The second new concept was a drinking tube. The

drinking capability allowed a soldier to drink from

his canteen in a contaminated battlefield without

unmasking. This was considered critical because of

the longer times required to wear protective gear

around persistent nerve agents and the possible use

of the mask in desert and tropical climates.30

The need to provide air conditioning and protection against chemical and biological agents to

workers in the army’s NIKE missile-control vans

resulted in the development of a trailer-mounted

unit adopted for limited production in 1961. After

some improvements, the unit was standardized in

1963 as the M1 Collective Protection Equipment.

Initially, 288 of the units were ordered, but additional similar needs for collective protection quickly

became apparent.160

For the U.S. Army, one requirement that was

further supported by lessons learned from the 1967

Six-Day War was the need for an automatic fieldalarm system. In 1968, the army solved the 2-decadesold problem by standardizing the M8 Portable

Automatic Chemical Agent Alarm. The 4-year development effort covered the gap that had left U.S.

soldiers vulnerable to a surprise nerve agent attack.

The unit consisted of the M43 detector unit and the

M42 alarm unit. Additional alarms could be connected.3

The alarm used an electrochemical pointsampling system that continuously monitored the

atmosphere and sounded an audible or visible

warning of even very low concentrations of nerve

agents. Actual detection occurred when air was

passed through an oxime solution surrounding a

silver analytical electrode and a platinum reference

electrode. Presence of an agent caused a reaction in

the solution, which increased the potential between
History of Chemical and Biological Warfare: An American Perspective

61

EXHIBIT 2-2

CONSENT TO INOCULATION WITH EXPERIMENTAL BIOLOGICAL PRODUCTS

It has been explained to me that it is necessary for my safety and

protection to be inoculated with certain biological products approved by

the Army Investigational Drug Review Board but not yet approved by the

Commissioner of Food and Drugs, Department of Health, Education and

Welfare. I understand that the administration of these products will

provide future additional evidence of their safety and usefulness.

I hereby consent* to inoculation with any or all of the following

biological products to include the initial series and booster immunizations as required:

1) Venezuelan Equine Encephalomyelitis Vaccine, Live, Attenuated.

2) Live Tularemia Vaccine.

3) Anthrax Vaccine (non-viable), aluminum hydroxide adsorbed.

4) Botulinum Toxoid, Types A B C D E, aluminum phosphate adsorbed.

5) Tularemia Skin Test Antigen.

6) Rift Valley Fever Virus Vaccine.

7) Q Fever Vaccine.

8) Eastern Equine Encephalomyelitis Vaccine.

9) Western Equine Encephalomyelitis Vaccine.

WITNESSES:

(Date) (Signature) (Signature)

(Date) (Signature) (Signature)

SMUFD FORM 8 (Rev)

May 65

*It is unclear how the volunteer signified consent. Note that this form does not contain a blank for the volunteer’s signature.
Medical Aspects of Chemical and Biological Warfare

62

the electrodes. The change in potential, when amplified, triggered the alarm signal. The unit could

detect almost all chemical agents, including the

nerve agents.161

In 1960, the Chemical Corps made a significant

improvement in the area of decontamination.

DANC had proven to be particularly corrosive to

the brass parts of the M2 Decontaminating Apparatus, so the Chemical Corps spent almost 2 decades

developing Decontaminating Solution 2 (DS2,

manufactured then by Pioneer Chemical Co., Long

Island City, New York). DS2 was a clear solution of

70% diethylenetriamine, 28% methyl cellosolve

(ethylene glycol monomethyl ether), and 2% sodium hydroxide. This decontaminating agent did

not solve all problems, either. It was known to remove and soften new paint, and to discolor old

paint. It was also irritating to the skin. Its good

points were that DS2 was less corrosive to metals

and less destructive to plastics, rubber, and fabrics.161 In conjunction with the standardization of

DS2, the Chemical Corps also developed the M11

1.5-qt Portable Decontaminating Apparatus, a fire

extinguisher–type unit compatible with DS2, which

was used to decontaminate vehicles and weapons.3

Public Hostility Toward Chemical and Biological

Weapons

The growing protests over the U.S. Army’s role

in Vietnam, the use of defoliants, the use of riot control agents both in Southeast Asia and on the home

front, and heightened concern for the environment

all gradually increased the public hostility toward

chemical and biological weapons. Three events particularly galvanized public attention: the sheep-kill

incident at Dugway Proving Ground, Operation

CHASE, and an accident with sarin at Okinawa.

Dugway Sheep-Kill Incident

The first event, according to Dugway Proving

Ground’s incident log, started with a telephone call

on Sunday, 17 March 1968:

At approximately 1230 hours, Dr. Bode, University

of Utah, Director of Ecological and Epidemiological contract with Dugway Proving Ground (DPG),

called Dr. Keith Smart, Chief, Ecology and Epidemiology Branch, DPG at his home in Salt Lake City

and informed him that Mr. Alvin Hatch, general

manager for the Anschute Land and Livestock

Company had called to report that they had 3,000

sheep dead in the Skull Valley area.162(pA-1)

Skull Valley was adjacent to Dugway, one of the

army’s open-air testing sites for chemical weapons.

Although the findings were not definite, the general opinion seemed to be that nerve agents had

somehow drifted out of the test area during aerial

spraying and had killed the sheep. Whether the

army was guilty or not, the end result was bad publicity and, even more damaging, congressional outrage.

Operation CHASE

The second event was actually a series of sea

dumps of surplus chemical warfare agents and a

problem weapon system (Figure 2-55). These sea

dumps created significant environmental concerns

throughout the country. The surplus agents were

mustard agent (primarily) and some nerve agent.

The problem weapon system was the relatively new

M55 rocket system. Although the M55 had been

standardized only 7 years before, the thin aluminum head design proved faulty for long-term storage. The problem of leaking rockets started in 1966,

Fig. 2-55. The disposal at sea of surplus and leaking chemical munitions

and radiological wastes generated

environmental concerns that eventually brought sea dumping to a halt.

Photograph: Chemical and Biological

Defense Command Historical Research and Response Team, Aberdeen

Proving Ground, Md.
History of Chemical and Biological Warfare: An American Perspective

63

and a year later, the army began disposing of the

rockets, sealed in concrete vaults in the hulls of

ships that were then sunk in ocean-disposal sites.

Operation Cut Holes and Sink ’Em (CHASE), an

ongoing program for disposing of conventional

ammunition, began accepting chemical weapons in

1967. That year, CHASE 8 disposed of mustard

agent in ton containers, and M55 sarin rockets. In

June 1968, CHASE 11 disposed of sarin and VX in

ton containers, along with additional M55 sarin and

VX rockets. In August 1968, CHASE 12 disposed of

mustard agent in ton containers.3

The sea dumps created two major concerns. The

first was that the weapons were being shipped from

their storage depots by train to the loading docks.

Fear of an accident along the way was paramount.

Second, sea dumping and its effects on marine life

were sources of environmental and commercial concern and protest.

Accident at Okinawa

The third event was a serious accident. On 8 July

1969, the army announced that 23 U.S. soldiers and

1 U.S. civilian had been exposed to sarin on

Okinawa. The soldiers were cleaning sarin-filled

bombs preparatory to repainting them when the

accident occurred.3

Although none of the individuals died, the public announcement created two controversies. First,

up until that time, the army had kept secret the forward positioning of chemical weapons on Okinawa.

The acknowledgment created international concerns. Second, the accident pointed out the dangers

of storing chemical weapons. With chemical weapons known to be stored at sites in the continental

United States near cities and residential areas, the

fear of an accident escalated. In response to these

concerns, the Defense Department announced on

22 July 1969 that they would accelerate the previously planned removal of the chemical agents from

Okinawa.163

Changes to the Chemical and Biological Warfare

Programs

In April 1969, the secretary of defense tried to

explain the U.S. chemical warfare policy to both the

general public and to congress. In part, he stated:

It is the policy of the United States to develop and

maintain a defensive chemical–biological (CB) capability so that U.S. military forces could operate

for some period of time in a toxic environment if

necessary; to develop and maintain a limited offensive capability in order to deter all use of CB

weapons by the threat of retaliation in kind; and to

continue a program of research and development

in this area to minimize the possibility of technological surprise.164(p193)

The explanation did not help. In July, the United

Nations released a report on chemical and biological weapons that condemned production and stockpiling of weapons of mass destruction. Six days

later, the United States acknowledged the Okinawa

accident.3

Congress stepped in and on 11 July 1969 revealed

that the army was conducting open-air testing with

nerve agents at Edgewood Arsenal (the name of the

Army Chemical Center had reverted back in 1963)

and at Fort McClellan during training events.

Shortly after the disclosure, more than 100 protesters were at the gates of Edgewood Arsenal. Three

days later, buckling to the pressure, the army announced suspension of open-air testing at the two

sites. Quickly rushing an independent committee

together, the army promised to conduct a safety

review of all such testing. The positive publicity of

creating the new committee was soon forgotten

when the army revealed that they had also conducted nerve agent testing in Hawaii between 1966

and 1967, something the army had previously denied.3

In October, the secretary of the army announced

that the committee had completed its study. The

committee reached the following conclusion:

The lethal testing program at Edgewood Arsenal

during the past two decades has compiled an enviable record for safety. The testing procedures that

have been evolved are clearly effective in minimizing danger to base personnel and civilians in adjacent areas.165(p16)

The committee’s only major concern was the movement of chemical agents by truck on public roads;

the committee recommended resumption of lethalagent, open-air testing at Edgewood.165

Before testing resumed, however, the U.S. Congress passed Public Law 91-121 in November. This

law imposed controls on the testing and transportation of chemical agents within the United States;

and the storage, testing, and disposal of agents outside the United States. Further open-air testing of

lethal chemical agents was effectively banned.3

In November 1969, President Richard M. Nixon

took action against chemical and biological warfare.

First, he reaffirmed the no-first-use policy for

chemical weapons:
Medical Aspects of Chemical and Biological Warfare

64

I hereby reaffirm that the United States will never

be the first country to use chemical weapons to kill.

And I have also extended this renunciation to

chemical weapons that incapacitate.166(p5)

Second, he decided to resubmit the 1925 Geneva

Protocol to the U.S. Senate for ratification. The senate had refused to ratify the treaty when it was first

signed, and President Harry S Truman had withdrawn the treaty from the senate in 1947.

Third, President Nixon renounced the use of biological weapons and limited research to defensive

measures only:

I have decided that the United States of America

will renounce the use of any form of deadly biological weapons that either kill or incapacitate. Our

bacteriological programs in the future will be confined to research in biological defense on techniques of immunization and on measures of controlling and preventing the spread of disease. I have

ordered the Defense Department to make recommendations about the disposal of the existing

stocks of bacteriological weapons.166(p5)

He concluded by explaining his future hopes:

Mankind already carries in its own hands too many

of the seeds of its own destruction. By the examples

that we set today, we hope to contribute to an atmosphere of peace and understanding between all

nations.166(p4)

These actions effectively stopped the production of

chemical and biological weapons in the United

States.166

THE 1970S: THE NEAR END OF THE CHEMICAL CORPS

Throughout the 1970s, the chemical and biological warfare programs experienced further restrictions and tightened controls. In February 1970,

President Nixon added toxins to the banned weapons and ordered all existing stocks of toxin agents

destroyed. About a month later, the army revealed

that it had conducted both chemical and biological

testing in Alaska but reported that the testing had

stopped. The army also announced that the chemical weapons on Okinawa would be moved to

Umatilla Army Depot in Oregon. This triggered a

series of lawsuits that attracted the concern of congress. The next year, Public Law 91-672 was enacted,

which prohibited the army from moving the weapons from Okinawa to anywhere on the U.S. mainland. Finally, Operation Red Hat moved the stockpile on Okinawa to Johnston Atoll, a small U.S.

island in the South Pacific, for long-term storage

and eventual demilitarization.

Demilitarization was not an easy project; heightened environmental concerns characterized the

1970s. One last sea dump took place in 1970, when,

despite much negative press, CHASE 10 disposed

of more M55 sarin rockets. (CHASE 10 had originally been scheduled earlier; although now out of

numerical order, the designation was unchanged.)

Two years later, Public Law 92-532 was enacted,

which prohibited the sea dumping of chemical

munitions.

Between 1971 and 1973, all remaining biological

weapons were destroyed at Pine Bluff Arsenal,

Rocky Mountain Arsenal, and Fort Detrick. In 1972,

the United States signed the Convention on the Prohibition of the Deployment, Production, and Stockpiling of Bacteriological and Toxin Weapons. This

convention banned development, production,

stockpiling, acquisition, and retention of biological

agents, toxins, and the weapons to deliver them.

The senate ratified the Biological Warfare Convention

in 1974 and President Gerald R. Ford signed it in 1975.

Although President Nixon had called in 1969 for

the ratification of the Geneva Protocol, it took a few

more years. In 1974, the U.S. Senate ratified the Protocol, and President Ford officially signed it on 22

January 1975. He did, however, exempt riot control

agents and herbicides from inclusion in the agreement.3

The events of 1969 had a severe impact on the

future of the U.S. Army Chemical Warfare Program.

Two senior department of defense personnel

reflected on the impact the restrictions had during

the 1970s:

During most of the 1970s, the United States allowed

its chemical retaliatory capability to decline, did

little to improve chemical protection, and neglected

relevant training and doctrine. The United States

has not produced lethal or incapacitating chemical

agents, or filled munitions since 1969.167(p3)

The army actually made plans to abolish the

Chemical Corps entirely. In 1973, with the signing

in Paris, France, of the peace pacts to end the Vietnam War, and with the end of the draft, the army

recommended reducing the Chemical Corps in size

and eventually merging it with the Ordnance Corps.

As the first step, the army disestablished the Chemical School at Fort McClellan, Alabama, and combined it with the Ordnance School at Aberdeen
History of Chemical and Biological Warfare: An American Perspective

65

Proving Ground, Maryland. Congress, however,

blocked the complete disestablishment of the

corps.168–171 Still, one observer noted: “As an additional ordnance career field, the chemical specialty

almost withered and died at Aberdeen.”171(p15)

1973 Arab–Israeli Yom Kippur War

Then another war quickly brought chemical warfare preparedness back to the forefront. The Arab–

Israeli Yom Kippur War lasted only from 6 October

to 24 October 1973, but the ramifications for the U.S.

chemical program lasted much longer. The Egyptian and Syrian attack against Israel on Yom Kippur and the successful Israeli counterattacks ended

with a cease fire. Both sides took enormous losses

in personnel and equipment.

Following the Yom Kippur War, the Israelis analyzed the Soviet-made equipment they captured

from the Egyptians and Syrians. They discovered

(a) portable chemical-proof shelters, (b) decontamination equipment for planes and tanks, and (c) that

most Soviet vehicles had air-filtration systems on

them to remove toxic chemicals.

Another item of note was a Soviet PKhR-MV

Chemical Agent Detector Kit for Medical and Veterinary Services. The set consisted of a hand pump,

detector tubes, reagents in ampules, dry reagents,

test tubes, and accessories. It was designed to detect nerve, blister, and blood agents. Exploitation

by the U.S. specialists determined that it could detect low concentrations of nerve agents, mustard

agent, cyanide, Lewisite, and heavy metals in aqueous solutions. It could also detect the same agents

in addition to cyanogen chloride and phosgene in

the atmosphere. One noted problem with the kit

was that the procedures for using it were extremely

difficult to carry out while wearing a protective suit.

In addition, the glass ampules were fragile and

broke easily.172

Overall, the experts reported finding sophisticated chemical defense materiel and a “superior

quantitative capability for waging a chemical

war.”173(p3-4) The indications were that the Soviets

were ready for extensive chemical warfare and

might actually be planning to initiate chemical warfare in a future war. Soviet division commanders

were thought to already have authority to initiate

chemical warfare.173–176

Restoring the Chemical Corps

The combination of (a) the findings of sophisticated Soviet chemical defense materiel and their

capability for waging chemical war and (b) the decline of the U.S. Army Chemical Corps called for

corrective action. The army concluded the following:

To offset this, U.S. chemical/biological (CB) defense

materiel must not only provide a protective system

equivalent to or better than that of any potential

enemy but the physiological and logistics burdens

must be such as to permit long-term use. To cope

with the hazards of any potential CB-threat environment requires the development of an integrated

CB defense system. This system must contain items

for individual protection, collective protection,

decontamination, warning and detection, and safe

devices and concepts to achieve realistic training.

An effective technological base is needed from

which such materiel, responsive to user needs, can

be quickly developed.173(p3-4)

In 1976, the secretary of the army reversed the

decision to abolish the Chemical Corps. He cited

the heightened awareness of the Soviet Union’s capability to wage chemical warfare as the primary

reason. In 1977, the United States started a new effort

to reach an agreement with the Soviets on a verifiable

ban on chemical weapons. This effort was unsuccessful. Partly as a result, the Chemical School was reestablished at Fort McClellan in 1979.167,177–181

Binary Weapons Program

The end of the chemical weapons production

program had stopped production but left one type

of chemical retaliatory weapon still in development.

Back in the 1950s, the army had begun looking at

binary weapons. Until that time, chemical weapons

were unitary chemical munitions, meaning that the

agent was produced at a plant, filled into the munitions, and then stored ready to be used. Since most

agent was extremely corrosive, unitary munitions

were logistical nightmares for long-term storage.

The binary concept was to mix two less-toxic materials and thereby create the nerve agent within the

weapon after it was fired or dropped. Because the

two precursors could be stored separately, the problems of long-term storage and safe handling of

chemical weapons were therefore solved. The navy

took the greater interest in the binary program during the 1960s and requested a 500-lb bomb designated the BIGEYE. Only after the production of

unitary chemical munitions was halted did the binary program receive high priority in the army,

however. In fact, the last open-air test with lethal

agents had taken place at Dugway Proving Ground

on 16 September 1969, when a 155-mm projectile
Medical Aspects of Chemical and Biological Warfare

66

filled with sarin binary reactants was test fired.

Throughout the early 1970s, additional test firings

took place using simulants. In 1976, the army standardized the M687 Binary GB2 155-mm Projectile.

The binary projectile used a standard M483A1

155-mm projectile as the carrier of the chemical

payload (Figure 2-56). Binary chemical reactants

were contained in two separate, plastic-lined, hermetically sealed containers. These leakproof canisters were loaded through the rear of the shell and

fitted one behind the other in the body of the projectile. The forward canister contained methylphosphonic difluoride (DF) and the rear canister

contained isopropyl alcohol and isopropylamine

solution (OPA).

To ensure safe handling, M687 projectiles were

shipped and stored with only the forward DF-filled

canister in place. A fiberboard spacer occupied the

cavity provided for the OPA canister. Projectiles

were secured horizontally on a pallet, as opposed

to the conventional vertical position for other 155-

mm projectiles. This orientation permitted rapid

removal of the projectile’s base using a special

wrench. The fiberboard spacers were removed and

replaced with the OPA canisters. The fuze was then

installed just prior to firing. Upon firing, setback

and spin forces caused the facing disks on the canisters to rupture, allowing the reactants to combine

to form sarin en route to the target.182,183

In addition to the M687 projectile, the army also

worked on the BLU-80/B (BIGEYE) VX2 bomb

and projectiles of other size, including an 8-in.

projectile. None of these, however, were ever

standardized. Standardization of the M687 did

not lead immediately to production. The same year

the M687 was standardized, the U.S. Congress

passed the Department of Defense Appropriation

Authorization Act, which restricted the development and production of binary chemical weapons

unless the president certified to congress that such

production was essential to the national interest.

Thus, the army would take another decade to locate the production plants, pass environmental inspection, receive presidential approval, and begin

production.3

Detection Improvements

Although the M8 detector/alarm solved the advance warning problem, soldiers still needed a

quick test to confirm the presence of chemical

agents. The problem was solved with the standardization of M8 detector paper in 1973. The paper was

a Canadian development. It was packaged in booklets of 25 sheets (perforated for easy removal) sized

4 x 21⁄2 in. M8 detector paper turned dark blue for

V agents, yellow for G-series agents, and red for

mustard agent.161

Fig. 2-56. (a) The M687 GB2 binary 155-mm projectile,

which was standardized in 1976 but not produced until

a decade later. (b) A diagram of the M687 GB2 binary

155-mm projectile. To appreciate the sophistication of this

weapon, the reader should compare this drawing with

Figure 2-2. Photograph (a): Chemical and Biological Defense Command Historical Research and Response Team,

Aberdeen Proving Ground, Md. Photograph (b): Reprinted from Department of the Army. Binary Chemical

Munitions Program. Aberdeen Proving Ground, Md:

Chemical Systems Laboratory; 1981: 5. Programmatic

Environmental Impact Statement ARCSL-EIS-8101.

a b
History of Chemical and Biological Warfare: An American Perspective

67

There were some problems with the paper, the

most important of which was that some less-dangerous agents gave responses similar to mustard

agent. Benzene, DANC, and defoliating agents produced a red response; sulfuric acid produced a black

response; and organophosphate insecticides produced a yellow response.184

Collective Protection Improvements

One particular area of development that gained

significantly from the resurgent interest in chemical and biological defense was collective protection.

Increasing numbers of combat and combat-support

vehicles with integrated chemical and biological

collective protection systems were reported to be

appearing throughout the Warsaw Pact area. These

reports resulted in a closer look at the U.S. situation.185

The army was already examining collective

protection for some military vehicles and, in particular, the missile-control vans. The need for collective protection for vans and vehicles used for

command posts, fire direction, rest and relief shelters, and medical aid stations resulted in the

standardization of the M14 Collective Protection

Equipment in 1970. This equipment was designed

to protect occupants of the M291A2 and M292 series of vans against airborne toxic agents.161

Work during the 1960s on the CB Pressurized Pod

resulted in the standardization of the M51 Shelter

System in 1971. The unit was an easily transportable, pressurized enclosure. It could be air-dropped

or towed to provide protection from chemical and

biological agents in the field for combat, combat

support, and combat service support troops. The

M51 was a double-walled, air-inflated, self-supporting shelter and airlock structure. When erected, the

shelter was semicircular in cross-section with a

maximum inside height of 7.5 ft, with inside dimensions of 15 x 14 ft. An airlock entrance (with a set of

double doors at each end) on the front was 11 (l) x

4.2 (w) x 6.7 (h) ft in dimension. The filter and support equipment were mounted on a two-wheeled

trailer.186

Despite these developments, congress got involved in 1977 and included in the Department of

Defense Appropriation Authorization Act a section

that stated:

The Secretary of the Army shall submit to the Committees on Armed Services of the Senate and House

of Representatives, no later than February 1, 1978,

a plan for the funding and scheduling necessary to

incorporate by October 1, 1980, collective system

protection against chemical and radiological agents

for all main battle tanks, mechanized infantry combat vehicles, armored personnel carriers, armored

self-propelled artillery vehicles, armored self-propelled air defense artillery vehicles, and other such

types of equipment associated with the above in

combat operations which will be in development

or procurement in fiscal year 1981.187

This law launched an intensive effort to determine

the chemical vulnerability of all army vehicles. The

initial concentration was on ventilated facepieces

and a mixture of positive-pressure and hybrid systems for selected rear-area vehicles.

Growing Danger of Chemical and Biological

Warfare

Starting in about 1975, reports of the use of

chemical and biological agents in various small

wars in Southeast Asia and Afghanistan began to

attract attention in the United States. Interviews

with Hmong villagers in Laos suggested that Vietnamese and Russian forces might have used chemical and possibly toxin weapons against these

people. Starting in 1978, similar reports from

Kampuchea claimed that the Vietnamese and their

allies had killed over 980 villagers using chemical

weapons. Prior to the Soviet invasion of Afghanistan in December 1979, reports were already circulating that Soviet troops were using chemical weapons against the mujahidin soldiers.

The Soviets legitimized their use of chemical and

biological weapons because, although they had

signed the Geneva Protocol in 1928, Laos, Kampuchea,

and Afghanistan were not signatories. The Soviet

Union, Laos, and Afghanistan signed the Biological Weapons Convention, but the allegations of

toxin use were never acknowledged by the Soviets

or their allies. In fact, when the Soviets signed the

Biological Weapons Convention in 1975, they added

the statement: “the Soviet Union does not possess

any bacteriological agents and toxins, weapons,

equipment or means of delivery.”188(p6) Other intelligence sources thought that the Soviets considered

most toxins to be chemical agents, and therefore not

subject to the Biological Weapons Convention. If

toxins were considered to be chemical agents, then

the Soviets would be permitted under the Geneva

Protocol to use them in retaliation or against

nonsignatories.189

The use of chemical and biological weapons by

the Soviets was taken as an indication that the So-
Medical Aspects of Chemical and Biological Warfare

68

viets were continuing an active chemical and biological program. This program, however, did not

continue without costs. In April 1979, a sudden outbreak of anthrax occurred in Sverdlovsk, in the Ural

Mountains. At the time, the etiology of the outbreak

was explained by the Soviets as human ingestion

of beef from cattle that had been contaminated by

naturally occurring anthrax spores in the soil. U.S.

intelligence officers doubted the story and used the

incident to push for better chemical and biological

preparedness in the army. In 1992, Russian President Boris Yeltsin confirmed that the epidemic had

been caused by military researchers working with

the agent. Izvestiya, the Russian newspaper, later reported that it took 5 years to clean up the plant after the accident.190–192

THE 1980S: THE RETURN OF THE CHEMICAL CORPS

The Haig Report

Despite denials by the governments involved, the

United States went public with charges that chemical warfare had been used in Southeast Asia and

Afghanistan in 1980. Problems with the collection

of samples and the remoteness of the sites, however, prevented definitive evidence from being obtained. Furthermore, the later identification, discussion, and media debate over the origin of possible

trichothecene mycotoxins in Southeast Asia also

took away a significant portion of the public interest in the alleged use of conventional chemical

munitions.

In 1982, Secretary of State Alexander M. Haig,

Jr., presented a report titled Chemical Warfare in

Southeast Asia and Afghanistan to the U.S. Congress.

After describing the evidence, he concluded:

Taken together, this evidence has led the U.S. Government to conclude that Laos and Vietnamese

forces, operating under Soviet supervision, have,

since 1975, employed lethal chemical and toxin

weapons in Laos; that Vietnamese forces have, since

1978, used lethal chemical and toxin agents in

Kampuchea; and that Soviet forces have used a variety of lethal chemical warfare agents, including

nerve gases, in Afghanistan since the Soviet invasion of that country in 1979.189(p6)

Based on this evidence, senior defense department

personnel concluded that the Soviet Union “possesses a decisive military advantage because of its

chemical capabilities.”167(p3)

The Haig report, however, was not able to galvanize world opinion. Much like the situation during the Yemen Civil War, the United States was unable to prove beyond a shadow of the doubt that

chemical agents and toxins had been used in Southeast Asia and Afghanistan. Instead, the accusation

became a political debate between the United States

and the Soviet Union during President Ronald

Reagan’s administration.

Chemical Warfare in the Afghanistan and Iran–

Iraq Wars

Afghanistan War

The U.S. Army monitored the war in Afghanistan throughout the 1980s. Often thinking of it as

the Soviet’s “Vietnam,” the lessons learned from

this war about chemical warfare provided extensive support to the U.S. chemical defense program.

The Soviets tended to use chemical weapons

much like the Italians did in Ethiopia and like the

U.S. Army had used nonlethal agents in Vietnam.

One military writer summed up the general lesson

learned:

The use of chemical weapons by Soviet forces in

Afghanistan is also significant. The use of these

weapons in Afghanistan confirms, not surprisingly,

that the Soviets find them put to their best use

against unprotected subjects incapable of retaliation. Afghanistan is proof positive that the Soviets

do not consider these devices as special weapons.

Considerations of utility and not morality will govern Soviet use of them in a future conflict.193(p27)

Despite the use of chemical weapons, the Soviets were unable to “win” the war and, in December

1988, met with rebel forces to discuss a withdrawal

of Soviet troops from Afghanistan. In January 1989

the Soviets announced the final withdrawal, which

was completed a month later.194

Iran–Iraq War

Although the Soviet Union continued to be the

number one potential chemical warfare opponent

and, therefore, the United States concentrated on

proposed chemical treaties with that country, the

beginning of a war in the Middle East gradually

began to erode that status. On 22 September 1980,

the armed forces of Iraq launched an invasion

against its neighbor Iran. The Iraqi army, trained
History of Chemical and Biological Warfare: An American Perspective

69

and influenced by Soviet advisers, had organic

chemical warfare units and possessed a wide variety of delivery systems. When neither side achieved

dominance, the war quickly became a stalemate.

To stop the human wave–attack tactics of the Iranians, the Iraqis employed their home-produced

chemical agents as a defensive measure against the

much-less-prepared Iranian infantry. The first reported use of chemical weapons occurred in November 1980. Throughout the next several years,

additional reports circulated of new chemical attacks. The result was that by November 1983, Iran

complained to the United Nations that Iraq was

using chemical weapons against its troops.195–198

After Iran repeated the claims and even sent

chemical casualties to several western nations for

treatment, the United Nations dispatched a team

of specialists to the area in 1984, and again in 1986

and 1987, to verify the claims. The conclusion from

all three trips was the same: Iraq was using chemical weapons against Iranian troops. In addition, the

second mission also stressed that the use of chemical weapons by Iraq appeared to be increasing despite the publicity of their use. The reports indicated

that mustard agent and the nerve agent tabun were

the primary agents used, and that they were generally delivered in airplane bombs. The third mission

also reported the use of artillery shells and chemical rockets and the use of chemical weapons against

civilian personnel. The third mission was the only

one allowed to visit Iraq.199–201

In the letter of transmittal to the United Nations

after the conclusion of the third mission, the investigators pointed out the dangers of this chemical

warfare:

It is vital to realize that the continued use of chemical weapons in the present conflict increases the

risk of their use in future conflicts. In view of this,

and as individuals who witnessed first hand the

terrible effects of chemical weapons, we again make

a special plea to you to try to do everything in your

power to stop the use of such weapons in the Iran–

Iraq conflict and thus ensure that they are not used

in future conflicts.

. . . .

In our view, only concerted efforts at the political

level can be effective in ensuring that all the signatories of the Geneva Protocol of 1925 abide by their

obligations. Otherwise, if the Protocol is irreparably weakened after 60 years of general international

respect, this may lead, in the future, to the world

facing the specter of the threat of biological weapons.199

This last comment was mirrored by another

analyst:

In a sense, a taboo has been broken, thus making it

easier for future combatants to find justification for

chemical warfare, this aspect of the Iran–Iraq war

should cause Western military planners the gravest concern.202(pp51–52)

The Iran–Iraq War failed to reach a military conclusion despite Iraq’s use of chemical weapons.

Roughly 5% of the Iranian casualties were caused

by chemical weapons. Although there were rumors

of Iranian use of chemical weapons also, less attention was devoted to verifying those reports. In August 1988, Iraq finally accepted a United Nations

cease-fire plan, and the war ended politically with

little gained from the original objectives.194

Additional Reports of Chemical Warfare

The end of the Iran–Iraq War, however, did not

end chemical warfare reports from circulating.

Within a month of the end of the war, Iraq was again

accused of using chemical weapons against the

Kurds, a minority group in Iraq seeking autonomy.

Shortly before, there were rumors that Libya had

used chemical weapons obtained from Iran during

an invasion of Chad. The United States rushed 2,000

gas masks to Chad in response. There were also reports of the Cuban-backed government of Angola

using nerve agents against rebel forces.203–206

New Defensive Equipment

In response to the continued use of chemical

agents in the Middle East and elsewhere, the army

instituted a three-pronged chemical program for the

1980s, intended both to drive the Soviets to the bargaining table and to restore the United States chemical defense and retaliatory capability. First, the army

improved its defensive equipment. Second, the

army began production of chemical weapons for the

first time since the 1969 ban. And third, the army

improved its chemical warfare training and updated

its training manuals.

A number of physical protection, collective protection, detection, and decontamination developments reflected the improved defensive equipment.

Perhaps the most significant development was the

type classification in 1987 of a new protective mask

for the infantry to replace the M17 series masks. The

new mask, designated the M40, returned to a can-
Medical Aspects of Chemical and Biological Warfare

70

ister design that provided increased protection

against everything from chemical agents to toxins,

smokes, and radioactive fallout particles. The canister used North Atlantic Treaty Organization

(NATO) standard threads and could be worn on

either side of the mask. The mask also had improved

fit and comfort, voice communications, and drinking capability. It came in three sizes—small, medium, and large—which helped eliminate the logistical burden of four sizes for the M17A2 and six different stock numbers for the M9A1. In conjunction

with M40, the army also standardized the M42

Combat Vehicle Mask to replace earlier tank masks

from the 1960s.207–209

For collective protection, the army standardized

the M20 Simplified Collective Protection Equipment

in 1986. This system turned one room of a building

into a protected area by (1) lining the walls with a

chemical/biological vapor–resistant polyethylene

liner and (2) providing 200 cu ft of filtered air per

minute. In addition, the army concentrated on

modular collective protection equipment for chemical threats to vehicles, vans, and shelters. The Department of the Army identified 43 systems in 1980

that required chemical protection. New systems that

were developed each year created a major, longterm project to correct the deficiency that had been

discovered after the 1973 Yom Kippur War.207,210

For detection, the army developed two new detectors, one using low technology and one high

technology. M9 Detector Paper was an adhesivebacked paper containing B-1 dye, which turned red

when contaminated with any known liquid agent.

Type classified in 1980, the paper was attached to a

soldier’s arms or legs, or to the outside of his vehicle,

and provided an indication of a chemical attack.210

The M1 Chemical Agent Monitor (CAM), standardized in 1988, was used to detect chemical agent

contamination on personnel and equipment. It detected vapors by sensing ions of specific mobilities

and used timing and microprocessor techniques to

reject interferences. Its developmental history was

particularly interesting, in that it was based on a

United Kingdom (U.K.) design originally standardized by the U.K. in 1984.3,211

There were several developments in the area of

decontamination. The M13 Portable Decontaminating Apparatus, designed to decontaminate large

military vehicles, was standardized in 1983; and the

M280 Individual Equipment Decontamination Kit,

designed to partially decontaminate a soldier’s personal equipment, including gloves, hood, mask, and

weapon, was standardized in 1985. Both items replaced older equipment.3

Not all research and development utilizing current technology or foreign intelligence resulted in

the standardization of a new item. One example was

the truck-mounted, jet-exhaust decontaminating

apparatus, designated the XM16. Based on intelligence collected on the Soviet TMS-65 decontamination system, the army started work on a similar

project. The U.S. project consisted of a J60-P-6 jet

engine with a control cab mounted on a 5-ton military truck. The idea was to direct high-velocity

streams of hot exhaust gases onto the outer surfaces

of vehicles for decontamination. In addition, the jet

engine could be used as a smoke generator by adding smoke liquids to the exhaust. Because of several deficiencies in the system, the project was canceled in 1986, but the principle was continued in

related developmental projects.212

Production of Binary Weapons

The subject of chemical weapon production was

a very sensitive one. In 1984, congress created the

Chemical Warfare Review Commission to look at

several issues related to the military’s chemical

warfare preparedness. This committee visited numerous sites, interviewed experts, reviewed policy,

and examined intelligence reports. Among their

findings, the commission concluded

that in spite of the approximately $4 billion that

the Congress has appropriated since 1978 for defense against chemical warfare, that defense, measured either for purposes of deterrence or for warfighting utility, is not adequate today and is not

likely to become so. Chemical combat as it would

exist in the late twentieth century is an arena in

which—because defense must be nearly perfect to

be effective at all, detection is so difficult, and surprise offers such temptation—the offense enjoys a

decisive advantage if it need not anticipate chemical counterattack. Defense continues to be important to pursue, because it can save some lives and

preserve some military capabilities. But for this

country to put its faith in defense against chemical

weapons as an adequate response to the Soviet

chemical threat would be a dangerous illusion.213(p50)

The answer to the problem was simply stated by

President Reagan:

The United States must maintain a limited retaliatory capability until we achieve an effective ban.

We must be able to deter a chemical attack against

us or our allies. And without a modern and credible deterrent, the prospects for achieving a comprehensive ban would be nil.214(p23)
History of Chemical and Biological Warfare: An American Perspective

71

In 1981, the secretary of defense issued a memorandum to proceed to acquire binary chemical

bombs. The appropriation restrictions of 1976, however, blocked procurement of binary munitions for

several more years. The next step came in 1985 when

the U.S. Congress passed Public Law 99-145 authorizing production of chemical weapons. The final

step came in 1987, when President Reagan certified

to congress that all their conditions had been met

to start production of binary chemical weapons.3

The production of the M687 binary projectile began on 16 December 1987 at Pine Bluff Arsenal. This

was no small feat considering modern environmental and general public concerns. To resolve political concerns, the M20 canisters were filled and

stored at Pine Bluff Arsenal, while the M21 canisters were produced and filled at Louisiana Army

Ammunition Plant. The filled M21 canisters and

shell bodies were then stored at Tooele Army Depot, Utah. In time of need, the parts could be combined and would provide the army with a chemical retaliatory capability.215

In addition to the M687 round, development

work continued on the BLU-80/B (BIGEYE) bomb

and the XM135 Multiple Launch Rocket System

(MLRS) Binary Chemical Warhead. Both utilized the

binary concept. The BIGEYE was in the 500-lb bomb

class and was compatible with fixed-wing aircraft

belonging to the air force, navy, and marine corps.

The bomb dispersed the persistent nerve agent VX

after mixing two nonlethal chemical agents (designated NE and QL). The XM135 binary chemical

warhead was designed as a free-flight, semipersistent, nerve agent–dispersing system. The XM135

was fired from the MLRS, a 12-round rocket

launcher mounted on a tracked vehicle.215,216

Chemical Training

In addition to establishing a retaliatory capability,

the army significantly improved its chemical training capability by (a) constructing a new facility at

the Chemical School and (b) conducting

more-realistic field training. In 1987, the Chemical

Decontamination Training Facility (CDTF) started

live–chemical agent training in a controlled environment. Major General Gerald G. Watson, the

school’s commandant, was “the first American to

wear the battledress overgarment in a toxic chemical environment”217(p15) when he entered the CDTF

on 19 February 1987.

For realistic field training, the army conducted

such training as Operation Solid Shield 87 to test

how the U.S. troops perform on a chemically contaminated battlefield. Over 40,000 personnel from

the U.S. Army, Navy, Marine Corps, Air Force, and

Coast Guard participated in the simulated chemical attacks. Many conclusions were drawn from the

training. Of particular concern was the impact on

the medical personnel trying to help both conventional and chemical casualties:

Use of chemical weapons in an otherwise conventional warfare scenario will result in significant

impact on the medical capability to treat and handle

casualties. Many medical facilities might be located

near chemical target areas and may be subject to

contamination.

These facilities include battalion aid stations, hospital and medical companies, casualty receiving

and treatment ships, fleet hospitals, and hospital

ships. Provision of medical care in a contaminated

environment is extremely difficult due to the encapsulation of medical personnel in their individual protective ensembles.

Medical care is best provided in an environment

free of toxic agents. This environment might be

provided by a collectively protected facility, or be

in an uncontaminated area. Medical units ashore

and afloat can expect to receive contaminated casualties and must be prepared to provide contaminated casualties with a comprehensive and thorough decontamination. This procedure is similar

whether processing patients into a collectively protected facility or processing from a contaminated

area to an area free of contamination.218(p30)

The conclusions of the training impacted all aspects of the military forces:

All organizations must be trained in NBC detection and identification procedures, particularly

units with an inherent reconnaissance mission. First

aid, and casualty handling, including mass casualty handling, must also be an integrated part of

training. NBC contamination, medical, operational,

and logistical problems should be evaluated and

responded to realistically at all command and staff

levels.

Particular emphasis must be placed on the ability

of personnel to remove contaminated clothing and

equipment while minimizing the transfer of contamination to unprotected skin or to nonprotective

underclothing.218(p31)

One officer summed up this new way of thinking about chemical training as demonstrated by

Solid Shield 87:

NBC warfare is not a separate, special form of war,

but is instead a battlefield condition just like rain,
Medical Aspects of Chemical and Biological Warfare

72

snow, darkness, electronic warfare, heat, and so on.

Units must train to accomplish their wartime missions under all battlefield conditions. Whenever

NBC is separated from other training events, we

condition our soldiers to regard operations under

NBC conditions as a separate form of warfare.218(p31)

To reflect the changes in concept and equipment,

the army’s field manuals were also rewritten and

updated to incorporate chemical warfare readiness

into the army’s air–land battle doctrine. The five

parts of the new doctrine called for contamination

avoidance, individual and collection protection,

decontamination, chemical weapons employment,

and the deliberate use of smoke.

Soviet–United States Agreement

The increase in the United States’s retaliatory and

defensive capability for chemical and biological

warfare, along with internal changes in the Soviet

Union, helped convince the Soviets to look closely

at a new chemical weapons treaty. In 1987, after

admitting for the first time that they possess chemical agents, they announced the halting of chemical

weapons production. In September 1989, the Memorandum of Understanding (MOU) Between the Government of the United States and the Government of the

USSR Regarding a Bilateral Verification Experiment and

Data Exchange Related to Prohibition of Chemical Weapons, otherwise known as the Wyoming MOU,

started the talks between the two countries.3

U.S. Demilitarization Program

While the army was producing the new binary

agent weapons, it was also discovering that the

destruction of the existing chemical weapons stockpile was proving a far greater challenge than originally expected. In 1982, the army announced that

incineration was the best option for disposing of

the chemical agents. The construction of the first

such disposal system was started on Johnston Atoll

in 1985. The following year, congress passed Public

Law 99-145, which mandated the destruction of the

U.S. stockpile of chemical weapons by 1994. This

also required that the army plan for maximum protection for the environment and human health during the destruction. In 1988, congress extended the

destruction date to 1997; later, this date was further extended to 2004. In 1989, construction on a

second disposal system was started at Tooele,

Utah.3,219

THE 1990S: THE THREAT MATERIALIZES

The success of the “carrot and stick” strategy

with the Soviet Union led to another change in

course for the chemical program. On 1 June 1990,

with the fall of many of the communist governments

in Eastern Europe and improved relations with the

Soviet Union, the United States and the Soviet

Union signed a bilateral chemical weapons destruction agreement. In support of this agreement, the

secretary of defense canceled most of the new

chemical retaliatory program, and the army decided

to mothball its new binary chemical production facilities in 1990.220

Shortly after the signing of the bilateral chemical weapons destruction agreement, the army began Operation Steel Box to remove all U.S. chemical weapons from Germany. The project started in

July and finished in November 1990, with all the

munitions safely moved to Johnston Atoll. The same

year, the Johnston Atoll Chemical Agent Destruction System (JACADS) incinerator on the island

became operational. The Tooele demilitarization

plant was not operational until 1996.

In 1992, however, Public Law 102-484 instructed

the army to restudy incineration as the best process for demilitarization due to continuing opposition by the general public. The army then began

researching both neutralization and neutralization

followed by biodegradation as alternate disposal

options.3,219

Persian Gulf War

Despite the ongoing political efforts to abolish

chemical warfare, world events dictated that chemical and biological weapons would again be the subject of daily news reports. On 2 August 1990,

Saddam Hussein sent Iraqi troops into Kuwait—

allegedly in support of Kuwaiti revolutionaries who

had overthrown the emirate. By 8 August, however,

the pretense was dropped and Iraq announced that

Kuwait had simply been annexed and was now a

part of their country. In response, President George

Bush ordered U.S. forces sent to Saudi Arabia at the

request of the Saudi government as part of what

became Operation Desert Shield, the buildup phase

of the Persian Gulf War.

The United States’s response to Iraq’s invasion

put the army’s chemical and biological warfare ex-
History of Chemical and Biological Warfare: An American Perspective

73

perience, training, production program, and lessons

learned in the limelight. Not since World War I had

U.S. troops been sent to face an enemy that had not

only used chemical weapons extensively within the

last few years, but also had publicly announced

their intentions to use chemical weapons against the

United States. William H. Webster, Director of Central Intelligence, estimated that Iraq had 1,000 tons

of chemical weapons loaded in bombs, artillery

rounds, rockets, and missiles. Much of Iraq’s biological weapon program remained unknown until

after the war.221–223

Iraq had a large biological agent production facility at al-Hakam that produced the agents that

cause botulism, anthrax, and others. Started in 1988,

the plant had produced about 125,000 gal of agent

by 1991. After stating for years that the plant was

used to produce animal feed, the Iraqis admitted in

1995 that the plant was a biological warfare production facility. In addition to producing biological warfare agents, they also conducted live-agent tests on

animals. The Iraqis also later admitted they had prepared about 200 biological missiles and bombs.224–227

The United States’s preparation for the military

phase of the Persian Gulf War had to consider all

these chemical and biological threats. Vaccines for

anthrax and botulinum toxin were given to U.S.

troops moving into the area.228 For nerve agent poisoning, troops had the MARK I nerve agent antidote kit, consisting of an atropine autoinjector and

a pralidoxime chloride (2-PAM Cl) autoinjector. The

atropine blocked the effects of nerve agent poisoning on the muscles, while the 2-PAM Cl reactivated

the acetylcholinesterase. Pyridostigmine bromide

tablets also were provided as a nerve agent pretreatment.229 All military units were fully equipped with

the latest chemical and biological defensive equipment, and training was continuous.

The actual attack on Iraq on 16 January 1991 as

part of the United Nations’s mandated effort to free

Kuwait, designated Operation Desert Storm by

the United States, escalated fears of a new chemical war to levels not seen since World War I. The

initial air attack concentrated on Iraqi chemical-production facilities, bunkers, and lines of supply.

While the air attacks were ongoing, daily news accounts addressed the potential for chemical and

biological warfare. On 28 January, Saddam Hussein

told Peter Arnett of CNN News that his Scud missiles, which were already hitting Israel and Saudi

Arabia, could be armed with chemical, biological,

or nuclear munitions.230 Vice President Dan Quayle,

while visiting the United Kingdom, was reported

to have told the prime minister that the United

States had not ruled out the use of chemical or

nuclear weapons.230 Likewise, the United States was

reported to have threatened to target Hussein personally if he used chemical weapons against Allied

troops.230,231 Iraq, in turn, reportedly threatened to

use chemical weapons against Allied troops if they

continued the high-level bombings against Iraqi

troops.230

Thus the stage was set for what many thought

was going to be the second major chemical war in

this century. When the Allies began the ground war

on 23 February 1991, the worst was expected and

planned for by chemical and biological defense specialists. Chemical alarms frequently went off across

the battlefield, but all were dismissed as false

alarms. On 27 February, Allied troops liberated

Kuwait City and finished destroying the Iraqi divisions originally in Kuwait. No known chemical and

biological attacks were made by the Iraqis.

A number of reasons surfaced after war as to why

the Iraqis had not initiated large-scale chemical

and biological warfare. Vice Admiral Stanley

Arthur, commander of U.S. naval forces, thought

that because the wind suddenly changed from

blowing south at the start of the land battle, the

Iraqis had probably realized that chemical weapons could harm their own troops. Some thought

the speed of the campaign was the critical reason.

Others reported that the combination of Allied

bombing and resulting Iraqi logistical nightmares prevented the chemical weapons from ever

reaching the front lines. General H. Norman

Schwarzkopf, commander of Allied forces,

mentioned that Iraq might have feared nuclear retaliation.223,230,232

After the war, however, allegations of chemical

and biological exposures began to surface. Initially,

the department of defense denied that any chemical and biological exposures had taken place. Veterans of the war claimed the opposite, and their

ailments collectively became known as Gulf War

Syndrome. By 1996, newspapers reported that almost 60,000 veterans of the Persian Gulf War

claimed some sort of medical problems directly related to their war activities. Extensive research by

the department of defense failed to find any single

cause for the problems.233,234

One controversial example of possible exposure

occurred on 4 March 1991 at the Kamisiyah arsenal, northwest of Basra, involving the U.S. Army

37th Engineer Battalion. After capturing the site, the

engineers blew up the Iraqi storage bunkers. Ac-
Medical Aspects of Chemical and Biological Warfare

74

cording to newspaper accounts, the engineers

claimed that their chemical agent detectors went off

during the explosions. Later the same year, a United

Nations inspection team reportedly found the remains of chemical rockets and shells in one of the

bunkers and found traces of sarin and mustard

agent. In 1996, the department of defense acknowledged that one of the bunkers probably contained

sarin- and mustard agent–filled munitions, and that

as many as 20,000 U.S. soldiers may have been exposed to chemical agents as a result.235 A Pentagon

spokesman summed up the continuing research into

the possible exposure: “Our understanding of this

episode is still partial.”234(pA-10)

Additional Allegations of Chemical Warfare

Shortly after the fighting was over between Iraq

and Allied forces, reports circulated that Hussein

was using chemical agents against rebellious Kurds

and Shiite Moslems. The United States intercepted

a message ordering the use of chemical weapons

against the cities of Najaf and Karbala. President

Bush’s response was that such use of chemical

weapons would result in Allied air strikes against

the Iraqi military organization using the chemicals.

Thus, despite the end of fighting, Iraqi chemical

weapons continued to be a problem for the

world.236,237

Likewise, U.S. intelligence sources detected increased chemical-development activity in Libya.

Libya constructed a chemical weapons plant at

Rabta that produced about 100 tons of chemical

agents. In 1990, Libya claimed that the plant was

destroyed by a fire. New disclosures surfaced in

1996 that Libya was constructing a second chemical production plant at Tarhunah. U.S. intelligence

sources claimed that this would be the largest underground chemical weapons plant in the world,

covering roughly 6 square miles and situated in a

hollowed-out mountain. With Scud missiles having

a range of 180 to 300 miles, this created a significant threat to Libya’s neighbors. Libya strongly

denied the accusation.238,239

New Defensive Equipment

During the 1990s, the army standardized several

new protective masks. In 1990, the M43 CB AH-64

Aircraft Mask was standardized for use in Apache

helicopters. The unique aspect of the mask was its

compatibility with AH-64 display sighting system.

Within 6 years, the army improved the mask and

standardized the new version as the M48 CB

Aviator’s Mask.3

Although the new M40 series was an improvement over the M17 series mask, complaints from

soldiers about the M40 masks resulted in the standardization of the M40A1 Field Mask and the

M42A1 Combat Vehicle Mask in 1993. The M40A1

Mask added the Quick Doff Hood/Second Skin

(QDH/SS), which allowed the hood to be doffed

without removing the mask. This feature resulted

in faster, more efficient decontamination operations. The M42A1 Mask added the QDH/SS and

a canister-interoperability system that allowed

the use of NATO canisters in the system. The

new masks also included an improved nosecup

that provided more comfort than the previous

one. These changes increased the likelihood that soldiers would survive on a chemical and biological

battlefield.3,240

The detection of chemical and biological agents

was made much easier in the 1990s. In 1990, the

army issued the first XM93 series NBC Reconnaissance Systems (the FOX), a dedicated system of

NBC detection, warning, and sampling equipment

integrated into a high-speed, high-mobility, armored carrier. A later version, the M93A1, was standardized in 1996. The FOX was capable of performing NBC reconnaissance on primary, secondary, or

cross-country routes throughout the battlefield and

had the capability to find and mark chemical and

biological contamination. While conducting the reconnaissance, the crew was protected by an onboard

overpressure system.3,240,241

The remote sensing research that started in the

1950s finally resulted in a detector in 1995, when

the M21 Remote Sensing Chemical Agent Alarm

was standardized. The M21 was an automatic scanning, passive infrared sensor that detected vapor

clouds of nerve and blister agents, based on changes

in the background’s infrared spectra caused by the

presence of agent vapor. The detector could “see”

agent clouds to 5 km.242

After the Persian Gulf War, General Colin Powell

testified to congress that the United States was vulnerable to biological warfare. One reason was that

the United States had been unable to standardize a

good biological agent detector. In 1995, the army

standardized the first biological alarm. The M31

Biological Integrated Detection System (BIDS) was

a small truck packed with sampling and detection

equipment. Each vehicle could provide 24-hour

monitoring, with identification of the agent following an alarm in about 30 minutes.3,243
History of Chemical and Biological Warfare: An American Perspective

75

The Chemical Weapons Convention

In 1993, the long-sought Chemical Weapons Convention was signed by the United States, Russia,

and other countries. This treaty prohibited development, production, stockpiling, and use of chemical weapons. Ratification by the U.S. Senate, however, was delayed for various reasons.3

 One reason

was that reports of a Russian chemical-development

program surfaced in U.S. newspapers. A Russian

scientist claimed that in 1991 Russia had developed

a new, highly toxic, binary nerve agent called

Novichok. According to the scientist, the nerve

agent was undetectable by U.S. chemical detectors

and may have been used in the Persian Gulf War

by Iraq to produce some of the Gulf War syndrome

symptoms. Despite these claims, the negotiations

continued and additional agreements were signed

with Russia. The United States even agreed to help

fund the Russian demilitarization program.244,245

Terrorism and Counterterrorism

The use of chemical and biological weapons for

terrorism became a key concern of the U.S. Army

in the 1990s. In 1994, a Japanese religious cult, Aum

Shinrikyo, reportedly released nerve agent in a residential area of Matsumoto, Japan, that killed 7 and

injured 500. A second attack on 20 March 1995

spread sarin through a crowded Tokyo subway. This

act of terrorism killed 12 and caused more than 5,500

civilians to seek medical attention. After the attacks,

news accounts reported that the cult had developed

a helicopter to spray toxins, a drone for unmanned

chemical and biological attacks, and their own

strains of botulism. They had also allegedly attempted to obtain the Ebola virus from Zaire.246–248

Chemical and biological terrorism was not limited to foreign countries. The first conviction under the Biological Weapons Anti-Terrorism Act of

1989 occurred in 1995, when a U.S. citizen was sentenced to 33 months in prison for possession of 0.7

g of ricin. The same year, a nonprofit organization

shipped plague bacteria, Yersinia pestis, to an alleged

white supremacist.249,250

Some of the items developed by the Chemical

Corps were also used as counterterrorism measures,

but sometimes with unintended consequences. For

example, in 1993 the Federal Bureau of Investigation decided to use a nonlethal riot control agent

while attacking the Branch Davidian compound in

Waco, Texas. Fires, however, destroyed the complex

and killed the 80 occupants.3,251

These examples, both good and bad, led many

state and local officials to notify congress that they

did not have the training or equipment to combat

an act of chemical or biological terrorism. Senator

Sam Nunn expressed similar concerns:

I, like many of my colleagues, believe there is a high

likelihood that a chemical or biological incident will

take place on American soil in the next several

years.252(pA-10)

In reference to the Tokyo subway incident, he added:

The activities of the Aum should serve as a warning to us all. This is a lesson that we will ignore at

our peril.251(pA-10)

A military expert described the dangers of covert biological warfare:

A terrorist attack using an aerosolized biological

agent could occur without warning, and the first

sign of the attack might be hundreds or thousands

of ill or dying patients, since biological clouds are

not visible.251(pA-10)

In 1996, the U.S. Congress responded by passing a

new antiterrorism training bill to prepare the United

States for future chemical and biological terrorism

incidents. In addition to using military experts to

equip and train local chemical and biological response

teams, the bill also provided funding for former Soviet

republics to destroy their own chemical and biological

weapons to keep them out of the hands of terrorists.251,253

SUMMARY

Many lessons can be learned from the past concerning chemical and biological warfare and the

U.S. experience combating it. So far, the United

States has been extremely lucky and has not experienced a chemical and biological “Pearl Harbor”

like some other countries have. To prevent that, the

U.S. military forces will have to continue to learn

about chemical and biological warfare and how to

accomplish their mission—on both a chemical and

biological battlefield and at a chemical and biological terrorist site anywhere in the world. In the words

of General Pershing, “we can never afford to neglect the question”43(p77) of chemical and biological

preparedness again.
Medical Aspects of Chemical and Biological Warfare

76

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187. Department of Defense Appropriation Authorization Act. Public Law 95-79, 30 Jul 1977.

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Historical Aspects of Medical Defense Against Chemical Warfare

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Chapter 3

HISTORICAL ASPECTS OF MEDICAL

DEFENSE AGAINST CHEMICAL WARFARE

ROBERT J. T. JOY, M.D., FACP*

INTRODUCTION

EARLY HISTORY

NINETEENTH CENTURY

WORLD WAR I

MEDICAL PROBLEMS CAUSED BY MUSTARD

THE INTERWAR YEARS

WORLD WAR II

THE POSTWAR YEARS: 1945 TO THE PRESENT

SUMMARY

*Colonel, Medical Corps, U.S. Army (Ret); Professor Emeritus, Department of Medical History, Uniformed Services University of the Health

Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4799
Medical Aspects of Chemical and Biological Warfare

88

INTRODUCTION

In discussing the history of the use of any new

weapon and the medical response to it, one must

also describe the context of the weapon: its scientific, social, and political aspects. For chemical warfare, there is the particular idea that chemical weapons are inhumane and immoral. Medical people,

who treat the wounded, may well believe that all

weapons are inhumane. Nevertheless, even the

terms are relative—consider Pope Innocent II, who,

in 1139, forbade the use of the relatively new crossbow as “Hateful to God and unfit for Christian

Use.”1(pp35–36) His prohibition was cheerfully ignored;

the crossbow was used for over 300 years. In this

essay, I will return to the issue of the moral use of

the chemical weapon, but let us begin with the early

history of chemical warfare itself.

EARLY HISTORY

In Thucydides’s History of the Peloponnesian War,

the 4th-century BC war between Athens and Sparta,

we find the earliest description of chemical warfare.

Thucydides describes how the Athenians were defending a fort at Delium in 423 BC, when the allies

of Sparta attacked:

The Boethians took the fort by an engine of the following description. They sawed in two and

scooped out a great beam from end to end and fitted [it] together again like a pipe. They hung by

chains a cauldron at one extremity, with which communicated an iron tube projecting from the beam,

and this they brought up on carts to the part of the

wall composed of vines and timber and inserted

huge bellows into their end of the beam and blew

with them. The blast passing closely confined into

the cauldron, filled with lighted coals, sulfur and

pitch made a great blaze and set fire to the wall.

The smoke made it untenable for the defenders who

left and fled, and the fort was taken.2(p262)

In AD 660, some thousand years later, a man

named Kalinkos, who was either a Greek architect

or a Syrian alchemist, invented Greek fire. The actual formula is lost, but it probably consisted of

resin, pitch, sulfur, naphtha, lime, and saltpeter.

Greek fire was an excellent naval weapon because

it would float on water and set fire to the wooden

ships of the era.3

In the 9th century, Leo IX of Byzantium, writing on warfare, described “vases filled with quicklime which were thrown by hand. When broken,

the vase would let loose an overpowering odor

which suffocates those who are near.”4(pp45–46) Historically, then, the chemical weapons were fire

and gas.

NINETEENTH CENTURY

In 1812, Admiral Thomas Cochrane of the Royal

Navy of Great Britain proposed packing ships with

sulfur, setting them afire, and having them sail

into the French ports during the Napoleonic

wars. Cochrane argued that the resultant sulfur

dioxide would be carried by prevailing winds into

the forts and thus incapacitate the enemy.5–7 The

Admiralty turned down his idea as impractical and

further stated, “It is against the rules of warfare.”7(p22–23)

Some 30 years later, during the Crimean War of

1854, Sir Lyon Playfair, a noted British chemist, proposed the use of cyanide-filled shells against the

Russian fort at Sebastapol. The War Office rejected

the idea, stating that it was “as bad as poisoning

the enemy’s water supply.”8(p23) Playfair was appalled by that decision and made an interesting

prophecy:

There is no sense to this objection. It is considered

a legitimate mode of warfare to fill shells with

molten metal, which, scattering among the enemy,

produced the most frightful modes of death. Why is

a poisonous vapor which would kill men without

suffering to be considered illegitimate? This is incomprehensible to me. But no doubt in time chemistry

will be used to lessen the suffering of combatants.8(p23)

When the American Civil War started in 1861, the

use of Greek fire was threatened but, in fact, never

used. Edwin Stanton, President Lincoln’s secretary

of war, received an interesting letter from Mr. John

Doughty of New York in 1862. Enclosing a sketch

of an artillery shell (Figure 3-1), Mr. Doughty wrote:

Above is the projectile I have devised for routing

an entrenched enemy. Chlorine is so irritating in

its effects upon the respiratory organs that a small
Historical Aspects of Medical Defense Against Chemical Warfare

89

Fig. 3-1. John W. Doughty’s original drawing of the artillery chlorine shell he proposed in a letter to Edwin M.

Stanton, Secretary of War, in 1862. Original drawing held

at Record Group 94, Records of the Adjutant General’s

office, entry 286, special file 62B (TR3), National Archives

Building, Washington, DC.

quantity produces incessant and uncontrollable

violent coughing. A shell holding two or three

quarts of liquid chlorine contains many cubic feet

of the gas.9(p9)

He went on at great length in his letter to describe

the potential of this shell against ships, trenches,

“casemates, and bomb-proofs.” He concluded by

stating:

As to the moral question involved, I have arrived

at the somewhat paradoxical conclusion that its

introduction would very much lessen the sanguine

character of the battlefield and render conflicts

more decisive in their results.9(p9)

Historians have been unable to find a written

response to that letter. Of course, the gas shell was

not used.10

After the American Civil War, chemistry advanced rapidly as a science. As early as the 1830s,

Frederick Woehler had synthesized urea, and organic chemistry began. In Germany in the 1840s,

Justus von Liebig had introduced isomer chemistry and chemical fertilizers. In Sweden in the 1860s,

Adolph Nobel produced trinitrotoluene (TNT) and

dynamite. In 1912, a German chemist, Fritz Haber

(Figure 3-2), developed the ammonia process for

making nitrates. By the turn of the century,

Germany had become the center of world chemistry. The six largest German firms held 950

chemical patents, whereas the six largest British

firms held only 86 patents. Ninety percent of the

dyes used around the world were produced in

Germany.11,12

As is usual with human advances, consideration

was given to the use of chemicals (or, in the vernacular of the time, poison gases) in war. The moral

question that Mr. Doughty had raised in 1862

during the American Civil War became an issue at

the Hague Convention of 1899, an international

meeting aimed at limiting the horrors of war.

Among the issues raised was that of poison gas.

The American military representative at that meeting was Rear Admiral Alfred Thayer Mahan of the

U.S. Navy, who stated the official military position

very well:

It seems to me that it cannot be proved that shells

Fig. 3-2. Fritz Haber (1867–1934) received the 1918 Nobel

prize for solving the heretofore intractable problem of

making atmospheric nitrogen available for use in myriad

industrial chemical processes, including making fertilizer and explosives. He became interested in toxic gas as

a weapon of war early in World War I. Along with

Walther Nernst, Haber was responsible for the German

chemical warfare program and directed the initial German attack on Ypres. He was also a strong advocate of

chemical warfare after World War I. Reprinted with permission from Goran M. The Story of Fritz Haber. Norman,

Okla: University of Oklahoma Press; 1957.

Figure 3-2 is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include

usage in electronic media. The current user must

apply to the publisher named in the figure legend

for permission to use this illustration in any type

of publication media.
Medical Aspects of Chemical and Biological Warfare

90

with asphyxiating gases are inhumane or unnecessarily cruel or that they could not produce decisive results. I represent a people, animated by a

lively desire to make warfare more humane, but

which nevertheless may find itself forced to wage

war, and therefore it is a question of not depriving

ourselves through hastily adopted resolutions of

means which we could later use with good

results.13(p46)

The Hague Convention did outlaw chemical

warfare, but the agreement had so many loopholes

that it made no real difference when it came to the

testing ground of World War I.

WORLD WAR I

During World War I, chemical warfare began

with the German introduction of portable flamethrowers, which were not terribly effective after the

initial shock wore off. There were a number of problems with flamethrowers: the flames lasted only a

minute or two; the devices had a tendency to blow

up and kill the operator; and they were easy to

counter by shooting the operator.

Chemical warfare began in a tentative way with

the French use of tear gas grenades in 1914 and early

1915. They were not particularly useful. The Germans began experimental work on chemical agents

in late 1914 and produced a tear gas artillery shell.

These were used against the Russians in January

1915 but were not particularly effective, owing to

the cold weather. Fritz Haber, Director of the Kaiser Wilhelm Institute of Physical Chemistry in Berlin, proposed the use of chlorine gas, to be released

from cylinders.14,15

By 1915, the trench line between the French and

British forces and the Germans was established

from the English Channel to the Swiss border, and

a stalemate set in. At the junction of the British Expeditionary Force and a French territorial division

near the old Belgian city of Ypres, an event occurred

on 22 April 1915 that marked a new kind of warfare (Figure 3-3):

Suddenly at about 4 p.m., there rose from the German trenches opposite the lines occupied by the

French Colonial troops, a strange opaque cloud of

greenish-yellow fumes. A light breeze from the

northwest wafted this cloud toward the French who

fell gasping for breath in terrible agony. Terror

spread through the ranks, and a panic followed

which quickly spread from front to rear lines.

We saw figures running wildly in confusion over

the fields. Greenish-gray clouds swept down upon

them, turning yellow as they traveled over the

country blasting everything they touched and

shriveling up the vegetation. No human courage

could face such a peril. Then there staggered into

our midst French soldiers, blinded, coughing,

chests heaving, faces an ugly purple color, lips

speechless with agony, and behind them in the gassoaked trenches, we learned that they had left hundreds of dead and dying comrades. It was the most

fiendish, wicked thing I have ever seen.16(p13)

Intelligence warnings had been available for

some 2 weeks about the Germans putting gas cylinders in the trenches, but the British and the French

failed to heed them. The Germans released 150 tons

of chlorine from 6,000 cylinders (50 lb of liquid per

cylinder), and their tactical success was immediate.

They punched a hole through 15,000 troops, leaving perhaps 800 dead and maybe another 2,500 to

3,000 incapacitated.

However, the German High Command was not

ready for follow-up, in part because they did not

trust the weapon. In part, they saw it as a civilian

Fig. 3-3. This photograph is reputed to show the historical German chlorine gas cloud attack at Ypres, Belgium,

on 22 April 1915. Although there is little evidence to support this claim, the photograph does show a visible cloud,

probably created by a cylinder attack. Photograph: Courtesy of Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving

Ground, Md.
Historical Aspects of Medical Defense Against Chemical Warfare

91

idea that had been pushed on them by professors

Walther Nernst of the University of Berlin and Fritz

Haber of the Kaiser Wilhelm Institute. (Haber had

developed the ammonia process and Nernst formulated the third law of thermodynamics. After the

war, both men won Nobel prizes for their work in

chemistry.) More importantly, reserve troops had

been diverted to the Russian front while the Germans had been waiting for the right weather for

their gas attack.17–20

Now began the race between weapon protection

and weapon development. Medical involvement in

chemical warfare began with the development of

protective systems as well as with the treatment of patients. The Germans were the first to develop a mask. It had pads soaked in bicarbonate and

sodium thiosulfate, 21(p538) with some charcoal

between the layers. The British began using “veil”

respirators: the soldier put a soaked gauze pad over

his nose and mouth and then wrapped millinery

veiling around his head to hold the gauze in place.

The British rapidly developed a flannel hood,

in which a flannel bag with eyepieces was soaked

in glycerin and sodium thiosulfate and then pulled

over the head (Figure 3-4). The French M2 mask

was similar to the British mask, in which air

was breathed through multiple layers of cloth

a

impregnated with neutralizing chemicals (Figure

3-5). In early 1916, the Germans introduced a far

more sophisticated mask, which featured a canister containing the neutralizing chemicals attached

to the front of the mask. Air was breathed through

the canister (Figure 3-6). Horses were the prime

movers in World War I and had to be protected

from chemicals by gas masks that looked like nose

bags. Artillerymen, quartermasters, and transport

personnel were directed to mask their horses

before masking themselves (you can’t teach a

horse to hold its breath). 17,19,22–26 But until a

gas-warning system was implemented and soldiers

routinely carried gas masks, casualty rates

approached 5%, with a 25% death rate (Table

3-1).18(App D)

By September 1915, the British were moving chlorine cylinders to the front. Major Liven of the British army developed the Livens projector, a mortar

that could throw shells holding 1.5 gal of either

chlorine or phosgene. The Germans continued

to use gas cloud attacks; by December 1915,

the standard mixture consisted of chlorine and

phosgene21(pp154–155) (Figure 3-7). In 1916, the British

developed a “box respirator” (Figure 3-8), in which

the mask was connected by a hose to a canister filled

with protective chemicals and filters and carried in

Fig. 3-4. Warfare in the chemical age. (a) British soldiers at the Battle

of the Somme appear to be wearing PH helmets in this photograph

dated July 1916. (b) The PH helmet was an improved version of the

earlier hypo and P helmets in which air was inhaled and exhaled

through the fabric. The PH helmet incorporated an expiratory valve,

and the cloth was impregnated with chemicals designed to destroy

phosgene (the active agent was hexamethylenetetramine). This protective mask was stiflingly hot, and prolonged wear resulted in carbon dioxide retention. Source for figure legend: Prentiss AM. Chemicals in War: A Treatise on Chemical Warfare. New

York, NY: McGraw-Hill; 1937: 536. Photograph a: Reprinted with permission from Imperial War Museum, London, England. Photograph b: Courtesy of Pictorial History, Gas Defense Division, Chemical Warfare Service, Vol 5, Edgewood

Historical Files. Held at Chemical and Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

b

Figure 3-4a is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include usage

in electronic media. The current user must apply to

the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

92

Adapted with permission from Moore W. Gas Attack. London,

England: Leo Cooper; 1987: Appendix D.

TABLE 3-1

SIX CHLORINE–PHOSGENE CLOUD ATTACKS:

BRITISH CASUALTIES DECEMBER 1915–

AUGUST 1916

Fig. 3-5. The French M2 protective mask was similar

to the British cloth helmets and the earliest German

masks in the sense that the nose and mouth were covered with cloth impregnated with neutralizing chemicals. Even though somewhat ineffective, the M2 protective mask was used throughout World War I and was

even used by members of the American Expeditionary

Force early in its deployment. By 1916, the French had

the makings of a vastly superior mask, designed by the

respiratory physiologist Tissot. This mask incorporated

inlet and outlet valves and contained a design feature

still found in today’s masks: the inhaled air passes over

the lenses, thereby preventing their fogging. Practical

problems prevented its widespread adoption by the

French army. Reprinted with permission from Hartcup

G. The War of Invention, 1914–18. London, England:

Brassey; 1988.

a canvas pouch. This was later copied by the Americans. Like the British protective mask, the early

American mask had a nose clip and an internal

mouthpiece. Dennis Winter quoted a British

officer’s view:

We gaze at one another like goggle-eyed, imbecile

frogs. The mask makes you feel only half a man.

The air you breathe has been filtered of all save a

few chemical substances. A man doesn’t live on

what passes through the filter—he merely exists.

He gets the mentality of a wide-awake vegetable.27(p124)

Fig. 3-6. The most widely used German mask was introduced in early 1916; this painting was made in 1917. The

neutralizing chemicals were placed in a canister attached

directly to the facepiece of the mask. The wearer both

inhaled and exhaled through the canister. Protection depended on a tight seal between the mask and the wearer’s

face so that only air that had passed through the canister

entered the respiratory tract. In addition, note the World

War I–vintage truncal armor worn by these storm troopers. Reprinted with permission from Smith B. France: A

History in Art. La Jolla, CA: Bradley Smith Productions; 1984.

Figure 3-5 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden Institute

to grant permission to other users and/or does

not include usage in electronic media. The current user must apply to the publisher named in

the figure legend for permission to use this illustration in any type of publication media.

Figure 3-6 is not shown because the

copyright permission granted to the

Borden Institute, TMM, does not allow

the Borden Institute to grant permission

to other users and/or does not include

usage in electronic media. The current

user must apply to the publisher named

in the figure legend for permission to

use this illustration in any type of publication media.

Table 3-1 is not shown because the copyright permission granted to the Borden Institute, TMM, does

not allow the Borden Institute to grant permission

to other users and/or does not include usage in electronic media. The current user must apply to the

publisher named in the figure legend for permission to use this illustration in any type of publication media.
Historical Aspects of Medical Defense Against Chemical Warfare

93

A new weapon had come to the battlefield. It was

not decisive in a strategic sense, and it did not break

the stalemate of trench warfare. At the tactical level

and to the soldier, however, it had a significant and

frightening impact (Figure 3-9). Frederic Brown

summarized it well:

Gas is insidious. It often causes casualties without

any warning. It exerts a tremendous effect on morale, especially in untrained troops. Uncertainty as

to when and where gas is present and how it will

act is demoralizing even to troops with high discipline. Nothing breaks a soldier’s will to fight so

quickly as being gassed, even slightly. His imagination magnifies his real injury 100-fold.20(p153)

In April 1917, the United States entered the war,

unprepared for chemical warfare. We had no organization, no equipment, and no personnel trained for

chemical warfare. The U.S. Bureau of Mines was given

the task of researching and developing chemical

Fig. 3-7. The Germans continued to use gas cloud attacks

throughout 1916, usually mixing chlorine with phosgene.

Colonel H. L. Gilchrist, medical director of the American Expeditionary Force for gas warfare, prepared this

illustration for chemical warfare training purposes. The

drawing is based on an actual German gas cloud in 1916

but an American division is substituted for the British

division that was actually attacked. The gas cloud is seen

as totally interrupting the division’s medical evacuation

system, as well as making inoperative its two “degassing stations” (see Figure 3-20). Reprinted from Gilchrist

HL. A Comparative Study of World War Casualties From Gas

and Other Weapons. Edgewood Arsenal, Md: Chemical

Warfare School; 1928: illustration 1.

Fig. 3-8. The British small-box respirator, introduced in

1916 and seen in 1918 in this photograph, was vastly more

satisfactory than the earlier British helmets. The wearer

breathed through a mouthpiece (like that worn by a scuba

diver). Since a spring clip was applied to the nose, only

air that had passed through the mouthpiece could enter

the lungs. An absolute seal between the face and mask

was unnecessary. The mouthpiece was connected by a

tube to the canister containing neutralizing chemicals,

which was worn around the trunk. Although the small-box

respirator was much more protective than its predecessors, it was probably even less user-friendly. Photograph:

Courtesy of Pictorial History, Gas Defense Division,

Chemical Warfare Service, Vol 5, Edgewood Historical

Files. Held at Chemical and Biological Defense Command

Historical Research and Response Team, Aberdeen Proving Ground, Md.

agents, primarily through contracts with universities. The Signal Corps was tasked with making the

gas alarms, the Ordnance Corps with making the

weapons and ammunition, and the Engineers with

providing troops with chemical weapons and training them in their use. The Army Medical Department was directed to manufacture protective equipment and provide troops with training in its use.

The Medical Department performed physiological

studies on the energy costs and pulmonary function of individuals wearing masks. It also conducted

controlled gas-exposure studies by exposing volunteers to low doses of gas to test the efficacy of various protective masks (Figure 3-10). In October 1917,

at Edgewood Arsenal, Maryland, the United States

began to build a huge industrial complex for making chemical warfare agents; this facility poured out
Medical Aspects of Chemical and Biological Warfare

94

chemical munitions by the ton for shipment overseas.28–30 (Chemical warfare research done at The

American University, Washington, DC, during

World War I had a long-delayed fallout. In 1993,

during construction of new homes in Spring Valley, a neighborhood located near the university,

chemical warfare munitions from World War I were

uncovered. It seems that the then-vacant wooded

area was used as a testing range. The material has

Fig. 3-11. This poster from World War I was designed to

encourage enthusiasm for quality assurance among

women who worked manufacturing protective masks.

Photograph: Courtesy of Pictorial History, Gas Defense

Division, Chemical Warfare Service, Vol 5, Edgewood

Historical Files. Held at Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

Fig. 3-10. The men are testing experimental canisters,

probably performing a primitive form of quality assurance for equipment to protect against chemical warfare

agents. Photograph: Courtesy of Chemical and Biological Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.

Fig. 3-9. In this posed instructional picture of a gas attack, the soldier on the right has removed his small-box

respirator and is inhaling poison gas. What message is

this training photograph illustrating? That the mask is

defective and is letting in the chemical agent? That the

soldier thought he smelled gas, and, fearing that the mask

was defective, ripped it off? Or perhaps that the soldier

could not see (the lenses of the small-box respirator were

notoriously subject to fogging), removed his mask, and

is now suffocating? Whatever its intended purpose, this

photograph reminds us that removal of the mask in the

presence of chemical agents was a major cause of chemical injury in World War I. Gilchrist pointed this out in

1928:

Investigation showed that these casualties were

caused by general lack of gas discipline. It was found

that the standing order that “Men will not remove

the mask until ordered to do so by an officer” was

absolutely disregarded by practically all units affected, and that fully 75 per cent of the casualties

were due to the disobedience of this order, casualties which efficient training and discipline would

have prevented.

Gas mask discipline was the key to low chemical casualty rates in the face of this insidious weapon. Quotation: Gilchrist HL. A Comparative Study of World War Casualties From Gas and Other Weapons. Edgewood Arsenal,

Md: Chemical Warfare School; 1928: 16. Photograph: Reprinted from Moore WE, Crussell J. US Official Pictures

of the World War. Washington, DC: Pictorial Bureau; 1920.
Historical Aspects of Medical Defense Against Chemical Warfare

95

been removed by the U.S. Army Chemical Corps, with

assistance from other agencies.31)

Unfortunately, the first masks sent overseas with

the AEF were defective (Figure 3-11), and the new

AEF arrivals were fitted with French masks. General Pershing, the commanding general of the AEF,

was very familiar with the divided responsibilities

for chemical warfare in the United States. To prevent this from occurring in the AEF in France, he

put an infantry colonel, Amos Fries, in charge of a

unified Gas Warfare Service, which later became the

Chemical Warfare Service (CWS, the forerunner of

today’s Chemical Corps). In turn, Colonel Fries

chose an army physician, Colonel Harry Gilchrist

(Figure 3-12), to head the medical section of his service. Gilchrist was very well known for his work in

infectious diseases and was highly regarded as a

Fig. 3-12. Harry L. Gilchrist (1870–1943), shown here as

a major general and head of the Chemical Corps, was

the preeminent figure in the history of the U.S. Army’s

medical defense against chemical agents. As a Medical

Corps colonel, he was medical director of the Gas Service, American Expeditionary Force 1917–1918, and was

responsible for all important aspects of chemical casualty care. He was chief of the medical division of the

Chemical Warfare Service at Edgewood Arsenal from

1922 to 1929 and head of the Chemical Corps from 1929

to 1934. Following his retirement from the army in 1934

and until 1940, he was editor of The Military Surgeon, the

predecessor journal of today’s Military Medicine. Photograph: Courtesy of Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

researcher. (In 1929, Gilchrist gave up his medical

commission, transferred to the Chemical Corps, and

became a major general and the head of the corps.)

Treatment regimens were directed toward the

lung irritants that produced pulmonary edema, alveolar disruption, vascular stasis, and thrombosis.

Therapy consisted of good nursing, rest, oxygen,

and venesection. Death from exposure to chlorine

or phosgene usually occurred within 48 hours after

cardiopulmonary collapse.

With the effects of the respiratory agents largely

defeated by masks, the Germans changed the rules.

In July 1917, they introduced dichlorethyl sulfide

(mustard) against British troops at Ypres, Belgium.

Delivered by artillery shells, mustard caused 20,000

casualties (Figure 3-13). To quote Gilchrist:

Fig. 3-13. This photograph from Gilchrist’s study of

World War I gas casualties has the following figure legend: “War photograph—Showing a small proportion of

many mustard gas casualties in the United States forces

resulting from a severe gas attack.” Note that none of

the healthcare providers are wearing protective equipment. Casualties are being unloaded from an ambulance

in preparation to being triaged. Effective triage of chemical casualties was very difficult, as is apparent from this

excerpt from an operational report:

Gas cases were the most difficult of all to handle. It

is impossible for the surgeon to properly diagnose

his cases. One has no means of knowing whether he

is dealing with delayed gas poisoning or with a

simple case of Gas Fright ... (but) all palpable cases

of poisoning were immediately evacuated, taking

precedence over other cases.

Quotation: Cochrane RC. The 3rd Division at Chateau

Thierry July 1918. In: US Army Chemical Corps Historical

Studies: Gas Warfare in World War I. Washington, DC: Office of the Chief Chemical Officer, US Army Chemical

Corps Historical Office; 1959: 90. Study 14. Photograph:

Reprinted from Gilchrist HL. A Comparative Study of World

War Casualties From Gas and Other Weapons. Edgewood Arsenal, Md: Chemical Warfare School; 1928: facing page 20.
Medical Aspects of Chemical and Biological Warfare

96

At first the troops didn’t notice the gas and were

not uncomfortable, but in the course of an hour or

so, there was marked inflammation of their eyes.

They vomited, and there was erythema of the skin.

Actually the first cases were diagnosed as scarlet

fever. Later there was severe blistering of the skin,

especially where the uniform had been contaminated, and by the time the gassed cases reached the

casualty clearing stations, the men were virtually

blind and had to be led about, each man holding

on to the man in front with an orderly in the lead

[Figure 3-14].32(p44)

Armies were now faced with a persistent agent.

In fact, mustard has remained active (in concrete)

for up to 25 to 30 years. It has a low-dose effect,

does not have a strong odor, and, in addition to

being a lung agent, is also a skin agent. Brown put

it well:

To the soldier, gr ave problems were presented

by the requirements for individual and collective

protection. The very air the soldier breathed and

the objects he touched became potential weapons.

How would the soldier eat, drink, sleep, perform

bodily functions, use his weapon, or give and receive commands? How would he know his area

was contaminated?20(pp34–35)

The presence of mustard gas meant that everyday living became a real problem. Areas previously

safe from the lung gases were no longer safe from

Fig. 3-14. Although this photograph is frequently held

to show the inhumanity of chemical warfare, the unequivocal fact is that very few mustard casualties developed permanent eye injuries—let alone blindness. Reprinted from Marshall SLA. American Heritage History of

World War I. New York: NY: Simon and Schuster; 1964: 167.

Fig. 3-15. This photograph from Gilchrist’s study of

World War I gas casualties has the following figure legend: “War photograph—An old ruin heavily contaminated with mustard. Warning sign on ruin; place guarded

by troops to prevent entrance.” More often than not, contaminated sites were not so clearly identified. Photograph

reprinted from Gilchrist HL. A Comparative Study of World

War Casualties From Gas and Other Weapons. Edgewood Arsenal, Md: Chemical Warfare School; 1928: facing page 27.

Fig. 3-16. Chemical agents used per year by major

belligerents in World War I, in thousands of tons. Data

source: Stockholm International Peace Research Institute

(SIPRI). The Rise of CB Weapons. Vol 1. In: The Problem of

Chemical and Biological Warfare. New York, NY: SIPRI;

1971: 128. Cited by: King CR. A Review of Chemical and

Biological Warfare During World War I. Aberdeen Proving

Ground, Md: US Army Materiel Systems Analysis Activity; 1979: Table 17, page 45. AMSAA-Tactical Operations

Analysis Office Interim Note T-18.

0

35

30

25

20

15

10

5

1915 1916 1917 1918

Germany, Austro-Hungary

France

British Empire

All others

Chemical Agents (000s tons)
Historical Aspects of Medical Defense Against Chemical Warfare

97

mustard (Figure 3-15). It is heavier than air and thus

settles. Because of its persistence, huge areas of

ground remained dangerous for days and weeks,

just as if they had been mined. Effective as mustard was, chemists continued to produce new agents

and combinations of agents. By the end of the war,

11 single agents and at least 7 combinations had

been developed. Thousands of tons of these new

weapons were produced by both sides (Figure 3-

16). By 1918, approximately 25% of all artillery fire

was chemical rounds. Whether for good or ill, this

new weapon had come to stay.17,33–39

MEDICAL PROBLEMS CAUSED BY MUSTARD

I will discuss in detail the medical problems with

mustard gas during World War I. I have chosen

mustard because the issues of diagnosis, evacuation, treatment, and contamination are similar to

those with nerve agents, and because mustard is still

used as a weapon today. During World War I, patients and stretcher-bearers alike had to don masks,

limiting their vision and activity and making headwounded patients difficult to mask and treat. In the

U.S. forces, gassed patients were identified by a

crayon cross on their foreheads because patients

could appear well when evacuated but suffer from

symptoms hours after exposure to mustard.

In addition to the problem of triage of patients

by type of exposure, there were the problems

of hysteria and malingering. New troops often

confused the smell of high explosives with that

of gas and, as a result, made honest errors of

self-diagnosis or suffered from “gas mania.” [A

graphic example of the problem of triage and diagnosis is apparent in the following U.S. Army

afteraction report, describing an event that took

place in 1918:

One form of psychoneurosis, “Gas Fright,” was

very common but most cases could be restored to

the lines after a few hours’ rest. One instance occurred where an entire platoon of machine gunners

developed this form of psychosis. These men were

eating their meal just before dark when a shell fell

and burst at a distance of about 100 meters. They

continued eating and many of them had finished

when someone yelled Gas! and said their food had

been gassed. All the men were seized with gas

fright and a few minutes later made their way to

the Aid Station. To an inexperienced eye they could

have easily been diagnosed as gassed patients.

They came in in a stooping posture, holding their

abdomens and complaining of pains in the stomach, while their faces bore anxious, frightened expressions and some had even vomited. After reassurance, treatment with tablets of sodium bicarbonate, and a night’s rest, they were quite well

again.40(p91)—RFB, ed.]

Gilchrist studied 281 cases consecutively admitted to a field hospital and found that only 90 of

them were true gas casualties. Some were malingerers, some were misdiagnosed by battalion surgeons, and some had made honest errors of selfreporting.13

The mass casualties that were generated by

mustard gas demanded a medical capability for

quick mass decontamination of those attacked

(Figure 3-17). Colonel Gilchrist organized a mobile degassing unit, a medical unit that provided

showers and uniform changes for 5% of division strength. The unit (12 men and 1 officer) had

the capability to decontaminate 24 men every 3

Fig. 3-17. The mobile decontamination facility was the

essential part of the degassing station, two of which were

to be added to each division. As events transpired, only

one experimental mobile decontamination facility was

actually constructed, but it was never used in combat.

Its objective was “to give hot baths and clean clothing to

those subjected to the fumes of mustard gas at the nearest possible points to where gas bombardments take

place.” Given what is now known about the speed with

which mustard injury develops, attempting to slow the

progression of mustard injury by this regimen was most

likely an exercise in futility. Nevertheless, by providing

a shower and clean clothing, the degassing station would

have played an important role in improving the general

sanitation and morale of combat troops. Quotation:

Gilchrist HL. Field arrangements for gas defense and the

care of gas casualties. In: Weed FM, ed. Medical Aspects

of Gas Warfare. Vol 14. In: Ireland MW, ed. The Medical

Department of the United States Army in the World War.

Washington, DC: Government Printing Office; 1926: Chap

4: 61. Photograph: Courtesy of Chemical and Biological

Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

98

Fig. 3-18. This photograph from Gilchrist’s study of

World War I gas casualties has the following figure legend: “War photograph—Special ambulances used for

transporting mustard gas casualties rendered necessary

due to insidiousness of mustard.” Note that the ambulance crews appear not to be protected against mustard.

Reprinted from Gilchrist HL. A Comparative Study of World

War Casualties From Gas and Other Weapons. Edgewood Arsenal, Md: Chemical Warfare School; 1928: facing page 30.

Fig. 3-19. This photograph from Gilchrist’s study of

World War I gas casualties has the following figure legend: “War photograph—Special gas aid station for administering to gas casualties. Here cases suffering from

different gases were, when possible, segregated.” Note

the lack of protective equipment; the casualty being

loaded into the ambulance was apparently not deemed

a threat, possibly because he was a victim of a respiratory agent. Reprinted from Gilchrist HL. A Comparative

Study of World War Casualties From Gas and Other Weapons. Edgewood Arsenal, Md: Chemical Warfare School;

1928: facing page 31.

Fig. 3-20. A nurse is irrigating the eyes of soldier who

has a probable mustard injury. Given the rapidity with

which mustard damages tissue, however, we know now

that eye irrigation would have provided only symptomatic relief. Reprinted from Moore WE, Crussell J. US

Official Pictures of the World War. Washington, DC: Pictorial Bureau; 1920.

minutes. This unit was not for treating patients

but for decontaminating troops who had been exposed to mustard but were not yet casualties. A

water tank truck carried enough water for 700

showers of 2 minutes’ duration; the water was

heated by a gasoline heater at the rear of the truck.

A long tent was erected, with the showers at the

back of the tent. At the front of the tent, the men

discarded their contaminated clothing and then

stepped under the showers. The men in the medical unit who handled the contaminated clothing

were protected by rubber-and-oilcloth uniforms and

gas masks.29,32

The low volatility of mustard and its ability to

cause injuries at very low doses required medics to

segregate the patients and to establish specialized

evacuation systems and equipment, because mustard contaminated everything it came in contact

with. Indeed, a single man with mustard on his

uniform could easily contaminate an entire ambulance or dugout (Figures 3-18 and 3-19).

The acute conjunctivitis induced by mustard

(Figures 3-20 and 3-21) required immediate eye irrigation. Most of the eye cleared up in several

weeks. Nevertheless, during the resolution stage of

mustard-related acute conjunctivitis, patients were

photophobic for a considerable period.

Skin burns were treated in a variety of ways (Figure 3-22). First, the patients were washed down by

corpsmen who wore protective clothing. Early in
Historical Aspects of Medical Defense Against Chemical Warfare

99

Fig. 3-22. An extensive mustard burn of the buttocks. This degree of mustard injury, analogous to a second- or third-degree

thermal burn, was unusual. The original description that accompanied this drawing, provided to the American Expeditionary

Force by the British (also see Figure 3-21), follows:

The man sat down on ground that was contaminated by the

poison and the vapour passed through his clothing, causing

inflammation of the buttocks and of the scrotum. A diffuse

reddening appeared twenty-four hours after exposure, and this

was followed by an outcrop of superficial blisters. On the

eighth day the erythema began to be replaced by a brown staining, and the drawing was made on the eleventh day during

this change of tints. Infection of the raw surface was avoided,

and the healing was complete in three weeks.

The blisters in this case were probably aggravated by pressure, for the inflamed skin becomes very fragile, so

that the surface layer is readily loosened by pressure or careless rubbing. The blisters may be very tiny bullae, as

on the eyelids, or they may coalesce into areas many inches across, covering a collection of serous fluid which

perhaps itself contains enough of the irritant substance to injure other skin if it is allowed to flow over it.

The blisters are usually quite superficial and almost painless in their development. But the raw surface that is

left after the blister has burst becomes most acutely sensitive to all forms of mechanical irritation. Deeper destruction of the dermis may be caused by spreading necrosis where the substance attacks the skin locally in high

concentration, or when secondary infections are implanted on the raw surface. Chronic and painful sores then

result, and in this event the skin does not regenerate completely, so that thinly covered scars for a long time will

mark the site of the burn.

Reprinted from An Atlas of Gas Poisoning. 1918: Plate 6. Handout provided by the American Red Cross to the American Expeditionary Force.

Fig. 3-21. In 1918, the British prepared for the American Expeditionary Force a series of color drawings and descriptions of injuries caused

by chemical warfare agents. This drawing depicts a severely burned

eye in the acute stage after exposure to mustard vapor. A portion of

the original description follows:

[Severely burned eyes] may be recognized by certain characteristic

features that are depicted in the drawing [right]. Whenever a dead

white band crosses the exposed area of the conjunctiva, while the

parts of this membrane covered by the upper and lower lids are red

and oedematous, serious injury from the burning is likely to have

occurred.

In the case illustrated, the caustic effect of the vapour is seen chiefly

in the interpalpebral aperture. On each side of the cornea there is a

dead white band due to coagulative oedema, which compresses the

vessels, impairs the circulation, and thus acts as a menace to the

nutrition of the cornea. The swelling in the region of this white band

is slight, while the protected conjunctiva above and below it is greatly

swollen and injected and may even bulge between the lids.

The exposed portion of the cornea is grey and hazy; it has lost its lustre, and when viewed with a bright light and

a magnifying glass it shows a blurred “window reflex” and a typical “orange-skinned” surface. The haze gradually fades off above in the region of the protected part of the cornea where the surface is usually bright and

smooth. The pupil is at first contracted as the result of irritation and congestion. In this drawing it is shown as

artificially dilated by atropine ointment, which should always be used early in severe cases or where there is

much pain and blepharospasm.

Reprinted from An Atlas of Gas Poisoning. 1918: Plate 11A. Handout provided by the American Red Cross to the American

Expeditionary Force.
Medical Aspects of Chemical and Biological Warfare

100

the conflict, burns were initially treated with grease,

which only enhanced infection. Later, sodium hypochlorite was used as a constantly running solution, soaking the skin.25

Patients who died from mustard inhalation

had gross destruction of the tracheobronchial

tree (Figure 3-23). In contrast to the pulmonary

Fig. 3-23. The figure legend that was published with this

photograph in the official history of the U.S. Army Medical Department in World War I reads: “Gross changes in

larynx and trachea of a soldier who died four days after

inhalation of mustard gas.” Purulent secretions in the

smaller bronchi rather than at the glottis caused the respiratory failure that lead to the death of this soldier. The

efficacy of tracheal suction in clearing the airway appears not to have been widely known during World War

I. Reprinted from Weed FM, ed. Medical Aspects of Gas

Warfare. Vol 14. In: Ireland MW, ed. The Medical Department of the United States Army in the World War. Washington, DC: Government Printing Office; 1926: Plate 10.

agents, mustard produced hemorrhage and alveolar

edema. Mustard-induced lesions were more difficult

to treat than those induced by phosgene or chlorine.

How dangerous were these chemical weapons

as killers? Gas was a major cause of casualties:

it accounted for up to 30% of hospitalized patients (Figure 3-24). Although gas was a significant

Fig. 3-24. Hospitalized casualties in World War I, in percentages by causative weapon (database: 224,089 casualties).

Adapted from Gilchrist HL. A Comparative Study of World War Casualties From Gas and Other Weapons. Edgewood

Arsenal, Md: Chemical Warfare School; 1928: Chart 7, page 19.

Gun Miscellaneous*

War Gas

Shrapnel†

Rifle Balls

Shells

Bombs

Grenades

Bayonets

Pistol Balls

Sabers

Unknown

0 5 10 15 20 25 30 35

Chemical Weapons

Conventional Weapons

†Majority of casualties were wounded by 

fragments of explosive munitions; only a 

fraction were injured by true shrapnel

*Penetrating missiles, sources unknown
Historical Aspects of Medical Defense Against Chemical Warfare

101

TABLE 3-3

AMERICAN EXPEDITIONARY FORCE:

HOSPITAL DAYS DUE TO CHEMICAL WARFARE

Chemical Average Days

Agent Casualties Hospitalized

Unknown 33,587 37.3

Chlorine 1,843 60.0

Phosgene 6,834 45.5

Mustard 27,711 46.0

Adapted from Gilchrist HL. A Comparative Study of World War

Casualties From Gas and Other Weapons. Edgewood Arsenal, Md:

Chemical Warfare School; 1928: Table 7, page 21.

TABLE 3-2

CHEMICAL CASUALTIES IN WORLD WAR I

Country Nonfatal Chemical Casualties Chemical Fatalities Percentage Fatal

Germany 191,000 9,000 4.5

France 182,000 8,000 4.2

British Empire 180,597 8,109 4.3

United States 71,345 1,462 2.0

Russia* 419,340 56,000 11.8

*[The data from which Prentiss (and before him, Gilchrist) derived these figures have apparently been lost to history. However, the

Russians themselves analyzed their casualty statistics from World War I. The Narkomzdrav Commission found the figures for

nonfatal and fatal gas casualties to be only about one tenth as great as Prentiss’s values, which are the ones commonly accepted in

the West (total gassed casualties: 40,000–65,000; died of gas: 6,340). Source for these data: Kohn S. The Cost of the War to Russia. New

York, NY: Howard Fertig: 1973: Table 75; page 136; Table 76. Originally published in 1932.—RFB, ed.]

Adapted from Prentiss AM. Chemicals in War: A Treatise on Chemical Warfare. New York, NY: McGraw-Hill; 1937: Table 11,

page 653.

factor in casualty production, it was not especially

lethal. [The AEF incurred 52,842 fatal battle injuries, but only about 1,500 were due to gas21(p652)—

RFB, ed.] (Table 3-2).

The Russians suffered out of proportion to the

rest of the belligerents because they were late in

deploying an effective mask. For the United States,

the chemical agents were minor contributors to the

number of soldiers killed in action: only about 200

of the total of more than 70,000 wounded by gas.13

The real problem was the imposition of a major

medical and logistical burden on the army. In the

AEF, for example, gas patients had significant hospitalization periods (Table 3-3), although the great

majority returned to duty. The generally low lethality and high morbidity rate led a great many people

to see the chemical weapon as holding much promise for the future of war.

THE INTERWAR YEARS

After World War I ended, work at the Edgewood

medical research laboratories continued. New gas

masks were developed, such as those with higheyepoint lenses for use with binoculars, and masks

with speaker diaphragms. As those who have worn

mission-oriented protective posture (MOPP) gear

know, one cannot really be heard through a mask.

Initially, scientists at Edgewood worked on oilclothand-rubber uniforms for mustard protection and

then developed the resin-and-chloramide uniform.

Smoke and gas delivery systems were added to

weapons such as tanks and airplanes. The U.S. military paid attention to gas; troops were trained, in

the interwar years, in both simulated and real

chemical environments.21,41,42 In short, we took the

threat of chemical warfare very seriously: research
Medical Aspects of Chemical and Biological Warfare

102

and training received considerable attention during the interwar years.5,9,26,30

The Army Medical Department made a big investment in research. In fact, it put more money into

research on the chemical weapon than into anything

else in the interwar period. Colonel Edward Vedder,

Medical Corps, U.S. Army (Figure 3-25), was in

charge of the medical laboratory at Edgewood that

produced new mask canisters that could filter

smoke in addition to the standard respiratory

agents. This development made possible the protection of American soldiers against respiratory

tract effects of arsenic-based compounds—the most

potent chemical agents of that period. Clinical cases

were studied and animal research was performed

with the agents, as well as experimentation in humans and attempts at new treatment.

In 1925, Vedder published Medical Aspects

of Chemical Warfare, a superb book that contains

excellent data on the pathology and physiology

of various chemical agents (particularly mustard).

Much of the text is still germane. On the inside front

cover of the book is a picture of a soldier horribly wounded by shrapnel, yet alive. Vedder

argued that if this is the result of a humane weapon, then the chemical weapon, by comparison, must

be much more humane.26 Vedder was not alone

in this view of the relative humanity of chemical

warfare. It was a predominant view of many writers who analyzed the subject.5,9,17,21,30,33,41–45 The

development of the lethal nerve gases by the Germans in World War II, however, has vitiated these

arguments.

In the interwar years, a number of medically

important spin-offs came from the chemical

warfare program. The Americans developed

Lewisite, an arsenical, at the end of World War I.

It did not turn out to be a particularly effective

agent, although it did lead to the development of

British anti-Lewisite (BAL), which is useful as a

chelating agent in metal poisoning. It was noticed

in soldiers who had been exposed to mustard during the war that the white blood count fell. This was

verified in 1919. Dougherty, Goodman, and Gilman

showed in 1942 that the nitrogen mustards could

be useful in the treatment of leukemia and lymphoma. This was the beginning of specific chemotherapy for cancer.46–48

Between World War I and World War II, disarmament conferences included discussions of

the prohibition of gas warfare.49 Nevertheless,

the chemical weapon continued to be used but

only against colonial native peoples. For example,

Fig. 3-25. Edward B. Vedder (1878–1952) was director of

pathology at the Army Medical School (now Walter Reed

Army Institute of Research) from 1904 to 1913. It was

during this period that he wrote his seminal book on

beriberi. After serving in the Philippines during World

War I, Colonel Vedder returned to the Army Medical

School in 1919. It was there that he wrote this still-useful

book on chemical casualties. From 1925 to 1929 he was

chief of medical research for the Chemical Warfare Service. He had an illustrious civilian academic career following his retirement from the army. Photograph: Courtesy of National Library of Medicine. Bethesda, Md.

in 1920, the British dropped mustard gas bombs

on Afghan tribesmen north of the Khyber Pass.

In 1925, the Spaniards used mustard bombs and

mustard artillery shells against Riff tribes in

Morocco. In 1935, when Mussolini moved from the

Italian colony in Libya to conquer Ethiopia, the

Italian troops were ambushed. Although equipped with modern arms they were heavily outnumbered, so Marshall Badoglio, the Italian commander,

used aerial delivery of mustard bombs against

Egyptian troop concentrations and saturated the ground on his road flanks to interdict the

movement of barefoot Ethiopian troops.50,51 (A complete list of proven or alleged use of chemical weapons between 1919 and 1970 can be found in A Review of Chemical/Biological Warfare During World

War I.25(pp13–14))
Historical Aspects of Medical Defense Against Chemical Warfare

103

WORLD WAR II

When World War II broke out, there was a general expectation and apprehension that the chemical weapon would be used. The Japanese practiced

civilian operations while wearing masks. British

troops trained with masks in the North African

desert. In London, during the height of the blitz,

schoolchildren were issued masks. German mothers and children had special capes and masks available. Americans came out with a whole series of

tactical and training masks. Walt Disney designed

a mask with a Mickey Mouse face for American

children, so they would not be frightened by wearing the mask (Figure 3-26). Fortunately, American

children never had to use these masks. By 1942, after the United States had entered the war, all U.S.

troops trained in masks. Full discussions of the

United States efforts in World War II are found in

the U.S. Army in World War II series published by

the Center of Military History.52–54

The United States developed a new generation

of protective uniforms, which soldiers carried,

along with their gas masks, on every D day in

Europe. Chemical weapons were indeed used in

World War II, in the form of smoke and flame.

Smoke was used for screening troops and movement, especially in Europe. Americans in the Pacific used the flame weapon against Japanese caves

and bunkers.

For reasons that historians are still debating, gas

itself was not used. One reason the Germans did

not use it was that they thought the Americans had

developed new, secret nerve gases—comparable to

tabun, sarin, and soman—which the Germans had

developed between 1936 and 1944. The Germans

may have been led to believe this because of the

alleged paucity of reports on insecticide research

published in the open literature in the United States,

and they wrongly deduced that the Americans were

now manufacturing nerve gas. In reality, however,

there was no industrial base in place ready to produce nerve agents in large quantities20—because

neither the British nor the Americans had discovered nerve agents.

Other historians have argued that because

Adolph Hitler had been a gas casualty in World War

I, he was personally opposed to the use of gas weapons in World War II. Similarly, many senior officers

on the Allied side in World War II had faced gas

as junior officers in World War I and were highly

resistant to its use in World War II. It was official

U.S. policy that the United States would not use

chemical warfare first but would retaliate if it were

used against us or our allies. Thus, the United States

was prepared to retaliate. It was in part because

of this preparation that American and British

troops had the only military gas casualties in World

War II.

In 1943, Bari, a city on the Achilles tendon of Italy,

was a major supply port for the British Eighth Army

fighting in Italy. The SS John Harvey, an American

ship in harbor, carried a highly classified load of

2,000 100-lb mustard bombs. When the Germans hit

Bari harbor in a surprise raid they got 17 ships (Figure 3-27); among them was the John Harvey. Fire on

the John Harvey caused a mustard-laden smoke that

spread through the city, producing eye inflammation, choking, pulmonary signs and symptoms, and

burns. No one really knows the extent of the civilian casualties; however, by the 9th day after the

bombing, 59 military deaths had been recorded.

Shortly after the bombing, Lieutenant Colonel

Stewart Alexander of the U.S. Army Medical Corps,

Fig. 3-26. Walt Disney helped design this Mickey Mouse

gas mask for American children. The intention was that

children would not be frightened of the cartoon character and would therefore be more willing to wear the

mask. Photograph: Courtesy of Chemical and Biological

Defense Command Historical Research and Response

Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

104

the chemical warfare consultant on General

Eisenhower’s staff, was sent to Bari, where he made

the diagnosis of mustard poisoning. He reported

6l7 cases in troops and merchant marine seamen,

with a 14% fatality rate. This fatality rate, 3-fold

higher that of World War I, was largely because the

merchant marine seamen had been thrown into the

sea, where they either got badly burned or swallowed mustard in the water.55,56

Lethal gases—pesticides, prussic acid, and cyanide, as well as carbon monoxide—were used as

killing agents in gas chambers in the Nazi death

camps.57 This is obviously not a military use of the

chemical weapon.

Fig. 3-27. The Bari mustard disaster, caused by a German air attack the night of 2 December 1943, resulted from the

need to have chemical munitions deployed in the combat zone. The presence of those weapons was necessary to

make possible an immediate retaliation should the enemy choose to initiate a chemical attack. However, the deployment of those munitions was kept secret so as not to give the enemy any justification for launching a preemptive

chemical attack. Although the merchant ship carrying the mustard bombs, the SS John Harvey, had been docked at

Bari for several days, the ship was not unloaded because the appropriate authorities did not know of the highly

dangerous nature of its cargo. No photograph exists showing the John Harvey after the German attack; the ship was

completely destroyed by the explosion of the conventional munitions that it was also carrying. Instead, this photograph shows the Bari harbor some hours after the attack. Reprinted with permission from Popperfoto. Northampton,

England.

THE POSTWAR YEARS: 1945 TO THE PRESENT

Chemical agents have been used in warfare since

World War II. There is a suggestion that they were

considered for employment in Korea in 1950.58 In

1963, the Egyptians used mustard bombs against

the Yemen royalists in the Arabian peninsula. The

United States used chemical defoliants in Vietnam

for canopy clearing and crop destruction, and used

tear gas for clearing tunnels and bunkers (Figure 3-

28).59 The Soviets used chemical warfare agents in

Afghanistan, probably mustard and a nerve agent.25

However, the discovery that Iraq had used chemical

agents (mustard and perhaps nerve gas) in its war

with Iran shocked the public in the western democracies in the 1980s.60 Iraqi use of hydrogen cyanide

and possibly a nerve gas against its own Kurdish

population in 1988 was universally condemned.61,62

In the United States, the congress has debated

the chemical agent issue over several years, with

much of the debate focused on the morality of the

weapon.63–65 Congress decided in 1988 to approve

the production of the binary nerve gas weapon, influenced then by increasing evidence that chemical

weapons were in hand and appeared to be increasing in the arsenals of nonfriendly nations (see Exhibit 4-1 in Chapter 4, Medical Implications of the

Chemical Warfare Threat).66 The accuracy of such information can clearly be challenged, and the lists

themselves vary from publication to publication.66–68

Nonetheless, interest began to increase in a new

United Nations treaty to ban chemical weapons.69,70

In September 1996, the U.S. Senate considered the

new treaty, which called for banning production of

chemical weapons and for an inspection program.

General John M. Shalikashvilli, Chairman of the Joint

Chiefs of Staff, urged ratification. Public debate varied widely.71–73 The U.S. Senate initially rejected the

Figure 3-27 is not shown because the copyright permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include usage in

electronic media. The current user must apply to the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Historical Aspects of Medical Defense Against Chemical Warfare

105

Fig. 3-28. Tear gas was used extensively by U.S. forces in

the Vietnam War, especially in clearing enemy tunnel

complexes. The U.S. government, however, did not consider tear gas to be a chemical weapon and therefore did

not consider its use to be banned by international law.

Many others outside of government disagreed, using as

evidence the fact that those who used tear gas wore protective masks. The soldiers shown here are wearing the

little-known M28 protective mask. This lightweight (and

perhaps more comfortable) mask was designed to be

worn in situations in which the threat was not from nerve

agents, and the heavy-duty protection offered by the standard masks was not necessary. Photograph: Chemical and

Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

treaty,74 but it has since been approved, not only by

the U.S. Senate (24 April 1997), but also by the 65

member nations of the United Nations required for

its enactment and enforcement.75

While it is true that there are residual effects—

physical, physiological, and psychological—after

every American war,76 the chemical weapon has

aroused persistent public interest, veterans complaints, and charges of medical indifference, coverup, and incompetence. After World War I, the issue

was tuberculosis caused by pulmonary agents.77

After World War II, there was the delayed discovery of cancer and cataracts in enlisted men who had

been test subjects for chemical exposures.78 After the

Vietnam War, the herbicide Agent Orange (specifically its dioxin component) had been the assigned

cause for a number of compensable diseases.79 And,

as of this writing (January 1997), some veterans of

the Persian Gulf War have an unexplained Gulf War

“syndrome,” with low-dose exposure to chemical

agents being suggested as a possible cause.80

It is obvious that use of the chemical weapon remains possible. This textbook documents this concern on the part of the U.S. Army Medical Department. I therefore believe that it is the responsibility of

the U.S. military medical community to prepare to

operate in a chemical environment. Fighting a chemical war will markedly hinder our medical, tactical,

and operational capacity (problems well discussed

in this textbook), and cause long-term postexposure

residual effects. Thus, students of this topic may still

find relevance in the words that Sir Charles Bell (who

was a surgeon at Waterloo in 1815) wrote in 1812:

When the drum beats to quarters there is now a

time of fearful expectation, and it is now the surgeon feels how much the nature of the wounds of

those who may be brought to him ought to have

occupied his mind in previous study.81

It is that “previous study” that is the purpose of

this book: to educate our military and civilian medical communities about chemical warfare and their

consequent medical responsibilities.

SUMMARY

The chemical weapon has a long and ancient history, especially in its presentation as flame and

smoke. Modern chemistry made possible the use

of chemical agents in a logistically and tactically

feasible way in World War I. Most of what was

known—and is still understood by the public—is

based on the gas warfare of 1915–1918. Since then,

“poison gas” has usually aroused public repugnance at its use as a weapon. Modest use in the 1930s

against tribes and its lack of employment in World

War II suggested that “gas warfare” had ended. The

discovery of the German nerve gases after World

War II, the Cold War, and the utility of tear gas in

Vietnam maintained a military interest in the chemical weapon.

The use of gas by Iraq against Iranian troops and

the threat of Iraqi use in the Persian Gulf War clearly

document that chemical warfare remains possible.

(This chapter was based on Dr. Joy’s lecture, “Historical

Aspects of Medical Defense Against Chemical Warfare.” The

figure legends were provided by the textbook editors.)
Medical Aspects of Chemical and Biological Warfare

106

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The Chemical Warfare Threat and the Military Healthcare Provider

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Chapter 4

THE CHEMICAL WARFARE THREAT AND

THE MILITARY HEALTHCARE PROVIDER

ERNEST T. TAKAFUJI, M.D., M.P.H.*; AND ALLART B. KOK, M.S.†

INTRODUCTION

THE CHEMICAL THREAT AND ENEMY CAPABILITY

THE STATUS OF CHEMICAL PROLIFERATION

Chemical Warfare Capabilities of Nations

International Agreements and Verification

Terrorism

MILITARY CHEMICAL AGENTS

TACTICAL AND STRATEGIC USE OF CHEMICAL WEAPONS

Chemical Agent Delivery Systems

Physical Properties of Chemical Agents

Strategic Concerns in the Use of Toxins

Choice of Agent and Delivery System

Detection and Protection

RESPONDING TO THE THREAT: MANAGING CASUALTIES

FUTURE CONFLICTS IN A CHEMICAL ENVIRONMENT

SUMMARY

*Colonel, Medical Corps, U.S. Army; Commander, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington,

D.C. 20307-5011

†Science Applications International Corporation, Joppa, Maryland 21085
Medical Aspects of Chemical and Biological Warfare

112

INTRODUCTION

Some military medical personnel view the specter of chemical warfare with fear and repugnance.

The images of clouds of poisonous chemicals; contaminated terrain and equipment; and the need to

work in protective masks and hot, cumbersome

overgarments are intimidating even to well-trained

soldiers. But for medical personnel there is an added

factor: the fear of the unknown. The milieu of the

chemical battlefield is especially alien since little in

the normal professional practice of most military

medical personnel has any resemblance to the management of casualties of chemical warfare.

Although military strategists might view chemical warfare agents as simply one of the means to

immobilize or destroy an enemy force, others may

view such weapons as abhorrent extensions of conventional warfare. Be that as it may, it is not the

intent of this chapter to justify the use of chemical

weapons in battle but rather to relate the use of

chemical warfare to health issues. Although current

policy of the United States government prohibits

using chemical weapons against an adversary, this

policy is not shared by all nations; therefore, to be

effective, military medical personnel must be

knowledgeable and trained.

To the military healthcare provider, chemical

warfare crosses over the lines of strategic and tactical purposes, where victory may be viewed as full

justification of

• the means;

• the difficult challenges associated with the

identification, treatment, and prevention of

specific injuries and illnesses in a deliberately contaminated and highly stressful environment;

• the psychologically demoralizing effect that

chemical weapons may cause; and

• the personal ethical concerns that many

medics may have about suffering resulting

from the deliberate use of weapons specifically targeted to the human element.

Although healthcare providers are usually not

involved in the political or military decisions surrounding use of chemical weapons, they must be

• prepared to deal with the military and civilian casualties resulting from use of such

agents;

• cognizant of what constitutes a chemical

threat and the military tactics that could be

employed against the force, since they may

be called on to render advice to their commanders from an individual and public

health perspective;

• familiar with the acute and chronic medical effects of chemical agents in order to

plan appropriate medical support; and

• fully knowledgeable of the diagnostic tools

available to identify specific etiologic

agents to which their patients may have

been exposed and the most effective methods of intervention and prevention.

The “chemical threat” can be defined as a statement of the who, what, when, where, and how of

chemical warfare. The threat may involve single or

multiple chemical agents—not only the classic

chemical agents specifically developed for military applications (ie, chemicals that had been

weaponized by the 1950s), but also highly toxic industrial compounds that could achieve the same

objective. Military medical care providers need to

be well-informed of the current chemical warfare

threat in environments in which they may be called

to serve. They should also be familiar with sociological and psychological factors motivating the use

of such weapons in a battlefield or terrorist scenario.

Chemical warfare agents do not need to be lethal to be disruptive. It is not difficult to envision a

scenario where medical practitioners may be the

first to observe and recognize the effects of chemical exposure—in the absence of warnings from the

intelligence community. Few physical indicators of

chemical attack may be evident, other than the initial observation of unusual signs and symptoms.

This scenario could occur when new agents, for

which there may be no environmental monitoring,

are used. An increased incidence of symptoms consistent with nerve, vesicant, blood, or respiratory

agent exposure should raise immediate suspicion

of poisoning, even among presumably protected

troops. The possibility of combined use of chemical and biological warfare agents should also be

considered.

Offensive use of chemical agents continues to be

attractive to some nations, for chemical agents can

be dispersed over large areas and can eventually

penetrate even the most well-defended positions.
The Chemical Warfare Threat and the Military Healthcare Provider

113

They can be employed against specific targets, including headquarters control centers and, depending on the agent or combination of agents used, the

effects can be immediate or delayed incapacitation,

disorientation, or death. The psychological impact

is ever-present, even among well-seasoned and

-trained troops equipped with full barrier protection. Many of the more common classic chemical

agents—which are generally believed favored by

possessor states—can be produced inexpensively

and quietly, and they can be stored indefinitely.

Their minimal cost has earned chemical warfare

agents the appellation “the poor man’s atomic

bomb.”

Although treaties dealing with control or elimination or both of classic chemical weapons may

reduce the danger that chemical warfare agents

will ever be used, difficulties in verification and

in controlling the manufacturing, acquisition, and

storage of precursor chemicals make chemical

war a continuing concern for the U.S. government.

Chemical proliferation has not decreased. Saddam

Hussein’s use of chemical warfare against the Kurds

in 1988 demonstrates how readily such weapons

can be used, even within the confines of one’s

own country. The 1994 and 1995 incidents involving the Aum Shinrikyo cult’s use of sarin (ie, the

nerve gas GB) to cause fatalities and disruption in

Matsumoto and in the Tokyo subway system demonstrate how easily a terrorist organization

can quietly produce and use a classic chemical

warfare agent.

THE CHEMICAL THREAT AND ENEMY CAPABILITY

The term “chemical threat” centers on enemy capability. The term capability encompasses1

• the availability and supply of specific

agents;

• the delivery system or systems that would

be used in different battle situations;

• the facilities to produce these agents and

munitions;

• plans and procedures for the employment

of such weapons, including training for the

delivery and handling of such weapons;

• protection of a nation’s own forces against

specific agents; and

• the national will to use such weapons.

Although international disapproval may discourage a country from using chemical agents, the aggressor nation may finally decide that protecting its

national interests and survivability is more important.

An active research and development program on

agents and delivery mechanisms supports the notion of operational use. Chemical warfare munitions

are particularly important, for weapon systems

must deliver agent to the target and distribute that

agent with maximal effective contact. Successful

chemical warfare munition use must also be combined with meteorological assessment capabilities.

For example, sarin, a highly volatile agent with little

persistence on the ground, must be delivered under specific environmental conditions and in a

timely manner that would allow greatest human

contact for optimal effectiveness. Ideal conditions

and carefully developed delivery systems are not

always necessary, however: Iraq simply pushed

containers of chemicals out of aircraft during the

Iran–Iraq War.

Ordinarily, an enemy with chemical warfare capability will be well equipped for chemical warfare

protection; they will have defined procedures on

decontamination, individual and equipment protection, and detection and surveillance. Since chemical warfare agents are nonselective in their human

targets and dangerous for the user as well as the

enemy, they require that offensive and defensive

programs be developed simultaneously. Special

military teams (eg, logistical, medical, and chemical corps teams trained to operate in a chemical

environment) and the ability to monitor meteorological conditions are characteristic of nations with

offensive or defensive programs or both. In the assessment of enemy capability, chemical stockpiles,

production capacities, and the control of use are

evaluated when an offensive or a defensive posture

is being determined. This is not easily accomplished, since industrial plants that are manufacturing products with peaceful applications may be

capable of having their manufacturing processes

redirected toward chemical agent production.

In a changing world, where the traditional East–

West conflict has subsided in the face of steadily

increased chemical agent proliferation among many

Third World nations, the chemical threat appears

to be increasing from smaller nations or political

splinter groups with little or no sophisticated

chemical warfare industrial capability. Hence we

must be prepared for chemical agent attack from

terrorist elements, and for crude delivery systems
Medical Aspects of Chemical and Biological Warfare

114

as well as highly developed offensive chemical

warfare operations. Political instabilities and

changes toward radicalism only heighten the dangers and concerns that defensive programs can be

converted to offensive efforts, and, although classic chemical warfare agents are harder to produce

and stockpile in large quantities without being noticed, small amounts of some older agents can be

manufactured in relatively crude laboratories and

used to create disruption.

THE STATUS OF CHEMICAL PROLIFERATION

Until 1987, when the Soviet Union admitted for

the first time that it possessed an offensive chemical warfare capability, the United States was the

only publicly declared state capable of conducting

chemical warfare. In July 1988, long after a United

Nations commission had confirmed Iraqi use of

chemical agents (mustard and nerve agent) against

Iran (a flagrant violation of the 1925 Geneva Protocol, which Iraq had signed in 1931), Iraq also declared an offensive capability. Apart from the three

nations mentioned, estimates of countries that possess chemical agents, and the nature of the agents

they possess, must rely on sources other than official statements. Given this, it is not surprising that

published lists of states with chemical warfare capability have varied widely. However, a key trend

in chemical warfare capability over the past 20 years

is evident: an increasing number of states are likely

to possess such weapons.

Chemical Warfare Capabilities of Nations

The magnitude of world interest in offensive

chemical warfare capability was made evident during an open hearing of the U.S. Senate Committee

on Governmental Affairs on 9 February 1989, when

William H. Webster, former Director of Central Intelligence, presented a list of weapon states. The

confirmed chemical weapon possessor states were

the United States, the Soviet Union, Iraq, and Iran.

France has subsequently declared a chemical warfare capability, bringing the number of possessor

nations to five. Countries currently suspected of

possessing chemical weapons or in the process of

acquiring them are identified in Exhibit 4-1. Several other nations are being closely monitored for

signs of an acquisition program.1

An article in the March 15, 1991, issue of The

Washington Post2 described the latest annual report

of the Office of Naval Intelligence, listing 14 nations

with “an offensive chemical-warfare capability”; the

list included Egypt, Israel, Pakistan, and South Korea, 4 nations that receive large quantities of military aid from the United States. Four additional

nations (Saudi Arabia, Indonesia, South Africa, and

Thailand) were purported to possibly possess such

a capability, and then more nations were believed

to be in the process of developing or seeking to develop chemical weapons. Interestingly, this list conflicts with a U.S. Department of Commerce list that

does not list the strong trade partners of South Korea, Indonesia, and Thailand as having definite offensive capability. In a 1993 U.S. House of Representatives Committee on Armed Services report, 31

nations were mentioned as possessing or having the

ability to develop offensive chemical weapons.3

Offensive chemical warfare capabilities depend

on such factors as chemical agent quantities, types

of agents weaponized, modes of delivery, doctrine

for use, means of self-protection, and other considerations that together characterize the total threat

posed by a chemical warfare–capable state. Such

detailed analysis of the threat posed by each possessor state is beyond the scope of this chapter, and

interested readers should review classified and

unclassified sources for each nation.

A general idea of the classic agents was provided

by the Soviets when chemical armaments were displayed for the first time to Western visitors in 1987,

and later by Iraq when its arsenal was inspected.

The Soviets showed a wide variety of chemical

weapons delivery systems that could carry blistering agents (mustard and Lewisite), nerve agents

(soman, sarin, and VX) or the riot control agent CS

(2-chlorobenzalmalononitrile). Some of these agents

were thickened to increase battlefield deposition and

persistence (see Military Chemical Agents, below).

United Nations weapons inspectors, on gaining

access to Iraq’s arsenal in 1991, found primarily

sulfur mustard, sarin (and a sarin analog, GF), and

another nerve agent, tabun.4

 The Iraqi chemical

warfare development program was well developed,

and included experimentation with VX. Far beyond

pushing barrels out of helicopters, the sophisticated

Iraqi chemical weapons delivery systems now included aerial bombs, artillery rockets, artillery

shells, cluster bombs, and mortars. Seventy-five

chemical warfare ballistic missile warheads were

also discovered, filled with sarin/GF mixtures or

binary nerve agent (in binary systems, two individually less-toxic reagents are mixed in the weapon

at the time of use to form the agent).
The Chemical Warfare Threat and the Military Healthcare Provider

115

EXHIBIT 4-1

CHEMICAL WARFARE CAPABILITIES OF NATIONS

Prior to its destruction, Iraq’s primary chemical

warfare agent production facility at Al Muthanna,

Iraq, produced thousands of tons of agent. The

complex included well-built, underground, bunkertype complexes, billed as sites for pilot plants

for pesticide production but apparently capable

of VX production. Another facility served as an

inhalation chamber for making lethality estimations. Two other sites were built at Fallujah, Iraq,

to make chemical precursors for use at the Al

Muthanna plant, although one of the Fallujah

plants, while containing stored agent precursors (for VX, GB, and HD [mustard]), was adapted

for malathion pesticide formulation. These

examples illustrate why it can be difficult, with

limited inspections or information from open

declarations, to distinguish facilities designed for

the chemical industry from those for munitions

generation.

These chemical manufacturing facilities are only

part of Iraq’s chemical warfare capability. Iraq, like

Libya, also invested heavily in the development of

facilities for the production of indigenously generated delivery components.

The current development of offensive chemical

warfare capabilities varies among the possessor

states and is now particularly dynamic. First, the

United States and Russia, which has inherited the

chemical weapons arsenals of the Soviet Union,

have embarked on a program to radically reduce

the chemical agent stocks held by both sides by the

late 1990s. Second, in January 1992, some 125 nations signed a treaty, formulated over 24 years, at

the Chemical Weapons Convention in France, calling for the prohibition of the production, storage,

use, and transfer of chemical weapons; and for the

elimination of chemical warfare arms and production facilities.5

 By January 1993, 130 nations had

signed the treaty, and more are expected to follow.

During the 1980s, some nations vastly increased

their development of offensive chemical capabilities, particularly in the Middle East, where chemical warfare capability substitutes in some respects

for a nuclear weapons capability. A rapid transition

Adapted with permission from Burck G, Flowertree CC. International Handbook on Chemical Weapons Proliferation. New York,

NY: Greenwood Press; 1991: 164–165.

Exhibit 4-1 is not shown because the copyright permission granted to the Borden Institute, TMM, does

not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure legend for permission to use this

illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

116

from nascent development programs to full

weaponization occurred in Iraq, Syria, and Libya,

and Iraq unleashed chemical weapons against Iran

in 1984. Iraqi use of mustard and nerve agents constituted the first full-scale use of chemical weapons in battle since World War I.

The effective elimination of the Warsaw Pact and

the dissolution of the Soviet Union have greatly

diminished and reconfigured the overall chemical

threat from that part of the world. The exportation

of Soviet technology has been a continuing process,

and it is likely that the chemical weaponry and technological know-how was well disseminated to developing nations. The Russians have declared a

chemical agent stockpile of about 40,000 tons

(higher than the 30,000 of the United States).6,7 As

of 1996, it appears that all of the former Soviet

Union’s chemical weapons containers and munition

components are maintained at seven sites in Russia. As is done in the United States, most of the agent

is primarily stored in nonweaponized containers;

the weaponizable portion appears to consist entirely

of soman- and VX-like nerve agents, sulfur mustard, and Lewisite. Mixed preparations are common

in the arsenal. With all chemical warfare agents

under a single central control, the possibility of

unauthorized weapons proliferation by former Soviet border nations, several of which are politically

unstable, should be greatly diminished, although

the possibility of chemical weapons proliferation

through theft under a climate of economic turmoil

remains real. Uncertainties regarding dispersal, and

management procedures concerning that stockpile,

suggest that some chemical weapons could be lost

while awaiting destruction.8

The Soviet military appeared to have invested

considerable effort toward the development of

forces capable of operating in a chemical warfare

environment.9 According to the U.S. Defense Intelligence Agency, Soviet facilities associated with the

production, testing, and storage of chemical or biological agents or both continued to expand through

1987.10 Today, a variety of chemical warfare delivery systems are available to Russian military forces,

including artillery, bombs, free rockets, ballistic

missiles, and cruise missiles.

The origin and nature of the overall chemical

agent exposure threat to U.S. troops changed considerably during the 1980s. Although the threat of

chemical warfare confrontation with former Warsaw Pact nations appears eliminated, the proliferation and use of chemical warfare agents within unstable sectors of the Third World has raised great

concern regarding the potential for future use of

chemical warfare agents both with respect to open

conflicts and to terrorist activities. For Third World

nations, chemical weapons are less expensive and

easier to acquire, and are a more credible threat than

nuclear weapons. The adaptation and incorporation

of chemical agent–containing munitions to conventional or missile delivery systems can give a weaker

nation a military threat with which to counterbalance that of neighbors that possess a greater conventional capability.

Nations may initially acquire a limited chemical

warfare capability through the transfer or purchase

of bombs or artillery-compatible chemical warfare

shells. In some cases, unweaponized agent may

have been transferred.11 Alternatively, nations may

invest in the development of chemical industries

that involve the manufacture or acquisition of

chemical precursors or intermediates. In this way,

wealthier nations (eg, Iraq, Libya) or those under a

strong, perceived threat (eg, Syria) may increase

their chemical warfare potential by acquiring the

technology and facilities to synthesize agents and

incorporate them into munitions that are compatible with existing or newly acquired delivery systems. Industrial compounds such as organophosphates (pesticides), phosgene, chlorine, and cyanide

are not difficult to obtain.

Economic factors such as wealth, profit incentives, international debt, and isolation can contribute to the proliferation of chemical warfare capabilities. For example, oil-rich nations ruled by dictators

(eg, Libya, Iraq) have been able to use their profits to

acquire expensive delivery systems such as ballistic

missiles and long-range bombers, along with associated support aircraft.12,13 When shunned by major arms-systems producers such as the United

States, Britain, France, and Russia, the oil-rich nations have approached other Western sources or

those in less-developed nations, some of them

deeply in need of foreign capital, such as Brazil,

Chile, Argentina, Yugoslavia, Israel, Egypt, North

Korea, or the People’s Republic of China.12–16

Inevitably, there is a trickle-down effect in the

arms world, as aging munitions and weapons systems are replaced and move from the major weapons producers to their Third World client states, and

from the latter to other nations. For example, the

Soviet Union probably supplied a chemical warfare

capability to Egypt,11 which, in turn, first supplied

Syria,15 which, in turn, supplied Iran.16 It should be

noted that some weapons systems, especially from

the former Eastern Bloc countries, were designed

to operate in a chemical warfare theater.9 As noted

earlier, a defensive capability is generally held to
The Chemical Warfare Threat and the Military Healthcare Provider

117

be prerequisite to an effective offensive chemical

warfare capability.

The profit motive has driven many private industries to supply Iraq and Libya with technology,

infrastructure, and chemical precursors for the synthesis of nerve and blister agents in large volume,

and the manufacture of artillery shells and bombs

required for their delivery. Until recently, West German government export control was minimal, resulting in the involvement of some 86 German firms

in Iraq’s development of chemical and nuclear

weapon capabilities and ballistic missile design. A

considerable number of companies in Austria, Britain, France, Italy, Switzerland, and the United States

were also involved in these efforts. Products included chemical agent production plants and precursor compounds, computer systems, machine

tools, casting and milling technology and facilities,

weapon and ammunition production facilities, missile technology and “super gun” components.16 Commercial dissemination of chemical warfare capabilities will be a continuing problem in the years ahead.

International Agreements and Verification

Despite such uncertainties, a chemical weapons

reduction agreement17 was reached in 1990 between

the United States and the Soviet Union that will (1)

effectively stop chemical weapon production and

(2) reduce each nation’s chemical agent stocks to a

value of 5,000 metric tons by the year 1999 (by the

end of the year 2002, this number will fall to 500

tons). Destruction of the remainder is contingent on

a commitment for similar, total chemical warfare

stock elimination by other chemical warfare–capable nations.18,19

On May 13, 1991, U.S. President George Bush

further advanced his 1989 plan before the United

Nations to destroy 98% of the U.S. stockpile in the

first 8 years under a new, proposed treaty. Under

its conditions, he pledged (1) to destroy all U.S.

chemical weapons within 10 years and (2) never to

use chemical weapons again.20 (However, anticipated difficulties in chemical weapon demilitarization and destruction may prolong the presence of

chemical weapon depots.) This message sent a clear

challenge to other powers to eliminate chemical

weapons. The United States ratified the treaty on

24 April 1997, which was a few days before the

treaty went into effect. Although signed by nearly

160 nations, it must still be ratified by most of those

nations. The treaty still leaves in doubt the development and use of chemical warfare agents by developing nations or nonsigners of such agreements

(most notably Libya, Iraq, and North Korea).

Chemical warfare treaty ratification by nations such

as Iran, given the behavior of its neighbor, Iraq, may

prove to be understandably difficult in the short term.

Reluctance by possessor states to employ chemical weapons, which could be termed “the chemical

warfare threshold,” has seemed to be relatively high

since World War I. However, the Iraqi precedent,

the ineffective world response to Iraq’s use of

chemical warfare, and the perceived effectiveness

of this use all suggest that the chemical warfare

threshold has been substantially lowered. The

growing list of states motivated, for reasons of offense or deterrence, to develop relatively low-technology, low-cost weapons of mass destruction

greatly increases the likelihood that military personnel will have to contend with casualties of

chemical warfare.

Finally, the problem of verification of treaty compliance continues to be difficult even with on-site

inspections. The former Director of Central Intelligence, William H. Webster, stated on 15 October 1988:

After all, any country with a petrochemical, pesticide, fertilizer, or pharmaceutical industry has the

potential in terms of equipment, raw materials

warfare, and technical expertise to produce some

chemical agents. Without direct access to such facilities, it is nearly impossible to know whether

activities being undertaken are of a commercial or

a military nature.21(p9)

This concern was reiterated in congressional testimony following the Persian Gulf War.18

Terrorism

Finally, no threat assessment would be complete

without addressing the terrorist dimension. Terrorism may derive from clandestine, state-directed initiatives22 or, more commonly, from small splinter

groups with special interests or agendas. Groups

with training and financial backing need only to set

up small laboratories to make chemical or biological warfare agents. For example, while investigating Red Army faction activities in 1980, French

police uncovered in an apartment a clandestine

laboratory capable of producing botulinum toxin.23

This suggests that state-sponsored terrorism could

serve as a conduit for the testing of the products of

rapidly emerging biotechnology techniques. It also

places healthcare providers in a position in which

they may be the first to encounter and evaluate the

dangers of new and emerging threats. Also notable

is the successful manufacture of a military nerve
Medical Aspects of Chemical and Biological Warfare

118

agent by able university students recruited by Aum

Shinrikyo. Psychological manipulation and religious zeal were combined to support the terrorist

actions of this organization, which was well funded

by its members.

Chemical and pharmaceutical industries continue to spread around the world, providing

unsponsored terrorist groups access to precursors

and chemicals. Compounds such as chlorine, phosgene, and cyanide are commonplace, and theft of

such materials has been reported.24

In addition to terrorist actions, accidents will

occur as manufacturing with potent industrial

chemicals becomes widespread. Although industrial compounds are not traditionally classified as

chemical agents, they are lethal and potent (eg, the

disaster in Bhopal, India, which is discussed later

in this chapter). Poor economic conditions may

also promote theft of agents and their chemical

precursors and illegal transfer of weapons—not

only by international brokers but also by industrial

workers.

MILITARY CHEMICAL AGENTS

Military chemical agents are characterized according to several features. Among them are

the nature of their use, their persistency in the

field, and their physiological action. Toxic chemical warfare agents are capable of producing incapacitation, serious injury, and death. These agents

are further characterized by their physiological action and are discussed in detail in their individual

chapters. Table 4-1 lists the major chemical warfare

agents.

Nerve agents such as tabun (GA), sarin (GB),

soman (GD), and VX inhibit acetylcholinesterase

enzyme throughout the body, notably in the nervous system. This causes hyperactivation of cholinergic pathways, causing convulsive seizures and

respiratory failure. VX differs from its “G” agent

counterparts in its low volatility.

Vesicants, such as sulfur mustard (HD) and the

arsenical Lewisite (L), cause irritation and vesication of the skin and mucous membranes, notably

of the lungs. Mustard exposure to the skin is insidious, causing no immediate discernible effects to the

skin for several hours; blistering occurs 12 to 24

hours after exposure.25 Although mustard causes

few deaths, its vesicating properties are incapacitating, and casualties require 1 to 4 months of hospitalization. Lewisite blisters heal within several

weeks.

Pulmonary toxicants, such as phosgene (CG)

and diphosgene (DP), injure the respiratory tract,

causing suffocation. Phosgene intoxication rapidly leads to pulmonary edema. The initial effects

of eye exposure resemble those of tear gas; severe pulmonary edema follows in about 4 hours,

eventually leading to death. It is notable that both

phosgene and elemental chlorine (an immediate

phosgene precursor), which can cause pulmonary

edema and hemorrhaging, are industrial compounds.

Finally, cyanides such as hydrogen cyanide (AC)

and cyanogen chloride (CK) both release cyanide

ions in the body. Lower doses cause headaches,

weakness, disorientation, and nausea; higher doses

cause circulatory effects, seizures, and respiratory

and cardiac failure. While often attributed to its

blockade of energy metabolism, the mechanisms of

cyanide intoxication remain unclear and may include cellular targets more sensitive to inhibition

than cytochrome oxidase.

The most common agents in modern arsenals are

vesicants and nerve agents. Cyanides and pulmonary toxicants are thought to be represented in some

stockpiles, but are typically less toxic and more difficult to employ because of their physical characteristics. Some cyanides and pulmonary toxicants

have specific characteristics that make them appropriate for military use, such as rapid rate of action,

very low persistency, and the ability to penetrate

or damage protective equipment.

Other chemicals present in military arsenals include incapacitating agents, which produce physiological or mental effects, or both, rendering individuals incapable of performing their assigned

duties. Recovery may take several hours to several

days, although intensive medical treatment may not

be required. Riot control agents produce intense

effects, such as irritation of the skin, eyes, and respiratory tract, but recovery is normally rapid when exposure is terminated. Unfortunately, little is known

about the long-term effects of many of these agents,

and this is an area of increasing medical concern.

Chemical smoke agents are used to obscure objects or areas from observation or from engagement

by weapons with electro-optical control systems.

They are usually not toxic in field concentrations,

but may cause eye or respiratory irritation in higher

concentrations. Some smokes have adverse chronic

exposure effects. Other compounds with military
The Chemical Warfare Threat and the Military Healthcare Provider

119

TABLE 4-1

CHEMICAL WARFARE AGENTS

U.S. Army Code Agent

Cyanides

AC Hydrogen cyanide

CK Cyanogen chloride

Nerve Agents

GA (Tabun) Ethyl N,N-dimethyl-phosphoramidocyanidate

GB (Sarin) Isopropyl-methylphosphonofluoridate

GD (Soman) 1,2,2-Trimethylpropyl methylphosphonofluoridate

GF Cyclohexyl-methylphosphonofluoridate

VX o-Ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothiolate

Lung Toxicants

CG (Phosgene) Carbonyl chloride

DP (Diphosgene) Trichloromethyl chloroformate

Vesicants

HD (Mustard) bis-2-Chloroethyl sulfide

L (Lewisite) 2-Chlorovinyl dichloroarsine

HL Mustard–Lewisite mixture

Incapacitating Agent

BZ 3-Quinuclidinyl benzilate (QNB)

Tear Gases

CN 2-Chloro-1-phenylethanone

CS 2-Chlorobenzalmalononitrile

Vomiting Gas

DM (Adamsite) 10-Chloro-5,10-dihydrophenarsazine

applications include agents used in flame warfare,

such as thickeners for napalm and incendiary materials, and herbicides (defoliants).

Thus far, discussion has centered on chemical

compounds with a military application. Other

highly toxic industrial chemicals also pose a potential risk to the military. The disaster in Bhopal, India, in December 1984, when an estimated 8,000 persons died and another 30,000 were injured from

breathing methylisocyanate and chlorine released

in an industrial accident, is just one of many examples of the devastating effect of poisonous

gases.26

Chlorine and phosgene are industrial compounds that have been and could again be used as

military weapons by an enemy with access to such

materials, and medical personnel should also be

prepared for such emergencies should military missions be in close proximity to industrial plants. The

first large-scale use of a chemical compound in

Ypres, Belgium, on 22 April 1915, the beginning of

chemical warfare as we know it today, involved the

dispersal of 180 tons of chlorine from over 5,700 canisters by the German forces. During that war, the

list of chemical agents was expanded to include

mustard, phosgene, adamsite, and cyanide.
Medical Aspects of Chemical and Biological Warfare

120

Fig. 4-1. Four modes of chemical agent release. (a) Explosive-release devices are predominantly represented among

the major chemical warfare arsenals. While some agent is lost to decomposition, their simplicity makes these the

weapons of choice. Point-source explosives are single detonation devices, while line-source munitions release a series of time-delayed explosions that lay agent toward the end of the trajectory. (b) Bulk-release munitions spill agent

into the airstream of the projectile. (c) Base-ejection devices are relatively uncommon owing to their cost and complexity. Like explosives and bulk-release devices, these munitions can be carried on longer-range missiles. (d) Spray

delivery can be used to achieve large-area coverage, such as that required for terrain denial. However, because of

aircraft vulnerability, spray delivery is generally limited to application on undefended territory or against a poorly

defended foe.

TACTICAL AND STRATEGIC USE OF CHEMICAL WEAPONS

Delivery of chemical agents can be accomplished

by a full range of weaponry. Liquid agents may be

dispensed from land mines and spray tanks to artillery projectiles, aerial bombs, rocket and missile

warheads, or even cruise missiles. This means that

all battlefield areas, from front lines to rear reserves,

are vulnerable to chemical warfare attack, and that

medical practitioners should be fully prepared to

treat chemical warfare casualties from a variety of

locations. It is also important to note that, while this

section largely focuses on the use of chemical warfare agents on the battlefield, medical personnel

must also be prepared for the possibility of isolated

and spontaneous chemical attacks on both military

personnel and civilians in areas subject to low-intensity conflict and isolated acts of terrorism.

To be effective, chemical agents must be efficiently dispersed over their intended targets. Most

applications call for large-scale agent distribution

over large target areas that are occupied by, or may

be of interest to, military units. For example, documents recovered from the former German Democratic Republic called for Warsaw Pact forces to

employ heavy chemical warfare attacks early in any

conflict with the West.23 Considerable quantities of

an agent may have to be applied to ensure good

coverage in the face of such factors as wind, heat,

and agent volatility, and surprising the enemy so

as to find them unprotected (eg, unmasked).

Chemical Agent Delivery Systems

The four methods of delivering chemical agents

are explosive release, bulk release, base ejection, and

spray delivery (Figure 4-1). The most common

method is explosive release. Bursts from individual

explosive munitions are, effectively, point sources

for chemical warfare dissemination. Chemical warfare artillery shells, which serve as smaller point

sources, could be laid down in a grid to cover a large

area. The same could be accomplished with fewer

missiles, which carry larger payloads and have

longer ranges. Agents can also be delivered from

multiple explosive point sources using submuni-
The Chemical Warfare Threat and the Military Healthcare Provider

121

tions to cover a larger area or, if detonated in sequence, to lay down the agent along a trajectory

line. Such line deliveries may be delivered directly

over the target, or upwind of the target, preferably

perpendicular to the wind.

Bulk release, base ejection, and spray delivery

also deliver chemical warfare agents along trajectory lines. In bulk release, the forward covering, or

“skin,” of a warhead is blown off, exposing agent

to aerodynamic breakup by high-speed air flow. In

base ejection, an explosive charge causes an internal pistonlike action to force the agent out of the

back of the warhead—either through small apertures, aerosolizing it, or into a high-speed airstream

for aerodynamic breakup. Explosive, bulk release,

and base ejection methods are primarily suited for

the dispersal of liquid chemical agents. For the few

solid agents such as the tear gas CS and the incapacitating agent BZ (3-quinuclidinyl benzilate), effective aerosolization is often achieved by pyrotechnic munitions.

Spray delivery is more efficient than the other

three methods in providing a very fine aerosolization (average droplet diameter = < 5 μm) of

agent, which can be inhaled far down into the lungs.

This method is particularly suited to the delivery

of toxins, which require deep inhalation and which

differ from most chemical agents in that they are

solids and do not vaporize. Spray delivery requires

slow speeds and low altitudes, conditions that render aircraft particularly vulnerable to attack. Spray

tanks could also be mounted on trucks or boats, and

unmanned aircraft could be designed to perform

the task. The increased vulnerability of spray-delivery systems makes their use more likely against

unarmed or poorly equipped opponents, or on carefully targeted sites under cover of surprise. Spray

delivery could also be applied to closed ventilation

systems in more focal applications.

From a tactical military standpoint, explosive

munitions, the dominant mode of chemical agent

delivery, vary with respect to effective agent delivery. Disregarding differences among chemical warfare agents for now, Figure 4-2 describes chemical

agent dissemination with respect to explosive munitions in further detail and illustrates important

considerations regarding the chemical agent dynamics and toxicity. Explosion of a chemical agent

shell, at ground level or some height over the target site, generates two products: vapor and droplets. Droplets (average diameter range = 100 μm to

1 mm for pure agents) will fall to the ground in a fine

rain to coat the target surface with liquid.

Agent vapor, the greatest threat for inhalational

intoxication, derives from three sources. First, agent

vaporizes from explosive burst energy. This will

Fig. 4-2. Agent vaporization increases in

proportion to energy sources such as heat

from explosive charges or from ambient

heat (as measured by air or surface temperatures). Vapor persistence is then determined by weather factors such as wind and

humidity. Hydrolysis rates are affected

by factors such as temperature and solubility. Agents show characteristic hydrolysis rates in water, and water vapor, as described by humidity, may cause significant

hydrolysis of vaporized agent. The vesicant

Lewisite, for example, shows relatively

rapid hydrolysis in water vapor, while the

nerve agent VX is more resistant to hydrolysis.
Medical Aspects of Chemical and Biological Warfare

122

TABLE 4-2

COMPARATIVE VOLATILITIES OF

CHEMICAL WARFARE AGENTS

Agent Volatility*(mg/m3)

Hydrogen Cyanide 1,000,000

Sarin (GB) 22,000

Soman (GD) 3,900

Sulfur Mustard (HD) 900

Tabun (GA) 610

VX 10

*Approximate amount of agent (in milligrams) that 1 m3 of air

can hold at 25°C.

Adapted from US Departments of the Army, Navy, and Air

Force. Potential Military Chemical/Biological Agents and Compounds. Washington, DC: Headquarters, DA, DN, DAF; 12 Dec

1990: Appendix B, Table B, pp 95–97. Field Manual 3-9. Naval

Facility Command P-467. Air Force Regulation 355-7.

vary with shell design and specific agent payload.

Important shell design factors are shell casing thickness, shell casing material, and the agent-to-burster

ratio. Second, additional vapor will be generated

as falling droplets vaporize. Heat from the explosion dissipates quickly, and ambient air temperature is the most important factor in driving this

volatilization. Third, the liquid coating of agent on

the ground evaporates, ground temperature being

an important factor. Vapor produced by the first

two, explosive energy and droplet vaporization, is

called primary vaporization, while that rising from

the ground is secondary.

Considering these phenomena, we can appreciate, for example, the differences in agent threat

(liquid persistence and deposition vs vaporization)

in scenarios wherein chemical agent shells are

dropped on a desert area during different times of

the day. The influence of wide environmental temperature fluctuations over the 24-hour cycle, combined with the agent used (see below) can make a

large difference: we can expect increased surface

deposition and skin-contact threat during cool

nights, and a considerably increased inhalational

toxicity threat during the heat of the day.

Successful employment of chemical agents is influenced by many variables. Most notable among

these is the weather, in that the agent is transported

by the wind and air currents when released as a

vapor or an aerosol. Unfavorable meteorological

conditions frequently preclude successful agent

deployment owing to the inordinately high number of weapons used. Once deployed, the persistence of liquid contamination is affected by temperature, sunlight, wind action, and rainfall.

Physical Properties of Chemical Agents

Toxicity mechanisms aside, the physical properties of the agent itself and its formulation also

present similarly important threat considerations.

Selection of agents and agent formulations can be

used to effect differential impacts with respect to

droplet size and liquid deposition, agent persistence, and agent volatility. The classic chemical

warfare agents have a tremendous range of volatility (Table 4-2), and volatility can be a determinant

in deciding which agents will be used.27 Agents such

as hydrogen cyanide and sarin are relatively volatile; they present an immediate, but short-lived,

threat. These agents are referred to as nonpersistent

(ie, they vaporize rapidly after delivery). Alternatively, agents such as VX and sulfur mustard tend

to fall largely in droplets, with less vaporization,

and remain on exposed surfaces for a long time.

These agents are called persistent.

Formulation is also used to manipulate the fate

of the agent. Soman, VX, Lewisite, and sulfur mustard can be mixed with high-molecular-weight

thickeners to increase droplet size and thereby decrease primary vaporization. Such additives are

generally used to promote efficient agent deposition on the target site. Thickeners can also increase

agent persistence and may hamper decontamination efforts.

Nonpersistent Agents

In tactical use, the threat of nonpersistent, volatile agents such as hydrogen cyanide or sarin

is greatest to the respiratory systems of unprotected soldiers. A sudden, heavy bombardment of

these agents may effect many casualties if unmasked soldiers are caught by surprise. When used

against an unprotected force, nonpersistent agents

are particularly effective in generating casualties,

thereby creating breakthrough points in enemy

front lines. The successful use of nonpersistent

nerve agent was demonstrated by Iraqi counterattacks against Iranian forces during 1988.23 Nonpersistent agents can also be used to slow down the
The Chemical Warfare Threat and the Military Healthcare Provider

123

enemy by forcing him to wear protective equipment. Finally, they can also circumvent the enemy’s

protection against conventional high-explosive

munitions and may be used in night attacks to harass the enemy.

Persistent Agents

Given favorable weather conditions, the use of

persistent agents such as mustard and VX may pose

a threat for many days. Such agents can deny or

interfere with enemy occupation of terrain or use

of equipment and, in theory, could be used defensively to protect vulnerable flanks. However, although they can slow down enemy movement, they

can also hamper the movement of friendly forces

through a contaminated area. Delayed casualties

may occur even among protected troops operating

in a contaminated area for an extended period.

Hence, persistent agents may not be the agents of

choice when occupation of territory by friendly

forces is imminent.

Chemical land mines may be used in conjunction with military barrier systems to complicate

breaching or clearing the barriers by dispersing

persistent agent. The mines are typically based on

high-explosive mine designs, with several pounds

of agent being substituted for most of the explosive charge. High-explosive land mines will cause

contaminated open wounds, primarily on lower

extremities, that must be properly decontaminated;

this could be more difficult when persistent agents

are used.

Because of its action, sulfur mustard blistering

agent offers strategic benefits besides those considered above. Sulfur mustard was used very effectively

both during World War I and during the Iran–Iraq War

to generate thousands of casualties. Although deaths

among unprotected sulfur mustard exposure victims are relatively few,28 mustard injuries can tie up

medical treatment facilities with patients. While

survivors of other agents stabilize relatively soon

after exposure, mustard lesions demand months of

medical care. This was the fate of many thousands

of Iranian recruits, who were unprepared or poorly

equipped when they were exposed to sulfur mustard agent.

Underscoring the importance of ambient

temperature and climate, we should note that persistence can change greatly with temperature;

sulfur mustard volatility increases nearly 40-fold

between 0°C and 40°C: from 75 to 2,860 mg/m3. Although always present, the threat of respiratory intoxication from sulfur mustard is considerably greater

at higher temperatures, although its persistence is reduced.

Rapidity of action also factors into agent selection. Volatile agents such as cyanide and sarin can

act very swiftly, primarily via the respiratory tract.

In general, nerve agent effects follow immediately

after exposure, culminating in seizures and death

within a few minutes of inhalation, cutaneous dosing, or both. Other agents, such as mustard,

Lewisite, and phosgene act only after a delay. For

example, both the blistering and the edematous effects of skin exposure to sulfur mustard occur only

many hours after exposure.

Choice of Agent and Delivery System

By selecting the appropriate agents, formulations, and delivery systems, a well-equipped military will be in a better position to achieve its tactical objectives. U.S. Army Field Manual (FM) 3-10,

Employment of Chemical Agents, discusses how

chemical munitions could be used separately or integrated with conventional weapons. Chemical

warfare agents can be used to cause casualties, harass the enemy, and hamper or restrict the use of

terrain. Although an offensive capability no longer

exists, FM 3-10 provides useful information on how

chemical warfare agents can be used on the battlefield.29 Brigadier General Augustin M. Prentiss, a

Chemical Warfare Service officer, describes in his

classic 1937 book, Chemicals in War, the offensive

tactical uses of chemical agents that were in place

following World War I.30

The most militarily significant effects of chemical agents are through inhalation, in that most

agents are more toxic and faster acting by that route

of exposure. Almost without exception, modern

armies are equipped with protective equipment:

masks to protect the eyes and respiratory tract, and

protective clothing to prevent skin contamination.

However, the very act of donning protective equipment is an encumbrance. In hot weather, remaining

in protective clothing for more than a few minutes

can itself produce casualties. The mission-oriented

protective posture gear (MOPP) that the U.S. Army

issues, which was designed for use in the European

theater, can swiftly cause an active wearer to experience heat stress and dehydration under desert

conditions.31,32 The British protective counterpart,

the MK 4 suit, keeps the wearer cooler by allowing

perspiration to evaporate, although the heat stress

problem remains.33
Medical Aspects of Chemical and Biological Warfare

124

Detection and Protection

Adequate agent detection capabilities are essential for successful chemical agent defense. Although

U.S. Army doctrine prescribes donning full MOPP

4 gear if an attack is imminent or in progress, detection capabilities permit recognition of the true

agent threat and appropriate reductions to protective posture (ie, MOPP 3 or even MOPP 2). Detection capability for medical teams is essential to provide warning that casualties are contaminated, and

to avoid inappropriate assumption of high levels

of protective posture if they are not.

Well-equipped, well-trained troops who apply

high levels of discipline in using protective equipment are not very likely to become chemical casualties. Most casualties will have sustained respiratory injury due to failure to mask properly in time

when under attack. We can speculate that as the

length of time spent in protective posture increases,

the percentages of casualties with skin effects will

increase. Most of these effects will be from failures

in procedure when donning protective clothing and

removing contaminated protective clothing.

Among exposed populations, the range of agent

intoxication effects can be expected to correlate with

levels of protective equipment, training, and discipline. The healthcare provider should anticipate

that poorly trained soldiers will show an increased

incidence of skin contamination by vesicants, for

example. There will also be a greater need for decontamination. Civilian populations will generally

be the most vulnerable. Most will have little if any

protective equipment, and no means of detecting

the presence of agent.

Even with protective equipment, the threat of

agent intoxication is greater for casualties with facial, neck, or chest wounds that may compromise

the integrity of the protective mask seal. Based on

wound descriptions, a retrospective analysis34 of

2,021 casualties admitted to the Naval Support

Hospital in Da Nang, Vietnam, found that mask

failure could have been expected to affect 34% of

these patients.

RESPONDING TO THE THREAT: MANAGING CASUALTIES

The medical management of casualties, including triage, decontamination, and specific therapy,

is discussed in separate chapters. However, several

points need emphasis under a discussion of concerns for the healthcare provider.

First, many of the early signs and symptoms produced by chemical warfare agents may resemble

those of a variety of disorders, including stress.

Among unseasoned troops, especially those with

limited experience in a chemical environment, psychological withdrawal or physical complaints of

palpitation, gastrointestinal distress, headaches,

dizziness, and inattentiveness will present difficult

diagnostic dilemmas for medical personnel on the

battlefield. A clinical awareness of the early signs

and symptoms is critically important, but so is an

awareness of the medical problems associated with

stress. The potential for mass hysteria is also high,

even among troops with full individual protection,

and the horror of dying from a chemical agent attack is widespread. Apprehension will be a major

factor in the confusion of battle.

To minimize such problems, continuous training

is required so that soldiers are comfortable donning

their protective equipment and operating in a

chemically contaminated environment. Similarly,

soldiers must understand the rationale for taking

the nerve agent pretreatment, pyridostigmine, as an

added protective measure, not as a replacement for

masking. Such training should involve medical input.

Second, the risk of chemical contamination of

medical equipment and medical treatment facilities

is an added threat, and precautions need to be taken

to ensure that patients are properly decontaminated

before being brought into designated uncontaminated treatment areas. Frontline medics faced with

many casualties can only be expected to administer lifesaving procedures, such as opening the airway or preventing further hemorrhage; decontamination can be expected to be minimal.

In rear areas, chemical decontamination of open

wounds adds substantial complexity to otherwise

conventional wounds, which then require procedures different from those ordinarily established for

debridement. Some nations have adopted special

irrigation–suction devices to irrigate and clean

wounds, and air-flow protection methods to minimize the risk to hospital staff. The risk of wound

contamination may be higher with low-velocity

wounds, when pieces of contaminated clothing or

debris may be carried into the wound and remain

deeply imbedded for a time; this may be a greater

problem with persistent agents. Therefore medical

procedures must be well defined, and healthcare

providers should regularly review the steps required in handling a casualty.
The Chemical Warfare Threat and the Military Healthcare Provider

125

While chemical agents are an occupational hazard to the combat soldier, they are also a danger to

the emergency room and surgical staff, who must

rely on their hands and eyes to stabilize and treat

the casualty. Standard surgical latex gloves are not

sufficient protection against chemical agents, and

they provide little protection against a vapor hazard. Should hospital-based medical personnel in

critical specialties become casualties themselves, the

healthcare delivery system will be significantly

compromised. An improperly decontaminated casualty may also pose a risk to other patients.

Third, the patient flow pattern in a chemical environment will be substantially altered. Treatment

rates can be expected to be reduced because of the

decontamination procedures that must be in place.

Injuries that will be seen will range from severe to

minor, with the latter probably constituting the

majority. With some agents, the effects of chemical

injury may not be readily apparent until after a delay, and this must be considered in the disposition

of the patient. Therefore, the process of medical

evaluation and observation may tax the holding

capability of a facility.

Finally, the medical logistical requirements will

be increased. It has been stated that up to 40% more

transport is required to move a typical field hospital in a chemical environment, and the fuel necessary to power air pumps, special filtration units, and

air conditioners is an added requirement.35 Water

requirements may also be increased in a chemical

environment. Medical treatment facility planners

should recognize the importance of environmental

factors within a chemical warfare theater. For example, the MOPP gear may not be designed for the

climatic conditions on the battlefield. Tests have

shown that perspiration compromises the ability of

the battledress overgarment to protect the wearer

from chemical agents36 and may actually predispose

an individual to injury.32

FUTURE CONFLICTS IN A CHEMICAL ENVIRONMENT

From the standpoint of military strategy, two reasons are commonly cited for a combatant to employ

chemical weapons. First, they can be highly effective when densely applied onto concentrated,

largely immobile forces or populations. This factor

largely promoted their use against entrenched troop

positions during World War I. During the Cold War,

military strategists anticipated similar intense

chemical warfare bombardments from Warsaw Pact

forces in the European theater. Second, chemical attacks can be initiated at lower levels to encumber

an opponent with defensive equipment, or to create panic and disorder among poorly trained or

unprepared troops. Application onto enemy troops

or civilian populations can also have a strong demoralizing effect.

Two important influences on the decision to employ chemical attacks are weather patterns and user

objectives. Gas dispersal depends on wind speed

and direction. If the attacking force is in close proximity to the target area, it must use protective gear

in the event of wind shift. This handicap can be

avoided, if the situation allows, when agents can

be delivered from a remote location by either air or

long-range artillery. The objectives of an attacker

may also determine whether chemical warfare will

be employed and, if so, which agents are to be used.

Thickened nerve agents and sulfur mustard deny

free access to terrain and are not likely to be used

by forces intent on occupation. Nonthickened nerve

agents are not persistent and could be used by a

mobile, advancing force.

Western powers had contemplated using chemical weapons during World War II. Sir Winston

Churchill seriously contemplated resorting to

chemical warfare should the defense of Britain have

become desperate.37 Later in the war, U.S. military

commanders also contemplated the use of chemical agents to counter Japanese fanaticism, which,

even during imminent defeat in 1945, caused exceedingly high losses on both sides during island

warfare (nearly 110,000 Japanese died in the battle

for Okinawa alone). These circumstances led the

United States to resort to unconventional weaponry

(the atomic bomb). With Germany out of the war

and the death of President Roosevelt, who had opposed any first use of chemical weapons, the use of

sulfur mustard and other agents was seriously contemplated during the summer of 1945.38 Based on

recent events and decisions, however, it is unlikely

that an offensive chemical warfare program would

be initiated by Western powers. This does not negate the need for a strong defense posture, however, as long as chemical proliferation continues.

Fanaticism shown by Iranian Revolutionary

Guard units may have precipitated Iraqi use of

chemical warfare agents at the end of 1983.

Throughout the Iran–Iraq War, Iraq generally used

chemical weapons only when facing probable defeat with conventional weapons.39 History suggests
Medical Aspects of Chemical and Biological Warfare

126

that a cornered and besieged enemy, confronting

troops intent on inducing complete surrender, could

employ chemical warfare agents as a final resort or

act of vengeance. In 1937, Prentiss stated:

In the last analysis, war is not a sport, but a grim

contest between states for national existence. War

cannot be conducted by any code of sportsmanship,

but only by the law of military necessity, however

much civilization may deplore the results.31(p699)

Therefore, the United States military must maintain

a strong readiness posture in the face of a continuing chemical warfare threat.

SUMMARY

The military healthcare provider should be prepared to be the first to recognize military or civilian casualties of chemical warfare attack. This requires an informed understanding of the likelihood

of chemical warfare agent use or threat, and it requires the ability to clearly recognize agent-exposure symptoms against a varying background of unrelated injury and stress behaviors. The healthcare

provider should be informed, to the fullest extent

possible, when to anticipate chemical warfare attack by hostile forces or terrorist activities. This requires consideration of an adversary with regard

to political factors and motivation, chemical agent

possession or access, chemical warfare offensive

and defensive capabilities, and the strategic advantage to be realized through agent use.

When individuals suspected to have been exposed to chemical warfare agents are encountered,

initial recognition of the type of agent used may be

facilitated through an understanding of tactical

agent use, modes of agent dissemination, likely

routes of casualty exposure to agent, and physical

agent properties and other factors determining the

persistence of these toxicants in the operating environment. Finally, to protect both the injured and

medical personnel, casualty care must take place

within a framework of decontamination both in the

field and in forward medical support facilities.

REFERENCES

1. Burck G, Flowertree CC. International Handbook on Chemical Weapons Proliferation. New York, NY: Greenwood

Press; 1991: 3-4, 164–171.

2. Smith J. Confusing data on chemical capability: US intelligence, diplomatic lists of armed nations differ. Washington Post. 15 Mar 1991;A21.

3. Browder G, chairman. Countering the Chemical and Biological Weapons Threat in the Post-Soviet World. Report of

the special inquiry into the chemical and biological threat of the Committee on Armed Services, US House of

Representatives, 102nd Congress (2nd Session). Washington, DC: US Government Printing Office; 23 Feb 1993.

ISBN 0-16-040163-1.

4. Evans D, Bailey K, Lambakis S, Rudney B, Victory B. Iraqi Inspections: Lessons Learned. Washington, DC: Defense Nuclear Agency; 1992. Unclassified Technical Report. DTIC B170991.

5. Ember E. Chemical arms treaty ratification moves forward. Chemical and Engineering News. 1993;70(47):14–15.

6. Mathewson W. Soviets’ chemical weapons. Wall Street Journal. 3 Aug 1990:A10.

7. Ember E. Russia seeks US expertise, money to destroy its chemical arms. Chemical and Engineering News.

1992;71(4):18–19.

8. Felten E. Amid discontent, weapons could fall into unsafe hands. Washington Times (Insight). 29 Oct 1990;26–27.

9. Segal D. The Soviet Union’s mighty chemical warfare machine. Army. Aug 1987;37(8):26–35, 38.

10. Mohr H. Chemical weapons out of control. Washington Times. 17 Oct 1989;F3.

11. Livingstone NC, Douglass JD. Chemical and Biological Weapons: The Poor Man’s Atomic Bomb. Cambridge, Mass:

Institute for Foreign Policy Analysis; 1 Feb 1984. National Security Paper 1.
The Chemical Warfare Threat and the Military Healthcare Provider

127

12. Nolan JE, Wheelon AD. Third World ballistic missiles. Sci Am. 1990;263(2):34–40.

13. Kempster N. For the Middle East, arms control is no longer unthinkable. Los Angeles Times. 1 May 1990;H5.

14. Windrem R. Iraq’s most lethal weapons. Popular Science. Feb 1991:238(2):51–55, 84.

15. Rathmell A. Chemical weapons in the Middle East: Syria, Iraq, and Libya. Marine Corps Gazette. July 1990;59.

16. Timmerman KR. The poison gas connection: Western suppliers of unconventional weapons and technologies

to Iraq and Libya. Los Angeles, Calif: Simon Weisenthal Center; 1990. Special Report.

17. Felton J. Approval seen on chemical weapons. Congressional Quarterly Weekly Report. 9 June 1990;48

(23):1800.

18. The Committee on Armed Services, US House of Representatives. Countering the chemical and biological

weapons threat in the post-Soviet world. Report of the Special Inquiry Into the Chemical and Biological Threat.

Washington, DC: US Government Printing Office; 23 Feb 1993.

19. Towell P. In the bag: Chemical weapons pact. Congressional Quarterly. 26 May 1990;48(21):1664.

20. Smith RJ, Yang YE. Bush to scrap all US chemical arms. Washington Post. 14 May 1991;114(160)A-1, A-12.

21. Browder G, chairman. Countering the Chemical and Biological Weapons Threat in the Post-Soviet World. Report of

the special inquiry into the chemical and biological threat of the Committee on Armed Services, US House of

Representatives, 102nd Congress. Washington, DC: US. Government Printing Office; 23 Feb 1993: 9. ISBN

0-16-040163.

22. Wilkinson P. Terrorism, Iran and the Gulf region. Jane’s Intelligence Review. 1992;4(5):222–226.

23. US Army Chemical School. World-wide NBC threat briefing. Fort McClellan, Ala: US Army Chemical School

Threat Office; March 1992. Unclassified.

24. Agence France Presse. Cyanide stolen in Kyrgyzstan. Agence Presse English Wire. 25 September 1992.

25. Papirmeister B. A global picture of battlefield vesicants, I: A comparison of properties and effects. Medical

Chemical Defense. 1992;5(1):1–8.

26. Kurzman D. A Killing Wind: Inside Union Carbide and the Bhopal Catastrophe. New York, NY: McGraw-Hill; 1987.

27. US Departments of the Army, Navy, and Air Force. Potential Military Chemical/Biological Agents and Compounds.

Washington, DC: Headquarters, DA, DN, DAF; 12 December 90. Field Manual 3-9. Naval Facility Command P467. Air Force Regulation 355-7.

28. Gilchrist HL. Statistical consideration of gas casualties. In: Weed FW, ed. Medical Aspects of Gas Warfare. Vol 14.

In: Ireland MW. The Medical Department of the United States Army in the World War. Washington, DC: US Government Printing Office. 1926: 273–279.

29. US Departments of the Army, Navy, and Air Force. Employment of Chemical Agents. Washington, DC: Headquarters, DA, DN, DAF; Mar 1966. Field Manual 3-10. Naval Warfare Information Publication 36-2. Air Force Manual

355-4. Fleet Marine Force Manual 11-3.

30. Prentiss AM. Chemicals in War. New York, NY: McGraw-Hill; 1937.

31. 60 Minutes. Likely effects of Iraqi chemical weapons attack. Columbia Broadcasting System. 26 Aug 1990.

32. Carter BJ, Cammermeyer M. Emergence of real casualties during simulated chemical warfare environment.

Milit Med. 1985;150(12):657–665.
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33. Harrington L. US lightens up for chemical fight. Chicago Tribune. 26 November 1990;14.

34. McCaughey BG, Garrick J, Kelly JB. Combat casualties in a conventional and chemical warfare environment.

Milit Med. 1988;153 (5):227–229.

35. Hammick M. The chemical question. In: The cutting edge: Battlefield casualty management. International Defense Review. Mar 1992;25(3):250–251.

36. Greve F. US troops ill-equipped for desert gas warfare. Philadelphia Inquirer. 9 Aug 1990;1.

37. Taylor LB, Taylor CL. Chemical and Biological Warfare. New York, NY: Franklin Watts Press; 1985.

38. Van Courtland Moon JE. Project SPHINX: The question of the use of gas in the planned invasion of Japan.

Journal of Strategic Studies. September 1989;12(3):303–323.

39. Morrison DC. Chemical fears exaggerated. National Journal. 8 September 1990;22(36):2133.
Nerve Agents

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Chapter 5

NERVE AGENTS

FREDERICK R. SIDELL, M.D.*

INTRODUCTION

HISTORY

PHARMACOLOGY OF CHOLINESTERASE INHIBITORS

Cholinesterase in Tissue

Blood Cholinesterases

Nerve Agents

EXPOSURE ROUTES

Inhalational Exposure to Vapor

Dermal Exposure to Liquid

EFFECTS ON ORGANS AND ORGAN SYSTEMS

The Eye

The Nose

Pulmonary System

Skeletal Musculature

Central Nervous System and Behavior

Cardiovascular System

GENERAL TREATMENT PRINCIPLES

Terminating the Exposure

Ventilatory Support

Atropine Therapy

Oxime Therapy

Anticonvulsive Therapy

Therapy for Cardiac Arrhythmias

SPECIFIC TREATMENT BY EXPOSURE CATEGORY

Suspected Exposure

Minimal Exposure

Mild Exposure

Moderate Exposure

Moderately Severe Exposure

Severe Exposure

RETURN TO DUTY

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014
Medical Aspects of Chemical and Biological Warfare

130

INTRODUCTION

Nerve agents are extremely toxic chemicals that

were first developed in secrecy before and during

World War II primarily for military use. Related

substances are used in medicine, in pharmacology,

and for other purposes, such as insecticides, but

they lack the potency of the military agents. Much

of the basic knowledge about the clinical effects of

nerve agents comes from research performed in the

decades immediately following World War II.

The military stockpiles of several major powers

are known to include nerve agents, and the armamentaria of other countries are thought to contain

them as well (see Chapter 4, The Chemical Warfare Threat and the Military Healthcare Provider).

Because of the possibility of nerve agent use in

future conflicts, military medical personnel should

have some knowledge of these agents, their effects,

and the proper therapy for treating casualties.

HISTORY

Possibly the earliest recorded use of a substance

that works, like nerve agents, by inhibiting cholinesterase (ChE) is by native tribesmen of western

Africa who used the Calabar bean as an “ordeal

poison” in witchcraft trials.1,2 An extract, “the elixir

of the Calabar bean,” was later used medicinally,3

and in 1864, the active principle was isolated by

Jobst and Hesse and called physostigmine.1 Vee and

Leven independently isolated this same substance

in 1865 and named it eserine,1 hence its dual nomenclature.

The first organophosphorus ChE inhibitor was

probably tetraethyl pyrophosphate (TEPP), synthesized by Wurtz and tasted (with no ill results) by

Clermont in 1854.4 During the next 80 years, chemists (such as Michaelis, Arbusow, and Nylen) made

numerous advances in organophosphorus chemistry, but generally they did not realize the toxicity

of the substances with which they were working.4

In the early 1930s, interest in both physostigminetype (reversible) and organophosphorus-type (irreversible) ChE inhibitors increased. (The terms “reversible” and “irreversible” refer to the duration of

binding of the compound with the enzyme ChE; see

the Mechanism of Action section below.) The reversible type, most of which are carbamates, were developed for treating conditions such as intestinal

atony, myasthenia gravis, and glaucoma; for example, treating gastric atony with neostigmine was

described in 1931.1

Five organophosphorus compounds are generally regarded as nerve agents. They are commonly

known as tabun (North Atlantic Treaty Organization [NATO] military designation, GA), sarin (GB),

and soman (GD); and GF and VX (also NATO military designations; these compounds have no common names). The agents in the “G” series allegedly

were given the code letter G because they originated

in Germany; the “V” allegedly stands for venomous. GF is an old agent, previously discarded by

the United States as being of no interest. During the

Persian Gulf War, it was believed that Iraq might

have GF in its arsenal; however, interest has waned

again and GF has retreated to obscurity.

Lange and Krueger reported on the marked potency of organophosphorus compounds in 1932 after noting the effects of the vapors of dimethyl and

diethyl phosphorofluoridate on themselves.1,4

Shortly thereafter, the German company I. G.

Farbenindustrie developed an interest in organophosphorus compounds as insecticides. On 23 December 1936, Gerhard Schrader, who headed the

company’s research effort, synthesized what today

is known as tabun.5,6 Like Lange and Krueger, he

noted the toxicity (miosis and discomfort) of the

vapors of the substance in himself.

Over a year later, Schrader synthesized a second

organophosphorus compound and named it sarin

in honor of those who were instrumental in its development and production: Schrader, Ambros,

Rudriger, and van der Linde.5 Because the German

Ministry of Defense required that substances passing certain toxicity tests be submitted to the government for further investigation, these compounds

were examined for possible military use.

The potential of tabun and sarin as weapons

was soon realized. A large production facility was

built in Dyhernfurth and production of tabun was

begun in 1942. 5,6 Sarin was also produced in

Dyhernfurth and possibly at another plant in

Falkenhagen.6 Late in World War II, Soviet troops

captured the Dyhernfurth facility (then in Germany,

now in Poland), dismantled it, and moved it, along

with key personnel, to the former Soviet Union,

where production of the agents commenced in

1946.6
Nerve Agents

131

About 10,000 to 30,000 tons of tabun and smaller

quantities of sarin were produced and put into

munitions by the Germans during World War II, but

these weapons were never used.6 Why they were

not remains a matter of conjecture.

In the waning days of World War II, troops of

the United States and the United Kingdom captured

some of these munitions, which were being stored

at Raubkammer, a German testing facility. The munitions, which contained an agent unknown to scientists in the United Kingdom and the United

States, were taken to the two countries for examination. Over a single weekend, a small group of

scientists at the U.K. Chemical Defence Establishment, working despite miosis caused by accidental

exposure to the agent vapor, elucidated the pharmacology and toxicity of tabun and documented the

antidotal activity of atropine.7

Thus, during the latter part of World War II, Germany possessed chemical weapons against which

its foes had little protection and no antidotes.

Use of these weapons probably would have been

devastating and might have altered the outcome of

that conflict. The Germans had tested nerve agents

on inmates of concentration camps, not only to investigate their intoxicating effects but also to develop antidotes.8

 Many casualties, including some

fatalities, were reported among the plant workers at Dyhernfurth; the medical staff there eventually developed antidotal compounds.5

 The Allies

were unaware of these German experiments until

the close of the war, months after the initial U.K.

studies.7

Soman was synthesized in 1944 by Richard Kuhn

of Germany, again in a search for insecticides.6 Small

amounts were produced, but development had not

proceeded far by the end of the war. The nerve agent

VX was first synthesized by an industrial concern

in the United Kingdom in the early 1950s6 and was

given to the United States for military development.

Other potential nerve agents were synthesized

by scientists in the United States and United Kingdom but were not developed for military use. For

example, GF, which may have been first synthesized

about 1949 by a chemist in another country in the

search for other nerve agents, was studied in both

the United States and the United Kingdom. It was

then discarded for reasons that are not entirely clear.

Possible explanations are that it was too expensive

to manufacture or that there was no perceived need

for an agent with its properties. The manufacturing process for GF is apparently similar to that for

GB. During the Persian Gulf War (1990–1991), Iraq

was believed to have switched from the manufacture of GB to the manufacture of GF when the precursors of GB, but not those of GF, were embargoed.

The United States began to produce sarin in the

early 1950s, and VX in the early 1960s, for potential

military use; production continued for about a decade.6

 The U.S. munitions inventory today contains

these two nerve agents in 30- to 45-year-old M55

rockets; land mines; 105-mm, 155-mm, and 8-in.

projectiles; 500-lb and 750-lb bombs; wet-eye bombs

(one of a family of “eye” bombs, which has liquid

chemical [wet] contents); spray tanks; and bulk containers.9

 These munitions are stored at six depots

within the continental United States (CONUS) and

one outside the continent; the locations of these

depots are public knowledge.10 The six CONUS

depots are near Tooelle, Utah; Umatilla, Oregon;

Anniston, Alabama; Pine Bluff, Arkansas; Newport,

Indiana; and Richmond, Kentucky; the seventh depot is on Johnston Island in the Pacific Ocean.

Sarin has also been used in terrorist attacks. In

June 1994, members of a Japanese cult released sarin

in an apartment complex in Matsumoto, Japan. Although there were almost 300 casualties, including

7 dead, this event was not well publicized. On 20

March 1995, sarin was released on Tokyo subways.

More than 5,500 people sought medical care; about

4,000 had no effects from the agent but 12 casualties died. This incident required a major expenditure of medical resources to triage and care for the

casualties. (Also see Chapter 1, Overview: Defense

Against the Effects of Chemical and Biological Warfare Agents).

PHARMACOLOGY OF CHOLINESTERASE INHIBITORS

Cholinesterase in Tissue

Nerve agents are compounds that exert their biological effects by inhibition of the enzyme acetylcholinesterase (AChE), according to the current,

widely accepted explanation. Some other compounds cause similar effects by the same mechanism and, in a broad sense, can also be considered

nerve agents.

Acetylcholinesterase belongs to the class of enzymes called esterases, which catalyze the hydrolysis of esters. ChEs, the class of esterases to which

AChE belongs, have high affinities for the esters of

choline. Although there are several types of cho-
Medical Aspects of Chemical and Biological Warfare

132

line esters, acetylcholine (ACh), the neurotransmitter of the cholinergic portion of the nervous system, is most relevant to nerve agent activity.

The enzyme AChE, found at the receptor sites of

tissue innervated by the cholinergic nervous system, hydrolyzes ACh very rapidly: it has one of the

highest enzyme turnover numbers (number of molecules of substrate that it turns over per unit time)

known.11 A similar enzyme having ACh as its preferred substrate is found in or on erythrocytes (red

blood cells, RBCs) and is known as erythrocyte, or

true, ChE (RBC-ChE). Butyrocholinesterase (BuChE,

also known as serum or plasma cholinesterase, and

as pseudocholinesterase), another enzyme of

the ChE family, has butyrylcholine as its preferred

substrate. Butyrylcholine is present in plasma or serum and in some tissues. BuChE and RBC-ChE

are discussed in the Blood Cholinesterases section

below.

Cholinesterase-Inhibiting Compounds

Most ChE-inhibiting compounds are either carbamates or organophosphorus compounds. Among

the carbamates is physostigmine (eserine; elixir

of the Calabar bean), which has been used in

medicine for more than a century.3

 Neostigmine

(Prostigmin, manufactured by ICN Pharmaceuticals, Costa Mesa, Calif.) was developed in the early

1930s for management of myasthenia gravis;

ambenonium was developed later for this same

purpose. Pyridostigmine bromide (Mestinon,

manufactured by ICN Pharmaceuticals, Costa Mesa,

Calif.) has been used for decades for the management of myasthenia gravis. The military of the

United States and several other nations also field

pyridostigmine bromide (manufactured by Phillips

Duphar, Holland), known as PB or NAPP (nerve

agent pyridostigmine pretreatment), as a pretreatment, or antidote-enhancing substance, to be used

before exposure to certain nerve agents (see Chapter 6, Pretreatment for Nerve Agent Exposure). Today these carbamates are mainly used for treating

glaucoma and myasthenia gravis. Other carbamates, such as Sevin (carbaryl, manufactured by

Techne, St. Joseph, Mo.), are used as insecticides.

Most commonly used insecticides contain either

a carbamate or an organophosphorus compound.

The organophosphorus insecticide malathion has

replaced parathion, which was first synthesized in

the 1940s. The organophosphorus compound

diisopropyl phosphorofluoridate (DFP) was synthesized before World War II and studied by Allied

scientists before and during the war, but was rejected for use as a military agent. For a period of

time, this compound was used topically for treatment of glaucoma but later was rejected as unsuitable because it was found to produce cataracts. It

has been widely used in pharmacology as an investigational agent.

Mechanism of Action

Nerve agents inhibit ChE, which then cannot

hydrolyze ACh. This classic explanation of nerve

agent poisoning holds that the intoxicating effects

are due to the excess endogenous ACh. This explanation, however, may not account for all nerve agent

effects.

Research suggests that other nerve agent actions

may contribute to toxicity. For example, ChE inhibitors inhibit enzymes other than ChE; the effect of

this inhibition of additional enzymes on nerve agent

toxicity may be significant.12 Concentrations of ChE

inhibitors that are severalfold higher than lethal

concentrations produce direct effects on receptor

sites by blocking conductance through the ion channel or by acting as agonists at the channel complex.13

While these findings offer hope that better means

of therapy will be developed in the future, their

relevance to clinical effects is not clear at this time.

A detailed discussion of the chemistry of ChE

inhibition is beyond the scope of this chapter and

can be found in most textbooks of pharmacology

(eg, see Koelle11). The relevant aspects are summarized here.

The efferents of the human nervous system can

be subdivided according to the neurotransmitter

released. The adrenergic nervous system, for which

the neurotransmitter is adrenaline (epinephrine) or,

more correctly, noradrenaline (norepinephrine),

comprises one large subsection. Other, less prominent efferent tracts have γ-aminobutyric acid

(GABA), dopamine, or some other substance as the

neurotransmitter. The cholinergic nervous system,

a second major subdivision, has acetylcholine as the

neurotransmitter. Acetylcholine is the neurotransmitter of the neurons to skeletal muscle, of the

preganglionic autonomic nerves, and of the postganglionic parasympathetic nerves. Exogenous

ACh causes stimulation of the muscles and other

structures innervated by these fibers.

This portion of the cholinergic nervous system

can be further subdivided into the muscarinic and

nicotinic systems, because the structures that are

innervated have receptors for the alkaloids muscarine (mAChR) and nicotine (nAChR), respectively,

and can be stimulated by these compounds. Mus-
Nerve Agents

133

carinic sites are innervated by postganglionic parasympathetic fibers. These sites include glands (eg,

those of the mouth and the respiratory and gastrointestinal systems), the musculature of the pulmonary and gastrointestinal systems, the efferent

organs of the cranial nerves (including the heart via

the vagus nerve), and other structures. Nicotinic

sites are at the autonomic ganglia and skeletal

muscles.

The production of a response in an organ to a

neuromediated impulse consists of several stages.

Fig. 5-1. Diagram of neuromuscular

conduction. (a) Nerve fiber with axon

terminal in synaptic trough of muscle. (b) Close-up of axon terminal in

trough, with synaptic vesicles indicated. (c) Acetylcholine synthesis

from acetate and choline and storage

of acetylcholine in synaptic vesicles.

(d) Release of acetylcholine from synaptic vesicles after an action potential. (e) Acetylcholine stimulation of

endplate at receptor for site. (f) Hydrolysis of acetylcholine by membrane-bound acetylcholinesterase.

Reprinted with permission from

Clinical Symposia. 1(1,§8): 162, Plate

3118. West Caldwell, NJ: CIBAGEIGY Medical Education Division.

First, the impulse travels down a nerve to the axonal terminal, or presynaptic area, creating an action potential. (This action potential consists of a

change in the resting potential of the polarized

nerve membrane.) At the prejunctional area, the

action potential stimulates the release of the neurotransmitter ACh from storage in synaptic vesicles.

The ACh diffuses across the synaptic cleft and combines with specialized areas—the receptor sites—

on the postsynaptic membrane to produce a

postsynaptic potential, which may be either a deFigure 5-1 is not shown because the copyright permission granted to the

Borden Institute, TMM, does not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic media. The

current user must apply to the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

134

polarization or a hyperpolarization of the membrane. The postsynaptic activity thus initiated is a

contractile response in muscle or secretion in a

gland. (Events in the central nervous system [CNS]

are less clear.) Following each impulse, the neurotransmitter is destroyed to prevent further

postsynaptic potentials (Figure 5-1).

In the cholinergic portion of the nervous system,

ChE hydrolyzes the neurotransmitter ACh to terminate its activity at the receptor site (Figure 5-2).

Acetylcholine attaches to two sites on the ChE enzyme: the choline moiety to the anionic site and the

acetyl group to the esteratic site. The choline splits

off, leaving the acetylated esteratic site, which then

reacts very quickly with water to form acetic acid

and regenerated, or reactivated, enzyme.

If AChE were absent from the site, or if it were

unable to function, ACh would accumulate and

would continue to produce postsynaptic action

potentials and activity in the organ. The nerve

agents and other ChE-inhibiting substances produce biological activity by disabling (or inhibiting)

AChE, an action that leads to an accumulation of

ACh. The biological activity, or toxicity, of ChE inhibitors is due to this excess endogenous ACh,

which is not hydrolyzed.

Fig. 5-2. This schematic ribbon diagram shows the structure of Torpedo californica acetylcholinesterase. The diagram

is color-coded; green: the 537-amino acid polypeptide of

the enzyme monomer; pink: the 14 aromatic residues that

line the deep aromatic gorge leading to the active site;

and gold and blue: a model of the natural substrate for

acetylcholinesterase, the neurotransmitter acetylcholine,

docked in the active site. Reprinted with permission from

Sussman JL, Silman I. Acetylcholinesterase: Structure and

use as a model for specific cation–protein interactions.

Curr Opin Struct Biol. 1992;2:724.

The compounds in the two major categories of

AChE inhibitors, carbamates and organophosphorus compounds, also attach to the ChE enzyme.

There are some differences, however, between them

and the natural substrate ACh. Carbamates attach

to both the esteratic and the anionic sites. A moiety

of the carbamate is immediately split off, leaving

the enzyme carbamoylated at the esteratic site. Instead of hydrolysis occurring at this site within

microseconds, as it does with the acetylated enzyme, hydrolysis does not occur for minutes to

hours, and the enzyme remains inactive or inhibited

for about 1 hour after reacting with physostigmine

and 4 to 6 hours after reacting with pyridostigmine.

Most organophosphorus compounds combine

with the ChE enzyme only at the esteratic site, and

the stability of the bond (ie, the interval during

which the organophosphorus compound remains

attached) depends on the structure of the compound. Hydrolytic cleavage of the compound from

the enzyme may occur in several hours if the alkyl

groups of the organophosphorus compound are

methyl or ethyl, but if the alkyl groups are larger,

cleavage may not occur. Thus, the phosphorylated

form of the enzyme may remain indefinitely; in this

case, return of enzymatic activity occurs only with

the synthesis of new enzyme.

Since most of these compounds attach to the

esteratic site on AChE, a second binding compound

cannot attach on that site if the site is already occupied by a molecule. Thus a previously administered

ChE inhibitor will, in a manner of speaking, protect the enzyme from a second one.14,15 This activity

forms the pharmacological basis for administering

a carbamate (pyridostigmine) before expected exposure to some nerve agents to provide partial

protection (lasting 6–8 h) against the more permanently bound nerve agents. (This mode of protection is described in more detail in Chapter 6, Pretreatment for Nerve Agent Exposure). Because of

the different lengths of time required for carbamates and organophosphorus compounds to be hydrolyzed from the enzyme, they are sometimes referred to, respectively, as reversible and irreversible inhibitors.

After inhibition by irreversibly bound inhibitors,

recovery of the enzymatic activity in the brain seems

to occur more slowly than that in the blood ChE.16,17

However, one individual severely exposed to sarin

was alert and functioning reasonably well for several days while ChE activity in his blood was undetectable (Exhibit 5-1).18 This case study and other

data suggest that tissue function is restored at least

partially when ChE activity is still quite low.

Figure 5-2 is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include

usage in electronic media. The current user must

apply to the publisher named in the figure legend

for permission to use this illustration in any type

of publication media.
Nerve Agents

135

EXHIBIT 5-1

CASE REPORT: SARIN EXPOSURE OF A MAN IN FULL PROTECTIVE GEAR

Exhibit 5-1 (continues)

Exhibit 5-1 is not shown because the copyright permission granted to the Borden Institute, TMM, does not

allow the Borden Institute to grant permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure legend for permission to use this

illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

136

Exhibit 5-1 (continued)

Blood Cholinesterases

To review, there are two forms of ChE in the

blood: BuChE, which is found in plasma or serum,

and RBC-ChE, which is associated with erythrocytes. Neither enzyme is identical to the tissue enzyme with the corresponding substrate specificity

(butyrylcholine and ACh, respectively). However,

because blood can be withdrawn, the activities of

each of these enzymes can be assayed by standard,

relatively simple laboratory techniques, whereas

tissue enzyme is unavailable for assay. The measurements obtained from the blood assay can be

used as an approximation of tissue enzyme activity in the event of a known or possible exposure of

an animal, such as man, to an AChE inhibitor.

Persons who are occupationally exposed to ChEinhibiting substances are periodically monitored for

asymptomatic exposure by assays of blood-ChE

activity. Those at risk include crop sprayers and

orchard workers who handle ChE-inhibiting insecticides, and chemical agent–depot workers or

laboratory scientists who handle nerve agents. To be

meaningful, such monitoring must include knowledge of physiological variation in the blood enzymes.

Individuals who work with or around nerve

agents, such as laboratory investigators and depot

or storage-yard personnel, have their RBC-ChE activity monitored periodically. Before the individuals begin work, two measures of RBC-ChE, drawn

within 14 days but not within 24 hours of each other,

are averaged as a “baseline.” At periodic intervals,

the frequency of which depends on the individuals’ jobs, blood is drawn for measuring cholinesterase activity (for further discussion, see Chapter

17, Healthcare and the Chemical Surety Mission).

If the activity is 75% or more of their baseline, no

action is taken. If the activity is below 75% of their

baseline, they are considered to have had an asymptomatic exposure and they are withdrawn from

work. Investigations are undertaken to find how

they were exposed. Although asymptomatic, they

are not permitted to return to a work area around

nerve agents until their RBC-ChE activity is higher

than 80% of their baseline activity.19 If an individual

has symptoms from a possible nerve agent exposure or if an accident is known to have occurred in

his area, his RBC-ChE activity is immediately measured and the criteria noted above, as well as signs

and symptoms, are used for exclusion from and reQuoted with permission from Sidell FR. Soman and sarin: Clinical manifestations and treatment of accidental poisoning by

organophosphates. Clin Toxicol. 1974;7(1):6–8.

Exhibit 5-1 continued is not shown because the copyright permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the publisher named in the figure legend for permission to use

this illustration in any type of publication media.
Nerve Agents

137

turn to work. The values of 75% and 80% were selected for several reasons, including (a) the normal

variation of RBC-ChE in an individual with time

(discussed below), (b) laboratory reproducibility in

analysis of RBC-ChE activity, and (c) the lower tolerance to nerve agents with a low RBC-ChE as demonstrated in animals (discussed below). This topic

is also discussed in Chapter 14, Pesticides, in Occupational Health: The Soldier and the Industrial Base, another

volume in the Textbook of Military Medicine series.

Butyrocholinesterase

The enzyme BuChE is present in blood and

throughout tissue. Its physiological role in man is

unclear20; however, it may be important in canine

tracheal smooth muscle,21 the canine ventricular

conducting system,22 and rat atria.23

BuChE is synthesized in the liver and has a replacement time of about 50 days. Its activity is decreased in parenchymal liver disease, acute infections,

malnutrition, and chronic debilitating diseases, and

is increased in the nephrotic syndrome.20 This

enzyme has no known physiological function in

blood, but may assist in hydrolyzing certain choline esters.

Persons who have a prolonged paralysis caused

by succinylcholine, a muscle relaxant, usually are

found to have low BuChE activity.20 The structure

of BuChE is determined by two autosomal alleles.

The frequency of occurrence of the gene responsible

for abnormal ChE is about 1 in 2,000 to 1 in 4,000

people. Thus, about 96% of the population have the

usual phenotype, close to 4% have the heterozygous

phenotype, and about 0.03% have the homozygous

abnormal phenotype.20 In addition to having low

BuChE activity, which results from this genetic abnormality, in the usual assay, persons with abnormal ChE have low dibucaine numbers (the enzyme

activity in an assay in which dibucaine is used as

the ChE substrate). The mean dibucaine number for

the normal phenotype is about 79%, that for the

heterozygote is 62%, and that for the homozygous

abnormal phenotype is 16%.24

The relationship of BuChE activity and succinylcholine can be somewhat different, however. One

author25 reports on an individual whose BuChE activity was 3-fold higher than normal. His dibucaine

number was normal, and he was found to be relatively resistant to succinylcholine. His sister and

daughter also had high BuChE activities. The author of this report suggests that this abnormality is

autosomal dominant and that it represents another

genetic abnormality of BuChE.

Erythrocyte Cholinesterase

RBC-ChE is synthesized with the erythrocyte,

which has an average life of 120 days. The activity

of this enzyme is decreased in certain diseases involving erythrocytes (such as pernicious anemia)

and is increased during periods of active reticulocytosis (such as recovery from pernicious anemia)

because reticulocytes have higher ChE activity than

do mature cells. No other disease states are known

to affect RBC-ChE activity,20 but one report26 describes three members of one family who had

decreased RBC-ChE activity, suggesting that differences in this enzyme are genetic.

The physiological role of the enzyme in (or on

the stroma of) the erythrocyte is unknown. Recovery of RBC-ChE activity after irreversible inhibition

takes place only with the synthesis of new erythrocytes, or at a rate of approximately 1% per day.

Variation in Cholinesterase Activities

Butyrocholinesterase. In longitudinal studies27,28

lasting 3 to 250 weeks, the coefficient of variation

(standard deviation divided by the mean) for an

individual’s BuChE activity ranged from 5% to

11.8% in men and women. Of the ranges (range is

defined as the difference between the highest and

lowest activities divided by the mean) for individuals in the study, the lowest was 24% and the highest was 50% over 1 year.28

BuChE activity does not vary with age in

women29,30 until the age of 60 years, when higher

BuChE activities are seen.30 BuChE activities in men

have been reported in some studies to increase with

age and in other studies to decrease with age.20 In

matched age groups, BuChE activity was higher in

men than in women,20,30 and higher in women not

taking oral contraceptives than in those taking

them.30–32

Erythrocyte Cholinesterase. RBC-ChE activity is

more stable than the activity of the BuChE.28,33,34 In

a study28 that lasted 1 year, the coefficients of variation were 2.1% to 3.5% in men and 3.1% to 4.1% in

women, with ranges of 7.9% to 11.4% in men and

12.0% to 15.9% in women. This variation was less

than that observed for the hematocrits of these individuals.

It is unclear whether age affects RBC-ChE activity. In one study,29 RBC-ChE activity was unchanged

with age, while in another,30 enzyme activity increased with age from the third to the sixth decades

in men, with a less marked increase through the fifth

decade in women.
Medical Aspects of Chemical and Biological Warfare

138

Inhibition of Blood Cholinesterases

Some ChE-inhibiting substances inhibit BuChE

preferentially, and some inhibit RBC-ChE preferentially. Large amounts of ChE inhibitors will completely inhibit both enzymes.

The blood enzymes appear to act as buffers for

the enzymes in the tissue. There is little inhibition

of tissue enzyme until much of the blood enzyme

is inhibited. The RBC-ChE appears to be more important than the plasma enzyme in this regard. In

two studies,35,36 a small dose of DFP in humans inhibited about 90% of the plasma enzyme activity

but only 15% to 20% of RBC-ChE activity. Symptoms correlated with depression of RBC-ChE, but

not with depression of BuChE (see the Central Nervous System and Behavior section below). In humans, some pesticides, such as parathion,37–39

systox,37 and malathion,20 also preferentially inhibit

the plasma enzyme, while others, such as dimefox39

and mevinphos,40 initially bind with the RBC enzyme. In animals, there appears to be a species difference, inasmuch as parathion preferentially inhibits RBC-ChE in rats and the plasma enzyme in

dogs.20

The nerve agent VX preferentially inhibits RBCChE; in two studies,41,42 a small amount caused a

70% or greater decrease in the activity of this enzyme, whereas the activity of BuChE was inhibited

by no more than 20%. Sarin also preferentially inhibits the RBC-ChE; 80% to 100% inhibition of RBCChE activity was observed in two studies,35,43 while

BuChE was inhibited by 30% to 50%. Therefore, estimation of the RBC-ChE activity provides a better

indicator of acute nerve agent exposure than does

estimation of the plasma enzyme activity.

When the blood enzymes have been irreversibly

inhibited, recovery of ChE activity depends on production of new plasma enzymes or production of

new erythrocytes. Hence, complete recovery of

BuChE activity that has been totally inhibited by

sarin will occur in about 50 days, and recovery of

the RBC-ChE, in 120 days (about 1% per day).44 In

humans, after inhibition by VX, the RBC-ChE activity seems to recover spontaneously at the rate of

about 0.5% to 1% per hour for a few days, but complete recovery depends on erythrocyte production.41,42

Time Course of Inhibition. After very large

amounts of nerve agent (multiple LD50s [ie, multiples of the dose that is lethal to 50% of the exposed

population]) are placed on the skin, signs and symptoms occur within minutes, and inhibition of blood

ChE activities occurs equally quickly. However,

with smaller amounts of agent, the onset is not so

rapid. In studies in which small amounts of VX were

applied on the skin of humans, the onset of symptoms and the maximal inhibition of blood ChE

activity were found to occur many hours after application of the agent. In one study42 in which equipotent amounts of VX were applied to the skin in

different regions, the time to maximal inhibition

was 5 hours for the head and neck, 7 hours for

the extremities, and 10 hours for the torso. In a

similar study,45 the average time from placing VX

on the skin to the onset of nausea and vomiting and

maximal drop of blood ChE activity was 10.8

hours.

In a third study,46 VX was applied to the cheek

or forearm at environmental temperatures ranging

from 0°F to 124°F, and 3 hours later the subjects were

decontaminated and taken to a recovery area (about

80°F). In all temperature groups, the RBC-ChE activity continued to decline after decontamination,

and maximal inhibition occurred at 5.6 hours after

exposure at 124°F, 8.5 hours after exposure at 68°F,

10.4 hours after exposure at 36°F, and 12.2 hours

after exposure at 0°F. At the two lowest temperatures, the rates of agent penetration and of decline

in RBC-ChE activity increased after the subjects

were taken from the cold environment and deconTABLE 5-1

RELATION OF EFFECTS OF NERVE AGENT

EXPOSURE TO ERYTHROCYTE

CHOLINESTERASE ACTIVITY

Table 5-1 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden Institute to grant permission to other

users and/or does not include usage in electronic media. The current user must apply to the publisher named

in the figure legend for permission to use this illustration in any type of publication media.

Adapted with permission from Sidell FR. Clinical considerations

in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare Agents. New York, NY: Academic Press; 1992: 163.
Nerve Agents

139

taminated. These results suggest that agent absorption through the skin is more rapid and complete

at higher temperatures, and that even after thorough decontamination, a considerable amount of

agent remains in the skin to be absorbed.

Inhalation of nerve agent vapor inhibits blood

ChE activity and produces signs and symptoms of

exposure more rapidly than does dermal contact.

Although there is no correlation between ChE activity and clinical effects after exposure to small

amounts of vapor, both clinical effects and ChE inhibition occur within minutes. In one study,41 both

the maximal inhibition of RBC-ChE activity and the

appearance of signs and symptoms occurred about

1 hour after intravenous administration of small

amounts of VX. After ingestion of VX, the interval

was 2 to 3 hours.

Relation to Signs and Symptoms. The local signs

and symptoms in the eye, nose, and airways caused

by small amounts of vapor are due to the direct effect of the vapor on the organ; no correlation between the severity of these effects and the blood

ChE activity seems to exist. These early experimental data47–49 indicating the lack of correlation were

supported by a retrospective analysis of 62 individuals seen at the Edgewood Arsenal Toxic Exposure Aid Station between 1948 and 1972. Although

all individuals had physical signs or definite symptoms (or both) of nerve agent vapor exposure, there

was no correlation between local effects from vapor exposure and RBC-ChE activity (Table 5-1).50

Minimal systemic effects, such as vomiting, occur in half the population when the RBC-ChE is

inhibited to 25% of its control activity.41,42 In a

study42 in which VX was placed on the skin, no

vomiting occurred in 30 subjects whose minimal

RBC-ChE activities were 40% of control or higher.

Vomiting occurred in 9 (43%) of 21 subjects whose

minimal RBC-ChE activities were 30% to 39% of

control, in 10 (71%) of 14 subjects whose minimal

enzyme activities were 20% to 29% of control, and

in 3 (60%) of 5 subjects whose minimal RBC-ChE

activities were 0% to 19% of control. In other instances, patients had an RBC-ChE activity of 0%

without the expected symptoms; this inhibition was

acutely induced (personal observation).

Table 5-2 categorizes data from 283 individuals

(data are from published sources41,42 and unpublished research) who received VX by various routes;

the numbers of subjects, the activity ranges of RBCChE, and the numbers and percentages of those who

vomited are shown. The degree of inhibition needed

to cause vomiting in these 283 people corresponds

to that found in experimental data from other

TABLE 5-2

RELATION OF CHOLINESTERASE ACTIVITY

TO VOMITING AFTER EXPOSURE TO VX

sources, which indicate that “to exert significant

actions in vivo, an anti-ChE must inhibit from 50%

to 90% of the enzyme present.”11(p446)

Nerve Agents

Molecular models of the nerve agents tabun,

sarin, soman, and VX are shown in Figure 5-3. Table

5-3 summarizes the chemical, physical, environmental and biological properties of these compounds.

Nerve agents differ from commonly used ChE

inhibitors primarily because they are more toxic (ie,

a smaller amount is needed to cause an effect on an

organism). For example, an in vitro study43 with

ChE from human erythrocytes, brain, and muscle

showed that sarin had about 10-fold more inhibitory activity than TEPP, 30-fold more than neostigmine, 100-fold more than DFP, and 1,000-fold more

than parathion.

The vapor or aerosol exposure (the product of

concentration [C] and time [t]) needed to cause

Adapted with permission from Sidell FR. Clinical considerations

in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare Agents. New York, NY: Academic Press; 1992: 163.

Table 5-2 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden Institute to grant permission to other

users and/or does not include usage in electronic media. The current user must apply to the publisher named

in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

140

Fig. 5-3. Molecular models of (a) tabun (GA), (b) sarin (GB), (c) soman (GD), and (d) VX. Molecular models: Courtesy of Offie E. Clark, US Army Medical Research Institute of Chemical Defense, Aberdeen, Md.

a b

c

d

N

C

C

C

C

C

C

C

C

S

C

C

C

O

O

P

C

C

C

C

C

C C

F

O

O

P

N

N

C

C

C

C

C

O

P

O

C

C

C

C

F

O

O

P
Nerve Agents

141

death in 50% of the exposed population is known

as the LCt50 (Exhibit 5-2); the estimated LCt50s for

humans for these four agents are as follows:

• for tabun vapor, 400 mg•min/m3,

• for sarin vapor, 100 mg•min/m3,

• for soman vapor, 50 mg•min/m3, and

• for VX vapor, 10 mg•min/m3.

TABLE 5-3

CHEMICAL, PHYSICAL, ENVIRONMENTAL, AND BIOLOGICAL PROPERTIES OF NERVE AGENTS

Properties Tabun (GA) Sarin (GB) Soman (GD) VX

Chemical and Physical

Boiling Point

Vapor Pressure

Density:

Vapor (compared to

air)

Liquid

Volatility

Appearance

Odor

Solubility:

In Water

In Other Solvents

Environmental and

Biological

Detectability:

Vapor

Liquid

Persistency:

In Soil

On Materiel

Decontamination of

Skin

Biologically Effective

Amount:

Vapor

Liquid

230°C

0.037 mm Hg at 20°C

5.6

1.08 g/mL at 25°C

610 mg/m3 at 25°C

Colorless to brown

liquid

Fairly fruity

9.8 g/100 g at 25°C

Soluble in most

organic solvents

M8A1, M256A1,

CAM, ICAD

M8, M9 paper

Half-life 1–1.5 d

Unknown

M258A1, diluted

hypochlorite, soap

and water, M291 kit

LCt50:

400 mg•min/m3

LD50 (skin):

1.0 g/70-kg man

158°C

2.1 mm Hg at 20°C

4.86

1.10 g/mL at 20°C

22,000 mg/m3 at 25°C

Colorless liquid

No odor

Miscible

Soluble in all solvents

M8A1, M256A1,

CAM, ICAD

M8, M9 paper

2–24 h at 5°C–25°C

Unknown

M258A1, diluted

hypochlorite, soap

and water, M291 kit

LCt50:

100 mg•min/m3

LD50 (skin):

1.7 g/70-kg man

198°C

0.40 mm Hg at 25°C

6.3

1.02 g/mL at 25°C

3,900 mg/m3 at 25°C

Colorless liquid

Fruity; oil of camphor

2.1 g/100 g at 20°C

Soluble in some solvents

M8A1, M256A1, CAM,

ICAD

M8, M9 paper

Relatively persistent

Unknown

M258A1, diluted

hypochlorite, soap and

water, M291 kit

LCt50:

50 mg•min/m3

LD50 (skin):

350 mg/70-kg man

CAM: chemical agent monitor; ICAD: individual chemical agent detector; LCt50: vapor or aerosol exposure necessary to cause

death in 50% of the population exposed; LD50: dose necessary to cause death in 50% of the population with skin exposure; M8A1:

chemical alarm system; M256A1: detection card; M258A1: self-decontamination kit; M291: decontamination kit; M8 and M9: chemical

detection papers

298°C

0.0007 mm Hg at 20°C

9.2

1.008 g/mL at 20°C

10.5 mg/m3 at 25°C

Colorless to strawcolored liquid

Odorless

Miscible < 9.4°C

Soluble in all solvents

M8A1, M256A1, CAM,

ICAD

M8, M9 paper

2–6 d

Persistent

M258A1, diluted

hypochlorite, soap

and water, M291 kit

LCt50:

10 mg•min/m3

LD50 (skin):

10 mg/70-kg man

In comparison, the estimated LCt50 for hydrogen

cyanide is 2,500 to 5,000 mg•min/m3.

The estimated percutaneous LD50s for the four

compounds are as follows:

• for tabun, 1,000 mg,

• for sarin, 1,700 mg,

• for soman, 350 mg, and
Medical Aspects of Chemical and Biological Warfare

142

EXHIBIT 5-2

DEFINITIONS OF Ct, LCt50, AND LD50

For comparative purposes, the terms Ct and LCt50 are often used to express the dose of a vapor or aerosol.

However, the terms do not describe inhaled doses; they actually describe the amount of compound to which

an organism is exposed.

• The term Ct is used to describe an estimate of dose. C represents the concentration of the substance (as

vapor or aerosol) in air (usually expressed as mg/m3) and t represents time (usually expressed in minutes).

• The Ct value is the product of the concentration (C) to which an organism is exposed multiplied by the time

(t) during which it remains exposed to that concentration. Ct does not express the amount retained within

an organism; thus, it is not an inhalational dose.

• Since Ct is a product of C • t, a particular value can be produced by inversely varying the values of C and

t. The Ct to produce a given biological effect is usually constant over an interval of minutes to several hours

(Haber’s Law). Thus, an effect that is produced by an exposure to 0.05 mg/m3 for 100 minutes is

also produced by an exposure to 5 mg/m3 for 1 minute (Ct = 5 mg•min/m3 in both cases). This generalization usually is not valid for very short or very long times, however. The organism may hold its breath for

several seconds and not actually inhale the vapor; over many hours, some detoxification may occur in the

organism.

• The term LCt50 is often used to denote the vapor or aerosol exposure (Ct) necessary to cause death in 50% of

the population exposed (L denotes lethal, and 50 denotes 50% of the population). In the same manner, the

term LD50 is used to denote the dose that is lethal for 50% of the population exposed by other routes of

administration.

• for VX, 6 to 10 mg.

VX has a much lower LD50 because it is much less

volatile and remains intact on the skin, whereas the

other nerve agents will evaporate unless covered

(eg, by clothing).6,8 Different sources provide different estimates for these LD50 and LCt50 values;

however, those noted above seem to be the most

commonly accepted.

The four nerve agents are liquid at moderate temperatures; thus, the term “nerve gas” is a misnomer. In their pure state, they are clear, colorless, and,

at least in dilute solutions of distilled water, tasteless. Tabun has been reported to have a faint,

slightly fruity odor, and soman, to have an ill-defined odor; sarin and VX are apparently odorless.

The G agents are volatile; VX has very low volatility. Sarin, the most volatile, is somewhat less volatile than water; tabun and soman are less volatile

than sarin. The G agents present a definite vapor

hazard; VX is much less likely to unless the ambient temperature is high.

EXPOSURE ROUTES

Inhalational Exposure to Vapor

The effects produced by nerve agent vapor begin in seconds to minutes after the onset of exposure, depending on the concentration of vapor.

These effects usually reach maximal severity within

minutes after the individual is removed from or

protected from the vapor or may continue to worsen

if the exposure continues. There is no delay in onset as there is after liquid exposure.

At low Cts, the eyes, nose, airways, or a combination of these organs are usually affected. The eyes

and nose are the most sensitive organs; the eyes may

be affected equally or unequally. There may be some

degree of miosis (with or without associated conjunctival injection and pain) with or without rhinorrhea, or there may be rhinorrhea without eye involvement (Table 5-4).

As exposure increases slightly, the triad of ey e,

nose, and lung involvement is usually seen. The

casualty may or may not notice dim vision and may

complain of “tightness in the chest.” “Tightness in

the chest” may occur in the absence of physical findings. At higher exposures, the effects in these organs intensify. Marked miosis, copious secretions

from the nose and mouth, and signs of moderateto-severe impairment of ventilation are seen. The

casualty will complain of mild-to-severe dyspnea,
Nerve Agents

143

TABLE 5-5

EFFECTS OF DERMAL EXPOSURE TO LIQUID NERVE AGENTS

TABLE 5-4

EFFECTS OF EXPOSURE TO NERVE AGENT VAPOR

may be gasping for air, and will have obvious secretions.

In severe exposures, the casualty may not have

time to report the initial effects before losing consciousness, and may not remember them on awakening. One severely exposed individual later recalled that he noticed an increase in secretions and

difficulty in breathing, and another said he felt

giddy and faint before losing consciousness. In both

instances, the casualties were unconscious within

Adapted with permission from Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare

Agents. New York, NY: Academic Press; 1992: 173.

Adapted with permission from Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare

Agents. New York, NY: Academic Press; 1992: 175.

Table 5-4 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the

Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current

user must apply to the publisher named in the figure legend for permission to use this illustration in any type of

publication media.

Table 5-5 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the

Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current

user must apply to the publisher named in the figure legend for permission to use this illustration in any type of

publication media.
Medical Aspects of Chemical and Biological Warfare

144

less than a minute after exposure to agent vapor.

When reached (within minutes) by rescuers, both

were unconscious and exhibited convulsive jerking

motions of the limbs; copious secretions from the

mouth and nose; very labored, irregular, and gasping breathing; generalized muscular fasciculations;

and miosis. One developed flaccid paralysis and

apnea a minute or two later. The other received

immediate, vigorous treatment, and his condition

did not progress (personal observation).

Dermal Exposure to Liquid

The early effects of a drop of nerve agent on the

skin and the time of onset of these effects depend

on the amount of nerve agent and several other factors, such as the site on the body, the temperature,

and the humidity. After a delay during which the

individual is asymptomatic, localized sweating occurs at the site of the droplet; less commonly, there

are localized fasciculations of the underlying

muscle (Table 5-5). Unless the amount of the nerve

agent is in the lethal range, the next effects (or

perhaps the first effects, if the sweating and fasciculations do not occur or are not noticed) are gastrointestinal: nausea, vomiting, diarrhea, or a combination of these symptoms. The casualty may

notice generalized sweating and complain of tiredness or otherwise feeling ill. There may be a period

of many hours between exposure and the appearance of symptoms and signs. These signs and symptoms might occur even if the casualty has been decontaminated.46

After large exposures, the time to onset of effects

may be much shorter than for smaller exposures and

decreases as the amount of agent increases. For instance, two individuals were decontaminated

within minutes of exposure to a drop of nerve agent.

There was a 15- to 20-minute, asymptomatic interval before the precipitant onset of effects: collapse,

loss of consciousness, convulsive muscular jerks,

fasciculations, respiratory embarrassment, and copious secretions. Within several minutes, flaccid paralysis and apnea occurred in both (personal observation).

EFFECTS ON ORGANS AND ORGAN SYSTEMS

Most of the information on the effects of nerve

agents on organ systems in humans is derived from

studies done in the post–World War II period, from

reports of people exposed to pesticides, or from

clinical evaluations of accidental exposures of

people who worked in nerve agent–research laboratories, manufacturing facilities, or storage areas

or depots (Table 5-6). Some organ systems have been

studied more intensively than others; for some organ systems there are few human data. For example,

for the musculoskeletal system, there is a plethora

of data from animal studies and studies in isolated

neuromuscular preparations, but study results are

difficult to apply to a human clinical situation.

The Eye

Nerve agents in the eye may cause miosis, conjunctival injection, pain in or around the eye, and

dim or blurred vision (or both). Reflex nausea and

vomiting may accompany eye exposure. These effects are usually local, occurring when the eye is in

direct contact with nerve agent vapor, aerosol, or

liquid, but exposure by other routes (such as on the

skin) can also affect the eyes. Because eyes often

react late in the course of intoxication in the latter

case (exposure on the skin), they cannot be relied

on as an early indication of exposure.

Systemic (such as skin or peroral) exposure to a

nerve agent might be large enough to produce moderate symptoms (nausea, vomiting) without miosis. In studies41,42,45 in which VX was placed on the

skin, administered intravenously, or given orally, a

significant number of subjects experienced nausea,

vomiting, sweating, or weakness, but none had

miosis. In 47 patients with parathion poisoning, all

of the 14 severe cases had miosis, whereas 6 of 11

patients with moderate poisoning and only 5 of 22

patients with mild effects had miosis.51 On the other

hand, a vapor or aerosol exposure might cause miosis without other signs or symptoms and an exposure in one eye will cause miosis in that eye (a local

effect because of a mask leak in one eyepiece or

similar causes) without affecting the other eye.

If the eye exposure is not associated with inhalation of the nerve agent, there is no good correlation

between severity of the miosis and inhibition of

RBC-ChE activity. The latter may be relatively normal or may be inhibited by as much as 100% (see

Table 5-1), so the severity of the miosis cannot be

used as an index of the amount of systemic absorption of agent or amount of exposure. On the other

hand, an early study52 demonstrated a relationship

between the Ct of sarin and pupil size at the time

of maximal miosis, and the investigator suggested

that the pupil size might be used as an index of the

amount of exposure.

Unilateral miosis is sometimes seen in workers

handling nerve agents or insecticides and usually

occurs because of a small leak in the eyepiece of
Nerve Agents

145

TABLE 5-6

EFFECTS OF NERVE AGENTS IN HUMANS

the protective mask. Again, the RBC-ChE may or

may not be inhibited (see Table 5-1). The unilateral

miosis has no prognostic medical significance.

However, there may be problems with judging distances (that is, depth perception). This impairment

may cause difficulty in activities such as driving a

car or piloting an airplane, which require stereovisual coordination (the Pulfrich stereo effect).20

The onset of miosis may be within seconds to

minutes of the start of exposure; if the concentration of agent vapor or aerosol is quite low, maximal miosis may not occur until an hour or longer

following exposure. The duration varies according to

the amount of agent. The pupils may regain their ability to react to normal levels of indoor lighting within

several days after exposure, but their ability to dilate

maximally in total darkness may not return for as long

as 9 weeks (Figure 5-4 and Exhibit 5-3).18,53

The effects of nerve agents on vision have been

studied for decades. Characteristically, an unprotected individual exposed to nerve agent will have

the signs discussed above and may complain of dim

vision, blurred vision, or both.

Light Reduction

Dim vision is generally believed to be related to

the decrease in the amount of light reaching the

retina because of miosis. In a study54 in which miosis was induced in one eye by instillation of sarin,

the decrease in visual sensitivity correlated with the

reduction in the area of pupillary aperture. Fiftythree subjects accidentally exposed to G agents reported improvements in dim vision before the

miosis improved, which suggests that factors

other than a small pupil are responsible for the high

light threshold.55 In another study,56 however,

no change in visual threshold was measured after

miosis was induced by instillation of sarin onto the

eye; the light threshold increased after systemic

administration of sarin vapor with the eyes protected, so that no miosis occurred. The threshold

was reduced to normal following systemic administration of atropine sulfate (which enters the CNS),

but not after administration of atropine methylnitrate (which does not enter the CNS).57 The authors suggested that the dimness of vision was due

Adapted with permission from Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare

Agents. New York: Academic Press; 1992: 162.

Table 5-6 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the

Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current

user must apply to the publisher named in the figure legend for permission to use this illustration in any type of

publication media.
Medical Aspects of Chemical and Biological Warfare

146

to neural mechanisms in the retina or elsewhere in

the CNS.

Although the dim vision reported by persons

exposed to nerve agent vapor is generally ascribed

to miosis, the above accounts suggest that morecentral neural mechanisms may have equal or

greater importance. In the case of the carbamate

physostigmine, an increase in light sensitivity (a

decreased threshold) after intramuscular administration of the drug has been reported.58 However,

carbamates may differ from nerve agents in their

effects on vision.

Regardless of its cause, reduction in visual sensitivity impairs those who depend on vision in dim

light: individuals who watch a tracking screen,

monitor visual displays from a computer, or drive

a tank in the evening or at night. As a practical

matter, anyone whose vision has been affected by

Fig. 5-4. This man was accidentally

exposed to an unknown amount of

nerve agent vapor. The series of photographs shows his eyes gradually recovering their ability to dilate. All

photographs were taken with an electronic flash (which is too fast for the

pupil to react) after the subject had

been sitting in a totally dark room for

2 minutes. These photographs were

taken (from top to bottom) at 3, 6, 13,

20, 41, and 62 days after the exposure.

Subsequent photographs indicate

that the eyes did not respond fully to

darkness for 9 weeks; maximal dilation was reached on day 62 after the

exposure. Reprinted with permission

from Sidell FR. Soman and sarin:

Clinical manifestations and treatment

of accidental poisoning by organophosphates. Clin Toxicol. 1974;7:11.

exposure to a nerve agent should not be allowed to

drive in dim light or in darkness.

Visual Acuity

Persons exposed to nerve agents sometimes complain of blurred as well as dim vision. In one study,59

visual acuity was examined in six subjects before

and after exposure to sarin vapor at a Ct of 15

mg•min/m3. Near visual acuity was not changed

in any of the six after exposure and was worsened

after an anticholinergic drug (cyclopentolate) was

instilled in the eyes. Far visual acuity was unchanged after sarin exposure in five of the six subjects and was improved in the sixth, who nonetheless

complained that distant vision was blurred after sarin.

Two presbyopic workers who were accidentally

exposed to sarin had improved visual acuity for days

Figure 5-4 is not shown because the copyright permission granted to

the Borden Institute, TMM, does not allow the Borden Institute to grant

permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure

legend for permission to use this illustration in any type of publication

media.
Nerve Agents

147

EXHIBIT 5-3

CASE REPORT: EXPOSURE OF THREE MEN TO SARIN

after exposure. As the effects of the agent decreased,

their vision returned to its previous state; in each case,

this took about 35 days.53 The author suggested, as

others have previously, that miosis accounted for the

improvement in visual acuity (the pinhole effect).

Eye Pain

Eye pain may accompany miosis, but the reported incidence varies. A sharp pain in the eyeball or an aching pain in or around the eyeball is

common. A mild or even severe headache (unilateral if the miosis is unilateral) may occur in the frontal area or throughout the head. This pain is probably caused by ciliary spasm and is worsened by

looking at bright light, such as the light from a

match a person uses to light a cigarette (the “match

test”). Sometimes this discomfort is accompanied

by nausea, vomiting, and malaise.

Local instillation of an anticholinergic drug such

as atropine or homatropine usually brings relief

from the pain and systemic effects (including the

nausea and vomiting), but because these drugs

cause blurring of vision, they should not be used

unless the pain is severe.59

The Nose

Rhinorrhea is common after both local and systemic nerve agent exposure. It may occur soon after exposure to a small amount of vapor and sometimes precedes miosis and dim vision, or it may

occur in the absence of miosis. Even a relatively

small exposure to vapor may cause severe rhinorrhea. One exposed worker compared the nasal secretions to the flow from a leaking faucet, and another said that they were much worse than those

produced by a cold or hay fever (personal observation).

Rhinorrhea also occurs as part of an overall,

marked increase in secretions from glands (salivary,

pulmonary, and gastrointestinal) that follows a severe systemic exposure from liquid on the skin

and, under this circumstance, becomes a secondary concern to both the casualty and the medical

care provider.

Pulmonary System

After exposure to a small amount of nerve agent

vapor, individuals often complain of a tight chest

Quoted with permission from Sidell FR. Soman and sarin: Clinical manifestations and treatment of accidental poisoning by

organophosphates. Clin Toxicol. 1974;7(1):9.

Exhibit 5-3 is not shown because the copyright permission granted to the Borden Institute, TMM, does not

allow the Borden Institute to grant permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure legend for permission to use this

illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

148

(difficulty in breathing), which is generally attributed to spasm or constriction of the bronchiolar

musculature. Secretions from the goblet and other

secretory cells of the bronchi also contribute to the

dyspnea. Exposure to sarin at a Ct of 5 to 10

mg•min/m3 will produce some respiratory discomfort in most individuals, with the discomfort and

severity increasing as the amount of agent increases.

Several decades ago, investigators attempted to

characterize pulmonary impairment caused by exposure to nerve agents by performing pulmonary

function studies (such as measurements of vital capacity and maximal breathing capacity) on subjects

exposed to small amounts of sarin vapor (the Ct

values for sarin ranged up to 19.6 mg•min/m3).60

Some observers found increases in airway resistance61 and other changes, while other researchers

did not.62

Although these studies yielded conflicting results, clinical practitioners have found that the inhalation of nerve agent vapor or aerosol causes

dyspnea and pulmonary changes that usually are

audible on auscultation. These changes are noticeable after low Ct exposures (5–10 mg•min/m3) and

intensify as the Ct increases. The pulmonary effects

begin within seconds after inhalation. If the amount

inhaled is large, the effects of the agent include severe dyspnea and observable signs of difficulty with

air exchange, including cyanosis.

If the amount of the inhaled agent is small, a casualty may begin to feel better within minutes after moving into an uncontaminated atmosphere,

and may feel normal in 15 to 30 minutes. It was not

uncommon, for example, for individuals who had

not received atropine or other assistance to arrive

at the Edgewood Arsenal Toxic Exposure Aid Station about 15 to 20 minutes after exposure and report that their initial, severe trouble in breathing

had already decreased markedly (personal observation). If the exposure was larger, however, relief

was likely to come only after therapeutic intervention, such as administration of atropine.

Attempts to aid ventilation in severely poisoned

casualties can be greatly impeded by constriction

of the bronchiolar musculature and by secretions.

One report63 mentions thick mucoid plugs that hampered attempts at assisted ventilation until the

plugs were removed by suction. Atropine may contribute to the formation of this thicker mucus because it dries out the thinner secretions.

A severely poisoned casualty becomes totally

apneic and will die as a result of ventilatory failure, which precedes collapse of the circulatory system. Many factors contribute to respiratory failure,

including obstruction of air passages by bronchoconstriction and secretions; weakness followed by

flaccid paralysis of the intercostal and diaphragmatic musculature, which is needed for ventilation;

and a partial or total cessation of stimulation to the

muscles of respiration from the CNS, indicating a

defect in central respiratory drive.

Older data on the relative contributions of each

of these factors in causing death were summarized

in a report64 describing original studies in nine species. The authors concluded that central respiratory

failure appeared to dominate in most species, but

its overall importance varied with the species, the

agent, and the amount of agent. For example, under the circumstances of the studies, failure of the

central respiratory drive appeared to be the major

factor in respiratory failure in the monkey, whereas

bronchoconstriction appeared early and was severe

in the cat. The authors of another report65 suggest

that the presence of anesthesia, which is used in

studies of nerve agent intoxication in animals, and

its type and depth are also factors in establishing

the relative importance of central and peripheral

mechanisms.

In another study,66 bronchoconstriction seen in

the dog after intravenous sarin administration was

quite severe compared with that found in the monkey (however, the dog is known to have thick airway musculature). Differences in circulatory and

respiratory effects were seen between anesthetized

and unanesthetized dogs given sarin.67 Convulsions

and their associated damage were not seen in the

anesthetized animals. In this study, there were no

significant differences in the cardiovascular and

respiratory effects when the agent was given intravenously, percutaneously, or by inhalation. In a

study68 of rabbits poisoned with sarin, bronchoconstriction appeared to be a minor factor, while neuromuscular block (particularly at the diaphragm)

and central failure were the primary factors in respiratory failure.

In a recent review69 describing studies in anesthetized cats given tabun, sarin, soman, or VX, the

loss of central respiratory drive was found to be the

predominant cause of respiratory failure with each

of the agents, and the contribution of bronchoconstriction was apparently insignificant (in contrast

to the severe bronchoconstriction noted in the earlier study64). Thus, respiratory failure was the predominant cause of death in the species studied inasmuch as significant cardiovascular depression

occurred only after cessation of respiration.68,69
Nerve Agents

149

When atropine was administered in adequate

amounts before the failure of circulation, it reversed

the central depression and bronchoconstriction but not

the neuromuscular block, a finding that might be expected, because the neuromuscular effects of poisoning with these nerve agents occur at a nicotinic site.64,68

In a recent study,70 pyridostigmine, a drug currently fielded as a pretreatment, was administered

to primates, which then were exposed to a nerve

agent and given the standard therapeutic drugs,

atropine and 2-pyridine aldoxime methyl chloride

(2-PAM Cl, also called 2-pralidoxime chloride; pyridine-2-aldoxime methyl chloride; 2-formyl-1-

methylpyridinium chloride; Protopam chloride,

manufactured by Wyeth-Ayerst Laboratories, Philadelphia, Pa; see section below on oximes). Pyridostigmine does not appear to enter the CNS because

it is a quaternary compound and thus would not

be expected to protect central sites of respiratory

stimulation against the effects of a nerve agent. The

pretreated animals continued to breathe, however,

in contrast to controls that did not receive pyridostigmine pretreatment but were otherwise treated

in the same manner.

The results of this study suggest that pyridostigmine protects against the cessation of respiration.

Since pyridostigmine appears not to enter the

CNS, this suggests that peripheral mechanisms

of breathing (skeletal muscles and airways) must

predominate in sustaining breathing. Alternatively,

the blood–brain barrier may change in the presence

of a nerve agent (as with other types of poisoning

or hypoxia) to allow the penetration of drugs it

otherwise excludes. For example, when 2-PAM Cl,

which is also a quaternary compound, is administered to animals poisoned with a ChE inhibitor,

it can be found in their CNS, but it is not found in

the brains of normal animals after they receive

2-PAM Cl.71

Skeletal Musculature

The neuromuscular effects of nerve agents have

been the subject of hundreds of studies since nerve

agents were first synthesized in 1936. Much of our

information on the mechanism of action of nerve

agents and potential therapeutic measures has come

from these studies. Because this chapter is primarily concerned with clinical effects of nerve agent

poisoning, a comprehensive review of these studies is not presented here.

The effects of nerve agent intoxication on skeletal muscle are caused initially by stimulation of

muscle fibers, then by stimulation of muscles and

muscle groups, and later by fatigue and paralysis of

these units. These effects on muscle may be described

as fasciculations, twitches (or jerks), and fatigue.

Fasciculations are the visible contractions of a

small number of fibers innervated by a single motor nerve filament. They appear as ripples under

the skin. They can occur as a local effect at the site

of a droplet of agent on the skin before enough agent

is absorbed to cause systemic effects. They also can

appear simultaneously in many muscle groups after a large systemic exposure. A casualty who has

sustained a severe exposure will have generalized

fasciculations, a characteristic sign of poisoning by

a ChE inhibitor; typically, fasciculations will continue long after the patient has regained consciousness and has voluntary muscle activity.

After a severe exposure, there are intense and

sudden contractions of large muscle groups, which

cause the limbs to flail about or momentarily become rigid or the torso to arch rigidly in hyperextension. Whether these movements, which have

been described as convulsive jerks, are part of a

generalized seizure or originate lower in the nervous system is unclear. Occasionally, these disturbances may be a local effect on the muscle groups

below or near the site of exposure—for instance, the

marked trismus and nuchal rigidity in an individual

who pipetted soman into his mouth (Exhibit 5-4).18

After several minutes of hyperactivity (fasciculations or twitching), the muscles fatigue and flaccid

paralysis occurs. This, of course, stops convulsive

activity and respiration.

Central Nervous System and Behavior

Behavioral and psychological changes in humans

exposed to ChE-inhibiting substances have been

discussed in numerous reports. The incidence of

psychological effects is higher in individuals who

have had more severe exposures to nerve agents,

but they may occur—probably more frequently than

is commonly recognized—in individuals who have

received a small exposure and have no or minimal

physical signs or symptoms. Although the effects

may begin as late as 1 day after exposure, they usually start within a few hours and last from several

days to several weeks. Common complaints include

feelings of uneasiness, tenseness, and fatigue. Exposed individuals may be forgetful, and observers

may note that they are irritable, do not answer

simple questions as quickly and precisely as usual,

and generally display impaired judgment, poor
Medical Aspects of Chemical and Biological Warfare

150

EXHIBIT 5-4

CASE REPORT: ACCIDENTAL EXPOSURE OF A MAN TO LIQUID SOMAN

Exhibit 5-4 is not shown because the copyright permission granted to the Borden Institute, TMM, does not

allow the Borden Institute to grant permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure legend for permission to use this

illustration in any type of publication media.
Nerve Agents

151

Exhibit 5-4 (continued)

Quoted with permission from Sidell FR. Soman and sarin: Clinical manifestations and treatment of accidental poisoning by

organophosphates. Clin Toxicol. 1974;7(1):2–6.

Exhibit 5-4 continued is not shown because the copyright permission granted to the Borden Institute,

TMM, does not allow the Borden Institute to grant permission to other users and/or does not include usage

in electronic media. The current user must apply to the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

152

comprehension, decreased ability to communicate,

or occasional mild confusion. Gross mental aberrations, such as complete disorientation or hallucinations, are not part of the symptom complex.

Studies of Behavioral and Psychological Changes

In one of the earliest studies of the effects of ChEinhibiting substances,36 behavioral and psychological changes were reported in 49 of 60 subjects (of

whom 50 were normal and 10 had myasthenia

gravis) after daily intramuscular doses (1.5–3.0 mg)

of DFP. Changes were reported about 1 hour after

dose administration. The most prominent CNS effects reported were excessive dreaming (33 subjects); insomnia (29 subjects); and jitteriness, restlessness, increased tension, emotional lability, and

tremulousness (29 subjects). The authors noted,

without comment, that one subject reported visual

hallucinations. Hallucinations are not mentioned

elsewhere as an effect of ChE inhibitors. Later, similar effects were reported as sequelae of accidental

exposure to nerve agent poisoning.72

One report63 suggests that several workers accidentally exposed to sarin had some behavioral effects. Another report73 lists “weakness” (actually

tiredness), nervousness, and drowsiness as complaints from 16 of 40 workers accidentally exposed

to small amounts of nerve agent vapor.

In a series55 of 49 workers who were accidentally

exposed to sarin or tabun (a total of 53 exposures),

13 workers reported sleep disturbances, 12 reported

mood changes, and 10 reported easy fatigability.

Overall, 51% had CNS effects. The authors pointed

out that the complex of CNS symptoms may not

fully develop until 24 hours after exposure. The data

on blood ChE activities (both RBC-ChE and BuChE)

in these workers were scanty. The individual with

the greatest ChE inhibition, however, had an RBCChE activity of 33% of his personal control value,

which suggests that the exposures were not severe.

No correlation between the presence or severity of

symptoms and the degree of ChE inhibition was

seen, and most of the effects of exposure disappeared within 3 days. Systemic atropine was not

given to any of these individuals, which suggests

that therapy is unnecessary if a paucity of physical

signs exists. The authors concluded that mild intoxication by nerve agents may cause psychological disturbances and that these disturbances might

have serious consequences to the individuals and

to those dependent on their judgment.55

In a series74 of 72 workers exposed to sarin, 2 reported difficulty in concentration, 5 reported mental confusion, 5 reported giddiness, and 4 reported

insomnia. All but 2 of these individuals were considered to have been exposed to a small amount of

sarin; these 2 were given 2 mg of atropine intramuscularly, and 12 others received atropine orally (0.4–

0.8 mg). RBC-ChE ranged from less than 9% to more

than 100% of the individual’s control activity.

Behavioral changes and whole-blood ChE activities were reported in another study75 in which VX

was placed on the skin of volunteers. Since VX preferentially inhibits RBC-ChE and has relatively little

effect on BuChE, the decreases in whole-blood ChE

activities were assumed to indicate mainly inhibition of RBC-ChE. In subjects with whole-blood ChE

activities of 10% to 40% of control (RBC-ChE activities < 20% of control), 30% reported anxiety, 57%

had psychomotor depression, 57% had intellectual

impairment, and 38% had unusual dreams. Of those

with whole-blood ChE activities of 41% to 80% of

control (RBC-ChE activities of 20%–40% of control),

8% reported anxiety, 4% had psy chomotor depression, 4% had intellectual depression, and 33% had

unusual dreams. Nausea and vomiting were the

other symptoms noted. Some subjects had both psychological and gastrointestinal effects, with onsets

often separated by several hours. Some subjects had

symptoms related to only one organ system.

Overall, the onset of signs and symptoms occurred 3.5 to 18 hours after percutaneous exposure,

and maximal depression in blood ChE occurred 3

to 8 hours after exposure. However, no measurements were taken between 8 and 24 hours, and the

maximal inhibition might have been in this period.

(It is not often recognized that there may be a long

delay between exposure on the skin and onset of

signs or symptoms.) The authors stressed that psychological impairment might occur before the onset of other signs or symptoms or might occur in

their absence.75

Although the frequency, onset, and duration of

each reaction were not noted, some of the behavioral effects reported in the VX subjects were fatigue, jitteriness or tenseness, inability to read with

comprehension, difficulties with thinking and expression, forgetfulness, inability to maintain a

thought trend, a feeling of being mentally slowed,

depression, irritability, listlessness, poor performance on serial 7s and other simple arithmetic tests,

minor difficulties in orientation, and frightening

dreams. Illogical or inappropriate trends in language and thinking were not noted, nor was there

evidence of conceptual looseness. The investigators

found no evidence of perceptual distortion resulting in delusions or hallucinations.
Nerve Agents

153

A severe, accidental exposure to soman caused

one person to become depressed, withdrawn, and

subdued, have antisocial thoughts, and sleep restlessly with bad dreams for several days immediately after the exposure (see Exhibit 5-4).18 He received oral doses of scopolamine hydrobromide on

3 of the following 6 days and was given scopolamine methylbromide, which does not enter the

CNS, on the other days to mimic the peripheral effects of the hydrobromide salt, such as dry mouth.

On the hydrobromide days, the subject was more

spontaneous and alert, less depressed, and slept

better; his performance on a simple arithmetic test

also improved. Because scopolamine hydrobromide

is more effective in the CNS than the methylbromide

salt of scopolamine or atropine, it seemed likely that

the drug reversed the CNS effects, at least temporarily. The subject’s performance on standard psy -

chological tests 16 days after exposure was below

that expected for one of his intellectual capabilities,

but it improved to his expected level of functioning when he was tested 4 months later and again at

6 months later when he was discharged from further care. The author suggested that the use of scopolamine hydrobromide deserves further evaluation in patients who have these lingering effects

while recovering from nerve agent poisoning.

Changes in the ability to perform certain laboratory or field tests after exposure to sarin have been

reported. Generally, at the exposures used (Cts of

4–14.7 mg•min/m3), there was some impairment

on tasks requiring vision, hand–eye coordination,

dexterity, response time, comprehension, and judgment.76,77 No decrements were found on physical

tasks78 (at a Ct of 14.7 mg•min/m3). On a military

field exercise,79 most tasks were performed satisfactorily, if suboptimally, in the day light. Nighttime

performance, however, was difficult, if not downright hazardous.

Electroencephalographic Effects

Information is scanty on the electroencephalographic (EEG) effects in humans who have been

severely poisoned by ChE-inhibiting substances. In

an early study,80 DFP, administered intramuscularly

daily, caused EEG changes in 19 of 23 subjects (19

normal, 4 with myasthenia gravis). The changes were

• greater-than-normal variations in potential;

• increased frequency, with increased beta

rhythm; and

• more irregularities in rhythm and the intermittent appearance of abnormal waves

(high-voltage, slow waves; these were most

prominent in the frontal leads).

These changes usually followed the onset of CNS

symptoms, they could be correlated with decreases

of RBC-ChE activity (but not with BuChE decreases), and they were decreased or reversed by

atropine 1.2 mg, administered intravenously.

In another study,81 the EEG of a subject who was

severely intoxicated with sarin was recorded after

the loss of consciousness but before the onset of

convulsions. The recording showed marked slowing of activity, with bursts of high-voltage,

5-Hz waves in the temporofrontal leads. These

waves persisted for 6 days despite atropine administration.

In one study43 in which subjects were exposed

to smaller amounts of sarin, the EEG changes

coincided with severity of symptoms. With mild

symptoms, there was a slight diminution of voltage. Irregularities in rhythm, variation in potential,

and intermittent bursts of abnormal waves (slow,

elevated-voltage waves) occurred with moderate

symptoms. These changes persisted for 4 to 8 days

after the disappearance of symptoms and decreased

somewhat (decreases in voltage, in irregular frequency and potential, and in slow waves) after administration of atropine 1 mg, administered intravenously.

Long-Term Effects

Long-term effects on the human CNS after poisoning with nerve agents or organophosphate insecticides have been reported.18,82,83 These reports are

based on clinical observations, which occasionally

are supported by psychological studies. In general,

the behavioral effects have not been permanent but

have lasted weeks to several months, or possibly

several years.84

Necropsy findings from animal studies suggest

that there are long-lasting or permanent CNS effects

after exposures to lethal or near-lethal amounts of

nerve agents. In one study,85 264 rats were given

approximately 1 LD50 of soman. Some animals died

shortly after agent administration; others were sacrificed at intervals up to 39 days. In those surviving for 39 days, no neurological sequelae were reported. On microscopic examination of the brains

of the deceased animals, neuronal changes similar

to those seen after hypoxic encephalopathy were

found in some animals, but only in those that had

exhibited respiratory distress and repeated or prolonged convulsions.
Medical Aspects of Chemical and Biological Warfare

154

In another study86 with a similar protocol, brains

of rats were examined 15 to 28 days after the animals were given a single dose of soman. Lesions

were seen in all of the animals that had convulsions,

in three of four that had tremors but not convulsions, and in none of the others. The author concluded that the convulsions were not necessary for

the lesions to occur.86

The neuronal degeneration and necrosis seen in

the brains of soman-poisoned rats in another study87

suggested a “hypoxic pattern” or the type of lesion

seen after status epilepticus. The lesions were seen

only in animals that survived prolonged convulsions, and the authors surmised that the brain damage was seizure mediated.

Although most studies have been with soman,

similar damage has been reported after exposure

to sarin.88 Also, in one elegant study,89 VX was microinjected into specific brain regions. The investigators concluded that neuropathology was not due

to a direct neurotoxic effect of the agents on brain

neurons, that systemic hypoxia is probably not a

mechanism for their toxicity, and that the brain

damage produced by nerve agents is probably seizure mediated.

In addition to having morphologically detectable

brain lesions, animals surviving severe soman intoxication have been shown to have decrements in

performance, as measured on a variety of behavioral tests.90–92 These decrements lasted for about 4

months, when the last survivors were sacrificed.

There is conflicting evidence regarding the possible role of hypoxia as an etiologic factor in brain

damage following seizure activity—whether this

activity is caused by nerve agents or other factors.

Rats given bicuculline convulsed for 2 hours under

controlled conditions. Those given a lower percentage of oxygen in their inspired air to keep the

partial pressure of arterial oxygen (PaO2) close to

50 mm Hg did not have brain lesions, whereas those

with normal air intake and PaO2 higher than 128

mm Hg developed brain lesions.93 Although this

evidence does not eliminate the possibility of localized hypoxic areas in the brain as a factor in nerve

agent-induced damage, it does suggest that systemic hypoxia is not a factor. On the other hand, a

similar study94 (hypoxic rats with bicuculline-induced convulsions that lasted 2 h) suggested that

there were slightly more brain lesions in the hypoxic

animals than in normoxic animals.

In studies in which cynomolgus86 or rhesus95

monkeys were given nearly lethal amounts of

soman, the animals that convulsed were later found

to have morphologically detectable brain damage.

Monkeys that were pretreated with pyridostigmine,

given soman, and treated with atropine and 2-PAM

Cl in another study70 had severe and prolonged

tremors and convulsions. Although the survival rate

was much higher than that for the control group,

one might expect that more of the survivors would

have brain lesions because of the prolonged seizure

activity.

In general, in untreated or inadequately treated

nerve agent–poisoned animals, convulsive (and seizure) activity usually stops very shortly after respiration ceases. Often these animals die. Occasionally they recover after some degree of apnea, but in

either case, the duration of convulsive and seizure

activity is brief. In a few reported cases of severe

nerve agent intoxication in humans,18,63,81 convulsive

activity has also been brief. Animals given adequate

therapy and, in particular, those given pyridostigmine before exposure to the agent are more

likely to recover. They also are more likely to have

long and recurrent convulsive episodes, since respiration does not stop. The chance of survival increases but, possibly, at the cost of prolonged or

permanent CNS damage.

Therapy

Diazepam, an anticonvulsant of the benzodiazepine family, has been shown to control soman-induced convulsions in monkeys96 and convulsions

induced by other ChE inhibitors in the rabbit.97,98

There have also been anecdotal reports of its effectiveness in controlling convulsions induced by organophosphate insecticides. In rats, diazepam has

been reported to decrease the frequency of convulsions and brain lesions (although, when given without atropine, it did not decrease mortality).99 When

given with 2-PAM Cl, with or without atropine, diazepam reduced the severity, but not the incidence,

of brain lesions in soman-poisoned rats.100

In another study,101 three groups of monkeys were

given pyridostigmine before soman exposure and

were treated with atropine and 2-PAM Cl after exposure. One group was also given diazepam, the

second was given midazolam, and the third (the

control group) was given water. The incidence of

tremors decreased in the anticonvulsant-treated

animals, and convulsions were absent in these

groups. Overall, the brain lesions in the treatment

groups in this study were less severe than those seen

in animals in a previous study95 in which animals

had received neither pretreatment nor treatment.

Although the occurrence of brain lesions in most

brain areas was lower in the anticonvulsant-treated
Nerve Agents

155

groups than in the control group, the difference was

statistically significant (P < .05) for only one of these

five brain areas studied. Lesions occurred more frequently (P < .05) in the frontal cortex in the diazepam-treated group than in the other groups. The

reason for this finding and its physiological significance were not apparent to the investigators.

At a workshop102 on this topic, many investigators in the field reviewed and discussed findings

and future avenues for research. It was generally

agreed that brain lesions did not occur if convulsions lasted less than 45 minutes, and that brain

damage was found if convulsions lasted longer than

45 minutes. This distinction is not apparent in most

reports, which specify only that convulsions were

“prolonged” or “repeated.”

A report103 notes that brain damage after convulsions was first reported over a century ago, and that

the relationship between seizure activity and brain

damage has been the subject of numerous studies

in past decades. For example, well-oxygenated rats

had lesions after 30 minutes of flurothyl-induced

convulsions104; similar results were found using

another volatile convulsant gas in rats.105 Similarly,

baboons that had convulsions for 82 to 299 minutes

after bicuculline administration had brain damage.106 These and other studies, such as that by

McDonough and associates,89 suggest that the brain

damage is not caused by the agent per se, but rather

by the prolonged seizure and associated disturbances.

The efficacy of diazepam in stopping seizures is

generally accepted, and there is evidence that the

drug also reduces brain damage. Rats given

bicuculline had convulsions for 1 hour; the convulsions were then terminated with diazepam. Rats

sacrificed 5 minutes later had fewer brain lesions

than did those sacrificed immediately after the cessation of the convulsion. Rats that recovered longer

and were sacrificed 2 hours after termination of the

convulsion had even less brain damage.107

Most reports in the clinical literature recommend

stopping the convulsion within 1 hour, using drastic measures, such as hypothermia and barbiturate

coma, if necessary.108 The mortality of status epilepticus (usually defined as a convulsion lasting 60 min,

or a series of convulsions lasting 60 min without

consciousness intervening) is said to be 6% to 30%.

Moreover, twice that number of victims acquire

irreversible neurological deficits as a result of

status epilepticus.108 (In a study of children, permanent deficits were found to occur in 34%.109) These

data emphasize the need for an effective anticonvulsant.

Soldiers are issued three MARK I kits (Figure 5-5).

Each MARK I kit contains two autoinjectors: an

AtroPen containing 2 mg of atropine in 0.7 mL

of diluent, and a ComboPen containing 600 mg

of 2-PAM Cl in 2 mL of diluent (autoinjectors and

their contents manufactured by Survival Technology, Rockville, Md.). During the Persian Gulf War,

the U.S. military also issued an autoinjector containing 10 mg of diazepam to all military personnel. This ComboPen was not intended for self-use,

but rather for use by a buddy when a soldier exhibited severe effects from a nerve agent. The buddy

system was used because any soldier able to selfadminister diazepam does not need it. Medics and

unit lifesavers were issued additional diazepam

autoinjectors and could administer two additional

doses at 10-minute intervals to a convulsing casualty. Current policy states that diazepam is given

following the third MARK I when three MARK I

kits are given at one time. The contents and use of

MARK I kits are further described throughout this

chapter.

Cardiovascular System

Few data on the cardiovascular effects of nerve

agents in humans exist. In mild-to-moderate intoxiFig. 5-5. The MARK I kit with its

two autoinjectors: the AtroPen

(containing atropine), labeled 1,

and the ComboPen (containing 2-

pyridine aldoxime methyl chloride, 2-PAM Cl), labeled 2. (a) The

two unused injectors in the safety

clip, and the black carrier. (b) The

used injectors and empty safety

clip.

a b
Medical Aspects of Chemical and Biological Warfare

156

cation from nerve agents, blood pressure may be

elevated, presumably because of cholinergic stimulation of ganglia or other factors, such as stress reaction.

Arrhythmias

After nerve agent exposure, the heart rate may

decrease and some atrial-ventricular (A-V) heart

block (first-, second-, or third-degree) with bradycardia (personal observation) may occur because of

the stimulation of the A-V node by the vagus nerve.

In some cases, an increase in heart rate may occur

because of stress, fright, or some degree of hypoxia.

Since the initiation of treatment is of great urgency

in severely intoxicated patients, electrocardiograms

(ECGs) have not been done before administration

of atropine. However, if possible, an ECG should

be done before drugs are given if the procedure will

not delay therapy. In normal subjects, atropine may

cause a very transient A-V dissociation before the

onset of bradycardia (which precedes the familiar

tachycardia), and ChE-inhibiting substances may

cause bradycardia and A-V block. For reasons noted

above, these transient rhythm abnormalities have

not been recorded in patients with nerve agent intoxication. These rhythm disturbances are probably

not important clinically.

Reports of patients exposed to pesticides and the

results of animal studies provide additional information about cardiovascular reactions to nerve

agents. In one study,110 dogs exposed to lethal

amounts of sarin vapor had idioventricular rhythms

within minutes after exposure; following atropine

therapy, some of the dogs had third- and first-degree heart blocks before a normal rhythm returned.

In another study,111 conscious dogs had few cardiac

rhythm changes after sublethal doses (0.25–0.5 LD50,

administered subcutaneously) of VX. Four of five

anesthetized dogs receiving a 1-LD50 dose had

arrhythmias, including first-degree heart block and

premature ventricular complexes; one had torsade

de pointes (a type of ventricular tachycardia). Cardiac arrhythmias are not uncommon in humans after organophosphate pesticide poisoning.112

Dogs were instrumented to examine the cardiac

changes occurring for a month after intravenous

administration of 2 LD50 of soman.113 Atropine and

diazepam were administered shortly after soman

exposure to control seizure activity. During the

study period, there was an increased frequency of

episodes of bradycardia with ventricular escape,

second- and third-degree heart block, and independent ventricular activity (single premature beats,

bigeminy, or runs of ventricular tachy cardia).

In a similar study,114 rhesus monkeys were given

the standard military regimen of pyridostigmine

before exposure to soman (1 LD50, administered intramuscularly), and atropine and 2-PAM Cl after the

agent. The monkeys were monitored continuously

for 4 weeks. Except for the period immediately after agent administration, the incidence of arrhythmias was the same as or less than that observed

during a 2-week baseline period.

Torsade de pointes has been reported after nerve

agent poisoning in animals111 and after organophosphate pesticide poisoning in humans.115 Torsade de

pointes is a ventricular arrhythmia, usually rapid,

of multifocal origin, which on ECGs resembles a

pattern midway between ventricular tachycardia

and fibrillation. It is generally preceded by a prolongation of the QT interval, it starts and stops suddenly, and it is refractory to commonly used

therapy. It was first described as a clinical entity in

the late 1960s; undoubtedly it was seen but called

by another name in experimental studies with nerve

agents before then.

Ventricular fibrillation, a potentially fatal arrhythmia, has been seen after administration of a

ChE inhibitor and atropine. It can be precipitated

by the intravenous administration of atropine to an

animal that has been rendered hypoxic by administration of a ChE inhibitor.116,117 Although this complication has not been reported in humans, atropine

should not be given intravenously until the hypoxia

has been at least partially corrected.

Heart Rate

Although it is frequently stated that a patient

intoxicated with a nerve agent will have bradycardia, this is not borne out by clinical data. In a review of the records of 199 patients seen at the

Edgewood Arsenal Toxic Exposure Aid Station for

mild-to-moderate nerve agent exposure (one or more

definite signs or symptoms of nerve agent intoxication, such as miosis or a combination of miosis

with dim vision or a tight chest), 13 presented with

heart rates less than 64 beats per minute. There were

13 patients with heart rates of 64 to 69 beats per

minute, 63 with heart rates of 70 to 80, 41 with heart

rates of 81 to 89, 38 with heart rates of 90 to 99, and

31 with heart rates higher than 100. A heart rate of

64 to 80 beats per minute is considered normal in

adults.118 Thus, 13 patients (6.5%) had low heart

rates, and 110 patients (55%) had high heart rates;

(69 of these patients [35%] had heart rates > 90).

Reports of the heart rates of patients severely
Nerve Agents

157

intoxicated by insecticides vary. In a report119 describing 10 patients (9 of whom had moderate-tosevere impairment of consciousness), 7 presented

with heart rates over 100 and the other 3 had heart

rates over 90 (5 had a systolic blood pressure of 140

mm Hg or higher, a diastolic blood pressure of 90

mm Hg or higher, or both). In another report,120 the

heart rates of 3 unconscious patients were slow (1

had cardiac arrest). In a comprehensive review of

organophosphate poisoning,51 2 acutely ill, unconscious patients were described; 1 had a heart rate

of 108 beats per minute and the other, 80. The authors of the study pointed out that cardiovascular

function is usually maintained until the terminal

stage and that blood pressure and heart rate increase in the acute stage but may decline later. Heart

rate was not listed in their tabulation of signs and

symptoms.

GENERAL TREATMENT PRINCIPLES

The principles of treatment of nerve agent poisoning are the same as they are for any toxic substance exposure: namely, terminate the exposure;

establish or maintain ventilation; administer an antidote, if one is available; and correct cardiovascular abnormalities.

Most importantly, medical care providers or rescuers must protect themselves from contamination.

If the caregiver becomes contaminated, there will

be one more casualty and one fewer rescuer. Protection of the rescuer can be achieved by physical

means, such as masks, gloves, and aprons, or by

ensuring that the casualty has been thoroughly decontaminated. The importance of casualty decontamination should be obvious, but, unfortunately,

it is often forgotten or overlooked. There were reports that in several instances during the Iran–Iraq

War (1981–1988), incompletely decontaminated

mustard casualties who were transported to European medical centers for further care caused contamination of others, who then also became casualties.

This section discusses the general principles of

treating nerve agent poisoning. The specific treatment of casualties in the six exposure categories

(suspected, minimal, mild, moderate, moderately

severe, and severe) is addressed in the next section.

Terminating the Exposure

Decontamination is performed for two reasons:

1. to prevent further absorption of the agent

by the casualty or further spread of the

agent on the casualty, and

2. to prevent spread of the agent to others,

including medical personnel, who must

handle or who might come into contact

with the casualty.

Because of the small amount of nerve agent needed

to cause death and because of the short time (10–15

min) in which a lethal amount will cause severe effects in an untreated casualty, it is unlikely that a

living nerve agent–poisoned casualty with nerve

agent on his skin will be brought to a medical care

facility. To successfully reduce damage to the casualty, decontamination must be performed within

minutes after exposure. The only decontamination

that prevents or significantly reduces damage from

a chemical agent, whether a nerve agent or another

agent, is that done within the first several minutes:

self-decontamination.

The importance of rapid self-decontamination

cannot be overemphasized and must be clearly understood by anyone who might be exposed to

chemical agents. Because the skin absorbs most

chemical agents rapidly and because of evaporation (even “persistent” agents, such as VX and mustard, evaporate from skin rather quickly), it is unlikely that there will be a significant amount of

agent on the skin by the time the casualty reaches a

medical treatment facility. However, agent may be

in areas, such as in hair or on clothing, where it will

not be readily absorbed percutaneously. Skin decontamination is not necessary after exposure to nerve agent

vapor.

If vapor is the only exposure source, the exposure can be terminated by putting a protective mask

on the casualty or by moving him to an environment free of toxic vapor (eg, by moving the casualty outside and sealing the doors if the vapor is in

a room or building). The standard M40 (or M17A2)

protective mask will protect against any likely field

concentration of nerve agent vapor for days.

Liquid agent on the skin or clothing should be

physically removed and detoxified by chemical

degradation or neutralization. Nerve agents penetrate clothing; mere removal of contaminated apparel is not adequate since some agents may reach

the skin before the clothing is removed. If the contamination is localized, cutting out the affected section of clothing (leaving very wide margins) may

be adequate. If there is doubt, however, all cloth-
Medical Aspects of Chemical and Biological Warfare

158

ing should be removed. The underlying skin should

then be decontaminated thoroughly.

The M291 decontamination kit contains charcoal

and sorptive resins; the agent is physically removed

and adsorbed. The M258A1 is a standard decontamination kit that contains two moistened towelettes. One is intended for use with the G agents,

and the other with VX and mustard. Since the agent

probably would not be identified at the time of exposure in the field, both towelettes should be used

to physically remove the chemical agent by blotting,

not wiping, it; the towelettes also aid in decontamination by chemically neutralizing the agent, although this chemical reaction is slow. (See Chapter

15, Decontamination, and Chapter 16, Chemical

Defense Equipment, for details about the decontamination kits.)

A solution that releases chlorine, such as household bleach (5% sodium hypochlorite) or a solution

that is sufficiently alkaline to neutralize the agent,

such as dilute hydroxide, can also be used for physical removal and chemical neutralization of a chemical agent. Because of the potential for skin damage

from 5% hypochlorite, the current military procedure is to use 0.5% hypochlorite for skin decontamination. Dilute hydroxide and the contents of the

M258A1 kit are damaging to the skin, however, and

should be thoroughly rinsed off.

Water is also a decontaminant since, when used

in large amounts, it physically removes and dilutes

chemical agents. (Most agents hydrolyze to some

degree in water, but hydrolysis usually takes hours

to days.) If used alone, water is not ideal; however,

if nothing else is available, flushing with large

amounts of water to physically remove the chemical agent is satisfactory. Water should be used to

wash off the other decontaminants. Commonly

available products (such as tissue paper and flour)

that can help remove or adsorb the agent should be

used if other decontaminants are not available.121

Ventilatory Support

Ventilatory support is a necessary aspect of

therapy if a casualty with severe respiratory compromise is to be saved. Antidotes alone may be effective in restoring ventilation and saving lives in

some instances; in animal studies,122,123 antidotes

alone, given intramuscularly at the onset of signs,

were adequate to reverse the effects of agent doses

of about 3 LD50, but their effectiveness was greatly

increased with the addition of ventilation. Pyridostigmine, given as pretreatment and followed by the

current therapy after challenges with higher

amounts of two agents, appears to prevent apnea

(see Chapter 6, Pretreatment for Nerve Agent Exposure).

Impairment of breathing is an early effect of exposure to nerve agent vapor or aerosol. When the

exposure is small, the casualty may have mild to

severe dyspnea, with corresponding physical findings, and the impairment will be reversed by the

administration of atropine. If the distress is severe

and the casualty is elderly or has pulmonary or cardiac disease, the antidote may be supplemented by

providing oxygen by inhalation. In most other circumstances, supplementation with oxygen is unnecessary.

Severely exposed casualties lose consciousness

shortly after the onset of effects, usually before any

signs of respiratory compromise. They have generalized muscular twitching or convulsive jerks and

may initially have spontaneous but impaired respiration. Breathing ceases completely within several minutes after the onset of exposure in a severely

poisoned person who has not been pretreated with

pyridostigmine.

Assisted ventilation may be required to supplement gasping and infrequent attempts at respiration, or it may be required because spontaneous

breathing has stopped. In addition to a decrease in

central respiratory drive, weakness or paralysis of

thoracic and diaphragmatic muscles, and bronchospasm or constriction, there are copious secretions

throughout the airways. These secretions tend to

be thick, mucoid, and “ropy,” and may plug up the

airways. Postural drainage can be used, and frequent and thorough suctioning of the airways is

necessary if ventilation is to be successful. In one

instance, efforts to ventilate a severely apneic casualty were markedly hindered for 30 minutes until

adequate suction was applied to remove thick mucoid plugs.63

Initially, because of the constriction or spasm of

the bronchial musculature, there is marked resistance to attempts to ventilate. Pressures of 50 to 70

cm H2O or greater may be needed. After the administration of atropine, resistance decreases to 40

cm H2O or lower, and the secretions diminish (although they may thicken), creating less obstruction

to ventilatory efforts.

There are numerous mechanical devices, including sophisticated ventilators, that can be used to

provide ventilatory assistance in an apneic casualty.

None of these is available to the soldier or his

buddy, and only a few—the mask-valve-bag venti-
Nerve Agents

159

lation device, the RDIC (resuscitation device, individual, chemical), and a simple ventilator—are

available at the battalion aid station. Whatever device is used, it must be able to overcome the initial

high resistance in the airways. If a casualty is apneic or has severe respiratory compromise and

needs assisted ventilation, then endotracheal intubation, which will enable better ventilation and

suction of secretions, can and should be attempted.

Mouth-to-mouth ventilation might be considered

by a soldier who wants to assist an apneic buddy

when no aid station is nearby. A major drawback is

the likelihood of contamination. Before even considering this method, the rescuer should be sure that

there is no vapor hazard, which is not always possible, and that there is no liquid contamination on

the individual to be ventilated. The expired breath

of the casualty is a lesser hazard. Studies124–126 involving sarin have shown that only 10% or less of

inspired nerve agent is expired, and that the toxicant is expired immediately after inspiration of the

agent.

The Schäfer method of assisted ventilation (ie,

gentle, intermittent pressure applied to the lower

part of the thorax of a prone person to mimic breathing) was formerly used in severely poisoned individuals until other means became available. Generally, this is not a reliable method of ventilation

even in an individual with normal airways.

In summary, spontaneous respiration will stop

within several minutes after onset of effects caused

by exposure to a lethal amount of nerve agent. Antidotes alone are relatively ineffective in restoring

spontaneous respiration. Attempts at ventilation are

hindered by the high resistance of constricted bronchiolar muscles and by copious secretions, which

may be thick and plug the bronchi. Ventilatory assistance may be required briefly (20–30 min) or for

a much longer period. In several instances, assistance was required for 3 hours18,63; this seems to be

the longest reported use of ventilation.

Atropine Therapy

The antagonism between the ChE-inhibiting substance physostigmine and a cholinergic blocking

substance has been recognized for well over a century.127 In the early 1950s, atropine was found to

reduce the severity of effects from ChE-inhibitor

poisoning, but it did not prevent deaths in animals

exposed to synthetic ChE-inhibiting insecticides.128

Cholinergic blocking substances act by blocking

the effects of excess acetylcholine at muscarinic receptors. Acetylcholine accumulates at these receptors because it is not hydrolyzed by ChE when the

enzyme is inactivated by an inhibitor. Thus, cholinergic blocking substances do not block the direct

effect of the agent (ChE inhibition); rather, they

block the effect of the resulting excess ACh.

Many cholinergic blocking substances have been

tested for antidotal activity. Among the findings are

the following:

• Almost any compound with cholinergic

blocking activity has antidotal activity.

• Atropine and related substances reduce the

effects of the ChE inhibitors, primarily in

those tissues with muscarinic receptor sites.

• Antidotal substances with higher lipoid

solubility, which penetrate the CNS more

readily, might be expected to have greater

antidotal activity, since some of the more

severe effects of ChE inhibitor poisoning

(such as apnea and seizures) are mediated

in the CNS.

For example, the combination of benactyzine and atropine was shown to be more

effective than atropine alone in reducing

lethality from sarin128; 3-quinuclidinyl

benzilate (BZ, also called QNB; see Chapter 11, Incapacitating Agents) is an excellent antidote. Benactyzine was part of a

mixture (plus atropine and N,N’-trimethylenebis-[pyridine-4-aldoxime bromide]

[TMB4]) fielded as a nerve agent antidote

(known as TAB) for several years in the late

1970s. However, these substances have CNS

effects in the absence of nerve agents; this

was one of the reasons that this mixture was

withdrawn.

In the late 1940s, atropine was chosen as the standard antidote; despite extensive searches for other

antidotes since, it has remained the standard. A dose

of 2 mg was chosen for self- or buddy-administration (the AtroPen automatic injector included in the

MARK I kit contains 2 mg) because it reverses the

effects of nerve agents, the associated side effects

of a dose this size can be tolerated, and reasonably

normal performance can be maintained by the individual receiving it. The rationale for this choice

of dose was expressed (in the unclassified portion

of a classified document) as follows:

The dose of atropine which the individual serviceman can be allowed to use must be a compromise

between the dose which is therapeutically desir-
Medical Aspects of Chemical and Biological Warfare

160

able and that which can be safely administered to

a nonintoxicated person. Laboratory trials have

shown that 2 mg of atropine sulfate is a reasonable

amount to be recommended for injection by an individual and that higher doses may produce embarrassing effects on troops with operational responsibilities.

When given to a normal individual (one without nerve agent intoxication), a dose of 2 mg of atropine will cause an increase in heart rate of about

35 beats per minute (which usually is not noticed

by the recipient), a dry mouth, dry skin, mydriasis,

and some paralysis of accommodation. Most of

these effects will dissipate by 4 to 6 hours, but near

vision may be blurred for 24 hours, even in healthy

young men. The decrease in sweating caused by 2

mg of atropine is a major, potentially harmful side

effect that may cause some people who work in the

heat to become casualties. For example, when 35

soldiers were given 2 mg of atropine and asked to

walk for 115 minutes at 3.3 mph at a temperature

of about 83°F (71°F wet bulb), more than half

dropped out because of illness or were removed

from the walk because of body temperature of

103.5°F or above; on another day, without atropine,

they all successfully completed the same march.129

The 6 mg of atropine contained in the three injectors given each soldier may cause mild mental

aberrations (such as drowsiness or forgetfulness) in

some individuals if administered in the absence of

nerve agent intoxication. Atropine given intravenously to healthy young people causes a maximal

increase in the heart rate in 3 to 5 minutes, but other

effects (such as drying of the mouth and change in

pupil size) appear later. In one study,130 when atropine was administered with the AtroPen, the greatest degree of bradycardia occurred at 2.5 minutes

(compared with 4.3 min when administered by standard needle-and-syringe injection); a heart rate increase of 10 beats per minute occurred at 7.9 minutes (vs 14.7 min with needle-and-syringe injection);

and maximal tachycardia (an increase of 47 beats

per min) occurred at 34.4 minutes (compared with

an increase of 36.6 beats per min at 40.7 min with

needle-and-syringe injection).

Thus, the autoinjector is not only more convenient to use than the needle and syringe, but its use

causes more rapid absorption of the drug. Needleand-syringe delivery produces a “glob” or puddle

of liquid in muscle. The AtroPen, on the other hand,

sprays the liquid throughout the muscle as the

needle goes in. The greater dispersion of the

AtroPen deposit results in more rapid absorption.

It has not been determined whether the onset of

beneficial effects in treating nerve agent intoxication corresponds to the onset of bradycardia, the

onset of tachycardia, or to other factors.

When administered in an adequate amount, atropine reverses the effects of the nerve agent in tissues that have muscarinic receptor sites. It decreases

secretions and reverses the spasm or contraction of

smooth muscle. The mouth dries, secretions in the

mouth and bronchi dry, bronchoconstriction decreases, and gastrointestinal musculature will be

less hyperactive. However, unless given in very

large doses, intravenous or intramuscular atropine

does not reverse miosis caused by nerve agent vapor in the eyes. A casualty with miosis alone should

not be given atropine, therefore, and pupil size

should not be used to judge the adequacy of atropine dosage. Whether atropine controls convulsions

in humans is unclear.

The amount of atropine to administer is a matter

of judgment. In a conscious casualty with mild-tomoderate effects who is not in severe distress, 2 mg

of atropine should be given intramuscularly at 5-

to 10-minute intervals until dyspnea and secretions

are minimized. Usually no more than a total dose

of 2 to 4 mg is needed. In an unconscious casualty,

atropine should be given (a) until secretions are

minimized (those in the mouth can be seen and

those in the lungs can be heard by auscultation) and

(b) until resistance to ventilatory efforts is minimized (atropine decreases constriction of the bronchial musculature and airway secretions). If the casualty is conscious, he will report less dyspnea, and

if assisted ventilation is underway, a decrease in

airway resistance will be noted. Secretions alone

should not be the reason for administering more

atropine if the secretions are diminishing and are

not clinically significant. Mucus blocking the

smaller airways may remain a hindrance despite

adequate amounts of atropine. In severe casualties

(unconscious and apneic), 5 to 15 mg of atropine

has been used before spontaneous respiration resumed and the casualty regained consciousness

(which occurred 30 min to 3 h after exposure).18,63

Several recovering casualties have had non–lifethreatening adverse effects (such as nausea and

vomiting) 24 to 36 hours after exposure for which

atropine was administered (personal observation).18

However, there would appear to be no reason to

give atropine routinely in this period.

In contrast, much larger amounts of atropine

(500–1,000 mg) have been required in the initial 24

hours of treatment of individuals severely poisoned

by organophosphorus pesticides.131–133 Medical care

providers must recognize that the amount of atropine
Nerve Agents

161

needed for treatment of insecticide poisoning is different from the amount needed for treatment of nerve agent

poisoning. Pesticides may be sequestered in the body

or metabolized at a slower rate than nerve agents;

whatever the reason, they continue to cause acute

cholinergic crises for a much longer period (days

to weeks).

The goal of therapy with atropine should be to

minimize the effects of the agent (ie, to remove the

casualty from a life-threatening situation and to

make him comfortable), which may not require

complete reversal of all of the effects (such as miosis). However, in a casualty with severe effects, it is

better to administer too much atropine than too

little. Too much atropine does far less harm than

too much unantagonized nerve agent in a casualty

suffering severe effects. However, a moderately

dyspneic casualty given atropine 2 mg, administered intramuscularly, will report improvement

within 5 minutes. A caregiver should resist the

temptation to give too much atropine to a walking,

talking casualty with dyspnea. In general, the correct dose of atropine for an individual exposed to a

nerve agent is determined by the casualty’s signs

and symptoms, the route of exposure (vapor or liquid), and the amount of time elapsed since exposure.

Atropine Therapy After Inhalational Exposure to

Vapor

After vapor exposure, the effects of nerve agents

appear very quickly and reach their maximum activity within seconds or minutes after the casualty

is removed from or protected against the vapor. In

what were apparently high concentrations of nerve

agent vapor, two individuals collapsed, unconscious, almost immediately after taking one or two

breaths, and 4 to 5 minutes later they were flaccid

and apneic.18,63 Even at very low concentrations,

maximal effects occur within minutes of termination of exposure. Because effects develop so rapidly, antidotal therapy should be more vigorous for

a casualty seen during or immediately after exposure than for a casualty seen 15 to 30 minutes later.

For example, if a soldier’s buddy in the field or a

coworker in a laboratory suddenly complains of

dim vision in an environment suspected of containing nerve agent vapor, the buddy or worker should

immediately administer the contents of one MARK

I antidote kit. There may be continuing exposure

before the casualty can exit the environment or don

a mask, or the effects from the exposure already

absorbed may continue to develop for several minutes. On the other hand, if the casualty is seen at

the medical aid station (installation or field) 15 to

30 minutes after the vapor exposure has terminated,

an antidote is not needed if miosis is the only sign

(atropine given intramuscularly has very little effect on miosis). Effects caused by nerve agent vapor will not progress after this time.

As a general rule, if a casualty is seen immediately after exposure from vapor only, the contents

of one MARK I kit should be given if miosis is the

only sign, the contents of two kits should be administered immediately if there is any dyspnea, and

the contents of three kits should be given for severe dyspnea or any more-severe signs or symptoms. When seen 15 to 30 minutes after an exposure to vapor alone, the casualty should receive no

antidote if miosis is the only sign, the contents of

one MARK I kit for mild or moderate dyspnea, the

contents of two kits for severe dyspnea (obvious

gasping), and the contents of three kits and diazepam (with additional atropine, but no more oxime)

if there are more serious signs (such as collapse or

loss of consciousness). If dyspnea is the most severe symptom, relief should begin within 5 minutes, and the drugs should not be repeated until

this interval has passed. Remember that the aggressive therapy given immediately after the onset of

effects is not for those early effects per se (eg, atropine is relatively ineffective against miosis), but is

in anticipation of more-severe effects within the

following minutes.

Atropine Therapy After Dermal Exposure to

Liquid

The therapy for an individual whose skin has

been exposed to nerve agent is less clear. The onset

of effects is rarely immediate; they may begin within

minutes of exposure or as long as 18 hours later. As

a general rule, the greater the exposure, the sooner

the onset; and the longer the interval between exposure and onset of effects, the less severe the eventual effects will be. Effects can begin hours after

thorough decontamination; the time of onset may

be related to the duration of time the agent was in

contact with the skin before decontamination.

The problem with treating dermal exposure is not

so much how to treat a symptomatic casualty as

whether to treat an asymptomatic person who has

had agent on the skin. Medical personnel usually

have little or no information about the exposure

incident, because the casualty often does not know

the duration or amount of exposure.

The first effects of agent on the skin are localized sweating and fasciculations of underlying
Medical Aspects of Chemical and Biological Warfare

162

musculature (rippling), which usually are not observed. If these effects are noted, however, the casualty should immediately self-administer or be

given the contents of one MARK I kit. These signs

indicate that the chemical agent has penetrated the

skin layers.

In general, an asymptomatic person who has had

skin contact with a nerve agent should be kept

under medical observation, because effects may

begin precipitately hours later. Caregivers should

not administer the contents of a MARK I kit to an

asymptomatic person, but should wait for evidence

of agent absorption. However, if an individual is

seen minutes after a definite exposure to a large

amount of nerve agent on the skin (“large” is relative; the LD50 for skin exposure to VX is only 6–10

mg, which is equivalent to a single drop 2–3 mm

in diameter), there may be some benefit in administering antidotes before the onset of effects. When

the occurrence of exposure is uncertain, the possible

benefits of treatment must be weighed against the

side effects of antidotes in an unpoisoned individual.

Antidotes should be administered until ventilation is adequate and secretions are minimal. In a

mildly to moderately symptomatic individual who

is complaining of dyspnea, relief is usually obtained

with 2 or 4 mg of atropine (the amount of atropine

in one or two MARK I kits). In a severely exposed

person who is unconscious and apneic or nearly

apneic, at least 6 mg of atropine (the amount in three

MARK I kits), and probably more, should be administered initially, and ventilatory support should

be started. Atropine should be continued at appropriate intervals until the casualty is breathing adequately with a minimal amount of secretions in the

mouth and lungs. The initial 2 or 4 mg has proven

adequate in conscious casualties. Although 6 to 15

mg has been required in apneic or nearly apneic

casualties, the need for continuing atropine has not

extended beyond 2 to 3 hours (although distressing but not life-threatening effects, such as nausea

and vomiting, have necessitated administering additional atropine in the following 6–36 h). This is in

contrast to the use of atropine to treat intoxication

by organophosphorus insecticides, which may

cause cholinergic crises (such as an increase in secretion and bronchospasm) for days to weeks after

the initial insult.131–133

Oxime Therapy

Oximes are nucleophilic substances that reactivate the organophosphate-inhibited ChE (the phosphorylated enzyme) by removing the organophosphoryl moiety. There are limitations to oxime

therapy, however.

Mechanism of Action

After the organophosphorus compound attaches

to the enzyme to inhibit it, one of the following processes may occur:

• the enzyme may be spontaneously reactivated by hydrolytic cleavage, which breaks

the organophosphoryl–ChE bond, reactivating the enzyme; or

• the organophosphoryl–ChE bond may

“age,” or become resistant to reactivation

by water or oxime.

Both of these processes are related to the size of the

alkyl group attached to the oxygen of the organophosphorus compound, the group attached to the

first carbon of this alkyl group, and other factors.

Once the organophosphoryl–enzyme complex ages,

it cannot be broken by an oxime. (Further discussion of the chemical process can be found elsewhere;

for a brief discussion, see Chapter 6, Pretreatment

for Nerve Agent Exposure; for more detailed information, see Koelle.11) Oxime therapy is not effective after aging occurs.

Because the nerve agents differ in structure, their

rates of spontaneous reactivation and aging differ.

For example, when complexed with VX, RBC-ChE

spontaneously reactivates at a rate of roughly 0.5%

to 1% per hour for about the first 48 hours; the VX–

enzyme complex ages very little during this period.42,45,83 The soman–enzyme complex does not

spontaneously reactivate; the half-time for aging is

about 2 minutes. The half-time for aging of the

sarin–RBC-ChE complex is about 5 hours, and a

small percentage (5%) of the enzyme undergoes

spontaneous reactivation.83 The half-time for aging

of the tabun–enzyme complex is somewhat longer.

(See Table 6-1 in Chapter 6, Pretreatment for Nerve

Agent Exposure, for nerve agent–aging times.)

In the mid 1950s, Wilson and coworkers reported

that hydroxamine reactivated organophosphorylinhibited ChE faster than water did,134 and later reported that an oxime (pyridine-2-aldoxime methiodide [2-PAMI]) was far more effective than

hydroxamine in reactivating the enzyme.135

The oximes differ in their required doses, their

toxicity, and their effectiveness (for example, TMB4

is more effective against tabun poisoning than is 2-

PAM Cl). After thorough study of many of these
Nerve Agents

163

compounds, 2-PAM Cl was chosen for use in the

United States. The choice was made because of research in both the civilian and military sectors and

also because of the demonstrated efficacy of 2-PAM

Cl in treating organophosphorus insecticide poisoning.136–142 At present, the only oxime approved by

the Food and Drug Administration for use in the

United States is 2-PAM Cl. The methanesulfonate

salt of pralidoxime (P2S) is the standard oxime in

the United Kingdom, whereas TMB4 and Toxogonin

(obidoxime) are used in other European countries.

Since oximes reactivate the ChE inhibited by a

nerve agent, they might be expected to completely

reverse the effects caused by nerve agents. However, because nerve agents possibly produce biological activity by mechanisms other than inhibition of ChE or because of reasons not understood,

oximes are relatively ineffective in reversing effects

in organs with muscarinic receptor sites. They are

much more effective in reversing nerve agent–induced changes in organs with nicotinic receptor

sites. In particular, when oximes are effective (ie, in

the absence of aging), they decrease the abnormality in skeletal muscle, improving strength and decreasing fasciculations.

Dosage

The therapeutic dosage of 2-PAM Cl has not been

established, but indirect evidence suggests that it

is 15 to 25 mg/kg. The effective dose depends on

the nerve agent, the time between poisoning and

oxime administration, and other factors. An early

study143 showed that a plasma concentration of

about 4 μg/mL in blood reversed the sarin-induced

neuromuscular block in anesthetized cats; for years

this concentration was generally accepted as being

therapeutic for sarin. There are few data to support

or disprove this contention. The 2-PAM Cl administered with the ComboPen autoinjector (600 mg)

produces a maximal plasma concentration of 6.5

μg/mL when injected intramuscularly in the average soldier (8.9 mg/kg in a 70-kg man).130

Different doses of 2-PAM Cl were administered

(with atropine) in several studies. In sarin-poisoned

rabbits, the protective ratio (PR: the ratio of the LD50

with treatment to the LD50 without treatment) increased from 25 to 90 when the intravenous dose of

2-PAM Cl increased from 5 mg/kg to 10 mg/kg144;

the PR increased from 1.6 to 4.2 when the intramuscular dose of 2-PAM Cl increased from 30 mg/kg

to 120 mg/kg in sarin-poisoned rats122; and the PR

increased from 1.9 to 3.1 when the intramuscular

dose of 2-PAM Cl increased from 11.2 mg/kg to 22.5

mg/kg in VX-poisoned rabbits.123 (In the first two

studies, the antidote was given immediately after

the nerve agent; in the third, it was given at the

onset of signs. No ventilatory support was used.)

In humans, when 2-PAM Cl was administered intravenously 1 hour after sarin, a dose of 10 mg/kg

reactivated 28% of the RBC-ChE, and doses of 15 or

20 mg/kg reactivated 58% of the enzyme. When

given 3 hours after sarin, 5 mg/kg of 2-PAM Cl

reactivated only 10% of the inhibited RBC-ChE, and

10 mg/kg or more reactivated more than 50%. When

2-PAM Cl was given at times from 0.5 to 24 hours

after VX, doses of 2.5 to 25 mg/kg were found to

reactivate 50% or more of the inhibited enzyme.83

For optimal therapy, 2-PAM Cl should be given

intravenously, but usually this is not possible in the

field. Even at small doses (2.5–5.0 mg/kg), the drug,

when given intravenously in the absence of nerve

agent poisoning, may cause transient effects, such

as dizziness and blurred vision, which increase

as the dose increases. Transient diplopia may occur

at doses higher than 10 mg/kg. These effects, if they

occur, are insignificant in a casualty poisoned with

a ChE-inhibiting substance. Occasionally, nausea

and vomiting may occur. The most serious side

effect is hypertension, which is usually slight and

transient at intravenous doses of 15 mg/kg or less,

but may be marked and prolonged at higher

doses.145 2-PAM Cl is commercially available as

the cryodesiccated form (Protopam Chloride, manufactured by Wyeth-Ayerst Laboratories, Philadelphia, Pa.) in vials containing 1 g, or about 14 mg/

kg for a 70-kg person. Blood pressure elevations

greater than 90 mm Hg systolic and 30 mm Hg diastolic may occur after administration of 45 mg/

kg, and the elevations may persist for several

hours.145 Giving the oxime slowly (over 30–40 min)

may minimize the hypertensive effect, and the hypertension can be quickly but transiently reversed

by phentolamine 5 mg, administered intravenously

(Figure 5-6).

2-PAM Cl is rapidly and almost completely excreted unchanged by the kidneys: 80% to 90% of an

intramuscular or intravenous dose is excreted in 3

hours,146 probably by an active tubular excretory

mechanism (its renal clearance is close to that of paminohippurate147), with a half-time of about 90

minutes.146 Both clearance and amount excreted are

decreased by heat, exercise, or both.148 Thiamine

also decreases excretion (presumably by blocking

tubular excretion), prolongs the plasma half-life,

and increases the plasma concentration for the duration of thiamine activity147–150; some151 question the

therapeutic benefit of thiamine, however.
Medical Aspects of Chemical and Biological Warfare

164

An early clinical report152 on the use of 2-PAM Cl

in insecticide-poisoned persons indicated that the

oxime reversed the CNS effects of the poison (eg,

patients regained consciousness and stopped convulsing shortly after the oxime was given). However, other early investigators found no oxime in

the brain of animals153,154 or the cerebrospinal fluid

of humans155 after experimental administration of

2-PAM Cl. Other investigators71,156 found small

amounts of 2-PAM Cl or reversal of the brain ChE

inhibition in brains of animals poisoned with organophosphorus compounds.

Administration

Initially, an oxime should be administered with

atropine. In cases of severe exposure, the contents

of three MARK I kits should be administered; if the

kits are not available, then oxime 1 to 1.5 g should

be administered intravenously over a period of 20

to 30 minutes or longer. Additional atropine should

be given to minimize secretions and to reduce ventilatory problems, thereby relieving the casualty’s

distress and discomfort.

Since an improvement in the skeletal muscle effects of the agent (ie, an increase or decrease in

muscle tone and reduced fasciculations) may be

seen after oxime administration, medical personFig. 5-6. An infusion of 25 mg/kg of pralidoxime chloride (2-PAM Cl) over about 25 minutes produces marked

hypertension, which is rapidly but transiently reversed

by phentolamine 5 mg. The mean blood pressure is the

diastolic plus one third of the difference between the systolic and the diastolic. Reprinted with permission from

Sidell FR. Clinical considerations in nerve agent intoxication. In: Somani SM, ed. Chemical Warfare Agents. New

York, NY: Academic Press; 1992: 181.

nel may be tempted to repeat the oxime along with

atropine. Because of side effects, however, no more

than about 2.5 g of oxime should be given within 1

to 1.5 hours. If the oxime is effective, it can be repeated once or twice at intervals of 60 to 90 minutes.

2-PAM Cl can be administered intravenously,

intramuscularly, and orally. Soon after it became

commercially available, 2-PAM Cl was administered orally both as therapy and as a pretreatment

for those in constant contact with organophosphorus compounds (eg, crop dusters). At one time, the

United Kingdom provided its military personnel

with a supply of oxime tablets for pretreatment use,

but it no longer does so. Enthusiasm for this practice waned for a number of reasons:

• erratic absorption of the drug from the gastrointestinal tract, leading to large differences (both between individuals and in the

same person at different times) in plasma

concentration;

• the large dose required (5 g to produce an

average plasma concentration of 4 μg/mL);

• the unpopularity of the large, bitter 0.5-g

or 1.0-g tablets; and

• the relatively slow absorption compared

with that for administration by other routes.

In addition, the frequent administration (every 4–6

h) required by workers at risk caused gastrointestinal irritation, including diarrhea. It is also no

longer common practice for crop workers to be

given 2-PAM Cl as a pretreatment, the rationale

being that crop workers who take the medication

might have a false sense of security and therefore

might tend to be careless with safety measures.

Despite these drawbacks, 2-PAM Cl tablets might

be the best alternative in certain cases, such as a

depot worker exposed to a nerve agent who shows

no effects except for an inhibition of RBC-ChE activity. An oxime might be given to restore his RBCChE activity to 80% of his baseline value, which is

necessary for his return to work. (See Blood Cholinesterases section, above, for discussion of monitoring RBC-ChE activity.) Administration by the

oral route might be considered preferable (although

less reliable) to administration by a parenteral route

because tablets can be self-administered and taking tablets avoids the pain of an injection.

Intramuscular administration of 2-PAM Cl with

the ComboPen results in a plasma concentration of

4 μg/kg at 7 minutes versus 10 minutes for conFigure 5-6 is not shown because the copyright permission granted to the Borden Institute, TMM, does

not allow the Borden Institute to grant permission to

other users and/or does not include usage in electronic

media. The current user must apply to the publisher

named in the figure legend for permission to use this

illustration in any type of publication media.
Nerve Agents

165

ventional needle-and-syringe injection.130 (A maximal plasma concentration of 6.9 μg/kg occurs at 19

min vs 6.5 μg/kg at 22 min for the needle-and-syringe method.) About 80% to 90% of the intact drug

is excreted unmetabolized in the urine; the half-life

is about 90 minutes. When a 30% solution of 2-PAM

Cl was injected intramuscularly at doses ranging

from 2.5 to 30 mg/kg, the drug caused no change

in heart rate or any signs or symptoms (except for

pain at the injection site, as expected after an injection of 2 mL of a hypertonic solution).146,147 When

given intramuscularly, 30 mg/kg caused an elevation in blood pressure and minimal ECG changes,

but no change in heart rate.146

Because of the very rapid aging of the soman–

AChE complex, oximes are often considered ineffective in treating soman poisoning. Experimental

studies in animals have shown that oximes are not

nearly as effective in treating soman intoxication

as in sarin intoxication, but they do provide some

therapeutic benefit (a 5%–10% reactivation of the

inhibited enzyme).157,158 Suggested reasons for this

benefit are that an oxime acts as a cholinergic blocking drug at the nicotinic sites, analogous to atropine at the muscarinic sites157 or that it causes the

circulation to improve, possibly by stimulating the

release of catecholamines.158

Anticonvulsive Therapy

Convulsions occur after severe nerve agent exposure. In reports18,63,81 of severe cases, convulsions

(or what were described as “convulsive jerks” or

“spasms”) started within seconds after the casualty

collapsed and lost consciousness, and persisted for

several minutes until the individual became apneic

and flaccid. The convulsions did not recur after atropine and oxime therapy and ventilatory support

were administered. In these instances, no specific

anticonvulsive therapy was needed nor was it

given.

Laboratory studies indicate that the convulsive

period lasts much longer (hours) in animals, even

those given therapy. However, the antidotes are

given in a standard dose to experimental animals

rather than titrated to a therapeutic effect as they

are in human patients; this difference may account

for the greater duration of convulsions in animals.

In animals, convulsions occur more frequently and

are more severe when the animal is pretreated with

pyridostigmine and given nerve agent followed by

standard therapy than when no pyridostigmine

pretreatment is used. For these reasons, it is anticipated that humans pretreated with pyridostigmine

would also have more frequent and more severe

convulsions when pretreated with pyridostigmine

than when not pretreated with pyridostigmine.

Diazepam has been used successfully to terminate convulsions caused by organophosphate insecticide poisoning (see discussion of behavioral effects above) and has been fielded in the U.S. military.

As discussed earlier, each soldier is issued one

autoinjector (ComboPen) containing 10 mg of diazepam in 2 mL of diluent. When a soldier exposed

to a nerve agent is unable to help himself, a buddy

should administer diazepam as well as the contents

of three MARK I kits—whether or not there are indications of seizure activity. In fact, it is preferable

to administer diazepam before the onset of seizure

activity. The medic carries additional diazepam injectors and is authorized to administer two additional injectors to a convulsing casualty at 10-

minute intervals. Current military doctrine is for

the buddy to administer the diazepam immediately

following the administration of the third MARK I

when the three MARK I kits are given together. This

is not only military doctrine, it is sound medical

advice, and this action should be taken automatically when assisting a casualty with severe exposure to organophosphate nerve agents.

Therapy for Cardiac Arrhythmias

Transient arrhythmias occur after nerve agent

intoxication and after atropine administration in a

normal individual. However, the irregularities generally terminate after the onset of atropine-induced

sinus tachycardia (see discussion of cardiac effects,

above).

Experimental studies117,159 have shown that when

animals are poisoned with ChE inhibitors and then

allowed to become cyanotic, rapid intravenous administration of atropine will cause ventricular

fibrillation. Ventricular fibrillation after rapid intravenous administration of atropine has not been reported in humans.

After severe intoxication from exposure to an

organophosphate insecticide, a 20-year-old patient

was stabilized with atropine and ventilatory support, but her ECG showed depression of the ST segment and flattening of the T wave, presumably because of persistent sinus tachycardia secondary to

large doses of atropine (287 mg in 4 days; total of

830 mg). She was given a β-adrenergic blocking

agent (propranolol), which slowed the heart rate to

107 beats per minute, normalizing the ST-T changes.
Medical Aspects of Chemical and Biological Warfare

166

The normal ECG pattern and heart rate of 107 beats

per minute persisted despite repeated doses of atropine. In effect, a pharmacologically isolated heart

(with both cholinergic and adrenergic blockade)

was produced; the authors reporting on the case

suggested that propranolol might be of value in

protecting against the effects of atropine and organophosphorus intoxication.160

SPECIFIC TREATMENT BY EXPOSURE CATEGORY

The goals of medical therapy are, in most cases,

fairly straightforward: to minimize the patient’s discomfort, to relieve distress, and to stop or reverse

the abnormal process. These goals are the same in

the treatment of a patient with nerve agent intoxication.

If a patient has severe dyspnea or vomiting (or

retching), he or she may be unable to vocalize, but

it can be assumed that the discomfort is severe.

Therapy should be titrated against the complaints

of dyspnea and objective manifestations such as

retching; administration of the contents of MARK I

kits (or atropine alone) should be continued at intervals until relief is obtained. Seldom are more than

two to three MARK I kits required to provide relief. Because eye or head pain is not relieved by

MARK I injections, a patient with severe eye or head

pain from miosis will complain when he has no

other injury that causes more overwhelming discomfort. Topical application of atropine or homatropine is quite effective in relieving this severe pain.

The signs of severe distress in a fellow soldier,

such as twitching, convulsions, gasping for breath,

and apnea, can be recognized by even a relatively

untrained observer. A casualty’s buddy will usually act appropriately, but because a buddy’s resources are few, the level of assistance is limited: a

buddy can administer three MARK I kits and diazepam and then seek medical assistance. In a more

sophisticated setting, adequate ventilation is the

highest priority, but even the best ventilators help

little in the presence of copious secretions and high

resistance in the airways. Atropine must be given

until secretions (nose, mouth, airways) are decreased and resistance to assisted ventilation is

minimal.

The goals of therapy must be realistic. Current

drugs will not immediately restore consciousness

or respiration or completely reverse the skeletal

muscle abnormalities, nor will intramuscular or

intravenous drug therapy reverse miosis. Muscular fasciculations and small amounts of twitching

may continue in a conscious patient long after adequate ventilation is restored and the patient is

walking and talking.

Although in practice exposure categories are

never clear-cut, different therapeutic measures are

recommended for treating nerve agent casualties

who have different degrees of exposure severity.

Treatment is based on the signs and symptoms

caused by the particular exposure (Table 5-7). The

following suggested exposure categories are based

on the casualty’s presenting signs and symptoms.

Suspected Exposure

Suspected, but unconfirmed, exposure to a nerve

agent sometimes occurs in an area where liquid

agent was present. A person without signs or symptoms may be unsure whether he is contaminated.

In such cases, the suspected casualty should be thoroughly and completely decontaminated and kept

under close medical observation for 18 hours. If a

laboratory facility is available, blood should be

drawn for measurement of RBC-ChE activity.

An individual working with nerve agent in an

industrial or laboratory environment will have a

baseline RBC-ChE activity value on record. If this

value is still at baseline after a possible exposure,

then no significant absorption has occurred, and the

new value provides confirmation of the baseline.

(See Blood Cholinesterases section, above, on RBCChE activity monitoring.) If the activity is decreased, however, then absorption of the agent has

occurred, but the decision to begin therapy should

be based on signs or symptoms, not on the RBCChE activity (with one possible exception: an asymptomatic worker with decreased ChE activity; see

Oxime Therapy section, above). The medical care

provider must remember that the nadir of RBCChE activity may not occur for 18 to 24 hours, and

if there has been no oxime therapy, then the final

sample for analysis must be drawn during that time

period.

Since the onset of effects caused by nerve agent

exposure may occur as long as 18 hours after skin

contact, prolonged observation is prudent. The

longer the interval until the onset of signs and

symptoms, the less severe they will be, but medical

assistance will still be necessary. Since vapor (or

inhaled aerosol) causes effects within seconds or

minutes, it is extremely unlikely that a “suspected”

asymptomatic casualty would be produced by this

route.
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167

TABLE 5-7

RECOMMENDED THERAPY FOR CASUALTIES OF NERVE AGENTS

Exposure

Exposure Route Category Signs and Symptoms Therapy

Minimal Miosis with or without rhinorrhea; < 5 min of exposure: 1 MARK I kit

reflex nausea and vomiting > 5 min of exposure*: observation

Mild Miosis; rhinorrhea; mild dyspnea; < 5 min of exposure: 2 MARK I kits

reflex nausea and vomiting > 5 min of exposure: 0 or 1 MARK I

kit, depending on severity of

dyspnea

Moderate Miosis; rhinorrhea; moderate to < 5 min of exposure: 3 MARK I kits

severe dyspnea; reflex nausea + diazepam

and vomiting > 5 min of exposure: 1–2 MARK I kits

Moderately severe Severe dyspnea; gastrointestinal 3 MARK I kits; standby ventilatory

or neuromuscular signs support; diazepam

Severe Loss of consciousness; convulsions; 3 MARK I kits; ventilatory support,

flaccid paralysis; apnea suction; diazepam

Mild Localized sweating, fasciculations 1 MARK I kit

Moderate Gastrointestinal signs and symptoms 1 MARK I kit

Moderately severe Gastrointestinal signs plus 3 MARK I kits; standby ventilatory

respiratory or neuromuscular signs support

Severe Same as for severe vapor exposure 3 MARK I kits; ventilatory support,

suction; diazepam

*Casualty has been out of contaminated environment during this time.

Dermal (Liquid on

Skin)

Inhalational (Vapor)

Minimal Exposure

Miosis, with accompanying eye symptoms, and

rhinorrhea are signs of a minimal exposure to a

nerve agent, either vapor or vapor and liquid. This

distinction is quite important in the management

of this casualty. There are many situations in which

one can be reasonably certain that exposure was by

vapor alone (if the casualty was standing downwind from a munition or container, for example, or

standing across a laboratory or storeroom from a

spilled agent or leaking container). On the other

hand, if an unprotected individual is close to an

agent splash or is walking in areas where liquid

agent is present, exposure may be by both routes.

Effects from vapor exposure occur quickly and are

at their maximum within minutes, whereas effects

from liquid agent on the skin may not occur until

hours later.

Atropine (and oxime) should not be given for

miosis because it is ineffective in the usual doses (2

or 4 mg). If eye pain (or head pain) is severe, topical atropine or homatropine should be given. However, the visual blurring caused by atropine versus

the relatively small amount of visual impairment

caused by miosis must be considered. If the rhinorrhea is severe and troublesome, atropine (the 2 mg

contained in one MARK I kit) may give some relief.

If liquid exposure is suspected, the patient must

be kept under observation, as noted above. If liquid exposure can be excluded, there is no reason

for prolonged observation.

Mild Exposure

An individual with mild or moderate dyspnea

and possibly with miosis, rhinorrhea, or both

can be classified as having a mild exposure to

nerve agent. The symptoms indicate that the casualty has been exposed to a nerve agent vapor

and may or may not have been contaminated by a

liquid agent.

If an exposed person in this category is seen

within several minutes after exposure, he should
Medical Aspects of Chemical and Biological Warfare

168

receive the contents of two MARK I kits immediately. If 5 to 10 minutes have passed since exposure,

the contents of only one kit should be given immediately. If no improvement occurs within 5 minutes

under either circumstance, the casualty should receive the contents of another MARK I kit. The contents of an additional kit may be given if the

casualty’s condition worsens 5 to 10 minutes later,

but it is unlikely that it will be needed. Only three

oxime autoinjectors should be given; further

therapy should be with atropine alone.

A person having mild exposure to a nerve agent

should be thoroughly decontaminated (exposure to

vapor alone does not require decontamination) and

have blood drawn for measurement of RBC-AChE

activity prior to MARK I administration if facilities

are available for the assay. As noted above, if there

is reason to suspect liquid exposure, the casualty

should be observed longer.

Moderate Exposure

A casualty who has had moderate exposure to

either a nerve agent vapor alone or to vapor and

liquid will have severe dyspnea, with accompanying physical signs, and probably also miosis and

rhinorrhea. The casualty should be thoroughly decontaminated (REMEMBER: exposure to vapor alone

does not require decontamination) and blood

should be drawn for assay of RBC-ChE activity if

assay facilities are available. The contents of three

MARK I kits and diazepam should be given if the

casualty is seen within minutes of exposure. If seen

later than 10 minutes after exposure, the casualty

should receive the contents of two kits. Additional

atropine should be given at 5- to 10-minute intervals until the dyspnea subsides. No more than three

MARK I kits should be used; however, additional

atropine alone should be administered if the contents of three kits do not relieve the dyspnea after

10 to 15 minutes. If there is reason to suspect liquid

contamination, the patient should be kept under

observation for 18 hours.

Nausea and vomiting are frequently the first effects from liquid contamination; the sooner after

exposure they appear, the more ominous the outlook. Therapy should be more aggressive when

these symptoms occur within an hour after exposure than when there is a longer delay in onset. If

the onset is about an hour or less from the known

time of liquid exposure, the contents of two MARK

I kits should be administered initially, and further

therapy (the contents of MARK I kits to a total of

three, then atropine alone) given at 5- to 10-minute

intervals, with a maximum of three oxime injections. If the onset is several hours after the time of

known exposure, the contents of one MARK I kit

should be given initially, and additional MARK I

kits as needed to a total of three. Atropine alone

should be used after the third MARK I. If the time

of exposure is unknown, the contents of two MARK

I kits should be administered.

Nausea and vomiting that occur several hours

after exposure have been treated successfully with

2 or 4 mg of atropine, and the symptoms did not

recur. However, the exposure was single-site exposure (one drop at one place). It is not certain that

this treatment will be successful if exposure is from

a splash or from environmental contamination with

multiple sites of exposure on the skin. Therefore,

casualties with this degree of exposure should be

observed closely for at least 18 hours after the onset of signs and symptoms.

Moderately Severe Exposure

In cases of moderately severe exposure, the casualty will be conscious and have one or more of

the following signs and symptoms: severe respiratory distress (marked dyspnea and objective signs

of pulmonary impairment such as wheezes and

rales), marked secretions from the mouth and nose,

nausea and vomiting (or retching), and muscular

fasciculations and twitches. Miosis may be present

if exposure was by vapor, but it is a relatively insignificant sign as a guideline for therapy in this

context.

The contents of three MARK I kits should be administered immediately. Preferably, if the means are

available, 2 or 4 mg of atropine should be given intravenously, and the remainder of the total amount

of 6 mg of atropine, along with the three oxime injections, should be given intramuscularly. The anticonvulsant diazepam should always be given

when the contents of three MARK I kits are administered together. The casualty should be thoroughly

decontaminated and have blood drawn for AChE

assay before oxime is given.

Again, knowledge of the route of exposure is

useful in planning further treatment. If the exposure was by vapor only and the casualty is seen in

a vapor-free environment some minutes later, drug

therapy should result in improvement. If the casualty has not lost consciousness, has not convulsed,

and has not become apneic, he should improve. If

the exposure was the result of liquid agent or a combination of liquid and vapor, there may be a reservoir of unabsorbed agent in the skin; despite the
Nerve Agents

169

initial therapy, the casualty’s condition may worsen.

In either case, medical care providers should be

prepared to provide ventilatory assistance, including adequate suction, and additional drug therapy

(atropine alone) if there is no improvement within

5 minutes after intravenous administration of atropine, or 5 to 10 minutes after intramuscular administration of atropine.

The triad of consciousness, lack of convulsive

activity, and spontaneous respiration is an indicator of a good outcome, provided adequate therapy

is given early.

Severe Exposure

A casualty who is severely exposed to a nerve

agent will be unconscious. He may be apneic or

gasping for air with marked cyanosis, and may be

convulsing or postictal. The casualty will have copious secretions from the mouth and nose and will

have generalized fasciculations in addition to convulsive or large-muscle twitching movements. If the

casualty is postictal, he may be flaccid and apneic.

If the casualty shows no movement, including

no signs of respiration, the initial response should

be to determine if the heart is beating. This is not

an easy task when the rescuer and the casualty are

both in full mission-oriented protective posture

(MOPP 4) gear, but it must be accomplished because

a nonmoving, nonbreathing casualty without a

heartbeat is not a candidate for further attention on

the battlefield. In a medical treatment facility, the

medical personnel may be slightly more optimistic

and proceed with aggressive therapy. After the sarin

release in the Tokyo, Japan, subways, several casualties who were not breathing and who had no cardiac activity were taken to a hospital emergency

department. Because of very vigorous and aggressive medical management, one or two of these casualties were able to walk out of the hospital several days later.

Despite the circumstances, self-protection from

contamination from the patient is important. Since

decontamination of the patient may not be the first

priority, caregivers must wear appropriate protective equipment until they have an opportunity to

decontaminate the casualty and to remove him and

themselves from the contaminated area.

The success of therapy under these circumstances

is directly proportional to the viability of the

casualty’s cardiovascular system. If the heart rate

is very slow or nonexistent or if there is severe hypotension, the chances for success are poor, even in

the best possible circumstances.

First, medical personnel must provide oxygenation and administer atropine by a technique that

ensures it will be carried to the heart and lungs. If

ventilatory assistance is not immediately available,

the best treatment is to administer the contents of

three MARK I kits and diazepam. If ventilatory assistance will be forthcoming within minutes, the

contents of the three MARK I kits should be administered whether the circulation is intact or not. When

there is no chance of rapid ventilatory assistance,

little is gained by MARK I therapy, but an attempt

at treatment should be made anyway.

In the case of a failed or failing cardiovascular

system, routes of atropine administration other than

intramuscular should be considered. The intravenous

route generally provides the fastest delivery of the

drug throughout the body, but it is not without danger in an apneic and cyanotic patient. Whether or not

concomitant ventilatory support can be provided,

military medical personnel might want to consider

administering atropine intratracheally by needle and

syringe, if available, or with the atropine autoinjector

(the AtroPen). Even if the casualty’s systemic blood

pressure is low, the peribronchial circulation may

still have adequate blood flow to carry the drug to

vital areas. If an endotracheal tube can be inserted,

atropine could be injected into the tube either by

needle and syringe or with the injector.

For severely exposed casualties, the initial dose

of atropine should be at least the 6 mg from the three

autoinjectors, but an additional 2 mg or 4 mg should

also be given intravenously—if the capability is

available and if the casualty is not hypoxic (ventilatory support must be started before intravenous

atropine is given). If additional atropine cannot be

given intravenously, then the amount should be

given intramuscularly. The total initial dose of atropine can be as much as 10 mg, but this dose should

not be exceeded without allowing at least several

minutes for a response. Further atropine administration depends on the response. If secretions decrease or if there are attempts at breathing, it might

be prudent to wait even longer before administering additional atropine. All three injectors of 2-PAM

Cl should be given with the initial 6 mg of atropine,

but no more oxime should be given for an hour.

Possibly the most critical factor in treatment of

severely exposed casualties is restoration of oxygenation. Atropine alone might restore spontaneous

breathing in a small number of apneic individuals. Ideally, an apparatus that delivers oxy gen under positive pressure will be available. Even an

RDIC or a mask-valve-bag apparatus used with

ambient air will provide some assistance.
Medical Aspects of Chemical and Biological Warfare

170

When the contents of three MARK I kits are administered together to a severely poisoned casualty,

diazepam should be administered with the contents

of the third MARK I—whether or not there are indications of seizure activity. The risk of respiratory

depression from this amount of diazepam given

intramuscularly is negligible.

Hypotension per se need not be treated, at least

initially. Generally the restoration of oxygenation

and the increase in heart rate caused by atropine,

aided perhaps by the hypertensive effects of 2-PAM

Cl, will cause the blood pressure to increase to an

acceptable level.

Even with adequate oxygenation and large

amounts of atropine, immediate reversal of all of

the effects of the nerve agent will not occur. The

casualty may remain unconscious, without spontaneous respiration and with muscular flaccidity or

twitching, for hours. Even after respiration is at least

partly spontaneous, secretions are minimized, and

the casualty is partly alert, close monitoring is necessary. Muscular fasciculations may continue for

hours after the casualty is alert enough and has

strength enough to get out of bed.

RETURN TO DUTY

Various factors should be considered before an

individual who has been a nerve agent casualty is

returned to duty. In an industrial setting (depot or

laboratory), the criteria for reactivation are that the

individual’s RBC-ChE activity must have returned

to within 80% of its baseline value and that the individual is otherwise symptom- and sign-free.

In a military field setting, however, ChE-activity

measurements are not available, and the need to

return the fighting soldier to duty may be more

acute. The decision is largely a matter of judgment

and should include the following considerations:

• If exposed to nerve agent again, will the

soldier be in greater danger because of the

previous exposure?

• How well can the soldier function?

• What is the military need for the soldier?

In the absence of blood ChE measurements, it is

difficult to predict whether a soldier would be at

greater risk from a second nerve agent exposure.

Even an individual with rather mild effects (miosis

and rhinorrhea) may have marked ChE inhibition.

On the other hand, if an oxime (contained in the

MARK I kit) was given and the agent was one susceptible to oxime therapy, then the enzy me activity

may be restored. In a field setting, neither the identity of the agent nor the degree of ChE inhibition or

restoration will be known. In any case, proper use

of MOPP 4 gear should protect against further exposure. If the soldier is able and needed, he should

be returned to duty.

A soldier who has had signs of severe exposure,

with loss of consciousness, apnea, and convulsions,

may have milder CNS effects for many weeks after

recovery from the acute phase of intoxication. Except

in dire circumstances, return to duty during this period should not be considered for such casualties.

An individual with relatively mild effects (miosis, dyspnea, rhinorrhea) may be returned to duty

within 1 to several days or even hours, depending

on the assignment and the military need. However,

the soldier may experience visual problems in dim

light and may have mental lapses for as long as 6 to

8 weeks18 (and personal observation); these factors

must be considered before returning a soldier to

duty. Several observations support this conclusion.

In one case, troops who were symptomatic (miosis,

rhinorrhea, dyspnea) as a result of nerve agent exposure carried out maneuvers (including firing

weapons) in a satisfactory, although suboptimal,

manner. They did not do nearly as well at night

because of visual problems.79

In another instance, workers in an industrial operation learned the effects of the agent after they

had accidentally been exposed several times. They

also learned that it was a bigger problem to seek

medical aid (with the ensuing administrative processes) than to continue working in the presence of

symptoms. They stopped going to the aid station if

they noted the onset of only mild effects. These

workers were generally not in positions requiring

acute vision or complex decisions; it is not known

how well they performed while symptomatic. However, they could continue to perform their jobs, and

their supervisors apparently did not notice a decrement (personal observation).

The need for soldiers in a frontline military

operation may require that every walking casualty be returned to duty. In an otherwise asymptomatic casualty, the primary limiting factors will

be (1) the soldier’s visual acuity compared with

the visual demands of the job and (2) the soldier’s

mental status compared with the intellectual demands of the job. Prolonged mental changes can be

subtle and may require a careful examination to

detect.
Nerve Agents

171

SUMMARY

crine glands, hyperactivity of skeletal muscles

leading to fatigue and paralysis, hyperactivity

of smooth muscles with bronchoconstriction,

and CNS changes, including seizure activity and

apnea.

Therapy is based on the administration of atropine, which interferes with receptor binding of acetylcholine at muscarinic but not nicotinic receptors,

and the oxime 2-PAM Cl, which breaks the agent–

enzyme bond formed by most agents. Assisted ventilation and other supportive measures are also required in severe poisoning.

Nerve agents are the most toxic chemical warfare agents known. They cause effects within seconds and death within minutes. These agents are

in the military stockpiles of several countries but

have been used in only one war. They can be manufactured by terrorist groups and have been used in

terrorist attacks.

Nerve agents cause biological effects by inhibiting the enzyme AChE, causing an excess of

the neurotransmitter to accumulate. Hyperactivity in those organs innervated by cholinergic nerves

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Pretreatment for Nerve Agent Exposure

181

Chapter 6

PRETREATMENT FOR NERVE

AGENT EXPOSURE

MICHAEL A. DUNN, M.D., FACP*; BRENNIE E. HACKLEY, JR., PH.D.†; AND FREDERICK R. SIDELL, M.D.‡

INTRODUCTION

AGING OF NERVE AGENT–BOUND ACETYLCHOLINESTERASE

PYRIDOSTIGMINE, A PERIPHERALLY ACTING CARBAMATE COMPOUND

Efficacy

Safety

Wartime Use

Improved Delivery

CENTRALLY ACTING NERVE AGENT PRETREATMENTS

NEW DIRECTIONS: BIOTECHNOLOGICAL PRETREATMENTS

SUMMARY

*Colonel, Medical Corps, U.S. Army; Director, Clinical Consultation, Office of the Assistant Secretary of Defense (Health Affairs), Washington, D.C. 20301-1200; formerly, Commander, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425

†Scientific Advisor, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425

‡Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014
Medical Aspects of Chemical and Biological Warfare

182

INTRODUCTION

Nerve agents are rapidly acting chemical compounds that can cause respiratory arrest within

minutes of absorption. Their speed of action imposes a need for rapid and appropriate reaction by

exposed soldiers, their buddies, or medics, who

must administer antidotes quickly enough to save

lives. A medical defense against nerve agents that

depends completely on postexposure antidote treatment, however, has two key limitations:

• In the stress of a chemical environment,

even well-trained military personnel will

not be uniformly successful in performing

such tasks as self- and buddy-administration of nerve agent antidotes.1

• Aging, a change over time in the interaction of nerve agents with the target enzyme

acetylcholinesterase (AChE), renders oxime

therapy (an important component of nerve

agent antidotes) much less effective.2 As

explained below, aging poses an especially

difficult problem for treating effects from

the nerve agent soman.

Because of these limitations of postexposure protection, military physicians have focused on the

possibility of protecting soldiers from nerve agents

by medical prophylaxis, or pretreatment, designed

to limit the toxicity of a subsequent nerve agent exposure. A significant problem with pretreatments,

however, has been their own potential for adverse

effects. In general, the pharmacological pretreatments

that protect humans from the toxic effects of nerve

agents are themselves neuroactive compounds.

Thus, their principal adverse actions are neurological as well and may impair physical and mental

performance. A pretreatment must be administered

to an entire force under a nerve agent threat. Any

resulting performance decrement, even a comparatively minor one, would make pretreatment use

unacceptable in battlefield situations requiring

maximum alertness and performance for survival.

In the late 1980s, the United States, following the

example of Great Britain, stocked the compound

pyridostigmine for its combat units as a wartime

contingency pretreatment adjunct for nerve agent

exposure.3

 Several other Allies, including most

members of the North Atlantic Treaty Organization

(NATO), did so as well. At the recommended dose,

pyridostigmine is free of performance-limiting side

effects. Unfortunately, pyridostigmine by itself is

ineffective as a pretreatment against subsequent

nerve agent exposure and thus it is not a true pretreatment compound. Pyridostigmine pretreatment

does provide greatly improved protection against

soman exposure, however, when combined with

postexposure antidote therapy. For this reason,

pyridostigmine is classified as a pretreatment adjunct.

Research workers have attempted to develop true

nerve agent pretreatments whose own neurotoxicity is balanced or diminished by coadministration

of a pharmacological antagonist to their undesirable properties (eg, the carbamate compound physostigmine, which is administered in combination

with a cholinolytic compound, such as scopolamine). The potential and the problems of this pretreatment approach are considered in this chapter,

along with a new pretreatment concept that involves inactivating or binding nerve agents with

scavenger macromolecules in the circulation.

AGING OF NERVE AGENT–BOUND ACETYLCHOLINESTERASE

Organophosphate nerve agents inhibit the active

site of AChE, a key enzymatic regulator of cholinergic neurotransmission. As noted in Chapter 5,

Nerve Agents, agent-bound AChE can be reactivated by a class of antidote compounds, the oximes,

which remove the nerve agent molecule from the

catalytic site of AChE.

During the attachment of the agent with the enzyme, a portion of the agent—the leaving group—

breaks off. During a second, later reaction, one of

the nerve agent’s alkyl groups leaves: this is the

process known as aging. The rate at which this dealkylation of the AChE-bound nerve agent molecule proceeds depends on the nature of the nerve agent.

Table 6-1 shows the aging half-time of each of the

five chemical compounds commonly considered to

be nerve agents: tabun (GA), sarin (GB), soman

(GD), GF, and VX.

Aging is an irreversible reaction. After dealkylation, an AChE-bound nerve agent molecule

can no longer be removed from the enzyme by

an oxime. Thus, aging of enzyme-bound nerve

agent prevents oxime antidotes from reactivating

AChE. This is an extremely difficult problem in the
Pretreatment for Nerve Agent Exposure

183

case of poisoning with soman, which ages within 2

minutes.

Aging appears to be a key limiting factor in the

efficacy of postexposure oxime therapy for soman

poisoning. One method for assessing the relative

efficacy of antidotes and other countermeasures is

the determination of their protective ratios. The

protective ratio (PR) of an antidote is the factor by

which it raises the LD50 or the LCt50 of a toxic nerve

agent challenge. Readers will remember that LD50

is defined as the dose (D) of liquid or solid nerve

agent that is lethal (L) to 50% of the subjects exposed to it; LD50 is also described as the median

lethal dose. LCt50 is the term used to describe the

median lethal concentration for an aerosol or vapor agent, expressed as concentration (C) • time (t)

PYRIDOSTIGMINE, A PERIPHERALLY ACTING CARBAMATE COMPOUND

Pyridostigmine is one of a class of neuroactive compounds called carbamates. Its chemical

structure and that of a related carbamate, physostigmine, are shown below. Like the nerve agents,

carbamates inhibit the enzymatic activity of AChE.

As a quaternary amine, pyridostigmine is ionized

under normal physiological conditions and penetrates poorly into the central nervous system

(CNS). Pyridostigmine has been used for many

years in the therapy of neurological disorders,

especially myasthenia gravis, a disease of neuromuscular transmission. In patients with myasthenia gravis, inhibition of synaptic AChE is clinically

beneficial.

As an inhibitor of AChE, pyridostigmine in large

doses mimics the peripheral toxic effects of the orof exposure (mg•min). For example, a PR of 1.0

would indicate a completely ineffective antidote,

because it means that the LD50 or LCt50 is the same

for subjects who received an antidote and those who

did not. A PR of 5, on the other hand, indicates that

the LD50 or LCt50 for subjects who received an antidote is 5-fold higher than that for subjects who

did not receive one. A PR of 5 or greater is considered to represent a reasonable level of effectiveness

for medical countermeasures against nerve agents.

This value was determined through threat analysis

of battlefield conditions and consideration of the

fact that trained and equipped soldiers will be able

to achieve at least partial protection against nerve

agent attacks by rapid donning of masks and use

of chemical protective clothing.

TABLE 6-1

AGING HALF-TIME OF NERVE AGENTS

Aging

Nerve Agent RBC-ChE Source Half-Time

GA (Tabun) Human (in vitro) >14 h1

Human (in vitro) 13.3 h2

GB (Sarin) Human (in vivo) 5 h3

Human (in vitro) 3 h1

GD (Soman) Marmoset (in vivo) 1.0 min4

Guinea pig (in vivo) 7.5 min4

Rat (in vivo) 8.6 min4

Human (in vitro) 2–6 min1

GF Human (in vitro) 40 h1

Human (in vitro) 7.5 h5

VX Human (in vivo) 48 h3

RBC-ChE: erythrocyte cholinesterase

Data sources: (1) Mager PP. Multidimensional Pharmacochemistry.

San Diego, Calif: Academic Press; 1984: 52–53. (2) Doctor BP,

Blick DW, Caranto G, et al. Cholinesterases as scavengers for

organophosphorus compounds: Protection of primate performance against soman toxicity. Chem Biol Interact. 1993;87:285–

293. (3) Sidell FR, Groff WA. The reactivatibility of cholinesterase inhibited by VX and sarin in man. Toxicol Appl Pharm.

1974;27:241–252. (4) Talbot BG, Anderson DR, Harris LW,

Yarbrough LW, Lennox WJ. A comparison of in vivo and in vitro

rates of aging of soman-inhibited erythrocyte acetylcholinesterase in different animal species. Drug Chem Toxicol. 1988;11:289–

305. (5) Hill DL, Thomas NC. Reactivation by 2-PAM Cl of Human Red Blood Cell Cholinesterase Poisoned in vitro by Cyclohexylmethylphosphonofluoridate (GF). Edgewood Arsenal, Md: Medical Research Laboratory; 1969. Edgewood Arsenal Technical

Report 43-13.
Medical Aspects of Chemical and Biological Warfare

184

ganophosphate nerve agents. At first it might seem

paradoxical that carbamate compounds should help

protect against nerve agent poisoning, but two critical characteristics of the carbamate–enzyme bond

explain the usefulness of the carbamates.

First, carbamoylation, the interaction between

carbamates and the active site of AChE, is freely

and spontaneously reversible, unlike the normally

irreversible inhibition of AChE by the nerve agents.

No oxime reactivators are needed to dissociate, or

decarbamoylate, the enzyme from a carbamate compound. Carbamates do not undergo the aging reaction of nerve agents bound to AChE.

Second, carbamoylated AChE is fully protected

from attack by nerve agents because the active site

of the carbamoylated enzyme is not accessible for

binding of nerve agent molecules. Functionally,

sufficient excess AChE activity is normally present

in synapses so that carbamoylation of 20% to 40%

of the enzyme with pyridostigmine does not significantly impair neurotransmission.

When animals are challenged with a lethal dose

of nerve agent, AChE activity normally decreases

rapidly, becoming too low to measure. In pyridostigmine-pretreated animals with a sufficient quantity of protected, carbamoylated enzyme, spontaneous decarbamoylation of the enzyme regenerates

enough AChE activity to sustain vital functions,

such as neuromuscular transmission to support

respiration. Prompt postexposure administration

of atropine is still needed to antagonize acetylcholine (ACh) excess, and an oxime reactivator

must also be administered if an excess of nerve

agent remains to attack the newly uncovered

AChE active sites that were protected by pyridostigmine.

Efficacy

Exposure of humans to soman is virtually unknown in Western countries, with the exception of

a single laboratory accident.4

 The decision to provide military forces with pyridostigmine is therePyridostigmine Physostigmine

fore based on a series of animal efficacy studies5–7

conducted with several species in a number of countries that found evidence that pyridostigmine pretreatment strongly enhances postexposure antidote

therapy for soman poisoning.

Data from one experiment are shown in Table 6-

2. In this study7 with male rhesus monkeys, pretreatment with orally administered pyridostigmine

inhibited circulating red blood cell AChE (RBCAChE) by 20% to 45%. (Inhibition of RBC-AChE by

pyridostigmine is a useful index of its inhibition of

AChE in peripheral synapses). Monkeys that had

no pyridostigmine pretreatment were not well protected from soman by the prompt administration

of atropine and 2-pyridine aldoxime methyl chloride (2-PAM Cl). The PR of 1.64 in these monkeys is

typical of the most effective known postexposure

antidote therapy in animals not given pretreatment

before a soman challenge. In contrast to this low

level of protection, however, the combination of

pyridostigmine pretreatment and prompt postchallenge administration of atropine and 2-PAM Cl

resulted in greatly improved protection (PR > 40

when compared with the control group; PR = 24

when compared with the group given atropine and

2-PAM Cl).7

Limitation of the number of animals available for

soman challenge at extremely high doses made accurate calculation of a PR indeterminate in this experiment. The PR was well in excess of 40, clearly

meeting the requirement for effectiveness of 5-fold

improved protection. In a later study,8

 four of five

rhesus monkeys receiving pyridostigmine pretreatment and postexposure therapy of atropine and 2-

PAM Cl survived for 48 hours after being challenged

with soman at a level 5-fold higher than its LD50.

Pyridostigmine pretreatment shows its strongest

benefit (compared with atropine and oxime therapy

alone) in animals challenged with soman and tabun

and provides no benefit against challenge by sarin

or VX.9–11 Table 6-3 shows the PRs obtained in animals given atropine and oxime therapy after challenge with the five nerve agents with and without

N N

CH3

CH3 CH3

C O

O

H3C N

H

C O N CH3

O

N

H3C

H3C

+
Pretreatment for Nerve Agent Exposure

185

TABLE 6-2

EFFECT OF THERAPY ON LD50 IN MONKEYS EXPOSED TO SOMAN

Group Mean LD50(μg/kg) [95% CL] Mean Protective Ratio [95% CL]

Control (no treatment) 15.3 [13.7–17.1] —

Postexposure atropine + 2-PAM Cl 25.1 [22.0–28.8] 1.64 [1.38–19.5]

Pyridostigmine pretreatment

+ postexposure atropine + 2-PAM Cl > 617 > 40*

*Indeterminate because of small number of subjects; PR relative to the atropine plus 2-PAM Cl group > 24 (617 ÷ 25.1)

CL: confidence limit (based on a separate slopes model)

LD50: the dose that is lethal to 50% of the exposed population

PR: factor by which the LD50 of a nerve agent challenge is raised (in this experiment, the LD50 for group given therapy divided by

the LD50 for control group)

2-PAM Cl: 2-pyridine aldoxime methyl chloride

Adapted from Kluwe WM. Efficacy of pyridostigmine against soman intoxication in a primate model. In: Proceedings of the Sixth

Medical Chemical Defense Bioscience Review. Aberdeen Proving Ground, Md: US Army Medical Research Institute of Chemical Defense; 1987: 233.

pyridostigmine pretreatment.9 As shown, pyridostigmine pretreatment is essential for improved

survival against soman and tabun challenge. With

sarin or VX, depending on the animal system studied, pyridostigmine causes either no change or a

minor decrease in PRs, which still indicate strong

efficacy of atropine and oxime therapy for exposure

to these agents. The data for GF show no benefit

from pyridostigmine pretreatment for mice and a

small benefit for guinea pigs. The only published

data8 on protection of primates from GF show a PR

of more than 5 with pyridostigmine pretreatment

and atropine/oxime therapy, but a control group

treated with atropine/oxime alone for comparison

was not included. Clinical experts from all countries who have evaluated pyridostigmine have concluded from these data that it is an essential pretreatment adjunct for nerve agent threats under

combat conditions, where the identity of threat

agents is virtually never known with certainty.

Pyridostigmine was used to protect soldiers from

an actual nerve agent threat in the Persian Gulf War.

NATO Allies using pyridostigmine followed their

national policies on chemical protection. British

soldiers, for example, were ordered to take pyridostigmine for over a month while they were positioned near the Iraqi border. U.S. forces followed

the doctrine of only using pyridostigmine when a

nerve agent threat was assessed to be imminent by

the responsible division- or corps-level commander.

Thus, soldiers of the U.S. XVIII Airborne Corps took

pyridostigmine for several days in January 1991

until it was determined that SCUD missiles fired

against them did not have chemical loads. Later,

U.S. ground forces attacking into Iraq and Kuwait

used pyridostigmine only as long as the corps-level

commanders on the ground considered the Iraqi

chemical capability a threat.

U.S. and Allied decisions to use pyridostigmine

followed established doctrine, taking into account

Iraqi capabilities and intentions. Iraq was known

to have substantial stocks of sarin and VX, for which

pyridostigmine pretreatment is unnecessary, as discussed above. However, Iraq was also known to be

keenly interested in acquiring any compounds that

might defeat Allied protection, such as soman. The

security of Warsaw Pact stocks of soman, for example, was a growing concern in 1990.

In 1990, it was also known that Iraq had begun

large-scale production of GF, a laboratory compound that had not earlier been manufactured in

weapons quantity. International restrictions on the

purchase of chemical precursors of the betterknown nerve agents may have led Iraq to acquire

cyclohexyl alcohol, which it then was able to use to

produce GF. Very limited data on medical protection against GF were not reassuring. Although GF’s

aging time with AChE was reported to be relatively

long (see Table 6-1), unpublished information from

Allied countries suggested that postexposure atropine/oxime therapy in rodents exposed to GF did

not protect against the effects of GF poisoning. As

confirmed by the later studies shown in Table 6-3,

atropine/oxime therapy only provided rodents
Medical Aspects of Chemical and Biological Warfare

186

TABLE 6-3

EFFECT OF THERAPY WITH AND WITHOUT PYRIDOSTIGMINE PRETREATMENT ON

PROTECTIVE RATIOS IN ANIMALS EXPOSED TO NERVE AGENTS

Protective Ratio

Nerve Agent Animal Tested Atropine + Oxime Pyridostigmine + Atropine + Oxime

GA (Tabun) Rabbit 2.4 3.91

Mouse 1.3 1.7/2.1*2

Guinea pig 4.4 7.8/12.1*2

Rabbit 4.2 > 8.53

GB (Sarin) Mouse 2.1 2.2/2.0*2

Guinea pig 36.4 34.9/23.8*2

GD (Soman) Mouse 1.1 2.54

Rat 1.2 1.45

Guinea pig 1.5 6.4/5.0*6

Guinea pig 2.0 2.7/7.1*7

Guinea pig 1.9 4.98

Guinea pig 1.7 6.89

Rabbit 1.4 1.51

Rabbit 2.2 3.14

Rabbit 1.9 2.83

Rhesus monkey 1.6 > 4010

GF Mouse 1.4 1.411

Guinea pig 2.7 3.411

Rhesus monkey —- > 512

VX Mouse 7.8 6.0/3.9*2

Rat 2.5 2.15

Guinea pig 58.8 47.1/45.3*2

*Two doses of pyridostigmine were used.

Data sources: (1) Joiner RL, Dill GS, Hobson DW, et al. Task 87-35: Evaluating the efficacy of antidote drug combinations against

soman or tabun toxicity in the rabbit. Columbus, Oh: Battelle Memorial Institute; 1988. (2) Koplovitz I, Harris LW, Anderson DR,

Lennox WJ, Stewart JR. Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX

poisoning in rodents. Fundam Appl Toxicol. 1992;18:102–106. (3) Koplovitz I, Stewart JR. A comparison of the efficacy of HI6 and 2-

PAM against soman, tabun, sarin, and VX in the rabbit. Toxicol Lett. 1994;70:269–279. (4) Sultan WE, Lennox WJ. Comparison of the

Efficacy of Various Therapeutic Regimens, With and Without Pyridostigmine Prophylaxis, for Soman (GD) Poisoning in Mice and Rabbits.

Aberdeen Proving Ground, Md: US Army Chemical Systems Labororatory; 1983. ARCSL Technical Report 83103. (5) Anderson DR,

Harris LW, Woodard CL, Lennox WJ. The effect of pyridostigmine pretreatment on oxime efficacy against intoxication by soman or

VX in rats. Drug Chem Toxicol. 1992;15:285–294. (6) Jones DE, Carter WH Jr, Carchman RA. Assessing pyridostigmine efficacy by

response surface modeling. Fundam Appl Toxicol. 1985;5:S242–S251. (7) Lennox WJ, Harris LW, Talbot BG, Anderson DR. Relationship between reversible acetylcholinesterase inhibition and efficacy against soman lethality. Life Sci. 1985;37:793–798. (8) Capacio

BR, Koplovitz I, Rockwood GA, et al. Drug Interaction Studies of Pyridostigmine With the 5HT3 Receptor Antagonists Ondansetron and

Granisetron in Guinea Pigs. Aberdeen Proving Ground, Md: US Army Medical Research Institute of Chemical Defense; 1995.

USAMRICD Training Report 95-05. AD B204964. (9) Inns RH, Leadbeater L. The efficacy of bispyridinium derivatives in the treatment of organophosphate poisoning in the guinea pig. J Pharm Pharmacol. 1983;35:427–433. (10) Kluwe WM. Efficacy of pyridostigmine

against soman intoxication in a primate model. In: Proceedings of the 6th Medical Chemical Defense Bioscience Review. Aberdeen Proving Ground, Md: US Army Medical Research Institute of Chemical Defense; 1987: 227–234. (11) Stewart JR, Koplovitz I. The effect of

pyridostigmine pretreatment on the efficacy of atropine and oxime treatment of cyclohexylmethylphosphonofluoridate (CMPF)

poisoning in rodents. Aberdeen Proving Ground, Md: US Army Medical Research Institute of Chemical Defense; 1993. Unpublished manuscript. (12) Koplovitz I, Gresham VC, Dochterman LW, Kaminskis A, Stewart JR. Evaluation of the toxicity, pathology,

and treatment of cyclohexylmethlyphosphonofluoridate (CMFF) poisoning in rhesus monkeys. Arch Toxicol. 1992;66:622–628.
Pretreatment for Nerve Agent Exposure

187

with PRs in the range of 1.4 to 2.7. The only primate data available showed that rhesus monkeys

given pyridostigmine pretreatment and atropine/

oxime therapy uniformly survived a 5-LD50 challenge with GF.8

 Concern about Iraq’s new GF capability, added to its known interest in acquiring

soman, made Allied use of pyridostigmine a reasonable course of action.

The fact that pyridostigmine inhibits AChE has

raised one theoretical problem with its use: if 20%

to 40% of AChE has been inhibited by pyridostigmine, would a subsequent low-level exposure

to a nerve agent, which might be well tolerated with

no pretreatment, be converted to a toxic dose if it

raised the total percentage of AChE inhibition into

a toxic range? In practice, it has not been possible

to clearly demonstrate such additive toxicity in

animal experiments, perhaps because the increase

in nerve agent toxicity from initial signs to lethality rises very sharply over a narrow exposure range.

A minor additive toxicity effect would therefore be difficult to detect. The signs of mild nerve

agent exposure are easily managed with antidote

therapy, and the benefit of a pretreatment in lifethreatening exposures is so great as to clearly warrant pyridostigmine pretreatment for soldiers

whose exact extent of nerve agent exposure is not

predictable.

The fact that an ionized, hydrophilic carbamate

compound such as pyridostigmine is effective as a

pretreatment adjunct against soman suggests that

its critical sites of action and, therefore, the critical

sites where soman exerts its lethal effects, are outside the blood–brain barrier. As noted in Chapter

5, Nerve Agents, respiratory arrest after lethal nerve

agent exposure appears to be a summation of the

agent’s effects on tracheobronchial secretions and

bronchoconstriction with obstruction, impairment

of neuromuscular transmission with respiratory

muscle insufficiency, and direct depression of central respiratory drive. Electrophysiological monitoring suggests that of these processes, central respiratory drive may be the most susceptible to nerve

agent toxicity.12

The effectiveness of pyridostigmine pretreatment

may not be conclusive evidence against the importance of central mechanisms in respiratory arrest;

it appears that there is at least partial permeability

of the blood–brain barrier to polar compounds such

as pyridostigmine, specifically in the regions of the

fourth ventricle and brainstem, where respiratory

centers are located. In addition, an increase in

blood–brain barrier permeability occurs rapidly

after soman administration.13,14 The key observation

remains that animals pretreated with pyridostigmine that receive atropine and oxime therapy

promptly after an otherwise lethal soman exposure

are able to maintain adequate respiration and survive.

The major deficiency of pyridostigmine pretreatment is also related to its poor penetration into the

brain. Animals that survive challenge with a supralethal dose of nerve agent because of pyridostigmine

pretreatment frequently show severe histological

evidence of brain injury, prolonged convulsions,

and long-lasting performance impairments.15 Although centrally acting carbamate pretreatment

compounds, such as physostigmine, offer a degree

of protection against nerve agent–induced brain

injury, pretreatment with known brain-protecting

compounds such as physostigmine, the benzodiazepine anticonvulsants, and benactyzine has not

been acceptable because of their known decremental effects on performance. Postexposure anticonvulsant therapy appears to be the most practical,

readily available approach to minimizing nerve

agent–induced brain injury and promoting rapid

recovery of normal function after severe nerve agent

exposure (for further discussion, see Chapter 5,

Nerve Agents).

Safety

Pyridostigmine has had a good safety record over

the years of its administration to patients with myasthenia gravis. Known adverse reactions have been

limited to infrequent drug rashes after oral administration and the complete set of signs of peripheral cholinergic excess, which have been seen only

when the dosage in patients with myasthenia gravis

was increased to AChE inhibition levels well beyond the 20% to 40% range desired for nerve agent

pretreatment. The effects of excessive pyridostigmine—miosis, sweating, intestinal hypermotility, and salivation—could clearly degrade soldiers’

performance.

When the recommended adult dose of 30 mg of

pyridostigmine bromide, one tablet orally every 8

hours, has been followed, no significant decrements

have been found in the performance of a variety of

military tasks. A review of British studies reported16

that pyridostigmine caused no changes in memory,

manual dexterity, vigilance, day and night driving

ability, or in psychological tests for cognitive and

psychomotor skills. No significant changes in sensory, motor, or cognitive functioning at ground

level, at 800 ft, and at 13,000 ft were noted in 12

subjects in another study17 after their fourth 30-mg

dose of pyridostigmine.
Medical Aspects of Chemical and Biological Warfare

188

The flight performance of subjects taking

pyridostigmine in two studies18,19 was not affected,

no impairment in neuromuscular function was

noted in a study20 in which subjects took pyridostigmine for 8 days, and cardiovascular and pulmonary function were normal at high altitudes in

pyridostigmine-treated subjects in another study.21

However, one study22 noted a slight decrement in

performance in subjects taking pyridostigmine

when they tried to perform two tasks at the same

time; these subjects also had a slight decrement on

a visual probability monitoring task. Two studies23,24

found an increase in sweating and a decrease in skin

blood flow in pyridostigmine-treated subjects subjected to heat/work stress.

Although there has been wide experience with

long-term administration of pyridostigmine to patients with myasthenia gravis, until recently there

was no comparable body of safety data in healthy

young adults. Short-term pyridostigmine administration (one or two 30-mg doses) has been conducted in peacetime in some countries, including

the United States, to screen critical personnel, such

as aircrew, for unusual or idiosyncratic reactions,

such as drug rash. The occurrence of such reactions

appears to be well below the 0.1% level, and no military populations are now routinely screened with

administration of a test dose of pyridostigmine.

Pyridostigmine for military use by the United

States is approved only as a wartime contingency

measure. After the Persian Gulf War, there was

much discussion about the use of pyridostigmine

under an Investigational New Drug (IND) application.25–32 The Food and Drug Administration (FDA)

waived informed consent for its use to make the

best medical treatment available in a specific combat situation.26 The FDA based this waiver on (a)

data from animal studies conducted in both the

United States and other NATO countries that found

that pyridostigmine increases survival when used

as pretreatment against challenge by certain nerve

agents (data on efficacy in humans challenged by

nerve agents is not experimentally obtained), and

(b) a long history of safety when the drug was used

for approved indications at doses severalfold higher

than the doses administered in the military. Rarely

considered in postwar discussions was the ethical

issue of nonuse: If pyridostigmine had not been

used, and Iraq had used nerve agents causing large

numbers of casualties, should the military have

been held responsible for withholding this drug?

A limited number of animal studies of toxicological abnormalities and teratogenicity and mutagenicity in animals that were given pyridostigmine

have had negative results (Hoffman-LaRoche, proprietary information).33 In a study34 in which

pyridostigmine was administered to rats, either

acutely or chronically, in doses sufficient to cause

an average 60% AChE inhibition, ultrastructural

alteration of a portion of the presynaptic mitochondria at the neuromuscular junction resulted, as well

as alterations of nerve terminal branches, postsynaptic mitochondria, and sarcomeres. These morphological findings, which occurred at twice the AChE

inhibition level desired in humans, have not been

correlated with any evidence of functional impairment at lower doses, but they emphasize the need

to limit enzyme inhibition to the target range of 20%

to 40%. Pyridostigmine has been used by pregnant

women with myasthenia gravis at higher doses and

for much longer periods than it was used during

the Persian Gulf War and has not been linked to

fetal malformations.35 Because safety in pregnancy

has not been completely established, the Food and

Drug Administration considers pyridostigmine a

Class C drug (ie, the risk cannot be ruled out).

Several studies have sought information on

pyridostigmine use under certain conditions: soldiers in combat who frequently take other medications; wounding and blood loss; and use while undergoing anesthesia. The possible interaction of

pyridostigmine with other commonly used battlefield medications was reviewed by Keeler.36 There

appears to be no pharmacological basis for expecting adverse interactions between pyridostigmine

and commonly used antibiotics, anesthetics, and

analgesic agents. In a study37 of pyridostigminetreated swine, for example, the autonomic circulatory responses to hemorrhagic shock and resuscitation appeared normal. One potentially important

effect of pyridostigmine deserves consideration by

field anesthesiologists and anesthetists using

muscle relaxants for anesthesia induction: depending on the duration of muscle-relaxant administration, there may be either up- or down-regulation of

postsynaptic ACh receptors.36 Clinical assessment

of the status of neuromuscular transmission using

a peripheral nerve stimulator should provide a basis for adjusting the dose of both depolarizing and

nondepolarizing muscle relaxants to avoid an undesirable duration of muscle paralysis.

Wartime Use

Pyridostigmine bromide tablets, 30 mg, to be

taken every 8 hours, are currently maintained in war
Pretreatment for Nerve Agent Exposure

189

Fig. 6-1. A pyridostigmine blister pack containing 21

30-mg tablets, along with the carrying sleeve. This is the

nerve agent pyridostigmine pretreatment set (NAPPS)

that was used by designated military personnel during

the Persian Gulf War.

stocks of U.S. combat units. The compound is packaged in a 21-tablet blister pack called the nerve

agent pyridostigmine pretreatment set (NAPPS,

Figure 6-1). One NAPPS packet provides a week of

pyridostigmine pretreatment for one soldier.3

The decision to begin pretreatment with pyridostigmine is made by commanders at army division

level or the equivalent, based on assessment of the

nerve agent threat by their chemical, intelligence,

and medical staff officers.3 Because of the lack of

data on long-term administration of pyridostigmine

to healthy adults, current doctrine calls for a maximum pretreatment period of 21 days, with reassessment at frequent intervals of the need for continued

pretreatment. A senior commander’s judgment about

the severity of a nerve agent threat beyond 21 days

determines whether pretreatment should continue.

Pyridostigmine is poorly absorbed when taken

orally; its bioavailability is 5% to 10%.38 Ideally, two

doses of pyridostigmine, taken 8 hours apart, should

be administered prior to any risk of nerve agent exposure.3

 However, some benefit would be expected

even if the first pyridostigmine dose is taken an hour

before nerve agent exposure. Because excessive AChE

inhibition can impair performance, no more than one

30-mg tablet should be taken every 8 hours. If a dose

is forgotten or delayed, administration should simply be resumed on an 8-hour schedule as soon as

possible, without making up missed doses.

In Operation Desert Storm in 1991, pyridostigmine was administered under combat conditions for the first time to U.S. and Allied soldiers

thought to be at risk for nerve agent exposure. Data

on safety and possible adverse responses were collected from the unit medical officers caring for the

41,650 soldiers of the XVIII Airborne Corps who

took from 1 to 21 doses of pyridostigmine during

January 1991.39 Most major unit commanders continued the medication for 6 to 7 days, with over

34,000 soldiers taking it for that time. There was

nearly total compliance with the regimen by these

soldiers, who were fully aware of the nerve agent

threat. They were able to perform their missions

without any noticeable impairment, similar to findings with peacetime volunteers participating in

studies.16 However, they reported a higher than expected incidence of side effects, as noted in Table 6-4.

Gastrointestinal changes included flatus, loose

stools, and abdominal cramps that were noticeable

but not disabling. Together with urinary urgency,

many soldiers reported a sense of awareness that

they were taking a medication. In most soldiers,

these changes were noticed within hours of taking

the first tablet. In many, the effects subsided after a

day or two of administration, and in others they

persisted as long as pyridostigmine was administered. Some units adopted a routine of taking

pyridostigmine with meals, which was thought to

minimize gastrointestinal symptoms.

Soldiers taking pyridostigmine during this period were also experiencing a wide range of other

wartime-related stresses, such as repeatedly donTABLE 6-4

EFFECTS OF PYRIDOSTIGMINE

PRETREATMENT* ON U.S. SOLDIERS

IN THE PERSIAN GULF WAR

Effect Incidence (%)

N=41,650

Gastrointestinal symptoms ≥ 50

Urinary urgency and frequency 5–30

Headaches, rhinorrhea, diaphoresis,

tingling of extremities < 5

Need for medical visit < 1

Discontinuation on medical advice < 0.1

*Dose was 30 mg pyridostigmine bromide, administered orally

every 8 h for 1 to 7 d.

Adapted from Keeler JR, Hurst CG, Dunn MA. Pyridostigmine

used as a nerve agent pretreatment under wartime conditions.

JAMA. 1991;266:694.
Medical Aspects of Chemical and Biological Warfare

190

ning and removing their chemical protective suits

and masks in response to alarms, sleep deprivation,

and anticipation of actual combat. Because there

was no comparable group of soldiers undergoing

identical stresses without taking pyridostigmine,

it is not clear to what extent pyridostigmine

itself was responsible for the symptoms noted

above. The findings are thus a worst-case estimate

for effects attributable to pyridostigmine use in

wartime.

Among these soldiers, fewer than 1% sought

medical attention for symptoms possibly related to

pyridostigmine administration (483 clinic visits).

Most of these had gastrointestinal or urinary disturbances. Two soldiers had drug rashes; one of

them had urticaria and skin edema that responded

to diphenhydramine. Three soldiers had exacerbations of bronchospasm that responded to bronchodilator therapy. Because the units of the XVIII

Airborne Corps had been deployed to a desert environment for 5 months before pyridostigmine was

used, most soldiers with significant reactive airways

disease had already developed symptoms and had

been evacuated earlier. The consensus among medical personnel more recently arrived was that they

saw more pyridostigmine-related bronchospasm in

their soldiers, who had not been present in theater

as long.

Because of increased exposure to the work-ofbreathing requirements of being masked, as well as

inhaled dust, smoke, and particles, it was unclear

whether pyridostigmine was a major causative factor in those who had bronchospasm at the onset of

hostilities. Two soldiers from the XVIII Airborne

Corps had significant blood pressure elevations, with

diastolic pressures of 110 to 120 mm Hg, that manifested as epistaxis or persistent bleeding after a cut

and subsided when pyridostigmine was stopped.

Another soldier who took two pyridostigmine tablets together to make up a missed dose experienced

mild cholinergic symptoms, self-administered an

atropine autoinjector, and recovered fully after several hours. There were no hospitalizations or medical evacuations attributable to pyridostigmine

among XVIII Airborne Corps soldiers. In other units,

at least two female soldiers, both weighing approximately 45 to 50 kg, noted increased salivation, muscular twitching, severe abdominal cramps, and

sweating that prompted medical observation. The

symptoms subsided after pyridostigmine was

stopped. This experience suggests that cholinergic

symptoms may occur in a small number of persons

of relatively low body weight.

Later in the Persian Gulf War, more than 200,000

service members took pyridostigmine for 1 to 4 days

during the ground attack into Iraq and Kuwait.

Their medical experience, as personally reported to

us by many unit medical officers, was similar to that

reported above. It is now clear that pyridostigmine

can be used effectively in large military populations

under combat conditions without impairing mission performance. Soldiers must have a clear understanding of the threat and the need for this medication, however. Otherwise, it seems unlikely that

they would have the same degree of willingness to

accept the gastrointestinal and urinary symptoms

noted above or to comply with an 8-hour dosage

schedule.

In a group of 213 soldiers in Israel who took

pyridostigmine (30 mg every 8 h), 75% reported at

least one symptom. Included among these symptoms were excessive sweating (9%), nausea (22.1%),

abdominal pain (20.4%), diarrhea (6.1%), and urinary frequency (11.3%). In a smaller group of 21

soldiers, pseudocholinesterase (also called butyrocholinesterase, which is discussed later in this chapter) activity was the same in the 12 who were symptomatic and the 9 who were not symptomatic.40

An Israeli soldier who developed cholinergic

symptoms after taking pyridostigmine was reported41 to have a genetic variant of serum butyrocholinesterase. The variant enzyme has low

binding affinity for pyridostigmine and other carbamates. The authors of the report suggested that

persons who are homozygous for the variant enzyme could therefore show exaggerated responses

to anticholinesterase compounds. The soldier had

a history of prolonged apnea after receiving succinylcholine premedication for surgery. Persons with

similar histories of severe adverse responses to cholinergic medications should be carefully assessed

concerning their potential deployability to combat,

where they might face either a nerve agent threat

or the potential need for resuscitative surgery involving emergency induction of anesthesia36 using

cholinergic medications.

Since the Persian Gulf War, veterans of that

conflict have experienced a range of illnesses

in themselves, in their spouses, and in children

conceived after the conflict. Combinations of symptoms have included fatigue, skin rash, muscle and

joint pain, headache, loss of memory, shortness

of breath, and gastrointestinal and respiratory

symptoms, which could be explained by a variety

of conditions, but do not fit readily into a single

diagnostic pattern.42
Pretreatment for Nerve Agent Exposure

191

The possible interaction of multiple, potentially

toxic compounds has generated interest in the

context of these problems. With respect to pyridostigmine, one report43 was published of neurotoxicity in chickens that received pyridostigmine together

with large parenteral doses of the insect repellent

DEET (diethyltoluamide) and the insecticide

permethrin. The relevance of this report is doubtful, because systemic administration of the two interacting compounds to the chickens was at least

10,000-fold in excess of their maximum potential

absorption from skin or clothing of soldiers.

Both the National Institutes of Health and the

National Institute of Medicine of the National Academy of Sciences established expert panels to evaluate these problems and to suggest an etiology or

etiologies. Both panels held public hearings, which

included testimony from veterans with the symptoms. The initial reports44,45 of these panels found

no evidence to suggest that pyridostigmine use was

related to the problems reported.

Improved Delivery

The currently stocked 30-mg pyridostigmine bromide tablets were purchased for wartime contingency use because of their ready availability.

Clearly, the need to maintain an 8-hour schedule of

pyridostigmine pretreatment under the conditions

of actual or anticipated combat stress is a major

practical deficiency in our medical defense against

nerve agents.

The United States is considering the development

of sustained-release forms of pyridostigmine that

would permit maintenance of an adequate level of

AChE inhibition with once-daily oral administration. To date, however, no sustained-release preparation has shown sufficient promise to warrant advanced testing. Unfortunately as well, efforts to

provide transdermal delivery of pyridostigmine

with skin patches have had disappointing results,

as would be expected because of the polar nature

of the compound.

CENTRALLY ACTING NERVE AGENT PRETREATMENTS

The inability of pyridostigmine to provide protection against nerve agent–induced CNS injury has

led to two different pharmacological approaches to

protection. The first involves improving postexposure treatment with brain-protecting anticonvulsant compounds, such as benzodiazepines. While

these compounds have a clear-cut, intrinsic potential for functional impairment and incapacitation,

their administration to casualties who are already

incapacitated by nerve agents will not increase the

total number of casualties. In fact, clinical observation of nonhuman primates suggests that postexposure therapy with the benzodiazepines diazepam

and midazolam actually decreases the time to recovery of consciousness after soman intoxication.46

An alternative to postexposure therapy is protection of the CNS with pretreatment compounds

that penetrate the blood–brain barrier, such as physostigmine, a tertiary amine that freely enters the

CNS. Physostigmine is often used as a model compound for reproducing in laboratory animals the

clinical signs of nerve agent intoxication. This nonpolar compound carbamoylates CNS AChE and

protects experimental animals from nerve agent

challenge more effectively than does pretreatment

with pyridostigmine.47 Another centrally acting carbamate compound, cui-xing-ning, with characteristics that are apparently similar to those of physostigmine, has been evaluated in China.48

Neuroactive compounds that penetrate the CNS

generally cause some degree of performance impairment in experimental animals, as well as a variable incidence of symptoms, such as nausea and

light-headedness, in humans. Even a slight degree

of impaired performance of critical battlefield tasks

would be life-threatening in itself and therefore

would be unacceptable in a pretreatment to be administered to all combatants. A possible solution to

this problem is antagonism of the undesirable effects of carbamates, which are generally cholinergic

in nature, by simultaneous administration of a

cholinolytic pretreatment adjunct, such as atropine,

scopolamine, or trihexyphenidyl (Artane, manufactured by Lederle Laboratories, Wayne, NJ). Animals

treated with what has been called a behavior-deficit-free combination of physostigmine and a cholinolytic compound, for example, show excellent protection against subsequent nerve agent challenge and

rapid clinical recovery of normal function.49

In theory, it is possible to offset the side effects

of physostigmine and achieve a performance-deficit-free effect by careful titration with a cholinergic

blocking drug. The severely limiting factor in

developing a physostigmine combination pretreatment for practical use is an unacceptable degree

of interindividual variation in the bioavailability of

this short half-life compound when administered

to humans.50,51 At present, it would appear necessary
Medical Aspects of Chemical and Biological Warfare

192

to define, for each recipient, an acceptable dose

ratio for physostigmine and a cholinolytic adjunct to

avoid performance deficits. The effort required for

protecting a total force is clearly beyond our current capability. In the event of a technological breakthrough in individual drug delivery of a wellmatched, centrally acting pair of carbamate and

adjunct compounds, the possibility of developing

centrally acting pretreatments would merit further

study.

NEW DIRECTIONS: BIOTECHNOLOGICAL PRETREATMENTS

Until recently, medical defense against nerve

agents has focused on preventing or reversing the

binding of the agents to AChE, as well as on limiting the effects of the agents on neurotransmission

by administration of pharmacological antagonists

such as atropine. An intriguing new concept for

dealing with nerve agent toxicity involves taking

advantage of naturally occurring macromolecules,

such as a circulating nerve agent scavenger or a metabolizing enzyme, that would, respectively, bind

to or catalyze the hydrolysis of nerve agents. These

macromolecules have the potential of providing

protection against all effects of nerve agents with

minimal side effects, since they would stoichiometrically bind or metabolize a nerve agent before

its distribution to the site of toxic effect.

The first evidence that circulating macromolecules have potential for protecting animals from

nerve agents came from study of the remarkably

broad range of toxic doses of the nerve agents in

different animal species. For example, the LD50 of

soman in mice and rats is about 10-fold higher than

the LD50 in monkeys or guinea pigs.52 An enzyme,

plasma carboxylesterase, binds to and thus inactivates soman and other nerve agents in the G series

(but not VX). The different amounts of this enzyme

in the blood of various species can adequately explain their differential sensitivity to the G-series

nerve agents.53

In addition to carboxylesterase, blood contains

two forms of cholinesterase, AChE in the red cells

(RBC-AChE) and butyrocholinesterase (BuChE; also

called pseudocholinesterase and plasma cholinesterase) in the plasma. Both of these forms of cholinesterase bind and inactivate nerve agents. In

preloading experiments in which exogenous AChE

from fetal bovine serum or BuChE from equine or

human sources was administered to animals (nonhuman primates, mice, or rats) intravenously or

intramuscularly, a stoichiometric degree of protection against subsequent nerve agent challenge was

provided.54–57 Investigators supported by the U.S.

Army Medical Research Institute of Chemical Defense have recently cloned and expressed the genes

for both human AChE and human BuChE.58,59 Administration of either of these human bioproducts,

with a potential plasma half-life of up to 12 days

for BuChE, may be able to provide similar protection against nerve agent challenge for humans. The

main obstacles to development of these products

at the present time appear to be the high cost of

production of the quantities involved and the possible need for frequent parenteral administration of

a relatively short-lived product.

Another biotechnological protective strategy under active study is the production of monoclonal

antibodies with high affinity for nerve agents.60,61 If

a human-derived monoclonal antibody of the immunoglobulin G (IgG) class could be produced,

theoretically it would have the advantage of being

able to bind and thus protect against a soman challenge in man after administration of about 2 g of

antibody protein, similar to the amount of polyclonal antibody routinely administered in 10 mL of

standard immune serum globulin. The 6-week

plasma half-life of IgG in man would make the use

of such a product more acceptable.

Nerve agents, like other reactive small molecules,

pass through a high-energy transition state during

their reaction with water or with tissue targets such

as AChE. By preparing antigens with a geometry

that spatially mimics the transition states of these

small molecules,62 researchers have raised antibodies which not only bind to the nerve agent molecules

but also catalyze their hydrolysis.63 These catalytic

antibodies have a major advantage over the other

bioproducts noted above in that they could continue

to inactivate multiple nerve agent molecules. For

this reason, the preparation of catalytic antibodies

to nerve agents, if successful, may result in the development of a superior, long-term nerve agent pretreatment.

Enzymes found in hepatocytes,64 neuronal cells,65

and plasma also hydrolyze nerve agents, albeit comparatively weakly. Study of the requirements for

hydrolysis at the enzyme active sites could potentially lead to the design of more efficient hydrolytic

enzymes that could be used as catalytic scavengers.66

The major reason for interest in biotechnologically derived nerve agent pretreatments lies in their
Pretreatment for Nerve Agent Exposure

193

unique mechanism of action as potential circulating nerve agent scavengers and hydrolytic catalysts.

Animals protected against nerve agent challenge

with these compounds have shown no evidence

of toxicity or performance impairment from

the nerve agents.54–56 Thus, soldiers pretreated

with these products might be able to function

normally in a chemical environment contaminaed with levels of agent below the limits of their circulating protection without requiring the use of

masks or protective clothing. The operational

advantage that these soldiers would have over opponents encumbered by chemical protective equipment adds considerable appeal to exploring the

potential of these newer nerve agent countermeasures.

SUMMARY

The inadequacy of postexposure therapy

for nerve agent casualties, particularly those with

potentially lethal exposures to soman, has been

of great concern. Development of pyridostigmine,

a peripherally active carbamate compound, as

a nerve agent pretreatment adjunct has substantially improved the ability of the U.S. military to protect its soldiers from the lethal effects of nerve

agents. A major deficiency of this pretreatment program—that it does not protect the CNS against

nerve agent–induced injury—may be overcome by

postexposure administration of anticonvulsants.

While centrally acting pretreatments offer more effective protection than does pyridostigmine, their

development is limited because of their potential

for impairing soldier performance. New research

may provide a revolutionary advance in protection

against nerve agents with biotechnologically derived pretreatments that bind or inactivate nerve

agents in the circulation.

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Vesicants

197

Chapter 7

VESICANTS

FREDERICK R. SIDELL, M.D.*; JOHN S. URBANETTI, M.D., FRCP(C), FACP, FCCP†; WILLIAM J. SMITH, PH.D.‡;

AND CHARLES G. HURST, M.D.§

INTRODUCTION

MUSTARD

Military Use

Properties

Toxicity

Biochemical Mechanisms of Injury

Metabolism

Clinical Effects

Diagnosis

Laboratory Tests

Patient Management

Long-Term Effects

LEWISITE

Military Use

Properties

Toxicity

Biochemical Mechanisms of Injury

Clinical Effects

Diagnosis

Laboratory Tests

Patient Management

Long-Term Effects

PHOSGENE OXIME

Military Use

Properties

Biochemical Mechanisms of Injury

Clinical Effects

Patient Management

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014

†Assistant Clinical Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510

‡Supervisor, Cellular Pharmacology Team, Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen

Proving Ground, Maryland 21010-5425

§Colonel, Medical Corps, U.S. Army; currently, Special Assistant for Medical Programs, Office of the Deputy Assistant Secretary of Defense,

Counterproliferation and Chemical/Biological Matters, Room 3E808, 3050 Defense Pentagon, Washington, D.C. 20301-3050; formerly, Commander, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425
Medical Aspects of Chemical and Biological Warfare

198

INTRODUCTION

A vesicant (ie, an agent that produces vesicles or

blisters) was first used as a chemical weapon on the

battlefields of World War I1–3; that same vesicant—

sulfur mustard—is still considered a major chemical agent. In the intervening years between World

War I and today, there have been a number of recorded and suspected incidents of mustard use,

culminating with the Iran–Iraq War in the 1980s.

During this conflict, Iraq made extensive use of

mustard against Iran. Popular magazines and television brought the horrors of chemical warfare to

the public’s attention with graphic images of badly

burned Iranian casualties. When, in the fall of 1990,

the U.S. military joined the United Nations forces

in preparation to liberate Kuwait, one of the major

concerns was the threat that Iraq would again use

mustard. Fortunately, chemical agents were not

used in the short ground phase of the Persian Gulf

War; however, the threat of an enemy’s using chemical weapons against U.S. forces is ever present. Although mustard is the most important vesicant militarily, the vesicant category includes other agents,

such as Lewisite and phosgene oxime (Table 7-1).

The clinical differences among the vesicants discussed in this chapter are shown in Table 7-2.

There are two types of mustard: sulfur mustard

and nitrogen mustard. An impure sulfur mustard

was probably synthesized by Despretz in 1822, but

it was not identified. Riche, in 1854, and Guthrie,

several years later, repeated Despretz’s reaction to

obtain the same product. Guthrie described the

product as smelling like mustard, tasting like garlic, and causing blisters after contact with the skin.

Niemann, in 1860, also synthesized the compound.

In 1886, Meyer prepared a much purer mustard but

discontinued his research because of the hazards

involved. During World War I, the Germans used

Meyer’s method of synthesis to manufacture mustard.3

Nitrogen mustard (or more correctly, the nitrogen mustards) was first synthesized in the late

1930s; and although the properties of nitrogen mustard were only slightly different from those of sulfur mustard, none was found to be suitable for use

as a weapon. However, a nitrogen mustard (HN2,

Mustargen, manufactured by Merck & Co., West

Point, Pa.) was found useful for chemotherapy of

certain neoplasms4–7; for years, it was a mainstay in

cancer therapy until it was replaced by other compounds.

A second group of vesicants is the arsenicals. The

major compound in this group is Lewisite. It was

synthesized and developed in the United States

during the late stages of World War I1

 and was

manufactured for battlefield use. The shipment of

Lewisite was on its way to Europe when the war

ended, so it was destroyed at sea. There are no data

on Lewisite from battlefield use. Lewisite has some

advantages and disadvantages over mustard that

are discussed later in this chapter.

The third compound considered to be a vesicant

by the U.S. military is phosgene oxime. This is not

a true vesicant because, unlike mustard and

Lewisite, it does not produce fluid-filled blisters;

rather, it produces solid lesions resembling urticaria. There has been no verified battlefield use of

this compound, and there has been little study of it

in the western world.

MUSTARD

Mustard [bis-(2-chloroethyl) sulfide; also called

2,2'-dichlorethyl sulfide] is one of the two most important known chemical agents (the group of nerve

agents is the other). Although mustard was introduced late in World War I (July 1917), it caused more

chemical casualties than all the other agents combined: chlorine, phosgene, and cyanogen chloride.

While lethality from mustard exposure was low,

casualties filled the medical facilities. Despite 75

years of research, there is still no antidote for mustard. This fact is especially crucial when we consider that probably at least a dozen countries have

mustard in their arsenals today.

Allegedly, mustard received its name from its

smell or taste (onion, garlic, mustard)3,8 or its color

(which varies from yellow, to light tan, to dark

brown). When mustard was first used by the Germans, the Allies called it Hun Stoffe (German stuff),

abbreviated HS; later, it became known as H. Mustard manufactured by the Levinstein process is also

known as H; it contains about 20% to 30% impurities (mostly sulfur). Distilled, or nearly pure, musS

CH2CH2 Cl

CH2CH2 Cl

HD
Vesicants

199

TABLE 7-1

CHEMICAL, PHYSICAL, ENVIRONMENTAL, AND BIOLOGICAL PROPERTIES OF VESICATING AGENTS

Properties Impure Sulfur Mustard Distilled Sulfur Mustard Phosgene Oxime Lewisite

(H) (HD) (CX) (L)

Chemical and Physical

Boiling Point Varies 227°C 128°C 190°C

Vapor Pressure Depends on purity 0.072 mm Hg at 20°C 11.2 mm Hg at 25°C (solid) 0.39 mm Hg at 20°C

13 mm Hg at 40°C (liquid)

Density:

Vapor approx 5.5 5.4 < 3.9? 7.1

Liquid approx 1.24 g/mL at 25°C 1.27 g/mL at 20°C ND 1.89 g/mL at 20°C

Solid NA Crystal: 1.37 g/mL at 20°C NA NA

Volatility approx 920 mg/m3 at 25°C 610 mg/m3 at 20°C 1,800 mg/m3 at 20°C 4,480 mg/m3 at 20°C

Appearance Pale yellow to dark brown Pale yellow to dark brown Colorless, crystalline solid Pure: colorless, oily

liquid liquid or a liquid liquid

As agent: amber to dark

brown liquid

Odor Garlic or mustard Garlic or mustard Intense, irritating Geranium

Solubility:

In Water 0.092 g/100 g at 22°C 0.092 g/100 g at 22°C 70% Slight

In Other Solvents Complete in CCl4, acetone, Complete in CCl4, acetone, Very soluble in most Soluble in all common

other organic solvents other organic solvents organic solvents organic solvents

Environmental and Biological

Detection Liquid: M8 paper Liquid: M8 paper M256A1 ticket or card Vapor, M256A1 ticket or

card, ICAD

Vapor: CAM Vapor: CAM, M256A1 kit,

ICAD

Persistence:

In Soil Persistent 2 wk–3 y 2 h Days

On Materiel Temperature-dependent; Temperature-dependent; Nonpersistent Temperature-dependent;

hours to days hours to days hours to days

Skin

Decontamination M2581 kit M258A1 kit Water Dilute hypochlorite

Dilute hypochlorite Dilute hypochlorite M258A1 kit

Water Soap and water Water

M291 kit M291 kit M291 kit

Biologically Effective

Amount:

Vapor LCt50: 1,500 LCt50: 1,500 (inhaled) Minimum effective Ct: Eye: < 30

(mg•min/m3) 10,000 (masked) approx 300; Skin: approx 200

LCt50: 3,200 (estimate) LCt50: 1,200–1,500 (inhaled)

100,000 (masked)

Liquid LD50: approx 100 mg/kg LD50: 100 mg/kg No estimate 40–50 mg/kg

CAM: chemical agent monitor

ICAD: individual chemical agent detector

LD50: dose that is lethal to 50% of the exposed population (liquid, solid)

LCt50: (concentration • time of exposure) that is lethal to 50% of the exposed population (vapor, aerosol)

NA: not applicable

ND: not determined
Medical Aspects of Chemical and Biological Warfare

200

tard is known as HD. Both forms of mustard, H

and HD, can still be found today in munitions

manufactured over 50 years ago. Sulfur mustard

has also been called LOST or S-LOST (for the two

German chemists who suggested its use as a chemical weapon: Lommell and Steinkopf); “yellow

cross” (for the identifying mark on the World War I

shells); and yperite (for the site of its first use).

Nitrogen mustard has not been used on the

battlefield and is not thought to be an important

military agent. There are three forms of this compound (HN1, HN2, HN3); for several reasons, the

nitrogen mustards were not suitable as military

agents. These agents are similar to sulfur mustard

in many ways, but they seem to cause more severe

systemic effects, particularly in the central nervous

system (CNS): they regularly caused convulsions

when administered intravenously to animals.9

 Because nitrogen mustards have not been used militarily, they will not be discussed further. Unless

stated otherwise, in this chapter the term “mustard”

refers to sulfur mustard.

Military Use

Mustard has been contained in the arsenals of

various countries since it was first used on July 12,

1917, when the Germans fired shells containing

mustard at British troops entrenched near Ypres,

Belgium.1,2 Soon both sides were using mustard.

When a single agent was identified as the source

of injury, it was estimated that mustard caused

about 80% of the chemical casualties in World War I;

the remaining 20% were caused by other agents such

as chlorine and phosgene (see Chapter 9, Toxic Inhalational Injury). The British had 180,983 chemical casualties; the injuries of 160,970 (88%) were caused

solely by mustard. Of these casualties, 4,167 (2.6%)

died. Of the 36,765 single-agent U.S. chemical casualties, the injuries of 27,711 (75%) were caused solely

by mustard. Of the casualties who reached a medical treatment facility (MTF), 599 (2.2%) died.10

Although mustard caused large numbers of casualties during World War I, very few of these casualties died. Most of those who did eventually die

had been hospitalized for several days. Mustard

survivors, likewise, required lengthy hospitalization: the average length of stay was 42 days. Combine this length of hospitalization with the vast

number of casualties caused by mustard and we can

easily see how the use of mustard can greatly reduce an enemy’s effectiveness.

Since the first use of mustard as a military weapon,

there have been a number of isolated incidents in

which it was reportedly used. In 1935, Italy probably

used mustard against Abyssinia (now Ethiopia);

Japan allegedly used mustard against the Chinese

from 1937 to 1944; and Egypt was accused of using

the agent against Yemen in the mid 1960s.11

Chemical agents were not used during World

War II: it is thought that Germany did not use mustard because Hitler had been a mustard victim during World War I and was loath to use it. However,

in December 1943, the USS John Harvey, which was

carrying a large number of mustard bombs, was

attacked while docked in Bari, Italy. There were

617 U.S. mustard casualties (83 fatal) from exploded

shells in the water and from the smoke of the burning mustard. In addition, an unknown number of

Italian civilians were casualties from the smoke.12,13

(The incident at Bari is discussed in greater detail

in this volume in Chapter 3, Historical Aspects of

Medical Defense Against Chemical Warfare, and in

Occupational Health: The Soldier and the Industrial

Base,

14 another volume in the Textbook of Military

Medicine series.)

Iraq employed mustard against Iran during the

Iran–Iraq War (1982–1988). One source15 estimates

that there were 45,000 mustard casualties. In 1989,

the journal Annales Medicinae Militaris Belgicae pubTABLE 7-2

CLINICAL DIFFERENCES AMONG VESICANTS

Onset

Chemical Agent Pain Tissue Damage Blister

Mustard Hours later Immediate; onset of clinical effects is hours later Fluid filled

Lewisite Immediate Seconds to minutes Fluid filled

Phosgene Oxime Immediate Seconds Solid wheal
Vesicants

201

lished a monograph by Jan L. Willems16 that reported the western European experience treating a

selected population of Iranian casualties of mustard.

Willems reports that in March 1984, February 1985,

and March 1986, Iranian casualties were sent to

hospitals in Ghent, Belgium, and other western

European cities for treatment. More casualties arrived in 1987. Because the hospital physicians

lacked clinical experience in treating chemical warfare casualties, treatment policies varied.

In an attempt to establish whether chemical warfare agents had been used during the war, three

United Nations missions (in 1984, 1986, and 1987)

conducted field inspections, clinical examination of

casualties, and laboratory analyses of chemical

ammunition. The missions concluded that16

• aerial bombs containing chemical weapons

were used in some areas of Iran,

• sulfur mustard was the primary chemical

agent used, and

• there was some use of the nerve agent

tabun.

Since mustard was introduced, a number of

nonbattlefield exposures have occurred. Several

occurred in the North Sea, where fishermen were

exposed to mustard after dredging up munitions

dumped there after World War II.17–20 Others occurred when children found and played with mustard shells; the children were injured when the

shells exploded, and several of the children died.21,22

There have also been reported incidents of laboratory workers23 and, in one instance, of soldiers in

their sleeping quarters24 who were accidentally exposed to mustard. In yet another incident, a souvenir collector unearthed a mustard shell.25

Properties

Mustard is an oily liquid and is generally regarded

as a “persistent” chemical agent because of its low

volatility. In cool weather there is little vapor; however, mustard’s evaporation increases as the temperature increases. At higher temperatures, such as those

in the Middle East during the hot season, 38°C to 49°C

(100°F–120°F), mustard vapor becomes a major hazard. For example, the persistency of mustard (in sand)

decreased from 100 hours to 7 hours as the temperature rose from 10°C to 38°C (50°F–100°F).26 Although

heat increases the vapor hazard, the rapid evaporation decreases the task of decontamination.

World War I data27 suggest that the warming of

the air after sunrise caused significant evaporation

of mustard from the ground. Mustard attacks were

frequently conducted at night, and the liquid agent

did not readily evaporate in the cool night air. Several hours after daybreak, however, the sunwarmed air would cause the mustard to vaporize.

By this time, thinking the danger from the attack

was over, the soldiers had removed their masks;

thus they fell victim to the evaporating mustard.

This combination of events produced a significant

number of casualties among the soldiers. Because

of these nighttime shellings, it soon became standard policy not to unmask for many hours after

daybreak.

Mustard vapor has a density 5.4-fold greater than

that of air, causing it to hug the ground and sink

into trenches and gullies. When mustard slowly

evaporates, a detector held 3 to 6 feet above the

ground may indicate no agent in the air; but closer

to the ground, at 6 to 12 inches, the concentration

might range from 1 to 25 mg/m3. Despite this low

volatility, more than 80% of the mustard casualties

during World War I were caused by vapor, not the

liquid form of mustard.27

The freezing temperature for mustard is 57°F.

This high freezing point makes mustard unsuitable

for delivery by aircraft spraying or for winter dispersal. Therefore, to lower the freezing point, mustard must be mixed with another substance. During

World War I, mustard was mixed with chloropicrin,

chlorobenzene, or carbon tetrachloride to lower

its freezing point.1 Today, mustard can be mixed

with Lewisite to increase its volatility in colder

weather.

Mustard’s high freezing point made it useful

during those times of the year when the nighttime

temperature was about 10°C (50°F) and the daytime

temperature was in the 15°C to 21°C (60°F–70°F)

range. In warm weather, mustard is 7- to 8-fold

more persistent than Lewisite; therefore, it is highly

desirable for use in such geographical areas as the

Middle East.

Toxicity

For liquid mustard on the skin, the dose that is

lethal to 50% of the exposed population (LD50) is

about 100 mg/kg, or about 7.0 g for a person weighing 70 kg. This is about 1.0 to 1.5 teaspoons of liquid; this amount will cover about 25% of the body

surface area. An area of erythema with or without

blisters caused by liquid mustard that covers this

or a larger area of skin suggests that the recipient

has received a lethal amount of mustard. A 10-μg

droplet will produce vesication.
Medical Aspects of Chemical and Biological Warfare

202

On the other hand, exposure to a vapor or aerosol in air is usually described as the product of the

concentration (C, expressed as milligrams per cubic meter) and the time the exposure lasted (t, expressed as minutes):

Ct = mg•min/m3

Thus, the effect produced by an aerosol or vapor

exposure to 0.05 mg/m3 • 100 minutes is equal to

the effect produced by an exposure to 5 mg/m3 • 1

minute; in either case, Ct = 5 mg•min/m3. (Ct, and

particularly its relation to LD, are discussed in

greater detail in Chapter 5, Nerve Agents; see Exhibit 5-1.)

Eye damage was produced by a Ct of 10 mg•min/

m3 or less under laboratory conditions28; other estimates29 for the eye damage threshold under field

conditions range from 12 to 70 mg•min/m3. The

estimated Ct for airway injury ranges from 100 to

500 mg•min/m3. The threshold for skin damage is

highly dependent on skin site, heat, sweating, and

other factors (localized sweating will lower the

threshold on the portion of the skin that is sweating30); the threshold is generally in the range of 200

to 2,000 mg•min/m3.

Biochemical Mechanisms of Injury

Although mustard has been considered a major

chemical weapon for 75 years, there is still no clear

understanding of its biochemical mechanism of action; therefore, no specific therapy for its effects

exists. While the chemistry of mustard interaction

with cellular components is well defined, the correlation of this interaction with injury has not been

made. Over the past few decades, scientists have

made major advances in understanding the cellular and biochemical consequences of exposure to

mustard and have put forth several hypotheses, two

of which are discussed below, to account for mustard injury (Figure 7-1).29,31,32

The mustards—both sulfur and nitrogen—are

alkylating agents that act through cyclization of an

ethylene group to form a highly reactive sulfonium

or immonium electrophilic center. This reactive

electrophile is capable of combining with any of the

numerous nucleophilic sites present in the macromolecules of cells. The products of these reactions

are stable adducts that can modify the normal function of the target macromolecule. Because nucleophilic areas exist in peptides, proteins, ribonucleic

Fig. 7-1. The putative mechanisms by which sulfur mustard causes tissue damage. Adapted from US Army Medical

Research Institute of Chemical Defense. A global picture of battlefield vesicants, I: A comparison of properties and

effects. Med Chem Def. 1992;5(1):6.

• DNA breaks

• Activation of poly-

(ADP-ribose) polymerase

• Depletion of NAD+

• Inhibition of glycolysis

• Loss of ATP

• Cell death

• Acute tissue injury

• Inhibition of transcription 

and protein synthesis

• Disinhibition of processors, 

phospholipases and nucleases

• Autolysis

• Cell death

• Acute tissue injury

• Loss of protein thiol status

• Loss of Ca++ homeostatis

• Oxidation stress

• Lipid peroxidation

• Membrane damage

• Cell death

• Acute tissue injury

Sulfur Mustard

Hypothesis 1 Hypothesis 2

DNA Alkylation Reactions With 

Glutathione

Metabolic Effects
Vesicants

203

acid (RNA), deoxyribonucleic acid (DNA), and

membrane components, researchers have tried to

identify the most critical biomolecular reactions

leading to mustard injury.

Due to the highly reactive nature of mustard, it

is conceivable that the injury following tissue exposure may result from a combination of effects

described below in both hypotheses; or injury may

result from additional changes not yet described in

a formal hypothesis. Whether the initiating event

is alkylation of DNA or modification of other cellular macromolecules, however, these steps would

disrupt the epidermal–dermal junction. Once the

site of tissue injury is established, the pathogenic

process leading to formation of fully developed blisters must involve an active inflammatory response

and altered fluid dynamics in the affected tissue.

Mustard also has cholinergic action stimulating

both muscarinic and nicotinic receptors.33

Alkylation of Deoxyribonucleic Acid

The first proposed hypothesis for the possible

mechanism of injury for mustard links alkylation

of DNA with the cellular events of blister formation.34 According to this proposal, alkylation of

DNA by sulfur mustard results in strand breaks.

The strand breaks trigger activation of a nuclear

DNA repair enzyme, poly(ADP-ribose) polymerase

(PADPRP). Excessive activity of this enzyme depletes cellular stores of nicotinamide adenine dinucleotide (NAD+), a critical cofactor and substrate

needed for glycolysis.35–37 Inhibition of glycolysis

would cause a buildup of glucose-6-phosphate, a

substrate in the hexose monophosphate shunt.38

Stimulation of the hexose monophosphate shunt

results in activation of cellular proteases.39 Since a

principal target of mustard in the skin is the basal

epidermal cell,40 protease from these cells could

account for the cleavage of the adherent fibrils connecting the basal epidermal cell layer to the basement membrane.

Thus far, data in animal and cellular systems are

consistent with many aspects of this hypothesis,

which has DNA damage as the initiating step and

PADPRP activation as a critical event. Studies in

human skin grafts,35 epidermal keratinocytes,41 and

leukocytes in culture36; and in the euthymic hairless guinea pig42 have shown decreases in cellular

NAD+ as a consequence of PADPRP activation following sulfur mustard–induced DNA damage.

Niacinamide and other inhibitors of the PADPRP

can ameliorate the pathology developing in both

living animal and cellular models.35,36,42,43 Unfortunately, while niacinamide has some beneficial actions, the protection it affords is never complete and

is limited in duration.41,42 No evidence currently

shows activation of the hexose monophosphate

shunt following mustard exposure, but significant

metabolic disruptions in human keratinocytes have

been reported after mustard exposure.44 Protease

activity is increased in human cells exposed in vitro

to mustard.45–47

While many aspects of the PADPRP hypothesis

have been verified, and there is good linkage between proposed steps of this pathway and mustardinduced cytotoxicity, no direct correlation with the

full range of tissue pathologies seen following mustard exposure has yet been established. Even though

DNA is an important macromolecular target of

mustard alkylation in the cell, several other hypotheses of mustard toxicity have been developed that

are based on mustard’s reaction with other cellular

components. For a review of all such hypotheses,

see Medical Defense Against Mustard Gas: Toxic

Mechanisms and Pharmacological Implications29;

only those undergoing active investigation are discussed here.

Reactions With Glutathione

The second major hypothesis to explain the effects of mustard is that it reacts with the intracellular free radical scavenger glutathione, GSH, thereby

depleting it, resulting in a rapid inactivation of sulfhydryl groups and the consequent loss of protection against oxygen-derived free radicals, specifically those causing lipid peroxidation.48 In 1987,

Orrenius and Nicotera49 established that menadione-induced depletion of GSH resulted in loss of

protein thiols and inactivation of sulfhydryl-containing enzymes. Included in this class of thiol proteins are the calcium and magnesium adenosine

triphosphatases, which regulate calcium homeostasis. With the inactivation of the enzymes that control thiol proteins, intracellular calcium levels

would increase. High calcium levels within the cell

trigger activation of protease, phospholipases, and

endonucleases, which could give rise to the breakdown of membranes, cytoskeleton, and DNA that

would result in cell death.

A report50 suggested that this mechanism could

be activated by mustards and might be the mechanism of mustard injury. While several aspects of

the thiol–calcium hypothesis (eg, release of arachidonic acid and decrease in membrane fluidity) have

been observed in cell cultures following sulfur

mustard exposure,51 no definitive studies have
Medical Aspects of Chemical and Biological Warfare

204

TABLE 7-3

INITIAL CLINICAL EFFECTS FROM

MUSTARD EXPOSURE

Onset of

OrganSeverity Effects First Effect

Eyes Mild Tearing 4–12 h

Itchy

Burning

Gritty feeling

Moderate Above effects, plus: 3–6 h

Reddening

Lid edema

Moderate pain

Severe Marked lid edema 1–2 h

Possible corneal

damage

Severe pain

Airways Mild Rhinorrhea 6–24 h

Sneezing

Epistaxis

Hoarseness

Hacking cough

Severe Above effects, plus: 2–6 h

Productive cough

Mild-to-severe

dyspnea

Skin Mild Erythema 2–24 h

Severe Vesication

drawn an association between calcium disruptions

and mustard-induced pathology.

Another proposed consequence of the mechanism—based on the depletion of GSH following

mustard exposure—is lipid peroxidation.52,53 According to this hypothesis, depletion of GSH allows

the formation of oxygen-derived free radicals. The

oxidizing compounds thus formed will react with

membrane phospholipids to form lipid peroxides

that could, in turn, lead to membrane alterations,

changes in membrane fluidity, and eventual breakdown of cellular membranes.

As previously mentioned, studies51 have shown

changes in membrane fluidity following sulfur

mustard exposure. In addition, in 1989, Elsayed and

colleagues54 demonstrated the presence of lipid

peroxidation indicators in the tissue of mice exposed to subcutaneous butyl mustard. However,

as with the thiol–calcium hypothesis, no studies

have directly linked lipid peroxidation with the

mustard-induced injury.

Metabolism

The mechanism or mechanisms by which mustard is thought to cause tissue damage are described

above. As the first step in any of the theories, mustard cyclizes to a sulfonium electrophilic center.

This highly reactive moiety, in turn, combines with

peptides, proteins, DNA, or other substances. After a few minutes in a biological milieu, intact mustard is no longer present; the reactive electrophile

has attached to another molecule and is no longer

reactive. The rapidity of this reaction also means

that within a few minutes mustard has started to

cause tissue damage. The clinical relevance is that

intact mustard or its reactive metabolic product is

not present in tissue or biological fluids, including

blister fluid, a few minutes after the exposure; however, clothing, hair, and skin surfaces may still be

contaminated hours later.

Several studies29,31,32,55 support the observation

that intact or active mustard is not present in tissue

or biological fluids after a few minutes. Occluding the blood supply to areas of the intestinal tract

or to selected bone marrow for a few minutes protected these organs from the effects of a lethal

amount of intravenously administered mustard.

Approximately 85% of S-labeled mustard36 disappeared from the blood of humans after several minutes,56 and the half-life for intravenously administered mustard to disappear from the blood of piglets was about 2 minutes.57 Mustard blister fluid did

not produce a reaction when instilled into the eyes

of animals or humans58 or onto the skin of humans.59

A continuing outbreak of smaller vesicles near a

source of blister fluid is probably the result of these

areas having received an additional amount of exposure and not from contamination by the blister

fluid.58,60

Clinical Effects

The organs most commonly affected by mustard

are the skin, eyes, and airways (Table 7-3): the organs with which mustard comes in direct contact.

After a significant amount of mustard has been absorbed through the skin or inhaled, the hemopoietic system, gastrointestinal tract, and CNS are also
Vesicants

205

damaged. Mustard may also affect other organs but

rarely do these produce clinical effects.

During World War I, 80% to 90% of U.S. mustard

casualties had skin lesions, 86% had eye involvement, and 75% had airway damage.61 These percentages are somewhat different from those seen in Iranian casualties, however. Of a group of 233 severely

injured Iranian soldiers sent to western European

hospitals by the Iranian government for treatment

during the Iran–Iraq War, 95% had airway involvement, 92% had eye signs and symptoms, and 83%

had skin lesions.62 In a series of 535 Iranian casualties, including civilians, admitted to a dermatology

ward, 92% had skin lesions and 85% had conjunctivitis; of the total number of patients, 79% had

erythema and 55% had blisters. (Casualties with

more serious problems, including injury to the pulmonary tract, were admitted to other wards).63

The slightly higher percentage of airway and eye

involvement in Iranian soldiers versus U.S. World

War I casualties is perhaps attributable to the higher

ambient temperature in the area (compared with

Europe), which caused more vaporization; it might

also have been because Iranian protective equipment was not as good as that used during World

War I, or the masks may not have been completely

sealed because of facial hair. In 1984, the year the

first Iranian casualties were treated in Europe, protective clothing and gas masks were not commonly

worn by Iranian soldiers. Later, when gas masks

became available, they probably were not fully effective; it is not known whether masking drills were

carefully performed by the soldiers.16

Mustard-related death occurs in about 3% of the

casualties who reach an MTF; of those who die, most

die 4 or more days after exposure. Table 7-4 illustrates the breakdown, in percentages, of British

troops who died after exposure to mustard during

World War I.61 Of the casualties who died, 84% required at least 4 days of hospitalization. The causes

of death are usually pulmonary insufficiency from

airway damage, superimposed infection, and sepsis. Rarely, the amount of mustard will be overwhelming and cause death within 1 to 2 days; in

these circumstances, death might be due to neurological factors9,22 or massive airway damage.

Willems’s report16 on Iranian casualties treated

in western European hospitals gives some idea of

the effect of medical advances since World War I

on the management of mustard casualties. Clinical

files of 65 of these casualties were studied in detail.

Eight patients died between 6 and 15 days after exposure. One patient died 185 days after exposure:

he had received ventilatory support for an extended

TABLE 7-4

WORLD WAR I DEATHS AFTER EXPOSURE

TO MUSTARD*

Day of Death Percentage of

(After Exposure) Deaths

< 1 1

2 2

3 5

4 8

5 22

> 6 62

*In 4,167 fatal mustard casualties among British troops

Data source: Gilchrist HL. A Comparative Study of WWI Casualties From Gas and Other Weapons. Edgewood Arsenal, Md: US

Chemical Warfare School; 1928: Chart 3, p 14.

period because of severe bronchiolitis complicated

by a series of loculate pneumothoraces. Most

patients returned to Iran in fairly good condition

after 2 to 10 weeks of treatment. Their lesions were

nearly completely healed, although some lesions remained. The duration of hospitalization was determined mainly by the time needed for healing of the

deeper skin lesions.

Skin

The threshold amount of mustard vapor required

to produce a skin lesion (erythema) is a Ct of about

200 mg•min/m3. This varies greatly depending on

a number of factors, including temperature, humidity, moisture on the skin, and exposure site on the

body. Warm, moist areas with thin skin such as the

perineum, external genitalia, axillae, antecubital

fossae, and neck are much more sensitive. As was

stated earlier, a liquid droplet of about 10 μg will

produce vesication. About 80% of this 10 μg evaporates and 10% enters the circulation, leaving about

1 μg to cause the vesicle. Evaporation of small droplets is rapid and nearly complete in 2 to 3 minutes;

amounts larger than several hundred milligrams

may remain on the skin for several hours.64 Mustard vapor rapidly penetrates the skin at the rates

of 1.4 μg/cm2/min at 70°F, and 2.7 μg/cm2/min at

88°F.26 Liquid mustard penetrates the skin at 2.2

μg/cm2/min at 60°F and at 5.5 μg/cm2/min at

102°F. Once mustard penetrates the skin, it is

“fixed” to components of tissue and cannot be extracted.64
Medical Aspects of Chemical and Biological Warfare

206

In one group of people, large differences in skin

sensitivity to mustard were noted; some individuals were much more sensitive than others, although

their skin pigment appeared to be equal. Darkly pigmented individuals were much more resistant than

lightly pigmented people. Repeated exposures caused

an increase in sensitivity. The horse was the most sensitive among eight nonhuman species tested; the

guinea pig and monkey were the least sensitive; the

dog most closely matched the sensitivity of humans.30

The mildest and earliest form of visible skin injury is erythema, which resembles sunburn (Figure

7-2). It is usually accompanied by pruritus, burning, or stinging. After a small exposure, this might

be the extent of the lesion. More commonly, small

vesicles will develop within or on the periphery of

Fig. 7-4. Large and extensive

bullae on (a) the hands and (b)

the feet of Iranian casualties as

they appeared 5 days after exposure to mustard. (c) Some of

the bullae are disrupted and

have a purulent base. Note the

extensive edema that afflicts

the surrounding skin. The whitish material is an antimicrobial

salve. Photographs: Reprinted

with permission from Willems

JL. Clinical management of

mustard gas casualties. Ann

Med Milit Belg. 1989;3S:14, 15.

Fig. 7-2. Erythema of the chest of an Iranian casualty as

it appeared 5 days after his exposure to mustard. He also

had a pulmonary injury with an associated bronchopneumonia due to infection with Haemophilus influenzae.

The presence of a nasal oxygen catheter is indicative of

the pulmonary insufficiency. Photograph: Reprinted with

permission from Willems JL. Clinical management of

mustard gas casualties. Ann Med Milit Belg. 1989;3S:13.

Fig. 7-3. The back of an Iranian casualty seen 16 hours

after exposure to mustard. Note the small vesicles in

proximity to the large bullae. Photograph: Reprinted with

permission from Willems JL. Clinical management of

mustard gas casualties. Ann Med Milit Belg. 1989;3S:8.

a b

c

Figures 7-2 and 7-3 are not shown because the copyright permission granted to the Borden Institute,

TMM, does not allow the Borden Institute to grant permission to other users and/or does not include

usage in electronic media. The current user must apply to the publisher named in the figure legend for

permission to use this illustration in any type of publication media.

Figure 7-4 is not shown because the copyright permission granted to the

Borden Institute, TMM, does not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic media.

The current user must apply to the publisher named in the figure legend

for permission to use this illustration in any type of publication media.
Vesicants

207

the erythematous areas (like a string of pearls); these

vesicles will later coalesce to form larger blisters

(Figure 7-3). Erythema begins to appear 1 to 24

hours after the skin is exposed to mustard, although

onset can be later. The effects from liquid mustard

appear more rapidly than the effects from mustard

vapor. Characteristically, the onset of erythema is

about 4 to 8 hours after mustard exposure. Vesication begins about 2 to 18 hours later and may not

be complete for several days.

The typical bulla is dome-shaped, thin-walled,

superficial, translucent, yellowish, and surrounded

by erythema. Generally, it is 0.5 to 5.0 cm in diameter,

although it can be larger (Figure 7-4). The blister

fluid is initially thin and clear or slightly strawcolored; later it turns yellowish and tends to coagulate.16,64,65 The blister fluid does not contain mustard

and is not itself a vesicant. Vapor injury is generally a first- or second-degree burn; liquid mustard

may produce deeper damage comparable to a thirddegree burn.

After exposure to extremely high doses, such as

those resulting from exposure to liquid mustard,

lesions may be characterized by a central zone of

coagulation necrosis, with blister formation at the

periphery. These lesions are more severe, take

longer to heal, and are more prone to secondary

infection.29 Necrosis and secondary inflammation,

which were the expected prominent pathophysiological characteristics of a deep burn in the preantibiotic era, are evident.

Fig. 7-5. The spectrum of cutaneous mustard injury as seen on light microscopy extends from superficially intact skin

to sloughing of the epidermis. (a) A skin biopsy taken from an Iranian casualty on the 11th day following exposure to

mustard. The gross appearance was of erythema. A cleavage plane is apparent between the dermis and epidermis,

with edema extending into the stratum spinosum. (Note the enlarged spaces between individual cells.) Changes in

cells of the stratum germinativum are difficult to ascertain at this level of magnification, but nuclei of cells on the

extreme right of the figure appear to be pyknotic (shrunken and dark). (b) The biopsy was taken at the site of an

erosion. The epidermis has sloughed, and the superficial dermis is necrotic. White blood cells have infiltrated the

deeper layers of the dermis. Part of an intact hair follicle is seen; the epidermis will ultimately regenerate from such

structures. Reprinted with permission from Willems JL. Clinical management of mustard gas casualties. Ann Med

Milit Belg. 1989;3S:19.

The major change at the dermal–epidermal junction, visualized by light microscopy, is liquefaction

necrosis of epidermal basal cell keratinocytes (Figure 7-5). Nuclear swelling within basal cells starts

as early as 3 to 6 hours after exposure,66 and

progresses to pyknosis of nuclei and disintegration

of cytoplasm. The pathological process can be described as follows (Figure 7-6 illustrates this process further):

By a coalescence of neighboring cells undergoing

the process of swelling, vacuolar, or hydropic degeneration (“liquefaction necrosis”) and rupture,

spaces of progressively increasing size are formed.

This usually involves dissolution of cells of the

basal layer, resulting in defects in the basal portion of the epidermis and separation of the upper

layers of the epidermis from the corium....At first,

there are multiple focal areas of such microvesicle

formation, with septa of as yet uninvolved epidermal cells. Progressive dissolution of the cells of

such septa follows, and although intact or partially

degenerated basal cells may remain in the floor of

the microvesicles at first, these also soon disintegrate as the vesicles enlarge.67

An electron microscopy study68 published in

1990, of mustard lesions in human skin grafted onto

nude mice, confirmed that damage to the basal cells

(nucleus, plasma membrane, anchoring filaments)

resulted in the separation of epidermis from dermis and the formation of a subepidermal microblister.

a b

Figure 7-5 is not shown because the copyright permission granted to the Borden

Institute, TMM, does not allow the Borden Institute to grant permission to other users

and/or does not include usage in electronic media. The current user must apply to

the publisher named in the figure legend for permission to use this illustration in any

type of publication media.
Medical Aspects of Chemical and Biological Warfare

208

Fig. 7-6. Light and electron microscopic analysis of hairless guinea pig skin exposed to sulfur mustard vapor reveals

that the epithelial basal cell of the stratum germinativum is selectively affected to the exclusion of other epidermal

cells. Following an apparent latency period of 4 to 6 hours, the basal cell pathology progresses to include extensive

hydropic vacuolation, swollen endoplasmic reticulum, coagulation of monofilaments, nuclear pyknosis, and cell death.

At 12 to 24 hours, characteristic microvesicles/microblisters form at the dermal–epidermal junction, which cleave

the epidermis from the dermis. The cavity formed within the lamina lucida of the basement membrane as a consequence of basal cell pathology—and perhaps as the result of disabling of adherent basement membrane proteins—is

infiltrated with cellular debris, inflammatory cells, fibers, and tissue fluid. (a) This hairless guinea pig perilesional

skin site not exposed to mustard (HD) vapor serves as the control. Epidermis (ep); dermis (d); basement membrane

(arrows); basal cells of stratum germinativum (bc). (b) At 9 hours after exposure to HD vapor, degenerating basal

cells with karyorrhectic and pyknotic nuclei (pyk) can be seen. (c) At 12 hours after HD exposure, microvesicles (mv)

are forming at the basement membrane zone in association with degenerating basal cells. (d) At 24 hours after HD

exposure, microvesicles have coalesced to form a characteristic microblister (mb), which separates the epidermis

from the dermis. Original magnification x 220. Photographs: Courtesy of John P. Petrali, Ph.D., U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Md.

The healing time for mustard skin lesions depends

on the severity of the lesion. Erythema heals within

several days, whereas severe lesions may require several weeks to several months to heal, depending on

the anatomical site, the total area of skin surface affected, and the depth of the lesion (Figure 7-7).16

One of the interesting characteristics of the cutaneous mustard injury that Willems16 reported in the

Iranian casualties was the transient blackening, or

hyperpigmentation, of the affected skin (Figure 7-8).

When the hyperpigmented skin exfoliated, epithelium of normal color was exposed. Vesication was

not necessary for hyperpigmentation to occur. The

syndrome of hyperpigmentation and exfoliation

was commonly recognized in World War I casualties, but less commonly in laboratory experiments

a b

c d

in which liquid mustard was used.16 A punctate

hyperpigmentation—possibly due to postinflammatory changes—may be apparent in healed, deep

mustard burns (Figure 7-9).

Eye

The eye is the organ most sensitive to mustard.

The Ct required to produce an eye lesion under field

conditions is 12 to 70 mg•min/m3.

29 The effective

Ct for conjunctivitis, or slightly more severe damage, was just under 10 mg/m3 in 13 subjects; several

subjects had lesions at Cts of 4.8 to 5.8 mg•min/m3.

69

One subject had no symptoms after several hours;

however, by 12 hours after the exposure, marked

blepharospasm and irritation were apparent.
Vesicants

209

a b

Fig. 7-7. Healing of a deep erosive mustard burn

of the hand. (a) The appearance on day 49. Epithelialization occurred by ingrowth of cells from

patches of less injured skin. (b) The appearance

on day 66, by which time complete epithelialization had occurred. The thin and fragile nature of

the new skin is clearly apparent. Reprinted with

permission from Willems JL. Clinical management of mustard gas casualties. Ann Med Milit

Belg. 1989;3S:36.

Fig. 7-8. Transient hyperpigmentation of the injured skin is observed frequently following mustard exposure. It is

caused by the collection of melanin from dead melanocytes at the base of the soon-to-desquamate epidermis and

disappears when the involved skin desquamates. Hyperpigmentation is not dependent on the formation of bullae.

(a) An Iranian casualty as he appeared 5 days following exposure to mustard. Note the extensive desquamation of

hyperpigmented skin on his back and the normal appearance of the underlying skin. This casualty developed a

profound leukopenia (400 cells per μL) and a bronchopneumonia of 10 days’ duration. Resolution of these problems

required a 5-week hospitalization. (b) A different Iranian casualty, seen 12 days after exposure to mustard, has darkening of the skin, desquamation, pink areas showing regeneration of the epidermis, and yellow-white areas of deeper

necrosis. (c) Another casualty’s blackening of the skin and beginning desquamation of the superficial layer of the

epidermis is seen 15 days after mustard exposure. Note the prominence of these changes in the skin of the axilla. (d)

The appearance on light microscopy of a hyperpigmented area. Note the melanin in the necrotic epidermal layer

under which is found a layer of regenerating epidermis. Reprinted with permission from Willems JL. Clinical management of mustard gas casualties. Ann Med Milit Belg. 1989;3S:13, 18, 29, 30.

d

a b

c

Figure 7-7 is not shown because the copyright permission granted to the Borden Institute, TMM, does not

allow the Borden Institute to grant permission to other

users and/or does not include usage in electronic media. The current user must apply to the publisher named

in the figure legend for permission to use this illustration in any type of publication media.

Figure 7-8 is not shown because the copyright permission granted to the Borden Institute,

TMM, does not allow the Borden Institute to grant permission to other users and/or does not

include usage in electronic media. The current user must apply to the publisher named in the

figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

210

Fig. 7-9. By 32 days after exposure, this Iranian casualty

has punctate hyperpigmentation in a healing deep mustard burn. This condition is perhaps indicative of

postinflammatory changes in the epidermis that has regenerated from hair follicles. Reprinted with permission

from Willems JL. Clinical management of mustard gas

casualties. Ann Med Milit Belg. 1989;3S:34.

Generally, the asymptomatic period varies with

the concentration of mustard vapor (or the amount

of liquid) and individual sensitivity. The latent

period for eye damage is shorter than that for skin

damage. Eye irritation within minutes after exposure has been reported,16,69 but the authors of these

reports speculate that the irritation might have been

due to other causes.

After a low Ct exposure, a slight irritation with

reddening of the eye may be all that occurs (Figure

7-10). As the Ct increases, the spectrum of injury is

characterized by progressively more severe conjunctivitis, blepharospasm, pain, and corneal damage.29,65 Photophobia will appear and, even with

mild exposures, may linger for weeks.

Corneal damage consists of edema with clouding (which affects vision), swelling, and infiltration

of polymorphonuclear cells. Clinical improvement

occurs after approximately 7 days with subsiding

edema. Corneal vascularization (pannus development, which causes corneal opacity) with secondary edema may last for weeks. Vision will be lost if

the pannus covers the visual axis. Severe effects

from mustard exposure may be followed by scarring between the iris and the lens, which restricts

pupillary movements and predisposes the individual to glaucoma.29,70

The most severe eye damage is caused by liquid

mustard, which may be delivered by an airborne

droplet or by self-contamination.60 Symptoms may

become evident within minutes after exposure.65

Severe corneal damage with possible perforation of

the cornea can occur after extensive eye exposure

to liquid mustard. The patient may lose his vision

or even his eye from panophthalmitis, particularly

if drainage of the infection is blocked, such as by

adherent lids.65 Miosis sometimes occurs, probably

due to the cholinergic activity of mustard.

During World War I, mild conjunctivitis accounted for 75% of the eye injuries; complete recovery took 1 to 2 weeks. Severe conjunctivitis with

minimal corneal involvement, blepharospasm,

edema of the lids and conjunctivae, and orange-peel

roughening of the cornea accounted for 15% of the

cases; recovery occurred in 2 to 5 weeks. Mild corneal involvement with areas of corneal erosion, superficial corneal scarring, vascularization, and iritis accounted for 10% of the cases; convalescence

took 2 to 3 months. Lastly, severe corneal involvement with ischemic necrosis of the conjunctivae,

dense corneal opacification with deep ulceration,

and vascularization accounted for about 0.1% of the

injuries; convalescence lasted more than 3 months.

Of 1,016 mustard casualties surveyed after World

War I, only 1 received disability payments for defective vision.10

Studies conducted on rabbit eyes indicate that

mustard injury to the cornea is characterized by

initial degeneration of the epithelial cells, with

changes ranging from nuclear swelling and nuclear

vacuolization to pyknosis and nuclear fragmentation. Epithelial loosening and sloughing occurs either by separation of the basal cells from the basement membrane or by shearing of the cell just above

its attachment to the basement membrane.71,72

Fig. 7-10. An eye injury of lesser severity in an Iranian

casualty (shown 7 d after exposure) caused by exposure

to mustard. The characteristic findings were edema of

the lid and conjunctival injection. Corneal ulcerations

were found with more severe exposure. Reprinted with

permission from Willems JL. Clinical management of

mustard gas casualties. Ann Med Milit Belg. 1989;3S:12.

Figure 7-9 is not shown because the

copyright permission granted to the

Borden Institute, TMM, does not allow the

Borden Institute to grant permission to

other users and/or does not include usage in electronic media. The current user

must apply to the publisher named in the

figure legend for permission to use this

illustration in any type of publication media.

Figure 7-10 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden Institute to grant permission to other users and/

or does not include usage in electronic media.

The current user must apply to the publisher

named in the figure legend for permission to

use this illustration in any type of publication

media.
Vesicants

211

Mustard initially causes vasodilation and increased vascular permeability in the conjunctiva,

which lead to progressive edema. Secretion of mucus occurs within minutes of exposure. Pyknosis of

epithelial cells begins concurrently with or shortly

after these changes, leading to desquamation of the

epithelium. In the later stages, inflammatory infiltration of connective tissue and exudation are

present.71,72 Medical personnel have reported seeing delayed keratitis in humans months to years

after mustard exposure.28,73

Within approximately 5 minutes, liquid mustard

dropped into the eyes of rabbits was absorbed, had

disappeared from the eye’s surface, had passed

through the cornea and the aqueous, and had produced hyperemia of the iris. Likewise, damage to

other structures (eg, Descemet’s membrane) also

occurred within a similar length of time.28 Decontamination must be performed immediately after

liquid mustard contaminates the eye because absorption and ocular damage occur very rapidly;

after a few minutes, there will be no liquid remaining on the surface of the eye to decontaminate.

Airways

Mustard produces dose-dependent damage to

the mucosa of the respiratory tract, beginning with

the upper airways and descending to the lower airways as the amount of mustard increases. The inflammatory reaction varies from mild to severe,

with necrosis of the epithelium. When fully developed, the injury is characterized by an acute inflammation of the upper and lower airways, with discharge in the upper airway, inflammatory exudate,

and pseudomembrane formation in the tracheobronchial tree. The injury develops slowly, intensifying over a period of days.

After a low-dose, single exposure, casualties

might notice a variety of catarrhal symptoms accompanied by a dry cough; on examination, they

might have pharyngeal and laryngeal erythema.

Hoarseness is almost always present, and the patient often presents with a barking cough. Typically,

this hoarseness may progress to a toneless voice,

which appears to be particularly characteristic of

mustard exposure. Patients characteristically note

a sense of chest oppression. All of these complaints

typically commence approximately 4 to 6 hours after exposure, with sinus tenderness appearing

hours later. Vapor concentrations sufficient to cause

these symptoms typically produce reddened eyes,

photophobia, lacrimation, and blepharospasm.

There may be loss of taste and smell. Patients occasionally experience mild epistaxis and sore throat.

In individuals with abnormal sensitivity (smokers

and patients with irritable airways or acute viral

illness), prominent wheezing and dyspnea may be

present.58

Exposures to higher concentrations of vapor result in an earlier onset and greater severity of the

above effects. Hoarseness rapidly progresses to

aphonia. Severe tachypnea and early radiological

infiltrates may appear. More-intense respiratory

exposures create necrotic changes in the respiratory

epithelium that result in epithelial sloughing and

pseudomembrane formation. There may be substantial airway occlusion from the inflammatory

debris or from pseudomembranes, which can obstruct the upper airways as they form or can break

off and obstruct lower airways.16,58,60

The initial bronchitis is nonbacterial. White blood

cell elevation, fever, pulmonary infiltrates seen on

radiograph, and colored secretions may all

be present to mimic the changes of a bacterial process. This process is sterile during the first 3 to 4

days; bacterial superinfection occurs in about 4 to

6 days. Careful assessment of the sputum by Gram’s

stain and culture should be done daily.60

Mustard has little effect on lung parenchyma.

Its damage is confined to the airways and the

tissue immediately surrounding the airways, except

after an overwhelming exposure to mustard and

as a terminal event.74 These changes are most intense in the upper airways and decrease in the

trachea, bronchi, and smaller bronchioles—

presumably reflecting a differential disposition of

Fig. 7-11. A surgically excised lung from an Iranian mustard casualty showing bronchiectasis and severe chronic

infection. Reprinted with permission from Freitag L,

Firusian N, Stamatis G, Greschuchna D. The role of bronchoscopy in pulmonary complications due to mustard

gas inhalation. Chest. 1991;100:1438.

Figure 7-11 is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include

usage in electronic media. The current user must

apply to the publisher named in the figure legend

for permission to use this illustration in any type

of publication media.
Medical Aspects of Chemical and Biological Warfare

212

vapor on the mucosal surface.71,75 Pulmonary

edema is not a feature; however, it may occur in

the terminal stages.60,74

The lungs of animals exposed to mustard show

alternating areas of atelectasis and emphysema.

Atelectasis is thought to be caused by the clogging

of bronchioles with mucus, and the emphysema is

compensatory.76 These findings were confirmed

when lungs resected at thoracotomy from Iranian

casualties from the Iran–Iraq War showed similar

effects.77 As seen in Figure 7-11, the lungs showed

bronchiectasis and severe chronic inflammation.

The bronchiectasis was due to full-thickness injury

of the airways. In some casualties, this injury healed

by scarring of such intensity that severe and unrelenting tracheobronchial stenosis developed.

Gastrointestinal Tract

Nausea and vomiting are common within the

first few hours after mustard exposure, beginning

at about the time the initial lesions become apparent. The early nausea and vomiting, which are generally transient and not severe, may be caused by

the cholinergic activity of mustard,9,33 by a general

reaction to injury, or because of the unpleasant

odor.33 Nausea and vomiting that occur days later

are probably due to the generalized cytotoxic activity of mustard and damage to the mucosa of the

gastrointestinal tract.

Diarrhea is not common, and gastrointestinal

bleeding seems to be even less common. Animals

that were given approximately 1 LD50 of mustard

(administered either intravenously or subcutaneously) had profuse diarrhea, which was frequently

bloody60,78; however, this was unusual when mustard was administered percutaneously or by inhalation. (Diarrhea was more common after nitrogen

mustard.9)

Diarrhea and gastrointestinal bleeding do not

seem to be common in humans. Of 107 autopsied

cases, none had experienced diarrhea; and in the

57 cases in which the gastrointestinal tract was thoroughly examined, none had significant lesions.75 In

several reported series of Iranian casualties, totaling about 700 casualties, few had diarrhea and only

a very few who died had bloody diarrhea.16,62,79

Constipation was noted in casualties with mild exposure.60

Central Nervous System

Although the effects are not usually prominent

clinically, mustard affects the CNS. Reports of

World War I casualties described apathy, depression, intellectual dullness, and languor.60 Of 233 Iranian casualties sent to various western European

hospitals for medical care during the Iran–Iraq War,

about 83% had CNS complaints; most complaints,

however, were mild and nonspecific.62

Large amounts of mustard administered to animals (via the inhalational, intravenous, subcutaneous, or intramuscular routes) caused hyperexcitability, abnormal muscular movements, convulsions,

and other neurological manifestations.60,80 Animals

died a “neurological death” a few hours after receiving a lethal amount of mustard.9

 Autopsies of

these animals disclosed few abnormalities.80

After three children were accidentally exposed

to a large amount of mustard, two of them presented

with abnormal muscular activity, and the third

alternated between coma and agitation. The first

two children died 3 to 4 hours after exposure, possibly from neurological mechanisms.22 Whether

these CNS manifestations are from a cholinergic

activity of mustard or from other mechanisms is

unknown.

Death

Most casualties die of massive pulmonary damage complicated by infection (bronchopneumonia)

and sepsis (resulting from loss of the immune

mechanism). When exposure is not by inhalation,

the mechanism of death is less clear. In studies with

animals in which mustard was administered via

routes other than inhalational, the animals died

from 3 to 7 days after the exposure; they had no

signs of pulmonary damage and often had no signs

of sepsis. The mechanism of death was not clear,

but autopsy findings resembled those seen after

radiation.81 (Mustard is considered to be a radiomimetic because it causes tissue damage similar to

that seen after radiation.)

Diagnosis

The differential diagnosis of mustard casualties

on the battlefield after a known chemical attack is

not difficult. The history of a chemical attack is useful, particularly if the chemical agent is known.

Simply questioning the casualty about when the

pain started—whether it started immediately after

the exposure or hours later—is very helpful.

Whereas pain from Lewisite (the other vesicant that

causes blistering) begins seconds to minutes after

exposure, pain from mustard does not begin until

the lesion develops hours later.
Vesicants

213

Blisters appearing simultaneously in a large

number of people, in the absence of a known chemical attack, should alert medical personnel to search

the area with a chemical agent detector. Because

naturally occurring organisms, both plants and insects, cause similar blisters, the appearance of one

or more blisters in only a single individual makes

exposure to a natural substance the more likely

possibility.

Laboratory Tests

There is no specific laboratory test for mustard

exposure. As inflammation and infection occur,

signs of these (eg, fever and leukocytosis) will develop. Several investigational studies have demonstrated the presence of significant amounts of

thiodiglycol, a major metabolite of mustard, in the

urine of mustard casualties. In two studies,82,83 Iranian casualties had higher amounts of thiodiglycol

in their urine than did control subjects. In a third

study, the urinary thiodiglycol secreted by a laboratory worker accidentally exposed to mustard was

quantitatively measured for a 2-week period (his

postrecovery urine was used as a control); the halflife of thiodiglycol was 1.18 days.23 The procedure

for analysis of thiodiglycol is described in Technical Bulletin Medical 296.84

Patient Management

Decontamination within 1 or 2 minutes after exposure is the only effective means of preventing or decreasing tissue damage from mustard. This decontamination is not done by medical personnel. It must be

performed by the soldier himself immediately after the exposure. Generally, a soldier will not seek

medical help until the lesions develop, hours later.

By that time, skin decontamination will not help the

soldier because mustard fixes to the skin within minutes, and tissue damage will already have occurred.64

If any mustard remains on the skin, late decontamination will prevent its spreading to other areas of the skin; but after several hours, spreading

will probably already have occurred. Decontamination will, however, prevent mustard from spreading to personnel who handle the casualty.

By the time a skin lesion has developed, most of

the mustard will already have been absorbed (and

the chemical agent will have fixed to tissue); and,

unless the site was occluded, the remaining unabsorbed agent will have evaporated. Mustard droplets

disappear from the surface of the eye very quickly, so

late flushing of the eye will be of no benefit, either.

However, all chemical agent casualties must be

thoroughly decontaminated before they enter a

clean MTF. This should be done with the realization that by the time a contaminated soldier reaches

an MTF, this decontamination will rarely help the

casualty; it does, however, prevent exposure of

medical personnel.

Mustard casualties generally fall into three

categories. The first is the return to duty category. These individuals have a small area of

erythema or one or more small blisters on noncritical areas of their skin; eye irritation or mild conjunctivitis; and/or late-onset, mild upper respiratory symptoms such as hoarseness or throat irritation and a hacking cough. If these casualties are seen

long after exposure, so that there is good reason to

believe that the lesion will not progress significantly, they can be given symptomatic therapy and

returned to duty.

The second category includes casualties who

appear to have non–life-threatening injuries but

who are unable to return to duty. Casualties with

the following conditions must be hospitalized for

further care:

• a large area of erythema (with or without

blisters),

• an extremely painful eye lesion or an eye

lesion that hinders vision, and

• a respiratory injury with moderate symptoms that include a productive cough and

dyspnea.

Some of these conditions may develop into lifethreatening injuries, and these categories, therefore,

should be used only to assess a casualty’s presenting condition. For example, an area of erythema

caused by liquid mustard that covers 50% or more

of the body surface area suggests that the individual

was exposed to 2 LD50 of the agent. Likewise, dyspnea occurring within 4 to 6 hours after the exposure suggests inhalation of a lethal amount of

mustard.

The third category comprises those casualties

who appear to have life-threatening injuries when

they first present at an MTF. Life-threatening injuries include large skin burns caused by liquid

mustard, and early onset of moderate-to-severe pulmonary symptoms. Most of the casualties in this

category will die from their injuries.

Many mustard casualties will fall into the first

category, the majority will fall into the second category, and only a very small percentage of casualties will fall into the third category. Data from World
Medical Aspects of Chemical and Biological Warfare

214

War I, in which only 3% of mustard injuries were

lethal despite the unsophisticated medical care at

that time (eg, no antibiotics), suggest that most

mustard casualties are not severely injured and that

most of them will survive.

Most casualties of mustard exposure will, however, require some form of medical care—from a few

days to many weeks. Eye care and airway care will

promote healing within weeks; skin lesions take the

longest to heal and may necessitate hospitalization

for months.16 Casualties with mild-to-moderate

mustard damage will need supportive care. Pain

control is extremely important. Fluids and electrolytes should be carefully monitored. Although there

is not a great deal of fluid loss from mustard burns

(compared with thermal burns), a casualty will

probably be dehydrated when he enters the MTF;

and a sick patient usually does not eat or drink

enough. Parenteral fluid supplements and vitamins

may be of benefit. Casualties who have lost their

eyesight because of mustard exposure should be

reassured that they will recover their vision.

Casualties who do become critically ill from their

exposure to mustard will present with large areas

of burns, major pulmonary damage, and immunosuppression. Some of the casualties may die from

sepsis or from overwhelming damage to the airways

and lungs. Medical officers should remember, however, that even with the limited medical care available in World War I, very few deaths were caused

by mustard exposure.

Despite the attention given to mustard since

World War I, research has not produced an antidote.

Because casualties have been managed in different

eras and, more recently, in different medical centers, there have been no standard methods of casualty management, nor have there been any controlled studies of one method compared to another.

The following advice describes care by organ system. Most casualties will have more than one system involved, and many of these casualties will be

dehydrated and have other injuries as well.

Skin

The general principles for managing a mustard

skin lesion are to keep the casualty comfortable,

keep the lesion clean, and prevent infection. The

burning and itching associated with erythema can

be relieved by calamine or another soothing lotion

or cream such as 0.25% camphor and menthol.

These lesions should heal without complication.

Small blisters (< 1 cm) should be left alone; however, the surrounding area should be cleaned (irrigated) at least once daily. An application of a topical antibiotic should immediately be applied to the

blisters and the surrounding area. The blisters and

the surrounding area do not need to be bandaged

unless the casualty will be returning to duty.

Larger blisters (> 1 cm) should be unroofed

and the underlying area should be irrigated (2 to 4

times daily) with saline, sterile water, or clean soapy

water, and liberally covered (to a depth of 1 mm)

with a topical antibiotic cream or ointment (silver

sulfadiazine, mafenide acetate, bacitracin, or

Neosporin [Burroughs Wellcome Co., Research Triangle Park, N. C.]). Dakin’s solution (hypochlorite)

was used on patients in World War I60 and during

the Iran–Iraq War16 as an irrigating solution. It does

not detoxify the chemical agent in the skin, as was

once thought; however, it is an adequate antiseptic

and keeps the area clean. Multiple or large areas of

vesication necessitate hospitalization for frequent

and careful cleaning; a whirlpool bath is a useful

means of irrigation. In general, care of mustard

skin lesions is the same as that of second-degree

thermal burns, although the pathophysiology is

different.

Systemic analgesics should be given liberally,

particularly before manipulation of the burned area.

Systemic antipruritics (eg, trimeprazine) may be

useful. Fluid balance and electrolytes should be

monitored. Fluids are lost into the edematous areas, but fluid replacement is of less magnitude than

that required for thermal burns. Medical personnel

accustomed to treating patients with thermal burns

must resist the temptation to overhydrate mustard

burn patients, which could lead to untoward consequences such as pulmonary edema.16

Skin healing can take weeks to months but usually is complete, although pigment changes may

persist. Scarring is proportional to the depth of the

burn. Skin grafting is rarely needed, but it was successful in one person who had a deep burn.25

Eyes

The basic principles of eye care are to prevent

infection and to prevent scarring. Although it is

unlikely that mustard will still be in the eye by the

time the casualty is seen, the eye should be irrigated

to remove any possible chemical agent that might

be on the lashes and to remove any inflammatory

debris that might be on the surface of the eye. Mild

lesions (eg, conjunctivitis) can be treated three to

four times daily with a soothing eye solution.

Casualties with more-severe eye lesions should

be hospitalized. Care for these patients should con-
Vesicants

215

sist of at least one daily irrigation, preferably more,

to remove inflammatory debris; administration of

a topical antibiotic three to four times daily; and

administration of a topical mydriatic (atropine or

homatropine) as needed to keep the pupil dilated

(to prevent later synechiae formation). Vaseline or

a similar material should be applied to the lid edges

to prevent them from adhering to each other; this

reduces later scarring and also keeps a path open

for possible infection to drain. (When animals’ eyes

were kept tightly shut, a small infection could not

drain, and a panophthalmitis developed that completely destroyed the eyes.65)

Topical analgesics may be used for the initial examination; however, they should not be used routinely as they might cause corneal damage. Pain

should be controlled with systemic analgesics. The

benefit of topical steroids is unknown; however,

some ophthalmologists feel that topical steroids

may be helpful if used within the first 48 hours after the exposure (but not after that). In any case,

an ophthalmologist should be consulted as early

as possible on this and other questions of care.

Keeping the casualty in a dim room or providing

sunglasses will reduce the discomfort from photophobia.

The transient loss of vision is usually the result

of edema of the lids and other structures and not

due to corneal damage. Medical personnel should

assure the patient that vision will return. Recovery

may be within days for milder injuries, while those

with severe damage will take approximately a

month or longer to recover.

Airways

The therapeutic goal in a casualty with mild

airway effects (eg, irritation of the throat, nonproductive cough) is to keep him comfortable. In a casualty with severe effects, the goal is to maintain

adequate oxygenation. Antitussives and demulcents are helpful for persistent, severe, nonproductive cough. Steam inhalation might also be

useful.

Hypoxia is generally secondary to the abnormalities in the ventilation–perfusion ratio caused by

toxic bronchitis. Mucosal sloughing further complicates this abnormality. Underlying irritable airways

disease (hyperreactive airways) is easily triggered;

consequently, therapy with bronchodilators may be

necessary. Casualties with hyperreactive airways

may benefit from steroid treatment with careful attention to the added risk of superinfection. Oxygen

supplementation may be necessary for prolonged

periods; this will depend, primarily, on the intensity of mustard exposure and the presence of any

underlying pulmonary disorder.

Hypercarbia may result from a previously unrecognized hyperreactive airways state or from abnormal central sensitivity to carbon dioxide, complicated by increased work of respiration (this state

may result from bronchospasm). Bronchodilators

are acceptable initial therapy. Ventilatory support

may be necessary to assist adequate carbon dioxide clearance. The use of certain antibiotic skin

creams (such as mafenide acetate) to treat skin lesions may complicate the acid–base status of the

individual by inducing a metabolic acidosis. Steroids should be considered if a prior history of

asthma or hyperreactive airways disease is obtained.

Initially, the bronchitis resulting from mustard

exposure is nonbacterial. White blood cell elevation, fever, pulmonary infiltrates on a chest radiograph, and colored sputum may all be present; however, careful assessment of sputum by Gram’s stain

and culture demonstrates that bacterial superinfection typically is not present during the first 3 to 4

days. Antibiotic therapy should be withheld until

the identity of a specific organism becomes available. Of particular importance is the patient’s immune status, which may be compromised by a progressive leukopenia beginning about day 4 or 5. The

development of leukopenia signals severe immune

system dysfunction; massive medical support may

become necessary for these patients. In these instances, sepsis typically supervenes, and despite

combination antibiotic therapy, death commonly

occurs.

A casualty with severe pulmonary signs should

be intubated early, before laryngeal spasm makes

it difficult or impossible. Intubation assists in ventilation and also allows suction of necrotic and inflammatory debris. Bronchoscopy may be necessary

to remove intact pseudomembranes or fragments

of pseudomembranes; one of the Iranian casualties

treated in western European hospitals during the

Iran–Iraq War died of tracheal obstruction by

a pseudomembrane. Early use of positive end-expiratory pressure or continuous positive airway

pressure may be beneficial. The need for continuous ventilatory support suggests a bad prognosis;

of the Iranian casualties treated in western European hospitals who needed assisted ventilation,

87% died.16

An especially devastating pulmonary complication, severe and progressive stenosis of the tracheobronchial tree (Figure 7-12), was found in about
Medical Aspects of Chemical and Biological Warfare

216

10% of the Iranian casualties treated in western European hospitals during the Iran–Iraq War. This

complication was not recognized in World War I

mustard casualties because the degree of exposure

required to cause severe tracheobronchial injury

resulted in early death from pneumonia: we must

remember the primitive nature of early 20th-century medicine and its lack of antibiotics. With the

Iranian casualties, bronchoscopy was of value when

used both for diagnosis and for therapeutic dilation.77 However, given the progressive nature of the

scarring, unnaturally early death from respiratory

failure is to be expected in all such casualties.

Gastrointestinal Tract

The initial nausea and vomiting are rarely severe

and can usually be relieved with atropine or common antiemetics. Later vomiting and diarrhea are

usually indicative of systemic cytotoxicity and require fluid replacement.

Bone Marrow

Suppression of the hemopoietic elements cannot

be predicted from the extent of skin lesions (eg, the

lesions might be from vapor and therefore superfiFig. 7-12. (a) Bronchoscopic view of the trachea in an Iranian casualty 3 weeks after exposure to mustard. Severe hemorrhagic bronchitis, mucosal necrosis, and early scarring

are apparent. (b) Bronchogram from an Iranian casualty 1 year after his exposure to

mustard. The tip of a 10-mm rigid bronchoscope can be seen at the upper margin of the

figure. Severe generalized narrowing of the

entire tracheobronchial tree is apparent. The

casualty presented with dyspnea, cough, hypoxia, and hypercarbia. (c) Bronchoscopic

appearance of the carina of an Iranian casualty who had been exposed to mustard

several years before. There is nearly total occlusion of the left main-stem bronchus. Reprinted with permission from Freitag L,

Firusian N, Stamatis G, Greschuchna D. The

role of bronchoscopy in pulmonary complications due to mustard gas inhalation. Chest.

1991;100:1437–1438.

a c

b

Figure 7-12 is not shown because the copyright permission granted to the Borden

Institute, TMM, does not allow the Borden Institute to grant permission to other

users and/or does not include usage in electronic media. The current user must

apply to the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Vesicants

217

cial, but significant amounts of mustard may have

been absorbed by inhalation). Frequent counts of

the formed blood elements must be done on a casualty who has significant skin lesions or airway

damage. Mustard destroys the precursor cells, and

cell elements in the blood are depressed. Because

white blood cells have the shortest life span, their

numbers decrease first; the red blood cells and the

thrombocytes soon follow if the casualty lives long

enough or does not start to recover. Typically, leukopenia begins at day 3 through day 5 after the exposure, and reaches a nadir in 3 to 6,60 or 7 to 9,16

days. Leukopenia with a cell count lower than 200

cells/mm3 usually signifies a bad prognosis,16 as

does a rapid drop in the cell count; for example,

from 30,000 to 15,000 cells/mm3 in a day.60

Medical personnel should institute therapy that

sterilizes the gut with nonabsorbable antibiotics at

the onset of leukopenia.16 Cellular replacement,

either peripheral or marrow, may also be successful.

Other Treatment Modalities

A variety of antiinflammatory and sulfhydrylscavenging agents (such as promethazine, vitamin

E, heparin, and sodium thiosulfate) have been

suggested as therapeutic drugs. Although animal

studies suggest the value of these agents for prophylactic therapy (or therapy immediately after the

exposure), there are no data to support their use

after the lesions develop.85–87

Activated charcoal, administered orally, has been

tried with unknown results16; however, it may provide some benefit if given immediately after mustard is ingested. Hemodialysis was not only without benefit, it appeared to have deleterious effects.16

This is not surprising because mustard becomes

fixed to tissue within minutes.

Long-Term Effects

Mustard burns may leave areas of hypopigmentation or hyperpigmentation, sometimes

with scarring. Individuals who survive an acute,

single mustard exposure with few or no systemic

or infectious complications appear to recover fully.

Previous cardiopulmonary disorders, severe or

inadequately treated bronchitis or pneumonitis,

a prior history of smoking, and advanced age

all appear to contribute to long-term chronic bronchitis; there is no definitive way to determine

whether these conditions are the result of aging,

smoking, or a previous mustard exposure. Casualties with severe airway lesions may later have

postrecovery scarring and stenosis, which predisposes the individual to bronchiectasis and recurrent

pneumonia.58

An important late sequela of mustard inhalation

is a tracheal/bronchial stenosis that necessitates

bronchoscopy and other procedures.77 Mustard has

been reported to create a long-term sensitivity to

smoke, dust, and similar airborne particles, probably as a result of clinically inapparent bronchospasm.58,88

The relationship between mustard exposure and

subsequent cancer has been the subject of much

study. It seems clear that individuals who were

exposed to mustard daily for long periods (eg,

workers in mustard production plants) have a

slightly higher incidence of cancer of the airways,

primarily the upper airways.89–91 According to two

separate reports,92,93 the association of one or two

exposures on the battlefield with subsequent cancer is not clear; in a third report,94 the relation between mustard exposure and subsequent cancer is

equivocal. Interested readers may consult Watson

and associates’ 1989 review95 of the mustard exposure–cancer incidence relation.

In 1991, the National Academy of Science appointed a committee to survey the health effects of

mustard and Lewisite.94 Veterans of World War II,

who, as subjects in test programs, had been exposed

to mustard and Lewisite, were presenting at Veterans Administration hospitals with complaints of illnesses that they believed were associated with these

test programs. The committee was requested to survey the literature to assess the strength of association

between these chemical agents and the development of specific diseases. The committee reported

finding a causal relationship between exposure and

various cancers and chronic diseases of the respiratory system; cancer and certain other problems

of the skin; certain chronic eye conditions; psychological disorders; and sexual dysfunction. They

found insufficient evidence for a causal relationship

between exposure and gastrointestinal diseases,

hematological diseases, neurological diseases, and

cardiovascular diseases (except those resulting from

infection following exposure). Some of these conclusions were not well supported. For example,

there were no cases of skin cancer reported, and the

alleged psychological disorders were from the

trauma of exposure, not from the agent (see Chapter 8, Long-Term Health Effects of Nerve Agents and

Mustard).
Medical Aspects of Chemical and Biological Warfare

218

LEWISITE

Lewisite (β-chlorovinyldichloroarsine) is an arsenical vesicant but of only secondary importance

in the vesicant group of agents. It was synthesized96

in the early 20th century and has seen little or no

battlefield use. Lewisite is similar to mustard in

that it damages the skin, eyes, and airways; however, it differs from mustard because its clinical

effects appear within seconds of exposure. An

antidote, British anti-Lewisite (BAL), can ameliorate the effects of Lewisite if used soon after exposure. Lewisite has some advantages over mustard

but also some disadvantages.

Military Use

A research team headed by U.S. Army Captain

W. L. Lewis is generally credited with the synthesis of Lewisite in 1918,96–98 although German scientists had studied this material earlier.1,58 Large

quantities were manufactured by the United States

for use in Europe; however, World War I ended

while the shipment was at sea and the vessel was

sunk.1,98

There has been no verified use of Lewisite on a

battlefield, although Japan may have used it

against China between 1937 and 1944.93 Currently,

this vesicant is probably in the chemical warfare

stockpile of several countries. Lewisite is sometimes mixed with mustard to lower the freezing

point of mustard; Russia has this mixture.99

Properties

Pure Lewisite is an oily, colorless liquid, and impure Lewisite is amber to black. It has a characteristic odor of geraniums. Lewisite is much more

volatile and persistent in colder climates than mustard. Lewisite remains fluid at lower temperatures,

which makes it perfect for winter dispersal.

Lewisite hydrolyzes rapidly, and, on a humid day,

maintaining a biologically active concentration of

vapor may be difficult.100

Toxicity

The toxicity of Lewisite vapor is very similar to

that of mustard vapor; the LCt50 (the concentration • time that is lethal to 50% of the exposed

population) by inhalation is estimated to be about

1,500 mg•min/m3, and the LCt50 for eye and airway

damage are about 150 and 500 mg•min/m3, respectively. Vesication is caused by 14 μg of liquid, and

the LD50 of liquid on the skin is about 30 mg/kg100

(or probably higher98). Blister fluid from a Lewisitecaused blister is nonirritating,58,98 but it does contain

0.8 to 1.3 mg/mL of arsenic.

Biochemical Mechanisms of Injury

Lewisite shares many biochemical mechanisms of

injury with the other arsenical compounds. It inhibits many enzymes: in particular, those with thiol

groups, such as pyruvic oxidase, alcohol dehydrogenase, succinic oxidase, hexokinase, and succinic

dehydrogenase (Figure 7-13). As is true with mustard,

the exact mechanism by which Lewisite damages cells

has not been completely defined. Inactivation of carbohydrate metabolism, primarily because of inhibition

of the pyruvate dehydrogenase complex, is thought

to be a key factor.98

Clinical Effects

Lewisite damages skin, eyes, and airways by direct contact and has systemic effects after absorption. Unlike mustard, it does not produce immunoFig. 7-13. The putative mechanisms by which Lewisite

causes tissue damage. Adapted from US Army Medical

Research Institute of Chemical Defense. A global picture

of battlefield vesicants, I: A comparison of properties and

effects. Med Chem Def. 1992;5(1):6.

L

• Loss of protein thiol status

• Loss of Ca++ homeostatis

• Oxidation stress

• Lipid peroxidation

• Membrane damage

• Cell death

• Acute tissue injury

• Inhibition of pyruvate 

dehydrogenase complex

• Inhibition of glycolysis

• Loss of ATP

• Cell death

• Acute tissue injury

Reactions with Adjacent 

Sulfhydryl Groups of Enzymes

Reactions with 

Glutathione

Lewisite

Cl C C As

Cl

H H Cl
Vesicants

219

suppression. Data on human exposure are few.

Lewisite was applied to human skin in a few studies58,101–103; however, most information on its clinical effects is based on animal studies.

Skin

Lewisite liquid or vapor produces pain or irritation within seconds to minutes after contact. Pain

caused by a Lewisite lesion is much less severe than

that caused by mustard lesions, and it diminishes

after blisters form.58

Erythema is evident within 15 to 30 minutes after exposure to liquid Lewisite, and blisters start

within several hours; these times are somewhat

longer after vapor exposure. Lewisite is absorbed

by the skin within 3 to 5 minutes (compared with

20–30 min for an equal amount of mustard) and

spreads over a wider area than the same amount of

mustard. The Lewisite blister begins as a small blister in the center of the erythematous area and expands to include the entire inflamed area, whereas

vesication from mustard begins as a “string of pearls”

at the periphery of the lesion, small blisters that eventually merge.58 Other differences between the lesions

produced by these two chemical agents are

• the inflammatory reaction from Lewisite

generally occurs much faster,

• the lesions from Lewisite heal much faster,

• secondary infection is less common after

Lewisite exposure, and

• subsequent pigmentation is likewise less

common.58

See Goldman and Dacre104 for a further review of

Lewisite and its toxicology.

Eyes

A person is less likely to receive severe eye injury from Lewisite vapor than from mustard vapor

because the immediate irritation and pain caused

by Lewisite will produce blepharospasm, effectively

preventing further exposure. A small droplet of

Lewisite (0.001 mL) can cause perforation and loss

of an eye.105

In tests performed on rabbits,105 Lewisite caused

almost immediate edema of the lids, conjunctiva,

and cornea (which was maximal after the lid edema

had subsided) and early and severe involvement of

the iris and ciliary body, followed by gradual depigmentation and shrinkage of the iris stroma.

Miosis appeared early. In this same study, miosis

was not noted after mustard exposure. No longterm effects of Lewisite were noted, such as the

delayed keratitis seen after mustard.

Airways

Lewisite vapor is extremely irritating to the nose

and lower airways, causing individuals exposed to

it to seek immediate protection, thus limiting further exposure. The airway lesion of Lewisite is very

similar to the lesion caused by mustard exposure

except that the Lewisite vapor is extremely irritating to the mucous membranes. In large amounts,

Lewisite causes pulmonary edema.

After exposure to Lewisite, dogs exhibited massive nasal secretions, lacrimation, retching, vomiting, and labored respiration. These symptoms worsened until death finally occurred. On autopsy, the

lungs were edematous, and a pseudomembrane often extended from the nostrils to the bronchi. Tracheal and bronchial mucosa was destroyed and the

submucosa was congested and edematous. Bronchopneumonia was commonly mixed with edema.60

Other Effects

“Lewisite shock” is seen after exposure to large

amounts of Lewisite. This condition is the result of

protein and plasma leakage from the capillaries and

subsequent hemoconcentration and hypotension.

A small amount of Lewisite on the skin will cause

local edema because of the effects of this agent on

local capillaries. With a large amount of Lewisite,

the pulmonary capillaries are also affected (because

they are more sensitive to Lewisite than other capillaries or because absorbed Lewisite reaches the

lungs before it reaches the systemic circulation);

there is edema at the site of exposure and pulmonary edema. With even larger amounts of Lewisite,

all capillaries are affected, and proteins and plasma

leak from the circulation into the periphery. Even

after small amounts of Lewisite, the fluid loss can

be sufficient to cause diminution of renal function

and hypotension.104

Arsines are known to cause hemolytic anemia,

but there is little mention of this in reports on

Lewisite exposure. A “true or hemolytic anemia”

was noted with Lewisite shock.104

Diagnosis

Lewisite exposure can be distinguished from

mustard exposure by the history of pain on contact

with the agent. Phosgene oxime also causes pain
Medical Aspects of Chemical and Biological Warfare

220

on contact, but phosgene oxime does not produce a

liquid-filled blister. If a single individual has an

isolated blister, other plant or animal causes of vesication should be sought.

Laboratory Tests

There is no specific laboratory test for Lewisite.

Urinary arsenic excretion might be helpful in identifying possible exposure to Lewisite, however.

Patient Management

Medical personnel should follow the same principles for managing Lewisite skin, eye, and airway

lesions that they follow for managing mustard

lesions. A specific antidote, BAL (dimercaprol),

will prevent or greatly decrease the severity of

skin and eye lesions if applied topically within

minutes after the exposure and decontamination (however, preparations of BAL for use in

the eyes and on the skin are no longer available).

Given intramuscularly, BAL will reduce the severity of systemic effects. BAL binds to the arsenic of

Lewisite more strongly than do tissue enzymes,

thereby displacing Lewisite from the cellular receptor sites.98,104

BAL reduced the mortality in dogs when it was

given within 100 minutes after they had inhaled a

lethal amount of Lewisite.106 Burns of the eyes from

Lewisite can be prevented if BAL is applied within

2 to 5 minutes of exposure104; when it was applied

within an hour after exposure, BAL prevented vesication in humans.107 BAL has some unpleasant side

effects, including hypertension and tachycardia; the

user should read the package insert.

Long-Term Effects

There are no data on human exposure from which

to predict the long-term effects from Lewisite. There

is no substantial evidence to suggest that Lewisite

is carcinogenic, teratogenic, or mutagenic.104 The

committee appointed by the National Academy of

Science reported94 a causal relationship between

Lewisite exposure and chronic respiratory diseases,

and also that acute, severe injuries to the eye from

Lewisite will persist.

PHOSGENE OXIME

Phosgene oxime (CX) is not a true vesicant

because it does not produce vesicles. Instead,

phosgene oxime is an urticant or nettle agent:

it causes erythema, wheals, and urticaria. Its lesions have been compared with those caused by

nettle stings. Because it causes extensive tissue damage, phosgene oxime has been called a corrosive

agent. Phosgene oxime is not known to have been

used on a battlefield, and there is very little information regarding its effects on humans. This compound must be distinguished from phosgene (CG),

which exerts its effects on the alveolar–capillary

membrane.

Military Use

German scientists first synthesized phosgene

oxime in 1929,108 and Russia as well as Germany had

developed it before World War II. Both countries

may have had weapons that contained this agent.109

The United States also had studied phosgene oxime

before World War II but rejected it as a possible chemical agent because of its biological effects—or lack

thereof—and its instability.109 The apparent lack of

biological effects was later found to be due to the low

concentrations (1%–2%) used in the pre–World War

II studies. Later studies indicated that concentrations below 8% cause no or inconsistent effects.109,110

Phosgene oxime is of military interest because

• it penetrates garments and rubber much

more quickly than do other chemical agents,

and

• it produces a rapid onset of severe and prolonged effects.

When mixed with another chemical agent (eg, VX),

the rapid skin damage caused by phosgene oxime

will render the skin more susceptible to the second

agent. Also, if an unmasked soldier were exposed

to phosgene oxime before donning his mask, the

pain caused by phosgene oxime will prompt him

to unmask again.

Properties

Pure phosgene oxime (dichloroformoxime) is a

colorless, crystalline solid; the munitions grade

C N OH

Cl

Cl

CX
Vesicants

221

compound is a yellowish-brown liquid. Its melting

point is 35°C to 40°C (95°F–104°F). The solid material

will produce enough vapor to cause symptoms.100

Biochemical Mechanisms of Injury

Phosgene oxime is the least well studied of the

chemical agents discussed in this volume, and its

mechanism of action is unknown. It might produce

biological damage because of the necrotizing effects

of the chlorine, because of the direct effect of the

oxime, or because of the carbonyl group (Figure 7-

14). The skin lesions, in particular, are similar to

those caused by a strong acid. This agent seems to

cause its greatest systemic effects in the first capillary bed it encounters. For example, cutaneous application or intravenous injection of phosgene

oxime causes pulmonary edema, while injection

into the portal vein produces hepatic necrosis but

not pulmonary edema.110

Clinical Effects

Phosgene oxime affects the skin, the eyes, and

the lungs. The effects are almost instantaneous, and

it causes more severe tissue damage than other vesicants. A characteristic of phosgene oxime is the

immediate pain or irritation it produces on the skin,

in the eyes, and in the airways. No other chemical

agent produces such an immediately painful onset

that is followed by rapid tissue necrosis.

Skin

Pain occurs immediately on contact with the liquid or solid form of this agent. Approximately 5 to

20 seconds after solutions containing 8% to 70%

phosgene oxime were applied, pain and blanching

occurred at the application site. Following the initial exposure, the site became grayish with a border

of erythema. Within 5 to 30 minutes after the exposure, edema formed around the edges of the tissue;

the tissue later became necrotic. During the next 30

minutes, a wheal formed but disappeared overnight. The edema regressed over the following 24

hours and the original blanched area became pigmented. A dark eschar formed over the following 7

days; this gradually healed from below by granulation. The lesion extended into the underlying panniculus and muscle and was surrounded by an

inflammatory reaction. In some subjects, healing

was incomplete 4 to 6 months after exposure.109 In

both animal and human subjects, the skin had

completely absorbed the phosgene oxime within

seconds—by the time pallor appeared.110

Eyes

The eye lesions from phosgene oxime are similar to those caused by Lewisite; these lesions result

in immediate pain, conjunctivitis, and keratitis.109–111 An exact description of these effects, however, is not available.

Airways

The main lesion of phosgene oxime in the lungs

is pulmonary edema. This effect occurs after either

inhalation or systemic absorption of the agent. The

pulmonary edema may be accompanied by necrotizing bronchiolitis and thrombosis of pulmonary

venules. A large amount of phosgene oxime on the

skin may produce pulmonary edema after a severalhour delay; pulmonary thromboses are prominent.110

Patient Management

There is no antidote for phosgene oxime, nor is

there a recommended therapeutic regimen. Medical personnel should treat necrotic areas of the skin

Fig. 7-14. The putative mechanisms by which phosgene

oxime causes tissue damage. Adapted from US Army

Medical Research Institute of Chemical Defense. A global picture of battlefield vesicants, I: A comparison of

properties and effects. Med Chem Def. 1992;5(1):6.

• Enzyme inactivation

• Cell death

• Corrosive injury

• Rapid local destruction of

tissue (eg, vesication)

• Activation of alveolar

macrophages

• Recruitment of neutrophils

• Release of H2O2

• Delayed tissue injury 

(eg, pulmonary edema)

Phosgene Oxime

Indirect Injury

Mechanism

Direct Injury

Mechanism

Cellular Targets

Not Known
Medical Aspects of Chemical and Biological Warfare

222

the same way other necrotic lesions are treated—

by keeping them clean and avoiding infection. The

eye lesions require the same care as one would supply for damage from a corrosive substance. The

pulmonary lesion, noncardiac pulmonary edema,

should be managed as suggested in Chapter 9, Toxic

Inhalational Injury.

Decontamination, or self-aid, must be accomplished immediately after contact because the agent

is absorbed from the skin within seconds.

SUMMARY

The military has considered vesicants to be major chemical warfare agents since 1917. Mustard,

however, is the only vesicant known to have been

used on the battlefield. Mustard and Lewisite, in

much smaller amounts, are known to be in the

stockpiles of other countries.

Mustard was used on a large scale in World War

I, causing a great number of casualties; it was also

used during the Iran–Iraq War. Data from the Iran–

Iraq War are scanty; however, data from World War

I indicate that more than 95% of mustard casualties

survived but most required lengthy hospitalizations. If mustard is ever used again, military medical personnel must be prepared to accept and care

for large numbers of casualties, who will require

long-term hospitalization.

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Long-Term Health Effects of Nerve Agents and Mustard

229

Chapter 8

LONG-TERM HEALTH EFFECTS OF

NERVE AGENTS AND MUSTARD

FREDERICK R. SIDELL, M.D.*; AND CHARLES G. HURST, M.D.†

INTRODUCTION

Nerve Agents

Mustard

NERVE AGENTS

Polyneuropathy

Muscle Necrosis

Intermediate Syndrome

Neuropsychiatric Effects

Electroencephalographic Abnormalities

Toxicological Studies on Nerve Agents

MUSTARD

Carcinogenesis

Chronic Pulmonary Disease

Chronic Eye Disease

Scarring of Epithelial Surfaces

Central Nervous System

Mutagenesis, Teratogenesis, and Reproductive Toxicity

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014

†Colonel, Medical Corps, U.S. Army; currently, Special Assistant for Medical Programs, Office of the Deputy Assistant Secretary of Defense,

Counterproliferation and Chemical/Biological Matters, Room 3E808, 3050 Defense Pentagon, Washington, D.C. 20301-3050; formerly, Commander, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425
Medical Aspects of Chemical and Biological Warfare

230

INTRODUCTION

Chemical warfare agents were used extensively

in World War I (the United States had approximately 70,000 chemical casualties1

) and have been

employed or allegedly employed in a dozen or so

conflicts since.2 The most recent large-scale use of

these weapons was by Iraq in its war with Iran in

the late 1980s. During that conflict, Iraq used nerve

agents and the vesicant mustard3

 and maintained a

stockpile of, and a manufacturing capability for,

these two agents after the war. Before the coalition

forces liberated Kuwait early in 1991 during the

Persian Gulf War, Iraq was expected to use these

agents when attacked. No reports of the use of

chemical weapons during that conflict were made,

however, despite the watchfulness of a vigilant

press corps, who expected such use; and personnel

of the military medical departments, who were

trained to report, investigate, and care for chemical

casualties.4,5 One U.S. soldier developed skin blisters

8 hours after exploring an underground bunker.4

 His

clinical findings and mass spectroscopy readings (performed by a chemical detection team) from his clothing and the bunker supported a diagnosis of accidental mustard exposure, which was mild and resulted

in no loss of duty time. The exposure was not confirmed by later testing of clothing samples, from

which trace amounts of the agent may have dissipated.

Although the acute effects of the nerve agents

and of mustard agent are well known,6,7 the longterm effects after a single exposure or multiple exposures are less well recognized. The nerve agents

are the subject of Chapter 5, Nerve Agents, and

mustard is a subject of Chapter 7, Vesicants, but this

chapter focuses on the long-term effects. A synopsis of the nature and activity of the agents follows.

Nerve Agents

Nerve agents are esters of phosphonic acid and

are extremely potent chemicals. Their military designations are GA (tabun), GB (sarin), GD (soman),

GF, and VX. The agents GF and VX have no common names.

The toxic effects of nerve agents are due primarily to their inhibition of acetylcholinesterase and the

resulting accumulation of acetylcholine.8

 Other biological activities of these agents have been described, but the relation of these activities to clinical effects has not been recognized. For example,

some nerve agents affect ionic channels,9 and all

affect structures other than acetylcholinesterase.10

Several milligrams of VX, the least volatile nerve

agent, absorbed through the skin will cause clinical signs and symptoms.11,12 A Ct (the concentration

[C] of agent vapor or aerosol in air, as mg/m3, multiplied by the time [t] of exposure, in minutes) of 2

to 3 mg•min/m3 of sarin will produce miosis and

rhinorrhea in man.13 This Ct can be attained with

exposure to a concentration of 2 mg/m3 for 1 minute

or a concentration of 0.05 mg/m3 for 40 minutes.

The initial signs of exposure to small quantities

of agent vapor are miosis, rhinorrhea, and airway

constriction.7,14 Larger amounts will cause loss of

consciousness, seizure activity,14 cessation of respiration15 and cardiac activity, and death, unless there

is medical intervention. Effects occur within minutes of exposure,14,15 and after a large exposure (Ct

of 10–200 mg•min/m3, depending on the agent16),

death occurs in 10 to 15 minutes.

After exposure to a sublethal amount on the skin

(1–3 mg), the onset time for clinical effects may be

hours.11,12 The initial effect is usually vomiting,

which may be followed by muscular weakness. A

lethal amount on the skin (10 mg of VX, the most

toxic by percutaneous absorption16) will cause effects within several minutes14 and death will occur

shortly afterwards.

Treatment consists of the administration of atropine, a drug that blocks the effects of the excess acetylcholine at muscarinic acetylcholine receptor sites;

and of 2-pyridine aldoxime methyl chloride (2-PAM

Cl, also called pralidoxime chloride), an oxime that

will remove the agent from acetylcholinesterase,

thereby reactivating the enzyme after poisoning by

some agents.17 2-PAM Cl, however, is ineffective

against soman intoxication14 because of soman’s rapid

aging. (Aging is the process by which one of the nerve

agent’s alkyl groups leaves the molecule. After dealkylation, an acetylcholinesterase-bound nerve

agent molecule can no longer be removed from the

enzyme by an oxime. The aging half-time of soman

is about 2 min.) Ventilatory support is necessary when

breathing has stopped or is inadequate,14,15 and the

anticonvulsant diazepam may need to be administered.

Mustard

Two well-known forms of mustard exist. Sulfur

mustard (designated by the military as H or HD)

was first synthesized in the early 1800s, has been
Long-Term Health Effects of Nerve Agents and Mustard

231

used in warfare on several occasions, and is a major chemical warfare agent.6

 Nitrogen mustard is of

more recent origin, has not been used in warfare,

and is a cancer chemotherapeutic agent. Throughout this report, the word mustard will refer to sulfur mustard.

Mustard is best known as a skin vesicant, but in

a series of Iranian patients exposed to mustard, 95%

had airway effects, 92% had eye injuries, and

83% had skin lesions.18 After absorption, mustard,

an extremely potent alkylating agent, has the potential to damage all cells and all organs.6

 Absorption and systemic distribution of a significant

amount of mustard damages the bone marrow

(where it destroys the precursor cells, leading to

pancytopenia).6 Less commonly, clinical effects are

seen in the gastrointestinal tract (usually as a terminal event)19,20 and in the central nervous system

(CNS) (with ill-defined symptoms such as lethargy

and apathy).18,21

On the skin, a Ct of 50 mg•min/m3 or a droplet

of 10 μg of mustard is adequate to produce vesication.6 (One study22 indicates that 8 of the 10 μg

evaporate and 1 μg enters the systemic circulation,

leaving 1 μg to produce the skin lesion.) Eye lesions

can be produced by a Ct of 10 mg•min/m3.

23 Airway injury occurs at a Ct of 100 mg•min/m3 or

higher.6

The mode of biological activity of mustard is less

well defined than that of the nerve agents. The initial event is felt to be a reaction of mustard and

deoxyribonucleic acid (DNA) with subsequent

damage to the DNA. A series of intracellular events

then occur, leading to cellular damage accompanied

by inflammation and cellular death. Cellular damage begins within 1 to 2 minutes of contact of mustard to skin or mucous membranes.6

The onset of clinical effects following exposure

to mustard occurs hours after the exposure.6 The

delay usually ranges from 2 to 24 hours and is inversely proportional to the amount of mustard and

other factors.

No specific therapy for mustard exposure exists.6

Decontamination within a minute or two will prevent or diminish the lesion, and later care consists

of symptomatic management of the lesion.

NERVE AGENTS

Much information on both the short-term and the

long-term effects of mustard in man comes from its

battlefield use in World War I and the Iran–Iraq War,

and from experimental studies during the World

War I and World War II periods.24 In contrast, no

data from the battlefield use of nerve agents are

available. Information on the effects of nerve agents

in man comes from the accidental exposure of hundreds of people who were mildly or moderately

exposed while working with nerve agents and from

a handful of workers who had severe exposures.

Investigational studies carried out in hundreds of

people also provide information.

Information on the effects of organophosphorus

insecticides is included so that medical officers can

compare and contrast the two. Because nerve agents

and insecticides are both organophosphates, people

often tend to extrapolate from the biological effects

of one of these types to the other, but in fact the

differences between insecticides and nerve agents

are great. The authors of some reports did not recognize the differences and grouped them together.25,26

Although the organophosphate insecticides are

similar to nerve agents in inhibiting cholinesterase,

they differ in other characteristics. For example, the

cholinergic crisis caused by acute, severe intoxication with the insecticides is generally much longer

than that caused by nerve agents (days to weeks

for insecticides27,28 vs hours for nerve agents14,15).

Not only do the insecticides differ from nerve

agents, they also differ among themselves in some

of their biological effects; for example, some cause

polyneuropathy, others do not.29 Because of these

differences, all of which have probably not been

defined, the similarity between the effects of insecticides in man and the effects of nerve agents in man

cannot be assumed. We repeat, insecticides are included in this review only so that the similarities

can be noted and the differences contrasted. The

reader should be careful not to confuse one with

the other.

Polyneuropathy

Insecticides

Organophosphorus ester–induced delayed neurotoxicity (OPIDN) has been recognized as a clinical syndrome in humans and animals for over 50

years. After an exposure to certain organophosphates occurs, incoordination, ataxia, spasticity, and

flaccid paralysis develop over the following 1 to 3

weeks; the paralysis begins distally in the lower

limbs and eventually spreads to the upper limbs.

Part or all of the lesion may be reversible, but in its
Medical Aspects of Chemical and Biological Warfare

232

most severe form it can cause lifetime quadriplegia. Structural changes begin at the distal, nonmyelinated portion of the nerve, followed by progressive demyelination associated with degeneration of

more proximal nerve segments.29

This syndrome was initially associated with ingestion of triorthocresyl phosphate (TOCP), not an

insecticide. After organophosphate insecticides became available, the syndrome was seen after exposure to some, but not all, of them.29

The best animal model for studying the effects

of exposure to organophosphates is the chicken.29,30

Extensive studies have been performed to elucidate

the mechanism of action that causes OPIDN and to

screen new organophosphate insecticides for this

effect.29,30 The exact mechanism of action is still unknown, but much evidence suggests that the inhibition of neurotoxic esterase in nerve tissue is involved.31 Administration of oximes and atropine has

no effect on the production of this neurotoxicity.32

OPIDN is not seen with all insecticides.29,30 Generally, insecticides that have been shown to cause

polyneuropathy have been removed from the market; only those that have been demonstrated not to

cause this effect in animal models are available.

Nerve Agents

Nerve agents have caused polyneuropathy in

animals only at doses manyfold greater than the

LD50 (the dose [D] that is lethal [L] to 50% of the

exposed population)—doses that require massive

pretreatment and therapy to ensure survival of the

animals. Davies et al33 produced polyneuropathy in

chickens with sarin only at 60 or more times the

LD50. (The animals were protected with atropine

and oxime to permit survival.) Neuropathy was not

detected at 8 times the medial lethal dose of soman.

Davies’s group also detected no polyneuropathy at

doses of VX of 45 μmol/kg.34

In another study,35 polyneuropathy was found in

hens after 30 to 60 times the LD50 for sarin was administered, but not at 38 times the LD50 for soman

or 82 times the LD50 for tabun. VX was not examined in this study because its ability to inhibit neurotoxic esterase is negligible. At 120 times the acute

LD50 in hens, soman and tabun caused polyneuropathy in some surviving animals.36 GF is a stronger inhibitor of neurotoxic esterase in vitro than the

other nerve agents.37 However, GF, along with

tabun, soman, and VX, did not cause polyneuropathy at very high doses.38 This syndrome has not been

noted in the handful of humans severely exposed

to nerve agents or in the hundreds of humans with

mild-to-moderate effects from nerve agents. Studies using smaller doses of tabun, sarin, and soman

are described later in this chapter, in the section on

toxicology.

Muscle Necrosis

Insecticides

Necrosis of rat skeletal muscle in the region of

the motor endplate has been noted after administration of cholinesterase-inhibiting compounds in

amounts sufficient to cause signs.39 Swelling, eosinophilia, and loss of striations of myofibers can be

observed by light microscopy in the motor endplate

regions as early as 2 hours after administration of

the organophosphate, and the lesion is fully developed in 12 to 24 hours. In affected fibers, the sarcolemma remains intact and is the focus of later repair of the fiber. Recovery begins in 2 days and is

complete by 2 weeks. The lesion can be prevented

or lessened by denervation or by administration of

atropine and oxime within the first 2 hours; the lesion is more severe in muscles of high activity, such

as the diaphragm, and in Type II muscle fibers of

the “fast twitch” category.39

Muscle necrosis was seen in the diaphragm of a

man who died after drinking parathion. No cholinesterase could be demonstrated in the myoneural junctions of any muscle, but necrosis was limited to the diaphragm. Each focus involved 1 to 4

sarcomeres of both types of myofibers and varied

from acute swelling to vacuolar disintegration of

the fibers. The nerve endings in the segmental necrotic zones were degenerated.40

Nerve Agents

The circumscribed muscular necrosis seen with

insecticides has also been seen after sarin41,42 and

tabun43 administration to experimental animals.

Soman produced necrosis in one study,44 but not in

another.43 On stimulation of the nerve, the muscle

was unable to sustain a tetanic contraction at frequencies of 100 and 200 Hz.43

Intermediate Syndrome

Insecticides

A second type of delayed neurological manifestation of organophosphate insecticide poisoning

is the “intermediate syndrome.” In a series of

200 consecutive cases of organophosphate insecti-
Long-Term Health Effects of Nerve Agents and Mustard

233

cide poisoning, 36 patients developed a weakness

of the proximal muscles of the limbs, cranial nerve

weaknesses, bilateral pyramidal tract signs, and

areflexia.45 This disturbance began 12 to 84 hours

after hospital admission. In most cases, the cholinergic crisis had resolved, and the 21 patients who

survived recovered completely by 96 hours. The

lesion was unresponsive to large amounts of atropine; 2-PAM Cl was not available.

The authors of the report45 divided the signs of

organophosphate intoxication into two groups,

which they called Type I and Type II. According to

these authors, Type I signs were muscarinic in nature and were amenable to atropine therapy, and

Type II signs were nicotinic in nature, appeared 12

to 48 hours after exposure, and were resistant to

atropine therapy.

Ten additional cases were later described.46 These

patients received atropine (up to 40 mg every 24 h)

and 2-PAM Cl (1 g every 12 h for 24 to 48 h) during

the cholinergic-crisis phase. About 24 to 96 hours

after poisoning, the 10 patients developed a syndrome that included palsies of cranial nerves III,

IV, VI, VII, and X; weakness of the respiratory

muscles (four patients required immediate intubation and assisted ventilation at the onset of the syndrome); weakness of the proximal limb muscles;

and pyramidal tract signs. Recovery occurred in 5

to 18 days. Electromyography in limb muscles and

nerve conduction were normal. Tetanic stimulation

of the abductor pollicis brevis showed a marked

fade with no posttetanic facilitation. The authors

of this report46 called this the “intermediate syndrome,” meaning that it is intermediate between the

acute cholinergic effects and the later, well-recognized delayed polyneuropathy. Consequently, the

term intermediate syndrome, rather than Type II

signs, has been adopted.

Two additional cases of this syndrome were reported several years later; both patients required

ventilatory support during the paralytic phase.47 In

another series, 29 of 90 patients with organophosphate poisoning had the intermediate syndrome.48

Tetanic fade with no posttetanic facilitation was

maximal between days 4 and 6, and the response to

electrical stimulation had returned to normal by 8

to 10 days. The author suggested that a neuromuscular junction defect was responsible for the lesion.

Other cases have since been reported49–52 and in

some, the weakness or paralysis lasted for days to

weeks. One suggestion was that lack of early oxime

therapy might contribute to the development of the

syndrome,53 but it has occurred with adequate

amounts of oxime.49,50,54 The cause of this neuromuscular dysfunction has not been elucidated, nor has

an animal model been described. Intermediate syndrome may be related to the myopathy seen at the

neuromuscular junction.

Nerve Agents

The intermediate syndrome, associated with insecticide poisoning, has not been described after

administration of nerve agents to animals, nor has

it been noted in the handful of individuals severely

exposed to nerve agents.

Neuropsychiatric Effects

Many neuropsychiatric problems have been associated with a single exposure or repeated exposures to insecticides and to nerve agents. Generally,

these symptoms were studied shortly after the patients were exposed, and the duration of the problems was not noted. However, several studies examined the effects long after the acute insult. The

effects include disturbances in memory, sleep, and

vigilance; depression; anxiety and irritability; and

problems with information processing.

Insecticides

In 1961, Gershon and Shaw55 described 16 patients with psychiatric problems who had been exposed to pesticides repeatedly over a 1.5- to 10-year

period. Five were schizophrenic, 7 were severely

depressed, 1 was in a state of fugue, and all had

impairment of memory and concentration. These

conditions followed multiple symptomatic exposures to organophosphate insecticides, and the patients recovered within 6 to 12 months after the

onset of their signs and symptoms. Because neuropsychiatric sequelae of organophosphate insecticides had not been widely recognized, the authors

suggested that these sequelae might be more common than generally thought.

Gershon and Shaw’s report was criticized56,57 because no information on the exposure history was

included; because few objective measures, either of

mental status or of blood cholinesterase were used;

and because the conditions reported had not been

reported in much larger series of patients exposed

to organophosphate insecticides. Later studies

failed to find evidence of thought disorders after

pesticide exposure, 58,59 although diisopropyl

fluorophosphate (DFP) administration aggravated

psychosis.60 Less-severe neuropsychiatric manifestations of organophosphate insecticide exposure,
Medical Aspects of Chemical and Biological Warfare

234

occurring either acutely or as sequelae, have been

subsequently reported.

Durham et al61 examined 187 individuals who

were routinely involved in pesticide work (eg, crop

dusters) for mental alertness. His subjects were

studied, using a complex reaction time, (a) at the

time of maximal work with insecticides and (b)

during “nonexposure” periods. Control subjects

were studied at similar times. Both groups, subjects

and controls, did better on the tests during

nonexposure periods, and both groups scored

poorer during the higher risk periods. The performance of the exposed subjects improved during and

after convalescence. The authors emphasized repeatedly that mental effects were not seen in the

absence of clinical signs of poisoning.

Problems with memory after insecticide exposure

were reported by Gershon and Shaw55 (the problems cleared in 6 to 12 months after the acute exposure) and by Metcalf and Holmes59 (the patients

were studied more than a year after exposure). In

the latter study, testing was performed to corroborate the report of memory deficit. Other reports

have mentioned memory problems, but they provide few data.

Anxiety, irritability, giddiness, tension, and restlessness persisting for months after exposure to insecticides were reported by Namba et al62 and by

Gershon and Shaw.55 (Both studies emphasized that

these effects occurred only in patients who had

demonstrated symptoms of exposure.) Metcalf and

Holmes59 reported similar effects, but did not indicate their duration or the time after exposure that

they occurred.

Depression has been reported62 from insecticide

exposure immediately following the acute symptomatic exposure, but it did not persist. More-prolonged (6 to 12 mo) depression has been reported55

after insecticide exposure. In contrast, Levin et al58

found no evidence of depression using a structured

interview and a depression inventory in asymptomatic workers with histories of chronic exposure.

Sleep disturbances, such as excessive dreaming,

nightmares, and insomnia, have been reported59,62

after insecticide exposure and generally are of relatively short duration (days to weeks).

Psychomotor performance has been evaluated

after exposure to insecticides. Rowntree et al60 found

that daily administration of an organophosphate

compound caused slowness in thought and decreased performance speed. Metcalf and Holmes59

noted slowed thinking and calculation in patients

who had been exposed to insecticides more than a

year previously.

Difficulties in concentration and vigilance have

been reported after insecticide exposure.55,59,61–63

Some studies indicate marginal decreases, and others lack objective data (eg, Gershon and Shaw55). In

all, the impairment occurred after an episode in

which the patient had exhibited symptoms of exposure to the compound.

Tabershaw and Cooper64 evaluated 87 patients

who had been exposed to an organophosphate insecticide more than 3 years previously and who had

had persistent complaints for over a 6-month period. The symptoms involved the visual, gastrointestinal, cardiorespiratory, and neuropsychiatric systems. In each instance, the complaint could

be attributed to other problems; for example, several cases of visual blurring were due to presbyopia, a case of chronic abdominal pain was due to a

peptic ulcer, and in one case, nervousness and tremors were due to chronic alcoholism.

In a more recent study, Rosenstock et al65 examined 38 patients more than a year after their hospitalization for organophosphate insecticide exposure.

Control subjects had also worked with organophosphate insecticides but had not had a symptomatic

exposure. The poisoned group did significantly less

well than the control group on tests assessing a wide

variety of neuropsychological functions, including

auditory attention, visual memory, visuomotor

speed, sequencing and problem solving, and motor steadiness, reaction, and dexterity.

Nerve Agents

Bowers et al11 reported that subjects had difficulty

with memory for 24 hours after they were given VX,

but had no evidence of major thought disorders.

Other investigators66 noted depression acutely after nerve agent exposure,66 but the depression did

not persist. Sleep disturbances were also shortlived.11,66,67 After exposure to VX, subjects had

decreased performance on an arithmetic test, decreased reading comprehension, and decreased

ability to play chess.11 In some instances these performance decrements occurred before other signs

of intoxication or in the absence of other signs. Impaired concentration and vigilance have been reported after nerve agent exposure.66 These effects

can persist for several weeks after symptomatic exposure to nerve agents (personal observations, F.R.S.).

A report67 of 297 cases of accidental exposure to

nerve agent among manufacturing workers indicated that about 20% of the individuals had

neuropsychiatric effects such as disturbed sleep,

disturbance in mood, irritability, nervousness, dis-
Long-Term Health Effects of Nerve Agents and Mustard

235

turbance in ability to think clearly, absentmindedness, fatigability, and lightheadedness. The duration of these effects was not indicated, but the report noted that supervisors and coworkers detected

these effects when the casualties returned to work

prematurely.

A single subject, a biochemist exposed to soman,

was evaluated at 2 weeks, at 4 months, and at 6

months after exposure, using a psychiatric interview and a battery of psychological tests (this case

is also discussed in Chapter 5, Nerve Agents).14 The

person had been severely exposed, requiring ventilatory support for about 30 minutes. On initial testing, he had high scores on the hypochondriasis and

hysteria scales on the Minnesota Multiphasic Personality Inventory; these improved on later testing.

On the initial testing he did poorly on a visual retention task, on word association, proverbs, and an

ink blot test. While taking the tests, he used delaying tactics, had difficulty generating verbal associations, and failed the harder proverbs. Results on

the later tests were much improved and indicated

full use of his intellectual facilities.

In another case, a physician was severely exposed

to sarin and required ventilatory support for longer

than 3 hours. Although psychiatric and psychological studies were not performed, after recovery he

returned to work with no apparent problems.15

While few data on the duration of these neuropsychiatric effects in people exist, evidence suggests

that they are relatively short-lived (days, weeks).

Because of the nature of the work, people employed

in manufacturing, at depots, or in research and development facilities were relatively few in number,

tended to remain in the same job for a long period,

and were a closely knit group. Most were thoroughly familiar with the effects of nerve agents, and

most knew their coworkers very well. If a worker

did not seem “right,” his coworker or supervisor

recognized it.67 A medical facility dedicated to the

treatment of nerve agent casualties and with a staff

experienced in this type of injury was always available; workers were encouraged to use it, and supervisors were instructed to send employees who were

not “normal” to the medical facility for evaluation.

One of the authors (F.R.S.) worked in such a

medical facility for over a decade. While there was

no routine, formal follow-up procedure, (eg, psychological testing of exposed casualties), informal

follow-up visits for several weeks after the incident

for eye examinations (miosis takes 3–6 wk to recede14) and to discuss general health problems were

common. Significant lingering effects were very

likely to be mentioned, therefore, and detected.

No formal follow-up program existed for subjects exposed to nerve agents experimentally,

but again, these individuals were seen on a regular basis for several weeks after exposure. Since

these people were the subjects of research study on

the effects of nerve agents, lingering effects were

very likely to be carefully sought and reported if

found.

In summary, studies intended to examine the

neuropsychiatric effects of organophosphate

compounds vary in their adequacy, and in some

instances the results are contradictory. Most studies agree, however, that acute neuropsychiatric

effects result from exposure to both insecticides

and nerve agents. These effects include inability

to concentrate, memory problems, sleep disturbances, anxiety, irritability, depression, and problems with information processing and psychomotor tasks. With pesticides, these effects do not

occur in the absence of the conventional signs of

poisoning.

The duration of these effects is less well studied.

Some studies suggest that after exposure to insecticides, problems might persist for a year or longer,

but supporting data are not always provided. The

two reports of patients exposed to nerve agents and

personal observation suggest that these effects are

of shorter duration in this class of compounds.

Electroencephalographic Abnormalities

Insecticides and Other Organophosphates

Electroencephalographic abnormalities were reported in subjects given daily doses of diisopropyl

fluorophosphate for 2 to 7 days.68 These abnormalities consisted of faster frequencies, higher voltages,

and occasional bursts of slow waves of high voltage at 3 to 6 Hz. Their severity was directly related

to the degree of initial cholinesterase inhibition. The

changes persisted for 3 to 4 weeks.

Changes were noted in the electroencephalograms (EEGs) of 50 industrial and agricultural

workers within 72 hours of accidental exposure to

insecticides (both organophosphate and chlorinated

hydrocarbons, on separate occasions), although the

relationship to work history; blood cholinesterase;

and exposure type, duration, and severity were not

mentioned.59

Nerve Agents

In a patient severely intoxicated with sarin, an

EEG (taken after the loss of consciousness but be-
Medical Aspects of Chemical and Biological Warfare

236

fore the onset of convulsions) showed marked slowing, with bursts of high-voltage slow waves at 5 Hz

in the temporofrontal leads. These abnormalities

persisted for 6 days, after which no residual effects

were noted.66

Because of the reports on insecticides and concern for employees working with or in the vicinity of nerve agents, the U.S. government sponsored

a series of studies69–72 on the long-term effects

of sarin exposure as seen in EEG examinations. In

the first study, monkeys were dosed with sarin

in one of two dose schedules: (1) a single, large dose

that produced convulsions or (2) a series of

10 weekly doses that caused no clinical effects. In

the second study, workers who had had at least

one documented exposure to sarin (signs, cholinesterase depression) more than a year before the

study were evaluated. Control subjects were coworkers who had no possibility of organophosphate

exposure.

In the nonhuman primates, animals from both

dose schedules had increases in high-frequency beta

activity a year after exposure. Spectral analysis of

the EEGs of the humans showed increased beta activity in the sarin-exposed population compared to

the control population. Visual reading of the records

suggested decreased amounts of alpha and increased amounts of slow delta and theta activity in

the exposed group. Increased amounts of rapid-eyemovement sleep in the exposed group were also

found. Individual records could not be categorized.

The investigators noted that the relationship between these changes and alterations in brain function was not known.

Toxicological Studies on Nerve Agents

The effects of exposure to nerve agents on a

chronic or subchronic basis were reported in two

studies on animals. In a two-part, 90-day study73,74

of subchronic exposure, rats were given one of three

doses of tabun or soman 5 days per week by gavage. At the end of the study, no abnormalities were

found on gross or histological examination of tissue. In a study75 of chronic exposure to sarin, dogs

received a Ct of 10 mg•min/m3 of sarin over a 6-

month period. Some animals were dosed 5 days per

week, and some were dosed 7 days per week. No

tissue abnormalities that could be attributed to the

agent were noted on gross or microscopic examination. Several of the male animals were bred after

the exposure and the pups were normal.

No evidence of polyneuropathy was noted clinically or on microscopic examination in studies76–79

in which tabun, sarin, and soman were given to hens

in single or multiple doses. The doses were those

maximally tolerated with the coadministration of

atropine.

Sarin and soman were deemed not mutagenic

after they were studied using the Ames Salmonella,

mouse lymphoma, and Chinese hamster ovary cell

systems.80 Tabun was found to be weakly mutagenic

in the mouse lymphoma cell test81 and in the Chinese hamster ovary82 and Ames bacterial systems.83

MUSTARD

Studies have established that the chemical agent

mustard has long-term sequelae. Both Morgenstern

et al84 and Buscher85 emphasize that chronic lowdose exposure over months to years in occupationally exposed workers leads to chronic bronchitis,

bronchial asthma, hoarseness, aphonia, and hypersensitivity to smoke, dust, and fumes. Such individuals typically show persistent disability,

with increased susceptibility to respiratory tract

infections and evidence of bronchitis and bronchiectasis.6,84,85

Laboratory animal studies86–88 have found that

mustard is mutagenic and carcinogenic, and thus it

is not surprising that it is carcinogenic in man.24

In 1993, a study24 sponsored by the Veterans Administration and conducted by the Institute of

Medicine reported that a causal relationship exists

between mustard exposure and the following conditions:

• chronic respiratory diseases (asthma, chronic

bronchitis, emphysema, chronic obstructive

pulmonary disease, chronic laryngitis),

• respiratory cancers (nasopharyngeal, laryngeal, and lung),

• pigmentation abnormalities of the skin,

• chronic skin ulceration and scar formation,

• skin cancer,

• chronic conjunctivitis,

• recurrent corneal ulcerative disease,

• delayed recurrent keratitis,

• leukemia (nitrogen mustard),

• bone marrow depression and (resulting)

immunosuppression,

• psychological disorders (mood disorders,

anxiety disorders, and traumatic stress disorders), and

• sexual dysfunction as a result of scrotal and

penile scarring.
Long-Term Health Effects of Nerve Agents and Mustard

237

Although there may be laboratory evidence to

suggest that all of these might occur, there are no

data in humans to indicate that all have occurred.

The study report recognized this by stating, “It is

also possible that skin cancers did not occur in the

studied populations...”24(p218) and “...underrepresented in human studies is information on chronic

or delayed effects [on the bone marrow and immune

system].”24(p220) The report also pointed out that the

psychological disorders were from the stress of the

exposure and not from the agent, and there seemed

to be no data on sexual dysfunction. Moreover, it is

not clear from the report whether the relationship

between mustard exposure and these effects follows

one or multiple exposures.

All human studies dealing with chronic mustard

disease processes are retrospective and fraught with

the problems inherent in retrospective studies.

These problems include bias in the sampling populations; lack of epidemiological controls for the effects of smoking, lifestyle, race, gender, age, or exposure to other chemicals; differential quality of

available health care; and incorrect diagnosis.6

These limitations make absolute interpretation of

the studies difficult.

Carcinogenesis

Mustard is an alkylating agent similar to drugs

that have been used in cancer chemotherapy, such

as nitrogen mustard, Cytoxan (manufactured by

Bristol-Myers Squibb Oncology Division, Princeton,

N. J.), and methotrexate. Since DNA is one of

mustard’s most sensitive targets, it is not surprising

that carcinogenesis and radiomimetic effects are seen.

In studies88–90 conducted from 1949 through 1953

by W. E. Heston with mustard and strain-A mice

(immunocompromised), the occurrence of pulmonary tumors was easily demonstrated. Studies conducted at Edgewood Arsenal, Maryland, examined

the carcinogenic effects on rats in whole-body chamber exposures. Mustard readily produced skin malignancies in rats, but no excess tumors at other

sites.91 Subcutaneous injections totaling about 6

mg/kg of mustard produced sarcomas and other

malignancies at injection sites in C3H, C3Hf, and

strain-A mice, but did not produce an increase of

malignancies at other sites.90

Human data on the carcinogenicity of mustard

are from (a) battlefield exposures, (b) accidents, and

(c) workers in chemical factories. Both British and

American studies have investigated the increased

incidence of pulmonary carcinoma arising from

World War I battlefield exposure. All are difficult

to interpret, owing to the lack of controls for age,

chronic pulmonary disease, cigarette smoking, and

other factors that might affect the outcome.92–94

In contrast to battlefield exposures, studies of

factory workers involved in the production of mustard have shown a definite link between prolonged

exposure to low doses of mustard and cancer.6 Several studies87,95–99 have provided evidence of an increased risk of respiratory tract cancers in factory

workers. Easton et al96 found a 45% increase in

deaths due to lung cancer, a 170% increase in death

from cancer of the larynx, and a 450% increase in

deaths from cancer of the pharynx, compared with

expected deaths in the general population. The risks

for cancer of the pharynx and lung were significantly related to the duration of employment at the

factory. For reasons analyzed more fully elsewhere,100

the association between a single exposure to mustard

and airway cancer is not as well established.

Japanese studies suggest a greater potential risk

of cancer due to mustard than do the British studies. Easton et al96 and Manning87 suggest that the

difference is related to the design of the Japanese

studies and to the lower industrial hygiene standards in Japan at the time of the studies.6

 The weight

of the evidence—cellular, epidemiological, and toxicological—indicates a causal association between

mustard exposure and the occurrence of excess respiratory cancer, skin cancer, and possibly leukemia.

Inadequate exposure information limits accurate estimation of the cancer excesses that may be expected.24

Chronic Pulmonary Disease

Inhalation of mustard vapor primarily affects the

laryngeal and tracheobronchial mucosa.6 Evidence

exists that suggests that mustard inhalation causes

sustained respiratory difficulties even after the

acute lesions have healed. Clinical follow-ups on

200 Iranian soldiers who were severely injured by

mustard during the Iran–Iraq War indicate that

about one third had experienced persistent respiratory effects 2 years after initial exposure. Reported

problems included chronic bronchitis, asthma, rhinopharyngitis, tracheobronchitis, laryngitis, recurrent pneumonia, bronchiectasis, and in some cases,

severe, unrelenting tracheobronchial stenosis.101–105

Of the British soldiers exposed to mustard in

World War I, 12% were awarded disability compensation for respiratory disorders that were believed

to be due to mustard exposures during combat.106

Bronchitis was the major complaint; emphysema

and asthma were also reported. However, epidemiological studies of the relationship between agent
Medical Aspects of Chemical and Biological Warfare

238

exposure and subsequent respiratory disability

were severely limited for several reasons. Often,

individuals had experienced multiple combined

exposures to mustard and other chemical agents.

Also, influenza and other respiratory ailments frequently made diagnosis of the mustard vapor injury difficult.6

 Finally, no epidemiological controls

for smoking or for postexposure environmental and

occupational histories were included in the studies.107

Wada et al95 suggest a causal relationship between mustard exposure and subsequent bronchitis, tuberculosis, and pneumonia in factory workers involved in the production of mustard. Again

Morgenstern et al84 and Buscher85 emphasize that

chronic low-dose exposure over prolonged periods

(presumably months to years) leads to lingering

bronchitis, bronchial asthma, hoarseness, aphonia,

and hypersensitivity to smoke, dust, and fumes.

Such individuals typically show persistent disability, with increased susceptibility to respiratory tract

infections and evidence of bronchitis and bronchiectasis.6

Little contemporary information regarding the

pathogenesis of the respiratory lesions is available,

and few data from people or animals exposed to

nonlethal concentrations of mustard vapor exist.

Even fewer studies investigate the histopathology

of the recovery process in animals exposed to mustard.24 However, two studies19,108 conducted during

World War I suggest that low-level exposure or survivable exposures in dogs and rabbits may produce

scar tissue following small ulcerations in the trachea and larynx, causing contractions of these areas.

The more severe respiratory tract lesions described

in animals exposed to mustard vapor appear to be

quite similar in type and location to those described

in humans.6

Chronic Eye Disease

Individuals who sustain acute ocular injury due

to high-dose mustard exposure may experience difficulties even after the initial effects of the injury

have subsided.109–112 Recurrent or persistent corneal

ulceration can occur after latent periods of 10 to 25

years. This delayed keratopathy111,113 may be accompanied by chronic conjunctivitis and corneal

clouding. Anecdotal accounts suggest that low-dose

exposure also causes increased sensitivity to later

exposures to mustard,114 although the existence of

increased sensitivity is difficult to substantiate with

available scientific evidence.6 About 10% of those

with eye injury in World War I had severely affected

eyes, with both the cornea and the conjunctiva being involved. Members of this group developed the

“delayed keratitis” noted above 8 to 25 years later.110

The 1993 Institute of Medicine study24 of the effects of mustard and Lewisite exposure on the

health of veterans concluded that acute, severe injury of the eye with mustard might result in recurrent corneal ulcerative disease for the remainder of

the patient’s life, with a maximum incidence occurring 15 to 20 years after the injury. Based on extensive data, the study concluded that a causal relationship between severe exposure to mustard and

the development of delayed recurrent keratitis exists.109 The study also found a causal relationship

between exposure to mustard and the development

of prolonged, intractable conjunctivitis.

Scarring of Epithelial Surfaces

Residual cutaneous lesions most often take the

form of scars that result from uncontrolled fibroblastic activity and overgrowth of connective tissue during the process of wound repair. Even

wounds that are well cared for on body sites and

parts that are not easily immobilized, such as shoulders, knees, elbows, and male genitalia, often heal

with severe residual scar formation. Pigmentation

is often altered (either increased or decreased) at

these sites, although the degree of alteration does

not differ from that observed in injuries caused by

burns and other forms of physical and chemical

insult. In the absence of melanocyte destruction,

hyperpigmentation predominates. If melanocytes

are locally destroyed, and inward migration from

destroyed adnexal structures does not occur, depigmentation predominates. Some previously injured

sites have been described as being “sensitive” to

subsequent mechanical injury. These sites may show

recurrent blisters after mild injury.24

Skin cancers occurring at the site of old scar formation is an acknowledged biological phenomenon.115,116 Cutaneous cancers resulting from acute

mustard exposure usually localize in scars, whereas

those caused by chronic exposure can occur on any

exposed site.117

In a prospective study of delayed toxic effects

from mustard exposure, Balali-Mood104 followed a

group of Iranian solders exposed to mustard gas

during the Iran–Iraq War. After 2 years, 41% of the

exposed victims were experiencing pigmentary disorders.

Renshaw22 reported on the development of contact sensitivity in man following localized exposure

to liquid mustard. Cutaneous sensitivity may be

seen within 8 days following the first application,
Long-Term Health Effects of Nerve Agents and Mustard

239

and a more pronounced effect is seen after 4 weeks.

The incidence of hypersensitivity varies between

30% and 65% of exposed individuals. Sensitivity

may be immediate hives or delayed dermatitis and

appears to last a lifetime. Sensitivity may also take

the form of flares of old, healed mustard injury sites

after a fresh application of mustard to normal, unaffected skin.22

In its study of mustard and Lewisite effects,24 the

Institute of Medicine concluded that

• the evidence indicates a causal relation between acute, severe exposure to mustard

agents and increased pigmentation and

depigmentation in human skin;

• acute and severe exposure can lead to

chronic skin ulceration, scar formation, and

the development of cutaneous cancer (but

see the caveat in the previous discussion of

this report’s conclusions); and

• chronic exposure to minimally toxic and

even subtoxic doses can lead to skin pigmentation abnormalities and cutaneous

cancer.

Central Nervous System

Excitation of the CNS after mustard exposure,

resulting in convulsions and followed by CNS depression, has been reported.118 Convulsions and cardiac irregularities appear to occur only after extremely acute, high doses,119 which are probably

attainable only in laboratory settings.6 Mustard casualties of the Iran–Iraq War did not display severe

CNS or cardiac abnormalities.101

Acute neuropsychiatric symptoms, including

severe depression and changes in mentation, are

common after high-dose exposures to mustard

agents. These symptoms are produced both directly

by the chemical and secondarily to other physiological changes.24 Follow-up of workers in German

chemical warfare plants showed a high prevalence

of various neurological disorders, including impaired concentration, diminished libido, and sensory hypersensitivity.120 To what extent mustard

agents were responsible is not clear because multiple exposures to other agents, including nerve

agents, were known to have occurred.

Mutagenesis, Teratogenesis, and Reproductive

Toxicity

Mustard causes cross-linking of DNA and is

known to alkylate DNA at the O6 position of guanine. Some authors121,122 suggest that intrastrand

DNA cross-links, rather than interstrand crosslinks,123,124 are the lesions primarily responsible for

producing chromosomal aberrations. Mustard

causes chromosomal breakage and induces sister

chromatid exchanges in a wide variety of cells including mammalian cells.125 The International

Agency for Research on Cancer, Lyon, France (an

agency of the World Health Organization), has classified mustard as a human carcinogen based on the

findings of epidemiological studies. Taken together,

these observations highlight the potential of this

compound to induce genetic damage and become a

long-term health hazard. They also suggest that

mustard could be a reproductive toxin.24

The 1993 Institute of Medicine report24 noted that

the quality of human data on the reproductive toxicity of mustard is quite poor. Follow-up of the occupational or battlefield cohorts to determine the

nature of any reproductive toxicity or teratogenic

effects attributable to these exposures has been

insufficient. The evidence suggests a causal relationship between mustard exposure and reproductive toxicity in laboratory animals, but the database

is far too small and unreliable to allow a clear understanding of human reproductive risk from exposure to mustard. Mustard can cause genetic alterations in the sperm of male rats after inhalation

or gastric exposure, but rodent studies126 showed

that mustards are not detectable teratogens in animals. The human data are insufficient for reliable

interpretation.24

SUMMARY

Available information implicates the nerve

agents and mustard as the cause or probable cause

of several long-term health effects.

Polyneuropathy, the major neuromuscular manifestation seen after exposure to organophosphate

pesticides, has not been reported in humans after exposure to nerve agents. Studies suggest that

these agents cause polyneuropathy in animals

only at doses so high that survival is questionable

even with massive pretreatment and therapy.

The intermediate syndrome, a syndrome characterized by weakness of the proximal muscles of

the limbs, weakness of the respiratory muscles,

cranial nerve weaknesses, bilateral pyramidal tract

signs, and areflexia, has not been reported in animals or humans after nerve agent exposure. Mus-
Medical Aspects of Chemical and Biological Warfare

240

cular necrosis, the neuromuscular effect that can

be produced by nerve agent administration, occurs after high-dose exposure, is short-lived,

reverses within weeks, and has not been reported

in humans.

Other long-term consequences of exposure to

organophosphate pesticides are neuropsychiatric

effects and possible EEG changes. Both are documented as acute manifestations of nerve agent poisoning; mild neuropsychiatric changes occur after

even low-dose nerve agent exposure. Several studies of people exposed to insecticides, in which the

subjects were chosen because they had experienced

one or more episodes of symptomatic poisoning (including cholinesterase inhibition), report neuropsychiatric changes a year or longer after the acute

manifestation. The duration of the neuropsychiatric effects after nerve agent exposure is less well

documented, but available information suggests

that these effects persist for several weeks or possibly several months. Studies of EEG changes following organophosphate nerve agent exposure found

differences between the exposed and control populations but suggested no relationship between their

findings and alterations in brain function.

The many studies of English and Japanese mustard factory workers establish repeated symptomatic exposures to mustard over a period of years as

a causal factor in an increased incidence of airway

cancer. The association between a single exposure

to mustard and airway cancer is not as well established. The association between one-time mustard

exposure and other chronic airway problems, such

as chronic bronchitis, which is based on World War

I data, seems more clearly established. In some

cases, the long-term damage was probably a continuation of the original insult resulting from insufficient therapy in the preantibiotic era.

Several eye diseases, such as chronic conjunctivitis, appear after an acute, usually severe, insult to

the eye. In particular, delayed keratitis has appeared

more than 25 years after the acute, severe lesion.

Similarly, skin scarring, pigment changes, and even

cancer have either followed the initial wound as a

continuation of the process (scarring) or later appeared at the site of the lesion.

The production of nonairway cancer by mustard

has been demonstrated in animals, but scant evidence exists to implicate mustard as a causative factor in nonairway cancer in humans.

Mustard causes chromosomal breakage and induces sister chromatid exchanges in man and has

been classed as a mutagen. No data that implicate

mustard as a reproductive toxin in man seem to be

available, despite the many thousands of people

exposed to mustard in the past 80 years.

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Chapter 9

TOXIC INHALATIONAL INJURY

JOHN S. URBANETTI, M.D., FRCP(C), FACP, FCCP*

INTRODUCTION

TOXIC INHALATIONAL INJURY

Physical Aspects

Clinical Effects

Physiology

Evaluation of Injury

GENERAL THERAPEUTIC CONSIDERATIONS

Further Exposure

Critical Care Concepts

Clinical Abnormalities

Steroid Therapy

EXERTION AND TOXIC INHALATIONAL INJURY

Interactions of Pulmonary Toxic Inhalants and Exercise

Therapy

HISTORICAL WAR GASES

Chlorine

Phosgene

SMOKES AND OTHER SUBSTANCES

Zinc Oxide

Phosphorus Smokes

Sulfur Trioxide–Chlorosulfonic Acid

Titanium Tetrachloride

Nitrogen Oxides

Organofluoride Polymers: Teflon and Perfluoroisobutylene

SUMMARY

*Clinical Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510
Medical Aspects of Chemical and Biological Warfare

248

INTRODUCTION

Pulmonary toxic inhalants have been a military

concern since the Age of Fire. Thucydides, in 423

BC, recorded the earliest belligerent use of a toxic

inhalant. The Spartans used a burning mixture of

pitch, naphtha, and sulfur to produce sulfur dioxide that was used in sieges of Athenian cities.1

 There

is scant reference in the literature to further military use of toxic inhalants until World War I. In early

1914, both the French and Germans investigated

various tear gases, which were later employed. By

early 1915, the German war effort expanded its gas

research to include inhaled toxicants. As a result,

on 22 April 1915, at Ypres, Belgium, the Germans

released about 150 tons of chlorine gas along a

7,000-m battlefront within a 10-minute period. Although the exact number of injuries and deaths are

unknown, this “new form” of warfare produced a

degree of demoralization theretofore unseen.2 Although phosgene and chlorine have not been used

militarily since 1918, vast amounts are produced

annually for use in the industrial sector. The potential for accidental or deliberate exposure to a toxic

inhalant exists, and military personnel should be

prepared.

TOXIC INHALATIONAL INJURY

Physical Aspects

Airborne (and consequently inhaled) toxic material may be encountered in gaseous or particulate form (Exhibit 9-1). Airway distribution of toxic

inhalants as a gas or vapor follows normal respiratory gas flow patterns. The central airways exchange gases with the environment as a result of

the mechanical aspects of breathing. Each breath

dilutes central airway gas with newly inhaled gas.

EXHIBIT 9-1

DEFINITIONS OF AIRBORNE TOXIC MATERIAL

Gas The molecular form of a substance, in which molecules are dispersed

widely enough to have little physical effect (attraction) on each other; therefore, there is no definite shape or volume to gas.

Vapor A term used somewhat interchangeably with gas, vapor specifically refers

to the gaseous state of a substance that at normal temperature and pressure would be liquid or solid (eg, mustard vapor or water vapor compared with oxygen gas). Vaporized substances often reliquefy and hence

may have a combined inhalational and topical effect.

Mist The particulate form of a liquid (ie, droplets) suspended in air, often as a

result of an explosion or mechanical generation of particles (eg, by a spinning disk generator or sprayer). Particle size is a primary factor in determining the airborne persistence of a mist and the level of its deposition in

the respiratory tract.

Fumes, Smokes, and Dusts Solid particles of various sizes that are suspended in air. The particles may

be formed by explosion or mechanical generation or as a by-product

of chemical reaction or combustion. Fumes, smokes, and dusts may themselves be toxic or may carry, adsorbed to their surfaces, any of a variety

of toxic gaseous substances. As these particles and surfaces collide,

adsorbed gases may be liberated and produce local or even systemic toxic

injury.

Aerosol Particles, either liquid or solid, suspended in air. Mists, fumes, smokes,

and dusts are all aerosols.
Toxic Inhalational Injury

249

Gas moves by convection into the peripheral airways (airways of ≤ 2-mm diameter) and then by

diffusion to the alveolar-capillary membranes. Consequently, there is a much slower dilution of gas at

this level. Therefore, toxic inhalants reaching this

level may have a more profound effect due to

greater relative duration of exposure.

Particles (such as those present in mists, and in

fumes, smokes, and dusts) present a more complex

distribution pattern because the particle size affects

its deposition at various levels of the airway. Such

factors as sedimentation and impact rates also control particle deposition. Therefore, heavier particles

may settle in the nasopharynx or upper airways,

whereas lighter or smaller particles may reach

more-peripheral airways. Once they have impacted,

particles are susceptible to a variety of respiratory

defense mechanisms. These mechanisms determine the efficiency with which particle removal

progresses, thereby determining the particle’s ultimate degree of adverse effects.

Clinical Effects

Toxic inhalants may cause damage in one or more

of the following ways:

• Asphyxiation may result from a lack of oxygen (eg, as in closed-space fires) or by interference with oxygen transport (eg, by

cyanide, which compromises oxygen uptake by preventing its transport to cellular

metabolic sites).

• Topical damage to the respiratory tract may

occur due to direct toxic inhalational injury

to the airways or alveoli. Cellular damage

with consequent airway obstruction, pulmonary interstitial damage, or alveolarcapillary damage ultimately compromises

adequate oxygen–carbon dioxide exchange.

Some substances are relatively more toxic

to the central airways, whereas others are

more toxic to the peripheral airways or alveoli.

• Systemic damage may occur as a result of

systemic absorption of a toxicant through

the respiratory membranes (eg, leukopenia

following mustard inhalation) with consequent damage to other organ systems. Effects on other organ systems may be more

obvious than the respiratory effects of exposure (as with mercury).

• Allergic response to an inhaled toxicant

may result in a pulmonary or systemic reaction, which may be mediated by one or

more of a variety of immunoglobulins. Secondary by-products of this reaction may

cause cellular destruction or tissue swelling; consequently, oxygen–carbon dioxide

exchange may be compromised, and there

may be systemic inflammatory damage.

Physiology

The ultimate effect of a particular toxic inhalant

on the respiratory system or the whole organism is

the result of a complex interaction of multiple factors, including the intensity of exposure, condition

of exposed tissues, and intrinsic protective and reparative mechanisms.

Intensity of Exposure

The intensity of exposure variable is partially

affected by the physical state and properties of the

toxicant. Heavier-than-air gases are particularly

affected by environmental conditions; for example,

warm environments increase the vaporization of

some substances (such as mustard), making inhalational toxicity more likely. Increased humidity

increases particle size by hygroscopic effects. Increased particle size may decrease the respiratory

exposure to a toxicant because larger particles may

precipitate prior to inhalation, or they may be collected preferentially in the upper airways, which

have better clearance mechanisms.

The intensity as well as the site of exposure is

partially affected by the toxic inhalant’s degree of

water solubility: more soluble toxicants (such as

chlorine) primarily affect the upper airways and the

more central airways. Despite the relatively high

rate of airflow in central airways, the more soluble

toxic gases are almost entirely deposited there. The

less-soluble gases tend to produce effects in the

peripheral airways or alveoli. In peripheral airways,

air motion is relatively slow, occurring primarily

by molecular diffusion. Foreign substances (such as

cigarette smoke and toxic gases) that have not been

trapped at more-central sites tend to remain longer

in the peripheral airways. These substances may

induce a surprising degree of damage due to their

prolonged effect.

The intensity of exposure is commonly measured

by multiplying the concentration (C, in milligrams

per cubic meter) of a substance by the time of exposure (t, in minutes); the product is known as the Ct;

the units of measurement as mg•min/m3. Precise

measurement of the toxicant’s concentration at the
Medical Aspects of Chemical and Biological Warfare

250

site of topical effect is not possible. An inhaled

breath of toxic inhalant is mixed into a greater volume of airway gas (containing oxygen, nitrogen,

carbon dioxide, and water vapor). The distribution

of that breath then depends on such variables as

speed of inhalation, depth of inhalation, and even

body position during inhalation. Additionally, the

duration of exposure, particularly in a combat setting, may be exceptionally difficult to assess. Finally,

little attention is paid to the additional variable of

depth and frequency of respiration (minute ventilation). This variable is highly affected by the exercise state or metabolic rate of the soldier. Deeper

and more frequent breathing during combat may

expose the airways to a greater amount of toxic inhalants compared to the exposure of an individual

at rest.

Because of difficulties in accurately measuring

Ct, the threshold limit value (TLV) of a substance is

used more often; a thorough discussion of TLV can

be found in another volume in the Textbook of Military Medicine series, Occupational Health: The Soldier

and the Industrial Base.

3

 Calculations are made of a

maximum allowable exposure to a toxicant, typically expressed for a 15-minute or an 8-hour period.

This calculation makes the development of environmental standards and alarm detection systems

somewhat simpler. The TLV should not, however,

be considered a definition of a safe level. The concept of safe level wrongly implies that exposure to

toxicants below that level has no effect. Rather, the

TLV should be considered an expedient method of

defining the statistical risk of injury resulting from

an exposure. As biological and medical testing techniques undergo revision, toxic inhalants are often

found to have histological or physiological effects

in experimental animals at levels well below the

established TLV. Therefore, rather than defining a

“safe” level of a toxicant, the TLV may simply describe a level at which there is no recognized biological effect.

Condition of Exposed Tissues

Preexisting airway damage (such as that caused

by prior toxic inhalant exposure) may seriously

compromise the respiratory system’s normal protection and clearance mechanisms. Specifically,

there may be depletion of critical enzyme systems.

Cigarette smoking may severely compromise airway function with respect to both airway patency

and clearance mechanisms. Hyperreactive airways

(asthma in varying degrees) are seen in up to 15%

of the adult population. Toxic inhalant exposures

may trigger bronchospasm in these individuals.

This bronchospasm may delay the clearance of the

toxicant, interfering further with gas transport. The

development of an acute interstitial process (eg,

phosgene-related pulmonary edema) may also trigger bronchospasm. Individuals with any of the following characteristics should be considered likely

to develop bronchospasm as the result of a toxic

inhalant exposure:

• prior history of asthma or hay fever (even

as a child),

• prior history of eczema, or

• family history of asthma, hay fever, or eczema.

Individuals with hyperreactive airways will benefit from bronchodilator therapy and possibly from

steroids after exposure to a toxic inhalant. This

statement, however, does not constitute an endorsement for routine steroid use in all toxic inhalational

injuries.

Evaluation of Injury

Individuals exposed to a toxic inhalant should

be carefully examined by medical personnel who

are well versed in military medicine in the area of

pulmonary injury. Obtaining a medical history and

examining an exposed individual require the examiner to have an extensive knowledge of military

toxicology and a thorough background in the fundamental aspects of medical practice. Casualties

with toxic inhalational injuries present with a history that is characteristically different from that of

most injuries; the cause–effect relationship may be

particularly difficult to assess. The possibility of

delayed effects caused by toxic inhalants cannot be

overemphasized. Evidence of physiological damage

may not become apparent for 4 to 6 hours after a

lethal exposure (eg, to mustard or phosgene). If such

an exposure is suspected, the patient must be observed for at least 4 to 6 hours. Even if there is no

obvious injury noted during the observation period,

the patient must be carefully reassessed before being discharged from the medical system.

History

Collecting historical data from the casualty is a

critical aspect of assessing and treating toxic inhalational injury. Careful questioning of an exposed

individual will often greatly simplify the diagnosis

and therapy of the injury.
Toxic Inhalational Injury

251

• Environment. Were explosions observed?

Was there obvious smoke? If so, what color

was it? Was the smoke heavier than air?

What were the weather conditions (temperature, rain, wind, daylight, fog)? Were

pools of liquid or a thickened substance in

evidence?

• Protective Posture. What was the level of

mission-oriented protective posture (MOPP)?

Was there face mask or suit damage? Did

the face mask fit adequately? When was the

filter changed? How well trained was the

soldier in using the appropriate protective

posture, in making clinical observations,

and in choosing appropriate therapy? Were

other factors present (eg, consumption of

alcoholic beverages, exposure to other

chemicals, psychiatric status)?

• Prior Exposure. Was there prior exposure

to other chemical agents? Is the individual

a cigarette smoker? (For how long? How

recently? How many?)

• Pulmonary History. Is there a prior history

of chest trauma, hay fever, asthma, pneumonia, tuberculosis, exposure to tuberculosis, recurrent bronchitis, chronic cough or

sputum production, or shortness of breath

on exertion?

• Cardiac and Endocrine History. Is there a

history of cardiac or endocrine disorder?

• Acute Exposure History. What were the initial signs and symptoms?

° Eyes. Is there burning, itching, tearing,

or pain? How long after exposure did

symptoms occur: minutes, hours, days?

° Nose and sinuses. Was a gas odor detected? Is there rhinorrhea, epistaxis, or

pain? How long after exposure did

symptoms occur: minutes, hours, days?

° Mouth and throat. Is there pain, choking, or cough? How long after exposure

did symptoms occur: minutes, hours,

days?

° Pharynx and larynx. Are there swallowing difficulties, cough, stridor, hoarseness, or aphonia? How long after exposure did symptoms occur: minutes,

hours, days?

° Trachea and mainstem bronchi. Is there

coughing, wheezing, substernal burning, pain, or dyspnea? How long after

exposure did symptoms occur: minutes,

hours, days?

° Peripheral airways and parenchyma. Is

there dyspnea or chest tightness? How

long after exposure did symptoms occur:

minutes, hours, days?

° Heart. Are there palpitations, angina, or

syncope? How long after exposure did

symptoms occur: minutes, hours, days?

° Central nervous system. Is there diffuse

or focal neurological dysfunction?

Physical Examination

Physical examination may be particularly difficult in the event of combined toxic and conventional

injuries; therefore, it is essential that medical personnel note the following conditions:

• Reliability. Is the casualty alert and oriented?

• Appearance. Is he anxious or tachypneic?

• Vital Signs. What are his weight, blood pressure, pulse, and temperature?

• Trauma. Is there a head injury? Are there

burns in the region of the eyes, nose, or

mouth?

• Skin. Are there signs of burns, erythema,

sweating, or dryness?

• Eyes. Is there conjunctivitis, corneal burns

or abrasion, miosis, or mydriasis?

• Nose. Is there erythema, rhinorrhea, or

epistaxis?

• Oropharynx. Is there evidence of perioral

burns or erythema?

• Neck. Is there hoarseness, stridor, or subcutaneous emphysema?

• Chest. Is there superficial chest wall

trauma, tenderness, crepitation, dullness, or

hyperresonance? Are crackles present? This

measurement should be made by asking the

patient to hold a forced expiration at residual volume for 30 seconds, then listening carefully at the lung bases for inspiratory crackles. Is wheezing present? This

examination should be undertaken by listening for wheezes bilaterally in the chest

both posteriorly and anteriorly under circumstances of forced expiration.

Laboratory Measurements

Sophisticated laboratory studies are of limited

value in the immediate care of an exposed, injured

individual. The following studies are of some predictive value in determining the severity of exposure and the likely outcome.
Medical Aspects of Chemical and Biological Warfare

252

Chest Radiograph. The presence of hyperinflation suggests toxic injury of the smaller airways,

which results in air being diffusely trapped in the

alveoli (as occurs with phosgene exposure). The

presence of “batwing” infiltrates suggests pulmonary edema secondary to toxic alveolar capillary

membrane damage (as occurs with phosgene exposure). Atelectasis is often seen with more-central

toxic inhalant exposures (such as with chlorine

exposure). As radiological changes may lag behind

clinical changes by hours to days, the chest radiograph

may be of limited value, particularly if normal.

Arterial Blood Gases. Hypoxia often results from

exposure to toxicants, such as occurs following exposure to chlorine. Measurement of the partial pressure of oxygen (PO2) is a sensitive but nonspecific tool

in this setting; both the central and peripheral effects

of toxic inhalant exposure may produce hypoxia. At

4 to 6 hours, normal arterial blood gas (ABG) values are a strong indication that a particular exposure has little likelihood of producing a lethal effect. Typically, carbon dioxide elevation is seen in

individuals with underlying hyperreactive airways;

in this circumstance, it is thought that bronchospasm

is triggered by exposure to the toxic inhalant.

Pulmonary Function Tests. A variety of airway

function measures and pulmonary parenchymal function measures can be performed in rearechelon facilities. Initial and follow-up measurements of the flow-volume loop, lung volumes,

and the lung diffusing capacity for carbon monoxide (DLCO) are particularly useful in assessing and

managing long-term effects of a toxic inhalant

exposure. Although such laboratory studies are

of minimal value in an acute-care setting, flow volume loop measures may document a previously unrecognized degree of airway obstruction. A degree

of reversibility may also be demonstrated if

bronchodilators are tested at the same time. Substantial airway obstruction may be present with

little clinical evidence. In all cases of unexplained

dyspnea, regardless of clinical findings, careful

pulmonary function measurements should be undertaken. Ideally, these studies should be performed

in an established pulmonary function laboratory

and would include DLCO and ABG measurements.

These studies should also be performed during exertion if dyspnea on exertion is noted that cannot

otherwise be explained by pulmonary function

studies performed at rest.

GENERAL THERAPEUTIC CONSIDERATIONS

Further Exposure

A soldier’s exposure to toxic inhalants is limited

by removing him from the environment in which the

toxicant is present. Careful decontamination serves

to limit reexposure to the toxicant from body surfaces

or clothing. Furthermore, decontamination reduces

the risk of secondary exposure of other personnel.

Critical Care Concepts

Life-threatening pathophysiological processes

arising from toxic inhalants usually develop in the

upper airway, where laryngeal obstructions can

cause death in a few minutes, and in the lower respiratory tract, where bronchospasm can cause death

almost as rapidly. Severe bronchospasm may indicate exposure to a nerve agent. If there is any possibility that exposure to nerve agents has occurred,

the use of one or more of the three Mark I AutoInjector kits that are provided to all military members (see Chapter 5, Nerve Agents) should be considered an urgent part of initial therapy. Like the

airway and breathing, cardiac function must likewise be assessed immediately.

Adequate control of the airway is important in

all toxic inhalant exposures. Exposure to centrally

absorbed toxic inhalants (such as chlorine) and to

fires may be particularly dangerous, insofar as

laryngeal or glottal edema may rapidly compromise

upper airway patency. Evidence of perinasal or

perioral inflammation indicates the need for

more careful investigation of the oropharynx for

erythema. Subsequent laryngoscopy or bronchoscopy may be of particular value and should be undertaken along with preparations for expedient intubation. The presence of stridor indicates the need

for immediate airway control.

Primary failure of respiration after exposure to

toxicants other than nerve agents suggests a severity of exposure that requires intensive medical support; at this point, a triage decision may be needed.

The presence of wheezing indicates severe bronchospasm, which requires immediate therapy. The presence of dyspnea necessitates careful observation of

the patient for at least 4 to 6 hours, until severe,

potentially lethal respiratory damage can be reasonably excluded.

Primary failure of cardiac function, like respiration, is a grave sign after exposure to toxicants other
Toxic Inhalational Injury

253

than nerve agents. Cardiac rate and rhythm abnormalities are often seen after toxicant exposure.

These abnormalities are often transient and improve

once the casualty is removed from the toxic environment and is provided with supplemental oxygen. Hypotension is a grave prognostic sign if not

immediately reversed by fluid and volume resuscitation and intensive medical care.

Clinical Abnormalities

Clinical abnormalities that may lead to respiratory failure can also be observed after pulmonary

toxic inhalational injury. These include hypoxia,

hypercarbia, pulmonary edema, which are all signs

of possible toxic inhalant exposure; and infection,

which is a frequent complication, particularly in

intubated patients.

Oxygen supplementation should be provided to

maintain a PO2 greater than 60 mm Hg. Very early

application of positive end-expiratory pressure

(PEEP) is important, with progression to intubation

and positive pressure ventilation if PEEP fails to

normalize the PO2. Note that PEEP application may

precipitate hypotension in individuals with marginally adequate intravascular volume (such as those

with conventional trauma or pulmonary edema) or

in individuals previously treated with drugs that

have venodilating properties (such as morphine or

diazepam). Particular attention to anemia is necessary if hypoxia is present.

An elevation of the partial pressure of carbon

dioxide (PCO2) greater than 45 mm Hg suggests that

bronchospasm is the most likely cause of hypercarbia; therefore, bronchodilators should be used

aggressively. If the patient has a prior history of

clinical bronchospasm, steroids should be added

immediately; steroids should also be considered if

the patient has a history of hay fever or eczema and

obvious bronchospasm with the current exposure.

Occasionally, positive pressure ventilation may also

be necessary. Interstitial lung water (early pulmonary edema) may trigger bronchospasm in individuals who are otherwise hyperreactive (such as

those with “cardiac” asthma). Steroids are not primarily useful in this circumstance.

Pulmonary edema noted after a toxic inhalant

exposure should be treated similarly to adult respiratory distress syndrome (ARDS) or “noncardiac”

pulmonary edema. The early application of PEEP

is desirable, possibly delaying or reducing the severity of pulmonary edema. Diuretics are of limited value; however, if diuretics are used, it is useful to monitor their effect by means of the pulmonary artery wedge pressure measurement because

excessive diuretics may predispose the patient to

hypotension if PEEP or positive-pressure ventilation is applied.

Toxic inhalant exposures typically cause acute

fever, hypoxia, elevated polymorphonuclear

white cell count, and radiologically detectable

infiltrates. These changes should not be taken to

indicate bacteriological infection during the first 3

to 4 days postexposure. Thus, routine or prophylactic use of antibiotics is not appropriate during

this period.

Infectious bronchitis or pneumonitis commonly

supervenes 3 or more days postexposure to a toxic

inhalant, particularly in intubated patients. Close

observation of secretions, along with daily surveillance bacterial culture, will permit the early

identification and specific treatment of identified

organisms.

Steroid Therapy

Systemic steroid therapy has been considered

for use in certain toxic inhalational exposures.

U.S. Army Field Manual 8-285, Treatment of

Chemical Agent Casualties and Conventional Military

Chemical Injuries,

4

 suggests a benefit in phosgene

exposure, but human data supporting this approach

are scanty. There is some support in the literature

for steroid use in exposure to zinc/zinc oxide

and oxides of nitrogen. However, there is no other

strong support in the literature for the treatment

of other specific toxic inhalations with systemic

steroids.

A significant percentage of the population has a

degree of airway irritability or hypersensitivity, as

exemplified by persons with asthma. These individuals are likely to display heightened sensitivity

or even bronchospasm, nonspecifically after an

inhalational exposure. The use of systemic steroids

would be indicated in this population if their bronchospasm were not readily controlled with more

routine bronchodilators. Systemic steroids may,

if used in this setting, be required for prolonged

periods, particularly if superinfection should

supervene.

Inhaled steroids may be less effective than

systemic steroids in circumstances of acute exposure—especially if later infected. Inhaled steroids

appear most useful as an adjunct to the gradual reduction or weaning or both from a systemic steroid

use.
Medical Aspects of Chemical and Biological Warfare

254

EXERTION AND TOXIC INHALATIONAL INJURY

“The extra amount of oxygen needed in the exertion could not be supplied and the results showed

at once.... [M]en who had been comfortable while

lying became rapidly worse and sometimes died

suddenly if they walked or sat about,”5(p424) wrote

Herringham in his article describing gassed casualties in World War I.

There is scant, primarily anecdotal, information

relating to the effects of exercise postexposure

to toxic inhalants. During World War I, attempts

to assess the effects of toxic inhalant exposure on

exercise tolerance were severely constrained by

a limited understanding of basic exercise physiology and by limited technological capacity. Some

early observations in exercise-limited victims

of gassing included observations of limited “depth

of respiration” and tachycardia after “mildest

exercise”6(p3); and a heartbeat that “rises more than

normal for given exercise...returns to normal more

slowly after exercise [seen in 116 of 320 gassed

patients].”7(p10)

As a result of the World War I experience, it

was clear that cardiorespiratory damage resulting

from toxic inhalant exposures could severely limit

exercise capacity. Of primary concern, however,

was whether exercise undertaken after a toxic inhalant exposure could, in some way, exacerbate the

effects of that exposure and thus increase the morbidity or mortality of exposed individuals. This

was a particularly practical concern in light of the

military needs to return soldiers to active duty as

soon as possible and to require soldiers to participate (insofar as they appeared able) in their own

evacuation.

Toxic inhalant exposures may produce direct

pulmonary effects, indirect cardiac effects, and

other systemic effects (eg, central nervous system

[CNS] effects of mercury inhalation). Severe damage to those systems will be readily apparent; however, identification of lesser damage may require

increasingly sophisticated examination. Minor organ dysfunction is best identified during stress; that

is, an organ system that is functioning near its maximum capacity is more likely to demonstrate physiological limitation than a system that is functioning under conditions of rest. The principle of organ

stress as a method of functional assessment is well

recognized. Both cardiologists and endocrinologists

have devised stress testing methods that allow earlier and more sensitive demonstration of cardiac

and endocrine limitations. Systems with small degrees of physiological limitation are much more

likely to display such limitations during stress than

at rest. Conversely, an organ system that is impaired

may become so dysfunctional during stress that it

exceeds its compensatory mechanisms (and those

of other support systems) and fails, with resulting

catastrophic consequences for the organism as a

whole.

The normal human body is designed to function

at a wide range of activity. Normal cardiopulmonary reserves permit a 25- to 30-fold increase in

oxygen delivery to working muscles. Other compensatory mechanisms permit transient activities

even beyond these limits. Ultimately, however, any

activity requires adequate oxygen delivery and carbon dioxide extraction for cell function. A damaged

cardiorespiratory system that is unable to accomplish normal oxygen–carbon dioxide exchange will

first appear limited at the extreme of exertion. Maximum exercise capacity will be restricted. With increasing damage to the cardiorespiratory system,

exercise capacity becomes further limited until

symptoms (eg, dyspnea or orthopnea) appear even

at rest.

Although oxygen–carbon dioxide exchange may

be adequate at rest (oxygen delivery of approximately 250 mL/min), the requirements of oxygen

delivery during exercise (up to 5,000 mL/min)

 cannot be met if there is cardiorespiratory damage:

with cardiorespiratory damage, cellular hypoxia results during exercise. Anaerobic mechanisms

are transiently effective but are inadequate to

provide energy for extended periods of time, and

metabolic acidosis ensues. Ordinarily the metabolic

acidosis (lactate-predominant) causes enough discomfort and discoordination of activity to limit the

exertion. Lactate is then cleared from the circulation and excreted from the body as carbon dioxide.

However, should respiratory limitation also be

present, then excess carbon dioxide load is not

readily exchanged. A respiratory acidosis is superimposed. Acidosis develops more rapidly than systemic buffer systems can accommodate it. The resulting hydrogen ion excess compromises myocardial

contractility, increases pulmonary artery resistance,

and causes peripheral venous dilation. Cardiac

output then diminishes relative to metabolic

needs.

Furthermore, a diminished intravascular blood

volume—which is secondary to losses to the extravascular space, particularly to lung paren-
Toxic Inhalational Injury

255

chyma—and increased intrathoracic pressure (air

trapping secondary to bronchospasm) reduce

venous return. This contributes to a further, severe

compromise of cardiac output. Hypotension then

exceeds other compensatory mechanisms (such

as tachycardia), with further restriction of oxygen

delivery to metabolizing tissue. Finally, more

intense acidosis occurs and, ultimately, death supervenes.

Interactions of Pulmonary Toxic Inhalants and

Exercise

Airway resistance may increase because of toxic inhalational injury, resulting in increased

work of respiration. Air trapping secondary to increased airway resistance increases intrathoracic

pressure. Increased work of respiration and decreased venous return result in exercise limitation.

Ventilation–perfusion abnormalities of disordered

airway function limit oxygen delivery and carbon

dioxide clearance, which also compromises exercise

tolerance.

Acute, short-term changes in interstitial function

secondary to pulmonary edema, or long-term

changes secondary to interstitial inflammation or

fibrosis subsequently limit diffusing capacity, a particularly exercise-sensitive portion of the gas exchange system.

During exercise, the airways and the alveoli have

greater exposure to a toxicant because of increased

ventilation. Hyperventilation may itself induce

mild bronchospasm, delaying toxicant clearance

from the lung periphery. Already limited oxygen

delivery may be critically compromised by exercise,

resulting in systemic hypoxia (including cerebral,

cardiac, renal, and hepatic systems).

With regard to interstitial mechanisms, increments of pulmonary arterial pressure with increased cardiac output may aggravate capillary

leaks, increasing interstitial edema. Inflammatory

cells may accumulate in the interstitium, creating

local toxicity as they degenerate.

Therapy

After a toxic inhalational exposure, exercise may

further compromise the patient. Hypoxia is a primary factor. Oxygen supplementation is necessary

at rest and especially during exercise. Exercise may

aggravate the effects of toxicant exposure and

should be limited or restricted if possible.

Toxicant exposure may produce pulmonary abnormalities which result in dyspnea. Clinical or

laboratory testing may fail to confirm this symptom in the early hours postexposure; hence examination of the patient must also take place at 4 to 6

hours postexposure, if no abnormalities are initially

identified.

Dyspnea may be present long after the chest

radiograph, physical examination, and resting

values for ABG return to normal. Exercise evaluation of these individuals (with ABG readings

as a necessary part of that evaluation) must be

undertaken to understand the exposed individual’s complaints. Failure to make these measurements in a soldier complaining of exercise

limitation displays a lack of understanding of

both toxic inhalant exposures and basic exercise

physiology.

HISTORICAL WAR GASES

A variety of chemical agents were used as toxic

inhalants during World War I; of these, several are

considered current threats. Some toxicants have

current military relevance either because of their

presence in stockpiles or because of their current

or recent use in military operations in other countries. Other toxicants exist in large quantities as a

result of their industrial use. Because of the

military’s preparedness in managing large-scale

exposure to toxicants, such as poisonous gases,

military assistance may be required in the event of

a major accident involving toxic inhalants.

The following section discusses chlorine and

phosgene, the two war gases that were used during World War I. Although they are not considered

current threats, under the right conditions they

could pose a threat to military personnel.

Chlorine

Chlorine is a dense, acrid, pungent, greenish-yellow gas that is easily recognized by both color and

odor. Because of its density and tendency to settle

in low-lying areas, this gas is hazardous in closed

spaces. Because the gas has a characteristic odor and

its odor threshold is well below acute TLVs, chlorine is said to have good warning properties. However, chronic exposures are thought to lead to a progressive degradation of the odor threshold. As a

result, workers with frequent or long-term occupa-
Medical Aspects of Chemical and Biological Warfare

256

tional exposures to chlorine are at greater risk of

inhalational damage in later years.8–10

Clinical Effects of Exposure

An almost characteristic initial complaint of chlorine exposure is that of suffocation: the inability to

get enough air.11 Typically, low exposures produce a

rapid-onset ocular irritation with nasal irritation, followed shortly by spasmodic coughing and a rapidly

increasing choking sensation. Substernal tightness is

noted early. Complaints are particularly evident in

individuals who have a history of hyperreactive airways (asthma). Minimal to mild cyanosis may be evident during exertion, and complaints of exertional

dyspnea are prominent. Deep inspiration produces

a typical persistent, hacking cough.

Moderate chlorine exposures result in an immediate cough and a choking sensation. Severe substernal discomfort and a sense of suffocation develop early. Hoarseness or aphonia is often seen,

and stridor may follow. Symptoms and signs of

pulmonary edema may appear within 2 to 4 hours;

radiological changes typically lag behind the clinical symptoms. There may be retching and vomiting, and the gastric contents often have a distinctive odor of chlorine. Figure 9-1 shows the chest

radiograph of a chemical worker 2 hours postexposure to chlorine: note the diffuse pulmonary

edema without significant cardiomegaly. This patient experienced severe resting dyspnea, diffuse

crackles on auscultation, and had a PO2 of 32 mm

Fig. 9-1. The chest radiograph of a 36-year-old female

chemical worker 2 hours postexposure to chlorine inhalant. She had severe resting dyspnea during the second

hour, diffuse crackles/rhonchi on auscultation, and a PO2

of 32 mm Hg breathing room air. The radiograph shows

diffuse pulmonary edema without significant cardiomegaly.

Fig. 9-2. A section from a lung biopsy (from the patient

whose chest radiograph is seen in Figure 9-1) taken 6

weeks postexposure to chlorine. At that time, she had no

clinical abnormalities and a PO2 of 80 mm Hg breathing

room air. The section shows normal lung tissues without evidence of interstitial fibrosis/inflammation. Hematoxylin and eosin stain; original magnification x 100.

Hg breathing room air. Figure 9-2 is a section of lung

biopsy taken from the same worker 6 weeks

postexposure. The section shows no residual injury

from the chlorine exposure. The patient’s PO2 was

80 mm Hg breathing room air.

Intense toxic inhalant exposures may cause pulmonary edema within 30 to 60 minutes. Secretions

from both the nasopharynx and the tracheobronchial tree are copious, with quantities of up to 1 L/

h reported.12 Severe dyspnea is so prominent that

the patient may refuse to move. On physical examination, the chest may be hyperinflated. Mediastinal

emphysema secondary to peripheral air trapping may

dissect to the skin and present as subcutaneous

emphysema. The sudden death that occurs with

massive toxic inhalant exposure is thought to be

secondary to laryngeal spasm.13

Therapy

There is no chemically specific prophylactic or

postexposure therapy for chlorine inhalation; therefore, postexposure therapy is directed toward treating the observed physiological signs and symptoms.

Most deaths occur within the first 24 hours and are

caused by respiratory failure.

Individuals who survive a single, acute exposure

generally demonstrate little or no long-term pathological or physiological sequelae. Individuals with

underlying cardiopulmonary disease or those who

suffer complications (such as pneumonia) during

therapy are at risk for developing chronic bronchi-
Toxic Inhalational Injury

257

tis or (rarely) a gradual and progressive bronchiolitis obliterans. Chronic bronchitis was thought to

be common after World War I chlorine inhalant exposures. Current assessment of these gassed individuals suggests that their chronic or progressive

illness is more likely to have resulted from a combination of inadequately treated complicating infections and cigarette smoking than from the destructive effects of a single, acute exposure.14,15

Secretions are typically copious but generally

thin; mucolytics are not required. Careful attention

to the appearance of secretions will assist in the

early identification of bacterial superinfection,

which may be associated with secretions that are

other than clear or white.

Bacterial superinfection is commonly noted 3 to

5 days postexposure. Early, aggressive antibiotic

therapy should be directed as specifically as possible against identified organisms. Careful, frequent

Gram’s stains and cultures of sputum are used to

identify a predominant organism. Persistent fever,

infiltrates, or elevated white blood cell count in the

presence of thickened, colored secretions should

prompt the institution of a broad-spectrum antibiotic (such as ampicillin or a cephalosporin). The

choice of antibiotic should be based on local experience with either community-acquired or nosocomial organisms. Antibiotics are not used prophylactically in this setting; such therapy would only

serve to select a resistant bacterial population in the

injured individual.

Bronchospasm is an early and prominent complication of chlorine exposure. Aggressive bronchodilator therapy (a combination of adrenergic

agent and theophylline) is appropriate. Steroids are

used if the patient has a history of hyperreactive

airways. Bronchodilators are used at least until the

antibiotics are discontinued and there is no further

evidence of clinical response (eg, as indicated by

laboratory testing). Steroid doses should be tapered

as rapidly as clinical circumstances warrant after

the first 3 to 4 days of (uncomplicated) recovery.

Superinfection may complicate prolonged steroid

therapy.

Hypoxia improves as the bronchospasm improves, and long-term oxygen supplementation is

rarely required. If long-term oxygen supplementation is needed, a search for other causes of hypoxia

should be undertaken. Early institution of positive

airway pressure (such as using a PEEP mask) may

be useful. Positive pressure ventilation may be necessary if PEEP is insufficient to maintain PO2 greater

than 60 mm Hg. Occasional reports of subcutaneous emphysema after chlorine exposure should not

be considered a contraindication to using PEEP or

positive pressure ventilation.16,17

Generally, the patient gradually recovers from his

acute injury in 36 to 72 hours, depending on the

degree of exposure. Delay in recovery may be the

result of superinfection. Pleural effusions of up to

600 mL have been identified, generally in association with pulmonary edema. Areas of pneumonic

consolidation may be evident on the chest radiograph.16 Follow-up studies of acute toxic inhalant

exposures have generally demonstrated that patients who had no acute complications developed

no significant long-term effects.15 Pulmonary function and respiratory symptoms in individuals with

repetitive, long-term, or low-dose toxic inhalant

exposures have been reviewed in a number of reports.18 Although accurate records are difficult to

maintain and, consequently, the data may be somewhat difficult to interpret, long-term or multiple,

low-dose toxic inhalant exposures appear to produce no significant physiological defects when the

results are corrected for smoking.18

Clinical Summary

Long-term complications from chlorine exposure

are not found in those individuals who survive an

acute exposure. There is little or no evidence that

significant long-term respiratory compromise occurs, unless there has been a superimposed bronchitis or pneumonitis. The toxic effects of chlorine

in the absence of superinfection are relatively short

lived. Bronchospasm may require prolonged

therapy, occasionally with steroids. There is little

evidence for significant long-term pathophysiological abnormalities with either acute, severe chlorine

exposure or repetitive low-dose, long-term exposures. A patient’s failure to demonstrate substantial recovery within 3 to 4 days should prompt an

investigation for the possible presence of bacterial

superinfection or other complicating features.

Phosgene

Phosgene (military designation, CG) appears at

usual battlefield temperatures as a white cloud

whose density is due, in part, to hydrolysis. The gas

is heavier than air and at low concentrations has a

characteristic odor of newly mown hay. At higher

concentrations, a more acrid, pungent odor may be

noted. An odor threshold of 1.5 ppm has been reported but does not apply to all observers. This odor

threshold is inadequate to protect against toxic inhalant exposures to this substance. Furthermore, a
Medical Aspects of Chemical and Biological Warfare

258

relatively rapid nasal adaptation limits the usefulness of odor as a detection mechanism.19 Synonyms

for phosgene include carbonyl chloride, D-Stoff,

and green cross.

Clinical Effects of Exposure

In the first 30 minutes following exposure to

phosgene, low concentrations may produce mild

cough, a sense of chest discomfort, and dyspnea.

Exposure to moderate concentrations triggers lacrimation and the unique complaint that smoking

tobacco produces an objectionable taste.20 High concentrations may trigger a rapidly developing pulmonary edema with attendant severe cough, dyspnea, and frothy sputum. Onset of pulmonary edema

within 2 to 6 hours is predictive of severe injury.

High concentrations may produce a severe cough

with laryngospasm that results in sudden death;

this could possibly be due to phosgene hydrolysis,

which releases free hydrochloric acid at the level of

the larynx.21

In the first 12 hours after toxic inhalant exposure,

depending on the intensity of exposure, a substernal tightness with moderate resting dyspnea and

Fig. 9-4. A lung section of the patient whose chest radiograph is seen in Figure 9-3. This patient died 6 hours after exposure to phosgene; the biopsy section was taken

at postmortem examination. The section shows nonhemorrhagic pulmonary edema with few scattered inflammatory cells. Hematoxylin and eosin stain; original magnification x 100.

Fig. 9-3. The chest radiograph of a 42-year-old female

chemical worker 2 hours postexposure to phosgene. Dyspnea progressed rapidly over the second hour; PO2 was

40 mm Hg breathing room air. This radiograph shows

bilateral perihilar, fluffy, and diffuse interstitial infiltrates. The patient died 6 hours postexposure.

prominent exertional dyspnea become evident.

These symptoms are often a prelude to the characteristic development of pulmonary edema. Initially

small, then greater, amounts of thin airway secretions may appear. The delayed and insidious onset

of severe pulmonary edema often has resulted in a

casualty’s being medically evaluated and discharged from the medical facility, only to return

some hours later with severe and occasionally lethal pulmonary edema. The chest radiograph of a

female chemical worker 2 hours postexposure to

phosgene (Figure 9-3) shows bilateral perihilar,

fluffy, and diffuse interstitial infiltrates. A section

of the lung (Figure 9-4) from the same patient shows

nonhemorrhagic pulmonary edema with few scattered inflammatory cells.

An individual may remain relatively asymptomatic for up to 72 hours after inhalant exposure. During that time, dyspnea or pulmonary edema may

be triggered by exertion (see the preceding section,

Exertion and Toxic Inhalational Injury).

Therapy

Pulmonary edema is the most serious clinical

aspect of phosgene exposure and begins with few,

if any, clinical signs. Consequently, early diagnosis

of pulmonary edema requires that careful attention

be paid to the patient’s symptoms of dyspnea or

chest tightness. The presence of these symptoms in

a setting of possible inhalant exposure requires ex-
Toxic Inhalational Injury

259

peditious auscultation, chest radiograph, and ABG

measurements.

If abnormal, these measurements mandate close

observation and support at the intensive care level.

If the measurements are normal, they all must be

repeated 4 to 6 hours after the suspected exposure;

only then can an individual be released to a lower

medical priority status. Abnormality of any one of

those measures, in the absence of other explanation,

should prompt institution of therapy for noncardiac

pulmonary edema. At the early stages of treatment,

therapy should include positive airway pressure

with early application of the PEEP mask. Later application of positive pressure ventilation through

intubation may be required if the PEEP mask fails

to maintain adequate arterial PO2.

Figures 9-5 and 9-6 are the chest radiographs

of a male chemical worker 2 hours and 7 hours,

respectively, postexposure to phosgene. The

chest radiograph taken 2 hours postexposure was

normal. The patient presented with mild resting

dyspnea, but otherwise his physical examination was normal. The same individual, 7 hours

postexposure, presented with moderate resting

dyspnea and a few crackles on auscultation. His

chest radiograph showed mild interstitial edema.

Figure 9-7 is a lung section from this patient, who

died 4 years later from unrelated causes. These tissues are normal, and there is no evidence of interstitial fibrosis.

Diuretics may be of minor value in reducing capillary pressure and consequently decreasing the rate

Fig. 9-5. The chest radiograph of a 40-year-old male chemical worker 2 hours postexposure to phosgene. The patient

experienced mild resting dyspnea for the second hour; however, his physical examination was normal with a PO2 of 88

mm Hg breathing room air. This radiograph is normal.

Fig. 9-6. The same patient seen in Figure 9-5, now 7 hours

postexposure to phosgene. He had moderate resting dyspnea, a few crackles on auscultation, and a PO2 of 64 mm

Hg breathing room air. This radiograph shows mild interstitial edema.

Fig. 9-7. A lung section from the patient whose chest radiographs are shown in Figures 9-5 and 9-6, who died 4

years later from causes unrelated to his exposure to phosgene. This section shows normal lung tissues without

evidence of interstitial fibrosis or inflammation. Hematoxylin and eosin stain; original magnification x 400.
Medical Aspects of Chemical and Biological Warfare

260

of fluid loss through a (presumptively) damaged

alveolar–capillary membrane. It should be kept in

mind that intravascular volume reduction (such as

that induced by diuretics) may lead to serious

hypotension if positive pressure ventilation is

required. Steroids have not been found to be clinically useful in treating phosgene-induced pneumonitis. There has been some discussion in the

literature concerning the use of hexamethamine

tetramine. However, reliable comparative data

supporting this therapeutic intervention are not

available.22–24

Clinical Summary

The toxic effects of phosgene in the absence of

superinfection or other complications are relatively

short-lived. There is little evidence of significant

long-term pathophysiological abnormalities with

either acute, severe phosgene exposures or repetitive, low-dose, long-term exposures. A patient’s failure to demonstrate substantial recovery within 3 to

4 days should prompt an investigation for the possible presence of bacterial superinfection or other

complicating features.25

SMOKES AND OTHER SUBSTANCES

Smokes and obscurants comprise a category of

materials that are not used militarily as direct

chemical agents. They may, however, produce toxic

injury to the airways. The particulate nature of

smokes may lead to a mechanical irritation of the

upper and lower airways—therefore inducing bronchospasm in some hypersensitive individuals (eg,

those with asthma). Certain smokes contain chemicals with a degree of tissue reactivity that results in

damage to the airways. A discussion of obscurant

smokes is followed by a discussion of certain explosion-related (oxides of nitrogen) or pyrolysisrelated (perfluoroisobutylene) substances that are

important in military practice.

Zinc Oxide

During World War I, the difficulties experienced

by the Allies in using white phosphorus as an

obscurant smoke led both the French and the

U.S. Chemical Warfare Service to search for

other smokes; zinc oxide (military designation, HC

or HC smoke) is an outgrowth of that search. HC

contains equal percentages of zinc oxide and

hexachloroethane, with approximately 7% grained

aluminum. The material is currently formulated for

use in smoke pots, smoke grenades, and artillery

rounds.

On combustion, the reaction products are zinc

chloride and up to 10% chlorinated hydrocarbons

such as phosgene, carbon tetrachloride, ethyl tetrachloride, hexachloroethane, and hexachlorobenzene. In addition to these products, hydrogen

chloride, chlorine, and carbon monoxide are also

produced. As the zinc chloride particles form, they

hydrolyze in ambient water vapor to produce a

dense white smoke. The toxicity of this chemical

agent is generally attributed to the topical toxic effects of zinc chloride. However, carbon monoxide,

phosgene, hexachloroethane, and other combustion

products may also contribute to the observed respiratory effects, depending on the circumstances of

the munitions ignition.26

Clinical Effects of Exposure

Since World War I, there have been numerous

reports of accidental exposures to the combustion products of HC. Depending on the intensity

of the exposure, a wide range of clinical effects occurs; exposures as brief as 1 minute may lead to

death.

Low-dose toxic inhalant exposures are characterized by sensations of dyspnea without subsequent

radiological, auscultatory, or blood gas abnormalities. These patients should be watched carefully for

4 to 6 hours postexposure (see the earlier discussion on phosgene); however, severe clinical sequelae

are uncommon.

Moderate exposures to HC are characterized

by severe dyspnea, which may show a relatively

rapid clinical improvement during the first 4 to 6

hours. Because the chest radiograph is typically unremarkable at this time, the patient is often inappropriately discharged. These patients usually return to the medical facility within 24 to 36 hours

complaining of rapidly increasing shortness of

breath. By that time, the chest radiograph typically

demonstrates dense infiltrative processes, which

clear slowly with further care. Moderate to severe

hypoxia may persist during the period of radiological abnormality.

After exposure, the chest radiograph is characteristically unremarkable within the first hours despite severe clinical symptoms, which include rapid

respirations and severe dyspnea. An elevated temperature is often noted within the first 4 to 6 hours

and may remain over the ensuing days. At 4 to 6
Toxic Inhalational Injury

261

hours, the chest radiograph begins to show a dense

infiltrative process that is thought to represent

edema. However, bronchopneumonia may supervene in the following days; a long-standing, diffuse

interstitial fibrosis may become evident, with only

very gradual recovery.27,28

Figure 9-8 is the chest radiograph of a 60-yearold male 8 hours postexposure to HC; it shows diffuse, dense, peripheral pulmonary infiltrates. The

patient presented with moderately severe resting

dyspnea and diffuse coarse crackles on auscultation. Taken 14 weeks postexposure, Figure 9-9 is a

section from an open lung biopsy from the same

patient. Diffuse interstitial fibrosis with inflammatory cells are evident. This patient presented with a

persistent, moderate resting dyspnea. At this point,

the patient had not been treated with steroids.

Exposures to very high doses of HC commonly result in sudden, early collapse and death,

which are thought to be due to rapid-onset laryngeal edema and glottal spasm with consequent

asphyxia. Exposures to high but nonlethal doses

typically produce very early, severe hemorrhagic ulceration of the upper airway. Such exposures may

also produce a relatively rapid onset of pulmonary

edema.

Prolonged, severe exposures typically result in

relatively rapid onset of severe dyspnea, tachypnea,

sore throat, and hoarseness. A characteristic paroxysmal cough often produces bloody secretions. An

acute tracheobronchitis may lead to death within

hours.

Fig. 9-8. The chest radiograph of a 60-year-old male sailor

who inhaled zinc oxide (HC) in a closed space, taken 8

hours postexposure. He had moderately severe resting

dyspnea during the seventh and eighth hours, diffuse

coarse crackles on auscultation, and a PO2 of 41 mm Hg

breathing room air. The radiograph shows diffuse dense

peripheral pulmonary infiltrates.

Fig. 9-9. A section from an open lung biopsy of the patient whose chest radiograph is shown in Figure 9-8, 14

weeks postexposure to zinc oxide (HC). He had persistent moderate dyspnea at rest and a PO2 of 61 mm Hg

breathing room air. Steroids had not been used. The section shows diffuse interstitial fibrosis with few inflammatory cells. Hematoxylin and eosin stain; original magnification x 400.

Therapy

There is no chemically specific prophylactic or

postexposure therapy for exposure to HC. Routine

clinical support for specific complaints of acute tracheobronchitis and noncardiac pulmonary edema

has been detailed previously (see the section titled

General Therapeutic Considerations). Systemic steroid therapy is thought to be useful in treatment of

the inflammatory fibrosis seen with this disorder.29–32

There are no reports of the clinical efficacy of

chelating agents; however, the use of such agents

as British anti-Lewisite (BAL) and calcium ethylenediaminetetraacetic acid (CaEDTA) has been

suggested because of their capacity to reduce serum zinc levels. After acute exposure, however,

long-term pulmonary function testing is indicated

until the patient’s condition is stable by that measurement. The continued presence of exertional

dyspnea 2 to 3 months postexposure implies further development of interstitial fibrotic changes.

Exercise testing would be of value to obtain a more

accurate assessment of the degree of oxygen transport limitation. There are no data evaluating the use

of long-term steroid therapy in the treatment of interstitial disease secondary to HC inhalation.29–32

Clinical Summary

Although most patients with zinc chloride inhalational injuries progress to complete recovery, a
Medical Aspects of Chemical and Biological Warfare

262

smaller group of approximately 10% to 20% of exposed individuals may go on to develop fibrotic

pulmonary changes. Both groups show early clinical recovery, making it difficult to distinguish patients who are likely to recover from those who are

likely to develop more permanent changes. Early

steroid use may modify the intensity of pulmonary

reaction and the resulting fibrosis; therefore, steroids appear indicated in the acute therapy of zinc

oxide exposure.

Phosphorus Smokes

Phosphorus occurs in three allotropic forms:

white, red, and black. Of these, white phosphorus

was used most often during World War II in military formulations for smoke screens, marker shells,

incendiaries, hand grenades, smoke markers, colored flares, and tracer bullets.

White phosphorus is a very active chemical that

will readily combine with oxygen in the air, even at

room temperature. As oxidation occurs, white phosphorus becomes luminous and bursts into flames

within minutes. Complete submersion in water is

the only way to extinguish the flames. Vapors from

white phosphorus are toxic; however, because these

vapors quickly oxidize into phosphorus pentoxide

and phosphoric acid, they are harmless to humans

and animals at usual field concentrations.

Clinical Effects of Exposure

At room temperature, white phosphorus is somewhat volatile and may produce a toxic inhalational

injury. Over a period of years, repetitive exposures

can result in systemic poisoning.33 At warmer temperatures, a slow oxidation to phosphorus trioxide

(P2O3), which smells like garlic, can occur. At still

higher temperatures (approximately 32°C [90°F])

and with adequate air exposure, dense white clouds

of phosphorus pentoxide (P2O5) result from the

combustion of phosphorus.

In moist air, the phosphorus pentoxide produces

phosphoric acid. This acid, depending on concentration and duration of exposure, may produce a

variety of topically irritative injuries. Irritation of

the eyes and irritation of the mucous membranes

are the most commonly seen injuries. These complaints remit spontaneously with the soldier’s removal from the exposure site. With intense exposures,

a very explosive cough may occur, which renders

gas mask adjustment difficult. There are no reported

deaths resulting from exposure to phosphorus

smokes.

Because of the toxicity associated with the manufacture of white phosphorus and because of its field

risks, a gradual shift to red phosphorus (95% phosphorus in a 5% butyl rubber base) was undertaken

after World War II. The British smoke grenade (L8-

A1-3), which used red phosphorus, produced adequate field concentrations of smoke and functioned as an effective tank screen. Oxidation of red

phosphorus produces a variety of phosphorus acids that, on exposure to water vapor, produce

polyphosphoric acids. These acids may produce

mild toxic injuries to the upper airways that result

in a cough and irritation. There are no reported deaths

resulting from exposure to red phosphorus smokes.

Therapy

Phosphorus smokes are generated by a variety

of munitions. Some of these munitions (such as the

MA25 155-mm round) may, on explosion, distribute particles of incompletely oxidized white phosphorus. Contact with these particles can cause local burns, and systemic toxicity may occur if

therapy is not administered. Therapy consists of

topical use of a bicarbonate solution to neutralize

phosphoric acids and mechanical removal and debridement of particles. A Wood’s lamp in a darkened room may help to identify remaining luminescent particles.

Clinical Summary

The principal form of toxicity of absorbed elemental phosphorus, a destructive jaw process

(phossy jaw), has been virtually eliminated by using (a) less white phosphorus in all industrial settings

other than the military and (b) efficient adjunctive

dental screening of exposed individuals for periods of up to 2 years postexposure. Careful dental

screening consists of regular radiological assessment of the mandible for characteristic lesions, early

and aggressive treatment of those lesions, and absolute prohibition of further phosphorus exposure.33

Sulfur Trioxide–Chlorosulfonic Acid

Sulfur trioxide–chlorosulfonic acid (military designation, FS smoke) consists of 50% (weight/

weight) sulfur trioxide (SO3) and 50% (weight/

weight) chlorosulfonic acid [SO2(OH)Cl]. FS smoke

is typically dispersed by spray atomization. The

sulfur trioxide evaporates from spray particles, reacts with moisture in the air, and forms sulfur acid,

which condenses into droplets that produce a dense
Toxic Inhalational Injury

263

white cloud. The highly corrosive nature of FS

smoke in the presence of moisture resulted in the

army’s abandoning its use.

Clinical Effects of Exposure

Contact with liquid FS smoke produces a typical

mineral acid burn of exposed tissues. Exposure to

the smoke—which constitutes exposure to sulfuric

acids—produces irritation of the eyes, nose, and

exposed skin and complaints of cough, substernal

ache, and soreness. After a severe exposure to FS

smoke, a casualty demonstrates profuse salivation

and an explosive cough, which could render respirator adjustment difficult. The highly irritative nature of the substance acts as an adequate warning,

however, and prompts an immediate evacuation

from the smoke cloud.

Therapy

Severe exposures (sufficient to give rise to the

rapid onset of symptoms) may require therapeutic

intervention similar to that for chlorine exposure.

Individuals with highly reactive airways are particularly at risk. In the event of triggered bronchospasm, these patients would benefit from aggressive bronchodilator use; consideration should also

be given to the early use of steroids as well as positive-pressure ventilation.4,29,34

Titanium Tetrachloride

Titanium tetrachloride (military designation, FM

smoke) is a corrosive substance typically dispersed

by spray or explosive munitions. A dense, white

smoke results from the decomposition of FM smoke

into hydrochloric acid, titanium oxychloride, and

titanium dioxide. Because titanium tetrachloride

is extremely irritating and corrosive in both liquid

and smoke formulations, FM smoke is not commonly used.

Exposure to the liquid may create burns similar

to those of mineral acids on conjunctiva or skin.

Exposure to the dense, white smoke in sufficient

concentration may produce conjunctivitis or cough.

There are no reports of exposure-related human

deaths, nor are data available regarding pulmonary

function assessment in extensively exposed individuals. Individuals with hyperreactive airways

would be expected to develop bronchospasm with

exposure to this substance.

Aggressive bronchodilator therapy and, possibly,

steroid therapy should be considered.4

Nitrogen Oxides

The oxides of nitrogen (military designation,

NOx), particularly nitrogen dioxide, are components of photochemical smog. Their concentrations

in smog are generally thought to be low enough to

be of no significant clinical concern for the normal,

healthy individual.35

There are four forms of nitrogen oxide. The first

is nitrous oxide (N2O), which is commonly used as

an anesthetic; however, in the absence of oxygen, it

acts as an asphyxiant. The second is nitric oxide

(NO), which rapidly decomposes to nitrogen dioxide in the presence of moisture and air. Nitrogen

dioxide exists in two forms: NO2 and N2O4. At room

temperatures, nitrogen dioxide is a reddish brown

vapor consisting of approximately 70% N2O4 and

30% NO2. Injuries from this toxic inhalant are seen

most often in nonmilitary settings of silage storage.36,37

In a military or industrial setting, nitrogen dioxide occurs in the presence of electric arcs or other

high-temperature welding or burning processes,

and particularly where nitrate-based explosives are

used in enclosed environments (such as tanks and

ships). Diesel engine exhaust also contains substantial quantities of nitrogen dioxide.36–39

Clinical Effects of Exposure

At NOx concentrations of 0.5 ppm or less, individuals with preexisting airways disease show no

clinical effects postexposure. At 0.5 ppm to approximately 1.5 ppm, individuals with asthma may note

minor airway irritation. Concentrations of 1.5 ppm

may produce changes in pulmonary function measurements in normal individuals, including airway

narrowing, reduction of diffusing capacity of the

lung, and widening of the alveolar–arterial difference in the partial pressure of oxygen (PAO2 – PaO2)

gradient.

This level of toxic exposure may occur with little

initial discomfort. The soldier may ignore the resultant mild coughing or choking. Because of rapid

symptomatic accommodation to this cough, continued exposure may occur. A lethal exposure can occur within 0.5 hour, with the soldier only experiencing a minimal sense of discomfort.

The clinical response to NOx exposure is essentially triphasic. In phase 1, symptoms appear more

or less quickly, depending on the intensity of exposure. With a low dose, initial eye irritation, throat

tightness, chest tightness, cough, and mild nausea

may appear. Once the casualty is removed from the

source of exposure, these symptoms disappear
Medical Aspects of Chemical and Biological Warfare

264

spontaneously over the next 24 hours. However, at

24 to 36 hours postexposure, a particularly severe

respiratory symptom complex may appear suddenly; exertion seems to be a prominent precipitating factor. There may be severe cough, dyspnea, and

rapid onset of pulmonary edema. If the patient survives this stage, spontaneous remission occurs

within 48 to 72 hours postexposure. More intense

exposures produce a relatively rapid onset of acute

bronchiolitis with severe cough, dyspnea, and

weakness, without the above-mentioned latent period. Again, spontaneous remission occurs at approximately 3 to 4 days postexposure.40

Phase 2 is a relatively asymptomatic period lasting approximately 2 to 5 weeks. There may be a mild

residual cough with malaise and perhaps minimal

shortness of breath, and there could be a sense of

weakness that may progress. The chest radiograph,

however, typically is clear.

In phase 3, symptoms may recur 3 to 6 weeks

after the initial exposure. Severe cough, fever, chills,

dyspnea, and cyanosis may develop. Crackles are

identified on physical examination of the lung. The

polymorphonuclear white blood cell count is elevated, and the partial pressure of carbon dioxide

(PCO2) may be elevated as well.41 The chest radiograph demonstrates diffuse, scattered, fluffy nodules of various sizes, which may become confluent

progressively, with a butterfly pulmonary edema

pattern and a prominent acinar component. At this

point, pathological study demonstrates classic bronchiolitis fibrosa obliterans, which may clear spontaneously or may progress to severe, occasionally

lethal respiratory failure. The fluffy nodular

changes noted in the chest radiograph typically

show no clinical improvement. Pulmonary function

testing may show long-term persistence of airways

obstruction.37,42,43

Therapy

There is no chemically specific prophylactic or

postexposure therapy for NOx inhalational injury.

Current therapy consists of intervention directed at

specific symptoms (see the earlier discussion titled

General Therapeutic Considerations). Pneumonitis

appears to complicate the initial pulmonary edema

relatively early; nevertheless, the use of prophylactic antibiotics is not indicated.

The use of steroids early in phase 3 has been reported; and although controlled studies are not

available, these reports strongly suggest the value

of steroid therapy in modifying the bronchiolitis

obliterans that develops in the third stage.42 Despite

therapy, persistent limitation of airway function is

typically seen, as demonstrated by long-term abnormalities in pulmonary function.44

Clinical Summary

Exposure to NOx may produce a variety of delayed and severe pulmonary sequelae that are not

readily predicted from early clinical or laboratory

data. Careful, long-term observation appears to be

important. Steroid therapy may be a useful therapeutic tool.

Organofluoride Polymers: Teflon and

Perfluoroisobutylene

Teflon (polytetrafluoroethylene, manufactured

by Du Pont Polymers, Wilmington, Del.) and other

similar highly polymerized organofluoride polymers (eg, perfluoroethylpropylene) enjoy widespread use in a variety of industrial and commercial settings. Because of their desirable chemical and

physical properties (eg, lubricity, high dielectric

constant, chemical inertness), organofluoride polymers are considered important and are used extensively in military vehicles such as tanks and aircraft.

The occurrence of closed-space fires in such settings

has led to toxicity studies of the resultant by-products created from incinerated organofluorines. Inhalation of a mixture of pyrolysis by-products of

these substances produces a constellation of symptoms termed polymer fume fever.

A primary high-temperature pyrolysis by-product of these substances is perfluoroisobutylene

(PFIB). Inhalation of this material may produce a

“permeability” or “noncardiac” type of toxic pulmonary edema very much like that produced by

phosgene.

General Description of Polymer Fume Fever

Teflon pyrolysis occurring at temperatures of

approximately 450°C produces a mixture of particulate and gaseous by-products; in 1951, Harris45 was

the first to describe polymer fume fever, the clinical syndrome that resulted from inhaling this mixture. Within 1 to 2 hours postexposure, a syndrome

known as polymer fume fever appears. Often mistaken for influenza, polymer fume fever causes malaise, chills, fever to 104°F (40°C), sore throat, sweating, and chest tightness. Once the patient is removed

from the site of exposure, the symptoms spontaneously and gradually disappear over 24 to 48 hours

without any specific treatment. The patient typically
Toxic Inhalational Injury

265

has no long-term complaints or sequelae.46 Much

of this symptomatology may be due to a milliporefiltrable particulate. Animal studies have shown an

alleviation of symptoms with filtration of the pyrolyzed materials47 and restoration of symptoms with

parenteral injection of the filtered material.48

Polymer fume fever may be induced by smoking Teflon-contaminated cigarettes (the burning tip

temperature reaches 884°C46). Smoking contaminated cigarettes can also induce the signs and symptoms of pulmonary edema. Onset of pulmonary

edema is typically rapid (2–4 h), mild in degree

(rarely requiring oxygen supplementation as part of

treatment, and rapidly remits (clears within 48 h).49

As Teflon is pyrolyzed at a higher temperatures,

more variety and higher concentrations of organofluoride by-products are noted.50 Among these, PFIB

is found to be the most toxic (Exhibit 9-2), with an

LCt50 (ie, the vapor or aerosol exposure [concentration • time] that is lethal to 50% of the exposed

population) of 1,500 mg•min/m3 (in comparison,

the LCt50 of phosgene is 3,000 mg•min/m3).51

Clinical Effects of Exposure to Perfluoroisobutylene

Inhalation of PFIB is followed by a very rapid

toxic effect on the pulmonary tissues (see the section below titled Clinical Pathology), with microscopic changes of perivascular edema evident

within 5 minutes.52 Exposure to a very high concentration of this colorless, odorless gas may produce early conjunctivitis53; in animal studies, it has

produced sudden death (“lightning death” reported

by Karpov, which occurred within 1 min).54 No such

sudden human deaths have been reported.

Less-intense exposures to PFIB are followed by

a clinically asymptomatic period (clinical latent

period) of a variable duration. During this period,

normal biological compensatory mechanisms control the developing pulmonary edema until those

compensatory mechanisms are overwhelmed. The

length of this interval depends on the intensity and

duration of exposure and on the presence or absence

of postexposure exercise. Recent animal studies of

PFIB inhalation strongly support World War I anecdotal human observations (with phosgene) that

the resulting toxic pulmonary edema appears earlier and with more intensity when the casualty is

required to exercise postexposure. It may be that

increased pulmonary blood flow increases the permeability of the already damaged alveolar-capillary

membrane.55

The clinical latent period for PFIB injury is 1 to 4

hours (compared with 1–24 h for phosgene). Subsequent symptoms of pulmonary edema progressively appear: initially, dyspnea on exertion; then

orthopnea; and later dyspnea at rest. Radiological

signs and clinical findings of pulmonary edema

progress for up to 12 hours, then gradually clear

with complete recovery by 72 hours. Typically, there

are no long-term sequelae49,56–59; however, two

deaths have been reported.53,60 The death reported

by Auclair et al53 occurred after very severe pulmonary edema (requiring intubation), hypotension,

and ultimately, Gram-negative superinfection.

Four reports on the long-term effects of PFIB exposure are available. Brubaker56 reported a decrement in DLCO 2 months after a single exposure.

Capodaglio et al61 reported that 3 of 4 exposed individuals showed pulmonary function test (PFT)

abnormalities 6 weeks to 6 months postexposure.

Paulet and Bernard62 reported four workers with

abnormal PFTs and DLCOs during the 4 months following exposure. Williams et al63 reported an individual with pulmonary interstitial fibrosis after

multiple episodes of polymer fume fever.

Clinical Pathology of PFIB Inhalation

PFIB primarily affects the pulmonary system.

Although animal studies occasionally report disseminated intravascular coagulation and other organ involvement, these effects only occur with subEXHIBIT 9-2

PROPERTIES OF

PERFLUOROISOBUTYLENE (PFIB)

Chemical formula: (CF3)2C=CF2

Molecular weight: 200

Boiling point at 1 atm: 7.0°C

Gas density (dry air,

at 15°C and 760

mm Hg = 1.22 g/L): 8.2 g/L

Colorless

Odorless

Very slightly soluble

Data source: Smith W, Gardner RJ, Kennedy GL. Shortterm inhalation toxicity of perfluoroisobutylene. Drug

and Chemical Toxicology. 1982;5:295–303.
Medical Aspects of Chemical and Biological Warfare

266

stantial pulmonary injury, suggesting that systemic

hypoxia is a major factor.64 No human studies report organ involvement other than the respiratory

system.

Pathological data on acute human exposure to

PFIB are not available; however, pathological data

on animals show both histological and ultramicroscopic changes occurring within 5 minutes of exposure.52 Interstitial edema with alveolar fibrin

deposition progresses rapidly over the next 24

hours, then gradually subsides until the patient is

fully recovered. At 72 hours, a type II pneumocyte

hyperplasia is seen (interpreted as consistent with

known reparative processes). Although some longterm animal pathological changes have been reported,54 most animal studies do not identify such

long-term changes.

Human long-term pathological data are available

in only one reported case: a 50-year-old female

experienced approximately 40 episodes of polymer

fume fever—typically occurring from smoking

contaminated cigarettes. Eighteen months after her

last episode, progressive exercise dyspnea was

noted. A cardiopulmonary physical examination,

chest radiograph, and ABG were all normal. Pulmonary function testing supported a provisional

diagnosis of alveolar capillary block syndrome (decreased DLCO, increased exercise PAO2 – PaO2 gradient, and minimal airway disease). Death occurred

from an unrelated cause. The autopsy provided

histological evidence of moderate interstitial fibrosis with minimal chronic inflammatory cell infiltrate.63 Only two human deaths from pyrolysis

products of polymerized organofluorides have been

reported.53,60

Therapy

There is no recognized prophylactic therapy for

human PFIB exposure. Animal studies suggest that

increasing pulmonary concentrations of oxygen

free-radical scavengers containing thiol groups may

be of value; N-acetyl cysteine has been found effective.65,66 No postexposure medical or chemical

therapy that effectively impedes or reverses the effects of this toxic inhalational injury is known.

Specific therapy for the observed “noncardiac”

pulmonary edema symptoms has been derived from

clinical experience with ARDS. Pulmonary edema

responds clinically to application of positive airway

pressure. PEEP/CPAP (continuous positive airway

pressure) masks are of initial value. Intubation may

be required.

Oxygen supplementation is provided for evident

hypoxia or cyanosis. Expeditious fluid replacement

is mandatory when hypotension is present. Combined systemic hypotension and hypoxia may damage other organ systems. Bacterial superinfection

is sufficiently common to warrant careful surveillance cultures. There is no literature support, however, for use of routine prophylactic antibiotics.

Steroid therapy for PFIB exposure has been reported in only two instances—both for the same

worker.49 The fact that recovery may be spontaneous and rapid makes it difficult to decide whether

steroid use improves recovery.

Laboratory studies clearly support the observation that rest subsequent to exposure is useful. Because the intensity of injury and the duration of the

clinically latent period are both affected by exercise, bed rest and litter transport are preferred.

SUMMARY

During World War I, the number and types of

pulmonary toxicants available to the military increased substantially. At least 14 different respiratory agents were used, as well as obscurants

(smokes), harassing agents (chloracetone), and vesicants (mustard) that could cause pulmonary injury.

Today, only a handful of these toxicants still exist

in stockpiles around the world, but several, such

as chlorine and phosgene, are currently produced

in large quantities for industrial purposes. Whether

produced for military or industrial uses, these

chemical agents pose a very real threat to military

personnel.

Toxic inhalational injury poses a 2-fold problem

for military personnel:

1. No specific therapy exists for impeding or

reversing toxic inhalant exposures.

2. Toxic inhalational injury can cause large

numbers of casualties that can significantly

burden medical facilities.

The pathophysiological processes that develop

in the upper and lower respiratory tract can greatly

incapacitate a casualty or result in death within minutes of exposure. It is therefore imperative that adequate control of the casualty’s airways be maintained. Medical personnel should look for hypoxia,

hypercarbia, and pulmonary edema, all of which

are signs of possible toxic inhalant exposure. Infectious bronchitis or pneumonitis (particularly in in-
Toxic Inhalational Injury

267

tubated patients) is a frequent complication. The

importance of chronic health problems that occur

postexposure to toxic inhalants is a contentious subject because of the nebulous signs and symptoms

that mimic degenerative diseases, such as emphysema, common to the general population.

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60. Makulova ID. Clinical picture of acute poisoning with perflurosebutylene. Gig Tr Prof Zabol. 1965;9:20–23.

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Cyanide Poisoning

271

Chapter 10

CYANIDE POISONING

STEVEN I. BASKIN, PHARM.D., PH.D., FCP, FACC, DABT, FATS*; AND THOMAS G. BREWER, M.D., FACP†

INTRODUCTION

HISTORY AND USE

Military Uses

Nonmilitary Uses

BIOCHEMICAL BASIS FOR POISONING

Cyanide Pharmacokinetics and Pharmacodynamics

Toxicity

CLINICAL PRESENTATION AND MANAGEMENT OF CASUALTIES

Laboratory Findings

Principles of Therapy

SPECIFIC ANTIDOTES

Drugs Used in the United States

Other Therapeutic Drugs

Investigational Drugs

SUMMARY

*Pharmacology Division, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425

†Colonel, Medical Corps, U.S. Army; formerly, Experimental Therapeutics Division, Walter Reed Army Institute of Research, Washington,

D.C. 20307-5100; currently, Commander, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, APO Area

Pacific 96546, 315/6 Rajvithi Road, Bangkok 10400, Thailand
Medical Aspects of Chemical and Biological Warfare

272

TABLE 10-1

CHEMICAL, PHYSICAL, ENVIRONMENTAL, AND BIOLOGICAL PROPERTIES OF CYANIDES

Properties Hydrogen Cyanide (AC) Cyanogen Chloride (CK)

Chemical and Physical

Boiling Point 25.7°C 12.9°C

Vapor Pressure 740 mm Hg 1,000 mg Hg

Density:

Vapor 0.99 at 20°C 2.1

Liquid 0.68 g/mL at 25°C 1.18 g/mL at 20°C

Solid Crystal: 0.93 g/mL at –40°C

Volatility 1.1 x 106 mg/m3 at 25°C 2.6 x 106 mg/m3 at 12.9°C

Appearance and Odor Gas: Odor of bitter almonds or Colorless gas or liquid

peach kernels

Solubility:

In Water Complete at 25°C 6.9 g/100 mL at 20°C

In Other Solvents Completely miscible in almost all Most organic solvents (mixtures

organic solvents are unstable)

Environmental and Biological

Detection ICAD; M254A1 kit M256A1 kit

Persistency:

In Soil < 1 h Nonpersistent

On Materiel Low Nonpersistent

Skin Decontamination Water; soap and water Water; soap and water

Biologically Effective Amount:

Vapor (mg•min/m3) LCt50: 2,500–5,000 (time-dependent) LCt50: 11,000

Liquid (mg/kg) LD50 (skin): 100 —

ICAD: individual chemical agent detector

LCt50: the vapor or aerosol exposure [concentration • time] that is lethal to 50% of the exposed population

LD50: the dose that is lethal to 50% of the exposed population

INTRODUCTION

Cyanide, long considered a toxic, deadly substance, has been used as a poison for thousands

of years. It was not highly successful as a chemical warfare agent in World War I, possibly because

of the way it was delivered. The effects of a high

dose of cyanide are quick, and death occurs within

minutes. Antidotes are effective if administered in

time.

Cyanide is ubiquitous. It is present in some foods,

in the products of combustion of synthetic materials, and is widely used in industry. Much of

the cyanide used is in the form of salts, such as sodium, potassium, or calcium cyanide. The cyanides

of military interest are the volatile liquids hydrocyanic acid (hydrogen cyanide, HCN; North American Treaty Organization [NATO] designation: AC)

and cyanogen chloride (NATO designation: CK)

(Table 10-1).
Cyanide Poisoning

273

HISTORY AND USE OF CYANIDE

Although substances containing cyanide had

been used for centuries as poisons, it was not until

1782 that cyanide itself was identified. It was first

isolated by the Swedish chemist Scheele, who later

may have died from cyanide poisoning in a laboratory accident.

Military Uses

Since the days of ancient Rome, cyanide and the

derivatives of this highly toxic substance have been

used as weapons.1

 Nero used cherry laurel water,

which contains cyanide as its chief toxic component,

to poison members of his family and others who

displeased him. Napoleon III proposed the use of

cyanides to enhance the effectiveness of his soldiers’

bayonets during the Franco–Prussian War.

During World War I, in late 1915 and early 1916,

the French were the only proponents for using cyanide and its derivative, hydrocyanic acid. This was

made by distilling a concentrated solution of potassium cyanide with dilute sulfuric acid. Its use,

however, proved to produce less than its desired

effect. A highly volatile gas and lighter than air,

hydrocyanic acid persisted for only a few minutes

in the open air; this made it difficult to disperse a

lethal concentration (also, the munitions used had

a small payload). The effects of cyanide were not

cumulative. In addition, the Germans, on learning of

its use, equipped their troops with a mask that was

capable of filtering out the gas. These combined factors made hydrocyanic acid less effective as a weapon.

About September 1916, the French tried another

cyanide-based poison, cyanogen chloride, which is

heavier and less volatile than hydrocyanic acid and

which had a cumulative effect on its victims. Cyanogen chloride was produced by chlorinating a

saturated solution of potassium cyanide at 0°C

(32°F). Its toxicity was similar to that of hydrocyanic acid, but cyanogen chloride was more effective

at low concentrations (it irritated the eyes and

lungs). Cyanogen chloride also had a delayed toxic

effect similar to such lung irritants as chlorine and

phosgene. At high concentrations, cyanogen chloride is capable of killing by rapidly paralyzing the

respiratory system’s nerve center.2

At about the same time that the French launched

cyanogen chloride, the Austrians introduced their

own poisonous gas, which was derived from potassium cyanide and bromine. The resulting cyanogen bromide was highly volatile, yet it had only a

quarter of the volatility of hydrocyanic acid and was

less toxic. Cyanogen bromide had a strong irritating effect on the conjunctiva and on the mucous

membranes of the respiratory system; however,

because it corroded metals and was unstable in storage (gradually polymerizing into a toxicologically

inert substance), the Austrians abandoned its use.2

During World War II, the Nazis employed hydrocyanic acid adsorbed onto a dispersible pharmaceutical base (Zyklon B) to exterminate millions

of civilians and enemy soldiers in the death

camps.3,4 Zyklon B was a fumigant and rodenticide.

One of its uses in the United States and other countries was to rid ships of rodents.

In the late 1980s, reports indicated that cyanidelike agents may have been used against the inhabitants of the Syrian city of Hama5

 and the inhabitants of the Kurdish city of Halabja, Iraq,6 and possibly in Shahabad, Iran, during the Iran–Iraq War.7

Based on this recent history, acute cyanide poisoning

continues to constitute a threat for U.S. soldiers in

future conventional or nonconventional conflicts.

Nonmilitary Uses

There has been little use of cyanide by the military; most of the information on cyanide poisoning

has been from civilian experience in poisoning, fires,

and industrial accidents. Most people probably contact cyanide in some form almost every day. Hundreds of thousands of tons of cyanide are manufactured annually in this country. Cyanide is used in

many chemical syntheses, electroplating, plastics

processing, gold and silver extraction, tanning,

metallurgy, and as a fumigant. Cyanides are in some

foods; are pyrolysis products of many substances;

and have gained notoriety for their use in executions, homicides, and suicides.

Cyanide poisoning has been reported8

 from eating chokecherries, bitter almonds, and apricot pits.

In addition, cyanide is found in lima beans and cassava beans and roots. Cassava is a staple in certain

countries and is blamed for the high incidence of

tropical ataxic neuropathy in those areas.

Combustion of synthetic products that contain

carbon and nitrogen, such as plastics and synthetic

fibers, releases cyanide. Cigarette smoke contains

cyanide; the nonsmoker averages 0.06 μg/mL of

cyanide in blood, whereas the smoker has 0.17 μg/

mL.9

 The effects of cyanide and of carbon monoxide, also formed in fires, are additive because they
Medical Aspects of Chemical and Biological Warfare

274

TABLE 10-2

BLOOD CYANIDE LEVELS IN VICTIMS OF

SMOKE INHALATION

Total Subjects Blood Cyanide Levels

(Mean ± SD)

Fire Victims* (N = 109)

Survivors (n = 66) 21.6 ± 36.4 μmol/L (P < .001)

Fatalities (n = 43) 116.4 ± 89.6 μmol/L (P < .001)

Controls (N = 114) 5.0 ± 5.5 μmol/L

*Of the 66 fire victims who survived, 9 had blood cyanide levels above 40 μmol/L and 3 had levels above 100 μmol/L. Of the

43 fire victims who died, 32 had blood cyanide levels above 40

μmol/L and 20 had levels above 100 μmol/L.

Data source: Baud FJ, Barriot P, Toffis V, et al. Elevated blood

cyanide concentrations in victims of smoke inhalation. N Engl J

Med. 1991;325(25):Fig 1:1763.

both contribute to tissue hypoxia by different

mechanisms. The two gases are major causes of

combustion-related fatalities.10 In residential fires,

cyanide poisoning may be more significant than has

previously been appreciated. The short half-life of

cyanide in blood contributes to the low concentrations of cyanide found in fire victims when blood

is drawn after the victims reach the hospital.

From April 1988 through April 1989, a team of

French investigators11 collected samples—on the

scene—from 109 victims of residential fires in and

around Paris, France. The data they gathered were

compared with data from a control group (N = 114) of

individuals whose injuries were not caused by fire.

Blood cyanide concentrations were much higher

in the fire victims than in the control group (Table

10-2), and victims who died had significantly higher

levels (> 5-fold) than victims who survived.

Contrary to what previous researchers have concluded, the results from this study “suggest that

cyanide poisoning may prevail over carbon monoxide poisoning as the cause of death in some fire

victims.”11(p1765) Therefore, military medical officers

need to be aware that victims of smoke inhalation

from fires may be suffering the effects of cyanide

poisoning, and might benefit from early antidotal

cyanide therapy.

In addition, cyanide is used by governments, terrorists, corporations, and individuals to achieve

various economic, beneficial, humanitarian, or

harmful ends:

• Cyanide is the agent used in “gas chambers,” in which a cyanide salt is dropped

into an acid to produce HCN. (These chemicals—an acid and a cyanide salt—were

found in several subway restrooms in Tokyo, Japan, in the weeks following the release of nerve agents in Tokyo in March

1995.)12

• It was illicitly placed in bottles of Tylenol

(acetaminophen, manufactured by McNeill

Consumer Products Co., Fort Washington,

Pa.) in the Chicago area in 1982, killing

seven people.13

• In 1978 near Port Kaituma, Guyana, the followers of the Reverend Jim Jones drank a

grape-flavored drink laced with cyanide,

and more than 900 children and adult members of the People’s Temple committed

mass suicide.14

• Furthermore, cyanide is a metabolic product of ingested Laetrile (an alleged cancer

chemotherapeutic compound not available

in this country) and may have been responsible for the deaths of some patients who

took this substance.

Chronic ingestion of cyanide in the form of organic cyanogens is a public health problem in areas

such as East Africa and Southeast Asia. Several common plants contain cyanogenic glycosides15,16; ingestion coupled with improper processing of such

cyanogenic glycosides can result in death. Consumption of foodstuffs such as cassava result in

tropical neuropathies in Africa17 and in other diseases, such as tropical thyroid disease and tobacco

amblyopia.

BIOCHEMICAL BASIS FOR POISONING

Although cyanide is known to bind and inactivate several enzymes, it is thought to exert its ultimate lethal effect of histotoxic anoxia by binding to

the active site of cytochrome oxidase (Figure 10-1),

thereby stopping aerobic cell metabolism18,19 after

an initial effect on excitable tissue. The binding to

the cytochrome oxidase can occur over minutes. A

more rapid effect appears to occur on neuronal

transmission. No antagonists are known for the latter

reaction, although it appears to be feasible to develop competitive antagonists for cyanide at a cytochrome oxidase–binding site.20
Cyanide Poisoning

275

Fig. 10-1. The possible detoxification reactions for cyanide are shown for this hypothetical cell.

Cyanide can be removed by several processes before it can enter the cell. Perhaps of greatest importance is the

formation of cyanomethemoglobin (CNMetHb), which is produced when the cyanide ion (CN–) reacts with MetHb.

Methemoglobin is formed when hemoglobin (Hb) reacts with a variety of oxidants (eg, nitrite, dimethylaminopheno

[DMAP], and p–aminopropiophenone [PAPP]). Cyanide may complex with endothelial-derived relaxing factor (EDRF,

which is thought to be nitric oxide). Cyanide can interfere with the action of carbonic anhydrase and lower pH,

thereby decreasing the concentration of CN– in the extracellular space. Heavy metals (eg, gold, molybdenum, or

cobalt salts) or organic compounds (eg, hydroxocobalamin) may scavenge CN–, effectively removing it from the

milieu of the cell. Finally, albumin can exhibit enzymelike behavior and use bound elemental sulfur1

 to detoxify

cyanide. It is also theoretically possible to prevent entrance of cyanide ions into the cell by blocking transport mechanisms with substances such as DIDS.

At lease four intracellular enzymes may be involved for cyanide detoxification. The generalized reactions of

rhodanese, mercaptopyruvate sulfurtransferase, thiosulfate reductase, and cystathionase are shown within the cell.

Several broad classes of reactions may serve to ameliorate cyanide toxicity. They include but are not limited to the

following. Metabolic respiratory stimulants may cross into the cell and stimulate adenosine triphosphate (ATP) production through a scavenger-ATP pathway (ie, ribose) or substrate augmentation (ie, creatinol-o-phosphate) or a free

radical mechanism (ie, centrophenoxine). Hyperbaric oxygen or perhaps oxygen itself can reduce cyanide toxicity by

competing with cyanide at some site (such as cytochrome oxidase in the mitochondria, which is thought to be a

primary site for cyanide poisoning). Substances that act as hyperpolarizing agents or that antagonize depolarizing

amino acids at ion channel receptors may ameliorate the convulsions from cyanide. Other possible reactions are

formation of cyanohydrin with α-keto acids, competitive blockade by other nitriles, and reaction with other sites

such as myoglobin, cytochrome b5, or other electron transport system (ETS) compounds (eg, dinitropheno [DNP]).

(1) Source for this statement: Lieske CN, Clark CR, Zoeffel LD, et al. Temperature effects in cyanolysis using elemental sulfur. J Appl Toxicol. 1996;16:171–175.

DIDS: 4,4'-diisothiocyano-2,2'-disulfonic stilbene

2

Enzyme

Detoxification

Systems:

1

3

4

5

Rhodanese

Mercaptopyruvate

Sulfurtransferase

Thiosulfate

Reductase

Cystathionase

Albumin (enzymelike behavior in cyanide detoxification)

1

2

3

4

5

ATP

SCN

Rhodanese CNO

Cyanate

RS

ADP

Other Protein Receptors:

• Myoglobin

• Cytochromes (b5?)

e'

Uncoupler

(DNP)

CN–

CN–

CN– + HS — CH2 — CCOO

CN– + Cystine

CN– + –S — S — R

Metabolic Respiratory Stimulants:

• Ribose

• Creatinol-o-Phosphate

• Centrophenoxine (?)

Sulfane Sulfur Donor

(thiosulfate)

(cysteine persulfide)

R — S — S

CN– + Cystine

2-Aminothiazolidine

4-Carboxylic Acid

O2

O2?, Hyperbaric O2

Cobalt, Gold,

Molybdenum,

Porphyrins (eg, 

 methemoglobin, 

 hydroxycobalamine)

X: pH Control

Anion Transport Blockade (eg, DIDS)

Albumin HCN

HCN

CN– + H+ Scavenger XCN

K1

K2

K3

K4

Carbonic

(EDRF) Anhydrase

?

M+ (NO) CN5

Oxidant: Complex

Nitrile

Cytochrome Oxidase

 (a primary toxic site)

O

R — C — COOH + CN–

SCN– + Acetate

O

α−Keto acid

Cysteine + SCN–

RS + R — SCN

OH

R — CH — CN

Cyanohydrin

Hyperpolarizing

Amino Acids

Antagonists of

Depolarizing Amino Acids 

(can exist both inside and 

outside the membrane)

Hb

MetHb + CN–

NO2

DMAP

PAPP

CNMetHb

Mitochondria

Receptor

X
Medical Aspects of Chemical and Biological Warfare

276

Cyanide is readily diffusible through epithelium.

This property contributes to its lethal toxicity after

inhalation of hydrogen cyanide (HCN) gas (the usual

route of military exposure), ingestion of cyanide salts

or cyanogens, or percutaneous absorption of cyanide

from high-concentration solutions. Because cyanides

are present at low concentrations in several naturally

occurring environmental sources, it is not surprising

that most animals have intrinsic biochemical pathways for detoxification of the cyanide ion.

The most important route of cyanide excretion

is by formation of thiocyanate (SCN–), which is subsequently excreted in the urine.17 Thiocyanate possesses a less inherent toxicological hazard than cyanide, cyanate, or isocyanate. Thiocyanate formation

is catalyzed directly by the enzyme rhodanese

(EC 2.8.1.1) and indirectly via a spontaneous reaction between cyanide and the persulfide sulfur

products of the enzymes 3-mercaptopyruvate

sulfurtransferase (EC 2.8.1.2)21 and thiosulfate reductase (EC number unassigned) (see Figure 10-1).

The mechanisms of all three enzymes22 as well as

the pharmacokinetics of thiocyanate formation23

have been studied. Although 3-mercaptopyruvate

functions to convert cyanide to this cyanate, its instability and sulf-auto-oxidation at a basic pH may

mask this effect.24 The enzymatic routes are efficient

but have an insufficient capacity for detoxification

in acute poisoning because of lack of sulfur donors.

The mitochondrial sulfurtransferase reactions are

exploited by the administration of sodium thiosulfate (used in therapy and discussed later in this

chapter) in the treatment of acute poisonings. It is

still not known with any certainty, however, what

specific endogenous sulfur sources participate in

the formation of thiocyanate from cyanide.25

A minor route of metabolism is the oxidation of

cyanide to cyanate (CNO–), which occurs via enzymatic and nonenzymatic pathways. The interaction

of cystine and cyanide to form 2-amino thiazoline

4-carboxylic acid and its tautomer accounts for approximately 20% of cyanide metabolism. This increases with toxic doses of cyanide. However, the

protection conferred by forming cyanate derivatives

is limited because of the cell’s inability to utilize

oxygen during cyanide intoxication.

Combined, these metabolic routes detoxify 0.017

mg of cyanide per kilogram of body weight per

minute in the average human. Cyanide is one of the

few chemical agents that does not follow Haber’s

law, which states that the Ct (the product of concentration and time) necessary to cause a given biological effect is constant over a range of concentrations and times. For this reason, the LCt50 (the vapor

or aerosol exposure that is lethal to 50% of the exposed population) for a short exposure to a high

concentration is different from a long exposure to a

low concentration.

Cyanide Pharmacokinetics and Pharmacodynamics

Cyanide appears to display first-order kinetics

during the period of initial toxicity.23 The volume

of distribution for cyanide appears to change as the

blood levels of the chemical change,26 but these alterations probably reflect the marked intracellular

sequestration of the molecule. Animal studies27,28

show a differential disposition of inhaled HCN,

with the highest tissue levels found in the lung,

heart, and brain. These data seem to corroborate the

evidence from other animal studies and from clinical reports that emphasize the importance of these

organs in cyanide toxicity. Ingestion of cyanide results in much higher levels in the liver than does

inhalation; this is a useful differential point in forensic investigations. Cyanide also has wide-ranging

cardiovascular effects, including a poorly understood increase in vascular resistance in the early

phases of poisoning29 and a marked increase in cerebral blood flow in dogs.30

Data from rodent studies suggest that a single,

acute administration of a cyanide salt leads either

to death or to complete recovery. However, data

from HCN inhalational studies in dogs, rabbits,

monkeys, and humans suggests that death may be

delayed for up to 8 days.31,32 The neurological sequelae of cyanide intoxication may be delayed for

up to a year.1 These delayed changes in regional

sensitivities of the brain are thought to be due to

hypoxic stress and are analogous to those seen following sublethal carbon monoxide poisoning.

Toxicity

Although they are generally considered to

be very toxic substances, when compared with

other lethal chemical warfare agents, cyanides are

among the least toxic. The LCt50 for hydrogen cyanide (hydrocyanic acid) is generally stated to be

2,500–5,000 mg•min/m3; for cyanogen chloride,

about 11,000 mg•min/m3. (Comparable values for

the nerve agents are 10–200 mg•min/m3; for sulfur mustard, 1,500 mg•min/m3; and for phosgene,

3,000 mg•min/m3.)

The estimated intravenous dose that is lethal to

50% of the exposed population (LD50) of hydrogen

cyanide for man is 1.0 mg/kg, and the estimated

LD50 for liquid on the skin is about 100 mg/kg.
Cyanide Poisoning

277

CLINICAL PRESENTATION AND MANAGEMENT

The effects from cyanide poisoning are those of

progressive histotoxic tissue hypoxia (Figure 10-2).

The symptoms, signs, and physical findings are directly related to the dose of cyanide, the route of

exposure, and the type of cyanide compound. In

addition to the effects described below, cyanogen

chloride also produces irritation of the eyes and

mucous membranes similar to that produced by riot

control agents.

On a military battlefield, casualties will be from

exposure to cyanide gas; this can be fatal within

minutes after exposure to high concentrations. An

initial hyperpnea (15 sec after exposure), due to the

effect of cyanide on the chemoreceptor bodies, is

Fig. 10-2. Cyanide can affect many functions in the body, including the vascular, visual, pulmonary, central nervous,

cardiac, autonomic, endocrine, and metabolic systems. The toxicodynamic effects can vary depending on the dose,

route and speed of administration, chemical form of the cyanide, and other factors including the gender, age, weight,

stress level, and general physical condition of the recipient. Proceeding clockwise from the top of the diagram: Vascular effects for cyanide can include an initial transient increase, followed by a decrease, in cardiac output. Blood

pressure falls as the cardiac inotropic effect decreases and as vasodilation occurs. Visual effects can include a decrease in the capacity to focus, with late-onset mydriasis secondary to hypoxia. One of the first pulmonary effects

from cyanide is a respiratory gasp, which is caused by stimulation of chemoreceptor bodies near the aortic bifurcation. Hyperventilation follows this response. Over time (the response is dose-dependent, but seconds to minutes),

the frequency and depth of breathing diminish. Central nervous system effects initially manifest as decreased awareness and increased release of enkephalins followed by loss of consciousness and convulsions. Cardiac effects after

cyanide exposure are an increase in heart rate, then a decrease; both are accompanied by arrhythmias and negative

inotropy. Cyanide produces a number of autonomic nervous system effects, based on the route and dose of the agent.

Cyanide can also produce multiple endocrine effects including epinephrine and histamine release, and metabolic

actions that decrease energy production by the inhibition of the use of cytochrome oxidase.

PCr: phosphocreatine

ATP: adenosine triphosphate

C.O.: cardiac output

Metabolic

Visual

Endocrine

Pulmonary

Autonomic CNS

Cardiac

Cyanide

Respiratory Gasp

Frequency and Depth

Time

Frequency and Depth

Vascular

Histamine Release

Epinephrine Release

Spleen Contraction

Emesis

Defecation?

Urination?

Salivation?

Acidosis

PCr

ATP

Shunting Blood 

 to Brain and Heart

Vasodilation

BP BP

C.O.

Focus

Late Mydriasis

Awareness

Consciousness

Convulsions

SA Node

Arrythmias

Force of Contraction
Medical Aspects of Chemical and Biological Warfare

278

TABLE 10-3

BLOOD CONCENTRATIONS OF CYANIDE

AND ASSOCIATED CLINICAL EFFECTS

Cyanide

Concentration (μg/mL) Signs and Symptoms

0.2–0.5 None

0.5–1.0 Flushing, tachycardia

1.0–2.5 Obtunded

2.5–3.0 Coma

> 3.0 Death

Reprinted from Rumack BH. Cyanide poisoning. In: Newball

HH, ed. Respiratory care of chemical casualties. In: Proceedings

of the Symposium on Respiratory Care of Chemical Casualties. Fort

Detrick, Frederick, Md: US Army Medical Research and Development Command; 28–30 November 1983: 186.

closely followed by a loss of consciousness (30 sec

after exposure). This progresses to apnea (3–5 min

after exposure), cessation of cardiac activity (5–8

min after exposure), and death.

After exposure to lower concentrations, or exposure to lethal amounts via the oral or percutaneous

routes, the effects are slower to develop. For example, after ingestion of a lethal dose of a cyanide

salt, the casualty might have 15 to 30 minutes of

survival time during which an antidote could be

administered.

Prominent early signs and symptoms of cyanide

poisoning include a transient hyperpnea, headache,

dyspnea, and findings of general central nervous

system (CNS) excitement, including anxiety, personality changes, and agitation progressing to

seizures.33 Diaphoresis, flushing, weakness, and

vertigo may also be present. Late-appearing indications of CNS depression, such as coma and dilated, unresponsive pupils, are prominent signs of

cyanide intoxication.33–35 These signs are not specific for cyanide poisoning, which makes the distinction from other types of poisoning very difficult without a history of exposure. The telltale odor

of bitter almonds cannot be used as a guide because

40% to 60% of the population is unable to detect

the odor.36

Because the toxic effect of cyanide is to block tissue uptake and utilization of oxygen, the casualty

is transiently flushed and may have other, related

signs of poor tissue oxygen extraction. For example,

funduscopic examination shows an equally bright

red color for retinal arteries and veins because of

poor oxygen extraction. Increased oxygenation of

venous blood is also responsible for a “cherry-red”

skin color, but this sign may not always be present.

Laboratory Findings

Relevant laboratory findings include an early decreased arteriovenous difference in the partial pressure of oxygen (PO2) with progressive lactic acidosis.

Timely measurements of blood and urine concentrations for suspected intoxicants are useful in guiding clinical therapy, especially when there is toxicity

associated with the treatment agents. Unfortunately,

analysis of cyanide in biological fluids is a difficult

task for a variety of reasons.37 Also, measurements

of blood cyanide concentrations are almost never

available during the treatment phase. Blood concentrations of cyanide and associated clinical effects

are shown in Table 10-3.

Documentation of blood cyanide levels is useful

in confirming the clinical diagnosis and in subsequent follow-up investigations. The red blood cells

contain most of the cyanide in the blood, so an assay of whole blood is necessary. Furthermore, cyanide levels tend to fall in stored samples because of

the compound’s short half-life, and this process can

only partially be limited by optimal storage conditions. Therefore, the time of sampling and the conditions of storage are very important factors to consider and record.

Cyanide concentrations in tissue, such as liver,

lung, spleen, and heart, may be more accurate indicators of the blood cyanide intoxication levels.

Estimates of tissue levels are necessary adjunctive

studies in forensic cases.38 For details on collecting

and analyzing blood and tissue for cyanide, see

Assay Techniques for Detection of Exposure to Sulfur

Mustard, Cholinesterase Inhibitors, Sarin, Soman, GF,

and Cyanide, Technical Bulletin Medical 296.39

Principles of Therapy

An understanding of the toxicology and pathophysiology of cyanide poisoning leads directly

to the principles of therapy: eliminate further exposure, and institute supportive and specific antidotal therapy. (The specific antidotes are discussed

separately in the section that follows.) In addition

to the difficulties of diagnosing cyanide poisoning,

each of the specific antidotal therapies discussed

in this chapter has its own inherent toxicity. This

knowledge should temper their use in the typical

field medical treatment facility and other emergency setting.
Cyanide Poisoning

279

Elimination of Further Exposure

The first principle of therapy is the obvious one:

eliminate any potential source of continuing cyanide poisoning:

• Remove the patient from an environment

containing cyanide.

• Remove all contaminated clothing; rinse

skin with soap and water or water alone if

there is liquid on the skin.

• Gavage and administer activated charcoal

if cyanide was ingested.

Following these steps can significantly decrease the

amount of poison that has to be eliminated from

the body.40

Supportive Therapy

Possibly the most important elements of therapy

are general supportive actions, which, by themselves, can effect the recovery of most casualties

without further risk from specific antidotal

therapy.41 They are probably the only indicated therapies for casualties of cyanide poisoning who arrive

conscious at the emergency medical treatment station.

As early as 1840, Blake42 found that the lethal effects of cyanide are neutralized by mechanical resuscitation. The use of hyperbaric oxygen in cyanide intoxication is still controversial. Supplemental oxygen with or without assisted ventilation

clearly augments the effect of specific antidotes in

animal studies; however, despite encouraging reports,43,44 there is inconclusive evidence of further

benefit from the use of hyperbaric oxygen.

Lactic acidosis resulting from anaerobic metabolism should be treated by intravenous administration of sodium bicarbonate, and seizures should be

controlled by the administration of anticonvulsants

such as diazepam.45 Because correction of deficiencies

in tissue perfusion and oxygenation is the ultimate

goal of supportive therapy and is also important for

the success of specific antidotal therapy, it is critically

important to maintain an effective cardiac rhythm; this

can be accomplished with cardiopulmonary resuscitation, if necessary, in the early stages of treatment.

Specific Antidotal Therapy

Casualties with advanced toxicity from a large

amount of cyanide may require specific antidotal

therapy in addition to the vigorous supportive

therapy outlined above. The recommended agents or

components of specific antidotal therapies for cyanide

TABLE 10-4

CYANIDE ANTIDOTAL COMPOUNDS IN USE

Antidote

(Route of Administration) Country

Sodium nitrite and United States,1 Yugoslavia2

sodium thiosulfate (IV)

4-Dimethylaminophenol

(IV or IM) and sodium Germany3,4

 thiosulfate (IV)

Dicobalt edetate (IV) United States,5 Netherlands6

Hydroxocobalamin (IV) United States,7,8 France9

IM: intramuscular; IV: intravenous

Sources: (1) Chen KK, Rose CL, Clowes GHA. Methylene blue,

nitrites and sodium thiosulfate against cyanide poisoning. Proc

Soc Exp Biol Med. 1933;31:250–251. (2) Binenfeld Z. Antidote

therapy in cases of poisoning by some heavy metals and cyanides and its risks. Farm Glas. 1971;27:1–6. (3) Bright JE, Marrs

TC. A model for the induction of moderate levels of methaemoglobinaemia in man using 4-methylaminophenol. Arch Toxicol.

1982;50:57–64. (4) Kiese M. Methemoglobinemia: A Comprehensive

Treatise. Cleveland, Ohio: CRC Press; 1974. (5) Marrs TC,

Swanston DW, Bright JE. 4-Dimethylaminophenol and dicobalt

edetate (Kelocyanor) in the treatment of experimental cyanide

poisoning. Hum Toxicol. 1985;4:591–600. (6) Nagler J, Provoost

RA, Parizel G. Hydrogen cyanide poisoning: Treatment with

cobalt EDTA. J Occup Med. 1978;20:414–416. (7) Cottrell JE,

Casthely P, Brodie JD, Patel K, Klein A, Turndorf H. Prevention

of nitroprusside-induced cyanide toxicity with hydroxocobalamin. JAMA. 1978;298:809–811. (8) Mushett CW, Kelley KL,

Boxer GE, Rickards JC. Antidotal efficacy of vitamin B12a (hydroxocobalamin) in experimental cyanide poisoning. Proc Soc

Exp Biol Med. 1952;81:234–237. (9) Yacoub J, Faure J, Morena H,

Vincent M, Faure H. Acute cyanide poisoning: Current data on

the metabolism of cyanide and treatment with vitamin B12a.

Eur J Toxicol. 1974;7:22–29.

poisoning vary according to country and medical

custom (Table 10-4). This diversity seems to be

based, in part, on where the drugs were initially

developed and used. The aims of the recommended

therapies are generally similar, however, in that one

drug is given for immediate relief from the histotoxic

effect of cyanide complexed with cytochrome oxidase.

In most of the regimens discussed below, the action of displacing cyanide from cytochrome oxidase

is accomplished by the formation of methemoglobin. Methemoglobin removes cyanide from the extracellular fluid space and, by so doing, displaces

cyanide from the intracellular fluid. The second

component of most regimens is sodium thiosulfate,

which is given as a specific antidote to augment the

systemic clearance of cyanide via thiocyanate formation by sulfur transferases.
Medical Aspects of Chemical and Biological Warfare

280

SPECIFIC ANTIDOTES

The clinical use of most antidotes is based on

animal experiments46 and on extrapolations made

from a small number of clinical cases. Comparing

results from animal studies has limitations because

of the differences in experimental design from one

study to another as well as marked interspecies differences in cyanide and drug metabolism. Moreover, the studies were not designed to resemble the

usual emergency medical or battlefield scenario.

The disparity of antidotes for cyanide is due to the

following factors47,48:

• the small number of patients;

• the fact that most cyanide victims understandably receive several treatment agents;

• the lack of readily available, adequate

analysis of blood and tissue concentrations;

and

• the limited comparison studies that are

available in animal models.

Antidotes are usually unnecessary if the casualty

is conscious.

Drugs Used in the United States

Nitrites

Amyl nitrite and sodium nitrite, with or without

sodium thiosulfate, are used as antidotes for cyanide.49 The antidotal action of amyl nitrite was first

noted as early as 1888.50

The oxidized form of heme iron (Fe3+) in methemoglobin has a higher binding affinity for cyanide than does cytochrome oxidase. The preferential binding of cyanide to methemoglobin to form cyanomethemoglobin frees cytochrome oxidase to resume its role in aerobic metabolism.51 In the United

States and other countries, sodium nitrite has been

used as the methemoglobin-inducing drug of choice.

In addition to methemoglobin formation, both

sodium and amyl nitrite cause significant vasodilation, which warrants careful monitoring of blood

pressure. Marked vasodilation with orthostatic

hypotension, dizziness, and headache, in addition

to the unpredictable levels of methemoglobin

formed,52 limit the utility of amyl nitrite in an upright casualty. Therefore, if a casualty is conscious

and able to stand, he should not receive any nitrite.

These factors, together with other concerns, have

caused amyl nitrite to be removed from the cyanide

antidote kit in the U.S. Army formulary for field units.

Sodium nitrite is available in the Lilly Cyanide

Antidote Kit (manufactured by Eli Lilly and Company, Indianapolis, Ind.) in 10-mL ampules containing 300 mg for intravenous administration. (The kit

also contains amyl nitrite encased in glass “pearls,”

which are meant to be broken so the drug can be

inhaled.) The solution of sodium nitrite (30 mg/mL)

should be given to an adult intravenously over 5 to

15 minutes, with careful monitoring of blood pressure. A single dose is sufficient to raise the methemoglobin level to 20% in an adult,53 and a second

dose, up to half as large as the initial one, can be

given. Methemoglobin levels should be monitored

if possible and kept below 35% to 40%, the range

that is associated with oxygen-carrying deficits

caused by methemoglobin itself.54

Because most automated clinical analyzers do

not detect cyanomethemoglobin, the residual normal hemoglobin capable of oxygen transport can

be overestimated by measuring total hemoglobin

only. Methemoglobin-inducing substances should

not be given to fire victims, even if cyanide intoxication is suspected, because neither methemoglobin nor carboxyhemoglobin (formed by carbon

monoxide) transport oxygen. Alternative therapy

in this situation consists of administering oxygen,

thiosulfate, and other standard supportive measures.

In children, sodium nitrite can cause lethal methemoglobin levels if the dose is too high. The recommended dose for children is 0.33 mL of the 10%

solution per kilogram of body weight.34,55

Some data indicate that nitrites exert their action

by a mechanism other than methemoglobin formation. It has been suggested that the protective effect is due to the vasodilating effect of nitrite.52 Several α-adrenergic antagonists (eg, chlorpromazine,

promethazine, promazine, and phenoxybenzamine)

that cause vasodilation also antagonize cyanide toxicity.56,57 Further information is needed to determine

the mechanism or mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide

intoxication.57

Several alternative methemoglobin-forming

drugs that have different pharmacological properties from sodium nitrite have been investigated and

used in other countries (see Table 10-4).

Other Methemoglobin-Forming Drugs

4-Dimethylaminophenol (4-DMAP), p-aminopropiophenone (PAPP), p-aminoheptanoylphenone
Cyanide Poisoning

281

(PAHP), and p-aminooctanoylphenone (PAOP) are

also methemoglobin-forming compounds that have

protective effects against cyanide. 4-DMAP was

proposed as a fast-acting antidote with low toxicity.58,59 This German-developed compound is used

in the German military and by the civilian population. In humans, intravenous injection of 4-DMAP

(3 mg/kg) can produce a level of 15% methemoglobin within 1 minute.60 In dogs, a dose of 4-DMAP

that produces a 30% level of methemoglobin will

save animals that have received 2 to 3 LD50 of cyanide.61

The disadvantages of 4-DMAP are (1) the appearance of necrosis in the area of injection after intramuscular administration and (2) the possibility that

extremely high levels of methemoglobin may occasionally result. Increases in pain, fever, and muscle

enzymes also occur after intramuscular administration of the drug. 4-DMAP has been reported to produce positive results in the Ames test, which suggests that the compound may be a mutagen. PAHP

appears to be the safest phenone of the series.62

Thiosulfate and Other Sulfur Donors

Thiosulfate has been used primarily with sodium

nitrite in a fixed antidotal regimen. The standard

dose of sodium thiosulfate, which is supplied in the

Lilly Cyanide Antidote Kit in 50-mL ampules, is 50

mL of the 250 mg/mL (12.5 g), given intravenously.

A second treatment with half of the initial dose may

be given. The pediatric dose is 1.65 mL per kilogram of body weight.55

The utility of thiosulfate is limited because of

its short biological half-life and its small volume

of distribution.23 This combination of pharmacological properties, in addition to the suggestion that the presence of cyanide increases the

intracellular availability of the thiosulfate,63 indicates that this compound probably cannot be used

as a prophylactic but only as an antidote. Compounds containing the more-lipophilic sulfane sulfur (R—S—S–) or compounds that can be actively

transported into the cells may be more beneficial

as cyanide antagonists,64–66 but none are commercially available.

Other Therapeutic Drugs

Cobalt Salts

Cobalt salts have been shown to be an effective

means for binding cyanide in vitro and in vivo.67,68

Kelocyanor, the cobalt salt of ethylenediaminetetraacetic acid (EDTA), which is commercially

available in Europe but not in the United States, is

administered intravenously.69 In comparison studies against nitrite and hyposulfite, the cobalt chelate was thought to be superior31; however, in other

studies the nitrite-thiosulfate combination was

found to be superior.70

The drawback of cobalt compounds is their rather

severe toxicity. Cardiac effects such as angina pectoris and ventricular arrhythmias, edema around

the eyes, vomiting, and death have been observed.71

A clinical caveat is that severe toxicity from cobalt

can be seen even after initial recovery from acute

cyanide poisoning.

Hydroxocobalamin

Hydroxocobalamin (vitamin B12a) is an effective

antagonist of cyanide intoxication that binds cyanide

directly without forming methemoglobin. It is useful under certain conditions such as in fire victims

who may already have a decreased concentration

of functioning hemoglobin.72 It has a low toxicity

even at high doses.73 In addition, in vitro cyanide

studies74 have shown a greater affinity for hydroxocobalamin than for cytochrome oxidase. Sodium

thiosulfate can improve the protection provided by

hydroxocobalamin alone.46

There are several disadvantages in the clinical

use of this drug. In rare instances, urticaria can result from hydroxocobalamin administration. More

importantly, hydroxocobalamin has a relatively

short shelf life because it decomposes in light. It

may cause tachyphylaxis, which may limit its usefulness.75 The cost of the drug is high, in part because so much is needed on a molar basis. At 1,346

grams per mole of hydroxocobalamin, a dose of at

least 4 g is needed to neutralize a lethal amount of

cyanide.

Investigational Drugs

Prophylactic Drugs

PAPP and PAOP are also aminophenol derivatives. PAPP may not be active against cyanide intoxication; its metabolite, p-hydroxylaminopropiophenone, may be the active compound. This

could account, in part, for the fact that cyanide toxicity itself changes the pharmacokinetics of the antidote.76 PAPP reduces cyanide levels within red

blood cells,77 and its effect is greatly enhanced in

the presence of sodium thiosulfate.78 PAPP, PAHP,

and PAOP all have pharmacokinetics that may al-
Medical Aspects of Chemical and Biological Warfare

282

low for prophylactic administration.62,79 Prophylactic methemoglobin formation could present its own

problems, however, for victims of smoke inhalation

or in other settings where high levels of carbon

monoxide occur.33,80

A number of 8-aminoquinoline analogs of primaquine have also been studied as potential prophylactic drugs because they create elevated methemoglobin levels of long duration. Only preliminary

information is available regarding the methemoglobin-forming potential of these drugs in

humans.62,81,82

Cyanohydrin-Forming Drugs

Aldehydes and carbonyl-related compounds

(such as pyruvate, α-ketoglutaric acid, glyoxal, and

reducing sugars) form cyanohydrins from cyanide.

This action may be a mechanism for improving the

protection provided by nitrites.83 Steinberg and

Thomas84 found that glyoxal trimer may be the most

effective compound of the group that they examined. The relatively short half-lives of these reversible reactions and the drug dose required85 may

limit the clinical utility of this class of compounds.24

SUMMARY

Cyanide, an ancient compound, is often associated with murders and assassinations. Because of

the high amount needed to cause death and the inefficient weapons in which it was used, cyanide was

not an effective chemical weapon in World War I;

however, it was possibly used by Iraq against the

Kurds in the Iran–Iraq War during the late 1980s.

Cyanide causes intracellular hypoxia by inhibiting the intracellular electron transport mechanism, the cytochrome enzymes. After inhalation of a

large amount of cyanide—as either hydrocyanic

acid or cyanogen chloride—the onset of effects

is within seconds, symptoms are few, physical

findings are scanty, and death occurs within minutes.

The antidotes used in the United States, sodium

nitrite and sodium thiosulfate, are quite effective if

given before cessation of cardiac activity.

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Chapter 11

INCAPACITATING AGENTS

JAMES S. KETCHUM, M.D., ABPN*; AND FREDERICK R. SIDELL, M.D.†

INTRODUCTION

USE OF INCAPACITATING AGENTS

Historical Precedents

Contemporary Use

POSSIBLE APPROACHES TO INCAPACITATION

Nonchemical Agents

Chemical and Biological Warfare Agents

Psychochemical Agents

THE ANTICHOLINERGICS AS CANDIDATE INCAPACITATING AGENTS

General Characteristics of Anticholinergics

The Most Likely Candidate: BZ or a Related Glycolate

Clinical Pharmacology of BZ

Anticholinergic Delirium Produced by BZ

DIAGNOSIS OF INCAPACITATING AGENT SYNDROMES

MEDICAL MANAGEMENT

BZ and Other Anticholinergics

LSD, Other Indoles, and Phenethylamine Derivatives

Opioids

SUMMARY

*Colonel, Medical Corps, U.S. Army (Ret); Assistant Clinical Professor, Department of Psychiatry, University of California at Los Angeles,

Los Angeles, California 90024

†Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014
Medical Aspects of Chemical and Biological Warfare

288

EXHIBIT 11-1

CRITERIA FOR THE IDEAL INCAPACITATING AGENT

1. Effectiveness The agent must be able to severely impair or completely disrupt an enemy’s

ability to fight.

2. Relative lack of toxicity When used as intended, the agent must produce few deaths or permanent

injuries.

3. Persistence Effects must be temporary: preferably minutes to hours; at most, a few

days.

4. Logistical feasibility The compound must be potent, chemically stable, and capable of being

incorporated into practical munitions.

5. Treatability Effects brought about by the agent should be fully or partially reversible

by relatively simple medical treatment. Even without treatment, ill effects

should not cause permanent disability.

6. Predictability The behaviors produced by the agent must be relatively predictable and

unlikely to bring about disastrous secondary consequences to civilians

or other noncombatants. Nor should the agent increase the likelihood of

the senseless activation of weapons of mass destruction by affected individuals.

7. Manageability of casualties Once captured, incapacitated individuals should be controllable. Deaths

and injuries due to an interaction between the altered mental state and

natural dangers in the immediate environment must be prevented.

8. Expense The cost of production must be affordable within the context of the overall

military budget.

Source: Departments of the Army, Navy, and Air Force, and Commandant, Marine Corps. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries. Washington, DC: HQ: DA, DN, DAF, Commandant, MC; 22 Dec 95: 3–1. Field

Manual 8-285, NAVMED P-5041, Air Force Joint Manual 44-149, Fleet Marine Force Manual 11-11.

INTRODUCTION

As defined in The American Heritage Dictionary of

the English Language, to “incapacitate” means “to

deprive of strength or ability.” The word is not synonymous with paralysis, confusion, or any other

specific affliction. It is a general term, implying

neither global inability to act nor any particular type

of disability. For example, blurred near vision might

be incapacitating for a computer programmer or air

traffic controller but probably would not be incapacitating for a laborer or a football player. Consequently, when the word incapacitating is used, we

should ask, “incapacitating for what activity?”

Used in a military context, incapacitation is understood to mean inability to perform one’s military mission. Since missions vary, we could theoretically consider a particular agent to be incapacitating if it disrupts aspects of performance vital to

a particular mission. Impaired hearing might incapacitate a translator, a severe tremor might incapacitate a sniper, and so forth. In this chapter, however,

incapacitation means the inability to perform any

military task effectively and implies that the condition was achieved via the deliberate use of a nonlethal weapon.

Finding a suitable nonlethal weapon to substitute for a lethal one poses formidable problems.

Consider the criteria—military, medical, and budgetary—that should govern the selection of an ideal
Incapacitating Agents

289

incapacitating agent: effectiveness, relative lack of

toxicity, persistence, logistical feasibility, treatability, predictability, manageability of casualties, and

expense (Exhibit 11-1). No proposed incapacitating

agent meets all of these demanding requirements,

but any compound worthy of standardization (ie,

production without further modification) needs to

fulfill most of them.

Further considerations would come into play

before such an agent could be used. For example,

methods and equipment must be designed to manufacture, store, and transport the agent. Troops in the

field would need training to operate what might

prove to be quite complex delivery systems. Medical

personnel would need to learn how best to treat casualties, working within the confines of the battlefield.

USE OF INCAPACITATING AGENTS

Historical Precedents

Few references to the historical use of drugs for

military purposes appear in contemporary publications. Scholars interested in chemical warfare,

therefore, may easily assume that this concept is

of recent origin, arising out of the technological

revolution of the late 20th century. Actually, a

substantial literature describing a variety of

tactical efforts to incapacitate enemy forces by

intoxicating them with mind-altering chemicals

is available. The fact that such material is rarely

cited in current publications, both lay and professional, probably has several explanations. The

exponential expansion of pharmaceutical discovery,

for example, has shifted attention from those

few drugs that were the mainstay of medical treatment before the turn of the century. In addition, in

the wake of an explosion of new information and

the exponential proliferation of journals and textbooks, the older literature has been eclipsed and is

rarely included in current indexes and computerized databases.

In 1961, Goodman1

 carried out a systematic perusal of 100 years of four leading American and

British medical journals (Journal of the American

Medical Association, Boston Medical and Surgical Journal [continued as New England Journal of Medicine],

Lancet, and British Medical Journal) and a more limited survey of several respected German medical

periodicals (Fuhner-Wielands Sammulung von

Vergiftungsfallen [continued as Archiv fur Toxikologie]

1930–1961, and Deutsche Zeitschrift fur die Gersamte

Gerichtliche Medizin 1922–1939). Goodman uncovered an astonishing variety of reports of the deliberate pharmacological induction, particularly by

atropine and related drugs, of “behavioral toxicity”

(a term introduced by Brady in 1956). Most of these

were individual cases of poisoning for nefarious

purposes, but many can be considered instances of

the early use of drugs as “weapons of mass destruction” (a late–20th-century term that seemingly does

not ethically distinguish nonlethal incapacitating

chemical agents from lethal chemical agents, or

from biological and nuclear weapons).

A few excerpts from Goodman’s lengthy historical review are worthy of inclusion here, if only to

show that incapacitating agents are by no means a

new approach to military conflict:

According to Sextus Julius Frontinus, Maharbal, an

officer in Hannibal’s army about 200 BC,...sent by

the Carthaginians against the rebellious Africans,

knowing that the tribe was passionately fond of

wine, mixed a large quantity of wine with mandragora, which in potency is something between a

poison and a soporific. Then, after an insignificant

skirmish, he deliberately withdrew. At dead of

night, leaving in the camp some of his baggage and

all the drugged wine, he feigned flight. When the

barbarians captured the camp and in frenzy of delight greedily drank the drugged wine, Maharbal

returned, and either took them prisoners or slaughtered them while they lay stretched out as if

dead.2(p139)

. . . .

Another example of the use of atropinic plants for

military purposes occurred during the reign of

Duncan, the 84th King of Scotland (AD 1034–1040),

who used wine dosed with “sleepy nightshade”

against the troops of Sweno, King of Norway. After a battle near Culross, Duncan sent messengers

to Sweno to negotiate surrender, and during the

discussions supplied the Norwegians with provisions. As expected, this was looked on as a sign of

weakness. The Scottish forces under Bancho entered Sweno’s camp while the invaders were intoxicated and rapidly vanquished them.3,4(pp537–538),5

. . . .

During his assault in 1672 on the city of Groningen,

the Bishop of Muenster tried to use grenades and

projectiles containing belladonna against the

defender. Unfortunately, capricious winds often

blew the smoke back, creating effects opposite to

those intended. As a result of this and other incidents in which chemicals were used in battle, a

treaty was signed in 1675 between the French and

the Germans, outlawing further use of chemical

warfare.4(p563)
Medical Aspects of Chemical and Biological Warfare

290

. . . .

In 1813 the inhabitants of an area being invaded

by French troops received fortuitous help from local flora. A company of starving French soldiers was

rendered helpless when they impulsively consumed

wild berries containing belladonna alkaloids.

Gaultier, the company surgeon, vividly recorded

the generalized confusion and self-destruction that

took place as delirious soldiers wandered halfclothed through the bog. Others, in response to

their hallucinations, cried out “Aux armes!” and

threw themselves into blazing campfires.6

. . . .

Later in the same century a peaceful railway surveying expedition under Lieutenant-Colonel Paul

Flatters was proceeding to the Sudan from Algeria, through the territory of the Touareg. These Barbers, who, unlike other North African, veil the men

and not the women, are a raider people who did

not completely surrender to French authorities

until 1943. They called themselves “the Blue Men”

and “the People of the Veil”; the other inhabitants,

however, called them “the Abandoned of God.”7,8

Flatters, ignoring a warning letter from the Touareg

marched into an ambush on 16 February 1881, losing approximately the entire “assault group,”

which constituted half of his entire force. As his

sixty-one remaining personnel tried to march to a

French Outpost, they were trailed by approximately two hundred Touareg. On 8 March 1881,

their supplies having been observed to be low, they

were approached by three men who claimed to be

members of another tribe. They were sold three

bundles of dried dates, which were thrown into

their camp the following day, and consumed in

varying quantities by the troops. Shortly thereafter they exhibited the signs of solanaceous intoxication.9

Five men disappeared in the first minutes of confusion, and 31 of the remainder were so sick that

they were unable to look after themselves. In the

evening some attempted to crawl away into the

desert. The other Frenchmen had been tied down

by the senior indigenous soldier to prevent injury.

The next morning, somewhat improved, “...they

set off, half mad, bent double under excruciating

pain, their legs crumbling away under them, their

voices shrill, their words unintelligible.” On the

second day after the poisoning they reached an

oasis, where a force of Touareg awaited them. By

this time, however, the survivors were able to function as an effective fighting force and repulsed the

attack. After finding water, and resorting to cannibalism to sustain life, 12 of the original soldiers

reported to a French outpost 20 days after their initial “chemical warfare attack” by an “incapacitating agent” (later identified as Hyoscyamus falezlez).9

. . . .

Ironically, the first recorded 20th century use of

solanaceae in a military situation occurred in

Hanoi, French Indo-China (later known as North

Vietnam) on 27 June 1908. On that day, two hundred French soldiers were poisoned by datura in

their evening meal. One of the intoxicated soldiers

saw ants on his bed, a second fled to a tree to escape from an hallucinated tiger and a third took

aim at birds in the sky. The delirious troops were

soon discovered and all recovered after medical

attention. Two indigenous non-commissioned officers and an artilleryman were later convicted by

courts-martial of plotting with ex-river pirates who

had been influenced by “Chinese reformer agitators.”10,11

Goodman’s scholarly review1 provides other examples, including the alleged use of cauldrons of

burning hemp (containing tetrahydrocannabinol) or

smoke from opium (morphine alkaloids) dating as

far back as the first century BC; however, the foregoing examples should suffice to correct the notion

that incapacitating chemical weapons are a modern invention.

Contemporary Use

Although warfare is tantamount to death and

destruction, the international community, particularly

in the latter half of the 20th century, has repeatedly

tried to find ways to make war more “humane.” Remorse and indignation were widely expressed following the use during World War I of such repugnant weapons as chlorine, mustard, and phosgene,

which killed or injured hundreds of thousands of

soldiers in the European trenches. One consequence

of this outcry was an international ban on chemical

weapons adopted by the Geneva Convention in

1925. The United States, although not a signatory

to this document until 1975, strongly supported its

purpose.

Chemical weapons were apparently not used

during World War II, although the German military

was later found to have developed and stockpiled several different lethal anticholinesterase

nerve agents. Fortunately they were not used,

perhaps because of the swift and overwhelming invasion by Allied forces. Following the end of the

war in 1945, research and development of nerve

agents (GA [tabun], GB [sarin], and later GD [soman] and VX) continued in a number of countries,

including the United States. Other than in a few isolated instances, however, (such as the Iraqi use

against Iran in the 1980s) these agents have not been

used in warfare. They remain in the United States
Incapacitating Agents

291

arsenal, presumably as defensive weapons of last

resort.

What was thought to be a novel concept—using

chemicals to produce temporary disability—began

to attract increasing interest as the acceptance

of lethal agents declined. (As Goodman reported, of course, attempts to use various drugs and

potions for this purpose are nothing new.) As credible military weapons, however, drugs did not

receive serious consideration until the 1950s, when

scientific psychopharmacology first came of age.

At about this time, a number of research laboratories began to explore this possibility. During

the next two decades, the feasibility of chemical

incapacitation was systematically studied by nations on both sides of the Iron Curtain. The following, also from Goodman’s review, might be

considered an example of “Cold War chemical

warfare”1

:

A double agent revealed that in Munich, in 1959,

salt shakers in a cafeteria serving 1,248 employees

of Radio Free Europe were dosed with atropine.

Chemical analysis of the contents of two shakers

showed the presence of 2.36 per cent by weight of

atropine.12,13 (One gram of this concoction would

thus contain almost 24 mg of atropine, more than

enough to produce severe delirium.) Fortunately,

the attempt was aborted.

In the United States, substantial resources were

allocated for this study, reaching a peak in the mid1960s. After extensive clinical study, a single incapacitating agent (BZ) was chosen for standardization by the U.S. Army Chemical Corps. By 1966,

munitions capable of delivering BZ had been stockpiled and stored in military depots. In recent years,

however, these have been dismantled and the contents destroyed. At the present time, incapacitating

munitions are no longer in our armamentarium.

POSSIBLE APPROACHES TO INCAPACITATION

Virtually every imaginable chemical technique

for producing military incapacitation has been tried

at some time. Between 1953 and 1973, at the predecessor laboratories to what is now the U.S. Army

Medical Research Institute of Chemical Defense,

many of these were discussed and, when deemed

feasible, systematically tested. Chemicals whose

predominant effects were in the central nervous

system were of primary interest and received the

most intensive study. But other substances capable

of disrupting military performance were also investigated, including some biological toxins. Nor were

chemical agents and toxins the only possibilities

considered; other candidates included noise, microwaves, light, and foul odors.

Nonchemical Agents

Physical disturbances (including loud noises,

microwaves, and high-intensity light) and substances capable of causing intense sensory stimulation are among the nonchemical methods explored to impair performance.

Noise

Devices to produce loud or unpleasant sounds

were built and, in some cases, were tested fairly

extensively. Various sound patterns, including

white noise and high frequencies, were tried. Although the sounds produced were annoying, they

were relatively ineffective unless used at intensities

that were either impractical to deliver over a large area

or too likely to cause permanent hearing impairment.

It is interesting to note that the blare of trumpets

has been used in battle throughout history to demoralize or confuse enemy forces. In addition, journalists reported that irritating rock-and-roll music

was played during Operation Just Cause, the 1989

mission to Panama that resulted in the capture of

Panamanian President Manuel Noriega. Similar

loud music was played by the U.S. Treasury

Department’s Alcohol, Firearms, and Tobacco team

for the same purpose during the siege of the Branch

Davidians in 1993 at Waco, Texas.

Microwave Bombardment

Microwave effects on the central nervous system

were investigated (in laboratory animals) beginning

in the late 1960s. Consideration was given to the

possibility of using a microwave generator to produce military incapacitation. Concern about longterm adverse effects, however, caused this idea to

be abandoned.

High-Intensity Photostimulation

Light sources of high intensity, adjusted to oscillate at frequencies that theoretically might impair

visual perception and concentration were also studied for a short period, but this approach was ulti-
Medical Aspects of Chemical and Biological Warfare

292

mately judged to be impractical and probably unsafe (ie, it could cause retinal damage).

Olfactory Assault

Even the concept of olfactory incapacitating

agents was briefly explored. Various obnoxious

odors, including those produced by skatole derivatives, were found to be highly aversive, possibly

sufficiently to impair performance. However, the

relative ease of protecting against such odors (eg,

wearing masks) and the probability that a highly

motivated enemy would not be appreciably deterred by aversive odors alone caused this line of

investigation (which was never very popular with

the research team) to be abandoned.

Chemical and Biological Warfare Agents

A variety of chemicals—most of them known

before 1950 and usually grouped with the chemical

warfare agents—produce incapacitation through

physiological rather than psychological effects. This

category is included in this historical review of incapacitating agents only for the sake of completeness; each agent is discussed in detail in a separate

chapter in this textbook.

Likewise, a number of noninfectious biological

agents (eg, the staphylococcal enterotoxins) can cause

severe malaise and other systemic symptoms, which

would severely impair the ability to fight. The same

is true of sublethal doses of organophosphates (cholinesterase inhibitors) such as VX or GB. None of these

systemic agents are acceptable for use as incapacitating agents because of their unacceptable safety margins (ie, the ratio of the lethal to the incapacitating dose).

Vesicants

The vesicants, which include such substances as

mustard, produce painful burns of the skin and respiratory tract. These chemical warfare agents were

used extensively during World War I, with disastrous

consequences. They have been used by some Third

World nations, however, in the recent past. Similarly,

phosgene and chlorine are generally not used.

Although all vesicants can certainly incapacitate, they

also often produce death and extreme suffering. (For

further discussion, see Chapter 7, Vesicants.)

Irritants and Nausea-Producing Agents

Irritant agents, including lacrimators (such as

CN, the original tear gas, and CS, its more potent

successor), are generally fairly effective and safe

when properly used. Their drawbacks are twofold:

(1) their duration of action is relatively brief (adaptation to the chemical insult usually occurs after less

than 30 min of continuous exposure) and (2) highly

motivated individuals can fight through (ie, ignore)

their effects. Thus, agents of this type would be relatively ineffective against dispersed, well-trained

troops.

Nausea-producing agents (eg, DM) may have

substantial effectiveness but they can be toxic.

Highly potent relatives of apomorphine (a wellknown emetic) are known but they have rather low

safety margins. (For further discussion of CN, CS,

and DM, see Chapter 12, Riot Control Agents.)

Psychochemical Agents

Virtually all drugs whose most prominent effects

are psychological or behavioral (sometimes referred

to as psychochemicals) can be classified into four

fairly discrete categories: stimulants, depressants,

pyschedelics, and deliriants. These drugs all can

cross the blood–brain barrier with ease, and they

exert their most dramatic effects on the central nervous system. Their interference with higher functions (as opposed to basic vegetative functions,

which are primarily under brainstem control) are

of greatest relevance to the goal of producing military incapacitation. The higher functions of the

brain (attention, orientation, perception, memory,

motivation, conceptual thinking, planning, and

judgment) are more easily disrupted than are the

more robust systems that regulate the physiological functions that are essential to life. Thus, it is

possible to disable intelligent behavior at doses

much lower than those that might have a direct

lethal effect.

Stimulants

Stimulants include amphetamines, cocaine, caffeine, nicotine, and epileptogenic substances such

as strychnine and metrazole. Some phenethylamines (among which the amphetamines are perhaps the best known) have additional effects that

can best be classified as “psychedelic” and will be

discussed below. None of the conventional stimulants appears to have sufficient potency to be usable as an airborne incapacitating agent, and low

doses could even prove counterproductive, since

moderate stimulation might easily lead to a

soldier’s more energetic and aggressive performance. Amphetamines, in fact, have successfully
Incapacitating Agents

293

been employed to offset fatigue and enhance cognitive function.

Depressants

A large variety of compounds come under the

heading of depressants, but none holds much promise as a practical incapacitating agent. Barbiturates

generally require doses of several hundred milligrams to produce heavy sedation. For example, 200

mg of secobarbital was found to produce a decline

of only about 20% in a 25-trial, time-reproduction

task14; other studies have produced similar results.

Morphine and other opioids could be incapacitating, and very potent analogs (eg, etorphine) have

been synthesized,15 but the lethal dose is only 10-

to 20-fold greater than the incapacitating dose.

The more potent antipsychotic (neuroleptic) major tranquilizers such as haloperidol and other

butyrophenones often produce relatively little sedation, although they reduce hyperactivity. Their

tendency to produce extrapyramidal symptoms

such as acute dystonia is an additional liability, and

their potency, although considerable, generally

would not satisfy logistical constraints. The minor

tranquilizers would be virtually useless because of

their relatively mild effects and limited potency.

Psychedelics

The psychedelic group includes D-lysergic acid

diethylamide (LSD-25) as its most well known

member. LSD was, in fact, a drug of great interest

to the military (as well as the whole nation) for

many years starting in the early 1950s. Systematic

testing of LSD as a possible incapacitating agent was

done mostly between 1959 and 1965. Although

highly potent (capable of producing complete incapacitation after oral doses of approximately 2.5

μg/kg), LSD tends to produce unpredictable (although well-coordinated) behavior. Affected individuals usually cannot carry out a series of instructions or concentrate on a complex task, but might

be capable of isolated, impulsive actions such as

firing a weapon accurately enough to be dangerous. Studies16 conducted in simulated military settings demonstrated conclusively that even welltrained units become totally disorganized following

total oral doses of less than 200 μg. Phenothiazines

and benzodiazepines provide partial antidote effects,

but there is no known complete antagonist.

The term psychedelic means “mind-manifesting”

and refers to the alleged opening up and expansion

of awareness that early clinicians attributed to LSD.

This led to its popularity for many years as a psychotherapeutic agent (or as an adjunct to therapy).

The flood of ideas and images released by LSD accounts for its disorganizing effects; for example,

soldiers under the influence of LSD would find it

impossible to carry out an assigned task because of

distracting, sometimes amusing, thoughts.

When administered by the aerosol route, using a

particle size of approximately 5 μm, the ID50 (ie,

the dose that incapacitates 50% of the exposed

population; this dose is retained in the lungs and is

available for absorption) was estimated to be 5.6

μg/kg, approximately twice the ID50 by the

parenteral route.17

LSD analogs are numerous, but none exceed it

in potency. Several other naturally occurring

psychedelics (structurally related to LSD in that

they contain an indole ring) are known. Psilocybin,

ibogaine, and harmine are examples, but none of

these shares the potency of LSD. Studies in several

species of animals have shown that the lethal dose

is at least 1,000-fold greater than the incapacitating

dose. On the other hand, a single, intramuscular

dose of 297 mg (about 100 μg/kg) caused sudden

death in an elephant tested in the Lincoln Park Zoo

in Oklahoma City, Oklahoma.18 In humans, doses

above 10 μg/kg have occasionally produced grand

mal seizures,19 although in recreational users, ingestion of as much as 50 μg/kg without serious

consequences has also been observed.20

Although substituted indoles were apparently

the only known synthetic psychedelic drugs prior

to 1955, compounds with psychedelic properties

have since been produced by making appropriate

additions to the phenethylamine skeleton (the

nuclear constituent of dopamine and norepinephrine). They include 3,4-methylenedioxymethylamphetamine (MDMA), the drug popularly known as

“ecstasy.” This and a number of related synthesized

compounds21 share many of the properties of LSD

in that they induce an alteration of consciousness

with startling perceptual changes that range from

frightening to fascinating, depending on the user,

his mental set, and the setting in which the drugs

are taken. Some are very potent, but the same caveats that apply to LSD apply to their use in a military situation.

Phencyclidine (PCP) and the related compound

ketamine have a mixture of clinical effects that reflects their complex pharmacology. Although acting on a specific subset of serotonin-type (HT-2)

receptors in the forebrain,22 PCP also has affinity

for cholinergic, opiate, and dopamine receptors.

This may explain PCP’s ability to produce subjec-
Medical Aspects of Chemical and Biological Warfare

294

tive changes ranging from euphoria to terror, as well

as the apparent analgesia and “superman” effects

described by police officers who have tried to arrest individuals under its influence. It was concluded quite early that PCP was not a suitable drug

for military use, after its effects were observed in a

few volunteers.

Deliriants

The fourth major group of psychoactive drugs

can usefully be described as the deliriants. This category includes compounds that in small doses may

produce clinically useful effects but in doses a few

times larger produce delirium. Delirium is an incapacitating syndrome, involving confusion, hallucinosis, disorganized speech and behavior, as well as

other features that will be described in greater detail below. Many drugs (and a number of metabolic

alterations caused by disease states) can produce

delirium. In their classic 1935 monograph, Wolff and

Curran23 enumerated more than 100 distinct etiologies of delirium. Many other drugs, some of them

recently synthesized, could be added to that list.

From this large number of possibilities, chemical

compounds in a single subgroup—the “anticholinergics”—are regarded as most likely to be used as

military incapacitating agents.

THE ANTICHOLINERGICS AS CANDIDATE INCAPACITATING AGENTS

“Anticholinergics” is the term generally used to

refer to drugs that block the muscarinic effects of

acetylcholine, in either the peripheral or the central nervous system. The best known are atropine

and scopolamine, which are derived from solanaceous plants such as Jimson weed. Of course, many

drugs in large overdose can produce delirium: tricyclic antidepressants, antihistamines, barbiturates,

and phencyclidine are a few examples. But the anticholinergic BZ and a few structurally close synthetic relatives are the only ones known to be capable of producing delirium at very low dosage

with a high safety margin—apart from scopolamine,

which is one third as potent as BZ. A detailed discussion of BZ, and the nature of the delirium it produces, follows.

General Characteristics of Anticholinergics

The term anticholinergic as used in the context

of this discussion refers more specifically to compounds that selectively block the brain’s muscarinic receptor (now known to consist of several subtypes). Atropine (hyoscyamine) and scopolamine

(hyoscine) are the most familiar medicinal anticholinergics. Historically, they were obtained from of

the botanical family Solanaceae, which includes

Jimson (or loco) weed, mandrake root, henbane,

belladonna, and nightshade. Atropine and scopolamine are esters of tropic acid and contain a tertiary nitrogen moiety. This gives them the ability to

cross the blood–brain barrier and block central muscarinic cholinergic receptors by competitive inhibition with acetylcholine, the natural neurotransmitter at these sites.

With regard to central activity, scopolamine is

about 7-fold more potent than atropine but is

shorter acting. An injection of as little as 1.5 mg of

scopolamine hydrobromide is sufficient to cause the

average 70-kg soldier to become delirious (and thus

incapacitated) for 2 to 4 hours. Ten to twelve milligrams of atropine sulfate produces a similar effect,

lasting 4 to 8 hours. In the peripheral cholinergic

nervous system, both drugs produce parasympathetic blockade, causing tachycardia, elevation of

blood pressure, hyperthermia (through blockade of

sweat production), decrease in salivation, and reduction of gastrointestinal and urinary tract functions.

Impairment of near vision, attributable to a mixture of central and peripheral actions, is due to loss

of accommodation (owing to ciliary muscle paralysis) and reduced depth of field (owing to pupillary

enlargement). Alteration of skeletal muscle reflexes

and tonus is related to central influences on the

Renshaw interneurons in the spinal cord. Interaction between peripheral and central effects of anticholinergic drugs at different times following administration can cause biphasic changes in such

parameters as heart rate and peripheral spinal reflexes. For example, heart rate may be slowed initially

due to brainstem influences, after which vagal blockade tends to predominate, causing tachycardia. Similarly, knee and ankle reflexes may be exaggerated

at first, but later are reduced. The pharmacokinetics

that govern speed of distribution to the various drug

compartments probably explain these biphasic phenomena. Although these variations in effects may

seem to be academic distinctions, medical officers

need to be aware of them when attempting to diagnose anticholinergic drug intoxication (which is discussed later in this chapter).

The above general characterization of anticholinergic drug effects produced by the familiar medications atropine and scopolamine also applies quite
Incapacitating Agents

295

well to a number of synthetic anticholinergic compounds. Many of these compounds are more potent than atropine or scopolamine. In some cases,

their duration of action is quite short and in other

cases much longer than either atropine or scopolamine; furthermore, a few display even greater preferential central activity than scopolamine. Some

synthetic agents24 can cause delirium with little or

no change in heart rate or other of the signs of peripheral muscarinic blockade.

The degree of preferential affinity for various

muscarinic cholinergic receptors in brain, heart, and

smooth muscle probably explains the relative lethality of the various anticholinergics.25 For example,

estimated potency of five different anticholinergics

in man based on heart rate is closely correlated with

their relative lethality in the rat,26 suggesting that

death at high doses is probably due to cardiotoxicity. Previously, central toxicity was considered to

be the cause of death from atropine. For humans,

the dose that is lethal to 50% of the exposed population (LD50) has been estimated to be about 100

mg.27 However, using data from numerous reports

of lethality and survival from high doses of atropine after reviewing more than 1,000 cases,

Goodman calculated, using probit analysis,28 the LD50

to be 453 mg (95% confidence level: 335–612 mg).

Combining these two analyses allows us to estimate the safety margin of various anticholinergics

in humans. For BZ and atropine, the ID50 is approximately 40-fold lower than the LD50; for scopolamine

and other more centrally potent anticholinergics,

the ID50 is approximately 100-fold lower than the

LD50. Computer models of dose distribution (using “Monte Carlo” statistical techniques) could perhaps use these dose ratios to help predict the probable number of lethalities (eg, if 50% of the target

population were to be incapacitated by a particular

agent, using a particular delivery system in a particular field situation). Clearly, however, this calculation would not be highly reliable.

The Most Likely Candidate: BZ or a Related

Glycolate

BZ was first experimentally studied for therapy

of gastrointestinal diseases. However, reports were

received of confusion and hallucinations, suggesting that even small excesses of dosage were likely

to cause problems. BZ was quickly withdrawn from

commercial study and turned over to the U.S. Army

as a drug of possible interest as an incapacitating

agent.

Structurally, BZ is 3-quinuclidinyl benzilate, today known to neuropharmacologists as QNB, a research standard for measuring central antimuscarinic activity.29,30 The code name BZ is probably

derived from benzilate, a molecular member of the

larger chemical family known as glycolates (glycolic

acid esters). BZ is a stable (environmentally persistent), crystalline solid, which makes it suitable for

dissemination by heat-producing (thermal) munitions.

Clinical Pharmacology of BZ

BZ’s clinical profile closely resembles that of atropine, differing significantly only in duration of

action and potency. Whereas the ID50 of atropine

(as free base) is approximately 140 μg/kg (8–14 mg

per soldier), the ID50 for BZ is only 6.2 μg/kg

(roughly 0.5 mg per soldier).31 Although BZ is

roughly 25-fold more potent centrally than atropine,

BZ is only 3-fold more potent than scopolamine.

This distinction is often not appreciated by

nonpharmacologists, and BZ erroneously gained

the reputation as an exceptionally potent and dangerous drug—not only in the popular press but also

in scientific publications. As a result, regulations

were issued by the U.S. Army Chemical Corps prohibiting the transport of even a few milligrams of

BZ (or any related agent of similar potency) aboard

a commercial airline!

Unlike the much-shorter-acting scopolamine,

BZ’s effectiveness by the oral route of administration is about 80% that of the intravenous or intramuscular routes (which are virtually identical). By

inhalation, if disseminated at an optimal particle

size (diameter about 1.0 μm), BZ is approximately

40% to 50% as effective as it is by injection. When

applied to the skin dissolved in propylene glycol

(a common vehicle for transdermal administration),

apparent absorption is only 5% to 10% and the effects are delayed approximately 24 hours. (This is

surprising since historical treatises suggest that belladonna drugs are readily absorbed from poultices.31)

MED50 is defined as the dose that is minimally

BZ effective for mild cognitive impairment in 50% of

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Medical Aspects of Chemical and Biological Warfare

296

the exposed population; it produces mild impairment (25% decrease) in Number Facility (NF) performance.32 The MED50 for BZ is approximately 2.5

μg/kg.33 Recovery from this dose occurs within 24

hours. As stated above, the ID50 for BZ is 6.2 μg/kg

and is defined as a persistent drop in performance

on the NF to below 10% of baseline.

The effects of BZ by any route are slow in onset

and long in duration. Performance decline is usually barely measurable at 1 hour, reaches a peak at

about 8 hours, and subsides gradually over the next

48 to 72 hours. The duration of incapacitation (defined as the period during which NF performance

remains below 25% of baseline) is approximately

24 hours at the ID50. Doubling the dose produces

incapacitation within 1 hour and prolongs recovery by approximately 48 hours. The effects of higher

doses in humans are not known but would presumably occur even more rapidly and last considerably

longer. In a field situation, wide variations in dosage would occur and mathematical models have

been used to calculate the results under various conditions, but these can only give approximate predictions.

Anticholinergic Delirium Produced by BZ

As mentioned earlier, delirium is a nonspecific

syndrome. Prior to the systematic study of anticholinergic delirium, however, correlation of the clinical features of delirium with performance of cognitive and other tasks under controlled conditions had

not been accomplished. In the following discussion,

aspects of delirium produced by anticholinergic

agents will be described in relation to associated

impairment in performance of various scoreable

tasks of military relevance.

Following the administration of BZ at the MED50,

delirium appears in its mildest form, represented

by a drowsy state, with occasional lapses of attention and slight difficulty following complex instructions. Moderate delirium (following doses of about

4 μg/kg) generally is manifested by somnolence or

mild stupor, indistinct speech, poor coordination,

and a generalized slowing in thought process, with

some confusion and perplexity.

Individuals receiving the ID50 or higher almost

always develop the full syndrome of delirium.

There is surprisingly little variation among individuals when anticholinergics are given. Perhaps

this is because these drugs operate more directly

on the “hardware” of the brain—neuronal systems

where “all-or-none” activity is more characteristic.

Drugs such as LSD or the amphetamines, for example, act on serotonin or dopamine systems. These

are modulatory rather than discrete in their actions;

that is, their effects may vary in accordance with

the prevailing mood, arousal, and motivational state

of the subject.

When delirium is present in its full-blown state,

the individual seems to be in a “waking dream,”

often staring and muttering, sometimes shouting,

as simple items in the environment are variably perceived as elaborate structures, animals, or people.

These hallucinations may arise from some trivial

aspect of the surroundings, such as a strip of molding, a pillow, or an irregular spot on the floor. A

total lack of insight generally surrounds these

misperceptions.

Another striking characteristic of delirium is its

fluctuation from moment to moment, with occasional lucid intervals and appropriate responses. An

individual might answer “Shakespeare” when

asked who wrote Hamlet, but when asked the same

question 5 minutes later, might get down on the

floor and attempt to remove an imaginary manhole

cover, or become absorbed in a miniature World

Series game being played out before his eyes.

“Phantom” behaviors, such as plucking or picking at the air or at garments, is characteristic

(whence the old term “woolgathering”). This “carphologia,” as it was known in the 19th century, can

be comical at times. When two individuals are

both delirious they may play off of each other’s

imaginings. A subject was once observed to

mumble, “Gotta cigarette?” and when his companion held out an invisible pack, he followed with,

“S’okay, don’t wanna take your last one.”

Recovery from drug-induced delirium is gradual,

with a duration presumably determined by the

pharmacokinetic persistence of the causative agent.

The more spectacular and florid hallucinations are

gradually replaced by more modest distortions in

perception. (Instead of large animals, mice and insects are described by the subject.) Awareness

gradually returns and with it comes the subject’s

partial insight that his mental faculties are not what

they should be. Ironically, paranoid tendencies

often emerge at this stage, as the individual senses

that something is amiss but cannot carry out the

reality testing required to rule out malevolent manipulation of the environment by others. A period

of restorative sleep generally precedes the return

to normal cognitive function.
Incapacitating Agents

297

DIAGNOSIS OF INCAPACITATING AGENT SYNDROMES

There is little likelihood that incapacitating

agents other than anticholinergics would be used

on the battlefield. They are the only type known to

be at all practical, as discussed earlier. Furthermore,

most potential enemies on today’s horizon seem to

have little inclination to use weapons of great

subtlety or ones that are designed to minimize lethality. There seems little probability that reversible incapacitating agents would even exist in their

arsenals.

Nonetheless, in view of the elusive maladies reported following Agent Orange exposure in the

Vietnam War and the so-called “Persian Gulf War

syndrome,” it is important that medical officers be

able to recognize chemical intoxication if it should

occur, lest impaired performance be inappropriately

attributed to stress, lack of motivation, or psychiatric illness. Fortunately, the effects of most anticholinergic agents are usually easily recognized. Medical students were long taught the old medical adage

“dry as a bone, red as a beet, hot as a hare, and mad

as a hatter” as a means of remembering belladonna

poisoning. The most useful diagnostic features of

anticholinergics, indoles, cannabinoids, and anxiety reactions, all which can be confused with the

signs of incapacitating agents, are summarized in

Table 11-1.

Depending on dosage and time elapsed following exposure, certain features may be more apparent. As mentioned earlier, peripheral symptoms of

tachycardia, dryness of skin and mucous membranes, and moderately elevated blood pressure

may be the most conspicuous signs during the first

few hours. Incoordination, confusion, and slurred

speech also appear early. Soon thereafter, mydriasis, stupor, and even coma may develop. If casualties are not examined until many hours have

elapsed, peripheral cholinergic blockade may have

largely subsided. Bizarre behavior (eg, groping,

undressing, mumbling) with failure to respond to

TABLE 11-1

DIFFERENTIAL DIAGNOSIS FOR INCAPACITATING AGENTS

Sign or Symptom Possible Etiology

Restlessness, dizziness, giddiness, failure to obey orders,

confusion, erratic behavior, stumbling or staggering,

vomiting

Dryness of mouth, tachycardia at rest, elevated temperature, flushed face, blurred vision, pupillary dilation,

slurred or nonsensical speech, hallucinatory behavior,disrobing, mumbling, picking behavior, stupor,

coma

Inappropriate smiling or laughing, irrational fear, distractibility, difficulty expressing self, perceptual distortions, labile increases in pupil size, heart rate, and blood

pressure, stomach cramps and vomiting

Euphoria, relaxation, day-dreaming, unconcerned attitude, easy laughter, hypotension and dizziness onsudden

standing

Tremor, clinging or pleading, crying, clear answers, decrease in disturbance with reassurance, history of nervousness or immaturity, phobias, bodily disturbances

such as blindness and paralysis

Anticholinergics, indoles, cannabinoids, anxiety reaction,

other intoxications (such as alcohol, bromides, lead,

barbiturates)

Anticholinergics

Indoles (may mimic schizophrenic psychosis in some

respects)

Cannabinoids

Anxiety reaction

Adapted from Departments of the Army, Navy, and Air Force, and Commandant, Marine Corps. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries. Washington, DC: HQ: DA, DN, DAF, Commandant, MC; 22 Dec 95: 3–1. Field

Manual 8-285, NAVMED P-5041, Air Force Joint Manual 44-149, Fleet Marine Force Manual 11-11.
Medical Aspects of Chemical and Biological Warfare

298

commands or conversation may then be the most

conspicuous feature.

As recovery begins, apparent normality may be

punctuated by sudden paranoid attempts to escape,

or fleeting but vivid hallucinations may impinge on

seemingly intact mentation. This is a time when

panic, with its well-known dangers, may suddenly

develop; vigilance (including restraint, if necessary)

may be medically needed.

As noted earlier, the synthetic glycolate anticholinergics (those that are known so far) vary tremendously in their potency and duration of action. Signs

and symptoms may last as little as 2 hours or as

long as several weeks. Also, unfortunately, some

glycolates produce few or no peripheral antimuscarinic features at the low end of the incapacitating

dose range. Even the pupils may not be greatly enlarged. Such agents may produce signs that are difficult to distinguish from naturally occurring psychoses, unless the observer is well versed in the

distinctly different pattern of cognitive changes that

are pathognomonic of delirium. The occurrence of

behaviors such as phantom drinking or smoking, picking or groping behavior, nonsensical speech, random

disrobing, and the inability to follow simple instructions should greatly assist in making the differential diagnosis in such cases.

Detecting the covert use of other agents (those

not suitable for large-scale dissemination) requires

some knowledge of the effects of LSD and other

psychedelics. Since LSD is a stimulant and usually

prevents sleep, medical officers should not expect to

see drowsiness or sedation. Staring, enigmatic smiling, and unusual preoccupation with ordinary objects are not uncommon. Responses to commands may

be superficially normal, but laughter may supervene,

or insubordinate and oppositional behavior. There are

no practical diagnostic tests (although a sensitive

fluorometric method for quantitative detection of

LSD is known,34 and blood samples could be useful

in making a definitive diagnosis at a later time).

Marijuana intoxication is common in areas where

the drug is indigenous, and the presence of reddened conjunctivae, along with the insouciance and

relaxed joviality that marijuana produces, should

make the diagnosis obvious. There is little likelihood that purified THC (tetrahydracannabinol, the

active component of cannabis) would be used in a

general military setting. Testing of blood and urine

could be used if there is a need for definitive proof

of its presence, but such tests are not always feasible or available.

With regard to covert use of incapacitating

agents, the differential diagnostic problem is no

different from that encountered in emergency

rooms, and standard textbooks and manuals provide adequate guidelines. The possibility that secret research might produce some highly potent,

unfamiliar variant of a known psychoactive drug

cannot, of course, be ruled out, and blood analysis

would seem the only way to determine its presence

and chemical structure. However, medical officers

in the field will be unlikely to encounter casualties

produced by totally unfamiliar chemical substances.

MEDICAL MANAGEMENT

BZ and Other Anticholinergics

Prior to the mid 1960s, standard pharmacological textbooks taught that no antidote was available

for the reversal of delirium caused by belladonnoid

drugs. In fact, however, such an antidote had been

reported by Kleinwachter35 in the German literature

in 1864. He noted that a lump of sugar saturated

with extract of the Calabar bean (a natural source

of physostigmine) proved efficacious in restoring

lucid mental function to a prisoner who had become

disoriented after drinking tincture of belladonna,

thinking it was alcohol. Apparently this serendipitous finding was overlooked by early 20th-century

clinical pharmacologists.

Nevertheless, reports36,37 of reversal by physostigmine of coma (produced by injected doses of atropine as high as 212 mg, as therapy for certain psychiatric disorders) reappeared during the 1950s.

Once again, this useful finding apparently received

little attention from mainstream clinicians. The fact

that physostigmine had been largely replaced in

clinical practice by neostigmine and pyridostigmine, neither of which has much central

antimuscarinic activity, may account for this curious oversight.

In 1963, the usefulness of physostigmine as an

antidote was once again reestablished during investigations of BZ’s effects in volunteers.31 In 1967, U.S.

Army physicians published the first double-blind

controlled study demonstrating the effectiveness of

physostigmine in reversing scopolamine delirium.38

Later, they reconfirmed this finding in studies39 of

atropine and Ditran (a mixture of two synthetic

belladonnoid glycolates, no longer available, that

had enjoyed brief popularity as a treatment for depression40). In the course of other military medical

studies, the drug was also noted to reverse the de-
Incapacitating Agents

299

lirium produced by a variety of synthetic anticholinergic glycolates.24,31,41–43 Similar findings were soon

reported in civilian studies.44 Deliria produced by

overdose with other drugs possessing anticholinergic

side effects, such as tricyclic antidepressants45 and

antihistamines (personal observation, J.S.K.), were

also noted to be treatable with physostigmine.

When given by the intravenous route, a dose of

30 μg/kg of physostigmine was found in further

military studies46 to be quite effective in the reversal of a variety of anticholinergics, although 45 μg/kg

was the initial dose needed to reverse more-severe

effects of delirium. It is interesting that physostigmine has also been used and reported to be effective for morphine-induced respiratory depression;

alcohol withdrawal; and the effects of heroin, diazepam, ketamine, and fentanyl. In these instances,

its activity may be due to a general direct cholinergic arousal effect, rather than to the inhibition of

cholinesterase.47 Case reports have come from the

director of the Rocky Mountain Poison Control Center, near Denver, Colorado,48 and the use of physostigmine as an antidote was reviewed by the director

of the Munich, Germany, Poison Control Center.49

Although doses of as little as 2 to 3 mg of physostigmine alone may cause nausea and other signs

of cholinergic excess (eg, salivation, intestinal

cramping, and diarrhea), an intramuscular dose of

4 mg is generally well tolerated without any side

effects when given as an antagonist to belladonnoid

intoxication. In more than 100 subjects treated by

one of the authors (J.S.K.), the only side effects were

transient fasciculations in the platysmal area in one

subject, and transient nausea and vomiting in a few

others. If physostigmine should be given in error

when no anticholinergic is present, its effects can

be reversed by intravenous or intramuscular administration of 1 to 2 mg of atropine. Rapid intravenous use of physostigmine is not recommended

because, in some individuals, the bolus effect on cardiovascular receptors may cause cardiac arrhythmias or even cardiac arrest. Most of these untoward

outcomes, however, have occurred in patients who

were in poor general health or suffering from heart

disease.

When in doubt as to diagnosis, an intramuscular test dose of 1 to 2 mg, repeated after 20 minutes

if no effects are noted, is recommended. Once the

diagnosis is established by a definite improvement

in mental status, improvement can be sustained by

repeating the treatment at intervals of 1 to 4 hours.

Dosage and frequency should be dictated by clinical judgment. For example, after 30 to 60 minutes,

heart rate will rise as the effects of physostigmine

wane, and intellectual acuity will fade. Mental status can easily be estimated by having the subject

do serial subtraction by 7 or 3; or by asking him to

repeat a sentence containing a name, location, occupation, and employer; or by asking him simple

questions regarding time, place, and person.

A solution of physostigmine is best administered

orally, mixed with fruit juice to mask its bitter taste.

Administered parenterally, only two thirds as much

drug would be required to produce the same effects.

A publication50 distributed within the U.S. Army

Medical Department contains detailed directions on

how to dilute the parenteral preparation for oral

use. In a combat zone, the oral route may be the

only practical method to treat large number of casualties, relying on technicians (or, if necessary,

other soldiers who are unaffected) to give measured

amounts at specified intervals. With skillful titering,

performance close to preexposure levels can be

maintained. If the situation requires only that the

soldier be comfortable and manageable, it is better

to use a more conservative approach (eg, 1–2 mg

by intramuscular injection or 2–4 mg administered

orally every 2 h).

Once a suitable level of reversal is achieved (after 3 to 4 doses), delirium caused by BZ or other

long-acting glycolates will usually relapse to its

untreated severity in about 6 hours. (Shorter-acting belladonnoids such as atropine and scopolamine may be cleared from the brain by that time

and thus further treatment may not be required.)

The value of physostigmine in restoring and maintaining normal performance in a soldier given an incapacitating dose of BZ is illustrated in Figure 11-1.

51

In another study, a single individual was given

6.4 mg of BZ intramuscularly and treated with a

placebo; he was totally unable to perform simple

arithmetic (the NF test) for approximately 48 hours.

On a second occasion 14 days later, he was given

the same dose of BZ and treated with a total of more

than 200 mg of physostigmine over a 72-hour period

without apparent ill effect. Not only could he perform

at levels close to his baseline, but he generally felt

normal and could eat, play pool, and read without

difficulty as long as treatment was continued.31

For reasons that are not fully understood, physostigmine is relatively ineffective if given during

the first 4 to 6 hours following the onset of BZ effects. Physostigmine is likewise ineffective if given

earlier than 45 minutes following administration of

the shorter-acting scopolamine.38 Also, use of the

antagonist does seem to not shorten the duration

of the underlying intoxication; in fact, if treatment

is not maintained, recovery from intoxication may
Medical Aspects of Chemical and Biological Warfare

300

Fig. 11-1. The effectiveness of physostigmine in the treatment of 3-quinuclidinyl benzilate (QNB) intoxication. The

three graphs above are the summary record of Number Facility performance, top, and heart rate (HR), bottom, in a

single volunteer after the administration of QNB (the Rx), center. An aerosol dose (particle size < 1.0 μm) of approximately 7.5 μg/kg (120% of the incapacitating dose) was administered via the inhalational route. Treatment with

physostigmine was begun 6 hours after aerosol exposure (peak impairment occurs at 6–10 h). Without treatment,

recovery from an incapacitating dose of QNB is gradual, requiring 72 to 96 hours. The effectiveness of physostigmine

is evident. Adapted from Ketchum JS, Tharp B, Crowell E, Sawhill D, Vancil M. The Human Assessment of BZ Disseminated Under Field Conditions. Edgewood Arsenal, Md; 1967. Edgewood Arsenal Technical Report 4140.

Elapsed Time (h)

Elapsed Time (h)

Heart Rate (beats/min) Physostigmine (mg) Number Facility Score (as % of baseline)

Elapsed Time (h)
Incapacitating Agents

301

be slightly prolonged.31 Unknown pharmacokinetic

or metabolic factors may underlie these curious

phenomena. The practical implication, in any case,

is that the treatment team should not be discouraged if early administration of physostigmine fails

to bring about immediate, dramatic improvement.

Whether or not physostigmine is a fielded drug

and therefore available to medical officers in

deployable hospitals, ancillary supportive measures

for such signs and symptoms of delirium as disorientation, hyperthermia, decreased salivation, and

self-inflicted injuries to the skin are important, as is

evacuation to an appropriate hospital (Exhibit 11-2).

As pharmacologists know well, physostigmine

is an acetyl (or “true”) cholinesterase inhibitor and,

as discussed above, is an effective antagonist to

cholinergic blocking compounds. A simplistic view

of this phenomenon is that the excess acetylcholine

created by the inhibition of the enzyme might antagonize (overcome) the effects of the blocker. The

nerve agent VX, also an acetylcholinesterase inhibitor, has also been used successfully in the reversal

of BZ.52 Pseudocholinesterase inhibitors, such as

diisopropyl fluorophosphate (DFP), are less effective.39 Tetrahydroaminoacridine (THA, also called

tacrine), currently approved for use in senile dementia, Alzheimer’s type, is also primarily a

pseudocholinesterase inhibitor. In four subjects, 200

mg of oral THA was administered as an antagonist

against BZ and proved moderately effective.31 It was

noted, however, to cause temporary changes in hepatic function tests and therefore was abandoned.

Physostigmine is probably not as highly regarded

as it was during the 1970s and 1980s, when it was

given to patients with a variety of intoxications,

often without a rational indication. On the other

hand, physostigmine is probably not as dangerous

as current thinking and textbooks would indicate.

It has predictable effects, and there are specific indications for its use. A drug with such potent vagal

blocking activity probably should not, as mentioned

earlier, be given rapidly by the intravenous route

(risking a sudden bolus effect on cardiovascular

receptors), since it is almost equally effective when

given intramuscularly. The brief delay in absorption will rarely make a significant difference.

EXHIBIT 11-2

ANCILLARY SUPPORTIVE MEASURES FOR THE TREATMENT OF DELIRIUM

1. Control and containment are of primary concern since delirium can easily lead to accidents and

inadvertent injury to others. Comatose or stuporous casualties may emerge from immobility into a

stage of persistent crawling or attempted climbing (primitive behaviors sometimes called “progresso

ostinato” [obstinate progression] in 19th-century descriptions of delirium). It is better to tether or

otherwise loosely restrain individuals who are disoriented than to let them move about freely without

close supervision.

2. The danger of hyperthermia must be considered if the environment is warmer than 75°F. Death from

relatively low doses of anticholinergics has occurred due to impairment of sweating. Wet cloth is effective to reduce body temperature, and the casualty should be placed in the shade, if available.

3. Dryness of the mouth and parching of the lips should be managed with moist swabs and small amounts

of vaseline or unguents. Hard candy may induce sufficient salivation to keep the tongue moist. Fluids

should be given sparingly and food withheld until the individual is obviously capable of normal chewing and swallowing.

4. Significant skin abrasions can be caused by persistent repetitive movements, especially against rough

surfaces. The use of wrappings or gloves may be useful. A tendency to remove clothing is common,

and reflects a general regression to simple habitual behaviors. If the environment is harsh, the casualty’s

clothing may have to be secured so it cannot be removed.

5. Evacuation from the field to more adequate medical facilities is desirable in most cases. If not possible,

separation of affected individuals into small groups (eg, in tents) is preferable to large aggregations, where a few confused and hyperactive individuals can lead to an escalating problem of crowd

control.
Medical Aspects of Chemical and Biological Warfare

302

If administered by the intravenous route, a dose

of 30 μg/kg (about 2 mg in a 70- to 75-kg person) is

quite effective in reducing peripheral effects such

as tachycardia and hypertension; higher doses (at

least 45 μg/kg) are usually needed to significantly

reverse the more-severe central cognitive effects.46

Again, this route of administration should be used

with great caution in patients who are already receiving other drugs that predispose to convulsions

or cardiac arrhythmias.53 If in doubt, medical officers might consider trying a small (< 1 mg) test dose

before administering fully effective quantities. This

amount will not generally completely reverse the

central nervous system signs but may give detectable indications that the antidote is effective. Furthermore, a dose this small will not adversely affect the average adult who has not been exposed to

an anticholinergic compound.

LSD, Other Indoles, and Phenethylamine

Derivatives

In the unlikely scenario where psychedelic compounds such as LSD or one of the more potent

phenethylamine analogs are encountered on the

battlefield, depressant drugs are useful, even if suboptimal, antidotes. For many years, chlorpromazine

(Thorazine, manufactured by SmithKline Beecham

Pharmaceuticals, Philadelphia, Pa.) was the preferred treatment of “bad trips” caused by LSD. Only

moderate (although dose-related) improvement in

performance was demonstrated in our laboratories

when a 50- to 100-μg/kg dose of Thorazine was

administered orally, 60 minutes following intravenous administration of 2 μg/kg of LSD.54 More recently, the short-acting benzodiazepines, such as

lorazepam (Ativan, manufactured by Wyeth-Ayerst

Laboratories, Philadelphia, Pa.), have been widely

used to good effect. Surprisingly, a leading clinical

psychopharmacologist55 recommended barbiturates

to one of the authors (J.S.K.) during a recorded interview, on the grounds that LSD was a highly effective antagonist to barbiturates in laboratory studies. To our knowledge, this suggestion has not systematically been tested in humans.

Opioids

The treatment of opioid overdose is well established. Naloxone (Narcan, manufactured by Du

Pont Multi-Source Products, Garden City, N. Y.) in

doses of 0.4 to 1.0 mg has been recommended,56 and

is the standard treatment in most emergency rooms.

Naloxone can be given subcutaneously or, if the

soldier appears to be deeply comatose with severely

depressed respirations, by the intravenous route.

Repeated injections at intervals as short as 30 to 60

minutes are usually required in the presence of a

large overdose to prevent relapse into coma with a

possibly fatal outcome.

SUMMARY

Incapacitating agents, capable of temporarily

preventing military personnel from performing

their duties (without permanent injury), have a long

and colorful history. For a variety of reasons, they

have not generally been used in overt warfare in

the 20th century. Preference for conventional lethal

weapons by most aggressors, and the many uncertainties applying to their use by friendly nations,

have led to their elimination from the United

States’s arsenal. However, in the attempt to find an

incapacitating agent that would meet the numerous constraints imposed by practical and political

concerns, many studies were conducted, especially

by the U.S. Army, during the 1960s. Although an

ideal incapacitating agent was never found, much

was learned from the search.

Of all known psychochemical options, anticholinergics appear to be the most feasible for military

use. 3-Quinuclidinyl benzilate (BZ) or a related

potent glycolate seem to be the most likely candidates among the many that have been studied. Following an absorbed dose of less than 1 mg, BZ produces an acute brain syndrome, best described as

delirium, that lasts 2 to 3 days.

Reversal of the effects of BZ by physostigmine

and other anticholinesterase agents has been clearly

demonstrated to be both effective and safe when

properly used in otherwise healthy individuals. The

benefits and methods of use of physostigmine were

brought to the attention of modern medicine by U.S.

Army medical officers, who conducted these studies.

Incapacitation produced by less likely candidates

such as LSD and other indole derivatives, psychedelic phenethylamines, and potent opioids is theoretically possible, but it is unlikely that any of these

compounds would be employed militarily. Covert

use, which is logistically easier to accomplish and

has fewer constraints, opens a broader spectrum of

possibilities. This, however, is a concept that involves considerations that generally extend beyond

the scope of chemical warfare.
Incapacitating Agents

303

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Drug Intoxication. Biomedical Laboratory, Edgewood Arsenal, Md; 1976. EB-TR-76-12.

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50. Directorate of Medical Research. Guide to the Management of BZ Casualties, I. Edgewood Arsenal, Md; 1965.

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Conditions. Edgewood Arsenal, Md; 1967. Edgewood Arsenal Technical Report 4140.

52. Sidell FR, Aghajanian GK, Groff WA. The reversal of anticholinergic intoxication in man with the cholinesterase inhibitor VX. Proc Soc Exp Biol Med. 1973;144:725–730.

53. Lipka LJ, Lathera CM. Psychoactive agents, seizure production, and sudden death in epilepsy. J Clin Pharmacol.

1987;27:169–183.

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55. Freedman DX. Chairman and Professor of Psychiatry and Pharmacology, University of Chicago Medical School,

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307

Chapter 12

RIOT CONTROL AGENTS

FREDERICK R. SIDELL, M.D.*

INTRODUCTION

HISTORY

CS (o-CHLOROBENZYLIDENE MALONONITRILE)

Physical Characteristics

Clinical Effects

CN (1-CHLOROACETOPHENONE)

Physical Characteristics

Clinical Effects

SEVERE MEDICAL COMPLICATIONS FROM THE USE OF CS AND CN

OTHER RIOT CONTROL COMPOUNDS

DM (Diphenylaminearsine)

CR (Dibenz(b,f)-1:4-oxazepine)

CA (Bromobenzylcyanide)

MEDICAL CARE

Decontamination

Skin

Eye

Respiratory Tract

Cardiovascular System

FUTURE USE

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014
Medical Aspects of Chemical and Biological Warfare

308

INTRODUCTION

Riot control agents are compounds that cause

temporary incapacitation by irritation of the eyes

(tearing and blepharospasm), causing them to close,

and irritation of the upper respiratory tract. They

are often called irritants, irritating agents, and harassing agents; the general public usually calls them

tear gas. Like most of the other chemical agents discussed in this textbook, riot control agents are

known by two-initial designators that are neither

abbreviations nor acronyms of their chemical names

but are most akin to code names. Hence an explanation of the derivations of the names is usually

not attempted here.

Three types of riot control agents are recognized:

lacrimators, which primarily cause lacrimation and

eye irritation; sternutators, which mainly cause

sneezing and irritation of the upper respiratory

tract; and vomiting agents, which additionally

cause vomiting. Because these compounds—CS,

CN, DM, CR, and CA—have a number of characteristics in common, they are grouped together as

riot control agents in this chapter. The small distinctions among them are noted in the discussion

of each agent. Table 12-1 lists the chemical, physical, environmental, and biological properties of the

three major agents: CS, CN, and DM. Characteristics common to all compounds in this category are

• a rapid time of onset of effects (seconds to

several minutes),

• a relatively brief duration of effects (15–30

min) once the victim has escaped the contaminated atmosphere and has decontaminated (ie, removed the material from his

clothing), and

• a high safety ratio (the ratio of the lethal

dose [estimated] to the effective dose).

Riot control agents all produce effects by sensory

irritation, causing extreme discomfort or pain in the

organs affected. The eyes, nose, and respiratory tract

are the primary organs affected, although the skin

is also often involved. The compounds produce

temporary disability because the extreme eye irritation and blepharospasm cause the eyes to close

temporarily, and the irritation of the airways causes

coughing, shortness of breath, and sometimes retching or vomiting. One of these compounds, DM, is

noted for also causing vomiting and malaise.

The United States does not recognize riot control agents as chemical warfare agents as defined

in the Geneva Convention of 1925. The Geneva Gas

Protocol of 1925 was ratified by the United States

on 22 January 1975. At that time, the United States

interpreted the protocol as prohibiting the first use

of lethal chemicals, but not of nonlethal ones such

as riot control agents or herbicides.

During the Vietnam War, before the protocol ratification, the United States had used the riot control

agent CS (o-chlorobenzylidene malononitrile) extensively. On 8 April 1975, President Ford signed Executive Order 11850, which unilaterally renounced

first use of riot control agents in armed conflict, with

specified exceptions. These exceptions include first

use for riot control in areas under direct U.S. military control (including control of rioting prisoners

of war), use in rescue operations, use in situations

in which civilians screen or mask attacks, and use

in rear echelons to protect convoys from terrorists

or similar groups. Presidential approval is required

in advance for either first or retaliatory use of riot

control agents in war.

Of all the compounds discussed in this book, riot

control agents are perhaps the most scrutinized by

the public. In civilian life, law enforcement agencies use riot control agents in civil disturbances,

riots, or to avoid using deadly force. The military

commonly uses them in training. The symptoms

described below, therefore, will be familiar to most

military personnel.

HISTORY

Irritant compounds were allegedly used by

Marcus Fulvius against the Ambracians in the second century BC. The Byzantines apparently knew

of the efficacy of using irritant substances to harass

the enemy. Plutarch described a Roman general who

used an irritant agent cloud in Spain to drive the

enemy out of concealment in caves,1

 a use similar to

that of the United States in Vietnam 2,000 years later.

Modern use probably began in the 1910–1914 period, when ethylbromoacetate was employed against

criminals by French police. At the beginning of World

War I, some of these former policemen, who were then

in the French army, began to use some of these munitions on the battlefield with some degree of success.

Although the German use of chlorine at Ypres, Belgium, on 22 April 1915 is generally heralded as the
Riot Control Agents

309

TABLE 12-1

CHEMICAL, PHYSICAL, ENVIRONMENTAL, AND BIOLOGICAL PROPERTIES OF CS, CN, AND DM

Properties o-Chlorobenzylidene 1-Chloroacetophenone Diphenylaminearsine

Malononitrile (CS) (CN) (DM)

Chemical and Physical

Boiling point 310°C 248°C 410°C with decomposition

Vapor pressure 0.00034 mm Hg at 20°C 0.0041 mm Hg at approx 20°C 4.5 x 10-11 mm Hg at 25°C

Density:

Vapor — 5.3* —

Liquid — 1.187 g/mL at approx 58°C —

Solid Bulk: 0.24–0.26 g/cm3 1.318 g/cm3 at approx 20°C Bulk: < 1 g/cm3

Crystal: 1.04 g/cm3 Crystal: 1.65 g/cm3 at 20°C

Volatility 0.71 mg/m3 at 25°C 34.3 mg/m3 at approx 20°C Not of practical significance

Appearance and odor White crystalline powder Fragrant (like apple blossoms) Yellow-green, odorless,

with pungent odor (pepper) crystalline substance

Solubility:

In Water Insoluble Insoluble 0.0064 g/100 g at room

temperature

In Other Solvents Organic solvents: complete Organic Best: acetone, 13.03 g/100 g

at 15°C

Environmental and Biological

Detection No detector No detector No detector

Persistency:

In Soil Varies Short Persistent

On Materiel Varies Short Persistent

Skin Decontamination Soap and water Soap and water Soap and water

Biologically Effective

Amount:

Aerosol LCt50: 60,000 LCt50: 7,000–14,000 LCt50: 11,000–35,000

(mg•min/m3) ICt50: 3–5 ICt50: 20–40 ICt50: 22–150; nausea,

vomiting: approx 370

*Compared with the density of air

LCt50: the concentration • time (Ct) that is lethal to 50% of the population exposed

ICt50: the Ct that incapacitates 50% of the population exposed

beginning of chemical warfare on the modern battlefield, irritating substances had already been in use for

about a year. During World War I, approximately 30

different compounds were tried for their irritant effects, usually without much success.2

 As noted above,

a riot control agent was widely used in the Vietnam War.

Riot control agents gained some notoriety when

they were used in civil disturbances in Paris, France,

in 1968; in Londonderry, Northern Ireland, in

1969; in several protest demonstrations in the
Medical Aspects of Chemical and Biological Warfare

310

United States in the late 1960s; and in prison riots.

More recently, riot control agents were used in an

unsuccessful attempt to drive the Branch Davidians

from their compound near Waco, Texas, in February 1993.

Probably the best known of these compounds is

CN (1-chloroacetophenone); it has been used for

many years and is commercially available in devices

for self-protection under its proprietary name, Mace

(the chemical, not the devices, is manufactured by

General Ordnance Equipment Corp., Pittsburgh,

Pa.). CS is the compound that is used by the military in most countries and almost exclusively by

law enforcement agencies throughout the world.

CS (o-CHLOROBENZYLIDENE MALONONITRILE)

The riot control agent known as CS (o-chlorobenzylidene malononitrile) was first synthesized in

1928 by Corson and Stoughton (hence its code

name). It replaced CN as the standard riot control

or irritant agent in the U.S. Army in 1959. In the

late 1950s, CS was also adopted by most U.S. law

enforcement agencies and by the military and law

enforcement agencies of other countries, because CS

is more effective than CN (it causes effects at lower

doses) and is less toxic (ie, its LCt50, the vapor or

aerosol exposure [concentration • time] that is lethal to 50% of the exposed population, is higher).

Physical Characteristics

CS is a white, crystalline solid with a low vapor

pressure. It is almost insoluble in water and only

slightly soluble in ethyl alcohol and carbon tetrachloride. Because of these physical characteristics,

decontaminating buildings, furniture, and other

material after CS use in urban riots is difficult. Dissemination of CS can be by explosive dispersion of

a powder or solution, by dispersion of the powder

in a fine state, by spraying a solution, or by releasing as smoke from a pyrotechnic mixture.3

 The

method of dissemination may influence the severity of the injury (see eye injury for CN). The Material Safety Data Sheet, which the manufacturer includes in each package, assigns it a flammability

rating of 4 (on a scale of 0 to 4). The agent was a

large contributor in the conflagration that burned

the Branch Davidian compound and its inhabitants

in Waco, Texas, in 1993.

CS tends to agglomerate when used and resists

weathering poorly (losing its effectiveness). During the mid 1960s, hydrophobic formulations of CS,

CS1 and CS2, were developed. The former is a micronized powder with 5% hydrophobic silica aerogel; the latter is a siliconized, microencapsulated

form of CS1. CS1 and CS2 last for several weeks

and are a persistent hazard during military operations. Because of their persistence, they have not

been used for civil disturbances.

Clinical Effects

Clinical effects common to all of these riot control agents are listed in Exhibit 12-1. In the eye, an

initial burning feeling or irritation progresses to

pain accompanied by blepharospasm, lacrimation,

and conjunctival injection. The intense blepharospasm causes the eyes to close. Photophobia is often present and may linger for an hour. The mucous membranes of the mouth, including the tongue

and palate, have a sensation of discomfort or burning, with excess salivation. Rhinorrhea is accompanied by pain inside the nose and perhaps around

the external nares. When inhaled, these compounds

cause a burning sensation or a feeling of tightness

in the chest, with coughing, sneezing, and increased

secretions. On unprotected skin, especially if the air

is warm and moist (see skin effects of CS), these

agents cause tingling or burning; within a few minutes, erythema may develop at the exposed sites.

Tolerance to Exposure

Typically, effects appear within seconds of exposure to an aerosolized compound and worsen as

long as one remains in the cloud. Most effects slowly

dissipate, starting within a few minutes after one

leaves the contaminated area. By 30 minutes, most

effects have completely abated, although the usually mild erythema may persist for 1 to 2 hours. If

one does not leave shortly after the onset of irritation, the effects might become more severe, with

marked coughing, gagging, retching, and vomiting.

Most individuals note marked harassment at a

concentration of 3 to 5 mg/m3 and leave the area

Cl

C

H

C

CN

CN

CS
Riot Control Agents

311

EXHIBIT 12-1

CLINICAL EFFECTS OF RIOT CONTROL

AGENTS

Eye

Burning, irritation

Conjunctival injection

Tearing

Blepharospasm

Photophobia

Skin

Burning

Erythema

Gastrointestinal Tract

Gagging

Retching

Vomiting

Airways

Sneezing

Coughing

Tightness in

the chest

Irritation

Secretions

Nose

Rhinorrhea

Burning pain

Mouth

Burning of mucous

membranes

Salivation

as soon as possible.4 Tolerance develops, however,

in those who have been in close contact with CS for

a period of time, such as production or laboratory

workers. Those who have developed tolerance can

stay in their accustomed concentration of CS and

the discomfort does not increase, and, in fact, may

decrease. Those who work in a CS environment and

get CS on their clothing often become so accustomed to its effects that they wear the clothing out

of the area without remembering, only to have others complain.

Tolerance was examined experimentally in an

early study5

 in which men were placed in a concentration of 0.43 mg/m3; the concentration was slowly

increased to 2.0 mg/m3 over 60 minutes. If the men

were able to withstand the initial effects, they could

remain at the higher concentration. During this time,

some subjects played cards and two attempted to read.

In a similar study,4 when four subjects were exposed to a low concentration that was increased to

6 mg/m3 over 10 minutes, three subjects left before

the time was up. In contrast, when the same subjects were exposed to the same low concentration

that was slowly increased to 6 mg/m3 over a 30-

minute period, three remained for 30 more minutes

(the fourth subject left after 2 min because of coughing, but voluntarily returned for the remainder of

the period). Individuals did not develop tolerance

to the compound after ten exposures of 1 to 13 mg/

m3 over a 2-week period.

Duration of tolerance was reduced in exercising

individuals, presumably because of deeper breathing and deeper penetration of the particles into the

lung, and chest symptoms were more pronounced

than when the subjects were exposed while resting.

An increase in tolerance was noted when the temperature was low (–18°C; 0°F); a slight decrease in

tolerance occurred in a hot environment (36°C). Skin

symptoms (such as a burning sensation) were more

prominent at the hot temperature than at moderate

(20°C–32°C) temperatures.4

One might expect that personality and mental set

could determine tolerance to CS; a dedicated hijacker,

for example, might be able to resist its effects. To

test for a correlation between personality and tolerance to an irritant compound, a group of men

were exposed to CS, then tested on the Minnesota

Multiphasic Personality Inventory (MMPI).6

 Those

individuals with less tolerance to CS were characterized by the MMPI by greater use of denial, repression, and somatic complaints than the more

tolerant group. Furthermore, the more tolerant

group had a higher mean general intelligence score

(127 compared with 100 for the less tolerant group).

In a similar study,7 subjects with high scores classified as abnormal on certain MMPI scales tolerated

less CS than did subjects with normal scores. After

the administration of diazepam, the tolerance to CS

was significantly increased in the group with abnormal scores, but not in the group with normal

scores. This result suggests that anxiety, which was

reduced more by diazepam in the group with abnormal scores, plays a role in tolerance.

Respiratory Tract Effects

Inasmuch as CS is usually disseminated as an

aerosol (powder or in solution), the most common

route of absorption is by inhalation. In an LCt50

study,8 four species (rat, rabbit, guinea pig, and

mouse) were exposed to aerosolized CS powder for

5 to 60 minutes. The LCt50 values (based on mortality within 14 d) ranged from 50,010 mg•min/m3

(in the mouse) to 88,480 mg•min/m3 (in the rat).

No animal died during exposure; most of those that

died afterwards did so within 2 days. The lungs of

those dying were congested and edematous, and

many had hemorrhages. The trachea was congested

with moderate amounts of mucus. On microscopical examination, moderate to marked congestion of
Medical Aspects of Chemical and Biological Warfare

312

alveolar capillaries and intrapulmonary veins, inter- and intraalveolar hemorrhages, and excess secretions in the smaller airways were seen. Animals

that died after 48 hours also had evidence of early

bronchopneumonia. Those that survived for 14 days

had normal lungs on gross and microscopic examination.

Pyrotechnically dispersed smoke from a CS grenade was used in a similar study design with the

same four species.9 At high concentrations and exposure times of 5 to 20 minutes, the LCt50 values

(based on mortality within 14 days) ranged from

35,000 mg•min/m3 (in the guinea pig) to 76,000

mg•min/m3 (in the mouse). No animal died during exposure, and only two died within 12 hours of

removal from the chamber. With concentrations

ranging from 31.9 to 56.4 mg/m3 and a 5-hour per

day exposure for 1 to 7 days, the LCt50 values (14-

day mortality) were from 25,000 mg•min/m3 (rat)

to 54,000 mg•min/m3 (rabbit).

The lungs of animals that died before 14 days

were edematous and congested, with areas of hemorrhage and excessive amounts of mucus in the trachea and bronchi. The alveolar capillaries and intrapulmonary veins were congested, with areas of

alveolar hemorrhages and hemorrhagic atelectasis.

A few had edema, but no inflammatory cell infiltration was noted. In addition, most animals had evidence of circulatory failure, with dilated right ventricles and enlarged livers, kidneys, and spleens.9

Animals that survived 14 days had no abnormalities on pathological examination. The investigators

pointed out that the presence of pulmonary edema

and hemorrhages in the absence of inflammatory

cell infiltration suggests that the smoke caused direct injury to the pulmonary capillary endothelium

and that the main cause of death was pulmonary

damage. They also commented that, because of the

agglomeration of the smoke particles and subsequent precipitation of the compound, concentrations as high as those used could not be maintained

under operational conditions.9

Two hundred sixty-four rats and 250 hamsters

were exposed to CS concentrations of 750, 480, or

150 mg/m3 for 30, 60, or 120 minutes, respectively

(the calculated Ct values were 22,500, 28,800, and

18,000 mg•min/m3, respectively). Only one animal

died in the first 6 hours after exposure; 33 died

within 48 hours, and 31 of these were in the 480-

mg/m3 (60-min) group. Those dying within 48

hours had moderately severe congestion in the

lungs, with alveolar hemorrhage and edema in

some. Acute tubular necrosis was present in some

of the animals. In contrast, no deaths occurred (in

48 animals) within 48 hours in the 750-mg/m3

group, and only two deaths (in 240 animals) occurred in the 150-mg/m3 group. In these animals

and in those sacrificed at 24 hours and onward,

minimal abnormalities were found.9

In a continuation of this study,9 rats were exposed

to CS at 1,000 to 2,000 mg/m3 for 5 minutes per day

for 5 days. None of the rats died. Minimal pathological changes were found on sacrifice of the animals, but 5 of 56 had bronchopneumonia. A group

of 50 rats was exposed to a concentration of 12 to

15 mg/m3 for 80 minutes daily for 9 days.9 Five rats

died from bronchopneumonia and on sacrifice, 5 of

the remaining 45 rats were found to have bronchopneumonia.

In a long-term study,10 mice were exposed to 3 or

30 mg/m3 of CS for 60 minutes per day for 55 exposures and then observed for 6 months longer. A

daily exposure of 192 mg/m3 for 60 minutes per

day was stopped after three exposures because of

deaths. Rats and mice were also exposed to these

doses daily for 120 days; daily exposure at 236 mg/

m3 was stopped after 5 days. At the two low concentrations (3 and 30 mg/m3), the number of deaths

over the year of study did not exceed the number

of deaths in control groups, which were exposed to

air in the exposure chamber daily. After a year, mice

receiving 30 mg/m3 had a statistically significant

increase in chronic laryngitis and tracheitis, but otherwise the pathological findings for these animals

were not different from those of the control group.

In particular, no relationship was found between

specific tumors and the total dose of CS.

Dermatological Effects

CS is a primary irritant to the skin. In addition,

individuals may develop allergic contact dermatitis after an initial, uneventful exposure to it.

Typically, several minutes after an acute exposure to a low concentration of CS, a prickly feeling

or burning is felt in exposed areas of skin. This sensation is more noticeable if the skin is wet or freshly

abraded (eg, after shaving). The sensation may be

accompanied or followed by erythema, which usually persists for an hour or less. Under certain circumstances—involving the amount of CS, the temperature, and the humidity—a more intense

erythema may follow about 2 hours later. If the

amount of CS, the temperature, and the humidity

are all high, the erythema becomes even more severe, and edema and vesication appear hours later.

The time course is the same as that for the skin damage after exposure to mustard.
Riot Control Agents

313

To test the effects of CS on human skin, the arms

of volunteers were exposed to high concentrations

of CS thermally generated from an M7 grenade.11

The exposure was at a temperature of 36°C and

humidity of 100%; the average concentration was

300 mg/m3, and exposure times ranged from 15 to

60 minutes. All subjects noted stinging about 5 minutes after onset of exposure. After being withdrawn

from the apparatus, the arms were rinsed with cold,

running water to remove the powder that clung to

hairs; this procedure caused the stinging to increase.

Ct values of 4,440 and 9,480 mg•min/m3 caused

an immediate skin response: a patchy, vascular

erythema, which subsided after 30 minutes with no

further reaction.

Ct values of 14,040 and 17,700 mg•min/m3

caused a more severe initial dermal response, which

required 3 hours to disappear. After 12 to 24 hours,

a delayed reaction, consisting of first- and seconddegree burns, appeared. Blistering occurred in four

of the eight subjects (Figure 12-1). With treatment

(discussed below), these lesions resolved in 10 to

14 days; by 6 weeks later, a small amount of postinflammatory pigmentation remained.11

By means of a sleeve with removable patches,

arms of volunteers in another study12 were exposed

to CS thermally generated from an M7 grenade. The

patches were removed at appropriate times to give

Ct exposures of 1,550 to 33,120 mg•min/m3 at tropical conditions (37°C; 98% relative humidity) or at

one of three temperate conditions (14°C and 41%

relative humidity; 20°C and 95% relative humidity;

22°C and 72% relative humidity). No subjects at

14°C or 22°C had the delayed erythema at Ct values of up to 25,560 mg•min/m3. At 20°C (95% relative humidity), all four subjects had minimal delayed erythema at Ct values of 26,025 or 30,240

mg•min/m3. In contrast, at the tropical conditions,

the effective Ct for producing delayed erythema

was 3,500 mg•min/m3.

The authors of the study pointed out that many

variables make it difficult to predict which individuals might be more sensitive than others. Among

these variables are skin pigmentation, eye color,

complexion, and susceptibility to sunburn.12

Although the conditions of these studies were

severe, serious skin reactions can occur under

milder, more common conditions. First- and seconddegree burns were produced in a group of

U.S. Army Chemical Corps officers on a field exercise.13 Temperature and humidity were high, it had

been raining heavily, and their uniforms were

soaked through. The officers, who were wearing

fatigues, ponchos, and M17 protective masks, were

hit with a cloud of micropulverized CS1 from a disperser; soon afterwards, they noted burning of their

unprotected skin. About 2 hours later, some of the

men hosed off and some changed clothes, but most

did neither. About 14 to 16 hours after exposure,

blistering began, and all of the men who had not

hosed off or changed clothes eventually developed

vesication.

Firemen in Washington, D. C., were frequently

exposed to CS during the riots of April 1968; in addition, they were exposed to CS as they entered

buildings in which CS had been disseminated. The

CS on floors or furniture was reaerosolized both by

their movement and by the force of water from their

hoses. They later developed erythema and edema

of periorbital skin and other exposed areas.14

b

Fig. 12-1. (a) Erythema 25 hours after exposure to a high Ct (the product of concentration of vapor or aerosol • time

of exposure; in this instance, 14,040 mg•min/m3) of CS at 97°F and 100% humidity. (b) The same skin lesions at 45

hours, with vesication. Reprinted from Hellreich A, Goldman RH, Bottiglieri NG, Weimer JT. The Effects of ThermallyGenerated CS Aerosols on Human Skin. Edgewood Arsenal, Md: Medical Research Laboratories; 1967: 19. Technical

Report 4075.

a
Medical Aspects of Chemical and Biological Warfare

314

Earlier investigators reported vesication after CS

patch testing.4 They also mixed CS with sodium

hypochlorite (household bleach) and found that in

all subjects tested, the product caused a reaction that

was much more severe than that produced by CS

alone. For that reason, hypochlorite is not recommended for decontamination of CS on skin. (A hypochlorite is successfully used as a decontaminant for

most other chemical agents.)

CS is a primary irritant and causes contact dermatitis, typically in workers in CS-manufacturing

or -packing plants. A reaction is more common in

warm weather and high humidity or in sweating

subjects. The lesion begins some hours after exposure as an erythema, with burning and stinging; the

area becomes edematous at about 24 hours, then

vesicles or bullae may appear. Common sites are

those of partial occlusion, such as the areas under

the cuff or glove and under the shirt collar.

CS is also a sensitizer and can cause allergic contact dermatitis, which is the result of a delayed hypersensitivity reaction. An initial exposure may not

cause a reaction, but a later exposure to even a small

amount produces an often severe dermatitis, with

erythema, edema, vesication, and, in severe instances, purpura and necrosis.

Differentiation of the two reactions—primary

irritant dermatitis and allergic contact dermatitis—

is often difficult clinically and usually requires

patch testing.

Ophthalmological Effects

The eye is a sensitive target organ of riot control

agents. In studies14,15 on humans, CS (0.1% or 0.25%

CS in water; 1.0% CS in trioctyl phosphate), when

placed or sprayed into the eyes, caused inability to

open the eyes for 10 to 135 seconds. A transient conjunctivitis but no corneal damage as assessed by

slitlamp biomicroscopy resulted.

In another study,16 subjects were exposed to CS2

(powder dispersal) or CS powder (thermally disseminated) at 0.1 to 6.7 mg•min/m3 for 20 seconds

to 10 minutes. Their visual acuity was tested at intervals during and after the exposure. Subjects who

could keep their eyes open during the exposure to

read the chart had minimally impaired visual acuity, and no appreciable change in acuity from

preexposure readings was found.

In an investigation of the ophthalmic toxicity of

CS,17 rabbit eyes were contaminated with CS in solution (0.5%–10% in polyethylene glycol), as a solid,

and as a pyrotechnically generated smoke (15 minutes at 6,000 mg/m3). The effects were most severe

with the solution and least severe with the smoke.

After exposure to the smoke, the eyes had a transient, slight excess of lacrimation and congestion

of conjunctival vessels lasting 24 hours; the tissues

were normal when examined 7 days later.

The solid (0.5–5.0 mg) caused lacrimation at all

doses, blepharitis that increased with dose and

lasted up to a week, and chemosis at 5 mg, which

was mild and lasted 3 days. Minimal iritis and

keratitis, of 24 hours’ duration, were seen in two of

five animals receiving 5 mg. At concentrations of

1% and higher, CS in solution caused conjunctivitis

and iritis, chemosis, keratitis, and corneal vascularization; the lesion was more severe and lasted

longer with the higher doses. Histological examination indicated patchy denudation of corneal epithelium and a neutrophilic infiltration of the cornea.17

Reports of severe eye injuries from riot control

agents have involved the agent CN. They are discussed below in the CN section.

Gastrointestinal Tract Disturbances

A handful of instances in which an individual

ate CS are known. In all but two cases, children were

the victims. Typically, they were playing in an old

impact area on a military installation and came

across some shells containing a powdery substance,

which they ate. One adult ingestion was an attempt

at suicide by an otherwise healthy young man; the

other was an individual who ate a CS pellet (820

mg) after a friend told him it was a vitamin pill.18

The oral LD50 (dose that is lethal to 50% of the

exposed population) of CS was found to be 143 mg/

kg in the female rabbit, the most sensitive of three

species studied (the rat, about 1,300 mg/kg; the

guinea pig, 212 mg/kg; and the male rabbit, 231

mg/kg).8 The animals that died had multiple, extensive hemorrhagic erosions of the gastric mucosa,

with perforation of the wall, and a few had increased peritoneal fluid. In those surviving for several days, intraabdominal adhesions were found.

After male rats and female guinea pigs received 0.5

LD50 of CS by stomach tube, and male rabbits received 0.3 LD50 by this route, the incidence of wet

or runny stools was no greater than that for the control vehicle, polyethylene glycol 300 (PEG300).19 The

investigators concluded that diarrhea is not an

effect of ingested CS. They also suggested that rioters would not have diarrhea from CS exposure,

since they would be unlikely to swallow this much,

but that an intensely emotional experience such as

being in a riot may itself be a cause of disturbed

bowel function. In another study,20 the oral LD50
Riot Control Agents

315

varied widely in rats (178–358 mg/kg), depending

on the solvent used. After death, moderate to severe

gastroenteritis was noted on gross examination.

No deaths or severe complications in humans

from ingestion of CS are known. The young man

mentioned above who had attempted suicide by CS

ingestion was given large amounts of what were

described as “saline cathartics” and over the next

24 hours had repeated episodes of severe abdominal cramps and diarrhea; whether these symptoms

were due to the illness or the treatment is unknown.

A surgical team examined the patient early and

stood by during the acute phase. The patient recovered uneventfully. The adult who ate a CS pellet

was given liquid antiacid and viscous lidocaine

orally and droperidol intravenously. He vomited

twice, had six voluminous watery bowel movements without blood, and otherwise recovered uneventfully. Blood cyanide was less than 1 μg/dL 18

hours after ingestion (see section on metabolism).18

Metabolic Effects

Both in vivo and, in water, in vitro, CS (ochlorobenzylidene malononitrile) is hydrolyzed to

2-chlorobenzaldehyde and malononitrile. Malononitrile contains two cyanide moieties, and it is

thought that at least one of these is liberated and

attaches to sulfur via the enzyme rhodanese to form

thiocyanate, which is excreted in the urine.

Some authors have suggested that cyanide contributes to mortality in CS-caused deaths.21,22 In dogs

given CS by the aerosol or intravenous routes, the

plasma concentrations of thiocyanate increased over

the following 24 to 48 hours, presumably because of

transformation of the liberated cyanide to thiocyanate by combination with endogenous sulfur.21 After CS was given intraperitoneally, the mortality

was markedly decreased by the intravenous administration of thiosulfate, which may have provided

additional sulfur for the transformation of cyanide to

thiocyanate.21 Also, after intravenous administration

of CS or malononitrile, the signs and the times to death

were similar (15–60 min), suggesting that both caused

effects by the same mechanism.22 In this report, the

authors also noted the similarities of signs and times

of death for these two compounds, compared with

cyanide administered intravenously.

One author of the latter report, however, clearly

notes in a later communication23 that the mode and

time of death differ depending on whether CS is

administered by the intravenous route or by aerosol. As noted earlier in the discussion of respiratory effects for CS, animals exposed to far greater

than the lethal Ct do not die during exposure or

immediately afterwards, but many die hours later,

in contrast to the usually rapid death caused by cyanide. Moreover, the lung damage found on pathological examination is adequate to explain death.8,9

In addressing this issue, a British report3 suggests

that whereas cyanide might be a causative factor in

the rapid deaths occurring after intravenous administration, it is not a factor in death after aerosol administration. If one were to absorb completely all

the CS during a 1-minute exposure at 10 mg/m3,

and if both cyanides on the molecule were liberated—

and evidence suggests that only one is liberated—the

total amount of cyanide received would be equivalent to that received from two puffs of a cigarette.

Other Physiological Responses

When subjects were exposed to CS concentrations of 1 to 13 mg/m3 daily for 10 days, their airway resistances, measured 2 to 4 minutes after the

fourth and tenth exposures, were unchanged from

the preexposure values.4 Tidal volume, vital capacity, and peak flow in 36 subjects also were unchanged when they were measured immediately

and 24 hours after exposure to CS.5

Heart rates of subjects were lower immediately

after exposure compared with preexposure values.4

Subjects entered a chamber of CS with masks on;

immediately on removing their masks, their mean

blood pressure increased by 20 mm Hg systolic and

11 mm Hg diastolic. After they had remained in the

CS for 20 minutes, however, their blood pressures

were comparable to the preexposure values.4 The

blood pressures of subjects drenched with dilute

solutions of CS were transiently elevated to about

150/90 mm Hg.24

After daily exposures to CS for 10 days, seven

subjects had no alterations in blood sodium, potassium, alkaline phosphatase, or bromsulfophthalein;

one of the seven had an increase in thymol turbidity. No chest radiograph or urinary changes were

seen.4

 In another study,5 although significant

changes were seen in some blood chemistries after

exposure, all values were within the normal range.

Pregnant rats and rabbits were exposed to CS

aerosols at concentrations of 6, 20, or 60 mg/m3 for

5 minutes on days 6 to 15 and 6 to 18 of gestation,

respectively. In addition, rats were given CS (20

mg/kg) intraperitoneally on days 6, 8, 10, 12, and

14 of gestation. No embryolethality or teratogenicity was evident.25

CS and some of its metabolites were found not

to have mutagenic effects in the Ames Salmonella
Medical Aspects of Chemical and Biological Warfare

316

typhimurium assay with microsome supplementation.26 In addition, no mutagenic effects were

found in assays for reverse mutations in S typhimurium after exposure to CS, in assays for sex-linked,

recessive lethal mutations in sperm cells after Drosophila were fed CS, or in chromosomes of bone marrow erythrocytes of mice exposed to CS.27 The

authors of another study28 of rats and Salmonella

concluded that CS did not induce point mutations

or carcinogenic processes mediated by DNA binding. However, CS did give a positive response in the

forward mutation assay in mouse lymphoma cells.29

CN (1-CHLOROACETOPHENONE)

CN

trachea, bronchi, and bronchioles; and more evidence of early bronchopneumonia.

Dermatological Effects

A textbook published in 1925 states that CN in

field concentrations does not damage human skin;

however, the powder might produce burning:

“slight rubefaction, and sometimes small vesicles

appear.”31(p171) Early cases of CN dermatitis—one of

primary irritant dermatitis in a soldier and three in

civilian employees who probably had allergic dermatitis from working around CN for years—were

described several years later.32

A severe allergic reaction to CN developed after

a 43-year-old military recruit went through the

CN training chamber routine (ie, an individual

spends 5 min in the chamber masked, then removes the mask and exits the chamber). Within 5

minutes after exiting, the patient complained of

generalized itching, which became progressively

worse over the following hours. Four hours after

exiting, he had a diffuse and intense erythema over

his entire body except his feet and the portion of

his face covered by the mask. His temperature was

38.9°C (102°F) and rose to 39.4°C (103°F) the next

day. By 48 hours after exposure, he had vesication

and later developed severe subcutaneous edema

that “strikingly altered the appearance of the

face”33(p1879) and severe generalized itching. Over the

next 4 days, the signs subsided, and desquamation,

which was profuse at day 6, gradually decreased.

The patient had developed itching during a tear gas

exercise 17 years previously but had not been exposed in the interim.33

A police officer received an initial exposure to

CN and 5 years later, on repeated exposure, developed recurrent attacks of what was probably allergic contact dermatitis. The source of the repeated

exposures was unrecognized until he realized that

he had been using outdated CN bombs for eradication of rodents on his property.34

CN (0.5 mg), when left in place for 60 minutes,

caused irritation and erythema on the skin of all

C

O

C

H2

Cl

Physical Characteristics

Like CS, the riot control agent known as CN (1-

chloroacetophenone) is a solid or powder and can

be disseminated as a smoke generated from a grenade or other device, or in powder or liquid formulations. Under the trade name Mace, it is in most

devices sold for self-protection, although today it

is commonly mixed with or is being replaced by

capsaicin (pepper spray).

CN was first synthesized by Graebe in 1871 and

was used in World War I. Before the late 1950s, it

was the standard tear gas used by the military and

law enforcement agencies.

The harassing concentration for CN is about 10

mg/m3, compared with about 4 mg/m3 for CS. It is

more toxic than CS, and the human LCt50 (median

lethal Ct) has been estimated to be 7,000 mg•min/

m3 for pure aerosol and 14,000 mg•min/m3 for a

commercial grenade.30

Clinical Effects

In general, the clinical effects caused by CN are

the same as those caused by CS. The harassing dose

is higher and CN is more toxic and more likely to

cause serious effects, particularly in skin and eyes

(see below). Most effects from exposures to a low

concentration will disappear within 20 to 30 minutes.

Respiratory Tract Effects

In studies parallel to those described above for

CS, CN was found to be 3- to 10-fold more toxic

(lower LCt50) than CS in rats, rabbits, guinea pigs,

and mice.8 In addition, the pathological findings in

the lungs were more severe, with more edema;

patchy acute inflammatory cell infiltration of the
Riot Control Agents

317

humans tested in one study,35 whereas CS caused

no effects in amounts less than 20 mg. When the

CN was moist, 0.5 mg caused vesication in most

subjects, whereas vesication was not seen after exposure to 30 mg or less of CS.

In addition to being a more potent primary irritant on the skin than CS, CN is also a more potent

skin sensitizer.36 Several people developed allergic

contact sensitivity to CN after patch testing.37 Because of the high incidence of sensitization in test

subjects, CN should be considered a potent allergic

sensitizer, and those who are frequently exposed

should be aware of the high likelihood of developing allergic dermatitis.38

Ophthalmological Effects

The irritation caused by CN in the eye signals

avoidance and, by causing lacrimation and blepharospasm, initiates a defense mechanism. High concentrations of CN sprayed into the eyes from a distance have caused edema of the corneal epithelium

and conjunctiva and many minute epithelial defects

in the cornea.39 Healing was rapid, however.

More lasting or permanent effects may occur

when CN is released at close range (within a

few meters), particularly if it is from a forceful

blast from a cartridge, bomb, pistol, or spray. One

study40 based on case records from the files of the

Armed Forces Institute of Pathology in Washington, D. C., reviewed eye injuries from tear gas; unfortunately, many of the histories were incomplete.

In about half the cases, the injuries were selfinflicted and accidental; in the other half, the

injuries were caused by a second person firing a

weapon from close range with intent to injure the

patient. In some instances, particles of agglomerated agent were driven into the eye tissues by the

force of the blast; the authors of the study suggested

that a chemical reaction caused damage over

months or years. In other instances, the injury was

probably caused by the blast or other foreign particles rather than by CN. The authors carefully

pointed out that features of the weapon, such as the

blast force, the propellant charge, the wadding, and

the age of the cartridge (in older cartridges, the

powder agglomerates and forms larger particles)

should be considered in evaluating eye damage due

to CN.

The author of another review41 came to the same

conclusion: the traumatic effect of the blast is a considerable factor, and one cannot always be sure that

CN per se is the cause of permanent injury.

In a study20 comparing the effects of CN and CS

in the eyes of rabbits, CN at a concentration of 10%

(wt/vol) caused iritis and conjunctivitis lasting

longer than 7 days and corneal opacity lasting

longer than 55 days. In contrast, CS, at the same

concentration, caused moderate conjunctivitis but

no iritis or corneal opacities; all eyes were normal

at 7 days. Other evidence30 indicates that when CN

is applied directly to the eye in powder form or is

sprayed at close range, a more severe reaction than

that seen with CS may result.

Although permanent eye damage has been reported from the use of CN weapons at close range,

separating the effects of the weapon from those of

the compound is difficult. There is no evidence that

CN at harassing or normal field concentrations

causes permanent damage to the eye.

SEVERE MEDICAL COMPLICATIONS FROM THE USE OF CS AND CN

The indiscriminate use of large amounts of CN

in confined spaces has caused injuries requiring

medical attention and death. An incident of injury

to an infant from CS has also been reported.

A 4-month-old infant was in a house into which

police fired CS tear gas canisters for 2 to 3 hours to

subdue a disturbed adult. Immediately on being

removed from the house, the infant was taken to a

hospital, where he was observed to have copious

secretions of the nose and mouth and frequent

sneezing and coughing. He required frequent

suctioning to relieve upper airway obstruction.

Physical examination was unremarkable except for

the secretions, slight conjunctival injection, and

rapid heart rate and respirations. On the second day,

he had an episode of cyanosis, which cleared with

suctioning. On examination, he was in respiratory

distress with suprasternal retraction, wheezes, and

rales bilaterally. The chest radiograph was clear.

Antibiotics, high-dose steroids, and positive-pressure breathing were started. He slowly improved

until the seventh hospital day, when his temperature rose to 40.4°C (104.4°F) and coughing increased. An infiltrate was noted on the chest radiograph. Physical findings were unremarkable except

for coarse breath sounds throughout the lungs. He

improved with further antibiotic and ventilatory

therapy and was discharged on day 12, only to be

readmitted on day 13 with an increasing cough and

a progression of the infiltrate. With more antibiot-
Medical Aspects of Chemical and Biological Warfare

318

ics and other therapy, he gradually recovered and

was discharged after 28 days in the hospital.42

In a prison incident, 44 inmates were in a cell

block sprayed with CN; 28 inmates later sought

medical attention, and 8 were hospitalized. All eight

complained of malaise, lethargy, and anorexia. Five

had pharyngitis, three of whom developed pseudomembranous exudates several days later. Three also

developed tracheobronchitis with purulent sputum,

but no infiltrates on chest radiograph. Four patients

had facial burns, and three had bullae on the legs;

the most severely affected had first- and seconddegree burns over 25% of his body. One patient was

admitted 5 days after the incident with a papulovesicular rash of his face, scalp, and trunk, which had

appeared 2 days earlier. Ten prisoners were treated

as outpatients for first- and second-degree burns,

and six had localized papulovesicular rashes. Ten

had conjunctivitis with edema of the conjunctiva,

and in some the eyelids were closed by the swelling, but no patient had corneal injuries or permanent eye damage. The patients with laryngotracheobronchitis were given bronchodilators, postural

drainage, and positive-pressure exercises. Two were

given short-term, high-dose steroids, but none received antibiotics. One required bronchodilator

therapy 3 months later, but the others made prompt

recoveries.43

The skin lesions were treated with debridement

and applications of silver sulfadiazine and, in some

cases, with topical steroids and antihistamines. Skin

color was almost normal 3 months later. Topical steroids caused the conjunctival edema to begin to resolve in 48 hours. The only estimate of the amount

of CN used was obtained from the prisoners, each

of whom claimed to have been sprayed multiple

times. Although the first- and third-floor windows

were open, the exhaust system was off during the

incident.43

In another prison incident, the windows and

doors were closed and ventilation was off during

what was described as a “prolonged gassing” of

inmates confined to individual cells. It was later

estimated that the incident lasted 110 minutes.

Among the dispensers used were at least six thermal grenades of CN, fourteen 100-g projectiles of

CN, and more than 500 mL of an 8% CS solution.

Using only the amount in the CN projectiles, the

authors of the report calculated that the prisoners

were exposed to a Ct of 41,000 mg•min/m3. The

total number of prisoners exposed was not noted.

Afterward, some had coughing with varying degrees of illness, and at least three received medical

treatment (the authors carefully pointed out that

they were unable to obtain details).44

A prisoner was found dead under his bunk 46

hours later. Other prisoners reported that he had

had “red eyes,” had vomited “bloody” material, and

had sought medical attention on several occasions.

On autopsy, he was noted to have rigor mortis, cyanosis of the face and head, and no evidence of

physical injury. His lungs had subpleural petechiae,

hyperemia, mild edema, and patchy areas of consolidation; microscopic examination showed bronchopneumonia clustered around exudate-filled

bronchioles. His larynx and tracheobronchial tree

were lined with an exudative pseudomembrane;

microscopic examination showed this was a fibrinrich exudate containing polymorphonuclear leukocytes and their degenerating forms. There was no

evidence of gastrointestinal hemorrhage; other organs had passive hyperemia.44

Another individual had an altercation with the

police and locked himself into a room in his house.

A single CN grenade (128 g) was thrown into the

room (approximately 27 m3), where the patient remained for 30 more minutes (128,000 mg • 30 min

÷ 27 m3 provides an estimated Ct of about 142,500

mg•min/m3, or an exposure 10-fold higher than the

estimated lethal Ct50).45

On admission to the hospital, his respirations were

24 per minute, his conjunctiva were suffused, his pupils were small and unreactive, mucoid discharge

from his nose and mouth was abundant, his lungs

were clear, and an occasional premature ventricular

contraction was evident on the electrocardiogram. He

remained “in a semicomatose condition for approximately 12 hours and then suddenly developed pulmonary edema and died.”45(p375) Relevant findings on

autopsy included cyanosis, frothy fluid in the mouth

and nose, acute necrosis of the mucosa of the respiratory tree with pseudomembrane formation, desquamation of the lining of the bronchioles with edema

and inflammation of the walls, and a protein-rich fluid

in most of the alveolar spaces. Foci of early bronchopneumonia were present.45

Information on three other cases of death from

CN, which the authors obtained from other medical examiners, are summarized in the same report.45

Details were scanty, but the autopsy findings were

similar; in each case, the individual was confined

in a relatively small space. Exposure was for 10

minutes in one instance and for hours in the others

(details of exposure were unknown).
Riot Control Agents

319

OTHER RIOT CONTROL COMPOUNDS

DM (Diphenylaminearsine) which last for several hours after exposure. DM and

related compounds are known as vomiting agents,

but the incidence of vomiting and the amount of

compound necessary to cause it are not known with

certainty. In studies dating from 1922 to 1958,46 humans were exposed to Cts ranging from 4.6 to 144

mg•min/m3; nausea was noted in fewer than 10%

of the subjects. Because of the lack of data, the Ct

necessary to cause nausea and vomiting has not

been established,46 but has been estimated to be

about 370 mg•min/m3.

24

One death has been reported46 from DM inhalation (the information on this fatality is incomplete).

A DM generator was operated in a barrack, exposing 22 sleeping men. The estimated concentration

was 1,130 to 2,260 mg/m3, and the duration of exposure was estimated to be 5 minutes (by one

source) or 30 minutes (by a second source). For a 5-

minute exposure, the estimated Ct would be 5,650 to

11,300 mg•min/m3; for a 30-minute exposure, 33,900

to 67,800 mg•min/m3. One individual died; the postmortem findings were severe airway and lung damage, similar to those seen after death from CN.

Another source47 reported severe pulmonary injury

and death after accidental exposure to high concentrations of DM in confined spaces, but no details

were given.

CR (Dibenz(b,f)-1:4-oxazepine)

The riot control agent known as DM (diphenylaminearsine) is one of a group of compounds that

are known as vomiting agents. The others, which

are of much less military importance, are the agents

DA (diphenylchlorarsine) and DC (diphenylcyanoarsine). DM was first synthesized by the German

chemist Wieland in 1915 and, independently, by the

U.S. chemist Adams in 1918. DM is also known as

adamsite.

DM is a yellow-green, odorless, crystalline substance that is not very volatile. It is insoluble in

water and relatively insoluble in organic solvents.

Its primary action is on the upper respiratory tract,

causing irritation of the nasal mucosa and nasal sinuses, burning in the throat, tightness and pain in

the chest, and uncontrollable coughing and sneezing. It also causes eye irritation and burning, however, with tearing, blepharospasm, and injected conjunctiva.

DM is more toxic than other riot control agents;

the LCt50 for humans has been estimated to be

11,000 mg•min/m3.

46 The amount that is intolerable for humans has been estimated by some to be

22 mg•min/m3 and by others to be 150 mg•min/

m3.

46 The threshold for irritation in humans is about

1 mg/m3, but men have tolerated Ct exposures of

100 to 150 mg•min/m3.

Two characteristics make this class of compounds

unique among the riot control agents. The first is

that the effects do not appear immediately on exposure or seconds afterwards, but several minutes

later. In the absence of symptoms, a soldier will not

mask immediately; by the time he masks, he will

have absorbed a significant amount. The effects may

then cause him to unmask.

The second characteristic of these compounds is

that there may be more prolonged systemic effects,

such as headache, mental depression, chills, nausea, abdominal cramps, vomiting, and diarrhea,

DM

As

Cl

H

N

The riot control agent known as CR (dibenz(b,f)-

1:4-oxazepine) is a relatively new compound, first

synthesized in 1962 by Higginbottom and Suschitzkey.

CR is more potent and less toxic than CS. Because

of the low vapor pressure of CR solution, no respiratory tract effects are anticipated from its use. The

LCt50 for animals exposed to grenade-generated

smokes was found to be 167,500 mg•min/m3. The

estimated LCt50 for humans is probably higher than

100,000 mg•min/m3.

24

CR is sparingly soluble in water, and a cosolvent

(PEG300 is frequently used) is necessary when it is

CR

O

N C

H
Medical Aspects of Chemical and Biological Warfare

320

to cause effects—and it appears to be much safer,

as judged from the higher LCt50 and the lack of

persistent skin and eye effects.

CA (Bromobenzylcyanide)

dispersed in solution. Since CR does not degrade

in water, it resists weathering and persists in the

environment.

In humans, the effects caused by CR are qualitatively similar to those caused by CS, but there is an

approximately 5-fold difference in potency. A splash

of a solution in the range of 0.01% to 0.1% causes

immediate eye pain, blepharospasm, and lacrimation, which persist for 15 to 30 minutes, and conjunctival injection and minimal edema of lid margins, which last for 3 to 6 hours. A solution splashed

in the mouth causes burning of the tongue and palate and salivation for 5 to 10 minutes. If a splash

enters the nose, it causes irritation and rhinorrhea.

Skin exposure causes burning within a few minutes,

which persists for 15 to 30 minutes, and an erythema

lasting for 1 to 2 hours. A blood pressure increase

may accompany the subjective discomfort; this is

thought to be caused by the stress of the irritation,

since the amount of CR that could be absorbed is

much too small to cause a pharmacological effect.24

A transient erythema (1–2 h) occurs, but CR does

not induce inflammatory cell infiltration, vesication,

or contact sensitization, and it does not delay the

healing of skin injuries.24,48 The potential for eye

damage is also significantly less than it is from CS

or CN.24 CR was neither teratogenic nor embryolethal in one study49 when given as an aerosol or

by gavage.

Compared with other riot control agents, CR is

relatively new; no data from its use exist. Experimental studies indicate that its effects are similar

to those of CS except that it causes almost no effects in the lower airways and lungs. It is much more

potent than CS—a smaller concentration is needed

The riot control agent known as CA (bromobenzylcyanide) was the last irritating agent introduced by the Allies in World War I, and it was the

most potent. It corrodes iron and steel, is not chemically stable in storage, and is sensitive to heat, all

characteristics that made it unsuitable for storage

and use in artillery shells.50

CA irritates the eyes and causes lacrimation at

concentrations of 0.15 and 0.3 mg/m3; the LCt50

was estimated to be 27,000 mg•min/m3.

50 More

recent studies indicate that the estimated LCt50 for

humans is 11,000 mg•min/m3,

51 indicating that it

is among the more toxic riot control agents. The

health effects caused by CA are very similar to those

caused by CS and CN.

CA is rarely used and is a relatively unimportant agent of this class. The compound is included

here primarily because it is discussed in Treatment

of Chemical Agent Casualties and Conventional Military Chemical Casualties,52–54 field manuals published

by the Department of Defense for use by the U.S.

Army, Navy, and Air Force.

MEDICAL CARE

CA

The effects from riot control agents are usually

self-limiting, and medical attention is usually not

required. Exiting the contaminated area should

bring some measure of relief in 15 to 30 minutes or

sooner. In rare circumstances, complications may

occur on the skin, in the eyes, or in the airways.

Decontamination

The use of water on the skin may result in transient worsening of the burning sensation. Soap and

water may be more effective but may also cause

a momentary increase in the symptoms. CS rapidly hydrolyzes in an alkaline solution; a solution

containing 6% sodium bicarbonate, 3% sodium carbonate, and 1% benzalkonium chloride was found

to bring prompt relief of symptoms and to hydrolyze the agent.13 No form of hypochlorite should be

used.

Skin

For dermatitis, a topical steroid preparation (eg,

triamcinolone acetonide, fluocinolone acetonide,

flurandrenolone, or betamethasone-17-valerate) is

the principal therapeutic agent. Oozing lesions

should be treated with wet dressings (moistened

with fluids such as 1:40 Burow’s solution). Appropriate antibiotics should be given for secondary

infection, and oral antihistamines for itching.13 Vesicating lesions have been successfully treated with

compresses of a cold silver nitrate solution (1:1,000)

C

Br

C N

H
Riot Control Agents

321

for 1 hour, applied six times daily.11 One person with

severe lesions and marked discomfort was given a

short course of an oral steroid. An antibiotic ointment was applied locally, but systemic antibiotics

were not used.11

Eye

A local anesthetic might be applied once for severe pain, but continued use should be restricted.

The eye should be thoroughly flushed to remove

any particles of the agent. If the lesion is severe,

the patient should be sent to an ophthalmologist.

Respiratory Tract

Usually, the cough, chest discomfort, and mild

dyspnea are gone 30 minutes after exposure to clean

air. However, both the animal data (detailed in the

section on CS) and the clinical experience with the

infant exposed to CS suggest that severe respiratory effects may not become manifest until 12 to 24

hours after exposure. An individual who has prolonged dyspnea or objective signs should be hospitalized under careful observation. Further care

should be as described in Chapter 9, Toxic Inhalational Injury. Although people with chronic bronchitis have been exposed to riot control agents without untoward effects, any underlying lung disease

(eg, asthma, which affects one person in six in the

general, or the military, population) might be exacerbated by exposure to CS.3

Cardiovascular System

Transient hypertension has been noted after exposure to riot control agents, primarily because of

the anxiety or pain of exposure rather than a pharmacological effect of the compound. Whatever the

cause, adverse effects may be seen in individuals

with hypertension, cardiovascular disease, or an aneurysm.

FUTURE USE

More research is needed to illuminate the full

health consequences of riot control agents, as one

report55 has suggested. Information gaps in this

chapter indicate areas that might fruitfully be explored, although funding for such research is problematic. The limited resources of the military program in chemical defense are probably more wisely

spent on investigating better defense against and

medical care for victims of agents that cause more

severe consequences and are more likely to be used

on a battlefield. Law enforcement agencies generally have few funds for these purposes. Manufacturers probably do not have a large interest in this

topic; it is unlikely that their profits from these compounds are large enough to support such an effort.

Federal medical funding is generally concerned

with more serious diseases affecting larger segments of the population.

Other concerns discussed in the report55 were the

“pattern of use” of these compounds. Are there circumstances in which the use of riot control agents

can, or cannot, be condoned? The “pattern of use”

might be difficult to regulate, particularly in the

areas and under the circumstances in which the use

of CS or CN has apparently been abused (eg, the

West Bank and the Gaza Strip in the Middle East,

and Seoul, South Korea). Public opinion and the

Geneva Protocol did not dissuade Iraq from using

several types of chemical weapons in the conflict

with Iran, or prevent Libya from constructing a

large manufacturing facility at Rabta, apparently for

the manufacture of chemical weapons. Despite the

concern about the loss of innocent lives and injury

among innocent bystanders, there is serious doubt

that a prohibition of the use of riot control agents

would be effective.

While it is true that in some instances dialogue

and negotiation should precede the use of riot control agents, one wonders how this suggestion might

have been received by the desperate refugees. Although CS allegedly caused injury, the amount of

injury was probably small compared to what might

have been inflicted if CS had not been available and

more extreme measures had been used. Possibly, the

use of CS is sometimes the most benign solution in

ugly and dangerous circumstances.

SUMMARY

Riot control agents are intended to harass or to

cause temporary incapacitation. Their intended target might be the foe in an armed conflict—with the limitations outlined above—or rioters in a civil disturbance.

Much evidence suggests that riot control agents

are safe if they are used as intended and if the response is as intended. When they are not used as

intended, and the response is not as intended, how-
Medical Aspects of Chemical and Biological Warfare

322

ever, there may be devastating consequences (eg,

the deaths of the Branch Davidians at Waco, Tex.).

Almost all of the reported adverse effects have resulted from indiscriminate use of weapons containing riot control agents or from resistance to the effects of the compounds, which increases the amount

of exposure. Sometimes injury results from the effects of the delivery system of the weapon rather

than from the compound; these two sources of injury should not be confused.

Indiscriminate or uncontrolled use of CS, or any

riot control compound, is obviously not desired, nor

is it necessary in circumstances in which a better,

less drastic solution is possible. But the use of CS

or CN might be more benign than the use of more

deadly alternatives in desperate circumstances. As

the data clearly suggest, CS is a relatively safe compound when used as intended.

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43. Thorburn KM. Injuries after use of the lacrimatory agent chloroacetophenone in a confined space. Arch Environ

Health. 1982;37:182–186.

44. Chapman AJ, White C. Death resulting from lacrimatory agents. J Forensic Sci. 1978;23:527–530.

45. Stein AA, Kirwan WE. Chloracetophenone (tear gas) poisoning: A clinico-pathologic report. J Forensic Sci.

1964;9:374–382.

46. Owens EJ, McNamara BP, Weimer JT, et al. The Toxicology of DM. Edgewood Arsenal, Md: Medical Research

Laboratories; 1967. Technical Report 4108.

47. Medical Manual of Defence Against Chemical Agents. London, England: Ministry of Defence; 1987.

48. Holland P. The cutaneous reactions produced by dibenzoxazepine (CR). Br J Dermatol. 1974;90:657–659.

49. Upshall DG. The effects of dibenz (b,f)-1:4 oxazepine (CR) upon rat and rabbit embryonic development. Toxicol

Appl Pharmacol. 1973;24:45–59.

50. Prentiss AM. Chemicals in War. New York, NY: McGraw-Hill; 1937.

51. Oberst FW, Crook JW, Swaim SF, et al. Toxic Effects of High Concentrations of Bromobenzylnitrile (CA) Vapor in

Various Animal Species. Edgewood Arsenal, Md: Medical Research Laboratories; 1967. Technical Report 4078.

52. US Department of the Army. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries.

Washington, DC: US Department of Defense; 1990. Field Manual 8-285.

53. US Department of the Navy. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries.

Washington, DC: US Department of Defense; 1990. NAVMED P5041.

54. US Department of the Air Force. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries. Washington, DC: US Department of Defense; 1990. Air Force Manual 160-11.

55. Hu H, Fine J, Epstein P, Kelsey K. Tear gas—Harassing agent or toxic chemical weapon? JAMA. 1989;262:660–663.
Field Management of Chemical Casualties

325

Chapter 13

FIELD MANAGEMENT OF CHEMICAL

CASUALTIES

FREDERICK R. SIDELL, M.D.*; RONALD R. BRESELL, M.S.†; ROBERT H. MOSEBAR, M.D.‡;

K. MILLS MCNEILL, M.D., PH.D., FACPM§; AND ERNEST T. TAKAFUJI, M.D., M.P.H.¥

INTRODUCTION

HEALTH SERVICE SUPPORT ON THE BATTLEFIELD

Echelon I: The Unit Level

Echelon II: The Division Level

Echelon III: The Corps Level

Echelon IV: The Echelon Above Corps

Echelon V: The Continental United States

MEDICAL SUPPORT IN A CHEMICAL ENVIRONMENT

First Aid for a Chemical Casualty

Casualty-Receiving Area

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014

†Major, Medical Service Corps, U.S. Army (Ret); Formerly, NBC Branch, Preventive Medicine Department, U.S. Army Medical Department

Center and School, Fort Sam Houston, Texas 78234-6100; currently, Assistant Director, Safety, Radiation Safety Officer, University of

Wisconsin, Madison, 30 North Murray Street, Madison, Wisconsin 53715

‡Colonel, Medical Corps, U.S. Army (Ret); Chief of Clinical Consultants Division, Directorate of Combat and Doctrine Development, U.S.

Army Medical Department Center and School, Fort Sam Houston, Texas 78234-6175

§Colonel, Medical Corps, U.S. Army; Director, Preventive Medicine Services, Dwight David Eisenhower Army Medical Center, Fort Gordon,

Georgia 30905-5650

¥Colonel, Medical Corps, U.S. Army; Commander, Walter Reed Army Institute of Research, Washington, D. C. 20307-5010
Medical Aspects of Chemical and Biological Warfare

326

INTRODUCTION

In the event of an enemy attack with chemical

agents, those in the military medical departments

must consider first aid, treatment, evacuation, and

decontamination procedures of contaminated casualties—some of whom may have injuries made by

conventional weapons in addition to their chemical injuries. The ultimate objective in the management of all contaminated casualties is to provide

the earliest and most effective treatment without

compounding injuries or contaminating medical

personnel and treatment facilities.

Although first aid will be initiated on the battlefield and continued during evacuation, these casualties must be moved to an uncontaminated environment as early as possible to permit the removal

of protective gear and to allow initiation of optimal treatment in a “shirtsleeve” environment unencumbered by protective clothing or masks. Otherwise, medical personnel must don protective gear,

which will significantly compromise their efficiency.

The basic threat to and management principles

for chemical casualties have not changed since World

War I. To survive and to accomplish the mission on

the chemical battlefield, medical care providers

must be able to respond quickly and effectively.

Soldiers must be trained in first-aid procedures. Decontamination procedures must be practiced. And

medical care providers must know how to perform

their mission in a chemical environment. Continued, careful attention to each of these requirements

will significantly reduce the chemical threat to our

military personnel.

HEALTH SERVICE SUPPORT ON THE BATTLEFIELD

A brief review of pertinent Health Service Support (HSS) doctrine will provide a background for

the discussion of chemical casualty care. The basic

objectives of HSS are to

• reduce the incidence of disease and nonbattle injury;

• provide treatment of acute illness, injury,

and wounds; and

• return to duty as many soldiers as possible

at each echelon or level.

These will be accomplished by emphasizing prevention, by providing far forward medical treatment

including advanced trauma management (ATM)

and by providing timely and efficient casualty

evacuation. Determination of which casualties

can be returned to duty will be made at the lowest

possible level to preclude their being evacuated

farther back than is necessary to provide appropriate care. HSS operations must conform to the tactical plan, allowing for rapid reinforcement or replacement of the forward echelon of medical

support. It must provide for a continuum of care

from the forward line of troops (FLOT) back to

the continental United States (CONUS), emphasizing centralized control with flexibility of execution. Table 13-1 summarizes the various echelons

of care and the treatment capabilities at each command level. Each higher echelon reflects an increase

in medical capability while it retains the capabilities found in the lower echelons. Echelons I, II, and

III are found in the combat zone; Echelon IV is in

the communication zone; and Echelon V is in the

Zone of the Interior (ZOI).

In the past, the terms “echelon,” “level of care,”

and “level,” have sometimes been used in a confusing and seemingly indiscriminate manner. In an

attempt to clarify this semantic imprecision, we use

the definitions provided in the American, British,

Canadian, Australian Armies Medical Interoperability

Handbook:

[T]he term echelon is used to describe the phased

system of health care delivery in the Theater of

Operations (such as far forward care is provided

at Echelon I). The term level is used to describe the

level of command (such as division, regiment, or

corps).1(p1-1)

Echelon I: The Unit Level

Echelon I medical care, found at the unit level

and all higher levels, consists of ATM, sick call, and

evacuation capability provided by the medical platoon/section organic to combat maneuver battalions and to some combat support battalions. Major

emphasis is placed on those measures necessary to

resuscitate, stabilize, and prepare for the evacuation of the casualty to the next higher echelon of

care. This care may be in the form of self-aid/buddy

aid or it may be treatment provided by the combat

lifesaver or the combat medic.
Field Management of Chemical Casualties

327

TABLE 13-1

TREATMENT EMPHASIS AT THE ECHELONS OF CARE

CZ COMMZ ZOI

Treatment Emphasis Level I (Unit) Level II (Division) Level III (Corps) Level IV (EAC) Level V (CONUS)

Emergency medical

treatment, first aid,

self-aid, buddy aid

Combat medic,

combat lifesaver, all

soldiers

Echelon I:

Aid station of the

troop medical clinic

Echelon I:

Aid station of the

troop medical clinic

Echelon II:

Clearing station of

the forward

support medical

company in the

brigade support

area

Clearing stations of

the medical

battalion, or the

medical company of

the main support

battalion in the

division rear

Echelon I:

Battalion/squadron

aid stations

Echelon II:

Clearing stations of

the medical

companies of the

area support

medical battalion

Echelon III:

Mobile army surgical

hospitals,* combat

surgical hospitals

Echelon II:

Clearing stations of

the medical

companies of the

area support

medical battalion

Echelon III:

Field hospitals

Echelon V:

Medical centers,

medical

department

activities, federal

hospitals

Emergency medical

care (advanced

trauma management)

Beginning resuscitation and emergency

medical care

(advanced trauma

management)

Resuscitative surgery

Definitive care

Definitive and

restorative care

*In the future, resuscitative surgery will be provided by forward surgical teams deployed at Level II

COMMZ: Communications Zone

CONUS: Continental United States

CZ: Combat Zone

EAC: Echelon Above Corps

ZOI: Zone of the Interior

The combat lifesaver is not a medic but is an ordinary soldier who has received, in addition to his primary military training, additional training beyond

basic first aid and, when the situation permits, assists

the combat medic by providing immediate care. The

combat medic is the first individual in the HSS chain

who makes medically substantiated decisions (including triage decisions) based on military occupation

specialty (MOS) training. This individual is capable

of providing emergency medical treatment.

The treatment squad or battalion aid station

(BAS) is the other source of Echelon I care. Personnel here are trained and equipped to provide ATM

as well as routine sick call.

Echelon II: The Division Level

Echelon II medical care, found at the division

level and all higher levels, is provided at the clearing station by the treatment platoon of the medical

company of the main support battalion and the

forward support battalion of the Division Support Command (DISCOM). Here the casualty is

evaluated to determine the priority for continued

Echelon IV:

General hospitals
Medical Aspects of Chemical and Biological Warfare

328

evacuation to the rear, or is treated and returned

to duty.

Echelon II possesses an increased medical treatment capability plus emergency and sustaining

dental care, radiology, laboratory, optometry, patient holding, preventive medicine, mental health,

and medical supply capabilities. However, these

capabilities do not exceed levels dictated by immediate necessity. Nondivisional units in the division

sector receive medical support on an area basis from

the nearest medical treatment facility (MTF). In the

division, Echelons I and II medical care will not be

bypassed, although this may occur in the corps area.

Echelon III: The Corps Level

Echelon III medical care, found at the corps level

and higher, is at present provided in a Mobile Army

Surgical Hospital (MASH), Combat Support Hospital (CSH), or Field Hospital (FH). A hospital presently being designed as part of the Medical

Reengineering Initiative (MRI) is planned to replace

these hospitals in the near future. In addition, resuscitative surgical care will be provided by forward surgical teams at both Echelon III and the

brigade division level. Echelon III facilities are

staffed and equipped to provide care for all categories of casualties. Those whose injuries permit additional transportation without detriment to their

conditions receive surgical care in a hospital farther

to the rear.

Echelon IV: The Echelon Above Corps

Echelon IV medical care, found at the Echelon

Above Corps (EAC) and higher, is presently provided in a General Hospital (GH). The MRI plans

to replace the GH with a hospital of similar capability at the EAC. The GH or its replacement consists of general and specialized medical and surgical

capability, including treatment that may be required

to stabilize the casualties who require evacuation

to CONUS.

Echelon V: The Continental United States

Echelon V medical care, provided by hospitals

in the ZOI and CONUS, is the most comprehensive

care available within the U.S. Army Medical Department (AMEDD) HSS system. Echelon V hospitals

also provide all the types of medical care found at

lower echelons.

MEDICAL SUPPORT IN A CHEMICAL ENVIRONMENT

Medical units, like their line counterparts, must

be able to survive a chemical attack if they are to

successfully perform their primary mission. Protective measures available to them fall into three categories: preattack, attack, and postattack.

Preattack measures include

• gaining knowledge of the characteristics of

anticipated chemical agents and the effects

of these agents on individuals and on unit

operations;

• proper defensive planning (including use

of individual protective equipment);

• a full understanding of self-aid, buddy aid,

and medical pretreatment;

• casualty decontamination; and

• activation of collective protection and

detection/monitoring equipment. An ability to implement protective measures

including use of shelters, dispersal,

and camouflage is essential, as is the accurate correlation of alert states with mission-oriented protective posture (MOPP)

levels.

Attack measures during enemy use of one or

more chemical agents include

• detection and monitoring for the continued

presence of chemical agent,

• guidance to commanders on potential performance degradation,

• first aid measures,

• initial treatment and evacuation of casualties, and

• individual protection and collective protection, including chemically hardened shelters.

Postattack measures consist of

• monitoring and reporting of chemical contamination and effects;

• control of contamination (avoidance, limitation of spread, weathering/decay);

• damage assessment and control;

• monitoring for effects on command, control

and communications elements;

• medical treatment, evacuation and/or

quarantine of chemical casualties;
Field Management of Chemical Casualties

329

• use of casualty wraps;

• operation and supervision of casualty decontamination centers; and

• preparation for future attacks.

Several categories of casualties will require treatment depending on whether they sustain conventional wounds, chemical poisoning, or both. The

number of chemical casualties is dependent on the

level of unit training and discipline and the preparedness of the unit. Casualties’ conditions may

also be adversely affected because normal tasks

such as driving an ambulance will take longer in

protective equipment, thereby delaying the arrival

of the casualty at the point of definitive medical

care. For example, at MOPP 4 (ie, full protection), it

is generally assumed that all operations will be performed at approximately 50% efficiency. Additionally, medical services must decontaminate liquid

agent on individual protective equipment to the

vapor-free state to permit entry into collective protection. This will further delay definitive treatment

of the casualty, potentially aggravating the injuries.

Key objectives in the management of chemical

casualties include

• minimizing chemical agent injuries,

• preventing aggravation of conventional injuries during first aid and decontamination

procedures,

• controlling the spread of chemical contamination, and

• continuation of the primary medical mission.

The accomplishment of these objectives plus patient

decontamination will require augmentation of the

BAS and Forward Support Medical Company

(FSMC) by 10 to 20 personnel from the supported

unit.

Another important factor is heat stress. The wet

bulb globe thermometer (WBGT) index determines

the heat condition; this condition is assigned a number (1–5) or a corresponding color code (white,

green, yellow, red, black) that can be displayed with

flags or other devices. MOPP gear increases the

ambient WBGT index by about 10°F; that is, 10° is

added to the WBGT reading before the heat condition is designated. The recommended amount of

water intake per hour for each heat condition and

physical activity for each condition are shown in

Table 13-2. Individuals wearing butyl rubber aprons

on the decontamination line while at MOPP 4 may

experience an even greater heat load. For someone

at MOPP 4, a relatively comfortable WBGT of 82°F

(heat category 2, green) would increase to a level of

over 92°F (heat category 5, black), the most severe

and debilitating level of heat stress. Therefore, frequent rotation of personnel to reduce the occurrence

of heat injuries is another factor to consider when

determining total manpower requirements.

Specific medications and items of equipment to

treat chemical casualties will be carried by units

operating in an area of chemical threat. When collective protection systems are not available, casualties will be taken upwind 100 m or more to permit treatment to occur in a shirtsleeve environment.

Chemical agent detection equipment, such as

the chemical agent monitor (CAM), should be available to determine (a) if agent vapors have been absorbed on surfaces of the casualty’s clothing or

equipment before entering a treatment area, and (b)

if decontamination procedures have been properly

accomplished.

Medical facilities treating chemical casualties

must divide their operations into two categories:

contaminated (dirty) and uncontaminated (clean).

Contaminated operations include triage, emergency

treatment, and patient decontamination. Uncontaminated operations include treatment and final

disposition. All activities conducted in the Casualty

Decontamination Center (CDC) and not inside a

collective protection shelter must be conducted at

MOPP 4. Operational flexibility is essential. Therefore, the number and arrangement of functional

areas will be adapted to both medical and tactical

situations.

First Aid for a Chemical Casualty

The most important care for a chemical casualty

is that provided within the first few minutes. This

cannot be provided by medical personnel and must

be done by each individual. This self-aid includes

decontamination and the self-administration of the

antidote kit if exposure was to a nerve agent.

After exposure to chemical agent vapor, the most

important aspect of care is for the soldier to don

his mask immediately to prevent further exposure.

If the soldier is symptomatic from nerve agent exposure, he should immediately administer the contents of one MARK I kit to himself and notify his

buddy of the exposure. For other agents (vesicants,

cyanide, and pulmonary agents) there is no self-aid

or first-aid therapy.

After exposure to liquid agent, the most important aspect of care is to decontaminate (ie, remove
Medical Aspects of Chemical and Biological Warfare

330

the agent) as quickly as possible. Decontamination

done within a minute or two after exposure to mustard will decrease skin damage; the severity of subsequent skin damage increases greatly each minute

the agent is in contact with skin. Immediate decontamination of nerve agent droplets from the skin

can prevent severe poisoning or death. Large

amounts of cyanide must be present on skin to cause

clinical effects, and pulmonary agents generally

penetrate the skin poorly or cause no effects by this

route of exposure, so decontamination is of much

less importance when exposure is to these agents.

A soldier who is symptomatic from a nerve agent

should immediately take steps to prevent further

exposure, and then he should self-administer the

nerve agent antidote kit (the MARK I). Each member of the military is taught to administer one kit if

he has minimal or moderate symptoms from a nerve

agent. He administers one and waits 10 minutes. If

he is no better after this time, he seeks out a buddy

to evaluate him; if there has been no improvement,

a second MARK I kit is given.2

For a casualty who is able to administer a MARK

I kit and seek out a buddy, a total of two antidote

kits usually will be sufficient. On the other hand, a

soldier with effects so severe that he is unable to

self-administer the antidotes must depend on

buddy-aid. A soldier who is not walking or talking

should be given three MARK I antidote kits and

diazepam by his buddy as quickly as they can be

administered. When the unit medic or combat lifesaver arrives, he can administer additional atropine

and one or two more injectors of diazepam as conditions indicate.2

Casualties who improve significantly from one

or two MARK I kits given for nerve agent symptoms will continue their mission on improvement.

Those casualties who later develop symptoms after vesicant or pulmonary agent exposure will seek

medical aid either at the unit aid station or at the

BAS. Generally, they will decide to seek assistance

before the effects become severe, and they will transTABLE 13-2

HEAT CATEGORIES AND WORK/REST CYCLES

Criteria* Controls: Physical Activity for Soldiers

Heat Condition/ WBGT Index Water Intake Work/Rest† Cycles for

Color Code (°F) (Qt/h) Acclimatized‡ Soldiers Unacclimatized Soldiers and Trainees

1/White 78–81.9 At least 0.5 Continuous

2/Green 82–84.9 At least 0.5 50 min work/10 min rest

3/Yellow 85–87.9 At least 1.0 45/15

4/Red 88–89.9 At least 1.5 30/30 Curtail strenuous exercise for all

personnel with < 12 wk of hot-weather

training.

5/Black > 90 > 2 20/40 Physical training and strenuous exercise

are suspended. Essential operational

commitments not for training, where

risk of heat casualties is warranted, are

excluded from suspension. Enforce

water intake to minimize expected

heat injuries.

*Wearing mission-oriented protective posture (MOPP) gear or body armor adds 10°F to the wet bulb globe thermometer (WBGT)

index.

†Rest: minimal physical activity, which should be accomplished in the shade if possible; however, any activity requiring only

minimal physical activity can be performed during “rest” periods (training by lecture/demonstration, minor maintenance of

vehicles/weapons, personal hygiene activities).

‡Acclimatized: the soldier has worked in the given heat condition for 10–14 d.

Adapted from Department of the US Army. Field Hygiene and Sanitation. Washington, DC: HQ, DA; Nov 1988: 39. Field Manual 21-10.

Use discretion in planning heavy

exercises. Suspend strenuous exercise

during the first 3 wk of training.

Training activities may be continued

on a reduced scale after week 2 of

training. Avoid activity in direct

sunlight.
Field Management of Chemical Casualties

331

port themselves to the medical site before they have

received assistance from a combat lifesaver or medic.

Casualties with severe effects, those who require

on-the-spot assistance from the unit lifesaver or

medic, will generally be sent back to the aid post or

BAS for further care. The decision by the unit lifesaver or medic to call for the litter team or ambulance team to evacuate that casualty is the first of

many levels at which triage decisions are made on

each casualty.

Ambulances that transport casualties from the

FLOT to the first-echelon MTF are generally contaminated, or “dirty,” and the personnel on these

vehicles are at MOPP 4.

Casualty-Receiving Area

Any MTF that receives contaminated casualties will

have a casualty-receiving area, which consists of a

dirty side and a clean side, separated by a “hotline”

that must not be crossed by contaminated casualties,

garments, or equipment. The area where casualties

are received, on the dirty side of the line, is where

initial triage is done, emergency medical care is provided, and the casualty is decontaminated (Figure 13-1).

The number and types of personnel in this area

will be different at each echelon of care. For example, at a BAS, a single senior medic may staff

both the triage and emergency treatment areas, but

at a hospital, physicians’ assistants or physicians

might be present at each area. Similarly, what is

done with the casualty at each station will be different at each echelon. At the BAS or other firstechelon MTF, the goals are to return casualties with

minor injuries to duty, and to stabilize casualties

with more-severe injuries for evacuation to higher

echelons of care. Of these, only two categories of

casualties will be decontaminated. Those who have

severe injuries will be decontaminated to enter the

clean medical treatment area; those who can return

to duty may go through a MOPP-gear exchange

process or go through decontamination to enter the

clean area to don new protective gear, providing

they have their own second set of gear.

Casualties with severe but stable injuries or others who must be evacuated without treatment will

be sent directly from the triage area to the ambulance area to be evacuated dirty. At a higher-echelon MTF, such as a hospital, where more-complete

care can be provided, all casualties will be decontaminated for entry into the clean treatment area.

Behind the contaminated receiving area and

separated from it by a hotline is the clean treatment

area.

A clearing company or a clearing company team

will set up ambulance exchange points, which have

a treatment squad to perform first aid and the capability to perform patient decontamination before

further evacuation. As a rule, contaminated ambulances operate from the FLOT, transporting contaminated casualties back to the exchange point,

while clean vehicles transport decontaminated casualties to Echelon III medical treatment facilities.

The Entry Point

The entry point is a clearly demarcated area into

which all casualties arrive. Ambulances unload casualties at this point, and ambulatory casualties report to this point. The entry and exit roads must

also be clearly marked. Organic (ie, intrinsic) staffing in this area may be minimal, and all casualties

arriving at this area will be sent to the triage station.

The Triage Station

The triage officer sorts each casualty into one of

the four triage categories: immediate, minimal, delayed, or expectant (Exhibit 13-1). At lower echelons

of care, the triage officer may be a senior medic (who

may also be the staff at the emergency treatment

station); at higher echelons, he may be a physician’s

assistant, dentist, or physician.

As discussed in greater detail in Chapter 14,

Triage of Chemical Casualties, the triage officer

must know the natural history of the injuries he

faces, including chemical injuries. He must also

have knowledge of evacuation capabilities and the

facilities at higher echelons of care as well as his

own decontamination capabilities and assets for

medical care.

The triage officer will send casualties (a) back to

duty, (b) to the emergency treatment station, (c) to

the decontamination area, or (d) to the dirty evacuation area.

The Emergency Treatment Station

In the most forward MTF, the emergency treatment station will likely be staffed by the same senior medic who functions as the triage officer. At

higher echelons of care, a physician’s assistant or

physician might staff this station.

At the emergency treatment station, the casualty

is provided emergency lifesaving medical care and

is stabilized for the 10- to 20-minute decontamination

procedure that is necessary before he can enter the

clean area of the MTF for more-elaborate treatment.
Medical Aspects of Chemical and Biological Warfare

332

Fig. 13-1. A casualty receiving area, or chemical decontamination receiving area, is located in front of any medical treatment facility (MTF) that receives chemically contaminated casualties. Although the precise details will vary depending on

the echelon of medical care and the resources available, any MTF at any echelon of care that might receive contaminated

casualties will have a receiving area for contaminated casualties. This area, seen in the drawing, consists of the casualty

arrival point, triage point, emergency medical treatment (EMT) station, decontamination area, and the hotline, which is

set perpendicular to the wind direction. Only after a casualty has been decontaminated can he be taken across the hotline

into the clean treatment area for more complete chemical casualty care. The pathway for nonambulatory casualties shown

in this figure is shaded yellow; ambulatory casualties, further medical treatment, and the disposition of contaminated

equipment and garments are not addressed in the following discussion. Clockwise, from bottom left: (a) At the arrival

point, the healthcare provider uses a chemical agent monitor (CAM) to assess the nature and magnitude of the casualty’s

chemical contamination. (b) After the casualty has been triaged, treatment at the EMT station may involve emergency first

aid for conventional injuries as well as the administration of chemical agent antidotes. Note that healthcare providers are

at mission-oriented protective posture (MOPP) 4 and, in addition, are wearing butyl rubber aprons. At the litter decona

b

c d e

Arrival, Triage, and 

Emergency Medical Treatment Areas

Return to Duty

Evacuate to Rear

Arrival

Point

Contam

EMT

Station

Triage

Point
Field Management of Chemical Casualties

333

tamination station, (c) the casualty’s hood is decontaminated with 5% hypochlorite solution and (d) is being cut away

prior to removal; (e) the outer garment is being excised prior to removal (not seen: the medical record card is inserted in a

plastic bag and placed under the casualty’s mask headstrap); (f) the overboots are removed; and (g) the battledress uniform is being excised prior to removal. After the casualty’s underwear has been excised and removed, the casualty is

monitored for additional contamination and (h) the skin is spot decontaminated with 0.5% hypochlorite solution. (i) At

the shuffle pit, the still-masked, litter-borne casualty is transferred to the clean side of the hotline for further treatment at

the MTF. (Not shown: the clean casualty is checked with the CAM before crossing the hot line.) The bag containing the

casualty’s medical record card, which has also been decontaminated with 5% hypochlorite solution, is transferred with the

casualty. Total elapsed time for decontamination of a litter-borne casualty to this point is 10 to 20 minutes.

Diagram: Adapted from Combat Casualty Care Office. Medical Management of Chemical Casualties Handbook. Aberdeen

Proving Ground, Md: US Army Medical Research Institute of Chemical Defense; 1994: 194. Photographs: Reproduced

electronically from US Army Chemical Decontamination of Nonambulatory Casualties. Fort Sam Houston, Tex: Health Sciences

Media Division, US Army Medical Department Center and School; 1995. Training videorecording 710175; TVT 8-252.

f g h

i

Shuffle

Pit

Shuffle

Pit

Decontamination Area Clean Treatment Area

Wind Direction ± 45°

Ambulatory

Decon Monitor

Monitor

Mask

Removal

Clean

Treatment

Area

(Dirty Side)

(Clean Side)

30–60 m 

Hotline

Litter 

Decon

Return to Duty

Evacuate to Rear
Medical Aspects of Chemical and Biological Warfare

334

EXHIBIT 13-1

TRIAGE CATEGORIES FOR CASUALTIES OF CHEMICAL WARFARE AGENTS

Immediate

A casualty in the immediate category needs to have a medical procedure performed within an hour or so to

save his life. This may be something as simple as giving more atropine and additional diazepam, and inserting

an airway for ventilation in a nerve agent casualty who is convulsing or who has just become apneic. In this

instance, the triage officer would send the casualty to the emergency treatment station in the contaminated

area. If the casualty needs more care and that care can be provided in his facility, the triage officer sends the

patient for decontamination for entry into the clean (ie, not contaminated) medical treatment area of his facility. However, he might send the casualty to the contaminated emergency treatment area for stabilization before the 10- to 20-minute decontamination procedure. Rarely, he might send an immediate casualty for urgent

evacuation to a facility at a higher echelon, but he would do this only if he were certain that the casualty could

reach that echelon in a timely fashion and that that facility could provide the needed care on arrival.

In a higher-echelon medical facility, all immediate patients will be sent through decontamination for entry

into the clean area. However, the casualty might require stabilization at the contaminated emergency treatment facility before entry into the lengthy decontamination process.

Minimal

A casualty in the minimal category is one who needs minor care and who is expected to return to duty within

hours after that care is provided. In a noncontaminated environment, these casualties will generally not be

evacuated.

In a contaminated environment, a minimal casualty might be one with a tear in his battledress overgarment

through which he became wounded by chemical or conventional means (eg, a small tear through which he

became exposed to mustard). At a lower-echelon medical treatment facility (MTF) the medical care can be

provided, but a replacement for his torn garment cannot be provided by that facility. He can return to duty

shortly, but needs new protective clothing; he can (a) go through ambulatory decontamination at that MTF

and replace his protective gear with his own second set, (b) go through procedure for exchanging his missionoriented protective posture gear if he has his own second set of protective gear, or (c) return to his unit for

resupply. In the latter case, the triage officer might send the casualty to the contaminated evacuation area for

evacuation in a dirty (ie, contaminated) vehicle. Or he might send him to be evacuated in a clean ambulance,

in which case the casualty must go through decontamination.

Delayed

A casualty in the delayed category is one who has a serious injury, but who can wait for care. The delay will

not change the ultimate outcome. Most vesicant casualties with skin lesions will be in this category. Generally,

delayed casualties will not be sent to the emergency treatment area and will not be decontaminated at the

lower-echelon facility. They will be evacuated in a dirty vehicle.

Expectant

A casualty in the expectant category is one who needs care that is beyond the capability of that MTF to provide. In addition, the needed care is required before the casualty can be evacuated to the MTF that can provide

such care. Depending on his condition and the circumstances in the MTF at the time, the casualty will initially

be set aside but will be decontaminated. As circumstances permit, he will be reexamined and possibly be

retriaged to a higher category.

Casualties with minor wounds might be treated

here if they can be returned to duty. However, most

will need to have their protective garments replaced

and will (1) go through decontamination, or (2) go

through a MOPP exchange procedure if they have

a second set of garments, or (3) be returned to their

own units for resupply. These latter casualties may

be evacuated in a dirty vehicle, or they might be

decontaminated and sent in a clean vehicle.

Care at the emergency treatment station is limited. The care provider and the casualty are both in

MOPP 4. The care provider can apply dressings,

start intravenous fluids, and insert an endotracheal

tube. In each case, the care provider must decon-
Field Management of Chemical Casualties

335

taminate the casualty’s skin in the areas that he will

touch, and he must ensure that his hands (gloves)

are decontaminated. Although he will be able to

insert an endotracheal tube, he may not have a ventilator, or if he has a mask-valve-bag device, he may

not have the personnel to use it.

From the emergency treatment station the casualty will (a) return to duty, (b) go to the decontamination area, or (c) go to the ambulance area for

evacuation in a dirty ambulance.

The Decontamination Area

At the first echelons of care the organic staff is

small, and dedicated personnel are not available to

decontaminate casualties. Personnel from the supported unit must be assigned to the MTF for this

purpose, to allow all medical care providers to care

for casualties. These augmentees should be identified early and be thoroughly trained for these tasks.

To most effectively decontaminate a patient on a

litter, three—or possibly two—people are needed.

The actual size of the augmented decontamination

staff needed, however, will be severalfold larger

than this number because the personnel will need

rest periods, the frequency and duration of which

will depend on the ambient temperature.

A minority of casualties who are able to walk will

be decontaminated at the BAS or other low echelon

of care. Most walking casualties who require significant medical attention will have nonurgent injuries and can be evacuated to a higher echelon for

needed care. Casualties in either of these categories, those who need significant care and those who

can be returned to duty after MOPP replacement,

can be evacuated in a dirty vehicle.

Casualties who need care at the first-echelon MTF

or who need stabilization before evacuation will be

decontaminated on a litter by the decontamination

staff, who are supervised by a medic. The first stage

in this process is the removal of the outer garment,

followed by removal of the casualty’s battledress

uniform, gloves, protective boots, and boots. The

field medical card (FMC) is placed in a sealed plastic bag and will remain with the casualty until the

information is copied onto another FMC; personal

effects will be bagged and tested later for contamination.

This is followed by decontamination of exposed

areas of skin with 0.5% hypochlorite solution or the

M291 (or M258A1) decontamination kits. The CAM

or M8 paper may be used to test for contamination

before and after decontamination. It is generally

believed that removal of the protective clothing will

remove 90% of contamination and removal of the

uniform will remove 5% more, leaving only a small

amount to be removed by skin decontamination.

The decontamination team then hands the nude,

decontaminated casualty across the hotline to the

medical staff. As a final step, far from the hotline

the casualty’s mask is removed. All contaminated

material is placed in a dirty dump, which is located

100 m downwind and marked with the North Atlantic Treaty Organization “gas” marking.

During the decontamination process, the medic

overseeing decontamination is responsible for

splints, tourniquets, and bandages. Splints are

soaked thoroughly with the decontaminating solution but are not removed. Tourniquets are removed

after a new one is placed proximally over decontaminated skin. Bandages are removed and not replaced except as needed (ie, to control bleeding).

Wounds that are neither truncal nor neurological

are flushed with 0.5% hypochlorite; other wounds

are thoroughly flushed with water or saline.

The decontamination process will usually take

about 10 to 20 minutes; a well-trained team can

decontaminate a casualty in slightly less than 10

minutes.

As the capability to provide medical care increases at higher echelons of care, a larger number

of casualties will be decontaminated, and at hospitals, all contaminated casualties will go through this

procedure.

The Clean Treatment Area

The capability to care for casualties increases

greatly from the lowest echelon of care to the highest. The BAS will have a physician’s assistant, a

physician, or both, and several medics. The higher

echelons, the hospitals, will have a full surgical staff

including subspecialists, surgical facilities, and full

support capabilities to provide all needed immediate care.

With limited resources available, the major tasks

of the BAS are to provide lifesaving care and to prepare the casualty for evacuation. By necessity these

must be short, simple procedures. After receiving

care in a low-echelon MTF, the casualty is evacuated in a clean vehicle to a higher echelon for further

care. If clean vehicles are not available, the casualty

may be placed in a patient protective wrap and evacuated in a dirty vehicle (see Figure 16-42 in Chapter

16, Chemical Defense Equipment). At higher echelons, the treatment area will be located in a collective protection shelter; otherwise, this should be at

least 100 m upwind from the receiving area.
Medical Aspects of Chemical and Biological Warfare

336

SUMMARY

Field management of a contaminated casualty or

of a casualty in a contaminated environment is cumbersome and manpower-intensive. In front of each

medical care facility, from battalion aid station to

field hospital, there must be a casualty-receiving

station if casualties are contaminated, or if casualties are entering from a contaminated area. In this

station, casualties are (a) triaged, (b) given the emergency care that can be provided with both casualty

and medical care provider encapsulated in protective garments, (c) decontaminated, and then (d)

taken into a noncontaminated—or clean—area for

further care. At this stage or after the initial triage,

the casualty may be evacuated to a higher-echelon

facility, depending on the needs of the casualty and

on the resources available. Initial triage is greatly hampered by the partial loss of the senses of sight and

touch because of the protective garments. Initial medical care in the contaminated area is rudimentary

because of potential contamination on the casualty

and because of the protective equipment. Decontamination of a casualty takes about 10 to 20 minutes.

REFERENCES

1. American, British, Canadian, Australian Armies Medical Interoperability Handbook. ABCA: March 1996. Initial draft.

2. Departments of the Army, the Navy, and the Air Force, and Commandant, Marine Corps. Treatment of Chemical

Agent Casualties and Conventional Military Chemical Injuries. Washington, DC: Headquarters, DA; DN; DAF; and

Commandant, MC; 22 Dec 1995: Chap 2, Nerve Agents. Army FM 8-285, Navy NAVMED P-5041, Air Force

AFJMAN 44-149, Marine Corps FMFM 11-11.
Triage of Chemical Casualties

337

Chapter 14

TRIAGE OF CHEMICAL CASUALTIES

FREDERICK R. SIDELL, M.D.*

INTRODUCTION

TRIAGE OF CHEMICAL CASUALTIES

REVIEW OF CHEMICAL AGENT EFFECTS

Nerve Agents

Cyanide

Vesicants

Phosgene

Incapacitating Agents

CATEGORIES FOR TRIAGE OF CHEMICAL CASUALTIES

Immediate

Delayed

Minimal

Expectant

CASUALTIES WITH COMBINED INJURIES

Nerve Agents

Mustard

Phosgene

Cyanide

Incapacitating Agents

SUMMARY

*Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical

Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14

Brooks Road, Bel Air, Maryland 21014
Medical Aspects of Chemical and Biological Warfare

338

INTRODUCTION

The word triage comes from the French word

trier, meaning to sort, to cull, or to select. Simply

stated, triage is the process of sorting or prioritizing casualties when providing immediate and maximal care to each is impossible. Triage is practiced

only when a mass casualty situation occurs and the

needs of the casualties for care overwhelm the medical capabilities to provide that care. A triage situation need not involve large numbers of casualties:

for example, when only one chest surgeon is available in a hospital to care for two auto accident victims with chest wounds needing immediate surgical

intervention. More commonly, triage in peacetime is

used in a large hospital after a disastrous accident

with large numbers of casualties. On a battlefield,

triage is required at a unit-level medical facility

(such as the battalion aid station [BAS]), where

medical personnel and capabilities are limited and

the casualties are numerous. In addition to the sorting of casualties for care, the triage process on a

battlefield also requires setting evacuation priorities; do not, however, confuse evacuation priorities

with triage.

The intent of triage is to provide immediate help

to those who need it; to delay care for those who

have less threatening injuries; and to set aside, at

least temporarily, both those who need care beyond

the capabilities of the available medical assets (personnel, equipment, and facilities) and those who

require such extensive care that the time and assets

spent would delay or prevent care for those more

likely to recover.

The latter concept, setting aside casualties who

are in need, is unpopular among medical care providers, whose goal is to provide the ultimate care

for each patient. It is understandable that the

thought of setting aside a critically sick or injured

patient is repugnant to someone who has not been

in a mass casualty situation or who has given little

thought to such situations. After all, in peacetime,

every patient who enters the hospital emergency

room receives the full attention of all personnel

needed to provide optimal care. Barring a mass

casualty situation, no need for triage exists under

these circumstances and most medical care providers do not live with it or the thought of it.

In a mass casualty situation, whether in peacetime or on a battlefield, triage is carried out to provide immediate and appropriate care for casualties

with treatable injuries, to delay care for those with

less immediate needs, and to set aside those for

whom care would be too time- or asset-consuming.

It ensures the greatest care for the greatest number

and the maximal utilization of medical assets: personnel, supplies, and facilities.

It is essential that a triage officer know

• the natural course of a given injury,

• the medical resources on hand,

• the current and likely casualty flow, and

• the medical evacuation capabilities.

Commonly, the most experienced surgeon available

performs triage. A surgeon is selected because

physical injuries are involved in most triage situations, and surgeons have the most extensive training

and experience in evaluating them. An experienced

surgeon is desirable because he is most familiar with

the natural course of the injury presented. Part of

the triage process is the evaluation of the benefit

that immediate assistance will provide. This evaluation is based, in part, on the natural course of the

injury or disease. For example, dedicating medical

assets to a casualty with an injury that will either

heal or prove fatal no matter what immediate care is

given would be of little benefit.

When working in a chemically contaminated

environment, the triage officer is in protective gear

and is not immediately available to assist with casualty care, which, ideally, is done within a collective protection area (a “shirtsleeve” environment).

Examination of the casualty will not be as thorough

as it might be in a clean (ie, not contaminated) environment, and very little care can be given a casualty

in the emergency treatment section in the contaminated area. In chemically contaminated environments,

therefore, in contrast to other triage situations, the

most experienced surgeon is in the clean treatment

area where he can provide maximum care. In these

cases, the triage officer is a senior corpsman or someone else with medical training, such as a dentist.

In addition to knowing the natural course of the

disease or injury, the triage officer also should be

aware of the current medical assets, the current casualty population, the anticipated number and

types of incoming casualties, the current status of

the evacuation process, and the assets and casualty

population at the evacuation site. Committing assets to the stabilization of a seriously injured casualty in anticipation of early evacuation and more

definitive care would be pointless if evacuation

could not be accomplished within the time needed
Triage of Chemical Casualties

339

for the casualty’s effective care, or if the assets at

the evacuation site were already committed. The

officer might also triage differently if, for example,

he knew that the 10 casualties present were all that

would need care in the next 24 hours or, on the other

hand, that those 10 casualties were to be followed

by 50 more within an hour.

Triage is not a static process but a dynamic one

that occurs at every echelon of medical care, preferably several times. The first triage is done by the

field medic or unit lifesaver when he encounters

an injured soldier in the field. The medic first decides whether anything can be done for that soldier to save life or limb. If the answer is no, the

medic moves on, perhaps after administering an

analgesic. More commonly, the medic decides that

care is indicated. Can the medic provide that care

on the spot to return the soldier to duty quickly?

Can the care wait until the battle is less intense or

an ambulance arrives? Or must the care be given

immediately if the casualty is to survive? In the latter case, the medic will do what is possible to return the casualty to the medical facility.

A casualty is triaged once more upon entry into

a medical care facility and is triaged again and again

within that facility as circumstances change. Those

circumstances include the casualty’s condition and

the assets available. For example, a casualty set

aside as expectant (see Triage Groups, below, for

definitions of classification categories) because personnel are occupied with more salvageable casualties might be reclassified as immediate when those

personnel become free. On the other hand, a casualty with a serious wound but in no immediate danger of loss of life might initially be classified as delayed, but if he suddenly developed unanticipated

bleeding and if assets were available to care for him,

he might be retriaged as immediate.

In an unfavorable tactical situation, another consideration may arise. Casualties with minor

wounds, who otherwise may be classified minimal,

might have highest priority for care to enable them

to return to duty. The fighting strength thus preserved could save medical personnel and casualties from attack.

Even in the most sophisticated medical setting,

a form of triage is usually performed, perhaps not

always consciously by those doing it: separation of

those casualties who will benefit from medical intervention from those who will not be helped by

maximal care. However, in most circumstances in a

large medical facility, care is administered anyway;

for instance, an individual with a devastating head

injury might receive life-support measures. The realization that in some settings assets cannot be spent

in this manner is an integral part of triage.

TRIAGE OF CHEMICAL CASUALTIES

In the simplest form of triage, patients or casualties are separated into three groups. The first group

is those for whom medical care cannot be provided

because medical assets and time are not available

to care for a wound or illness of the severity presented, and because the triage officer knows from

experience that the casualty will die no matter what

care is given. Again, a casualty’s classification might

change as assets become available or when later

reevaluation shows that the casualty’s condition

was not as serious as first anticipated. The second

group consists of casualties who require immediate intervention to save life. In a conventional situation (ie, a noncontaminated environment), these

casualties usually have injuries affecting the airway,

breathing, or circulation—the “ABCs”—which can

be treated effectively with the assets available

within the time available. The third group consists

of casualties who have injuries that place them in

no immediate danger of loss of life. Casualties in

this group might include someone with a minor

injury who merely needs suturing and a bandage

before being returned to duty, or someone who has

an extensive injury necessitating long-term hospitalization, but who at present is stable.

The triage system commonly used by U.S. military medical departments and by civilian medical

systems contains four categories: immediate, delayed,

minimal, and expectant (Exhibit 14-1). Sometimes, as

was done in the NATO Emergency War Surgery Handbook,1

 a fifth category, urgent, is added to denote a

casualty for whom intervention must occur within

minutes to save life. In Exhibit 14-1, this concept is

included in the immediate category. Also, in some

schemes, the term chemical intermediate is used for a

casualty who requires that antidotes be given immediately to save life (as in nerve agent or cyanide

poisoning). The triage categories used in this chapter do not make the distinction between chemical

casualties and casualties whose injuries are caused

by conventional weapons.

Triage categories are based on the need for medical care, and they should not be confused with categories for evacuation to a higher-echelon medical

treatment facility (MTF) for definitive care. The

need for evacuation and, more importantly, the
Medical Aspects of Chemical and Biological Warfare

340

availability of evacuation assets will certainly influence the medical triage decision. For example,

if a casualty at a BAS is urgently in need of shortterm surgery to control bleeding and evacuation is

not possible for several hours, his triage category

might be expectant instead of immediate. The

evacuation categories are urgent (life immediately

threatened), priority (life or limb in serious jeopardy), and routine.

Because this is a textbook on the management of

chemical casualties, triage of the conventionally

wounded casualty is not discussed except in the

context of combined casualties (ie, casualties whose

wounds were caused by conventional weapons but

who have also been exposed to a chemical agent;

see Casualties With Combined Injuries, below). The

distinction between the urgent and immediate

groups has been ignored, as has the separation of

the chemical immediate and immediate groups.

Chemical casualties are discussed under the commonly used groups of immediate, minimal, delayed, and expectant.

At the first echelon of medical care, the chemical

casualty is contaminated and both he and the triage officer are in protective clothing. Furthermore,

the first medical care given to the casualty is in a

contaminated area, on the “hot” or dirty side of the

“hotline” at the emergency treatment station (see

Figure 13-1 in Chapter 13, Field Management of

Chemical Casualties). This is unlike the clean side

of the hotline at any echelon of care where casualties are decontaminated before they enter, or unlike a hospital in peacetime where usually there is

no contamination.

It must be remembered that triage refers to priority for medical or surgical care, not priority for

decontamination. All chemical casualties require

decontamination. One might argue that a casualty

exposed to vapor from a volatile agent, such as cyanide or phosgene, or from some of the volatile nerve

agents does not need to be decontaminated. However, one can seldom be certain that in a situation

in which vapor and liquid both exist, some liquid

is not also present on the casualty.

It is extremely unlikely that immediate decontamination at the first echelon of medical care will

change the fate of the chemical casualty or the outcome of the injury. Various estimates indicate that

the casualty usually will not reach the first echelon

of care for 15 to 60 minutes after the injury or onset

of effects, except when the MTF is close to the battle

line or is under attack and the injury occurs just

outside. The casualty is unlikely to seek care until

the injury becomes apparent, which is usually long

after he becomes contaminated. For example, mustard, a vesicant, may be on the skin for many hours

before a lesion becomes noticeable. Thus, it is likely

that the agent has been completely absorbed or has

evaporated from the skin by the time the casualty

reaches the MTF. The small amount unabsorbed or

the amount absorbed during a wait for decontamination is very unlikely to be significant.

The process of patient decontamination must be

a factor in the judgment of the triage officer during

EXHIBIT 14-1

U.S. ARMY MEDICAL DEPARTMENT MASS CASUALTY TREATMENT PRIORITIES

Treatment priorities for mass casualties are as follows:

1. Immediate: casualties who require lifesaving care within a short time, when that care is available and of

short duration. This care may be a procedure that can be done within minutes at an emergency treatment

station by a corpsman (eg, relief of airway obstruction) or may be acute lifesaving surgery.

2. Delayed: casualties with severe injuries who are in need of major or prolonged surgery or other care and

who will require hospitalization, but delay of this care will not adversely affect the outcome of the injury. Fixation of a stable fracture is an example.

3. Minimal: casualties who have minor injuries, can be helped by nonphysician medical personnel, will not

be evacuated, and will be able to return to duty shortly.

4. Expectant: casualties with severe life-threatening injuries who would not survive with optimal medical

care, or casualties whose injuries are so severe that their chance of survival does not justify expenditure

of resources.
Triage of Chemical Casualties

341

triage. In a contaminated environment, emergency

care is given by personnel in the highest level of

mission-oriented protective posture (MOPP 4),

whose capabilities are limited by their protective

gear. After receiving emergency care, a casualty

must go through the decontamination station before receiving more definitive care in a clean environment. Decontamination takes 10 to 20 minutes.

No medical care is provided during this time or

during the time spent waiting to begin the decontamination process. Therefore, before leaving the

emergency care area, the patient must be stabilized

to an extent that his condition will not deteriorate

during this time. If stabilization cannot be achieved,

the triage officer must consider this factor when

making the triage judgment. A different type of

decontamination—immediate spot-decontamination—must be performed at the triage or emergency

treatment station in the dirty (ie, contaminated) area

when there is a break in the clothing or a wound

that is suspected to be the source of contamination.

Casualties from certain chemical agents, such as

nerve agents, may be apneic or nearly apneic; one

of the first interventions required is assisted ventilation. It is unlikely that the equipment and personnel needed to provide assistance will be available in the contaminated area. However, if a device

for ventilatory assistance, such as a mask-valve-bag

device, is available, should it be used in a contaminated area? If there is a brisk wind and if the medical facility is far upwind from the source of contamination, there will be very little agent vapor in

the air. One may choose the lesser of two undesirable circumstances and ventilate with air that is

possibly minimally contaminated rather than let the

casualty continue to be apneic. The apnea is certain

to be fatal, whereas with further but minimal vapor inhalation, the casualty may possibly be assisted. The knowledge that a limited number of

medical care providers are available in the contaminated area might affect the decision, however, because when care providers begin ventilation, they

are committed to that process and cannot care for

other casualties. However, a walking wounded (a

casualty in the minimal category) can quickly be

taught how to ventilate these casualties.

REVIEW OF CHEMICAL AGENT EFFECTS

mal because he can self-administer the antidote (or

it can be given by a medic), evacuation is not

anticipated, and he will return to duty shortly.

If the casualty has received the contents of all

three MARK I kits and continues to have dyspnea,

if his dyspnea is increasing, or if he is beginning to

have other systemic symptoms (such as nausea and

vomiting, muscular twitching, or weakness), he

should be classified as immediate. A source of continuing contamination, such as a break in protective clothing or a wound, should be sought and

spot-decontaminated and irrigated. The progression of his illness can be stopped or reversed with

a minimal expenditure of time and effort in the

emergency treatment area. More atropine should

help considerably.

One additional consideration, which is contrary

to the general advice about decontamination, must

be remembered. It is quite possible that the condition of the casualty described above, who had a

vapor exposure and administered the contents of

his MARK I kits, continues to worsen because he

also has had a liquid exposure, which is being absorbed through the skin. A break in his protective

garb should be sought; if one is found, the skin

under it should be quickly spot-decontaminated

using whatever liquid is available (preferably

bleach, but saline or water will help). If the casuBefore discussing the triage groups and the types

of chemical casualties that might be placed in each,

a brief review of the type of casualty seen with each

chemical agent is presented. Under the best of circumstances, a casualty probably will not reach a

medical treatment area until at least 15 minutes after exposure (or after onset of effects, if onset immediately follows exposure). Moreover, a casualty

will not seek medical attention until effects are apparent; an appreciable amount of time, therefore,

may elapse before the casualty is seen.

Nerve Agents

In a unit-level MTF, nerve agent casualties might

be classified as immediate, minimal, delayed, or

expectant. In a full-care MTF, it would be unlikely

to classify one as expectant.

If a nerve agent casualty is walking and talking,

he can generally be treated and returned to duty

within a short period (see Chapter 5, Nerve Agents,

for a more complete discussion of nerve agent effects and treatment). In most cases he should not

present himself at the triage point, but should selfadminister his MARK I autoinjectors, which usually will be enough to reverse the respiratory effects of vapor exposure. If the casualty appears at

the triage station, he should be classified as mini-
Medical Aspects of Chemical and Biological Warfare

342

alty is conscious, has not convulsed, and is still

breathing, prevention of further illness will ensure

a quick return to duty. He will survive unless he

continues to absorb agent.

At the other end of the spectrum, casualties who

are seriously poisoned will usually not survive long

enough to reach an MTF. There are exceptions. If

the attack is near an MTF, casualties who are unconscious, apneic, and convulsing or postictal might

be seen within minutes of exposure. Or, if the casualties have taken pyridostigmine, a nerve agent pretreatment, they might remain unconscious, convulsing, and with some impairment (but not cessation)

of respiration for many minutes to hours. These

patients, as well as those in a similar condition who

have not used pyridostigmine, require immediate

care. If they receive that care before circulation fails

and convulsions have become prolonged (see Chapter 5, Nerve Agents), they eventually will recover

and be able to return to duty.

Supporting this view is a report from the Tokyo

subway terrorist incident of 1995. One hospital

received two casualties who were apneic with no

heartbeat. With vigorous resuscitation, cardiac

activity was established in both. One resumed spontaneous respiration and walked out of the hospital

several days later, and the other did not start breathing spontaneously and died days later. These anecdotes suggest that when circumstances permit, resuscitation should be attempted. In a contaminated

area where resources, including personnel, are limited, the use of ventilatory support and closed chest

cardiac compression must be balanced against other

factors (see above), but the immediate administration

of diazepam and additional atropine requires little

effort and can be very rewarding in the casualty

who still has apparent cardiopulmonary function.

Cyanide

Cyanide casualties present the triage officer with

few problems. In general, a person exposed to a

lethal amount of cyanide will die within 5 to 10 minutes and will not reach the MTF. Conversely, a person who does reach the MTF will not require

therapy and will probably be in the minimal group,

able to return to duty soon. If the exposure occurs

near the treatment area, a severely exposed casualty might appear for treatment. He will be unconscious, convulsing or postictal, and apneic. If the

circulation is still intact, the antidotes will restore

the casualty to a reasonably functional status within

a short period of time. The triage officer, however,

must keep in mind that it takes 5 to 10 minutes to

inject the two antidotes needed. In a unit-level MTF,

a cyanide casualty might be immediate, minimal,

or expectant; the last classification would apply if

the antidote could not be administered or if the circulation had failed before the casualty reached

medical care. In a full-care facility, the casualty

might be classified as immediate or minimal.

Vesicants

Most casualties from mustard exposure will require evacuation to a facility where they can receive

care for several days to months. The exceptions are

those with small areas of erythema and those with

only a few small, discrete blisters. Even these guidelines are not as clear-cut as they seem. If the casualty is seen early after exposure, erythema may be

the only manifestation, but it may be the precursor

of blister formation. Small, discrete blisters may

appear innocuous, but on certain areas of the body

they can be quite incapacitating, rendering the soldier unfit for duty (see Chapter 7, Vesicants, for a

more complete discussion).

Mustard casualties, especially those with eye involvement, are often classified erroneously as immediate for purposes of decontamination. Little is

to be gained by this. By the time the mustard lesion

forms, the agent has been in contact with the skin,

eye, or mucous membrane for a number of hours

and the agent that will absorb into the skin or eye tissue has already been absorbed. Immediate decontamination at this time, rather than 30 to 60 minutes later,

might prevent the last fraction of a percent of agent

penetration, but this will rarely have a significant

impact on the care of a casualty or the outcome.

These casualties should be decontaminated only

after those who require urgent medical care.

Casualties who have liquid mustard burns over

50% or more of body surface area or burns of lesser

extent but with more than minimal pulmonary involvement pose a problem for the triage officer. An

estimated LD50 (ie, the dose that is lethal to 50% of

the exposed population) of liquid mustard, 100 mg/

kg, will cover 20% to 25% of body surface area. It is

unlikely that a casualty will survive 2 LD50 because

of the tissue damage from the radiomimetic effects

of mustard. Two LD50 of liquid will cover about 50%

of body surface area, and casualties with a burn this

size or greater from liquid mustard should be considered expectant. They will require intensive care

(which may include care in an aseptic environment

because of leukopenia) for weeks to months, which

can be provided only at the far-rear echelons or in

the continental United States. Chances of survival
Triage of Chemical Casualties

343

are very low in the best of circumstances and are

decreased by delays in evacuation. Furthermore,

even in a major hospital, long-term care will require

assets that might be used for more salvageable casualties. When such casualties are the only casualties, they will receive this care, but in a wartime situation, when beds and medical care are at a premium,

medical care assets might best be used for more

salvageable casualties elsewhere.

Under battlefield or other mass casualty conditions, casualties with conventional thermal burns

covering greater than 70% of body surface area are

usually put in the expectant group1 when medical

facilities are limited. This percentage is subject to

downward modification (in increments of 10%) by

other factors, including further restriction of

healthcare availability, coexisting inhalational injury, and associated traumatic injury. There are differences between mustard burns and conventional

burns. Conventional burns are likely to have a

larger component of third-degree burns, whereas

mustard burns are mostly second-degree. On the

other hand, exposure to mustard causes problems

not seen with conventional burns: hemopoietic suppression and the ensuing susceptibility to systemic

infection, which is greater than that seen with conventional burns.

In general, mustard casualties will be classified

delayed for both medical attention and decontamination. Exceptions are casualties with a very small

lesion (< 5% of body surface area) in a nonsensitive

area, who would be classified as minimal and returned to duty; those with large burn areas from

liquid mustard (> 50% of body surface area)

and those with more than minimal pulmonary involvement, who might be classified as expectant;

and those with more than minimal pulmonary

involvement, who might also be expectant. In a

more favorable medical environment, every effort

would be made to provide care for these casualties;

at least those in the latter group would be classified as immediate.

In a unit-level MTF, a mustard casualty might be

categorized as minimal, delayed, or expectant, but

probably not immediate, because the care this

casualty would require would not be available.

Even if immediate evacuation is possible, the eventual cost in medical care for a casualty needing

evacuation must be compared to the probable cost

and outcome of care for a casualty of another type.

In a large medical facility where optimum care is

available and the cost is negligible, a mustard casualty might be classified as minimal, delayed, or

immediate.

Phosgene

The phosgene casualty also may present a dilemma to the triage officer. A casualty who is in

marked distress, severely dyspneic, and coughing

up frothy sputum might be saved if he entered a

fully equipped and staffed hospital; at least, he

would receive the full capabilities of that facility. If

this casualty does not receive some ventilatory

assistance within minutes to an hour, he will not

survive. In a forward echelon, this care is not possible, nor is it possible to transport the casualty to a

hospital within the critical period. A casualty with

mild or moderate respiratory distress and physical

findings of pulmonary edema must also be evacuated immediately (even though not triaged in the

immediate treatment category because immediate

therapy will not be provided). Capability for the immediate care that this moderately distressed individual needs is probably unavailable at the first

echelons; if evacuation to a full-care MTF is not

forthcoming in a reasonably short period, the prognosis becomes grim. Thus, with phosgene casualties, availability of both evacuation and further

medical care is important in the triage decision.

Phosgene-induced pulmonary edema varies in

severity; a casualty might recover with the limited

care given at the unit-level MTF. The real dilemma

for the triage officer is a casualty who complains of

dyspnea but has no physical signs. One should keep

in mind that malingering and “gas hysteria” were

common in World War I. To evacuate this casualty

might encourage others to come to the MTF with

the same complaint, anticipating evacuation from

the battle area; not to evacuate might preclude

timely care and potentially cause an unnecessary

fatality. To observe the individual until signs of illness appear might also postpone medical intervention until the damage is irreversible.

Knowledge about the following physical manifestations of phosgene intoxication2

 may be helpful to the triage officer if a reliable history of the

time of exposure is available:

• The first physical signs of phosgene intoxication (crackles or rhonchi) occur at about half

the time it takes for the injury to become fully

evident. Thus if crackles (rales) are first heard

3 hours after exposure, the lesion will increase

in severity for the next 3 hours.

• If there are no signs of intoxication within

the first 4 hours, the chance for survival is

good, although severe disease may ultimately develop. In contrast, if the first sign
Medical Aspects of Chemical and Biological Warfare

344

is within 4 hours of exposure, the prognosis is not good, even with care in a medical

center. The shorter the onset time, the more

ominous the outlook.

Thus, if the triage officer sees a casualty with

crackles or rhonchi 3 hours after exposure, the officer can assume that the casualty will be severely

ill in 3 hours; within that time, the casualty must

reach a medical facility where care can be provided.

Even with optimal care, the chances of survival are

not good. It should be emphasized that these guidelines apply only to objective signs, not the casualty’s

symptoms (such as dyspnea). In a contaminated

area, it will not be easy and may not be possible to

elicit these signs.

In a unit-level MTF, a phosgene casualty might

be minimal or expectant, with a separate evacuation group for those who require immediate care if

they can be evacuated in time to a facility that can

provide it. In a large, higher-echelon MTF, phosgene

casualties might be classified as minimal or immediate since there should be no delayed or expectant casualties at a facility in which full care can be provided.

Incapacitating Agents

Casualties showing the effects of exposure to an

incapacitating agent may be confused, incoherent,

disoriented, and disruptive. They cannot be held at

the unit-level MTF but should not be evacuated

ahead of those needing lifesaving care unless they

are completely unmanageable and are threatening

harm to themselves or others. A casualty may be

only mildly confused from exposure to a small

amount of such an agent, or his history may indicate that he is improving or near recovery. In such

instances, the casualty may be held and reevaluated

in 24 hours.

In a unit-level MTF, a casualty from exposure to

an incapacitating agent might be minimal or delayed, with little need for high priority in evacuation. In a higher-echelon MTF, these casualties

would be cared for on a nonurgent basis.

CATEGORIES FOR TRIAGE OF CHEMICAL CASUALTIES

The categories of triage for chemical casualties

and the types of chemical casualties that might be

placed in each group (Exhibit 14-2) follow.

Immediate

Nerve Agents

A casualty of nerve agents who is in severe distress would be classified as immediate. He may or

may not be conscious. He may be in severe respiratory distress, or may have become apneic minutes

before reaching the facility. He may not have convulsed, or he may be convulsing or immediately

postictal. Often the contents of three MARK I kits

(or more) plus diazepam and, possibly, short-term

ventilatory assistance will be all that is required to

prevent further deterioration and to save a life. In

addition, a casualty with signs in two or more systems (eg, neuromuscular, gastrointestinal, respiratory—but excluding eyes and nose) should be classified as immediate and given the contents of three

MARK I kits and diazepam.

Cyanide

A casualty of cyanide who is convulsing or became apneic minutes before reaching the medical

station and has adequate circulation would be in

the immediate group. If the circulation is still adequate, the administration of antidote may be all

that is required for complete recovery. Since death

may occur within 4 to 5 minutes of exposure to a

lethal amount of cyanide unless treatment is immediate, this type of casualty is unlikely to be seen in

the MTF.

Phosgene and Vesicants

Casualties of phosgene or vesicant agents who

have moderate or severe respiratory distress should

be placed in the immediate group when intense

ventilatory and other support are immediately

available. In a BAS or other unit-level MTF, these

support systems will not be available immediately

and probably will not be available during the hours

required to transport this casualty to a large medical

facility. In general, limited assets would best be used

for other casualties more likely to benefit from them.

Delayed

Nerve Agents

Casualties who require hospitalization but have

no immediate threat to life should be placed in the
Triage of Chemical Casualties

345

EXHIBIT 14-2

CHARACTERISTICS OF CHEMICAL CASUALTIES BY TRIAGE GROUP

Immediate

• Nerve Agent

° Talking, not walking (severe distress with dyspnea, twitching, and/or nausea and vomiting);

moderate-to-severe effects in two or more systems (eg, respiratory, gastrointestinal, muscular);

circulation intact

° Not talking (unconscious), not walking; circulation intact

° Not talking, not walking; circulation not intact (if treatment facilities are available; if not, classify as

expectant)

• Cyanide

Severe distress (unconscious, convulsing or postictal, with or without apnea) with circulation intact

• Vesicant

Airway injury; classify as immediate if help can be obtained (rare)

• Phosgene

Classify as immediate if help can be obtained

Delayed

• Nerve Agent

Recovering from severe exposure, antidotes, or both

• Vesicant

Skin injury > 5% but < 50% (liquid exposure) of body surface area; any body surface area burn (vapor

exposure); most eye injuries; airway problems starting > 6 hours after exposure

• Cyanide

Recovering; has survived more than 15 minutes after vapor exposure

Minimal

• Nerve Agent

Casualty walking and talking; capable of self-aid; return to duty imminent

• Vesicant

Skin injury < 5% of body surface area in noncritical areas; minor eye injuries; minor upper-airway

injury

Expectant

• Nerve Agent

Not talking; circulation failed (with adequate treatment resources, should classify as immediate)

• Vesicant

Over 50% body surface area skin injury from liquid; moderate-to-severe airway injury, particularly

with early onset (< 6 h after exposure)

• Cyanide

Circulation failed

• Phosgene

Moderate-to-severe injury with early onset
Medical Aspects of Chemical and Biological Warfare

346

delayed group. This is generally limited to a casualty who has survived a severe nerve agent exposure, is regaining consciousness, and has resumed

spontaneous respiration. This casualty will require

further medical care but cannot be held in the unitlevel MTF for the time necessary for recovery.

Vesicants

A casualty with a vesicant burn exceeding about

5% and less than 50% of body surface area (if by

liquid) or with eye involvement will require hospitalization, but needs no immediate, lifesaving care.

He must be observed for respiratory and hemopoietic complications, although, in general, respiratory

complications occur at about the time the dermal

injury becomes apparent.

Cyanide

After cyanide injury, a casualty will recover completely within the period that he can be held at the

unit-level MTF (72 h) and need not be evacuated.

Phosgene

For casualties with significant phosgene injury,

evacuation should not be delayed. Pulmonary

edema can become life-threatening shortly after

onset. If the casualty is to be saved, medical intervention must occur as quickly as possible. As noted

above, however, this may not be possible.

Incapacitating Agents

A casualty showing signs of exposure to an incapacitating agent (such as BZ; see Chapter 11, Incapacitating Agents) usually does not have a life-threatening injury, but will not recover within days and must

be evacuated. A casualty who has had a very large

exposure, however, and is convulsing or has cardiac

arrhythmias might be an exception. He requires immediate attention if it can be made available.

Minimal

Nerve Agents

A nerve agent casualty who has only mild effects

from the agent vapor (such as miosis, rhinorrhea,

or mild-to-moderate respiratory distress) should be

categorized as minimal. He can be treated satisfactorily with the contents of one or more MARK I kits

if any treatment is indicated. A casualty who has

administered self-aid for these effects may need no

further therapy and can often be returned to duty

in 24 hours or sooner.

Vesicants

A vesicant casualty with a small area of burn—

generally less than 5% of body surface area in a

noncritical site, but the area size depends on the

site (see Chapter 7, Vesicants)—can possibly be

cared for and returned to duty. Lesions covering

larger areas or evidence suggesting more than minimal pulmonary involvement would place this

casualty in another triage group.

Cyanide

A casualty who has been exposed to cyanide and

has not required therapy will recover quickly.

Phosgene

A casualty exposed to phosgene rarely belongs

in the minimal group. If development of pulmonary

edema is suspected, the casualty is placed in a different triage group. On the other hand, if a casualty gives a reliable history of exposure several days

before, reports mild dyspnea in the intervening

time, and is now improving, the triage officer should

consider holding the casualty for 24 hours for reevaluation, with the intent of returning him to duty.

Incapacitating Agents

The evaluation of a casualty exposed to an incapacitating agent should be similar to that of a phosgene casualty. If the casualty’s condition is worsening, evacuation is necessary. On the other hand,

if there is a reliable history of exposure with an intervening period of mild effects and evidence of

recovery, he could be observed for 24 hours on-site

with the intent of returning him to duty.

Expectant

Nerve Agents

Any nerve agent casualty who does not have a palpable pulse or is apneic with the onset time of apnea

unknown should be categorized as expectant. (However, as noted above, some of these casualties may

survive if prolonged, aggressive care is possible.)
Triage of Chemical Casualties

347

Cyanide

A cyanide casualty who does not have a palpable

pulse belongs in the expectant group.

Vesicants

A vesicant casualty who has burns covering more

than about 50% of body surface area from liquid

exposure, or who has definite signs of more than

minimal pulmonary involvement, will survive only

with extensive medical care, which will not be forthcoming in forward echelons. This care might be

available at rear echelons, but care there should be

reserved primarily for those with greater chances

of survival at a lower expenditure of medical assets.

Phosgene

A casualty with moderate or severe dyspnea and

signs of advanced pulmonary edema from phosgene exposure requires a major expenditure of reararea medical assets if evacuation could be accomplished quickly enough.

CASUALTIES WITH COMBINED INJURIES

Casualties with combined injuries not only have

wounds that were caused by conventional weapons but also have been exposed to a chemical agent.

The conventional wounds may or may not be contaminated with chemical agent. Few experimental

data on this topic exist, and little has been written

specifically about these casualties from experiences

in World War I or the Iran–Iraq War.

Some factors that might influence triage decisions at a unit-level MTF are discussed below. As

noted above, most of these factors would not apply

or would be ignored at a higher-level MTF that is

relatively fully staffed and equipped, where the

capability for medical care is not at a premium.

Nerve Agents

In a casualty with mild-to-moderate intoxication

from exposure to nerve agent vapor, administering

the contents of MARK I kits can rapidly and completely reverse the nerve agent effects. Further triage decisions and medical care should focus on the

conventional wound.

In a casualty with severe systemic effects from

agent exposure, the effects should be treated before

all but the most emergent wound care is given. Of

course, airway support (including removal of obstruction) must be given and bleeding controlled if the casualty is to be saved. Which is done first—airway

management, bleeding control, or antidote administration—will depend on which problem, in the judgment of the emergency care provider, is the most immediate threat to life. (Immediate spot-decontamination or thorough flushing of the wound and surrounding skin, if these are possibly sites of exposure, must

be done at once.) If the casualty is convulsing, bleeding might be difficult to control; on the other hand,

his airway is probably at least minimally intact.

In general, if a casualty is walking and talking,

the agent injury should not influence judgments

about treatment of conventional injuries. If the casualty is talking but not walking because of the

agent injury, the casualty is immediate because of

the agent injury. He should be given the contents

of three MARK I kits and diazepam immediately.

His response will determine his further triage.

Muscular paralysis or weakness, however, and its

cause, inhibition of cholinesterase (pyridostigmine,

the nerve agent pretreatment drug, also inhibits

cholinesterase), might influence later decisions

about anesthesia.3

If the casualty is not breathing because of nerve

agent effects, attempting to provide ventilatory assistance might preclude the immediate care of a

severe wound or other assistance in the contaminated area. If ventilation is marginal and the wound

alone would classify the casualty as immediate, the

time and effort required to stabilize ventilation

might preclude timely wound care. The dual requirements might require more care providers than

are available.

A casualty who has a wound that needs immediate care, but who is unconscious and has impaired

ventilation resulting from nerve agent intoxication

might initially be considered expectant, particularly

if other, more salvageable casualties exist. One

should administer the contents of three MARK I kits

and diazepam and reevaluate this casualty when

time becomes available. A major medical facility

would have the personnel to devote to simultaneous

care of ventilation and the wound.

Mustard

In the front echelon, devoting a large effort to

wound care in a patient whose long-term progno-
Medical Aspects of Chemical and Biological Warfare

348

sis is poor from the effects of chemical agent exposure alone may not be warranted. A patient with a

wound that would warrant a classification of immediate might become expectant with the addition

of a significant skin lesion or more than minimal

pulmonary effects from mustard exposure. Similarly, classifying a casualty as delayed on the basis

of a wound may not be appropriate if liquid mustard burns are spread over more than 50% of his

body surface or if the casualty has more than minimal pulmonary effects. Hemopoietic suppression

may influence wound healing and will certainly

decrease resistance to infection and the ability to

recover from it. The long-term care of a major

wound, whether initially classified as immediate or

delayed, will often be unsuccessful in a patient with

moderate or severe pulmonary signs and symptoms

or with dermal involvement of more than 50% of

body surface (from liquid) when first seen.

Phosgene

Several factors in the pathophysiology and natural course of phosgene intoxication suggest that a

casualty with moderate-to-severe effects from phosgene exposure is not a good candidate to survive

major wounding. The pulmonary edema causes

hypoxia, which must be corrected before surgery.

In addition, the fluid causing pulmonary edema is

fluid lost from the circulation, which results in significant volume depletion, hypotension, and a large

degree of hemoconcentration (eg, a hematocrit of

0.65–0.70). A wound with more than minimal blood

loss further impairs the circulating volume, and the

hypotension would be more difficult than usual to

correct. The administration of fluid to correct the

hypovolemia and hypotension potentially causes

more fluid to leak through the alveolar-capillary

membranes into the alveoli, which increases the

pulmonary lesion and further reduces the capacity

for oxygen and carbon dioxide exchange. Fluids

must be given, however, to prevent failure of other

organs. Even if it were possible to repair the traumatic wound, several days later the lung would

inevitably become the focus for bacterial colonization. The ensuing pneumonitis or pneumonia often

becomes a nidus for sepsis, which might impair

healing.

In the forward echelons, these problems cannot be

corrected; the triage officer must judge whether the

casualty can be evacuated to a higher-level MTF where

they can be addressed, and whether evacuation can

be carried out before the damage becomes irreversible. The treatment of phosgene injury alone requires

a significant expenditure of assets. When that injury

is complicated by factors that tend to worsen the

pathophysiology, treatment becomes a major problem that might be insurmountable in all but the

most fully staffed and equipped medical centers.

Cyanide

A casualty from exposure to a lethal amount of

cyanide will die within a few minutes if he receives

no therapy. If antidotes are given in time, he will

recover with no serious adverse effects or sequelae

to interfere with wound care. One of the antidotes,

sodium nitrite, causes vasodilation and orthostatic

hypotension, but these effects are short and should

not be factors in overall patient care. If a casualty

with a conventional wound and severe effects from

cyanide poisoning presented at the unit-level MTF

(or even at a major hospital), the procedure would

be to give the antidote immediately. If the effects of

cyanide are reversed, he should receive further care.

Incapacitating Agents

A serious problem in treating a casualty presenting with a major wound and intoxication by an

incapacitating compound is that he might be delirious and unmanageable. If the compound is a cholinergic blocking agent, such as BZ (3-quinuclidinyl

benzilate), the administration of the antidote physostigmine will calm him temporarily (the effects

dissipate in 45–60 min) so that care can be given.

At some stage of their effects, these incapacitating

compounds cause tachycardia, suggesting that

heart rate may not be a reliable indication of cardiovascular status. Otherwise, nothing known

about these compounds suggests that they will interfere with wound healing or further care.

SUMMARY

Triage of casualties of chemical agents is based

on the same principles as the triage of conventional

casualties. The triage officer tries to provide immediate care to those who need it to survive; he sets

aside temporarily or delays treatment of those who

have minor injuries or do not need immediate

medical intervention; and he does not use limited

medical assets on the hopelessly injured. At the first

echelon of medical care on a battlefield, medical

capabilities are very limited. When chemical agents
Triage of Chemical Casualties

349

are present or suspected, medical capabilities

are further diminished because early care must

be given while the medical care provider and casualty are in protective clothing. Decontamination,

a time-consuming process, must be carried out before the casualty receives more definitive care, even

at this level. At the rear echelons of care—or at a

hospital in peacetime—medical capabilities are

much greater and decontamination has already

been accomplished before the casualty enters for

treatment.

Triage is a matter of judgment by the triage officer. This judgment should be based on knowledge

of medical assets, the casualty load, and, at least at

unit-level MTFs, the evacuation process. Most importantly, the triage officer must have full knowledge of the natural course of an injury and its potential complications.

REFERENCES

1. Bowen TE, Bellamy RF, eds. Emergency War Surgery NATO Handbook. 2nd rev US ed. Washington, DC: Department of Defense, Government Printing Office; 1988.

2. Urbanetti JS. Clinical Assistant Professor of Medicine, Yale University School of Medicine, New Haven, Conn.

Personal communication, 1989.

3. Keeler JR. Interactions between nerve agent pretreatment and drugs commonly used in combat anesthesia.

Milit Med. 1990;155:527–533.
Decontamination

351

Chapter 15

DECONTAMINATION

CHARLES G. HURST, M.D.*

INTRODUCTION

METHODS OF DECONTAMINATION

Physical Removal

Chemical Methods

Certification of Decontamination

WOUND DECONTAMINATION

Initial Decontamination

General Considerations

Thickened Agents

Off-Gassing

Foreign Material

Wound Contamination Assessment

Dilute Hypochlorite Solution

Wound Exploration/Debridement

BIOLOGICAL AGENT DECONTAMINATION

Chemical Method

Physical Method

SUMMARY

*Colonel, Medical Corps, U.S. Army; currently, Special Assistant for Medical Programs, Office of the Deputy Assistant Secretary of Defense,

Counterproliferation and Chemical/Biological Matters, Room 3E808, 3050 Defense Pentagon, Washington, D.C. 20301-3050; formerly,

Commander, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425
Medical Aspects of Chemical and Biological Warfare

352

INTRODUCTION

Decontamination is defined as the reduction or

removal of chemical (or biological) agents so they

are no longer hazards. Agents may be removed by

physical means or be neutralized chemically

(detoxification). Decontamination of skin is the primary concern, but decontamination of eyes and

wounds must also be done when necessary. Decontamination can be further defined:

• personal decontamination refers to decontamination of oneself,

• casualty decontamination refers to the decontamination of casualties, and

• personnel decontamination usually refers to

decontamination of noncasualties.

The most important and most effective decontamination after any chemical or biological exposure is that decontamination done within the first

minute or two after exposure. This is personaldecontamination. Early action by the soldier to decontaminate himself will make the difference between survival (or minimal injury) and death (or

severe injury). Good training can save lives.

Decontamination of chemical casualties is an

enormous task. The process requires dedication of

both large numbers of personnel and large amounts

of time. Even with appropriate planning and training, decontamination of casualties demands a significant contribution of resources. Liquids and solids are the only substances that can be effectively

removed from the skin. It is generally not possible

or necessary to decontaminate skin following vapor exposure. Removal from the atmosphere containing the vapor is all that is required.

Many substances have been evaluated for their

usefulness in skin decontamination. The most common problems with potential decontaminants are

irritation of the skin, toxicity, ineffectiveness, or

high cost. An ideal decontaminant will rapidly and

completely remove or detoxify all known chemical

and biological warfare agents. Furthermore, a suitable skin decontaminant must have certain properties that are not requirements for decontaminants

for equipment.1,2 Recognized desirable traits of a

skin decontaminant are shown in Exhibit 15-1.

Decontamination issues have been explored since

the beginning of modern chemical warfare. After years

of research worldwide, simple principles that consistently produce good results are still recommended.

The first, which is without equal, is timely physical removal of the chemical agent. To remove the

substance by the best means available is the primary

objective. Chemical destruction (detoxification) of

the offending agent is a desirable secondary objective. Physical removal is imperative because none

of the chemical means of destroying these agents

destroy them instantaneously. While decontamination preparations such as fresh hypochlorite (either

sodium or calcium hypochlorite) react rapidly with

some chemical agents (eg, the half-time for destruction of the nerve agent VX by hypochlorite at pH

10 is 1.5 min), the half-times of destruction of other

agents, such as mustard, are much longer.3

 If a large

amount of agent is present initially, a longer time is

EXHIBIT 15-1

DESIRABLE TRAITS OF A SKIN

DECONTAMINANT

• Neutralizes all chemical and biological agents

• Is safe (nontoxic and noncorrosive)

• Is applied easily by hand

• Is readily available

• Acts rapidly

• Produces no toxic end products

• Is stable in long-term storage

• Is stable in the short term (after issue to unit/

individual)

• Is affordable

• Does not enhance percutaneous agent

absorption

• Is nonirritating

• Is hypoallergenic

• Is easily disposed of

Sources: (1) Chang M. A Survey and Evaluation of

Chemical Warfare Agent Contaminants and Decontamination. Dugway Proving Ground, Utah: Defense Technical Information Center; 1984. AD-202525. (2) Baker JA.

COR Decontamination/Contamination Control Master

Plan Users’ Meeting. 11–13 September 1985. Unpublished.
Decontamination

353

needed to completely neutralize the agent to a

harmless substance.

Decontamination studies have been conducted

using common household products. The goal of

these studies was identification of decontaminants

for civilians as well as field expedients for the soldier. Timely use of water, soap and water, or flour

followed by wet tissue wipes produced results

equal, nearly equal, or in some instances better than

those produced by the use of fuller’s earth, Dutch

Powder, and other compounds.4 (Fuller’s earth [diatomaceous earth] and Dutch Powder [Dutch variation of fuller’s earth] are decontamination agents

currently fielded by some European countries.) Because no topical decontaminant has ever shown efficacy with chemical agent that has penetrated into

the skin, and because chemical agents may begin

penetrating the skin before complete reactive decontamination (detoxification) takes place, early

physical removal is most important.

Military personnel may be questioned for guidance by local civilian authorities or may deal with

supply shortages in the field. Knowledge of the U.S.

doctrinal decontaminating solutions may not suffice in these situations, and awareness of alternative methods of decontamination will prove very

beneficial. What decontamination method is used

is not as important as how and when it is used.

Chemical agents should be removed as quickly

and completely as possible by the best means

available.

The M291 resin kit and 0.5% hypochlorite for

chemical casualty decontamination are currently

fielded by the U.S. military. The M291 kit is

new, whereas hypochlorite solution has been

around since World War I. The M291 kit is our best

universal dry decontaminant for skin. Fresh 0.5%

hypochlorite solution with an alkaline pH is our

universal liquid decontaminating agent and is recommended for all biological agents.

The M291 resin kit is best for spot-decontamination of skin (Figure 15-1). The dry, black resin rapidly adsorbs the chemical agent, with carbonaceous

material physically removing the agent from skin

contact. Later, an ion-exchange resin neutralizes the

offending agent by chemical detoxification. Since

the M291 kit is small and dry and easily carried by

the soldier, it is well suited for field use.5,6 Early

intervention with the use of this kit will reduce

chemical injury and save life in most cases.

Decontamination of the casualty using an M291

kit does not obviate the need for decontamination at a field medical treatment facility (MTF).

Fig. 15-1. The six individual decontamination pads of the

M291 kit are impregnated with the decontamination compound Ambergard XE-555 Resin, which is the black, freeflowing, resin-based powder. Each pad has a loop that

fits over the hand. As the soldier holds the pad in one

hand, he scrubs the pad over his contaminated skin. The

chemicals are rapidly transferred into and trapped in the

interior of the resin particles. The presence of acidic and

basic groups in the resin promotes the destruction of

trapped chemical agents by acid and base hydrolysis.

Because the resin is black, the area that has been decontaminated is easy to see. Photograph: Courtesy of Michael

R. O’Hern, Sergeant First Class, US Army (Ret) and Larry

L. Harris, Sergeant First Class, US Army (Ret).

Chemical agent transfer is a potential problem that

can be resolved by a second, deliberate decontamination. This thorough decontamination at the MTF

prevents spread of the agent to areas of the body previously uncontaminated, contamination of personnel

assisting the patient, and contamination of the MTF

itself.

Liquids are best for decontaminating large or irregular surface areas. Hypochlorite solutions are

well suited for MTFs with adequate water supplies.

For hypochlorite to be most effective, it has to be

relatively fresh (made daily or more frequently,

particularly in a warm environment where evaporation will occur) and have a concentration of 0.5%

at an alkaline pH (pH 10–11). Hypochlorite solutions are for use on skin and soft-tissue wounds

only. Hypochlorite should not be used in abdominal wounds, in open chest wounds, on nervous tissue, or in the eye. Surgical irrigation solutions

should be used in liberal amounts in the abdomen

and chest. All such solutions should be removed

by suction instead of sponging and wiping. Only

copious amounts of water, normal saline, or eye

solutions are recommended for the eye. Contaminated wounds are discussed later in this chapter.
Medical Aspects of Chemical and Biological Warfare

354

METHODS OF DECONTAMINATION

Three basic methods of decontamination are

physical removal, chemical deactivation, and biological deactivation of the agent. Biological deactivation has not been developed to the point of being practical.

Physical Removal

Several types of physical and chemical methods

are at least potentially suitable for decontaminating equipment and material. Flushing or flooding

contaminated skin or material with water or aqueous solutions can remove or dilute significant

amounts of chemical agent. Scraping with a wooden

stick (ie, a tongue depressor or Popsicle stick) can

remove bulk agent by physical means. A significant

advantage of most physical methods is their

nonspecificity. Since they work nearly equally well

on chemical agents regardless of chemical structure,

knowledge of the specific contaminating agent or

agents is not required.

Flushing With Water or Aqueous Solutions

When animal skin contaminated with the nerve

agent GB was flushed with water at 2 minutes (a

method in which physical removal predominates

over hydrolysis of the agent), 10.6 times more GB was

required to produce the same mortality rate as when

no decontamination occurred.7

 In another study, the

use of water alone produced better results than high

concentrations of hypochlorite (ie, 5% or greater,

which is not recommended for skin).8 Timely copious flushing with water physically removes the

chemical agent and will produce good results.

Adsorbent Materials

Adsorption refers to the formation and maintenance of a condensed layer of a substance, such as

a chemical agent, on the surface of a decontaminant,

as illustrated by the adsorption of gases by charcoal particles and by the decontaminants described

in this section. Some North Atlantic Treaty Organization (NATO) nations use adsorbent decontaminants in an attempt to reduce the quantity of chemical agent available for uptake through the skin. In

emergency situations, dry powders such as soap or

detergents, earth, and flour may be useful. Flour

followed by wiping with wet tissue paper is reported4

 to be effective against the nerve agents soman (GD) and VX and against mustard.

M291 Resin

The current method of battlefield decontamination by the individual soldier involves the use of a

carbonaceous adsorbent, a polystyrene polymeric, and

ion-exchange resins (the M291 kit; see Figure 15-1).

The resultant black powder is both reactive and adsorbent. The M291 kit has been extensively tested and

has proven highly effective for skin decontamination.5,6 It consists of a walletlike carrying pouch containing six individual decontamination packets.

Each packet contains a nonwoven, fiberfill, laminated pad impregnated with the decontamination

compounds. Each pad provides the individual with

a single-step, nontoxic, nonirritating decontamination application, which can be used on the skin, including the face and around wounds. Instructions

for use are marked on the case and packets.

Chemical Methods

Three types of chemical mechanisms have been

used for decontamination: water/soap wash; oxidation; and acid/base hydrolysis.9

 Mustard (HD) and

the persistent nerve agent VX contain sulfur molecules

that are readily subject to oxidation reactions. VX and

the other nerve agents (tabun [GA], sarin [GB], soman [GD], and GF) contain phosphorus groups that

can be hydrolyzed. Therefore, most chemical decontaminants are designed to oxidize mustard and VX

and to hydrolyze nerve agents (VX and the G series).1

Water and Water/Soap Wash

Both fresh water and sea water have the capacity to remove chemical agents not only through

mechanical force but also via slow hydrolysis; however, the generally low solubility and slow rate of

diffusion of chemical warfare agents in water significantly limit the agent hydrolysis rate.10

The predominant effect of water and water/soap

solutions is the physical removal or dilution of

agents; however, slow hydrolysis does occur, particularly with alkaline soaps. In the absence of hypochlorite solutions or other appropriate means of

removing chemical agents, these methods are considered reasonable options.4

Oxidation

The most important category of chemical decontamination reactions is oxidative chlorination. This
Decontamination

355

term covers the “active chlorine” chemicals like

hypochlorite. The pH of a solution is important in

determining the amount of active chlorine concentration. An alkaline solution is advantageous. Hypochlorite solutions act universally against the organophosphorus and mustard agents.11

Both VX and HD contain sulfur atoms that are

readily subject to oxidation. Current U.S. doctrine

specifies the use of a 0.5% sodium or calcium hypochlorite solution for decontamination of skin and

a 5% solution for equipment.

Hydrolysis

Chemical hydrolysis reactions are of two types:

acid and alkaline. Acid hydrolysis is of negligible

importance for agent decontamination because the

hydrolysis rate of most chemical agents is slow,

and adequate acid catalysis is rarely observed.11

Alkaline hydrolysis is initiated by the nucleophilic

attack of the hydroxide ion on the phosphorus

atoms found in VX and the G agents. The hydrolysis rate is dependent on the chemical structure and

reaction conditions such as pH, temperature,

the kind of solvent used, and the presence of catalytic reagents. The rate increases sharply at pH

values higher than 8 and increases by a factor

of four for every 10°C rise in temperature. Several

of the hydrolytic chemicals are effective in detoxifying chemical warfare agents; unfortunately,

many of these (eg, sodium hydroxide) are unacceptably damaging to the skin. Alkaline pH hypochlorite hydrolyses VX and the G agents quite

well.3,12

Certification of Decontamination

Regardless of the method used to decontaminate,

certification of chemical decontamination is accomplished by any of the following: processing through

the decontamination facility; M8 paper; M9 tape;

M256A1 ticket; or by the CAM (chemical agent

monitor). (See Chapter 16, Chemical Defense Equipment, for a discussion of this detection equipment.)

If proper procedure is followed, the possibility of

admitting a chemically contaminated casualty to a

field MTF is extremely small. The probability of

admitting a dangerously contaminated casualty is

minuscule to nonexistent. Fear is the worst enemy,

not the contaminated soldier.

WOUND DECONTAMINATION

All casualties entering a medical unit after experiencing a chemical attack are to be considered contaminated unless there is certification of noncontamination. The initial management of a casualty

contaminated by chemical agents will require removal of mission-oriented protective posture

(MOPP) gear and decontamination with 0.5% hypochlorite before treatment within the field MTF.

Initial Decontamination

During initial decontamination in the decontamination areas, bandages are removed and the

wounds are flushed; the bandages are replaced only

if bleeding recurs. Tourniquets are replaced with

clean tourniquets and the sites of the original tourniquets decontaminated. Splints are thoroughly

decontaminated, but removed only by a physician.

The new dressings are removed in the operating

room and submerged in 5% hypochlorite or placed

in a plastic bag and sealed.

General Considerations

Of the chemical agents discussed, only two types,

the vesicants and the nerve agents, might present a

hazard from wound contamination. Cyanide is

quite volatile, so it is extremely unlikely that liquid

cyanide will remain in a wound. A very large

amount of liquid cyanide is required to produce

vapor sufficient to cause effect.

Mustard converts to a cyclic compound within

minutes of absorption into a biological milieu, and

the cyclic compound reacts rapidly (ie, within minutes) with blood and tissue components.13 These

reactions will take place with the components of the

wound—the blood, the necrotic tissue, and the remaining viable tissue. If the amount of bleeding and

tissue damage is small, mustard will rapidly enter

the surrounding viable tissue, where it will quickly

biotransform and attach to tissue components (and

its biological behavior will be much like an intramuscular absorption of the agent).

Although nerve agents cause their toxic effects

by their very rapid attachment to the enzyme acetylcholinesterase, they also quickly react with other

enzymes and tissue components. As they do with

mustard, the blood and necrotic tissue of the wound

will “buffer” the nerve agents. Nerve agent that

reaches viable tissue will be rapidly absorbed, and

since the toxicity of the nerve agents is quite high

(a lethal amount is a small fraction of a drop), it is
Medical Aspects of Chemical and Biological Warfare

356

unlikely that casualties whose wounds are contaminated with much liquid nerve agent will survive to

reach medical care.14

Potential risk to the surgeon from contaminated

wounds arises from chemical agent on foreign bodies in the wound and from thickened agents.15 Medical personnel treating biological casualties have

only a minimal risk from secondary aerosolization

of biological agents.

Thickened Agents

Thickened agents are chemical agents that have

been mixed with another substance (commonly an

acrylate) to increase their persistency. They are not

dissolved as quickly in biological fluids nor are they

absorbed by tissue as rapidly as other agents. VX,

although not a thickened agent, is absorbed less

quickly than other nerve agents and may persist in

a wound longer than other nerve agents.

Thickened agents in wounds require more precautions. Casualties with thickened nerve agents in

wounds (eg, from pieces of a contaminated battledress uniform or protective garment being carried

into the wound tract) are unlikely to survive to

reach surgery. Thickened mustard has delayed systemic toxicity and can persist in wounds even when

large fragments of cloth have been removed. Although the vapor hazard to surgical personnel is

extremely low, contact hazard from thickened agents

does remain and should always be assumed.14

No country is currently known to stockpile thickened agents. In a chemical attack, the intelligence

and chemical staffs should be able to identify thickened agents and to alert the medical personnel of

their use.

Off-Gassing

The risk from vapor off-gassing from chemically

contaminated fragments and cloth in wounds is

very low and not significant. Further, there is no

vapor release from contaminated wounds without

foreign bodies. Off-gassing from a wound during

surgical exploration will be negligible or zero. No

eye injury will result from off-gassing from any of

the chemical agents. A chemical-protective mask is

not required for surgical personnel.14

Biological agents can only be transmitted to

medical personnel from secondary aerosolization

from dry agents. Decontamination with 0.5% hypochlorite solution or flooding with water or saline

will make this risk negligible. No protective equipment is necessary for surgical personnel other than

standard barrier protections, unless the patient is

infected with the plague bacillus, smallpox, or a hemorrhagic fever virus, or if procedures likely to generate bloody aerosols are employed. In such cases, wearing of a filtered respirator is recommended.

Foreign Material

The contamination of wounds with mustard or

nerve agents is basically confined to the pieces of

contaminated fabric in the wound tract. The removal of this cloth from the wound effectively

eliminates the hazard. There is little chemical risk

associated with individual fibers left in the wound.

No further decontamination of the wound for

unthickened chemical agent is necessary.14

Wound Contamination Assessment

The CAM can be used to assist in locating contaminated objects within a wound; however, 30 seconds are required to achieve a bar reading. The

CAM detects vapor but may not detect liquid (a

thickened agent or liquid on a foreign body) deep

within a wound. A single-bar reading on CAM with

the inlet held a few millimeters from the wound surface indicates that a vapor hazard does not exist.14

Dilute Hypochlorite Solution

Dilute hypochlorite (0.5%) is an effective skin

decontaminant for patient use. The solution should

be made fresh daily with a pH in the alkaline range

(pH 10–11). Plastic bottles containing 6 ounces of

calcium hypochlorite crystals are currently fielded

for this purpose.

Dilute hypochlorite solution is contraindicated

for the eye; it may cause corneal injuries. This substance is also not recommended for brain and spinal cord injuries. Irrigation of the abdomen with

hypochlorite solution may lead to adhesions and is

therefore also contraindicated. The use of hypochlorite in the thoracic cavity may be less of a problem,

but the hazard is still unknown.

Wound Exploration and Debridement

Surgeons and assistants are advised to wear a

pair of well-fitting (thin) butyl rubber gloves or

double latex surgical gloves and to change them

often until they are certain there are no foreign bodies or thickened agents in the wound. Thin butyl
Decontamination

357

rubber gloves will have no breakthrough for 60 or

more minutes in an aqueous base. Double latex surgical gloves will have no breakthrough for 29 minutes in an aqueous medium; they should be changed

every 20 minutes.16 This is especially important

where puncture is likely because of the presence of

bone spicules or metal fragments.14

The wound should be explored with surgical instruments rather than with the fingers. Pieces of

cloth and associated debris must not be examined

closely but quickly disposed of in a container of 5%

hypochlorite. The wound can then be checked with

the CAM, which may direct the surgeon to further

retained material. It takes about 30 seconds to get a

stable reading from the CAM. A rapid pass over the

wound will not detect remaining contamination.

The wound should be debrided and excised as

usual, maintaining a no-touch technique. Removed

fragments of tissue should be dropped into a container of 5% to 10% hypochlorite. Bulky tissue such

as an amputated limb should be placed in a plastic or

rubber bag (chemical proof), which is then sealed.14

Dilute hypochlorite solution (0.5%) may be instilled into deep, noncavity wounds following the

removal of contaminated cloth. This solution should

be removed by suction to a disposal container.

Within a short time (ie, 5 min), this contaminated

solution will be neutralized and rendered nonhazardous. Subsequent irrigation with saline or other

surgical solutions should be performed.

Penetrating abdominal wounds caused by large

fragments or containing large pieces of chemically

contaminated cloth will be uncommon. Surgical

practices should be effective in the majority of

wounds for identifying and removing the focus of

remaining agent within the peritoneum. When possible, the CAM may be used to assist.

Saline, hydrogen peroxide, or other irrigating

solutions do not necessarily decontaminate agents

but may dislodge material for recovery by aspiration with a large-bore suction tip. The irrigation

solution should not be swabbed out manually with

surgical sponges. Although the risk to patients and

medical attendants is minuscule, safe practice suggests that any irrigation solution should be considered potentially contaminated. Following aspiration

by suction, the suction apparatus and the solution

should be decontaminated in a solution of 5% hypochlorite. Superficial wounds should be subjected

to thorough wiping with 0.5% hypochlorite and

subsequent irrigation with normal saline or sterile

water.

Surgical and other instruments that have come

into contact with possible contamination should be

placed in 5% hypochlorite for 10 minutes prior to

normal cleansing and sterilization. Reusable linen

should be checked with the CAM, M8 paper, or M9

tape for contamination. If found to be contaminated,

the linen should be soaked in a 5% to 10% hypochlorite solution.

BIOLOGICAL AGENT DECONTAMINATION

Decontamination of personnel and equipment

after a biological warfare attack is a lesser concern

than after a chemical warfare attack because most

biological warfare agents are not dermally active

(the trichothecene mycotoxins are an exception).

Still, decontamination remains an effective way to

decrease the spread of infection from potential secondary aerosolization.

For biological agents, contamination is defined as

the introduction of microorganisms into tissues or

sterile materials, whereas decontamination is defined

as disinfection or sterilization of infected articles to

make them suitable for use (the reduction of microorganisms to an acceptable level). Disinfection is

defined as the selective elimination of certain undesirable microorganisms to prevent their transmission (the reduction of the number of infectious

organisms below the level necessary to cause infection), and sterilization is defined as the complete

killing of all organisms. Biological warfare agents

can be decontaminated by chemical and physical

methods.

Chemical Method

Chemical decontamination renders biological

warfare agents harmless by the use of disinfectants.

Dermal exposure to a suspected biological warfare

agent should be immediately treated by soap and

water decontamination. Careful washing with soap

and water removes a very large amount of the agent

population from the surface. It is important to use

a brush to ensure mechanical loosening from the skin

surface structures, and then to rinse with copious

amounts of water. This method is often sufficient

to avert contact infection. The contaminated areas

should then be washed with a 0.5% hypochlorite

solution, if available, with a contact time of 10 to 15

minutes. The solution should be applied with a

cloth or swab or can be sprayed on. As with hy-
Medical Aspects of Chemical and Biological Warfare

358

pochlorite in chemical decontamination, this solution should not be used in the eyes, abdominal cavity, or on nerve tissue. It will neutralize and render

nonhazardous any biological agent within approximately 5 minutes.

For decontamination of fabric clothing or equipment, a 5% hypochlorite solution should be used.

For decontamination of equipment, a contact time

of 30 minutes prior to normal cleaning is required.

Use of hypochlorite solution in this way is corrosive to most metals and injurious to most fabrics,

so they should be rinsed thoroughly and metal surfaces should be oiled after completion.

An important point to remember is that soap and

water washing followed by hypochlorite washing

to decontaminate for biological agents should be

prompt but should follow any needed use of

decontaminants for chemical agents. Ampules of

calcium hypochlorite granules are currently fielded

in the chemical agent decontamination kit for mixing hypochlorite solutions. The 0.5% solution can

be made adding one 6-ounce container of calcium

hypochlorite granules to 5 gallons of water. The 5%

solution can be made by adding eight 6-ounce containers of calcium hypochlorite granules to 5 gallons of water. These solutions evaporate quickly at

high temperatures, so if they are made in advance,

they should be stored in closed containers. The hypochlorite solutions should be placed in distinctly

marked containers because it is very difficult to distinguish visually a 0.5% solution from a 5% solution.

Physical Method

Physical methods are concerned with rendering

biological warfare agents harmless through such

physical means as heat and radiation. To render

agents completely harmless, dry heat requires 2

hours of treatment at 160°C. If steam is used at

121°C and 1 atm of overpressure (15 psi), the time

may be reduced to 20 minutes, depending on volume. This last method is also known as autoclaving. The part of solar ultraviolet radiation that

reaches the Earth’s surface has a certain disinfectant effect, often in combination with drying.

Ultraviolet radiation is effective but hard to standardize into practical usage for disinfection or decontamination purposes.

SUMMARY

Decontamination at the MTF is directed toward

(1) eliminating any chemical agent transferred to

the patient during removal of protective clothing;

(2) decontaminating or containing of contaminated

clothing and personal equipment; and (3) maintaining an uncontaminated MTF.

Current doctrine specifies the use of 0.5% hypochlorite solution for chemical or biological skin contamination or the M291 kit for chemically contaminated skin. Fabric and other foreign bodies that

have been introduced into a wound can sequester

and slowly release chemical agent, presenting a liquid hazard to both the patient and medical personnel. Dry biological agent could be a hazard through

secondary aerosolization. Adequate liquid decontamination will mitigate this hazard. There is no

vapor hazard, and protective masks are not necessary for surgical personnel.

REFERENCES

1. Chang M. A Survey and Evaluation of Chemical Warfare Agent Contaminants and Decontamination. Dugway Proving Ground, Utah: Defense Technical Information Center; 1984. AD-202525.

2. Baker JA. COR Decontamination/Contamination Control Master Plan Users’ Meeting; 11–13 September 1985.

Unpublished.

3. Yurow HW. Decontamination methods for HD, GB and VX: A literature survey. Aberdeen Proving Ground,

Md: Army Armament Research and Development Command; Chemical Systems Laboratory; 1981. AD-B057349L.

4. van Hooidonk C. CW agents and the skin: Penetration and decontamination. In: Proceedings of the International Symposium on Protection Against Chemical Warfare Agents; June 6–9, 1983; Stockholm, Sweden. National Defense Research Institute.

5. Hobson D, Blank J, Menton R. Comparison of Effectiveness of 30 Experimental Decontamination Systems and Evaluation of the Effect of Three Pretreatment Materials Against Percutaneous Application of Soman, Thickened Soman, VX,

and Sulfur Mustard to the Rabbit. Edgewood Area, Aberdeen Proving Ground, Md; 1985. MREF Task 85-12: Final

Report.
Decontamination

359

6. Hobson D, Blank J, Menton R. Testing of Candidate CSM Decontamination Systems. Edgewood Area, Aberdeen

Proving Ground, Md; 1986. MREF Task 86-25: Final Report.

7. Zvirblis P, Kondritzer AA. Protective ointment M5, water and bleaches as skin decontaminants for GB, I. In:

Studies on Skin Decontamination. Army Chemical Center, Md: Medical Laboratories; 1953. Report 193.

8. Zvirblis P. Bleaching powder and related items as decontaminants for liquid GB, II. In: Studies on Skin Decontamination. Army Chemical Center, Md: Medical Laboratories; 1954. Report 307.

9. Gum R, Madsen J, Keeler J, Hurst C. Decontamination White Paper. Aberdeen Proving Ground, Md: US Army

Medical Research Institute of Chemical Defense; 1991. Unpublished.

10. Chang AMH, Ciegler A. Chemical warfare, I. Chemical Decontamination, NBC Defense and Technical International. 1986;1(40):60.

11. Trapp R. The Detoxification and Natural Degradation of Chemical Warfare Agents. Stockholm, Sweden: Stockholm

International Peace Research Institute (SIPRI); 1985: 44–75.

12. Block F, Davis GT. Survey of Decontamination Methods Related to Field Decontamination of Vehicles and Materiel.

Dugway Proving Ground, Utah: Defense Technical Information Center; 1978: 59–60. AD-B031659.

13. Papirmeister B, Feister A, Robinson S, Ford R. Medical Defense Against Mustard Gas: Toxic Mechanisms and

Pharmacological Implications. Boca Raton, Fla: CRC Press; 1991: 92.

14. Cooper GJ, Ryan JM, Galbraith KA. The surgical management in war of penetrating wounds contaminated

with chemical warfare agents. J R Army Med Corps. 1994;140:113–118.

15. Hobson D, Snider T. Evaluation of the Effects of Hypochlorite Solutions in the Decontamination of Wounds Exposed

to Either the Organophosphanate Chemical Surety Materiel VX or the Vesicant Chemical Surety Materiel HD. Columbus, Ohio: Battelle Memorial Institute; 1992. Task 89-04.

16. Smith W, PhD. US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Md.

Personal communication, 1996.
Chemical Defense Equipment

361

Chapter 16

CHEMICAL DEFENSE EQUIPMENT

MICHAEL R. O’HERN*; THOMAS R. DASHIELL†; AND MARY FRANCES TRACY‡

INTRODUCTION

INDIVIDUAL PROTECTION EQUIPMENT

Respiratory Protection

Protective Clothing

DETECTION AND WARNING

Chemical Detection and Warning

Integrated Mobile Systems

COLLECTIVE PROTECTION

DECONTAMINATION EQUIPMENT

ADDITIONAL PATIENT PROTECTION AND TRANSPORT EQUIPMENT

SUMMARY

PSYCHOLOGICAL PROBLEMS ASSOCIATED WITH WEARING MISSIONORIENTED PROTECTIVE POSTURE GEAR

HISTORY

THE CURRENT SITUATION

Modern Case Studies

Treatment

SUMMARY

*Sergeant First Class, U.S. Army (Ret); PO Box 46, Aberdeen, Maryland 21010; formerly, Noncommissioned Officer in Charge, Chemical

Casualty Care Office, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425

†Consultant, Life Sciences and NBC Defense, 504 Thomas Avenue, Frederick, Maryland 21701-6251; formerly, Director, Environmental and

Life Sciences, Office of the Director of Defense Research, Office of the Secretary of Defense, Department of Defense, Washington, D. C.

‡Research Scientist, Chemical Warfare/Chemical and Biological Defense Information Center (CBIAC): a Department of Defense Information

Analysis Center operated by Battelle Memorial Institute and sponsored by Defense Technical Information Center, Aberdeen Proving Ground,

Maryland 21010-5425
Medical Aspects of Chemical and Biological Warfare

362

INTRODUCTION

to permit all potentially exposed forces to adopt an

adequate posture, since the effects of agents can

sometimes occur in less than a minute. Vesicant

agents and some nerve agents (eg, VX and some

of the G series), which can remain active for long

periods of time, can affect individuals via the dermal route, thus requiring that a proper overgarment

be part of the protective ensemble. Likewise, detection equipment is also used to confirm agent

hazard reduction and facilitates reducing the mission-oriented protective posture (MOPP) level and

the removal of protection equipment: the “all clear”

signal.

Decontamination of equipment, facilities, and

personnel is also required after an attack if effective military operations are to be maintained. Some

of this decontamination burden can be mitigated

by the use of effective collective protection equipment, which can allow continuing operations such

as communications and medical care within protected facilities.

One criterion for the selection and use of protective equipment items is the need for joint service

use, although there are some differences between

the missions of air and ground crews that must be

accommodated. This chapter is not intended to be

all-encompassing in chemical defense equipment;

rather, it is intended to describe the items and operations that are of greatest interest to the medical

community.

The following sections address each of the protection areas described above in detail, with the

current equipment items featured and items in development that are designed to overcome the deficiencies of present equipment briefly described.

Sufficient technical data are included to allow the

healthcare professional to become familiar with

the operation, components, and the limitations of

the present chemical defense equipment. Should the

interested reader desire more detail on chemical

defense equipment, several sources are available.

First, the written references and expert consultants

to this chapter are sources of vast amounts of information. Possibly of more value to the healthcare

professional is the nuclear, biological, and chemical (NBC) officer who is an integral part of each

combat element and who is available to provide

detailed advice as well as hands-on assistance.

Several tangential issues must be noted that impact on the area of chemical defense equipment,

especially in the future. First, a continuing intelliA number of countries around the world have

the capability to use chemical weapons. In fact,

within the past decade, several events have been

well documented where chemical weapons were

used in armed conflict, most notably during the

Iran–Iraq War. The most recent threat of such use

was during the Persian Gulf War, where U.S. forces

might have been exposed to the effects of both

chemical and biological agents. An essential part

of preparedness to continue operations in a chemical environment is adequate equipment.1,2 Such

equipment must encompass all areas of concern:

detection and warning, personal protective equipment, decontamination and medical prophylaxis,

and treatment. Only an integrated approach to the

problem of protection can allow individuals to provide an effective response in a chemical warfare

environment with a minimum degradation in human performance.

The primary item of protection is the personal

respirator, designed to protect individuals against

volatile agents and aerosols. The respirator must be

carefully fitted on the face to ensure minimal leakage, and individuals must be well trained in the

donning of masks (a maximum of ≤ 9 sec being

desirable). In addition to the respiratory hazard,

many chemical agents are dermally active. This requires that a proper overgarment, usually containing an activated charcoal layer to adsorb chemical

agent, be donned, along with protective gloves and

boots. The complete ensemble can seriously degrade individual performance; 50% reduction of

mission-related task performance has routinely

been measured in tests. (The physiological effects

of wearing chemical and biological protective gear

are discussed in detail in Environmental Hazards of

the Battlefield, a forthcoming volume in the Textbook

of Military Medicine series.) In addition to physical

performance degradation, there are reports of psychological problems with some individuals while

wearing the complete ensemble, owing to the claustrophobic effects.3

 This subject is discussed separately at the end of this chapter, in a section titled

Psychological Problems Associated With Wearing Mission-Oriented Protective Posture Gear.

The rapid detection and warning of an opponent’s use of chemical agents is critical to the protection of forces.4,5 Usually, the chemical agent will be

delivered via an aerial or missile attack, or an upwind release where the cloud of agent passes over

a troop concentration. Timely detection is required
Chemical Defense Equipment

363

gence need exists to identify new agents that may

be used against combat forces and ensure that the

defense equipment meets the new threats. Second,

it cannot be overemphasized that a viable, active,

training program be maintained. And third, medical input into operations while participants are

wearing protective equipment is vital to maintenance of a combat operation. Rest periods consonant with work loads and MOPP gear will allow

continuing operations even in a contaminated environment. The development program will provide

continuing improvements in the chemical defense

equipment available to the forces, and updates will be

required as new and better equipment comes on line.

INDIVIDUAL PROTECTION EQUIPMENT

The chemical–biological warfare threat can come

in three possible physical forms: gas, liquid, and

aerosol (ie, a suspension in air of liquid or solid

particles). Protection against chemical agents disseminated as aerosols is especially difficult because

the individual particles deliver a large amount of

agent at a tiny site, thereby overwhelming the local

capacity of the adsorbent.

Chemical agents can gain entry into the body

through two broad anatomical routes: (1) the mucosa of the oral and respiratory tracts and (2) the

skin. The icon of chemical warfare—the gas mask—

protects the oral and nasal passages (as well as

the eyes), while the skin is protected by the overgarment.

As noted earlier, total individual protection requires an integrated approach with the primary

mechanism being respiratory protection which,

when combined with an overgarment, gloves, and

boots all properly fitted and used correctly, can provide excellent protection against chemical agents of

all known types.

Respiratory Protection

Much of the basis of our understanding of the

general principles of respiratory protection is contained in four source documents:

• Chemical Warfare Respiratory Protection:

Where We Were and Where We Are Going, an

unpublished report prepared for the U.S.

Army Chemical Research, Development,

and Engineering Center6

;

• Jane’s NBC Protection Equipment (the most

recent edition available), particularly the

chapter titled “Choice of Materials for Use

With NBC Protection Equipment”7;

• Basic Personal Equipment, volume 5 of

NATO’s NAIG Prefeasibility Study on a Soldier Modernisation Program, published in

19948

; and

• Worldwide NBC Mask Handbook, published

in 1992.9

Readers interested in greater detail can consult

these sources and the authors of this chapter.

The fundamental question of protective mask

design was first addressed in World War I: should

the mask completely isolate the soldier from the

poisonous environment or should the mask simply

remove the specific threat substance from the ambient air before it can reach the respiratory mucosa?

The first approach requires that a self-contained

oxygen supply be provided. Because of a multitude

of practical logistical constraints (eg, weight, size,

expense), this approach is not used except for specialty applications in which the entire body must

be enclosed.

The more common practice has been to follow

the second approach: to prevent the agent from

reaching the respiratory mucosa by chemically destroying it, removing it in a nonspecific manner by

physically adsorbing it, or both. Destruction by

chemical reaction was adopted in some of the earliest protective equipment such as the “hypo helmet”

of 1915 (chlorine was removed by reaction with

sodium thiosulfate) and in the British and German

masks of 1916 (phosgene was removed by reaction

with hexamethyltetramine).6

 More commonly, the

removal of the agent was brought about by its

physical adsorption onto activated charcoal. (Due

to its mode of formation, this substance has an extraordinarily large surface area, some 300–2,000 m2/

g,10 with a corresponding plethora of binding sites.)

It was soon recognized that impregnation of the

charcoal with substances such as copper oxide,

which reacted chemically with certain threat agents,

further increased protection.6

The effectiveness of modern masks depends on

both physical adsorption and chemical inactivation

of the threat agent. For example, in the M17 protective mask the adsorbent, known as ASC Whetlerite

charcoal, is charcoal impregnated with copper oxide and salts of silver and chromium.6

 The M40 protective mask uses an ASZ impregnated charcoal,

which substitutes zinc for the hexavalent chromium

(CrVI). The Centers for Disease Control and Prevention and the National Institute for Occupation
Medical Aspects of Chemical and Biological Warfare

364

Safety and Health have identified CrVI as a potential human carcinogen.11 A filter layer to remove

particles and aerosols greater than 3 μm in diameter is also a component of all protective masks.

The location of the filters and adsorbent vis-àvis the respiratory tract was also one of the questions that mask designers addressed in World War

I. In the standard British mask (the small box respirator of 1916), the filter and the adsorbent were contained in a separate container worn around the

soldier’s trunk and connected to the mask by a hose.

By way of contrast, in the standard German mask

introduced in late 1915, the filter and adsorbent,

contained in a small can (canister), were attached

directly to the mask. The advantages of the canister arrangement were lighter weight and reduced

work of breathing. But these advantages were

gained at the expense of a smaller protective capacity and a degree of clumsiness associated with motion of the head. The canister is attached directly to

the mask in the majority of modern protective

masks. The contents of a modern canister are shown

in Figure 16-1.

Several of the essential features of modern protective mask design—features that might be thought

to be more recent—also originated during World

War I. For example, designing the inside of the mask

Fig. 16-1. The C2A1 canister is used with the M40 protective mask. After ambient air enters through the orifice on the left side, it passes first through the pleated

white filter (where aerosols are removed), then through

the layer of ASZ charcoal, then through a second filter

(to remove charcoal dust), and finally exits the canister

through the orifice on the right side. Photograph: Courtesy of Visual Information Division, US Army Chemical

and Biological Defense Command, Aberdeen Proving

Ground, Md.

so that inhaled air is first deflected over the lenses

(which prevents exhaled air, saturated with water

vapor, from fogging the lenses) and the use of separate one-way inlet and outlet valves (to minimize

the work of breathing) were World War I–era inventions. The need of masked soldiers to be able to

talk to one another was also recognized then. Interestingly, in the period after World War I, the U.S.

Navy introduced the first useful solution to this

problem: a moveable diaphragm held in place by

perforated metal plates in the front of the mask. This

device ultimately became the voicemitter found in

today’s protective masks.6

An important question of mask design is the composition of the elastic material used to cover the

face: the faceblank. The first masks introduced in

World War I were made of rubberized cloth or

leather. Subsequent masks used natural rubber, but

recently, sophisticated synthetic polymers using silicone, butyl, and perfluorocarbon rubbers have been

used.6

 Silicone rubber has the advantage of making

possible a tight fit or seal between the mask and

skin, with a correspondingly decreased potential for

leaking (a factor said to be responsible for about

5% of mask failures).12

Unfortunately, silicone rubber offers rather low

resistance to the penetration of common chemical

agents. Perfluorocarbon rubber is very impermeable

but is expensive and tears easily. Butyl rubber

offers both good protection and seal and has therefore become the material of choice.7

 Even this description of materials used to construct the

faceblank underestimates the complexity of actual

mask design. In today’s standard U.S. military

masks, the faceblank consists of two separate layers: an inner later made of silicone rubber (for maximum seal) and an outer layer made of butyl rubber

for maximum protection (Figure 16-2).

The design of the modern protective mask is a sophisticated process. This is nowhere more apparent

than in the designers’ recognition of the dictates of

respiratory physiology: specifically, the importance of

dead space. The greater the space between the back

of the mask and the face of the wearer in relation to

the tidal volume, the smaller the proportion of inhaled

air that will reach the alveoli. To minimize dead-space

ventilation, modern protective masks have what is

equivalent to a second mask—the nosecup—which is

fitted separately from the mask proper and inserted

between the main mask and the wearer’s midface (Figure 16-3). The smaller volume encompassed by the

nosecup, rather than the total volume enclosed by the

entire mask, is responsible for most of the dead space

added by the mask. Furthermore, the nosecup provides an extra seal against entry of threat agents.6
Chemical Defense Equipment

365

Fig. 16-2. The M45 protective mask facepiece has two

skins. The inner skin is composed of silicone rubber, and

the outer skin is composed of butyl rubber. This arrangement maximizes both mask-to-skin seal and chemical

agent impermeability. A similar design is used in the M40

protective mask. Photograph: Courtesy of Visual Information Division, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Md.

Fig. 16-3. The nosecup of the M45 protective mask has a

single, large hole in the center through which exhaled

air is expelled on its way to the exit valve in the main

mask. Inhaled air, which has passed through the canister, passes up and around the side of the nosecup, preventing fogging of the mask’s lenses, after which it passes

through the valve (seen on the reader’s left) on its way

to the soldier’s respiratory tract. Photograph: Courtesy

of Visual Information Division, US Army Chemical and

Biological Defense Command, Aberdeen Proving

Ground, Md.

The work of breathing added by the mask is an

important factor; it determines not only soldiers’

acceptance of a given mask, but more importantly,

the degree that a soldier’s exercise tolerance is degraded. Since the pressure gradient that is required

to move a given mass of air is flow-rate dependent,

to make a quantitative comparison between the

work of respiration of different masks, it is necessary to specify a specific flow rate. For example, at

a flow rate of 85 L/min, a pressure gradient of about

8 cm H2O is observed in World War II–vintage

masks. At the same flow rate, the gradient for the

M17 is 4.5 cm H2O, and for the M40, 5 cm H2O.6 By

way of contrast, breathing at a rate of 85 L/min

without a mask requires a pressure gradient of 1.5

cm H2O.13 Some mask wearers perceive the 3-fold

increase in the work of breathing as “shortness of

breath.”

Developmental objectives in personal respiratory

protection equipment generally encompass factors

such as personal comfort, breathing resistance,

mask weight, and the ability to provide protection

from new agents. Present equipment has met a

number of these objectives but much remains to be

done, especially in the area of new and improved

chemical-resistant materials, manufacturing methods, and scratch-resistant lenses. All of these items

must be integrated into a new, reliable, less cumbersome, and less degrading system.

Ground Crew Personal Protective Equipment

The equipment described below is generally suitable for use by all services, although oceanic environments may require that other construction materials be developed for the navy and marine corps.

The masks protect against all known chemical and

biological agents, whether in droplet, aerosol, or

vapor form. However, a protective mask is only as

good as its fit. In the past, the degree of fit was assessed by field-expedient qualitative indices (eg, the

degree to which the mask collapsed with its inlet

valve obstructed). The modern technology incorporated into the M41 Protection Assessment Test System allows the degree of fit to be quantitated.

M41 Protection Assessment Test System

The protective masks issued to members of the

U.S. armed forces protect the individual’s face, eyes,

and respiratory tract from field concentrations of

chemical–biological agents, toxins, and radioactive

fallout particles. Several critical steps must be taken

to ensure that an assigned mask will function properly in a toxic chemical environment:
Medical Aspects of Chemical and Biological Warfare

366

• select the correct mask size,

• properly fit the selected mask,

• validate the mask protection,

• train the user in the proper wear and use of

the mask, and

• perform preventive maintenance checks on

the mask as required.

The M41 Protection Assessment Test System (PATS)

was fielded to validate the protection afforded by the

M40, M42, and M17 series masks (Figure 16-4). The

PATS is a miniature, continuous flow, condensation

nuclei counter. It samples particles from ambient air

and compares them with particles in the air contained

inside the wearer’s mask. The resulting numerical

values are then used to determine the protection factor (PF) of the mask. The result of the pass/fail test is

determined by the mask’s ability to provide a PF of

1,667 or greater, which is the minimum army requirement. The PATS ensures that the mask is the proper

size for the individual wearer, and that there are no

critical leaks in the mask system due to missing or

defective parts or improper maintenance.

Two PATS are fielded for each battalion-sized

unit, and are located at the headquarters company.

One PATS is fielded for each separate companysized unit. To date, the PATS is used by the army

and has been ordered for the marines and air force.

Mask, Chemical–Biological: Field, M17A2

The blended natural rubber faceblank of the

M17A2 Chemical–Biological Field Mask protects the

wearer’s face, eyes, and respiratory tract, while the

attached M6A2 hood protects the exposed portions

of the head and neck (Figure 16-5). The M17A2 protects the face, eyes, and respiratory tract from field

concentrations of chemical and biological agents.

When used together, the natural rubber facepiece

and the M6A2 hood resist liquid chemical and biological agents. In fact, the hood was designed to

completely cover not only the rubber components

of the mask but also the head and neck so as to augment protection against liquid agents.

The M17A2 protective mask provides respiratory

protection through the use of two M13A2 filter elements. Each filter element is “pork chop” shaped and

is internally mounted within the cheek pouches of the

mask. Each also consists of an activated charcoal gas

filter paper and a particulate filter laminated together.

This mask can be used in any climatic condition,

but the M4 winterization kit must be installed when

used in temperatures of –20°F or below. A voicemitter outlet valve, provided on the front of the

facepiece, transmits the user’s voice outside the

mask. A drinking tube assembly is attached just

below the voicemitter and allows the user to drink

while wearing the protective mask. The drink system couples with the M1 canteen cap (Figure 16-6).

The forehead straps, temple straps, and cheek

straps come together at a head pad for ease of fitting. The M17A2 mask is manufactured in four sizes

to accommodate all personnel: extra small, small,

medium, and large. For personnel requiring vision

correction, optical inserts are provided. The optical

inserts are both prong-type and wire frame–types;

the wire frame–type is easier to mount inside the

mask.

The mask is compatible with shoulder-fired

weapons, night-vision devices, and sighting devices. A variety of accessory items is available, including the M1 waterproof bag, the M4 winterization kit, the M6A2 hood, the M15A1 carrier, and

optical inserts and outserts. This series of mask is currently being replaced by the M40 protective mask.14,15

Mask, Chemical–Biological: Field, M40

The M40 Chemical–Biological Field Mask series

represents the latest generation of protective mask

to be issued to the U.S. military. The inner layer of

the facepiece is composed of molded silicone rubber that fits tightly against the face, and has an inturned peripheral seal, which increases comfort and

fit. The mask’s two ridged eyelenses are approximately 35% larger than the type used in the M17A2,

thus providing a better field of view (Figure 16-7).

Filtration is provided in the M40 mask by one

C2A1 filter canister, which, at the user ’s conFig. 16-4. The M41 Protection Assessment Test System

(PATS). Ambient air is assessed through the green hose.

Air inside the mask is assessed through the colorless

hose, which couples with the protective mask by means

of the drinking tube extension. For further information,

see Department of the Army. Protection Assessment Test

System (PATS). Washington, DC: DA; 14 January 1995.

Training Circular 3-41.
Chemical Defense Equipment

367

Fig. 16-5. (a) The M17A2 Chemical–Biological Field Mask. (b) The M17A2 protective mask with hood. (c) This transparent

version of the M17A2 protective mask was prepared in the hope that wearers could recognize each other. Now this unique

design, which was never fielded, serves only to show where the two pork chop–shaped M13A2 filter elements are located.

Photographs (a) and (b): Reprinted from Brletich NR, Tracy MF, Dashiell TR. Worldwide NBC Mask Handbook. Edgewood,

Md: Chemical Warfare/Chemical and Biological Defense Information Center; September 1992: 371. Photograph (c): Courtesy of Visual Information Division, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Md.

a b c

Fig. 16-7. The M40 Chemical–Biological Field Mask. Reprinted from Brletich NR, Tracy MF, Dashiell TR. Worldwide

NBC Mask Handbook. Edgewood, Md: Chemical Warfare/

Chemical and Biological Defense Information Center; September 1992: 385.

Fig. 16-6. The M17A2 Chemical–Biological Field Mask with

drinking tube assembly allows the soldier to drink without unmasking. Soldiers wearing mission-oriented protective posture (MOPP) gear must drink water to prevent heat

stress. The drinking tube, essentially a flexible straw,

couples with the canteen cap. The soldier holds the canteen upright and inverted, then sips water through the tube.

After a few sips, the soldier needs to puff his own exhaled

air back into the canteen to equalize the atmospheric pressure without introducing contaminated air. Then he can

take a few more sips of water before he needs to equalize

the pressure again. Photograph: Courtesy of Chemical and

Biological Defense Command Historical Research and Response Team, Aberdeen Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

368

venience, can be mounted on either cheek. Two canisters may be mounted on both cheeks for specialpurpose activities such as explosive ordnance disposal

or technical escort. The standard C2A1 canister will

protect against 16 attacks of nerve and vesicant agents.

For each exposure, the Ct can be as great as 20,000 Ct

mg•min/m3 (Ct represents the product of concentration [in milligrams per cubic meter of air] and time

[in minutes] of exposure to a gas or aerosol, and is

discussed in other chapters in this textbook, in particular Chapter 5, Nerve Agents). Any other standardthread canister issued by North Atlantic Treaty Organization (NATO) countries will fit the M40 mask.

Communication is provided by two voicemitters.

One is mounted in the front to allow face-to-face

communication; the second is located in the cheek

to permit the use of a radio telephone handset. A

drinking system consists of internal and external

drink tubes; the external tube has a quick-disconnect coupling that connects with the M1 canteen

cap. A six-point, adjustable harness with elastic

straps located at the forehead, temples, and cheeks

comes together at a rectangular head pad.

The M40 mask comes in three sizes: small, medium, and large. Optical inserts are provided for

Fig. 16-8. The M42 Chemical–Biological Field Mask. Reprinted from Brletich NR, Tracy MF, Dashiell TR. Worldwide NBC Mask Handbook. Edgewood, Md: Chemical

Warfare/Chemical and Biological Defense Information

Center; September 1992: 383.

vision correction and outserts are available to reduce fogging and sun glare and to protect against

scratching. A check valve on the nosecup prevents

exhaled air from fogging the lenses inside, and an

air deflector directs inhaled air over the lenses,

which also helps prevent fogging. Accessory items

available include a carrier, a hood to protect the neck

areas, and a waterproof bag.16–18

Mask, Chemical–Biological: Field, M42

The M42 Chemical–Biological Field Mask is

the same series as the M40. The materials of construction and the basic features are identical, but

the M42 protective mask is used by combat vehicle

crews (Figure 16-8).

Filtration is provided by a C2A1 canister attached

to the mask by a corrugated hose; the canister is

housed in a specially designed canister carrier. The

M42 integrates with the combat vehicle filtration

protection system. The M42 also has a dynamic microphone that integrates with the combat vehicle

via a microphone cable.19,20

Mask, Chemical–Biological: MCU-2/P

The MCU-2/P Chemical–Biological Mask is used

by U.S. Air Force ground crews and aircrews when

not in flight. This protective mask is constructed of

molded silicone rubber facepiece material, and an

integral, molded, polyurethane, one-piece panoramic lens is bonded to it (Figure 16-9).

Filtration is provided by one C2A1 canister

mounted on either side of the facepiece. The primary voicemitter is located over the mouth area

with a secondary voicemitter in the cheek area to

utilize telephone handsets. The mask incorporates

a drinking tube, which connects to the M1 canteen

cap. The mask has a six-point, adjustable head harness suspension made of elastic, which comes together in the center head back into a rectangular

patch of woven material. The mask comes in three

sizes: small, medium, and large. Accessories include

a carrier bag, a butyl-coated nylon cloth hood,

outserts to protect the lens in storage, and a waterproof bag.

Aircrew Personal Protective Equipment

Each protective mask in current use is described

in detail. There are some differences between the

masks designed for helicopter use and high-performance aircraft, owing notably to the operational
Chemical Defense Equipment

369

Fig. 16-9. The MCU-2/P Chemical–Biological Mask. Reprinted from Brletich NR, Tracy MF, Dashiell TR. Worldwide NBC Mask Handbook. Edgewood, Md: Chemical

Warfare/Chemical and Biological Defense Information

Center; September 1992: 401.

battery. A constant overpressure is maintained

within the mask by the motor blower unit.

The mask has an inhalation air-distribution assembly for regulating the flow of air to the mouth

and nose, eyelenses, and hood assembly. The M43

mask has a drink capability which couples with

the canteen cap. The mask is produced in four

sizes from small to extra-large. Accessories include a mask carrier, vision correction outserts,

winterization kit, nuclear hood, facepiece carrier,

eyelens cushions, and a blower and harness assembly.

This new design effort was based on the need

for little-to-no visual impairment. The requirement was met by placing the protective mask’s

eyelens 14 mm from the eye, which kept the spherical curvature equidistant from the corneal

surface to eliminate parallax. This lens configuration increased visual capability to within 4% of

nonmasked vision in the same individual. Each

mask is fitted to an individual crewman and remains with that crewman while he remains on flight

status.21,22

Mask, Chemical–Biological: Aircrew MBU-I9/P

The MBU-19/P Chemical–Biological Aircrew Mask

is the newest generation to be fielded by the U.S. Air

Force exclusively for aircrews. This mask, dubbed the

Aircrew Eye/Respiratory Protection (AERP) system,

Fig. 16-10. The M43 Chemical–Biological Aircraft Mask.

Photograph: Courtesy of Visual Information Division, US

Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Md.

envelope. All masks protect against all known

chemical and biological agents whether in droplet,

aerosol, or vapor form.

Mask, Chemical–Biological: Aircraft, M43

The facepiece of the M43 Chemical–Biological

Aircraft Mask is fabricated of bromo butyl and natural rubber with an integral butyl hood and skulltype suspension system (Figure 16-10). The M43 has

two models, designated Type I and Type II. The two

models are identical with the following exceptions:

Type I has a notch in the right eyepiece that accommodates a special sighting device used by Apache

helicopter pilots, and uses a different microphone

for communication; Type II has two spherical lenses

and uses a dynamic microphone. Both microphones

interface with the helicopter communications systems.

The mask is connected to two C2A1 canisters,

which lower breathing resistance. A hose assembly

that attaches to the two C2A1 canisters is located

on the left cheek. The canisters are attached to a

motor blower unit (capacity: 4 cu ft/min), which is

powered either by aircraft electrical power or a
Medical Aspects of Chemical and Biological Warfare

370

is issued in a helmeted version for fighter pilots and

in a nonhelmeted version for aircrew and pilots of

other types of aircraft (Figure 16-11).

The AERP mask-hood subsystem has a hood

composed of bromo butyl coated fabric that incorporates standard MBU-19/P oxygen mask, clear

plastic lens, neckdam, drinking facility, and communications systems. The MBU-19/P breathing

subsystem consists of a chemical-resistant delivery hose, a chemical–biological canister, in-line

filter, and manifold assembly including an emergency oxygen filter. The breathing system will operate whether or not supplemental oxygen is

present.

The blower system incorporates a variable-speed

motor, battery, external power-supply cable, housing assembly, control switch, chemical–biological

canister, and a means of securing the blower while

the crew member is mobile. The mask receives filtered air from the blower unit, which also allows

overpressure within the hood which defogs the lens

and is vented through an exhaust valve.

The communication system consists of the intercommunication unit, battery, electrical branch assembly, microphone, and bracket.

Fig. 16-11. The MBU-19/P Chemical–Biological Aircrew

Mask. Reprinted from Brletich NR, Tracy MF, Dashiell

TR. Worldwide NBC Mask Handbook. Edgewood, Md:

Chemical Warfare/Chemical and Biological Defense Information Center; September 1992: 395.

Developmental Respiratory Protection Equipment

The objective of development systems is to provide the next generation of respiratory protection

equipment that will minimize mission degradation

and assure compatibility with future weapons systems and equipment while maintaining protection

levels. RESPO 21 is the latest generation wherein

new materials and manufacturing technology are

being investigated and evaluated.23 New and improved filtration systems designed to remove or

degrade new classes of agents are under evaluation.

Systems designed to meet all service needs in one

equipment item are in the design phases. It is hoped

that these systems will overcome the deficiencies

found in current equipment (eg, excessive weight

and performance degradation).

Protective Clothing

An overgarment can be made to protect skin from

chemical agents by either physical or chemical

means:

1. The overgarment can be made of fabric that

is impermeable to most molecules, even to

air and water vapor.

2. The overgarment can be made of fabric that

is permeable to most molecules, but that also

chemically alters or physically removes

chemical agents before they reach the skin.

In the first method, the chemical agent is totally

excluded because the agent is physically prevented

from penetrating the substance of the overgarment.

In the second method, the agent enters into the fabric of the overgarment but is absorbed before it can

reach the skin. An overgarment made of an impermeable material such as Saran wrap or butyl rubber can offer complete protection against threat

agents but at the unacceptable cost of causing heat

injury. Cooling by sweating is not possible if water

vapor cannot pass through to the ambient environment. Most fielded overgarments, therefore, depend

on the fabric’s ability to adsorb the threat agent. Activated charcoal is used for this purpose in U.S. military designs.

Placing a soldier into full chemical protective

equipment—mask, overgarment, gloves, and

boots—is a decision that appropriately considers

not only the protection aspect but also the added

heat stress and potential for dehydration. The heat

stress problem must be recognized from the start.
Chemical Defense Equipment

371

Personnel must begin a drinking regimen prior to

encapsulation to ensure that they do not become

dehydrated quickly. The physical burden of a full

ensemble can add 9 to 14 lb to a normal load; this

added weight combined with heat stress, dehydration, and physical exertion can cause significant

impairment to any mission.

Because of these factors, the completeness of protection is stratified by the anticipated magnitude

of the threat from chemical–biological agents: that

is, the mission-oriented protective posture (Figure 16-

12). Five MOPP levels have been recognized previously, but with Change 2 to Field Manual 3-4, NBC

Protection, the number was updated to seven in 1996

(Exhibit 16-1).5

 The two new MOPP levels are MOPP

Ready and Mask-Only Command, but readers

should be aware that MOPP levels are revised frequently to meet newly defined needs.

The MOPP level must be coordinated with the

work load if troops are to remain effective. The overgarments in present use must be redesigned to

reduce heat stress, reduce weight and bulk, and provide increased comfort as well as reduce the logistical burden. The present clothing will be described

in detail except for the special-purpose equipment

used by demilitarization personnel or special-purpose forces.

Fig. 16-12. From left to right, the soldiers’ gear is for mission-oriented protective posture (MOPP) levels 2, 3, and

4. Photograph: Courtesy of Visual Information Division,

US Army Chemical and Biological Defense Command,

Aberdeen Proving Ground, Md.

The sources for the following discussion are Items

of Combat Clothing and Equipment,24 and experts at

the U.S. Army Natick Research, Development, and

Engineering Center, Natick, Massachusetts,25 whom

interested readers can consult for greater detail.

Protective Ensembles

Like various other armies of the world, the U.S.

Army has chemical protective clothing available for

individual protection. Several types are available,

depending on the protection required to perform a

specific mission and whether the protective clothing needs to be permeable or impermeable. Most

troops use permeable protective clothing, which

allows for air and moisture to pass through the fabric without hindering the chemical protection capabilities of the clothing. This type of permeable protective clothing is described in the following section.

Battledress Overgarment

The current standard A protective overgarment

is the battledress overgarment (BDO). The BDO

protects the wearer from all chemical agent vapors,

liquid droplets, biological agents, toxins, and radioactive alpha and beta particles; however, the BDO

does not stop either X or gamma radiation. For

weartime and protective capabilities of the BDO

following removal from the protective bag, refer to

Field Manual 3-4/Fleet Marine Force Manual 11-9,

NBC Protection.

5

 The BDO protects the wearer for

24 hours after contamination from chemical agent

vapors, liquids, and droplets; and biological agents

and toxins.

The effectiveness of the BDO is in its serviceability. Weartime of the BDO begins when it is removed

from the sealed vapor-barrier bag and stops when

it is returned to the vapor-barrier bag. Wearing the

BDO for any part of a day constitutes a day’s wear. The

BDO becomes unserviceable if it is torn, ripped, a

fastener is missing or broken, or petroleum, oils, or

lubricants are splashed or spilled on the overgarment.

This unserviceableness necessitates replacement.

The BDO is manufactured in two layers: a tightly

woven outer layer and a charcoal-impregnated inner layer to adsorb agent liquid or vapor (Figure

16-13). The garment consists of a hip-length coat

and trousers with appropriate fasteners and multiple pockets. It is manufactured in eight sizes ranging from XXX Small through XX Large. The BDO is

not designed to be decontaminated or reimpregnated for reuse.
Medical Aspects of Chemical and Biological Warfare

372

EXHIBIT 16-1

LEVELS OF MISSION-ORIENTED PROTECTIVE POSTURE (MOPP)

MOPP Ready Soldiers carry their protective masks with their load-carrying equipment. The

soldier’s MOPP gear is labeled and stored no further back than the battalion support area and is ready to be brought forward to the soldier when needed. The time

necessary to bring the MOPP gear forward should not exceed 2 hours. A second set

of MOPP gear is available within 6 hours. Units at MOPP Ready are highly vulnerable to attacks with persistent agents and will automatically upgrade to MOPP

Zero when they determine, or are notified, that chemical weapons have been used

or that the threat for use of chemical weapons has risen. When a unit is at MOPP

Ready, soldiers will have field-expedient items identified for use.

MOPP Zero Soldiers carry their protective masks with their load-carrying equipment. The standard battledress overgarment and other individual protective equipment that make

up the soldier’s MOPP gear are readily available. “Readily available” means that

equipment must either be carried by each soldier or be stored within the soldier’s

arms’ reach (eg, within the work area, vehicle, or fighting position). Units at MOPP

Zero are highly vulnerable to attacks with persistent agents and will automatically

upgrade to MOPP 1 when they determine, or are notified, that persistent chemical

weapons have been used or that the threat for use of chemical weapons has risen.

MOPP 1 When directed to MOPP 1, soldiers immediately don the battledress overgarment.

In hot weather, the overgarment jacket may be unbuttoned and the battledress overgarment may be worn directly over the underwear. M9 or M8 chemical detection

paper is attached to the overgarment. MOPP 1 provides a great deal of protection

against persistent agents. The level is automatically assumed when chemical weapons have been employed in an area of operations or when directed by higher commands.

MOPP 2 Soldiers put on their chemical protective footwear covers, green vinyl overboots,

or a field-expedient item (eg, vapor-barrier boots), and the protective helmet cover

is worn. As with MOPP 1, the overgarment jacket may be left unbuttoned but the

trousers remain closed.

MOPP 3 Soldiers wear the protective mask and hood. Again, flexibility is built into the system to allow the soldier relief at MOPP 3. Particularly in hot weather, soldiers may

open the overgarment jacket and roll the protective mask hood for ventilation but

the trousers remain closed.

MOPP 4 Soldiers will completely encapsulate themselves by closing their overgarments,

rolling down and adjusting the mask hood, and putting on the NBC rubber gloves

with cotton liners. MOPP 4 provides the highest degree of chemical protection, but

it also has the most negative impact on an individual’s performance.

Mask-Only Command Only the protective mask is worn. The mask-only command is given in these situations: 1. When riot control agents are being employed and no chemical or biological threat exists. 2. In a downwind vapor hazard of a nonpersistent chemical agent.

The mask-only command is not appropriate when blister agents or persistent nerve

agents are present.

Adapted from Avery M. Major, Chemical Corps, US Army; US Army Chemical School, Doctrine Development Division,

Fort McClellan, Ala. New MOPP Levels and Peacetime Filter Changeout Criteria. (Summary of Change 2 to Field Manual 3-4, 21

Feb 1996.) Internet Chemical-Doctrine discussion site, 24 Jul 1996.
Chemical Defense Equipment

373

Fig. 16-13. A soldier wearing the battledress overgarment

(BDO) and battledress uniform (BDU) is afforded five

layers of protection. Although allowing body moisture

to evaporate, the garments repel rain, wind, airborne viruses, liquid chemicals, and bacteria. (1) The BDO consists of two layers. The outer layer is a 50% nylon–50%

cotton, twill weave, Quarpel-treated fabric in woodland

camouflage pattern. (2) The inner layer of the BDO is

made of 90-mil polyurethane foam impregnated with

activated carbon and laminated on the inner side with

nylon-tricotton knit. (3) The BDU for temperate-zone

wear is made of 50% cotton–49% nylon–1% static dissipative fiber, twill weave fabric. (4) The drawers and undershirt are made of 100% cotton. (5) Human skin surface. Drawing: Courtesy of US Army Research Institute

of Environmental Medicine, Biophysics and Biomedical

Modeling Division, Natick, Mass.

Body moisture

Aircrew Uniform, Integrated Battlefield

The aircrew uniform, integrated battlefield

(AUIB) is designed to replace the BDO, the chemical protective overgarment (CPOG), and the Nomex

(a synthetic aramid polymer, manufactured by Du

Pont Advanced Fiber Systems, Wilmington, Del.)

flight suit for aircrews operating in a contaminated

environment (Figure 16-14). It is also designed to

protect against petroleum and oils. It provides flame

resistance as well as NBC protection. The outer shell

is a laminate of 95% Nomex/5% Kevlar (polyparaphenyleneterephthalamide, manufactured by Du

Pont Advanced Fiber Systems, Wilmington, Del.),

while the inner layer is a 90-mil, carbon-impregnated, flame-resistant foam/nylon laminate. The

AUIB is designed as a two-piece garment with a

coat and trousers with appropriate fasteners and is

available in woodland or desert camouflage. The heat

stress burden of the AUIB is similar to that of the BDO.5

Chemical Defense Aircrew Ensemble

The chemical defense aircrew ensemble (CDAE)

is the newest generation of aircrew protective clothRain Airborne viruses

Bacteria

Liquid chemicals

Wind

ing to be fielded by the U.S. Air Force. It is a onepiece garment consisting of the Nomex flight suit,

a charcoal undergarment, and long cotton underwear. The CDAE incorporates carbon-sphere technology to adsorb chemical agent. It is basically two

suits differing in color: the CWU-66/P is green and

the CWU-77/P is brown. It may be laundered as

many as 10 times prior to chemical agent exposure

without destroying the protective capabilities of the

coverall.26

Protective Boots and Gloves

A soldier wearing the chemical protective boots

and gloves discussed here will soon realize that

mobility is compromised by the boots and that tactile ability is degraded by the gloves. The present

boots provide good protection against chemical

warfare agents but are only an interim solution to

the need for combined chemical protection, ease of

decontamination, and safety. Wearers are at serious

risk of falls due to the lack of adequate traction, and

the weight of the boot contributes to the increased

fatigue from complete protection ensemble wear.

Fig. 16-14. The aircrew uniform, integrated battlefield

(AUIB).
Medical Aspects of Chemical and Biological Warfare

374

The boots do not protect the wearer from heat or

cold and in some cases may contribute to medical

problems such as trench foot, frost bite, or other cold

weather injuries. The protective gloves degrade tactility and again will not protect against heat or cold

and may increase the chance of cold weather injuries if the work glove is not worn over the protective glove. The following descriptions of protective

boots and gloves are based on information from

NBC Protection.

5

Green and Black Vinyl Overboots

The green vinyl overboot (GVO) and the black

vinyl overboot (BVO) (Figure 16-15) are used to

protect the individual’s combat boots against

all known chemical and biological agents, vectors,

and radioactive (alpha and beta) particles. The

overboots also provide protection from the environmental effects of snow, rain, and mud. (However,

GVOs and BVOs issued and worn for environmental protection should not be used for NBC protection. A new pair should be issued with NBC protective gear.)27 Following contamination by liquid

agent, the boots will provide protection for a limited time. Following exposure to liquid agents, the

boots should be decontaminated with a 5% household bleach–and-water or a 5% high-test hypochlorite (HTH)–and-water solution. This allows the

overboots to be worn additional days before replacement. Should DS2 (Decontaminating Solution

2; diethylenetriamine, ethylene glycol monomethyl

ether, sodium hydroxide; manufactured by Dalden

Corp., Anaheim, Calif.) come into contact with the

overboots during decontamination operations, they

must be washed as soon as possible since it will

soften and discolor the overboots. For additional

information about weartimes and protective capabilities, refer to NBC Protection.

5

Chemical Protective Footwear Cover

The chemical protective footwear cover (CPFC)

is an impermeable black butyl rubber footwear

cover that protects the combat boot from all agents

(Figure 16-16). The CPFC has an unsupported butyl rubber sole and butyl rubber uppers with long

laces, which fasten a front eyelet with side and rear

eyelets. The CPFC can be decontaminated with 5%

chlorine solution, then inspected and reused. If exposed to DS2, the CPFC should be washed since DS2

causes the rubber to deteriorate. The CPFC offers

poor traction and the laces can cause a tripping

hazard when the wearer is moving. Again, the CPFC

offers no protection against cold; therefore, suitable

precautions must be taken. Refer to NBC Protection5

for protective capabilities.

Chemical Protective Glove Set

The chemical protective glove set consists of an

outer glove for chemical protection and an inner

glove for perspiration absorption. The outer glove

is made of impermeable butyl rubber and the inner

glove is made of white cotton. The gloves come in

three thicknesses: 7, 14, and 25 mil. Soldiers such

as medical, teletypist, and electronic repair personnel, whose tasks require extreme tactility and sensitivity, and who will not expose the gloves to harsh

treatment, will use the 7-mil glove set. Aviators,

vehicle mechanics, weapons crews, and other soldiers whose tasks require tactility and sensitivity

will use the 14-mil glove set (Figure 16-17). Soldiers

who perform close combat tasks and other heavy

labor tasks will use the 25-mil glove set.

All of the glove sets protect against liquid chemical agents and vapor hazards. However, if the 7-

mil glove set is contaminated, it must be replaced

Fig. 16-15. The black vinyl overboot (BVO).

Fig. 16-16. The chemical protective footwear cover (CPFC).
Chemical Defense Equipment

375

or decontaminated within 6 hours after exposure.

The 14-mil and 25-mil glove sets will provide protection following contamination for 24 hours. All

three glove sets can be decontaminated with a

5% bleach-and-water solution or a 5% HTH-andwater solution, then inspected, and reused. All

gloves will become sticky and soft if exposed to DS2

or petroleum-based fluids and must be replaced. Replacement must occur following damage or degradation or both. Refer to NBC Protection5

 for protective capabilities.

Developmental Whole-Body-Protection

Equipment Items

The Joint Service Lightweight Integrated Suit

Technology (JSLIST) program is developing the next

generation of overgarment, which will be fielded

in Fiscal Year 1997. The JSLIST program provides

the future whole-body chemical–biological protective equipment for the joint services (U.S. Army,

Navy, Air Force, and Marine Corps). The JSLIST

program encompasses a lightweight garment (undergarment, overgarment, duty uniform) and improved chemical protective handwear and chemical protective overboot. It will provide less bulk and

heat stress by being constructed of state-of-the-art

materials (the exact materials are not yet known,

however) and will be more durable and launderable

than current designs. The items in the JSLIST series

are joint-service standardized items and are planned

to be used by all services.28,29

In addition to the JSLIST, new agent-impermeable

materials are being evaluated in conjunction with

advanced fabrics to replace the carbon-impregnated

fabrics, which have limited lifetimes. These new materials will be lighter, allow permeation of moisture

while retaining protection, and cause less heat stress.

JSLIST Overgarment

The JSLIST Overgarment (OG) is a universal,

lightweight, two-piece, front-opening garment that

can be worn as an overgarment or as a primary uniform over personal underwear (Figure 16-18). It has

an integral hood, bellows-type pockets, high-waist

trousers, adjustable suspenders, adjustable waistband, and waist-length jacket. This design improves

system compatibility, user comfort, and system acceptance, and maximizes individual equipment

compatibility. The JSLIST OG provides optimum

liquid, vapor, and aerosol protection and also flame

protection.

JSLlST Aviation Overgarment

The JSLIST Aviation Overgarment (AVOG) is the

aviator’s version of the JSLIST OG and Duty Uniform

(DU) configurations. It is a two-piece, front-opening,

flame-resistant garment designed as a chemical protective overgarment or uniform. For cockpit compatibility, the integral hood and bellows-type pockets of

the OG and the DU have been replaced with a crewtype collar and sewn-down pockets (Figure 16-19).

JSLIST Duty Uniform

The JSLIST Duty Uniform (DU) is a universal,

lightweight, two-piece, front-opening garment that

is worn as a primary uniform over personal underwear. It has an integral hood, bellows-type pockets, high-waist trousers, adjustable suspenders,

adjustable waistband, and waist-length jacket (Figure 16-20). This improves system compatibility, user

comfort, system acceptance, and ensures maximum

individual equipment compatibility. The DU provides

optimum liquid, vapor, and aerosol protection as well

as flame protection.

JSLIST Vapor Protective Flame-Resistant Undergarment

The JSLIST Vapor-Protective, Flame-Resistant Undergarment (VPFRU) is a two-piece (jacket and drawers), front-opening, vapor-protective garment (Figure

16-21). It is configured with an integral form-fitting

hood and detached vapor-protective, fire-resistant

socks. Worn under standard duty uniforms, including the combat vehicle crewman coveralls and battledress uniform, the VPFRU is designed to provide the

Fig. 16-17. The 14-mil chemical protective glove set.
Medical Aspects of Chemical and Biological Warfare

376

Fig. 16-18. The Joint Service

Lightweight Integrated Suit

Technology Overgarment

(JSLIST OG). Reprinted from

US Marine Corps, Army,

Navy, and Air Force. Joint

Service Lightweight Integrated Suit Technology

Program. Joint Service

Lightweight Integrated Suit

Technology (JSLIST) Program.

Columbus, Ohio: Battelle

Memorial Institute; May

1996: unpaginated brochure.

Fig. 16-19. The Joint Service

Lightweight Integrated Suit

Technology Aviation Overgarment (JSLIST AVOG). Reprinted from US Marine

Corps, Army, Navy, and Air

Force. Joint Service Lightweight Integrated Suit Technology Program. Joint Service

Lightweight Integrated Suit

Technology (JSLIST) Program.

Columbus, Ohio: Battelle

Memorial Institute; May

1996: unpaginated brochure.

Fig. 16-20. The Joint Service

Lightweight Integrated Suit

Technology Duty Uniform

(JSLIST DU). Reprinted from

US Marine Corps, Army,

Navy, and Air Force. Joint

Service Lightweight Integrated Suit Technology Program. Joint Service Lightweight Integrated Suit Technology (JSLIST) Program.

Columbus, Ohio: Battelle

Memorial Institute; May

1996: unpaginated brochure.

Fig. 16-21. The Joint Service

Lightweight Integrated Suit

Technology Vapor-Protective, Flame-Resistant Undergarment (JSLIST VPFRU).

Reprinted from US Marine

Corps, Army, Navy, and Air

Force. Joint Service Lightweight Integrated Suit Technology Program. Joint Service

Lightweight Integrated Suit

Technology (JSLIST) Program.

Columbus, Ohio: Battelle

Memorial Institute; May

1996: unpaginated brochure.

Fig. 16-22. The Joint Service Lightweight Integrated Suit Technology Improved Chemical and Biological Protective Glove (JSLIST

ICBPG). Reprinted from US Marine Corps, Army, Navy, and Air

Force. Joint Service Lightweight Integrated Suit Technology Program.

Joint Service Lightweight Integrated Suit Technology (JSLIST) Program.

Columbus, Ohio: Battelle Memorial Institute; May 1996: unpaginated

brochure.
Chemical Defense Equipment

377

chemical vapor and biological agent protective layer.

For Special Operations Forces and armor crews, the

VPFRU is intended to provide maximum vapor and

aerosol protection and MOPP flexibility.

JSLIST Improved Chemical and Biological Protective Glove

The JSLIST Improved Chemical and Biological Protective Glove (ICBPG) is designed to provide protection against chemical and biological agents in liquid,

vapor, and aerosol form (Figure 16-22). Its protection

performance is not degraded by exposure to petroleum, oil, and lubricants and to field decontaminants.

To prevent excessive moisture buildup and improve

user comfort, the ICBPG is semipermeable. The glove

can be worn for up to 30 days without performance

degradation and is flame resistant.

JSLlST Multipurpose Overboot

The JSLIST Multipurpose Overboot (MULO) is

designed to be used for daily wear as required by the

weather and is flame resistant. It is a single-piece design with webbed straps, side-to-back chemical-resistant plastic buckle closures, and improved tread design (Figure 16-23). Protection is provided for environmental hazards as well as chemical and biological

agents. Additionally, the resistance to agents is not

degraded by exposure to petroleum, oil, and lubricants, and decontaminants.

Fig. 16-23. The Joint Service Lightweight Integrated Suit

Technology Multipurpose Overboot (JSLIST MULO).

Reprinted from US Marine Corps, Army, Navy, and Air

Force. Joint Service Lightweight Integrated Suit Technology Program. Joint Service Lightweight Integrated Suit Technology (JSLIST) Program. Columbus, Ohio: Battelle Memorial Institute; May 1996: unpaginated brochure.

DETECTION AND WARNING

As noted in the introduction, timely detection

and warning are critical to the protection of forces—

especially since chemical agents act very quickly.

Detection of an attack, with subsequent warning of

affected forces downwind, can allow adoption of an

effective protective posture and continuation of military operations with minimal degradation of operations. We discuss here those instruments most

widely fielded; some special-purpose items are not

discussed.

The army has recently fielded two new systems,

the FOX and the Biological Integrated Detection

System (BIDS), which are discussed below. Each of

these new systems integrates a variety of detectors

into a mobile, crew-served system; the composite

detectors are vastly superior to any individual detector previously available.

Sources for this discussion are the Worldwide

Chemical Detection Equipment Handbook30 and experts

at Aberdeen Proving Ground, whom readers who

are interested in greater detail can consult.

Chemical Detection and Warning

This section briefly describes some of the fielded

chemical detectors that may be of most use within

the medical community. These detectors are divided

into two groups: point detectors and standoff detectors.

Point Detectors

Point detectors sample the immediate area to determine the presence of chemical agents. The sample

is most often taken from the atmosphere; however,

specialized detection kits can be used to sample the

soil or water. In addition to monitoring the atmosphere, the point detectors provide monitoring after an attack, identify the contaminated area, monitor collective protection areas, monitor effectiveness

of decontamination, and identify chemical contamination during reconnaissance efforts.

M8 Chemical Agent Detection Paper

M8 Chemical Agent Detection Paper detects and

identifies liquid chemical agents. It is tan in color

and comes in a booklet containing 25 perforated

sheets (2 in. x 3 in.), which are heat sealed in a polyethylene envelope. There are three sensitive indicator dyes suspended in the paper matrix. The

paper is blotted on a suspected liquid agent and
Medical Aspects of Chemical and Biological Warfare

378

Chemical Agent Monitor and Improved Chemical

Agent Monitor

The chemical agent monitor (CAM) and improved chemical agent monitor (ICAM) are handheld, soldier-operated devices designed for monitoring chemical agent contamination on personnel,

equipment, and surfaces. They use ion mobility

spectrometry technology to detect and discriminate

between mustard and nerve agent vapor. The concentrations of agents detected by the CAM and ICAM

areas are as follows: for sarin (GB), 0.03 mg/m3; for

VX, 0.1 mg/m3; and for mustard (HD), 0.1 mg/m3.

The units are simple to operate, can be held in

either hand while the user is wearing chemical protective equipment, and operate day or night (Figure 16-26).

Relative vapor hazard and malfunction information is displayed by bars on a liquid crystal display.

As an example, the bar readings for concentrations

of the nerve agent sarin are shown in Table 16-1.

The CAM and ICAM are point monitors only and

observed for a color change, which will occur within

30 seconds: VX turns the paper dark green, the G

series of agents turn the paper yellow (see Chapter

5, Nerve Agents), and blister agent turns it red (Figure 16-24). M8 paper will change color with many

interferents such as sodium hydroxide and petroleum products; thus, it is unreliable to use to check

for completeness of personnel decontamination and

should always be verified with another means of

identification.

M9 Chemical Agent Detection Paper

M9 Chemical Agent Detection Paper is a portable,

single roll of paper that comes with a Mylar adhesive-backed and -coated tape. It contains a suspension of an agent-sensitive dye in a green-colored paper matrix. The agent-sensitive dye will turn pink,

red, reddish brown, or red-purple when exposed

to agent but does not identify the specific agent. M9

paper is more sensitive to nerve and blister agents

and reacts more rapidly than M8 paper, although it

also reacts to a wide range of interferents such as

petroleum products, brake fluid, aircraft cleaning

compounds, DS2, insect repellent, defoliant, and

antifreeze.

M9 paper, which is similar to masking tape, is

used by attaching strips to the individual overgarment and to equipment such as vehicle controls. The

strips are then inspected routinely for color change

(Figure 16-25). The paper should not be attached to

hot surfaces, as this will discolor the tape and lead

to a false positive reaction.

Fig. 16-25. Field use of M9 paper. Reprinted from Brletich

NR, Waters MJ, Bowen GW, Tracy MF. Worldwide Chemical Detection Equipment Handbook. Edgewood, Md: Chemical Warfare/Chemical and Biological Defense Information Analysis Center; October 1995: 417. Photograph:

Courtesy of US Army Edgewood Research, Development,

and Engineering Center, Aberdeen Proving Ground, Md.

Fig. 16-24. M8 Chemical Agent Detection Paper. A drop

of mustard (H) simulant from the vial has turned the

paper red. Reprinted from Brletich NR, Waters MJ, Bowen

GW, Tracy MF. Worldwide Chemical Detection Equipment

Handbook. Edgewood, Md: Chemical Warfare/Chemical

and Biological Defense Information Analysis Center;

October 1995: 407. Photograph: Courtesy of US Army

Edgewood Research, Development, and Engineering

Center, Aberdeen Proving Ground, Md.
Chemical Defense Equipment

379

TABLE 16-1

BAR READINGS FOR CONCENTRATIONS

OF SARIN (GB)

Bar Reading Concentration (mg/m3)

1 0.03

2 0.05

3 0.08

4 0.14

5 0.30

6 1.0

7 10.0

8 30.1

cannot give an assessment of an area vapor hazard.

The two may give false readings when used in enclosed spaces or when sampling near strong vapor

sources such a dense smoke, aromatic vapors, cleaning compounds, exhausts from some rocket motors,

and fumes from some munitions. Because of the

technology employed, the CAM and ICAM are subject to saturation; they must be cleared to function

properly.

Fig. 16-27. (a) The M256A1 Chemical Agent Detector Kit

and (b) the sampler/detector found inside the carrying

case. Reprinted from Brletich NR, Waters MJ, Bowen GW,

Tracy MF. Worldwide Chemical Detection Equipment Handbook. Edgewood, Md: Chemical Warfare/Chemical and

Biological Defense Information Analysis Center; October 1995: 429. Photograph (a): Courtesy of Environmental Technologies Group, Inc, Baltimore, Md.

a

b

Specific information in this discussion of the

CAM and ICAM is drawn from Chemical Agent

Monitor Employment31 and Operator’s and Organizational Maintenance Manual for the Chemical Agent

Monitor (CAM),32 which interested readers may wish

to consult.

Chemical Agent Detector Kit

The M256A1 Chemical Agent Detector Kit is a

portable, expendable item capable of detecting and

identifying hazardous concentrations of nerve and

blister agents and cyanide (Figure 16-27). The kit is

used after a chemical attack to determine if it is safe

for personnel to unmask. Each kit consists of 12 disposable plastic sampler-detectors (ticket or card),

one booklet of M8 paper, and a set of instruction

cards. Each ticket (card) contains laboratory filter

paper test spots for the various agents. The technology used is wet chemistry, enzymatic substrate–

based reactions, where the presence of agents is inFig. 16-26. The chemical agent monitor (CAM). Photograph: Courtesy of Visual Information Division, US Army

Chemical and Biological Defense Command, Aberdeen

Proving Ground, Md.
Medical Aspects of Chemical and Biological Warfare

380

dicated by a specific color change. Response time

is about 15 minutes. Some smokes, DS2, petroleum

products, and high temperatures may produce false

readings.

The detection limits for the M256A1 are as follows: for the G series of nerve agents, 0.005 mg/

m3; for VX, 0.02 mg/m3; for the vesicants mustard

(HD) and Lewisite, above threshold concentrations

of 3.0 mg/m3 and 14 mg/m3, respectively; and for

hydrogen cyanide (AC), 11 mg/m3, and cyanogen

chloride (CK), 10 mg/m3.

The M256A1 kit cannot be used to detect agent

in water. It can, however, be used to check an area

before a military unit moves in or to define clean

areas or routes. Some chemical ingredients in the

kit are considered possible carcinogens and should

be handled as such. The emissions produced by this

kit are also toxic; a mask and gloves must be worn

while the kit is being used.

Chemical Agent Water Testing Kit

The M272 Chemical Agent Water Testing Kit is

designed to detect and identify, via colorimetric

reactions, hazardous levels of nerve agents, mustard, Lewisite, and cyanide in treated or untreated

water (Figure 16-28). A full kit contains enough supplies to perform 25 tests for each agent, and

simulants are included for training use. About 20

minutes is required to perform all four tests. All

bodily contact should be avoided with the kit

chemicals, as some can be very harmful and should

only be handled while wearing protective gloves

and equipment.

Detection limits are as follows: for the G-series

nerve agents and VX: 0.02 mg/L; for the vesicants

Lewisite (L) and mustard (H and HD): 2.0 mg/L;

and for the cyanides (AC and CK), 20 mg/L.

Automatic Chemical Agent Alarm

The M8A1 Automatic Chemical Agent Alarm is

an automatic chemical agent detection and warning system designed to provide real-time detection

of the presence of nerve agent vapors or inhalable

aerosols. The M8A1 consists of the M43A1 detector

and up to five M42 alarms, which will provide both

an audible and a visible warning (Figure 16-29). The

M43A1 is an ionization product diffusion/ion mobility type detector; it will sound a false alarm

in the presence of heavy concentrations of rocket

propellant smoke, screening smoke, signaling

smoke, engine exhausts, and whenever a nuclear

blast occurs.

Fig. 16-28. The M272 Chemical Agent Water Testing Kit

and its components. New kits have a test strip instead of

a thermometer; this illustration shows both. Reprinted

from Brletich NR, Waters MJ, Bowen GW, Tracy MF.

Worldwide Chemical Detection Equipment Handbook.

Edgewood, Md: Chemical Warfare/Chemical and Biological Defense Information Analysis Center; October

1995: 433. Drawing: Courtesy of US Army Edgewood

Research, Development, and Engineering Center, Aberdeen Proving Ground, Md.

The M8A1 can be located within a hospital complex, with alarm units placed to cover all critical

care, treatment, and support areas. The M43A1 detects nerve agent vapors at concentrations of 0.2

mg/m3 for sarin (GB) and 0.4 mg/m3 for VX.

Standoff Detection

Early warning of chemical agents provides troops

the necessary time to increase protective posture

and to avoid contaminated areas. Standoff detectors provide this early warning at a distance of 1 to

5 km.

Optical remote sensing (ORS) technologies,

employing infrared spectral analysis techniques,

have been utilized in the development of chemical

agent standoff detection technologies. Within the

ORS technologies, there are two types of remote

sensing systems: passive and active (laser). The

section below only looks at the passive system,

which employs a Fourier Transform Infrared (FTIR)

spectrometer.
Chemical Defense Equipment

381

Fig. 16-29. The M8A1 Automatic Chemical Agent Alarm

system consists of (a) the M43A1 Detector and (b) the

M42 Alarm. Reprinted from Brletich NR, Waters MJ,

Bowen GW, Tracy MF. Worldwide Chemical Detection Equipment Handbook. Edgewood, Md: Chemical Warfare/

Chemical and Biological Defense Information Analysis

Center; October 1995: 411. Photographs: Courtesy of US

Army Edgewood Research, Development, and Engineering Center, Aberdeen Proving Ground, Md.

a b

Fig. 16-30. Field use of the M21 Remote Sensing Chemical Agent Alarm (RSCAAL). Reprinted from Brletich NR,

Waters MJ, Bowen GW, Tracy MF. Worldwide Chemical

Detection Equipment Handbook. Edgewood, Md: Chemical Warfare/Chemical and Biological Defense Information Analysis Center; October 1995: 425. Photograph:

Courtesy of Brunswick Corporation (now Intellitec),

DeLand, Fla.

Alarm: Remote Sensing Chemical Agent Alarm M21

The M21 Remote Sensing Chemical Agent Alarm

(RSCAAL) is an automatic scanning, passive, infrared sensor. The M21 detects nerve and blister agent

clouds based on changes in the background infrared spectra caused by the presence of the agent vapor. It scans a horizontal 60° arc and can recognize

agent clouds at line-of-sight ranges up to 5 km (Figure 16-30).

Usually, the M21 is placed facing into the wind.

It measures and stores a background spectrum that

is then compared by an onboard microcomputer,

which makes agent/no agent decisions based on

ambient radiance levels. Response time is 1 minute

or less. The system is fielded to NBC reconnaissance

units.

The sensitivity of the M21 for detecting nerve

agents (GA, GB, and GD) is 90 mg/m3; and for vesicants is 500 mg/m3 for Lewisite and 2,300 mg/m3

for HD mustard.

Developmental Detection and Warning Items

In the area of chemical detection, the next developments are

1. standoff detection systems that use laser

systems and can provide advance warning

from 30 to 50 km distant, and

2. point detectors that will be placed on attended air vehicles, with warning sent back

by radio or forward-emplaced point detectors with radio links to a headquarters or a

central warning network.

Combined nuclear, chemical, and biological detectors, which could serve as joint detection and

warning devices, are also being developed and

fielded.

Integrated Mobile Systems

M93A1 FOX Nuclear, Biological, Chemical Reconnaissance System

The M93A1 FOX Nuclear, Biological, Chemical

Reconnaissance System (NBCRS) is a recently

deployed, comprehensive solution to the prob-
Medical Aspects of Chemical and Biological Warfare

382

a

f

Fig. 16-31. (a) The M93A1 FOX Nuclear Biological Chemical (NBC) Reconnaissance System. The M21 remote sensing

chemical agent stand-off detector is not shown in its deployed configuration. (b) The schematic shows important components of the FOX. Entries in black boxes are components that have been added to the original version. GPS indicates the

location of the global positioning system instrument. (c) A FOX NBC suite operator is seen controlling the M21 detector.

(d) The instrument at the top is the ANVDR2 Radiation Detector. Below it is the M43A1 Chemical Vapor Detector. (e)

Chemical agents present on the ground adhere to the silicone-tired sampling wheels.

b

e

lem of early recognition of NBC threats on the modern battlefield. Numerous sophisticated instruments have been mounted in a fast, mobile, 6x6 armored vehicle that weighs about 19 tons and is

manned by a crew of three (Figure 16-31). The vehicle is of German origin, and the name FOX is a translation of Fuchs, for whom the design was named.

The FOX is instrumented to detect chemical contamination in its immediate vicinity with a variety

of probes, and at a distance via a standoff detector

(M21). Meteorological data are also sensed. Data are

analyzed, synthesized, and transmitted to higherechelon units by a secure, jam-resistant communication system. The local area is marked by warning

markers ejected through a hatch in the rear of the

vehicle. A global positioning system makes possible

accurate marking of the contaminated locale. The

interior of the vehicle is pressurized and offers collective protection against threat agents.

XM31 Biological Integrated Detection System

The XM31 Biological Integrated Detection System (BIDS) consists of a lightweight, multipurpose,

collective protection shelter mounted on a heavy

high-mobility, multipurpose, wheeled vehicle
Chemical Defense Equipment

383

c d

After sampling, the wheels are elevated into proximity of the vacuum port of the chemical sampling probe (black

tubular object), which is connected to the MM1 mass spectrometer. Chemically contaminated terrain is marked by

flags ejected from the FOX. (f) Objects that are possibly contaminated are retrieved by a pair of tongs manually

operated from inside the FOX. The sample is placed in the small box-like receptacle for latter analysis. (g) The gloved

arm of a crew member is shown manipulating a thermal probe used to measure ground temperature. This information is valuable in estimating the vapor hazard from liquid agent. Photographs: Courtesy of Visual Information Division, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Md.

g

(HMMWV) and equipped with a biological detection suite (Figure 16-32). In its present configuration, the BIDS can detect the bacteria Bacillus

anthracis and Yersinia pestis, and the toxins botulinum toxin A and staphylococcal enterotoxin B.

Several technological approaches are used sequentially to detect and confirm the presence of

specific biological threat agents. Since biological

threat agents are likely to be dispersed as aerosols,

ambient air is continuously sampled and the background distribution of aerosol particles determined.

Aerosol particles in the 2- to 10-μm diameter range

are concentrated and then subjected to analysis for

1. adenosine 5'-triphosphate (ATP) by bioluminescence,

2. bacterial cells by flow cytometry, and

3. specific antigens by two different antigen–

antibody reactions.

Individual BIDS are combined together into a

corps-wide network by a secure communication

system. An improved BIDS is being developed with

the capability to detect two species of Brucella,

Francisella tularensis, and ricin toxin. Detection capabilities for additional agents will no doubt be

added to future models.33
Medical Aspects of Chemical and Biological Warfare

384

Fig. 16-33. The chemically protected deployable medical

system (CP DEPMEDS).

Fig. 16-32. (a) The XM31 Biological Integrated Detection System (BIDS) in its present configuration. Electric power is

provided by a towed 15-kW tactical quiet generator. An additional high-mobility, multipurpose, wheeled vehicle

(HMMWV) is used as a support vehicle for the crew of four, two of whom are required to operate the equipment that

comprises the biological detection suite. The stovepipe-like structures perform the aerosol-sampling function. (b)

Interior view of the biological detection suite. Photographs: Courtesy of Visual Information Division, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Md.

a

COLLECTIVE PROTECTION

Collective protection serves a vital role in the

medical area since treatment of casualties must continue even in a contaminated environment, thus collective protection is required to allow this critical

function to continue. In addition, it allows individuals to rest and eat, and provides temporary relief

from the individual protection equipment thus allowing continuing military operations in the contaminated environment. Collective protection systems have been designed to be used in either a

medical or a nonmedical application.

The sources for this discussion are experts at the

U.S. Army Chemical and Biological Defense Command,34 and Collective Protective Equipment, U.S.

Army Training Manual 34240-338-10,35 which interested readers can consult for greater detail.

Medical Collective Protection Systems

The Medical Collective Protection Systems provide ample floor space and are accessible for litter

patients through airlocks. Additionally, some of

the systems provide airlocks through which ambulatory patients can pass. These options aid

the medical community in its tasks when dealing

with casualties in a chemically contaminated environment.

Chemically Protected Deployable Medical System

The chemically protected deployable medical

system (CP DEPMEDS) consists of the M28 collective protection equipment (CPE), which is designed to protect critical areas within the hospital

complex from chemical–biological contamination

(Figure 16-33). The M28 CPE can only be used with

the TEMPER (tent, extendable, modular, personnel)

system. The entire composite hospital ensemble

Liquid Sampler

b

Biological Sampler Flow Cytometer

Display for Flow Cytometer

Environmental Control Unit

Aerodynamic

Particle Sizer

Threshold System

Power Supply for

Flow Cytometer
Chemical Defense Equipment

385

consists of expandable tentage, passageways, environmental control units, and ISO (International

Organization for Standardization, from the French)

shelters.

The M28 CPE consists of the following items: end

sections, center sections, and vestibule liner fabricated from a plastic film that is resistant to liquid

and vapor agents; a protective entrance airlock for

ambulatory personnel that is made from a butylcoated material and hung in a collapsible aluminum

frame, creating a triangular shape; a tunnel airlock

for litter-borne patients, consisting of a collapsible

frame with entry and exit doors at opposite ends

fabricated from an NBC protective cover; the hermetically sealed filter canister and the accessory

package, which support the purge requirement

during collective protective entry; and the recirculation filter, which is a portable self-contained unit designed to filter any chemical agent vapors brought in

through the entry or exit.

Chemically Hardened Air Transportable Hospital

The U.S. Air Force utilizes the Chemically Hardened Air Transportable Hospital (CHATH) in its

operations. The CHATH is basically the same as the

CP DEPMEDS. The air force is developing a chemically hardened air-management plant (CHAMP),

which will provide 800 cu ft/min of filtered air,

environmental control, and power generation integrated into a single (albeit very large) package. The

CHAMP is intended to replace all M20/M28 filter

blower sets. Although the CHAMP is intended to

be used with the CHATH, it is competing with the

air force’s field deployable environmental control

unit (FDECU) as the system to actually be applied

to the CHATH.

Chemical and Biological Protected Shelter

The Chemical and Biological Protected Shelter

(CBPS) is a direct replacement for the M51 C/B shelter, which eliminates the excessive erection/striking

time, the insufficient floor space, lack of natural

ventilation, and the unavailability of prime movers, which were the problems with the M51. The

CBPS can be set up or struck three times daily when

operating as a Battalion Aid Station. Set-up times

of the inflatable rib tent have been established at 15

to 20 minutes, and tear-down times at approximately 30 minutes. The CBPS consists of a power/

support system and inflatable tent. The primary

power source is the engine of a HMMWV variant

Fig. 16-34. The litter-patient airlock of the Chemical and

Biological Protected Shelter. Treating casualties on a

chemical-biological warfare battleground requires complicated procedures, even to get the casualty into a protected environment for examination. Special air locks for

casualties and new procedures had to be developed. Photograph: Courtesy of Chemical and Biological Defense

Command Historical Research and Response Team, Aberdeen Proving Ground, Md.

and a backup generator mounted in a high-mobility multipurpose trailer. This system provides air

conditioning or heating and electricity for lighting,

equipment, and filter air.

The CBPS is staffed by a crew of four, who are carried in the HMMWV. The inflatable rib tent provides

300 sq ft of usable floor space, with a litter-patient

airlock (Figure 16-34) and optional ambulatorypatient airlock. The CBPS has removable side entrances to allow side-to-side setup of additional CBPS.

Nonmedical Collective Protection

The nonmedical collective protection systems

provide protection for two or more individuals from

the effects of chemical agents present in the environment. These systems provide an area for individuals to perform their functions without experiencing deleterious effects.

M20 Simplified Collective Protection Equipment

The M20 Simplified Collective Protective Equipment (SCPE) is designed to provide a clean-air shelter for use in a contaminated environment, espe-
Medical Aspects of Chemical and Biological Warfare

386

cially for command, control, and communication.

The SCPE has a collapsible protective entrance, a

hermetically sealed filter canister, a blower unit, and

an accessory pack (Figure 16-35). It is designed to

be employed inside an existing room of 200 sq ft of

usable space, with or without a collapsible liner. The

SCPE can be used without the liner only in rooms

that are tightly sealed.36

Developmental Collective Protection Items

New developments in collective protection will

center on

• improved adsorbents and impregnants as

replacements for activated charcoal,

• methods to better determine filter lifetime,

and

• new systems, such as pressure- and temperature-swing adsorption, which may provide significant improvements for collective

protection applications in ships, aircraft,

and armored vehicles.

Possible applications to military uses will be

made of a number of civilian developments in environmental pollution abatement.

For these systems to provide environmentally

controlled atmospheres, environmental control

units are being developed to be compatible with

collective protection systems. At the present, however, there are neither heaters nor air conditioners

that can be used with collective protection equipment. The air force’s FDECU, currently in late-stage

development, is the primary candidate and is able

to heat and cool.

Fig. 16-35. The M20 Simplified Collective Protective

Equipment (SCPE).

DECONTAMINATION EQUIPMENT

The physical properties of chemical agents are

highly variable. They range from nerve agent vapor, which usually dissipates in a few minutes to a

few hours, to vesicants such as mustard, which can

remain active for weeks (or in some cases, years:

buried and recovered World War I mustard projectiles are often still quite toxic). It is imperative, then,

that timely decontamination of the skin and personal equipment that has been exposed to agent,

especially liquid agent, be completed. Skin decontamination should take place within 2 minutes if

possible, and equipment decontamination should

be completed within 1 hour.

To effectively perform complete personnel and

equipment decontamination operations, decontamination units use truck-mounted tanks, pumps, and

water heater units; and trailer-mounted pumps and

water heater units. In these processes, reducing the

exposure time of the individual or piece of equipment

to the chemical contaminant is of the highest priority.

The sources for this discussion are Decontamination of Chemical Warfare Agents37 and NBC Decontamination,38 and experts at the U.S. Army Chemical and

Biological Defense Command.39 Readers interested

in greater detail can consult these sources and the

authors of this chapter.

Personnel Decontamination Items

Personnel decontamination is performed to

reduce the level of contamination so it is no longer

a hazard to the individual. Personnel decontamination consists of removal of clothing and

decontamination of the skin. To expedite this procedure, personnel decontamination kits are used to

remove the gross contamination. Complete decontamination, which is conducted by specialized decontamination units, is provided to troops to reduce

the requirement for wearing complete NBC protective equipment. Additionally, when both crews and

equipment are contaminated, combined complete

personnel and equipment decontamination operations are scheduled as the situation and mission

permit, bearing in mind the lengthy time required

for such an operation. It is during this complete decontamination that commanders can give their soldiers rest and a change of personal protection equipment.40
Chemical Defense Equipment

387

Fig. 16-36. The M258A1 Skin Decontamination Kit.

The personnel decontamination items described

below would be used to quickly decontaminate the

skin of an exposed individual. Open wounds, however, should be decontaminated with water, saline,

or dilute hypochlorite solutions.

M258A1 Skin Decontamination Kit

The M258A1 Skin Decontamination Kit is designed to remove and neutralize liquid chemical

agents on the skin. The kit consists of three number

1 liquid packets and three number 2 liquid packets

(Figure 16-36). The number 1 packet will neutralize G-series nerve agents by hydrolysis, and the

number 2 packet will neutralize VX and mustard

agents by oxidation.41

The contents of the kit are highly caustic and

should not be used near the eyes or mouth or

to decontaminate wounds. A training kit that contains only an alcohol and water solution, the

M58A1, has been developed to be used in lieu of

the M258A1.

M291 Skin Decontamination Kit

The M291 Skin Decontamination Kit is a soft

package consisting of two flexible pockets, each

Fig. 16-37. The M291 Skin Decontamination Kit.

of which contains three decontamination packets

(Figure 16-37). Each of the packets contains a black

resin (a mixture of a carbonaceous adsorbent, a

polystyrene polymeric compound, and an ionexchange resin) that is both reactive and adsorbent.

The decontamination pad is made from a nonwoven

fiberfill that is impregnated with the dry resin

mixture.42

The decontamination is accomplished by merely

opening the packet and scrubbing the skin surface

with the applicator pad until an even coating of the

resin is achieved. Use normal precautions to keep

the powder from wounds, the eyes, and the mouth.

The M291 kit is also used for training.

Equipment Decontamination Items

Equipment decontamination items are used to

destroy, remove, or neutralize most of the NBC

hazards from personal gear or unit equipment.

Although all of the items that could be used

for equipment decontamination are not listed below, those most useful to the medical community

are described.

M295 Decontamination Kit, Individual Equipment

The M295 Decontamination Kit, Individual

Equipment (DKIE) consists of a pouch containing

four wipedown mitts, each enclosed in a soft protective packet (Figure 16-38). Each wipedown mitt

is made of a dry, adsorbent, black resin (the same

as in the M291 kit) contained within a nonwoven

polyester material and a polyethylene film backing.

This kit allows decontamination of exposed areas

of the protective mask and hood, personal equipment, and protective boots. Decontamination is

Fig. 16-38. The M295 Decontamination Kit, Individual

Equipment (DKIE).
Medical Aspects of Chemical and Biological Warfare

388

accomplished by adsorption of the liquid agent by

the resin and the pad.

M11 Portable Decontamination Apparatus

The M11 Portable Decontamination Apparatus

(PDA) is a hand-held, pressure-spray apparatus

used to coat a surface with DS2 by equipment operators (Figure 16-39). The M11 contains 11⁄3 quarts

of DS2 and will neutralize all agents within 30 minutes. It is pressurized using a nitrogen cylinder with

a life of only 30 seconds. Any use of DS2 should be

made with a protective mask and gloves, since it is

highly irritating to the skin and can cause blindness. In addition, DS2 is highly flammable.

M17 Lightweight Decontamination System

The M17 Lightweight Decontamination System

(LDS) is designed to draw water from any source

and deliver it to the two installed spray wands at

pressures up to 100 psi and at temperatures up to

120°C (Figure 16-40). The M17 LDS can be used to

provide pressurized hot water before or after application of decontaminant at regulated pressures

and temperatures. It has a liquid soap siphon hose

attachment for use with mud, dirt, or grease removal (these may have absorbed chemical agent).

Fig. 16-39. The M11 Portable Decontamination Apparatus (PDA).

Fig. 16-40. The M17 Lightweight Decontamination System (LDS).

The M17 LDS has a 3,000-gal collapsible water tank

that can be prepositioned and filled for hot water

showers or hospital use.

M12A1 Power-Driven Decontamination Apparatus

The M12A1 Power-Driven Decontamination Apparatus (PDDA) is used to apply decontamination

solutions or hot soapy water and rinses during field

decontamination operations. The M12A1 PDDA

consists of a pump unit, 500-gal tank, personnel

shower assembly, and M2 water heater, all of which

is mounted on a 5- or 10-ton truck with drop sides

(Figure 16-41). The pump assembly can deliver 50

gal of water or super tropical bleach (STB) decontaminating agent per minute at a pressure of 105

psi to the two spray wands.

Fig. 16-41. The M12A1 Power-Driven Decontamination

Apparatus (PDDA).
Chemical Defense Equipment

389

Developmental Decontamination Items

There is a need for an effective and environmentally

safe reactive decontaminant that does not harm equipment and personnel. Bacterial enzymes, catalytic-type

compounds, and other stable decontaminants (eg, quaternary ammonium complexes) are under consideration.

Sorbent compounds and nonaqueous decontaminants

are also being investigated for use on electronic components and other sensitive equipment.

ADDITIONAL PATIENT PROTECTION AND TRANSPORT EQUIPMENT

Patient Protective Wrap

The patient protective wrap (PPW) is designed

to protect a patient during evacuation after the BDO

has been removed and the patient has received

medical treatment (Figure 16-42). A patient can remain in the PPW for 6 hours. The protective mask

is not needed inside the PPW, but it should be

evacuated with the patient.

The PPW is for one patient only and weighs approximately 5.5 lb. The top of the PPW is made of a

material similar to that used in the BDO, with a

charcoal lining and in a camouflage pattern. The

bottom is made of impermeable rubber. The PPW

has a continuous zipper along the outer edge for

ease of patient insertion; a large, transparent window in the top to view the patient (or for him to see

out); and a pocket for medical records. The patient’s

breathing air comes through the permeable top of

the PPW.

Fig. 16-43. The decontaminable litter.

Patient Transport: Decontaminable Litter

The decontaminable litter has been developed to

meet the need for a litter that can withstand decontamination (Figure 16-43). The cover fabric is a honeycomb weave of monofilament polypropylene,

which will not absorb agent and is not degraded

by decontamination fluids. The cover fabric is flame

retardant and rip resistant, and is treated to withstand weather and sunlight. It has aluminum poles,

painted with chemical agent resistant coating, with

round, grip-molded, retractable, black nylon

handles. It conforms to all NATO standards and

weighs about 15 pounds.

SUMMARY

An integrated system of chemical defense equipment is required if we are to be successful in providing an adequate protective posture for all forces.

The principal elements of that system include the

following:

• Real-time detection and warning, preferably

from remote sensors. This will provide more

time, first, to assume a protective posture, and

second, to identify the chemical agent.

• Personal protective equipment, consisting

of a properly fitted mask and overgarment

with gloves and boots as required. This

equipment is the most critical component

of chemical defense equipment, the first line

of defense.

• Collective protection, which is necessary for

optimal combat casualty care in a contaminated environment, whether the casualty’s

injuries are from exposure to chemical–bioFig. 16-42. A volunteer demonstrates the patient protective wrap (PPW).
Medical Aspects of Chemical and Biological Warfare

390

logical weapons alone, or are combined

with injuries from conventional weapons.

• Decontamination, which is required for personnel and equipment to maintain combat

operations in a contaminated environment.

Medical treatment for chemical casualties has not

been covered here since it is covered in other chapters, but it is essential that protective equipment be

available to allow the proper treatment to be administered.

ACKNOWLEDGMENT

The authors thank the following experts for their technical assistance and generous help in illustrating and preparing this chapter: Major M. L. Malatesta, Chemical Corps, US Army, Deputy Program Director, Office of the Program Director for Biological Defense Systems; Bryan J. Keirn, Engineering Technician for the Program Manager, Nuclear, Biological, Chemical Defense Systems; John

A. Scavnicky, Project Manager for Nuclear, Biological, Chemical Defense Systems, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground, Maryland; and Sergeant First Class

Larry L. Harris, US Army (Ret).

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1. US Army Armament Munitions and Chemical Command. Chemical Defensive Equipment (General Information

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Command; October 1984.

2. Department of the Army. NBC Handbook. Washington, DC, DA; September 1990. Field Manual 3-7.

3. Ramirez TL, Rayle ME, Crowley PA, Derringer, CV. The Thermal Effects of the Chemical Defense Ensemble on

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1988. CB-010358. ADB131 710.

4. Department of the Army. NBC Contamination Avoidance. Washington DC: DA; November 1992. Field Manual 3-3.

5. Department of the Army. NBC Protection. Washington, DC: DA; February 1996: Chap 2. Field Manual 3-4 With

Change 2. Fleet Marine Force Manual 11-9.

6. Weiss RA, Weiss MP, Church JK Jr, Strawbridge JB, Decker RW II, Martin FA. Chemical Warfare Respiratory

Protection: Where We Were and Where We Are Going. Aberdeen Proving Ground, Md: US Army Chemical Research, Development, and Engineering Center; n.d. Unpublished report.

7. Gander TJ, ed. Jane’s NBC Protection Equipment, 1992–93. Alexandria, Va: Jane’s Information Group Inc; 1992: 21–25.

8. North Atlantic Council, NATO Industrial Advisory Group, Sub-Group 48. Basic Personal Equipment. Vol 5. In:

NIAG Prefeasibility Study on a Soldier Modernisation Program. Brussels, Belgium: NIAG; September 1994. NATO

unclassified document NAIG-D(94)3.

9. Brletich NR, Tracy MF, Dashiell TR. Worldwide NBC Mask Handbook. Edgewood, Md: Chemical Warfare/Chemical

and Biological Defense Information Center; September 1992.

10. McHenry R, ed. The New Encyclopædia Britannica. Vol 3, Micropædia. 15th ed. Chicago, Ill: Enclycopædia

Britannica, Inc; 1993: 98.

11. Bender TR, MD, MPH. Director, Division of Safety Research, Centers for Disease Control, National Institute

for Occupation Safety and Health, Morgantown, WVa. Letter to all Respirator Manufacturers; June 15, 1990.

12. Klenke WJ. Lieutenant Colonel, Medical Service, US Army. Medical NBC Defense Staff Office, Office of The

Surgeon General. Personal communication, June 1996.
Chemical Defense Equipment

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13. Phillips YY. Colonel, Medical Corps, US Army; Chief, Department of Medicine, Walter Reed Army Medical

Center, Washington, DC. Personal communication, July 1996.

14. Masks, Chemical–Biological, Field, M17A1. Military Specification MIL-M-51282D(EA). November 1986.

15. Church JK. Chemical Engineer, US Army Chemical and Biological Defense Command, Edgewood Area, Aberdeen Proving Ground, Md. Letter to MF Tracy, May 1996.

16. Mask, Chemical–Biological, Protective Field, M40. US Army Chemical Research, Development and Engineering Center Purchase Description EA-M-1377A. Edgewood Area, Aberdeen Proving Ground, Md; January 1990.

17. Mask, Chemical–Biological, Protective Field, M40. US Army Chemical Research, Development and Engineering Center Purchase Description EA-M-1377A, Amendment 1. Edgewood Area, Aberdeen Proving Ground,

Md; September 1990.

18. Department of the Army. Operator’s Manual Chemical–Biological Mask: Field, M40. Washington, DC: DA; June

1988. Training Manual 3-4240-300-l0-l.

19. Mask, Chemical–Biological Protective, Combat Vehicle, M42. US Army Chemical Research, Development and

Engineering Center Purchase Description EA-M-1389A. Edgewood Area, Aberdeen Proving Ground, Md; December 1990.

20. Department of the Army. Operator’s Manual Chemical–Biological Mask: Combat Vehicle, M42. Washington, DC:

HQ, DA; August 1988. Training Manual 34240-300-10-2.

21. Mask, Chemical–Biological Protective Aircraft, M43. US Army Chemical Research, Development and Engineering Center Purchase Description EA-M-1352A. Edgewood Area, Aberdeen Proving Ground, Md; January 1988.

22. Department of the Army. Operator’s and Organizational Manual: Mask, Chemical–Biological: Aircraft M43. Washington, DC: HQ, DA; June 1988. Training Manual 34240 312-12&P.

23. Grove CM, Scavnicky JA. Concept Development Studies for Respiratory Protection System 21. Edgewood Area,

Aberdeen Proving Ground, Md: US Army Edgewood Research Development and Engineering Center; September 1995.

24. US Army Natick Research, Development, and Engineering Center. Items of Combat Clothing and Equipment.

Natick, Mass: US Army Natick Research, Development, and Engineering Center; September 1991. Natick P-32-1.

25. Wajda DJ. US Army Natick Research, Development and Engineering Center, Natick, Mass. Letter to MF Tracy,

May 1996.

26. Winfield Manufacturing Co. Chemical Protective PBI Saratoga CWU/66P Air Force Flight Coverall. New York, NY:

Winfield Manufacturing Co; June 1989. Technical Bulletin SAr3.

27. US Department of the Army and US Marine Corps. Operator’s Manual for Individual Chemical Protective Clothing.

Washington, DC: HQ, DA, USMC; March 1993. Training Manual 10-8415-209-10. Fleet Marine Force Manual

8415 10/2.

28. US Marine Corps. Joint Operational Requirement Document for a Lightweight Integrated Nuclear, Biological, and

Chemical (NBC) Protective Garment. Washington, DC: USMC; June 1995. NBC 215.2.1.

29. US Marine Corps, Army, Navy, and Air Force. Joint Service Lightweight Integrated Suit Technology Program.

Joint Service Lightweight Integrated Suit Technology (JSLIST) Program. Columbus, Ohio: Battelle Memorial Institute; May 1996.

30. Brletich NR, Waters MJ, Bowen GW, Tracy MF. Worldwide Chemical Detection Equipment Handbook. Edgewood,

Md: Chemical Warfare/Chemical and Biological Defense Information Analysis Center; October 1995.
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31. Department of the Army. Chemical Agent Monitor Employment. Washington, DC: DA; July 1991. TC 34-1.

32. Department of the Army. Operator’s and Organizational Maintenance Manual for the Chemical Agent Monitor (CAM).

Washington, DC: DA; June 1992. Training Manual 3-6665-331-10.

33. Malatesta ML. Major, Chemical Corps, US Army. Deputy Program Director, Office of the Program Director for

Biological Defense Systems, US Army Chemical and Biological Defense Command, Aberdeen Proving Ground,

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34. Blewett WK. Chemical Engineer, Team Leader for Ventilation Kinetics, US Army Chemical and Biological Defense Command Edgewood Area, Aberdeen Proving Ground, Md. Letter to MF Tracy, May 1996.

35. Department of the Army. Collective Protection Equipment. Washington, DC: DA; July 1991. Training Manual

34240-338-10.

36. Department of the Army. Operator’s and Organizational Manual for the Simplified Collective Protective Equipment,

M20. Washington, DC: DA. August 1987. Training Manual 4240-288-12&P.

37. Edgewood Research Development and Engineering Center. Decontamination of Chemical Warfare Agents. Aberdeen Proving Ground, Md: Edgewood Research Development and Engineering Center; December 1992. ERDECTR-004.

38. Department of the Army. NBC Decontamination. Washington, DC: DA; June 1985. Field Manual 3-5.

39. Christian IL. Quality Assurance Engineer, US Army Chemical and Biological Defense Command, Edgewood

Area, Aberdeen Proving Ground, Md. Letter to MF Tracy, May 1996.

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Washington, DC: DA; February 1980. Field Manual 3-87.

41. Department of the Army. Operator’s Manual for Decontaminating Kit, Skin: M258A1 and Training Aid, Skin Decontaminating: M58A1. Washington, DC: DA; October 1989. Training Manual 34230-216-10.

42. Department of the Army. Operator’s Manual for Skin Decontamination Kit, M291. Washington, DC: DA; October

1989. Training Manual 34230-229-10
Chemical Defense Equipment

393

PSYCHOLOGICAL PROBLEMS ASSOCIATED WITH WEARING

MISSION-ORIENTED PROTECTIVE POSTURE GEAR

Prepared for this textbook by Elspeth Cameron Ritchie, M.D., Major, Medical Corps, U.S. Army, Department of Psychiatry, Walter

Reed Army Medical Center, Washington D. C. 20307-5001

Personal respirators or protective masks, incorrectly but commonly called gas masks, have been worn since the

Germans used gas in World War I. Now they are a routine part of a soldier’s field gear, and in planning for combat,

the military relies on the putative saving graces of protective masks. However, a few soldiers are unable to tolerate

wearing a gas mask for a few minutes even in a peaceful garrison setting. Most soldiers have decrements in cognitive

and physical functioning when the mission-oriented protective posture (MOPP) gear is worn for a few hours. How

well would these soldiers tolerate wearing MOPP 4 gear for hours or days in a chemical environment?

There are three principal psychological reasons to avoid wearing gas masks: (1) “gas mask phobia,” a form of

claustrophobia; (2) malingering; and (3) feeling embarrassed at being thought a coward. “Gas hysteria,” the panicked feeling that one has been gassed, can also occur.

Gas mask phobia may be categorized as a form of claustrophobia occasioned by the wearing of a protective mask.

In psychiatric terms, it could be defined as a simple phobia.1

 Symptoms include hyperventilation, sweating, and

panic. These usually cause the eyepieces to fog up, leading to an inability to see, move, shoot, and communicate.

Many soldiers either break the seal and lift the mask off the face, or remove the mask completely. Prevention and

initial treatment of gas mask phobia and malingering should be command issues, handled though the NBC (nuclear,

biological, and chemical) officers; recalcitrant cases may be referred to the mental health service for further evaluation and desensitization techniques.

Prevention of fear of the mask is an important training issue. Consideration should be given to having soldiers in

basic training wear the mask in a relaxed setting the first few times. Soldiers then need to train in MOPP gear to learn

(a) how to handle communication obstacles, and (b) what they should do if they or their buddy develop difficulties

with the equipment. Often proper fit is not given adequate attention when the mask is issued. If women wear their

hair pinned up or if men have facial hair, for example, a tight fit is very difficult to obtain.

An ethical dilemma is raised with having soldiers in a potentially toxic environment who cannot wear the mask.

Should these soldiers be removed from the combat environment, thereby risking an epidemic of soldiers claiming

that they cannot wear the mask? Or should the soldiers be kept in that environment, risking their injury or death if

gas is used?

Not discussed here but a factor to be considered in any potential deployment of soldiers in a biological or chemical

environment is the intense fear of that form of warfare. The feelings of helplessness in the face of a ubiquitous and

unseen killer can be overwhelming.

HISTORY

Gas was first used extensively in early 1915 by the Germans against both the French and the British. In the

accounts of that war, over and over poor discipline is recorded as a significant source of gas casualties.2 The American Expeditionary Forces used primarily the British small-box respirator, with the French M2 mask as a reserve. Both

masks were very uncomfortable, and soldiers took them off at the first opportunity, often while gas still lingered in

the area. Many casualties were sustained.3 “In the recent gas attack practically all casualties had been caused

by ignorance of the officers concerning the persistency of mustard, premature removal of masks, and failure to evacuate

the camp promptly.”4(p11)

Shame was another source of casualties:

It is almost unbelievable nowadays that at one time one of the chief sources of these constantly occurring casualties

was shamefacedness at being seen in a mask. Men would not protect themselves until absolutely forced to do so, for

fear others would regard them as being too easily frightened....They (the soldiers) were met with jeers from some of

the supporting troops who shouted “Hello, got the wind up?” and in this way induced the corporal, really against his

better judgement, to order masks off. Not more than twenty or thirty yards further along the party ran into a particularly bad pocket of Green Cross and the corporal and several of his men were so badly gassed that they had to be sent

to the rear.5(pp166–167)

Malingering and gas hysteria were two other sources of casualties. In World War I, many soldiers were evacuated

to the aid stations who probably were suffering from gas hysteria. A Division Medical Gas Officer

capped this account with his report that from 1–13 November a total of 763 men came in to aid stations and field

hospitals as gassed. Of these, 339 were not considered gassed and were returned to their units via the casual camp set

up in the rear.6(p73)

How many of these were judged malingerers is not recorded.
Medical Aspects of Chemical and Biological Warfare

394

In World War II, gas was not a significant threat. The first volume of Neuropsychiatry in World War II, part of the

official history of World War II issued by the Office of The Surgeon General, does not discuss difficulties with the

protective mask as a problem leading to psychiatric disability.7 Similarly in the Korean and Vietnam wars, gas posed

little danger. Until 1990 and the outbreak of the Persian Gulf War, if a soldier in a routine job could not wear the

protective mask, that fact was often ignored by the chain of command.

THE CURRENT SITUATION

American soldiers typically first learn to put on a mask during basic training, in a tear gas–filled tent. The environment is tense, and soldiers are burdened with hot, unfamiliar gear. They may be told to remove their masks long

enough to get a whiff of tear gas, causing watery eyes and coughing. When soldiers put their masks back on, they are

then sweating and teary, adding to their psychological and physical distress. In many cases, the mask is then worn in

strenuous, hot conditions, such as on a road march or a field exercise. In practice, the mask interferes with verbal and

visual communication, adding to a sense of isolation. Real casualties from heat stroke or injury are often suffered.8–10

Respirators are used in many occupations in the civilian world, including firefighting, and there are similar problems associated with industrial use. However, the self-selection process may eliminate those who can not tolerate a

mask.11

In the military, donning the rest of the MOPP gear causes additional physiological and psychological difficulties.

The wearing of the suit increases body temperature, which may be compounded by doing tasks in the hot sun. Numerous studies12–18 have documented the decrement in function caused by wearing MOPP 4 for extended periods.

Studies have also tested the effects on soldier performance of administering the nerve agent–antidotes atropine sulfate and pralidoxime chloride (2-PAM Cl)19 and pyridostigmine bromide20,21; the combination of atropine and 2-PAM

Cl significantly shortened endurance time for heat sessions for soldiers wearing MOPP 4 gear.19

Modern Case Studies

The following three case studies are of soldiers who could not tolerate wearing their protective masks during the

Persian Gulf War. Little on the phenomenon had been published in the medical or military literature by the early

1990s; it is probable that many more cases were undiagnosed. These three previously published22,23 cases highlight

two issues: the question of trying to get out of combat by not being able to wear the mask, and the reluctance of

motivated or senior soldiers to admit that they have had a problem with the MOPP gear.

Case 1. A 19-year-old single white male, stationed at the Demilitarized Zone in Korea, was unable to finish a 2-mile road

march while wearing his protective mask. His chief complaint was “It’s embarrassing to be unable to finish the march.” This

soldier had difficulty wearing his mask for more than a few minutes. After the first mile of a road march, he experienced

confusion, shortness of breath, blurry vision, fainting sensations, and intense thirst. His background, past psychiatric history,

and medical history were unremarkable. He did remember an incident when he was 6 years of age, when he and his friends

were playing “mummy.” He felt hot and agitated and scared; later his grandmother told him that he had been hyperventilating.

A diagnosis of simple phobia was made. Treatment principles outlined below were followed. Initially he was told to wear his

mask while listening to music. He did, but still felt “confined.” He would try to adjust his mask constantly by moving it around,

and getting cool air underneath. Gradually he felt more confident while wearing the mask and could increase the time he

wore it. He was able to wear his entire MOPP gear during the annual “Team Spirit” exercise.22(p105)

Case 2. An officer with 20 years of military service was referred with depressive symptoms. These followed in the wake of

a chronic gas mask phobia that had gone untreated for years because the officer had been too ashamed to admit it to

anyone. He had remained on the front lines, enduring several gas mask alerts, and was identified when he finally sought

assistance. He was eventually evacuated because his depression and phobia could not safely be treated in the desert

environment.23(ppA10–A11)

Case 3. A specialist was brought to the hospital for treatment of gas mask phobia, which had been refractory to systemic

desensitization by a unit medic. The treatment had been notable for the patient’s overall compliance but insufficient “effort.”

She would remove the mask frequently and inexplicably during low subjective anxiety, or with sudden incongruous elevation

in anxiety unaccompanied by any objective signs. It was decided to send the patient to the division rear to provide some

improved safety, given that malingering could not be judged as certain.23(pA-11)

Treatment

The basic techniques of treating gas mask phobia are similar to those of treating other phobias, modified for the

military culture and environment. They are desensitization, relaxation, and flooding. To avoid malingering, any secondary gain (ie, other benefits accrued by not being able to wear the mask, such as evacuation from the field environment) should be avoided.

In desensitization, the soldier needs to wear the mask enough that it becomes routine. Secondly, he needs to relax

while wearing it. Thus, soldiers should begin by wearing the mask while watching television, ironing, or doing other

household or barrack tasks. They should start wearing it for short periods (5 min), then lengthen the time (30 min).
Chemical Defense Equipment

395

Flooding, the next step, refers to the technique of having a patient imagine wearing a mask in tense situations. Gradually, the soldier actually wears the mask in more-tense and -fatiguing situations. To avoid secondary gain, benefits of

not being able to wear a mask should be minimized. Therefore, soldiers should not be excused from road marches,

field exercises, or other duties because they are unable to wear MOPP gear.24

Other primary strategies include (a) simulation training; (b) modeling training (ie, observation of live peer models); (c) self-management training (ie, training in self-control techniques); and (d) inoculation training, both as a

soldier and as a casualty. Secondary prevention strategies include: (a) self-care; (b) buddy care; (c) leader management, to minimize the risk of symptom spread; and (d) medic care.18

SUMMARY

As threats of chemical and biological warfare become more routine, it is imperative that soldiers can wear their

protective gear. Frequent practice should increase comfort and decrease problems with claustrophobia and embarrassment. In those who cannot initially tolerate the gas masks, treatment should be initiated as close to the front lines

as possible, to minimize casualties in training and in combat.

REFERENCES

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington DC: APA

Press, 1994.

2. Spencer EW. The History of Gas Attacks Upon the American Expeditionary Force During the World War. Book 1, Part I.

Carlisle Barracks, Pa: Military Historical Institute; 1928: 146–150. Bound typescript.

3. Spencer EW. The History of Gas Attacks Upon the American Expeditionary Force During the World War. Book 3. Carlisle

Barracks, Pa: Military Historical Institute; 1928: 409–415. Bound typescript.

4. Cochrane RC. Gas Warfare at Chateau Thierry. Carlisle Barracks, Pa: Military Historical Institute; July 1956. Bound

typescript.

5. Auld SJM. Gas and Flame in Modern Warfare. New York, NY: George H Doran Co; 1918.

6. Office of the Chief Chemical Officer. The 92nd Division in the Marbache Sector. Washington, DC: US Army Chemical

Corps Historical Office; 1918.

7. Carter J, Cammermeyer M. Biopsychological responses of medical unit personnel wearing chemical defense ensemble

in a simulated chemical warfare environment. Milit Med. 1985;150(5):234–248.

8. Glass AJ, Bernucci RJ, eds. Zone of Interior. Vol 1. In: Mullins WS, Glass AJ, eds. Neuropsychiatry in World War II.

Washington, DC: US Department of the Army, Office of The Surgeon General; 1966.

9. Carter BJ, Cammermeyer M. Emergence of real casualties during simulated chemical warfare training under high

heat conditions. Milit Med. 1985;150(12):657–663.

10. Cole RD. Heat stroke during training with nuclear, biological and chemical protective clothing: Case report. Milit

Med. 1983;148:624–625.

11. Morgan WP. Psychological problems associated with the wearing of industrial respirators: A review. Am Ind Hyg

Assoc J. 1983;44(9):671–676.

12. Boer LC, vd Linde LC. Psychological Fitness With NBC Clothing. Soesterberg, The Netherlands: Netherlands Organization for Applied Scientific Research; 1990.

13. Rauch TM, Banderet LE, Tharion WJ, Munro I, Lussier AR, Shukitt B. Factors Influencing the Sustained Performance

Capabilities of 155mm Howitzer Sections in Simulated Conventional and Chemical Warfare Environments. Natick, Mass: US

Army Research Institute of Environmental Medicine; 1986. Technical Report TII/86.

14. Munro I, Rauch TM, Tharion WJ, Banderet LE, Lussier AR, Shukitt B. Factors Limiting Endurance of Armor, Artillery

and Infantry Units Under Simulated NBC Conditions. Natick, Mass: US Army Research Institute of Environmental Medicine; 1986. Presentation.

15. Kelley JL. The Effects of Chemical Protective Gear, Heat and Cold on Cognitive Performance. Natick, Mass: Army Research

Laboratory; July 1994. ARL-TN-36.

16. Kelly TL. Annotated Bibliography for Gas Mask and Chemical Defense Gear Related Papers. San Diego, Calif: Naval Health

Research Center; 1988. Technical Report 88-7.
Medical Aspects of Chemical and Biological Warfare

396

17. Ryman DH, Kelly TL, Englund CE, Naitoh P, Sinclair M. Psychological and Physiological Effects of Wearing a Gas Mask or

Protective Suit Under Non Exercising Conditions. San Diego, Calif: Naval Health Research Center; 1998.

18. Brooks FR, Ebner DG, Xenakis SN, Balson PM. Psychological reactions during chemical warfare training. Milit Med.

1983;148:232–235.

19. Kobrick JL, Johnson RF, McMenemy DJ. Effects of nerve agent antidote and heat exposure on soldier performance in

the BDU and MOPP-IV ensembles. Milit Med. 1990;155:250–254.

20. Cook JE, Kolka MA, Wenger CB. Chronic pyridostigmine bromide administration: Side effects among soldiers working in a desert environment. Milit Med. 1992;157:159–162.

21. Arad M, Varssano D, Moran D, Arnon R, Vazina A, Epstein Y. Effects of heat-exercise stress, NBC clothing, and

pyridostigmine treatment on psychomotor and subjective measures of performance. Milit Med. 1992;157:210–214.

22. Ritchie EC. Treatment of gas mask phobia. Milit Med. 1992;157(2):104–106.

23. Sandman L. Gas mask phobia. Milit Med. 1992;157:A10–A11. Letter.

24. Deakins DE. Further cases of gas mask phobia. Milit Med. 1993;158:A-4. Letter.
Healthcare and the Chemical Surety Mission

397

Chapter 17

HEALTHCARE AND THE CHEMICAL

SURETY MISSION

ROBERT GUM, D.O., M.P.H.*

INTRODUCTION

CHEMICAL PERSONNEL RELIABILITY PROGRAM

HEALTH SURVEILLANCE FOR CHEMICAL WORKERS

Preplacement Examination

Baseline Data for Future Exposures

Periodic Medical Examinations

Termination Examination

HEAT STRESS

HEALTH EDUCATION FOR CHEMICAL WORKERS

MANAGEMENT OF THE CONTAMINATED PATIENT

CHEMICAL ACCIDENT OR INCIDENT RESPONSE AND ASSISTANCE

DEMILITARIZATION OF CHEMICAL WARFARE AGENTS

SUMMARY

*Lieutenant Colonel, Medical Corps, U.S. Army; Combat Casualty Care Office, U.S. Army Medical Research Institute of Chemical Defense,

Aberdeen Proving Ground, Maryland 21010-5425
Medical Aspects of Chemical and Biological Warfare

398

INTRODUCTION

Medical officers with assignments to U.S. Army

depots or other installations storing chemical warfare agents face a number of unique challenges. Not

only will newly assigned general medical officers

provide patient care to both military and civilian

workers, they will also have a myriad of additional

duties unique to chemical weapons storage sites.

The depot may be physically isolated and a

considerable distance away from the Medical Center (MEDCEN) or Medical Department Activity

(MEDDAC) responsible for providing medical support and consultation. The preventive/occupational

medicine physicians are usually responsible for providing this support and are a source of information

and guidance. Other governmental agencies have

also been identified to assist medical personnel in

acquiring solutions to unfamiliar medical problems

related to chemical exposure (Exhibit 17-1).

Physicians assigned to installations with a chemical surety mission (the term encompasses safety,

security, and reliability) must be able to recognize

and treat a wide variety of chemically related diseases and injuries. Time or assets are seldom available, however, to train a general medical officer in

the unique occupational setting of depot operations.

At the present time, newly assigned general medical officers are required to complete the Medical

Management of Chemical Casualties Course given

at Aberdeen Proving Ground, Maryland. This

course provides the basic concepts needed to recognize the clinical signs and symptoms of a chemical agent exposure and the appropriate therapeutic

interventions used in treating and managing chemical agent casualties. In addition, the Office of The

Surgeon General sponsors the Toxic Chemical Training for Medical Support Personnel Course, which

is conducted at the Chemical Demilitarization Training Facility at the Edgewood Area of Aberdeen

Proving Ground. This training course has incorporated presentations on medical diagnosis and treatment that are essential to managing the healthrelated concerns of the chemical surety mission.

These orientation courses provide essential information to the medical officer beginning his atypical assignment.

As used in this chapter, a chemical agent is defined as a chemical substance intended for use

in military operations to kill, seriously injure, or

incapacitate a person through its physiological effects. Riot control agents, chemical herbicides,

smoke, and flame are not officially defined as

chemical agents.

Although the chemical agents discussed are

unique to the military, the hazards to the workers

are common to many industries. Examples include

pesticide workers who are exposed to acetylcholinesterase inhibitors (the operative mechanism of

nerve agents) and carbonyl chloride (phosgene),

EXHIBIT 17-1

ADVISING AGENCIES FOR TREATMENT OF CHEMICAL AGENT INJURY

The Preventive or Occupational Medicine department

of the supporting Medical Department Activity or

Medical Center

U.S. Army Center for Health Promotion and

Preventive Medicine

ATTN: HSHB-MO

Aberdeen Proving Ground, Maryland 21010-5422

Office of The Surgeon General

Chemical Surety Consultant

ATTN: SFIL-CMS

Aberdeen Proving Ground, Maryland 21010-5401

U.S. Army Medical Research Institute of Chemical

Defense

ATTN: SGRD-UV-ZM

Aberdeen Proving Ground, Maryland 21010-5425

U.S. Army Materiel Command

ATTN: AMCSG

5001 Eisenhower Avenue

Alexandria, Virginia 22333-0001

U.S. Army Depot System Command

ATTN: AMSDS-SU

Chambersburg, Pennsylvania 17201-4170
Healthcare and the Chemical Surety Mission

399

which is used in the production of foams and plastics. Both are transported daily on the nation’s highways. In addition to these chemical threats, many

physical hazards found in the chemical storage depot are shared by other types of operations. The

operation of forklifts, the presence of excessive

noise, heat stress, lifting, and other chemical exposures (in addition to chemical warfare agents) are

only a few of the more common hazards.

The intended use, packaging, and storage of

chemical munitions, however, present different hazards and therefore require different controls. The

system of controls, procedures, and actions that

contribute to the safety, security, and reliability of

chemical agents and their associated weapon systems throughout their life cycle without degrading

operational performance is known as chemical

surety.

An integral part of a physician’s practice is addressing the occupational healthcare needs of the

patients. This responsibility includes identification of

occupational and environmental health risks, treatment of disease and injury, and patient counseling

concerning preventive behavior. This task by itself

is time-consuming and presents demands that, in

part, can be performed by the occupational health

nurse, the industrial hygienist, and other clinic staff

members.

Although industrial hygienists are often not assigned to the health clinic, they are an integral part of

the healthcare team. The industrial hygienist maintains a hazard inventory that contains conventional

hazards as well as a list of chemical agents located at

the installation. He routinely designs primary prevention strategies and frequently oversees hearing conservation, respiratory protection, and occupational

vision programs. The information he provides is

necessary to evaluate the work environment and to

determine the appropriate frequency of periodic medical examinations. Close and frequent coordination

with this individual is imperative for developing a

knowledge of the worksite and the subsequent development of a medical surveillance program.

Just as it is imperative to work closely with industrial hygiene and safety personnel, medical personnel must also work in accord with the command,

supervisors, personnel officers, and the workers.

Maintaining these relationships is frequently difficult, but by identifying and addressing concerns of

both the management and the individual workers,

medical personnel can establish a basis for formulating appropriate preventive medical measures.

CHEMICAL PERSONNEL RELIABILITY PROGRAM

The Chemical Personnel Reliability Program

(CPRP) is a management tool used within the army

to identify chemical surety duty positions and to

manage the persons assigned to these positions. It

also provides a way to assess the reliability and acceptability of personnel being considered for and

assigned to chemical duty positions. Chemical

surety material is defined in Army Regulation 50-

6, Chemical Surety, as “chemical agents and their

associated weapon system, or storage and shipping

containers, that are either adopted or being considered for military use.”1(p43)

The program was established to ensure that the

personnel assigned to positions involving access to

or responsibility for the security of chemical surety

material are emotionally stable, loyal to the United

States, trustworthy, and physically fit to perform

assigned duties. The certifying official is the

commander’s representative for the CPRP and ultimately responsible for its administration. The decision to qualify or disqualify personnel for CPRP

duties is made by the certifying official, with input

from the personnel officer and medical personnel.

The certifying official must also determine the appropriate medical surveillance category for each

worker (see below for a discussion of the four categories) based on the worker’s potential for exposure.

The CPRP requires both preassignment screening and continuing evaluation. This screening and

evaluation is performed when an individual is assigned initial CPRP duties, when a new assignment

is being considered by the certifying official, and

once every 5 years thereafter. The CPRP screening/

evaluation consists of an initial interview with the

certifying official, personnel records screen, medical evaluation, and a final evaluation and briefing

by the certifying official.

During each portion of the screening process,

evaluators look for any evidence of potentially disqualifying factors that may affect personnel reliability or suitability for CPRP duties. The potential disqualifying factors of medical relevance include:

alcohol abuse, drug abuse, inability to wear protective clothing and equipment required by the assigned position, or any significant physical or mental condition that in the judgment of the certifying

official may be prejudicial to the reliable perfor-
Medical Aspects of Chemical and Biological Warfare

400

EXHIBIT 17-2

ADMINISTRATIVE DOCUMENTATION TO SUPPORT A CHEMICAL SURETY INSPECTION

Army Regulations

AR 11-34, 15 Feb 90 The Army Respiratory Protection Program

AR 40-2, 15 Mar 83 Army Medical Treatment Facilities

AR 40-3, 15 Feb 85 Medical, Dental and Veterinary Care

AR 40-5, 15 Oct 90 Preventive Medicine

AR 40-13, 1 Feb 85 Medical Support: Nuclear/Chemical Accidents and Incidents

AR 40-63, 1 Jan 86 Ophthalmic Services

AR 40-66, 20 Jul 92 Medical Record Administration

AR 40-68, 20 Dec 89 Quality Assurance Administration

AR 40-400, 1 Oct 83 Patient Administration

AR 50-6, 12 Nov 86 Chemical Surety

AR 385-10, 23 May 88 Army Safety Program

AR 385-32, 1 May 84 Protective Clothing and Equipment

AR 385-40, 1 Apr 87 Accident Reporting and Records

AR 385-64, 22 May 87 Ammunition and Explosives Safety Standards

AR 600-85, 21 Oct 88 Alcohol and Drug Abuse Prevention and Control Program

HSC-R 10-1, 25 Sep 91 Organization and Functions Policy

HSC-R 40-5, 1 Sep 87 Ambulatory Primary Care

HSC Supplement 1 to AR 40-2, 3 Jun 91 Army Medical Treatment Facilities

HSC Supplement 1 to AR 40-3, 1 May 92 Medical, Dental and Veterinary Care

HSC Supplement 1 to AR 50-6, 10 Feb 88 Chemical Surety

AMC-R 385-131, 9 Oct 87 Safety Regulation for Chemical Agents H, HD, HT, GB, and VX

7th MEDCOM-R 40-8, 24 Apr 87 Medical and Dental Management of the Personnel Reliability

Program

Department of the Army Pamphlets and Technical Bulletins Medical

DA PAM 40-8, 4 Dec 90 Occupational Health Guidelines for the Evaluation and Control of

Occupational Exposures to Nerve Agents GA, GB, GD, and VX

DA PAM 40-173, 30 Aug 91 Occupational Health Guidelines for the Evaluation and Control of

Occupational Exposures to Mustard Agents H, HD, and HT

DA PAM 40-501, 27 Aug 91 Hearing Conservation

DA PAM 50-6, 17 May 9 Chemical Accident or Incident Response and Assistance (CAIRA)

Operations

HSC PAM 40-2, June 83 Occupational Health Program

TB MED 502, 15 Mar 82 Respiratory Protection Program

TB MED 503, 1 Feb 85 Industrial Hygiene Program

TB MED 506, 15 Dec 81 Occupational Vision

TB MED 507, 25 Jul 80 Prevention, Treatment, and Control of Heat Injury

TB MED 509, 24 Dec 86 Spirometry in Occupational Health Surveillance

Field Manuals

FM 3-5, 24 Jun 85 NBC Decontamination

FM 8-285, 28 Feb 90 Treatment of Chemical Agent Casualties and Conventional Military

Chemical Injuries
Healthcare and the Chemical Surety Mission

401

Personnel Documents

• Table of Distribution and Allowances with mission statement for medical treatment facility or activity

• Intraservice Support Agreement between tenant health clinic and the host installation

• Job descriptions with performance standards (or support forms for active duty)

• Scopes of practices

• Individual or categorical credentials for health care practitioners

• Current certificates of licensure for physicians and nurses

• Advanced Trauma Life Support/Advanced Cardiac Life Support certification for physicians (nurses

optional)

• Basic Life Support certification for all personnel with patient care responsibilities

• Certificate of completion of Medical Management of Chemical and Biological Casualties Course for

physicians

Memorandums of Understanding and Mutual Aid Agreements

• With local civilian hospitals or ambulance services

• With the supporting medical center or medical department activity

• Between Health Services Command and Army Materiel Command (or other major army commands, if

appropriate)

Standing Operating Procedures

• Spirometry

• Audiometry

• Vision screening

• Optical insert program for protective masks

• Medical surveillance examination (agent-specific)

• Pregnancy surveillance/reproductive hazards

• Medical screening of Personnel Reliability Program records

• Illness absence monitoring vis-à-vis Personnel Reliability Program records

• Incorporation of air monitoring results into the medical record

• Interface with Alcohol and Drug Abuse Prevention and Control officer

• Ambulance operation and stockage

• Preparation and review of first aid briefings

• Chemical accident and incident response

• Handling of contaminated casualties at the clinic

Medical Directives

• Administration of nerve agent antidotes in the clinic

• Administration of intravenous solutions

• First aid for minor illnesses or injuries

Other

• Medical Management of Chemical Casualties Handbook, September 1994

Available from Chemical Casualty Care Office, U.S. Army Medical Research Institute of Chemical

Defense, Aberdeen Proving Ground, Maryland 21010

AMC: Army Materiel Command; HSC: Health Services Command; MEDCOM: Medical Command; NBC: nuclear, biological, and chemical

Exhibit 17-2 (continued)
Medical Aspects of Chemical and Biological Warfare

402

mance of CPRP duties. Factors that restrict the wearing of protective clothing include: (a) the inability

to obtain a seal with the protective mask, (b) an allergy to protective clothing and equipment, (c) any

medical condition that precludes correct wear and

use of protective clothing, and (d) poor visual acuity that requires the use of glasses unless mask

optical inserts are used. Contact lenses are not

permitted to be worn with the protective mask because they can concentrate agent beneath the lens,

or, more commonly, a foreign body will become

lodged beneath a contact lens, necessitating immediate removal. This cannot be done in a chemical

environment!

Any medical conditions, including the use of any

prescribed medications, that may detract from an

individual’s ability to perform assigned chemical

surety duties must be communicated to the certifying official by oral notification and confirmed in

writing. In addition, the physician must provide a

recommendation as to the suitability of the worker

to continue CPRP duties. Documentation of these

communications should be included on the Standard Form 600. As in all healthcare, documentation

is extremely important and, in this case, subject to

examination during a Chemical Surety Inspection

(CSI). Exhibit 17-2 lists the administrative documentation necessary to support a CSI.

While the medical officer does not decide the

suitability of a candidate for CPRP duties, the certifying official makes a decision based on the medical information and recommendations he provides.

The recommendation should state: (a) no restriction,

(b) restrictions or limitations on duties, (c) temporary disqualification, or (d) permanent disqualification. Potentially disqualifying information is provided in a sealed envelope marked “EXCLUSIVE

FOR” the certifying official. Temporarily disqualified

personnel remain in the CPRP; therefore, their medical records must be treated in the same manner as the

medical records of other personnel in the program.

A chemical-duty position roster lists all individuals assigned to chemical-duty positions in the CPRP

by name, social security number, and job title. This

roster also contains the name of the certifying official, the organization, and the medical surveillance

exposure category of each worker. The roster must

be periodically reviewed to verify that a change in

duty position that requires a change in category is

incorporated into the medical record, and that periodic surveillance is changed to match. Medical

records for personnel in the CPRP are required to

be identified in accordance with Army Regulation

40-66, Medical Record Administration.2

 These medical records are required to be segregated from

records of personnel not in the CPRP.

HEALTH SURVEILLANCE FOR CHEMICAL WORKERS

Medical surveillance is the systematic collection,

analysis, and dissemination of disease data on

groups of workers. It is designed to detect early

signs of work-related illness.3 A chemical work site

medical program should provide the following surveillance: preplacement screening, periodic medical examinations (with follow-up examinations,

when appropriate), and termination examinations.

Additional follow-up examinations are required if

an individual has been exposed or if a potential

exposure has occurred. An efficient medical surveillance program will assist in detecting a relationship

between exposure to a hazard and a disease. In addition, the medical surveillance system will assist

in identifying an occupational disease at an early

stage, when medical intervention can be beneficial.

Since the purpose of medical surveillance is to

identify work-related disease at an early stage, it

may be considered a type of screening. Screening is

the search for a previously unrecognized disease or

pathophysiological condition at a stage when intervention can slow, halt, or reverse the progression

of the disorder.3

 Screening for the CPRP must be

performed by a physician or other qualified medical staff member (physician’s assistant, dentist, or

dental assistant) who has been officially designated

to perform this function.

Additional examinations that are independent of

medical surveillance will be required. These include

fitness evaluations for personal protective equipment and evaluation of a potential worker’s ability

to meet the functional requirements of the job.

Engineering and individual protective measures

are the primary disease prevention methods; medical screening is a tertiary measure. The importance

of engineering and individual protective measures

must continually be stressed. An individual that

shows signs or complains of symptoms of occupationally related illness should be identified as a

possible sentinel case. Not only must the individual

be treated, but the cause must also be investigated

thoroughly by the Installation Medical Authority

(IMA), the industrial hygienist, and the safety personnel. The cause may be related to improper work

practices of the affected individual or it may be related to a failure of engineering devices or personal
Healthcare and the Chemical Surety Mission

403

protective measures. In the latter case, further morbidity can be avoided if identification of the problem is prompt.

The IMA, or contract physician, is responsible for

establishing and supervising the medical surveillance system. Not all individuals working at the

installation, or even in a particular work area, need

to be on the same surveillance program. The type

of work, work area, and required personal protective equipment are factors in determining the type

and frequency of surveillance.

For additional information and direction concerning the development of an occupational medicine program, the installation medical officer is encouraged to seek advice from the regional MEDCEN

or MEDDAC. In addition, the Occupational and

Environmental Medicine Division of the U. S. Army

Center for Health Promotion and Preventive Medicine may be of assistance.

Preplacement Examination

Prior to evaluating a patient history and completing a physical examination, the physician should

acquire an accurate and current job description listing the specific tasks the worker will be required to

accomplish. The type of respiratory protection and

protective clothing required must also be ascertained, because these will affect an individual’s

ability to perform his job.

Not all individuals are required to wear protective clothing all the time; the frequency of use, the

exertion level associated with the personal protective clothing, and the environmental conditions in

which they are worn will have a dramatic influence

on how well an individual will perform. Changing

environmental conditions must be considered; a

worker at Tooele, Utah, may be very comfortable

in the winter in protective clothing and unable

to tolerate the same level of protection in the heat

of the summer. Work–rest cycles become very

important.

Preplacement examination has two major functions: (1) determination of an individual’s fitness

for duty, including the ability to work while wearing protective equipment, and (2) provision of

baseline medical surveillance for comparison with

future medical data.4

 The chemical agent worker

must be evaluated to ensure that he is not predisposed to physical, mental, or emotional impairment,

which may result in an increased vulnerability to

chemical warfare agent exposure. This examination is performed at no cost to the applicant. Abnormalities identified during the course of the

preplacement examination, however, need to be

followed up by the applicant, at his expense, with

a private physician.

An occupational and medical history questionnaire is the first step in acquiring necessary information from the prospective worker. A thorough

review, by the medical officer, is required to identify past illnesses and diseases that may prevent the

individual from satisfactory performance of job requirements. It is particularly important to inquire

about atopic dermatitis, pulmonary disease, and

cardiovascular disease.

A review of symptoms will enable the medical

officer to evaluate the ability of an individual to

work in protective ensemble. Questions concerning

shortness of breath or labored breathing on exertion, asthma, other respiratory symptoms, chest

pain, high blood pressure, and heat intolerance

will provide helpful information. Questions about

allergic reactions to rubber products and cold-induced bronchospasm should be asked and a brief

psychiatric history directed toward the individual’s

ability to be encapsulated in personal protective

equipment should be taken. Questions about panic

attacks, syncopal episodes, or hyperventilation will

also offer valuable information.

For those who are not clearly disqualified by their

medical history and physical examination, it is necessary for the medical officer to determine their

ability to function while wearing respiratory protective equipment. This can be done by either pulmonary function testing or a “use” test. The former

is effective, although costly; the latter provides necessary information and can be performed safely by

the majority of applicants. Caution must be exercised, however, in requiring an individual to perform a use test. A worker with a questionable history (eg, angina or previous myocardial infarction)

should not be required to complete a use test prior

to pulmonary function testing. Input from the industrial hygienists concerning the required tasks

will produce more useful results than a generic use

test. The outcome of either test must be documented

in the individual’s medical record.

Contact lenses must be replaced by optical inserts whenever a full-face respirator is worn. Personnel who require glasses must also have optical

inserts. Permitting a worker to begin work in a

chemical environment without appropriate optical

inserts, or while wearing contact lenses, places both

the worker and the coworkers at an unacceptable

risk for accidents.

The physical examination should be comprehensive and focus on the skin, cardiovascular, pulmo-
Medical Aspects of Chemical and Biological Warfare

404

nary, and musculoskeletal systems. Obesity, lack of

physical strength, and poor muscle tone are indicators of increased susceptibility to heat injury, a condition which will be amplified by working in chemical protective clothing. Factors such as facial hair,

scarring, dentures, and arthritic hands or fingers can

affect a worker’s ability to wear or don a respirator

and protective clothing.

Baseline Data for Future Exposures

Baseline data acquired during the preplacement

screening can be used following a subsequent exposure event to determine the extent of the exposure. It can also be used to verify the engineering

controls in effect. Additionally, baseline data may

be used to determine if the worker has been adversely affected by the exposures. Red blood cell

cholinesterase (RBC-ChE) baseline levels are essential for workers assigned in areas in which nerve

agent munitions are stored. Workers are categorized

by the area they are assigned to and the frequency

with which they are in a chemical environment. The

frequency of follow-up examinations are determined by the category in which prospective workers are placed. These categories are discussed in the

following section.

Periodic Medical Examinations

Periodic medical examinations should be developed and used in conjunction with preplacement

screening examinations.4

 Comparing the data obtained through periodic monitoring with the

preplacement baseline data is essential for identifying early signs of occupationally induced diseases. The primary purpose of the periodic medical examination is to identify conditions for which

early interventions can be initiated, so that progression of the adverse effects can be curtailed prior to

significant injury or disease.

The interval medical history and physical should

focus on changes in health status, illness, and possible work-related signs and symptoms. The examining physician must be aware of the work environment and potentially hazardous exposures in

order to identify work-related conditions or disease.

Unlike patients seen in a private office, chemical

surety workers who show a change in health status

in the periodic evaluation make an evaluation of

the work site necessary. Additional workers may

require examination on the basis of conditions identified. At a minimum, coordination must be made

with industrial hygiene personnel to determine if

there has been a change in the work environment

that could be causally related.

The frequency and extent of the periodic medical examination will be determined by the toxicity

of the potential or actual exposures, frequency and

duration of contact, and the information obtained

in the preplacement history and physical examination. The data obtained from these periodic examinations can serve as a guide to the future frequency

of physical examinations or tests. Data consistently

within acceptable limits for several months may

indicate that the frequency can be safely decreased,

provided that the work situation remains constant.

Biological monitoring for nerve agent exposure

consists of RBC-ChE measurement. Determining

who will be monitored, and the frequency, is the

responsibility of the IMA. The certifying official is

responsible for supplying information concerning

the duties the worker performs; an accurate job

description is essential. The surety officer and the

safety officer may provide advisory input to the

monitoring strategy for nerve agent exposures.

In accordance with Department of the Army

Pamphlet 40-8, Occupational Health Guidelines for the

Evaluation and Control of Occupational Exposure to

Nerve Agents GA, GB, GD, and VX, the following four

categories of personnel are required to have their

RBC-ChE measured5

:

1. Category A: personnel with a high risk of

potential exposure due to the nature of the

agent operations being conducted. Examples of such operations might include

(but are not limited to) storage monitoring

inspections of M55 rockets, periodic inspections, toxic chemical munitions maintenance operations that involve movement

of munitions from storage locations, work

in known contaminated environments, and

first-entry monitoring. Category A personnel may be routinely required to work for

prolonged periods in areas with high levels of nerve agents where the use of either

of the following are required:

• toxicological agent protective (TAP) ensembles, or

• protective ensembles with a self-contained or supplied-air breathing apparatus.

2. Category B: personnel with both

• a low risk or infrequent potential exposure to nerve agents in routine industrial,

laboratory, or security operations (examples of such operations might include
Healthcare and the Chemical Surety Mission

405

but are not limited to daily site security

checks and accident/incident response

by initial response force members), and

• job requirements involving the prolonged wearing of protective ensembles

during training and emergency responses.

3. Category C: personnel with minimal probability of exposure to nerve agents, even

under accident conditions, but whose activities may place them in close proximity

to agent areas.

4. Category D: transient visitors to agent areas where a potential for exposure exists

and who are not included in the medical

surveillance program for nerve agents at

the visited installation.

An individual in category A must have a monthly

determination of the RBC-ChE level; an individual

in category B will have an annual RBC-ChE determination. Inaccurate categorization of workers will

either fail to provide adequate surveillance or cause

exorbitant cost and effort without benefits.

Termination Examination

At the termination of employment or at the termination of duty in a chemical surety position, a

worker should have a medical examination. Unless

otherwise specified by a local regulation, this examination may be done within 30 days before or

after termination of employment. In the event the

worker is exposed after his termination examination, it will be necessary to evaluate for and thoroughly document that specific exposure. In most

cases, exposure is not expected to occur, and completing the termination examination within the 30

days before the worker departs is advisable. Medical personnel must be aware that although it is in

the worker’s best interest to have a termination examination, it can be difficult for him return to his

former place of employment to complete a medical

examination once employment is terminated.

HEAT STRESS

Heat stress is a constant and potentially severe

health threat to the worker in toxicological protective clothing. The combination of exposure to solar

radiant energy or enclosed areas with high temperatures, metabolic heat production, and the use of

impermeable clothing (which prevents evaporative

cooling) place the chemical worker at high risk for

heat injury.

Encapsulating uniforms increase the heat strain

associated with most environments and work rates

by creating a microenvironment of small volume

around the worker. The impermeability to vapor of

the suit (which is, after all, the characteristic that

makes it protective) creates high local humidity,

restricting evaporative cooling and conductive/

convection cooling. In effect, the suit creates an environment at the body surface hotter and wetter

under almost any circumstances than the environment outside the suit. Moderating the heat strain

associated with an encapsulating ensemble is accomplished in the following ways:

• microclimate cooling: direct removal of

heat, water vapor, or both from the worker’s microenvironment;

• heat sinks in the suit: ice vests;

• increasing the temperature gradient across

the suit: shielding workers from radiant

heat sources, cooling the work space or, in

dry environments, wetting the surface of

the suit; and

• work–rest cycles to permit cooling and rehydration.

Heat-induced occupational injury or illness occurs when the total heat load from the environment

and metabolism exceeds the cooling ability of the

body. The resultant inability to maintain normal

body temperature results in heat strain (the body’s

responses to total heat stress).6

The reduction of adverse health effects can be

accomplished by the proper application of engineering and work-practice controls, worker training and

acclimatization, measurements and assessment of

heat stress, medical supervision, and proper use of

heat-protective clothing and equipment.6

 Worker

training and adequate supervision are basic requirements that need constant reinforcement. The occurrence of heat-induced illness or injury is an indication that (a) the worker has engaged in a careless

act that should have been avoided and detected by

adequate training and supervision, (b) the individual’s medical status has changed and requires

further or more frequent evaluation, or (c) supervisory enforcement of work–rest cycles or of adequate

rehydration is lacking. In all cases, the healthcare

provider must investigate the cause. If the individual’s health status has changed, further medi-
Medical Aspects of Chemical and Biological Warfare

406

cal evaluation is indicated. The worker may require

temporary duties commensurate with his present

health status or a permanent change of duties if his

medical condition warrants. Should the injury appear to be a result of carelessness or lack of attention to changing environmental conditions, further

training is indicated. Eliciting the worker’s support

may be necessary to acquire the appropriate support of intermediate supervisors.

Numerous textbooks and other sources discuss

thermoregulation and physiological responses to

heat; healthcare providers may benefit from a review of these subjects. This chapter will address the

evaluation of heat stress and preventive measures.

The preplacement physical examination is designed for workers who have not been employed

in areas exposed to heat extremes. It should be assumed that such individuals are not acclimatized

to work in hot climates. The physician should obtain the following information6

:

• A medical history that addresses the cardiovascular, respiratory, neurological, renal,

hematological, gastrointestinal, and reproductive systems and includes information

on specific dermatological, endocrine, connective tissue, and metabolic conditions

that might affect heat acclimatization or the

ability to eliminate heat.

• A complete occupational history, including

years of work in each job, the physical and

chemical hazards encountered, the physical

demands of these jobs, intensity and duration of heat exposure, and nonoccupational

exposures to heat and strenuous activities.

The history should identify episodes of

heat-related disorders and evidence of

successful adaptation to work in heat environments as part of previous jobs or in nonoccupational activities.

• A list of all prescribed and over-the-counter

medications used by the worker. In particular, the physician should consider the possible impact of medications that potentially

can affect cardiac output, electrolyte balance, renal function, sweating capacity, or

autonomic nervous system function. Examples of such medications include diuretics, antihypertensive drugs, sedatives,

antispasmodics, anticoagulants, psychotropic medications, anticholinergics, and

drugs that alter the thirst (haloperidol) or

sweating mechanism (phenothiazines, antihistamines, and anticholinergics).

• Information about personal habits, including the use of alcohol and other social

drugs.

• Data on height, weight, gender, and age.

The direct evaluation of the worker should include the following6

:

• Physical examination, with special attention to the skin and cardiovascular, respiratory, musculoskeletal, and nervous systems.

• Clinical chemistry values needed for clinical

assessment, such as fasting blood glucose,

blood urea nitrogen, serum creatinine, serum electrolytes (sodium, potassium, chloride, bicarbonate), hemoglobin, and urinary

sugar and protein.

• Blood pressure evaluation.

• Assessment of the ability of the worker to

understand the health and safety hazards

of the job, understand the required preventive measures, communicate with fellow

workers, and have mobility and orientation

capacities to respond properly to emergency situations.

A more detailed medical evaluation may be required. Communication between the physician performing the preplacement evaluation and the

worker’s private physician may be appropriate and

is encouraged.

Follow-up evaluations may be warranted during

the acclimatization period for selected workers. The

phenomenon of heat acclimatization is well established, but for an individual worker, it can be documented only by demonstrating that after completion of an acclimatization regimen, the worker can

work without excessive physiological heat strain in

an environment that an unacclimatized worker

could not withstand. The IMA needs to be intimately involved in developing the acclimatization

program for the installation.

Annual or periodic examinations should monitor individuals for changes in health that might

affect heat tolerance and for evidence suggesting

failure to maintain a safe working environment.

Education of the workers and supervisors, however,

is the single most important preventive measure in

avoiding heat casualties.

Personnel required to wear toxic-agent protective clothing are also at high risk for dehydration,

which is a contributing factor for developing heat

injury. The thirst mechanism is not adequate to
Healthcare and the Chemical Surety Mission

407

stimulate a worker to consume as much as a liter of

water per hour that may be lost in sweat. If weight

loss exceeds 1.5% to 2.0% of body weight, heart rate

and body temperature increase, and work capacity

(physical and psychological) decreases.7 Workers

should be required to consume at least 8 oz of cool

water at each break period; for moderate work in

greater than 80°F wet bulb globe temperature

(WBGT), the average male should plan on 1 qt of

fluid per hour; more water may be required depending on the ambient temperature and humidity.

The average diet in the United States provides

adequate salt intake for the acclimatized worker.

The unacclimatized worker may excrete large

amounts of salt: another reason that he will need

close monitoring while adjusting to the evaluated

temperatures and decreased evaporative cooling.

Individuals on medications that further deplete

sodium (ie, diuretics) will need even closer monitoring and medical follow-up. The judicious use of

sodium replacement may be required during the

acclimatization period.

HEALTH EDUCATION FOR CHEMICAL WORKERS

All personnel entering an area where chemical

munitions are stored must recognize and understand the potential hazards to their health and

safety associated with chemical agents. Workers

must be required to recognize signs and symptoms

of exposure to these agents. They must be totally

familiar with the procedures to assist a coworker

and to summon assistance in the event of an accident. Visitors must be briefed on basic procedures

that will permit them to complete their visit safely.

Visitors must also be evaluated to ensure they can

wear a mask appropriately should escape become

necessary.

The objectives of training programs for chemical

workers are to provide awareness of the potential

hazards they may encounter and to provide the

knowledge and skills necessary to perform the work

with minimal risk. Additional requirements are to

make workers aware of the purpose and limitations

of safety equipment and to ensure that they can safely

avoid or escape during an emergency situation.

Although the IMA may be requested to present

a discussion of medical topics, he is responsible for

reviewing the training program’s lesson plans and

the SOPs to ensure the correctness and comprehensiveness of the medical aspects. The level of training should be commensurate with the workers’ job

function and responsibilities, which will necessitate

a modification of training material and techniques

to accommodate the audience. The training programs should consist of both classroom didactic

instruction and hands-on practice, when feasible.

Although this chapter primarily addresses the

principles of occupational medicine as they apply

to working in a chemical environment, it should be

recognized that other workplace hazards exist.

Training programs may focus on chemical warfare

agents, but they should also address any additional

physical and chemical hazards. A number of these

hazards may be obvious and directly related to the

primary mission; for example, the heat stress associated with wearing chemical protective clothing.

Additionally, certain occupational medical hazards

are common to all industrial operations (eg, lowback strain), which may produce excessive absenteeism and disability. By working closely with management, medical officers can minimize the impact

of these additional safety and industrial hazards.

Special consideration should be given to training workers in the recognition of signs of exposure

in a coworker wearing chemical agent protective

clothing. Describing fasciculations and localized

diaphoresis will be of limited value because the

coworker will be wearing full protective clothing.

Alerting the workers to watch for lack of coordination, inappropriate activity, and pinpoint pupils

would be of far greater value. Moreover, discussions

of the early symptomatology will give the workers

the capability of recognizing chemical agent exposure early enough to permit evaluation prior to the

onset of serious injury. These signs and symptoms

are discussed at length in other chapters of this text.

Each employee should be thoroughly familiar

with the requirements for providing effective selfaid and buddy-aid. The first rule of protection—to

protect oneself from injury—must be emphasized.

There are numerous case reports of individuals or

groups attempting to assist someone exposed to

toxic compounds only themselves to become casualties. Workers will require training in proper lifts

and carries, both with and without a litter.

All workers should know the procedure for requesting medical assistance. Many installations

have one “hotline” for medical, technical escort

unit, and security support. Workers should be

aware of any set format for reporting emergencies

that will expedite the report and response time.

Once assistance has arrived, the support personnel

should be given accurate and complete information

about the accident or incident. Teaching the worker
Medical Aspects of Chemical and Biological Warfare

408

a logical format in which to present this information is extremely helpful. Their reports should include the nature of the accident or incident (ie, the

agent involved and number of casualties), what

has been done for the victims to that point (eg, the

number of MARK I injectors administered), and

whether personnel are missing. Support personnel

can ask for additional information as the situation

progresses.

Decontamination procedures must be well

known to all chemical workers. The training class

should present the M258 and M291 kits and their

contents and make clear the use of household bleach

in the decontamination process. Current doctrine

specifies that in a tactical environment 0.5% bleach

be used for skin decontamination. In depot operations, however, 5% bleach is used. This stronger

concentration may be used because workers exposed at the depot will be decontaminated and then

thoroughly rinsed in a fixed facility in a relatively

short time. Soldiers in the field, however, may be

decontaminated several times and not be rinsed

thoroughly for several hours. Repeated applications

of 5% bleach without a complete and thorough rinse

will cause skin injury.

The bleach used for decontamination should be

stored in airtight containers and dated. Bleach deteriorates and may not be as effective after several

months.

Decontamination includes removal of contaminated clothing and the decontamination of skin using the bleach solution. Care must be used to avoid

putting bleach in open wounds and the eyes. These

areas must be rinsed with copious quantities of

water. The bleach requires a contact time of approximately 15 minutes to be fully effective. Small areas

can be decontaminated by removing the contaminated section of clothing and following the directions on the M258 or M291 kits. Medical evaluation,

treatment, or both is always required.

Several additional decontaminants are used at

the depot. They are generally very caustic and are

not to be used on the skin. They include super tropical bleach (STB), high-test hypochlorite (HTH), 10%

sodium carbonate, and 10% sodium hypochlorite.

Healthcare personnel must be aware what decontaminants are stocked and what they are used for

in case they are used inappropriately and a worker

develops a medical problem. The industrial hygienist should be able to furnish this information.

Outergarments should never leave the installation, even for laundering. If the clothing is contaminated, it will pose a chemical agent exposure hazard to the launderer. The use of disposable outer

garments or decontamination prior to washing will

generally solve this problem; however, a change in

contractor or new personnel involved in the transportation or laundering process must be addressed.

MANAGEMENT OF THE CONTAMINATED PATIENT

Clinics located at depots with a chemical surety

mission should have an area designated for the decontamination of exposed patients. Generally the

treatment area for these patients is separate from

the normal patient treatment areas. These facilities

are rarely used for an actual chemically contaminated patient, however. A conscious effort must be

made to keep these rooms at 100% operational capability. To maintain this capability, the medical

staff must develop standing operating procedures

(SOPs) that are comprehensive and detailed.

The planning phase is essential to a successful

operation, but the plan is useless if the personnel

involved are not totally familiar with their responsibilities. Planning is an ongoing process that must

be kept current in an ever-changing world. If the

planning and updating process stops, the resulting

document loses its usefulness. Unfortunately, many

SOPs are written, only to be placed in a file for

months without being reviewed by assigned personnel, only a few of whom may have been involved

in initially producing the document. A routinely

scheduled review and update of the clinic’s SOPs

not only keeps the document current but, more

importantly, requires that the healthcare personnel

think about the plan and refamiliarize themselves

with the operating procedures.

In addition to producing viable internal SOPs,

external coordination dictates Memorandums of

Agreement (MOAs) with local agencies. The nature

of the chemical agents being stored or demilitarized

requires that preparations be made for receiving

and treating casualties beyond the capability of the

installation clinic. While stabilization may be done

at the clinic, hospitalization will require outside

facilities. The specter of chemical casualties may

make local hospitals needlessly reluctant to accept

chemical casualties even after decontamination.

Existing MOAs will make the transfer much

smoother and will stimulate the local hospital to

do preaccident planning and training themselves.

Much of the coordination required for outside

agreements will be handled through command

channels. The medical officer and medical admin-
Healthcare and the Chemical Surety Mission

409

istrator can accomplish much, however, by interpersonal contact with the medical facilities and the

emergency medical personnel who will respond to an

installation emergency. Coordination and interaction

between civilian and military medical resources

should be a continuous process. The IMA must take

the lead to ensure the limited post resources are adequately augmented by off-post medical facilities.

Staffing and treatment capabilities of off-site

emergency medical facilities should be verified to

ensure appropriate resources are available. Training of civilian resources is coordinated through the

Chemical Stockpile Emergency Preparedness Program (CSEPP); the Program Director for CSEPP is

located at the Edgewood Area of Aberdeen Proving Ground, Maryland. Unfortunately, the many

demands placed on the IMA limits the amount of

time he can devote to coordinating with local

healthcare providers and administrators. Communicating with local supporting agencies, however, will

be extremely valuable should an incident occur.

The physician assigned as the IMA should have

attended the Toxic Agent Training Course and the

Medical Management of Chemical Casualties

Course prior to reporting for duty. Enlisted personnel and civilian healthcare providers will require

training by the medical officer. Evacuation plans,

coordination with off-post civilian medical facilities, MOAs, and periodic inventories (with restocking of supplies and equipment) are the responsibility

of the IMA. As individual training continues, collective training in the form of drills should become

a routine part of the clinic schedule. Only the successful completion of all of the above will ensure

readiness for proper management of a chemically

contaminated patient.

CHEMICAL ACCIDENT OR INCIDENT RESPONSE AND ASSISTANCE

Each installation with a chemical surety mission

is required to develop detailed plans and procedures to be implemented by the emergency actions

community in response to a Chemical (Surety Material) Accident or Incident (CAI). Health services

support during Chemical Accident or Incident Response and Assistance (CAIRA) operations involves

personnel with a wide range of medical expertise

who will be involved in providing emergency care.

A decontamination area must be a part of the

early medical care to limit the degree of exposure

to the casualty. Emergency medical care will, initially, be provided by nonmedical workers who are

responsible for removing the casualties from the site

of injury through a personnel decontamination station and to the waiting medical team. Further evacuation may be required for one or more victims, either to the Installation Medical Facility (IMF) or to

an off-post medical treatment facility (MTF). Civilian medical facilities may be required to receive the

injured personnel, and they also will need their own

supplies, equipment, and training appropriate for

treating these casualties.

The fundamental pathophysiological threats to

life (namely, airway compromise, breathing difficulties, and circulatory derangement [the ABCs])

are the same for chemical casualties as they are for

casualties of any other type. Because these are

chemical agent casualties, all personnel involved

must be provided additional training. The IMA,

whether military or civilian, must be very proactive in developing medical teams, medical training

programs, and strong community relations.

A list of chemical agents, the number of personnel involved, the location of the work area, a summary of work procedures, and the duration of the

operation is necessary to develop appropriate emergency medical plans. This information is available

through the installation commander or the certifying

official. In addition, the most probable event (MPE)

and maximum credible event (MCE) must be defined

to determine the anticipated casualty loads in either

situation. An MPE is the worst potential event likely

to occur during routine handling, storage, maintenance, or demilitarization operations that results in

the release of agent and exposure of personnel. An

MCE is the worst single event that could reasonably occur at any time, with maximal release of agent

from munitions, bulk container, or work process as a

result of an accidental occurrence. The Office of The

Surgeon General will develop guidance for use by

installations in estimating the chemical agent casualties expected from an MPE or an MCE.

For planning purposes, medical staffing requirements are based on the MPE for the installation.

Because an MCE is expected to exceed the capabilities of the Installation Medical Facility, medical contingency plans and coordination with local, state,

and federal emergency medical authorities is essential. The IMA is responsible for developing and periodically updating MOAs with local civilian hospitals and supporting military MTFs to augment the

installation medical treatment capabilities.

The IMA must actively participate in training

both medical and nonmedical personnel. Nonmedical workers require training in self-aid and buddy
Medical Aspects of Chemical and Biological Warfare

410

aid as a minimum. The Installation Response Force

(IRF) is responsible for providing the immediate

safety, security, rescue, and control at the chemical

accident or incident site to save lives and reduce

exposure to hazards. The IMA must approve the

training program for both workers and the IRF and

must review their lesson plans for accuracy and

completeness. The essentials of this training include

recognizing signs and symptoms of agent exposure,

first aid, self-aid, buddy aid, individual protection,

personnel decontamination (including decontamination of a litter patient), and evacuation of casualties. Active participation in the training by the IMA

will ensure that the personnel understand their role,

and that the medical care given by people who are

not healthcare professionals meets acceptable standards.

Healthcare providers, as well as local officials,

are concerned about the spread of contamination.

The procedure for decontamination of litter patients

can be found in Appendix E of U.S. Army Field

Manual 8-10-4, Medical Platoon Leaders’ Handbook:

Tactics, Techniques and Procedures.

8

 The IRF will decontaminate patients and pass them across a hotline

to the Medical Response Team (MRT). At that point

the casualty should be completely clean. Civilian

officials may require a casualty “certified clean”

before moving the patient off the military installation. This requirement may be avoided through

adequate coordination and training prior to an exercise or an actual chemical accident or incident.

Building confidence in the civilian sector through

education and communication is essential in providing a rapid and adequate medical response.

Chemical Accident or Incident Response and

Assistance encompasses actions taken to save life

and preserve health and safety. This support involves a continuum of medical care, ranging from

self-aid/buddy-aid in the field to treatment at a tertiary care facility. Due to the nature of some chemical warfare agents, proper care and adequate decontamination must be provided early in the care

to avoid serious injury or death. The levels of medical care include the following:

• Level I: composed of IRF nonmedical installation personnel. The local commander appoints the IRF members and ensures they

are provided initial and ongoing training

as described in Department of the Army

Pamphlet 50-6, Chemical Accident or Incident

Response and Assistance (CAIRA) Operations.

9

The Office of The Surgeon General and the

U.S. Army Medical Department Center and

School are developing a list of essential

medical tasks for this group. Additional

tasks may be added at the discretion of the

IMA or the local commander.

• Level II: the MRT, composed of on-post

medical personnel. The leader of the MRT

is a physician and is responsible for training the team in triage, treatment, stabilization, and evacuation of casualties from the

accident site to the appropriate MTF. The

MRT must have adequate personnel, supplies, and equipment to provide healthcare

to casualties generated by a MPE. The specific tasks for the MRT leader and members

are specified in DA PAM 50-6, Tables 6-3

and 6-4.9 One member of the MRT should

be issued toxicological agent protective

gear so he may cross the hotline and provide emergency medical care to casualties

as required. The remaining members of the

MRT should be available on the clean side

of the hotline to perform triage and provide

immediate care.

• Level III: the Medical Augmentation Team

(MAT), provided by the MEDDAC or

MEDCEN to an installation having chemical surety missions. This team must have

the capability to augment the MRT in the

event of an MCE. The MAT leader’s responsibilities are also delineated in DA PAM 50-

6, Table 6-5.9

• Level IV: The Chemical Casualty Site Team

(CCST) is provided by the U.S. Army Medical Research Institute of Chemical Defense

(USAMRICD) located at Aberdeen Proving

Ground, Maryland. This team provides

clinical consultation and subject-matter experts in chemical casualty care. In addition,

a veterinarian may be a designated member of this team. During the initial phases

of an exercise, concern is primarily for casualties. In previous service response force

exercises, however, many questions have

also been asked about the safety of livestock, pets, and wildlife. The veterinarian

has proven to be an extremely valuable source

of information and an asset to this team.

The installation commander looks initially to the

IMA for medical support and advice. If the chemical accident or incident exceeds the capability of the

installation, a Service Response Force (SRF) is provided to assume control of the situation. The SRF

surgeon assumes operational control of the MRT,
Healthcare and the Chemical Surety Mission

411

the MAT, and the Medical Chemical Advisory Team

(MCAT) at the accident site.

MOAs are required with local MTFs, local emergency medical services, ambulance services, and

regional or state emergency medical services officials. The MOAs and frequent coordination with

these agencies are necessary to ensure that appropriate off-post resources will be available for support during a chemical accident or incident.

Because of the unique nature of chemical agents,

training, as defined in an MOA, must be provided

to the supporting civilian agencies. A proactive

stance in giving and sustaining education will enhance the relationship with the civilian community.

Many civilian medical personnel and officials are

very supportive and willing to play an active role

in Chemical Accident or Incident Response and

Assistance exercises. Assisting them in training

and providing them with appropriate supplies and

equipment will go far in enlisting their future support and allaying some of their fears of the unknown.

DEMILITARIZATION OF CHEMICAL WARFARE AGENTS

The U.S has produced and stored a stockpile of

chemical warfare agents since World War I. These

projectiles, rockets, mines, and ton containers have

been maintained at eight depots in eight states:

Aberdeen Proving Ground, Maryland; Anniston

Army Depot, Alabama; Blue Grass Army Depot, Kentucky; Newport Army Ammunition Plant, Indiana;

Pine Bluff Arsenal, Arkansas; Pueblo Army Depot

Activity, Colorado; Tooele Army Depot, Utah; and

Umatilla Army Depot, Oregon. In addition, two additional states could possibly be affected should there

be a large release of agents: Washington and Illinois.

The majority of chemical agents are stored in bulk

containers that do not have explosive components.

Leaking chemical agents have not presented a

health threat to areas surrounding these depots.

However, continuing to store the aging munitions

may present a risk of chemical agent exposure. The

M55 rocket is the most hazardous of the chemical

munitions. The rocket contains propellant and a stabilizer that could degrade and form reaction products that might cause ignition.

In 1985, the U.S. Congress initiated a program to

dispose of our entire stockpile of lethal chemical

agents. There are multiple reasons for destroying

these chemical warfare agents:

• Congress has required that the U.S. Army

destroy the chemical stockpile by the year

2004,

• ratification of a multilateral chemical arms

control treaty requires the destruction of the

weapons,

• the need for the stockpile no longer exists, and

• the stockpile is slowly deteriorating with

age; although the risk of continued storage

is small, it will increase with time.

The prototype destruction plant for lethal agents

was erected on Johnston Island: the Johnston Atoll

Chemical Agent Destruction System (JACADS). A

second destruction facility was built at Tooele Army

Depot, Tooele, Utah, as a pilot plant for other facilities to be located at the remaining depots.

Incineration has been determined to be the process that will safely treat all components of the

weapons. The destruction facilities were built with

back-up systems to prevent environmental release

of agent. The U.S. Public Health Service reviews

plans and monitors operations of these chemical

destruction plants. The appropriate state environmental authorities must issue permits prior to beginning the incineration process.

Despite the extensive precautions in building the

destruction plants, the U.S. Army and the Federal

Emergency Management Agency (FEMA) are working with local emergency responders to enhance

their capabilities. Training in the medical management of chemical agent casualties specific to the

installation is provided frequently to first responders

and emergency management officials through CSEPP.

Critics of the army’s high-temperature incineration on Johnston Island have found the method to

be very controversial and undesirable. The disagreement among scientific experts concerning the

incineration process and the emotional concerns of

populations surrounding the eight U.S. depots have

created numerous debates over the chemical agent

destruction program. This controversy has presented the army with numerous challenges in risk

communication and preparation to complete the

destruction mission.

Extensive security and safety measures have been

adopted to ensure that an accident or incident involving the chemical warfare agents and chemical

surety material is avoided. The containers are typically stored in an igloo (ie, a storage building topped

with 3–4 ft of earth and concrete) and transported

in large overpack containers (ie, a container within a

heavy container) designed to withstand an explosion.
Medical Aspects of Chemical and Biological Warfare

412

The agent is destroyed at 2,700°F. Metal parts are

also incinerated. Exhaust gases are passed through

extensive pollution-control systems. Munitions are

destroyed in small quantities in thick-walled rooms

that are designed to withstand detonation. The likelihood of an accident that results in exposure of

surrounding off-post areas is extremely remote in

day-to-day operations.

The solid residue remaining from ash, fiberglass,

and wooden dunnage are evaluated for contamination and are transported to approved landfills.

Brine (a by-product waste) is packaged and also sent

to approved landfills. There is no water discharge

resulting from the incineration process.

Stack effluent must meet all requirements of the

Clean Air Act,10 especially the amendments that

were passed in 1970,11 1977,12 and 199013; (these last

three versions were codified in the United States

Code in 199014). In addition to carbon dioxide and

oxygen, small quantities of sulfur dioxide, oxides

of nitrogen, carbon monoxide, and particulate are

discharged. Special precautions have been taken to

reduce and eliminate the formation of furans and

dioxans from the incineration process. Discharges

from the stack are continuously monitored to ensure that the requirements of the Clean Air Act are

met. Even though the possibility of an event leading to the contamination of an area surrounding a

community is remote, extensive planning and

preparation have been accomplished. The U.S.

Army and FEMA have jointly enhanced the emergency preparedness of these communities.

SUMMARY

The unique challenges of chemical warfare

agents, aging munitions, and protecting worker

health in a chemical environment can prove a rewarding experience for healthcare providers. The

personnel reliability program places numerous

safety and administrative demands that require that

the physician acquire knowledge in occupational

medicine that many physicians never experience.

Unlike many clinicians, the IMA is thrust into an

environment that requires interaction with multiple

professional groups. Coordination with industrial

hygienists and safety officers will result in an awareness of the workplace and the work conditions that

is seldom appreciated by other physicians.

Designing a medical surveillance program

to prevent illness and injury is seldom attempted

by most physicians in clinical practice. This

secondary preventive measure will augment and reinforce the primary preventive efforts of safety

and industrial hygiene measures. Appropriate surveillance requires a thorough knowledge of the

chemical agents. Requisite information is available through mandatory courses and on-the-job

training.

The chemical demilitarization process places

additional demands on U.S. Army Medical Department personnel. In addition to the many responsibilities inherent to the chemical surety mission, the

IMA may be challenged with risk communication.

Many of the civilians living near depot storage facilities do not approve of the plan to incinerate

the 30,000 tons of agents stored at these sites.

Healthcare providers can play an important role in

providing information and building confidence in

the U.S. Army’s ability to safely destroy these agents

through incineration.

REFERENCES

1. US Department of the Army. Chemical Surety. Washington, DC: DA; 1986. Army Regulation 50-6.

2. US Department of the Army. Medical Record Administration. Washington DC: DA; 1992. Army Regulation 40-66.

3. McCunney RJ. Handbook of Occupational Medicine. Boston, Mass: Little Brown; 1988.

4. National Institute of Occupational Safety and Health. Occupational Safety and Health Guidance Manual for Hazardous Waste Site Activities. Cincinnati, Ohio: US Department of Health and Human Services, Public Health

Service; 1985.

5. US Department of the Army. Occupational Health Guidelines for the Evaluation and Control of Occupational Exposure to Nerve Agents GA, GB, GD, and VX. Washington, DC: HQ, DA; 1990. DA Pamphlet 40-8.

6. National Institute of Occupational Safety and Health. Occupational Exposure to Hot Environments. Revised Criteria. Cincinnati, Ohio: US Department of Health and Human Services; 1986.
Healthcare and the Chemical Surety Mission

413

7. Greenleaf JE, Harrison MH. Water and electrolytes. In: Layman DK, ed. Exercise, Nutrition and Health. Washington, DC: American Chemical Society; 1986: 107–123.

8. US Department of the Army. Medical Platoon Leaders’ Handbook: Tactics, Techniques and Procedures. Washington,

DC: November 1990. Field Manual 8-10-4.

9. US Department of the Army. Chemical Accident or Incident Response and Assistance (CAIRA) Operations. Washington, DC: HQ, DA; May 1991. DA Pamphlet 50-6.

10. Clean Air Act of 1963. Pub L No. 88-206.

11. Clean Air Act of 1970. Pub L No. 91-604.

12. Clean Air Act of 1977. Pub L No. 95-95.

13. Clean Air Act of 1990. Pub L No. 101-549.

14. Clean Air Act. 42 USC § 7401–7671 (1990).
Historical Overview of Biological Warfare

415

*Colonel, Medical Corps, U.S. Army; Chief, Operational Medicine Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort

Detrick, Frederick, Maryland 21702-5011

†Colonel, Medical Corps, U.S. Army; Commander, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington,

D. C. 20307-5100

Chapter 18

HISTORICAL OVERVIEW OF

BIOLOGICAL WARFARE

EDWARD M. EITZEN, JR., M.D., M.P.H., FACEP, FAAP*; AND ERNEST T. TAKAFUJI, M.D., M.P.H.†

INTRODUCTION

EARLY USE

DURING AND AFTER WORLD WAR II

THE 1972 BIOLOGICAL WEAPONS CONVENTION

RECENT EVENTS: 1972 TO 1994

CONCLUSIONS
Medical Aspects of Chemical and Biological Warfare

416

INTRODUCTION

have provided our nation with a wake-up call. The

importance of education regarding this unpalatable

subject cannot be overestimated. Before our soldiers

deploy again against an aggressor likely to use biological weapons, our military healthcare providers

need to be confident that they understand both the

threat and the medical countermeasures to the

threat. This chapter and the ones that follow will

help meet that need.

The possibility that biological weapons will be

used against us is no longer unthinkable. Until recently, medical officers and other healthcare practitioners may have considered this topic more suitable for academic than practical pursuit. The fact

is, however, that biological agents have been used

as weapons since antiquity, and the threat that modern weapons will be used is real. In fact, Saddam

Hussein’s aggression in the Persian Gulf War may

EARLY USE

Warfare with biological weapons has been attempted many times dating back to antiquity. It is

appropriate that a discussion of early use of biological agents begin with the accomplishment of

Hannibal, the great Carthaginian leader, who, in

preparation for a naval battle against King Eumenes

of Pergamum in 184 BC, ordered that earthen pots

be filled with “serpents of every kind.”1(p12) During

the heat of battle, Hannibal hurled the earthen pots

onto the decks of the puzzled Pergamene warriors,

who remained amused only until they saw their

ships crawling with serpents. The battle was won

by Hannibal’s forces, as the Pergamene soldiers

battled two enemies.1

Recognition of the devastating impact that infectious diseases could have on an army resulted in

the often crude but ingenious use of disease organisms and poor sanitation to weaken the enemy. The

use of corpses of men and animals to pollute wells

and other sources of water of the opposing forces

was a common strategy. The fouling of water supplies continued to be used through the many European wars, the American Civil War, and into the

20th century.1,2 In his Memoirs, General W. T.

Sherman expressed discontent with Confederate

troops, who were deliberately shooting farm animals in ponds so that their “stinking carcases”1(p12)

would compromise the water supplies of the Union

forces. Not only did such actions have a demoralizing impact on the enemy, but the consumption of

contaminated water probably also accounted for

many undocumented epidemics of gastrointestinal

disease.

Military leaders during the Middle Ages recognized that victims of infections could become weapons in themselves. Gabriel de Mussis, a notary, saw

the Tatar attack on Caffa, a well-fortified, Genoesecontrolled seaport (modern Feodosiya, Ukraine), in

1346. De Mussis described how the plague-weakened aggressors catapulted victims of plague into

the town:

[The Tatars], fatigued by such a plague and pestiferous disease, stupefied and amazed, observing

themselves dying without hope of health ordered

cadavers placed on their hurling machines and

thrown into the city of Caffa, so that by means of

these intolerable passengers the defenders died

widely.3(p180)

An epidemic of plague followed, forcing a retreat

of the Genoese forces. The exported disease continued to spread in Europe.4,5

During the Black Plague, which killed 25 million

Europeans in the 14th and 15th centuries, bodies

of dead soldiers and “2,000 cartloads of excrement”6(p59) were hurled into the ranks of the enemy

at Carolstein in 1422. A similar strategy was used

in 1710, when Russian troops battling Swedish

forces in Reval resorted to throwing plague victims

over the city walls.2

On several occasions, smallpox has been used as

a biological weapon in the New World. Pizarro is

said to have presented indigenous peoples of South

American with variola-contaminated clothing in the

15th century, and the English did the same when

Sir Jeffery Amherst provided Indians loyal to the

French with smallpox-laden blankets during the

French and Indian War (1754–1767). Native Americans defending Fort Carillon sustained epidemic

casualties that directly contributed to the loss of the

fort to the English.7

 In 1763, Captain Ecuyer of the

Royal Americans, out of concern that an Indian attack was possible in the near future and under the

pretense of friendship, deliberately distributed two

variola virus–contaminated blankets and a handkerchief from a smallpox hospital to enemy Indian

forces.5,8,9 This was followed several months later

by large outbreaks of smallpox among various
Historical Overview of Biological Warfare

417

Indian tribes in the Ohio region. A similar strategy

(deliberately infecting adversaries with variola virus) was used during the Revolutionary War by

smallpox-immune colonists, whose vaccinations

against smallpox had been made mandatory by

General George Washington.2,10

Biological warfare became more sophisticated

during the 1900s—against both humans and animals. During World War I, reports circulated of attempts by the Germans to ship horses and cattle

inoculated with disease-producing bacteria, such as

Bacillus anthracis (the bacterium that causes anthrax)

and Pseudomonas pseudomallei (the bacterium that

causes glanders in livestock), to the United States

and elsewhere.2 This accusation was difficult to substantiate, since glanders was widespread in Europe

at the time. However, a German saboteur, who supposedly infected 4,500 mules with glanders, was

arrested in 1917 in Mesopotamia.2,5 Other allegations

of attempts by Germany to spread cholera in Italy

and plague in St. Petersburg, Russia, in 1915 followed; the dropping of contaminated fruit, chocolate, and children’s toys into Romanian cities such

as Bucharest by German planes was also alleged.2

Germany denied all allegations, including the

accusation that biological bombs were being

dropped over British positions. In 1924, a subcommittee of the Temporary Mixed Commission of the

League of Nations, in support of Germany, stated

that, in contradistinction to the chemical arm, there

was no hard evidence that the bacteriological arm

had been employed in war.2

On 17 June 1925, the Protocol for the Prohibition

of the Use in War of Asphyxiating, Poisonous or

Other Gases and of Bacteriological Methods of Warfare, commonly called the Geneva Protocol of 1925,

was signed. This was the first multilateral agreement that extended prohibition of chemical agents

to biological agents.2,5 Since viruses were not differentiated from bacteria at the time, they were not

specifically mentioned in the protocol. However,

subsequent interpretations of the agreement considered the term “bacteriological” to include viruses, rickettsiae, and fungi, and to be synonymous

with the term “biological.” A total of 108 nations,

eventually including the five permanent members

of the United Nations Security Council, signed the

agreement, which became known as the Geneva

Protocol.

Nations currently implicated with chemical and

biological weapons (ie, Iraq and Libya) also signed

the protocol, raising questions about the agreement’s true effectiveness. Verification of compliance

was not addressed.

DURING AND AFTER WORLD WAR II

ecution difficult. It is worth noting that a Japanese

document dated 1 October 1941, “Defense and Security Intelligence Report No. 8: Chinese Employment of

Chemical and Bacteriological Warfare Against the Japanese,” revealed a paranoia about secret Chinese initiatives:

There is evidence that during the China Incident

the enemy has skillfully and secretly carried out

chemical and bacteriological warfare activities

against personnel, animals, natural resources, water and food supplies. It may be presumed that the

enemy will become increasingly active in such

methods. Therefore, security and defense measures

must be thorough during advances and halts.2(p221)

At least 3,000 prisoners of war (including Chinese, Koreans, Mongolians, Soviets, Americans,

British, and Australians) are alleged to have been

used as guinea pigs by Japan’s Imperial Unit 731.2,11

Conservatively, more than 1,000 of these prisoners

are estimated to have died in experiments with

agents causing anthrax, botulism, brucellosis, cholera, dysentery, gas gangrene, meningococcal infection, and plague.2

 Experiments with tetrodotoxin

Events during and after World War II were

clouded by charges and countercharges of experimentation with biological warfare agents. The Japanese were accused of using biological agents

against the Soviet Union and Mongolia in 1939,

against Chinese civilians from 1940 to 1944,

and against Chinese troops in 1942.2,5 In October

1940, a Japanese plane supposedly scattered contaminated rice and fleas over the city of Chuhsien

in Chekiang province. This event was soon followed

by an outbreak of bubonic plague, a disease never

recorded previously in Chuhsien. Several other

mysterious flights of Japanese aircraft over at least

11 Chinese cities—with the dropping of grain

(wheat, rice, sorghum, or corn), strange granules

containing Gram-negative bacilli, and other materials suspected of being contaminated with the

plague organism—took place through August 1942.

Thousands are estimated to have been hospitalized

and 700 became victims of artificially spread plague

bacilli.5

 However, despite compelling evidence, testimony, and documents, failure to associate directly

the isolation of plague bacilli in the laboratory with

actual materials dropped by the planes made pros-
Medical Aspects of Chemical and Biological Warfare

418

(highly poisonous fugu toxin) were also conducted.

These experiments were later considered to be

“most regrettable from the view point of humanity”11(p11) by the Japanese government.

In fact, Japan had been conducting experiments

on biological and chemical warfare in occupied

Manchuria from approximately 1932 until the end

of World War II. There were actually several special Japanese experimental units in Manchuria, including the more infamous Units 731 and 100.12 Unit

731 was formed to prepare for biological warfare,

and Unit 100’s purpose was to ready bacteriological weapons for use.13 Experimental work on human prisoners was carried out in Ping Fan outside

Harbin (Unit 731), Changchun, Nanking, and other

sites. The number of people exterminated at Ping

Fan alone is estimated to have been more than 3,000.

Subjects either died in the experiments or were “sacrificed” when they were no longer useful to the

Japanese.12 The Japanese death factories may also

have led to the epidemics of plague that occurred

in the Harbin area after World War II, possibly due

to the release of thousands of infected animals during the Japanese evacuation in 1945.12 No prisoner

left Unit 731 alive.13

In December 1949, 12 Japanese prisoners of war,

including the Commander in Chief of the Japanese

Kwantung Army, were tried by a Soviet military

tribunal in Khabarovsk, USSR, for preparing and

using biological weapons, including agents causing plague, typhoid, paratyphoid, and typhus.11

Major General Kawashima, former head of Unit

731’s First, Third, and Fourth Sections, testified that

no fewer than 600 prisoners were killed yearly at

Unit 731.12 The Japanese, in turn, accused the Soviets of experimentation with biological warfare

agents, citing, as an example, glass bottles and ampules containing Shigella (bacillary dysentery), Bacillus anthracis (anthrax), and Vibrio cholerae (cholera) organisms recovered from Russian spies.2

Although German medical researchers during

World War II experimentally infected prisoners with

disease-producing organisms such as Rickettsia

prowazeki, R mooseri, hepatitis A virus, and malaria,

no charges were pressed at the conclusion of the

war. In December 1941, the British reported finding Colorado beetles in areas of the United Kingdom in which they were not normally found, and

suggested that they might have been released by

the Germans.14 In May 1945, apparent intentional

fecal pollution of a large reservoir in northwestern

Bohemia caused an outbreak of dysentery.2 However, an offensive biological warfare program by

Nazi Germany could never be documented, although some in the Third Reich were interested in

developing an adequate defense against biological

agents.2

On the other hand, the Germans also accused the

Allies of using biological weapons, causing a widespread plague of Colorado beetles on their potato

crops.14 Dr. Joseph Goebbels, German Minister of

Propaganda, also accused the British of attempting

to introduce yellow fever into India by transporting infected mosquitoes from West Africa.7

 This was

believable to many, for the British were indeed experimenting with at least one biological agent during 1941 and 1942. British trials with Bacillus

anthracis were held on Gruinard Island off the coast

of Scotland. The small bomb experiments resulted

in heavy contamination: persistent anthrax spores

contaminated parts of the island for many years.8,15

Winston Churchill is said to have seriously considered using anthrax if Nazi Germany used biological agents against Britain.5

During the years immediately following World

War II, newspapers were filled with articles of disease outbreaks supposedly caused by foreign agents

armed with biological weapons.2 Outbreaks of cholera in Egypt in 1947 were reportedly caused by Zionist infiltrators. In 1951, a Soviet navy newspaper

reported that the United States had tested biological weapons against Eskimos in Canada, leading to

an epidemic of plague in 1949. In 1950, East Germany accused the United States of spreading Colorado beetles over parts of Germany.

During the Korean War, the Soviet Union, China,

and North Korea accused the United States of using biological warfare against North Korea and

China.2,16 In 1952, an international group of scientists—formed as a result of North Korean complaints—concluded that tests of bacteriological

weapons were being conducted against North Korea and China. These experiments supposedly included mosquitoes carrying yellow fever virus and

other means of disseminating infectious agents. The

United States admitted that it had the capability to

produce biological agents but denied conducting

germ warfare. The International Red Cross suggested that a special commission be created to investigate the charges, but the request was refused

by the Chinese and the Koreans.8,17

There is a total lack of scientific basis for these

allegations, and at least one American military historian18 believes that the charges were blatant propaganda. Epidemics occurred in North Korea and

China not because biological warfare attacks were

perpetrated by the United States but because the

devastation of “war caused a collapse of the mea-
Historical Overview of Biological Warfare

419

ger health system. The [biological warfare] propaganda was an attempt to conceal the inability to

control epidemics.”18(p97)

Moreover, recent access to material from the

Korean War era, contained in the Archives of the

Polish Academy of Science, sheds additional new

light on allegations that biological warfare attacks

were launched against North Korea and China.

Among the official documents now available to

western investigators is a letter, written when the

allegations of biological warfare were at their

height, containing a request from the Korean government that Polish funds be redirected. Amazingly,

the Korean request was that Polish funds be used

to pay for clothing instead of the sera and vaccines

that the Koreans had been receiving. “This letter,

dated August 1952, at the height of the [biological

warfare] propaganda, casts doubt on the widely

advertised existence of biological warfare at that

time.”17(p98)

Other events and allegations included the following2:

• accusations by the Eastern European press

that Britain used biological agents in Oman

in 1957;

• Brazilian landowners’ deliberate infection

of Indian tribes in 1970, to remove them

from parts of the Amazon;

• Chinese accusations that the United States

started a cholera epidemic in Hong Kong

in 1961;

• accusations in July 1964 by the Soviet newspaper Pravda that Colombian troops and the

U.S. Military Commission in Colombia had

used biological agents against the peasants

of Colombia and Bolivia; and

• accusations in 1969 by Egyptians that the

“imperialist aggressors” had used biological warfare agents in the Middle East, specifically cholera in Iraq in 1966.

In 1970, South Korea maintained that North Korea was planning to launch a biological warfare attack, based on a North Korean facility’s placing a

large order from a Japanese trading firm for anthrax,

cholera, and plague bacteria. Although the situation

was peacefully resolved, biological warfare merely

provided one more issue on which North and South

Korea could disagree and distrust each other.

During the Vietnam War in the 1960s, many considered the use of fecally contaminated spear traps

(“pungi sticks”) to be the Vietcong’s adaptation of

biological warfare. Emphasis in that conflict was

largely on conventional warfare and special operations in the jungles of Southeast Asia, although concern continued over endemic and artificially introduced infectious agents. “Yellow rain” (which is

discussed in Chapter 34, Trichothecene Mycotoxins) became an issue later, along with controversies

surrounding use of the chemical herbicide Agent

Orange (an approximately 50%–50% mixture of

dichlorophenol [2,4-D] and trichlorophenol 2,4,5-T,

with trace amounts of the contaminant 2,3,7,8

tetrachlorodibenzo-p-dioxin [TCDD]).

In November 1969, the World Health Organization

of the United Nations issued a report on chemical and

biological weapons. This report (and an earlier report

by the 18-Nation Committee on Disarmament) described the unpredictability of biological warfare

weapons and the attendant risks and lack of control when such weapons are used. The effectiveness

of biological weapons was not questioned; estimated casualty figures were staggering.19 In July

1969, Great Britain submitted a recommended statement to the Conference of the Committee on Disarmament prohibiting the “development, production,

and stockpiling of bacteriological (biologic) and

toxin weapons.”20(p116) Then in September 1969, the

Soviet Union unexpectedly recommended a disarmament convention to the United Nations General

Assembly.

THE 1972 BIOLOGICAL WEAPONS CONVENTION

As a follow-on to the 1925 Geneva Protocol, the

1972 Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological

(Biological) and Toxin Weapons and on their Destruction, commonly known as the Biological Weapons

Convention, was convened.2,5 Agreement was eventually reached among the 103 co-signing nations

never to develop, produce, stockpile, or otherwise

acquire or retain microbial or other biological

agents or toxins, whatever their origin or method

of production, of types and in quantities that have

no justification for prophylactic, protective or other

peaceful purposes; and weapons, equipment or

means of delivery designed to use such agents or

toxins for hostile purposes or in armed conflict.5(p135)

The agreement went into effect in March 1975 and

reduced the concerns that some nations had over

the development and use of biological agents. However, problems with verification and the interpretation of “defensive” research continued.
Medical Aspects of Chemical and Biological Warfare

420

Every year, signatories to the agreement are required to submit to the United Nations information on

• facilities where biological defense research

is being conducted;

• scientific conferences that are held at specified facilities;

• exchanges of scientists or information;

and

• disease outbreaks.

The Security Council, of which the United States

and Russia are members, reserves the right to veto

any request for an investigation, should any allegations of infractions be lodged with the United Nations.

In 1986 and again in September 1991, review conferences were held to resolve continuing problems.

RECENT EVENTS: 1972 TO 1994

Since the signing of the Biological Weapons Convention in 1972, the U.S. intelligence community has

identified many significant events and emerging

threats in the area of offensive biological warfare.

The number and identity of countries engaged in

offensive biological warfare work is classified; however, we can accurately state that the number of

state-sponsored programs of this type has increased

significantly. Also, several terrorist or assassination

attacks have been documented.

On April 3, 1979, a mysterious explosion at the

Soviet Institute of Microbiology and Virology in

Sverdlovsk raised questions about the effectiveness

of any weapons-control agreements.5,21,22 At least 66

persons, most of them civilians (the area affected was

downwind of the military compound), are believed

to have been killed (most with inhalation anthrax),

and many more to have been infected with Bacillus

anthracis. For years, the Soviets maintained that this

incident had not been due to an accidental release

of anthrax from the military research facility, but

instead was due to ingestion by the local residents

of contaminated animal products. Controversy

raged back and forth in the lay press over the incident. Finally, in 1992, the President of Russia, Boris

Yeltsin, admitted that there had, in fact, been an accidental airborne release of anthrax spores from the

research facility in question, confirming the long-held

belief of many in the United States.23 (This incident is

discussed more fully in Chapter 22, Anthrax.)

In 1978, before the Sverdlovsk incident, a Bulgarian exile named Georgi Markov was attacked in

London, England, with a device disguised as an

umbrella (Figure 18-1). This weapon discharged a

tiny pellet (Figure 18-2) into the subcutaneous tissue of his leg while he was waiting for a bus. He

died several days later. On autopsy, the pellet, crossdrilled as if designed to be filled with another material, was found. This assassination, it was later

revealed, was carried out by the communist Bulgarian government, and the technology to commit

the crime was supplied to the Bulgarians by the

Soviet Union.7

 (This incident is discussed more fully

in Chapter 32, Ricin Toxin.)

Another attempted killing of another Bulgarian

exile, Vladimir Kostov, had occurred in Paris, France,

10 days before the Markov assassination. Kostov was

a defector who worked for Radio Free Europe, broadcasting opposition to the Bulgarian government. As

he was leaving a metro stop in Paris, Kostov felt a

sharp pain in his back. Turning quickly, he observed

a man with an umbrella running away.24 Only the

heavy clothing worn by Kostov prevented the pellet shot at him from penetrating any deeper than

the subcutaneous tissue of his back.25

The pellet remained in Kostov’s back until after

he learned of Markov’s death, about 2 weeks later,

whereupon French doctors examined his back. They

removed a similar pellet, which was made from an

exotic alloy of iridium and platinum and contained

the toxin ricin, in time to save Kostov’s life. The riPoison

Pellet

Release

Catch

Gas

Cylinder

Trigger Spring Piercer Barrel

Fig. 18-1. An umbrella gun of this type was the clandestine weapon used to assassinate Bulgarian exile Georgi

Markov in London in 1978. The weapon consisted of a

spring-loaded piston, which would drive a carbon dioxide cartridge forward into a firing pin. The gas would

then propel a poison projectile out of the hollow tip of

the umbrella gun, through the clothing, and into the flesh

of the intended victim. Reprinted from van Keuren RT.

Chemical and Biological Warfare, An Investigative Guide.

Washington, DC: Office of Enforcement, Strategic Investigations Division, US Customs Service; October 1990: 89.
Historical Overview of Biological Warfare

421

cin was kept in the pellet by a wax plug designed to

melt at body temperature. Fortunately for Kostov,

the wax did not melt.

Similar pellet-firing weapons may have been responsible for at least six assassinations in recent

years.26 In addition, an attempted assassination with

ricin may have occurred in the United States—in a

shopping mall parking lot in Tyson’s Corner, Virginia27—although this incident is less well documented than the two previous ones.

In the late 1970s, there were indications that inhabitants of Laos and Kampuchea may have been

attacked by planes and helicopters delivering aerosols of several colors. After being exposed, people

and animals allegedly became disoriented and ill,

and a small percentage of those stricken died. Some

of these clouds were thought to be comprised of

trichothecene toxins (in particular, T-2 mycotoxin).

These attacks are lumped under the label “yellow

rain.” A great deal of controversy has raged over

whether these clouds were in fact biological warfare agents. Some28 in the scientific community have

summarized the available evidence and concluded

Fig. 18-2. A pellet of this type, designed to contain ricin

toxin, was used to assassinate Georgi Markov in London

and in the attempt on the life of Vladimir Kostov in Paris.

The tiny, platinum–iridium pellet—the size of the head

of a pin (0.068 in. diameter)—was cross-drilled with

0.016-in. holes in which ricin (or another toxin) could be

placed. Reprinted from van Keuren RT. Chemical and Biological Warfare, An Investigative Guide. Washington, DC:

Office of Enforcement, Strategic Investigations Division,

US Customs Service; October 1990: 90.

that the yellow rain was most likely the fecal matter of wild honeybees dropped during their “cleansing flights.” Others believe that “there is enough

evidence to make agent use in these reported attacks highly probable.”7(p100) The controversy remains unresolved. For a more complete discussion,

see Chapter 34, Trichothecene Mycotoxins.

During Operation Desert Shield, the build-up

phase of the Persian Gulf War (fall and winter, 1990)

after Iraq invaded and occupied Kuwait, the United

States and the coalition of allies faced the threat of

biological and chemical warfare. Fortunately,

Saddam Hussein did not use unconventional weapons, but the allies believe that he retained this capability after his defeat.

In August 1991, the first United Nations inspection of Iraq’s biological warfare capabilities was

carried out in the aftermath of the Persian Gulf War.

On 2 August 1991, representatives of the Iraqi government announced to leaders of United Nations

Special Commission Team 7 (of which one of the

authors, E.M.E., was a member) that Iraq had conducted research into the offensive use of Bacillus

anthracis, botulinum toxins, and Clostridium

perfringens (presumably one of its toxins). This was

the first open admission in recent memory of biological weapons research by any country, and it

publicly verified many of the concerns of the U.S.

intelligence community. Iraq had extensive and redundant research facilities at Salman Pak, Al

Hakam, and other sites, only some of which were

destroyed during the Persian Gulf War.

Subsequent United Nations inspections have further elucidated Iraqi biological warfare intentions,

identified some of the Iraqi capabilities, and, we

hope, decreased the likelihood that Iraq will use

biological warfare in future conflicts. However,

since the defection of Iraqi General Hussein Kamal

Hassan on 7 August 1995, it has become clear that

the Iraqi biological warfare program was even further advanced than United Nations inspectors had

suspected. Iraq has disclosed in the wake of

Hussein’s defection that it had actually filled biological warfare agents into weapons immediately

before the outbreak of the Persian Gulf War. These

weapons included the following29:

• 166 bombs (100 botulinum toxin, 50 anthrax, 16 aflatoxin);

• 25 Scud/A1 Hussein missile warheads (13

botulinum toxin, 10 anthrax, 2 aflatoxin);

• 122-mm rockets filled with anthrax, botulinum toxin, and aflatoxin;
Medical Aspects of Chemical and Biological Warfare

422

• spray tanks capable of being fitted to a

fighter aircraft or remotely piloted aircraft,

and spraying 2,000 L over a target; and

• artillery shells.

It is now clear that U.S. forces faced a significant

biological warfare capability in the desert in this

decade. Fortunately, Iraq chose not to use biological weapons against us.

CONCLUSIONS

The threat of biological warfare has increased

over the past 2 decades, with a number of countries working on offensive use of these agents. The

extensive program of the former Soviet Union is

now controlled largely by Russia. Admitting that a

biological warfare program existed until early

1992—nearly 20 years after the USSR signed the

Biological Weapons Convention in 1972—Russian

president Boris Yeltsin has stated23 that he will put

an end to further offensive biological research.

However, the degree to which the program has been

scaled back is not known.

There is intense concern in the West about the

possibility of proliferation or enhancement of offensive programs in countries hostile to the western democracies, due to the potential hiring of expatriate Russian scientists. There is also a certain

amount of concern over the possibility that terrorists might use biological agents to threaten either

military or civilian populations. Certainly the threat

that biological weapons will be used against U.S.

military forces is broader and more likely in various geographic scenarios now than it has been at

any point in our history.

REFERENCES

1. Rothschild JH. Tomorrow’s Weapons. New York, NY: McGraw-Hill; 1964.

2. Stockholm International Peace Research Institute (SIPRI). The Rise of CB Weapons. Vol 1. In: The Problem of

Chemical and Biological Warfare. New York, NY: Humanities Press; 1971.

3. De Mussis G. Historica de Morbo s. Mortalitate quae fuit Anno Dni MCCCXLVIII. Cited in: Derbes VJ. De Mussis

and the great plague of 1348: A forgotten episode of bacteriological warfare. JAMA. 1966;196(1):179-182.

4. Derbes VJ. De Mussis and the great plague of 1348: A forgotten episode of bacteriological warfare. JAMA.

1966;196(1):59–62.

5. Geissler E, ed. Biological and Toxin Weapons Today. Oxford, England: Oxford University Press, Stockholm International Peace Research Institute; 1986.

6. Varillas. Historie de l’Hérésie de Viclef, Jean Hus, et de Jerome de Prague. Vol 2. Lyon, France: Chez Iean Certe. 1682:

117. Quoted in: Derbes VJ. De Mussis and the great plague of 1348: A forgotten episode of bacteriological

warfare. JAMA. 1966;196(1):59–62.

7. US Army Medical Research Institute of Infectious Diseases. Medical Management of Biological Casualties Handbook. 2nd ed. Fort Detrick, Frederick, Md: USAMRIID; 1996.

8. Cole LA. Clouds of Secrecy: The Army’s Germ Warfare Tests Over Populated Areas. Totowa, NJ: Rowman and

Littlefield; 1988.

9. Cartwright FF. Disease and History. New York, NY: New American Library; 1974.

10. Bayne-Jones S. The Evolution of Preventive Medicine in the United States Army, 1607–1939. Washington, DC: Department of the Army, Office of The Surgeon General; 1968.

11. Hersh SM. Chemical and Biological Warfare: America’s Hidden Arsenal. Indianapolis, Ind: Bobbs-Merrill; 1968.

12. Harris SH. Factories of Death. New York, NY: Routledge; 1994.
Historical Overview of Biological Warfare

423

13. Tomilin VV, Berezhnai RV. Exposure of criminal activity of the Japanese military authorities regarding preparation for bacteriological warfare. Voen Med Zh. 1985;8:26–29.

14. Harris R, Paxman J. A Higher Form of Killing. New York, NY: Hill and Wang; 1982: 87, 99.

15. Manchee R, Stewart W. The decontamination of Gruinard Island. Chem Br. 1988;July:690–691.

16. Cowdrey AE. The Medics’ War. Washington, DC: Center of Military History, US Army; 1987.

17. Rolicka M. New studies disputing allegations of bacteriological warfare during the Korean War. Milit Med.

1995:160:97–100.

18. Cowdrey AE. Germ warfare and public health in the Korean conflict. J Hist Med All Sci. 1984;39:179–268. Cited

in: Rolicka M. New studies disputing allegations of bacteriological warfare during the Korean War. Milit Med.

1995:160:97–100.

19. Report of a WHO Group of Consultants. Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970.

20. Bernstein BJ. The birth of the US biological-warfare program. Sci Am. 1987;256:116–121.

21. Defense Intelligence Agency. Soviet Biological Warfare Threat. Washington, DC: Department of Defense, DIA;

1986. DST-1610F-057-86.

22. Meselson M, Guillemin J, Hugh-Jones M, et al. The Sverdlovsk anthrax outbreak of 1979. Science. 1994;

266(5188):1202–1208.

23. Smith JR. Yeltsin blames ’79 anthrax on germ warfare efforts. Washington Post. 1992;June 16:A-1.

24. van Keuren RT. Chemical and Biological Warfare, An Investigative Guide. Washington, DC: Office of Enforcement,

Strategic Investigations Division, US Customs Service; 1990.

25. Murphy S, Hay A, Rose S. No Fire No Thunder: The Threat of Chemical and Biological Weapons. New York, NY:

Monthly Review Press; 1984: 145.

26. Livingstone NC, Douglass JDJ. CBW: The Poor Man’s Atomic Bomb. Cambridge, Mass: Institute for Foreign Policy

Analysis, Inc.; 1984.

27. Douglas JDJ, Livingstone NC. America the Vulnerable. Lexington, Mass: Lexington Books; 1987.

28. Robinson J, Guillemin J, Meselson M. Yellow rain: The story collapses. Foreign Policy. 1987;68:101–117.

29. Secretary-General of the United Nations. Note by the Secretary-General. New York: NY: United Nations Security Council; 11 October 1995. S/1995/864. Original in English.
The U.S. Biological Warfare and Biological Defense Programs

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Chapter 19

THE U.S. BIOLOGICAL WARFARE AND

BIOLOGICAL DEFENSE PROGRAMS

DAVID R. FRANZ, D.V.M., PH.D.*; CHERYL D. PARROTT†; AND ERNEST T. TAKAFUJI, M.D., M.P.H.‡

INTRODUCTION

A SECRET BIOLOGICAL WARFARE PROGRAM

The Secret Program Is Acknowledged

Field Testing in the United States

AN EXPANDED DEFENSE PROGRAM

A COMPREHENSIVE MEDICAL BIOLOGICAL DEFENSE PROGRAM

Safety in Research and Patient Care

A National Resource

SUMMARY

*Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011

†Formerly, Technical Writer, Public Affairs Office, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702; currently, Biomedical Writer, Office of Communications, National Institute of Allergy and Infectious Diseases, Bethesda,

Maryland 20892

‡Colonel, Medical Corps, U.S. Army; Commander, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington,

D. C. 20307-5100
Medical Aspects of Chemical and Biological Warfare

426

Biological agents have been used in war for centuries. After World War I, Major Leon Fox, Medical

Corps, U.S. Army, prepared a lengthy report1

 that

concluded that biological warfare was no longer a

concern because of the development of modern

sanitary procedures. However, as he wrote, the

Japanese were already developing an offensive biological warfare program involving an extensive list

of biological agents, capable of causing diseases

such as anthrax, tularemia, plague, botulinum,

smallpox, glanders, and typhoid.

The United States conducted a second review of

the potential of biological warfare during 1941 and

1942 and implemented its program to develop biological weapons in 1943. The biological warfare program of the United States was conducted under

military auspices and was characterized during its

early years by a high degree of secrecy and controversial testing programs. By the 1960s, U.S. scientists had clearly established that the development

of biological weapons was feasible and that their

use on the battlefield could be effective.

The purpose of the U.S. program in the early

years was to deter the use of biological agents

INTRODUCTION

against the United States and its military forces,

and to retaliate only if deterrence was unsuccessful. The program was characterized by an aggressive offensive and defensive research and development effort that would be modified to one based

on maintaining a strong defense against biological

agents.

When the biological warfare program was established, the United States was fighting World War II

on two fronts. After the war ended, the Cold War

developed and our security was still threatened. The

United States maintained an active offensive biological warfare program until it unilaterally renounced the use of biological weapons in two National Security Memoranda in 1969 and 1970. The

United States ratified the Biological Weapons Convention in 1975. Although capabilities of the world’s

military forces have changed significantly in the

years following the disestablishment of the U.S. biological warfare program—and despite the Biological Weapons Convention—a biological warfare

threat still exists; therefore, the United States maintains a program for medical defense against biological warfare agents.

A SECRET BIOLOGICAL WARFARE PROGRAM

In 1941, Secretary of War Henry L. Stimson asked

the National Academy of Sciences to evaluate the

feasibility of biological warfare. The academy concluded that biological warfare was feasible and recommended that steps be taken to reduce U.S. vulnerability and also to conduct research to explore

the offensive potential of bacteriological weapons.

In April 1942, Stimson recommended to President

Franklin D. Roosevelt the creation of a civilian advisory group that would coordinate governmental

and privately owned institutions in a biological

warfare effort.2,3 (What he did not tell Roosevelt was

that the Army Chemical Warfare Service had begun its own biological warfare research in 1941.)

The idea of biological weaponry was controversial, since little was known about the predictability

or effectiveness of biological weapons in wartime.

President Roosevelt approved the plan in 1942, and

the War Reserve Service, headed by George W.

Merck, was established and attached to the Federal

Security Agency, a New Deal agency of the Department of Agriculture. The War Reserve Service

started out in mid 1942 with a budget of $200,000.

Secret work began under Merck’s direction at 28

American universities, including Harvard, Stanford,

and other top schools. This agency received consultative advice from national scientific committees

and organizations, including the National Academy

of Sciences and the National Research Council.

The War Reserve Service also empowered the

U.S. Army’s Chemical Warfare Service to greatly expand its efforts in regard to biological weapons. The

army’s efforts were better funded than those of the

War Reserve Service: in 1942 and 1943, the Chemical Warfare Service received millions of dollars to

build research facilities. Several locations were selected for the army’s biological research, with the

main headquarters at Camp Detrick, Frederick,

Maryland, a small National Guard airfield (designated Fort Detrick in 1956). The army also made

plans to build a manufacturing plant near Terre

Haute, Indiana, and built a 2,000-acre field test site

on Horn Island in Pascagoula, Mississippi. It is

ironic that much of the United States’s biological

warfare effort during World War II was in response

to a perceived threat from Germany, when in fact

the Japanese were much more actively building

their biological warfare capability.2
The U.S. Biological Warfare and Biological Defense Programs

427

In the spring of 1942, President Roosevelt and

British Prime Minister Winston Churchill announced policies limiting the use of biological

weapons to retaliation only, closely paralleling previous decisions, such as the Geneva Protocol of

1925, on the limited use of chemical weapons. But

these new policies did not prevent the United States

and Great Britain from beginning to amass arsenals

of biological weapons.4 By 1943, the research center and pilot plant at Camp Detrick employed approximately 3,800 military and 100 civilian personnel. In 1944, Dugway Proving Ground, Utah, was

established to replace the Mississippi site, and the

production plant was constructed near Terre Haute,

Indiana.2

The United States exchanged information with

Great Britain and Canada, two other nations concerned about the biological warfare threat, but the

general public was unaware of a biological warfare

program in the United States until 4 months after

the war was over. During World War II, the United

States worked primarily on anthrax and botulism;

however, brucellosis, psittacosis, tularemia, and

glanders were also studied. There was also considerable work on agents for use against plants, and

records show that there were plans drawn up to

decimate Japan’s rice crops.2

At the end of World War II, construction and testing slowed to a stop, and the effort on biological

warfare development was largely limited to research. The production plant in Indiana was sold

to the Charles A. Pfizer Company for commercial

use. Although the highly classified program was

initially defensive, and closely tied with the chemical weapons program, research continued on developing an independent retaliatory capability using

various disease agents.

The Secret Program Is Acknowledged

Since 1937, Japan had conducted a large biological warfare program, including human testing, at

its Unit 731 in Manchuria.5 After the war, the United

States granted amnesty to Japanese scientists who

had participated in the research; however, a condition of the amnesty was full disclosure of research

information. Two scientists from Camp Detrick, Dr.

Edwin Hill and Dr. Joseph Victor, went to Japan in

1945 and interviewed 22 scientists. They learned

that many of the classical biological warfare agents

had been studied, and that approximately 1,000

autopsies had been performed in Unit 731, most of

these on humans who had been exposed to anthrax.

They also learned that the Japanese had stockpiled

400 kg of anthrax spores, which were to be used in

a specially designed fragmentation bomb.

In January 1946, the War Department made public for the first time the fact that the United States

had been conducting biological warfare research

and testing. The press release emphasized the high

priority placed on safety:

In all work on biological warfare carried on in the

United States, extreme care was taken to protect

the participating personnel from infection. Many

new techniques were devised to prevent infection

and proved highly successful. Hospitals and dispensaries were maintained at all installations,

staffed with both Army and Navy personnel and

were equipped to treat accidental infections. As the

result of the extraordinary precautions taken, there

occurred only sixty cases of proven infection caused

by accidental exposure to virulent biological warfare agents which required treatment. Fifty-two of

these recovered completely; of the eight cases remaining, all were recovering satisfactorily. There

were, in addition to the sixty proven cases, 159 accidental exposures to agents of unknown concentrations. All but one of these received prompt treatment and did not develop any infection. In one

instance, the individual did not report exposure,

developed the disease, but recovered after treatment.3(vol 1, p1-4)

Mr. Merck, the head of the War Reserve Service,

in his final report6 to the secretary of war noted that

although remarkable achievements had been made,

the potential of biological warfare had by no means

been completely measured. He recommended that

the program be continued on a sufficient scale to

provide an adequate defense.

In 1948, the Research and Development Board

(then under the secretary of defense), which had

been given the responsibility to supervise the governmental research program, requested an evaluation of biological agents as weapons of sabotage.

The Committee on Biological Warfare was formed,

and the Baldwin Report7 prepared by the committee stated that the United States was particularly

vulnerable to covert attack with biological agents.

It also stated that the current research and development program was “not now authorized to meet

the requirements necessary to prepare the defensive measures against special [biological warfare]

operations.”7(p1)

The Baldwin Report recommended7 that

• means be developed to detect and identify

biological warfare agents;

• methods be developed for decontamina-
Medical Aspects of Chemical and Biological Warfare

428

tion, protection, prophylaxis, and treatment; and

• methods be assessed for dissemination of

biological agents, with emphasis on application to special operations.

Specifically recommended were research programs,

such as the testing of “innocuous organisms”7(p7) in

ventilation systems, subway systems, and public

water supplies. This guidance influenced several

subsequent administrations over the next 20 years,

and the United States conducted a sequence of

highly classified scientific tests on unknowing

populations throughout the country, with agents

and materials believed to be nonpathogenic. In fact,

not until early 1977 was the extent of the military

biological weapons testing program publicly disclosed before Congress.3,4

The biological warfare research program in the

early 1940s and 1950s involved antipersonnel,

anticrop, and, for a brief period, antianimal studies.8

 Field trials included open-air vulnerability testing, and contamination of public water systems

with live organisms such as Serratia marcescens.

Covert programs were conducted by the Central Intelligence Agency. Pathogenic organisms were also

tested in Florida and the Bahamas in the 1940s.

Chemical anticrop studies evaluated defoliation

and crop destruction. Explosive munitions tests

with pathogens were begun in 1949.

In 1950, the first open-air tests with biological

simulants were conducted in various locales, one

of which was off the coast of Norfolk, Virginia. This

was followed by limited zinc cadmium sulfide dispersal tests in Minneapolis, Minnesota, and St.

Louis, Missouri, in 1953; and Bacillus subtilis var

niger dispersal in the New York City subway system in 1966.3,4 The Special Operations Division at

Camp Detrick conducted much of the research on

possible methods of covert attack and sabotage, and

many environmental studies—often without informing local or state governmental agencies or the

general population.

Between 1948 and 1950, several reviews were conducted by the Research Review Board of the biological, chemical, and radiological warfare programs.

Recommendations included the creation of a specific

biological warfare production facility, continued field

tests with biological warfare agents and munitions,

and expansion of the overall program. In 1949, an

enclosed, 1-million-liter steel test sphere was built at

Camp Detrick, and biological warfare explosive munitions tests with agents were begun (Figure 19-1).

Fig. 19-1. These workers are standing outside the “8-

Ball,” a 1-million-liter sphere used for testing static aerosols of biological agent preparations during the United

States’s offensive biological warfare program. The building enclosing the 8-Ball and its supporting infrastructure

were destroyed by fire in 1974. The sphere remains today as a historical monument at Fort Detrick, Frederick,

Maryland. Photograph: Public Affairs Office, Fort Detrick, Frederick, Md. circa 1968.

During the early 1950s, Major General George E.

Armstrong, The U.S. Army Surgeon General (1951–

1955) became concerned about medical defense

issues. Lieutenant Colonel Abram S. Benenson,

a medical officer from the Walter Reed Army Institute of Research, was appointed medical liaison

with the biological warfare laboratories at Fort Detrick. A joint agreement was signed, and beginning

in 1953, studies on medical defense against biological weapons were conducted cooperatively by the

Chemical Corps and the U.S. Army Medical Department. In 1954, a congressionally approved medical

volunteer program, designated “Project Whitecoat,”

was established after a series of meetings with representatives of the General Conference of the Seventh-Day Adventist Church and The Surgeon General, U.S. Army.
The U.S. Biological Warfare and Biological Defense Programs

429

Field Testing in the United States

The Korean War, which began in June 1950,

added justification for continuing the biological

warfare program, when the possible entry of the

Soviet Union into the war was feared. Concerns

over the Soviet Union were justified, for the Soviet

Union would pronounce in 1956 that chemical and

biological weapons would, indeed, be used for mass

destruction in future wars.9 In October 1950, the

secretary of defense approved continuation of the

program, based largely on the Soviet threat and a

belief that the North Korean and Chinese communists would use biological weapons.10

The first large-scale aerosol vulnerability test was

conducted in the San Francisco Bay area in September 1950, using two species of bacteria (Bacillus

globigii and Serratia marcescens) and fluorescent

particles. Various Bacillus species were used in

many experiments because of their spore-forming

capabilities and their similarities to Bacillus

anthracis. S marcescens was used because its red pigment made it readily identifiable. What was unexpected was the increased number of cases of Serratia

infections over the next few years in communities

that had been sprayed earlier with the organisms.4

The military considered the situations coincidental, but many civilian physicians believed them to

be directly related. Other limited-scale field

tests with pathogenic organisms were conducted

at Dugway Proving Ground, Utah. Antianimal

studies were conducted at Eglin Air Force Base,

Florida.

The biological warfare research facilities at Camp

Detrick were expanded, and a biological warfare

production facility was created at Pine Bluff Arsenal, Arkansas, in 1951. The first limited, biological

warfare retaliatory capability was achieved when

an anticrop bomb was developed, tested, and placed

in production for the U.S. Air Force. Anticrop–agent

production sites were carefully selected for safety

with the coordination and approval of the U.S. Department of Agriculture. This marked the first

peacetime biological weapons production by the

United States.11

By 1954, the Pine Bluff laboratory produced Brucella suis (the causative agent of brucellosis, also

called undulant fever) and Francisella tularensis (tularemia, or rabbit fever). Hardware for antipersonnel biological cluster bombs was delivered to Pine

Bluff for filling with Brucella suis to support air force

requirements. By 1955, the accelerated program was

producing stocks of B suis and F tularensis as biological warfare agents. While many of the efforts

involved military researchers, others from the Public Health Service, other Federal departmental agencies, and civilian scientific institutions were also

involved in the research.

The general public was uninformed of these ongoing studies, especially the environmental and

open-air experiments that were being conducted.

A controversial environmental test occurred in 1951,

when army researchers deliberately exposed a disproportionate number of black citizens to the fungus Aspergillus fumigatus, to see if African Americans were more susceptible to such infection, like

they were already known to be to coccidioidomycosis (Coccidioides immitis). Some in the scientific community believed that such knowledge

would assist in preparing defenses against a more

virulent form of this fungus. Similarly, in 1951, unsuspecting workers at the Norfolk Supply Center,

Norfolk, Virginia, were exposed to crates contaminated with A fumigatus spores.

Needless to say, there was a public outcry several years later when much of this information was

released, and the biological warfare research program would be forever tainted as operating within

“clouds of secrecy.”4

 The first lawsuit against the

U.S. government was filed by family members of

an individual who had died, allegedly as a result

of the San Francisco experiments in 1950. The court

decided that the U.S. government could not be sued

(under the Federal Tort Claims Act), since the decision to spray S marcescens was a part of national

defense planning. Several of the organisms (such

as S marcescens and A fumigatus), which were considered at one time to be innocuous, are now recognized to cause infections in humans, on occasion.

Immunocompromised or debilitated persons appear to be at greatest risk. Early experiments conducted with such organisms involving subjects or

populations who were unaware of the ongoing experiments may have posed a health risk to highly

susceptible persons.

During the two decades following the second

World War, laboratories for biological and chemical warfare research continued to increase in

size, and programs were expanded with a multimillion dollar budget. The Fort Detrick research

program was complemented by contractual civilian institutions; for example, Ohio State University

was tasked with making vaccines. Human volunteers were used in many of the studies. Vaccines

against diseases, such as Q fever and tularemia,

were developed.
Medical Aspects of Chemical and Biological Warfare

430

AN EXPANDED DEFENSE PROGRAM

With expansion of the biological warfare retaliatory program, the scope of the defensive program

was nearly doubled. Data were obtained on personnel protection, decontamination, and immunization. Early detection research produced prototype

alarms for use on the battlefield, but progress was

slow, apparently limited by technology.

The U.S. Army Medical Unit, under the direction

of The U.S. Army Surgeon General, began formal

operations in 1956. One of the Unit’s first missions

was to manage all aspects of Project CD-22, the exposure of volunteers to aerosols containing a pathogenic strain of Coxiella burnetii, the etiologic agent

of Q fever. The volunteers were closely monitored

and antibiotic therapy was administered when appropriate. All volunteers recovered from Q fever

with no adverse aftereffects. One year later, the Unit

submitted to the U.S. Food and Drug Administration an Investigational New Drug application for a

Q fever vaccine.

The United States was now accumulating invaluable data on personnel protection, decontamination,

and immunization; and, in the offensive program,

on the potential for mosquitoes to be used as biological vectors. A new Department of Defense Biological and Chemical Defense Planning Board was

created in 1960 to establish program priorities and

objectives. Preventive approaches toward infections

of all kinds were funded under the auspices of biological warfare. As concern increased over the biological warfare threat during the Cold War, so did

the budget for the program: to $38 million by fiscal

year 1966.

The U.S. Army Chemical Corps was given the

responsibility to conduct biological warfare research for all of the services.3

 In 1962, the responsibility for the testing of promising biological warfare agents was given to a separate Testing and

Evaluation Command. Depending on the particular program, different test centers were used, such

as the Deseret Test Center at Fort Douglas, Utah,

the headquarters for the new biological and chemical warfare testing organization. In response to increasing concerns over public safety and the environment, the Testing and Development Command

implemented a complex system of approval of its

research programs that included the U.S. Army

Chief of Staff, the Joint Chiefs of Staff, the Secretary of Defense, and the President of the United

States.

During the last 10 years of the offensive research

and development program, many scientific advances were made that proved that biological warfare was clearly feasible, although dependent on

careful planning, especially with regard to meteorological conditions. Large-scale fermentation, purification, concentration, stabilization, drying, and

weaponization of pathogenic microorganisms could

be done safely. Furthermore, modern principles of

biosafety and containment were established at Fort

Detrick that have greatly facilitated biomedical research; still today, these are copied throughout the

world. Arnold G. Wedum, M.D., Ph.D., a civilian

scientist who was Director of Industrial Health and

Safety at Fort Detrick, was the leader in the development of containment facilities (Figure 19-2).

Fig. 19-2. Technicians in Class III hood lines

are seen working with preparations of biological agents at Fort Detrick, Frederick,

Maryland, circa 1968, when the United

States had an offensive biological warfare

program. The completely enclosed hood

lines provide total containment of hazardous organisms. Hoods were maintained at

a pressure negative to ambient by constantly drawing air out through high-efficiency particulate air (HEPA) filters. Workers wore heavy rubber gloves to access

material inside the hoods. Photograph:

Public Affairs Office, Fort Detrick, Frederick, Md.
The U.S. Biological Warfare and Biological Defense Programs

431

During the 1960s, the country experienced a

philosophical change, and attention was now directed toward biological agents that could incapacitate but not kill. In 1964, research programs involved staphylococcal enterotoxins capable of

causing food poisoning. Research initiatives also included new therapy and prophylaxis. Pathogens

studied included the agents causing anthrax, glanders, brucellosis, melioidosis, plague, psittacosis,

Venezuelan equine encephalitis, Q fever, coccidioidomycosis, and a variety of plant and animal

pathogens.10,12

Particular attention was directed at chemical and

biological detectors during the 1960s. The first devices were primitive field alarms to detect chemicals. Although the development of sensitive biological warfare agent detectors was at a standstill, two

systems were, nonetheless, investigated. The first

was a monitor that detected increases in the number of particles sized 1 to 5 μm in diameter, based

on the assumption that a biological agent attack

would include airborne particles of this size. The

second system involved the selective staining of

particles collected from the air. Both systems lacked

enough specificity and sensitivity to be of any practical use.8

But in 1966, a research effort directed at detecting the presence of adenosine triphosphate (a

chemical found only in living organisms) was begun. By using a fluorescent material found in fireflies, preliminary studies indicated that it was possible to detect the presence of a biological agent in

the atmosphere. The important effort to find a satisfactory detection system continues today, for

timely detection of a biological attack would allow

the attacked force to use its protective masks effectively, and identification of the agent would allow

any pretreatment regimens to be instituted.

The army also experimented with and developed

highly effective barrier protective measures against

both chemical and biological agents. Special impervious tents and personal protective equipment were

developed, including individual gas masks even for

military dogs.

During the late 1960s, funding for the biological

warfare program decreased temporarily, to make up

for the accelerating costs of the Vietnam War. The

budget for fiscal year 1969 was $31 million, decreasing to $11.8 million by fiscal year 1973. Although

the offensive program had been stopped in 1969,

both offensive and defensive programs continued

to be defended. John S. Foster, Director of Defense

Research and Engineering, responded to a query by

Congressman Richard D. McCarthy:

It is the policy of the U.S. to develop and maintain

a defensive chemical-biological (CB) capability so

that our military forces could operate for some period of time in a toxic environment, if necessary;

to develop and maintain a limited offensive capability in order to deter all use of CB weapons by

the threat of retaliation in kind; and to continue a

program of research and development in this area

to minimize the possibility of technological

surprise.13(pp153–154)

On 25 November 1969, President Nixon visited

Fort Detrick to announce a new policy on biological warfare. In two National Security Memoranda,14,15 the U.S. government renounced all development, production, and stockpiling of biological

weapons and declared its intent to maintain only

small research quantities of biological agents, such

as are necessary for the development of vaccines,

drugs, and diagnostics.

Ground was broken in 1967 for construction of a

new, modern laboratory building at Fort Detrick.

The building would open in phases during 1971 and

1972. With the disestablishment of the biological

warfare laboratories, the name of the U.S. Army

Medical Unit, which was to have been housed in

the new laboratories, was formally changed to U.S.

Army Medical Research Institute of Infectious

Diseases (USAMRIID) in 1969. The institute’s new

mission was stated in General Order 137, 10 November 1971 (since superseded):

Conducts studies related to medical defensive aspects of biological agents of military importance

and develops appropriate biological protective

measures, diagnostic procedures and therapeutic

methods.16

The emphasis shifted away from offensive weapons to development of vaccines, diagnostic systems,

personal protection, chemoprophylaxis, and rapid

detection systems.

In response to President Nixon’s decision in 1969,

all antipersonnel biological warfare stocks were destroyed between 10 May 1971 and 1 May 1972. The

A COMPREHENSIVE MEDICAL BIOLOGICAL DEFENSE PROGRAM

laboratory at Pine Bluff Arsenal, Arkansas, was converted to a toxicological research laboratory, and

was no longer under the direction or control of the
Medical Aspects of Chemical and Biological Warfare

432

Department of Defense. Biological anticrop agents

were destroyed by February 1973. Biological warfare demilitarization continued through the 1970s,

with input provided by the U.S. Department of

Health, Education and Welfare; Department of the

Interior; Department of Agriculture; and the Environmental Protection Agency. Fort Detrick and

other installations involved in the biological warfare program took on new identities, and their missions were changed to biological defense and the

development of medical countermeasures. The necessary containment capability, Biosafety Levels 3

and 4 (BL-3 and BL-4, which are discussed below)

continued to be maintained at USAMRIID.

In 1984, the Department of Defense requested

funds for the construction of another biological

aerosol test facility in Utah. The proposal submitted by the army called for BL-4 containment, although maintaining that the BL-4 inclusion was

based on a possible need in the future and not on a

current research effort. The proposal was not well

received in Utah, where many citizens and government officials still recalled the secretive projects of

the military: the areas on Dugway Proving Ground

still contaminated with anthrax spores, and the

well-publicized accidental chemical poisoning of a

flock of sheep in Skull Valley, Utah, in March 1968.10

Questions arose over the safety of the employees

and the surrounding communities, and a suggestion was even made to shift all biological defense

research to a civilian agency, such as the National

Institutes of Health. The plan for a new facility was

revised to utilize a Biosafety Level 3 (BL-3) facility,

but not before congress had instituted more surveillance, reporting, and control measures on the army

to ensure compliance with the Biological Weapons

Convention of 1972.

Safety in Research and Patient Care

Currently, the medical biological defense research effort (part of the U.S. Army’s Biological

Defense Research Program [BDRP]) is concentrated

at USAMRIID at Fort Detrick. The army maintains

state-of-the-art containment laboratory facilities at

USAMRIID, with more than 10,000 ft2 of BL-4 and

50,000 ft2 of BL-3 laboratory space. BL-4, the highest containment level, includes laboratory suites

that are isolated by internal walls and protected by

rigorous entry restrictions, air-locks, negative-pressure air-handling systems, and filtration of all outflow air through high-efficiency particulate air

(HEPA) filters. Workers in BL-4 laboratories also

wear filtered positive-pressure total body suits,

which isolate the worker from the internal air of

the laboratory. BL-3 laboratories have a similar design, but do not require that personnel wear positive-pressure suits. Workers in BL-3 suites are protected immunologically by vaccines. U.S. governmental standards provide guidance as to which organisms may be handled under various containment levels in laboratories such as USAMRIID.17

The unique facilities available at USAMRIID also

include a 16-bed clinical research ward capable of

BL-3 containment, and a 2-bed patient care isolation suite where ICU-level care can be provided

under BL-4 containment. Here, healthcare personnel wear the same positive-pressure suits as are

worn in BL-4 research laboratories. The level of

patient isolation required depends on the infecting

organism and the risk to healthcare providers. Patient care can be provided at BL-4. There is no patient-care category analogous to BL-3; humans who

are ill as a result of exposure to BL-3 agents are cared

for in an ordinary hospital room with barrier nursing procedures.

USAMRIID guidelines have been prepared to

determine which level of containment should be

employed for individual patients who require BL-4

isolation or barrier nursing care (Exhibit 19-1). Staff

augmentation for BL-4 critical care expertise comes

from Walter Reed Army Medical Center, Washington, D.C., under an existing Memorandum of

Agreement. Patients can be brought directly into the

BL-4 suite from the outside through specialized

ports with unique patient-isolation equipment.

Finally, USAMRIID maintains a unique evacuation capability called the Aeromedical Isolation

Team (AIT). Led by a physician and a registered

nurse, each of the two teams consists of eight volunteers who train intensively to provide an evacuation capability for casualties suspected of being infected with highly transmissible, life-threatening

BL-4 infectious diseases (eg, hemorrhagic fever viruses). The unit uses special adult-sized Vickers isolation units (Vickers Medical Containment Stretcher

Transit Isolator, manufactured by Isolators Ltd.,

Shropshire, U.K.) (Figure 19-3). These units are aircraft transportable and isolate a patient placed inside from the external environment. The AIT can

transport two patients simultaneously; obviously,

it is not designed for a mass casualty situation.

During the 1995 outbreak of Ebola fever in Zaire,

the AIT remained on alert to evacuate any Americans who might have become ill while working to

control the disease in that country.
The U.S. Biological Warfare and Biological Defense Programs

433

EXHIBIT 19-1

ISOLATION PROCEDURES FOR PATIENT CARE AT USAMRIID, BY DISEASE AGENT OR

TYPE OF EXPOSURE

Biosafety Level 4 (BL-4) isolation suite admission; care providers in positive-pressure protective suits

Ebola virus

Marburg virus

Crimean-Congo hemorrhagic fever virus

Variola (smallpox) and monkeypox viruses

A patient presumed to be a victim of biological agent attack until definitive diagnosis is made

Biosafety Level 4 (BL-4) isolation suite admission; barrier nursing procedures*

Yersinia pestis (pneumonic form)†

Lassa fever virus

Argentine hemorrhagic fever (Junin) virus

Bolivian hemorrhagic fever (Machupo) virus

Venezuelan hemorrhagic fever (Guanarito) virus

Normal hospital room; barrier nursing procedures* or secretion precautions,‡ depending on the agent

Tick-borne encephalitis complex

Yellow fever virus§

Venezuelan equine encephalitis virus§

Rift Valley fever virus§

Chikungunya virus§

Dengue virus§

Brucella species

Vibrio cholerae

Bacillus anthracis (pulmonary or cutaneous forms)

Francisella tularensis (pulmonary form)

Yersinia pestis (bubonic or septicemic form)

Normal hospital room; no special precautions

Eastern equine encephalitis virus

Western equine encephalitis virus

Hemorrhagic fever with renal syndrome (Hantaan, Seoul, Puumala viruses)

Japanese encephalitis virus

Sandfly fever viruses

Coxiella burnetii (Q fever)

Chlamydia psittaci

Botulinum toxin

Staphylococcal enterotoxin B

Ricin toxin

Saxitoxin

Trichothecene mycotoxins

*Barrier nursing procedures: wearing gown, gloves, and surgical mask, but caring for patients in isolation suites.

†Pneumonic plague initially requires respiratory protection: full-face respirator or Racal hood (manufactured by Racal Health

and Safety, Inc, Frederick, Md).

‡Secretion precautions: wearing gown and gloves; special handling of potentially infectious dressings, drainage, and/or

excreta.

§The patient must be protected from potential arthropod vectors: windows should be screened and/or closed.

USAMRIID: U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md.
Medical Aspects of Chemical and Biological Warfare

434

Fig. 19-3. Members of the Aeromedical Isolation Team (AIT) prepare to transfer a patient from a stretcher isolator into the

Biosafety Level 4 (BL-4) isolation suite at the

U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland. The interior of the isolator is maintained at a pressure negative to the external

environment by a high-efficiency particulate air (HEPA) filtered blower. The isolator can be attached directly to a transfer

port, visible on the external wall of the

building, to allow movement of the patient

into the suite without exposing the environment to the patient. Team members are

seen wearing protective suits and positivepressure, HEPA-filtered Racal hoods (manufactured by Racal Health & Safety, Inc,

Frederick, Md). Photograph: Public Affairs

Office, Fort Detrick, Frederick, Md.

Some biological defense research also continues

at the U.S. Army Medical Research Institute of

Chemical Defense, Edgewood Arsenal, Maryland,

and the Walter Reed Army Institute of Research,

Washington, D. C. USAMRIID and these laboratories conduct basic research in support of the medical component of the Biological Defense Research

Program, which develops strategies, products, information, procedures, and training for medical

defense against biological warfare agents. The products include diagnostic reagents and procedures,

drugs, vaccines, toxoids, and antitoxins. Emphasis

is placed on protecting personnel before any potential exposure to the biological agent occurs.18

A National Resource

Since biological warfare agents are often etiologic

agents for naturally occurring diseases, the military

research effort provides substantive benefits for civilian populations also. Products produced or being developed through military research include

• vaccines to prevent tularemia, Q fever, Rift

Valley fever, Venezuelan equine encephalitis, Eastern and Western equine encephalitis, chikungunya fever, Argentine hemorrhagic fever, the botulinum toxicoses, and

anthrax;18,19

• antitoxins for diseases such as botulism;

• human immune globulin preparations (passive antibody protection) against various

bacteria and viruses; and

• antiviral drugs against multiple viral

agents.

Some vaccines also have applicability for diseases

of domestic animals (eg, Rift Valley fever and Venezuelan equine encephalitis). In addition, vaccines

are provided to persons who may be occupationally exposed to such agents (eg, laboratory workers, entomologists, and veterinary personnel)

throughout government, industry, and academe.

USAMRIID also provides diagnostic and epidemiological support to federal, state, and local agencies and foreign governments. Examples of assistance

rendered to civilian health efforts by the former U.S.

Army Medical Research and Development Command

(renamed the U.S. Army Medical Research and Materiel Command in October 1994) include

• the massive immunization program instituted during the Venezuelan equine encephalitis outbreak in the Americas in 1971;

• the laboratory support provided to the U.S.

Public Health Service during the outbreak

of Legionnaire’s disease in Philadelphia,

Pennsylvania, in 1976;

• the management of patients suspected of

having African viral hemorrhagic fever in

Sweden during the 1980s;

• international support during the outbreak

of Rift Valley fever in Mauritania in 1989;

• assistance with the outbreak of Ebola infections among monkeys imported to Reston,

Virginia, in 1990; and
The U.S. Biological Warfare and Biological Defense Programs

435

• epidemiological and diagnostic support to

the World Health Organization–Centers for

Disease Control and Prevention field team

that studied the Ebola outbreak in Zaire in

1995.

The current research effort combines new technological advances, such as genetic engineering and

molecular modeling, applying them toward development of prevention and treatment of diseases of

military significance. The program is conducted in

full compliance with requirements set forth by the

U.S. Food and Drug Administration, U.S. Public

Health Service, Nuclear Regulatory Commission,

U.S. Department of Agriculture, Occupational

Safety and Health Administration, and Biological

Weapons Convention.18

Even though the United States stopped all offensive biological warfare research in 1969, the Biological Defense Research Program must remain strong

in view of

• evidence that some countries are not complying with the Biological Weapons Convention;

• the difficulty of verifying compliance with

the Convention;

• the potential use of biological warfare by

terrorists;

• the increased possibility of new threat

agents based on advances in biotechnology;

and

• the belief that a strong defense serves as a

deterrent.

While some of the military’s biological defense

programs remain classified, based on worldwide threats and uncertainties, the medical Biological Defense Research Program is unclassified and continues to be an invaluable resource for the nation.

SUMMARY

Although biological agents have been used in

warfare for centuries to produce death or disease

in humans, animals, or plants, the United States did

not begin a biological warfare offensive program

until 1941. It was concern about the Japanese biological warfare threat that motivated the United

States to begin to develop biological weapons. During the next 28 years, the United States initiative

evolved into an effective, military-driven research

and acquisition program, shrouded in controversy

and secrecy. Most research and development was

done at Fort Detrick, Maryland, while production

and testing occurred at Pine Bluff, Arkansas, and

Dugway Proving Ground, Utah. Field testing was

done secretly and successfully with simulants and

actual agents disseminated over wide areas. A small

defensive effort paralleled the weapons development and production program.

With the presidential decision in 1969 to halt offensive biological weapons production, and the

agreement in 1972 at the international Biological

Weapons Convention never to develop, produce,

stockpile, or retain biological agents or toxins,

the program became entirely defensive, with medical and nonmedical components. The U.S. Biological Defense Research Program exists today, conducting research to develop physical and medical

countermeasures to protect service members and

civilians from the threat of modern biological

warfare.

REFERENCES

1. Fox LA. Bacterial warfare: The use of biologic agents in warfare. Milit Surg. 1933;72(3):189–207.

2. Bernstein BJ. The birth of the US biological-warfare program. Sci Am. 1987;256:116–121.

3. Department of the Army. Special Report to Congress. US Army Activity in the US Biological Warfare Programs,

1942–1977. Vols 1 and 2. Washington, DC: DA. 24 Feb 1977. Unclassified.

4. Cole LA. Clouds of Secrecy: The Army’s Germ Warfare Tests Over Populated Areas. Totowa, NJ: Rowman and

Littlefield; 1988.

5. Williams P, Wallace D. Unit 731: Japan’s Secret Biological Warfare in World War II. New York, NY: Free Press; 1989.
Medical Aspects of Chemical and Biological Warfare

436

6. Report to the Secretary of War by Mr. George W. Merck, Special Consultant for Biological Warfare, 3 Jan 1946.

Cited in: Department of the Army. Special Report to Congress. US Army Activity in the US Biological Warfare

Programs, 1942–1977. Vol 2, annex 1. Washington, DC: DA. 24 Feb 1977. Unclassified.

7. Baldwin IL. Special BW Operations. Washington, DC: The National Military Establishment Research and Development Board; 5 Oct 1948. Memorandum for Executive Secretary, Research and Development Board. Unclassified.

8. Hersh SM. Chemical and Biological Warfare: America’s Hidden Arsenal. Indianapolis, Ind: Bobbs-Merrill; 1968.

9. Geissler E, ed. Biological and Toxin Weapons Today (Stockholm International Peace Research Institute). Oxford,

England: Oxford University Press; 1986.

10. Harris R, Paxman J. A Higher Form of Killing: The Secret of Chemical and Biological Warfare. New York, NY: Hill

and Wang; 1982.

11. Cowdrey AE. The Medics’ War. Washington DC: Center of Military History, US Army; 1987.

12. Stockholm International Peace Research Institute (SIPRI). The Rise of CB Weapons. Vol 1. In: The Problem of Chemical

and Biological Warfare. New York, NY: Humanities Press; 1971.

13. Foster JS, Director of Defense Research and Engineering, US Department of Defense. Letter dated 15 April

1965 to Honorable Richard D. McCarthy, US House of Representatives. Cited in: McCarthy RD. The Ultimate

Folly: War by Pestilence, Asphyxiation, and Defoliation. New York, NY: Alfred A. Knopf; 1969: 153–154.

14. Kissinger HA. N.S. Decision Memorandum 35. 25 November 1969.

15. Kissinger HA. N.S. Decision Memorandum 44. 20 February 1970.

16. Department of the Army. General Order 137. Washington, DC: Headquarters, DA; 10 November 1971.

17. Centers for Disease Control and Prevention. Biosafety in Microbiological and Biomedical Laboratories. 3rd ed. Washington, DC: US Department of Health and Human Services, Public Health Service, Centers for Disease Control

and Prevention. May 1993. HHS Publication (CDC) 93-8395.

18. Huxsoll DL, Parrott CD, Patrick WC III. Medicine in defense against biological warfare. JAMA. 1989;265:677–679.

19. Takafuji ET, Russell PK. Military immunizations: Past, present and future prospects. Infect Dis Clin North Am.

1990;4:143–157.
The Biological Warfare Threat

451

Chapter 21

THE BIOLOGICAL WARFARE THREAT

LESTER C. CAUDLE III, M.D., M.T.M. & H.*

INTRODUCTION

EVIDENCE OF A SOVIET BIOLOGICAL WARFARE PROGRAM

Indirect Evidence

Direct Evidence

Current Evidence

PROLIFERATION OF BIOLOGICAL WEAPONS

Military Incentives

Technical Incentives

Economic Incentives

Political Incentives

NONHUMAN TARGETS OF ATTACK

Animals

Crops

Material

THE CURRENT THREAT

North Korea and China

Iraq

Foreign and Domestic Terrorism

SUMMARY

*Lieutenant Colonel, Medical Corps, U.S. Army; formerly, Command Surgeon, On-Site Inspection Agency, P.O. Box 17498, 201 West Service

Road, Dulles International Airport, Washington, D.C. 20041-0498; currently, Assistant Chief, Department of Retrovirology, U.S. Army

Medical Component, Armed Forces Research Institute of Medical Sciences, APO Area Pacific 96546, 315/6 Rajvithi Road, Bangkok 10400,

Thailand
Medical Aspects of Chemical and Biological Warfare

452

INTRODUCTION

Biological warfare agents may be more potent

than the most lethal chemical warfare agents and

provide a broader area of coverage per pound of

payload than any other weapons system. The proliferation of technology and the scientific progress

in biochemistry and biotechnology have simplified

production requirements and provided the opportunity for creation of exotic agents.1

Genetic engineering holds perhaps the most dangerous potential. Pathogenic microorganisms capable of creating a novel disease, perhaps on an

epidemic scale, could be tailor-made. Suppose that

an adversary inserted a gene lethal to humans into

a virus or bacterium. This agent could then spread

a disease that could overwhelm the diagnostic,

therapeutic, and preventive capacity of a country’s

health service.2

 The threat posed by new biological

and chemical weapons requires our urgent attention:

Certainly it is of great importance that new and

insidious biochemical weapons are being developed and deployed, in total disregard for existing

treaties, while the perpetrators routinely deny all

charges and, in turn, counter that their accusers are

fabricating the allegations as a propaganda device.

It seems clear that the highest priority should

be afforded this issue for efforts toward its

resolution.3(p498)

The use of biological agents in future wars and

terrorist attacks is a realistic concern. The difficult

issues of degraded troop performance and healthcare delivery are serious threats, and resources must

be allocated to develop an effective response plan.

Countering this threat will require that the highest

levels of our government find ways to1

• strengthen and verify international arms

control agreements,

• maintain the United States’s ability to respond with a broad range of alternatives

against any aggressor who attempts to proliferate biological weapons, and

• maintain a robust biological defense effort

for our U.S. armed forces, one that would

equally and effectively apply to our civilian population in case of use by terrorists.

Unfortunately, biological weapons are considered by some nations to be part of their military

armamentarium, and there are military, technical,

economic, and political incentives for nations to develop and maintain such a program. A goal of this

chapter is to present the evidence in such a way

that the reader can conclude that the threat is real

and significant; it is neither in the realm of science

fiction nor confined to our own nation. As a Russian writer stated in 1993:

I have been gathering information on bacteriological weapons (BW) for several years. Out of all the

means of mass destruction, this kind can be considered as the most mysterious.4(p15)

EVIDENCE OF A SOVIET BIOLOGICAL WARFARE PROGRAM

We have known for many years that the Soviet

Union maintained an offensive biological warfare

program in violation of the 1972 Biological Weapons Convention, which they initiated and signed

without reservation. This knowledge has been reported to the U.S. Congress and the American public since 1984, and our government has repeatedly

raised this subject, first with the Soviet leadership, and

more recently with the current Russian leadership.5

Indirect Evidence

Beginning in the latter 1970s and continuing

throughout the 1980s, U.S. intelligence agencies repeatedly alleged the existence of a Soviet biological weapons program. Then in April 1979, a major

outbreak of anthrax in the city of Sverdlovsk (now

Yekaterinburg) caused the death of a number of

Soviet citizens from pulmonary anthrax.1

 (This

event is also discussed in Chapter 22, Anthrax.)

Details about this epidemic were not disseminated

by the Soviets, and it was not until much later that

the Western communications media became aware

of it.

On February 13, 1980, the widely circulated German magazine Bild Zeitung carried a story describing an accident in a military settlement in Sverdlovsk

in which an anthrax cloud resulted, which prevailing winds carried into the outskirts of the city. The

magazine article went on to state that only a chance

change in wind direction prevented the cloud from

passing through the main section of the city. When

this story was published, major Western newspapers finally began to take an interest in the event.
The Biological Warfare Threat

453

Several weeks later, the U.S. government asked

the Soviet government for an explanation of the epidemic—specifically, whether this was a biological

warfare experiment gone awry. Moscow denounced

the suggestion as slanderous propaganda but did

acknowledge the outbreak of anthrax. They insisted

that the outbreak was caused by poor food control,

which had somehow allowed contaminated meat

to be dispensed to the population of Sverdlovsk.6

However, a recently released report7 on a series

of 42 autopsies, done on what is thought to be the

majority of the fatalities from this outbreak, consistently revealed pathological lesions diagnostic of

inhalational anthrax: hemorrhagic necrosis of the

thoracic lymph nodes involved in the lymphatic

drainage of the lungs, and hemorrhagic mediastinitis. These are not findings seen in gastrointestinal anthrax associated with contaminated meat.

The U.S. government found Moscow’s explanation disturbing for several reasons, including strong

U.S. intelligence reporting that listed Sverdlovsk as

a site of a biological warfare establishment; the fact

that shortly after 3 April 1979, D.F. Ustinov, then

the Soviet Minister of Defense, visited Sverdlovsk;

and the difficulty in imagining an anthrax epidemic

attributable to contaminated meat in a developed

nation with a highly effective and functioning public health service.6 Last and perhaps even more compelling, satellite photography had revealed some

time earlier that the compound in which the accident took place (Military Compound 19) was

heavily guarded, had special security precautions,

and had ventilation and animal pens typical of a

biological weapons facility.8

In February 1992, Russian President Boris Yeltsin

admitted that the 1979 outbreak of anthrax in

Sverdlovsk was indeed linked to an accident at a

secret biological weapons facility. He went on to

reveal that the former Soviet Union had conducted

an illegal biological warfare program in violation

of the 1972 Biological Weapons Convention. He further acknowledged that the Soviet Union had failed

(1) to implement its commitment under the convention to destroy existing biological weapons and (2)

to conduct research only for defensive purposes. He

also said that “past military efforts had crossed the

line set by international treaties.”1(p16)

The Washington Post published an article in August 1992 that stated that shortly after Yeltsin’s admission, a confidential report on the extent of the

Russian biological weapons program had been prepared by Anatoly Kuntsevich, a retired Russian

general and a former director of Soviet research on

chemical arms. Kuntsevich stated in the report that

the military had illicitly developed aerial bombs

and rocket warheads. These warheads were capable

of carrying several biological warfare agents, including anthrax, tularemia, and Q fever. General

Kuntsevich revealed that the biological weapons

effort had been maintained through at least 1990

but had been scaled down during the 6 years of

Mikhail Gorbachev’s presidency.9

In April 1992, Yeltsin issued a decree that outlawed all activities that were prohibited by the 1972

Convention. General Kuntsevich stated, following

Yeltsin’s decree, that all offensive biological weapons programs in territorial Russia had been banned

and placed under firm control of the government;

that the large biological test area near the Aral Sea,

Vozrozhdeniya Island, had been closed; and that

Russia had no stockpiles of biological weapons.

Unfortunately, that same month, Russia failed to

meet the deadline set forth for all Convention signatories to declare their total inventory, stockpiles,

and production sites for offensive and defensive

biological weapons programs. This requirement had

been established in the set of confidence-building

measures that had been agreed upon at the Third

Review Conference on the Biological Weapons Convention in September 1991, at which Russia was a

participant. The Russian government finally submitted their report in late July 1992, but, according

to U.S. officials, the report lacked key details. This

delay only strengthened our heightened concerns

about the extent of the former or still-existent Soviet program.9

The Soviet offensive biological weapons program

was monitored by the United States for decades.

We know that scientific personnel at a number of

microbiological research institutes in the former

Soviet Union are capable of performing research

and development with highly infectious disease

agents and very potent plant, animal, and microbial toxins. Likewise, their considerable work in

aerobiology, cloud physics, airborne infections, and

disease-agent stabilization has direct application to

biological warfare. Much of the knowledge and

technical expertise at these institutes was in the recent past and possibly still is funded and utilized

by the Ministry of Defense for offensive purposes

as well as for defensive and protective aspects of

biological warfare.10

Direct Evidence

Much of our current knowledge concerning the

former Soviet Union’s biological warfare program

has been gleaned from Vladimir Pasechnik, a mi-
Medical Aspects of Chemical and Biological Warfare

454

crobiologist who defected to the West in 1989 while

attending a scientific conference in London, England. For years, Pasechnik had pled with Soviet

officials to allow him to switch some of his research

effort to civilian purposes, for which it had originally been established.

Pasechnik was born in 1939 in Stalingrad, a city

that was largely destroyed during World War II. He

became one of the brightest young scientists in the

Soviet Union, determined to use his talent working

for peace and never allowing his research in biophysics to be used to further a means of destruction that had cost the lives of his family. In 1974, a

general from the Soviet Ministry of Defense offered

Pasechnik the opportunity to set up and run his own

biotechnology laboratory. The offer included an

unlimited budget to buy Western equipment and

the ability to recruit the best scientists in the Soviet

Union.

Pasechnik was not concerned that the offer had

come from the Ministry of Defense, as the military

was the driving force behind most research conducted in the Soviet Union, even projects that had

strictly civilian application. He built up his laboratory over the better part of the next decade, hiring

400 well-credentialed scientists to staff the facility,

acquiring a relatively unlimited budget that gave

his staff access to the latest Western biotechnology.

The laboratory began operating in 1981, and during the next 2 years Pasechnik realized the truth:

far from running a state-of-the-art civilian research

operation, he was part of a vast network of laboratories and factories working on deadly new weapons of war. A newspaper story quoted Pasechnik as

stating:

Officially we were involved in vaccine development and in producing preparations for protecting

crops, but in fact, we were developing methods of

production and equipment for a huge biological

warfare program.11(p1)

He revealed a network of nominally civilian research institutes known as Biopreparat. This organization was created in 1973 by the Soviet Central

Committee and the Council of Ministers as a cover

for the existing military program. Biopreparat was

a huge organization, employing more than 25,000

people at 18 or more research and development facilities, including six mothballed production plants

and a major storage complex in Siberia.12 Their budget in the early 1980s was 200 million rubles and

tens of millions of U.S. dollars per year.

One of the goals was to genetically alter known

pathogens in the hope of making the pathogens resistant to Western drugs. The institutes were also

directed to produce new strains of diseases, more

powerful than those previously known to science,

and to produce them in aerosol form. In 1983, at a

Biopreparat research institute in Obolensk, 60 miles

south of Moscow, scientists developed their first

superplague: a new strain of tularemia. Testing revealed such favorable results that Moscow gave

permission for full-scale development and production. Then in 1985, scientists at the same institute

were asked to develop a more deadly strain of pneumonic plague.

Pasechnik’s role was to refine the production

process to make the development more efficient. He

claims that by 1987 the Soviet Union had sufficient

industrial capability within Biopreparat to manufacture 200 kg of the superplagues every week,

enough to kill up to 500,000 people. Owing to the

fairly short half-life of the agent, these agents were

never produced on this scale; in fact, only enough

for testing was produced.

The fact remains, however, that the Biopreparat

network stood ready to begin full production when

told, at a time in the future designated as Day X.

The Soviet Defense Ministry built these biological

weapons, known as Weapons of Special Designation, into their military planning. They were to be

used not only as a last resort but also as support

weapons in a conventional (nonnuclear) conflict, to

attack the enemy’s troop reserves and hamper his

operations at ports and rail centers.11

Pasechnik had first-hand knowledge of the program: he was a director of the Biopreparat organization known as the Institute of Especially Pure

Biopreparations in Leningrad, and was also a

member of the Scientific and Technical Committee,

which was composed of institute heads. An article

in the popular press12 noted that, according to

Pasechnik, Biopreparat officials had discussed putting weaponized forms of these agents into terrorists hands.

Current Evidence

Vladimir Pasechnik’s story has been confirmed

by another well-placed defector from the Biopreparat program whom the Central Intelligence

Agency (CIA) brought out in late 1992. This second

defector even stated that the research and development of new strains of genetically engineered superweapons were continuing up to the time of his

defection, despite Yeltsin’s decree that the program

be dismantled. Again in the fall of 1993, a third

defector from the Biopreparat group spoke to Brit-
The Biological Warfare Threat

455

ish intelligence and confirmed the stories of both

previous defectors.11

Sound, compelling evidence from these recent

defectors; confrontations among the leaders of the

United States (President Bush), United Kingdom

(Prime Minister Thatcher, Prime Minister Major),

and the Soviet Union (President Gorbachev); and

confrontations between U.S. President Clinton and

Russian President Yeltsin have all failed to alleviate U.S. concerns about the current Russian biological warfare program. Invited by the Russians, a joint

United States–United Kingdom delegation visited

several Russian sites in 1990. The trip was intended

to be reassuring but had the opposite effect. The

team discovered a large aerosol test chamber that

was designed to spray aerosols on animals tied

down at various locations within the chamber. They

also discovered a chamber used to test delivery systems for biological weapons. At another site, they

saw row after row of huge fermentation vessels. All

this evidence corroborates what Vladimir Pasechnik

told.11

In 1992, in an attempt to meet the concerns

expressed by the United States and the United

Kingdom, Russia emphasized its commitment to

comply with the Biological Weapons Convention officially, in a three-way agreement with the United

States and the United Kingdom. The agreement,

officially known as the Trilateral Agreement, was

struck after negotiations in Moscow between U.S.

Undersecretary of State Frank Wisner and senior

British and Russian officials. This meeting resulted

from an official request by the U.S. State Department on 31 August 1992 to the Russians for reassurance that the germ weapons program of the

former Soviet Union has been terminated.13

The Trilateral Agreement (1) is intended to build

confidence that the Russians will dismantle the

former Soviet Union’s offensive biological weapons

program; (2) commits Russia to (a) open suspect

facilities to inspection, (b) convert biological warfare facilities to civilian production, and (c) end biological weapons projects except for defensive programs; and (3) provides for mutual inspection of

biological sites in the United States, the United

Kingdom, and Russia. U.S. and British inspectors

may visit any suspect site and conduct inspections

as intrusive as necessary to resolve concerns. Russian inspectors will be permitted to visit U.S. and

British civilian biological research facilities once the

initial round of inspections within Russia is completed.1

 Military facilities will be open to inspection after the suspect civilian facilities have been

inspected.

In 1991, a United States–United Kingdom delegation visited the St. Petersburg Institute of Especially

Pure Biopreparations, which Vladimir Pasechnik

had said was the site of work on biological weapons. The first visit under the Trilateral Agreement

occurred in the fall of 1993, after a year of talks concerning the protection of proprietary information

during the visits to the three participating countries.

The delegation to this visit toured two sites: an installation at Berdsk, a town near Novosibirsk, Siberia, and Pokrov, a site outside Moscow. In January

1994, the United States–United Kingdom delegation

visited two more sites in the former Soviet Union;

later that year, a Russian delegation visited one

nonmilitary site in the United Kingdom and three

in the United States. Anatoly Kuntsevich, director

of Russia’s Presidential Committee on Problems of

Chemical and Biological Disarmament, stated that

these visits should put the Western concerns to rest;

however, American officials say that ambiguities

remain and that a working group should be formed

to discuss the two sides’ past biological warfare

programs.14

Not fully alleviating the United States’s concerns

about the continuation of the former Soviet program, but a positive step forward, was Yeltsin’s

firing of Kuntsevich in April 1994. Kuntsevich had

played a leading role in development of the former

Soviet Union’s chemical arsenal. He was regarded

by some in Washington as an obstacle to progress

on the germ weapon issue, and, in fact, was one of

the main persons behind the attempt to hide the

continuation of the Russian program from Yeltsin

after Yeltsin had stated that it would be dismantled.

President Yeltsin’s office attributed Kuntsevich’s

dismissal to a “gross violation of his duties.”15(pA-28)

A news brief reported on 7 April 1994 by the Information-Telegraph Agency of Russia–Telegraph

Agency of the Soviet Union (ITAR-TASS) stated that

a Moscow daily newspaper, Kommersant, speculated

that a connection existed between Western press

accusations of continuing Russian work on biological warfare and the firing of Anatoly Kuntsevich.

Doubts linger in the West about Russia’s claims

that no biological weapons were ever produced and

that all activities have been halted, never to be restarted. Moreover, the West worries that the political leadership in Moscow may be unable to ever get

a full disclosure or a firm commitment to cease all

biological warfare activities beyond those permitted by the Biological Weapons Convention of 1972.16

In light of all these revelations, it is clear that the

United States must maintain a strong Biological

Defense Research Program.
Medical Aspects of Chemical and Biological Warfare

456

PROLIFERATION OF BIOLOGICAL WEAPONS

International proliferation of biological weapons

programs broadens the range of agents that U.S.

forces may encounter. The modernization of many

Third World nations with the subsequent development of industrial, medical, pharmaceutical, and

agricultural facilities needed to support these advancing societies also provides the basis for development of a biological weapons program should

that nation decide to pursue such an endeavor. A

biological weapons program can be easily concealed

within legitimate research and development and

industrial programs within those countries that seek

such capabilities.1

 In December 1991, Robert Gates,

then Director of Central Intelligence, stated in testimony before the U.S. House of Representatives

Armed Services Committee’s Defense Policy Panel:

The accelerating proliferation of nuclear, biological, and chemical weapons in other countries

around the world is probably of gravest concern.

The more countries that possess such weapons—

even if acquired for deterrent purposes—the

greater the likelihood that such weapons will be

used.1(p2)

A report issued by the Committee on Armed Services, U.S. House of Representatives, on its inquiry

into the chemical and biological threat noted that

11 nations possess or could develop an offensive

biological weapons capability (Exhibit 21-1). These

nations are in addition to the 31 that already possess or could develop an offensive chemical weapons capability.1

 While many in government, intelligence, and diplomatic circles express grave concern

about the proliferation of biological weapons, there

has been relatively little carryover into the general

public. In part, the relative lack of interest in the

proliferation of biological weapons can be attributed to the view that the Biological Weapons Convention successfully deters nations from pursuing

a biological warfare capability. But another explanation is that the facts are hidden from the public

domain: much of the information on biological

weapons and proliferation is classified, and only

those with a “need to know” have access.

An analysis of the incentives associated with a

biological weapons program may offer the best insight into the current proliferation problem. Such a

program has military, technical, and economic, as

well as political, incentives.17 Unless positive international controls can be established, the proliferation of biological weapons will probably proceed

unchecked.

EXHIBIT 21-1

INTERNATIONAL BIOLOGICAL

WEAPONS PROGRAMS

Known

Iraq

Former Soviet Union

Probable

China

Iran

North Korea

Libya

Syria

Taiwan

Possible

Cuba

Egypt

Israel

Source: Committee on Armed Services, House of Representatives. Special Inquiry Into the Chemical and Biological Threat. Countering the Chemical and Biological Weapons

Threat in the Post-Soviet World. Washington, DC: US Government Printing Office; 23 Feb 1993. Report to the Congress.

Military Incentives

From a military viewpoint, the ability of biological warfare to produce large numbers of casualties

makes these weapons highly attractive for longrange targeting of populations. Detailed in a report

from the World Health Organization on the health

aspects of the use of these weapons, the enormous

impact these weapons would have on a population

can readily be seen. According to this study, if a biological agent such as anthrax were used on an urban population of approximately 5 million people

in an economically developed country such as the

United States, an attack on a large city from a single

plane disseminating 50 kg of the dried agent in a

suitable aerosol form would affect an area far in

excess of 20 km downwind, with approximately

100,000 deaths and 250,000 being incapacitated or

dying. In the same scenario but using a different

agent (such as Q fever), we would expect to find
The Biological Warfare Threat

457

only several hundred deaths but the same number

of people temporarily incapacitated.18

The U.S. military confirmed the magnitude of the

effects on a population such as that described above

when it looked at the combat effects of major biological agents in studies conducted at Dugway

Proving Ground, Utah.19 We cannot help but ask: Is

our medical system (civilian or military) ready for

such a casualty situation—from either the purely

medical patient-management perspective or the

psychological perspective that the mass casualty

situation would incite?

For the sake of argument, we might agree at this

point that if nuclear weapons are not attainable,

then biological weapons could be a feasible and

economical alternative, filling the strategic role of

nuclear weapons. Biological weapons could very

easily fill an intimidation role. Further, if the agent

and means of delivery were both carefully selected,

biological weapons could also play a tactical role

against a wide array of battlefield targets, including communications and logistical centers as well

as areas of high troop concentrations. Because some

biological agents (eg, Q fever, staphylococcal enterotoxin) are likely to incapacitate more victims than

they kill and do not cause substantial collateral destruction, they have some significant advantages

over nuclear weapons.17

It seems logical to conclude that countries might

want to add biological warfare weapons to their

military armamentaria out of fear, believing that

they may be at a military disadvantage if their enemies have these weapons. Robert Gates, former

Director of Central Intelligence, stated, in a speech

delivered in San Francisco, California, to the

Comstock Club on 15 December 1992, that for some,

these weapons represent symbols of technical sophistication and military prowess—and that acquiring powerful weapons has become the hallmark of acceptance as a world power.1(p4)

Technical Incentives

In analyzing the biological weapons proliferation

problem by scrutinizing the technical incentives

that might attract a country to pursue such a program, we quickly see the comparative ease with

which production of many biological warfare agents

can be accomplished. Virtually all the technology

needed to support a biological weapons program

is dual use, obtainable off the shelf for a variety of

legitimate purposes, and widely available.16 This

technology is very different from nuclear warfare

technology, which requires dedicated facilities, or

chemical warfare technology, where the agents have

little if any civilian application. In addition, both

nuclear and chemical technologies require raw materials that make innocent and legitimate use difficult to explain to the international community.

On the other hand, the equipment and technology used for offensive biological weapons research

is no different from that used in legitimate biomedical research anywhere in the world. Equipment for

processing and production of such agents is found

in such diverse industries as wine and beer manufacture, pharmaceutical research and development,

and the food and agriculture industries.17 Few items

need to be purchased from the “outside,” and

simple fermentation media are easy to make.20

Advanced capabilities have proliferated as Western universities have produced an abundance of

graduate students in the biological sciences with

training and expertise on the leading edge of biotechnology. Third-world facilities engaged in

biological research are rapidly becoming more advanced as the dissemination of scientific information is at an all-time high. Dissemination equipment

that could be purchased and used as off-the-shelf

items, with few or minor modifications, may be found

in the agriculture industry (sprayers) and hardware

stores (paint sprayers), to name just a few.17

The potential agents may themselves be considered dual-use items. For example, botulinum toxin

has been used investigationally for many years to

treat ocular muscle disorders, and was approved

in 1990 by the U.S. Food and Drug Administration

(FDA) for intramuscular treatment of strabismus

and blepharospasm.21 As another example, saxitoxin

has been widely used for decades to study the sodium channel in nerve tissue, and algal toxins are

used in research as potential antineoplastic agents.

Stating this concept another way, all of the infectious agents (bacteria, fungi, and viruses) as well

as the toxins can be considered dual use in this

sense: they can be used purposefully to inflict disease in humans, animals, and plants. Therefore, research needs to be done (and is, in fact, ongoing)

on these agents so that better means of detection,

prevention, and treatment of disease may be devised. Thus, we must acknowledge that potential

biological warfare agents are currently found

worldwide in laboratories and medical centers.17

Economic Incentives

In analyzing the biological weapons proliferation

problem through economic incentives that might
Medical Aspects of Chemical and Biological Warfare

458

attract a country to pursue such a program, we realize that the start-up costs of biological weapons

programs are not prohibitive. This becomes a major incentive, especially relative to the cost of embarking on a nuclear weapons program.17 The cost

of a biological program is much less than either a

nuclear or chemical program: estimates vary from

$2 billion to $10 billion for a nuclear program; to

tens of millions for a chemical program; to less than

$10 million for a biological program.20 From a purely

economic standpoint, we can understand why biological weapons, according to a famous saying, are

a poor man’s nuclear bomb and can be produced

by Third World countries.4

Even the weapons used to deliver these agents

are relatively cost-effective. A group of chemical and

biological experts, appearing before a United Nations panel in 1969, estimated that

for a large-scale operation against a civilian population, casualties might cost about $2,000 per square

kilometer with conventional weapons, $800 with

nuclear weapons, $600 with nerve-gas weapons,

and $1 with biological weapons.22(p16)

Unfortunately, long-range delivery systems are

also proliferating. Aging ballistic missiles that the

superpowers have discarded as obsolete are being

acquired by Third World nations. The lighter biological warhead seems to extend the range of these

missiles, and inaccuracy is a lesser problem with

biological weapons, as dissemination of the agent

depends on environmental conditions.23

Political Incentives

Two distinct political incentives might persuade

a country to pursue a biological weapons program:

(1) domestic and international status and (2) a favorable risk–benefit ratio. First, a country’s ability

to threaten its enemies with a weapon capable of

inflicting mass casualties offers some tangible advantages.17 W. Seth Carus, Director for Defense

Strategy on the Policy Planning Staff in the Office

of the Secretary of Defense, summarizes this political incentive in the following statement:

The perceived need for deterrence or compellence

[sic] capabilities, a desire to influence the politicalmilitary calculations of potential adversaries, the

search for national status, and even bureaucratic

and personal factors can play a role in the initiation of such programs.16(p22)

Second, detecting a clandestine biological warfare program is difficult. The risk is relatively low

that biological weapons research and development

will be uncovered and confirmed—unlike a nuclear

or chemical weapons program. Because virtually all

of the equipment associated with biological weapons can be used for legitimate purposes, there is no

easily discriminated, unambiguous signature.16

A country can undertake many illicit biological

warfare activities—save actual use—toward developing a sophisticated offensive biological warfare

program without provoking inquiries from the international community.17 Even signatories to the

Biological Weapons Convention can investigate,

for public health and commercial purposes, the

properties of bacteria, viruses, and toxins that are

considered to be biological warfare agents without

ever violating the convention. Legitimate production facilities can produce such agents for offensive

purposes on short notice, and with no more than a

temporary slowdown on their routine production

output. Because biological weapons can be configured out of preexisting conventional or chemical

munitions that have already been declared to international groups, such weapons do not always

require extensive testing. Thus, biological weapons

can be a nation’s “silent equalizer” but not cost a

large percentage of the country’s gross national

product.

Weapons of mass destruction should be compared from such perspectives as technology, cost,

signature, effectiveness on troops—protected and

unprotected—and tactics as well as strategy (Table

21-1). We can see from looking at Table 21-1 that a

nuclear weapons program requires a very high level

of technology and a significant investment in a

unique and distinctive infrastructure for research,

development, production, and support of such

weapons on the battlefield.1

 The outlay of facilities

that are associated with a nuclear weapons program

usually results in a distinctive and readily observable signature. Chemical and biological weapons

programs, on the other hand, usually require lower

levels of technology and monetary investment. The

infrastructure for development and production of

chemical and biological agents can be embedded

in the industrial chemical and pharmaceutical infrastructure of any modern or developing state, thus

resulting in a nondistinctive and readily observable

signature.

In trying to ascertain these weapons’ effectiveness, we must keep in mind that nuclear weapons

have immediate and decisive effects, whether employed tactically on the battlefield or strategically

against rear areas, and regardless of whether per-
The Biological Warfare Threat

459

sonnel in the area are protected or not. On the other

hand, protective measures can provide a high level

of protection against chemical and biological weapons if they are in use at the time these weapons are

employed. This requires an effective and timely

detection system, as these protective measures cannot continually be in place. Finally, the delayed effect of most biological weapons (as a result of the

incubation period before becoming ill) causes us to

question the tactical utility of biological weapons.1

NONHUMAN TARGETS OF ATTACK

We must remember that humans need not be the

only target of biological weapons. These weapons

might be meant to attack a country’s animal herds,

crops, or even a material supply that is vital for revenue. For example, if purposely introduced into a

large pig population, swine fever virus, also known

as wart hog disease, could destroy the herd. This

attack could be carried out with relative ease and

virtually no immediately visible signature. The

usual method of controlling such widespread disease—mass slaughter of the infected animals—can

be economically devastating to many countries.22

The main purpose of this use of biological agents

is to affect humans indirectly by limiting their food

supply.24 Such use of biological agents could initiate

a longer-term decline in food stores, which could

then add the prospect of starvation of a population

to the immediate devastating effects of conventional

weapons. A population dependent on a staple crop

such as rice could be rendered helpless by the introduction of a specific disease that devastated their

unprotected rice crop.25

Likewise, a purposely introduced organism that

degrades specific metals and renders them useless

could also be devastating for a small country’s

economy. With increasing technology, specific

antimaterial agents could be designed and could

create enormous problems.

Animals

The purposeful spreading of infectious agents

that attack cattle or other domestic animals can lead

to serious consequences for a country’s food supply or export of animal products (hides, wool, fats,

and biological medicinal products such as adrenalin, insulin, pituitary extracts, cortisone, vaccines,

and antisera).26 The first 20th-century allegations of

the use of biological warfare were made against the

Germans, this being in the form of antianimal use.

In 1915, the Germans were alleged to have inoculated horses and cattle with disease-producing bacteria before the animals were shipped from the

United States to our allies in Europe. The following

year, the Germans again allegedly inoculated horses

with glanders and cattle with anthrax, this time in

Bucharest, Romania.27 Then in 1917, they supposedly employed similar tactics to infect 4,500 mules

in Mesopotamia. As expected, Germany issued official denials of these allegations.28

An example of economic setback (albeit as a result of unfortunate natural circumstances) caused

by disease among animals occurred when African

swine fever was spread from Africa to the Iberian

peninsula during the latter 1950s. The annual loss

amounted to $9 million as a result of reduced pig

production.29

TABLE 21-1

COMPARISON OF WEAPONS OF MASS DESTRUCTION

Effectiveness

Protected Troops Unprotected Troops

Type Technology Cost Signature Tactical Strategic Tactical Strategic

Nuclear ++ ++ ++ ++ ++ ++ ++

Chemical + + + – – ++ +

Biological + – – – – + ++

++: very high; +: high; –: lower

Adapted from Committee on Armed Services, House of Representatives. Special Inquiry Into the Chemical and Biological Threat.

Countering the Chemical and Biological Weapons Threat in the Post-Soviet World. Washington, DC: US Government Printing Office; 23

Feb 1993: 7. Report to the Congress.
Medical Aspects of Chemical and Biological Warfare

460

A much more recent occurrence was in January

1984, in the state of Queensland, Australia, when

an extortionist threatened to infect the livestock

with foot-and-mouth disease if certain prison reforms were not undertaken. Authorities could not

afford to take this threat lightly: Queensland is

home to 60% of the Australian beef industry. The

Australian government sought urgent and highly

secret consultations with the United States and

some of its other allies. The threat was ultimately

determined to be a hoax perpetrated by a local convict; however, the economic implications of such an

attack are obvious, and even the Australian authorities concluded that it would have been almost impossible to prevent.22

It seems reasonable that aggressor forces will use

this deliberate spreading of infectious agents—either in peacetime or immediately before an outbreak

of war—with the intention of initiating economic

breakdowns. From the very beginnings of our biological warfare program, our scientists felt confident of their abilities to cause catastrophic epidemics in domestic animal populations with such viral

diseases as foot and mouth, rinderpest, wart hog

disease, fowl pest, and hog cholera. Each disease

had devastating mortality and could render a predictable epidemic-producing agent in the animal

population, much more certain than the predictability of agents inducing epidemics in humans.30

Antianimal research began in 1942 in the United

States and was initially concerned with developing

methods for protecting our large livestock population against biological warfare attack. This research

resulted in the development of vaccines to protect

against rinderpest, a deadly cattle disease and

Newcastle disease, a serious poultry affliction. Research was initially carried out at Camp Detrick

(now Fort Detrick), Frederick, Maryland, but when

research on a larger scale was needed, a facility was

established at Camp Terry on Plum Island, New

York. Two field tests of potential antianimal agents

were conducted using hog cholera virus and

Newcastle virus. The program at Camp Detrick was

terminated in 1954. By agreement between the secretaries of defense and agriculture, the Department

of Agriculture assumed responsibility for the defense of our livestock against biological warfare attack, and the Plum Island facilities were transferred

to that agency.31

Crops

Plants, like man, have been plagued with numerous diseases, and history is dotted with recordings

of human suffering caused by naturally occurring

plant epidemics (epiphytotics). Biological antiplant

agents (ie, living organisms that cause disease or

damage to plants; note that this definition includes

insects and other crop-eating pests in addition to

plant diseases), may be used intentionally by an

enemy to attack food or economically valuable

crops, thereby reducing a nation’s ability to resist

aggression.26

Attacks with biological weapons on a country’s

agriculture could have serious economic consequences and, if international sanctions or an embargo were in place, could prove devastating in the

production of foodstuffs. Modern agricultural

methods dictate that large areas be planted with

genetically identical crops. This genetic homogeneity leaves entire regions susceptible to attack with

an antiplant agent to which the crop is not resistant. Entire crops are thus susceptible to being

wiped out during a single harvest season.29 Resistant crops could eventually be planted, but enough

seeds could not be produced in a short enough time

to prevent dire economic consequences.

Speculations as to how to destroy a nation’s agricultural base are not idle fantasy. Both the U.S.32

and the British33 governments sponsored extensive

anticrop research programs during World War II.

Not only were powerful herbicides developed but,

in addition, fungi capable of eradicating specific

crops were identified, and efforts were made to

mass-produce them. In 1944 and 1945, serious consideration was given to destroying the Japanese rice

crop using the fungus Helminthosporium oryzae van

Brede de Haan. That this did not happen reflects not

so much legal or moral factors but practical problems, notably the relative delay with which the desired effect would be obtained against the Japanese,

compared to the effect of more conventional weapons such as firebombs.33

Research on biological warfare agents included

strain selection, evaluation of nutritional requirements, development of optimal growth conditions

and harvesting techniques, and preparation in

a form suitable for dissemination. 31 Much of

our knowledge in this area of anticrop biological

warfare came from the British. In fact, the United

States is said to have provided the money and resources, and the British provided the brains, as they

had begun experimenting with this form of

warfare much earlier than the United States.33 Between 1951 and 1969, the U.S. Army carried out at

least 31 anticrop tests, and rice and wheat blast

fungi were stored at Fort Detrick and at Edgewood Arsenal, both in Maryland, and the Rocky
The Biological Warfare Threat

461

Mountain Arsenal, Denver, Colorado. Experiments

showed that 3 g of the rice blast fungi per hectare

could infect between 50% and 90% of the crops

exposed.30

The CIA was also involved in antiplant agents

about the same time as the U.S. Army. In materials

provided to the U.S. Senate Select Committee on

Intelligence Activities by the CIA during the mid

1970s, the agency acknowledged that it had developed “methods and systems for carrying out a covert attack against crops and causing severe crop

loss.”34(p16) The CIA denied that it had ever employed such systems, and there is no evidence that

it has ever used herbicides or biological agents

against the crops of another nation.34

Some have wondered whether the United States

may have been a target of bioterrorism as recently

as the late 1980s. A very peculiar pattern had

emerged in the spread of the Mediterranean fruit

fly, a major threat to agriculture in California. In

1989, a panel of scientists led by Roy Cunningham,

U.S. Department of Agriculture, met in Los Angeles, California, to discuss possible reasons for this

unexpected ecological anomaly. Despite heroic

attempts to eradicate this insect, new infestations

repeatedly appeared in odd and unexpected places.

Some members of the panel questioned whether a

person or group was purposely breeding and releasing Mediterranean fruit flies. This scenario

might have seemed totally farfetched had not the

mayor of Los Angeles, Tom Bradley, received several letters during this time frame from a group calling itself The Breeders, which claimed to be spreading the insect to protest California’s agricultural

practices.35

Material

Antimaterial biological warfare might be

attempted by an adversary because biological

agents are hard to detect and identify, are readily

concealed, and can plausibly be denied. Antimaterial agents are organisms that degrade some

item of material. Most of the material damage done

by microorganisms is a result of natural contamination that grows only under special conditions of

temperature and relative humidity. Fungi, for example, damage fabrics, rubber products, leather

goods, and foodstuffs. Some bacteria produce

highly acidic compounds that cause pitting in metals; these agents could create potential problems

with stockpiled material.24

Other bacteria can use petroleum products as an

energy source, producing organic residues that

might clog fuel or oil lines. Imagine the disastrous

implications for the military if such a residue-producing bacterial agent were purposely introduced

into a jet fighter aircraft’s fuel system. If the residue were to clog the fuel line, the fuel pumps would

be rendered inoperable.24

THE CURRENT THREAT

Despite the end of the Cold War, the United States

still faces a range of serious national security issues.

One at the forefront is the issue of the proliferation

of biological weapons, and the accelerated development of the capabilities to design and produce

biological weapons on the part of many Third World

nations.17 The Committee on Armed Services of the

U.S. House of Representatives, in their Special Inquiry Into the Chemical and Biological Threat, concluded that despite the demise of the Soviet Union,

with its sizable chemical and biological arsenal, the

threat has increased in terms of widespread proliferation, technological diversity, and the probability of use.1

Of the nations currently believed to have an offensive biological warfare program, only a few are

candidates for a direct armed conflict with the

United States. The most likely route for the United

States or our allies to become involved in a biological conflict would be as third parties in regional

conflicts, whether as members of a United Nations

peacekeeping force or through an act of terrorism.17

This is due to our increased participation in lowintensity operations, however, and does not diminish the threat that biological warfare poses to our

forces fighting a conventional war.

North Korea and China

During the 1990s, hostilities have mounted in

North Korea over allegations that evidence of

nuclear weapons activities is being hidden from

international inspectors. This is the kind of future

conflict that could involve the United States. In

1993, the Russian Foreign Intelligence Service, successor to the Soviet Union’s KGB, released a statement that said, in part:

North Korea is performing applied military-biological research in a whole number of universities,

medical institutes and specialized research institutes. Work is being performed in these research
Medical Aspects of Chemical and Biological Warfare

462

centers with inducers of malignant anthrax, cholera, bubonic plague and smallpox. Biological weapons are being tested on the island territories belonging to the DPRK (Democratic Peoples Republic of

Korea).36(pA-10)

Mr. Gordon Oehler, director of the CIA’s Non-Proliferation Center, confirmed this Russian report.36

The use of smallpox in a weapon, whether the use

be tactical or strategic, would have disastrous effects, as the military and civilians are not immunized against this disease nor have they been for

many years.

In his last message to congressional leaders on

19 January 1993, outgoing President George Bush

revealed intelligence reports (previously highly

classified) that China still has an active biological

warfare program—despite their having signed the

international treaty banning such weapons.37 Even

as recently as May 1994, a reporter investigating

China’s military–industrial complex stated that

arms sales, especially unreported sales and transfers of weapons of mass destruction to some of the

most dangerous governments in the world, are part

of the dark side of China’s commercial activities.

The newspaper report went on to state: “China has

violated every non-proliferation pledge it has ever

made, including its pledge not to engage in an offensive biological warfare program.”38(pC-3) This is

alarming, especially as we consider the close relationship between China and North Korea.

Iraq

As reported by the department of defense in

1992,39 by the time Iraq invaded Kuwait, Iraq had

developed the most extensive biological warfare

program in the Arab world (despite having been a

signatory to the 1972 Biological Weapons Convention outlawing such endeavors). After the Persian

Gulf War (1990–1991), Iraqi authorities admitted the

program included anthrax bacteria and botulinum

toxin.1 Then in August 1995, Iraq revealed to United

Nations inspectors that it had had a far more extensive and aggressive biological warfare program

prior to the Persian Gulf War than had previously

been admitted. The Iraqi authorities claimed production of thousands of liters of botulinum toxin and of

Bacillus anthracis. Additionally, they stated that unspecified amounts of both agents were loaded on

Scud missile warheads and aerial bombs. In this same

revelation to United Nations inspectors, the Iraqis

claimed to have destroyed the agents during the

January–February 1991 time frame, but they have

yet to produce evidence to support their claim.40

Iraq’s biological capabilities, described as “a sizable stockpile,”41(pA-1) by William Webster, former

Director of Central Intelligence, caused the coalition forces to procure large quantities of special biological warfare vaccines (against anthrax and botulinum) for their military personnel. These vaccines

were in extremely limited supplies, forcing commanders to allocate vaccine only to troops they believed were at greatest risk to the use of these

agents. Situations like this require commanders to

make ethical decisions, as it was not known definitively who was at greatest risk.

The anthrax vaccine, which is licensed by the

FDA, was given to approximately 150,000 military

personnel (25%–30% of the deployed U.S. forces).42

The botulinum toxoid vaccine was given to approximately 8,000 military personnel (1% of deployed

U.S. forces).42 The biological weapons threat posed

by Iraq during this crisis has been characterized as

the most serious such threat faced by U.S. forces

since World War I.1 During January 1991, the image

of a scared, shaking television reporter wearing a

gas mask and the trembling of his voice as he reported the detonation of an incoming Iraqi Scud

missile near Tel Aviv, Israel, brought home to all a

frightening view of the increasing sophistication of

the chemical and biological threat and the apparent vulnerability of soldiers and civilians alike.

The reasons why Iraq did not use these weapons

during the Persian Gulf War, the subject of much

speculation, will probably never be known with

certainty. However, this Iraqi threat highlighted the

problems posed by the proliferation of weapons of

mass destruction among Third World nations and

the potential threat posed to U.S. forces as well as

other nations. On 3 April 1991, the United Nations

Security Council passed Resolution 687, which required that

• Iraq’s chemical, biological, and nuclear

weapons be registered;

• these weapons and all production and research facilities be destroyed, rendered unusable, or removed;

• Iraq disclose all its holdings and programs

and allow unhindered on-site inspections,

and destroy the weapons-making potential

on its territory itself or permit those weapons to be destroyed.

In conjunction with a longer-term verification regime established by United Nations Resolution 715,

Iraq was also required to renounce the possession

of any weapons of mass destruction. On 6 April
The Biological Warfare Threat

463

1991, Iraq accepted the terms of Resolution 687.

However, the Iraqi government has steadfastly

refused to accept Resolution 715 and regards the

resolution as an unwarranted infringement on its

sovereignty.

The Security Council entrusted implementation

of the resolution to a special commission known as

UNSCOM (United Nations Special Commission),

which was set up by the United Nations SecretaryGeneral in May 1991. UNSCOM has carried out a

series of inspections of Iraqi facilities, but relations

with Iraq have been marked by frequent instances

of misinformation, concealment, lack of cooperation, and obstruction and harassment of the inspection teams. Before the 1995 admission by Iraq of

having weaponized biological agents, inspections

into two suspected key Iraqi biological warfare facilities—Salmon Pak and Al Hakam—found no conclusive evidence of an Iraqi offensive biological

program. However, evidence (such as Iraq’s inability to explain the use of tons of growth media suitable for biological agent production) strongly

pointed to the existence of a program. Furthermore,

the inspection teams had only obtained an admission by Iraqi officials that Iraq had carried out a

program of biological research for military purposes.1

 The UNSCOM experience underscores the

difficulty of monitoring compliance with the Biological Weapons Convention.

Foreign and Domestic Terrorism

Although biological warfare is most often discussed in terms of weapons of mass destruction,

usually in the context of war, terrorist use of biological agents cannot be excluded. Biological warfare agents are, for the most part, inexpensive and

readily obtainable, and “cookbook” approaches are

readily available. One such book is Silent Death, by

an author who calls himself Uncle Fester.43 Other

titles from the same publisher include The Poisoner’s

Handbook and Crimes Involving Poisons.

Unfortunately, recent examples of possible intent

to use are not difficult to find. A laboratory in a safe

house of the Red Army Faction in Paris, France, was

found to have made quantities of botulinum toxin;

it is believed that none was used.16 More alarming

were the actions of the Aum Shinrikyo cult in Japan in early 1995. In addition to releasing the nerve

agent sarin in the Tokyo subway on 18 March 1995,

cult members were preparing vast quantities of

Clostridium difficile bacterial spores for terrorist

use.44 Although possibly not producing large numbers of casualties, the use of even small amounts of

such an agent would almost assuredly create major

panic.

In March 1989, the most intensive food safety

investigation in FDA history took place when a terrorist threatened to poison this nation’s fresh fruit

supply, to focus attention on the living conditions

of the lower classes in Chile. The terrorist made

good on his phone call to the FDA, as two grapes

were found laced with small amounts of cyanide.

Fortunately no one was poisoned, but the incident

cost millions of dollars to investigate in this country, and had a significant impact on Chile’s national

economy, where fruit and vegetable exports are second in importance only to copper.45 A biological

toxin could have been used just as easily as cyanide in this instance.

The amounts of toxin needed to obtain the desired effect are exceedingly small. “For example,

about 30 grams of the toxin ricin, easily concealed

in a pocket, would be sufficient to lethally poison

one batch of 150 pounds of meat, enough to produce 1,500 hot dogs.”46 The threat is real. And the

knowledge required is not esoteric:

To engage in bioterrorism requires only the type of

knowledge that Kateuas found in his herbals—that

is, a sophisticated understanding of the properties

of various edible plants, medicinal herbs, toxins

and venoms, and infectious and pharmaceutical

agents.35(p45)

The use of biological agents in domestic terrorism has been attempted on several occasions in recent years, causing alarm and illustrating the ease

of obtaining these agents. In May 1995, the American Type Culture Collection (ATCC), a nonprofit

organization in Rockville, Maryland, that supplies

biological specimens to scientists all over the world,

shipped a package containing three vials of Yersinia

pestis to the home of a white supremacist in Ohio.47

(This organism, which causes plague, killed one

quarter of the population when it struck Europe in

the 14th century and wreaked havoc in India as recently as 1994.48) The American Type Culture Collection has tightened its controls on whom it will

provide hazardous materials to, but even terrorists

can produce legitimate request documents: the

white supremacist is a qualified microbiologist.

When his house was searched, police reported finding hand grenade triggers, homemade explosive

devices, and detonating fuzes.47 Fortunately, he was

caught prior to any intentional use.

Two members of the Minnesota Patriots Council

were convicted in 1995 for planning to use a lethal

biological agent against U.S. marshals and Internal
Medical Aspects of Chemical and Biological Warfare

464

Revenue Service agents. According to trial testimony, they planned to poison U.S. agents by placing ricin toxin on doorknobs.49

Lastly, in March 1992, a Tyson’s Corner, Virginia,

man was arrested and charged with malicious

wounding in a hoax in which he sprayed his roommates with a fluid that he claimed contained anthrax bacteria. The house was placed under quarantine immediately after the incident, and while

awaiting test results, 20 people—one a pregnant

woman—were treated for possible exposure to

anthrax.50

The threat that terrorists will use biological

agents cannot be ignored and we have to remain

strong, vigilant, and determined to defeat this form

of terrorism as we do every other act of terrorism.

SUMMARY

International proliferation of biological warfare

programs broadens the range of agents that members of the U.S. armed forces may encounter. Ironically, the modernization of many Third World

nations—with the subsequent development of industrial, medical, pharmaceutical, and agricultural facilities needed to support these advancing societies—

provides the basis for development of a biological

weapons program, should a nation decide to pursue such an endeavor. A biological weapons program can easily be concealed within legitimate

research-and-development and industrial programs, even by countries that are signatories to the

1972 Biological Weapons Convention. Actions such

as these are grave threats to our national security.

Biological warfare agents may be more potent

than the most lethal chemical warfare agents, and

provide a broader area coverage per pound of payload than any other weapons system. The proliferation of technology and of scientific progress in

biochemistry and biotechnology has simplified production requirements and provided the opportunity

for the creation of exotic agents. This could involve

the tailoring of pathogenic microorganisms capable

of creating a novel disease, perhaps on an epidemic

scale. Humans need not be the only target of biological weapons. These weapons might be meant

to attack a country’s revenue or food crop, animal

herds, or even a supply of a material that is vital

for revenue or defense.

Despite the end of the Cold War, the United States

still faces serious national security issues. One at

the forefront is the issue of the proliferation of biological weapons, especially in Third World nations

that have compelling military, technical, economic,

and political incentives to pursue this capability.

The use of biological agents in future wars and actions by terrorists—foreign and domestic—is a

legitimate issue of concern. Resolution of this problem should be given the highest priority.

REFERENCES

1. Committee on Armed Services, House of Representatives. Special Inquiry Into the Chemical and Biological

Threat. Countering the Chemical and Biological Weapons Threat in the Post-Soviet World. Washington, DC: US Government Printing Office; 23 Feb 1993. Report to the Congress.

2. Chemical and bacteriological weapons in the 1980s. Lancet. 1984;Jul 21:141–143.

3. Harruff RC. Chemical-biological warfare in Asia. JAMA. 1983;250(4):497–498.

4. Leskov S; Kogan V, trans. Military bacteriological programs in Russia and USA are strictly secretive and represent a terrible threat to the world. Izvestiya. 26 Jun 1993;15.

5. Department of State. Joint US/UK/Russian Statement on Biological Warfare. Washington, DC: USSD, Office of the

Assistant Secretary/Spokesmen, 14 Sep 1992. Statement for Immediate Release by Richard Boucher, Spokesman.

6. Zilinskas RA. Anthrax in Sverdlovsk? Bull At Sci. 1983;Jun/Jul:24–27.

7. Abramova FA, Grinberg LV, Yampolskaya OV, Walker DH. Pathology of inhalational anthrax in 42 cases from

the Sverdlovsk outbreak of 1979. Proc Natl Acad Sci. 1993;90(Mar):2291–2294.

8. Storella MC. Poisoning Arms Control: The Soviet Union and Chemical/Biological Weapons. Cambridge, Mass: Institute for Foreign Policy Analysis, Inc; 1984.
The Biological Warfare Threat

465

9. Smith RJ. Russia fails to detail germ arms. Washington Post. 3 Aug 1992;A-1.

10. Defense Intelligence Agency. Soviet Biological Warfare Threat. Washington, DC: Department of Defense, 1986.

Report DST-1610F-057-86.

11. Adams J. The untold story of Russia’s secret biological weapons. Sunday Times (London). 27 Mar 1994;4-1.

12. Barry J. Planning a plague? Newsweek. 1993;Feb 1:40–41.

13. Smith RJ. Russia agrees to inspection of biological research facilities. Washington Post. 15 Sep 1992;A-14.

14. Gordon MR. Moscow is making little progress in disposal of chemical weapons. New York Times. 1 Dec 1993;A-1.

15. Smith RJ. US wary of Russian germ arms. Washington Post. 8 Apr 1994;A-1.

16. Roberts B. Biological Weapons: Weapons of the Future? Washington, DC: The Center for Strategic and International Studies; 1993.

17. Spertzel RO, Wannemacher RW, Linden CD. Biological Weapons Proliferation. Fort Detrick, Frederick, Md: US

Army Medical Research Institute of Infectious Diseases; 1993. Defense Nuclear Agency Report

DNA-TR-92-116.

18. Report of a WHO Group of Consultants. Health Aspects of Chemical and Biological Weapons. Geneva, Switzerland: World Health Organization; 1970: 98–99.

19. Tomich N, ed. Medicine in the Gulf War: Policy and policymakers. US Med. 1991;27(15, 16):6–18.

20. Huxsoll DL. The nature and scope of the BW threat. Director’s Series on Proliferation, 4. Lawrence Livermore

National Laboratory, University of California; May 23, 1994. Report UCRL-LR-114070-4.

21. Abramowicz M, ed. Botulinum toxin for ocular muscle disorders. Med Lett. 1990:32(830):100–101.

22. Douglass JD Jr, Livingston NC. America the Vulnerable: The Threat of Chemical/Biological Warfare. Lexington, Mass:

DC Heath; 1987.

23. Orient JM. Chemical and biological warfare: Should defenses be researched and deployed? JAMA.

1989;262(5):644–648.

24. Department of the Army. Potential Military Chemical/Biological Agents and Compounds. Washington, DC: DA;

1990. Field Manual 3-9.

25. Gander TJ, ed. Jane’s NBC Protection Equipment, 1992–93. Alexandria, Va: Jane’s Information Group Inc; 1992.

26. Department of the Army. Technical Aspects of Biological Defense. Washington, DC: DA; 1971. Technical

Manual 3-216.

27. Somani SM. Chemical Warfare Agents. San Diego, Calif: Academic Press; 1992.

28. Poupard JA, Miller LA. History of biological warfare: Catapults to capsomeres. In: Zilinskas RA, ed. The microbiologist and biological defense research: Ethics, politics, and international security. Ann N Y Acad Sci.

1992;666:9–18.

29. Gripstad B, ed. Biological Warfare Agents. Stockholm, Sweden: Swedish National Defense Research Institute; 1986.

30. Beckett B. Weapons of Tomorrow. New York, NY: Plenum Press; 1983.

31. Department of the Army. US Army Activity in the US Biological Warfare Programs 1942–1977. Vol 2. Washington,

DC: DA; 1977.
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32. Bernstein BJ. The birth of the US biological-warfare program. Sci Am. 1987; 256:116–121.

33. Harris R, Paxman J. A Higher Form of Killing: The Secret Story of Chemical and Biological Warfare. New York, NY:

Hill and Wang, The Noonday Press; 1982.

34. Livingstone NC, Douglass JD. CBW: The poor man’s atomic bomb. National Security Papers. Vol 1. Cambridge,

Mass: Institute for Foreign Policy Analysis, Inc; 1984.

35. Root RS. Infectious terrorism. Atlantic Monthly. 1991;May:44–50.

36. Fialka J. CIA says North Korea appears active in biological, nuclear arms. Wall Street Journal. 25 Feb 1993;A-10.

37. Fenyvesi C, ed. Washington whispers. US News World Rep. 22 Feb 1993:22.

38. Triplett WC. A look at Asia past and present: Inside China’s scary new military–industrial complex. Washington Post. 8 May 1994;C3.

39. US Department of Defense. Conduct of the Persian Gulf War. Washington, DC: DOD; Apr 1992.

40. Office of the Secretary of Defense. Proliferation: Threat and Response. Washington, DC: US Government Printing

Office; 1996. Document ISBN 0-16-048591-6.

41. Moore M. Iraq said to have supply of biological weapons. Washington Post. 29 Sep 1990;A1,A24.

42. Persian Gulf Veterans Coordinating Board. Summary of the Issues Impacting Upon the Health of Persian Gulf Veterans. Washington, DC: PGVCB; 18 Apr 1994: Version 2.2.

43. Uncle Fester. Silent Death. Port Townsend, Wash: Loompanics Unlimited; 1989.

44. Garrett L. The return of infectious disease. Foreign Affairs. 1996;Jan/Feb:66–79.

45. Grigg B, Modeland V. The cyanide scare: A tale of two grapes. FDA Consumer. Jul–Aug 1989;7–11.

46. Zilinskas RA. Terrorism and biological weapons: Inevitable alliance? Perspect Biol Med. 1990;34(1):44–72.

47. Birch D. Bubonic plague sample delivered to white racist. Baltimore Sun. 18 May 1995;A-4.

48. Reuter. Plague reaches Calcutta’s millions. Toronto Star. 29 Sep 1994;A-3.

49. Smith RM, Parker M, eds. Poison probe. Newsweek. 1995;May 29:4. Periscope.

50. Bates S. Fairfax man accused of anthrax threat. Washington Post. 3 Mar 1992;C-3.
467

Anthrax

Chapter 22

ANTHRAX

ARTHUR M. FRIEDLANDER, M.D.*

INTRODUCTION AND HISTORY

THE ORGANISM

EPIDEMIOLOGY

PATHOGENESIS

CLINICAL DISEASE

Cutaneous Anthrax

Inhalational Anthrax

Oropharyngeal and Gastrointestinal Anthrax

Meningitis

DIAGNOSIS

TREATMENT

PROPHYLAXIS

Prophylactic Treatment After Exposure

Active Immunization

Side Effects

SUMMARY

*Colonel, Medical Corps, U.S. Army; Chief, Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick,

Frederick, Maryland 21702-5011; and Clinical Associate Professor of Medicine, Uniformed Services University of the Health Sciences, 4301

Jones Bridge Road, Bethesda, Maryland 20814-4799
Medical Aspects of Chemical and Biological Warfare

468

INTRODUCTION AND HISTORY

bacterial vaccine was developed, in 1881, by Louis

Pasteur.3

 During the latter half of the 19th century,

a previously unrecognized form of anthrax appeared for the first time, namely, inhalational anthrax.4

 This occurred among woolsorters in England, due to the generation of infectious aerosols

of anthrax spores under industrial conditions, from

the processing of contaminated goat hair and alpaca

wool. It probably represents the first described occupational respiratory infectious disease.

Owing to the infectiousness of anthrax spores by

the respiratory route and the high mortality of inhalational anthrax, the military’s concern with anthrax is with its potential use as a biological weapon.

This concern was heightened by the revelation that

the largest epidemic of inhalational anthrax in this

century, in Sverdlovsk, Russia, in 1979, occurred

after anthrax spores were released from a military

research facility located upwind from where the

cases occurred. Cases were also reported in animals

located more than 50 km from the site.5,6

Anthrax, a zoonotic disease caused by Bacillus

anthracis, occurs in domesticated and wild animals—primarily herbivores, including goats, sheep,

cattle, horses, and swine. Humans usually become

infected by contact with infected animals or contaminated animal products. Infection occurs most

commonly via the cutaneous route and only very

rarely via the respiratory or gastrointestinal routes.

Anthrax has a long association with human history. The fifth and sixth plagues described in Exodus may have been anthrax in domesticated animals followed by cutaneous anthrax in humans. The

disease that Virgil described in his Georgics is clearly

anthrax in domestic and wild animals.1 And during the 16th to the 18th centuries in Europe, anthrax

was an economically important agricultural disease.

Anthrax was intimately associated with the origins of microbiology and immunology, being the

first disease for which a microbial origin was definitively established, in 1876, by Robert Koch.2

 It

also was the first disease for which an effective live

Bacillus anthracis is a large, Gram-positive, sporeforming, nonmotile bacillus (1–1.5 μm x 3–10 μm).

The organism grows readily on sheep blood agar

aerobically and is nonhemolytic under these conditions. The colonies are large, rough, and grayishwhite, with irregular, curving outgrowths from

the margin. Both in vitro in the presence of bicarbonate and carbon dioxide, and in tissue in vivo,

the organism forms a prominent capsule. In tissue,

the encapsulated bacteria occur singly or in chains

of two or three bacilli (Figure 22-1). The organism

does not form spores in living tissue; sporulation

THE ORGANISM

Fig. 22-1. Gram’s stain of peripheral blood smear from a

rhesus monkey that died of inhalational anthrax.

Fig. 22-2. Scanning electron micrograph of a preparation

of Bacillus anthracis spores. Two elongated bacilli are also

present among the oval-shaped spores. Original magnification x 2620. Photograph: Courtesy of John Ezzell,

Ph.D., US Army Medical Research Institute of Infectious

Diseases, Fort Detrick, Frederick, Md.
469

Anthrax

occurs only after the infected body has been opened

and exposed to oxygen. The spores, which cause

no swelling of the bacilli, are oval and occur centrally or paracentrally (Figure 22-2). They are

very resistant and may survive in the environment for decades in certain soil conditions. Bacterial identification is confirmed by demonstration

of the protective antigen toxin component, lysis by

a specific bacteriophage, detection of capsule by

fluorescent antibody, and virulence for mice and

guinea pigs. Additional confirmatory tests to identify toxin and capsule genes by the polymerase

chain reaction have also been developed as research

tools.

Anthrax occurs worldwide. The organism exists

in the soil as a spore. The question remains unsettled

as to whether its persistence in the soil is due to significant multiplication of the organism in the soil, or

if it is due solely to cycles of bacterial amplification in

infected animals whose carcasses then contaminate

the soil.7,8 The form of the organism in infected animals is the bacillus. Only when the organism in the

carcass is exposed to air does sporulation occur.

Animals, domestic or wild, become infected

when they ingest spores while grazing on contaminated land or eating contaminated feed. Environmental conditions such as drought, which may promote trauma in the oral cavity on grazing, are

thought to increase the chances of acquiring anthrax,

as Pasteur originally reported.9

 Spread from animal

to animal by mechanical means—by the biting flies,10

and from one environmental site to another by the

nonbiting flies and by vultures8—has been suggested.

Anthrax in humans is associated with agricultural, horticultural, or industrial exposure to infected animals or contaminated animal products.

In the less-developed countries, primarily in Africa,

Asia, and the Middle East, disease occurs from contact with infected domesticated animals or contaminated animal products. This includes handling contaminated carcasses, hides, wool, hair, and bones;

and ingesting contaminated meat. Cases associated

with industrial exposure, rarely seen today, occur

in workers processing contaminated hair, wool,

hides, and bones. Direct contact with contaminated

material leads to cutaneous disease, while ingestion of infected meat gives rise to oropharyngeal or

gastrointestinal forms of anthrax. Inhalation of a

sufficient quantity of spores, usually seen only during generation of aerosols in an enclosed space associated with processing contaminated wool or hair,

gives rise to inhalational anthrax.

Unreliable reporting makes it difficult to estimate

with accuracy the true incidence of human anthrax.

It was estimated in 1958 that worldwide between

20,000 and 100,000 cases occurred annually.11 In

more recent years, anthrax in animals has been reported from 82 countries, and human cases continue

to be reported from Africa, Asia, Europe, and the

Americas.12 In the United States, the annual incidence of human anthrax has steadily declined—

from about 127 cases in the early years of this century to about one per year for the past 10 years. The

vast majority of cases have been cutaneous. Under

natural conditions, inhalational anthrax is exceedingly rare, with only 18 cases having been reported

in the United States in the 20th century.13 In the early

years of this century, cases of inhalational anthrax

were reported in rural villagers in Russia who

worked with contaminated sheep wool inside their

homes.14 Five cases of inhalational anthrax occurred

in woolen mill workers in New Hampshire in the

1950s.15 During times of economic hardship and

disruption of veterinary and human public health

practices, such as occurs during war, there have

been large epidemics of anthrax. The largest reported epidemic of human anthrax occurred in Zimbabwe from 1978 through 1980, with an estimated

10,000 cases. Essentially all were cutaneous, with

very rare cases of gastrointestinal disease and eight

cases of inhalational anthrax, although no autopsy

confirmation was reported.16

EPIDEMIOLOGY

PATHOGENESIS

B anthracis possesses three known virulence factors: an antiphagocytic capsule and two protein exotoxins, called the lethal and the edema toxins. The

role of the capsule in pathogenesis was demonstrated in the early 1900s, when anthrax strains lacking a capsule were shown to be avirulent.17 In more

recent years, the genes encoding synthesis of the

capsule were found to be encoded on a 110-kilobase

(kb) plasmid. Molecular analysis revealed that

strains cured of this plasmid no longer produced

the capsule and were attenuated,18 thus confirming

the critical role of the capsule in virulence. The capsule is composed of a polymer of poly-D-glutamic

acid, which confers resistance to phagocytosis and
Medical Aspects of Chemical and Biological Warfare

470

may contribute to the resistance of anthrax to lysis

by serum cationic proteins.19

It was Koch, in his initial studies on anthrax, who

first suggested the importance of toxins. In 1954,

Smith and Keppie20 demonstrated a toxic factor in

the serum of infected animals that was lethal when

injected into other animals. The role of toxins in

virulence and immunity was firmly established by

many workers in the ensuing years.21–23 Advances

in molecular biology in the last decade have produced a more complete understanding of the biochemical mechanisms of action of the toxins and

have begun to provide a more definitive picture of

their role in the pathogenesis of the disease.

The genes encoding the synthesis of the two

protein exotoxins are located on a 60-kb plasmid,

distinct from that encoding for the capsule. In an

environment of increased bicarbonate and carbon

dioxide and increased temperature, such as is found

in the infected host, there is increased transcription

of the genes for synthesis of the two toxins,24–26 as

well as for the capsule.27

The anthrax toxins, like many bacterial and plant

toxins, possess two components: a cell-binding, or

B, domain; and an active, or A, domain that has the

toxic and, usually, the enzymatic activity (Figure 22-

3). The B and A anthrax toxin components are synthesized from different genes and are secreted as

noncovalently linked proteins. The two toxins are

unusual in that the B protein, called protective antigen (MW 83,000), is shared by both toxins. Thus the

lethal toxin is composed of the protective antigen

combined with a second protein, which is known

as the lethal factor (MW 90,000). The lethal toxin is

lethal for experimental animals28,29 and the lethal

factor has been shown to possess homology to

metalloproteases, although no direct enzymatic activity has yet been discovered.30

The edema toxin, consisting of the same protective antigen together with a third protein, edema

factor (MW 89,000), causes edema when injected

into the skin of experimental animals.28,29 The edema

factor is a calmodulin-dependent adenylate cyclase,

which elevates intracellular cyclic adenosine monophosphate, and which is likely to be responsible for

the marked edema often present at the site of bacterial replication.

Each of the three toxin proteins—the B protein

and both A proteins—individually is without biological activity. The critical role of the toxins in

pathogenesis was established when it was shown

that deletion of the toxin encoding plasmid18,31 or

the protective antigen gene alone32 attenuates the

organism. The lethal toxin also appears to be more

important for virulence in a mouse model than the

edema toxin.33

Recent studies in cell culture models have given

a clearer understanding of the molecular interactions of the toxin proteins. Protective antigen first

binds, most likely by a domain at its carboxy-terminus,34,35 to a specific cell receptor.36 Once bound,

it is cleaved by a protease located on the cell surface,37,38 resulting in retention on the cell surface of

a 63-kilodalton (kd) fragment of protective antigen.

This cleavage creates a binding site on the protective antigen to which either the lethal factor or the

edema factor can bind with high affinity. The complex is then internalized and passes through an

acidic vesicle and is translocated to the cell cytosol,

where it expresses its toxic activity.

The situation in the infected animal may be somewhat different, since the toxin proteins may exist

in the serum as a complex of protective antigen and

lethal factor.39 It is possible that the proteolytic activation of protective antigen necessary to form

lethal or edema toxin may occur in interstitial fluid

or serum rather than on the cell surface. The lethal

or the edema toxin may then bind to target cells

and be internalized.

Infection begins when the spores are inoculated

through the skin or mucosa. It is thought that spores

are ingested at the local site by macrophages, in

which they germinate to the vegetative bacillus with

production of capsule and toxins. At these sites, the

Fig. 22-3. Composition of anthrax lethal and edema protein toxins.

Lethal Factor (A Protein) Protective Antigen (B Protein) Edema Factor (A Protein)

Lethal Toxin Edema Toxin

(MW 90,000)

?Metalloprotease

(MW 83,000)

Cell-binding component

(MW 89,000)

Adenylate cyclase
471

Anthrax

riod is 1 to 5 days. The disease first appears as a

small papule that progresses over a day or two to a

vesicle containing serosanguinous fluid with many

organisms and a paucity of leukocytes. The vesicle,

which may be 1 to 2 cm in diameter, ruptures, leaving a necrotic ulcer. Satellite vesicles may also be

present. The lesion is usually painless, and varying

degrees of edema may be present around it. The

edema may occasionally be massive, encompassing

the entire face or limb, and is described by the term

“malignant edema.” Patients usually have fever,

bacteria proliferate and produce the edema and lethal toxins that impair host leukocyte function and

lead to the distinctive pathological findings: edema,

hemorrhage, tissue necrosis, and a relative lack of

leukocytes. In inhalational anthrax, the spores are

ingested by alveolar macrophages, which transport

them to the regional tracheobronchial lymph nodes,

where germination occurs.40

Once in the tracheobronchial lymph nodes, the

local production of toxins by extracellular bacilli

gives rise to the characteristic pathological picture:

massive hemorrhagic, edematous, and necrotizing

lymphadenitis; and mediastinitis (the latter is almost pathognomonic of this disease).41 The bacilli

can then spread to the blood, leading to septicemia

with seeding of other organs and frequently causing hemorrhagic meningitis. Terminally, toxin is

present in high concentrations in the blood,21 but

both the site of toxin action and the molecular

mechanism of death remain unknown. Death is the

result of respiratory failure associated with pulmonary edema, overwhelming bacteremia, and, often,

meningitis.

Crude toxin preparations have been shown to

impair neutrophil chemotaxis,42 phagocytosis,19 and

killing.43 More recent work has shown that purified

edema toxin impairs phagocytosis44 and priming for

the respiratory burst45 in neutrophils, and also inhibits the production of interleukin-6 (IL-6) and

tumor necrosis factor (TNF) by monocytes, which

may further impair host resistance.46 The lethal

toxin is directly cytolytic for macrophages,47 causing release of the potentially toxic cytokines IL-1

and TNF.48 Experimentally, animals can be protected

against death from lethal toxin by depleting them

of macrophages or blocking the effect of IL-1,48 but

the role of these cytokines in death from infection

remains to be established.

CLINICAL DISEASE

The military’s interest in anthrax is with defense

against its use as an inhalational biological weapon.

However, other forms of the disease are far more

likely to be seen by medical officers—particularly

when deployed to Third World countries—and are

therefore included for completeness.

Cutaneous Anthrax

More than 95% of cases of anthrax are cutaneous

(Figure 22-4). After inoculation, the incubation peFig. 22-4. (a) Cutaneous lesion of anthrax demonstrating eschar and edema in a man, following his handling of a contaminated cow carcass in a rendering plant in Colorado. (b) Cutaneous lesion of anthrax with eschar (on the patient’s neck), on

approximately day 15 of disease. The patient had worked with air-dried goat skins from Africa. Photograph a: Courtesy of

Arnold Kaufmann, Ph.D., National Center for Infectious Disease, Centers for Disease and Control and Prevention, Atlanta, Ga. Photograph b: Reprinted from Binford CH, Connor DH, eds. Pathology of Tropical and Extraordinary Diseases. Vol

1. Washington, DC: Armed Forces Institute of Pathology; 1976: 121. AFIP Negative 75-4203-7.

a b
Medical Aspects of Chemical and Biological Warfare

472

malaise, and headache, which may be severe in

those with extensive edema. There may also be local lymphadenitis. The ulcer base develops a characteristic black eschar and after a period of 2 to 3

weeks the eschar separates, often leaving a scar.

Septicemia is very rare, and with treatment mortality should be less than 1%.

Inhalational Anthrax

Inhalational anthrax begins after an incubation

period of 1 to 6 days with nonspecific symptoms of

malaise, fatigue, myalgia, and fever. There may be

an associated nonproductive cough and mild chest

discomfort. These symptoms usually persist for 2

or 3 days, and in some cases there may be a short

period of improvement. This is followed by the sudden onset of increasing respiratory distress with

dyspnea, stridor, cyanosis, increased chest pain, and

diaphoresis. There may be associated edema of the

chest and neck. Chest X-ray examination usually

shows the characteristic widening of the mediastinum and, often, pleural effusions (Figure 22-5).

Pneumonia has not been a consistent finding but

can occur in some patients.5

 While cases of inhalational anthrax have been rare in this century, several have occurred in patients with underlying pulmonary disease, suggesting that this condition may

increase susceptibility to the disease.13 Meningitis

is present in up to 50% of cases, and some patients

may present with seizures. The onset of respiratory

Fig. 22-5. This roentgenogram, taken on day 2 of illness,

shows the lungs of a 51-year-old laborer with occupational exposure to airborne anthrax spores. Marked mediastinal widening is evident, with a small parenchymal

infiltrate. Reprinted from Binford CH, Connor DH, eds.

Pathology of Tropical and Extraordinary Diseases. Vol 1.

Washington, DC: Armed Forces Institute of Pathology;

1976: 119. AFIP Negative 71-1290-2.

distress is followed by the rapid onset of shock and

death within 24 to 36 hours. Mortality has been essentially 100% despite appropriate treatment.

Oropharyngeal and Gastrointestinal Anthrax

Oropharyngeal and gastrointestinal anthrax result from the ingestion of infected meat that has not

been sufficiently cooked. After an incubation period

of 2 to 5 days, patients with oropharyngeal disease

present with severe sore throat or a local oral or tonsillar ulcer, usually associated with fever, toxicity, and

swelling of the neck due to cervical or submandibular lymphadenitis and edema. Dysphagia and respiratory distress may also be present. Gastrointestinal anthrax begins with nonspecific symptoms of

nausea, vomiting, and fever; these are followed in

most cases by severe abdominal pain. The presenting sign may be an acute abdomen, which may be

associated with hematemesis, massive ascites, and

diarrhea. Mortality in both forms may be as high as

50%, especially in the gastrointestinal form.

Meningitis

Meningitis may occur following bacteremia, as a

complication of any of the other clinical forms of

the disease. Meningitis may also occur, very rarely,

without a clinically apparent primary focus. It is

very often hemorrhagic, which is important diagnostically, and almost invariably fatal (Figure 22-6).

Fig. 22-6. Meningitis with subarachnoid hemorrhage in

a man from Thailand who died 5 days after eating

undercooked carabao (water buffalo). Reprinted from

Binford CH, Connor DH, eds. Pathology of Tropical and

Extraordinary Diseases. Vol 1. Washington, DC: Armed

Forces Institute of Pathology; 1976: 121. AFIP Negative

75-12374-3.
473

Anthrax

DIAGNOSIS

The most critical aspect in making a diagnosis of

anthrax is a high index of suspicion associated with

a compatible history of exposure. Cutaneous anthrax should be considered following the development of a painless pruritic papule, vesicle, or ulcer

—often with surrounding edema—that develops

into a black eschar. With extensive or massive

edema, such a lesion is almost pathognomonic.

Gram’s stain or culture of the lesion will usually

confirm the diagnosis. The differential diagnosis

should include tularemia, staphylococcal or streptococcal disease, and orf (a viral disease of sheep

and goats, transmissible to humans).

The diagnosis of inhalational anthrax is extraordinarily difficult, but the disease should be suspected with a history of exposure to a B anthracis–

containing aerosol. The early symptoms are entirely

nonspecific. However, (1) the development of respiratory distress in association with radiographic evidence of a widened mediastinum due to hemorrhagic

mediastinitis, and (2) the presence of hemorrhagic

pleural effusion or hemorrhagic meningitis should

suggest the diagnosis. Sputum examination is not

helpful in making the diagnosis, since pneumonia

is not usually a feature of inhalational anthrax.

Gastrointestinal anthrax is exceedingly difficult

to diagnose because of the rarity of the disease and

its nonspecific symptoms. Only with a history of

ingesting contaminated meat in the setting of an

outbreak is diagnosis usually considered. Microbiologic cultures are not helpful in confirming the diagnosis. The diagnosis of oropharyngeal anthrax

can be made from the clinical and physical findings in a patient with the appropriate epidemiological history.

Meningitis due to anthrax is clinically indistinguishable from meningitis due to other etiologies.

An important distinguishing feature is that the

cerebral spinal fluid is hemorrhagic in as many as

50% of cases. The diagnosis can be confirmed by

identifying the organism in cerebral spinal fluid by

microscopy, culture, or both.

Serology is generally only of use in making a retrospective diagnosis. Antibody to protective antigen or the capsule develops in 68% to 93%49–52

of reported cases of cutaneous anthrax and 67%

to 94%51,52 of reported cases of oropharyngeal anthrax. A positive skin test to anthraxin (an undefined antigen derived from acid hydrolysis of the

bacillus that was developed and evaluated in the

former Soviet Union) has also been reported53 to be

of value in the retrospective diagnosis of anthrax.

Western countries have limited experience with this

test.54

TREATMENT

tive. The optimal protection was afforded by combining antibiotics with active immunization.

Active Immunization

The only licensed human vaccine against anthrax

is produced by the Michigan Department of Public

Health. This vaccine is made from sterile filtrates

Prophylactic Treatment After Exposure

Experimental evidence58 has demonstrated that

treatment with antibiotics beginning 1 day after

exposure to a lethal aerosol challenge with anthrax

spores can provide significant protection against

death. All three drugs used in this study—ciprofloxacin, doxycycline, and penicillin—were effecPenicillin is the drug of choice for anthrax. Cutaneous anthrax without toxicity or systemic symptoms

may be treated with oral penicillin. If evidence of

spreading infection or systemic symptoms is present,

then intravenous therapy with high-dose penicillin

(2 million units administered every 6 h) may be initiated until a clinical response is obtained. Effective

therapy will reduce edema and systemic symptoms

but will not change the evolution of the skin lesion

itself. Treatment should be continued for 7 to 10 days.

Tetracycline, erythromycin, and chloramphenicol have also been used successfully. These drugs

may be used for treatment of the rare case caused

by naturally occurring penicillin-resistant organisms. Additional antibiotics shown to be active in vitro

include ciprofloxacin, gentamicin, cefazolin, cephalothin, vancomycin, clindamycin, and imipenem.55–57

These drugs should be effective in vivo, but there

is no reported clinical experience.

Inhalational, oropharyngeal, and gastrointestinal

anthrax should be treated with large doses of intravenous penicillin (2 million units administered every 2 h) with appropriate vasopressors, oxygen, and

other supportive therapy.

PROPHYLAXIS
Medical Aspects of Chemical and Biological Warfare

474

of microaerophilic cultures of an attenuated, unencapsulated, nonproteolytic strain (V770-NP1-R) of

B anthracis. The filtrate, containing predominantly

protective antigen, is adsorbed to aluminum hydroxide. The final product also contains formaldehyde, in a final concentration of no more than 0.02%,

and benzethonium chloride 0.0025%, as preservatives. Some vaccine lots contain very small amounts

of lethal factor and lesser amounts of edema factor,

as determined by antibody responses in vaccinated

animals,18,59,60 although this antibody response has

not been reported in the limited observations in

human vaccinees.61 Although protective antigen by

itself is an effective immunogen,62 it is unknown

whether the small amounts of lethal or edema factor that are present in some lots of the vaccine contribute to its protective efficacy. The potency of vaccine lots is determined by showing protection of

parenterally challenged guinea pigs. There is no

characterization of the amount and form of the protective antigen or other toxin components in the

vaccine. The vaccine is stored at 2°C to 8°C. The

recommended schedule for vaccination is 0.5 mL

given subcutaneously at 0, 2, and 4 weeks, followed

by boosters of 0.5 mL at 6, 12, and 18 months. Annual boosters are recommended if the potential for

exposure continues.

The vaccine should be given to industrial workers exposed to potentially contaminated animal

products imported from countries in which animal

anthrax remains uncontrolled. These products include wool, goat hair, hides, and bones. People in

direct contact with potentially infected animals as

well as laboratory workers should also be immunized. Vaccination is also indicated for protection

against the use of anthrax in biological warfare.

Approximately 150,000 service members received

this licensed MDPH vaccine between 11 January

and 28 February 1991 (25%–30% of the total U.S.

forces deployed during the Persian Gulf War).

A live, attenuated, unencapsulated, spore vaccine

is used for humans in the former USSR. The vaccine is given by scarification or subcutaneously. Its

developers claim it to be reasonably well tolerated

and to show some degree of protective efficacy

against cutaneous anthrax in clinical field trials.53

In the United States, immunization with the licensed vaccine induced an immune response, measured by indirect hemagglutination, to protective

antigen in 83% of vaccinees 2 weeks after the first

three doses,63 and in 91% of those tested after receiving two or more doses.50 One hundred percent

of the vaccinees develop a rise in titer in response

to the yearly booster dose. When tested by an enzyme-linked immunosorbent assay, the current serological test of choice, more than 95% of vaccinees

seroconvert after the initial three doses.61,64

A rough correlation between antibody titer to

protective antigen and protection of experimental

animals from infection exists after vaccination with

the human vaccine. However, the exact relationship

between antibody to protective antigen as measured

in these assays, and immunity to infection remains

obscure because the live, attenuated Sterne veterinary vaccine (made from an unencapsulated, toxinproducing strain) protects animals better than the

human vaccine, yet it induces lower levels of antibody to protective antigen.59–61

The protective efficacy of experimental protective antigen-based vaccines produced from sterile

culture filtrates of B anthracis was clearly demonstrated using various animal models and routes of

challenge.21,65 A placebo-controlled clinical trial was

conducted with a vaccine similar to the currently

licensed U.S. vaccine.66 This field-tested vaccine was

composed of the sterile, cell-free culture supernatant from an attenuated, unencapsulated strain of

B anthracis—different from that used to produce the

licensed vaccine and grown under aerobic, rather

than microaerophilic, conditions.67 It was precipitated with alum rather than adsorbed to aluminum

hydroxide. The study population worked in four

mills in the northeastern United States where B

anthracis–contaminated imported goat hair was

used. The vaccinated group, compared to a placeboinoculated control group, was afforded 92.5% protection against cutaneous anthrax, with a lower 95%

confidence limit of 65% effectiveness. There were

insufficient cases of inhalational anthrax to determine whether the vaccine was effective against this

form of the disease. This same vaccine was previously shown to protect rhesus monkeys against an

aerosol exposure to anthrax spores.67

There have been no controlled clinical trials in

humans of the efficacy of the currently licensed U.S.

vaccine. This vaccine has been extensively tested

in animals and has protected guinea pigs against

both an intramuscular60,61 and an aerosol challenge.59 The licensed vaccine has also been shown

to protect rhesus monkeys against an aerosol challenge.58,68

Side Effects

In two different studies, the incidence of significant local and systemic reactions to the vaccine used

in the placebo-controlled field trial was 2.4% to

2.8%66 and 0.2% to 1.3%.67 The vaccine currently
475

Anthrax

licensed in the United States is reported to have a

similar incidence of reactions.64,69 Local reactions

considered significant consist of induration,

erythema in an area larger than 5 cm in diameter,

edema, pruritus, warmth, and tenderness. These

reactions peak at 1 to 2 days and usually disappear

within 2 to 3 days. Very rare reactions include

edema extending from the local site to the elbow

or forearm, and a small, painless nodule that may

persist for weeks. People who have recovered from

a cutaneous infection with anthrax may have

very severe local reactions.66 Systemic reactions are

characterized by mild myalgia, headache, and mildto-moderate malaise that lasts for 1 to 2 days.

There are no long-term sequelae of local or systemic

reactions.

SUMMARY

Anthrax is a zoonotic disease that occurs in domesticated and wild animals. Humans become infected

by contact with infected animals or contaminated

products. Under natural circumstances, infection occurs by the cutaneous route and only extremely rarely

by the inhalational or gastrointestinal routes.

An aerosol exposure to spores causes inhalational

anthrax. This form of the disease, which is of military concern because of its potential for use as a

biological warfare agent, begins with nonspecific

symptoms followed in 2 to 3 days by the sudden

onset of respiratory distress with dyspnea, cyanosis, and stridor. It is rapidly fatal. Radiographic examination of the chest often reveals the characteristic mediastinal widening, indicative of hemorrhagic mediastinitis. Hemorrhagic meningitis frequently coexists. Given the rarity of the disease and

its rapid progression, the diagnosis of inhalational

anthrax is difficult to make. Treatment consists of

massive doses of antibiotics and supportive care.

Postex-posure antibiotic prophylaxis is effective in

experimental animals and should be instituted as

soon as possible after exposure. A licensed nonliving vaccine is available for human use.

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51. Sirisanthana T, Nelson KE, Ezzell J, Abshire TG. Serological studies of patients with cutaneous and oral-oropharyngeal anthrax from northern Thailand. Am J Trop Med Hyg. 1988;9:575–581.

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of man. J Bacteriol. 1963;85:230–236.
Plague

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Chapter 23

PLAGUE

THOMAS W. McGOVERN, M.D., FAAD*; AND ARTHUR M. FRIEDLANDER, M.D.†

INTRODUCTION

HISTORY

The First Pandemic

The Black Death (The Second Pandemic)

The Third Pandemic

PLAGUE AND WARFARE

Endemic Disease

Plague as a Biological Warfare Agent

THE INFECTIOUS AGENT

EPIDEMIOLOGY

INCIDENCE

PATHOGENESIS

CLINICAL MANIFESTATIONS

Bubonic Plague

Septicemic Plague

Pneumonic Plague

Plague Meningitis

Pharyngeal Plague

Cutaneous Manifestations

DIAGNOSIS

Signs and Symptoms

Laboratory Confirmation

TREATMENT

Isolation

Antibiotics

PREVENTION

Postexposure Prophylaxis

Immunization

SUMMARY

*Major, Medical Corps, U.S. Army; Chief, Dermatology Service, Irwin Army Community Hospital, Fort Riley, Kansas 66442

†Colonel, Medical Corps, U.S. Army; Chief, Bacteriology Division, U.S. Army Medical Research Institute of Infections Diseases, Fort Detrick,

Frederick, Maryland 21702-5011; and Clinical Associate Professor of Medicine, Uniformed Services University of the Health Sciences, 4301

Jones Bridge Road, Bethesda, Maryland 20814-4799
Medical Aspects of Chemical and Biological Warfare

480

INTRODUCTION

Plague is a zoonotic infection caused by Yersinia

pestis, a Gram-negative bacillus, which has been the

cause of three great pandemics of human disease

in the common era: in the 6th, 14th, and 20th centuries. The naturally occurring disease in humans is

transmitted from rodents and is characterized by

the abrupt onset of high fever, painful local lymphadenopathy draining the exposure site (ie, a bubo,

the inflammatory swelling of one or more lymph

nodes, usually in the groin; the confluent mass of

nodes, if untreated, may suppurate and drain pus),

and bacteremia. Septicemic plague can sometimes

ensue from untreated bubonic plague or, de novo,

after a flea bite. Patients with the bubonic form of

the disease may develop secondary pneumonic

plague (also called plague pneumonia); this complication can lead to human-to-human spread by

the respiratory route and cause primary pneumonic

plague, the most severe and frequently fatal form

of the disease.

During the last four millennia, plague has played

a role in many military campaigns. During the Vietnam War, plague was endemic among the native

population, but U.S. soldiers escaped relatively unaffected. This excellent protection of troops was

largely due to our understanding of the rodent

reservoirs and flea vectors of disease, the pathophysiology of the various clinical forms of plague, the widespread use throughout the war of a plague vaccine,

and prompt treatment of plague victims with effective antibiotics. Mortality from endemic plague continues at low rates throughout the world despite

the availability of effective antibiotics. People continue to die of plague, not because the bacilli have

become resistant but, most often, because physicians do not include plague in their differential diagnosis (in the United States) or because treatment

is absent or delayed (in underdeveloped countries).

To be best prepared to treat soldiers who are

plague victims of endemic or biological agent attack by an enemy, military physicians must understand the natural mechanisms by which plague

spreads between species, the pathophysiology of

disease in fleas and humans, the minimal diagnostic information necessary to begin treatment with

effective antibiotics, and the proper use and capabilities of the presently available plague vaccine.

The United States military’s concern with plague

is both as an endemic disease and as a biological

warfare threat. A better understanding of the preventive medicine aspects of the disease will aid in

the prompt diagnosis and effective treatment necessary to survive an enemy attack of plague.

Key terms in this chapter include enzootic and

epizootic. These refer, respectively, to plague that is

normally present in an animal community at all

times but that occurs in only a small number of animals and in a mildly virulent form, and to widespread plague infections leading to death within an

animal community (ie, equivalent to an epidemic in

a human population). The death of a rodent pressures the living fleas to leave that host and seek

other mammals, including humans. Understanding

these two simple concepts will help us to understand how and when humans may be attacked, both

in endemic and biological warfare scenarios.

HISTORY

The biblical book of I Samuel records what may

be the oldest reference to bubonic plague. In approximately 1320 BC, the Philistines stole the Ark of

the Covenant from the Israelites and returned home.

Then, I Samuel continues,

[t]he Lord’s hand was heavy upon the people of

Ashdod and its vicinity; he brought devastation

upon them and afflicted them with tumors. And

rats appeared in their land, and death and destruction were throughout the city... [T]he Lord’s hand

was against that city, throwing it into a great panic.

He afflicted the people of the city, both young and

old, with an outbreak of tumors in the groin.1

After this time, plague became established in the

countries bordering the eastern Mediterranean Sea.2

In 430 BC, Sparta won the Peloponnesian War partly

because of the plague of Athens.3 Some scholars believe that this was the bubonic plague, but others

suggest that it may have been due to other bacterial or viral diseases.4

The First Pandemic

Procopius gave us the first identifiable description of epidemic plague in his account of the plague

of the Byzantine empire during the reign of Justin-
Plague

481

ian I (AD 541–542),5 which we now consider to be

the first great pandemic of the common era. As

many as 100 million Europeans, including 40% of

the population of Constantinople, died during this

epidemic.6,7 Repeated, smaller epidemics followed

this plague.8

The Black Death (The Second Pandemic)

The second plague pandemic, known as the Black

Death, thrust this dread disease into the collective

memory of western civilization.8

 Plague bacilli in

fleas on the fur of marmots (a rodent of the genus

Marmota) probably entered Europe via the transAsian silk road during the early 14th century. When

bales of these furs were opened in Astrakhan and

Saray, hungry fleas jumped from the fur seeking the

first available blood meal, often a human leg.8–10 In

1346, plague arrived in Caffa (modern Feodosiya,

Ukraine), on the Black Sea. The large rat population there helped spread the disease as they stowed

away on ships bound for major European ports such

as Pera, a suburb of Constantinople, and Messina,

in Sicily. By 1348, plague had already entered Britain at Weymouth.5

The Black Death took the lives of 24 million

people between the years 1346 and 1352 and

claimed perhaps another 20 million by the end of

the 14th century.6 However, the plague continued

through 1720, with a final foray into Marseilles.

Thirty percent to 60% of the populations of major

cities such as Genoa, Milan, Padua, Lyons,

and Venice succumbed during the 15th to the 18th

centuries.10

Physicians of the time offered no effective treatment

because they did not understand the epidemiology

of plague. At the highly regarded University of

Paris, physicians theorized that a conjunction of

the planets Saturn, Mars, and Jupiter at 1:00 PM on

March 20, 1345, caused a corruption of the surrounding atmosphere that led to the plague.6

 They

recommended a simple diet; avoidance of excessive

sleep, exercise, and emotion; regular enemas; and

abstinence from sexual intercourse.11 While some

people killed cats and dogs, thinking them to be

carriers of disease, no one ever thought to kill the

rats.6 Christians blamed the disease on Muslims,

Muslims on Christians, and both Christians and

Muslims on Jews or on witches.8

In 1666, a church rector in Eyam, Derbyshire,

England, persuaded the whole community to quarantine itself when plague erupted there. This was

the worst possible solution, since the people then

stayed in close proximity to the infected rats. The

city experienced virtually a 100% attack rate with

72% mortality (the average mortality for the Black

Death was consistently 70%–80%).8,12

Accurate clinical descriptions of the Black Death

were written by contemporary observers such as

Boccaccio, who wrote in his Decameron:

The symptoms were not the same as in the East,

where a gush of blood from the nose was a plain

sign of inevitable death, but it began both in men

and women with certain swellings [buboes] in the

groin or under the armpit. They grew to the size of

a small apple or an egg, more or less, and were

vulgarly called tumours. In a short space of time

these tumours spread from the two parts named

all over the body. Soon after this, the symptoms

changed and black or purple spots appeared on the

arms or thighs or any other part of the body, sometimes a few large ones, sometimes many little

ones.13(p646)

Guy de Chauliac in Avignon added his own commentary, describing pneumonic plague and the axillary and groin forms of bubonic plague:

Doctors dared not visit the sick for fear of infection; or, when they did, they helped little and

gained nothing.14(p646)

. . . .

The disease is three fold in its infection; that is to

say, firstly, men suffer in their lungs and breathing

and whoever have these corrupted, or even slightly

attacked, cannot by any means escape nor live beyond two days...and it is found that all those who

have died thus suddenly have had their lungs infected and have spat blood. There is another form

of the sickness, however, at present running its

course concurrently with the first; that is, certain

aposthumes appear under both arms and by these

also people quickly die. A third form of the disease—like the two former, running its course at the

same time with them—is that from which people

of both sexes suffer from aposthumes in the groin.

This is likewise quickly fatal.15(p646)

Some writers described bizarre neurological disorders, which gave rise to the term “Dance of

Death,” followed by anxiety and terror, resignation,

blackening of the skin, and death. The sick gave off

a terrible stench: “Their sweat, excrement, spittle,

breath, [were] so foetid as to be overpowering”[; in

addition, their urine was] “turbid, thick, black, or

red.”6(p70)
Medical Aspects of Chemical and Biological Warfare

482

The second great pandemic slowly died out in

Europe by 1720. Many reasons, including the following, have been suggested to explain its decline:

• The oriental rat flea, Xenopsylla cheopis, the

main vector of the plague bacillus, could no

longer exist in the cool European climate.5

• The black rat, Rattus rattus, was replaced by

the brown rat, Rattus norvegicus, which was

less likely to live in close proximity to man.5,8

• A new and less virulent species of Y pestis, or

a related Yersinia species such as Y pseudotuberculosis, may have developed, causing natural immunization of infected rats and humans.8

• The European population was generally iron

deficient, and iron is an essential factor for

the bacterium’s virulence.12

• Flea density on humans decreased as the use

of soap became more widespread.5

The Third Pandemic

The third, or modern, plague pandemic arose in

1894 in China and spread throughout the world via

modern transportation.12,16 It was also in 1894 that

Alexandre J. E. Yersin discovered that Yersinia pestis satisfied Koch’s postulates for bubonic plague.17

The reservoir of plague bacilli in the fleas of the

Siberian marmot was likely responsible for the

Manchurian pneumonic plague epidemic of 1910–

1911, which caused 50,000 deaths.2 The modern

pandemic arrived in Bombay in 1898, and during

the next 50 years, more than 13 million Indians died

of plague.2,18

The disease officially arrived in the United States

in March 1900, when the lifeless body of a Chinese

laborer was discovered in a hotel basement in San

Francisco, California19; the disease appeared in New

York City and Washington state the same year.20

New Orleans, Louisiana, was infected in 1924 and

1926.20 Rodents throughout the western United

States were probably infected from the San Francisco focus, leading to more infected rodents in the

western United States than existed in Europe at the

time of the Black Death.12 Therefore, human plague

was initially a result of urban rat epizootics until

1925. After general rat control and hygiene measures

were instituted in various port cities, urban plague

vanished—only to spread into rural areas, where virtually all cases in the United States have been acquired

since 1925.21

PLAGUE AND WARFARE

It is an axiom of warfare that battle casualties are

far fewer than casualties caused by disease and nonbattle injuries.3 Y pestis can cause disease both through

endemic exposure and as a biological warfare agent.

Medical officers need to be able to distinguish likely

from unlikely cases of endemic disease, and to keep

the possible biological warfare threat in mind.

Endemic Disease

Just as plague befell armies of antiquity, so the

disease has also afflicted armies in more recent

times. Frederick the Great’s troops were devastated

by plague in 1745, as were Catherine the Great’s in

1769–1771 when they returned from the Balkans

with plague. In 1798, French military operations in

Egypt were significantly impeded by plague, which

even caused them to abandon their attack on Alexandria. The modern pandemic began in China,

when Chinese troops were deployed in an epidemic

plague area to suppress a Muslim rebellion. Military traffic is responsible for the rapid spread of

disease to nearly every country in Asia.2

For the U.S. military since the mid 20th century,

endemic plague has not been a source of disease

and nonbattle injuries. During World War II and the

Vietnam War, U.S. forces were almost entirely free

of plague. However, the disease remains on and

near our military bases because local mammal

populations maintain reservoirs of infection.

World War II

Endemic plague has been established in Hawaii

(on the islands of Hawaii and Maui) since December 1899. No evidence of the disease, however, in

either rodents or humans, has been found on the

islands of Oahu or Kauai since the first decade of

this century. A “small outbreak”22(p667) occurred during World War II on the island of Hawaii (in 1943)

but was contained by means of

very strenuous rat control measures [that] were carried out in each of the endemic plague areas....

[T]hese measures were of sufficient thoroughness

to prevent any spread of plague to military personnel during the war in the Pacific.22(p667)

Official policy during World War II was to vaccinate U.S. troops with a killed plague vaccine. No
Plague

483

U.S. troops contracted plague, although they served

in known endemic areas.22,23

Vietnam War

Plague entered Vietnam in Nha Trang in 189816

and several pneumonic epidemics have occurred

since (in 1911, 1915, 1925, and 1941).2,24 Cases have

been reported from Vietnam every year since 1898

except during the Japanese occupation during

World War II.2 When French forces departed Vietnam after the Indochina War, public health conditions deteriorated and plague flourished. The reported plague incidence increased from 8 cases in

1961, to 110 cases in 1963, to an average of 4,500

cases from 1965 through 1969.21,25–28 The mortality

in clinically diagnosed cases was between 1% and

5%. In untreated individuals, it was much higher

(60%–90%).2,26 Only 8 American troops were affected

(1 case per 1 million man-years) during the Vietnam War.28 American success was attributed to

• the use of flea insecticide (Xenopsylla cheopis

became resistant to the insecticide dichlorodiphenyltrichloroethane [DDT] during the

war, but others were employed)26;

• immunization of virtually all American

troops with plague vaccine2; and

• a thorough understanding of the epidemiology of disease, which led to the use of

insect repellents, protective clothing, and

rat-proofed dwellings.2

It was during the 1960s that our knowledge

of plague grew dramatically. This is due in great

part to the work of two officers of the Medical

Service Corps, U.S. Army, Lieutenant Colonel Dan

C. Cavanaugh and Lieutenant Colonel John D.

Marshall. These scientists studied plague ecology,

related plague epidemics to weather as a function

of flea physiology (epidemics virtually disappeared

when the temperature rose above 28°C),2

 developed

serologic tests for plague infection, and developed

the data to demonstrate the efficacy of the wholecell killed plague vaccine.29

Disease Threat on U.S. Military Installations

Human exposure to plague on military installations may occur when pets bring home infected rodents, their fleas, or both; at recreation areas with

sick or dead rodents and their infected fleas; or at

field training and bivouac sites. The consequences

of plague at a military installation include human

illness, death, or both; pet or other animal illness,

death, or both; lost use of training and bivouac sites;

large expenditures of money, manpower, and equipment to eliminate the plague risk; and the lost use

of recreation areas.21 Plague risk has been identified on and near several U.S. military installations

(Exhibit 23-1).

Plague as a Biological Warfare Agent

The first attempt at what we now call “biological warfare” is purported to have occurred at the

Crimean port city of Caffa on the Black Sea during

the years 1346–1347.2,6 During the conflict between

Christian Genoese sailors and Muslim Tatars, the

Tatar army was struck with plague. The Tatar leader

catapulted corpses of Tatar plague victims at the

Genoese sailors. The Genoese became infected with

plague and fled to Italy. However, the disease was

most likely spread by the local population of infected rats, not by the corpses, since an infected flea

leaves its host as soon as the corpse cools.6

The 20th-century use of plague as a potential biological warfare weapon is the immediate concern

of this chapter. Medical officers need to keep this

use of plague in mind, particularly when the disease appears in an unlikely setting.

World War II

During World War II, the Japanese army established a secret biological warfare research unit (Unit

731) in Manchuria, where epidemics of pneumonic

plague had occurred in 1910–1911, 1920–1921, and

1927, and a cholera epidemic had spread in 1919.

General Shiro Ishii, the physician leader of Unit 731,

was fascinated by plague because it could create

casualties out of proportion to the number of bacteria disseminated, the most dangerous strains

could be used to make a very dangerous weapon,

and its origins could be concealed to appear as a

natural occurrence. Early experiments, however,

demonstrated that dropping bacteria out of aerial

bombs had little effect because air pressure and high

temperatures that were created by the exploding

bombs killed nearly 100% of the bacteria.30

One of Ishii’s greatest achievements was his use

of the human flea, Pulex irritans, as a stratagem to

simultaneously protect the bacteria and target humans. This flea is resistant to air drag, naturally

targets humans, and could also infect a local rat

population to prolong an epidemic. Infected fleas

may regurgitate up to 24,000 organisms in a single

feeding. Spraying fleas out of compressed-air con-
Medical Aspects of Chemical and Biological Warfare

484

EXHIBIT 23-1

U.S. MILITARY INSTALLATIONS WITH IDENTIFIED PLAGUE RISKS*

Plague-infected animals on the installation; human case reported on post:

Fort Hunter Liggett, California

United States Air Force Academy, Colorado†

Human case reported in the same county:

Edwards Air Force Base, Colorado‡

F. E. Warren Air Force Base, Wyoming

Kirtland Air Force Base, New Mexico§

Peterson Air Force Base, Colorado

Plague-infected animals on the installation:

Dugway Proving Ground, Utah

Fort Carson, Colorado

Fort Ord, California

Fort Wingate Army Depot Activity, New Mexico

Marine Corps Mountain Warfare Training Center, Bridgeport, California

Navajo Army Depot Activity, Arizona

Pueblo Army Depot Activity, Colorado

Rocky Mountain Arsenal, Colorado

Vandenberg Air Force Base, California

White Sands Missile Range, New Mexico

Plague-infected animals or fleas are not on the installation but are in the same county:

Bridgeport Naval Facility, California

Camp Roberts, California

Dyess Air Force Base, Texas

Fort Bliss, Texas

Fort Lewis, Washington

Sierra Army Depot, California

Tooele Army Depot, Utah

Umatilla Army Depot Activity, Oregon

Nellis Air Force Base, Nevada

Plague-infected animals or fleas are not on the installation or in the county, but susceptible animals are

present:

Fort Huachuca, Arizona

*Does not include military installations near Los Angeles and San Francisco, California, where urban plague cases and

deaths were not uncommon in the first quarter of the 20th century; no plague cases have occurred in these urban areas

since the mid-1920s.

†Fatality: 18-mo-old child died of pneumonic plague; rock squirrels and their fleas had taken up residence in the ducts of

the on-base house.

‡Two human cases in the same county in 1995; animal surveillance on base began in 1996.

§Plague-infected animals in the county in 1995; last human case in the county in 1993; no animal surveillance on base since

1986.

Sources: (1) Harrison FJ. Prevention and Control of Plague. Aurora, Colo: United States Army Center for Health Promotion

and Preventive Medicine, Fitzsimons Army Medical Center; September 1995: 3–8. Technical Guide 103. (2) Data collected

from Preventive Medicine Officers on 30 military bases in the United States, March 1996.
Plague

485

tainers was not successful since aircraft had to fly

too low for safety. High flying meant too much dispersion. Clay bombs solved these problems and

resulted in an 80% survival rate of fleas.30

The Japanese apparently used plague as a biological warfare agent in China several times during World War II. At 0500 hours on a November

morning in 1941, a lone Japanese plane made three

low passes over the business center of Changteh, a

city in the Hunan province. Although no bombs

were dropped, a strange mixture of wheat and rice

grains, pieces of paper, cotton wadding, and other

unidentified particles were. Within 2 weeks, individuals in Changteh started dying of plague. This

miniepidemic was thought to be of human origin

for the following reasons30:

• Changteh and the whole surrounding area

of China had never been afflicted by plague.

• Plague usually spreads with rice (because

rats infest the grain) along shipping routes,

but the nearest epidemic center was 2,000 km

away by land or river. Changteh exported,

not imported, rice. No individual who contracted plague had recently traveled outside the city.

• All reported instances of human plague

occurred in the area of the city where the

strange particles were dropped.

• No evidence of excessive rat mortality occurred until 2 months after the people began dying.

• The first six human cases occurred within

15 days of the aerial incident.

Applying the concepts implicit in these five points

will help medical officers differentiate endemic

plague from plague used as a biological warfare

agent. In fact, these concepts are important in making a diagnosis of most forms of biological warfare.

In another incident, on October 4, 1940, a Japanese plane dropped rice and wheat grains mixed

with fleas over the city of Chuhsien, in Chekiang

province. A month later, bubonic plague appeared

for the first time there, in the area where the particles had been dropped. There were 21 plague

deaths in 24 days. Again, on October 27, 1940, a

Japanese plane was seen releasing similar particles

over the city of Ningpo, in Chekiang province. Two

days later, bubonic plague occurred for the first time

in that city, producing 99 deaths in 34 days. No epizootic or excessive mortality was found in the rat

population.30

Since World War II

An article31 published in the popular press in

1993 stated that in the 1970s and 1980s the Soviet

Union created lethal diseases that defied cures. This

included a genetically engineered, dry, antibioticresistant form of plague. In this article, a defecting

Soviet microbiologist was quoted as saying that producing this form of plague had been a top priority

of the Soviets in the 5-year plan that started in 1984.

During the Korean War, allied forces were accused of dropping on North Korea insects that were

capable of spreading plague, typhus, malaria, Japanese B encephalitis, and other diseases. No evidence

exists to support such claims.32

The known virulence factors of Y pestis are encoded on the chromosome and its three plasmids.

A chromosomal locus responsible for pigmentation

phenotype, iron-inducible proteins, and iron uptake

is necessary for virulence from a peripheral route

of inoculation.33 The pH 6 antigen (also encoded on

the chromosome), a protein located on the surface

of the bacterium, is necessary for complete virulence.34 It is induced in vitro at low pH, perhaps in

vivo at sites of inflammation and cellular necrosis,

and within phagocytic cells.

The low calcium response (Lcr) plasmid of approximately 75 kilobase (kb), which is homologous

in Y pestis and the other two Yersinia pathogens, Y

pseudotuberculosis and Y enterocolitica, encodes for

several secreted proteins, including Yersinia outermembrane proteins (Yops), necessary for viruY pestis is a Gram-negative, nonacid-fast, nonmotile, nonsporulating, nonlactose-fermenting, bipolar

coccobacillus measuring 0.5–0.8 x 1.5–2.0 μm. The

Yersinieae comprise Genus XI of the family Enterobacteriaceae, which includes the related enteropathogenic bacteria Y enterocolitica and Y pseudotuberculosis. Its bipolar appearance is best appreciated when

Wright-Giemsa, Wayson’s, and Gram’s stains are used

(Figure 23-1). Y pestis grows optimally at 28°C, producing tiny, 1- to 3-mm “beaten-copper” colonies

after 48 hours on blood or MacConkey’s agar. After

24 hours’ growth in standard peptone broth, moderate growth with little or no turbidity is observed.

Biochemically, the plague bacillus produces no

hemolysins; is positive for catalase; and is negative

for hydrogen sulfide, oxidase, urease, and fermentation of lactose, sucrose, rhamnose, and melibiose.2

THE INFECTIOUS AGENT
Medical Aspects of Chemical and Biological Warfare

486

Fig. 23-1. This Wright-Giemsa stain

of a peripheral blood smear from a

patient with septicemic plague demonstrates the bipolar, safety-pin staining of Yersinia pestis. Gram’s and

Wayson’s stains can also demonstrate

this pattern. Photomicrograph: Courtesy of Ken Gage, Ph.D., Centers for

Disease Control and Prevention, Fort

Collins, Colo.

lence.35 These proteins are produced in vitro in a

low-calcium environment and, in some instances,

by attachment to eucaryotic cells.36 They include

• the V antigen, which is involved in regulation of growth and other plasmid-encoded

secreted virulence proteins,37 and which may

also have a more direct role in virulence33;

• Yop M, which binds thrombin, inhibits

platelet aggregation, and may prevent an

effective inflammatory response38;

• Yops K and L, of unknown function39; and

• several proteins that interfere with phagocytic cell function, including Yop H, a tyrosine phosphatase,40 and Yop E.41

Although additional virulence factors encoded on

the Lcr plasmid have been described35 for the other

Yersinia species, confirmation of their importance

in plague is not yet established.

Y pestis also possesses two additional plasmids

not present in the other Yersinia species. First, a 9.5-

kb plasmid encodes for a plasminogen activator

protease, which is most active at temperatures

higher than 30°C.33 This proteolytic enzyme is necessary for systemic spread of infection from a peripheral subcutaneous site, perhaps by causing degradation of fibrin and extracellular matrix proteins,

and by impairing the inflammatory response.42 This

same protease has predominantly coagulase activity at temperatures lower than 30°C.33

The second unique plasmid, of approximately

100 kb, codes for the protein capsule (fraction 1

antigen) of Y pestis. The capsule is antiphagocytic

and necessary for full virulence in some animal species.43 The 100-kb plasmid also encodes for an exotoxin that is active in the mouse and rat but not in

primates.33

EPIDEMIOLOGY

During the modern pandemic, W. G. Liston, a

member of the Indian Plague Commission (1898–

1914), made the association of plague with rats and

incriminated the rat flea as a vector.2 Subsequently,

more than 200 species of animals and 80 species of

fleas have been implicated in maintaining Y pestis

endemic foci throughout the world.21

Throughout history, the oriental rat flea (Xenopsylla cheopis) has been largely responsible for

spreading bubonic plague.5 After the flea ingests a

blood meal on a bacteremic animal, bacilli can multiply and eventually block the flea’s foregut, or

proventriculus, with a fibrinoid mass of bacteria

(Figure 23-2).2

 When an infected flea with a blocked

foregut attempts to feed again, it regurgitates clotted blood and bacteria into the victim’s bloodstream, and so passes the infection on to the next

mammal—whether rat or human. As many as 24,000

organisms may be inoculated into the mammalian

host.2 This flea desiccates rapidly in very hot and

dry weather when away from its hosts, but flourishes at humidity just above 65% and temperatures
Plague

487

Fig. 23-2. The oriental rat flea (Xenopsylla cheopis) has

historically been most responsible for the spread of

plague to humans. This flea has a blocked proventriculus, equivalent to a human’s gastroesophageal region. In

nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood

and bacteria. The ensuing biting of the nearest mammal

will clear the proventriculus through regurgitation of

thousands of bacteria into the bite wound, thereby inoculating the mammal with the plague bacillus. Photomicrograph: Courtesy of Ken Gage, Ph.D., Centers for

Disease Control and Prevention, Fort Collins, Colo.

between 20°C and 26°C,2 and can survive 6 months

without a feeding.21

Although the largest outbreaks of plague have

been associated with X cheopis, all fleas should be

considered dangerous in plague endemic areas.2

During the Black Death, the human flea, Pulex

irritans, may have aided in human-to-human spread

of plague; and during other epidemics, bedbugs

(Cimex lectularius), lice, and flies have been found

to contain Y pestis.

5

 The presence of plague bacilli

in these latter insects is associated with ingestion

of contaminated blood from plague victims, however, and plays little or no role as a vector for the

disease. The most important vector of human

plague in the United States is Diamanus montanus,

the most common flea on rock squirrels and California ground squirrels.21

Throughout history, the black rat, Rattus rattus,

has been most responsible worldwide for the persistence and spread of plague in urban epidemics.

R rattus is a nocturnal, climbing animal that does

not burrow. Instead, it nests overhead and lives in

close proximity to humans.5 In the United Kingdom

and much of Europe, the brown rat, R norvegicus,

has replaced R rattus as the dominant city rat.44

Unlike R rattus, R norvegicus is essentially a burrowing animal that lives under farm buildings and in

ditches. However, R norvegicus may be involved in

both rural and urban outbreaks of plague.5

Most carnivores, except cats, are resistant to

plague infection, but animals such as domestic dogs,

all rodents, and even burrowing owls may mechanically transmit fleas. Mammals that are partially resistant to plague infection serve as continuous reservoirs

of plague. In the United States, deer mice (Peromyscus species) and ground squirrels (Spermophilus

species) are thought to serve as the main reservoirs.

Some susceptible mammals are only occasionally

infected: chipmunks, tree squirrels, cottontail rabbits,

and domestic cats (Figure 23-3).

Highly susceptible animals amplify both fleas

and bacilli. Such epizootics occur in chipmunks,

ground squirrels, and wood rats, but especially in

prairie dogs, rock squirrels (Spermophilus variegatus), and California ground squirrels (Spermophilus beechyi). Although prairie dog fleas rarely bite

humans, the infectious rodents can transmit plague

to humans via direct contact (eg, handling a live or

dead animal; stumbling into a nest while walking; or

dissecting specimens [primarily laboratory personnel]). Rock squirrels and California ground squirrels

both infect humans via direct contact and fleas.5,21,45,46

Many mammals in the United States harbor

plague (Exhibit 23-2). Knowledge of this widespread harborage is important, because certain

mammal–flea complexes found in the United States

are dangerous: they contain both a susceptible

mammal and a flea known to bite humans. These

pairings include the following21:

• the rock squirrel (S variegatus) or California

ground squirrel (S beechyi) and the fleas

Diamanus montanus or Hoplopsyllus anomalus;

• the prairie dog (Cynomys species) and the

flea Opisochrostis hirsutus; and

• Richardson’s ground squirrel (Spermophilus

richardsoni) or the golden-mantled ground

squirrel (S lateralis) and the fleas Oropsylla

labis, O idahoensis, or Thrassus bacchi.

Plague exists in one of two states in nature, enzootic or epizootic. An enzootic is the state of a

stable rodent–flea infection cycle in a relatively resistant host population, without excessive rodent

mortality. Importantly for humans, when the disease is in an enzootic state, the fleas have no need to

seek less desirable hosts—such as ourselves. During

an epizootic, on the other hand, plague bacilli have

been introduced into moderately or highly susceptible

mammals. High mortality occurs, most conspicuously

in larger colonial rodents such as prairie dogs.47

Man is an accidental host in the plague cycle (Figure 23-4) and is not necessary for the persistence of

the organism in nature. Humans usually acquire

plague from
Medical Aspects of Chemical and Biological Warfare

488

a b c

d e f

g h i

Fig. 23-3. Known mammalian reservoirs of plague in the United States (noninclusive). The common North American

marmot (a) and the brown rat (Rattus norvegicus) (b), which has largely replaced the black rat, are considered to be

reservoirs of plague (ie, hosts to infected fleas). Other reservoirs of plague during enzootics are thought to include

the deer mouse (c), the California ground squirrel (d), and the 13-lined ground squirrel (e). Other infective mammals

that can spread plague to humans include the chipmunk (f), prairie dogs (g), and the coyote (h). Domestic and

nondomestic cats are also reservoirs of plague. This cat (i), which died of pneumonic plague, demonstrates a necrotic

head. Photographs a, h: Courtesy of Denver Zoological Society, Denver, Colo. Photographs b–g, i: Courtesy of Centers for Disease Control and Prevention, Fort Collins, Colo.

EXHIBIT 23-2

MAMMALS KNOWN TO HARBOR PLAGUE IN THE UNITED STATES

Carnivores

Black bears, cats (including bobcats and mountain lions), coyotes, dogs, foxes, martens, raccoons, skunks,

weasels, wolverines, wolves

Rodents

Chipmunks, gophers, marmots, mice, prairie dogs, rats, squirrels, voles

Lagomorphs

Hares, rabbits

Hooved Stock

Pigs, mule deer, pronghorn antelope

Adapted from Harrison FJ. Prevention and Control of Plague. Aurora, Colo: US Army Center for Health Promotion and Preventive Medicine, Fitzsimons Army Medical Center; September 1995: 25–28. Technical Guide 103.
Plague

489

Fig. 23-4. Plague cycles in the United

States. This drawing shows the usual,

occasional, and rare routes by which

plague is known to have spread between various mammals and humans. Reprinted with permission

from Poland JD. Plague. In: Hoeprich

PD, Jordan MC, eds. Infectious Diseases: A Modern Treatise of Infectious

Processes. Philadelphia, Pa: Lippincott; 1989: 1297.

• fleas whose usual host is another mammal

(eg, from flea bites, flea feces inoculated

into skin with bites, and by directly biting

the fleas [during the grooming behavior

practiced in some cultures]);

• fleas whose usual host is a human;

• infected animals (eg, from aerosols, draining abscesses, eating infected tissue, and

handling infected pelts); and

• other humans, via aerosol or direct contact

with infected body substances.

The greatest risk to humans occurs when large concentrations of people live under unsanitary conditions in close proximity to large commensal or wild

rodent populations that are infested with fleas that

bite both humans and rodents.2

Human-to-human transmission of plague can occur from patients with pulmonary infection. However, understanding of the epidemiology of pneumonic plague is incomplete. Most epidemics have

occurred in cool climates with moderate humidity

and close contact between susceptible individuals.

Outbreaks of pneumonic plague have been rare in

tropical climates even during epidemics of bubonic

disease. Respiratory transmission may occur more

efficiently via larger droplets or fomites rather than

via small-particle aerosols.48

Worldwide cases of plague and mortalities are

shown in Figure 23-5, and the known foci of plague

in Figure 23-6. In 1992, most of the reported 1,582

cases occurred in Myanmar and Vietnam in

Asia, and Zaire and Madagascar in Africa. Worldwide mortality was 8.7%. The outbreaks in 1994

of pneumonic and bubonic plague in India, and

bubonic plague in Tanzania and Peru, highlight

the potential for epidemics to arise from these

foci.49

Plague has been endemic in the continental

United States since at least 190020 and now is permanently established from the eastern slope of the

Rocky Mountains westward—especially in pine–

INCIDENCE

oak or piñon–juniper woodland habitats at altitudes

of 5,000 to 9,000 ft, or on lower, dry grassland or

desert scrub areas.21 Between 1970 and 1990, 56%

of all cases occurred in New Mexico, 14% in Arizona, and 10% in Colorado.45

In the first quarter of this century, virtually all

432 cases and 284 deaths (65.7% mortality) in the

United States occurred in urban port cities. Epidemics occurred in San Francisco, California, during the

years 1900–1904 (118 deaths) and 1907–1908 (78

deaths). The last time plague was transmitted between humans in the United States was during the

1924–1925 pneumonic plague epidemic in Los Angeles, California. Eighty percent of cases since 1925 have

Figure 23-4 is not shown because the copyright permission granted to

the Borden Institute, TMM, does not allow the Borden Institute to grant

permission to other users and/or does not include usage in electronic media. The current user must apply to the publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

490

Fig. 23-5. Absolute numbers of annual worldwide plague cases, 1976–1994. Fatalities (a subset of the total cases) are

shown in red, total cases in green. Data are as of 7 February 1996; reports for 1995 were not complete at that time.

Note that the mortality rate continues between 5% and 12% despite the availability of effective antibiotics. Data

sources: (1) Human plague in 1990. WHO Weekly Epidemiological Record. 1 Nov 1991;44:321–324. (2) Human plague in

1993. WHO Weekly Epidemiological Record. 17 Feb 1995;7:45–48. (3) Barkway J. World Health Organization, Geneva,

Switzerland. Personal communication, 7 February 1996.

Fig. 23-6. Known worldwide foci of human plague infection. Data sources:

(1) Human plague in 1990. WHO

Weekly Epidemiological Record. 1 Nov

1991;44:321–324. (2) Human plague

in 1993. WHO Weekly Epidemiological Record. 17 Feb 1995;7:45–48. (3)

Barkway J. World Health Organization, Geneva, Switzerland. Personal

communication, February 1996. (4)

Ken Gage, Ph.D., Centers for Disease

Control and Prevention, Fort Collins,

Colorado. Personal communication,

March 1996.

3,000

2,000

1,500

1,000

500

0

2,500

1976 1978 1980 1982 1984 1986 1988 1990 1992 1994

Cases

Fatalities

Data incomplete for this year
Plague

491

been sylvatic, involving contact with wild-rodent

habitats.20 Most cases (58%) are in men and occur

within a 1-mile radius of home,21 and half the victims

in the United States have been younger than 20 years

old.20

Between 1926 and 1960, the United States averaged only 1 case of plague per year. This number

steadily rose to 3 per year during the 1960s, 11 during the 1970s, 18 during the 1980s, and then decreased to 9 per year since 1990.45 The number of

states reporting human plague cases has steadily

increased over the last 5 decades, most likely because increasing encroachment of humans on previously wild areas brings people closer to infected

animals and their fleas.21

In the United States, 93% of cases have occurred

between April and November, peaking in July. During the last 25 years, pneumonic plague accounted

for 11% of cases, and bubonic or septicemic plague,

or both, for 89%. One case of meningitic plague also

occurred.45

Epizootic cycles occur approximately every 5

years. The last large epizootic with a large die-off

of rodents (1982–1984) was accompanied by the

highest number of humans infected with plague

since the urban epidemics of the first quarter of the

century. The numbers of rodents slowly recovered

to their characteristic levels by 1991, and the stage

is now set for another epizootic, with the potential

for increased human plague infections.45,46

As few as 1 to 10 Y pestis organisms are sufficient to infect rodents and primates via the oral, intradermal, subcutaneous, and intravenous routes.33

Estimates of infectivity by the respiratory route for

nonhuman primates vary from 100 to 20,000 organisms.50,51

After being introduced into the mammalian host

by a flea, where it had been at ambient temperature, the organism is thought to be initially susceptible to phagocytosis and killing by neutrophils.

However, some of the bacteria may grow and proliferate within tissue macrophages.52 Within the

human host, several new environmental signals (including elevated temperature of 37°C, contact with

eucaryotic cells, and perhaps the location within

cells or in necrotic foci at low pH) are thought to

induce the synthesis and activity of a multitude of

factors contributing to virulence. These include the

antiphagocytic fraction 1 capsule, pH 6 antigen, the

antiphagocytic Yops H and E, V antigen, Yop M, and

plasminogen activator. The bacteria in this state are

now resistant to phagocytosis and they proliferate

unimpeded extracellularly.

During the incubation phase, the bacilli most

commonly spread to regional lymph nodes, where

suppurative lymphadenitis develops, producing the

characteristic bubo. Dissemination from the local

site is thought to be related to the action of both

plasminogen activator and Yop M. Infection will

progress if untreated; septicemia will develop and

the infection will spread to other organs. The endotoxin of Y pestis probably contributes to the development of septic shock, which is similar to the

shock state seen in other causes of Gram-negative

sepsis. The endotoxin also contributes to the resistance of the organism to the bactericidal activity of

serum.33 The acral cyanosis and necrosis seen in

some cases of septicemic plague may also be related

to the coagulase activity of the plasminogen activator, which occurs at temperatures lower than 37°C.2

Tissues most commonly infected include the

spleen, liver, lungs, skin, and mucous membranes.

Late infection of the meninges also occurs, especially if suboptimal antibiotic therapy has been

given.

Primary pneumonic plague, the most severe form

of disease, arises from inhalation of an infectious

aerosol. Primary pneumonic plague is more rapidly

fatal than secondary, because the inhaled droplets

already contain phagocytosis-resistant bacilli,

which have arisen from their growth at 37°C in the

vertebrate host.47

Primary septicemic plague can occur from direct

inoculation of bacilli into the bloodstream, bypassing initial multiplication in the lymph nodes. Asymptomatic pharyngeal carriage of plague has been

reported to occur in contacts of patients with either

bubonic or pneumonic plague.53,54

PATHOGENESIS

CLINICAL MANIFESTATIONS

In the United States, most patients (85%–90%)

with human plague present clinically with the bubonic form, 10% to 15% with the primary septicemic form, and 1% with the pneumonic form. Secondary septicemic plague occurs in 23% of patients

who present with bubonic plague, and secondary

pneumonic plague occurs in 9%.46 If Y pestis were

used as a biological warfare agent, the clinical mani-
Medical Aspects of Chemical and Biological Warfare

492

festations of plague would be (a) epidemic pneumonia with blood-tinged sputum if aerosolized bacteria were used or (b) bubonic or septicemic plague,

or both, if fleas were used as carriers.

Bubonic Plague

Buboes manifest after a 1- to 8-day incubation

period, with the regular onset of symptoms of sudden fever, chills, and headache often followed several hours later by nausea and vomiting. Presenting symptoms include prostration or severe malaise (75%), headache (20%–85%), vomiting (25%–

49%), chills (40%), altered mentation (26%–38%),

cough (25%), abdominal pain (18%), and chest pain

(13%).2 Six to 8 hours after onset of symptoms, buboes, heralded by severe pain, occur in the groin

(90%, with femoral more frequent than inguinal),

axillary, or cervical lymph nodes—depending on

the site of bacterial inoculation (Figure 23-7). Buboes become visible within 24 hours; they are so

intensely painful that even nearly comatose patients

will attempt to shield them from trauma and will

abduct their extremities to decrease pressure. Other

manifestations of bubonic plague include bladder

distention, apathy, confusion, fright, anxiety, oliguria, and anuria. Tachycardia, hypotension, leukocytosis, and fever are frequently encountered. Untreated, septicemia will develop in 2 to 6 days.55

Approximately 5% to 15% of bubonic plague patients will develop secondary pneumonic plague

and, as a result, the potential for airborne transmission.56

Septicemic Plague

Septicemic plague may occur primarily, or secondarily as a complication of hematogenous dissemination of bubonic plague. Presenting signs and

symptoms of primary septicemic plague are essentially the same as those for any Gram-negative septicemia: fever, chills, nausea, vomiting, and diarrhea. Later, purpura (Figure 23-8), disseminated

intravascular coagulation (DIC), and acral cyanosis and necrosis (Figure 23-9) may be seen.

In New Mexico between 1980 and 1984, plague

was suspected in 69% of patients who had bubonic

plague, but in only 17% of patients who had the

septicemic form. The mortality was 33.3% for septicemic plague versus 11.5% for bubonic, thus highlighting the difficulty of diagnosing septicemic

plague. Diagnosis of septicemic plague took longer

(5 vs 4 d) after onset, although patients sought physicians earlier (1.7 vs 2.1 d) and were hospitalized

Fig. 23-7. A femoral bubo (a), the most common site of an erythematous, tender, swollen, lymph node in patients with

plague. This painful lesion may be aspirated in a sterile fashion to relieve pain and pressure; it should not be incised

and drained. The next most common lymph node regions involved are the inguinal, axillary (b), and cervical areas.

Bubo location is a function of the region of the body in which an infected flea inoculates the plague bacilli. Photographs: Courtesy of Ken Gage, Ph.D., Centers for Disease Control and Prevention, Fort Collins, Colo.

b

a
Plague

493

Fig. 23-8. Purpuric lesions can be seen

on the upper chest of this girl with

plague. The bandage on her neck indicates that a bubo has been aspirated. Photograph: Courtesy Ken

Gage, Ph.D., Centers of Disease Control and Prevention, Fort Collins,

Colo.

sooner (5.3 vs 6.0 d) than patients with bubonic

plague. The only symptom present significantly

more frequently in septicemic than in bubonic

plague was abdominal pain (40% vs < 10%), probably due to hepatosplenomegaly.57

The risk of developing septicemic plague is higher

for individuals older than 40 years of age, although

the risk of dying from septicemic plague is higher

for those younger than 30 years. This difference is

most likely due to older undiagnosed patients

Fig. 23-9. This patient is recovering from bubonic plague that disseminated to the blood (septicemic form) and the

lungs (pneumonic form). Note the dressing over the tracheostomy site. At one point, the patient’s entire body was

purpuric. Note the acral necrosis of (a) the patient’s nose and fingers and (b) the toes. Photographs: Courtesy Ken

Gage, Ph.D., Centers of Disease Control and Prevention, Fort Collins, Colo.

b

a
Medical Aspects of Chemical and Biological Warfare

494

Fig. 23-10. This chest roentgenogram shows right middleand lower-lobe involvement in a patient with pneumonic

plague. Photograph: Courtesy Ken Gage, Ph.D., Centers

for Disease Control and Prevention, Fort Collins, Colo.

being treated empirically with antibiotics that kill

Y pestis, and younger undiagnosed patients being

treated with antibiotics (such as penicillin) that

do not affect Y pestis. Earlier diagnosis and appropriate therapy, not newer antibiotics, will have

the greatest effect on reducing mortality from septicemic plague.57

Pneumonic Plague

Pneumonic plague may occur primarily, from

inhalation of aerosols, or secondarily, from hematogenous dissemination. Patients typically have a

productive cough with blood-tinged sputum within

24 hours after onset of symptoms.2 The findings on

chest roentgenography may be variable, but bilateral alveolar infiltrates appear to be the most common finding in pneumonic plague (Figure 23-10).58,59

Plague Meningitis

Plague meningitis is seen in 6% to 7% of cases.

The condition manifests itself most often in children

after 9 to 14 days of ineffective treatment. Symptoms are similar to those of other forms of acute

bacterial meningitis.60

Pharyngeal Plague

Asymptomatic pharyngeal carriage has been reported to occur in contacts of plague patients.53,54 Rarely, pharyngitis—resembling tonsillitis and associated with cervical lymphadenopathy—has

been reported.17,55 A plague syndrome of cervical buboes, peritonsillar abscesses, and fulminant pneumonia has also been reported to occur among

Indians of Ecuador, who are known to catch and

kill fleas and lice with their teeth. It is thought, although not proven, that endobronchial aspiration

from peritonsillar abscesses leads to fulminant

pneumonia. A similar syndrome may have occurred

in Vietnam.55

Cutaneous Manifestations

Approximately 4% to 10% of plague patients are

said to have an ulcer or pustule at the inoculation

site (Figure 23-11).59,61 The flea typically bites the

lower extremities; therefore, femoral and inguinal

buboes are the most common. Infection arising from

the skinning of infected animals typically produces

axillary buboes. Buboes may point and drain spontaneously or, rarely, they may require incision and

drainage because of pronounced necrosis.

Fig. 23-11. This child has left axillary bubonic plague.

The erythematous, eroded, crusting, necrotic ulcer on the

child’s left upper quadrant is located at the presumed

primary inoculation site. Photograph: Courtesy of Ken

Gage, Ph.D., Centers for Disease Control and Prevention,

Fort Collins, Colo.
Plague

495

Petechiae and ecchymoses may occur during

hematogenous spread to such an extent that the

signs mimic severe meningococcemia, and the microscopic lesions are almost indistinguishable.

The pathogenesis of these lesions is probably that

of a generalized Shwartzman reaction (DIC secondary to the Y pestis endotoxin). Purpura and acral

gangrene may also be due to the activities of the

plasminogen activator/coagulase enzyme, and

prognosis is poor when these signs occur.2,62 Patients

in the terminal stages of pneumonic and septicemic plague often develop large ecchymoses on the

back. Lesions like these are likely to have given rise

to the medieval epithet “the Black Death.”

Ecthyma gangrenosum has been reported in several patients.53,62 The only case cultured grew Y pestis, which suggests that the skin lesions were the

result of septicemic seeding of the organism.62

DIAGNOSIS

The differential diagnosis of septicemic plague

also includes meningococcemia, Gram-negative

sepsis, and the rickettsioses. The patient with pneumonic plague who presents with systemic toxicity,

a productive cough, and bloody sputum suggests a

large differential diagnosis. However, demonstration of Gram-negative rods in the sputum should

readily suggest the correct diagnosis, because Y pestis is perhaps the only Gram-negative bacterium

that can cause extensive, fulminant pneumonia with

bloody sputum in an otherwise healthy, immunocompetent host.

Laboratory Confirmation

In patients with lymphadenopathy, a bubo aspirate should be obtained by inserting a 20-gauge

needle attached to a 10-mL syringe containing 1 mL

of sterile saline. Saline is injected and withdrawn

several times until it is tinged with blood. Repeated,

sterile bubo aspiration may also be done to decompress buboes and relieve pain. Drops of the aspirate should be air-dried on a slide for one of the

following stains: Gram’s, Wright-Giemsa, or

Wayson’s. If available, a direct fluorescent antibody

(DFA) stain of bubo aspirate for the presence of Y

pestis capsular antigen should be performed; a positive DFA result is more specific for Y pestis than are

the other listed stains (Figure 23-13).63,64

Both Wright-Giemsa stain and DFA stain for Y pestis should also be performed on peripheral blood

smears and sputum specimens, when applicable. Although a bipolar, safety-pin staining morphology

has been reported to be specific for Y pestis, it is

not. Other bacteria such as Pasteurella species, Escherichia coli, Klebsiella species, and diplococci (Streptococcus) may also exhibit this morphology. None

of the listed stains is better than any other for demonstrating the bipolar, safety-pin morphology. In

fact, even Y pestis will sometimes not exhibit this

morphology.64

Signs and Symptoms

A patient with a typical presentation of bubonic

plague (eg, with a painful bubo in the setting of

fever, prostration, and possible exposure to rodents

or fleas in an endemic area) should readily suggest the diagnosis of plague. However, if the medical officer is not familiar with the disease or if the

patient presents in a nonendemic area or without

a bubo, then the diagnosis can be most difficult.

When a bubo is present, the differential diagnosis should include tularemia, cat scratch disease,

lymphogranuloma venereum, chancroid, tuberculosis, streptococcal adenitis, and scrub typhus

(Figure 23-12). In both tularemia and cat scratch disease, the inoculation site will usually be more

evident and the patient will usually not be septic.

In chancroid and scrofula, the patient has less local

pain, the course is more indolent, and there is

no sepsis. Patients with chancroid and lymphogranuloma venereum will have a recent history of sexual contact and genital lesions. Those

with the latter disease may be as sick as patients

with plague. Streptococcal adenitis may be difficult

to distinguish initially, but the patient is usually not

septic, and the node is more tender when plague is

present.

The implications of the absence of a bubo were

clearly demonstrated in a review of 27 cases of

plague seen in New Mexico.59 There were no deaths

among 10 patients with typical bubonic plague.

However, 3 of 5 patients died who presented with

an upper respiratory infection syndrome of fever,

sore throat, and headache. Similarly, 3 of 5 patients

died who presented with fever, chills, and anorexia.

The other 7 patients presented with nonspecific

gastrointestinal and urinary tract symptoms without a bubo. Thus, other causes of lymphadenitis,

upper respiratory tract infection, gastrointestinal

disease including appendicitis, and nonspecific febrile illnesses, must all be considered.
Medical Aspects of Chemical and Biological Warfare

496

c

b d

a

Fig. 23-12. (a) Small femoral bubo and presumed inoculation site (on the inferior thigh) in a patient with tularemia. This

Gram-negative bacterial infection (with Francisella tularensis) may closely mimic bubonic plague and is successfully treated

with the same antibiotics. (b) Axillary bubo seen in child with cat scratch disease. (c) Greenblatt’s sign of ipsilateral femoral and inguinal buboes with intervening depression over the inguinal ligament, seen in a patient with lymphogranuloma

venereum caused by Chlamydia trachomatis. (d) Large inguinal bubo seen in a patient with chancroid caused by Haemophilus

ducreyi. Photographs: Courtesy of Dermatology Service, Fitzsimons Army Medical Center, Aurora, Colo.

Fig. 23-13. These Yersinia pestis fluorescent cells are

from infected mouse spleen. Notice how the outlines of the coccobacilli “light up” in this direct

fluorescent antibody (DFA) test. The DFA test is

specific and therefore better than the other stains

discussed in this chapter (original magnification

x 1,000). Photograph: Courtesy of M. C. Chu, Centers for Disease Control and Prevention, Fort

Collins, Colo.
Plague

497

Cultures of blood, bubo aspirate, sputum, and

cerebrospinal fluid (if indicated) should be performed. Tiny, 1- to 3-mm “beaten-copper” colonies

will appear on blood agar by 48 hours, but it is

important to remember that cultures may be negative at 24 hours. In a recent study, 24 (96%) of

25 blood cultures of patients with bubonic plague

were positive on standard supplemented peptone

broth.59

Complete blood counts often reveal leukocytosis with a left shift. Leukemoid reactions with up

to 100,000 white blood cells per microliter may be

seen, especially in children. Platelet counts may

be normal or low, and partial thromboplastin times

are often increased. When DIC is present, fibrin degradation products will be elevated. Because of liver

involvement, alanine aminotransferase, aspartate

aminotransferase, and bilirubin levels are often

increased.

Serologic assays measuring the immune response

to plague infection are mainly of value retrospectively, since patients present clinically before they

develop a significant antibody response. Enzymelinked immunosorbent assay (ELISA) tests and the

older, less-sensitive passive hemagglutination assay (PHA) both measure antibodies to the fraction

1 capsule. They are available from the Centers for

Disease Control and Prevention, Fort Collins, Colorado, and the U.S. Army Medical Research Institute

of Infectious Diseases, Fort Detrick, Frederick,

Maryland. Rapid diagnostic tests are available on

an investigative basis.

An immunological assay to detect circulating

fraction 1 antigen in the serum of acutely infected

patients can detect levels as low as 0.4 ng/mL serum.65

During plague infection, fraction 1 antigenemia

may reach levels of 4 to 8 μg/mL serum. During a

plague outbreak in Namibia, 38 cases of plague

were confirmed: 50% by culture, 34% by antibody

response, and 16% by antigenemia.66 Because fraction 1 antigen and antibody do not occur simultaneously in serum, and because neither may be

present early in infection, titers for both should be

performed on several sequential blood specimens.

A polymerase chain reaction (PCR) test, using

primers for the plasminogen activator gene, can

detect as few as 10 Y pestis organisms, even in the

presence of flea tissue. This test may be useful in

surveillance of rats and could be adapted to aid in

the diagnosis of human infection.67

TREATMENT

streptomycin or given together with chloramphenicol. Treatment should be continued for a minimum

of 10 days or 3 to 4 days after clinical recovery. If

clinically indicated, oral tetracycline can be used to

complete a 10-day course of treatment after at least

5 days of systemic therapy. In patients with very

mild bubonic plague who are not septic, tetracycline can be used orally at a dose of 2 g/d in 4 divided doses for 10 days. Doxycycline should be an

acceptable alternative, although there are no published data on its efficacy in humans. Doxycycline,

ofloxacin, and ceftriaxone have all been shown to

be effective in experimental animal models of septicemic plague.68

In pregnant women, streptomycin or gentamicin

should be used unless chloramphenicol is specifically indicated. Streptomycin is also the treatment

of choice in newborns.

If treated with antibiotics, buboes typically recede in 10 to 14 days and do not require drainage.

Patients are unlikely to survive primary pneumonic

plague if antibiotic therapy is not initiated within

18 hours of the onset of symptoms. Without treatment, mortality is 60% for bubonic plague and 100%

for the pneumonic and septicemic forms.53

Isolation

All patients with plague should be isolated for

the first 48 hours after the initiation of treatment.

Special care must be taken in handling blood and

bubo discharge. If pneumonic plague is present,

then strict, rigidly enforced respiratory isolation

procedures must be followed, including the use of

gowns, gloves, and eye protection. Patients with

pneumonia must be isolated until they have completed at least 4 days of antibiotic therapy. If patients have no pneumonia or draining lesions at 48

hours, they may be taken out of strict isolation.

Antibiotics

Since 1948, streptomycin has remained the treatment of choice for bubonic, septicemic, and pneumonic plague. It should be given intramuscularly

in a dose of 30 mg/kg/d in two divided doses. In

cases of suspected meningitis or in patients who are

hemodynamically unstable, intravenous chloramphenicol (50–75 mg/kg/d in four divided doses)

should be added. Gentamicin has had much less

clinical usage but can be used as an alternative to
Medical Aspects of Chemical and Biological Warfare

498

PREVENTION

All plague-control measures must include insecticide use, public health education, and reduction

of rodent populations with chemicals such as cholecalciferol.2,25 Fleas must always be targeted before

rodents, because killing rodents may release massive amounts of infected fleas.56 Use of insecticides

in rodent areas is effective because rodents pick up

dust on their feet and carry it back to their nests,

where they distribute it over their bodies via constant preening.2

 Plague must be reported to the

World Health Organization as an internationally

quarantinable disease for which travelers may be

detained up to 6 days.

Postexposure Prophylaxis

Not only contacts of patients with pneumonic

plague but also individuals who have been exposed

to aerosols (eg, in a biological warfare attack) should

be treated with tetracycline 15 to 30 mg/kg/d (1–2

g/d) administered in four divided doses for 7 days.

Doxycycline 100 mg administered twice daily is

probably an effective alternative if tetracycline

is not available. Pregnant women and children under 8 years of age should receive trimethoprim/

sulfamethoxazole (40 mg sulfa/kg/d) administered

orally in two divided doses for 7 days.

Hospital personnel who are observing recommended isolation procedures do not require prophylactic therapy, nor do contacts of patients with

bubonic plague. However, people who were in the

same environment and who were potentially exposed to the same source of infection as the contact

case should be given prophylactic antibiotics. In

addition, previously vaccinated individuals should

receive prophylactic antibiotics if they have been

exposed to a plague aerosol.

Immunization

The first plague vaccine, consisting of killed

whole cells, was developed by Russian physician

Waldemar M. W. Haffkine, working in India in 1897.

In 1942, Karl F. Meyer, D.V.M., began developing

an immunogenic and less-reactogenic vaccine for

the U.S. Army from an agar-grown, formalin-killed,

suspension of virulent plague bacilli. With minor

modifications, this is the same procedure used to

prepare the licensed vaccine we have available today. Live-attenuated vaccines have been unsuccessful, since they are much more reactogenic than the

present killed vaccine.23

Only individuals at high risk for plague should

be immunized—such as military troops and other

field personnel working in plague endemic areas

in which exposure to rats and fleas cannot be controlled. Laboratory personnel working with Y pestis, people who reside in enzootic or epidemic

plague areas, and those whose vocations bring them

into regular contact with wild animals, particularly

rodents and rabbits, should also be vaccinated.69

The dose schedule for adults is 1.0 mL initially,

with 0.2 mL at 1 to 3 months, followed by a third

dose 5 to 6 months later. Booster doses of 0.2 mL

are given every 6 months for 1.5 years, and then

every 1 to 2 years thereafter if risk for exposure continues. If an accelerated schedule is essential, then

0.5 mL at 0, 7, and 14 days has been recommended,

although no supporting data exist.69

Approximately 92% to 93% of vaccinees will produce antibody titers after the initial series of three

injections.69–71 Local side effects include erythema,

soreness, or swelling, in any combination, in 11% of

vaccinees and 6% of injections. Systemic side ef

fects include headache, malaise, and myalgias

in 4% of vaccinees and 1% of injections. Rarely, sterile abscesses, necrotic lesions, or anaphylaxis may

occur.72

Data from animal and human investigations suggest that the killed plague vaccine is effective for

preventing or ameliorating bubonic but not pneumonic plague.50,51,73–75 A recombinant vaccine candidate that protects laboratory animals from inhalational challenge is being studied.

SUMMARY

Plague is a zoonotic infection caused by the

Gram-negative bacillus Yersinia pestis. Three great

human pandemics have been responsible for more

deaths than any other infectious agent in history.

Plague is maintained in nature, predominantly

in urban and sylvatic rodents, by a flea vector.

Humans are not necessary for persistence of the organism, and we acquire the disease from animal

fleas, contact with infected animals, or, rarely, from

other humans, via aerosol or direct contact with

infected secretions.

To be able to differentiate endemic disease

from plague used in biological warfare, medical

officers must understand the typical way in which
Plague

499

and headache. Septicemic plague without localized

lymphadenopathy occurs less commonly and is difficult to diagnose. Secondary pneumonia may follow either the bubonic or the septicemic form. Primary pneumonic plague is spread by airborne

transmission, when aerosols from an infected human or animal are inhaled.

Diagnosis is established by isolating the organism from blood or other tissues. Rapid diagnosis

may be made with fluorescent antibody stains of

sputum or tissue specimens. Patients should be isolated and treated with aminoglycosides, preferably

streptomycin, plus chloramphenicol when meningitis is suspected or shock is present. A licensed,

killed, whole-cell vaccine is available to protect

humans against bubonic, but not against primary

pneumonic, plague.

humans contract plague in nature. First, a dieoff of animals in the mammalian reservoir that harbors bacteria-infected fleas will occur. Second,

troops who have been in close proximity to such

infected mammals will become infected. By contrast, in the most likely biological warfare scenario, plague would be spread via aerosol. A rapid,

person-to-person spread of fulminant pneumonia,

characterized by blood-tinged sputum, would then

ensue. If, on the other hand, an enemy force were

to release fleas infected with Y pestis, then soldiers would present with classic bubonic plague

before a die-off in the local mammalian reservoir

occurred.

The most common form of the disease is bubonic

plague, characterized by painful lymphadenopathy

and severe constitutional symptoms of fever, chills,

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Office of The Surgeon General and Center of Military History; 1982: Chap 8, Sec 1.

3. Doyle RJ, Lee NC. Microbes, warfare, religion, and human institutions. Can J Microbiol. 1985;32:193–200.

4. Langmuir DA, Worthen TD, Solomon J, et al. The Thucydides syndrome: A new hypothesis for the cause of

the plague at Athens. N Engl J Med. 1985;313:1027–1030.

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761–762.

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51. Speck RS, Wolochow H. Studies on the experimental epidemiology of respiratory infections, VIII: Experimental pneumonic plague in Macacus rhesus. J Infect Dis. 1957;100:58–68.

52. Cavanaugh DC, Randall R. The role of multiplication of P pestis in mononuclear phagocytes in the pathogenesis of flea-borne plague. J Immunol. 1959;83:348–363.

53. Legters LJ, Cottingham AJ Jr, Hunter DH. Clinical and epidemiologic notes on a defined outbreak of plague in

Vietnam. Am J Trop Med Hyg. 1970;19(4):639–652.

54. Marshall JD, Quy DV, Gibson FL. Asymptomatic pharyngeal plague infection in Vietnam. Am J Trop Med Hyg.

1967;16(2):175–177.

55. Conrad FG, LeCocq FR, Krain R. A recent epidemic of plague in Vietnam. Arch Intern Med. 1968;122(3):193–198.

56. Poland JD. Plague. In: Hoeprich PD, ed. Infectious Diseases: A Guide to the Understanding and Management of

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57. Hull HF, Montes JM, Mann JM. Septicemic plague in New Mexico. J Infect Dis. 1987;155(1):113–118.

58. Alsofrom DJ, Mettler FA Jr, Mann JM. Radiographic manifestations of plague in New Mexico, 1975–1980: A

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59. Crook LD, Tempest B. Plague: A clinical review of 27 cases. Arch Intern Med. 1992;152(June):1253–1256.

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61. Welty TK. Plague. Am Fam Phys. 1986;33(6):159–164.

62. Welty TK, Grabman J, Kompare E, et al. Nineteen cases of plague in Arizona: A spectrum including ecthyma

gangrenosum due to plague and plague in pregnancy. West J Med. 1985;142(May):641–646.

63. Tikomirov EV, Gratz NA, eds. WHO Plague Manual. Rev 3rd ed. Fort Collins, Colo: Centers for Disease Control

and Prevention; 1996.

64. Chu MC. Acting Chief, Diagnostic and Reference Section, National Center for Infectious Diseases, Centers for

Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Fort Collins, Colo. Personal

communication, 7 February 1996.

65. Williams JE, Gentry MK, Braden CA, Leister F, Yolken RH. Use of an enzyme-linked immunosorbent assay to

measure antigenaemia during acute plague. Bull WHO. 1984;62(3):463–466.

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clinically suspect plague in Namibia, 1982. Bull WHO. 1986;64(5):745–752.

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68. Bonacorsi SP, Scavizzi MR, Guiyoule A, Amouroux JH, Carniel E. Assessment of a fluoroquinolone, three betalactams, two aminoglycosides, and a tetracycline in treatment of murine Yersinia pestis infection. Antimicrob

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Med. 1973;(11):720-722.

71. Marshall JD Jr, Cavanaugh DC, Bartelloni PJ, Meyer KF. Plague immunization, III: Serologic response to multiple inoculations of vaccine. J Infect Dis. 1974;129(suppl):S26-S29.

72. Marshall JD Jr, Baratelloni PJ, Cavanaugh DC, Kadull PJ, Meyer KF. Plague immunization, II: Relation of adverse clinical reactions to multiple immunizations with killed vaccine. J Infect Dis. 1974;129(suppl):S19–S25.

73. Williams JE, Cavanaugh DC. Measuring the efficacy of vaccination in affording protection against plague. Bull

WHO. 1979;57(2):309–313.

74. Cavanaugh DC, Elisberg BL, Llewellyn CH, et al. Plague immunization, V: Indirect evidence for the efficacy of

plague vaccine. J Infect Dis. 1974;129(suppl):S37-S40.

75. Pitt MLM, Estep JE, Welkos SL, Friedlander AM. Efficacy of killed whole-cell vaccine against a lethal aerosol

challenge of plague in rodents. Annual meeting, American Society for Microbiology; 1994; Las Vegas, Nev.

Abstract E-45.
Tularemia

503

Chapter 24

TULAREMIA

MARTIN E. EVANS, M.D.*; AND ARTHUR M. FRIEDLANDER, M.D.†

INTRODUCTION

THE INFECTIOUS AGENT

THE DISEASE

Epidemiology

Pathogenesis

Clinical Manifestations

Diagnosis

Treatment

PROPHYLAXIS

SUMMARY

*Lieutenant Colonel (Ret), Medical Corps, U.S. Air Force; Assistant Professor of Internal Medicine, Uniformed Services University of the

Health Sciences, Bethesda, Maryland 20814-4799; currently, Associate Professor, Division of Infectious Diseases, Department of Internal

Medicine, University of Kentucky School of Medicine, Lexington, Kentucky 40536-0084

†Colonel, Medical Corps, U.S. Army; Chief, Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick,

Frederick, Maryland 21702-5011; and Clinical Associate Professor of Medicine, Uniformed Services University of the Health Sciences, 4301

Jones Bridge Road, Bethesda, Maryland 20814-4799
Medical Aspects of Chemical and Biological Warfare

504

INTRODUCTION

ease was reported in 1914.4 Edward Francis subsequently described transmission by deer flies via

infected blood and coined the term tularemia in

1921.5

 Transovarian transmission in ticks was reported in 1926.6

 In 1959, the Soviets proposed

changing the genus name to Francisella in recognition of the contributions of Edward Francis to

the understanding of this disease.7 F tularensis has

been considered an important biological warfare

threat because of its very high infectivity after aerosolization.

Tularemia is a zoonosis caused by the Gramnegative, facultative intracellular bacterium,

Francisella tularensis. The disease is characterized by

fever, localized skin or mucous membrane ulceration, regional lymphadenopathy, and, occasionally, pneumonia.

In 1911, G. W. McCoy discovered the disease in

Tulare County, California, as a cause of a plaguelike illness in ground squirrels.1 An organism

was isolated and named Bacterium tularense.2,3 The

first bacteriologically confirmed case of human disTHE INFECTIOUS AGENT

F tularensis is a nonmotile, obligately aerobic,

Gram-negative coccobacillus. There are two

biovars8

:

• F tularensis biovar tularensis is the most

common isolate in the United States. It is

recovered from rodents and ticks, and is

highly virulent for rabbits and humans. It

produces acid from glycerol and has citrulline ureidase activity.

• F tularensis biovar palearctica is more common outside the United States. It is recovered from water, mosquitoes, and aquatic

mammals, and is relatively avirulent for

rabbits and humans. It does not produce

acid from glycerol, and does not have citrulline ureidase activity.

The subspecies are indistinguishable serologically,

although they may be distinguished by 16S ribosomal ribonucleic acid (rRNA) analysis.9

 A capsule has

been reported that may contribute to virulence.10,11

F tularensis may have a lipopolysaccharide (LPS),12

but the biological activity of the LPS has not been

well characterized and its role in pathogenicity is

unclear. No known toxins are produced.

THE DISEASE

Epidemiology

Tularemia occurs in North America, Europe, the

Middle East, Russia, and Japan, but is rare in the

United Kingdom, Africa, and Central and South

America. In the United States, the disease is most

prevalent in Arkansas, Illinois, Missouri, Texas, Virginia, and Tennessee, although cases have been reported from all states except Hawaii.13,14

The principal reservoir of tularemia in North

America is the tick; more than 10 species have been

implicated.13,14 F tularensis is maintained in tick

populations by transovarial passage, and is probably transmitted to humans via feces since the bacterium has not been found in the tick salivary

glands. The bacterium has been isolated from 55

other arthropods and more than 100 nonarthropods.13 In North America, the rabbit is the most common vertebrate associated with transmission of tularemia. In other areas of the world, such as the

former Soviet Union, tularemia is maintained in

water rats and other aquatic mammals. Pharyngitis,

abdominal pain, and fever may result from the ingestion of contaminated water in these areas.15 With

the disruption of normal sanitation during World War

II, hundreds of thousands of civilians and large

numbers of Russian troops contracted tularemia.16

The reported incidence in the United States since

1967 has been fewer than 200 cases per year. This

compares with 2,291 cases reported in 1939 and

more than 1,100 cases per year during the 1940s.17,18

The decline in incidence may be due to a declining

interest in rabbit hunting, less recognition of the

disease by physicians, or inadvertent cure of the

disease by physicians who treat febrile patients with

aminoglycoside antibiotics.13

Pathogenesis

F tularensis is usually introduced into the host

through breaks in the skin, or through the mucous

membranes of the eye, respiratory tract, or gas-
Tularemia

505

trointestinal tract.19–23 Ten virulent organisms injected subcutaneously, and 10 to 50 organisms given

by aerosol can cause infection in humans.23–25

After inoculation, F tularensis is ingested by and

multiplies within macrophages.26 The host defense

against F tularensis is mediated primarily by (a) Tcell–independent mechanisms, which appear early

(< 3 days after infection), and (b) T-cell–dependent

mechanisms, which appear later (> 3 days after infection). In the T-cell–independent mechanisms,

macrophages, which have ingested bacteria, secrete

tumor necrosis factor–alpha (TNF-alpha). TNF-alpha stimulates natural killer (NK) cells to produce

interferon-gamma (IFN-γ), which, in turn, feeds

back on macrophages and stimulates the cells to kill

intracellular bacteria through the production of nitric oxide.26–28 In the T-cell–dependent mechanism,

macrophages present bacterial antigen in the context of the major histocompatibility complex (MHCII) to cluster of differentiation 4+ (CD4+) T lymphocytes. These cells respond by proliferating and

secreting TNF-alpha, IL-2, and IFN-γ, which stimulate the macrophages to kill intracellular bacteria.27–32

Cell-mediated immunity constitutes the major protective mechanism.33

The role of humoral immunity and neutrophils

in the host defense against F tularensis is unclear.

Specific immunoglobulins (IgG, IgA, and IgM) appear within 1 week of infection, and passive transfer of immune serum protects naive mice against

challenge with attenuated vaccine strains.34–37 This

protection, however, is not evident when mice are

challenged with virulent wild-type strains.38 Although some of the antibodies produced are opsonic

and facilitate phagocytosis by neutrophils, neutrophils are not efficient in killing ingested bacteria.39,40

Recent studies using animals depleted of neutrophils suggest that neutrophils are important in resistance to infection with attenuated strains, but the

relevance of these findings to virulent wild-type

tularemia is unknown.41 Overall, these data suggest

that the humoral immune response plays a limited

role in the host defense against naturally acquired

infection.33

Clinical Manifestations

Tularemia can be divided into the ulceroglandular (75% of patients) and the typhoidal (25% of

patients) forms, based on the clinical signs. Patients

with ulceroglandular tularemia have lesions on the

skin or mucous membranes (including the conjunctiva), lymph nodes larger than 1 cm in diameter, or

both. Patients with typhoidal tularemia, on the

other hand, present with lymph nodes smaller than

1 cm in diameter and without skin or mucous membrane lesions. This simplified scheme is suggested

instead of the more-complicated, previous classification (ie, ulceroglandular, glandular, oculoglandular, typhoidal), because it is more in keeping with

the clinical, pathophysiological, and prognostic aspects of the disease.13

After an incubation period of 3 to 6 days,42–45 patients with the ulceroglandular form of the disease

develop a constellation of symptoms consisting of

fever (85%), chills (52%), headache (45%), cough

(38%), and myalgias (31%). The fever is often accompanied by a pulse–temperature disassociation

(ie, the pulse increases less than 10 beats per min

per 1°F increase in temperature above normal46).

Patients may also complain of chest pain, vomiting, arthralgia, sore throat, abdominal pain, diarrhea, dysuria, back pain, or stiff neck.13

A cutaneous ulcer occurs in approximately 60%

of patients and is the most common sign of tularemia. Ulcers are generally single lesions of 0.4 to 3.0

cm in diameter, with heaped-up edges (Figure 24-1).

Lesions associated with infection acquired from

mammalian vectors are usually located on the upper extremities, whereas lesions associated with

infection acquired from arthropod vectors are usually located on the lower extremities. Ulcerative

lesions are almost always accompanied by regional

lymphadenopathy.13

Enlarged lymph nodes are seen in approximately

85% of patients, and may be the initial, or the only,

sign of infection. Nodes are usually tender and

0.5 to 10 cm in diameter (mean 2.0 cm). Although

enlarged nodes usually occur as single lesions,

they may appear in groups or in a sporotrichoid

distribution. The appearance of enlarged nodes

in upper or lower extremities and the correlation

Fig. 24-1. Cutaneous ulcer of tularemia. Photograph:

Courtesy of William Beisel, M.D., Colonel, Medical

Corps, US Army (Ret).
Medical Aspects of Chemical and Biological Warfare

506

with the vector is the same as for ulcerative lesions.19 Enlarged lymph nodes may become fluctuant, drain spontaneously, or persist for as long as

3 years.22

Pharyngitis may occur in up to 25% of patients

with tularemia. 13,22,47,48 The posterior pharynx

may not be inflamed; however, there may be

erythema, exudate, petechiae, hemorrhage, or ulcers. On occasion, patients with pharyngitis may

also develop a retropharyngeal abscess or suppuration of regional lymph nodes.47,49–51 Pneumonia

commonly accompanies pharyngitis, perhaps reflecting acquisition of the disease by the aerosol

route.

The lower respiratory tract is involved in 47% to

94% of patients.13,52,53 The variability in these figures

is probably due to the variable use of chest radiographs during patient evaluations. Patients present

with nonproductive or productive cough, and less

commonly with pleuritic chest pain, shortness of

breath, or hemoptysis. Examination of the sputum

is not helpful for making the diagnosis of tularemia pneumonia. Chest radiographs show that approximately 50% of patients have pneumonia, and

1% or fewer have hilar adenopathy without parenchymal involvement. Pleural effusions are seen in

15% of patients with pneumonia. Interstitial patterns, cavitary lesions, bronchopleural fistulae, and

calcifications have been reported in patients with

tularemia pneumonia (Figure 24-2).53–62 Approximately 30% of patients with ulceroglandular tularemia and 80% of patients with typhoidal tularemia have pneumonia. The higher incidence of

pneumonia in patients with typhoidal tularemia

probably accounts for the higher mortality associated with this form of the disease.13

Other, infrequent clinical syndromes associated

with tularemia include pericarditis, enteritis, appendicitis, peritonitis, erythema nodosum, and meningitis.13,22,63–66

Patients usually do not have abnormalities in the

hematocrit, hemoglobin, or platelet levels. The peripheral white blood cell count may range between

5,000 and 22,000 cells per microliter, but it is usually only mildly elevated. Differential blood cell

counts are usually normal, although patients may

have a lymphocytosis late in the disease.13,67 Patients

may have microscopic pyuria, which may lead to

the erroneous diagnosis of a urinary tract infection.13,68 Mild elevations in lactic dehydrogenase,

serum transaminases, and alkaline phosphatase are

commonly seen. Some patients may experience

rhabdomyolysis associated with elevations in the

serum creatine kinase and urinary myoglobin levFig. 24-2. Chest roentgenogram of tularemia pneumonia showing bilateral infiltrates. Photograph: Courtesy

of William Beisel, M.D., Colonel, Medical Corps, US

Army (Ret).

els.69 The cerebrospinal fluid is usually normal, although mild abnormalities in protein, glucose, and

blood cell count have been reported.13

Diagnosis

Tularemia can be diagnosed by recovery of

F tularensis in culture, or from serologic evidence

of infection in a patient with a compatible clinical

syndrome. Although the organism is difficult to

culture,24,25,53,70 it can be recovered from blood, ulcers, conjunctival exudates, sputum, gastric

washings, and pharyngeal exudates.23,70 Recovery

may be possible even after the institution of appropriate antibiotic therapy. 23 The organism

grows poorly on standard media. On media containing cysteine or other sulfhydryl compounds (eg,

glucose cysteine blood agar, thioglycollate broth),

F tularensis appears as small, smooth, opaque

colonies after 24 to 48 hours of incubation at 37°C.

The bacterium has occasionally been recovered on

charcoal yeast extract (CYE),71 or Thayer-Martin

agar,72 or from radiometric detection systems if

the media are subcultured onto chocolate agar.73,74

The organism can readily be recovered from animals inoculated with infectious materials, but
Tularemia

507

this is rarely done because of the likelihood of epizootics within the animal colony and the risk of

infection to laboratory workers.75,76 Identification

of the organism is made on the basis of its growth

characteristics and bacterial agglutination or fluorescent staining using antisera specific for

F tularensis.

Most diagnoses of tularemia are made serologically using bacterial agglutination or enzyme-linked

immunosorbent assay (ELISA). Measurable levels

of antibodies that agglutinate F tularensis appear

within 1 week of infection,35,77 but levels high

enough to allow confidence in the specificity of the

serologic diagnosis (an agglutination titer > 1:160,

for example) do not appear until more than 2 weeks

after infection.13,34–36 The serologic response may be

blunted by prior administration of antibiotics.78

Because antibodies to F tularensis may cross-react

with Brucella,

79–81 Proteus OX19,30,82 and Yersinia organisms,30,36,82,83 and because detectable antibody

levels may persist for many years after a bout of

tularemia,13,36 the serologic diagnosis of an acute

infection should, ideally, be made only if a 4-fold

or greater increase in serologic response is seen

during the course of the patient’s illness.

Treatment

Patients with tularemia who do not receive appropriate antibiotic treatment may have a prolonged illness characterized by malaise, weakness,

weight loss, and other symptoms that last for

months.22,82,84,85 Before the availability of effective antibiotics, ulceroglandular and typhoidal tularemia had

mortalities of approximately 4% and 35%, respectively.44,57 With appropriate treatment, tularemia has

an overall mortality of approximately 1% to 2.5%.13,86,87

Streptomycin is the drug of choice for the treatment of tularemia. The drug is bactericidal, and

patients treated with streptomycin usually respond

within 48 hours of its administration.19,42,58,88 Relapses are uncommon, and resistance has not been

reported.70,89 Other aminoglycosides such as gentamicin have been used with some success and are

probably reasonable alternatives.13 Bacteriostatic

drugs such as chloramphenicol and tetracycline are

often efficacious, but relapses occur if the drug is

given too early in the course of the disease or if is

not continued long enough.13,23,70 To date, there is

only limited clinical experience with erythromycin

and the fluoroquinolones.31,71,90–92

Tularemia is a zoonotic disease caused by infection with the Gram-negative, facultative intracellular bacterium, Francisella tularensis. The organism

PROPHYLAXIS

is highly infectious by both the cutaneous and aerosol routes. Naturally occurring tularemia occurs

most commonly in its ulceroglandular form; paSUMMARY

Antibiotic prophylaxis after exposure to tularemia is difficult. The optimal bactericidal antibiotics such as streptomycin are impractical because

they must be given parenterally. Limited studies93

carried out in small numbers of human volunteers

showed that treatment with tetracycline begun 24

hours after exposure to an aerosol of tularemia protected subjects from disease. An oral dose of 2 g/d

for 14 days was necessary.

Vaccines to prevent tularemia have included

those made from killed, whole cells and live, attenuated strains. A whole-cell, killed vaccine was developed by L. Foshay and associates94 in the 1930s,

but proved to be of limited efficacy. Experimental

studies24 done with human volunteers showed that

this vaccine reduced the frequency of systemic

symptoms but did not prevent the local lesion after

intracutaneous challenge. Additional studies25 with

aerosol challenge in humans showed that the killed

vaccine neither prevented nor modified the disease.

A live, attenuated vaccine had been developed

and used in humans in the Soviet Union in the 1940s

and 1950s.95 The vaccine proved to be a mixture of

variants of varying virulence. At the U.S. Army

Medical Research Institute of Infectious Diseases,

Fort Detrick, Frederick, Maryland, in 1961, H. T.

Eigelsbach and C. M. Downs96 further purified and

characterized a strain from this vaccine. This derivative was called live vaccine strain (LVS). Extensive evaluations16,25,97,98 have demonstrated that the

LVS vaccine protected human volunteers against an

aerosol challenge with virulent F tularensis.

Evidence based on an analysis of laboratory-acquired infections99 indicates that immunization with

the live, attenuated LVS vaccine prevents the typhoidal and ameliorates the ulceroglandular forms

of tularemia. The LVS vaccine is currently available

as an Investigational New Drug from the U.S. Army

Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland 21702-5011.
Medical Aspects of Chemical and Biological Warfare

508

tients present with a cutaneous ulcer or mucous–

membrane lesion and regional tender lymphadenopathy. The typhoidal form occurs in 25% of naturally occurring cases; patients present with systemic

symptoms without local lesions or marked lymphadenopathy. Pneumonia occurs in up to 80% of patients with typhoidal tularemia.

A biological warfare attack with aerosolized F

tularensis would probably produce pneumonia with

or without accompanying mucous membrane lesions. Diagnosis is usually established by serology,

as the organism is difficult to culture. The treatment

of choice is streptomycin, with other aminoglycoside drugs being reasonable alternatives. Immediate postexposure antibiotic prophylaxis with

tetracycline prevents disease. A live, attenuated vaccine, available as an Investigational New Drug, is

effective against aerosol infection.

REFERENCES

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Chapter 25

BRUCELLOSIS

DAVID L. HOOVER, M.D.*; AND ARTHUR M. FRIEDLANDER, M.D.†

INTRODUCTION

THE INFECTIOUS AGENT

THE DISEASE

Epidemiology

Pathogenesis

Clinical Manifestations

Diagnosis

Treatment

PROPHYLAXIS

SUMMARY

*Colonel, Medical Corps, U.S. Army; Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, D. C. 20307-

5100; and Associate Professor of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799

†Colonel, Medical Corps, U.S. Army; Chief, Bacteriology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick,

Frederick, Maryland 21702-5011; and Clinical Associate Professor of Medicine, Uniformed Services University of the Health Sciences, 4301

Jones Bridge Road, Bethesda, Maryland 20814-4799
Medical Aspects of Chemical and Biological Warfare

514

suffering from contagious abortion.6 In 1917, A. C.

Evans recognized that Bang’s organism was identical to that described by Bruce as the causative agent

of human brucellosis. The organism infects mainly

cattle, sheep, goats, and other ruminants, in which

it causes abortion, fetal death, and genital infection.7,8 Humans, who are usually infected incidentally by contact with infected animals or ingestion

of dairy foods, may develop numerous symptoms

in addition to the usual ones of fever, malaise, and

muscle pain. Disease frequently becomes chronic

and may relapse, even with treatment.

The ease of transmission by aerosol suggests that

Brucella organisms might be a candidate for use as

a biological warfare agent. Indeed, the United States

began development of B suis as a biological weapon

in 1942. The agent was formulated to maintain longterm viability, placed into bombs, and tested in field

trials during 1944–1945 using animal targets. By

1967, the United States terminated its offensive program for development and deployment of Brucella

as a biological weapon. Although the munitions

developed were never used in combat, the studies

reinforced the concern that Brucella organisms

might be used against U.S. troops as a biological

warfare agent.9

THE INFECTIOUS AGENT

thionine or basic fuchsin dyes; agglutination by

antisera directed against certain lipopolysaccharide

epitopes; and by susceptibility to lysis by bacteBrucellae are small, nonmotile, nonsporulating,

nontoxigenic, nonfermenting, aerobic, Gram-negative coccobacilli that may, based on DNA homology, represent a single species.10 Conventionally,

however, they are classified into six species, each

comprising several biovars. Each species has a characteristic, but not an absolute, predilection to infect certain animal species (Table 25-1). Only Brucella melitensis, B suis, B abortus, and B canis cause

disease in man. Infection of humans with B ovis and

B neotomae has not been described.

Brucellae grow best on trypticase, soy-based, or

other enriched media with a typical doubling time

of 2 hours. Most biovars of B abortus require incubation in an atmosphere of 5% to 10% carbon dioxide for growth. Brucellae may produce urease, oxidize nitrite to nitrate, and are oxidase and catalase

positive. Species and biovars are differentiated by

their carbon dioxide requirements; ability to use

glutamic acid, ornithine, lysine, and ribose; hydrogen sulfide production; growth in the presence of

INTRODUCTION

Brucellosis is a zoonotic infection of domesticated

and wild animals, caused by organisms of the genus Brucella. Humans become infected by ingestion

of animal food products, direct contact with infected

animals, or inhalation of infectious aerosols.

Brucellosis in humans has a strong association

with military medicine.1

 In 1751, Cleghorn, a British

army surgeon stationed on the Mediterranean island

of Minorca, described cases of chronic, relapsing

febrile illness and cited Hippocrates’s description

of a similar disease more than 2,000 years earlier.2

Three additional British army surgeons working on

the island of Malta during the 1800s were responsible

for important observations of the disease. J. A.

Marston described clinical characteristics of his own

infection in 1861.3

 In 1887, David Bruce, for whom the

genus Brucella is named, isolated the causative organism from the spleens of five fatal cases and

placed it within the genus Micrococcus.

4

 Ten years

later, M. L. Hughes, who had coined the name “undulant fever,” published a monograph that

detailed clinical and pathological findings in 844

patients.5

In that same year, B. Bang, a Danish investigator, identified an organism, which he called the “Bacillus of abortion,” in placentas and fetuses of cattle

TABLE 25-1

TYPICAL HOST SPECIFICITY OF BRUCELLA

SPECIES

Brucella Animal Human

Species Host Pathogenicity

B suis Swine High

B melitensis Sheep, goats High

B abortus Cattle, bison Intermediate

B canis Dogs Intermediate

B ovis Sheep None

B neotomae Rodents None
Brucellosis

515

riophage. Recently, analysis of fragment lengths of

deoxyribonucleic acid (DNA) cut by various restriction enzymes has also been used to differentiate

brucellae groupings.10

The lipopolysaccharide (LPS) component of the

outer cell membranes of brucellae is quite different—both structurally and functionally—from that

of other Gram-negative organisms.11,12 The lipid A

portion of a Brucella organism LPS contains fatty

acids 16 carbons long, and lacks the 14-carbon

myristic acid typical of lipid A of Enterobacteriaceae. This unique structural feature may underlie

the remarkably reduced pyrogenicity (less than

1/100th) of Brucella LPS, compared with the pyrogenicity of Escherichia coli LPS.13 In addition, the

O-polysaccharide portion of LPS from smooth organisms contains an unusual sugar, 4,6-dideoxy-4-

formamido-alpha-D-mannopyranoside, which is

expressed either as a homopolymer of alpha-1,2-

linked sugars (A type), or as 3 alpha-1,2 and 2 alpha-1,3-linked sugars (M type). These variations in

O-polysaccharide linkages lead to specific, taxonomically useful differences in immunoreactivity

between A and M sugar types.14

THE DISEASE

Epidemiology

Animals may transmit Brucella organisms during septic abortion, at the time of slaughter, and in

their milk. Brucellosis is rarely, if ever, transmitted

from person to person. The incidence of human disease is thus closely tied to the prevalence of infection in sheep, goats, and cattle, and to practices that

allow exposure of humans to potentially infected

animals or their products. In the United States,

where most states are free of infected animals and

where dairy products are routinely pasteurized, illness occurs primarily in individuals such as veterinarians, shepherds, cattlemen, and slaughterhouse

workers who have occupational exposure to infected animals. In many other countries, humans

more commonly acquire infection by ingestion of

unpasteurized dairy products, especially cheese.

Less obvious exposures can also lead to infection.

In Kuwait, for example, disease with a relatively

high proportion of respiratory complaints has occurred in individuals who have camped in the

desert during the spring lambing season.15 In Australia, an outbreak of B suis infection was noted in

hunters of infected feral pigs.16 B canis, a naturally

rough strain that typically causes genital infection

in dogs, can rarely infect man.

Brucellae are also highly infectious in laboratory

settings; numerous laboratory workers who culture

the organism become infected. Fewer than 200 total cases per year (0.04 cases per 100,000 population) are reported in the United States. The incidence is much higher in other regions such as the

Middle East; countries bordering the Mediterranean

Sea; and China, India, Mexico, and Peru; for example, 33 cases per 100,000 population in Jordan

(1987) and 88 cases per 100,000 population in Kuwait (1985), respectively.17,18

Pathogenesis

Brucellae can enter mammalian hosts through

skin abrasions or cuts, the conjunctiva, the respiratory tract, and the gastrointestinal tract.19 In the

gastrointestinal tract, the organisms are phagocytosed by lymphoepithelial cells of gut-associated

lymphoid tissue, from which they gain access to the

submucosa.20 Organisms are rapidly ingested by

polymorphonuclear leukocytes, which generally

fail to kill them,21,22 and are also phagocytosed by

macrophages (Figure 25-1). Bacteria transported in

macrophages, which traffic to lymphoid tissue

draining the infection site, may eventually localize

Fig. 25-1. Cultured human monocyte-derived macrophage infected with Brucella melitensis. The bacteria, which

replicate in phagolysosomes, have a coccobacillary appearance (eosin Y–methylene blue–azure A, original

magnification x 1,000). Photograph: Courtesy of Robert

Crawford, Ph.D., Senior Scientist, American Registry of

Pathology, Washington, DC.
Medical Aspects of Chemical and Biological Warfare

516

in lymph nodes, liver, spleen, mammary gland,

joints, kidneys, and bone marrow.

In macrophages, brucellae may inhibit fusion of

phagosomes and lysosomes, and replicate in the

phagosome.23 If unchecked by macrophage microbicidal mechanisms, the bacteria destroy their host

cells and infect additional cells. Brucellae can also

replicate extracellularly in host tissues. Histopathologically, the host cellular response may range from

abscess formation to lymphocytic infiltration to

granuloma formation with caseous necrosis.

Studies in experimental models have provided

important insights into host defenses that eventually control infection with Brucella organisms. Serum complement effectively lyses some rough

strains (ie, those that lack O-polysaccharide side

chains on their LPS), but has little effect on smooth

strains (ie, bacteria with a long O-polysaccharide

side chain); B melitensis may be less susceptible than

B abortus to complement-mediated killing.24,25 Administration of antibody to mice prior to challenge

with rough or smooth strains of brucellae reduces

the number of organisms that appear in liver and

spleen. This effect is due mainly to antibodies directed against LPS, with little or no contribution of

antibody directed against other cellular components.26

Reduction in intensity of infection in mice can

be transferred from immune to nonimmune animals

by both cluster of differentiation 4+ (CD4+) and

CD8+ T cells27 or by immunoglobulin (Ig) fractions

of serum. Administration of antibody to interferon

gamma (IFN-γ) worsens experimental infection.28

Moreover, macrophages treated with IFN-γ in vitro

inhibit intracellular bacterial replication.29 In ruminants, vaccination with killed bacteria provides

some protection against challenge, but live vaccines

are much more effective.

These observations suggest that brucellae, like

other facultative or obligate intramacrophage

pathogens, are primarily controlled by macrophages activated to enhanced microbicidal activity

by IFN-γ and other cytokines produced by immune

T lymphocytes. It is likely that antibody, complement, and macrophage-activating cytokines produced by natural killer (NK) cells play supportive

roles in early infection or in controlling growth of

extracellular bacteria.

In ruminants, Brucella organisms bypass the most

effective host defenses by targeting embryonic and

trophoblastic tissue. In cells of these tissues, the

bacteria grow not only in the phagosome but also

in the cytoplasm and the rough endoplasmic reticulum.30 In the absence of effective intracellular microbicidal mechanisms, these tissues permit exuberant bacterial growth, which leads to fetal death and

abortion. In ruminants, the presence in the placenta

of erythritol may further enhance growth of brucellae. Products of conception at the time of abortion may contain up to 1010 bacteria per gram of

tissue.31 When septic abortion occurs, the intense

concentration of bacteria and aerosolization of infected body fluids during parturition often result

in infection of other animals and people.

Clinical Manifestations

Clinical manifestations of brucellosis are diverse

and the course of the disease is variable.32 Patients

with brucellosis may present with an acute, systemic febrile illness; an insidious chronic infection;

or a localized inflammatory process. Disease may

be abrupt or insidious in onset, with an incubation

period of 3 days to several weeks. Patients usually

complain of nonspecific symptoms such as fever,

sweats, fatigue, anorexia, and muscle or joint aches

(Table 25-2). Neuropsychiatric symptoms, notably

depression, headache, and irritability, occur frequently. In addition, focal infection of bone, joints,

or genitourinary tract may cause local pain. Cough,

pleuritic chest pain, and dyspepsia may also be

noted. Symptoms of patients infected by aerosol are

indistinguishable from those of patients infected by

other routes. Chronically infected patients freTABLE 25-2

SYMPTOMS AND SIGNS OF BRUCELLOSIS

Symptom or Sign Patients Affected (%)

Fever 90–95

Malaise 80–95

Body Aches 40–70

Sweats 40–90

Arthralgia 20–40

Splenomegaly 10–30

Hepatomegaly 10–70

Data sources: (1) Mousa AR, Elhag KM, Khogali M, Marafie AA.

The nature of human brucellosis in Kuwait: Study of 379 cases.

Rev Infect Dis. 1988;10(1):211–217. (2) Buchanan TM, Faber LC,

Feldman RA. Brucellosis in the United States, 1960–1972: An

abattoir-associated disease, I: Clinical features and therapy.

Medicine (Baltimore). 1974;53(6):403–413. (3) Gotuzzo E, Alarcon

GS, Bocanegra TS, et al. Articular involvement in human brucellosis: A retrospective analysis of 304 cases. Semin Arthritis

Rheum. 1982;12(2):245–255.
Brucellosis

517

quently lose weight. Symptoms often last for 3 to 6

months and occasionally for a year or more. Physical examination is usually normal, although

hepatomegaly, splenomegaly, or lymphadenopathy

may occur. Brucellosis does not usually cause leukocytosis, and some patients may be moderately

neutropenic.33 Although disease manifestations cannot be strictly related to the infecting species, B

melitensis tends to cause more severe, systemic illness than the other brucellae; B suis is more likely

to cause localized, suppurative disease.

Infection with B melitensis leads to bone or joint

disease in about 30% of patients; sacroiliitis develops in 6% to 15%, particularly in young adults.34–36

Arthritis of large joints occurs with about the same

frequency as sacroiliitis. In contrast to septic arthritis caused by pyogenic organisms, joint inflammation seen in patients with B melitensis is mild, and

erythema of overlying skin is uncommon. Synovial

fluid is exudative, but cell counts are in the low

thousands with predominantly mononuclear cells.

In both sacroiliitis and peripheral joint infections,

destruction of bone is unusual. Organisms can be

cultured from fluid in about 20% of cases; culture

of the synovium may increase the yield. Spondylitis,

another important osteoarticular manifestation of

brucellosis, tends to affect middle-aged or elderly

patients, causing back (usually lumbar) pain, local

tenderness, and occasionally radicular symptoms.37

Radiographic findings, similar to those of tuberculous infection, typically include disk space narrowing and epiphysitis, particularly of the anterosuperior quadrant of the vertebrae, and presence

of bridging syndesmophytes as repair occurs. Bone

scan of spondylitic areas is often negative or only

weakly positive. Paravertebral abscess occurs rarely.

In contrast with frequent infection of the axial skeleton, osteomyelitis of long bones is rare.38

Infection of the genitourinary tract, an important

target in ruminant animals, also may lead to signs

and symptoms of disease in man.39,40 Pyelonephritis and cystitis and, in males, epididymoorchitis,

may occur. Both diseases may mimic their tuberculous counterparts, with “sterile” pyuria on routine

bacteriologic culture. With bladder and kidney infection, Brucella organisms can be cultured from the

urine. Brucellosis in pregnancy can lead to placental and fetal infection.41 Whether abortion is more

common in brucellosis than in other severe bacterial infections, however, is unknown.

Lung infections have also been described, particularly before the advent of effective antibiotics.

Although up to one quarter of patients may complain of respiratory symptoms, mostly cough,

dyspnea, or pleuritic pain, chest X-ray examinations

are usually normal.42 Diffuse or focal infiltrates,

pleural effusion, abscess, and granulomas may be

noted.

Hepatitis and, rarely, liver abscess also occur.

Mild elevations of serum lactate dehydrogenase and

alkaline phosphatase are common. Biopsy may

show well-formed granulomas or nonspecific hepatitis with collections of mononuclear cells.32

Other sites of infection include the heart, central

nervous system, and skin. Brucella endocarditis, a

rare, but most feared complication, accounts for 80%

of deaths from brucellosis.43 Central nervous system infection usually manifests itself as chronic

meningoencephalitis, but subarachnoid hemorrhage and myelitis also occur. A few cases of skin

abscesses have been reported.

Diagnosis

A thorough history that elicits details of appropriate exposure (eg, laboratories, animals, animal

products, or environmental exposure to locations

inhabited by potentially infected animals) is the

most important diagnostic tool. Brucellosis should

also be strongly considered in differential diagnosis of febrile illness if troops have been exposed to

a presumed biological attack. Polymerase chain reaction and antibody-based antigen detection systems may demonstrate the presence of the organism in environmental samples collected from the

attack area.

When the disease is considered, diagnosis is usually made by serology. Although a number of serologic techniques have been developed and tested,

the tube agglutination test remains the standard

method.44 This test, which measures the ability of

serum to agglutinate killed organisms, reflects the

presence of anti–O-polysaccharide antibody. Use of

the tube agglutination test after treatment of serum

with 2-mercaptoethanol or dithiothreitol to dissociate IgM into monomers detects IgG antibody. A

titer of 1:160 or higher is considered diagnostic.

Most patients already have high titers at the time

of clinical presentation, so a 4-fold rise in titer may

not occur. IgM rises early in disease and may persist at low levels (eg, 1:20) for months or years after

successful treatment. Persistence or increase of 2-

mercaptoethanol–resistant titers has been associated with persistent disease or relapse.45 Serum testing should always include dilution to at least 1:320,

since inhibition of agglutination at lower dilutions

may occur. The tube agglutination test does not

detect antibodies to B canis because this rough or-
Medical Aspects of Chemical and Biological Warfare

518

ganism does not have O-polysaccharide on its surface. Immunoenzymatic assays (eg, enzyme-linked

immunosorbent assays [ELISAs]) have been developed for use with B canis, but are not well standardized. ELISAs developed for other brucellae similarly

suffer from lack of standardization.

In addition to serologic testing, diagnosis should

be pursued by microbiologic culture of blood or

body fluid samples. Cultures should be held for at

least 2 months, with weekly subcultures onto solid

medium. Because it is extremely infectious for laboratory workers, the organism should be subcultured

only in a biohazard hood. The reported frequency

of isolation from blood varies widely, from less than

10% to 90%; B melitensis is said to be more readily

cultured than B abortus. Culture of bone marrow

may increase the yield.46

Treatment

Brucellae are sensitive in vitro to a number of oral

antibiotics and to aminoglycosides. Therapy with

a single drug has resulted in a high relapse rate, so

combined regimens should be used whenever possible.47 A 6-week regimen of doxycycline 200 mg/d

administered orally, with the addition of streptomycin 1 g/d administered intramuscularly for the

first 2 to 3 weeks is effective therapy for adults with

most forms of brucellosis.48 Patients with spondylitis may require longer treatment. A 6-week oral regimen of both rifampin 900 mg/d and doxycycline

200 mg/d is also effective, and should result in

nearly 100% response and a relapse rate lower than

10%.49 Several studies,48,50,51 however, suggest that

treatment with a combination of streptomycin and

doxycycline may result in less frequent relapse than

treatment with the combination of rifampin and

doxycycline. Notable failures have occurred when

spondylitis was treated with the latter combination.50

Endocarditis may best be treated with rifampin,

streptomycin, and doxycycline for 6 weeks; infected

valves should be replaced early in therapy.52 Central nervous system disease responds to a combination of rifampin and trimethoprim/sulfamethoxazole, but may need prolonged therapy. The latter

antibiotic combination is also effective for children

under 8 years of age.53 The Joint Food and Agriculture Organization–World Health Organization Expert Committee recommends treatment of pregnant

women with rifampin.49

Organisms used in a biological attack may be

resistant to these first-line antimicrobial agents.

Medical officers should make every effort to obtain

tissue and environmental samples for bacteriological culture, so that the antibiotic susceptibility profile of the infecting brucellae may be determined

and the therapy adjusted accordingly.

To prevent brucellosis, animal handlers should

wear appropriate protective clothing when working with infected animals. Meat should be wellcooked; milk should be pasteurized. Laboratory

workers should culture the organism only with appropriate Biosafety Level 2 or 3 containment (see

Chapter 19, The U.S. Biological Warfare and Biological Defense Programs, for a discussion of the

biosafety levels that are used at the U.S. Army Medical Research Institute of Infectious Diseases, Fort

Detrick, Frederick, Maryland).

PROPHYLAXIS

In the event of a biological attack, the standard

gas mask should adequately protect personnel from

airborne brucellae, since the organisms are probably unable to penetrate intact skin. After personnel have been evacuated from the attack area, clothing, skin, and other surfaces can be decontaminated

with standard disinfectants to minimize risk of infection by accidental ingestion, or by conjunctival

inoculation of viable organisms.

There is no commercially available vaccine for

humans.

SUMMARY

Brucellosis is a zoonosis of large animals, especially cattle, camels, sheep, and goats. Although

humans usually acquire Brucella organisms by ingestion of contaminated foods (oral route) or slaughter

of animals (percutaneous route), the organism is

highly infectious by the airborne route; this is the

presumed route of infection of the military threat.

Laboratory workers commonly become infected when

cultures are handled outside a biosafety cabinet.

Individuals presumably infected by aerosol have

symptoms indistinguishable from patients infected

by other routes: fever, chills, and myalgia are most

common, occurring in more than 90% of cases.

Since the bacterium disseminates throughout the

reticuloendothelial system, it may cause disease in

virtually any organ system. Large joints and the
Brucellosis

519

axial skeleton are favored targets; arthritis appears

in approximately one third of patients. Fatalities

occur rarely, usually in association with central nervous system or endocardial infection.

Serologic diagnosis uses an agglutination test

that detects antibodies to lipopolysaccharide. This

test, however, is not useful to diagnose infection

caused by B canis, a naturally O-polysaccharide

deficient strain. Infection can be most reliably confirmed by culture of blood, bone marrow, or other

infected body fluids, but the sensitivity of culture

varies widely.

Nearly all patients respond to a 6-week course

of oral therapy with a combination of rifampin and

doxycycline; fewer than 10% of patients relapse. Six

weeks of doxycycline with addition of streptomycin for the first 3 weeks is also effective therapy. No

vaccine is available for humans.

REFERENCES

1. Evans AC. Comments on the early history of human brucellosis. In: Larson CH, Soule MH, eds. Brucellosis.

Baltimore, Md: Waverly Press; 1950: 1–8.

2. Cleghorn G. Observations of the Epidemical Diseases of Minorca (From the Years 1744 to 1749). London, England;

1751. Cited in: Evans AC. Comments on the early history of human brucellosis. In: Larson CH, Soule MH, eds.

Brucellosis. Baltimore, Md: Waverly Press; 1950: 1–8.

3. Marston JA. Report on fever (Malta). Army Medical Rept. 1861;3:486–521. Cited in: Evans AC. Comments on the

early history of human brucellosis. In: Larson CH, Soule MH, eds. Brucellosis. Baltimore, Md: Waverly Press;

1950: 1–8.

4. Bruce D. Note on the discovery of a micro-organism in Malta fever. Practitioner (London). 1887;39:161–170.

Cited in: Evans AC. Comments on the early history of human brucellosis. In: Larson CH, Soule MH, eds.

Brucellosis. Baltimore, Md: Waverly Press; 1950: 1–8.

5. Hughes ML. Mediterranean, Malta or Undulant Fever. London, England: Macmillan and Co; 1897. Cited in: Evans

AC. Comments on the early history of human brucellosis. In: Larson CH, Soule MH, eds. Brucellosis. Baltimore,

Md: Waverly Press; 1950: 1–8.

6. Bang B. Die Aetiologie des seuchenhaften (“infectiösen”) Verwerfens. Z Thiermed (Jena). 1897;1:241–278. Cited

in: Evans AC. Comments on the early history of human brucellosis. In: Larson CH, Soule MH, eds. Brucellosis.

Baltimore, Md: Waverly Press; 1950: 1–8.

7. Meador VP, Hagemoser WA, Deyoe BL. Histopathologic findings in Brucella abortus–infected, pregnant goats.

Am J Vet Res. 1988;49(2):274–280.

8. Nicoletti P. The epidemiology of bovine brucellosis. Adv Vet Sci Comp Med. 1980;24(69):69–98.

9. Department of the Army. US Army Activity in the US Biological Warfare Programs, Vols 1 and 2. Washington, DC:

HQ, DA; 24 February 1977. Unclassified.

10. Grimont F, Verger JM, Cornelis P, et al. Molecular typing of Brucella with cloned DNA probes. Res Microbiol.

1992;143(1):55–65.

11. Bundle DR, Cherwonogrodzky JW, Caroff M, Perry MB. The lipopolysaccharides of Brucella abortus and B

melitensis. Ann Inst Pasteur Microbiol. 1987;138(1):92–98.

12. Moreno E, Borowiak D, Mayer H. Brucella lipopolysaccharides and polysaccharides. Ann Inst Pasteur Microbiol.

1987;138(1):102–105.

13. Goldstein J, Hoffman T, Frasch C, et al. Lipopolysaccharide (LPS) from Brucella abortus is less toxic than that

from Escherichia coli, suggesting the possible use of B abortus or LPS from B abortus as a carrier in vaccines.

Infect Immun. 1992;60(4):1385–1389.

14. Cherwonogrodzky JW, Perry MB, Bundle DR. Identification of the A and M antigens of Brucella as the Opolysaccharides of smooth lipopolysaccharides. Can J Microbiol. 1987;33(11):979–981.
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15. Mousa AR, Elhag KM, Khogali M, Marafie AA. The nature of human brucellosis in Kuwait: Study of 379 cases.

Rev Infect Dis. 1988;10(1):211–217.

16. Robson JM, Harrison MW, Wood RN, Tilse MH, McKay AB, Brodribb TR. Brucellosis: Re-emergence and changing epidemiology in Queensland. Med J Aust. 1993;159(3):153–158.

17. Dajani YF, Masoud AA, Barakat HF. Epidemiology and diagnosis of human brucellosis in Jordan. J Trop Med

Hyg. 1989;92(3):209–214.

18. Mousa AM, Elhag KM, Khogali M, Sugathan TN. Brucellosis in Kuwait: A clinico-epidemiological study. Trans

R Soc Trop Med Hyg. 1987;81(6):1020–1021.

19. Buchanan TM, Hendricks SL, Patton CM, Feldman RA. Brucellosis in the United States, 1960–1972: An abattoir-associated disease, III: Epidemiology and evidence for acquired immunity. Medicine (Baltimore).

1974;53(6):427–439.

20. Ackermann MR, Cheville NF, Deyoe BL. Bovine ileal dome lymphoepithelial cells: Endocytosis and transport

of Brucella abortus strain 19. Vet Pathol. 1988;25(1):28–35.

21. Elsbach P. Degradation of microorganisms by phagocytic cells. Rev Infect Dis. 1980;2:106–128.

22. Braude AI. Studies in the pathology and pathogenesis of experimental brucellosis, II: The formation of the

hepatic granulomas and its evolution. J Infect Dis. 1951;89:87–94.

23. Harmon BG, Adams LG, Frey M. Survival of rough and smooth strains of Brucella abortus in bovine mammary

gland macrophages. Am J Vet Res. 1988;49(7):1092–1097.

24. Young EJ, Borchert M, Kretzer FL, Musher DM. Phagocytosis and killing of Brucella by human polymorphonuclear leukocytes. J Infect Dis. 1985;151(4):682–690.

25. Corbeil LB, Blau K, Inzana TJ, et al. Killing of Brucella abortus by bovine serum. Infect Immun. 1988;56(12):

3251–3261.

26. Montaraz JA, Winter AJ, Hunter DM, Sowa BA, Wu AM, Adams LG. Protection against Brucella abortus in mice

with O-polysaccharide-specific monoclonal antibodies. Infect Immun. 1986;51(3):961–963.

27. Araya LN, Elzer PH, Rowe GE, Enright FM, Winter AJ. Temporal development of protective cell-mediated and

humoral immunity in BALB/c mice infected with Brucella abortus. J Immunol. 1989;143(10):3330–3337.

28. Zhan Y, Cheers C. Endogenous gamma interferon mediates resistance to Brucella abortus infection. Infect Immun.

1993;61(11):4899–4901.

29. Jiang X, Baldwin CL. Effects of cytokines on intracellular growth of Brucella abortus. Infect Immun. 1993;61(1):

124–134.

30. Anderson TD, Cheville NF. Ultrastructural morphometric analysis of Brucella abortus–infected trophoblasts in

experimental placentitis: Bacterial replication occurs in rough endoplasmic reticulum. Am J Pathol.

1986;124(2):226–237.

31. Anderson TD, Cheville NF, Meador VP. Pathogenesis of placentitis in the goat inoculated with Brucella abortus,

II: Ultrastructural studies. Vet Pathol. 1986;23(3):227–239.

32. Young EJ. Human brucellosis. Rev Infect Dis. 1983;5(5):821–842.

33. Crosby E, Llosa L, Miro QM, Carrillo C, Gotuzzo E. Hematologic changes in brucellosis. J Infect Dis.

1984;150(3):419–424.
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34. Gotuzzo E, Alarcon GS, Bocanegra TS, et al. Articular involvement in human brucellosis: A retrospective analysis

of 304 cases. Semin Arthritis Rheum. 1982;12(2):245–255.

35. Alarcon GS, Bocanegra TS, Gotuzzo E, Espinoza LR. The arthritis of brucellosis: A perspective one hundred

years after Bruce’s discovery. J Rheumatol. 1987;14(6):1083–1085.

36. Mousa AR, Muhtaseb SA, Almudallal DS, Khodeir SM, Marafie AA. Osteoarticular complications of brucellosis: A study of 169 cases. Rev Infect Dis. 1987;9(3):531–543.

37. Howard CB, Alkrinawi S, Gadalia A, Mozes M. Bone infection resembling phalangeal microgeodic syndrome

in children: A case report. J Hand Surg [Br]. 1993;18(4):491–493.

38. Rotes-Querol J. Osteo-articular sites of brucellosis. Ann Rheum Dis. 1957;16:63–68.

39. Ibrahim AIA, Shetty SD, Saad M, Bilal NE. Genito-urinary complications of brucellosis. Br J Urol. 1988;61:

294–298.

40. Kelalis PP, Greene LF, Weed LA. Brucellosis of the urogenital tract: A mimic of tuberculosis. J Urol. 1962;88:

347–353.

41. Lubani MM, Dudin KI, Sharda DC, et al. Neonatal brucellosis. Eur J Pediatr. 1988;147(5):520–522.

42. Buchanan TM, Faber LC, Feldman RA. Brucellosis in the United States, 1960–1972: An abattoir-associated disease, I: Clinical features and therapy. Medicine (Baltimore). 1974;53(6):403–413.

43. Peery TM, Belter LF. Brucellosis and heart disease, II: Fatal brucellosis. Am J Pathol. 1960;36:673–697.

44. Young EJ. Serologic diagnosis of human brucellosis: Analysis of 214 cases by agglutination tests and review of

the literature. Rev Infect Dis. 1991;13(3):359–372.

45. Buchanan TM, Faber LC. 2-mercaptoethanol Brucella agglutination test: Usefulness for predicting recovery

from brucellosis. J Clin Microbiol. 1980;11(6):691–693.

46. Gotuzzo E, Carrillo C, Guerra J, Llosa L. An evaluation of diagnostic methods for brucellosis—The value of

bone marrow culture. J Infect Dis. 1986;153(1):122–125.

47. Hall WH. Modern chemotherapy for brucellosis in humans. Rev Infect Dis. 1990;12(6):1060–1099.

48. Luzzi GA, Brindle R, Sockett PN, Solera J, Klenerman P, Warrell DA. Brucellosis: Imported and laboratoryacquired cases, and an overview of treatment trials. Trans R Soc Trop Med Hyg. 1993;87(2):138–141.

49. Joint FAO/WHO expert committee on brucellosis. World Health Organ Tech Rep Ser. 1986;740(1):1–132.

50. Ariza J, Gudiol F, Pallares R, et al. Treatment of human brucellosis with doxycycline plus rifampin or doxycycline plus streptomycin: A randomized, double-blind study. Ann Intern Med. 1992;117(1):25–30.

51. Montejo JM, Alberola I, Glez ZP, et al. Open, randomized therapeutic trial of six antimicrobial regimens in the

treatment of human brucellosis. Clin Infect Dis. 1993;16(5):671–676.

52. Chan R, Hardiman RP. Endocarditis caused by Brucella melitensis. Med J Aust. 1993;158(9):631–632.

53. Lubani MM, Dudin KI, Sharda DC, et al. A multicenter therapeutic study of 1,100 children with brucellosis.

Pediatr Infect Dis J. 1989;8(2):75–78.
Q Fever

523

Chapter 26

Q FEVER

WILLIAM R. BYRNE, M.D., FACP*

INTRODUCTION

MILITARY RELEVANCE

HISTORY

THE INFECTIOUS AGENT

THE DISEASE

Epidemiology

Pathogenesis

Clinical Disease in Domestic Animals

Clinical Disease in Humans

Diagnosis

TREATMENT

PROPHYLAXIS

SUMMARY

*Colonel, Medical Corps, U.S. Army; Chief, Genetics and Physiology Branch, Bacteriology Division, U.S. Army Medical Research Institute of

Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

524

INTRODUCTION

Q fever is a zoonotic disease caused by Coxiella

burnetii, a rickettsia-like organism of low virulence

but remarkable infectivity. A single organism may

initiate infection. In addition, despite the fact that

C burnetii is unable to grow or replicate outside host

cells, there is a sporelike form of the organism that

is extremely resistant to heat, pressure, desiccation,

and many standard antiseptic compounds; this allows C burnetii to persist in the environment for long

periods (weeks or months) under harsh conditions.

This persistence, coupled with a primary mode of

transmission by inhalation of infected aerosols, allows for the development of acute infection following only indirect exposure to an infected source. In

contrast to this high degree of inherent resilience

and transmissibility, the acute clinical disease associated with Q fever infection is usually a benign,

although a temporarily incapacitating, illness in

humans. Even without treatment, the vast majority

of patients recover. Chronic disease as a result of Q

fever is rare, although it is frequently fatal.

The primary reservoir for natural human infection is livestock, particularly parturient females,

and the distribution is worldwide. Outbreaks of Q

fever are infrequently reported, however, and the

disease may be endemic in areas where cases are

rarely or never reported. Humans who work in

animal husbandry, especially those who assist during parturition (eg, calving or lambing) are at

risk for acquiring Q fever. However, a definite risk

also exists for persons who live in close proximity

to, or who pass through, an area where animal

birthing is occurring, even if this occurred months

previously.

MILITARY RELEVANCE

Since the disease was described in 1937, thousands of cases involving military personnel of many

countries have been reported (an excellent review

was published in 19781

), and infection with C

burnetii should be considered a possibility whenever troops are present in an area with infected animals.

American soldiers in Italy during World War II

were affected, with 5 confirmed outbreaks of Q fever during the winter of 1944 and spring of 1945,2

usually in troops occupying farm buildings recently

or concurrently inhabited by farm animals.3 This

degree of close contact with farm animals was not

an absolute requirement for infection, however:

approximately 1,700 cases occurred in late spring,

1945, at an airbase in southern Italy as a result of

sheep and goats herded in pastures nearby.4

 During World War II, cases of acute Q fever were also

identified in soldiers in Virginia shortly after debarking from a 9-day voyage from Naples, Italy,4,5

and a single case was identified in a soldier stationed in Panama.6

Hundreds of cases consistent with Q fever were

observed in German soldiers in Serbia and southern Yugoslavia during World War II. Outbreaks

occurred in the apparent absence of disease in the

indigenous population. The disease was most commonly referred to as “Balkengrippe”; infection with

C burnetii was not confirmed by laboratory testing,

but the clinical and epidemiological features of the

illness described were most consistent with Q fever. Similar cases were observed in German troops

during World War II in Italy, Crimea, Greece,

Ukraine, and Corsica.1

An outbreak of acute Q fever associated with an

epidemic of spontaneous abortion in sheep and

goats occurred in 78 British troops stationed in

Cyprus, from December 1974 to June 19757; Swedish troops were also affected.8

 Q fever outbreaks

have also been described1 among Swiss soldiers in

1948, Greek soldiers from 1946 to 1956, and Royal

Air Force airmen on the Isle of Man in 1958. These

outbreaks occurred in the soldiers’ home countries

when the troops were stationed or training in close

proximity to sheep or goats, particularly parturient animals. Outbreaks attributed to sheep or goat

exposure in deployed soldiers have been described1

in American airmen in Libya in 1951 and French

soldiers in Algeria in 1955.

Among American military personnel in the Persian Gulf War, one case of meningoencephalitis associated with acute Q fever was reported, with the

onset of symptoms 2 weeks after return from the

Persian Gulf.9 One other soldier, with acute Q fever

pneumonia, was diagnosed in Saudi Arabia in

March 1991.10 This occurred in a first sergeant in an

engineering battalion. Subsequent epidemiological

evaluation and serologic testing of the unit identified three additional acute seroconversions among

soldiers of the same battalion.11 Exposure to sheep,

goats, or camels was identified in all of these infections acquired in Saudi Arabia.
Q Fever

525

Q fever is probably endemic in Somalia,12 and

serologic evidence of acute Q fever was identified

in two American soldiers evaluated in Somalia for

fever of unknown origin.11,13

These reports all underscore the importance of

considering the diagnosis of Q fever in a febrile

soldier in or recently returned from an area where

the disease may be present. This is particularly true

if the soldier has been in close proximity to or in an

area previously occupied by animals which may

harbor C burnetii.

The potential of C burnetii as a biological warfare threat is directly related to its infectivity. It has

been estimated that 50 kg of dried, powdered C

burnetii would produce casualties a rate equal to

that of similar amounts of anthrax or tularemia organisms.14 Q fever has been evaluated as a potential biological warfare agent by the United States,15

but munitions and stocks (except that required for

vaccine research) were publicly destroyed by executive order of President Richard M. Nixon between

May 1971 and May 1972.16

HISTORY

Q fever was first described in 1937 by Edward

Derrick,17 while he was the Director of Microbiology and Pathology for the Queensland (Australia)

Health Department at Brisbane. In 1935, he was

contacted about a febrile illness that had been occurring among abattoir workers in Brisbane. When

routine blood cultures and serologic testing did not

reveal a diagnosis, Derrick suspected that he was

dealing with a new illness. He thoroughly described

the clinical characteristics and designated the disease Q (for query) fever. Derrick’s laboratory investigation demonstrated that it was possible to transmit the disease to animals by inoculating guinea

pigs and mice with the blood of humans suffering

from acute Q fever. Although Derrick had initially

concluded that the infectious agent was a virus,

studies of a guinea pig liver emulsion sent to

MacFarlane Burnet in Melbourne subsequently indicated that the causative organism was a rickettsia,18 according to the terminology used at that time.

Interestingly, Derrick may not have been the first

to transfer the disease to laboratory animals. Hideyo

Noguchi, working at the Rockefeller Institute in

New York City in 1925, may have passed C burnetii

to guinea pigs from ticks that had been collected at

Saw Tooth Canyon by Ralph Parker at the Rocky

Mountain Laboratory in Hamilton, Montana.19 This

agent, however, was ultimately lost in animal

passage.

About the same time that the investigations were

being done in Australia, Gordon Davis was studying Rocky Mountain Spotted Fever at the Rocky

Mountain Laboratory. He observed that a febrile

illness resulted when ticks collected from the area

around the nearby Nine Mile Creek were allowed

to feed on guinea pigs.20 The disease produced in

guinea pigs did not, however, resemble Rocky

Mountain Spotted Fever. Herald Cox was subsequently able to characterize the organism (then

called the “Nine Mile Agent”) as similar to rickettsia and to cultivate this organism in the yolk sac

membrane of embryonated hen eggs.21 The relation

of Q fever to the Nine Mile Agent was established

by Rolla Dyer, director of the National Institutes of

Health at the time, after the spleens of infected mice

were sent to him by Burnet. In an event that presaged the problems of transmission of Q fever in

laboratory workers, Dyer himself acquired acute Q

fever during a visit to Hamilton in 1938.22

The work of Ralph Parker, also at the Rocky

Mountain Laboratory, indicated that ticks are the

reservoir of the “Nine Mile Agent.” Derrick had also

suspected tick transmission from a primary reservoir, and from a secondary reservoir of domestic

animals. The significance of exposure to parturient

animals was not, however, recognized until 1950.

The causative agent of Q fever was ultimately

designated Coxiella burnetii to recognize the outstanding contributions of both Cox and Burnet to

the isolation and characterization of this new pathogen.23 The disease, following clinical description

and microbiological characterization of the etiologic

agent, has been identified in at least 51 countries

on 5 continents.24

THE INFECTIOUS AGENT

Coxiella burnetii is classified in the family

Rickettsiaceae, but is not included in the genus Rickettsia and therefore is not a true rickettsia. It is not

closely related to any other bacterial species when

comparative 16s ribosomal ribonucleic acid (RNA)

analysis is performed,25 thus the genus Coxiella has

only one species. The closest relative according to

16s ribosomal RNA analysis is Legionella,

25,26 but

Legionella has different growth characteristics

(Legionella, being a facultative intracellular parasite,
Medical Aspects of Chemical and Biological Warfare

526

is able to survive and multiply extracellularly) and

causes a different clinical syndrome.

C burnetii must occupy an intracellular environment in order to grow or reproduce, similar to true

rickettsia, although, as previously stated, the organism has a sporelike form that is very resistant to

heat and desiccation.27 This sporelike form may be

observed in human tissue.28 The particular cytological niche occupied by C burnetii is the usually very

destructive environment of the phagolysosome of

eukaryotic cells (Figure 26-1), which has a strongly

acidic milieu (normal pH is 4.5) and numerous digestive enzymes. While inhabiting the phagolysosome, C burnetii usually lives in relatively peaceful

coexistence with the host, causing little direct damage to the cell, at least initially.

Replication occurs by binary fission within the host

cell; the dormant, sporelike form, is produced under

certain circumstances.29 Dormant C burnetii can be

stimulated to a brief period of growth by exposure to

an acidic environment.30 Sustained growth and replication of C burnetii outside a host cell is not possible.

Fig. 26-1. Electron micrograph of Coxiella burnetii in the

phagolysosome of an infected yolk sac cell, demonstrating both large (LCV) and small (SCV) cell variants. The

bar in the lower right corner represents 0.6 μm. After

Renografin (manufactured by Squibb Diagnostics,

Princeton, NJ) purification, the cells were fixed with primary fixative and stained with potassium permanganate. The phagolysosome contains many pleomorphic C

burnetii organisms. Multiplication by binary transverse

fission with septa formation (arrows) is seen.

The LCVs resemble Gram-negative bacteria, with

outer and cytoplasmic membranes separated by a

periplasmic space. The LCV is more metabolically active

than the SCV, has less peptidoglycan in the cell wall, and

is capable of production of the sporelike form. The loose

outer membrane, increased periplasmic space, and bleb

formation of some of the LCVs probably indicate that

they are undergoing deterioration or have been damaged

during preparation. The SCVs appear as extremely dense

organisms and are heat-resistant, relatively dormant

structures which have the ability to survive in an adverse

environment. Reprinted with permission from McCaul

TF, Williams JC. Developmental cycle of Coxiella burnetii:

Structure and morphogenesis of vegetative and sporogenic differentiations. J Bacteriol. 1981;147:1067.

Phase variation has been described with C

burnetii maintained in the laboratory.31 The virulent

organism, which is associated with natural infection and a smooth lipopolysaccharide (LPS), is designated as Phase I. This phase is resistant to complement and is a potent immunogen. Serial passage of

C burnetii in eggs eventually results in the bacterium’s conversion to Phase II, which has a rough LPS

and is much less virulent than Phase I. This phase

is sensitive to complement and is a poor immunogen. The conversion from Phase I to Phase II is irreversible32 and is the result of a mutation caused by

a chromosomal deletion.

Coxiella burnetii also contains several plasmids,

and dissimilar plasmid types may be associated

with different manifestations of disease.33 The cell

wall of a Phase I C burnetii organism contains, in

association with lipopolysaccharide, an immunomodulatory complex,34 which produces toxic reactions in mice (eg, hepatomegaly, splenomegaly, liver

necrosis) and lymphocyte hyporesponsiveness in

vitro.

THE DISEASE

Epidemiology

Coxiella burnetii is extremely infectious. Under

experimental conditions, a single organism is capable

of producing infection and disease in humans.35

The host range of C burnetii is very diverse and

includes a large number of mammalian species

and arthropods. Among these, however, man is the

only host identified that normally experiences an

illness as a result of infection. A number of differFigure 26-1 is not shown because the

copyright permission granted to the Borden

Institute, TMM, does not allow the Borden

Institute to grant permission to other users

and/or does not include usage in electronic

media. The current user must apply to the

publisher named in the figure legend for

permission to use this illustration in any type

of publication media.
Q Fever

527

ent strains of C burnetii have been identified worldwide, and different clinical manifestations and complications may be associated with the various

strains.

Humans have been infected most commonly by

contact with domestic livestock, particularly goats,

cattle, and sheep. The risk of infection is substantially

increased if humans are exposed to these animals at

parturition. During gestation, the proliferation of

C burnetii in the placenta facilitates aerosolization

of large numbers of the pathogen during parturition. Coxiella organisms thus produced may persist

in the local environment, and produce infection, for

weeks or months afterwards.

C burnetii is also shed in the urine and feces

of infected animals, in addition to being present

in the blood and tissues. Survival of the organism

on inanimate surfaces, such as straw, hay, or clothing, allows for transmission to individuals who are

not in direct contact with infected animals; for example,

• soldiers sleeping in barns previously occupied by infected animals,3

• laundry workers handling infected clothing,36

• coworkers of an individual with an infected

cat in the home,37 and

• residents of an urban community living

along a road utilized by farm vehicles.38

Investigation of outbreaks of Q fever frequently

report a significant proportion of patients who have

no identifiable risk factor. Human-to-human transmission has been reported,39 but it is a very rare

event.

As mentioned previously, the distribution of C

burnetii is worldwide.24 With the exception of a few

countries (New Zealand is an example), Q fever

cases have been identified practically everywhere

that an attempt has been made to identify evidence

of infection, either in man or in animals.

In the United states, the epidemiology of Q fever is variable. Sporadic but regularly occurring

cases have been observed40 in areas with endemic

foci in cattle, and clusters of cases have been described41 in areas with infected dairy herds. Livestock is not the only source of Q fever infections in

this country: a small outbreak in Maine associated

with exposure to a parturient cat has been described,42 similar to an outbreak in Nova Scotia,

Canada.43 Since 1985, outbreaks of Q fever in the

United States have been reported in five states

among differing groups of individuals:

• slaughterhouse workers in California44;

• faculty, laboratory workers, and staff exposed to sheep at a medical school in Colorado45;

• individuals exposed to sheep at a sheep research station in Idaho46;

• laboratory animal personnel in Arkansas

working with parturient sheep47; and

• workers in an animal research laboratory

in South Carolina who handled and performed surgery on sheep.48

Although reported outbreaks49,50 of Q fever in the

United States have been relatively uncommon in

recent years, underreporting undoubtedly occurs.

For example, although the first 2 cases of Q fever

from 2 adjacent rural counties in Michigan were

reported in 1984, a study51 published just 4 years

later showed that 15% of the general population

surveyed in those 2 counties and 43% of goat owners

were seropositive.

Pathogenesis

Human infection with C burnetii is usually the

result of inhalation of infected aerosols. Following

this, the organisms are phagocytized by host cells,

predominately unstimulated macrophages. This

uptake of C burnetii by host phagocytic cells is not

energy dependent, but is probably the result of contact by the pathogen with an existing receptor. After phagocytosis by host cells, conditions within the

phagolysosome trigger growth and multiplication

of C burnetii, with little initial damage to the host

cell. Eventually the cytoplasm becomes engorged

with C burnetii organisms and lysis of the host cell

occurs. Dissemination of the pathogen occurs as a

result of circulation of organisms free in the plasma,

on the surface of cells, and carried by circulating

macrophages.

In animals, infection frequently lasts for the life

of the animal, in a more-or-less dormant state, with

periodic increases in organism numbers during

periods of relative immunosuppression, particularly parturition,52 but also in laboratory animals

treated with adrenocorticosteroids53 or irradiation.54

C burnetii causes little overt disease in animals (and

no apparent disease in ticks), except that luxuriant

growth in the placenta may increase the rate of

spontaneous abortion in some species. Edema and

thrombohemorrhagic lesions may be identified in

the placentas of infected animals.

There is little host reaction at the initial portal of

entry, either in the lung following inhalation of aero-
Medical Aspects of Chemical and Biological Warfare

528

sol or in the skin following a tick bite. Q fever develops without formation of a primary infectious

focus in the area of the tick bite, and the organism

does not infect the vascular endothelium as do true

rickettsial pathogens.

In man, polyclonal production of antibody represents the initial immune response to C burnetii,

but humoral immunity alone is ineffective for control of the organism, although the presence of antibody does contribute significantly to antibodydependent cellular cytotoxicity later in the course

of the infection. Passive transfer of immune serum

to laboratory animals does not improve clearance

of organisms from the spleen.55 Pretreatment of

laboratory animals with cyclophosphamide, an antineoplastic agent that severely inhibits production

of antibody, does not adversely affect the course of

infection.56 C burnetii organisms that have been

opsonized, however, are much more efficiently destroyed by host phagocytic cells than are unopsonized organisms. Control of the infection by the

host eventually results from the development of

specific cell-mediated immunity, with killing by

activated macrophage and natural killer cells. This

process may result in a granulomatous reaction

without the scarring and tissue reaction observed

with true granulomata.

The host immune response in man appears to be

modified by the C burnetii organism itself in chronic

infection, in that the lymphocytes of patients with

Q fever endocarditis exhibit profound hyporesponsiveness to C burnetii antigen, although they retain

their reactivity to other antigens.57

The presence of LPS on the cell surface of C

burnetii protects the pathogen from host microbicidal activities. The phase variation previously described is the result of alteration of the LPS, with

the virulent Phase I organism having a smooth LPS.

The Phase II organism, the result of serial passage

of C burnetii in eggs, has a rough LPS, is much less

immunogenic than the Phase I, and is less virulent.58

Phase I organisms are resistant to the lytic action of

complement, while Phase II organisms are sensitive

to the alternate pathway of complement.59

Clinical Disease in Domestic Animals

Except for spontaneous abortion, illness in domestic animals as a result of C burnetii infection is

unusual, although the organism has a propensity

for proliferation in the female reproductive system—particularly the uterus and the mammary

glands. Differences between the manifestations in

domestic animals, however, are worthy of comment.

In sheep, the infection tends to be transient, followed by spontaneous remission. Infected sheep

will usually cease shedding the pathogen after a few

months and no longer be infectious to other animals in the flock, except during parturition. Although C burnetii has frequently been recovered

from the placentas of sheep and has been associated with epidemic abortions, shedding in the milk

is rare.

By contrast, chronic shedding—over months or

years—of Coxiella in the milk of lactating cows can

be expected. This aspect of the infection can facilitate maintenance of Coxiella in a herd, particularly

a dairy herd. Infection in cows is also associated

with an increased incidence of spontaneous abortion and may be associated with infertility.

Goats also show an increased disposition for

abortion during epizootics of Q fever, and infection

in a herd may be maintained by chronic shedding.

Clinical Disease in Humans

Man is the only host susceptible to infection by

C burnetii that commonly develops an illness as a

result of the infection. The incubation period varies from 10 to 40 days, with the duration of the incubation period being inversely correlated with the

magnitude of the inoculum.35 A higher inoculum

also increases the severity of the disease. Q fever in

humans may be manifested by asymptomatic

seroconversion, acute illness, or chronic disease.

The frequency of these manifestations parallels this

order in decreasing magnitude. In epidemiological

surveys, most seropositive individuals do not recall having the illness. The frequency of chronic

disease (usually endocarditis) compared with acute

disease is difficult to determine precisely due to

underreporting of acute infection but is probably

less than 1% of the total infected population.

The tendency for C burnetii to produce asymptomatic seroconversion has been documented in

several publications. In one study,35 experimental

infection in humans showed that in 2 of 4 volunteers infected with a single organism by aerosol, a

diagnosis could be established by serologic conversion without clinical illness. Asymptomatic seroconversion did not occur with higher infecting

doses (5–1,500 organisms). In an outbreak in Canada

attributed to indirect exposure to contaminated

clothing, 6 (37.5%) of 16 individuals diagnosed by

seroconversion did not have an associated illness.37

In Switzerland in 1983, during the course of a

serosurvey to investigate a large outbreak of Q

fever, more than half of the 415 serologically con-
Q Fever

529

firmed patients were asymptomatic or minimally

ill.60 These reports underscore the value of an epidemiological investigation when even a single case

of acute Q fever is recognized.

 Infection with C burnetii has been reported61 to

persist in humans, as it does in animals, in an asymptomatic state. Phase I C burnetii has been recovered

from the placentas of asymptomatic women infected from 1 to 6 months,62 to 3 years63 previously.

Infection with Q fever may rarely affect the outcome

of pregnancy adversely.64

Acute Q Fever

There is no characteristic illness for acute Q

fever, and manifestations may vary considerably

between locations where the disease is acquired.

When symptomatic, the onset of Q fever may be

abrupt or insidious, with fever, chills (including

frank rigors), and headache being the most common signs and symptoms (Table 26-1). The headache is usually described as severe, throbbing, and

frontal or retro-orbital in location. Diaphoresis,

malaise, fatigue, and anorexia are also very common. Weight loss of 7 kg or more during the course

of acute illness has been reported with surprising

frequency, particularly when other general symptoms lasted more than 2 weeks.2,65 Myalgias are also

a frequent complaint, while arthralgias are relatively unusual. Cough tends to appear later in the

illness than some of the other more common symptoms, such as fever, chills, and headache, and may

not be a prominent complaint. Chest pain occurs in

a minority of patients and may be pleuritic or a

vague substernal discomfort.

Relatively infrequent symptoms include sore

throat, gastrointestinal upset, and neck stiffness,

although this last symptom has been severe enough

in reported cases of acute Q fever to warrant a lumbar puncture to exclude bacterial meningitis. Although nonspecific evanescent skin eruptions have

been reported,66,67 there is no characteristic rash.

Most patients appear mildly to moderately ill—

when the onset is abrupt, Q fever has been mistaken

for influenza. The temperature tends to fluctuate,

with peaks of 39°C to 40°C, and in approximately

one fourth of the cases is biphasic; in two thirds of

patients with acute disease, the febrile period lasts

13 days or less. The duration of fever is usually

longer in older patients.68

Neurological symptoms are not uncommon and

in one study65 were observed in up to 23% of acute

cases. Encephalopathic symptoms, hallucinations

(visual and auditory), expressive dysphasia, hemiTABLE 26-1

SIGNS AND SYMPTOMS IN ACUTE Q FEVER

Signs and Symptoms Frequency (%)

Onset*

Gradual 30–70

Abrupt 30–70

Fever 80–100

Chills, rigors 75–100

Headache, retro-orbital pain 50–100

Diaphoresis 40–100

Malaise 50–100

Weakness, fatigue 40–85

Anorexia 35–45

Weight loss ( > 7 kg) 50–80

Myalgias 45–85

Arthralgias 10–20

Chest pain 40–50

Cough 50–60

Sore throat 5–35

Nausea, vomiting 15–20

Diarrhea 5–20

Neck stiffness 5–7

Neurological signs 10–35

*Some report gradual onset; others, abrupt onset; coincidentally,

the frequency is the same.

Data sources: (1) Robbins FC, Ragan CA. Q fever in the Mediterranean area: Report of its occurrence in Allied troops, I: Clinical

features of the disease. Am J Hyg. 1946;44:6–22. (2) Feinstein M,

Yesner R, Marks JL. Epidemics of Q fever among troops returning from Italy in the spring of 1945, I: Clinical aspects of the

epidemic at Camp Patrick Henry, Virginia. Am J Hyg. 1946;44:72–

87. (3) Marrie TJ, Langille D, Papukna V, Yates L. Truckin’ pneumonia—An outbreak of Q fever in a truck repair plant probably

due to aerosols from clothing contaminated by contact with a

newborn kitten. Epidem Inf. 1989;102:119–127. (4) Langley JM,

Marrie TJ, Covert A, et al. Poker players pneumonia: An urban

outbreak of Q fever following exposure to a parturient cat. N Engl

J Med. 1988;319:354–356. (5) Raoult D, Marrie TJ. State-of-the-art

clinical lecture: Q fever. Clin Inf Dis. 1995;20:489–496. (6) Clark WH,

Lennette EH, Railsback OC, Romer MS. Q fever in California.

Arch Intern Med. 1951;88:155–161. (7) Dupont HT, Raoult D,

Brouqui P, et al. Epidemiologic features and clinical presentation

of acute Q fever in hospitalized patients: 323 French cases. Am J

Med. 1992;93:427–434. (8) Tselentis Y, Gikas A, Kofteridis D, et al.

Q fever in the Greek island of Crete: Epidemiologic, clinical, and

therapeutic data from 98 cases. Clin Inf Dis. 1995;20:1311–1316.
Medical Aspects of Chemical and Biological Warfare

530

facial pain resembling trigeminal neuralgia, diplopia, and dysarthria were also reported. Other manifestations involving the central nervous system,

such as encephalitis, encephalomyelitis, optic neuritis, or myelopathy may also occur,9,69,70 particularly

late in the acute illness.

Physical findings in acute Q fever are as nonspecific as the clinical symptomatology. Rales are probably the most commonly observed physical finding; evidence of pleural effusion (including friction

rub) and consolidation may also be noted, but not

in the majority of infections. Although hepatomegaly, splenomegaly, jaundice, pharyngeal injection,

and hepatic and splenic tenderness have all been

reported, they are relatively unusual in acute infection.

Reports of abnormalities on chest X-ray examination vary with locale, but abnormalities are probably seen in 50% to 60% of patients.71 An abnormal

chest radiograph may be seen in the absence of

pulmonary symptoms, while a normal chest radiograph may be observed in a patient with pulmonary symptoms. The most common abnormality

observed in a recent report from England was a

unilateral, homogenous infiltrate involving one or

two lobes,71 although lobar consolidation and pleural effusions72 may also be seen. Rounded opacities

and hilar adenopathy are not uncommon,43 at least

in Canada, and the diagnosis of Q fever should be

at least be considered when these abnormalities are

observed in the setting of acute pneumonia.

Laboratory abnormalities of routine tests most

commonly involve tests of liver function, and patients with acute Q fever may present with a clinical picture of acute hepatitis. Depending on the

locale, reported elevations of aspartate aminotransferase, alanine transferase, or both, in the range of

2- to 3-fold higher than the upper limit of normal,

are observed in 50% to 75% of patients, while elevation of the alkaline phosphatase is observed in

10% to 15% of patients. The total bilirubin can be

expected to be elevated in 10% to 15% of patients

with acute Q fever. The white blood cell count is

usually normal; the erythrocyte sedimentation rate

is elevated in one third of patients.65 Mild anemia

or thrombocytopenia may also be observed.

Complications recorded in a recent outbreak involving 147 symptomatic cases of Q fever included

2 of acute endocarditis, 2 of renal failure, and 1 of

reactive polyarthropathy.65 Persistent nonspecific

symptoms, such as fatigue and malaise, were reported in 32% of the patients in this series, while

weight loss (defined as > 7 kg) was identified in

71%, although none developed serologic evidence

suggestive of chronic Q fever. An interesting epidemiological feature identified in the study was a

significantly higher percentage of smokers in the

affected group than in the general population of the

area surveyed.

Chronic Q Fever

Chronic infection with C burnetii is usually manifested by infective endocarditis, which is also the

most severe complication of Q fever. In addition, a

report73 from France of 92 cases published in 1993

also listed hepatitis, infected vascular prostheses

and aneurysms, osteomyelitis, pulmonary infection,

cutaneous infection, and an asymptomatic form. In

addition, 7 of the 92 patients described in this report experienced fever only. Also noted was the

observation that although 81% of patients had an

identifiable risk factor, only 31% lived in a rural

area. In addition, some form of immunodeficiency

was observed in 20% of the patients, raising the

possibility that chronic Q fever occurs as a result of

reactivation of latent infection.73 Inflammatory

pseudotumor of the lung as a chronic complication

of Q fever has also been reported.74,75

In Q fever endocarditis, fever has been recorded

in 85% of patients, along with other systemic symptoms, such as chills, headache, myalgias, and weight

loss, in a recent study73 of 84 cases. Fever was not

as prominent, however, in chronic compared to

acute Q fever. Other frequently reported clinical

features of Q fever endocarditis in this very large series included congestive heart failure (76%), splenomegaly (42%), hepatomegaly (41%), clubbing (21%), and

cutaneous signs, often the result of a leukocytoclastic vasculitis (22%). Approximately 90% of

patients in this study had preexisting valvular heart

disease; more than half had a vascular prosthesis.

Routine blood cultures in Q fever endocarditis

are negative, and Q fever should be considered

when culture-negative endocarditis is encountered.

The diagnosis of infective endocarditis secondary

to Q fever is confirmed by serologic testing: antibody to Phase I organisms is usually higher than

that for Phase II, and, more significantly, immunoglobulin A (IgA) antibody to C burnetii is also

present.76

Diagnosis

Diagnosis of Q fever is usually accomplished by

serologic testing because culture of C burnetii is

potentially hazardous to laboratory personnel and

requires animal inoculation or cell culture.
Q Fever

531

A number of serologic methods are used, including complement fixation (CF), indirect fluorescent

antibody (IFA), macroagglutination and microagglutination, and enzyme-linked immunosorbent

assay (ELISA). Significant antibody titers are usually not identifiable until 2 to 3 weeks into the illness. In 1987, the sensitivities of the different antibody assay methods were reported77 as 94% for

ELISA, 91% for IFA, and 78% for CF. Following infection, significant antibody titers may be present

for years, particularly with more sensitive assays,

such as the ELISA.

Of the methods currently utilized for the diagnosis of Q fever, the ELISA is the most sensitive and

the easiest to perform. The utility of the ELISA

for epidemiological screening and diagnosis of Q

fever has recently been confirmed.78 This assay, performed at the United States Army Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland, can establish a diagnosis of acute Q fever from a single serum specimen, with a sensitivity of 80% to 84% in early convalescence and 100%

in intermediate and late convalescence.79 In general,

antibodies to the rough Phase II organism are identified earlier in the illness, during the first few

months following infection, followed by a decline

in antibody to Phase II organisms and a rise in antibody to the smooth, virulent Phase I organism.

Antibodies of the IgM type are usually observed

within the first 6 to 12 months following infection,

with persistence of IgG antibodies afterward.

Polymerase chain reaction (PCR) may also be

useful in the future for the diagnosis of Q fever,80–83

but remains to be validated in acute clinical cases.

TREATMENT

The treatment of Q fever was the subject of an excellent review that was published in 1993.84 Tetracyclines have been the mainstay of therapy since the

1950s. When initiated within the first few days of illness, treatment with a tetracycline shortens the course

of the disease. Attempted prophylaxis with a tetracycline (20 g of oxytetracycline administered over 5–6

d), however, has produced mixed results.35 Initiation

of the antibiotic early in the incubation period (24 h

after exposure) merely prolonged the incubation

period, while initiation of therapy late in the incubation period prevented the development of disease.

Macrolide antibiotics, such as erythromycin, are

also effective for the treatment of acute Q fever.72,85 A

new macrolide, azithromycin, has also demonstrated

efficacy in a few cases, but experience is very limited.86

When chronic Q fever infection is manifested by

infective endocarditis, treatment is very difficult;

the mortality is 24% even when patients receive

appropriate treatment.73 At least 2 years of therapy

are required, usually with a tetracycline combined

with rifampin or a quinolone, although trimethoprim-sulfamethoxazole has also been used.84

Quinolones alone or in combination have also been

effective. Most recently, the addition of hydroxychloroquine to tetracycline has shown promising

results both in vitro87 and in a small number of

patients.88

PROPHYLAXIS

Q fever can be prevented by immunization. Vaccine prophylaxis for Q fever has been studied and

used almost since the discovery that the responsible

organism could be propagated in the yolk sac of

eggs. Immunization with formalin-killed C burnetii

confers protection against Q fever in laboratory

personnel,89 abattoir workers,90,91 and human volunteers experimentally exposed to aerosolized C

burneti.92 In Australian abattoir workers, the results

of efficacy studies were impressive: a single injection of 30 μg of vaccine antigen (Q-Vax, manufactured by CSL Ltd., Parkville, Victoria, Australia)

conferred protective immunity that began 2 weeks

after immunization and persisted for at least 5

years.90 Protection depends primarily on cellmediated immunity, the presence of which may be

detected by positive skin test reactions and in vitro

lymphocyte transformation in response to C burnetii

antigen,93 although these tests are not positive in

all individuals previously infected with C burnetii.

These long-lasting indicators of cell-mediated

immunity develop in most individuals after natural

infection, but are also seen after immunization,90,93

although to a lesser extent. Conversion from a negative lymphocyte proliferative response to a positive

was observed in 11 (85%) of 13 of the individuals

vaccinated.93 In the same study, only 5 (38%) of 13

of vaccinated subjects seroconverted, and 31 (60%)

of 52 developed a positive skin test following vaccination. Therefore, although the whole cell Q fever vaccine used in the Australian abattoirs confers

protection, there does not appear to be a measurable response reliably associated with protective

immunity.
Medical Aspects of Chemical and Biological Warfare

532

C burnetii formalin-killed whole cell vaccines are

generally well tolerated after subcutaneous injection, although some individuals develop severe

local reactions at the site of injection. These reactions can involve formation of sterile abscesses that

may drain spontaneously or may require surgical

incision.94 The incidence of severe, persistent local

reactions is immunologically mediated by a delayed

hypersensitivity response, resulting from previous

natural infection with C burnetii or repeated immunization92; the risk of severe local reaction increases

with the number of Q fever immunizations. This

observation led to the development of an intradermal skin test using 0.02 μg of specific formalinkilled whole cell vaccine to detect presensitized or

immune individuals.95

Severe local reactions to the vaccine were found

to be associated with induration of 5 mm or larger

at the skin test site by 7 days after inoculation. Although cumbersome, inconvenient, and costly, this

prior screening procedure proved to be very effective in reducing the number of severe local reactions to Q fever vaccine. Subsequent experience

with this skin test at the Rocky Mountain Laboratory in Montana showed that there were no severe

local reactions in 80 individuals whose skin tests

were negative when they were immunized with one

or two doses of vaccine. Prior to the availability of

skin test screening, severe local reactions occurred

in 42 (45%) of 94 vaccinated individuals.95 Additionally, in Australian abattoirs, more than 4,000 individuals whose skin tests were negative received the

formalin-killed vaccine during the course of vaccine efficacy studies, and of these, only 1 developed

a significant chronic reaction.90 The advisability of

prior skin testing was further reinforced when

severe local reactions were observed in 3 of 10 individuals with a positive skin test to C burnetii

antigen who mistakenly received a single dose of

vaccine.96

Although an effective Q fever vaccine is licensed

in Australia, all Q fever vaccines used in the United

States are currently investigational. Certain groups

of individuals should be considered for vaccine

prophylaxis, including the following:

• veterinarians, veterinary technicians, and

animal care workers who may come into

contact with C burnetii–infected animals,

particularly pregnant animals;

• laboratory investigators, technicians, and

other personnel who perform research on

live C burnetii organisms; and

• abattoir workers who have contact with

cattle, sheep, or goats (particularly pregnant animals) that may be infected with C

burnetii.

Research efforts are currently underway to develop a Q fever vaccine that is safe to administer to

anyone, including Q fever–immune individuals.

The residue of C burnetii organisms following chloroform-methanol extraction (CMR vaccine) has been

tested for safety in nonimmune volunteers97 and is

currently being tested for safety in Q fever–immune

individuals. Antibiotic prophylaxis of Q fever has

been tested with a tetracycline, as was discussed in

the treatment section of this chapter.

SUMMARY

Q fever, a zoonotic disease caused by the rickettsia-like organism Coxiella burnetii, is important to military medicine primarily because of its exceptional

infectivity. The disease is transmitted mainly by inhalation of infected aerosols, and a single organism

may cause infection in humans. The disease is worldwide in distribution; the primary reservoir for human

infection is livestock, particularly goats, sheep, and

cattle. Contact with parturient animals or products of

conception poses especially high risk, since the organism is present in very high numbers in this setting.

The organism is also very resistant to pressure and desiccation, and may persist in a sporelike form in the environment for months after the source has left the area.

Diagnosis of Q fever is performed by serologic

testing. Treatment with tetracyclines is effective.

Prevention is possible with a formalin-killed,

whole-cell vaccine, but prior skin testing to exclude

immune individuals is necessary to avoid severe

local reactions to the vaccine. A Q fever vaccine is

licensed in Australia, but not in the United States,

where all Q fever vaccines are investigational.

REFERENCES

1. Spicer AJ. Military significance of Q fever: A review. J R Soc of Med. 1978;71:762–767.

2. Robbins FC, Ragan CA. Q fever in the Mediterranean area: Report of its occurrence in Allied troops, I: Clinical

features of the disease. Am J Hyg. 1946;44:6–22.
Q Fever

533

3. Robbins FC, Gauld RL, Warner FB. Q fever in the Mediterranean area: Report of its occurrence in Allied troops,

II: Epidemiology. Am J Hyg. 1946;44:23–50.

4. The Commission of Acute Respiratory Diseases, Fort Bragg, North Carolina. Epidemics of Q fever among

troops returning from Italy in the spring of 1945, III: Etiological studies. Am J Hyg. 1946;44:88–102.

5. Feinstein M, Yesner R, Marks JL. Epidemics of Q fever among troops returning from Italy in the spring of 1945,

I: Clinical aspects of the epidemic at Camp Patrick Henry, Virginia. Am J Hyg. 1946;44:72–87.

6. Cheney G, Geib WA. The identification of Q fever in Panama. Am J Hyg. 1946;44:158–172.

7. Spicer AJ, Crowther RW, Vella EE, Bengtsson E, Miles R, Pitzolis G. Q fever and animal abortion in Cyprus.

Trans R Soc Trop Med Hyg. 1977;71(1):16–20.

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29. McCaul TF, Williams JC. Developmental cycle of Coxiella burnetii: Structure and morphogenesis of vegetative

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31. Stoker MGP, Fiset P. Phase variation of the Nine Mile and other strains of Rickettsia burnetii. Can J Microbiol.

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32. Baca OG, Paretsky D. Q fever and Coxiella burnetii: A model for host parasite interactions. Microbiol Rev.

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33. Samuel JE, Frazier ME, Mallavia LP. Correlation of plasmid type and disease caused by Coxiella burnetii. Infect

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34. Waag DM, Williams JC. Immune modulation by Coxiella burnetii: Characterization of a Phase I immunosuppressive complex expressed among strains. Immunopharmacol Immunotoxicol. 1988;10:231–260.

35. Tigertt WD, Benenson AS. Studies on Q fever in man. Trans Assoc Am Phys. 1956;69:98–104.

36. Oliphant JW, Gordon DA, Meis A, et al. Q fever in laundry workers presumably transmitted from contaminated clothing. Am J Hyg. 1949;49:76–82.

37. Marrie TJ, Langille D, Papukna V, Yates L. Truckin’ pneumonia—An outbreak of Q fever in a truck repair plant

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119–127.

38. Salmon MM, Howells B, Glencross EJG, et al. Q fever in an urban area. Lancet. 1982;1:1002–1004.

39. Mann JS, Douglas JG, Inglis JM, et al. Q fever: Person to person transmission within a family. Thorax. 1986;41:

974–975.

40. Wisniewski HJ, Piraino FF. Review of virus infections in the Milwaukee area, 1955–1965. Public Health Reports.

1969;84:175–181.

41. Epidemiology of a Q fever outbreak in Los Angeles County, 1966. Health Services and Mental Health Administration Health Reports. 1972;87:71–74.

42. Pinsky RL, Fishbein DB, Greene CR, Gensheimer KF. An outbreak of cat-associated Q fever in the United States.

J Inf Dis. 1991;164(July):202–204.

43. Langley JM, Marrie TJ, Covert A, et al. Poker players pneumonia: An urban outbreak of Q fever following

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44. Centers for Disease Control. Q fever among slaughterhouse workers—California. MMWR. 1986;35:223–226.

45. Meiklejohn G, Reimer LG, Graves PS, Helmick C. Cryptic epidemic of Q fever in a medical school. J Inf Dis.

1981;144(2):107–113.

46. Rauch AM, Tanner M, Pacer RE, Barrett MJ, Brokopp CD, Schonberger LB. Sheep-associated outbreak of Q

fever, Idaho. Arch Intern Med. 1987;147:341–344.

47. Graham CJ, Yamauchi T, Rountree P. Q fever in animal laboratory workers: An outbreak and its investigation.

Am J Inf Con. 1989;17:345–348.

48. Hamedeh GN, Turner BW, Trible W, et al. Laboratory outbreak of Q fever. J Fam Pract. 1992;35:683–685.

49. D’Angelo LJ, Baker EF, Schlosser W. Q fever in the United States, 1948–1977. J Infect Dis. 1979;139:613–615.

50. Sawyer LA, Fishbein DB, McDade JE. Q fever in patients with hepatitis and pneumonia: Results of a laboratory-based surveillance in the United States. J Infect Dis. 1988;158:497–498.

51. Sienko DG, Bartlett PC, McGee HB, Wentworth BB, Herndon JL, Hall WN. Q fever: A call to heighten our

index of suspicion. Arch Intern Med. 1988;148:609–612.

52. Sidwell RW, Gebhardt LP. Studies of latent Q fever infection, III: Effects of parturition upon latently infected

guinea pigs and white mice. Am J Epidemiol. 1967;84:132–137.

53. Sidwell RW, Thorpe BD, Gebhardt LP. Studies of latent Q fever infections, II: Effects of multiple cortisone

injections. Am J Hyg. 1964;79:320–327.

54. Sidwell RW, Thorpe BD, Gebhardt LP. Studies of latent Q fever infections, I: Effects of whole body X-irradiation upon latently infected guinea pigs, white mice, and deer mice. Am J Hyg. 1964;79:113–124.

55. Humphres RC, Hinrichs DJ. Role of antibody in Coxiella burnetii infection. Infect Immun. 1981;31:641–645.

56. Kazar J, Rajcani J, Schramek S. Differential effects of cyclophosphamide on Coxiella burnetii infection in mice.

Acta Virol. 1982;26:174–182.

57. Koster FT, Williams JC, Goodwin JS. Cellular immunity in Q fever: Modulation of responsiveness by a suppressor T-cell monocyte circuit. J Immunol. 1985;135:1067–1072.

58. Hackstadt T, Peacock MG, Hitchcock PJ, Cole RL. Lipopolysaccharide variations in Coxiella burnetii: Intrastrain

heterogenicity in structure and antigenicity. Infect Immun. 1985;48:359–365.

59. Vishwanath S, Hackstadt T. Lipopolysaccharide phase variation determines the complement-mediated serum susceptibility of Coxiella burnetii. Infect Immun. 1988;56:40–44.

60. Dupuis G, Petite J, Olivier P, Vouilloz. Int J Epidemiol. 1987;16:282–287.

61. Fergusson RJ, Shaw TRD, Kitchin AH, et al. Subclinical chronic Q fever. Q J Med. 1985;57:669–676.

62. Marrie TJ. Q fever in pregnancy: Report of two cases. Inf Dis Clin Pract. 1993;2:207–209.

63. Syrucek L, Sobeslavsky O, Gutvirth I. Isolation of Coxiella burnetii from human placentas. J Hyg Epidemiol

Microbiol Immunobiol. 1958;2:29–35.

64. Friedland JS, Jeffrey I, Griffin GE, Booker M, Courtney-Evans R. Q fever and intrauterine death. Lancet.

1994;343:288.

65. Smith DL, Ayres JG, Blair I, et al. A large Q fever outbreak in the West Midlands: Clinical aspects. Respir Med.

1993;87:509–516.
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66. Clark WH, Lennette EH, Railsback OC, Romer MS. Q fever in California. Arch Intern Med. 1951;88:155–161.

67. Dupont HT, Raoult D, Brouqui P, et al. Epidemiologic features and clinical presentation of acute Q fever in

hospitalized patients: 323 French cases. Am J Med. 1992;93:427–434.

68. Derrick EH. The course of infection with Coxiella burnetii. Med J Aust. 1973;1:1051–1057.

69. Hwang YM, Lee MC, Suh DC, Lee WY. Coxiella (Q fever)-associated myelopathy. Neurology. 1993;43:338–342.

70. Sempere AP, Elizaga J, Duarte J, et al. Q fever mimicking herpetic encephalitis. Neurology. 1993;43:2713–2714.

71. Smith DL, Wellings R, Walker C, et al. The chest x-ray report in Q fever: A report on 69 cases from the 1989 West

Midlands outbreak. Br J Radiol. 1991;64:1101–1108.

72. Tselentis Y, Gikas A, Kofteridis D, et al. Q fever in the Greek island of Crete: Epidemiologic, clinical, and

therapeutic data from 98 cases. Clin Inf Dis. 1995;20:1311–1316.

73. Brouqui P, Dupont HT, Drancourt M, et al. Chronic Q fever: Ninety-two cases from France, including 27 cases

without endocarditis. Arch Intern Med. 1993;153:642–648.

74. Janigan DT, Marrie TJ. An imflammatory pseudotumor of the lung in Q fever pneumonia. N Engl J Med.

1983;308:86–88.

75. Lipton JH, Fong TC, Gill MJ, et al. Q fever inflammatory pseudotumor of the lung. Chest. 1987;92:756–757.

76. Peacock MG, Philip RN, Williams JC, et al. Serological evaluation of Q fever in humans: Enhanced phase I

titers of immunoglobulins G and A are diagnostic for Q fever endocarditis. Infect Immun. 1983;41:1089–1098.

77. Peter O, Dupuis D, Bee R, et al. Comparison of enzyme-linked immunosorbent assay for diagnosis of Q fever.

J Clin Microbiol. 1987;25:1063–1067.

78. Uhaa IJ, Fishbein DB, Olson JG, et al. Evaluation of specificity of indirect enzyme-linked immunosorbent assay

for diagnosis of human Q fever. J Clin Microbiol. 1994;32:1560–1565.

79. Waag D, Chulay J, Marrie T, England M, Williams J. Validation of an enzyme immunoassay for serodiagnosis

of acute Q fever. Eur J Clin Microbiol Infect Dis. 1995;14(5):421–427.

80. Hoover TA, Vodkin MH, Williams JC. A Coxiella burnetii repeated DNA element resembling a bacterial insertion sequence. J Bacteriol. 1992;174:5540–5548.

81. Stein A, Raoult D. Detection of Coxiella burnetii by DNA amplification using polymerase chain reaction. J Clin

Microbiol. 1992;30:2462–2466.

82. Willems H, Thiele D, Krauss H. Plasmid based differentiation and detection of Coxiella burnetii in clinical samples.

Eur J Epidemiol. 1993;9:411–418.

83. Fritz E, Thiele D, Willems H, Wittenbrink M-M. Quantitation of Coxiella burnetii by polymerase chain reaction

and a colorimetric microtiter plate hybridization assay. Eur J Epidemiol. 1995;11:549–557.

84. Raoult D. Treatment of Q fever. Antimicrob Agents Chemother. 1993;37:1733–1736.

85. Sobradillo V, Zalacain R, Capelastegui A, Uresandi F, Corral J. Antibiotic treatment in pneumonia due to Q

fever. Thorax. 1992;47:276–278.

86. Schonwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M. Comparison of three-day and five-day

courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Microbiol Infect Dis. 1991;10(10):877–880.
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87. Maurin M, Benoliel AM, Bongard P, Raoult D. Phagolysosomal alkalinization and the bactericidal effect of

antibiotics: The Coxiella burnetii paradigm. J Infect Dis. 1992;166:1097–1102.

88. Raoult D, Marrie TJ. State-of-the-art clinical lecture: Q fever. Clin Inf Dis. 1995;20:489–496.

89. Marmion BP. Development of Q fever vaccines, 1937–1967. Med J Aust. 1967;2:1074–1078.

90. Marmion BP, Ormsbee RA, Kyrkou M, et al. Vaccine prophylaxis of abattoir-associated Q fever: Eight years’

experience in Australian abattoirs. Epidemiol Infect. 1990:104:275–287.

91. Shapiro RA, Siskind V, Schofield FD, Stallman N, Worswick DA, Marmion BP. A randomized, controlled, doubleblind, cross-over, clinical trial of Q fever vaccine in selected Queensland abattoirs. Epidemiol Infect. 1990;104:

267–273.

92. Benenson AS. Q fever vaccine: Efficacy and present status. In: Smadel JE, ed. Symposium on Q fever by the

Committee on Rickettsial Diseases. Washington, DC: Armed Forces Epidemiology Board; 1959: 47–60.

93. Izzo AA, Marmion BP, Worswick DA. Markers of cell-mediated immunity after vaccination with an inactivated, whole-cell Q fever vaccine. J Infect Dis. 1988;157:781–789.

94. Bell JF, Lackman DB, Meis A, Hadlow WJ. Recurrent reaction at site of Q fever vaccination in a sensitized

person. Milit Med. 1964;124:591–595.

95. Lackman DB, Bell EJ, Bell JF, Pickens EG. Intradermal sensitivity testing in man with a purified vaccine for Q

fever. Am J Publ Health. 1962;52:87–93.

96. Luoto L, Bell JF, Casey M, Lackman D. Q fever vaccination of human volunteers, I: The serologic and skin-test

response following subcutaneous injections. Am J Hyg. 1963;78:1–15.

97. Fries LF, Waag DM, Williams JC. Safety and immunogenicity in human volunteers of a chloroform-methanol

residue vaccine for Q fever. Infect Immun. 1993;61:1251–1258.

RECOMMENDED READING

Interested readers will find thorough reviews of both organism and disease in the following outstanding monographs:

Marrie TJ, ed. Q Fever: The Disease. Vol 1. Boca Raton, Fla: CRC Press; 1990.

Williams TC, Thompson HA, eds. Q Fever: The Biology of Coxiella burnetii. Boca Raton, Fla: CRC Press; 1991.
Smallpox

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Chapter 27

SMALLPOX

DAVID J. MCCLAIN, M.D.*

INTRODUCTION

SMALLPOX AND BIOLOGICAL WARFARE

STRUCTURE AND BIOLOGY OF POXVIRUSES

PATHOGENESIS AND CLINICAL MANIFESTATIONS

DIAGNOSIS

MEDICAL MANAGEMENT

Active Immunoprophylaxis

Passive Immunoprophylaxis

Chemoprophylaxis and Chemotherapy

SUMMARY

*Research Medical Officer, Division of Virology, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

540

INTRODUCTION

The poxviruses (of the family Poxviridae) are a

family of large, enveloped deoxyribonucleic acid

(DNA) viruses.1

 The most notorious poxvirus is

variola, the causative agent of smallpox. Smallpox

was an important cause of morbidity and mortality

in the developing world until recent times. Since

the host range of the variola virus is confined to

humans, aggressive case identification and contact

vaccination were ultimately successful in controlling the disease. The last occurrence of endemic

smallpox was in Somalia in 1977, and the last human cases were laboratory-acquired infections in

1978.2

 By 1980, the World Health Organization

(WHO) General Assembly ratified the declaration

of success made by the Global Commission for the

Certification of Smallpox Eradication.

SMALLPOX AND BIOLOGICAL WARFARE

The concept of using variola virus in warfare is

an old one. British colonial commanders considered

distributing blankets from smallpox victims among

Native Americans as a biological weapon.3–5 During the American Civil War, allegations were made

about the use of smallpox as a biological weapon,

although there subsequently proved to be no definite evidence for such.6,7 In the years leading up to

and during World War II, the Japanese military explored weaponization of smallpox during the operations of Unit 731 in Mongolia and China.8,9

Nevertheless, the actual potential of variola virus as a biological weapon remains controversial.

Given the ease of administration and the availability of the vaccinia virus as a vaccine against smallpox,10 some have argued that smallpox would have

limited biological warfare potential.11 The Centers

for Disease Control and Prevention (CDC), Atlanta,

Georgia, presently maintains over 12 million doses

of vaccinia vaccine in storage, and WHO has in storage enough vaccine to protect 200 to 300 million

people.12 On the other hand, the potency of stockpiled vaccine will gradually decline. The discontinuation of routine vaccination has rendered civilian and military populations more susceptible to

a disease that is not only infectious by aerosol but

also infamous for its devastating morbidity and

mortality. WHO voiced concerns that smallpox “can

easily be produced in large quantities in the laboratory and...freeze-dried and its virulence thus preserved for months or years.”13(p69)

Since 1983, there have existed two WHO-approved and -inspected repositories of variola virus:

the CDC in the United States and Vector Laboratories in Russia. WHO continues to debate whether,

given the completion of sequencing of several reference strains, all stocks of variola virus should be

destroyed. Proponents of retaining these smallpox

stocks argue that military or terrorist use of variola

virus as a weapon would readily be countered by

rigorous case contact evaluation and vaccination.

Furthermore, they reason that even if the repositories are eliminated, other potential sources of smallpox exist:

• Given the fact that viable variola virus

could be recovered from scabs up to 13

years after collection,14 it is conceivable that

cadavers preserved in permafrost15 or dry

crypts16 could release the virus.

• Virus specimens from the smallpox-eradication campaign may remain unrecognized

or unreported.

• Using the published sequence of variola

and its significant homology with other

Orthopoxviruses, a malevolent laboratory

could theoretically engineer a recombinant

virus exhibiting variola virus’s virulence by

starting with monkeypox virus.

Additionally, in the event that smallpox should reemerge under one of the above scenarios, destroying the legitimate repositories of variola virus

would hinder investigation into both (a) the mechanisms of viral pathogenesis, so as to effect countermeasures, and (b) detailed molecular epidemiology,

so as to establish the precise phylogenetic relationship of an isolate to other known strains. Lastly,

extinction of smallpox would disallow study of its

unique proteins that interfere with host immune

and regulatory functions (eg, homologues of epidermal growth factor, transforming growth factor,

interleukin-1β, interferon-γ, and zinc-finger protein).17,18

Those who advocate eradication of the official

variola virus repositories cite the possibility of accidental or intentional release of the virus as a threat

to international public health; political instability
Smallpox

541

in Russia has reemphasized this concern. In addition, retention of these repositories might legitimize

clandestine stockpiling or offensive biological warfare research on variola virus. Even if a virulent

variola-like poxvirus could be engineered by an

offensive biological warfare power, the lack of an

animal model that accurately reflects human pathology19 would severely limit how it could be selected

and tested. From the standpoint of understanding

Orthopoxvirus biology, published sequence information on variola would be adequate to confirm the

identity of any smallpoxlike virus that might

emerge in the future. Finally, further studies on

poxvirus pathogenesis would be much more safely

and successfully pursued using a poxvirus that

does possess a good animal model, such as ectromelia (ie, mouse pox).20 Despite the promise of variola

virus’s extinction as a biological entity, the prospect

of surreptitious weaponization of smallpox remains

vexing, and vaccination of military personnel

could be seen as a defensive posture implying willingness to use variola virus as a weapon.21

STRUCTURE AND BIOLOGY OF POXVIRUSES

Possessing one of the largest genomes of any virus, an Orthopoxvirus consists of one piece of

double-stranded DNA, which is cross-linked at each

end.22 With their brick-shaped morphology, poxviruses have a biconcave core containing the DNA

genome. The virus-encoded enzymes in the core are

critical to transcription of the viral DNA. Genes

encoding the nonessential functions important for

virus virulence are arrayed near the ends of the

genome; as would be expected, the greatest heterogeneity between poxviruses is at these genomic

ends.23,24 There are 187 putative proteins identified

from the sequencing of variola virus, of which 150

bear marked similarity to those of vaccinia virus.

Encoded sequences include one for hemagglutinin,

an envelope protein, and proteins that enhance

growth in human cells. The other 37 proteins represent either variola-specific sequences, or open reading frame (ie, DNA sequences that are transcribed

into ribonucleic acid [RNA], and hence are translated, via reading of the genetic code, into amino

acid sequences) divergences from vaccinia counterparts.25 These relatively small differences in vaccinia

and variola virus proteins suggest that the variolaunique proteins act synergistically in bringing about

the local and systemic manifestations for which

smallpox is noted.

Most poxvirus virions appear to enter cells by

pinocytosis, and then to uncoat within cytoplasmic

vesicles. Poxvirus replication occurs in these discrete cytoplasmic inclusions, independent of the cell

nucleus. Host biosynthetic processes are inhibited

soon after poxvirus infection occurs. Virus transcription initiates almost immediately after entry,

as DNA transcription is initiated by core enzymes

while the genome is still in the core. Early gene

products have to do with DNA synthesis, ensuring

adequate levels of precursors for DNA synthesis

and inhibition of host defense mechanisms.26 This

is followed by release of DNA and subsequent synthesis of RNA and proteins.27 It has been postulated28 that viral DNA is transcribed and replicated

from viral cores, or “deoxyribonucleoproteids.”

Although the virus encodes a DNA-dependent RNA

polymerase, there is evidence29 that subunits of cellular RNA polymerase II from the nucleus are somehow used in replication. Recombination events occur with high frequency during the replication process30; these may also occur among different species of Orthopoxviruses.

31

Viral DNA synthesis and intermediate regulatory

genes are required for late gene expression.32 Proteins that are translated late include most of the

structural proteins, as well as enzymes required for

assembly of virion progeny. Maturation of virions

is a complicated process entailing sequential assembly of poxvirus-specified macromolecules into particles. Unlike membranes of other enveloped viruses that are contiguous with host membranes,

poxviruses assemble in the viroplasm into uniform,

spherical, immature particles. This immature particle subsequently undergoes extensive conformational and biochemical changes before release, although most virions remain within the cell at the

end of the growth cycle.33 On release from the cell,

the virion’s outer (second) membrane fuses with the

cell membrane; thus the released virion presents

viral antigens not displayed in intracellular forms.34

The sequence of events leading to release and dissemination of virions varies widely among different poxviruses.35

Compared with other genera of vertebrate poxviruses (Table 27-1), members of the Orthopoxvirus

genus (a) possess similar morphology and host

range and (b) are antigenically related. Cross-reacting and species-specific neutralizing antigens have

been identified by serum absorption and monoclonal antibody studies.36,37 Up to six antigens have
Medical Aspects of Chemical and Biological Warfare

542

been identified as neutralizing epitopes of Orthopoxviruses, one of these existing on naturally released but not on artificially released virions.38

Undoubtedly, both cellular and humoral immune

responses are important to recovery from smallpox.

The inability of poxviruses to persist stably within

the host cell accounts for their infections being relatively short-lived, without establishment of a latent

infection. The importance of cellular immunity in

recovery from infection has been demonstrated with

other poxviruses,39 and the same is generally assumed with variola. Vaccination experiences demonstrated the rare but terrible consequence of vaccinia necrosum in persons with defects of cellular

immunity. Early presentation on the host cell membrane of virus-encoded proteins provides means for

immune recognition.40 It has been demonstrated

that both antibody-dependent cellular cytotoxicity41

and heterogeneous cluster of differentiation (CD)

4+ cytotoxic T-lymphocyte clones42 are induced in

response to vaccinia infection, and some immunodominant B-cell epitopes have been defined in both

mice and vaccinated humans.43 The relatively large

size of poxvirus polypeptides facilitates their recTABLE 27-1

CLASSIFICATION OF CHORDOPOXVIRIDAE

(VERTEBRATE POXVIRUSES)

Genera Representative Species

Orthopoxvirus Variola, vaccinia, monkeypox,

cowpox, rabbitpox, raccoon pox,

tatera pox, buffalopox, camelpox

Avipoxvirus Fowlpox, canary pox

Capripoxvirus Goatpox, sheeppox, lumpy skin

disease

Leporipoxvirus Myxoma, hare fibroma

Parapoxvirus Orf (milker’s nodule), pseudocowpox

Suipoxvirus Swinepox

Molluscipoxvirus Molluscum contagiosum

Yatapoxvirus Tanapox, Yaba

ognition and phagocytosis by the reticuloendothelial system. Viral antigens contained in the viral envelope are of preeminent importance with regard

to protective antibody responses: envelope antigens

were absent from virion suspensions used for inactivated smallpox vaccines, which proved to be ineffective.44–47

A naturally occurring relative of variola, monkeypox virus, is found in Africa, and the disease it

causes, monkeypox, is clinically indistinguishable

from smallpox, with the exception of notable enlargement of cervical and inguinal lymph nodes.

The disease occurs mostly in monkeys from the

tropical rain forests of central Africa, with sporadic

transmission to humans. Some evidence supports

the role of squirrels as the principal animal reservoir of the virus.48 Over a span of 3 years, 331 cases

of monkeypox disease in a population of 5 million

have been reported.49 Under natural conditions, the

virus is transmitted by direct contact with an infected

individual, fomites, and, occasionally by aerosol.

Concern has been raised whether the monkeypox

virus could be weaponized and, if so, whether it

would constitute a threat similar to that posed by

variola virus. However, epidemiological evidence

indicates that monkeypox virus has limited potential for person-to-person transmission, accounting

for about 30% of the observed cases.50 There is one

report of its spread though four human generations.51 A stochastic model for interhuman spread

of monkeypox indicates that it is very unlikely that

the virus could sustain itself indefinitely in a community by interhuman transmission.52 The finite

transmission potential of monkeypox prompted

WHO to maintain active surveillance rather than a

vaccination program in the endemic areas. Successful vaccinia virus immunization, as judged by the

presence of a preexisting vaccination scar, affords

approximately 85% protection against monkeypox. 53 Nevertheless, (a) the pathogenicity of

monkeypox for humans, (b) the potential morbidity of an aerosolized monkeypox virus attack, and

(c) the theoretical potential that genetic recombination could produce a modified animal poxvirus with

enhanced virulence for humans have raised the

specter that another poxvirus besides variola might

constitute either a serious biowarfare threat or a

reemergent public health problem.

PATHOGENESIS AND CLINICAL MANIFESTATIONS

Variola virus is highly stable and retains its infectivity for long periods outside the host.54 It is

infectious by aerosol,55 but natural airborne spread

to other than close contacts is controversial.56,57

Approximately 30% of susceptible contacts became

infected during the era of endemic smallpox,58 and
Smallpox

543

the WHO eradication campaign was predicated on

close person-to-person proximity being required for

transmission to occur reliably. Nevertheless, variola virus’s potential in low relative humidity for

airborne dissemination was alarming in two hospital outbreaks.59 Patients with smallpox were

infectious from the time of onset of their eruptive

exanthem, most commonly from days 3 through 6

after onset of fever. Infectivity was markedly enhanced if the patient manifested a cough. Indirect

transmission via contaminated bedding or other

fomites was infrequent.60 Some close contacts harbored virus in their throats without developing disease, and hence might have served as a means of

secondary transmission.61 There is no animal reservoir for variola virus, although monkeys are susceptible to infection.62

On natural exposure to aerosolized virus, variola travels from the upper or the lower respiratory

tract to regional lymph nodes, where it replicates

and gives rise to viremia, which is followed soon

thereafter by a rash.63 The incubation period of

smallpox averages 12 days, and contacts are quarantined for a minimum of 16 to 17 days following

exposure. Following infection via the respiratory

route and replication in local lymph nodes, variola

virus disseminates systemically to other lymphoid

tissues, spleen, liver, bone marrow, and lung. During this prodromal period, variola virus can be recovered from the blood, but the yield is much lower

later in the illness. Clinical manifestations begin

acutely with malaise, fever, rigors, vomiting, headache, and backache; 15% of patients develop delirium. Approximately 10% of light-skinned patients exhibit an erythematous rash during this

phase.64 Two to 3 days later, an enanthem appears

concomitantly with a discrete rash about the face,

hands, and forearms. Owing to the lack of a keratin

layer on mucous membranes, lesions there shed

infected epithelial cells and give rise to infectious

oropharyngeal secretions in the first few days of the

eruptive illness.65 These respiratory secretions are

the most important but not the sole means of virus

transmission to contacts.

Following subsequent eruptions on the lower

extremities, the rash spreads centrally during

the next week to the trunk. Lesions quickly progress from macules to papules and eventually to

pustular vesicles (Figure 27-1). Lesions are more

abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to the lesions seen in varicella, smallpox lesions on various segments of the

body remain generally synchronous in their stage

of development. From 8 to 14 days after onset, the

pustules form scabs, which leave depressed

depigmented scars on healing. Although variola

titers in the throat, conjunctiva, and urine diminish

with time,66 virus can readily be recovered from

scabs throughout convalescence.67 Therefore, patients should be isolated and considered infectious

until all scabs separate.

For the past century, two distinct types of smallpox have been recognized. Variola major, the prototypical disease, was prevalent in Asia and parts

of Africa. Variola minor, or alastrim, was distinguished by milder systemic toxicity and more diminutive pox lesions (Figure 27-2). Variola minor

was found in Africa, South America, and Europe

before the eradication of endemic disease, and

caused 1% mortality in unvaccinated victims.

Three quarters of endemic cases of variola major

fell into the classic, or ordinary, variety (see Figure

27-1). The fatality rate was 3% in vaccinated patients

and 30% in unvaccinated. Other clinical forms of

smallpox were associated with variola major, and

it is likely that differences in both strain virulence

and host response were responsible for these variations in clinical manifestations.68 Flat-type smallpox,

noted in 2% to 5% of patients, was typified by (a)

severe systemic toxicity and (b) the slow evolution

of flat, soft, focal skin lesions (Figure 27-3). This syndrome caused 66% mortality in vaccinated patients

and 95% mortality in unvaccinated. Hemorrhagictype smallpox, seen in fewer than 3% of patients,

was heralded by the appearance of extensive petechiae (Figure 27-4), mucosal hemorrhage, and intense toxemia; death usually intervened before the

development of typical pox lesions.69

Bacterial superinfection of pox lesions was relatively uncommon except in the absence of proper

hygiene and medical care. Arthritis and osteomyelitis developed late in the course of disease in about

1% to 2% of patients, more frequently occurred in

children, and was often manifested as bilateral joint

involvement, particularly of the elbows.70 Viral inclusion bodies could be demonstrated in the joint

effusion and bone marrow of the involved extremity. This complication reflected infection and inflammation of a joint followed by spread to contiguous

bone metaphyses, and sometimes resulted in permanent joint deformity.71 Cough and bronchitis

were occasionally reported as prominent manifestations of smallpox, with attendant implications for

spread of contagion; however, pneumonia was unusual.72 Pulmonary edema occurred frequently in

hemorrhagic- and flat-type smallpox. Orchitis was

noted in approximately 0.1% of patients. Encepha-
Medical Aspects of Chemical and Biological Warfare

544

Fig. 27-1. This series of photographs illustrates the evolution of skin lesions in an unvaccinated infant with the classic

form of variola major. (a) The third day of rash shows synchronous eruption of skin lesions; some are becoming

vesiculated. (b) On the fifth day of rash, almost all papules are vesicular or pustular. (c) On the seventh day of rash,

many lesions are umbilicated, and all lesions are in the same general stage of development. Photographs: Reprinted

with permission from Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva,

Switzerland: World Health Organization; 1988: 10–14. Photographs by I. Arita.

a. Third Day of Rash b. Fifth Day of Rash c. Seventh Day of Rash

The series of illustrations in Figure 27-1 is not shown because the copyright permission granted to the Borden Institute,

TMM, does not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic

media. The current user must apply to the publisher named in the figure legend for permission to use this illustration in

any type of publication media.
Smallpox

545

Fig. 27-2. Variola minor in an unvaccinated

woman 12 days after onset of rash. The facial lesions (a) are more sparse and evolve

more rapidly than those on the arms (b) or

legs (c). Reprinted with permission from

Fenner F, Henderson DA, Arita I, Jezek Z,

Ladnyi ID. Smallpox and Its Eradication.

Geneva, Switzerland: World Health Organization; 1988: 36. Photographs by I. Arita.

Fig. 27-3. Flat-type smallpox in an unvaccinated woman on the sixth day of rash. Extensive flat lesions (a and b) and

systemic toxicity with fatal outcome were typical. Reprinted with permission from Fenner F, Henderson DA, Arita I,

Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva, Switzerland: World Health Organization; 1988: 33. Photographs by F. Dekking.

Fig. 27-4. Early hemorrhagic-type smallpox with cutaneous signs of hemorrhagic diathesis. Death usually intervened before the complete evolution of pox lesions.

Reprinted with permission from Herrlich A, Mayr A,

Munz E, Rodenwaldt E. Die pocken; Erreger, Epidemiologie

und klinisches Bild. 2nd ed. Stuttgart, Germany: Thieme;

1967. In: Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi

ID. Smallpox and Its Eradication. Geneva, Switzerland:

World Health Organization; 1988: 35.

a b c

a b

Figure 27-2 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow

the Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current

user must apply to the publisher named in the figure legend for permission to use this illustration in any type of

publication media.

Figure 27-3 is not shown because the copyright permission granted to the Borden Institute, TMM, does

not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the publisher named in the figure legend for permission to use

this illustration in any type of publication media.

Figure 27-4 is not shown because the copyright permission granted to the Borden Institute, TMM, does not

allow the Borden Institute to grant permission to other

users and/or does not include usage in electronic media. The current user must apply to the publisher named

in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

546

litis developed in 1 in 500 cases of variola major,

compared with 1 in 2,000 cases of variola minor.73

Keratitis and corneal ulcers were important

complications of smallpox, progressing to blindness in slightly fewer than 1% of cases.74 Disease

during pregnancy precipitated high perinatal

mortality, and congenital infection was also recognized.75,76

Partial immunity from vaccination resulted in

modified-type smallpox, in which sparse skin lesions evolved variably, often without pustules, and

quickly, with crusting occurring as early as the seventh day of illness. Some fully immune individuals

would develop fever, sore throat, and conjunctivitis (called contact fever), on exposure to smallpox.

This lasted several days, but did not give rise to

the toxicity or minor skin lesions that signify variola sine eruptione.

Persons who recovered from smallpox possessed

long-lasting immunity, although a second attack

could occur in 1 in 1,000 persons after an intervening period of 15 to 20 years.77 As discussed earlier,

both humoral and cellular responses are important

components of recovery from infection. Neutralizing antibodies peak 2 to 3 weeks following onset,

and last longer than 5 years.78

DIAGNOSIS

Given modern clinicians’ lack of experience with

smallpox, greater perspicacity is required to distinguish the forme fruste of this disease from other

vesicular exanthems, such as those of chickenpox, erythema multiforme with bullae, or allergic contact dermatitis. Table 27-2 delineates some of

the key features that differentiate variola from

varicella (chickenpox virus). The failure to recognize relatively mild cases of smallpox in persons

with partial immunity, who could unwittingly

contribute to secondary spread by ambulating

with their contagious exanthems undiagnosed,

would present a particular problem to infection control. An additional threat to effective quarantine is the fact that exposed persons may shed

virus from the oropharynx without ever manifesting disease. Therefore, quarantine and initiation of

medical countermeasures should be followed

promptly by an accurate diagnosis so as to avert

panic.

Rapid diagnostic tests may play an important

role in discriminating smallpox from other diseases.79,80 The usual method of diagnosis is demonstration of characteristic virions on electron microscopy of vesicular scrapings. Under light microscopy,

aggregations of variola virus particles, called

Guarnieri bodies, correspond to B-type poxvirus

inclusions (Figure 27-5). These cytoplasmic inclusions are hematoxylinophilic, stain reddish purple

with Giemsa stain, and contain Feulgen-positive

material.81 Another rapid but relatively insensitive

test for Guarnieri bodies in vesicular scrapings is

Gispen’s modified silver stain, in which cytoplasmic inclusions appear black. The gel diffusion test,

in which vesicular fluid from a pox lesion was incubated with vaccinia hyperimmune serum, conTABLE 27-2

DIFFERENTIATION BETWEEN SMALLPOX AND CHICKENPOX

Variola Varicella

Incubation Period 7–17 d 14–21 d

Prodrome Fever and malaise for 2–4 d before onset of rash Minimal to none

Pock Distribution Centrifugal; usually on palms and soles Centripetal; seldom on palms and soles

Pock Appearance Vesicular—> pustular—> umbilicated—> scab Vesicular on erythematous base—>

pustular—> scab

Evolution of Pocks Synchronous Asynchronous

Scab Formation 10–14 d after onset of rash 4–7 d after onset of rash

Scab Separation 14–28 d after onset of rash Within 14 d after onset of rash

Infectivity From onset of enanthem until all scabs separate From 1 d before rash until all vesicles scab
Smallpox

547

stitutes a rapid and inexpensive method when microscopy is not available.82

None of the above laboratory tests are capable

of discriminating smallpox from vaccinia, monkeypox, or cowpox. Classically, this differentiation required isolation of the virus and characterization

of its growth on chorioallantoic membrane. Pocks

produced by smallpox are small and grayish white,

Fig. 27-5. Cytoplasmic inclusion bodies in cells infected with Orthopoxviruses. (a) B-type (pale-red, irregular) inclusion, or Guarnieri, bodies, and A-type (large eosinophilic, with halo) inclusion bodies in ectodermal cells of the

chorioallantoic membrane, in a pock produced by cowpox virus. A number of nucleated erythrocytes are in the ectoderm and free in the mesoderm, and the surface of the pock is ulcerated. Hematoxylin-eosin stain. (b) This section of

the skin of a patient with hemorrhagic-type smallpox shows Guarnieri bodies and free erythrocytes below an early

vesicle. Hematoxylin-eosin stain. Photographs: Reprinted with permission from Fenner F, Henderson DA, Arita I,

Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva, Switzerland: World Health Organization; 1988: 85.

whereas those for vaccinia are larger and sometimes

hemorrhagic. Variola minor exhibited greater temperature sensitivity on chorioallantoic membranes

than did variola major.83 The development of polymerase chain reaction diagnostic techniques promises a more accurate and less cumbersome method

of discriminating among variola virus and other

Orthopoxviruses.

MEDICAL MANAGEMENT

Medical personnel must be prepared to recognize

a vesicular exanthem in possible biowarfare theaters

as potentially smallpox, and to initiate appropriate

countermeasures. Any confirmed case should be

considered an international emergency, with an immediate report made not only to the chain of command but also to public health authorities. Strict

quarantine with respiratory isolation should be

applied for 17 days to all persons in direct contact

with the index case or cases, especially the unvaccinated. Immediate vaccination should also be undertaken for all personnel exposed to either

weaponized variola or monkeypox virus or a clinical case of smallpox. Medical personnel should have

a history of vaccination and should undergo immediate revaccination to ensure solid immunity.

Vaccination with a verified clinical take (ie, the

local response to vaccination whereby a vesicle

forms with surrounding erythema and induration)

within the past 3 years is considered to render a

a b

Figure 27-5 is not shown because the copyright permission granted to the Borden Institute,

TMM, does not allow the Borden Institute to grant permission to other users and/or does not

include usage in electronic media. The current user must apply to the publisher named in the

figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

548

person immune to naturally occurring smallpox.

However, given the difficulties and uncertainties

under wartime conditions of verifying the adequacy

of troops’ prior vaccination, routine revaccination

of all potentially exposed personnel would seem

prudent if a significant prospect of smallpox exposure is believed to exist.

The key to control and eventual eradication of

endemic smallpox was vigorous case identification,

followed by quarantine and immunization of contacts. The fact that heterologous immunity provided

by vaccination wanes with time is not fully appreciated: two thirds of smallpox victims in the 1960s

had preexisting vaccination scars. Passive immunoprophylaxis using immune globulin was also examined, but, owing to the accepted efficacy of active immunization, the two methods were never

compared against each other. No chemotherapy

demonstrated efficacy against smallpox disease, but

modest efficacy was shown in chemoprophylaxis.

Present speculation regarding smallpox chemotherapy relies on in vitro data only.

Active Immunoprophylaxis

Vaccinia Vaccine

Early attempts to control smallpox included inoculation with material from smallpox lesions. This

practice, known as variolization, caused severe

cases of smallpox in about 1 in 200 inoculations.84

In 1796, Jenner noted that milkmaids were free of

the facial scars that marked most of the population

during the smallpox epidemics of that time. The observation that they “cannot take smallpox” was

attributed to the localized pox lesions that they developed on their hands. Jenner reasoned that infectious material (which he dubbed a “virus”) from

cowpox lesions provided protection from smallpox,

and used it to vaccinate an 8-year-old boy. The boy

later resisted variolation, demonstrating that an

animal poxvirus that is not virulent for humans

could be used as a potent vaccine against smallpox.85

Vaccinia virus is another member of the orthopox

genus of the Poxvirus family that possesses little

pathogenicity for immunocompetent humans. Although the exact origin of vaccinia virus remains

obscure,86 it is related to cowpox, and strains of vaccinia virus became the vaccines of choice for the prevention of smallpox. The smallpox vaccines used

in the eradication effort were prepared on a large

scale by inoculating the shaved abdomens of calves,

sheep, or water buffalo with seed stocks of vaccinia

virus, harvesting the infected exudative lymph from

the inoculation sites, and bottling the product with

phenol or brilliant green as a bacteriostatic agent.

Smallpox vaccines were most often administered

by intradermal inoculation with a bifurcated needle,

a process that became known as scarification because

of the permanent scar that resulted. This method

proved effective and successful when applied in the

worldwide campaign to eradicate endemic smallpox, which primarily employed the New York City

Board of Health (NYCBOH), EM-63, Lister,

and Temple of Heaven strains. Although the Lister

and Temple of Heaven vaccines putatively derived

from transformation of variola into an attenuated

virus, both animal studies87 and restriction endonuclease analyses88 indicate that they actually resulted from contamination with vaccinia during

animal passages.

The human dose for vaccinia immunization is

approximately 5 log10 plaque-forming units given

percutaneously. A vesicle typically appears at the

vaccination site 5 to 7 days after the inoculation,

with surrounding erythema and induration. The

lesion forms a scab and gradually heals over the

next 1 to 2 weeks.

Vaccination Complications

Side effects arising from vaccination are relatively uncommon but nevertheless finite. Lowgrade fever and axillary lymphadenopathy may

coincide with the culmination of the cutaneous pox

lesion. The attendant erythema and induration of

the vaccination vesicle is frequently misdiagnosed

as bacterial superinfection. Formation of a scar on

healing of the vesicle occurs routinely, and constitutes a permanent record of a take, or a successful

primary vaccination.

One of the most thorough surveys of adverse reactions associated with vaccinia vaccines was conducted in the United States and published by the

CDC in 1968,89 and is summarized in Table 27-3. As

a consequence of percutaneous inoculation, infectious vaccine virus is present in the local lesion.

Consequently, inadvertent inoculation to other skin

and mucous membrane sites (autoinoculation) or

to other persons (secondary inoculation) is the most

frequent complication of vaccinia intradermal

vaccination.90–92 Ocular vaccinia is a particularly

troublesome problem resulting from secondary inoculation (Figure 27-6). Erythematous or urticarial

rashes may occur approximately 10 days after primary vaccination and, rarely, Stevens-Johnson syndrome occurs. Generalized vaccinia is characterized
Smallpox

549

TABLE 27-3

RATES* OF REPORTED COMPLICATIONS ASSOCIATED WITH VACCINIA VACCINATIONS

Fig. 27-6. Ocular vaccinia following inadvertent autoinoculation with vaccine. This complication can cause corneal

scarring and hence visual impairment. Ocular vaccinia

should be treated aggressively with a topical antiviral drug

under close ophthalmological supervision. Reprinted

with permission from Fenner F, Henderson DA, Arita I,

Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva,

Switzerland: World Health Organization; 1988: 298. Photograph by C. H. Kempe.

Figure 27-6 is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the publisher named in the figure legend for

permission to use this illustration in any type of

publication media.

*Cases per million vaccinations

†Includes patients with lesions that had bacterial superinfection, or that made the patient uncomfortable enough to consult a

physician. Unusual complications included were a patient with fetal vaccinia, a patient with a melanoma developing in the vaccine

scar, and a patient with monoarticular arthritis following vaccination.

Table 27-3 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden

Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the

publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

550

by a vesicular rash of varying extent occurring 6 to

9 days after primary vaccination; this complication

is usually self-limited.

More severe complications of vaccinia vaccination

include eczema vaccinatum, progressive vaccinia,

and postvaccinial encephalitis. These complications

are rare, but occur at least 10 times more often

among primary vaccinees than among revaccinees.

Eczema vaccinatum is a localized or systemic dissemination of vaccinia virus among persons who

have eczema (Figure 27-7). Although usually mild

and self-limited, this complication could be severe

or even fatal in up to 10% of cases.

Progressive vaccinia (vaccinia necrosum) is a

progressive necrosis in the area of vaccination, often with metastatic lesions (Figure 27-8). This complication occurred almost exclusively in persons

with cellular immunodeficiency,93 with a case fatality rate of higher than 75%.94

Postvaccinial encephalitis most frequently affects

primary vaccinees, with attendant mortality and

serious neurologic morbidity of 25%.95 Although the

U.S. survey indicated the opposite, most countries

reported a greater incidence of postvaccinial encephalitis from primary vaccination of older children and adults than of infants.96

Vaccinia-immune globulin (VIG) is of value in

the treatment of progressive vaccinia, eczema

vaccinatum,97 and perhaps ocular vaccinia (VIG is

discussed below in the section titled Passive

Immunoprophylaxis). Topical idoxuridine may benefit vaccinia keratitis.98,99

Fig. 27-7. Eczema vaccinatum. The widespread pox lesions on this patient’s eczematous skin illustrate the severe illness that can occur in up to 10% of cases. Reprinted

with permission from Fenner F, Henderson DA, Arita I,

Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva,

Switzerland: World Health Organization; 1988: 298. Photograph by I. D. Ladyni.

Fig. 27-8. Progressive vaccinia or vaccinia necrosum. As

seen in this child, progressive viral replication at the inoculation site in an immunocompromised individual

leads to inexorable local tissue destruction. Reprinted

with permission from Fenner F, Henderson DA, Arita I,

Jezek Z, Ladnyi ID. Smallpox and Its Eradication. Geneva,

Switzerland: World Health Organization; 1988: 298. Photograph by C. H. Kempe.

Vaccination is contraindicated in the following

conditions:

1. Immunosuppression, such as occurs with

agammaglobulinemia, leukemia, lymphoma, generalized malignancy, or therapy

with alkylating agents, antimetabolites, radiation, or large doses of corticosteroids.

Such persons are at increased risk of progressive vaccinia.

2. Human immunodeficiency virus (HIV) infection. Severe vaccinia infections have

been reported in persons immunosuppressed as a consequence of HIV disease.100,101

3. Either history or evidence of eczema. Other

exfoliative or extensive skin lesions (eg,

atopic dermatitis, psoriasis, burns) may

also place a person at increased risk for

vaccination.

4. Current household, sexual, or other close

physical contact with a person or persons

possessing the condition or conditions listed

in exclusion criteria 1 through 3, above.

Figure 27-8 is not shown because the

copyright permission granted to the Borden

Institute, TMM, does not allow the Borden

Institute to grant permission to other users

and/or does not include usage in electronic

media. The current user must apply to the

publisher named in the figure legend for

permission to use this illustration in any type

of publication media.

Figure 27-7 is not shown because the copyright

permission granted to the Borden Institute, TMM,

does not allow the Borden Institute to grant permission to other users and/or does not include

usage in electronic media. The current user must

apply to the publisher named in the figure legend for permission to use this illustration in any

type of publication media.
Smallpox

551

5. Pregnancy. There have been rare instances

of fetal vaccinia, usually following primary

vaccination of pregnant women.102,103 This

complication usually resulted in fetal demise or early postnatal mortality.

Despite the caveats listed above, most authorities state that, with the exception of significant impairment of systemic immunity, there are no absolute

contraindications to postexposure vaccination of a

person who experiences bona fide exposure to variola virus. However, in such circumstances, concomitant administration of VIG is recommended for

pregnant women and individuals with eczema.

Indicators of Immunity

Vaccination with live vaccinia virus remains the

principal defensive measure against smallpox, and

against monkeypox, as well. Immunity to smallpox

is gauged by the local response to vaccination (the

take). However, not all vaccinations giving clinical

takes will boost neutralizing antibody responses.104

Evidence indicates that vaccinia provides protection against smallpox for at least 3 years after the

vaccination.105 With longer intervals between exposure and primary vaccination (or revaccination),

protection is reduced. If vaccination is accomplished

within a few days after exposure, then protection

is also demonstrable,106 approaching complete protection in those who have had their primary vaccination previously.107 Postexposure vaccine failures

were reported during trials in the smallpox era.

Combined active immunization and passive immunization with VIG may provide improved postexposure prophylaxis. However, concomitant administration of VIG may attenuate the immune response

to vaccination.108

Protection following vaccinia immunization, like

immunity following recovery from smallpox, has

both a humoral and a cellular basis. One prospective study109 of 146 contacts of patients with smallpox demonstrated that no contacts with significant

titers of neutralizing antibody titer contracted the

disease. However, 2 contacts with detectable titers

still contracted the disease, and some persons with

no neutralizing antibody were spared. In another

investigation110 of 57 contacts of smallpox cases, all

6 who subsequently developed smallpox had neither a vaccination scar nor detectable neutralizing

antibody. Therefore, data indicate that adequate

serum titers of vaccinia-neutralizing antibody are

usually sufficient, but not always necessary, for protection against variola virus. Neutralizing antibody

decreases during the first 3 years after vaccination,

but titers remain sustained for several years following a second booster (ie, primary immunization and

two revaccinations).111,112

Contact Precautions

Vaccinia virus may be cultured from the site of

primary vaccination for a time that begins at the

development of a papule (2–5 d postvaccination)

and lasts until the lesion has fully scabbed with no

remaining vesicle (10–17 d postvaccination). During this period, infection-control measures are paramount in preventing secondary inoculation of the

virus to other body sites or other persons. The lesion should be covered at all times with a dry dressing, and strict handwashing should be practiced

after changing the dressing or touching the vaccination site. Semipermeable dressings predispose to

accumulation of exudate beneath the dressing, with

maceration and local secondary inoculation. Medical personnel should be excluded from caring for

persons with active vaccinia lesions if the former

are immunocompromised or possess chronic exfoliative skin lesions. Medical personnel who come

in contact with contaminated materials (eg, dressings) from vaccinees are at relatively low risk of

inadvertent inoculation, provided that they use

appropriate infection control measures.113 The CDC

has recommended that laboratory personnel who

work with vaccinia or recombinant vaccinia viruses

be vaccinated; this recommendation is controversial,114 however, and the risks of deliberate vaccination versus those of accidental inoculation must be

weighed.

Vaccine Availability

The remaining vaccinia vaccine licensed in the

United States (Dryvax, manufactured by Wyeth,

Philadelphia, Pa.) is a live, infectious virus prepared

from calf lymph. Like all smallpox vaccines that

were marketed in the United States, it derived from

the NYCBOH strain and contains 108 plaque-forming units per milliliter. Current vaccinia vaccine

stocks (> 12 million doses) are held by the CDC. It

must be noted that the potency of several lots of

this lyophilized vaccine has fallen. Pharmaceutical

companies in the United States lack interest in

manufacturing new lots of vaccine, owing to the

absence of a profitable retail market, antiquation of

calf-lymph production techniques and facilities, and

the manufacturer’s legal liability for vaccination

complications.
Medical Aspects of Chemical and Biological Warfare

552

Because of the declining potency of the existing

smallpox vaccines and continued concerns about

the prospect of the use of variola virus in biological

warfare, a new vaccinia vaccine is in clinical testing by the U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland.

This vaccine was derived from a NYCBOH strain

of vaccinia and then produced in human diploid

lung fibroblast cell cultures. Unlike calf-lymph vaccines, this cell culture–derived vaccinia vaccine contains no adventitious agents.

Injectable Smallpox Vaccines

It has long been desired that vaccinia vaccine

could be administered by injection; this route would

preclude the complication of inadvertent inoculation of virus that was so prominent with the scarified calf-lymph vaccine. A potential disadvantage

to subcutaneous or intramuscular inoculation

would be the preclusion of a visible vesicle and scar

as a means of assessing the take of a vaccination,

which historically has been correlated to protection

against smallpox. Plaque reduction neutralization

antibody responses necessarily serve as the surrogate marker for an immune response that would

protect against smallpox. Since the 1930s, at least

eight strains of vaccinia virus were developed for

parenteral administration. None were shown to be

as immunogenic as standard calf-lymph strains

administered by scarification, since they produced

lower neutralizing antibody levels after primary

and booster inoculations.115 Therefore, evidence indicates that subcutaneous, intramuscular, and intradermal vaccination without concomitant formation of a cutaneous pox lesion does not elicit as

strong a serologic response as that obtained through

scarification.116,117

Recombinant Vaccinia Vaccines

Vaccinia virus has been proposed as a vaccine

vector for foreign genes. This approach has been

employed for expression of HIV proteins118 as well

as other antigens. Vaccinia-naive individuals inoculated with this vaccine developed antibodies not

only to HIV-1119 but also to vaccinia. Therefore, it is

possible that a future recombinant vaccinia vaccine

containing a variety of viral or bacterial genes could

serve multiple purposes, including immunity

against smallpox. However, those vaccinia vectors

engineered to be more attenuated120 should be considered questionable in their ability to protect

against variola virus. Neither would protection

against variola be expected from immunization

with other vertebrate poxviruses, especially those

of another genus such as Avipox.

Passive Immunoprophylaxis

Evidence indicates that vaccinia-immune globulin is of value in postexposure prophylaxis of smallpox when given (a) within the first week following

exposure and (b) concurrently with vaccination.121

However, the prophylactic use of VIG should be

carefully weighed vis-à-vis the risk of attenuating

the immune response to booster vaccination.

VIG is available in the United States from the

Drug Service of the CDC; the U.S. Army maintains

a supply for its own use. The dose for prophylaxis

or treatment is 0.6 mL/kg, administered intramuscularly. Administration immediately after or within

the first 24 hours of exposure would provide the

highest level of protection, especially in unvaccinated persons. VIG is prepared from the plasma of

repeatedly vaccinated persons. Development of

humanized monoclonal antibodies against neutralizing epitopes that are conserved between vaccinia

and variola viruses is a promising alternative to this

older, cumbersome, and expensive method of VIG

production.

Chemoprophylaxis and Chemotherapy

During the 1960s, methisazone (Marboran, no

longer available; then manufactured by Burroughs

Wellcome, Research Triangle Park, N. C.; also called

1-methylisatin 3’-β-thiosemicarbazone) received

extensive attention as an antiviral chemotherapy for

variola virus infections. Although some clinical

studies found only a trend toward decreased attack

rates,122,123 most evidence suggested that methisazone decreased both morbidity and mortality

when administered prophylactically to susceptible

contacts of patients with smallpox.124–127 Although

a variety of dosages and schedules were tested,

most experience was with 3 g administered orally,

at least two doses given 8 hours apart. Gastrointestinal intolerance (nausea and vomiting) significantly hampered both medication administration

and patient compliance.

Although clinical trials128,129 showed no therapeutic efficacy of thiosemicarbazones against smallpox,

anecdotal reports130,131 suggest some usefulness of

methisazone in treating progressive vaccinia.

Other antiviral compounds, such as rifampin132

and S-adenosylhomocysteine hydrolase inhibitors,133–135 have activity against vaccinia, and hence
Smallpox

553

may be useful in the prophylaxis or treatment of

smallpox. However, it should be noted that despite

their in vitro efficacy against vaccinia, neither cytosine arabinoside (Ara-C)136 nor adenine arabinoside (Ara-A)137 demonstrated benefit in treatmentof smallpox in small clinical studies.

SUMMARY

Despite the eradication of naturally occurring

smallpox and the availability of a vaccine, the potential weaponization of variola virus continues to

pose a military threat. This threat can be attributed

to the aerosol infectivity of the virus, the relative

ease of large-scale production, and an increasingly

Orthopoxvirus-naive human populace.

Although the fully developed cutaneous eruption of smallpox is unique, earlier stages of the rash

could be mistaken for varicella. Secondary spread

of infection constitutes a nosocomial hazard from

the time of onset of a smallpox patient’s enanthem

until scabs have separated. Quarantine with respiratory isolation should be applied to secondary contacts for 17 days after the exposure.

Vaccinia vaccine remains the preeminent countermeasure for preexposure prophylaxis against

smallpox. Vaccinia vaccination, vaccinia immune

globulin, and methisazone each possess some efficacy in postexposure prophylaxis.

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Chapter 28

VIRAL ENCEPHALITIDES

JONATHAN F. SMITH, PH.D.*; KELLY DAVIS, D.V.M.†; MARY KATE HART, PH.D.‡; GEORGE V. LUDWIG, PH.D.§;

DAVID J. MCCLAIN, M.D.¥; MICHAEL D. PARKER, PH.D.¶; AND WILLIAM D. PRATT, D.V.M., PH.D.**

INTRODUCTION

HISTORY AND SIGNIFICANCE

ANTIGENICITY AND EPIDEMIOLOGY

Antigenic Relationships

Epidemiology

STRUCTURE AND REPLICATION OF ALPHAVIRUSES

Virion Structure

Replication

PATHOGENESIS

CLINICAL DISEASE AND DIAGNOSIS

Venezuelan Equine Encephalitis

Eastern Equine Encephalitis

Western Equine Encephalitis

Differential Diagnosis of Alphavirus Encephalitis

Medical Management and Prevention

IMMUNOPROPHYLAXIS

Relevant Immune Effector Mechanisms

Passive Immunization

Active Immunization

SUMMARY

*Chief, Department of Viral Biology, Virology Division

†Lieutenant Colonel, Veterinary Corps, U.S. Army; Chief, Experimental Pathogenesis, Pathology Division

‡Department of Viral Pathogenesis and Immunology, Virology Division

§Chief, Department of Cell Culture/Hybridoma, Virology Division

¥Department of Viral Biology, Virology Division

¶Department of Viral Biology, Virology Division

**Lieutenant Colonel, Veterinary Corps, U.S. Army; Chief, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases,

Fort Detrick, Frederick, Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

562

INTRODUCTION

During the 1930s, three distinct but antigenically

related viruses were recovered from moribund

horses and were shown to be previously unrecognized agents of severe equine encephalitis. Western equine encephalitis (WEE) virus was isolated

in the San Joaquin Valley in California in 1930,1

 eastern equine encephalitis (EEE) virus in Virginia and

New Jersey in 1933,2,3 and Venezuelan equine encephalitis (VEE) virus in the Guajira peninsula of Venezuela in 1938.4

 By 1938, it was clear that EEE and

WEE viruses were also natural causes of encephalitis in humans,5–7 and naturally acquired human

infections with VEE virus were documented in Colombia in 1952 in association with an equine epizootic.8

 Although these viruses cause similar clinical syndromes in horses, the consequences of the

infections they cause in humans differ. EEE is the most

severe of the arboviral encephalitides, with case fatality rates of 50% to 70% and with neurological sequelae common in survivors. WEE virus appears to

be less neuroinvasive but has a pathology similar

to that of EEE in patients with encephalitis. In contrast, severe encephalitis is rare in humans infected

with VEE virus—except in children. In adults, the

usual VEE syndrome is an acute, febrile, incapacitating disease with prolonged convalescence.

The three viruses under discussion in this chapter are all members of the Alphavirus genus of the

family Togaviridae. As with all the alphavirus group,

VEE, EEE, and WEE are transmitted in nature by

mosquitoes and are maintained in cycles with various vertebrate hosts. Thus, the natural epidemiology of these viruses is controlled by environmental

factors that affect the relevant mosquito and reservoir host populations and their interactions. Of the

28 viruses currently classified within this group,

VEE, EEE, and WEE are the only viruses regularly

associated with encephalitis. Although these encephalitic strains are restricted to the Americas, as

a group, alphaviruses have worldwide distribution

and include other epidemic human pathogens such

as chikungunya virus (Asia and Africa), Mayaro

virus (South America), O’nyong-nyong virus (Africa), Ross River virus (Australia), and Sindbis virus (Africa, Europe, and Asia). These viruses cause

an acute febrile syndrome often associated with

debilitating polyarthritic syndromes.

Although natural infections with the encephalitic alphaviruses are acquired by mosquito bite, the

viruses are also highly infectious by aerosol. VEE

virus has caused more laboratory-acquired disease

than any other arbovirus. Since its initial isolation,

at least 150 laboratory infections that have resulted

in disease have been reported; most were known

or thought to be aerosol infections.9

 Before vaccines

were developed, most laboratories working with

VEE virus reported disease among their personnel.

In one incident at the Ivanovskii Institute in Moscow, USSR, which was reported in 1959, at least

20 individuals developed disease, most within

28 to 33 hours, after an accident in which a small

number of vials containing a minute amount of

lyophilized virus were dropped and broken in a

stairwell.10,11

Perhaps as a consequence of their adaptation to

dissimilar hosts in nature, the alphaviruses replicate readily, and generally to very high titers, in a

wide range of cell types and culture conditions in

vitro. Virus titers of 1 billion infectious units per

milliliter are not unusual, and the viruses are stable

in storage and in a variety of laboratory procedures.

Because of the relative ease with which these viruses can be manipulated in the laboratory, they

have long served as model systems by which to

study various aspects of virus replication, pathogenesis, induction of immune responses, and virus–

vector relationships. As a result, the alphaviruses

are well described and their characteristics well

defined.12,13

Therefore, the collective in vitro and in vivo characteristics of alphaviruses, especially the equine

encephalomyelitis viruses, lend themselves very

well to weaponization. This fact was recognized by

the designers of offensive biological warfare programs that were initiated before or during World

War II.14 Although other encephalitic viruses could

be considered as potential weapons (eg, the tickborne encephalitis viruses), few possess as many

of the required characteristics for strategic or tactical weapons development as the alphaviruses:

• These viruses can be produced in large

amounts in inexpensive and unsophisticated systems.

• They are relatively stable and highly infectious for humans as aerosols.

• Strains are available that produce either

incapacitating or lethal infections.

• The existence of multiple serotypes of VEE

and EEE viruses, as well as the inherent
Viral Encephalitides

563

difficulties of inducing efficient mucosal

immunity, confound defensive vaccine development.

The equine encephalomyelitis viruses remain as

highly credible threats today, and intentional release

as a small-particle aerosol, from a single airplane,

could be expected to infect a high percentage of individuals within an area of at least 10,000 km2. As

a further complication, these viruses are readily

amenable to genetic manipulation by modern recombinant deoxyribonucleic acid (DNA) technology. This capability is being used to develop safer

and more effective vaccines,15,16 but, in theory, could

also be used to increase the weaponization potential of these viruses.

HISTORY AND SIGNIFICANCE

Descriptions of epizootics in horses, characterized by encephalitis and death and likely to have

been caused by EEE virus, have been recorded as

early as 1831 in Massachusetts.17 However, it was

not until the outbreaks of EEE in Delaware, Maryland, and Virginia in 1933 and 1934 that the virus

was isolated, and not until a similar outbreak in

North Carolina in 1935 that birds were suspected

as the natural reservoir.18 The initial isolation of EEE

virus from a bird19 and from Culiseta melanura mosquitoes,20 the two major components of the EEE

natural cycle, were both reported in 1951. Outbreaks

of EEE virus have occurred in most eastern states

and in southeastern Canada but have been concentrated along the eastern and Gulf coasts. Although

only 211 cases of EEE in humans were reported21

between 1938 (the first documented human cases5)

and 1985, the social and economic impact of this

disease has been larger than might be expected because of the high fatality rate, equine losses, extreme

concern among individuals living in endemic areas during outbreaks, and the surveillance and

mosquito-control measures required. Isolation of

EEE virus from Aedes albopictus mosquitoes, which

have recently been introduced into EEE endemic

areas in the United States, has heightened concern

because of the opportunistic feeding behavior of

these mosquitoes as well as their apparent high

vector competence for EEE virus.22

The initial isolation in 1930 of WEE virus from

the brain tissues of a horse with encephalitis was

made in the midst of a large and apparently unprecedented epizootic in California, which involved

at least 6,000 horses and with approximate mortality of 50%.1

 Cases of human encephalitis in California were not linked to WEE until 1938, when the

virus was isolated from the brain of a child. During

the 1930s and 1940s, several other very extensive

epizootics occurred in western and north-central

states, as well as Saskatchewan and Manitoba,

Canada, which affected large numbers of equines

and humans. For example, it has been estimated

that during 1937 and 1938, more than 300,000

equines were infected in the United States, and in

Saskatchewan, 52,500 horse infections resulted in

15,000 deaths.23,24 In 1941, unusually high numbers

of human cases were reported: 1,094 in Canada and

2,242 in the United States. The attack rate in these

epidemics ranged from 22.9 to 171.5 per 100,000,

with case fatality rates of 8% to 15%.24

In the early 1940s, workers isolated WEE virus

from Culex tarsalis mosquitoes25 and demonstrated

the presence of specific antibody to WEE virus in

birds,26 suggesting that birds are the reservoirs of

the virus in nature. The annual incidence of disease

in both equines and humans continues to vary

widely, as would be expected of an arthropod-borne

disease, and significant epidemics occurred in 1952,

1958, 1965, and 1975.24

The initial isolation of VEE virus was made during investigations of an epizootic occurring in

horses in Venezuela in 1936, and the isolate was

shown to be antigenically different from the EEE

and WEE viruses isolated previously in the United

States.4,27 Over the next 30 years, many VEE outbreaks were reported among horses, and it soon

became apparent that humans were also infected

in large numbers in association with these epizootics.28 Most of those infected recovered after suffering an acute, febrile episode, but severe disease with

encephalitis and death also occurred, mostly in children and older individuals. In the 1960s, major epizootics occurred in Venezuela, Colombia, Peru, and

Ecuador, and apparently spread to Central America

in 1969.29 These and previous epizootics were associated with immeasurable human suffering, especially among rural people, who suffered not only

from disease but also from the loss of their equines,

which were essential for transportation and agriculture. Between 1969 and 1971, epizootics were

reported in essentially all of Central America and

subsequently continued north to Mexico and into

Texas. The most recent major epizootic occurred in

Venezuela and Colombia in 1995.30
Medical Aspects of Chemical and Biological Warfare

564

Between active epizootics it was not possible to

isolate the equine virulent viruses. During the 1950s

and 1960s, however, several other antigenically different VEE strains were isolated from different geographical areas; these were attenuated in equines

and persisted indefinitely in endemic areas. These

enzootic strains could be differentiated antigenically not only among themselves but also from the

epizootic strains,31 they utilized different mosquito

vectors than the epizootic strains,32 and they utilized rodents as reservoir hosts.33 Many of the enzootic strains, however, proved equally pathogenic

for humans.

Therefore, within 30 years of the initial isolation

of the EEE, WEE, and VEE viruses, an essentially

accurate picture had emerged with respect to their

endemic and epidemic behavior, arthropod vectors,

reservoir hosts, and the diseases produced. Although not yet understood at the molecular level

(this would come with the techniques of molecular

biology that were developed during the 1970s and

1980s), these three viruses were reasonably well

described as agents of disease, and the basic assays

for their manipulation and production were known.

The development of this body of knowledge occurred during the same period of war and political

instability that fostered the establishment of biological warfare programs in the United States34 and elsewhere, and it was evident that the equine encephalomyelitis viruses were preeminent candidates for

weaponization. The viruses were incorporated into

these programs for both potential offensive and

defensive reasons. In 1969, the offensive biological

warfare program in the United States was completely disestablished and all stockpiles destroyed14

by executive order, which stated:

The United States shall renounce the use of lethal

biological agents and weapons and all other methods of biological warfare. The United States shall

confine its biological research to defensive measures such as immunization and safety measures.35

However, defensive concerns remained, and efforts within the defensive program in the 1960s and

1970s produced four vaccines for the encephalomyelitis viruses: live-attenuated (TC-83) and formalin-inactivated (C84) vaccines for VEE, and formalininactivated vaccines for EEE and WEE. These vaccines are used under Investigational New Drug

(IND) status for at-risk individuals, are distributed

freely under the provisions of the IND, and are recommended for use by any laboratory working with

these viruses.9

 Although these vaccines have proven

quite useful, they have certain disadvantages

(which are discussed later in this chapter), and second-generation vaccines are under development.16

ANTIGENICITY AND EPIDEMIOLOGY

Antigenic Relationships

The American equine encephalitides comprise

three virus complexes, VEE, EEE, and WEE, which,

based on their serologic cross-reactivity, have been

grouped with four additional virus complexes into

the Alphavirus genus (Table 28-1).13

Venezuelan Equine Encephalitis Virus Complex

The VEE virus complex consists of six closely

related subtypes that manifest different characteristics with respect to ecology, epidemiology,

and virulence for humans and equines (Table

28-2). The IA/B and C varieties are commonly

referred to as epizootic strains. These strains have

been responsible for extensive epidemics in North,

Central, and South America and are highly pathogenic for humans and equines. All of the epizootic

strains are exotic to the United States and have been

isolated from natural foci in the world only once

since 1973.36 Subtypes II, III, IV, V, and VI and varieties ID, IE, and IF are referred to as the enzootic

strains.37–42

Like the epizootic strains, the enzootic strains

may cause disease in humans, but they differ from

the epizootic strains in their lack of virulence for

equines. The enzootic viruses are commonly isolated in specific ecological habitats, where they circulate in transmission cycles primarily involving rodents and Culex mosquitoes of the Melanoconion

subgenus.43–45 Infection of equines with some enzootic subtypes leads to an immune response capable of protecting the animals from challenge with

epizootic strains.46 Limited data, acquired following laboratory exposures, suggest that cross-protection between epizootic and enzootic strains may be

much less pronounced in humans.47–49

Eastern Equine Encephalitis Virus Complex

The EEE virus complex consists of viruses in essentially two antigenically distinct forms: the North

American and the South American variants.50 The
Viral Encephalitides

565

TABLE 28-1

ANTIGENIC CLASSIFICATION OF ALPHAVIRUSES

Adapted with permission from Peters CJ, Dalrymple JM. Alphaviruses. In: Fields BM, Knipe DM, eds. Virology. 2nd ed, Vol 1. New

York, NY: Raven Press; 1990: 716.

Table 28-1 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden

Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the

publisher named in the figure legend for permission to use this illustration in any type of publication media.
Medical Aspects of Chemical and Biological Warfare

566

TABLE 28-2

THE VENEZUELAN EQUINE ENCEPHALOMYELITIS COMPLEX

two forms can be distinguished readily by hemagglutination-inhibition (HI) tests. All North American and Caribbean isolates show a high degree of

genetic and antigenic homogeneity; they are distinct

from the South American and Central American isolates, which tend to be more heterogeneous.51,52

EEE is endemic to focal habitats ranging from

southern Canada to northern South America. The virus has been isolated as far west as Michigan but is

most common along the eastern coast of the United

States between New England and Florida. Enzootic

transmission of EEE virus occurs almost exclusively

between passerine birds (ie, the perching songbirds)

and the mosquito Culiseta melanura. Because of the

strict ornithophilic feeding behavior of this mosquito, human and equine disease requires the involvement of more general feeders, known as bridging vectors, such as members of the genera Aedes and

Coquilletdia. Mosquito vectors belonging to Culex

species are thought to play a role in maintaining

and transmitting South American EEE strains.53

Western Equine Encephalitis Virus Complex

Six viruses—WEE, Sindbis, Y 62-63, Aura, Fort

Morgan, and Highlands J—make up the WEE comSources that contain original descriptions of or additional information about this strain: (1) Young NA, Johnson KM. Antigenic

variants of Venezuelan equine encephalitis virus: Their geographic distribution and epidemiologic significance. Am J Epidemiol.

1969;89:286. (2) Walton TE. Virulence properties of Venezuelan equine encephalitis virus serotypes in horses. In: Venezuelan Encephalitis: Proceedings of the Workshop-Symposium on Venezuelan Encephalitis Virus, Washington, DC, 14–17 Sep 1971. Washington, DC: Pan American Health Organization; 1972:134. PAHO Scientific Publication 243. (3) Johnson KM, Shelokov A, Peralta

PH, Dammin GJ, Young NA. Recovery of Venezuelan equine encephalomyelitis virus in Panama: A fatal case in man. Am J Trop

Med Hyg. 1968;17:432–440. (4) Walton TE, Grayson MA. Venezuelan equine encephalitis. In: Monath TP, ed. The Arboviruses: Epidemiology and Ecology. Vol 4. Boca Raton, Fla: CRC Press; 1988: 203–231. (5) Chamberlain RW, Sudia WD, Coleman PH, Work TH.

Venezuelan equine encephalitis virus from South Florida. Science. 1964;145:272. (6) Shope RE, Causey OR, de Andrade AHP, Theiler

Table 28-2 is not shown because the copyright permission granted to the Borden Institute, TMM, does not allow the Borden

Institute to grant permission to other users and/or does not include usage in electronic media. The current user must apply to the

publisher named in the figure legend for permission to use this illustration in any type of publication media.
Viral Encephalitides

567

plex. Several antigenic subtypes of WEE virus have

been identified, but their geographical distributions

overlap.36 Most of the members of the WEE complex

are distributed throughout the Americas, but subtypes

of Sindbis virus and Y 62-33 have strictly Old World

distributions.13 The New World WEE complex viruses

can be distinguished readily by neutralization tests.

In addition, WEE complex viruses isolated in the western United States (ie, WEE) are antigenically and

genetically distinct from those commonly found in

the eastern United States (ie, Highlands J).52,54

The best studied member of the WEE virus complex—in terms of its epidemiology—is WEE virus

itself. The virus is maintained in cycles involving

passerine birds and the mosquito Culex tarsalis.

Humans (and equines) become involved only tangentially and are considered to be dead-end hosts,55

indicating that they do not normally contribute

to further spread of the virus in nature. Recent

studies have isolated WEE virus from male Aedes

dorsalis mosquitoes reared in the laboratory from

larvae collected in salt marsh habitats.56 These data

indicate that vertical transmission (ie, direct transmission from one generation to the next) in mosquitoes

may be an important mechanism for persistence and

overwintering in endemic areas.

Epidemiology

The epidemiology of the equine encephalitides

in humans is closely tied to the ecology of these viruses in naturally occurring endemic foci. Most

commonly, human involvement occurs following

intrusion into geographical regions where natural

transmission cycles are in progress, or following perturbation of those cycles by environmental changes57

or the addition of other vectors.22 The dramatic exception to this is epizootic VEE, in which the spreading waves of the epizootic among equines can move

rapidly over large distances, and humans become

infected by mosquitoes that have fed on viremic

equines. The high levels of viremia in equines infected with epizootic VEE make them efficient amplifying hosts, with the result that equine infections

normally precede human infections by days to

weeks.58 Medical officers should view with some suspicion evidence of widespread human VEE infections

outside of endemic areas, in the absence of mosquito

vectors, or in the absence of equine disease, as this

combination of circumstances could indicate an

unnatural release of virus into the environment.

Enzootic VEE virus subtypes, as described above,

are maintained quite efficiently in transmission

cycles involving mainly mosquitoes belonging to

the subgenus Melanoconion. These mosquitoes often occur in very humid localities with abundant

open spaces—such as sunny, swampy pastures cut

by slowly flowing streams. The mosquitoes are

ground feeders, seldom found higher than 8 m

above ground, and prefer feeding on mammals

rather than birds.59 In part because their ecologies

are similar to that of the mosquito vector’s, grounddwelling rodents serve as the primary vertebrate

hosts for the enzootic forms of VEE virus. Following infection, these animals develop viremias of

sufficient magnitude and duration to infect mosquitoes during their acquisition of a blood meal.60

Other animals such as bats and certain birds may

play a secondary role.61

Seroprevalence rates among human populations

living in or near endemic VEE areas vary but can

approach 100%, suggesting that continuous transmission occurs.58 However, virus activity within

endemic zones can also be highly focal. In one incident at the Fort Sherman Jungle Operations Training Center in the Panama Canal Zone in December

1967, 7 of 12 U.S. soldiers camped in one area developed VEE disease within a 2-day period, but

another group camped only a few yards away

showed no disease.62,63

The incidence of disease during epizootics also

varies, but it is often very high. During an outbreak

in Venezuela, attack rates of 119 per 1,000 inhabitants per month were reported.64 Following an epizootic in Guatemala and El Salvador, overall seroprevalence was estimated at 20%.65

Unlike the enzootic strains, the fate of the epizootic

strains during interepidemic periods is unclear. Of

several theories on how epizootic strains arise, the

most appealing suggests that they evolve by genetic

drift from enzootic strains. Results from oligonucleotide fingerprinting and sequence analysis of I-D isolates from Colombia and Venezuela reveal a close similarity to the epizootic strains, suggesting that the

equine virulent epizootic strains arise naturally

from variants present in populations of I-D virus.66,67

While the genetic evidence suggests that genetic

drift of enzootic strains may lead to the development of epizootic strains, ecological data suggest

that there is also a strong selective pressure to maintain the enzootic genotype in certain habitats. The

enzootic VEE vector Culex (Melanoconion) taeniopus

is fully susceptible to both I-AB and I-E strains following intrathoracic inoculation. Orally exposed

mosquitoes, however, are fully competent vectors

of the enzootic strain, but they fail to develop disseminated infection and transmit epizootic virus.32,68

This observation suggests that genetic drift of en-
Medical Aspects of Chemical and Biological Warfare

568

zootic strains may be selected against with this combination of vector and virus. Mosquito resistance

to epizootic strains of VEE virus is rare; epizootic

strains have been isolated from a large number of

mosquito species, and many have been shown to

be efficient vectors.69 Thus, host switching from

enzootic to epizootic vectors may be an important

factor in the evolution of epizootic VEE strains. The

introduction of mosquito species into previously

unoccupied geographical ranges (eg, Aedes albopictus into North America) may, therefore, offer the

opportunity for epizootic strains to reemerge.

A major outbreak of epizootic VEE occurred in

the late 1960s and early 1970s. Epizootic virus first

reached North America in 1966 but did not reach

the United States until 1971. Studies of this epizootic

demonstrated that the virus easily invaded territories in which it was formerly unknown,64 presumably as a result of (1) the availability of large numbers of susceptible equine amplifying hosts and (2)

the presence of competent mosquito vectors. The

initial outbreak in North America, and the first recorded such epizootic, occurred in 1966 in Tampico,

Mexico, involving approximately 1,000 equines.

By the end of 1969 and the beginning of 1970, the

outbreak had expanded to such an extent that the

Fig. 28-1. This photograph was taken in 1995 near Buena

Vista, Colombia. During large Venezuelan equine encephalitis (VEE) epizootics, typical morbidity rates among unvaccinated equines are 40% to 60%, with at least half of the

affected animals progressing to lethal encephalitis. Note the

disruption of the ground surface, which is caused by the

characteristic flailing or swimming syndromes of moribund

animals. Although clinically indistinguishable from the

syndromes produced by eastern equine encephalitis (EEE)

and western equine encephalitis (WEE) viruses, the capability of VEE to initiate explosive and rapidly expanding

epizootics makes reliable diagnostic tests essential for the initiation of appropriate veterinary and public health measures.

Fig. 28-2. This photograph was taken in 1995 near Maicao,

Colombia. Equine vaccination is the most effective means

available to prevent Venezuelan equine encephalitis (VEE)

epizootics as well as to control emerging outbreaks. Equines

are the major amplifying hosts, and maintaining a high rate

of immunity in the equine population will largely prevent

human infection with the epizootic strains of VEE. Both

inactivated and live-attenuated vaccines are available for

veterinary use, but the ability of the live-attenuated vaccine to induce immunity in 7 to 10 days with a single inoculation makes it the only practical vaccination strategy

in the face of an outbreak. Other measures used to control

outbreaks include using insecticides to reduce mosquito

populations and prohibiting the transportation of equines

from affected areas.

Mexican government requested the TC-83 vaccine

from the U.S. Army through the U.S. Department

of Agriculture.70 Despite the immunization of nearly

1 million equines, the epizootic continued to spread

and reached the United States in June 1971. The

nature of the virus and the number of human

and equine cases prompted the secretary of agriculture to declare a national emergency on July 16,

1971.71 Subsequent immunization of over 2 million

horses and unprecedented mosquito abatement efforts eventually stopped the epizootic before it was

able to spread from Texas. Epizootic VEE has not

been isolated in the United States since the 1971 outbreak.

The first large outbreak since the 1969–1971 epizootic occurred in 1995 (Figures 28-1 and 28-2). The

epizootic began in northwestern Venezuela and

spread across the Guajira peninsula into northeastern Colombia. An estimated 75,000 to 100,000 humans were infected, with more than 20 deaths reported. This outbreak was caused by an IC strain

of VEE virus. By sequence analysis, this strain

proved to be essentially identical to a virus that

caused an outbreak in Venezuela in 1963.30
Viral Encephalitides

569

STRUCTURE AND REPLICATION OF ALPHAVIRUSES

Virion Structure

The alphavirus virion, a spherical particle approximately 60 to 65 nm in diameter, is typically

composed of three different structural proteins enclosing a single molecule of single-stranded RNA.

The RNA genome is packaged within an icosahedral nucleocapsid, which is constructed from multiple copies of a single species of capsid (C) protein

(Figure 28-3). The nucleocapsid is, in turn, surrounded by a lipid envelope that is derived from

areas of the host cell plasma membrane that had

previously been modified by the insertion of two

viral glycoproteins. These envelope glycoproteins,

E1 and E2, form heterodimers that associate further

into trimers72,73 to form the short spikes on the surface of the virion. The glycoproteins are the primary

targets of the neutralizing antibody response74 and

are the determinants of tropism and virulence.75

Semliki Forest virus contains a third glycoprotein,

E3, which is associated with the E1–E2 dimers on

the virion surface. With other alphaviruses, the E3

protein is shed from the infected cell and does not

appear in the mature virion.

Replication

Viral Infection. The infection cycle is initiated

when the glycoprotein spikes on the virion bind to

receptors on the cell surface. The virus is localized

initially to coated pits, where it is engulfed in a

coated vesicle and transported to the endosomal

compartment within the interior of the cell. A decrease in the pH in the interior of the vesicle induces a conformational change in the glycoprotein

spikes, and rearrangement of the E1 glycoprotein

mediates fusion of the virion envelope with the

endosomal membrane.76 This fusion results in the

release of the nucleocapsid into the cytoplasm,

where disassembly of the nucleocapsid releases the

viral RNA genome to the synthetic apparatus of the

cell.

Genomic RNA. The viral genome is a positivestranded RNA of approximately 11,700 nucleotides

and has the structural features of messenger RNA

(ie, mRNA, a 5’ methylated cap [m7GpppA] and a

poly-A tract at the 3’ end).77 As a complete and functional mRNA, genomic RNA purified from virions

is fully infectious when artificially introduced (ie,

transfected) into susceptible cells. Similarly, RNA

transcribed from a full-length complementary DNA

(cDNA) clone of an alphavirus is also infectious,

and it is this property that allows genetic manipulation of these viruses. Mutations introduced into a

cDNA clone by site-directed mutagenesis will be

reflected in the RNA transcribed from the altered

clone and in the virus obtained from transfected

cells. These procedures are being utilized to develop

Fig. 28-3. Structure of an alphavirus. Shown is the threedimensional reconstruction of Sindbis virus at 28 Å resolution from computer-processed images taken by electron cryomicroscopy. (a) The original electron micrograph

shows virus particles in vitreous ice. (b) The surface view

of the virus shows details of the 80 trimeric spikes, which

are arranged in a T=4 icosahedron. Each spike protrudes

50 Å from the virion surface and is believed to be composed of three E1–E2 glycoprotein heterodimers. (c) The

cross-sectional view shows the outer surface spikes (yellow) and the internal nucleocapsid (blue), composed

of the capsid and viral RNA. The space between the

spikes and the nucleocapsid would be occupied by the

lipid envelope. The green arrows mark visible points

of interaction between the nucleocapsid and transmembranal tails of the glycoprotein spikes. (d) The

reconstructed capsid also exhibits a T=4 icosahedral

symmetry. Computer models: Courtesy of Angel M.

Paredes, Cell Research Institute and Department of

Microbiology, The University of Texas at Austin, Austin,

Tex. Similar but not identical versions of these computer

models were published in Paredes AM, Brown DT,

Rothnagel R, et al. Three-dimensional structure of a membrane-containing virus. Proc Natl Acad Sci USA. 1993;

90:9095–9099.
Medical Aspects of Chemical and Biological Warfare

570

improved vaccines,16 but conceivably could be used

also to enhance specific characteristics required for

weaponization.

Glycoprotein Synthesis. The alphavirus genome

contains two protein coding regions. The 5’ proximal 7,500 nucleotides encode a 220,000-dalton precursor polypeptide, which is proteolytically processed to produce four components of the viral RNA

polymerase. The polymerase genes are followed by

a second coding region of approximately 3,800

nucleotides, which contains the information that

directs the synthesis of the viral structural proteins.

Soon after release of the viral genome from the

nucleocapsid, the 5’ 7,500 nucleotides of the genome RNA are translated to produce the viral RNA

polymerase. Early in infection, the incoming viral

genome is also utilized as a template for the synthesis of a negative-stranded 45S RNA, identical in

length to the genome RNA but of opposite polarity.

The negative-stranded 45S RNA subsequently

serves as a template for the synthesis of additional

genomic RNA. The negative-stranded RNA is also

utilized as a template for transcription of a 26S

subgenomic mRNA, which is identical to the 3’

third of the genome. The 26S RNA is capped and

polyadenylated, and is then translated to yield a

precursor polypeptide that is proteolytically processed by cotranslational and posttranslational

cleavages to produce the viral structural proteins.

The order of the structural proteins within the precursor is C-E3-E2-6K-E1.

As the 26S mRNA is translated, the C protein is

produced first and catalyzes its own cleavage from

the nascent polypeptide soon after the ribosome

transits into the sequences that encode E3. After

release of the C protein, the free amino terminus of

E3 is bound to the membranes of the rough endoplasmic reticulum. As the synthesis of nascent E3

and E2 continues, the polypeptide is translocated

into the lumen of the endoplasmic reticulum, where

oligosaccharides and fatty acids are added.78 A domain of hydrophobic amino acids near the carboxyl

terminus of E2 inhibits further transmembranal

movement so that the last 30 to 40 amino acids of

the E2 polypeptide remain exposed on the cytoplasmic side of the membrane. It is thought that the 6K

polypeptide serves as an internal signal for membrane insertion of the second glycoprotein, E1, and

is subsequently cleaved from both E2 and E1 by the

signal peptidase.79 A hydrophobic anchor sequence

present near the carboxyl terminus of E1 secures

the protein in the membrane.

Budding and Release of Progeny Virus Particles.

Soon after synthesis, the precursor E2 (pE2) and E1

interact to form multimeric complexes,80 which are

then transported through the Golgi apparatus,

where the final modifications of the oligosaccharide

are made. The precursor pE2 is cleaved to the mature E2 and E3 glycoproteins soon after the glycoproteins leave the Golgi apparatus,81 and the mature viral spikes assume an orientation in the plasma

membrane with the bulk of the E2 and E1 polypeptides exposed on the exterior surface of the cell. Final

assembly, or budding, of progeny virus particles takes

place exclusively at the plasma membrane in vertebrate cells,82 whereas in arthropod cells, budding

can also occur at intracellular membranes.83

Budding is initiated when intracellular nucleocapsids bind to the 30– to 40–amino acid cytoplasmic domain of the E2 glycoprotein,84–86 inducing the

formation of a locally ordered array of glycoprotein spikes and excluding most of the cellular membrane proteins from the region. Additional lateral

associations between the individual spikes stabilize

the lattice and promote additional E2–C protein

interactions. The growing lattice is thought to draw

the membrane around the nucleocapsid, completing the process of envelopment with the release of

the spherical virus particle.

Maximal amounts of virus are typically produced

from mammalian cells within 8 to 10 hours after

infection, and disintegration of the infected cell is

likely due to programmed cell death (apoptosis)

rather than direct effects of the virus on cellular

function.87 In contrast, alphaviruses initially replicate to high titer in arthropod cells with little or no

evidence of cytopathology. The surviving cells continue to produce lesser amounts of virus, often for

weeks or months. The ability of the virus to replicate without causing cell death in arthropod cells

may be critical for maintenance of the virus in the

mosquito vector in nature.

PATHOGENESIS

In humans, the pathogenesis of VEE, EEE, and

WEE infections acquired by aerosol—the route of

biological defense concern—is unknown. Indeed,

little is known of the pathogenesis following natural vector-borne infections of humans, mainly because of the limited availability of autopsy material. Much of the information on VEE pathogenesis

in humans is based on a histological review of 21

human fatalities from the 1962–1963 VEE epidemic

in Zulia, Venezuela.88 With few exceptions, the his-
Viral Encephalitides

571

topathological lesions in these cases were comparable to those observed in experimentally infected

animals. Tissues that were commonly affected in

both humans88 and animals89–97 include those of the

lymphoid and reticuloendothelial systems and the

central nervous system (CNS). Interestingly, widespread hepatocellular degeneration and interstitial

pneumonia, not ordinarily seen in experimental

animals, were frequent histological findings in these

cases of severe human disease.

The clinical and pathological responses of the

host to VEE infection are highly dependent on a number of host and viral factors. These factors include

• the species, immune status, and age of the

host animal;

• the route of infection; and

• the strain and dose of virus.

Most of the existing experimental data have come

from studies using rodent models challenged subcutaneously with the Trinidad donkey (TrD) strain

of VEE, an epizootic IA serotype virus. The lymphatic system and the CNS appear to be universal

target organs in experimental animal models, as was

seen in humans. However, the relative degree of

injury caused by the TrD strain of VEE to these tissues varied among the species. TrD caused only

mildly severe and reversible lesions to the lymphoid

organs in the mouse and monkey,89,90 but was extremely destructive and irreversible to those organs

in the guinea pig90 and hamster.89,90,94,97 The virus

causes lymphatic necrosis within the nodes associated with the gut; normal gut flora escape, leading

to systemic bacterial infections. The severity of the

viral infection in the lymphoreticular tissues (in

particular the Peyer’s patches of the distal intestine

in hamsters) appears to contribute to the bacteremia

and endotoxic shock syndrome that lead to early

death.97

The effects of virus infection with the TrD strain

of VEE on the CNS also demonstrated considerable

species variability. Mice exhibited a severe paralytic

episode prior to death from diffuse encephalomyelitis.89,90 Monkeys, however, showed few if any

clinical signs of CNS involvement following peripheral inoculation, and only modest pathological

changes in the CNS (found mainly in the thalamus,

hypothalamus, and olfactory areas of the brain).90

However, the extent of neuroinvasion in animals is

also a function of both the strain of VEE and the

route of infection. Cynomolgus monkeys infected

by the intranasal route developed immunoglobulin (Ig) M and IgG antibodies in the cerebrospinal

fluid (CSF) and showed moderate areas of perivascular cuffing and nodular and diffuse gliosis, especially in the cortex and hypothalamus.98 A Colombian epizootic strain of VEE given by the aerosol

route caused severe clinical and pathological CNS

signs and resulted in death in approximately 35%

of rhesus monkeys.91 Mice and cynomolgus monkeys challenged intracerebrally with TrD or a serologically related strain of VEE developed severe and

lethal neurological signs with moderate to severe

brain histopathology.98

VEE virus can infect the CNS directly through

the olfactory nervous system. In rhesus monkeys

intranasally inoculated with VEE virus, the virus

gained access to the olfactory bulb within 24 hours

after infection and before the onset of viremia, suggesting direct neuroinvasion via olfactory neurons.99 However, in inoculated monkeys whose olfactory nerves had been surgically removed, VEE

virus was nonetheless able to reach the olfactory

bulb by 36 hours after infection, presumably by the

vascular route. Although the olfactory bulb and

tract were sites of early viral replication, viral infection did not appear to spread to the rest of the

brain along the neural tracts in these monkeys. In

1991, researchers100 concluded from studies carried

out in outbred mice that aerosolized VEE virus can

enter the CNS of nonimmunized mice by both the

vascular and the olfactory pathways. Morphologic

evidence of virus multiplication was observed in

olfactory epithelial cells and in secretory cells of

Bowman’s glands. These researchers suggest two

possible routes for viral spreading from the nasal

mucosa: (1) virus entry into the blood stream

through the fenestrated capillaries of the olfactory

zone, with subsequent systemic infection; and (2)

axonal transport along the olfactory nerves, allowing direct virus entry into the olfactory bulbs.

In more recent studies, BALB/c mice were challenged either subcutaneously or by aerosol with the

V3000 strain16 of VEE, and brain and nasal tissues

taken from animals sacrificed at daily intervals were

examined immunocytochemically for viral antigen.101 In mice challenged by aerosol, both the nasal olfactory epithelium and the olfactory nerve

axon bundles in the underlying connective tissue

were immunoreactive for VEE virus antigen within

24 hours after infection (Figure 28-4). Within 48

hours after infection, olfactory nerves, nasal-associated lymphoid tissue (NALT), and olfactory bulbs

were immunoreactive (Figure 28-5). In a bilaterally

symmetrical pattern, the prepiriform area and the

piriform cortex were also immunoreactive by 48

hours after infection. Other areas of the brain were
Medical Aspects of Chemical and Biological Warfare

572

Fig. 28-5. Olfactory bulb, BALB/c mouse, 2 days after

exposure to aerosolized VEE virus. Note immunoreactive cells. Alkaline phosphatase-labeled streptavidin method using rabbit antiserum to VEE virus

(Mayer’s hematoxylin counterstain, original magnification x 150).

Fig. 28-4. Nasal tissue, BALB/c mouse, 2 days after exposure to aerosolized VEE virus. Note immunoreactive

olfactory epithelium and olfactory nerves. Alkaline phosphatase-labeled streptavidin method using rabbit antiserum to VEE virus (Mayer’s hematoxylin counterstain,

original magnification x 300).

immunoreactive at 4 days after infection. In subcutaneously challenged mice, the olfactory nerves and

nasal olfactory epithelium were not immunoreactive at any time, and the olfactory bulbs, prepiriform

area and piriform cortex, and NALT were not positive until 3 days after infection. By day 4 after infection, subcutaneously challenged mice also had

immunoreactive cells in other areas of the brain.

These immunocytochemical findings are consistent

with previous studies carried out in rodents and

primates; they indicate not only that aerosolized

VEE virus may enter the mouse brain by means of

the olfactory nerves but also that this process is very

rapid. The efficiency with which this process occurs

with the equine encephalomyelitis viruses will put

very high demands on the vaccines used for

immunoprophylaxis (vaccines are discussed later

in this chapter).

CLINICAL DISEASE AND DIAGNOSIS

The three equine encephalomyelitis virus complexes within the Alphavirus genus—EEE, WEE, and

VEE—are also recognized for their potential for

neuroinvasion and encephalitis in humans, sometimes in epidemic proportions. However, many of

the infections caused by these viruses are manifested as systemic viral febrile syndromes, and infections by EEE and WEE viruses may remain subclinical. Furthermore, these alphaviruses vary

markedly in both their neurotropism and the severity of their neurological sequelae. Depending on the

virus, patients presenting with the general syndrome of alphavirus encephalitis have a varying

combination of fever, headache, confusion, obtundation, dysphasia, seizures, paresis, ataxia, myoclonus, and/or cranial nerve palsies.

Venezuelan Equine Encephalitis

The IA, IB, and IC variants of VEE virus are

pathogenic for equines and have the capacity for

explosive epizootics with epidemic human disease.

Epidemics of VEE affecting 20,000 to 30,000 people,

or more, have been documented in Venezuela and

Ecuador. In contrast to the other alphavirus encephalitides, EEE and WEE, epizootic strains of VEE

are mainly amplified in equines, rather than birds,

so that equine disease normally occurs prior to reports of human disease. Enzootic VEE strains (variants ID, IE, and IF and subtypes II, III, IV, V, and

VI) are not recognized as virulent for equines, but

disease has been documented with most of these

variants in humans who reside in or move into enzootic foci, or after laboratory infections (see Table

28-2). The resulting syndromes appear to be similar, if not indistinguishable, from the syndrome produced by epizootic variants, which ranges from undifferentiated febrile illness to fatal encephalitis.

Following an incubation period that can be as

short as 28 hours10 but is usually 2 to 6 days, patients typically develop a prostrating syndrome of

chills, high fever (38°C–40.5°C), headache, and mal-
Viral Encephalitides

573

aise.102 Photophobia, sore throat, myalgias, and

vomiting are also common symptoms. Frequent

signs noted on physical examination include conjunctival injection, erythematous pharynx, and

muscle tenderness. Although essentially all human

infections with VEE virus are symptomatic,62,63 only

a small percentage manifest neurological involvement.103 In one epidemic, it was estimated that the

ratio of encephalitis to infections is less than 0.5%

in adults, although possibly as high as 4% in children.104 Mild CNS involvement is evidenced by lethargy, somnolence, or mild confusion, with or without

nuchal rigidity.105 Seizures, ataxia, paralysis, or coma

herald more severe CNS involvement. In children with

overt encephalitis, case fatalities range as high as 35%

compared with 10% for adults.106 However, for those

who survive encephalitic involvement, neurological

recovery is usually complete.107 School-age children

are believed to be more susceptible to a fulminant

form of disease, in which depletion of lymphoid tissues is prominent and which follows a lethal course

over 48 to 72 hours.88,108,109

In the first 3 days of illness, leukopenia and elevated serum glutamic-oxaloacetic transaminase

(SGOT) are common. For those with CNS involvement, a lymphocytic pleocytosis of up to 500 cells

per microliter will be observed in the CSF. The CSF

pleocytosis may acutely be polymorphonuclear but

soon becomes predominantly lymphocytic.

Specific diagnosis of VEE can be accomplished

by virus isolation, serologic testing, or both.110 During the first 1 to 3 days of symptoms of nonspecific

febrile illness, VEE virus may be recovered from

either the serum or the nasopharynx.111 Despite the

theoretical possibility of person-to-person transmission of virus present in the nasopharynx, no evidence of such occurrences has been reported. Identification of the VEE subtype of an isolate involved

can be accomplished by cross-neutralization tests.

HI, enzyme-linked immunosorbent assay (ELISA),

or plaque reduction neutralization (PRN) antibodies appear as viremia diminishes. Complement-fixing (CF) antibodies make their appearance later

during convalescence. VEE IgM antibodies are

present in acute phase sera,63 and it has been reported that the VEE IgM tests do not react with sera

from patients with EEE or WEE.112 Since patients

with encephalitis typically come to evaluation later

in the course of clinical illness, virus is recovered

less often from them,112 and they usually have serum antibody by the time of clinical presentation.113

Immunity after infection is probably lifelong to

the homologous serotype, but cross-immunity is

weak or nonexistent to heterologous serotypes.47–49

Thus, when viewed either as an endemic disease

threat or as a potential biological warfare threat,

adequate immunization will require polyvalent

vaccines.

Eastern Equine Encephalitis

EEE is maintained in a natural transmission cycle

between Culiseta melanura mosquitoes and passerine birds in swampy and forested areas. EEE outbreaks are typically recognized when severe equine

or human encephalitis occurs near such areas.114

During vector-borne EEE epidemics, the incidence

of human infection is low (< 3% of the population

at risk),115 and the neurological attack rate in one

outbreak was estimated as 1 in every 23 cases of

human infection.116 However, the effect on morbidity and mortality of aerosol-acquired EEE infection

(which would be the expected route of infection in

a biological warfare offensive) is unknown. The incubation period in humans varies from 5 to 15 days.

Adults typically exhibit a febrile prodrome for up

to 11 days before the onset of neurological disease117;

however, illness in children exhibits a more sudden onset.118 Viremia occurs during the febrile prodrome,119 but is usually undetectable by the time

clinical encephalitis develops, when HI and neutralizing antibodies become evident.120 Despite the

development of a prompt and neutralizing humoral

response, virus is not eradicated from the CNS, and

progressive neuronal destruction and inflammation

continue.

EEE is the most severe of the arboviral encephalitides, with high mortality and severe neurological

sequelae.121 During outbreaks of EEE, the attack,

morbidity, and fatality rates are highest in young

children122 and the elderly.123 Case fatality rates are

estimated to be from 50% to 75%, but asymptomatic infections and milder clinical illness are certainly underreported. The illness is characterized

by rapid onset of high fever, vomiting, stiff neck,

and drowsiness. Children frequently manifest generalized, facial, or periorbital edema. Motor involvement with paresis is common during the acute

phase of the illness. Major disturbances of autonomic function, such as impaired respiratory regulation or excess salivation, may dominate the

clinical picture. Up to 30% of survivors are left

with neurological sequelae such as seizures, spastic

paralysis, and cranial neuropathies. Cognitive impairment ranges from minimal brain dysfunction

to severe dementia.

Clinical laboratory findings in patients with EEE

often demonstrate an early leukopenia followed by
Medical Aspects of Chemical and Biological Warfare

574

a leukocytosis. Elevated opening pressure is commonly noted on lumbar puncture, and in children,

especially, the CSF lymphocytic pleocytosis may

reach a cell count of thousands of mononuclear cells

per microliter. Specific diagnosis of EEE depends

on virus isolation or serologic testing in which rising titers of HI, CF, or neutralizing antibodies are

observed. IgM antibodies are usually detectable in

acute-phase sera.112 As with other alphaviruses, neutralization tests are considered to be the most specific.

Western Equine Encephalitis

Like VEE, WEE is less virulent for adult humans

than it is for equines and children, with lower rates

of fatalities and neurological sequelae.124 As with

EEE, infants and the elderly are especially susceptible to severe clinical illness and neurological sequelae, with case fatality rates of about 10%. Highlands J (HJ) virus, an antigenically related member

of the WEE complex that is isolated frequently in

the eastern United States, rarely infects humans.

The incubation period is 5 to 10 days. A large

percentage of patients with vector-borne infections

are either asymptomatic or present with a nonspecific febrile illness or aseptic meningitis. The ratio

of encephalitis cases per infection has been estimated to vary from 1:1,150 in adults, to 1:58 in children, to 1:1 in infants.57 However, the severity of

the syndrome and the incidence of inapparent infection almost certainly depend on the strain and

dose of virus and the route of infection. Some unusual isolates show very high virulence in laboratory animals,125 and in one study of laboratory-acquired infections in adults, 2 of 5 patients died.126

Symptoms usually begin with malaise, headache,

and fever, followed by nausea and vomiting.127 Over

the next few days the symptoms intensify, and somnolence or delirium may progress into coma. The

severity of neurological involvement is inversely

related to age, with more than 90% of children

younger than 1 year old exhibiting focal or generalized seizures.128 Physical examination typically

reveals nuchal rigidity, impaired sensorium, and

upper motor neuron deficits with pathologically

abnormal reflexes.

Patients with the severest infections usually die

within the first week of clinical illness, with overall case fatalities averaging 10%. Other patients begin a gradual convalescence after the first week of

encephalitic symptoms. Most adults recover completely, but may take months to years to recuperate

from fatigability, recurrent headaches, emotional

lability, and impaired concentration.129 Some patients are left with permanent residua of motor

weakness, cognitive deficits, or a seizure disorder.

Children carry a higher incidence of neurological

sequelae, ranging from less than 1% in those older

than 1 year old, to 10% in infants 2 to 3 months old,

to more than 50% in newborns. Congenital infection in the last trimester of pregnancy has been described, with resultant encephalitis in the infants.130

Viremia is rarely detectable by the time patients

present with encephalitic symptoms, but IgM, HI,

and neutralizing antibodies can generally be found

by the end of the first week of illness, and they increase in titer during the next week.112,131,132 CF serologic responses generally appear in the second

week and rise thereafter. Isolation of virus or 4-fold

titer rises are diagnostic, but because of serologic

cross-reactions with other alphaviruses, neutralization tests are preferred. Examination of the CSF reveals a lymphocytic pleocytosis ranging from 10 to

400 mononuclear cells per microliter. WEE virus

may occasionally be isolated from the CSF or throat

swabs taken within the first 2 days of illness, and is

frequently recovered from brain tissue on postmortem examination.133 Natural infection presumably

confers long-term immunity.

Differential Diagnosis of Alphavirus Encephalitis

Most acute infections with VEE and WEE produce a moderately severe but nonspecific clinical

illness consisting of fever, headache, and myalgias.

Therefore, in a potential biological warfare scenario,

alphaviruses should be considered in the differential diagnosis whenever epidemic febrile illness

occurs, especially if a number of patients progress

to neurological disease. Sick or dying equines in the

vicinity of an epidemic febrile illness among troops

should immediately suggest the possibility of largescale alphavirus exposure. Other potential biowarfare agents that may infrequently produce or

imitate a meningoencephalitic syndrome include

Brucella species, Yersinia pestis, Salmonella typhi, Coxiella burnetii, and botulinum toxin. As with any diagnosis of meningoencephalitis, it is imperative to

rule out any potential cause that may be specifically

treatable.

For encephalitis cases that are more sporadic in

their occurrence, other important viral etiologies

that might not be readily discriminated from the

alphaviruses by clinical features are listed in Table

28-3. This list is not all-inclusive but suggests other

viral encephalitides that should be considered if a
Viral Encephalitides

575

patient presents, a priori, with an encephalitic syndrome. Epidemiological, historical, and laboratory

information remain critical to differential diagnosis. Immediate and careful consideration must be

given to treatable infections that may mimic viral

encephalitis (Exhibit 28-1), since prompt and appropriate intervention can be lifesaving. In addition, it

should be kept in mind that vascular, autoimmune,

and neoplastic diseases may imitate infectious meningoencephalitis.

TABLE 28-3

SOME IMPORTANT VIRAL CAUSES* OF ENDEMIC ENCEPHALOMYELITIS

Virus Family Genus Species

Togaviridae Alphavirus Eastern equine

Western equine

Venezuelan equine

Flaviviridae St. Louis

Murray Valley

West Nile

Japanese

Dengue

Tick-borne complex

Bunyaviridae LaCrosse

Rift Valley

Toscana

Paramyxoviridae Paramyxovirus Mumps

Morbillivirus Measles

Arenaviridae Arenavirus Lymphocytic choriomeningitis

Machupo

Junin

Picornaviridae Enterovirus Poliovirus

Coxsackievirus

Echovirus

Reoviridae Colorado tick fever

Rhabdoviridae Rabies

Herpesviridae Herpesvirus Herpes simplex virus types 1 and 2

Epstein-Barr virus

Cytomegalovirus

Adenoviridae Adenovirus

*Not all-inclusive
Medical Aspects of Chemical and Biological Warfare

576

For endemic meningoencephalitic disease that

occurs outside biowarfare theaters, the geographical locale and the patient’s travel history are of preeminent importance in diagnosing an arboviral encephalitis. Risk for disease is increased relative to

the patient’s amount of arthropod contact near

EXHIBIT 28-1

NONVIRAL CAUSES OF

ENCEPHALOMYELITIS

Treatable infectious conditions that can mimic

viral encephalitis:

Partially treated bacterial meningitis

Brain abscess

Subdural empyema

Embolic encephalitis associated with

bacterial endocarditis

Lyme disease

Tuberculous meningitis

Fungal meningitis

Rocky Mountain spotted fever

Cat scratch disease

Cerebral malaria

Trypanosomiasis

Toxoplasmosis

Vascular, autoimmune, and neoplastic diseases

that can mimic infectious meningoencephalitis:

Lupus cerebritis

Cerebral and granulomatous arteritis

Lymphomatous cerebritis

Whipple’s disease

Behçet syndrome

Carcinomatosis meningitis

swampy or forested areas during the summer. Encephalitic illness of equines in the surrounding locale is an important indication of ongoing transmission of encephalitic alphaviruses. Examination of

the CSF, to include viral cultures, is critical in differentiating bacterial from viral infections, and infectious from noninfectious etiologies. Serum and

CSF tests based on polymerase chain reaction (PCR)

techniques hold great promise in more-rapid diagnosis of infectious encephalitis. In some instances

it will be necessary to (a) institute chemotherapy

for possible, treatable, infecting organisms and (b)

await definitive laboratory diagnostic tests.

Medical Management and Prevention

No specific therapy exists for the togaviral encephalitides; hence, treatment is aimed at management of specific symptoms (eg, anticonvulsant

medication, protection of the airway). The extremes

of high fever occasionally produced by WEE infection in humans is a special problem among the

arboviral encephalitides that may require aggressive antihyperthermia measures.

The U.S. Army has extensive experience with a

live-attenuated vaccine for VEE (TC-83) in humans.

However, this vaccine would be expected to protect efficiently against only IA/B and IC serotypes.

The TC-83 vaccine is also reactogenic, with more

than 20% of vaccine recipients experiencing fever,

malaise, and headache after the vaccination. Half

of these patients experience symptoms severe

enough to warrant bed rest for 1 to 2 days.

Use of an effective vaccine in horses would prevent outbreaks of epizootic VEE, as equines are the

major amplifying species for VEE virus. Vaccination of horses is not a useful public health tool for

EEE, WEE, or enzootic VEE, however, since horses

are not important as amplifying hosts for these

diseases. Investigational formalin-inactivated vaccines for humans are available for WEE and EEE,

but they require multiple injections and are poorly

immunogenic. Insecticide measures of vector control may also have an impact on ameliorating epidemic transmission.

IMMUNOPROPHYLAXIS

Relevant Immune Effector Mechanisms

The equine encephalomyelitis viruses constitute

both an endemic disease threat as well as a biological warfare threat; therefore, adequate immunoprophylaxis of military personnel will require protection against both vector-borne and aerosol-acquired

infection. The requirements for protection against

parenteral infection are well described, but the requirements for protection against infectious aero-
Viral Encephalitides

577

sols are certainly more stringent, and are largely

unidentified. Within a few days of infection with

an alphavirus, specific antibodies can be detected

in the serum of animals or humans. Within 7 to 14

days, a virus-neutralizing antibody response develops, as measured by the ability of serum antibodies to block virus infectivity in vitro or in vivo. Protection from mosquito-vectored alphavirus disease

is believed to be primarily mediated by this virusspecific neutralizing antibody response, which is

largely directed against epitopes on the E2 glycoprotein. Protection mediated by nonneutralizing

antibodies to alphaviruses, directed largely at

epitopes on the E1 glycoprotein, has also been described.134–136 However, it has proven more difficult

to correlate protection from aerosol exposure with

serum neutralization or antibody titers.137

Other nonspecific or immune responses that

occur following alphavirus infection include the

induction of secretion of interferon138–141 and the

activation of cytotoxic macrophages.142 There

have also been reports of virus-specific cytotoxic T

cell responses induced against alphaviruses,143–146

although it has proven difficult to show that these

T cell responses play a significant role in protection.

Passive Immunization

Passive transfer of neutralizing antisera or monoclonal antibodies to naive recipients protects animals from subsequent parenteral challenge with

homologous VEE strains.136,140,147 Passive transfer of

nonneutralizing, anti-E1 monoclonal antibodies

directed against appropriate epitopes is also protective against Sindbis,134 WEE,135 and VEE136 viruses. However, for the respiratory route of infection, uniform protection was not observed after

passive transfer of hyperimmune serum to hamsters137 or neutralizing monoclonal antibodies to

mice,148 suggesting that either additional immune

mechanisms or the presence of protective antibodies along the respiratory tract may be needed. The

time between the administration of immune serum

and virus exposure may also be relevant. Protection of mice from intracerebral inoculation with

WEE virus was observed if immune serum was

given no more than 3 days prior to virus exposure.149,150 Similarly, monkeys passively immunized

with horse antiserum to EEE or WEE resisted intranasal challenge from homologous virus 24 hours

later, but they were unable to resist a second challenge with the same virus 7 weeks later.151 However,

as the immune serum given in both studies was xenogeneic, the loss of protective capacity was presumably related in part to active clearance of the immune

serum by the recipients.

The effect of giving immune serum to animals

after the establishment of intracerebral infections

has also been evaluated. Several studies, employing different alphaviruses, have demonstrated at

least partial protection if the immune serum was administered within 24 hours of infection.149,150,152–154

Other studies have suggested that postinfection

serum transfer may also cause a more severe pathology, or may merely delay the onset of disease

symptoms.152,155 Aggressive serotherapy following

infections of two laboratory workers who developed acute WEE encephalitis resulted in the survival of one patient156 but was ineffective in the second patient.157

In an EEE outbreak in New Jersey in 1959, 22 of

32 diagnosed patients died. Most patients had demonstrable antibody during the onset or progression of encephalitis, and neutralizing antibody titers in sera from patients who died were generally

similar to those observed in patients who recovered.116 This finding, coupled with animal studies

indicating that transfer of virus-neutralizing antisera was unable to prevent progression of disease

if infection of the brain was firmly established (described above149,150,152–154), suggests that serotherapy

would be an ineffective means of treatment for these

virus infections, unless initiated very early in the

course of disease.

Active Immunization

Vaccines currently available for use against the

equine encephalomyelitis viruses include TC-83,

which is a live attenuated vaccine for VEE, and inactivated vaccines for VEE, EEE, and WEE. All are

used under IND status. The characteristics of these

vaccines and the responses induced in human

vaccinees are summarized in Table 28-4.

Live Vaccines

The TC-83 VEE vaccine was developed in 1961

by serial passage of the virulent TrD strain in fetal

guinea pig heart cells,158 and is administered subcutaneously (0.5 mL) at 1 x 104 to 2 x 104 plaqueforming units (pfu) per dose. The vaccine was used

initially in laboratory and field personnel at risk for

exposure to VEE,159 and more than 6,000 people received the vaccine between 1964 and 1972.160 For
Medical Aspects of Chemical and Biological Warfare

578

reasons that remain unclear, approximately 20% of

the people who receive TC-83 fail to make a minimum neutralizing antibody response and presumably would not be protected should they be exposed

to the virus. Another 25% of vaccine recipients experience clinical reactions ranging from mild transient symptoms to fever, chills, sore throat, and

malaise sufficient to require bed rest.161 However,

for recipients who respond with postvaccination

titers of at least 1:20, long-term follow-up studies have

shown that titers persist for several years.162 In humans, documented vaccine-breakthrough infections

have been attributed largely to exposure to heterologous, enzootic strains of VEE virus.47–49 Although

pregnant mares were not adversely affected by TC83,163 pregnant women are advised not to receive

the TC-83 vaccine, as wild-type VEE may have been

associated with spontaneous abortions or stillbirths

during an epidemic in Venezuela in 1962.164

In animals, TC-83 vaccination will protect hamsters from a lethal VEE subcutaneous or aerosol

challenge,137 although up to 20% of hamsters may

die of reactions to the vaccine.95,165 Subcutaneous

immunization of monkeys98 with the vaccine produces (a) neutralizing antibody responses in serum

and (b) protection from virulent VEE virus delivered by peripheral or intranasal challenge. However, TC-83 provides only partial protection against

aerosol challenge in outbred mice.100 TC-83 has been

extensively administered to horses, burros, and

mules, in part because large numbers of equines

were vaccinated during the 1969–1970 epizootic.

TC-83 immunization produces febrile responses and

leukopenia in some equines,166,167 but neutralizing

antibody responses to homologous (serotype IA)

virus eventually develop in 90% of these animals.166,168 Although it was difficult to accurately

assess vaccine efficacy under the conditions of an

ongoing epizootic, herds of animals known to have

been immunized at least 2 weeks prior to any disease occurrence in the area did not sustain any VEErelated deaths, whereas unimmunized herds experienced up to 60% mortality rates.161

An unresolved problem with the use of TC-83,

and presumably with other live-attenuated alphavirus vaccines, is the phenomenon of vaccine interference, in which prior immunity to heterologous

alphaviruses inhibits vaccine virus replication and

subsequent immune responses. This occurrence has

been observed in horses,169,170 in which preexisting

antibodies to EEE and WEE may have interfered

with TC-83 vaccination. Interference has also been

observed in humans, in whom prior vaccination

with Chikungunya virus has reduced the response

to TC-83, and vice versa (D.J.McC., unpublished

research, 1994).

id: intradermal

IND: investigational new drug

sc: subcutaneous

TC: tissue culture

TrD: Trinidad donkey

VEE: Venezuelan equine encephalitis

WEE: western equine encephalitis

TABLE 28-4

VACCINES CURRENTLY AVAILABLE FOR VEE, EEE, AND WEE VIRUSES

Dose (mL)/

Route of Responding Booster Dose/

Vaccine Form/Strain Administration Schedule % Duration* Route

VEE (TC-83) Attenuated TrD 0.5 mL/sc Day 0 82% 92% C-84/sc

VEE (C-84)† Inactivated TC-83 0.5 mL/sc After TC-83 76% NR‡ 60% 0.5 mL/sc

100% WT§ 100%

EEE Inactivated PE-6¥ 0.5 mL/sc Days 0, 28 58% 75% 0.1 mL/id

WEE Inactivated CM-4884¥ 0.5 mL/sc Days 0, 7, 28 50% 20% 0.5 mL/sc

*% of responders whose virus-neutralizing titers persist for at

least 1 y

†current IND protocols specify use of C-84 only as a booster vaccine ‡

TC-83 nonresponders

§

TC-83 responders given C-84 to boost waning titers

¥

laboratory designation

EEE: eastern equine encephalitis
Viral Encephalitides

579

Inactivated Vaccines

Against VEE (C-84). Early attempts to develop

an inactivated vaccine against VEE resulted in

preparations that contained residual live virus and

caused disease in 4% of those who received it.158,171

Because of the problems associated with incomplete

inactivation, development of an inactivated VEE

vaccine (C-84) was begun, using the TC-83 attenuated strain of virus.172 Initial clinical trials with the

C-84 inactivated vaccine were begun in 1976 in 14

volunteers previously immunized with TC-83, and

subsequently in 14 naive volunteers.173 The vaccine

was found to be safe and elicited only mild tenderness at the site of injection. Although C-84 was immunogenic, three doses were required to maintain

neutralizing antibody titers in recipients. A subsequent study has shown that most TC-83 nonresponders and 100% of individuals with waning

titers from TC-83 immunizations respond to a

booster dose of C-84 and have a high probability of

maintaining a titer for 3 years.160

The observation that hamsters given C-84 vaccine were protected from subcutaneous challenge

but not from an aerosol exposure to VEE virus137

raised concerns that C-84 vaccination may not protect at-risk laboratory workers from aerosol exposure. Therefore, C-84 is currently administered only

as a booster immunogen.

Against EEE and WEE. The PE-6 strain of EEE

virus was passed in primary chick-embryo cell cultures, and then was formalin-treated and lyophilized to produce an inactivated vaccine for

EEE.174 This vaccine is administered as a 0.5-mL

dose subcutaneously on days 0 and 28, with 0.1-

mL intradermal booster doses given as needed to

maintain neutralizing antibody titers. Mild reactions to the vaccine were observed, and immunogenicity was demonstrated in initial clinical trials.175

The vaccine was given to 896 at-risk laboratory

workers between 1976 and 1991. No significant

clinical reactions have been observed. A long-term

follow-up study of 573 recipients indicated a 58%

response rate after the primary series, and a 25%

chance of failing to maintain adequate titers for 1

year. Response rates and persistence of titers increased with the administration of additional

booster doses.176

The WEE vaccine was similarly prepared using

the B-11 or CM-4884) virus strain, and caused only

mild clinical reactions when administered to WEEnaive individuals.177 Between 1976 and 1990, 359

laboratory workers were immunized with this vaccine. Long-term follow-up studies have indicated

that administration of three doses of 0.5 mL subcutaneously on days 0, 7, and 28 results in a 50% responder rate (neutralization titer > 1:40) after the

primary series. Only 20% of recipients maintain a titer for 1 year, although this level can be increased to

60% to 70% with additional booster immunizations.176

SUMMARY

fected individuals develop a prostrating syndrome

of high fever, headache, malaise, and prolonged

convalescence.

Although natural infections are acquired by mosquito bite, these viruses are also highly infectious

in low doses as aerosols. They can be produced in

large amounts in inexpensive and unsophisticated

systems, are relatively stable, and are readily amenable to genetic manipulation. For these reasons,

the equine encephalomyelitis viruses are classic biological warfare threats.

No specific therapy exists for infections caused

by these viruses. A live-attenuated vaccine for VEE

(TC-83) and inactivated vaccines for VEE, EEE,

and WEE have been developed and are used under

IND status. Although these vaccines are useful

in protecting at-risk individuals, they have certain

disadvantages, and improved vaccines are under

development.

The equine encephalomyelitis viruses consist of

three antigenically related viruses within the

Alphavirus genus of the family Togaviridae: Venezuelan equine encephalomyelitis (VEE), western

equine encephalomyelitis (WEE), and eastern

equine encephalomyelitis (EEE). These viruses are

vectored in nature by various species of mosquitoes and cause periodic epizootics among equines.

Infection of equines with virulent strains of any

these viruses produces a similar clinical course

of severe encephalitis with high mortality. However, the clinical course following infection of humans differs. EEE is the most severe of the arbovirus encephalitides, with case fatality rates of 50%

to 70%. WEE virus is generally less virulent for

adults, but the infection commonly produces severe

encephalitis in children, with case fatality rates approaching 10%. In contrast, encephalitis is rare following VEE virus infection, but essentially all in-
Medical Aspects of Chemical and Biological Warfare

580

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against Semliki Forest virus. Br J Exp Pathol. 1966;47:361–371.

140. Rabinowitz SG, Adler WH. Host defenses during primary Venezuelan equine encephalomyelitis virus infection in mice, I: Passive transfer of protection with immune serum and immune cells. J Immunol. 1973;110(5):1345–

1353.

141. Tazulakhova EB, Novokhatsky AS, Yershov FI. Interferon induction by, and antiviral effect of, poly(rI)-poly

(rC) in experimental viral infection. Acta Virol. 1973;17:487–492.

142. Rodda SJ, White DO. Cytotoxic macrophages: A rapid nonspecific response to viral infection. J Immunol.

1976;117(6):2067–2072.

143. McFarland HF. In vitro studies of cell-mediated immunity in an acute viral infection. J Immunol. 1974;113(1):173–180.

144. Mullbacher A, Blanden RV. Murine cytotoxic T-cell response to alphavirus is associated mainly with H-2Dk.

Immunogenetics. 1978;7:551–561.

145. Mullbacher A, Blanden RV. H-2-linked control of cytotoxic T-cell responsiveness to alphavirus infection: Presence of H-2Dk during differentiation and stimulation converts stem cells of low responder genotype to T cells

of responder phenotype. J Exp Med. 1979;149:786–790.

146. Peck R, Brown A, Wust CJ. In vitro heterologous cytotoxicity by T effector cells from mice immunized with

Sindbis virus. J Immunol. 1979;123(4):1763–1766.

147. Roerhig JT, Mathews JH. The neutralization site on the E2 glycoprotein of Venezuelan equine encephalitis (TC83) virus is composed of multiple conformationally stable epitopes. Virology. 1985;142:346–356.

148. Kinney RM, Esposito JJ, Mathews JH, et al. Recombinant vaccinia virus/Venezuelan equine encephalitis (VEE)

virus protects mice from peripheral VEE virus challenge. J Virol. 1988;(62):4697–4702.

149. Howitt BF. Equine encephalomyelitis. J Infect Dis. 1932;51:493–510.

150. Olitsky PK, Schlesinger RW, Morgan IM. Induced resistance of the central nervous system to experimental infection

with equine encephalomyelitis virus, II: Serotherapy in western virus infection. J Exp Med. 1943;77:359–375.

151. Wyckoff RWG, Tesar WC. Equine encephalomyelitis in monkeys. J Immunol. 1939;37:329–343.

152. Berge TO, Gleiser CA, Gochenour WS, Miesse ML, Tigertt WD. Studies on the virus of Venezuelan equine

encephalomyelitis, II: Modification of specific immune serum of response of central nervous system of mice.

J Immunol. 1961;87:509–517.

153. Griffin DE, Johnson RT. Role of the immune response in recovery from Sindbis virus encephalitis in mice.

J Immunol. 1978;118(3):1070–1075.

154. Igarashi A, Fukuoka T, Fukai K. Passive immunization of mice with rabbit antisera against Chikungunya virus

and its components. Biken J. 1971;14:353–355.
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155. Seamer JH, Boulter EA, Zlotnik I. Delayed onset of encephalitis in mice passively immunised against Semliki

Forest virus. Br J Exp Path. 1971;52:408–414.

156. Gold H, Hampil B. Equine encephalomyelitis in a laboratory technician with recovery. Ann Intern Med. 1942;16:

556–569.

157. Helwig FC. Western equine encephalomyelitis following accidental inoculation with chick embryo virus. JAMA.

1940;115:291–292.

158. Berge TO, Banks IS, Tigertt WD. Attenuation of Venezuelan equine encephalomyelitis virus by in vitro cultivation in guinea-pig heart cells. Am J Hyg. 1961;73:209–218.

159. McKinney RW, Berge TO, Sawyer WD, Tigertt WD, Crozier D. Use of an attenuated strain of Venezuelan equine

encephalomyelitis virus for immunization in man. Am J Trop Med Hyg. 1963;12:597–603.

160. Pittman PR, Makuch RS, Mangiafico JA, Cannon TL, Gibbs PH, Peters CJ. Long-term duration of detectable

neutralizing antibodies after administration of live-attenuated VEE vaccine and following booster vaccination

with inactivated VEE vaccine. Vaccine. 1996;14(4):337–343.

161. McKinney RW. Inactivated and live VEE vaccines—A review. In: Venezuelan Encephalitis: Proceedings of the

Workshop-Symposium on Venezuelan Encephalitis Virus; 14–17 September 1971. Washington, DC: Pan American Health Organization; 1972: 369–377. PAHO Scientific Publication 243.

162. Burke DS, Ramsburg HH, Edelman R. Persistence in humans of antibody to subtypes of Venezuelan equine

encephalitis (VEE) virus after immunization with attenuated (TC-83) VEE virus vaccine. J Infect Dis.

1977;136(3):354–359.

163. Eddy GA, Martin DH, Reeves WC, Johnson KM. Field studies of an attenuated Venezuelan equine encephalomyelitis vaccine (strain TC-83). Infect Immunol. 1972;5(2):160–163.

164. Wenger F. Venezuelan equine encephalitis. Teratology. 1977;16:359–362.

165. Austin FJ, Scherer WF. Studies of viral virulence, I: Growth and histopathology of virulent and attenuated

strains of Venezuelan encephalitis virus in hamsters. Am J Pathol. 1971;62:195–209.

166. Spertzel RO, Kahn DE. Safety and efficacy of an attenuated Venezuelan equine encephalomyelitis vaccine for

use in equidae. J Am Vet Med Assoc. 1971;159(6):731–738.

167. Monlux WS, Luedke AJ, Browne J. Central nervous system response of horses to Venezuelan equine encephalomyelitis vaccine (TC-83). J Am Vet Med Assoc. 1972;161(3):265–269.

168. Walton TE, Alvarez O, Buckwalter RM, Johnson KM. Experimental infection of horses with an attenuated Venezuelan equine encephalomyelitis vaccine (strain TC-83). Infect Immunol. 1972;5(5):750–756.

169. Jochim MM, Barber TL, Luedke AJ. Venezuelan equine encephalomyelitis: Antibody response in vaccinated

horses and resistance to infection with virulent virus. J Am Vet Med Assoc. 1973;162(4):280–283.

170. Calisher CH, Sasso DR, Sather GE. Possible evidence for interference with Venezuelan equine encephalitis

virus vaccination of equines by pre-existing antibody to eastern or western equine encephalitis virus, or both.

Appl Microbiol. 1973;26:485–488.

171. Sutton LS, Brooks CC. Venezuelan equine encephalomyelitis due to vaccination in man. JAMA.

1954;155(17):1473–1478.

172. Cole FE Jr, May SW, Eddy GA. Inactivated Venezuelan equine encephalomyelitis vaccine prepared from attenuated (TC-83 strain) virus. Appl Microbiol. 1974;27(1):150–153.
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173. Edelman R, Ascher MS, Oster CN, Ramsburg HH, Cole FE, Eddy GA. Evaluation in humans of a new, inactivated vaccine for Venezuelan equine encephalitis virus (C-84). J Infect Dis. 1979;140(5):708–715.

174. Maire LF III, McKinney RW, Cole FE Jr. An inactivated eastern equine encephalomyelitis vaccine propagated

in chick-embryo cell culture, I: Production and testing. Am J Trop Med Hyg. 1970;19(1):119–122.

175. Bartelloni PJ, McKinney RW, Duffy TP, Cole FE Jr. An inactivated eastern equine encephalomyelitis vaccine

propagated in chick-embryo cell culture, II: Clinical and serologic responses in man. Am J Trop Med Hyg.

1970;19(1):123–126.

176. Pittman PR. Lieutenant Colonel, Medical Corps, US Army. Chief, Special Immunizations Program, Medical

Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal

communication, October 1996.

177. Bartelloni PJ, McKinney RW, Calia FM, Ramsburg HH, Cole FE Jr. Inactivated western equine encephalomyelitis vaccine propagated in chick embryo cell culture: Clinical and serological evaluation in man. Am J Trop Med

Hyg. 1971;20(1):146–149.
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Chapter 29

VIRAL HEMORRHAGIC FEVERS

PETER B. JAHRLING, PH.D.*

INTRODUCTION

EPIDEMIOLOGICAL OVERVIEW

The Arenaviridae

The Bunyaviridae

The Filoviridae

The Flaviviridae

CLINICAL FEATURES OF THE VIRAL HEMORRHAGIC FEVER SYNDROME

DIAGNOSIS

MEDICAL MANAGEMENT

Supportive Care

Isolation and Containment

Specific Antiviral Therapy

IMMUNOPROPHYLAXIS AND IMMUNOTHERAPY

Passive Immunization

Active Immunization

SUMMARY

*Senior Research Scientist, Headquarters, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland

21702-5011
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INTRODUCTION

opportunity for humans to contract these infections.

The VHF agents are all highly infectious via the

aerosol route, and most are quite stable as respirable aerosols. This means that they satisfy at least

one criterion for being weaponized, and some

clearly have the potential to be biological warfare

threats. Most of these agents replicate in cell culture to concentrations sufficiently high to produce

a small terrorist weapon, one suitable for introducing lethal doses of virus into the air intake of an

airplane or office building. Some replicate to even

higher concentrations, with obvious potential ramifications. Since the VHF agents cause serious diseases with high morbidity and mortality, their existence as endemic disease threats and as potential

biological warfare weapons suggests a formidable

potential impact on unit readiness. Further, returning troops may well be carrying exotic viral diseases

to which the civilian population is not immune, a

major public health concern.

The concept of a viral hemorrhagic fever (VHF)

syndrome is useful in clinical medicine. VHF syndrome can be described as an acute febrile illness

characterized by malaise, prostration, generalized

signs of increased vascular permeability, and abnormalities of circulatory regulation. Bleeding manifestations often occur, especially in the more

severely ill patients, but this does not result in a

life-threatening loss of blood volume. Rather, these

signs are the result of damage to the vascular endothelium and are an index of how severe the disease is in specific target organs.

The viral agents that cause VHFs are taxonomically diverse; they are all ribonucleic acid (RNA)

viruses and are transmitted to humans through contact with infected animal reservoirs or arthropod

vectors. They are all natural infectious disease

threats although their geographical ranges may be

tightly circumscribed. The recent advent of jet travel

coupled with human demographics increase the

EPIDEMIOLOGICAL OVERVIEW

The VHF agents are a taxonomically diverse

group of RNA viruses whose major characteristics

are summarized in Table 29-1. Four virus families

contribute pathogens to the group of VHF agents:

the Arenaviridae, Bunyaviridae, Filoviridae, and

Flaviviridae. Despite their diverse taxonomy,

all these viruses share some common characteristics. They are all relatively simple RNA viruses,

and they all have lipid envelopes. This renders

them relatively susceptible to detergents, as well

as to low-pH environments and household bleach.

Conversely, they are quite stable at neutral pH,

especially when protein is present. Thus, these

viruses are stable in blood for long periods, and

can be isolated from a patient’s blood after weeks

of storage at refrigerator or even at ambient temperatures.

These viruses tend to be stable and highly infectious as fine-particle aerosols. These characteristics have great significance in not only the natural transmission cycle for arenaviruses and

bunyaviruses (from rodents to man) but also make

nosocomial transmission a concern. As a group, the

viruses are also linked to the ecology of their vectors or reservoirs, whether rodents or arthropods.

In that regard, most of these reservoirs tend to be

rural, and a patient’s history of being in a rural

locale is an important factor to consider when reaching a diagnosis. Human-to-human spread is possible, but pandemics are unlikely.

The Arenaviridae

The arenaviruses are classified into the Old

World and New World groups. All the arenaviruses

are maintained in nature by a life-long association

with a rodent reservoir. Rodents spread the virus

to humans, and outbreaks can usually be related to

some perturbation in the ecosystem that brings man

into contact with the rodents.

Lassa virus causes Lassa fever, a major febrile

disease of West Africa, where it is associated with

10% to 15% of adult febrile admissions to the hospital and perhaps 40% of nonsurgical deaths.1

 In

addition, Lassa fever is a pediatric disease and the

cause of high mortality in pregnant women. While

nosocomial infections do occur, most Lassa virus

infections can be traced to contact with the carrier

rodent, Mastomys natilensis.

The Junin virus that causes Argentine hemorrhagic fever is carried by a field mouse, Calomys

colosus, and is associated with agricultural activities in the pampas of Argentina, where 300 to 600

cases have occurred every year since 1955.2

 In Bo-
Viral Hemorrhagic Fevers

593

TABLE 29-1

RECOGNIZED VIRAL HEMORRHAGIC FEVERS OF HUMANS

Virus Family Source of Human Infection Incubation

Genus Disease (Virus) Natural Distribution Usual Less Likely (Days)

Arenaviridae

Arenavirus Lassa fever Africa Rodent Nosocomial 5–16

Argentine HF (Junin) South America Rodent Nosocomial 7–14

Bolivian HF (Machupo) South America Rodent Nosocomial 9–15

Brazilian HF (Sabia) South America Rodent Nosocomial 7–14

Venezuelan HF (Guanarito) South America Rodent Nosocomial 7–14

Bunyaviridae

Phlebovirus Rift Valley fever Africa Mosquito Slaughter of 2–5

domestic animal

Nairovirus Crimean-Congo HF Europe, Asia, Africa Tick Slaughter of 3–12

domestic animal;

nosocomial

Hantavirus HFRS (Hantaan and Asia, Europe; possibly Rodent 9–35

related viruses) worldwide

Filoviridae

Filovirus Marburg and Ebola HF Africa Unknown Nosocomial 3–16

Flaviviridae

Flavivirus

(Mosquito–borne) Yellow fever Tropical Africa, Mosquito 3–6

South America

Dengue HF Asia, Americas, Africa Mosquito Unknown for

dengue HF,

but 3–5 for

uncomplicated

dengue

(Tick–borne) Kyasanur Forest disease India Tick 3–8

Omsk HF Soviet Union Tick Muskrat– 3–8

contaminated

water

HF: hemorrhagic fever; HFRS: hemorrhagic fever with renal syndrome

livia, Machupo virus is the agent associated with

Bolivian hemorrhagic fever,3 a disease that was associated with outbreaks in the 1960s but only with

sporadic disease subsequently. Guanarito virus is

a newly described arenavirus, first recognized in

association with an outbreak of VHF involving several hundred patients in Venezuela beginning in

1989.4 More recently, yet another VHF arenavirus

has been recognized: Sabia virus was associated

with a fatal VHF infection in Brazil in 1990, followed

by a severe laboratory infection in Brazil in 1992

and another laboratory infection in the United

States in 1994.5

The Bunyaviridae

Among the bunyaviruses, the significant human

pathogens include the phlebovirus Rift Valley fever (RVF) virus, which causes Rift Valley fever. This

major African disease is frequently associated with

unusual increases in mosquito populations.6 Rift

Valley fever is also a disease of domestic livestock,

and human infections have resulted from contact

with infected blood, especially around slaughter

houses.

A nairovirus, Crimean-Congo hemorrhagic fever

(C-CHF) virus is carried by ticks, and has been
Medical Aspects of Chemical and Biological Warfare

594

associated with sporadic, yet particularly severe,

VHF in Europe, Africa, and Asia.7 Crimean-Congo

hemorrhagic fever has frequently occurred as small,

hospital-centered outbreaks, owing to the copious

hemorrhage and highly infective nature of this virus via the aerosol route.

Hantaviruses, unlike the other bunyaviruses, are

not transmitted via infected arthropods; rather, they

infect man via contact with infected rodents and

their excreta. Hantavirus disease was described

prior to World War II in Manchuria along the Amur

River, and later among United Nations troops during the Korean War, where it became known as

Korean hemorrhagic fever.8 The prototype virus

from this group, Hantaan, is the cause of Korean

hemorrhagic fever as well as the severe form of

hemorrhagic fever with renal syndrome (HFRS).

Hantaan virus is borne in nature by the striped field

mouse, Apodemus agrarious.

Hantaan virus is still active in Korea, Japan, and

China. Seoul virus causes a milder form of HFRS,

and may be distributed worldwide. There are a

number of other hantaviruses that are associated

with HFRS, including Puumala virus, which is associated with chronically infected bank voles

(Clethrionomys glareolus). Recently in the United

States, a new hantavirus (Sin nombre virus) has

been associated with the hantavirus pulmonary

syndrome (HPS).9

The Filoviridae

The Filoviridae includes the causative agents of

Ebola and Marburg hemorrhagic fevers. These

filoviruses have an exotic, threadlike appearance

when observed via electron microscopy. Marburg

virus was first recognized in 1967 when a lethal

epidemic of VHF occurred in Marburg, Germany,

among laboratory workers exposed to the blood and

tissues of African green monkeys that had been

imported from Uganda; secondary transmission to

medical personnel and family members also occurred.10 In all, 31 patients became infected, 9 of whom

died. Subsequently, Marburg virus has been associated with sporadic, isolated, usually fatal cases

among residents and travelers in southeast Africa.11

Ebola viruses are taxonomically related to

Marburg viruses; they were first recognized in association with explosive outbreaks that occurred

almost simultaneously in 1976 in small communities in Zaire12 and Sudan.13 Significant secondary

transmission occurred through reuse of unsterilized

needles and syringes and nosocomial contacts.

These independent outbreaks involved serologically distinct viral strains. The Ebola–Zaire outbreak

involved 277 cases and 257 deaths (92% mortality),

while the Ebola–Sudan outbreak involved 280 cases

and 148 deaths (53% mortality). Sporadic cases occurred subsequently. In 1989, a third strain of Ebola

virus appeared in Reston, Virginia, in association

with an outbreak of VHF among cynomolgus monkeys imported to the United States from the Philippines.14 Hundreds of monkeys were infected (with

high mortality) but no human cases occurred, although four animal caretakers seroconverted without overt disease. Recently, small outbreaks involving new strains of Ebola virus occurred in human

populations in Côte d’Ivorie in 1994 and Gabon in

1995; a larger outbreak involving the Ebola-Zaire

strain involved more than 300 people, with 75%

mortality, in Zaire in 1995.15

Very little is known about the natural history of

any of the filoviruses. Animal reservoirs and arthropod vectors have been aggressively sought without success.

The Flaviviridae

Finally, the flaviviruses include the agents of yellow fever, found throughout tropical Africa and

South America; and dengue, found throughout the

Americas, Asia, and Africa, both transmitted by

mosquitoes.16 Both yellow fever and dengue have

had major impact on military campaigns and military medicine. The tick-borne flaviviruses include

the agents of Kyasanur Forest disease, which occurs in India,17 and Omsk hemorrhagic fever, which

occurs in the former Soviet Union.18 Both diseases

have a biphasic course; the initial phase includes a

prominent pulmonary component, followed by a

neurological phase with central nervous system

manifestations.

CLINICAL FEATURES OF THE VIRAL HEMORRHAGIC FEVER SYNDROME

The VHF syndrome develops to varying degrees

in patients infected with these viruses. The exact

nature of the disease depends on viral virulence and

strain characteristics, routes of exposure, dose, and

host factors. For example, dengue hemorrhagic fever is typically seen only in patients previously exposed to heterologous dengue serotypes.19 The target organ in the VHF syndrome is the vascular bed;
Viral Hemorrhagic Fevers

595

correspondingly, the dominant clinical features are

usually a consequence of microvascular damage

and changes in vascular permeability.20 Common

presenting complaints are fever, myalgia, and prostration; clinical examination may reveal only conjunctival injection, mild hypotension, flushing, and

petechial hemorrhages. Full-blown VHF typically

evolves to shock and generalized bleeding from the

mucous membranes, and often is accompanied by

evidence of neurological, hematopoietic, or pulmonary involvement. Hepatic involvement is common,

but a clinical picture dominated by jaundice and

other evidence of hepatic failure is seen in only a

small percentage patients with Rift Valley fever,

Crimean-Congo hemorrhagic fever, Marburg hemorrhagic fever, Ebola hemorrhagic fever, and yellow fever. Renal failure is proportional to cardiovascular compromise, except in HFRS caused by

hantaviruses, where it is an integral part of the disease process; oliguria is a prominent feature of the

acutely ill patient.8

 VHF mortality may be substantial, ranging from 5% to 20% or higher in recognized

cases. Ebola outbreaks in Africa have had particularly high case fatality rates, from 50% up to 90%.12,13

The clinical characteristics of the various VHFs

are somewhat variable. For Lassa fever patients,

hemorrhagic manifestations are not pronounced,

and neurological complications are infrequent, occurring only late and in only the most severely ill

group. Deafness is a frequent sequela of severe

Lassa fever. For the South American arenaviruses,

(Argentine and Bolivian hemorrhagic fevers), neurological and hemorrhagic manifestations are much

more prominent. RVF virus is primarily hepatotropic; hemorrhagic disease is seen in only a small

proportion of cases. In recent outbreaks in Egypt,

retinitis was a frequently reported component of

Rift Valley fever.21

Unlike Rift Valley fever, where hemorrhage is not

prominent, Crimean-Congo hemorrhagic fever infection is usually associated with profound disseminated intravascular coagulation (DIC) (Figure 29-1).

Patients with Crimean-Congo hemorrhagic fever

may bleed profusely; and since this occurs during

the acute, viremic phase, contact with the blood of

an infected patient is a special concern: a number

of nosocomial outbreaks have been associated with

C-CHV virus.

The picture for diseases caused by hantaviruses

is evolving, especially now in the context of HPS

syndrome. The pathogenesis of HFRS may be somewhat different; immunopathological events seem to

be a major factor. When patients present with HFRS,

Fig. 29-1. Massive cutaneous ecchymosis associated with

late-stage Crimean-Congo hemorrhagic fever virus infection, 7 to 10 days after clinical onset. Ecchymosis is indicative of multiple abnormalities in the coagulation system, coupled with loss of vascular integrity. Epistaxis and

profuse bleeding from puncture sites, hematemesis, melena, and hematuria often accompany spreading ecchymosis, which may occur anywhere on the body as a result of needlesticks or other minor trauma. The sharply

demarcated proximal border of this patient’s lesion is not

explained. Photograph: Courtesy of Robert Swanepoel,

PhD, DTVM, MRCVS, National Institute of Virology,

Sandringham, South Africa.

they are typically oliguric. Surprisingly, the oliguria occurs while the patient’s viremia is resolving

and they are mounting a demonstrable antibody

response. This has practical significance in that renal dialysis can be started with relative safety.

For the diseases caused by filoviruses, little clinical data from human outbreaks exist. Although mortality is high, outbreaks are rare and sporadic.

Marburg and Ebola viruses produce prominent maculopapular rashes, and DIC is a major factor in their

pathogenesis. Therefore, treatment of the DIC should

be considered, if practicable, for these patients.

Among the flaviviruses, yellow fever virus is, of

course, hepatotropic: black vomit caused by hematemesis has been associated with this disease.

Patients with yellow fever develop clinical jaundice

and die with something comparable to hepatorenal

syndrome. Dengue hemorrhagic fever and shock are

uncommon, life-threatening complications of dengue, and are thought—especially in children—to

result from an immunopathological mechanism

triggered by sequential infections with different

dengue viral serotypes.19 Although this is the general epidemiological pattern, dengue virus may also

rarely cause hemorrhagic fever in adults and in primary infections.22
Medical Aspects of Chemical and Biological Warfare

596

DIAGNOSIS

The natural distribution and circulation of VHF

agents are geographically restricted and mechanistically linked with the ecology of the reservoir species and vectors. Therefore, a high index of suspicion and elicitation of a detailed travel history are

critical in making the diagnosis of VHF. Patients

with arenaviral or hantaviral infections often recall

having seen rodents during the presumed incubation period, but, since the viruses are spread to humans by aerosolized excreta or environmental contamination, actual contact with the reservoir is not

necessary. Large mosquito populations are common

during the seasons when RVF virus and the

flaviviruses are transmitted, but a history of mosquito bite is sufficiently common to be of little assistance in making a diagnosis, whereas tick bites

or nosocomial exposure are of some significance

when Crimean-Congo hemorrhagic fever is suspected. History of exposure to animals in slaughterhouses should raise suspicions of Rift Valley fever and Crimean-Congo hemorrhagic fever in a

patient with VHF. When large numbers of military

personnel present with VHF manifestations in the

same geographical area over a short period of time,

medical personnel should suspect either a natural

outbreak (in an endemic setting) or possibly a

biowarfare attack (particularly if the virus causing

the VHF is not endemic to the area).

VHF should be suspected in any patient presenting with a severe febrile illness and evidence of

vascular involvement (subnormal blood pressure,

postural hypotension, petechiae, hemorrhagic diathesis, flushing of the face and chest, nondependent edema) who has traveled to an area where the

etiologic virus is known to occur, or where intelligence suggests a biological warfare threat. Signs

and symptoms suggesting additional organ system

involvement are common (headache, photophobia,

pharyngitis, cough, nausea or vomiting, diarrhea,

constipation, abdominal pain, hyperesthesia, dizziness, confusion, tremor), but they rarely dominate

the picture. A macular eruption occurs in most patients who have Marburg and Ebola hemorrhagic

fevers; this clinical manifestation is of diagnostic

importance.

Laboratory findings can be helpful, although

they vary from disease to disease and summarization is difficult. Leukopenia may be suggestive, but

in some patients, white blood cell counts may be

normal or even elevated. Thrombocytopenia is a

component of most VHF diseases, but to a varying

extent. In some, platelet counts may be near normal, and platelet function tests are required to explain the bleeding diathesis. A positive tourniquet

test has been particularly useful in diagnosing dengue hemorrhagic fever, but this sign may be associated with other hemorrhagic fevers as well. Proteinuria or hematuria or both are common in VHF,

and their absence virtually rules out Argentine hemorrhagic fever, Bolivian hemorrhagic fever, and

hantaviral infections. Hematocrits are usually normal, and if there is sufficient loss of vascular integrity perhaps mixed with dehydration, hematocrits

may be increased. Liver enzymes such as aspartate

aminotransferase (AST) are frequently elevated.

VHF viruses are not primarily hepatotropic, but livers are involved and an elevated AST may help to

distinguish VHF from a simple febrile disease.

For much of the world, the major differential diagnosis is malaria. It must be borne in mind that

parasitemia in patients partially immune to malaria

does not prove that symptoms are due to malaria.

Typhoid fever and rickettsial and leptospiral diseases are major confounding infections; nontyphoidal salmonellosis, shigellosis, relapsing fever,

fulminant hepatitis, and meningococcemia are some

of the other important diagnoses to exclude. Ascertaining the etiology of DIC is usually surrounded

by confusion. Any condition leading to DIC could

be mistaken for diseases such as acute leukemia,

lupus erythematosus, idiopathic or thrombotic

thrombocytopenic purpura, and hemolytic uremic

syndrome.

Definitive diagnosis in an individual case rests

on specific virological diagnosis. Most patients have

readily detectable viremia at presentation (the exception is those with hantaviral infections). Infectious virus and viral antigens can be detected and

identified by a number of assays using fresh or frozen serum or plasma samples. Likewise, early immunoglobulin (Ig) M antibody responses to the

VHF-causing agents can be detected by enzymelinked immunosorbent assays (ELISA), often during the acute illness. Diagnosis by viral cultivation

and identification requires 3 to 10 days for most

(longer for the hantaviruses); and, with the exception of dengue, specialized microbiologic containment is required for safe handling of these viruses.23

Appropriate precautions should be observed in collection, handling, shipping, and processing of diagnostic samples.24 Both the Centers for Disease

Control and Prevention (CDC, Atlanta, Georgia.)

and the U.S. Army Medical Research Institute of

Infectious Diseases (USAMRIID, Fort Detrick,
Viral Hemorrhagic Fevers

597

Frederick, Maryland.) have diagnostic laboratories

operating at the maximum Biosafety Level (BL-4;

see Chapter 19, The U.S. Biological Warfare and Biological Defense Programs, for further discussion of

BLs). Viral isolation should not be attempted without BL-4 containment.

In contrast, most antigen-capture and antibodydetection ELISAs for these agents can be performed

with samples that have been inactivated by treatment with β-propiolactone (BPL).25 Likewise, diagnostic tests based on reverse transcriptase polymerase chain reaction (RT-PCR) technology are

safely performed on samples following RNA extraction using chloroform and methanol. RT-PCR has

been successfully applied to the real-time diagnosis of most of the VHF agents.26,27 When isolation

of the infectious virus is difficult or impractical,

RT-PCR has proven to be extremely valuable; for

example, with HPS, where the agent was recognized by PCR months before it was finally isolated

in culture.9

When the identity of a VHF agent is totally unknown, isolation in cell culture and direct visualization by electron microscopy, followed by immunological identification by immunohistochemical

techniques is often successful.14 Immunohistochemical techniques are also useful for retrospective diagnosis using formalin-fixed tissues, where

viral antigens can be detected and identified using

batteries of specific immune sera and monoclonal

antibodies.

Although intensive efforts are being directed toward the development of simple, qualitative tests

for rapid diagnosis in the field, definitive diagnosis for these diseases today requires, at a minimum,

an ELISA capability coupled with specialized immunological reagents, supplemented (ideally) with

an RT-PCR capability.

MEDICAL MANAGEMENT

Patients with VHF syndrome require close supervision, and some will require intensive care. Since

the pathogenesis of VHF is not entirely understood

and availability of specific antiviral drugs is limited, treatment is largely supportive. This care is

essentially the same as the conventional care provided to patients with other causes of multisystem

failure. The challenge is to provide this support

while minimizing the risk of infection to other patients and medical personnel.

Supportive Care

Patients with VHF syndrome generally benefit

from rapid, nontraumatic hospitalization to prevent

unnecessary damage to the fragile capillary bed.

Transportation of these patients, especially by air, is

usually contraindicated because of the effects of drastic changes in ambient pressure on lung water balance. Restlessness, confusion, myalgia, and hyperesthesia occur frequently and should be managed by

reassurance and other supportive measures, including the judicious use of sedative, pain-relieving, and

amnestic medications. Aspirin and other antiplatelet

or anticlotting-factor drugs should be avoided.

Secondary infections are common and should be

sought and aggressively treated. Concomitant malaria should be treated aggressively with a regimen

known to be effective against the geographical

strain of the parasite; however, the presence of malaria, particularly in immune individuals, should

not preclude management of the patient for VHF

syndrome if such is clinically indicated.

Intravenous lines, catheters, and other invasive

techniques should be avoided unless they are

clearly indicated for appropriate management of the

patient. Attention should be given to pulmonary

toilet, the usual measures to prevent superinfection,

and the provision of supplemental oxygen. Immunosuppression with steroids or other agents has no

empirical and little theoretical basis, and is contraindicated except possibly for HFRS.

The diffuse nature of the vascular pathological

process may lead to a requirement for support of

several organ systems. Myocardial lesions detected

at autopsy reflect cardiac insufficiency antemortem.

Pulmonary insufficiency may develop, and, particularly with yellow fever, hepatorenal syndrome is

prominent.16

Treatment of Bleeding

The management of bleeding is controversial.

Uncontrolled clinical observations support vigorous administration of fresh frozen plasma, clotting

factor concentrates, and platelets, as well as early

use of heparin for prophylaxis of DIC. In the absence of definitive evidence, mild bleeding manifestations should not be treated at all. More-severe

hemorrhage indicates that appropriate replacement

therapy is needed. When definite laboratory evidence of DIC becomes available, heparin therapy

should be employed if appropriate laboratory support is available.
Medical Aspects of Chemical and Biological Warfare

598

Treatment of Hypotension and Shock

Management of hypotension and shock is difficult. Patients often are modestly dehydrated from

heat, fever, anorexia, vomiting, and diarrhea, in any

combination. There are covert losses of intravascular volume through hemorrhage and increased vascular permeability.28 Nevertheless, these patients

often respond poorly to fluid infusions and readily

develop pulmonary edema, possibly due to myocardial impairment and increased pulmonary vascular permeability. Asanguineous fluids—either

colloid or crystalloid solutions—should be given,

but cautiously. Although it has never been evaluated critically for VHFs, dopamine would seem

to be the agent of choice for patients with shock

who are unresponsive to fluid replacement. α-Adrenergic vasoconstricting agents have not been clinically helpful except when emergent intervention

to treat profound hypotension is necessary. Vasodilators have never been systematically evaluated.

Pharmacological doses of corticosteroids (eg,

methylprednisolone 30 mg/kg) provide another

possible but untested therapeutic modality in treating shock.

Particular Problems With Dengue and Hantaviral

Infections

Two hemorrhagic fevers should be clearly separated from the other VHF diseases. Severe consequences of dengue infection are largely due to systemic capillary leakage syndrome and should be

managed initially by brisk infusion of crystalloid,

followed by albumin or other colloid if there is no

response.29

Severe hantaviral infections have many of the

management problems of the other hemorrhagic

fevers but will culminate in acute renal failure with

a subsequent polyuria during the patient’s recovery. Careful fluid and electrolyte management,

and often renal dialysis, are necessary for optimal

treatment.

Isolation and Containment

Patients with VHF syndrome generally have significant quantities of virus in their blood, and

perhaps in other secretions as well (with the exceptions of dengue and classic hantaviral disease).

Well-documented secondary infections among

contacts and medical personnel not parenterally

exposed have occurred. Thus, caution should be

exercised in evaluating and treating patients with

suspected VHF syndrome. Over-reaction on the

part of medical personnel is inappropriate and

detrimental to both patient and staff, but it is prudent to provide isolation measures as rigorous as

feasible.30 At a minimum, these should include the

following:

• stringent barrier nursing;

• mask, gown, glove, and needle precautions;

• hazard-labeling of specimens submitted to

the clinical laboratory;

• restricted access to the patient; and

• autoclaving or liberal disinfection of contaminated materials, using hypochlorite or

phenolic disinfectants.

For more intensive care, however, increased precautions are advisable. Members of the patient care

team should be limited to a small number of

selected, trained individuals, and special care

should be directed toward eliminating all parenteral

exposures. Use of endoscopy, respirators, arterial

catheters, routine blood sampling, and extensive

laboratory analysis increase opportunities for

aerosol dissemination of infectious blood and body

fluids. For medical personnel, the wearing of flexible plastic hoods equipped with battery-powered

blowers provides excellent protection of the mucous

membranes and airways.

Specific Antiviral Therapy

Ribavirin is a nonimmunosuppressive nucleoside

analogue with broad antiviral properties,31 and is

of proven value for some of the VHF agents.

Ribavirin reduces mortality from Lassa fever in

high-risk patients,32 and presumably decreases

morbidity in all patients with Lassa fever, for whom

current recommendations are to treat initially with

ribavirin 30 mg/kg, administered intravenously,

followed by 15 mg/kg every 6 hours for 4 days, and

then 7.5 mg/kg every 8 hours for an additional 6

days.30 Treatment is most effective if begun within

7 days of onset; lower intravenous doses or oral

administration of 2 g followed by 1 g/d for 10 days

also may be useful.

The only significant side effects have been anemia and hyperbilirubinemia related to a mild

hemolysis and reversible block of erythropoiesis.

The anemia did not require transfusions or cessation of therapy in the published Sierra Leone study32

or in subsequent unpublished limited trials in West
Viral Hemorrhagic Fevers

599

Africa. Ribavirin is contraindicated in pregnant

women, but, in the case of definite Lassa fever, the

predictability of fetal death and the need to evacuate the uterus justify its use. Safety of ribavirin in

infants and children has not been established.

A similar dose of ribavirin begun within 4 days

of disease is efficacious in patients with HFRS.33 In

Argentina, ribavirin has been shown to reduce virological parameters of Junin virus infection (ie, Argentine hemorrhagic fever), and is now used routinely as an adjunct to immune plasma. However,

ribavirin does not penetrate the brain and is expected to protect only against the visceral, not the

neurological phase of Junin infection.

Small studies investigating the use of ribavirin

in the treatment of Bolivian hemorrhagic fever and

Crimean-Congo hemorrhagic fever have been

promising, as have preclinical studies for Rift Valley fever.33 Conversely, ongoing studies conducted

at USAMRMC predict that ribavirin will be ineffective against both the filoviruses and the flaviviruses.

No other antiviral compounds are currently available for the VHF agents.

Interferon alpha has no role in therapy, with the

possible exception of Rift Valley fever,34 where fatal hemorrhagic fever has been associated with low

interferon responses in experimental animals. However, as an adjunct to ribavirin, exogenous interferon gamma holds promise in treatment of

arenaviral infections.

IMMUNOPROPHYLAXIS AND IMMUNOTHERAPY

Passive immunization has been attempted for

treatment of most VHF infections. This approach has

often been taken in desperation, owing to the limited

availability of effective antiviral drugs. Anecdotal case

reports describing miraculous successes are frequently

tempered by more systematic studies, where efficacy

is less obvious. For all VHF viruses, the benefit of

passive immunization seems to be correlated with the

concentration of neutralizing antibodies, which are

readily induced by some—but not all—of these viruses.

Passive Immunization

Antibody therapy (ie, passive immunization)

also has a place in the treatment of some VHFs.

Argentine hemorrhagic fever responds to therapy

with two or more units of convalescent plasma that

contain adequate amounts of neutralizing antibody

(or an equivalent quantity of immune globulin),

provided that treatment is initiated within 8 days

of onset.35 Antibody therapy is also beneficial in the

treatment of Bolivian hemorrhagic fever. Efficacy

of immune plasma in treatment of Lassa fever36 and

Crimean-Congo hemorrhagic fever37 is limited by

low neutralizing antibody titers and the consequent

need for careful donor selection.

In the future, engineered human monoclonal

antibodies may be available for specific, passive

immunization against the VHF agents. In HFRS, a

passive immunization approach is contraindicated

for treatment, since an active immune response is

usually already evolving in most patients when they

are first recognized, although plasma containing

neutralizing antibodies has been used empirically

in prophylaxis of high-risk exposures.

Active Immunization

The only established and licensed virus-specific

vaccine available against any of the hemorrhagic

fever viruses is yellow fever vaccine, which is

mandatory for travelers to endemic areas of Africa

and South America. For prophylaxis against Argentine hemorrhagic fever (AHF) virus, a liveattenuated Junin vaccine strain (Candid #1) was

developed at USAMRMC and is available as

an Investigational New Drug (IND). Candid #1

was proven to be effective in Phase III studies in

Argentina, and plans are proceeding to obtain

a New Drug license. This vaccine also provides

some cross-protection against Bolivian hemorrhagic fever in experimentally infected primates.

Two IND vaccines were developed at USAMRMC

against Rift Valley fever; an inactivated vaccine that

requires three boosters, which has been in use

for 20 years; and a live-attenuated RVF virus strain

(MP-12), which is presently in Phase II clinical

trials.

For Hantaan virus, a formalin-inactivated rodent

brain vaccine is available in Korea, but is not generally considered acceptable by U.S. standards. Another USAMRMC product, a genetically engineered

vaccinia construct, expressing hantaviral structural

proteins, is in Phase II safety testing in U.S. volunteers. For dengue, a number of live attenuated

strains for all four serotypes are entering Phase II

efficacy testing. However, none of these vaccines

in Phase I or II IND status will be available as licensed products in the near term. For the remaining VHF agents, availability of effective vaccines is

more distant.
Medical Aspects of Chemical and Biological Warfare

600

SUMMARY

The VHF agents are a taxonomically diverse

group of RNA viruses that cause serious diseases

with high morbidity and mortality. Their existence

as endemic disease threats or their use in biological warfare could have a formidable impact on unit

readiness. Significant human pathogens include the

arenaviruses (Lassa, Junin, and Machupo viruses,

the agents of Lassa fever and Argentinean and Bolivian hemorrhagic fevers, respectively). Bunyavirus pathogens include RVF virus, the agent of Rift

Valley fever; C-CHF virus, the agent of CrimeanCongo hemorrhagic fever; and the hantaviruses.

Filovirus pathogens include Marburg and Ebola

viruses. The flaviviruses are arthropod-borne viruses and include the agents of yellow fever, dengue, Kyasanur Forest disease, and Omsk hemorrhagic fever.

The dominant clinical features of VHF are a consequence of microvascular damage and changes

in vascular permeability. Patients commonly

present with fever, myalgia, and prostration. Fullblown VHF syndrome typically evolves to shock

and generalized mucous membrane hemorrhage,

and often is accompanied by evidence of neurological, hematopoietic, or pulmonary involvement.

A viral hemorrhagic fever should be suspected in

any patient who presents with a severe febrile

illness and evidence of vascular involvement

(subnormal blood pressure, postural hypotension,

petechiae, easy bleeding, flushing of the face and

chest, nondependent edema), and who has traveled

to an area where the virus is known to occur, or

where intelligence suggests a biological warfare

threat.

Definitive diagnosis rests on specific virological

diagnosis, including detection of viremia or IgM by

ELISA at presentation. Diagnosis by viral cultivation and identification requires 3 to 10 days or

longer and specialized microbiologic containment.

Appropriate precautions should be observed in collection, handling, shipping, and processing of diagnostic samples. It is prudent to provide isolation

measures that are as rigorous as feasible.

Patients with viral hemorrhagic fevers generally

benefit from rapid, nontraumatic hospitalization to

prevent unnecessary damage to the fragile capillary

bed. Aspirin and other antiplatelet or anticlottingfactor drugs should be avoided. Secondary and concomitant infections including malaria should be

sought and aggressively treated. The management

of bleeding includes administration of fresh frozen

plasma, clotting factor concentrates and platelets,

and early use of heparin to control DIC. Fluids

should be given cautiously, and asanguineous colloid or crystalloid solutions should be used. Multiple organ system support may be required.

Ribavirin is an antiviral drug with efficacy for

treatment of the arenaviruses and bunyaviruses.

Passively administered antibody is also effective in

therapy of some viral hemorrhagic fevers. The only

licensed vaccine available for VHF agents is for yellow fever. Experimental vaccines exist for Junin,

RVF, hantaan, and dengue viruses, but these will

not be licensed in the near future.

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15. Sanchez A, Ksiazek TG, Rollin PE, et al. Reemergence of Ebola virus in Africa. Emerging Infectious Diseases.

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16. Monath TP. Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years

and prospects for the future. Am J Trop Med Hyg. 1991;45(1):1–43.

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1989;11(May–Jun):S854–859.

18. Chumakov MP. Studies of virus hemorrhagic fevers. J Hyg Epidemiol Microbiol Immunol. 1959;7:125–135.

19. Halstead SB. Antibody, macrophages, dengue virus infection, shock, and hemorrhage: A pathogenetic cascade.

Rev Infect Dis. 1989;11(May–Jun):S830–S839.

20. McKay DG, Margaretten W. Disseminated intravascular coagulation in virus diseases. Arch Intern Med.

1967;120:129–152.

21. WHO Collaborating Centre for Research and Training in Veterinary Epidemiology and Management. Report of

the WHO/IZSTE Consultation on Recent Developments in Rift Valley Fever (With the Participation of FAO and OIE).

1993;128:1–23. Civitella del Tronto, Italy; 14–15 September 1993. WHO/CDS/VPH.

22. Rosen L. Disease exacerbation caused by sequential dengue infections: Myth or reality? Rev Infect Dis.

1989;11(May–Jun):S840–S842.

23. Centers for Disease Control and Prevention, National Institutes of Health. Biosafety in Microbiology and Biomedical Laboratories. Washington, DC: US Government Printing Office; 1993. HHS Publication (CDC) 93-8395.

24. 49 CFR, Ch 1, § 173.196. Infectious substances (etiologic agents). 1 October 1994.

25. van der Groen G, Elliot LH. Use of betapropiolactone inactivated Ebola, Marburg and Lassa intracellular antigens in immunofluorescent antibody assay. Ann Soc Belg Med Trop. 1982;62:49–54.

26. Trappier SG, Conaty AL, Farrar BB, Auperin DD, McCormick JB, Fisher-Hoch SP. Evaluation for the polymerase chain reaction for diagnosis of Lassa virus infection. Am J Trop Med Hyg. 1993;49:214–221.

27. Ksiazek TG, Rollin PE, Jahrling PB, Johnson E, Dalgard DW, Peters CJ. Enzyme immunosorbent assay for

Ebola virus antigens in tissues of infected primates. J Clin Microbiol. 1992;30(4):947–950.

28. Fisher-Hoch SP. Arenavirus pathophysiology. In: Salvato MS, ed. The Arenaviridae. New York, NY: Plenum

Press; 1993: Chap 17: 299–323.
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29. Bhamarapravati N. Hemostatic defects in dengue hemorrhagic fever. Rev Infect Dis. 1989;11(4):S826–S829.

30. Centers for Disease Control. Management of patients with suspected viral hemorrhagic fever. MMWR.

1988;37(suppl 3):1–16.

31. Canonico PG, Kende M, Luscri BJ, Huggins JW. In-vivo activity of antivirals against exotic RNA viral infections. J Antimicrob Chemother. 1984;14(suppl A):27–41.

32. McCormick JB, King IJ, Webb PA, et al. Lassa fever: Effective therapy with ribavirin. N Engl J Med. 1986;314:20–

26.

33. Huggins JW. Prospects for treatment of viral hemorrhagic fevers with ribavirin, a broad-spectrum antiviral

drug. Rev Infect Dis. 1989;11(4):S750–S761.

34. Morrill JC, Jennings GB, Cosgriff TM, Gibbs PH, Peters CJ. Prevention of Rift Valley fever in rhesus monkeys

with interferon-α. Rev Infect Dis. 1989;11(May–Jun):S815–825.

35. Enria DA, Fernandez NJ, Briggiler AM, Lewis SC, Maiztegui JI. Importance of neutralizing antibodies in treatment of Argentine haemorrhagic fever with immune plasma. Lancet. 1984;4:255–256.

36. Jahrling PB, Frame JD, Rhoderick JB, Monson MH. Endemic Lassa fever in Liberia, IV: Selection of optimally

effective plasma for treatment by passive immunization. Trans R Soc Trop Med Hyg. 1985;79:380–384.

37. Shepherd AJ, Swanepoel R, Leman PA. Antibody response in Crimean-Congo hemorrhagic fever. Rev Infect

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Defense Against Toxin Weapons

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Chapter 30

DEFENSE AGAINST TOXIN WEAPONS

DAVID R. FRANZ, D.V.M., PH.D.*

INTRODUCTION

UNDERSTANDING THE THREAT

Toxins Compared With Chemical Warfare Agents

Toxicity, Ease of Production, and Stability

Sources of Toxins and Their Mechanisms of Action

Mechanisms of Action and the Development of Countermeasures

Populations at Risk

COUNTERMEASURES

Physical Protection

Real-Time Detection of an Attack

Diagnosis: General Considerations

Approaches to Prevention and Treatment

Decontamination and Protection of Medical Personnel

Sample Collection: General Rules for Toxins

Toxin Analysis and Identification

Water Treatment

THE FUTURE

Toxins as Weapons

Countermeasures to Toxins

SUMMARY

*Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

604

INTRODUCTION

Toxins are biological agents that are produced by

living organisms: bacteria, plants, or animals. Toxins differ significantly from replicating agents (viruses and bacteria) and from classic chemical

agents. The physical characteristics and mechanisms of action of toxins, as a group, dictate how

they must be used as weapons and how they may

be defended against. The terminology used in

the field of toxin weapons is specific, and the definitions given in Exhibit 30-1 will be used in this

textbook.

Some of the toxins described in the chapters that

follow have been identified by the intelligence

community as biological warfare threats. The likely

route of intoxication for soldiers or victims of

EXHIBIT 30-1

TOXIN WEAPONS TERMINOLOGY

Any toxic substance that can be produced by an animal, plant, or microbe. Some

toxins can also be produced by molecular biological techniques (protein toxins) or

by chemical synthesis (low-molecular-weight toxins). Chemical agents, such as soman, sarin, VX, cyanide, and mustard agents, typically man-made for weaponization,

are not included in this discussion except for comparison.

Any toxin weapon capable of causing death or disease on a large scale, such that the

military or civilian infrastructure of the state or organization being attacked is overwhelmed. (NOTE: The commonly accepted term for this category of weapons is “weapons of mass destruction,” although the term brings to mind destroyed cities, bomb

craters, and great loss of life; MCBWs might cause loss of life only. I do not anticipate that “MCBW” will replace the term “weapons of mass destruction” in common

usage, but it is technically more descriptive of toxin, and other biological, weapons.)

Any weapon capable of affecting—directly or indirectly, physically, or through psychological impact—the outcome of a military operation.

Toxin

Mass Casualty

Biological (Toxin)

Weapon (MCBW)

Militarily Significant

(or Terrorist Weapon)

Source: Franz DR. Defense Against Toxin Weapons. Fort Detrick, Frederick, Md: US Army Medical Research Institute of Infectious Diseases; 1996: 4–5.

terrorist attack is through the lung by respirable

aerosols; another possibility is through the gastrointestinal tract by contamination of food or water supplies, although the latter would be difficult

in chlorinated water; or in rivers, lakes, or reservoirs because of dilution effects. The effects of most

toxins are more severe when inhaled than when

consumed in food or injected by bites or stings.

Other toxins can elicit a significantly different clinical picture when the route of exposure is changed,

a phenomenon that may confound diagnosis and

delay treatment. For the most part, physical measures, such as the protective mask and decontamination systems developed for the chemical threat,

can protect against toxins.

UNDERSTANDING THE THREAT

Replicating agents (bacteria and viruses) are clearly

accepted throughout the medical defense community to be biological agents—and there is no

argument that classic chemicals are chemical agents.

Toxins, however, have sometimes been claimed to be

chemicals (saxitoxin and ricin are included in the

chemical weapons convention as placeholders) and

at other times to be biological agents. Even Article I

of the 1972 Biological Weapons Convention contributes to this ambiguity by describing the agents in

question as “Microbial or other biological agents,

or toxins.”1

The purpose of this chapter is to introduce toxins and describe their physical and biochemical

characteristics, and the implications for medical

defense, in the context of the clearly defined, and
Defense Against Toxin Weapons

605

universally accepted, mass-casualty–producing

agent classes. The following theoretical discussion

is based on an understanding of physical and biochemical characteristics of toxins. It is not an intelligence assessment of the threat.

Toxins Compared With Chemical Warfare Agents

Toxins differ from classical chemical agents by

source and physical characteristics. When considering them as biological warfare agents, the physical characteristics of the toxins are much more important than their source. Table 30-1 compares both

types of agents. These are generalizations, and there

are exceptions. The most important differences are

in the areas of volatility and dermal activity. Toxins

also differ from bacterial agents (eg, those causing

anthrax or plague) and viral agents (eg, those causing viral equine encephalitides, or smallpox) in that

toxins do not reproduce themselves.

Because toxins are not volatile, as are chemical

agents, and with rare exceptions, do not directly

affect the skin, an aggressor would have to present

toxins to target populations in the form of respirable aerosols, which allow contact with the more

vulnerable inner surfaces of the lung. This, fortunately, complicates an aggressor’s task by limiting

the number of toxins available for an arsenal. Aerosol particles between 0.5 and 5 μm in diameter are

typically retained within the lung. Smaller particles

can be inhaled, but most are exhaled. Particles larger

than 5 to 15 μm lodge in the nasal passages or trachea and do not reach the lung. A large percentage

of aerosol particles larger than 15 to 20 μm simply

drop harmlessly to the ground. Because they are not

volatile they are no longer a threat—even to unprotected troops. Although there are few data on aerosolized toxins, it is unlikely that secondary aerosol

formation (ie, formation of 1–5 μm particles from

larger, previously deposited droplets) caused by

vehicular or troop movement over ground previously exposed to a toxin aerosol would generate a

respirable toxin aerosol within the breathing zone

of mounted or dismounted troops. (However, this

may not be true with very heavy contamination

with infectious agents such as anthrax spores, which

might occur near the point of agent release from a

munition.)

Toxicity, Ease of Production, and Stability

A toxin’s toxicity, ease of production, and stability are inextricably interconnected. Regardless of its

toxicity, a toxin that cannot be produced in sufficient quantity or is too unstable to survive as an

aerosol after delivery cannot be an effective mass

casualty biological weapon (MCBW). Slightly less

toxic toxins that are easy and inexpensive to produce and deliver, and that are stable as aerosols,

could be real threats, however.

TABLE 30-1

COMPARISON OF TOXINS AND CHEMICAL AGENTS

Characteristics Toxins Chemical Agents

Origin Natural Man-made

Production Difficult, small-scale Large-scale industrial

Volatility None volatile Many volatile

Relative Toxicity Many are more toxic Less toxic than many toxins

Dermal Activity Not dermally active* Dermally active

Use Legitimate medical use No use other than as weapons

Odor and Taste Odorless and tasteless Noticeable odor or taste

Toxic Effects Diverse toxic effects Fewer types of effects

Immunogenicity Many are effective immunogens† Poor immunogens

Delivery Aerosol delivery Mist/droplet/aerosol delivery

*Exceptions are trichothecene mycotoxins, lyngbyatoxin, and some of the blue-green algal toxins. The latter two cause dermal

injury to swimmers in contaminated waters, but are generally unavailable in large quantities and have low toxicity, respectively. †The human body recognizes them as foreign material and makes protective antibodies against them.

Adapted from Franz DR. Defense Against Toxin Weapons. Fort Detrick, Frederick, Md: US Army Medical Research Institute of Infectious Diseases; 1996: 6.
Medical Aspects of Chemical and Biological Warfare

606

Because it must be delivered as a respirable aerosol, the utility of a toxin as an MCBW is limited by

its toxicity and ease of production. The laws of

physics dictate how much toxin of a given toxicity

is needed to fill a given space with a small-particle

aerosol. Figure 30-1 is a schematic representation

of a theoretical calculation of the approximate quantities of toxins of varying toxicities required to intoxicate people exposed in large, open areas on the

battlefield under optimal meteorological conditions. This figure is based on a mathematical model

that was field tested in the 1960s (open-air testing)

and found to be valid. It shows that a toxin with an

aerosol toxicity of 0.025 mg/kg would require 80

kg of toxin to cover 100 km2 with an effective cloud

that exposes individuals within the cloud to a dose

that would be lethal to approximately 50% of those

exposed (LD50). For example, a typical 70-kg soldier would have a 50% chance of surviving after

receiving a 70-mg dose of a toxin with an LD50 of

1.0 mg/kg. Note that for toxins less toxic than botulinum or the staphylococcal enterotoxins, hundreds

of kilograms or even tons would be needed to cover

an area of 100 km2 with an effective aerosol. Table

30-2 shows the mouse LD50s of 25 toxins and chemical warfare agents.

During the U.S. biological warfare program,

which ended in 1969, toxicity calculations were

based on LD50 values as described above. The mathematical formulae developed by Calder and validated in field trials used the LD50 as a measure

of toxicity.2

 Calculation of the LD50 of an aerosol

requires a number of assumptions regarding respiratory minute volume of the experimental animal,

and the percentage of the inhaled aerosol retained

in the lung and airways during the period of exposure. In an attempt to improve accuracy, reproducibility, and data comparability within and between

species, values called LCt50 values have been generated in recent years for aerosols. LCt50 is the product of the average concentration (C, in mg/m3) and

the exposure time (t, in min) that is lethal (L) to

50% of the population exposed (the units are expressed as mg•min/m3). LCt50 values for selected

toxins in mice and rhesus monkeys are shown in

Table 30-3.

Fig. 30-1. Toxicity, in mouse LD50 (see Table 30-2), plotted against the quantity of toxin required to provide a theoretically effective open-air aerosol exposure, under ideal meteorological conditions, to an area of 100 km2. Although the

toxicity is based on direct studies with mice, it is believed to be very similar in humans. The mathematical model

corrects for human parameters such as respiration. Ricin, saxitoxin, and botulinum, and trichothecene mycotoxins

(T-2) kill at the concentrations depicted. Adapted from Spertzel RO, Wannemacher RW, Patrick WC, Linden CD,

Franz DR. Technical Ramifications of Inclusion of Toxins in the Chemical Weapons Convention (CWC). Alexandria, Va:

Defense Nuclear Agency; 1992: 18. DNA Technical Report 92-116.

Botulinum Toxins 0.0025

0.025

0.25

2.5

25

250

2,500

8 80 800 8 80 800 8,000

Ricin/Saxitoxin

Aerosol Toxicity (μg/kg)

Most

Toxic

Highly

Toxic

T-2 Mycotoxin

Moderately

Toxic

Kilogram Metric Tonne
Defense Against Toxin Weapons

607

TABLE 30-2

COMPARATIVE LETHALITY OF SELECTED TOXINS AND CHEMICAL AGENTS IN

LABORATORY MICE

Agent LD50 (μg/kg)* Molecular Weight† Source

Botulinum Toxin 0.001 150,000 Bacterium

Shiga Toxin 0.002 55,000 Bacterium

Tetanus Toxin 0.002 150,000 Bacterium

Abrin 0.04 65,000 Plant (rosary pea)

Diphtheria Toxin 0.10 62,000 Bacterium

Maitotoxin 0.10 3,400 Marine dinoflagellate

Palytoxin 0.15 2,700 Marine soft coral

Ciguatoxin 0.40 1,000 Fish, marine dinoflagellate

Textilotoxin 0.60 80,000 Elapid snake

Clostridium perfringens toxins 0.1–5.0 35,000–40,000 Bacterium

Batrachotoxin 2.0 539 Arrow-poison frog

Ricin 3.0 64,000 Plant (castor bean)

α-Conotoxin 5.0 1,500 Cone snail

Taipoxin 5.0 46,000 Elapid snake

Tetrodotoxin 8.0 319 Puffer fish

α-Tityustoxin 9.0 8,000 Scorpion

Saxitoxin 10.0 (Inhal: 2.0) 299 Marine dinoflagellate

VX 15.0 267 Chemical agent

Staphylococcus Enterotoxin B 27.0 28,494 Bacterium

(Rhesus/Aerosol)

Anatoxin-A(s) 50.0 500 Blue-green algae

Microcystin 50.0 994 Blue-green algae

Soman (GD) 64.0 182 Chemical agent

Sarin (GB) 100.0 140 Chemical agent

Aconitine 100.0 647 Plant (monkshood)

T-2 Toxin 1,210.0 466 Fungal mycotoxin

*LD50s are approximate, drawn from numerous published and unpublished sources. Routes of administration are typically intraperitoneal or intravenous.

†Note the general inverse relation between toxicity and molecular weight.

Reprinted from Medical Management of Biological Casualties Handbook. Fort Detrick, Frederick, Md: US Army Medical Research Institute of Infectious Diseases; Aug 1993: Appendix.

Ignoring other characteristics, if a toxin is not

adequately toxic, sufficient quantities cannot be

produced to make even one weapon. Because of

their low toxicity, therefore, hundreds of toxins can

be eliminated as ineffective as MCBWs. Certain

plant toxins with marginal toxicity could be produced in large (ton) quantities. These toxins could

possibly be weaponized. At the other extreme, several bacterial toxins are so lethal that MCBW quantities are measured not in tons, but in kilograms—
Medical Aspects of Chemical and Biological Warfare

608

quantities more easily produced. Such toxins are

potential threats to our soldiers on the battlefield.

Stability of toxins after aerosolization is also an

important factor, because it further limits toxin

weapon effectiveness. Some toxins are adequately

toxic and can be produced in sufficient quantities

for weapons, but are too unstable in the atmosphere

to be candidates for weaponization. Although stabilization of naturally unstable toxins and enhanced

production of those toxins now difficult to produce

are possibilities for the future, no evidence exists

at this time for successful amplification of toxicity

of a naturally occurring toxin.

Incapacitation as well as lethality to humans

must be considered. A few toxins cause illness at

levels many times less than the concentration

needed to kill. For example, toxins that directly affect the membranes, fluid balance, or both within

the lung may greatly reduce gas transport without

causing death. Less-potent toxins could also be significant threats as aerosols in a confined space such

as a building; delivery could be into the filtration,

heating, and air-conditioning systems. Finally,

breakthroughs in delivery-vehicle efficiency or

toxin “packaging” by an aggressor might alter the

relation between toxicity and quantity; but even at

best, the quantities needed could probably be reduced by only one half for a given toxicity. For now,

however, the relation shown in Figure 30-1 provides

a reasonable and valid way to sort potential threat

toxins.

Militarily significant weapons need not be

MCBWs. Thirty-nine Iraqi-modified Scud missiles

reached Israel from 18 January through 28 FebruTABLE 30-3

LCt50S FOR SELECTED TOXINS IN MICE AND

RHESUS MONKEYS

Toxin Mouse LCt50 Rhesus Monkey LCt50

(mg•min/m3) (m g•min/m3)

Botulinum A 0.0225 0.0225

Ricin 3–7 114

Saxitoxin 3 —

T-2 Toxin 200 —

Staphylococcus

Enterotoxin B NA 80–100

Source: Pitt L, PhD. Chief, Department of Aerobiology and Product Evaluation, Toxinology Division, US Army Medical Research

Institute of Infectious Diseases, Fort Detrick, Frederick, Md.

Personal communication, July 1996.

ary 1991. Although many of the Scuds were off target or malfunctioned, some of them landed in and

around Tel Aviv. Approximately 1,000 people

were treated as a result of the missile attacks,

but only 2 died. Anxiety was listed as the reason

for admitting 544 patients and atropine overdose for hospitalization of 230 patients.3

 The remainder (226 patients) suffered traumatic injury.

Clearly, these Scuds were not effective mass

casualty weapons, yet they caused significant disruption to the population of Tel Aviv. Approximately 75% of the 1,000 casualties were injured as

a result of their own inappropriate actions or reactions. Had one of the warheads contained a toxin

that killed or intoxicated a few people, the “terror

effect” would have been even greater. Therefore,

many toxins that are not sufficiently toxic for use

in an open-air MCBW could probably be used to produce a militarily significant weapon. However, the

likelihood that such a toxin weapon will cause panic

among military personnel decreases when the leaders and troops become better educated regarding

toxins.

Sources of Toxins and Their Mechanisms of Action

Toxins vary as to their source of production,

molecular structure and size, and mechanism of

action. Article I of the 1972 Biological Weapons

Convention includes the concept of “toxins whatever their origin or method of production”1

 for good

reason. Although in nature toxins are produced by

microorganisms, plants, and animals, many of them

can also be produced synthetically; this is generally not true of replicating agents. Ease of production—whether natural or synthetic—is obviously an

important factor in evaluating a threat toxin, but a

toxin’s method of production does not change its

molecular structure or mechanism of action.

Regarding molecular structure and size, the

terms “low-molecular-weight” and “protein” toxins are commonly used. Low-molecular-weight

toxins are typically less than 1,000 dalton (d), or

approximately 10 amino acids, and may be either

organic molecules or peptides. Protein toxins are

proteins generally greater than approximately 10

amino acids.

The mechanism of action of a toxin does not necessarily correlate with either its source or its molecular structure or size. Understanding the mechanism of toxicity by the threat route of challenge is,

however, the first step in developing medical countermeasures for a toxin, and is often the most important factor influencing what approach will be
Defense Against Toxin Weapons

609

taken to protect soldiers. For toxins, there are two

general categories of mechanism of action:

1. Neurotoxins exert direct effects on nervous

system function, most often the peripheral

nervous system. These effects are typically

temporary or reversible.

2. Membrane-damaging toxins actually

destroy or damage tissues or organs, directly or indirectly through the release of

mediators of disease. The effects of membrane-damaging toxins are less commonly

reversible.

Although each of these factors will be discussed

in detail in individual agent chapters, the concepts

and their implications for the protection of soldiers

are introduced here. There is little correlation between the artificial groupings (source, molecular

structure, and mechanism of action) commonly

used to categorize toxins. The natural source and

the implications of mechanism of action of toxins

on the development of medical countermeasures are

discussed below.

Bacterial Toxins

The most toxic biological materials known are

protein toxins produced by bacteria. They are generally more difficult to produce on a large scale than

are the plant toxins, but they are many, many times

more toxic. Botulinum toxins (seven related toxins),

the staphylococcal enterotoxins (also seven different toxins), diphtheria, and tetanus toxin are wellknown examples of bacterial toxins.

The botulinum toxins are so very toxic that lethal aerosol MCBW weapons could be produced

with quantities of toxin that are relatively easily attainable with present technology. They cause death

through paralysis of respiratory muscles without

producing microscopic change in the tissues.

Staphylococcal enterotoxins, when inhaled, cause

fever, headache, diarrhea, nausea, vomiting, muscle

aches, shortness of breath, and a nonproductive

cough within 2 to 12 hours after exposure. They can

also kill, but only at much higher doses. Staphylococcal enterotoxin B (SEB) can incapacitate at levels at least 100-fold lower than the lethal level. These

toxins, too, would probably be delivered as respirable aerosols.

Other bacterial toxins, classified generally as

membrane-damaging, are derived from Escherichia

coli (which produces hemolysins), Aeromonas,

Pseudomonas, and Staphylococcus, (which also produce cytolysins and phospholipases), and are moderately easy to produce, but they vary a great deal

in stability. Many of these toxins affect bodily functions or even kill by forming pores in cell membranes. In general, their lower toxicities make them

less likely battlefield threats.

Marine Toxins

A number of the toxins produced by marine organisms, or by bacteria that live in marine organisms, might be used in terrorist biological weapons

(where less agent would be needed to achieve the

desired effect), but they are unlikely threats on the

open battlefield. For many of these low-molecularweight marine toxins, either difficulty of production or lack of sufficient toxicity limits the likelihood of their use as MCBWs.

Saxitoxin, the best known example of this group,

is a potent neurotoxin found in shellfish such as

mussels, clams, and scallops. Saxitoxin is a sodium

channel–blocking agent and is more toxic by inhalation than by other routes of exposure. Unlike oral

intoxication with saxitoxin (paralytic shellfish poisoning), which has a relatively slow onset, inhalational intoxication with saxitoxin can be lethal in a

few minutes. Saxitoxin could be used against our

troops as an antipersonnel weapon, but because it

cannot currently be chemically synthesized efficiently, or produced easily in large quantities from

natural sources, it is unlikely to be seen as an area

aerosol weapon on the battlefield.

Tetrodotoxin, from the puffer fish and other

members of the order Tetraodontiformes, is a neurotoxin much like saxitoxin in its mechanism of action, toxicity, and physical characteristics. Palytoxin,

from the soft coral Palythoa tuberculosa, is extremely

toxic and quite stable in impure form, but difficulty

of production or harvest from nature reduces the

likelihood that an aggressor would use it as an

MCBW. The brevetoxins, commonly associated with

“red tide” dinoflagellate blooms, and the blue-green

algal toxins like microcystin, a hepatotoxin, have

limited toxicity.

Fungal Toxins

The trichothecene mycotoxins, which are toxins

produced by various species of fungi, are also examples of low-molecular-weight toxins (MW <

1,000 d). The yellow rain incidents in Southeast Asia

in the early 1980s are believed to have demonstrated

the utility of one of the trichothecene mycotoxins,

T-2, as a biological warfare agent.
Medical Aspects of Chemical and Biological Warfare

610

T-2 is one of the more stable toxins, retaining its

bioactivity even when heated to high temperatures.

High concentrations of sodium hydroxide and sodium hypochlorite are required to detoxify it. Aerosol toxicities are generally too low to make this class

of toxins useful to an aggressor as an MCBW as

defined in Figure 30-1; however, unlike most toxins, these are dermally active. Clinical presentation

includes nausea, vomiting, weakness, low blood

pressure, and burns in exposed areas.

Plant Toxins

Toxins derived from plants are generally very

easy to produce in large quantities at minimal cost

in a low-technology environment. Ricin, a protein

derived from the bean of the castor plant, and abrin,

a very similar toxin from Abrus precatorius are typical plant toxins.

Worldwide, approximately 1 million tons of castor beans are processed annually in the production

of castor oil. The resulting waste mash is approximately 3% to 5% ricin by weight. Because of its marginal toxicity, at least 1 tonne (1,000 kg) of the toxin

would be necessary to produce an MCBW (see Figure 30-1). Unfortunately, the precursor raw materials

are available in these quantities throughout the world.

Venom Toxins

Animal venoms often contain a number of toxic

and nontoxic proteins. Until recently, it would have

been practically impossible to collect enough of

these materials to develop them as biological weapons. However, many of the venom toxins have now

been sequenced (ie, their molecular structure has

been determined), and some have been cloned and

expressed (ie, produced by molecular biological techniques). Some of the smaller ones could also be produced by relatively simple chemical synthesis methods. The following are examples of the mechanisms

of action and sources of venom toxins:

• ion channel (cationic) toxins, such as those

found in the venoms of the rattlesnake,

scorpion, and cone snail;

• presynaptic phospholipase A2 neurotoxins

of the banded krait, Mojave rattlesnake, and

Australian taipan snake;

• postsynaptic (curare-like alpha toxin) neurotoxins of the coral, mamba, cobra, and sea

snakes, and the cone snail;

• membrane-damaging toxins of the Formosan cobra and rattlesnake; and

• coagulation/anticoagulation toxins of the

Malayan pit viper and carpet viper.

Some of the toxins in this group must be considered potential future threats to our soldiers as largescale production of peptides becomes more efficient.

However, because many of these toxins are difficult to produce in large quantities, their threat potential may be limited.

Mechanisms of Action and the Development of

Countermeasures

Unlike chemical agents, toxins differ widely in

their mechanisms of action. The medical protection

of soldiers is therefore difficult; seldom will a vaccine or therapy be effective against more than one

toxin. (NOTE: We can prepare for a battlefield

threat—unlike a terrorist threat—by developing

specific medical countermeasures. Vaccines and

other prophylactic measures can be given before

combat, and therapies can be kept at the ready.)

Countermeasures are discussed in general later in

this chapter and in detail in specific agent chapters

in this textbook.

Neurotoxins

Saxitoxin. Some neurotoxins, such as saxitoxin

and tetrodotoxin, can kill an individual very quickly

after inhalation of a lethal dose (within minutes).

These toxins act by blocking nerve conduction directly and cause death by paralyzing muscles of

respiration. Yet, at just less than a lethal dose, the

exposed individual may not even feel ill, or may

only feel dizzy.

Because of the rapid onset of signs after inhalation, prophylaxis (either immunization or pretreatment) would be required to protect soldiers from

these two rapidly acting neurotoxins. Unprotected

soldiers who inhale a lethal dose would probably

die before they could be helped, unless they could

be intubated and artificially ventilated immediately.

Although the mechanism of death after inhalation

of saxitoxin is believed to be the same as when the

toxin is administered intravenously, it is more toxic

if inhaled.

Botulinum Toxins. Other neurotoxins, such as the

botulinum toxins, must enter nerve terminals before they can block the release of neurotransmitters,

which normally cause muscle contraction. These

large-protein neurotoxins generally kill by relatively slow onset respiratory failure (within hours

to days). The intoxicated individual may not show
Defense Against Toxin Weapons

611

signs of disease for 24 to 72 hours. The toxin blocks

biochemical action in the nerves that activate the

muscles necessary for respiration, leading to suffocation.

Intoxications such as this can be treated with

antitoxin injected hours after exposure to a lethal

dose of toxin (< 24 h in monkeys, and probably also

in humans), and still prevent illness and death. Although the mechanisms of toxicity of the botulinum

toxins appear to be the same after any route of exposure, the actual toxicity of the botulinum toxins

is less by inhalation.

Membrane-Damaging Toxins

While neurotoxins effectively stop nerve and

muscle function without causing microscopic damage to the tissues, membrane-damaging toxins destroy or damage tissue directly. For these toxins,

prophylaxis is important, because the point at

which the pathological change becomes irreversible

often occurs within minutes to a few hours after

exposure.

Microcystin. An example of this type of toxin is

microcystin (produced by blue-green algae), which

binds covalently to a phosphatase inside liver cells;

this toxin does not damage other cells of the body.

Unless uptake of the toxin by the liver is blocked,

irreversible damage to the organ occurs within 15

to 60 minutes after exposure to a lethal dose. When

this happens, the tissue damage to the liver is so

severe that therapy may have little or no value. For

microcystin, unlike most toxins, the toxicity is the

same, no matter what the route of exposure.

Ricin. When dealing with membrane-damaging

toxins, the consequences of intoxication, thus the

pathogenesis of disease, may vary widely with

route of exposure, even with the same toxin. Ricin,

a plant toxin, kills by blocking protein synthesis in

many cells of the body, but no lung damage occurs

with any exposure route except inhalation. If ricin

is inhaled, however, as would be expected during a

biological attack, microscopic damage is limited

primarily to the lung, and death is caused by a

mechanism different from that of injected toxin.

Furthermore, when equivalent doses of toxin are

used, much more protective antibody must be injected to protect from inhalational exposure than

from intravenous injection. Finally, although signs

of intoxication may not be noted for 12 to 24 hours,

microscopic damage to lung tissue begins within 8

to 12 hours or less. Irreversible biochemical changes

may occur within 60 to 90 minutes after exposure,

again making therapy difficult.

Trichothecene Mycotoxins. Only one class of easily produced, membrane-damaging toxins, the

trichothecene mycotoxins, is dermally active. Therefore, they must be considered by standards different from those for all other toxins. Trichothecenes

can cause skin lesions and systemic illness without

being inhaled and absorbed through the respiratory

system. Skin exposure and ingestion of contaminated food are the two likely routes of exposure of

soldiers; oral intoxication is unlikely in modern,

well-trained armies. Nanogram quantities per

square centimeter of skin cause irritation, and microgram quantities cause necrosis. If the eye is exposed, microgram doses can cause irreversible injury to the cornea.

The aerosol toxicity of even the most toxic

trichothecene is low enough that the large-quantity

production required (approximately 80 tonnes to

expose a 10-km2 area with respirable aerosol) makes

an inhalational threat unlikely on the battlefield.

These toxins, therefore, might be dispersed as larger

particles, probably visible in the air and on the

ground and foliage.

In contrast to treatment for exposure to any of

the other toxins, simply washing the skin with soap

and water within 1 to 3 hours after exposure to the

trichothecene mycotoxins will eliminate or greatly

reduce the risk of illness or injury.

Populations at Risk

Because there are hundreds of toxins available

in nature, the job of protecting troops against them

seems overwhelming. It might seem that an aggressor would need only to discover the toxins against

which we can protect our troops, and then pick a

different one to weaponize. In reality, however, it

is not that simple. The utility of toxins as MCBWs

is limited by their toxicity (see Figure 30-1). This

criterion alone reduces the list of potential openair, weaponizable toxins for MCBWs from hundreds

to fewer than 20. Issues related to stability and

weaponization will not be addressed here, but

would further reduce the list and make the

aggressor’s job more difficult.

An armored or infantry division in the field is

not at great risk of exposure to a marine toxin whose

toxicity is so low that 80 tonnes is needed to produce an MCBW covering 10 km2. Most marine toxins are simply too difficult to produce in such quantities. Military leaders on today’s battlefield should be

concerned first about the most toxic bacterial toxins.

The more confined the military or terrorist target (eg, inside shelters, buildings, ships, or vehicles),
Medical Aspects of Chemical and Biological Warfare

612

TABLE 30-4

ARBITRARY CATEGORIZATIONS* OF TOXIN

TOXICITY

Most Highly Moderately

Toxic Toxic Toxic

(Number of toxins in each category)

Bacteria 17 12 > 20 > 49

Plants 5 > 31 > 36

Fungi > 26 > 26

Marine

organisms > 46 > 65 > 111

Snakes 8 >116 >124

Algae 2 > 20 > 22

Insects > 22 > 22

Amphibians > 5 > 5

Total 17 > 73 >305 >395

*Most toxic (LD50 < 0.025 μg/kg), highly toxic (LD50 0.025–2.5

μg/kg), moderately toxic (LD50 > 2.5 μg/kg)

Adapted from Spertzel RO, Wannemacher RW, Patrick WC, Linden CD, Franz DR. Technical Ramifications of Inclusion of Toxins

in the Chemical Weapons Convention (CWC). Alexandria, Va: Defense Nuclear Agency; 1992: 13. DNA Technical Report 92-116.

the greater the list of potential toxin threats that

might be effective. This concern is countered, however, by the fact that toxins are not volatile like the

chemical agents and are thus more easily removed

from air-handling systems. It is probably most cost

effective to protect our personnel from these lesstoxic toxins through the use of collective filtration

systems.

Nonetheless, we must consider subpopulations

of troops and areas within which they operate when

we estimate vulnerability to a given toxin threat.

Because of differences in operational environments,

situations could well occur in which different populations of troops require protection from different

toxins. To protect them effectively, military decision

makers and leaders must understand the nature of

the threat and the physical and medical defense

solutions.

Table 30-4 gives the approximate number of

known toxins by toxicity level and source. To simplify our approach to the development of medical

countermeasures, we have divided them into “Most

Toxic,” “Highly Toxic,” and “Moderately Toxic” categories (also see Figure 30-1). The most toxic toxins

could probably be used in an MCBW; it is feasible

to develop individual medical countermeasures

against them. The highly toxic toxins could probably be used in closed spaces such as the air-handling system of a building or as relatively ineffective terror weapons in the open; collective filtration

would be effective against these toxin aerosols targeted to enclosed spaces. The moderately toxic toxins would likely be useful only as assassination

weapons, which would require direct attack against

an individual; it is not feasible to develop medical

countermeasures against all of the toxins in this

group. Such reasoning allows us to use limited resources most effectively and to maximize protection, and thus effectiveness, of our fighting force.

COUNTERMEASURES

Physical Protection

As stated above, most toxins are neither volatile

nor dermally active. Therefore, an aggressor would

most likely attempt to present them as respirable

aerosols. Toxin aerosols should pose neither a

significant residual environmental threat nor

remain on the skin or clothing. The typical toxin cloud would, depending on meteorological conditions, either drift with the wind close to

the ground or rise above the surface of the Earth

and be diluted in the atmosphere. There may, however, be residual contamination near the munitionrelease point. Humans in the path of a true aerosol

cloud would be exposed as the agent drifts through

that area. The principal way humans are exposed

to such a cloud is through breathing. Aerosol particles must be drawn into the lungs and retained to

cause harm.

The protective mask, worn properly, is effective

against toxin aerosols. Its efficacy, however, depends on two factors: (1) mask-to-face or hood-tohead fit and (2) use during an attack. Proper fit is

vital. Because of the extreme toxicity of some of the

bacterial toxins, a relatively small leak could result

in a significant exposure. Eyes should be protected

when possible. Definitive studies have not been

done to assess the effects of aerosolized toxins on

the eyes. In general, however, ocular exposure to a

toxin aerosol, unless the exposed individual is near

the release point, would be expected to cause few

systemic effects because of the low doses absorbed.

A few toxins have direct effects on the eyes, but

these are generally not toxins we would expect to

be used as aerosols. Donning the protective mask

prior to exposure would, of course, protect the eyes.

Because important threat biological warfare

agents are not dermally active and must be preSource of

Toxin Total
Defense Against Toxin Weapons

613

sented as respirable aerosols, special protective

clothing other than the mask is less important in a

toxin attack than in a chemical attack. Presently

available protective clothing should be effective

against biological threats as we know them. Commanders should carefully consider the relative impact of thermal load and the minimal additional

protection provided by protective clothing.

Real-Time Detection of an Attack

Because of the nature of the threat, soldiers may

be dependent on a mechanical detection-and-warning system to notify them of impending or ongoing

attack. Without timely warning, their most effective generic countermeasure, the protective mask, may

be of limited value. Real-time detectors of a chemical

agent attack have been successfully developed. Biological agent detectors will be more difficult to develop, for several reasons. As stated above, these

agents must be presented as respirable aerosols,

which act as a cloud, not as droplets (as the chemical agents are delivered) that fall to the ground and

evaporate with time. The toxin cloud, typically delivered at night with a slight wind, would be expected to move across the battlefield until it either

rises into the atmosphere to be diluted or settles,

relatively harmlessly, to the ground. Unlike chemical agents, which might be detectable for hours,

toxins might be detectable in the air at one location

only for a few minutes. Definitive, specific toxin

detectors would have to sample continuously or be

turned on by a continuous sampler of some kind.

Furthermore, toxin detectors (assuming the

present state of technology) would probably require

the specificity of immunoassays to identify a toxin

and differentiate it from other organic material in

the air. Continuous monitoring by such equipment

would be extremely costly, reagent-intensive, and

very difficult to support logistically because of the

reagent requirements. Identifying each toxin would

require a different set of reagents if an immunoassay system were used.

Analytical assays would necessarily be more

complex and less likely to identify distinct toxins,

but they might detect that something unusual was

present. Imagine the difficulty of developing a detection system based on molecular weight or other

physical characteristics to differentiate among the

seven botulinum toxins (molecular weight is the

same for all, but each requires a different, specific

antibody for identification or therapy).

Finally, to be effective, a detector would have to

be located where it could “sniff” a toxin cloud in

time to warn the appropriate population. This might

be possible on a battlefield but would be nearly

impossible, except in selected high-risk facilities, in

the case of a terrorist attack. However, if all the capabilities described were developed and available

at the right place and time, it is possible that an

aerosol cloud of almost any of the toxins of concern could be detected and identified. Future advances in technology could well resolve our present

technical difficulties.

Diagnosis: General Considerations

Medical personnel often ask whether they will

be able to tell the difference among cases of inhalational botulinum, staphylococcal enterotoxin intoxication, and chemical nerve agent poisoning. Table

30-5 describes these differences. In general, nerve

agent poisoning has a rapid onset (minutes) and

induces increased body secretions (saliva, airways

secretions), pin-point pupils, and convulsions or

muscle spasms. Botulinum intoxication has a slow

onset (12–72 h) and manifests as visual disturbance,

skeletal muscle weakness and/or paralysis of

oropharyngeal muscles. Staphylococcal enterotoxin

B poisoning has an intermediate (few hours) time

of onset and is typically not lethal but is severely

incapacitating. Chemical nerve agent poisoning is

a violent illness resulting in respiratory failure because of muscle spasm, airway constriction, and

excessive fluid in the airways. Botulinum-intoxicated patients simply get very tired and very weak;

if they die, it is because the muscles of respiration

fail. Staphylococcal enterotoxin B–intoxicated patients become very sick but typically survive with

supportive therapy.

Medical personnel should consider toxins in the

differential diagnosis, especially when multiple

patients present with similar clinical syndromes.

Patients should be viewed epidemiologically and

asked about where they were, whom they were

with, what they observed, how many other soldiers

were and are involved, and so forth. Inhaled and retained doses of toxins will differ among soldiers exposed to the same aerosol cloud. Those who received

the highest dose typically will show signs and symptoms first. Others will present somewhat later, while

still others in the same group may be unaffected. The

distribution of severities within the group of soldiers

may vary with type of exposure and type of toxin.

For example, exposing a group of individuals to the

staphylococcal enterotoxins by inhalation would

likely make a large percentage (80%) of them sick,

but would result in few deaths. Exposing a group
Medical Aspects of Chemical and Biological Warfare

614

of soldiers to a cloud of botulinum toxin might kill

50%, make 20% very sick, and leave 30% unaffected.

Medical personnel must consider the varying latent periods before onset of clinical signs. For patients exposed to toxins by aerosol, the latent period varies from minutes (saxitoxin, microcystin) to

hours (the staphylococcal enterotoxins), even to

days (ricin, the botulinum toxins).

Medical personnel must also save clinical and

environmental samples for diagnosis. Immunoassays and analytical tests are available for many of

the toxins. Environmental toxin samples taken directly from a weapon or other hardware are often

easier to test than biological samples because they

do not contain body proteins and other interfering

materials.

The best early diagnostic sample for most toxins

is a swab from the nasal mucosa. In general, the

more-toxic toxins are more difficult to detect in tissues and body fluids, because so little toxin needs

to be present in the body to exert its effect. The capability exists however, to identify most of the important toxins in biological fluids or tissues, and

many other toxins in environmental samples. Definitive laboratory diagnosis might take 48 to 72

hours; however, prototype field assays that can

identify some toxins within 30 minutes have been

developed recently. For individuals who survive an

attack with toxins of lower toxicity, immunoassays

that detect immunoglobulins M or G offer a means

of diagnosis, identification, or confirmation of agent

within 2 to 3 weeks after exposure.

Approaches to Prevention and Treatment

In developing medical countermeasures, each

toxin must be considered individually. Some incapacitate so quickly that there would be little time

for therapy after an attack. Others cause few or no

clinical signs for many hours, but they set off irreversible biochemical processes in minutes or a few

hours that lead to severe debilitation or death several

days later. Fortunately, some of the most potent bacterial protein toxins act slowly enough that, if they

are identified, therapy initiated 12 to 24 hours after

exposure is usually successful. Active and passive

immunoprophylaxes are currently available but are

not licensed for all high-threat toxins. ImmunizaTABLE 30-5

DIFFERENTIAL DIAGNOSIS OF CHEMICAL NERVE AGENT, BOTULINUM TOXIN, AND

STAPHYLOCOCCAL ENTEROTOXIN B INTOXICATION FOLLOWING INHALATIONAL EXPOSURE

Chemical Nerve Agent

Signs and Symptoms (Organophosphate) Botulinum Toxin Staphylococcal Enterotoxin B

Time to Onset

Nervous

Cardiovascular

Respiratory

Gastrointestinal

Ocular

Salivary

Death

Response to Atropine/

2-PAM Cl

Minutes

Convulsions, fasciculations

Bradycardia

Difficult breathing,

constricted airways

Increased motility, pain,

diarrhea

Small pupils

Profuse, watery saliva

Minutes

Yes

Hours (12–72)

Progressive paralysis

Normal rate

Normal, then progressive

paralysis

Decreased motility

Droopy eyelids

Normal, but swallowing

difficult

2–10 d

No

Hours (2–12)

Headache, muscle aches

Normal rate or tachycardia

Nonproductive cough

In severe cases: chest pain,

difficult breathing

Nausea, vomiting and/or

diarrhea

Conjunctival injection

possible

Slightly increased quantities

of saliva possible

Unlikely

Atropine may reduce

gastrointestinal symptoms

2-PAM Cl: 2-pyridine aldoxime methyl chloride
Defense Against Toxin Weapons

615

tion, pretreatment, and specific drug therapies are

the subjects of considerable research interest.

Active Immunization

It is always better to prevent casualties than to

treat injured soldiers. For most of the significant

threat toxins in military situations, vaccination is

the most effective means of preventing casualties.

Unlike the chemical warfare agents, many of the

important threat toxins are highly immunogenic.

Immunized laboratory animals are totally protected

from high-dose aerosols of these toxins. Immunization requires a knowledge of the threat, an available vaccine, and time. The minimum time needed

to allow the body to make its own protective antibodies to a toxin may range from 4 to 6 weeks, to

12 to 15 weeks, or longer. Some vaccines currently

in use require multiple injections, often administered weeks apart. The logistical burden of assuring that troops are given booster immunizations at

the correct time could be overwhelming in a fastmoving buildup to hostilities.

The time and effort required for immunization

can possibly be reduced. For example, antigens are

being microencapsulated to form timed-release vaccines that might provide the primary immunization,

a booster dose 2 weeks later, and another booster

dose 10 weeks after that—all with one injection.

Another approach is being evaluated with current

Medical Biological Defense Research Program vaccines. Soldiers could be given a priming dose and

the first booster dose 2 weeks apart, while in basic

training. The response generated by the immune

system’s memory cells (ie, the B lymphocytes) might

last for many months or even years, although not

all soldiers would develop fully protective immunity after only two immunizations. Shortly before

the onset of hostilities, or when the soldier is assigned to a rapidly deployable unit, one booster

dose could provide protective immunity quickly,

and preclude the need for additional booster doses

after deployment. Preliminary data suggest that a

booster dose administered up to 24 months (the

greatest interval thus far tested) after two initial

priming doses will be effective, even with moderately immunogenic vaccines such as the current

botulinum toxoid.

Passive Antibody Prophylaxis

Passive antibody prophylaxis is generally quite

effective in protecting laboratory animals from toxin

exposure. However, this option is of little real utility for large groups of people for several reasons.

The protection provided by human antibody may

last for only 1 to 2 months, and protection afforded

by despeciated horse antibody may last for only a

few weeks. Therefore, antibody prophylaxis would

be practical only when the threat is both clearly

understood and imminent. Furthermore, it is unlikely that animal antibody would be used in an

individual before intoxication because of the risk,

albeit small, of an adverse reaction to foreign protein. The latter problem may be overcome within

the next few years, as the production of human

monoclonal antibodies or the “humanization” of

mouse monoclonal antibodies becomes practical.

Unfortunately, single monoclonal antibodies are

seldom as effective against toxins as polyclonal antibodies, such as those produced naturally in other

humans or horses. However, combined antibody

therapy, or “cocktails” of more than one monoclonal

antibody, may overcome this problem in the future.

Postexposure prophylaxis (ie, treatment after

exposure but before signs and symptoms develop)

with antibodies from human or animal sources is

feasible for some of the threat toxins. Passive immunotherapy is very effective after exposure to

botulinum toxin if treatment is begun soon enough,

up to 24 hours after high-dose aerosol exposure to

the toxin. The utility of antibody therapy drops

sharply at or shortly after the onset of the first signs

of disease. It appears that a significant amount of

the toxin has, at that time, been taken up by areas

of the body that cannot be reached by circulating

antibodies. Antibody therapy given after the onset

of signs may shorten the time that a patient must

be given ventilatory support. The available antibody to botulinum toxin is produced in horses, and

then despeciated to make a product with a reduced

risk of adverse reaction that can be given to humans.

Human monoclonal antibodies, or cocktails of two

or more monoclonal antibodies, may be the next

generation of antibody therapy. Passive antibody

therapy such as that described here is more likely

to be effective against neurotoxins like the botulinum toxins, which do not cause tissue damage, than

against membrane-damaging toxins that induce

mediator release (eg, staphylococcal enterotoxins),

directly damage tissues (eg, ricin), or both.

Specific Therapy

Specific therapy with drugs presently has little

value: most of the toxins either physically damage
Medical Aspects of Chemical and Biological Warfare

616

cells and tissues very quickly (eg, ricin), or affect

such basic mechanisms within the cell (eg, the neurotoxins) that drugs designed to reverse their effects are toxic themselves. Nevertheless, at the U.S.

Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, Maryland, we have shown that rifampin stops the lethal

intoxication by microcystin if it is given therapeutically to laboratory animals soon (15–30 min) after

the toxin is administered.

Development of therapeutic drugs for toxins is

presently aimed at several more general approaches. When the toxin’s mechanism of action is

understood and covalent (permanent) binding of

the toxin to cellular protein does not occur (eg, ionchannel toxins), attempts are being made to discover drugs that compete with or block the toxin

from binding to its site of action. For toxins with enzymatic activities, such as ricin and the botulinum

toxins, drugs that serve as surrogate targets of such

enzymatic action may be developed. For toxins such

as botulinum, which block the release of a neural

transmitter, there have been attempts to enhance the

release of the needed transmitter by other means;

the diamino pyridines are temporarily effective in

reversing botulinum intoxication by this mechanism.

Finally, for toxins like the staphylococcal enterotoxins and ricin, which induce the release of secondary

mediators, specific mediator-blocking agents are being studied. In the future, drugs may well find a place

in the therapy of some intoxications as adjuncts to

vaccination or passive antibody therapy, or they

may be used to delay onset of toxic effects.

Symptomatic Therapy

General supportive measures are likely to be

effective in therapy of intoxication. Artificial ventilation could be lifesaving in the case of neurotoxins

such as the botulinum toxins and saxitoxin. Oxygen therapy, with or without artificial ventilation,

may be beneficial for intoxication with toxins such

as ricin that directly damage the alveolar-capillary

membrane of the lung. Vasoactive drugs and volume

expanders could be used to treat the shocklike state

that accompanies some intoxications (eg, with staphylococcal enterotoxin B). These measures could be

used in conjunction with more specific therapies.

Decontamination and Protection of Medical Personnel

Recall that a true respirable aerosol will leave less

residue on clothing and environmental objects than

would the larger particles produced by a chemical

munition. This suggests that decontamination

would be relatively unimportant after a toxin aerosol attack. Because we lack field experience, however, prudence dictates that soldiers decontaminate

themselves after an attack.

As a general rule, the decontamination procedure

recommended for chemical warfare agents4

 effectively destroys toxins. Exposure to 0.1% sodium

hypochlorite solution (household bleach) for 10

minutes destroys most protein toxins. The trichothecene mycotoxins require more stringent measures to inactivate them, but even they can be removed from the skin (although not inactivated) simply by washing with soap and water. Soap and

water, or even just water, can be very effective in

removing most toxins from skin, clothing, and

equipment.

For the same reason that decontamination is only

moderately important after individuals are exposed

to a respirable toxin aerosol, medical personnel are

probably at only limited risk from secondary aerosols. Because toxins are not volatile, casualties of a

toxin attack can, for the most part, be handled safely

and moved into closed spaces or buildings, unless

they were very heavily exposed. Prudence dictates,

however, that patients be handled as if they were

chemical casualties or, at a minimum, that they be

washed with soap and water. The risk to medical

personnel is of greater concern with some agents.

Secondary exposure might be a hazard with very

potent bacterial protein toxins, such as botulinum

toxin or the staphylococcal enterotoxins. (NOTE:

Decontamination and isolation of patients or remains could be much more important and difficult

after an attack with a bacteria or virus that replicates within the body.)

Remains of persons possibly contaminated with

toxins should be handled the same as chemically

contaminated remains. For the most part, toxins are

more easily destroyed than chemical agents, and

they are much more easily destroyed than anthrax

spores. Chemical disinfection of remains in 0.2%

sodium hypochlorite solution for 10 minutes would

destroy all surface toxin (and even anthrax spores),

greatly reducing the risk of secondary exposure.

Sample Collection: General Rules for Toxins

Identifying toxins or their metabolites (breakdown products) in biological samples (blood, urine,

feces, saliva, or body tissues) is difficult for several

reasons. First, for most toxic toxins, relatively few
Defense Against Toxin Weapons

617

molecules of toxin need be present in the body to

cause an effect; therefore, finding them requires

extremely sensitive assays. Second, the most toxic

toxins, and those most likely to be seen on the battlefield, are proteins. Therefore, after they break down,

these toxins and toxin fragments can be unidentifiable in the human body.

Third, we must generally look for the toxin itself

or its metabolites, not an antibody response, as can

be done with infectious agents. Anyone receiving a

lethal dose of any of the toxins would be unlikely

to live long enough to be able to mount an antibody response. However, with certain protein toxins (ricin and the staphylococcal enterotoxins) that

are highly immunogenic and less lethal, we might

see antibodies produced in soldiers who received a

single exposure and survived. These might be seen

as early as 2 weeks after exposure.

Certain toxins can be identified in the sera of

animals, and therefore probably of humans,

exposed by inhalation. Blood samples should be

collected in sterile tubes and kept frozen, or at

least cold, preferably after clotting and removal

of cells. If collected within the first day, swab

samples taken from the nasal mucosa are the best

early diagnostic samples in which to identify several of the toxins. These too, should be kept cold.

As a general rule, all samples that are allowed to

remain at room temperature (approximately 75°F–

80°F) or higher for any length of time will have little

value.

Biological samples from patients are generally

not as useful for diagnosis of intoxications as they

are for diagnosis of infectious diseases or chemical

intoxications. The same is true of postmortem

samples. Ricin can be identified with immunoassays in extracts of lung, liver, stomach, and intestines up to 24 hours after aerosol exposure. High

doses of ricin can be identified in fixed lung tissue

of aerosol-exposed laboratory animals by immunohistochemical methods. The staphylococcal enterotoxins can be detected by immunoassay in bronchial

washes. Like blood and swab samples, postmortem

tissue or fluid samples should be kept cold, preferably frozen, until they can be assayed.

Environmental samples from munitions or swabs

from environmental materials should be placed in

sealed glass or Teflon (polytetrafluoroethylene,

manufactured by Du Pont Polymers, Wilmington,

Delaware) containers, and kept dry and as cold as

possible. CAUTION: Handling a dry or powdered

toxin can be very dangerous because the toxin may

adhere to skin and clothing and could be inhaled.

Toxin Analysis and Identification

Immunological or analytical assays or both

are available for most of the toxins discussed in

this chapter. Immunological methods, typically

enzyme-linked immunosorbent assays (ELISAs)

or receptor-binding assays, are sensitive to 1 to

10 ng/mL and require approximately 4 hours

to complete; these are being developed as the

definitive diagnostic tests for deployed units. Analytical (chemical) methods are sensitive at lowmicrogram to high-nanogram amounts, and take

approximately 2 hours to run plus time for instrument setup and isolation or matrix removal

(ie, removal of normal body proteins and other

contaminating material) when necessary; the latter

can add days to the process. A small, sensitive,

far-forward, fieldable assay for several toxins has

been developed, and similar kit assays are being

developed for many of the other toxins described in this chapter. The polymerase chain reaction

(PCR) technique, which provides very sensitive

means of detecting and identifying the genetic

material of any living organism, can be used to detect remnants of the bacterial, plant, or animal cells

that might remain in the crude, impure toxin that

we would expect to find in a weapon. Finally, a

new method of combining immunoassays with PCR

may allow us to detect extremely small quantities

of the toxins themselves. In their present state,

PCR assays are best suited for use in the reference

laboratory.

Water Treatment

Questions often arise regarding the protection of

water supplies from toxins. It is unlikely that a

small-particle aerosol attack with toxins of military

concern would significantly contaminate water supplies. Furthermore, as a general rule, direct contamination of water supplies by pouring toxins into the

water would need to be done downstream of the

processing plant and near the end user, even for the

most toxic bacterial toxins—and ordinary chlorination methods are effective against some of the most

potent toxins. Because of dilution, adding toxins to

a lake or reservoir would be unlikely to cause

human illness. Natural production of algal toxins

(eg, microcystin) in stagnant bodies of water could

produce enough toxin to cause illness if that water

were used for drinking. Three methods of water purification have been tested for the threat toxins

(Table 30-6).5
Medical Aspects of Chemical and Biological Warfare

618

TABLE 30-6

WATER PURIFICATION METHODS EFFECTIVE AGAINST TOXINS

Method Toxin (MW in d) Effectiveness

Reverse Osmosis Ricin (64,000) Effective

Microcystin (1,000) Effective

T-2 mycotoxin (466) Effective

Saxitoxin (294) Effective

Botulinum toxins (150,000) —*

Staphylococcal Enterotoxin B (28,494) —*

Coagulation/Flocculation Ricin Not effective

Microcystin Not effective

T-2 mycotoxin Not effective

Saxitoxin Not effective

Botulinum toxins —†

Staphylococcal Enterotoxin B —†

Free Chlorine (household bleach) Ricin Not effective

5 mg/L (5 ppm) for 30 min Microcystin Not effective

T-2 mycotoxin Not effective

Saxitoxin Not effective

Botulinum toxins Destroys the toxins

Staphylococcal Enterotoxin B —†

*Not tested but expected to be effective

†Not tested but not expected to be effective

Data source: Wannemacher RW Jr, Dinterman RE, Thompson WL, Schimdt MO, Burrows WD. Treatment for Removal of Biotoxins

From Drinking Water. Fort Detrick, Frederick, Md: US Army Biomedical Research and Development Laboratory; Sept 1993. Technical Report 9120.

THE FUTURE

Toxins as Weapons

Research literature suggests that the majority

of the “most toxic” (LD50 < 0.025 μg/kg) naturally

occurring toxins have already been discovered.

New toxins of lesser toxicity, especially the venom

toxins, are being discovered at the rate of perhaps 10 to 20 per year. There is little precedence in

the literature for artificially increasing the toxicities of naturally occurring toxins; however, it might

be possible to increase the physical stability of toxins that are toxic enough but too unstable to

weaponize. This could increase the effectiveness of

a toxin that is currently considered to be a low

threat.

It is unlikely that chemical synthesis of complex

nonprotein toxins will become significantly easier

in the near future. It is likely, however, that largescale biosynthesis of peptide toxins of 10 to 15

amino acids (some of the venom toxins) will become

possible in the next few years.

Countermeasures to Toxins

Although the threat of toxin weapons of the future is formidable, the prospect of new and better

medical countermeasures is brighter than ever before. Biotechnology may have more value to those

of us who are developing countermeasures than to

those who would use toxins maliciously. Molecular biological techniques that have been developed

in the last few years now allow us to produce moreeffective and less-expensive vaccines against the

protein and peptide toxins. Such vaccines will likely
Defense Against Toxin Weapons

619

be available for the most important toxins within

the next few years.

We are making good progress on developing recombinant vaccines for certain high-threat toxins.

In the future, protection of our soldiers from toxin

threats will be limited only by our willingness to

use the vaccines. Similar technology allows us to

produce human antibodies, which will eventually

replace those now produced in animals. Human

antibodies will be a significant advance over despeciated horse antibodies, possibly allowing us to

protect unvaccinated soldiers by simply giving

them an injection before they go into battle, thereby

providing immediate protection. Human antibodies could also be used therapeutically in treating

victims of a terrorist attack.

SUMMARY

Protecting soldiers on the battlefield from toxins—and replicating agents—is possible if we use

our combined resources effectively. Physical countermeasures such as the protective mask, protective

clothing, and decontamination capabilities exist and

are effective. As we improve our battlefield detection systems, early warning of our soldiers may

become a reality, at least in subpopulations within

our forces. These assets, unlike most medical countermeasures, are generally generic and protect

against most or all of the agents.

Among the medical countermeasures, vaccines

are available and effective for some of the

most important agents, and therapies exist for others. Because of limited resources available to develop vaccines, diagnostic methodologies, and

therapies, we can field specific medical countermeasures only to a relatively small group of threat

agents. Our efforts in this area must be carefully

focused.

A third and complementary element of our defensive program must be good intelligence. Only

through knowledge of specific threat agents, delivery systems, and national capabilities can we assure the effective development and use of our physical and medical countermeasures.

Finally, our renewed understanding of the real

strengths and weaknesses of toxins as weapons allows us to put them in perspective in educating our

soldiers, removing much of the mystique—and associated fear—surrounding toxins. Knowledge of

the threat thus reduces the threat to our soldiers.

REFERENCES

1. The 1972 Biological Weapons Convention. Convention on the Prohibition of the Development, Production and

Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction. Signed at London,

Moscow, and Washington on 10 April 1972. Entered into force on 26 March 1975. Depositaries: UK, US, and

Soviet governments.

2. Calder KL. Mathematical models for dosage and casualty coverage resulting from single point and line source

release of aerosol near ground level. BWL Tech Study 3. Defense Technical Information Center AD310-361; Dec

1957. Cited in: Spertzel RO, Wannemacher RW, Patrick WC, Linden CD, Franz DR. Technical Ramifications of

Inclusion of Toxins in the Chemical Weapons Convention (CWC). Alexandria, Va: Defense Nuclear Agency; 1992:

18. DNA Technical Report 92-116.

3. Karsenty E, Shemer J, Alshech I, et al. Medical aspects of the Iraqi missile attacks on Israel. Isr J Med Sci. 1991;

27(11–12):603–607.

4. Department of the Army. Treatment of Chemical Agent Casualties and Conventional Military Chemical Injuries.

Washington, DC: DA; Feb 1990. Army Training Manual 8-285.

5. Wannemacher R. Assistant Chief, Toxinology Division, US Army Research Institute of Infectious Diseases, Fort

Detrick, Frederick, Md. Personal communication, July 1994.
Staphylococcal Enterotoxin B and Related Pyrogenic Toxins

621

Chapter 31

STAPHYLOCOCCAL ENTEROTOXIN B

AND RELATED PYROGENIC TOXINS

ROBERT G. ULRICH, PH.D.*; SHELDON SIDELL, M.D.†; THOMAS J. TAYLOR, M.D.‡;

CATHERINE L. WILHELMSEN, D.V.M., PH.D.§; AND DAVID R. FRANZ, D.V.M, PH.D.¥

INTRODUCTION

DESCRIPTION OF THE AGENT

PATHOGENESIS

CLINICAL DISEASE

Fever and Myalgia

Respiratory Signs and Symptoms

Headache

Gastrointestinal Symptoms

Other Signs and Symptoms

DETECTION AND DIAGNOSIS

MEDICAL MANAGEMENT

PROPHYLAXIS

Immunotherapy

Vaccines

SUMMARY

*Microbiologist, Department of Immunology and Molecular Biology, Toxinology Division, U.S. Army Medical Research Institute of Infectious

Diseases, Fort Detrick, Frederick, Maryland 21702-5011

†Diablo Internal Medical Group, Inc., 2121 Ygnacio Valley Road, Suite 206-E, Walnut Creek, California 94598

‡Colonel, Medical Corps, U.S. Army; Chief, Endocrinology, Department of Medicine, Tripler Army Medical Center, Honolulu, Hawaii 96859-

5000

§Lieutenant Colonel, Veterinary Corps, U.S. Army; formerly, Department of Comparative Pathology, Pathology Division; currently, Chief,

Toxinology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011

¥Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

622

INTRODUCTION

Staphylococcal enterotoxin B (SEB) is one of

seven enterotoxins produced by strains of Staphylococcus aureus. SEB, the best understood of the staphylococcal enterotoxins, can be regarded as the

“type” enterotoxin. Staphylococcal enterotoxins,

toxic shock syndrome toxin–1 (TSST-1), and certain

other bacterial products (such as streptococcal pyrogenic exotoxins [SPE]) and viral products (which

are not discussed in this chapter) are commonly referred to as superantigens because of their profound

effects on the immune system. Minute concentrations of superantigens can activate the immune system receptors because they bind with strong avidity to T-cell antigen receptors and class II molecules

of the major histocompatibility complex (MHC).

The staphylococcal enterotoxins are the most frequent cause of food poisoning. However, more severe physiological consequences, such as a lifethreatening toxic shock–like syndrome, may result

from exposure to these toxins through a nonenteric

route. Although high-dose exposures may well

cause fatalities, it is the incapacitating consequences

of inhalational exposure to agents such as SEB on

the battlefield that are of most concern in the context of biological defense.

During the 1960s, when the United States had an

offensive biological warfare program, SEB (then

code-named PG) was studied extensively as a biological incapacitant. This toxin was especially attractive as a biological agent because much lower

quantities were needed to produce the desired effect than were required with synthetic chemicals.

The dose that is incapacitating for 50% of the human population exposed (also called the effective

dose [ED50]) was found to be 0.0004 μg/kg, and the

dose that is lethal for 50% of the human population

exposed (LD50) was estimated to be approximately

0.02 μg/kg, both by the inhalational route.1

DESCRIPTION OF THE AGENT

The staphylococcal and streptococcal toxins with

superantigen-like properties are 23- to 29-kilodalton

(kd) proteins (referred to here as pyrogenic toxins)

that can be categorized into three distinct amino

acid–sequence homology groups2:

1. The staphylococcal enterotoxin serotypes

SEA, SED, and SEE are closely related; they

form the first homology group.

2. Staphylococcal enterotoxin serotypes SEB,

SEC1, SEC2, SEC3, and the streptococcal

pyrogenic exotoxins A and C (SPE-A and

SPE-C) form the second homology group.

3. The third homology group comprises toxic

shock syndrome toxin (TSST-1) and SPEB, which share key amino acid residues

with the other toxins but exhibit only weak

sequence homology overall. However, data

from X-ray crystallography of SEB2

 and

TSST-13,4 indicate that these representatives of the two groups have considerable

similarities in their three-dimensional

structures.

The pyrogenic toxins bind to MHC class II molecules and this complex, in turn, stimulates T cells.5–8

In contrast, MHC-independent binding induces Tcell anergy. It is likely that all pyrogenic toxins share

a common mode for binding MHC class II molecules, with additional stabilizing interactions that

are unique to each toxin.9

 A second, zinc-dependent

molecular binding mode for SEA and SEE increases

T-cell signaling and may account for the greater

toxicities of these toxins. In conventional antigenspecific responses, the cluster of differentiation 4

(CD4) molecule stabilizes interactions between Tcell antigen receptors and MHC class II molecules

on antigen presenting cells. The pyrogenic toxins

may mimic CD4 binding10 and, by so doing, stimulate large numbers of T cells in a manner independent of antigen recognition.

In addition, each superantigen stimulates T cells

bearing characteristically distinct variable domainβ(Vβ) subsets of antigen receptors (Table 31-1). It is

thought that a massive release of cytokines (such

as interferon gamma, interleukin-6, and tumor necrosis factor–alpha) is responsible for the systemic

effects of the toxins.11 In contrast, the gastrointestinal illness especially prominent after ingestion of

staphylococcal enterotoxins is associated with histamine and leukotriene release from mast cells.12

Endotoxin from Gram-negative bacteria may act in

concert with pyrogenic toxins to greatly amplify

lethality. For example, mice are ordinarily unaffected by SEB and related toxins, but they become

susceptible to doses in nanogram amounts when

coadministered with nonlethal amounts of endotoxin.11
Staphylococcal Enterotoxin B and Related Pyrogenic Toxins

623

Primates, including humans, are most sensitive

to pyrogenic toxins because the binding affinity of

their MHC class II molecules is greater. Lymphocyte responses of chimpanzees and humans are very

similar, while rhesus monkeys are more sensitive

to toxin stimulation. These differences in primate

lymphocyte responses appear to be more dependent

on the T cell than the cells presenting the MHC class

II receptor.13 However, pyrogenic toxins do vary in

their affinity toward different MHC class II isotypes

and alleles. Therefore, it is possible that MHC polymorphisms within the human population may also

contribute to individual differences in susceptibility to the toxic effects of the pyrogenic toxins. Inbred mice differing in MHC alleles, for example,

have widely varying sensitivities to the staphylococcal enterotoxins.

Although little information is available concerning environmental reservoirs, domestic infections

of rodents and other animals with strains that

produce TSST-1 and the staphylococcal enterotoxins have been demonstrated.14,15 Both ovine- and

bovine-specific staphylococcal toxins, which are

associated with mastitis, are almost identical to

TSST-1 in their amino acid sequence.16 Pyrogenic

toxin–producing strains of Staphylococcus aureus and

group A streptococcus are appearing with increasing frequency in clinical isolates. Approximately 50% of nonmenstrual toxic shock syndrome

cases are linked to TSST-1, while the remaining

cases are attributable to enterotoxins, with SEB predominating.17 Kawasaki disease and some forms of

arthritis have been causally linked to organisms

producing streptococcal pyrogenic exotoxins, SEA,

and TSST-1, although this is still controversial.18 In

addition, a severe form of streptococcal pneumonia, with accompanying toxic shock syndrome–like

symptoms is caused by SPE-producing bacterial

strains.19 It is of interest also to note that the majority of group A streptococcal cultures produce pyrogenic exotoxins.

Most of the pyrogenic toxins are encoded by

mobile genetic elements. SPE-A, SPE-C, SEA, and

SEE are all phage-borne, while SED is plasmidencoded. Insufficient data are available to clearly define the nature of SEB and TSST-1 genetic elements.20

Because there is little evidence of genetic drift, it

has been suggested that the majority of staphylococcal and streptococcal toxic shock–like syndrome

bacterial isolates have each descended from single

clones.21 Production of the various staphylococcal

pyrogenic toxins is dependent on the phase of cell

growth cycle, environmental pH, and glucose concentration. Transcriptional control of TSST-1, SEB,

SEC, and SED is mediated through the accessory

gene regulator (agr) locus,20 while SEA expression

appears to be independent of agr. Strains that are

agr negative are generally low toxin producers.

However, there are also considerable differences in

production levels between agr positive isolates.

PATHOGENESIS

Rhesus macaques (Macaca mulatta) have been

used extensively as a model for lethal inhaled intoxication of SEB. Efforts to develop lethal aerosolized SEB animal models in rabbits and endotoxin-primed mice are ongoing. The following previously unpublished information is derived from a

study of dose ranging during the development of a

sublethal model conducted by one of the authors

of this chapter (C.L.W.) in 1994 at U.S. Army Medical Research Institute of Infectious Diseases, Fort

TABLE 31-1

HUMAN T-LYMPHOCYTE RESPONSE TO

BACTERIAL SUPERANTIGENS

Superantigen T-Cell Receptor Vβ Used by

(Pyrogenic Toxin) Responding Lymphocytes*

SEA 1.1, 5.3, 6.3, 6.4, 7.3, 7.4, 9.1

SEB 3, 12, 14, 15, 17, 20

SEC1 12

SEC2 12, 13.1, 13.2, 14, 15, 17, 20

SEC3 5, 12

SED 5, 12

SEE 5.1, 6.1, 6.2, 6.3, 8.1, 18

TSST-1 2

*These T cells are the predominant phenotypes stimulated by

each toxin, independent of the donor.

Vβ: variable domain-β

SE: staphylococcal enterotoxin

TSST-1: toxic shock syndrome toxin 1

Data sources: (1) Kappler J, Kotzin B, Herron L, et al. Vβ-specific stimulation of human T cells by staphylococcal toxins. Science. 1989;244:811–813. (2) Marrack P, Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990;248:705–711.

(3) Champagne E, Huchenq A, Sevin J, Casternan N, Rubin B.

An alternative method for T-cell receptor repertoire analysis:

Clustering of human V-beta subfamilies selected in responses

to staphylococcal enterotoxins B and E. Mol Immunol. 1993;

30(10):877–886.
Medical Aspects of Chemical and Biological Warfare

624

Detrick, Frederick, Maryland. Similar information,

from another study using different monkeys, was

published in 1995 from the same laboratory.22

In recent studies, young and mature adult male and

female rhesus monkeys developed signs of SEB intoxication after being exposed to a lethal dose of aerosolized

SEB for 10 minutes in a modified Henderson head-only

aerosol exposure chamber.23 These animals demonstrated

no detectable anti-SEB antibody prior to exposure.

Generally, SEB-intoxicated monkeys developed gastrointestinal signs within 24 hours after the exposure. Clinical signs were mastication, anorexia, emesis, and diarrhea. Following mild, brief, self-limiting gastrointestinal

signs, the monkeys had a variable period of up to 40 hours

of clinical improvement. At approximately 48 hours after

the exposure, intoxicated monkeys generally had an

abrupt onset of rapidly progressive lethargy, dyspnea, and

facial pallor, culminating in death or euthanasia within 4

hours of onset.

At postmortem examination, most monkeys had similar gross pulmonary lesions. Lungs were diffusely heavy

and wet, with multifocal petechial hemorrhages and areas

of atelectasis. Clear, serous-to-white, frothy fluid often

drained freely from the laryngeal orifice. The small and

large intestines frequently had petechial hemorrhages and

mucosal erosions. Typically, monkeys had mildly swollen

lymph nodes, with moist and bulging cut surfaces.

Most monkeys had similar microscopic pulmonary

lesions (Figure 31-1). The most obvious lesion was

marked multifocal-to-coalescing interstitial pulmonary

edema involving multiple lung lobes. Peribronchovascular

connective tissue spaces were distended by pale, eosinophilic, homogeneous, proteinaceous material (edema);

Fig. 31-1. Lung of a rhesus monkey that died of inhaled staphylococcal enterotoxin B (SEB) intoxication. (a) Marked

perivascular interstitial edema and focal loss of bronchial epithelium can be seen (hematoxylin-eosin stain, original

magnification x 10). (b) The intravascular mononuclear cells include lymphocytes, lymphoblasts, monocytes, and

mononuclear phagocytes (hematoxylin-eosin stain, original magnification x 50).

Fig. 31-2. Lung of a rhesus monkey that died of inhaled staphylococcal enterotoxin B (SEB) intoxication. (a) Intraalveolar

fibrin deposition and hyaline membrane formation can be seen (hematoxylin-eosin stain, original magnification x

50). (b) Intraalveolar deposition of polymerized fibrin can be seen (phosphotungstic acid hematoxylin stain, original

magnification x 50).

a b

a b
Staphylococcal Enterotoxin B and Related Pyrogenic Toxins

625

Fig. 31-3. Mediastinal lymph node of a rhesus monkey

that died of inhaled staphylococcal enterotoxin B (SEB)

intoxication. Paracortical lymphoproliferation with lymphoblasts can be seen (hematoxylin-eosin stain, original

magnification x 100).

Fig. 31-4. Small intestine of a rhesus monkey that died of

inhaled staphylococcal enterotoxin B (SEB) intoxication.

Intraepithelial lymphoblastic leukocytes can be seen (hematoxylin-eosin stain, original magnification x 100).

variably accompanied by entrapped, beaded fibrillar

(fibrin) strands; and extravasated erythrocytes, neutrophils, macrophages, and small and large lymphocytes.

Perivascular lymphatics were generally distended by similar eosinophilic material and inflammatory cells. Most

monkeys had intravascular circulating and marginated

neutrophils, monocytes, mononuclear phagocytes, and

lymphocytes, including large lymphocytes with prominent

nucleoli (lymphoblasts), some in mitosis. Extravascular

extension of these cell types was interpreted as exocytosis/chemotaxis.

Loss of airway epithelium was inconsistent. Some

monkeys had multifocal, asymmetric denudation of bronchial epithelium, with near total loss of the bronchiolar

epithelium. Former bronchioles were recognized only by

their smooth-muscle walls. Scant bronchial intraluminal

exudate consisted of mucoid material, neutrophils, macrophages, and sloughed, necrotic cells.

A common finding was the combination of multifocal

alveolar flooding and acute purulent alveolitis. Alveolar septa were distended by congested alveolar capillaries. Alveolar spaces were filled with eosinophilic,

pale, homogeneous material (edema); with embedded,

more deeply eosinophilic, beaded fibrillar strands (fibrin);

or with condensed, eosinophilic, curvilinear deposits hugging the alveolar septal contours (hyaline membranes)

(Figure 31-2). A variably severe, intraalveolar, cellular

infiltrate of neutrophils, eosinophils, small lymphocytes,

large lymphocytes (lymphoblasts), erythrocytes, and

alveolar macrophages filled the alveolar spaces. Replicate pulmonary microsections stained with phosphotungstic acid–hematoxylin demonstrated alveolar fibrin deposition. Replicate microsections stained with Giemsa

revealed scarce, sparsely granulated connective tissue

mast cells.

In the upper respiratory tract, the tracheal and bronchial lamina propria was thickened by clear space or pale,

eosinophilic, homogeneous material (edema); and neutrophils, small and large lymphocytes, and (possibly preexisting) plasma cells. The edema and cellular infiltrate

extended transtracheally into the mediastinum, with moderate-to-marked mediastinal lymphangiectasia.

Lymphoid tissues of the respiratory tract had depletion of B-cell dependent areas and hyperplasia of T-cell

dependent areas. The bronchus-associated lymphoid tissue (BALT) in some of the monkeys had follicular lymphocytic depletion. Most monkeys’ mediastinal lymph

nodes had subcapsular and medullary sinus edema and

histiocytosis and paracortical lymphoid hyperplasia, characterized by numerous, closely packed, small lymphocytes, with interspersed macrophages bearing tingible

bodies and large lymphocytes having prominent nucleoli

(lymphoblasts) (Figure 31-3). There were scattered mitoses, including atypical mitoses. Cortical follicles had small,

solid centers, or had hypocellular, hyalinized (depleted)

centers.

Microscopic changes of lymphoid tissues elsewhere

in the body mirrored changes in the respiratory mucosal

lymphoid tissue. Mesenteric, axillary, inguinal, and

retropharyngeal lymph nodes had sinus edema and histiocytosis, paracortical lymphocytic and lymphoblastic

hyperplasia, and unstimulated or depleted follicular

centers. Also depleted were follicular germinal centers of

gut-associated lymphoid tissue (GALT). Splenic T-cell

dependent periarteriolar sheath zones were hypercellular,

populated by a mix of small and large lymphocytes and

macrophages, whereas B-cell dependent follicular areas

were not recognized. Several monkeys had marked diffuse depletion of cortical thymocytes, with a “starry sky”

appearance attributed to the presence of numerous thymic macrophages bearing tingible bodies.

Many monkeys had a mild, erosive enterocolitis, with

slight multifocal, superficial mucosal loss, and with numerous lamina proprial macrophages bearing engulfed

cellular debris. Crypt enterocytes had a high nuclear-tocytoplasmic ratio and numerous mitoses. The crypt epi-
Medical Aspects of Chemical and Biological Warfare

626

thelium had a conspicuous population of large, mononuclear, intraepithelial leukocytes interpreted as lymphoblasts (Figure 31-4). Some monkeys’ colons contained

many small crypt abscesses.

Generalized vascular changes in most monkeys were

congestion; swollen endothelial cells, with many intravascular large lymphocytes or lymphoblasts; and inconsistent widening of perivascular connective tissue spaces

(by edema). Hepatic lesions were portal infiltrates of lymphocytes, lymphoblasts, macrophages, and occasional

neutrophils. The choroid plexus was slightly thickened (by

edema).

True inhaled SEB pathogenesis studies, in which

monkeys are killed and necropsied at sequential times after the exposure, have not been conducted in recent years. To the best of our knowledge, there are no recently published reports of

SEB pathogenesis studies in monkeys in the open

literature.

Inhaled SEB appears to be a potent stimulant of

the immune system of rhesus monkeys. Following

inhalational exposure, there was microscopic

lymphoproliferation of T-cell dependent areas of the

lymphoid system. Recent immunohistochemical

analysis of the large lymphocytes present in the

pulmonary vasculature of rhesus monkeys lethally

intoxicated with aerosolized SEB identified them as

T cells, using anti-CD3 antibody.22

CLINICAL DISEASE

The clinical documentation of toxic shock syndrome provides perhaps the most comprehensive

source of information on the pathology of pyrogenic

toxin exposure. To meet the strict Centers for Disease Control criteria for toxic shock syndrome,24

negative (except for S aureus) cultures of the blood,

throat, or cerebrospinal fluid should be obtained;

negative serologic tests for Rocky Mountain spotted fever, leptospirosis, and measles should also be

obtained. Most of the pyrogenic toxins produce the

same signs and symptoms as toxic shock syndrome:

a rapid drop in blood pressure, elevated temperature, and multiple organ failure. However, the respiratory route of exposure to toxins may involve

some unique mechanisms. The profound hypotension characteristic of toxic shock syndrome is not

observed, and respiratory involvement is rapid.

Fever, prominent after aerosol exposure, is generally not observed in cases of SEB ingestion.

A previously unpublished report from the laboratory of one of the authors of this chapter (S.S.)

documents an accidental laboratory inhalational

exposure of nine laboratory workers to SEB, and

best exemplifies the clinical disease. At least one and

perhaps two other workers were in the building at

the time of the accident. They were examined but

remained completely asymptomatic; they might not

have been exposed. These additional workers are

not included in this report; the nine mentioned are

those who are known to have been exposed (because they became ill).

This report describes a severely incapacitating

illness of rapid onset (3–4 h) but modest duration

(3–4 d). The degree of illness can be categorized as

follows: three of the nine patients were seriously

ill, and one of these three was profoundly ill; two

of nine were moderately ill; and four of nine were

mildly ill.

Fever and Myalgia

Fever was prominent in all nine of those exposed. Eight

of the individuals experienced at least one shaking chill

that heralded the onset of illness. Using the morning peak

level of SEB aerosol generation in the laboratory as the

most likely time of exposure, onset of fever occurred from

8 to 20 hours after the initial exposure, with a mean time

of onset of 12.4 ± 3.9 (standard deviation) hours. Duration of fever was from 12 to 76 hours after onset, with a

mean duration of 50 ± 22.3 hours. Fever reached as high

as 106°F acutely.

Myalgias were often associated with the initial fever.

Onset of myalgia was from 8 to 20 hours, with a mean

onset of 13 ± 5 hours. Duration of myalgia was from 4 to

44 hours, and the mean duration was 16 ± 15 hours.

Respiratory Signs and Symptoms

All nine patients were admitted to the hospital with a

generally nonproductive cough. Onset of respiratory

symptoms was 10.4 ± 5.4 hours, and duration was 92 ±

41 hours. Five of the nine patients had inspiratory rales

with dyspnea. The three most seriously compromised

patients had dyspnea, moist inspiratory and expiratory

rales, and orthopnea; these signs gradually cleared. One

of these three patients had profound dyspnea for the first

12 hours, which moderated to exertional dyspnea and

rales that persisted for 10 days.

Chest radiographs taken on admission showed, in the

three patients with inspiratory rales, densities compatible with “patches of pulmonary edema” and Kerley lines

suggesting interstitial edema. During recovery, discoid

atelectasis was noted. Moderate compromise of the respiratory system was often accompanied by radiographic

evidence of peribronchial accentuation or “cuffing.” The

three mildly ill patients had normal radiographs.

The one profoundly ill patient had severe pulmonary

compromise and profound dyspnea, and received

only slight relief when treated with an aminophylline

suppository. Moderately intense chest pain, of a substernal pleuritic type, occurred in seven of the nine
Staphylococcal Enterotoxin B and Related Pyrogenic Toxins

627

individuals. Onset of chest pain was 12 ± 6.5 hours; duration ranged from 4 to 84 hours, with a mean duration of

23 ± 27 hours.

Headache

Eight of the nine patients experienced headache. Onset ranged from 4 to 36 hours, and the mean time of

onset was 13.3 ± 10 hours. Duration ranged from 8 to 60

hours, with a mean duration of 30.6 ± 19 hours. The headaches ranged from severe to mild, but usually were mild

by the second hospital day. Five individuals’ headache

responded to Darvon (propoxyphene hydrochloride,

manufactured by Eli Lilly and Company, Indianapolis,

Indiana) or codeine.

Gastrointestinal Symptoms

Gastrointestinal symptoms occurred in most of the individuals: nausea and anorexia in six and vomiting in four.

The onset of nausea ranged from 8 to 24 hours, with a

mean onset of 17 ± 6.3 hours. Duration ranged from 4 to

20 hours, with a mean of 9 ± 5.5 hours. Onset of anorexia ranged from 8 to 24 hours, with a mean onset of 18.5 ±

5.6 hours. Duration of anorexia ranged from 4 to 136

hours, and the mean duration was 44.5 ± 45 hours. Vomiting occurred in four patients and sometimes occurred

after prolonged paroxysms of coughing. The range of

onset of vomiting was 8 to 20 hours, with a mean time to

onset of 14 ± 5.1 hours. Duration was not prolonged

and usually consisted of one episode. Compazine

(prochlorperazine, manufactured by SmithKline Beecham

Pharmaceuticals, Philadelphia, Pennsylvania) and

Benadryl were employed successfully.

Only one individual demonstrated hepatomegaly and

bile in the urine, although another patient also demonstrated mildly elevated liver function tests. (The liver function tests on this last patient remained elevated for years,

but it is unclear whether this is actually a sequela of this

illness. In addition, this individual had previous exposures

to staphylococcal enterotoxins while working at a different laboratory.) No diarrhea was reported in any of the

exposed individuals.

Other Signs and Symptoms

All patients who experienced chest pain had normal

electrocardiograms. Throughout the illness, all were normotensive. Vomiting was of relatively brief duration and

no patients, including those vomiting, required intravenous fluid administration. Pulse rate, when elevated, paralleled temperature elevation.

Leukocytosis was observed in most patients 12 to 24

hours after exposure to the toxin.

None of these individuals experienced conjunctivitis,

although one individual later remembered that his eyes

had “burned” during the believed time of exposure.

DETECTION AND DIAGNOSIS

The staphylococcal enterotoxins are moderately

stable proteins; therefore, immunological evaluation should be possible on samples collected

in either deployed or fixed medical treatment

facilities. Immunoassays can detect picogram quantities of toxins in environmental samples. For

comparison, 440 pg/mL was reported as the

mean concentration of TSST-1 in human sera from

patients with toxic shock syndrome.25 Anti-TSST-1

antibody titers are either suppressed or depleted

in patients with toxic shock syndrome26,27 and the

levels only recover during convalescence. In addition, most normal human serum samples contain detectable levels of antibody reacting with several different bacterial pyrogenic toxins, including

SEB. Therefore, serum antibody titers are of little

diagnostic value. If actual bacterial involvement

is suspected, and if cultures can be obtained, the

detection of extremely minute quantities of potentially toxigenic strains is possible by using (1) polymerase chain reaction (PCR) amplification and (2)

toxin gene–specific oligonucleotide primers. The

results from both methods are rapid, allowing quantitative or qualitative measurements in less than 24

hours.

Finally, for at least 12 to 24 hours after the exposure, toxins should be identifiable in nasal swabs

from individuals exposed to a respirable aerosol.

This may be the best approach to early diagnosis

on the battlefield.

MEDICAL MANAGEMENT

Supportive therapy seems to have been adequate

care in the nine patients described above with mild,

accidental, respiratory exposure to aerosolized SEB.

Symptoms of fever, muscle aches, and arthralgias

may respond to cool compresses, fluids, rest, and

judicious use of acetaminophen or aspirin. For

nausea, vomiting, and anorexia, symptomatic

therapy should be considered. Antihistamines

(eg, diphenhydramine) and phenothiazine derivatives (eg, prochlorperazine) were used parenterally

or as suppositories. The success of these drugs in

controlling nausea may have been augmented

by the relatively short duration of nausea and vomiting induced by aerosolized SEB. Because of

the brevity of vomiting episodes, fluid replacement

was not considered or required in the series dis-
Medical Aspects of Chemical and Biological Warfare

628

cussed. However, in the event of prolonged vomiting resulting in fluid and electrolyte depletion,

replacement may be necessary. Diarrhea was not

observed in the nine human accidental exposure

cases, but deposition of toxin on foodstuff could

produce the syndrome. Diarrhea should be treated

symptomatically.

Cough suppressants containing dextromethorphan or codeine should be employed initially for

symptomatic therapy of respiratory symptoms. Prolonged coughing unrelieved by codeine might benefit from a semisynthetic, centrally acting narcotic

antitussive containing hydrocodone (dihydrocodeinone). Monitoring of pulmonary status by

pulse oximetry with prompt evacuation to a site

with the capacity for intensive respiratory care by

mechanical ventilation should be considered when

respiratory status is compromised. No specific

therapy has been identified or described for managing the respiratory effects of intoxication with

aerosolized SEB. Experimental intervention in

cytokine cascades has been a proposed therapy.

Animal models have not yet indicated any therapeutic value for steroids.

PROPHYLAXIS

Immunotherapy

Infusion of intravenous gamma globulins has been

successfully used28,29 to treat episodes of Kawasaki

disease (which is linked to the staphylococcal enterotoxins and TSST-1). Unpublished studies have documented prophylaxis and the therapeutic value of

affinity-purified chicken anti-SEB antibody administered intravenously, in rhesus monkey inhalation of

SEB. Monkeys given antibody just prior to, or 4 hours

after, lethal challenge (5 LD50, or 135 μg/kg) were

protected from death. Although the animals survived,

they did develop signs of intoxication. Efforts to devise both passive and active immunoprotection are

being pursued. Because of the rapidity of MHC class

II receptor binding by these toxins (apparent saturation < 5 min, in vitro), active immunity should be

considered the best defense.30

Vaccines

A formalin-treated SEB toxoid has demonstrated

some degree of efficacy in animal trials,31 but has

not yet been approved for human use. In an attempt

to stimulate the requisite secretory antibody titers,

a variety of different immunization routes and adjuvants have been explored, although the intramuscular immunization route has proven effective. Vaccines

produced by genetic inactivation of the toxins

have shown promising results in animal trials.32

This strategy is based on substitution of active receptor-binding amino acid side chains to reduce

affinities and consequential T-cell activation,9 without altering the three-dimensional structure of the

antigen. It is anticipated that this second-generation vaccine will be more antigenic and more likely

to induce neutralizing antibodies than the toxoid.

SUMMARY

The staphylococcal enterotoxins are a family of

superantigen protein toxins produced by strains of

Staphylococcus aureus. Staphylococcal enterotoxin B

(SEB), a toxin often associated with food poisoning, was weaponized as an incapacitating agent by

the United States during in the 1960s. When inhaled

as a respirable aerosol, SEB causes fever, severe respiratory distress, headache, and sometimes nausea

and vomiting. The mechanism of intoxication is

thought to be from a massive release of cytokines

such as interferon-gamma, interleukin-6 and tumor

necrosis factor–alpha. Diagnosis can be confirmed

through the use of enzyme-linked immunosorbent

assays of tissues or body fluids. Prophylactic administration of an investigational vaccine protects

laboratory animals from inhalational challenge.

Supportive care is useful in reducing toxicity in unprotected individuals.

REFERENCES

1. Hursh S, McNally R, Fanzone J Jr, Mershon M. Staphylococcal Enterotoxin B Battlefield Challenge Modeling with

Medical and Non-Medical Countermeasures. Joppa, Md: Science Applications International Corp; 1995. Technical

Report MBDRP-95-2.

2. Ulrich RG, Bavari S, Olson M. Bacterial superantigens in human diseases: Structure, function and diversity.

Trends Microbiol. 1995;3:463–468.
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3. Prasad GS, Earhart CA, Murray DL, Novick RP, Schlievert PM, Ohlendorf DH. Structure of toxic shock toxin.

Biochemistry. 1993;32:13761–13766.

4. Acharya RK, Passalacqua EF, Jones EY, et al. Structural basis of superantigen action inferred from crystal structure of toxic-shock syndrome toxin-1. Nature. 1994;367:94–97. Letter.

5. Fraser JD. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989;339:

221–223.

6. Mollick JA, Cook RG, Rich RR. Class II MHC molecules are specific receptors for staphylococcal enterotoxin A.

Science. 1989;244:817–820.

7. Uchiyama T, Tadakuma T, Imanishi K, et al. Activation of murine T cells by toxic shock syndrome toxin–1: The

toxin-binding structures expressed on murine accessory cells are MHC class II molecules. J Immunol.

1989;43:3175–3183.

8. Kappler J, Kotzin B, Herron L, et al. V β-specific stimulation of human T cells by staphylococcal toxins. Science.

1989;244:811–813.

9. Ulrich RG, Bavari S, Olson M. Staphylococcal enterotoxins A and B share a common structural motif for binding class II major histocompatibility complex molecules. Nat Struct Biol. 1995;2:554–560.

10. Bavari S, Ulrich RG. Staphylococcal enterotoxin A and toxic shock syndrome toxin compete with CD4 for human major histocompatibility complex class II binding. Infect Immun. 1995;63(2):423–429.

11. Stiles BG, Bavari S, Krakauer T, Ulrich RG. Toxicity of staphylococcal enterotoxins potentiated by lipopolysaccharide: Major histocompatibility complex class II molecule dependency and cytokine release. Infect Immun.

1993;61:5333–5338.

12. Scheuber PH, Denzlinger C, Wilker D, Beck G, Keppler D, Hammer DK. Cysteinyl leukotrienes as mediators of

staphylococcal enterotoxin B in the monkey. Eur J Clin Invest. 1987;117:455–459.

13. Bavari S, PhD. Research Chemist, US Army Medical Research Institute of Infectious Diseases, Fort Detrick,

Frederick, Md. Personal communication, 1994.

14. Kenny K, Reiser RF, Bastida-Corcuera FD, Norcross NL. Production of enterotoxins and toxic shock syndrome

toxin by bovine mammary isolates of Staphylococcus aureus. J Clin Microbiol. 1993;31:706–707.

15. Ho G, Campbell WH, Bergdoll MS, Carlson E. Production of a toxic shock syndrome toxin variant by Staphylococcus aureus strains associated with sheep, goats, and cows. J Clin Microbiol. 1989;27(9):1946–1948.

16. Lee PK, Kreiswirth BN, Deringer JR, et al. Nucleotide sequences and biologic properties of toxic shock syndrome toxin 1 from ovine- and bovine-associated Staphylococcus aureus. J Infect Dis. 1992;165:1056–1063.

17. Crass BA, Bergdoll MS. Involvement of staphylococcal enterotoxins in non-menstrual toxin shock syndrome. J

Clin Microbiol. 1986;23:1138–1139.

18. Freedman JD, Beer DJ. Expanding perspectives on the toxic shock syndrome. Adv Intern Med. 1991;36:363–397.

19. Reichardt W, Muller-Alouf H, Alouf JE, Kohler W. Erythrogenic toxins A, B and C: Occurrence of the genes and

exotoxin formation from clinical Streptococcus pyogenes strains associated with streptococcal toxic shock–like

syndrome. FEMS Microbiol Lett. 1992;79:313–322.

20. Betley MJ, Borst DW, Regassa LB. Staphylococcal enterotoxins, toxic shock syndrome toxin and streptococcal

pyrogenic exotoxins: A comparative study of their molecular biology. Chem Immunol. 1992;55:1–35.

21. Lee PK, Schlievert PM. Molecular genetics of pyrogenic exotoxin superantigens of group A streptococci and

Staphylococcus aureus. Curr Top Microbiol Immunol. 1991;174:1–19.
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22. Mattix ME, Hunt RE, Wilhelmsen CL, Johnson AJ, Baze WB. Aerosolized staphylococcal enterotoxin B–induced pulmonary lesions in rhesus monkeys (Macaca mulatta). Toxicol Pathol. 1995;23:262–268.

23. Henderson DW. An apparatus of the study of airborne infection. J Hyg. 1952;50:53–68.

24. Centers for Disease Control. Modifications: Toxic shock syndrome, United States, 1970–1982. MMWR.

1982;31:201–204.

25. Miwa K, Fukuyama M, Kunitomo T, Igarashi H. Rapid assay for detection of toxic shock syndrome toxin 1

from human sera. J Clin Microbiol. 1994;32:539–542.

26. Crass BA, Bergdoll MS. Toxin involvement in toxic shock syndrome. J Infect Dis. 1986;153:918–926.

27. Chesney PJ, Bergdoll MS, Davis JP, Vergeront JM. The disease spectrum, epidemiology, and etiology of toxicshock syndrome. Annu Rev Microbiol. 1984;38:315–338.

28. Takei S, Arora YK, Walker SM. Intravenous immunoglobulin contains specific antibodies inhibitory to activation of T cells by staphylococcal toxin superantigens. J Clin Invest. 1993;91:602–607.

29. Leung DY, Meissner HC, Fulton DR, Murray DL, Kotzin BL, Schlievert PM. Toxic shock syndrome toxin–secreting Staphylococcus aureus in Kawasaki syndrome. Lancet. 1993;342:1385–1388.

30. Lemley P, PhD, Lieutenant Colonel, US Army. Principal Investigator, Immunology and Molecular Biology Department, Toxinology Division, US Army Medical Research Institute of Infectious Disease, Fort Detrick, Frederick, Md. Personal communication, June 1995.

31. Tseng J, Komisar JL, Trout RN, et al. Humoral immunity to aerosolized staphylococcal enterotoxin B (SEB), a

superantigen, in monkeys vaccinated with SEB toxoid–containing microspheres. Infect Immun. 1995;63(8):2880–

2885.

32. Bavari S, Olson M, Dyas B, Ulrich RG. Bacterial superantigen vaccines. In: Brown F, Burton D, Collier J,

McKalanos J, Norrby E, eds. Vaccines. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1996: 135.
Ricin Toxin

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Chapter 32

RICIN TOXIN

DAVID R. FRANZ, D.V.M., PH.D.*; AND NANCY K. JAAX, D.V.M.†

INTRODUCTION

HISTORY AND MILITARY SIGNIFICANCE

DESCRIPTION OF THE AGENT

Toxicity

Pathogenesis

CLINICAL SYMPTOMS, SIGNS, AND PATHOLOGY

Oral Intoxication

Injection

Inhalation

Cause of Death

DIAGNOSIS

MEDICAL MANAGEMENT

Immunization and Passive Protection

Supportive and Specific Chemotherapy

SUMMARY

*Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases

†Colonel, Veterinary Corps, U.S. Army; Chief, Pathology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick,

Frederick, Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

632

INTRODUCTION

eucaryotic ribosomes to block protein synthesis. The

toxicity of castor beans has been known since

ancient times, and more than 750 cases of intoxication in humans have been described.2

 Although

ricin’s lethal toxicity is approximately 1,000-fold

less than that of botulinum toxin, ricin may have

significance as a biological weapon because of

its heat stability and worldwide availability, in

massive quantities, as a by-product of castor oil production.

Ricin toxin, found in the bean of the castor plant,

Ricinis communis, is one of the most toxic and easily

produced plant toxins. It is a lectin consisting of

two polypeptide chains, the A-chain and the

B-chain, linked by a disulfide bond. It is one of

a group of dichain ribosome-inactivating proteins, which are specific for the depurination of

a single adenosine in ribosomal ribonucleic acid

(RNA).1

 The active chain (ie, the A-chain) has the

ability to modify catalytically the 28S subunit of

HISTORY AND MILITARY SIGNIFICANCE

Ricinis communis was cultivated in ancient Egypt

for its oil’s lubricating and laxative effects; both the

oil and the whole seeds have been used in various

parts of the world in the treatment of other diseases

as well. During World War I and World War II, the

lubricating oil was used in aircraft. Because of shortages of castor oil during World War II, the United

States government subsidized the cultivation of castor beans in the San Joaquin Valley of California

until the 1960s, when artificial oils replaced castor

oil in the aircraft industry.

Although the industry is no longer active in this

country, castor oil is still produced in large quantities throughout the world. The toxin, which remains

in the castor meal after the oil has been extracted

with hexane or carbon tetrachloride, is easily extracted through a simple salting-out procedure.3

In the late 1800s, Stillmark4 discovered that the

beans of the castor plant contained a toxic protein,

which he named ricin. He discovered that ricin

caused agglutination of erythrocytes and precipitation of serum proteins. (The lectin properties of

ricin and abrin [a closely related toxin from the bean

of Abrus precatorius] and their use as tools for research were described in 1972 by Sharon and Lis.5

)

Paul Ehrlich studied ricin6 and abrin7 during the

1890s; Ehrlich’s work with these lectins became the

very foundation of the discipline of immunology.

Since the toxins are much less toxic when given by

mouth than by injection, Ehrlich was able to induce

immunity by feeding mice or rabbits small amounts

of the seeds. This seminal work provided evidence

that specific serum proteins are induced, capable

of precipitating and neutralizing the toxin antigens.

Using the same model, he also showed that, during

pregnancy, specific antitoxin activity is transferred

from mother to offspring through the blood and,

during lactation, the same protective components

are transferred through the milk.

Native ricin was first shown to inhibit tumor

growth in 1951. The toxin was tested by various

routes—local application, intratumor, and intraarterial—in patients with tumors, with varying results.8

 In recent years, with the advent of new immunotherapeutic techniques, ricin has once again

found a niche in the armamentarium of the medical profession. It has been studied as a component

of antitumor agents called immunotoxins or, more

specifically, chimeric toxins.9

The native ricin, or just the ricin A-chain, is conjugated to tumor cell–specific monoclonal antibodies (technically, to other ligands, which target the

active component of the toxin to tumor cells for selective killing).10 A number of these compounds

have undergone Phase I or Phase II clinical trails as

anticancer agents.11,12 Although results have been

promising, two factors appear to limit ricin

immunotoxin efficacy: (1) lack of specificity of the

antibody and (2) significant immunogenicity of the

toxin moiety, which results in relatively rapid onset of refractory immunity to the therapeutic

agent.13,14

Because of its relatively high toxicity and its extreme ease of production, ricin, code-named Compound W, was considered for weaponization by the

United States during its offensive Biological Warfare Program. The U.S. Chemical Warfare Service began studying ricin as a weapon of war near the end

of World War I. Work done in collaboration with the

British resulted in the development of a W bomb in

World War II. The weapon was tested but apparently never used in battle.15 Ricin was used in the

highly publicized assassination of Bulgarian defector Georgi Markov16; this incident is discussed in

greater detail later in this chapter. However, because

ricin intoxication is a relatively uncommon occur-
Ricin Toxin

633

rence in human medicine, no concerted effort was

made to produce specific therapies or prophylactic

measures until the early 1990s, when it was perceived to be a significant biological warfare threat.

In recent years, ricin has become a favorite tool

of extremist individuals or groups who seek to harm

others, as the following examples demonstrate:

• Two tax protesters were convicted in February 1995 of possessing ricin as a biological weapon. This was the first case of prosecution under the 1989 Biological Weapons

Anti-terrorism Act.17

• A retired electrician who had worked on the

trans-Alaska pipeline recently committed

suicide in an Arkansas jail after being arrested under the antiterrorism act for possessing castor beans. Two years before, a

large quantity of ricin toxin and weapons,

ammunition, and gold were found in his car

by Canadian customs officials as he crossed

the border from Alaska to Canada.18,19

Ricin’s appeal to individuals such as these is likely

related to its ready availability, relative ease of extraction, and its popularization by the press.20

DESCRIPTION OF THE AGENT

Ricin is a 66-kilodalton (kd) globular protein that

makes up 1% to 5% by weight of the bean of the

castor plant, Ricinis communis. The toxic heterodimer consists of a 32-kd A-chain that is disulfidebonded to a 32-kd B-chain.21 The toxin is stored in

the matrix of the castor bean, together with a

120,000-d ricinus lectin.22 Both chains are glycoproteins containing mannose carbohydrate groups; the

two 32-kd chains must be associated for toxicity.

Several investigators have purified and characterized ricin22 and have succeeded in crystallizing it.

The crystal structure has been determined to 2.5 Å.23

The A- and B-chains are globular proteins, with the

A-chain tucked into a gap between two roughly

spherical domains of the B-chain. A lactose disaccharide moiety is bound to each of the spherical domains of the B-chain. The disulfide bond links amino

acid 259 of the A-chain and amino acid 4 of the Bchain. The crystal structure demonstrates a putative active cleft in the A-chain, which is believed to be

the site of the enzymatic action of the toxin. Recombinant A- and B-chains, as well as mutants of the

chains, have been expressed in Escherichia coli and

other expression systems. The chains have been crystallized and their structures derived (Figure 32-1).24-27

Toxicity

There is a 100-fold variation in the lethal toxicity

of ricin for various domestic and laboratory animals, per kilogram of body weight. Of animals

tested, the chicken and frog are least sensitive, while

the horse is the most.28

Toxicity of ricin also varies with route of challenge. In laboratory mice, the approximate dose that

is lethal to 50% of the exposed population (LD50)

and time to death are, respectively, 3 to 5 μg/kg and

60 hours by inhalation, 5 μg/kg and 90 hours by

Fig. 32-1. The crystallographically determined structure of ricin. The molecule is

depicted using a ribbon representation,

with the A-chain colored red; the B-chain,

blue; and the disulfide bonds, yellow. Illustration: Courtesy of Mark A. Olson,

PhD, Toxinology Division, US Army

Medical Research Institute of Infectious

Diseases, Fort Detrick, Frederick, Md.

Ricin A-chain

Ricin B-chain
Medical Aspects of Chemical and Biological Warfare

634

Fig. 32-2. Cartoon depicting ricin (A—B) binding to coated

pits on the surface of the cell (1), internalization via endocytosis (2), and transport through the Golgi complex (3);

and enzymatic inactivation of protein synthesis via cleavage of adenine residue (A4324), and blockage of elongation factor-2 binding (4). Arrows with “?” indicate other

possible routes of entry to the cytosol. Illustration: Courtesy of Bob Wellner, PhD, Toxinology Division, US Army

Medical Research Institute of Infectious Diseases, Fort

Detrick, Frederick, Md.

intravenous injection, 22 μg/kg and 100 hours by

intraperitoneal injection, 24 μg/kg and 100 hours

by subcutaneous injection, and 20 mg/kg and 85

hours by intragastric administration. Low oral toxicity reflects poor absorption of the toxin from the

gastrointestinal tract. Higher toxicities by other

routes may be directly related to accessibility of target-cell populations and the ubiquity of “toxin receptors” throughout the cells of the body. When skin

tests were performed on mice, no dermal toxicity

was observed at the 50-μg spot.29

Pathogenesis

The B-chain has lectin properties that allow it to

bind to complex galactosides of cell-surface carbohydrates, while the A-chain has enzymatic activity.

Binding of the B-chain to glycoside residues on glycoproteins and glycolipids appears to trigger endocytotic uptake of the protein. Internalization of

the toxin occurs, primarily via uncoated pits,30,31

within a few hours; the dissociation rate of ricin for

its binding sites is increased in the presence of lactose.32 Almost all of the toxin entering the cytosol

does so via the Golgi apparatus.33 As with other

protein toxins such as diphtheria toxin, Pseudomonas exotoxin A, and modeccin, transport to the cytosol is the rate-limiting step during the decline of

protein synthesis.34 Presence of the B-chain facilitates transport of the A-chain into the cytosol.35 The

latent periods of 1 to 3 hours in vitro and 8 to 24

hours in vivo, before cell death or clinical signs,

respectively, are probably related to the necessary

transport of the toxin into cells, the site of activity.

Once in the cytoplasm of a eukaryotic cell, the Achain enzymatically attacks the 28S ribosomal subunit. Ricin has a Michaelis constant (KM) of 0.1

μmol/L for ribosomes and an enzymatic constant

(Kcat) of 1,500/min. Ricin cleaves one adenine residue (A4324) near the 3' end of 28S RNA. This deletion causes elongation factor-2 to fail to bind and

thereby blocks protein synthesis.36,37 At the cellular

level, ricin kills through inhibition of protein synthesis (Figure 32-2).

1.

2.

3.

4.

Invagination

Endosome

Golgi Complex

Endoplasmic Reticulum
Ricin Toxin

635

CLINICAL SYMPTOMS, SIGNS, AND PATHOLOGY

The clinical signs, symptoms, and pathological

manifestations of ricin toxicity vary with the dose

and the route of exposure.38 Experimental animal

studies indicate that clinical signs and pathological changes are largely route specific; for example,

inhalation results in respiratory distress and airway

and pulmonary lesions; ingestion causes gastrointestinal signs and gastrointestinal hemorrhage

with necrosis of liver, spleen, and kidneys; and intramuscular intoxication causes severe localized

pain, muscle and regional lymph node necrosis, and

moderate involvement of visceral organs. The routespecific pathology is probably due to the lectin

properties of ricin, which cause it to bind rapidly

to complex galactosides of cell-surface carbohydrates. Transient leukocytosis appears to be a constant feature in humans, whether intoxication is via

injection or oral ingestion. Leukocyte counts 2- to

5-fold higher than the normal value are characteristic findings in cancer patients, and also occurred

in the Markov case.16

Oral Intoxication

Ricin is less toxic by oral ingestion than by other

routes, probably because of poor absorption and

some enzymatic digestion in the digestive tract. In

oral (and parenteral) intoxication, cells in the reticuloendothelial system, such as Kupffer cells and

macrophages, are particularly susceptible, due to

the mannose receptor present exclusively in macrophages.39 In 1985, A. Rauber and J. Heard2

 summarized the findings from their study of 751 cases

of castor bean ingestion. There were 14 fatalities in

this study, constituting a death rate of 1.9%—much

lower than traditionally believed. Twelve of the 14

cases resulting in death occurred before 1930. Even

with little or no effective supportive care, the death

rate in symptomatic patients has been low—in the

range of 6%. The reported number of beans taken

by patients who died varied greatly. Of the two

cases of lethal oral intoxication documented since

1930, one was of a 24-year-old man who ate 15 to

20 beans, and the other was a 15-year-old boy who

ate 10 to 12 beans. All of the reported serious or

fatal cases of castor bean ingestion have the same

general clinical history: rapid (less than a few hours)

onset of nausea, vomiting, and abdominal pain; followed by diarrhea; hemorrhage from the anus;

anuria; cramps; dilation of the pupils; fever; thirst;

sore throat; headache; vascular collapse; and shock.

Death occurred on the third day or later. The most

common autopsy findings in oral intoxication are

multifocal ulcerations and hemorrhages of gastric

and small-intestinal mucosa, which may be quite

severe; lymphoid necrosis in the mesenteric lymph

nodes, gut-associated lymphoid tissue (GALT), and

spleen; Kupffer cell and liver necrosis; diffuse nephritis; and diffuse splenitis.

Injection

In one large clinical trial,40 low doses (18–20 μg/

m2) of intravenous ricin administered to cancer patients were well tolerated. Flulike symptoms with

fatigue—in some cases very pronounced fatigue—

and muscular pain were common, and sometimes

nausea and vomiting occurred. The symptoms began 4 to 6 hours after administration and lasted for

1 to 2 days. Two toxic deaths were reported in Phase

I clinical trails of the closely related protein toxin,

abrin; these patients had general seizures and other

signs of central nervous system toxicity.

In the case of Mr. Markov, whose assassination

was mentioned earlier,16 injection of a lethal dose

of ricin, estimated to be as much as 500 μg, resulted

in almost immediate local pain, then a feeling of

weakness within about 5 hours. Fifteen to 24 hours

later, he had a high temperature, nausea, and vomiting. Thirty-six hours after the incident, he was

admitted to the hospital feeling very ill. He had fever, tachycardia, and normal blood pressure; lymph

nodes in the affected groin were swollen and sore;

and a 6-cm diameter area of induration and inflammation was observed at the injection site on his

thigh. Just over 2 days after the attack, he became

suddenly hypotensive and tachycardic; the pulse

rate was 160 beats per minute, and vascular collapse

and shock had set in. His white blood count was

26,300/mm3. Early on the third day after the attack,

he became anuric and began vomiting blood. An

electrocardiogram demonstrated complete atrioventricular conduction block. Mr. Markov died

shortly thereafter; at the time of death, his white

blood count was 33,200/mm3.

Intramuscular or subcutaneous injection of high

doses of the toxin in humans, as occurred in the

assassination, results in severe local lymphoid necrosis, gastrointestinal hemorrhage, liver necrosis,

diffuse nephritis, and diffuse splenitis. In the case

of Mr. Markov, a mild pulmonary edema was

thought to have been secondary to cardiac failure.

Similar results have been reported in experimental

animal studies.
Medical Aspects of Chemical and Biological Warfare

636

Fig. 32-3. Lung from a rat exposed to ricin by aerosol. Immunocytochemical stain for ricin demonstrates strong reactivity for (a) airway epithelial cells and alveolar macrophages (arrows) and (b) alveolar lining cells. Original magnification x 50, immunocytochemical stain. Photographs: Courtesy of CL Wilhelmsen, DVM, PhD, Lieutenant Colonel,

Veterinary Corps, US Army; Division of Pathology, US Army Medical Research Institute of Infectious Diseases, Fort

Detrick, Frederick, Md.

Inhalation

Although data on aerosol toxicity exposure are

not available for humans, lesions induced by oral

and parenteral exposure are consistent with those

seen in experimental animal studies, suggesting that

the same would hold true for aerosol exposures. The

only information on inhalation of ricin in humans

is an allergic syndrome reported in workers exposed

to castor bean dust in or around castor oil processing plants.41 The clinical picture is characterized by

sudden onset of congestion of the nose and throat,

itchiness of the eyes, urticaria, and tightness of the

chest. In more severe cases, wheezing, leading to

bronchial asthma, may also occur, and may last for

several hours. Affected individuals respond to

symptomatic therapy and removal from the source

of exposure.

Inhalational exposure of rats to lethal ricin challenge results in a diffuse necrotizing pneumonia of

the airways, with interstitial and alveolar inflammation and edema.42 No notable changes in lung

injury parameters occur before 8 hours after the

challenge. By 12 hours, inflammatory cell counts

and total protein (both from fluid obtained via

bronchoalveolar lavage) increase, suggesting both

increased permeability of the air–blood barrier and

cytotoxicity; these findings are associated with a

blood-cell analysis indicative of inflammation. By

18 hours after the challenge, alveolar flooding is

present, and extravascular lung water is increased.

Both continue to increase up to 30 hours after the

challenge. At 30 hours after the challenge, arterial

hypoxemia and acidosis are present and histopathological evidence of alveolar flooding becomes significant. Recently completed immunohistochemical

studies43 in rats exposed to ricin via aerosol indicate that aerosolized ricin binds to ciliated bronchiolar lining cells, alveolar macrophages, and alveolar lining cells (Figure 32-3).

In a recent study44 of nonhuman primates, inhalational toxicity was characterized by a dose-dependent preclinical period of 8 to 24 hours, followed

by anorexia and progressive decrease in physical

activity. Death occurred 36 to 48 hours after the

challenge, time to death also being dose dependent.

Relevant gross and histopathological changes were

confined to the thoracic cavity (Figure 32-4). All

monkeys had acute marked-to-severe fibrinopurulent pneumonia, with variable degrees of diffuse

necrosis and acute inflammation of airways. There

were also diffuse, severe alveolar flooding and

peribronchovascular edema (Figure 32-5), acute tracheitis, and marked-to-severe purulent mediastinal

lymphadenitis. Two monkeys had acute adrenalitis.

Cause of Death

The exact cause of death is unknown and probably varies with route of intoxication. Results of ricin A-chain immunotoxin clinical trial studies demonstrated that ricin A-chain caused a vascular leak

syndrome characterized by hypoalbuminemia and

edema; subsequent in vitro studies with human

umbilical vein endothelial cells showed that ricin

damaged endothelial cells.45 In mice, rats, and primates, high doses via inhalation appear to produce

severe enough pulmonary damage to cause death,

a b
Ricin Toxin

637

Fig. 32-4. Lungs from a monkey exposed to ricin by aerosol. (a) The lungs are edematous, with accompanying hemorrhage and necrosis. (b) Histologically, the microscopical changes are characterized by fibrinopurulent pneumonia.

The fibrin has been specifically stained by phosphotungstic acid hematoxylin to appear purple (original magnification x 25). Photographs: Courtesy of CL Wilhelmsen, DVM, PhD, Lieutenant Colonel, Veterinary Corps, US Army;

Division of Pathology, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md.

a b

Fig. 32-5. Widespread perivascular and peribronchiolar

edema in a monkey, a characteristic finding in aerosol

ricin intoxication (hematoxylin-eosin stain; original magnification x 10). Photograph: Courtesy of CL Wilhelmsen,

DVM, PhD, Lieutenant Colonel, Veterinary Corps, US

Army; Division of Pathology, US Army Medical Research

Institute of Infectious Diseases, Fort Detrick, Frederick, Md.

probably due to hypoxemia resulting from massive

pulmonary edema and alveolar flooding. High doses

administered intravenously in experimental animals

are associated with disseminated intravascular coagulation8

; it has been suggested that hepatocellular and

renal lesions are the result of vascular disturbances

induced by the toxin rather than a direct effect of the

toxin itself.46 Studies published in 198747 clearly establish that in intravenous administration of ricin

toxin to rats, diffuse Kupffer cell damage occurred

within 4 hours, followed by endothelial cell damage,

formation of thrombi in the liver vasculature, and finally, hepatocellular necrosis, confirming studies that

had been published in 1976.48

DIAGNOSIS

Like other potential intoxications on the unconventional battlefield, epidemiological findings will

likely play a central role in diagnosis. The observation of multiple cases of very severe pulmonary

distress in a population of previously healthy young

soldiers, linked with a history of their having been
Medical Aspects of Chemical and Biological Warfare

638

at the same place and time during climatic conditions suitable for biological warfare attack, would

be suggestive.

The differential diagnoses of aerosol exposure to

ricin would include staphylococcal enterotoxin B,

exposure to pyrolysis by-products of organofluorine

polymers (eg, Teflon [polytetrafluoroethylene,

manufactured by Du Pont Polymers, Wilmington,

Delaware], Kevlar [polyparaphenyleneterephthalamide, manufactured by Du Pont Advanced Fiber

Systems, Wilmington, Delaware]) or other organohalides, oxides of nitrogen, and phosgene. Insecticides such as paraquat and α-naphthylthiourea

(ANTU), although not expected in a battlefield scenario, can be spread aerially over large geographical areas and are also potent edemagenic agents.

Confirmation of ricin inhalational intoxication

would most likely be through enzyme-linked

immunosorbent assay analysis of a swab sample

from the nasal mucosa; ricin can be identified by

this method for at least 24 hours after the challenge.49 Because ricin is extremely immunogenic,

individuals surviving a ricin attack would likely

have circulating antibody within 2 weeks after the

exposure; serum samples should be obtained from

survivors. Following inhalational intoxication in

laboratory animals, laboratory findings are generally nonspecific.

Enzyme-linked immunosorbent assays (for blood

or other body fluids)50 or immunohistochemical

techniques (for direct analysis of tissues) may be

useful in confirming ricin intoxication. However,

because ricin is bound very quickly regardless of

route of challenge, and metabolized before excretion, identification in body fluids or tissues is difficult. In rats exposed to ricin labeled with iodine 125

by intravenous injection, the radioactive label was

found in liver (46%), muscle (13%), and spleen (9%)

30 minutes after intravenous injection.51 Ricin was

quickly cleared from the animals, with only 11%

remaining after 24 hours; 70% was excreted in the

urine as low-molecular-weight metabolites. Attempts at identification of the toxin may also include introduction of biological autopsy materials

into mice or cultured cells and neutralization

through the use of specific antibodies.

MEDICAL MANAGEMENT

The most likely scenarios in which ricin intoxication might be seen by military medical personnel

are (1) small-scale battlefield or terrorist delivery

of an aerosol and (2) parenteral administration of

the toxin to an individual as an assassin’s tool. Because ricin acts rapidly and irreversibly (directly on

lung parenchyma after inhalation, or is distributed

quickly to vital organs after parenteral exposure),

postexposure therapy is more difficult than with

slowly processed, peripherally acting agents (such

as the botulinum toxins or bacterial agents) that can

be treated with antibiotics. Therefore, immunization of personnel at risk for ricin exposure is even

more important than it is for some of the other potential biological warfare agents.

Immunization and Passive Protection

Animal studies have shown that either active

immunization or passive prophylaxis or therapy (if

the therapy is given within a few hours) is extremely

effective against intravenous or intraperitoneal

intoxication with ricin. On the other hand, inhalational exposure is best countered with active immunization or prophylactic administration of aerosolized specific antiricin antibody. Active prophy laxis

through immunization is the only effective medical countermeasure within our grasp at this time.

Prophylactic immunization of mice, rats, and subhuman primates with two to three doses of the toxoid (3–5 μg per dose), with or without adjuvant (aluminum hydroxide), protects against death and

incapacitation following inhalational exposure to

multiple lethal doses of ricin toxin.52 Either a toxoid of the native toxin or a preparation of the purified A-chain produces a measurable antibody response that correlates with protection from lethal

aerosol exposure. The toxoid has been microencapsulated in glactide-glycolyde microparticles and, in

mice, provides effective immune protection after

one immunization.53 As this is written, the only

potential approved medical countermeasures for

human use are the formalin-treated toxoid, which

has gone through preclinical testing and has been

submitted to the Food and Drug Administration as

an Investigational New Drug, and the deglycosylated A-chain, which has also shown promise as

an antigen in preclinical trials. The toxoid has

proven safe and effective in rodents and nonhuman

primates exposed to ricin aerosol by inhalation, the

route of challenge believed to be the most likely

threat on the battlefield.

In seeking an approach to passive protection of

soldiers without immunization, animal studies have

been conducted in the laboratory to evaluate the

short-term efficacy of prophylactically inhaled spe-
Ricin Toxin

639

cific antibody. Preliminary data54 suggest that (a)

when mice are exposed for 20 minutes to aerosolized specific immunoglobulin G (about 24 μg

antibody per mouse, the lowest dose tested), they are

completely protected from lethal aerosol challenge

1 hour later; and (b) more than 95% of them are protected from pulmonary lesions. These findings suggest that inhalation of protective antibody from a portable nebulizer just before an attack might provide

some protection in unimmunized individuals. These

studies also suggest that intravenous administration

or inhalation of specific antibody after exposure to

aerosolized ricin will be of little value in blocking

or reversing the toxin’s pathological effects.

Supportive and Specific Chemotherapy

As is the case in toxicity and pathogenesis of intoxication, the route of exposure is important in

relation to possible modes and their likelihood of

success of prophylaxis and therapy. For oral intoxication, supportive therapy includes activated charcoal administration and intravenous fluid and electrolyte replacement. For inhalational intoxication,

supportive therapy to counteract acute pulmonary

edema and respiratory distress is indicated. Symptomatic care is the only intervention presently available to clinicians for the treatment of incapacitating

or lethal doses of inhaled ricin. Positive end-expiratory ventilatory therapy, fluid and electrolyte replacement, antiinflammatory agents, and analgesics

would likely be of benefit in treating aerosolintoxicated humans. As we learn more about the

pathogenesis of intoxication by this route, specific

mediator blocking agents may prove valuable, as well.

In recent years, a wide variety of chemotheraputic agents has systematically been screened in an

in vitro Vero cell inhibition of protein synthesis

assay for efficacy against ricin toxicity.55 More than

150 agents, including cellular membrane effectors,

calcium channel–blocking agents, sodium–calcium

exchangers, reducing agents, antioxidants, effectors

of endocytosis, nucleoside derivatives, antibacterials, ricin analogs, effectors of cellular metabolism,

and competitors for binding have been tested. Of

these, only five agents showed promise in vitro and

were screened in mouse-protection assays:

• D-galactose and its derivatives, which are

competitors for binding,

• azidothymidine (AZT) and a purine derivative, BM33203, both of which are nucleoside derivatives, and

• brefeldin-A, which is a Golgi transport inhibitor.

None of the compounds have proven useful for protecting laboratory animals, even from intravenous

exposure to the toxin. Efforts are also underway to

synthesize very specific compounds, transitionstate inhibitors, which block the enzymatic effects

of the A-chain.

SUMMARY

Ricin is a large, moderately toxic, protein dichain toxin from the bean of the castor plant,

Ricinis communis. It can be produced easily in

relatively large quantities. Ricin was developed

as a biological weapon by the United States and

its allies during World War II. Although ricin is

toxic by several routes, when inhaled as a respirable aerosol, it causes severe necrosis of the airways and increased permeability of the alveolar-capillary membrane. The inhalational route

is presumed to be the likeliest threat on the battlefield.

Death after inhalation of a lethal dose appears to

be caused by hypoxemia resulting from massive

pulmonary edema and alveolar flooding. Diagnosis can be confirmed through the use of enzymelinked immunosorbent assays of tissues or body

fluids. Prophylactic administration of an investigational vaccine protects laboratory animals from inhalational and other routes of challenge.

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53. Yan C, Resau JH, Hewetson J, West M, Rill W, Kende M. Characterization and morphological analysis of protein-loaded poly(lactide-co-glycolide) microparticles prepared by water-in-oil-in-water emulsion technique.

Journal of Controlled Release. 1994;32:231–241.

54. Poli M, Virera V, Pitt L, Vogel P. Aerosolized specific antibody protects mice from lung injury associated with

aerosolized ricin exposure. In: 11th World Congress on Animal, Plant, and Microbial Toxins; 1994; Tel Aviv,

Israel. Abstract.

55. Thompson W, Scovill J, Pace J. Drugs that show protective effects from ricin toxicity in in-vitro protein synthesis assays. Natural Toxins. 1995;3:369–377.
Botulinum Toxins

643

Chapter 33

BOTULINUM TOXINS

JOHN L. MIDDLEBROOK, PH.D.*; AND DAVID R. FRANZ, D.V.M., PH.D.†

INTRODUCTION

HISTORY AND MILITARY SIGNIFICANCE

DESCRIPTION OF THE AGENT

Serology

Genetics

PATHOGENESIS

Relation to Other Bacterial Toxins

Stages of Toxicity

CLINICAL DISEASE

DIAGNOSIS

MEDICAL MANAGEMENT

SUMMARY

*Chief, Life Sciences Division, West Desert Test Center, Dugway Proving Ground, Dugway, Utah 84022; formerly, Scientific Advisor, Toxinology

Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011

†Colonel, Veterinary Corps, U.S. Army; Commander, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick,

Maryland 21702-5011
Medical Aspects of Chemical and Biological Warfare

644

INTRODUCTION

The clostridial neurotoxins are the most toxic substances known to science. The neurotoxin produced

from Clostridium tetani (tetanus toxin) is encountered

by humans as a result of wounds and remains a serious public health problem in developing countries

around the world. However, nearly everyone reared

in the western world is protected from tetanus toxin

as a result of the ordinary course of childhood immunizations. Humans are usually exposed to the neurotoxins produced by Clostridium botulinum (ie, the botulinum toxins, of which there are seven in all) by means

of food poisoning, although there are rare incidents

of wound botulism and a colonizing infection of neonates known as infant botulism.1

 Since the incidence

of botulinum poisoning by all routes is very rare,

immunization of the general population is not warranted on the basis of cost and the expected rates

of adverse reactions to even the best vaccines.

Thus, humans are not protected from botulinum

toxins and, because of their relative ease of production and other characteristics, these toxins are likely

biological warfare agents. Indeed, the United States

itself explored the possibility of weaponizing botulinum toxin after World War II, as is discussed elsewhere in this textbook. Although the United States

disavowed any further research on developing the

botulinum toxins as biological warfare agents, great

concern remains that other nations might employ

them, and ongoing research seeks ways to protect

our armed forces from their use.

HISTORY AND MILITARY SIGNIFICANCE

Because of the extreme toxicity of botulinum toxin,

it was one of the first agents to be considered as a

biological weapons agent. Before offensive research

on biological warfare was renounced, researchers in

the United States worked on the weaponization of

botulinum toxin for over two decades. Efforts began

early during World War II (Exhibit 33-1). Intelligence

information indicated that Germany was attempting

to develop botulinum toxin as a cross-channel weapon

to be used against invasion forces.2 At the time the

Allied work began, the composition of the toxic agent

produced by C botulinum was not clear, nor was the

mechanism of lethality in animals and man. Therefore, the earliest goals of research on botulinum toxin

were to isolate and purify the toxin and to determine

its pathogenesis. Botulinum toxin was referred to as

agent X.

Strains that produced each of the five serotypes

known at the time were obtained and those expressing the most toxin were selected for use in further

study, although most of the research involved serotype A.2

 Culture conditions required to produce maximal levels of toxin were established, and techniques

appropriate for purification and concentration were

perfected. An important advance was “crystallization” of the toxin. The preferred method of toxin purification involved an initial acid precipitation from

the culture supernatants, followed by redissolving the

toxin in an aqueous buffer. At that point, the addition

of ammonium sulfate produced toxin in a form called

“crystalline.” To a protein chemist of today, this term

means a highly purified protein that may be suitable

for three-dimensional structure determination. The

scientists of that time thought that their crystalline

preparations were pure, but we now know that these

preparations were far from pure—although the procedure did put the toxin in a physical state of high

stability. The crystalline toxin they produced was authentic neurotoxin with an accompanying protein or

proteins (hemagglutinin, in most cases) that stabilizes

the toxin from thermal and proteolytic degradation.

Further technical advances in analytical protein chemistry were required before the true physical state of

the toxin became evident. However, a good deal of

work was carried out with this form of the toxin, and

nearly all the insights and conclusions derived from

the work remain valid.

One of the more lasting legacies of the early botulinum toxin biowarfare research was the development of the botulinum vaccine that is used even

today. It was clear that the scientists working with

large quantities of the toxin needed to be protected

from possible laboratory exposures and that a vaccine would serve them, as well as the armed forces

at risk of biological warfare attack. A formalininactivated toxoid (ie, a toxin that has been treated

so as to destroy its toxicity but retain its antigenicity) proved effective in animal studies, and large

quantities were prepared for human use.3

 A large store

of vaccine was shipped to England for possible use

by the expeditionary forces, but for reasons that are

not elaborated in the official history,2

 the decision

was made not to vaccinate the troops. Many humans

have since been vaccinated with this and similarly prepared botulinum toxin vaccines, and clinical experience has indicated that they are safe and effective.
Botulinum Toxins

645

EXHIBIT 33-1

A FOOTNOTE TO HISTORY: WAS BOTULINUM TOXIN USED IN THE ASSASSINATION

OF REINHARD HEYDRICH?

Reinhard Heydrich, head of the Gestapo and Security Service in Germany during World War II, was arguably second only to Hitler as the chief perpetrator of the Holocaust. He was assassinated in Prague in the

spring of 1942 by Czech patriots who were trained and equipped by the British. The fatal injury resulted from

the detonation of a bomb, which drove fragments through a seat in Heydrich’s car and into his left flank,

injuring the lung, diaphragm, and spleen.

The surgical care he received was surprisingly good, even when judged by today’s standards. Heydrich’s

initial postoperative course was satisfactory, although he was modestly febrile and there was drainage from

the wound of entrance. His condition worsened suddenly on the seventh postoperative day and he died early

the next day.

An autopsy showed no apparent gross or microscopic cause of death; specifically, there was no missed

injury, evidence of peritonitis, abscess, wound tract infection, or retained foreign bodies; and the heart and

lungs appeared normal.1

 The senior German pathologists in attendance wrote that “...death occurred as a

consequence of ... bacteria and possibly by poisons carried ... by the bomb splinters....”2(p17) Although when we

use modern terminology their assessment can be interpreted to mean that death was due to septic shock or

multiple organ failure, looking at the incident from the vantage point of 50 years also allows for a more diabolical interpretation.

The extraordinary efforts made by the British and Americans to develop biological weapons in World War

II are not generally known. For instance, by 1944, it would have been possible for the Allies to drop tens of

thousands of bombs containing Bacillus anthracis (ie, anthrax) spores on major German cities.3

 Other potential

biological warfare agents were also being investigated, among them the neurotoxins of Clostridium botulinum.

It is here that Heydrich’s death becomes relevant. Although we have no official written documentation, the

chief scientist in charge of the British biological warfare program, Paul Fildes, is recorded as having made

remarks to colleagues that can only be interpreted to mean that he and, by implication, a biological warfare

agent, played a role in Heydrich’s death: “[I] had a hand [in Heydrich’s death]”3(p94) and “[Heydrich] was the

first notch on my pistol.”3(p94)

There is reason to believe that Fildes’s research group was actively developing botulinum toxin as a weapon.

That the British were very knowledgeable about the potential use of botulinum toxin in war is apparent from

their request to the Canadian government for several hundred thousand doses of toxoid as a defense against

possible German use. Although not carrying the weight of written documentation, Fildes’s recorded statements, together with the known British interest in botulinum toxin, have led two British historians to propose

that the bomb used to assassinate Heydrich contained botulinum toxin in addition to the usual explosive charge.3

How likely is it that botulinum toxin played a role in Heydrich’s death? Certain observations are possible:

• The bomb used in the assassination was not of standard issue but instead was of distinctly unusual

design: the upper third of a British hand grenade had been cut off and the open end and sides wrapped

with tape.2

 This strange modification becomes understandable if a way was needed to contaminate its

contents with a foreign substance.

• Heydrich’s clinical course does not explain his death. Although infection was likely to accompany his

injury, his sudden deterioration and death do not conform to the usual expression of fatal sepsis. It is

noteworthy that infection was not a prominent finding at autopsy. Heydrich’s death is actually much

more suggestive of a massive pulmonary embolism, yet his heart and lungs were said to be normal.1

• Heydrich’s death is not especially suggestive of botulism. The clinical course of wound botulism (albeit

with a more-rapid onset) probably comes close to what should have happened if Heydrich’s wound was

actually contaminated with botulinum toxin. However, the apparent absence of such expected signs and

symptoms as ptosis, diplopia, dysphonia, dysarthria, dysphagia, facial paralysis, and generalized muscular weakness culminating in respiratory insufficiency developing over several days speak against

botulism.

The answer will probably never be known, although the British archives for this period, which are scheduled

to be opened early in the 21st century, may contain relevant information.

(1) Davis RA. The assassination of Reinhard Heydrich. Surg Gynecol Obstet. 1971;August:304–318. (2) Ramsey WG, ed. The

assassination of Reinhard Heydrich. After the Battle. 1979;24:cover 2–37. (3) Harris R, Paxman J. A Higher Form of Killing.

New York, NY: Hill and Wang; 1982.
Medical Aspects of Chemical and Biological Warfare

646

DESCRIPTION OF THE AGENT

C botulinum and C tetani are spore-forming,

anaerobic bacteria found worldwide in soil. As

mentioned previously, however, the organisms produce their toxicoses in very different manners. Victims of tetanus present clinical symptoms of a rigid

tetanic paralysis, whereas the victims of botulinum

poisoning present with a radically different symptom: peripheral, flaccid paralysis. Poisoning by tetanus toxin is a result of wound contamination and is

an infectious disease like cholera or diphtheria, in

which invading organisms multiply within the

body and produce their toxin. The disease is very

old, with descriptions and drawings of victims going back to the Middle Ages.

In contrast, poisoning by botulinum toxin (ie,

the disease we call botulism) seems to have been

more rare, especially during ancient times. Although there may have been ancient cases of wound

botulism, there is little or no evidence for such

infections until much more recent times. Food

poisoning due to botulinum toxin emerged as

a problem when food preservation became a

widespread practice. Since the outbreaks were

so dramatic, they soon received the attention of

scientists and the etiology of the poisoning was

elucidated. It is now clear that C botulinum grows

and produces neurotoxin in the anaerobic conditions frequently encountered in the canning or

preservation of foods. The spores are very hardy,

and special efforts in sterilization are required

to ensure that the organisms are inactivated and

unable to grow and synthesize their toxin. Modern

commercial procedures have virtually eliminated

the problem of food poisoning by botulinum toxin,

and most of the cases now seen are associated

with home-canned foods or meals produced by

restaurants.

One other mode of botulinum toxin poisoning

has a significant number of cases in the United

States: infant botulism.1

 These cases involve an ongoing colonization of the intestines of infants, usually in the first year of life, by the usually benign C

botulinum organism. Apparently, the flora of newborns, their intestinal environment, or both is such

that the organism can grow and produce toxin; there

are no well-documented cases of intestinal infections in adult humans.

Serology

The initial identification of botulinum toxin as

the etiologic agent in poisoning came after isolation of organisms from the victims, followed by

growth in the laboratory and demonstration of toxigenicity by injection of animals with culture filtrates. After inactivation, the culture filtrates were

used to raise (ie, produce) toxin-neutralizing antiserum. This antiserum was used to confirm poisoning

 by C botulinum until victims with similar symptoms

appeared, but the antiserum did not neutralize the

toxin in animal experiments. However, when the

entire process of antiserum production was repeated with the new isolates, neutralization was

observed. It soon became clear that medicine was

dealing with a family of toxins that produced related poisoning sequelae, but that differed immunologically. Thus, seven distinct serotypes of botulinum toxin have now been isolated, designated A

through G. Interestingly, not all serotypes have been

associated with poisoning of humans. Serotypes A,

B, E, and F have been clearly identified in numerous human poisoning episodes. Serotype G is the

most recently isolated toxin and has only been identified in a few outbreaks. For serotypes C and D,

respectively, only a single anecdotal human case of

intoxication has been reported. These serotypes

have been found in outbreaks involving various

animals including chickens and mink in domestic

settings and ducks in wild environments. Why it is

that humans are typically not poisoned by serotypes

C and D is not clear.

Because the clostridial toxins are so potent, they

have been the subjects of many studies by laboratories throughout the world. In nearly every case,

multiple strains have been isolated that produce the

same serotype of botulinum toxin. (Strangely, however, C tetanus strains all produced the same serotype of tetanus toxin.) Many of the strains are available from microbiological repositories such as the

American Type Culture Collection. However, due

to the ubiquitous nature of the organisms, we could

simply isolate anaerobic organisms from the soil in

nearly any country and expect to obtain one or more

serotypes of toxin-producing C botulinum. In fact,

there is recent evidence that other clostridia can

carry and express the genes for the botulinum neurotoxins.4

 In addition, with the emergence of molecular genetics as a readily available technology,

nearly any laboratory with such expertise could

move the gene for botulinum toxin into other organisms. Although such research is forbidden by

law in most western nations, including the United

States, there is no international legal prohibition of

such work.
Botulinum Toxins

647

Genetics

Our understanding of many important details of

the action of botulinum and tetanus toxins has been

slow in progressing. However, enormous strides

have been made during the last 5 years, and science is now closing in on a detailed description of

how these toxins work. The most important breakthrough involved cloning and sequencing of the

genes for tetanus and all seven serotypes of botulinum neurotoxins.5–14 With that information, the

amino acid sequences could be deduced, and this

led to other important insights into the molecular

mechanisms of action.

The family of structural genes for the clostridial

neurotoxins is unrestricted in its location, being

both chromosomal and extrachromosomal. The

structural gene for tetanus toxin is on a plasmid, as is

probably the structural gene for botulinum toxin

serotype G.15 The structural genes for botulinum

toxin serotypes C and D are found on bacteriophages.16,17 The remainder are believed to be chromosomal in location, but this is not definitely proven.

The isolation of clostridia not classified as C botulinum, yet expressing botulinum toxin and involved

in human disease,18,19 raises several interesting

questions. Does the gene for botulinum neurotoxin move from species to species in the clostridia

family? Have the toxin genes always been resident

in clostridia other than C botulinum and either

not expressed or expressed at low levels, therefore

remaining unrecognized? Why is the gene for

tetanus toxin not found (thus far) in other clostridial species? Why are there multiple serotypes

of botulinum, but not of tetanus toxin? Have we

found all existing serotypes of botulinum toxin,

or are there additional serotypes lurking in the

environment waiting to be discovered? And probably the most intriguing question of all: What is

the real function of these neurotoxins? Surely not

to poison humans. Humans are not predators of

clostridia and can hardly be viewed as prey, either.

The neurotoxins probably serve some important

function in the natural environment or life cycle of

clostridia, and humans just happen to get in the

way.

PATHOGENESIS

As mentioned earlier, botulinum toxins are the

most poisonous substances known. The dose that

is lethal to 50% of the population exposed (ie, the

LD50) has been estimated20 to be approximately 1 ng/

kg. This is similar to LD50s reported for most laboratory animal species when the toxin is administered

intravenously, subcutaneously, or intraperitoneally.

All of the botulinum toxins are slightly less toxic when

exposure is by the pulmonary route: a recent estimate

for the human LD50 by inhalation is 3 ng/kg.21

The extreme toxicity of the botulinum toxins

would lead us to believe that they must have some

highly potent and efficient mechanism of action.

This probability made botulinum toxin the subject

of work by many laboratories, especially after we

learned that it is a neurotoxin. Experiments with in

vitro neuromuscular models established that the

toxin acts presynaptically to prevent the release of

acetylcholine. In many of those same models, very

high doses of botulinum toxin will block the release

of neurotransmitters other than acetylcholine, but

there seems to be a marked toxin specificity involving acetylcholine.22

Relation to Other Bacterial Toxins

With the development of such techniques as

sodium dodecyl sulfate (SDS) polyacrylamide gel

electrophoresis, it became evident that the crystalline toxin was really an aggregate of proteins, and

that the molecular species responsible for poisoning was a single protein of about MW 150,000. However, because the molecular events underlying

neurotransmitter release were poorly understood,

little progress was made in understanding the details

involved in botulinum toxin’s pathogenesis during the

1970s and 1980s. As is true for science in general, it

was research in related areas that provided the framework for the next round of advances with botulinum

toxin. Studies with another microbial toxin, that

produced by Corynebacterium diphtheriae, provided

several important insights that some scientists believed could be applied to botulinum toxin. Most importantly, the realization that diphtheria toxin is an

enzyme permitted researchers to understand how

certain toxins could be so much more potent than others. Curare, for example, binds to the acetylcholine

receptor and acts in a stoichiometric relationship to

exert toxicity. Diphtheria toxin, being an enzyme, can

act many times over on (or, more properly, in) a cell

and therefore exert a much more powerful effect (for

a given number of molecules) than a stoichiometrically acting toxin. Because botulinum toxin is much

more potent than even diphtheria toxin, many laboratories embarked on a search for the (putative)

enzymatic activity expressed by botulinum toxin.
Medical Aspects of Chemical and Biological Warfare

648

Stages of Toxicity

The second insight provided by the work on

diphtheria toxin was the recognition that microbial

toxins have structural domains (or subunits) that

serve common general functions related to a threestage mechanism of action: binding, internalization,

and enzymatic activity.23 Figure 33-1 depicts these

stages.

All three functions are normally required for expression of toxicity in cells or animals, but under

certain experimental circumstances these functions

can be blocked or overcome. Thus, if the enzyme

domain of a toxin is removed or specifically inactivated, the toxin is rendered inactive and could be

used as a vaccine. It could bind to a target cell and

enter the interior, but without its functional component, no toxicity would result. A derivative of

diphtheria toxin called CRM-197 is a perfect example of this type of alteration. On the other hand,

the active enzyme domain by itself is virtually nontoxic if it is added to cells or given to animals. The

enzyme domain alone is unable to recognize and

bind specifically to target cells. If, however, the enzyme domain is linked to other cell-binding ligands,

the toxicity can be redirected to new target cells.

This type of construction is the basis for many attempts to treat cancer or other diseases (eg, the fusion of diphtheria toxin fragment A, its enzymatic

component, with tumor-directed antibodies).

Binding

What about (a) the receptor for botulinum toxin,

(b) the means by which the toxin enters neurons,

and (c) the toxin’s enzymatic activity? First, the receptor. For many years, the observation that complex sphingolipids prevented toxicity was taken to

indicate that gangliosides were receptors for the

toxins. However, there is as much evidence suggesting that gangliosides are not the receptor (or receptors) as there is that they are.

24 An important study25

published in 1986 presented good evidence that the

different serotypes of botulinum toxin do not share

the same receptor. It is not yet clear if there are distinct receptors for each serotype.

As this is written (1996), it is fair to say that science does not know the structure of the receptors

for either botulinum or tetanus toxins. A report

published in 199426 suggesting that a synaptic

vesicle–associated protein called synaptotagmin

may be the receptor for botulinum toxin serotype

B. This intriguing work has yet to be confirmed, and

Fig. 33-1. The three stages in the mechanism of action of

dichain microbial toxins (ie, two protein chains connected

by a disulfide bond). In the first stage, a domain (the

sphere at the end of the heavy chain) at the carboxyl end

of the holotoxin recognizes and binds to a receptor or

acceptor on the surface of the target neuron. The internalization stage follows, which results in delivery of the

light chain of the toxin into the cytoplasm. The internalization stage is directed by a domain adjacent to the receptor-recognition domain on the heavy chain. Whether

all or part of the heavy chain also enters the cytoplasm

remains unclear, but the light chain certainly gains entry

into that compartment. Finally, once in the cytoplasm,

the light chain acts like an enzyme and catalyzes specific reactions described in the text, preventing both (a)

the vesicle from fusing to the membrane and (b) neurotransmitter release.

as it stands, it lacks one key piece of information.

The researchers elegantly demonstrate that serotype

B binds to synaptotagmin, but the crucial evidence

showing that synaptotagmin binding results in internalization and toxicity is not yet available.

Internalization

A substantial body of evidence indicates that

botulinum toxin enters neurons by the general pathway used by several other bacterial toxins, a number of polypeptide hormones or growth factors, and

even some viruses.27 This pathway has come to be

known as receptor-mediated endocytosis (RME).

Briefly, ligands are concentrated on the cell surface by virtue of binding to receptors that are localized in specialized regions called coated pits. The

pits invaginate, becoming vesicles, and are transported to one or more sites in the cell interior, carMuscle

Botulinum toxin

receptor

Heavy chain

Neuron

s s

s s

s s s

Synaptic vesicle

Disulfide bond

Light chain
Botulinum Toxins

649

rying along the contents. At various stages of vesicle

trafficking, some of the contents escape or are released into the cytoplasm, where, in the case of bacterial toxins, they act on the intracellular substrates.

This action leads to toxicity.

One general feature of the process is a gradual

decrease in the intravesicular pH as a result of a

protein pump in the membrane; this may drop as

low as pH 4.5. Certain drugs or compounds called

lysosomotropic amines prevent this pH drop and, in

nearly all cases, inhibit the release of ligands. Because

of this known effect, inhibition of a specific biological process by lysosomotropic amines is widely accepted as a hallmark of the presence of an RME process. Indeed, this is the case for botulinum toxin.

The presence of lysosomotropic drugs will inhibit,

or at least delay, the onset of botulinum toxin paralysis23; this fact has led most scientists in the field

to believe that the toxin enters the neurons by RME.

Enzymatic Activity

Finally, the enzymatic activity of botulinum

toxin. A critical key to the identification of this enzymatic activity was provided by the cloning and

sequencing of tetanus toxin and all seven serotypes

of botulinum toxin—work that was performed by

several laboratories. Initially, a scientist not in the

neurotoxin field noted28 that tetanus toxin has an

amino acid sequence in its light chain that is similar to that seen in zinc-dependent proteases. When

the amino acid sequences of the botulinum toxins

became available, they, too, were seen to have this

sequence in the light chain. This remarkable similarity led several laboratories to seek to determine

if botulinum and tetanus toxins might exhibit a zincdependent proteolytic activity.29

Demonstration of this activity was initially difficult because the toxins are very specific for their

substrates. However, it is now clear that (a) the

clostridial neurotoxins express proteolytic activity

and (b) this activity is absolutely required for toxicity.30 The substrate proteins for this action appear

to be part of a hetero-oligomeric assembly associated with the synaptic vesicles. Interestingly, the

specific target site for cleavage seems to be different for each serotype of the botulinum toxins: in

some cases, different locations on the same protein;

in others, different proteins of the assembly.30 The

basis of this marked specificity is not yet clear

and remains fascinating to scientists interested in

neurosecretion.

CLINICAL DISEASE

Botulism is a feared and dramatic disease and is

frequently fatal for animals and humans alike. In

food poisoning, the symptoms appear several hours

to 1 or 2 days after contaminated food is consumed.

The earliest symptoms are difficult to associate with

poisoning and, depending on their severity, might

result in a number of clinical effects: blurred vision,

ptosis, dysphagia, dysarthria, and apparent muscle

weakness. As the neuromuscular symptoms progress and respiratory distress begins, healthcare

providers usually consider botulism. A confirmatory diagnosis comes from mouse bioassays demonstrating toxin in blood or stool, neutralized by

the appropriate antisera. Many times, the organism

can be isolated from the offending food, and toxin

and neutralizing tests can then be run again using

food samples. Established effective treatments are

few or none, save artificial ventilation and other

forms of life support.

Inhalational botulism, the syndrome most likely

to be seen on the battlefield, is rare. One incident

involving accidental exposure of humans to botulinum toxin occurred in a laboratory in Germany

and was reported in 1962.31 After conducting a postmortem examination of laboratory animals that had

been exposed, whole-body, to botulinum toxin type

A, three laboratory workers experienced symptoms

of botulinum intoxication. Three days after exposure, they described having (a) a “mucous plug

in the throat,” (b) difficulty in swallowing solid

food, and (c) “the beginning of a cold without

fever” and were hospitalized. On the fourth day,

their signs were more severe. The patients complained of “mental numbness” and retarded ocular

motions; their pupils were moderately dilated with

slight rotary nystagmus. Speech became indistinct

and gait uncertain as patients complained of extreme weakness. The patients were given antibotulinum serum on the fourth and fifth days. Between

the sixth and tenth days after exposure, the patients

experienced steady reductions in their visual

disturbances, numbness, and difficulties in swallowing. They were discharged from the hospital

less than 2 weeks after the exposure, with only

a mild general weakness remaining. The signs

and symptoms of inhalational botulinum intoxication, listed in order of onset, are found in

Exhibit 33-2.
Medical Aspects of Chemical and Biological Warfare

650

More data are available on exposure of animals

to toxin aerosols. Rhesus monkeys were exposed by

inhalation to botulinum toxin, type A, in conjunction with toxoid and hyperimmune globulin efficacy trials.32 Exposure to 5 to 10 monkey LD50 (ie, 5

to 10 times the LD50 for monkeys) resulted in death

in 2 to 4 days. Clinical signs of intoxication were

noted 12 to 18 hours before death; they are also

listed in order of onset in Exhibit 33-2. Preliminary

studies with small numbers of animals (N = 3 per

serotype) have recently demonstrated that serotypes C, D, and G are also toxic to rhesus monkeys.33

EXHIBIT 33-2

SIGNS AND SYMPTOMS OF INHALATIONAL BOTULISM, IN ORDER OF ONSET

Humans1 (sublethal dose)

Third day postexposure:

Mucous in the throat

Difficulty swallowing solid food

Feeling of catching a cold but without fever

Fourth day postexposure:

Mental numbness

Retarded ocular motions

Pupils moderately dilated with slight nystagmus

Indistinct speech

Uncertain gait

Extreme weakness

Monkeys2 (lethal dose)

Mild muscular weakness

Intermittent ptosis

Severe weakness of postural muscles of the neck

Occasional mouth breathing

Serous nasal discharge

Salivation, dysphagia

Mouth breathing

Rales

Anorexia

Severe generalized weakness

Lateral recumbency

Data sources: (1) Holzer E. Botulism caused by inhalation. Med Klin. 1962;41:1735–1740. (2) Franz DR, Pitt LM, Clayton MA,

Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. In: Das

Gupta B, ed. Botulinum and Tetanus Neurotoxins and Biomedical Aspects. New York, NY: Plenum Press; 1993: 473–476.

DIAGNOSIS

Making a diagnosis of botulism under battlefield

conditions might be very difficult during the early

stages of a biological warfare attack. A history

of simultaneous onset of bulbar and neuromuscular disease in a group of soldiers would alert

medical personnel to botulism. The symptoms listed

in Exhibit 33-2 are nearly pathognomonic of

botulism prior to development of respiratory failure. The absence of convulsions would differentiate botulinum intoxication from chemical nerve

agent poisoning. However, a wide variety of

natural neurotoxins not related to botulinum toxin

could produce roughly the same sequelae. For example, the bite of a snake that produces venom neurotoxins would lead to many, if not all, of the symptoms of botulinum toxin poisoning. However, the

patient or soldier or his buddies would probably

mention the bite if it had occurred, the telltale fang

puncta would be seen on physical examination, and

numerous patients simultaneously exhibiting these

signs and symptoms can hardly all have been bitten by snakes.

Medical personnel must remember, however, that

with the advances of molecular genetics, it is possible to clone and produce many natural neurotoxins in relatively large quantities. For the present

(1996), botulinum poisoning is a much more likely

biological warfare agent than snake venom toxins.

In future years, other (cloned) neurotoxins should

be considered in the diagnosis.

Because of the small quantity of toxin protein

needed to kill, botulinum toxin exposure does not

typically induce an antibody response after exposure. The most likely means of laboratory diagnosis is through enzyme-linked immunosorbent assay identification of botulinum toxin from swabs

taken from the nasal mucosa within 24 hours of inhalational exposure.
Botulinum Toxins

651

MEDICAL MANAGEMENT

Because the incidence of botulinum poisoning is

so low in the United States, vaccination of the general public is unwarranted. It is only because of the

possible use of the toxin as a biological warfare

agent that vaccine and antiserum development have

taken place, and this work has been done almost

entirely by the U.S. Army. For this reason, nearly

all stocks of these products are presently held by

the army. There are two basic alternatives for prophylaxis from botulinum poisoning: active immunization using a vaccine, or passive immunotherapy

using immunoglobulin.

The vaccine currently available is a toxoid that

protects from serotypes A through E. This material

is used under Investigational New Drug (IND) status, with a license held by the Centers for Disease

Control and Prevention (CDC), Atlanta, Georgia.

The toxoid was developed by scientists at Fort

Detrick, Frederick, Maryland, during the 1950s.3

It is a formalin-fixed crude culture supernatant

from strains of C botulinum that produce the appropriate serotypes. Vaccinations are administered at

0, 2, and 12 weeks, followed by annual booster

doses.

Nearly 80% of recipients exhibit protective titers

(according to the CDC standard of > 0.25 international units per milliliter) at 14 weeks.3

 However,

hardly anyone has a measurable titer just prior to

receiving the first annual booster dose. The kinetics of this loss are imperfectly understood at the

present. A booster dose administered at 1 year leads

to a robust response from approximately 90% of the

recipients. Although currently an IND vaccine, the

botulinum toxoid has been administered to hundreds of humans over many years and is widely

regarded as safe. (Approximately 8,000 service

members received the toxoid between 23 January

and 28 February 1991, as part of the U.S. force deployed to the Persian Gulf War. A significant fraction of recipients experience stinging immediately

after injection and a sore arm for 2 to 4 days. However, in the experience of most recipients, including the authors, the short-lived symptoms are not

significantly different from those produced by tetanus vaccination. Work is currently underway in U.S.

Army laboratories to develop a new generation recombinant botulinum vaccine that would protect

from all known serotypes.

Passive protection can be afforded by administration of immunoglobulin products of various

types. The earliest developed was a horse antibotulinum serum (ie, globulin). Because of the relatively

high risk of serum sickness, a despeciated globulin

(ie, the species-specific antigenic properties were removed from the equine immunoglobulin) was produced. Thus, the product currently held in quantity is horse antibotulinum toxin immunoglobulin

that has been treated with pepsin to produce the

fragment F(ab’)2 (ie, the basic immunoglobulin

molecule has been altered by removal of the complement fixing [Fc] region to concentrate the antigen

binding sites). This material has been tested for efficacy in studies with monkeys. Animals given one

human dose, or one tenth of one human dose of the

F(ab’)2 antitoxin, and challenged with approximately 10 LD50 of serotype A by inhalation, survived without signs of intoxication.32 Antibody titers ranging from 0.6 to 0.38 international units per

milliliter, in those given one human dose, and from

0.02 to not measurable after one tenth of one human dose of F(ab’)2, were fully protective.

When given as therapy after exposure, one tenth

of one human dose of the F(ab’)2 product was protective if given before onset of clinical signs of disease. If given after onset of signs, however, even a

dose 3-fold greater than the recommended human

dose was not protective. We believe that toxin is

already inside neurons and producing the symptoms of poisoning, and cannot be reached by circulating antibody. These data demonstrate that, at

least in monkeys, titers much lower (< 0.02) than

0.25 international units (as recommended for the

vaccine) are protective and suggest that humans

may be more easily protected by vaccination than

previously believed.

In addition to the recombinant vaccine presently

in development, research on cocktails of monoclonal antibodies is being conducted at the U.S.

Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, Maryland, to replace the despeciated horse serum. The

cocktail approach will enhance the safety of the

immunotherapy, and recombinant techniques will

probably also reduce the cost of therapeutic antibody.

Although some investigators34 have reported limited success in treating human serotype A poisoning with aminopyridines, controlled animal experiments35 performed at USAMRIID showed no effect

on non–type A poisoning and only delays in time

to death with type A. Obviously, no controlled human trials can be done, so whether the drugs helped
Medical Aspects of Chemical and Biological Warfare

652

at all remains unclear. Since the drugs have significant toxicity themselves, they have largely been

abandoned as a treatment for botulism.

Research is also ongoing (by J.L.M.) to target

therapy directly to intoxicated nerves by making a

chimer of the receptor binding portion of the botulinum molecule and either monoclonal antibodies

or drugs that neutralize intracellularly. Just as the

available toxoid and prototype second-generation

vaccines provide solid protection against this most

toxic of agents, we hope that second-generation

therapeutics will allow us to reverse the lethal effects of this toxin after it has been internalized in

the cell.

SUMMARY

The seven serotypes of botulinum toxin produced

by Clostridium botulinum are the most toxic

substances known. They are associated with lethal

food poisoning after the consumption of canned

foods. This family of toxins was evaluated by the

United States as a potential biological weapon in

the 1960s and is believed to be an agent that could

be used against our troops. Unlike other threat

toxins, botulinum neurotoxin appears to cause

the same disease after inhalation, oral ingestion,

or injection. Death results from skeletal muscle paralysis and resultant ventilatory failure. Because

of its extreme toxicity, the toxin typically cannot

be identified in body fluids, other than nasal

secretions, after inhalation of a lethal dose. The

best diagnostic sample for immunologic identification of the toxin is from swabs taken from the nasal

mucosa within 24 hours after inhalational exposure.

Because of the small quantity of toxin protein

needed to kill, botulinum toxin exposure does

not typically induce an antibody response after

exposure.

Prophylactic administration of a licensed pentavalent vaccine fully protects laboratory animals

from all routes of challenge. Passive immunotherapy with investigational hyperimmune plasma

also prevents illness if it is administered before the

onset of clinical intoxication.

REFERENCES

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NY: Academic Press; 1989: 351–378.

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World War II. Historical Section, Plans, Training and Intelligence Division, Office of Chief, Chemical Corps, US

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3. Middlebrook JL. Contributions of the U.S. Army to botulinum toxin research. In: Das Gupta B, ed. Botulinum

and Tetanus Neurotoxins and Biomedical Aspects. New York, NY: Plenum Press; 1993: 515–519.

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botulism. J Clin Microbiol. 1986;23:201–202.

5. Eisel U, Jarausch W, Goretzki K, et al. Tetanus toxin: Primary structure, expression in E coli, and homology

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7812.

7. Binz T, Kurazono H, Wille M, Frevert J, Wernars K, Nieman H. The complete sequence of botulinum neurotoxin type A and comparison with other clostridial neurotoxins. J Biol Chem. 1990;265:9153–9158.

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type A neurotoxin, deduced by nucleotide sequence analysis of the encoding gene. Eur J Biochem. 1990;189:73–81.

9. Whelan SM, Elmore MJ, Bodsworth NJ, Brehm JK, Atkinson T, Minton NP. Molecular cloning of the Clostridium

botulinum structural gene encoding the type B neurotoxin and determination of its entire nucleotide sequence.

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11. Binz T, Kurazono H, Popoff MR, et al. Nucleotide sequence of the gene encoding Clostridium botulinum neurotoxin type D. Nucleic Acids Res. 1990;18:5556–5557.

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Biochem. 1992;204:657–667.

13. Alison K, Richardson PT, Allaway D, Collins MD, Roberts TA, Thompson DE. Sequence of the gene encoding

type F neurotoxin of Clostridium botulinum. FEMS Microbiol Lett. 1992;96:225–230.

14. Campbell KD, Collins MD, East AK. Nucleotide sequence of the gene coding for Clostridium botulinum

(Clostridium argentinese) type G neurotoxin: Genealogical comparison with other clostridial neurotoxins. Biochim

Biophys Acta. 1993;1216:487–491.

15. Eklund MW, Poysky FT, Mseitif LM, Strom MS. Evidence for plasmid-mediated toxin and bacteriocin production in Clostridium botulinum type G. Appl Environ Microbiol. 1988;54:1405–1408.

16. Eklund MW, Poysky FT, Reed SM, Smith CA. Bacteriophages and toxigenicity of Clostridium botulinum C. Science. 1971;172:480–482.

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botulism in Italy caused by neurotoxigenic Clostridium butyricum. J Infect Dis. 1986;154:201–211.

19. Hall JD, McCroskey LM, Pincomb BJ, Hathaway CL. Isolation of an organism which produces type E botulinal

toxin from an infant with botulism. J Clin Microbiol. 1985;21:654–655.

20. Gill DM. Bacterial toxins: A table of lethal amounts. Microbiol Rev. 1982;46(1):86–94.

21. McNally RE, Morrison MB, Berndt JE, et al. Effectiveness of Medical Defense Interventions Against Predicted Battlefield Levels of Botulinum Toxin A. Vol 1. Joppa, Md: Science Applications International Corporation; 1994: 3.

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23. Simpson LL. Peripheral actions of the botulinum toxins. In: Simpson LL, ed. Botulinum Neurotoxin and Tetanus

Toxin. New York, NY: Academic Press, Inc; 1989: 153–178.

24. Middlebrook JL. Cell surface receptors for protein toxins. In: Simpson LL, ed. Botulinum Neurotoxin and Tetanus

Toxin. New York, NY: Academic Press, Inc; 1989: 95–119.

25. Black JD, Dolly O. Interaction of 125I-botulinum neurotoxins with nerve terminals: Ultrastructural autoradiographic localization and quantitation of distinct membrane acceptors for types A and B on motor nerves. J Cell

Biol. 1986;103:521–534.

26. Nishiki T-I, Kamata Y, Nemoto Y, et al. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes. J Biol Chem. 1994;269(14):10498–10503.

27. Goldstein JL, Anderson RGW, Brown MS. Coated pits, coated vesicles and receptor-mediated endocytosis.

Nature. 1979;279:679–689.

28. Jongeneel CV, Bouvier J, Bairoch A. A unique signature identifies a family of zinc-dependent metallopeptidases.

FEBS Lett. 1989;242:211–214.
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29. Schiavo G, Benfenati F, Poulain B, et al. Tetanus and botulinum-B neurotoxins block neurotransmitter release

by proteolytic cleavage of synaptobrevin. Nature. 1992;359:832–835.

30. Nieman H, Blasi J, Jahn R. Clostridial neurotoxins: New tools for dissecting exocytosis. Trends in Cell Biology.

1994;4:179–185.

31. Holzer E. Botulism caused by inhalation. Med Klin. 1962;41:1735–1740.

32. Franz DR, Pitt LM, Clayton MA, Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration

of antitoxin for inhalation botulism. In: Das Gupta B, ed. Botulinum and Tetanus Neurotoxins and Biomedical

Aspects. New York, NY: Plenum Press; 1993: 473–476.

33. Hunt R. Lieutenant Colonel, Veterinary Corps, US Army. Principal Investigator, Toxinology Division, Department of Aerobiology and Product Development, US Army Medical Research Institute of Infectious Diseases,

Fort Detrick, Frederick, Md. Personal communication, February 1996.

34. Ball AP, Hopkinson RB, Farrell ID, et al. Human botulism caused by Clostridium botulinum type E: the Birmingham outbreak. Q J Med. 1979;48(191):473–491.

35. Siegel LS, Johnson-Winegar AD, Sellin LC. Effect of 3,4-diaminopyridine on the survival of mice injected with

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Trichothecene Mycotoxins

655

Chapter 34

TRICHOTHECENE MYCOTOXINS

ROBERT W. WANNEMACHER, JR., PH.D.*; AND STANLEY L. WIENER, M.D.†

INTRODUCTION

HISTORY AND MILITARY SIGNIFICANCE

Use in Biological Warfare

The Yellow Rain Controversy

Weaponization

DESCRIPTION OF THE AGENT

Occurrence in Nature

Chemical and Physical Properties

TOXICOLOGY AND TOXICOKINETICS

Mechanism of Action

Metabolism

CLINICAL DISEASE

Acute Effects

Chronic Toxicity

DIAGNOSIS

Battlefield Diagnosis

Confirmatory Procedures

MEDICAL MANAGEMENT

Individual and Unit

Specific or Supportive Therapy

Prophylaxis

SUMMARY

*Assistant Chief, Toxinology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011 †Colonel, Medical Corps, U.S. Army Reserve; Professor of Medicine and Chief, Section of General Internal Medicine, Department of Medicine,

University of Illinois College of Medicine, 840 Wood Street, Chicago, Illinois 60612
Medical Aspects of Chemical and Biological Warfare

656

INTRODUCTION

mental conditions. The distinguishing chemical

feature of trichothecenes is the presence of a

trichothecene ring, which contains an olefinic bond

at C-9, 10; and an epoxide group at C-12, 12.5 All

trichothecenes are mycotoxins, but not all mycotoxins are trichothecenes. This family of mycotoxins

causes multiorgan effects including emesis and diarrhea, weight loss, nervous disorders, cardiovascular alterations, immunodepression, hemostatic

derangements, skin toxicity, decreased reproductive

capacity, and bone marrow damage.4,6

In this chapter, we will concentrate on T-2 mycotoxin, a highly toxic trichothecene that, together

with some closely related compounds, has been the

causative agent of a number of illnesses in humans

and domestic animals.1,2,4 During the 1970s and

1980s, the trichothecene mycotoxins gained some

notoriety as putative biological warfare agents

when they were implicated in “yellow rain” attacks

in Southeast Asia.7–11

Mycotoxins, by-products of fungal metabolism,

have been implicated as causative agents of adverse health effects in humans and animals that

have consumed fungus-infected agricultural products.1,2 Consequently, fungi that produce mycotoxins, as well as the mycotoxins themselves, are potential problems from both public health and

economic perspectives. The fungi are a vast assemblage of living organisms, but mycotoxin production is most commonly associated with the

terrestrial filamentous fungi called the molds.3

Various genera of toxigenic fungi are capable

of producing such diverse mycotoxins as the aflatoxins, rubratoxins, ochratoxins, fumonisins, and

trichothecenes.1,2

The trichothecenes are a very large family of

chemically related toxins produced by various species of Fusarium, Myrotecium, Trichoderma, Cephalosporium, Verticimonosporium, and Stachybotrys.

4

They are markedly stable under different environHISTORY AND MILITARY SIGNIFICANCE

Fungi that produce trichothecenes are plant

pathogens and invade various agricultural products

and plants. Since Fusarium and other related fungi

infect important foodstuff, they have been associated worldwide with intoxication of humans and

animals. Thus, these fungi have potential as biological weapons.

Use in Biological Warfare

From 1974 to 1981, toxic agents were used by the

Soviet Union and its client states in such Cold War

sites as Afghanistan, Laos, and Kampuchea (Cambodia). Aerosol-and-droplet clouds were produced

by delivery systems in the Soviet arsenal such as

aircraft spray tanks, aircraft-launched rockets,

bombs (exploding cylinders), canisters, a Soviet

hand-held weapon (DH-10), and booby traps. Aircraft used for delivery included L-19s, AN-2s, T-28s,

T-41s, MiG-21s (in Laos) and Soviet MI-24 helicopters (in Afghanistan and Laos).

Attacks in Laos (1975–1981) were directed against

Hmong villagers and resistance forces who opposed

the Lao People’s Liberation Army and the North

Vietnamese. In Kampuchea, North Vietnamese

troops used 60-mm mortar shells; 120-mm shells;

107-mm rockets; M-79 grenade launchers containing chemicals; and chemical rockets, bombs, and

sprays delivered by T-28 aircraft (1979–1981) against

Khmer Rouge troops. The chemical munitions were

supplied by the Soviets and delivered by North

Vietnamese or Laotian pilots. In Afghanistan, the

chemical weapons were delivered by Soviet or Afghan pilots against Mujahidin guerrillas (1979–

1981). Lethality of the attacks is documented by a

minimum of 6,310 deaths in Laos (from 226 attacks);

981 deaths in Kampuchea (from 124 attacks); and

3,042 deaths in Afghanistan (from 47 attacks).7

Trichothecenes appear to have been used in some

of these attacks.

The air attacks in Laos have been described as

“yellow rain” and consisted of a shower of sticky,

yellow liquid that sounded like rain as it fell from

the sky. Other accounts described a yellow cloud

of dust or powder, a mist, smoke, or insect spray–

like material. Liquid agent rapidly dried to a

powder. In Laos, 50% to 81%7

 of attacks involved

material associated with a yellow pigment. Other

attacks were associated with red, green, white, or

brown smoke or vapor. More than 80%7 of attacks

were delivered by air-to-surface rockets; the remainder, from aircraft spray tanks or bombs. Intelligence

information and some of the victims’ descriptions

of symptoms raised the possibility that chemical

warfare agents such as phosgene, sarin, soman,

mustards, CS, phosgene oxime, or BZ may also
Trichothecene Mycotoxins

657

have been used. These agents may have been used

in mixtures or alone, and with or without the

trichothecenes.

Unconfirmed reports have implicated the use

of trichothecenes in the 1964 Egyptian (or Russian) attacks on Yemeni Royalists in Yemen12 and in

combination with mustards during chemical warfare attacks in the Iran–Iraq War (1983–1984).13 According to European sources, Soviet–Cuban forces

in Cuba are said to have been equipped with mycotoxins, and a Cuban agent is said to have died of a

hemorrhagic syndrome induced by a mycotoxin

agent.14

The Yellow Rain Controversy

Actual biological warfare use of trichothecenes

in Southeast Asia and Afghanistan is strongly supported by the epidemiological and intelligence assessments and trichothecene assays, although reports in the open literature have discounted this

contention. An article written by L. R. Ember,15

published in 1984 in Chemical Engineering News, is

the most exhaustive and authoritative account of

the controversy surrounding the use of trichothecene mycotoxins in Southeast Asia during the

1970s.

The United States government, its allies, and

journalists exhaustively studied the possibility that

yellow rain attacks had occurred, based on evidence7,14,15 such as the following:

• interviews of Hmong survivors of and eyewitnesses to lethal yellow rain attacks in

Laos, who provided consistent descriptions

of the episodes;

• interrogations of a defecting Laotian Air

Force officer and North Vietnamese ground

troops, who corroborated the descriptions

of attacks and admitted using the chemicals;

• interrogations of prisoners of war, who admitted being involved in attacks where unconventional weapons were used (ie, in

Afghanistan);

• laboratory confirmations of Soviet use of

chemical agents, and

• the presence of Soviet-manufactured chemical agents and Soviet technicians in Laos.

The evidence supports the contention that trichothecene mycotoxins were used as biological warfare agents in Southeast Asia and Afghanistan by

the former Soviet Union and its surrogates. The

Russians have not recently denied such use but have

declined to discuss the subject.

In addition to the evidence stated above, elevated

levels and naturally rare mixtures of trichothecene toxins were recovered from the surfaces of

plants, fragments of plastic, and rocks in areas attacked9,11,15,16; and were detected in the blood of

attack survivors and the tissues of a dead casualty.10,15 Control samples that were taken (a) from

an environment that had not been attacked, and

during another season of the year,15 and (b) from

Hmong who had never been exposed to an attack

were consistently negative.

The evidence that trichothecenes were used in

Southeast Asia has been challenged: questions have

been raised about the interview methodology used

by U.S. Army physicians and U.S. State Department

personnel in Hmong refugee camps in Thailand to

obtain descriptions of the attacks. Some inconsistencies of specific individuals’ stories were demonstrated, but the frequency of unreliable information

has not been reported and is unlikely to be large

enough to discredit all witnesses.15 Symptom descriptions are generally consistent with known

trichothecene effects.

The paucity of positive evidence of the presence

of trichothecenes (5 positive environmental and 20

positive biomedical samples) has been used to challenge the belief that biological warfare attacks occurred, since only 10% of samples were positive.

However, 32% of samples from victims were positive, a value too high for natural causes (eg, food

contamination) to be used as an explanation, since

98% of controls in nonattack areas of Thailand were

negative.17 The 2% of samples that were positive

could represent either a nonspecific result or lowprevalence food contamination. The paucity and

type of control samples have also been questioned.

Some experts18–21 have claimed that yellow rain

was not a biological warfare attack at all, but that

the yellow residue was caused by showers and deposits of bee feces—the result of massive bee

swarming and cleansing–defecation flights over

some areas of Southeast Asia. The presence of pollen in bee feces and some samples has not only

added confusion18 but is also the supporting evidence used by the skeptics. It is important to remember that persons caught in a shower of bee feces do not get sick and die. Although bee flights

have occurred before and since 1982, reports of attacks of yellow rain and death in Asia have not.

Then what explains the symptoms consistent

with trichothecene effects in the casualties, and the

pollen and bee feces in some of the yellow spots on
Medical Aspects of Chemical and Biological Warfare

658

vegetation in the area? Bee feces do not contain

trichothecenes, yet pollen and trichothecenes without mold are found together in some samples from

attack areas. The most likely explanation is that

during biological warfare attacks, dispersed

trichothecenes landed in pollen-containing areas.

French scientists have reported the simultaneous

synthesis of three trichothecene toxins by Fusarium

growing on corn, but actual production of these

toxins by Fusarium species in Southeast Asia has not

been demonstrated, presumably because of high

environmental temperature (ie, toxin production

usually increases at low temperatures). Whether

or not Fusarium toxin is produced in the high-mountain temperate regions of Laos inhabited by the

Hmong remains unanswered. The presence of toxin

on leaves without accompanying mold also is unexplained by critics of the trichothecene weapon

hypothesis. In vivo studies have demonstrated that

F semitectum var semitectum will grow on leaves in

Southeast Asia, but have not shown that it will produce toxin in vivo.15

In support of the weapon hypothesis are the positive trichothecene analyses performed by two leading researchers9,10 in the detection of trichothecenes;

the Defense Research Establishment, Ottawa,

Canada11,22; and the U.S. Army Chemical Research

and Development Center, Edgewood, Maryland.23

Negative results of analyses of biomedical and environmental samples from Southeast Asia have

come from Porton Down Laboratory in England,17,24

but according to the British, such results do not exclude sampling problems, including delay in

sample collection after an attack, as a cause of the

negative results.15

Proponents have been accused of analyzing

samples that were purposely contaminated with

toxin, either after collection or during the analysis.

Other methodological criticisms include poor recovery (< 10% of one sample spiked with T-2 toxin);

low precision of quantitative data when analyzing

two portions of the same leaf; and lack of well-documented, confirming, replicate analyses in Mirocha’s

or a similarly equipped second laboratory.15 The

presence of polyethylene glycol in the sample analyzed by Rosen9

 also indicates that the trichothecene

mixture detected was manufactured, not natural.

Many experts in the intelligence community,16

academia,8,9 the U.S. Department of State,7 and

the authors of this chapter believe that trichothecenes were used as biological weapons in Southeast Asia and Afghanistan. However, a weapon

containing trichothecenes was not found in Southeast Asia, and the Soviets have not declared any

stockpiles of trichothecenes among their chemical

or biological weapons. Thus, it has not been possible for the United States to prove unequivocally

that trichothecene mycotoxins were used as biological weapons.

Weaponization

Trichothecene mycotoxins can be delivered as

dusts, droplets, aerosols, or smoke from aircraft,

rockets, missiles, artillery, mines, or portable sprayers. Because of their antipersonnel properties, ease

of large-scale production, and apparent proven delivery by various aerial dispersal systems, the

trichothecene mycotoxins (especially T-2 toxin)

have an excellent potential for weaponization.

When delivered at low doses, trichothecene mycotoxins cause skin, eye, and gastrointestinal problems. In nanogram amounts,4,25 they (T-2 toxin, in

particular) cause severe skin irritation (erythema,

edema, and necrosis).4,6 Skin vesication has been

observed in a number of humans exposed to yellow rain attacks.4,14,15 T-2 toxin is about 400-fold

more potent (50 ng vs 20 μg) than mustard in producing skin injury.26 Lower-microgram quantities

of trichothecene mycotoxins cause severe eye irritation, corneal damage, and impaired vision.4,16,26,27

Emesis and diarrhea have been observed at amounts

that are one fifth to one tenth the lethal doses of

trichothecene mycotoxins.26

Depending on the species of experimental animal tested and the exposure procedure,28,29 the lethality of T-2 toxin by aerosol exposure can be 10-

to 50-fold greater than when injected parenterally.30

With larger doses in humans, aerosolized trichothecenes may produce death within minutes to

hours.7,14,15 The term LCt50 (the concentration • time

that is lethal to 50% of the exposed population) is

used to describe exposure to vapors and aerosols;

milligrams • minutes per cubic meter is the conventional unit of measurement. LCt50 and its relation to LD50 (the dose that is lethal to 50% of the

exposed population) are discussed in detail in

Chapter 5, Nerve Agents, and will not be further

explicated here.

The toxicity of T-2 toxin by the inhalational route

of exposure (LCt50 range: 200–5,800 mg•min/m3)

28–30

is similar to that observed for mustards or Lewisite

(LCt50 range: 1,500–1,800 mg•min/m3).31 However, the lethality of T-2 toxin by the dermal route

(LD50 range: 2–12 mg/kg6) is higher than that for

liquid Lewisite (LD50: approximately 30 mg/
Trichothecene Mycotoxins

659

kg31(p39)) or liquid mustards (LD50: approximately

100 mg/kg31(p32)). Therefore, the trichothecene

mycotoxins are considered to be primarily blister

agents that, at lower exposure concentrations, can

cause severe skin and eye irritation, and at larger

doses can produce considerable incapacitation and

death within minutes to hours.

By solid substrate fermentation, T-2 toxin can be

produced at approximately 9 g/kg of substrate,

with a yield of 2 to 3 g of crystalline product.32 Several of the trichothecene mycotoxins have been produced in liquid culture at medium yields and large

volumes of culture for extraction.33 Thus, using

existing state-of-the-art fermentation processes that

were developed for brewing and antibiotics, it

would be fairly simple to produce ton quantities of

a number of the trichothecene mycotoxins.

In Southeast Asia, most of the yellow rain attacks

were delivered by aircraft or helicopter spray,

bombs, and air-to-surface rockets. The attacks were

described as a shower of sticky liquid, a yellow

cloud of dust or powder, or a mist (like an insect

spray).7,15 The delivery of the trichothecene mycotoxins was similar in many aspects to the spraying of

pesticides on agricultural crops. This would result

in a very low-efficiency respiratory aerosol (1–5 μm

particles)34 but a highly effective droplet aerosol that

could cause severe skin and eye irritation.

DESCRIPTION OF THE AGENT

Occurrence in Nature

Potentially hazardous concentrations of the

trichothecene mycotoxins can occur naturally in

moldy grains, cereals, and agricultural products.4,35

Toxigenic species of Fusarium occur worldwide in

habitats as diverse as deserts, tidal salt flats, and

alpine mountain regions.35 For example, a foodrelated disease has been recorded in Russia from

time to time, probably since the 19th century.36 Over

the period 1942 through 1947, more than 10% of the

population in Orenburg, near Siberia, were fatally

affected by overwintered millet, wheat, and barley.4,36 The syndrome was officially named alimentary toxic aleukia (ATA). Extensive investigations

in Russia indicated that a toxin from Fusarium species of fungi was the causative agent of ATA.36,37

Subsequently, it was demonstrated that T-2 toxin, a

potent trichothecene mycotoxin, was the likely

agent.37

Stachybotryotoxicosis has been reported among

farm workers in Russia, Yugoslavia, and Hungary.38,39 This disease is caused by the presence of

a mold, Stachybotrys atra (S alternans), on the hay

fed to domestic animals. A macrocyclic trichothecene (satratoxin) produced by the Stachybotrys

species of the mold may be in part responsible for

this toxicosis.40 The only literature citation on

apparent human cases of stachybotryotoxicosis in

the United States occurred in people living in a

water-damaged house with a heavy infestation of

S atra.

41

Russian scientists have reported a case of “cotton lung disease,” which was brought about by the

inhalation of cotton dust that was contaminated

with Dendrochium toxicum. This fungus is considered to be synonymous with Myrothecium verrucaria

(a natural producer of the verrucarin class of

trichothecenes).42

The “red mold disease” of wheat and barley

in Japan is prevalent in the region that faces the

Pacific Ocean.4 Toxic trichothecenes, including nivalenol, deoxynivalenol, and monoacetylnivalenol (fusarenon-X) from Fusarium nivale,

can be isolated from moldy grains. In the suburbs of Tokyo, an illness similar to “red mold

disease” was described in an outbreak of a foodborne disease, as a result of the consumption

of Fusarium-infected rice.35 Ingestion of moldy

grains that are contaminated with trichothecenes

has been associated with mycotoxicosis in domestic farm animals.4

Fig. 34-1. The general structure, numbering system, and

variable side groups of the tetracyclic trichothecene

nucleus.

O

O

H

R2

R1

H

16 1

4

3

12

2

5

R3

13

14

6

R4

15

7

8

9

10

H

11

R5
Medical Aspects of Chemical and Biological Warfare

660

Chemical and Physical Properties

The trichothecenes make up a family of closely

related chemical compounds called sesquiterpenoids

(Figure 34-1). The structures of close to 150 derivatives of the trichothecenes are described in the scientific literature.35,43 The specific side structures of

the most abundant of the naturally occurring

trichothecenes are shown in Table 34-1. Because of

its availability and relatively high toxicity, T-2 toxin

has been the most extensively studied trichothecene

mycotoxin.

The trichothecene mycotoxins are nonvolatile,

low-molecular-weight (MW 250–550) compounds.43

This group of mycotoxins is relatively insoluble in

water but highly soluble in acetone, ethyl acetate,

chloroform, dimethyl sulfoxide (DMSO), ethanol,

methanol, and propylene glycol.43 Purified trichothecenes generally have a low vapor pressure, but

TABLE 34-1

SPECIFIC SIDE GROUPS OF THE MOST ABUNDANT TRICHOTHECENE MYCOTOXINS

Trichothecene R1 R2 R3 R4 R5

T-2 Toxin –OH –OCOCH3 –OCOCH3 –H –OCOCH2CH(CH3)2

HT-2 Toxin –OH –OH –OCOCH3 –H –OCOCH2CH(CH3)2

4,15-Diacetoxyscripenol–OH –OCOCH3 –OCOCH3 –H –H

(DAS, also called anguidine)

Nivalenol –OH –OH –OH –OH =O

Deoxynivalenol (DON) –OH –H –OH –OH =O

Macrocyclics –H –O–R’–O– –H –H

R’: Macrocyclic ester or ester–ether bridge between carbons 4 and 15. The most abundant macrocyclic trichothecenes are verrucarins,

roridins, and satratoxin H. Source for this statement: Jarvis BB. Macrocyclic trichothecenes. In: Sharma RP, Salunkhe DK, eds.

Mycotoxins and Phytoalexins. Boca Raton, Fla: CRC Press; 1991: 361–421.

they do vaporize when heated in organic solvents.

Extraction of trichothecene mycotoxins from fungal cultures with organic solvents yields a yellowbrown liquid, which, if allowed to evaporate, forms

a greasy, yellow crystalline product. Some experts10,16 believe this extract to be the yellow contaminate of yellow rain. In contrast, highly purified toxins form white, crystalline products that

have characteristic melting points.35

When maintained as either crystalline powders

or liquid solutions, trichothecene mycotoxin compounds are stable when exposed to air, light, or

both.35,44 Moreover, these mycotoxins are not inactivated by autoclaving but require heating at 900°F

for 10 minutes or 500°F for 30 minutes for complete

inactivation. A 3% to 5% solution of sodium hypochlorite is an effective inactivation agent for

them.44 The efficacy of this solution can be increased

by the addition of small amounts of alkali.

TOXICOLOGY AND TOXICOKINETICS

The trichothecene mycotoxins are toxic to humans, other mammals, birds, fish, a variety of

invertebrates, plants, and eukaryotic cells in general. The acute toxicity of the trichothecene

mycotoxins varies somewhat with the particular

toxin and animal species studied (Table 34-2). Differences are noted among the various species in

their susceptibility to trichothecene mycotoxins, but

they are small compared with the divergence obtained by diverse routes of administration of the

toxins (Table 34-3). Once the trichothecene mycotoxins enter the systemic circulation, regardless

of the route of exposure, they affect rapidly proliferating tissues.1,2,4,6,35,42,45

Mechanism of Action

The trichothecene mycotoxins are cytotoxic to

most eukaryotic cells.46 A number of cytotoxicity

assays have been developed and include survival

and cloning assays, measuring protein and deoxyribonucleic acid (DNA) synthesis by radiolabeling

procedures, and a neutral red cell–viability assay.

A minimum of 24 to 48 hours is required to measure the effects of the trichothecene mycotoxins on

cell viability.

These mycotoxins inhibit protein synthesis in a

variety of eukaryotic cells.46–48 Similar sensitivity

to T-2 toxin was observed in established cell lines
Trichothecene Mycotoxins

661

TABLE 34-3

COMPARATIVE TOXICITY OF T-2 TOXIN BY VARIOUS ROUTES OF ADMINISTRATION

Mammals Tested

Mouse Rat Guinea Pig Rabbit Cat Pig Monkey

Route of Administration T-2 Toxin LD50 (mg/kg)

Intravenous 4.2–7.3 0.7–1.2 1.0–2.0 — — 1.2 —

Intraperitoneal5.2–9.1 1.3–2.6 — — — — —

Subcutaneous 2.1–3.3 0.6–2.0 1.0–2.0 — < 0.5 — —

Intramuscular — 0.5–0.9 1.0 1.1 — — 0.8

Intragastric 9.6–10.5 2.3–5.2 3.1–5.3 — — — —

Intranasal— 0.6 — — — — —

Intratracheal0.16 0.1 — — — — —

Inhalational 0.24 0.05 0.6–2.0 — — — —

Intracerebral— 0.01 — — — — —

Dermal in DMSO 6.6 4.3 2.2 10 — — > 8.0

Dermal in Methanol — > 380 > 80 — — — —

DMSO: dimethyl sulfoxide

—: Not determined

Data sources: (1) Ueno Y. Trichothecene mycotoxins: Mycology, chemistry, and toxicology. Adv Nut Res. 1989;3:301–353. (2)

Wannemacher RW Jr, Bunner DL, Neufeld HA. Toxicity of trichothecenes and other related mycotoxins in laboratory animals. In:

Smith JE, Henderson RS, eds. Mycotoxins and Animal Foods. Boca Raton, Fla: CRC Press; 1991: 499–552. (3) Sharma RP, Kim Y-W.

Trichothecenes. In: Sharma RP, Salunkhe DK, eds. Mycotoxins and Phytoalexins. Boca Raton, Fla: CRC Press; 1991: 339–359.

TABLE 34-2

RELATIVE ACUTE PARENTERAL TOXICITY OF THE MOST ABUNDANT TRICHOTHECENE

MYCOTOXINS

Mammals Tested

Mouse Rat Guinea Pig Rabbit Cat Dog Pig Monkey

Trichothecenes Tested LD50 (mg/kg)

T-2 Toxin 5.2 (IV) 0.9 (IV) 1.0 (IV) 1.0 (IM) < 0.5 (SC) — 1.2 (IV) 0.8 (IM)

HT-2 Toxin 9.0 (IP) — — — — — — —

4,15-Diacetoxyscripenol (DAS) 12.0 (IV) 1.3 (IV) — 1.0 (IV) — 1.1 (IV) 0.38 (IV) —

Nivalenol 6.3 (IV) — — — — — — —

Deoxynivalenol (DON) 43 (SC) — — — — — — —

Verrucarin A 1.5 (IV) 0.8 (IV) — 0.54 (IV) — — — —

Roridin A 1.0 (IV) — — — — — — —

Satratoxin H 1.0 (IP) — — — — — — —

Routes of administration of the mycotoxin: IV: intravenous; IM: intramuscular; SC: subcutaneous; IP: intraperitoneal

—: Not determined

Data sources: (1) Ueno Y. Trichothecene mycotoxins: Mycology, chemistry, and toxicology. Adv Nut Res. 1989;3:301–353. (2)

Wannemacher RW Jr, Bunner DL, Neufeld HA. Toxicity of trichothecenes and other related mycotoxins in laboratory animals. In:

Smith JE, Henderson RS, eds. Mycotoxins and Animal Foods. Boca Raton, Fla: CRC Press; 1991: 499–552. (3) Sharma RP, Kim Y-W.

Trichothecenes. In: Sharma RP, Salunkhe DK, eds. Mycotoxins and Phytoalexins. Boca Raton, Fla: CRC Press; 1991: 339–359. (4) Jarvis

BB. Macrocyclic trichothecenes. In: Sharma RP, Salunkhe DK, eds. Mycotoxins and Phytoalexins. Boca Raton, Fla: CRC Press; 1991:

361–421.
Medical Aspects of Chemical and Biological Warfare

662

and primary cell cultures.46,48 Inhibition of protein

synthesis is observed 5 minutes after exposure of

Vero cells to T-2 toxin, with a maximal response

noted by 60 minutes after the exposure.46 Researchers47 have concluded that the trichothecene mycotoxins act by inhibiting either the initiation or the

elongation process of translation, by interfering

with peptidyl transferase activity.

Substantial inhibition of ribonucleic acid (RNA)

synthesis (86% inhibition) by trichothecene mycotoxin was observed in human (HeLa) cells,47 but

T-2 toxin had minor effects (15% inhibition) on RNA

synthesis in Vero cells.46 The trichothecene mycotoxin–related inhibition of RNA synthesis is probably a secondary effect of the inhibition of protein

synthesis. Scheduled DNA synthesis is strongly

inhibited in various types of cells that are exposed

to trichothecene mycotoxins. In mice or rats treated

with trichothecene mycotoxins, DNA synthesis in

all tissues studied was suppressed, although to a

lesser degree than protein synthesis.49 The pattern

by which DNA synthesis is inhibited by the

trichothecene mycotoxins is consistent with the primary effect of these toxins on protein synthesis. In

appropriate cell models, for the most part, trichothecene mycotoxins demonstrate neither mutagenic

activity nor the capacity to damage DNA.50

Studies with radiolabeled trichothecene mycotoxins suggest that the toxin interaction with cells

is best viewed as (1) a free, bidirectional movement

of these low-molecular-weight chemicals across the

plasma membrane; and (2) specific, high-affinity

binding to ribosomes.51 Thus, further evidence indicates that the primary toxic effects of the

trichothecene mycotoxins is caused by their properties as potent inhibitors of protein synthesis.

Since the trichothecene mycotoxins are amphophilic molecules, an investigation52 that focused on

various kinds of interaction with cellular membranes concluded that T-2 exerts multiple effects on

the cell membrane. Lipid peroxidation is increased

in liver, spleen, kidney, and thymus; and bone marrow when rats are treated with a single, oral dose

of T-2 toxin.53 These observations led to the suggestion that the trichothecene mycotoxins might

induce some alterations in membrane structure,

which consequently stimulates lipid peroxidation.

Once trichothecene mycotoxins cross the plasma

membrane barrier, they enter the cell, where they

can interact with a number of targets, including ribosomes47 and mitochondria.54

These toxins inhibit electron transport activity,

as the inhibition of succinic dehydrogenase activity and mitochondrial protein synthesis implies.

Toxin-stimulated alteration in mitochondrial membranes contributes to the effects on cellular energetics and cellular cytotoxicity. Although initial

investigations on the mechanism of action of the

trichothecene mycotoxins suggested that the inhibition of protein synthesis as the principal mechanism of action, the above observations indicate that

the effects of these toxins are much more diverse.

Metabolism

Compared with some of the other mycotoxins

such as aflatoxin, the trichothecenes do not appear

to require metabolic activation to exert their biological activity.50 After direct dermal application or

oral ingestion, the trichothecene mycotoxins can

cause rapid irritation to the skin or intestinal mucosa. In cell-free systems or single cells in culture,

these mycotoxins cause a rapid inhibition of protein synthesis and polyribosomal disaggregation.35,47,50 Thus, we can postulate that the trichothecene mycotoxins have molecular capability of

direct reaction with cellular components. Despite

this direct effect, it is possible to measure the

toxicokinetics and the metabolism of the trichothecene mycotoxins.

The lipophilic nature of these toxins suggests that

they are easily absorbed through skin, gut, and

pulmonary mucosa. Absorption of a single, oral

dose of T-2 toxin is rapid, with concentration of labeled toxin peaking in the blood within 1 hour.55

This indicates that the trichothecene mycotoxins

rapidly pass through the intestinal mucosa. The

inhaled median lethal dose of T-2 toxin is equal to29

or less than28,30 the systemic dose. Mice, rats, and

guinea pigs die rapidly (within 1–12 h) after exposure to high concentrations of aerosolized mycotoxin, with no apparent lung lesions or pulmonary

edema.28–30 This finding is in contrast to the effect

of an oral dose of T-2 toxin, which causes direct

damage to the intestinal mucosa.55

From these data, we can conclude that the

trichothecene mycotoxins very rapidly cross the

pulmonary and intestinal mucosa and enter the systemic circulation to induce the toxin-related toxicoses. In contrast, trichothecene mycotoxins are

only slowly absorbed through skin, especially when

applied as a dust or powder.56 Systemic toxicity and

lethality can be produced by dermal exposure to

higher concentrations of T-2 toxin, however, especially if the mycotoxin is dissolved in a penetrant

such as DMSO.6

Various cell culture lines and ruminal bacteria

metabolize T-2 toxin by deacylation of specific
Trichothecene Mycotoxins

663

Fig. 34-2. Metabolic pathway of T-2 toxin both in vitro and in vivo.

Glucuronide conjugate

Glucuronide conjugate

O

OAc

OH

O

O

O

OAc

T-2 Toxin

O

OAc

OH

O

O

O

OH

OAc

3'-Hydroxy T-2

O

OAc

OH

HO

O

OAc

Neosolaniol

O

OH

OH

O

O

O

OAc

HT-2 Toxin

O

OAc

OH

HO

O

OH

15-Deacetylneosolaniol

O

OH

OH

HO

O

OAc

4-Deacetylneosolanide

O

OH

OH

O

O

O

OH

T-2 Triol

O

OH

OH

O

O

O

OH

OAc

3'-Hydroxy HT -2

O

OH

OH

HO

O

OH

T-2 Tetraol

O

OH

OH

O

O

O

OH

OH

3'-Hydroxy T-2 triol
Medical Aspects of Chemical and Biological Warfare

664

deepoxidylation (ie, removal of the oxygen from the

epoxide ring at the C-12, 13 position to yield a carbon–carbon double bond) and oxidization of the C3' and C-4' positions on the isovaleryl side chains

of T-2 toxin and HT-2 toxin, a metabolite (Figure

34-2).57–59 A number of different cell types contain

the metabolic processes necessary to metabolize

trichothecene mycotoxins.

Pharmacokinetic studies60,61 have demonstrated

T-2 toxin in the plasma of animals that were administered this mycotoxin both intravascularly and by

aerosol. As plasma concentrations of the parent

trichothecene mycotoxin decrease, the deacylated

and hydroxylated metabolites and their glucuronide conjugates rapidly appear and disappear

from circulation. From these various observations,

we can conclude that the pharmacokinetics of the

trichothecene mycotoxins are functions of the rate

of absorption into the general circulation, metabolism, tissue distribution, and excretion.

Tissue-distribution studies55 suggest that the liver

is the major organ for metabolism of the trichothecene mycotoxins. The bile and the gastrointestinal tract contained large amounts of radioactivity

after intravascular, intramuscular, oral, or dermal

administration of radiolabeled T-2 toxin. Although

the liver is the major organ for the metabolism of

the trichothecene mycotoxins, other tissues such as

the intestine are capable of metabolic alteration of

these toxins. After an intravenous dose of T-2 toxin,

95% of the total radioactivity was excreted in the

urine and feces, in a ratio of 3 to 1.61 The majority

of the excreted products were either metabolites or

glucuronide conjugates of the metabolites.

Regardless of the route of administration or the

species of animal tested, the trichothecene mycotoxins were rapidly metabolized and excreted in urine

and feces. The route of exposure to the toxins and

the species can, however, influence the pattern of

metabolites that are excreted in the urine. The

deacetylated and hydroxylated metabolites appear

to be present in most of the species that have been

evaluated to date.

A microsomal, nonspecific carboxylesterase [EC

3.1.1.1] from liver selectively hydrolyses the C-4

acetyl group of T-2 toxin to yield HT-2 toxin.62 In

addition to hepatic microsomes, the trichothecenespecific carboxylesterase activity has been detected

in brain, kidney, spleen, intestine, white blood cells,

and erythrocytes. These findings emphasize the

importance of carboxylesterase in detoxifying the

trichothecene mycotoxins. A hepatic cytochrome,

P-450, is responsible for catalyzing the hydroxylation of the C-3' and C-4' positions on the isovaleryl

side chain of the T-2 and HT-2 toxins.59 When oxygen is removed from the epoxide group of a

trichothecene mycotoxin to yield the carbon–carbon

bond, deepoxy metabolites are formed. The deepoxy metabolites are essentially nontoxic.58 This

latter observation indicates that epoxide reduction

is a single-step detoxification reaction for trichothecene mycotoxins.

Four hours after swine received intravenous tritium-labeled T-2 toxin, glucuronide conjugates represented 63% of the metabolic residues in urine, and

77% in bile.63 The formation of glucuronide conjugates generally results in the elimination of toxicological activity of xenobiotics, which in certain species could represent a major route of detoxification

of trichothecene mycotoxins.

In summary, then, very little of the parent

trichothecene mycotoxin is excreted intact. Rather,

elimination by detoxification of the toxin is the result of extensive and rapid biotransformation.

CLINICAL DISEASE

The degree of illness in an individual exposed to

trichothecene mycotoxins could be affected by a

number of factors, including the nutritional status

of the host, liver damage, intestinal infections, route

of toxin administration, and stress.

The pathological effects and clinical signs for

many toxic materials can vary with the route and

type (acute, single dose vs chronic, subacute doses)

of exposure. For the trichothecene mycotoxins,

however, a number of the toxic responses are similar, regardless of the route of exposure. As we discussed earlier in this chapter, once they enter the

systemic circulation, trichothecene mycotoxins affect rapidly proliferating tissue regardless of the

route of exposure.

In contrast, the symptoms and clinical signs of

trichothecene intoxication can vary depending on

whether the exposure is acute or chronic. Acute

exposure to trichothecene mycotoxins used as biological warfare agents is the major concern for military

medicine, but for continuity and historical implications, chronic intoxication will also be addressed

in this chapter.

Acute Effects

Acute oral, parenteral, dermal, or aerosol exposures to trichothecene mycotoxins produce gastric
Trichothecene Mycotoxins

665

and intestinal lesions. Hematopoietic and immunosuppressive effects are radiomimetic. Central

nervous system toxicity causes anorexia, lassitude,

and nausea; suppression of reproductive organ

function; and acute vascular effects leading to hypotension and shock. While a number of toxic effect are common to different routes of exposure,

route-specific effects have been observed in animal

models. Examples of local, route-specific effects

include the following:

• dermal exposure: local cutaneous necrosis

and inflammation6;

• oral exposure: lesions to the upper gastrointestinal tract64; and

• ocular exposure: corneal injury.6

In Southeast Asia during the 1970s, symptoms

began within minutes after an exploding munition

(air-to-surface rocket, aerial bomb, cylinder) caused

a yellow, oily, droplet mist to fall on individuals

within 100 m of the explosion site. The falling droplet rain was inhaled, swallowed, and collected on

skin and clothing; contaminated the terrain and

food and water supply; and caused humans and

animals to become acutely ill and to die after a variable period.7

 Massive cutaneous contact was prevalent when the sources of exposure were sprays or

coarse mists that were used deliberately to contaminate humans and the environment. Although the

suspected trichothecene mycotoxin attacks in

Southeast Asia would have involved multiple

routes of exposure, we can postulate that the skin

would have been the major site for deposition of a

aerosol spray or coarse mist.

Early symptoms and signs included severe nausea, vomiting, burning superficial skin discomfort,

lethargy, weakness, dizziness, and loss of coordination. Within minutes to hours, diarrhea—at first

watery brown and later grossly bloody—began.

During the first 3 to 12 hours, dyspnea, coughing,

sore mouth, bleeding gums, epistaxis, hematemesis,

abdominal pain, and central chest pain could occur. The exposed cutaneous areas could become

red, tender, swollen, painful, or pruritic, in any combination. Small or large vesicles and bullae might

form; and petechiae, ecchymoses, and black, leathery areas of necrosis might appear. After death, the

necrotic areas might slough easily when the corpse

was moved.

Marked anorexia and dehydration were frequent.

Dying patients became hypothermic and hypotensive, and developed tachycardia. A bloody ooze from

the nares and mouth and an associated hematochezia

occurred in severely poisoned individuals. Death

could occur within minutes, hours, or days, and was

often preceded by tremors, seizures, and coma, in

any combination.

The most common symptoms in both Southeast

Asia and Afghanistan included vomiting (71%);

diarrhea (53%); skin irritation, burning, and itching (44%); rash or blisters (33%); bleeding (52%);

and dyspnea (48%).7,15,27 All of the symptoms listed could be attributed to trichothecene mycotoxin

toxicity.

Dermal Exposure

Similar cutaneous irritations have been observed

in numerous accidental and experimental settings:

• Individuals who were exposed to hay or

hay dust contaminated with trichotheceneproducing molds developed severe cutaneous irritations.38

• In working up large batches of fungal cultures from trichothecene-producing organisms, laboratory personnel suffered facial

inflammation followed by desquamation of

the skin and considerable local irritation.65

• When trichothecene mycotoxins of relatively low toxicity (crotocin and trichotecin) were applied to the volar surface of

human forearm or to the human head, reddening and irritation occurred within a few

hours of exposure, and was followed by

inflammation or scrabbling that healed in

1 to 2 weeks.66

• The hands of two laboratory workers were

exposed to crude ethyl acetate extracts containing T-2 toxin (approximately 200 μg/

mL) when the extract accidently got inside

their plastic gloves.66 Even though the

workers thoroughly washed their hands

with a mild detergent within 2 minutes after contact, they experienced severe cutaneous irritations.

These observations provide evidence that when

human skin is exposed in vivo to small amounts of

trichothecene mycotoxins, severe cutaneous irritations develop and can last 1 to 2 weeks after acute

exposure.

A number of animal models have been used

to assess local and systemic toxicity and lethality

from skin exposure to trichothecenes.6

 In a dermal

study that used a mouse model, necrosis in the skin

was present by 6 hours after dermal application
Medical Aspects of Chemical and Biological Warfare

666

Fig. 34-3. Skin lesions on the back of a hairless guinea

pig at (a) 1, (b) 2, (c) 7, and (d) 14 days after application

of (bottom to top) 25, 50, 100, or 200 ng of T-2 toxin in

2 μL of methanol.

of T-2 toxin, with inflammation observed by

12 hours. The hairless guinea pig is an excellent model

to illustrate the local skin lesions produced by a

dermal application of T-2 toxin (Figure 34-3). The

lesions are easily identified by 24 hours after the

exposure, with maximal response at 48 hours. Some

small lesions are still present 14 days after exposure to the toxin. From this experimental evidence,

we can postulate that dermal exposure to trichothecene mycotoxins played a major role in the clinical illnesses that were seen following the yellow rain

attacks.

Ocular Exposure

Victims of yellow rain attacks frequently reported

tearing, eye pain, conjunctivitis, burning sensations

about the eyes, and blurred vision for up to 1

week.7,16 A Canadian Forces medical team interviewed Khmer Rouge causalities after a chemical/

toxin attack at Tuol Chrey, Kampuchea.27 Soldiers

located 100 to 300 m from the artillery impact had

onset of symptoms 2 to 5 minutes after exposure;

these, likewise, included tearing, burning sensations, and blurred vision that lasted from 8 to 14

days. Analysis of autopsy samples from one of the

casualties identified T-2, HT-2, and diacetoxyscripenol (DAS, also called anguidine) in his tissues.

When the culture filtrates containing trichothecenes

were instilled into the conjunctival sacs of rabbits,

reddening and edema of the conjunctive membrane

were observed within 1 or 2 days. Later, the cornea

became opaque and developed scars that persisted

for as long as 5 months.67

From these reports, we conclude that trichothecene mycotoxins can cause severe eye injury that

can lead to a marked impairment of vision. This

could be a severe incapacitating problem for unprotected military personnel. No systemic toxicity has

been documented from the instillation of trichothecene mycotoxins into the eye of experimental animals, however.

Respiratory Exposure

Victims of yellow rain reported a variety of upper respiratory signs and symptoms.7,27 The major

subdivisions of the respiratory tract that were affected include the nose (itching, pain, rhinorrhea,

and epistaxis); the throat (sore/pain, aphonia, and

voice change); and the tracheobronchial tree (cough,

hemoptysis, dyspnea, and deep chest pain or pressure or both). Agricultural workers who were exposed to hay or hay dust contaminated with trichothecene mycotoxins developed similar signs and

symptoms of upper respiratory injury. The descriptions of the yellow rain attacks in Southeast Asia

(ie, the droplets, heavy mist, vapor), suggest that

the aerosols were larger than 1 to 4 μm—the particle size required for deposition in the alveoli.

Thus, respiratory tract exposure from the largerparticle aerosols would involve mycotoxin deposition in the upper respiratory and tracheobronchial

region, followed by secondary gastrointestinal tract

exposure after clearance from the lungs.

We can postulate that multiple routes of exposure (topical, upper respiratory, and secondary enteral) to trichothecene mycotoxins occurred in victims of the yellow rain attacks. The symptoms of

vomiting, diarrhea, melena, abdominal pain, and

acute gastroenteritis with hematemesis7

 could be

related to ingestion of toxin that was deposited in

the upper respiratory tract and tracheobronchial

region. Autopsies in the field of victims who died

24 to 48 hours after a yellow rain attack disclosed

severe gastroenteritis with bleeding in the lower

esophagus, stomach, and duodenum.27 In humans,

many of the acute enteral effects (from either yellow rain or contaminated hay and dust particles)

of the trichothecene mycotoxins are probably the

result of secondary ingestion of toxins that originally were deposited in the respiratory tract by

large-particle aerosol.

a b

c d
Trichothecene Mycotoxins

667

Chronic Toxicity

Chronic exposure to subacute doses of trichothecene mycotoxins is not thought to be an effect of

biological warfare. This type of exposure, however,

was responsible for ATA toxicosis in humans and

mycotoxicosis in domestic animals. In addition,

chronic toxicity has been iatrogenically induced when

repeated subacute doses of a trichothecene mycotoxin

were administrated intravenously to cancer patients

as a chemotherapy for colon adenocarcinoma.

Alimentary Toxic Aleukia Toxicosis

The clinical course of ATA is divided into four

stages. The first stage develops immediately or several days after consumption of grain products that

are contaminated with trichothecene mycotoxins.

Inflammation of the gastric and intestinal mucosa

causes vomiting, diarrhea, and abdominal pain. In

most cases, excessive salivation, headache, dizziness, weakness, fatigue, and tachycardia accompany this stage, and fever and sweating may also

be present.36

The disease progress to the second stage—the leukopenic or latent stage—which is characterized by

leukopenia, granulopenia, and progressive lymphocytosis. When the ingestion of the toxin-contaminated food is not interrupted or if large doses are

consumed, the next stage develops.36

The third stage is characterized by the appearance

of a bright red, or dark cherry-red, petechial rash

on the skin of the chest and other areas of the body.

At first, the petechiae are localized in small areas,

but they then spread and become more numerous.

In the most severe cases, intensive ulceration and

gangrenous processes develop in the larynx, leading to aphonia and death by strangulation. At the

same time, affected individuals have severe hemorrhagic diathesis of the nasal, oral, gastric, and

intestinal mucosa.36

As the necrotic lesions heal and the body temperature falls, the fourth stage—the recovery stage—

begins. During this period, exposed patients are

susceptible to various secondary infections, including pneumonia. Convalescence is prolonged and

can last for several weeks. Usually, 2 months or

more are required for the blood-forming capacity

of the bone marrow to return to normal.36

Cancer Chemotherapy

The inhibitory effect of trichothecene mycotoxins on rapidly dividing cells was the basis for their

evaluation as antitumor chemotherapy drugs during the late 1970s and early 1980s.68 Phase I and

phase II clinical evaluations of DAS (anguidine) in

patients with cancer disclosed significant toxicity

with intravenous doses 3.0 mg/m2 (0.077 mg/kg)

daily for 5 days, particularly in patients with

hepatic metastases. The signs and symptoms included nausea, vomiting, diarrhea, burning erythema, confusion, ataxia, chills, fever, hypotension,

and hair loss. 69,70 Antitumor activity of the

trichothecenes was minimal or absent in the patients

treated with DAS. Because of the marked toxicity

of the drug, the life-threatening hypotensive effects,

and the poor tolerance by patients, the evaluation

of trichothecenes as chemotherapeutic drugs was

discontinued.

DIAGNOSIS

Battlefield Diagnosis

In the absence of a biological detector or a particular characteristic of the aerosol (such as color

or odor), diagnosis of an attack with trichothecene

would depend on clinical observations of casualties and identification of the toxins in biological or

environmental samples. This would involve a combined effort between the medical and chemical units

in the field. The early signs and symptoms of an

aerosol exposure to trichothecene mycotoxins

would depend on particle size and toxin concentration. For a large-particle aerosol (particles > 10

μm, found in mist, fog, and dust; similar to that

used in Southeast Asia), the signs and symptoms

would include rhinorrhea, sore throat, blurred vision, vomiting, diarrhea, skin irritation (burning

and itching), and dyspnea. Early (0–8 h) signs and

symptoms from a deep-respiratory aerosol exposure

(from aerosol particles in the 1- to 4-μm range) have

not been fully evaluated but could include vomiting, diarrhea, skin irritation, and blurred vision.

Later signs and symptoms (8–24 h) would probably be similar (except for the degree of skin rash

and blisters) for both large-particle and deeprespiratory aerosol exposure to trichothecene mycotoxins. They could include continued nausea and

vomiting, diarrhea, burning erythema, skin rash

and blisters, confusion, ataxia, chills, fever, hypotension, and bleeding.

Nonspecific changes in serum chemistry and

hematology occurred in monkeys exposed to an
Medical Aspects of Chemical and Biological Warfare

668

acute dose of T-2 toxin. Alterations in serum chemistry included elevations in serum creatinine, serum

enzymes (especially creatine kinase), potassium,

phosphorous, and serum amino acids; and, due to

decreased coagulation factors, elevations in prothrombin time and partial thromboplastin time. An

initial rise in the absolute number of neutrophils

and lymphocytes may occur within hours, followed

by a decrease in lymphocyte counts by 48 hours.

Survival beyond several days may be associated

with a fall in all blood cellular elements.6 Although

it is likely that these acute changes will also be seen

in humans, careful clinical observations of human

victims of acute trichothecene mycotoxicosis have

not been reported to date. In patients with chronic

toxicity (ie, ALA) resulting from repeated ingestion

of contaminated bread, pancytopenia is an important part of the clinical picture.36

In the yellow rain attacks in Southeast Asia, diagnosis of the causative agent was difficult and involved ruling out the presence of conventional

chemical warfare agents. Contamination of the environment and clothing by nerve and blistering

agents would be absent, and these were, in fact, not

detectable in such samples from Southeast Asia.

Sarin, soman, or other nerve agents could be missed

unless thickened soman or VX was used.

The following events should suggest to medical

officers that a biological warfare attack with

trichothecene mycotoxins has occurred:

• clinical findings that match the symptoms

listed above;

• high attack and fatality rates;

• all types of dead animals; and

• onset of symptoms after a yellow rain or

red, green, or white smoke or vapor attack.

At present, we do not have a fieldable identification kit for any of the trichothecene mycotoxins.

Several commercial immunoassay kits are marketed

for the detection of trichothecene mycotoxins (T-2

toxin, deoxynivalenol, and their metabolites) in

grain extracts or culture filtrates of Fusarium species.71,72 These kits have not been evaluated against

biomedical samples that contain typical concentrations of the mycotoxins, however. Screening tests

for presumptive identification of trichothecene

mycotoxins in the biomedical samples would probably involve bioassays, thin-layer chromatography,

or immunological assays, in any combination. At a

national laboratory, confirmatory methodology

would involve the use of various combinations of

gas chromatography, high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectrometry.

In areas that have experienced a yellow rain attack, environmental assays have been in the range

of 1 to 150 parts per million (ppm) and blood

samples in the range of 1 to 296 parts per billion

(ppb).8–10,16,22 In the laboratory, at 10 and 50 minutes after an intramuscular exposure to 0.4 mg/kg

of T-2 toxin in the dog, plasma concentrations of T2 toxin were 150 and 25 ppb, and for HT-2 toxin

were 50 and 75 ppb, respectively.60 Thus, any

screening procedure for trichothecene mycotoxins

in biomedical samples must have detection limits

of 1 to 100 ppb. Most of the analytical procedures

require extraction and cleanup treatment to remove

interfering substances.73

Screening tests for the trichothecene mycotoxins

are generally simple and rapid but, with the exception of the immunochemical methods, are nonspecific. A number of bioassay systems have been used

for the identification of trichothecene mycotoxins.73

Although most of these systems are very simple,

they are not specific, their sensitivity is generally

relatively low compared to other methods, and they

require that the laboratory maintain vertebrates,

invertebrates, plants, or cell cultures. Thin-layer

chromatography (TLC) is one of the simplest and

earliest analytical methods developed for mycotoxin analysis. Detection limits for trichothecene

mycotoxins by TLC is 0.2 to 5 ppm (0.2 to 5 μg/

mL). Therefore, extracts from biomedical samples

would have to be concentrated 10- to 1,000-fold to

screen for trichothecene mycotoxins.

To overcome the difficulties encountered with the

bioassays and TLC methods, immunoassays using

specific polyclonal and monoclonal antibodies have

been developed for most of the major trichothecene

mycotoxins and their metabolites.73 These antibodies have been used to produce simple, sensitive, and

specific radioimmunoassays (RIAs) and enzymelinked immunosorbent assays (ELISAs) for the

mycotoxins. In the presence of the sample matrix,

the lower detection limits for identification of

trichothecene mycotoxins by RIA is about 2 to 5

ppb73 and by ELISA, 1 ppb.74 We conclude that immunoassays are useful tools for screening biomedical samples for evidence of a biological warfare attack with trichothecene mycotoxins.

Confirmatory Procedures

Gas-liquid chromatography (GLC) is one of the

most commonly used methods for the identification

of the trichothecene mycotoxins in both agricultural
Trichothecene Mycotoxins

669

products and biomedical samples.75 Before GLC

analysis, the polar groups in mycotoxin molecules

must first be converted to their esters or ethers.

Extensive treatment to clean up the sample is required

before derivatization and subsequent analysis can be

performed. By the most sensitive procedures, the

detection limit for trichothecene mycotoxins is 10 ppb.

If the analysis is on a sample that contains an unknown toxic material, such as those from the yellow rain attacks, then the GLC method can only

provide presumptive evidence of a trichothecene

mycotoxin exposure. Confirmation will require the

identification with more definitive physicochemical procedures.

Mass spectrometry (MS) is the physicochemical

method of choice for characterizing, identifying,

and confirming the presence of trichothecene

mycotoxins.76,77 Picogram quantities of trichothecene mycotoxins are readily detectable by MS

methods. In some cases, extensive cleanup steps

are unnecessary.

The combination of GLC and MS techniques

(GLC–MS) has proven to be a more-specific method

for identifying mycotoxins than is GLC alone.76,77

As a result, the GLC–MS method has become the

standard for identifying trichothecene mycotoxins

in agricultural products as well as in biomedical

samples. As little as 1 ppb of T-2 toxin can be identified without extensive cleanup.76 One major drawback of this methodology is the time-consuming

derivatization step that trichothecene mycotoxin

identification by GLC–MS requires. A high-performance liquid chromatography–mass spectrometry

(HPLC–MS) procedure was described in 1991 and

provides a specific and reliable method for the identification of trichothecene mycotoxins without

derivatization.78 The HPLC–MS procedure achieves

sensitivity at the 0.1-ppb level. This technology will

require further evaluation and development, but it

appears to be a promising approach for the rapid

confirmation of trichothecene mycotoxins in a biomedical sample.

MEDICAL MANAGEMENT

Individual and Unit

The immediate use of protective clothing and

mask at the first sign of a yellow rain–like attack

should protect an individual from the lethal effects

of this mycotoxin. The mask can be applied in less

than 9 seconds and can be worn at first sighting of

an incoming rocket or enemy aircraft. Contaminated battle dress uniforms (BDUs) should be removed before protective clothing is donned. Since

the area covered with agent is likely to be small,

another helpful tactic is to leave the area after taking samples to document the attack. Vulnerability

is increased by lack of protective clothing, mask, or

training (as was demonstrated in Laos) or by a surprise biological warfare attack (such as a night or

an undetected attack). A lightweight face mask,

outfitted with filters that block the penetration of

aerosol particles 3 to 4 μm or larger, should provide respiratory protection against yellow rain.

Only 1% or 2% of aerosolized T-2 toxin penetrated

nuclear, biological, chemical protective covers

(NBC–PC).79 Regular BDUs would offer some protection, but the degree would be functions of the

age and condition of the fabric, and the type of environmental conditions.

Two topical skin protectants (TPS1 and TSP2) are

in advanced development for protection against

chemical warfare agents. When applied to the skin

of rabbits 60 minutes before exposure to 50 μg of T2 toxin, both topical skin protectants completely

protected the rabbits from the dermal irritating effects of this mycotoxin for at least 6 hours.80

As soon as individuals or units suspect that they

have been exposed to a mycotoxin attack, they

should remove their BDUs, wash their contaminated skin with soap and water, and then rinse with

water. Washing the contaminated area of the skin

within 4 to 6 hours after exposure to T-2 toxin removed 80% to 98% of the toxin and prevented dermal lesions and death in experimental animals.25

Contaminated BDUs as well as wash waste from

personnel decontamination should be exposed to

household bleach (5% sodium hypochlorite) for 6

hours or more to inactivate any residue mycotoxin.

Two skin decontamination kits, the M258A1 and

the M238A1, have been designed for the removal

and detoxification of chemical warfare agents. The

M258A1 kit is the currently fielded standard. When

evaluated against trichothecene mycotoxins, however, the M238A1 kit effectively removed T-2 toxin

from the skin of rats but did not detoxify this biological warfare agent.81 Several of the components

of the M258A1 kit are themselves highly toxic, caustic compounds that caused dermal irritation and

lethality in rats and rabbits.82

A second-generation skin decontamination kit,

the XM291, has been developed, and contains an

XE-555 resin material as the active component. This

skin decontamination kit is efficacious against most
Medical Aspects of Chemical and Biological Warfare

670

chemical warfare agents and presents no serious

human factor or human safety problems. The XE556 resin, a similar but different formulation, was

effective in the physical removal of T-2 toxin from

the skin of rabbits and guinea pigs.83 The foregoing observations suggest that the skin decontamination kits that were designed specifically for removal and detoxification of chemical warfare agents

could also afford a significant degree of protection

through the physical removal of mycotoxins from

the skin of exposed individuals.

Specific or Supportive Therapy

No specific therapy for trichothecene-induced

mycotoxicosis is known or is presently under experimental evaluation. Several therapeutic approaches have been evaluated in animal models. It

is perhaps significant, however, that although experimental procedures for treatment of systemic

exposure have been successful in reducing mortality in animal models, they have not been tested in

primates. Thus, these treatments are not available

for field use for humans exposed to trichothecene

mycotoxins.

Individuals exposed to a yellow rain–like attack

should be treated with standardized clinical toxicology and emergency medicine practices for ingestion of toxic compounds. After an aerosol exposure to a yellow rain–like attack, mycotoxins will

be trapped in the nose, throat, and upper respiratory tract. The particles will be returned by ciliary

action to be swallowed, resulting in a significant

oral exposure. Superactive charcoal has a very high

maximal binding capacity (0.48 mg of T-2 toxin per

1 mg of charcoal), and treatment either immediately

or 1 hour after oral or parenteral exposure to T-2

toxin significantly improves the survival of mice.84

Superactivated charcoal with magnesium sulfate is

stocked in the chemical and biological warfare kits

of U.S. Army field hospitals.

Symptomatic measures for the treatment of exposure to trichothecene mycotoxins are modeled after the care of casualties of mustard poisoning.85 Irrigation of the eyes with large volumes of isotonic

saline may assist in the mechanical removal of trichothecene mycotoxins, but would have limited useful

therapeutic effects. After the skin has been decontaminated, some erythema may appear, accompanied by burning and itching. Most casualties whose

skin has been treated with soap and water within 12

hours of exposure will have mild dermal effects; these

should be relieved by calamine and other lotion or

cream, such as 0.25% camphor and methanol.

Limited data are available on the respiratory effects of inhaled trichothecene mycotoxins, although

acute pulmonary edema is one of the serious, often

lethal consequences of a yellow rain attack.16,27 One

of the major symptoms following the yellow rain

attacks was an upper respiratory irritation (sore

throat, hoarseness, nonproductive cough),7,16,27

which can be relieved by steam inhalation, codeine,

or another substance to suppress the cough, and

other simple measures.85 A casualty who develops

severe respiratory symptoms should be under the

care of a physician skilled in respiratory care.

The early use of high doses of systemic glucocorticosteriods increases survival time by decreasing the primary injury and the shocklike state that

follows exposure to trichothecene mycotoxins.86 A

selective platelet activating factor antagonist, BN

52021, can prolong the survival of rats exposed to a

lethal intravenous dose of T-2 toxin.87 This finding

suggests that platelet activating factor is an important mediator of T-2 toxicosis. Dosing before and

after the exposure with diphenhydramine (an

antihistaminic agent) or naloxone (an opioid antagonist) prolonged the survival times of mice exposed subcutaneously or topically with lethal doses

of T-2 toxin.88

We can postulate that a number of bioregulators

are the mediators of the shocklike state of trichothecene mycotoxicosis. Methylthiazolidine-4-carboxylate increased hepatic glutathione content and

enhanced the survival of mice after an acute intraperitoneal exposure to T-2 toxin.89 The protective

effects of this drug may be the result of increased

detoxification and excretion of the glucuronide conjugate of T-2 toxin. A general therapeutic protocol

that included combinations of metoclopramide, activated charcoal, magnesium sulfate, dexamethasone, sodium phosphate (which had very little effect), sodium bicarbonate, and normal saline as the

therapeutic agents was evaluated in swine given an

intravenous LD50 dose of T-2 toxin.90 All treatment

groups showed improved survival times when compared with the nontreated T-2 controls.

Prophylaxis

The mycotoxins are low-molecular-weight compounds that must be conjugated to a carrier protein to produce an effective antigen.73 When T-2

toxin is conjugated to a protein, it develops relatively low antibody titers and is still a marked skin

irritant.91 This would preclude mycotoxins’ use

as immunogens in the production of protective immunity. To circumvent such problems, a deoxy-
Trichothecene Mycotoxins

671

verrucarol (DOVE)–protein conjugate was used to

immunize rabbits.92 Antibody titers to DOVE developed rapidly after immunization, but they were

highly specific for DOVE rather than a common

trichothecene backbone.92

Another approach was to develop antibodybased vaccines (anti-idiotype) against T-2 toxin.

Protective monoclonal antitoxin antibodies were

first generated and then used to induce specific

monoclonal anti-idiotype antibodies. When mice

were immunized with specific monoclonal antiidiotype antibodies, they developed neutralizing

antibodies and were protected against challenge

with a lethal dose of T-2 toxin.93 Thus, it would be

feasible to develop a despeciated monoclonal antiidiotype antibody that could be a vaccine candidate

against T-2 toxin.

Several monoclonal antibodies against T-2 toxin

will protect against the T-2–induced cytotoxicity

in various cell lines.94,95 When a monoclonal antibody against T-2 toxin (15H6) was given to rats

(250 mg/kg) 30 minutes before or 15 minutes after

a lethal dose of mycotoxin, it conferred 100% survival.94 Thus, monoclonal antibodies do have some

prophylactic and therapeutic value against T-2

toxicosis, but very large quantities are required for

protection.

Prophylactic induction of enzymes involved in

the conjugation of xenobiotics reduced or prevented

the acute toxic effects of T-2 toxin in the rat, while

inhibition of these enzymes resulted in a higher toxicity for this trichothecene.96 Pretreatment with flavonoids,97 ascorbic acid,98 vitamin E,99 selenium,100

or chemoprotective compounds such as emetine101

that block trichothecene–cell association all reduce

acute toxicity of these mycotoxins. However, none

of these chemoprotective treatments have undergone extensive efficacy studies to evaluate their

ability to protect against an aerosol or dermal exposure to trichothecene mycotoxins.

SUMMARY

Trichothecene mycotoxins are noted for their

marked stability under different environmental conditions. On a weight-for-weight basis, they are less

toxic than other toxins such as ricin, botulinum, and

staphylococcal enterotoxin B, but trichothecene

mycotoxins are proven lethal agents in warfare.

Symptoms include vomiting, pain, weakness, dizziness, ataxia, anorexia, diarrhea, bleeding, skin

redness, blistering, and gangrene, as well as shock

and rapid death. Sensitive immunoassays and

chemical procedures are available for the identification of trichothecene mycotoxins in biological

samples, but no detection kits have been fielded.

Prevention of exposure is the only current defense, with a protective mask and clothing worn

when under attack. Previous successful lethal attacks have always occurred against unprotected civilians and soldiers. Skin decontamination with

water and soap can be used effectively up to 6 hours

after exposure. Experimental treatments for systemic toxicity are being investigated, but no therapy

is available for humans.

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1993;25(3):281–323.

61. Wannemacher RW Jr, Pace JG. Medical defense against biological warfare: Exploratory immunotherapy studies on toxins of potential BW threat. In: US Army Medical Research Institute of Infectious Diseases Annual Report

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urine. J Agric Food Chem. 1985;33(6):1085–1089.

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68. Claridge CA, Schmitz H, Bradner WT. Antitumor activity of some microbial and chemical transformation products of anguidine (4,15-diacetoxyscirpene–3-ol). Cancer Chemother Pharmacol. 1979;2(3):181–182.

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to T-2 Toxin. Fort Detrick, Frederick, Md: US Army Medical Research Institute of Infectious Disease. Memorandum to US Army Armament, Munitions, and Chemical Command, Chemical Research and Development Command, 10 May 1983.

82. Jederberg WW, Fruin JT. Primary Dermal Irritation Potential of Components of the M256A–1 Decontamination Kit

(Study 8). San Francisco, Calif: Letterman Army Institute of Research; 1981. LAIR Technical Report 82–27TN.

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Material for Removing T-2 Mycotoxin From Exposed Skin of Guinea Pigs and Rabbits. Fort Detrick, Frederick, Md:

US Army Medical Research Institute of Infectious Diseases. Memorandum to US Army Medical Material Development Activity, 10 January 1987.

84. Fricke RF, Jorge J. Assessment of efficacy of activated charcoal for treatment of acute T-2 toxin poisoning. J

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New York, NY: Academic Press; 1992: 51–66.

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88. Ryu J, Shiraki N, Ueno Y. Effects of drugs and metabolic inhibitors on the acute toxicity of T-2 toxin in mice.

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1991;11(2):135–140.

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treatment of acute T-2 toxicosis in swine. Vet Hum Toxicol. 1987;29(3):237–239.

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93. Chanh TC, Siwak EB, Hewetson JF. Anti-idiotype–based vaccines against biological toxins. Toxicol Appl Pharmacol.

1991;108(2):183–193.

94. Feuerstein G, Powell JA, Knower AT, Hunter KW. Monoclonal antibodies to T-2 toxin: In vitro neutralization of

protein synthesis inhibition and protection of rats against lethal toxemia. J Clin Invest. 1985;76(6):2134–2138.

95. Chanh TC, Hewetson JF. Structure/function studies of T-2 mycotoxin with a monoclonal antibody. Immunopharmacology. 1991;21(2):83–90.

96. Kravchenko LV, Avreneva LI, Tutelian VA. Lowering the content of SH-glutathione and glutathione transferase

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97. Markham RJ, Erhardt NP, Di Ninno VL, Penman D, Bhatti AR. Flavonoids protect against T-2 mycotoxins both

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(Cavea cavea). Biomed Lett. 1994;49(195):213–217.

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from Russian.

100. Tutelyan VA, Kravchenko LV, Kuzmina EE, Avrenieva LI, Kumpulainen JT. Dietary selenium protects against

acute toxicity of T-2 toxin in rats. Food Addit Contam. 1990;7(6):821–827.

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mammalian cells. J Pharmacol Exp Ther. 1993;266(2):741–748.
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Chapter 35

MEDICAL CHALLENGES IN CHEMICAL

AND BIOLOGICAL DEFENSE FOR THE

21ST CENTURY

ERNEST T. TAKAFUJI, M.D., M.P.H.*; ANNA JOHNSON-WINEGAR, PH.D.†; AND RUSS ZAJTCHUK, M.D., FACS‡

INTRODUCTION

PROLIFERATION OF BIOLOGICAL WEAPONS

BIOTECHNOLOGY

Enhanced Pathogenicity

Antibiotic Resistance

Bioengineered Toxin Production

Genetic Weaponry

The Human Genome Project

New Medical Countermeasures

MILITARY SCENARIOS

SUMMARY

*Colonel, Medical Corps, U.S. Army; Commander, Walter Reed Army Institute of Research, Walter Reed Army Medical Center, Washington,

D. C. 20307-5100

†Director, Medical Chemical–Biological Defense Research Program, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick,

Maryland 21702-5012

‡Brigadier General, Medical Corps, U.S. Army; Commanding General, U.S. Army Medical Research and Materiel Command, Fort Detrick,

Frederick, Maryland 21702-5000
Medical Aspects of Chemical and Biological Warfare

678

INTRODUCTION

Biological and chemical warfare has long concerned military planners, strategists, and tacticians.

Experiences in the Persian Gulf War (1990–1991),

the rising concern over terrorist groups and their

interest in weapons of mass destruction, and the

continuing difficulties with curbing the proliferation of traditional chemical and biological weapons

have resulted in continuing modifications in policies that would be employed in future scenarios.

The use of such agents against the United States or

its allies or both, including military and civilian

populations, remains a distinct and perhaps increasing possibility.

Recent events in the world, including the terrorist attack with the nerve agent sarin in a subway in

Tokyo, Japan, in March 1995, have demonstrated

both the willingness of extremist organizations

to use these agents and the ready availability of

deadly agents. Biological organisms continue to be

readily available throughout the world, obtainable

in nature or through biological supply houses or

medical laboratories. Dangerous chemicals already

exist in local communities and in hardware and gardening shops.

The current threat posed by weapons of biological and chemical origin has been discussed extensively in previous chapters of this textbook. This

chapter discusses three issues that will likely have

a significant effect on chemical and biological defense in the next century:

• the global proliferation of biological weapons;

• the advances in technology, particularly

biotechnology, that will affect the development of weapons and their countermeasures; and

• possible changes in the future use of chemical and biological weapons by the enemy

that will make delivery of medical care even

more challenging.

Efforts at counterproliferation will not be discussed in this chapter. This should not be construed

as a reflection of its reduced importance, for limiting the proliferation of weapons of mass destruction continues to be a large effort of the United

States government. Instead, emphasis is placed here

on the issue of biotechnology, for this is the area

where medical personnel will find the greatest controversy and conflict. For the interested reader who

desires a more in-depth review of the subject of future prospects of biological weapons and proliferation, we refer you to two excellent sources: Biological Weapons: Weapons of the Future? and Director’s

Series on Proliferation (see Recommended Reading

at the end of this chapter).

The potential exists for both (a) misuse of the biotechnology for refinement of current biological

weapons and (b) development of new agents with

added potency. The profound impact that biotechnology will continue to have on biological weapons and their countermeasures is of particular concern when put in the context of the worldwide

deployability of military forces, the potential use

of genetic engineering for both peaceful and sinister purposes, and continued attractiveness of biological warfare as an option by adversaries in future conflicts.

PROLIFERATION OF BIOLOGICAL WEAPONS

The limitation and eventual elimination of both

chemical and biological weapons are two of the

greatest challenges facing the international community. Unfortunately, proliferation of such weapons

is continuing despite the best efforts of many

nations, including the United States, to prevent

proliferation.1

 Biological weaponry is the most worrisome issue because of the relative ease in developing and mass-producing potent agents, the

continuing difficulties in identifying enemy capabilities and limiting their development, and the

potential ability for adversaries to bioengineer and

deliver new organisms using the latest advances in

technology.

On 23 February 1993, following the Persian Gulf

War and the breakup of the Soviet Union, a panel

of the U.S. House of Representatives Committee on

Armed Services submitted a special report,2 Special

Inquiry of the House Armed Services Committee Into

the Chemical and Biological Weapons Threat. This report concluded that despite the decrease in absolute quantities of chemical weapons, the potential

diversity and the frequency with which such weapons could be encountered were increasing. The

threat had shifted to Third World scenarios, with

deployed U.S. military forces facing new threats

from chemical and biological weapons. Technological advances have increased the diversity of poten-
Medical Challenges in Chemical and Biological Defense for the 21st Century

679

tial weapons of each variety. The report stated the

following concern, which goes to the heart of the

problems that the U.S. military medical departments will face in the 21st century:

Genetic tailoring and the speed of technological

innovation create opportunities for the creation of

exotic new agents which may be difficult to detect

or defend against.2(p7)

In addition, the report of the House of Representatives Special Committee alluded to 31 nations that

either possess or have the ability to develop an offensive chemical weapons capability, and 11 nations

that either possess or have the ability to develop an

offensive biological weapons capability. The Special Committee realized that while it would be more

difficult for a country to mass-produce classic

chemical warfare agents in large quantities without detection, it would be very easy for a country

or organized group to develop the technological

capabilities to produce other agents.2

The former Soviet Union, long suspected of having an aggressive research and development program despite its participation in international agreements to curtail such development, has continued

to be a major factor in the global threat. Covert programs continued, at least through 1992, despite

open declarations to the contrary. With the dissolution of the Soviet Union, concern has been generated about the export of the scientific technology

and weaponry beyond its borders. Cooperation between the Russian Federation and the United States

is making progress in reducing this potentially dangerous situation.

North Korea, Iran, and Iraq are three examples

of countries with biological warfare potential. North

Korea has continued to have a program of cooperation with several countries in the Middle East, and

the prospect of biological weapons being used on

the Korean peninsula is a genuine concern. Iraq was

known to have an active research, development, and

weaponization program at the time of the Gulf War,

although whether Saddam Hussein intended to use

such weapons is controversial. If chemical weapons agreements are any indication of national compliance and intent, it should be noted that Iraq secretly constructed chemical warfare production

plants and imported chemical warfare technology

from the West in violation of the Geneva Protocol.3

The use of chemical weapons on Kurdish forces has

now been well documented.

The Persian Gulf War and continuing problems with Iraq resulted in the creation of a unique

United Nations organization known as The United

Nations Special Commission on Iraq (UNSCOM).3

UNSCOM was established specifically by a United

Nations Security Council resolution that spelled out

conditions for cease-fire and the destruction, removal, or rendering harmless of chemical, biological, and nuclear weapons and ballistic missiles with

a range greater than 150 km. UNSCOM unilaterally

defined the terms for its inspections of Iraqi facilities and has continued to direct and support compliance inspections.

The United States has been active in its participation in international efforts to specifically control the spread of biological and chemical weapons.

The Convention on the Prohibition of the Development, Production, and Stockpiling of Bacteriological and Toxin Weapons and their Destruction (also

known as the Biological Weapons Convention) and

the Chemical Weapons Convention have been discussed in detail in other publications,4,5 as have various confidence-building measures,5

 which have met

with limited success.

It should be noted that UNSCOM activities are

not directly associated with the Biological Weapons and Chemical Weapons Convention agreements, although elimination of weapons of mass

destruction continues to be a goal of most nations.

It is plausible to assume that should international

situations arise in the future regarding proliferents

with biological warfare capabilities, the United

Nations may again take actions similar to those it

took with Iraq.

The “dual-use” issue, in which the technologies

used to develop and produce biological or chemical

weapons are very similar to those that would be

needed for human and veterinary healthcare research

and production and the agricultural industry, has

created many challenges. The technologies involved

in pesticide dispersal, for example, could easily be

adapted for the delivery of aerosols containing biological agents. Verification inspections and confidence-building measures have had limited success,

but efforts continue to strengthen the conventions.

BIOTECHNOLOGY

Since 1953, when James D. Watson and Francis

Crick identified the genetic code contained in

deoxyribonucleic acid (DNA), discoveries in the

field of molecular genetics have skyrocketed. Breakthroughs in genetic engineering have allowed

genes to be substantially altered and combined with
Medical Aspects of Chemical and Biological Warfare

680

other genes in ways that have benefited mankind tremendously. Over the last 30 years, for example, the number of recognized human genetic

disorders has risen from fewer than 500 to more

than 4,200, primarily as a result of the ability to sequence genes quickly and precisely.6–8 Since 1990,

gene therapy experiments have been approved involving numerous human studies aimed at 12 genetic disorders, including cystic fibrosis, severe

combined immune deficiency, familial hypercholesterolemia, acquired immunodeficiency syndrome,

and several cancers.

However, the progress in genetic engineering and

molecular biology has raised serious ethical issues,

such as man’s apparent ability to freely manipulate nature without clear societal controls; the potentially dangerous effects of bioengineered organisms of plant and animal origin on the environment;

the arbitrary use of human embryonic tissue in research; and the control, storage, and access of genetic information.7,9 These controversies have arisen

as scientific accomplishments have proceeded at a

more accelerated pace than has society’s ability to

resolve such complex issues.

For the military, knowledge of man’s specific

genetic defects or vulnerabilities (or ways to create

such defects) and the ability to modify microorganisms or toxins that would increase pathogenicity

take on added concern. Biotechnology theoretically

provides opportunities for adversaries to modify

existing organisms with specific characteristics,

such as increased virulence, infectivity, or stability.

Modern advances also allow for the inexpensive

production of large quantities of replicating microorganisms for weaponization through recombinant

methodologies, and the possibility to create “new”

agents for future warfare that bypass current preventive or therapeutic interventions. These could

be accomplished through secretive research programs that are superimposed on open biomedical

research efforts in pharmaceutical firms or government laboratories. Ironically, while such possibilities continue to generate fear, the same technological

advances can and do contribute to the development

of new medical countermeasures, such as new vaccines, drugs, and diagnostic tests.

Enhanced Pathogenicity

Splicing genes for virulence, infectivity, stability,

or other factors into the genome of an existing organism is one possibility for manipulating potential biological warfare agents. Microorganisms are

able to cause disease through a variety of mechanisms that may involve interactions at the cellular

level or at target organs. An understanding of the

basic mechanisms of action that determine or influence cellular attachment, penetration, and genetic alteration is critical in the redesign of microorganisms.

Infectivity

Although influenza A virus has not been known

to be bioengineered as an offensive biological

weapon, it serves as an example of opportunities

for viral modification. Naturally occurring mutations that result in antigenic drifts and shifts suggest that with today’s technology, man could

achieve deliberately what nature is already accomplishing naturally. If we are to develop effective

countermeasures, we must understand how a virus

penetrates the host’s natural defenses and modifies

itself genetically to promote its spread and ultimate

survivability.

Influenza A possesses a neuraminidase that

cleaves the terminal neuraminic acid residue at the

cell surface carbohydrates. This simple enzymatic

action allows the virus to attach to the cell surface

and penetrate the membrane. Once infection has

occurred, the body gradually develops specific antibodies to the infecting viral strain. Humoral immunity could also be elicited through immunization with an attenuated strain or a nonreplicating

portion of the influenza virus itself.

The infectivity of “new” influenza virus strains

is based on the ability of such strains to evade the

body’s preexisting immune defenses. The virus’s

genes and their products—hemagglutinin and

neuraminidase—are altered enough that the body

perceives it to be a new virus. This antigenic change

could theoretically occur through man-made genetic alterations. The concept for developing new

biological weapons is a basic one: develop a virus

that evades the protective immunological system,

reaches a target organ or tissue quickly, and causes

significant disease, disability, or death. Viruses that

debilitate or cause chronic illnesses may be just as

militarily significant as those that cause acute disease, depending on specific scenarios.

Paradoxically, it may be advantageous for a biologically weaponized virus to cause a severe protracted illness with high communicability rather

than quick death with little opportunity for continued spread. The only factor that prevents this from

becoming an easy option for adversaries is the

aggressor’s need to develop a protective vaccine

against the modified virus for use in their troops.
Medical Challenges in Chemical and Biological Defense for the 21st Century

681

The fact that new influenza vaccines are needed

every year to provide protection against new or

modified circulating strains of virus illustrates the

difficulties in developing a long-lasting, immunologically based defense against such viruses.

Virulence

Several bacterial agents have virulence factors

that would enhance their pathogenicity in man.

Such additions to a highly infectious but less pathogenic strain could make the modified organisms

more attractive candidates for offensive weapons.

Countermeasures, including vaccines and antimicrobial drugs, must be developed with this possibility in mind to provide the broadest measure of

protection.

Moreover, when used in combination, microorganisms have the potential to create a more severe

disease state. Similarly, infection with one agent

with a shorter incubation period that may weaken

overall resistance may provide easier opportunities

for infection with a second organism with greater

morbidity and mortality. The ability of multiple

organisms with different levels of virulence to confuse medical officers looking for a common etiology accentuates the need for sensitive and specific

diagnostic tests to be available in the field setting.

These diagnostic tests must be able to decipher genetic differences and differentiate endemic from

nonendemic forms of microorganisms.

Genetic Recombination

The ability for some genes to transpose themselves on chromosomes, rearrange and combine

with other genes in a manner that may result in radical phenotypic and genotypic changes in the original organism, or to form plasmids that may sit quiescently for the right moment to exert their effect,

has been demonstrated in the laboratory. The ability for cancer-producing genes (oncogenes) to be

produced through genetic insertion or to be “turned

on” by enzymes produced by other genes has given

rise to the now-proven theory that some cancers are

caused by infectious agents.7

In addition, retroviruses that attach to and invade

specific cells of the body, inserting themselves into

host genes and disrupting the normal DNA, can

create long-lasting changes in the host that may

eventually weaken overall immunity to diseases.

While such discoveries lend themselves well to a

better understanding of the pathological processes,

they also provide opportunities that may not be as

readily apparent for the development of sinister

weapons.

Immunity

It is now recognized that protection against respiratory challenge by pathogens may require that a

certain level of mucosal immunity be maintained.

Cytokines released by leukocytes and other cells are

extremely important in the development of the immune response; they modulate the differentiation

and division of hematopoietic stem cells, activate

lymphocytes and phagocytes, and are very much

involved in the development of humoral and cellmediated immunity. An understanding of the importance of cytokines in the immunological process,

as well as factors leading to immunopotentiation

and immunosuppression, could be applied practically to enhancement of vaccine efficacy or the prevention of release of potentially dangerous substances in the body.

These are just a few of the current immunological challenges in research. Advances in our understanding of immunomodulation allow for breakthroughs in cancer therapy or immunodeficient

states to be applied to the development of new protective strategies against a broad spectrum of

biowarfare agents. We can only speculate that future medical interventions will incorporate new

knowledge on such processes.

Antibiotic Resistance

It has been recognized for many years that the

uncontrolled use of antibiotics will promote the selective development of certain resistant strains of

many microorganisms. Bacterial agents may rely on

a variety of mechanisms to increase their virulence

or resistance to antibiotics: through more permanent chromosomal mediation; or through plasmids,

independently replicating extrachromosomal DNA

segments floating freely in the cytoplasm that are

capable of being ejected when antibiotic pressures

are absent. Modified biological agents with resistance factors may be unaffected by therapeutic and

chemoprophylactic regimens directed against sensitive organisms.

Biotechnology allows for the introduction of factors into many replicating organisms that would

promote resistance to antibiotics. With human

pathogens, concerns center on bacterial, viral, rickettsial, and fungal agents capable of causing acute

and chronic infections. An armamentarium of structurally different, broad-spectrum drugs, which have
Medical Aspects of Chemical and Biological Warfare

682

been developed to initiate their specific therapeutic effects via different mechanisms, will allow some

circumvention of the resistance threat.

Bioengineered Toxin Production

Taking bacterial organisms one step further, the

combination of a known pathogenic biological

agent with genes for producing toxin from another

organism spliced into it generates a series of potential issues, including the ability of the original

organism to retain enough of its previous pathogenicity; and its ability to replicate, spread, and produce enough toxin to cause symptoms. Although

this concept may sound intriguing, naturally occurring organisms that already produce toxins may

achieve the same desired effect. Recent experiences

with Escherichia coli 0157:H7 causing hemorrhagic

colitis and a hemolytic uremic syndrome as a result of consumption of contaminated meat demonstrate the devastating effect that the presence of a

shigalike toxin may have. Identification of specific

pathogens and their toxins require current technologies, including polymerase chain reaction and gene

probe technologies, to be readily available even in

a field setting.

A more worrisome concept involves the hybridization of two or more genes, such as combining

a toxin with a monoclonal or polyclonal antibody directed against specific target cells in the

body. Oncological immunotherapy is based on this

concept and is effective in treating several types of

cancers. While cancer therapy may depend on

strong affinity of molecules for specific receptors,

biological defense may favor deactivation of receptors or blocking of attachment. Molecular modeling would be helpful in understanding this phenomenon.

Genetic Weaponry

“Genetic warfare” has been raised as an issue,

whereby targeting of specific populations or individuals with specific genotypic characteristics could

theoretically be accomplished. Fortunately, although several replicating agents and toxins can

now be mass produced with relative ease, entirely

different types of biological agents are still difficult

to create. This may not be the case in the next century, where emerging pathogens will include biological agents.7,10

It has been postulated that “genetic weapons”

might very well be developed in the wake of increased knowledge about the human genome and

genetic diversity. We would hope that the development of genocidal agents is so repulsive a concept

that it would never be accepted by the international

community. Racial differences do exist with bloodgroup proteins and histocompatibility proteins, and

genetic susceptibilities to specific diseases have

been demonstrated. However, it has been estimated

that only 0.1% to 1% of the human genome can clearly

be associated with pure ethnic differences10; whether

this diversity is enough for the development of

tailored agents is an open question. And whether a

nation would find it necessary to specifically pursue a course to develop such targeted offensive

weaponry remains to be seen.

It is improbable that such weapons would pose

a serious threat to the forces of this nation, since

the population of the United States is more heterogeneous than more segregated homogeneous societies. It is unrealistic to consider this a real threat

anytime soon.

The Human Genome Project

The Human Genome Project, begun in the mid

1980s, has as its goal to have genetically sequenced

over 100,000 genes in the human genome by year

2005. The information will be placed in a gene bank

for international access.6,7,9 The Human Genome

Organization (HUGO) was established to coordinate the human genomic analyses being performed

internationally and to maintain the database repository of all sequence information. The purpose of the

project is to provide information on the chemical

structure of humans. This will allow for a better

understanding of hereditary diseases, the immune

response, and certain chronic diseases. An understanding of what constitutes a healthy state may

tempt proponents of offensive warfare to develop

agents that create a state of poor health in their enemies. This could be accomplished through minor

alterations in genes that control enzymatic actions

in the body or changes in genes that control other

genes. Although legal patent issues appear to be the

principal difficulty currently, nations that have provided data in the project will claim a right to have

access to all information.

New Medical Countermeasures

Advances in technology now allow for more

directed and coordinated approaches in vaccine

development against biological warfare agents

and endemic diseases. The development of combination vaccines that eliminate the need for multiple
Medical Challenges in Chemical and Biological Defense for the 21st Century

683

vaccinations is of practical importance to the

military. But efforts to increase the immunogenicity of vaccines—in particular, recombinant subunit vaccines that have traditionally been associated with lower antibody titer responses than

live attenuated vaccines—may result in the discovery of better adjuvants or slow-release formulations (eg, microencapsulation) that will result

in highly satisfactory and long-lasting immunological responses. Reversion of attenuated strains is

always a concern with live vaccines, although this

has not been shown to be a significant problem

up to now. Recombinant vector vaccines, including those against vaccinia, adenovirus, and Salmonella, also offer some safer prospects,11,12 but when

vaccines against specific biological warfare agents

are developed, the soldier’s immunological responses to other vaccines administered need to be

considered.

It is impossible to provide protection against

every conceivable agent, but it seems likely that future medical protective measures will need to be

more broadly based if they are to provide the best

protection against biowarfare agents in the future.

Current and future research must evaluate how to

best stimulate the immunological response that will

protect against categories of agents, while at the

same time ensuring that those agents highest on the

threat list are adequately covered.

As mentioned earlier, an understanding of the

role of the mucosal response is critical, especially

for protection via the respiratory or gastrointestinal tracts, as well as the importance of the humoral

versus the cell-mediated response. Antimicrobial

drug supplementation may also provide added benefit for immediate or short-term protection.

The abilities to develop monoclonal antibodies

against specific antigens and to be able to develop

transgenic animal models to form chimeras have

opened large windows of research opportunity.7

 For

example, the ability to microinject human genes into

the pronuclei of fertilized mouse eggs and replace

original genetic segments permits sophisticated animal models to be developed that can be used in challenge studies with specific infectious agents. The ethical animal-rights issues associated with creating and

using such chimeras in research are obvious, but the

opportunities for medical advancement are equally

certain. Although transgenic mice currently provide

little to new weapons development, they may be extremely helpful in the development of effective countermeasures. Transgenic plant research, leading to the

development of resistance to insects and plant diseases, is another extension of genetic research.

MILITARY SCENARIOS

The threat that chemical agents will be used by

hostile forces continues to be a military concern.

However, effective personal protective measures

and environmental detection systems will likely

provide satisfactory protection for the forces in

nearly all perceived scenarios involving agents described in earlier chapters of this textbook. Carefully

followed decontamination procedures will reduce the

possibility of further injury and allow medical personnel to render appropriate care to casualties.

Scenarios of the future may be complicated by

the possible use of multiple agents, or the delivery

of chemical and replicating agents and/or their toxins that have been carefully matched, based on their

stability and ability to generate specific symptoms.

Health effects could be potentiated. Therefore, from

a medical perspective, detection requires the availability of rapid diagnostic methods and procedures

to assess illnesses that will be the result of multiple

agents.

Stated another way, detecting the presence of one

single agent may not be adequate, since detectors

can detect only what they were designed to detect.

The classic chemical agents described earlier in this

textbook will be only part of the concern, for readily

available, highly toxic, industrial compounds that

are not under the same degree of international

monitoring as well-recognized chemical warfare

agents could be used as weapons.

The deployment of troops to foreign lands provides opportunities for biological and chemical incidents to occur. In 1993, the United States, along

with 71 other countries belonging to the United

Nations, contributed troops to over a dozen peacekeeping missions throughout the world. These deployments involved military medical elements from

different countries, but many of the smaller nations,

in particular, possess limited abilities to deal with

a nuclear, biological, or chemical warfare situation.

As of this writing (1996), no chemical or biological

warfare incidents have occurred during such peacekeeping missions, although sabotage and terrorism

have occurred.

Since the military has the greatest capability in

this country to address chemical and biological

warfare, the missions for the military have now included the domestic front. Military medical practitioners will very likely find it necessary to be famil-
Medical Aspects of Chemical and Biological Warfare

684

iar with the diagnosis, treatment, and prevention of

injuries and illness caused by chemical and biological agents, for we will frequently be consulted for

our expertise.

Biological warfare, in particular, is of great concern for the military for several reasons:

• Many potent agents are readily available.

Theoretically, any microorganism or toxin

capable of inflicting death or disease has the

potential of being adapted for use as a biological weapon.

• Naturally occurring infectious agents could

be used to generate epidemics among susceptible troops, creating confusing disease

situations on the battlefield. Naturally occurring or deliberately disseminated sporeforming microbes could continue to persist

in the environment, and some aerosolization might occur during military maneuvers; environmental detectors may not necessarily be able to differentiate between

natural and man-generated contamination.

• Many classic agents can be mass-produced

in a short time using very basic laboratory

techniques. Large fermenters may not be

necessary if a small amount of agent is all

that is required.

• Theoretically, biological agents can be genetically altered to escape detection.

• Biological agents require no precursors for

development, unlike chemical and nuclear

agents, and a covert program is much more

difficult to detect.

SUMMARY

The future requires that we carefully and continually assess the evolving threat from chemical

and biological weapons. This can be predicted with

certainty: the threat will change with time. As stronger countermeasures are developed by the United

States and its allies, the employment of certain

agents may become less appealing to adversaries

on the battlefield. From that standpoint, medical

countermeasures may be an effective deterrent. Biotechnology itself may be the threat of the future,

and not specific agents, as adversaries may attempt

to evade effective preventive measures with

bioengineering. The employment of multiple chemical and biological agents is a very likely scenario of

the future, thereby challenging the medical community to be much more proactive in its development

of appropriate countermeasures.

The missions of the United States military are

changing, and deployments will require a capability to address potential chemical and biological incidents on the domestic and international

fronts. Military medical personnel must, therefore,

be continually prepared to deal with such contingencies as we become an even more important asset to this nation’s defense and healthcare

structures.

REFERENCES

1. ter Haar B. The Future of Biological Weapons. New York, NY: Praeger; 1991.

2. House of Representatives, 102nd Cong, 2nd Sess. Report of the Special Inquiry Into the Chemical and Biological

Threat of the Committee on Armed Services. Washington, DC: US Government Printing Office; 23 Feb 1993.

3. Spertzel RO, Wannemacher RW, Linden CD. Global Proliferation—Dynamics, Acquisition, Strategies, and Responses.

Vol 4. In: Biological Weapons Proliferation. Alexandria, Va: Defense Nuclear Agency; September 1994. DNA Technical Report 93-129-V4.

4. Geissler E, ed. Biological and Toxin Weapons Today. Oxford, England: Stockholm International Peace Research

Institute, Oxford University Press; 1986: 135–137.

5. Roberts B, ed. Ratifying the Chemical Weapons Convention. Washington, DC: Center for Strategic and International Studies; 1994.

6. Friedman T. Molecular medicine. In: Davis BD. The Genetic Revolution. Baltimore, Md: The Johns Hopkins University Press; 1991.

7. Lee TF. Gene Future: The Promise and Perils of the New Biology. New York, NY: Plenum Press; 1993.
Medical Challenges in Chemical and Biological Defense for the 21st Century

685

8. Weiss R. Gene therapy at a crossroads. Washington Post. 18 Oct 1994;Health:12.

9. Drlica KA. Double-Edged Sword: The Promises and Risks of the Genetic Revolution. Reeding, Mass: Addison-Wesley;

1994.

10. Dubuis B. Recombinant DNA and Biological Warfare. Zurich, Switzerland: Institut für Militarishe Sicherheitstechnik;

October 1994.

11. Rabinovich NR, McInnes P, Klein DL, Hall BF. Vaccine technologies: View to the future. Science. 1994;265:1401–

1404.

12. Ellis RW, Douglas RG Jr. New vaccine technologies. JAMA. 1994;271:929–931.

RECOMMENDED READING

Roberts B, ed. Biological Weapons: Weapons of the Future? Washington, DC: The Center for Strategic and International Studies; 1993. This 101-page book is a collection of essays on various aspects of biological warfare and

covers in depth some of the concepts presented briefly in this chapter.

Bailey KC, ed. Director’s Series on Proliferation. University of California: Lawrence Livermore National Library;

1994. This 112-page book is a collection of essays compiled under a US Department of Energy contract (UCRLLR-11470-4) on various aspects of the biological warfare threat and proliferation. The document is available

from the National Technical Information Service, US Department of Commerce, 5285 Port Royal Road, Springfield, Virginia 22161.
Index

687

ACRONYMS AND ABBREVIATIONS

A

ABC: airway, breathing, and circulation

ABG: arterial blood gas

AC: hydrogen cyanide

ACh: acetylcholine

AChE: acetylcholinesterase

ADAPC: Alcohol and Drug Abuse Prevention and Control

AEF: American Expeditionary Force

AERP: Aircrew Eye/Respiratory Protection

agr: accessory gene regulator

AHF: Argentine hemorrhagic fever virus

AIT: Aeromedical Isolation Team

AMC: Army Materiel Command

AMEDD: U.S. Army Medical Department

ANTU: -naphthylthiourea

Ara-A: adenine arabinoside

Ara-C: cytosine arabinoside

ARDS: adult respiratory distress syndrome

AST: aspartate aminotransferase

ATA: alimentary toxic aleukia

ATCC: American Type Culture Collection

ATM: advanced trauma management

ATP: adenosine 5'-triphosphate

AUIB: Aircrew Uniform, Integrated Battlefield

A-V: atrial-ventricular

AVOG: Aviation Overgarment

AZT: azidothymidine

B

BAL: British anti-Lewisite

BALT: bronchus-associated lymphoid tissue

BAS: battalion aid station

BDO: battledress overgarment

BDRP: Biological Defense Research Program

BG: Bacillus globigii

BIDS: Biological Integrated Detection System

BL: Biosafety Level

BPL: -propiolactone

BuChE: butyrocholinesterase

BVO: Black Vinyl Overboot

BZ: 3-quinuclidinyl benzilate (now called QNB)

C

C: capsid protein

CA: bromobenzylcyanide

CaEDTA: calcium ethylenediaminetetraacetic acid

CAI: Chemical (Surety Material) Accident or Incident

CAIRA: Chemical Accident or Incident Response and

Assistance

CAM: Chemical Agent Monitor

CBPS: Chemical and Biological Protected Shelter

C-CHF: Crimean-Congo hemorrhagic fever virus

CCST: Chemical Casualty Site Team

CD: cluster of differentiation

CDAE: Chemical Defense Aircrew Ensemble

CDC: Casualty Decontamination Center

CDC: Centers for Disease Control and Prevention

CDTF: Chemical Decontamination Training Facility

CF: complement fixation

CG: phosgene

CHAMP: chemically hardened air-management plant

CHASE: Cut Holes and Sink ’Em

CHATH: Chemically Hardened Air Transportable Hospital

ChE: cholinesterase

CIA: Central Intelligence Agency

CK: cyanogen chloride

CMR: chloroform-methanol residue vaccine

CN: 1-chloroacetophenone

CN: chloroacetophenone

CNS: central nervous system

CONUS: continental United States

CP DEPMEDS: Chemically Protected Deployable Medical

System

CPAP: continuous positive airway pressure

CPE: collective protection equipment

CPFC: Chemical Protective Footwear Cover

CPOG: Chemical Protective Overgarment

CPRP: Chemical Personnel Reliability Program

CR: dibenz (b,f)-1:4-oxazepine

CS: 2-chlorobenzylidene malononitrile

CSEPP: Chemical Stockpile Emergency Preparedness Program

CSF: cerebrospinal fluid

CSH: Combat Support Hospital

CSI: Chemical Surety Inspection

Ct: the product of the concentration (in milligrams per cubic

meter of air) and the time (in minutes) of exposure to a gas

or aerosol

CWS: Chemical Warfare Service

CX: phosgene oxime

CYE: charcoal yeast extract

D

d: dalton

DA PAM: Department of the Army Pamphlet

DA: diphenylchlorarsine

DANC: Decontaminating Agent, Non-Corrosive

DAS: diacetoxyscripenol, also called anguidine

DC: diphenylcyanoarsine

DF: methylphosphonic difluoride

DFA: direct fluorescent antibody

DFP: diisopropyl fluorophosphate

DIC: disseminated intravascular coagulation

DISCOM: Division Support Command

DKIE: Decontamination Kit, Individual Equipment

DLCO: lung diffusing capacity for carbon monoxide

DM: diphenylaminearsine, also called adamsite

4-DMAP: 4-dimethylaminophenol

DMSO: dimethyl sulfoxide

DNA: deoxyribonucleic acid

DOVE: deoxyverrucarol

DP: diphosgene

DPRK: Democratic Peoples Republic of Korea

DS2: Decontaminating Solution 2

DU: Duty Uniform

E

EAC: Echelon Above Corps

ECG: electrocardiogram

ED50: effective dose (also called the incapacitating dose) for

humans for 50% of the population exposed

EDTA: ethylenediaminetetraacetic acid

EEE: eastern equine encephalitis

EEG: electroencephalogram
Medical Aspects of Chemical and Biological Warfare

688

ELISA: enzyme-linked immunosorbent assay

EMS: emergency medical services

F

FDA: U.S. Food and Drug Administration

FDECU: field deployable environmental control unit

FEMA: Federal Emergency Management Agency

FLD: Field Hospital

FLOT: forward line of troops

FM: Field Manual

FM: titanium tetrachloride

FMC: Field Medical Card

FSMC: Forward Support Medical Company

FTIR: Fourier Transform Infrared spectrometer

G

G: German (G-series agents)

GA: tabun

GABA: -aminobutyric acid

GALT: gut-associated lymphoid tissue

GB: sarin

GC–MS: combination of GLC and MS techniques

GD: soman

GF: cyclohexylmethylphosphonofluoridate

GH: General Hospital

GLC: gas–liquid chromatography

GVO: Green Vinyl Overboot

H

HC: hexachlorethane

HCN: hydrocyanic acid

HD: distilled mustard agent

HD: sulfur mustard

HEPA: high-efficiency particulate air (filter)

HFRS: hemorrhagic fever with renal syndrome

HHS: US Department of Health and Human Services

HI: hemagglutination-inhibition

HIV: human immunodeficiency virus

HMMWV: high-mobility, multipurpose, wheeled vehicle

HPLC–MS: high-performance liquid chromatography–mass

spectrometry

HPS: hantavirus pulmonary syndrome

HS: mustard agent

HSC: Health Services Command

HSS: Health Service Support

HTH: high-test hypochlorite

HUGO: Human Genome Organization

I

ICAM: Improved Chemical Agent Monitor

ICBPG: Improved Chemical and Biological Protective Glove

ID50: the dose that incapacitates 50% of the exposed population

ID: incapacitating dose

IFA: indirect fluorescent antibody

IFN- : interferon gamma

Ig: immunoglobulin

IL-6: interleukin-6

IMA: Installation Medical Authority

IMF: Installation Medical Facility

IMS: ion mobility spectroscopy

IND: Investigational New Drug

IRF: Installation Response Force

ISO: International Organization for Standardization (from the

French)

ITAR-TASS: Information-Telegraph Agency of Russia–

Telegraph Agency of the Soviet Union

J

JACADS: Johnston Atoll Chemical Agent Destruction

System

JSLIST: Joint Service Lightweight Integrated Suit Technology

K

KB: kilobase

kd: kilodalton

KTM: Kops Tissot Monro (mask)

L

L: Lewisite

LAC: Large Area Coverage

Lcr: low calcium response

LCt

50: the vapor or aerosol exposure (Ct, concentration •

time) that is lethal (L) to 50% of the exposed population

LD50: the dose (D) that is lethal (L) to 50% of the exposed

population

LDS: Lightweight Decontamination System

LOPAIR: long-path infra red

LPS: lipopolysaccharide

LSD-25: D-lysergic acid diethylamide

LSD: lysergic acid

LVS: live vaccine strain

M

MACOM: Major Army Command

MASH: Mobile Army Surgical Hospital

MAT: Medical Augmentation Team

MCAT: Medical Chemical Advisory Team

MCBW: mass casualty biological weapon

MCE: maximum credible event

MD: methyldifluorarsine

MDMA: 3,4-methylenedioxymethylamphetamine

MED50: the dose that is minimally effective for mild cognitive

impairment in 50% of the exposed population

MEDCEN: Medical Center

MEDCOM: Medical Command

MEDDAC: Medical Department Activity

MHC: major histocompatibility complex

MLRS: Multiple Launch Rocket System

MMPI: Minnesota Multiphasic Personality Inventory

MOA: Memorandum of Agreement

MOPP: mission-oriented protective posture

MOS: military occupation specialty

MOU: Memorandum of Understanding

MPE: most probable event

MRI: Medical Reengineering Initiative

mRNA: messenger RNA

MRT: Medical Response Team

MS: mass spectrometry

MTF: medical treatment facility

MULO: Multipurpose Overboot

N

NAD+: nicotinamide adenine dinucleotide

NALT: nasal-associated lymphoid tissue

NAPP: nerve agent pyridostigmine pretreatment

NATO: North Atlantic Treaty Organization

NBC: nuclear, biological, and chemical

NBCRS: Nuclear Biological Chemical Reconnaissance

System

NBC–PC: nuclear, biological, chemical protective covers

NF: Number Facility

NK: natural killer
Index

689

NRC: National Research Council

NYCBOH: New York City Board of Health

O

OG: Overgarment

OPA: isopropyl alcohol and isopropylamine solution

OPIDN: organophosphorus ester–induced delayed neurotoxicity

ORS: optical remote sensing

OTSG: Office of The Surgeon General

P

PADPRP: poly(ADP-ribose) polymerase

PAHP: p-aminoheptanoylphenone

PAO2 – Pa O2: alveolar–arterial difference in the partial

pressure of oxygen

PaO2: partial pressure of arterial oxygen

2-PAM Cl: 2-pyridine aldoxime methyl chloride, also called

pralidoxime chloride

PAOP: p-aminooctanoylphenone

PAPP: p-aminopropiophenone

PATS: Protection Assessment Test System

PCO2: partial pressure of carbon dioxide

PCR: polymerase chain reaction

PDA: Portable Decontamination Apparatus

PDDA: Power-Driven Decontamination Apparatus

PDS: personnel decontamination station

PEEP: positive end-expiratory pressure

PEG300: polyethylene glycol 300

PF: protection factor

PFIB: perfluoroisobutylene

PFT: pulmonary function test

pfu: plaque-forming units

PHA: passive hemagglutination assay

PO2: partial pressure of oxygen

ppb: parts per billion

PPE: personal protective equipment

ppm: parts per million

PPW: patient protective wrap

PR: protective ratio

PRN: plaque reduction neutralization

PS: chloropicrin

Q

Q: query

QDH/SS: Quick Doff Hood/Second Skin

QNB: 3-quinuclidinyl benzilate (current name for BZ)

R

RBC-ChE: red blood cell cholinesterase

RBC: red blood cell

RDIC: resuscitation device, individual, chemical

RFK: Richardson, Flory, and Kops mask

RIA: radioimmunoassay

RME: receptor-mediated endocytosis

RNA: ribonucleic acid

rRNA: ribosomal ribonucleic acid

RSCAAL: Remote Sensing Chemical Agent Alarm

RT-PCR: reverse transcriptase polymerase chain reaction

RVF: Rift Valley fever virus

S

SBR: small-box respirator

SCPE: Simplified Collective Protective Equipment

SDS: sodium dodecyl sulfate

SE: staphylococcal enterotoxins

SEB: staphylococcal enterotoxin B

SGOT: serum glutamic-oxaloacetic transaminase

SIPRI: Stockholm International Peace Research Institute

S-LOST: sulfur mustard, for Lommell and Steinkopf

SOP: standing operating procedure

SPE: streptococcal pyrogenic exotoxins

SRF: Service Response Force

SS: shotgun shell (bomb)

STB: super tropical bleach

T

TAP: toxicological agent protective (ensemble)

TB MED: Technical Bulletin Medical

TCDD: 2,3,7,8 tetrachlorodibenzo-p-dioxin

TEMPER: tent, extendable, modular, personnel

TEPP: tetraethyl pyrophosphate

THA: tetrahydroaminoacridine, also called tacrine

THC: tetrahydracannabinol

TLC: thin-layer chromatography

TLV: threshold limit value

TNF-alpha: tumor necrosis factor–alpha

TNF: tumor necrosis factor

TOCP: triorthocresyl phosphate

TPS: topical skin protectant

TrD: Trinidad donkey

TSS: toxic shock syndrome

TSST-1: toxic shock syndrome toxin–1

U

UNSCOM: United Nations Special Commission

USAMRICD: U.S. Army Medical Research Institute of

Chemical Defense, Aberdeen Proving Ground, Maryland

USAMRIID: U.S. Army Medical Research Institute of

Infectious Diseases, Fort Detrick, Frederick, Maryland

USAMRMC: U.S. Army Medical Research and Materiel

Command, Fort Detrick, Frederick, Maryland

V

V: venomous (V-series agents)

VEE: Venezuelan equine encephalitis

VHF: viral hemorrhagic fever

VIG: vaccinia immune globulin

VKA: vegetable killer acid

VKL: vegetable killer liquid

VPFRU: Vapor-Protective, Flame-Resistant Undergarment

VX: ethyl-S-dimethylaminoethyl methylphosphonothiolate

W

WBGT: wet bulb globe temperature

WEE: western equine encephalitis

WHO: World Health Organization

WP: white phosphorus

WRS: War Research Service

Y

Yops: Yersinia outer-membrane proteins

Z

ZOI: Zone of the Interior

Acronyms and Abbreviations
Index

691

INDEX

A

Aberdeen Proving Ground, Maryland, 398, 409–410

See also Edgewood Arsenal, Maryland

ABG

See Arterial blood gases (ABG)

Abortion

septic, in brucellosis, 516

Abrin, 610, 632

Abrus precatorius, 610, 632

AC

See Hydrogen cyanide (AC)

Acetaminophen, 627

Acetylcholine (ACh), 132–134, 136, 159, 647

Acetylcholinesterase (AChE), 131–132, 134, 182–184

Acetylene tetrachloride, 34

Acid hydrolysis, 355

Action potential, 133

Activated charcoal, 217, 362–363, 366, 370, 373, 670

Adamsite

See DM (diphenylaminearsine)

Additives, 122

Adenine arabinoside (Ara-A), 553

Adenosine triphosphate (ATP), 275, 383, 431

S-Adenosylhomocysteine hydrolase inhibitors, 552

Adenoviridae, 575, 683

Adrenaline, 132

Adrenergic nervous system, 132

Adsorbent materials, 354, 363–364, 370

Advanced trauma management (ATM), 326–327

Aedes albopictus, 563, 566, 568

Aedes dorsalis, 567

Aeromedical Isolation Team (AIT), 432, 434

Aeromonas, 609

Aerosol

definition, 248

detection, 383, 448

LCt

50 calculation, 606

LD50 calculation, 606

particle size, for biological agents, 440

Aerosolization, 121

of biological agents, 440–442

of toxins, 605–608, 612

See also Inhalational injury; specific agent

Aerosol vulnerability testing, 429

AERP system

See Aircrew Eye/Respiratory Protection (AERP) system

Afghanistan, 3, 67–68, 102, 104, 656–658, 665

Aflatoxins, 656, 662

African swine fever, 459

African viral hemorrhagic fever, 434

Agent Orange, 105, 297, 419

Agent Purple, 51

Agent X

See Botulinum toxins

Aging, of organophosphoryl–cholinesterase bond, 162, 182–

183, 230

AHF

See Argentine hemorrhagic fever (AHF)

Airborne toxic material

definitions, 248

See also Aerosol; Inhalational injury; specific material

Aircraft masks, 74

Aircrew Eye/Respiratory Protection (AERP) system, 369–370

Aircrew personal protective equipment, 368–370

Aircrew uniform, integrated battlefield (AUIB), 373

Air delivery

history, 28, 31, 34–35, 49–50

See also Aerosol; Inhalational injury; specific agent

Airplane smoke tanks, 31

AIT

See Aeromedical Isolation Team (AIT)

Alarms, 377–383

biological agent, 431

history, 23, 53, 60–62, 66–67

LOPAIR, E33 Area Scanning, 53

M8A1 Automatic Chemical Agent, 380–381

M21 Remote Sensing Chemical Agent (RSCAAL), 381

Portable Automatic Chemical Agent, 60–62

See also Detection

Alastrim, 543

Alexander, Stewart, 103

Algal toxins, 457, 609, 617

Alimentary toxic aleukia (ATA), 659, 667

Alkaline hydrolysis, 355

Allergic contact sensitivity, 238–239, 249, 314, 316–317

-Naphthylthiourea (ANTU), 638

Alphaviruses, 562

antigenic classification, 564–565

structure and replication, 569–570

See also Viral encephalitides; specific virus

Alphavirus virion, 569

Ambergard XE-555 Resin, 353

Ambulance exchange points, 331

AMEDD

See U.S. Army Medical Department (AMEDD)

American Civil War, 11, 13, 88, 416, 540

American Cyanamid Company, 38

American Type Culture Collection (ATCC), 463, 646

American University, 94

Amherst, Sir Jeffery, 416

Aminoglycosides, 518

Aminopyridines, 651

2-Amino thiazoline 4-carboxylic acid, 276

Amphetamines, 292

Amyl nitrite, 280

Angola, 69

Anguidine

See 4,15-Diacetoxyscripenol (DAS)

Animals

that harbor disease, 487–488, 514, 524, 527–528

transgenic research involving, 683

vaccines for, 434, 460, 464, 568, 576, 578

weapons directed against, 12, 16, 34–35, 37, 51, 60, 428–

429, 459–460

See also specific agent or animal

Animal venom toxins, 610, 650

Anthrax, 5, 467–475

in animals, 468–469

clinical manifestations, 471–472

cutaneous, 471–473

delivery, 442, 446

diagnosis, 473

epidemiology, 469

gastrointestinal, 472–473

history, 10, 16, 32, 42–44, 50, 68, 417–418, 420, 427, 431–432,

459, 468, 645

inhalational, 469, 471–473

lethality, 443–444, 456

occupational exposure, 468–469, 474
Medical Aspects of Chemical and Biological Warfare

692

oropharyngeal, 472–473

pathogenesis, 469–471

prophylaxis, 473–475

recent use, 4, 420–421, 452–453, 462, 464, 468

spore stability after production, 441

treatment, 473

vaccination, 73, 462, 468, 473–475

See also Bacillus anthracis

Anthraxin, 473

Antianimal weapons, 459–460

history, 12, 16, 34–35, 37, 51, 60, 428–429

See also specific agent or animal

Antibiotics

for anthrax, 473

for brucellosis, 518

cream/ointment, 214

for plague, 497–498

for Q fever, 531

resistance, 681–682

for tularemia, 507

See also specific antibiotic

Anticholinergics, 294–302

See also specific agent

Anticonvulsants, 154–155, 165, 187, 191, 279

See also specific drug

Antidote kits, 73

Antidotes

anticholinergic, 298–302

cyanide, 279–282

Lewisite, 102, 218, 220

nerve agent, 158–159, 329

self-administration, 329–331

See also specific antidote

Antigens

detection, 383, 517

viral, 541–542

Antihistamines, 627

See also specific drug

Antimaterial agents, 459, 461

Anti-O-polysaccharide antibody, 517

Antiplant balloon bomb, 51–52

Antiplant weapons, 460–461

history, 44, 51–52, 60, 427–429, 431

See also Defoliants; specific agent or plant

Antiricin antibody, 638–639

Antitoxins, 434, 632

Antitussives, 628

Antiviral drugs, 434, 598–599

See also specific drug

ANTU

See -Naphthylthiourea (ANTU)

Anxiety reactions

differential diagnosis, 297–298

Apodemus agrarious, 594

Ara-A

See Adenine arabinoside (Ara-A)

Arab–Israeli Six-Day War (1967), 57, 65

Arab–Israeli War of 1973, 3

Ara-C

See Cytosine arabinoside (Ara-C)

Arenaviridae, 575, 592–593

Argentine hemorrhagic fever (AHF), 592–593, 595–596, 599

Armstrong, George E., 428

Arrhythmias, 156, 165–166, 239, 253, 277

Arsenicals, 42, 198

See also specific agent

Artane

See Trihexyphenidyl

Arterial blood gases (ABG), 252

Arthur, Stanley, 73

Artificial ventilation

See Ventilatory support

Artillery shells, 120

Ascorbic acid, 671

ASC Whetlerite charcoal, 363

Ash, Charles A., 13

Aspartate aminotransferase (AST), 596

Aspergillus fumigatus, 429

Asphyxiation, 249

Aspirin, 597, 627

Assassinations

using biological weapons, 420–421, 446, 645

ASZ impregnated charcoal, 363–364

ATA

See Alimentary toxic aleukia (ATA)

ATCC

See American Type Culture Collection (ATCC)

Atelectasis, 252

Ativan

See Lorazepam

ATM

See Advanced trauma management (ATM)

ATP

See Adenosine triphosphate (ATP)

AtroPen, 155, 159–160, 169

Atropine sulfate, 159–162

administered in absence of nerve agent intoxication, 160

cardiovascular effects, 156, 160, 165

contraindications, 167

decrease in sweating caused by, 160

for dermal exposure, 161–162

dosage and administration, 160–161, 169

and endurance time in protective gear, 394

history, 47, 54, 60, 131, 291

ID50, 295

as incapacitating agent, 294–295, 299

for inhalational exposure, 161

injectors, 54, 73, 155, 159–161, 169

LD50, 295

for nausea and vomiting, 168

and nerve agent cardiovascular effects, 156

and nerve agent–induced seizures, 154–155

and nerve agent pretreatments, 184–187, 191

pulmonary effects, 148–149, 158

topical ocular administration, 147, 166–167, 215

Attack measures

for medical support, 328

AUIB

See Aircrew uniform, integrated battlefield (AUIB)

Aum Shinrikyo, 4, 75, 113, 118, 131, 169, 274, 342, 438, 463, 678

Aura virus, 566

Australia, 460

Autoclaving, 358

Autoinjectors, 54, 73, 155, 159–161, 163–165, 169, 252, 341

Autoinoculation

and vaccinia vaccination, 548–549

Automatic Chemical Agent Alarm

M8A1, 380–381

Automatic G-Agent Field Alarm, 53

Automatic G-Agent Fixed Installation Alarm, 53

Autonomic nervous system

effects of cyanides on, 277

Aviator’s masks, 74

Avipoxvirus, 542

Azidothymidine (AZT), 639

Azithromycin, 531
Index

693

B

Bacillus anthracis, 383, 439, 468–469, 474

See also Anthrax

Bacillus globigii, 43, 60, 429

Bacillus subtilis, 428

Bacitracin, 214

Bacteria

possible biological warfare agents, 439

See also Biological agents; specific agent

Bacterial toxins, 609, 647

See also specific toxin

Bacterium tularense

See Francisella tularensis

Badoglio, Pietro, 34

Baker, Newton D., 25

BAL

See British anti-Lewisite (BAL)

Baldwin Report, 427–428

“8-Ball,” 428

Bang, B., 514

Barbiturates, 293, 302

Bari mustard disaster (Italy), 40, 103–104, 200

Barmah Forest virus, 565

Barrier nursing procedures, 432–433, 598

Barton, Samuel, 13

Base-ejection devices, 120–121

Battalion aid station (BAS), 327, 329, 331, 335

Battledress overgarment (BDO), 371, 373

Battledress uniform (BDU), 373, 669

Battlefield health service support, 326–328

Bedbugs, 487

Bell, Sir Charles, 105

Belladonna, 289–290, 294–295, 297–299

Benactyzine, 159, 187

Benenson, Abram S., 428

Benzilate, 295

Benzodiazepines, 302

Berlin Blockade, 47

Berthollet, Claude Louis, 10

-Propiolactone (BPL), 597

Bhopal disaster (India), 119

Bicuculline, 154–155

BIDS

See Biological Integrated Detection System (BIDS)

BIGEYE bomb, 65–66, 71

Binary weapons programs, 65–66, 70–72, 75, 104

Biological agents

aerosolization, 440–442

availability or ease of production, 438–439, 457, 678

containment precautions, 430, 432–434

decontamination, 357–358

defense against, 1–6, 425–435, 438, 443–446, 677–684

delivery systems, 121, 420–421, 429, 438–442, 446, 457, 656,

658–659

detection, 74, 377, 382–384, 431, 447–449

differential diagnosis, 438, 448–449

dispersal, 5

dual use, 679

ease of dissemination, 440, 457

enhanced pathogenicity, 680–681

epidemiological surveillance, 448

field testing in U.S., 429

genetic recombination, 681

ideal, requirements for, 438–441

incapacitation caused by, 292, 431, 439–440

incubation periods, 439

infectivity, 680–681

inhalational injury, 440

introduction to, 4–6

laboratory testing, 448–449

lethality, 439–440, 444

nonmilitary sources, 5–6, 10

nonreplicating, 4–5

occupational exposure, 398–399, 402–408, 432, 434

patient isolation procedures, 432–433

protective equipment against, 431, 447–448

replicating, 4–5

risk of transmission to medical staff, 356

stability after production, 441

susceptibility and nonsusceptibility, 441

vaccines, 60–61, 73, 434, 441, 460, 462, 681–683

virulence, 681

See also specific agent

Biological bombs, 32–33, 44, 51–52, 59, 441–442, 444

Biological defense equipment, 431

Biological Defense Research Program, 434–435

Biological Integrated Detection System (BIDS), 74, 377, 382–

384, 448

Biological warfare

attempts to control, 13, 419–420, 678–679

Cold War, 50–52, 55, 58–60, 420–422, 426, 430, 656

definition, 10

early proposals and usage, 12, 88, 416–417

history, 9–75, 87–105, 415–422

indications of possible attack, 448–449

and military healthcare provider, 6, 445, 447, 683–684

pre–World War I, 10–13, 88–90

psychological factors, 445

1920s, 28–29

1930s, 31–33

1960s, 58–60, 104–105

1970s, 64, 67–68, 104–105, 420–421

1990s, 74–75, 104–105, 420–422

strategic and tactical concerns, 445–446, 456–458

threat, 451–464, 683–684

unconventional/clandestine use, 442, 446–447, 458

World War I, 16, 21–22, 90–97, 417, 446, 459, 540

World War II, 36–37, 42–44, 103–104, 417–419, 426–427, 446,

483–485, 540, 632, 644–645

Biological Warfare Convention, 64, 67

Biological weapons

advantages and disadvantages, 442–445, 456–459, 684

demilitarization, 431–432, 525, 564

nations with capability for use, 679

nonhuman targets of attack, 434, 459–461

versus nuclear and chemical weapons, 458–459

proliferation, 456–459, 678

use, 437–449

Biological Weapons Anti-Terrorism Act, 75, 633

Biological Weapons Convention, 419–420, 422

compliance, 432, 435, 455, 458, 462–463, 679

and Soviet biological warfare program, 4, 452–453, 455–456

Third Review Conference, 453

and toxin definition, 604, 608

Trilateral Agreement, 455

and U.S. biological warfare program, 426

Biopreparat, 454

Biosafety levels, 430, 432–434, 597

Biotechnology, 678–683

and nerve agent pretreatments, 192–193

Birds

viral encephalitides carried by, 567, 573

Blackburn, Luke, 12

Black Death, 481–482, 487, 495

Blackford, William W., 11
Medical Aspects of Chemical and Biological Warfare

694

Black Plague, 416

Black vinyl overboot (BVO), 374

Bleach

See Hypochlorite solution

Bleaching powder, 22–23, 33–34, 54

Bleeding

in viral hemorrhagic fevers, 597

Blood–brain barrier permeability

and nerve agent pretreatments, 187, 191

Blood cell counts, 497, 506, 530, 635

Blood cholinesterases, 132, 136–139

Blue-X, 3

BN 52021, 670

Boer War, 11

Bolivian hemorrhagic fever, 593, 595–596, 599

Bombs

biological, 32–33, 44, 51–52, 59, 441–442, 444

chemical, 28, 40, 49–50, 59, 65–66, 71

See also specific type of bomb

Bone disease, 215–217, 517

Boots

protective, 373–375

Botulinum toxins, 5, 643–652

and assassination of Reinhard Heydrich, 645

crystalline, 644

decontamination, 616

detection, 383

dual use, 457

genetics, 647

history, 32, 43, 417, 421, 427, 644–645

lethality, 608

mechanism of action, 609–611, 647–649

military significance, 644

recent use, 462–463

relation to other bacterial toxins, 647

serology, 646

stages of toxicity, 648

versus tetanus toxin, 646

treatment, 611

vaccination, 73, 462, 644, 651

Botulism, 646

clinical manifestations, 649–650

diagnosis, 650

differential diagnosis, 574, 613–614

infant, 644, 646

inhalational, 647, 649–650

pathogenesis, 647–649

treatment, 616, 651–652

wound, 644

Bouquet, Henry, 12

Boynton, E. C., 11

BPL

See -Propiolactone (BPL)

Bradley, Tom, 461

Bradycardia, 156–157

Brain lesions

nerve agent–induced, 154–155, 187

Brazil

hemorrhagic fever outbreak, 593

Breathing difficulties

with mask use, 365, 403

nerve agent–induced, 145, 147–149, 158, 167–168, 170

and toxic inhalational injury, 255

See also Ventilatory support

The Breeders, 461

Brefeldin-A, 639

Brevetoxins, 609

Bristol-Myers Squibb Oncology Division, 237

British anti-Lewisite (BAL), 102, 218, 220, 261

British anti-Lewisite (BAL) Eye Ointment, 42

British smoke grenade, 262

Bromine, 273

Bronchiectasis, 211–212, 215, 238

Bronchitis, 211, 238, 253, 257

Bronchoconstriction, 148–149, 158

Bronchodilators, 253, 257

Bronchospasm, 250, 253, 257

Brown, Frederic, 93, 96

Bruce, David, 10, 514

Brucella, 383, 514–515

See also Brucellosis

Brucella abortus, 514, 516, 518

Brucella canis, 514–515, 517–518

Brucella endocarditis, 517–518

Brucella melitensis, 514–518

Brucella neotomae, 514

Brucella ovis, 514

Brucella suis, 51, 429, 514–515, 517

Brucellosis, 5, 513–519

clinical manifestations, 516–517

diagnosis, 517–518

differential diagnosis, 574

epidemiology, 515

history, 10, 43–44, 417, 427, 429–430, 514

lethality, 444

pathogenesis, 515–516

prophylaxis, 518

treatment, 518

See also Brucella

Bubo aspiration, 495

Bubonic plague, 480, 486, 491–492, 497

BuChE

See Butyrocholinesterase (BuChE)

Buddy-aid, 155, 159, 161, 165, 166

and chemical workers, 407, 409–410

Bulk-release munitions, 120–121

Bullene, Egbert F., 48, 50

Bunyaviridae, 575, 592–594

Burnet, MacFarlane, 525

Burns

CS-induced, 313

mustard, 98–100, 202, 205–208, 214, 238, 342–343

thermal, 343

Burroughs Wellcome Co., 214, 552

Bush, George, 72, 74, 117, 455, 462

Butyl rubber aprons, 329, 332

Butyl rubber gloves, 356–357

Butyl rubber masks, 364–365, 369–370

Butyl rubber overgarments, 370

Butyrocholinesterase (BuChE), 132, 136–139, 192, 301

Butyrophenones, 293

Butyrylcholine, 132, 134

BVO

See Black vinyl overboot (BVO)

BZ (3-Quinuclidinyl benzilate), 5, 119, 159, 294–296

anticholinergic delirium produced by, 296

chemical structure, 295

clinical pharmacology, 295–296

delivery systems, 121

history, 5, 57–59, 291

ID50, 295

MED50, 296

treatment, 298–302

C

CA (bromobenzylcyanide), 320
Index

695

Caffeine, 292

CAI

See Chemical (Surety Material) Accident or Incident (CAI)

CAIRA

See Chemical Accident or Incident Response and Assistance (CAIRA)

Calabar bean, 130, 298

Calamine, 670

Calcium ethylenediaminetetraacetic acid (CaEDTA), 261

Calcium hypochlorite

See Hypochlorite solution

Calomys colosus, 592

CAM

See Chemical Agent Monitor (CAM)

Cambodia

See Kampuchea

Camp Detrick

See Fort Detrick, Maryland

Camphor, 670

Camp Terry, Plum Island, New York, 460

Canada, 32, 427

Canister mask arrangement, 364, 366–369

Cannabinoids, 297–298

Canvas Trench Fan, 22–23

Capripoxvirus, 542

Capsaicin, 316

Carbamates, 130, 132, 134, 183–184

See also specific agent

Carbamoylation, 184

Carbaryl

See Sevin

Carbon tetrachloride, 199, 201, 310

Carbonyl chloride

See Phosgene (CG)

Carcinogenesis

and mustard exposure, 217, 237–238

Cardiovascular effects

of brucellosis, 517–518

of cyanides, 277

of mustard, 217

of nerve agents, 145, 155–157, 165–166, 169

of Q fever, 528

of riot control agents, 315, 321

of staphylococcal enterotoxin B, 626

of toxic inhalational injury, 252–253

of viral hemorrhagic fevers, 596

Carus, W. Seth, 458

Cassava, 273–274

Castor beans, 610, 632–633, 635

Castor oil, 610, 632, 636

Casualty arrival point, 331–332

Casualty decontamination, 329, 331–335, 340–341, 352, 386–

387, 408–410

Casualty Decontamination Center (CDC), 329

Casualty-receiving area, 331–335

Cats, 487–488

Cat scratch disease, 495–496

Cattle, 417, 459–460, 548

Cavanaugh, Dan C., 483

CB Pressurized Pod, 67

CBPS

See Chemical and Biological Protected Shelter (CBPS)

C-CHF

See Crimean-Congo hemorrhagic fever (C-CHF)

CCST

See Chemical Casualty Site Team (CCST)

CD

See Cluster of differentiation (CD)

CDAE

See Chemical defense aircrew ensemble (CDAE)

CDC

See Casualty Decontamination Center (CDC); Centers for

Disease Control and Prevention (CDC)

cDNA

See Complementary DNA (cDNA)

CDTF

See Chemical Decontamination Training Facility (CDTF)

Cefazolin, 473

Ceftriaxone, 497

Centers for Disease Control and Prevention (CDC), 540, 551–

552, 596, 626, 651

Central Intelligence Agency (CIA), 428, 454, 456–457, 461–462

Central nervous system effects

of brucellosis, 517

of cyanides, 277

of mustard, 212, 239

of nerve agents, 145, 149–155, 170, 233–234

of Q fever, 529–530

in toxic inhalational injury, 254

of viral encephalitides, 571–574, 576

Centro Chemico Militaire, 29

Cephalosporium, 656

Cephalothin, 473

Cerebrospinal fluid (CSF) examination, 576

CF

See Complement fixation (CF)

CG

See Phosgene (CG)

Chad, 69

CHAMP

See Chemically Hardened Air-Management Plant

(CHAMP)

Chancroid, 495–496

CHASE (Operation Cut Holes and Sink ’Em), 62–64

CHATH

See Chemically Hardened Air Transportable Hospital

(CHATH)

ChE

See Cholinesterase (ChE)

Chemical accident/incident response and assistance, 409–411

Chemical (Surety Material) Accident of Incident (CAI), 409

Chemical Accident or Incident Response and Assistance

(CAIRA), 409–411

Chemical agent monitor (CAM), 70, 378–379

decontamination certification with, 355–357

and medical management, 332, 335

Chemical agents, 4–6, 10, 18–19, 22–24, 27, 29–31, 34–35, 37–

39, 41, 52–53, 57, 62–63, 66–69, 72–74, 118–119

defense against, 1–6, 677–684

definition, 398

demilitarization, 115, 117, 411–412

detection, 377–381

deterrents to use, 6

dispersal, 5

incapacitation caused by, 292

lethality, 607

nonmilitary uses, 5–6, 115–116, 679

nonpersistent, 5, 122–123

offensive use, 112–117

persistent, 5, 122–123, 157

physical properties, 122–123

release, See Delivery systems; specific system

review of effects, 341–344

storage, 411–412

volatility, 122–123

See also specific agent
Medical Aspects of Chemical and Biological Warfare

696

Chemical and Biological Protected Shelter (CBPS), 385

Chemical bombs, 28, 40, 49–50, 59, 65–66, 71

Chemical casualties

advising agencies for treatment, 398

with combined injuries, 340, 347–348

decontamination, 329, 331–335, 340–341, 352

diagnosis, 112, 124

field management, 325–336

first aid for, 329–332

medical management, 124–125, 329

World War I, 6, 24, 91–92, 100–101, 200, 205

Chemical Casualty Site Team (CCST), 410

Chemical Corps

biological warfare programs, 430

creation of, 45

post–World War II programs, 46–47

1950s programs, 47–55

1960s programs, 55, 57–62

1970s programs, 64–68

1980s programs, 68–72

See also Chemical Warfare Service (CWS)

Chemical decontamination methods, 158, 354–355, 357–358,

363

Chemical Decontamination Training Facility (CDTF), 71

Chemical defense aircrew ensemble (CDAE), 373

Chemical defense equipment, 124

aircrew, 368–370

and chemical warfare capability, 113

Cold War, 52–53, 60–62, 67, 69–70

developmental, 375

early, 12–13

ground crew, 365–368

individual, 363–377

joint service use, 362, 375

and medical personnel, 329, 331–332, 334, 338, 340–341

post–World War II, 47

1920s, 27–28, 101–102

1930s, 33–34, 101–102

1960s, 60–62

1980s, 69–70

1990s, 74

World War I, 15–18, 22, 91–94, 363–364, 393

World War II, 37, 40–43, 103, 365, 394

See also Collective protection; Masks; Mission-oriented

protective posture (MOPP); specific item

Chemically Hardened Air-Management Plant (CHAMP), 385

Chemically Hardened Air Transportable Hospital (CHATH),

385

Chemically protected deployable medical system (CP

DEPMEDS), 384

Chemical Personnel Reliability Program (CPRP), 399–402

baseline data for future exposures, 404

periodic medical examinations, 404–406

preplacement examination, 403–404, 406

screening/evaluation, 399–404

termination examination, 405

Chemical protective footwear cover (CPFC), 374

Chemical protective glove set, 374–375

Chemical protective overgarment (CPOG), 373

Chemical rockets, 40, 58–59, 62, 71

Chemicals in War (Prentiss), 123

Chemical Stockpile Emergency Preparedness Program

(CSEPP), 409

Chemical Surety Inspection (CSI)

documentation, 400–402

Chemical surety material

definition, 399, 402

Chemical surety mission

civil–military relations and, 408–411

definition, 398

duty positions, 399–402

healthcare and, 397–412

Chemical threat

definition, 112

and enemy capability, 113–114

Chemical warfare

attempts to control, 13, 115, 117, 411–412, 678–679

capability for, 113–117

definition, 10

early proposals and usage, 11–12, 88

future, 125–126

history, 9–75, 87–105

and military healthcare provider, 6, 111–126, 328–335, 683–

684

pre–World War I, 10–13, 88–90

1920s, 25–29, 101–102

1930s, 29–36, 101–102

1950s, 47–55, 104–105

1960s, 55–64, 104–105

1970s, 64–68, 104–105

1980s, 68–72, 104–105

1990s, 72–75, 104–105

training, 48, 55–56, 71–72, 94, 124

World War I, 13–25, 90–97, 290

World War II, 36–47, 103–104, 125, 131, 200, 290

Chemical Warfare in Southeast Asia and Afghanistan (Haig), 68

Chemical Warfare Review Commission, 70

Chemical Warfare School, 26, 29, 35, 48, 71

Chemical Warfare Service (CWS)

biological warfare programs, 426, 428, 632

creation of, 18–19, 95

permanent establishment of, 25–27

post–World War II demobilization, 45

1920s programs, 27–29

1930s programs, 29–31

World War I programs, 19–22

World War II programs, 37–44

See also Chemical Corps

“Chemical warfare threshold,” 117

Chemical weapons

nations with capability for use, 114, 116, 679

versus nuclear and biological weapons, 458–459

proliferation, 114–118

reduction or elimination, 115, 117, 411–412

tactical and strategic use, 120–125

versus toxin weapons, 605, 607

Chemical Weapons Convention, 75, 115, 117, 679

Chemical workers

health education for, 407–410

health surveillance for, 402–405

Chest radiography

and inhalational injury, 252, 259–261, 264

and pneumonic plague, 494

and Q fever, 530

and tularemia, 506

Chickenpox

versus smallpox, 546

Chikungunya virus, 562, 578

Chile, 463

China

biological warfare program, 461–462

Japanese invasion of, 35–36, 200, 218, 417–418, 485

Chipmunks, 487–488

Chlamydia trachomatis, 496
Index

697

Chloramphenicol, 473, 497, 507

Chloride of lime

See Hypochlorite solution

Chlorine (Cl), 118, 255–257

clinical effects, 256

history, 5, 11, 14–15, 27, 88–93, 95, 119, 248

long-term health effects, 257

physical properties, 255–256

treatment, 256–257

1-Chloroacetophenone

See CN (1-Chloroacetophenone)

2-Chlorobenzaldehyde, 315

Chlorobenzene, 201

o-Chlorobenzylidene malononitrile

See CS (o-Chlorobenzylidene malononitrile)

Chloroform, 11

Chloroform–methanol extraction (CMR vaccine), 532

Chloropicrin (PS), 10, 12, 19, 27, 201

Chlorosulfonic acid

See Sulfur trioxide–chlorosulfonic acid (FS smoke)

Chlorpromazine, 280, 302

Cholecalciferol, 498

Cholera, 10, 12, 16, 33, 37, 42, 417–419, 462

Cholinergic nervous system, 132–134

Cholinesterase (ChE), 130–139, 159

Cholinesterase (ChE) inhibitors, 130–142, 164, 236

See also Nerve agents; Organophosphorus compounds;

specific agent

Chromium, hexavalent (CrVI), 363

Chronic pulmonary disease, 237–238

Churchill, Winston, 14, 125, 418, 427

CIA

See Central Intelligence Agency (CIA)

Cigarettes

Teflon-contaminated, 265–266

Cigarette smoke

cyanide content, 273

Cigarette smoking

and toxic inhalational injury, 250

Cimex lectularius, 487

Ciprofloxacin, 473

Civil defense program

and biological warfare, 434–435, 446

World War II, 41

Civil disturbances

riot control agent use during, 309–310, 313

Civilian resources

training, 409–410

Civil–military relations

and biological defense program, 434–435

and chemical surety mission, 408–411

CK

See Cyanogen chloride (CK)

Clean Air Act, 412

Clean treatment area, 331, 333, 335

Cleghorn, G., 514

Clethrionomys glareolus, 594

Clindamycin, 473

Clinton, William, 455

Clostridium botulinum, 644, 646–647

See also Botulinum toxins; Botulism

Clostridium difficile, 463

Clostridium perfringens, 421

Clostridium tetani, 644, 646–647

See also Tetanus toxin

Clothing decontamination, 358, 408

Cluster of differentiation (CD), 542, 622

CMR

See Chloroform–methanol extraction (CMR vaccine)

CN (1-Chloroacetophenone), 27, 119, 292, 309–310, 316–321

Cobalt salts, 281

Cocaine, 292

Coccidioides immitis, 429

Coccidioidomycosis, 429, 431

Cochrane, Thomas, 88

Codeine, 628

Cold War, 47–64

binary weapons programs, 65–66, 70–71

biological warfare programs, 50–52, 55, 58–60, 420–422,

426, 430, 656

detection developments, 53–54, 60–62, 66–67, 70

nerve agent production and development, 49

offensive chemical agent developments, 49–50, 57–59

protective device developments, 52–53, 60–62, 67, 69–70

Soviet threat, 54–55

Collective protection, 384–386

developmental, 386

history, 33, 42, 60, 67, 70

medical systems, 384–385

for military vehicles, 67

preattack measures, 328

Collective protection equipment (CPE)

M28, 384

Colorado beetles, 418

Combat lifesaver, 327, 339

Combat medic, 327, 339

Combat Service Mask, 41

Combat Support Hospital (CSH), 328

Combat vehicle filtration protection system, 368

Combat Vehicle Mask, 70, 74

Combined injuries, 340, 347–348

See also Wounds

ComboPen, 155, 163–165

Committee on Biological Warfare, 427

Complementary DNA (cDNA), 569

Complement fixation (CF), 531, 573

Compound W

See Ricin toxin

Conjunctivitis, 98–99, 208, 210, 214–215, 238, 314

Contact lenses

and protective masks, 402–403

Containment precautions, 430, 432–434

Contamination

of medical equipment and facilities, 124–125, 157, 353, 357

wound, 124, 347–348, 356

Continental United States (CONUS), 326, 328

Convention on Prohibition of Bacteriological and Toxin

Weapons

See Biological Weapons Convention

Convulsions, 154–155, 158, 165, 187, 239

Copper oxide, 363

Coquilletdia, 566

Corneal damage, 210, 238, 317

Corticosteroids, 598

Corynebacterium diphtheriae, 647

Cotton lung disease, 659

Cough suppressants, 628

Counterterrorism, 75

Cowpox, 548

Cows, 417, 459–460, 548

Cox, Herald, 525

Coxiella burnetii, 430, 524–526, 528–529

See also Q fever

Coyotes, 488
Medical Aspects of Chemical and Biological Warfare

698

CP DEPMEDS

See Chemically protected deployable medical system (CP

DEPMEDS)

CPE

See Collective protection equipment (CPE)

CPFC

See Chemical protective footwear cover (CPFC)

CPOG

See Chemical protective overgarment (CPOG)

C protein, 570

CPRP

See Chemical Personnel Reliability Program (CPRP)

CR (dibenz(b,f)-1:4-oxazepine), 319–320

Crackles, 251, 343–344

Crick, Francis, 679

Crimean-Congo hemorrhagic fever (C-CHF), 439, 593–596,

599

Crimean War, 11, 13, 88

Crimes Involving Poisons, 463

CRM-197, 648

Cross-neutralization tests, 573–574

Crotocin, 665

CS ( o-Chlorobenzylidene malononitrile), 119, 292, 310–316

cardiovascular effects, 315, 321

chemical structure, 310

clinical effects, 310–316

delivery systems, 121

dermatological effects, 312–314, 320–321

future use, 321

gastrointestinal effects, 314–315

history, 5, 310, 313

metabolic effects, 315

mutagenic effects, 315–316

nations with capability for use, 114

ocular effects, 314, 321

physical characteristics, 310

properties, 309

pulmonary effects, 311–312, 321

severe medical complications from, 317–318

tolerance to exposure, 310–311

CSEPP

See Chemical Stockpile Emergency Preparedness Program

(CSEPP)

CSF examination

See Cerebrospinal fluid (CSF) examination

CSH

See Combat Support Hospital (CSH)

CSI

See Chemical Surety Inspection (CSI)

Ct

definition, 142, 202, 249–250

Cuba, 657

Cui-xing-ning, 191

Culex taeniopus, 567

Culex tarsalis, 563–564, 566

Culiseta melanura, 563, 566, 573

Cunningham, Roy, 461

Curare, 647

CWS

See Chemical Warfare Service (CWS)

Cyanate, 276

Cyanides, 118–119, 271–282

antidotes, 279–282

biochemical basis for poisoning, 274–276

and combined injuries, 348, 355

and CS-caused deaths, 315

decontamination, 279

detection, 380

food poisoning with, 463

food sources, 273–274

history, 5, 119, 273–274, 447

laboratory findings, 278

military uses, 273

nonmilitary uses, 273–274

pharmacokinetics and pharmacodynamics, 276

poisoning presentation and management, 277–279, 342

properties, 272

prophylactic drugs, 281–282

toxicity, 276

triage considerations, 342, 344–347

and wound decontamination, 355–356

See also specific agent

Cyanogen bromide, 273

Cyanogen chloride (CK), 118, 272–282

detection, 380

history, 10, 16, 38, 40, 273–274

properties, 272

toxicity, 276

Cyanohydrin-forming drugs, 282

Cyanomethemoglobin (CNMetHb), 275, 280

Cyclohexyl alcohol, 185

Cyclopentolate, 146

Cyclophosphamide, 528

Cynomys species, 487

Cyprus, 524

Cystathionase, 275

Cytochrome oxidase, 274, 280

Cytokines, 681

Cytolysins, 609

Cytosine arabinoside (Ara-C), 553

Cytoxan, 237

D

DA (diphenylchlorarsine), 319

Dakin’s solution

See Hypochlorite solution

Dalden Corp., 374

DANC

See Decontaminating Agent, Non-Corrosive (DANC)

DAS

See 4,15-Diacetoxyscripenol (DAS)

Davaine, Casimir-Joseph, 10

da Vinci, Leonardo, 11–12

Davis, Gordon, 525

Davy, Humphry, 10

DC (diphenylcyanoarsine), 319

DDT

See Dichlorodiphenyltrichloroethane (DDT)

Dead-space ventilation, 364

Decontaminable litter, 389

Decontaminating Agent, Non-Corrosive (DANC), 34, 62

Decontaminating Apparatus, 62, 70

Decontaminating Solution 2 (DS2), 62, 374, 388

Decontamination, 351–358, 362

biological agents, 357–358

casualty, 329, 331–335, 340–341, 352, 386–387, 408–410

certification, 355

chemical methods, 158, 354–355, 357–358, 363

clothing, 358, 408

definition, 352, 357

equipment, 124–125, 353, 357, 387–388

eyes, 352–353

history, 22–24, 33–34, 42, 47, 54, 62, 70, 97–98

importance, 157, 329

and inhalational injury, 252
Index

699

methods, 354–355

nerve agents, 47, 157–158, 168–169, 354–355, 387

by oxidative chlorination, 354–355

personal (self-), 157, 329–330, 352

personnel, 352, 386–387

personnel requirements for, 335

physical methods, 354, 358, 363–364, 370

skin, 157–158, 333, 335, 352–353, 356, 386–387, 408, 669–670

spot, 333, 341, 353

surgical instruments, 357

time required for, 333, 335, 341

toxins, 616, 660, 669–670

training, 352, 387, 408

vapor, 352, 356

wounds, 352, 355–357, 387

See also specific agent or method

Decontamination apparatus/systems, 62, 70, 97–98, 388

Decontamination area, 332–333, 335, 409

Decontamination equipment, 386–389

Decontamination Kit, Individual Equipment (DKIE)

M295, 387–388

Decontamination kits, 158, 335, 353–354, 387–388

Deer mice, 487–488

DEET (diethyltoluamide), 191

Defense Research Establishment, Ottawa, Canada, 658

Defoliants, 119

history, 44, 51, 56, 60, 62, 104, 419, 428

Dehydration

and protective clothing use, 370–371, 406–407

Deliriants, 294

See also specific agent

Delirium

anticholinergic-induced, 296, 298–301

Delivery systems, 120–122

biological agents, 121, 420–421, 429, 438–442, 446, 457, 656,

658–659

and chemical warfare capability, 114, 116

and choice of agent, 123

history, 27, 31, 36–37, 39–40, 51–52, 58–59

vapor, 121–122

weather conditions and, 122–123, 125

See also specific system

de Mussis, Gabriel, 416

Demustardizing Apparatus, Commercial Type, 33

Dendrochium toxicum, 659

Dengue hemorrhagic fever, 593–596, 598–599

Deoxynivalenol (DON), 659–661, 668

Deoxyribonucleic acid (DNA), 515, 660–662, 679

alkylation, 203, 239

complementary, 569

Deoxyribonucleic acid (DNA) viruses, 540–541

Deoxyribonucleoproteids, 541

Deoxyverrucarol (DOVE)–protein conjugate, 671

Department of Defense Appropriation Authorization Act, 66–

67

Department of Defense Biological and Chemical Defense

Planning Board, 430

Depressants, 293

See also specific agent

Dermal effects

of anthrax, 471–473

of Lewisite, 219

of mustard, 201–202, 205–210, 214, 217, 238–239, 342–343

of nerve agents, 143–145, 161–162, 167

of phosgene oxime, 221

of plague, 494–495

of riot control agents, 312–314, 316–317, 320–321

of smallpox, 543–545, 548–550

of trichothecene mycotoxins, 658, 665–666, 670

of tularemia, 505

of viral hemorrhagic fevers, 595–596

Derrick, Edward, 525

Deseret Test Center, Fort Douglas, Utah, 430

Detection, 124, 362, 377–383, 683

aerosol, 383, 448

biological agent, 74, 377, 382–384, 431, 447–449

chemical agent, 377–381

Cold War, 53–54, 60–62, 66–67, 70

developmental, 381

integrated mobile systems, 381–383

and medical management, 329

point, 377–380

post–World War II, 46

preattack measures, 328

1960s, 60–62

1970s, 66–67

1980s, 70

1990s, 74

standoff, 53–54, 74, 380–381, 447–448

toxins, 613

World War I, 23

World War II, 42

See also specific detector

Detection paper

M8 Chemical Agent, 335, 355, 357, 377–379

M9 Chemical Agent, 378

Detector crayon, 42

Detector kits, 42, 46

M256A1 Chemical Agent, 379–380

Detector paint, 42, 46

Detector paper, 42, 46, 66–67, 70

Detoxification, 352

Dexamethasone, 670

Dextromethorphan, 628

DFA staining

See Direct fluorescent antibody (DFA) staining

DFP

See Diisopropyl fluorophosphate (DFP)

4,15-Diacetoxyscripenol (DAS), 660–661, 666

Diamanus montanus, 487

Dianisidine chlorosulfate, 14

Diaphragm masks, 33

Diarrhea, 212, 216, 314–315

Diatomaceous earth, 353

Diazepam, 154–155, 165–169, 191, 279, 347

Dibucaine numbers, 137

DIC

See Disseminated intravascular coagulation (DIC)

Dichlorodiphenyltrichloroethane (DDT), 483

Dichloroformoxime

See Phosgene oxime (CX)

2,4-Dichlorophenoxyacetic acid (VKA), 44

Dicobalt edetate, 279, 281

DIDS, 275

Dihydrocodeinone, 628

Diisopropyl fluorophosphate (DFP), 132, 152–153, 233, 301

Dilger, Anton, 16

Dilger, Carl, 16

Dimefox, 138

Dimercaprol

See British anti-Lewisite (BAL)

Dimethylaminopheno (DMAP), 275

4-Dimethylaminophenol (4-DMAP), 279–281

Dinitropheno (DNP), 275

Diphenhydramine, 627, 670

Diphenylaminearsine
Medical Aspects of Chemical and Biological Warfare

700

See DM (diphenylaminearsine)

Diphosgene (DP), 16, 118–119

Diphtheria toxin, 609, 647–648

Direct fluorescent antibody (DFA) staining, 495–496

DISCOM

See Division Support Command (DISCOM)

Disinfection

definition, 357

Disney, Walt, 41, 103

Disseminated intravascular coagulation (DIC), 595–597

Distilled mustard agent (HD), 38–39, 198–200

Ditran, 298

Diuretics, 253, 259–260

Division Support Command (DISCOM), 327

DKIE

See Decontamination Kit, Individual Equipment (DKIE)

DM (diphenylaminearsine), 27, 119, 292, 309, 319

4-DMAP

See 4-Dimethylaminophenol (4-DMAP)

DNA

See Deoxyribonucleic acid (DNA)

DON

See Deoxynivalenol (DON)

Dopamine, 132, 598

Doughty, John W., 11, 14, 88–89

Doxycycline, 473, 497–498, 518

DR1 emulsion, 33

Drinking tubes, 60, 366–370

Drones

for agent delivery, 59

Dry heat decontamination, 358

Dryvax, 551

DS2

See Decontaminating Solution 2 (DS2)

D-Stoff

See Phosgene (CG)

Dugout blanket, 22

Dugway Proving Ground, Utah, 427, 429, 432, 457

Dugway sheep-kill incident, 62, 432

Du Pont Advanced Fiber Systems, 373, 638

Du Pont Company, 33, 38

Du Pont Multi-Source Products, 302

Du Pont Polymers, 264, 617, 638

Dusts

definition, 248

Dutch Powder, 353

Dyer, Rolla, 525

Dynamite, 89

Dysentery, 12, 42, 417–418

Dyspnea

nerve agent–induced, 145, 147–149, 158, 167–168, 170

in toxic inhalational injury, 252, 255–256, 258–261, 265

E

EAC

See Echelon Above Corps (EAC)

Eastern equine encephalitis (EEE), 570–574, 576–579

Eastern equine encephalitis (EEE) virus, 562–564

PE-6 strain vaccine, 579

Eastern equine encephalitis (EEE) virus complex, 564–566

Ebola hemorrhagic fever, 432, 434–435, 439, 593–596

Ebola viruses, 594

Ebola–Zaire strain, 594

ECG

See Electrocardiography (ECG)

Echelon Above Corps (EAC), 328

Echelons of care

definition, 326

I: Unit Level, 326–327, 340

II: Division Level, 327–328

III: Corps Level, 328

IV: Echelon Above Corps (EAC), 328

V: Continental United States (CONUS), 328

treatment emphasis at, 327

Ecstasy

See 3,4-Methylenedioxymethylamphetamine (MDMA)

Eczema vaccinatum, 549–550

ED50

See Effective dose (ED50)

Edema toxin, 470

Edgewood Arsenal, Maryland, 19, 26, 30, 38–39, 49, 93, 101,

434, 460, 658

EEE

See Eastern equine encephalitis (EEE)

EEG

See Electroencephalography (EEG)

Effective dose (ED50), 622

Eglin Air Force Base, Florida, 429

Egypt, 56, 104, 200, 418–419, 657

Ehrlich, Paul, 632

Electrocardiography (ECG), 156, 165–166

Electroencephalography (EEG), 153, 235–236

Electron transport system (ETS), 275

ELISAs

See Enzyme-linked immunosorbent assays (ELISAs)

Ember, L. R., 657

Emergency medical treatment (EMT) station, 331–335

Emetics

See Nausea-producing agents; specific agent; Vomiting

agents

Emetine, 671

Encephalitis

equine, 562–579

lethality, 444

postvaccinial, 549–550

Encephalomyelitis

nonviral causes, 576

viral causes, 575

Encephalomyelitis viruses

See Viral encephalitides; specific virus

Endocarditis

brucella, 517–518

Q fever, 528, 530

Endocrine system

effects of cyanides on, 277

Endothelial-derived relaxing factor (EDRF), 275

Enterocolitis, 625–626

Entry point, 331–332

Environmental concerns

with sea dumping, 62–64

Environmental conditions

and agent delivery, 122–123

Environmental samples

for toxin exposure diagnosis, 614, 617, 627, 668

Enzootics

definition, 480

genetic drift, 567–568

and plague, 487

and viral encephalitides, 564, 567–568, 572

Enzyme-linked immunosorbent assays (ELISAs)

in biological agent diagnosis, 448–449

in toxin exposure diagnosis, 617

See also specific agent diagnosis

Epileptogenic substances, 292

Epinephrine
Index

701

See Adrenaline

Epiphytotics, 460

Epizootics

definition, 480

genetic drift, 567–568

and plague, 487, 491

and viral encephalitides, 564, 567–568, 571–572

Epoxide group, 656

Equine encephalitis, 562–579

Equipment decontamination, 124–125, 353, 357, 387–388

Erythema multiforme, 549

Erythrocyte cholinesterase (RBC-ChE), 132, 136–137

baseline and periodic measurements, 404–405

inhibition, 138–139

as nerve agent pretreatment, 192

Erythromycin, 473, 507, 531

Escherichia coli, 609, 633, 682

Eserine

See Physostigmine

Ethiopia, 34–35, 102, 200

Ethyl bromoacetate, 12–13, 308

Ethylenediaminetetraacetic acid (EDTA)

cobalt salt, 279, 281

Ethyl iodoacetate, 13

Evacuation categories, 340

Evans, A. C., 514

Executive Order 11850, 308

Exertion

and mask use, 365

and toxic inhalational injury, 254–255

Explosive-release devices, 120–122

Export controls

and chemical manufacturing, 116–117

Eye decontamination, 352–353

Eye irrigation

for mustard injuries, 98

Eye pain, 147, 166–167, 215

Eyes

protection from toxins, 612

See also under Ocular

F

Faceblank, 364

Fasciculations, 149, 168–170

FDA

See Food and Drug Administration (FDA)

FDECU

See Field deployable environmental control unit (FDECU)

Feather bombs, 51

Federal Emergency Management Agency (FEMA), 411–412

Federal Security Agency, 426

FH

See Field Hospital (FH)

Field deployable environmental control unit (FDECU), 385

Field Hospital (FH), 328

Field management

of chemical casualties, 325–336

Field manuals

for chemical surety inspection, 400

Field Masks, 74

Field medical card (FMC), 333, 335

Field mouse, 592, 594

Fildes, Paul, 645

Filoviridae, 592–594

Filter mask layer, 364–368, 370

Finlay, Carlos, 10

First aid

for chemical casualties, 329–332

Fiske, Norman E., 34–35

Fitness evaluations

for Chemical Personnel Reliability Program, 402–403

Flaccid paralysis, 149

Flame warfare agents, 90, 119

Flannel hoods, 91

Flaviviridae, 575, 592–594

Flavonoids, 671

Fleas

as bacterial agent vector, 33, 380, 482–489, 498

Flechettes, 439–440, 442

Flettner rotor, 441–442

FLOT

See Forward line of troops (FLOT)

Flour

decontamination with, 353–354

Fluoroquinolones, 507, 531

FM

See Titanium tetrachloride (FM)

FMC

See Field medical card (FMC)

Food and Drug Administration (FDA), 188, 463

Food Machinery and Chemical Company, 49

Food poisoning, 463, 622, 644, 646, 649, 659

Food supply contamination, 442, 446–447, 459, 469

Foot-and-mouth disease, 51, 460

Ford, Gerald R., 64, 308

Foreign material

in wounds, 356

Formulation, 122

2-Formyl-1-methylpyridinium chloride

See 2-Pralidoxime chloride (2-PAM Cl)

Fort Detrick, Maryland, 43–44, 426–432, 434, 460, 616, 623–

624, 651

Fort Morgan virus, 566

Forward line of troops (FLOT), 326

Forward Support Medical Company (FSMC), 329

Foster, John S., 431

Fourier Transform Infrared (FTIR) spectrometer, 380

Fowl pest, 460

Fox, Leon A., 31–32, 426

FOX Nuclear, Biological, Chemical Reconnaissance System

(NBCRS), 74, 377, 381–383

France

biological warfare programs, 32

chemical warfare programs, 114

See also World War I; World War II

Francis, Edward, 504

Francisella tularensis, 383, 429, 504, 506–507

See also Tularemia

Freeze drying, 440–441

French and Indian War, 416

Fries, Amos A., 18, 25–26, 28, 95

FSMC

See Forward Support Medical Company (FSMC)

FS smoke

See Sulfur trioxide-chlorosulfonic acid (FS smoke)

FTIR spectrometer

See Fourier Transform Infrared (FTIR) spectrometer

Fugu toxin

See Tetrodotoxin

Fuller, J.F.C., 35

Fuller’s earth, 353

Fumes

definition, 248

Fumonisins, 656

Fungal toxins, 609–610, 656
Medical Aspects of Chemical and Biological Warfare

702

See also specific toxin

Fusarenon-X

See Monoacetylnivalenol

Fusarium, 656, 658–659, 668

Fusarium nivale, 659

Fusarium semitectum var semitectum, 658

G

GA

See Tabun (GA)

D-Galactose, 639

-Aminobutyric acid (GABA), 132

Gangliosides, 648

Gases

airway distribution, 248–249

definition, 248

historical war, 255–260

See also specific gas

“Gas Fright,” 95, 97, 343, 393

Gas gangrene, 417

Gas–liquid chromatography (GLC), 668–669

Gas mask phobia, 393–395

Gastrointestinal disturbances

anthrax-induced, 472–473

CS-induced, 314–315

mustard-induced, 212, 216

nerve agent–induced, 145, 168

staphylococcal enterotoxin–induced, 622–627

See also Diarrhea; Nausea; Vomiting

Gas Warfare Service, 95

See also Chemical Warfare Service (CWS); Chemical Corps

Gates, Robert, 456–457

GB

See Sarin (GB)

GD

See Soman (GD)

Gel diffusion test, 546

General Hospital (GH), 328

General Ordnance Equipment Corp., 310

Genetic engineering, 452, 454, 680

Genetic recombination, 681

Genetic weaponry, 682

Geneva Protocol

history, 29, 34, 57, 64, 67, 69, 290, 427

and riot control agents, 308, 321

and status of chemical proliferation, 114, 679

Genitourinary tract infection, 517

Gentamicin, 473, 497, 507

Germany

biological warfare programs, 16, 32, 36–37, 418, 426, 459,

644

chemical warfare programs, 5, 14–15, 89, 130–131

post–World War II weapons disposal, 46

viral hemorrhagic fever outbreak, 594

See also World War I; World War II

GF, 119, 130–131, 230

aging half-time, 183

decontamination, 354

Iraqi production, 185–186

and pyridostigmine pretreatment, 185–186

GH

See General Hospital (GH)

Gilchrist, Harry L., 93, 96–98

Glanders, 10, 16, 427, 431, 459

GLC

See Gas–liquid chromatography (GLC)

Gloves

protective, 373–375

rubber/surgical, 356–357

Glucocorticosteroids, 670

Glucose-6-phosphate, 203

Glutathione (GSH), 203–204

Glycolates, 295–296, 298

See also specific agent

Glycoprotein synthesis, 570

Goats, 528

Goebbels, Joseph, 418

Gorbachev, Mikhail, 453, 455

Grains

moldy, 659

See also Antiplant weapons; specific grain

Greek fire, 88

Green cross

See Phosgene (CG)

Green vinyl overboot (GVO), 374

Grenades

hydrocyanic acid, 40–42

smoke, 262

tear gas, 90

Ground crew personal protective equipment, 365–368

Ground squirrels, 487–488, 504

Gruinard Island, Scotland, 418, 441

GSH

See Glutathione (GSH)

Guanarito virus, 593

Guanine, 239

Guarnieri bodies, 546

Gulf War syndrome, xvi, 73, 105, 190, 191, 195, 297

GVO

See Green vinyl overboot (GVO)

H

H

See Impure mustard agent (H)

Haber, Fritz, 14, 25, 89–91

Haber’s law, 276

Ha bomb, 33

Haemophilus ducreyi, 496

Haffkine, Waldemar M. W., 498

Hague Convention of 1899, 89–90

Hague Peace Conferences, 13

Haig, Alexander M., 68

Haloperidol, 293

Hantaan virus, 593–594, 599

Hantavirus disease, 594, 598

Hantaviruses, 593–596

Hantavirus pulmonary syndrome (HPS), 594–595

Harassing agents

See Riot control agents; specific agent

Harmine, 293

Hart, B. H. Liddell, 35

Haslett, Lewis P., 13

HC

See Hexachloroethane (HC); Zinc oxide (HC)

HD

See Distilled mustard agent (HD)

Healthcare

and biological warfare, 445, 447, 683–684

and chemical surety mission, 397–412

and chemical warfare, 111–126, 328–335, 683–684

Health education

for chemical workers, 407–408

Health service support (HSS), 326–328

Heart block
Index

703

atrial–ventricular (A–V), 156

Heart rate

effects of CS on, 315

effects of cyanides on, 277

effects of nerve agents on, 156–157

in toxic inhalational injury, 253

Heat categories

and work/rest cycles, 329–330, 371, 403, 405

Heat stress

and protective gear, 125, 329–330, 367, 370–371, 394, 403,

405–407

Helminthosporium oryzae van Brede de Haan, 460

Hemagglutination assays, 497, 507, 517–518, 531

Hemagglutination-inhibition (HI) tests, 566, 573

Hemodialysis, 217

Hemolysins, 609

Hemopoietic changes

mustard-induced, 215–217

Hemorrhagic fevers

See also Viral hemorrhagic fevers; specific virus

Hemorrhagic fever with renal syndrome (HFRS), 593–595,

597, 599

Hemorrhagic meningitis, 471

Henbane, 294

HEPA filters

See High-efficiency particulate air (HEPA) filters

Heparin, 217, 597

Hepatitis, 517

Hepatitis A virus, 418

Herbicides, 460

Herpesviridae, 575

Hexachloroethane (HC), 27, 260

Hexamethamine tetramine, 260

Hexamethyltetramine, 363

Hexose monophosphate shunt, 203

Heydrich, Reinhard, assassination of, 645

HFRS

See Hemorrhagic fever with renal syndrome (HFRS)

High-efficiency particulate air (HEPA) filters, 430, 432, 434

Highlands J (HJ) virus, 566–567, 574

High-mobility, multipurpose, wheeled vehicle (HMMWV),

382–385

High-performance liquid chromatography–mass spectrometry

(HPLC-MS), 669

Hill, Edwin, 427

Hinsch, Frederick, 16

HI tests

See Hemagglutination-inhibition (HI) tests

Hitler, Adolph, 103

HJ virus

See Highlands J (HJ) virus

HL, 119

HMMWV

See High-mobility, multipurpose, wheeled vehicle

(HMMWV)

Hmong, 3, 67–68, 656–658

HN-1/HN-2/HN-3

See Nitrogen mustard

Hoffman, Theodore A., 12–13

Hog cholera, 460

Homatropine, 147, 166–167, 215

Honest John rocket, 59

Hoods

M6A2, 366

Hoplopsyllus anomalus, 487

Horses

biological warfare involving, 417, 459

encephalitis viruses, 562–579

protective equipment for, 31, 91

vaccination, 568, 576, 578

Hospitals

Chemically Hardened Air Transportable (CHATH), 385

combat support, 328

Echelon V (CONUS and ZOI), 328

field, 328

general, 328

mobile surgical, 328

personnel needs, 331

Hotline

in casualty-receiving area, 331–333, 335, 340, 410

HPLC-MS

See High-performance liquid chromatography–mass

spectrometry (HPLC-MS)

HPS

See Hantavirus pulmonary syndrome (HPS)

HS

See Mustard (HS)

HSS

See Health service support (HSS)

HTH solution

See Hypochlorite solution

HT-2 toxin, 660–661, 664, 666

Hughes, M. L., 514

HUGO

See Human Genome Organization (HUGO)

Human Genome Organization (HUGO), 682

Human Genome Project, 682

Human immune globulin preparations, 434

Human immunodeficiency virus (HIV) infection, 550, 552

Humoral immunity, 505, 528, 542, 551, 683

Hun Stoffe (Germany stuff)

See Mustard (HS)

Hussein, Saddam, 72–74, 113, 416, 421, 679

Hussein Kamal Hussein, 421

Hydrocodone, 628

Hydrogen cyanide (AC), 118, 272–282

detection, 380

history, 10, 16, 37–38, 40–42, 104, 273–274

physical properties, 122–123

properties, 272

toxicity, 141, 276

Hydrolysis, 121, 354–355, 387

Hydroxamine, 162

Hydroxide

dilute, 158

Hydroxocobalamin (vitamin B12a), 279, 281

Hyoscine

See Scopolamine

Hyoscyamine

See Atropine sulfate

Hyoscyamus falezlez, 290

Hypertension

pralidoxime chloride–induced, 163–164, 170

Hypochlorite solution, 352–358, 387, 408

contraindications, 314, 353, 356, 358

for nerve agent decontamination, 158, 341

preparation, 358

for riot control agent decontamination, 314

spot decontamination with, 333, 335

for toxin decontamination, 616, 660, 669

for vesicant decontamination, 214

World War I use, 22–23

“Hypo helmet,” 363

Hypotension, 170, 598

Hypoxia

and inhalational injury, 252, 257
Medical Aspects of Chemical and Biological Warfare

704

I

Ibogaine, 293

ICAM

See Improved Chemical agent monitor (ICAM)

ICN Pharmaceuticals, 132

Idoxuridine, 550

IFA staining

See Indirect fluorescent antibody (IFA) staining

Ig

See Immunoglobulin (Ig)

I. G. Farbenindustrie, 130

IL-6

See Interleukin-6 (IL-6)

IMA

See Installation Medical Authority (IMA)

Imipenem, 473

Immune response, 681, 683

to brucellosis, 515–516

to Q fever, 528

to smallpox, 542, 551

to staphylococcal enterotoxins, 622–623

to tularemia, 505

to viral encephalitides, 573, 576–577

Immunization, 681–683

against anthrax, 473–474

against botulinum toxins, 651

against plague, 498

against Q fever, 531–532

against smallpox, 540, 546–551

against staphylococcal enterotoxin B, 628

against toxins, 615, 618–619

against trichothecene mycotoxins, 671

against viral encephalitides, 564, 576–579

against viral hemorrhagic fevers, 599

See also Vaccines

Immunoglobulin (Ig), 434, 516

Immunology, 632, 681–683

Immunotoxins, 632

Imperial Chemicals, Ltd., 49

Improved Chemical agent monitor (ICAM), 378–379

Impure mustard agent (H), 199–200

Incapacitating agents, 118–119, 287–302

biological, 292, 431, 439–440

chemical, 292

and combined injuries, 348

delivery systems, 121

differential diagnosis, 297–298

historical precedents, 52, 57, 289–290

ideal, criteria for, 288–289

medical management, 298–302

nonchemical, 291–292

toxin, 608, 622

triage considerations, 344, 346

use, 289–291

See also specific agent

Incapacitation

definition, 288

possible approaches to, 291–294

Incineration

of surplus chemical weapons, 72, 411–412

Indirect fluorescent antibody (IFA) staining, 531

Individual Equipment Decontamination Kit, 70

Indoles, 297–298, 302

Industrial accidents, 119

Industrial hygienist, 399, 402

Infant botulism, 644, 646

Influenza viruses, 680–681

Information-Telegraph Agency of Russia–Telegraph Agency

of Soviet Union (ITAR-TASS), 455

Inhalational injury, 123, 247–267

biological agents, 440

clinical effects, 249, 253

and condition of exposed tissues, 250

evaluation, 250–252

exertion and, 254–255

and intensity of exposure, 249–250

laboratory measurements, 251–252

nerve agent–induced, 139–144, 157, 161, 167

patient history, 250–251

physical aspects, 248–249, 251

physiology, 249–250

pulmonary effects, 253, 256, 258–259, 265–266, 343

therapeutic considerations, 252–253, 255

See also specific agent

Injectors

atropine, 54, 73, 155, 159–161, 169

diazepam, 165

2-pralidoxime chloride (2-PAM Cl), 73, 155, 163, 169

Insecticides

and plague prevention, 498

See also Organophosphorus compounds; Carbamates;

specific agent

Insects

as bacterial agent vectors, 33, 50

See also specific insect or agent

Installation Medical Authority (IMA), 402–404, 406–407, 409

Installation Response Force (IRF), 410

Institute of Especially Pure Biopreparations, 454–455

Integrated mobile systems, 381–383

Interferon-alpha (IFN- ), 599

Interferon-gamma (IFN- ), 505, 516, 599

Interleukin-6 (IL-6), 471

Intermediate syndrome, 232–233

International Declaration Concerning the Laws and Customs

of War, 13

Iran

biological warfare program, 679

Iran–Iraq War, 68–69, 321, 362

chemical casualties death rate, 6

cyanide use during, 273

mustard use during, 3–4, 104, 114, 116–117, 157, 198, 200–

201, 205, 214–216, 230, 237–239

nerve agent use during, 104, 114, 116–117, 122–123, 230,

290

Iraq

biological warfare program, 421–422, 462–463, 657, 679

chemical warfare capability, 114–115, 117, 185–186

Iraqi Kurds, 4, 69, 74, 104, 273, 679

IRF

See Installation Response Force (IRF)

Irrigation solutions, 353, 357

Irritants

See Riot control agents; specific agent

Ishii, Shiro, 32–33, 483

Isolation procedures, 432–433, 497, 547, 598

Isolators Ltd., 432

Israel, 190, 608

Italian–Ethiopian War, 34–35, 102, 200

ITAR-TASS

See Information-Telegraph Agency of Russia–Telegraph

Agency of Soviet Union (ITAR-TASS)

Ivanovskii Institute (Moscow), 562
Index

705

J

JACADS

See Johnston Atoll Chemical Agent Destruction System

(JACADS)

Japan

biological warfare programs, 32, 36–37, 417–418, 426–427,

446, 483–485, 540

chemical warfare programs, 37

Imperial Unit 100, 418

Imperial Unit 731, 417–418, 427, 483, 540

invasion of China, 35–36, 200, 218, 417–418, 485

sarin incidents in, 4, 75, 113, 118, 131, 169, 274, 342, 438,

463, 678

Jenner, Edward, 548

Jerks, 149, 158, 168–169

Jimson weed, 294

Johnston Atoll, 64, 72, 411

Johnston Atoll Chemical Agent Destruction System

(JACADS), 72, 411

Joint disease, 517

Joint Service Lightweight Integrated Suit Technology

(JSLIST), 375–376

Aviation Overgarment (AVOG), 375–376

Duty Uniform (DU), 375–376

Improved Chemical and Biological Protective Glove

(ICBPG), 376–377

Multipurpose Overboot (MULO), 377

Overgarment (OG), 375–376

Vapor-Protective, Flame-Resistant Undergarment

(VPFRU), 375–377

Joint United States/United Kingdom/Russia Trilateral

Statement on Biological Weapons, 4

Junin virus, 592–593, 599

K

K-agents, 52

Kampuchea, 3, 67–68, 421, 656, 666

Kawasaki disease, 623, 628

Kelocyanor, 281

Keratitis

vaccinia, 550

Keratopathy

delayed, 238

-Ketoglutaric acid, 282

Kevlar, 373, 638

Khmer Rouge, 656, 666

Kitchener, Field Marshal Lord, 13

Koch, Robert, 10, 468, 470

Kops Tissot Monro (KTM) mask, 22, 28, 92

Korea, North, 461–462, 679

Korean hemorrhagic fever, 594

Korean War, 47–48, 104, 394, 418–419, 429, 485, 594

Kostov, Vladimir, 420–421

Kuhn, Richard, 131

Kuntsevich, Anatoly, 453, 455

Kyasanur Forest disease, 593–594

L

L

See Lewisite (L)

LAC

See Operation Large Area Coverage (LAC)

Lacrimators, 292, 308

See also specific agent

Lactic acidosis, 279

Laetrile, 274

Lane, Benjamin I., 13

Laos, 3, 67–68, 421, 656–658, 665

Laser detection systems, 380

Lassa fever, 592–593, 595, 598–599

Lassa virus, 592

LCt

50, 142, 183, 606

LD50, 142, 183, 606

LDS

See Lightweight Decontamination System (LDS)

Le 100

See Tabun (GA)

League of Nations, 28–29, 34

Lederle Laboratories, 191

Legionella, 525

Legionnaire’s disease, 434

Leporipoxvirus, 542

Lethal factor, 470

Leukocytosis, 635

Leukopenia, 215–217, 667

Lewis, W. Lee, 19

Lewisite (L), 118–119, 218–220

antidote, 102, 218, 220

biochemical mechanisms of injury, 218

chemical structure, 218

clinical effects, 218–219

delivery systems, 121

dermatological effects, 219

detection, 42, 380–381

differential diagnosis, 200, 212, 219–220

history, 19, 36–38, 40, 46, 102, 198

laboratory tests, 220

long-term health effects, 217, 220

military use, 218

mixed with mustard, 201, 218

nations with capability for use, 114, 116

ocular effects, 219

pharmacology, 199

physical properties, 122–123, 218

pulmonary effects, 219

toxicity, 218

treatment, 220

vapor, 218–219

Lewisite shock, 219

Libya, 4, 69, 74, 321, 524

Lice, 487

Light reduction, 145–146

Light sources, high intensity

incapacitation by means of, 291–292

Lightweight Decontamination System (LDS)

M17, 388

Eli Lilly and Company, 280

Lilly Cyanide Antidote Kit, 280–281

Limitation of Arms Conference, 29

Line source

for aerosol delivery, 441–442

Lipid peroxidation, 204

Lipopolysaccharide (LPS), 504, 515, 526, 528

Liston, W. G., 486

Litter

decontaminable, 389

Litter decontamination station, 332–333, 410

Litter-patient airlock

in chemical shelter, 385

Little John rocket, 59

Livens projector, 20–21, 31, 91

Live vaccine strain (LVS), 507

Loco weed, 294

Loffler, F., 10
Medical Aspects of Chemical and Biological Warfare

706

LOPAIR (long-path infra red) alarm, 53–54

Lorazepam, 302

LOST

See Mustard (HS)

Lott, Joseph, 11

LPS

See Lipopolysaccharide (LPS)

LVS

See Live vaccine strain (LVS)

Lymphogranuloma venereum, 495–496

Lymphoid changes, 471, 495, 505–506, 571, 625

D-Lysergic acid diethylamide (LSD), 52, 293, 302

M

MacArthur, Douglas, 29

Mace

See CN (1-Chloroacetophenone)

Machupo virus, 593

Macrocyclics, 660

Macromolecules, 192

Macrophages, 515–516, 528

Mafenide acetate, 214

Magnesium sulfate, 670

Mahan, Alfred T., 13

Major, John, 455

Major histocompatibility complex (MHC), 505, 622–623

Malaria, 32, 418, 596–597

Malathion, 132, 138

Malononitrile, 315

Manchuria, 418, 427, 483, 594

Mandrake root, 289

Manning, Van H., 17

Marboran

See Methisazone

Marburg hemorrhagic fever, 439, 593–596

Marburg virus, 594–595

March, Peyton C., 25

Marijuana intoxication, 298

Marine toxins, 609

See also specific toxin

MARK I kits, 252

atropine therapy, 161–162

and combined injuries, 347

Persian Gulf War use, 73, 155

pralidoxime chloride therapy, 164–170

self-administration, 329–330, 341

Markov, Georgi, 420–421, 632

Marmots, 481–482, 488

Marshall, John D., 483

Marston, J. A., 514

MASH

See Mobile Army Surgical Hospital (MASH)

Mask-Only Command, 371–372

Masks, 123, 362–370

Chemical–Biological: Aircraft, M43, 369

Chemical–Biological: Aircrew MBU-19/P, 369–370

Chemical–Biological: Field, M40, 363–364, 366–368

Chemical–Biological: Field, M42, 368

Chemical–Biological: Field, M17A2, 363, 366–367

Chemical–Biological: MCU-2/P, 368

Cold War, 53–54, 105

and contact lenses, 402–403

design, 364–365

developmental, 370

discipline in use, 94, 124, 393

drinking tubes in, 60, 366–370

early, 12–13

function testing, 365–366, 403

for horses, 31, 91

microphones in, 364, 366, 368–370

M45 protective, 365

M1 Service, 28, 33

M2 Service, 40

and nerve agent exposure, 157

post–World War II, 46–47

psychological effects of wearing, 393–395

quality assurance concerns, 94

1920s, 28, 101

1930s, 33, 101

1960s, 60, 105

1980s, 69–70

1990s, 74

and toxin protection, 612, 669

training, 393–395

winterization kits, 366

work of breathing added by use of, 365

World War I, 15–18, 22, 91–94, 363–364, 393

World War II, 37, 40–41, 43, 103, 365, 394

Mask-to-mouth resuscitator, 54

Mass casualty biological (toxin) weapon (MCBW), 605–606,

611

Mass hysteria, 124

Mass spectrometry (MS), 669

Mastomys natilensis, 592

MAT

See Medical Augmentation Team (MAT)

Material

biological agents directed against, 459, 461

M256A1 ticket, 355

Maximum credible event (MCE), 409

Mayan, Thayer, 89

Mayaro virus, 562

MCAT

See Medical Chemical Advisory Team (MCAT)

McAuliffe, Anthony C., 47

McBride, Lewis M., 27

MCBW

See Mass Casualty Biological (Toxin) Weapon (MCBW)

McCarthy, Richard D., 431

McCoy, G. W., 504

MCE

See Maximum credible event (MCE)

McNamara, Robert S., 55

McNeill Consumer Products Co., 274

MD

See Methyldifluorarsine (MD)

MDMA

See 3,4-Methylenedioxymethylamphetamine (MDMA)

Meade, John, 34–35

MED50, 295–296

MEDCEN

See Medical Center (MEDCEN)

MEDDAC

See Medical Department Activity (MEDDAC)

Mediastinitis, 471–473

Medical Aspects of Chemical Warfare (Vedder), 102

Medical assistance

procedures for requesting, 407–408

Medical Augmentation Team (MAT), 410

Medical Biological Defense Research Program, 615

Medical care

levels of, 410

safe environment for, 71, 124–125

Medical Center (MEDCEN), 398

Medical Chemical Advisory Team (MCAT), 411
Index

707

Medical Collective Protection Systems, 384–385

Medical defense

history, 87–105

Medical Department Activity (MEDDAC), 398

Medical directives

for chemical surety inspection, 401

Medical Management of Chemical Casualties Course, 398, 409

Medical Management of Chemical Casualties Handbook, 401

Medical record card, 333, 335

Medical Reengineering Initiative (MRI), 328

Medical research

on human volunteers, 52, 60–61

Medical Response Team (MRT), 410

Medical support

in biological warfare environment, 445, 447, 683–684

in chemical warfare environment, 111–126, 328–335, 683–

684

Medical surveillance

for chemical workers, 402–405

definition, 402

Medical treatment facility (MTF), 328, 409

casualty-receiving area, 331–335

contamination, 124–125, 353, 357

Mediterranean fruit fly, 461

Melanoconion, 564, 567

Melioidosis, 431

Membrane-damaging toxins

mechanism of action, 609, 611

See also specific toxin

Memorandum on Gas Poisoning in Warfare with Notes on its

Pathology and Treatment (U.S. Army War College), 23–24

Memorandums of Agreement (MOAs), 401, 408–409, 411

Meningitic plague, 491, 494

Meningitis

anthrax-induced, 471–473

hemorrhagic, 471

Meningococcal infection, 417

Meningoencephalitic syndrome, 574

Meningoencephalitis, 517

Menthol, 670

Mercaptopyruvate sulfurtransferase, 275

3-Mercaptopyruvate sulfurtransferase, 276

Merck, George W., 43, 426–427

Merck Company, 43, 198

Mescaline, 52

Metabolic disturbances, 277, 315

Metals

contamination with biological agents, 459, 461

Methanesulfonate salt of pralidoxime (P2S), 163

Methemoglobin, 275, 280

Methemoglobin-forming drugs, 280–282

See also specific drug

Methisazone, 552

Methyldifluorarsine (MD), 27

3,4-Methylenedioxymethylamphetamine (MDMA), 293

Methylisocyanate, 119

Methylthiazolidine-4-carboxylate, 670

Metoclopramide, 670

Metrazole, 292

Mevinphos, 138

Meyer, Karl F., 498

Meyer, Victor, 10, 198

MHC

See Major histocompatibility complex (MHC)

Mice, 487–488, 592, 594

Michigan Department of Public Health, 473

Mickey Mouse gas mask, 41, 103

Microcystin, 609, 611, 616–617

Microphones

in masks, 364, 366, 368–370

Microwave bombardment

incapacitation by means of, 291

Midazolam, 154, 191

Middelburg virus, 565

Militarily significant weapon

definition, 604

Military healthcare providers

biological warfare threat and, 6, 445, 447, 683–684

chemical warfare threat and, 6, 111–126, 328–335, 683–684

detection capability, 124

safety from chemical contamination, 125, 157

Military installations

plague on, 483–484

Military medical facilities

contamination, 124–125, 157, 353, 357

Military occupation specialty (MOS), 327

Military vehicles

collective protection for, 67

Mines, 31, 52, 58, 123

Minnesota Multiphasic Personality Inventory (MMPI), 311

Minnesota Patriots Council, 463–464

Miosis

nerve agent–induced, 144–147, 166–168, 170

Missile-control vans

collective protection for, 67

Missiles, 120, 446

Mission-oriented protective posture (MOPP) gear, 101, 123–

125, 169–170, 362, 371

exchange procedure, 331, 334

and heat stress, 125, 329–330, 367, 370–371, 394, 403, 405–

407

level of efficiency in, 329, 362

and medical personnel, 329, 331–332, 334, 338, 340–341

postattack measures, 329

preattack measures, 328

psychological effects of wearing, 362, 393–395

removal of, 333, 335, 355, 386, 669

training, 393–395

Mission-oriented protective posture (MOPP) levels, 328, 372

Mist

definition, 248

MK 4 suit, 123

MLRS

See Multiple Launch Rocket System (MLRS) Binary

Chemical Warhead

MOAs

See Memorandums of Agreement (MOAs)

Mobile Army Surgical Hospital (MASH), 328

Mobile decontamination facilities

World War I, 97–98

Molasses residuum, 37

Molds, 656, 659

Molluscipoxvirus, 542

Monkeypox virus, 542, 547, 551

Monoacetylnivalenol, 659

Monoclonal antibodies

as nerve agent pretreatment, 192

in toxin prophylaxis, 615, 651, 671, 682–683

MOPP

See Mission-oriented protective posture (MOPP)

gear,Mission-oriented protective

 posture (MOPP) levels

MOPP Ready, 371–372

Morocco, 102

Morphine, 293

Mortars, 21, 27, 31, 39, 48
Medical Aspects of Chemical and Biological Warfare

708

MOS

See Military occupation specialty (MOS)

Mosquito, 418, 430

as viral encephalitides vector, 562–564, 566–568, 573, 577

as viral hemorrhagic fever vector, 593–594, 596

as yellow fever vector, 50

Most probable event (MPE), 409–410

Mouth-to-mouth ventilation, 159

MRI

See Medical Reengineering Initiative (MRI)

MRT

See Medical Response Team (MRT)

MS

See Mass spectrometry (MS)

M9 tape, 355, 357

MTF

See Medical treatment facility (MTF)

Mucoid plugs, 148, 158

Multiple Launch Rocket System (MLRS) Binary Chemical

Warhead, 71

Muscarine (mAChR), 132–133

Muscular system

effects of nerve agents on, 145, 149, 232

Mussolini, Benito, 34

Mustard (H)

impure, 199–200

Mustard (HD)

distilled, 38–39, 198–200

Mustard (HS), 118–119, 198–217, 230–231

biochemical mechanisms of injury, 202–204

carcinogenic effects, 217, 237–238

cardiovascular effects, 217

central nervous system effects, 212, 239

clinical effects, 204–212, 342–343

and combined injuries, 347–348, 355–356

deaths related to, 205, 212

decontamination, 22–24, 33–34, 54, 157–158, 213, 354–355,

387

dermatological effects, 98–100, 201–202, 205–210, 214, 217,

238–239, 342–343

detection, 42, 66, 378, 380–381

differential diagnosis, 200, 212–213, 219–220, 343

exposure categories, 213–214

gastrointestinal effects, 212, 216

history, 5, 10, 27, 29–31, 34–40, 46, 56–57, 62–63, 102–104,

198

inhalation, 100

laboratory test for, 213

long-term health effects, 97–101, 217, 230, 236–239

metabolism, 204

military use, 200–201

mixed with Lewisite, 201, 218

mutagenic effects, 239

nations with capability for use, 114–116

neuropsychiatric effects, 239

ocular effects, 202, 208–211, 214–215, 238

pharmacology, 199

physical properties, 122–123, 199, 201

pulmonary effects, 211–212, 215–217, 237–238

recent use, 3–4, 69, 198, 200–201, 205, 214–216, 230, 237–239

reproductive toxicity, 239

teratogenic effects, 239

thickened, 356

toxicity, 201–202, 276

treatment, 213–217

triage considerations, 342–343

vapor, 201–202, 237

World War I use, 16, 19–24, 95–101, 119, 198, 200–201, 205,

210, 212–214, 216, 237–238, 393

and wound decontamination, 355–356

Mustard burns, 98–100, 202, 205–208, 214, 238, 342–343

Mustard shell, 40

Mustargen, 198

Mutagenesis, 239, 315–316

Mutual aid agreements

for chemical surety inspection, 401

Mycotoxicosis, 659, 670

Mycotoxins, 656

See also Trichothecene mycotoxins; specific toxin

Myrotecium, 656

Myrothecium verrucaria, 659

N

NAD+ (nicotinamide adenine dinucleotide), 203

Nairovirus, 593

Naloxone, 302, 670

Napalm, 119

NAPP (nerve agent pyridostigmine pretreatment)

See Pyridostigmine bromide

NAPPS

See Nerve agent pyridostigmine pretreatment set (NAPPS)

Narcan

See Naloxone

Nasal effects

of nerve agents, 145, 147, 167–168, 170

Nasal mucosal swabs

for toxin exposure diagnosis, 614, 617, 627, 638, 650

National Academy of Science, 43, 217, 220, 426

National Research Council (NRC), 17, 43, 426

National Security Memoranda

on use of biological weapons, 426, 431

NATO

See North Atlantic Treaty Organization (NATO)

Natural killer (NK) cells, 505, 516, 528

Nausea, 145, 168, 212, 216, 314–315

Nausea-producing agents, 292

See also specific agent; Vomiting agents

NBC officer

See Nuclear, biological, and chemical (NBC) officer

NBC-PC

See Nuclear, biological, chemical protective covers (NBCPC)

NBCRS

See FOX Nuclear, Biological, Chemical Reconnaissance

System (NBCRS)

NBC Warning and Reporting System, 448

Nduma virus, 565

Nebelwerfer launcher, 36

Neoprene masks, 41

Neosporin, 214

Neostigmine, 132, 298

Nernst, Walther, 14, 91

Nerve agent pretreatments, 132, 134, 181–193

biotechnological, 192–193

and cardiopulmonary response, 156

centrally acting, 191–192

and central nervous system effects, 154, 187

oxime, 164

and pulmonary response, 149

See also Pyridostigmine; specific agent

Nerve agent pyridostigmine pretreatment set (NAPPS), 189

Nerve agents, 118–119, 129–171, 230

aging, 162, 182–183, 230

antidotes, 158–159, 329

binary weapons, 65–66, 70–72, 75, 104
Index

709

and blood cholinesterase activity, 138–139

cardiovascular effects, 145, 155–157, 165–166, 169

central nervous system effects, 145, 149–155, 170, 233–234

and combined injuries, 347, 355–356

versus commonly used cholinesterase inhibitors, 139

in contemporary U.S. munitions inventory, 131

decontamination, 47, 157–158, 168–169, 354–355, 387

dermal exposure, 143–145, 161–162, 167

detection, 53, 66, 378, 380–381

differential diagnosis, 613–614, 638

effects on organs and organ systems, 144–157, 230, 341–342

electrocardiographic (ECG) effects, 156, 165–166, 235–236

electroencephalographic (EEG) effects, 153

exposure categories, 166–170

exposure routes, 142–144

gastrointestinal effects, 145, 168

“G” series, 130

history, 5, 30, 36, 46, 49, 56–58, 62–63, 103–104, 130–131,

290

inhalational injury, 139–144, 157, 161, 167

intermediate syndrome caused by, 232–233

long-term health effects, 153–154, 170, 230–236

mechanism of action, 132–136, 230

mild exposure, 167–168

minimal exposure, 167

moderate exposure, 168

moderately severe exposure, 168–169

muscular effects, 145, 149, 232

nasal effects, 145, 147, 167–168, 170

nations with capability for use, 114, 116

neuropsychiatric effects, 145, 149–155, 233–235

occupational exposure, 136, 236

ocular effects, 144–147, 166–168, 170

oral effects, 145

versus organophosphorus compounds, 231

pharmacology, 139–142

physical properties, 123

polyneuropathy caused by, 231–232

pulmonary effects, 145, 147–149, 167–168, 170

and return to duty, 170

severe exposure, 169

suspected exposure, 166

thickened, 356

toxicological studies, 236

treatment, 54, 73, 154–155, 157–170, 230

triage considerations, 341–342, 344–346

vapor exposure, 142–144, 157, 161, 167

ventilatory support, 148, 158–159, 166–169

“V” series, 130

and wound decontamination, 355–356

See also specific agent

Neuromuscular conduction, 132–134, 647

Neuropsychiatric effects

of brucellosis, 516

of mustard exposure, 239

of nerve agents, 145, 149–155, 233–235

of Q fever, 529–530

of viral encephalitides, 573–574

Neurotoxins

clostridial, 644, 647

differential diagnosis, 650

mechanism of action, 609–611

See also specific toxin

Neutrophils, 505

Newcastle disease, 460

New York State Psychiatric Institute, 52

Niacinamide, 203

Nicotine (nAChR), 132–133, 292

Nightshade, 289, 294

NIKE missile-control vans, 60

“Nine Mile Agent,” 525

Nitric oxide, 263

Nitrites, 280–281

See also specific agent

Nitrogen dioxide, 263

Nitrogen mustard, 198, 200, 231

history, 30, 36, 38, 46

See also Mustard (HS)

Nitrogen oxides (NOX), 263–264

Nitrous oxide, 263

Nivalenol, 659–661

Nixon, Richard M., 63–64, 431, 525

NK cells

See Natural killer (NK) cells

Nobel, Adolph, 89

Noguchi, Hideyo, 525

Noise

incapacitation by means of, 291

Nomex, 373

Noradrenaline (norepinephrine), 132

Norfolk Supply Center, Norfolk, Virginia, 429

Noriega, Manuel, 291

North Atlantic Treaty Organization (NATO), 70, 74, 182, 185,

354, 368

Nosecup, 364–365

Nosocomial transmission

of viral hemorrhagic fevers, 592–593, 595–596

NOx

See Nitrogen oxides (NOx)

NRC

See National Research Council (NRC)

Nuclear, biological, and chemical (NBC) officer, 362, 445

Nuclear, biological, chemical protective covers (NBC-PC), 669

Nuclear age, 36–47

Nuclear weapons

versus chemical and biological weapons, 458–459

Number Facility (NF) performance, 296

Nunn, Sam, 75

Nursing care

for biological agent–exposed patients, 432–433, 598

O

Obidoxime

See Toxogonin

Obscurants, 260–266

See also specific agent; Smokes

Occupational exposure, 119

to anthrax, 468–469, 474

and chemical surety mission, 398–399, 402–408

to Q fever, 524, 532

to ricin toxin, 636

and U.S. biological warfare program, 398–399, 432, 434

Ochratoxins, 656

Ocular effects

of cyanides, 277

of Lewisite, 219

of mustard, 202, 208–211, 214–215, 238

of nerve agents, 144–147, 166–168, 170

of phosgene oxime, 221

of riot control agents, 314, 317, 321

of trichothecene mycotoxins, 665–666

Ocular vaccinia, 549–550

Oehler, Gordon, 462

Off-gassing, 356

Ofloxacin, 497
Medical Aspects of Chemical and Biological Warfare

710

Okinawa accident, 63–64

Olfactory assault

incapacitation by means of, 292

Olfactory nervous system

viral encephalitides infection through, 571–572

Oligonucleotide primers, 627

Omsk hemorrhagic fever, 593–594

O’nyong-nyong virus, 562

Open reading frame, 541

Operation Cut Holes and Sink ‘Em (CHASE), 62–64

Operation Davy Jones Locker, 46

Operation Desert Shield, Operation Desert Storm

See Persian Gulf War

Operation Geranium, 46

Operation Just Cause, 291

Operation Large Area Coverage (LAC), 52

Operation Red Hat, 64

Operation Solid Shield 87, 71

Operation Steel Box, 72

OPIDN

See Organophosphorus ester–induced delayed neurotoxicity (OPIDN)

Opioids, 293, 302

Opisochrostis hirsutus, 487

Optical remote sensing (ORS), 380

Oral exposure

to nerve agents, 145

to trichothecene mycotoxins, 665

Orenburg, 659

Orf, 473

Organofluoride polymers, 264–266, 638

Organophosphorus compounds, 130, 132, 231, 233–234

long-term health effects, 231–236

mechanism of action, 134

versus nerve agents, 231

treatment of exposure, 163

See also Nerve agents; specific agent

Organophosphorus ester–induced delayed neurotoxicity

(OPIDN), 231–232

Oropharyngeal anthrax, 472–473

Oropsylla idahoensis, 487

Oropsylla labis, 487

ORS

See Optical remote sensing (ORS)

Orthopoxvirus, 540–542

Overgarments, 363, 370–377

See also Mission-oriented protective posture (MOPP) gear

Oxidation

decontamination by, 354–355, 387

Oximes, 162–165

contraindications, 167

dosage and administration, 163–164, 169

mechanism of action, 162–163

for pretreatment use, 164, 183

and pyridostigmine pretreatment, 184–187

treatment, 164–165

See also 2-Pralidoxime chloride (2-PAM Cl); specific drug

Oxygen supplementation, 253, 255, 257, 266, 279

Oxytetracycline, 531

P

PADPRP

See Poly(ADP-ribose) polymerase (PADPRP)

Palmer, John M., 55

Palythoa tuberculosa, 609

Palytoxin, 609

2-PAM Cl

See Pralidoxime chloride (2-PAM Cl)

p-Aminoheptanoylphenone (PAHP), 280–281

p-Aminooctanoylphenone (PAOP), 281

p-Aminopropiophenone (PAPP), 275, 280–281

Panama, 291, 524

Paramyxoviridae, 575

Parapoxvirus, 542

Paraquat, 638

Parathion, 132, 138, 232

Paratyphoid, 42

Parker, Ralph, 525

Partial pressure of carbon dioxide (PCO2), 253, 264

Partial pressure of oxygen (PO2), 252, 278

Particles

and toxic inhalational injury, 249, 260

Pasechnik, Vladimir, 453–455

Passive hemagglutination assays (PHAs), 497

Pasteur, Louis, 468–469

Pasteurella tularensis, 60

Patient decontamination, 329, 331–335, 340–341, 352, 386–387,

408–410

Patient flow pattern

in chemical environment, 125

Patient-isolation procedures, 432–433, 497, 547, 598

Patient protection, 389

Patient protective wrap (PPW), 335, 389

Patient transport equipment, 389

PATS

See Protection Assessment Test System (PATS)

PB

See Pyridostigmine bromide

PCP

See Phencyclidine (PCP)

PCR

See Polymerase chain reaction (PCR)

PDA

See Portable Decontamination Apparatus (PDA)

PDDA

See Power-Driven Decontamination Apparatus (PDDA)

PEEP

See Positive end-expiratory pressure (PEEP)

Pellets

biological agent delivery via, 420–421, 442

Penicillin, 473

Pepper spray, 316

Perfluorocarbon rubber masks, 364

Perfluoroethylpropylene, 264

Perfluoroisobutylene (PFIB), 264–266

Permethrin, 191

Peromyscus species, 487

Pershing, John J., 6, 18, 25, 95

Pershing missile, 59

Persian Gulf War

anthrax vaccination during, 474

biological warfare threat during, 2, 6, 72–74, 416, 421, 438,

444–445, 462, 608, 678–679

botulinum vaccination during, 651

chemical warfare threat during, 2, 6, 72–74, 117, 130–131,

198, 230, 362, 394, 678–679

MARK I kits issued during, 73, 155

medical aftermath of, xvi, 73, 105, 190, 191, 195, 297

pyridostigmine pretreatment use during, 185, 188–191

Q fever cases during, 524

Personal decontamination, 157, 329–330, 352, 408

Personnel decontamination, 352, 386–387

Personnel decontamination kits, 386

Personnel documents

for chemical surety inspection, 401–402
Index

711

Petroleum products

biological agents directed against, 461

PFIB

See Perfluoroisobutylene (PFIB)

PG

See Staphylococcal enterotoxin B (SEB)

Pharyngeal plague, 494

Pharyngitis, 506

PHAs

See Passive hemagglutination assays (PHAs)

P helmet, 17

Phencyclidine (PCP), 293–294

Phenethylamine derivatives, 302

Phenethylamines, 292

Phenothiazine derivatives, 627

Phenoxybenzamine, 280

Phentolamine, 163–164

PH helmet, 91

Phillips Duphar, 132

Phlebovirus, 593

Phosgene (CG), 118–119, 257–260

clinical effects, 258, 343–344

and combined injuries, 348

detection, 42

history, 5, 10, 27, 29–30, 36–38, 40, 248

long-term health effects, 260

physical properties, 123

therapy, 258–260

toxicity, 276

triage considerations, 343–347

World War I use, 16, 19, 21, 91–93, 95, 119

Phosgene oxime (CX), 220–222

biochemical mechanisms of injury, 221

chemical structure, 220

clinical effects, 221

dermatological effects, 221

differential diagnosis, 200, 219–220, 638

history, 220

military use, 220

ocular effects, 221

pharmacology, 198–199

physical properties, 220–221

pulmonary effects, 221

treatment, 221–222

Phospholipases, 609

Phosphoric acid, 262

Phosphorus pentoxide, 262

Phosphorus smokes, 262

Phosphorus trioxide, 262

Phossy jaw, 262

Photochemical smog, 263

Photostimulation, high intensity

incapacitation by means of, 291–292

p-Hydroxylaminopropiophenone, 281

Physical decontamination methods, 354, 358, 363–364, 370

Physical disturbances

incapacitation by means of, 291

Physical examinations

for Chemical Personnel Reliability Program, 403–406

Physostigmine, 130, 132

as anticholinergic antidote, 298–302

chemical structure, 184

dosage and administration, 299, 302

mechanism of action, 134, 299

as nerve agent pretreatment, 187, 191–192

side effects, 191

Picornaviridae, 575

Pine Bluff Arsenal, Arkansas, 429, 431

Pioneer Chemical Co., 62

Plague, 479–499

as biological warfare agent, 482–485

bubonic, 480, 486, 491–492, 497

clinical manifestations, 491–495

cutaneous manifestations, 494–495

cycles, 489

diagnosis, 495–497

differential diagnosis, 574

epidemiology, 486–489

history, 10, 16, 32–33, 37, 42, 75, 416–417, 431, 454, 462–463,

480–482

incidence, 489–491

laboratory confirmation, 495–497

lethality, 439

meningitic, 491, 494

pathogenesis, 491

patient isolation procedures, 497

pharyngeal, 494

pneumonic, 454, 489, 491, 494, 497

prophylaxis, 498

septicemic, 480, 491–494, 497

treatment, 497

on U.S. military installations, 483–484

vaccination, 498

See also Yersinia pestis

Plants

transgenic research involving, 683

weapons directed against, 44, 51–52, 60, 427–429, 431, 460–

461

See also Defoliants; specific agent or plant

Plant toxins, 610

See also specific toxin

Plaque reduction neutralization (PRN) antibodies, 573

Plasma carboxylesterase, 192

Plasma cholinesterase

See Butyrocholinesterase (BuChE)

Plasminogen activator, 491

Playfair, Sir Lyon, 11, 88

Pneumonia, 506, 623

Pneumonic plague, 454, 489, 491, 494, 497

Pneumonitis, 253

Point detectors, 377–380

Point source

for aerosol delivery, 442

Point-source explosives, 120

The Poisoner’s Handbook, 463

Polish Academy of Science, 419

Pollution control

and weapons disposal programs, 412

Poly(ADP-ribose) polymerase (PADPRP), 203

Poly- D-glutamic acid, 469

Polymerase chain reaction (PCR)

in biological agent diagnosis, 448–449

in toxin exposure diagnosis, 617

See also specific agent diagnosis

Polymer fume fever, 264–265

Polyneuropathy, 231–232

Polyparaphenyleneterephthalamide

See Kevlar

Polytetrafluoroethylene

See Teflon

Portable Decontamination Apparatus (PDA), 62, 70, 388

Porter, William N., 37–38, 45

Porton Down Laboratory, England, 658

Positive end-expiratory pressure (PEEP), 253, 257, 259, 266

Positive-pressure total body suits, 432–434

Postattack measures
Medical Aspects of Chemical and Biological Warfare

712

for medical support, 328–329

Postsynaptic potential, 133–134

Potassium cyanide, 273

Poultry, 460

Powders

biological agent dispersal as, 441

decontamination with, 353–354

Powell, Colin, 74

Power-Driven Decontamination Apparatus (PDDA), 388

Poxviruses, 540–542

See also specific virus

Poxvirus virions, 541

PPW

See Patient protective wrap (PPW)

Prairie dogs, 487–488

2-Pralidoxime chloride (2-PAM Cl), 149, 162–165

dosage and administration, 163–165, 169

and endurance time in protective gear, 394

injectors, 73, 155, 163, 169

and nerve agent cardiovascular effects, 156

and nerve agent–induced seizures, 154–155

pharmacokinetics, 163

and pyridostigmine pretreatment, 184–187

side effects, 163–164, 170

Preattack measures

for medical support, 328

Prentiss, Augustin M., 123

Preplacement examination

for Chemical Personnel Reliability Program, 403–404, 406

Presidential Decision Directive 39, 6

Prison incidents

use of riot control agents during, 318

PRN antibodies

See Plaque reduction neutralization (PRN) antibodies

Prochlorperazine, 627

Project 80, 55

Project 112, 55

Project CD-22, 430

“Project Whitecoat,” 428

Promazine, 280

Promethazine, 217, 280

Propranolol, 165

Prostigmin

See Neostigmine

Protection and Detection Sets, 54

Protection Assessment Test System (PATS), 365–366

Protection factor (PF), 366

Protective antigen, 470

Protective boots, 373–375

Protective ensembles, 371–373

Protective equipment, 363, 370–377

acclimatization period, 406

biological, 431, 447–448

factors that restrict wearing of, 402

toxins, 612–613, 669

See also Chemical defense equipment; Masks; Missionoriented protective posture (MOPP) gear; specific item

Protective gloves, 373–375

Protective Ointment Kit, 42

Protective ointment sets, 54

Protective ratio (PR), 183, 186

Protein exotoxins, 469–470

Protopam Chloride

See 2-Pralidoxime chloride (2-PAM Cl)

PS

See Chloropicrin (PS)

P2S

See Methanesulfonate salt of pralidoxime (P2S)

Pseudocholinesterase

See Butyrocholinesterase (BuChE)

Pseudomonas, 609

Psilocybin, 293

Psittacosis, 43–44, 427, 431

Psychedelics, 293–294

See also specific agent

Psychochemical agents, 292–294

See also specific agent

Psychochemical Agents project, 52

Psychological effects

of wearing mission-oriented protective posture gear, 362,

393–395

See also Neuropsychiatric effects

Public hostility, 62–63

Public Law 91-121, 63

Public Law 91-672, 64

Public Law 92-532, 64

Public Law 99-145, 71–72

Public Law 102-484, 72

Public Law 607, 45

Public water systems

biological warfare testing involving, 428–429

Pulex irritans, 483, 487

Pulmonary effects

of anthrax, 472

of brucellosis, 517

of cyanides, 277

of Lewisite, 219

of mustard, 211–212, 215–217, 237–238

of nerve agents, 145, 147–149, 167–168, 170

of phosgene oxime, 221

of Q fever, 530

of ricin toxicity, 636–637

of riot control agents, 311–312, 315–316, 321

of staphylococcal enterotoxin B, 624–627

of toxic inhalational injury, 253, 256, 258–259, 265–266, 343

of trichothecene mycotoxins, 666, 670

of tularemia, 506

Pulmonary function tests (PFT), 252, 265

Pulmonary toxicants, 118–119, 247–267

See also Inhalational injury; specific agent

Pungi sticks, 419

Puumala virus, 594

Pyridine-2-aldoxime methyl chloride

See 2-Pralidoxime chloride (2-PAM Cl)

2-Pyridine aldoxime methyl chloride

See 2-Pralidoxime chloride (2-PAM Cl)

Pyridostigmine, 124, 183–191, 298

blister pack, 189

blood–brain barrier permeability, 187

chemical structure, 184

dosage and administration, 187–188, 191

drug interactions, 188

efficacy, 184–187

FDA informed consent waiver for, 188

mechanism of action, 134

and nerve agent cardiovascular effects, 156

and nerve agent–induced pulmonary effects, 158

and nerve agent–induced seizures, 154–155, 165

as nerve agent pretreatment, 134, 149, 154–156, 158, 165,

182

pharmacology, 183–184

precautions, 187

safety, 187–188

side effects, 187, 189–190

wartime use, 185, 188–191

Pyridostigmine bromide, 73, 132
Index

713

Pyrogenic toxins

See Staphylococcal enterotoxin B; specific toxin

Pyruvate dehydrogenase complex, 218

Q

QDH/SS

See Quick Doff Hood/Second Skin (QDH/SS)

Q fever, 5, 523–532

acute, 529–530

chronic, 528, 530

clinical manifestations, 528–530

diagnosis, 530–531

differential diagnosis, 574

in domestic animals, 528

epidemiology, 526–527

history, 52, 430–431, 525

lethality, 444

military relevance, 524–525

occupational exposure, 524, 532

pathogenesis, 527–528

prophylaxis, 531–532

treatment, 531

vaccination, 430, 531–532

See also Coxiella burnetii

Q fever endocarditis, 528, 530

QNB

See BZ (3-Quinuclidinyl benzilate)

Quarpel-treated fabric, 373

Quayle, Dan, 73

Quick Doff Hood/Second Skin (QDH/SS), 74

3-Quinuclidinyl benzilate

See BZ (3-Quinuclidinyl benzilate)

R

Rabbits, 504

Radiation Detector

ANVDR2, 382

Radiographic findings

in brucellosis, 517

See also Chest radiography

Radioimmunoassays (RIAs), 448, 668

Rales, 343, 530

Rapidity of action, 123

Rats, 481–482, 486–488

Rattus norvegicus, 482, 487–488

Rattus rattus, 482, 487

RBC-ChE

See Erythrocyte cholinesterase (RBC-ChE)

RDIC (resuscitation device, individual, chemical), 159, 169

Reagan, Ronald, 68, 70–71

Receptor-mediated endocytosis (RME), 648–649

Red mold disease, 659

Red phosphorus, 262

Reed, Walter, 10

Remote sensing capability, 53–54, 74, 380–381, 447–448

Remote Sensing Chemical Agent Alarm (RSCAAL)

M21, 74, 381–382

Reoviridae, 575

Replicating agents, 604

Reproductive toxicity

and mustard exposure, 239

Resin kit

M291, 353–354, 387

Respiration

depth and frequency of, and toxic inhalational injury, 250,

255

Respirators

See Masks

Respiratory failure, 148, 252

RESPO 21, 370

Resuscitation

See Ventilatory support

Return to duty, 170, 213, 331

Reverse transcriptase polymerase chain reaction (RT-PCR),

597

Revolutionary War, 417

RFK mask

See Richardson, Flory, and Kops (RFK) mask

RH-195, 33–34

Rhabdoviridae, 575

Rhinorrhea, 145, 147, 167–168, 170

Rhodanese, 275

Rhonchi, 343–344

RIAs

See Radioimmunoassays (RIAs)

Ribavirin, 598–599

Ribonucleic acid (RNA), 541, 569, 662

genomic, 569–570

Ribonucleic acid (RNA) viruses, 592

Ribosomal ribonucleic acid (rRNA) analysis, 504, 525

Rice, George S., 17

Rice blast disease, 60, 460–461

Rice fungus, 44, 427, 460

Richardson, Flory, and Kops (RFK) mask, 22

Ricinis communis

See Castor beans

Ricin toxin, 604, 631–639

anticancer effects, 632

availability or ease of production, 438

cause of death, 636–637

clinical manifestations and pathology, 635–637

detection, 383

diagnosis, 637–638

history, 10, 420–421, 446, 463–464, 632–633

immunization, 638–639

inhalation, 636–639

injection, 635

lethality, 608

mechanism of action, 610–611

military significance, 632–633

native, 632

occupational exposure, 636

oral intoxication, 635

pathogenesis, 634

sample collection, 617

structure, 633

toxicity, 633–634

treatment, 611, 616, 638–639

Ricketts, Howard T., 10

Rickettsia mooseri, 418

Rickettsia prowazeki, 418

Rifampin, 518, 531, 552, 616

Rift Valley fever (RVF), 434, 444, 593, 595–596, 599

Rift Valley fever (RVF) virus, 593, 595, 599

Rinderpest, 51, 460

Riot control agents, 118–119, 292, 307–322

characteristics, 308–309

decontamination, 320

definition, 308

future use, 321

history, 5, 48, 56, 62, 75, 308–310

medical care, 320–321

nations with capability for use, 114

severe medical complications from, 317–318

types, 308
Medical Aspects of Chemical and Biological Warfare

714

See also Tear agents; specific agent

Ripley, James W., 11

RME

See Receptor-mediated endocytosis (RME)

RNA

See Ribonucleic acid (RNA)

Rockets

chemical, 40, 58–59, 62, 71

Rock squirrels, 487

Rocky Mountain Arsenal, Denver, Colorado, 460–461

Rocky Mountain spotted fever, 10, 525

Rodents

that harbor plague, 480–482, 486–488, 498

that harbor viral encephalitides, 567

that harbor viral hemorrhagic fevers, 592–594, 596

See also specific rodent

Roosevelt, Franklin D., 36, 43–44, 125, 426–427

Roridin A, 661

Ross River virus, 562

Royall, Kenneth C., 45

RSCAAL

See Remote Sensing Chemical Agent Alarm (RSCAAL)

Rubratoxins, 656

Russia

biological warfare programs, 420, 422, 453, 455, 679

chemical warfare capability, 75, 115–116, 218, 679

Russo–Japanese War, 11

RVF

See Rift Valley fever (RVF)

S

Sabia virus, 593

Sacroiliitis, 517

Sag Paste (Salve Antigas), 22

Salmonella, 12, 447, 574, 683

Salt intake

and protective gear use, 407

Sanders, Murray, 32

San Francisco Bay

biological agent testing, 429

Sarin (GB), 118–119, 130, 230

aging half-time, 162, 183

and blood cholinesterase activity, 138

cardiovascular effects, 156

case reports, 135–136, 147

decontamination, 354

detection, 378–381

electroencephalographic (EEG) effects, 153, 236

history, 30, 36, 46, 49–50, 58–59, 63–64, 66, 103, 130–131

LCt

50, 141

long-term health effects, 154, 232, 235–236

molecular model, 140

nations with capability for use, 114–115

neuropsychiatric effects, 152–153, 235

ocular effects, 144–147

pharmacology, 141

physical properties, 122–123

polyneuropathy caused by, 232

pulmonary effects, 148

and pyridostigmine pretreatment, 184–186

recent use in Japan, 4, 75, 113, 118, 131, 169, 274, 342, 438,

463, 678

toxicological studies, 236

treatment, 163, 165

Satratoxin, 659, 661

Saxitoxin, 604, 609

availability or ease of production, 439

dual use, 457

lethality, 608

mechanism of action, 610

treatment, 610, 616

SBR

See Small-box respirator (SBR)

Scarification, 548

Schäfer method of assisted ventilation, 159

Scheele, Carl, 10

Schrader, Gerhard, 30, 130

Schutz, W., 10

Schwarzkopf, H. Norman, 73

Scopolamine, 191, 294–295, 298–299

ID50, 295

Scopolamine hydrochloride, 153

Scopolamine methylbromide, 153

SCPE

See Simplified Collective Protective Equipment (SCPE)

Screening

for Chemical Personnel Reliability Program, 399–404

Scrub typhus, 495

SDS polyacrylamide gel electrophoresis

See Sodium dodecyl sulfate (SDS) polyacrylamide gel

electrophoresis

SEA

See Staphylococcal enterotoxin A (SEA)

Sea dumping

of surplus chemical agents, 45–46, 62–64

SEB

See Staphylococcal enterotoxin B (SEB)

Secobarbital, 293

Secondary inoculation

and vaccinia vaccination, 548–549

Secretion precautions

with biological agent–exposed patients, 433

SED

See Staphylococcal enterotoxin D (SED)

SEE

See Staphylococcal enterotoxin E (SEE)

Seizures, 154–155, 165, 187, 279

Selassie, Haile, 34

Selenium, 671

Self-aid

and chemical workers, 407, 409–410

Self-decontamination, 157, 329–330, 352, 408

Semliki Forest virus, 565, 569

Sensory stimulation

incapacitation by means of, 291

Seoul virus, 594

Septic abortion, 516

Septicemic plague, 480, 491–494, 497

Sergeant missile system, 59

Serotherapy

for viral encephalitides, 577

Serratia marcescens, 32, 428–429

Service Response Force (SRF), 410–411

Sesquiterpenoids, 660

Sevin, 132

Shalikashvilli, John M., 104

Shanty, Frank, 53

Sheep, 528

Shellfish toxins, 439

See also specific toxin

Shelter System, 67

Shepherd, Forrest, 11

Sherman, W. T., 416

Shigella
Index

715

See Dysentery

Shuffle pit, 333

Sibert, William L., 19, 25, 28

Silent Death (Uncle Fester), 463

Silicone rubber masks, 364–366

Silver nitrate solution, 320

Silver sulfadiazine, 214

Simplified Collective Protective Equipment (SCPE), 385–386

Sindbis virus, 562, 566–567, 577

Sin nombre virus, 594

Skin decontamination, 157–158, 333, 335, 352–353, 356, 386–

387, 408, 669–670

Skin Decontamination Kit

M291, 387

M238A1, 669

M258A1, 387, 669

XM291, 669–670

S-LOST

See Mustard (HS)

Small-box respirator (SBR), 18, 91, 93–94, 364, 393

Smallpox, 539–553

and biological warfare, 540–541

chemoprophylaxis and chemotherapy, 552–553

versus chickenpox, 546

clinical manifestations, 542–546

complications, 543–544

diagnosis, 546–547

eradication, 540, 543

flat-type, 543, 545

hemorrhagic-type, 543, 545

history, 10, 12, 416–417, 462, 540

immunoprophylaxis, 548–552

modified-type, 546

pathogenesis, 542–546

patient-isolation procedures, 547

treatment, 547–553

vaccination, 540, 546–551

See also Variola virus; Vaccinia vaccines

SmithKline Beecham Pharmaceuticals, 302

Smoke inhalation

and cyanide poisoning, 273–274, 280, 282

Smokes, 118, 260–266

definition, 248

See also specific agent

Smoke tank

airplane, 31

Snake venom toxins, 610, 650

Soap and water

decontamination with, 353–354, 357–358, 388, 616, 669–670

Sodium bicarbonate, 279, 670

Sodium carbonate, 408

Sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, 647

Sodium hypochlorite

See Hypochlorite solution

Sodium nitrite, 279–280

Sodium phosphate, 670

Sodium thiosulfate, 217, 279, 281, 363

Solanaceae, 290, 294

Somalia, 525, 540

Soman (GD), 118–119, 130, 230

aging half-time, 162, 183

blood–brain barrier permeability, 187

cardiovascular effects, 156

case report, 150–151

decontamination, 354

detection, 381

history, 3, 103, 131

LCt

50, 141

long-term health effects, 153–154, 232, 235

molecular model, 140

muscle necrosis caused by, 232

nations with capability for use, 114, 116

neuropsychiatric effects, 153, 235

pharmacology, 141

physical properties, 122

polyneuropathy caused by, 232

pretreatments, 183–187, 192

pulmonary effects, 148–149

toxicological studies, 236

treatment, 165

SOPs

See Standing operating procedures (SOPs)

Southeast Asia

trichothecene mycotoxin use, 419, 421, 609, 657–658

See also specific country

Soviet Institute of Microbiology and Virology, 420

Soviet PKhR-RM Chemical Agent Detector Kit for Medical

and Veterinary Services, 65

Soviet Union

biological warfare program, 4, 29, 55, 67–68, 418, 429, 452–

455, 485, 656–658, 679

chemical warfare program, 47, 54–55, 67–68, 72, 104, 114–

117, 130–131, 679

SPE

See Streptococcal pyrogenic exotoxins (SPE)

SPE-A

See Streptococcal enterotoxin A (SPE-A)

SPE-C

See Streptococcal enterotoxin C (SPE-C)

Spermophilus, 487

Spermophilus beechyi, 487

Spermophilus lateralis, 487

Spermophilus richardsoni, 487

Spermophilus variegatus, 487

Spondylitis, 517

Spot decontamination, 333, 341, 353

Spray delivery, 40, 120–121, 441–442

Spray drying, 440–441

Squirrels, 487–488, 504

SRF

See Service Response Force (SRF)

SS John Harvey, 40, 103–104, 200

Stachybotryotoxicosis, 659

Stachybotrys, 656

Stachybotrys atra, 659

Standing operating procedures (SOPs), 401, 407–408

Standoff detection, 53–54, 74, 380–381, 447–448

Stanton, Edwin, 88

Staphylococcal enterotoxin A (SEA), 622–623

Staphylococcal enterotoxin B (SEB), 621–628

clinical manifestations, 626–627

detection, 383, 627

diagnosis, 627

differential diagnosis, 473, 613–614, 638

immunotherapy, 628

incapacitation caused by, 622

inhalational exposure, 623–626

mechanism of action, 609

pathogenesis, 623–626

prophylaxis, 628

toxicity, 608, 622

treatment, 627–628

vaccines, 628
Medical Aspects of Chemical and Biological Warfare

716

Staphylococcal enterotoxin C1 (SEC1), 622

Staphylococcal enterotoxin C2 (SEC2), 622

Staphylococcal enterotoxin C3 (SEC3), 622

Staphylococcal enterotoxin D (SED), 622–623

Staphylococcal enterotoxin E (SEE), 622

Staphylococcal enterotoxins, 5, 622–623

classification, 622

decontamination, 616

diagnosis, 613

incapacitation caused by, 431

mechanism of action, 609

sample collection, 617

treatment, 616

Staphylococcus, 609

Staphylococcus aureus, 622–623, 626

Status epilepticus, 155

STB

See Super tropical bleach (STB)

Steam heat, 358

Stenhouse, John, 10, 13

Sterilization

definition, 357

Sternutators, 308

Steroid therapy

contraindications, 597

for riot control agent exposure, 320–321

for toxic inhalational injury, 253, 257, 264, 266

Stimson, Henry L., 29, 43, 426

Stimulants, 292–293

See also specific agent

Stokes mortar, 21, 27, 31

Strategic Biological Standoff Detection System, 448

Streptococcal adenitis, 495

Streptococcal disease, 473

Streptococcal enterotoxin A (SPE-A), 622–623

Streptococcal enterotoxin C (SPE-C), 622–623

Streptococcal pneumonia, 623

Streptococcal pyrogenic exotoxins (SPE), 622–623

Streptomycin, 497, 507, 518

Stress testing, 254

Strychnine, 292

Stubbs, Marshall, 54–55

Submarine mine, 52

Succinylcholine, 137

Sudan, 594

Suipoxvirus, 542

Sulfur dioxide, 13–14

Sulfur donors, 281

Sulfur mustard

See Mustard (HS)

Sulfur trioxide-chlorosulfonic acid (FS smoke), 262–263

Superantigens, 622–623

Super tropical bleach (STB), 54, 388, 408

Surgical gloves, 356–357

Surgical instruments

decontamination, 357

Surgical irrigation solutions, 353, 357

Survival Technology, 155

Sverdlovsk accident, 4, 68, 420, 452–453, 468

Synaptotagmin, 648

Systox, 138

T

T-144

See Sarin (GB)

TAB

See N,N’-Trimethylenebis-[pyridine-4-aldoxime bromide]

(TMB4)

Tabun (GA), 118–119, 130, 230

aging half-time, 162, 183

behavioral effects, 152

decontamination, 354

detection, 381

history, 30, 36, 46, 103, 130–131

LCt

50, 141

long-term health effects, 232

molecular model, 140

nations with capability for use, 114

pharmacology, 141

physical properties, 122

polyneuropathy caused by, 232

pulmonary effects, 148–149

and pyridostigmine pretreatment, 184–186

recent use, 69

toxicological studies, 236

Tacrine

See Tetrahydroaminoacridine (THA)

Tactical Biological Standoff Detection System, 448

Tank Collective Protector, 53

Tank masks, 53, 70, 74

TAP ensemble

See Toxicological agent protective (TAP) ensemble

T cells, 505, 577, 622–623, 628

Tear agents, 118–119, 308

delivery systems, 121

history, 11, 13, 35–36, 56, 90, 104–105

See also Riot control agents; specific agent

Techne, 132

Teflon, 264–266, 617, 638

Temperature

and agent delivery, 122–123

and protective gear use, 125, 329–330, 367, 370–371, 394,

403, 405–407

TEMPER (tent, extendable, modular, per sonnel) system, 384

TEPP

See Tetraethyl pyrophosphate (TEPP)

Teratogenesis

and mustard exposure, 239

Terrorism, 6, 75, 117–118, 678, 683

and biological weapons, 117–118, 422, 438, 446–447, 461,

463–464, 604, 609, 611, 633, 678, 683

and toxin weapons, 604, 609, 611, 633

Terrorist weapon

definition, 604

Tetanus toxin, 609, 644, 646–647

Tetracycline, 473, 497–498, 507, 531–532

Tetraethyl pyrophosphate (TEPP), 130

Tetrahydroaminoacridine (THA), 301

Tetrahydrocannabinol (THC), 52, 298

Tetrodotoxin, 417–418, 609–610

Thermal burns, 343

Thiamine, 163

Thickeners, 122, 356

Thin-layer chromatography (TLC), 668

Thiocyanate, 276

Thiodiglycol, 213

Thiolcalcium hypothesis

of mustard injury, 203–204

Thiosulfate reductase, 275–276

Third World nations

biological weapons programs, 456–458, 461, 678–679

chemical warfare capabilities, 116–117

See also specific nation

Thorazine

See Chlorpromazine
Index

717

Thrassus bacchi, 487

Threshold limit value (TLV), 250

Tick-born encephalitis, 444

Ticks

as biological agent vector, 504, 525, 528, 593–594, 596

Titanium tetrachloride (FM), 27, 263

TLC

See Thin-layer chromatography (TLC)

TMB4

See N,N’-Trimethylenebis-[pyridine-4-aldoxime bromide]

(TMB4)

TNF

See Tumor necrosis factor (TNF)

TOCP

See Triorthocresyl phosphate (TOCP)

Togaviridae, 562, 575

Tooele demilitarization plant (Utah), 72, 411

Topical skin protectants

for chemical warfare agents, 669

Torsade de pointes, 156

Tourniquet test, positive, 596

Towelettes

decontamination, 158

Toxic Agent Training Course, 409

Toxic Chemical Training for Medical Support Personnel

Course, 398

Toxicological agent protective (TAP) ensemble, 404

Toxic shock syndrome, 623, 626–627

Toxic shock syndrome toxin-1 (TSST-1), 622–623, 627–628

Toxins

aerosolized, 605–608, 612

analysis and identification, 617

bacterial, 609, 647

bioengineered production, 682

chimeric, 632

countermeasures, 610–619

decontamination, 616, 660, 669–670

definition, 604

detection, 613

diagnosis, 613–614

ease of production, 605–608

fungal, 609–610, 656

immunization, 615, 618–619

incapacitation caused by, 608, 622

marine, 609

mechanisms of action, 608–611, 648–649

physical protection, 612–613

plant, 610

prevention, 614–616

route of exposure, 604

sample collection, 616–617

shellfish, 439

sources, 608–610

stability, 605–608

toxicity, 605–608, 612

treatment, 614–616

venom, 610, 650

water purification methods effective against, 617–618

See also Biological agents; specific agent

Toxin weapons

versus chemical weapons, 605, 607

defense against, 603–619

populations at risk, 611–612

possible, 439

terminology, 604

Toxogonin, 163

TPS1/TPS2

See Topical skin protectants

Tracheobronchial destruction, 100

Tracheobronchial stenosis, 215–217

Training

chemical warfare, 48, 55–56, 71–72, 94, 124

for chemical workers, 407–410

of civilian resources, 409–410

decontamination, 352, 387, 408

protective gear, 393–395

Training Mask, 40

Tranquilizers, 293

Transport equipment, 389

Treaties

chemical weapons, 4, 13, 72, 75, 104–105, 113, 115, 117, 411

verification of compliance, 117, 420

See also specific treaty

Treaty of Versailles, 29

Trench fan, 22–23

Triage, 337–349

definition, 338

objective, 338

Triage categories, 331, 334, 339–341, 344–347

chemical intermediate, 339

delayed, 340, 344–346

expectant, 340, 345–347

immediate, 340, 344–345

minimal, 340, 345–346

urgent, 339

Triage officer, 331

qualifications, 338

Triage station, 331–332

Trichloromethyl chloroformate

See Diphosgene (DP)

Trichoderma, 656

Trichotecin, 665

Trichothecene mycotoxins, 655–671

acute effects, 664–666

aerosolized, 658–659, 666–667, 670

anticancer potential, 667

chemical and physical properties, 660

chronic toxicity, 667

clinical manifestations, 658, 664–667

decontamination, 616, 660, 669–670

dermal exposure, 665–666, 670

diagnosis, 667–669

ease of production, 659

history, 655–659

lethality, 658–659

mechanism of action, 611, 660–662

metabolism, 662–664

military significance, 655–659

occurrence in nature, 659

ocular exposure, 666

prophylaxis, 670–671

protective equipment, 669

recent use, 3, 68, 419, 421

respiratory exposure, 666, 670

structure, 659

toxicology and toxicokinetics, 660–664

treatment, 611, 669–671

use in Southeast Asia, 419, 421, 609, 657–660, 665–666, 668

See also specific toxin

Trichothecene ring, 656

Trihexyphenidyl, 191

Trilateral Agreement, 455

Trilon-46

See Sarin (GB)

Trilon-83

See Tabun (GA)
Medical Aspects of Chemical and Biological Warfare

718

Trimethoprim/sulfamethoxazole, 498, 518, 531

N,N’-Trimethylenebis-[pyridine-4-aldoxime bromide]

(TMB4), 159, 163

Trinitrotoluene (TNT), 89

Triorthocresyl phosphate (TOCP), 232

Truman, Harry S, 64

T-Shell, 14

TSST-1

See Toxic shock syndrome toxin-1 (TSST-1)

T-2 toxin, 608–610, 659

aerosolized, 658–659

chemical and physical properties, 660

clinical manifestations, 658

decontamination, 670

dermal exposure, 665–666

diagnosis, 668

ease of production, 659

lethality, 658–659

mechanism of action, 660–662

metabolism, 662–664

ocular exposure, 666

prophylaxis, 671

protective equipment, 669

toxicity, 661

treatment, 670

Tuberculosis, 495

Tularemia, 5, 503–508

clinical manifestations, 505–506

diagnosis, 506–507

differential diagnosis, 473, 495–496

epidemiology, 504

history, 10–11, 427, 429, 454, 504

lethality, 444

pathogenesis, 504–505

prophylaxis, 507

treatment, 507

typhoidal, 505–507

ulceroglandular, 505–507

vaccination, 507

See also Francisella tularensis

Tumor necrosis factor (TNF), 471, 505

Twitches, 149, 158, 168–169

Tylenol, 274, 447

Typhus, 10, 33, 37, 42, 444, 495

U

UJI bomb, 32–33

Ultraviolet radiation

decontamination with, 358

Umbrella gun, 420–421

United Kingdom

anticrop research programs, 460–461

biological warfare programs, 32, 418–419, 427, 455, 645

chemical warfare divisions

See World War I; World War II

United Nations, 683

chemical/biological weapons reports/inspections, 63, 104–

105, 419–422, 444, 458, 461

and Iraqi chemical weapons program, 69, 73–74, 114, 201,

462–463, 679

Resolution 687, 462–463, 679

Resolution 715, 462–463, 679

Security Council, 420, 462–463, 679

Yemen Civil War investigation, 56–57

United Nations Special Commission (UNSCOM), 421, 463, 679

United States

animals that harbor plague in, 487–488

anticrop research programs, 460–461

biological field testing in, 429

biological warfare and defense programs, 425–435, 455,

645

chemical warfare agencies

See Chemical Warfare Service (CWS); Chemical Corps

chemical warfare policies, 29, 36, 44–45, 48, 56, 63, 72, 75,

89–90, 104–105, 112, 117

nerve agent inventory, 131

plague cycles in, 489

Q fever epidemiology in, 527

See also Continental United States (CONUS)

UNSCOM

United Nations Special Commission (UNSCOM)

U.S. Army Chemical Research and Development Center,

Edgewood, Maryland, 658

U.S. Army General Order No. 100, 13

U.S. Army Medical Department (AMEDD), 328, 428

U.S. Army Medical Research Institute of Chemical Defense

(USAMRICD), 410, 434

U.S. Army Medical Research Institute of Infectious Diseases

(USAMRIID), 431–434, 596, 599, 616, 623, 651

U.S. Army Medical Unit, 430–431

See also U.S. Army Medical Research Institute of Infectious

Diseases (USAMRIID)

U.S. Army regulations/publications

for chemical surety inspection, 400

U.S. Biological Warfare Committee, 43

U.S. Biological Warfare Program, 59–60

U.S. Biological Weapons Program, 44

U.S. House of Representatives Committee on Armed Services,

114

Defense Policy Panel, 456

Special Inquiry Into the Chemical and Biological Threat,

461, 678–679

U.S. Public Health Service, 411

U.S. Senate Committee on Governmental Affairs, 114

USAMRICD

See U.S. Army Medical Research Institute of Chemical

Defense (USAMRICD)

USAMRIID

See U.S. Army Medical Research Institute of Infectious

Diseases (USAMRIID)

Ustinov, D. F., 453

U Thant, 57

V

Vaccine interference, 578

Vaccines

for animals, 434, 460, 464, 568, 576, 578

biological agent, 60–61, 73, 434, 441, 460, 462, 681–683

live attenuated, 507, 683

recombinant vector, 683

verified clinical take, 547

See also specific agent or vaccine

Vaccinia

generalized, 549

ocular, 549–550

progressive, 549–550

Vaccinia-immune globulin (VIG), 550–552

Vaccinia keratitis, 550

Vaccinia necrosum, 549–550

Vaccinia vaccines, 540, 548–551, 683

Vancomycin, 473

V antigen, 486, 491

Vapor, 121–122

airway distribution, 248–249
Index

719

decontamination, 352, 356

definition, 248

delivery systems, 121–122

Lewisite, 218–219

mustard, 201–202, 237

nerve agent, 142–144, 157, 161, 167

off-gassing from contaminated wounds, 356

Vapor Detector Kit, 42

Variable domain- (V ), 622

Varicella

versus variola, 546

Variola major, 543–544, 547

Variola minor, 543, 545, 547

Variola virus, 540–542

See also Smallpox

Variolization, 548

Vector Laboratories (Russia), 540

Vectors

for bacterial agent dispersal, 33, 37, 50

See also specific vector or agent

Vedder, Edward B., 102

VEE

See Venezuelan equine encephalitis (VEE)

Vegetable killer acid

See 2,4-Dichlorophenoxyacetic acid (VKA)

Vegetable killer liquid (VKL), 44

“Veil” respirators, 91

Venezuela

hemorrhagic fever outbreak, 593

Venezuelan equine encephalitis (VEE)

clinical manifestations, 572–573

diagnosis, 573

enzootic, 567–568, 572

epizootic, 567–568, 571–572

history, 44, 431, 434

immunization, 576–579

incapacitation caused by, 439

pathogenesis, 570–572

Venezuelan equine encephalitis (VEE) virus, 5, 562–564

C-84 strain vaccine, 578–579

TC-83 strain vaccine, 577–578

Trinidad donkey (TrD) strain, 571, 577–578

Venezuelan equine encephalitis (VEE) virus complex, 564–566

Venom toxins, 610, 650

See also specific toxin

Ventilatory support

for cyanide poisoning, 279

for first interventions, 341

history, 54, 60

for mustard-exposed patients, 215

for nerve agent–exposed patients, 148, 158–159, 166–169

for toxic inhalational injury, 252–253, 257, 259, 266

for toxin exposure, 616

for viral hemorrhagic fevers, 597

Ventricular fibrillation, 156

Verrucarin A, 661

Verticimonosporium, 656

Vesicants, 118–119, 197–222

clinical differences among, 200

definition, 198

detection, 378, 380–381

incapacitation caused by, 292

pharmacology, 199

triage considerations, 342–347

and wound decontamination, 355

See also specific agent

VHF syndrome

See Viral hemorrhagic fever (VHF) syndrome

Vibrio cholerae

See Cholera

Vickers Medical Containment Stretcher Transit Isolator, 432

Victor, Joseph, 427

Vietnam, North, 656–657

Vietnam War

adaptation of biological warfare during, 419

and biological defense program, 431

defoliant use during, 56, 62, 104–105, 297

mask use during, 124, 394

plague outbreaks during, 480, 483

riot control agent during, 56, 62, 104–105

riot control agent use during, 308–309

VIG

See Vaccinia-immune globulin (VIG)

Viral encephalitides, 561–579

aerosolized, 570–572

alphavirus structure and replication, 569–570

antigenicity, 564–567

clinical manifestations, 572–576

diagnosis, 572–576

differential diagnosis, 574–576

epidemiology, 567–568

history and significance, 563–564

immunoprophylaxis, 564, 576–579

pathogenesis, 570–572

treatment, 576

weaponization, 562–564

See also specific virus

Viral hemorrhagic fevers, 591–600

aerosolized agents, 592

antiviral therapy, 598–599

classification, 593

clinical manifestations, 594–595

diagnosis, 596–597

epidemiology, 592–594

immunoprophylaxis and immunotherapy, 599

infectivity, 592

isolation and containment procedures, 598

nosocomial transmission, 592–593, 595–596

treatment, 597–599

See also specific virus

Viral hemorrhagic fever (VHF) syndrome, 592

Viruses

modification, 680–681

possible biological warfare agents, 439

See also Biological agents; specific agent

Virus particles

progeny, budding and release, 570

Vitamin B12a

See Hydroxocobalamin

Vitamin E, 217, 671

VKA

See 2,4-Dichlorophenoxyacetic acid (VKA)

Voicemitters, 364, 366, 368–370

Volatility, 122–123

Voles, 594

Vomiting

CS-induced, 314–315

mustard-induced, 212, 216

nerve agent–induced, 145, 168

relation of cholinesterase activity to, 139

Vomiting agents, 119, 292, 308, 319

See also specific agent

von Deimling, General, 15

von Liebig, Justus, 89
Medical Aspects of Chemical and Biological Warfare

720

von Steinmetz, Erich, 16

von Tappen, Hans, 14

VX, 118–119, 130, 230

aging half-time, 162, 183

as anticholinergic antidote, 301

and blood cholinesterase activity, 138–139

decontamination, 158, 354–355, 387

delivery systems, 121

detection, 378, 380

history, 49–50, 57–58, 63, 70, 131

LCt

50, 141–142

long-term health effects, 234

molecular model, 140

nations with capability for use, 114–116

neuropsychiatric effects, 152, 234

pharmacology, 141

physical properties, 122–123

pulmonary effects, 148–149

and pyridostigmine pretreatment, 184–186

treatment, 163

and wound decontamination, 356

W

Waco, Texas, 75, 291, 310

Waitt, Alden H., 29–30, 45, 47

Walcott, C. D., 17

Walter Reed Army Medical Center, Washington, D. C., 432,

434

Ward, Kyle, Jr., 30

Warning systems

See Alarms; Detection; specific detector

War Research Service (WRS), 43, 426–427

Wart hog disease, 460

Washington, George, 417

Washington Post, 114

Water

decontamination with, 158, 353–354, 357–358, 388, 616,

669–670

Water intake

and protective gear use, 370–371, 406–407

Water solubility

of toxic inhalants, 249

Water supply contamination, 442, 446, 459

Water testing kit

M272 Chemical Agent, 380

Water treatment

for toxin contamination, 617–618

Watson, Gerald G., 71

Watson, James D., 679

WBGT index

See Wet bulb globe thermometer (WBGT) index

W bomb, 632

Weapons disposal programs, 45–46, 62–64, 72, 411–412, 431,

525, 564

Weapons of mass destruction

comparison, 458–459

Weather

and agent delivery, 122–123, 125

and protective gear use, 125, 329–330, 367, 370–371, 394,

403, 405–407

Webster, William H., 73, 114, 117, 462

Wedum, Arnold G., 430

Western equine encephalitis (WEE)

clinical manifestations, 574

diagnosis, 574

immunization, 576–579

pathogenesis, 570–572

treatment, 576

Western equine encephalitis (WEE) virus, 562–564

B-11 strain vaccine, 579

CM-4884 strain vaccine, 579

Western equine encephalitis (WEE) virus complex, 565–567

Wet bulb globe thermometer (WBGT) index, 329–330, 407

Wheat blast fungus, 460

Wheat stem rust, 51, 60

Wheezing, 251–252

White phosphorus (WP), 27, 260, 262

Whole-body-protection equipment items, 375

Wilson, George, 13

Wilson, Woodrow, 16–17, 19

Winter, Dennis, 92

Winterization kits

for masks, 366

Wipedown mitts, 387

Wisner, Frank, 455

Woehler, Frederick, 89

Work/rest cycles

heat categories and, 329–330, 371, 403, 405

World Health Organization, 419, 443, 456, 540, 542–543

World Trade Center bombing (New York), 446

World War I, 5, 13–25, 90–97

Allied chemical warfare program, 13–16, 93–94

biological warfare programs, 16, 21–22, 90–97, 417, 446,

459, 540

chemical casualties, 6, 24, 91–92, 100–101, 200, 205

chemical warfare usage, 14–20, 96, 290

cyanide use during, 273

decontamination facilities, 97–98

detection, 23

gas casualty treatments, 23–24, 95–101

mustard use during, 16, 19–24, 95–101, 119, 198, 200–201,

205, 210, 212–214, 216, 237–238, 393

protective devices, 15–18, 22, 91–94, 363–364, 393

riot control agent use during, 309–310, 320

smokes used during, 260

toxic inhalational injury during, 248, 254–260, 343

World War II, 36–47, 103–104

anticrop research programs, 460

biological warfare programs, 36–37, 42–44, 103–104, 417–

419, 426–427, 446, 483–485, 540, 632, 644–645

chemical warfare preparations, 37–40, 125, 131, 200, 290

civil defense program, 41

cyanide use during, 273

defensive equipment, 40–42

demilitarization of captured weapons after, 45–46

detection, 42

plague outbreaks during, 482

protective devices, 37, 40–43, 103, 365, 394

Q fever outbreaks during, 524

smokes used during, 262

tularemia outbreaks during, 504

U.S. chemical warfare policy, 44–45

Wound botulism, 644

Wound contamination, 124, 347–348, 356

Wound decontamination, 352, 355–357, 387

Wounds

in casualties with combined injuries, 340, 347–348

exploration and debridement, 356–357

foreign material in, 356

off-gassing from, 356

thickened agents in, 356

WP

See White phosphorus (WP)

Wyeth, 551

Wyeth-Ayerst Laboratories, 149, 163, 302
Index

721

Wyoming MOU, 72

X

Xenopsylla cheopis, 482–483, 486–487

Xylyl bromide, 14

Y

Yatapoxvirus, 542

Yellow cross

See Mustard (HS)

Yellow fever, 593–595, 599

history, 10, 12, 32, 37, 50, 418

Yellow rain, 419, 421, 609, 656–660, 665–666, 668

Yeltsin, Boris, 4, 68, 420, 422, 453–455

Yemen Civil War, 56, 104, 200, 657

Yersin, Alexandre J. E., 482

Yersinia enterocolitica, 485

Yersinia pestis, 75, 463, 482, 485–486, 491

detection, 383

lethality, 439

outer-membrane proteins (Yops), 485–486, 491

staining for, 495–496

virulence factors, 485–486

See also Plague

Yersinia pseudotuberculosis, 482, 485

Yom Kippur War

See Arab–Israeli War of 1973

Yperite

See Mustard (HS)

Ypres, Belgium, 14–15, 90, 200, 248, 308

Y 62-63 virus, 566–567

Z

Zaire, 432, 435, 594

Zhukov, Georgi, 54

Zinc, 363

Zinc cadmium sulfide, 52

Zinc oxide (HC), 260–262

Zone of Interior (ZOI), 326

Zyklon B, 273