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Bioterrorism Summaries from Annual Session 2002

Course Title: Chemical and Environmental Weapons
Section: Disaster Preparedness
Faculty Member: David H. Moore, DVM, PhD
Date/time: 13 April 2002/8:45 AM
Course Number: MTP 135

Introduction

Chemical agents have a long history of military use, dating to use of flame by the ancient Greeks and poisons by Venetians in the 15th and 16th centuries. The first widespread use of chemical agents occurred during World War I, when more than 1 million casualties resulted from use of sulfur, mustard, and chlorine gases.

Large industrial facilities have often been the target of chemical attacks. Toxic chemicals have been used more frequently by radical groups (eg, anti-abortion or animal rights organizations) than by terrorist organizations. Such groups have used chemical weapons that are inexpensive to manufacture and are most frequently delivered by food, water, and other consumable items.

Although the United States has responded adequately to most of these attacks, it is less prepared to respond to chemical attacks by terrorist organizations. Even more important, the threat of such attacks is thought to be increasing. According to the Federal Bureau of Investigation, chemical weapons were once thought to be unattractive to terrorists because they cause death and thus may result in negative publicity; however, the apocalyptic thinking of many terrorist organizations orients their activities toward their God, not the public. Therefore, physicians should be well versed in recognizing and treating casualties of chemical attacks.

Factors that make toxic chemicals attractive to terrorists include the following:

  • the materials used to make chemical weapons are inexpensive, easily accessible, and easily disseminable
  • the goal of terrorists is often to incite fear and panic
  • chemical attacks can easily overwhelm medical capabilities, especially in urban areas (eg, the release of sarin gas in the Tokyo subway system by Aum Shinrikyo in 1995)

Key Points

  • Many people exposed to chemical agents are asymptomatic
  • Chemical agents can be found as solids, liquids, gases, vapors, and aerosols
  • The five main classes of chemical warfare agents are nerve (anticholinesterase) agents, blister (vesicant) agents, blood (cyanogen) agents, lung-damaging (pulmonary) agents, and incapacitating agents
  • Although exposure does not necessarily lead to absorption, many agents are lipophilic and absorbed extremely rapidly through the epidermal surface
  • It is more important to know the ID50 of a liquid chemical agent than its LD50, and the ICt50 and LCt50 are important for vapors and gases
  • Nerve agents often have a simple molecular structure and often are highly toxic
  • The most sensitive indicator of exposure to nerve agents is acetylcholinesterase inhibition, and for pesticides is butyrylcholinesterase inhibition
  • Nerve agents have both muscarinic and nicotinic effects
  • Protecting the physical and respiratory health of the physician and first-responders is the first step in managing chemical exposures, followed by administration of antidotes, protection of the medical facility, and decontamination of the casualty and protection of his or her respiratory system
  • Vesicants are oily liquids that are often simple in structure, heavier than air and water, and highly persistent
  • Sulfur mustard exposure can affect the eyes, skin, and airways; large exposures can have systemic effects involving the GI tract, CNS, lymphoid tissue, and bone marrow and immune suppression.
  • Clinical effects of sulfur mustard are dose dependent and appear 2 to 48 hours after exposure, but usually within 4 to 8 hours
  • Cyanogens have a rapid onset and block cellular respiration

Discussion

Overview of Chemical Warfare Agents

A chemical agent is a toxic chemical that is used or intended to be used in a way that will kill, seriously injure, or incapacitate humans (or animals) through its toxicologic effects. A chemical warfare agent is a member of a special class of compounds that have been produced in large bulk, weaponized, and designed to inflict serious injury or death on humans or animals. A toxin is an agent of biological origin, such as Botulinum toxin.)

Large quantities of chemical warfare agents were developed and stockpiled after World War II by the United States and Soviet Union, and also are currently held by other countries. The five main classes of chemical warfare agents are nerve (anticholinesterase) agents, blister (vesicant) agents, blood (cyanogen) agents, lung-damaging (pulmonary) agents, and incapacitating agents. Nerve agents include tabun, sarin, cyclosarin, soman, and the viscous agent VX; blister agents include sulfur mustard, nitrogen mustard, Lewisite, and phosgene oxime; cyanogens include hydrogen cyanide and cyanogen chloride; and lung-damaging (pulmonary) agents include chlorine, chloropiricin, phosgene, diphosgene, isocyanates, and oxides of nitrogen.

States and Persistence
Chemical agents can be found as solids, liquids, gases, or vapors, and many are also available as aerosols. Of these states, liquids (eg, VX, soman, mustard gas) and solids (eg, phosgene oxime) are the most persistent, whereas gases (eg, chlorine, phosgene, sarin) are the least persistent. The persistence of a chemical agent often is closely related to its intended use, and depends on temperature, wind conditions, agent-surface interactions, and the agent's volatility.

Exposure and Absorption
Although exposure (ie, contact with an agent) does not necessarily lead to absorption (ie, penetration of the epithelial barrier), many agents are extremely lipophilic and are absorbed extremely rapidly through the epidermal surface. Many agents also are mixed with additional agents to increase the extent to which they can penetrate protective clothing and other barriers.

Toxicity
Chemical agents often are used to incapacitate rather than to kill. Therefore, it is important to know the ID50 (ie, the incapacitating dose for 50% of exposed individuals) of a liquid chemical agent in addition to its LD50 (ie, the lethal dose for 50% of exposed individuals), the former often being far lower than the latter. For example, the LD50 of sulfur mustard is 3000 to 7000 mg for a 70-kg man, whereas the ID50 is only 770 mg for a the same sized man.

For vapors or gases, the concentration of and length of time an individual is exposed to the agent also are important. The relationship between these variables can be expressed as Ct, or concentration x time, and the concentration and time of exposure can be altered to achieve the same Ct value (eg, 1 mg/m3 x 8 min = 8 mg-min/m3, and 4 mg/m3 x 2 min = 8 mg-min/m3). Therefore, when describing the toxicity of vapors or gases, the ICt50 (ie, the incapacitating Ct for 50% of exposed individuals) and LCt50 (ie, the lethal Ct for 50% of exposed individuals) also must be considered. These Ct50 values assess the external dose, rather than the internal dose, of the agent to which an individual is exposed and depend on the route of exposure, respiratory rate, and other factors such as skin moisture.

Nerve Agents

There are several classes of anticholinesterase agents, many of which are used in clinical practice or as insecticides, such as carbamates (eg, physostigmine, neostigmine, pyridostigmine, sevin), organophosphates (eg, malathion, diazinon), and organophosphonates (the so-called "nerve agents"). Many of nerve agents, such as sarin, have a relatively simple molecular structure, and many are highly toxic.

Indicators and Effects of Exposure
The most sensitive indicator of exposure to nerve agents is inhibition of the enzyme acetylcholinesterase; for exposure to pesticides, the most sensitive indicator is inhibition of butyrylcholinesterase. The effects of exposure are both muscarinic and nicotinic. Muscarinic effects involve the smooth muscles (bronchoconstriction, increased gastric motility, myosis), the glands (lacrimation, rhinorrhea, salivation, increased secretion gastrointestinal [GI] tract and airways), and the heart (bradycardia), and . nicotinic effects include fasciculations, twitching, fatigue, and paralysis, as well as tachycardia and hypertension. Therefore, heart rate cannot be used as an indicator for exposure or when assessing prognosis.

The central nervous system (CNS) effects of these agents depend on the degree of exposure and the state of the agent. Large exposures to vapors (ie, exposure to multiple LD50 levels) can result in almost instantaneous loss of consciousness—that is not accompanied by inhibition of cholinesterases in blood samples—followed by seizures, apnea, paralysis, and death. By contrast, small exposures to vapors are associated with transient CNS effects, including slowness in thinking and decision-making; visual, sleep, and emotional disturbances; poor concentration; possible nausea and vomiting; rhinorrhea and salivation; and bronchoconstriction. Large, but not lethal, exposures always include GI signs, such as nausea and vomiting, abdominal pain, diarrhea, and involuntary defecation or urination. Much of our information about small exposures was gained from industrial accidents, occupational exposures, and human testing.

The effects of skin exposure to liquid agents are similar to those of vapor exposure. Exposure to small droplets may be associated with local effects such as sweating and fasciculations, medium droplets also with GI (eg, diarrhea) and other systemic effects, and large droplets also with serious CNS effects, including loss of consciousness, seizures, apnea, paralysis, and death. However, liquid agents are highly lipophilic and may cross the epidermis very quickly. Therefore, the effects may occur despite decontamination, and they may worsen with time, because these agents can accumulate in fat and release slowly.

Management
Management of patients exposed to nerve agents includes ABCs, drug therapy, decontamination, and supportive care. However, the most important aspect of management is to protect the physical and respiratory health of the physician. After the safety of the caregiver is assured, antidotes should be administered, the medical facility should be protected, and, finally, the casualty should be decontaminated and his or her respiratory system protected.

Decontamination should occur as soon as possible—ideally within 1 to 2 minutes—but sooner than 30 minutes following exposure, after which time it is of little benefit. Physicial removal of skin contaminants with soap and forceful flush with water is the most effective. Hypochlorite (0.5% solution) is also recommended but is not instantaneously effective.

Antidotes include blocking excess acetylcholine (eg, atropine) and reactivating the inhibitied enzyme with an oxime (eg, pralidoxime chloride). Oximes remove the agent from the affected enzyme at nicotinic sites, but are not effective after aging has occurred. Aging refers to the process by which the nerve agent covalently binds to the acetylcholinesterase enzyme and cannot be removed after a period of time that depends on the agent. In clinical practice, a 1-g IV dose of pralidoxime chloride should be administered slowly over 20 to 30 minutes, and repeated in 1 hour. If seizures occur, brain damage may result and, therefore, anticonvulsants (eg, diazepam) should be administered.

Vesicants (Focus on Sulfur Mustard)

Vesicants are oily liquids that are often simple in structure, heavier than air and water, and highly persistent. For example, sulfur mustard that was used in World War I is still found by and causes injury to farmers in France and Belgium. This agent penetrates the skin in less than 2 minutes, but is difficult to detect because exposure is not immediately associated with a burning sensation (by contrast, Lewisite causes almost instantaneous burning). After 2 minutes, decontamination is ineffective. Once absorbed, sulfur mustard incapacitates victims by quickly denaturing and alkylating cell components such as DNA and other proteins.

Exposure and Effects of Sulfur Mustard Exposure
Sulfur mustard exposure can affect the eyes, skin, and airways; large exposures also can have systemic effects that involve the GI tract, CNS, lymphoid tissue, and bone marrow and immune suppression. Clinical effects are dose dependent and appear 2 to 48 hours after exposure, but usually within 4 to 8 hours. Signs of exposure begin with erythema and small vesicles that coalesce over time to form large bullae. Ocular injuries include mild to moderate conjunctivitis and blepharospasm; followed by lid inflammation and edema and corneal roughening with larger droplets; severe exposure is associated with corneal opacification, ulceration, and/or perforation. Pulmonary effects include from vapor mustard usually involves the upper airways and includes bronchospasm, whereas massive exposures are usually lethal and involve the small airways and alveoli, causing hemorrhagic edema, severe infection, immune suppression, sepsis, and stem cell damage.

Management
Unlike nerve agents, there are no antidotes for vesicants. Most important is the safety of the caregiver or treating physician, followed by decontamination of the casualty (within minutes) using 0.5% hypochlorite solution and flushing with soap and water, and protection of the medical facility.

Blood Agents

Cyanogens, which are available in large quantity in gaseous form, have a rapid onset, and block cellular respiration. Antidotes for cyanogens that utilize sodium nitrate and sodium thiosulfate are available but must be quickly administered intravenously following exposure and are not practical for large exposures. The primary threat of exposure resulting from a terrorist attack lies in the breach of large industrial facilities (eg, chemical processing plants, metal plating/finishing plants, iron and steel mills, gold and silver mines) that use cyanide as a precursor in the manufacturing process.

Lung-damaging Agents

Many pulmonary agents are ubiquitous in industrial use and are precursors to many chemical synthesis reactions. For example, exposure to methyl isocyanate resulted in about 8000 deaths in Bhopal, India, in a documented act of sabotage to an industrial facility. Perfluoroisobutylene (PFIB) is an odorless gas that causes lung injury and can penetrate some charcoal filters.. Chlorine and phosgene, both classic examples of pulmonary agents, are gases at standard room temperature and cause pulmonary edema. Treatment of exposure to these agents is supportive, including rest.

Q&A

Q: What is the utility of gas masks?
A: Although gas masks can be effective in some circumstances, their distribution to the entire general public is not recommended However, medical and safety professionals should have access to these devices.

Q: How effective are the standard latex gloves used in emergency departments at protecting physicians who may treat chemical exposures?
A: If only standard latex gloves are available, most authorities suggest doubling or tripling them, although they do not provide particularly good protection against nerve agents. Butyl rubber gloves also are standard issue for military personnel and should be available for use at civilian medical facilities.

Q: What is the best way to prepare for possible civilian exposure to chemical agents?
A: Training, training, training. For example, George Washington University Hospital has established decontamination stations in the emergency department that include showers, receptacles for contaminated clothing, etc. In general, however, most medical facilities in the United States are better prepared to respond to chemical than to biological incidents.

References/Suggested Reading

Chemical and Biological Terrorism: Research and Development to Improve Civilian Medical Response. Committee on R&D Needs for Improving Civilian Medical Response to Chemical and Biological Terrorism Incidents, Health Sciences Policy Program, Institute of Medicine and Board on Environmental Studies and Toxicology, Commission on Life Sciences, National Research Council. Washington, DC: National Academy Press; 1999.

Medical Management of Chemical Casualties Handbook. 3rd ed. Chemical Casualty Care Division, US Army Medical Research Institute for Chemical Defense (USAMRICD): Aberdeen, MD; 1999. Accessed 5 May 2002.

  • focuses on operational military significance, but also discusses triage, mass casualty decontamination, and treatment.

Somani SM, Romano JA, eds. Chemical Warfare Agents: Toxicity at Low Levels. Boca Raton (FL): CRC Press; 2001.

  • addresses psychological impact of exposure, pathophysiology of chemical agents, domestic preparedness, and Gulf War syndrome.
  • available at retail booksellers.

Recommended Web Sites

Agency for Toxic Substances and Disease Registry [home page]. Accessed 5 May 2002.

  • provides wealth of resources for treating patients with chemical exposures, including basic chemical and exposure information, summary of potential health effects, prehospital management information, and patient information.
  • see also the ATSDR page on "Medical Management Guidelines for Acute Chemical Exposure"
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