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 significant residual environmental threat, nor remain on the skin or clothing. The typical toxin cloud would, depending on meteorologic 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 munition release point. Humans in the target area of a true aerosol would be exposed as the agent drifted 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 is, however, dependent on two factors: 1) mask-to-face 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 easily 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. One would expect that, in general, ocular exposure to a toxin aerosol, unless the exposed individual is near the release point, would result in few systemic effects because of the low doses absorbed. Certain toxins have direct effects on the eyes, but these are generally not toxins we would expect to face 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, special protective clothing, other than the mask, is less important in at toxin attack than a chemical attack. Presently available 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. There have been successful efforts in the past to develop real-time detectors of a chemical agent attack. It will be more difficult to develop such detectors for toxins for several reasons. As stated above, toxins must be presented as respirable aerosols, which act as a cloud, not as droplets (as the chemical agents) 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 likely have to have 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 logistically very difficult to support because of 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 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 of the botulinum toxins, while all seven require a different 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 facilities, in the case of a terrorist attack. It is possible that, if all the capabilities described were developed and available at the right place and time, 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
Health-care providers often ask whether they will be able to tell the difference among cases of inhalation botulinum, staphylococcal enterotoxin intoxication, and chemical nerve agent poisoning Table 4. describes these differences. In general, nerve agent poisoning has a rapid onset (minutes) and induces increased body secretions (saliva, airways secretions), pinpoint pupils and convulsions or muscle spasms. Botulinum intoxication has a slow onset (24-72 hours) and manifests as visual disturbance and muscle weakness, (often seen first as droopy eyelids). SEB poisoning has an intermediate (few hours) time of onset and is typically not lethal, but 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, very weak and, if they die, it is because the muscles of respiration fail. SEB-intoxicated patients become very sick, but typically survive.
TABLE 4: Differential Diagnosis of Chemical Nerve Agent, Botulinum toxin
and Staphylococcal Enterotoxin B Intoxication.
CHEMICAL NERVE AGENT BOTULINUM TOXIN STAPHYLOCOCCAL Time to Symptoms Minutes Hours (24-72) Hours (1-6) Nervous Convulsions, Muscle Twitching Progressive Paralysis Headache, Muscle Aches Cardiovascular Slow Heart Rate Normal Rate Normal or Rapid Heart Rate Respiratory Difficult Breathing, Airways Contriction Normal, Then Progressive Paralysis Nonproductive Cough, Severe Cases; Chest Pain/difficult breathing Gastrointestinal Increased Motility, Pain, Diarrhea Decreased Motility Nausea, Vomiting and/or Diarrhea Ocular Small Pupils Droopy Eyelids May see "red eyes" (Conjuntival Injection) Salivary Profuse, Watery Saliva Normal, but Swallowing Diffucult May be Slightly Increased Quantities of Saliva Death Minutes 2-3 Days Unlikely Response to Atropine/2PAM-CI Yes No Atrophine may Reduce Gastrointestinal Symptoms
Health-care providers should consider toxins in the differential diagnosis, especially when multiple patients present with a similar clinical syndrome. 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, etc. 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 others in the same group may show no signs of intoxication. 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 would likely make a large percentage (80%) of them sick, but would result in few deaths. Exposing a group of soldiers to a cloud of botulinum toxin might kill half, make 20% very sick, and leave 30% unaffected.
One must consider the varying latent periods before onset of clinical signs. For patients exposed to toxins by aerosol, the latent or asymptomatic period varies from minutes (saxitoxin, microcystin) to hours (the staphylococcal enterotoxins), even to days (ricin, the botulinum toxins).
Save clinical and environmental samples for diagnosis. Both immunoassays and analytical tests are available for many of the toxins. Toxin samples taken directly from a weapon 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 of 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 48-72 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 IgM or IgG (immunoglobulins produced by the body after exposure to a toxin) offer a means of diagnosis or confirmation or indirect identification of agent within 2-3 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 set off irreversible biochemical processes in minutes or a few hours which 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 is usually successful 1224 hours after exposure.
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 (exposing the body to small doses of the inactivated toxin causes the body to make antibodies that protect against subsequent actual toxin exposure). Immunized laboratory animals are totally protected from high-dose aerosols of these toxins. Immunization requires a knowledge of the threat, availability of a vaccine, and time. The time needed to allow the body to make its own protective antibodies to a toxin may range from a minimum of 4-6 weeks to 12-15 weeks or longer. Some vaccines currently in use require multiple injections, often weeks apart. The logistical burden of assuring that troops are given booster immunizations at the correct time could be overwhelming in a fast-moving build-up to hostilities.
It may be possible to reduce the time required for immunization. For example, antigens (materials that stimulate the body to develop antibodies) are being microencapsulated (entrapped in a synthetic polymer that breaks down, slowly releasing the material) to form timed-release vaccines that might provide the primary immunization, a boost two weeks later, and another boost 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 boost two weeks apart while in basic training. The response generated by the immune system's memory cells might last for many months or even years, although not all soldiers would develop fully protective immunity at that time after two immunizations. Shortly before the onset of hostilities, or when the soldier is assigned to a rapidly deployable unit, one boost could provide protective immunity quickly, and preclude the need for additional boosts after deployment. Preliminary data suggest that a boost 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. Studies are ongoing to determine the maximum reasonable interval between initial immunization series and the predeployment boost.
Passive antibody prophylaxis (the soldier doesn't make his own antibodies, but is given antibody preparations produced in animals or other humans)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 1-2 months, and protection afforded by despeciated (animal antibodies altered chemically to reduce the likelihood of the human body identifying them as foreign protein) horse antibody may last for only a few weeks. Therefore, antibody prophylaxis would be practical only when the threat is 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 (homogeneous populations of antibodies directed against one, very specific site on the toxin) or "humanization" of mouse monoclonal antibodies become 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.
Pretreating soldiers with drugs is feasible, but little success has been achieved in the discovery or development of drugs that block the effects of toxins. Many toxins affect very basic mechanisms within body cells, tissues and organs; therefore, drugs that block these effects often have debilitating or toxic side effects. An exception is rifampin, the anti-tuberculosis drug, which protects laboratory animals exposed to the blue-green algal toxin, microcystin, and is safe for use in humans.
Pretreatment (treatment after exposure) with antibodies from human or animal sources is feasible for some of the 35 threat toxins. Passive immunotherapy (treatment with other than one's own antibodies) 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. Even so, we have preliminary evidence that antibody therapy is at least partially effective after onset of signs of intoxication (36-48 hours after aerosol exposure) in monkeys exposed to botulinum toxin. 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 toxins that induce mediator release (the staphylococcal enterotoxins) or directly damage tissues (ricin).
Specific therapy with drugs (drugs that alter the action of the toxin o reverse its toxic effects directly) present) has little value because most of the toxins either physically damage cells and tissues very quickly (ricin), or affect such basic mechanisms within the cell (the neurotoxins) that drugs designed to reverse their effects are toxic themselves. Nevertheless, we have shown that rifampin stops the lethal intoxication by microcystin if given to laboratory animals therapeutically soon after toxin administration (within 15-30 min). Development of therapeutic drugs for toxins is presently aimed at several more general approaches. Where the mechanism of action of the toxin is understood and covalent (permanent) bonding of the toxin to cellular protein does not occur (example: ion-channel toxins), attempts are being made to discover drugs that compete 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 alternate targets of such enzymatic action may be developed. For toxins such as botulinum, which block the release of a neural transmitter, attempts can be made to enhance the release of the needed transmitter by other means; the diaminopyridines are temporarily effective in reversing botulinum intoxication by this mechanism.
Finally, for toxins like staphylococcal enterotoxins and ricin, which induce the release of secondary mediators (actually, a natural part of the body's defense mechanism that overreacts), specific mediator blockers are being studied. It is likely that, in the next few years, drugs may 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.
Other general supportive measures (Symptomatic Therapy) are likely to be effective in therapy of intoxication. Artificial ventilation could be life-saving in the case of neurotoxins, which block nerves that drive muscles of respiration (botulinum toxins and saxitoxin). Oxygen therapy, with or without artificial ventilation, may be beneficial for intoxication with toxins that directly damage the alveolar-capillary membrane (the site of movement of molecules between the inhaled air and the blood) of the lung. Vasoactive drugs (drugs that cause blood vessels to dilate or contract) and volume expanders could be used to treat the shock-like state that accompanies some intoxications. These measures could be used in conjunction with more specific therapies.
DECONTAMINATION: Is It Necessary?
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 agents (Army FM 8-285) 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.
Again, because most toxins are not volatile or dermally active, decontamination is less critical than after a chemical attack.
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