As stated above, most toxins are neither volatile nor dermallyactive. Therefore, an aggressor would most likely attempt to presentthem as respirable aerosols. Toxin aerosols should pose neithersignificant residual environmental threat, nor remain on the skinor clothing. The typical toxin cloud would, depending on meteorologicconditions, either drift with the wind close to the ground orrise 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 target area of a true aerosol wouldbe exposed as the agent drifted through that area. The principalway humans are exposed to such a cloud is through breathing. Aerosolparticles must be drawn into the lungs and retained to cause harm.
The protective mask, worn properly, is effective against toxinaerosols. Its efficacy is, however, dependent on two factors:1) mask-to-face fit and 2) use during an attack. Proper fit isvital. Because of the extreme toxicity of some of the bacterialtoxins, a relatively small leak could easily result in a significantexposure. Eyes should be protected when possible. Definitive studieshave not been done to assess the effects of aerosolized toxinson the eyes. One would expect that, in general, ocular exposureto a toxin aerosol, unless the exposed individual is near therelease point, would result in few systemic effects because ofthe low doses absorbed. Certain toxins have direct effects onthe eyes, but these are generally not toxins we would expect toface as aerosols. Donning the protective mask prior to exposurewould, of course, protect the eyes.
Because important threat biological warfare agents are not dermallyactive, special protective clothing, other than the mask, is lessimportant in at toxin attack than a chemical attack. Presentlyavailable clothing should be effective against biological threatsas we know them. Commanders should carefully consider the relativeimpact of thermal load and the minimal additional protection providedby protective clothing.
REAL-TIME DETECTION OF AN ATTACK
Because of the nature of the threat, soldiers may be dependenton a mechanical detection and warning system to notify them ofimpending or ongoing attack. Without timely warning, their mosteffective generic countermeasure, the protective mask, may beof limited value. There have been successful efforts in the pastto develop real-time detectors of a chemical agent attack. Itwill be more difficult to develop such detectors for toxins forseveral reasons. As stated above, toxins must be presented asrespirable aerosols, which act as a cloud, not as droplets (asthe chemical agents) that fall to the ground and evaporate withtime. The toxin cloud, typically delivered at night with a slightwind, would be expected to move across the battlefield until iteither rises into the atmosphere to be diluted or settles, relativelyharmlessly, to the ground. Unlike chemical agents, which mightbe detectable for hours, toxins might be detectable in the airat one location only for a few minutes. Definitive, specific toxindetectors would have to sample continuously or be turned on bya 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 atoxin 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 ofreagent requirements. Identifying each toxin would require a differentset of reagents if an immunoassay system were used. Analytical assayswould necessarily be more complex and less likely to identify distincttoxins, but might detect that something unusual was present. Imagine thedifficulty of developing a detection system based on molecular weight orother physical characteristics to differentiate among the sevenbotulinum toxins (molecular weight is the same for all of the botulinumtoxins, while all seven require a different antibody for identificationor therapy). Finally, to be effective, a detector would have to belocated where it could "sniff" a toxin cloud in time to warnthe appropriate population. This might be possible on a battlefield, butwould be nearly impossible, except in selected facilities, in the caseof a terrorist attack. It is possible that, if all the capabilitiesdescribed were developed and available at the right place and time, anaerosol cloud of almost any of the toxins of concern could be detectedand identified. Future advances in technology could well resolve ourpresent technical difficulties.
DIAGNOSIS: General Considerations
Health-care providers often ask whether they will be able to tellthe difference among cases of inhalation botulinum, staphylococcalenterotoxin intoxication, and chemical nerve agent poisoning Table4. describes these differences. In general, nerve agent poisoninghas a rapid onset (minutes) and induces increased body secretions(saliva, airways secretions), pinpoint pupils and convulsionsor muscle spasms. Botulinum intoxication has a slow onset (24-72hours) 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 severelyincapacitating. Chemical nerve agent poisoning is a violent illnessresulting in respiratory failure because of muscle spasm, airwayconstriction and excessive fluid in the airways. Botulinum-intoxicatedpatients simply get very tired, very weak and, if they die, itis 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 differentialdiagnosis, especially when multiple patients present with a similarclinical syndrome. Patients should be viewed epidemiologicallyand asked about where they were, whom they were with, what theyobserved, how many other soldiers were and are involved, etc.Inhaled and retained doses of toxins will differ among soldiersexposed to the same aerosol cloud. Those who received the highestdose typically will show signs and symptoms first. Others willpresent somewhat later, while others in the same group may showno signs of intoxication. The distribution of severities withinthe group of soldiers may vary with type of exposure and typeof toxin. For example, exposing a group of individuals to thestaphylococcal enterotoxins would likely make a large percentage(80%) of them sick, but would result in few deaths. Exposing agroup 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 clinicalsigns. For patients exposed to toxins by aerosol, the latent orasymptomatic period varies from minutes (saxitoxin, microcystin) tohours (the staphylococcal enterotoxins), even to days (ricin, thebotulinum toxins).
Save clinical and environmental samples for diagnosis. Both immunoassaysand analytical tests are available for many of the toxins. Toxin samplestaken directly from a weapon are often easier to test than biologicalsamples because they do not contain body proteins and other interferingmaterials. The best early diagnostic sample for most toxins is a swab ofthe nasal mucosa. In general, the more toxic toxins are more difficultto detect in tissues and body fluids, because so little toxin needs tobe present in the body to exert its effect. The capability existshowever, to identify most of the important toxins in biological fluidsor tissues, and many other toxins in environmental samples. Definitivelaboratory diagnosis might take 48-72 hours; however, prototype fieldassays that can identify some toxins within 30 minutes have beendeveloped recently. For individuals who survive an attack with toxins oflower toxicity, immunoassays that detect IgM or IgG (immunoglobulinsproduced by the body after exposure to a toxin) offer a means ofdiagnosis or confirmation or indirect identification of agent within 2-3weeks after exposure.
APPROACHES TO PREVENTION AND TREATMENT
In developing medical countermeasures, each toxin must be consideredindividually. Some incapacitate so quickly that there would belittle time for therapy after an attack. Others cause few or noclinical signs for many hours, but set off irreversible biochemicalprocesses in minutes or a few hours which lead to severe debilitationor death several days later. Fortunately, some of the most potentbacterial 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 injuredsoldiers. For most of the significant threat toxins in militarysituations, vaccination is the most effective means of preventingcasualties. Unlike the chemical warfare agents, many of the importantthreat toxins are highly immunogenic (exposing the body to smalldoses of the inactivated toxin causes the body to make antibodiesthat protect against subsequent actual toxin exposure). Immunizedlaboratory animals are totally protected from high-dose aerosolsof these toxins. Immunization requires a knowledge of the threat,availability of a vaccine, and time. The time needed to allowthe body to make its own protective antibodies to a toxin mayrange from a minimum of 4-6 weeks to 12-15 weeks or longer. Somevaccines currently in use require multiple injections, often weeksapart. The logistical burden of assuring that troops are givenbooster immunizations at the correct time could be overwhelmingin 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 developantibodies) are being microencapsulated (entrapped in a syntheticpolymer that breaks down, slowly releasing the material) to formtimed-release vaccines that might provide the primary immunization,a boost two weeks later, and another boost 10 weeks after that-allwith one injection. Another approach is being evaluated with currentMedical Biological Defense Research Program vaccines. Soldierscould be given a priming dose and the first boost two weeks apartwhile in basic training. The response generated by the immunesystem's memory cells might last for many months or even years,although not all soldiers would develop fully protective immunityat that time after two immunizations. Shortly before the onsetof hostilities, or when the soldier is assigned to a rapidly deployableunit, 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 greatestinterval thus far tested) after two initial priming doses willbe effective, even with moderately immunogenic vaccines such asthe current botulinum toxoid. Studies are ongoing to determinethe maximum reasonable interval between initial immunization seriesand the predeployment boost.
Passive antibody prophylaxis (the soldier doesn't make his ownantibodies, but is given antibody preparations produced in animals orother humans)is generally quite effective in protecting laboratoryanimals from toxin exposure. However, this option is of little realutility for large groups of people for several reasons. The protectionprovided by human antibody may last for only 1-2 months, and protectionafforded by despeciated (animal antibodies altered chemically to reducethe likelihood of the human body identifying them as foreign protein)horse antibody may last for only a few weeks. Therefore, antibodyprophylaxis would be practical only when the threat is clearlyunderstood and imminent. Furthermore, it is unlikely that animalantibody would be used in an individual before intoxication because ofthe risk, albeit small, of an adverse reaction to foreign protein. Thelatter problem may be overcome within the next few years, as theproduction of human monoclonal antibodies (homogeneous populations ofantibodies directed against one, very specific site on the toxin) or"humanization" of mouse monoclonal antibodies becomepractical. Unfortunately, single monoclonal antibodies are seldom aseffective against toxins as polyclonal antibodies, such as thoseproduced naturally in other humans or horses. However, combined antibodytherapy, or "cocktails" of more than one monoclonal antibody,may overcome this problem in the future.
Pretreating soldiers with drugs is feasible, but little successhas been achieved in the discovery or development of drugs thatblock the effects of toxins. Many toxins affect very basic mechanismswithin body cells, tissues and organs; therefore, drugs that blockthese effects often have debilitating or toxic side effects. Anexception is rifampin, the anti-tuberculosis drug, which protectslaboratory animals exposed to the blue-green algal toxin, microcystin,and is safe for use in humans.
Pretreatment (treatment after exposure) with antibodies from humanor 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 treatmentis begun soon enough, up to 24 hours after high-dose aerosol exposureto the toxin. The utility of antibody therapy drops sharply ator shortly after the onset of the first signs of disease. It appearsthat a significant amount of the toxin has, at that time, beentaken up by areas of the body that cannot be reached by circulatingantibodies. Even so, we have preliminary evidence that antibodytherapy is at least partially effective after onset of signs ofintoxication (36-48 hours after aerosol exposure) in monkeys exposedto botulinum toxin. The available antibody to botulinum toxinis produced in horses, and then despeciated to make a productwith a reduced risk of adverse reaction that can be given to humans.Human monoclonal antibodies, or cocktails of two or more monoclonalantibodies, may be the next generation of antibody therapy. Passiveantibody therapy such as that described here is more likely tobe effective against neurotoxins like the botulinum toxins, whichdo not cause tissue damage, than against toxins that induce mediatorrelease (the staphylococcal enterotoxins) or directly damage tissues(ricin).
Specific therapy with drugs (drugs that alter the action of thetoxin o reverse its toxic effects directly) present) has littlevalue because most of the toxins either physically damage cellsand tissues very quickly (ricin), or affect such basic mechanismswithin the cell (the neurotoxins) that drugs designed to reversetheir effects are toxic themselves. Nevertheless, we have shownthat rifampin stops the lethal intoxication by microcystin ifgiven to laboratory animals therapeutically soon after toxin administration(within 15-30 min). Development of therapeutic drugs for toxinsis presently aimed at several more general approaches. Where themechanism 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 drugsthat compete or block the toxin from binding to its site of action.For toxins with enzymatic activities, such as ricin and the botulinumtoxins, drugs that serve as alternate targets of such enzymaticaction may be developed. For toxins such as botulinum, which blockthe release of a neural transmitter, attempts can be made to enhancethe release of the needed transmitter by other means; the diaminopyridinesare temporarily effective in reversing botulinum intoxicationby this mechanism.
Finally, for toxins like staphylococcal enterotoxins and ricin,which induce the release of secondary mediators (actually, a naturalpart of the body's defense mechanism that overreacts), specificmediator blockers are being studied. It is likely that, in thenext few years, drugs may find a place in the therapy of someintoxications 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 likelyto be effective in therapy of intoxication. Artificial ventilationcould be life-saving in the case of neurotoxins, which block nervesthat drive muscles of respiration (botulinum toxins and saxitoxin).Oxygen therapy, with or without artificial ventilation, may bebeneficial for intoxication with toxins that directly damage thealveolar-capillary membrane (the site of movement of moleculesbetween the inhaled air and the blood) of the lung. Vasoactivedrugs (drugs that cause blood vessels to dilate or contract) andvolume expanders could be used to treat the shock-like state thataccompanies some intoxications. These measures could be used inconjunction with more specific therapies.
DECONTAMINATION: Is It Necessary?
Recall that a true respirable aerosol will leave less residueon clothing and environmental objects than would the larger particlesproduced by a chemical munition. This suggests that decontaminationwould be relatively unimportant after a toxin aerosol attack.Because we lack field experience, however, prudence dictates thatsoldiers decontaminate themselves after an attack. As a generalrule, the decontamination procedure recommended for chemical warfareagents (Army FM 8-285) effectively destroys toxins. Exposure to0.1% sodium hypochlorite solution (household bleach) for 10 minutesdestroys most protein toxins. The trichothecene mycotoxins requiremore stringent measures to inactivate them, but even they canbe removed from the skin (although not inactivated) simply bywashing with soap and water. Soap and water, or even just water,can be very effective in removing most toxins from skin, clothingand equipment.
Again, because most toxins are not volatile ordermally active, decontamination is less critical than after achemical attack.
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