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Defense Against Toxic Weapons: Countermeasures
by David R. Franz
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Defense Against Toxic Weapons
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 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 sple 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 AGENTBOTULINUM
TOXINSTAPHYLOCOCCALTime to SymptomsMinutesHours (24-72)Hours (1-6)
NervousConvulsions, Muscle TwitchingProgressive ParalysisHeadache, Muscle
AchesCardiovascularSlow Heart RateNormal RateNormal or Rapid Heart
RateRespiratoryDifficult Breathing, Airways ContrictionNormal, Then
Progressive ParalysisNonproductive Cough, Severe Cases; Chest Pain/difficult
breathingGastrointestinalIncreased Motility, Pain, DiarrheaDecreased
MotilityNausea, Vomiting and/or DiarrheaOcularSmall PupilsDroopy EyelidsMay
see "red eyes" (Conjuntival Injection)SalivaryProfuse, Watery SalivaNormal,
but Swallowing DiffucultMay be Slightly Increased Quantities of
SalivaDeathMinutes2-3 DaysUnlikelyResponse to Atropine/2PAM-CIYesNoAtrophine
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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