Understanding the Threat
The following is a theoretical discussion based on an understandingof physical and biochemical characteristics of toxins. It is notan intelligence assessment of the threat.
TOXINS COMPARED TO CHEMICAL WARFARE AGENTS
Toxins differ from classical chemical agents by source and physicalcharacteristics. When considering how to protect soldiers fromtoxins, physical characteristics are much more important thansource.
TABLE 1: Comparison of Chemical Agents and Toxins Toxins Chemical Agents Natural Origin
Difficult, small-scale production
Large-scale industrial production
Many are more toxic
Less toxic than many toxins
Not dermally active*
Legitimate medical use
No use other than mony toxins
Noticeable odor or taste
Odorless and tasteless Noticeable odor or taste Diverse toxic effects
Many are effective immunogens**
Fewer types of effects
* 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.
The most important differences to understand are volatility anddermal activity. Toxins also differ from bacterial agents (e.g.:those causing anthrax or plague) and viral agents (such as thosethat cause VEE, smallpox, flu, etc.), in that toxins do not reproducethemselves.
TOXINS ON THE BATTLEFIELD
Because toxins are not volatile, as are chemical agents, and withrare exceptions, do not directly affect the skin, an aggressorwould have to present toxins to target populations in the formof respirable aerosols, which allow contact with the more vulnerableinner surfaces of the lung. This, fortunately, complicates anaggressor's task by limiting the number of toxins available foran arsenal. Aerosol particles between 0.5 and 5 m in diameterare typically retained within the lung. Smaller particles canbe inhaled, but most are exhaled. Particles larger than 5-15 gmlodge in the nasal passages or trachea and do not reach the lung.A large percentage of aerosol particles larger than 15-20 m simplydrop harmlessly to the ground. Because they are not volatile,they are no longer a threat, even to unprotected troops. Althoughthere are few data on aerosolized toxins, it is unlikely thatsecondary aerosol formation caused by vehicular or troop movementover ground previously exposed to a toxin aerosol would generatea significant threat; this may not be true with certain chemicalsor with very heavy contamination with infectious agents such asanthrax spores.
TOXICITY, EASE OF PRODUCTION AND STABILITY
Because they must be delivered as respirable aerosols, toxins'utility as effective MCBW are limited by their toxicities andease of production. The laws of physics dictate how much toxinof a given toxicity is needed to fill a given area of space witha small-particle aerosol. Figure 1 presents a theoretical calculationof the approximate quantities of toxins of varying toxicitiesrequired to intoxicate people exposed in large open areas on thebattlefield under optimal meteorological conditions. The figureis based on a mathematical model that has been field tested andfound to be valid. It shows that a toxin with an aerosol toxicityof 0.025 g/kg would require 80 kg of toxin to cover 100 km2 withan effective cloud exposing individuals to approximately a lethaldose 50 (LD50). LD50 means, for example, that a person weighing 70 kg would have a 50% chance of surviving after receiving a 701lg dose of a toxin with an LD50 of 1.0 11g/kg. Note that fortoxins less toxic than botulinum or the staphylococcal enterotoxins,hundreds of kilograms or even ton quantities would be need tocover an area of 10x10 km (100 km2) with an effective aerosol.Assuming this to be true, the number of toxins which can be usedas MCBW is very limited; most of the less toxic agents eithercannot be produced in quantity with current technology, or deliveredto cover large areas of the battlefield. That could change, however,especially for the peptide toxins, as techniques for generatinggenetic recombinants improve. Stability of toxins after aerosolizationis also an important factor, because it further limits toxin weaponeffectiveness.
It is readily apparent that, ignoring other characteristics, ifa toxin is not adequately toxic, sufficient quantities cannotbe produced to make even one weapon. Because of low toxicity.hundreds of toxins can be eliminated as ineffective for use inMCBWs. Certain plant toxins, with marginal toxicity, could beproduced in large (ton) quantities. These toxins could possiblybe weaponized. At the other extreme, several bacterial toxinsare so lethal that MCBW quantities are measured not in tons, butin kilograms-quantities more easily produced. Such toxins arepotential threats to our soldiers on the battlefield.
Figure 1. Toxicity in LD50 (see Table 2) vs. quantity of toxin required to provide a theoretically effective open-air exposure.under ideal meteorological conditions. to an area 100 km2. (Patrick and Spertzel, 1992: based on Calder K.L., BWL Tech Study #3, Mathematical models for dosage and casualty coverage resulting from singlepoint and line source release of aerosol near ground level, DTIC#AD3 10-361, Dec. 1957.) Ricin, saxitoxin and botulinum toxinskill at the concentrations depicted; the staphylococcal enterotoxinsincapacitate.
TABLE 2: Comparative Lethality Of Selected ToxinsAnd Chemical Agents In Laboratory Mice AGENT LD50(µ/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 C. 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) -Conotoxin 5.0 1,500 Cone Snail Taipoxin 5.0 46,000 Elapid Snake Tetrodotoxin 8.0 319 Puffer Fish -Tityustoxin 9.0 8,000 Scorpion Saxitoxin 10.0 (Inhal;2.0) 299 Marine Dinoflagellate VX 15.0 267 Chemical Agent SEB (Rhesus/Aerosol) 27.0 (ED50~pg) 28,494 Bacterium Anatoxin-A(s) 50.0 500 Blue-Green Alga Microcystin 50.0 994 Blue-Green Alga 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
Incapacitation, as well as lethality, to humansmust be considered. A few toxins cause illness at levels manytimes less than the concentration needed to kill. For example,toxins that directly affect membranes and/or fluid balance withinthe lung may greatly reduce gas transport without causing death.Less potent toxins could also be significant threats as aerosolsin a confined space, such as the air-handling system of a building.Finally, breakthroughs in delivery vehicle efficiency or toxin"packaging" by an aggressor might alter the relationshipbetween toxicity and quantity, as depicted in Figure 1; but evenat best, quantities needed could likely be reduced only by one-halffor a given toxicity. For now, however, the figure provides areasonable and valid way of sorting toxins.
Some toxins are adequately toxic and can be produced in sufficientquantities for weapons, but are too unstable in the atmosphereto be candidates for weaponization. Although stabilization ofnaturally unstable toxins and enhanced production of those toxinsnow difficult to produce are possible ties for the future, thereexists no evidence at this time for successful amplification oftoxicity of a naturally occurring toxin. Militarily significant weapons need not be MCBW From 18 January to 28 February 1991, some 39 Iraqi-modified Scud missiles reached Israel. Althoughmany were off target or malfunctioned, some of them landed inand around Tel Aviv. Approximately 1,000 people were treated asa result of missile attacks, but only two died. Anxiety was listedas the reason for admitting 544 patients and atropine overdosefor hospitalization of 230 patients. (Karsenty et al., MedicalAspects of the Iraqi Missile Attacks on Israel, Isr J Med Sci1991: 27: 603-607). Clearly, these Scuds were not effective masscasualty weapons, yet they caused significant disruption to thepopulation of Tel Aviv. Approximately 75% of the casualties resultedfrom inappropriate actions or reactions on the part of the victims.Had one of the warheads contained a toxin which killed or intoxicateda few people, the "terror effect" would have been evengreater. Therefore, many toxins that are not sufficiently toxicfor use in an open-air MCBW could probably be used to producea militarily significant weapon. However, the likelihood of sucha toxin weapon causing panic among military personnel decreaseswhen the leaders and troops become better educated regarding toxins.
CLASSES AND EXAMPLES OF TOXINS
The most toxic biological materials known are protein toxins producedby bacteria. They are generally more difficult to produce on alarge scale than are the plant toxins, but are many, many timesmore toxic. Botulinum toxins (seven related toxins), the staphylococcalenterotoxins (also seven different toxins), diphtheria and tetanustoxin are well-known examples of bacterial toxins. The botulinumtoxins are so very toxic that lethal aerosol MCBW weapons couldbe produced with quantities of toxin that are attainable relativelyeasily with present technology. They cause death through paralysisof respiratory muscles. Staphylococcal enterotoxins, when inhaled,cause fever, headache, diarrhea, nausea, vomiting, muscle aches,shortness of breath, and a nonproductive cough within 2-12 hoursafter exposure; they can also kill, but only at much higher doses.Staphylococcal enterotoxin B (SEB) can incapacitate at levelsat least one hundred times lower than the lethal level. Thesetoo would likely be delivered as a respirable aerosol.
Other bacterial toxins, classified generally as membrane-damaging,are derived from Escherichia coli (hemolysins), Aeromonas, Pseudomonas and Staphylococcus alpha, (cytolysins and phospholipases), andare moderately easy to produce, but vary a great deal in stability.Many of these toxins affect body functions or even kill by formingpores in cell membranes. In general, their lower toxicities makethem less likely battlefield threats.
A number of the toxins produced by marine organisms or by bacteriathat live in marine organisms might be used to produce terroristbiological weapons. Saxitoxin, the best known example of thisgroup, is a sodium-channel blocker and is more toxic by inhalationthan by other routes of exposure. Unlike oral intoxication withsaxitoxin (paralytic shellfish poisoning), which has a relativelyslow onset, saxitoxin can be lethal in a few minutes by inhalation.Saxitoxin could be used against our troops as an antipersonnelweapon, but because it cannot currently be chemically synthesizedefficiently, or produced easily in large quantities from naturalsources, it is unlikely to be seen as an area aerosol weapon onthe battlefield. Tetrodotoxin is much like saxitoxin in mechanismof action, toxicity and physical characteristics. Palytoxin, froma soft coral, is extremely toxic and quite stable in impure form,but difficulty of production or harvest from nature reduces thelikelihood of an aggressor using it as an MCBW. The brevetoxins,produced by dinoflagellates, and the bluegreen algal toxins likethe hepatotoxin, microcystin, have limited toxicity. For manyof these toxins, either difficulty of production or lack of sufficienttoxicity limits the likelihood of their use as MCBW.
The trichothecene mycotoxins, produced by various species of fungi,are also examples of low molecular weight toxins (molecular weight:400-700 daltons). The yellow rain incidents in Southeast Asiain the early 1980s are believed to have demonstrated the utilityof T-2 mycotoxin as a biological warfare agent. T-2 is one ofthe more stable toxins, retaining its bioactivity even when heatedto high temperatures. High concentrations of sodium hydroxideand sodium hypochlorite are required to detoxify it. Aerosol toxicitiesare generally too low to make this class of toxins useful to anaggressor as an MCBW as defined in Figure 1; however, unlike mosttoxins, these are dermally active. Clinical presentation includesnausea, vomiting, weakness, low blood pressure, and burns in exposedareas.
Toxins derived from plants are generally very easy toproduce in large quantities at minimal cost in a low-tech environment.A typical plant toxin is ricin, a protein derived from the beanof the castor plant. Approximately 1 million tons of castor beansare processed annually worldwide in the production of castor oil.The resulting waste mash is 3-5% ricin by weight. Because of itsmarginal toxicity, at least a ton of the toxin would be necessaryto produce an MCBW (as defined in Figure 1). Unfortunately, theprecursor raw materials are available in those quantities throughoutthe world.
Animal venoms often contain a number of protein toxins as wellas nontoxic proteins. Until recently, it would have been practicallyimpossible to collect enough of these materials to develop themas biological weapons. However, many of the venom toxins havenow been sequenced (their molecular structure is known) and somehave been cloned and expressed (produced by molecular biologicaltechniques). Some of the smaller ones could also be produced byrelatively simple chemical synthesis methods. Examples of thevenom toxins are 1) the ion channel (cationic) toxins suchas those found in the venoms of the rattlesnake, scorpion andcone snail; 2) the presynaptic phospholipase A2 neurotoxins ofthe banded krait. Moiave rattler and Australian taipan snake;3) the postsynaptic (curare-like alpha toxin) neurotoxins of thecoral, mamba, cobra, sea snake and cone snail; 4) the membranedamaging toxins of the Formosan cobra and rattlesnake and 5) thecoagulation/antlcoagulation toxins of the Malayan pit viper andcarpet viper. Some of the toxins in this group must be consideredpotential future threats to our soldiers as large-scale productionof peptides becomes more efficient; however, difficulty of productionin large quantity presently may limit the threat potential ofmany of them.
HOW TOXINS WORK
Unlike chemical agents, there are many classes of toxins, andthey differ widely in their mechanisms of action. makes the jobof medically protecting soldiers difficult, as there are seldominstances where one vaccine or therapy would be effective againstmore than one toxin. Time from exposure to onset of clinical signsmay also vary greatly among toxins.
(Note that, unlike a terrorist threat, one can prepare for a battlefield threat through development of specific medical countermeasures.Vaccines and other prophylactic measures can be given before combat,and therapies kept at the ready.)
Some neurotoxins, such as saxitoxin, can kill an individual veryquickly (minutes) after inhalation of a lethal dose. This toxinacts by blocking nerve conduction directly and causes death byparalyzing muscles of respiration. Yet, at just less than a lethaldose, the exposed individual may not even feel ill or just dizzy.Because of the rapid onset of signs after inhalation, prophylaxis(immunization or pretreatment with drugs) would be required toprotect soldiers from these rapidly acting neurotoxins. Unprotectedsoldiers inhaling a lethal dose would likely die before they couldbe helped, unless they could be intubated (a breathing tube placedin the airway) and artificially ventilated immediately. A1thoughthe mechanism of death after inhalation of saxitoxin is believedto be the same as when the toxin is administered intravenously,it is more toxic (a smaller dose will kill) if inhaled.
Other neurotoxins, such as the botulinum toxins, must enter nerveterminals before they can block the release of neurotransmitterswhich normally cause muscle contraction. Botulinum neurotoxinsgenerally kill by relatively slow onset (hours to days) respiratoryfailure. The intoxicated individual may not show signs of diseasefor 24-72 hours. The toxin blocks biochemical action in the nervesthat activate the muscles necessary for respiration, leading tosuffocation. Intoxications such as this can be treated with antitoxin(a preparation of antibodies from humans or animals) that canbe injected hours (up to 24 hours in monkeys, and probably humans) after exposure to a lethal dose of toxin, and still prevent illness and death. Although the mechanisms of toxicity of the botulinum toxins appear to bethe same after any route of exposure, unlike saxitoxin, the actualtoxicity is less by inhalation (i.e., the lethal dose of botulinumtoxin is slightly greater by inhalation).
While neurotoxins effectively stop nerve and muscle function withoutcausing microscopic damage to the tissues, other toxins destroyor damage tissue directly. For these, prophylaxis (pretreatmentof some kind) is important because the point at which the pathologicalchange becomes irreversible often occurs within minutes or a fewhours after exposure. An example of this type of toxin is microcystin,produced by blue-green algae, which binds very specifically toan important enzyme inside liver cells; this toxin does not damageother cells of the body. Unless uptake of the toxin by the liveris blocked, irreversible damage to the organ occurs within 15-60minutes after exposure to a lethal dose. In this case, the tissuedamage to a critical organ, the liver, is so severe that therapymay have little or no value. For this toxin, unlike most, thetoxicity is the same, no matter what the route of exposure.
The consequences of intoxication may vary widely with route of exposure,even with the same toxin. The plant toxin, ricin, kills by blockingprotein synthesis in many cells of the body, but no lung damageoccurs with any exposure route except inhalation. If ricin isinhaled, as would be expected during a biological attack, microscopicdamage is limited primarily to the lung, and that damage may becaused by a mechanism different from that which occurs if thetoxin is injected. Furthermore, when equivalent doses of toxinare used, much more protective antibody must be injected to protectfrom inhalation exposure compared to intravenous injection ofthe toxin. Finally, although signs of intoxication may not benoted for 12-24 hours, microscopic damage to lung tissue beginswithin 8-12 hours or less. Irreversible biochemical changes mayoccur in 6090 minutes after exposure, again making therapy difficult.
The toxicities of some bacterial toxins are too low to make themeffective lethal MCBWs, according to the standards described inFigure 1. However, some cause incapacitating illness at extremelylow levels. Therefore, lethality alone is not an appropriate criterionon which to base a toxin's potential as a threat. The staphylococcalenterotoxins are examples. They can cause illness at extremelylow doses, but relatively high doses are required to kill. Thesetoxins are unusual, in that they act by causing the body to releaseabnormally high levels of certain of its own chemicals, which,in very small amounts, are beneficial and necessary for life,but at higher levels are harmful.
Only one class of easily produced toxins, the trichothecene mycotoxins,is dermally active. Therefore, trichothecenes must be consideredby different standards than all other toxins. They can cause skinlesions and systemic illness without being inhaled and absorbedthrough the respiratory system. Skin exposure or ingestion ofcontaminated food are the two likely routes of exposure of soldiers;oral intoxication is unlikely in modern, welltrained armies. Nanogram(one billionth of a gram) quantities per square centimeter ofskin cause irritation, and microgram (one millionth of a gram)quantities cause necrosis (destruction of skin cells). If theeye is exposed, microgram doses can cause irreversible injuryto the cornea (clear outer surface of the eye). The aerosol toxicityof even the most toxic member of this group is low enough thatlarge-quantity production (approximately 80 metric tons to exposea 10 km2 area with respirable aerosol) makes an inhalation threatunlikely on the battlefield. These toxins, therefore, might bedispersed as larger particles, probably visible in the air andon the ground and foliage. In contrast to treatment for exposureto any of the other toxins, simply washing the skin with soapand water within 1-3 hours after an exposure would eliminate orgreatly reduce the risk of illness or injury.
MANY TOXINS, BUT NOT AN OVERWHELMING PROBLEM
Because there are hundreds of toxins available in nature, thejob of protecting troops against them seems overwhelming. Onewould think that an aggressor would need only to discover thetoxins against which we can protect our troops and pick a differentone to weaponize. In reality, it is not quite that simple. Theutility of toxins as MCBWs is limited by toxicity (Figure 1).This criterion alone reduces the list of potential open-air weaponizabletoxins for MCBWs from hundreds to fewer than 20. Issues relatedto stability and weaponization will not be addressed here, butwould only further reduce the list and make the aggressor's jobmore difficult.
POPULATIONS AT RISK
An armored or infantry division in the field is not at great riskof exposure to a marine toxin whose toxicity is such that 80 tonsare needed to produce an MCBW covering 10 km2. Most marine toxinsare simply too difficult to produce in such quantities. Militaryleaders on today's battlefield should be concerned first aboutthe most toxic bacterial toxins and possibly some of the planttoxins that are slightly less toxic but available in large quantitiesin nature. The more confined the military or terrorist target(e.g., inside shelters, buildings, ships or vehicles) the greaterthe list of potential toxin threats which might be effective.This concern is countered, however, by the fact that toxins arenot volatile like the chemical agents and are thus more easilyremoved from air-handling systems than are volatile agents. Itis probably most cost-effective to protect our personnel fromthese toxins through the use of collective filtration systems.
Nonetheless, we must consider subpopulations of troops and areaswithin which they operate when we estimate vulnerability to agiven toxin threat. Situations could well occur in which differentpopulations of troops require protection from different toxins,because of differences in operational environments. To protect them effectively, decision makers and leaders must understand the nature of the threat and the physical and medical defense solutions.
Table 3 lists the approximate number of known toxins by toxicitylevel and source. To simplify our approach to development of medicalcountermeasures, we have divided them into "Most Toxic,""Highly Toxic" and "Moderately Toxic" categories(also see Figure 1). The Most Toxic toxins could probably be usedin an MCBW; it is feasible to develop individual medical countermeasuresagainst them. The Highly Toxic toxins could probably be used inclosed spaces such as the air-handling system of a building oras ineffective terror weapons in the open; collective filtrationwould be effective against these toxin aerosols targeted to enclosedspaces. The Moderately Toxic toxins would likely be useful onlyas assassination weapons which would require direct attack againstan individual; it is not feasible to develop medical countermeasuresagainst all of the toxins in this group. Such reasoning allowsus to use limited resources most effectively and maximize protection,and thus effectiveness, of our fighting force.
SOURCE Most Toxic Highly Toxic Moderately Toxic Total (Number of toxins in each category) Bacterium 17 12 >20 >49 Plant 5 >31 >36 Fungus >26 >26 Marine Organism >46 >65 >111 Snake 8 >116 >124 Alga 2 >20 >22 Insect >22 >22 Amphibian >5 >5 Total 17 >73 >305 >395 Table 3. Approximate number of toxins arbitrarily categorized as Most Toxic (LD50 <0.025 µg/kg), Highly Toxic (LD50, 0.025-2.5 µg/kg) and Moderately Toxic (LDso >2.5 g/kg). From DNA-TR-92-116, Technical Ramifications of Inclusion of Toxins in the Chemical Weapons Convention (CWC). [ Introduction ][ Table of Contents ][ Understanding the Threat ][ Countermeasures ][ Answers to Often-Asked Questions ]
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